HK1151795A - Novel hsp90 inhibitory carbazole derivatives, compositions containing same, and use thereof - Google Patents

Description

Novel HSP90 inhibitory carbazole derivatives, compositions containing the same and uses thereof

The present invention relates to novel compounds which are heterocyclic derivatives of carbazole, to compositions containing them and to their use as medicaments.

More particularly, according to a first aspect, the present invention relates to novel heterocyclic derivatives of carbazole, which exhibit anticancer activity, in particular inhibitory activity of Hsp90 chaperonin (chaperone protein), more particularly by inhibiting ATPase-type catalytic activity of Hsp90 chaperonin.

Chaperonin protein:

the molecular chaperones of the "heat shock protein" (Hsp) family are classified according to their molecular weight (Hsp27, Hsp70, Hsp90, etc.), which are key elements of the balance between cellular protein synthesis and degradation, which determine the rational folding of the protein. They play an extremely important role in cellular stress. These Hsps, in particular Hsp90, are also involved in the regulation of the respective major functions of cells by their association with the respective user proteins involved in Cell proliferation or apoptosis (Jolly C. and Morimoto R.I., J.N.cancer Inst., (2000), 92, 1564-72; Smith D.F. et al, pharmaceutical Rev., (1998), 50, 493-513; Smith D.F., Molecular chapters in the Cell, 165-178, Oxford University Press 2001).

Hsp90 chaperones and Hsp90 inhibitors in the treatment of cancer:

the Hsp90 chaperone is 1-2% of the protein content of the cell, and this chaperone has recently proven to be a particularly promising target in anticancer therapy (see: Moloney Ar and Workman p., Expert opin. biol. ther., (2002), 2(1), 3-24; Choisis et al, Drug Discovery Today, (2004), 9, 881-888). This benefit is particularly relevant to cytoplasmic interactions of Hsp90 with the major client proteins of Hsp90 (i.e., proteins involved in six mechanisms of tumor development), such as those defined by Hanahan d. and Weinberg r.a. (Cell, (2002), 100, 57-70), i.e.:

-proliferative capacity in the absence of growth factors: EGFR-R/HER2, Src, Akt, Raf, MEK, Bcr-Abl, Flt-3, and the like,

ability to avoid apoptosis: p53, Akt, survivin mutant forms, and the like,

insensitivity to stop proliferation signal: cdk4, Plk, Weel, etc.,

-having the ability to activate angiogenesis: VEGF-R, FAK, HIF-1, Akt, etc.,

ability to proliferate without replication limitation: hTert, and the like,

-having the ability to invade new tissue and metastasize: c-Met.

Among other client proteins of Hsp90, steroid hormone receptors, such as estrogen receptors or androgen receptors, are also of great interest in anticancer therapy.

It has recently been demonstrated that the alpha form of Hsp90 also has an extracellular role through its interaction with the metalloprotease MMP-2, which is itself also involved in tumor invasion (eutace b.k. et al, Nature Cell Biology, (2004), 6, 507-.

Hsp90 is composed of two N-and C-terminal domains separated by a strongly charged region. The kinetic interaction between these two domains, coordinated by nucleotide and co-partner binding, determines the partner conformation and its activation state. Client protein association depends primarily on the nature of the co-partners Hsp70/Hsp40, Hop60, etc., the nature of the ADP or ATP nucleotides attached to the N-terminal domain of Hsp 90. Thus, hydrolysis of ATP to ADP and ADP/ATP exchange factors control the entire chaperone "mechanism, which has been found to be sufficient to prevent ATPase activity of ATP hydrolysis to ADP-Hsp 90-thereby releasing the client protein into the cytoplasm, which is then degraded by proteasomes (Neckers L and Neckers K, Expert Optin. emitting Drugs, (2002), 7, 277-.

Use of Hsp90 and inhibitors thereof in pathologies other than cancer

Various pathologies in humans are the result of unreasonable folding of key proteins, particularly neurodegenerative diseases caused by aggregation of certain proteins, such as in Alzheimer's disease and Huntington's disease or diseases associated with infectious protein microparticles (prion-related diseases) (Typell M. and Hooper P.L., emitting the target, (2001), 5, 267-287). Among these pathologies, methods aimed at inhibiting Hsp90 (e.g., Hsp70) with the aim of activating stress pathways may be beneficial (Nature Reviews Neuroscience 6: 11, 2005). Some examples are as follows:

i) huntington's disease: this neurodegenerative disease is due to the extension of the triplet CAG in exon 1 of the huntingtin coding gene. Geldanamycin (geldanamycin) has been shown to inhibit this protein aggregation by overexpression of the chaperones Hsp70 and Hsp40 (Human Molecular Genetics, 10: 1307, 2001).

ii) Parkinson's disease: this disease is caused by the progressive loss of dopaminergic neurons and is characterized by alpha-synuclein (alpha-synuclein) aggregation. Geldanamycin has been shown to protect Drosophila against the toxicity of alpha-synuclein on these dopaminergic neurons.

iii) focal cerebral ischemia (focal cerebral ischemia): it was demonstrated using rat animal models that geldanamycin prevents brain ischemia due to the effect of Hsp90 inhibitors stimulating transcription of genes encoding "heat shock proteins".

iv) Alzheimer's disease and multiple sclerosis: these diseases are caused in part by the expression of pro-inflammatory cytokines and NOS (nitric oxide synthase) -induced forms in the brain, and this detrimental expression is suppressed by stress. In particular, Hsp90 inhibitors maintain this stress response and demonstrate, ex vivo, that geldanamycin and 17-AAG have anti-inflammatory activity in brain glial cells (j. neuroscience res., 67: 461, 2002).

v) amyotrophic lateral sclerosis: the neurodegenerative disease is caused by progressive loss of motor neurons. Arimoclomol, a heat shock protein inducer, has been shown to slow the progression of the disease in animal models (Nature Medicine, 10: 402, 2004). Since Hsp90 inhibitors are also heat shock protein inducers (mol. CeII biol., 19: 8033, 1999; mol. CeII biol., 18: 4949, 1998), it is likely that such inhibitors may obtain beneficial effects in this pathology.

On the other hand, Hsp90 protein inhibitors may be particularly effective in a variety of diseases other than the cancers listed above, such as parasitic, viral or fungal diseases, or neurodegenerative diseases, as well as diseases caused by direct action on Hsp90 and specific client proteins. Several examples are given below:

vi) malaria: protein Hsp90 of plasmodium falciparum is 59% identical and 69% similar to the human protein Hsp90, and geldanamycin has been shown to inhibit the growth of ectoparasites (Malaria Journal, 2: 30, 2003; j.biol. chem.278: 18336, 2003; j.biol. chem., 279: 46692, 2004).

vii) filariasis maleate and bamcroft's filariasis: these lymphofilaria parasites have the protein Hsp90 which is likely to be inhibited by this human protein inhibitor. In fact, the other close parasite, Bruguerella, has been shown to be sensitive to inhibition with geldanamycin. The sequence of Bruguiella is 80% identical and 87% similar to human (int.J. for Parasitology, 35: 627, 2005).

viii) toxoplasmosis: toxoplasma (i.e. the parasite causing toxoplasmosis) has the chaperonin Hsp90, which has been shown to correspond to the induction of chronic infection to active toxoplasmosis by the chaperonin Hsp90 during tachyzoite-bradyzoite transition. In addition, geldanamycin blocks this tachyzoite-bradyzoite transition in vitro (j.mol.biol., 350: 723, 2005).

ix) resistance to the treatment of mycoses: it is likely that the protein Hsp90 has the potential to develop anti-narcotics, while allowing new mutations to develop. Therefore, Hsp90 inhibitors, alone or in combination with other antifungal therapies, may be shown to be effective in treating certain resistant strains (Science, 309: 2185, 2005). In addition, the anti-Hsp 90 antibody developed by Neu Tec Pharma demonstrated in vivo activity of Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, Candida and Candida parapsilosis sensitive and resistant to fluconazole (Current Molecular Medicine, 5: 403, 2005).

x) hepatitis B: hsp90 is one of the host proteins that interacts with the antisense transcriptase of the hepatitis b virus during the viral replication cycle. Geldanamycin has been shown to inhibit viral DNA replication and viral RNA encapsulation (proc.natl.acad.sci.usa, 93: 1060, 1996).

xi) hepatitis c: the human protein Hsp90 is involved in the cleavage step between proteins NS2 and NS3 by viral proteases. Geldanamycin and radicicol inhibit this NS2/3 division in vitro (proc.natl.acad.sci.usa, 98: 13931, 2001).

xii) herpes virus: geldanamycin has been shown to inhibit viral HSV-1 replication activity in vitro and also to have a good therapeutic index (antibacterial Agents and Chemotherapy, 48: 867, 2004). These authors also found geldanamycin activity against other viruses HSV-2, VSV, CoxB3, H1V-1, and SARS coronavirus (data not shown).

xiii) dengue (or tropical influenza): the human protein Hsp90 has been shown to be involved in the entry step of the virus, with the formation of a complex also containing Hsp70, Hsp70 acting as a receptor for the virus; anti-Hsp 90 antibodies reduced the in vitro infectivity of the virus (J.of Virology, 79: 4557, 2005).

xiv) Spinal and Bulbar Muscular Atrophy (SBMA): inherited neurodegenerative diseases are characterized by an extension of the CAG triplet in the androgen receptor gene. 17-AAG (geldanamycin derivative) has been shown to have in vivo activity on transgenic animals used as experimental models for this disease (Nature Medicine, 11: 1088, 2005).

Hsp90 inhibitors:

the first known inhibitor of Hsp90 is a compound of the amsamycin family, in particular geldanamycin (1) and herbimycin a (herbimycin a). X-ray studies have shown that geldanamycin is linked to the ATP site of the N-terminal domain of Hsp90, where it inhibits ATPase activity of this partner (Prodromou c. et al, Cell, (1997), 90, 65-75).

Currently, NIH and Kosan BioSciences ensure the clinical development of 17-AAG (2), which is an Hsp90 inhibitor derived from geldanamycin (1), which blocks the ATPase activity of Hsp90 by linking to the N-terminal ATP recognition site. Phase I clinical trial results for 17-AAG (1) led to the start of phase II trials, but these studies were also directed to more soluble derivatives such as analogue 3 (17-DMAG from Kosan BioSciences), a transporter for the dimethylamino chain, instead of the methoxy residue, and to an optimized formulation for 17AAG (CNF 1010 from Conforma Therapeutics):

Geldanamycin (1) 17-AAG (2) 17-DMAG (3)

Also recently, the reduced analogue of 17-AAG (reduced analogue) has been subjected to phase I clinical studies by the company Infinity Pharmaceuticals (WO 2005/063714/US 2006/019941). Novel geldanamycin (geldanamycin) or ansamycin (ansamycin) derivatives have been described (WO2006/016773/US6855705/US 2005/026894/WO2006/050477/US2006/205705/WO2007/001049/WO2007/064926/WO2007/074347/WO2007/098229/WO2007/128827/WO 2007/128829).

Radicicol (4) is also an Hsp90 inhibitor of natural origin (Roe s.m. et al, j.med chem., (1999), 42, 260-66). However, if it is far from a good in vitro inhibitor of Hsp90, its metabolic instability towards nucleophiles makes it difficult to use in vivo. Oxime derivatives with very good stability were developed by Kyowa Hakko Kogyo, such as KF55823(5) or KF 25706(Soga et al, Cancer Research, (1999), 59, 2931-.

Structures belonging to natural sources of radicicol have also recently been described, such as zearalenone (6) (WO 2003/041643) or compounds (7-9) from Conforma Therapeutics.

Patent application US 2006/089495 describes mixed compounds containing a quinone ring, such as amsamycin derivatives and resorcinol rings, such as radicicol analogues, as Hsp90 inhibitors.

As a naturally derived inhibitor of Hsp90, novobiocin (10) was linked to a different ATP site located in the C-terminal domain of the protein (Itoh H. et al, Biochem J., (1999), 343, 697-703). Simplified analogs of novobiocin have recently been identified as more potent Hsp90 inhibitors than novobiocin itself (j. amer. chem. soc. (2005), 127(37), 12778-.

Patent applications WO2006/050501 and US2007/270452 claim neomycin analogs as Hsp90 inhibitors.

Patent application WO2007/117466 claims derivatives of celastrol and gedunin (gelonine) as Hsp90 inhibitors.

Depsipeptides known as Pipalomycin or ICI101 have recently been described as non-competitive inhibitors of the ATP site of Hsp90 (J.Pharmacol. Exp. Ther., (2004), 370, 1288-1295).

Sherperdine, an KHSSGCAFL nonapeptide, mimics a portion of the K79-K90 sequence of survivin (KHSSGCAFLSVK) and blocks the in vivo interaction of IAP family proteins with Hsp90 (WO 2006/014744).

Small peptides (Small peptides) containing the sequence of otoferlin type (YSLPGYMVKKLLGA) have been described as Hsp90 inhibitors (WO 2005/072766).

Purines such as PU3(11) (Chiosis et al, chem. biol., (2001), 8, 289-299) and PU24FCI (12) (Chiosis et al, curr. cane. drug Targets, (2003), 3, 371-376; WO 2002/036075) have also been described as inhibitors of Hsp 90:

the purine derivative, CNF2024(13), has been introduced into the clinic by the company Conforma therapeutics in cooperation with Sloan Kettering medical Institute for Cancer Research (WO 2006/084030).

Patent application FR 2880540(Aventis) claims another class of purines that inhibit Hsp 90.

Patent application WO2004/072080(Cellular Genomics) claims 8-heteroaryl-6-phenyl-imidazo [1, 2-a ] pyrazines as modulators of the activity of Hsp 90.

Patent application WO 2004/028434 (conformama Therapeutics) claims aminopurines, aminopyrrolopyrimidines, aminopyrazolopyrimidines and aminotriazolopyrimidines as Hsp90 inhibitors.

Patent application WO2004/050087(Ribotarget/Vernalis) claims a class of pyrazoles which are useful for the treatment of pathologies associated with the inhibition of "heat shock proteins" (e.g. Hsp90 chaperones).

Patent application WO2004/056782(Vernalis) claims a new class of pyrazoles which are useful in the treatment of pathologies associated with the inhibition of "heat shock proteins" (e.g. Hsp90 chaperones).

Patent application WO2004/07051(Vernalis) claims aryl iso-formsAzole derivatives for use in the treatment of pathologies associated with the inhibition of "heat shock proteins" (e.g. Hsp90 chaperones).

Patent application WO2004/096212(Vernalis) claims pyrazoles of a third class, which are useful for the treatment of pathologies associated with the inhibition of "heat shock proteins" (e.g. Hsp90 chaperones).

Patent application WO2005/00300(Vernalis) more generally claims 5-membered heterocycles substituted with aryl groups for the treatment of pathologies associated with the inhibition of "heat shock proteins" (e.g. Hsp90 chaperones).

Patent application JP 2005/225787(Nippon Kayaku) claims another class of pyrazoles as Hsp90 inhibitors.

Patent application WO2005/00778(Kyowa Hakko Kogyo) claims a class of benzophenone derivatives as HsP90 inhibitors, which are useful for the treatment of tumors.

Patent application WO2005/06322(Kyowa Hakko Kogyo) claims a class of resorcinol derivatives as Hsp90 inhibitors.

Patent application WO2005/051808(Kyowa Hakko Kogyo) claims a class of resorcinol benzoic acid derivatives as Hsp90 inhibitors.

Patent applications WO2005/021552, WO2005/0034950, WO2006/08503, WO2006/079789 and WO2006/090094(Vernalis) claim several classes of pyrimidothiophenes or pyridothiophenes which can be used for the treatment of pathologies associated with the inhibition of heat shock proteins such as Hsp90 chaperones.

Application WO2006/018082(Merck) claims another class of pyrazoles as Hsp90 inhibitors.

Application WO2006/010595(Novartis) claims a class of indazoles as Hsp90 inhibitors.

Application WO2006/010594(Novartis) claims a class of dihydrobenzimidazolones as Hsp90 inhibitors.

Patent application WO2006/055760(Synta Pharma) claims a class of diaryltriazoles as Hsp90 inhibitors.

Patent application WO2006/087077(Merck) claims a class of (s-triazol-3-yl) phenols as Hsp90 inhibitors.

Patent application FR2882361(Aventis) claims a class of 3-aryl-1, 2-benzisoxazinesAzoles act as Hsp90 inhibitors.

Patent application WO2006/091963(Serenex) claims several classes of tetrahydroindolone (tetrahydroindolone) and tetrahydroindazolone as Hsp90 inhibitors.

Patent application DE10200509440(Merck) claims a class of thienopyridines as Hsp90 inhibitors.

Patent application W02006/095783(Nippon Kayaku) claims a class of triazoles as Hsp90 inhibitors.

Patent application WO2006/101052(Nippon Kayaku) claims a class of acetylene (acetylene) derivatives as Hsp90 inhibitors.

Patent application WO2006/105372(Conforma Therapeutics) claims a class of alkynyl pyrrolo [2, 3-d ] pyrimidines as Hsp90 inhibitors.

Patent application FR2884252(Aventis) claims a class of isoindoles as Hsp90 inhibitors.

Patent application WO2006/1009075(Astex Therapeutics) claims a class of benzamides as Hsp90 inhibitors.

Patent application WO2006/109085(Astex Therapeutics) claims a class of hydroxybenzamides as Hsp90 inhibitors.

Patent application WO2006/113498(Chiron) claims a class of 2-aminoquinazolin-5-ones as Hsp90 inhibitors.

Patent application JP200606755(Nippon Kayaku) claims a class of pyrazoles as Hsp90 inhibitors.

Patent application WO2006/117669(Pfizer) claims a class of hydroxyarylcarboxamides as Hsp90 inhibitors.

Patent applications WO2006/122631 and DE102006008890(Merck GmbH) claim a class of amino-2-phenyl-4-quinazolines as Hsp90 inhibitors.

Patent application WO2006/123061(Aventis) claims a class of azabenzimidazolylfluorene or benzimidazolylfluorene derivatives as Hsp90 inhibitors.

Patent application WO2006/123065(Astex Therapeutics) claims a class of biazamines (amino-2-pyrimidines or triazines) as Hsp90 inhibitors.

Patent application WO2006/125531(Merck GmbH) claims a class of thieno [2, 3b ] pyridines as Hsp90 inhibitors.

Patent applications WO2006/125813 and WO2006/125815(Altana Pharma) claim a class of tetrahydropyridothiophenes as Hsp90 inhibitors.

Patent application WO2007/017069(Merck GmbH) claims a class of adenine derivatives as Hsp90 inhibitors.

Patent applications WO2007/021877 and WO2007/01966(Synta Pharma) claim several classes of arylpyrazoles and arylimidazoles, respectively, as Hsp90 inhibitors.

Patent application WO2007/022042(Novartis) claims a class of pyrimidylaminobenzamides as Hsp90 inhibitors.

Patent application WO2007/034185(Vernalis) claims a class of heteroaryl purines as Hsp90 inhibitors.

Patent application WO2007/041362(Novartis) claims a class of 2-amino-7, 8-dihydro-6H-pyrido [4, 3-d ] pyrimidin-5-ones as Hsp90 inhibitors.

Patent application WO2007/104944(Vernalis) claims a class of pyrrolo [2, 3b ] pyridines as Hsp90 inhibitors.

Patent application US2007/105862 claims a class of azole (azole) derivatives as Hsp90 inhibitors.

Patent application WO2007/129062(Astex Therapeutics) claims a class of diazoles (arylpyrazoles) as Hsp90 inhibitors.

Patent application US2007/129334 (conformama Therapeutics) claims a class of arylthiopurines as Hsp90 inhibitors, which are orally active.

Patent application WO2007/155809(Synta Pharma) claims several classes of phenyl triazoles as Hsp90 inhibitors.

Patent application WO2007/092496(Conforma Therapeutics) claims a class of 7, 9-dihydropurin-8-ones as Hsp90 inhibitors.

Patent application WO2007/207984(Serenex) claims a class of cyclohexylaminobenzene derivatives as Hsp90 inhibitors.

Patent applications DE10206023336 and DE10206023337(Merck GmbH) claim several classes of 1, 5-diphenylpyrazoles and 1, 5-diphenylpyrazoles, respectively, as Hsp90 inhibitors.

Patent application WO2007/134298(Myriad Genetics) claims a class of purinamines as Hsp90 inhibitors.

Patent application WO2007/138994(Chugai) claims several classes of 2-aminopyrimidines or 2-aminotriazines as Hsp90 inhibitors.

Patent applications WO2007/139951, WO2007/139952, WO2007/139960, WO2007/139967, WO2007/139968, WO2007/139955 and WO2007/140002(Synta Pharma) claim several classes of triazoles as Hsp90 inhibitors and agents for the treatment of non-Hodgkin's lymphoma.

The present invention relates to carbazole derivatives which are products of formula (I):

wherein:

het represents a mono-or bicyclic, aromatic or partially unsaturated heterocyclic-dihydro or tetrahydro-type-having 5 to 11 ring members containing 1 to 4 heteroatoms selected from N, O or S, optionally substituted by one or more R1 or R' 1 groups which may be the same or different as described below,

R is selected from

Wherein R1 and/or R' 1 may be the same or different and are selected from H, halogen, CF₃Nitro, cyano, alkyl, hydroxyl, mercapto, amino, alkylamino, dialkylamino, alkoxy, phenylalkoxy, alkylthio, carboxyl in free form or esterified with alkyl, carboxamide, CO-NH (alkyl), CON (alkyl)₂NH-CO-alkyl, sulphonamides, NH-SO₂Alkyl, S (O)₂-NH alkyl and S (O)₂) -N (alkyl)₂All said alkyl, alkoxy and alkylthio groups are themselves optionally substituted by one or more groups which may be the same or different selected from: halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

w1, W2 and W3 independently represent CH or N;

x represents an oxygen atom or a sulfur atom, or NR2, C (O), S (O) or S (O)₂A group;

z represents a hydrogen atom or a halogen atom or a group-O-R2 or a group-NH-R2, wherein:

r2 represents a hydrogen atom or C₁-C₆Alkyl radicals or C₃-C₈Cycloalkyl radicals or C₃-C₁₀A heterocycloalkyl group that is monocyclic or bicyclic; these alkyl, cycloalkyl and heterocycloalkyl groups are optionally substituted by one or more groups which may be the same or different selected from:

-O-PO₃H₂、O-PO₃Na₂、-O-SO₃H₂、-O-SO₃Na₂、-O-CH₂-PO₃H₂、-O-CH₂-PO₃Na₂O-CO-alanine, O-CO-serine, O-CO-lysine, O-CO-arginine, O-CO-glycine-lysine, -O-CO-alanine-lysine;

Halogen, hydroxy; a mercapto group; an amino group; carboxamide (CONH)₂) (ii) a A carboxyl group;

heterocycloalkyl, such as aziridinyl; an azetidinyl group; an oxetanyl group; a tetrahydrofuranyl group; a piperidinyl group; a tetrahydropyranyl group; a piperazinyl group; an alkyl piperazinyl group; a pyrrolidinyl group; morpholinyl; homopiperidinyl; a homopiperazinyl group; quinuclidinyl; cycloalkyl, heteroaryl; a carboxyl group esterified with an alkyl group; CO-NH (alkyl); -O-CO-alkyl, -NH-CO-alkyl; an alkyl group; an alkoxy group; a hydroxyalkoxy group; an alkylthio group; an alkylamino group; a dialkylamino group; in all of these groups, the alkyl, alkoxy and alkylthio groups themselves are optionally substituted with: hydroxy, mercapto, amino, alkylamino, dialkylamino, CO₂Alkyl, NHCO₂An alkyl group; azetidinyl (azetidino), oxetanyl (oxyetheno), pyrrolidinyl (pyrrolidino), tetrahydrofuryl (tetrahydrofurano), piperidinyl (piperidino), tetrahydropyranyl (tetrahydropyrano), piperazinyl (piperazino), morpholinyl (morpholino), homopiperidinyl (homoperidino), homopiperazinyl (homopiperazino), or quinuclidineA radical (quinuclidino) group; in all of these groups, all cyclic groups, cycloalkyl, heterocycloalkyl and heteroaryl groups are themselves optionally substituted by one or more groups which may be the same or different selected from: hydroxy, alkyl, alkoxy, CH ₂OH; amino, alkylamino, dialkylamino, CO₂Alkyl or NHCO₂An alkyl group;

the product of formula (I) is in all its possible tautomeric and isomeric forms: racemates, enantiomers and diastereomers, and addition salts of the product of formula (I) with an inorganic or organic acid or base, and prodrugs of the product of formula (I).

The invention therefore relates in particular to products of formula (I) as defined above or below, in which:

het is selected from:

wherein one of R '3 and R3 represents a hydrogen atom and the other is a value selected from R1 and R' 1;

r1 and/or R' 1 may be the same or different and are selected from H, halogen, CF₃Nitro, cyano, alkyl, hydroxyl, mercapto, amino, alkylamino, dialkylamino, alkoxy, phenylalkoxy, alkylthio, carboxyl in free form or esterified with alkyl, carboxamide, CO-NH (alkyl), CON (alkyl)₂NH-CO-alkyl, sulphonamides, NH-SO₂Alkyl, S (O)₂-NH alkyl and S (O)₂) -N (alkyl)₂All said alkyl, alkoxy and alkylthio groups are themselves optionally substituted by one or more groups which may be the same or different selected from: halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

The substituents R of the product of formula (I) are selected from the values defined above or below,

the product of formula (I) is in all its possible tautomeric and isomeric forms: racemates, enantiomers and diastereomers, and addition salts of the product of formula (I) with an inorganic or organic acid or base, and prodrugs of the product of formula (I).

The invention therefore relates to a product of formula (I) as defined above or below, wherein:

het is selected from:

wherein one of R' 3 and R3 represents a hydrogen atom and the other is selected from the group-NH₂；-CN、-CH₂-OH、-CF₃、-OH、-O-CH₂-phenyl, -O-CH₃、-CO-NH₂；

R1 and/or R' 1 are selected from H, halogen, CF₃Nitro, cyano, alkyl, hydroxy, mercapto, amino, alkylamino, dialkylamino, alkoxy, alkylthio, carboxyl in free form or esterified with alkyl, carboxamide, CO-NH (alkyl) and CON (alkyl)₂NH-CO-alkyl, sulphonamides, NH-SO₂Alkyl, S (O)₂-NH (alkyl) and S (O)₂-N (alkyl)₂All said alkyl, alkoxy and alkylthio groups are themselves optionally substituted by one or more groups which may be the same or different selected from: halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

The substituents R of the product of formula (I) are selected from the values defined above or below,

the product of formula (I) is in all its possible tautomeric and isomeric forms: racemates, enantiomers and diastereomers, and addition salts of the product of formula (I) with an inorganic or organic acid or base, and prodrugs of the product of formula (I).

The invention therefore relates to a product of formula (I) as defined above or below, wherein:

het is selected from:

wherein one of R' 3 and R3 represents a hydrogen atom and the other is selected from the group-NH₂；-CN、-CH₂-OH、-CF₃、-OH、-O-CH₂-phenyl, -O-CH₃and-CO-NH₂；

R is selected from:

wherein R1 and/or R' 1 may be the same or different and are selected from H, halogen, CF₃Nitro, cyano, alkyl, hydroxy, mercapto, amino, alkylamino, dialkylamino, alkoxy, -O-CH₂Phenyl, alkylthio, carboxyl in free form or esterified with alkyl, carboxamide, CO-NH (alkyl), CON (alkyl)₂NH-CO-alkyl, sulphonamides, NH-SO₂Alkyl, S (O)₂-NH alkyl and S (O)₂) -N (alkyl)₂All said alkyl, alkoxy and alkylthio groups are themselves optionally substituted by one or more groups which may be the same or different selected from: halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

W1, W2 and W3 independently represent CH or N;

x represents an oxygen atom or a sulfur atom, or NR2, C (O), S (O) or S (O)₂A gene;

z represents a hydrogen atom or a halogen atom or-O-R₂A radical or-NH-R₂A group wherein:

r2 represents a hydrogen atom or C₁-C₆Alkyl radicals or C₃-C₈Cycloalkyl radicals or C₃-C₁₀A heterocycloalkyl group that is monocyclic or bicyclic; these alkyl, cycloalkyl and heterocycloalkyl groups are optionally substituted by one or more groups which may be the same or different selected from:

halogen, hydroxy; a mercapto group; an amino group; carboxamide (CONH)₂) (ii) a A carboxyl group;

heterocycloalkyl, such as piperidinyl or pyrrolidinyl; a cycloalkyl group; heteroaryl groups, such as furyl, pyridyl, pyrazolyl,an azole or imidazole group; a carboxyl group esterified with an alkyl group; CO-NH (alkyl); -O-CO-alkyl, -NH-CO-alkyl; an alkyl group; an alkoxy group; a hydroxyalkoxy group; an alkylthio group; an alkylamino group; a dialkylamino group; in all of these groups, the alkyl, alkoxy and alkylthio groups are themselves optionally substituted with: hydroxy, mercapto, amino, alkylamino, dialkylamino, CO₂Alkyl, NHCO₂An alkyl group; azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or quinuclidinyl groups; in all of these groups, all cyclic groups, cycloalkyl, heterocycloalkyl and heteroaryl groups are themselves optionally substituted by one or more groups which may be the same or different selected from: hydroxy, alkyl, alkoxy, CH ₂OH; amino, alkylamino, dialkylamino, CO₂Alkyl or NHCO₂An alkyl group;

the product of formula (I) is in all its possible tautomeric and isomeric forms: racemates, enantiomers and diastereomers, and addition salts of the product of formula (I) with an inorganic or organic acid or base, and prodrugs of the product of formula (I).

The present invention relates to carbazole derivatives as described above or below, which are products of formula (I)

Wherein:

het represents a mono-or bicyclic, aromatic or partially unsaturated heterocyclic ring-dihydro or tetrahydro-type-having 5 to 11 ring members containing 1 to 4 heteroatoms selected from N, O or S, optionally substituted by one or more groups R1 or R' 1 which may be the same or different,

r is selected from:

r1 and/or R' 1 are selected from H, halogen, CF₃Nitro, cyano, alkyl, hydroxy, mercapto, amino, alkylamino, dialkylamino, alkoxy, alkylthio, carboxyl in free form or esterified with alkyl, carboxamide, CO-NH (alkyl), CON (alkyl)₂NH-CO-alkyl, sulphonamides, NH-SO₂Alkyl, S (O)₂-NH alkyl and S (O)₂) -N (alkyl)₂All said alkyl, alkoxy and alkylthio groups are themselves optionally substituted by one or more groups which may be the same or different selected from: halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

W1, W2 and W3 independently represent CH or N;

x represents an oxygen atom or a sulfur atom, or NR2, C (O), S (O) or S (O)₂A group;

r2 represents a hydrogen atom or C₁-C₆Alkyl radicals or C₃-C₈Cycloalkyl radicals or C₃-C₁₀A heterocycloalkyl group, which is monocyclic or bicyclic, these alkyl, cycloalkyl and heterocycloalkyl groups being optionally substituted by one or more groups which may be the same or different, selected from:

a hydroxyl group; a mercapto group; an amino group; aziridinyl (aziridino); an azetidinyl group; an oxetanyl group; a tetrahydrofuranyl group; a piperidinyl group; a tetrahydropyranyl group; a piperazinyl group; an alkyl piperazinyl group; a pyrrolidinyl group; morpholinyl; homopiperidinyl; a homopiperazinyl group; quinuclidinyl; carboxamide (CONH)₂) (ii) a A carboxyl group;

a carboxyl group esterified with an alkyl group; CO-NH (alkyl); -O-CO-alkyl; NH-CO-alkyl; an alkoxy group; a hydroxyalkoxy group; an alkylthio group; an alkylamino group; a dialkylamino group; all the latter alkyl, alkoxy and alkylthio groups are themselves optionally substituted by: a hydroxy, mercapto, amino, alkylamino, dialkylamino, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or quinuclidinyl group;

The product of formula (I) is in all its possible tautomeric and isomeric forms: racemates, enantiomers and diastereomers, as well as addition salts of the products of formula (I) with inorganic or organic acids or bases, and prodrugs of the products of formula (I).

In the products of formula (I) and hereinafter, the terms indicated have the following meanings:

the term "halogen" denotes fluorine, chlorine, bromine or iodine, and preferably fluorine, chlorine or bromine.

The term "alkyl group" refers to a linear or branched group containing up to 12 carbon atoms, selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl and heptyl, octyl, nonyl, decyl, undecyl and dodecyl groups, and also to linear or branched positional isomers thereof. More specifically, mention may be made of alkyl groups having up to 6 carbon atoms, in particular the following groups: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl which may be linear or branched and hexyl which may be linear or branched.

The term "alkoxy group" means a linear or branched group containing up to 12 carbon atoms and preferably 6 carbon atoms, selected for example from the following groups: methoxy, ethoxy, propoxy, isopropoxy, straight-chain butoxy, sec-butoxy or tert-butoxy, pentyloxy, hexyloxy or heptyloxy, and straight-chain or branched positional isomers thereof.

The term "alkylthio" or "alkyl-S-" denotes straight-chain or branched radicals containing up to 12 carbon atoms, in particular the methylthio, ethylthio, isopropylthio and heptylthio radicals. In the radicals containing sulfur atoms, the sulfur atoms may be oxidized to SO or S (O)₂A group.

The term "carboxamide" means CONH₂。

The term "sulphonamide" means SO₂NH₂。

The term "acyl group or r-CO-group" means a straight-chain or branched group containing up to 12 carbon atoms, in which the group r represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl or aryl group, which has the values indicated above and is optionally substituted as indicated: mention may be made of formyl, acetyl, propionyl, butyryl or benzoyl groups, or pentanoyl, hexanoyl, acryloyl, crotonyl or carbamoyl groups.

The term "cycloalkyl group" refers to a monocyclic or bicyclic carbocyclic group containing from 3 to 10 ring members and particularly to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

The term "cycloalkylalkyl group" refers to a group wherein cycloalkyl and alkyl are selected from the values defined above: thus, the radicals are, for example, the cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl radicals.

The term "acyloxy group" is intended to denote an acyl-O-group, wherein acyl has the meaning as indicated above: mention may be made, for example, of acetoxy or propionyloxy groups.

The term "acylamino group" is intended to denote an acyl-N-group, wherein acyl has the meaning indicated above.

The term "aryl group" means a carbocyclic unsaturated group which is monocyclic or consists of fused rings. Mention may be made, as examples of such aryl groups, of phenyl or naphthyl groups.

The term "arylalkyl" is intended to denote a group formed by the combination of an optionally substituted alkyl group as defined above and an optionally substituted aryl group as defined above: mention may be made, for example, of benzyl, phenylethyl, 2-phenylethyl, triphenylmethyl or naphthylmethyl groups.

The term "heterocyclic group" means a saturated (heterocycloalkyl) or partially or fully unsaturated (heteroaryl) carbocyclic group containing from 4 to 10 ring members interrupted by one or more heteroatoms which may be the same or different, selected from oxygen, nitrogen or sulfur atoms.

As heterocyclic groups, mention may in particular be made of dioxolanes, bisAlkanes, dithiolanes, thiaoxolanes (thioxolones), thiaoxolanes, oxacyclopropanes (oxiranyls), oxacyclopentyls (oxonnyls), dioxolanyls (dioxirannyls), piperazinyls, piperidinyls, pyrrolidinyls, imidazolidinyl-2, 4-diketones, pyrazolidinyls, morpholinyls, tetrahydrofuryls, hexahydropyrans, tetrahydrothiophenyls, chromans, dihydrobenzofuransPyranyl, indolinyl, perhydropyranyl, dihydropyridinyl (pyridindolinyl), tetrahydroquinolinyl, tetrahydroisoquinolinyl, or thiopyrrolidinyl (thiozolidinyl) groups, all of which are optionally substituted.

Among the heterocycloalkyl radicals, mention may in particular be made of optionally substituted piperazinyl, N-methylpiperazinyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl, hexahydropyran or thiazolidinyl radicals.

The term "heterocycloalkylalkyl group" is intended to denote a group in which the heterocycloalkyl and alkyl residues have the above-mentioned meanings.

Among the heteroaryl groups having 5 ring members, mention may be made of furyl, pyrrolyl, tetrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, thiatriazolyl, thiadiazolyl,azolyl group,Oxadiazolyl, isoxazolylOxazolyl, imidazolyl, pyrazolyl, thienyl and triazolyl groups.

Among heteroaryl groups having 6 ring members, particular mention may be made of pyridyl groups such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl groups.

As condensed heteroaryl groups containing at least one heteroatom selected from the group consisting of a sulfur atom, a nitrogen atom and an oxygen atom, mention may be made, for example, of benzothienyl, benzofuranyl, benzopyrolyl, benzothiazolyl, benzimidazolyl, imidazopyridinyl, purinyl, pyrrolopyrimidyl, pyrrolopyridinyl, benzopyropyridyl, benzopyrodenylAzolyl, benzisoylOxazolyl, benzisothiazolyl, thionaphthyl, chromenyl, indolizinyl, quinazolinyl, quinoxalinyl, indolyl, indazolyl, purinyl, quinolinyl, isoquinolinyl and naphthyridinyl.

The term "alkylamino group" is intended to mean a group wherein the alkyl group is selected from the alkyl groups mentioned above. Preference is given to alkyl radicals having up to 4 carbon atoms, and mention may be made, for example, of methylamino, ethylamino, propylamino or straight-chain or branched butylamino radicals.

The term "dialkylamino group" is intended to mean a group wherein the alkyl groups can be the same or different selected from the above-mentioned alkyl groups. As mentioned above, preference is given to alkyl groups having up to 4 carbon atoms, and mention may be made, for example, of dimethylamino, diethylamino or methylethylamino groups, which may be linear or branched.

The term "patient" refers to humans, as well as other mammals.

The term "prodrug" refers to a product that can be converted in vivo by metabolic mechanisms (e.g., hydrolysis) to a product of formula (I). For example, esters of the hydroxyl-containing product of formula (I) can be converted in vivo to their parent molecule by hydrolysis. Alternatively, esters of the products of formula (I) containing carboxyl groups can be converted in vivo by hydrolysis into their parent molecules.

By way of example, mention may be made of esters of the products of formula (I) containing hydroxyl groups, such as acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-di- β -hydroxynaphthoates, glycocholates, isethionates, di-p-toluoyl tartrate, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, camphorsulfonates (camphorsylsulfonates), cyclohexylsulfamates (cyclohexexyl-sulphosulfonates) and quinic acid esters (quinate).

Particularly useful esters of hydroxyl-containing products of formula (I) can be prepared from acid residues such as those described in Bundgaard et al, J.Med.Chem., 1989, 32, pages 2503-2507: these esters include, in particular, substituted (aminomethyl) benzoates, dialkylamino-methylbenzates in which the two alkyl groups may be linked together or may be interrupted by an oxygen atom or an optionally substituted nitrogen atom (i.e. an alkylated nitrogen atom), or (morpholinomethyl) benzoates, for example 3-or 4- (morpholinomethyl) benzoates and (4-alkylpiperazin-1-yl) benzoates, for example 3-or 4- (4-alkylpiperazin-1-yl) benzoates.

The carboxyl groups of the products of formula (I) can be salified or esterified in various ways known to those skilled in the art, among which mention may be made of the following non-limiting examples of compounds:

among the salt-forming compounds, inorganic bases such as sodium, potassium, lithium, calcium, magnesium or ammonium in equal amounts, or organic bases such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N-dimethylethanolamine, tris (hydroxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine or N-methylglucamine;

-in esterifying a compound, the alkyl group thereby forming an alkoxycarbonyl group, for example, a methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl group, which alkyl group may be substituted by a group selected from, for example: halogen atoms and hydroxy, alkoxy, acyl, acyloxy, alkylthio, amino or aryl groups, for example chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl.

The term "esterified carboxy" is intended to denote a group such as an alkyloxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl or tert-butyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl group.

Mention may also be made of groups formed with an ester residue which is readily removable, such as a methoxymethyl or ethoxymethyl group; an acyloxyalkyl group such as a pivaloyloxymethyl group, a pivaloyloxyethyl group, an acetoxymethyl group or an acetoxyethyl group; an alkyloxycarbonyloxyalkyl group such as a methoxycarbonyloxymethyl or methoxycarbonyloxyethyl group, an isopropyloxycarbonyloxymethyl group or an isopropyloxycarbonyloxyethyl group.

A list of such groups can be found, for example, in european patent EP 0034536.

The term "amidated carboxy" is intended to mean-CONH₂Groups of the type whose hydrogen atom is optionally substituted by one or two alkyl groups to form an alkylamino or dialkylamino group, which is itself optionally substituted as described above or below, can also form, together with the nitrogen atom to which they are attached, a cyclic amine as defined above.

The term "salified carboxy" is intended to mean a salt formed with an equivalent amount of sodium, potassium, lithium, calcium, magnesium or ammonium. Mention may also be made of salts with organic bases such as methylamine, propylamine, trimethylamine, diethylamine or triethylamine. Sodium salts are preferred.

When the products of formula (I) comprise amino groups which can form salts with acids, it is clearly understood that these acid addition salts (acid salts) are also part of the invention. Mention may be made, for example, of salts with hydrochloric acid or methanesulfonic acid.

The addition salts of the products of formula (I) with inorganic or organic acids may, for example, be those formed with: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, propionic acid, acetic acid, trifluoroacetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, ascorbic acid, alkyl monosulfonic acids (alkylmonosulfonic acids) such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkyl disulfonic acids (alkyldisulfonic acids) such as methanedisulfonic acid (methanedisulphosphonic acid), alpha-and beta-ethanedisulfonic acids, aryl monosulfonic acids such as benzenesulfonic acid and aryldisulfonic acids.

It will be appreciated that a stereoisomer in the broadest sense may be defined as an isomer of a compound having the same formula but with some groups spatially arranged differently, for example, in particular in a monosubstituted cyclohexane in which the substituents may be in the axial or equatorial (equi) position, and in the various possible rotational configurations of the ethane derivative. Then, another type of stereoisomer exists due to the different spatial arrangement of substituents attached at the double bond or ring, which is often referred to as a geometric isomer or cis-trans isomer. The term "stereoisomer" is used herein in its broadest sense and thus relates to all of the above-identified compounds.

The invention therefore relates in particular to the products of formula (I) as defined above, in which:

het is selected from:

r1 and/or R' 1 are selected from H, halogen, CF₃Nitro, cyano, alkyl, hydroxyl, mercapto, amino, alkylamino, dialkylamino, alkoxy, alkylthio, carboxyl in free form or esterified with alkyl, carboxamide, CO-NH (alkyl), CON (alkyl)₂NH-CO-alkyl, sulphonamides, NH-SO₂Alkyl, S (O)₂-NH (alkyl) and S (O)₂-N (alkyl)₂All said alkyl, alkoxy and alkylthio groups are themselves optionally substituted by one or more groups which may be the same or different selected from: halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

The substituents R of the product of formula (I) are selected from the values defined above and below,

the product of formula (I) is in all its possible tautomeric and isomeric forms: racemates, enantiomers and diastereomers, as well as addition salts of the products of formula (I) with inorganic or organic acids or bases, and prodrugs of the products of formula (I).

The invention therefore relates in particular to the products of formula (I) as defined above, in which:

r is selected from:

w1 and W2 represent CH, or one represents CH and the other represents N;

x represents an oxygen atom or a NR2 group,

r2 represents a hydrogen atom or C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl or C₄-C₈Heterocycloalkyl groups, these alkyl, cycloalkyl and heterocycloalkyl groups being optionally substituted by one or more groups which may be the same or different, selected from:

a hydroxyl group; a mercapto group; an amino group; an azetidinyl group; an oxetanyl group; a tetrahydrofuranyl group; a piperidinyl group; a tetrahydropyranyl group; a piperazinyl group; an alkyl piperazinyl group; a pyrrolidinyl group; morpholinyl; homopiperidinyl; a homopiperazinyl group; quinuclidinyl; carboxamides; a carboxyl group;

a carboxyl group esterified with an alkyl group; CO-NH (alkyl); -O-CO-alkyl; NH-CO-alkyl; an alkoxy group; a hydroxyalkoxy group; a methylthio group; an alkylamino group; a dialkylamino group; all the latter alkyl and alkoxy groups are themselves optionally substituted by: a hydroxy, mercapto, amino, alkylamino, dialkylamino, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or quinuclidinyl group;

The substituents Het of the product of formula (I) are selected from the values defined above or below,

the product of formula (I) is in all its possible tautomeric and isomeric forms: racemates, enantiomers and diastereomers, as well as addition salts of the products of formula (I) with inorganic or organic acids or bases, and prodrugs of the products of formula (I).

The invention therefore relates in particular to a product of formula (I) as defined above or below, in which:

het is selected from:

r is selected from:

r1 is selected from H, F, Cl, Br, CF₃、NO₂、CN、CH₃、OH、OCH₃、OCF₃、CO₂Me、CONH₂、CONHMe、CONH-(CH₂)₃-OMe、CONH-(CH₂)₃-N(Me)₂、NHC(O)Me、SO₂NH₂And SO₂N(Me)₂；

R' 1 is selected from H, CONH₂CONHMe and OMe;

r' 1 is selected from F, Cl, OH, OMe, CN, O- (CH)₂)₃OMe and O- (CH)₂)₃-N(Me)₂；

W1 and W2 represent CH, or one represents CH and the other represents N;

r2 generationIs hydrogen atom or C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl or C₄-C₈Heterocycloalkyl groups, all of these alkyl, cycloalkyl and heterocycloalkyl groups being optionally substituted by one or more groups which may be the same or different selected from:

a hydroxyl group; a mercapto group; an amino group; an azetidinyl group; an oxetanyl group; a tetrahydrofuranyl group; a piperidinyl group; a tetrahydropyranyl group; a piperazinyl group; an alkyl piperazinyl group; a pyrrolidinyl group; morpholinyl; homopiperidinyl; a homopiperazinyl group; quinuclidinyl; carboxamides; a carboxyl group;

A carboxyl group esterified with an alkyl group; CO-NH (alkyl); -O-CO-alkyl; NH-CO-alkyl; an alkoxy group; a hydroxyalkoxy group; a methylthio group; an alkylamino group; a dialkylamino group; all the latter alkyl and alkoxy groups are themselves optionally substituted by: a hydroxy, mercapto, amino, alkylamino, dialkylamino, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or quinuclidinyl group;

the product of formula (I) is in all its possible tautomeric and isomeric forms: racemates, enantiomers and diastereomers, as well as addition salts of the products of formula (I) with inorganic or organic acids or bases, and prodrugs of the products of formula (I).

The invention therefore relates in particular to a product of formula (I) as defined above or below, in which:

het is selected from:

r is selected from:

r1 is selected from H, F, Cl, Br, CF₃、NO₂、CN、CH₃、OH、OCH₃、OCF₃、CO₂Me、CONH₂、CONHMe、CONH-(CH₂)₃-OMe、CONH-(CH₂)₃-N(Me)₂、NHC(O)Me、SO₂NH₂And SO₂N(Me)₂；

R' 1 is selected from H, CONH₂CONHMe and OMe;

r' 1 is selected from F, Cl, OH, OMe, CN, O- (CH)₂)₃OMe and O- (CH)₂)₃-N(Me)₂；

W1 and W2 represent CH, or one represents CH and the other represents N;

y represents OH, O-PO ₃H₂、O-PO₃Na₂、O-SO₃H₂、O-SO₃Na₂、O-CH₂-PO₃H₂、O-CH₂-PO₃Na₂、O-CO-CH₂-CO₂tBu、O-CO-CH₂-NH₂Or O-CO-glycine, O-CO-CH₂-N(Me)₂、O-CO-CH₂-NHMe, O-CO-alanine, O-CO-serine, O-CO-lysine, O-CO-arginine, O-CO-glycine-lysine, O-CO-alanine-lysine;

n represents 2 or 3;

the product of formula (I) is in all its possible isomeric forms: racemates, enantiomers and diastereomers, and addition salts of the product of formula (I) with an inorganic or organic acid or base.

At a group-O-CO-glycine, -O-CO-CH as defined above or below₂-N(Me)₂、-O-CO-CH₂-NHMe, -O-CO-alanine, -O-CO-serine, -O-CO-lysine, -O-CO-arginine, -O-CO-glycineIn lysine and O-CO-alanine-lysine, the terms glycine, -alanine, -serine, -lysine and-arginine represent amino acid residues known and described in the general handbook of the person skilled in the art.

Subject of the invention is in particular a product of formula (I) as defined above, in which:

het is selected from:

wherein:

r1 represents H, F, Cl, Br, CF₃、NO₂、CN、CH₃、OH、OCH₃、OCF₃、CO₂Me、CONH₂、CONHMe、CONH-(CH₂)₃-OMe、CONH-(CH₂)₃-N(Me)₂、NHC(O)Me、SO₂NH₂Or SO₂N(Me)₂；

R' 1 represents H, CONH₂CONHMe or OMe;

r' 1 represents F, Cl, OH, OMe, CN, O- (CH)₂)₃OMe or O- (CH)₂)₃-N(Me)₂；

And R is selected from:

wherein:

w1 and W2 represent CH, or one represents CH and the other represents N;

R2 represents hydrogen, or 2-substituted ethyl, 3-substituted n-propyl, 4-trans-substituted cyclohexyl, wherein the substituents are selected from OH, SH, NH₂、OMe、NHMe、N(Me)₂、N(Et)₂Azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, quinuclidinyl, CONH₂Or COOH;

y represents OH, O-PO₃H₂、O-PO₃Na₂、O-SO₃H₂、O-SO₃Na₂、O-CH₂-PO₃H₂、O-CH₂-PO₃Na₂、O-CO-CH₂-CO₂tBu、O-CO-CH₂-NH₂Or O-CO-glycine, O-CO-CH₂-N(Me)₂、O-CO-CH₂-NHMe, O-CO-alanine, O-CO-serine, O-CO-lysine, O-CO-arginine, O-CO-glycine-lysine or O-CO-alanine-lysine, wherein n represents 2 or 3;

and prodrugs thereof, the product of formula (I) being in all its possible isomeric forms: racemates, enantiomers and diastereomers, and addition salts of the product of formula (I) with an inorganic or organic acid or base.

Subject of the invention is in particular a product of formula (I) as defined above, in which:

r is selected from:

w1 represents CH or N;

x represents an oxygen atom or a NR2 group;

r2 represents a hydrogen atom or C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl or C₄-C₈Heterocycloalkyl groups, these alkyl, cycloalkyl and heterocycloalkyl groups being optionally substituted by one or more groups which may be the same or different, selected from:

A hydroxyl group; a mercapto group; an amino group; an azetidinyl group; an oxetanyl group; a tetrahydrofuranyl group; a piperidinyl group; a tetrahydropyranyl group; a piperazinyl group; an alkyl piperazinyl group; a pyrrolidinyl group; morpholinyl; homopiperidinyl; a homopiperazinyl group; quinuclidinyl; carboxamides; a carboxyl group;

a carboxyl group esterified with an alkyl group; CO-NH (alkyl); -O-CO-alkyl; NH-CO-alkyl; an alkoxy group; a hydroxyalkoxy group; a methylthio group; an alkylamino group; a dialkylamino group; all these latter alkyl and alkoxy groups are themselves optionally substituted by: a hydroxy, mercapto, amino, alkylamino, dialkylamino, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or quinuclidinyl group;

the substituents Het of the product of formula (I) are selected from the values defined above or below,

the product of formula (I) is in all its possible tautomeric and isomeric forms: racemates, enantiomers and diastereomers, and addition salts of the product of formula (I) with an inorganic or organic acid or base, and prodrugs of the product of formula (I).

Subject of the invention is in particular a product of formula (I) as defined above, in which:

het is selected from:

r is selected from:

r1 is selected from H, F, Cl, Br, CF₃、NO₂、CN、CH₃、OH、OCH₃、OCF₃、CO₂Me、CONH₂、CONHMe、CONH-(CH₂)₃-OMe、CONH-(CH₂)₃-N(Me)₂、NHC(O)Me、SO₂NH₂And SO₂N(Me)₂；

R' 1 is selected from H, CONH₂CONHMe and OMe;

r' 1 is selected from F, Cl, OH, OMe, CN, O- (CH)₂)₃OMe and O- (CH)₂)₃-N(Me)₂；

W1 represents CH or N;

r2 represents a hydrogen atom or C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl or C₄-C₈Heterocycloalkyl groups, all of these alkyl, cycloalkyl and heterocycloalkyl groups being optionally substituted by one or more groups which may be the same or different selected from:

a hydroxyl group; a mercapto group; an amino group; an azetidinyl group; an oxetanyl group; a tetrahydrofuranyl group; a piperidinyl group; a tetrahydropyranyl group; a piperazinyl group; an alkyl piperazinyl group; a pyrrolidinyl group; morpholinyl; homopiperidinyl; a homopiperazinyl group; quinuclidinyl; carboxamides; a carboxyl group;

carboxy, CO-NH (alkyl), -O-CO-alkyl, NH-CO-alkyl, alkoxy, hydroxyalkoxy, methylthio, alkylamino, dialkylamino esterified with an alkyl group, all the latter alkyl and alkoxy groups themselves being optionally substituted by: a hydroxy, mercapto, amino, alkylamino, dialkylamino, azetidinyl, oxetanyl, pyrrolidinyl (prolino), tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or quinuclidinyl group;

The product of formula (I) is in all its possible tautomeric and isomeric forms: racemates, enantiomers and diastereomers, and addition salts of the product of formula (I) with an inorganic or organic acid or base, and prodrugs of the product of formula (I).

Subject of the invention is in particular a product of formula (I) as defined above, in which:

het is selected from:

r is selected from:

r1 is selected from H, F, Cl, Br, CF₃、NO₂、CN、CH₃、OH、OCH₃、OCF₃、CO₂Me、CONH₂、CONHMe、CONH-(CH₂)₃-OMe、CONH-(CH₂)₃-N(Me)₂、NHC(O)Me、SO₂NH₂And SO₂N(Me)₂；

R' 1 is selected from H, CONH₂CONHMe and OMe;

r' 1 is selected from F, Cl, OH, OMe, CN, O- (CH)₂)₃OMe and O- (CH)₂)₃-N(Me)₂；

W1 represents CH or N;

y represents OH, O-PO₃H₂、O-PO₃Na₂、O-SO₃H₂、O-SO₃Na₂、O-CH₂-PO₃H₂、O-CH₂-PO₃Na₂、O-CO-CH₂-CO₂tBu、O-CO-CH₂-NH₂O-CO-glycine, O-CO-CH₂-N(Me)₂、O-CO-CH₂-NHMe, O-CO-alanine, O-CO-serine, O-CO-lysine, O-CO-arginine, O-CO-glycine-lysine(ii) alanine or O-CO-alanine-lysine;

n represents 2 or 3;

the product of formula (I) is in all its possible isomeric forms: racemates, enantiomers and diastereomers, and addition salts of the product of formula (I) with an inorganic or organic acid or base.

Subject of the invention is in particular a product of formula (I) as defined above, in which:

het is selected from:

wherein:

r1 represents H, F, Cl, Br, CF₃、NO₂、CN、CH₃、OH、OCH₃、OCF₃、CO₂Me、CONH₂、CONHMe、CONH-(CH₂)₃-OMe、CONH-(CH₂)₃-N(Me)₂、NHC(O)Me、SO₂NH₂Or SO₂N(Me)₂；

R' 1 represents H, CONH ₂CONHMe or OMe;

r' 1 represents F, Cl, OH, OMe, CN, O- (CH)₂)₃OMe or O- (CH)₂)₃-N(Me)₂；

And R is selected from:

wherein:

r2 represents hydrogen, or 2-substituted ethyl, 3-substituted n-propyl, 4-trans-substituted cyclohexyl, whichWherein the substituent is selected from OH, SH, NH₂、OMe、NHMe、N(Me)₂、N(Et)₂Azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, quinuclidinyl, CONH₂Or COOH;

y represents OH, O-PO₃H₂、O-PO₃Na₂、O-SO₃H₂、O-SO₃Na₂、O-CH₂-PO₃H₂、O-CH₂-PO₃Na₂、O-CO-CH₂-CO₂tBu、O-CO-CH₂-NH₂Or O-CO-glycine, O-CO-CH₂-N(Me)₂、O-CO-CH₂-NHMe, O-CO-alanine, O-CO-serine, O-CO-lysine, O-CO-arginine, O-CO-glycine-lysine or O-CO-alanine-lysine, wherein n represents 2 or 3;

and prodrugs thereof, the product of formula (I) being in all its possible isomeric forms: racemates, enantiomers and diastereomers, and the pharmaceutically acceptable addition salts of the product of formula (I) with an inorganic or organic acid or an inorganic or organic base.

The subject of the invention is more particularly the products of formula (I) as defined above, with the following names:

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-trans-hydroxycyclohexylamino) benzamide

-2- (4-trans-hydroxycyclohexylamino) -4- [ (4-quinolin-3-yl) -9H-carbazol-9-yl ] benzamide

-2- (2-diethylaminoethylamino) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide

-2- (4-trans-hydroxycyclohexylamino) -4- [4- (3H-imidazo [4, 5-c ] pyridin-2-yl) -9H-carbazol-9-yl ] benzamide

-acetic acid 4- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } cyclohexyl ester

-2-cyclohexylamino-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [2- (2-hydroxyethoxy) ethylamino ] benzamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (3-hydroxypropylamino) benzamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-cis-hydroxycyclohexylamino) benzamide

-2-amino-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (2-pyrrolidin-1-ylethylamino) benzamide

-6- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -1H-indazol-3-ylamine

-6- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-1, 2-benzisoxazo(ii) an azol-3-ylamine,

-3- (trans-4-hydroxycyclohexylamino) -5- [ (4-quinolin-3-yl) -9H-carbazol-9-yl) pyridine-2-carboxamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (tetrahydropyran-4-ylamino) benzamide

-4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2- [ (1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) amino ] benzamide

-aminoacetic acid 4- { [ 2-carbamoyl-5- (quinolin-3-yl) -9H-carbazol-9-yl ] -pyridin-3-ylamino } cyclohexyl ester

-4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2- [ (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) amino ] benzamide

-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -3- (tetrahydropyran-4-yl) amino) pyridine-2-carboxamide

-2- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -4- (tetrahydropyran-4-yl) -amino) pyridine-5-carboxamide

-2- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) amino-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide

-3- [ (2-hydroxy-2-methylpropylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-2-carboxamide

And addition salts of the products of formula (I) with inorganic or organic acids or with inorganic or organic bases.

The products of formula (I) according to the invention can be prepared according to methods known to the person skilled in the art and in particular according to the methods described below: the subject of the present invention is therefore a process for the synthesis of the product of formula (I) according to the invention, in particular the general process described in the scheme below.

General procedure for the synthesis of compounds of general formula (I):

the products of formula (I) can be prepared from 4-hydroxy-9H-carbazole derivatives of formula (II) according to the following general scheme (1): by first introducing the heterocyclic ring Het to form a compound of the general formula (III) or introducing a precursor group R to form a product of the general formula (IV):

scheme (1)

The subject of the present invention is therefore in particular the above scheme (1) for the synthesis of the products of formula (I) as defined above.

Subject of the invention are also the synthetic intermediates of formulae (III), (IV), (V) and (VI) as defined above, in which the substituents Het, R2, W1 and W2 have the meanings indicated in the products of formula (I) as defined above, and z has the meanings indicated above in scheme (1), as industrial products.

Preparation of the Compounds of the general formula (II)

The subject of the invention is therefore a process for the synthesis of a product of formula (II) in which Z represents a triflate group, a boronic acid or a boronic ester, which is optionally cyclic.

Products of general formula (II) wherein Z represents a benzyloxy group can be obtained according to biorg.med.chem.2005, 13(13), 4279.

The product of general formula (II) wherein Z represents a trifluoromethanesulfonyloxy group (also referred to as "triflate" in the remainder of the present invention) can be obtained according to scheme (2) below by the action of a triflating agent, such as N-phenyl bis (trifluoromethanesulfonimide), in the presence of an organic solvent, such as dichloromethane, in the presence of an organic base, such as triethylamine.

Scheme (2)

The products of the general formula (II) in which Z represents a methyl carboxylate group can be obtained by carrying out the process according to Tetrahedron Letters (1985), 26(13), 1647-50. However, it has been found that in the present invention, the methyl carboxylate can be advantageously obtained according to scheme (3) by: carbonylation in methanol catalyzed by palladium complexes such as palladium acetate in the presence of phosphine type ligands such as 1, 3-diphenylphosphinopropane:

scheme 3

The product of the general formula (II) wherein Z represents a carboxyl group can be obtained by carrying out the process according to the Journal of the Chemical Society (1937), 1125-9.

The product of formula (II) wherein the Z-carbamoyl group may be obtained by carrying out a process according to the Journal of the Chemical Society (1957), 2210-5.

The product of the general formula (II) wherein Z represents a bromine atom can be obtained by carrying out the process according to Journal of the Chemical Society (1945), 530-3.

The products of general formula (II) wherein Z represents an iodine atom can be obtained by the action of n-butyllithium and then iodine on 4-bromocarbazole at low temperature in an organic solvent such as tetrahydrofuran and according to scheme (4):

scheme (4)

The product of general formula (II), optionally cyclic, in which Z represents a boronic acid or boronic ester, can advantageously be prepared according to the process of scheme (5) by: n-butyllithium and then a borate ester such as dimethyl borate, di-n-butyl borate, diisopropyl borate or pinacol borate, on 4-bromocarbazole at low temperatures in organic solvents such as tetrahydrofuran, or on derivatives of 4-iodocarbazole or derivatives of 4-trifluoromethylsulfonyloxy in the presence of a palladium (0) catalyst.

Scheme (5)

Preparation of the Compounds of the general formula (III)

Subject of the present invention is therefore a process for the synthesis of a product of formula (III) in which R1 and/or R' 1 are as defined above, Het is selected from:

more particularly, when Het does not represent a heterocycle of imidazol-2-yl, triazol-3-yl, benzimidazol-2-yl or azabenzimidazol-2-yl type, optionally substituted by one or more radicals R1 as defined above, it is particularly advantageous to prepare according to the invention compounds of general formula (III)

Or by coupling of 4-bromocarbazole, 4-iodocarbazole or 4-trifluoromethylsulfonyloxycarbazole with heterocyclic boronic acid (boronic) derivatives, which may be acids or esters

Or by coupling carbazole-4-boronic acid or esters thereof, such as the methyl, n-butyl, isopropyl or pinacol (pinacol) ester, with bromine or iodine heterocycles,

by carrying out the process according to scheme (6) under Suzuki reaction conditions in the presence of a palladium (0) derivative as catalyst:

scheme (6)

More particularly, when the heterocycle Het is of the benzimidazole or azabenzimidazole type-or benzo-which is attached via its 2-position to the 4-position of the carbazoleAzole or azabenzoOf the azole, benzothiazole or azabenzothiazole type, particular advantage is gained byThe heterocyclic ring is formed as follows by applying the method according to scheme (7): coupling o-phenylenediamine or diaminopyridine or derivatives of o-aminophenol or o-aminothiophenol or aminohydroxypyridine or aminomercaptopyridine, which are ortho-substituted by an acid, acid chloride, methyl or ethyl ester or an aldehyde, at the 4-position of the carbazole which is N-protected by a protecting group, such as a tert-butyloxycarbonyl (Boc) group or a tert-butyldimethylsilyl (TBDMS) group or a 2- (trimethylsilyl) ethoxymethyl (SEM) group, followed by cyclization in an acidic medium, which leaves the carbazole either carried by the nitrogen atom or the TBDMS protecting group:

A＝NH，O，S

Z＝COOH，COCl，COOMe，COOEt，CHO

V1＝N，CR1

PG ═ TBDMS or Boc

R1 is as defined above

Scheme (7)

In the present invention, it is advantageous to protect the nitrogen of carbazole derivatives carrying an acid, ester or aldehyde group at the 4-position, protected with a tert-butyloxycarbonyl (Boc) group-via Boc₂O, BocCl or BocON in an organic solvent such as dichloromethane or tetrahydrofuran in the presence of an organic or inorganic base-or protected with tert-butyldimethylsilyl group (TBDMS) -by the action of tert-butyldimethylsilylchlorosilane (TBDMSCl) in an organic solvent such as dichloromethane or tetrahydrofuran in the presence of an organic or inorganic base-or protected with a 2- (trimethylsilyl) ethoxymethyl (SEM) group-by the action of 2- (trimethylsilyl) ethoxymethyl chloride (SEMCl) in an organic solvent such as dichloromethane or tetrahydrofuran in the presence of an organic or inorganic base.

When using N-protected carbazolesDerivatives of (E) -4-carboxylic acid, it is particularly advantageous to use coupling agents known to the person skilled in the art, such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) in 1-Hydroxybenzotriazole (HOBT) or O- ((ethoxycarbonyl) cyanomethyleneamino) -N, N, N ', N' -tetramethylureaThe acid was activated in the presence of tetrafluoroborate (TOTU).

When derivatives of methyl or ethyl esters of N-protected carbazole-4-carboxylic acids are used, the process is advantageously carried out in the present invention in the presence of trimethylaluminum in halogenated organic solvents such as dichloromethane or dichloroethane.

When using N-protected derivatives of carbazole-4-carbaldehyde, the following process is advantageously carried out in the present invention:

or by microwave heating in the presence of silica according to Tetrahedron lett.1998, 39, 4481-84;

-or according to Tetrahedron 1995, 51, 5813-18 in the presence of dichlorodicyanobenzoquinone (DDQ);

-or according to e.p.511187 in the presence of a mixture of thionyl chloride and pyridine;

-or according to eur.j.med.chem.2006, 31, 635-42 in the presence of ferric chloride.

Various conditions for cyclizing the mixture of amide intermediates can be used in the present invention, such as acetic acid or a mixture of trifluoroacetic acid and trifluoroacetic anhydride. It is also particularly advantageous in the context of the present invention to carry out this type of thermal cyclisation in an acidic medium by heating in a microwave reactor.

More specifically, when the heterocyclic ring is an imidazole linked via its 2-position to the 4-position of the carbazole,Of the oxazole or thiazole type, particular advantage is given by Carrying out the method according to embodiment (8), the heterocycle is formed at the 4-position of the N-protected carbazole derivative using an acid, acid chloride, ester, or aldehyde:

scheme (8)

In the present invention, it is advantageous to protect the nitrogen of carbazole derivatives carrying an acid, ester or aldehyde group at the 4-position, protected with a tert-butyloxycarbonyl (Boc) group-via Boc₂O, BocCl or BocON in an organic solvent such as dichloromethane or tetrahydrofuran in the presence of an organic or inorganic base-or protected with tert-butyldimethylsilyl group (TBDMS) -by the action of tert-butyldimethylsilylchlorosilane (TBDMSCl) in an organic solvent such as dichloromethane or tetrahydrofuran in the presence of an organic or inorganic base-or protected with a 2- (trimethylsilyl) ethoxymethyl (SEM) group-by the action of 2- (trimethylsilyl) ethoxymethyl chloride (SEMCl) in an organic solvent such as dichloromethane or tetrahydrofuran in the presence of an organic or inorganic base.

In the present invention, it is particularly advantageous to carry out the following process:

1. in the case where the heterocycle is imidazole or imidazoline:

according to Tetrahedron, 47(38), 1991, 8177-94, 2-azidoethylamine is used,

according to Biorg. Med. chem Lett.12(3), 2002, 471-75, ethylene diamine is used,

According to j.med.chem., 46(25), 2003, 5416-27, glyoxal and ammonia water are used;

2. in the heterocyclic ring isAzole orIn the case of oxazolines:

according to J.org.chem., 61(7), 1996, 2487-96, 2-azidoethanol is used,

according to J.Med.chem.47(8), 2004, 1969-86 or Khim.Geterosikl.Soed.1984(7), 881-4, 2-aminoethanol is used,

use of 2-aminoacetaldehyde diacetal according to Heterocycles, 39(2), 1994, 767-78;

3. in the case where the heterocycle is thiazole or thiazoline:

according to Helv. Chim. acta, 88(2), 2005, 187-95, using 2-chloroethylamine and Rous's reagent (Lawesson's reagent),

according to J.org.chem.69(3), 2004, 811-4, or Tetrahedron Lett., 41(18), 2000, 3381-4, 2-aminoethanethiol is used.

More particularly, it is advantageous in the present invention to use triflates, brominated or iodinated derivatives, boronic acids or esters, carboxylic acids, acid chlorides of esters of carboxylic acids, or aldehydes to form Heterocycles of the products of formula (III) at the 4-position of the carbazole by any of the methods known to those skilled in the art, such as those described in Comprehensive Organic Chemistry, by D.H.R.Barton et al (Pergamon Press) or Advances in heterogenics Chemistry (Academic Press) or heterogenics Compounds (Wiley Intersciences).

Preparation of the Compounds of the general formula (IV)

The subject of the invention is therefore a process for the synthesis of a product of formula (IV) in which Z represents a carboxylate, in particular a methyl or ethyl ester or a benzyloxy group.

The products of the general formula (IV) in which Z represents a carboxylate or a benzyloxy group can advantageously be prepared in the present invention by reacting products of the general formula (II) in which Z represents a carboxylate or a benzyloxy group,

1) or by carrying out the method according to embodiment (9):

by aromatic nucleophilic substitution reaction of 2-bromo-4-fluorobenzonitrile or 4-bromo-5-cyano-2-fluoropyridine or 5-bromo-2-cyano-3-fluoropyridine in a solvent such as Dimethylformamide (DMF), Dimethylsulfoxide (DMSO) or N-methylpyrrolidone (NMP) after pretreatment of the carbazole derivative of the general formula (II) with a strong base such as sodium hydride,

followed by Buchwald-Hartwig amination with an amine R2-NH (where R2 is as defined above) in the presence of a base such as potassium tert-butoxide and a palladium (0) derivative such as "palladium-dppf" (formed from palladium acetate and 1, 1' -bis (diphenylphosphino) ferrocene) in a solvent such as toluene.

Scheme (9)

2) Or by carrying out the method according to embodiment (10)

By reacting 4-bromo-2-fluorobenzonitrile or 2-bromo-5-cyano-4-fluoropyridine or 5-bromo-2-cyano-3-fluoropyridine with a carbazole of the general formula (II) in the presence of a base such as cesium carbonate and a palladium (0) derivative such as "palladium-Xanthphos" (formed from palladium acetate and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) in a solvent such as bis (diphenylphosphino) Buchwald-Hartwig reaction in alkane,

followed by the reaction with an amine R2-NH₂(wherein R2 is as defined above) in the presence of a base such as potassium carbonate in a solvent such as DMSO.

Scheme (10)

The products of general formula (IV), wherein Z represents a carboxylic acid or a hydroxyl group, can be prepared by alkaline hydrolysis of the corresponding ester or by hydrolysis of the corresponding benzyloxy derivative, respectively, according to conventional methods known to the person skilled in the art.

The product of general formula (IV), wherein Z represents a trifluoromethanesulfonyloxy group, can be obtained as described in scheme (2) by the action of N-phenyl bis (trifluoromethanesulfonimide) on the product of general formula (IV), wherein Z represents a hydroxy group, in an organic solvent such as dichloromethane in the presence of an organic base such as triethylamine.

Preparation of Compounds of the formula (V)

The subject of the invention is therefore a process for the synthesis of a product of formula (V) in which Z represents a carboxylate group, in particular a methyl or ethyl ester or a benzyloxy group.

Compounds of formula (V) wherein R is of type A may be prepared by hydrolysis of the cyano group of compounds of formula (IV). This hydrolysis can advantageously be carried out in the present invention by the action of an aqueous hydrogen peroxide solution according to scheme (11):

Scheme (11)

The compounds of formula (V) wherein R is of type B and X is an NH group, can advantageously be prepared in the present invention according to scheme (12) by aromatic nucleophilic substitution reaction followed by intramolecular cyclization by the action of hydrazine hydrate in a polar solvent such as n-butanol on the nitrile of formula (IV) wherein the halogen atom is particularly preferably ortho-substituted with respect to the fluorine atom:

scheme (12)

Compounds of general formula (V) (wherein R is of type B and X is a NR2 group, R2 is as defined above) may be prepared according to scheme (13):

or, advantageously, in the present invention, the action of hydrazine monosubstituted by the radical R2 on nitriles of formula (IV) ortho-substituted by halogen atoms, particularly preferably fluorine atoms, in a polar solvent such as n-butanol,

-or, by N-alkylation, of a product of general formula (V) of type B (X ═ NH). This alkylation can be carried out according to methods known to the person skilled in the art, in particular by treatment with a base such as sodium hydride followed by the action of the halogenated derivative R2-Hal.

By carrying out the process in this manner, a mixture of N1-N3-alkylated regioisomers (regioisomers) is generally obtained, which can be separated using conventional methods known to those skilled in the art.

Scheme (13)

The compounds of general formula (V) wherein R is of type B and X is an oxygen atom, can advantageously be prepared in the present invention by a process according to embodiment (14) as follows: by the action of an N-protected hydroxylamine, such as N-tert-butyloxycarbonylhydroxylamine, in the presence of a strong base, such as potassium tert-butoxide, of a nitrile of the formula (IV) ortho-substituted with respect to the halogen atom, particularly preferably with respect to the fluorine atom, in a solvent, such as DMF:

scheme (14)

Compounds of general formula (V) wherein R is of type B and X is a sulphur atom, can advantageously be prepared in the present invention by carrying out the process according to scheme (15), in particular under the conditions described in biorg.med.chem lett. (2007), 17(6), 4568, as follows: by the action of sodium sulphide in a solvent such as DMSO on a nitrile of formula (IV) ortho-substituted by a halogen atom, particularly preferably a fluorine atom, followed by the action of aqueous ammonia in the presence of sodium hypochlorite:

scheme (15)

The compounds of the general formula (V) in which R is of the type C can advantageously be prepared in the present invention by carrying out the process according to embodiment (16), in particular under the conditions described in Zeitschrift fur Chemie (1984), 24(7), 254, as follows: by the action of hydroxylamine hydrochloride on nitriles of the general formula (IV) ortho-substituted by halogen atoms, particularly preferably fluorine atoms:

Scheme (16)

Compounds of general formula (V) wherein R is of type D and W3 is a nitrogen atom, may advantageously be prepared in the present invention by carrying out the process according to scheme (17), in particular under the conditions described in j.het.chem. (2006), 43(4), 913, as follows: by the action of aqueous ammonia on nitriles of formula (IV) ortho-substituted by halogen atoms, particularly preferably fluorine atoms, followed by the action of a mixture of ethyl orthoformate and ammonium acetate:

scheme (17)

Compounds of general formula (V) wherein R is of type E, may advantageously be prepared in the present invention by carrying out the general method according to scheme (18), in particular under the conditions described in chem. pharm. bull. (1986), 34, 2760, as follows: the alkynyl intermediate is obtained by the action of trimethylsilylacetylene on a compound of general formula (IV) ortho-substituted by a bromine atom in the presence of a base such as triethylamine or n-butylamine in the presence of cuprous iodide and tetrakis (triphenylphosphine) palladium, which is then treated in turn with sodium ethoxide in ethanol, then with a solution of hydrogen peroxide in an alkaline medium and finally heated in the presence of p-toluenesulfonic acid.

Scheme (18)

Compounds of general formula (V) (wherein R is of type D, W1, W2 and W3 ═ CH) can be advantageously prepared in the present invention by carrying out the process according to scheme (19), in particular under the conditions described in bioorg.med.chem. (2006), 14(20), 6832, as follows: by the action of phosphorus trichloride and then of acetamide on the product of general formula (V) of type E at temperatures close to 180 ℃ in the presence of a base such as potassium carbonate.

Scheme (19)

Preparation of Compounds of the general formula (VI)

The subject of the present invention is therefore a process for the synthesis of the product of formula (VI).

A) From products of the general formula (IV)

More specifically, when Het does not represent a heterocycle of imidazol-2-yl, triazol-3-yl, benzimidazol-2-yl or azabenzimidazol-2-yl type, optionally substituted by one or more radicals R1 as defined above, it is particularly advantageous to prepare the compounds of general formula (VI) by coupling according to the invention as follows:

or, the reaction of a product of general formula (IV) in which Z represents a trifluoromethylsulfonyloxycarbazole group with a heterocyclic boronic acid derivative, which may be an acid or an ester such as a methyl, n-butyl, isopropyl or pinacol ester, under Suzuki reaction conditions in the presence of a palladium (0) derivative as catalyst,

or, the products of formula (IV) (in which Z represents a boronic acid derivative, which may be an acid or an ester such as a methyl, n-butyl, isopropyl or pinacol ester) with brominated or iodinated heterocyclic derivatives,

by carrying out the process according to embodiment (20):

scheme (20)

More particularly, when Het is of the benzimidazole or azabenzimidazole type or benzo connected via its 2-position to the 4-position of the carbazoleAzole or azabenzo When heterocycles of the azole, benzothiazole or azabenzothiazole type are used, it is particularly advantageous to form them by carrying out the process according to scheme (21) as follows: coupling of a derivative of o-phenylenediamine or diaminopyridine or o-aminophenol or o-aminothiophenol or aminohydroxypyridine or aminomercaptopyridine, which are ortho-disubstituted, with a derivative of general formula (IV) wherein Z represents an acid or an ester, in particular a methyl or ethyl ester:

scheme (21)

When using products of the general formula (IV) in which Z is an acid, it is particularly advantageous to use coupling agents known to the person skilled in the art, such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) in 1-Hydroxybenzotriazole (HOBT) or O- ((ethoxycarbonyl) cyanomethyleneamino) -N, N, N ', N' -tetramethylureaThe acid was activated in the presence of tetrafluoroborate (TOTU).

When using a product of formula (IV) wherein Z is methyl or ethyl ester, the process is advantageously carried out in the present invention in the presence of trimethylaluminum in a halogenated organic solvent such as dichloromethane or dichloroethane.

Various conditions for cyclizing the mixture of amide intermediates can be used in the present invention, such as acetic acid or a mixture of trifluoroacetic acid and trifluoroacetic anhydride. It is also particularly advantageous in the context of the present invention to carry out this type of thermal cyclisation in an acidic medium by heating in a microwave reactor.

More specifically, when the heterocyclic ring is an imidazole linked via its 2-position to the 4-position of the carbazole,When an azole or thiazole is used, it is particularly advantageous to form the heterocyclic ring by carrying out the method according to embodiment (22) using an acid or an ester:

scheme (22)

In the present invention, it is particularly advantageous to carry out the following process:

1. in the case where the heterocycle is imidazole or imidazoline:

according to Tetrahedron, 47(38), 1991, 8177-94, 2-azidoethylamine is used,

according to Biorg. Med. chem Lett.12(3), 2002, 471-75, ethylene diamine is used,

according to j.med.chem., 46(25), 2003, 5416-27, glyoxal and ammonia water are used;

2. in the heterocyclic ring isAzole orIn the case of oxazolines:

according to J.org.chem., 61(7), 1996, 2487-96, 2-azidoethanol is used,

according to J.Med.chem.47(8), 2004, 1969-86 or Khim.Geterosikl.Soed.1984(7), 881-4, 2-aminoethanol is used,

according to Heterocycles, 39(2), 1994, 767-78, 2-aminoacetaldehyde diacetal is used;

3. in the case where the heterocycle is thiazole or thiazoline:

according to Helv. Chim. acta, 88(2), 2005, 187-95, using 2-chloroethylamine and Rous's reagent,

according to J.org.chem.69(3), 2004, 811-4, or Tetrahedron Lett., 41(18), 2000, 3381-4, 2-aminoethanethiol is used.

More generally, it is advantageous in the present invention to use triflates, carboxylic acids or carboxylic esters to form Heterocycles of the products of formula (III) by any of the synthetic methods known to those skilled in the art, such as those described in Comprehensive Organic Chemistry, D.H.R.Barton et al (Pergamon Press) or Advances in Heterocycles Chemistry (Academic Press) or Heterocycles Compounds (Wiley Interscience).

B) From products of the general formula (III)

More particularly, when Het does not represent a heterocycle of imidazol-2-yl, triazol-3-yl, benzimidazol-2-yl or azabenzimidazol-2-yl type, and is optionally substituted by one or more radicals R1 as defined above, it is particularly advantageous to prepare, according to the invention, compound (VI) of general formula (III) from the product of general formula (III):

1) alternatively, by carrying out the method according to embodiment (23):

by aromatic nucleophilic substitution reaction of 2-bromo-4-fluorobenzonitrile or 4-bromo-5-cyano-2-fluoropyridine or 5-bromo-2-cyano-3-fluoropyridine in a solvent such as Dimethylformamide (DMF), Dimethylsulfoxide (DMSO) or N-methylpyrrolidone (NMP) after pretreatment of the carbazole derivative of the general formula (III) with a strong base such as sodium hydride,

-optionally followed by Buchwald-Hartwig amination with an amine R2-NH (wherein R2 is as defined above) in the presence of a base such as potassium tert-butoxide and a palladium (0) derivative such as "palladium-dppf" (formed from palladium acetate and 1, 1' -bis (diphenylphosphino) ferrocene) in a solvent such as toluene.

Scheme (23)

2) Alternatively, by carrying out the method according to embodiment (24)

By reacting 4-bromo-2-fluorobenzonitrile or 2-bromo-5-cyano-4-fluoropyridine or 5-bromo-2-cyano-3-fluoropyridine with a carbazole of the general formula (III) in the presence of a base such as cesium carbonate and a palladium (0) derivative such as "palladium-Xanthphos" (formed from palladium acetate and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) in a solvent such as bis (diphenylphosphino)Buchwald-Hartwig reaction in alkane,

optionally followed by an amine R2-NH₂(wherein R2 is as defined above) in the presence of a base such as potassium carbonate in a solvent such as DMSO.

Scheme (24)

When Het represents a heterocycle of imidazol-2-yl, triazol-3-yl, benzimidazol-2-yl or azabenzimidazol-2-yl type, optionally substituted by one or more radicals R1 as defined above, it is likewise advantageous to prepare the compounds of general formula (VI) from the products of general formula (III) by carrying out the process according to the above-described schemes (23) and (24). In these cases, however, it is advisable to protect the NH-type nitrogen of the heterocyclic Het with a protecting group such as a Boc, TBDMS or SEM group according to any of the methods described above or known to the person skilled in the art before Buchwald-Hartwig and/or aromatic nucleophilic reactions. The protecting group may leave spontaneously during the Buchwald-Hartwig and/or aromatic nucleophilic reactions, using any method known to those skilled in the art, or after these reactions.

Preparation of the Compounds of the general formula (I)

The subject of the present invention is therefore a process for the synthesis of the product of formula (I).

A) From products of the general formula (III)

It is particularly advantageous according to the invention to prepare the compounds of the general formula (I) from the products of the general formula (III) as follows: Buchwald-Hartwig reaction between heterocyclic carbazole derivatives of the general formula (III) and aromatic derivatives R-Br, R-I or R-OTf (where R is as defined above). However, the device is not suitable for use in a kitchenThe procedure according to scheme (25) is followed in the presence of a base such as cesium carbonate and a palladium (0) derivative such as "palladium-Xanthphos" (formed from palladium acetate and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) in a solvent such as bisThe process is carried out in an alkane:

scheme (25)

(B) From products of the general formula (V)

More particularly, when Het does not represent a heterocycle of imidazol-2-yl, triazol-3-yl, benzimidazol-2-yl or azabenzimidazol-2-yl type, optionally substituted by one or more radicals R1 as defined above, it is particularly advantageous to prepare according to the invention compounds of general formula (I) by coupling:

or, a product of the general formula (V) in which Z represents a trifluoromethylsulfonyloxycarbazole group, with a heterocyclic boronic acid derivative which is an acid or an ester such as a methyl ester, n-butyl ester, isopropyl ester or pinacol ester, under Suzuki reaction conditions in the presence of a palladium (0) derivative as catalyst,

Or, the products of formula (V) (in which Z represents a boronic acid derivative which is an acid or an ester such as methyl, n-butyl, isopropyl or pinacol ester) with brominated or iodinated heterocyclic derivatives,

by carrying out the method according to embodiment (26):

scheme (26)

Furniture setWhen the heterocyclic ring Het is of the benzimidazole or azabenzimidazole type or benzo connected via its 2-position to the 4-position of the carbazoleAzole or azabenzoOf the azole, benzothiazole or azabenzothiazole type, it is particularly advantageous to form the heterocycle by carrying out the process according to scheme (27) as follows: coupling of a derivative of o-phenylenediamine or diaminopyridine or o-aminophenol or o-aminothiophenol or aminohydroxypyridine or aminomercaptopyridine, which are ortho-disubstituted, with a derivative of general formula (V) wherein Z represents an acid or an ester, in particular a methyl or ethyl ester:

scheme (27)

When using products of the general formula (V) in which Z is an acid, it is particularly advantageous to use coupling agents known to the person skilled in the art, such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) in 1-Hydroxybenzotriazole (HOBT) or O- ((ethoxycarbonyl) cyanomethyleneamino) -N, N, N ', N' -tetramethylurea The acid was activated in the presence of tetrafluoroborate (TOTU). When using products of the general formula (V) in which Z is a methyl or ethyl ester, the process is advantageously carried out in the present invention in the presence of trimethylaluminum in a halogenated organic solvent such as dichloromethane or dichloroethane.

Various conditions for cyclizing the mixture of amide intermediates can be used in the present invention, such as acetic acid or a mixture of trifluoroacetic acid and trifluoroacetic anhydride. It is also particularly advantageous in the context of the present invention to carry out this type of thermal cyclisation in an acidic medium by heating in a microwave reactor.

More particularly, when the heterocyclic ring Het is an imidazole, which is linked via its 2-position to the 4-position of the carbazole,When an azole or thiazole is used, it is particularly advantageous to form the heterocyclic ring by carrying out the method according to embodiment (28) using an acid or an ester:

scheme (28)

In the present invention, it is particularly advantageous to carry out the following method:

1. in the case where the heterocycle is imidazole or imidazoline:

according to Tetrahedron, 47(38), 1991, 8177-94, 2-azidoethylamine is used,

according to Biorg. Med. chem Lett.12(3), 2002, 471-75, ethylene diamine is used,

according to j.med.chem., 46(25), 2003, 5416-27, glyoxal and ammonia water are used;

2. In the heterocyclic ring isAzole orIn the case of oxazolines:

according to J.org.chem., 61(7), 1996, 2487-96, 2-azidoethanol is used,

according to J.Med.chem.47(8), 2004, 1969-86 or Khim.Geterosikl.Soed.1984(7), 881-4, 2-aminoethanol is used,

use of 2-aminoacetaldehyde diacetal according to Heterocycles, 39(2), 1994, 767-78;

3. in the case where the heterocycle is thiazole or thiazoline:

according to Helv. Chim. acta, 88(2), 2005, 187-95, using 2-chloroethylamine and Rous's reagent,

according to J.org.chem.69(3), 2004, 811-4 or Tetrahedron Lett., 41(18), 2000, 3381-4, 2-aminoethanethiol is used.

Advantageously in the present invention, the heterocyclic ring of the product of formula (I) is formed using triflates, carboxylic acids or carboxylates by any of the synthetic methods known to the person skilled in the art, such as those described in Comprehensive Organic Chemistry, D.H.R.Barton et al (Pergamon Press) or Advances in Heterocycles Chemistry (Academic Press) or Heterocycles Compounds (Wiley Interscience).

C) From products of the general formula (VI)

Compounds of formula (I) wherein R is of type A may be prepared by hydrolysis of the cyano group of compounds of formula (VI). This hydrolysis can advantageously be carried out in the present invention according to scheme (29) as follows: by the action of aqueous hydrogen peroxide in an alkaline medium in a mixture of DMSO and ethanol:

Scheme (29)

Compounds of general formula (I) wherein R is of type B and X is an NH group, can advantageously be prepared in the present invention according to scheme (30) as follows: by aromatic nucleophilic substitution reaction, followed by intramolecular cyclization by hydrazine hydrate in a polar solvent such as n-butanol, of a nitrile of formula (VI) ortho-substituted by a halogen atom, particularly preferably a fluorine atom:

scheme (30)

Compounds of general formula (I) wherein R is of type B and X is a NR2 group wherein R2 is as defined above, can advantageously be prepared in the present invention according to scheme (31) as follows: the nitrile of the formula (VI) which is ortho-substituted by halogen atoms, particularly preferably fluorine atoms, is acted on by hydrazine monosubstituted by the radical R2 in a polar solvent such as n-butanol.

Scheme (31)

Compounds of general formula (I) wherein R is of type B and X is an oxygen atom, can advantageously be prepared in the present invention by a process according to embodiment (32) as follows: by the action of an N-protected hydroxylamine, such as N-tert-butyloxycarbonylhydroxylamine, in the presence of a strong base, such as potassium tert-butoxide, on a compound of the formula (VI) ortho-substituted by halogen atoms, particularly preferably fluorine atoms, in a solvent such as DMF:

scheme (32)

Compounds of general formula (I) wherein R is of type B and X is a sulphur atom, can advantageously be prepared in the present invention by carrying out the process according to scheme (33), in particular under the conditions described in biorg.med.chem lett. (2007), 17(6), 4568, as follows: by reacting a nitrile of the general formula (VI) ortho-substituted by halogen atoms, particularly preferably fluorine atoms, with sodium sulfide in a solvent such as DMSO, followed by aqueous ammonia in the presence of sodium hypochlorite:

Scheme (33)

The compounds of the general formula (I) in which R is of the type C can advantageously be prepared in the present invention by carrying out the process according to embodiment (34), in particular under the conditions described in Zeitschrift fur Chemie (1984), 24(7), 254, as follows: by the action of hydroxylamine hydrochloride on nitriles of the general formula (VI) ortho-substituted by halogen atoms, particularly preferably fluorine atoms:

scheme (34)

Compounds of general formula (I) wherein R is of type D and W3 is a nitrogen atom, may advantageously be prepared in the present invention by carrying out the process according to embodiment (35), in particular under the conditions described in j.het.chem. (2006), 43(4), 913 as follows: by the action of aqueous ammonia on nitriles of formula (VI) ortho-substituted by halogen atoms, particularly preferably fluorine atoms, followed by the action of a mixture of ethyl orthoformate and ammonium acetate:

scheme (35)

Compounds of general formula (I) wherein R is of type E, may advantageously be prepared in the present invention by carrying out the process according to general scheme (36), in particular under the conditions described in chem. pharm. bull. (1986), 34, 2760, as follows: the alkynyl intermediate is obtained by the action of trimethylsilylacetylene on a compound of formula (VI) ortho-substituted by a bromine atom in the presence of a base such as triethylamine or n-butylamine in the presence of cuprous iodide and tetrakis (triphenylphosphine) palladium, which is then treated in turn with sodium ethoxide in ethanol, then with a solution of hydrogen peroxide in an alkaline medium and finally heated in the presence of p-toluenesulfonic acid.

Scheme (36)

D) From products of the general formula (I)

Compounds of general formula (I) wherein R is of type B and X is a NR2 group wherein R2 is as defined above and wherein Het does not represent a heterocycle of imidazol-2-yl, triazol-3-yl, benzimidazol-2-yl or azabenzimidazol-2-yl type, may be prepared according to scheme (37) as follows: by N-alkylation of a product of general formula (I) of type B (X ═ NH). This alkylation can be carried out according to methods known to the person skilled in the art, in particular by treatment with a base such as sodium hydride followed by the action of the halogenated derivative R2-Hal. By carrying out the process in this manner, a mixture of N1-and N3-alkylated regioisomers is generally obtained, which can be separated using conventional methods known to those skilled in the art.

Scheme (37)

Compounds of general formula (I) (wherein R is of type A' wherein Y represents O-PO₃H₂、O-PO₃Na₂、O-SO₃H₂、O-SO₃Na₂、O-CH₂-PO₃H₂、O-CH₂-PO₃Na₂O-CO-alkyl (including in particular O-CO-CH)₂-CO₂tBu、O-CO-CH₂-NHMe、O-CO-CH₂-N(Me)₂) And is natural orEster derivatives of amino acids of the non-natural series, as well as ester derivatives of di-or tripeptides, more particularly O-CO-glycine, O-CO-alanine, O-CO-serine, O-CO-lysine, O-CO-arginine, O-CO-glycine-lysine or O-CO-alanine-lysine, and n represents 2 or 3) can be prepared from compounds of general formula (I) wherein R is of type a', Y represents OH, by carrying out the process according to scheme (38).

Scheme (38)

Compounds of general formula (I) (wherein R is of type B', wherein Y represents O-PO₃H₂、O-PO₃Na₂、O-SO₃H₂、O-SO₃Na₂、O-CH₂-PO₃H₂、O-CH₂-PO₃Na₂O-CO-alkyl (including in particular O-CO-CH)₂-CO₂tBu、O-CO-CH₂-NHMe、O-CO-CH₂-N(Me)₂) And ester derivatives of amino acids of the natural or non-natural series, as well as ester derivatives of di-or tripeptides, more particularly O-CO-glycine, O-CO-alanine, O-CO-serine, O-CO-lysine, O-CO-arginine, O-CO-glycine-lysine, O-CO-alanine-lysine, and n represents 2 or 3) can be prepared from compounds of the general formula (I) in which R is of the type B' and Y represents OH, by carrying out the process according to scheme (39).

Scheme (39)

More specifically, when Y represents a phosphate group in acid or salt form, the process can be generally carried out by: the action of di-O-benzyl-or di-O-phenylphosphonic acid chloride on derivatives of general formula (I) of type A 'or B', wherein Y is OH, in a solvent such as pyridine, followed by hydrogenolysis in the presence of a palladium catalyst (palladium on charcoal or palladium hydroxide). When the heterocycle Het is of the benzimidazole or azabenzimidazole or imidazole type attached via its 2-position to the 4-position of the carbazole, it is advantageous in the present invention to protect the NH of the heterocycle in the form of N-Boc, N-TBDMS or N-SEM.

More specifically, when Y represents a sulfate group in acid or salt form, the process can be generally carried out by: sulfuric acid anhydride-or sulfur trioxide-or oleum-a mixture of sulfuric acid and sulfuric acid anhydride-works on derivatives of formula (I) of type a 'or B', wherein Y is OH, in a solvent such as pyridine. When the heterocycle Het is of the benzimidazole or azabenzimidazole or imidazole type attached via its 2-position to the 4-position of the carbazole, it is advantageous in the present invention to protect the NH of the heterocycle in the form of N-Boc, N-TBDMS or N-SEM.

More specifically, when Y represents a phosphonooxymethyloxy (phosphonooxymethyloxy) group, the process may generally be carried out by: a strong base such as sodium hydride and then di-tert-butyl or chloromethyl phosphate acts on a derivative of general formula (I) of type A 'or B', in which Y is OH, in a solvent such as DMF, followed by hydrolysis in an acidic medium such as 4N hydrochloric acid solution. When the heterocycle Het is of the benzimidazole or azabenzimidazole or imidazole type attached via its 2-position to the 4-position of the carbazole, it is advantageous in the present invention to protect the NH of the heterocycle in the form of N-Boc, N-TBDMS or N-SEM.

More specifically, when Y represents a carboxylate group, the process may be generally carried out by: reagents for activating acid function of carboxylic acids such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and bases such as 4-Dimethylaminopyridine (DMAP) or O- ((ethoxycarbonyl) cyanomethyleneamino) -N, N, N ', N' -tetramethylureaAction of tetrafluoroborate (TOTU) in a solvent such as dichloromethane. When the ester is amino acid-derived, dipeptide-derivedOr tripeptide derived esters, it is advantageous in the present invention to use amino acid or dipeptide derived or tripeptide derived acids, the amino and/or hydroxyl residues to be protected being in the form of e.g. NH-Boc, NH-Fmoc or O-Su.

Compounds of general formula (I) wherein R is of type D, W1, W2 and W3 ═ CH, can be advantageously prepared in the process according to scheme (39) in the present invention, in particular under the conditions described in bioorg.med.chem. (2006), 14(20), 6832, as follows: phosphorus trichloride and then acetamide are reacted at temperatures close to 180 ℃ with a product of general formula (I) of type E in the presence of a base such as potassium carbonate. When the heterocycle Het is of the benzimidazole or azabenzimidazole or imidazole type attached via its 2-position to the 4-position of the carbazole, it is advantageous in the present invention to protect the NH of the heterocycle in the form of N-Boc, N-TBDMS or N-SEM.

Scheme (39)

E) General procedure for the synthesis of compounds of formula (I) wherein W1 represents CH and W2 represents N:

a compound (IA) of the general formula (la) wherein R represents the group:

can be advantageously prepared from 4, 6-dichloronicotinamide by carrying out the following process:

-or, according to scheme (40), using a compound of general formula (II) and 4-amino (substituted) -6-chloronicotinamide, which can be prepared by implementing the process according to patent US 2006/027417:

scheme (40)

Alternatively, according to scheme 41, using a compound of formula (VII) (which can be obtained from a compound of formula (II) and 4-amino (substituted) -6-chloronicotinamide), which can itself be obtained by implementing the process according to patent US 2006/027417:

Scheme (41)

Process for the synthesis of a compound F-of general formula (I) wherein Het represents substituted via its 5-position 2-cyanopyridine attached to the carbazole core:

more specifically, compounds of general formula (I) wherein R represents the following group:

can be advantageously prepared from compounds of general formula (III) by carrying out the process according to embodiment (42):

scheme (42)

The following reactions were carried out in this order:

a product of the general formula (III) in which Het represents a 2-cyanopyridin-5-yl group with 4-bromo-2-fluorobenzeneTert-butyl formate in the presence of a base such as cesium carbonate and a palladium (0) derivative such as "palladium-Xanthphos" (formed from palladium acetate and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) in a solvent such as bisBuchwald-Hartwig reaction in alkane to obtain the compound of the general formula (VIII-A),

then with an amine R2-NH₂(wherein R2 is as defined above) in the presence of a base such as potassium carbonate in a solvent such as DMSO to give a compound of the general formula (VIII-B),

then by reaction with hydrochloric acid in a solvent such as diIn an alkane at a temperature close to 100 ℃ to hydrolyze the ester of formula (VIII-A) to the acid of formula (VIII-C) to obtain the product of formula (VIII-C),

finally, by reacting an acid of the general formula (VIII-C) (with (1H-benzotriazol-1-yloxy) [ tris (dimethylamino) ]Hexafluorophosphate (BOP) and Hydroxybenzotriazole (HOBT) preactivated) are coupled with ammonium chloride in the presence of a base such as diisopropylethylamine in a solvent such as N, N-dimethylformamide to form the carbamoyl group.

The above reactions can be carried out according to the conditions described in the preparations exemplified below and according to the general methods known to the person skilled in the art, in particular those described in: comprehensive Organic Chemistry, d.h.r.barton et al (permamon Press); advanced Organic Chemistry, by j.

The products which are the object of the present invention have advantageous pharmacological properties: they have been found to be inhibitory, in particular, against chaperones, in particular against their ATPase activity.

Among these chaperones, the human chaperone Hsp90 is specifically mentioned.

The products corresponding to the general formula (I) as defined above thus have a significant inhibitory activity against the Hsp90 chaperone.

The tests given in the experimental section below show that the products of the invention have inhibitory activity against these chaperones.

These properties may therefore indicate that the products of general formula (I) according to the invention may be used as medicaments in the treatment of malignant tumors.

The products of formula (I) can also be used in the veterinary field.

A subject of the present invention is therefore the use of the products of formula (I) as defined above as medicaments.

Subject of the invention is in particular the use, as a medicine, of a product of formula (I) as defined above, named:

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-trans-hydroxycyclohexylamino) benzamide

-2- (4-trans-hydroxycyclohexylamino) -4- [ (4-quinolin-3-yl) -9H-carbazol-9-yl ] benzamide

-2- (2-diethylaminoethylamino) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide

-2- (4-trans-hydroxycyclohexylamino) -4- [4- (3H-imidazo [4, 5-c ] pyridin-2-yl) -9H-carbazol-9-yl ] benzamide

-acetic acid 4- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } cyclohexyl ester

-2-cyclohexylamino-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [2- (2-hydroxyethoxy) ethylamino ] benzamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (3-hydroxypropylamino) benzamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-cis-hydroxycyclohexylamino) benzamide

-2-amino-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (2-pyrrolidin-1-yl-ethylamino) benzamide

-6- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -1H-indazol-3-ylamine

-6- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-1, 2-benzisoxazo(ii) an azol-3-ylamine,

-3- (trans-4-hydroxycyclohexylamino) -5- [ (4-quinolin-3-yl) -9H-carbazol-9-yl) pyridine-2-carboxamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (tetrahydropyran-4-ylamino) benzamide

-4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2- [ (1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) amino ] benzamide

-aminoacetic acid 4- { [ 2-carbamoyl-5- (quinolin-3-yl) -9H-carbazol-9-yl ] -pyridin-3-ylamino } cyclohexyl ester

-4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2- [ (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) amino ] benzamide

-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -3- (tetrahydropyran-4-yl) amino) pyridine-2-carboxamide

-2- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -4- (tetrahydropyran-4-yl) -amino) pyridine-5-carboxamide

-2- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) amino-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide

-3- [ (2-hydroxy-2-methylpropylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-2-carboxamide

And pharmaceutically acceptable addition salts of said product of formula (I) with inorganic or organic acids or with inorganic or organic bases.

Subject of the present invention is in particular the use as a medicine of a product of formula (I) as defined above:

het is selected from:

wherein:

r1 represents H, F, Cl, Br, CF₃、NO₂、CN、CH₃、OH、OCH₃、OCF₃、CO₂Me、CONH₂、CONHMe、CONH-(CH₂)₃-OMe、CONH-(CH₂)₃-N(Me)₂、NHC(O)Me、SO₂NH₂Or SO₂N(Me)₂；

R' 1 represents H, CONH₂CONHMe or OMe;

r' 1 represents F, Cl, OH, OMe, CN, O- (CH)₂)₃OMe or O- (CH)₂)₃-N(Me)₂；

R is selected from:

wherein:

r2 represents hydrogen, or 2-substituted ethyl, 3-substituted n-propyl, 4-trans-substituted cyclohexyl, wherein the substituents are selected from OH, SH, NH₂、OMe、NHMe、N(Me)₂、N(Et)₂Azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, quinuclidinyl, CONH₂Or COOH;

and Y represents OH, O-PO₃H₂、O-PO₃Na₂、O-SO₃H₂、O-SO₃Na₂、O-CH₂-PO₃H₂、O-CH₂-PO₃Na₂、O-CO-CH₂-CO₂tBu、O-CO-CH₂-NH₂Or O-CO-glycine, O-CO-CH₂-N(Me)₂、O-CO-CH₂-NHMe, O-CO-alanine, O-CO-serine, O-CO-lysine, O-CO-arginine, O-CO-glycine-lysine or O-CO-alanine-lysine, wherein n represents 2 or 3;

and prodrugs thereof, the product of formula (I) being in all its possible isomeric forms: racemates, enantiomers and diastereomers, and the pharmaceutically acceptable addition salts of the product of formula (I) with an inorganic or organic acid or an inorganic or organic base.

The product can be administered parenterally, orally, sublingually, rectally or topically (topically).

The subject of the invention is also pharmaceutical compositions, characterized in that they contain, as active ingredient, at least one drug of general formula (I).

These compositions may be provided in the form of injection solutions or suspensions, tablets, sugar-coated tablets, capsules, syrups, suppositories, ointments and lotions. These pharmaceutical dosage forms can be prepared according to conventional methods. The active ingredient may be incorporated in excipients conventionally used in such compositions, for example aqueous or non-aqueous carriers, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, fats of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, or preservatives.

The usual dosage may vary depending on the individual treated and the relevant disease, and may be, for example, from 10mg to 500mg per person per day.

The present invention therefore relates to the use of a product of formula (I) as defined above or a pharmaceutically acceptable salt of said product of formula (I) in the manufacture of a medicament for the inhibition of the activity of chaperones, in particular Hsp 90.

The invention therefore relates in particular to the use of a product of formula (I) as defined above, or a pharmaceutically acceptable salt of said product of formula (I), wherein the chaperone is Hsp 90.

The present invention therefore relates to the use of a product of formula (I) as defined above or of a pharmaceutically acceptable salt of said product of formula (I) for the preparation of a medicament for the prevention or treatment of a disease characterized by a disorder of chaperone activity of the Hsp90 type, in particular for the prevention or treatment of such a disease in a mammal.

The present invention relates to the use of a product of formula (I) as defined above or a pharmaceutically acceptable salt of said product of formula (I) in the manufacture of a medicament for the prevention or treatment of a disease selected from: neurodegenerative diseases such as Huntington's disease, Parkinson's disease, focal cerebral local hemorrhage, Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis, malaria, malaysia (Brugia filiasis), Bancroft's filariasis, toxoplasmosis, treatment-resistant mycoses (fungal-resistant pathogens), hepatitis B, hepatitis C, herpes virus, dengue fever (or tropical influenza), spinal and bulbar muscular atrophy, mesangial cell proliferation disorders (mesangial proliferation disorders), thrombosis, retinopathy, psoriasis, muscular degeneration (tumor degeneration), neoplastic diseases and cancer.

The invention therefore relates to the use of a product of formula (I) as defined above or a pharmaceutically acceptable salt of said product of formula (I) in the manufacture of a medicament for the treatment of a neoplastic disease.

The invention relates in particular to the use of a product of formula (I) as defined above or of a pharmaceutically acceptable salt of said product of formula (I) in the manufacture of a medicament for the treatment of cancer.

Of these cancers, the most particular focus of the present invention is on the treatment of solid tumors, and the treatment of cancers that are resistant to cytotoxic agents.

The invention therefore relates in particular to the use of a product of formula (I) as defined in any one of the preceding claims, or of a pharmaceutically acceptable salt of said product of formula (I), in the manufacture of a medicament for the treatment of cancers including lung, breast and ovarian cancers, glioblastoma, chronic myelogenous leukemia, acute lymphocytic leukemia, prostate, pancreatic and colon cancers, metastatic melanoma, thyroid tumors and renal cancers.

Thus, among the main possible indications for Hsp90 inhibitors, non-limiting examples may be mentioned:

"non-small cell" lung cancer, breast cancer, ovarian cancer and glioblastoma, which overexpress EGF-R or HER 2;

-chronic myeloid leukemia, which overexpresses Bcr-Abl;

-acute lymphoblastic leukemia, which overexpresses Flt-3;

-breast, prostate, lung, pancreatic, colon or ovarian cancer, which overexpress Akt;

metastatic melanoma and thyroid tumors, which overexpress mutant forms of the B-Raf protein;

-androgen-dependent and androgen-independent prostate cancer;

-estrogen-dependent and non-estrogen-dependent breast cancer;

renal cancers, which overexpress HIF-1a or mutein c-met, etc.

The present invention is more particularly concerned with the treatment of breast, colon and lung cancer.

The invention also relates to the use of a product of formula (I) as defined above or a pharmaceutically acceptable salt of said product of formula (I) in the manufacture of a medicament for cancer chemotherapy.

As the medicament of the present invention for cancer chemotherapy, the formula (I) product of the present invention may be used alone, or in combination with chemotherapy or radiotherapy, or in combination with other therapeutic agents.

The invention therefore relates in particular to these pharmaceutical compositions as defined above, which contain, in addition to the active ingredient, other drugs for anticancer chemotherapy.

Such therapeutic agents may be commonly used antineoplastic agents.

As examples of known protein kinase inhibitors, mention may in particular be made of butyrolactone, flavopiridol, 2- (2-hydroxyethylamino) -6-benzylamino-9-methylpurine, olomoucine (olomcutine), gleevec (Gleevec) and Iressa.

The products of formula (I) according to the invention can therefore advantageously be used in combination with antiproliferative agents: as examples of such antiproliferative agents, but not limited to this list, mention may be made of aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, antitumor antimetabolites, platinum compounds, proteasome inhibitors such as Bortezomib (Bortezomib), Histone Deacetylase (HDACs) inhibitors such as SAHA, in particular HDAC6 inhibitors, compounds capable of reducing the activity of protein kinases and anti-angiogenic compounds, gonadotropin releasing hormone agonists, anti-androgens, benzamides, bisphosphonates and trastuzumab.

Thus, mention may be made, as examples, of anti-microtubule agents, such as taxanes, epothilones, thermocar-alkaloids (vinka-alkloids), alkylating agents, such as cyclophosphamide, DNA-intercalating agents, such as cis-platinum and oxaliplatin, topoisomerase-interacting agents, such as camptothecin and derivatives, anthracyclines, such as doxorubicin, antimetabolites, such as 5-fluorouracil and derivatives and analogues.

The present invention therefore relates to a product of formula (I) as an Hsp90 chaperone inhibitor, in all its possible isomeric forms: racemates, enantiomers and diastereomers, as well as the pharmaceutically acceptable addition salts of the product of formula (I) with an inorganic or organic acid or an inorganic or organic base, and prodrugs thereof.

The invention relates in particular to a product of formula (I) as described above as an Hsp90 inhibitor.

The products of formula (I) according to the invention can be prepared by applying and adapting known methods, in particular those described in the literature, for example in r.c. laroc: comprehensive Organic Transformations, VCH publishers, 1989.

In the reactions described below, it may be necessary to protect reactive functional groups, such as hydroxyl, amino, imino, thio or carboxyl groups, when the latter are desired in the final product but their participation in the reaction for the synthesis of the product of formula (I) is not desired. Conventional protecting Groups may be used in accordance with common standard practice, such as those described in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991, of T.W. Greene and P.G.M.Wuts.

Non-limiting examples of starting products are given in the experimental section below: other starting products are commercially available or can be prepared according to common methods known to those skilled in the art.

Examples of the present invention are explained: the following examples illustrate the invention without limiting it.

All described examples were characterized by proton NMR spectroscopy and mass spectroscopy, most of which were also characterized by infrared spectroscopy.

Unless different conditions are specifically described, the LC/MS mass spectra reported in the description of the various examples below were performed under the following liquid chromatography conditions:

the method A comprises the following steps:

column: ACQUITY BEH C₁₈1.7μm 2.1x 50mm

Solvent: a: h₂O (0.1% formic acid) B: CH (CH)₃CN (0.1% formic acid)

Column temperature: 50 deg.C

Flow rate: 1 ml/min

Gradient (2 min): 5 to 50% B, 0.8 min; 1.2 minutes: 100% of B; 1.85 min 100% B; 1.95 min 5% B

The method B comprises the following steps:

column: xbridge C₁₈ 2.5μm 3x 50mm

Solvent: a: h₂O (0.1% formic acid) B: CH (CH)₃CN (0.1% formic acid)

Column temperature: 70 deg.C

Flow rate: 0.9 ml/min

Gradient: 5% to 100% B, 5.3 minutes; 5.5 minutes: 100% of B; 6.3 minutes: 5% of B

The method C comprises the following steps:

column: ACQUITY BEH C₁₈1.7μm 2.1x 50mm

Solvent: a: h ₂O (0.1% formic acid) B: CH (CH)₃CN (0.1% formic acid)

Column temperature: 70 deg.C

Flow rate: 0.7 ml/min

Gradient: 5% of B, 0.1 min; 5% to 95% B, 8.3 minutes; 95% B, 8.5 min; 95% to 5% B, 9.5 min; 95% B, 12 min

Example 1: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (4-trans-hydroxycyclohexylamino) benzamide

Step 1: a mixture of 4.78g of 4-hydroxycarbazole, 9.32g of N-phenylbis (trifluoromethanesulfonimide) and 3.64ml of triethylamine in 200ml of dichloromethane is stirred in a 250ml round-bottom flask at ambient temperature under argon for 24 hours. The reaction medium is evaporated to dryness in vacuo and the black residue is chromatographed on silica gel (40-63 μm) eluting with dichloromethane. 7.07g of 4-trifluoromethanesulfonyloxycarbazole are obtained in the form of a white solid, which is characterized as follows:

melting point (Kofler bench): 90 deg.C

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 7.21(d, J ═ 8.0Hz, 1H); 7.30(t, J ═ 8.0Hz, 1H); 7.48-7.57(m, 2H); 7.63(m, 2H); 8.11(d, J ═ 8.0Hz, 1H); 11.89 (width s, 1H).

-mass spectrometry spectrum (EI): 315(M +)

Step 2: in a reaction vessel, a mixture of 2.0g of 4-trifluoromethanesulfonyloxycarbazole obtained according to the preceding procedure, 142mg of palladium acetate, 262mg of 1, 3-diphenylphosphinopropane and 0.88ml of triethylamine in 35ml of methanol and 85ml of dimethylformamide was kept at 50 ℃ for 8 hours at 2 bar of carbon monoxide. After flushing with argon, the reaction medium is evaporated to dryness in vacuo and the orange residue is chromatographed on silica gel (40-63 μm) eluting with dichloromethane. 1.29g of 9H-carbazole-4-carboxylic acid methyl ester are obtained in the form of a green solid, which is characterized as follows:

Melting point (Kofler bench): 95 deg.C

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 4.00(s, 3H); 7.18(m, 1H); 7.43-7.57(m, 3H); 7.75(dd, J ═ 7.8Hz and 1.1Hz, 1H); 7.78(dd, J ═ 8.8Hz and 1.1Hz, 1H); 8.69 (width d, J ═ 8.3Hz, 1H); 11.67 (width s, 1H).

-mass spectrometry spectrum (EI): 225(M +) is defined as M/z

And step 3: in a 250ml round-bottom flask, under argon atmosphere, in 4 steps¹/₂391mg of a 60% suspension of sodium hydride in petroleum jelly are added in the course of hours to a solution of 2.0g of the methyl 9H-carbazole-4-carboxylate obtained according to the preceding procedure and 1.95g of 2-bromo-4-fluorobenzonitrile in 50ml of dimethylformamide. The mixture was stirred at ambient temperature for 3 hours. The reaction medium is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (40-63 μm) eluting with a mixture of dichloromethane and cyclohexane (50: 50).

3.2g of methyl 9- (3-bromo-4-cyanophenyl) -9H-carbazole-4-carboxylate are obtained in the form of a white solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 4.03(s, 3H); 7.36(m, 1H); 7.47(d, J ═ 7.8Hz, 1H); 7.50-7.60(m, 2H); 7.72(d, J ═ 7.8Hz, 1H); 7.87(d, J ═ 7.8Hz, 1H); 7.91(dd, J ═ 8.3Hz and 2.0Hz, 1H); 8.26(m, 2H); 8.75(d, J ═ 7.8Hz, 1H).

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 6.08; m/z 405(M +).

And 4, step 4: in a microwave reactor, a mixture of 405mg of methyl 9- (3-bromo-4-cyanophenyl) -9H-carbazole-4-carboxylate obtained according to the preceding step, 461mg of trans-4-aminocyclohexanol, 45mg of palladium acetate, 192mg of sodium tert-butoxide and 111mg of 1, 1' -bis (diphenylphosphino) ferrocene in 18ml of toluene was heated at 115 ℃ for 30 minutes. The reaction medium is filtered through clarcel and washed with 200ml ethyl acetate. The filtrate was evaporated to dryness in vacuo and the residue was chromatographed on silica gel (40-63 μm) eluting with a mixture of dichloromethane and methanol (97.5: 2.5). 222mg of methyl 9- [ 4-cyano-3- (4-trans-hydroxycyclohexylamino) phenyl ] -9H-carbazole-4-carboxylate are obtained in the form of a brown oil which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.21(m, 2H); 1.41(m, 2H); 1.78(m, 2H); 1.91(m, 2H); 3.32-3.50(m, 2H); 4.03(s, 3H); 4.47(d, J ═ 4.4Hz, 1H); 5.88(d, J ═ 8.1Hz, 1H); 6.82(dd, J ═ 8.3Hz and 2.0Hz, 1H); 7.06(d, J ═ 2.0Hz, 1H); 7.32(m, 1H); 7.42 (width d, J ═ 8.1Hz, 1H); 7.48-7.58(m, 2H); 7.64-7.68(dd, J ═ 8.1Hz and 1.3Hz, 1H); 7.75(d, J ═ 8.3Hz, 1H); 7.84(dd, J ═ 7.5Hz and 1.1Hz, 1H); 8.74 (width d, J ═ 8.1Hz, 1H).

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 4.77; m/z 438 (M-H-); 440(M + H +).

And 5: in a 250ml round bottom flask, a mixture of 220mg of methyl 9- [ 4-cyano-3- (4-trans-hydroxycyclohexylamino) phenyl ] -9H-carbazole-4-carboxylate obtained according to the preceding step and 401. mu.l of a 2.5N solution of sodium hydroxide in 20ml of methanol was refluxed for 7 hours. The reaction medium is evaporated to dryness in vacuo. The residue is taken up in 20ml of 1M hydrochloric acid and extracted 3 times with 30ml of ethyl acetate. The combined organic phases are washed with 25ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The oily residue is chromatographed on silica gel (15-40 μm) eluting with a mixture of dichloromethane and methanol (95: 5). 157mg of 9- [ 4-cyano-3- (4-trans-hydroxycyclohexylamino) phenyl ] -9H-carbazole-4-carboxylic acid are obtained in the form of a beige foam, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.14-1.29(m, 2H); 1.41(m, 2H); 1.77(m, 2H); 1.91(m, 2H); 3.34-3.51(m, 2H); 4.47 (width d, J ═ 4.2Hz, 1H); 5.87(d, J ═ 8.3Hz, 1H); 6.82(dd, J ═ 8.3Hz and 2.0Hz, 1H); 7.05(d, J ═ 2.0Hz, 1H); 7.30(m, 1H); 7.40 (width d, J ═ 8.0Hz, 1H); 7.44-7.59(m, 2H); 7.61(dd, J ═ 8.0Hz and 1.1Hz, 1H); 7.75(d, J ═ 8.3Hz, 1H); 7.83(dd, J ═ 8.0Hz and 1.1Hz, 1H); 8.88(d, J ═ 7.8Hz, 1H); 13.24 (width m, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.96; m/z 424 (M-H-); 426(M + H +).

Step 6: 155mg of 9- [ 4-cyano-3- (4-trans-hydroxycyclohexylamino) phenyl obtained according to the preceding procedure in a 50ml round bottom flask]-9H-carbazole-4-carboxylic acid, 48mg of 4-fluoro-O-phenylenediamine, 131mg of O- ((ethoxycarbonyl) cyanomethyleneamino) -N, N' -tetramethylureaTetrafluoroborate (TOTU) and 70. mu.l of diisopropylethylamine in 20ml of dimethylformamide were stirred at ambient temperature for 3.5 hours. The reaction medium is evaporated to dryness in vacuo. The residue is taken up in 40ml of ethyl acetate. The organic phase is washed 3 times with 30ml of saturated sodium bicarbonate solution and once with 30ml of saturated sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness in vacuo.

185mg of 9- [ 4-cyano-3- (4-trans-hydroxycyclohexylamino) phenyl ] -9H-carbazole-4-carboxylic acid (2-amino-4-fluorophenyl) amide are obtained in the form of a brown foam, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.14-1.27(m, 2H); 1.42(m, 2H); 1.80(m, 2H); 1.93(m, 2H); 3.34-3.50(m, 2H); 4.48(d, J ═ 4.4Hz, 1H); 5.30 (width s, 2H); 5.92(d, J ═ 8.3Hz, 1H); 6.46(td, J ═ 8.4Hz and 2.7Hz, 1H); 6.61(dd, J ═ 11.2Hz and 2.7Hz, 1H); 6.83(dd, J ═ 8.3Hz and 2.2Hz, 1H); 7.02(d, J ═ 2.2Hz, 1H); 7.26(m, 1H); 7.38-7.64(m, 6H); 7.76(d, J ═ 8.3Hz, 1H); 8.32(d, J ═ 7.8Hz, 1H); 9.81(s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.03; m/z 532 (M-H-); 534(M + H +).

And 7: 185mg of 9- [ 4-cyano-3- (4-trans-hydroxycyclohexylamino) phenyl ] -9H-carbazole-4-carboxylic acid (2-amino-4-fluorophenyl) amide obtained according to the preceding procedure are refluxed in 15ml of glacial acetic acid in a 100ml round-bottom flask for 1 hour. The reaction medium is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (15-40 μm) eluting with a mixture of dichloromethane and methanol (99: 1).

121mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-trans-hydroxycyclohexylamino) benzonitrile are obtained in the form of a brown foam, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.14-1.28(m, 2H); 1.43(m, 2H); 1.80(m, 2H); 1.93(m, 2H); 3.34-3.54(m, 2H); 4.48(d, J ═ 4, 4Hz, 1H); 5.90(d, J ═ 8.3Hz, 1H); 6.86(dd, J ═ 8.2Hz and 2.0Hz, 1H); 7.08(d, J ═ 2.0Hz, 1H); 7.10-7.23(m, 2H); 7.33-7.51(m, 2.5H); 7.54-7.69(m, 4H); 7.77(d, J ═ 8.3Hz, 1H); 7.84(dd, J ═ 8.8Hz and 5.1Hz, 0.5H); 8.61(d, J ═ 7.8Hz, 0.5H); 8.66(d, J ═ 7.8Hz, 0.5H); 13.08(s, 1H) (2 conformers 50: 50).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.98; m/z 514 (M-H-); 516(M + H +).

And 8: in a 100ml round bottom flask, 0.4ml of 30% aqueous hydrogen peroxide solution was added to a mixture of 111mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-trans-hydroxycyclohexylamino) benzonitrile obtained according to the preceding step in 2ml of ethanol and 0.8ml of dimethyl sulfoxide and 0.4ml of 1M sodium hydroxide and the mixture was stirred at ambient temperature for 1/4 hours. 40ml of distilled water was added, and the resulting mixture was extracted 3 times with 30ml of ethyl acetate. The combined organic phases are washed with 30ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (15-40 μm) eluting with a mixture of dichloromethane and methanol (95/5).

105mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-trans-hydroxycyclohexylamino) benzamide are obtained in the form of a beige solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.16-1.32(m, 4H); 1.78(m, 2H); 1.99(m, 2H); 3.33(m partially masked, 1H); 3.47(m, 1H); 4.47(d, J ═ 4.6Hz, 1H); 6.70(dd, J ═ 8.3Hz and 2.0Hz, 1H); 6.88(d, J ═ 2.0Hz, 1H); 7.11-7.22(m, 2H); 7.27 (width m, 1H); 7.39-7.50(m, 2H), 7.50-7.80(m, 5H); 7.91(d, J ═ 8.3Hz, 1H); 7.96 (width m, 1H); 8.46(d, J ═ 7.8Hz, 1H); 8.65(d, J ═ 7.8Hz, 1H); 13.08 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.8; m/z 532 (M-H-); 534(M + H +).

Example 2:2- (4-trans-hydroxycyclohexylamino) -4- [ (4-quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

Step 1: 78.8mg of 9-H-carbazol-4-yl trifluoromethanesulfonate obtained according to step 1 of example 1, 2.5ml of toluene, 56.2mg of quinoline-3-boronic acid, 55.6mg of sodium carbonate and 57.8mg of tetrakis (triphenylphosphine) palladium (0) are introduced in succession into a 5ml microwave reactor. After stirring for 30 seconds at ambient temperature, the reaction medium is heated with stirring for 30 minutes at 115 ℃. After cooling to ambient temperature, the reaction medium is taken up in 5ml of ethyl acetate and 2ml of water. After insoluble material was filtered off and separated by settling, the organic phase was washed twice with 2ml of water, dried over magnesium sulfate and concentrated under reduced pressure. After purification by silica gel chromatography (15-40 μm), elution with a mixture of cyclohexane and ethyl acetate (80/20 then 70/30, vol) gave 27mg of 4- (quinolin-3-yl) -9H-carbazole in the form of a white solid, which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 6.90(m, 1H)7.18(dd, J ═ 7.5, 1.0Hz, 1H)7.22 (width d, J ═ 8.0Hz, 1H)7.34(m, 1H)7.53(m, 2H)7.61(dd, J ═ 8.3, 1.0Hz, 1H)7.71(m, 1H)7.86(m, 1H)8.11 (width d, J ═ 8.3, 1H)8.17 (width d, J ═ 8.3Hz, 1H)8.59(d, J ═ 2.4Hz, 1H)9.13(d, J ═ 2.4Hz, 1H)11.55 (width s, 1H).

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 0.95; MH₊＝295₊；MH_-＝293。

Step 2: in a 20ml single neck round bottom flask, 80mg of 4- (quinolin-3-yl) -9H-carbazole obtained according to the preceding step and 60mg of 2-bromo-4-fluorobenzonitrile were dissolved in 2ml of anhydrous Dimethylformamide (DMF) under an argon atmosphere. Then 16.3mg of sodium hydride (60% in oil) was added and the mixture was stirred at ambient temperature for 4 hours. After addition of 15ml of ethyl acetate and 3ml of water, the organic phase is separated by settling, washed 3 times with 3ml of water, dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (15-40 μm), eluting with dichloromethane, 95mg of 2-bromo-4- [ (4-quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile are obtained in the form of a beige lacquer, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 7.08(m, 1H)7.24(d, J ═ 8.1Hz, 1H)7.36(dd, J ═ 6.4, 2.0Hz, 1H)7.43(m, 1H)7.49-7.53(m, 1H)7.57-7.67(m, 2H)7.74(m, 1H)7.89(m, 1H)7.96(dd, J ═ 8.3, 2.0Hz, 1H)8.14 (width d, J ═ 7.9Hz, 1H)8.19 (width d, J ═ 8.2Hz, 1H)8.28(d, J ═ 8.3Hz, 1H)8.30(d, J ═ 2.0Hz, 1H)8.63(d, J ═ 2.2, 1H)8.14 Hz, 1H).

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 1.22; MH₊＝474₊。

And step 3: 95mg of 2-bromo-4- [ (4-quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained in the preceding step, 92mg of trans-4-aminocyclohexanol, 9mg of palladium (II) acetate, 38.5mg of potassium tert-butoxide and 3.6ml of toluene were introduced in succession into a 5ml microwave reactor. After stirring for 30 seconds at ambient temperature, the reaction medium is heated with stirring for 15 minutes at 115 ℃. After cooling, 5ml of ethyl acetate and 3ml of water were added. The organic phase is separated by settling, washed twice with 2ml of water, dried over magnesium sulfate and concentrated under reduced pressure. After purification by silica gel chromatography (15-40 μm), eluting with a mixture of dichloromethane and methanol (98/2 vol), 73mg of 2- (4-trans-hydroxycyclohexylamino) -4- [ (4-quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile are obtained in the form of a beige foam, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.23(m, 2H)1.43(m, 2H)1.81(m, 2H)1.94(m, 2H)3.34-3.54(m, 2H)4.49(d, J ═ 4.4Hz, 1H)5.89(d, J ═ 8.3Hz, 1H)6.89(dd, J ═ 8.3, 2.0Hz, 1H)7.04(m, 1H)7.10(d, J ═ 2.0Hz, 1H)7.24 (width d, J ═ 8.3Hz, 1H)7.32 (width d, J ═ 7.8Hz, 1H)7.37-7.48(m, 2H)7.54 (width d, J ═ 8.3Hz, 1H)7.60(t, J ═ 8.3, 1H) 7.7.7.7, 1H) 7.54 (width d, J ═ 8.3Hz, 1H)7.8, 1H (1H), 1H)7.8, 1H)7.3 Hz, 1H (d, 8H) 7.3 Hz, 1H)7.8, 1, 1.8H) 7.8, 1H, 8H, 1H.

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 1.14; MH₊＝509₊。

And 4, step 4: in a 10ml single-neck round-bottom flask, 72mg of 2- (4-trans-hydroxycyclohexylamino) -4- [ (4-quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained in the preceding step were dissolved in 1.2ml of ethanol and 0.5ml of dimethyl sulfoxide (DMSO), and then 269. mu.l of a 1N aqueous solution of sodium hydroxide followed by 960. mu.l (2.55mmol) of a 30% aqueous solution of hydrogen peroxide were added in that order using a syringe. After stirring for 20 minutes at ambient temperature, the reaction medium is taken up in 25ml of ethyl acetate and 5ml of water. The organic phase is separated by settling, washed 3 times with 5ml of water, dried over magnesium sulphate and concentrated under reduced pressure. After purification by crystallization from 1ml of a mixture of dichloromethane and ethyl acetate (50/50 vol), 71mg of 2- (4-trans-hydroxycyclohexylamino) -4- [ (4-quinolin-3-yl) -9H-carbazol-9-yl ] benzamide are obtained, in the form of a white powder, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.25(m, 4H)1.79(m, 2H)2.00(m, 2H)3.33(m, 1H)3.47(m, 1H)4.47(d, J ═ 4.4Hz, 1H)6.72(dd, J ═ 8.3, 2.1Hz, 1H)6.91(d, J ═ 2.1Hz, 1H)7.03(m, 1H)7.19-7.37(m, 3H)7.36-7.46(m, 2H)7.53 (width d, J ═ 8.2Hz, 1H)7.60(t, J ═ 8.2Hz, 1H)7.73(m, 1H)7.85-7.93(m, 2H)7.98 (width m, 1H)8.14 (d, J ═ 8.8.8, 8.19, 8.8H) 7.63 (d, 8.8, 8H), 8.8.8 (d, 8.8, 8H) 7.8, 8.8 (d, 8.8, 8H) 1H) 7.46 (d, 8, 1H)7.8 (d, 8, 8.8.8, 8, 1H); 9.16(d, J ═ 2.4Hz, 1H).

Mass spectrometry (LC/MS method B): retention time Tr (min) ═ 0.99; MH₊＝527₊。

Example 3:2- (2-diethylaminoethylamino) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

Step 1: 0.43g of 4-bromo-2-fluorobenzonitrile, 2.2g of cesium carbonate, 0.12g of 9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene and 0.04g of palladium acetate were added in succession to 30ml of bis-methyl 9H-carbazole-4-carboxylate obtained in step 2 of example 1 under an inert argon atmosphereIn solution in an alkane. The reaction mixture was refluxed for 3 hours, then cooled, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of heptane and ethyl acetate (96/4, vol) to give 496mg of methyl 9- (4-cyano-3-fluorophenyl) -9H-carbazole-4-carboxylate, which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 4.03(s, 3H)7.36(m, 1H)7.47-7.62(m, 3H)7.73-7.79(m, 2H)7.87(dd, J ═ 7.7, 1.1Hz, 1H)8.02(d d, J ═ 10.3, 2.0Hz, 1H)8.26(t, J ═ 7.5Hz, 1H)8.75(d, J ═ 8.1Hz, 1H).

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 1.14; MH₊＝345₊。

Step 2: 5.44ml of a 2M solution of trimethylaluminum in toluene are added to a solution of 0.69g of 1, 2-diamino-4-fluorobenzene in 40ml of toluene and 20ml of tetrahydrofuran at ambient temperature in 5 minutes under argon. After stirring for 15 minutes at ambient temperature, a solution of 1.25g of methyl 9- (4-cyano-3-fluorophenyl) -9H-carbazole-4-carboxylate obtained according to the preceding step in 20ml of tetrahydrofuran is added and the mixture is refluxed for 1 hour. After returning to ambient temperature, 50ml of water and 2M aqueous HCl are slowly added, thereby adjusting the pH to about 6. The aqueous phase is extracted with 100ml of ethyl acetate and the organic phase is then washed once with 20ml of water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in 20ml of acetic acid and then heated at 110 ℃ for 1 hour. After cooling and evaporation of the solvent, 30ml of water are added and the aqueous phase is adjusted to pH 8-9 by addition of a saturated solution of potassium bicarbonate. The resulting crude solid was purified by chromatography on silica gel (15-40 μm) eluting with a mixture of dichloromethane and ammonia in methanol at 7N (95/5, vol.). This gives 0.82g of 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 7.16(m, 1H)7.25(t, J ═ 7.6Hz, 1H)7.36-7.84(m, 8H)8.04(d, J ═ 10.3Hz, 1H)8.27(t, J ═ 7.7Hz, 1H)8.64(d, J ═ 8.3Hz, 1H)13.12 (width s, 1H).

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 1.02; MH₊＝421₊；MH_-＝419_-。

And step 3: 100mg of 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained in the preceding step, 0.8ml of dimethyl sulfoxide, 263mg of potassium carbonate and 111mg of N, N-diethylethylenediamine were introduced in this order into a 2ml microwave reactor. After stirring for 10 seconds at ambient temperature, the reaction medium is heated with stirring for 45 minutes at 100 ℃. After cooling, 2ml ethanol, 0.4ml 1M sodium hydroxide and 0.4ml 30% aqueous hydrogen peroxide were added in that order and the mixture was stirred for 1/4 hours at ambient temperature. 20ml of distilled water was added, and the resulting mixture was extracted twice with 30ml of ethyl acetate. The combined organic phases are washed with 20ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The crude residue obtained is purified by chromatography on silica gel (15-40 μm), eluting with a mixture of dichloromethane and ammonia in methanol at 7N (95/5, vol.). This gave 70mg of 2- (2-diethylamino-ethylamino) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide as a white solid, which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 0.95(t, J ═ 7.1Hz, 6H)2.50(m partial mask, 4H)2.63(t, J ═ 6.2Hz, 2H)3.15(m, 2H)6.74(dd, J ═ 8.3, 2.1Hz, 1H)6.84(d, J ═ 2.1Hz, 1H)7.12-7.21(m, 2H)7.25 (wide m, 1H)7.41-7.87(m, 7H)7.90(d, J ═ 8.3Hz, 1H)7.93 (wide m, 1H)8.47 (wide t, J ═ 5.1Hz, 1H)8.62 (wide d, J ═ 8.2Hz, 1H); 13.09 (width m, 1H).

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 0.68; MH₊＝535₊；MH_-＝533_-。

Example 4:2- (4-trans-hydroxycyclohexylamino) -4- [4- (3H-imidazo [4, 5-c)]Pyridin-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

Step 1: 545mg of 9- [ 4-cyano-3- (4-trans-hydroxycyclohexylamino) phenyl according to example 1 step 5 in a 250ml round bottom flask]-9H-carbazole-4-carboxylic acid, 147mg of 3, 4-diaminopyridine, 462mg of O- [ (ethoxycarbonyl) cyanomethyleneamino]-N, N, N ', N' -tetramethylureaA mixture of tetrafluoroborate (TOTU) and 245. mu.l of diisopropylethylamine in 75ml of dimethylformamide was stirred at ambient temperature for 4 hours. The reaction medium is evaporated to dryness in vacuo. The residue is taken up in 100ml of ethyl acetate. The organic phase is washed 3 times with 60ml of saturated sodium bicarbonate solution and once with 60ml of saturated sodium chloride solution, dried over magnesium sulfate and then in vacuo The mixture was evaporated to dryness. The residue was chromatographed on silica gel (15-40 μm), eluting with pure dichloromethane then with a mixture of dichloromethane and methanol (90/10, vol). 599mg of 9- [ 4-cyano-3- (4-trans-hydroxycyclohexylamino) phenyl are obtained]-9H-carbazole-4-carboxylic acid (3-aminopyridin-4-yl) amide, in the form of an orange oil, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.11-1.31(m, 2H); 1.42(m, 2H); 1.80(m, 2H); 1.93(m, 2H); 3.35-3.51(m, 2H); 4.48(d, J ═ 4.4Hz, 1H); 5.26 (width s, 2H); 5.92(d, J ═ 8.1Hz, 1H); 6.84(dd, J ═ 8.3Hz and 1.9Hz, 1H); 7.02(d, J ═ 1.9Hz, 1H); 7.26(m, 1H); 7.41-7.53(m, 2H); 7.52-7.66(m, 3H); 7.77(m, 2H); 7.88(d, J ═ 5.4Hz, 1H); 8.13(s, 1H); 8.24(d, J ═ 8.1Hz, 1H); 10.06(s, 1H).

Mass Spectrometry (LC/MS; method A): retention time Tr (min) ═ 0.75; m/z 515 (M-H-); 517(M + H +).

Step 2: in a 250ml round bottom flask 590mg of 9- [ 4-cyano-3- (4-trans-hydroxycyclohexylamino) phenyl ] -9H-carbazole-4-carboxylic acid (3-aminopyridin-4-yl) amide obtained according to the preceding procedure were refluxed in 50ml of glacial acetic acid for 1 hour. The reaction medium is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (15-40 μm) eluting with a mixture of dichloromethane and methanol (99/1 then 90/10). 244mg of 2- (4-trans-hydroxycyclohexylamino) -4- [4- (3H-imidazo [4, 5-c ] pyridin-2-yl) -9H-carbazol-9-yl ] benzonitrile are obtained in the form of a brown foam, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.22(m, 2H); 1.43(m, 2H); 1.80(m, 2H); 1.94(m, 2H); 3.34-3.53(m, 2H); 4.48(d, J ═ 4.4Hz, 1H); 5.91(d, J ═ 8.1Hz, 1H); 6.87(dd, J ═ 8.2Hz and 2.0Hz, 1H); 7.09(d, J ═ 2.0Hz, 1H); 7.21(m, 1H); 7.41-7.52(m, 2H); 7.59-7.74(m, 4H); 7.78(d, J ═ 8.2Hz, 1H); 8.41(d, J ═ 5.4Hz, 1H); 8.58 (width d, J ═ 8.3Hz, 1H); 9.09 (width s, 1H); 13.40 (width m, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.71; m/z 497 (M-H-); 499(M + H +).

And step 3: in a 100ml round bottom flask, 0.98ml of 30% aqueous hydrogen peroxide solution was added to a mixture of 240mg of 2- (4-trans-hydroxycyclohexylamino) -4- [4- (3H-imidazo [4, 5-c ] pyridin-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained in the preceding step in 7ml of ethanol and 3.5ml of dimethyl sulfoxide and 0.96ml of 1M sodium hydroxide and the mixture was stirred at ambient temperature for 1/4 hours. 40ml of distilled water were added, and the mixture was extracted 3 times with 40ml of ethyl acetate. The combined organic phases are washed twice with 40ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (15-40 μm) eluting with a mixture of dichloromethane and methanol (97/3, then 90/10). 188mg of 2- (4-trans-hydroxycyclohexylamino) -4- [4- (3H-imidazo [4, 5-c ] pyridin-2-yl) -9H-carbazol-9-yl ] benzamide are obtained in the form of a beige solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.15-1.31(m, 4H); 1.78(m, 2H); 1.99(m, 2H); 3.21-3.53(m partially masked, 2H); 4.47(d, J ═ 4.4Hz, 1H); 6.70(dd, J ═ 8.3Hz and 2.0Hz, 1H); 6.89(d, J ═ 2.0Hz, 1H); 7.20(m, 1H); 7.28 (width m, 1H); 7.39-7.52(m, 2H); 7.54-7.76(m, 4H); 7.91(d, J ═ 8.3Hz, 1H); 7.97 (width m, 1H); 8.41(d, J ═ 5.6Hz, 1H); 8.46(d, J ═ 7.6Hz, 1H); 8.59(d, J ═ 8.6Hz, 1H); 9.09 (width s, 1H); 13.40 (width m, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.54; m/z 515 (M-H-); 517(M + H +).

Example 5: acetic acid 4- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of phenylamino } -trans-cyclohexyl ester

Step 1: a solution of 2.2g of 9- [ 4-cyano-3- (4-trans-hydroxycyclohexylamino) phenyl ] -9H-carbazole-4-carboxylic acid (2-amino-4-fluorophenyl) amide obtained according to step 6 of example 1 in 100ml of acetic acid was refluxed for 1.5 hours. After work-up as in step 7 of example 1, the residue was purified by chromatography on silica gel (15-40 μm), eluting with a mixture of dichloromethane and methanol (96/4 vol). By recovering the eluted first fraction 0.2g of acetic acid 4- { 2-cyano-5- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } -trans-cyclohexyl ester is obtained, after concentration, in the form of a beige solid, which is used as such in the subsequent step. By recovering the eluted second fraction, 1.6g of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-trans-hydroxycyclohexylamino) benzonitrile as described in step 7 of example 1 were obtained.

Step 2: in a 50mL three-necked flask, 1.36mL of 30% aqueous hydrogen peroxide solution was added to a mixture of 200mg of the solution of 4- { 2-cyano-5- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } -trans-cyclohexyl acetate obtained in the preceding step in 7.5mL of ethanol and 3mL of dimethyl sulfoxide and 0.96mL of 1M sodium hydroxide, and the mixture was stirred at ambient temperature for 1/4 hours. 40ml of distilled water were added, and the mixture was extracted 3 times with 40ml of ethyl acetate. The combined organic phases are washed twice with 40ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (15-40 μm) eluting with a mixture of dichloromethane and methanol (96/4, vol). 170mg of acetic acid 4- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } -trans-cyclohexyl ester are obtained in the form of an off-white solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.25-1.53(m, 4H)1.87(m, 2H)1.95(s, 3H)2.03(m, 2H)3.44(m, 1H)4.66(m, 1H)6.72(dd, J ═ 8.3, 2.0Hz, 1H)6.92(d, J ═ 2.0Hz, 1H)7.04-7.23(m, 2H)7.29 (wide m, 1H)7.39-7.78(m, 7H)7.92(d, J ═ 8.3Hz, 1H)7.99 (wide m, 1H)8.51(d, J ═ 7.8Hz, 1H)8.65(d, J ═ 8.8Hz, 1H)13.08 (wide m, 1H).

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 0.99; MH₊＝576₊；MH_-＝574_-。

Example 6: 2-cyclohexylamino-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 100mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 263mg of potassium carbonate and 94mg of cyclohexylamine in 0.8ml of dimethyl sulfoxide. Then 0.4ml of 1M aqueous sodium hydroxide solution, 0.4ml of 30% aqueous hydrogen peroxide solution and 2ml of ethanol are added to the reaction medium. After work-up and purification as in step 3 of example 3, 40mg of 2-cyclohexylamino-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide are thus obtained in the form of a white solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.16-1.40(m, 5H)1.50(m, 1H)1.64(m, 2H)1.92(m, 2H)3.24-3.43(m partial mask, 1H)6.70(dd, J ═ 8.3, 2.0Hz, 1H)6.86(d, J ═ 2.0Hz, 1H)7.10-7.85(m, 10H)7.92(d, J ═ 8.3Hz, 1H)7.98 (width m, 1H)8.56(d, J ═ 7.8Hz, 1H)8.63(d, J ═ 7.8Hz, 1H)13.07 (width m, 1H).

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 1.07; MH + — 518 +; MH- ═ 516-.

Example 7: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [2- (2-hydroxyethoxy) ethylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 84mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 83mg of potassium carbonate and 421mg of 2- (2-aminoethoxy) ethanol in 0.67ml of dimethyl sulfoxide. Then 0.4ml of 1M aqueous sodium hydroxide solution, 0.4ml of 30% aqueous hydrogen peroxide solution and 2ml of ethanol are added to the reaction medium. After work-up and purification as in step 3 of example 3, 76mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [2- (2-hydroxyethoxy) ethylamino ] benzamide are thus obtained in the form of a white solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 3.31(m partial mask, 2H)3.39-3.56(m, 4H)3.64(t, J ═ 5.6Hz, 2H)4.53(t, J ═ 5.6Hz, 1H)6.76(dd, J ═ 8.3, 2.1Hz, 1H)6.90(d, J ═ 2.1Hz, 1H)7.08-7.86(m, 10H)7.92(d, J ═ 8.3Hz, 1H)7.99 (width m, 1H)8.54(t, J ═ 5.4Hz, 1H)8.62(d, J ═ 8.3Hz, 1H)13.08 (width m, 1H).

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 0.78; MH ₊＝524₊；MH_-＝522。

Example 8: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (3-hydroxypropylamino) benzamide

The process is carried out as in example 3 step 3, but using 84mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 83mg of potassium carbonate and 300mg of 3-amino-1-propanol in 0.67ml of dimethyl sulfoxide. Then 0.4ml of 1M aqueous sodium hydroxide solution, 0.4ml of 30% aqueous hydrogen peroxide solution and 2ml of ethanol are added to the reaction medium. After work-up and purification as in step 3 of example 3, 85mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (3-hydroxypropylamino) benzamide are thus obtained in the form of a white solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.73(m, 2H)3.19(q, J ═ 5.4Hz, 2H)3.50(q, J ═ 5.4Hz, 2H)4.49(t, J ═ 5.4Hz, 1H)6.74(dd, J ═ 8.3, 2.1Hz, 1H)6.86(d, J ═ 2.1Hz, 1H)7.08-7.83(m, 9H)7.92(d, J ═ 8.3Hz, 1H)7.99 (width m, 1H)8.45(t, J ═ 5.4Hz, 2H)8.62(d, J ═ 8.3Hz, 1H)13.08 (width m, 1H).

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 0.78; MH + ═ 494 +; MH- ═ 492-.

Example 9:4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (4-cis-hydroxycyclohexylamino) benzamide

The process is carried out as in example 3 step 3, but using 84mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 111mg of potassium carbonate and 607mg of cis-4-aminocyclohexanol hydrochloride in 0.67ml of dimethyl sulfoxide. Then 0.4ml of 1M aqueous sodium hydroxide solution, 0.4ml of 30% aqueous hydrogen peroxide solution and 2ml of ethanol are added to the reaction medium. After work-up and purification as in step 3 of example 3, 85mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) carbazol-9-yl ] -2- (4-cis-hydroxycyclohexylamino) benzamide are thus obtained in the form of a white solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.44-1.76(m, 8H)3.48(m, 1H)3.59(m, 1H)4.48(d, J ═ 3.7Hz, 1H)6.71(dd, J ═ 8.3, 2.1Hz, 1H)6.86(d, J ═ 2.1Hz, 1H)7.05-7.86(m, 10H)7.93(d, J ═ 8.3Hz, 1H)7.98 (width m, 1H)8.62(d, J ═ 8.2Hz, 1H)8.70(d, J ═ 7.9Hz, 1H)13.08 (width m, 1H).

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 0.86; MH ₊＝534₊；MH_-＝532_-。

Example 10:2-amino-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

Step 1: in a microwave reactor, 1.015g of methyl 9- (3-bromo-4-cyanophenyl) -9H-carbazole-4-carboxylate, obtained according to step 3 of example 1, 444mg of acetamide, 71mg of trans-N, N' -dimethylcyclohexane-1, 2-diamine, 1.039g of potassium carbonate and 95mg of cuprous iodide were placed in 20ml of di-methyl acetateThe mixture in the alkane was heated at 160 ℃ for 1.5 hours. The reaction medium is poured into 200ml of ethyl acetate. The organic phase is washed with 100ml of saturated sodium bicarbonate solution. The aqueous phase was back-extracted twice with 100ml ethyl acetate. The combined organic phases are washed twice with 50ml of saturated sodium bicarbonate solution and once with 100ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (40-63 μm) eluting with pure dichloromethane. 520mg of methyl 9- (3-acetylamino-4-cyanophenyl) -9H-carbazole-4-carboxylate are obtained in the form of an off-white solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 2.15(s, 3H); 4.03(s, 3H); 7.35(m, 1H); 7.52-7.60(m, 3H); 7.63(dd, J ═ 8.3Hz and 2.0Hz, 1H); 7.77(d, J ═ 7.8Hz, 1H); 7.85(d, J ═ 7.8Hz, 1H); 7.96(d, J ═ 2.0Hz, 1H); 8.11(d, J ═ 8.3Hz, 1H); 8.74(d, J ═ 7.8Hz, 1H); 10.42(s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.08; m/z 382 (M-H-); 384(M + H +).

Step 2: in a 250ml round-bottom flask, a mixture of 300mg of methyl 9- (3-acetylamino-4-cyanophenyl) -9H-carbazole-4-carboxylate obtained in the preceding step and 66mg of lithium hydroxide monohydrate in 30ml of methanol was refluxed for 2 hours. The reaction medium is evaporated to dryness in vacuo, the residue is taken up in 30ml of 1M hydrochloric acid and extracted 3 times with 30ml of dichloromethane. The combined organic phases are washed with 30ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (15-40 μm) eluting with pure dichloromethane. 113mg of methyl 9- (3-amino-4-cyanophenyl) -9H-carbazole-4-carboxylate are obtained in the form of a white foam, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 4.03(s, 3H); 6.40(s, 2H); 6.83(dd, J ═ 8.3Hz and 2.0Hz, 1H); 7.03(d, J ═ 2.0Hz, 1H); 7.32(m, 1H); 7.46(d, J ═ 8.3Hz, 1H); 7.49-7.58(m, 2H); 7.70(m, 2H); 7.84 (width d, J ═ 7.6Hz, 1H); 8.73(d, J ═ 8.3Hz, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.14; m/z is 342(M + H +).

And step 3: in a 100ml round-bottom flask, a mixture of 113mg of methyl 9- (3-amino-4-cyanophenyl) -9H-carbazole-4-carboxylate obtained in the preceding step and 0.3ml of 2.5M sodium hydroxide in 10ml of methanol was refluxed. After 3.5 hours, 0.3ml of 2.5M sodium hydroxide was added and reflux continued for a total of 5 hours, after which the mixture was returned to ambient temperature overnight. The following day, the reaction medium is evaporated to dryness and the residue is taken up in 10ml of 1M hydrochloric acid. The suspension was stirred for 1/2 hours at ambient temperature, and the solid was filtered off and washed with 50ml of distilled water. The yellow solid was chromatographed on silica gel (15-40 μm) eluting with a mixture of dichloromethane and methanol (95/5). 77mg of 9- (3-amino-4-cyanophenyl) -9H-carbazole-4-carboxylic acid are obtained in the form of a pale yellow solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 6.40(s, 2H); 6.83(dd, J ═ 8.3Hz and 2.0Hz, 1H); 7.03(d, J ═ 2.0Hz, 1H); 7.30(td, J ═ 7.8Hz and 1.0Hz, 1H); 7.44(d, J ═ 7.8Hz, 1H); 7.46-7.56(m, 2H); 7.65(d, J ═ 7.8Hz, 1H); 7.71(d, J ═ 8.3Hz, 1H); 7.83(d, J ═ 7.8Hz, 1H); 8.87(d, J ═ 8.3Hz, 1H); 13.37 (width m, 1H).

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 3.90; 326 (M-H-).

And 4, step 4: in a 250ml round bottom flask 77mg of 9- (3-amino-4-cyanophenyl) -9H-carbazole-4-carboxylic acid obtained in the previous step, 30mg of 4-fluoro-O-phenylenediamine, 81mg of O- ((ethoxycarbonyl) cyanomethyleneamino) -N, N, N ', N' -tetramethylureaA mixture of tetrafluoroborate (TOTU) and 43. mu.l of diisopropylethylamine in 10ml of dimethylformamide was stirred at ambient temperature for 3 hours. The reaction medium is evaporated to dryness in vacuo and the residue is taken up in 75ml of ethyl acetate and 50ml of saturated sodium bicarbonate solution. The resulting product was separated by settling and the aqueous phase was back-extracted twice with 50ml ethyl acetate. The combined organic phases are washed twice with 50ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. 155mg of 9- (3-amino-4-cyanophenyl) -9H-carbazole-4-carboxylic acid (2-amino-4-fluorophenyl) amide are obtained as a light brown solid, which is used without further characterization for the subsequent steps.

And 5: in a 250ml round bottom flask, a mixture of 155mg of 9- (3-amino-4-cyanophenyl) -9H-carbazole-4-carboxylic acid (2-amino-4-fluorophenyl) amide obtained in the previous step and 10ml of acetic acid was refluxed for 1 hour. The reaction medium is evaporated to dryness in vacuo and the residue is chromatographed twice on silica gel (15-40 μm), eluting with a mixture of dichloromethane and methanol (95/5). 40mg of 2-amino-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile are obtained in the form of a brown foam, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 6.42(s, 2H); 6.87(dd, J ═ 8.3Hz and 2.0Hz, 1H); 7.08(d, J ═ 2.0Hz, 1H); 7.10-7.24(m, 2H); 7.35-7.80 (width m, 2H); 7.47(m, 2H); 7.60-7.69(m, 3H); 7.73(d, J ═ 8.3Hz, 1H); 8.59(d, J ═ 8.3Hz, 1H); 13.10 (width m, 1H).

Step 6: in a 50ml round-bottom flask, 0.2ml of 30% aqueous hydrogen peroxide was added to 40mg of 2-amino-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl group obtained in the previous step]A solution of benzonitrile in 1.0ml of ethanol and 0.4ml of dimethyl sulfoxide and 0.2ml of 1M sodium hydroxide are mixed and the mixture is stirred at ambient temperature¹/₄And (4) hours. 20ml of distilled water were added, and the mixture was extracted 3 times with 30ml of ethyl acetate. The combined organic phases are washed with 30ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (15-40 μm) eluting with a mixture of dichloromethane and methanol (95/5, vol). 24mg of 2-amino-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl are obtained]Benzamide, in the form of a beige solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 6.73(dd, J ═ 8.6Hz and 2.2Hz, 1H); 6.92(s, 2H); 6.97(d, J ═ 2.2Hz, 1H); 7.10-7.30(m, 3H); 7.42-7.50(m, 3H); 7.58-7.66(m, 4H); 7.86(d, J ═ 8.6Hz, 1H); 7.90 (width m, 1H); 8.59(d, J ═ 8.3Hz, 1H); 13.09 (width m, 1H).

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 3.41; m/z 434 (M-H-); 436(M + H +).

Example 11:4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (2-pyrrolidin-1-ylethylamino) benzamide

The process is carried out as in example 3 step 3, but using 67mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained in example 3 step 2, 66mg of potassium carbonate and 364mg of N- (2-aminoethyl) pyrrolidine in 0.54ml of dimethyl sulfoxide. Then 0.32ml of 1M aqueous sodium hydroxide solution, 0.32ml of 30% aqueous hydrogen peroxide solution and 1.6ml of ethanol are added to the reaction medium. After work-up and purification as in step 3 of example 3, 62mg of 4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] -2- (2-pyrrolidin-1-ylethylamino) benzamide are thus obtained in the form of a white solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.67(m, 4H)2.42-2.54(m partial mask, 4H)2.67(t, J ═ 6.5Hz, 2H)3.23(m, 2H)6.75(dd, J ═ 8.2, 2.1Hz, 1H)6.86(d, J ═ 2.1Hz, 1H)7.04-7.79(m, 10H)7.90(d, J ═ 8.3Hz, 1H)7.93-8.02 (width m, 1H)8.49(t, J ═ 5.4Hz, 1H)8.63(d, J ═ 8.2Hz, 1H)13.12 (width m, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.67; MH₊＝533₊；MH_-＝531_-。

Example 12:6- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -1H-indazol-3-ylamine

200mg of 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained in step 2 of example 3, 2ml of n-butanol and 61mg of hydrazine hydrate were introduced in this order into a 5ml microwave reactor. After stirring for 10 seconds at ambient temperature, the reaction medium is heated with stirring for 10 minutes at 150 ℃. After cooling, a further 61mg of hydrazine hydrate are added and the reaction medium is heated at 150 ℃ for a further 20 minutes with stirring. After cooling, the reaction medium is diluted with 5ml of ethyl acetate and the mixture is evaporated to dryness in vacuo. The resulting crude residue was purified by chromatography on silica gel (15-40 μm), eluting with a mixture of dichloromethane and ammonia (7N in methanol) (95/5, vol). This gave 60mg of 6- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -1H-indazol-3-ylamine as an amber solid, which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 5.54 (width s, 2H)7.08(dd, J ═ 8.5, 1.6Hz, 1H)7.11-7.23(m, 2H)7.32-7.91(m, 9H)7.99(d, J ═ 8.5Hz, 1H)8.64 (width m, 1H)11.63 (width m, 1H).

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 3.39; MH + ═ 433 +; MH- ═ 431-.

Example 13:6- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-1, 2-benzisoxazoSynthesis of oxazol-3-ylamine

190mg of N-Boc-hydroxylamine, 160mg of potassium tert-butoxide and 5ml of dimethylformamide are introduced successively into a round-bottomed flask at ambient temperature. The reaction medium is stirred for 40 minutes, then 200mg of 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl) obtained according to step 2 of example 3 are added]Benzonitrile and the mixture was stirred for 12 hours. Then, 100ml of a saturated aqueous sodium chloride solution was added, and the mixture was extracted with 100ml of ethyl acetate. The organic phase is washed successively with 50ml of water and 50ml of saturated aqueous sodium chloride solution, then dried over magnesium sulfate and evaporated to dryness in vacuo. The resulting crude residue was purified by chromatography on silica gel (15-40 μm) eluting with a mixture of dichloromethane and ammonia (7N in methanol) (95/5, vol). This gives 100mg of 6- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-1, 2-benzisoxazoOxazol-3-ylamine, in the form of an amber solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 6.61 (width s, 2H)7.08-7.19 (width m, 1H)7.21(t, J ═ 7.4Hz, 1H)7.36-7.70(m, 7H)7.82 (width s, 1H)7.86 (width m, 1H)8.13(d, J ═ 8.5Hz, 1H)8.49-8.73 (width m, 1H)13.12 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.86; MH₊＝434₊；MH_-＝432_-。

Example 14:2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

150mg of 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to step 2 of example 3, 1ml of dimethyl sulfoxide, 2ml of ethanol, 0.5ml of 1M sodium hydroxide and 0.5ml of 30% aqueous hydrogen peroxide are introduced into a round-bottomed flask in this order, and the mixture is stirred at ambient temperature for 1/4 hours. 20ml of distilled water are added and the suspension is filtered through sintered glass. This gave 141mg of 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide in the form of a white solid, which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 7.05-7.31(m, 3H)7.36-7.92(m, 10H)7.99(t, J ═ 8.2Hz, 1H)8.65(d, J ═ 8.1Hz, 1H)13.10 (width m, 1H).

Example 15: tert-butyl and 4- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] malonic acid]Synthesis of phenylamino cyclohexyl ester

200mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-trans-hydroxycyclohexylamino) benzamide obtained in example 1 and 0.120g of malonic acid tert-butyl monoester were dissolved in 20mL of dichloromethane and 2mL of dimethylformamide under an argon atmosphere in a 50mL three-necked flask. 45.8mg of 4-dimethylaminopyridine and 144mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are added successively. The reaction medium is stirred at ambient temperature for 20 hours and then concentrated under reduced pressure. The residue was taken up in a mixture of 25m1 water and 50ml dichloromethane and methanol (9/1, vol). The organic phase was separated by settling and the aqueous phase was back-extracted twice with 50ml of a mixture of dichloromethane and methanol (9/1 vol). The combined organic phases are washed with 25ml of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The crude product thus obtained was purified by flash chromatography on 15g silica gel eluting with a mixture of dichloromethane and ethanol (95/5, vol). 165mg of tert-butyl and 4- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } cyclohexyl malonate were thus obtained, in the form of a white powder, which was characterized as follows:

-1H NMR spectrum (400MHz, DMSO) δ ppm: 1.30-1.56(m, 4H)1.37(s, 9H)1.83-1.93(m, 2H)1.97-2.08(m, 2H)3.30(s, 2H)3.41-3.54(m, 1H)4.66-4.80(m, 1H)6.71(dd, J ═ 8.4, 1.6Hz, 1H)6.94(d, J ═ 1.0Hz, 1H)7.10-7.22(m, 2H)7.30(br.s., 1H)7.39-7.68(m, 7H)7.72(br.s., 1H)7.92(d, J ═ 8.6Hz, 1H)8.52(d, J ═ 7.6Hz, 1H)8.66(d, J ═ 8.6Hz, 1H)8.66(d, J ═ 8.13H) 1H (13H) 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.11; [ M + H ] + M/z 676; [ M + H ] -M/z 674.

Example 16:2- { 3-amino-6- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of indazol-1-yl } ethanol

200mg of 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to step 2 of example 3, 2ml of ethanol and 161mg of 2-hydrazinoethanol were introduced in succession into a 5ml microwave reactor. After stirring for 10 seconds at ambient temperature, the reaction medium is heated with stirring for 2 times 30 minutes at 150 ℃. After cooling, the solvent was evaporated to dryness in vacuo. The resulting crude residue was purified by chromatography on silica gel (15-40 μm), eluting with a mixture of dichloromethane and ammonia (7N in methanol) (95/5, vol). This gave 60mg of 2- { 3-amino-6- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] indazol-1-yl } ethanol as an off-white solid, which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 3.74(br.s., 2H)4.20(t, J ═ 5.5Hz, 2H)4.76(br.s., 1H)5.62(s, 2H)7.07(dd, J ═ 8.3, 1.7Hz, 1H)7.11-7.24(m, 2H)7.38-7.48(m, 2H)7.49-7.69(m, 5H)7.84(br.s., 1H)7.96(d, J ═ 8.3Hz, 1H)8.65(br.s., 1H)13.13 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.75; MH₊＝477₊，MH_-＝475_-。

Example 17:2- (2-Acetylaminoethylamino) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 150mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 148mg of potassium carbonate and 810mg of N-acetylethylenediamine in 1.2ml of dimethyl sulfoxide. Then 0.4ml of 1M aqueous sodium hydroxide solution, 0.4ml of 30% aqueous hydrogen peroxide solution and 2ml of ethanol are added to the reaction medium. After work-up and purification as in step 3 of example 3, 72mg of 2- (2-acetylaminoethylamino) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide are thus obtained in the form of a white solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.76(s, 3H)3.19-3.27(m, 4H)6.75(dd, J ═ 8.1, 1.7Hz, 1H)6.94(d, J ═ 1.7Hz, 1H)7.09-7.23(m, 2H)7.31(br.s., 1H)7.41-7.50(m, 2H)7.57-7.75(m, 5H)7.84-8.06(m, 3H)8.50(br.s., 1H)8.62(d, J ═ 7.8Hz, 1H)13.09 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.75; MH₊＝521₊，MH_-＝519_-。

Example 18:2- (2-aminoethylamino) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

60mg of 2- (2-acetylaminoethylamino) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl radical obtained according to example 17 are introduced]Benzamide, 3.4ml of bisAlkane and 0.68ml of 2M hydrochloric acid were introduced sequentially into a 5ml microwave reactor. After stirring for 10 seconds at ambient temperature, the reaction medium is heated with stirring twice for 30 minutes at 100 ℃. After cooling, the solvent was evaporated to dryness in vacuo. The resulting crude residue was purified by chromatography on silica gel (15-40 μm), eluting with a mixture of dichloromethane and ammonia (7N in methanol) (90/10, vol). This gave 20mg of 2- (2-aminoethylamino) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Benzamide, in the form of an off-white solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 2.77(t, J ═ 6.2Hz, 2H)3.14(q, J ═ 6.0Hz, 2H)6.74(dd, J ═ 8.3, 1.5Hz, 1H)6.88(d, J ═ 1.2Hz, 1H)7.10-7.35(m, 3H)7.38-7.85(m, 8H)7.87-8.04(m, 2H)8.50(t, J ═ 5.4Hz, 1H)8.63(d, J ═ 8.6Hz, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.64; MH₊＝479₊，MH_-＝477_-。

Example 19:6- [4- (6-fluoro-1H-benzimidazol-2-yl) carbazol-9-yl]Synthesis of nicotinamide

Step 1: 0.49g of 2-bromo-5-cyanopyridine, 2.2g of cesium carbonate, 0.12g of 9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene and 0.04g of palladium acetate were added in this order under an inert argon atmosphere to 0.40g of 9H-carbazole-4-carboxylic acid methyl ester obtained according to step 2 of example 1 in 30ml of bisIn an alkane. The reaction mixture was refluxed for 2 hours, then cooled, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (15-40 μm), eluting with a mixture of petroleum ether and dichloromethane (60/40 vol) to give 376mg of methyl 9- (5-cyanopyridin-2-yl) -9H-carbazole-4-carboxylate in the form of a yellow powder, which was characterised as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆)δppm 4.03(s，3H)7.39(t，J＝8.1Hz，1H)7.51-7.64(m，2H)7.84-7.92(m，2H)8.04(d，J＝8.6Hz，1H)8.15(d，J＝8.3Hz，1H)8.61(dd，J＝8.6，2.2Hz，1H)8.70(d，J＝7.8Hz，1H)9.21(d，J＝2.2Hz，1H)。

Mass Spectrometry (LC/MS; method A): retention time Tr (min) ═ 1.11; 328[ M + H ] +; m/z is 326[ M-H ] -.

Step 2: 1.6ml of 2M sodium hydroxide were added to a solution of 0.33g of methyl 9- (5-cyanopyridin-2-yl) -9H-carbazole-4-carboxylate obtained according to the preceding procedure in 30ml of methanol, and the mixture was heated at 60 ℃ for 2 hours. After returning to ambient temperature, the reaction mixture was concentrated under reduced pressure. Then 20ml of water and 1M aqueous HCl were added to adjust the pH to about 6. The aqueous phase was extracted with 3 × 100ml ethyl acetate, then the organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure. This gives 0.24g of 9- (5-carbamoylpyridin-2-yl) -9H-carbazole-4-carboxylic acid in the form of a rubber-like residue which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆) δ ppm 7.35(t, J ═ 7.7Hz, 1H)7.46-7.59(m, 2H)7.71(br.s., 1H)7.80(d, J ═ 8.3Hz, 1H)7.86(d, J ═ 7.5Hz, 1H)7.90(d, J ═ 8.3Hz, 1H)8.03(d, J ═ 8.3Hz, 1H)8.30(br.s., 1H)8.54(dd, J ═ 8.3, 2.4Hz, 1H)8.86(d, J ═ 7.9Hz, 1H)9.20(d, J ═ 2.2Hz, 1H)13.35 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.60; 332[ M + H ] +; m/z is 330[ M-H ] -.

And step 3: in a 50ml round bottom flask, 210mg of 9- (5-carbamoylpyridin-2-yl) -9H-carbazole-4-carboxylic acid obtained according to the preceding procedure, 105mg of 4-fluoro-O-phenylenediamine, 273mg of O- ((ethoxycarbonyl) cyanomethyleneamino) -N, N, N ', N' -tetramethylureaA mixture of tetrafluoroborate (TOTU) and 138. mu.l of diisopropylethylamine in 36ml of dimethylformamide was stirred at ambient temperature for 12 hours. 300ml of water are added to the reaction medium, and the aqueous phase is then extracted twice with 300ml of ethyl acetate. The organic phases are combined, washed with 100ml of saturated sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness in vacuo. The crude residue obtained was dissolved in 8.5ml of glacial acetic acid in a 20ml tube reactor and heated in a microwave at 110 ℃ for 1 hour. After returning to ambient temperature, the reaction mixture was concentrated under reduced pressure. Then 10ml of water and 10% aqueous sodium bicarbonate solution were added to adjust the pH to about 8. The aqueous phase was extracted with 1 × 100ml ethyl acetate, then the organic phase was concentrated under reduced pressure. The crude residue obtained is purified by chromatography on silica gel (15-40 μm) using A mixture of dichloromethane and ammonia (7N in methanol) (95/5, vol.) was eluted. This gave 110mg of 6- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Niacinamide, in the form of a beige solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 7.16(dd, J ═ 9.8, 2.4Hz, 1H)7.24(t, J ═ 8.1Hz, 1H)7.41-7.58(m, 2H)7.58-7.79(m, 4H)7.84(d, J ═ 8.3Hz, 1H)7.94(d, J ═ 8.1Hz, 1H)8.01(dd, J ═ 8.1, 1.2Hz, 1H)8.30(br.s., 1H)8.48(d, J ═ 8.1Hz, 1H)8.56(dd, J ═ 8.3, 2.4Hz, 1H)9.22(d, J ═ 2.2Hz, 1H)13.12 (width s, 1H)

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.69; m/z 422 (M-H-); 420(M + H +).

Example 20: 4- [4- (6-aminopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (4-trans-hydroxycyclohexyl) amino]Synthesis of benzamide

Step 1: under argon atmosphere, 1.85g of [5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl]2-methylpropan-2-yl carbamate, 2.48g cesium carbonate and 70mg 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (as complex with dichloromethane (1/1) [ PdCl [)₂(dppf).CH₂Cl₂]) To 0.6g of the 4-trifluoromethanesulfonyloxycarbazole obtained in step 1 of example 1 in 28ml were added successively Alkane and 9ml water. The reaction mixture was refluxed for 5 hours and concentrated under reduced pressure. The brown residue was taken up in dichloromethane, treated with animal charcoal (animal black), filtered through celite (celite), and concentrated under reduced pressure to give a yellow oil, which was subsequently purified by chromatography on silica gel, with cyclohexane anda mixture of ethyl acetate (85/15, vol.) was eluted. This gives 0.39g of [5- (9H-carbazol-4-yl) pyridin-2-yl]2-methylpropan-2-yl carbamate, in the form of a white solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.52(s, 9H)6.97(m, 1H)7.02(dd, J ═ 7.5, 1.1Hz, 1H)7.31-7.42(m, 2H)7.43-7.55(m, 3H)7.93-8.02(m, 2H)8.44(dd, J ═ 2.3, 1.1Hz, 1H)9.92 (width s, 1H)11.47 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.11; m/z is 360[ M + H ] +

Step 2: 0.217g of 4-bromo-2-fluorobenzonitrile, 0.9g of cesium carbonate, 0.05g of (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphine) and 0.016g of palladium acetate are added in this order to 0.26g of [5- (9H-carbazol-4-yl) pyridin-2-yl ] acetate under an argon atmosphere]2-methylpropan-2-yl carbamate in 15ml di Solution in an alkane. The reaction mixture was refluxed for 5 hours, cooled to ambient temperature, and filtered through celite. The filtrate was concentrated under reduced pressure to give a brown oil which, after trituration with diisopropyl ether, gave a yellow solid which was purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (90/10 vol). This gave 0.11g of {5- [9- (4-cyano-3-fluorophenyl) -9H-carbazol-4-yl]2-methylpropan-2-yl pyridin-2-yl } carbamate, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.53(s, 9H)7.15(m, 1H)7.21(m, 1H)7.38-7.47(m, 2H)7.51-7.59(m, 3H)7.77(dd, J ═ 8.4, 2.0Hz, 1H)7.95-8.05(m, 3H)8.25(m, 1H)8.46(dd, J ═ 2.4, 1.0Hz, 1H)9.97 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.26; m/z +479 [ M + H ] +

And step 3: 0.095g of potassium carbonate and 0.53g of trans-4-aminocyclohexanol are added in succession to a solution of 0.11g of 2-methylpropan-2-yl {5- [9- (4-cyano-3-fluorophenyl) -9H-carbazol-4-yl ] pyridin-2-yl } carbamate in 1ml of dimethyl sulfoxide. The reaction mixture was heated in a microwave at 90 ℃ for 1 hour, then 2.5ml of ethanol were added, followed by 0.46ml of 1N sodium hydroxide solution and 0.46ml of 30% aqueous hydrogen peroxide solution. The reaction mixture was stirred at ambient temperature for 15 minutes and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with a mixture of cyclohexane and ethyl acetate (94/6, vol). This gives 0.04g of 2-methylpropan-2-yl [5- (9- { 4-carbamoyl-3- [ (4-trans-hydroxycyclohexyl) amino ] phenyl } -9H-carbazol-4-yl) pyridin-2-yl ] carbamate in the form of a white solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.24(m, 4H)1.53(s, 9H)1.78(m, 2H)1.99(m, 2H)3.33(m partial masking, 1H)3.47(m, 1H)4.47(d, J ═ 4.2Hz, 1H)6.69(dd, J ═ 8.3, 2.0Hz, 1H)6.87(d, J ═ 2.0Hz, 1H)7.10(m, 1H)7.14(dd, J ═ 7.2, 1.0Hz, 1H)7.25 (width m, 1H)7.35-7.48(m, 4H)7.52(dd, J ═ 8.5, 7.2Hz, 1H)7.89(d, J ═ 8.5, 1H)7.95 (m, 1H) 1.99 (d, J ═ 8.5, 1H)7.95 (m, J ═ 8.5, 1H) 7.5 (dd, 8.5, 1H) 7.7.5 (1H), 8, 1H) 7.5 (1H), 8.5, 1H) 1, 8.7.8, 8 (dd, 8H) 1, 1H) 1H, 8, 1H) 7.5 (dd, 1H) 1, 1H)7.9 (1H) 1.

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 4.73; m/z 592[ M + H ] +; 590[ M-H ] -

And 4, step 4: 0.13ml of 1N hydrochloric acid was added to 0.04g of 4-carbamoyl-3- [ (4-trans-hydroxycyclohexyl) amino]Phenyl } -9H-carbazol-4-yl) pyridin-2-yl]2-methylpropan-2-yl carbamate in 1ml diIn an alkane. The reaction mixture was heated in a microwave at 100 ℃ for 15 minutes and then concentrated under reduced pressure. The residue was triturated with diisopropyl ether and the solid formed was filtered off to give 37mg of 4- [4- (6-aminopyridine-3)-yl) -9H-carbazol-9-yl]-2- [ (4-trans-hydroxycyclohexyl) amino]Benzamide hydrochloride, in the form of a white solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.16-1.31(m, 4H)1.78(m, 2H)1.97(m, 2H)3.29(m, 1H)3.48(m, 1H)6.67(dd, J ═ 8.3, 2.2Hz, 1H)6.84(d, J ═ 2.2Hz, 1H)7.11-7.35(m, 4H)7.43-7.68(m, 6H)7.90(d, J ═ 8.3Hz, 1H)7.97 (width m, 1H)8.10-8.29(m, 4H)8.49 (width m, 1H)13.85 (width m, 1H).

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 2.84; 492[ M + H ] +; 490[ M-H ] -

Example 21: tert-Butoxycarbonylaminoacetic acid 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of phenylamino cyclohexyl ester

The process is carried out as in example 15, but using 267mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-trans-hydroxycyclohexylamino) benzamide obtainable in example 1, 175mg of N-tert-butoxycarbonylglycine, 61mg of 4-dimethylaminopyridine and 192mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 50ml of dichloromethane and 5ml of dimethylformamide at 45 ℃ for 20 hours. A further 175mg of N-tert-butoxycarbonylglycine, 61mg of 4-dimethylaminopyridine and 192mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were then added and the mixture was stirred at ambient temperature for 3 days. After work-up and purification by flash chromatography, the process was carried out as in example 15, and the product was then crystallized from 5ml of diisopropyl ether. 275mg of 4- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } cyclohexyl tert-butoxycarbonylaminoacetate were thus obtained in the form of pale beige fine crystals, which were characterized as follows:

A 1H NMR spectrum (400MHz, δ ppm, DMSO-d6)1.36(s, 9H)1.40-1.56(m, 4H)1.80-1.95(m, 2H)1.97-2.09(m, 2H)3.39-3.52(m, 1H)3.59(d, J ═ 6.1Hz, 2H)4.65-4.81(m, 1H)6.72(dd, J ═ 8.3, 1.7Hz, 1H)6.93(s, 1H)7.08-7.23(m, 3H)7.30(br.s., 1H)7.39-7.68(m, 7H)7.72(br.s., 1H)7.92(d, J ═ 8.3Hz, 1H)8.53 (J ═ 1H), 1H ═ 8.66(d, 1H) 1H, 13H) (d, 1H) 3Hz, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.05; [ M + H ] + M/z 691; [ M + H ] -M/z 689

Example 22: 2(S) -tert-Butoxycarbonylaminopropionic acid 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of phenylamino cyclohexyl ester

The process is carried out as in example 15, but using 534mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-trans-hydroxycyclohexylamino) benzamide obtainable from example 1, 189mg of N-tert-butoxycarbonylalanine, 122mg of 4-dimethylaminopyridine and 383.5mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 50ml of dichloromethane and 5ml of dimethylformamide at 45 ℃ for 20 hours. 189mg of N-tert-butoxycarbonylalanine, 122mg of 4-dimethylaminopyridine and 383.5mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were then added and the mixture was stirred at ambient temperature for 3 days. After work-up, purification by flash chromatography and crystallization, as in example 16, gave 435mg of 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } cyclohexyl 2(S) -tert-butoxycarbonylaminopropionate, in the form of pale beige fine crystals, which were characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.19(d, J ═ 7.3Hz, 3H)1.35(s, 9H)1.40-1.56(m, 4H)1.78-1.92(m, 2H)1.96-2.08(m, 2H)3.41-3.52(m, 1H)3.85-3.96(m, 1H)4.64-4.76(m, 1H)6.72(dd, J ═ 8.3, 1.7Hz, 1H)6.93(s, 1H)7.09-7.24(m, 3H)7.30(br.s., 1H)7.40-7.68(m, 7H)7.92(d, J ═ 8.3Hz, 1H)8.00(br.s., 1H)8.55(d, J ═ 7.1H ═ 8.66, 1H) 8.08 (d, 1H) 13H, 13H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.08; [ M + H ] + M/z 705; [ M + H ] -M/z 703.

Example 23: 3-tert-Butoxycarbonylaminopropionic acid 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of phenylamino cyclohexyl ester

In a 250ml three-necked flask, 750mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-trans-hydroxycyclohexylamino) benzamide which can be prepared in example 1 and 532mg of N-tert-butoxycarbonyl- β -alanine were dissolved in 70ml of dichloromethane and 14ml of dimethylformamide under an argon atmosphere. 343.5mg of 4-dimethylaminopyridine and 923mg of O- [ (ethoxycarbonyl) cyanomethyleneamino ] -N, N, N ', N' -tetramethylurea (TOTU) are added successively, and the mixture is stirred at ambient temperature for 20 hours. 750mg of N-tert-butoxycarbonyl-. beta. -alanine, 343.5mg of 4-dimethylaminopyridine and 923mg of O- [ (ethoxycarbonyl) cyanomethyleneamino ] -N, N, N ', N' -tetramethylurea (TOTU) were then added, and the mixture was stirred again at ambient temperature for 20 hours. After work-up, purification by flash chromatography and crystallization, as in example 16, gave 725mg of 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } cyclohexyl 3-t-butoxycarbonylaminopropionate, in the form of pale beige fine crystals, which were characterized as follows:

A 1H NMR spectrum (400MHz, DMSO) δ ppm 1.33(s, 9H)1.37-1.51(m, 4H)1.83-1.92(m, 2H)1.97-2.07(m, 2H)2.36(t, J ═ 6.8Hz, 2H)3.12(q, J ═ 6.7Hz, 2H)3.38-3.52(m, 1H)4.61-4.78(m, 1H)6.72(dd, J ═ 8.1, 1.5Hz, 1H)6.74-6.83(m, 1H)6.91(s, 1H)7.10-7.22(m, 2H)7.30(br.s., 1H)7.37-7.68(m, 7H)7.92(d, J ═ 8.6.7H) 7.19 (m, 1H) 7.13, 13H (d, 1H) 7.8, 1H) 7.13, 1H).

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 4.47; [ M + H ] + M/z 705; [ M + H ] -M/z 703.

Example 24: 3-aminopropionic acid 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of trifluoroacetate salt of phenylamino } cyclohexyl ester

In a 50ml single neck round bottom flask, 560mg of 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) carbazol-9-yl ] phenylamino } cyclohexyl 3-tert-butoxycarbonylaminopropionate obtained in example 23 were dissolved in 15ml of dichloromethane. The resulting solution was cooled to 0 ℃, then 10ml of trifluoroacetic acid was added, and the mixture was stirred at 0 ℃ for 2 hours. The reaction medium is concentrated under reduced pressure. The residue was then dissolved in a minimum amount of methanol (1.2ml) and then precipitated by slow addition of 5ml of diisopropyl ether. After stirring for 30 minutes at 0 ℃, the precipitate formed is dried by rotary filtration (spin-filter-dried), washed twice with 5ml of diisopropyl ether and dried in an oven under vacuum in the presence of potassium hydroxide fragments at 50 ℃ for 4 hours. This gave 559mg of the trifluoroacetate salt of 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } cyclohexyl 3-aminopropionate in the form of an off-white powder, which was characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6+ TFA, δ ppm): 1.38-1.59(m, 4H)1.89-2.01(m, 2H)2.03-2.14(m, 2H)2.59-2.69(m, 2H)2.98-3.11(m, 2H)3.44-3.57(m, 1H)4.73-4.83(m, 1H)6.83(d, J ═ 7.8Hz, 1H)7.01(s, 1H)7.27 (width s, 1H)7.52-7.63(m, 3H)7.67-7.93(m, 5H)7.97-8.09(m, 2H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.73; [ M + H ] + M/z 605; [ M + H ] -M/z 603

Example 25: aminoacetic acid 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of trifluoroacetate salt of phenylamino } cyclohexyl ester

The process is carried out as in example 24, but using 400mg of 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } cyclohexyl tert-butoxycarbonylaminoacetate obtained in example 21 in 10ml of dichloromethane and 10ml of trifluoroacetic acid at 0 ℃ for 1.5 hours. After work-up as in example 24, 347mg of the trifluoroacetate salt of 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } cyclohexyl glycinate are obtained in the form of a very pale yellow powder which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6+ TFA, δ ppm): 1.37-1.63(m, 4H)1.89-2.01(m, 2H)2.02-2.15(m, 2H)3.45-3.57(m, 1H)3.78(s, 2H)4.82-4.94(m, 1H)6.79(d, J ═ 7.6Hz, 1H)6.99(s, 1H)7.26 (width s, 1H)7.49-7.62(m, 3H)7.67-7.92(m, 5H)7.94-8.10(m, 2H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.70; [ M + H ] + M/z 591; [ M + H ] -M/z 589.

Example 26: 2(S) -aminopropionic acid 4-trans- { 2-carbamoyl-5-[4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of trifluoroacetate salt of phenylamino } cyclohexyl ester

The process is carried out as in example 24, but using 300mg of 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } cyclohexyl 2(S) -tert-butoxycarbonylaminopropionate obtained in example 22 in 7.5ml of dichloromethane and 10ml of trifluoroacetic acid at 0 ℃ for 2 hours. After work-up as in example 24, 290mg of the trifluoroacetate salt of 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } cyclohexyl 2(S) -aminopropionate are obtained in the form of pale yellow fine crystals which are characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 1.35(d, J ═ 6.8Hz, 3H)1.39-1.60(m, 4H)1.87-1.97(m, 2H)2.00-2.10(m, 2H)3.44-3.54(m, 1H)4.00-4.11(m, 1H)4.79-4.88(m, 1H)6.73(d, J ═ 8.1Hz, 1H)6.93(s, 1H)7.16-7.24(m, 2H)7.31 (width s, 1H)7.41-7.69(m, 7H)7.71-7.79(m, 1H)7.93(d, J ═ 8.6Hz, 1H)8.01 (width s, 1H)8.25 (width s, 3H)8.56(d, J ═ 8.1H) 8.25 (width s, 3H).

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 3.14; [ M + H ] + M/z 605; [ M + H ] -M/z 603

Example 27:2- [ (4-trans-hydroxycyclohexyl) amino]-4- [4- (5-methoxypyridin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

Step 1: 0.54g of (5-methoxypyridin-3-yl) boronic acid, 3.3g of caesium carbonate and 93mg of 1, 1' -bis (diphenylphosphino) dicyclopentadieneIron palladium (II) dichloride (as a complex with dichloromethane (1/1) [ PdCl₂(dppf).CH₂Cl₂]) To 0.8g of 4-trifluoromethanesulfonyloxycarbazole obtained in step 1 of example 1 in 37ml of bis (methyl) phosphonium chloride were added in succession under argonAlkane and 12ml water. The reaction mixture was refluxed for 3.5 hours, filtered through celite, and concentrated under reduced pressure. The residue was then purified by silica gel chromatography, eluting with a mixture of cyclohexane and ethyl acetate (75/25, vol) to give 0.7g of 4- (5-methoxypyridin-3-yl) -9H-carbazole as a colourless oil, which was characterised as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 3.90(s, 3H)6.97(td, J ═ 7.6, 1.0Hz, 1H)7.07(dd, J ═ 7.2, 1.1Hz, 1H)7.30-7.38(m, 2H)7.48(dd, J ═ 8.1, 7.2Hz, 1H)7.52(d, J ═ 8.1Hz, 1H)7.55-7.59(m, 2H)8.39(d, J ═ 1.9Hz, 1H)8.44(d, J ═ 2.9Hz, 1H)11.51 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.77; 275[ M + H ] +; 273[ M-H ] -

Step 2: 0.74g of 4-bromo-2-fluorobenzonitrile, 3.07g of cesium carbonate, 0.172g of (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphine) and 0.055g of palladium acetate are added in succession under argon to 0.68g of 4- (5-methoxypyridin-3-yl) -9H-carbazole in 30ml of bisIn an alkane. The reaction mixture was refluxed for 2.5 hours, cooled to ambient temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (80/20 vol) to give 0.78g of 2-fluoro-4- [4- (5-methoxypyridin-3-yl) -9H-carbazol-9-yl]Benzonitrile is in the form of a colorless oil, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 3.91(s, 3H)7.15(m, 1H)7.26(dd, J ═ 7.1, 1.2Hz, 1H)7.33(d, J ═ 8.1Hz, 1H)7.44(m, 1H)7.51-7.63(m, 4H)7.78(dd, J ═ 8.3, 2.0Hz, 1H)8.01(dd, J ═ 10.5, 2.0Hz, 1H)8.26(m, 1H)8.39(d, J ═ 2.0Hz, 1H)8.48(d, J ═ 2.9Hz, 1H).

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 4.72; m/z ═ 394[ M + H ] +

And step 3: 0.316g of potassium carbonate and 1.75g of 4-trans-aminocyclohexanol are added in succession to a solution of 0.3g of 2-fluoro-4- [4- (5-methoxypyridin-3-yl) -9H-carbazol-9-yl ] benzonitrile in 3.3ml of dimethyl sulfoxide. The reaction mixture was heated in a microwave at 90 ℃ for 1 hour, then 7.6ml of ethanol were added, followed by 1.51ml of 1N sodium hydroxide solution and 1.51ml of 30% aqueous hydrogen peroxide solution. The reaction mixture was stirred at ambient temperature for 10 minutes and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting white solid was purified by silica gel chromatography eluting with a mixture of dichloromethane, acetonitrile and methanol (90/5/5 vol) to give 0.2g of 2- [ (4-trans-hydroxycyclohexyl) amino ] -4- [4- (5-methoxypyridin-3-yl) -9H-carbazol-9-yl ] benzamide as a white solid which was characterized as follows:

melting point (Kofler bench): 263 deg.C.

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.24(m, 4H)1.78(m, 2H)1.99(m, 2H)3.30 (masked m, 1H)3.48(m, 1H)3.91(s, 3H)4.47(d, J ═ 4.2Hz, 1H)6.70(dd, J ═ 8.4, 2.0Hz, 1H)6.87(d, J ═ 2.0Hz, 1H)7.09(m, 1H)7.19(dd, J ═ 7.1, 1.1Hz, 1H)7.26 (width m, 1H)7.34(d, J ═ 8.1Hz, 1H)7.38-7.45(m, 2H)7.48(dd, J ═ 8.3, 1.1, 1H)7.54 (J, J ═ 8.3, 1H), 7.54(dd, 7.9, 7.8H), 7.9H) 7.7.8 (dd, 7.8, 7H) 7.8, 7.8 (d, 1H), 7.7.8, 7.8H) 1, 1H) 7.7.7.9 (dd, 1H)7.9, 1H) 7.7.8, 1H) 1, 7.8, 1H, 7.9 (d, 1H)7.9, 1H)7.9, 1, 7.9, 1.

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 3.76; 507[ M + H ] +; 505[ M-H ] -

Example 28:5- (9- { 4-carbamoyl-3- [ (4-trans-hydroxycyclohexyl) amino]Synthesis of phenyl } -9H-carbazol-4-yl) pyridine-2-carboxamides

Step 1: 0.72g of 2-cyano-5- (4, 4, 5, 5-tetramethyl [1, 3, 2 ]]Dioxaborolan-2-yl) pyridine, 3.3g cesium carbonate and 92mg of 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (as complex with dichloromethane (1/1) [ PdCl [)₂(dppf).CH₂Cl₂]) To 0.8g of 4-trifluoromethanesulfonyloxycarbazole obtained in step 1 of example 1 in 37ml of bis (methyl) phosphonium chloride were added in succession under argonA mixture of an alkane and 12ml of water. The reaction mixture was refluxed for 4 hours, cooled to ambient temperature, filtered through celite, and concentrated under reduced pressure. The residue was then purified by silica gel chromatography, eluting with a mixture of cyclohexane and ethyl acetate (85/15, vol) to give 0.24g of 5- (9H-carbazol-4-yl) pyridine-2-carbonitrile as a yellow solid, which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 6.98(m, 1H)7.10(dd, J ═ 7.2, 1.1Hz, 1H)7.28(d, J ═ 8.1Hz, 1H)7.38(m, 1H)7.48-7.56(m, 2H)7.63(d, J ═ 8.2, 1.0Hz, 1H)8.24(dd, J ═ 8.0, 1.0Hz, 1H)8.31(dd, J ═ 8.0, 2.2Hz, 1H)8.99(dd, J ═ 2.2, 1.0Hz, 1H)11.60 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.99; m/z 270[ M + H ] +; 268[ M-H ] -

Step 2: 0.267g of 4-bromo-2-fluorobenzonitrile, 1.1g of cesium carbonate, 0.06g of (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphine) and 0.02g of palladium acetate were reacted under an argon atmosphereTo 0.24g of 5- (9H-carbazol-4-yl) pyridine-2-carbonitrile in 10ml were added successivelyIn an alkane. The reaction mixture was refluxed for 3 hours, cooled to ambient temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (85/15 vol) to give 0.2g of 5- [9- (4-cyano-3-fluorophenyl) -9H-carbazol-4-yl]Pyridine-2-carbonitrile, in the form of an off-white solid, which is characterized as follows:

-1H NMR spectrum (400MHz,. delta. pppm, DMSO-d 6): 7.16(m, 1H)7.27-7.32(m, 2H)7.46(m, 1H)7.53-7.68(m, 3H)7.78(dd, J ═ 8.4, 2.0Hz, 1H)8.01(dd, J ═ 10.5, 2.0Hz, 1H)8.24-8.30(m, 2H)8.34(d, J ═ 7.9, 2.2Hz, 1H)9.01(dd, J ═ 2.2, 1.0Hz, 1H)

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.16; m/z is 389[ M + H ] +

And step 3: 0.21g of potassium carbonate and 1.2g of 4-trans-aminocyclohexanol are added in succession to a solution of 0.2g of 5- [9- (4-cyano-3-fluorophenyl) -9H-carbazol-4-yl ] pyridine-2-carbonitrile in 2.2ml of dimethyl sulfoxide. The reaction mixture was heated in a microwave at 90 ℃ for 1 hour, then 5.1ml of ethanol was added followed by 1ml of 1N sodium hydroxide solution and 1ml of 30% aqueous hydrogen peroxide solution. The reaction mixture was stirred at ambient temperature for 5 minutes and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The off-white solid obtained was purified by chromatography on silica gel eluting with a mixture of dichloromethane, acetonitrile and methanol (92/4/4 vol) and recrystallised from ethanol to yield 0.13g of 5- (9- { 4-carbamoyl-3- [ (4-trans-hydroxycyclohexyl) amino ] phenyl } -9H-carbazol-4-yl) pyridine-2-carboxamide as a white solid characterized as follows:

Melting point (Kofler bench) > 260 ℃.

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.24(m, 4H)1.78(m, 2H)1.99(m, 2H)3.32(m partial mask, 1H)3.47(m, 1H)4.47(d, J ═ 4.2Hz, 1H)6.70(dd, J ═ 8.2, 1.9Hz, 1H)6.88(d, J ═ 1.9Hz, 1H)7.09(m, 1H)7.22(dd, J ═ 7.1, 1.2Hz, 1H)7.26 (width m, 1H)7.31(d, J ═ 8.1Hz, 1H)7.39-7.46(m, 2H)7.51(dd, J ═ 8.3, 1.0, 1H)7.57(dd, J ═ 8.3, 7.7.7, 1H)7.57(dd, 7.7, 1H) 7.7.7 (m, 2H) 7.7.7.7, 8H) 7.3, 1H (d, 8.3, 1H) 7.7.7.7, 8H) 1, 1H (d, 1H) 1, 1H) 7.7.7.7.7.7.7.7.7, 8H) 1H (d, 1H) 1, 1H) 1H.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.81; m/z 520[ M + H ] +

Example 29:2- [ (4-trans-hydroxycyclohexyl) amino]-4- {4- [6- (hydroxymethyl) pyridin-3-yl]Synthesis of-9H-carbazol-9-yl } benzamide

Step 1: 0.54g of [6- (hydroxymethyl) pyridin-3-yl]Boric acid, 3.3g cesium carbonate and 93mg of 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (as a complex with dichloromethane (1/1) [ PdCl₂(dppf).CH₂Cl₂]) 0.8g of 4-trifluoromethanesulfonyloxycarbazole obtained in step 1 of example 1 in 37ml of bis (methyl) phosphonium chloride are added in succession under argonA mixture of an alkane and 12ml of water. The reaction mixture was refluxed for 5 hours, cooled to ambient temperature and concentrated under reduced pressure. The residue is then taken up in a mixture of dichloromethane and ethyl acetate, treated with carbon black, filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (55/45 vol) to give 0.33g of [5- (9H-carbazol-4-yl) pyridin-2-yl ]Methanol was in the form of a colorless oil, which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 4.71(d, J ═ 5.7Hz, 2H)5.50(t, J ═ 5.7Hz, 1H)6.95(m, 1H)7.03(dd, J ═ 7.2, 1.1Hz, 1H)7.31(d, J ═ 8.1Hz, 1H)7.35(m, 1H)7.44-7.49(dd, J ═ 8.1, 7.6Hz, 1H)7.51(d, J ═ 8.1Hz, 1H)7.56(dd, J ═ 8.1, 1.1Hz, 1H)7.67 (wide d, J ═ 8.1, Hz, 1H)8.02(dd, J ═ 8.1, 2.4Hz, 1H)8.68(dd, J ═ 2.4, 1H) 11.49(s).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.54; 275[ M + H ] +; 273[ M-H ] -.

Step 2: 0.34g of 4-bromo-2-fluorobenzonitrile, 1.4g of cesium carbonate, 0.08g of (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphine) and 25mg of palladium acetate are added in this order to 0.31g of [5- (9H-carbazol-4-yl) pyridin-2-yl ] pyridine under an argon atmosphere]Methanol in 15mlIn an alkane. The reaction mixture was refluxed for 4 hours, cooled to ambient temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (85/15 vol) to give 70mg of 2-fluoro-4- {4- [6- (hydroxymethyl) pyridin-3-yl ]-9H-carbazol-9-yl } benzonitrile, in the form of a yellow solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 4.73(d, J ═ 5.6Hz, 2H)5.53(t, J ═ 5.6Hz, 1H)7.13(m, 1H)7.22(m, 1H)7.33(d, J ═ 8.0Hz, 1H)7.43(m, 1H)7.52-7.60(m, 3H)7.70(dd, J ═ 8.0, 1.0Hz, 1H)7.78(dd, J ═ 8.4, 2.0Hz, 1H)7.99-8.06(m, 2H)8.25(t, J ═ 8.0Hz, 1H)8.70(dd, J ═ 2.0, 1.0Hz, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.94; m/z is 394[ M + H ] +.

And step 3: 73mg of potassium carbonate and 0.4g of 4-trans-aminocyclohexanol are added in succession to a solution of 70mg of 2-fluoro-4- {4- [6- (hydroxymethyl) pyridin-3-yl ] -9H-carbazol-9-yl } benzonitrile in 2ml of dimethyl sulphoxide. The reaction mixture was heated in a microwave at 90 ℃ for 1 hour 15 minutes, then 1.8ml of ethanol was added, followed by 0.35ml of 1N sodium hydroxide solution and 0.35ml of 30% aqueous hydrogen peroxide solution. The reaction mixture was stirred at ambient temperature for 40 minutes and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The off-white solid obtained was purified by chromatography on silica gel, eluting with a mixture of dichloromethane, acetonitrile and methanol (90/5/5 vol), and triturated in dichloromethane, to give 0.13g of 2- [ (4-trans-hydroxycyclohexyl) amino ] -4- {4- [6- (hydroxymethyl) pyridin-3-yl ] -9H-carbazol-9-yl } benzamide, in the form of a white solid, which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.25(m, 4H)1.79(m, 2H)1.99(m, 2H)3.33(m, 1H)3.47(m, 1H)4.47(d, J ═ 4.4Hz, 1H)4.74(d, J ═ 5.4Hz, 2H)5.53(t, J ═ 5.4Hz, 1H)6.70(dd, J ═ 8.3, 2.0Hz, 1H)6.88(d, J ═ 2.0Hz, 1H)7.08(m, 1H)7.16(dd, J ═ 7.2, 1.0Hz, 1H)7.26 (width m, 1H)7.32-7.57(m, 5H)7.71(d, J ═ 8.2, 1H)7.90(d, 8.8, 8H) 1, 8.7.7, 8(d, 8.7.7, 8H) 3 (d, 8.06, 8.7, 8H) 3, 8H) 3 (d, 1H) 7.06 (1H) 7.7.7.7.7.7.7.7, 8H) 1H) 7.7.7.7.7.7.7.7.7.7.7.7.7.7.7 (d.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.67; m/z is 507[ M + H ] +.

Example 30: 4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

Step 1: the process was carried out as in step 3 of example 2, but using 100mg of 4- (quinolin-3-yl) -9H-carbazole obtained in step 2 of example 2, 32.28. mu.l of 3-aminopropanol, 206mg of caesium carbonate, 5mg of palladium acetate and 14.6mg of 4, 5-bis (diphenylphosphino) -9, 9-dimethylphosphino)Xanthene in 10ml diRefluxing in alkane for 2 hours. After work-up as in step 3 of example 1, it was then purified by flash chromatography on 15g of silica gel, eluting with a mixture of cyclohexane and ethyl acetate (50/50 vol), and the second eluting fraction was recovered, yielding 35mg of [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -9 ]Benzonitrile, characterized as follows:

LC/MS (method C): retention time 5.98 min

Step 2: by the method as in example 2 step 4, but using 34mg of the compound obtained in the preceding step, 172 μ l of 1N sodium hydroxide solution and 0.158 μ l of 30% aqueous hydrogen peroxide, kept at ambient temperature in 1ml of ethanol and 0.44ml of dimethyl sulfoxide for 30 minutes, after purification on a preparative silica plate, elution is carried out with a mixture of dichloromethane and methanol (80/20, vol) to give 11mg of 4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide in the form of a white powder, which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm)7.05(ddd, J ═ 8.0, 6.5, 1.6Hz, 1H)7.27(d, J ═ 8.1Hz, 1H)7.33(d, J ═ 7.1Hz, 1H)7.37-7.45(m, 2H)7.49-7.54(m, 2H)7.60(dd, J ═ 8.3, 7.3Hz, 1H)7.70-7.80(m, 3H)7.89(t, J ═ 8.3Hz, 1H)8.11-8.24(m, 5H)8.64(d, J ═ 2.0Hz, 1H)9.17(d, J ═ 2, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.00; m/z is 414[ M + H ] +

Example 31: 2- (3-hydroxypropyl) amino-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

Step 1: in a 250ml three-necked flask 1g of 4- (quinolin-3-yl) -9H-carbazole obtained in step 2 of example 2 are dissolved in 75ml of bis (ethanol) under argonTo the alkane, 3.32g of cesium carbonate and 1.019g of 4-bromo-2-fluorobenzonitrile were then added in that order. The reaction medium is degassed by bubbling argon for 10 minutes, then 3.3mg of palladium acetate and 236mg of 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene are added in succession and the mixture is refluxed for 2 hours under argon. The reaction medium is filtered through kieselguhr, concentrated under reduced pressure and taken up with 100ml of water and 100ml of ethyl acetate. The organic phase is separated by settling and the aqueous phase is back-extracted twice with 50ml of ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on 200g silica eluting with dichloromethane. This gives 1.05g of 2-fluoro- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Benzonitrile, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 7.08(t, J ═ 7.8Hz, 1H)7.24(d, J ═ 7.8Hz, 1H)7.36(dd, J ═ 6.7, 1.6Hz, 1H)7.43(t, J ═ 8.2Hz, 1H)7.56(d, J ═ 8.3Hz, 1H)7.59-7.67(m, 2H)7.73(t, J ═ 7.8Hz, 1H)7.81(dd, J ═ 8.3, 2.0Hz, 1H)7.89(t, J ═ 8.4Hz, 1H)8.04(dd, J ═ 10.3, 1.7Hz, 1H)8.13(d, J ═ 7.8Hz, 1H)8.19(d, J ═ 8.8, 8, 1H) 8.9 (d, J ═ 8.8, 1H), 1H (d, 8.9, 1H) 8.9, 1H, 1.9 (d, 1H), 1.8.8, 1H)8, 1H (d ═ 8.3Hz, 1.9H) 8, 1H).

Step 2: in a 100ml three-necked flask, 584mg of the compound obtained in the preceding step was dissolved in 20ml of dimethylformamide, and then 424mg of 3-aminopropanol and 1.562g of potassium carbonate were sequentially added. The mixture was heated at 140 ℃ for 2 hours, then 100ml of water and 100ml of ethyl acetate were added. The aqueous phase was separated by settling and the organic phase was back-extracted twice with 50ml of ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified on 30g silica gel, eluting with a mixture of cyclohexane and ethyl acetate (50/50, vol.). This gave 565mg of 2- (3-hydroxypropyl) amino- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile, which was characterized as follows:

LC/MS (method C): retention time 5.52 min

And step 3: by the method as in example 2 step 4, but using 565mg of the compound obtained in the previous step, 2.41ml of 1N sodium hydroxide solution and 2.22ml of 30% aqueous hydrogen peroxide for 30 minutes, kept at ambient temperature in 15ml of ethanol and 6.2ml of dimethyl sulfoxide for 30 minutes, purification by flash chromatography on 70g of silica gives, after elution with a mixture of dichloromethane and methanol (95/5, vol.), 334mg of 2- (3-hydroxypropyl) amino-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide in the form of a white powder, which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 1.74 (quintuple, J ═ 6.6Hz, 2H)3.20(q, J ═ 6.6Hz, 2H)3.51(q, J ═ 6.0Hz, 2H)4.50(t, J ═ 5.1Hz, 1H)6.77(dd, J ═ 8.2, 1.8Hz, 1H)6.88(d, J ═ 1.7Hz, 1H)7.02(t, J ═ 7.6Hz, 1H)7.25(d, J ═ 8.1Hz, 1H)7.28(br.s., 1H)7.30(dd, J ═ 6.6, 1.7Hz, 1H)7.40(t, J ═ 7.6Hz, 1H)7.48(d, J ═ 8.3, J ═ 6.6, 1.7Hz, 1H)7.8 (J ═ 8.3.7H), 7.8 (t, J ═ 8.8H), 7.8H) (J ═ 1.8, 3.7.8, 7.8H, 3.8H) 3.7.8 (d, 1.8H) 3.7.8, 1H, 3.8H, 1, 3.8H, 1.8H, 1H, 1.8H 8H, 1.8 (d, 1.8H) 7.8H) 7.7.8, 3.8H, 1.8, 1H, 3.8H, 1.8H, 1H, 1.7.7.8H, 1H, 3.8H, 1.6, 1.7.7.8H, 1, 1H) in that respect

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 1.00; [ M + H ] + M/z 487; [ M + H ] -M/z 485

Example 32: 2- (3-hydroxybutyl) amino-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

Step 1: the process is carried out as in step 2 of example 31, but using 150mg of 2-fluoro- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained in step 2 of example 31, 129mg of 3-aminobut-2-ol and 401mg of potassium carbonate in 5ml of dimethylformamide at 140 ℃ for 1 hour. After workup and purification by flash chromatography under the conditions described in example 31, step 2, 149mg of 2- (3-hydroxybutyl) amino- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile are obtained, which are characterized as follows:

LC/MS (method C): retention time 5.48 minutes.

Step 2: by the method as in example 2 step 4, but using 149mg of the compound obtained in the preceding step, 0.62ml of 1N sodium hydroxide solution and 0.568ml of 30% aqueous hydrogen peroxide solution for 1 hour at ambient temperature in 3.7ml of ethanol and 1.57ml of dimethyl sulfoxide, purification by flash chromatography on 10g of silica gives, after elution with a mixture of dichloromethane and methanol (97/3 vol), 106mg of 2- (3-hydroxybutyl) amino-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide in the form of a white powder, which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 1.09(d, J ═ 6.1Hz, 3H)1.60-1.68(m, 2H)3.16-3.24(m, 2H)3.69-3.77(m, 1H)4.50(d, J ═ 4.6Hz, 1H)6.77(dd, J ═ 8.3, 1.7Hz, 1H)6.87(d, J ═ 2.0Hz, 1H)7.02(t, J ═ 7.9Hz, 1H)7.25(d, J ═ 7.8Hz, 1H)7.28 (width s, 1H)7.30(dd, J ═ 6.4, 1.7Hz, 1H)7.40(t, J ═ 8.1, 1H)7.49(d, J ═ 8.3, 1H)7.8, 7H, 1H (d, J ═ 8.8, 7.8, 7H, 7H, 1H (d, 8, 7.7, 7, 7.8, 7, 8, 7, 8, 7, 8, 7, 8, 7, 8, 7, j ═ 2.0Hz, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.03; [ M + H ] + M/z 501; [ M + H ] -M/z 499.

Example 33: 2- (3-methoxypropyl) amino-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

Step 1: the process is carried out as in example 3 step 3, but using 206mg of 2-fluoro- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained in example 31 step 1, 177mg of 3-methoxypropylamine and 551mg of potassium carbonate at 140 ℃ in 7ml of dimethylformamide for 1 hour. After work-up as in step 2 of example 31, followed by purification by flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (70/30, vol) gave 190mg of 2- (3-methoxypropyl) amino- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile which was characterized as follows:

LC/MS (method C): retention time 6.02 min.

Step 2: by the method as in example 2 step 4, but using 190mg of the compound obtained in the preceding step, 0.787ml of 1N sodium hydroxide solution and 0.724ml of 30% aqueous hydrogen peroxide solution for 1 hour at ambient temperature in 4.8ml of ethanol and 2ml of dimethyl sulfoxide, purification by flash chromatography on 15g of silica gives 113mg of 2- (3-methoxypropyl) amino-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide, after elution with a mixture of ethyl acetate and heptane (60/40, vol), in the form of a white powder, which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 1.82 (quintuple, J ═ 6.5Hz, 2H)3.17-3.23(m, 5H)3.42(t, J ═ 6.2Hz, 2H)6.78(dd, J ═ 8.3, 2.0Hz, 1H)6.88(d, J ═ 2.0Hz, 1H)7.02(t, J ═ 7.9Hz, 1H)7.25(d, J ═ 8.1Hz, 1H)7.30(dd, J ═ 6.6, 1.5Hz, 1H)7.31 (width s, 1H)7.40(t, J ═ 8.1Hz, 1H)7.48(d, J ═ 8.3Hz, 1H)7.54-7.62(m, 2H)7.73(t, J ═ 8.8, 8.1H), 8.8, 8H, 1H (d, 1H)7.3 Hz, 1H)7.8, 1H (d, 8.8.3 Hz, 1H)7.8, 1H) 7.6, 1H (d, 1H) 7.6, 1H.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.12; [ M + H ] + M/z 501.

Example 34: 2- (2-carbamoylethylamino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

Step 1: the process is carried out as in step 2 of example 31, but using 206mg of 2-fluoro- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained in step 1 of example 31, 248mg of β -alaninamide hydrochloride, 551mg of potassium carbonate and 139. mu.l of triethylamine in 7ml of dimethylformamide at 140 ℃ for 3 hours. After work-up as in step 2 of example 31, 160mg of a mixture are obtained which is used as such in the subsequent step and contains about 40% of 2- (2-carbamoylethylamino) - [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile, which is characterized as follows:

LC/MS (method C): retention time 5.15 minutes.

Step 2: by the method as in example 2 step 4, but using 160mg of the compound obtained in the preceding step, 0.665m1 in 1N sodium hydroxide solution and 0.61ml of 30% aqueous hydrogen peroxide solution for 1 hour at ambient temperature in 4ml ethanol and 2ml dimethyl sulfoxide, purification by flash chromatography on 10g silica gives, after elution with a mixture of dichloromethane and methanol (97/3 vol), 34mg of 2- (2-formylaminoethyl) amino-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide, in the form of a white powder, which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 2.38(t, J ═ 6.6Hz, 2H)3.37(q, J ═ 6.4Hz, 2H)6.78(dd, J ═ 8.3, 1.7Hz, 1H)6.83(br.s., 1H)6.91(d, J ═ 1.7Hz, 1H)7.03(t, J ═ 7.6Hz, 1H)7.25(d, J ═ 7.8Hz, 1H)7.28(br.s., 1H)7.30(dd, J ═ 5.1, 3.2Hz, 1H)7.37 (width s, 1H)7.40(t, J ═ 8.2Hz, 1H)7.51(d, J ═ 8.3Hz, 1H)7.57-7.63 (m), 7.8 (t, J ═ 8.2Hz, 1H)7.51(d, J ═ 8.3, 1H) 7.7.7.63 (t, 7.8.8, 7.7.8H), 7.7.7.7.8 (d, 8.5H), 8H) 7.7.7.7.7.7.7.8 (d, 8H) 1H, 1H) 7.7.7.8 (d, 8(d, 8.7.7.7.7.8, 8H, 1H, 8H, 1H) 1H, 1H) 7.7.6H, 1H, 7.6H, 1H, 8H, 1.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.36; [ M + H ] + M/z 500; [ M + H ] -M/z 498.

Example 35: 2(R, S) - (1-hydroxypropan-2-yl) amino-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

300mg of 2-fluoro- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained in step 1 of example 31, 1.073g of DL-aminopropanol, 296mg of potassium carbonate and 3ml of dimethyl sulfoxide were introduced in succession into a 5ml special test tube (microwave tube) in a microwave reactor. The tube was then sealed and then heated in a microwave at 100 ℃ for 45 minutes. After cooling to ambient temperature, 7ml of ethanol, 1.357ml of 1N sodium hydroxide solution and 1.313ml of 30% aqueous hydrogen peroxide solution were added in succession, and the mixture was stirred at ambient temperature for 5 minutes. The reaction medium is poured into a mixture of 50ml of water and 50ml of ethyl acetate. The organic phase was separated by settling and the aqueous phase was back-extracted twice with 25ml ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography on 70g silica eluting with a mixture of dichloromethane and ethanol (95/5, vol). This gives 115mg in the form of a beige powder, which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 1.16(d, J ═ 6.1Hz, 3H)3.34-3.56(m, 3H)4.79(t, J ═ 4.9Hz, 1H)6.72(dd, J ═ 8.3, 1.7Hz, 1H)6.91(d, J ═ 1.7Hz, 1H)7.11-7.21(m, 2H)7.26 (width s, 1H)7.44-7.47(m, 2H)7.48-7.56(m, 1H)7.58-7.62(m, 2H)7.62-7.67(m, 1H)7.68-7.75(m, 1H)7.90(d, J ═ 8.6Hz, 1H)7.95 (width s, 1H)8.46(d, J ═ 6, 1H) 7.65 (J ═ 1H), 1H)7.6 (d, 13H) 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.80; [ M + H ] + M/z 494; [ M + H ] -M/z 492.

Example 36: (S) -2, 6-Diaminohexanoic acid 4-trans- { 2-carbamoyl-5- [4 (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of trifluoroacetate salt of phenylamino } cyclohexyl ester

Step 1: 534mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) carbazol-9-yl ] -2- (4-trans-hydroxycyclohexylamino) benzamide obtained in example 1 and 258.5mg of 2, 6-di-N, N' -tert-butoxycarbonyllysine were dissolved in 50ml of dichloromethane and 10ml of dimethylformamide under an argon atmosphere in a 250ml three-necked flask. 0.349ml of N, N-diisopropylethylamine, 244.3mg of 4-dimethylaminopyridine and 656mg of O- [ (ethoxycarbonyl) cyanomethyleneamino ] -N, N, N ', N' -tetramethylurea (TOTU) were added successively, and the mixture was stirred at ambient temperature for 20 hours. Then 258.5mg of 2, 6-di-N, N ' -tert-butoxycarbonyllysine, 0.349ml of N, N-diisopropylethylamine, 244.3mg of 4-dimethylaminopyridine and 656mg of O- [ (ethoxycarbonyl) cyanomethyleneamino ] -N, N, N ', N ' -tetramethylurea were added thereto, and the mixture was stirred at ambient temperature for another 20 hours. After work-up, purification by flash chromatography and crystallization, as in example 16, gave 725mg of 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] phenylamino } cyclohexyl (S) -2, 6-di-tert-butoxycarbonylaminocaproate, in the form of a beige powder, which was characterized as follows:

Mass Spectroscopy (LC/MS; method C): the retention time was 5.44 minutes.

Step 2: 687mg of the compound obtained in the preceding step were dissolved in 20ml of dichloromethane in a 50ml single-neck round-bottom flask. The resulting solution was cooled to 0 ℃ and then 10ml of trifluoroacetic acid was added and the mixture was stirred at 0 ℃ for 30 minutes and then at ambient temperature for 1 hour. The reaction medium is concentrated under reduced pressure. The residue was then taken up in 5ml of diisopropyl ether. After stirring for 30 minutes at 0 ℃, the precipitate formed was dried by rotary filtration, washed twice with 5ml of diisopropyl ether and dried in an oven under vacuum in the presence of potassium hydroxide fragments for 4 hours at 50 ℃. This gave 559mg of the trifluoroacetate salt of 4-trans- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) carbazol-9-yl ] phenylamino } cyclohexyl (S) -2, 6-diaminohexanoate, in the form of a pale beige powder, which was characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 1.19-1.60(m, 8H)1.68-1.77(m, 2H)1.88-1.97(m, 2H)2.01-2.10(m, 2H)2.31(s, 6H)2.65-2.77(m, 2H)3.43-3.48(m, 1H)3.91-4.00(m, 1H)4.80-4.91(m, 1H)6.74(d, J ═ 8.1Hz, 1H)6.90(s, 1H)7.20(t, J ═ 7.8Hz, 1H)7.31 (width s, 1H)7.41-7.51(m, 2H)7.52-7.70(m, 6H)7.76 (width s, 1H)7.94(d, J ═ 8.3, 1H) 7.02 (m, 2H) 7.58 (s, 1H) 7.26 (d, 8H) 2H) 7.26 (s, 26H) width.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.60; [ M + H ] + M/z 662; [ M + H ] -M/z 660.

Example 37: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- [3(R, S) hydroxybutylamino) benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 296mg of potassium carbonate and 1.273g of 4-aminobut-2 (R, S) -ol in 3ml of dimethyl sulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel eluting with a mixture of dichloromethane and ethanol (95/5 vol), thus giving 270mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [3(R, S) -hydroxybutylamino ] benzamide, in the form of a beige solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6,ppm): 1.08(d, J ═ 6.1Hz, 3H)1.57-1.71(m, 2H)3.13-3.24(m, 2H)3.66-3.77(m, 1H)4.49(d, J ═ 4.2Hz, 1H)6.74(d, J ═ 7.8Hz, 1H)6.85(s, 1H)7.10-7.23(m, 2H)7.28 (width s, 1H)7.41-7.79(m, 7H)7.92(d, J ═ 8.1Hz, 1H)7.98(br.s., 1H)8.44(br.s., 1H)8.62(d, J ═ 7.8Hz, 1H)13.08 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.81; [ M + H ] + M/z 508; [ M + H ] -M/z 506.

Example 38: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (3-methoxypropylamino) benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 296mg of potassium carbonate and 1.273g of 3-methoxypropylamine in 3ml of dimethyl sulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), to give 285mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (3-methoxypropylamino) benzamide as an off-white solid, which was characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 1.81 (quintuple, J ═ 6.4Hz, 2H)3.16-3.23(m, 5H)3.41(t, J ═ 6.2Hz, 2H)6.75(d, J ═ 8.3Hz, 1H)6.86(s, 1H)7.12-7.22(m, 2H)7.30 (width s, 1H)7.46(d, J ═ 3.9Hz, 1H)7.48-7.55(m, 1H)7.59-7.67(m, 4H)7.67-7.76(m, 1H)7.92(d, J ═ 8.3Hz, 1H)7.99 (width s, 1H)8.48(t, J ═ 5.3Hz, 1H)8.63(d, J ═ 7.8, 1H)13.08 (width s).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.35; [ M + H ] + M/z 508; [ M + H ] -M/z 506.

Example 39: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (4-hydroxybutan-3 (R, S) -ylamino) benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 296mg of potassium carbonate and 1.273g of 3(R, S) -aminopropanol in 3ml of dimethyl sulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by crystallization from 10ml of diisopropyl ether, thereby affording 165mg of 4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-hydroxybutane-3 (R, S) -ylamino) benzamide, in the form of a beige solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 1.18(d, J ═ 6.1Hz, 3H)1.54-1.79(m, 2H)3.46-3.52(m, 2H)3.62-3.71(m, 1H)4.42(t, J ═ 4.5Hz, 1H)6.72(d, J ═ 8.1Hz, 1H)6.89(s, 1H)7.11-7.21(m, 2H)7.28 (width s, 1H)7.47(d, J ═ 3.9Hz, 1H)7.49-7.56(m, 1H)7.59-7.67(m, 4H)7.67-7.76(m, 1H)7.91(d, J ═ 8.3Hz, 1H)7.97 (width s, 1H)8.43(d, J ═ 8.8, 8, 1H) 7.09 (d, 1H) 7.13H) 7.09 (d, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.28; [ M + H ] + M/z 508; [ M + H ] -M/z 506

Example 40: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (2(R, S) -hydroxypropylamino) benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 296mg of potassium carbonate and 1.073g of 1-amino-2 (R, S) -propanol in 3ml of dimethyl sulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 to 90/10 by volume), followed by crystallization from 10ml of diisopropyl ether, thus obtaining 180mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (2(R, S) -hydroxypropylamino) benzamide, in the form of a beige solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 1.11(d, J ═ 6.1Hz, 3H)2.96-3.17(m, 2H)3.79-3.89(m, 1H)4.78(d, J ═ 4.2Hz, 1H)6.73(d, J ═ 8.3Hz, 1H)6.88(s, 1H)7.10-7.22(m, 2H)7.26 (width s, 1H)7.46(d, J ═ 3.4Hz, 1H)7.47-7.56(m, 1H)7.57-7.67(m, 4H)7.67-7.76(m, 1H)7.91(d, J ═ 8.1Hz, 1H)7.96 (width s, 1H)8.55(t, J ═ 5.1Hz, 1H)8.63(d, J ═ 8.1H, 1H) width s.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.80; [ M + H ] + M/z 494; [ M + H ] -M/z 492.

EXAMPLE 41: 2- [ 1-hydroxybutan-3 (R, S) -ylamino]-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

Step 1: the process is carried out as in step 2 of example 31, but using 206mg of 2-fluoro- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained in step 1 of example 31, 177mg of 3(R, S) -aminobutane-1-ol and 551mg of potassium carbonate in 7ml of dimethylformamide at 140 ℃ for 3 hours. After work-up as in step 2 of example 31, followed by purification by silica gel chromatography eluting with a mixture of ethyl acetate and heptane (50/50 vol), 110mg of 2- [ 1-hydroxybutan-3 (R, S) -ylamino ] -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile were obtained, which were characterized as follows:

LC/MS (method C): retention time 5.46 minutes.

Step 2: by the method as in example 2 step 4, but using 110mg of the compound obtained in the preceding step, 0.456ml of 1N sodium hydroxide solution and 0.419ml of 30% aqueous hydrogen peroxide solution for 1 hour at ambient temperature in 2.8ml of ethanol and 1.2ml of dimethyl sulfoxide, purification by flash chromatography on 10g of silica gives, after elution with a mixture of ethyl acetate and heptane (90/10, vol), 33mg of 2- [ 1-hydroxybutane-3 (R, S) -ylamino ] -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide in the form of a white powder which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 1.19(d, J ═ 6.4Hz, 3H)1.55-1.79(m, 2H)3.45-3.53(m, 2H)3.62-3.71(m, 1H)4.42(t, J ═ 4.9Hz, 1H)6.74(dd, J ═ 8.3, 1.7Hz, 1H)6.91(s, 1H)7.02(t, J ═ 7.5Hz, 1H)7.25(d, J ═ 8.1Hz, 1H)7.27 (width s, 1H)7.30(dd, J ═ 6.5, 1.6Hz, 1H)7.40(t, J ═ 7.6Hz, 1H)7.49(d, J ═ 8.3Hz, 1H)7.55-7.63, 7.8H (t, 7.8H) 7.8 (d, 8.3H), 7.8H) 7.8 (d, 8.8H), 8H) 7.8.8 (d, 8.3, 8H) 7.8 (d, 1H) 7.8.8 (1H), 1H)7.8 (d, 8.8.8, 8.8, 1H) 1H, 1H) 7.8.8 (d, 1H) 1H, 1H) 7.8.8.8, 1H) 7.8.8 (d, 1H)7.8, 1H) 1H, 1.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.03; [ M + H ] + M/z 501; [ M + H ] -M/z 499

Example 42: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (2-hydroxyethylamino) benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 296mg of potassium carbonate and 0.872g of 2-aminoethanol in 3ml of dimethyl sulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 to 90/10 by volume), followed by crystallization from 10ml of diisopropyl ether, thereby yielding 180mg of 4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] -2- (2-hydroxyethylamino) benzamide in the form of an off-white solid characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 3.18-3.50(m, 2H)3.60 (width s, 2H)4.78 (width s, 1H)6.75(d, J ═ 8.1Hz, 1H)6.89(s, 1H)7.09-7.23(m, 2H)7.27 (width s, 1H)7.40-7.55(m, 2H)7.57-7.78(m, 5H)7.91(d, J ═ 8.3Hz, 1H)7.97 (width s, 1H)8.51(s, 1H)8.63(d, J ═ 7.6Hz, 1H)13.09 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.76; [ M + H ] + M/z 480; [ M + H ] -M/z 478

Example 43: 2- (2-dimethylaminoethylamino) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 296mg of potassium carbonate and 1.259g of N, N-dimethylethylenediamine in 3ml of dimethylsulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ammonia in 7M solution in methanol (from 95/5 to 90/10 by volume), followed by crystallization from 10ml of diisopropyl ether, whereby 200mg of 2- (2-dimethylaminoethylamino) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide were obtained in the form of a beige solid, which was characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 2.18(s, 6H)3.15-3.22(m, 2H)3.30 (mask, 2H)6.75(d, J ═ 8.6Hz, 1H)6.85(s, 1H)7.10-7.21(m, 2H)7.25 (width s, 1H)7.42-7.55(m, 2H)7.57-7.77(m, 5H)7.90(d, J ═ 8.6Hz, 1H)7.96 (width s, 1H)8.42 (width s, 1H)8.62(d, J ═ 8.1Hz, 1H)13.09 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.62; [ M + H ] + M/z 507; [ M + H ] -M/z 505.

Example 44: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (methylcarbamoylmethylamino) benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 296mg of potassium carbonate, 1g of N-methylglycine hydrochloride and 820mg of triethylamine in 3ml of dimethyl sulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ammonia in 7M solution in methanol (from 95/5 to 90/10 by volume), followed by crystallization from 5ml of ethyl acetate, thus obtaining 55mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (methylcarbamoylmethylamino) benzamide, in the form of a beige solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 2.63(d, J ═ 4.4Hz, 3H)3.81(d, J ═ 5.6Hz, 2H)6.66(d, J ═ 1.5Hz, 1H)6.84(dd, J ═ 8.3, 1.5Hz, 1H)7.12-7.22(m, 2H)7.31-7.39(m, 1H)7.42-7.50(m, 3H)7.55-7.78(m, 4H)7.87-7.92(m, 1H)7.94(d, J ═ 8.6Hz, 1H)8.01 (width s, 1H)8.59(d, J ═ 8.1Hz, 1H)8.70(t, J ═ 5.5Hz, 1H)13.08 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.19; [ M + H ] + M/z 507; [ M + H ] -M/z 505.

Example 45: 2- [2- (1-Oxopyrrolidin-1-yl) ethylamino]-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

Step 1: the process is carried out as in step 2 of example 31, but using 230mg of 2-fluoro- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained in step 1 of example 31, 254mg of N- (2-aminoethyl) pyrrolidine and 615mg of potassium carbonate in 7ml of dimethylformamide at 140 ℃ for 3 hours. After work-up as in step 2 of example 31, 273mg of a mixture containing predominantly 2- [2- (pyrrolidin-1-yl) ethylamino ] -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile are obtained, which is used as such in the subsequent steps and is characterized as follows:

LC/MS (method C): retention time 3.98 minutes.

Step 2: by the method as in example 2 step 4, but using 273mg of the compound obtained in the preceding step, 1.076ml of 1N sodium hydroxide solution and 0.998ml of 30% aqueous hydrogen peroxide solution for 1 hour at ambient temperature in 2.8ml of ethanol and 1.2ml of dimethyl sulfoxide, purification by flash chromatography on 10g of silica gives, after elution with a mixture of dichloromethane, methanol and 5M aqueous ammonia solution (90/10/1, vol), 126mg of 2- [2- (1-oxypyrrolidin-1-yl) ethylamino ] -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide, in the form of a pale beige powder, which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 1.76-1.85(m, 2H)2.07-2.17(m, 2H)3.11-3.19(m, 2H)3.30 (width s, 2H)3.43(t, J ═ 6.2Hz, 2H)3.78(q, J ═ 5.8Hz, 2H)6.79(dd, J ═ 8.3, 1.7Hz, 1H)7.02(t, J ═ 7.5Hz, 1H)7.09(d, J ═ 1.7Hz, 1H)7.24(d, J ═ 8.1Hz, 1H)7.27-7.32(m, 1H)7.34 (width s, 1H)7.39(t, J ═ 7.3, 1H)7.50(d, J ═ 8.3, 7.7, 1H)7.3, 7.7.3, 1H)7.3, 7.7, 7.7.3, 7H, 7.3, 7H, 7.7H, 7.3, 7H, 7.3, 7H, 3, 7H, 1H, 7H, 3, 7H, 3, 1H) in that respect

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.84; [ M + H ] + M/z 542; [ M + H ] -M/z 541.

Example 46: 2- (2-ethoxyethylamino) -4- [4- (6-fluoro-1H-benzimidazole-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 296mg of potassium carbonate and 1.273g of 2-ethoxyethylamine in 3ml of dimethyl sulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (from 95/5 to 90/10 by volume), followed by crystallization from 5ml of ethyl acetate, thus obtaining 205mg of 2- (2-ethoxyethylamino) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide, in the form of a beige solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d6, δ ppm): 1.12(t, J ═ 7.1Hz, 3H)3.30-3.33(m, 2H)3.48(q, J ═ 6.8Hz, 2H)3.58(t, J ═ 5.4Hz, 2H)6.76(dd, J ═ 8.2, 1.8Hz, 1H)6.90(d, J ═ 1.7Hz, 1H)7.11-7.21(m, 2H)7.29 (width s, 1H)7.41-7.55(m, 3H)7.56-7.81(m, 4H)7.92(d, J ═ 8.3Hz, 1H)7.98 (width s, 1H)8.55(t, J ═ 5.4, 1H)8.62(d, J ═ 7.6, 1H)13.08 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.37; [ M + H ] + M/z 508; [ M + H ] -M/z 506.

Example 47: 2- (2-carbamoylethylamino) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 296mg of potassium carbonate, 1.779g of β -alanine amide hydrochloride and 1.445g of triethylamine in 3ml of dimethyl sulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (from 95/5 to 90/10 by volume), followed by crystallization from 10ml of diisopropyl ether, thereby obtaining 200mg of 2- (2-carbamoylethylamino) -4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzamide, in the form of a beige solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 2.38(t, J ═ 6.6Hz, 2H)3.36(q, J ═ 6.3Hz, 2H)6.76(dd, J ═ 8.3, 1.5Hz, 1H)6.82 (width s, 1H)6.89(d, J ═ 1.5Hz, 1H)7.12-7.22(m, 2H)7.27 (width s, 1H)7.36 (width s, 1H)7.43-7.54(m, 3H)7.54-7.81(m, 4H)7.92(d, J ═ 8.3Hz, 1H)7.97 (width s, 1H)8.44(t, J ═ 5.5Hz, 1H)8.61(d, J ═ 7.8, 1H)13.07 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.72; [ M + H ] + M/z 507; [ M + H ] -M/z 505.

Example 48: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [ (furan-2-ylmethyl) amino group]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 296mg of potassium carbonate and 1.387g of furfurylamine in 3ml of dimethyl sulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (96/4 vol), followed by crystallization from 10ml of diisopropyl ether, thereby yielding 160mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [ (furan-2-ylmethyl) amino ] benzamide, in the form of an off-white solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 4.46(d, J ═ 5.9Hz, 2H)6.29(d, J ═ 3.2Hz, 1H)6.45-6.50(m, 1H)6.81(dd, J ═ 8.2, 1.8Hz, 1H)7.00(d, J ═ 1.7Hz, 1H)7.11-7.22(m, 2H)7.34-7.79(m, 9H)7.94(d, J ═ 8.6Hz, 1H)8.03(br.s., 1H)8.59(d, J ═ 8.1Hz, 1H)8.82(t, J ═ 5.9Hz, 1H)13.07 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.96; [ M + H ] + M/z 516; [ M + H ] -M/z 514.

Example 49: 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (4-trans-hydroxycyclohexyl) amino]Synthesis of benzamide

Step 1: 0.63g of 2-methylpropan-2-yl 4-bromo-2-fluorobenzoate, 1.88g of cesium carbonate, 0.11g of (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphine) and 0.03g of palladium acetate are added in succession under argon to 0.41g of 5- (9H-carbazol-4-yl) pyridine-2-carbonitrile obtained in step 1 of example 28 in 20ml of bis (diphenylphosphine)In an alkane. The reaction mixture was refluxed for 4.5 hours, cooled to ambient temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (90/10 vol.)Elution was carried out, whereby 0.48g of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]2-methylpropan-2-yl 2-fluorobenzoate, in the form of a light brown oil, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.60(s, 9H)7.15(t, J ═ 7.8Hz, 1H)7.27(dd, J ═ 6.9, 1.2Hz, 1H)7.31(d, J ═ 7.8Hz, 1H)7.45(t, J ═ 7.8Hz, 1H)7.52(d, J ═ 7.8Hz, 1H)7.56-7.65(m, 3H)7.74(dd, J ═ 11.4, 1.7Hz, 1H)8.13(t, J ═ 8.3Hz, 1H)8.29(d, J ═ 8.1Hz, 1H)8.34(dd, J ═ 8.1, 2.2Hz, 1H)9.02(d, J ═ 2.2, 1H)

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 5.81; m/z 464[ M + H ] +.

Step 2: 0.3g of potassium carbonate and 1.68g of 4-trans-aminocyclohexanol are added in succession to a solution of 0.34g of 2-methylpropan-2-yl 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2-fluorobenzoate in 6ml of dimethyl sulphoxide. The reaction mixture was heated in a microwave at 90 ℃ for 2 hours and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (75/25 vol) to give 0.15g of 2-methylpropan-2-yl 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2- [ (trans-4-hydroxycyclohexyl) amino ] benzoate as a white solid, which was characterised as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.20-1.35(m, 4H)1.55-1.85(m, 3H)1.59(s, 9H)2.01(m, 1H)3.30-3.52(m, 2H)4.50(d, J ═ 4.3Hz, 1H)6.75(dd, J ═ 8.5, 2.2Hz, 1H)6.99(d, J ═ 2.2Hz, 1H)7.11(ddd, J ═ 8.2, 6.9, 2.2, 1H)7.23(dd, J ═ 6.9, 2.2Hz, 1H)7.31(d, J ═ 8.3Hz, 1H)7.40-7.48(m, 2H)7.52-7.61(m, 2H)7.85(dd, J ═ 8.3Hz, 1H) 7.8.8, 8.5 (d, J ═ 8.9, 1H) 7.9, 1H (dd, 8.5, 8.9, 1H) 7.9 (dd, 1H) 7.5 (d, 1H).

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 5.95; m/z 559[ M + H ] +.

And step 3: 1.5ml of 1N hydrochloric acid are added to 0.14g of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (4-trans-hydroxycyclohexyl) amino]Benzoic acid 2-methylpropan-2-yl ester in 5ml diIn an alkane. The reaction mixture was heated in a microwave at 100 ℃ for 1 hour 50 minutes and then concentrated under reduced pressure. The residue was triturated with diisopropyl ether and the solid formed was filtered off to give 100mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (4-trans-hydroxycyclohexyl) amino]Benzoic acid, in the form of a white solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.27(m, 4H)1.79(m, 2H)2.01(m, 2H)3.39(m, 1H)3.48(m, 1H)4.48(d, J ═ 4.3Hz, 1H)6.72 (wide d, J ═ 8.3Hz, 1H)6.94 (wide s, 1H)7.11(m, 1H)7.23(m, 1H)7.32(d, J ═ 8.0Hz, 1H)7.40-7.50(m, 2H)7.53-7.61(m, 2H)8.07(d, J ═ 8.3Hz, 1H)8.19 (wide m, 1H)8.29(d, J ═ 8.2Hz, 1H)8.35(dd, J ═ 8.2, 1H) 8.4, 1H) 8.03 (d, 1H) 8.79 (d, 1H)8.2, 1H, and 1H)

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 4.56; m/z 503[ M + H ] +; 501[ M + H ] -.

And 4, step 4: 132mg of (1H-benzotriazol-1-yloxy) [ tris (dimethylamino)]Hexafluorophosphate (BOP), 40mg of Hydroxybenzotriazole (HOBT), 21mg of ammonium chloride and 0.13ml of diisopropylethylamine were added in that order to 100mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (4-trans-hydroxycyclohexyl) amino]Benzoic acid in 10ml of N, N-dimethylformamide. The reaction mixture was stirred at ambient temperature for 4.5 hours, then diluted with distilled water and extracted with ethyl acetate. The organic phase is then washed with distilled water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. Passing the residue through siliconPurification by gel chromatography eluting with a mixture of dichloromethane, acetonitrile and methanol (96/2/2 vol) and trituration in diisopropyl ether afforded 35mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (4-trans-hydroxycyclohexyl) amino]Benzamide, in the form of a white solid, characterized as follows:

melting point (Buchi melting point B-545) ═ 274 ℃.

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.24(m, 4H)1.78(m, 2H)1.98(m, 2H)3.30(m partial mask, 1H)3.46(m, 1H)4.48(d, J ═ 4.2Hz, 1H)6.69(dd, J ═ 8.6, 1.9Hz, 1H)6.88(d, J ═ 1.9Hz, 1H)7.11(m, 1H)7.23(d, J ═ 7.0Hz, 1H)7.27 (width m, 1H)7.32(d, J ═ 8.2Hz, 1H)7.44(m, 2H)7.51-7.61(m, 2H)7.90(d, J ═ 8.4Hz, 1H)7.97 (width m, 1H)8.29(d, J ═ 8.29, 1H) 7.35 (d, J ═ 8.7.7, 8H) 7.7.0 Hz, 1H) 7.7.45 (d, 1H) 7.7.7.9, 1H)7.9 (d, 1H) 7.9H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.99; m/z 502[ M + H ] +; 500[ M-H ] -.

Example 50: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [ (furan-3-ylmethyl) amino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 296mg of potassium carbonate and 1.387g of 3-furylmethylamine in 3ml of dimethyl sulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (96/4 vol), followed by crystallization from 5ml of ethyl acetate, thus obtaining 220mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [ (furan-3-ylmethyl) amino ] benzamide, in the form of an off-white solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 4.27(d, J ═ 5.4Hz, 2H)6.48(s, 1H)6.79(d, J ═ 8.1Hz, 1H)6.91(s, 1H)7.10-7.21(m, 2H)7.29-7.76(m, 10H)7.93(d, J ═ 8.3Hz, 1H)8.01 (width s, 1H)8.59(d, J ═ 7.8Hz, 1H)8.70(t, J ═ 5.3Hz, 1H)13.09 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.95; 516[ M + H ] +; 514[ M-H ] -.

Example 51: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [ (2H-pyrazol-3-ylmethyl) amino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 296mg of potassium carbonate and 1.387g of 2H-pyrazol-3-ylmethylamine in 3ml of dimethyl sulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by crystallization from 2ml of ethyl acetate, thus obtaining 50mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [ (2H-pyrazol-3-ylmethyl) amino ] benzamide, in the form of a beige solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 4.38 (width s, 2H)6.19(s, 1H)6.77(d, J ═ 6.1Hz, 1H)6.95(s, 1H)7.11-7.22(m, 2H)7.28-8.10(m, 11H)8.55(s, 1H)8.80(t, J ═ 5.5Hz, 1H)12.63 (width s, 1H)13.07 (d, J ═ 6.1Hz, 1H)6.77 (m, J ═ 7.11H) 8.55(s, 1H)8.80(t, J ═ 5.5Hz Width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.78; 516[ M + H ] +; 514[ M-H ] -.

Examples 52 and 53: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- (2-hydroxy-1-hydroxymethylethylamino) benzamide and 2- (2-amino-1-hydroxymethylethyloxy) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 296mg of potassium carbonate and 1.301g of 2-amino-1, 3-propanediol in 3ml of dimethyl sulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. The reaction medium is treated as in step 3 of example 3. The resulting residue was purified by preparative HPLC on a Whelk 01SS chiral column (10 μ M, 250x 4.6mm), eluting with a mobile phase containing a mixture of heptane, ethanol, methanol and triethylamine (30/60/10/0.1, volume).

By concentrating the first eluted fraction (retention time ═ 4.19 minutes), 18.1mg of 4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] -2- (2-hydroxy-1-hydroxymethylethylamino) benzamide, example 52, are obtained in the form of a white foam, which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆+TFA，δppm)：3.39-3.45(m，1H)3.49-3.58(m，4H)6.74(dd，J＝8.1，1.7Hz，1H)7.00(d，J＝1.7Hz，1H)7.23(ddd，J＝8.1，5.7，2.3Hz，1H)7.51-7.59(m，3H)7.66(d，J＝8.1Hz，1H)7.72-7.77(m，2H)7.81-7.87(m，2H)7.91(d，J＝8.3Hz，1H)8.01(dd，J＝8.8，4.4Hz，1H)。

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 3.22; m/z 510[ M + H ] +; 508[ M-H ] -.

By concentrating the second eluted fraction (retention time ═ 9.36 min), 45.3mg of 2- (2-amino-1-hydroxymethylethyloxy) -4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzamide, example 53, in the form of a white foam, was obtained, which was characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.94 (width s, 2H)3.06-3.17(m, 1H)3.39-3.50(m, 2H)4.05(dd, J-10, 5Hz, 1H)4.20(dd, J-10, 5Hz, 1H)4.71(t, J-5.3 Hz, 1H)7.08-7.26(m, 2H)7.31(dd, J-8.2, 1.8Hz, 1H)7.36-7.44(m, 2H)7.44-7.52(m, 2H)7.57-7.70(m, 4H)7.79-7.90(m, 1H)8.12(d, J-8.1 Hz, 1H)8.17 (width s, 1H)8.65(dd, J-9.19, 1H) 8.09 (width s, 1H)8.65(dd, J-9.19, 1H) 13H).

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 2.77; m/z 510[ M + H ] +; 508[ M-H ] -.

Example 54: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) carbazol-9-yl]-2- [3(S) -methoxypropylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 3, 296mg of potassium carbonate and 1.273g of 1-methoxy-2 (S) -propylamine in 3ml of dimethyl sulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. The reaction medium is treated as in step 2 of example 3. The resulting residue was purified by preparative HPLC on a Chiralpak AD silica column (20 μm, 250 × 4.6mm), eluting with a mixture of heptane, ethanol and trifluoroacetic acid (80/20/0.1, volume). This gave 155mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) carbazol-9-yl ] -2- [3(S) -methoxypropylamino ] benzamide, in the form of a white foam, which was characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆+TFA，δppm)：1.18(d，J＝6.4Hz，3H)3.29(s，3H)3.37-3.41(m，2H)3.68-3.78(m，1H)6.76(dd，J＝8.2，1.8Hz，1H)6.94(d，J＝1.5Hz，1H)7.10-7.24(m，2H)7.42-7.50(m，3H)7.57-7.68(m，4H)7.92(d，J＝8.3Hz，1H)8.57(d，J＝7.6Hz，1H)。

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.93; m/z 508[ M + H ] +; 506[ M-H ] -.

Example 55: 4- [4- (2-aminopyrimidin-5-yl) -9H-carbazol-9-yl]-2- [ (4-trans-hydroxycyclohexyl) amino]Synthesis of benzamide hydrochloride

Step 1: 2.72g (12.4mmol) of di-tert-butyl dicarbonate and 6.6mg (0.54mmol) of 4-dimethylaminopyridine are added in succession to a solution of 1.2g of 2-amino- [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine in 50ml of dichloromethane. The reaction mixture was stirred at ambient temperature for 15 hours, poured into distilled water and then extracted with dichloromethane. The organic phase is then washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with diisopropyl ether to give 1.7g of bis (2-methylpropan-2-yl) bis [5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidin-2-yl ] iminodicarbonate as a white solid characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.32(s, 12H)1.40(s, 18H)8.93(s, 2H).

-mass spectrometry spectrum (EI): m/z 421(M +).

Step 2: 1.7g of [5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidin-2-yl radical obtained in the preceding step]Dicarbamic acid 2-methylpropan-2-yl ester, 3.72g cesium carbonate and 100mg 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (as complex with dichloromethane (1/1) [ PdCl₂(dppf).CH₂Cl₂]) 0.96g of 4-trifluoromethanesulfonyloxycarbazole obtained in step 1 of example 1 in 36ml of bis (methylene chloride) was added in succession under argonAlkane and 12ml water. The reaction mixture was refluxed for 4 hours, cooled to ambient temperature, filtered through celite, and concentrated under reduced pressure. The brown residue was purified by chromatography on silica eluting with a mixture of cyclohexane and ethyl acetate (85/15, vol). This gives 0.56g of [5- (9H-carbazol-4-yl) pyrimidin-2-yl]2-methylpropan-2-yl dicarbamate, in the form of a white solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.46(s, 18H)6.92(m, 1H)7.14(d, J ═ 7.4Hz, 1H)7.21(d, J ═ 8.1Hz, 1H)7.39(m, 1H)7.49-7.57(m, 2H)7.64(dd, J ═ 8.1, 1.0Hz, 1H)9.11(s, 2H)11.62 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.16; m/z 461[ M + H ] +; 459[ M-H ] -.

And step 3: 0.325g of 4-bromo-2-fluorobenzonitrile, 1.3g of cesium carbonate, 75mg of (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphine) and 24mg of palladium acetate are added in this order to 0.5g of [5- (9H-carbazol-4-yl) pyrimidin-2-yl ] under an argon atmosphere]2-methylpropan-2-yl dicarbamate in 30ml diIn an alkane. The reaction mixture was refluxed for 6 hours, cooled to ambient temperature, filtered through celite, and concentrated under reduced pressure. The residue is purified by chromatography on silica gel using cyclohexane and ethyl acetate: (80/20, volume) was eluted. This gave 0.51g of {5- [9- (4-cyano-3-fluorophenyl) -9H-carbazol-4-yl group]2-methylpropan-2-yl pyrimidin-2-yl dicarbamate, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.47(s, 18H)7.10(m, 1H)7.23(d, J ═ 8.0Hz, 1H)7.34(dd, J ═ 7.2, 1.1Hz, 1H)7.48(m, 1H)7.55-7.69(m, 3H)7.78(dd, J ═ 8.3, 2.0Hz, 1H)8.02(dd, J ═ 10.2, 2.0Hz, 1H)8.27(t, J ═ 8.0Hz, 1H)9.15(s, 2H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.26; m/z 580[ M + H ] +.

And 4, step 4: 0.18g of potassium carbonate and 1.01g of 4-trans-aminocyclohexanol are added in succession to a solution of 0.25g of 2-methylpropan-2-yl { {5- [9- (4-cyano-3-fluorophenyl) -9H-carbazol-4-yl ] pyrimidin-2-yl } dicarbamate in 6ml of dimethyl sulfoxide. The reaction mixture was heated in a microwave at 90 ℃ for 1 hour 15 minutes, then 4.5ml of ethanol were added, followed by 0.86ml of 1N sodium hydroxide solution and 0.86ml of 30% aqueous hydrogen peroxide solution. The reaction mixture was stirred at ambient temperature for 1 hour and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with a mixture of dichloromethane, acetonitrile and methanol (92/4/4, vol). This gives 0.1g of 2-methylpropan-2-yl [5- (9- { 4-carbamoyl-3- [ (4-trans-hydroxycyclohexyl) amino ] phenyl } -9H-carbazol-4-yl) pyrimidin-2-yl ] carbamate in the form of a white solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.24(m, 4H)1.52(s, 9H)1.78(m, 2H)1.99(m, 2H)3.30 (mask m, 1H)3.46(m, 1H)4.47(d, J ═ 4.6Hz, 1H)6.69(dd, J ═ 8.3, 2.0Hz, 1H)6.87(d, J ═ 2.0Hz, 1H)7.14(m, 1H)7.20(dd, J ═ 7.1, 1.0Hz, 1H)7.26 (width m, 1H)7.41-7.45(m, ddh) 7.4 (J ═ 8.6, 1.0Hz, 1H)7.55(dd, J ═ 8.6, 7.1, 1H)7.89(d, J ═ 8.6, 1H)7.95 (d, 8.6, 8H) 1, 8H (1H) 7.86 (d, 8H) 1, 8(d, 8.6, 8H) 1, 8 (H) 1, 8, 1H) 8(d, 1H)8, 8H) 1H (H) 1H)7.6, 1H)6, 1H.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.00; m/z 593[ M + H ] +.

And 5: 0.32ml of 1N hydrochloric acid was added to 0.1g (0.17mmol) of [5- (9- { 4-carbamoyl-3- [ (4-trans-hydroxycyclohexyl) amino group ]]Phenyl } -9H-carbazol-4-yl) pyrimidin-2-yl]2-methylpropan-2-yl carbamate in 1.3ml diIn an alkane. The reaction mixture was heated in a microwave at 100 ℃ for 15 minutes and then concentrated under reduced pressure. The residue was triturated with diisopropyl ether and the solid formed was filtered off to give 87mg of 4- [4- (2-aminopyrimidin-5-yl) -9H-carbazol-9-yl]-2- [ (4-trans-hydroxycyclohexyl) amino]Benzamide hydrochloride, in the form of a white solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.24(m, 4H)1.78(m, 2H)1.98(m, 2H)3.33(m, 1H)3.50 (mask m, 1H)6.68(dd, J ═ 8.5, 2.0Hz, 1H)6.86(d, J ═ 2.0Hz, 1H)7.13-7.19m, 2H)7.27 (width m, 1H)7.41-7.46(m, 2H)7.51(t, J ═ 8.0Hz, 1H)7.61(d, J ═ 8.0Hz, 1H)7.89(d, J ═ 8.5Hz, 1H)7.96 (width m, 1H)8.60(s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.73; 493[ M + H ] +, M/z.

Example 56: 4- [4- (2-aminopyrimidin-5-yl) -9H-carbazol-9-yl]-2- [ (3-hydroxypropyl) amino]Synthesis of benzamide hydrochloride

Step 1: 0.18g of potassium carbonate and 0.64g of 3-amino-1-propanol were successively added to a solution of 0.25g of 2-methylpropan-2-yl { {5- [9- (4-cyano-3-fluorophenyl) -9H-carbazol-4-yl ] pyrimidin-2-yl } dicarbamate obtained in step 3 of example 55 in 6ml of dimethyl sulfoxide. The reaction mixture was heated in a microwave at 90 ℃ for 1 hour 15 minutes, then 4.5ml of ethanol were added, followed by 0.86ml of 1N sodium hydroxide solution and 0.86ml of 30% aqueous hydrogen peroxide solution. The reaction mixture was stirred at ambient temperature for 1 hour and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with a mixture of dichloromethane, acetonitrile and methanol (92/4/4, vol). This gives 0.15g of 2-methylpropan-2-yl [5- (9- { 4-carbamoyl-3- [ (3-hydroxypropyl) amino ] phenyl } -9H-carbazol-4-yl) pyrimidin-2-yl ] dicarbamate in the form of a white solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.52(s, 9H)1.72(m, 2H)3.18(m, 2H)3.49(m, 2H)4.48(t, J ═ 5.1Hz, 1H)6.73(dd, J ═ 8.4, 2.1Hz, 1H)6.84(d, J ═ 2.1Hz, 1H)7.14(m, 1H)7.20(m, 1H)7.27 (width m, 1H)7.39-7.58(m, 5H)7.91(d, J ═ 8.5Hz, 1H)7.98 (width m, 1H)8.44(t, J ═ 5.7Hz, 1H)8.86(s, 2H)10.29 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.11; m/z is 553[ M + H ] +.

Step 2: 0.51ml of 1N hydrochloric acid was added to 0.15g of [5- (9- { 4-carbamoyl-3- [ (3-hydroxypropyl) amino ] chloride]Phenyl } -9H-carbazol-4-yl) pyrimidin-2-yl]2-methylpropan-2-yl dicarbamate in 2mlIn an alkane. The reaction mixture was heated in a microwave at 100 ℃ for 15 minutes and then concentrated under reduced pressure. The residue was triturated with diisopropyl ether and the solid formed was filtered off to give 130mg of 4- [4- (2-aminopyrimidin-5-yl) -9H-carbazol-9-yl]-2- [ (3-hydroxypropyl) amino]Benzamide hydrochloride, in the form of a white solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.72(m, 2H)3.18(t, J ═ 6.9Hz, 2H)3.50 (mask m, 2H)6.73(dd, J ═ 8.3, 2.0Hz, 1H)6.83(d, J ═ 2.0Hz, 1H)7.11-7.20(m, 2H)7.29 (width m, 1H)7.38-7.56(m, 4H)7.60(d, J ═ 8.1Hz, 1H)7.91(d, J ═ 8.4Hz, 1H)7.98 (width m, 1H)8.58(s, 2H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.70; m/z 453[ M + H ] +.

Example 57: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [ (1H-imidazol-4-yl) methylamino]Synthesis of benzamide

Step 1: the process was carried out as in step 2 of example 31 but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained in step 3 of example 3, 121.4mg of (1H-imidazol-4-yl) methylamine hydrochloride, 789mg of potassium carbonate and 289mg of triethylamine in 7ml of dimethylformamide at 140 ℃ for 3 hours. After work-up as in step 2 of example 31, 421mg of a mixture which is used as such in the subsequent steps and which contains predominantly 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [ (1H-imidazol-4-yl) methylamino ] benzonitrile are obtained, which are characterized as follows:

LC/MS (method C): retention time 3.23 min.

Step 2: by the method as in step 4 of example 2, but using 421mg of the compound obtained in the preceding step, 1.816ml of 1N sodium hydroxide solution and 1.668ml of 30% aqueous hydrogen peroxide solution, held at ambient temperature for 10 minutes in 10ml of ethanol and 4ml of dimethyl sulfoxide, purification by flash chromatography on 15g silica eluting with a mixture of dichloromethane, methanol and 5M aqueous ammonia (80/20/1 then 75/25/1 vol) gave 33mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [ (1H-imidazol-4-yl) methylamino ] benzamide as a beige powder characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 3.64(s, 2H)7.13(t, J ═ 10.8Hz, 1H)7.19-7.25(m, 1H)7.32(s, 1H)7.43-7.89(m, 14H)8.03 (width s, 1H)8.72(d, J ═ 8.1Hz, 1H).

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 2.70; 516[ M + H ] +; m/z 514[ M-H ] -.

Example 58:3- (4-trans-hydroxycyclohexylamino) -5- [ (4-quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of pyridine-2-carboxamides

Step 1: in a 20ml round-bottom flask, 60mg of sodium hydride (60%, dispersed in oil) were added in small portions to a mixture of 500mg of 4- (quinolin-3-yl) -9H-carbazole obtained according to step 1 of example 2 and 262mg of 2-cyano-3, 5-difluoropyridine dissolved in 6ml of anhydrous dimethylformamide under an argon atmosphere. The reaction medium is stirred continuously for 3 hours at ambient temperature, then 262mg of 2-cyano-3, 5-difluoropyridine and 60mg of sodium hydride (60%, dispersed in oil) are added. The reaction medium is stirred at ambient temperature under argon overnight and then poured into distilled water containing a small amount of sodium chloride. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (15-40 μm) eluting with a gradient of dichloromethane and diisopropyl ether (from 99/1 to 90/10 by volume). 483mg of a mixture of positional isomers are obtained, which is separated by chromatography on silica gel (15-40 μm), eluting with a gradient of ethyl acetate and heptane (90/10 to 80/20, vol.). 129mg of 3-fluoro-5- [ (4-quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-2-carbonitrile were obtained in the form of a white solid, which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 7.11(t, J ═ 7.3Hz, 1H); 7.25(d, J ═ 7.8Hz, 1H); 7.39(d, J ═ 6.6Hz, 1H); 7.44(t, J ═ 8.2Hz, 1H); 7.61(d, J ═ 7.6Hz, 1H); 7.65(d, J ═ 7.3Hz, 1H); 7.70(d, J ═ 8.3Hz, 1H); 7.74(t, J ═ 7.5Hz, 1H); 7.89(t, J ═ 8.3Hz, 1H); 8.14(d, J ═ 7.8Hz, 1H); 8.19(d, J ═ 8.6Hz, 1H); 8.63(d, J ═ 2.0Hz, 1H); 8.70(dd, J ═ 9.8 and 2.0Hz, 1H); 9.07(s, 1H); 9.13(d, J ═ 2.2Hz, 1H).

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 1.16; [ M + H ]]₊＝415。

251mg of the isomer of 5-fluoro-3- [ (4-quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-2-carbonitrile were also obtained.

Step 2: 127mg of 3-fluoro-5- (4-quinolin-3-yl-carbazol-9-yl) pyridine-2-carbonitrile obtained according to the preceding step, 706mg of 4-trans-aminocyclohexanol, 127mg of potassium carbonate and 1.5ml of dimethyl sulfoxide were introduced in succession into a 2ml microwave reactor. After stirring for 30 seconds at ambient temperature, the reaction medium is heated with stirring for 45 minutes at 100 ℃. After cooling, the mixture was transferred to a 25ml round-bottom flask and 3ml ethanol, and 0.58ml of 1N sodium hydroxide and 0.57ml of 30% aqueous hydrogen peroxide solution were added successively at ambient temperature under argon atmosphere. After stirring for 30 minutes at ambient temperature, the reaction medium is poured into distilled water and the aqueous phase is extracted 3 times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (15-40 μm) eluting with a gradient of dichloromethane and methanol (from 99/1 to 95/5, vol.). After combining and evaporating the advantageous fractions, the solid is formed into a paste (paste) in diisopropyl ether, filtered, washed with pentane and dried in vacuo. 81mg of 3- (4-trans-hydroxycyclohexylamino) -5- [ 4-quinolin-3-yl ] -9H-carbazol-9-yl ] pyridine-2-carboxamide are obtained in the form of an off-white solid which is characterized in that:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.21-1.36(m, 4H); 1.75-1.84(m, 2H); 1.97-2.04(m, 2H); 3.44-3.53(m, 2H); 4.51 (width s, 1H); 7.05(t, J ═ 8.1Hz, 1H); 7.26(d, J ═ 8.1Hz, 1H); 7.33(d, J ═ 7.1Hz, 1H); 7.39-7.47(m, 2H); 7.50-7.57(m, 3H); 7.58-7.65(m, 1H); 7.74(t, J ═ 7.5Hz, 1H); 7.89(t, J ═ 8.1Hz, 1H); 7.99(d, J ═ 1.7Hz, 1H); 8.11-8.16(m, 2H); 8.19(d, J ═ 8.3Hz, 1H); 8.62(d, J ═ 1.7Hz, 1H); 8.74(d, J ═ 8.1Hz, 1H); 9.15(d, J ═ 2.2Hz, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.07; [ M + H ]]₊＝528。

Example 59: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (tetrahydropyran-4-ylamino) benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 296mg of potassium carbonate and 1.444g of 4-aminotetrahydropyran in 3ml of dimethyl sulfoxide. Then 1.357ml of 1M aqueous sodium hydroxide solution, 1.313ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (97/3 vol), followed by crystallization from 2ml of ethyl acetate, thus obtaining 150mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (tetrahydropyran-4-ylamino) benzamide, in the form of an off-white solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.35-1.50(m, 2H)1.89-1.97(m, 2H)3.36-3.46(m, 2H)3.56-3.68(m, 1H)3.80(dt, J ═ 11.6, 3.8Hz, 2H)6.73(dd, J ═ 8.3, 1.7Hz, 1H)6.96(d, J ═ 1.7Hz, 1H)7.10-7.23(m, 2H)7.32 (width s, 1H)7.37-7.67(m, 6H)7.67-7.78(m, 1H)7.93(d, J ═ 8.3Hz, 1H)8.01 (width s, 1H)8.58(d, J ═ 7.6, 1H)8.66(d, J ═ 8.3Hz, 1H) 8.08 (width s, 1H).

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 3.83; [ M + H ]]₊＝520；[M-H]_-＝518。

Example 60: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (3-methoxypropoxy) benzamide

Step 1: in a 25mL three-necked flask, 1.257g of 3-methoxypropanol are dissolved in 10mL of dimethylformamide under argon, 228.5mg of sodium hydride (60% in oil) are then added and the mixture is stirred at ambient temperature for 30 minutes until no more gas evolution is observed. Then 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile from example 3, step 3, are added and the mixture is stirred again for 30 minutes at ambient temperature. The reaction medium is poured into 200ml of water and extracted 3 times with 50ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue obtained is stirred into 2ml of diisopropyl ether and crystals are formed, dried by rotary filtration and washed with diisopropyl ether. This gives 300mg of a mixture which is used as such in the subsequent step and contains predominantly 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (3-methoxypropoxy) benzonitrile and is characterized by the following:

LC/MS (method C): retention time was 4.93 minutes.

Step 2: by the method as in example 2 step 4, but using 450mg of the crude compound identical to that obtained in the previous step, 1.742ml of 1N sodium hydroxide solution and 1.6686ml of 30% aqueous hydrogen peroxide solution, kept at ambient temperature in 9ml of ethanol and 4ml of dimethyl sulfoxide for 15 minutes, 345mg of 4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] -2- (3-methoxypropoxy) benzamide is obtained, after purification by crystallization from 15ml of diisopropyl ether, in the form of a beige powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 2.00-2.10(m, 2H)3.24(s, 3H)3.53(t, J ═ 4.9Hz, 2H)4.26(t, J ═ 4.8Hz, 2H)7.10-7.25(m, 2H)7.31(d, J ═ 7.8Hz, 1H)7.40(s, 1H)7.43-7.56(m, 3H)7.57-7.76(m, 5H)7.88 (width s, 1H)8.15(d, J ═ 7.8Hz, 1H)8.66(d, J ═ 7.6Hz, 1H)13.06 (width s, 1H).

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 3.82; [ M + H ]]₊＝509；[M-H]_-＝507。

Example 61: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (3-hydroxy-3-methylbutylamino) benzamide

The process is carried out as in example 3 step 3, but using 155.6mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 153.4mg of potassium carbonate, 1.033g of 4-amino-2-methylbutan-2-ol hydrochloride and 0.749g of triethylamine in 2ml of dimethyl sulfoxide. Then 0.703ml of 1M aqueous sodium hydroxide solution, 0.681ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by crystallization from 5ml of ethyl acetate, thus obtaining 185mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (3-hydroxy-3-methylbutylamino) benzamide, in the form of a beige solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-δ ppm): 1.11(s, 6H)1.71(t, J ═ 7.8Hz, 2H)3.16-3.23(m, 2H)4.26(s, 1H)6.74(dd, J ═ 8.3, 1.5Hz, 1H)6.86(d, J ═ 1.7Hz, 1H)7.11-7.22(m, 2H)7.29 (width s, 1H)7.44-7.57(m, 3H)7.58-7.67(m, 3H)7.68-7.75(m, 1H)7.92(d, J ═ 8.3Hz, 1H)7.98 (width s, 1H)8.40(t, J ═ 4.9Hz, 1H)8.62(d, J ═ 8.3, 1H)13.08 Hz, 1H (width).

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 3.70; [ M + H ]]₊＝522；[M-H]_-＝520。

Example 62: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (2-fluoroethylamino) benzamide

The process is carried out as in example 3 step 3, but using 500mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 493mg of potassium carbonate, 1.78g of 2-fluoroethylamine hydrochloride and 1.805g of triethylamine in 5ml of dimethyl sulfoxide. Then 2.26ml of 1M aqueous sodium hydroxide solution, 2.19ml of 30% aqueous hydrogen peroxide solution and 10ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by purification by crystallization from 1ml of ethyl acetate, thus obtaining 390mg of 4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] -2- (2-fluoroethylamino) benzamide, in the form of a beige solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 3.51(dq, J ═ 27.9, 5.1Hz, 2H)4.61(dt, J ═ 47.7, 4.6Hz, 2H)6.80(dd, J ═ 8.3, 2.0Hz, 1H)6.97(d, J ═ 2.0Hz, 1H)7.10-7.21(m, 2H)7.35 (width s, 1H)7.39(dd, J ═ 8.8, 2.4Hz, 1H)7.45-7.48(m, 2H)7.57-7.66(m, 3H)7.84(dd, J ═ 8).8, 4.9Hz, 1H)7.94(d, J ═ 8.3Hz, 1H)8.03 (width s, 1H)8.58 to 8.70(m, 2H)13.08 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.87; [ M + H ]]₊＝482；[M-H]_-＝480。

Example 63: 4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (4-hydroxy-3 (R, S) -methylbutylamino) benzamide

The process is carried out as in example 3 step 2, but using 300mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile according to example 32 step 1, 301mg of potassium carbonate and 1.50g of 4-amino-2 (R, S) -methylbutanol in 3ml of dimethyl sulfoxide. Then 1.38ml of 1M aqueous sodium hydroxide solution, 1.336ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by crystallization from 5ml of ethyl acetate, thus obtaining 225mg of 4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -2- (4-hydroxy-3 (R, S) -methylbutylamino) benzamide, in the form of an off-white solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 0.87(d, J ═ 6.6Hz, 3H)1.31-1.43(m, 1H)1.58-1.68(m, 1H)1.70-1.80(m, 1H)3.10-3.22(m, 2H)3.24-3.28(m, 2H)4.44(t, J ═ 5.4Hz, 1H)6.77(dd, J ═ 8.3, 1.7Hz, 1H)6.88(d, J ═ 1.7, 1H)7.02(t, J ═ 7.6Hz, 1H)7.25(d, J ═ 8.1Hz, 1H)7.28 (wide s, 1H)7.30(dd, J ═ 5.9, 2.2, 1H)7.40(t, J ═ 8.1H) 7.8, 1H)7.28 (d, J ═ 7.7, J ═ 8.7, 8, 7.7, 8H) 7.7.9 (d, J ═ 5.9, 2, 1H, 7.8, J ═ 8, 7.8, 8, 7.8 (H) 1, 1H, 1, j ═ 5.0Hz, 1H)8.63(d,J＝2.0Hz，1H)9.16(d，J＝2.0Hz，1H)。

mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.07; [ M + H ]]₊＝515；[M-H]_-＝513。

Example 64: 2- (2-hydroxy-2-cyclopentylethylamino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

Step 1: the process is carried out as in step 2 of example 31, but using 300mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to step 1 of example 32, 375mg of 1- (2-aminoethyl) cyclopentanol and 803mg of potassium carbonate at 140 ℃ in 10ml of dimethylformamide for 3 hours. After work-up as in step 2 of example 31, 537mg of a mixture which is used as such in the subsequent step and mainly contains 2- (2-hydroxy-2-cyclopentylethylamino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile, which is characterized as follows:

LC/MS (method C): retention time 5.87 min.

Step 2: by the method as in example 2 step 4, but using the crude compound obtained in the previous step, 2.054ml of 1N sodium hydroxide solution and 1.89ml of 30% aqueous hydrogen peroxide solution, kept at ambient temperature in 13.6ml of ethanol and 5.7ml of dimethyl sulfoxide for 1 hour, purification by flash chromatography on 30g of silica gives, after elution with a mixture of dichloromethane and ethanol (97/3, vol), 246mg of 2- (2-hydroxy-2-cyclopentylethylamino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide, in the form of a beige powder, which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆，δppm)：1.40-1.71(m，8H)1.81-1.85(m，2H)3.21-3.29(m，2H)4.14(s，1H)6.76(dd，J＝8.3，2.0Hz, 1H)6.88(d, J ═ 1.7Hz, 1H)7.03(t, J ═ 8.1Hz, 1H)7.25(d, J ═ 7.8Hz, 1H)7.28 (width s, 1H)7.30(dd, J ═ 6.4, 2.0Hz, 1H)7.40(t, J ═ 8.3Hz, 1H)7.49(d, J ═ 8.1Hz, 1H)7.55-7.62(m, 2H)7.73(t, J ═ 8.1Hz, 1H)7.86-7.91(m, 1H)7.92(d, J ═ 8.3Hz, 1H)7.97 (width s, 1H)8.13(d, J ═ 8.3, 8.8H), 8.19 (t, 8.8, 8H), 8.3H), 8.8, 8H, 1H (d, 1H)7.8, 1H)8, 1H, 1Hz, 1H)7.8 (d, 1H)7.8, 1H.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.3; m/z 541[ M + H ] +; 539[ M-H ] -, M/z.

Example 65: 2- [2- (4-hydroxy-1-methylpiperidin-4-yl) ethylamino]-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

Step 1: the process is carried out as in step 2 of example 31, but using 300mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to step 1 of example 31, 460mg of 4- (2-aminoethyl) -1-methylpiperidin-4-ol and 803mg of potassium carbonate at 140 ℃ in 10ml of dimethylformamide for 3 hours. After work-up as in step 2 of example 31, 487mg of a mixture is obtained which is used as such in the subsequent steps and essentially contains 2- [2- (4-hydroxy-1-methylpiperidin-4-yl) ethylamino ] -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile and is characterized as follows:

LC/MS (method C): retention time 3.77 minutes.

Step 2: by the method as in step 4 of example 2, but using the compound obtained in the previous step, 1.768ml of 1N sodium hydroxide solution and 1.625ml of 30% aqueous hydrogen peroxide, held at ambient temperature in 11.7ml of ethanol and 4.9ml of dimethyl sulfoxide for 1 hour, purification by flash chromatography on 25g of silica, elution being carried out with a mixture of dichloromethane and ammonia in 7M methanol (96/4 then 90/10 then 80/20, vol.), 130mg of 2- [2- (4-hydroxy-1-methylpiperidin-4-yl) ethylamino ] -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide are obtained in the form of a white powder, which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.44-1.52(m, 4H)1.67-1.75(m, 2H)2.10(s, 3H)2.17-2.25(m, 2H)2.28-2.36(m, 2H)3.18-3.26(m, 2H)4.11(s, 1H)6.76(dd, J-8.3, 2.0Hz, 1H)6.89(d, J-2.0 Hz, 1H)7.02(t, J-8.1, 1H)7.25(d, J-8.1 Hz, 1H)7.28 (width s, 1H)7.30(dd, J-6.5, 1.6Hz, 1H)7.40(t, J-8.2, 1H)7.48(d, J-8.8, 8H) 7.8, 3, 8H) 7.63, 7.8H, 3H (d, 8H) 1H)7.3, 8H, 7.8H, 7.3H, 7.8H (d, 8H) 1, 8H) 1, 7.3, 7.8H, 8H, 1H, 7.3, 8H, 7.3, 1H, 7.8, 1H, 7.8, 3H, 1H, 8H, 1H, 7.8, 7.1, 7.8H, 7.1, 7.8, j ═ 2.0Hz, 1H)9.16(d, J ═ 2.2Hz, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.81; m/z 570[ M + H ] +; 568[ M-H ] -, where M/z is equal to.

Example 66:2- [ (3-hydroxypropyl) amino]-4- [4- (5-methoxypyridin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

0.85g of potassium carbonate and 3.14ml of 3-amino-1-propanol were added in this order to a solution of 0.81g of 2-fluoro-4- [4- (5-methoxypyridin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained in step 2 of example 27 in 7ml of dimethyl sulfoxide. The reaction mixture was heated in a microwave at 90 ℃ for 1 hour 20 minutes, then 20.9ml of ethanol were added, followed by 4ml of 1N sodium hydroxide solution and 4ml of 30% aqueous hydrogen peroxide solution. The reaction mixture was stirred at ambient temperature for 2 hours and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The white solid obtained was purified by trituration in diisopropyl ether to give 0.45g of 2- [ (3-hydroxypropyl) amino ] -4- [4- (5-methoxypyridin-3-yl) -9H-carbazol-9-yl ] benzamide, in the form of a white solid, which was characterized as follows:

Melting point (koflebench): 198 deg.C.

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.73(m, 2H)3.19(m, 2H)3.50(m, 2H)3.91(s, 3H)4.48(t, J ═ 5.3Hz, 1H)6.74(dd, J ═ 8.4, 2.0Hz, 1H)6.84(d, J ═ 2.0Hz, 1H)7.09(m, 1H)7.19(m, 1H)7.28 (width m, 1H)7.34(d, J ═ 8.2Hz, 1H)7.41(m, 1H)7.47(d, J ═ 8.1Hz, 1H)7.49-7.57(m, 2H)7.61(dd, J ═ 2.9, 1.9Hz, 1H)7.91(d, J ═ 8.3, 1H) 3.50(m, 2H)3.91(s, J ═ 8.8H) 8, 1H) 7.8 (d, 8H) 7.8, 1H) 7(d, 8.8, 8H) 1, 1H, 8(d, 8H) 1H) 7.6 (d, 8H) 1

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.84; m/z 467[ M + H ] +.

Example 67:4- {4- [5- (benzyloxy) pyridin-3-yl]-9H-carbazol-9-yl } -2- [ (4-trans-hydroxycyclohexyl) amino]Synthesis of benzamide

Step 1: 1.91g of 3-bromo-5-benzyloxypyridine are added under argon to a solution of 2ml of triisopropyl borate in a mixture of 12ml of toluene and 3ml of tetrahydrofuran. The solution was cooled to-70 ℃ and 5.42ml of N-butyllithium (1.6N in hexane) were added dropwise. The reaction medium is stirred for 3 hours, brought to-20 ℃ and 7.23ml of 2N hydrochloric acid are added dropwise. The reaction mixture was returned to ambient temperature and poured into distilled water. The aqueous phase is extracted with ethyl acetate, and the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Thus 0.21g of [5- (benzyloxy) pyridin-3-yl ] was obtained ]Boric acid in the form of a white powder (according to Wenjie Li et al, an Improved Protocol for the Prepa)3-pyridine-and Some aryl Acids J.org.chem., of ration, (2002),67(15) 5394-5397 regulation) characterized as follows:

mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.44; 230[ M + H ] +; 228[ M + H ] -.

Step 2: 1.63g of [5- (benzyloxy) pyridin-3-yl]Boric acid, 6.4g cesium carbonate and 0.182g 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (as a complex with dichloromethane (1/1) [ PdCl₂(dppf).CH₂Cl₂]) To 1.57g of 4-trifluoromethanesulfonyloxycarbazole obtained in step 1 of example 1 in 71ml of bis (methyl) phosphonium chloride were added in succession under argonAlkane and 24ml water. The reaction mixture was refluxed for 5 hours, filtered through celite, and concentrated under reduced pressure. The residue was then purified by chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (80/20 vol) to give 1.4g of 4- [5- (benzyloxy) pyridin-3-yl]-9H-carbazole, in the form of a pale yellow oil, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 5.27(s, 2H)6.94(m, 1H)7.05(dd, J ═ 7.3, 1.1Hz, 1H)7.28(d, J ═ 8.2Hz, 1H)7.31-7.53(m, 8H)7.56(dd, J ═ 8.1, 1.1Hz, 1H)7.66(dd, J ═ 3.0, 1.9Hz, 1H)8.39(d, J ═ 1.9Hz, 1H)8.50(d, J ═ 3.0Hz, 1H)11.51 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.05; m/z is 351[ M + H ] +.

And step 3: 1.08g of 4-bromo-2-fluorobenzonitrile, 4.48g of cesium carbonate, 0.25g of (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphine) and 0.08g of palladium acetate were added in this order to 1.27g of 4- [5- (benzyloxy) pyridin-3-yl ] under an argon atmosphere]-9H-carbazole in 100mlSolutions in alkanesIn (1). The reaction mixture was refluxed for 2.5 hours, cooled to ambient temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (80/20 vol) to give 1.1g of 4- {4- [5- (benzyloxy) pyridin-3-yl]-9H-carbazol-9-yl } -2-fluorobenzonitrile in the form of a colourless oil, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 5.29(s, 2H)7.12(m, 1H)7.24(dd, J ═ 7.0, 1.3Hz, 1H)7.29(d, J ═ 8.1Hz, 1H)7.32-7.62(m, 9H)7.68(dd, J ═ 2.9, 1.9Hz, 1H)7.78(dd, J ═ 8.4, 2.1Hz, 1H)8.01(dd ═ 10.4, 2.1Hz, 1H)8.25(m, 1H)8.39(d, J ═ 1.9Hz, 1H)8.55(d, J ═ 2.9Hz, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.22; 470[ M + H ] +, M/z.

And 4, step 4: 0.47g of potassium carbonate and 2.6g (22mmol) of 4-trans-aminocyclohexanol are added in succession to a solution of 0.55g of 4- {4- [5- (benzyloxy) pyridin-3-yl ] -9H-carbazol-9-yl } -2-fluorobenzonitrile in 6ml of dimethyl sulfoxide. The reaction mixture was heated in a microwave at 90 ℃ for 1 hour 20 minutes, then 11.5ml of ethanol were added, followed by 2.2ml of 1N sodium hydroxide solution and 2.2ml of 30% aqueous hydrogen peroxide solution. The reaction mixture was stirred at ambient temperature for 1 hour and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The white solid obtained was purified by chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97/3), to give 0.3g of 4- {4- [5- (benzyloxy) pyridin-3-yl ] -9H-carbazol-9-yl } -2- [ (4-trans-hydroxycyclohexyl) amino ] benzamide, in the form of a white solid, which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.24(m, 4H)1.78(m, 2H)1.99(m, 2H)3.33(m partial mask, 1H)3.47(m, 1H)4.47(d, J ═ 4.3Hz, 1H)5.29(s, 2H)6.69(dd, J ═ 8.4, 2.0Hz, 1H)6.87(d, J ═ 2.0Hz, 1H)7.06(m, 1H)7.17(dd, J ═ 7.2, 1.1Hz, 1H)7.30-7.58(m, 11H)7.69(dd, J ═ 2.9, 1.9Hz, 1H)7.89(d, J ═ 8.5Hz, 1H)7.96 (width m, 1H)8.41(d, J ═ 8.8.5 Hz, 1H)7.96 (width m, 1H)8.41(d, J ═ 8.9, 1.8, 8H) 3.8, 1H) 1H (d, 8.8, 1H)8 (d, 1H)8.55(d, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.06; m/z 583[ M + H ] +.

Example 68:4- {4- [5- (benzyloxy) pyridin-3-yl]-9H-carbazol-9-yl } -2- [ (3-hydroxypropyl) amino]Synthesis of benzamide

0.47g of potassium carbonate and 1.7g of 3-amino-1-propanol are added in succession to a solution of 0.55g of 4- {4- [5- (benzyloxy) pyridin-3-yl ] -9H-carbazol-9-yl } -2-fluorobenzonitrile obtained in step 3 of example 67 in 6ml of dimethyl sulfoxide. The reaction mixture was heated in a microwave at 90 ℃ for 1 hour 20 minutes, then 11.5ml of ethanol were added, followed by 2.2ml of 1N sodium hydroxide solution and 2.2ml of 30% aqueous hydrogen peroxide solution. The reaction mixture was stirred at ambient temperature for 1 hour and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with dichloromethane and diisopropyl ether to give 0.29g of 4- {4- [5- (benzyloxy) pyridin-3-yl ] -9H-carbazol-9-yl } -2- [ (3-hydroxypropyl) amino ] benzamide as a white solid, which was characterized as follows:

melting point (Kofler bench): 168 ℃.

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.73(m, 2H)3.19(m, 2H)3.50(m, 2H)4.48(t, J-5.2 Hz, 1H)5.29(s, 2H)6.74(dd, J-8.4, 2.0Hz, 1H)6.84(d, J-2.0 Hz, 1H)7.06(m, 1H)7.17(m, 1H)7.20-7.57(m, 11H)7.70(dd, J-2.9, 1.8Hz, 1H)7.91(d, J-8.4 Hz, 1H)7.96 (width m, 1H)8.41(d, J-1.8 Hz, 1H)8.44(t, J-5.4 Hz, 1H)8.54(d, 1H-1H) 8.54(d, 1H) 8.9, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.05; 543[ M + H ] +; 541[ M-H ] -.

Example 69:2- [ (3-hydroxypropyl) amino]-4- {4- [6- (trifluoromethyl) pyridin-3-yl]Synthesis of-9H-carbazol-9-yl } benzamide

Step 1: 0.96g of [ 2-trifluoromethylpyridin-5-yl]Boric acid, 4.55g cesium carbonate and 0.13g 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (as a complex with dichloromethane (1/1) [ PdCl₂(dppf).CH₂Cl₂]) To 1.1g of the 4-trifluoromethanesulfonyloxycarbazole obtained in step 1 of example 1 in 50ml of bis (methyl) carbazole in succession under argonAlkane and 17ml water. The reaction mixture was refluxed for 5 hours, filtered through celite, and concentrated under reduced pressure. The residue was then purified by chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (85/15 vol) to give 0.54g of 4- [6- (trifluoromethyl) pyridin-3-yl]-9H-carbazole in the form of a pale yellow oil, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 6.98(d, J ═ 7.1Hz, 1H)7.11(dd, J ═ 7.1, 1.0Hz, 1H)7.26(d, J ═ 8.1Hz, 1H)7.37(t, J ═ 8.2Hz, 1H)7.49-7.57(m, 2H)7.63(dd, J ═ 8.1, 1.0Hz, 1H)8.12(d, J ═ 7.8Hz, 1H)8.34(dd, J ═ 8.1, 1.7Hz, 1H)9.00(d, J ═ 2.0Hz, 1H)11.59 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.11; 313[ M + H ] +; 311[ M-H ] -.

Step 2: 0.52g of 4-bromo-2-fluorobenzonitrile, 2.14g of carbonic acidCesium, 0.12g of (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphine) and 39mg of palladium acetate were added in this order to 0.54g of 4- [6- (trifluoromethyl) pyridin-3-yl ] under argon]-9H-carbazole in 50mlIn an alkane. The reaction mixture was refluxed for 6 hours, cooled to ambient temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (96/4 vol) to give 0.37g of 2-fluoro-4- {4- [6- (trifluoromethyl) pyridin-3-yl]-9H-carbazol-9-yl } benzonitrile in the form of a white powder, characterized as follows:

mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 5.44; m/z 432[ M + H ] +.

And step 3: 0.17g of potassium carbonate and 0.64ml of 3-amino-1-propanol are added in succession to a solution of 0.18g of 2-fluoro-4- {4- [6- (trifluoromethyl) pyridin-3-yl ] -9H-carbazol-9-yl } benzonitrile in 2ml of dimethyl sulfoxide. The reaction mixture was heated in a microwave at 90 ℃ for 1 hour 20 minutes, then 4.2ml of ethanol were added, followed by 0.8ml of 1N sodium hydroxide solution and 0.8ml of 30% aqueous hydrogen peroxide solution. The reaction mixture was stirred at ambient temperature for 2 hours and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting white solid was purified by silica gel chromatography eluting with a mixture of dichloromethane, acetonitrile and methanol (96/2/2 vol) to give 24mg of 2- [ (3-hydroxypropyl) amino ] -4- {4- [6- (trifluoromethyl) pyridin-3-yl ] -9H-carbazol-9-yl } benzamide as a white solid, which was characterized as follows

Melting point (Kofler bench): 180 ℃ is carried out.

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.73 (quintuple, J ═ 6.5Hz, 2H)3.15-3.22(m, 2H)3.50(d, J ═ 6.1Hz, 2H)4.48(t, J ═ 5.1Hz, 1H)6.74(dd, J ═ 8.3, 2.0Hz, 1H)6.85(d, J ═ 2.0Hz, 1H)7.07-7.13(m, 1H)7.24(dd, J ═ 5.3, 3.1Hz, 1H)7.25 (width s, 1H)7.29(d, J ═ 8.1Hz, 1H)7.39-7.50(m, 2H)7.56-7.59(m, 2H)7.91(d, J ═ 8.3, 1H)7.97 (t, J ═ 8.0, 8.8, 1H)7.9 (d, 8.0, 8H) 7.9 (d, 8.8, 8H) 7.9, 1Hz, 1H)7.9 (d, 1H)7.9 (1 Hz, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.09; m/z 505[ M + H ] +; 503[ M + H ] -.

Example 70: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [2- (4-hydroxy-1-methylpiperidin-4-yl) ethylamino]Synthesis of benzamide

Step 1: the process was carried out as in step 2 of example 31, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-9-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to step 2 of example 3, 452mg of 4- (2-aminoethyl) -1-methylpiperidin-4-ol and 789mg of potassium carbonate in 10ml of dimethylformamide at 140 ℃ for 3 hours. After work-up as in step 2 of example 31, 527mg of a mixture was obtained which was used as such in the subsequent step and which contained predominantly 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [2- (4-hydroxy-1-methylpiperidin-4-yl) ethylamino ] benzonitrile, which was characterized as follows:

LC/MS (method C): retention time 3.41 minutes.

Step 2: by the method as in step 4 of example 2, using the crude compound obtained in the previous step, 1.886ml of 1N sodium hydroxide solution and 1.733ml of 30% aqueous hydrogen peroxide solution in 13.3ml of ethanol and 5.6ml of dimethyl sulfoxide at ambient temperature for 1 hour, purification by flash chromatography on 25g of silica was carried out, after elution with a mixture of dichloromethane and ammonia in 7M methanol (90/10, vol.), 80mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [2- (4-hydroxy-1-methylpiperidin-4-yl) ethylamino ] benzamide are obtained in the form of a white powder, which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.43-1.52(m, 4H)1.70(t, J ═ 7.8Hz, 2H)2.10(s, 3H)2.16-2.26(m, 2H)2.28-2.37(m, 2H)3.18-3.25(m, 2H)4.11(s, 1H)6.74(dd, J ═ 8.3, 2.0Hz, 1H)6.87(d, J ═ 2.0Hz, 1H)7.09-7.22(m, 2H)7.24-7.44(m, 1H)7.46(d, J ═ 3.9Hz, 2H)7.57-7.68(m, 4H)7.78-8.02(m, 2H)7.91(d, J ═ 8.3, 1H)8.63, t ═ 38, 1H (t, 1H) 1.08 (s, 1H) width.

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 2.92; m/z 577[ M + H ] +; m/z-575 [ M-H ] -.

Example 71: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [2- (1-hydroxycyclopentyl) ethylamino]Synthesis of benzamide

Step 1: the process is carried out as in step 2 of example 31, but using 300mg of 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-9-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to step 2 of example 3, 92.5mg of 1- (2-aminoethyl) cyclopentanol and 789mg of potassium carbonate in 10ml of dimethylformamide at 140 ℃ for 3 hours. After working up as in step 2 of example 31, 581mg of a mixture was obtained which was used as such in the subsequent steps and which predominantly contained 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [2- (1-hydroxycyclopentyl) ethylamino ] benzonitrile and was characterized as follows:

LC/MS (method C): retention time was 4.82 minutes.

Step 2: by the method as in example 2 step 4, but using the crude compound obtained in the previous step, 2.12ml of 1N sodium hydroxide solution and 1.95ml of 30% aqueous hydrogen peroxide solution, kept at ambient temperature in 15ml of ethanol and 6.3ml of dimethyl sulfoxide for 1 hour, purification by flash chromatography on 25g of silica, after elution with a mixture of dichloromethane and ethanol (94/6 vol), gives 112mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [2- (1-hydroxycyclopentyl) ethylamino ] benzamide in the form of a white powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.39-1.70(m, 8H)1.82(t, J ═ 7.6Hz, 2H)3.20-3.28(m, 2H)4.12(s, 1H)6.74(dd, J ═ 8.3, 2.0Hz, 1H)6.86(d, J ═ 2.0Hz, 1H)7.10-7.22(m, 2H)7.23-7.42(m, 1H)7.46(d, J ═ 3.4Hz, 2H)7.57-7.67(m, 4H)7.83 (width s, 1H)7.92(d, J ═ 8.3Hz, 1H)7.96 (width s, 1H)8.42(t, J ═ 5.3Hz, 1H)8.62 (width s, 1H)13.08 (width s, 1H).

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 3.96; 548[ M + H ] +; 546[ M-H ] -

Example 72: 2- (3-hydroxy-3-methylbutylamino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3, step 2, but using 153mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile according to example 32, step 1, 153.4mg of potassium carbonate, 1.033g of 5-aminopentan-2-ol and 0.749g of triethylamine in 2ml of dimethyl sulfoxide. Then 0.703ml of 1M aqueous sodium hydroxide solution, 0.681ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by crystallization from 5ml of ethyl acetate, thus obtaining 165mg of 2- (3-hydroxy-3-methylbutylamino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide, in the form of an off-white solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.11(s, 6H)1.66-1.77(m, 2H)3.16-3.25(m, 2H)4.28(s, 1H)6.76(d, J ═ 7.8Hz, 1H)6.88(s, 1H)7.02(t, J ═ 7.3Hz, 1H)7.25(d, J ═ 7.6Hz, 1H)7.28 (wide s, 1H)7.30(d, J ═ 5.6Hz, 1H)7.37-7.43(m, 1H)7.49(d, J ═ 7.8Hz, 1H)7.55-7.62(m, 2H)7.73(t, J ═ 7.1Hz, 1H)7.85-7.94(m, 2H)7.97 (s, 1.8H) 7.8 (s, 1H)7.8 (d, 8H) 7.8 (t, 1H)7.8 (d, 8H) 1H)7.8 (t, 1H) 8H, 1H)8 (d, 8H) 1H, 1H)7.8 (d, 8H) 1H)7.8, 1H)7.8 (1H) 7.8H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.06; m/z 515[ M + H ] +; 513[ M-H ] -

Example 73:2- [ (4-trans-hydroxycyclohexyl) amino]-4- [4- (5-hydroxypyridin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

0.19g of 4- {4- [5- (benzyloxy) pyridin-3-yl ] -9H-carbazol-9-yl } -2- [ (4-trans-hydroxycyclohexyl) amino ] benzamide obtained in step 4 of example 67 and 0.16g of ammonium formate were added in succession to a suspension of 5.2mg of palladium on charcoal (10%) in 5ml of methanol. The reaction mixture was refluxed for 2 hours, then filtered through celite, washing with methanol. The filtrate was concentrated under reduced pressure. Purification by silica gel chromatography eluting with a mixture of dichloromethane and methanol (95/5 vol) gave 94mg of 2- [ (4-trans-hydroxycyclohexyl) amino ] -4- [4- (5-hydroxypyridin-3-yl) -9H-carbazol-9-yl ] benzamide as a white solid characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.15-1.32(m, 4H)1.78(br.s., 2H)1.99 (s, 2H)3.33 (s, 1H)3.47 (s, 1H)4.47(d, J ═ 3.9Hz, 1H)6.70(dd, J ═ 8.3, 2.0Hz, 1H)6.89(d, J ═ 1.7Hz, 1H)7.09(ddd, J ═ 8.1, 5.7, 2.6Hz, 1H)7.14(d, J ═ 7.1Hz, 1H)7.26 (s, 1H)7.33-7.55(m, 6H)7.89(d, J ═ 8.3Hz, 1H)7.96 (s, 1H)8.24(s, 1H)8.30(d, 8.8, 1H) 1H, 1H) 7.41 (d, 1H) 7.8.8, 1H).

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 3.06; 493[ M + H ] +; 491[ M + H ] -.

Example 74:2- [ (4-trans-hydroxycyclohexyl) amino]-4- {4- [6- (trifluoromethyl) pyridin-3-yl]Synthesis of-9H-carbazol-9-yl } benzamide

0.17g of potassium carbonate and 0.96g of 4-trans-aminocyclohexanol are added in succession to a solution of 0.18g of 2-fluoro-4- {4- [6- (trifluoromethyl) pyridin-3-yl ] -9H-carbazol-9-yl } benzonitrile obtained in step 2 of example 69 in 2ml of dimethyl sulfoxide. The reaction mixture was heated in a microwave at 90 ℃ for 1 hour 20 minutes, then 4.2ml of ethanol were added, followed by 0.8ml of 1N sodium hydroxide solution and 0.8ml of 30% aqueous hydrogen peroxide solution. The reaction mixture was stirred at ambient temperature for 2 hours and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting white solid was purified by silica gel chromatography eluting with a mixture of dichloromethane, acetonitrile and methanol (95/2.5/2.5, vol) to give 21mg of 2- [ (4-trans-hydroxycyclohexyl) amino ] -4- {4- [6- (trifluoromethyl) pyridin-3-yl ] -9H-carbazol-9-yl } benzamide as a white solid characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.17-1.32(m, 4H)1.78 (width s, 2H)1.99(br.s., 2H)3.32 (width s, 1H)3.47(br.s., 1H)4.47(d, J ═ 4.4Hz, 1H)6.70(dd, J ═ 8.3, 2.0Hz, 1H)6.89(d, J ═ 1.7Hz, 1H)7.11(ddd, J ═ 8.1, 4.9, 3.2Hz, 1H)7.24(dd, J ═ 7.1, 1.2Hz, 1H)7.27 (width s, 1H)7.30(d, J ═ 8.1Hz, 1H)7.42-7.46(m, 2H)7.50-7.62(m, 7.90H) (width s, 7.8H) 7.9, 8.8H, 8H (d, 1Hz, 1H) 7.8.8H) 7.8, 8(dd, 8H) 7.8, 8H, 8(d, 8.9H, 8H) 7.9, 8H, 1Hz, 8H) 7.8 (d, 8H, 1H)7.9, 1Hz, 1H) 7.8H, 8H, 1H, 8H, 1H) 7.8H, 8H, 1H.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.10; m/z 545[ M + H ] +; 543[ M + H ] -.

Example 75: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (3-fluoropropylamino) benzamide

The process is carried out as in example 3 step 3, but using 200mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 197.3mg of potassium carbonate, 1.081g of 3-fluoropropylamine hydrochloride and 0.963g of triethylamine in 2ml of dimethyl sulfoxide. Then 0.904ml of 1M aqueous sodium hydroxide solution, 0.875ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by crystallization from 2ml of ethyl acetate, thereby affording 175mg of 4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -carbazol-9-yl ] -2- (3-fluoropropylamino) benzamide, in the form of an off-white solid, characterized as follows:

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.92; m/z 496[ M + H ] +; m/z is 494[ M-H ] -.

Example 76: 2- (3-fluoropropylamino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 196.8mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to step 1 of example 32, 197.3mg of potassium carbonate, 1.081g of 3-fluoropropylamine hydrochloride and 0.963g of triethylamine in 2ml of dimethyl sulfoxide. Then 0.904ml of 1M aqueous sodium hydroxide solution, 0.875ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by crystallization from 1ml of ethyl acetate, thereby affording 185mg of 2- (3-fluoropropylamino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide, in the form of an off-white solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆) δ ppm 1.88-2.07(m, 2H)3.23-3.35(m, 2H)4.55(dt, J-47.4, 5.9Hz, 2H)6.79(dd, J-8.3, 2.0Hz, 1H)6.91(d, J-1.7 Hz, 1H)7.02(t, J-7.9 Hz, 1H)7.25(d, J-7.8 Hz, 1H)7.30(dd, J-6.6, 1.7Hz, 1H)7.33(br.s., 1H)7.40(t, J-8.2 Hz, 1H)7.48(d, J-8.1 Hz, 1H)7.54-7.62(m, 2H)7.73(d, 8.8H) 1H, 8.8H, 8H, 1H, 8(d, 8.8H) 7.8, 8H) 1H)7.8, 1H, 1.8, 1H, 8H, 1H, 8H, 1H, 8H, 1H, 8H, 1H, 8H, 1H, 8H.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.12; m/z 489[ M + H ] +; m/z is 487[ M-H ] -.

Example 77: 2- (2-fluoroethylamino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process was carried out as in example 3 step 2, but using 196.8mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 32 step 1, 197.3mg of potassium carbonate, 0.948g of 2-fluoroethylamine hydrochloride and 0.963g of triethylamine in 2ml of dimethyl sulfoxide. Then 0.904ml of 1M aqueous sodium hydroxide solution, 0.875ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by crystallization from 1ml of ethyl acetate, thereby yielding 165mg of 2- (2-fluoroethylamino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide, in the form of an off-white solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆) δ ppm 3.52(dq, J-27.9, 5.1Hz, 2H)4.61(dt, J-47.7, 4.6Hz, 2H)6.82(dd, J-8.3, 2.0Hz, 1H)6.99(d, J-1.7 Hz, 1H)7.02(t, J-7.8 Hz, 1H)7.25(d, J-7.8 Hz, 1H)7.30(dd, J-5.9, 2.2Hz, 1H)7.35 (width s, 1H)7.40(t, J-8.3 Hz, 1H)7.49(d, J-8.3 Hz, 1H)7.54-7.64(m, 2H)7.73(t, J-7.88, 1H)7.8, 1H) 7.19 (d, J-8.3 Hz, 1H)7.54-7.64(m, 2H)7.73(t, J-8.8.8, 1H)7.8, 1H)7.8 (d, 1H)7.8, 1H, and 7.9H) 7.9 (d, 1H)7.9, 1H, 8H, 1H.

Example 78: to obtain [4- (quinoline-3-yl) -9H-carbazole-9-yl]Application of compound library of aryl carboxamides to 5- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of pyridine-2-amides

A library of 40 derivatives of the type [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -arylcarboxamides can be prepared according to the following scheme,

and was prepared by carrying out the method according to the following experimental design:

step 1: in a 250ml three-necked flask, 800mg of sodium hydride (60% in oil) are stirred in 10ml of heptane for 5 minutes under argon atmosphere, and the mixture is then separated by settling for 15 minutes. The supernatant was removed by pipette. 80ml of anhydrous dimethylformamide were then added, followed by 2.944g of the 4- (quinolin-3-yl) -9H-carbazole obtained in step 1 of the example, which were added in portions over 30 minutes. The reaction medium is stirred until no hydrogen is produced. The resulting solution was divided into 40 identical 2ml samples and each transferred to a 5ml tube reactor. 0.25mmol of different aryl fluorides were added to each tube under argon atmosphere. The tube reactor was sealed with a septum and then heated at 60 ℃ overnight. 0.1ml of trifluoroacetic acid was then added to each tube reactor. 40 reaction media were obtained while extraction was carried out by adding 20ml of ethyl acetate, washing with 10ml of 5% aqueous sodium bicarbonate solution, drying over a magnesium sulfate column and evaporation to dryness under reduced pressure. The 40 residues thus obtained are purified by simultaneous supercritical chromatography to give 40 [4- (quinolin-3-yl) -9H-carbazol-9-yl ] arylnitriles, which are used in step 2.

Step 2: the 40 aryl nitrile excretions obtained in step 1 were transferred to forty 5ml tube reactors, where they were dissolved in 3ml of a mixture of ethanol and dimethyl sulfoxide (2/1, volume). Then 0.25ml of 2N aqueous sodium hydroxide solution and 0.5ml of 30-35% aqueous hydrogen peroxide solution were added to each tube reactor. After stirring for 1 hour at ambient temperature, 40 reaction media are simultaneously extracted by addition of 20ml of ethyl acetate, washed with 10ml of 10% aqueous sodium chloride solution, dried over a magnesium sulfate column and evaporated to dryness under reduced pressure. This gives 40 [4- (quinolin-3-yl) -9H-carbazol-9-yl ] arylcarboxamides.

Example 78 was prepared in this library and yielded 37.2mg of 5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-2-amide, example 78, in the form of a pale beige powder, which was characterized as follows:

-1H NMR spectrum (DMSO, 500MHz, δ ppm): 9.20(d, J ═ 2.3Hz, 1H), 9.02(m, 1H), 8.68(d, J ═ 2.3Hz, 1H), 8.39(m, 2H), 8.32(s, 1H), 8.22(d, J ═ 8.7Hz, 1H), 8.17(d, J ═ 8.7Hz, 1H), 7.91(td, J ═ 8.7, 1.4Hz, 1H), 7.85(s, 1H), 7.76(m, 1H), 7.62(dt, J ═ 8.7, 7.6Hz, 1H), 7.56(d, 8.1Hz, 1H), 7.45(d, 8.1Hz, 1H), 7.42(m, 1H), 7.36(d, J ═ 7.5, 1H), 7.26(d, 8.1H), 7.01(m, 1H), 1 dm (m, 1H).

Example 79: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [2- (pyridin-2-yl) ethylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 250mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 247.6mg of potassium carbonate and 1.454g of 2- (2-aminoethyl) pyridine in 2.5ml of dimethyl sulfoxide. Then 1.131ml of 1M aqueous sodium hydroxide solution, 1.094ml of 30% aqueous hydrogen peroxide solution and 6ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (from 96/4 to 94/6, vol.) followed by crystallization from 5ml of diisopropyl ether, thus obtaining 261mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [2- (pyridin-2-yl) ethylamino ] benzamide, in the form of a beige solid, characterized as follows:

TLC (silica gel): rf ═ 0.27 (dichloromethane/ethanol 95/5).

-1H NMR spectrum (400MHz, DMSO-d)₆，δppm)：3.05(t，J＝6.8Hz，2H)3.54(q，J＝6.6Hz，2H)6.75(dd，J＝8.2，1.6Hz，1H)6.93(d，J＝1.7Hz，1H)7.11-7.22(m, 3H)7.27 (width s, 1H)7.31(d, J ═ 7.6Hz, 1H)7.42-7.55(m, 3H)7.57-7.80(m, 5H)7.91(d, J ═ 8.3Hz, 1H)7.96 (width s, 1H)8.43(d, J ═ 4.2Hz, 1H)8.54(t, J ═ 5.4Hz, 1H)8.62(d, J ═ 8.1Hz, 1H)13.08 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.68; m/z 541[ M + H ] +; 539[ M-H ] -, M/z.

Example 80: 4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]-2- [2- (pyridin-2-yl) ethylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 250mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained in example 32 step 1, 250.7mg of potassium carbonate and 1.477g of 2- (2-aminoethyl) pyridine in 2.5ml of dimethyl sulfoxide. Then 1.149ml of 1M aqueous sodium hydroxide solution, 1.111ml of 30% aqueous hydrogen peroxide solution and 6ml of ethanol were added to the reaction medium. After work-up as in step 3 of example 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by crystallization from 5ml of diisopropyl ether, thereby obtaining 167mg of 4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -2- [2- (pyridin-2-yl) ethylamino ] benzamide, in the form of white crystals, characterized as follows:

TLC (silica gel): rf ═ 0.29 (dichloromethane/ethanol 95/5).

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 3.06(t, J ═ 6.8Hz, 2H)3.51-3.59(m, 2H)6.78(dd, J ═ 8.3, 2.0Hz, 1H)6.95(d, J ═ 2.0Hz, 1H)7.03(t, J ═ 8.1Hz, 1H)7.19(ddd, J ═ 7.5, 4.9, 1.1Hz, 1H)7.23-7.35(m, 4H)7.40(t, J ═ 8.3Hz, 1H)7.49(d, J ═ 8.3Hz, 1H)7.55-7.62(m, 2H)7.68(td, J ═ 7.6, 1.8Hz, 1H)7.73(t, J ═ 8.1, 7.85H), 7.93(m, 2H) 7.93(m, 1H)7.85 (m, 1H) 7.3H) 7.6 (t, 1H) 7.3 (t, 1H) 7.3H) )8.14(d，J＝7.6Hz，1H)8.19(d，J＝8.3Hz，1H)8.44(ddd，J＝4.9，1.7，1.0Hz，1H)8.54(t，J＝5.5Hz，1H)8.63(d，J＝1.7Hz，1H)9.16(d，J＝2.2Hz，1H)。

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.88; m/z is 534[ M + H ] +.

Example 81: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [ (pyridin-2-ylmethyl) amino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 150mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 148mg of potassium carbonate and 0.772g of 2- (aminomethyl) pyridine in 2ml of dimethyl sulfoxide. Then 0.678ml of 1M aqueous sodium hydroxide solution, 0.656ml of 30% aqueous hydrogen peroxide solution and 3ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ammonia in 7M solution in methanol (from 95/5 to 80/20 by volume), followed by crystallization from 2ml of ethyl acetate, thus obtaining 75mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [ (pyridin-2-ylmethyl) amino ] benzamide, in the form of a beige solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 4.55(d, J ═ 5.9Hz, 2H)6.74(d, J ═ 1.5Hz, 1H)6.79(dd, J ═ 8.3, 1.7Hz, 1H)7.09-7.21(m, 3H)7.30-7.43(m, 5H)7.49(t, J ═ 7.8Hz, 1H)7.56-7.65(m, 2H)7.80-7.87(m, 2H)7.94(d, J ═ 8.3Hz, 1H)8.03 (width s, 1H)8.47-8.57(m, 2H)9.09(t, J ═ 6.0Hz, 1H)13.06 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.73; 527[ M + H ] +; m/z is 525[ M-H ] -.

Example 82: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [2- (1H-imidazol-1-yl) ethylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 150mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 148mg of potassium carbonate, 1.314g of 2- (1H-imidazol-1-yl) ethylamine dihydrochloride and 1.445g of triethylamine in 2ml of dimethyl sulfoxide. Then 0.678ml of 1M aqueous sodium hydroxide solution, 0.656ml of 30% aqueous hydrogen peroxide solution and 3ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (90/10 vol), followed by crystallization from 2ml of ethyl acetate, thus obtaining 130mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [2- (1H-imidazol-1-yl) ethylamino ] benzamide, in the form of a beige solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 3.56(q, J ═ 5.4Hz, 2H)4.20(t, J ═ 5.6Hz, 2H)6.77(d, J ═ 8.3Hz, 1H)6.86(s, 1H)6.95(s, 1H)7.12-7.22(m, 3H)7.33 (width s, 1H)7.45 (width s, 2H)7.57-7.67(m, 5H)7.82 (width s, 1H)7.92(d, J ═ 7.8Hz, 1H)8.01 (width s, 1H)8.56-8.66(m, 2H)13.08(br.s., 1H).

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 2.91; 530[ M + H ] +; m/z 528[ M-H ] -.

Example 83: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- (2, 2, 6, 6-tetramethyl-1H-piperidin-4-ylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 250mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 247.6mg of potassium carbonate and 1.86g of 4-amino-2, 2, 6, 6-tetramethylpiperidine in 2.5ml of dimethyl sulfoxide in a microwave at 110 ℃ for 1 hour 30 minutes. Then 1.131ml of 1M aqueous sodium hydroxide solution, 1.094ml of 30% aqueous hydrogen peroxide solution and 6ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ammonia in 7M solution (95/5 vol) in methanol, followed by crystallization from 10ml of diisopropyl ether, whereby 142mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (2, 2, 6, 6-tetramethyl-1H-piperidin-4-ylamino ] benzamide were obtained in the form of beige fine crystals characterized as follows:

TLC (silica gel): rf ═ 0.43 (dichloromethane/ammonia in 7M methanol 90/10).

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm)1.02-1.08(m, 14H)1.95(d, J ═ 10.0Hz, 2H)3.72-3.83(m, 1H)6.80(d, J ═ 8.1Hz, 1H)6.95(s, 1H)7.11-7.23(m, 2H)7.29 (width s, 1H)7.43-7.56(m, 3H)7.58-7.78(m, 4H)7.93(d, J ═ 8.3Hz, 1H)7.99 (width s, 1H)8.36(d, J ═ 7.3Hz, 1H)8.59(d, J ═ 7.8Hz, 1H)13.08 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.69; m/z 575[ M + H ] +; m/z is 573[ M-H ] -.

Example 84: 4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]-2- (2, 2, 6, 6-tetramethyl-1H-piperidin-4-ylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 250mg of 2-fluoro-4- [4- (quinolin-3-yl) carbazol-9-yl ] benzonitrile according to example 32 step 1, 251mg of potassium carbonate and 1.891g of 4-amino-2, 2, 6, 6-tetramethylpiperidine in 2.5ml of dimethyl sulfoxide. Then 1.15ml of 1M aqueous sodium hydroxide solution, 1.113ml of 30% aqueous hydrogen peroxide solution and 6ml of ethanol were added to the reaction medium. After work-up as in example 3, step 3, and then purification by flash chromatography on silica gel, elution being carried out with a mixture of dichloromethane and ammonia in 7M solution (96/4 vol) in methanol, followed by crystallization from 10ml of diisopropyl ether, 306mg of 4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -2- (2, 2, 6, 6-tetramethyl-1H-piperidin-4-ylamino ] benzamide are thus obtained in the form of beige fine crystals, characterized as follows:

TLC (silica gel): rf ═ 0.13 (dichloromethane/ammonia in 7M methanol 95/5).

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.04-1.10(m, 14H)1.96(dd, J-12.0, 2.4Hz, 2H)3.73-3.85(m, 1H)6.81(dd, J-8.3, 1.5Hz, 1H)6.99(s, 1H)7.03(t, J-7.5 Hz, 1H)7.25(d, J-8.1 Hz, 1H)7.28 (width s, 1H)7.31(d, J-6.8 Hz, 1H)7.41(t, J-7.8 Hz, 1H)7.53-7.67(m, 3H)7.73(t, J-7.7 Hz, 1H)7.88(t, J-8.2, 1H)7.94(d, J-8, 8H) 1H)7.8, 1H) 1.8, 1H (d, 1H)7.8, 1H)8, 1H (d, 8, 1H)7.8, 1H)7.8 (d, 1H)7.8, 1H) 7.13 (d, 1H) 7.13, 1H) 1, 1H) 7.6, 1H) 1, 1H).

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 3.50; 568[ M + H ] +; m/z is 566[ M-H ] -.

Example 85: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- (1, 2, 2, 6, 6-pentamethyl-1H-piperidin-4-ylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 150mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 148mg of potassium carbonate and 0.486g of 4-amino-1, 2, 2, 6, 6-pentamethylpiperidine in 1.5ml of dimethyl sulfoxide in a microwave at 110 ℃ for 1 hour 30 minutes. Then 0.678ml of 1M aqueous sodium hydroxide solution, 0.656ml of 30% aqueous hydrogen peroxide solution and 3.5ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a gradient of a mixture of dichloromethane and ethanol (from 95/5 to 85/15 by volume), followed by crystallization from 10ml of diisopropyl ether, whereby 56.5mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (1, 2, 2, 6, 6-pentamethyl-1H-piperidin-4-ylamino ] benzamide were obtained in the form of beige fine crystals, which were characterized as follows:

TLC (silica gel): rf ═ 0.09 (dichloromethane/ethanol 90/10).

-1H NMR spectrum (400MHz, DMSO-d)₆+TFA，δppm)：1.35(s，6H)1.48(s，6H)1.73(t，J＝12.5Hz，2H)2.32(d，J＝12.7Hz，2H)2.75(s，3H)4.09(t，J＝11.7Hz，1H)6.92(d，J＝8.3Hz，1H)7.20(s，1H)7.27(t，J＝7.6Hz，1H)7.54-7.61(m，2H)7.64-7.81(m，4H)7.88(d，J＝7.8Hz，1H)7.95(d，J＝7.3Hz，1H)8.01-8.08(m，2H)。

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.74; 589[ M + H ] +; m/z is 587[ M-H ] -.

Example 86: 2- [ (pyridin-2-ylmethyl) amino group]-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 150mg of 2-fluoro-4- [4- (quinolin-3-yl) carbazol-9-yl ] benzonitrile obtained according to step 1 of example 32, 150.5mg of potassium carbonate and 0.785g of 2- (aminomethyl) pyridine in 2ml of dimethyl sulfoxide. Then 0.69ml of 1M aqueous sodium hydroxide solution, 0.667ml of 30% aqueous hydrogen peroxide solution and 3ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and a 7M solution of ammonia in methanol (from 90/10 to 80/20 by volume), followed by crystallization from 1ml of ethyl acetate and 3ml of diisopropyl ether, thus obtaining 95mg of 2- [ (pyridin-2-ylmethyl) amino ] -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide, in the form of an off-white solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d) ₆δ ppm): 4.56(d, J ═ 5.9Hz, 2H)6.75(d, J ═ 1.7Hz, 1H)6.81(dd, J ═ 8.3, 2.0Hz, 1H)6.99(t, J ═ 7.6Hz, 1H)7.17-7.22(m, 2H)7.24-7.31(m, 3H)7.33-7.37(m, 1H)7.37 (width s, 1H)7.41(d, J ═ 7.8Hz, 1H)7.47(dd, J ═ 8.3, 7.3Hz, 1H)7.72(t, J ═ 8.1Hz, 1H)7.80-7.91(m, 2H)7.94(d, J ═ 8.3, 1H) 7.03 (t, J ═ 8.1Hz, 1H) 7.91(m, 2H)7.94(d, J ═ 8.3, 1H)8.03, 1H) 6.6 (d, 8.6H), 8H) 1H (d, 1H) 7.6H, 1Hz, 1H) 7.6 (d, 1H) 7.6, 1, 1.8.8, 8, 1H) 7.6 (d, 1H)7.8, 1H) 7.6 (d, 1H) 7.6 (d, 1H)7.8, 1.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.93; m/z 520[ M + H ] +; 518[ M-H ] -

Example 87: 2- [2- (1H-imidazol-1-yl) ethylamino]-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 150mg of 2-fluoro-4- [4- (quinolin-3-yl) carbazol-9-yl ] benzonitrile obtained according to step 1 of example 32, 150.5mg of potassium carbonate, 1.336g of 2- (1H-imidazol-1-yl) ethylamine dihydrochloride in 2ml of dimethyl sulfoxide. Then 0.69ml of 1M aqueous sodium hydroxide solution, 0.667ml of 30% aqueous hydrogen peroxide solution and 3ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (90/10 vol), followed by crystallization from 1ml of ethyl acetate and 3ml of diisopropyl ether, whereby 130mg of 2- [2- (1H-imidazol-1-yl) ethylamino ] -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide were obtained in the form of a beige solid, which was characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 3.53-3.60(m, 2H)4.21(t, J ═ 6.1Hz, 2H)6.80(dd, J ═ 8.2, 1.8Hz, 1H)6.87(s, 1H)6.98(d, J ═ 2.0Hz, 1H)7.03(t, J ═ 7.9Hz, 1H)7.19(s, 1H)7.25(d, J ═ 8.1Hz, 1H)7.30(dd, J ═ 6.8, 1.2Hz, 1H)7.34 (width s, 1H)7.40(t, J ═ 8.1Hz, 1H)7.48(d, J ═ 8.1Hz, 1H)7.54-7.63(m, 3H)7.73(t, J ═ 8.1Hz, 1H) 7.8.1H), 1H)7.48(d, J ═ 8.1Hz, 1H)7.8, 1H) 7.7.3.3 (m, 3H)7.73(t, J ═ 8, 8.1H), 1H)7.8, 1H (d, 1H)7.8, 1H, 1.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.81; 523[ M + H ] +; m/z is 521[ M-H ] -.

Example 88: (1, 2, 2, 6, 6-pentamethyl-1H-piperidin-4-ylamino)]-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of (E) -2-benzamide

The process is carried out as in example 3 step 3, but using 147.6mg of 2-fluoro-4- [4- (quinolin-3-yl) carbazol-9-yl ] benzonitrile obtained according to step 1 of example 32, 148mg of potassium carbonate and 0.486g of 4-amino-1, 2, 2, 6, 6-pentamethylpiperidine in 1.5ml of dimethyl sulfoxide and maintaining the mixture at 110 ℃ for 1 hour and 30 minutes in a microwave. Then 0.678ml of 1M aqueous sodium hydroxide solution, 0.656ml of 30% aqueous hydrogen peroxide solution and 3.5ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by crystallization from 10ml of diisopropyl ether, whereby 61.9mg of (1, 2, 2, 6, 6-pentamethyl-1H-piperidin-4-ylamino ] -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -2-benzamide were obtained in the form of off-white fine crystals, which were characterized as follows:

TLC (silica gel): rf ═ 0.21 (dichloromethane/ethanol 95/5).

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 0.96(s, 6H)1.12(s, 6H)1.27(t, J ═ 10.8Hz, 2H)1.97(d, J ═ 10.3Hz, 2H)2.16(s, 3H)3.61-3.76(m, 1H)6.82(d, J ═ 8.3Hz, 1H)6.99(s, 1H)7.03(t, J ═ 7.6Hz, 1H)7.25(d, J ═ 8.3Hz, 1H)7.28 (width s, 1H)7.31(d, J ═ 6.8Hz, 1H)7.40(t, J ═ 7.6Hz, 1H)7.53-7.67(m, 3H)7.73(t, J ═ 7.6, 1H)7.88(t, J ═ 7.8H) 7.19 (m, 3H)7.73(t, J ═ 7.6, J ═ 8, 1H)7.8 (H), 1H)7.8 (d, J ═ 8H), 1H) 7.8H, 1H)7.8 (d, 1.8, 1H)7.8 Hz, 1H) 7.6, 1.8, 1H) 7.6Hz, 1H) 7.6 (d, 1.8H) 7.6, 1H) 7.6, 1.6, 1H) 7.6, 1.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.88; m/z is 582[ M + H ] +.

Example 89: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (3(R, S) -hydroxycyclohexyl-1 (R, S) -amino) benzamide

The process is carried out as in example 3 step 3, but using 200mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 263mg of potassium carbonate and 0.658g of 3(R, S) -aminocyclohexan-1 (R, S) -ol in 4.7ml of dimethyl sulfoxide in a microwave at 110 ℃ for 1 hour 30 minutes. 0.952ml of 1M aqueous sodium hydroxide solution, 0.875ml of 30% aqueous hydrogen peroxide solution and 9.5ml of ethanol are then added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a gradient of a mixture of dichloromethane and ethanol (from 94/6 to 92/8 by volume), followed by crystallization from 10ml of diisopropyl ether, thus obtaining 98.7mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (3(R, S) -hydroxycyclohexyl-1 (R, S) -amino) benzamide, in the form of beige fine crystals, characterized as follows:

TLC (silica gel): rf ═ 0.11 (dichloromethane/ethanol 95/50).

-1H NMR spectrum (400MHz, DMSO-d)₆+TFA，δppm)：1.10-1.29(m，2H)1.63-1.85(m，4H)1.93-2.26(m，2H)3.35-3.47(m，1H)3.73-3.92(m，1H)6.82-6.89(m，1H)6.93-7.01(m，1H)7.26(ddd，J＝8.0，5.8，2.3Hz，1H)7.52-7.61(m，3H)7.67-7.90(m，5H)7.98-8.06(m，2H)。

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.85; 534[ M + H ] +; m/z is 532[ M-H ] -.

Example 90: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (2-hydroxy-2-methylpropylamino) benzamide

The process is carried out as in example 3 step 3, but using 150mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 148mg of potassium carbonate and 0.477g of 1-amino-2-methylpropan-2-ol in 2ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 15 minutes. Then 0.678ml of 1M aqueous sodium hydroxide solution, 0.656ml of 30% aqueous hydrogen peroxide solution and 3ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by crystallization from 1ml of ethyl acetate and 4ml of diisopropyl ether, thus obtaining 85mg of 4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] -2- (2-hydroxy-2-methylpropylamino) benzamide, in the form of a beige-beige solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.17(s, 6H)3.04(d, J ═ 5.4Hz, 2H)4.52(s, 1H)6.71(dd, J ═ 8.3, 2.0Hz, 1H)6.89(d, J ═ 2.0Hz, 1H)7.10-7.21(m, 2H)7.25 (width s, 1H)7.34-7.53(m, 3H)7.57-7.67(m, 3H)7.84(dd, J ═ 8.6, 5.1Hz, 1H)7.90(d, J ═ 8.3Hz, 1H)7.96 (width s, 1H)8.58-8.69(m, 2H)13.08 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.84; m/z 508[ M + H ] +; m/z is 506[ M-H ] -.

Example 91: (2-hydroxy-2-methylpropylamino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of (E) -2-benzamide

The process is carried out as in example 3 step 3, but using 150mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to step 1 of example 32, 155.5mg of potassium carbonate and 0.485g of 1-amino-2-methylpropan-2-ol in 2ml of dimethyl sulfoxide and holding in a microwave at 100 ℃ for 1 hour. Then 0.69ml of 1M aqueous sodium hydroxide solution, 0.667ml of 30% aqueous hydrogen peroxide solution and 3ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and a 7M solution of ammonia in methanol (from 95/5 to 80/20 by volume), followed by crystallization from 1ml of ethyl acetate and 4ml of diisopropyl ether, whereby 155mg of (2-hydroxy-2-methylpropylamino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -2-benzamide were obtained in the form of beige fine crystals, which were characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.17(s, 6H)3.05(d, J ═ 5.4Hz, 2H)4.52(s, 1H)6.73(dd, J ═ 8.2, 1.8Hz, 1H)6.91(d, J ═ 1.7Hz, 1H)7.02(t, J ═ 7.5Hz, 1H)7.25(d, J ═ 8.1Hz, 1H)7.27 (wide s, 1H)7.30(dd, J ═ 6.8, 1.2Hz, 1H)7.39(t, J ═ 7.6Hz, 1H)7.46(d, J ═ 8.3Hz, 1H)7.53-7.62(m, 2H)7.73(t, J ═ 8.1, 1H)7.86 (d, J ═ 8.6Hz, 1H) 7.92 (d, J ═ 8.3Hz, 1H) 7.65 (d, 8.8, 8H) 7.8, 1H)7.8 (d, 8.8, 8H) 7.8 (d, 8H) 7.8, 1H)7.8 (d, 8H) 7.8 (d, 1H)7.8, 1H) 7..

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.06; m/z 501[ M + H ] +; m/z is 499[ M-H ] -.

Example 92:4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2-[(Oxazol-4-ylmethyl) amino]Synthesis of benzamide

The process was carried out as in example 3 step 3, but using 195mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl-obtained according to example 3 step 2]Benzonitrile, 256.5mg potassium carbonate, 499.5mgAzol-4-ylmethyl amine hydrochloride and 187.8mg of triethylamine are kept in 4ml of dimethyl sulphoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.928ml of 1M aqueous sodium hydroxide solution, 0.853ml of 30% aqueous hydrogen peroxide solution and 8ml of ethanol are added to the reaction medium. After work-up as in example 3 step 3, it was then purified by flash chromatography on silica gel, eluting with a gradient of a mixture of dichloromethane and ethanol (from 97/3 to 92/8, vol.) Followed by crystallization from 10ml of diisopropyl ether, whereby 111mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -was obtained]-2-[(Oxazol-4-ylmethyl) amino]Benzamide, in the form of a pale yellow powder, characterized as follows:

TLC (silica gel): rf 0.31 (dichloromethane/ethanol 95/5)

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 4.34(s, 2H)6.78(dd, J ═ 8.1, 1.7Hz, 1H)6.98(d, J ═ 1.5Hz, 1H)7.09-7.19(m, 2H)7.34-7.74(m, 9H)7.90-7.95(m, 2H)8.27(s, 1H)8.54(d, J ═ 7.8Hz, 1H)8.68 (width s, 1H)12.83 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.82; m/z 517[ M + H ] +; m/z 515[ M-H ] -.

Example 93:4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of-2- { [1(R, S), 2(R, S) -2-hydroxycyclohexylmethyl) amino } benzamide

The process is carried out as in example 3 step 3, but using 160mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 210mg of potassium carbonate, 504mg of cis-2-aminomethylcyclohexane-1-ol hydrochloride and 308mg of triethylamine in 3.2ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.7ml of 30% aqueous hydrogen peroxide solution and 6.5ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a gradient of a mixture of dichloromethane and ethanol (from 95/5 to 92/8, vol), followed by crystallization from 10ml of diisopropyl ether, whereby 165mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- { [ (1(R, S), 2(R, S) -2-hydroxycyclohexylmethyl) amino } benzamide were obtained in the form of beige fine crystals characterized as follows:

TLC (silica gel): rf 0.19 (dichloromethane/ethanol 95/5)

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.18-1.73(m, 9H)2.90-3.22(m, 2H)3.82 (width s, 1H)4.41(d, J ═ 2.9Hz, 1H)6.74(d, J ═ 8.1Hz, 1H)6.83(s, 1H)7.11-7.23(m, 2H)7.31 (width s, 1H)7.39-7.68(m, 6H)7.84 (width s, 1H)7.92(d, J ═ 8.3Hz, 1H)8.01 (width s, 1H)8.54(t, J ═ 4.9Hz, 1H)8.63 (width s, 1H)10.22 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.96; 548[ M + H ] +; m/z is 546[ M-H ] -.

Example 94:2-[(oxazol-4-ylmethyl) amino]-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 165.4mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl-obtained according to example 32 step 1]Benzonitrile, 221mg of potassium carbonate, 431mg ofAzol-4-ylmethyl amine hydrochloride and 324mg of triethylamine are kept in 3.5ml of dimethyl sulphoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.8ml of 1M aqueous sodium hydroxide solution, 0.735ml of 30% aqueous hydrogen peroxide solution and 7ml of ethanol are added to the reaction medium. After work-up as in step 3 of example 3, it is then purified by flash chromatography on silica gel, with dichloromethane and Elution was performed with a mixture of ethanol (96/4, vol), followed by crystallization from 10ml of diisopropyl ether, whereby 36mg of 2- [ (R) ((R)) ]Oxazol-4-ylmethyl) amino]-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Benzamide, in the form of a pale yellow powder, characterized as follows:

TLC (silica gel): rf 0.21 (dichloromethane/ethanol 95/5)

-1H NMR spectrum (400MHz, DMSO-d)₆+TFA，δppm)：4.39(s，2H)6.86(d，J＝8.1Hz，1H)6.99(s，1H)7.06(t，J＝7.2Hz，1H)7.40-7.50(m，4H)7.58-7.66(m，2H)7.96-8.03(m，2H)8.07(t，J＝7.5Hz，1H)8.26(t，J＝7.6Hz，1H)8.37(s，1H)8.44(d，J＝8.3Hz，1H)8.49(d，J＝8.3Hz，1H)9.56(s，1H)9.80(s，1H)。

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 4.38; m/z 510[ M + H ] +.

Example 95:2- { [ (1(R, S), 2(R, S) -2-Hydroxycyclohexylmethyl) -amino } -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 157mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile according to example 32 step 1, 210mg of potassium carbonate, 504mg of cis-2-aminomethylcyclohexane-1-ol hydrochloride and 308mg of triethylamine in 2.5ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.7ml of 30% aqueous hydrogen peroxide solution and 5ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5, vol), followed by crystallization from 10ml of diisopropyl ether, whereby 127mg of 2- { [ (1(R, S), 2(R, S) -2-hydroxycyclohexylmethyl) amino } -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide were obtained, in the form of a light yellow powder, characterized as follows:

TLC (silica gel): rf 0.17 (dichloromethane/ethanol 95/5)

-1H NMR spectrum (400MHz, DMSO-d)₆+ TFA, δ ppm): 1.16-1.79(m, 9H)2.93-3.27(m, 2H)3.85 (width s, 1H)6.81(d, J ═ 7.6Hz, 1H)6.88(s, 1H)7.07(t, J ═ 6.7Hz, 1H)7.38-7.59(m, 4H)7.68(s, 2H)7.96(d, J ═ 7.8Hz, 1H)8.06(t, J ═ 6.6Hz, 1H)8.25(t, J ═ 7.5Hz, 1H)8.42(d, J ═ 8.6Hz, 1H)8.48(d, J ═ 7.6Hz, 1H)9.52(s, 1H)9.77(s, 1H).

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 4.89; m/z 541[ M + H ] +; 539[ M-H ] -, M/z.

Example 96:4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [1(R, S), 2(R, S) -2-hydroxymethylcyclohexyl-1-amino]) Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 160mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 210mg of potassium carbonate, 504mg of cis-2-hydroxymethylcyclohexane hydrochloride and 308mg of triethylamine in 3.2ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.7ml of 30% aqueous hydrogen peroxide solution and 6.5ml of ethanol are added to the reaction medium. After work-up as in step 3 of example 3, followed by purification by flash chromatography on silica gel eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by crystallization from 10ml of diisopropyl ether, 110mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [1(R, S), 2(R, S) -2-hydroxymethylcyclohexyl-1-amino ] benzamide are obtained in the form of pale beige fine crystals, which are characterized as follows:

TLC (silica gel): rf ═ 0.10 (dichloromethane/ethanol 95/5).

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.12-1.88(m, 9H)3.21-3.34(m, 2H)3.87(d, J-4.9 Hz, 1H)4.45(t, J-5.0 Hz, 1H)6.70(d, J-8.3 Hz, 1H)6.94(s, 1H)7.06-7.23(m, 2H)7.30 (wide s, 1H)7.37-7.52(m, 2H)7.58-7.72(m, 4H)7.85(dd, J-8.8, 4.9Hz, 1H)7.93(d, J-8.3 Hz, 1H)8.03 (wide s, 1H)8.62(dd, J-19.8, 8.1, 1H)8.93(d, J-8.13H) 1.13 Hz, 13H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.93; 548[ M + H ] +; m/z is 546[ M-H ] -.

Example 97:4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [1(S, R), 2(R, S) -2-hydroxymethylcyclohexyl-1-amino]) Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 160mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 210mg of potassium carbonate, 504mg of trans-2-hydroxymethylcyclohexane hydrochloride and 308mg of triethylamine in 3.2ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.7ml of 30% aqueous hydrogen peroxide solution and 6.5ml of ethanol are added to the reaction medium. After work-up as in step 3 of example 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (96/4 vol), followed by crystallization from 10ml of diisopropyl ether, whereby 99mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [1(S, R), 2(R, S) -2-hydroxymethylcyclohexyl-1-amino ] benzamide were obtained, in the form of bright beige crystals, which were characterized as follows:

TLC (silica gel): rf ═ 0.10 (dichloromethane/ethanol 95/5).

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.11-1.32(m, 4H)1.37-1.51(m, 1H)1.50-1.73(m, 2H)1.81(d, J ═ 6.8Hz, 1H)2.02(d, J ═ 12.7Hz, 1H)3.24-3.48 (mask m, 2H)3.49-3.60(m, 1H)4.43(t, J ═ 4.9Hz, 1H)6.68(d, J ═ 8.8Hz, 1H)6.91(s, 1H)7.05-7.25(m, 2H)7.24-7.51(m, 3H)7.54-7.73(m, 4H)7.76-7.96(m, 2H)8.01 (width s, 1H)8.45-8.74(m, 2H) 8.13 (m, 1H) 13 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.94; 548[ M + H ] +; m/z is 546[ M-H ] -.

Example 98:2- { (R) - (1-azabicyclo [2.2.2]Oct-3-yl) amino } -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 160mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 210mg of potassium carbonate, 806mg of (R) - (+) -3-aminoquinuclidine hydrochloride and 308mg of triethylamine in 3.2ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.7ml of 30% aqueous hydrogen peroxide solution and 6.5ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ammonia in 7M solution (95/5, vol) in methanol, followed by crystallization from 10ml of diisopropyl ether, whereby 67mg of 2- { (R) - (1-azabicyclo [2.2.2] oct-3-yl) amino } -4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzamide were obtained, in the form of a beige foam, characterized as follows:

TLC (silica gel): rf ═ 0.13 (dichloromethane/ammonia in 7M methanol 95/5).

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.32-1.68(m, 3H)1.75 (width s, 1H)1.90 (width s, 1H)2.45(d, J ═ 12.7Hz, 1H)2.54-2.87(m, 4H)3.11-3.28(m, 1H)3.54 (width s, 1H)6.59-6.88(m, 2H)7.19(t, J ═ 7.1Hz, 2H)7.25-7.51(m, 3H)7.53-7.74(m, 4H)7.72-8.01(m, 2H)8.06 (width s, 1H)8.64 (width s, 1H)8.97(d, J ═ 6.6Hz, 1H)13.14 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.67; m/z 545[ M + H ] +; m/z is 543[ M-H ] -.

Example 99:2- { (S) - (1-azabicyclo [2.2.2]Oct-3-yl) amino } -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 160mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 210mg of potassium carbonate, 806mg of (S) - (-) -3-aminoquinuclidine hydrochloride and 308mg of triethylamine in 3.2ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.7ml of 30% aqueous hydrogen peroxide solution and 6.5ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ammonia in 7M solution (95/5, vol) in methanol, followed by crystallization from 10ml of diisopropyl ether, whereby 42mg of 2- { (S) - (1-azabicyclo [2.2.2] oct-3-yl) amino } -4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzamide were obtained in the form of a beige powder, characterized as follows:

TLC (silica gel): rf 0.13 (dichloromethane/ammonia 7M methanol solution 95/5)

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.66; m/z 545[ M + H ] +; m/z is 543[ M-H ] -.

Example 100:2- [1(R, S), 2(R, S) -2-hydroxymethylcyclohexyl-1-amino]-4- [4- (quinolin-3-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 157mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 32 step 1, 210mg of potassium carbonate, 504mg of trans-2-hydroxymethylcyclohexane hydrochloride and 308mg of triethylamine in 3.2ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.7ml of 30% aqueous hydrogen peroxide solution and 6.5ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by crystallization from 10ml of diisopropyl ether, thereby yielding 100.5mg of 2- [1(R, S), 2(R, S) -2-hydroxymethyl-cyclohexyl-1-amino ] -4- [4- (quinolin-3-2-yl) -9H-carbazol-9-yl ] benzamide in the form of an off-white powder characterized as follows:

TLC (silica gel): rf 0.20 (dichloromethane/ethanol 95/5)

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.09-1.35(m, 4H)1.34-1.52(m, 1H)1.51-1.73(m, 2H)1.73-1.89(m, 1H)1.94-2.10(m, 1H)3.41-3.63 (mask m, 3H)4.45 (width s, 1H)6.70(d, J ═ 8.3Hz, 1H)6.93 (width s, 1H)6.97-7.09(m, 1H)7.25-7.36(m 4H)7.57(m, 3H)7.74(t, J ═ 7.5Hz, 1H)7.82-7.95(m, 2H)8.01 (width s, 1H)8.14(d, J ═ 8.3, 1H)8.19(d, 1H ═ 8.3H), 1H (d, 1H) 8.1H)8.58(d, J ═ 7.6Hz, 1H)8.64 (width s, 1H)9.16 (width s, 1H).

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 4.83; m/z 541[ M + H ] +; 539[ M-H ] -, M/z.

Example 101:2- [1(S, R), 2(R, S) -2-hydroxymethylcyclohexyl-1-amino]-4- [4- (quinolin-3-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 157mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile according to example 32 step 1, 210mg of potassium carbonate, 504mg of cis-2-hydroxymethylcyclohexane hydrochloride and 308mg of triethylamine in 3.2ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.7ml of 30% aqueous hydrogen peroxide solution and 6.5ml of ethanol are added to the reaction medium. After work-up as in step 3 of example 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), followed by crystallization from 10ml of diisopropyl ether, whereby 93mg of 2- [1(S, R), 2(R, S) -2-hydroxymethylcyclohexyl-1-amino ] -4- [4- (quinolin-3-2-yl) -9H-carbazol-9-yl ] benzamide were obtained, in the form of an off-white powder, which was characterized as follows:

TLC (silica gel): rf 0.20 (dichloromethane/ethanol 95/5)

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.20-1.88(m, 9H)3.23-3.33 (mask m, 2H)3.88(d, J-4.4 Hz, 1H)4.46(t, J-5.0 Hz, 1H)6.72(d, J-8.1 Hz, 1H)6.96(s, 1H)7.03(t, J-7.6 Hz, 1H)7.19-7.36(m, 3H)7.40(t, J-7.7 Hz, 1H)7.50(d, J-8.3 Hz, 1H)7.55-7.64(m, 2H)7.67-7.81(m, 1H)7.89(t, J-7.7 Hz, 1H)7.93(d, J-8.6, 1H)8.03, 1H (1H) 8, 1H) 1H, 1H)7.8, 1H (d, 1H)7.8, 1H9(d，J＝8.6Hz，1H)8.64(d，J＝1.7Hz，1H)8.94(d，J＝8.6Hz，1H)9.16(d，J＝2.0Hz，1H)。

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 4.77; m/z 541[ M + H ] +; 539[ M-H ] -, M/z.

Example 102:[4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [ (4-hydroxy-1-methylpiperidin-4-ylmethyl) amino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 150mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 148mg of potassium carbonate and 412mg of 4-aminomethyl-1-methylpiperidin-4-ol in 1.5ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.678ml of 1M aqueous sodium hydroxide solution, 0.656ml of 30% aqueous hydrogen peroxide solution and 3.6ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ammonia in 7M solution (95/5 vol) in methanol, thus giving 3mg of [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [ (4-hydroxy-1-methylpiperidin-4-ylmethyl) amino ] benzamide, in the form of a white powder, characterized as follows:

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 4.48; 562[ M + H ] +; m/z 560[ M-H ] -.

Example 103:2- [ (4-hydroxy-1-methylpiperidin-4-ylmethyl) -amino]- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 147.6mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to step 1 of example 32, 148mg of potassium carbonate and 412mg of 4-aminomethyl-1-methylpiperidin-4-ol in 1.5ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.678ml of 1M aqueous sodium hydroxide solution, 0.656ml of 30% aqueous hydrogen peroxide solution and 3.6ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ammonia in 7M solution (95/5, vol) in methanol, thus obtaining 15mg of 2- [ (4-hydroxy-1-methylpiperidin-4-ylmethyl) amino ] - [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide, in the form of a white powder, characterized as follows:

mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 3.33; 556[ M + H ] +; m/z is 554[ M-H ] -.

Example 104:4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [ (pyridin-3-ylmethyl) amino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 168.2mg of 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 166mg of potassium carbonate and 346mg of 3- (aminomethyl) pyridine in 1.7ml of dimethyl sulfoxide and holding in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.735ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), thus obtaining 35mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [ (pyridin-3-ylmethyl) -amino ] benzamide, in the form of a white powder, characterized as follows:

-1H NMR spectrum (300MHz, DMSO-d)₆δ ppm): 4.54(d, J ═ 5.6Hz, 2H)6.66-6.88(m, 2H)6.99-7.21(m, 3H)7.25(d, J ═ 8.2Hz, 1H)7.33(t, J ═ 7.7Hz, 1H)7.37-7.56(m, 4H)7.61(d, J ═ 7.3Hz, 1H)7.64-7.79(m, 2H)7.95(d, J ═ 8.4Hz, 1H)8.05 (width s, 1H)8.51-8.62(m, 3H)8.97(t, J ═ 6.3Hz, 1H)13.05 (width s, 1H).

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 0.68; [ M + H ] + M/z 527; [ M + H ] -M/z 525.

Example 105:2- [ (pyridin-3-ylmethyl) amino group]-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 165.4mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile according to example 32 step 1, 166mg of potassium carbonate and 346mg of 3- (aminomethyl) pyridine in 1.7ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.735ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol are added to the reaction medium. After work-up as in step 3 of example 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), thus obtaining 98mg of 2- [ (pyridin-3-ylmethyl) amino ] -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide, in the form of a white powder, characterized as follows:

-1H NMR spectrum (300MHz, DMSO-d)₆δ ppm): 4.55(d, J ═ 6.0Hz, 2H)6.73-6.86(m, 2H)6.98(t, J ═ 7.5Hz, 1H)7.09-7.32(m, 5H)7.33-7.52(m, 3H)7.64-7.80(m, 2H)7.88(t, J ═ 7.7Hz, 1H)7.95(d, J ═ 8.4Hz, 1H)8.05 (width s) ，1H)8.12(d，J＝7.8Hz，1H)8.18(d，J＝8.7Hz，1H)8.50-8.58(m，2H)8.60(d，J＝1.6Hz，1H)8.98(t，J＝6.0Hz，1H)9.12(d，J＝2.2Hz，1H)

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 0.85; [ M + H ] + M/z 520; [ M + H ] -M/z 518.

Example 106:4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [2- (pyridin-3-yl) ethylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 168.2mg of 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 166mg of potassium carbonate and 391mg of 3- (2-aminoethyl) pyridine in 1.7ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.735ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), thus obtaining 70mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [2- (pyridin-3-yl) -ethylamino ] benzamide, in the form of a white powder, characterized as follows:

-1HNMR map (400MHz, DMSO-d)₆δ ppm): 2.94(t, J ═ 7.0Hz, 2H)3.41-3.50(m, 2H)6.79(dd, J ═ 8.3, 1.7Hz, 1H)6.97(d, J ═ 1.7Hz, 1H)7.03(t, J ═ 7.6Hz, 1H)7.25(d, J ═ 7.8Hz, 1H)7.27-7.33(m, 2H)7.36(br.s., 1H)7.40(t, J ═ 7.7Hz, 1H)7.49(d, J ═ 8.1Hz, 1H)7.54-7.63(m, 2H)7.66-7.78(m, 2H)7.89(t, J ═ 7.6, 1H)7.93(d, 3.8, 8H), 1H) 7.59 (d, 8.8H) 7.6, 8H, 1H) 7.6 (d, 8.8H) 7.8, 1H) 7.6 (d, 8.8.5H) 1H, 1H) 7.6 (d, 8.6, 8H) 7.6, 1H) 7.6 (d, 1H) 7.6, 1.6H) 7.6, 1H) 7.6, 1.6H) 7.6, 1.6H, 1.6 (d, 1.6, 1.6.6.6.6.6.6, 1H) 7.6, 1 ＝2.2Hz，1H)9.16(d，J＝2.2Hz，1H)。

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 0.87; [ M + H ] + M/z 534; [ M + H ] -M/z 532.

Example 107:2- [2- (pyridin-3-yl) ethylamino]-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 165.4mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile according to example 32 step 1, 166mg of potassium carbonate and 346mg of 3- (2-aminoethyl) pyridine in 1.7ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.735ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol are added to the reaction medium. After work-up as in step 3 of example 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), thus obtaining 84mg of 2- [2- (pyridin-3-yl) -ethylamino ] -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide, in the form of a white powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 2.93(t, J ═ 6.8Hz, 2H)3.44(q, J ═ 6.8Hz, 2H)6.77(dd, J ═ 8.1, 1.2Hz, 1H)6.95(d, J ═ 1.2Hz, 1H)7.07-7.25(m, 2H)7.30(dd, J ═ 7.8, 4.6Hz, 1H)7.36 (width s, 1H)7.47(d, J ═ 3.7Hz, 2H)7.56-7.73(m, 5H)7.79 (width s, 1H)7.93(d, J ═ 8.3Hz, 1H)8.03 (width s, 1H)8.41(d, J ═ 4.6, 1H)8.49(d, J ═ 8.7, 1H)8.59 (d, 1H), 1H (1H) 8.13H, 13 Hz, 13H) 1H, 13 Hz, 1H) 7.7.7.7.7.7 (d, 5H).

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 0.70; [ M + H ] + M/z 541; [ M + H ] -M/z 539.

Example 108：2- { (R) - (1-azabicyclo [2.2.2]Oct-3-yl) amino } -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 157.4mg of 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 210mg of potassium carbonate, 806mg of (R) - (+) -3-aminoquinuclidine hydrochloride and 308mg of triethylamine in 3.2ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.7ml of 30% aqueous hydrogen peroxide solution and 6.5ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ammonia in 7M solution (95/5, vol) in methanol, followed by crystallization from 10ml of diisopropyl ether, whereby 61.5mg of 2- { (R) - (1-azabicyclo [2.2.2] oct-3-yl) amino } -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide were obtained in the form of a beige powder, characterized as follows:

TLC (silica gel): rf 0.12 (dichloromethane/ammonia in 7M methanol 95/5).

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.36-1.65(m, 3H)1.69-1.84(m, 1H)1.92 (width s, 1H)2.40-2.46(m, 1H)2.56-2.85(m, 3H)3.14-3.29(m, 2H)3.54 (width s, 1H)6.70-6.85(m, 2H)7.02(t, J ═ 7.6Hz, 1H)7.19-7.35(m, 3H)7.36-7.49(m, 2H)7.50-7.63(m, 2H)7.73(t, J ═ 7.5Hz, 1H)7.89(t, J ═ 7.6Hz, 1H)7.95(d, J ═ 8.3, 1H)8.02 (width s, 1H)8.14 (width s, J ═ 8.8, J ═ 8H) 8, 1H (d, 8H) 8.95(d, 8H) 8, 1H)8 (d, 8H) 8.8, 1H)8, 1H (1H) 8, 1H)8 (d, 1H)8, 1H)7.8, 1H)7, 1H (1H) 7.8, 1H)7, 1H

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 0.82; [ M + H ] + M/z 538.

Example 109: 2- (3(R, S) -hydroxycyclohexyl-1 (R, S) -amino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 157mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 32 step 1, 210mg of potassium carbonate and 0.525g of 3(R, S) -aminocyclohexan-1 (R, S) -ol in 3.8ml of dimethyl sulfoxide and maintaining the temperature at 115 ℃ for 1 hour and 30 minutes in a microwave. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.7ml of 30% aqueous hydrogen peroxide solution and 7.5ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (94/6 vol), followed by crystallization from 10ml of diisopropyl ether, thereby yielding 137mg of 2- (3(R, S) -hydroxycyclohexyl-1 (R, S) -amino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide, as an about 70/30 mixture of two diastereomers, in the form of an off-white powder, characterized as follows:

TLC (silica gel): rf ═ 0.14 (dichloromethane/ethanol 96/4).

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.32-1.82(m, 4H)1.96(d, J ═ 11.7Hz, 2H)2.20(d, J ═ 11.2Hz, 2H)3.33-3.49(m, 1H)3.70-3.88(m, 1H)4.43-4.60(m, 1H)6.73(d, J ═ 8.3Hz, 1H)6.89(d, J ═ 10.5Hz, 1H)7.02(t, J ═ 7.3, 1H)7.16-7.34(m, 3H)7.36-7.48(m, 2H)7.48-7.56(m, 1H)7.60(t, JJ ═ 7.7Hz, 1H)7.73(t, J ═ 7.6, 1H)7.80 (m, 1H) 7.95(m, 1H) 7.8H 8(m, 8H) 7.8 (m, 8H) 1H)7.8 (1H) 7.8H) 1H)7.8 (d, 8H) 1H)8 (1H) 8H) 1H)6, 8H) 1H 8 (d, 8H) 6H) 1H)6, 8H) 1H 8 (1H) 6

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 1.05; [ M + H ] + M/z 527.

Example 110:4- [4- (6-fluoro-1H-benzimidazole)-2-yl) -9H-carbazol-9-yl]-2- [ (1-methyl-1H-imidazol-4-yl) methylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 160mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 210mg of potassium carbonate and 338.5mg of (1-methyl-1H-imidazol-4-yl) methylamine in 3.3ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.70ml of 30% aqueous hydrogen peroxide solution and 6.6ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (95/5 vol), thus obtaining 78mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [ (1-methyl-1H-imidazol-4-yl) methylamino ] benzamide, in the form of a beige powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 3.64(s, 3H)4.22(d, J ═ 5.1Hz, 2H)6.76(dd, J ═ 8.3, 2.0Hz, 1H)6.96(d, J ═ 2.0Hz, 1H)6.99(s, 1H)7.07-7.49(m, 5H)7.52(s, 1H)7.54-7.69(m, 4H)7.73-8.07(m, 3H)8.49-8.62(m, 1H)8.69(t, J ═ 5.3Hz, 1H)13.08 (width s, 1H)

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 0.64; [ M + H ] + M/z 530; [ M + H ] -M/z 528.

Example 111:4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [ (1-hydroxycyclopent-1-yl) methylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 160mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 210mg of potassium carbonate and 351mg of 1- (aminomethyl) cyclopent-1-ol in 3.3ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.70ml of 30% aqueous hydrogen peroxide solution and 6.6ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95/5 vol), thus giving 14.4mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [ (1-hydroxycyclopent-1-yl) methylamino ] benzamide, in the form of a beige powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.43-1.79(m, 8H)3.14(d, J ═ 5.1Hz, 2H)4.48(s, 1H)6.71(dd, J ═ 8.2, 1.8Hz, 1H)6.88(d, J ═ 1.7Hz, 1H)7.00-7.34(m, 3H)7.35-7.76(m, 7H)7.77-8.00(m, 2H)8.50-8.74(m, 2H)13.08 (width s, 1H)

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 0.92; [ M + H ] + M/z 534; [ M + H ] -M/z 532.

Example 112:4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (3-hydroxypropyl) amino]Synthesis of benzamide

Step 1: 0.9g of potassium carbonate and 3.3ml of 3-amino-1-propanol were added in succession to a solution of 1g of 2-methylpropan-2-yl 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2-fluorobenzoate obtained in step 1 of example 49 in 8ml of dimethyl sulfoxide. The reaction mixture was heated in a microwave at 90 ℃ for 1.5 hours and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and filtered. The residue was purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (70/30 vol) to give 0.7g of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2- [ (3-hydroxypropyl) amino ] -benzoic acid 2-methylpropan-2-yl ester as a yellow oil, which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.60(s, 9H)1.76 (quintuple, J ═ 6.4Hz, 2H)3.23-3.30(m, 2H)3.47-3.54(m, 2H)4.59(t, J ═ 5.0Hz, 1H)6.80(dd, J ═ 8.3, 2.0Hz, 1H)6.95(d, J ═ 2.0Hz, 1H)7.08-7.15(m, 1H)7.24(dd, J ═ 6.5, 1.8Hz, 1H)7.31(d, J ═ 8.1Hz, 1H)7.44(td, J ═ 7.7, 1.2Hz, 1H)7.51(d, J ═ 8.1, 1H)7.55-7.63(m, t ═ 2H) 7.51(d, J ═ 8.1, 1H)7.5, J ═ 8.8.8.8.1 Hz, 1H) 7.8.8, 7.8, 7.5 (t, J ═ 8.5, J ═ 8.7.8, 8H) 7.7.7, 8, 1H, 1, 8.7.7.7.7, 8, 1, 8.5, 8, 1H, 1H, 1, 8.7.7.7.7

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.27; 519[ M + H ] +, M/z.

Step 2: 8ml of 1N hydrochloric acid are added to 0.7g of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (3-hydroxypropyl) amino]Benzoic acid 2-methylpropan-2-yl ester in 10ml diIn an alkane. The reaction mixture was heated in a microwave at 100 ℃ for 2 hours and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (96/4 vol) to give 190mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (3-hydroxypropyl) amino]Benzoic acid, in the form of a pale yellow powder, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.75 (quintuple, J ═ 6.4Hz, 2H)3.20-3.27(m, 2H)3.48-3.55(m, 2H)4.52(t, J ═ 4.9Hz, 1H)6.77(dd, J ═ 8.3, 2.0Hz, 1H)6.92(d, J ═ 2.0Hz, 1H)7.11(td, J ═ 7.8, 0.7Hz, 1H)7.23(dd, J ═ 6.7, 1.6Hz, 1H)7.31(d, J ═ 7.8Hz, 1H)7.44(td, J ═ 7.7, 1.0Hz, 1H)7.51(d, J ═ 8.3, 1H)7.55-7.63, m ═ 2H (m, 8H) 3, 8.8, 8H (J ═ 8H) 7.8, J ═ 8H) 7.7.7.8, 1H (dd, 8H) 7.7.7.8, 8H) 7.7.7.7.7, 8 (dd, 8H) 7.8H, 1.8H, 8H, 1H)7.3 (1.8, 8H) 7.8H, 1H) 7.8, 8H, 1H, 8H (dd, 1H) 7.7.7.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.05; m/z 463[ M + H ] +; 461[ M + H ] -.

And step 3: 260mg of (1H-benzotriazol-1-yloxy) [ tris (dimethylamino)]Hexafluorophosphate (BOP), 79mg of Hydroxybenzotriazole (HOBT), 41mg (0.8mmol) of ammonium chloride and 0.26ml of diisopropylethylamine were added successively to 180mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (3-hydroxypropyl) amino]Benzoic acid in 10ml of N, N-dimethylformamide. The reaction mixture was stirred at ambient temperature for 4 hours, then diluted with distilled water and extracted with ethyl acetate. The organic phase is then washed with distilled water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (96/4 vol) and triturated in diisopropyl ether to give 60mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ]-2- [ (3-hydroxypropyl) amino]Benzamide, in the form of a white solid, characterized as follows:

melting Point (Buchi melting Point B-545) ═ 204 ℃ C

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.72 (quintuple, J ═ 6.5Hz, 2H)3.15-3.22(m, 2H)3.46-3.53(m, 2H)4.48(t, J ═ 5.0Hz, 1H)6.74(dd, J ═ 8.3, 1.7Hz, 1H)6.84(d, J ═ 1.7Hz, 1H)7.07-7.14(m, 1H)7.22(dd, J ═ 5.0, 3.5Hz, 1H)7.30 (width s, 1H)7.31(d, J ═ 7.8Hz, 1H)7.40-7.50(m, 2H)7.55-7.59(m, 2H)7.91(d, J ═ 8.3, 1H)7.98 (t, 8.8H), 1H) 7.35 (t, 8H, 1H) 7.5 (d, 1H) 7.5 Hz, 1H) 7.6, 1H) 7.6 (d, 8H) 7.3, 1H) 7.6, 1H) 7.6 (d, 1H) 7.6.5 Hz, 1H) 7.6.8H) 1H, 1H) 7.6.6, 1H

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.97; m/z 462[ M + H ] +; 460[ M-H ] -.

Example 113: 4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (tetrahydropyran-4-yl) amino) benzamide

The process is carried out as in example 3 step 3, but using 150mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to step 1 of example 32, 150.5mg of potassium carbonate, 0.500g (3.63mmol) of 4-aminotetrahydropyran hydrochloride and 0.367g of triethylamine in 1.5ml of dimethyl sulfoxide and maintaining the mixture at 115 ℃ for 1 hour and 30 minutes in a microwave. Then 0.69ml of 1M aqueous sodium hydroxide solution, 0.667ml of 30% aqueous hydrogen peroxide solution and 3.5ml of ethanol are added to the reaction medium. After work-up as in step 3 of example 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (97/3 vol), followed by crystallization from 2ml of diisopropyl ether, thereby obtaining 65mg of 4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -2- (tetrahydropyran-4-yl) amino) benzamide, in the form of a beige powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.36-1.50(m, 2H)1.95(d, J ═ 10.8Hz, 2H)3.41(t, J ═ 9.8Hz, 2H)3.62-3.70(m, 1H)3.81(dt, J ═ 11.9, 3.9, 3.8Hz, 2H)6.76(dd, J ═ 8.3, 2.0Hz, 1H)6.98(d, J ═ 1.7Hz, 1H)7.02(ddd, J ═ 8.0, 6.8, 1.6Hz, 1H)7.25(d, J ═ 7.8Hz, 1H)7.30(d, J ═ 6.6Hz, 1H)7.33 (width s, 1H)7.36-7.46(m, 2H)7.50(d, J ═ 7.8H) 7.7.7.7, 1H)7.8 (d, 1H) 7.7.8H, 1H, 7.7.7 (d, 7.8H) 7.7.7.8H, 7.7.7 (d, 7.8H) 7.7.7, 7.8H) 7.7.7.7.7.8 (d, 1H) 7.8H) 7.7.7.8H, 7.7.7.7.7.7, 7.8H, 1H, 7.8H, 7.7.8H, 7.8H, 1H, 7.7, 7 (d, 7.7.7.8H) 1H, 7.7.7.7.7.7.7, 7, 7.8H) 1H, 7, 1H)9.15(d, J ═ 2.2Hz, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.09; m/z 513[ M + H ] +.

Example 114:4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [ (1-hydroxycyclopropan-1-yl) methylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 168.2mg of 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 165.8mg of potassium carbonate and 279mg of 1- (aminomethyl) cyclopropan-1-ol in 1.7ml of dimethyl sulphoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.735ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95/5 vol), thus obtaining 26mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [ (1-hydroxycyclopropan-1-yl) methylamino ] benzamide, in the form of a light yellow powder, characterized as follows:

1H NMR Spectrum (400MHz, DMSO-d)₆，δppm)：0.39-0.55(m，2H)0.56-0.72(m，2H)3.23(d，J＝5.6Hz，2H)5.41(s，1H)6.73(dd，J＝8.3，1.7Hz，1H)6.89(d，J＝2.0Hz，1H)7.02-7.32(m，3H)7.33-7.82(m，7H)7.84-8.06(m，2H)8.57-8.70(m，2H)13.07(s，1H)。

Example 115:4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [ (1-methyl-1H-pyrazol-4-yl) methylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 168.2mg of 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 165.8mg of potassium carbonate and 356mg of 4-aminomethyl-1-methyl-1H-pyrazole in 1.7ml of dimethyl sulphoxide and holding in the microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.735ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95/5 vol), thus obtaining 95mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [ (1-methyl-1H-pyrazol-4-yl) methylamino ] benzamide, in the form of a pale yellow powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 3.82(s, 3H)4.24(d, J ═ 4.9Hz, 2H)6.77(dd, J ═ 8.3, 2.0Hz, 1H)6.89(d, J ═ 1.7Hz, 1H)7.09-7.21(m, 2H)7.24-7.39(m, 3H)7.43(t, J ═ 8.2Hz, 1H)7.46-7.54(m, 2H)7.57(t, J ═ 7.8Hz, 1H)7.60-7.80(m, 3H)7.87-8.07(m, 2H)8.56-8.65(m, 2H)13.07 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.82; 530[ M + H ] +; m/z 528[ M-H ] -.

Example 116: 5- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of (E) -3- (tetrahydropyran-4-yl) amino) pyridine-2-carboxamide

Step 1: a solution of 200mg of 2-cyano-3, 5-difluoropyridine, 236mg of 4-aminotetrahydropyran hydrochloride, 395mg of potassium carbonate and 173.4mg of triethylamine in 3ml of dimethyl sulfoxide is introduced into a 5ml microwave tube reactor. The mixture was then heated in a microwave at 115 ℃ for 1 hour. The reaction medium is poured into 50ml of water and 50ml of ethyl acetate. The aqueous phase was back-extracted twice with 25ml ethyl acetate. The combined organic phases were washed with water and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash chromatography on 25g silica gel, eluting with a mixture of ethyl acetate and heptane (40/60 then 60/40, vol), the first eluting product was recovered, thereby yielding 80mg of 2-cyano-5-fluoro-3- (tetrahydropyran-4-yl) aminopyridine in the form of a beige powder characterized as follows:

-1H NMR spectrum (500MHz, DMSO-d)₆)δppm 1.55-1.68(m，2H)1.78(dd，J＝12.5，2.2Hz，2H)3.40(td，J＝11.7，1.5Hz，2H)3.56-3.69(m，1H)3.87(dd，J＝11.5，2.7Hz，2H)6.48(d，J＝7.8Hz，1H)7.40(dd，J＝12.0，2.2Hz，1H)7.89(d，J＝2.4Hz，1H)。

By recovering the second eluted product, 150mg of 2-cyano-3-fluoro-5- (tetrahydropyran-4-yl) aminopyridine was also isolated.

Step 2: 98mg of 4- (quinolin-3-yl) -9H-carbazole obtained according to step 1 of example 2 are dissolved in 5mL of dimethylformamide under argon in a 25mL three-necked flask. Then 20mg of sodium hydride (60% in oil) was added and the mixture was stirred at ambient temperature for 30 minutes, then at 30 ℃ for 30 minutes. Then 81mg of 2-cyano-5-fluoro-3- (tetrahydropyran-4-yl) aminopyridine obtained in the previous step was added and the mixture was heated at 50 ℃ overnight. The reaction medium is poured into 50ml of water and 50ml of ethyl acetate. The aqueous phase was back-extracted twice with 25ml ethyl acetate. The combined organic phases were washed with water and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash chromatography on 15g of silica gel, elution was carried out with a gradient of a mixture of ethyl acetate and heptane (30/70 to 50/50 by volume), thus obtaining 95mg, in the form of a beige powder, characterized as follows:

LC/MS (method C): retention time 5.28 minutes.

And step 3: 95mg of 5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -3- (tetrahydropyran-4-yl) aminopyridinecarbonitrile obtained in the preceding step was dissolved in 1ml of dimethyl sulfoxide and 2.5ml of ethanol, and then 0.384ml of a 1M aqueous solution of sodium hydroxide and 0.352ml of a 30% aqueous solution of hydrogen peroxide were added in this order. After stirring for 1 hour at ambient temperature, the reaction medium is poured into 50ml of water and 50ml of ethyl acetate. The aqueous phase was back-extracted twice with 25ml ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash chromatography on 10g silica gel, elution was carried out with a mixture of dichloromethane and methanol (98/2 vol), followed by crystallization from 2ml of diethyl ether, whereby 64mg of 5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -3- (tetrahydropyran-4-yl) amino) pyridine-2-carboxamide was obtained in the form of a beige powder, which was characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆，δppm)：1.38-1.53(m，2H)1.96(d，J＝12.5Hz，2H)3.39-3.48(m，2H)3.66-3.79(m，1H)3.83(dt，J＝11.5，3.5Hz，2H)6.99-7.09(m，1H)7.26(d，J＝8.1Hz，1H)7.33(d，J＝6.8Hz，1H)7.37-7.47(m，2H)7.52(d，J＝8.3Hz，1H)7.56-7.65(m，3H)7.74(t，J＝7.6Hz，1H)7.89(td，J＝7.6，1.3Hz，1H)8.03(d，J＝2.0Hz，1H)8.09-8.24(m，3H)8.62(d，J＝2.0Hz，1H)8.87(d，J＝7.8Hz，1H)9.15(d，J＝2.2Hz，1H)。

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.11; m/z 514[ M + H ] +.

Example 117:4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [ (1-methyl-1H-imidazol-4-yl) ethylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 168.2mg of 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 165.8mg of potassium carbonate, 517mg of 2- (1-methyl-1H-imidazol-4-yl) ethylamine hydrochloride and 324mg of triethylamine in 1.7ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.735ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on 10g of silica gel, eluting with a mixture of dichloromethane and methanol (95/5 vol), thus obtaining 34mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [ (1-methyl-1H-imidazol-4-yl) ethylamino ] benzamide, in the form of a white solid, characterized as follows:

-1HNMR map (400MHz, DMSO-d) ₆δ ppm): 2.72(t, J ═ 7.0Hz, 2H)3.31-3.35 (mask m, 2H)3.74(s, 3H)6.76(dd, J ═ 8.2, 1.8Hz, 1H)6.88(d, J ═ 2.0Hz, 1H)7.09-7.22(m, 2H)7.24-7.38(m, 2H)7.39-7.56(m, 4H)7.56-7.81(m, 4H)7.93(d, J ═ 8.3Hz, 1H)7.99 (width s, 1H)8.53(t, J ═ 5.1Hz, 1H)8.63(d, J ═ 8.3Hz, 1H)13.08 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.86; m/z 544[ M + H ] +; m/z is 542[ M-H ] -.

Example 118:4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [2(R, S) -hydroxymethylcyclopent-1 (S, R) -amino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 150mg of 2-fluoro-4- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 148mg of potassium carbonate and 493mg of cis- (2-aminocyclopentyl) methanol in 2ml of dimethyl sulfoxide at 115 ℃ for 1 hour and 15 minutes in a microwave. Then 0.678ml of 1M aqueous sodium hydroxide solution, 0.656ml of 30% aqueous hydrogen peroxide solution and 3ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95/5 vol), then crystallized from 1ml of ethyl acetate, thus obtaining 75mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [2(R, S) -hydroxymethylcyclopentane-1 (S, R) -amino ] benzamide, in the form of a beige solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆+TFA，δppm)：1.29-1.96(m，6H)2.14-2.29(m，1H)3.44-3.62(m，2H)3.87-3.99(m，1H)6.83(d，J＝8.6Hz，1H)7.03(s，1H)7.26(t，J＝7.6Hz，1H)7.45-8.10(m，10H)。

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.89; 534[ M + H ] +; m/z is 532[ M-H ] -.

Example 119:2- [ (1-methyl-1H-pyrazol-4-yl) methylamino]-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 165.4mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to step 1 of example 32, 165.8mg of potassium carbonate and 356mg of 4-aminomethyl-1-methyl-1H-pyrazole in 1.7ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.735ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol are added to the reaction medium. After work-up as in step 3 of example 3, it was then purified by flash chromatography on 10g of silica gel, eluting with a mixture of dichloromethane and methanol (95/5 vol), thus obtaining 2- [ (1-methyl-1H-pyrazol-4-yl) methylamino ] -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide in the form of a white powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆+TFA，δppm)：3.86(s，3H)4.29(s，2H)6.85(dd，J＝8.2，2.1Hz，1H)6.92(d，J＝1.7Hz，1H)6.99-7.11(m，1H)7.35-7.46(m，5H)7.50-7.57(m，1H)7.58-7.69(m，2H)7.98(d，J＝8.1Hz，1H)8.05(t，J＝7.7Hz，1H)8.24(t，J＝8.3Hz，1H)8.42(d，J＝8.3Hz，1H)8.47(d，J＝8.6Hz，1H)9.49(d，J＝1Hz，1H)9.74(d，J＝1.5Hz，1H)。

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.03; 523[ M + H ] +, M/z.

Example 120:2- [ (1-methyl-1H-imidazol-4-yl) ethylamino]-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 165.4mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to step 1 of example 32, 165.8mg of potassium carbonate, 517mg of 2- (1-methyl-1H-imidazol-4-yl) ethylamine hydrochloride and 324mg of triethylamine in 1.7ml of dimethyl sulfoxide in a microwave at 115 ℃ for 1 hour 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.735ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on 10g of silica gel, eluting with a mixture of dichloromethane and methanol (95/5 vol), thus obtaining 49mg of 2- [ (1-methyl-1H-imidazol-4-yl) ethylamino ] -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide, in the form of a white solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 2.73(t, J ═ 6.7Hz, 2H)3.30-3.34 (mask m, 2H)3.75(s, 3H)6.78(dd, J ═ 8.3, 1.7Hz, 1H)6.90(d, J ═ 2.0Hz, 1H)6.95-7.08(m, 1H)7.25(d, J ═ 8.1Hz, 1H)7.27-7.33(m, 3H)7.40(ddd, J ═ 8.3, 7.2, 1Hz, 1H)7.45-7.51(m, 1H)7.51(s, 1H)7.54-7.64(m, 3H)7.68-7.78(m, 1H)7.80-8.06(m, 3H)8.14(d, 7.8.8, 8H) 8.19, 8H (J ═ 8, 8.8, 8H) 7.8.8.8 (t, 8H) 7.8, 8(d, 1H)7.8, 1Hz, 1H) 7.8.8, 1Hz, 1H) 7.8.8.8, 1Hz, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.06; 537[ M + H ] +; 535[ M-H ] -, where M/z is.

Example 121:4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]-2- [ (1-hydroxycyclopropan-1-yl) methylamino]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 165.4mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 3 step 2, 165.8mg of potassium carbonate and 279mg of 1- (aminomethyl) cyclopropan-1-ol in 1.7ml of dimethyl sulphoxide and maintaining the mixture in a microwave at 115 ℃ for 1 hour and 30 minutes. Then 0.76ml of 1M aqueous sodium hydroxide solution, 0.735ml of 30% aqueous hydrogen peroxide solution and 4ml of ethanol are added to the reaction medium. After work-up as in step 3 of example 3, it was then purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95/5 vol), thus obtaining 11mg of 4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -2- [ (1-hydroxycyclopropan-1-yl) methylamino ] benzamide, in the form of a pale yellow powder, characterized as follows:

mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.04; m/z 499[ M + H ] +; m/z is 497[ M-H ] -.

Example 122 : 3- [1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) amino]-5- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of pyridine-2-carboxamides

Step 1: a solution of 682mg of 2-cyano-3, 5-difluoropyridine, 995mg of 4-amino-1, 2, 2, 6, 6-pentamethylpiperidine and 1.346mg of potassium carbonate in 10ml of dimethyl sulfoxide is introduced into a 20ml microwave tube reactor. The mixture was then heated in a microwave at 115 ℃ for 1 hour. The reaction medium is poured into 100ml of water and 100ml of ethyl acetate. The aqueous phase was extracted twice with 50ml of ethyl acetate. The combined organic phases were washed with water and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash chromatography on 70g of silica gel, eluting with a mixture of dichloromethane, methanol and 4N aqueous ammonia (99/1/0.8, vol), the first eluted product is recovered, thus obtaining 290mg of 2-cyano-5-fluoro-3- (1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) aminopyridine in the form of a beige powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆)δppm 1.07(s，6H)1.08(s，6H)1.46(t，J＝12.1Hz，2H)1.73(dd，J＝12.5，3.5Hz，2H)2.18(s，3H)3.70-3.82(m，1H)6.27(d，J＝8.6Hz，1H)7.18(dd，J＝11.8，2.4Hz，1H)7.89(d，J＝2.4Hz，1H)。

Step 2: 102mg of 4- (quinolin-3-yl) -9H-carbazole obtained according to step 1 of example 2 are dissolved in 5.5mL of dimethylformamide under argon in a 25mL three-necked flask. Then 21mg of sodium hydride (60% in oil) was added and the mixture was stirred at ambient temperature for 30 minutes and then at 30 ℃ for 30 minutes. Then 100.6mg of 2-cyano-5-fluoro-3- (1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) aminopyridine obtained in the previous step was added, and the mixture was heated at 50 ℃ overnight. The reaction medium is poured into 50ml of water and 50ml of ethyl acetate. The aqueous phase was back-extracted twice with 25ml ethyl acetate. The combined organic phases were washed with water and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. This gave 191mg of a mixture containing predominantly 3- (1, 2, 2, 6, 6-pentamethylpiperidin-4-ylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridinecarbonitrile in the form of a beige powder, which was used in the subsequent steps as it was and was characterized as follows:

LC/MS (method C): retention time 3.68 minutes.

And step 3: 190mg of 3- (1, 2, 2, 6, 6-pentamethylpiperidin-4-ylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridinecarbonitrile obtained in the preceding step was dissolved in 2ml of dimethyl sulfoxide and 5ml of ethanol, followed by addition of 0.673ml of a 1M aqueous sodium hydroxide solution and 0.618ml of a 30% aqueous hydrogen peroxide solution in this order. After stirring for 1 hour at ambient temperature, the reaction medium is poured into 50ml of water and 50ml of ethyl acetate. The aqueous phase was back-extracted twice with 25ml ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash chromatography on 15g silica gel, elution is carried out with a mixture of dichloromethane, methanol and 4N aqueous ammonia (93/7/0.5, vol), thus obtaining 89mg of 3- [1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) amino ] -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-2-carboxamide, in the form of a beige powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆，δppm)：0.98(s，6H)1.12(s，6H)1.30(t，J＝12.0Hz，2H)1.96(d，J＝11.2Hz，2H)2.17(s，3H)3.70-3.87(m，1H)7.06(t，J＝7.6Hz，1H)7.26(d，J＝8.1Hz，1H)7.34(d，J＝6.6Hz，1H)7.42(t，J＝7.8Hz，1H)7.50-7.68(m，5H)7.73(t，J＝7.9Hz，1H)7.89(t，J＝7.6Hz，1H)8.10(d，J＝2.0Hz，1H)8.11-8.17(m，2H)8.19(d，J＝8.3Hz，1H)8.54-8.66(m，2H)9.15(d，J＝2.2Hz，1H)。

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.89; m/z 583[ M + H ] +.

Example 123:4- { 2-carbamoyl-5- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of phenylamino piperidine-1-carboxylic acid tert-butyl ester

Step 1: the process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 31 step 1, 2.035g of 4-amino-1-tert-butoxycarbonylpiperidine and 301mg of potassium carbonate in 3ml of dimethyl sulfoxide at 110 ℃ for 1H 15 min. After work-up as in example 3, step 3, followed by purification by flash chromatography on silica gel, eluting with a mixture of dichloromethane and ethanol (99/1 vol), 330mg of tert-butyl 4- { 2-cyano-5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] phenylamino } piperidine-1-carboxylate were obtained in the form of a beige solid, which was characterized as follows:

LC/MS (method C): retention time 6.22 minutes.

Step 2: by the method as in example 2 step 4, but using 400mg of tert-butyl 4- { 2-cyano-5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] phenylamino } piperidine-1-carboxylate, obtained according to the preceding step, 1.28ml of 1N sodium hydroxide solution and 1.24ml of 30% aqueous hydrogen peroxide solution at ambient temperature in 6.5ml of ethanol and 4ml of dimethyl sulfoxide for 5 minutes, purification by flash chromatography on silica gel gives, after elution with a mixture of dichloromethane and ethanol (95/5 vol), 300mg of tert-butyl 4- { 2-carbamoyl-5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] phenylamino } piperidine-1-carboxylate, in the form of a white powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-δ ppm)1.24-1.37(m, 2H)1.39(s, 9H)1.88-1.98(m, 2H)2.89-3.07(m, 2H)3.56-3.68(m, 1H)3.75(d, J-12.7 Hz, 2H)6.68-6.80(m, J-10.3 Hz, 1H)6.98(d, J-1.5 Hz, 1H)7.02(t, J-8.1 Hz, 1H)7.25(d, J-8.3 Hz, 1H)7.30(d, J-6.8 Hz, 1H)7.33 (width s, 1H)7.36-7.48(m, 2H)7.49-7.55(m, 1H)7.55 (m, 7.8H) 7.8 (t, 7.8H) 7.8 (H), 7.8H) 7.8 (t, 1H)7.8 (H), 1H)7.8 (d, 1H)7.8 (H) 7.8, 1H)7.8 (d, 1H)7.8, 7.8H) 7.3 (H) 7.3, 7.3H) 7.7.7.7.7.8, 7.8 (H) 1, 7.8, 7.3 (d, 7.8, 7.3H) 1, 7.3 (, 1H)9.15(d, J ═ 2.2Hz, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.21; m/z 612[ M + H ] +; m/z is 610[ M + H ] +.

Example 124:2- (piperidin-4-ylamino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide hydrochloride

370mg of 4- { 2-carbamoyl-5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] obtained in example 123 were placed in a 25mL three-necked flask]Phenylamino } piperidine-1-carboxylic acid tert-butyl ester dissolved in 3ml of diAlkane, then 2.845 hydrochloric acid in twoA 4M solution in alkane, and the mixture was stirred at ambient temperature overnight. The precipitate formed is spin-dried on sintered glass and washed successively with 5ml of dichloromethane and 5ml of diisopropyl ether. After drying in an oven under vacuum at 50 ℃ 320mg of 2- (piperidin-4-ylamino) -4- [4- (quinolin-3-yl) -9H-carbazol-9-yl are thus obtained ]Benzamide hydrochloride as a light yellow solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.53-1.73(m, 2H)2.12(d, J ═ 13.4Hz, 2H)2.81-3.05(m, 2H)3.23(d, J ═ 13.2Hz, 2H)3.73(t, J ═ 10.0Hz, 1H)6.79(d, J ═ 8.3Hz, 1H)6.96-7.10(m, 2H)7.20-7.49(m, 5H)7.51-7.68(m, 2H)7.87(t, J ═ 7.2Hz, 1H)7.97(d, J ═ 8.3Hz, 1H)8.04(t, J ═ 7.7Hz, 1H)8.10 (width s, 1H)8.28(d, J ═ 8.3, 1H) 8.12 (d, J ═ 8.3H), 8.34(d, 8.8, 8H) 8, 8.84 (t, 8H) 8, 8.7.7 (s, 1H)8.8 (t, 8H) 8, 8 (s, 8H) 8 (s, 1H)8, 8.8 (t, 8H) 8, 8.

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 3.35; m/z 512[ M + H ] +; m/z 510[ M + H ] +.

Example 125:4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (3-hydroxy-3-methylbutyl) amino group]Synthesis of benzamide

Step 1: 0.26g of potassium carbonate and 1.35g of 4-amino-2-methylbutan-2-ol are added in succession to a solution of 0.22g of 2-methylpropan-2-yl 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2-fluorobenzoate obtained in step 1 of example 49 in 8ml of dimethyl sulphoxide. The reaction mixture was heated in a microwave at 90 ℃ for 1 hour 20 minutes and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (80/20 vol) to give 0.17g of 2-methylpropan-2-yl 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2- [ (3-hydroxy-3-methylbutyl) amino ] benzoate as a yellow oil, which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.12(s, 6H)1.59(s, 9H)1.70-1.78(m, 2H)3.23-3.29(m, 2H)4.32(s, 1H)6.78(dd, J ═ 8.3, 2.0Hz, 1H)6.95(d, J ═ 2.0Hz, 1H)7.11(td, J ═ 8.1, 0.7Hz, 1H)7.23(dd, J ═ 6.6, 1.5Hz, 1H)7.31(d, J ═ 8.1Hz, 1H)7.44(td, J ═ 7.8, 1.2Hz, 1H)7.51(d, J ═ 8.3Hz, 1H)7.55-7.63(m, 2H)7.91(t, J ═ 8.5, J ═ 8.3Hz, 1H) 7.6.6, 1H (d, 8.3Hz, 1H)7.3 Hz, 1H (d, 8.3Hz, 1H) 7.8, 8H, 1H) 7.8 (d, 8H) 7.3Hz, 1H) 7.8, 1H, 8H, 1H.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.32; m/z 547[ M + H ] +.

Step 2: 1.6ml of 1N hydrochloric acid are added to 0.15g of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (3-hydroxy-3-methylbutyl) amino group]Benzoic acid 2-methylpropan-2-yl ester in 8ml diIn an alkane. The reaction mixture was heated in a microwave at 100 ℃ for 2 hours and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (97/3 vol) to give 20mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (3-hydroxy-3-methylbutyl) amino group]Benzoic acid, in the form of a pale yellow powder, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.11(s, 6H)1.69-1.76(m, 2H)3.20-3.26(m, 2H)4.28(s, 1H)6.73(d, J ═ 8.8Hz, 1H)6.88(s, 1H)7.11(td, J ═ 7.8, 0.7Hz, 1H)7.23(dd, J ═ 6.6, 1.5Hz, 1H)7.31(d, J ═ 8.1Hz, 1H)7.44(td, J ═ 8.3, 1.0Hz, 1H)7.51(d, J ═ 8.1Hz, 1H)7.55-7.63(m, 2H)8.07(d, J ═ 8.6Hz, 1H)8.28(dd, J ═ 8.1, 8.35H), 1H) 7.35 (dd, 1H) 7.9, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.09; 491[ M + H ] +, M/z.

And step 3: 108mg of (1H-benzotriazol-1-yloxy) [ tris (dimethylamino)]Hexafluorophosphate (BOP), 33mg of Hydroxybenzotriazole (HOBT), 17mg of ammonium chloride and 0.1ml of diisopropylethylamine were added in that order to 80mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (3-hydroxy-3-methylbutyl) amino group]Benzoic acid in 10ml of N, N-dimethylformamide. The reaction mixture was stirred at ambient temperature for 12 hours, then diluted with distilled water and extracted with ethyl acetate. The organic phase is then washed with distilled water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (96/4 vol) to give 18mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ]-2- [ (3-hydroxy-3-methylbutyl) amino group]Benzamide, in the form of a white solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.10(s, 6H)1.66-1.74(m, 2H)3.15-3.22(m, 2H)4.26(s, 1H)6.73(dd, J ═ 8.2, 2.1Hz, 1H)6.85(d, J ═ 2.0Hz, 1H)7.11(ddd, J ═ 8.1, 6.8, 1.0Hz, 1H)7.23(t, J ═ 4.2Hz, 1H)7.32(d, J ═ 7.8Hz, 1H)7.43(ddd, J ═ 8.3, 6.8, 1.0Hz, 1H)7.48(d, J ═ 8.3Hz, 1H)7.58(d, J ═ 4.2, 2H)7.66 (s, 1.90H) 7.15 (H, 1H), 1.8 (H), 1H) 7.8 (ddh), 8 (ddh) 7.8, 1H) 7.8 (d, 8.3Hz, 1H) 7.8 (ddh, 8H) 7.8 (ddh, 1H) 7.8, 8H) 7.8 (ddh, 1H) 7.8, 8, 1.8, 8 (ddh) 7.8, 1H, 8 (ddh) 7.8, 8H, 1H) 7.8H, 1H.

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 4.36; 490[ M + H ] +; 488[ M-H ] -.

Example 126:4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (tetrahydro-2H-pyran-4-ylamino) benzamide

Step 1: 0.95g of potassium carbonate and 4.62g of 4-aminotetrahydropyran are added in succession to a solution of 1.06g of 2-methylpropan-2-yl 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2-fluorobenzoate in 8ml of dimethyl sulphoxide in step 1 of example 49. The reaction mixture was heated in a microwave at 90 ℃ for 3 hours and then diluted with distilled water. The aqueous phase was washed twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and filtered. The residue was purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (85/15 vol) to give 0.5g of 2-methylpropan-2-yl 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2- (tetrahydro-2H-pyran-4-ylamino) benzoate as a white foam, which was characterised as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.42-1.54(m, 2H)1.60(s, 9H)1.92-2.01(m, 2H)3.36-3.45(m, 2H)3.65-3.76(m, 1H)3.78-3.86(m, 2H)6.78(dd, J-8.6, 2.0Hz, 1H)7.07(d, J-2.0 Hz, 1H)7.11(ddd, J-8.1, 5.4, 2.6Hz, 1H)7.23(dd, J-6.8, 1.2Hz, 1H)7.31(d, J-8.1 Hz, 1H)7.40-7.47(m, 2H)7.51-7.61(m, 2H)7.92(d, J-8, 1H) 7.8 (dd, 8H) 7.8, 8, 1H) 7.8 (ddd, 8H) 7.8, 8H) 7.8 (ddd, 8H) 1H) 7.8, 8, 1H) 7.8 (ddd, 8H) 7.7.7.7.7.7.7.7.7.7.06-7.8, 8H) 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.34; m/z is 545[ M + H ] +.

Step 2: 5ml of 1N hydrochloric acid are added to 0.47g of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]2-methylpropan-2-yl (E) -2- (tetrahydro-2H-pyran-4-ylamino) benzoate in 4ml diIn an alkane. The reaction mixture was heated in a microwave at 100 ℃ for 2 hours and then concentrated under reduced pressure. The residue was purified twice by silica gel chromatography, eluting sequentially with a mixture of dichloromethane and methanol (98/2, vol) and then with a mixture of cyclohexane and ethyl acetate (50/50, vol) to give 150mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ]-2- (tetrahydro-2H-pyran-4-ylamino) benzoic acid, in the form of a yellow powder, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.38-1.49(m, 2H)1.90-1.98(m, 2H)3.36-3.46(m, 2H)3.61 (width s, 1H)3.77-3.86(m, 2H)6.67(d, J ═ 7.8Hz, 1H)6.87(s, 1H)7.09(ddd, J ═ 8.0, 5.1, 3.1Hz, 1H)7.21(dd, J ═ 6.8, 1.2Hz, 1H)7.31(d, J ═ 7.8Hz, 1H)7.41-7.45(m, 2H)7.50-7.60(m, 2H)8.11(d, J ═ 8.3Hz, 1H)8.28(dd, J ═ 7.8, 0.5, 1H) 8.11(d, J ═ 8.3Hz, 1H)8.28 (ddh, J ═ 7.8, 1H) 8.9, 1H (ddh) 7.8, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.11; m/z 489[ M + H ] +; 487[ M + H ] -.

And step 3: 0.2g of (1H-benzotriazol-1-yloxy) [ tris (dimethylamino)]Hexafluorophosphate (BOP), 62mg of Hydroxybenzotriazole (HOBT), 33mg of ammonium chloride and 0.25ml of diisopropylethylamine were added successively to 0.15g of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- (tetrahydro-2H-pyran-4-ylamino) benzoic acid in a solution of 20ml of N, N-dimethylformamide. The reaction mixture was stirred at ambient temperature for 12 hours, then diluted with distilled water and extracted with ethyl acetate. The organic phase is washed successively with distilled water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (70/30 vol) to give 100mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ]-2- (tetrahydro-2H-pyran-4-ylamino) benzamide, in the form of a white solid, characterized as follows:

melting point (Buchi melting point B-545) ═ 256 ℃.

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.37-1.47(m, 2H)1.89-1.97(m, 2H)3.37-3.44(m, 2H)3.57-3.67(m, 1H)3.76-3.83(m, 2H)6.73(dd, J-8.3, 2.0Hz, 1H)6.95(d, J-1.7 Hz, 1H)7.07-7.13(m, 1H)7.22(dd, J-7.1, 1.0, 1H)7.30 (width s, 1H)7.32(d, J-7.8 Hz, 1H)7.41-7.45(m, 2H)7.50-7.61(m, 2H)7.92(d, J-8.3, 1H)8.00 (J-8.00, 1H) 7.9, 8H) 7.9 (dd, 1H)6.9 (dd, 1H) 6.1, 1H) 6.0 Hz, 1H)7.0 (1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.05; m/z 488[ M + H ] +; 486[ M-H ] -.

Example 127:4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) amino]Synthesis of benzamide

Step 1: 0.95g of potassium carbonate and 7.8ml of 4-amino-1, 2, 2, 6, 6-pentamethylpiperidine are added in succession to a solution of 1.06g of 2-methylpropan-2-yl 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2-fluorobenzoate obtained in step 1 of example 49 in 8ml of dimethyl sulfoxide. The reaction mixture was heated in a microwave at 90 ℃ for 2 hours and 15 minutes, and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution and dried over magnesium sulfate. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (97/3 vol) to give 0.8g of 2-methylpropan-2-yl 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2- [ (1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) amino ] benzoate as a yellow oil characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 0.95(s, 6H)1.13(s, 6H)1.32(t, J ═ 11.0Hz, 2H)1.59(s, 9H)1.99(d, J ═ 11.7Hz, 2H)2.16(s, 3H)3.77 (width s, 1H)6.85(dd, J ═ 8.4, 1.6Hz, 1H)7.05(s, 1H)7.12(td, J ═ 8.1, 1.0Hz, 1H)7.24(dd, J ═ 7.2, 0.9Hz, 1H)7.31(d, J ═ 7.8Hz, 1H)7.44(dd, J ═ 8.3, 7.2, 1.1Hz, 1H)7.54-7.61(m, 7.2 (m, 7.7.7H) 7.32 (t, J ═ 8.7.7H), 7.7.7.7.7.7.7.7.7.7.7.7.8H, 1Hz, 1H, 7.3 (dd, 8H), 7.3, 7.7.7.7.7.3, 7.7.7.7.7.7, 8H, 1Hz, 1H.

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 4.30; m/z 614[ M + H ] +.

Step 2: 7.7ml of 1N hydrochloric acid are added to 0.79g of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) amino]Benzoic acid 2-methylpropan-2-yl ester in 5ml diIn an alkane. The reaction mixture was heated in a microwave at 100 ℃ for 2 hours and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (95/5 vol) to give 280mg of 4- [4- (6-cyanopyridin-3-yl) -9H -carbazol-9-yl]-2- [ (1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) amino]Benzoic acid, in the form of a pale yellow powder, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMS0-d 6): 1.22 (width s, 6H)1.36 (width s, 6H)1.70 (width s, 2H)2.09-2.22(m, 2H)2.56 (width s, 3H)3.97 (width s, 1H)6.80(d, J ═ 8.1Hz, 1H)7.08-7.14(m, 2H)7.23(dd, J ═ 7.1, 0.7Hz, 1H)7.32(d, J ═ 8.1Hz, 1H)7.44(td, J ═ 8.6, 1.0Hz, 1H)7.55-7.61(m, 2H)7.68(d, J ═ 8.3Hz, 1H)8.12(d, J ═ 8.6Hz, 1H)8.28(dd, J ═ 8.8, 8, 1H)8.12 (dd, 8.6Hz, 1H, 8.8, 8, 1H) 1H, 1H (dd, 8.9, 1H).

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 3.66; 558[ M + H ] +; 556[ M + H ] -.

And step 3: 330mg of (1H-benzotriazol-1-yloxy) [ tris (dimethylamino)]Hexafluorophosphate (BOP), 100mg of Hydroxybenzotriazole (HOBT), 54mg of ammonium chloride and 0.41ml of diisopropylethylamine were added in that order to 280mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) amino]Benzoic acid in 30ml of N, N-dimethylformamide. The reaction mixture was stirred at ambient temperature for 12 hours, then diluted with distilled water and extracted with ethyl acetate. The organic phase is then washed with distilled water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane, acetonitrile and methanol (85/7.5/7.5, vol) to give 60mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ]-2- [ (1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) amino]Benzamide, in the form of a white solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 0.94(s, 6H)1.11(s, 6H)1.26(t, J ═ 11.4Hz, 2H)1.91-1.99(m, 2H)2.15(s, 3H)3.67 (width s, 1H)6.78(dd, J ═ 8.2, 1.8Hz, 1H)6.95(d, J ═ 2.0Hz, 1H)7.11(td, J ═ 7.8, 0.7Hz, 1H)7.23(dd, J ═ 7.2, 0.9Hz, 1H)7.29 (width s, 1H)7.31(d, J ═ 7.8Hz, 1H)7.44(ddd, J ═ 8.4, 7.3, 0.9, 1H) 7.53-7.65 (m, 7.8H), 7.8H (ddh), 7.8H, 1H)7.44(ddd, J ═ 8.4, 7.3, 0.9, 1H) 7.53-7.8 (d, 7.8H), 7.8H, 7.8 (ddh, 1H) 7.8H, 7.8, 1H, 7.8H, 1H, 8H, 1H, 7.8H, 1H, 8H, 1H, 8H, 7.8H, 1.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.84; m/z 557[ M + H ] +; 555[ M-H ] -.

Example 128: aminoacetic acid 4-trans- { [ 2-carbamoyl-5- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of pyridin-3-ylamino } cyclohexyl ester

Step 1: a solution of 500mg of 2-cyano-3, 5-difluoropyridine, 493mg of trans-4-aminocyclohexanol and 987mg of potassium carbonate in 7.5ml of dimethyl sulfoxide was introduced into a 5ml microwave tube reactor. The mixture was then heated in a microwave at 115 ℃ for 1 hour. The reaction medium is poured into 100ml of water and 100ml of ethyl acetate. The aqueous phase was back-extracted twice with 50ml ethyl acetate. The combined organic phases were washed with water and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash chromatography on 40g silica gel, eluting with a mixture of ethyl acetate and cyclohexane (50/50 vol), the first eluting product was recovered, thereby affording 309mg of 2-cyano-5-fluoro-3- (4-trans-hydroxycyclohexylamino) pyridine, in the form of a white powder, characterized as follows:

TLC (silica gel): rf is 0.20 (ethyl acetate/cyclohexane 50/50).

-1H NMR spectrum (400MHz, DMSO-d)₆，d ppm)：1.20-1.47(m，4H)1.75-1.89(m，4H)3.32-3.45(m，2H)4.54(d，J＝4.4Hz，1H)6.23(d，J＝8.1Hz，1H)7.30(dd，J＝12.1，2.3Hz，1H)7.85(d，J＝2.4Hz，1H)。

Step 2: 338.5mg of 4- (quinolin-3-yl) -9H-carbazole obtained according to step 1 of example 2 are dissolved in 20mL of dimethylformamide under argon in a 50mL three-necked flask. 69mg of sodium hydride (60% in oil) was then added and the mixture was stirred at ambient temperature for 30 minutes, then at 50 ℃ for 30 minutes. 297.6mg of 2-cyano-5-fluoro-3- (4-trans-hydroxycyclohexylamino) pyridine obtained in the preceding step were then added at 50 ℃ and the mixture was heated at 80 ℃ for 2 hours. The reaction medium is poured into 50ml of water and 50ml of ethyl acetate. The aqueous phase was back-extracted twice with 25ml ethyl acetate. The combined organic phases were washed with water and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. This gives 580mg of a mixture containing predominantly 3- (4-trans-hydroxycyclohex-1-ylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridinecarbonitrile as a beige powder, which is used as such in the subsequent steps and is characterized as follows:

LC/MS (method C): retention time 4.92 minutes.

And step 3: 575mg of 3- (4-trans-hydroxycyclohex-1-ylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridinecarbonitrile obtained in the preceding step were dissolved in 6ml of dimethyl sulfoxide and 15ml of ethanol, followed by addition of 2.25ml of a 1M aqueous sodium hydroxide solution and 2.07ml of a 30% aqueous hydrogen peroxide solution in that order. After stirring for 5 minutes at ambient temperature, the reaction medium is poured into 100ml of water and 100ml of ethyl acetate. The aqueous phase is back-extracted 3 times with 25ml of ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography on 50g silica gel eluting with a mixture of dichloromethane and ethanol (95/5 vol) gave 512mg of 3- (4-trans-hydroxycyclohexyl) amino ] -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-2-carboxamide which had been described in example 58, but using a different synthetic route, in the form of an off-white powder, which was characterized as follows:

LC/MS (method C): retention time 4.84 minutes.

And 4, step 4: the process is carried out as in example 23, but using 180mg of 3- (4-trans-hydroxycyclohexyl) amino ] -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-2-carboxamide obtained in the preceding step, 119.5mg of N-tert-butoxycarbonylglycine, 83.3mg of 4-dimethylaminopyridine and 224mg of O- [ (ethoxycarbonyl) cyanomethyleneamino ] -N, N, N ', N' -tetramethylurea (TOTU) in 17ml of dichloromethane and 3ml of dimethylformamide and holding at ambient temperature for 20 hours. Then, 119.5mg of N-tert-butoxycarbonylglycine, 83.3mg of 4-dimethylaminopyridine and 224mg of O- [ (ethoxycarbonyl) cyanomethyleneamino ] -N, N, N ', N' -tetramethylurea (TOTU) were added again, and the mixture was stirred at 40 ℃ for 6 hours. After workup and purification by flash chromatography on 70g of silica gel, elution is carried out with a gradient of a mixture of dichloromethane and ethanol (from 100/0 to 97/3 by volume), whereby 223mg of 4-trans- { 2-carbamoyl-5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] phenylamino } cyclohexyl tert-butoxycarbonylaminoacetate are obtained in the form of a beige powder, which is characterized as follows:

LC/MS (method C): the retention time Tr (min) was 5.51 min.

And 5: the process is carried out as in example 25, but using 215mg of 4-trans- { 2-carbamoyl-5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] phenylamino } cyclohexyl tert-butoxycarbonylaminoacetate obtained in the preceding step, in 5.4ml of dichloromethane and 5.4ml of trifluoroacetic acid, held at ambient temperature for 1 hour. After concentration under reduced pressure, the residue was dissolved in 20ml of ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and then with water. After drying over magnesium sulfate and concentration to about 1ml, the crystals formed were spin-dried over sintered glass and washed twice with 1ml of diisopropyl ether. This gave 139mg of 4-trans- { [ 2-carbamoyl-5- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridin-3-ylamino } cyclohexyl aminoacetate in the form of pale beige fine crystals, which were characterized as follows:

TLC (silica gel): rf ═ 0.6 (dichloromethane/ammonia in 7M methanol 90/10).

-1H NMR Spectrum(400MHz，DMSO-d₆，δppm)：1.34-1.58(m，4H)1.91(d，J＝12.2Hz，2H)2.05(d，J＝10.8Hz，2H)3.24-3.29(m，2H)3.49-3.61(m，1H)4.68-4.79(m，1H)7.06(t，J＝8.1Hz，1H)7.27(d，J＝7.8Hz，1H)7.34(d，J＝7.3Hz，1H)7.38-7.48(m，2H)7.49-7.66(m，4H)7.74(t，J＝7.3Hz，1H)7.90(td，J＝7.7，1.2Hz，1H)8.01(d，J＝2.0Hz，1H)8.10-8.23(m，3H)8.62(d，J＝2.0Hz，1H)8.80(d，J＝7.8Hz，1H)9.15(d，J＝2.4Hz，1H)。

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 0.88; [ M + H ]]₊＝585。

Example 129: 3- (2-fluoroethylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of pyridine-2-carboxamides

Step 1: a solution of 500mg of 2-cyano-3, 5-difluoropyridine, 426mg of 2-fluoroethylamine hydrochloride, 987mg of potassium carbonate and 433mg of triethylamine in 10ml of dimethyl sulfoxide was introduced into a 20ml microwave tube reactor. The mixture was then heated in a microwave at 115 ℃ for 1.5 hours. The reaction medium is poured into 100ml of water and 100ml of ethyl acetate. The aqueous phase was back-extracted twice with 50ml ethyl acetate. The combined organic phases were washed with water and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash chromatography on 70g of silica gel, eluting with a mixture of ethyl acetate and cyclohexane (30/70 vol), the first eluting product was recovered, thus obtaining 125mg of 2-cyano-5-fluoro-3- (2-fluoroethylamino) pyridine, in the form of a white powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆) δ ppm 3.55(dq, J ═ 26.0, 5.0, 5.0Hz, 2H)4.57(dd, J ═ 47.4, 5.0Hz, 2H)6.91 (width s, 1H)7.33(dd, J ═ 12.0, 2.2Hz, 1H)7.90(d, J ═ 2.4Hz, 1H).

400mg of 2-cyano-3-fluoro-5- (2-fluoroethylamino) pyridine was isolated by recovering the second eluted product.

Step 2: 192.8mg of 4- (quinolin-3-yl) -9H-carbazole obtained according to step 1 of example 2 are dissolved in 10mL of dimethylformamide under argon in a 25mL three-necked flask. Then 32mg of sodium hydride (60% in oil) was added and the mixture was stirred at ambient temperature for 30 minutes. Then 120mg of 2-cyano-5-fluoro-3- (2-fluoroethylamino) pyridine obtained in the previous step was added, and the mixture was heated at 50 ℃ overnight. The reaction medium is poured into 50ml of water and 50ml of ethyl acetate. The aqueous phase was back-extracted twice with 25ml ethyl acetate. The combined organic phases were washed with water and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash chromatography on silica gel, elution is carried out with dichloromethane, thus obtaining 150mg of a mixture which is used as such in the subsequent steps and mainly contains 35% of 3- (2-fluoroethylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridinecarbonitrile, which is characterized as follows:

LC/MS (method C): the retention time was 5.23 minutes,

and 65% of the starting 4- (quinolin-3-yl) -9H-carbazole.

And step 3: 160mg of the mixture obtained in the preceding step was dissolved in 2ml of dimethyl sulfoxide and 4ml of ethanol, and then 0.233ml of a 1M aqueous sodium hydroxide solution and 0.225ml of a 30% aqueous hydrogen peroxide solution were sequentially added. After stirring for 5 minutes at ambient temperature, the reaction medium is poured into 50ml of water and 50ml of ethyl acetate. The aqueous phase was back-extracted twice with 50ml ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash chromatography on 15g silica gel, elution was carried out with a mixture of dichloromethane and ethanol (94/6 vol), thus obtaining 35mg of 3- (2-fluoroethylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-2-carboxamide, in the form of a beige powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆，δppm)：3.62(dq，J＝27.9，5.0Hz，2H)4.63(dt，J＝47.7，5.0Hz，2H)7.06(t，J＝7.5Hz，1H)7.25(d，J＝8.1Hz，1H)7.33(dd，J＝6.4，2.0Hz，1H)7.41(t，J＝7.1Hz，1H)7.50(d，J＝8.1Hz，1H)7.54-7.65(m，4H)7.74(t，J＝7.6Hz，1H)7.89(t，J＝7.7Hz，1H)8.08(d，J＝2.0Hz，1H)8.11-8.22(m，3H)8.62(d，J＝1.7Hz，1H)8.97(t，J＝5.0Hz，1H)9.15(d，J＝2.2Hz，1H)。

Mass spectrometry (LC/MS method a): retention time Tr (min) ═ 1.10; [ M + H ]]₊＝476。

Examples 130 and 131: 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-2- [1(S, R), 2(R, S) -2-hydroxymethylcyclohexyl-1-amino]) Separation of enantiomers of benzamides

80mg of the product obtained in example 97 are resolved on a Chiralpack T30420 μm 700g silica column eluting at 150ml/min with a mixture of heptane, ethanol and trifluoroacetic acid (90/10/0.1 as a mixture).

When the first eluted product was recovered, 33mg of the dextrorotatory enantiomer of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [1(S, R), 2(R, S) -2-hydroxymethylcyclohexyl-1-amino ]) benzamide were obtained, in the form of a beige solid, characterized as follows:

-optical activity: alpha is alpha₅₈₉ ²⁰Plus 30 ° +/-1.1 ° (C0.26% in methanol).

Analytical HPLC (Chiralpak T30420 μm column; 6X 250 mm; 90/10/0.1 heptane/ethanol/TFA, 1 ml/min): retention time 23 minutes.

-1H NMR spectrum (400MHz, DMSO-d)₆+TFA，δppm)：1.23-1.39(m，4H)1.43-1.54(m，1H)1.56-1.70(m，2H)1.76-1.88(m，1H)1.98-2.09(m，1H)3.25-3.36(m，1H)3.42-3.60(m，2H)6.75(dd，J＝8.3，2.0Hz，1H)6.98(d，J＝1.7Hz，1H)7.22-7.29(m，1H)7.52-7.63(m，3H)7.69(d，J＝8.1Hz，1H)7.71-7.79(m，2H)7.82-7.91(m，2H)7.96(d，J＝8.3Hz，1H)8.04(dd，J＝9.0，4.4Hz，1H)。

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.94; [ M + H ]]₊＝548；[M-H]_-＝546。

-when the second eluted product is recovered, 32mg of the levorotatory enantiomer of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [1(S, R), 2(R, S) -2-hydroxymethylcyclohexyl-1-amino ]) benzamide are obtained, in the form of a beige solid, characterized as follows:

-optical activity: alpha is alpha₅₈₉ ²⁰-18 ° +/-0.9 ° (C ═ 0.3% in methanol).

Analytical HPLC (Chiralpak T30420 μm column; 6X 250 mm; 90/10/0.1 heptane/ethanol/TFA, 1 ml/min): retention time 42.5 minutes.

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.17-1.35(m, 4H)1.44 (width s, 1H)1.51-1.69(m, 2H)1.72-1.87(m, 1H)2.02(d, J ═ 10.3Hz, 1H)3.20-3.28 (mask, 1H)3.37-3.60(m, 2H)4.38(t, J ═ 4.4Hz, 1H)6.67(dd, J ═ 8.3, 2.0Hz, 1H)6.91(d, J ═ 2.0Hz, 1H)7.08-7.21(m, 2H)7.25(br.s., 1H)7.41-7.47(m, 2H)7.52-7.69(m, 5H)7.90(d, J ═ 8.6, 1H) 7.44 (d, J ═ 8.6, 1H) 7.19 (d, 8.19, 8H), 8H, 1H, 13H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.94; [ M + H ]]₊＝548；[M-H]_-＝546。

Example 132:synthesis of 5- [4- (quinolin-3-yl) -9H-carbazol-9-yl) -3- (2, 2, 6, 6-tetramethylpiperidin-4-ylamino) pyridine-2-carboxamide

5- [4- (quinolin-3-yl) -9H-carbazol-9-yl) -3- (2, 2, 6, 6-tetramethylpiperidin-4-ylamino) pyridine-2-carboxamide obtained by carrying out the method as in example 122, but using 4- (quinolin-3-yl) -9H-carbazole and 5-fluoro-3- (1, 2, 2, 6, 6-tetramethylpiperidin-4-ylamino) pyridine-2-carbonitrile obtained according to step 1 of example 2, as such by carrying out the process used for the preparation of 5-fluoro-3- (1, 2, 2, 6, 6-tetramethylpiperidin-4-ylamino) pyridine-2-carbonitrile in step 1 of example 122, according to the following scheme:

example 133:3- [ (2-pyridin-2-yl) ethylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of pyridine-2-carboxamides

Step 1: a solution of 841mg of 2-cyano-3, 5-difluoropyridine, 880mg of 2- (2-aminoethyl) pyridine and 1.658g of potassium carbonate in 12.5ml of dimethyl sulfoxide is introduced into a 20ml microwave tube reactor. The mixture was then heated in a microwave at 115 ℃ for 1.5 hours. The reaction medium is poured into 100ml of water and 100ml of ethyl acetate. The aqueous phase was back-extracted twice with 50ml ethyl acetate. The combined organic phases were washed with water and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography on 70g of silica gel eluting with a mixture of ethyl acetate and cyclohexane (40/60 vol) recovered the first eluting product, thereby affording 549mg of 2-cyano-5-fluoro-3- (2-pyridin-2-ylethylamino) pyridine, in the form of a beige powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 3.02(t, J ═ 7.1Hz, 2H)3.57(q, J ═ 6.8Hz, 2H)6.94 (width s, 1H)7.15-7.27(m, 2H)7.33(d, J ═ 7.8Hz, 1H)7.71(td, J ═ 7.6, 1.8Hz, 1H)7.86(d, J ═ 2.4Hz, 1H)8.51(d, J ═ 4.9Hz, 1H).

Step 2: 236.5mg of 4- (quinolin-3-yl) -9H-carbazole obtained according to step 1 of example 2 are dissolved in 20mL of dimethylformamide under argon in a 50mL three-necked flask. Then 48mg of sodium hydride (60% in oil) was added and the mixture was stirred at 50 ℃ for 30 minutes. Then 213mg of 2-cyano-5-fluoro-3- (2-pyridin-2-ylethylamino) pyridine obtained in the previous step was added, and the mixture was heated at 80 ℃ for 4 hours. The reaction medium is poured into 50ml of water and 50ml of ethyl acetate. The aqueous phase was back-extracted twice with 25ml ethyl acetate. The combined organic phases were washed with water and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. This gives 420mg of a mixture which is used as such in the subsequent step and contains predominantly 3- [ (2-pyridin-2-yl) ethylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-2-carbonitrile, which is characterized by:

LC/MS (method C): retention time 4.55 minutes.

And step 3: 300mg of the mixture obtained in the subsequent step was dissolved in 3.3ml of dimethyl sulfoxide and 8ml of ethanol, and then 1.25ml of a 1M aqueous solution of sodium hydroxide and 1.15ml of a 30% aqueous solution of hydrogen peroxide were sequentially added. After stirring for 5 minutes at ambient temperature, the reaction medium is poured into 50ml of water and 50ml of ethyl acetate. The aqueous phase was back-extracted twice with 50ml ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash chromatography on 35g of silica gel, elution was carried out with a mixture of dichloromethane and ethanol (96/4 vol), followed by crystallization from 5ml of diisopropyl ether, whereby 128mg of 3- [ (2-pyridin-2-yl) ethylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-2-carboxamide was obtained in the form of an off-white powder, which was characterized as follows:

TLC (silica gel): rf ═ 0.21 (dichloromethane/ethanol 95/5).

-1H NMR spectrum (400MHz, DMSO-d)₆)δppm 3.08(t，J＝6.6Hz，2H)3.64(q，J＝5.8Hz，2H)7.06(t，J＝7.6Hz，1H)7.19(dd，J＝6.2，5.0Hz，1H)7.26(d，J＝7.8Hz，1H)7.34(d，J＝7.3Hz，2H)7.42(t，J＝7.7Hz，1H)7.46-7.65(m，5H)7.65-7.78(m，2H)7.89(t，J＝7.5Hz，1H)8.04(s，1H)8.07-8.17(m，2H)8.19(d，J＝8.6Hz，1H)8.45(d，J＝4.4Hz，1H)8.63(s，1H)8.84(br.s.，1H)9.16(s，1H)。

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 3.83; 535[ M + H ] +, M/z.

Example 134:4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (2-fluoroethyl) amino group]Synthesis of benzamide

Step 1: 4.83g of potassium carbonate and 3g (40mmol) of 2-fluoroethylamine are added in succession to a solution of 0.7g of 2-methylpropan-2-yl 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2-fluorobenzoate obtained in step 1 of example 49 in 5ml of dimethyl sulphoxide. The reaction mixture was heated in a microwave at 90 ℃ for 2 hours and 50 minutes, and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by chromatography on silica gel eluting with dichloromethane to give 0.15g of 2-methylpropan-2-yl 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2- [ (2-fluoroethyl) amino ] benzoate as a white powder, which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.60(s, 9H)3.59(dq, J ═ 28.4, 5.4Hz, 2H)4.64(dt, J ═ 47.9, 4.9Hz, 2H)6.84(dd, J ═ 8.6, 2.0Hz, 1H)7.06(d, J ═ 2.0Hz, 1H)7.11(t, J ═ 6.6Hz, 1H)7.23(dd, J ═ 6.7, 1.3Hz, 1H)7.31(d, J ═ 8.1Hz, 1H)7.43(t, J ═ 7.3Hz, 1H)7.51(d, J ═ 7.8Hz, 1H)7.54-7.63(m, 2H)8.07(d, J ═ 8.6, 1H)8.12(t, J ═ 8.8, 8, 1H) 7.02 (d, 8.8, J ═ 8.8, 8H) 7.8, 1H (d, 1H) 8.9, 8(d, 8.9H), 1H) 1.9, 1H) 7.9.9.9 (d, 1.0 Hz, 1H)7.0 Hz, 1.0 Hz, 1H) 7.9H) 7.7.7.7.7.7..

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.32; m/z is 507[ M + H ] +.

Step 2: 1.54ml of 1N hydrochloric acid are added to 0.13g of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (2-fluoroethyl) amino group]Benzoic acid 2-methylpropan-2-yl ester in 6ml diIn an alkane. The reaction mixture was heated in a microwave at 100 ℃ for 2 hours and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (97/3 vol) to give 40mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (2-fluoroethyl) amino group]Benzoic acid is in the form of an off-white powder, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 3.45-3.63(m, 2H)4.62(dt, J ═ 47.9, 4.6Hz, 2H)6.70-6.84(m, 1H)6.96(s, 1H)7.10(t, J ═ 7.6Hz, 1H)7.22(dd, J ═ 7.5, 0.9Hz, 1H)7.31(d, J ═ 8.1Hz, 1H)7.40-7.46(m, 1H)7.51(d, J ═ 8.6Hz, 1H)7.54-7.63(m, 2H)8.10(d, J ═ 8.6Hz, 1H)8.28(d, J ═ 7.8Hz, 1H)8.35(dd, J ═ 8.1, 2.0, 1H) 8.03 (d, 2H), 1H).

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 4.76; 451[ M + H ] +; 449[ M + H ] -.

And step 3: 58mg of (1H-benzotriazol-1-yloxy) [ tris (dimethylamino)]Hexafluorophosphate (BOP), 18mg of Hydroxybenzotriazole (HOBT), 9mg of ammonium chloride and 0.07ml of diisopropylethylamine were added successively to 40mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (2-fluoro)Ethyl) amino group]Benzoic acid in 30ml of N, N-dimethylformamide. The reaction mixture was stirred at ambient temperature for 2 hours, then diluted with distilled water and extracted with ethyl acetate. The organic phase is then washed with distilled water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane, acetonitrile and methanol (96/2/2 vol) to give 30mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ]-2- [ (2-fluoroethyl) amino group]Benzamide, in the form of a white solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 3.50(dq, J-27.9, 5.4Hz, 2H)4.60(dt, J-47.9, 4.9Hz, 2H)6.79(dd, J-8.1, 1.7Hz, 1H)6.96(d, J-1.5 Hz, 1H)7.10(td, J-7.3, 1.0Hz, 1H)7.20-7.25(m, 1H)7.31(d, J-8.3 Hz, 1H)7.35 (width s, 1H)7.40-7.51(m, 2H)7.55-7.59(m, 2H)7.93(d, J-8.3 Hz, 1H)8.02 (width s, 1H)8.28(d, J-7.8, 8H) 8.02 (d, J-8.6H, 1H)8.6, 1H) 6.6 (dd, 1H)6.9, 1H) 6Hz, 1H, and 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.06; m/z 450[ M + H ] +; 448[ M-H ] -.

Example 135:4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (8-methyl-8-azabicyclo [ 3.2.1)]Oct-3-yl) amino]Synthesis of benzamide

Step 1: 0.89g of potassium carbonate and 6g of 8-methyl-8-azabicyclo [3.2.1] oct-3-amine are added in succession to a solution of 1g of 2-methylpropan-2-yl 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2-fluorobenzoate obtained in step 1 of example 49 in 8ml of dimethyl sulfoxide. The reaction mixture was heated in a microwave at 100 ℃ for 1 hour 40 minutes and then diluted with distilled water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (92/8 as a mixture) to give 0.34g of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2- [ (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) amino ] benzoic acid 2-methylpropan-2-yl ester as a white powder characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.60(s, 9H)1.62-1.67(m, 2H)1.86-1.93(m, 2H)2.01-2.12(m, 4H)2.17(s, 3H)3.07(s, 2H)3.65-3.72(m, 1H)6.74-6.80(m, 2H)7.11(td, J ═ 7.8, 1.2Hz, 1H)7.23(dd, J ═ 4.4, 3.7Hz, 1H)7.30(d, J ═ 8.1Hz, 1H)7.40-7.46(m, 1H)7.48(d, J ═ 8.1Hz, 1H)7.56-7.60(m, 2H)8.05(d, J ═ 9.0, 1H)8.28 (m, J ═ 8.8, 7.8, 8, 7H) 7.6 (dd, 8.6, 6H), 1H) (dd, 8.7.6, 8.7 Hz, 1H).

Mass Spectroscopy (LC/MS; method B): retention time Tr (min) ═ 4.30; 584[ M + H ] +.

Step 2: 3.49ml of 1N hydrochloric acid are added to 340mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (8-methyl-8-azabicyclo [ 3.2.1)]Oct-3-yl) amino]Benzoic acid 2-methylpropan-2-yl ester in 6ml diIn an alkane. The reaction mixture was heated in a microwave at 100 ℃ for 2 hours and then concentrated under reduced pressure. The residue was purified by trituration with diisopropyl ether to give 330mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (8-methyl-8-azabicyclo [ 3.2.1)]Oct-3-yl) amino]Benzoic acid hydrochloride, in the form of a pale yellow powder, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 2.05-2.14(m, 2H)2.19-2.44(m, 6H)2.70(d, J-4.9 Hz, 3H)3.80-3.95(m, 3H)6.85(dd, J-8.6, 2.0Hz, 1H)6.93(d, J-1.7 Hz, 1H)7.12(t, J-7.5 Hz, 1H)7.24(dd, J-6.8, 1.0Hz, 1H)7.31(d, J-8.1 Hz, 1H)7.43(t, J-7.8 Hz, 1H)7.49-7.66(m, 3H)8.14(d, J-8.8 Hz, 1H)8.29(d, J-8, 1H) 8.8, 1H) 8.14(d, J-8.8, 1H) 2.8, 13H) 2.70(d, J-1H) 1H, 1H) 7.8 (1H) 7.8, 1H) 7.8 (d, 13H) 1H, 1H) 7.8, 1H) 7.8 (1H) 1H, 1H.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.87; m/z 528[ M + H ] +; 526[ M + H ] -.

And step 3: 390mg of (1H-benzotriazol-1-yloxy) [ tris (dimethylamino)]Hexafluorophosphate (BOP), 120mg of Hydroxybenzotriazole (HOBT), 60mg of ammonium chloride and 0.48ml of diisopropylethylamine were added in that order to 330mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl]-2- [ (8-methyl-8-azabicyclo [ 3.2.1)]Oct-3-yl) amino]Benzoic acid in 10ml of N, N-dimethylformamide. The reaction mixture was stirred at ambient temperature for 4 hours, then diluted with distilled water and extracted with ethyl acetate. The organic phase is then washed with distilled water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a gradient of methanol in dichloromethane to give 107mg of a solid which was taken up in dichloromethane and washed successively with 1M dipotassium hydrogen phosphate (potassium monopophospate), saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. This gave 15mg of 4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ]-2- [ (8-methyl-8-azabicyclo [ 3.2.1)]Oct-3-yl) amino]Benzamide, in the form of a white solid, characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.61(d, J ═ 14.2Hz, 2H)1.86-2.09(m, 6H)2.16(s, 3H)3.04(s, 2H)3.53-3.66(m, 1H)6.66(d, J ═ 2.0Hz, 1H)6.71(dd, J ═ 8.1, 2.0Hz, 1H)7.10(ddd, J ═ 8.1, 6.5, 1.7Hz, 1H)7.22(dd, J ═ 6.1, 2.2Hz, 1H)7.31(d, J ═ 8.1Hz, 1H)7.39-7.49(m, 2H)7.53-7.59(m, 2H)7.93(d, J ═ 8.3, 1H)8.28, J ═ 8.9, 8, 8.9, 1H) 7.9, 1Hz, 1H) 7.9 (dd, 1H) 7.9, 1Hz, 1H) 7.9 (dd, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.80; 527[ M + H ] +, M/z.

Example 136: 5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -3- (tetrahydropyran-4-yl) amino) pyridine-2-carboxamide

Step 1: 172mg of the methyl 9H-carbazole-4-carboxylate obtained according to example 3, step 1 were dissolved in 5.5mL of dimethylformamide under argon in a 25mL three-necked flask. 45.9mg of sodium hydride (60% in oil) was then added and the mixture was stirred at ambient temperature for 30 minutes, then at 50 ℃ for 30 minutes. 169mg of 2-cyano-5-fluoro-3- (tetrahydropyran-4-yl) aminopyridine obtained according to example 116, step 1 were added successively, and the mixture was heated at 50 ℃ overnight. The reaction medium is poured into 50ml of water and 50ml of ethyl acetate. The aqueous phase was back-extracted twice with 25ml ethyl acetate. The combined organic phases were washed with water and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash chromatography on 20g silica gel, elution was carried out with a mixture of dichloromethane and acetonitrile (95/5, vol), whereby 120mg of methyl 1H-1- [3- (tetrahydropyran-4-yl) amino-2-carbamoylpyridin-5-yl ] carbazole-4-carboxylate were obtained, in the form of a beige powder, which was characterized as follows:

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.10; m/z is 427[ M + H ] +.

Step 2: 53.2mg of 1, 2-diamino-4-fluorobenzene are dissolved in 4mL of toluene and 2mL of tetrahydrofuran under argon in a 25mL three-necked flask, 0.422mL of a 2M solution of trimethylaluminum in toluene is then added dropwise, and the mixture is stirred for 15 minutes at ambient temperature. A solution of 120mg of the methyl 1H-1- [3- (tetrahydropyran-4-yl) amino-2-carbamoylpyridin-5-yl ] carbazole-4-carboxylate obtained in the preceding step in 2ml of toluene is then added dropwise. The reaction medium is refluxed for 3 hours. After cooling to ambient temperature, 10ml of water and a few drops of 1M aqueous hydrochloric acid were added to adjust the mixture to pH 4-5, and the mixture was extracted 3 times with 10ml of ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. This gave 165mg of a mixture of regioisomers of 1H-1- [3- (tetrahydropyran-4-yl) amino-2-carbamoylpyridin-5-yl ] carbazole-4-carboxylic acid 1, 2-diamino-4-fluorobenzamide, which was used as such in the subsequent step.

And step 3: 165mg of the mixture obtained in the preceding step and 2ml of acetic acid were introduced into a 5ml microwave tube reactor. The mixture was then heated at 100 ℃ for 45 minutes, then at 120 ℃ for 1.5 hours, and finally at 150 ℃ for 30 minutes in that order. After concentrating the acetic acid under reduced pressure, the residue was taken up with 20ml of water and 20ml of ethyl acetate, and then a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7-8. The organic phase is separated by settling and the aqueous phase is back-extracted twice with 20ml of ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash chromatography on 15g silica, elution with a mixture of heptane and ethyl acetate (55/45, vol) gave 18mg of 5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -3- (tetrahydropyran-4-yl) amino) pyridine-2-carboxamide in the form of a beige powder, which was characterized as follows:

-1H NMR spectrum (400MHz, DMSO-δ ppm): 1.37-1.52(m, 2H)1.95(d, J ═ 15.2Hz, 2H)3.37-3.46(m, 2H)3.65-3.78(m, 1H)3.78-3.89(m, 2H)7.17 (width s, 1H)7.23(t, J ═ 7.6Hz, 1H)7.36-7.53(m, 3H)7.54-7.73(m, 5H)7.85 (width s, 1H)8.00(d, J ═ 2.0Hz, 1H)8.21(br.s., 1H)8.74 (width s, 1H)8.88(d, J ═ 7.8Hz, 1H)13.14 (width s, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.91; 521[ M + H ] +; 519[ M-H ] -.

Example 137: 2- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of (E) -4- (tetrahydropyran-4-yl) amino) pyridine-5-carboxamide

Step 1: in a 25ml single neck round bottom flask, 300mg of 4, 6-dichloronicotinamide was dissolved in 4.5ml of ethanol and 4.5ml of dimethylacetamide, followed by addition of 238mg of 4-aminotetrahydropyran hydrochloride and 711mg of diisopropylethylamine. The mixture was then heated at 60 ℃ overnight. After concentration under reduced pressure, the residue was extracted with dichloromethane, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. After purification by flash chromatography on 25g silica, elution with a mixture of ethyl acetate and heptane (85/15, vol.) gave 132.5mg of 6-chloro-4- (tetrahydropyran-4-yl) aminonicotinamide, which was characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.32-1.46(m, 2H)1.88(d, J ═ 11.2Hz, 2H)3.47(td, J ═ 11.2, 2.2Hz, 2H)3.66-3.77(m, 1H)3.82(dt, J ═ 11.7, 3.6Hz, 2H)6.82(s, 1H)7.45 (width s, 1H)8.07 (width s, 1H)8.41(s, 1H)8.86(d, J ═ 8.1Hz, 1H).

Step 2: in a 25mL three-necked flask, 80mg of 6-chloro-4- (tetrahydropyran-4-yl) aminonicotinamide obtained in the previous step and 184.3mg of 4- (quinolin-3-yl) -9H-carbazole obtained according to step 1 of example 2 are dissolved under a nitrogen atmosphere in 7mL of a di-necked flaskIn an alkane, argon was then bubbled through the solution for 10 minutes, with prior heating at about 50 ℃. 306mg of cesium carbonate, 7mg (31. mu. mol) of palladium acetate and 22mg of 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene are then added in this order, and the mixture is heated at 90 ℃ for 3 hours under an argon atmosphere. After cooling, the reaction medium is treated with 20ml of acetic acidThe ethyl ester was diluted and the insoluble material was filtered through celite, rinsing twice with 10ml ethyl acetate. The combined filtrates were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by flash chromatography on 25g silica eluting with a gradient of a mixture of dichloromethane and methanol (from 98/2 to 95/5, vol.) gives 11.8mg of 2- [4- (quinolin-3-yl) -9H-carbazol-9-yl ]-4- (tetrahydropyran-4-yl) amino) pyridine-5-carboxamide, in the form of an off-white powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm)1.32-1.46(m, 2H)1.88(d, J ═ 11.2Hz, 2H)3.47(td, J ═ 11.2, 2.2Hz, 2H)3.66-3.77(m, 1H)3.82(dt, J ═ 11.7, 3.6Hz, 2H)6.82(s, 1H)7.45 (width s, 1H)8.07 (width s, 1H)8.41(s, 1H)8.86(d, J ═ 8.1Hz, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.95; m/z 514[ M + H ] +; m/z is 512[ M-H ] -.

Example 138:2- (8-methyl-8-azabicyclo [3.2.1]]Oct-3-yl) amino-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

The process is carried out as in example 3 step 3, but using 300mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained according to example 32 step 1, 301mg of potassium carbonate and 3g of 8-methyl-8-azabicyclo [3.2.1] oct-3-amine in 1.7ml of dimethyl sulfoxide and holding in a microwave at 115 ℃ for 1 hour and 15 minutes. Then 1.38ml (1.38mmol) of 1M aqueous sodium hydroxide solution, 1.33ml (13mmol) of 30% aqueous hydrogen peroxide solution and 8ml of ethanol are added to the reaction medium. After work-up as in example 3, step 3, it was then purified by flash chromatography on 10g of silica gel, eluting with a mixture of dichloromethane and ammonia in 7M solution (97/3, vol) in methanol, to give 150mg of 2- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) amino-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide, in the form of an off-white solid, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm)1.62(d, J-13.4 Hz, 2H)1.88-2.11(m, 6H)2.16(s, 3H)3.04 (width s, 2H)3.61(q, J-6.5 Hz, 1H)6.69(s, 1H)6.74(dd, J-8.4, 1.3Hz, 1H)7.02(t, J-7.5 Hz, 1H)7.24(d, J-8.1 Hz, 1H)7.29(d, J-6.6 Hz, 1H)7.33 (width s, 1H)7.39(t, J-7.6 Hz, 1H)7.47(d, J-8.1, 1H)7.51-7.63(m, 2H)7.73(t, J-7.6 Hz, 1H)7.47(d, J-8.1, 1H)7.51-7.63(m, 7.73, 7.8H) 7.8, 8H, 1H, 8H, 1H, 8H, 1H, 8H, and 7H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.82; m/z 552[ M + H ] + -.

Example 139:3- [ (2-hydroxy-2-methylpropylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of pyridine-2-carboxamides

Step 1: by the same operation in three times in succession, a solution of 1.8g of 2-cyano-3, 5-difluoropyridine, 1.375g of 2- (2-aminoethyl) pyridine and 3.552g of potassium carbonate in 27ml of dimethyl sulfoxide was introduced into a 20ml microwave tube reactor. The mixture was then heated in a microwave at 115 ℃ for 1 hour. The reaction medium is poured into 100ml of water and 200ml of ethyl acetate. The aqueous phase was back-extracted twice with 250ml ethyl acetate. The combined organic phases were washed with water and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash chromatography on 200g silica gel, eluting with a mixture of ethyl acetate and cyclohexane (50/50 vol), the first eluting product was recovered, thereby affording 768mg of 2-cyano-5-fluoro-3- (2-hydroxy-2-methylpropylamino) pyridine, in the form of a beige powder, which was characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆δ ppm): 1.14(s, 6H)3.16(d, J ═ 5.9Hz, 2H)4.67(s, 1H)6.21 (width s, 1H)7.36(dd, J ═ 12.0, 2.4Hz, 1H)7.86(d, J ═ 2.4Hz, 1H).

Step 2: 338.5mg of 4- (quinolin-3-yl) -9H-carbazole obtained according to step 1 of example 2 are dissolved in 20mL of dimethylformamide under argon in a 50mL three-necked flask. 69mg of sodium hydride (60% in oil) were then added and the mixture was stirred at 50 ℃ for 30 minutes. 265mg of 2-cyano-5-fluoro-3- (2-hydroxy-2-methylpropylamino) pyridine obtained in the preceding step are then added and the mixture is heated at 80 ℃ for 2 hours. The reaction medium is taken up in 50ml of ethanol and concentrated to dryness under reduced pressure. The resulting brown oil was purified by flash chromatography on 30g silica eluting with a mixture of dichloromethane and ethanol (95/5 vol). This gives 419mg of a mixture which is used as such in the subsequent steps and contains predominantly 3- [ (2-hydroxy-2-methylpropylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-2-carbonitrile, which is characterized by:

LC/MS (method C): retention time 5.39 minutes.

And step 3: 415mg of the mixture obtained in the preceding step was dissolved in 4.5ml of dimethyl sulfoxide and 11ml of ethanol, and then 1.71ml of a 1M aqueous solution of sodium hydroxide and 1.58ml of a 30% aqueous solution of hydrogen peroxide were added in this order. After stirring for 15 minutes at ambient temperature, the reaction medium is poured into 50ml of water and 50ml of ethyl acetate. The aqueous phase was back-extracted twice with 50ml ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated under reduced pressure. After crystallization from 20ml of diisopropyl ether and then from 5ml of ethyl acetate in this order, 401mg of 3- [ (2-hydroxy-2-methylpropylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-2-carboxamide are obtained in the form of a pale yellow foam, which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆，δppm)：1.18(s，6H)3.16(d，J＝5.6Hz，2H)4.58(s，1H)7.05(t，J＝7.6Hz, 1H)7.26(d, J ═ 8.1Hz, 1H)7.33(dd, J ═ 7.1, 1.2Hz, 1H)7.41(t, J ═ 7.7Hz, 1H)7.48(d, J ═ 8.1Hz, 1H)7.51 (width s, 1H)7.54-7.63(m, 3H)7.74(t, J ═ 7.6Hz, 1H)7.89(ddd, J ═ 8.4, 7.0, 1.5Hz, 1H)8.00(d, J ═ 2.0Hz, 1H)8.11 (width s, 1H)8.14(dd, J ═ 8.4, 0.9Hz, 1H)8.19(d, J ═ 8.6, 1H)8.62 (t, 1H), 1H (d, 1H) 8.7.5 Hz, 1H) 8.7.7.7.7.7.5 Hz, 1H (d, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.08; m/z 502[ M + H ] + -.

Example 140: dimethylaminoacetic acid 4-trans- { 2-carbamoyl-5- [4 (6-fluoro-1H-benzimidazol-2-yl) carbazol-9-yl]Synthesis of phenylamino cyclohexyl ester

The process is carried out as in example 15, but using 100mg of 4- [4- (6-fluoro-1H-benzimidazol-2-yl) carbazol-9-yl ] -2- (4-trans-hydroxycyclohexyl-amino) benzamide, which can be obtained as in example 1, 38.7mg of N, N-dimethylglycine, 23mg of 4-dimethylaminopyridine and 71.9mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 10ml of dichloromethane and 2ml of dimethylformamide for 20 hours at 45 ℃. After work-up as in example 15, purification by chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (95/5 as a mixture), and then crystallization from 5ml of diisopropyl ether, gave 75mg of 4-trans- { 2-carbamoyl-5- [4 (6-fluoro-1H-benzoimidazol-2-yl) carbazol-9-yl ] phenylamino } cyclohexyl dimethylaminoacetate, characterized as an off-white solid, as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆+TFA，δppm)：1.37-1.68(m，4H)1.98(d，J＝10.3Hz，2H)2.09(d，J＝10.3Hz，2H)2.86(s，6H)3.48-3.58(m，1H)4.18(s，2H)4.79-5.10(m，1H)6.80(dd，J＝8.3，1.7Hz，1H)6.99(d，J＝1.7Hz，1H)7.15-7.35(m，1H)7.47-7.63(m，3H)7.66-7.81(m，3H)7.83(dd，J＝7.6，1.5Hz，1H)7.88(dd，J＝8.4，2.3Hz，1H)7.99(d，J＝8.3Hz，1H)8.04(dd，J＝8.9，4.5Hz，1H)。

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.73; m/z 619[ M + H ] +; 617[ M + H ] -.

Example 141:2- [ (3-hydroxypropyl) amino]-4- [4- (5-hydroxypyridin-3-yl) -9H-carbazol-9-yl]Synthesis of benzamide

0.3g of 4- {4- [5- (benzyloxy) pyridin-3-yl ] -9H-carbazol-9-yl } -2- [ (3-hydroxypropyl) amino ] benzamide obtained in example 67 and 0.28g of ammonium formate were added in succession to a suspension of 8.8mg of palladium on charcoal (10%) in 8ml of methanol. The reaction mixture was refluxed for 2.5 hours, then filtered through celite, washing with methanol. The filtrate was concentrated under reduced pressure. Washed successively with diethyl ether, dichloromethane and water, then taken up in a dichloromethane/methanol mixture and concentrated under reduced pressure, to give 20mg of 2- [ (3-hydroxypropyl) amino ] -4- [4- (5-hydroxypyridin-3-yl) -9H-carbazol-9-yl ] benzamide, in the form of a white solid, which is characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.73 (quintuple, J ═ 6.4Hz, 2H)3.15-3.22(m, 2H)3.46-3.54(m, 2H)4.49(t, J ═ 5.1Hz, 1H)6.74(dd, J ═ 8.4, 1.8Hz, 1H)6.85(d, J ═ 1.0Hz, 1H)7.05-7.11(m, 1H)7.14(dd, J ═ 5.7, 2.1Hz, 1H)7.27 (width s, 1H)7.33-7.55(m, 6H)7.91(d, J ═ 8.3Hz, 1H)7.97 (width s, 1H)8.24(s, 1H)8.30(d, J ═ 2.4, 1H)8.44(t, 10H) 8.22 (t, 1H) 8.7.7.7.7 (d, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.61; 453[ M + H ] +; 451[ M + H ] -.

Practice ofExample 142: 2- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of (E) -4- (4-trans-hydroxycyclohexylamino) pyridine-5-carboxamide

Step 1: in a 50ml single neck round bottom flask 500mg of 4, 6 dichloronicotinamide was dissolved in 7.5ml ethanol and 7.5ml dimethylacetamide, followed by 663mg of trans-4-aminocyclohexanol was added. The mixture was then heated at 60 ℃ overnight. After concentration under reduced pressure, 360mg of 6-chloro-4- (4-trans-hydroxycyclohexyl) aminonicotinamide are obtained, which is characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆) δ ppm 1.09-1.42(m, 4H)1.79(dd, J ═ 13.1, 2.8Hz, 2H)1.91(dd, J ═ 12.8, 2.6Hz, 2H)3.38-3.52(m, 2H)4.56(d, J ═ 3.9Hz, 1H)6.73(s, 1H)7.41 (width s, 1H)8.03 (width s, 1H)8.38(s, 1H)8.76(d, J ═ 7.8Hz, 1H).

Step 2: in a 25mL three-necked flask, 150mg of 6-chloro-4- (4-trans-hydroxycyclohexyl) aminonicotinamide obtained according to step 1 of example 2 and 327g of 4- (quinolin-3-yl) -9H-carbazole are dissolved under a nitrogen atmosphere in 13mL of bisIn an alkane, argon was then bubbled through the solution for 10 minutes, with prior heating at about 50 ℃. 544mg of cesium carbonate, 12.5mg of palladium acetate and 39mg of 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene are then added in this order, and the mixture is heated at 90 ℃ for 3 hours under an argon atmosphere. After cooling, the reaction medium is diluted with 20ml of ethyl acetate, the insoluble material is filtered off over kieselguhr and rinsed twice with 10ml of ethyl acetate. The combined filtrates were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by flash chromatography on 70g silica, eluting with a mixture of dichloromethane and methanol (96/4 vol) gave 20mg of 2- [4- (quinolin-3-yl) -9H-carbazol-9-yl ]-4- (4-trans-hydroxycyclohexylamino) pyridine-5-carboxamide,in the form of an off-white powder, characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆) δ ppm 1.26-1.39(m, 4H)1.76-1.86(m, 2H)1.97-2.07(m, 2H)3.44-3.56(m, 2H)4.52(d, J-4.2 Hz, 1H)6.97(s, 1H)7.04(t, J-7.5 Hz, 1H)7.21(d, J-7.8 Hz, 1H)7.32(d, J-7.3 Hz, 1H)7.41(t, J-7.6 Hz, 1H)7.47 (width s, 1H)7.61(t, J-8.3 Hz, 1H)7.70-7.79(m, 2H)7.80-7.93(m, 2H)8.10 (s, 1H)8.14(d, J-8.8.8H), 1H) 1H (d, 1H-8.8 Hz, 1H) 8H) 1H (d, 1H)8, 1H) 8.8 (d, 1H)8, 1H) 1.8, 1H)8 (d, 1H)8, 1H)8, 1.8, 1H) 1.8 (d, 1.8, 1H) 1.8, 1H, 1.

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.83; m/z 526[ M + H ] +.

Example 143: 5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -3- (4-trans-hydroxycyclohexylamino) pyridine-2-carboxamide

Step 1: 676mg of the methyl 9H-carbazole-4-carboxylate obtained according to example 3, step 1, were dissolved in 50mL of dimethylformamide under an argon atmosphere in a 50mL three-necked flask. 180mg of sodium hydride (60% in oil) are then added and the mixture is stirred at ambient temperature for 30 minutes and then at 50 ℃ for 30 minutes. 706mg of 2-cyano-5-fluoro-3- (4-trans-hydroxycyclohexyl) aminopyridine according to example 128 step 1 were then added and the mixture was heated at 60-65 ℃ for 6 h. The reaction medium is poured into 50ml of water and 50ml of ethyl acetate. The aqueous phase was back-extracted twice with 25ml ethyl acetate. The combined organic phases were washed with water and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. After purification by flash chromatography successively on 200g then 80g of silica gel, eluting with a gradient of a mixture of dichloromethane and acetonitrile (from 95/5 to 90/10 by volume), 454mg of methyl 1H-1- [3- (4-trans-hydroxycyclohexyl) amino-2-carbamoylpyridin-5-yl ] carbazole-4-carboxylate are thus obtained, in the form of a colourless gum, which is characterized as follows:

TLC (silica gel): rf 0.25 (dichloromethane/acetonitrile 9/1).

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 4.47; m/z 441[ M + H ] +.

Step 2: in a 100ml three-necked flask, 195mg of 1, 2-diamino-4-fluorobenzene are dissolved in 15ml of toluene and 10ml of tetrahydrofuran under argon, then 1.55ml of a 2M solution of trimethylaluminum in toluene are added dropwise and the mixture is stirred for 15 minutes at ambient temperature. 454mg of the methyl 1H-1- [3- (4-trans-hydroxycyclohexyl) amino-2-carbamoylpyridin-5-yl ] carbazole-4-carboxylate obtained in the preceding step in 5ml of toluene are then added dropwise. The reaction medium is refluxed for 3 hours. After cooling to ambient temperature, 50ml of water and a few drops of 1M aqueous hydrochloric acid are added to adjust the pH to 4-5, and the mixture is extracted 3 times with 50ml of ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography on 30g silica, eluting with a mixture of dichloromethane, methanol and 4M aqueous ammonia (96/4/1 vol) gave 120mg of a mixture of regioisomers of 1H-1- [3- (4-trans-hydroxycyclohexyl) amino-2-carbamoylpyridin-5-yl ] carbazole-4-carboxylic acid 1, 2-diamino-4-fluorobenzamide, which was characterized as follows:

Mass Spectroscopy (LC/MS; method C): retention time Tr (min) ═ 5.59; m/z is 534[ M + H ] +.

And step 3: 120mg (0.224mm0l) of the mixture of regioisomers obtained in the preceding step and 1.5ml of acetic acid were introduced into a 5ml microwave tube reactor. The mixture was then heated twice at 100 ℃ for 30 minutes each. After concentrating the acetic acid under reduced pressure, the residue was taken up in 20ml of water and 20ml of ethyl acetate, and then a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7-8. The organic phase is separated by settling and the aqueous phase is back-extracted twice with 20ml of ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated under reduced pressure. This gave 144mg of 5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -3- (4-trans-hydroxycyclohexylamino) pyridine-2-carbonitrile as a beige powder, which was used as such in the subsequent steps.

And 4, step 4: 144mg of 5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -3- (4-trans-hydroxycyclohexylamino) pyridine-2-carbonitrile obtained in the preceding step were dissolved in 1.5ml of dimethyl sulfoxide and 3.7ml of ethanol, followed by addition of 0.56ml of a 1N aqueous sodium hydroxide solution and 0.51ml of a 30% aqueous hydrogen peroxide solution in this order. After stirring for 40 minutes at ambient temperature, 50ml of water and 50ml of ethyl acetate are added. The aqueous phase was back-extracted twice with 25ml ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on 10g silica, elution with a mixture of dichloromethane and methanol (95/5 vol) gave 80.6mg of 5- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] -3- (4-trans-hydroxycyclohexylamino) pyridine-2-carboxamide in the form of a beige powder, which was characterized as follows:

-1H NMR spectrum (400MHz, DMSO-d)₆) δ ppm 1.19-1.36(m, 4H)1.71-1.86(m, 2H)1.94-2.07(m, 2H)3.38-3.53(m, 2H)4.49(d, J ═ 3.9Hz, 1H)7.10-7.19(m, 1H)7.22(t, J ═ 7.6Hz, 1H)7.42(d, J ═ 8.1Hz, 1H)7.48(t, J ═ 7.7Hz, 1H)7.51-7.60(m, 4H)7.62(t, J ═ 7.7Hz, 1H)7.66-7.71(m, 1H)7.73 (width s, 1H)7.96(d, J ═ 2.0, 1H)8.13 (s, 1H)8.13 (d, 8H) 1, 8H) 7.09 (d, 1H) 7.75 (d, 1H) 7.0, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 0.84; 535[ M + H ] +; m/z is 533[ M-H ] -.

Example 144: 4- [4- (quinolin-3-yl) -9H-carbazol-9-yl]-2- (exo-7-oxabicyclo [ 2.2.1)]Synthesis of hept-2-ylamino) benzamides

Step 1: the exo N-benzyloxycarbonyl-7-oxabicyclo [2.2.1] hept-2-ylamine was prepared by carrying out the method described in the synthesis of exo N-ethoxycarbonyl-7-oxabicyclo [2.2.1] hept-2-ylamine according to WO 2008/0154043 of P.Spurr et al, wherein ethanol was replaced by benzyl alcohol during the Curtius reaction for the final step. This gives 3.21g of exo-N-benzyloxycarbonyl-7-oxabicyclo [2.2.1] hept-2-ylamine in the form of a dark yellow thick oil which is characterized as follows:

Mass Spectrometry (LC/MS; method B): retention time Tr (min) ═ 3.42; MH₊＝248₊。

Step 2: 3.81g of exo-N-benzyloxycarbonyl-7-oxabicyclo [2.2.1] hept-2-ylamine, 0.82g of palladium on charcoal (10%) and 40ml of ethanol are introduced in succession into the reaction vessel, and the reaction medium is then hydrogenated at 2 bar at 25 ℃ with stirring for 16 hours. The mixture was then filtered through Clarcel and the solid was washed with ethanol. The filtrate was concentrated to dryness under pressure and the resulting crude residue was purified by chromatography on a 30g silica gel column (15-40 μm) eluting with a mixture of chloroform, methanol and 28% aqueous ammonia (55/6/1, vol.) at a flow rate of 40 ml/min. 647mg of 2-exo-7-oxabicyclo [2.2.1] heptylamine are thus obtained in the form of a yellow liquid, which is characterized as follows:

mass Spectrometry (LC/MS; method A): retention time Tr (min) ═ 0.11; MH₊＝114₊。

And step 3: 210mg of 2-fluoro-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzonitrile obtained in step 1 of example 32, 2.1ml of dimethyl sulfoxide, 211mg of potassium carbonate and 460mg of 2-exo-7-oxabicyclo [2.2.1] heptamine obtained in the preceding step were introduced in this order into a 5ml microwave reactor. 1 minute after stirring at ambient temperature, the reaction medium is heated with stirring in microwave radiation at 115 ℃ for 90 minutes. After cooling, 5ml ethanol, 0.97ml 1M sodium hydroxide and 0.93ml 30% aqueous hydrogen peroxide were added in that order and the mixture was stirred for 5 minutes at ambient temperature. Then 20ml of distilled water were added and the mixture was extracted 3 times with 25ml of ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness in vacuo. The resulting crude residue was purified by chromatography on a 70g silica gel column (15-40 μm) eluting with a mixture of dichloromethane and ethanol (97/3 vol) followed by a mixture of chloroform, methanol and 28% aqueous ammonia (12/3/0.5 vol) at a flow rate of 50 ml/min. This gave 250mg of a yellow liquid which was purified again by chromatography on a 25g silica gel column (15-40 μm), eluting with a mixture of dichloromethane and ethanol (97/3, vol.) at a flow rate of 20 ml/min. The product obtained is triturated with 4ml of diisopropyl ether, filtered, spin-dried and then dried in an oven under vacuum (40 ℃, 20 mbar) for 2 hours. This gave 189mg of 4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -2- (exo-7-oxabicyclo [2.2.1] hept-2-ylamino) benzamide in the form of a light yellow powder which was characterized as follows:

-1H NMR spectrum (400MHz, δ ppm, DMSO-d 6): 1.31-1.59(m, 5H)2.04(dd, J-12.3, 7.5Hz, 1H)3.64(td, J-7.1, 2.9Hz, 1H)4.40(d, J-4.6 Hz, 1H)4.60(t, J-4.5 Hz, 1H)6.81(dd, J-8.2, 1.8Hz, 1H)6.85(d, J-1.7 Hz, 1H)7.03(t, J-7.6 Hz, 1H)7.25(d, J-8.1 Hz, 1H)7.30(dd, J-6.1, 2.0Hz, 1H)7.33 (width s, 1H)7.41(t, J-8.1H) 7.7.33 (width s, 1H)7.41 (d, J-8.1H), 1H) 7.3.3 (dd, 7.8H), 7H) 7.3 (d, 7.3H, 7H, 7.7H, 7H (d, 7.8, 7.7.7H) 3, 7.7.7H, 7.7H, 7H, 3(d, 3, 7.7.7.7.7.7.7.7.7, 7.7H) and 7.7.7.7.7.7.7.7.7.7.7.7.7.7.7 (d, 7.7H) H, 7.7.7.7.7H, 7.7 (d, 7.7, 7H) H, 7, 7.7.7.7.7, 7, j2.0 Hz, 1H)9.16(d, J2.0 Hz, 1H).

Mass Spectroscopy (LC/MS; method A): retention time Tr (min) ═ 1.12; MH₊＝525₊。

Example 145: 5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of (E) -2- (1, 2, 2, 6, 6-pentamethylpiperidin-4-ylamino) pyridine-2-carboxamide

5- [4- (6-fluoro-1H-benzoimidazol-2-yl) -9H-carbazol-9-yl ] -2- (1, 2, 2, 6, 6-pentamethylpiperidin-4-ylamino) pyridine-2-carboxamide was obtained by carrying out the method as in example 143, but using methyl 9H-carbazole-4-carboxylate obtained according to example 3 step 1 and 5-fluoro-3- (1, 2, 2, 6, 6-pentamethylpiperidin-4-ylamino) pyridine-2-carbonitrile obtained according to example 132 step 1 according to the following scheme:

Example 146: 4- (1, 2, 2, 6, 6-pentamethylpiperidin-4-ylamino) -2- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of pyridine-5-carboxamides

4- (1, 2, 2, 6, 6-pentamethylpiperidin-4-ylamino) -2- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-5-carboxamide obtained by implementing the procedure as in example 142, but using 4- (quinolin-3-yl) -9H-carbazole obtained according to step 1 of example 2 and 1, 2, 2, 6, 6-pentamethylpiperidin-4-amine and 4, 6 dichloronicotinamide, according to the following scheme:

example 147: 4- (2-hydroxy-2-methylpropylamino) -2- [4- (quinolin-3-yl) -9H-carbazol-9-yl]Synthesis of pyridine-5-carboxamides

4- (2-hydroxy-2-methylpropylamino) -2- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-5-carboxamide was obtained by performing the method as in example 142, but using 4- (quinolin-3-yl) -9H-carbazole and 1-amino-2-methylpropan-2-ol and 4, 6-dichloronicotinamide obtained according to step 1 of example 2, according to the following scheme:

example 148: 2- [ (8-methyl-8-azabicyclo [3.2.1]]Oct-3-yl) amino]-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]Synthesis of benzamide

2- [ (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) amino ] -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide was obtained by carrying out the method as in example 3 step 3, but using 2-fluoro-4- [4- (6-fluoro-1H-benzimidazol-2-yl) carbazol-9-yl ] benzonitrile and (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) amine obtained according to example 3 step 2, according to the following scheme:

Example 149: the pharmaceutical composition comprises:

tablets were prepared according to the following formulation:

example 12 product 0.2g

The excipients make the total weight of the tablet 1g

(excipients: lactose, talc, starch, magnesium stearate).

Example 150: the pharmaceutical composition comprises:

tablets were prepared according to the following formulation:

0.2g of the product of example 7

The excipients make the total weight of the tablet 1g

(excipients: lactose, talc, starch, magnesium stearate).

The invention also includes all pharmaceutical compositions prepared using any of the formula (I) products of the invention.

Biological assays for biologically characterizing the products of the invention:

1) and (3) biological activity:

bioactive compounds can be evaluated specifically by the "Hsp 82/ATPase" assay described below:

the inorganic phosphate released during ATP hydrolysis by the ATPase activity of Hsp82 was quantified using the malachite green method. In the presence of this reagent, an inorganic phosphate-molybdate-malachite green complex is formed, which absorbs at a wavelength of 620 nm.

The product to be evaluated was assayed in a 30. mu.l reaction volume in the presence of 1. mu.M Hsp82 and 250. mu.M Medium (ATP) in a medium consisting of 50mM Hepes-NaOH (pH7.5), 1mM DTT, 5mM MgCl ₂And 50mM KCl for 60 minutes at 37 ℃. In parallel, there is 1-40. mu.M of inorganic phosphate in the same buffer. ATPase activity was then revealed by addition of 60. mu.l of the biomol green reagent (Tebu). After incubation for 20 minutes at room temperature, the absorbance of the different wells was measured at 620nm using a microplate reader. The inorganic phosphate concentration of each sample was then calculated using the calibration curve. The ATPase activity of Hsp82 was generated within 60 minutesInorganic phosphate concentration. The effect of the different test products is expressed as a percentage inhibition of the ATPase activity.

ADP generated as a result of ATPase activity of Hsp82 was used to develop another method for evaluating the enzymatic activity of Pyruvate (PK) and Lactate Dehydrogenase (LDH) by using an enzyme-coupled system involving such enzymes. In this kinetic class of spectrophotometric methods, PK catalyzes the production of ATP and pyruvate from phosphoenolpyruvate (PEP), and ADP is produced by HSP 82. The pyruvate produced, i.e. the culture medium for LDH, is then converted to lactate in the presence of NADH. In this case, the decrease in NADH concentration, measured by the decrease in absorbance at a wavelength of 340nm, is proportional to the ADP concentration produced by HSP 82.

These test products were incubated in a reaction volume of 100. mu.l of a buffer composed of 100mM Hepes-NaOH (pH7.5), 5mM MgCl₂1mM DTT, 150mM KCl, 0.3mM ADH, 2.5mM PEP and 250. mu.M ATP. This mixture was pre-incubated at 37 ℃ for 30 minutes before the addition of 3.77 units LDH and 3.77 units PK. This reaction was initiated by the addition of various concentrations of the product to be evaluated and Hsp82 at a concentration of 1 μ M. The enzymatic activity of Hsp82 was then measured continuously at a wavelength of 340nm at 37 ℃ using a microplate reader. The reaction initiation rate was obtained by measuring the tangent slope at the beginning of the recorded curve. The enzyme activity is expressed in μ M per minute of ADP produced. The effect of the different test products is expressed as a percentage inhibition of ATPase activity according to the following code:

A：IC₅₀＜1μM

B：1μM＜IC₅₀＜10μM

2) cell activity:

the cellular activity of the compounds can be assessed in particular by the phenotypic "SKBr 3/HER 2" cell test described below:

SKBr3 mammalian adenocarcinoma cells overexpressing Her2 tyrosine kinase receptor, derived from ATCC (HTB-30), and cultured in McCoy's 5A medium supplemented with 10% FBS and 1% L-glutamine.

Cells were seeded in 12-well plates at a ratio of 125000 cells/well in 1ml of complete medium. The next day, the product was added at different concentrations. After 24 hours of incubation, cells were trypsinized, washed with PBS and incubated with 100ng of anti-Her 2 antibody (conjugated to PE (phycoerythrin) (BD 340552)) for 30 minutes at 4 ℃ in the dark. The fluorescence due to Her2 receptor expression at the cell surface was then read using a FACS Calibur flow cytometer (Becton-Dickinson). The percent inhibition of Her2 expression was expressed as a function of the tested concentration and was fitted by a non-linear regression technique (XLfit, equalisation 205) to measure the IC of each product ₅₀The value is obtained.

The activities of these products are encoded as follows:

A：IC₅₀＜1μM

B：1μM＜IC₅₀＜10μM

the following summary table shows the biochemical and cellular activities of representative compounds of the invention.

Result list

Claims (29)

1. A product of the formula (I)

Wherein:

het represents a mono-or bicyclic, aromatic or partially unsaturated heterocyclic ring-dihydro or tetrahydro-type-having 5 to 11 ring members containing 1 to 4 heteroatoms selected from N, O or S, optionally substituted by one or more groups R1 or R' 1 which may be the same or different,

r is selected from

Wherein R1 and/or R' 1 may be the same or different and are selected from H, halogen, CF₃Nitro, cyano, alkyl, hydroxyl, mercapto, amino, alkylamino, dialkylamino, alkoxy, phenylalkoxy, alkylthio, carboxyl in free form or esterified with alkyl, carboxamide, CO-NH (alkyl), CON (alkyl)₂NH-CO-alkyl, sulphonamides, NH-SO₂Alkyl, S (O)₂-NH alkyl and S (O)₂) -N (alkyl)₂All alkyl, alkoxy and alkylthio groups are themselves optionally substituted by one or more groups which may be the same or different selected from: halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

w1, W2 and W3 independently represent CH or N;

x represents an oxygen atom or a sulfur atom, or NR2, C (O), S (O) or S (O)₂A group;

z represents a hydrogen atom or a halogen atom or a group-O-R2 or a group-NH-R2, wherein:

R2 represents a hydrogen atom or C₁-C₆Alkyl radicals, or C₃-C₈Cycloalkyl radicals or C₃-C₁₀A heterocycloalkyl group that is monocyclic or bicyclic; these alkyl, cycloalkyl and heterocycloalkyl groups are optionally substituted by one or more identical or different groups selected from:

--O-PO₃H₂、O-PO₃Na₂、-O-SO₃H₂、-O-SO₃Na₂、-O-CH₂-PO₃H₂、-O-CH₂-PO₃Na₂O-CO-alanine, O-CO-serine, O-CO-lysine, O-CO-arginine, O-CO-glycine-lysine, -O-CO-alanine-lysine;

-halogen, hydroxy; a mercapto group; an amino group; carboxamide (CONH)₂) (ii) a A carboxyl group;

-heterocycloalkyl, such as aziridinyl; an azetidinyl group; an oxetanyl group; a tetrahydrofuranyl group; a piperidinyl group; a tetrahydropyranyl group; a piperazinyl group; an alkyl piperazinyl group; a pyrrolidinyl group; morpholinyl; homopiperidinyl; a homopiperazinyl group; quinuclidinyl; cycloalkyl, heteroaryl; a carboxyl group esterified with an alkyl group; CO-NH (alkyl); -O-CO-alkyl, -NH-CO-alkyl; an alkyl group; an alkoxy group; a hydroxyalkoxy group; an alkylthio group; an alkylamino group; a dialkylamino group; in all of these groups, the alkyl, alkoxy and alkylthio groups themselves are optionally substituted with: hydroxy, mercapto, amino, alkylamino, dialkylamino, CO₂Alkyl, NHCO ₂An alkyl group; azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or quinuclidinyl groups; in all of these groups, all cyclic groups, cycloalkyl, heterocycloalkyl and heteroaryl groups are themselves optionally substituted by one or more identical or different groups selected from: hydroxy, alkyl, alkoxy, CH₂OH, amino, alkylamino, dialkylamino, CO₂Alkyl or NHCO₂An alkyl group;

the product of formula (I) is in all its possible tautomeric and isomeric forms: racemates, enantiomers and diastereomers, and addition salts of the product of formula (I) with inorganic or organic acids or with inorganic or organic bases, and prodrugs of the product of formula (I).

2. A product of formula (I) as defined in any one of the other claims, wherein:

het is selected from:

wherein one of R '3 and R3 represents a hydrogen atom and the other is a value selected from R1 and R' 1;

r1 and-Or R' 1, which may be identical or different, are selected from H, halogen, CF₃Nitro, cyano, alkyl, hydroxyl, mercapto, amino, alkylamino, dialkylamino, alkoxy, phenylalkoxy, alkylthio, carboxyl in free form or esterified with alkyl, carboxamide, CO-NH (alkyl), CON (alkyl) ₂NH-CO-alkyl, sulphonamides, NH-SO₂Alkyl, S (O)₂-NH alkyl and S (O)₂) -N (alkyl)₂All of said alkyl, alkoxy and alkylthio groups are themselves optionally substituted by one or more groups which may be the same or different selected from: halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

the substituents R of the product of formula (I) are selected from the values defined above or below,

the product of formula (I) is in all its possible tautomeric and isomeric forms: racemates, enantiomers and diastereomers, and addition salts of the product of formula (I) with inorganic or organic acids or with inorganic or organic bases, and prodrugs of the product of formula (I).

3. A product of formula (I) as defined in any one of the other claims, wherein:

het is selected from:

wherein one of R' 3 and R3 represents a hydrogen atom and the other is selected from the group consisting of: -NH₂、-CN、-CH₂-OH、-CF₃、-OH、-O-CH₂-phenyl, -O-CH₃、-CO-NH₂；

R1 and/or R' 1 are selected from H, halogen, CF₃Nitro, cyano, alkyl, hydroxyl, mercapto, amino, alkylamino, dialkylamino, alkoxy, alkylthio, carboxyl in free form or esterified with alkyl, carboxamide, CO-NH (alkyl) and CON (alkyl) ₂NH-CO-alkyl, sulphonamides, NH-SO₂Alkyl, S (O)₂-NH (alkyl) and S (O)₂-N (alkyl)₂All of said alkyl, alkoxy and alkylthio groups are themselves optionally substituted by one or more groups which may be the same or different selected from: halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

the substituents R of the product of formula (I) are selected from the values defined above or below,

the product of formula (I) is in all its possible tautomeric and isomeric forms: racemates, enantiomers and diastereomers, and addition salts of the product of formula (I) with an inorganic or organic acid or base, and prodrugs of the product of formula (I).

4. A product of formula (I) as defined in any one of the claims wherein:

het is selected from:

wherein one of R' 3 and R3 represents a hydrogen atom and the other is selected from the group consisting of: -NH₂、-CN、-CH₂-OH、-CF₃、-OH、-O-CH₂-phenyl, -O-CH₃and-CO-NH₂；

R is selected from:

wherein R1 and/or R' 1 may be the same or different and are selected from H, halogen, CF₃Nitro, cyano, alkyl, hydroxy, mercapto, amino, alkylamino, dialkylamino, alkoxy, -O-CH₂Phenyl, alkylthio, carboxyl in free form or esterified with alkyl, carboxamide, CO-NH (alkyl), CON (alkyl) ₂NH-CO-alkyl, sulphonamides, NH-SO₂Alkyl, S (O)₂-NH alkyl, S (O)₂) -N (alkyl)₂All said alkyl, alkoxy and alkylthio groups are themselves optionally substituted by one or more groups which may be the same or different selected from: halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino;

w1, W2 and W3 independently represent CH or N;

x represents an oxygen atom or a sulfur atom, or NR2, C (O), S (O) or S (O)₂A group;

z represents a hydrogen atom or a halogen atom or-O-R₂A radical or-NH-R₂A group wherein:

r2 represents a hydrogen atom or C₁-C₆Alkyl radicals or C₃-C₈Cycloalkyl radicals or C₃-C₁₀A heterocycloalkyl group that is monocyclic or bicyclic; these alkyl, cycloalkyl and heterocycloalkyl groups are optionally substituted by one or more groups which may be the same or different selected from: halogen, hydroxy; a mercapto group; an amino group; carboxamide (CONH)₂) (ii) a A carboxyl group; heterocycloalkyl such as piperidinyl or pyrrolidinyl; a cycloalkyl group; heteroaryl groups such as furyl, pyridyl, pyrazolyl,An azole or imidazole group; a carboxyl group esterified with an alkyl group; CO-NH (alkyl); -O-CO-alkyl, -NH-CO-alkyl; an alkyl group; an alkoxy group; a hydroxyalkoxy group; an alkylthio group; an alkylamino group; a dialkylamino group; in all of these groups, the alkyl, alkoxy and alkylthio groups are themselves optionally substituted with: hydroxy, mercapto, amino, alkylamino, dialkylamino, CO ₂Alkyl, NHCO₂An alkyl group; azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or quinuclidinyl groups; in all of these groups, all cyclic groups, cycloalkyl, heterocycloalkyl and heteroaryl groups are themselves optionally substituted by one or more groups which may be the same or different selected from: hydroxy, alkyl, alkoxy, CH₂OH; amino group,Alkylamino, dialkylamino, CO₂Alkyl or NHCO₂An alkyl group;

the product of formula (I) is in all its possible tautomeric and isomeric forms: racemates, enantiomers and diastereomers, and addition salts of the product of formula (I) with an inorganic or organic acid or base, and prodrugs of the product of formula (I).

5. A product of formula (I) as defined in any one of the other claims, wherein:

het is selected from:

r is selected from:

r1 is selected from H, F, Cl, Br, CF₃、NO₂、CN、CH₃、OH、OCH₃、OCF₃、CO₂Me、CONH₂、CONHMe、CONH-(CH₂)₃-OMe、CONH-(CH₂)₃-N(Me)₂、NHC(O)Me、SO₂NH₂And SO₂N(Me)₂，

R' 1 is selected from H, CONH₂The group consisting of CONHMe and OMe,

r' 1 is selected from F, Cl, OH, OMe, CN, O- (CH)₂)₃OMe and O- (CH)₂)₃-N(Me)₂；

W1 and W2 represent CH, or one represents CH and the other represents N;

Y represents OH, O-PO₃H₂、O-PO₃Na₂、O-SO₃H₂、O-SO₃Na₂、O-CH₂-PO₃H₂、O-CH₂-PO₃Na₂、O-CO-CH₂-CO₂tBu、O-CO-CH₂-NH₂Or O-CO-glycine, O-CO-CH₂-N(Me)₂、O-CO-CH₂-NHMe, O-CO-alanine, O-CO-serine, O-CO-lysine, O-CO-arginine, O-CO-glycine-lysine, O-CO-alanine-lysine;

n represents 2 or 3;

the product of formula (I) is in all its possible isomeric forms: racemates, enantiomers and diastereomers, and addition salts of the product of formula (I) with inorganic or organic acids or with inorganic or organic bases.

6. A product of formula (I) as defined in any one of the other claims, wherein:

het is selected from:

wherein:

r1 represents H, F, Cl, Br, CF₃、NO₂、CN、CH₃、OH、OCH₃、OCF₃、CO₂Me、CONH₂、CONHMe、CONH-(CH₂)₃-OMe、CONH-(CH₂)₃-N(Me)₂、NHC(O)Me、SO₂NH₂Or SO₂N(Me)₂；

R' 1 represents H, CONH₂CONHMe or OMe;

r' 1 represents F, Cl, OH, OMe, CN, O- (CH)₂)₃OMe or O- (CH)₂)₃-N(Me)₂；

And R is selected from:

wherein:

w1 and W2 represent CH, or one represents CH and the other represents N;

r2 represents hydrogen, or ethyl substituted in the 2-position, n-propyl substituted in the 3-position, or cyclohexyl substituted in the 4-position, wherein the substituents are OH, SH, NH₂、OMe、NHMe、N(Me)₂、N(Et)₂Azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, quinuclidinyl, CONH ₂Or a group of COOH,

y represents OH, O-PO₃H₂、O-PO₃Na₂、O-SO₃H₂、O-SO₃Na₂、O-CH₂-PO₃H₂、O-CH₂-PO₃Na₂、O-CO-CH₂-CO₂tBu、O-CO-CH₂-NH₂Or O-CO-glycine, O-CO-CH₂-N(Me)₂、O-CO-CH₂-NHMe, O-CO-alanine, O-CO-serine, O-CO-lysine, O-CO-arginine, O-CO-glycine-lysine or O-CO-alanine-lysine, wherein n represents 2 or 3;

and prodrugs thereof, the product of formula (I) being in all its possible isomeric forms: tautomers, racemates, enantiomers and diastereomers, and pharmaceutically acceptable addition salts of the product of formula (I) with an inorganic or organic acid or an inorganic or organic base.

7. The products of formula (I) as defined in any one of the preceding claims, having the following names:

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-trans-hydroxycyclohexylamino) benzamide

-2- (4-trans-hydroxycyclohexylamino) -4- [ (4-quinolin-3-yl) -9H-carbazol-9-yl ] benzamide

-2- (2-diethylaminoethylamino) -4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide

-2- (4-trans-hydroxycyclohexylamino) -4- [4- (3H-imidazo [4, 5-c ] pyridin-2-yl) carbazol-9-yl ] benzamide

-acetic acid 4- { 2-carbamoyl-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] phenylamino } cyclohexyl ester

-2-cyclohexylamino-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- [2- (2-hydroxyethoxy) ethylamino ] benzamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (3-hydroxypropylamino) benzamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (4-cis-hydroxycyclohexylamino) benzamide

-2-amino-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] benzamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (2-pyrrolidin-1-ylethylamino) benzamide

-6- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -1H-indazol-3-ylamine

-6- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl]-1, 2-benzisoxazo(ii) an azol-3-ylamine,

-3- (trans-4-hydroxycyclohexylamino) -5- [ (4-quinolin-3-yl) -9H-carbazol-9-yl) pyridine-2-carboxamide

-4- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -2- (tetrahydropyran-4-ylamino) benzamide

-4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2- [ (1, 2, 2, 6, 6-pentamethylpiperidin-4-yl) amino ] benzamide

-aminoacetic acid 4- { [ 2-carbamoyl-5- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridin-3-ylamino } cyclohexyl ester

-4- [4- (6-cyanopyridin-3-yl) -9H-carbazol-9-yl ] -2- [ (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) amino ] benzamide

-5- [4- (6-fluoro-1H-benzimidazol-2-yl) -9H-carbazol-9-yl ] -3- (tetrahydropyran-4-yl) amino) pyridine-2-carboxamide

-2- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] -4- (tetrahydropyran-4-yl) -amino) pyridine-5-carboxamide

-2- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) amino-4- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] benzamide

-3- [ (2-hydroxy-2-methylpropylamino) -5- [4- (quinolin-3-yl) -9H-carbazol-9-yl ] pyridine-2-carboxamide

And addition salts of the products of formula (I) with inorganic or organic acids or with inorganic or organic bases.

8. Process for the preparation of the product of formula (I) as defined in the preceding claims, characterized by the following scheme (1):

scheme (1)

Wherein the substituents Het, R2, W1 and W2 have the meanings indicated in the products of formula (I) as defined in the preceding claims and z has the meaning given in scheme (1) above.

9. A process for the preparation of a product of formula (I) wherein W1 represents N, W2 represents CH, and Het and R2 are as defined in the preceding claims, and a compound of formula (VII) wherein W1 represents N, W2 represents CH, Z represents a carboxylic acid or a methyl or ethyl ester, and R2 is as defined in the preceding claims, characterized by the following schemes (40) and (41):

Scheme (40)

Scheme (41).

10. A process for the preparation of a product of formula (I) wherein Het represents a 2-cyanopyridin-5-yl group, W1 and W2 represent CH and R2 is as defined in the preceding claims, and of compounds of formulae (VIII-a) and (VIII-B) and (VIII-C) wherein Het represents a 2-cyanopyridin-5-yl group, W1 and W2 represent CH and R2 is as defined in the preceding claims, and of compounds of formulae (VIII-a) and (VIII-B) and (VIII-C), characterized by the fact that scheme (42):

scheme (42).

11. Synthetic intermediates of the formulae (III), (IV), (V), (VI), (VII), (VIII-A), (VIII-B) and (VIII-C) as new industrial products:

wherein in the products of formula (III), (IV), (V), (VI), (VII), (VIII-a), (VIII-B) and (VIII-C) the substituents Het, R2, W1 and W2 have the meanings indicated in the products of formula (I) as defined in the preceding claims, and z has the meaning in scheme (1) or scheme (42) above.

12. A product of formula (I) as defined in claims 1 to 7 in all its possible isomeric forms: racemates, enantiomers and diastereomers, and the pharmaceutically acceptable addition salts of the product of formula (I) with an inorganic or organic acid or with an inorganic or organic base.

13. A product of formula (I) as defined in claim 6 in all its possible isomeric forms: racemates, enantiomers and diastereomers, and the pharmaceutically acceptable addition salts of the product of formula (I) with an inorganic or organic acid or with an inorganic or organic base.

14. A product of formula (I) as defined in claim 7 in all its possible isomeric forms: racemates, enantiomers and diastereomers, and the pharmaceutically acceptable addition salts of the product of formula (I) with an inorganic or organic acid or with an inorganic or organic base.

15. A pharmaceutical composition containing at least one drug as defined in claims 10 to 12 as active ingredient.

16. The pharmaceutical composition as defined in the preceding claims, additionally containing active ingredients of other drugs for anticancer chemotherapy.

17. Pharmaceutical compositions as defined in any one of the preceding claims, characterized in that they are used as medicaments, in particular for cancer chemotherapy.

18. Use of a product of formula (I) or a pharmaceutically acceptable salt of said product of formula (I) as defined in any one of the preceding claims in the manufacture of a medicament for inhibiting the activity of a chaperone protein, in particular Hsp 90.

19. Use of a product of formula (I) or a pharmaceutically acceptable salt of a product of formula (I) as defined in any one of the preceding claims in the manufacture of a medicament for the prevention or treatment of a disease characterized by interference with the activity of Hsp90 type chaperones.

20. Use of a product of formula (I) or a pharmaceutically acceptable salt of a product of formula (I) as defined in any one of the preceding claims in the manufacture of a medicament for the prevention or treatment of: neurodegenerative diseases such as huntington's disease, parkinson's disease, focal cerebral ischemia, alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis, malaria, malaysia, bancroft's filariasis, toxoplasmosis, anti-therapeutic mycosis, hepatitis b, hepatitis c, herpes virus, dengue fever (or tropical influenza), spinal and bulbar muscular atrophy, mesangial cell proliferation disorders, thrombosis, retinopathy, psoriasis, muscular degeneration, neoplastic diseases and cancer.

21. Use of a product of formula (I) or a pharmaceutically acceptable salt of a product of formula (I) as defined in any one of the preceding claims in the manufacture of a medicament for use in the treatment of cancer.

22. Use of a product of formula (I) according to the preceding claim, wherein the disease to be treated is a cancer of a solid or fluid tumor.

23. Use of a product of formula (I) according to the preceding claim, wherein the disease to be treated is a cancer resistant to cytotoxic agents.

24. Use of a product of formula (I) or a pharmaceutically acceptable salt of a product of formula (I) as defined in any one of the preceding claims in the manufacture of a medicament for the treatment of cancer, lung, breast and ovarian cancer, glioblastoma, chronic myelogenous leukemia, acute lymphocytic leukemia, prostate, pancreatic and colon cancers, metastatic melanoma, thyroid tumors and renal cancers.

25. Use of a product of formula (I) or a pharmaceutically acceptable salt of a product of formula (I) as defined in any one of the preceding claims in the manufacture of a medicament for cancer chemotherapy.

26. Use of a product of formula (I) or a pharmaceutically acceptable salt of a product of formula (I) as defined in any one of the preceding claims in the manufacture of a medicament for separate use or for combined use in cancer chemotherapy.

27. Use of a product of formula (I) or a pharmaceutically acceptable salt of a product of formula (I) as defined in any one of the preceding claims in the manufacture of a medicament for use alone or in combination with chemotherapy or radiotherapy or in combination with other therapeutic agents.

28. Use of a product of formula (I) according to the preceding claim, wherein the therapeutic agent is an antineoplastic agent.

29. A product of formula (I) as defined in any one of the preceding claims, as an Hsp90 inhibitor, in the form of all possible tautomers and/or isomers thereof: racemates, enantiomers and diastereomers, as well as the pharmaceutically acceptable addition salts of the product of formula (I) with an inorganic or organic acid or with an inorganic or organic base, and prodrugs thereof.