# Patent

## Title
Pyrrolo[2,3-a] carbazoles and use thereof as PIM kinase inhibitors

## Abstract

The invention relates to pyrrolo[2,3-a]carbazole derivatives, to a method for preparing the same, and to the use thereof as PIM kinase inhibitors. The invention can particularly be used in the pharmaceutical field.

## Background
RELATED APPLICATIONS
The present application is a U.S. National Phase Application of International Application No. PCT/FR2009/000788 (filed Jun. 25, 2009) which claims priority to French Patent Application No. 0803752 (filed Jul. 3, 2008) which are hereby incorporated by reference in their entirety.
The invention relates to pyrrolo[2,3-a]carbazole derivatives, to a process for preparing them and to the use thereof.
PIM kinase inhibitors are particularly sought on account of their action in the cardiovascular field, on type 2 diabetes, their antiproliferative activity and their potential for inhibiting resistance to certain chemotherapy medicaments.
PIM kinases, i.e. the kinases PIM-1, PIM-2 and PIM-3, are protooncogenes involved in particular in the cancerization process.
They constitute a family of enzymes that plays an important role in regulating many processes, in particular cell survival and transcription regulation and proliferation.
These enzymes are overexpressed in various types of cancer, in particular leukemias, lymphomas and prostate cancers.
These enzymes are also involved in processes of resistance to chemotherapy agents such as rapamycin and growth factor receptor inhibitors with tyrosine kinase activity.
They are targets of choice for the development of novel therapeutic agents, as illustrated in the article by Giles et al., “A PIM kinase inhibitor, please”, Blood, 2005, 105, 4158-4159.
Very few specific inhibitors of PIM kinases exist. The term “specific PIM kinase inhibitor” means a compound that strongly inhibits only PIM kinases, and that exerts little or no inhibition on the majority of the other kinases.
The human genome codes for some 500 kinases, and as such the problem of selectivity is crucial.
In general, a compound is said to be a specific inhibitor of a particular type of kinase when it inhibits this type of kinase although it has been tested on at least 30 other kinases.
Many publications describe inhibitors of kinases, including PIM kinases, but these inhibitors are not selective.
The only families of compounds described as being selective for PIM kinases are the following:

    
    
        the imidazo[1,2-b]pyridazines described by Pogacic et al. in Cancer Research 2007, 67, 6916-6924,
        quercetagetin described by Holder et al. in Molecular Cancer Therapeutics 2007, 6, 163-172, and
        the ruthenium complexes described by Debreczeni et al. in Angewandte Chemie, Int. Ed., 2006, 45, 1580-1585.
    
    


The invention is based on the discovery that certain pyrrolo[2,3-a]-carbazole compounds are selective inhibitors of at least one of the PIM kinases, and that this selectivity is exerted among a panel of 67 tested kinases.
Thus, the invention proposes the use of at least one compound of formula I below:




in which:

    
    
        R1 is H or a sulfophenyl group,
        R2, R3 and R4 are identical or different and represent, independently of each other, a hydrogen atom, a halogen atom or a group from among nitro, nitrile, hydroxyl, linear or branched C1 to C6 alkoxy optionally substituted with one or more groups R5, C5 to C6 cycloalkoxy optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkoxy optionally substituted with one or more groups R5, —SH, linear or branched C1 to C6 alkylthio optionally substituted with one or more groups R5, C6 aryl optionally substituted with one or more groups R5, C6 aryloxy optionally substituted with one or more groups R5, —NRaRb, —NRaC(O)-T1, —C(N—OH)-T3, —C(O)-T1, —C(O)—C(O)-T3, —C(O)—NRa-T1, —NRa—C(O)-T1, —O—C(O)-T1, —C(O)—O-T1, —O-T2-NRaRb, —O-T2-ORa, —O-T2-CO2Ra, —NRa-T2-NRaRb, —NRa-T2-ORa, —NRa-T2-CO2Ra or —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa, linear or branched C1 to C6 alkyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkenyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkynyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryl optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryloxy optionally substituted with one or more groups R5,
        R5 represents a halogen atom or a group chosen among linear or branched C1 to C6 alkyl, C6 aryl, linear or branched C1 to C6 haloalkyl, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb, nitrile, nitro, —NRaC(O)-T1, C1 to C6 alkoxy, oxo, —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa,
        Ra and Rb are identical or different and represent, independently of each other, a hydrogen atom or a group chosen among linear or branched C1 to C6 alkyl, linear or branched C1 to C6 haloalkyl and C6 aryl, in which Ra+Rb form, together with the nitrogen atom to which they are attached, a saturated or unsaturated, monocyclic or bicyclic heterocycle of 5 to 10 atoms, optionally containing in the ring systems a second heteroatom chosen from oxygen and nitrogen, and being optionally substituted with one or more groups R5,
        T1 represents a hydrogen atom, a halogen atom or a linear or branched C1 to C6 alkyl group, optionally substituted with a group chosen from —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb,
        T2 represents a linear or branched (C1-C6)alkylidene chain,
        T3 represents a group chosen among -halogen, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb in which Ra and Rb are as defined previously,
        t represents an integer between 0 and 3 inclusive,
        A, B, C and D denote the rings constituting the compounds of formula I, and serve merely to identify each of these rings, or a salt, optical isomer or racemic mixture of these compounds, as an inhibitor of the activity of at least one of the kinases PIM-1, PIM-2 or PIM-3.
    
    


Preferably, the at least one compound used has the formula I in which:

    
    
        R1 is H or a sulfophenyl group,
        R2 represents H or a group from among CHO, (CH2)nOH, C(═O)NH2, C(═O)—CF3, (C═O)2Rc, (CH2)2NEt2, CH(OH)CH2N(Et)2, C(NOH)—(C═O)N(Et)2, NO2 and Br, with n=1 or 2 and Rc═OCH3, OC2H5, N(C2H5)2,
        R3 and R4 are identical or different and are chosen, independently of each other, from H, a halogen atom, a 5- or 6-membered heteroaryl group comprising one or two heteroatoms chosen from O and N, linear or branched C1 to C6 alkyl, methoxy, nitro, nitrile, carboxyl, trifluoromethyl, trifluoromethoxy, SO2Rd, C6 aryl optionally substituted with a group chosen from a group (C═O)CH3, phenyl, methoxy, trifluoromethoxy, trifluoromethyl and carboxyl or with 1 or 2 fluorine atoms, with Rd chosen from a group OH, CH3 or NH2.
    
    


More preferably, the at least one compound used has the formula I in which:

    
    
        R1 is H or a sulfophenyl group,
        R2 represents H or a group from among CHO, (CH2)nOH, C(═O)NH2, C(═O)—CF3, (C═O)2Rc, (CH2)2NEt2, CH(OH)CH2N(Et)2, C(NOH)—(C═O)N(Et)2, NO2 and Br, with n=1 or 2 and Rc represents a group OCH3 or OC2H5, or N(C2H5)2,
        R3 and R4 are identical or different and are chosen, independently of each other, from H, a halogen atom and a group from among methyl, ethyl, nitro, nitrile, trifluoromethyl, C6 aryl optionally substituted with a group chosen from a group (C═O)CH3, phenyl, methoxy, trifluoromethoxy and trifluoromethyl group, or with 1 or 2 fluorine atoms.
    
    


Most preferably, the at least one compound of formula I is chosen from 1,10-dihydropyrrolo[2,3-a]carbazole, 1,10-dihydropyrrolo[2,3-a]-carbazole-3-carbaldehyde, 1,10-dihydropyrrolo[2,3-a]carbazole-3-carboxamide, 1-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl-2,2,2-trifluoroethanone, 7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole, 7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 7-(2,4-difluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 6-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 9-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 7-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 9-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 6,8-dichloro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 9-ethyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde and 8-methyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde.
Even more preferentially still, the at least one compound of formula I used in the invention is chosen from 1,10-dihydropyrrolo[2,3-a]carbazole, 1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 1,10-dihydropyrrolo[2,3-a]carbazole-3-carboxamide, 1-(1,10-dihydropyrrolo[2,3-a]-carbazol-3-yl-2,2,2-trifluoroethanone, 7-bromo-1,10-dihydropyrrolo[2,3-a]-carbazole, 7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 7-(2,4-difluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 6-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 9-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 7-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 9-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 6,8-dichloro-1,10-dihydropyrrolo[2,3-a]-carbazole-3-carbaldehyde, 9-ethyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde and 8-methyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde.
The invention also proposes a process for synthesizing the compounds of formula I below:




in which:

    
    
        R1 is H or a sulfophenyl group,
        R2, R3 and R4 are identical or different and represent, independently of each other, a hydrogen atom, a halogen atom or a group chosen among nitro, nitrile, hydroxyl, linear or branched C1 to C6 alkoxy optionally substituted with one or more groups R5, C5 to C6 cycloalkoxy optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkoxy optionally substituted with one or more groups R5, —SH, linear or branched C1 to C6 alkylthio optionally substituted with one or more groups R5, C6 aryl optionally substituted with one or more groups R5, C6 aryloxy optionally substituted with one or more groups R5, —NRaRb, —NRaC(O)-T1, —C(N—OH)-T3, —C(O)-T1, —C(O)—C(O)-T3, —C(O)—NRa-T1, —NRa—C(O)-T1, —O—C(O)-T1, —C(O)—O-T1, —O-T2-NRaRb, —O-T2-ORa, —O-T2CO2Ra, —NRa-T2-NRaRb, —NRa-T2-ORa, —NRa-T2-CO2Ra or —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa, linear or branched C1 to C6 alkyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkenyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkynyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryl optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryloxy optionally substituted with one or more groups R5,
        R5 represents a halogen atom or a group from among linear or branched C1 to C6 alkyl, C6 aryl, linear or branched C1 to C6 haloalkyl, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb, nitrile, nitro, —NRaC(O)-T1, C1 to C6 alkoxy, oxo, —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa,
        Ra and Rb are identical or different and represent, independently of each other, a hydrogen atom or a group chosen among linear or branched C1 to C6 alkyl, linear or branched C1 to C6 haloalkyl and C6 aryl, in which Ra+Rb form, together with the nitrogen atom to which they are attached, a saturated or unsaturated, monocyclic or bicyclic heterocycle of 5 to 10 atoms, optionally containing in the ring systems a second heteroatom chosen from oxygen and nitrogen, and being optionally substituted with one or more groups R5,
        T1 represents a hydrogen atom, a halogen atom or a linear or branched C1 to C6 alkyl group, optionally substituted with a group chosen from —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb,
        T2 represents a linear or branched (C1-C6)alkylidene chain,
        T3 represents a group chosen from -halogen, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb in which Ra and Ric, are as defined previously,
        t represents an integer between 0 and 3 inclusive,
        A, B, C and D denote the rings constituting the compounds of formula I, and serve merely to identify each of these rings,
    
    


characterized in that it comprises a Fischer indolization of the compound I-benzenesulfonyl-1,4,5,6-tetrahydro-7H-indol-7-one of formula II below:




and of phenylhydrazine or of phenylhydrazine substituted on the phenyl with one or more groups R5, in the presence of an ionic liquid, which is 2/1 zinc chloride-choline chloride of formula III below:





The invention also proposes compounds of formula I below:




in which:

    
    
        R1 is H or a sulfophenyl group,
        R2, R3 and R4 are identical or different and represent, independently of each other, a hydrogen atom, a halogen atom or a group chosen among nitro, nitrile, hydroxyl, linear or branched C1 to C6 alkoxy optionally substituted with one or more groups R5, C5 to C6 cycloalkoxy optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkoxy optionally substituted with one or more groups R5, —SH, linear or branched C1 to C6 alkylthio optionally substituted with one or more groups R5, C6 aryl optionally substituted with one or more groups R5, C6 aryloxy optionally substituted with one or more groups R5, —NRaRb, —NRaC(O)-T1, —C(N—OH)-T3, —C(O)-T1, —C(O)—C(O)-T3, —C(O)—NRa-T1, —NRa—C(O)-T1, —O—C(O)-T1, —C(O)—O-T1, —O-T2-NRaRb, —O-T2-ORa, —O-T2CO2Ra, —NRa-T2-NRaRb, —NRa-T2-ORa, —NRa-T2-CO2Ra or —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa, linear or branched C1 to C6 alkyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkenyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkynyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryl optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryloxy optionally substituted with one or more groups R5,
        R5 represents a halogen atom or a group chosen among linear or branched C1 to C6 alkyl, C6 aryl, linear or branched C1 to C6 haloalkyl, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb, nitrile, nitro, —NRaC(O)-T1, C1 to C6 alkoxy, oxo, —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa,
        Ra and Rb are identical or different and represent, independently of each other, a hydrogen atom or a group from among linear or branched C1 to C6 alkyl, linear or branched C1 to C6 haloalkyl and C6 aryl, in which Ra+Rb form, together with the nitrogen atom to which they are attached, a saturated or unsaturated, monocyclic or bicyclic heterocycle of 5 to 10 atoms, optionally containing in the ring systems a second heteroatom chosen from oxygen and nitrogen, and being optionally substituted with one or more groups R5,
        T1 represents a hydrogen atom, a halogen atom or a linear or branched C1 to C6 alkyl group, optionally substituted with a group chosen from —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb,
        T2 represents a linear or branched (C1-C6)alkylidene chain,
        T3 represents a group chosen from -halogen, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb in which Ra and Rb are as defined previously,
        t represents an integer between 0 and 3 inclusive,
        A, B, C and D denote the rings constituting the compounds of formula I, and serve merely to identify each of these rings,
    
    


at the provisos:

    
    
        R1, R2, R3 and R4 are not all simultaneously H,
        when R1 is a sulfophenyl group, then R2, R3 and R4 are not all simultaneously H, and
        when R2 is a carboxamide or formyl group, then R1, R3 and R4 are not all simultaneously H.
    
    


Preferably, these compounds have the formula I in which:

    
    
        R1 is H or a sulfophenyl group,
        R2 represents H, or a group chosen among CHO, (CH2)nOH, C(═O)NH2, C(═O)—CF3, (C═O)2Rc, (CH2)2NEt2, CH(OH)CH2N(Et)2, C(NOH)—(C═O)N(Et)2, NO2 and Br with n=1 or 2 and Rc═OCH3, OC2H5 or N(C2H5)2,
        R3 and R4 are identical or different and are chosen, independently of each other, from H, a halogen atom, a 5- or 6-membered heteroaryl group comprising one or two heteroatoms chosen from O and N, linear or branched C1 to C6 alkyl, methoxy, nitro, nitrile, carboxyl, trifluoromethyl, trifluoromethoxy, SO2Rd, C6 aryl optionally substituted with a group chosen from a group (C═O)CH3, phenyl, methoxy trifluoromethoxy, trifluoromethyl and carboxyl or with 1 or 2 fluorine atoms, with Rd chosen from a group OH, CH3 or NH2.
    
    


More preferably, these compounds have the formula I in which:

    
    
        R1 is H or a sulfophenyl group,
        R2 represents H or a group from among CHO, (CH2)nOH, C(═O)NH2, C(O)—CF3, (C═O)2Rc, (CH2)2NEt2, CH(OH)CH2N(Et)2, C(NOH)—(C═O)N(Et)2, NO2 and Br, with n=1 or 2 and Rc represents a group OCH3, OC2H5 or N(C2H5)2,
        R3 and R4 are identical or different and are chosen, independently of each other, from H, a halogen atom and a group chosen among methyl, ethyl, nitro, nitrile, trifluoromethyl, C6 aryl optionally substituted with a group chosen from a group (C═O)CH3, phenyl, methoxy, trifluoromethoxy and trifluoromethyl, or with 1 or 2 fluorine atoms.
    
    


Even more preferably, the compounds of formula I are chosen from:

    (1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)methanol,
    1-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-2,2,2-trifluoroethanone,
    methyl 2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-2-oxoacetate,
    ethyl 2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-2-oxoacetate,
    2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)ethanol,
    2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-N,N-diethyl-2-oxoacetamide,
    2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-N,N-diethylethanamine,
    1-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-2-diethylaminoethanol,
    2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-N,N-diethyl-2-hydroxy-iminoethanamide,
    1-benzenesulfonyl-7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole,
    7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole,
    7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    7-(4-acetylphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
    7-(3-methoxyphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
    7-(4-biphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
    7-phenyl-1,10-dihydropyrrolo[2,3-a]carbazole,
    7-(4-fluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
    7-(2,4-difluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
    7-(4-trifluoromethylphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
    7-(4-trifluoromethoxyphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
    8-bromo-1,10-dihydropyrrolo[2,3-a]carbazole,
    6-bromo-1,10-dihydropyrrolo[2,3-a]carbazole,
    9-bromo-1,10-dihydropyrrolo[2,3-a]carbazole,
    7-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole,
    9-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole,
    6,8-dichloro-1,10-dihydropyrrolo[2,3-a]carbazole,
    1,10-dihydropyrrolo[2,3-a]carbazole-7-carbonitrile,
    7-nitro-1,10-dihydropyrrolo[2,3-a]carbazole,
    9-ethyl-1,10-dihydropyrrolo[2,3-a]carbazole,
    9-(trifluoromethyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
    8-methyl-1,10-dihydropyrrolo[2,3-a]carbazole,
    7-(3-methoxyphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    7-(4-biphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    7-phenyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    7-(4-fluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    7-(2,4-difluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    7-(4-trifluoromethylphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    7-(4-trifluoromethoxyphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    8-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    6-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    9-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    7-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    9-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    6,8-dichloro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    3-formyl-1,10-dihydropyrrolo[2,3-a]carbazole-7-carbonitrile,
    7-nitro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    9-ethyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
    8-methyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde.


The compounds of the invention that are the most preferred are 1,10-dihydropyrrolo[2,3-a]carbazol-3-yl-2,2,2-trifluoroethanone, 7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole, 7-bromo-1,10-dihydropyrrolo[2,3-a]-carbazole-3-carbaldehyde, 7-(2,4-difluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 6-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 9-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 7-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 9-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 6,8-dichloro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, 9-ethyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde and 8-methyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde.
The invention will be understood more clearly and other advantages and characteristics thereof will emerge more clearly on reading the explanatory description that follows.
The invention is based on the discovery that the compounds having the formula I below:




in which:

    
    
        R1 is H or a sulfophenyl group,
        R2, R3 and R4 are identical or different and represent, independently of each other, a hydrogen atom, a halogen atom or a group chosen among nitro, nitrile, hydroxyl, linear or branched C1 to C6 alkoxy optionally substituted with one or more groups R5, C5 to C6 cycloalkoxy optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkoxy optionally substituted with one or more groups R5, —SH, linear or branched C1 to C6 alkylthio optionally substituted with one or more groups R5, C6 aryl optionally substituted with one or more groups R5, C6 aryloxy optionally substituted with one or more groups R5, —NRaRb, —NRaC(O)-T1, —C(N—OH)-T3, —C(O)-T1, —C(O)—C(O)-T3, —C(O)—NRa-T1, —NRa—C(O)-T1, —O—C(O)-T1, —C(O)—O-T1, —O-T2-NRaRb, —O-T2-ORa, —O-T2-CO2Ra, —NRa-T2-NRaRb, —NRa-T2-ORa, —NRa-T2-CO2Ra or —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa, linear or branched C1 to C6 alkyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkenyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkynyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryl optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryloxy optionally substituted with one or more groups R5,
        R5 represents a halogen atom or a group chosen among linear or branched C1 to C6 alkyl, C6 aryl, linear or branched C1 to C6 haloalkyl, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb, nitrile, nitro, —NRaC(O)-T1, C1 to C6 alkoxy, oxo, —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa,
        Ra and Rb are identical or different and represent, independently of each other, a hydrogen atom or a group from among linear or branched C1 to C6 alkyl, linear or branched C1 to C6 haloalkyl and C6 aryl, in which Ra+Rb form, together with the nitrogen atom to which they are attached, a saturated or unsaturated, monocyclic or bicyclic heterocycle of 5 to 10 atoms, optionally containing in the ring systems a second heteroatom chosen from oxygen and nitrogen, and being optionally substituted with one or more groups R5,
        T1 represents a hydrogen atom, a halogen atom or a linear or branched C1 to C6 alkyl group, optionally substituted with a group chosen from —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb,
        T2 represents a linear or branched (C1-C6)alkylidene chain,
        T3 represents a group chosen from -halogen, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb in which Ra and Ric, are as defined previously,
        t represents an integer between 0 and 3 inclusive,
        A, B, C and D denote the rings constituting the compounds of formula I, and serve merely to identify each of these rings, are selective inhibitors of at least one kinase PIM-1, PIM-2 or PIM-3 when tested on 67 kinases.
    
    


Due to their properties of selective inhibition of at least one kinase PIM-1, PIM-2 or PIM-3, they have particularly advantageous properties in the anticancer field. These compounds may be used either alone or as a therapeutic combination, in particular with other anticancer agents, for instance paclitaxel, tamoxifen and derivatives thereof, cisplatin and analogs thereof, irinotecan and metabolites thereof, various alkylating agents, etoposide, Vinca alkaloids, anthracyclines, nitrosoureas, hormone therapy and radiotherapy.
These compounds of formula I may be used in their native form or in the form of optical isomers thereof or in the form of a racemic mixture of these optical isomers or of an addition salt of these compounds of formula I with a pharmaceutically acceptable acid or base.
The preferred, more preferred, most preferred and even more preferred compounds of formula I used as selective inhibitors of at least one kinase PIM-1, PIM-2 or PIM-3 have been defined above.
When the group R2, R3 and/or R4 is a group that is itself substituted with one or more groups R5, it is preferably substituted with at least two groups R5.
When the group R2, R3 and/or R4 is a group that is itself substituted with two groups R5, then the two groups R5 are preferably identical.
Certain compounds of formula I have already been described. These are compounds in which R1, R2, R3 and R4 are all simultaneously H, compounds in which R1 is a sulfophenyl group and R2, R3 and R4 are all simultaneously H, and compounds in which R2 is a carboxamide group or a formyl group and R1, R3 and R4 are all simultaneously H.
However, these compounds have never been described as selective inhibitors of at least one kinase PIM-1, PIM-2 or PIM-3. Nor has it ever been reported, before the invention, that they could be such inhibitors, and all the less so with such selectivity.
On the other hand, the compounds of formula I in which R1, R2, R3 and R4 are not all simultaneously H or in which R1 is a sulfophenyl group but in which R2, R3 and R4 are not all simultaneously H, or alternatively in which R2 is a carboxamide group or a formyl group, but in which R1, R3 and R4 are not all simultaneously H, have never been described previously.
These compounds are thus a subject of the invention.
Such preferred, more preferred and most preferred compounds have been described previously.
The invention also proposes a process for manufacturing the compounds of formula I, which may be used as an alternative to the standard process for manufacturing these pyrrolo[2,3-a]carbazole derivatives.
This process comprises a Fischer indolization reaction of 1-benzenesulfonyl-1,4,5,6-tetrahydro-7H-indol-7-one with phenylhydrazine or a phenylhydrazine substituted on the phenyl with one or more groups R5, in the presence of an ionic liquid, 2/1 zinc chloride-choline chloride.
In order to have the invention more clearly understood, several embodiments thereof will be described, as purely illustrative and non-limiting examples.


I) EXAMPLES OF SYNTHESES
The structures of the compounds described in the examples that follow are determined according to usual techniques (infrared spectrometry, mass spectrometry, nuclear magnetic resonance spectrometry, etc.). In the nuclear magnetic resonance spectrometry data, the abbreviation “bs” means a broadered signal.
Preparation A: synthesis of 1-benzenesulfonylpyrrole




1-Benzenesulfonylpyrrole serves to prepare 1-benzenesulfonyl-1,4,5,6-tetrahydro-7H-indol-7-one, which will be used for the synthesis of the compounds according to the invention.
This compound is obtained according to the process described by B. P. Smart et al. in J. Med. Chem., 2006, 49, 2858-2860.
Preparation B: synthesis of 1-benzenesulfonyl-1,4,5,6-tetrahydro-7H-indol-7-one




This product is obtained according to the process described by M. Kakushima et al. in J. Org. Chem., 1983, 48, pp. 3214-3219.
Preparation C: Preparation of the Ionic Liquid 2/1 Zinc Chloride-Choline Chloride




A mixture of choline chloride (10.0 g; 71.6 mmol) and zinc chloride (19.5 g; 143 mmol) in toluene (200 mL) is refluxed in Dean-Stark apparatus with vigorous stirring for 15 hours. After cooling and separation of the phases by settling, the ionic liquid is obtained in the form of a yellow oil. The ionic liquid, which is highly hygroscopic, may be used directly, or stored under argon in anhydrous ether.
Example 1
1-benzenesulfonyl-1,10-dihydropyrrolo[2,3-a]carbazole




Method 1:
Stage A:
A solution of the compound of Preparation B (9.65 g; 35.0 mmol) and of phenylhydrazine (6.92 mL; 70.3 mmol) in nitromethane (360 mL) is stirred for 3 hours at reflux.
Stage B:
P2O5 (9.91 g; 69.8 mmol) is added to a solution of hexamethyldisiloxane (23.9 mL; 112 mmol) in dichloromethane (350 mL) and the mixture is then stirred at reflux for 40 minutes. The solvent is removed by distillation and the residual liquid is heated at 180° C. for 5 minutes. The oil obtained (PPSE) is diluted in nitromethane (180 mL) and the solution is transferred into the preparation obtained from the preceding stage. The mixture is refluxed with stirring for 6 hours, and DDQ (3.50 g; 15.4 mmol) is then added. The mixture is stirred at room temperature for 12 hours and then filtered through Celite and concentrated under vacuum. Et2O is then added to the residue and the solution is filtered through silica. The filtrate is concentrated and then purified by chromatography on a column of flash silica (eluent: 9/1 cyclohexane/Et2O). After evaporation, the solid obtained is washed with methanol (20 mL) and then with Et2O (2×50 mL) to give the desired compound (4.40 g; 12.7 mmol; yield=36%) in the form of a beige-colored solid.
Method 2:
A mixture of phenylhydrazine (393 mg; 3.63 mmol), the compound of Preparation B (500 mg; 1.82 mmol) and the ionic liquid of Preparation C (5.25 g; 12.7 mmol) is stirred at 120° C. for 2 hours. The brown oil obtained is cooled and aqueous 0.5 M HCl solution is added. The mixture is extracted with ethyl acetate (3×50 mL). The combined organic phases are washed with saturated aqueous NaCl solution, dried over MgSO4 and filtered. The solution obtained contains the indolization product, as the major product, and the expected product, as the minor product.
DDQ (0.29 g; 1.28 mmol; the necessary amount of DDQ is determined from the 1H NMR spectrum of the intermediate mixture) is added to this solution and the mixture is stirred at room temperature for 15 hours. The mixture is washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and then concentrated on silica, followed by purification by chromatography on flash silica gel (95/5 and then 90/10 pentane/ethyl acetate) to give the expected compound (0.49 g; 1.41 mmol; yield=78%) in the form of a white solid.
Melting point: 148° C.
IR (KBr): 3430, 1630, 1610 cm−1 
High resolution mass spectrum (ESI+): calculated for C20H15N2O2S (M+H)+347.0854. found 347.0861.
1H NMR (400 MHz, DMSO-d6): 6.85 (1H, d, J=3.5 Hz); 7.28-7.39 (4H, m); 7.44-7.52 (2H, m); 7.53 (1H, d, J=3.5 Hz); 7.64 (1H, d, J=8.0 Hz); 7.75-7.80 (2H, m); 8.01 (1H, d, J=8.0 Hz); 8.12 (1H, d, J=8.0 Hz); 10.12 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 111.4; 112.6; 113.0; 117.1; 119.9 (2C); 125.5; 126.1; 126.7 (2C); 129.5 (2C); 133.9 (CH); 120.4; 121.9; 123.8; 127.0; 130.6; 137.9; 138.8 (C)
Example 2
1,10-dihydropyrrolo[2,3-a]carbazole




Aqueous 5M NaOH solution (125 mL) is added to a suspension of the compound of Example 1 (3.12 g; 9.0 mmol) in methanol (1.0 L). The mixture is stirred at reflux for 12 hours. The reaction mixture is concentrated under vacuum until a precipitate forms, which is recovered by filtration. The solid obtained is washed with MeOH (10 mL) and then with Et2O (2×30 mL) to give the expected compound (1.71 g; 8.3 mmol; yield=92%) in the form of an off-white solid.
Melting point: 295° C.
IR (KBr): 3420, 3385, 1650, 1455, 1445, 1395, 1345, 1310 cm−1 
High resolution mass spectrum (ESI+): calculated for C14H11N2 (M+H)+207.0922. found 207.0925.
1H NMR (400 MHz, DMSO-d6): 6.61 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.18 (1H, ddd, J1=8.0 Hz, J2=7.0 Hz, J3=1.0 Hz); 7.33 (1H, ddd, J1=8.0 Hz, J2=7.0 Hz, J3=1.0 Hz); 7.37 (1H, d, J=8.5 Hz); 7.42 (1H, t, J=3.0 Hz); 7.64 (1H, d, J=8.0 Hz); 7.75 (1H, d, J=8.5 Hz); 8.07 (1H, d, J=7.5 Hz); 10.88 (1H, bs, NH); 10.95 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 102.8; 111.2; 112.0; 112.1; 118.6; 119.0; 123.3; 123.6 (CH); 116.2; 121.8; 124.1; 126.2; 126.4; 138.1 (C)
Example 3
1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




A solution of oxalyl chloride (19.5 μL; 0.223 mmol) and of DMF (18.9 μL; 0.244 mmol) in anhydrous dichloromethane (6 mL) is stirred at 0° C. for 20 minutes. A solution of the compound of Example 2 (43.6 mg; 0.211 mmol) in anhydrous dichloromethane (6 mL) is then added dropwise. The mixture is stirred at 0° C. for 20 minutes and then for 2.5 hours at room temperature. The solvent is evaporated off and aqueous 5% m/v NaOH solution (12 mL) is then added. The mixture is stirred at room temperature for 12 hours and water is then added. After extracting with EtOAc, the organic phase is dried over MgSO4, filtered and evaporated. The residue is purified by chromatography on flash silica gel (elution gradient from 7/3 to 5/5 cyclohexane/EtOAc) to give the expected compound (32.4 mg; 0.138 mmol; yield=66%) in the form of an off-white solid.
Melting point >290° C.
IR (KBr): 3450-3150, 1630, 1615 cm−1 
High resolution mass spectrum (ESI+): calculated for C15H11N2O (M+H)+235.0871. found 235.0882.
1H NMR (500 MHz, DMSO-d6): 7.23 (1H, t, J=7.5 Hz); 7.40 (1H, t, J=7.5 Hz); 7.70 (1H, d, J=8.0 Hz); 7.96 (1H, d, J=8.5 Hz); 8.00 (1H, d, J=8.5 Hz); 8.15 (1H, d, J=7.5 Hz); 8.33 (1H, d, J=2.0 Hz); 10.07 (1H, s); 11.10 (1H, bs); 11.93 (1H, bs)
13C NMR (125 MHz, DMSO-d6): 111.5; 112.1; 115.0; 119.0; 119.5; 124.3; 136.7 (CH); 118.3; 119.5; 122.5; 122.8; 123.5; 126.0; 138.5 (C); 185.3 (C═O)
Example 4
(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)methanol




NaBH4 (320 mg; 8.46 mmol) is added to a solution of the compound of Example 3 (147 mg; 0.63 mmol) in methanol (30 mL) and the mixture is stirred at room temperature for 1 hour. Water (10 mL) is added and the precipitate is recovered by filtration. The solid obtained is washed with methanol (5 mL) and then with Et2O (2×20 mL) to give the expected compound (100 mg; 0.423 mmol; yield=67%) in the form of a gray solid.
Melting point >295° C.
IR (KBr): 3375, 1648, 1456 cm−1 
High resolution mass spectrum (ESI+): calculated for C15H11N2 (M−OH)+219.0922. found 219.0922.
1H NMR (400 MHz, DMSO-d6): 4.72 (2H, s); 4.54-4.96 (1H, bs); 7.14 (1H, t, J=7.5 Hz); 7.26-7.31 (2H, m); 7.40 (1H, d, J=8.5 Hz); 7.58 (1H, d, J=8.0 Hz); 7.71 (1H, d, J=8.5 Hz); 8.03 (1H, d, J=7.5 Hz); 10.48-11.46 (2H, 2 bs)
13C NMR (100 MHz, DMSO-d6): 55.7 (CH2); 110.9; 111.1; 111.5; 118.5; 119.0; 121.8; 123.3 (CH); 116.3; 117.7; 122.1; 124.1; 125.1; 126.4; 138.1 (C)
Example 5
1,10-dihydropyrrolo[2,3-a]carbazole-3-carboxamide




Chlorosulfonyl isocyanate (26.7 μL; 0.307 mmol) is added at 0° C. to a solution of the compound of Example 2 (57.4 mg; 0.278 mmol) in anhydrous acetonitrile (10 mL). The mixture is stirred at 0° C. for 1.5 hours, and an aqueous 1N HCl solution (5 mL) and THF (2 mL) are then added. The mixture is stirred at room temperature for 36 hours, and water is then added. After extracting with ethyl acetate, the combined organic phases are washed with saturated aqueous NaHCO3 solution and with saturated aqueous NaCl solution, and then dried over MgSO4, filtered and evaporated. The residue is purified by chromatography on flash silica gel (THF) to give the expected product (13.8 mg; 0.055 mmol; yield=20%) in the form of a beige-colored solid.
Melting point >300° C.
IR (KBr): 3430, 3370, 3335, 1650 cm−1 
High resolution mass spectrum (ESI+): calculated for C15H12N3O (M+H)+250.0980. found 250.0966.
1H NMR (500 MHz, DMSO-d6): 6.86 (1H, bs); 7.20 (1H, t, J=8.0 Hz); 7.36 (1H, ddd, J1=8.0 Hz, J2=7.0 Hz, J3=1.0 Hz); 7.46 (1H, bs); 7.65 (1H, d, J=8.0 Hz); 7.84 (1H, d, J=8.5 Hz); 8.02 (1H, d, J=8.5 Hz); 8.08 (1H, d, J=3.0 Hz); 8.10 (1H, d, J=8.0 Hz)
13C NMR (100 MHz, DMSO-d6): 111.3; 112.8; 113.2; 118.7; 119.2; 123.7; 126.8 (CH); 112.1; 116.8; 112.1; 123.8; 124.8; 126.2; 138.3 (C); 166.7 (C═O)
Example 6
1-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-2,2,2-trifluoroethanone




Trifluoroacetic anhydride (45 μL; 0.32 mmol) is added at room temperature to a solution of the compound of Example 2 (52 mg; 0.25 mmol) in DMF (10 mL). The mixture is stirred at room temperature for 18 hours, and ice and water are then added. The mixture is extracted with ethyl acetate (3×10 mL) and the combined organic fractions are then washed with saturated aqueous NaCl solution (15 mL), dried over MgSO4, filtered and evaporated. The residue obtained is triturated with Et2O (20 mL) and the mixture is filtered, to give the expected compound (32 mg; 0.106 mmol; yield=42%) in the form of a green solid.
Melting point >295° C.
IR (KBr): 3274, 1639 cm−1 
High resolution mass spectrum (ESI+): calculated for C16H10F3N2O (M+H)+303.0745. found 303.0732.
1H NMR (400 MHz, DMSO-d6): 7.22 (1H, t, J=7.5 Hz); 7.40 (1H, ddd, J1=8.0 Hz, J2=7.0 Hz, J3=1.0 Hz); 7.70 (1H, d, J=8.0 Hz); 8.01 (1H, d, J=8.5 Hz); 8.07 (1H, d, J=8.5 Hz); 8.15 (1H, d, J=8.0 Hz); 8.49-8.53 (1H, bs); 11.03 (1H, s); 12.39-12.48 (1H, bs)
13C NMR (100 MHz, DMSO-d6): 111.7; 112.1; 116.3; 119.3; 119.7; 124.7; 135.8 (q, JCF=5 Hz) (CH); 110.1; 117.0 (q, JCF=292 Hz); 119.1; 122.3; 123.2; 124.1; 126.0; 138.6 (C); 174.0 (q, JCF=34 Hz, C═O)
Example 7
methyl 2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-2-oxoacetate




Stage A:
oxalyl chloride (660 μL; 7.7 mmol) is added at 0° C. to a suspension of the compound of Example 2 (825 mg; 4.00 mmol) in anhydrous Et2O (40 mL). The mixture is stirred at room temperature for 4 hours. After filtration, the solid is washed with Et2O (2×40 mL) to give the intermediate acid chloride (972 mg) in the form of a red-brown solid, which is used without further purification.
Stage B:
Et3N (138 μL; 0.99 mmol) is added to a suspension of the intermediate acid chloride (243 mg) in methanol (5 mL). The mixture is stirred at room temperature for 4 hours. After filtration, the solid is washed with MeOH (5 mL) and then with Et2O (2×20 mL) to give the expected compound (176 mg; 0.60 mmol; yield=60% from the compound of Example 2) in the form of a dark orange solid.
Melting point >290° C.
IR (KBr): 3461, 3306, 1735, 1590 cm−1 
High resolution mass spectrum (ESI+): calculated for C17H12N2NaO3 (M+Na)+ 315.0746. found 315.0754.
1H NMR (400 MHz, DMSO-d6): 3.92 (3H, 5); 7.20 (1H, ddd, J1=8.0 Hz, J2=7.0 Hz, J3=1.0 Hz); 7.38 (1H, ddd, J1=8.0 Hz, J2=7.0 Hz, J3=1.0 Hz); 7.67 (1H, d, J=8.0 Hz); 7.99 (1H, d, J=8.5 Hz); 8.02 (1H, d, J=8.5 Hz); 8.13 (1H, d, J=8.0 Hz); 8.49 (1H, d, J=3.5 Hz); 11.05 (1H, s, NH); 12.14-12.21 (1H, bs)
13C NMR (100 MHz, DMSO-d6): 52.5 (CH3); 111.6; 112.3; 115.7; 119.1; 119.6; 124.5; 136.7 (CH); 113.7; 118.7; 122.4; 123.3; 123.8; 126.1; 138.5 (C); 164.1; 178.9 (C═O)
Example 8
ethyl 2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-2-oxoacetate




Et3N (275 μL; 1.97 mmol) is added to a suspension of the compound prepared in stage A and of Example 7 (486 mg) in ethanol (10 mL). The mixture is stirred at room temperature for 4 hours. After filtration, the solid is washed with EtOH (10 mL) and then with Et2O (2×20 mL) to give the expected compound (446 mg; 1.46 mmol; yield=73% from the compound of Example 2) in the form of a green-yellow solid.
Melting point >295° C.
IR (KBr): 3292, 1725, 1602 cm−1 
High resolution mass spectrum (ESI+): calculated for C18H14N2NaO3 
(M+Na)+ 329.0902. found 329.0907.
1H NMR (400 MHz, DMSO-d6): 1.37 (3H, t, J=7.0 Hz); 4.39 (2H, q, J=7.0 Hz); 7.20 (1H, t, J=7.5 Hz); 7.38 (1H, ddd, J1=8.0 Hz, J2=7.0 Hz, J3=1.0 Hz); 7.67 (1H, d, J=8.0 Hz); 7.98-8.03 (2H, m); 8.12 (1H, d, J=8.0 Hz); 8.47 (1H, d, J=3.0 Hz); 11.07 (1H, s); 12.09-12.20 (1H, bs)
13C NMR (100 MHz, DMSO-d6): 14.0 (CH3); 61.6 (CH2); 111.6; 112.3; 115.7; 119.1; 119.6; 124.5; 136.6 (CH); 113.7; 118.7; 122.4; 123.3; 123.8; 126.1; 138.5 (C); 163.7; 179.4 (C═O)
Example 9
2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)ethanol




LiAlH4 (2.00 mL; 2.00 mmol; 1M in THF) is added at room temperature to a suspension of the compound of Example 8 (153 mg; 0.50 mmol) in dioxane (10 mL). The THF is distilled off and the mixture is then refluxed for 12 hours. After cooling to room temperature, water (5 mL) is added and the mixture is extracted with EtOAc (3×10 mL). The combined organic fractions are washed with water (10 mL), dried over MgSO4, filtered and evaporated. The residue is triturated in Et2O (20 mL) and then filtered, to give the expected compound (90 mg; 0.36 mmol; yield=72%) in the form of a gray-brown solid.
Melting point: 269-271° C.
IR (KBr): 3416, 3382, 3234, 1649, 1457 cm−1 
High resolution mass spectrum (ESI+): calculated for C16H15N2O (M+H)+251.1184. found 251.1177.
1H NMR (400 MHz, DMSO-d6): 2.92 (2H, t, J=7.5 Hz); 3.71 (2H, dt, J1=7.5 Hz, J2=5.5 Hz); 4.63 (1H, t, J=5.5 Hz); 7.13 (1H, ddd, J1=8.0 Hz, J2=7.0 Hz, J3=1.0 Hz); 7.19 (1H, d, J=2.0 Hz); 7.28 (1H, ddd, J1=8.0, J2=7.0 Hz, J3=1.0 Hz); 7.31 (1H, d, J=8.5 Hz); 7.58 (1H, d, J=8.0 Hz); 7.70 (1H, d, J=8.5 Hz); 8.02 (1H, d, J=7.5 Hz); 10.53-10.57 (1H, bs); 10.86 (1H, s)
13C NMR (100 MHz, DMSO-d6): 29.1; 61.8 (CH2); 110.4; 111.1; 111.3; 118.5; 119.0; 121.2; 123.2 (CH); 113.3; 116.2; 121.9; 124.1; 125.9; 126.5; 138.1 (C)
Example 10
2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-N,N-diethyl-2-oxoacetamide




Diethylamine (305 μL; 2.92 mmol) is added to a suspension of the compound prepared in stage A of Example 7 (486 mg) in anhydrous Et2O (10 mL). The mixture is stirred at room temperature for 4 hours. After filtration, the solid is washed with MeOH (3 mL) and then with Et2O (2×20 mL) to give the expected compound (439 mg; 1.32 mmol; yield=66% from the compound of Example 2) in the form of a pale gray solid.
Melting point >295° C.
IR (KBr): 3450-3100, 1608, 1429 cm−1 
High resolution mass spectrum (ESI+): calculated for C20H20N3O2 (M+H)+334.1556. found 334.1543.
1H NMR (400 MHz, DMSO-d6): 1.10 (3H, t, J=7.0 Hz); 1.22 (3H, t, J=7.0 Hz); 3.28 (2H, q, J=7.0 Hz); 3.47 (2H, q, J=7.0 Hz); 7.20 (1H, ddd, J1=8.0 Hz, J2=7.0 Hz, J3=1.0 Hz); 7.37 (1H, ddd, J1=8.0 Hz, J2=7.0 Hz, J3=1.5 Hz); 7.66 (1H, d, J=8.0 Hz); 7.93 (1H, d, J=8.5 Hz); 7.99 (1H, d, J=8.5 Hz); 8.07 (1H, d, J=3.0 Hz); 8.12 (1H, d, J=8.0 Hz); 11.04 (1H, s, NH); 11.96-12.01 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 12.7; 14.1 (CH3); 38.1; 41.7 (CH2); 111.4; 112.1; 115.3; 119.0; 119.5; 124.4; 134.9 (CH); 114.3; 118.3; 122.7; 123.2; 123.4; 126.1; 138.4 (C); 167.2; 187.0 (C═O)
Example 11
2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-N,N-diethylethanamine




LiAlH4 (2.00 mL; 2.00 mmol; 1 M in THF) is added under argon at room temperature to a suspension of the compound of Example 10 (120 mg; 0.360 mmol) in dioxane (10 mL). The THF is distilled off and the mixture is then refluxed for 12 hours. After cooling to room temperature, a drop of water is added and the mixture is filtered. The filtrate is concentrated and the residue is then triturated with Et2O (20 mL). After filtration, the solid is washed with Et2O (20 mL) to give the expected compound (27 mg; 0.088 mol; yield=25%) in the form of a gray solid.
Melting point: 224-226° C.
IR (KBr): 3388, 1649, 1560, 1450 cm−1 
High resolution mass spectrum (ESI+): calculated for C20H24N3 (M+H)+306.1970. found 306.1960.
1H NMR (400 MHz, DMSO-d6): 1.02 (6H, t, J=7.0 Hz); 2.59 (4H, q, J=7.0 Hz); 2.71-2.76 (2H, m); 2.83-2.89 (2H, m); 7.13 (1H, ddd, J1=8.0 Hz, J2=7.0 Hz, J3=1.0 Hz); 7.18-7.20 (1H, m); 7.26-7.31 (2H, m); 7.58 (1H, d, J=8.0 Hz); 7.70 (1H, d, J=8.5 Hz); 8.02 (1H, d, J=7.5 Hz); 10.52-10.56 (1H, bs); 10.86 (1H, s)
13C NMR (100 MHz, DMSO-d6): 12.0 (CH3); 22.8; 46.3 (2C); 53.4 (CH2); 110.2; 111.1; 111.3; 118.5; 118.9; 120.9; 123.2 (CH); 114.7; 116.2; 121.9; 124.0; 125.8; 126.5; 138.1 (C)
Example 12
1-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-2-diethylaminoethanol




LiAlH4 (2.00 mL; 2.00 mmol; 1M in THF) is added to a suspension of the compound of Example 10 (181 mg; 0.543 mmol) in THF (10 mL) and the mixture is stirred at reflux for 24 hours. Water (76 μL), aqueous 15% NaOH solution (76 μL) and then water (228 μL) are successively added. The mixture is filtered and the filtrate is concentrated. The residue obtained is washed with water (3 mL), dried, washed with MeOH (3 mL) and then finally with Et2O (10 mL) to give the expected compound (57 mg; 0.177 mmol; yield=33%) in the form of an off-white solid.
Melting point: 148-150° C.
IR (KBr): 3274, 1652, 1615, 1455 cm−1 
High resolution mass spectrum (ESI+): calculated for C20H24N3O (M+H)+322.1919. found 322.1912.
1H NMR (400 MHz, DMSO-d6): 0.99 (6H, t, J=7.0 Hz); 2.53-2.69 (4H, m); 2.74 (1H, dd, J1=13.0 Hz, J2=5.0 Hz); 2.78 (1H, dd, J1=13.0 Hz, J2=7.5 Hz); 4.55-4.63 (1H, bs); 4.98 (1H, dd, J1=7.5 Hz, J2=5.0 Hz); 7.13 (1H, t, J=7.5 Hz); 7.26-7.31 (2H, m); 7.41 (1H, d, J=8.5 Hz); 7.58 (1H, d, J=8.0 Hz); 7.69 (1H, d, J=8.5 Hz); 8.02 (1H, d, J=7.5 Hz); 10.60-10.65 (1H, bs); 10.87 (1H, s)
13C NMR (100 MHz, DMSO-d6): 11.9 (CH3); 46.8 (2C); 60.3 (CH2); 65.0; 111.1; 111.3; 111.4; 118.5; 119.0; 120.7; 123.3 (CH); 116.1; 119.6; 122.2; 124.0; 124.4; 126.4; 138.1 (C)
Example 13
2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-N,N-diethyl-2-hydroxyiminoethanamide




Hydroxylamine hydrochloride (261 mg; 3.76 mmol) is added to a solution of the compound of Example 10 (167 mg; 0.50 mmol) in pyridine (5 mL) and the mixture is then refluxed for 12 hours. Water (5 mL) is added and the pyridine is evaporated off under reduced pressure. The mixture is extracted with ethyl acetate (3×10 mL) and the combined organic fractions are washed with saturated aqueous NaCl solution (10 mL), dried over MgSO4, filtered and evaporated. The residue obtained is triturated with EtOAc (20 mL) and the mixture is filtered, to give the expected compound (33 mg; 0.095 mmol; yield=19%) in the form of a beige-colored solid.
Melting point: 268-269° C.
IR (KBr): 3266, 1609, 1464 cm−1 
High resolution mass spectrum (ESI+): calculated for C20H21N4O2 (M+H)+349.1665. found 349.1675.
1H NMR (400 MHz, DMSO-d6): 1.03 (3H, t, J=7.0 Hz); 1.19 (3H, t, J=7.0 Hz); 3.26 (2H, q, J=7.0 Hz); 3.39-3.59 (2H, m); 7.17 (1H, t, J=7.5 Hz); 7.33 (1H, t, J=7.5 Hz); 7.36 (1H, d, J=2.5 Hz); 7.61 (1H, d, J=8.0 Hz); 7.83 (1H, d, J=8.5 Hz); 7.86 (1H, d, J=8.5 Hz); 8.07 (1H, d, J=7.5 Hz); 10.90 (1H, s); 11.03-11.07 (1H, bs); 11.21-11.26 (1H, bs)
13C NMR (100 MHz, DMSO-d6): 12.8; 13.8 (CH3); 37.6; 41.7 (CH2); 111.3; 113.2; 113.3; 118.7; 119.3; 123.8; 125.7 (CH); 109.7; 117.3; 122.5; 122.7; 123.7; 126.2; 138.3 (C); 150.6 (C═N); 164.4 (C═O)
Example 14
1-benzenesulfonyl-7-bromo-1,10-dihydropyrrolo-[2,3-a]carbazole




A suspension of 4-bromophenylhydrazine chloride (1.62 g; 7.3 mmol) and anhydrous sodium acetate (0.60 g; 7.3 mmol) in DME (20 mL) is stirred at room temperature for 1 hour. The compound of Preparation B (1.00 g; 3.63 mmol) and the ionic liquid of Preparation C (10.0 g; 24.3 mmol) are added. The solvent is evaporated off and the reaction mixture is stirred at 120° C. for 2 hours. The brown oil obtained is cooled and aqueous 0.5 M HCl solution is added. The mixture is extracted three times with ethyl acetate. The combined organic phases are washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and evaporated. The residue obtained is a mixture containing the indolization product, as the major product, and the expected product, as the minor product.
A solution of the residue obtained and of DDQ (0.7 g; 3.1 mmol; the required amount of DDQ is determined from the 1H NMR spectrum of the residue obtained) in dioxane (20 mL) is stirred at room temperature for 15 hours. After evaporating off the solvent, ethyl acetate is added and the mixture is washed with water and saturated aqueous NaCl solution. The organic solution is dried over MgSO4, filtered and then concentrated on silica, followed by purification by chromatography on flash silica gel (9/1 pentane/ethyl acetate) to give the expected compound (1.15 g; 2.70 mmol; yield=74%) in the form of a brown solid.
Melting point: 173-175° C.
IR (KBr): 3434, 1631 cm−1 
High resolution mass spectrum (ESI+): calculated for C20H1479BrN2O2S (M+H)+ 424.9959. found 424.9976.
1H NMR (400 MHz, DMSO-d6): 7.04 (1H, d, J=3.5 Hz); 7.41 (1H, d, J=8.0 Hz); 7.49-7.55 (3H, m); 7.62 (1H, t, J=7.5 Hz); 7.84 (1H, d, J=3.5 Hz); 7.92-7.99 (3H, m); 8.12 (1H, d, J=8.0 Hz); 8.38 (1H, d, J=1.5 Hz); 10.81 (1H, s, NH).
13C NMR (100 MHz, DMSO-d6): 112.4; 113.2; 114.9; 117.4; 121.9; 126.7 (2C); 127.0; 127.5; 129.9 (2C); 134.6 (CH); 111.7; 119.4; 120.1; 124.7; 126.6; 130.8; 136.8; 137.7 (C).
Example 15
7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole




Aqueous 5 N NaOH solution (10 mL) is added to a suspension of the compound of Example 14 (500 mg; 1.18 mmol) in methanol (100 mL). The mixture is refluxed for 12 hours. The reaction mixture is concentrated under vacuum until a precipitate forms. The mixture is neutralized with concentrated aqueous HCl solution and the solid is then collected by filtration and washed with water, to give the expected compound (310 mg; 1.09 mmol; yield=92%) in the form of a brown solid.
Melting point: 250° C. (decomposition)
High resolution mass spectrum (ESI+) calculated for C14H1079BrN2 (M+H)+285.0027. found 285.0040.
IR (KBr): 3400, 1648, 1438 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.59 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.35 (1H, d, J=8.5 Hz); 7.38-7.42 (2H, m); 7.58 (1H, d, J=8.5 Hz); 7.74 (1H, d, J=8.5 Hz); 8.25 (1H, d, J=2.0 Hz); 10.88-10.92 (1H, bs, NH); 11.05-11.09 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 102.9; 112.2; 112.6; 113.1; 121.5; 124.0; 125.6 (CH); 110.8; 115.3; 121.5; 126.1; 126.7; 127.1; 136.8 (C)
Example 16
7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




A solution of oxalyl chloride (32.5 μL; 0.38 mmol) and of DMF (31.2 μL; 0.40 mmol) in anhydrous dichloromethane (10 mL) is stirred at 0° C. for 20 minutes. A solution of the compound of Example 15 (100 mg; 0.35 mmol) in anhydrous dichloromethane (10 mL) is added dropwise. The mixture is stirred at 0° C. for 20 minutes and then allowed to warm to room temperature. The solvent is evaporated off and aqueous 5% m/v NaOH solution (20 mL) is then added. The mixture is stirred at room temperature for 12 hours and then extracted with ethyl acetate. The organic phase is washed with water, with saturated aqueous NaCl solution, dried over MgSO4, filtered and then evaporated. The residue is purified by chromatography on flash silica gel (7/3 and then 5/5 cyclohexane/EtOAc) to give the expected compound (72 mg; 0.230 mmol; yield=66%) in the form of a gray solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C15H1079BrN2O (M+H)+312.9976. found 312.9979.
IR (KBr): 3400-3100, 1630 cm−1 
1H NMR (400 MHz, DMSO-d6): 7.48 (1H, dd, J1=8.5 Hz, J2=2.0 Hz); 7.65 (1H, d, J=8.5 Hz); 7.94 (1H, d, J=8.5 Hz); 8.00 (1H, d, J=8.5 Hz); 8.31 (1H, d, J=3.0 Hz); 8.34 (1H, d, J=2.0 Hz); 10.04 (1H, s); 11.18-11.23 (1H, bs, NH); 11.89-11.96 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 112.6; 113.5; 115.3; 122.0; 126.6; 137.0 (CH); 111.2; 117.4; 119.5; 122.5; 123.1; 125.5; 126.6; 137.2 (C); 185.4 (C═O)
General Procedure for Preparing the Compounds of Examples 17-19
To a solution of the compound of Example 14 (425 mg; 1 mmol) in THF (5 mL) are added a solution of sodium carbonate (212 mg; 2 equivalents) in water (1 mL), Pd(PPh3)2Cl2 (35.1 mg; 5 mol %) and the corresponding boric acid (1.1 equivalents). The reaction mixture is refluxed overnight under argon. After cooling to room temperature, the mixture is filtered through Celite and the solid is washed with acetone. After evaporation, methanol (40 mL) and aqueous 5 M NaOH solution (20 mL) are added to the residue obtained, and the mixture is refluxed for 12 hours. The reaction mixture is concentrated under vacuum and then neutralized with concentrated aqueous HCl solution. Ethyl acetate is added, the organic phase is collected, and the aqueous phase is extracted with ethyl acetate (3×30 mL). The combined organic phases are washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and evaporated. The residue is purified by chromatography on flash silica gel (9/1, 8/2 and then 7/3 pentane/ethyl acetate) to give the expected compound.
Example 17
7-(4-acetylphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole




The expected compound (195 mg; 0.60 mmol; yield=60%) is obtained in the form of a brown solid.
Melting point: 185° C. (decomposition)
High resolution mass spectrum (ESI+): calculated for C22H17N2O (M+H)+325.1341. found 325.1354.
IR (KBr): 3700-3100, 1649, 1597 cm−1 
1H NMR (400 MHz, DMSO-d6): 2.63 (3H, s, CH3); 6.59-6.61 (1H, m); 7.38 (1H, d, J=8.5 Hz); 7.39-7.41 (1H, m); 7.71-7.73 (2H, m); 7.84 (1H, d, J=8.5 Hz); 7.96 (2H, d, J=8.5 Hz); 8.06 (2H, d, J=8.5 Hz); 8.48 (1H, s); 10.86-10.90 (1H, bs, NH); 11.05-11.08 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 26.7 (CH3); 102.9; 111.8; 112.2; 112.5; 117.7; 122.6; 123.9; 126.5 (2C); 128.9 (2C) (CH); 116.3; 121.7; 124.9; 126.6; 127.0; 129.6; 134.5; 138.3; 146.1 (C); 197.4 (C═O)
Example 18
7-(3-methoxyphenyl)-1,10-dihydropyrrolo[2,3-a]-carbazole




The expected compound (172 mg; 0.55 mmol; yield=55%) is obtained in the form of a brown solid.
Melting point: 202-205° C.
High resolution mass spectrum (ESI+) calculated for C21H17N2O (M+H)+313.1341. found 313.1343.
IR (KBr): 3390, 1654, 1609, 1584, 1461 cm−1 
1H NMR (400 MHz, DMSO-d6): 3.86 (3H, s, CH3); 6.59 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 6.90 (1H, ddd, J1=8.0 Hz, J2=2.5 Hz, J3=1.5 Hz); 7.29-7.31 (1H, m); 7.34 (1H, dt, J1=7.5 Hz, J2=1.5 Hz); 7.36 (1H, d, J=8.5 Hz); 7.39 (1H, t, J=7.5 Hz); 7.39 (1H, t, J=2.5 Hz); 7.61 (1H, dd, J1=8.5 Hz, J2=1.5 Hz); 7.67 (1H, d, J=8.5 Hz); 7.82 (1H, d, J=8.5 Hz); 8.36 (1H, d, J=1.5 Hz); 10.83-10.88 (1H, bs, NH); 10.95-11.0 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 55.1 (CH3); 102.8; 111.5; 111.8; 112.2 (3C); 117.3; 119.1; 122.6; 123.7; 129.8 (CH); 116.4; 121.8; 124.7; 126.4; 127.0; 131.0; 137.8; 143.2; 159.7 (C)
Example 19
7-(4-biphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole




The expected compound (230 mg; 0.64 mmol; yield=64%) is obtained in the form of a brown solid.
Melting point >250° C.
High resolution mass spectrum (ESI+): calculated for C26H18N2 (M)+358.1470. found 358.1492.
IR (KBr): 3650-3100, 1698, 1648 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.60 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.36-7.41 (3H, m); 7.47-7.52 (2H, m); 7.68 (1H, dd, J1=8.5 Hz, J2=1.5 Hz); 7.71 (1H, dd, J1=8.5 Hz, J2=0.5 Hz); 7.73-7.76 (2H, m); 7.77-7.80 (2H, m); 7.83 (1H, d, J=8.5 Hz); 7.87-7.91 (2H, m); 8.41-8.43 (1H, m); 10.83-10.89 (1H, bs, NH); 10.98-11.02 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 102.8; 111.6; 112.2; 112.3; 117.1; 122.4; 123.7; 126.4 (2C); 127.0 (2C); 127.1 (2C); 127.3; 128.9 (2C) (CH); 116.4; 121.8; 124.8; 126.5; 127.0; 130.4; 137.8; 137.9; 139.8; 140.6 (C)
Example 20
7-phenyl-1,10-dihydropyrrolo[2,3-a]carbazole




The expected compound (169 mg; 0.60 mmol; yield=60%) is obtained in the form of a gray solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C20H15N2 (M+H)+283.1235. found 283.1248.
IR (KBr): 3434, 3368, 1652 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.59 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.30-7.35 (1H, m); 7.37 (1H, J1=8.5 Hz, J2=0.5 Hz); 7.40 (1H, dd, J1=3.0 Hz, J2=2.5 Hz); 7.45-7.50 (2H, m); 7.61 (1H, dd, J1=8.5 Hz, J2=2.0 Hz); 7.68 (1H, dd, J1=8.5 Hz, J2=0.5 Hz); 7.76-7.79 (2H, m); 7.82 (1H, dd, J1=8.5 Hz, J2=0.5 Hz); 8.35 (1H, d, J=2.0 Hz); 10.83-10.89 (1H, bs, NH); 10.96-11.00 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 102.9; 111.6; 112.2; 112.3; 117.2; 122.5; 123.7; 126.2; 126.7 (2C); 128.8 (2C) (CH); 116.4; 121.8; 124.8; 126.4; 127.0; 131.1; 137.8; 141.6 (C)
Example 21
7-(4-fluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole




The expected compound (150 mg; 0.50 mmol; yield=50%) is obtained in the form of a gray-green solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C20H14FN2 (M+H)+301.1141. found 301.1154.
IR (KBr): 3410, 3397, 1651, 1605, 1514 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.59 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.27-7.33 (2H, m); 7.36 (1H, d, J=8.5 Hz); 7.39 (1H, dd, J1=3.0 Hz, J2=2.5 Hz); 7.58 (1H, dd, J1=8.5 Hz, J2=2.0 Hz); 7.68 (1H, dd, J1=8.5 Hz, J2=0.5 Hz); 7.77-7.83 (3H, m); 8.33 (1H, d, J=2.0 Hz); 10.84-10.87 (1H, bs, NH); 10.96-10.98 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 102.8; 111.6; 112.2; 112.3; 115.5 (2C, d, JCF=21 Hz); 117.2; 122.4; 123.8; 128.5 (2C, d, JCF=8 Hz) (CH); 116.3; 121.8; 124.8; 126.5; 127.0; 130.1; 137.7; 138.1 (d, JCF=3 Hz); 161.2 (d, JCF=243 Hz) (C)
Example 22
7-(2,4-difluorophenyl)-1,10-dihydropyrrolo[2,3-a]-carbazole




The expected compound (165 mg; 0.52 mmol; yield=52%) is obtained in the form of a gray-green solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C20H13F2N2 (M+H)+319.1047. found 319.1058.
IR (KBr): 3401, 1652, 1616, 1594, 1510 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.59 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.21 (1H, tdd, J1=8.5 Hz, J2=3.0 Hz, J3=1.0 Hz); 7.33-7.39 (2H, m); 7.40 (1H, t, J=2.5 Hz); 7.45 (1H, dt, J1=8.5 Hz, J2=2.0 Hz); 7.67 (1H, td, J1=9.0 Hz, J2=6.5 Hz); 7.69 (1H, d, J=8.5 Hz); 7.78 (1H, d, J=8.5 Hz); 8.19 (1H, s); 10.85-10.88 (1H, bs, NH); 11.03-11.06 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 102.9; 104.3 (dd, JCF1=27 Hz, JCF2=26 Hz); 111.3; 111.8 (dd, JCF1=21 Hz, JCF2=4 Hz); 112.1; 112.4; 119.4 (d, JCF=3 Hz); 123.8; 124.3 (d, JCF=3 Hz); 132.1 (dd, JCF1=10 Hz, JCF2=5 Hz) (CH); 116.2; 121.7; 124.4; 124.8 (d, JCF=1 Hz); 126.3 (dd, JCF1=14 Hz, JCF2=4 Hz); 126.5; 126.9; 137.7; 159.1 (dd, JCF1=247 Hz, JCF2=12 Hz); 161.1 (dd, JCF1=246 Hz, JCF2=12 Hz)
Example 23
7-(4-trifluoromethylphenyl)-1,10-dihydropyrrolo-[2,3-a]carbazole




The expected compound (227 mg; 0.65 mmol; yield=65%) is obtained in the form of a gray solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C21H14F3N2 (M+H)+351.1109. found 351.1125.
IR (KBr): 3390, 3362, 1654, 1614 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.60 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.39 (1H, d, J=8.5 Hz); 7.41 (1H, dd, J1=3.0 Hz, J2=2.5 Hz); 7.69 (1H, dd, J1=8.5 Hz, J2=2.0 Hz); 7.73 (1H, dd, J1=8.5 Hz, J2=0.5 Hz); 7.81 (2H, d, J=8.0 Hz); 7.84 (1H, d, J=8.5 Hz); 8.01 (2H, d, J=8.0 Hz); 8.47 (1H, d, J=1.5 Hz); 10.86-10.92 (1H, bs, NH); 11.06-11.10 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 102.9; 111.8; 112.2; 112.5; 117.7; 122.6; 123.9; 125.6 (2C, q, JCF=4 Hz); 127.2 (2C) (CH); 116.3; 121.8; 124.6 (q, JCF=272 Hz); 124.9; 126.5 (q, JCF=32 Hz); 126.6; 127.1; 129.3; 138.3; 145.6 (C)
Example 24
7-(4-trifluoromethoxyphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole




The expected compound (226 mg; 0.62 mmol; yield=62%) is obtained in the form of a gray solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C21H14F3N2O (M+H)+367.1058. found 367.1044.
IR (KBr): 3401, 1652, 1514, 1464 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.60 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.37 (1H, d, J=8.5 Hz); 7.40 (1H, t, J=2.5 Hz); 7.46 (2H, d, J=8.0 Hz); 7.62 (1H, dd, J1=8.5 Hz, J2=1.5 Hz); 7.70 (1H, d, J=8.5 Hz); 7.81 (1H, d, J=8.5 Hz); 7.87-7.91 (2H, m); 8.38 (1H, d, J=1.5 Hz); 10.85-10.90 (1H, bs, NH); 11.00-11.05 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 102.9; 111.7; 112.2; 112.4; 117.5; 121.4 (2C); 122.5; 123.8; 128.3 (CH); 116.3; 120.2 (q, JCF=256 Hz); 121.8; 124.8; 126.5; 127.0; 129.6; 138.0; 141.0; 147.0 (q, JCF=2 Hz) (C)
General Procedure for Preparing the Compounds of Examples 25-34
Stage A:
a suspension of substituted phenylhydrazine hydrochloride and of anhydrous sodium acetate in DME (20 mL) is stirred at room temperature for 1 hour. The compound of Preparation B (1.10 g; 4.0 mmol) and the ionic liquid of Preparation C (11.54 g; 28 mmol) are added. The solvent is evaporated off and the mixture is heated at 120° C. for 12 hours. After cooling, aqueous 0.5 M hydrochloric acid solution is added, followed by extraction with ethyl acetate. The organic fractions are washed with saturated aqueous NaCl solution, dried over MgSO4 and filtered. The solution contains the expected product, and is used directly for the following oxidation step.
Stage B:
DDQ is added to this solution and the reaction mixture is stirred at room temperature overnight. The mixture is washed with saturated aqueous NaCl solution, dried over MgSO4 and concentrated under vacuum.
Stage C:
the crude reaction product is dissolved in methanol (100 mL), aqueous 5 M KOH solution (25 mL) is added and the mixture is refluxed for 12 hours. After cooling, the solvent is removed under vacuum. The residue is neutralized with concentrated hydrochloric acid. After extracting with ethyl acetate, the organic fractions are combined and then washed with saturated aqueous NaCl solution, dried over MgSO4 and evaporated. The solid obtained is purified by chromatography on silica gel.
Example 25
8-bromo-1,10-dihydropyrrolo[2,3-a]carbazole and
Example 26
6-bromo-1,10-dihydropyrrolo[2,3-a]carbazole




Stage A: 3-bromophenylhydrazine hydrochloride (1.00 g; 4.47 mmol), sodium acetate (367 mg; 4.47 mmol); stage B: DDQ (454 mg; 2.00 mmol); stage C: chromatography on silica gel (9/1 and then 8/2 cyclohexane/EtOAc) allows isolation of the compound of Example 25 (513 mg; 1.80 mmol; yield=45%) and the compound of Example 26 (342 mg; 1.20 mmol; yield=30%) in the form of gray solids.
Example 25
Melting point >250° C.
Mass spectrum (EI) m/z: 284/286, M+
IR (ATR): 3397, 1649, 1607 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.59 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.27 (1H, dd, J1=8.5 Hz, J2=2.0 Hz); 7.37 (1H, dd, J1=8.5 Hz, J2=0.5 Hz); 7.40 (1H, dd, J1=3.0 Hz, J2=2.5 Hz); 7.71 (1H, dd, J1=8.5 Hz, J2=0.5 Hz); 7.85 (1H, dd, J1=2.0 Hz, J2=0.5 Hz); 7.99 (1H, d, J=8.5 Hz); 10.94 (1H, bs, NH); 11.01 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 102.9; 111.9; 112.7; 113.9; 120.7; 121.3; 124.0 (CH); 115.6; 115.8; 121.6; 123.3; 126.6; 126.7; 139.1 (C)
Example 26
Melting point: 249-251° C.
High resolution mass spectrum (ESI+) calculated for C14H1079BrN2 (M+H)+285.0027. found 285.0019.
IR (ATR): 3406, 3364, 1653, 1613 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.62 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.23 (1H, t, J=8.0 Hz); 7.35 (1H, dd, J1=7.5 Hz, J2=0.5 Hz); 7.42 (1H, d, J=8.5 Hz); 7.44 (1H, t, J=2.5 Hz); 7.66 (1H, dd, J1=8.0 Hz, J2=0.5 Hz); 8.24 (1H, d, J=8.5 Hz); 10.90 (1H, bs, NH); 11.31 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 102.8; 110.6; 112.3; 113.4; 122.5; 124.3; 124.4 (CH); 114.2; 115.4; 121.4; 122.4; 126.6; 127.0; 139.4 (C)
Example 27
9-bromo-1,10-dihydropyrrolo[2,3-a]carbazole




Stage A: 2-bromophenylhydrazine hydrochloride (1.00 g; 4.47 mmol), sodium acetate (367 mg; 4.47 mmol); stage B: DDQ (636 mg; 2.80 mmol); stage C: chromatography on silica gel (from 9/1 to 7/3 cyclohexane/EtOAc) allows isolation of the expected compound (780 mg; 2.74 mmol; yield=68%) in the form of a white solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C14H1079BrN2 (M+H)+285.0027. found 285.0012.
IR (ATR): 3314, 1636, 1622 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.60 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.11 (1H, t, J=7.5 Hz); 7.40 (1H, dd, J1=8.5 Hz, J2=0.5 Hz); 7.45 (1H, dd, J1=3.0 Hz, J2=2.5 Hz); 7.52 (1H, dd, J1=7.5 Hz, J2=1.0 Hz); 7.73 (1H, dd, J1=8.5 Hz, J2=0.5 Hz); 8.07 (1H, dt, J1=7.5 Hz, J2=0.5 Hz); 10.79 (1H, bs, NH); 11.12 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 103.0; 112.3; 113.2; 118.6; 120.3; 124.2; 125.7 (CH); 103.6; 116.4; 121.7; 125.9; 126.5; 126.7; 136.5 (C)
Example 28
7-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole




Stage A: 4-fluorophenylhydrazine hydrochloride (1.30 g; 8.0 mmol), sodium acetate (656 mg; 8.0 mmol); stage B: DDQ (545 mg; 2.40 mmol); stage C: chromatography on silica gel (from 9/1 to 7/3 cyclohexane/EtOAc) allows isolation of the expected compound (702 mg; 3.13 mmol; yield=78%) in the form of a gray-green solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C14H10FN2 (M+H)+225.0828. found 225.0815.
IR (ATR): 3418, 3387, 1645, 1584 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.58 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.12 (1H, ddd, J1=9.5 Hz, J2=9.0 Hz, J3=2.5 Hz); 7.34 (1H, d, J=8.5 Hz); 7.39 (1H, t, J=2.5 Hz); 7.60 (1H, dd, J1=8.5 Hz, J2=4.5 Hz); 7.71 (1H, d, J=8.5 Hz); 7.84 (1H, dd, J1=9.5 Hz, J2=2.5 Hz); 10.89 (1H, bs, NH); 10.92 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 102.9; 104.5 (d, JCF=24 Hz); 110.7 (d, JCF=25 Hz); 112.0 (d, JCF=9 Hz); 112.2 (2C); 123.9 (CH); 116.0 (d, JCF=4 Hz); 121.6; 124.6 (d, JCF=10 Hz); 126.5; 127.8; 134.6; 156.7 (d, JCF=232) (C)
Example 29
9-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole




Stage A: 2-fluorophenylhydrazine hydrochloride (1.00 g; 6.15 mmol), sodium acetate (505 mg; 6.16 mmol); stage B: DDQ (450 mg; 1.98 mmol); stage C: chromatography on silica gel (from 9/1 to 7/3 cyclohexane/EtOAc) allows isolation of the expected compound (495 mg; 2.21 mmol; yield=55%) in the form of a beige-colored solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C14H10FN2 (M+H)+225.0828. found 225.0832.
IR (ATR): 3424, 3376, 1651, 1578 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.60 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.08-7.19 (2H, m); 7.39 (1H, d, J=8.5 Hz); 7.42 (1H, t, J=2.5 Hz); 7.73 (1H, d, J=8.5 Hz); 7.88 (1H, d, J=7.5 Hz); 10.61 (1H, bs, NH); 11.40 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 102.9; 108.6 (d, JCF=16 Hz); 112.1; 112.9; 115.3 (d, JCF=3 Hz); 119.0 (d, JCF=6 Hz); 124.1 (CH); 116.2 (d, JCF=2.5 Hz); 121.7; 125.5 (d, JCF=13 Hz); 126.7; 126.9; 128.0 (d, JCF=6 Hz); 148.9 (d, JCF=241 Hz) (C)
Example 30
6,8-dichloro-1,10-dihydropyrrolo[2,3-a]carbazole




Stage A: 3,5-dichlorophenylhydrazine hydrochloride (1.00 g; 4.68 mmol), sodium acetate (384 mg; 4.68 mmol); stage B: DDQ (908 mg; 4.00 mmol); stage C: chromatography on silica gel (from 9/1 to 7/3 cyclohexane/EtOAc) allows isolation of the expected compound (971 mg; 3.53 mmol; yield=88%) in the form of a gray solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C14H935Cl2N2 (M+H)+275.0143. found 275.0135.
IR (ATR): 3431, 3368, 1653, 1616 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.62 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.27 (1H, d, J=1.5 Hz); 7.44 (1H, dd, J1=8.5 Hz, J2=0.5 Hz); 7.46 (1H, dd, J1=3.0 Hz, J2=2.5 Hz); 7.76 (1H, d, J=1.5 Hz); 8.05 (1H, d, J=8.5 Hz); 11.00 (1H, bs, NH); 11.42 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 102.9; 110.2; 113.3; 113.4; 118.9; 124.7 (CH); 114.4; 120.0; 121.2; 126.3; 126.9; 127.3; 127.5; 139.5 (C)
Example 31
1,10-dihydropyrrolo[2,3-a]carbazole-7-carbonitrile




Stage A: 4-cyanophenylhydrazine hydrochloride (1.36 g; 8.0 mmol), sodium acetate (656 mg; 8.0 mmol); stage B: DDQ (545 mg; 2.40 mmol); stage C: chromatography on silica gel (from 9/1 to 7/3 cyclohexane/EtOAc) allows isolation of the expected compound (517 mg; 2.24 mmol; yield=56%) in the form of a beige-colored solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C15H10N3 (M+H)+232.0875. found 232.0872.
IR (ATR): 3439, 3256, 2226, 1655, 1614 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.63 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.42-7.46 (2H, m); 7.67 (1H, dd, J1=8.5 Hz, J2=1.5 Hz); 7.78 (1H, dd, J1=8.5 Hz, J2=0.5 Hz); 7.83 (1H, d, J=8.5 Hz); 8.61 (1H, m); 10.97 (1H, bs, NH); 11.53 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 103.0; 112.2; 112.3; 113.5; 124.2; 124.6; 126.5 (CH); 100.3; 115.4; 120.9; 121.4; 124.3; 127.2; 127.3; 140.1 (C)
Example 32
7-nitro-1,10-dihydropyrrolo[2,3-a]carbazole




Stage A: 4-nitrophenylhydrazine hydrochloride (1.52 g; 8.0 mmol), sodium acetate (656 mg; 8.0 mmol); stage B: DDQ (545 mg; 2.40 mmol); stage C: chromatography on silica gel (from 9/1 to 3/7 cyclohexane/EtOAc) allows isolation of the expected compound (450 mg; 1.79 mmol; yield=45%) in the form of a yellow-brown solid.
Melting point: 220° C. (decomposition)
High resolution mass spectrum (ESI+) calculated for C14H10N3O2 (M+H)+252.0773. found 252.0763.
IR (ATR): 3406, 3298, 1655, 1616 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.64 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.46-7.49 (2H, m); 7.79 (1H, d, J=9.0 Hz); 7.93 (1H, d, J=8.5 Hz); 8.22 (1H, dd, J1=9.0 Hz, J2=2.5 Hz); 9.06 (1H, d, J=2.5 Hz); 11.00 (1H, bs, NH); 11.74 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 103.1; 111.4; 112.4; 113.9; 115.9; 119.1; 124.8 (CH); 116.3; 121.5; 123.9; 127.6; 127.9; 140.0; 141.7 (CH)
Example 33
9-ethyl-1,10-dihydropyrrolo[2,3-a]carbazole




Stage A: 2-ethylphenylhydrazine hydrochloride (1.00 g; 5.79 mmol), sodium acetate (475 mg; 5.79 mmol); stage B: DDQ (454 mg; 2.00 mmol); stage C: chromatography on silica gel (from 9/1 to 7/3 cyclohexane/EtOAc) allows isolation of the expected compound (490 mg; 2.09 mmol; yield=52%) in the form of a gray solid.
Melting point: 256-258° C.
High resolution mass spectrum (ESI+) calculated for C16H15N2 (M+H)+235.1235. found 235.1228.
IR (ATR): 3426, 3416, 1649 cm−1 
1H NMR (400 MHz, DMSO-d6): 1.40 (3H, t, J=7.5 Hz); 2.99 (2H, q, J=7.5 Hz); 6.57 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.09 (1H, t, J=7.5 Hz); 7.13-7.16 (1H, m); 7.33 (1H, dd, J1=8.5 Hz, J2=0.5 Hz); 7.40 (1H, dd, J1=3.0 Hz, J2=2.5 Hz); 7.69 (1H, d, J1=8.5 Hz, J2=0.5 Hz); 7.87 (1H, d, J=7.5 Hz); 10.59 (1H, bs, NH); 10.85 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 14.2 (CH3); 24.1 (CH2); 102.8; 112.1 (2C); 116.9; 118.9; 122.2; 123.5 (CH); 116.5; 121.9; 123.8; 126.0 (2C); 126.3; 136.6 (C)
Example 34
9-(trifluoromethyl)-1,10-dihydropyrrolo[2,3-a]carbazole




Stage A: 2-(trifluoromethyl)phenylhydrazine hydrochloride (1.00 g; 4.70 mmol), sodium acetate (386 mg; 4.71 mmol); stage B: DDQ (636 mg; 2.80 mmol); stage C: chromatography on silica gel (from 9/1 to 7/3 cyclohexane/EtOAc) allows isolation of the expected compound (550 mg; 2.01 mmol; yield=50%) in the form of a beige-colored solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C15H10F3N2 (M+H)+275.0796. found 275.0781.
IR (ATR): 3453, 3385, 1649 cm−1 
1H NMR (400 MHz, DMSO-d6): 6.62 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 7.32 (1H, t, J=7.5 Hz); 7.44 (1H, d, J=8.5 Hz); 7.47 (1H, t, J=2.5 Hz); 7.63 (1H, d, J=7.5 Hz); 7.80 (1H, d, J=8.5 Hz); 8.37 (1H, d, J=8.0 Hz); 10.86 (1H, bs, NH); 11.34 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 102.9; 111.9; 113.4; 118.3; 120.3 (q, JCF=4.5 Hz); 123.6; 124.3 (CH); 111.3 (q, JCF=32 Hz); 115.3; 121.5; 125.1 (q, JCF=271 Hz); 126.1; 126.9; 127.0; 133.2 (q, JCF=2 Hz) (C)
Example 35
8-methyl-1:10-dihydropyrrolo[2,3-a]carbazole




Stage A: a mixture of 3-methylphenylhydrazine (1.00 g; 8.2 mmol), the compound of Preparation B (1.65 g; 6.0 mmol) and the ionic liquid of Preparation C (11.54 g; 28 mmol) is stirred at 120° C. for 12 hours. After cooling, aqueous 0.5 M HCl solution is added, followed by extraction with ethyl acetate. The combined organic fractions are washed with saturated aqueous NaCl solution, dried over MgSO4 and filtered. The solution contains the expected product, and is used directly for the following oxidation step.
Stages B and C are performed in the same manner as for Examples 25 to 34.
Stage B: DDQ (953 mg; 4.20 mmol); stage C: chromatography on silica gel (from 9/1 to 7/3 cyclohexane/EtOAc) allows isolation of the expected compound (860 mg; 3.90 mmol; yield=65%) in the form of a gray solid.
Melting point >250° C.
Mass spectrum (EI) m/z: 220, M+
IR (ATR): 3410, 3387, 1649, 1622 cm−1 
1H NMR (400 MHz, DMSO-d6): 2.48 (3H, s); 6.55 (1H, dd, J1=3.0 Hz, J2=2.0 Hz); 6.95-6.98 (1H, m); 7.30 (1H, d, J=8.5 Hz); 7.35 (1H, t, J=2.5 Hz); 7.39 (1H, m); 7.65 (1H, d, J=8.5 Hz); 7.89 (1H, d, J=8.0 Hz); 10.73 (1H, bs, NH); 10.76 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 21.6 (CH3); 102.7; 111.2; 111.8; 111.9; 118.8; 120.1; 123.4 (CH); 116.2; 121.9 (2C); 125.9; 126.2; 132.6; 138.6 (C)
Example 36
7-(3-methoxyphenyl)-1,10-dihydropyrrolo[2,3-a]-carbazole-3-carbaldehyde




POCl3 (90 μL, 0.97 mmol) is added slowly at 0° C. to anhydrous DMF (2 mL). The mixture is stirred at 0-10° C. for 45 minutes until a yellow solution is obtained. A solution of the compound of Example 18 (100 mg; 0.320 mmol) in DMF (1 ml) is then added. The mixture is heated at 120° C. for 24 hours. After cooling, aqueous 5% NaOH solution (20 mL) is added and the mixture is stirred at room temperature overnight. After extracting with ethyl acetate, the combined organic fractions are dried over MgSO4 and evaporated, and the residue is purified by chromatography on silica gel (from 7/3 to 1/9 pentane/EtOAc) to give the expected compound (49 mg; 0.144 mmol; yield=45%) in the form of a light-brown solid.
Melting point 215° C. (decomposition)
High resolution mass spectrum (ESI+) calculated for C22H17N2O2 (M+H)+341.1290. found 341.1305.
IR (KBr): 3325, 1619 cm−1 
1H NMR (400 MHz, DMSO-d6): 3.87 (3H, s, CH3); 6.91 (1H, d, J=7.5 Hz); 7.31-7.42 (3H, m); 7.69 (1H, dd, J1=8.5 Hz, J2=1.5 Hz); 7.74 (1H, d, J=8.5 Hz); 7.95 (1H, d, J=8.5 Hz); 8.08 (1H, d, J=8.5 Hz); 8.31 (1H, d, J=3.0 Hz); 8.45 (1H, s); 10.04 (1H, s); 11.09-11.13 (1H, bs, NH); 11.88-11.92 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 55.1 (CH3); 111.8; 112.0; 112.2 (2C); 115.3; 117.8; 119.1; 123.5; 129.8; 136.9 (CH); 118.6; 119.6; 122.8 (2C); 124.1; 126.5; 131.4; 138.2; 142.9; 159.7 (C); 185.3 (C═O)
General Procedure for Preparing the Compounds of Examples 37-52
POCl3 (3 eq.) is added slowly at 0° C. to anhydrous DMF (2 mL). The solution is stirred at 0-10° C. for 45 minutes until a yellow solution is obtained, and is then added at 0° C. to a solution of the compounds of Examples 19-35 (100 mg) in DMF (1 mL), prepared in a 10 mL CEM tube. The tube is sealed and the mixture is heated at 100° C. under microwave irradiation (150 W) for 20 minutes. After cooling, the mixture is added to saturated aqueous NaHCO3 solution (20 mL). After stirring for 30 minutes, the solid is filtered off and aqueous 5% NaOH solution (20 mL) is added thereto. The mixture is stirred at room temperature overnight. The solid is filtered off and then purified by chromatography on silica gel.
Example 37
7-(4-biphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




Chromatography on silica gel (from 7/3 to 1/9 pentane/EtOAc) allows isolation of the expected compound (32 mg; 0.083 mmol; yield=30%) in the form of a dark brown solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C27H19N2O (M+H)+387.1497. found 387.1492.
IR (KBr): 3436, 1622 cm−1 
1H NMR (400 MHz, DMSO-d6): 7.36-7.41 (1H, m); 7.47-7.52 (2H, m); 7.73-7.81 (6H, m); 7.88-7.92 (2H, m); 7.96 (1H, d, J=8.5 Hz); 8.09 (1H, d, J=8.5 Hz); 8.31 (1H, d, J=3.0 Hz); 8.51 (1H, s); 10.05 (1H, s); 11.12-11.16 (1H, bs, NH); 11.90 (1H, bd, J=2.5 Hz, NH)
13C NMR (100 MHz, DMSO-d6): 112.0; 112.3; 115.3; 117.5; 123.3; 126.5 (2C); 127.1 (4C); 127.3; 129.0 (2C); 136.9 (CH); 118.6; 119.6; 122.8 (2C); 124.2; 126.5; 130.9; 138.0; 138.2; 139.8; 140.4 (C); 185.3 (C═O)
Example 38
7-phenyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




Chromatography on silica gel (from 7/3 to 1/9 pentane/EtOAc) allows isolation of the expected compound (57 mg; 0.184 mmol; yield=52%) in the form of a dark brown solid.
Melting point 205° C. (decomposition)
High resolution mass spectrum (ESI+) calculated for C21H15N2O (M+H)+311.1184. found 311.1201.
IR (KBr): 3260, 1622 cm−1 
1H NMR (400 MHz, DMSO-d6): 7.31-7.36 (1H, m); 7.46-7.51 (2H, m); 7.68 (1H, dd, J1=8.5 Hz, J2=2.0 Hz); 7.75 (1H, dd, J1=8.5 Hz, J2=0.5 Hz); 7.77-7.81 (2H, m); 7.95 (1H, d, J=8.5 Hz); 8.06 (1H, d, J=8.5 Hz); 8.31 (1H, d, J=3.0 Hz); 8.43 (1H, d, J=2.0 Hz); 10.04 (1H, s); 11.08-11.14 (1H, bs, NH); 11.86-11.93 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 111.9; 112.3; 115.3; 117.7; 123.4; 126.4; 126.7 (2C); 128.8 (2C); 136.9 (CH); 118.6; 119.6; 122.8 (2C); 124.2; 126.5; 131.5; 138.1; 141.4 (C); 185.4 (C═O)
Example 39
7-(4-fluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




Chromatography on silica gel (from 7/3 to 1/9 pentane/EtOAc) allows isolation of the expected compound (55 mg; 0.168 mmol; yield=50%) in the form of a light-brown solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C21H14N2OF (M+H)+329. 1090. found 329. 1101.
IR (KBr): 3436, 3297, 1619 cm−1 
1H NMR (400 MHz, DMSO-d6): 7.27-7.34 (2H, m); 7.65 (1H, dd, J1=8.5 Hz, J2=2.0 Hz); 7.74 (1H, d, J=8.5 Hz); 7.78-7.84 (2H, m); 7.95 (1H, d, J=8.5 Hz); 8.06 (1H, d, J=8.5 Hz); 8.31 (1H, 5); 8.41 (1H, d, J=1.5 Hz); 10.04 (1H, 5); 11.10-11.15 (1H, bs, NH); 11.88-11.95 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 112.0; 112.3; 115.3; 115.6 (2C, d, JCF=21 Hz); 117.7; 123.4; 128.5 (2C, d, JCF=8 Hz); 136.9 (CH); 118.6; 119.6; 122.8 (2C); 124.2; 126.6; 130.6; 137.9 (d, JCF=3 Hz); 138.1; 161.3 (d, JCF=243 Hz); 185.4 (C═O)
Example 40
7-(2,4-difluorophenyl)-1,10-dihydropyrrolo[2,3-a]-carbazole-3-carbaldehyde




Chromatography on silica gel (from 7/3 to 1/9 pentane/EtOAc) allows isolation of the expected compound (48 mg; 0.139 mmol; yield=44%) in the form of a beige-colored solid.
Melting point 220° C. (decomposition)
High resolution mass spectrum (ESI+) calculated for C21H13F2N2O (M+H)+347.0996. found 347.0996.
IR (KBr): 3264, 1645, 1616 cm−1 
1H NMR (400 MHz, DMSO-d6): 7.22 (1H, td, J1=8.5 Hz, J2=2.5 Hz); 7.37 (1H, ddd, J1=11.5 Hz, J2=9.5 Hz, J3=2.5 Hz); 7.52 (1H, dt, J1=8.5 Hz, J2=2.0 Hz); 7.69 (1H, td, J1=9.0 Hz, J2=7.0 Hz); 7.76 (1H, d, J=8.5 Hz); 7.95 (1H, d, J=8.5 Hz); 8.02 (1H, d, J=8.5 Hz); 8.27 (1H, 5); 8.31 (1H, s); 10.04 (1H, s); 11.19-11.26 (1H, bs, NH); 11.90-12.01 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 104.3 (dd, JCF1=27 Hz, JCF2=26 Hz); 111.6; 111.8 (dd, JCF1=21 Hz, JCF2=4 Hz); 112.4; 115.2; 119.9 (d, JCF=2 Hz); 125.2; 132.1 (dd, JCF1=9 Hz, JCF2=5 Hz); 136.9 (CH); 118.3; 119.6; 122.8 (2C); 123.8; 125.2; 126.1 (dd, JCF1=14 Hz, JCF2=4 Hz); 126.5; 138.1; 159.1 (dd, JCF1=247 Hz, JCF2=12 Hz); 161.1 (dd, JCF1=246 Hz, JCF2=12 Hz (C)); 185.3 (C═O)
Example 41
7-(4-trifluoromethylphenyl)-1,10-dihydropyrrolo-[2,3-a]carbazole-3-carbaldehyde




Chromatography on silica gel (from 7/3 to 1/9 pentane/EtOAc) allows isolation of the expected compound (70 mg; 0.185 mmol; yield=65%) in the form of a light-brown solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C22H14F3N2O (M+H)+379.1058. found 379.1059.
IR (KBr): 3460, 3294, 1617 cm−1 
1H NMR (400 MHz, DMSO-d6): 7.76 (1H, dd, J1=8.5 Hz, J2=1.5 Hz); 7.80 (1H, dd, J1=8.5 Hz, J2=1.0 Hz); 7.83 (2H, d, J=8.0 Hz); 7.97 (1H, d, J=8.5 Hz); 8.03 (2H, d, J=8.0 Hz); 8.09 (1H, d, J=8.5 Hz); 8.32 (1H, s); 8.56 (1H, s); 10.04 (1H, s); 11.18-11.25 (1H, bs, NH); 11.88-11.97 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 112.2; 112.5; 115.3; 118.2; 123.5; 125.7 (2C, q, JCF=4 Hz); 127.3 (2C); 137.0 (CH); 118.5; 119.6; 122.8; 122.9; 124.3; 124.6 (q, JCF=272 Hz); 126.6; 126.7 (q, JCF=32 Hz); 129.7; 138.7; 145.4 (C); 185.4 (C═O)
Example 42
7-(4-trifluoromethoxyphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




Chromatography on silica gel (from 7/3 to 1/9 pentane/EtOAc) allows isolation of the expected compound (72 mg; 0.183 mmol; yield=67%) in the form of a beige-colored solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C22H14F3N2O2 (M+H)+395.1007. found 395.1017.
IR (KBr): 3276, 1620 cm−1 
1H NMR (500 MHz, DMSO-d6): 7.46 (2H, d, J=8.5 Hz); 7.69 (1H, dd, J1=8.5 Hz, J2=2.0 Hz); 7.75 (1H, d, J=8.5 Hz); 7.88-7.92 (2H, m); 7.95 (1H, d, J=8.5 Hz); 8.06 (1H, d, J=8.5 Hz); 8.31 (1H, d, J=3.0 Hz); 8.46 (1H, d, J=2.0 Hz); 10.03 (1H, s); 11.15-11.18 (1H, bs, NH); 11.93 (1H, bd, J=2.5 Hz, NH)
13C NMR (125 MHz, DMSO-d6): 112.1; 112.5; 115.4; 118.0; 121.5 (2C); 123.6; 128.5 (2C); 137.0 (CH); 118.6; 119.7; 120.3 (q, JCF=256 Hz); 122.9; 123.0; 124.3; 126.7; 130.1; 138.4; 140.8; 147.2 (q, JCF=2 Hz) (C); 185.5 (C═O)
Example 43
8-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




Chromatography on silica gel (from 7/3 to 1/9 cyclohexane/EtOAc) allows isolation of the expected compound (66 mg; 0.21 mmol; yield=60%) in the form of a brown solid.
Melting point >250° C.
Mass spectrum (EI) m/z: 312/314, M+
IR (ATR): 3393, 3330-3160, 1624 cm−1 
1H NMR (400 MHz, DMSO-d6): 7.33 (1H, dd, J1=8.5 Hz, J2=2.0 Hz); 7.93 (1H, d, J=1.5 Hz); 7.94 (1H, d, J=8.5 Hz); 7.97 (1H, d, J=8.5 Hz); 8.07 (1H, d, J=8.5 Hz); 8.31 (1H, d, J=3.0 Hz); 10.03 (1H, s, CHO); 11.13 (1H, bs, NH); 11.96 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 112.7; 114.3; 115.1; 121.2; 121.8; 137.0 (CH); 116.8; 117.8; 119.5; 122.6; 122.7; 123.0; 126.3; 139.4 (C); 185.4 (C═O)
Example 44
6-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




Chromatography on silica gel (from 7/3 to 1/9 cyclohexane/EtOAc) allows isolation of the expected compound (55 mg; 0.176 mmol; yield=50%) in the form of a brown solid.
Melting point >250° C.
Mass spectrum (EI) m/z: 312/314, M+
IR (ATR): 3300, 1620 cm−1 
1H NMR (400 MHz, DMSO-d6): 7.30 (1H, t, J=8.0 Hz); 7.41 (1H, d, J=7.5 Hz); 7.73 (1H, d, J=8.0 Hz); 7.99 (1H, d, J=8.5 Hz); 8.34 (1H, d, J=3.0 Hz); 8.46 (1H, d, J=8.5 Hz); 10.05 (1H, s, CHO); 11.46 (1H, bs, NH); 11.91 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 111.0; 112.3; 116.3; 123.0; 125.2; 137.3 (CH); 114.6; 117.5; 119.5; 121.8; 122.4; 122.9; 126.6; 139.8 (C); 185.4 (C═O)
Example 45
9-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




Chromatography on silica gel (from 7/3 to 1/9 cyclohexane/EtOAc) allows isolation of the expected compound (90 mg; 0.287 mmol; yield=82%) in the form of a brown solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C15H1079BrN2O (M+H)+312.9976. found 312.9991.
IR (ATR): 3400-3100, 1630 cm−1 
1H NMR (400 MHz, DMSO-d6): 7.16 (1H, t, J=7.5 Hz); 7.59 (1H, dd, J1=7.5 Hz, J2=1.0 Hz); 7.98 (2H, s); 8.15 (1H, d, J=7.5 Hz); 8.34 (1H, d, J=3.0 Hz); 10.05 (1H, s, CHO); 11.27 (1H, bs, NH); 11.69 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 113.1; 115.4; 119.1; 120.6; 126.5; 137.1 (CH); 103.8; 118.5; 119.5; 122.7; 123.0; 125.2; 126.0; 136.7 (C); 185.5 (C═O)
Example 46
7-Fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




Chromatography on silica gel (from 3/7 to 1/9 cyclohexane/EtOAc) allows isolation of the expected compound (96 mg; 0.381 mmol; yield=85%) in the form of a brown solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C15H10FN2O (M+H)+253.0777. found 253.0773.
IR (ATR): 3314, 1636, 1622 cm−1 
1H NMR (400 MHz, DMSO-d6): 7.20 (1H, ddd, J1=9.5 Hz, J2=9.0 Hz, J3=2.5 Hz); 7.67 (1H, dd, J1=9.0 Hz, J2=4.5 Hz); 7.91 (1H, d, J=8.5 Hz); 7.92-7.95 (1H, m); 7.96 (1H, d, J=8.5 Hz); 8.30 (1H, d, J=3.0 Hz); 10.03 (1H, s, CHO); 11.07 (1H, bs, NH); 11.92 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 105.0 (d, JCF=24 Hz); 111.8 (d, JCF=25 Hz); 112.2; 112.4 (d, JCF=9 Hz); 115.4; 136.8 (CH); 118.2 (d, JCF=4 Hz); 119.6; 122.7; 122.9; 124.1 (d, JCF=10 Hz); 127.3; 135.0; 156.8 (d, JCF=232 Hz) (C); 185.4 (C═O)
Example 47
9-Fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




Chromatography on silica gel (from 8/2 to 3/7 cyclohexane/EtOAc) allows isolation of the expected compound (80 mg; 0.317 mmol; yield=71%) in the form of a brown solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C15H10FN2O (M+H)+253.0777. found 253.0792.
IR (ATR): 3450-3120, 1624 cm−1 
1H NMR (400 MHz, DMSO-d6): 7.17 (1H, dt, J1=5.0 Hz, J2=8.0 Hz); 7.24 (1H, ddd, J1=11.0 Hz, J2=8.0 Hz, J3=1.0 Hz); 7.94-7.97 (2H, m); 7.98 (1H, d, J=8.5 Hz); 8.31 (1H, d, J=3.0 Hz); 10.05 (1H, s, CHO); 11.52 (1H, bs, NH); 11.57 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 109.4 (d, JCF=16 Hz); 112.9; 115.2; 115.8 (d, JCF=3 Hz); 119.5 (d, JCF=6 Hz); 137.1 (CH); 118.3 (d, JCF=2.5 Hz); 119.5; 122.8; 123.0; 125.9 (d, JCF=13 Hz); 126.4; 127.4 (d, JcF=6 Hz); 148.9 (d, JCF=241 Hz) (C); 185.5 (C═O)
Example 48
6,8-dichloro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




Chromatography on silica gel (from 3/7 to 1/9 cyclohexane/EtOAc) allows isolation of the expected compound (52 mg; 0.172 mmol; yield=47%) in the form of a brown solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C15H935Cl2N2O (M+H)+303.0092. found 303.0073.
IR (ATR): 3352, 1717, 1630 cm−1 
1H NMR (400 MHz, DMSO-d6): 7.34 (1H, d, J=1.5 Hz); 7.84 (1H, d, J=1.5 Hz); 8.01 (1H, d, J=8.5 Hz); 8.27 (1H, d, J=8.5 Hz); 8.36 (1H, d, J=3.0 Hz); 10.05 (1H, s, CHO); 11.54 (1H, bs, NH); 11.99 (1H, bs, NH).
13C NMR (100 MHz, DMSO-d6): 110.5; 113.2; 116.4; 119.3; 137.4 (CH); 116.5; 119.4; 119.5; 122.3; 123.2; 126.7; 126.9; 128.4; 139.8 (C); 185.4 (C═O).
Example 49
3-formyl-1,10-dihydropyrrolo[2,3-a]carbazole-7-carbonitrile




Chromatography on silica gel (from 3/7 to 1/9 cyclohexane/EtOAc) allows isolation of the expected compound (58.3 mg; 0.225 mmol; yield=52%) in the form of a brown solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C16H10N3O (M+H)+260.0824. found 260.0833.
IR (ATR): 3287, 3239, 2212, 1630, 1618 cm−1 
1H NMR (400 MHz, DMSO-d6): 7.74 (1H, dd, J1=8.5 Hz, J2=1.5 Hz); 7.85 (1H, dd, J1=8.5 Hz, J2=0.5 Hz); 8.01 (1H, d, J=8.5 Hz); 8.08 (1H, d, J=8.5 Hz); 8.35 (1H, d, J=3.0 Hz); 8.70 (1H, d, J=1.5 Hz); 10.05 (1H, s, CHO); 11.65 (1H, bs, NH); 11.97 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 112.7; 113.4; 115.4; 124.8; 127.3; 137.3 (CH); 100.8; 117.6; 119.5; 120.6; 122.5; 123.6; 123.7; 126.8; 140.5 (C); 185.5 (C═O)
Example 50
7-nitro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




Chromatography on silica gel (from 3/7 to 1/9 cyclohexane/EtOAc) allows isolation of the expected compound (39 mg; 0.14 mmol; yield=35%) in the form of a yellow-brown solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C15H10N3O3 (M+H)+280.0722. found 280.0714.
IR (ATR): 3350-3150, 1636, 1614 cm−1 
1H NMR (400 MHz, DMSO-d6): 7.85 (1H, d, J=9.0 Hz); 8.04 (1H, d, J=8.5 Hz); 8.19 (1H, d, J=8.5 Hz); 8.28 (1H, dd, J1=9.0 Hz, J2=2.5 Hz); 8.37 (1H, d, J=2.5 Hz); 9.14 (1H, d, J=2.0 Hz); 10.06 (1H, s, CHO); 11.87 (1H, bs, NH); 12.03 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 111.8; 113.8; 115.7; 116.5; 119.9; 137.5 (CH); 118.4; 119.5; 122.6; 123.3; 123.9; 127.5; 140.3; 142.0 (C); 185.5 (C═O)
Example 51
9-ethyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




Chromatography on silica gel (from 8/2 to 3/7 cyclohexane/EtOAc) allows isolation of the expected compound (56 mg; 0.213 mmol; yield=50%) in the form of a brown solid.
Melting point >250° C.
High resolution mass spectrum (ESI+) calculated for C17H15N2O (M+H)+263.1184. found 263.1169.
IR (ATR): 3450-3150, 1626 cm−1 
1H NMR (400 MHz, DMSO-d6): 1.40 (3H, t, J=7.5 Hz); 3.00 (2H, q, J=7.5 Hz); 7.14 (1H, t, J=7.5 Hz); 7.20-7.23 (1H, m); 7.90 (1H, d, J=8.5 Hz); 7.93 (1H, d, J=8.0 Hz); 7.93-7.96 (1H, m); 8.29 (1H, d, J=3.0 Hz); 10.03 (1H, s, CHO); 11.00 (1H, bs, NH); 11.54 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 14.1 (CH3); 24.0 (CH2); 112.1; 115.1; 117.3; 119.3; 123.1; 136.7 (CH); 118.7; 119.5; 122.3; 122.9; 123.2; 125.9; 126.2; 137.0 (C); 185.4 (C═O)
Example 52
8-methyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde




Chromatography on silica gel (from 7/3 to 1/9 cyclohexane/EtOAc) allows isolation of the expected compound (65 mg; 0.26 mmol; yield=58%) in the form of a brown solid.
Melting point: 250° C. (decomposition)
High resolution mass spectrum (ESI+) calculated for C16H13N2O (M+H)+249.1028. found 249.1026.
IR (ATR): 3379, 3341, 1634 cm−1 
1H NMR (400 MHz, DMSO-d6): 2.49 (3H, s); 7.02 (1H, d, J=8.0 Hz); 7.46 (1H, s); 7.89 (2H, s); 7.97 (1H, d, J=8.0 Hz); 8.27 (1H, d, J=3.0 Hz); 10.02 (1H, s, CHO); 11.88 (1H, bs, NH); 11.81 (1H, bs, NH)
13C NMR (100 MHz, DMSO-d6): 21.6 (CH3); 111.5; 112.0; 114.8; 119.2; 120.6; 136.8 (CH); 118.5; 119.5; 121.3; 122.2; 122.8; 125.8; 133.7; 139.0 (C), 185.3 (C═O)
II) TEST OF ACTIVITY OF THE COMPOUNDS OF EXAMPLES 2, 3 And 5 ON 67 KINASES
The compounds of Example 2, i.e. 1,10-dihydropyrrolo[2,3-a]carbazole and of Example 3, i.e. 1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, and the compound of Example 5, i.e. 1,10-dihydropyrrolo[2,3-a]carbazole-3-carboxamide, were tested on the following 67 kinases:
MKK1, ERK 1, ERK 2, JNK1, JNK2, JNK3, p38a MAPK, p38b MAPK, p38g MAPK, p38s MAPK, ERK8, RSK1, RSK2, PDK1, PKBa, PKBb, SGK1, S6K1, PKA, ROCK2, PRK2, PKCa, PKC zeta, PKD1, MSK1, MNK1, MNK2, MAPKAP-K2, MAPKAP-K3, PRAK, CAMKKa, CAMKKb, CAMK1, SmMLCK, PHK, CHK1, CHK2, GSK3b, CDK2/cyclin A, PLK1, PLK1 (Okadaic acid), Aurora B, Aurora C, AMPK, MARK3, BRSK2, MELK, CK1, CK2, NEK2a, NEK6, NEK7, IKKb, PIM-1, PIM-2, PIM-3, SRPK1, MST2, EF2K, HIPK2, HIPK3, PAK-4, PAK5, PAK6, Src, Lck, CSK.
The results in terms of residual activity of the kinases after being placed in contact with the compounds of Examples 2, 3 and 5, at a concentration of 10 μM (10 μmol/L), are shown in Table 1 below.
The higher the residual activity of the kinase tested, the lower the inhibitory activity of the test compounds on the tested kinase.














Kinases tested













Compounds
% residual
% residual
% residual
% residual
% residual
% residual


of Formula I
activity
activity
activity
activity
activity
activity






MKK1
ERK1
ERK2
JNK1
JNK2
JNK3





Example 2
87
108
94
102
118
108


Example 3
50
 87
92
102
128
113


Example 5
80
 71
93
106
115
104






p38a
p38b
p38g
p38s





MAPK
MAPK
MAPK
MAPK
ERK8
RSK1





Example 2
108
100
111
78
55
105


Example 3
102
 80
 74
92
20
 38


Example 5
 96
 92
 96
76
46
 79






RSK2
PDK1
PKBa
PKBb
SGK1
S6K1





Example 2
129
86
120
107
82
89


Example 3
124
76
 96
 98
64
38


Example 5
 97
67
 97
103
71
72










PKC




PKA
ROCK2
PRK2
PKCa
zeta
PKD1





Example 2
95
86
95
111
91
83


Example 3
60
25
31
 84
83
28


Example 5
80
48
54
 80
78
19









MAPKAP-
MAPKAP-




MSK1
MNK1
MNK2
K2
K3
PRAK





Example 2
90
69
95
118
89
97


Example 3
71
27
55
 84
69
72


Example 5
91
19
57
 92
75
85






CAMKKa
CAMKKb
CAMK1
SmMLCK
PHK
CHK1





Example 2
76
93
29
86
90
123


Example 3
42
56
71
60
33
 97


Example 5
75
79
80
69
43
113










PLK1






CDK2-

(Okadaic
AURORA



CHK2
GSK3b
Cyclin A
PLK1
acid)
B





Example 2
58
111
97
111
103
67


Example 3
38
 88
74
 91
 83
68


Example 5
44
 91
53
100
 79
65






AURORA








C
AMPK
MARK3
BRSK2
MELK
CK1





Example 2
85
80
116
58
93
107


Example 3
79
59
 88
22
61
103


Example 5
61
85
 73
32
80
 96






CK2
NEK2a
NEK6
NEK7
IKKb
PIM-1





Example 2
91
104
90
96
106
20


Example 3
62
 88
78
89
 71
 2


Example 5
77
106
83
89
 80
 9






PIM-2
PIM-3
SRPK1
MST2
EF2K
HIPK2





Example 2
62
10
90
82
101
59


Example 3
 7
 1
84
63
 90
25


Example 5
27
 9
93
76
 92
42


















HIPK3
PAK4
PAK5
PAK6
Src
Lck
CSK





Example 2
97
84
82
92
98
88
98


Example 3
64
88
87
94
85
76
74


Example 5
87
16
70
83
96
78
65









III) TEST OF ACTIVITY OF THE COMPOUNDS OF THE INVENTION ON THE KINASES PIM-1, PIM-2 AND PIM-3
The compounds according to the invention were then tested on the kinases PIM-1, PIM-2 and PIM-3.
The results in terms of percentage of residual activity after placing the compounds according to the invention in contact with each of the kinases PIM-1, PIM-2 and PIM-3 are given in Table 2 below.
The higher the residual activity, the lower the inhibitory activity of the test compounds.







TABLE 2







Percentage of residual activity at a concentration of product


according to the invention of 10 μmol/L on the kinases


PIM-1, PIM-2 and PIM-3












Compounds
PIM-1
PIM-2
PIM-3
















Example 1
61
62
64



Example 2
20
62
10



Example 3
2
7
1



Example 4
28
47
18



Example 5
9
27
9



Example 6
20
30
7



Example 7

N.D.



Example 8
44
47
33



Example 9
35
50
21



Example 10
54
51
39



Example 11
39
78
25



Example 12
24
53
16



Example 13
41
27
21



Example 14
51
52
61



Example 15
12
46
8



Example 16
6
57
6



Example 17

N.D.



Example 18
46
51
39



Example 19

N.D.



Example 20

N.D.



Example 21

N.D.



Example 22

N.D.



Example 23

N.D.



Example 24

N.D.



Example 25
74
93
15



Example 26
8
37
11



Example 27
90
N.I.
43



Example 28
35
84
20



Example 29
N.I.
N.I.
43



Example 30
10
36
14



Example 31
9
26
4



Example 32
9
23
11



Example 33
28
96
23



Example 34
85
N.I.
45



Example 35
81
N.I.
13



Example 36
17
31
12



Example 37
39
70
48



Example 38
16
53
15



Example 39
15
55
15



Example 40
6
32
6



Example 41
28
52
23



Example 42
29
70
31



Example 43
44
39
15



Example 44
2
6
5



Example 45
3
28
9



Example 46
4
21
5



Example 47
5
11
3



Example 48
8
34
6



Example 49
92
N.I.
14



Example 50
N.I.
N.I.
35



Example 51
1
14
10



Example 52
15
39
8







N.D.: not determined



N.I.: not inhibitory






The preferred compounds of the invention are those with a percentage of residual activity of less than or equal to 10%, i.e. the compounds of Examples 2, 3, 5, 6, 15, 16, 40, 44, 45, 46, 47, 48, 51 and 52.
IV) DETERMINATION OF THE MEAN INHIBITORY CONCENTRATION OF THE PREFERRED COMPOUNDS OF THE INVENTION
The mean inhibitory concentrations (IC50) of certain preferred compounds of the invention were determined in the following manner: the IC50 values were measured after performing the inhibition tests on the kinases PIM-1, PIM-2 and PIM-3 at ten different concentrations for each test compound, and the IC50 value was determined from the dose-inhibition curves obtained.
The results are given in Table 3 below.







TABLE 3







IC50 (μmol/L) on the kinases PIM-1, PIM-2 and PIM-3













PIM-1
PIM-2
PIM-3
















Compound of Example 3
0.12
0.51
0.01



Compound of Example 5
0.78
N.D.
0.21



Compound of Example 6
N.D.
N.D.
0.17



Compound of Example 15
N.D.
N.D.
0.44



Compound of Example 16
0.57
N.D.
0.04



Compound of Example 40
0.66
N.D.
0.20







N.D.: not determined

## Claims

1. A method of treating a disease associated with the activity of at least one kinase selected from the group consisting of PIM-1, PIM-2 and PIM-3 comprising administering to a subject in need thereof an amount of at least one compound of formula I below effective to inhibit at least one of PIM-1, PIM-2 or PIM 3:




in which:
R1 is H or a sulfophenyl group,
R2, R3 and R4 are identical or different and represent, independently of each other, a hydrogen atom, a halogen atom or a group chosen among nitro, nitrile, hydroxyl, linear or branched C1 to C6 alkoxy optionally substituted with one or more groups R5, C5 to C6 cycloalkoxy optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkoxy optionally substituted with one or more groups R5, —SH, linear or branched C1 to C6 alkylthio optionally substituted with one or more groups R5, C6 aryl optionally substituted with one or more groups R5, C6 aryloxy optionally substituted with one or more groups R5, —NRaRb, —NRaC(O)-T1, —C(N—OH)-T3, —C(O)-T3, —C(O)—C(O)-T3, —C(O)—NRa-T1, —NRa—C(O)-T1, —O—C(O)-T1, —C(O)—O-T1, —O-T2-NRaRb, —O-T2-ORa, —O-T2CO2Ra, —NRa-T2-NRaRb, —NRa-T2-ORa, —NRa-T2-CO2Ra or —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa, linear or branched C1 to C6 alkyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkenyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkynyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryl optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryloxy optionally substituted with one or more groups R5,
R5 represents a halogen atom or a group chosen among linear or branched C1 to C6 alkyl, C6 aryl, linear or branched C1 to C6 haloalkyl, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb, nitrile, nitro, —NRaC(O)-T1, C1 to C6 alkoxy, oxo, —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa,
Ra and Rb are identical or different and represent, independently of each other, a hydrogen atom or a group chosen among linear or branched C1 to C6 alkyl, linear or branched C1 to C6 haloalkyl and C6 aryl, in which Ra+Rb form, together with the nitrogen atom to which they are attached, a saturated or unsaturated, monocyclic or bicyclic heterocycle of 5 to 10 atoms, optionally containing in the ring systems a second heteroatom chosen from oxygen and nitrogen, and being optionally substituted with one or more groups R5,
T1 represents a hydrogen atom, a halogen atom or a linear or branched C1 to C6 alkyl group, optionally substituted with a group chosen from —ORa, —NRa Rb, —CO2Ra, —C(O)Ra and —C(O)NRaRb,
T2 represents a linear or branched (C1-C6)alkylidene chain,
T3 represents a group chosen from -halogen, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb in which Ra and Rb are as defined previously,
t represents an integer between 0 and 3 inclusive, and
A, B, C and D denote the rings constituting the compounds of formula I, and serve merely to identify each of these rings,
or a salt, optical isomer or racemic mixture of these compounds.

2. The method as claimed in claim 1, wherein the at least one compound has the formula I in which:
R1 is H or a sulfophenyl group,
R2 represents H or a group chosen among CHO, (CH2)nOH, C(═O)NH2, C(═O)—CF3, (C═O)2Rc, (CH2)2NEt2, CH(OH)CH2N(Et)2, C(NOH)—(C═O)N(Et)2, NO2 and Br, with n=1 or 2 and Rc═OCH3, OC2H5, N(C2H5)2, and
R3 and R4 are identical or different and are chosen, independently of each other, from H, a halogen atom, a 5- or 6-membered heteroaryl group comprising one or two heteroatoms chosen from O and N, linear or branched C1 to C6 alkyl, methoxy, nitro, nitrile, carboxyl, trifluoromethyl, trifluoromethoxy, SO2Rd, C6 aryl optionally substituted with a group chosen from a group (C═O)CH3, phenyl, methoxy, trifluoromethoxy, trifluoromethyl and carboxyl or with 1 or 2 fluorine atoms, with Rd chosen from a group OH, CH3 or NH2.

3. The method as claimed in claim 1, wherein the at least one compound has the formula I in which:
R1 is H or a sulfophenyl group,
R2 represents H or a group chosen among CHO, (CH2)nOH, C(═O)NH2, C(═O)—CF3, (C═O)2Rc, (CH2)2NEt2, CH(OH)CH2N(Et)2, C(NOH)—(C═O)N(Et)2, NO2 and Br, with n=1 or 2 and Rc represents a group OCH3 or OC2H5, or N(C2H5)2, and
R3 and R4 are identical or different and are chosen, independently of each other, from H, a halogen atom and a group from among methyl, ethyl, nitro, nitrile, trifluoromethyl, C6 aryl optionally substituted with a group chosen from a group (C═O)CH3, phenyl, methoxy, trifluoromethoxy and trifluoromethyl, or with 1 or 2 fluorine atoms.

4. The method as claimed in claim 1, wherein the at least one compound of formula I is chosen from the group consisting of
1,10-dihydropyrrolo[2,3-a]carbazole,
1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
1,10-dihydropyrrolo[2,3-a]carbazole-3-carboxamide,
1-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl-2,2,2-trifluoroethanone,
7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole,
7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
7-(2,4-difluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
6-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
9-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
7-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
9-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
6,8-dichloro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
9-ethyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde and
8-methyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde.

5. The method as claimed in claim 1, wherein the at least one compound of formula I is chosen from the group consisting of
1,10-dihydropyrrolo[2,3-a]carbazole,
1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde and
1,10-dihydropyrrolo[2,3-a]carbazole-3-carboxamide.

6. A process for synthesizing the compounds of formula I below:




in which:
R1 is H or a sulfophenyl group,
R2, R3 and R4 are identical or different and represent, independently of each other, a hydrogen atom, a halogen atom or a group chosen among nitro, nitrile, hydroxyl, linear or branched C1 to C6 alkoxy optionally substituted with one or more groups R5, C5 to C6 cycloalkoxy optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkoxy optionally substituted with one or more groups R5, —SH, linear or branched C1 to C6 alkylthio optionally substituted with one or more groups R5, C6 aryl optionally substituted with one or more groups R5, C6 aryloxy optionally substituted with one or more groups R5, —NRaRb, —NRaC(O)-T1, —C(N—OH)-T3, —C(O)-T1, —C(O)—C(O)-T3, —C(O)—NRa-T1, —NRa—C(O)-T1, —O—C(O)-T1, —C(O)—O-T1, —O-T2-NRaRb, —O-T2-ORa, —O-T2-CO2Ra, —NRa-T2-NRaRb, —NRa-T2-ORa, —NRa-T2-CO2Ra or —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa, linear or branched C1 to C6 alkyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkenyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkynyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryl optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryloxy optionally substituted with one or more groups R5,
R5 represents a halogen atom or a group chosen among linear or branched C1 to C6 alkyl, C6 aryl, linear or branched C1 to C6 haloalkyl, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb, nitrile, nitro, —NRaC(O)-T1, C1 to C6 alkoxy, oxo, —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa,
Ra and Rb are identical or different and represent, independently of each other, a hydrogen atom or a group chosen among linear or branched C1 to C6 alkyl, linear or branched C1 to C6 haloalkyl and C6 aryl, in which Ra+Rb form, together with the nitrogen atom to which they are attached, a saturated or unsaturated, monocyclic or bicyclic heterocycle of 5 to 10 atoms, optionally containing in the ring systems a second heteroatom chosen from oxygen and nitrogen, and being optionally substituted with one or more groups R5,
T1 represents a hydrogen atom, a halogen atom or a linear or branched C1 to C6 alkyl group, optionally substituted with a group chosen from —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb,
T2 represents a linear or branched (C1-C6)alkylidene chain,
T3 represents a group chosen from -halogen, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb in which Ra and Rb are as defined previously,
t represents an integer between 0 and 3 inclusive, and
A, B, C and D denote the rings constituting the compounds of formula I, and serve merely to identify each of these rings,

comprising Fischer indolization of the compound 1-benzenesulfonyl-1,4,5,6-tetrahydro-7H-indol-7-one of formula II below:




and phenylhydrazine or phenylhydrazine substituted on the phenyl with one or more groups R5, in the presence of an ionic liquid, which is 2/1 zinc chloride-choline chloride of formula III below:

7. A compound of formula I below:




in which:
R1 is H or a sulfophenyl group,
R2, R3 and R4 are identical or different and represent, independently of each other, a hydrogen atom, a halogen atom or a group chosen among nitro, nitrile, hydroxyl, linear or branched C1 to C6 alkoxy optionally substituted with one or more groups R5, C5 to C6 cycloalkoxy optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkoxy optionally substituted with one or more groups R5, —SH, linear or branched C1 to C6 alkylthio optionally substituted with one or more groups R5, C6 aryl optionally substituted with one or more groups R5, C6 aryloxy optionally substituted with one or more groups R5, —NRaRb, —NRaC(O)-T1, —C(N—OH)-T3, —C(O)-T1, —C(O)—C(O)-T3, —C(O)—NRa-T1, —NRa—C(O)-T1, —O—C(O)-T1, —C(O)—O-T1, —O-T2-NRaRb, —O-T2-ORa, —O-T2-CO2Ra, —NRa-T2-NRaRb, —NRa-T2-ORa, —NRa-T2-CO2Ra or —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa, linear or branched C1 to C6 alkyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkenyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkynyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryl optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryloxy optionally substituted with one or more groups R5,
R5 represents a halogen atom or a group chosen among linear or branched C1 to C6 alkyl, C6 aryl, linear or branched C1 to C6 haloalkyl, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb, nitrile, nitro, —NRaC(O)-T1, C1 to C6 alkoxy, oxo, —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa,
Ra and Rb are identical or different and represent, independently of each other, a hydrogen atom or a group from among linear or branched C1 to C6 alkyl, linear or branched C1 to C6 haloalkyl and C6 aryl, in which Ra+Rb form, together with the nitrogen atom to which they are attached, a saturated or unsaturated, monocyclic or bicyclic heterocycle of 5 to 10 atoms, optionally containing in the ring systems a second heteroatom chosen from oxygen and nitrogen, and being optionally substituted with one or more groups R5,
T1 represents a hydrogen atom, a halogen atom or a linear or branched C1 to C6 alkyl group, optionally substituted with a group chosen from —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb,
T2 represents a linear or branched (C1-C6)alkylidene chain,
T3 represents a group chosen from -halogen, —ORa, —NRa Rb, —CO2Ra, —C(O)Ra and —C(O)NRaRb in which Ra and Rb are as defined previously,
t represents an integer between 0 and 3 inclusive, and
A, B, C and D denote the rings constituting the compounds of formula I, and serve merely to identify each of these rings,

on condition that:
R1, R2, R3 and R4 are not all simultaneously H,
when R1 is a sulfophenyl group, then R2, R3 and R4 are not all simultaneously H, and
when R2 is a carboxamide or formyl group, then R1, R3 and R4 are not all simultaneously H.

8. The compound of formula I as claimed in claim 7, wherein in formula I:
R1 is H or a sulfophenyl group,
R2 represents H, or a group from among CHO, (CH2)nOH, C(═O)NH2, C(═O)—CF3, (C═O)2Rc, (CH2)2NEt2, CH(OH)CH2N(Et)2, C(NOH)—(C═O)N(Et)2, NO2 and Br with n=1 or 2 and Rc═OCH3, OC2H5 or N(C2H5)2, and
R3 and R4 are identical or different and are chosen, independently of each other, from H, a halogen atom, a 5- or 6-membered heteroaryl group comprising one or two heteroatoms chosen from O and N, linear or branched C1 to C6 alkyl, methoxy, nitro, nitrile, carboxyl, trifluoromethyl, trifluoromethoxy, SO2Rd, C6 aryl optionally substituted with a group chosen from a group (C═O)CH3, phenyl, methoxy, trifluoromethoxy, trifluoromethyl and carboxyl or with 1 or 2 fluorine atoms, with Rd chosen from a group OH, CH3 or NH2.

9. The compound as claimed in claim 7, wherein in formula I:
R1 is H or a sulfophenyl group,
R2 represents H or a group from among CHO, (CH2)nOH, C(═O)NH2, C(O)—CF3, (C═O)2Rc, (CH2)2NEt2, CH(OH)CH2N(Et)2, C(NOH)—(C═O)N(Et)2, NO2 and Br, with n=1 or 2 and Rc represents a group OCH3, OC2H5 or N(C2H5)2, and
R3 and R4 are identical or different and are chosen, independently of each other, from H, a halogen atom and a group from among methyl, ethyl, nitro, nitrile, trifluoromethyl, C6 aryl optionally substituted with a group chosen from a group (C═O)CH3, phenyl, methoxy, trifluoromethoxy and trifluoromethyl, or with 1 or 2 fluorine atoms.

10. The compound of formula I as claimed in claim 7, selected from the group consisting of:
(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl) methanol,
1-(1,10-dihydropyrrolo[2,3-c]carbazol-3-yl)-2,2,2-trifluoroethanone,
methyl 2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-2-oxoacetate,
ethyl 2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl)-2-oxoacetate,
2-(1,10-dihydropyrrolo[2,3-a]carbazol-3-yl) ethanol,
2-(1,10-dihydropyrrolo[2,3-c]carbazol-3-yl)-N,N-diethyl-2-oxoacetamide,
2-(1,10-dihydropyrrolo[2,3-c]carbazol-3-yl)-N,N-diethylethanamine,
1-(1,10-dihydropyrrolo[2,3-c]carbazol-3-yl)-2-diethylaminoethanol,
2-(1,10-dihydropyrrolo[2,3-c]carbazol-3-yl)-N,N-diethyl-2-hydroxyiminoethanamide,
1-benzenesulfonyl-7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole,
7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole,
7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
7-(4-acetylphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
7-(3-methoxyphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
7-(4-biphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
7-phenyl-1,10-dihydropyrrolo[2,3-a]carbazole,
7-(4-fluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
7-(2,4-difluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
7-(4-trifluoromethylphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
7-(4-trifluoromethoxyphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
8-bromo-1,10-dihydropyrrolo[2,3-a]carbazole,
6-bromo-1,10-dihydropyrrolo[2,3-a]carbazole,
9-bromo-1,10-dihydropyrrolo[2,3-a]carbazole,
7-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole,
9-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole,
6,8-dichloro-1,10-dihydropyrrolo[2,3-a]carbazole,
1,10-dihydropyrrolo[2,3-a]carbazole-7-carbonitrile,
7-nitro-1,10-dihydropyrrolo[2,3-a]carbazole,
9-ethyl-1,10-dihydropyrrolo[2,3-a]carbazole,
9-(trifluoromethyl)-1,10-dihydropyrrolo[2,3-a]carbazole,
8-methyl-1,10-dihydropyrrolo[2,3-a]carbazole,
7-(3-methoxyphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
7-(4-biphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
7-phenyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
7-(4-fluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
7-(2,4-difluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
7-(4-trifluoromethylphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
7-(4-trifluoromethoxyphenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
8-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
6-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
9-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
7-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
9-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
6,8-dichloro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
3-formyl-1,10-dihydropyrrolo[2,3-a]carbazole-7-carbonitrile,
7-nitro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
9-ethyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde, and
8-methyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde.

11. The compound of formula I as claimed in claim 7, selected from the group consisting of
1,10-dihydropyrrolo[2,3-a]carbazol-3-yl-2,2,2-trifluoroethanone,
7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole,
7-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
7-(2,4-difluorophenyl)-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
6-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
9-bromo-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
7-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
9-fluoro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
6,8-dichloro-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde,
9-ethyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde and
8-methyl-1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde.

12. A method of treating prostate cancer, leukemia, lymphoma and ovarian cancer comprising administering to a subject in need thereof an effective amount of at least one compound of formula I below:




in which:
R1 is H or a sulfophenyl group,
R2, R3 and R4 are identical or different and represent, independently of each other, a hydrogen atom, a halogen atom or a group chosen among nitro, nitrile, hydroxyl, linear or branched C1 to C6 alkoxy optionally substituted with one or more groups R5, C5 to C6 cycloalkoxy optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkoxy optionally substituted with one or more groups R5, —SH, linear or branched C1 to C6 alkylthio optionally substituted with one or more groups R5, C6 aryl optionally substituted with one or more groups R5, C6 aryloxy optionally substituted with one or more groups R5, —NRaRb, —NRaC(O)-T1, —C(N—OH)-T3, —C(O)-T1, —C(O)—C(O)-T3, —C(O)—NRa-T1, —NRa—C(O)-T1, —O—C(O)-T1, —C(O)—O-T1, —O-T2-NRaRb, —O-T2-ORa, —O-T2CO2Ra, —NRa-T2-NRa Rb, —NRa-T2-ORa, —NRa-T2-CO2Ra or —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa, linear or branched C1 to C6 alkyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkenyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkynyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryl optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryloxy optionally substituted with one or more groups R5,
R5 represents a halogen atom or a group chosen among linear or branched C1 to C6 alkyl, C6 aryl, linear or branched C1 to C6 haloalkyl, —ORa, —NRa Rb, —CO2Ra, —C(O)Ra and —C(O)NRa Rb, nitrile, nitro, —NRaC(O)-T1, C1 to C6 alkoxy, oxo, —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa,
Ra and Rb are identical or different and represent, independently of each other, a hydrogen atom or a group chosen among linear or branched C1 to C6 alkyl, linear or branched C1 to C6 haloalkyl and C6 aryl, in which Ra+Rb form, together with the nitrogen atom to which they are attached, a saturated or unsaturated, monocyclic or bicyclic heterocycle of 5 to 10 atoms, optionally containing in the ring systems a second heteroatom chosen from oxygen and nitrogen, and being optionally substituted with one or more groups R5,
T1 represents a hydrogen atom, a halogen atom or a linear or branched C1 to C6 alkyl group, optionally substituted with a group chosen from —ORa, —NRa Rb, —CO2Ra, —C(O)Ra and —C(O)NRaRb,
T2 represents a linear or branched (C1-C6)alkylidene chain,
T3 represents a group chosen from -halogen, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb in which Ra and Rb are as defined previously,
t represents an integer between 0 and 3 inclusive, and
A, B, C and D denote the rings constituting the compounds of formula I, and serve merely to identify each of these rings,

or a salt, optical isomer or racemic mixture of these compounds.

13. A method of treating a disease associated with the activity of at least one kinase selected from the group consisting of PIM-1, PIM-2 and PIM-3 comprising administering to a subject in need thereof an amount of at least one compound of formula I below effective to inhibit at least one of PIM-1, PIM-2 or PIM-3:




in which:
R1 is H or a sulfophenyl group,
R2 is a formyl group,
R3 and R4 are identical or different and represent, independently of each other, a hydrogen atom, a halogen atom or a group chosen among nitro, nitrile, hydroxyl, linear or branched C1 to C6 alkoxy optionally substituted with one or more groups R5, C5 to C6 cycloalkoxy optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkoxy optionally substituted with one or more groups R5, —SH, linear or branched C1 to C6 alkylthio optionally substituted with one or more groups R5, C6 aryl optionally substituted with one or more groups R5, C6 aryloxy optionally substituted with one or more groups R5, —NRaRb, —NRaC(O)-T1, —C(N—OH)-T3, —C(O)-T1, —C(O)—C(O)-T3, —C(O)—NRa-T1, —NRa—C(O)-T1, —O—C(O)-T1, —C(O)—O-T1, —O-T2-NRaRb, —O-T2-ORa, —O-T2CO2Ra, —NRa-T2-NRaRb, —NRa-T2-ORa, —NRa-T2-CO2Ra or —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa, linear or branched C1 to C6 alkyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkenyl optionally substituted with one or more groups R5, linear or branched C1 to C6 alkynyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryl optionally substituted with one or more groups R5, 5- or 6-membered heterocycloalkyl optionally substituted with one or more groups R5, 5- or 6-membered heteroaryloxy optionally substituted with one or more groups R5,
R5 represents a halogen atom or a group chosen among linear or branched C1 to C6 alkyl, C6 aryl, linear or branched C1 to C6 haloalkyl, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb, nitrile, nitro, —NRaC(O)-T1, C1 to C6 alkoxy, oxo, —S(O)t—Ra, —S(O)t—ORa, —S(O)t—NRaRb, —P(O)t—Ra, —P(O)t—ORa,
Ra and Rb are identical or different and represent, independently of each other, a hydrogen atom or a group chosen among linear or branched C1 to C6 alkyl, linear or branched C1 to C6 haloalkyl and C6 aryl, in which Ra+Rb form, together with the nitrogen atom to which they are attached, a saturated or unsaturated, monocyclic or bicyclic heterocycle of 5 to 10 atoms, optionally containing in the ring systems a second heteroatom chosen from oxygen and nitrogen, and being optionally substituted with one or more groups R5,
T1 represents a hydrogen atom, a halogen atom or a linear or branched C1 to C6 alkyl group, optionally substituted with a group chosen from —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb,
T2 represents a linear or branched (C1-C6)alkylidene chain,
T3 represents a group chosen from -halogen, —ORa, —NRaRb, —CO2Ra, —C(O)Ra and —C(O)NRaRb in which Ra and Rb are as defined previously,
t represents an integer between 0 and 3 inclusive, and
A, B, C and D denote the rings constituting the compounds of formula I, and serve merely to identify each of these rings,

or a salt, optical isomer or racemic mixture of these compounds.