MXPA06011160A - Novel benzothiazoles and the use thereof as medicaments - Google Patents

Abstract

The invention especially relates to novel chemical compounds, especially novel benzothiazole derivatives, to compositions containing said compounds, and to the use thereof as medicaments.

Description

NEW BENZOTIAZOOLS AND THEIR USE AS MEDICINES The present invention relates mainly to new chemical compounds, especially new benzothiazole derivatives, compositions containing them, and their use as medicaments. More especially, the invention relates to new sulphonic esters of benzothiazoles having an anti-cancer activity, by modulating the activity of proteins, in particular of kinases. Until now, most of the commercial compounds used in chemotherapy are cytotoxic compounds that pose significant problems of side effects and tolerance for patients. These effects could be limited to the extent that the drugs used act selectively on the cancer cells, excluding healthy cells. One of the solutions to limit the undesirable effects of a chemotherapy can consist, therefore, in the use of drugs that act on metabolic routes or on constitutive elements of these routes, expressed mostly in cancer cells, and that are not expressed, or they are expressed minorityly in healthy cells. Protein kinases are a family of enzymes that catalyze the phosphorylation of hydroxyl groups of specific protein residues, such as tyrosine, serine or threonine residues. These phosphorylations can significantly modify the function of proteins; thus, protein kinases have an important role in the regulation of a wide variety of cellular processes, including mainly metabolism, cell proliferation, cell differentiation, cell migration or cell survival. Among the different cellular functions in which the activity of a protein kinase is involved, certain processes represent attractive targets for treating cancer diseases, as well as other diseases. Thus, one of the objectives of the present invention is to propose compositions that have an anti-cancer activity, which act in particular against the kinases. Among the kinases for which modulation of activity is investigated, cyclin-dependent kinases as well as Aurora-2 are preferred. The progression of the cell cycle is often directed by cyclin-dependent kinases (CDKs) that are activated by an interaction with proteins belonging to the cyclins family, activation that ends by the phosphorylation of substrates and finally by cell division. In addition, the endogenous inhibitors of the CDKs that are activated (family of INK4 and KI P / CI P) negatively regulate the activity of the CDKs. The growth of normal cells is due to a balance between the activators of the CDKs (the cyclins) and the endogenous inhibitors of the CDKs. The expression or aberrant activity of several of these cell cycle regulators has been described in numerous types of cancers. Cyclin E activates the Cdk2 kinase that then acts to phosphorylate the pRb protein (retinoblastoma protein) that results in an irreversible cell division action and a transition to the S phase (PL Toogood, Medicinal Research Reviews (2001), 21 ( 6); 487-498. CDK2 kinase and also CDK3 are necessary for progression in G1 phase and entry into S phase. During complex formation with cyclin E, they maintain hyperphosphorylation of pRb to facilitate progression from phase G1 to phase S. In complexes with Cyclin A, CDK2 plays a role in the inactivation of E2F and is necessary for the realization of phase S (TD Davies et al. (2001) Structure 9, 389 -3) The CDK1 / cyclin B complex regulates the progression of the cell cycle between the G2 phase and the M phase. The negative regulation of the CDK / Cyclin B complex prevents normal cells from entering the S phase until the G2 phase has been done correctly and completely. (K. K Roy and E.A. Sausville Current Pharmaceutical Design, 2001, 7, 1 669-1687. There is a level of regulation of the activity of the CDK. Activators of cyclin-dependent kinases (CAK) have a positive action of regulation of CDK. CAK phosphorylates the CDKs in the threonine residue to yield the fully active target enzyme. The presence of defects in the molecules that intervene in the cell cycle involves the activation of CDKs and the progression of the cycle, being normal to want to inhibit the activity of CDK enzymes to block the cell growth of cancer cells. In yeasts and in drosophila, numerous proteins involved in the segregation of chromosomes and spindle formation have been identified. The disorganization of these proteins leads to non-segregation of the chromosomes and monopolar or disorganized spindles. Among these proteins, certain kinases, such as Aurora and IpM, which come respectively from drosophila and S. cerevisiae, are necessary for the segregation of the chromosomes and the separation of the centrosome. A human analog of IpH from yeast has been cloned and recently characterized by different laboratories. This kinase, called aurora2, STK15 or BTAK belongs to the family of serine / threonine kinases. Bischoff et al. have shown that Aurora2 is an oncogene, and that it is amplified in human colorectal cancers (EMBO J, 1998, 17, 3052-3065). This has also been exemplified in cancers involving epithelial tumors such as breast cancer. The present invention relates to novel benzothiazole derivatives. It thus refers to the use of the benzothiazole derivatives as kinase inhibiting agents and, more particularly, as anticancer agents. Among these it preferably refers to the sulfonic esters of the benzothiazoles. It also refers to the use of said derivatives for the preparation of a medicament intended for the treatment of human beings. Among the prior techniques known hitherto describing the sulfonic esters of benzothiazoles, mention may be made of published patent application JP 0539036 which describes a process for the preparation of derivatives of the following general formula: wherein Y 1 may represent a sulfur atom , n can be equal to zero, Z can be an acylamino group, groups X1, X2, X3, X4, are equal to H or can represent an alkylsulfonyloxy group. Among the vast majority of the compounds included in the general formula of the previous patent none of the examples describes compounds corresponding to the active compounds according to the invention nor describes the synthesis of benzothiazoles. The compounds according to the invention correspond to the following general formula (I): wherein: X represents a group selected from a covalent bond, (CH2) n, with n equal to 1 or 2 - Ar represents an aryl or heteroaryl group; this group being optionally substituted with a group selected from the groups alkyl, halogen, NR? R2 (R1 and R2 being chosen from the groups hydrogen, alkyls, cycloalkyls or together may form a heterocyclic or heteroaryl radical, these groups themselves being optionally substituted), SO2alk, Salkyl, alkoxy, heteroaryls or aryls R represents a group selected from hydrogen, an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy or amino group; R may be optionally substituted with one or more groups selected from the same radicals as those defined for R. The optional substituents of the R- and R 2 groups are chosen primarily from the hydroxy, heteroaryl, cycloalkyl or aminoalkyls groups. It is understood in the context of the present invention by alkyl group straight or branched chains containing 1 to 10 carbon atoms. It is understood in the context of the present invention cycloalkyl group cyclic alkyl chains containing from 3 to 10 carbon atoms. It is understood in the context of the present invention by heterocycloalkyl group cyclic alkyl chains containing from 3 to 10 carbon atoms and containing at least one heteroatom chosen from O, N or S. It is understood in the context of the present invention by NRt R2 group the amino groups preferably secondary, ie the groups for which at least one of the substituents is hydrogen. All these groups are optionally substituted with an alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, amino, hydroxy, alkoxy or halogen group. It is understood in the context of the present invention by aryl and heteroaryl radicals monocyclic radicals optionally containing one or more heteroatoms chosen from O, N and S or the radicals fused to another cycle containing 5 or 6 links and optionally from one to three heteroatoms chosen from O, N and S. Preferably among the aryl or heteroaryl radicals there may be mentioned phenyl, pyridyl, pyrimidine, triazine, pyrrolyl, imidazolyl, thiazolyl, furyl, thienyl, indolyl, azaindazolyl, isobenzofuranyl, isobenzothienyl, benzoxazolyl, benzothiazolyl groups. , arylvinylene, arylamido, arylcarboxamide, aralkylamine, quinoline, isoquinoline, cinolyl, quinazolyl, naphthyridyl, triazolyl or tetrazolyl. It is preferred to choose among the aryl and heteroaryl groups the optionally substituted phenyl, thienyl, pyrazolyl or imidazolyl groups. Among substituents of the phenyl group, amino and halogen groups, in particular chlorine and fluorine, are preferred, and di and trifluorophenyls and monoalkylamino phenyls are more preferred among aryl groups, wherein the alkyl chain is optionally substituted with a hydroxy group. or dialkylamino. Furthermore, it is preferred to choose among the compounds of formula (I) those for which X represents a covalent bond and those for which R represents a cycloalkyl radical. Among the compounds of formula (I), mention may be made of the following compounds: 4- (2-hydroxy-2-methyl-propylamino) 2- (4- (2-hydroxy-2-methyl-propylamino) -3- ((piperidin-4-carbonyl) -amino] -benzothiazole-6-yl ester) -benzenesulfonic 2- (cyclopropanecarbonyl-amino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid 2- (cyclopropanecarbonylamino) -benzothiazole-6-yl acid ester 4-Cyclopentylamino-benzenesulfonic acid 2- (cyclopropanecarbonylamino) -benzothiazole-6-yl ester of 4- (3-imidazol-1-yl-propylamino) -benzenesulfonic acid 2- (cyclopropanecarbonylamino) -benzothiazole-6-yl acid ester 4-methylaminobenzenesulfonic acid 2- (cyclopropanecarbonylamino) -benzothiazole-6-yl ester of 4- (2-hydroxy-2-methyl-propylamino) -benzenesulfonic acid 2- (cyclopropanecarbonylamino) -benzothiazole-6-yl acid ester 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2- (cyclopropanecarbonylamino) -benzothiazole-6-yl ester 4- [4- (4-pyridin-3-yl-imidazol-1-yl) -butylamino] -benzenesulfonic acid ester 2- (2-piperidin-4-yl-acetylamino) -benzothiazole-6-yl ester hydrochloride - 2- (2-Piperidin-4-yl-acetylamino) -benzothiazole-6-yl ester of 4- (3-imidazol-1-yl-propylamino) -benzenesulfonic acid (2-α-propylamino-ethylamino) -benzenesulfonic acid hydrochloride 2- (2-piperidin-4-yl-acetylamino) -benzothiazole-6-yl ester of 4- (2-ethylamino-ethylamino) -benzenesulfonic acid ester 2- (2-piperidin-4-yl-acetylamino) ester hydrochloride ) 4- [2- (2-Hydroxy-ethylamino) -ethylamino] -benzenesulfonic acid 2- (2-piperidin-4-yl-acetylamino) -benzothiazole-6-yl ester acid benzothiazole-6-yl acid 4- (2-Hydroxy-2-methyl-propylamino) -benzenesulfonic acid ester 2- (8-amino-octanoylamino) -benzothiazole-6-yl ester of 4- (2-isopropylamino-ethylamino) -benzenesulfonic acid ester hydrochloride - (8-amino-octanoylamino) -benzothiazole-6-yl of 4- (3-imidazol-1-yl) -propylamino) -benzenesulfonyl ester 2- (8-amino-octanoylamino) -benzothiazole 2- (8-amino-octanoylamino) -benzothiazole-6-yl ester of 4- (2-ethylamino-ethylamino) -benzenesulfonic acid ester 2- (8-amino-octanoylamino) -benzothiazole ester hydrochloride 4- [2- (2-Hydroxy-ethylamino) -ethylamino] -benzenesulfonic acid hydrochloride 2- (8-amino-octanoylamino) -benzothiazole-6-yl ester of 4- (2- hydroxy-2-methyl-propylamino) -benzenesulfonic acid 2- (3-piperidin-4-yl-propionylamino) -benzothiazole-6-yl ester of 4- (2-iopropylamino-ethylamino) -benzenesulfonic acid hydrochloride 2- (3-Piperidin-4-yl-propionylamino) -benzothiazole-6-yl ester of 4- (3-imidazol-1-yl-propylamino) -benzenesulfonic acid ester 2- (3-piperidin-4-yl) ester 4- (2-ethylamino-ethylamino) -benzenesulfonic acid 2- (3-piperidin-4-yl-propionylamino) -benzothiazole-6-yl ester of 4- (2-ethylamino-ethylamino) -benzenesulfonic acid-2-propionylamino) -benzothiazole-6-yl acid - (2-hydroxy-ethylamino) -etiIamino] -benzenesulfonic hydrochloride 2- (2-piperidin-4-yl-acetylamino) -benzothiazole-6-yl ester of 4-isobutylamino-benzenesulfonic acid ester 2- (3-piperidin-4-yl-propionylamino) -benzothiazole-6-yl ester 4-Isobutylamino-benzenesulfonic acid hydrochloride ester 2- (8-amino-octanoylamino) -benzothiazole-6-yl ester of 4-isobutylamino-benzenesulfonic acid ester 2 - [(piperidin-4-carbonyl) -amino] -benzothiazole-6- thiophene-2-sulfonic acid; compound with trifluoroacetic acid 2- (3-piperidin-4-yl-propionylamino) -benzothiazole-6-yl ester of thiophen-2-sulfonic acid; compound with trifluoroacetic acid 2- (2-amino-acetylamino) -benzothiazole-6-yl ester of thiophen-2-sulfonic acid; 2- (2-methylamino-acetylamino) -benzothiazole-6-yl ester of thiophen-2-sulfonic acid; compound with trifluoroacetic acid 2- (3-amino-propionylamino) -benzothiazole-6-yl ester of thiophen-2-sulfonic acid; compound with trifluoroacetic acid 2- (8-amino-octanoylamino) -benzothiazole-6-yl ester of thiophen-2-sulfonic acid; compound with trifluoroacetic acid 2- (3-diethylamino-propionylamino) -benzothiazole-6-yl ester of thiophen-2-sulfonic acid; compound with trifluoroacetic acid 2- (cyclopropanecarbonyl-amino) -benzothiazole-6-yl ester of thiophen-2-suphonic acid 2 - [(azetidin-3-carbonyl) -amino] -benzothiazole-6-yl acid ester 4- (2-diisopropy lam i no-eti lami no) -benzenesulfonic 2- (8-amino-octanoylamino) -benzothiazole-6-yl ester of 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid ester 2- [ 4- (2-Diisopropylamino-ethylamino) -benzenesulfonic acid 2- (2-piperidin-4-yl-acetylamino) -benzothiazole-6-yl ester (1-amino-cyclopentanecarbonyl) -amino] -benzothiazole-6-yl ester 4- (2-diiso propyl am i no-eti lam ino) -benzenesulfonic acid 2- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2-acetylamino-benzothiazole-6-yl ester 2- (2-methoxy) ester acetylamino) -benzothiazole-6-yl of 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2- (cyclopentane-carbonyl-amino) -benzthiazole-6-yl ester of 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid One of the processes for the preparation of the compounds according to the invention can be schematized in the following manner: 1. The compounds of formula (I) for which R = alkyl, cycloalkyl, aryl or heteroaryl can be prepared according to synthesis scheme 1. Scheme 1 (4) V o- * b * (5) (8) The compounds of the present invention can be prepared easily from 5-methoxy-benzothiazol-2-ylamine (commercial compound). In a first step, the starting material is demethoxylated in an acid medium, preferably in a mixture of acetic acid / aqueous hydrobromic acid. In a second step, the 5-hydroxy-benzothiazol-2-ylamides (4) are obtained by reaction between 5-hydroxy-benzothiazol-2-ylamine (2) and an acid of formula (3) (R as defined in the general formula (I)) in the presence of a coupling agent such as HATU or HBTU and a base such as diisopropylethylamine or triethylamine in an appropriate solvent. Among the solvents that may be used, there may be mentioned dimethylformamide and dichloromethane. The temperature of choice to perform this operation is between the ambient temperature and reflux. In a third step, the sulfonyl esters of formula (6) are obtained by reaction between the 5-hydroxy-benzothiazol-2-ylamides (4) and a sulfonyl chloride of formula (5) (X and Ar such as defined in the general formula (I)) in an inert solvent (acetone, THF, dichloromethane or toluene) in the presence of a base such as triethylamine or pyridine. In the case where XAr corresponds to 4-fluorophenyl, the nucleophilic substitution of F with the amino acids of formula (7) (R 1 R 2 as defined in general formula (I)) to yield the formula derivatives ( 8) is carried out in an aprotic solvent such as N-methylpyrrolidone or dimethylformamide at a temperature ranging between 90 and 1 30 ° C in a sealed tube with microwaves. 2. The compounds of the present invention for which R = alkoxy, cycloalkoxy or heterocycloalkoxy can be prepared according to the synthesis scheme 2. Scheme 2 (8) The compounds of the present invention can be prepared easily from 5-methoxy-benzothiazol-2-ylamine (commercial compound). In a first step, the starting material is demethoxylated in an acid medium, preferably in a mixture of acetic acid / aqueous hydrobromic acid. In a second step, the sulfonyl esters of formula (4) are obtained by reaction between 5-hydroxy-benzothiazol-2-ylamine (2) and a sulfonyl chloride of formula (3) (X and Ar such as defined in the general formula (I)) in an inert solvent (acetone, THF, dichloromethane or toluene) in the presence of a base such as triethylamine or pyridine. In the case where XAr corresponds to 4-fluorophenyl, the nucleophilic substitution of F with the amines of formula (6) (R 1 R 2 as defined in general formula (I)) to yield the derivatives of formula (7) ) is carried out in an aprotic solvent such as N-methylpyrrolidone or dimethylformamide at a temperature ranging between 90 and 130 ° C in a sealed tube with microwaves. The carbamates (8) are obtained by reaction between the amines of formulas (4 and 7) and a chloroformate of formula (5) (R3 as defined in general formula (I)) in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine or inorganic such as potassium carbonate in an appropriate solvent. Among the solvents that may be used, there may be mentioned tetrahydrofuran, dichloromethane and dioxane. The temperature of choice to perform this operation is between 0 ° C and reflux. 3. The compounds of the present invention for which R = alkylamino, cycloalkylamino or heterocycloamino can be prepared according to the synthesis scheme 3. Scheme 3 (8) H (9) R4 '~ R5 (10) The ureas of formula (10) can be obtained by reaction between the carbamates of formula (8) (R3 = Me preferentially) and an amine of formula (9) (R4 and R5 ial as defined in general formula (I)) in an aprotic solution such as N-methylpyrrolidone or dimethylformamide at a temperature ranging from 90 ° C to 130 ° C in a sealed microwave oven. The compounds according to the invention can be used in human therapy and more especially in the treatment of cancer., more especially of cancers sensitive to the inhibitors of Aurora-2 and those of Cdk2. The present invention will be described more fully by way of the following examples, which should not be considered as limiting the invention. The DCI spectra were performed in chemical desorption-ionization (reactanle gas: ammonia, Finnigan SSQ7000 equipment). Specimens with electrospray (ES +) were performed in a Platform I I (Micromass). LC / MS analysis LC / MS analysis method (A1 method) LC / MS analyzes were performed using a Micromass LCT model connected to an HP 1 100 device. The abundance of the products was measured by a diode network detector HP G1315A in a wave length detector of 200-600 nm and a light scattering detector Sedex 65. Obtaining the mass spectra was performed in a range of 1 80 to 800. The data was analyzed using the program Micromass MassLynx computer The separation was carried out on a Hypersil BDS C18 column, 3 μm (50 x 4.6 mm), eluting with a linear gradient of 5 to 90% acetonitrile containing 0.05% (v / v) trifluoroacetic acid (TFA) ) in water containing 0.05% (v / v) of TFA, in 3, 5 min with a flow of 1 mL / min. The total analysis time, including the rebalancing period of the column, is 7 min. Method of analysis by LC / MS (A2 method) The LC / MS analyzes were performed in a Micromass model Platfom model. The abundance of the products was determined by an HP G 1315A diode network detector in a wavelength range of 200-400 nm and a Sedex 65 light scattering detector. The specification of the mass spectrums was performed in an estimate of 50 to 1,500. The dalos were analyzed using the Micromass MassLynx software. The separation was carried out on an XTerral 3.5 μm (50 x 2, 1 mm) column, eluting with a linear gradient of 5 to 95% acetonitrile in water containing 0.1% (v / v) of formic acid in 9 min with a flow of 0.7 mL / min. The total analysis time, including the rebalancing period of the column, is 9 min. Purification by preparative LC / MS (Method B): The products were purified by LC / MS using a system Waters FractionsLynx composed by a Waiers model 600 gradient pump, a Waiers Model 51 5 regeneration pump, a Waíers Reagení Manager dilution pump, a Waters model 2700 automatic injector, two Rheodyne model LabPro valves, a model Waders diode network detector 996, a Waters mass spectrometer model ZMD and a Gilson fraction collector model 204. The system is controlled by the Waters FractionLynx computer program. The separation was effected alternately in two Waters Symmetry columns (C18, 5 μM, 19 x 50 mm, catalog reference 186000210), one column being regenerated by means of a water / acetonitrile mixture 95/5 (v / v) which contains 0.07% (v / v) of trifluoroacetic acid, while the other column was in the process of separation. The elution of the columns was carried out using a linear gradient of 5 to 95% acetoniiril containing 0.07% (v / v) trifluoroacetic acid in water containing 0.07% (v / v) trifluoroacetic acid, with a flow of 10 mL / min. At the exit of the separation column, a thousandth part of the effluent is separated by an LC Packing Accurate, diluted with methyl alcohol with a flow of 0.5 mL / min and sent to the detectors, at a rate of 75% towards the diode network detector, and 25% reslunde towards the mass spectrometer. The rest of the effluent (999/1000) is sent to the fraction collector where the flow is eliminated as long as the mass of the expected product is not destroyed by the FractionLynx software. The molecular formulas of the expected products are provided to the FractionLynx software that starts the production collection when the detected mass signal corresponds to the ion [M + H] + and / or [M + Na] +. In certain cases, depending on the analytical LC / MS results, when an intense ion corresponding to [M + 2H] ++ has been detected, the FractionLynx computer program is also given the value corresponding to the milad of the calculated molecular mass ( PM / 2). Under these conditions, collection is also started when the mass signal of the ion [M + 2H] ++ and / or [M + Na + HJ ++. The products were collected in tared glass tubes. After being collected, the solvents were evaporated in a centrifugal evaporator Savant AES 2000 or Genevac HT8 and the masses of the products were determined by weighing the tubes after the evaporation of the solvents. Purification by flash chromatography: the crude products are purified by flash chromatography on silica of 15-35 μm granulometry under an argon pressure of 0.5 bar. The fractions corresponding to the expected product are combined and concentrated under reduced pressure in a rotary evaporator. The present invention will be described more fully by means of the following examples, which should not be considered as limiting the invention: I nrmedium 1: Preparation of 2-amino-benzothiazol-6-ol A solution of 2-amino-6-ethoxybenzothiazole (5 g, 25.74 mmol) and 48% hydrobromic acid in water (130 ml, 1.141 mol) in 65 ml of acetic acid is repaired in 10 tubes of 20 ml for microwaves and heated to 1 50 ° C with microwaves for 200 seconds. The reaction medium is concentrated. The residue is taken up in 200 ml of water, basified to pH 8 by the addition of 75 ml of a saturated solution of NaHCO 3 and extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over sodium sulfate, magnesium and concentrated to dryness to yield 3.4 g of 2-amino-benzothiazole-6-oI (gray powder). LC / MS (A1): [M + H] + = 167.00, retention time: 1. 07 min. Intermediate 2: Preparation of 4- (6-hydroxy-benzothiazol-2-ylcarbamoyl) -piperidin-1-carboxylic acid tert-buíyl ester A solution of the mono-tert-butyl ester of piperidin-1,4-dicarboxylic acid (276 mg, 1, 203 mmol), of HATU (549 mg, 1, 444 mmol) and of diisopropylethylamine (1 87 mg, 1.44 mmoles) in 3 ml of DMF is stirred at room temperature for 15 minutes. The 2-amino-benzothiazol-6-ol (intermediate 1) (200 mg, 1, 203 mmoles) in solution in 3 ml of DMF is added in one time. The reaction medium is stirred at ambient temperature for 2 hours, poured into a solution of 10% Na 2 CO 3 in water (20 ml) and extracted with ethyl acetate. The crude reaction product is purified by column chromatography (eluent: EOAc / heptane (1/1)) to yield 401 mg of 4- (6-hydroxy-benzothiazol-2-ylcarbamoyl) -piperidine-tert-butyl ester. 1 -carboxylic (white solid). LC / MS (method A2): [M + H] + = 378.0, retention time: 3.9 minutes.

Intermediate 3: Preparation of 4- [6- (4-fluoro-benzenesulfonyloxy) -benzoyiazole-2-carbamoyl] -piperidin-1-carboxylic acid tert-butanol ester A solution of 4- (6-hydroxy-benzoyiazol-2-ylcarbamoyl) -piperidin-1-carboxylic acid (2-mer) (454 mg, 1.20 mmol) of 4-fluoro-benzenesulfonyl chloride (234 mg, 1.20 mmol) and of eryrylamine (320 μl) in 10 ml of acetone is stirred at room temperature for 1 hour. The triethylamine hydrochloride is filtered and the filtrate is evaporated. The crude reaction product is purified by column chromatography (eluyenle: EtOAc / Heptane (7/3) to yield 400 mg of 2- (4- piperidin-4-carbonyl) -amino] benzothiazole-6-yl ester fluoro-benzenesulfonic (white solid) LC / MS (method A2): [M + H] + = 535.9, retention time: 4.9 minutes Intermediate 4: Preparation of the ester 2 - [(piperidin-4- carbonyl) -amino] benzothiazole-6-yl of 4-fluoro-benzenesulfonic acid A solution of 4- [6- (4-fluoro-benzenesulfonyloxy) -benzoliazol-2-yl carbamoyl] -p-peridin-1-carboxylic acid tert-butyl ester (intermediate 3) (100 mg, 0, 187 mmoles), of TFA (0.5 ml) in dichloromethane (4.5 ml) is stirred at room temperature for 1 hour. The reaction medium is brought to dryness. The residue is collected with the minimum amount of water, neutralized by the addition of a 10% aqueous solution of Na2CO3 and extracted with ethyl acetate to yield 55 mg of 2 - [(piperidine-4-carbonyl) -amino ester. ] benzothiazole-6-yl of 4-fluoro-benzenesulfonic acid (white solid). LC / MS (method A2): [M + H] + = 435.9, retention time: 3.0 minutes. Example 5: Preparation of the 4- (2-hydroxy-2-methyl-propylamino) -benzenesulfonic acid 2 - [(piperidin-4-carbonyl) -amino] -benzoliazole-6-yl ester A solution of the ester 2 - [(piperidin-4-carbonyl) -amino] benzothiazole-6-yl of 4-fluoro-benzenesulfonic acid (intermediate 4) (50 mg, 0.1-14 mmol) and 4- (4-) pyridin-3-yl-imidazol-1-yl) -butylamine (40.93 mg, 0.459 mmol) in 0.5 ml of NMP is heated at 130 ° C with microwaves for 5 min. The crude reaction product is purified by preparative LC / MS (basic medium (pH 9)) to yield after lyophilizing 21 mg of 2- (cyclopropanecarbonylamino) -benzothiazole-6-yl ester of 4- (2-hydroxy-2) acid. -methyl-propylamino) -benzenesulfonam (light yellow solid). LC / MS (method A2): [M + H] + = 505.2, retention time: 2.70 minutes. Intermediate 6: Preparation of (6-hydroxy-benzothiazol-2-yl) -amide of cyclopropanecarboxylic acid A solution of 2-amino-benzothiazol-6-ol (intermediate 1) (850 mg, 4.6 mmol) of cyclopropane-carboxylic acid is stirred in a 100 ml balloon fitted with a magnetic bar (1, 564). g, 18.1 mmol) of N, N-diisopropylethylamine (3.6 ml, 24.4 mmol) of HBTU (4.1 g, 5.53 mmol) in 40 ml of dimethylformamide at room temperature for 16 hours . 150 ml of water are added to the reaction medium, extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness. The remainder is washed with ethyl acetate which yields 893 mg of 2- (cyclopropanecarbonyl-amino) -benzoyiazole-6-yl ester of the cyclopropanecarboxylic acid. LC / MS: [M + H] + = 303, 18, RT = 3.53 min. To this product is added a solution of lithium hydroxide monohydrate (200 mg, 4.768 mmol) in 50 ml of methanol and 5 ml of water. The reaction medium is refluxed with stirring for one hour. The reaction medium is concentrated, acidified to pH 1 by a 2N hydrochloric acid solution, diluted with 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water, with a saturated solution of sodium chloride and brought to dryness yielding 500 mg of (6-hydroxy-benzothiazol-2-yl) -amide of cyclopropanecarboxylic acid in a yield of 72% (powder beige). NMR: 1 H NMR spectrum (400MHz) - d in ppm - in DMSO-d6: from 0.90 to 1.00 (mf, 4H); 1.98 (mf, 1 H7); 6.88 (dd, J = 8.5 and 3.0 Hz, 1 H); 7.27 (d, J = 3.0 Hz, 1 H); 7.54 (d, J = 8.5 Hz, 1 H); 9.51 (broad s, 1 H); 12.4 (broad s, 1 H). Example 7: Preparation of the 2- (cyclopropane-carbonyl-amino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid A solution of (6-hydroxy-benzothiazol-2-yl) -amide of the cyclopropanecarboxylic acid (intermediate 6) (1.81 g, 7.72 mmol) is placed in a 100 ml balloon fitted with a magnetic rod. ), of 4-fluorobenzenesulfonyl chloride (1.5 g, 7.72 mmol), of triethylamine (2.14 ml, 1 5.45 mmol) in 43 ml of acetone for one hour at room temperature. The precipitate obtained is filtered and the filtrate is evaporated. The residue is washed with acetone and ethyl ether, yielding 1.92 g of 2- (cyclopropanecarbonyl-amino) -benzoliazole-6-yl ester of 4-fluoro-benzenesulfonic acid (white powder) with a yield of 66%.

Mass: IE: m / z 392 [M +], m / z 324: [M +] -COC3H5, m / z 233: [M +] - SO2PhF, m / z 165 324-SO2PhF, m / z 69 (base peak) : [COC3H5] +. 1 H NMR Specimen (300MHz) - d in ppm - in DMSO-d6: from 0.92 to 1.03 (mf, 4H); 2.02 (mf, 1 H); 7, 04 (dd, J = 8.5 and 2.5 Hz, 1 H); 7.54 (mf, 2H); 7.70 (d, J = 8.5 Hz, 1 H); 7.80 (d, J = 2.5 Hz, 1 H); 7.97 (mf, 2H); 12.75 (broad s, 1 H). Example 8: Preparation of the 2- (cyclopropanecarbonylamino) -benzoliazole-6-yl ester of 4-cyclopentylamino-benzenesulfonic acid: A solution of the 2- (cyclopropanecarbonylamino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (example 7) (50 mg, 127.4 μmol) and of cyclopentylamine (51 μl, 0.51 mmol) in 0, 5 ml of NMP is heated at 1 50 ° C with microwave for 5 min. The reaction product is purified by means of preparative LC / MS (basic medium (pH 9)) to yield after lyophilizing 38 mg of 2- (cyclopropanecarbonylamino) -benzothiazole-6-yl ester of 4-cyclopentylamino-benzenesulfonic acid (white solid ). LC / MS (method A2): [M + H] + = 458.0, retention time: 4.39 minutes. Example 9: Preparation of 4- (3-imidazol-1-yl-propylamino) -benzenesulfonic acid 2- (cyclopropanecarbonylamino) -benzoyiazole-6-yl ester A solution of the 2- (cyclopropanecarbonylamino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (example 7) (100 mg, 0.255 mmol) and of 3-imidazol-1-yl-propylamine (123 μl, 1, 019 mmoles) in 2 ml of NMP is heated at 150 ° C with microwaves for 5 minutes. The crude reaction product is purified by preparative LC / MS (basic medium (pH 9)) to yield after freeze-drying 63 mg 2- (cyclopropanecarbonylamino) -benzothiazole-6-yl ester of 4- (3-imidazole-1) -iI-propylamino) -benzenesulfonic acid (white solid).

LC / MS (period A2): [M + H] + = 498.0, time of retention: 2.90 min.

Example 1 0: Preparation of the 2- (cyclopropanecarbonylamino) -benzofiazole-6-yl ester of 4-methylamino-benzenesulfonic acid: A solution of the 2- (cyclopropanecarbonylamino) -benzoliazole-6-yl ester of 4-fluoro-benzenesulfonic acid (example 7) (25 mg, 63.71 μmol) and of methylamine (2N in MeOH, 200 μl) in 300 μl of NMP is heated at 150 ° C with microwaves for 3 minutes. The crude reaction product is purified by preparative LC / MS (basic medium (pH 9)) to yield after lyophilizing 6.7 mg of 2- (cyclopropanecarbonylamino) -benzoyiazole-6-yl ester of 4-mephilaminobenzenesulfonic acid ( solid beige). LC / MS (period A2): [M + H] + = 404, 1, time of reention: 3.83 minutes. Example 1 1: Preparation of 2- (cyclopropanecarbonylamino) -benzoyiazole-6-yl ester of 4- (2-hydroxy-2-meityl-propylamino) -benzenesulfonic acid ester: A solution of the 2- (cyclopropanecarbonylamino) -benzofiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (example 7) (100 mg, 255 μmoles) and of 1-amino-2-mephyl-propan-2-ol (91 mg, 1. 02 mmoles) in 2 ml of NMP was heated at 150 ° C with microwaves for 5 min. The reaction product is purified by preparative LC / MS (basic medium (pH 9)) to yield after lyophilizing 61 mg of 2- (cyclopropanecarbonylamino) -benzoyiazole-6-yl ester of 4- (2-hydroxy-2) acid. -methyl-propylamino) -benzenesulfonic acid (beige solid). LC / MS (period A2): [M + H] + = 462, 1, refusal time: 3.83 min. Example 12: Preparation of 4- (2-diisopropylamino-yl-amino) -benzenesulfonic acid 2- (cyclopropanecarbonylamino) -benzoyiazole-6-yl ester A solution of the 2- (cyclopropanecarbonylamino) -benzoliazole-6-yl ester of 4-fluoro-benzenesulfonic acid (example 7) (100 mg, 255 μmoles) and of N, N-diisopropyl-yano-1,2-diamine (147 mg, 1. 02 mmoles) in 2 ml of NMP was heated at 1 1 0 ° C with microwaves for 10 minutes. The reaction mixture is purified by preparative LC / MS (basic medium (pH 9)) to yield after lyophilizing 66 mg of 2- (cyclopropanecarbonylamino) -benzoyiazole-6-yl ester of 4- (2-hydroxy-2) acid. -meii-propylamino) -benzenesulfonic acid (beige solid).

LC / MS (period A2): [M + H] + = 517, 1, retention time: 2.93 minutiae.

Example 1 3: Preparation of 4- [4- (4-pyridin-3-yl-imidazol-1-yl) -buylamino] -benzenesulfonic acid 2- (cyclopropanecarbonylamino) -benzofiazole-6-yl ester A solution of the 2- (cyclopropanecarbonylamino) -benzofiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (Example 7) (50 mg, 127.4 μmol) and of 4- (4-pyridin-3-yl-imidazol- 1-yl) -buyylamine (1 10.2 mg, 0.51 mmol) in 0.5 ml of NMP was heated at 150 ° C with microwave for 8 min. The crude reaction product is purified by preparative LC / MS (basic medium (pH 9)) to yield after lyophilizing 36 mg of 2- (cyclopropanecarbonylamino) -benzothiazole-6-yl ester of 4- (2-hydroxy-2-acid. -methyl-propylamino) -benzenesulfonic acid (beige solid). LC / MS (méfodo A2): [+ H] + = 589,0, refusal time: 3, 14 minutiae.

Inmediate 14: Preparation of the eerc-buílic ester of (6-hydroxy-benzofiazol-2-yl) -carbamic acid H wx In a 100 ml balloon, fitted with a magnetic bar, a solution of 2-amino-benzoyiazol-6-ol (in-house 1) (1.91 g, 1 1.49 mmol), of di-carbonated dihydrochloride was stirred. -ert-buyyl (7.52 g, 34.47 mmol), of idylamine (4.9 ml, 34.47 mmol), of 4-dimethylaminopyridine (168 mg, 1.38 mmol) in 50 ml of dichloromethane overnight at ambient temperature. The reaction medium is taken to dryness and the residue obtained is washed with dichloromethane and ethyl ether, yielding 4.2 g of 2-tert-buffoxycarbonylamino-benzolyzole-6-yl ester of tert-buffyl ester of carbonic acid with a yield quantifiable. LC / MS: [M + H] +: 31 1, 16, retention time: 5.27 min. To this product is added a solution of soda (920 g, 22.8 mmol) in 10 ml of methanol. The reaction medium is stirred for 2 hours at room temperature under ultrasound and acidified to pH4 with a 2N hydrochloric acid solution. The reaction medium is brought to dryness and the residue obtained is washed with dichloromethane and ethyl ether yielding 2.35 g of (6-hydroxy-benzothiazol-2-yl) -carbamic acid tert-buíyl ester (beige powder). with a yield of 77%. Mass: IE: m / z 266 [M +], m / z 166 (base peak): [M +] -CO2íBu IR: KBr 3.422; 3,263; 3.091; 2,981; 1,725; 1608; 1.562; 1,468; 1,278; 1,245; 1,154; 1,049; 862 and 852 cm "1 Specimen 1 H NMR (300MHz) - d in ppm - in DMSO-d6: 1.52 (s, 9H), 6.85 (dd, J = 9.0 and 3.0 Hz, 1H) 7.24 (d, J = 3.0 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 9.44 (mf, 1H), 11.5 (mf, ex. , 1H). Inmediate 15: Preparation of the 4-fluoro-benzenesulfonic acid 2-ert-buffoxycarbonylamino-benzoyiazole-6-yl ester In a 100 ml balloon, fitted with a magnetic rod, a solution of ε-butryl ester of (6-hydroxy-benzothiazol-2-yl) -carbamic acid (intermediate 14) (3.61 g, 13) is placed under stirring. , 08 mmoles), of 4-fluorobenzenesulfonyl chloride (2.56 g, 13.08 mmol), of triethylamine (3.63 ml, 26.16 mmol) in 65 ml of ambient oil at room temperature for one night. Filtering of the precipitate obfenido and the filtrate is brought to dryness. The dried residue is washed with ethyl acetate yielding 5.02 g of 4-fluoro-benzenesulfonic acid 2-ert-butoxycarbonylamino-benzothiazole-6-yl ester (white powder) in 62% yield. 1 H NMR spectrum (400MHz) - d in ppm - in DMSO-d6: 1.53 (s, 9H); 7.02 (dd, J = 9.0 and 2.5 Hz, 1H); 7.55 (t, J = 9.0 Hz, 2H); 7.65 (d, J = 9.0 Hz, 1H); 7.78 (d, J = 2.5 Hz, 1H); 7.98 (dd, J = 5.0 and 9.0 Hz, 2H); 11.9 (broad s, 1H).

Intermediate 16: Preparation of 2-amino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid In a 100 ml balloon, fitted with a magnetic rod, a solution of 4-fluoro-benzenesulfonic acid 2-ene-buloxycarbonylamino-benzoyiazole-6-yl ester (inverse 15) is placed in agifcation (1.7 g, 3 g). , 60 mmol), 10 ml of frifluoroacetic acid (1 30 mmol) in 10 ml of dichloromethane, and 1 ml of water last 2 hours at ambient temperature. The reaction medium is brought to dryness and the obtained residue is washed with ethyl ether which yields 1.31 g of 2-amino-benzothiazo-6-yl ester of 4-fluoro-benzenesulfonic acid in the form of trifluoroacetic acid salt ( white powder) with a yield of 83%. LC / MS (method A1): [M + H] +: 325, 1 3, re-time: 3, 12 min. Intermediate 17: Preparation of 4- tert -butyl ester. { [6- (4-Fluoro-benzenesulfonyl) -benzoiazol-2-ylcarbamoyl] -methyl} -piperidin-1 -carboxylic In a test tube, fitted with a magnetic rod, a solution of 2-amino-benzofiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (inverse 16) was stirred (580 mg, 1.32 mmol) of ester. 4-Carboxymethyl-piperidine-1-carboxylic acid ener-czylyl (640 mg, 2.63 mmol), of HBTU (1.1 g, 2.9 mmol), of N, N-diisopropylamine (1.2 ml, 6.89 mmoles) in 12 ml of dimethylformamide for 3 days at ambient temperature. 200 ml of water are added to the reaction medium which is exfoliated with ethyl acetate. The organic phase is washed with water, with a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated. The residue obtained is collected with ethyl acetate and purified in a Varian flash cartridge containing 50 g of porosity silica 15-35 μm with a gradient of 5 to 30% acetyl in cyclohexane in 100 min. After evaporating the solution, 700 mg of 4-acid euphoric acid ester are obtained. { [6- (4-Fluoro-benzenesulf onyl oxy) -benzoyiazol-2-ylcarba moi] -methyl} -piperidin-1-carboxylic acid (yellow oil) with a yield of 96%. LC / MS (method A1): [M + H] +: 550, 11, retention time: 4, 14 min. Example 1 8: Preparation of the 2- (2-piperidin-4-yl-acetylamino) -benzoliazole-6-yl ester of 4- (2-isopropylamino-ef-lam-n-benzenesulfonic) ester hydrochloride Step 1: In a test tube, fitted with a magnesium bar, a solution of tert-butyl ester of 4-acid is gite. { [6- (4-Fluoro-benzenesulfonyloxy) -benzothiazol-2-ylcarbamoyl] -melyl} -piperidine-1-carboxylic acid (inverse 1%) (174 mg, 0.318 mmol), of N-isopropyleylenediamine (97 mg, 0.954 mmol), of cesium carbonate (103 mg, 0.31 8 mmol) in 3 ml of dimethyl sulfoxide last one night at 90 ° C. 1 00 ml of water are added to the reaction medium which is extracted with ethyl acetate. The organic phase is washed with water and with a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated yielding 1 03 mg tert-buíyl ester of 4- (. {6- [4- ( 3- imidazol-1-yl-propylamino) -benzenesulfonyloxy] -benzothiazol-2-ylcarbamoyl.} - methyl) -piperidin-1-carboxylic acid (white powder) in 50% yield. 2nd step: A solution of 103 mg of 4- (. {6- [4- (3-i midazol-1-i I-propylamino) -benzenesulfonyloxy] -benzoyiazol-2-ylcarbamoyl tert-buíyl ester} -methyl) -piperidine-1-carboxylic acid, 2 ml of dioxane, 2 ml of 4N hydrochloric acid in dioxane was stirred for 3 hours at ambient temperature. The precipitate obtained is filtered and washed with dioxane and ethyl ether, yielding 10 mg of 4- (2- (2-piperidin-4-yl) -acetylamino) -benzothiazole-6-yl ester hydrochloride. isopropylamino-ethylamino) -benzenesulfonic acid (white powder) with a yield of 88%. Mass: LCMS: m / z 532 [M + H] +, m / z 407 (base peak): [M + H] + -C5H10NCH2CO IR: KBr 3.432; 2.960; 2,793; 2,464; 2.598; 1,560; 1 .470; 1 .364; 1 .162; 1 .120; 1 .093; 91 5; 853 and 753 cm'1 1 H NMR Specimen (400MHz) - d in ppm - in DMSO-d6: 1, 28 (d, J = 7.0 Hz, 6H); 1.48 (m, 2H); 1.83 (broad d, J = 12.5 Hz, 2H); 2, 12 (mf, 1 H); 2.52 (masked, 2H); 2.92 (m, 2H); 3, 10 (mf, 2H); 3.28 (broad d, J = 12.5 Hz, 2H); 3.36 (mt, J = 7.0 Hz, 1 H); 3.50 (t, J = 6.0 Hz, 2H); 6.78 (broad d, J = 9.0 Hz, 2H); 7.03 (dd, J = 8.5 and 2.5 Hz, 1 H); 7.30 (mf, ex., 1 H); 7.56 (broad d, J = 9, 0 Hz, 2H); 7.71 (d, J = 8.5 Hz, 1 H); 7.78 (d, J = 2.5 Hz, 1 H); 8.58 (mf ex., 1 H); 8.81 (mf ex., 1 H); 9.00 (mf ex., 2H); 12.5 (broad s, 1 H). Example 1: Using the same method as that of Example 18, the following examples are carried out using the 4-butyl-4-butyl ester. { [6- (4-fluoro-benzenesulfonyloxy) -benzothiazol-2-ylcarbamoyl] -methyl} -piperidin-1-carboxylic acid as a precursor (intermediate 17) combined with different amines. In the following examples, the compound obtained after the first step is purified in a flash cartridge of 5 g of Interchim silica (15-35 μm) by a gradient of 5 to 10% methanol in dichloromethane at a flow rate of 10 ml / min. . These examples are presented in the following table: 3.08 (mf, 2H); 3.13 (mf, 2H); 3.28 (broad d, J = 12.5 Hz, 2H); 3.45 (masked, 2H); 3J1 (t, J = 5.5 Hz, 2H); 6.77 (broad d, J = 9.0 Hz, 2H); 7.03 (dd, J = 8.5 and 2.5 Hz, 1H); 7.18 (mf, extended, 1H); 7.55 (broad d, J = 9.0 Hz, 2H) 7.72 (d, j = 8.5 Hz, 1H) 7.79 (d, j = 2.5 Hz, 1H) 8.51 ( mf extended, 1H) 8J5 (extended mf, 1H) 8.87 (extended mf, 2H) 12.5 (broad s, 1H). LCMS: [M + H] + = 519.08, retention time: 2.66min IR: KBr 3.415; 2.971; 1597; 1.563; 1.470; 1,365; 1,161; 1.094; 915; 854; 746 and 586 cm "1 1 H NMR spectrum (400MHz hydrochloride) - d in ppm - 2- (2- DMSO-d6: piperidin-4-yl-1,18 (s, 6H); 1,45 (m , acetylamino) -2H), 1.85 (broad d, j = benzothiazole-6- 12.5 Hz, 2H), 2.13 (mf, 19 d of 1H acid); 2.52 (masked, 4- (2-hydroxy-2H), 2.92 (m, 2H), 3.06 methyl- (s, 2H), 3.28 (broad d, j propylamino) - = 12.5 Hz, 2H); 6.78 (broad benzenesulfonic d, J = 9.0 Hz, 2H); or from 6T50 to 7.00 (extended mf, 1H); 7.02 (dd, j = 9.0 and 2.5 Hz, 1H); 7.45 (broad d, j = 9.0 Hz, 2H); 7.70 (d, j = 9.0 Hz, 1H); 7.75 (d, J = 2.5 Hz, 1H); 8.51 (extended mf, 1H); 8.78 (extended mf, 1H); 12.5 (broad s, 1H).

Intermediate 20: Preparation of 2- (8-tert-butoxycarbonylamino-octanoylamino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid According to the 1-7 method, the 2- (8-tert-butoxycarbonylamino-octanoylamino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid is prepared by combining the 2-amino-benzofiazole-6-yl ester of the acid 4-Fluoro-benzenesulfonic (intermediate 16) with Boc-8-aminocaprylic acid. LC / MS (method A1): [M + H] +: 566, 01, retention time: 4.21 min. Example 21: Preparation of 4- (2-isopropylamino-ethylamino) -benzenesulfonic acid 2- (8-amino-ocfanoylamino) -benzoyiazole-6-yl ester hydrochloride According to the method of Example 1 8, the 2- (8-amino-octanoylamino) -benzothiazole-6-yl ester hydrochloride of 4- (2-isopylamino-ethylamino) -benzenesulfonic acid is prepared by combining the ester 2- 4-Fluoro-benzenesulfonic acid (8-tert-buzoxycarbonylamino-octanylamino) -benzopiazole-6-yl ester (intermediate 20) with N-isopropylethylenediamine. The compound obtained in the first 2- (8-tert.-butoxycarbonylamino-ocnanoyamino) -benzothiazole-6-yl ester of (4- (2-isopropylamino-ethylamino) -benzenesulfonic acid ester is purified on silica with a gradient of 4 to 15. % meianol in dichloromethane Mass: El: m / z 406 [M +] - C8H16O, m / z 335: [M +] - C4H10N, m / z 72 C4H10N (base peak). Cl: m / z 548 [M + Hf (base peak), m / z 407: [M + H] + - C8H16NO IR: KBr 3.426; 2.923; 2,448; 1,717; 1,597; 1.563; 1,472; 1.371; 1,165; 1.092; 911; 857; 755; 574 and 548 cm "1 Spectrum 1 H NMR (400MHz) - d in ppm - in DMSO-d6: 1.30 (f, J = 7.0 Hz, 6H), 1.33 (mf, 6H), 1.58 (mf, 2H), 1.67 (mf, 2H), 2.52 (masked, 2H), 2.79 (mf, 2H), 3.01 (mf, 2H), 3.36 (me, J = 7.0 Hz, 1H), 3.48 (mf, 2H), 6.78 (d wide, J = 9.0 Hz, 2H), 7.02 (dd, J = 8.5 and 2.5 Hz , 1H), 7.30 (mf, 1H), 7.56 (broad d, J = 9.0 Hz, 2H), 7.70 (d, J = 8.5 Hz, 1H), 7.77 ( d, J = 2.5 Hz, 1H), 7.82 (mf exceeded, 3H), 9.00 (mf exceeded, 2H), 12.45 (s broad, 1H) Example 22: Using the same method as In the example 21, the following examples are carried out using the 2- (8-urea-buioxycarbonylamino-octanoylamino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (lower 20) as a precursor combined with amines. They appeared in the following day: No. Compound amine characterization Example 22a 1H NMR spectrum hydrochloride (300MHz) ester 2- (8- - d in ppm - in DMSO-d6: amino-1,31 (mf, 6H), from 1.49 to 1.68 octanoylamino) (mf, 4H); 2.11 (mt, J = 7.0 Hz, -benzothiazole-2H); 2.52 (masked, 2H); 6-lol of 2.75 (mf, 2H); 3.11 (t, J = 7.0 acid 4- (3 Hz, 2H), 4.32 (t, J = 7.0 Hz, imidazol-1-yl-2H), 6.68 (broad d , J = 9.0 propylamino) - Hz, 2H); 6.97 (dd, J = 9.0 and benzenesulfon 2.5 Hz, 1H); 7.20 (mf very ico extended, 1H); 7.50 (broad d, J = 9.0 Hz, 2H); 7.67 (d, J = 9.0 Hz, 1H); 7.72 (t, J = 2 Hz, 1H); 7.74 (d, J = 2.5 Hz, 1H); 7.85 (t, J = 2 Hz, 1H); 7.89 (extended mf, 3H); 9.24 (t, J = 2 Hz, 1H); 12.45 (broad s, 1H); 14.6 (extended mf, 1H). 22b ester 2- (8-IR: KBr amino-3,421; 2,931; 2,457; 11.7 71177; octanoylamino) 1,596; 1.563; 1,472; 11.3 37700; -benzothiazole-1,357; 1,199; 1,163; 11.0 09933; 6-í \\ co of 911; 857; 756; 677; 611; 574 acid 4- (2- and 547 cm "1 ethylamino- Mass: Cl: mm / / zz 553344 [[MM + + HH] 1+ ethylamino) - (base peak) benzenesulfon 1 H-NMR spectrum (400MHz) ico-d in ppm - in DMSO-d6: 1.22 (t, J = 7.0 Hz, 3H), 1.32 (mf, 6H), 1.56 (mf, 2H), 1.64 (mf, 2H); 2.52 (masked, 2H), 2J9 (mf, 2H), 3.01 (mf, 2H), 3.10 (mf, 2H), 3.45 (mf, 2H), 6J3 (broad d, J = 9.0 Hz, 2H), 7.02 (dd, J = 8.5 and 3.0 Hz, 1H), 7.22 (extended mf, 1f-f), 7.55 (d squared, j = 9 , 0 Hz, 2H), 7.67 (d, J = 8.5 Hz, 1H), 7J8 (d, J = 3.0 Hz, 1H), 7.82 (extended mf, 3H), 8.92 (mf extended, 2H); 12.4 (s broad, 1H) 22c 4- (2- (2-hydroxyethylamino) 2- (8-amino-ocfanoylamino) -benzothiazole-6-yl ester hydrochloride) - ethylaminoj-benzenesulfon ico IR: KBr 3,444, 2,926, 2,627, 2,416 1,715, 1597, 1,563, 1,473 1,370, 1,196, 1,165, 1,148 1,092, 911, 858, 849, 757 612, 574 and 549 cm. m / z 550 [M + H] +, m / z 409: [M - CO (CH2) 7NH2 + H] H + (base peak). 1 H NMR spectrum (300MHz) - d in ppm - in DMSO-d 6: 1.28 (mf, 6H); from 1.43 to 1.67 (mf, 4H); 2.52 (masked, 2H); 2J3 (mf, 2H); from 3.00 to 3.15 (mf, 4H); 3.45 (mf, 2H); 3.67 (mf, 2H); 6J2 (broad d, j = 9.0 Hz, 2H); 6.98 (broad d, J = 9.0 Hz, 1H); 7.20 (extended mf, 1H); 7.52 (broad d, J = 9.0 Hz, 2H); 7.65 (d, J = 9.0 Hz, 1H); 7J2 (broad s, 1H); 7.82 (extended mf, 3H); 8.92 (extended mf, 2H); 12.4 (broad s, 1H). 22 d o. Mass hydrochloride: LCMS: m / z 535 [M + H] + ester 2- (8- (base peak), m / z 463: [M + H] + to ino- - C4HgO octanoylamino) Cl: m / z 535 [M + H] + (peak -benzothiazole-base). 6-lly of the 1 H NMR Spectrum (300MHz) 4- (2- - d in ppm - in DMSO-d6: hrdroxy-2- 1,14 (s, 6H); 1,29 (mf, 6rt); - 1.53 (mf, 2?), 1.63 (mf, 2H), propylamino) -2.52 (masked, 2H), 2J5 benzenesulfone (mf, 2H), 3.03 (s, 2H), 6J5 (broad d, J = 9.0 Hz, 2H), 6.97 (dd, j = 9.0 and 2.5 Hz, 1H), 7.42 (broad d, j '= "9.0 Hz , 2H), 7.65 (d, j = 9.0 Hz, 1H), 7J0 (d, J = 2.5 Hz, 1H), 7J8 (extended mf, 3H), 12.4 (wide s, 1H ).

Iníermedio 23: Preparation of ester ferc-buííl of acid 4-. { 2- [6- (4-Fluoro-benzenesulfonyloxy) -benzoyiazol-2-ylcarbamoyl] -efil} -piperidine-1-carboxylic acid According to the method of inermedium 17, the ester ferc-buílic acid 4-. { 2- [6- (4-Fluoro-benzenesulfonyloxy) -benzothiazol-2-ylcarbamoyl] -ethyl} -piperidin-1-carboxylic acid is prepared by combining the 2-amino-benzoyiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (intermediate 16) with N-Boc-4-piperidinpropionic acid. LC / MS (method A1): [M + H] +: 564, 16, retention time: 4.24 min. Example 24: 2- (3-piperidin-4-yl-propionylamino) -benzoyiazole-6-yl ester hydrochloride of 4- (2-isopropylamino-ethylamino) -benzenes ulphonic acid According to the method of Example 18, 4- (2-isopropylamino-ethylamino) -benzenesulfonic acid 2- (3-piperidin-4-yl-propionylamino) -benzothiazole-6-yl ester hydrochloride is prepared by combining the ter- buíílico of acid 4-. { 2- [6- (4-Fluoro-benzenesulfonyloxy) -benzothiazol-2-ylcarbamoyl] -etiI} -piperidium-1 -carboxylic acid (intermediate 23) with N, N-diisopropylamine. The compound obtained in the first stage (4- (2- {6- [4- (2-isopropylamino-ethylamino) -benzenesulfonyl-oxy] -benzoyiazol-2-ylcarbamoyl} -eti-tert-buíyl ester) -piperidin-1-carboxylic acid) is purified in a flash cartridge of 5 g of silica of porosity 1 5-35 μm by a gradient of 1% to 10% methanol in dichloromethane. Mass: LCMS: m / z 546 [M + H] +, m / z 407: [M + H] + - C5H10NC2H4CO, m / z 274: [M + 2H] 2+ m / z 294 (base peak). 1 H NMR spectrum (300MHz) - den ppm - in DMSO-d6: 1, 25 (d, J = 7.0 Hz, 6H); 1.32 (m, 2H); from 1.45 to 1.65 (mf, 3H); 1.81 (broad d, J = 12.5 Hz, 2H); 2.52 (masked, 2H); 2.82 (m, 2H); 3.07 (mf, 2H); 3.25 (broad d, J = 12.5 Hz, 2H); 3.35 (masked, 1 H); 3.45 (mf, 2H); 6, 73 (broad d, J = 9.0 Hz, 2H); 6.99 (dd, J = 8.5 and 2.5 Hz, 1 H); 7.20 (mf, ex., 1 H); 7.52 (broad d, J = 9.0 Hz, 2H); 7.67 (d, J = 8.5 Hz, 1 H); 7.73 (d, J = 2.5 Hz, 1 H); 8.40 (mf ex., 1 H); 8.65 (extended mf, 1 H); 8, 87 (extended mf, 2H); 12.4 (broad s, 1 H). Example 25: Using the same method as that of example 24, the following examples are made using the tert-buíyl ester of 4-acid. { 2- [6- (4-Fluoro-benzenesulfonyloxy) -benzothiazol-2-ylcarbamoyl] -ethyl} -piperidin-1 -carboxylyl? as a precursor (inlemediate 23) combined with amines differentials. These examples are presented in the following table: 1.32 (m, 2H); from 1.45 to 1.65 (mf, 3H); 1.81 (broad d, J = 12.5 Hz, 2H); 2.10 (mf, 2H); 2.52 (masked, 2H); 2.82 (m, 2H); 3.10 (mf, 2H); '3.23 (broad d, J = 12.5 Hz, 2H); 4.29 (t, J = 7.0 Hz, 2H); 6.65 (broad d, J = 9.0 Hz, 2H); 6.98 (dd, J = 8.5 and 2.5 Hz, 1H); 7.10 (extended mf, 1H); 7.48 (broad d, J = 9.0 Hz, 2H); 7.67 (d, J = 8.5 Hz, 1H); 7J0 (broad s, 1H); 7J2 (d, J = 2.5 Hz, 1H); 7.81 (broad s, 1H); 8.45 (extended mf, 1H); 8J2 (extended mf, 1H); 9.17 (broad s, 1H); 12.4 (broad s, 1H); 14, 4 (extended mf, 1H). LCMS hydrochloride: m / z 532 [M + H] ", ester 2- (3 m / z 393: [M + H] + - piperidin-4-yl-C5H10N (CH2) 2CO, m / z propionylamino) - 267: [M + 2H], m / z 287 benzothiazole-6- (base peak) .silic acid 4- H NMR spectrum (2-ethylamino- (300MHz) - d in ppm - ethylamino) - in DMSO-d6 : 1.21 (t, benzenesulfonic J = 6.5 Hz, 3H), 1.30 (m, 2), d "1.45 to 1.65 (mf, 3H), 1.80 (d anchó, J = 12.5 Hz, 2H), 2.52 (masked, 2H), 2.83 (m, 2H), 2.97 (q, jb = 6.5 Hz, 2H), 3.07 (mf, 2H) ), 3.25"(broad d, J = 12.5 Hz, 2H); 3.44 (mf, 2H); 6J3 (d, width, J = 9.0 Hz, 2H); 6.99 (dd, J = 9.0 and 3.0 Hz, 1H); 7.15 (extended mf, 1H); 7.52 (broad d, J = 9.0 Hz, 2H); 7.67 (d, J = 9.0 Hz, 1H); 7J3 (d, J c 3.0 Hz, 1H); 8.35 (extended mf, 1H); 8.63 (extended mf, 1H); 8.81 (extended mf, 2H); 12.4 (broad s, 1H).

LCMS hydrochloride: m / z 548 [M + H] +, ester 2- (3 m / z 409: [M + H] + - piperidin-4-yl-C5H10NC2H4CO, m / z propionylamino) - 275: [ M + 2H,] 2 '+ miz 295 benzothiazole-6- (base peak). acidic acid 4- H NMR spectrum [2- (2-hydroxy- (300MHz) - d in ppm - ethylamino) - in DMSO-d6: 1.32 (m, ethylamino-2H); from 1.45 to 1.65 (mf, benzenesulfonic 3H); 1.80 (broad d, J = 12.5 Hz, 2H); 2.52 (masked, 2H); 2.82 (m, 2H); 3.03 (mf, 2H); 3, 10 (mf, 2H); 3.25 25c (broad d, J = 12.5 Hz, 2H); 3.45 (masked, 2H); 3.69 (t, J = 5.5 Hz, 2H); 6J2 (broad d, j = 9.0 Hz, 2H); 6, 99 (dd, J = 8.5 and 2.5 Hz, 1 H); 7, 18 (extended mf, 1 H); 7.52 (broad d, J = 9.0 Hz, 2H) 7.67 (d, J = 8.5 Hz, 1 H) 7J3 (d, J = 2.5 Hz, 1 H) 8.50 ( mf extended, 1 H) 8J5 (extended mf, 1 H) 8.91 (extended mf, 2H) 12.4 (broad s, 1 H).

Intermediate 26: Preparation of 2-tert-butoxycarbonylamino-benzothiazole-6-yl ester of 4-isobutylamine-benzenesulfonic acid A solution of the 2-tert-buoxycarbonylamino-benzofiazo I-6-yl ester of 4-fluoro-benzenesulfonic acid (inverse 15) (1 g, 2.32 mmol), of isobutylamine (517 mg, 7.07 mmol), of carbonate of cesium (845 mg, 2.59 mmol) in 12 ml of DMSO is stirred at 80 ° C for one night. 60 ml of water are added to the reaction medium. Exírae with aceíaío of efilo. The organic phase is washed with water, with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness. The remainder is washed with ethyl ether, yielding 880 mg of 2-ferc-buzoxycarbonylamino-benzoyiazole-6-yl ester of 4-isobuphylamino-benzenesulfonic acid (beige solid) with a yield of 80%. LC / MS (méfodo A1): [M + H] +: 478.01, re-time: 4.31 min. Intermediate 27: Preparation of 2-amino-benzothiazole-6-yl ester of 4-isobuylamino-benzenesulfonic acid A solution of the 2-tert-buoxycarbonylamino-benzoyiazole-6-yl ester of 4-isobuylamino-benzenesulfonic acid (intermediate 26) (880 mg, 1.93 mmol), of trifluoroacetic acid (5.7 ml, 74 mmol) in 6 ml of dichloromethane and 600 μl of water is stirred overnight at ambient temperature. The reaction medium is concentrated to dryness and the residue is washed with ethyl ether which yields 700 mg of 2-amino-benzoyiazole-6-yl ester of 4-isobuphylamino-benzenesulfonic acid in the form of the trifluoroacetic acid salt (white solid) with a yield of 52%. LC / MS (method A1): [M + H] +: 378.05, retention time: 3.60 min.

Example 28: Preparation of 2- (2-piperidin-4-yl-acetylamino) -benzothiazole-6-yl ester hydrochloride of 4-isobufiyl-amino-benzenesulfonic acid CIH 1 ßra efapa: A solution of the 2-amino-benzothiazole-6-yl ester of 4-isobutylamino-benzenesulfonic acid (below 27) (300 mg, 0.495 mmol) of tert-buíyl ester of 4-carboxymethyl-piperidin-1 - carboxyl (361 mg, 1, 485 mmol) of HBTU (563 mg, 1.485 mmol) of NN-diisopropylethylamine (432 μL, 2.475 mmol) in 4 mL of dimethylformamide was added at room temperature overnight. Water is added to the reaction medium which is extracted with ethyl acetate. The organic phase is washed with water, with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness. The rest obtained is purified by HPLC on a Dynamax C18, 60A, 21 x 300 mm column by means of a water / acetoniiryl mixture 95/5 for 5 min, by means of a gradient of 5 to 40% in water for 5 min, by means of a gradient of 40 to 80% acetylonitrile in water lasts 30 min, with a gradient of 80 to 95% acetonitrile in water for 5 min, and with a water / acetonitrile mixture 5/95 for 5 min with a flow of 20 ml / min . The solvents each contain 0.07% (v / v) of uro-fluoroacetic acid.

The fractions are collected every 30 seconds and are controlled by analytical HPLC on a Hypersil C 1 8 column, 4.6 x 50 mm. By means of a gradient of 0 to 1 00% of aniononiírilo in water in 10 min with a flow of 1 ml / min. The solvents each contain 0.07% (v / v) trifluoroacetic acid. The fractions that contain what is expected are concentrated to dryness, which yields tert-buílic ester of acid 4-. { [6- (4-iso-bu'i-lamino-benzenes-ulfon-loxi) -benzoic-azole-2-y-Icarbamoyl] -methyl} piperidin-1-carboxylic acid. 2nd stage: A solution of 4-acid eeryc-buyl ester. { [6- (4-iso bufi lam-no-benzenes ulfon i loxi) -benzothiazol-2-i Icarbamoi I] -methyl} piperidin-1-carboxylic acid (11.0 mg, 182 pmol), dioxane (2 ml) and 4N hydrochloric acid in dioxane are added to the reaction for 2 hours at ambient temperature. The reaction medium is concentrated to dryness and the residue obtained is washed with ethyl ether yielding 183 mg of 2- (2-piperidin-4-yl-acetylamino) -benzothiazole-6-yl ester of 4-isobutylamino acid -benzenesulfonic (white powder) with a yield of 64%. Mass: IE: m / z 502 [M +], m / z 377: [M +] - C7H12NO, m / z 212: [SO2PhNHiBu] + - m / z 165 [377 - 212] + \ m / z 126: [ C7H12NO] + - (base peak). 1 H NMR spectrum (300MHz) - d in ppm - in DMSO-d6: 0.94 (d, J = 6.5 Hz, 6H); 1.45 (m, 2H); from 1.77 to 1.88 (mf, 3H); 2, 10 (extended mf, 1 H); 2.52 (masked, 2H); 2.83 (m, 2H); 2.91 (d, J = 6.5 Hz, 2H); 3.25 (broad d, J = 12.5 Hz, 2H); 6.67 (broad d, J = 9.0 Hz, 2H); 7.00 (di, J = 9.0 Hz, 1 H); 7, 15 (mf very spread, 1 H); 7.45 (broad d, J = 9.0 Hz, 2H); 7.67 (d, J = 9, 0 Hz, 1 H); 7.73 (d, J = 2.5 Hz, 1 H); 8.62 (mf ex., 1 H); 8.85 (mf ex., 1 H); 12.5 (broad s, 1 H).

Example 29: Using the same method as that of Example 28, the following examples are made using the 2-amino-benzothiazole-6-yl ester of 4-isobuylamino-benzenesulfonic acid as a precursor (in-medium 27) combined with different acids. These examples are presented in the following table: nterme o: repair of er-erc- or oxcar-n-benzoyiazole-6-yl of phofen-2-sulfonic acid A solution of the (6-hydroxy-benzothiazol-2-yl) -carbamic acid tert-butyl ester (inmediate 14) (527 mg, 1.979 mmol), of 2-iiophenylsulfonyl chloride (433 mg, 2.37 mmol), of erytylamine (677 μl, 4.75 mmol) in 10 ml of aceilone is placed under agitation for one night at ambient temperature. The reaction medium is concentrated to dryness. The rest obtained is washed with water, with aceine and with ethyl ether which yields 621 mg of 2-tert-buloxycarbonylamino-benzoyiazole-6-yl ester of phofen-2-sulfonic acid (light gray powder) with a yield of 76% . LC / MS: [M + H] + = 412.98, re-time: 3.99 min. Inmediate 31: Preparation of the 2-amino-benzoyiazole-6-yl ester of thiophen-2-sulfonic acid A solution of the 2-tert-buzoxycarbonylamino-benzofiazole-6-yl ester of the phofen-2-sulfonic acid (inertiate 30) (1.5 g, 3.63 mmol), of urea-fluoride acid (15 ml, 196 mmol) in 1 5 m) of dichloromethane and 600 μl of water is agitated for 2 hours at room temperature. The reaction medium is concentrated to dryness yielding 900 mg of 2-amino-benzothiazole-6-yl ester of iophene-2-sulfonic acid in the form of trifluoroacetic acid salt (oil) in a yield of 76%. LC / MS (method A1): [M + H] +: 31 3, retention time: 3, 1 1 min. Example 32: Preparation of the 2 - [(piperidin-4-carbonyl) -amino | -benzoyiazole-6-yl ester of the phofen-2-sulfonic acid; compound with uro-fluoroacetic acid The step was: A solution of the 2-amino-benzothiazole-6-yl ester of thiophene-2-sulphonic acid (injector 31) (80 mg, 0.256 mmole), of Boc-isonipecic acid (176 mg, 0.768 mmol), HBTU (291 mg, 0J68 mmol) of N, N-diisopropylethylamine (223 μl, 1.28 mmol) in 4 ml of dimethylformamide is stirred for 3 days at room temperature. 30 ml of water are added to the reaction medium which is extracted with ethyl acetate. The organic phase is washed with water and with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness yielding 4- [6-iiophen-2-sulfonyloxy) benzopylacezole tert-buíyl ester. 2-ylcarbamoyl] -piperidine-1-carboxylic acid. LC / MS: [M + H] +: 523.96, refusal time: 4.00 min. 2nd step: A solution of 4- [6-phiofen-2-sulfonylloxy) benzothiazol-2-yl carbamoyl] -piperidin-1-carboxylic acid tert-buíyl ester of trifluoroacetic acid (1.5 ml) in 1.5 ml of dichloromethane and 100 μl of water is stirred overnight at room temperature. The reaction medium is concentrated to dryness, taken up in 500 μl of DMSO and a sample is purified by means of preparative LC / MS (method B), yielding 3 mg of ester 2 - [(piperidine-4-carbonyl) -am No] -benzoyiazole-6-yl of iiophen-2-sulfonic acid; compound with uro-fluoroacetic acid. LC / MS: [M + H] +: 423, 97, re-time: 2.74 min. Example 33: Using the same method as that of example 32, the following examples are carried out using the 2-amino-benzothiazole-6-yl ester of iophene-2-sulfonic acid as a precursor (intermediate 31) combined with different acids. These examples are presented in the following table, the LC / MS are carried out according to the A1 method: Intermediate 34: Preparation of 4- (2-diisopropylamino-elylamino) -benzenesulfonic acid 2-amino-benzothiazole-6-yl ester A solution of the 2-amino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (intermediate 16) (100 mg, 0.225 mmol) and of N, N-diisopropylethylenediamine (395 μl, 2.25 mmol) in 5 ml of NMP is heated at 150 ° C with microwaves "Emrys ™ Opimizer" for 20 minutes. The reaction mixture is taken up in 50 ml of ethyl acetate and the resulting solution is washed 5 times with 50 ml of water. After decanting, the organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure to give 1 00 mg of 4- (2-diisopropylamino-epilamino) 2-amino-benzothiazole-6-yl ester. benzenesulfonic LC / MS (method A1): [M + H] + = 449.22, retention time: 2.36 min. Intermediate 35: Preparation of the eerc-buílic ester of acid 3-. { 6- [4- (2-Diisopropylamino-elylamino) -benzenesulfonyloxy] -benzothiazol-2-ylca rbamoyl} -azel id i n-1 -carboxyl On a solution of 4- (2-diisopropylamino-yl-amino) -benzenesulfonic acid 2-amino-benzofiazole-6-yl ester (inertiate 34) (100 mg, 0.225 mmol) in 5 ml of dimethylylformamide are added 68 mg of mono-ester. β-bulyl acid azeidin-1,3-dicarboxylic acid, 256 mg HBTU and 235 μl DI DI. The solution obtained is stirred for 20 hours at room temperature. After adding 50 ml of water, the reaction mixture is extracted 3 times with 25 ml of ethyl acetate. The dried extracts over magnesium sulfate, filtered and evaporated under reduced pressure yield 700 mg of crude oil. This oil is purified by elution in a dichloromethane / methanol mixture 95: 5 flow of 10 ml / min in 20 g of silica to yield 39 mg of 3- ferric acid ester. { 6- [4- (2-d isopropyl to mino-eti lami no) -benzenesulf onyloxy] -benzof i azole-2-icarbam or i} -azetid i n-1 -carboxylic. LC / MS: [M + H] +: 632, 1 1 Retention time: 3.00 min. Method A1 Intermediate 36: Preparation of 4- (2-di isopropyl am i no-etiIamino) -benzenesulfonic acid 2- (8-ert-butoxycarbonylamino-octanoylamino) -benzothiazole-6-yl acid ester On a solution of the 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2-amino-benzothiazole-6-yl ester (intermediate 34) (100 mg, 0.225 mmol) in 5 ml of dimethylformamide are added 175 mg of acid. -lert-butoxycarbonylamino-octanoic, 256 mg of H BTU and 235 μl of DIEA. The solution obtained was stirred for 20 hours at ambient temperature. After adding 50 ml of water, the reaction mixture is extracted 3 times with 25 ml of ethyl acetate. The extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure yielding 338 mg of crude oil. This oil is purified by elution in a dichloromethane / methanol mixture 95: 5 flow of 10 ml / min in 10 g of silica to yield 153 mg of 2- (8-tert-buxoxycarbonylamino-ocyanoylamino) -benzofiazole-6-yl ester of the 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid. LC / MS: [M + H] +: 690.33 Retention time: 3.25 min. Method A1 Intermediate 37: Preparation of the 4- (2-diisopropylamino-eylamino) -benzenesulfonic acid 2 - [(1-tert-bufoxicarbonylamino-cyclopenianecarbonyl) -amino] -benzoyiazole-6-yl ester.

On a solution of the 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2-amino-benzothiazole-6-yl ester (intermediate 34) (100 mg, 0.225 mmol) in 5 ml of dimethylformamide is added 155 mg of acid. -terc-bufoxicarbonylamino-cyclopenianecarboxylic acid, 256 mg of HBTU and 235 μl of DI EA. The solution obtained is stirred for 20 hours at ambient temperature. After adding 50 ml of water, the reaction mixture is excreted 3 times with 25 ml of ethyl acetate. The extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure and yield 720 mg of crude oil. This oil is purified by elution in a dichloromethane / methanol mixture 95: 5 flow of 10 ml / min in 10 g of silica to yield 120 mg of ester 2 - [(1-ene-budoxycarbonylamino-cyclopenianecarbonyl) -amino] - 4- (2-diisopropylamino-eylamino) -benzenesulfonic acid benzothiazole-6-yl. LC / MS: [M + H] +: 660.56 Retention time: 3.1.1 min. Method A1 Intermediate 38: Preparation of 4- (. {6- [4- (2-di isopropyl am i no-ethylamino) -benzenesulf onyl oxy] -benzoti azol-2-carbamyl tert-butyl ester .}. -methyl) -pi perid in-1 -carboxylic To a solution of the 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2-amino-benzothiazof-6-yl ester (intermediate 34) (100 mg, 0.225 mmol) in 5 ml of dimethylformamide is added 164 mg of sodium ester. 4-carboxymethyl-piperidin-1-carboxylic acid butyl, 256 mg of HBTU and 235 μl of DIEA. The solution obtained is stirred for 20 hours at ambient temperature. After adding 50 ml of water, the reaction mixture is extracted 3 times with 25 ml of ethylene acelaide. The extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure and yield 380 mg of sour oil. That oil is purified by elution in a dichloromethane / mefanol 95: 5 mixture flow of 10 ml / min in 10 g of silica to yield 90 mg of 4- (. {6- [4- (2) tert-bufyl ester. -diisopropylamino-ethylamino) -benzenesulfonyloxy] -benzothiazole-2-carbamoyl.} - methyl) -piperidin-1-carboxylic acid. LC / MS: [M + H] +: 674.57 Retention time: 3, 1 1 min. MeOH A1 Example 39: Preparation of the 4- (2-diisopropylammon-ephilamino) -benzenesulfonic acid 2 - [(azephidin-3-carbonyl) -amino] -benzopiazole-6-yl ester.

To a solution of 39 mg of tert-buíyl ester of 3- acid. { 6- [4- (2-Diisopropylamino-eylamino) -benzenesulfonyloxy] -benzoyiazol-2-ylcarbamoyl} α-Zephidin-1-carboxylic acid (below 35) in 1.5 ml of dioxane is added 1.5 ml of hydrochloric dioxane. The resulting solution is stirred for 5 hours at ambient temperature and evaporated under reduced pressure to yield 49 mg of acelline which is purified by LC / MS and yields 9.7 mg of ester 2 - [(azeidin-3-carbonyl) -amino. ] -benzothiazole-6-yl of 4- (2-diisopropylamino-eylamino) -benzenesulfonic acid. MS: DCI: m / z = 532 [M + H] +; ES +: m / z = 532 [M + H] +; m / z = 266.8 [M + 2H] ++ Example 40: Preparation of 2- (8-amino-octanoylamino) -benzothiazole-6-yl ester of 4- (2-diisopropylamino-ylamino) -benzenesulfonic acid.

To a solution of 153 mg of tert-buíyl ester of 3-acid. { 6- [4- (2-Diisopropylamino-eylamino) -benzenesulfonyloxy] -benzothiazol-2-ylcarbamoyl} -zetidin-1-carboxylic acid (inmediate 36) in 3 ml of dioxane is added 3 ml of hydrochloric dioxane. The resulfanfe solution is stirred for 5 hours at room temperature and evaporated under reduced pressure to yield 152 mg of 4- (2-diisopropylamino-epilamino) 2- (8-amino-ocyanoylamino) -benzoyiazole-6-yl ester) benzenesulfonic MS: DCI: m / z = 590 [M + H] +; ES +: m / z = 590 [MH] +; m / z = 295, 95 [M + 2H] ++ 1 H-NMR spectrum (300MHz) -D in ppm-in DMSO-d6: 1.20 to 1.38 (mf, 16H); from 1.42 to 1.68 (mf, 6H); 2.29 (t, J = 7.0 Hz, 2H); 2.74 (mf, 4H); 3.16 (mf, 2H); from 3.50 to 3.80 (mf, 2H); 6.71 (broad d, J = 9.0 Hz, 2H); 6.96 (broad d, J = 9.0 Hz, 1 H); 7.33 (broad f, J = 6.0 Hz, 1 H); 7, 51 (broad d, J = 9.0 Hz, 2H); 7.64 (d, J = 9, 0 Hz, 1 H); 7.68 (broad s, 1 H); 7.85 (extended mf, 3H); 9.98 (mf, 1 H); 12.4 (broad s, 1 H). Example 41_: Preparation of 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2 - [(1-amino-cyclopenfanocarbonyl) -amino] -benzothiazole-6-yl ester of 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid To a solution of 120 mg of the 4- (2-diisopropylamino-eylamino) -benzenesulfonic acid 2 - [(1-tert-butoxycarbonylamino-cyclopentanecarbonyl) -amino] -benzoyiazole-6-yl ester (intermediate 37) in 3 ml of dioxane, 3 ml of hydrochloric dioxane are added. The resulting solution was stirred for 5 hours at ambient temperature and evaporated under reduced pressure to yield 90 mg of aceifene which is purified by LC / MS and yields 32 mg of ester 2 - [(1-amino-cyclopentanecarbonyl) -amino] - 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid benzothiazole-6-yl. 1 H NMR spectrum (300MHz) - D in ppm - in DMSO-d6 + 1 drop of AcCOD: 1, 26 (d, J = 6.5 Hz, 12H); from 1.85 to 2.02 (mf, 6H); 2.35 (mf, 2H); 3.19 (t, J = 7.0 Hz, 2H); 3.50 (,, J = 7.0 Hz, 2H); 3.68 (mt, J = 6.5 Hz, 2H); 6.72 (broad d, J = 9.0 Hz, 2H); 6.98 (dd, J = 8.5 and 2.5 Hz, 1 H); 7.55 (d wide, J = 9.0 Hz, 2H); 7.76 (d, J = 8.5 Hz, 1 H); 7.85 (d, J = 2.5 Hz, 1 H). Example 42: Preparation of the 4- (2-diisopropylamino-ylylamino) -benzenesulfonic acid 2- (2-piperidin-4-yl-acetylamino) -benzoyiazole-6-yl ester To a solution of 90 mg of 4- (. {6- [4- (2-diisopropylamino-ethylamino) -benzenesulfonyloxy] -benzothiazole-2-carbamoyl} -methyl) -piperidin-1-tert-butyl ester -carboxylic acid (intermediate 38) in 3 ml of dioxane is added 3 ml of hydrochloric dioxane. The resulting solution was stirred for 5 hours at room temperature and evaporated under reduced pressure to yield 90 mg of oil which is purified by LC / MS and yields 1 01 mg of 2- (2-piperidin-4-yl-acetylamino) ester. 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid-benzothiazole-6-yl acid. LC / MS: [M + H] +: 574.23 Retention time: 2.24 min. Method A1 MS: DCI: m / z = 574 [MH +] ES +: m / z = 574 [MH +]; m / z = 287.9 [(M + 2H) / 2] + 1 H NMR spectrum (400MHz) - D in ppm - in DMSO-d6 + 1 drop of AcCOD at 1 1 0 ° C (383 K): 1 , 33 (d, J = 7.0 Hz, 12H); from 1.42 to 1.58 (mf, 2H); from 1.85 to 1.95 (mf, 2H); 2, 15 (mf, 1 H); 2.31 (d, J = 7.0 Hz, 2H); from 2.87 to 2.97 (mf, 2H); 3.22 (t, J = 6.5 Hz, 2H); from 3.24 to 3.32 (mf, 2H); 3.58 (t, J = 6.5 Hz, 2H); from 3.65 to 3.75 (mf, 2H); 6.75 (broad d, J = 9.0 Hz, 2H); 7.08 (dd, J = 8.5 and 2.5 Hz, 1 H); 7, 58 (broad d, J = 9.0 Hz, 2H); 7.62 (d, J = 2.5 Hz, 1 H); 7.65 (d, J = 8.5 Hz, 1 H).

Example 43: Preparation of the 4- (2-diisopropylamino-erylamino) -benzenesulfonic acid 2-acetylamino-benzothiazole-6-yl ester On a solution of the 2- (2-amino-benzoyiazole-6-yl ester of 4- (2-diisopropylamino-ephilamino) -benzenesulfonic acid (inimer 34) (70 mg, 0.156 mmol) in 4 ml of dimethylylformamide is added 28 mg of acetic acid, 1 77.5 mg of HBTU and 163 μl of DI EA. The obtained solution is stirred for 20 hours at room temperature. After adding 50 ml of water, the reaction mixture is extracted 3 times with 25 ml of ethyl acetate. The dry extractions on magnesium sulfate, filtered and evaporated under reduced pressure yield 130 mg of crude oil. This oil is purified by LC / MS to yield 15 mg of 4- (2-diisopropylamino-erylamino) -benzenesulfonic acid 2-acetylamino-benzopiazole-6-ethyl ester. IR: 3,420; 2,989; 2,680; 1 .674; 1.599; 1.542; 1,452; 1 .367; 1 .268; 1,202; 1 . 176; 1,161; 1 . 134; 1.094; 914; 851; 831; 753; 720 and 579 c "1 1 H NMR spectrum (300MHz) - D in ppm - in DMSO-d6: 1, 30 (d, J = 6.5 Hz, 12H), 2.22 (s, 3H); 3, 23 (mf, 2H), 3.51 (mf, 2H), 3.72 (mf, 2H), 6.74 (broad d, J = 9.0 Hz, 2H), 6.90 (extended mf, 1 H), 7.03 (broad d, J = 9.0 Hz, 1 H), 7.56 (broad d, J = 9.0 Hz, 2H), 7.68 (d, J = 9.0 Hz) , 1 H), 7.70 (d, J = 3.0 Hz, 1 H), 8.46 (mf, 1 H), 12.4 (broad s, 1 H).

Example 44: 4- (2-diisopropylamino-eylamino) -benzenesulfonic acid 2- (2-methoxy-acetylamine) -benzoyiazole-6-yl ester On a solution of 2-amino-benzoyiazole-6-yl acid of 4- (2-diisopropylamino-ephilamino) -benzenesulfonic acid (intermediate 34) (70 mg, 0.156 mmol) in 4 ml of dimethylformamide are added 42.1 mg of methoxyacemic acid, 177.5 mg of HBTU and 163 μl of DI EA. The obfended solution is agitated for 20 hours at room temperature. After adding 50 ml of water, the reaction mixture is extracted 3 times with 25 ml of ethyl acetate. The dry extracts on magnesium sulfate, filtered and evaporated under reduced pressure yield 98 mg of crude oil. This oil is purified by LC / MS to yield 47.8 mg of 4- (2-d-isopropyl amino-ethylamine) -benzenesulfonic acid 2- (2-methoxy-a-methylamino) -benzoliazole-6-yl ester. IR: 3,390; -2,993; 2,666; 1 .674; 1.599; 1.535; 1,452; 1 .365; 1,269; 1,202; 1 .175; 1 .161; 1 .125; 1 .094; 914; 852; 830; 757; 720 and 570 cm "1 1 H NMR spectrum (300MHz) - D in ppm - in DMSO-d6: 1, 29 (d, J = 6.5 Hz, 12H), 3.23 (mf, 2H); 3, 40 (s, 3H); 3.52 (mf, 2H); 3.72 (extended mf, 2H); 4.22 (s, 2H); 6.75 (broad d, J = 9.0 Hz, 2H); ), 6.90 (broad t, J = 6.0 Hz, 1 H), 7.05 (dd, J = 9.0 and 2.5 Hz, 1 H), 7.55 (broad d, J = 9.0 Hz, 2H), 7.70 (d, J = 9.0 Hz, 1 H), 7.72 (d, J = 2.5 Hz, 1 H), 8.48 (mf, 1 H) ); 12.35 (s, 1 H).

Example 45: 4- (2-Diisopropylamino-ethylamino) -benzenesulfonic acid 2- (cyclopentanecarbonyl-amino) -benzothiazole-6-yl ester On a solution of 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2-amino-benzothiazole-6-yl ester (intermediate 34) (70 mg, 0.156 mmol) in 4 ml of dimethylformamide are added 42.1. mg of methoxyacemic acid, 177.5 mg of HBTU and 163 μl of DIEA. The obfended solution was stirred for 20 hours at ambient temperature. After adding 50 ml of water, the reaction mixture is extracted 3 times with 25 ml of ethyl ether. Dry extracts on magnesium sulfate, filtered and evaporated under reduced pressure yield 135 mg of crude oil. This oil is purified by LC / MS to yield 55.2 mg of 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2- (cyclopentane-carbonyl-amino) -benzothiazole-6-yl ester. IR: 3.423; 2,968; 2,672; 1 .673; 1.599; 1.535; 1, 451; 1 .365; 1,261; 1,202; 1 .175; 1 .161; 1 .137; 1 .094; 916; 852; 829; 752; 720 and 568 cm "1 1 H NMR spectrum (300MHz) - D in ppm - in DMSO-d6 + 1 drop of AcOD: 1, 27 (d, J = 6.5 Hz, 12H), from 1, 52 to 1 , 80 (mf, 7H), 1, 90 (mf, 1 H), 2.97 (m, J = 7.5 Hz, 1 H), 3.20 (I, J = 6.5 Hz, 2H); 3.50 (f, J = 6.5 Hz, 2H); 3.69 (me, J = 6.5Hz, 2H); 6.71 (broad d, J = 9.0 Hz, 2H); , 04 (dd, J = 9.0 and 2.5 Hz, 1 H), 7.53 (d wide, J = 9.0 Hz, 2H), 7.58 (d, J = 2.5 Hz, 1 H), 7.64 (d, J = 9.0 Hz, 1 H) Intermediate 46 Preparation of 2- (6-urea-buzoxycarbonylamino-hexanoylamino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid In a 20 ml balloon, fitted with a magnetic bar, a solution of 2-amino-benzoyiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (intermediate 16, patenyebenzoiazole-V2) (0.15 g, 0.46 g) was heated. mmoles), of BOC-6-aminohexanoic acid (0.128 g, 0.555 mmol), of HATU (0.21 g, 0.555 mmol), of N, N-diisopropylethylamine (95 μl, 0.555 mmol) in 2 ml of DMF approximately 60 ° C (ext.) for 5 h. The reaction medium is extracted with ethyl acetate, washed with a solution of hydrochloric acid N and with water. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The remainder is purified by chromatography with Quad 12/25 in a Bioiage-type cartridge (40 g of silica) eluting with a mixture of methylene chloride-lsopropanol 97: 3. After evaporating the solvent, 0.199 g are recovered. of 2- (6-urea-buoxycarbonylamino-hexanoylamino) -benzoyiazole-6-yl ester of 4-fluoro-benzenesulfonic acid with a yield of 80%. Intermediate 47 - Preparation of 4- (2-diisopropylamine-erylamino) -benzenesulfonic acid 2- (6-tert-buffoxycarbonylamino-hexanoylamino) -benzoyiazole-6-yl ester A solution of 0.1 94 g of 2- (6-tert-buffoxycarbonylamino-hexanoylamino) -benzoyiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (0.1 94 g, 0.36 mmol) and N, N-diisopropylethylenediamine (0.33 ml, 1.8 mmol) in 4 ml of NMP was heated for 10 min at 150 ° C with microwaves. The brute production of the reaction is exfoliated with AcOEí and washed with water. The organic phase is dried over sodium sulfafo, filtered and evaporated: 1.8 g (yellow liquid) is obtained. Chromatograph on silica 60 (40-63 μm) eluting with a 93: 7 CH2Cl2-MeOH mixture. After evaporating the solvent, a gum (0.215 g) is obtained which is triturated in water. The water is removed, the gum is collected with toluene and evaporated to dryness yielding 0.13 g of 2- (6-tert-butoxyGarbonilamino-hexanoylamino) -benzothiazole-6-yl ester of 4- (2-diisopropylamino) -ethylamino) -benzenesulfonic with a yield of 54%. Example 49 Preparation of the hydrochloride of the 2- (6-amino-hexanoylamino) -benzoyiazole-6-ylco ester of 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid ester.

In a 10 ml balloon, fitted with a magnetic rod, 0.12 g of 4- (2-diisopropylamino-elylamino) - 2- (6-etr-buloxycarbonylamino-hexanoylamino) -benzothiazole-6-yl ester are introduced. benzenesulfonic acid in 2 ml of AcOEt and 0.5 ml of hydrochloric acid in solution in AcOEt are added dropwise. A gum is formed which is stirred for 1 h at room temperature. The reaction medium is taken up with water and brought to pH 8 with 28% ammonia. Extract with AcOEt, wash with water and dry the organic phase over sodium sulfate. After filtration, the filtrate is evaporated to dryness, yielding 0.1 g of white powder which is put into solution in 5 ml of methanol and brought to pH 2 with hydrochloric acid in solution in AcOEt. The suspension is evaporated to dryness and taken up with 5 ml of water before freeze-drying yielding 91 mg of 4- (2-diisopropylamino) 2- (6-amino-hexanoylamino) -benzofiazole-6-yl ester hydrochloride. erylamino) -benzenesulfonic with a yield of 80%. Medium 50 Preparation of the 2- (7-ene-buzoxycarbonylamino-heptanoylamino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid According to the method of intermediate 46, the 2- (7-tert-butoxycarbonylamino-heptanoylamino) -benzofiazole-6-yl ester of 4-fluoro-benzenesulfonic acid is prepared by the 2-amino-benzothiazole-6-yl ester of the acid 4-fluoro-benzenesulfonic acid (intermediate 16, patenyebenzothiazole_V2) with BOC-7-aminoethylene glycol which yields 0.164 g of the product. Intermediate 51 Preparation of 2- (7-tert-budoxycarbonylamino-hepyaoylamino) -benzoyiazole-6-yl ester of 4- (2-diisopropylamino-erylamino) -benzenes ulphonic acid According to the method of intermediate 47, the 2- (7-tert-butoxycarbonylamino-hepyaoylamino) -benzothiazole-6-yl ester of 4- (2-diisopropylamino-eylamino) -benzenesulfonic acid is prepared by the action of 2- (7-) ester. 4-fluoro-benzenesulfonic acid tert-butoxycarbonylamino-heptanoylamino) -benzothiazal-6-yl with N, N-diisopropylethylenediamine. The product is purified by column chromatography of the Biotage type (8 g of silica) eluting with a CH 2 Cl 2 -MeOH 95: 5 mixture, yielding 86 mg of the product with a yield of 44%. Example 52 Preparation of 2- (7-amino-heptanoylamino) -benzothiazole-6-yl ester hydrochloride of 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid.

According to the method of Example 49, the 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2- (7-amino-heptanoylamino) -benzothiazole-6-yl ester hydrochloride is prepared by hydrolysis of the 2- (7-) ester. 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid ferc-bufoxycarbonylamino-hepfanoylamino) -benzothiazole-6-yl in the presence of hydrochloric acid in solution in AcOEt, which yields 47 mg of hydrochloride with a yield of 77%. Example 53 Preparation of 4- (2-isopropylamino-ethylamino) -benzenesulfonic acid 2- (cyclopropanecarbonylamino) -benzofiazole-6-yl ester hydrochloride A solution of 2- (cyclopropanecarbonylamino) -benzoyiazo-6-yl ester of 4-fluoro-benzenesulfonic acid (example 53, patentbenzothiazole-V2) (145 mg, 0.37 mmol) and N-isopropylethylenediamine (233 μl, 1.85 mmol) ) in 4.5 ml of NMP is heated at 150 ° C with microwaves for 5 minutes. The reaction mixture is diluted with AcOEt, washed 3 times with water and extracted twice with AcOEt. The organic phases are combined, dried over sodium sulfate, filtered and taken to dryness. The 165 mg of crude product is purified by chromatography on silica: column AIT 8 g. Eluent: CH2Cl2 / MeOH / NH4OH: 90/10/1. The solid obtained (96 mg) is placed in solution in AcOEt and brought to pH 2 with hydrochloric acid in solution in AcOEt. The suspension is evaporated to dryness and taken up with 5 ml of water and freeze-dried to yield 76 mg of 2- (2-pentapropylamino-eylamino) -benzenesulfonic acid 2- (cyclopropanecarbonylamino) -benzofiazole-6-yl ester hydrochloride. . Intermediate 54 Preparation of the 2-isobuyrylamino-benzofiazole-6-yl ester of 4-fluoro-benzenesulfonic acid According to the method of intermediate 46, the 2-isobutyrylamino-benzoyiazole-6-yl ester of 4-fluoro-benzenesulfonic acid is prepared by the 2-amino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (intermediate 16). , patenfebenzoyiazole_V2) with isobutyric acid. The reaction mixture is crystallized with ethyl ether and, after filtering with suction, 0.17 g of colorless solid are isolated in a yield of 86%. EXAMPLE 55 Preparation of 4- (2-diisopropylamine-erylamino) -benzenesulfonic acid 2-isobutyrylamino-benzoyiazole-6-yl ester hydrochloride According to the method of Example 53, the hydrochloride of the 2,4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2-isobuydylamino-benzofiazole-6-yl ester is prepared by the action of! 2-isobuyrylamino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid with N, N-diisopropyleylenediamine. The crude product of the reaction is extracted with AcOEf and washed with water. The organic phase is dried over sodium sulfate, filtered and evaporated: 0.277 g of the crude product is obtained which is chromatographed on a biogeo silica column (40 g), eluting with a CH 2 Cl 2 -MeOH 90: 10 mixture. The obtained oil is chrysalised. in heptane. The product is redissolved in 5 ml of AcOEi and a solution of hydrochloric acid in AcOEt is added dropwise until pH 2. The hydrochloride is filtered off with suction, washed with AcOEt and dried under vacuum at 40 ° C. 0.112 g of the hydrochloride of the 4- (2-diisopropylamino-eylamino) -benzenesulfonic acid 2-isobuydylamino-benzofiazof-6-yl ester hydrochloride are isolated in 42% yield. Intermediate 56 Preparation of 2-propionylamino-benzoyiazole-6-yl ester of 4-fluoro-benzenesulfonic acid -ot O-A o According to the method of intermediate 46, the 2-propionylamino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid is prepared by the action of the 2-amino-benzoyiazole-6-yl ester of 4-fluoro-benzenesulfonic acid. Fluorobenzenesulfonic acid (inlemediate 16, palenlebenzothiazole_V2) with propionic acid. The product, 0.397 g, is obtained with a yield of 93%.

Example 57 Preparation of 2- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2-propionylamino-benzothiazole-6-yl hydrochloride.

According to the method of example 53, the 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2-propionylamino-benzothiazole-6-yl ester is prepared by the action of the 2-propionylamino-benzothiazole-6-yl ester Fluoro-benzenesulfonic with N, N-diisopropylethylenediamine by heating 10 min with microwaves at 150 ° C. The product, 0.09 g, is obtained after purification with a 45% yield in the hydrochloride form. Example 58 Preparation of 4- (2-hydroxy-2-methyl-propylamino) -benzenesulfonic acid 2-propionylamino-benzothiazole-6-yl ester According to the method of example 53, 4- (2-hydroxy-2-methyl-propylamino) -benzenesulfonic acid 2-propionylaminobenzoylacezole-6-ester is prepared by the action of 2-propionyl-amino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid with 1-amino-2-meiyl-propan-2-ol heating for 20 min with microwaves at 150 ° C. The production, 0.096 g, is obtained after purification with a yield of 50% in the hydrochloride form. Intermediate 59 2- (cyclobutanecarbonyl-amino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid According to the method of intermediate 46, the 2- (cyclobufanocarbonyl-amino) -benzofiazole-6-yl ester of 4-phenyl-benzenesulfonic acid is prepared by the 2-amino-benzothiazole-6-yl ester of 4-fluorocarboxylic acid. benzenesulfonic acid with cyclobutanecarboxylic acid. EXAMPLE 60 Preparation of 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2- (cyclobutanecarbonylamino) -benzothiazole-6-yl ester hydrochloride According to the method of Example 53, the 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2- (cyclobutanecarbonyl-amino) -benzothiazole-6-yl ester is prepared by the action of the 2-propionylamino-benzofiazole-6-yl ester of 4-fluoro-benzenesulfonic acid with N, N-diisopropylethylenediamine by heating for 10 min with microwaves at 150 ° C. The product, 0.054 g, is obtained after purification with a yield of 1 8% in the hydrochloride form. Intermediate 61 Preparation of 2- (3-pyridin-3-yl-propionylamino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid According to the method of intermediate 46, the 2- (3-pyridin-3-yl-propionylamino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid is prepared by the action of the 2-amino-b.enzothiazole-6 ester -alkyl of 4-fluoro-benzenesulfonic acid with 3- (3-pyridyl) -propionic acid. The product is obtained with a quantitative yield. Example 62 Preparation of the 2- (3-pyridin-3-yl-propionylamino) -benzoyiazole-6-yl ester hydrochloride of 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid ester.

According to the method of Example 7, the 4- (2-diisopropylamino-ethylamino) -benzenesulfonic acid 2- (3-pyridin-3-yl-propionylamino) -benzothiazole-6-yl ester is prepared by the action of the 2- (2-ester. 3-pyridin-3-yl-propionylamino) -benzothiazole-6-yl of 4-fluorobenzenesulfonic acid with N, N-diisopropylethylenediamine by heating for 10 min with microwaves at 150 ° C. The product, 0.045 g, is obtained after purification with a 23% yield in the hydrochloride form. Example 63: Preparation of 4- (2-hydroxy-methyl-propylamino) -benzenesulfonic acid 2- (3-pyridin-3-yl-propionylamino) -benzothiazole-6-yl ester hydrochloride According to the method of Example 53, the 4- (2-hydroxy-methyl-propylamino) -benzenesulfonic acid 2- (3-pyridin-3-yl-propionylamino) -benzothiazole-6-yl ester is prepared by the action of ester 2 - (3-pyridin-3-yl-propionylamino) -benzothiazole-6-yl of 4-fluoro-benzenesulfonic acid with 1-amino-2-methyl-propan-2-ol heating 20 minutes with microwaves at 150 ° C. The product, 0.104 g, is obtained after purification with a yield of 52% in the hydrochloride form. Intermediate 64: Preparation of the 2-acetylamino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid In a test tube, provided with a magnetic bar, a solution of the 2-amino-benzothiazole-6-yl ester of the 4-fluoro-benzenesulfonic acid (intermediate 16) (101.2 mg, 0.312 mmol), acetic acid (56.2 mg, 0.936 mmol), HBTU (355 mg, 0.936 mmol), N, N- diisopropylamine (326 μl, 1.872 mmol) in 5 ml of dimethylformamide for 20 hours at room temperature. 1 00 ml of water is added to the reaction medium which is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated. The residue obtained is taken up in ethyl acetate and purified in a Varian flash cartridge containing 5 g of porosity silica 15-35 μm by mixing 1% methanol in dichloromethane. After evaporating the solvent, 66 mg of 2-acetylamino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (yellow oil) are obtained in 58% yield. LC / MS (method A1): [M + H] +: 367, 14, retention time: 3, _50 min. Example 65: Preparation of 4- (2-isopropylamino-ethylamino) -benzenesulfonic acid 2-acetylamino-benzothiazole-6-yl ester A solution of the 2-acetylamino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (intermediate 64) (66 mg, 0, 180 mmol) of N is stirred into a test tube fitted with a magnetic rod. - sopropylethylene diamine (55, 2 mg, 0.540 mmol), of cesium carbonate (58.6 mg, 0. 180 mmol) in 2 ml of dimethyl sulfoxide overnight at 80 ° C. 1 00 ml of water is added to the reaction medium which is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and evaporated. The residue purified by LC / MS yields 43 mg of 4- (2-isopropylamino-ethylamino) -benzenesulfonic acid 2-acetylamino-benzopiazole-6-yl ester (white powder) with a yield of 53%. LC / MS (method A1): [M + H] +: 449.35, retention time: 3.28 min. 1 H NMR spectrum at 300 MHz in BRUKER AVANCE DPX-300 spectrometer with chemical shifts (d in ppm) - in the solvent dimethisulfoxide-d6 (DMSO-d6) referred to 2.50 ppm: Solid presumption for the product salified with TFA with: 1, 21 (d, J = 7.0 Hz, 6H); 2.20 (s, 3H); 3.07 (m, 2H); from 3.20 a 3.35 (masked m, 1 H); 3.41 (m, 2H); 6.72 (broad d, J = 8.5 Hz, 2H); 6.93 (broad t, J = 6.0 Hz, 1 H); 7.01 (dd, J = 2.5 and 8.5 Hz, 1 H); 7.53 (broad d, J = 8.5 Hz, 2H); 7.68 (d, J = 8.5 Hz, 1 H); 7.69 (d, J = 2.5 Hz, 1 H); 8.30 (extended m, 2H); 12.4 (broad s, 1 H). Intermediate 66: Preparation of the 2- (2-methoxy-acylamino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid In a test tube, fitted with a magnetic bar, a solution of the 2-amino acid ester is stirred. benzothiazole-6-yl of 4-fluoro-benzenesulfonic acid (intermediate 16) (101.2 mg, 0.312 mmol), methoxyacetic acid (84.3 mg, 0.936 mmol), HBTU (355 mg, 0.936 mmol), N, N-diisopropylamine (326 μl, 1.872 mmol) in 5 ml of dimethylformamide for 20 hours at room temperature. 1 00 ml of water is added to the reaction medium which is exfoliated with elyl acetate. The organic phase is dried over magnesium sulphate and evaporated. The rest obtained is collected with elilo acetate and purified in a Varian flash cartridge containing 5 g of silica of porosity 1 5-35 μm with a mixture of 1% methanol in dichloromelane. After evaporating the solvent, 89 mg of 2-bul-3-enoylamino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (yellow oil) are obtained in a yield of 72%. LC / MS (method A1): [M + H] +: 397.1 1, retention time: 3.59 min. Example 67: Preparation of 2- (2-methoxy-acetylamino) -benzothiazole-6-yl ester of 4- (2-isopropylamino-ethylamino) -benzenesulfonic acid A solution of the 2- (2-methoxy-acetylamino) -benzothiazole-6-yl ester of 4- (2-isopropylamino-ethylamino) -benzenesulfonic acid (intermediate 66) is stirred in a test tube fitted with a magnetic rod. (89 mg, 0.224 mmol), of N-isopropyleylenediamine (68.7 mg, 0.672 mmol), of cesium carbonate (73 mg, 0.224 mmol) in 2 ml of dimethylsulfoxide overnight at 80 ° C. 100 ml of water are added to the reaction medium which is extracted with acetyl ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated. The purified resin medium LC / MS yields 46.6 mg of 4- (2-isopropylamino-eylamino) -benzenesulfonic acid 2- (2-meioxy-acetylamino) -benzopiazole-6-yl ester (white powder) in a yield 43% LC / MS (method A1): [M + H] +: 479.35, retention time: 3.33 min. 1 H NMR spectrum at 300 MHz in specimen of BRUKER ADVANCE DPX-300 with the chemical shifts (d in ppm) - in the solvent dimethisulfoxide-d6 (DMSO-d6) referred to 2.50 ppm: Solid presumption for the production salified with TFA with: 1, 21 (d, J = 7.0 Hz, 6H); 3. 07 (broad t, J = 6.5 Hz, 2H); from 3.15 to 3.35 (masked m, 1 H); 3.38 (s, 3H); 3.41 (m, 2H); 4.20 (s, 2H); 6.72 (broad d, J = 8.5 Hz, 2H); 6, 93 (broad, J = 6.0 Hz, 1 H); 7, 03 (dd, J = 2.5 and 8.5 Hz, 1 H); 7.53 (broad d, J = 8.5 Hz, 2H); 7.69 (d, J = 8.5 Hz, 1 H); 7.71 (d, J = 2.5 Hz, 1 H); from 8, 10 to 8,45 (Expected M, 2H); from 12.0 to 12.5 (m greatly exceeded, 1 H). Inmediate 68 - Preparation of the 2- (cyclopeniane-carbonyl-amino) -benzoyiazole-6-yl ester of 4-fluoro-benzenesulfonic acid.

In a test tube, provided with a magnetic rod, a solution of the 2-amino-benzopiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (intermediate 16) (101.2 mg, 0.312 mmol) was stirred. of cyclopentanecarboxylic acid (53.4 mg, 0.936 mmol), of H BTU (355 mg, 0.936 mmol), of N, N-diisopropylamine (326 μl, 1, 872 mmol) in 5 ml of dimefilformamide for 20 hours at ambient temperature. 100 ml of water are added to the reaction medium which is exfoliated with ethyl aceaium. The organic phase is dried over magnesium sulphate and evaporated. The rest obtained is collected with acetyl ether and purified in a Varian flash cartridge containing 5 g of porosity silica 15-35 μm by means of a mixture of 1% methanol in dichloromethane. After evaporating the solvent, 90 mg of 2- (cyclopentane-carbonyl-amino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (yellow oil) are obtained in 68% yield. LC / MS (method A1): [M + H] +: 421, 13, retention time: 4.05 rain. Example 69: Preparation of 4- (2-isopropylamino-erylamino) -benzenesulfonic acid 2- (cyclopentanecarbonyl-amino) -benzoliazole-6-yl ester In a test tube, fitted with a magnetic rod, a solution of the 2- (2-mephoxy-acetylamino) -benzoyiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (intermediate 68) was stirred (90 mg, 0.214 mmol). ), of N-isopropylethylenediamine (65.6 mg, 0.642 mmol), of cesium carbonate (69.7 mg, 0.214 mmol) in 2 ml of dimethyl sulfoxide overnight at 80 ° C. 1 00 ml of water is added to the reaction medium which is extracted with acetyl ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated. The residue purified by LC / MS yields 26.2 mg 2- (cyclopentanecarbonyl-amino) -benzoyiazole-6-yl ester of 4- (2-isopropylamino-eylamino) -benzenesulfonic acid (white powder) with a yield of 24% . LC / MS (method A1): [M + H] +: 503.39, re-use time: 3.68 min. 1 H NMR specimen at 300 MHz in spectrometer BRUKER ADVANCE DPX-300 with chemical displacements (d in ppm) - in the solvent dimethylsulfoxide-d6 (DMSO-d6) referred to 2.50 ppm: Solid presumption for the product salified with TFA with: 1, 21 (d, J = 7.0 Hz, 6H); from 1.50 to 1.80 (m, 6H); from 1, 82 to 1, 98 (m, 2H); 2.98 (m, 1 H); 3.04 (m, 2H); from 3.15 to 3.55 (m, 3H); 6.71 (broad d, J = 8.5 Hz, 2H); 6.92 (broad f, J = 6.0 Hz, 1H); 7.02 (dd, J = 2.5 and 8.5 Hz, 1H); 7.53 (broad d, J = 8.5 Hz, 2H); from 7.65 to 7.70 (m, 2H); from 8.05 to 8.45 (very widely used m, 2H); 12.4 (m extended, 1 H). Intermediate 70: Preparation of 2-propionylamino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid A solution of the 2-amino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (intermediate 16) (500 mg, 1.14 mmol), of propionic acid, (253 mg, 3.42 mmol), of HBTU (1.23 g, 3.42 mmol) of N, N-diisopropylamine (737 mg, 5.7 mmol) in 6.5 ml of dimethylformamide is stirred overnight at room temperature. The reaction medium is evaporated to dryness. The dried residue is extracted twice with 50 ml of ethyl acetate and washed with water. The organic phase is washed with a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and evaporated. The oil obtained is solubilized in 35 ml of dimethylsulfoxide, purified 7 times by preparative HPLC on a Nucleodur C18 reverse phase column, 100 A, 10 μm by a gradient in 52 minutes from 5 to 95% acetonitrile with 0.07% of trifluoroacetic acid in water, with 0.07% trifluoroacetic acid. The flow is 70 ml / min. The fractions containing the appropriate product are concentrated to obtain 300 mg of 2-propionylamino-benzofiazole-6-yl ester of 4-fluoro-benzenesulfonic acid in 69% yield. NMR: 1 H NMR spectrum at 300 MHz in BRUKER AVANCE DPX-300 spectrometer with chemical displacements (d in ppm) - in dimethyl sulfoxide solution - d6 (DMSO-d6) referred to 2.50 ppm: 1, 1 1 (t , J = 7.5 Hz, 3H); 2.50 (partially masked m, 2H); 7.01 (dd, J = 2.5 and 8.5 Hz, 1 H); 7.51 (broad t, J = 9, 0 Hz, 2H); 7.68 (d, J = 8.5 Hz, 1 H); 7.79 (d, J = 2.5 Hz, 1 H); 7.94 (broad dd, J = 5.5 and 9.0 Hz, 2H); 12.4 (broad s, 1 H). Example 71 - Preparation of the 4- (2-isopropylamino-etyl) -benzenesulfonic acid 2-propionylamino-benzothiazole-6-yl ester; compound with trifluoroacetic acid A solution of the 2-propionylamino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (intermediate 70) (300 mg, 0.789 mmol), of N-isopropylethylenediamine (242 mg, 2.37 mmol), of cesium carbonate (256 mg, 0.789 mmol) in 4 ml of dimethylsulfoxide is set at 80 ° C with stirring for 7 h 30, and at ambient temperature for 2 days. The reaction medium is filtered and washed with 8 ml of dimethyl sulfoxide. The expected product is purified 3 times by preparative HPLC under the same conditions as for intermediate 70. 205 mg of 4- (2-isopropylamino-ylamino) -benzenesulfonic acid 2-propionylamino-benzothiazole-6-yl ester are obtained; compound with trifluoroacetic acid with a yield of 56%. NMR: 1 H NMR spectrum at 300 MHz in BRUKER AVANCE DPX-300 spectrometer with chemical shifts (d in ppm) - in the solvent dimethylsulfoxide-d6 (DMSO-d6) referred to 2.50 ppm: 1, 1 1 (t , J = 7.5 Hz, 3H), 1, 22 (d, J = 6.5 Hz, 6H); from 2.45 to 2.54 (m, partially masked, 2H); 3.07 (m, 2H); from 3.22 to 3.47 (partially masked m, 3H); 6.72 (broad d, J = 9.0 Hz, 2H); 6.93 (broad t, J = 6.0 Hz, 1 H); 7.02 (dd, J = 2.5 and 8.5 Hz, 1 H); 7.53 (broad d, J = 9.0 Hz, 2H); 7.67 (d, J = 8.5 Hz, 1 H); 7.69 (d, J = 2.5 Hz, 1 H); from 8.22 to 8.38 (extended m, 2H); 12.35 (broad s, 1 H). Intermediate 72 - Preparation of 2-butyrylamino-benzoyiazole-6-yl ester of 4-fluoro-benzenesulfonic acid According to the method of intermediate 70, intermediate 72 is synthesized using butyric acid. 80 mg of 2-butyrylamino-benzoyiazole-6-yl ester of 4-fluoro-benzenesulfonic acid are obtained in a yield of 18%. NMR: 1 H NMR spectrum at 30Ó MHz in BRUKER AVX DPX-300 spectrometer with the chemical displacements (d in ppm) - in the solvent dimethisulfoxide - d6 (DMSO-d6) referred to 2.50 ppm:. 0.92 (t, J = 7.5 Hz, 3H); 1.64 (m, 2H); 2.48 (partially masked m, 2H); 7.01 (dd, J = 2.5 and 8.5 Hz, 1 H); 7.51 (broad t, J = 9.0 Hz, 2H); 7.68 (d, J = 8.5 Hz, 1 H); 7.78 (d, J = 2.5 Hz, 1 H); 7.93 (broad dd, J = 5.5 and 9.0 Hz, 2H); 12.4 (broad s, 1 H). Example 73 - Preparation of 4- (2-isopropylamino-erylamino) -benzenesulfonic acid 2-butyrylamino-benzothiazole-6-yl ester; compound with trifluoroacetic acid According to the method of example 71, example 73 is obtained using intermediate 72 with N-isopropylethylenediamine. 37 mg of 4- (2-isopropylamino-ethylamino) -benzenesulfonic acid 2-butyrylamino-benzoyiazole-6-yl ester are obtained; compound with trifluoroacetic acid with a yield of 36%. NMR: Spectroscopy 1 H NMR at 300 MHz in BRUKER spectrometer ADVANCEMENT DPX-300 with the chemical displacements (d in ppm) - in the dissolve dimefilsulfoxide-d6 (DMSO-d6) referred to 2.50 ppm: 0.91 (í, J = 7.5 Hz, 3H); 1, 22 (d, J = 6.5 Hz, 6H); 1.63 (m, 2H); 2.47 (partially masked t, J = 7.5 Hz, 2H); 3.07 (m, 2H); from 3.20 to 3.37 (masked m, 1 H); 3.41 (m, 2H); 6.72 (broad d, J = 9.0 Hz, 2H); 6.94 (broad, J = 6.0 Hz, 1 H); 7.02 (dd, J = 2.5 and 8.5 Hz, 1 H); 7.53 (broad d, J = 9.0 Hz, 2H); 7.66 (d, J = 8.5 Hz, 1 H); 7.69 (d, J = 2.5 Hz, 1 H); 8.32 (extended m, 2H); 12.4 (broad s, 1 H). Intermediate 74 - Preparation of 2-isobutyrylamino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid According to the method of intermediate 70, intermediate 74 is synthesized using isobutyric acid. 75 mg of 2-isobutyrylamino-benzoyiazole-6-yl ester of 4-fluoro-benzenesulfonic acid are obtained with a yield of 1.7%. NMR: 1 H NMR Specimen at 300 MHz in BRUKER AVANCE DPX-300 spectroscopy with the chemical shifts (d in ppm) - in the solvent dimethisulfoxide-d6 (DMSO-d6) referred to 2.50 ppm: 1, 14 (d, J = 7.0 Hz, 6H); 2.79 (m, 1 H); 7.02 (dd, J = 2.5 and 8.5 Hz, 1 H); 7.51 (broad t, J = 9.0 Hz, 2H); 7.68 (d, J = 8.5 Hz, 1 H); 7.79 (d, J = 2.5 Hz, 1 H); 7, 93 (broad dd, J = 5.5 and 9.0 Hz, 2H); 12.4 (broad s, 1 H). Example 75 - Preparation of the 4- (2-isopropylamino-ethylamino) -benzenesulfonic acid 2-isobuyrylamino-benzothiazole-6-yl ester; compound with trifluoroacetic acid According to the method of example 71, example 75 is obtained by using the medium 74 with N-isopropylephylenediamine. 49 mg of 4- (2-isopropylamino-ethylamino) -benzenesulfonic acid 2-isopylamino-benzoyiazole-6-yl ester are obtained; compound with trifluoroacetic acid with a yield of 44%. NMR: 1 H NMR spectrum at 300 MHz in BRUKER AVANCE DPX-300 spectrometer with chemical shifts (d in ppm) - in the solvent dimethisulfoxide-d6 (DMSO-d6) referred to 2.50 ppm: 1, 14 (d, J = 6.5 Hz, 6H); 1, 22 (d, J = 6.5 Hz, 6H); 2.79 (, 1 H); 3.07 (m, 2H); from 3.25 to 3.37 (masked m, 1 H); 3.41 (m, 2H); 6.72 (broad d, J = 9.0 Hz, 2H); 6.93 (broad, J = 6.0 Hz, 1 H); 7, 03 (dd, J = 2.5 and 8.5 Hz, 1 H); 7.53 (broad d, J = 9.0 Hz, 2H); from 7.64 to 7.70 (m, 2H); 8.30 (extended m, 2H); 12.4 (broad s, 1 H). Intermediate 76 - Preparation of 2- (cyclobutanecarbonyl-amino) -benzoyiazole-6-yl ester of 4-fluoro-benzenesulfonic acid According to the method of intermediate 70, infer 76 is synthesized using cyclobutanecarboxylic acid. 185 mg of 2- (cyclobufanocarbonyl-amino) -benzofiazole-6-yl ester of 4-fluoro-benzenesulfonic acid are obtained in a yield of 40%. Example 77 - Preparation of 4- (2-isopropylamino-ethylamino) -benzenesulfonic acid 2- (cyclobutanecarbonyl-amino) -benzopiazole-6-yl ester; compound with uro-fluoroacetic acidH.

According to the method of example 71, example 77 is obtained by using the intermediate 76 with N-isopropyleylenediamine. 41 mg of 4- (2-isopropylamino-ethylamino) -benzenesulfonic acid 2- (cyclobutanecarbonyl-amino) -benzoyiazole-6-yl ester are obtained; compound with trifluoroacetic acid with a yield of 37%. NMR: 1 H NMR spectrum at 300 MHz in the BRUKER AVANCE DPX-300 spectrosphere with the chemical shifts (d in ppm) - in the solvent dimethisulfoxide-d6 (DMSO-d6) referred to 2.50 ppm: 1, 22 (d, J = 6.5 Hz, 6H); 1.84 (m, 1 H); 1.99 (m, 1 H); from 2, 10 to 2.30 (m, 4H); 3.07 (m, 2H); from 3.20 to 3.47 (masked m, 4H); 6.72 (broad d, J = 9.0 Hz, 2H); 6.97 (broad t, J = 6.0 Hz, 1 H); 7.01 (dd, J = 2.5 and 8.5 Hz, 1 H); 7.53 (broad d, J = 9.0 Hz, 2H); 7.67 (d, J = 8.5 Hz, 1 H); 7.69 (d, J = 2.5 Hz, 1 H); from 8.27 to 8.44 (extended m, 2H); 12.3 (broad s, 1'H). Intermediate 78: Preparation of 4-fluoro-benzenesulfonic acid 2-buyrylamino-benzoliazole-6-yl ester In a 20 ml balloon, fitted with a magnetic bar, a solution of the 2-amino-benzoyiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (intermediate 1 6) (359 mg, 1. 107 mmoles) is stirred, of butyric acid (146 mg, 1.66 mmol), of HATU (631 mg, 1.66 mmol), of N, N-diisopropylethylamine (0.286 ml, 1.66 mmol) in 5.5 ml of dimethylformamide 8 hours a 60 ° C and then left overnight at room temperature. The reaction medium is extracted with ethyl ether, washed with water and with a 0.1 N hydrochloric acid solution. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. The obtained residue (567 mg of light yellow solid) is purified by chromatography on a Bioiage 40 g silica cartridge eluting with a toluene-isopropanol 9: 1 mixture. After evaporating the solvent, 239 mg of 4-fluoro-benzenesulfonic acid 2-buyrylamino-benzoyiazole-6-yl ester (white solid) was obtained in 55% yield. Mass: LC / MS: m / z 395: [M + H] +, m / z 393: [MH] "1 H NMR spectrum at 400 MHz with chemical shifts (d in ppm) - in the solvent dimethylsulfoxide - d6 (DMSO-d6) referred to 2.50 ppm: 0.9ns 1 (t, J = 7.5 Hz, 3H), 1.64 (m, 2H), 2.47 (partially masked t, J 7.5 Hz, 2H), 7.01 (dd, J = 2.5 and 8.5 Hz, 1 H), 7.51 (broad t, J = 9.0 Hz, 2H), 7.68 (d, J = 8.5 Hz, 1 H-), 7.79 (d, J = 2.5 Hz, 1 H), 7.93 (dd, J = 6.0 and 9.0 Hz, 2H); 12, 4 (s broad, 1 H) Example 79: Preparation of 4- (2-diisopropylamino-phiamino) -benzenesuiphoic acid 2-butyrylamino-benzothiazole-6-yl ester hydrochloride A solution of 2-butyrylamino-benzothiazole-6-yl ester of 4-fluorobenzenesulfonic acid (intermediate 78) (100 mg, 0.2 mmol) is heated in a 5 ml microwave vial fitted with a magnetic bar. , of N, N-diisopropylethylene diamine (1 85 μl, 1.01 mmol) in 3 ml of N-methylpyrrolidone 10 min at 150 ° C with microwaves. The reaction medium is extracted with ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. The residue obtained is purified by chromatography on Merck silica (40-63 μm). After evaporating the solvent, 41 mg of colorless oil is obtained (crystallized to dryness). The product is dissolved in the smallest possible amount of ethyl acetate and 4N hydrochloric acid in dioxane solution is added. The medium is precipitated and concentrated, collected with water and filtered on a Milex 45 μm filter. The solution precipitates and 31 mg (28% yield) of 4- (2-dithiolamyl) -benzylsulfonic acid 2-butyrylamino-benzothiazole-6-yl ester hydrochloride are obtained after filtering with suction and drying in vacuum at 40 ° C. Mass - IE: m / z 1 14: (C3H7) 2NCH2 + (base peak) Absence of molecular ion. CI: m / z 519 [M + H] + (base peak). LC / MS: m / z 51 9 [M + H] +, m / z 51 7: [MH] '1 H NMR spectrum at 300 MHz with chemical shifts (d in ppm) - in the solvent dimethylsulfoxide - d6 ( DMSO-d6) referred to 2.50 ppm: 0.91 (t, J = 7.5 Hz, 3H); from 1, 20 to 1, 32 (broad m, 12H); 1.63 (m, 2H); from 2.42 to 2.55 (partially masked t, J = 7.5 Hz, 2H); 3.19 (m, 2H); 3.51 (m, 2H); 3.69 (m extended, 2H); 6.72 (broad d, J = 9.0 Hz, 2H); 6, 97 (broad, J = 6.0 Hz, 1 H); 7.02 (dd, J = 2.5 and 8.5 Hz, 1 H); 7.53 (broad d, J = 9.0 Hz, 2H); from 7.63 to 7.69 (m, 2H); 8.78 (extended m, 1 H); 12.4 (broad s, 1 H). Example 80: Preparation of 4- (2-hydroxy-2-methyl-propylamino) -benzenesulfonic acid 2-butyrylamino-benzothiazole-6-yl ester hydrochloride Into a 5 ml microwave vial, fitted with a magnetic bar, a solution of 4-phenyl-benzenesulfonic acid 2-b.uyi-benzothiazole-6-yl ester (intermediate 78) is heated (135 mg, 0.34 mmoles), of 1-amino-2-methy1-propan-2-ol (153 mg, 1.718 mmol) in 3 ml of N-methylpyrrolidone 20 min at 150 ° C with microwaves. The reaction medium is extracted with acetyl ether (3 * 20 ml) and washed with water (4 * 25 ml). The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. The residue obtained is purified by chromatography on silica, column AIT 15-35 μm 8 g, eluting with an acetyl mixture of ethylene / cyclohexane 9: 1. After evaporating the solvent 55 mg of colorless solid are obtained. The product is dissolved in the smallest possible amount of dioxane and 4 N hydrochloric acid is added in solution in dioxane. The precipitate obtained is filtered with suction, washed with dioxane and dried under vacuum at 40 ° C, yielding 42 mg of hydrochloride of the 2- (2-butyrylamino-benzoyiazole-6-yl ester of 4- (2-hydroxy-2) acid. -methyl-propylamino) -benzenesulfonic acid with a yield of 25%. Mass IE: m / z 463: [M +], m / z 228: [M +] - SO2PhNHCH2C3H7O CI: m / z 464: [M + H] + - LC / MS: m / z 464: [M + H] +, m / z 462: [MH] "1 H NMR spectrum at 400 MHz (d in ppm) - in the solvent dimethisulfoxide - d6 (DMSO-d6) referred to 2.50 ppm: 0.93 (t, J = 7.5 Hz, 3H), 1.15 (s, 6H), 1.66 (m, 2H), 2.46 a 2.59 (partially masked m, 2H); 3.04 (s, 2H); 6.76 (broad d, J = 9.0 Hz, 2H); 6.98 (dd, J = 2.5 and 8.5 Hz, 1 H); 7.42 (broad d, J = 9.0 Hz, 2H); 7.66 (d; J = 8.5 Hz, 1 H); 7.70 (d, J = 2.5 Hz, 1 H); 12.4 (broad s, 1 H). Example 81: Preparation of 4- (2-hydroxy-2-methyl-propylamino) -benzenesulfonic acid 2-tert-buzoxycarbonylamino-benzothiazole-6-yl ester A solution of the 2-tert-butoxycarbonylamino-benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (intermediate 15) (300 mg, 0.707 mmol), cesium carbonate (230 mg, 0.707 mmol), of 1-amino -2- Methyl-propan-2-ol (126 mg, 1.414 mmol) in 5 ml of dimethyl sulfoxide is stirred at 80 ° C for 72 hours. Water is added to the reaction medium and extracted 3 times with ethyl acetate.The organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness yielding 290 mg of ethyl ester. 4- (2-hydroxy-2-methyl-propylamino) -benzenesulfonic acid-tert-butoxycarbonylamino-benzothiazole-6-yl in an 83% yield Intermediate 82: Preparation of the 2-amino-benzothiazole-6-yl ester 4- (2-hydroxy-2-methyl-propylamine) -benzenesulfonic acid; compound with trifluoroacetic acid A solution of the 2- (tert-butoxycarbonylamino-benzothiazole-6-yl ester of 4- (2-hydroxy-2-methyl-propylamino) -benzenesulfonic acid (intermediate 81) (170 mg, 0.344 mmol), of trifluoroacetic acid (14, 9 g, 130.7 mmol) in 10 ml of dichloromethane and 100 μl of water is stirred for 2 hours at room temperature. The reaction medium is evaporated to dryness, taken up in ethyl acetate and washed with water and with a saturated solution of sodium chloride. Drying over magnesium sulfate and concentration to dryness of the organic phase yield 130 mg of 4- (2-hydroxy-2-methyl-propylamino) -benzenesulfonic acid 2-amine-benzothiazole-6-yl ester; compound with trifluoroacetic acid with a yield of 96%. LC / MS: [M + H] + = 394.06, retention time = 2.90 min. In-termediate 83: Preparation of 4- (2- {6- [4- (2-hydroxy-2-mephyl-propylamino) -benzenesulfonyloxy] -benzothiazole-2-ylcarbamyl} -ercarboxylic acid ester. -efil) -piperidin-1 -carboxylic A solution of 1 -Boc-piperidin-4-ylpropionic acid (176 mg, 0.686 mmol), of HBTU (260 mg, 0.686 mmol), of N, N-diisopropylethylamine (185 mg, 1, 435 mmol) in 10 ml of dimethylformamide is stirred for 10 min. The 2-amino-benzoyiazole-6-yl ester of 4- (2-hydroxy-2-meityl-propylamino) -benzenesulfonic acid; Compound with uro-fluoroacetic acid (intermediate 82) (130 mg, 0.33 mmol) is added to the reaction medium which is stirred for 48 hours at room temperature. Water is added to the reaction medium and extracted several times with ethyl acephelius. The organic phase is dried over magnesium sulfate and concentrated to dryness. The dried residue is purified in reverse phase chromatography on a C 1 8 Dynamax 300 x 20 mm column, by a gradient in 5 minutes of 5 to 40% of aniononiiril in water with 0.07% of rhipifluoroacetic acid and from 40 to 80 % in 30 minutes. The fractions containing the product are evaporated to dryness which yields 11.1 mg of 4- (2- {6- [4- (2-hydroxy-2-methyl-propylamino) -benzenesulfonyloxy) tert-butyl ester. ] -benzothiazol-2-carbamoyl.] -elyl) -piperidine-1-carboxylic acid with a yield of 51%. LC / MS: [M + H] + = 633.00, re-use time: 3.94 min. Example 84: Preparation of 2- (3-piperidin-4-yl-propionylamino) -benzoyiazole-6-yl ester hydrochloride of 4- (2-hydroxy-2-methyl-propylamino) -benzenesulfonic acid A solution of 4- (2- {6- [4- (2-hydroxy-2-meityl-propylamino) -benzenesulfonyloxy] -benzothiazol-2-ylcarbamoyl} -yl) -piperidin} -trial acid ester. -1-oxoic acid (1 mg, 0.173 mmol) in 8 ml of dioxane and 8 ml of dioxane / HCl, 4N is stirred overnight at ambient temperature. The formed precipitate is filtered, solubilized in methanol and evaporated to dryness. The remainder is washed with ethyl ether, yielding 103 mg of 2- (3-piperidin-4-yl-propionylamino) -benzofiazole-6-yl ester hydrochloride of 4- (2-hydroxy-2-methyl-propylamino) -benzenesulfonic with a 95% yield. LC / MS (method A1): [M + H] + = 533.04, retention time = 2.66 min. NMR: Specimen 1 H NMR at 300 MHz in specimen of BRUKER ADVANCE DPX-300 with the chemical displacements (d in ppm) - in the dissolve dimefilsulfoxide-d6 (DMSO-d6) referred to 2.50 ppm: For 80% of mixture, we have: 1.13 (s, 6H); from 1.22 to 1.40 (m, 2H); from 1.42 to 1.65 (m, 3H); from 1.75 to 1.85 (m, 2H); from 2.40 to 2.58 (partially masked m, 2H); from 2.75 to 2.90 (m, 2H); 3.02 (s, 2H); from 3.15 to 3.30 (m, 2H); 6.73 (broad d, J = 9.0 Hz, 2H); 6.97 (dd, J = 2.5 and 8.5 Hz, 1H); 7.41 (broad d, J = 9.0 Hz, 2H); 7.65 (d, J = 8.5 Hz, 1H); 7.70 (d, J = 2.5 Hz, 1H); from 8.32 to 8.53 (extended m, 1H); from 8.65 to 8.80 (extended m, 1H); 12.4 (broad s, 1H). IR: KBr 3.405; 2.971; 1,725; 1,597; 1,539; 1.470; 1,365; 1,161; 1.094; 915; 856; 748 and 578 cm "1 Example 85 - Preparation of 2- (cyclopropanecarbonyl-amino) -benzothiazole-6-yl ester of 5-pyridin-2-yl-thiophen-2-sulfonic acid A solution of (6-hydroxy-benzothiazol-2-yl) -amide of cyclopropanecarboxylic acid (intermediate 6) (60 mg, 0.256 mmol), of pyridine (80 μl, 0.991 mmol), of 4-dimethylaminopyridine (3 mg, 0.025) mmoles), and 5- (2-pyridyl) thiophene-2-sulfonyl chloride (99 mg, 0.384 mmol) in 2 ml of acetone is stirred for 24 hours at 40 ° C. The reaction medium is concentrated to dryness and taken up in 2 ml of DMSO and purified 4 times by preparative LC / MS (method B) yielding 10 mg of 2- (cyclopropanecarbonyl-amino) -benzofiazole-6-ester. -5-pyridin-2-yl-iiophen-2-sulfonic acid. NMR: Specimen 1 H NMR at 300 MHz in BRUKER spectrometer ADVANCE DPX-300 with the chemical displacements (d in ppm) - in the solvent dimethisulfoxide-d6 (DMSO-d6) referred to 2.50 ppm: From 0.98 to 1.10 (m, 4H); 1.90 (m, 1 H); 7, 15 (broad d, J = 8.5 Hz, 1 HOUR); from 7.30 to 7.38 (m, 2H); 7.61 (d, J = 4.0 Hz, 1 H); 7.67 (broad s, 1 H); 7, 77 (d, J = 4.0 Hz, 1 H); 7.87 (broad t, J = 8.0 Hz, 1 H).; 7, 99 (broad d, J = 8.0 Hz, 1 H); 8.55 (broad d, J = 5.0 Hz, 1 H); 13, 5 (m extended, 1 H). MS: I E m / z = 457 M + m / z = 389 (M - C4H4O) + m / z = 325 (m / z = 389 - SO2) +. m / z = 69 C4H5O + base peak Example 87 - Preparation of the 2- (cyclopropanecarbonyl-amino) -benzothiazole-6-yl ester of 4- (1-oxyl-2,2,6,6-tetramethyl-p] peridin- 4-ylamino) -benzenesulfonic acid A solution of the 2- (cyclopropanecarbonyl-amino) -benzothiazole-6-yl ester of 4-fluoro-benzenesulfonic acid (example 7) (0.352 mmol, 1 38 mg), of 4-amino-TEMPO (0.387 mmol, 66 mg) of cesium carbonate (0.352 mmol, 14 mg) in 3.5 ml of dimethyl sulfoxide is heated with stirring for 24 hours. 4- Amino-TEMPO is added twice (2 times 66 mg) after 24 and 48 hours. After 48 hours, the reaction is placed at ambient temperature for 48 hours. The solution is diluted with water, extracted with ethyl acetate, washed with a saturated solution of sodium chloride and dried over sodium sulphate and evaporated to dryness yielding 258 mg of crude product. Esfe is purified by flash chromatography on a 5 g silica cartridge. The eluents used are respectively dichloromethane, dichloromethane with 1% ammoniacal methanol 0.01% to 7M. 28 mg of 2- (1-oxyl-2,2,6,6-tetramethyl-pipentin-4-ylamino) -benzenesulfonic acid 2- (cyclopropanecarbonyl-amino) -benzothiazole-6-yl ester are obtained in a yield of 14% MS: ES m / z = 544 MH + base peak IR: KBr 3.388; 3,252; 2.925; 1,686; 1,598; 1 .546; 1, 451; 1 .327; 1,266; 1 .167; 1 .094; 907; 852 and 747 cm "1 Intermediate 88: Synthesis of 4- [2- (bis-benzyloxy-phosphoryloxy) -2-methylene-propylamino-benzenesulfonic acid 2- (cyclopropanecarbonyl-amino) -benzoliazole-6-yl ester A solution of 2- (2-hydroxy-2-methyl-propylamino) -benzenesulfonic acid 2- (cyclopropanecarbonylamino) -benzothiazole-6-yl ester (Example 1) (0.855 mmol, 394 mg), of 1 H-tetrazole (2,563 mmol, 179 mg), of dibenzyl diisopropyl phosphoramidite (1.70 mmol, 590 mg) in 6.4 ml of dichloromethane is stirred at room temperature for 2 hours. The reaction medium is cooled to 7 ° C and a solution of 3-chloroperoxybenzoic acid (1.025 mmol, 252 mg) in 1.2 ml of dichloromethane is slowly added. The reaction medium is agitated overnight. 1 ml of a 1 M sodium metabisulphite solution is added. The organic phase is washed with 10 ml of a solution of 1 M sodium metabisulfite, 2 times with 10 ml of a saturated solution of sodium bicarbonate and with 10 ml of a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness. The dried residue obtained is solubilized in dichloromethane and purified in an Interchim flash cartridge containing 50 g of silica of porosity 1 5-35 μm by a gradient of 20 to 50% ethyl acetate in cyclohexane. After evaporating the solvent from the fractions containing the expected product, 419 mg of 2- (cyclopropanecarbonyl-amino) -benzothiazole-6-yl ester of 4- [2- (bis-benzyloxy-phosphoryloxy) -2- is obtained. meti I-pro pi lam i no] -benzenesulfonic with a yield of 68%. LC / MS (method A1): [M + H] + = 722, 13, retention time 4.13 min. Example 89: Synthesis of 2- (2-meiiii-2-phosphonooxy-propylamino) -benzenesulfonic acid 2- (cyclopropanecarbonyl-amino) -benzoyiazo-6-yl ester To a solution of 4- [2- (bis-benzyloxy-phosphoryloxy) -2-methyl-propylamino-benzenesulfonic acid 2- (cyclopropanecarbonyl-amino) -benzofiazole-6-yl ester (intermediate 88) (0.441 mmol, 318 mg ), of ammonium formate (4.41 mmol, 278 mg) in 15 ml of ethanol is added 300 mg of 10% palladium on carbon. The reaction medium is stirred under reflux overnight. An LC / MS analysis indicates that the monobenzylated product remains. 280 mg (4.41 mmol) of ammonium formate and 100 mg of 10% palladium on carbon are added to the reaction medium which is refluxed for 6 hours. The reaction medium is filtered and concentrated. The oil obtained is reactivated with 278 mg of ammonium formate (4.41 mmol) and 300 mg of 10% palladium on carbon in 15 ml of ethanol. The reaction medium is stirred and heated to reflux for 1 H20. The reaction medium is filtered and concentrated to dryness. The rest obtained is purified by preparative LC / MS (method B) yielding 6.2 mg of 4- (2-methyl-2-phosphonooxy) 2- (cyclopropanecarbonyl-amino) -benzoliazole-6-yl ester. propylamino) -benzenesulfonic acid with a yield of 3%. NMR: 1 H NMR spectrum at 300 MHz in BRUKER AVANCE DPX-300 spectrometer with chemical displacements (d in ppm) - in the solvent dimethisulfoxide - d6 (DMSO-d6) referred to.2, 50 ppm: From 0.90 to 1, 01 (m, 4H); 1, 41 (s, 6H); 2, 00 (m, 1 H); from 3, 10 to 3.50 (masked m, 2H); 6.75 (broad d, J = 9.0 Hz, 2H); 6.89 (broad t, J = 6.0 Hz, 1 H); 7.97 (dd, J = 2.5 and 8.5 Hz, 1 H); 7.43 (broad d, J = 9.0 Hz, 2H); 7.66 (d, J = 8.5 Hz, 1 H); 7.70 (d, J = 2.5 Hz, 1 H); 12.7 (s wide, 1 H). Experimental protocols of biochemical assays 1 Protocol CDK2 / cyclin E: Purification of the CDK2 / Cyclinase- (His) 6 complex by IMAC (Affinity Chromatography with Metal I immobilized): Two recombinant baculoviruses containing the human sequences that respectively encode CDK2 are used and Cyclin E (the latter contains a hexa-histidine tag at the C-terminus) to co-infect Sf21 insect cells. Two to three days after the start of co-infection, the cells are harvested by centrifugation and then stored at -40 ° C until used. After defrosting and lysing the cells mechanically, the complex present in the lysate supernatant is purified by means of nickel affinity chromatography (I MAC), and stored at -80 ° C. Ensavo Flashplate CDK2 / CiclinaE in the form of 96 wells. A format in 96-well plates coated with strepfavidin is used to test the acfivity of the compounds on the kinase activity of CDK2 / Cyclin E. To carry out this assay, the biotinylated peptide substrate, fragment of the protein pRb, is solubilized ( biotinyl- SACPLNLPLQNNHTAADMYLSPVRSPKKKGSTTR-OH), at the concentration 1 mM in the kinase buffer (HEPES / 50 mM NaOH, 1 mM NaCl, 5 mM MgCl2, pH 7.5) in order to form a stock solution stored at -20 ° C in aliquots of 10 μL. On the day of the experiment, an aliquot of this solution is thawed and diluted in kinase buffer containing 1 mM of Dithiothreitol and buffer is immediately added in order to obtain a concentration of 14.3 μM. 70 μL of this solution is added to each well of the Flashplate in order to obtain a final concentration of the subtraction of 10 μM when the enzymatic reaction is carried out in a final volume of reaction medium of 100 μL (compare, below). Intermediate dilutions of inhibitors (products of the invention) with different concentrations are prepared in DMSO from 10 mM stock solutions in independent tubes. In this manner, 1 000 μM, 333.3 μM, 1 1 1, 1 μM, 37.03 μM, 12.35 μM, 4.1 1 μM and 1.37 μM dilutions are made. One μL of each of these solutions (or 1 μL of DMSO for the controls) is transferred to the wells of the assay plate. To each well, 19 μl of a solution of a mixture of adenosine triphosphate (ATP) and ATPy33P in the kinase buffer is added at a concentration of 5.26 μM of photon ATP and 52.6 μCi / ml of 33P. The enzymatic reaction is initiated by the addition of 10 μL per well of a 200 nM CDK2 / Cyclin E 200 nM solution in the kinase buffer containing 1 mM dithiothreitol (or 10 μL of kinase buffer containing 1 mM of diiofreifol for the targets of the reaction). After the addition of each of the reagents, the final volume of each well is 1 00μL, the final concentration of the subtrauss is 10 μM, the final concentrations of the inhibitors are 10 μM, 3.33 μM, 1.1 1 μM , 0.37 μM, 0.123 μM, 0.041 μM and 0.014 μM (depending on the concentration of the intermediate dilution), the final concentration of ATP is 1 μM, the final amount of 33P is 1 μCi / well, and the final concentration of the CDK2 / Cyclin E complex is 20 nM. After addition of all reagents, the assay plate is incubated at 30 ° C with orbital shaking at 650 rpm. When the incubation is finished, the plate is washed several times with 300 μL per well of PBS (Phosphafe Buffered Saline, Saline Solution buffered with Phosphate, pH = 7.4 without calcium or magnesium, reference 1001 0-015, Gibco BRL). The incorporation of 33P into the peptide is quantified by scintillation counting with a Packard Topcounf coiler. NXT The inhibitory activity of the products of the invention is evaluated by eliminating the concentration of the inhibitor which produces a 50% decrease in enzyme activity (IC 50). 2 Protocol CDK4 / Cyclin D1: Purification of the CDK4-HA / Cyclin D1 - (His) 6 complex by MAC (Immobilized Metal Affinity Chromatography): Two recombinant baculoviruses containing the human sequences encoding respectively CDK4-HA ( C-terminal fusion with the label Hemagglutinin) and Cyclin D 1 - (His) 6 to coinfect the Sf9 insect cells. Sixty hours after the start of co-infection, the cells are harvested by centrifugation and frozen at -20 ° C until used. After thawing in buffer A (200 mM HEPES pH 7.0, 50 mM NaCl, 2 mM MgCl2, 25 mM imidazole, 1 mM TCEP, 10% glycerol (w / v), 1 mM NaF, 1 mM Na3VO4), Stir 1 h at 4 ° C, and centrifuge, the complex present in the lysis supernatant is purified by nickel affinity chromatography (IMAC) and stored at -80 ° C. Ensavo Flashplate CDK4 / CiclinaD1 in 96-well format. A "Flashplate" plate assay of 96 wells coated with sreptavidin is used to evaluate the inhibition of the CDK4 / cyclin D1 kinase complex by the products of the invention. To carry out this test, the bioinlated peptide substrate, fragment of the pRb protein, (biotinyl-RPPTLSPIPHIPRSPYKFPSSPLR-amide), is solubilized at the 2 mM concentration in the kinase buffer (50 mM HEPES / NaOH, 1 mM NaCl, 5 mM MgCl 2, pH = 7, 5) in order to constitute a stock solution that is stored at -20 ° C in aliquots of 10 μl. On the day of the experiment, an aliquot of this solution is thawed and diluted in kinase buffer containing 1 mM of dithioeryol and added immediately in order to obtain a final peptide concentration of 2.571 μM. Setenía μL of this solution is deposited in each well of the Flashplate plate in order to obtain a final substrate concentration of 1.8 μM when the enzymatic reaction is carried out in a final volume of 1 00 μL (compare, below). Intermediate dilutions of inhibitors (products of the invention) with different concentrations are prepared in DMSO from 1mM stock solutions in separate tubes. In this manner, 1 000 μM, 333.3 μM, 1 1 1, 1 μM, 37, 03 μM, 12.35 μM, 4.1, 1 μM and 1.37 μM dilutions are made. One μL of each of these solutions (or 1 μL of DMSO for the controls) is transferred to the wells of the assay plate. To each well, 1 μl of a solution of a mixture of adenosine triphosphate (ATP) and ATP 33P in the kinase buffer is added at the concentration of 5.26 μM of total ATP and 78.9 μCi / ml of 33P. . The enzymatic reaction is initiated by the addition of 10 μL per well of a solution of the 250 nM CDK4 / Cyclin D1 complex in the kinase buffer containing 1 mM di-triethyl diol (or 10 μL of kinase buffer containing 1 mM dithiothreitol for the targets of the reaction). At the end of the different additions the final volume of each well is 1000 μl, the final concentration of the substrate is 1.8 μM, the final concentrations of the inhibitors are 10 μM, 3.33 μM, 1.1 μM, 0 , 37 μM, 0.123 μM, 0.041 μM and 0.014 μM (depending on the concentration of the in-termediate dilution), the final concentration of ATP is 1 μM, the final amount of 33P is 1.5 μCi / μl and the final concentration of the CDK4 / Cyclin D1 complex is 25 nM. After additions of all reagents, the assay plate is incubated at 30 ° C with orbital shaking at 650 rpm. After incubation, the plate is washed three times with 300 μL per well of PBS buffer (Phosphate Buffered Saline, Saline Solution buffered with Phosphate, pH = 7.4 without calcium or magnesium, reference 10010-015, Gibco BRL). The incorporation of 33P into the peptide subtraction is determined by scintillation counting with a Packard Topcount counter. NXT The inhibitory activity of the products of the invention is evaluated by determining the inhibitor concentration that causes a 50% decrease in the enzymatic activity (IC 50). 3. Aurora2 The inhibitory effect of the compounds against the Aurora2 kinase is determined by a scintillation assay with radioactivity. A complete recombinant Aurora2 enzyme, the N-ferminal end of which was labeled with histidine, was expressed in E. coli and purified to a quality close to homogeneity. The C-terminal fragment (Q1687-H2101) of a NuMA (Nuclear protein that is associated with the Mitotic Apparatus) expressed in E. coli, and whose N-terminal end has been labeled with histidine, was purified by nickel chelate chromatography and it is used as a substrate in the Aurora2 kinase assay.

The kinase activity of Aurora2 is determined by nickel chelate saturated microplate scintillation (New England Nuclear, model SMP1 07). Each well contains 1000 μl of the following solution: 0.02 μM of Aurora2; 0.5 μM of NuMA susírate; 1 μM of ATP with 0.5 μCi of ATP- [33P]. The solutions are incubated for 45 minutes at 37 ° C. The test pad is removed and the wells are washed twice with 300 μl of the buffer kinase. The radioactivity is determined in each well by means of a Packard Model Top Count NXT device. The background noise is determined in duplicate in the wells containing radioactive ATP only that they contain the phlaced kinase in the same manner as the other samples. The control activity is carried out by determining in duplicate the radiation in the complete test mixture (ATP, Aurora2 and the NuMA subframe), in the absence of the test compound. The inhibition of the Aurora2 activity with a compound of the invention is expressed as a percentage of inhibition of the control activity in the absence of test compound. The isiaurosporin is added to each well as an inhibition control.

Claims (14)

1. CLAIMS 1. Compounds that correspond to the following general formula (I): wherein: X represents a group selected from a covalent bond, (CH2) n, with n equal to 1 or 2 - Ar represents an aryl or heteroaryl group; this group being optionally substituted with a group selected from the groups alkyl, halogen, NR1 R2 (F F and R2 being chosen from the groups hydrogen, alkyls, cycloalkyls or together can form a heterocyclic or heteroaryl radical, these groups themselves being optionally substituted) , SO2alkyl, Salkyl, alkoxy, heteroaryl or aryl-R represents a group selected from hydrogen, an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy or amino group; R may be optionally substituted with one or more groups chosen from the same radicals as those defined for R.
2. 2. Compounds according to claim 1 characterized in that the optional substituents of the groups R1 and R2 are selected from hydroxyl, heteroaryl, cycloalkyl or aminoalkyls
3. 3. Compounds according to claim 1, characterized in that the alkyl groups are straight or branched chains containing from 1 to 10 carbon atoms.
4. 4. Compounds according to claim 1, characterized in that the cycloalkyl groups are cyclic alkyl chains containing from 3 to 10 carbon atoms.
5. 5. Compounds according to claim 1, characterized in that the heterocycloalkyl groups are cyclic alkyl chains containing from 3 to 10 carbon atoms and contain at least one heteroatom chosen from O, N or S.
6. 6. Compounds according to claim 1, characterized in that NR- groups | R2 one of the groups R-i or R2 is a hydrogen atom.
7. 7. Compounds according to any of claims 1 to 6, characterized in that all the groups R, R- and R2 are optionally substituted with an alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, amino, hydroxyl, alkoxy or halogen group.
8. 8. Compounds according to claim 16 characterized in that the aryl and heteroaryl radicals are chosen from monocyclic radicals optionally containing one or more heteroatoms chosen from O, N and S or the radicals fused with another cycle containing 5 or 6 links and optionally one to three heteroatoms chosen from O, N and S.
9. 9. Compounds according to claim 1 characterized in that the aryl or heteroaryl radicals are chosen from the phenyl, pyridyl, pyrimidine, triazinyl, pyrrolyl, imidazolyl, thiazolyl, furyl, thienyl groups, indolyl, azaindazolyl, isobenzofuranyl, isobenzothienyl, benzoxazolyl, benzothiazolyl, arylvinylene, arylamido, arylcarboxamide, aralkylamine, quinolinyl, isoquinolyl, cinolyl, quinazolyl, naphthyridyl, triazolyl or tetrazolyl.
10. 10. Compounds according to claim 9, characterized in that the aryl and heteroaryl groups are selected from phenyl, thienyl, pyrazolyl or imidazolyl groups, optionally substituted. eleven .
11. Compounds according to claim 10, characterized in that the phenyl group is substituted with a group selected from amino groups and halogens, in particular chlorine and fluorine.
12. 12. Compounds according to claim 1 characterized in that the aryl groups are chosen from the di and trifluorophenyls and the monoalkylamino phenyls.
13. 13. Compounds according to claim 1 characterized in that X represents a covalent bond.
14. 14. Compounds according to claim 1, characterized in that R represents a cycloalkyl radical.