FR2943674A1 - New dipyrido-pyrrole compounds are protein kinase inhibitors useful for the treatment of cancer - Google Patents

Abstract

Dipyrido-pyrrole compounds (I) are new. Dipyrido-pyrrole compounds of formula (I) are new. Z 2>-Z 4> : C or N; R 3> : (hetero)aryl, C(O)Oalkyl or 1-10C alkyl optionally comprising heteroatom (all optionally mono, di or tri substituted), H, halo (F, Cl, Br, I), CF 3, CHF 2, OH, NH 2, CONH(alkyl), CON(alkyl) 2, alkoxy, NH(alkyl), or N(alkyl) 2(in which all the alkyl part is in CONH(alkyl), CON(alkyl) 2, alkoxy, NH(alkyl), or N(alkyl) 2are optionally mono, di or tri substituted); R 6> : heteroaryl (5 or 6 membered ring with 1-4 heteroatoms of N, S or O) connected to azacarboline unit, C or N of R 6>, where R 6>is optionally mono or polysubstituted; either R1a : CON(alkyl) 2, CONHalkyl, CONHcycloalkyl, CONHheterocycloalkyl or CON(alkyl)(heterocycloalkyl) (all optionally mono, di or tri substituted), CONHN(alkyl) 2(in which alkyl part is optionally mono, di or tri substituted) or CONH 2; and R1s : O-1-10C alkyl, N(1-10C alkyl or 3-7C cycloalkyl) 2(all optionally mono or polysubstituted), H, Cl, Br, I, OH, NH 2, NHCOR3a, N-1-10C alkylCOR3a, NHSO 2R3a, N-1-10C alkylSO 2R3a, CO 2R3a, SR3a, SOR3a or SO 2R3a; or R1aR1s : ring. [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Protein kinase inhibitor. The ability of (I) to inhibit Proto-oncogene serine/threonine-protein 2 (Pim 2) kinase was tested using time resolved-fluorescence resonance energy transfer assays. The result showed that N-cyclopropyl-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide exhibited an IC 5 0value of 1-5 mu M.

Description

The present invention relates to α-aza-13-carboline derivatives, to their preparation and to their therapeutic application. Α-aza-13-carbolines are defined by derivatives of 1,7 diaza carbazole or 8-aza - (3-carboline; in French IUPAC nomenclature (use of ACD / Name 12.00) the name of this tricyclic unit is 9H-pyrrolo [2,3-b: 5,4-c '] dipyridine.

The present invention relates to compounds acting on protein kinases such as for example: CHK1, CDK1, CDK2, dyrk2, FIt3, GSK3 beta, MNK2, PDGFR beta, PI3K, PIM1, PIM2, PIM3, PLK, TrkB, all of which are involved in the cancer development. More particularly, the present invention relates to compounds acting on a target called Pim involved in the development of cancers.

Pim kinases, encompassing Pim-1, Pim-2 and Pim-3, form a distinct family of serine / threonine kinases, and play a functional role in cell growth, differentiation and apoptosis. One of the mechanisms by which Pim kinases can increase cancer cell survival and promote cancer progression is through the modulation of ADB activity, a key regulator of apoptosis. Pim kinases are highly homologous to each other and display similar oncogenic behavior.

Clinical reports highlight the importance of the role of Pim kinases in the development of human cancers:

Pim kinases, particularly Pim-1 and Pim-2, have been found to be abnormally expressed in a large number of hematological malignancies. Amson et al. report overexpression of Pim-1 in acute myeloid leukemia and acute lymphoid leukemia, and that overexpression of Pim-1 appears to result from inappropriate activation in various leukemias (Proc Nat / Acad Sci, Vol 86 8857-8861 (1989)). Studies have demonstrated overexpression of Pim-1 in primary and metastatic CNS lymphoma, an aggressive form of non-Hodgkin lymphoma (Rubenstein et al., Blood, Vol 107, 9, 3716-3723 (2006)). ). Hüttmann et al. have also found overexpression of Pim-2 in B-cell chronic lymphocytic leukemia and suggest that upregulation of Pim-2 may be associated with a more aggressive course of the disease (Leukemia, 20, 1774-1782 ( 2006)). Abnormal expression of Pim-1 and Pim-2 has been linked to multiple myeloma (Claudio et al., Blood, v. 100, No. 6, 2175-2186 (2002)). Hypermutations of Pim-1 have been identified in diffuse large cell lymphomas (Pasqualucci et al., Nature, Vol 412, 2001, pp. 341-346 (2001)) and in predominantly lymphocytic nodular and nodular Hodgkin's lymphoma. (Liso et al., Blood, Vol 108, No. 3, 1013-1020 (2006)). Numerous studies have also linked an abnormal expression of Pim kinases to various non-hematological human cancers (prostate, pancreas, head and neck, etc.) and their presence is often associated with a more aggressive phenotype. For example, both Pim-1 and Pim-2 have been implicated in prostate cancer (Chen et al., Mol Cancer Res, 3 (8) 443-451 (2005)). Valdman et al. have demonstrated upregulation of Pim-1 in patients with prostate carcinoma and in high-grade prostatic intraepithelial neoplasia (precancerous lesions) (The Prostate, (60) 367-371 (2004) ), while Dai et al. suggest that overexpression of Pim-2 in prostate cancer is associated with more aggressive clinical features (The Prostate, 65: 276-286 (2005)). Xie et al. found that 44 kDa Pim-1 (Pim-1L) was significantly upregulated in human prostate tumor specimens, and indicate that Pim-1 L has an anti-apoptotic effect on cancer cells of the prostate. human prostate in response to chemotherapeutic drugs (Oncogene, 25, 70-78 (2006)). Pim-2 is linked to the perineural invasion (PNI), during which cancer cells curl around the nerves, which are often found in certain cancers such as cancers of the prostate, pancreas, ducts biliary and head and neck (Ayala et al., Cancer Research, 64, 6082-6090 (2004)). According to Li et al., Pim-3 is aberrantly expressed in human and mouse hepatocarcinomas and human pancreatic cancer tissues (Cancer Res 66 (13), 6741-6747 (2006)). Aberrant expression of Pim-3 has also been observed in gastric adenoma and metastatic sites of gastric carcinoma (Zheng et al., 35 J Cancer Res Clin Oncol, 134: 481-488 (2008)). Reports suggest that Pim kinase inhibitors are useful for the treatment of cancer, including leukemias, lymphomas, myelomas and various solid tumors, including head and neck cancers, colon cancer, cancer prostate, pancreatic cancer, liver cancer and oral cancer, for example. Since cancer remains a disease for which existing therapies are inadequate, it is clearly necessary to identify new inhibitors of Pim kinases that are effective in the treatment of cancer.

Among the patent applications claiming compounds of the azacarboline class, object of our invention, mention may be made of the following documents: The patent application WO 2007/044779 describes α-aza-G3-carbolines of the following general formula, partially restricted , in relation to the published demand: / R2 2 R7 ~ Z5 NH Where - Z5, Z4 and Z3 can represent C and - Z and Z2 can also represent C, - Z1 can finally represent C or N and - R2 can represent a carbon bond or an alkylene radical each of which may be substituted by numerous possibilities, among which are heteroaryloxy, heteroaryl (C1-5) alkyl, heteroaryl and heterobicycloaryl. The process of preparation as well as all the examples of this application are limited to derivatives substituted in the 2-position and 8-position and optionally in position 5. EP 1 209 158 claims compounds of the following formula: R5 3 \ 5Z2 ~ Z 1 811 'R6 ~~ ZZ \ ~ \ R4 There. In which B6, B7, B8, B9 may be C or N, but R7 is never heteroaryl. The activity of the compounds of this invention is particularly directed to the treatment of cardiac problems. The present invention relates to compounds of the following general formula: Ra in which -Z2, Z3, Z4 = CouN; R3 is selected from: 1. H; 2. halogen (F, Cl, Br, I); 3. CF3, CHF2; 4. alkoxy whose alkoxy part is optionally mono, di or tri substituted by R2a, R2b, R2c; 6. NH2, NH (alkyl), N (alkyl) 2 whose alkyl part is optionally mono, di or tri substituted by R2a, R2b, R2c; 7. C (O) Oalkyl optionally mono, di or tri substituted by R2a, R2b, R2c; 8. CONH (alkyl), CON (alkyl) 2 whose alkyl part is optionally mono, di or tri substituted by R2a, R2b, R2c; 9. C, -C, o linear, branched or cyclic alkyl optionally comprising a heteroatom and optionally mono, di or tri substituted by R2a, R2b, R2c; Aryl or heteroaryl optionally mono, di or tri substituted by R2a, R2b, R2c;

R 6 is a heteroaryl (5 or 6-membered with 1 to 4 heteroatoms chosen from N, S or O) bonded to the azacarboline unit, either by a C or by an N belonging to R 6, R 6 being optionally mono or poly substituted with R 2a, R 2b; R2c;

- Ra being obligatorily: 1. CONH2, 2. CONHalkyl, CONHcycloalkyl optionally mono, di or tri substituted by R2a, R2b, R2c; 3. CONHheterocycloalkyl optionally mono, di or tri substituted by R2a, R2b, R2c; 4. CON (alkyl) 2 optionally mono, di or tri substituted by R2a, R2b, R2c; 5. CON (alkyl) (heterocycloalkyl) optionally mono, di or tri substituted by R2a, R2b, R2c; 6. CONHN (alkyl) 2 whose alkyl part is optionally mono, di or tri substituted by R2a, R2b, R2c; Rs being selected from the following groups:

1. H; 2 F; Cl; Br; 1. 3. OH; 4. O-alkyl (C, -C, O) linear or branched optionally mono or poly substituted with different R3a; 5. NH2; 6. N (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl) each group being optionally mono or poly substituted with different R 3a; Ra and Rs may optionally form a ring. R 2a, R 2b or R 2c are independently selected from: 1. F; 2. Cl; 3. Br; 4. I; 5. CF3; CHF2. 6. -C, linear or branched alkyl optionally mono or poly substituted with different R3a; 7. C3-C; cycloalkyl optionally mono or poly substituted with different R3a; 8. OH; 9. Linear or branched (C 1 -C 10) O-alkyl optionally mono or poly substituted with different R 3a; O-cycloalkyl (C3-C7) optionally mono or poly substituted with different R3a; 11. O-aryl optionally mono or poly substituted different by R3a; 12. aryl optionally mono or poly substituted with different R3a; 13. heteroaryl optionally mono or poly substituted with different R3a; 14. heterocycloalkyl optionally mono or poly substituted with different R3a; 15. NO2 NHC (O) R3a; N (C 1 -C 10 alkyl) C (O) R 3 a, NHS (O 2) R 3 a, N (C 1 -C 10 alkyl) S (O 2) R 3 a, CO2R 3 a, SR 3 a, S (O) R 3 a; S (O 2) R 3a 16. NH 2; 17. NH- (C 1 -C 5 alkyl) or C 3 -C 7 cycloalkyl or heterocycloalkyl) each optionally mono or poly substituted with different R 3a; C, -C, o) or (C3-C7) cycloalkyl) each group being optionally mono or poly substituted with different R3a; 19. NHC (O) R3a; 20. N (C1-C5 alkyl) C (O) R3a; 21. NHS (O2) R3a; 22. N (C1-C5) alkyl (S2) R3a; 23. CO2R3a; 24. SR3a; S (O) R3a; S (O2); R3a;

The possible substituents of the groups R2a, R2b and R2c or the groups R3a are chosen from: 1. F; Cl; Br; I 2. CF3; 3. C, -C, o linear or branched alkyl 4. C3-C7 cycloalkyl; 5. C2-C6 aikenyl; 6. C2-C6 alkynyl; 7. OH; 8. linear, branched or cyclic (C3-C7) O-alkyl (C, -C, o); 9. C3-C7 heterocycloalkyl; 10. NH2; 11. NH- (C1-C10) alkyl or (C3-C7) cycloalkyl); 12. N (C 1 -C 10 alkyl) or C 3 -C (cycloalkyl) 2; 13. NH- (C 1 -C 5 alkyl) or C 3 -C 7 heterocycloalkyl); 14. N (C 1 -C 6 alkyl) or C 3 -C 7 heterocycloalkyl) 2; In the context of the present invention the positions 2 and 8 should not be substituted contrary to the documents of the prior art. Alkyl, (C 1 -C 10) alkyl or C 1 -C 4 alkyl means all carbon chains of 1 to 10 carbons, saturated, linear or branched. Aryl means phenyl or naphthyl.

Heteroaryl means all aromatic 5- or 6-membered aromatic monocycles having at least one heteroatom (N, O, S), especially: pyridine, pyrimidine, imidazole, pyrazole, triazole, thiophene, furan, thiazole, oxazole, etc. bicyclic aromatic compounds having at least one heteroatom (N, O, S), especially indole, benzimidazole, azaindole, benzofuran, benzothiophene ... Heterocycloalkyl means all non aromatic unicyclic monocycles and bicycles (with or without spiro) having at least one heteroatom (N, O , S at the various possible oxidation states) with or without unsaturation, in particular: morpholine, piperazine, piperidine, pyrrolidine, oxetane, epoxide, etc.

The compounds of formula (I) can comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention. The compounds of formula (I) may comprise one or more E / Z type stereochemies on double bonds or cis / trans bonds on nonaromatic rings. These different stereoisomers and their mixtures are part of the invention.

The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.

These salts can be prepared with pharmaceutically acceptable acids (P.Stahl, C.Wermuth, Handbook of Pharmaceutical Salts, Wiley Ed.), But salts of other acids useful, for example, for the purification or isolation of compounds of formula (I) are also part of the invention.

All synthesis intermediates not described in the literature leading to the production of compounds belonging to the general formula are also part of the invention.

The process for preparing the compounds having a (6'-pyridinyl) unit at the 6-position according to the invention consists in a first step in preparing 5-chloro-4- (trimethylstannanyl) -2,3'-bipyridine from 2 - (3'-pyridyl) -5-chloropyridine (Journal of the Chemical Society, Perkin Transactions 1 2002, (16), 1847-1849): In a second step to perform a coupling of Stille with a derivative 2- amino-3- (bromo or iodo) -pyridine optionally substituted in position 5: No SnMe3 LDA, THF, -78 ° C CI ~~ then Me3SnCl Pd (PPh3) 4 Cul dioxane 95 ° C 1 night NY Brou R3 N ~ \ In a third step, the tricyclic unit is obtained by an intramolecular aryl amination reaction catalyzed either by a palladium complex or by copper (I) iodide: Pd (OAc) 2, Josiphos tBuOK, dioxane 95 ° C 1 night or microwave 120 ° C 1h where Josiphos is a compound of the following formula: In a fourth step to achieve the functionalisate ion of position 4: R3 N or Cul C1 K2CO3, DMSO 170 ° C overnight R3 The end of the synthesis is carried out in 4 steps: Suzuki type coupling, deprotection by action of lithium, activation of the function acid by thionyl chloride and then reaction with the selected amine: R3 Pd (PPh3) 4 Cs2CO3 dioxane / water microwave 120-130 ° C 1 h 0 B so R3 LiOH, H2O THF, MeOH 1 °) SOCl2 reflux R3 2 °) RR'NH CH2Cl2, 25 ° C. According to the commercial availability of the boronic derivatives, the same type of structure can be obtained with a boronic derivative already having a carboxamido unit: R 3 LiOH, H 2 O THF, McOH N Pd (PPh3) 4 Cs2CO3 dioxane / microwave water 120-130 ° C 1 hr, N 1 R 'The process for preparing the compounds having a unit (1'-methyl-1'H-pyrazol-4'-yl) in position 6 according to the invention consists in a first step: \ / ~ Sn

In a second step, a coupling of Stille with a 2-amino-3- (bromo or iodo) -pyridine derivative optionally substituted in position 4 or 5, followed by an intramolecular aryl amination reaction catalyzed by by a palladium complex, or by copper (I) iodide: ON LiTMP, Me3SnCl THF, -78 ° C 0 N Pd (OAc) 2, Josiphos tBuOK, dioxane 95 ° C 1 night or microwave 120 1 ° C or K 2 CO 3, DMSO 170 ° C overnight R 4 R 3 R 3 N NH, The unit (1'-methyl-1'H-pyrazol-4'-yl) is installed by a sequence of three steps comprising: a demethylation reaction, the formation of a triflate derivative and a Suzuki coupling reaction: R4 HCl, AcOH R4 HO R3 O R3 microwave 1 h 120 ° C-150 ° C (CF3SO2) 2O Pyridine 1 The addition of the phenylcarboxamido unit takes place as previously by a palladium-catalyzed coupling of Suzuki type starting from a triflate or an iodide: Pd (PPh 3) 4 Cs 2 CO 3, N BO PdCl 2 (dppf) dioxane / water Cs 2 CO 3 R 3 R 3 d In another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredient, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, of said compound, as well as at least one pharmaceutically acceptable excipient. The said excipients are selected according to the pharmaceutical form and the desired mode of administration from the usual excipients which are known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous administration, the active ingredient of formula (I) above, or its salt, may be administered in unit dosage form. administration, in admixture with conventional pharmaceutical excipients, to animals and humans for the treatment of the above disorders or diseases.

Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, subcutaneous, intramuscular forms of administration. or intravenous.

These drugs find their therapeutic use, especially in the treatment of cancers sensitive to the deregulation of PIM kinases.

The Pim kinase inhibitors of the present invention are useful for the treatment of cancer. Since cancer remains a disease for which existing therapies are inadequate, it is clearly necessary to identify new inhibitors of Pim kinases that are effective in the treatment of cancer.

The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of pharmaceutically acceptable salts thereof.

The following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and only illustrate the present invention. The numbers of the compounds exemplified refer to those given in the table below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.

GENERAL: Abbreviations: 1H NMR: proton nuclear magnetic resonance DAD: wavelength scanning detector35 DCM: dichloromethane

DME: 1,2-dimethoxyethane

DMF: dimethylformamide

DMSO: dimethylsulfoxide ELSD: light scattering detector

HPLC, UPLC: LC high performance liquid chromatography: liquid chromatography

LDA: lithium diisopropylamide

LiTMP: lithium amide of 2,2,6,6-tetramethylpiperidine MS: mass spectrometry

THF: tetrahydrofuran

Tr: retention time - All reactions are performed with anhydrous solvents from the Acros Organics AcroSeal range. The solvents used for extractions and chromatographies come from SDS. Microwave reactions are performed on a Biotage or EMC device. Purifications on silica gel are carried out using VWR-MERCK silica cartridges (Silica gel 60 15-40pm). Preparative HPLC purifications are performed on Macherey-Nagel columns (NUCLEODUR C18 phase) or other phases (Chiralcel OD-1 or OJ-H or AS-H, Chiralpak, Kromasil C18) with appropriate eluents. - LC-MS-DAD-ELSD analysis: 2 possible experimental conditions: 0 LC-MS-DAD-ELSD analysis: MS = Waters ZQ; electrospray mode +/-; mass range m / z = 100-1200; LC = Agilent HP 1100; LC column = X Bridge 18 C Waters 3.0 x 50 mm -2.5 pm; oven LC = 60 ° C; flow rate = 1.1 ml / min.

Eluents: A = Water + 0.1% Formic acid B = Acetonitrile, with the following gradient: Time A% B% 0.0 95 5 5.0 0 100 5.5 0 100 6.5 95 5 7.0 95 5 O Analysis LC-MS-DAD-ELSD (MS = Platform II Waters Micromass, electrospray +/-, mass range m / z = 100-1100, LC Alliance 2695 Waters, column X Terra 18C Waters 4.6mm x 75mm - 2.5μm, furnace LC = 60 ° C, flow rate = 1.0 ml / min.

Time A% B% 0 95 5 6.0 5 95 8.0 5 95 9.0 95 5 13.0 95 5 - UPLC-MS-DAD-ELSD analysis: 2 possible experimental conditions: 10 O UPLC-MS-DAD-ELSD analysis: MS = Quattro Premier XE Waters; electrospray + 1-

; mass range m / z = 100-1100; UPLC Waters; Acquity column UPLC BeH C18 2.1 mm x 50 mm - 1.7 μm; UPLC oven = 70 ° C; flow rate = 0.7 ml / min.

Eluents: A = Water + 0.1% Formic acid B = Acetonitrile + 0.1% Formic acid, with gradient: UPLC-MS-DAD-ELSD analysis: MS = SQD Waters; electrospray +/-; mass range m / z = 100-1100; Waters UPLC-; Acquity column UPLC Beh C18 2.1 mm x 50 mm - 1.7 m; UPLC oven = 70 ° C; flow rate = 1 ml / min. Time A% B% 0 95 5 0.8 50 50 1.2 0 100 1.85 0 100 1.95 95 5 2.00 95 5 For detection: DAD considered wavelength at = 210-400 nm ELSD: Sedere SEDEX 85; nebulization temperature = 35 ° C; Nebulization pressure = 3.7 bar 40 N.B: Depending on the structures analyzed, the dilution solvents are: dimethylsulfoxide; methanol; acetonitrile; dichloromethane. Eluents: A = Water + 0.1% Formic acid B = Acetonitrile, with the following gradient: Time A% B% 0 95 5 5 0 100 5.5 95 5 6.0 95 5 25 Eluents: A = Water + 0.1% Formic acid B = Acetonitrile + 0.1% Formic acid, with gradient: EXAMPLES 5-chloro-4- (trimethylstannanyl) -2,3'-bipyridine A 5 LDA, Me3SnCl THF, 78 ° C / A mixture of 15 ml of diisopropylamine and 40 ml of tetrahydrofuran is cooled to -74 ° C. and then 64 ml of 1.6 N n-butyllithium in hexane are added in 20 minutes while keeping the temperature below -70 °. vs. To the reaction mixture was added 16.2 g of 2- (3'-pyridyl) -5-chloropyridine prepared according to the reference Journal of the Chemical Society, Perkin Transactions 1, 2002, 16, 1847-1849 dissolved in 170 ml. tetrahydrofuran, always keeping the temperature below -70 ° C. The mixture is stirred at -74 ° C. for 1 h 30 min and then 19.47 g of trimethyltin chloride dissolved in 100 ml of tetrahydrofuran is gradually added keeping the temperature below -70 ° C. The reaction mixture is stirred again for 1 h at a temperature below -72 ° C and then 100 ml of water are added. The mixture at room temperature is poured into 300 ml of water and 100 ml of saturated aqueous solution of potassium hydrogencarbonate and then extracted twice with 400 ml of ethyl acetate. The combined organic phases are concentrated to dryness under reduced pressure and then the residue is purified on a VARIAN SCX cartridge, eluting with pure methanol then 2N ammoniacal methanol and then chromatography on a silica column, eluting with a heptane: acetate mixture. ethyl 100: 0 to 50:50 to give 19.22 g of 5-chloro-4- (trimethylstannanyl) -2,3'-bipyridine A as a beige powder. UPLC-MS-DAD-ELSD: Tr (min) = 4.29; [M + H] +: m / z 355; purity: 98% 1H NMR (400 MHz, DMSO-d6): ppm 0.45 (s, 9H) 7.52 (dd, J = 7.6, 5.1 Hz, 1H) 7.94 (d, J = 1.0 Hz, 1H) 8.40 (dt, J = 7.9, 2.1Hz, 1H) 8.63 (s, 1H) 8.64 - 8.66 (m, 1H) 9.22 (d, J = 2.4Hz, 1H) Example 1: 5'-chloro 5 "-Fluoro-3,2 ': 4', 3" -terpyridin-2 "-amine FBr-NNH, Pd (PPh 3) a dioxane-Microwave Culinary 120 ° C A 1

A mixture of 10 g of 2-amino-3-bromo-5-fluoropyridine, 19.2 g of 5-chloro-4- (trimethylstannanyl) -2,3'-bipyridine A, 4.24 g of tetrakis (triphenylphosphine) palladium (0) and 2.095 g of copper (I) iodide in 120 ml of 1,4-dioxane is refluxed for 18 hours. The reaction medium is treated with a 10% aqueous solution of sodium hydrogencarbonate and then diluted with ethyl acetate. After decantation, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue is taken up in a mixture of dichloromethane: methanol 83:17 and then filtered to give 11.67 g of 5'-chloro-5 "-fluoro-3,2 ': 4', 3" -terpyridin-2 "- amine as a beige solid.

The filtrate is concentrated under reduced pressure and then taken up in dichloromethane and added with silica. After concentration under reduced pressure, the deposit is purified by chromatography on a silica column, eluting with a dichloromethane: methanol mixture 98: 2 to 90:10 to give 1.98 g of 5'-chloro-5'-fluoro-3, 2 ': 4', 3 "-terpyridin-2" -amine as a beige solid.

UPLC-MS-DAD-ELSD: Tr (min) = 2.71; [M + H] +: m / z 301; purity: 95%

1H NMR (400MHz, DMSO-d6): ppm: 5.78 (s, 2H) 7.47 (dd, J = 8.8, 2.9Hz, 1H) 7.55 (brs, 1H) 8.06 (s, 1H) ) 8.12 (s, 1H) 8.49 (d, J = 7.8 Hz, 1H) 8.68 (brs, 1H) 8.84 (s, 1H) 9.35 (brs, 1H) Example 2: 3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridine Pd (OAc) 2, Josiphos tBuOK, dioxane 100 ° C 1 night 1 2 In a 100 ml reactor is charged with 1.574 g of (R) - (-) - 1 - [(S) -2- (dicyclohexylphosphino) ferrocenyl] ethylditerbutylphosphine and 0.558 g of palladium (II) acetate in 40 ml of 1 Anhydrous 4-dioxane under an argon atmosphere and stirred for 10 min at 40 ° C. In a 500 ml reactor, 11.6 g of 5'-chloro-5 "-fluoro-3,2 ': 4', 3" -terpyridin-2 "-amine in 160 ml of 1.4 are placed under argon. The mixture is diluted with a dichloromethane: methanol 71: 29 mixture and then is filtered under vacuum. under reduced pressure, the deposit is purified by chromatography on a silica column, eluting with a dichloromethane: methanol mixture 98: 2 to 92: 8 to give 6.5 g of 3-fluoro-6- (pyridin-3-yl) 9H-pyrrolo [2,3-b: 5,4-c '] dipyridine as a brown solid UPLC-MS-DAD-ELSD: Tr (min) = 0.42; [M + H] +: m / z 265; [M-1-1y: m / z 263; purity: 98%

1H NMR (400 MHz, DMSO-d6); ppm 7.54 (ddd, J = 8.0, 4.7, 0.7Hz, 1H) 8.48 (dt, J = 7.8, 2.0Hz, 1H) 8.60 (dd, J = 4.6, 1.5Hz, 1H) 8.65 (s, 1 H) 8.65 - 8.68 (m, 1H) 8.90 (d, J = 1.2Hz, 1H) 9.05 (d, J = 1.2Hz, 1H) 9.34 (d, J = 1.5Hz, 1H) 12.39 (br. Example 3: 3-Fluoro-9 - [(4-methylphenyl) sulfonyl] -6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] In a 250-ml reactor, 3.20 g of 3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b] were placed under argon. 5.4-c '] dipyridine in 80 ml of dimethylformamide and 0.847 g of 60% sodium hydride in oil. After stirring for 3 hours at room temperature are added 4.61 g of paratoluenesulfonyl chloride dissolved in 20 ml of dimethylformamide. The reaction medium is stirred for 3 h at room temperature and then treated with a 10% aqueous sodium hydrogen carbonate solution and then diluted with ethyl acetate. After decantation, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with water and then dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The

The residue is purified by chromatography on a silica column, eluting with a 100: 0 to 95: 5 dichloromethane: methanol mixture to give 4.75 g of 3-fluoro-9 - [(4-methylphenyl) sulfonyl] -6- (pyridine -3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridine.

UPLC-MS-DAD-ELSD: Tr (min) = 0.90; [M + H] +: m / z 419; purity: 98%

1H NMR (400MHz, DMSO-d6) ppm: 2.32 (s, 3H) 7.39 (d, J = 8.1Hz, 2H) 7.59 (dd, J = 8.1, 4.6Hz, 1H) 8.03 (d, J) = 8.6 Hz, 2H) 8.51 (dt, J = 8.0, 2.0 Hz, 1H) 8.67 (dd, J = 4.8, 1.6Hz, 1H) 8.73 (dd, J = 8.3, 2.9)

Hz, 1H) 8.78 (dd, J = 2.9, 1.2 Hz, 1H) 8.98 (d, J = 0.5Hz, 1H) 9.36 (d, J = 1.7Hz, 1H) 9.70 (d, J = 0.7) Hz, 1H) Example 4: 3-Fluoro-9 - [(4-methylphenyl) sulfonyl] -6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridine 2 1 °) LDA. THF -78 ° C 2 ') 1, N 1 SO 4, ToI 4 3 In a flask, 0.43 ml of diisopropylamine are charged in 10 ml of tetrahydrofuran. After stirring and cooling to -78 ° C, 1.15 ml of 2.5 N n-butyllithium in hexane is added. The reaction mixture is stirred for 15 min at -78 ° C., then 0.800 g of 3-fluoro-9 - [(4-methylphenyl) sulfonyl] -6- (pyridin-3-yl) -9H-pyrrolo [2,3] are added. -b: 5,4-dipyridine in 50 ml of tetrahydrofuran. After stirring for 2 h at -78 ° C., 0.776 g of iodine in 5 ml of tetrahydrofuran is added. After stirring for 1 h, the reaction mixture is poured into 150 ml of a 10% aqueous solution of ammonium chloride and 50 ml of water, extracted twice with 150 ml of ethyl acetate. The organic phases are washed with an aqueous solution of 5% sodium thiosulfate, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. 1.03 g of 3-fluoro-4-iodo-9 - [(4-methylphenyl) sulfonyl] -6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5.4 is obtained. dipyridine. UPLC-MS-DAD-ELSD: Tr (min) = 1.05; [M + H] +: m / z 545; purity: 66% 1H NMR (400 MHz, DMSO-d6) ppm: 2.33 (s, 3H) 7.40 (d, J = 8.1 Hz, 2H) 7.60 (dd, J = 7.8, 4.6 Hz, 1H) 8.05 (d, J = 8.3Hz, 2H) 8.47 (dt, J = 7.9, 2.0Hz, 1H) 8.65 (s, 1H) 8.69 (dd, J = 4.8, 1.6Hz, 1H) 9.19 (s, 1H) 9.29 (d, J = 2.0 Hz, 1H) 9.79 (s, 1H) Example 5: 4- {3-Fluoro-9 - [(4-methylphenyl) sulfonyl] -6- (pyridin-3-yl) ) -9H-pyrrolo [2,3-b: 5,4-c '] dipyridin-4-yl} methyl benzoate o 4 Pd (PPh3) 4 Cs2CO3 dioxane / water In a reactor, 800 mg of 3 4-Fluoro-4-iodo-9 - [(4-methylphenyl) sulfonyl] -6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridine, 847 mg of 4-methoxycarbonylphenylboronic acid pinacol ester, 170 mg of tetrakis (triphenylphosphine) palladium (0), 718 mg of cesium carbonate in 12 ml of 1,4-dioxane and 3 ml of water, seals the tube and submits to microwave irradiation at 120 ° C for 1 h. To the reaction medium are added 3 ml of methanol and 100 ml of water, and this is then extracted with 5 times 150 ml of ethyl acetate. The organic phases are combined, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a silica column, eluting with a 100: 0 to 97: 3 dichloromethane: methanol mixture to give 793 mg of 4- {3-fluoro-9 - [(4-methylphenyl) sulfonyl] -6- Methyl (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] -dipyridin-4-yl} benzoate. UPLC-MS-DAD-ELSD: Tr (min) = 1.10; [M + H] +: m / z 553; purity: 40% 1H NMR (400 MHz, DMSO-d 6 ppm: 2.35 (s, 3H) 3.95 (s, 3H) 7.44 (d, J = 7.8 Hz, 2H) 7.47 - 7.52 (m, 2H) 7.87 (d, J = 7.8 Hz, 2H) 8.12 (d, J = 8.3 Hz, 2H) 8.13 - 8.17 (m, 1H) 8.26 (d, J = 8.3 Hz, 2H) 8.59 (dd, J) = 4.9, 1.5 Hz, 1H) 8.86 (d, J = 2.4 Hz, 1H) 8.89 (d, J = 1.5 Hz, 1H) 9.77 (s, 1H) Example 6: 4- [3-fluoro acid (6H-pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridin-4-yl] benzoic acid LiOH MeOH / THF / water 5 OH H 6 In a flask, 790 mg of 4- {3-fluoro-9 - [(4-methylphenyl) sulfonyl] -6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] was placed methyl dipyridin-4-yl} benzoate in 10 ml of methanol and 20 ml of tetrahydrofuran and then 479 mg of lithium hydroxide dissolved in 15 ml of water The reaction mixture is stirred for 2 hours at room temperature and then 30 ml are added of water and 10 ml of 2M aqueous hydrochloric acid solution. The precipitate is filtered off and dried in vacuo to give 340 mg of 4- [3-fluoro-6- (pyridin-3-yl) -9H- pyrrolo [2,3-b: 5,4-c '] dipyridin-4-yl] benzoic UPLC-MS-DAD-ELSD: Tr (min) = 0.56; [M + H] +: m / z 385; [M-H] -: m / z 383; purity: 95% 1H NMR (400 MHz, DMSO-d6 [ppm: 7.48 (dd, J = 7.6, 4.9 Hz, 1H) 7.68 (s, 1H) 7.91 (d, J = 8.1 Hz, 2H) 8.17 (d, J = 8.1 Hz, 1H) 8.27 (d, J = 8.3 Hz, 2H) 8.54 (d, J = 4.4Hz, 1H) 8.78 (d, J = 2.2Hz, 1H) 8.92 (s) , 1H) 9.09 (s, 1H) 12.65 (s, 1H) 13.24 (br.s., 1H) Example 7: 4- [3-Fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c '] dipyridin-4-yl] -N- (4-methylpiperazin-1-yl) benzamide -N N -NH, O DCM N OH 6 In a flask, a mixture of 150 mg of 4- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c '] dipyridin-4-yl] benzoic acid and 928 mg of thionyl chloride is heated under reflux for 12 h and then evaporated under reduced pressure To the residue are added 450 mg of 1-amino-4-methylpiperazine dissolved in 5 ml of dichloromethane After stirring for 1 hour at room temperature the reaction mixture is evaporated off under reduced pressure, taken up in dichloromethane and treated with 150 g of silica.The deposit is concentrated under reduced pressure and is then purified isolated by chromatography on a silica column, eluting with a dichloromethane: methanol mixture 98: 2 to 90:10 to give 34 mg of 4- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2, 3-b: 5,4-c '] dipyridin-4-yl] -N- (4-methylpiperazin-1-yl) benzamide.

UPLC-MS-DAD-ELSD: Tr (min) = 0.38; [M + H] +: m / z 482; [M-H] -: m / z 480; purity: 98% 1H NMR (400 MHz, DMSO-d6). ppm: 2.21 (s, 3H) 2.41 - 2.48 (m, 4H) 2.96 (t, J = 4.6 Hz, 4H) 7.46 (dd, J = 8.1, 4.6Hz, 1H) 7.67 (s, 1H) ) 7.85 (d, J = 8.3 Hz, 2H) 8.10 (d, J = 8.3 Hz, 2H) 8.12 - 8.16 (m, 1H) 8.54 (dd, J = 4.6, 1.2Hz, 1H) 8.77 ( d, J = 2.4Hz, 1H) 8.92 (d, J = 2.0Hz, 1H) 9.09 (s, 1H) 9.63 (s, 1H) 12.62 (brs, 1H) Example 8: 3 4-fluoro-4-iodo-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridine N 2 SO 4 4H 8 LiOH MeOH / THF / water In a flask, 2.2 g of 3-fluoro-4-iodo-9 - [(4-methylphenyl) sulfonyl] -6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4- c '] dipyridine in 50 ml of methanol and 100 ml of tetrahydrofuran and then 2.1 g of lithium hydroxide dissolved in 100 ml of water. The reaction mixture is stirred for 3 hours at room temperature and then 200 ml of water and a 2M aqueous solution of hydrochloric acid are added until pH 6. The precipitate is drained and dried in vacuo to give 1.16 g of water. fluoro-4-iodo-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c '] dipyridine.

UPLC-MS-DAD-ELSD: Tr (min) = 2.91; [M + H] +: m / z 391; [M-H] -: m / z 389; purity: 98% 1H NMR (400 MHz, DMSO-d6); ppm 7.56 (dd, J = 8.1, 4.6 Hz, 1H) 8.43 (dt, J = 7.8, 2.0Hz, 1H) 8.56 (s, 1H) 8.62 (dd, J = 4.6, 1.2Hz, 1H) 9.09 (s, 1H) 9.11 (s, 1H) 9.27 (d, J = 2.0Hz, 1H) 12.63 (brs, 1H) Example 9: N- [2- (dimethylamino) ethyl] 4- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] pyrimidin-4-yl] benzamido; In a 20 ml reactor, 1.1 g of 3-fluoro-4-iodo-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b] are placed in a reactor of 20 ml. 5,4-c '] dipyridine, 1.9 g N- (2-dimethylaminoethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide, 326 mg of tetrakis (triphenylphosphine) palladium (0), 1.84 g of cesium carbonate in 15 ml of 1,4-dioxane and 2.5 ml of water, sealed the tube and subjected to microwave irradiation for 1 hour at 130 ° C. . The reaction mixture is filtered and then poured into 100 ml of water and 250 ml of ethyl acetate with vigorous stirring. After decantation, the aqueous phase is extracted with 100 ml of ethyl acetate and the combined organic phases are dried over magnesium sulfate, filtered and then evaporated under reduced pressure. The residue is purified by chromatography on a silica column, eluting with a dichloromethane: methanol: aqueous ammonia 28% 100: 0: 0 to 90: 10: 0.2; the product is suspended in 15 ml of ethyl acetate. After 16 h with vigorous stirring at room temperature, the solid is drained under vacuum to give 1.02 g of N- [2- (dimethylamino) ethyl] -4- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c '] dipyridin-4-yl] benzamide. UPLC-MS-DAD-ELSD: Tr (min) = 0.41; [M + H] +: 455 m / z; [M-H] -: 453 m / z; purity: 95% 1H NMR (400 MHz, DMSO-d6) ppm 2.22 (s, 6 H) 2.45 - 2.49 (m, 2H) 3.44 (q, 10 J = 6.5 Hz, 2H) 7.46 (dd, J = 7.8, 4.6 Hz, 1H) 7.68 (s, 1H) 7.87 (d, J = 8.1 Hz, 2H) 8.11 - 8.15 (m, 1H) 8.16 (d, J = 8.1Hz, 2H) 8.54 ( dd, J = 4.6, 1.5 Hz, 1H) 8.61 (t, J = 5.6 Hz, 1H) 8.77 (d, J = 2.4 Hz, 1H) 8.91 (d, J = 2.0 Hz, 1H) 9.08 ( s, 1H) 12.61 (br.s, 1H) Example 10: N- [3- (dimethylamino) propyl] -4- [3-fluoro-6- (pyridin-3-yl) -9H-15 pyrrolo [2,3-b: 5,4-c '] dipyridin-4-yl] benzamide

VAS.AMS2.046: Pd (PPh3) 4 Cs2CO3 dioxane / water Analogously to Example 9, Example 10 is obtained from 150 mg of 3-fluoro-4-iodo-6- (pyridine) 3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridine and 383 mg of N- (3-dimethylaminopropyl) -4- (4,4,5,5-tetramethyl) -1 , 3,2-dioxaborolan-2-yl) benzamide.

UPLC-MS-DAD-ELSD: Tr (min) = 2.21; [M + H] +: m / z 469; [M-H] -: m / z 467; purity: 98% 1H NMR (400 MHz, DMSO-d6); ppm 1.72 (quin, J = 7.1 Hz, 2H) 2.16 (s, 6H) 2.31 (t, J = 7.1 Hz, 2H) 3.35 - 3.41 (m, 2H) 7.46 (dd, J = 7.9, 4.8 Hz, 1H) 7.68 (d, J = 1.1 Hz, 1H) 7.87 (d, J = 7.9 Hz, 2H) 8.12 -8.15 (m, 1H) 8.16 (d, J = 8.3 Hz, 2H) 8.53 (dd, J = 4.6, 1.5Hz, 1H) 8.73 - 8.77 (m, 1H) 8.77 (d, J = 2.4Hz, 1H) 8.91 (d, J = 1.8Hz, 1H) 9.09 ( d, J = 0.9 Hz, 1H) 12.62 (br.s, 1H) General procedure for Examples 11 to 17:, OR 'OR' Pd (PPh3) 4 Cs2CO3 dioxane / water H 8 In a reactor, place 0.2 mmol of 3-fluoro-4-iodo-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridine, 0.4 mmol of boronic reagent in 2 ml of 1,4-dioxane, 0.4 mmol of cesium carbonate in 0.5 ml of water, under argon 0.02 mmol of tetrakis (triphenylphosphine) palladium (0) in 0.5 ml of dimethylformamide, sealed the tube and stirred at 110 ° C. for 18 h After cooling, the reaction mixture is diluted with 6 ml of 1,4-dioxane, 2 ml of methanol and 0.1 ml of trifluoroacetic acid and then treated with 150 ml of mg of propanethiol resin grafted onto silica for 4 hours at room temperature. The reaction mixture is filtered and then washed twice with a 1,4-dioxane: methanol 4: 1 mixture. After evaporation under reduced pressure, the residue is dissolved in 2 ml of dimethylformamide and 0.1 ml of trifluoroacetic acid, filtered and then purified by preparative HPLC. Amides 11 to 17 are detailed in Table 1. Table 1: Reagent: Boronic acid or ester Name of neutral compound UPLC-MS-DAD-ELSD analysis: Tr (min) = 2.37; [M + H] +: m / z 424.09; purity: 100% 1H NMR (400 MHz, DMSO-d6): 8 ppm 0.62 - 0.69 (m, 2H) 0.72 - 0.81 (m, 2H) 2.91 - 3.02 (m, 1H) 7.48 (dd, J = 9.2, 4.6 Hz, 1H) 7.69 (s, 1H) 7.87 (d, J = 8.2 Hz, 2H) 8.16 (d, J = 8.7Hz, 2H) 8.56 (d, J = 6.1Hz, 1H) ) 8.67 (d, J = 4.8 Hz, 1H) 8.79 (d, J = 2.5Hz, 1H) 8.93 (d, J = 2.3Hz, 1H) 9.11 (s, Structure obtained 11 N-cyclopropyl-4- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridin-4-yl] benzamide 1H) 12.63 (s, 1H) UPLC- MS-DAD-ELSD: Tr (min) = 2.10; [M + H] +: m / z 455.11; purity: 100% 1H NMR (400 MHz, DMSO-d6): 8 ppm 2.84 (s, 6 H) 3.30 (t, J = 5.2 Hz, 2 H) 3.61 - 3.71 (m, 2H) 7.58 (dd, J) = 8.3, 5.0Hz, 1H) 7.78 (s, 1H) 7.91 (t, J = 8.0Hz, 1H) 8.03 (d, J = 7.4Hz, 1H) 8.23 (d, J = 8.1Hz, 1H) H) 8.31 (d, J = 8.1Hz, 1H) 8.33 (s, 1H) 8.63 (d, J = 3.8Hz, 1H) 8.86 (d, J = 2.3Hz, 1H) 8.96 (t, J) = 6.0 Hz, 1 H) 9.03 (ss, 1 H) 9.17 (s, 1 H) 9.40 (ss, 1 H) 12.75 (s, 1 H) UPLC-MS-DAD-ELSD: Tr (min) = 2.55; [M + H] +: m / z 454.07; purity: 100% 1H NMR (400 MHz, DMSOd6): 8 ppm 3.63 - 3.78 (masked m, 8H) 7.62 (dd, J = 8.3, 5.2Hz, 1H) 7.74 (s, 1H) 7.78 (d, J = 8.7 Hz, 2H) 7.83 - 7.93 (m, J = 8.2 Hz, 2H) 8.35 (d, J = 8.4 Hz, 1H) 8.65 (d, J = 6.1Hz, 1H) 8.81 (d, J = 2.3Hz, 1H) 8.99 (s, 1H) 9.13 (s, 1H) 12.69 (s, 1H) UPLC-MS-DAD-ELSD: Tr (min) = 2.34; [M + H] +: m / z 442.05; purity: 100% 1H NMR (400 MHz, DMSO-d6): 8 ppm 3.30 (s, 3 H) 3.46 - 3.56 (m, 4H) 7.73 (dd, J = 8.0, 5.4 Hz, 1H) 7.81 (s , 1H) 7.93 (d, J = 8.4 Hz, 2H) 8.24 (d, J = 8.6 Hz, 2H) 8.43 (d, J = 8.6 Hz, 1H) 8.72 (d, J = 4.3 Hz, 1H) 8.82 (t, J = 5.1 Hz, 1H) 8.86 (d, J = 2.5Hz, 1H) 9.11 (br.s, 1H) 9.19 (s, 1 13 12 N- [2- (dimethylamino)) ethyl] -3- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridin-4-yl] benzamide {4- [3- 6-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridin-4-yl] phenyl} (morpholin-4-yl) methanone 4- [3] Fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridin-4-yl] -N- (2-methoxyethyl) benzamide H 14 UPLC- MS-DAD-ELSD: Tr (min) = 2.05, [M + H] +: m / z 467.12, purity: 100% 1H NMR (400 MHz, DMSO-d6): 8 ppm 2.88 (s, 3H) 3.36 - 3.80 (masked m, 8H) 7.55 (dd, J = 8.5, 5.0 Hz, 1H) 7.77 (s, 1H) 7.85 (d, J = 8.4 Hz, 2H) 7.90 - 8.01 ( m, 2H) 8.30 (d, J = 8.7 Hz, 1H) 8.63 (d, J = 3.8 Hz, 1H) 8.85 (d, J = 2.3Hz, 1H) 9.01 (brs, 1H) ) 9.16 (s, 1 H) 12.71 (s, 1 H) UPLC-MS-DA D-ELSD: Tr (min) = 2.39; [M + H] +: m / z 456.09; purity 93% 1H NMR (400 MHz, DMSO-d6): δ ppm 1.81 (quin, J = 6.9 Hz, 2H) 3.27 (s, 3H) 3.35 - 3.46 (m, 4H) 7.47 (dd, J = 8.3, 5.0Hz, 1H) 7.69 (s, 1H) 7.88 (d, J = 8.4Hz, 2H) 8.12 - 8.22 (m, 3H) 8.56 (dd, J = 4.8, 1.5Hz, 1H) 8.71 (t, J = 5.9 Hz, 1H) 8.80 (d, J = 2.5Hz, 1H) 8.94 (d, J = 2.3Hz, 1H) 9.12 (s, 1H) 12.64 (s, 1H) H) 12.77 (s, 1H) UPLC-MS-DAD-ELSD: Tr (min) = 2.35; [M + H] +: m / z 454.07; purity: 94% 1H NMR (400 MHz, DMSO-d6): δ ppm3.54- 3.89 (masked m, 8H) 7.70 (dd, J = 8.2, 4.8 Hz, 1H) 7.73 - 7.79 (m, 1H) 7.80-7.94 (m, 4H) 8.54 (d, J = 7.9 Hz, 1H) 8.68 (br s, 1H) 8.83 (d, J = 2.5Hz, 1H) 9.15 (s, 1H) 9.20 (br.S., 1H) 12.73 (s, 1H) {3- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4- c] dipyridin-4-yl] phenyl (morpholinolin-4-yl) methanone-4- {4- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4- ['] dipyridin-4-yl] phenyl] (4-methylpiperazin-1-yl) methanone 16 F 4- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2], Example 18: 4- [3-fluoro-6- (pyridin-3-yl) -9H-chloride, 3-b: 5,4-c] dipyridin-4-yl] -N- (3-methoxypropyl) benzamide pyrrolo [2,3-b: 5,4-c '] dipyridin-4-yl] benzoyl 6 a mixture of 100 mg of 4- [3-fluoro-6- (pyridin-3-yl) - 9H-pyrrolo [2,3-b: 5,4-c '] dipyridin-4-yl] benzoic acid and 12 ml of thionyl chloride is heated at 70 ° C for 20 h. dry under reduced pressure to give 105 mg of 4- [3-f chloride luoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridin-4-yl] benzoyl as a yellow powder. The product is characterized by addition of methanol to give the corresponding ester. General Procedure for Examples 19 to 28: A mixture of 105 mg of 4- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2] chloride, 3-b: 5,4-c '] dipyridin-4-yl] benzoyl, 10 equivalents of amine (cf Table 2) and 10 ml of dichloromethane is stirred at ambient temperature for 20 h and then the reaction mixture is concentrated to dryness under reduced pressure. The residue is taken up in 300 ml of water and 300 ml of ethyl acetate. After decantation, the aqueous phase is extracted with 100 ml of ethyl acetate and the organic phases are combined and concentrated under reduced pressure.

The amides are detailed in Table 2 (yield between 10 and 79% depending on the reagents).

Table 2: UPLC-MS-DAD-ELSD: Tr (min) = 0.44; [M + H] +: m / z 595; purity: 70% 1H NMR (400 MHz, DMSO-d6): 8 ppm 1.64 - 1.70 (m, 4H) 1.76 (quin, J = 7.0 Hz, 2H) 2.42 - 2.47 (m, 4H) 2.48 - 2.54 (m, 2H) 3.35 - 3.43 (m, 2H) 7.46 (dd, J = 7.9, 4.8Hz, 1H) 7.67 (d, J = 1.0Hz, 1H) 7.86 (d, J = 7.8Hz, m.p. 2H) 8.10 - 8.18 (m, 3H) 8.53 (dd, J = 4.6, 1.7 Hz, 1H) 8.77 (d, J = 2.2Hz, 1H) 8.77 1-8.82 (m, 1H) 8.91 ( d, J = 2.2 Hz, 1H) 9.09 (d, J = 1.0Hz, 1H) 12.42 (brs, 1H) UPLC-MS-DAD-ELSD: Tr (min) = 2.23; [M + H] +: m / z 497; [M-H] -: m / z 495; purity: 95% 1H NMR (400 MHz, DMSO-d6): 8 ppm 2.44 - 2.57 (m, 8 H) 3.48 (q, J = 6.4 Hz, 2 H) 3.60 Reagent Structure obtained Name Analysis UPLC-MS-DAD- ELSD: Tr (min) = 0.42; [M + H] +: m / z 511; [M-H] -: m / z 509; purity: 95% 1H NMR (400 MHz, DMSO-d6): 8 ppm 1.76 (quin, J = 7.2 Hz, 2 H) 2.35 - 2.41 (m, 6 H) 3.38 (q, J = 6.6 Hz, 2H) 3.57 (t, J = 4.7 Hz, 4H) 7.46 (dd, J = 7.8, 4.9 Hz, 1H) 7.67 (s, 1H) 7.87 (d, J = 7.8 Hz, 2H) 8.12 - 8.15 (m, 1H) 8.16 (d, J = 8.3Hz, 2H) 8.53 (dd, J = 4.8, 1.6Hz, 1H) 8.71 (t, J = 5.6Hz, 1H) 8.77 (d, J = 2.2 Hz, 1H) 8.90 (d, J = 2.0Hz, 1H) 9.08 (s, 1H) 11.81 (br.w., 1H) / NH 2 4- [3-fluoro-6- (pyridin) 3-yl) -9H-N 'pyrrolo [2,3-b: 5,4-yl] dipyridin-4-yl] -N- [3- (morpholin-4-yl) propyl] benzamid e 19 4- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridin-4-yl] -N- [3- (pyrrolidin-1) O, NH 2 4- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridin-4-yl] -yl) propyl] benzamide N- [2- (morpholin-4-yl) ethyl] benzamide (t, J = 4.4 Hz, 2H) 7.46 (dd, J = 7.8, 4.9Hz, 1H) 7.68 (s, 1H) 7.87 (d , J = 8.3 Hz, 2H) 8.12 - 8.14 (m, 1H) 8.16 (d, J = 7.8Hz, 2H) 8.53 (dd, J = 4.9, 1.5Hz, 1H) 8.63 (t, J = 5.6 Hz, 1H) 8.77 (d, J = 2.0Hz, 1H) 8.91 (d, J = 2.0Hz, 1H) 9.09 (s, 1H) UPLC-MS -DAD-ELSD: Tr (min) = 0.42; [M + H] +: m / z 481; [M-H] -: m / z 479; purity: 80% 1H NMR (400 MHz, DMSO-d6): ppm 1.55 - 1.72 (m, 2H) 1.77 - 1.89 (m, 2H) 1.92 - 2.06 (m, 2H) 2.19 (s, 3H) 2.75 - 2.88 (m, 2H) 3.74 - 3.91 (m, 1H) 7.40 - 7.53 (m, 1H) 7.68 (s, 1H) 7.86 (d, J = 7.6Hz, 2H) 8.07 - 8.15 ( m, 1H) 8.17 (d, J = 8.3 Hz, 2H) 8.43 - 8.49 (m, 1H) 8.50 - 8.59 (m, 1H) 8.77 (s, 1 UPLC-MS-DAD-ELSD: Tr ( min) = 0.41, [M + H] +: m / z 469, [MH] -: m / z 467, purity: 95% 1H NMR (400 MHz, DMSO-d6 + ACOD): S ppm 2.89 (br ss, 6H) 3.12 (s, 3H) 3.38 (bursts, 2H) 3.90 (bursts, 2H) 7.46 (dd, J = 7.7, 4.8Hz, 1H) 7.69 (b) Brs., 1H) 7.82 (d, J = 8.1 Hz, 2H) 7.87 (d, J = 7.8 Hz, 2H) 8.19 (d, J = 7.6 Hz, 1H) 8.55 (dd, J = 4.6, 1.2 Hz, 1H) 8.76 (d, J = 2.4 Hz, 1H) 8.92 (br.s., 1H) 9.10 (d, J = 1.0 Hz, 1H) 21 22 4- [3-fluoro (6-pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridin-4-yl] -N- (1-methylpiperidin-4-yl) benzamide 23 N- [2- (dimethylamino) ethyl] -4- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridin-4-yl] HNN UPLC-MS-DAD-ELSD-N-methylbenzamide r (min) = 0.41; [M + H] +: m / z 510; [M-H] -: m / z 508; purity: 90% 1H NMR (400 MHz, DMSO-d6): 8 ppm 2.15 (s, 3 H) 2.25 - 2.38 (m, 4 H) 2.45 - 2.58 (m, 6 H) 3.41 - 3.51 (m, 2H) ) 7.46 (dd, J = 7.8, 4.6 Hz, 1H) 7.68 (d, J = 1.0 Hz, 1H) 7.87 (d, J = 7.8 Hz, 2H) 8.10 - 8.19 (m, 3H) 8.54 (dd , J = 4.8, 1.6 Hz, 1H) 8.61 (t, J = 5.1 Hz, 1H) 8.77 (d, J = 2.2Hz, 1H) 8.91 (dd, J = 2.2, 0.7Hz, 1H) 9.09 ( d, J = 1.0 Hz, 1H) 12.61 (brs, 1H) UPLC-MS-DAD-ELSD: Tr (min) = 2.23; [M + H] +: m / z 495; [M-H] -: m / z 493; purity: 97% 1H NMR (400 MHz, DMSO-d6): 8 ppm 1.24 (qd, J = 12.1, 3.2 Hz, 2H) 1.52 - 1.64 (m, 1H) 1.65 - 1.76 (m, 2H) 1.80 - 1.94 (m, 2H) 2.17 (s, 3H) 2.74 - 2.85 (m, 2H) 3.24 (t, J = 6.2 Hz, 2H) 7.45 (dd, J = 8.1.4, 6Hz, 1H) 7.65 (s, 1H) 7.86 (d, J = 8.1 Hz, 2H) 8.13 (dt, J = 8.1, 1.8 Hz, 1H) 8.17 (d, J = 8.3 Hz, 2H) 8.54 (dd, J = 4.9, 1.5 Hz, 1H) 8.68 (t, J = 5.5 Hz, 1H) 8.77 (d, J = 2.4 Hz, 1H) 8.91 (d, J = 2.2Hz, 1H) 9.08 (s, 1H) 12.62 ( brs, 1H) UPLC-MS-DAD-ELSD: Tr (min) = 2.21; [M + H] +: m / z 455; [M-Hr: m / z 453; purity: 97% 1H NMR (400 MHz, DMSO-d6): 8 ppm 1.08 (s, 6H) 3.25 - 3.28 (m, 2H) 7.44 (dd, J = 8.1, 4.6 Hz, 1H) 7.68 (s) 7.87 (d, J = 7.8 Hz, 2H) 8.13 (dt, J = 8.0, 2.0Hz, 1H NM NH 2 4- [3-fluoro-6- (pyridin-3-yl) -9H- pyrrolo [2,3-b: 5,4-c '] dipyridin-4-yl] -N- [2- (4-methylpiperazin-1-yl) ethyl] benzamide 4- [3-fluoro-6- (Pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c '] dipyridin-4-yl] -N - [(1-methylpiperidin-4-yl) methyl] benzamid eH 2 N N (2-amino-2-methylpropyl) -4- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridin-4-yl] benzamide H) 8.19 (d, J = 8.3 Hz, 2H) 8.48 (t, J = 5.3Hz, 1H) 8.54 (dd, J = 4.8, 1.6Hz, 1H) 8.77 (d, J = 2.2Hz, m.p. 1 H) 8.93 (d, J = 2.0Hz, 1H) 9.09 (s, 1H) UPLC-MS-DAD-ELSD: Tr (min) = 2.12; [M + H] +: m / z 471; [M-H] -: m / z 469; purity: 95 1H NMR (400 MHz, DMSO-d6): 8 ppm 2.62 - 2.69 (m, 2H) 2.76 (t, J = 6.4 Hz, 2H) 3.39 - 3.51 (m, 4H) 4.46 (br. s., 1H) 7.47 (dd, J = 8.1, 4.9 Hz, 1H) 7.69 (d, J = 1.0 Hz, 1H) 7.87 (d, J = 7.6 Hz, 2H) 8.12 - 8.15 (m, 1) H) 8.17 (d, J = 8.6 Hz, 2H) 8.54 (dd, J = 4.8, 1.6Hz, 1H) 8.64 (t, J = 5.9Hz, 1H) 8.77 (d, J = 2.2Hz, 1H) H) 8.92 (d, J = 1.5Hz, 1H) 9.09 (d, J = 1.0Hz, 1H) UPLC-MS-DAD-ELSD: Tr (min) = 0.39; [M + H] +: m / z 427; [M-H] -: m / z 425; purity: 1H NMR (400 MHz, DMSO-d6): δ ppm 2.75 (t, J = 6.6 Hz, 2H) 3.33 - 3.38 (m, 2H) 7.46 (dd, J = 8.2, 4.8 Hz, 1H) ) 7.69 (s, 1H) 7.86 (d, J = 7.8 Hz, 2H) 8.14 (dt, J = 8.0, 2.0 Hz, 1H) 8.18 (d, J = 8.6 Hz, 2H) 8.53 (d, J = 4.2 Hz, 1H) 8.62 (t, J = 5.7 Hz, 1H) 8.74 - 8.77 (m, 1H) 8.92 (d, J = 1.7 Hz, 1H) 9.08 (s, 1H) 5 chloro-2-methoxy-4- (trimethylstannanyl) pyridine B: HH 2 N N -O-OH 27, o 4- [3-fluoro-6- (pyridin-3-yl) -9H-pyrrolo [2,3-b] N- (2-aminoethyl) -4- [3-fluoro-6,4,5-b] dipyridin-4-yl] -N- {2 - [(2-hydroxyethyl) amino] ethyl} benzamide (pyridin-3-yl) -9H-pyrrolo [2,3-b: 5,4-c '] dipyridin-4-yl] benzamide 28, ~, NH 2 H 2 N 33 _-Sn CI LiTMP, Me SnCl 3 THF A mixture of 10 g of 5-chloro-2-methoxypyridine and 220 ml of tetrahydrofuran is cooled to -78 ° C. and a freshly prepared solution is then added progressively from 14.1 ml of 2-chloro-2-methoxypyridine. , 2,6,6-tetramethylpiperidine in 50 ml of tetrahydrofuran and 36.4 ml of 2,3 N n-butyllithium in hexane. After stirring for 4 hours at -78 ° C., 17.3 g of trimethyltin chloride dissolved in 30 ml of tetrahydrofuran are added to the reaction mixture. The reaction mixture is stirred at ambient temperature for 18 h and then treated with 200 ml of water and 200 ml of 10% aqueous ammonium chloride solution and extracted with 500 ml and then 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a silica column eluting with dichloromethane to give 17.7 g of 5-chloro-2-methoxy-4- (trimethylstannanyl) pyridine B as a colorless oil. UPLC-MS-DAD-ELSD: Tr (min) = 1.24; [M + H] +: m / z 308; purity: 98% 1H NMR (400 MHz, DMSO-d6) ppm 0.16 (t, J = 29.6 Hz, 9H) 3.62 (s, 3H) 6.61 (t, J = 20.5 Hz, 1H) 7.90 (t, J = 8.3 Hz, 1H) Example 29: 5'-Chloro-5-fluoro-2'-methoxy-3,4'-bipyridin-2-amine Pd (PPh3) 4 Cul dioxane microwaves 120 ° C lh ON B 29 OI A mixture of 13.2 g of 5-chloro-2-methoxy-4- (trimethylstannanyl) pyridine, 7.5 g of 2-amino-3-bromo-5-fluoropyridine, 3.1 g of tetrakis ( triphenylphosphine) palladium (0) and 1.6 g of copper iodide in 100 ml of 1,4-dioxane is refluxed for 18 h. The reaction mixture is hydrolysed with a mixture of 200 ml of 10% aqueous solution of sodium hydrogencarbonate and 100 ml of water and then extracted twice with 200 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The residue is purified by trituration in 120 ml of ethyl acetate to give 8.7 g of 5'-chloro-5-fluoro-2'-methoxy-3,4'-bipyridin-2-amine in the form of a colorless oil.

UPLC-MS-DAD-ELSD: Tr (min) = 0.94; [M + H] +: m / z 253; purity: 72% 1H NMR (400 MHz, DMSO-d6); ppm 3.89 (s, 3H) 5.65 (s, 2H) 6.86 (s, 1H) 7.33 (dd, J = 8.7, 3.1Hz, 1H) 8.01 (d, J = 2.9Hz, 1H) 8.32 (s) Example 30: 3-Fluoro-6-methoxy-9H-pyrrolo [2,3-b: 5,4-c '] dipyridine I H2N-NOF 1 NCIPd (OAc) 2, Josiphos tBuOK, DME 100 ° In a dry tube, 1.12 g of (R) - (-) - 1 - [(S) -2- (dicyclohexylphosphino) ferrocenyl] ethyldi-tert-butylphosphine are placed in a dry tube and 0, 40 g of palladium (II) acetate in 15 ml of anhydrous 1,2-dimethoxyethane and stirred for 10 min at 40 ° C. 250 g of 5'-chloro-5-fluoro-2'-methoxy-3,4'-bipyridin-2-amine in 80 ml of 1,2-dimethoxyethane are placed under argon in a 250 ml reactor. anhydrous and add the previously prepared solution and then 5.64 g of potassium tertbutylate. The reaction mixture is refluxed for 18 h and then 3 ml of a freshly prepared catalyst solution of the same concentration and 1.41 g of potassium tert-butoxide are added. After refluxing for 6 hours, 10 ml of methanol and 300 ml of ethyl acetate are added to the reaction mixture. The organic phase is washed with 200 ml of 5% aqueous sodium hydrogencarbonate solution and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is purified by trituration in 100 ml of ethyl acetate to give 2.23 g of 3-fluoro-6-methoxy-9H-pyrrolo [2,3-b: 5,4-c] dipyridine. UPLC-MS-DAD-ELSD: Tr (min) = 0.58; [M + H] +: m / z 218; purity: 98% 1H NMR (400 MHz, DMSO-d6) ppm 3.91 (s, 3H) 7.58 (s, 1H) 8.49 (s, 1H) 8.54 - 8.61 (m, 2H) 11.85 (brs) Example 31: 3-Fluoro-9H-pyrrolo [2,3-b: 5,4-c] dipyridin-6-ol 600 mg of 3-fluoro-6-methoxy are placed in a reactor -9H-pyrrolo [2,3-b: 5,4-c '] dipyridine in 3 ml of acetic acid and 2 ml of 37% aqueous hydrochloric acid solution, sealed the tube and subjected to microwave irradiation 30 min at 130 ° C. The reaction mixture is drained under vacuum and then washed with ethyl ether to give 755 mg of 3-fluoro-9H-pyrrolo [2,3-b: 5,4-c] dipyridin-6-ol in the form of a solid. yellow. UPLC-MS-DAD-ELSD (LS): Tr (min) = 0.45; [M + H] +: m / z 204; purity: 91% 1H NMR (400 MHz, DMSO-d6) ppm 5.47 (brs, 1H) 7.92 (s, 1H) 8.52 (s, 1H) 8.75 (dd, J = 2.7, 1.7Hz , 1H) 8.87 (dd, J = 8.7, 2.8 Hz, 1H) 12.52 (s, 1H) Example 32: 3-Fluoro-9H-pyrrolo [2,3-b: 5,4-trifluoromethanesulfonate] ] dipyridin-6-yl (CF 3 SO 2) pyridine HO 31 A mixture of 755 mg of 3-fluoro-9H-pyrrolo [2,3-b: 5,4-c] dipyridin-6-ol in 15 ml of pyridine and 4.32 ml of trifluoromethanesulfonic anhydride is stirred at room temperature for 30 minutes. The reaction mixture is diluted with 100 ml of ethyl acetate and washed with 100 ml of a saturated aqueous solution of sodium bicarbonate. After decantation, the aqueous phase is extracted with 100 ml of ethyl acetate and the organic phases are combined, dried over magnesium sulfate, filtered and then concentrated in vacuo to give 978 mg of 3-fluoro-9H-pyrrolo trifluoromethanesulfonate [ 2,3-b: 5,4-c '] dipyridin-6-yl as a brown solid.

UPLC-MS-DAD-ELSD: Tr (min) = 4.22; [M + H] +: m / z 336; [M-H] -: m / z 334; purity: 98% 1H NMR (400 MHz, DMSO-d) ppm 8.41 (d, J = 0.7 Hz, 1H) 8.71 - 8.78 (m, 3H) 12.69 (brs, 1H) Example 33: 3 Fluoro-6- (1-methyl-1H-pyrazol-4-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridine o. PdC12 (dppf)

In a reactor, 960 mg of 3-fluoro-9H-pyrrolo [2,3-b: 5,4-c] dipyridin-6-yl trifluoromethanesulfonate are placed in a reactor, 43.7 mg of 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium (II), 372 mg of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ) -1 H-pyrazole, 1.17 g of cesium carbonate in 10 ml of 1,4-dioxane and 2.5 ml of water, sealed the tube and subjected to microwave irradiation at 125 ° C for 1 h. The reaction mixture is diluted with 50 ml of ethyl acetate and washed with 50 ml of water. After decantation, the aqueous phase is extracted with 100 ml of ethyl acetate and the organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography on a silica column eluting with ethyl acetate to give 168 mg of 3-fluoro-6- (1-methyl-1H-pyrazol-4-yl) -9H-pyrrolo [2 , 3-b: 5,4-c '] dipyridine as a yellow solid.

UPLC-MS-DAD-ELSD: Tr (min) = 2.24; [M + H] +: m / z 268; [MH] +: m / z 266, purity: 98% 1H NMR (400 MHz, DMSO-d6) ppm 3.91 (s, 3H) 7.96 (d, J = 0.5 Hz, 1H) 8.19 (s, 1H) ) 8.41 (d, J = 1.OHz, 1H) 8.55 (dd, J = 8.8, 2.9 Hz, 1H) 8.59 - 8.61 (m, 1H) 8.86 (d, J = 1.2 Hz, 1H) 12.14 (br S., 1 H)

Example 34: 3-Fluoro-9 - [(4-methylphenyl) sulfonyl] -6- (1-methyl-1H-pyrazol-4-yl) -9H-pyrrolo [2,3-b: 5,4-c] '] dipyridine TsCl, NaH / F DMF

In a 100 ml flask, 168 mg of 3-fluoro-6- (1-methyl-1H-pyrazol-4-yl) -9H-pyrrolo [2] were placed under argon. 3-b: 5,4-c '] dipyridine in 10 ml of dimethylformamide and

add 11 mg of sodium hydride. The reaction mixture is stirred for 3 h at room temperature and then 240 mg of para-toluenesulfonyl chloride are added. The reaction mixture is stirred for 45 min at room temperature and then poured into a mixture of water and sodium hydrogencarbonate solution: a white precipitate appears. After stirring, it is drained under vacuum and then washed with diethyl ether. The white solid obtained is purified by chromatography on a silica column eluting with ethyl acetate to give 225 mg of 3-fluoro-9 - [(4-methylphenyl) sulfonyl] -6- (1-methyl-1 H-pyrazol-4-yl) -9H-pyrrolo [2,3-b: 5,4-c '] dipyridine as a white solid. UPLC-MS-DAD-ELSD (LS): Tr (min. ) = 1.26; [M + H] +: m / z 422.26; purity: 93%

Example 35: 3-Fluoro-4-iodo-9 - [(4-methylphenyl) sulfonyl] -6- (1-methyl-1H-pyrazol-4-yl) -9H-pyrrolo [2,3-b] A mixture of 53 μl of 2,2,6,6-tetramethylpiperidine and 2 ml of tetrahydrofuran is cooled to -78 ° C and then 100 μl of 2.7 N n-butyllithium are added to the mixture. hexane. After 15 minutes, 75 mg of 3-fluoro-9 - [(4-methylphenyl) sulfonyl] -6- (1-methyl-1H-pyrazol-4-yl) -9H-pyrrolo [2] were added to the reaction mixture. 3-b: 5,4-c '] dipyridine dissolved in 5 ml of tetrahydrofuran and this is stirred at -78 ° C for 1 hour and then 72 mg of iodine in solution in 2 ml of tetrahydrofuran are added. The reaction mixture is poured onto a mixture of water and a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate. The organic phase is washed with an aqueous solution of sodium thiosulfate, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a silica column eluting with ethyl acetate to give 60 mg of 3-fluoro-4-iodo-9 - [(4-methylphenyl) sulfonyl] -6- (1- methyl-1H-pyrazol-4-yl) -9H-pyrrolo [2,3-b: 5,4-c '] dipyridine as a yellow solid. UPLC-MS-DAD-ELSD (LS): Tr (min) = 1.37; [M + H] +: m / z 548; purity: 71% Example 36: 3-Fluoro-4-iodo-6- (1-methyl-1H-pyrazol-4-yl) -9H-pyrrolo [2,3-b: 5,4-c] In a flask, 60 mg of 3-fluoro-4-iodo-9 - [(4-methylphenyl) sulfonyl] -6- (1-methyl-1H-pyrazol-4-yl) is placed in a flask. ) -9H-pyrrolo [2,3-b: 5,4-c '] dipyridine in 5 ml of methanol and 5 ml of tetrahydrofuran and then added 60 mg of lithium hydroxide. The reaction mixture is stirred for 18 hours at room temperature and then a little water and a few ml of aqueous ammonium chloride solution are added. The precipitate is filtered off, washed with water, with ethyl acetate and with diethyl ether and then dried under vacuum to give 25 mg of 3-fluoro-4-iodo-6- (1-methyl-1H) pyrazol-4-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridine.

1H NMR (400 MHz, DMSO-d6) :. ppm 3.94 (s, 3H) 8.03 (s, 1H) 8.34 (s, 1H) 8.59 (s, 1H) 8.83 (s, 1H) 8.99 (s, 1H) 12.73 (br. H) Example 37: N- [3- (dimethylamino) propyl] -4- (3-fluoro-6- (1-methyl-1H-pyrazol-4-yl) -9H-pyrrolo [2,3-b: In a reactor, 55 mg of 3-fluoro-4-iodo-6- (1-methyl) -alpha-4-yl] -benzamide (Pd (PPh 2)) was placed in a reactor. 1H-pyrazol-4-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridine, 16 mg of tetrakis (triphenylphosphine) palladium (O), 134 mg of N- (2-dimethylaminoethyl) ) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide, 68 mg of cesium carbonate in 2 ml of 1,4-dioxane and 500 μl of water sealed the tube and subjected to microwave irradiation at 120 ° C. for 1 h The reaction mixture is diluted with ethyl acetate and water and the yellow precipitate formed is drained under vacuum and washed with water. ethyl acetate, water and diethyl ether to give 45 mg N- [3- (dimethylamino) propyl] -4- [3-fluoro-6- (1-methyl-1H-pyrazol-4 yl) -9H-pyrrolo [2,3- b: 5,4-c '] dipyridin-4-yl] benzamide as a yellow solid. UPLC-MS-DAD-ELSD: Tr (min) = 0.38; [M + H] +: m / z 458; ; [M-H] -: m / z 456; 5 purity: 98%

1H NMR (400 MHz, DMSO-d6): ppm 2.23 (s, 6H) 2.46 - 2.49 (m, 2H) 3.45 (q, J = 6.6 Hz, 2H) 3.85 (s, 3H) 7.29 (d , J = 1.2 Hz, 1H) 7.54 (d, J = 0.7Hz, 1H) 7.82 (d, J = 7.8Hz, 2H) 7.92 (s, 1H) 8.14 (d, J = 8.3Hz, 2H) H) 8.61 (t, J = 5.5Hz, 1H) 8.71 (d, J = 2.4Hz, 1H) 8.89 (d, J = 1.0Hz, 1H) 12.36 (brs, 1H) Example 38: N- [2- (dimethylamino) ethyl] -4- [3-fluoro-6- (1-methyl-1H-pyrazol-4-yl) -9H-pyrrolo [2,3-b: 5.4 [α] Dipyridin-4-yl] benzamide Similarly to Example 37, from 55 mg of the product of Example 36, 35 mg of N- [2- (dimethylamino) ethyl] are obtained. [3-fluoro-6- (1-methyl-1H-pyrazol-4-yl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridin-4-yl] benzamide in the form of a pale yellow solid. UPLC-MS-DAD-ELSD: Tr (min) = 0.39; [M + H] +: m / z 472; purity: 95% 1H NMR (400 MHz, DMSO-d6): ppm 1.73 (quin, J = 7.0 Hz, 2H) 2.17 (s, 6H) 2.32 (t, J = 7.0 Hz, 2H) 3.38 (q , J = 6.4 Hz, 2H) 3.84 (s, 3H) 7.30 (s, 1H) 7.54 (s, 1H) 7.81 (d, J = 8.1Hz, 2H) 7.92 (s, 1H) 8.14 (d, J = 8.1 Hz, 2H) 8.68 - 8.76 (m, 2H) 8.89 (s, 1H) 12.37 (br.s, 1H) Example 39: 5'-chloro-2 ', 4 In a tube, 368 mg of 5-chloro-2-methoxy-4- (trimethylstannanyl) pyridine B, 250 mg of 3-iodo-4-methoxy- pyridin-2-ylamine, 304 mg of cesium fluoride, 38 mg of copper iodide in 2 ml of dimethylformamide and then 116 mg of tetrakis (triphenylphosphine) palladium (0) and 2 ml of dimethylformamide, seal the tube and submit to microwave irradiation at 125 ° C for 2 hours. The reaction mixture is filtered on celite, rinsed with 10 ml of ethyl acetate and then washed twice with 10 ml of water. After decantation, the organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a silica column, eluting with a heptane / ethyl acetate mixture: 50/50 to 0/100 to give 125 mg of 5'-chloro-2 ', 4-dimethoxy-3,4' bipyridin-2-amine in the form of a white solid.

UPLC-MS-DAD-ELSD: Tr (min) = 0.44; [M + H] +: m / z 266; purity: 98% 1H NMR (400 MHz, DMSO-d6) ppm 3.68 (s, 3H) 3.87 (s, 3H) 5.40 (s, 2H) 6.42 (d, J = 5.9 Hz, 1H) 6.72 ( d, J = 0.5 Hz, 1H) 7.94 (d, J = 5.9 Hz, 1H) 8.28 (d, J = 0.5 Hz, 1H) Example 40: 4,6-Dimethoxy-9H-pyrrolo [2,3] -b: 5,4-c '] dipyridine Me0' SnMe, fYNI Cl Pd (PPh3) 4 Ass / CsF Cl N ~ \ o B DMF 39 Pd (OAc) 2 / Josiphos N ~~ \ CI tBuOK / dioxanne 39 In a 2 ml tube, 10.3 mg of (R) - (-) - 1 - [(S) -2- (dicyclohexylphosphino) ferrocenyl] ethylditerbutylphosphine and 3.8 mg of anion were placed under an argon atmosphere. palladium (II) acetate in 0.35 ml anhydrous 1,4-dioxane, and stirred for 10 min at 35 ° C. In a 2 ml reactor, 45 mg of 5'-chloro-2 ', 4-dimethoxy-3,4'-bipyridin-2-amine and 38 mg of potassium tert-butoxide in 0.35 ml of sodium are placed under argon under argon. Dry 4-dioxane, then add the previously prepared solution and 0.20 ml of 1,4-dioxane, seal the tube and microwave irradiate for 1 hour at 130 ° C. The reaction mixture is diluted with a 90:10 dichloromethane: methanol mixture and then filtered. After concentration under reduced pressure, the residue is purified by chromatography on a silica column, eluting with a dichloromethane: methanol mixture 98: 2 to 94: 6 to give 28.5 mg of 4,6-dimethoxy-9H-pyrrolo [2, 3-b: 5,4-c '] dipyridine as a yellow solid.

UPLC-MS-DAD-ELSD: Tr (min) = 0.40; [M + H] +: m / z 230; purity: 95% H NMR (400 MHz, DMSO-d 6); ppm 3.89 (s, 3H) 4.09 (s, 3H) 6.85 (d, J = 5.9Hz, 1H) 7.30 (d, J = 1.0Hz, 1H) 8.39 - 8.42 (m, 2H) 11.70 (d, J = 5Hz, 1H) Example 41: 9H-pyrrolo [2,3-b: 5,4-c '] dipyridine-4,6-diol hydrochloride H 2 OH NHH CIH 40 In a 20 ml reactor, 1.52 g of 4,6-dimethoxy-9H-pyrrolo [2,3-b: 5,4-c] dipyridine are placed in 22.1 ml of acetic acid and 7.3 ml of a solution of 37% hydrochloric acid, sealed the tube and subjected to microwave irradiation for 2 hours at 140 ° C. After concentration of the reaction mixture, the solid obtained is slurried in 2 times 25 ml of diethyl ether and then dried under reduced pressure for 18 hours to give 1.72 g of 9H-pyrrolo [2,3-b: 5,4-chlorohydrate. dipyridine-4,6-diol as a dark beige solid. UPLC-MS-DAD-ELSD: Tr (min) = 0.14; [M + H] +: m / z 202; [M-H] -: m / z 200; 25 purity: 98%

1H NMR (400MHz, DMSO-d6) ppm 6.48 (m, 1H) 7.62 (s, 1H) 8.06 (d, J = 7.1Hz, 1H) 8.34 (s, 1H)

12.48 (br.s, 11-1) Example 42: 9H-Pyrrolo [2,3-b: 5,4-c '] dipyridine-4,6-diyl bis (trifluoromethanesulfonate) Tf20 Py / TEA 41 A mixture of 1.72 g of 9H-pyrrolo [2,3-b: 5,4-c '] dipyridine-4,6-diol hydrochloride in 35 ml of pyridine and 9.1 ml of triethylamine is cooled to room temperature. C. and then 2.8 ml of trifluoromethanesulphonic anhydride are added. The reaction mixture is stirred at 0-5 ° C for 1 h and then poured into a mixture of 200 ml of water and 50 ml of saturated aqueous sodium chloride solution and extracted with 250 ml of ethyl acetate. After decantation, the aqueous phase is extracted with 200 ml of ethyl acetate and the organic phases are combined and concentrated in vacuo. The residue is taken up in a mixture of 100 ml of 80/20 dichloromethane: ethyl acetate mixture, supplemented with 6.0 g of silica and concentrated under reduced pressure. The solid deposit formed is purified by chromatography on a silica column, eluting with a dichloromethane: ethyl acetate mixture 100: 0 to 80: 20 to give 124 mg of 9H-pyrrolo [2,3-b: bis (trifluoromethanesulfonate): 5,4-c '] dipyridine-4,6-diyl as a rust solid.

UPLC-MS-DAD-ELSD: Tr (min) = 4.81; [M + H] +: m / z 466; [M-H] -: m / z 464; purity: 98% 1H NMR (400 MHz, DMSO-d6): ppm 7.59 (d, J = 5.6 Hz, 1H) 7.96 (s, 1H) 8.88 (d, J = 0.7Hz, 1H) 8.89 (d , J = 5.6 Hz, 1H) 13.32 (brs, 1H)

Example 43: 4- (4 - {(2- (Dimethylamino) ethyl] carbamoyl} phenyl) -9H-pyrrolo [2,3-b: 5,4-c] dipyridin-6-yl trifluoromethanesulfonate i 42 43 a reactor, 124 mg of 9H-pyrrolo [2,3-b: 5,4-c '] dipyridine-4,6-diyl bis (trifluoromethanesulphonate), 85 mg of N- (2-dimethylaminoethyl) -4- - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide, 130 mg of cesium carbonate in 1.2 ml of 1,4-dioxane and then under argon 19 mg of 1 , 1'-bis (diphenylphosphino) ferrocenedichloropalladium (II) and 0.12 ml of water, sealed the tube and subjected to microwave irradiation at 140 ° C. for 15 minutes The reaction mixture is diluted with 10 ml of acetate of After decantation, the aqueous phase is extracted with 10 ml of ethyl acetate and the organic phases are combined, dried over magnesium sulphate, filtered and concentrated in vacuo. in a mixture of 30 ml of 90:10 dichloromethane: methanol mixture, added 60 0 mg of silica and concentrated under reduced pressure. The solid deposit formed is purified by chromatography on a silica column, eluting with a dichloromethane: methanol 100: 0 to 90:10 mixture to give 56 mg of 4- (4 - {[2- (dimethylamino) ethyl] carbamoyl trifluoromethanesulfonate} phenyl) -9H-pyrrolo [2,3-b: 5,4-c '] dipyridin-6-yl as a beige solid.

UPLC-MS-DAD-ELSD: Tr (min) = 4.81; [M + H] +: m / z 466; [M-H] -: m / z 464; purity: 98% 1H NMR (400 MHz, DMSO-d6):. ppm 2.36 (s, 6H) 2.62 - 2.69 (m, 2H) 3.48 (q, J = 6.5 Hz, 2H) 7.33 -7.38 (m, 2H) 7.85 (d, J = 8.3 Hz, 2H) 8.12 (d, J = 8.3 Hz, 2H) 8.61 - 8.67 (m, 1H) 8.74 - 8.78 (m, 2H) 12.86 (brs, 1H) Example 44: N- [2- (dimethylamino) ) ethyl] -4- [6- (1-methyl-1H-pyrazol-4-yl) -9H-pyrrolo [2,3-b: 5,4-c] pyridin-4-yl] benzamate In a reactor, 53 mg of 4- (4 - {[2- (dimethylamino) ethyl] carbamoyl} phenyl) -9H-pyrrolo [2,3-b: 5,4-trifluoromethanesulphonate are placed in a reactor. c '] dipyridin-6-yl, 33 mg of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole, 51 mg of carbonate of cesium in 0.8 ml of 1,4-dioxane then under argon 8 mg of 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium (II) and 85 μl of water, seals the tube and subjected to microwave irradiation at 140 ° C for 30 min. 21 mg of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole and 8 mg of 1,1 'are added to the reaction mixture. -bis (diphenylphosphino) ferrocenedichloropalladium (II) then the mixture is again subjected to microwave irradiation at 140 ° C for 30 min.

The reaction mixture is diluted with 10 ml of ethyl acetate and treated with 10 ml of water. After decantation, the aqueous phase is extracted with 10 ml of ethyl acetate and the organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography on a silica column, eluting with a dichloromethane / methanol mixture 100: 0 to 88: 12; the solid obtained is washed with 1 ml of diethyl ether to give 7 mg of N- [2- (dimethylamino) ethyl] -4- [6- (1-methyl-1H-pyrazol-4-yl) -9H- pyrrolo [2,3-b: 5,4-c '] dipyridin-4-yl] benzamide as a beige solid.

UPLC-MS-DAD-ELSD: Tr (min) = 2.01; [M + H] +: m / z 440; [M-1H]: m / z 438, purity: 90% 1H NMR (500 MHz, DMSO-d6): ppm 2.22 (s, 6H) 2.44 - 2.49 (m, 2H) 3.45 (q, J = 6.6 Hz, 2H) 3.86 (s, 3H) 7.26 (d, J = 4.9Hz, 1H) 7.61 (s, 1H) 7.63 (s, 1H) 7.86 (d, J = 8.2Hz, 2H) 7.98 (s, 1H) 8.13 (d, J = 8.2 Hz, 2H) 8.60 (t, J = 5.4 Hz, 1H) 8.64 (d, J = 4.9Hz, 1H) 8.89 (s, 1H) The pharmacological properties of the compounds of the invention can be confirmed by a number of pharmacological assays.The following pharmacological dosage examples were made with compounds according to the present invention. the invention.

Example 1 TR-FRET Assay In order to determine the inhibition of Pim kinase activity, the compounds of the invention are tested in accordance with a TR-FRET assay ("Time Resolved-Fluorescence Resonance Energy Transfer"). in vitro resonance fluorescence) in vitro used routinely. The TR-FRET assay is based on the detection of phosphorylation of the Ser112 specific residue in the Bad protein, which has been shown to be a natural substrate of Pim kinases in cells. For the assay, the following reagents are used: Hisim-tagged recombinant full-length human Pim-protein, Pim-1, Pim-2, or Pim-3 (prepared according to J. Mol., Biol. (2005) 348, 183- 193); Bad - His6-tagged recombinant full-length human Bad Protein (prepared according to J. Mol Biol (2005) 348, 183-193); a-His6-APC-mouse monoclonal antibody conjugated to the SureLightTM allophycocyanin directed against the His6 tag (Perkin Elmer, No. AD0059H, Waltham, Mass., USA); a-PûBad-Eu - mouse monoclonal antibody (Cell Signaling Technology # 9296B, Danvers, Massachusetts, USA) directed against phosphoBad (Ser112) (7E11) labeled at the request by Perkin Elmer with LANCETM reagent Eu-W1024.

The assay is based on PerkinElmer's LANCETM technology: the Eu-labeled antibody binds to phospho-Ser112 and generates a TR-FRET signal by interaction with the label-bound, PCA-labeled His6 antibody His6 from Bad. The TR-FRET signal is detected using a SpectraMax M5 plate reader (Molecular Devices) with the following settings: tex = 340 nm, 2,, em1 = 615 nm, Xem2 = 665 nm. The fluorescence signal ratio at 665 nm on a fluorescence signal at 615 nm is used as a signal reading for the IC50 (calculations based on the 4-parameter logistic model). The assay is carried out in a 384-well format; liquid handling is carried out using a Beckman 3000 liquid handling station. The compounds under test are tested at 10 concentration points in duplicate; the highest compound concentration is typically 30 μM. The concentration of ATP is 40 μM.

Example 2 Determination of Cell Viability The representative compounds of the invention are also screened for their effects on cell proliferation and viability using a variety of tumor cell lines from humans. , representative of different pathological indications. These cell lines include:

Models of hematologic malignancies: TF-1 (acute myelogenous leukemia, AML M6 at the time of diagnosis); KG-1 (AML, erythroleukemia evolving in AML); KG-1a (AML, subclone derived from immature KG-1); EOL-1 (AML, eosinophilic leukemia); PL-21 (AML; M3); ML-2 (AML, T-NHL evolving into T-ALL evolving in AML M4); HL-60 (AML, M3); Kasumi-1 (AML); GDM-1 (AML); K-562 (CML - chronic myelogenous leukemia, blast crisis); JURL-MK1 (CML blast crisis); DND-41 (T-ALL - acute T cell lymphoblastic leukemia); Jurkat (T-ALL); NALM-6 (B-ALL ùALL to B cells); CEM (ALL, ALL lymphosarcoma); Jeko-1 (B-NHL or non-Hodgkin's B-cell lymphoma, large cell variant leukemia-derived mantle cell lymphoma); WSU-DLCL2 (B-NHL, diffuse large B-cell lymphoma); RL (B-NHL; undifferentiated diffuse); OCI-Ly10 (B-NHL); DoHH-2 (B-NHL); RPMI-8226 (MM multiple myeloma); JVM-2 (B-CLL - B-cell chronic lymphocytic leukemia); and JVM-3 (B-CLL).

Solid tumor models: HCT-116 (colon cancer); HT-29 (colon cancer); HC-15 (colon cancer); H460 (lung cancer, non-small cell lung cancer); A375 (melanoma); B16F10 (melanoma); MDA-A1 (breast cancer); MDA-MB231 (breast cancer); MDA-MB231 adr (breast cancer); PAN C-1 (pancreatic cancer); and PC-3 (prostate cancer).

In order to measure viability, the tumor cells are incubated in a 96-well or 384-well format for 48, 72 or 96 hours, preferably 72 hours, with a compound of the invention at 3-fold dilutions with in general, nine doses in total, the highest dose being 10 μM or 30 μM. Cell viability is assessed by the addition of CeIlTiter-Blue (Promega, Madison, Wisconsin, USA) for 4 hours and end point readings are performed using a SpectraMax Genmini EM plate reader (Molecular Devices, Sunnyvale, California, United States). The CeIlTiter-Blue cell viability assay measures the ability of cultured cells to effect reduction of resazurin to resorufin, the intensity of the fluorescence signal being directly proportional to the number of living cells. EC 50 represents the concentration of compound that leads to a 50% reduction in proliferative cell viability / expansion.

Example 3 The activity of the molecules is evaluated on the JEKO cell line by measuring the level of phosphorylation of Bad and the total Bad rate, and this, by the Elisa technique.

The JEKO cells are resuspended at a concentration of 500,000 cells per ml. The cells are then diluted in RPMI-1640 medium containing 20% fetal calf serum. 225 μl of cells are placed in a plate. The serial dilutions of the molecules are then carried out (8 points, dilution to 1/3, start of range to 10 mM). Each dilution point is then diluted 1/100 in medium. Then, 25 μl of each of the concentrations are added to the cells and then incubated for 3 hours at 37 ° C. 100 μl of the cells are transferred to a poly-D-Lysine treated plate. The plate is then incubated for 5-10 minutes at 37 ° C. and then centrifuged for 5 minutes at 1500 rpm. A volume of 100 μl of 8% fixing solution (formaldehyde solution in PBS buffer) is added to each of the wells. After being covered with a self-adhesive film and a lid, the plate is incubated for 20 minutes at room temperature and then stored at 4 ° C overnight. Then, the liquid is removed and two successive washes are carried out with washing buffer. 100 μl of quenching buffer are added and incubated for 15 minutes at room temperature. After washing, 100 μl of stop buffer is added followed by incubation for 1 hour at room temperature. After washing, 50 μl of the primary antibody diluted to 1/250 for pBAD (Cell Signaling Cat # 5284) and 1/500 for Bad (MBL Cat # 591) are added to each of the plates. Each of the plates is incubated for 2 hours at room temperature. After two washes, 50 μl of the secondary antibody (diluted 1/16) are added to the Pbad plate (tebu-bio ref: FE-021) and 50 μl of the HRP-conjugated secondary antibody IgG (Santa Cruz Cat # SC-2004, diluted 1/1000) are added to the Bad plate. An incubation of 1 hour at room temperature is performed. 4 washes with the washing solution are carried out followed by 3 washes with PBS. Finally, 100 μl of the revealing solution is added followed by a 10 minute incubation. Finally, 100 μl of the stop solution is added before reading at 450 nm.

BIOCHEMICAL RESULTS The biochemical results are expressed according to the following classification:

Class A: IC50 less than 100 nM Class B: IC50 between 100 nM and 1000 nM (or 1 μM) Class C: IC50 between 1 μM and 5 μM Class D: IC50 greater than 5 μM Compound no. IC50 Pim1 IC50 Pim2 IC50 Pim3 IC50 CDK1 IC50 PLK1 7 ABACB 9 AAABB 10 ABACC 11 ACB 12 ACACC 13 ACB 14 ACB 15 BDC 16 ACB 17 ACB 19 ABACB 20 ABABB 21 ACABC 22 ABACC 23 AAACB 24 ACACC 25 ACACC 26 AAACB 27 AAACB 28 AAABB 37 AAABC 38 AAABC AAABB CELLULAR RESULTS The cell proliferation results are expressed according to the following classification:

Class A: IC50 less than 100 nM Class B: IC50 between 100 nM and 1000 nM (or 1 μM) Class C: IC50 between 1 μM and 5 μM Compound No. EC50 EOL-1 IC50 MV4-11 IC50 MOLM- 13 IC50 NM pM pM phosphoBAD (lymphoma) (myeloma) (myeloma) (JEKO) 7 ABB 9 ABB 10 BBB 11 B 12 BCB 19 BB 20 BB 21 BBB 23 A5

Claims (26)

REVENDICATIONS1. Compounds of the following general formula: Ra in which -Z2, Z3, Z4 = CouN; R3 is selected from: 1. H; 2. halogen (F, Cl, Br, I); 3. CF3, CHF2; 4. OH Alkoxy whose alkyl part is optionally mono, di or tri substituted; 15 6. NH2, NH (alkyl), N (alkyl) 2, the alkyl part of which is optionally mono, di or tri substituted; 7. C (O) Oalkyl optionally mono, di or tri substituted; 8. CONH (alkyl), CON (alkyl) 2 whose alkyl part is optionally mono, di or tri substituted; 20 9. C, -C, o linear, branched or cyclic alkyl optionally comprising a heteroatom and optionally mono-, di or tri-substituted; Aryl or heteroaryl optionally mono-, di- or tri-substituted; R6 being a heteroaryl (5 or 6-membered with 1 to 4 heteroatoms selected from N, S or O) bonded to the azacarboline moiety either by a C or an N belonging to R6, R6 being optionally mono or poly substituted; - Ra being obligatorily: 1. CONH2i 2. CONHalkyle, CONHcycloalkyle possibly mono, di or tri substituted; 3. CONHheterocycloalkyl optionally mono, di or tri substituted; 4. CON (alkyl) 2 optionally mono, di or tri substituted; 5. CON (alkyl) (heterocycloalkyl) optionally mono, di or tri substituted; 6. CONHN (alkyl) 2 whose alkyl part is optionally mono, di or tri substituted; - Rs being selected from the following groups: 1. H; 2 F; Cl; Br; 1. 3. OH; 4. O-alkyl (C, -C, O) linear or branched optionally mono or poly substituted; 5. NH2; 6. N (C 1 -C 6 alkyl) or C 3 -C 7 cycloalkyl) each group being optionally mono or poly substituted; 7. NHC (O) R3a; 8. N (C 1 -C 6 alkyl) C (O) R 3a; 9. NHS (O 2) R 3a; 10. N (C 1 -C 10 alkyl) S (O 2) R 3a; 11. CO2R3a; 12. SR3a; S (O) R3a; S (O2) R3a Ra and Rs may optionally form a ring 2. Compounds according to claim 1 characterized in that the optional substituents of R3, R6 and Ra are chosen from R2a, R2b or R2c groups chosen from independently of each other from: 1. F; 2. Cl; 3. Br; 4. I; 5. CF3; CHF2 6. CI-C, linear or branched alkyl optionally mono or poly substituted; C3-C7 cycloalkyl optionally mono or poly substituted; 8. OH; 9. Linear or branched, optionally mono or poly substituted O-alkyl (C 1 -C 0); O-cycloalkyl (C3-C7) optionally mono or poly substituted; 11. O-aryl optionally mono or poly substituted; 12. optionally mono or poly substituted aryl; 13. optionally mono or poly substituted heteroaryl; 14. optionally mono or poly substituted heterocycloalkyl; 15. NO2; 16.NH2; 17. NH- (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl or heterocycloalkyl) each optionally mono or poly substituted group; 18. N (C 1 -C 6 alkyl) or C 3 -C 7 cycloalkyl) each group being optionally mono or poly substituted; 19. NHC (0) substituted; 20. N (C 1 -C 0) alkyl (C) substituted (C); 21. substituted NHS (O2); 22. N (substituted (C 1 -C 0) alkyl) S (O 2); 23. CO2substituted; 24. Substituted; 25. S (O2) substituted; 26. S (0) substituted; 3. Compounds according to claim 2 characterized in that the possible substituents of all the substituted groups and R2a, R2b and R2c groups or R3a groups are chosen from: 1. F; Cl; Br; I2. CF3; 3. C, -C, o linear or branched alkyl 4. C3-C7 cycloalkyl; C2-C6 alkenyl; 6. C2-C6 alkynyl; 7. OH; 8. linear, branched or cyclic (C3-C7) O-alkyl (C, -C, o); 9. C3-C7 heterocycloalkyl; 10.NH2; 11. NH- (C 1 -C 5 alkyl) or C 3 -C 5 cycloalkyl); 12. N (C 1 -C 10 alkyl) or C 3 -C (cycloalkyl) 2; 13. NH- (C 1 -C 5 alkyl) or C 3 -C 7 heterocycloalkyl); 14. N (C 1 -C 6 alkyl) or C 3 -C 7 heterocycloalkyl) 2; 4. Compounds according to the preceding claims characterized in that -Z2, Z3, Z4 = CouN; R3 is chosen from: 1-H-halogen (F, Cl, Br, I); 3- CF3, CHF2; 4-OH-alkoxy whose alkyl part is optionally mono, di or tri substituted by R2a, R2b, R2c; 6- NH2, NH (alkyl), N (alkyl) 2, the alkyl part of which is optionally mono, di or tri substituted by R2a, R2b, R2c; 7- C (O) Oalkyl optionally mono, di or tri substituted by R2a, R2b, R2c; 8-CONH (alkyl), CON (alkyl) 2 whose alkyl part is optionally mono, di or tri substituted by R2a, R2b, R2c; 9-C, -C, o linear, branched or cyclic alkyl optionally comprising a heteroatom and optionally mono, di or tri substituted by R2a, R2b, R2c; 10-aryl or heteroaryl optionally mono, di or tri substituted by R2a, R2b, R 2c; R 6 is a heteroaryl (5 or 6-membered with 1 to 4 heteroatoms chosen from N, S or O) bonded to the azacarboline unit, either by a C or by an N belonging to R 6, R 6 being optionally mono or poly substituted with R 2a, R 2b; R2c; - Ra being obligatorily: 1. CONH2, 2. CONHalkyl, CONHcycloalkyl optionally mono, di or tri substituted by R2a, R2b, R2c; 3. CONHheterocycloalkyl optionally mono, di or tri substituted by R2a, R2b, R2c; 4. CON (alkyl) 2 optionally mono, di or tri substituted by R2a, R2b, R2c; 5. CON (alkyl) (heterocycloalkyl) optionally mono, di or tri substituted by R2a, R2b, R2c; 6. CONHN (alkyl) 2 whose alkyl part is optionally mono, di or tri substituted by R2a, R2b, R2c; - Rs being selected from the following groups: 1.H, 2. F; Cl; Br; 1 3. OH; 4. O-alkyl (C, -C, O) linear or branched optionally mono or poly substituted with different R3a; 5. NH2; 6. N (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl) each group being optionally mono or poly substituted with different R 3a; 7. NHC (O) R3a; 8. N (C 1 -C 6) alkyl (C) (O) R 3a; 9. NHS (O 2) R 3a; 10. N (C 1 -C 10 alkyl) S (O 2) R 3a; 11. CO2R 3a; 12. SR3a; S (O) R3a; S (O2) R3aRa and Rs may optionally form a ring; R2a, R2b or R2c are independently selected from: 1.F, 2.Cl; 3. Br; 4. 5. CF3; CHF2 6. C, -C, o linear or branched alkyl optionally mono or poly substituted with different R3a; 7. C3-C7 cycloalkyl optionally mono or poly substituted with different R3a; 8 OH; 9. O-alkyl (C 1 -C 0) linear or branched optionally mono or poly substituted with different R 3a; 10. O-cycloalkyl (C 3 -C 7) optionally mono or poly substituted with different R 3a; aryl optionally substituted mono or poly substituted with R3a; 12. aryl optionally mono or poly substituted with different R3a; 13. heteroaryl optionally mono or poly substituted with different R3a; 14. heterocycloalkyl optionally mono or poly substituted with different R3a; 15. NO2 16. NH2; 17. NH- ( (C 1 -C 6) alkyl or (C 3 -C 7) cycloalkyl or heterocycloalkyl) each optionally mono or poly group substituted with different R 3a; 18. N (C 1 -C 10 alkyl) or C 3 -C 7 cycloalkyl) each group being optionally mono or poly substituted with different R 3a; 19. NHC (0) R3a; 20. N (C 1 -C 10 alkyl) C (O) R 3a, 21. NHS (O 2) R 3a, 22. N (C 1 -C 10 alkyl) S (O 2) R 3a, 23. CO2R 3a; 24. SR3a; S (O) R3a; S (O2) R3a; optionally substituents of R2a, R2b and R2c where R3a are selected from: 1. F; Cl; Br; 1 2. CF3; 3. C , -C, o linear or branched alkyl 4. C3-C7 cycloalkyl, 5. C2-C6 alkenyl, 6. C2-C6 alkynyl, 7. OH, 8. O-alkyl (C, -C, O) linear, branched or cyclic (C3-C7); 9. heterocycloalkyl (C3-C7); 10. NH2; 11. NH- (C1 -C4 alkyl) or cycloalkyl (C3-C)); 12. N (alkyl) (C, -C, o) or cycloalkyl (C 3 -C 4) 2; 13. NH- (C 1 -C 10 alkyl) or heterocycloalkyl (C 3 -C 7)); -C, o) or heterocycloalkyl (C3-C7)); 5. Pharmaceutical compositions containing as active ingredient, a compound according to any one of the preceding claims as well as at least one pharmaceutically compatible excipient 6. Pharmaceutical compositions according to the preceding claim used for the treatment of cancer.