FR2876377A1 - NOVEL 9H-PYRIDO [2,3-B] INDOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING SUCH COMPOUNDS - Google Patents

Abstract

The invention relates to the compounds of formula (I): with R0, R1, R2, R3 and R4 as defined in claim 1 as well as the pharmaceutical compositions containing such compounds and their use for the manufacture of a medicament intended for the treatment or prevention of cancers, Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis (ALS), viral infections, autoimmune diseases, and neurodegenerative disorders .

Description

(I)

  The present invention relates to novel 9H-pyrido [2,3-b] indole derivatives having inhibitory activity with respect to cyclin-dependent kinases, and especially CDK1 and CDK5, and / or glycogen synthase kinase-3 enzyme (GSK-3), their method of preparation, as well as pharmaceutical compositions containing such compounds and their use for the manufacture of medicaments.

  The passages at the different phases of the cell cycle of mitosis or meiosis are controlled by a set of proteins whose enzymatic activities are associated with different states of phosphorylation. The two major classes of enzymes involved are kinases and phosphatases.

  The transition from one phase to another in a cycle is under the control of a family of small serine / threonine kinase proteins, the cyclin-dependent kinases (CDKs) that regulate protein activity by phosphorylation. The level of CDK expression is approximately constant during the cell cycle, but these protein kinases are active in themselves and must be activated to acquire kinase activity. The enzymatic activity and the specificity of the CDKs depend on their association with a regulatory subunit belonging to the family of cyclins.

  Several cyclins and CDKs coexist in the cell, but the associations between cyclins and CDKs are specific. At this date, at least ten CDKs have been described (CDK1-10) (Detivaud et al., Eur J Biochem 1999, 264, 55-66). The cdc2 enzyme is also named CDK1 (Meijer et al., Eur J Biochem 1997, 243, 527-536).

  Several compounds blocking the kinase activity of CDKs are known: purines, paullones, flavopiridol, indirubins, olomoucine, roscovitine, butyrolactone-1, toyocamycin and others. Oxindole derivatives (WO 02/068411), triazolopyrazines (FR 2818278) or 1H-pyrrolo [2,3-b] pyridine (WO 01/98299), described as CDK inhibitors, are also found.

  As indicated, in particular in FR 2 818 278, they are studied in several therapeutic areas such as oncology to prevent the division of tumor cells (Mc Donald and el-Deiry, Int.J., Oncol., 2000, 16, 871-886). neurobiology to prevent natural or chemo-induced apoptosis of normal cells (e.g., neurons) (Maas et al., J. Neurochem, 1998, 70, 1401-1410, Park et al., J. Neurosci 1997, 17, 1256-1270), nephrology to restore impaired renal function in case of glomerulonephritis (Pipin et al., J. Clin Invest 1997, 100, 2512-2520) and parasitology to block the parasite reproductive cycle (Knockaert et al., Chem Biol., 2000, 7, 411-422, Roch et al., J. Biol Chem 2000, 275, 8952-8958).

  Cyclin-dependent kinase inhibitors are therefore likely to be used as drugs, particularly in the treatment of the diseases / disorders described in Meijer et al., Trends Pharmacol. Sci. 2002, 23, 417-425, and in particular for inhibiting the proliferation of tumor cells; to inhibit the proliferation of normal cells, especially for treating atherosclerosis, angiogenesis, psoriasis or restenosis; in the prevention of spontaneous alopecia, induced by exogenous products, or radiation-induced; in the prevention of spontaneous or induced nerve cell apoptosis (ischemia, cerebrovascular accident); in the prevention of meiosis and fertilization; in the prevention of oocyte maturation; in the treatment of viral or retroviral infections such as herpes, AIDS, or cytomegalovirus; in the prevention and treatment of neurodegenerative diseases such as tauopathies, including Alzheimer's disease; in the prevention and treatment of parasites, and in particular for controlling the proliferation of protozoa, for example Trypanosomes, Toxoplasmas or Plasmodium; in the treatment of myopathies.

  GSK-3 is, in turn, a serine / threonine kinase, involved in various biological processes, as described in particular in FR 2818278, to which reference may be made. Inhibitors of GSK-3 find different therapeutic applications (Greengard et al., Trends Pharmacol Sci., 2004, 25, 471-480), especially in the treatment of depression, mood disorders, neurodegenerative disorders such as Parkinson's disease, tauopathies such as Alzheimer's disease or certain dementias, diabetes or cell proliferation-related diseases such as cancer.

  According to the present invention, a new series of 9H-pyrido [2,3-b] indole derivatives having an inhibitory activity with respect to cyclin-dependent kinases, and especially CDK1, has now been found. CDK5 and / or GSK-3.

  More specifically, the subject of the present invention is the compounds of formula (I) in which: R 1 and R 1 represent, each independently of one another, a hydrogen or halogen atom or a group chosen from -CN, -OH, aryl, heteroaryl, methyl, alkenyl, -OCORa, -NRaRb, -NHCORa, -NHSO2Ra, -NHCONRaRb, -NHCOORa or -NHSO2Ra, with Ra and Rb each independently of one another a hydrogen atom, or an optionally substituted group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkenyl, heterocycloalkylalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, or Ra and Rb are linked together to form with the nitrogen atom to which they are bonded an optionally substituted heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, - one of the groups R2 or R3 represented is a -C (O) Rc group, and the other R2 or R3 group is a hydrogen atom or an optionally substituted alkyl, with: Re selected from the group ORd, -NRaRb, or -NHSO2Ra, with Rd which represents alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, heteroarylalkyl, - (CH2) -NRaRb, - (CH2) -NHCORa, - (CH2) n NHSO2Ra, n integer from 1 to 6 and Ra and Rb as defined above, as well as their pharmaceutically acceptable salts.

  According to a preferred variant, the present invention relates to the compounds defined above wherein R2 or R3 represents a C (O) ORd group, with Rd as defined above.

  According to a preferred variant, the present invention relates to the compounds defined above in which R2 or R3 represents a C (O) NRaRb group, with Ra and Rb as defined above.

  According to one of its aspects, the subject of the invention is the compounds of formula (Ia) C (O) ORd

H

  With Ro, R1 and Rd as defined above, as well as their pharmaceutically acceptable salts.

  According to another aspect, the invention relates to the compounds of formula (Ib) C (O) N RaRb

H

  with Ro, R ,, Ra and Rb as defined above, as well as their pharmaceutically acceptable salts.

  According to another aspect, the invention relates to compounds of formula (Ic)

H

  with Ro, RI and Rd as defined above, as well as their pharmaceutically acceptable salts.

  According to another aspect, the invention relates to the compounds of formula (Id) R, (O) NRaRb with Ro, R1, Ra and Rb as defined above, as well as their pharmaceutically acceptable salts.

  According to another preferred variant, the present invention relates to the above compounds in which R 1 is a hydrogen atom or a halogen atom, in particular a chlorine atom.

  According to another preferred variant, the present invention relates to the above compounds in which Ro is chosen from -NH 2, phenyl, morpholinyl, piperazinyl, piperidinyl, thienyl, (preferably 2- or 3-thienyl), cyano, furanyl (from preferably 2-furanyl), or -NHRa with Ra which represents an alkyl or arylalkyl group, preferably an optionally substituted methyl, ethyl or benzyl group, for example a hydroxy or methoxy group.

  According to a preferred aspect, the subject of the invention is the compounds of formula (I) in which R2 or R3 represents a C (O) ORd group, of formula (Ia) or (Ic), in which Rd represents a cycloalkyl group. , aryl, heteroaryl, arylalkyl, or an alkyl group optionally substituted by an alkylamino group, as well as their pharmaceutically acceptable salts.

  According to a preferred aspect, the subject of the invention is the compounds of formula (I) in which R2 or R3 represents a C (O) NRaRb group of formula (Ib) or (Id) in which Ra and Rb each represent independently from each other a hydrogen atom or a cycloalkyl, aryl, heteroaryl group, or an alkyl group optionally substituted by a hydroxy, dialkylamino, morpholinyl group, as well as their pharmaceutically acceptable salts. Preferably, one of the groups Ra or Rb represents a hydrogen atom.

  Particularly advantageously, the subject of the present invention is the compounds chosen from: ethyl 9H-pyrido [2,3-b] indole-6-carboxylate (Ia.1) -9H-pyrido [2,3-b] ] methyl indol-6-carboxylate (Ia.2) isopropyl 9H-pyrido [2,3-b] indole-6-carboxylate (Ia.3) 9H-pyrido [2,3-b] indole-6- cyclohexyl (Ia.4) 9H-pyrido [2,3-b] indole-6-carboxylate butyl ester (Ia.5) 9H-pyrido [2,3-b] indole-6-carboxylate (Ia. 6) 9H-pyrido [2,3-b] indole-6-carboxylic acid phenyl (Ia.7) 9H-pyrido [2,3-b] indole-6-carboxylate (Ia.8) 9H-pyrido [ 2-Aminomethyl-3-methylbutyl (lai O) N-methyl 3-pyridinyl (1a.9) -9-pyridinyl 2,3-b] indole-6-carboxylate [6-b] indole-6-carboxylate -9H-pyrido [2,3-b] indole-6-carboxamide (Ib.l) N-propyl-9H-pyrido [2,3-b] indole-6-carboxamide (Ib.2) N, N-diethyl 9Hpyrido [2,3-b] indole-6-carboxamide (Ib.3) N-pyridinyl-9H-pyrido [2,3-b] indole-6-carboxamide (Ib) N-cyclohexyl-9H pyrido [2] , 3-b] indole-6-carboxamide (Ib.5) - N- (pyridin-3-yl) -9H-pyri do [2,3-b] indole-6-carboxamide (Ib.6) N-phenyl-9H-pyrido [2,3-b] indole-6-carboxamide (Ib) N- (1-hydroxymethyl) methylpropyl ) -9H-pyrido [2,3-b] indole-6-carboxamide (Ib.8) N- (2-hydroxyethyl) -9H-pyrido [2,3-b] indole-6-carboxamide (Ib.9) N - [2- (dimethylamino) ethyl] -9H-pyrido [2,3-b] indole-6-carboxamide (Ib.10) N [2- (4-morphonyl) ethyl] -9H-pyrido [2] 3-b] indole-6-carboxamide (Ib.ll) methyl 9H-pyrido [2,3-b] indole-5-carboxylate (Ic.l) 9H-pyrido [2,3-b] indole-5- Butyl carboxylate (Ic.2) 9H-pyrido [2,3-b] indole-5-carboxylate propyl (Ic.sub.3) 9H-pyrido [2,3-b] indole-5-carboxylic acid cyclohexyl ester (Ic. 4) Phenyl 9H-pyrido [2,3-b] indole-5-carboxylate (Ic.sub.5) 9H-pyrido [2,3-b] indole-5-carboxylic acid (Ic.sub.6) 9H-pyrido [ 2,3-b] indole-5-carboxylate of 3-pyridinyl (Ic.7) 9H-pyrido [2,3-b] indole-5-carboxylate of 2-aminomethyl-3-methylbutyl (Ic. 8) N-methyl-9H-pyrido [2,3-b] indole-6-carboxamide (Id.1) N-propyl-9Hpyrido [2,3-b] indole-5-carboxamide (Id.2) N, N-diethyl-9H-pyrido [2,3-b] indole-6-carboxamide (Id.3) N-pyridinyl-9H-pyrido [2,3-b] indole-6-carboxamide (Id. cyclohexyl-9H-pyrido [2,3-b] indole-6-carboxamide (Id. 5) N-phenyl-9H-pyrido [2,3-b] indole-6-carboxamide (Id.6) N- (pyridine 3-yl) 9H-pyrido [2,3-b] indole-6-carboxamide (Id.7) N- (1-hydroxymethyl-2-methylpropyl) -9H-pyrido [2,3-b] indole-6 -carboxamide (Id.8) - N- (2-hydroxyethyl) -9H-pyrido [2,3-b] indole-6-carboxamide (Id.9) N- [2- (dimethylamino) ethyl] -9H-pyrido Ethyl [2,3-b] indole-6-carboxamide (Id.10) 4-chloro-9H-pyrido [2,3-b] indole-6-carboxylate (Ia.11) 4-chloro-N- (2-hydroxyethyl) -9H-pyrido [2,3-b] indole-6-carboxamide (Ib.12) 2- (4-methoxybenzylamino) -9H-pyrido [2,3-b] indole-6-carboxylate ethyl (1a.12) ethyl 2-amino-9H-pyrido [2,3-b] indole-5-carboxylate (Ia.13) 2-methylamino-9H-pyrido [2,3-b] indole- Ethyl 5-carboxylate (Ia.14) 2-morpholino-9-H-pyrido [2,3-b] indo ethyl-5-carboxylate (Ia.15) 2-piperidino-9H-pyrido [2,3-b] indole-5-carboxylic acid ethyl ester (Ia.16) 2-piperazino-9H-pyrido [2, Ethyl 3-b] indole-5-carboxylate (1a. 17) Ethyl 2- (2-hydroxyethylamino) -9H-pyrido [2,3-b] indole-5-carboxylate (1a.18) - 2 Ethyl (2-phenyl) -9H-pyrido [2,3-b] indole-5-carboxylate (Ia.19) 2- (2-thienyl) -9H-pyrido [2,3-b] indole- Ethyl 5-carboxylate (Ia.20) ethyl 2- (2-furanyl) -9H-pyrido [2,3-b] indole-5-carboxylate (1a.21) -2- (3-thienyl) Ethyl-9H-pyrido [2,3-b] indole-5-carboxylate ethyl (Ia.22) -2-cyano-9-H-pyrido [2,3-b] indole-5-carboxylate ( 1a.23) 2- (4-methoxybenzylamino) -N-methyl-9H-pyridin [2,3-b] indole-6-carboxamide (Ib.13) 2-amino-N-methyl-9H-pyrido [2,3-b] indole-5-carboxamide (Ib.14) 2-methylamino-N-methyl-9H-pyrido [2,3-b] indole-5-carboxamide (Ib.15) 2-morpholino-N methyl-9-H-pyrido [2,3-b] indole-5-carboxamide (Ib.16) 2-piperidino-N-methyl-9H-pyrido [2,3-b] indole-5-carboxamide (Ib .17) 2-piperazino-N-methyl-9H-pyrido [2,3 -b] indole-5-carboxamide (Ib.18) 2- (2-hydroxyethylamino) -N-methyl-9H-pyrido [2,3-b] indole-5-carboxamide (Ib.19) and their pharmaceutically acceptable salts .

  By alkyl is meant, when not more precise, a saturated monovalent hydrocarbon radical, linear or branched having 1 to 6 carbon atoms.

  As examples of alkyl group, there may be mentioned methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, hexyl and the like.

  Alkoxy means an O-alkyl radical.

  By halogen is meant a chlorine, bromine, iodine or fluorine atom.

  The terms alkenyl and alkynyl correspond to an alkyl group as defined above comprising respectively a double or a triple bond. Examples of alkenyl or alkynyl are, for example, vinyl, allyl, isopropenyl, 1-, 2- or 3-butenyl, pentenyl, hexenyl, ethynyl, 2-propynyl, butynyl.

  The term cycloalkyl denotes a cycloalkyl group comprising from 3 to 10 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bridged cycloalkyl groups such as adamantyl, bicyclo [3.2.1] optanyl groups.

  The term heterocycloalkyl refers to a cycloalkyl as defined above, comprising one or more heteroatoms selected from nitrogen, oxygen and sulfur.

  The aryl groups designate mono- or polycyclic carbocycles comprising at least one aromatic group.

  The term heteroaryl refers to an aryl group as defined above comprising at least one atom selected from a nitrogen atom, oxygen or sulfur.

  As the aryl or heteroaryl, there may be mentioned phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, biphenyl, benzocycloalkyl, ie bicyclo [4.2.0] octa-1,3,5- triene, benzodioxolyl, such as pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pirazinyl, pyrimidyl, tetrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, pyridazinyl, indolyl, pyrimidyl.

  The groups R 1, R 1, R 2, R 3 and R 4 may optionally be substituted, for example, with a group chosen from: halogens, cyano, alkyl, trifluoroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, amino, alkylamino, dialkylamino, hydroxy, alkoxy, aryloxy ...

  The terms used for the definition of substituents are those usually recognized by those skilled in the art.

  For example, a cycloalkylalkyl substituent means that the substituent is an alkyl group itself substituted with a cycloalkyl group.

  The salts of the compounds according to the invention are prepared according to techniques well known to those skilled in the art. The salts of the compounds of formula (I) according to the present invention include those with inorganic or organic acids which allow a suitable separation or crystallization of the compounds of formula (I), as well as pharmaceutically acceptable salts. Suitable acids are: picric acid, oxalic acid or an optically active acid, for example a tartaric acid, a dibenzoyltartric acid, a mandelic acid or a camphorsulfonic acid, and those which form salts physiologically acceptable such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, maleate, fumarate, 2-naphthalenesulfonate, paratoluenesulfonate.

  When a compound according to the invention has one or more asymmetric carbons, the optical isomers of this compound form an integral part of the invention. When a compound according to the invention has a stereoisomerism, for example of axial-equatorial or Z-E type, the invention comprises all the stereoisomers of this compound.

  The present invention comprises the compounds of formula (I) in the form of pure isomers but also in the form of a mixture of isomers in any proportion. The compounds (I) are isolated in the form of pure isomers by standard separation techniques: it is possible to use, for example, fractional recrystallizations of a racemic salt with an optically active acid or base whose principle is well known or classical techniques of chiral or non-chiral phase chromatography.

  The compounds of formula (I) above also include those in which one or more hydrogen, carbon or halogen atoms, in particular chlorine or fluorine atoms, have been replaced by their radioactive isotope, for example tritium or carbon. -14. Such labeled compounds are useful in research, metabolism or pharmacokinetic work in biochemical assays as receptor ligands.

  The functional groups optionally present in the molecule of the compounds of formula (I) and in the reaction intermediates may be protected, either in permanent form or in temporary form, by protecting groups which ensure an unambiguous synthesis of the expected compounds. The protection and deprotection reactions are carried out according to techniques well known to those skilled in the art. By temporary protective group of amines, alcohols or carboxylic acids is meant protective groups such as those described in Protective Groups in Organic Synthesis, Greene T.W. and Wuts P.G.M., ed. John Wiley and Sons, 1991 and in Protecting Groups, Kocienski P.J., 1994, Georg Thieme Verlag.

  The compounds of formula (Ia) and (Ib), for which Ro = R1 = H, can be prepared in the following way: the Horner-Emmons reaction between 1-benzenesulfonyl-7-azaindole-3-carboxaldehyde (Mérour et al. Tetrahedron Lett., 1999, 40, 5853-5854) and tert-butyl 3- (ethoxycarbonyl) -3- (diethylphosphono) propanoate (Owton et al., 1993, 23, 21192125) in a basic medium (diisopropylamide). lithium) leads to the preparation of compound 1. The hydrolysis of the tert-butyl ester of derivative 1 in acid medium (trifluoroacetic acid) followed by refluxing in acetic anhydride in the presence of sodium acetate gives the tricyclic compound 2 in 80% yield. The deprotection of the alcohol is carried out by treating the tricyclic compound 2 with one equivalent of sodium in ethanol at 0 ° C. for 2 hours. Compound 3 is isolated in 95% yield. Triflate 4 is obtained in a yield of 93% by reaction of 3 with trifluoromethanesulfonic anhydride in pyridine in the presence of 4-dimethylaminopyridine. Catalytic hydrogenation (H 2 (10 bar), Pd / C) of compound 4 at temperature for 4 hr led to deprotected compound 5 in quantitative yield. The second catalytic hydrogenation (H 2 (10 bar), Pd / C) carried out on 5 leads quantitatively to the detiflated compound Ia.l. The transesterification reactions with the appropriate alcohol and sodium alcoholate carried out on compound Ia. give access to the other esters (Ia). The amidation reactions carried out on compound Ia. give access to the corresponding amides (Ib).

SCHEME 1

N N N

  SO2Ph SO2Ph (EtO) 2OPCO2Et CHO CO2t-Bu LDA, THF, 0 C Na, EtOH CO2 and N OR SO2Ph3 R = H1 Tf2O, DMAP4 R = Tf pyridine H2, Pd / C CO2Et (Ia) for which Ro = R1 = H (Ib) for which Rp R1 = HN OTf H1H2, Pd / C CO2Et NHRaRb Compounds (Ic) and (Id), for which Ro = R1 = H, can be prepared analogously, according to SCHEME 2 .

  The deprotection reaction of methyl 9- (benzenesulfonyl) -9H-pyrido [2,3-b] indole5-carboxylate 6, obtained according to the protocol described by Mérour et al. (Tetrahedron 2000, 56, 3189-3196), is conducted in the presence of tributylammonium fluoride in tetrahydrofuran to give the derivative Ic.1 with 90% yield. The transesterification reactions carried out on compound Ic.l give access to the corresponding esters (Ic). The amidation reactions carried out on compound Ic.l give access to amides (Id).

SCHEME 2 McO2C McO2C TIBAF

H N H

  Ic.1 (Ic) RgOH, RgONa NHRaRb The compounds of formula (I) for which the substituents Ro and / or R1 are different from hydrogen may be synthesized in various ways. The following method illustrated by SCHEME 3 is purely illustrative: Ethyl 9H-pyrido [2,3-b] indole-6-carboxylate Ia.l is treated with metachloroperbenzoic acid in the following manner: acetone to yield the N-oxide derivative 7. The chlorination at the 4-position of the N-oxide derivative 7 is carried out in the presence of phosphorus oxychloride to give the compound Ia.l1 in a yield of 98%. The amidation reactions carried out on the N-oxide derivative 7 make it possible to access the corresponding amides (Ib) in which R1 = C1.

  The N-oxide derivative 7 heated in acetic anhydride leads to obtaining the O-acetyl compound 8 with a yield of 60%. The deacetylation reaction of O-acetylated compound 8 is carried out in a solution of ethanolate of sodium in ethanol to give compound 9. The latter, treated with trifluoromethanesulfonic anhydride in pyridine, leads to triflate (yield: 79 %). A nucleophilic addition reaction followed by elimination carried out on the triflate (10) in the presence of various nucleophiles leads to the corresponding derivatives (Ia) in which Ro = -NR'aR'b where R'a and R 'b are as previously defined for Ra and Rb. The amides (Ib) in which Ro = NHRa are isolated after the amidification reaction on the corresponding compound (Ia). The palladium-catalyzed coupling reactions carried out on triflate (10) in the presence of boronic acids, stannanes or Zn (CN) 2 lead to compounds (Ia). mcpba NReRb Ia.1 Ac2O

SCHEME 3 CO2Et CO2Et Cl

N CO2Et Ia.11

N N N

H H

  NHRaRb (Ia) with R1 = C1 and R = H C1 (CF3SO2) DMAP, pyridine CO2Et CO2Et NReRb NHR'R 'ab NHR'aR'b (Ia) with Ro = NR'aR'b and R, = H ( Ia) N with R = Me, aryl, heteroaryl, alkenyl, CN H and R1 = H (Ib) with R = NR'aR'b and R = H No evidence of toxicity is observed with these compounds at pharmacologically and their toxicity is therefore compatible with their use as medicinal products.

  In general, the compounds according to the invention may be used to prepare a medicament intended for the treatment, as a curative or preventive measure, of all the diseases / disorders corresponding to reported uses for inhibitors of CDKs and / or GSK. -3.

  In particular, the compounds of general formula (I) defined above, or their pharmaceutically acceptable salts, may be used to prepare a medicinal product intended to treat the following diseases / disorders / natural phenomena: tumor proliferation, proliferation of nerve cells, spontaneous alopecia, alopecia induced by exogenous products, radiation-induced alopecia, spontaneous or induced apoptosis of nerve cells (ischemia, cerebrovascular accident), meiosis, fertilization, oocyte maturation, infections viral or retroviral (herpes, AIDS, cytomegalovirus), neurodegenerative diseases (eg tauopathies including Alzheimer's disease), Parkinson's disease, proliferation of parasites (proliferation of protozoa, for example trypanosomes, Toxoplasma or Plasmodium) and myopathies.

  In particular, the compounds of formula (I), as well as their pharmaceutically acceptable salts, may be used for the manufacture of medicaments intended for the treatment or prevention of cancers, Alzheimer's disease, Parkinson's disease, d strokes, amyotrophic lateral sclerosis (ALS), viral infections, autoimmune diseases, and neurodegenerative disorders.

  In particular, there may be mentioned as cancers that can be treated with the compounds of the present invention, carcinoma, lymphoid lineage hematopoietic tumors, myeloid lineage hematopoietic tumors, mesingimal tumors, tumors of the central nervous system and peripheral, melanomas, seminomas, teratocarcinomas, osteosarcomas, xeroderma pigmentosum, chératoaquantum, follicular thyroid cancer, and Kaposi's sarcoma. Other pathologies that can be treated with the compounds according to the invention include benign prostatic hyperplasia, familial pyloposis adenomatosis, neurofibromatosis, psoriasis, vascular circulation disorders, such as atherosclerosis, pulmonary fibrosis, glomerulonephritis arthritis and surgical stenosis and restenosis.

  The subject of the present invention is therefore also the compounds of formula (I), as well as their pharmaceutically acceptable salts, or optionally solvates or hydrates, as medicaments, pharmaceutical compositions containing an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and suitable excipients.

  Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.

  In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal or intraocular administration, the active ingredients of formula (I) above, or their Salts, solvates and hydrates may be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, to animals and humans for the prophylaxis or treatment of the above disorders or diseases. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal, dosage forms. subcutaneous, intramuscular or intravenous administration and forms of rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments, lotions or eye drops.

  In order to achieve the desired prophylactic or therapeutic effect, each unit dose may contain from 1 to 500 mg of active ingredients in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times per day so as to administer a daily dosage to obtain the desired effect.

  When preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative, or other suitable materials or they can be treated in such a way that they have prolonged or delayed activity and continuously release a quantity predetermined active ingredient.

  A preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

  The pharmaceutical compositions containing a compound of the invention may also be in liquid form, for example, solutions, emulsions, suspensions or syrups. Suitable liquid carriers may be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.

  A preparation in the form of a syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably a calorie-free sweetener, methylparaben and propylparaben as an antiseptic, as well as a flavoring agent. and a suitable dye. Water-dispersible powders or granules may contain the active ingredient in admixture with dispersants or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or scavengers disgust.

  For rectal administration, suppositories are used which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols. For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol, are used. The active ingredient may also be formulated in the form of microcapsules, optionally with one or more supports or additives, or with matrices such as a polymer or a cyclodextrin (patch, sustained-release forms).

  The compositions of the present invention may contain, in addition to the products of formula (I) above or their pharmaceutically acceptable salts, solvates and hydrates, for example active principles which may be useful in the treatment of the disorders or diseases indicated in FIGS. -above.

  Thus, the subject of the present invention is also pharmaceutical compositions containing several active ingredients in combination, one of which is a compound according to the invention.

  The invention therefore relates to their use as medicaments that can be used alone or in combination with treatments such as chemotherapy, radiotherapy or anti-angiogenic treatments possibly involving other active substances.

  Furthermore, in general, the same preferences as those indicated above for the compounds of general formula (I) are applicable mutatis mutandis to the drugs, pharmaceutical compositions and use using the compounds according to the invention.

  EXAMPLE 1 Ethyl 9H-Pyrido [2,3-b] indole-6-carboxylate (Ia.1) a) 4- (1'-Benzenesulfonyl-1H-pyrrolo [2,3-b] pyridin-3 ' tert-butyl-3-yl (ethoxycarbonyl) but-3-enoate (1) at 0 ° C and under argon, a solution of 2M lithium isopropylamide (3.49 ml, 6.98 mmol) in THF is added dropwise to a solution of tert-butyl 3-carboxyethyl-3-phosphonodiethylpropionate (2.36 g, 6.98 mmol) in THF (30 mL). The solution is stirred at 0 ° C. for 20 minutes. A solution of 1-benzenesulfonyl-7-azaindole-3-carboxaldehyde (1.33 g, 4.65 mmol) is added dropwise at 0 C. The final solution is stirred at room temperature for 4 hours. After addition of water and evaporation of the THF, the mixture obtained is extracted with ethyl acetate (AcOEt) (twice). The organic phase is dried over MgSO 4 and evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica column (petroleum ether / AcOEt 85:15) to give 1 (1.68 g, 77%). Mp = 102-104 ° C (EtOH); R1VIN (300 MHz, CDCl3) 1.39 (t, 3H, J = 7.2 Hz, CH3), 1.56 (s, 9H, CH3), 3.61 (, 2H, CH2), 4, 34 (q, 2H, J = 7.2 Hz, CH 2), 7.29 (dd, 1H, J = 4.6, 7.9 Hz, Hnd), 7.53 (t, 2H, J = 7, 5 Hz, Hrr), 7.63 (t, 1H, J = 7.5 Hz, Hrr), 7.88 (s, 1H, Hh, d), 8.00 (dd, 1H, J = 1.3 , 7.9 Hz, Hnd), 8.02 (s, 1H, = CH), 8.25 (d, 2H, J = 7.5 Hz, Hrr), 8.51 (dd, 1H, J = 1, , 3, 4.6 Hz, Hh, d); MS (IS) m / z 471 (M + H +).

  b) Ethyl 8-acetoxy-9-benzenesulfonyl-8-hydroxy-9H-pyrido [2,3-b] indole-6-carboxylate (2) Compound 1 (570 mg, 1.21 mmol) dissolved in CH 2 Cl 2 ( 8 ml) is treated with a trifluoroacetic acid / H 2 O mixture (8.2 ml, 8: 0.2) at room temperature for 2 hours. The solvents are evaporated and without further purification, the residue is taken up in acetic anhydride (10 ml) and sodium acetate (220 mg). The final mixture is refluxed for 3 hours. After returning to ambient temperature, the acetic anhydride is evaporated under reduced pressure. The solid obtained is purified by chromatography on a silica column (EP / AcOEt 8: 2) to give 2 (340 mg, 80%). Mp = 178-180 ° C (EtOH); 1H NMR (300 MHz, CDCl3) δ 1.43 (t, 3H, J = 7.2 Hz, CH3), 2.47 (s, 3H, CH3), 4.43 (q, 2H, J = 7, 2 Hz, CH 2), 7.32 (dd, 1H, J = 4.9, 7.7 Hz, H 3), 7.39 (t, 2H, J = 7.4 Hz, HAr), 7.51 ( t, 1H, J = 7.4Hz, Hrr), 7.94 (d, 1H, J = 1.5Hz, H7), 7.99 (dd, 2H, J = 7.4Hz, Hm) , 8.22 (dd, 1H, J = 1.5, 7.7 Hz, H4), 8.49 (d, 1H, J = 1.5 Hz, H5), 8.56 (dd, 1H, J). = 1.5, 4.9 Hz, H2); MS (IS) m / z 439 (M + H +).

  c) Ethyl 9-benzenesulfonyl-8-hydroxy-9H-pyrido [2,3-b] indole-6-carboxylate (3) at 0 ° C. and under argon, sodium (18 mg, 0.8 mmol) is added in small pieces to a solution of compound 2 (340 mg, 0.8 mmol) in ethanol / THF solution (15 mL, 1: 2). The solution is stirred at 0 ° C. for 2 hours. The reaction is hydrolysed (addition H2O) at 0 ° C., then the ethanol is evaporated under reduced pressure. The residue dissolved in H2O / AcOEt (20 ml, 1: 1) is extracted. The organic phase is dried over MgSO 4 and evaporated under reduced pressure. The solid obtained is recrystallized from ethanol to give 3 (300 mg, 95%). Mp = 198-200 ° C (EtOH); 1 H NMR (300 MHz, CDCl 3) δ 1.44 (t, 3H, J = 7.2 Hz, CH 3), 4.43 (q, 2H, J = 7.2 Hz, CH 2), 7.32 (dd , 1H, J = 4.9, 7.7 Hz, H3), 7.41 (t, 2H, J = 7.4 Hz, HAr), 7.54 (t, 1H, J = 7.4 Hz, H, r), 7.87 (d, 1H, J = 1.5 Hz, H7), 7.98 (bd, 2H, J = 7.4 Hz, Hrr), 8.15 (d, 1H, J = 1.5 Hz, H5), 8.19 (dd, 1H, J = 1.5, 7.7 Hz, H4), 8.55 (dd, 1H, J = 1.5, 4.9 Hz , F12), 9.51 (s, 1H, OH); MS (IS) m / z 397 (M + H +).

  d) ethyl 9-Benzenesulfonyl-8-trifluoromethanesulfonyloxy-9H-pyrido [2,3-b] indole 6-carboxylate (4) at 0 ° C. and under argon, trifluoromethanesulphonic anhydride (0.16 ml, 0.94 g) mmol) is added to a solution of compound 3 (250 mg, 0.63 mmol) and 4-dimethylaminopyridine (77 mg, 0.63 mmol) in pyridine (9 ml). The solution is stirred at ambient temperature for 20 hours. After evaporation of the pyridine, AcOEt (10 ml) and H2O (10 ml) are added to effect the extraction. The organic phase is dried over MgSO 4 and evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica column (EP / AcOEt 8: 2 then 7: 3) to give 4 (310 mg, 93%). Mp = 187-188 ° C (EtOH); 1 H NMR (300 MHz, CDCl 3) δ 1.45 (t, 3H, J = 7.2 Hz, CH 3), 4.46 (q, 2H, J = 7.2 Hz, CH 2), 7.37 (dd , 1H, J = 4.9, 7.7 Hz, H3), 7.45 (t, 2H, J = 7.4 Hz, Hrr), 7.57 (t, 1H, J = 7.4 Hz, HAr), 8.19 (d, 2H, J = 7.4 Hz, HAr), 8.20 (bs, 1H, H7), 8.25 (dd, 1H, J = 1.5, 7.7 Hz, H4), 8.60 (d, 1H, J = 1.5 Hz, H5), 8.62 (dd, 1H, J = 1.5, 4.9 Hz, H2); MS (IS) m / z 529 (M + H +).

  e) Ethyl 8-trifluoromethanesulfonyloxy-9H-pyrido [2,3-b] indole-6-carboxylate (5) A solution of compound 4 (250 mg, 0.47 mmol), Pd / C 10% (250 mg ) and triethylamine (0.33 mL, 2.36 mmol) in EtOH / THF (20 mL, 1: 1) is stirred under hydrogen atmosphere (15 bar) at room temperature for 4 hours. The catalyst is removed by filtration on celite. The solvents are evaporated and the residue obtained is washed with cold ethanol. After filtration, the final product (183 mg) is quantitatively isolated. Mp> 210 ° C (EtOH); 1H NMR (300 MHz, acetone-d6) δ 1.42 (t, 3H, J = 7.4 Hz, CH 3), 4.44 (q, 2H, J = 7.4 Hz, CH 2), 7.41 (dd, 1H, J = 4.9, 7.7 Hz, H3), 8.02 (d, 1H, J = 1.3 Hz, H7), 8.60 (dd, 1H, J = 1.5 , 4.9 Hz, H2), 8.76 (dd, 1H, J = 1.5, 7.7 Hz, H4), 8.95 (d, 1H, J = 1.3 Hz, H5), 12 , 04 (s, 1H, NH); MS (IS) m / z 389 (M + H +).

  f) Ethyl 9H-pyrido [2,3-b] indole-6-carboxylate, compound (Ia.l) A solution of compound 5 (110 mg, 0.28 mmol), 10% Pd / C (110 mg ) and triethylamine (0.2 ml, 1.42 mmol) in EtOH / THF (15 ml, 1: 1) is stirred under hydrogen atmosphere (15 bar) at room temperature for 20 hours. The catalyst is removed by filtration on celite. The solvents are evaporated and the residue obtained is washed with cold ethanol. After filtration, the final product Ia.l (67 mg) is isolated quantitatively. Mp = 210-211 ° C (EtOH); 1H NMR (300 MHz, acetone-d6) 6 1, 41 (t, 3H, J = 7.4 Hz, CH 3), 4.39 (q, 2H, J = 7.4 Hz, CH 2), 7.29 (dd, 1H, J = 4.9, 7.7 Hz, H3), 7.65 (d, 1H, J = 8.7 Hz, H8), 8.16 (dd, 1H, J = 1.6 , 8.7 Hz, H7), 8.49 (dd, 1H, J = 1.3, 4.9 Hz, H2), 8.63 (dd, 1H, J = 1.3, 7.7 Hz, H4), 8.85 (d, 1H, J = 1.6 Hz, H5), 11.18 (s, 1H, NH); MS (IS) m / z 241 (M + H +).

  Example 2 Methyl 9H-pyrido [2,3-b] indole-6-carboxylate (Ia.2) A solution of compound la.l (20 mg, 0.08 mmol) and a catalytic amount of sodium in methanol (6 ml) is refluxed for 12 hours. After hydrolysis (addition of H2O) and evaporation of the solvents, the residue is taken up in an H2O / AcOEt mixture (10 ml, 1: 1) to carry out the extraction. The organic phase is dried over MgSO 4 and evaporated under reduced pressure. The solid is recrystallized from methanol to give Compound Ia.2 (17 mg, 90%). Mp = 238-240 ° C (acetone); 1 H NMR (300 MHz, acetone-d 6) δ 3.92 (s, 3H, CH 3), 7.30 (dd, 1H, J = 4.8, 7.7 Hz, H 3), 7.66 (d , 1H, J = 8.5 Hz, H8), 8.15 (dd, 1H, J = 1.5, 8.5 Hz, H7), 8.51 (bs, 1H, 112), 8.64 (broad d, 1H, J = 7.7 Hz, H4), 8.84 (d, 1H, J = 1.5 Hz, H5), 11.18 (s, 1H, NH); MS (IS) m / z 227 (M + H +).

  In the same way, the following compounds were prepared from compound Ia.1 in the presence of the corresponding alcohol: isopropyl 9H-pyrido [2,3-b] indole-6-carboxylate (Ia.3); Yield = 90%; Mp = 183-184 ° C (Et2O / PE); 1H NMR (300 MHz, acetone-d6) δ 1.34 (d, 6H, J = 6.2 Hz, CH3), 5.20 (septuplet, 1H, CH), 7.24 (dd, 1H, J = 4.8, 7.8 Hz, H3), 7.60 (d, 1H, J = 8.5 Hz, 118), 8.10 (dd, 1H); , J = 1.6, 8.5 Hz, H7), 8.44 (dd, 1H, J = 1.5, 4.8 Hz, 112), 8.56 (dd, 1H, J = 1.5 7.8 Hz, H4), 8.80 (d, 1H, J = 1.6 Hz, H5), 11.12 (s, 1H, NH); MS (IS) m / z 255 (M + H +). 9H-pyrido [2,3-b] indole-6-carboxylate propyl (Ia.4) 9H-pyrido [2,3-b] indole-6-carboxylic acid butyl ester (Ia.5) 9H-pyrido [2, 3-b] indole-6-carboxylate cyclohexyl (Ia.6) 9H-pyrido [2,3-b] indole-6-carboxylate phenyl (Ia.7) 9H-pyrido [2,3-b] indole- Benzoyl (Ia.8) 9H-pyrido [2,3-b] indole-6-carboxylic acid 3-pyridinyl ester (Ia.9) 9H-pyrido [2,3-b] indole-6-carboxylate aminomethyl-3-methylbutyl (Ia.10) Example 3: N-Methyl9H-pyrido [2,3-b] indole-6-carboxamide (Ib.1) A solution of compound Ia.1 (30 mg, 0.13 mmol ) and 33% methylamine in ethanol (5 ml) is heated in a sealed tube for 3 days. After room return, the ethanol is evaporated. The resulting residue is purified by silica column chromatography (98: 2 CH 2 Cl 2 / MeOH) to give compound Ib (1 mg, 36%). Mp> 285 ° C; 1H NMR (300MHz, CD3OD + D2O) δ 2.98 (s, 3H, CH3), 7.27 (dd, 1H, J = 5.0, 7.7Hz, 113), 7.56 (d. , 1H, J = 8.6 Hz, 118), 7.96 (dd, 1H, J = 1.8, 8.6 Hz, H7), 8.40 (dd, 1H, J = 1.3, 4). , 9 Hz, H2), 8.50 (dd, 1H, J = 1.3, 7.7 Hz, H4), 8.22 (d, 1H, J = 1.3 Hz, H5); MS (IS) m / z 226 (M + H +).

  In the same manner, the following compounds were prepared from compound Ia.l in the presence of the corresponding amine: N-propyl-9H-pyrido [2,3-b] indole-6-carboxamide (Ib.2) N, N-diethyl-9H-pyrido [2,3-b] indole-6-carboxamide (Ib.3) N-pyridinyl-9Hpyrido [2,3-b] indole-6-carboxamide (Ib.4) N- cyclohexyl-9H-pyrido [2,3-b] indole-6-carboxamide (Ib) N- (pyridin-3-yl) -9H-pyrido [2,3-b] indole-6-carboxamide (Ib. 6) N-phenyl9H-pyrido [2,3-b] indole-6-carboxamide (Ib.7) N- (1-hydroxymethyl-2-methylpropyl) -9H-pyrido [2,3-b] indole-6- carboxamide (Ib.8) - N- (2-hydroxyethyl) -9H-pyrido [2,3-b] indole-6-carboxamide (Ib.9); Yield = 56%; Mp> 210 ° C (acetone); 1H NMR (300 MHz, DMSO-d6) b 3.38 (q, 2H, J = 5.9 Hz, CH 2), 3.55 (q, 2H, J = 5.9 Hz, CH 2), 4, 75 (t, 1H, J = 5.5Hz, OH), 7.26 (dd, 1H, J = 4.9, 7.7Hz, H3), 7.51 (d, 1H, J = 8, 5 Hz, H8), 7.99 (dd, 1H, J = 1.5, 8.5 Hz, H7), 8.41 (t, 1H, J = 5.5 Hz, NH), 8.45 ( dd, 1H, J = 1.5, 4.9 Hz, H2), 8.53 (d, 1H, J = 7.7 Hz, H4), 8.72 (s, 1H, H5), 12.04 (s, 1H, NH); MS (IS) m / z 275 (M + H +).

  N- [2- (dimethylamino) ethyl] -9H-pyrido [2,3-b] indole-6-carboxamide (Ib.10) N- [2- (4-morphonyl) ethyl] -9H-pyrido [2, 3-b] indole-6-carboxamide (Ib.ll) Example 4: Methyl 9H-pyrido [2,3-b] indole-5-carboxylate (Ic.l) Under an inert atmosphere, a mixture of 9- (benzenesulphonyl) ) -9H-pyrido [2,3-b] indole-5-carboxylic acid methyl ester 6 (100 mg, 0.27 mmol) and 1M tetrabutylammonium fluoride (0.33 mL, 0.33 mmol) in THF ( 10 ml) is refluxed for 1 hour. After cooling, the THF is evaporated under reduced pressure. The residue taken up in a H2O / CH2Cl2 mixture (10 ml, 1: 1) is extracted. The organic phase is dried over MgSO 4 and evaporated under reduced pressure. The solid is recrystallized from methanol to give compound Ic.1 (55 mg, 90%). Mp = 206-208 ° C (MeOH); 1H NMR (300 MHz, CDCl3) b 4.06 (s, 3H, CH3), 7.26 (dd, 1H, J = 4.8, 7.7 Hz, H3), 7.53 (t, 1H, J = 7.6Hz, Hrr), 7.77 (d, 1H, J = 7.6Hz, Hrr), 7.97 (d, 1H, J = 7.6Hz, HAr), 8.58 ( broad, 1H, J = 4.8 Hz, H2), 9.29 (dd, 1H, J = 1.0, 7.7 Hz, H4), 12.07 (s, 1H, NH); MS m / z 227 (M + H +) + In the same manner as in Example 2, the following compounds (Ic) were prepared from compound Ic.l in the presence of the corresponding alcohol: 9H-pyrido [ 2,3-b] indole-5-butyl carboxylate (Ic.2) propyl 9H-pyrido [2,3-b] indole-5-carboxylate (Ic.3) 9H-pyrido [2,3-b] cyclohexyl indole-5-carboxylate (Ic.sub.4) 9H-pyrido [2,3-b] indole-5-carboxylic acid (Ic.sub.5) 9H-pyrido [2,3-b] indole-5-carboxylate benzyl (Ic.sub.6) 9H-pyrido [2,3-b] indole-5-carboxylic acid 3-pyridinyl ester (Ic.sub.7) 9H-pyrido [2,3-b] indole-5-carboxylate 2-aminomethyl-3- methylbutyl (Ic.8) In the same manner as in Example 3, the following compounds (Id) were prepared from compound Ic.1 in the presence of the corresponding amine: N-methyl-9H-pyrido [2 , 3-b] indole-6-carboxamide (Id.1) N-propyl-9H-pyrido [2,3-b] indole-5-carboxamide (Id.2) N, N-diethyl-9H-pyrido [2] , 3-b] indole-6-carboxamide (Id.3) N-pyridinyl-9Hpyrido [2,3-b] indole-6-carboxamide (Id.4) N-cyclohexyl-9H-pyrido [2,3] b) Indol-6-carboxamide (Id. 5) N-phenyl-9H-pyrido [2,3-b] indole-6-carboxamide (Id.6) N- (pyridin-3-yl) 9H-pyrido [ 2,3-b] indole-6-carboxamide (Id. 7) - N- (1-hydroxymethyl-2-methylpropyl) -9H-pyrido [2,3-b] indole-6-carboxamide (Id. N- (2-Hydroxyethyl) -9H-pyrido [2,3-b] indole-6-carboxamide (Id.9) N- [2- (dimethylamino) ethyl] -9H-pyrido [2,3-b] indole Ethyl 5-ethyl-9-chloro-9H-pyrido [2,3-b-foil-6-carboxylate (Ia.11) a) N-Oxide 9H-pyrido [2,3-carboxamide (Id. b] Indole-6-carboxylic acid ethyl ester (7) Under an inert atmosphere, meta-chloroperbenzoic acid (522 mg, 2.1 mmol) is added to a solution of compound Ia.l (330 mg, 1.38 mmol). ) in acetone (25 ml). The reaction mixture is stirred at room temperature overnight. The precipitate which appeared during the stirring was collected on sintered and washed with Et2O. Compound 7 (228 mg) is thus isolated with a yield of 69%. Mp> 210 ° C (washing Et2O); 1 H NMR (300 MHz, DMSO-d 6) δ 1.37 (t, 3H, J = 7.4 Hz, CH 3), 4.37 (q, 2H, J = 7.4 Hz, CH 2), 7.29 (t, 1H, J = 6.6 Hz, H3), 7.64 (d, 1H, J = 8.7 Hz, H8), 8.13 (d, 1H, J = 8.7 Hz, H7) , 8.36 (d, 1H, J = 7.9Hz, H2), 8.41 (d, 1H, J = 6.2Hz, H4), 8.90 (s, 1H, H5), 13, 03 (s, 1H, NH).

  b) Ethyl 4-chloro-9H-pyrido [2,3-b] indole-6-carboxylate (Ia.11) Under an inert atmosphere, a solution of compound 7 (40 mg, 0.16 mmol) in POC13 (10 ml) is refluxed for 4 hours. After cooling, POC13 is evaporated. The residue is taken up in an H2O / AcOEt mixture (10 ml, 1: 1) to carry out the extraction. The organic phase is dried over MgSO 4 and evaporated under reduced pressure. The solid is recrystallized from ethanol to give compound la (42 mg, 98%). Mp> 210 ° C (EtOH); 1 H NMR (300 MHz, DMSO-d6) δ 1.37 (t, 3H, J = 7.4 Hz, CH 3), 4.37 (q, 2H, J = 7.4 Hz, CH 2), 7.42. (d, 1H, J = 5.5Hz, H3), 7.65 (d, 1H, J = 8.5Hz, H8), 8.16 (d, 1H, J = 8.5Hz, H7) , 8.46 (d, 1H, J = 5.4 Hz, H 2), 8.96 (s, 1H, H 5), 12.64 (s, 1H, NH); MS (IS) m / z 275 (M + H +, 35Cl), 277 (M + H +, 37Cl).

  Example 6: 4-Chloro-N- (2-hydroxyethyl) -9H-pyrido [2,3-b] indole-6-carboxamide (Ib.12) A solution of compound Ia.11 (20 mg, 0.07 mmol), Aminoethanol (0.22 ml, 0.38 mmol) and NaH (4 mg, 0.15 mmol) in dioxane are heated at 100 ° C in a sealed tube for 2 h. After returning to ambient temperature, the hydrolysis is carried out by adding a few drops of H2O. The solvents are evaporated under reduced pressure. The residue is taken up in an H2O / AcOEt mixture (10 ml, 1: 1) to carry out the extraction. The organic phase is dried over MgSO 4 and evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica column (99: 1 CH2Cl2 / MeOH) to give (Ib) (21 mg, 100%). Mp> 210 ° C (MeOH); 1 H NMR (300 MHz, DMSO-d 6) δ 3.38 (q, 2H, J = 5.9 Hz, CH 2), 3.55 (q, 2H, J = 5.9 Hz, CH 2), 4, 75 (t, 1H, J = 5.5Hz, OH), 7.39 (d, 1H, J = 5.4Hz, H3), 7.58 (d, 1H, J = 8.5Hz, H8) ), 8.08 (dd, 1H, J = 1.5, 8.5 Hz, H7), 8.42 (d, 1H, J = 5.4 Hz, H2), 8.56 (t, 1H, J = 5.5 Hz, NH), 8.87 (s, 1H, H5), 12.44 (s, 1H, NH); MS (IS) m / z 289 (M + H +, 35Cl), 291 (M + H +, 37Cl).

  Example 7: Ethyl 2-trifluoromethylsulfonyl-9H-pyrido [2,3-b] indole-6-carboxylate (10) a) 2-Acetoxy-9-acetyl-9H-pyrido [2,3-b] indole-6-carboxylate (8) A solution of compound 7 (100 mg, 0.39 mmol) and acetic anhydride (5 ml) is refluxed for 2 hours. After returning to ambient temperature, the solvent is evaporated under reduced pressure. The residue is taken up in an H2O / AcOEt mixture (10 ml, 1: 1) to carry out the extraction. The organic phase is dried over MgSO 4 and evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica column (EP / AcOEt 8: 2 then 1: 1) to give 8 (80 mg, 60%). 1 H NMR (300 MHz, CDCl 3) δ 1.46 (t, 3H, J = 7.0 Hz, CH 3), 2.40 (s, 3H, COCH 3), 3.09 (s, 3H, COCH 3), 4.44 (q, 2H, J = 7.0 Hz, CH 2), 7.12 (d, 1H, J = 8.2 Hz, H 3), 8.23 (dd, 1H, J = 1.5, 8.8 Hz, H7), 8.40 (d, 1H, J = 8.2 Hz, H4), 8.65 (d, 1H, J = 1.5 Hz, H5), 8.74 (d, 1H, J = 8.8 Hz, H5); MS (IS) m / z 341 (M + H +).

  b) Ethyl 2-Oxo-2,9-dihydro-1H-pyrido [2,3-b] indole-6-carboxylate (9) Under an inert atmosphere, sodium (14 mg, 0.61 mmol) is added in small portions to a solution of compound 8 (80 mg, 0.24 mmol) in ethanol (5 mL). The final solution is refluxed for 20 minutes. After returning to ambient temperature, the solvent is evaporated under reduced pressure. The residue is taken up in an H2O / AcOEt mixture (10 ml, 1: 1) to carry out the extraction. The organic phase is dried over MgSO 4 and evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica column (95: 5 CH2Cl2 / MeOH) to give 9 (51 mg, 84%). Mp> 210 ° C (EtOH); 1 H NMR (300 MHz, DMSO-d 6) δ 1.35 (t, 3H, J = 7.4 Hz, CH 3), 4.34 (q, 2H, J = 7.4 Hz, CH 2), 6, 46 (d, 1H, J = 8.3 Hz, H3), 6.89 (s, 1H, NH), 7.47 (d, 1H, J = 8.5 Hz, H8), 7.92 (dd , 1H, J = 1.3, 8.5 Hz, H7), 8.42 (d, 1H, J = 8.3 Hz, H4), 8.60 (bs, 1H, H5), 11, 85 (s, 1H, NH); MS (IS) m / z 257 (M + H +).

  c) Ethyl 2-trifluoromethylsulfonyl-9H-pyrido [2,3-b] indole-6-carboxylate (10) at 0 ° C. and under argon, trifluoromethanesulphonic anhydride (50 l, 0, 30 mmol) is added to a solution of compound 9 (50 mg, 0.20 mmol) and 4-dimethylaminopyridine (24 mg, 0.20 mmol) in pyridine (9 ml). The solution is stirred at ambient temperature for 20 hours. After evaporation of the pyridine, the residue obtained is purified by chromatography on a silica column (EP / AcOEt 8: 2) to give 10 (60 mg, 79%). Mp 203-205 ° C; 1 H NMR (300 MHz, DMSO-d 6) δ 1.37 (t, 3H, J = 7.4 Hz, CH 3), 4.37 (q, 2H, J = 7.4 Hz, CH 2), 7, 40 (d, 1H, J = 8.3Hz, H3), 7.64 (d, 1H, J = 8.5Hz, H8), 8.14 (dd, 1H, J = 1.3, 8, 5 Hz, H7), 8.95 (bs, 1H, H5), 9.03 (d, 1H, J = 8.3 Hz, H4), 12.64 (s, 1H, NH); MS (IS) m / z 389 (M + H +).

  Example 8 Ethyl 2- (4-methoxybenzylamino) -9H-pyrido [2,3-b] indole-6-carboxylate (Ia.12) Triflate 10 (40 mg, 0.10 mmol) and 4methoxybenzylamine (40 0.30 mmol) in dry acetonitrile (2 ml) are refluxed for 72 hours. After evaporation of the solvent, the residue is taken up in an H2O / AcOEt mixture (10 ml, 1: 1) to carry out the extraction. The organic phase is washed with a solution of NaHCO 3, dried over MgSO 4 and evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica column (EP / AcOEt 7: 3) to give compound Ia.12 (22 mg, 60%). 1H NMR (300 MHz, CDCl3 + D2O) δ 1.44 (t, 3H, J = 7.4 Hz, CH3), 3.80 (s, 3H, CH3O), 4.42 (q, 2H, J); = 7.4 Hz, CH2), 4.56 (bs, 2H, CH2), 6.39 (d, 1H, J = 8.5 Hz, H3), 6, 89 (d, 2H, J = 8; , 7 Hz, HAr), 7.32 (d, 2H, J = 8.7 Hz, HAr), 7.44 (d, 1H, J = 8.7 Hz, 118), 8.06 (dd, 1H). , J = 1.5, 8.5 Hz, H7), 8.15 (d, 1H, J = 8.5 Hz, 114), 8.56 (bs, 1H, 115); MS (IS) m / z 376 (M + H +).

  In the same manner as in Example 8, the following compounds were prepared from ethyl 2-trifluoromethylsulfonyl-9H-pyrido [2,3-b] indol-6-carboxylate in the presence of the corresponding amine: Ethyl-amino-9H-pyrido [2,3-b] indole-5-carboxylate ethyl (Ia.13) 2-ethylamino-9H-pyrido [2,3-b] indole-5-carboxylate (Ia.14 ) Ethyl 2morpholino-9-H-pyrido [2,3-b] indole-5-carboxylate (Ia.15) ethyl 2-piperidino-9H-pyrido [2,3-b] indole-5-carboxylate (Ia.16) Ethyl 2-piperazino-9H-pyrido [2,3-b] indole-5-carboxylate (la) -17- (2-hydroxyethylamino) -9H-pyrido [2,3-b] ethyl indole-5-carboxylate (Ia.18) Example 9 2- (4-methoxybenzylamino) -N-methyl-9H-pyrido [2,3-b] indole-6-carboxamide (Ib.13) One solution Compound Ia.12 (20 mg, 0.05 mmol) and 33% methylamine in ethanol (5 mL) was heated in a sealed tube for 3 days. After returning to ambient temperature, the ethanol is evaporated. The residue obtained is purified by chromatography on a silica column (CH 2 Cl 2 / MeOH 98: 2) to give Ib 13 (11 mg, 60%). 1H NMR (300 MHz, CD3OD) δ 2.95 (s, 3H, CH3), 3.73 (s, 3H, CH3O), 4.60 (bs, 2H, CH2), 6.25 (d, 1H) , J = 8.5 Hz, H3), 6.92 (d, 2H, J = 8.6 Hz, HAr), 7.27 (d, 2H, J = 8.6 Hz, HA). , 40 (d, 1H, J = 8.6 Hz, H8), 8.10 (dd, 1H, J = 1.4, 8.6 Hz, H7), 8.09 (d, 1H, J = 8 , 5Hz, H4), 8.63 (brs, 1H, H5); MS (IS) m / z 361 (M + H +).

  In the same manner, the following compounds were prepared from the above compounds in the presence of the corresponding amine: 2-amino-N-methyl-9H-pyrido [2,3-b] indole-5-carboxamide ( Ib.14) 2-methylamino-N-methyl-9H-pyrido [2,3-b] indole-5-carboxamide (Ib.15) 2-morpholino-N-methyl-9-H-pyrido [2,3-b] b] indole-5-carboxamide (Ib.16) 2-piperidino-N-methyl-9H-pyrido [2,3-b] indole-5-carboxamide (Ib.17) 2-piperazino-N-methyl-9H- pyrido [2,3-b] indole-5-carboxamide (Ib.18) 2- (2-hydroxyethylamino) -N-methyl-9H-pyrido [2,3-b] indole-5-carboxamide (Ib.19) Example 10 Ethyl 2-Phenyl-9H-pyrido [2,3-b] indole-6-carboxylate (Ia.19) To a solution of compound 10 (32 mg, 0.08 mmol) in 3 ml of toluene Anhydrous is added the tetrakis (triphenylphosphine) palladium (5 mg, 0.004 mmol) freshly prepared. The solution is stirred for 15 minutes at room temperature. The phenylboronic acid (16 mg, 0.12 mmol), diluted in absolute ethanol (1 ml) is then added, followed immediately by a saturated solution of sodium hydrogencarbonate (1 ml). The heterogeneous solution is vigorously stirred at 80 ° C overnight. After cooling, a saturated solution of sodium chloride is added and the two phases are separated. The aqueous phase is extracted twice with dichloromethane. The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by flash chromatography on silica gel (PE / AcOEt 8: 2) to give Ia.19 (20 mg, 75%). Mp> 210 ° C (EtOH). 1 H NMR (300 MHz, DMSO-d 6) δ 1.38 (t, 3H, J = 7.4 Hz, CH 3), 4.37 (q, 2H, J = 7.4 Hz, CH 2), 7, 45-7.56 (m, 3H, Hphe), 7.58 (d, 1H, J = 8.6 Hz, H8), 7.89 (d, 1H, J = 8.1 Hz, H3), 8 , 08 (dd, 1H, J = 1.5, 8.6 Hz, H7), 8.20 (d, 2H, J = 7.83 Hz, Hphe), 8.77 (d, 1H, J = 8). , 1 Hz, H4), 8.85 (d, 1H, J = 1.5 Hz, 1H, H5), 12.31 (s, 1H, NH); MS (IS) m / z 317 (M + H +).

  In the same manner as in Example 10, the following compounds were prepared from ethyl 2-trifluoromethylsulfonyl-9H-pyrido [2,3-b] indole-6-carboxylate in the presence of the corresponding boronic acid or Zn (CN) 2: - Ethyl 2- (2-thienyl) -9H-pyrido [2,3-b] indole-5-carboxylate (Ia.20) -2- (2-furanyl) -9H-pyrido Ethyl [2,3-b] indole-5-carboxylate (Ia.21) ethyl 2- (3-thienyl) -9H-pyrido [2,3-b] indole-5-carboxylate (Ia.22) ) Ethyl 2-cyano-9-H-pyrido [2,3-b] indole-5-carboxylate (Ia.23)

DESCRIPTION OF BIOCHEMICAL TESTS

  Biochemical reagents The following reagents: sodium ortho-vanadate, EGTA, EDTA, Mops, 13.- glycerophosphate, phenylphosphate, sodium fluoride, dithiothreitol (DTT), glutathione-agarose, glutathione, bovine serum albumin (BSA), nitrophenylphosphate , leupeptin, aprotinin, pepstatin, trypsin inhibiting soybean, benzamidine, histone H1 (type III-S) are from Sigma Chemicals. [y32P] -ATP (PB 168) was purchased from Amersham. The peptide GS-1 (YRRAAVPPSPSLSRHSSPHQSpEDEEE) was synthesized by the Peptide Synthesis Unit of the Institute of Biomolecular Sciences of the University of Southampton, Southampton S016 7PX, UK Buffer Solutions: Homogenization Buffer: 60 mM (3- glycerophosphate, 15 mM pnitrophenylphosphate, 25 mM Mops (pH 7.2), 15 mM EGTA, 15 mM MgCl2, 1mM DTT, 1 mM sodium vanadate, 1 mM NaF, 1 mM phenylphosphate, 10 g leupeptin / ml, 10 g aprotinin / ml, 10 g soybean, trypsin inhibitor / ml and M benzamidine.

  Buffer for the beads: 50 mM Tris pH 7.4, 5 mM NaF, 250 mM NaCl, 5 mM EDTA, 5 mM EGTA, 0.1% Nonidet P-40, 10 μg leupeptin / ml, 10 μg aprotinin / ml, 10 g soybean, trypsin inhibitor / ml and 100 M benzamidine.

  Buffer A: 10 mM MgCl 2, 1 mM EGTA, 1 mM DTT, 25 mM Tris-HCl pH 7.5, 50 g heparin / ml.

  Buffer C: homogenization buffer, but with 5 mM EGTA, no NaF, or protease inhibitor.

  TBST buffer: 50 mM Tris pH 7.4, 150 mM NaCl, 0.1% Tween-20.

  Hypotonic lysis buffer (HLB): 50 mM Tris-HCl pH 7.4, 120 mM NaCl, 10% glycerol, 1% Nonidet-P40, 5 mM DTT, 1 mM EGTA, 20 mM NaF, 1 mM orthovanadate, 5 gM microcystin, 100 μg / ml leupeptin, 100 μg / ml aprotinin, 100 μg / ml pepstatin.

  Kinase Preparation and Testing: Kinase activity is assayed in buffers A or C (unless otherwise indicated), at 30 ° C and at a final concentration of ATP of 15 mol. The control values are subtracted and the activities calculated per pmoles of phosphate incorporated for 10 minutes of incubation. Activities are usually expressed as a percentage of maximum activity, ie, in the absence of an inhibitor. The controls are carried out with appropriate dilutions of dimethylsulfoxide. In some cases, phosphorylation of the substrate is determined by autoradiography after SDS-PAGE.

  GSK-3 (i is purified from porcine brains (Primot A. et al, Protein Expression, Purification 2000, 20, 394-404) The tests are carried out by carrying out a dilution of 1/1000 in 1 mg of BSA 10 mM DTT with 5 l of 40 M GS-1 peptide as substrate, in buffer A, in the presence of 15 M of γ-32 P ATP (3000 Ci / mmol, 1 mCi / ml) in a total volume of 30 L. After 30 minutes of incubation at 30 ° C., 25 μl of supernatant aliquots are deposited on 2.5 × 3 cm samples of Whatman P81 phosphocellulose paper and after 20 s, the filters are washed. 5 times (for at least 5 minutes each) with a solution of 10 ml of phosphoric acid per liter of water The wet filters are then analyzed in the presence of 1 ml of scintillation fluid ACS (Amersham).

  CDK1 / cyclin B: The activity of the CDK1 / cyclin B complex is evaluated by phophorylation of a histone H1 by ATP-32. The appearance of phophorylated histone H1 in the presence of inhibitors of the enzyme CDK1 is determined by counting the radioactivity.

  The CDK1 / cyclin B is extracted into the homogenization buffer from the M phase of starfish oocytes (Marthasterias glacialis) and purified by affinity chromatography on P9exshsI-sepharose beads which are eluted by free P9cxshsi. as previously described by Leclerc, S. et al., J. Biol. Chem. 2001, 276, 251-260 and Leost, M. et al., Eur. J. Biochem. 2000, 267, 5983-5994. The kinase activity was tested in buffer C with 1 mg histone H1 / ml, in the presence of 15 gM [γ-32 P] ATP (3000 Ci / mmol, 1 mCi / ml) in a final volume of 30 l. After 10 minutes of incubation at 30, 25 l of aliquots of the supernatant are deposited on P81 phosphocellulose papers and treated as previously described.

  CDK5 / p25 is reconstituted by mixing equivalent amounts of recombinant mammalian CDK5 and p25 expressed in E. coli as a GST (Glutathione-S-transferase) fusion protein and purified by affinity chromatography on glutathione sucrose (vector provided by Dr. JH Wang) (p25 is a truncated version of p35, the 35 kDa activator of CDK5). The activity is then measured in buffer C as previously described for CDK1 / cyclin B. The compounds of the present invention were tested according to the CDK1 / cyclin B, CDK5 and GSK-3 tests (3 previously described.) All compounds tested showed some significant inhibition of kinase activity, some of which showed a selectivity of inhibition against kinases tested.

  The compounds according to the invention have, most often, an IC 50 with respect to CDK1, CDK5 and GSK-3R of between 0.1 and 10 M.

Claims (11)

CLAIMS:   1 - Compound of formula (I): (I) in which: - Ro and RI represent, each independently of one another, a hydrogen or halogen atom, or a group chosen from -CN, - OH, aryl, heteroaryl, methyl, alkenyl, -OCORa, -NRaRb, -NHCORa, -NHSO2Ra, -NHCONRaRb, -NHCOORa or -NHSO2Ra, with Ra and Rb each independently of one another an atom of hydrogen, or an optionally substituted group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkenyl, heterocycloalkylalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, or Ra and Rb are bonded together to form with the nitrogen atom to which they are bonded an optionally substituted heterocycle selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, - one of the groups R2 or R3 represents a group -C (O) Rc, and the other R2 group or R3 represents a hydrogen atom or an optionally substituted alkyl, with: R, selected from -ORd, -NRaRb, or -NHSO2Ra, with Rd which represents an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, heteroarylalkyl, - (CH2) n-NRaRb, - (CH2) n -NHCORa, - (CH2) n -NHSO2Ra, n integer between 1 and 6 and Ra and Rb as defined above, as well as their salts pharmaceutically acceptable.   Compounds according to claim 1, characterized in that R2 or R3 represents a C (O) ORd group, with Rd as defined in claim 1.   3 - Compounds according to claim 1 characterized in that R2 or R3 represents a C (O) NRaRb group, with Ra and Rb as defined in claim 1. 4 - Compounds according to claim 1 or 2 of formula (Ia) R1 C (O) ORd with Ro, R1 and Rd as defined in claim 1, as well as their pharmaceutically acceptable salts.   - Compounds according to claim 1 or 3 of formula (Ib): C (O) NRaRb with Ro, R1, Ra and Rb as defined in claim 1, as well as their pharmaceutically acceptable salts.   6 - Compounds according to claim 1 or 2 of formula (Ie): C (O) ORd with Ro, RI and Rd as defined in claim 1, as well as their pharmaceutically acceptable salts.   7 - Compounds according to claim 1 or 3 of formula (Id): with Ro, R1, Ra and Rb as defined as defined in claim 1, and their pharmaceutically acceptable salts.   8 - Compounds according to one of claims 1 to 7 characterized in that RI 5 represent a hydrogen atom or a halogen atom, especially a chlorine atom.   9 - Compounds according to one of claims 1 to 7 characterized in that Ro is selected from -NH2, phenyl, morpholinyl, piperazinyl, piperidinyl, thienyl, (preferably 2- or 3-thienyl), cyano, furanyl (preferably 2-furanyl), -NHRa with Ra which represents an alkyl or arylalkyl group, preferably an optionally substituted methyl, ethyl or benzyl group, for example a hydroxy or methoxy group.   Compounds according to claim 2, 4 or 6, characterized in that Rd represents a cycloalkyl, aryl, heteroaryl, arylalkyl group, or an alkyl group optionally substituted with an alkylamino group.   11 - Compounds according to claim 3, 5 or 7 characterized in that Ra and Rb each independently represent a hydrogen atom or a cycloalkyl, aryl, heteroaryl group, or an alkyl group optionally substituted by a hydroxy, dialkylamino, morpholinyl group.   12 - Compound according to claim 1, chosen from: methyl 9H-pyrido [2,3-b] indole-6-carboxylate (Ia.) 9H-pyrido [2,3-b] indole-6-carboxylic acid methyl ester (Ia.2) Propyl isopropyl 9H-pyrido [2,3-b] indole-6-carboxylate (Ia.3) propyl 9H-pyrido [2,3-b] indole-6-carboxylate (Ia.4) Cyclohexyl 9H-pyrido [2,3-b] indole-6-carboxylate (Ia.5) 9H-pyrido [2,3-b] indole-6-carboxylate (Ia.6) 9H-pyrido [2, Benzyl (Ia.7) 9H-pyrido [2,3-b] indole-6-carboxylate (Ia.7) 9H-pyrido [2,3-b] indole-3-b] indole-6-carboxylate 2-Aminomethyl-3-methylbutyl (Ia. 10) -N-methyl-9H-pyrido [2-methyl-9H-pyrido [2,3-b] indol-6-carboxylic acid-6-carboxylate (Ia.9) , 3-b] indole-6-carboxamide (Ib.1) N-propyl-9H-pyrido [2,3-b] indole-6-carboxamide (Ib.2) N, N-diethyl-9H-pyrido [2] , 3-b] indole-6-carboxamide (Ib.3) -N-pyridinyl-9H-pyri [2,3-b] indol-6-carboxamide (Ib) Ncyclohexyl-9H-pyrido [2, 3-b] indole-6-carboxamide (Ib) N- (pyridin-3-yl) -9H-pyrido [2,3-b] indole-6-carboxamide (Ib) N-phenyl-9H -pyrido [2,3-b] indole-6-carboxamide (Ib.7) N- (1-hydroxymethyl-2-methylpropyl) -9H-pyrido [2,3-b] indole-6-carboxamide (Ib.8) N- (2-hydroxyethyl) -9H-pyrido [2,3-b] indole-6-carboxamide (Ib.9) 20-N- [2- (dimethylamino) ethyl] -9H-pyrido [2,3] b) Indole-6-carboxamide (Ib.10) - N- [2- (4-morphonyl) ethyl] -9H-pyrido [2,3-b] indole-6-carboxamide (Ib.ll) 9H-pyrido Methyl [2,3-b] indole-5-carboxylate (Ic.l) 9H-pyrido [2,3-b] indole-5-carboxylic acid (Ic.2) 9H-pyrido [2,3-b] ] cyclohexyl (Ic.4) 9H-pyrido [2,3-b] indole-5-carboxylate indole-5-carboxylate (Ic.sub.3) 9H-pyrido [2,3-b] indole-5-carboxylate benzyl (Ic.sub.6) -9H-pyrido [2,3-b] indole-5-carboxylic acid (Ic.sub.6) -3H-pyridinyl-9H-pyrido [2,3-b] indole-5-carboxylate (Ic. 7) - 2-Aminomethyl-3-methylbutyl-9H-pyrido [2,3-b] indole-5-carboxylate (Ic.8) N-methyl-9H-pyrido [2,3-b] indole-6-carboxamide (Id.l) N, N'-dihydro-9H-pyrido [2,3-b] indole-5-carboxamide (Id.2) N, N-diethyl-9H-pyrido [2,3-b] indole-6-carboxamide (Id.3) N-pyridinyl-9 H -pyrido [2,3-b] indole-6-carboxamide (Id.4) N-cyclohexyl-9Hpyrido [2,3-b] indole-6-carboxamide (Id.5) N-phenyl-9H-pyrido [ 2,3-b] indole-6-carboxamide (Id.6) N- (pyridin-3-yl) -9H-pyrido [2,3-b] indole-6-carboxamide (Id.7) - N- ( 1-Hydroxymethyl-2-methylpropyl) -9H-pyrido [2,3-b] indole-6-carboxamide (Id.8) - N- (2-hydroxyethyl) -9H-pyrido [2,3-b] indole- 6-carboxamide (Id.9) N- [2- (dimethylamino) ethyl] -9H-pyrido [2,3-b] indole-6-carboxamide (Id.10) 4-chloro-9H-pyrido [2,3] ethyl (4-chloroN- (2-hydroxyethyl) -9H-pyrido [2,3-b] indole-6-c arboxamide (Ib.12) 2- (b) indol-6-carboxylate Ethyl 4-methoxybenzylamino) -9H-pyrido [2,3-b] indo-6-c arboxylate (Ia. 12) Ethyl 2-amino-9H-pyrido [2,3-b] indole-5-carboxylate (Ia.13) 2-methylamino-9H-pyrido [2,3-b] indole-5-carboxylate ethyl (Ia.14) 2-morpholino-9-H-pyrido [2,3-b] indole-5-carboxylic acid ethyl (lai 5) 2-piperidino-9H-pyrido [2,3-b] indole- Ethyl 5-carboxylate (lad 6) 2-piperazino-9H-pyrido [2,3-b] indole-5-carboxylate ethyl (lad 7) 2- (2-hydroxyethylamino) -9H-pyrido [2, Ethyl 3-b] indole-5-carboxylate (Ia.18) Ethyl 2- (2-phenyl) -9H-pyrido [2,3-b] indole-5-carboxylate (Ia.19) - 2 Ethyl (2-thienyl) -9H-pyrido [2,3-b] indole-5-carboxylate (Ia.20) 2- (2-furanyl) -9H-pyrido [2,3-b] indole- Ethyl 5-carboxylate (Ia.21)  Ethyl 2- (3-thienyl) -9H-pyrido [2,3-b] indole-5-carboxylate (Ia.22) 2-cyano-9-H-pyrido [2,3-b] indole-5 ethylcarboxylate (Ia.23) 2- (4-methoxybenzylamino) -N-methyl-9H-pyrido [2,3-b] indole-6-carboxamide (Ib.13) -2-amino-N-methyl -9H-pyrido [2,3-b] indole-5-carboxamide (Ib.14) -2-methylamino-N-methyl-9H-pyrido [2,3-b] indole-5-carboxamide (Ib.15) 2-Morpholino-N-methyl-9-H-pyrido [2,3-b] indole-5-c arboxamide (Ib.16) 2-piperidino-N-methyl-9H-pyrido [2,3-b] indole 5-carboxamide (Ib.17) 2-piperazino-N-methyl-9H-pyrido [2,3-b] indole-5-carboxamide (Ib.18) 2- (2-hydroxyethylamino) -N-methyl-9H -pyrido [2,3-b] indole-5-carboxamide (Ib.19) and their pharmaceutically acceptable salts.   13 - Compounds according to one of claims 1 to 12 as a medicament.   14 - Pharmaceutical composition containing one of the compounds according to one of claims 1 to 13, in combination with at least one pharmaceutically acceptable excipient.   - Use of a compound according to one of claims 1 to 13 for the manufacture of a medicament for the treatment or prevention of cancers, Alzheimer's disease, Parkinson's disease, vascular accidents cerebral, amyotrophic lateral sclerosis (ALS), viral infections, autoimmune diseases, and neurodegenerative disorders.