WO2011070298A1 - Di-substituted 9h-pyrido[3,4-b]indole derivatives, preparation of same and therapeutic use thereof - Google Patents

Abstract

The invention relates to products of formula (I): as well as to the isomers and salts of said products of formula (I) and the therapeutic use thereof for treating cancer.

Description

 9H-PYRIDINOr3,4-b1INDOLE DISUBSTITUES DERIVATIVES, THEIR PREPARATION

AND THEIR THERAPEUTIC USE

The present invention relates to 9H-pyridino [3,4-b] indole derivatives, their preparation and their therapeutic application.

 The present invention relates to compounds acting on protein kinases, these kinases being involved in the development of cancers. 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 the 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 Natl 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)). ). Huttmann 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 more aggressive disease progression (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 nodular and predominantly nodular Hodgkin's lymphoma predominantly (Liso et al., Blood, Vol 108, No. 3, 1013-1020 (2006)). Numerous studies have also linked 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-1 L) was significantly upregulated in human prostate tumor samples, and indicate that Pim-1 L has an anti-apoptotic effect on cancer cells. 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., J Cancer Res Clin Oncol, 134: 481-488 (2008)).

Together, these 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, prostate cancer, 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.

The present invention relates to products of the following general formula (I):

 (I) in which

 Z 3 being a 5- or 6-membered heteroaryl with 1 to 4 heteroatoms chosen from N, S or O) linked to the carboline unit, either by a C or by an N belonging to Z 3, Z 3 being optionally mono or poly substituted;

 Z6 is chosen from:

 1. H;

 2. halogen;

 3. -OH

 Alkoxy whose alkyl part is optionally mono, di or tri substituted;

5. -Y-alkyl (Y = S, SO, SO 2) linear or branched optionally mono, di or tri substituted;

 6. -X-aryl (X = O, S, SO, SO2) optionally mono, di or tri substituted

7. -X-heteroaryl (X = O, S, SO, SO2, 5- or 6-membered heteroaryl with 1 to 4 heteroatoms selected from N, S or O bonded to X, either C or N) optionally mono, di or substituted tripping ÷

 8. -NH2,

9. -NH (alkyl), -N (alkyl) ₂ linear (s), branched (s) or cyclic (s) of which the alkyl part is optionally mono, di or tri substituted;

 10. -NH (aryl) whose aryl part is optionally mono, di or tri substituted;

1 1. -NH (heteroaryl) whose heteroaryl part (heteroaryl of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom by a C or an N) is optionally mono, di or substituted tri;

 12. -N (alkyl) (aryl) whose alkyl (linear, branched or cyclic) and aryl portions are optionally mono, di or tri substituted;

13. -N (alkyl) (heteroaryl) whose alkyl (linear, branched or cyclic) and heteroaryl (5- or 6-membered heteroaryl with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom with either C or N) are optionally mono, di or tri substituted;

 14. -C (0) OH

 15. -C (O) linear, branched or cyclic alkyl optionally mono-, di or tri-substituted;

 16. -C (O) Oaryl optionally mono, di or tri substituted;

 17. -C (O) Oheteroaryl (heteroaryl of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded to oxygen by a C atom) optionally mono, di or tri substituted;

 18. -CONH2;

 19. -CO-heterocycloalkyl mono, di or tri substituted

20. -CONH (alkyl), CON (alkyl) ₂ linear (s), branched (s) or cyclic (s) of which the alkyl part is optionally mono, di or tri substituted;

 21. -CON (alkyl) (aryl), linear, branched or cyclic alkyl of which the alkyl and aryl parts are optionally mono, di or tri substituted;

 22. -CON (alkyl) (heteroaryl), linear, branched or cyclic alkyl and heteroaryl of 5- or 6-membered with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom either by a C or by an N) of which the alkyl and the hetroaryl parts are optionally mono, di or tri substituted;

 23. -C1 -C10 linear, branched or cyclic alkyl optionally containing a heteroatom and optionally mono, di or tri substituted

 24. possibly mono, di or tri substituted aryl (

 25. heteroaryl (5- or 6-membered with 1 to 4 heteroatoms selected from N, S or O) linked to the carboline moiety either by a C or by an N belonging to Z6, Z6 being optionally mono or poly substituted;

 26. optionally mono or poly substituted heterocycloalkyl;

 27. -C2-C6 alkenyl optionally mono or disubstituted;

 28. -C 2 -C6 alkynyl optionally substituted;

said products of formula (I) being in all the possible isomeric, racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I) . The present invention relates in particular to compounds of general formula (I) as defined above in which Z3 has the meaning indicated above and Z6 represents in particular:

 1. H;

 2. halogen;

 3. -OH

 4. alkoxy whose alkyl part is optionally mono, di or tri substituted

 5. -NH2,

6. -NH (alkyl), -N (alkyl) ₂ linear (s), branched (s) or cyclic (s) of which the alkyl part is optionally mono, di or tri substituted;

 7. -NH (aryl), the aryl part of which is optionally mono, di or tri substituted;

 8. -NH (heteroaryl) whose heteroaryl part (heteroaryl of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom is a C or an N) is optionally mono , di or substituted tri;

 9. -N (alkyl) (aryl) whose alkyl (linear, branched or cyclic) and aryl portions are optionally mono, di or tri substituted;

 10. -N (alkyl) (heteroaryl) of which the alkyl (linear, branched or cyclic) and heteroaryl (heteroaryl) parts of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom either by a C or an N) are optionally mono, di or tri substituted;

 1 1. -C (0) OH

 12. -C (O) linear, branched or cyclic optionally mono, di or tri substituted alkyl;

 13. -C (O) Oaryl optionally mono, di or tri substituted;

 14. -C (O) Oheteroaryl (heteroaryl of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded to oxygen by a C atom) optionally mono, di or tri substituted;

15. -CONH2 16. -CONH (alkyl), CON (alkyl) ₂ linear (s), branched (s) or cyclic (s) of which the alkyl part is optionally mono, di or tri substituted;

 17. -CON (alkyl) (aryl), linear, branched or cyclic alkyl of which the alkyl and aryl parts are optionally mono, di or tri substituted;

 18. -CON (alkyl) (heteroaryl), linear, branched or cyclic alkyl and heteroaryl of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom either by a C or by an N) of which the alkyl and the hetroaryl parts are optionally mono, di or tri substituted;

 19. -Ci-Cio linear, branched or cyclic alkyl optionally comprising a heteroatom and optionally mono, di or tri substituted;

 20. aryl optionally mono, di or tri substituted;

 21. heteroaryl (5 or 6-membered with 1 to 4 heteroatoms selected from N, S or O) linked to the carboline unit either by a C or by an N belonging to Z6, Z6 being optionally mono or poly substituted;

 22. optionally mono or poly substituted heterocycloalkyl;

23. -C2-C6 alkenyl optionally mono or disubstituted;

 24. -C 2 -C6 alkynyl optionally substituted;

said products of formula (I) being in all the possible isomeric, racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I) .

 The present invention relates to products of general formula (I) as defined above in which the possible substituents of Z3 is the groups R2a, R2b, R2c, R2d or R2e are chosen independently of one another among:

 1. F;

 2. Cl;

 3. Br;

4. I; 5. -CIC-10 linear or branched alkyl optionally mono or poly substituted with R3a, R3b, R3c, identical or different

6. -C ₃ -C ₇ cycloalkyl optionally mono or poly substituted with R 3a, R 3b, R 3c, identical or different,

7. -OH;

 8. -O-alkyl (CrCio) linear or branched optionally mono or poly substituted with R3a, R3b, R3c, the same or different;

9. -Y-alkyl (Y = S, SO, SO2) linear or branched optionally mono, di or tri substituted by R3a, R3b, R3c, identical or different; 10. -O-cycloalkyl (C ₃ -C ₇ ) optionally mono or poly substituted by

R3a, R3b, R3c, identical or different;

 1 1. -O-aryl optionally mono or poly substituted with R3a, R3b, R3c, the same or different;

 12. aryl optionally mono or poly substituted with R3a, R3b, R3c, the same or different;

 13. heteroaryl consisting of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded either by a C or by N) optionally mono or poly substituted with R3a, R3b, R3c, the same or different;

14. heterocycloalkyl optionally mono or poly substituted with R3a,

R3b, R3c, identical or different;

15. -No ₂ ;

16. -NH ₂ ;

17. -NH- (alkyl (CrCio) or cycloalkyl (C ₃ -C ₇ ) or heterocycloalkyl) each optionally mono or poly substituted with R 3a,

R3b, R3c, identical or different;

18. -N (alkyl (d-Cio) or cycloalkyl (C ₃ -C ₇ )) 2 each group being optionally mono or poly substituted with R3a, R3b, R3c, identical or different;

19. -NHaryl or NH heteroaryl optionally mono or poly substituted with R3a, R3b, R3c, identical or different

 20. -NHC (O) substituted with R3a, R3b, R3c, the same or different;

21. -N (C 1 -C 10) alkyl (C) substituted by R 3a, R 3b, R 3c, the same or different; 22. -NHS (O ₂ ) substituted with R3a, R3b, R3c, same or different;

23. -N (C 1 -C 10) alkyl S (O ₂ ) substituted with R 3a, R 3b, R 3c, same or different;

24. -C0 ₂ substituted by R3a, R3b, R3c, identical or different;

 25. -Ssubstituted by R3a, R3b, R3c, identical or different;

26. -S (0 ₂ ) substituted with R3a, R3b, R3c, identical or different;

 27. -S (O) substituted with R3a, R3b, R3c, identical or different;

 28. oxo (double bond O);

 29. -C2-C6 alkenyl optionally mono or disubstituted by R3a, R3b identical or different;

 30. -C2-C6 alkynyl optionally substituted with R3a; the groups R3a, R3b, R3c, or the substituents of the groups R2a, R2b, R2c, R2d or R2e, are chosen independently of one another from:

 1. F;

 2. Cl;

 3. Br;

 4. I;

 5. -C-I-C-10 linear or branched alkyl optionally mono or poly substituted with R4a, R4b, R4c;

 6. -C3-C7 cycloalkyl optionally mono or poly substituted with R4a, R4b, R4c;

 7. -OH;

 8. Linear or branched, optionally mono- or poly-substituted O-alkyl (CrCio) by R4a, R4b, R4c;

 9. -Y-alkyl (Y = S, SO, SO2) linear or branched optionally mono, di or tri substituted by R4a, R4b, R4c;

10. -O-cycloalkyl (C ₃ -C ₇ ) optionally mono or poly substituted with R 4a, R 4b, R 4c;

 1 1. -O-aryl optionally mono or poly substituted with R4a, R4b, R4c;

 12. aryl optionally mono or poly substituted with R4a, R4b, R4c;

 13. heteroaryl optionally mono or poly substituted with R4a, R4b, R4c;

14. heterocycloalkyl optionally mono or poly substituted with R4a, R4b, R4c;

15. -No ₂ ;

17. -NH- (alkyl (CrCio) or cycloalkyl (C ₃ -C ₇ ) or heterocycloalkyl) each optionally mono or poly substituted with R4a, R4b, R4c;

18. -N (alkyl (d-Cio) or cycloalkyl (C ₃ -C ₇ )) 2 each group being optionally mono or poly substituted with R4a, R4b, R4c;

 19. -NHaryl or NH heteroaryl optionally mono or poly substituted with R4a, R4b, R4c;

 20. -NHC (O) substituted with R4a, R4b, R4c;

 21. -N (C 1 -C 10) alkyl (C) substituted with R 4a, R 4b, R 4c;

22. -NHS (O ₂ ) substituted with R4a, R4b, R4c;

23. -N (C 1 -C 10) alkyl S (O ₂ ) substituted with R 4a, R 4b, R 4c;

24. -C0 ₂ substituted with R4a, R4b, R4c;

26. -CONH (alkyl), CON (alkyl) ₂ linear (s), branched (s) or cyclic (s) of which the alkyl part is optionally mono, di or tri substituted by R4a, R4b, R4c;

 27. -C (O) heterocycloalkyl optionally mono, di or tri substituted by R4a, R4b, R4c;

 28. -S substituted with R4a, R4b, R4c;

29. -S (O ₂ ) substituted with R4a, R4b, R4c;

 30. -S (O) substituted with R4a, R4b, R4c;

 31. oxo (double bond O);

32. -C ₂ -C ₆ alkenyl optionally mono or poly substituted with R4a, R4b, R4c;

33. -C ₂ -C ₆ alkynyl optionally mono or poly substituted with R 4a, R 4b, R 4c;

the groups R4a, R4b, R4c, or the substituents of the groups R3a, R3b and R3c, are chosen independently of one another from:

 1. F;

 2. Cl;

 3. Br;

 4. I;

5. -CF ₃ ; -CHF ₂

6. -C1-C10 linear or branched alkyl; 7. -C ₃ -C ₇ cycloalkyl;

 8. -OH;

 9. linear or branched (C 1 -C 10) alkyl;

 10. -Y-alkyl (Y = S, SO, SO 2) linear or branched;

1 1. -O-cycloalkyl (C ₃ -C ₇ );

 12.-O-aryl;

 13. aryl;

 14. heteroaryl;

 15. heterocycloalkyl;

16. -No ₂ ;

18. -NH- (C ₁ -C ₁₀ ) alkyl or C ₃ -C ₇ cycloalkyl or heterocycloalkyl;

19. -N (C ₁ -C ₁₀ alkyl) or C ₃ -C ₇ cycloalkyl) ₂ ;

 20. -NHaryl or NH heteroaryl;

21. -NHS (O ₂ ) alkyl;

22. -N (C 1 -C ₁₀ ) alkyl (O ₂ ) alkyl;

23. -C0 ₂ alkyl;

24. -CONH ₂

25. -CONH (alkyl), CON (alkyl) ₂ linear (s), branched (s) or cyclic (s);

 26. -C (O) heterocycloalkyl;

 27.-S-alkyl;

28. -S (O ₂ ) alkyl;

 29.-S (O) alkyl;

 30. oxo (double bond O);

31. -C ₂ -C ₆ linear or branched alkenyl;

32. -C ₂ -C ₆ alkynyl linear or branched;

said products of formula (I) being in all the possible isomeric, racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I) .

The present invention relates to products of general formula (I) as defined above in which the possible substituents of Z6 is the groups R2a, R2b, R2c, R2d or R2e are chosen independently of one another among: 2. Cl;

 3. Br;

 4. I;

 5. -C-I-C-10 linear or branched alkyl optionally mono or poly substituted with R3a, R3b, R3c, identical or different

6. -C ₃ -C ₇ cycloalkyl optionally mono or poly substituted with R 3a, R 3b, R 3c, identical or different,

 7. -OH;

 8. -O-alkyl (CrCio) linear or branched optionally mono or poly substituted with R3a, R3b, R3c, the same or different;

 9. -Y-alkyl (Y = S, SO, SO2) linear or branched optionally mono, di or tri substituted by R3a, R3b, R3c, identical or different;

10. -O-cycloalkyl (C ₃ -C ₇ ) optionally mono or poly substituted with R 3a, R 3b, R 3c, identical or different;

1 1. -O-aryl optionally mono or poly substituted with R3a, R3b,

R3c, identical or different;

 12. aryl optionally mono or poly substituted with R3a, R3b, R3c, the same or different;

 13. heteroaryl consisting of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded either by a C or by N) optionally mono or poly substituted with R3a, R3b, R3c, the same or different;

 14. heterocycloalkyl optionally mono or poly substituted with R3a, R3b, R3c, the same or different;

15. -No ₂ ;

16. -NH ₂ ;

17. -NH- (alkyl (CrCio) or cycloalkyl (C ₃ -C ₇ ) or heterocycloalkyl) each optionally mono or poly group substituted by R3a, R3b, R3c, the same or different;

18. -N (alkyl (d-Cio) or cycloalkyl (C ₃ -C ₇ )) 2 each group being optionally mono or poly substituted with R3a, R3b, R3c, identical or different;

19. -NHaryl or NH heteroaryl optionally mono or poly substituted with R3a, R3b, R3c, identical or different 20. -NHC (O) substituted with R3a, R3b, R3c, the same or different;

21. -N (C 1 -C 10) alkyl (C) substituted by R 3a, R 3b, R 3c, the same or different;

22. -NHS (O ₂ ) substituted with R3a, R3b, R3c, same or different; 23. -N (C 1 -C 10) alkyl S (O ₂ ) substituted with R 3a, R 3b, R 3c, same or different;

24. -C0 ₂ substituted by R3a, R3b, R3c, identical or different;

 25. -Ssubstituted by R3a, R3b, R3c, identical or different;

26. -S (0 ₂ ) substituted with R3a, R3b, R3c, identical or different;

 27. -S (O) substituted with R3a, R3b, R3c, identical or different;

 28. oxo (double bond O);

 29. -C2-C6 alkenyl optionally mono or disubstituted by R3a, R3b identical or different;

 30. -C2-C6 alkynyl optionally substituted with R3a; the groups R3a, R3b, R3c, or the substituents of the groups R2a, R2b, R2c, R2d or R2e, are chosen independently of one another from:

 1. F;

 2. Cl;

 3. Br;

 4. I;

 5. -C-I-C-10 linear or branched alkyl optionally mono or poly substituted with R4a, R4b, R4c;

 6. -C3-C7 cycloalkyl optionally mono or poly substituted with R4a, R4b, R4c;

 7. -OH;

 8. Linear or branched, optionally mono- or poly-substituted O-alkyl (CrCio) by R4a, R4b, R4c;

 9. -Y-alkyl (Y = S, SO, SO2) linear or branched optionally mono, di or tri substituted by R4a, R4b, R4c;

10. -O-cycloalkyl (C ₃ -C ₇ ) optionally mono or poly substituted with R 4a,

R4b, R4c;

 1 1. -O-aryl optionally mono or poly substituted with R4a, R4b, R4c;

 12. aryl optionally mono or poly substituted with R4a, R4b, R4c;

13. heteroaryl optionally mono or poly substituted with R4a, R4b, R4c; 14. heterocycloalkyl optionally mono or poly substituted with R4a, R4b, R4c;

15. -No ₂ ;

16. -NH ₂ ;

17. -NH- (alkyl (CrCio) or cycloalkyl (C ₃ -C ₇ ) or heterocycloalkyl) each optionally mono or poly substituted with R4a, R4b, R4c;

18. -N (alkyl (d-Cio) or cycloalkyl (C ₃ -C ₇ )) 2 each group being optionally mono or poly substituted with R4a, R4b, R4c;

 19. -NHaryl or NH heteroaryl optionally mono or poly substituted with R4a, R4b, R4c;

 20. -NHC (O) substituted with R4a, R4b, R4c;

 21. -N (C 1 -C 10) alkyl (C) substituted with R 4a, R 4b, R 4c;

22. -NHS (O ₂ ) substituted with R4a, R4b, R4c;

23. -N (C 1 -C 10) alkyl S (O ₂ ) substituted with R 4a, R 4b, R 4c;

24. -C0 ₂ substituted with R4a, R4b, R4c;

26. -CONH (alkyl), CON (alkyl) ₂ linear (s), branched (s) or cyclic (s) of which the alkyl part is optionally mono, di or tri substituted by R4a, R4b, R4c;

 27. -C (O) heterocycloalkyl optionally mono, di or tri substituted by R4a,

R4b, R4c;

 28. -S substituted with R4a, R4b, R4c;

29. -S (O ₂ ) substituted with R4a, R4b, R4c;

 30. -S (O) substituted with R4a, R4b, R4c;

 31. oxo (double bond O);

32. -C ₂ -C ₆ alkenyl optionally mono or poly substituted with R4a, R4b, R4c;

33. -C ₂ -C ₆ alkynyl optionally mono or poly substituted with R 4a, R 4b, R 4c;

the groups R4a, R4b, R4c, or the substituents of the groups R3a, R3b and R3c, are chosen independently of one another from:

 1. F;

 2. Cl;

3. Br; 5. -CF ₃ ; -CHF ₂

 6. -C1-C10 linear or branched alkyl;

7. -C ₃ -C ₇ cycloalkyl;

 8. -OH;

 9. linear or branched (C 1 -C 10) alkyl;

 10. -Y-alkyl (Y = S, SO, SO 2) linear or branched;

1 1. -O-cycloalkyl (C ₃ -C ₇ );

 12.-O-aryl;

 13. aryl;

 14. heteroaryl;

15. heterocycloalkyl;

18. -NH- (C ₁ -C ₁₀ ) alkyl or C ₃ -C ₇ cycloalkyl or heterocycloalkyl;

19. -N (alkyl (CrCio) or cycloalkyl (C ₃ -C ₇ )) ₂ ;

 20. -NHaryl or NH heteroaryl;

21. -NHS (O ₂ ) alkyl;

22. -N (C 1 -C ₁₀ ) alkyl (O ₂ ) alkyl;

23. -C0 ₂ alkyl;

24. -CONH ₂

25. -CONH (alkyl), CON (alkyl) ₂ linear (s), branched (s) or cyclic (s);

 26. -C (O) heterocycloalkyl;

 27.-S-alkyl;

28. -S (O ₂ ) alkyl;

 29.-S (O) alkyl;

 30. oxo (double bond O);

31. -C ₂ -C ₆ linear or branched alkenyl;

32. -C ₂ -C ₆ alkynyl linear or branched;

said products of formula (I) being in all the possible isomeric, racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I) . The present invention relates to products of general formula (I) as defined above in which

 Z 3 represents a 5- or 6-membered heteroaryl radical with 1 to 4 heteroatoms chosen from N, S or O bonded to the carboline unit, either by a C or by an N belonging to Z 3, Z 3 being optionally mono or poly substituted with R 2a, R 2b R2c, R2d, R2e, the same or different;

 Z6 is chosen from:

 1. H;

 2. halogen;

 3. -OH

 Alkoxy whose alkyl part is optionally mono, di or tri substituted by R2a, R2b, R2c, which are identical or different;

 5. -Y-alkyl (Y = S, SO, SO 2) linear or branched optionally mono, di or tri substituted by R2a, R2b, R2c, identical or different; 6. -X-aryl (X = O, S, SO, SO2) optionally mono, di or tri substituted by R2a, R2b, R2c, the same or different;

 7. -X-heteroaryl (X = O, S, SO, SO2, 5- or 6-membered heteroaryl with 1 to 4 heteroatoms selected from N, S or O bonded to X, either C or N) optionally mono, di or tri substituted by R2a, R2b, R2c, the same or different;

 8. -NH2,

9. -NH (alkyl), -N (alkyl) ₂ linear (s), branched (s) or cyclic (s) of which the alkyl part is optionally mono, di or tri substituted by R2a, R2b, R2c, identical or different ;

 10. -NH (aryl), the aryl portion of which is optionally mono, di or tri substituted by R2a, R2b, R2c, which may be identical or different;

 1 1. -NH (heteroaryl) whose heteroaryl part (heteroaryl of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom by a C or an N) is optionally mono, di or tri substituted by R2a, R2b, R2c, the same or different;

12. -N (alkyl) (aryl) whose alkyl parts (linear, branched or cyclic) and aryl are optionally mono, di or tri substituted by R2a, R2b, R2c, identical or different; 13. -N (alkyl) (heteroaryl) whose alkyl (linear, branched or cyclic) and heteroaryl (5- or 6-membered heteroaryl with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom either by a C or an N) are optionally mono, di or tri substituted by R2a, R2b, R2c, identical or different;

 14. -C (0) OH

 15. -C (O) linear, branched or cyclic alkyl optionally mono-, di or tri substituted by R2a, R2b, R2c, identical or different;

 16. -C (O) Oaryl optionally mono, di or tri substituted by R2a, R2b, R2c, identical or different;

 17. -C (O) Oheteroaryl (5- or 6-membered heteroaryl with 1 to 4 heteroatoms selected from N, S or O bonded to oxygen by a C atom) optionally mono, di or tri substituted by R2a, R2b, R2c, identical or different;

18. -CONH2

 19. -CO-heterocycloalkyl mono, di or tri substituted

20. -CONH (alkyl), CON (alkyl) ₂ linear (s), branched (s) or cyclic (s) whose alkyl part is optionally mono, di or tri substituted by R2a, R2b, R2c, identical or different;

21. -CON (alkyl) (aryl), linear, branched or cyclic alkyl of which the alkyl and aryl parts are optionally mono, di or tri substituted by R2a, R2b, R2c, identical or different;

 22. -CON (alkyl) (heteroaryl), linear, branched or cyclic alkyl and heteroaryl of 5- or 6-membered with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom either by a C or by an N) of which the alkyl and the hetroaryl parts are optionally mono, di or tri substituted by R2a, R2b, R2c, which are identical or different;

23. -C1-C10 linear, branched or cyclic alkyl optionally comprising a heteroatom and optionally mono, di or tri substituted by R2a, R2b, R2c, which are identical or different;

 24. aryl optionally mono, di or tri substituted by R2a, R2b, R2c, the same or different;

25. heteroaryl (5- or 6-membered with 1 to 4 heteroatoms selected from N, S or O) linked to the carboline moiety either by C or N belonging to Z6, Z6 being optionally mono or poly substituted with R2a, R2b, R2c, R2d, R2e identical or different;

26. heterocycloalkyl optionally mono or poly substituted with R2a, R2b, R2c, the same or different;

 27. -C2-C6 alkenyl optionally mono or disubstituted by R2a, R2b, which may be identical or different;

 28. -C2-C6 alkynyl optionally substituted with R2a; the groups R2a, R2b, R2c, R2d or R2e are chosen independently of one another from:

 1. F;

 2. Cl;

 3. Br;

 4. I;

 5. -C-I-C-10 linear or branched alkyl optionally mono or poly substituted with R3a, R3b, R3c, identical or different

 -C3-C7 cycloalkyl optionally mono or poly substituted with R3a, R3b, R3c, the same or different,

 7. -OH;

 8. -O-alkyl (CrCio) linear or branched optionally mono or poly substituted with R3a, R3b, R3c, the same or different;

9. -Y-alkyl (Y = S, SO, SO2) linear or branched optionally mono, di or tri substituted by R3a, R3b, R3c, identical or different;

10. -O-cycloalkyl (C ₃ -C ₇ ) optionally mono or poly substituted with R 3a, R 3b, R 3c, identical or different;

 1 1. -O-aryl optionally mono or poly substituted with R3a, R3b, R3c, the same or different;

 12. aryl optionally mono or poly substituted with R3a, R3b, R3c, the same or different;

13. heteroaryl consisting of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded either by a C or by N) optionally mono or poly substituted with R3a, R3b, R3c, the same or different; 14. heterocycloalkyl optionally mono or poly substituted with R3a, R3b, R3c, the same or different;

15. -No ₂ ;

16. -NH ₂ ;

17. -NH- (C ₁ -C ₁₀ alkyl) or C ₃ -C ₇ cycloalkyl or heterocycloalkyl) each optionally mono or poly group substituted with R 3a, R 3b, R 3c, which may be identical or different;

18. -N (alkyl (d-Cio) or cycloalkyl (C ₃ -C ₇ )) 2 each group being optionally mono or poly substituted with R3a, R3b, R3c, identical or different;

 19. -NHaryl or NH heteroaryl optionally mono or poly substituted with R3a, R3b, R3c, identical or different

 20. -NHC (O) substituted with R3a, R3b, R3c, the same or different;

21. -N (C 1 -C 10) alkyl (C) substituted by R 3a, R 3b, R 3c, the same or different;

22. -NHS (O ₂ ) substituted with R3a, R3b, R3c, same or different;

23. -N (C 1 -C 10) alkyl S (O ₂ ) substituted with R 3a, R 3b, R 3c, same or different;

24. -C0 ₂ substituted by R3a, R3b, R3c, identical or different;

25. -Ssubstituted by R3a, R3b, R3c, identical or different;

26. -S (0 ₂ ) substituted with R3a, R3b, R3c, identical or different;

27. -S (O) substituted with R3a, R3b, R3c, identical or different;

28. oxo (double bond O);

 29. -C2-C6 alkenyl optionally mono or disubstituted by R3a,

R3b identical or different;

 30. -C2-C6 alkynyl optionally substituted with R3a;

the groups R3a, R3b, R3c, or the substituents of the groups R2a, R2b, R2c, R2d or R2e, are chosen independently of one another from:

 1. F;

 2. Cl;

 3. Br;

4. I; -CI-10 linear or branched alkyl optionally mono or poly substituted with R4a, R4b, R4c;

 6. -C3-C7 cycloalkyl optionally mono or poly substituted with R4a, R4b, R4c;

7. -OH;

 8. Linear or branched, optionally mono- or poly-substituted O-alkyl (CrCio) by R4a, R4b, R4c;

 9. -Y-alkyl (Y = S, SO, SO2) linear or branched optionally mono, di or tri substituted by R4a, R4b, R4c;

10. -O-cycloalkyl (C ₃ -C ₇ ) optionally mono or poly substituted with R 4a,

R4b, R4c;

 1 1. -O-aryl optionally mono or poly substituted with R4a, R4b, R4c;

 12. aryl optionally mono or poly substituted with R4a, R4b, R4c;

 13. heteroaryl optionally mono or poly substituted with R4a, R4b, R4c; 14. heterocycloalkyl optionally mono or poly substituted with R4a, R4b,

4c;

15. -No ₂ ;

17. -NH- (alkyl (CrCio) or cycloalkyl (C ₃ -C ₇ ) or heterocycloalkyl) each optionally mono or poly substituted with R4a, R4b, R4c;

18. -N (alkyl (d-Cio) or cycloalkyl (C ₃ -C ₇ )) 2 each group being optionally mono or poly substituted with R4a, R4b, R4c;

 19. -NHaryl or NH heteroaryl optionally mono or poly substituted with R4a, R4b, R4c;

20. -NHC (O) substituted with R4a, R4b, R4c;

 21. -N (C 1 -C 10) alkyl (C) substituted with R 4a, R 4b, R 4c;

22. -NHS (O ₂ ) substituted with R4a, R4b, R4c;

23. -N (C 1 -C 10) alkyl S (O ₂ ) substituted with R 4a, R 4b, R 4c;

24. -C0 ₂ substituted with R4a, R4b, R4c;

26. -CONH (alkyl), CON (alkyl) ₂ linear (s), branched (s) or cyclic (s) of which the alkyl part is optionally mono, di or tri substituted by R4a, R4b, R4c; 27. -C (O) heterocycloalkyl optionally mono, di or tri substituted by R4a, R4b, R4c;

 28. -S substituted with R4a, R4b, R4c;

29. -S (O ₂ ) substituted with R4a, R4b, R4c;

 30. -S (O) substituted with R4a, R4b, R4c;

 31. oxo (double bond O);

32. -C ₂ -C ₆ alkenyl optionally mono or poly substituted with R4a, R4b, R4c;

33. -C ₂ -C ₆ alkynyl optionally mono or poly substituted with R 4a, R 4b, R 4c;

the groups R4a, R4b, R4c, or the substituents of the groups R3a, R3b and R3c, are chosen independently of one another from:

 1. F;

 2. Cl;

 3. Br;

 4. I;

5. -CF ₃ ; -CHF ₂

 6. -C1-C10 linear or branched alkyl;

7. -C ₃ -C ₇ cycloalkyl;

 8. -OH;

 9. linear or branched (C 1 -C 10) alkyl;

 10. -Y-alkyl (Y = S, SO, SO 2) linear or branched;

1 1. -O-cycloalkyl (C ₃ -C ₇ );

 12.-O-aryl;

 13. aryl;

 14. heteroaryl;

15. heterocycloalkyl;

18. -NH- (C ₁ -C ₁₀ ) alkyl or C ₃ -C ₇ cycloalkyl or heterocycloalkyl;

19. -N (C ₁ -C ₁₀ alkyl) or C ₃ -C ₇ cycloalkyl) ₂ ;

 20. -NHaryl or NH heteroaryl;

21. -NHS (O ₂ ) alkyl;

22. -N (C 1 -C ₁₀ ) alkyl (O ₂ ) alkyl; 23. -C0 ₂ alkyl;

24. -CONH ₂

25. -CONH (alkyl), CON (alkyl) ₂ linear (s), branched (s) or cyclic (s);

 26. -C (O) heterocycloalkyl;

 27.-S-alkyl;

28. -S (O ₂ ) alkyl;

 29.-S (O) alkyl;

 30. oxo (double bond O);

31. -C ₂ -C ₆ linear or branched alkenyl;

32. -C ₂ -C ₆ alkynyl linear or branched;

said products of formula (I) being in all the possible isomeric, racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I) .

In particular when C1-C10 linear or branched alkyl or O-alkyl (C1-C10) is optionally mono or poly substituted by Hal, the substituent formed can be CF3, CHF2 or OCF3, -OCHF2.

 In the products of formula (I) of the present invention, Z3 may especially represent a pyridine, pyrazole, pyrimidine, imidazole, triazole or tetrazole radical, all optionally substituted by one or more radicals R2a, R2b, R2c, R2d and R2e as indicated. above.

said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

 Z3 can thus be substituted by one or more identical or different radicals chosen from halogen atoms and alkyl, alkoxy, alkylthio, NH 2, NHalk or N (alk) 2 radicals.

When Z6 represents a heteroaryl radical, Z6 represents in particular a pyrazolyl, isoxazolyl, oxazolyl, thiazolyl or thienyl radical, all optionally substituted by one or more radicals chosen from Ra, Rb, Rc, Rd and Re as indicated above for Z6. Z6 can thus be in particular substituted by one or more identical or different radicals chosen from halogen atoms and alkyl, alkoxy, alkylthio, NH 2, NHalk or N (alk) ₂ and especially alkyl radicals.

 The present invention relates in particular to products of general formula (I) as defined above in which Z3 represents a heteroaryl radical consisting of 5- or 6-membered with 1 to 4 N heteroatoms, linked to the carboline moiety either by a C or by a N belonging to Z3, Z3 being optionally mono or poly substituted as indicated above, and Z6 having the meanings indicated above,

said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

 The following terms used above or below have the following meanings:

Alkyl, (C ₁ -C ₁₀ ) alkyl or C ₁ -C 10 alkyl means all carbon chains of 1 to 10 carbons, saturated, linear or branched.

- C ₂ -C ₆ alkenyl means all carbon chains of 1 to 6 carbons, linear or branched, having at least one carbon-carbon double bond.

- C ₂ -C ₆ alkynyl means all carbon chains of 1 to 6 carbons, linear or branched, having at least one carbon-carbon triple bond.

- Aryl means phenyl or naphthyl.

 - Heteroaryl means all aromatic 5- or 6-membered aromatic monocycles having at least one heteroatom (N, O, S) in particular: pyridine, pyrimidine, imidazole, pyrazole, triazole, thiophene, furan, thiazole, oxazole, isoxazole, etc. that aromatic bicyclic systems possessing at least one heteroatom (N, O, S) in particular indole, benzimidazole, azaindole, benzofuran, benzothiophene, quinoloin, tetrazole

Heterocycloalkyl means all unicyclic monocycles and bicycles (spiro or non-aromatic) having at least one heteroatom (N, O, S at the different possible oxidation states) with or without unsaturation, in particular: morpholine, piperazine, piperidine, pyrrolidine, oxetane, epoxide, dioxane, imidazolone, imidazolinedione, 7-oxa-bicyclo [2.2.1] heptane, azetidine, azepine, hexahydropyrrolo [3,4-b] pyrrole, hexahydropyrrolo [2,3-b] pyrrole, hexahydropyrrolo [3,4- c] pyrrole, hexahydropyrrolo [2,3-c] pyrrole, 2,7-diazaspiro [4,4] nonane, 2,6-diazaspiro [4,4] nonane, 3,6-diazaspiro [4,4] nonane, 3,7-diazaspiro [4,4] nonane, 3,8-diazaspiro [4,4] nonane, 3,9-diazaspiro [4,4] nonane, 4,6-diazaspiro [4,4] diazaspiro [4.4] nonane, 4,7-diazaspiro [4,4] nonane, 4,8-diazaspiro [4,4] nonane, 4,9-diazaspiro [4,4] nonane, 1,6-diazaspiro [ 4,4] nonane, 1,7-diazaspiro [4,4] nonane, 1,8-diazaspiro [4,4] nonane, 1,9-diazaspiro [4,4] nonane, octahydropyrrolo [3,4-c] pyridine, octahydropyrrolo [3,4-d] pyridine, octahydropyrrolo [3,4-e] pyridine, octahydropyrrolo [2,3-c] pyridine, octahydropyrrolo [2,3-d] pyridine, octahydropyrrolo [2,3-e] pyridine.

- Cycloalkyl (C ₃ -C ₇ ) means all non-aromatic rings consisting solely of carbon atoms, especially cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane; but may also carry unsaturation, for example cyclopentene, cyclohexene, cycloheptene, bicyclo [2.2.1] heptane.

 - C-I-C-10 alkylhydroxy means all carbon chains of 1 to 10 carbons, saturated, linear or branched carrying at least one hydroxyl (OH) group.

 - C1-C10 alkoxy means all carbon chains of 1 to 10 carbons, saturated, linear or branched in which is at least one ether function (C-O-C). - C1-C10 alkylamino means all carbon chains of 1 to 10 carbons, saturated, linear or branched in which there is at least one amine function (primary, secondary or tertiary).

 The subject of the present invention is in particular the products of formula (I) as defined above whose names follow:

 6-Methoxy-3- (pyridin-3-yl) -9H-beta-carboline

 3- (pyridin-3-yl) -9H-beta-carboline

 6-bromo-3- (pyridin-3-yl) -9H-beta-carboline

 Methyl 3- (pyridin-3-yl) -9H-beta-carboline-6-carboxylate

 6-Methoxy-3- (5-methoxypyridin-3-yl) -9H-beta-carboline

 5- (6-methoxy-9H-beta-carbolin-3-yl) pyridin-2-amine

 3- (pyrimidin-5-yl) -9H-beta-carboline

 6-Methoxy-3- (6-methoxypyridin-3-yl) -9H-beta-carboline

 6-Methoxy-3- [6- (methylsulfanyl) pyridin-3-yl] -9H-beta-carboline

 3- (pyridin-3-yl) -6- (trifluoromethyl) -9H-beta-carboline

 3- (pyridin-3-yl) -6- (trifluoromethoxy) -9H-beta-carboline

 6-Fluoro-3- (pyridin-3-yl) -9H-beta-carboline

 N, N-diethyl-2- {4- [3- (pyridin-3-yl) -9H-beta-carbolin-6-yl] -1H-pyrazol-1-yl} ethanamine

N, N-diethyl-2- {4- [3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carbolin-6-yl] -1H-pyrazol-1-yl} ethanamine 6- {4- [3- (Piperidin-1-yl) propoxy] phenyl} -3- (pyridin-3-yl) -9H-beta-carboline

 3- (1-methyl-1H-pyrazol-4-yl) -6- {4- [3- (piperidin-1-yl) propoxy] phenyl} -9H-beta-carboline

 6- (difluoromethoxy) -3- (pyridin-3-yl) -9H-beta-carboline

 6- (difluoromethoxy) -3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carboline

 6-Methoxy-3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carboline

 The present invention also relates to the following products of formula (I):

6- (1H-pyrazol-4-yl) -3- (pyridin-3-yl) -9H-beta-carboline

 6- (1-methyl-1H-pyrazol-4-yl) -3- (pyridin-3-yl) -9H-beta-carboline

6- (3,5-dimethyl-1H-pyrazol-4-yl) -3- (pyridin-3-yl) -9H-beta-carboline

 6- (1,5-dimethyl-1H-pyrazol-4-yl) -3- (pyridin-3-yl) -9H-beta-carboline

 6- (3-methylthiophen-2-yl) -3- (pyridin-3-yl) -9H-beta-carboline

 6- (2-chloro-1-methyl-1H-imidazol-5-yl) -3- (pyridin-3-yl) -9H-beta-carboline

 6- (1-methyl-1H-imidazol-2-yl) -3- (pyridin-3-yl) -9H-beta-carboline

6- (1-methyl-1H-1,2,3-triazol-5-yl) -3- (pyridin-3-yl) -9H-beta-carboline

 3- (pyridin-3-yl) -6- (1,3-thiazol-5-yl) -9H-beta-carboline

 6- (3,5-dimethyl-1,2-oxazol-4-yl) -3- (pyridin-3-yl) -9H-beta-carboline

 6- (Cyclobutyloxy) -3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carboline

 3- (1-methyl-1H-pyrazol-4-yl) -6- (oxetan-3-yloxy) -9H-beta-carboline

6-methyl-3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carboline

 6- (2-methoxyethoxy) -3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carboline

 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 purification or isolation of compounds of formula (I) are also part of the invention. The compounds of formula (I) may comprise one or more isotopes of the atoms described above, in particular deuterium D, tritium T, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ O, ¹⁵ N, ¹⁸ F , ¹²³ l, ¹²⁴ l and ¹³⁵ l. These compounds, whatever their isotopic compositions, are part of the invention.

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

 The present invention also relates to any synthesis method known to those skilled in the art for preparing the products of formula (I) as defined above.

 The subject of the present invention is in particular a general process for the synthesis of the products of formula (I) as defined above, described hereinafter in general scheme 1:

General scheme 1:

In this scheme, the optionally reactive functions of the compounds are optionally protected by the protective groups known to those skilled in the art.

Compounds of general structure (II) are commercially available or may be prepared by application or adaptation of the described methodology such as, for example (nonexclusive list) in Canadian Journal of Chemistry, 67 (1 1), 1837, 1989; Journal of Organic Chemistry, 54 (19), 451 1, 1989 and International Journal of Peptide & Protein Research, 30 (1), 13, 1987 and cited references.

The subject of the present invention is in particular a process for the synthesis of the products of formula (I) as defined above, described in scheme 1. The preparation of the compound of structure (III) is obtained from compound (II) by the action of formaldehyde in the presence of a strong acid such as sulfuric acid, hydrochloric acid or phosphoric acid at a concentration of about 1 M in the presence of an alcohol such as methanol or isopropanol at ordinary temperature. The compound of structure (IV) may be prepared from (III) by the action of an alcohol such as methanol, ethanol or ispropanol in the presence of a strong acid such as hydrochloric acid or sulfuric acid under reflux of the reaction medium. The compound (V) can be obtained from the compound (IV) in an inert solvent such as xylene, p-cymene or decalin by the action of Pd / C (for example at 10%) at reflux of the reaction medium by application or adaptation of the methods described in J. Am. Chem. Soc., 82, 5233, 1960; J. Org. Chem., 17, 1295, 1952 and Organic Synthesis, IV page 536. The compound of structure (VI) can be prepared by hydrolysis of (V) using, for example, LiOH, NaOH or KOH in water at a temperature of temperature ranging from ordinary temperature to reflux of the reaction medium. The compound (VII) can be prepared from (VI) by the action for example of diphenyl phosphorazidoate in the presence of tert-butanol in an inert solvent such as DMF at a temperature ranging from ordinary temperature to the reflux of the reaction medium or by example by application or adaptation described in Journal of Medicinal Chemistry, 52 (10), 3205, 2009 which consists of reacting the starting acid in question in the presence of ter-butanol, 4-dimethylaminopyridine (4-DMAP) and 1 3-dicyclohexylcarbodiimine (DCC) at room temperature. The amine of structure (VIII) may be prepared from (VII) by the action of an acid such as trifluoroacetic acid for example (see Protective group in organic synthesis, 3rd edition p520).

The compound of structure (IX) can be obtained from (VIII) for example by the action of bromidic acid, copper bromide in a solvent mixture such as dichloromethane and polyethylene glycol (PEG 200) in the presence of nitrite of 3-methylbutyl at a temperature of -10 ° C to room temperature or by application or adaptation of the method described in Tetrahedron Asymetry, (1 1), 1673, 2004 which comprises reacting the starting amine with presence of copper bromide and sodium nitrite (NaNO 2) in the presence of HBr. Compound (Ia) can be obtained from (IX) by a so-called "Suzuki coupling" reaction by the action of either a cyclic dioxaborolane such as (4,4,5,5-tetramethyl [1, 3,2] dioxaborolane) aryl or boronic acid derivative such as an aryl-boronic acid in the presence of Pd (0) such as Pd (Ph3P) 4, in a solvent such as a cyclic ether such as dioxane or THF, whether or not micro-irradiation is wave at a temperature ranging from 100 ° C to 150 ° C in sealed tube or not. The compound of structure (Ia) can be prepared from (I), when Z6 represents a hydrogen atom, for example by the action of N-bromosuccinimide in a solvent such as dichloromethane or chloroform at a temperature ranging from the temperature common to the reflux of the reaction medium or by application or adaptation of the methods described in Organic Synthesis, III, 138. The compound of structure (I) can be prepared from (la) by the same methods as for the preparation of (I) from (IX). The products of formulas (Ia) are products of formulas (I) in which Z6 represents a bromine atom.

The compounds of structure (I) may also be prepared according to the following general scheme 2:

 The present invention thus relates in particular to a process for the synthesis of the products of formula (I) as defined above, described below in general scheme 2. General scheme 2:

 In this scheme, the optionally reactive functions of the compounds are optionally protected by the protective groups known to those skilled in the art.

The compound of general structure (X) may be prepared by application or adaptation of the described methodology as for example (non-exclusive list) in the Indian Pat patent. appl. 2004DEO2465, Nov 17, 2006; Journal of Heterocycle Chemistry, 44 (6), 1485, 2007, Journal of Combinatorial Chemistry, 7 (6), 879, 2005; US Patent 5502194, March 26, 1996; Eur. Pat. Appl., 591624, April 13, 1994 and in Chemical & Pharmaceutical Bulletin, 36 (6), 2244, 1988 and cited references. The compound of general structure (XI) can be prepared from (X) by a so-called "Suzuki coupling" reaction by the action of either a cyclic dioxaborolane such as (4,4,5,5-tetramethyl [1,3] , 2] dioxaborolane) of aryl or boronic acid derivative such as an aryl-boronic acid in the presence of Pd (0) such as Pd (Ph3P) 4, in a solvent such as a cyclic ether such as dioxane or THF, in the presence or absence of microwave irradiation at a temperature ranging from 100 ° C to 150 ° C in sealed tube or not. The compound of structure (XII) can be prepared from (XI) by action of a base such as LDA (lithium salt of diisopropylamine) or n-butyl lithium and a chlorinated derivative of tin , such as trimethyltin chloride or tributyltin chloride, in a solvent such as an ether such as for example THF or dioxane at a temperature ranging from -70 ° C to the reflux of the reaction mixture. The compound of structure (XIV) can be obtained from (XII) by a so-called "Stille coupling" reaction which consists in reacting, for example, the compound (XII) and the compound (XIII) in the presence or absence of iodide copper (Cul), Pd (O) such as Pd (Ph 3 P) 4 in a solvent such as a cyclic ether, THF or dioxane for example, under microwave irradiation or not at a temperature ranging from ordinary temperature to reflux of the reaction mixture. The compound (I) can be obtained from (XIV) by the action of a copper derivative at any of its oxidation levels in a solvent such as DMSO or by the action of a palladium complex (0 ) such tris (dibenzylideneacetone) dipalladium (0) in the presence of a ligand such as 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl and potassium tert-butoxide as a strong base in a cyclic ether such as THF or dioxane at a temperature ranging from ordinary temperature to reflux of the reaction mixture, or by application or adaptation of the methods described in Bioorganic & Medicinal Chemistry Letters, 17 (4), 1043, 2007 which consists in using Pd (Ph3P) 4 as palladium complex in the presence of a salt such as sodium carbonate. The compound of structure (XIII) is commercially available or can be obtained by application or adaptation of the method described in Syniett, 6, 450, 1994; Bulletin of the Chemical Society of France, 1, 93, 1990 or Tetrahedron Letters, 30 (45), 6209, 1989. The subject of the present invention is also, as medicaments, the products of formula (I) as defined above. and their prodrugs, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with acids inorganic and organic or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I).

The subject of the present invention is, in particular, as medicaments the products of formula (I) as defined above, whose names follow:

 6-Methoxy-3- (pyridin-3-yl) -9H-beta-carboline

 3- (pyridin-3-yl) -9H-beta-carboline

 6-bromo-3- (pyridin-3-yl) -9H-beta-carboline

 Methyl 3- (pyridin-3-yl) -9H-beta-carboline-6-carboxylate

 6-Methoxy-3- (5-methoxypyridin-3-yl) -9H-beta-carboline

 5- (6-methoxy-9H-beta-carbolin-3-yl) pyridin-2-amine

 3- (pyrimidin-5-yl) -9H-beta-carboline

 6-Methoxy-3- (6-methoxypyridin-3-yl) -9H-beta-carboline

 6-Methoxy-3- [6- (methylsulfanyl) pyridin-3-yl] -9H-beta-carboline

 3- (pyridin-3-yl) -6- (trifluoromethyl) -9H-beta-carboline

 3- (pyridin-3-yl) -6- (trifluoromethoxy) -9H-beta-carboline

 6-Fluoro-3- (pyridin-3-yl) -9H-beta-carboline

 N, N-diethyl-2- {4- [3- (pyridin-3-yl) -9H-beta-carbolin-6-yl] -1H-pyrazol-1-ylkethanamine

 N, N-diethyl-2- {4- [3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carbolin-6-yl] -1H-pyrazol-1-yl} ethanamine

 6- {4- [3- (Piperidin-1-yl) propoxy] phenyl} -3- (pyridin-3-yl) -9H-beta-carboline

 3- (1-methyl-1H-pyrazol-4-yl) -6- {4- [3- (piperidin-1-yl) propoxy] phenyl} -9H-beta-carboline

 6- (difluoromethoxy) -3- (pyridin-3-yl) -9H-beta-carboline

 6- (difluoromethoxy) -3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carboline

 6-Methoxy-3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carboline

 The subject of the present invention is also, as medicaments, the products of formula (I) as defined above whose names follow:

 6- (1H-pyrazol-4-yl) -3- (pyridin-3-yl) -9H-beta-carboline

6- (1-methyl-1H-pyrazol-4-yl) -3- (pyridin-3-yl) -9H-beta-carboline

 6- (3,5-dimethyl-1H-pyrazol-4-yl) -3- (pyridin-3-yl) -9H-beta-carboline

 6- (1,5-dimethyl-1H-pyrazol-4-yl) -3- (pyridin-3-yl) -9H-beta-carboline

 6- (3-methylthiophen-2-yl) -3- (pyridin-3-yl) -9H-beta-carboline

 6- (2-chloro-1-methyl-1H-imidazol-5-yl) -3- (pyridin-3-yl) -9H-beta-carboline

6- (1-methyl-1H-imidazol-2-yl) -3- (pyridin-3-yl) -9H-beta-carboline 6- (1-methyl-1H-1,2,3-triazol-5-yl) -3- (pyridin-3-yl) -9H-beta-carboline

 3- (pyridin-3-yl) -6- (1,3-thiazol-5-yl) -9H-beta-carboline

 6- (3,5-dimethyl-1,2-oxazol-4-yl) -3- (pyridin-3-yl) -9H-beta-carbo

 6- (Cyclobutyloxy) -3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carboline

3- (1-methyl-1H-pyrazol-4-yl) -6- (oxetan-3-yloxy) -9H-beta-carboline

 6-methyl-3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carboline

 6- (2-methoxyethoxy) -3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carboline, the said products of formula (I) being in all the possible isomeric forms, racemic, enantiomers and diastereoisomers, as well as addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I).

 The present invention also relates to pharmaceutical compositions containing as active ingredient, a compound according to any one of the preceding claims and at least one pharmaceutically compatible excipient.

 The present invention also relates to the pharmaceutical compositions according to the preceding claim used for the treatment of cancer.

 Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, 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 chosen 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, oral, subcutaneous, intramuscular or intravenous administration forms.

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.

 Among the examples of preparation of the products of formula I as defined above, certain examples constitute products of formula I as defined above or else synthesis intermediates making it possible to obtain the said products of formula I, as defined below:

 The subject of the present invention is therefore, as new industrial products, the synthetic intermediates of the products of formula (XIV) as defined in the general scheme above and hereinafter:

 (XIV)

in which the substituents Z3 and Z6 have the meanings indicated for the products of formula (I) as defined above; the possibly reactive functions of Z3 and Z6 being optionally protected by the protective groups known to those skilled in the art. GENERALITIES:

 Abbreviations:

 1 H NMR: proton nuclear magnetic resonance

DAD: wavelength scanning detector

DCM: dichloromethane

DME: 1, 2-dimethoxyethane

DMF: dimethylformamide

DMSO: dimethylsulfoxide

ELSD: light scattering detector

 HATU: O-Azabenzotriazol-1-y NN-N-tetra-methyluronium

hexafluorophosphate

 HPLC, UPLC: high performance liquid chromatography

 LC: liquid chromatography

LDA: lithium diisopropylamide

 LiTMP: lithium amide of 2,2,6,6-tetramethylpiperidine

 MS: mass spectrometry

 TFA: trifluoroacetic acid

 THF: tetrahydrofuran

Tr: retention time

► All reactions are carried out 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 commercial silica cartridges (Merck, Biotage, etc.). Preparative HPLC purifications are performed on Macherey-Nagel columns (NUCLEODUR C18 phase) or other phases (Chiralcel OD-I or OJ-H or AS-H, Chiralpak, Kromasil Ci ₈ ) with appropriate eluents.

 ► Basic preparative HPLC purification

 Method 1

 Injection 2 ml of DMSO.

Preparative HPLC: Macherey-Nagel column 100 x 21 mm reverse phase C18 Nucleodur 10 μηη; Eluent: acetonitrile and water at 10 mM ammonium hydrogen carbonate brought to pH = 9-10 with aqueous ammonia.

 Bearing 10% acetonitrile: 2 min, gradient up to 95% acetonitrile in 23 min and then bearing 95% acetonitrile 8 min.

 Collection according to UV absorption at 254nm.

 Method 2

 Injection 5ml of DMSO.

 Preparative HPLC: Macherey-Nagel column 250 x 40 mm reverse phase C18 Nucleodur Gravity 10 μηη.

 Eluent: acetonitrile and water at 10 mM ammonium hydrogen carbonate brought to pH = 9-10 with aqueous ammonia.

 Bearing 10% acetonitrile: 3 min, gradient up to 95% acetonitrile in 37 min and then bearing 95% acetonitrile 8 min.

 Collection based on UV absorption at 254 nm.

► Acidic preparative HPLC purification

 Method 3

 Injection into 2 ml of DMSO.

 Preparative HPLC column Macherey-Nagel 100 x 21 mm reverse phase C18 Nucleodur 10 μηη.

 Eluent: acetonitrile at 0.07% TFA and water at 0.07% TFA.

 Bearing 10% acetonitrile: 2 min, gradient up to 95% acetonitrile in 23 min and then bearing 95% acetonitrile 8 min.

 Collection according to UV absorption at 254nm.

 Method 4

 Injection into 5 ml of DMSO.

 Preparative HPLC column Macherey-Nagel 250 x 40 mm reverse phase C18 Nucleodur 10 μηη.

Eluent: acetonitrile at 0.07% TFA and water at 0.07% TFA. Bearing 10% acetonitrile: 3 min, gradient up to 95% acetonitrile in 37 min and then bearing 95% acetonitrile 8 min.

 Collection based on UV absorption at 254 nm.

 Spectral Analysis:

The ¹ H NMR spectra at 400 MHz and ¹ H at 500 MHz were carried out on the BRUKER AVANCE DRX-400 or BRUKER AVANCE DPX-500 spectrometer with the chemical shifts (δ in ppm) in the solvent dimethylsulfoxide-d ₆ (DMSO). d ₆ ) referenced at 2.5 ppm at the temperature of 303K.

 The mass spectra (SM) were obtained by one of the methods A to E described below:

 Method A:

WATERS UPLC-SQD apparatus; Ionisation: electrospray in positive and / or negative mode (ES +/-); Chromatographic conditions: Column: ACQUITY BEH C18 1, 7 μηι - 2, 1 x 50 mm; Solvents: A: H ₂ O (0, 1% formic acid) B: CH ₃ CN (0. 1% formic acid); Column temperature: 50 ° C; Flow rate: 1 ml / min;

Gradient (2 min): 5 to 50% B in 0.8 min; 1, 2 min: 100% B; 1.85 min: 100% B; 1, 95 min: 5% B; Retention time = Tr (min).

 Method B:

WATERS ZQ apparatus; Ionisation: electrospray in positive and / or negative mode (ES +/-); Chromatographic conditions: Column: XBridge Ci ₈ 2.5 μηη - 3 x 50 mm; Solvents: A: H ₂ 0 (0.1% formic acid), B: CH ₃ CN (0.1% formic acid); Column temperature: 70 ° C; Flow rate: 0.9 ml / min; Gradient (7 min): from 5 to 100% of B in 5.3 min; 5.5 min: 100% B; 6.3 min: 5% B; Retention time = Tr (min).

Method C:

 Waters apparatus QUATTRO PREMIER; Ionisation: electrospray in positive and / or negative mode (ES +/-); Chromatographic conditions: Column: ACQUITY BEH C18 1, 7 μηι 2, 1 x 100 mm; Solvents: A: H20 (0, 1% formic acid) B:

CH3CN (0.1% formic acid); Column temperature: 70 ° C; Flow rate: 0.7 ml / min; Gradient (1 1 min): from 5 to 95% of B in 8.3 min; 8.5 min: 100% B; 9.5 min: 5% of B. Method D:

 Waters Q-TOF-2 apparatus; Ionisation: electrospray in positive and / or negative mode (ES +/-); Chromatographic conditions: Column: Hypersil Hypurity C18 3 μηη 3 x 50 mm; Solvents: A: H20 (0.05% TFA) B: CH3CN (0.05% TFA); Column temperature: 40 ° C; Flow rate: 1 ml / min; Gradient (7 min): from 5 to 100% of B in 5 min; 6 min: 100% B; 6.5 min: 5% of B.

 Method E:

 Column: SYNERGY 2U HYDRO-RP 20 x 2.0 mm, 0.1% FA water / acetonitrile, 5 to 40% acetonitrile in 2 min, then 95% acetonitrile at 5 min. Ionisation method: ESI +, MICROMASS LCT-LCMS, scan m / z 100-1200.

 N.B: depending on the structures analyzed the dilution solvents are dimethylsulfoxide, methanol, acetonitrile, dichloromethane.

 EXAMPLES

 Exemplary: 6-methoxy-3- (pyridin-3-yl) -9H-beta-carboline

To 1 g of 5-methoxytryptophan are added 8 ml of water, 0.85 ml of 1N sulfuric acid, 3 ml of ethanol and 0.385 ml of formaldehyde. After stirring overnight in the mixture at a temperature in the region of 20 ° C., the suspension is dewatered. After drying the solid under a vacuum bell, 1.058 g of 6-methoxy-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid is obtained which will be used without further purification in the next step. . 2nd step:

 Me

 To a solution of 1 g of 6-methoxy-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid in 15 ml of methanol is added 16.25 ml of a hydrochloric acid solution. at 1.25 M in methanol. After stirring for 24 hours under reflux, 10 ml of a solution of hydrochloric acid at 1.25 M in methanol are added. After stirring for 24 hours under reflux, the mixture is evaporated to dryness under reduced pressure and then taken up in 50 ml of ethyl acetate and washed with a 5% aqueous solution of sodium hydrogencarbonate. The organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 1 g of methyl 6-methoxy-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate are obtained, the characteristics of which are as follows:

1H NMR Spectrum (400 MHz, d in ppm, DMSO-d 6): 2.71 (dd, J = 8.7 and 14.9 Hz, 1H); 2.71 (m spread, partially masked, 1H); 2.90 (dd, J = 4.6 and 14.9 Hz, 1H); 3.65 to 3.75 (m, 1H); 3.67 (s, 3H); 3.73 (s, 3H); 3.89 (broad d, J = 15.8 Hz, 1H); 3.97 (broad d, J = 15.8 Hz, 1H); 6.64 (dd, J = 2.5 and 8.8 Hz, 1H); 6.88 (d, J = 2.5 Hz, 1H); 7.14 (d, J = 8.8 Hz, 1H); 10.51 (s, 1 H)

 Step 3:

 OMe

To a solution of 0.9 g of methyl 6-methoxy-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate in 84 ml of xylene are added 526 mg of 10% palladium on charcoal. After stirring for 4 hours at reflux of the mixture and returning to a temperature in the region of 20 ° C., 40 ml of methanol are added. The suspension is filtered on celite, the solid rinsed with 150 ml of methanol containing 1% triethylamine, and the filtrate obtained is concentrated to dryness under reduced pressure. 790 mg of methyl 6-methoxy-9H-beta-carboline-3-carboxylate are obtained, the characteristics of which are as follows:

 1H NMR Spectrum (400 MHz, d at ppm, DMSO-d 6): 3.87 (s, 3H); 3.91 (s, 3H); 7.23 (dd, J = 2.5 and 8.9 Hz, 1H); 7.58 (d, J = 8.9 Hz, 1H); 8.01 (d, J = 2.5 Hz, 1H); 8.93 (s, 1H); 8.94 (s, 1H); 1 1, 95 (spread m, 1H)

 Step 4:

 OH

 To a solution of 3.69 g of lithium hydroxide in 100 ml of water are added 2.65 g of methyl 6-methoxy-9H-beta-carboline-3-carboxylate. After stirring for 12 hours at a temperature of 50 ° C., the suspension is filtered and 73 ml of a 2N aqueous solution of hydrochloric acid are added to the filtrate. The suspension obtained is drained, the solid is dried under a bell vacuum and 1 52 g of 6-methoxy-9H-beta-carboline-3-carboxylic acid are obtained, the characteristics of which are as follows:

 Mass spectrometry: method B

 Retention time Tr (min) = 1, 95

 [M + H] +: m / z 243; [M-H] -: m / z 241

 Step 5:

To a solution of 1.05 g of 6-methoxy-9H-beta-carboline-3-carboxylic acid in 35 ml of dimethylformamide is added 6.5 ml of terbutanol and 1.3 ml of triethylamine. The medium is stirred at a temperature of 80 ° C. and 1.4 ml of diphenylphosphorazidoate are slowly added. After four hours at 80 ° C. and returning to a temperature in the region of 20 ° C., the mixture is poured into a mixture of 20 ml of water and 250 ml of a 10% aqueous solution of sodium hydrogencarbonate. The aqueous phase is extracted twice with 150 ml of ethyl acetate and the combined organic phases are dried over anhydrous sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a silica column [eluent dichloromethane / methanol gradient from 99/1 to 93/7 with 1% triethylamine] and 803 mg of (6-methoxy-9H-beta-carbolin-3-yl are obtained. ) 2-methylpropan-2-yl carbamate whose characteristics are as follows:

 Mass spectrometry: method B

 Retention time Tr (min) = 2.89;

 [M + H] +: m / z 314; base peak: m / z 258;

[M-H] -: m / z 312

 Step 6:

To a solution of 800 mg of 2-methylpropan-2-yl (6-methoxy-9H-beta-carbolin-3-yl) carbamate in 25 ml of dichloromethane is added 5 ml of trifluoroacetic acid. After stirring overnight at a temperature in the region of 20 ° C., the mixture is concentrated to dryness under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed with 150 ml of a 10% aqueous solution of sodium hydrogencarbonate and 20 ml of water. The organic phase is dried over anhydrous sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a silica column (eluent dichloromethane / methanol gradient from 99/1 to 94/6 with 1% triethylamine) and 420 mg of 6-methoxy-9H-beta-carbolin-3-amine are obtained. the characteristics are as follows: Mass spectrometry: method C

Retention time Tr (min) = 0.75;

[M + H] +: m / z 214

Step 7:

 To a solution of 420 mg of 6-methoxy-9H-beta-carbolin-3-amine in 40 ml of dibromomethane are added 6 ml of polyethylene glycol (PEG 200), 0.539 ml of 48% hydrobromic acid and 282 mg of copper bromide. With stirring and at a temperature of -5 ° C is slowly added 0.292 ml of 3-methylbutyl nitrite. After stirring for one hour at a temperature of 0 ° C. and 2 hours at a temperature in the region of 20 ° C., 75 ml of a 28% aqueous ammonia solution and 25 ml of water are added. The aqueous phase is extracted twice with 100 ml of ethyl acetate and the combined organic phases are dried over anhydrous sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a silica column [eluent dichloromethane / methanol gradient from 99/1 to 95/5 with 1% triethylamine] and 232 mg of 3-bromo-6-methoxy-9H-beta-carboline are obtained. the characteristics are as follows:

 Mass spectrometry: method B

Retention time Tr (min) = 3.44

 [M + H] +: m / z 277; [M-H] -: m / z 275

Step 8:

 To a solution of 35 mg of 3-bromo-6-methoxy-9H-beta-carboline in a mixture of 0.48 ml of dioxane and 0.07 ml of water are added under argon in a microwave oven reactor. mg of 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine, 103 mg of cesium carbonate and 14.5 mg of tetrakistriphenylphosphine palladium. After 1 hour of microwave irradiation at a temperature of 140 ° C., 20 ml of a saturated aqueous solution of sodium hydrogencarbonate and 5 ml of water are added. The aqueous phase is extracted with twice 15 ml of ethyl acetate and the combined organic phases are dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is purified by preparative HPLC in basic medium (method 1). 15 mg of 6-methoxy-3- (pyridin-3-yl) -9H-beta-carboline are obtained, the characteristics of which are as follows:

 1 H NMR Spectrum (400 MHz, d at ppm, DMSO-d 6): 3.89 (s, 3H); 7.21 (dd, J = 2.4 and 8.8 Hz, 1H); 7.47 to 7.56 (m, 2H); 7.90 (d, J = 2.4 Hz, 1H); 8.51 (td, J = 1, 9 and 8.1 Hz, 1H); 8.56 (dd, J = 1, 9 and 4.6 Hz, 1H); 8.85 (s, 1H); 8.97 (s, 1H); 9.37 (d, J = 1, 9 Hz, 1H); 1 1, 52 (s wide, 1H)

 Mass spectrometry: method D

 Retention time Tr (min) = 2.58;

 [M + H] +: m / z 276

Example 2 3- (pyridin-3-yl) -9H-beta-carboline

To a solution of 4.89 g of commercial 9H-beta-carboline-3-carboxylic acid in 203 ml of water are added 4.87 g of lithium hydroxide. After stirring overnight at a temperature of 20 ° C the medium is placed at a temperature of 50 ° C. After 24 hours at this temperature, the mixture is cooled to a temperature of 5 ° C. and 42 ml of 5 N hydrochloric acid are added until pH = 4-5. The suspension is dewatered and the solid dried under vacuum. 5.1 g of 9H-beta-carboline-3-carboxylic acid are obtained, the characteristics of which are as follows:

 Mass spectrometry: method B

 Retention time Tr (min) = 1, 65

 [M + H] +: m / z 213; [M-H] -: m / z 21 1

 2nd step:

Le 9H-béta-carbolin-3-ylcarbamate de 2-méthylpropan-2-yle peut être préparé comme décrit pour la préparation du (6-méthoxy-9H-béta-carbolin-3-yl)carbamate de 2-méthylpropan-2-yle mais à partir de 4.4 g de l'acide 9H-bêta-carboline-3- carboxylique, dans 167 ml de diméthylformamide, 31 ml de terbutanol de 6.2 ml de triéthylamine et de 6.7 ml de phosphorazidoate de diphényle. Après quatre heures à une température de 80 °C et purification par chromatographie sur colonne de silice [éluant dichlorométhane / méthanol gradient de 98/2 à 92/8 avec 1 % de triéthylamine] on obtient 3.89 g de 9H-béta-carbolin-3-ylcarbamate de 2-méthylpropan-2-yle dont les caractéristiques sont les suivantes :

2-Methylpropan-2-yl 9H-beta-carbolin-3-ylcarbamate can be prepared as described for the preparation of 2-methylpropan-2- (6-methoxy-9H-beta-carbolin-3-yl) carbamate but from 4.4 g of 9H-beta-carbolin-3-carboxylic acid, in 167 ml of dimethylformamide, 31 ml of terbutanol of 6.2 ml of triethylamine and 6.7 ml of diphenylphosphorazidoate. After four hours at a temperature of 80 ° C. and purification by chromatography on a silica column (eluent dichloromethane / methanol gradient from 98/2 to 92/8 with 1% triethylamine), 3.89 g of 9H-beta-carbolin-3 are obtained. 2-methylpropan-2-yl-ethylcarbamate, the characteristics of which are as follows:

Mass spectrometry: method B

 Retention time Tr (min) = 2.93

 [M + H] +: m / z 284; base peak: m / z 228

 [M-H] -: m / z 282

 Step 3:

 9H-beta-carbolin-3-amine can be prepared as described for the preparation of 6-methoxy-9H-beta-carbolin-3-amine at but from 3.8 g of 9H-beta- carbolin-3-ylcarbamate. 2-methylpropan-2-yl in 100 ml of dichloromethane and 20 ml of trifluoroacetic acid. After stirring overnight at a temperature in the region of 20 ° C. and purification by chromatography on a silica column (eluent dichloromethane / methanol gradient from 99/1 to 94/6 with 1% triethylamine), 1.25 g of 9H-beta are obtained. -carbolin-3-amine whose characteristics are as follows:

 The spectra were carried out by direct introduction on a WATERS GCTof apparatus (direct introduction without LC): El: [M] + m / z = 183

Step 4:

 3-Bromo-9H-beta-carboline can be prepared as described for the preparation of 3-bromo-6-methoxy-9H-beta-carboline but from 820 mg of 9H-beta-carbolin-3-amine in 41 ml of dibromomethane, 13 ml of polyethylene glycol (PEG 200), 1.224 ml of 48% hydrobromic acid and 1.1 g of copper bromide and 0.663 ml of 3-methylbutyl nitrite. After purification by chromatography on a silica column (eluent dichloromethane / methanol gradient from 99/1 to 95/5 with 1% triethylamine), 540 mg of 3-bromo-9H-beta-carboline are obtained, the characteristics of which are as follows:

 The spectra were carried out by direct introduction on a WATERS GCTof apparatus (direct introduction without LC): El: [M] + m / z = 246

 Step 5:

3- (Pyridin-3-yl) -9H-beta-carboline can be prepared as described for the preparation of Example 1 but starting from 220 mg of 3-bromo-9H-beta-carboline in a mixture of 4.7 ml of dioxane and 0.5 ml of water, 255 mg of 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine, 725 mg of cesium carbonate and 103 mg of tetrakistriphenylphosphine palladium. After 1 hour of microwave irradiation at a temperature of 140 ° C. and purification by preparative HPLC in a basic medium (method 1), 75 mg of 3- (pyridin-3-yl) -9H-beta-carboline are obtained. whose characteristics are as follows:

1 H NMR spectrum (400 MHz, d ppm, DMSO-d 6): 7.26-7.32 (m, 1H); 7.51 (dd, J = 4.6 and 8.2 Hz, 1H); 7.55 to 7.60 (m, 1H); 7.62 (d, J = 8.3 Hz, 1H); 8.33 (d, J = 7.8 Hz, 1H); 8.52 (td, J = 2.0 and 8.2 Hz, 1H); 8.57 (dd, J = 2.0 and 4.6 Hz, 1H); 8.85 (d, J = 1.0 Hz, 1H); 9.01 (d, J = 1.0 Hz, 1H); 9.38 (d, J = 2.0 Hz, 1H); 1 1, 71 (s, 1 H)

 Mass spectrometry: method D

 Retention time Tr (min) = 2.56

 [M + H] +: m / z 246

Example 3: 6-Bromo-3- (pyridin-3-yl) -9H-beta-carboline

 A solution of 440 mg of N-bromosuccinimide in 30 ml of dichloromethane is slowly added at a temperature in the region of 20 ° C. to a solution of 550 mg of the product of Example 2 in 250 ml of dichloromethane. After stirring for one night, the suspension is drained and after drying of the solid 618 mg of 6-bromo-3- (pyridin-3-yl) -9H-beta-carboline are obtained, the characteristics of which are as follows:

1H NMR Spectrum (400 MHz, d at ppm, DMSO-d 6): 7.53 (dd, J = 4.7 and 8.3 Hz, 1H); 7.60 (d, J = 8.1 Hz, 1H); 7.69 (dd, J = 2.0 and 8.3 Hz, 1H); 8.49 (td, J = 2.0 and 8.1 Hz, 1H); 8.58 (dd, J = 2.0 and 4.7 Hz, 1H); 8.59 (d, J = 2.0 Hz, 1H); 8.93 (s, 1H); 9.04 (s, 1H); 9.36 (d, J = 2.0 Hz, 1H); 1 1, 89 (bs, 1H)

 The spectra were carried out by direct introduction on a WATERS GCTof apparatus (direct introduction without LC): El: [M] + m / z = 323

Example 4 Methyl 3- (pyridin-3-yl) -9H-beta-carboline-6-carboxylate

 250 mg of the product of Example 3, 1 g of carbon monoxide-molybdenum (6: 1), 56 mg of [1,1-bis (diphenylphosphino) ferrocene) are introduced into a reactor for a microwave oven. dichloropalladium (II) complexed with methylene chloride (1: 1), 351 mg of 2,3,4,6,7,8,9,10-octahydropyrimido [1,2-a] azepine in a mixture of 6 ml of dioxane and 1 ml of methanol. After 2 hours of microwave irradiation at a temperature of 160 ° C., the medium is poured into 50 ml of a 10% aqueous solution of sodium hydrogencarbonate and 5 ml of water. The aqueous phase is extracted twice with 50 ml of ethyl acetate. The combined organic phases are dried over anhydrous sodium sulphate and filtered and concentrated to dryness under reduced pressure. The residue is purified by preparative HPLC in basic medium (method 2) and 75 mg of methyl 3- (pyridin-3-yl) -9H-beta- carboline-6-carboxylate are obtained, the characteristics of which are as follows:

1 H NMR (400 MHz, d in ppm, DMSO-d 6): 3.92 (s, 3H); 7.53 (dd, J = 4.7 and 8.4 Hz, 1H); 7.70 (d, J = 8.8 Hz, 1H); 8.17 (dd, J = 2.0 and 8.8 Hz, 1H); 8.52 to 8.60 (m, 2H); 9.05-9.10 (m, 3H); 9.42 (d, J = 2.4 Hz, 1H); 12.15 (spread m, 1H)

Mass spectrometry: method B

 Retention time Tr (min) = 2.49;

 [M + H] +: m / z 304; [M-H] -: m / z 302

Example 5: 6-Methoxy-3- (5-methoxypyridin-3-yl) -9H-beta-carboline

 The compound can be prepared as described for the preparation of the product of Example 1 but starting from 60 mg of 3-bromo-6-methoxy-9H-beta-carboline in a mixture of 0.825 ml of dioxane and 0.12 ml of water, 71 mg of 3-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine, 176 mg of cesium carbonate and 25 mg of tetrakistriphenylphosphine palladium. After 1 hour of microwave irradiation at a temperature of 125 ° C., the residue is purified by preparative HPLC in basic medium (method 1). 18 mg of 6-methoxy-3- (5-methoxypyridin-3-yl) -9H-beta-carboline are obtained, the characteristics of which are as follows:

 1 H NMR Spectrum (400 MHz, d at ppm, DMSO-d 6): 3.89 (s, 3H); 3.95 (s, 3H); 7.21 (dd, J = 2.9 and 8.8 Hz, 1H); 7.53 (d, J = 8.8 Hz, 1H); 7.90 (d, J = 2.9 Hz, 1H); 8.08 (dd, J = 1, 9 and 2.9 Hz, 1H); 8.28 (d, J = 2.9 Hz, 1H); 8.88 (d, J = 1.0 Hz, 1H); 8.97 (d, J = 1.0 Hz, 1H); 8.99 (d, J = 1, 9 Hz, 1H); 1 1, 55 (s wide, 1H)

 Mass spectrometry: method B

 Retention time Tr (min) = 2.97

 [M + H] +: m / z 306; [M-H] -: m / z 304

Example 6 5- (6-Methoxy-9H-beta-carbolin-3-yl) pyridin-2-amine

The compound can be prepared as described for the preparation of the product of Example 1 but from 75 mg of 3-bromo-6-methoxy-9H-beta-carboline in a mixture of 1 ml of dioxane and 0.15 ml of water, 77 mg of 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine, 220 mg of cesium carbonate and 31 mg of tetrakistriphenylphosphine palladium. After 1 hour of microwave irradiation at a temperature of 125 ° C., the residue is purified by preparative HPLC in basic medium (method 1). 42 mg of 5- (6-methoxy-9H-beta-carbolin-3-yl) pyridin-2-amine are obtained, the characteristics of which are as follows:

 1 H NMR (400 MHz, d in ppm, DMSO-d 6): 3.88 (s, 3H); 6.00 (s wide, 2H); 6.55 (d, J = 8.8 Hz, 1H); 7.17 (dd, J = 2.7 and 8.8 Hz, 1H); 7.48 (d, J = 8.8 Hz, 1H); 7.86 (d, J = 2.7 Hz, 1H); 8.14 (dd, J = 2.7 and 8.8 Hz, 1H); 8.54 (brs, 1H); 8.73 (d, J = 2.7 Hz, 1H); 8.84 (d, J = 1.0 Hz, 1H); 1 1, 30 (s, 1 H)

 Mass spectrometry: method B

 Retention time Tr (min) = 2.28

 [M + H] +: m / z 291; [M-H] -: m / z 289

Example 7: 6-Methoxy-3-r6- (methylsulfanyl) pyridin-3-yn-9H-beta-carboline

6-Methoxy-3- [6- (methylsulfanyl) pyridin-3-yl-9H-beta-carboline can be prepared as described for the preparation of the product of Example 1 but from 75 mg of 3-bromine. 6-methoxy-9H-beta-carboline in a mixture of 1 ml of dioxane and 0.15 ml of water, 59.5 mg of (2-methylthio-5-pyridinyl) boronic acid, 220 mg of cesium and 31 mg of tetrakistriphenylphosphine palladium. After 1 hour of microwave irradiation at a temperature of 125 ° C., 20 ml of a saturated aqueous solution of NaHCO 3 and 5 ml of water are added. After extraction with 2 times 25 ml of ethyl acetate, drying over MgSO 4 and filtration, the dry extract is purified by preparative HPLC in basic medium (method 1). 28 mg of 6-methoxy-3- [6- (methylsulfanyl) pyridin-3-yl-9H-beta-carboline are obtained, the characteristics of which are as follows:

 LC / MS (Method B) Tr (min) = 3.22;

 [M + H] +: m / z 322; [M-H] -: m / z 320

Example 8: 6-Methoxy-3- (6-methoxypyridin-3-yl) -9H-beta-carboline

La 6-méthoxy-3-(6-méthoxypyridin-3-yl)-9H-bêta-carboline peut être préparée comme décrit pour la préparation du produit de l'exemple 1 mais à partir de 60 mg de 3-bromo-6-méthoxy-9H-béta-carboline dans un mélange de 0.8 ml de dioxanne et de 0.12 ml d'eau, de 57,5 mg du sel de l'acide chlorhydrique de d'acide (2-méthoxy-5-pyridinyle) boronique, 247 mg de carbonate de césium et de 25 mg de tetrakistriphenylphosphine palladium. Après 1 heure d'irradiation microondes à une température de 125 °C, on rajoute 20 ml d'une solution aqueuse saturée de NaHC03 et 5 ml d'eau. Après extraction par 2 fois 25 ml d'acétate d'éthyle, séchage sur MgS04 et filtration, l'extrait sec est purifié par HPLC préparative en milieu basique (méthode 1 ). On obtient 28 mg de la 6-méthoxy-3- (6-méthoxypyridin-3-yl)-9H-bêta-carboline dont les caractéristiques sont les suivantes :

6-Methoxy-3- (6-methoxypyridin-3-yl) -9H-beta-carboline can be prepared as described for the preparation of the product of Example 1 but from 60 mg of 3-bromo-6- methoxy-9H-beta-carboline in a mixture of 0.8 ml of dioxane and 0.12 ml of water, 57.5 mg of the hydrochloric acid salt of (2-methoxy-5-pyridinyl) boronic acid, 247 mg of cesium carbonate and 25 mg of tetrakistriphenylphosphine palladium. After 1 hour of microwave irradiation at a temperature of 125 ° C., 20 ml of a saturated aqueous solution of NaHCO 3 and 5 ml of water are added. After extraction with 2 times 25 ml of ethyl acetate, drying over MgSO 4 and filtration, the dry extract is purified by preparative HPLC in basic medium (method 1). 28 mg of 6-methoxy-3- (6-methoxypyridin-3-yl) -9H-beta-carboline are obtained, the characteristics of which are as follows:

 LC / MS (method B)

 Tr (min) = 2.96;

 [M + H] +: m / z 306; [M-H] -: m / z 304

Exe - (pyrimidin-5-yl) -9H-beta-carboline

3- (Pyrimidin-5-yl) -9H-beta-carboline can be prepared as described for the preparation of the product of Example 1 but from 220 mg of 3-bromo-9H-beta-carboline in a mixture 4.6 ml of dioxane and 0.5 ml of water, 256 mg of pinacolic ester of 5-pyrimidyl boronic acid, 725 mg of cesium carbonate and 103 mg of tetrakistriphenylphosphine palladium. After 1 hour of microwave irradiation at a temperature of 140 ° C. and purification by preparative HPLC in a basic medium (method 1), we obtain 19 mg of 3- (pyrimidin-5-yl) -9H-beta-carboline, the characteristics of which are as follows:

 LC / MS (method B)

 Tr (min) = 2.75; [M + H] +: m / z 247;

Example 10 3- (pyridin-3-yl) -6- (trifluoromethoxy) -9H-beta-carboline

 3- (Pyridin-3-yl) -6- (trifluoromethoxy) -9H-beta-carboline may be prepared as follows:

 Step 1 :

 5-chloro-4- (trimethylstannanyl) -2,3'-bipyridine

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 over 20 minutes keeping the temperature below -70 ° C. To the reaction mixture are 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 in solution in 170 ml of 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 are gradually added. now 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 the residue is then 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: ethyl acetate mixture. 100/0 to 50/50 to give 19.22 g of 5-chloro-4- (trimethylstannanyl) -2,3'-bipyridine as a beige powder.

 UPLC-MS-DAD-ELSD: Tr (min) = 4.29; [M + H] +: m / z 355;

 1H NMR (400MHz, DMSO-d6): ppm 0.45 (s, 9H) 7.52 (dd, J = 7.6, 5.1Hz, 1H) 7.94 (d, J = 1.0Hz, 1H) 8.40 (dt, J = 7.9, 2.1 Hz, 1H) 8.63 (s, 1H) 8.64 - 8.66 (m, 1H) 9.22 (d, J = 2.4 Hz, 1H)

2nd step:

 A mixture of 188 mg of 2-bromo-4-trifluoromethoxyaniline, 0.26 g of 5-chloro-4- (trimethylstannanyl) -2,3'-bipyridine (step 1), 29.5 mg of Cul and 59.5 mg of tetrakistriphenylphosphine palladium in 2 ml of dioxane is heated at 125 ° C. under microwave irradiation for one hour.

 After cooling the reaction medium, a mixture of 50 ml of a saturated aqueous solution of NaHCO 3 and 5 ml of water is added. After extraction with 2 times 50 ml of ethyl acetate, drying over MgSO 4 and filtration, the dry extract is purified on chromatography on silica using as eluent an n-heptane / ethyl acetate mixture in a 1: 2 ratio. then the pure ethyl acetate to provide, after evaporation, 131 mg of 4-trifluoromethoxy-2- {4- [5-chloro-2- (3-pyridinyl)] pyridinyl} -aniline having the following characteristics:

 LC / MS (method A)

Tr (min) = 3.86 [M + H] +: m / z 366 (1 CI)

 Step 3:

 In a 5 ml microwave tube, 130 mg of 4-trifluoromethoxy-2- {4- [5-chloro-2- (3-pyridinyl)] pyridinyl} -aniline (step 2), 16.2 mg of tris ( dibenzylideneacetone) dipalladium (0), 15.3 mg of 2-dicyclohexylphosphino-2 '- (n, n-dimethylamino) biphenyl, 55.8 mg of potassium tert-butoxide and 2 ml of dioxane. After heating under microwave for 1 hour at 130 ° C., the reaction medium is hydrolysed with 50 ml of 10% NaHCO 3 and 10 ml of water and then extracted with AcOEt (2 × 50 ml). The combined organic phases are dried over Na 2 SO 4, filtered and concentrated to obtain 195 mg of crude which is purified by chromatography (30 g SiO 2, eluent: pure AcOEt and then AcOEt / MeOH mixture, 95/5.

67 mg of 3- (pyridin-3-yl) -6- (trifluoromethoxy) -9H-beta-carboline are obtained.

LC / MS (method B)

Tr (min) = 3.01;

 [M + H] +: m / z 330; [M-H] -: m / z 328

Example 11 3- (pyridin-3-yl) -6- (trifluoromethyl) -9H-beta-carboline

Step 1 :

 In a 5 ml microwave tube, 215 mg of 4-amino-3-iodobenzotrifluoride, 265 mg of 5-chloro-4- (trimethylstannanyl) -2,3'-bipyridine (step 1 of example 10) are charged, 61 mg of tetrakistriphenylphosphine palladium and 30 mg of copper iodide (I) in 2 ml of dioxane After heating under microwave for 1 h at 125 ° C., the reaction medium is cooled to room temperature and then hydrolysed with a mixture of 50 ml of solution aqueous 10% NaHCO 3 and 5 ml of water and extracted with AcOEt (2 x 50 ml). The combined organic phases are dried over Na2SO4, filtered and concentrated to obtain 388 mg of crude product. This is purified by chromatography (30 g SiO 2, eluent n-Heptane / AcOEt 1/2 then pure AcOEt) to obtain 183 mg of 4-trifluoromethyl-2- {4- [5-chloro-2- (3-pyridinyl) )] - pyridinyl} - aniline.

 LC / MS (method A)

Tr (min) = 3.83;

[M + H] +: m / z 350 (1 Cl)

2nd step:

In a 5 ml microwave tube, 180 mg of the product of step 1, 24 mg of tris (dibenzylideneacetone) dipalladium (0), 22 mg of 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl are charged. , 81 mg of potassium tertbutylate in 2.5 ml of dioxane. After heating under microwave for 1 hour at 130 ° C., the reaction medium cooled to room temperature is hydrolysed with a mixture of 60 ml of 10% aqueous NaHCO 3 solution and 10 ml of water and then extracted with AcOEt (2x 50 ml). The combined organic phases are dried over Na 2 SO 4, filtered and concentrated to obtain 195 mg of crude which is purified by chromatography. (30 g SiO 2, pure AcOEt eluent and then a 95% mixture and AcOEt 5% MeOH). 91 mg of 3- (pyridin-3-yl) -6- (trifluoromethyl) -9H-beta-carboline are thus isolated.

 LC / MS (method B)

 Tr (min) = 2.96;

[M + H] +: m / z 314; [M-H] -: m / z 312

Example 12: 6-Fluoro-3- (pyridin-3-yl) -9H-beta-carboline

 In a vial of 5 ml for microwave, 100 mg of 5-chloro-4-trimethylstannanyl- [2,3 '] bipyridinyl (step 1 of example 10), 67 mg of 2-iodo-4- are introduced. fluoroaniline, 20 mg of bis (triphenylphosphine) palladium (II) dichloride, 11 mg of copper (I) iodide, and 86 mg of cesium fluoride in 2 ml of dimethylformamide. Evacuate 3 times and then put under argon 3 times, and the reaction mixture irradiated for 1 h at 100 ° C.

After cooling to room temperature, the mixture is poured into a mixture of water (50 ml) and ethyl acetate (50 ml) and then decanted and the aqueous phase re-extracted with ethyl acetate (2 × 20 ml). The organic phase is washed with brine (20 ml), dried over magnesium sulphate and concentrated to obtain 84 mg of crude product which is purified by chromatography on a cartridge of 10 g of silica 30-60 μηη with silica gel. ethyl acetate as eluent. 54 mg is thus obtained of 4-fluoro-2- {4- [5-chloro-2- (3-pyridinyl)] pyridinyl} aniline as a cream solid.

 LC / MS (method A):

Tr (min) = 0.93

 [M + H] +: m / z 299

2nd step:

 In a 20 ml vial for microwave, 494 mg of the compound of step 1, 94 mg of copper iodide (1), 683 mg of potassium carbonate in 15 ml of DMSO are introduced.

 The whole is subjected to irradiation for 5 h 30 min at 170 ° C. and then the cooled reaction medium is poured at room temperature into a mixture of 10% aqueous ammonia solution (50 ml) and ethyl acetate (50 ml). . The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine (20 ml), dried over magnesium sulphate and concentrated to obtain 562 mg of crude product. This crude is purified on a cartridge of 50 g of silica 30-60 μηη eluting with dichloromethane and then with a mixture of dichloromethane / MeOH, 95/5 and then with a mixture of dichloromethane 90-MeOH 10, ammonia 1. This gives 325 mg 6-fluoro-3- (pyridin-3-yl) -9H-beta-carboline in the form of beige crystals.

 LC / MS (method A)

Tr (min) = 0.52;

 [M + H] +: m / z 264; [M-H] -: m / z 262

Example 13: 6-Methoxy-3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carboline

 Step 1: 2,5-dichloro-4-trimethylstannanylpyridine

 A solution of 10.45 ml (74.32 mmol) of diisopropylamine in 1000 ml of tetrahydrofuran is stirred under an argon atmosphere at -78 ° C. 28.6 ml (74.32 mmol) of a solution of butyllithium (2.5 M) in hexane are added slowly keeping the temperature below -70 ° C. After stirring for 30 minutes at -78 ° C., a solution of 10 g (67.57 mmol) of 2,5-dichloropyridine in 200 ml of tetrahydrofuran is added over 25 minutes. After stirring for 1 h 30 min at -78 ° C., 17.5 g (87.84 mmol) of trimethyltin chloride and 100 ml of tetrahydrofuran are added dropwise. The reaction mixture is stirred for 14 hours at room temperature and then hydrolysed with 400 ml of saturated aqueous ammonium chloride solution and 350 ml of water. The suspension is extracted with 3 times 500 ml of ethyl acetate. The organic solution is decanted, dried over magnesium sulphate and then concentrated to dryness to give 27 g of a mobile oil which is purified by chromatography on silica (200 g), eluent: cyclohexane / ethyl acetate, 97.5 / 2 , 5 by volume. 12.46 g of desired product in the form of a white powder are obtained.

 2nd step:

Dans un vial Biotage de 5 ml, on place 202 mg de 2-bromo-4-methoxyaniline, 38 mg de iodure de cuivre, et 373 mg de dérivé stannylé [2,5-dichloro-4- (triméthylstannanyl)pyridine] (étape 1 de l'exemple 10) dans 3 ml de dioxanne sous argon puis on ajoute 1 16 mg de tetrakistriphenylphosphine palladium et 1 ml de dioxanne. On scelle le tube et chauffe le tout sous irradiation micro-onde à 140 °C pendant 1 h. Le milieu réactionnel refroidi à température ordinaire est versé sur 20 ml d'eau et extrait par 2 x 20 ml AcOEt. Les phases organiques réunies sont lavées par 2 fois 30 ml d'eau, séchées sur sulfate de magnésium, filtrées puis concentrées. On obtient ainsi 689 mg d'une huile brune.

In a 5 ml vial biotage, 202 mg of 2-bromo-4-methoxyaniline, 38 mg of copper iodide, and 373 mg of stannyl derivative [2,5-dichloro-4- (trimethylstannanyl) pyridine] (step 1 of Example 10) in 3 ml of dioxane under argon and then 1 16 mg of tetrakistriphenylphosphine palladium and 1 ml of dioxane are added. The tube is sealed and heated under microwave irradiation at 140 ° C for 1 h. The reaction medium cooled at room temperature is poured into 20 ml of water and extracted with 2 × 20 ml AcOEt. The combined organic phases are washed with twice 30 ml of water, dried over magnesium sulfate, filtered and concentrated. 689 mg of a brown oil are thus obtained.

Purification on a Biotage SNAP KP-SIL silica cartridge 50 g of 40-63 μηη silica with a 9/1 n-heptane / AcOEt gradient (8 column volumes) then n-heptane / AcOEt gradient 9/1 to 7/3 (8 column volumes) then n-heptane / AcOEt 7/3 gives 47 mg of the expected compound as a yellow solid.

LC / MS (method A)

 Tr (min) = 1, 19;

[M + H] +: m / z 269

 Step 3:

 In a 5 ml vial Biotage, 106 mg of the aniline from step 2, 76 mg of potassium carbonate and 72 mg of copper (II) acetylacetonate in 2.5 ml of DMSO are placed and the blue suspension obtained under microwave at 140 ° C for 2 hours.

The reaction medium cooled at room temperature is poured into 20 ml of saturated aqueous ammonium chloride solution and 20 ml AcOEt. The mixture is then filtered on celite. After decantation, the aqueous phase is extracted with 2 × 20 ml AcOEt. The combined organic phases are dried over magnesium sulfate, filtered and concentrated. 156 mg of a brown oil are obtained. Purification on Merck EVF silica cartridge D31 5 g Si60 15-40 μηη using as eluent CH ₂ Cl ₂ (10 column volumes) then a CH ₂ Cl ₂ / MeOH 100/0 gradient. 95/5 (5 column volumes), 15 ml / min, leads to 53 mg of expected product as a brown solid

LC / MS (method A)

Tr (min) = 1, 19;

[M + H] +: m / z 233

Step 4:

In a vial biotage of 5 ml, place 215 mg of the chlorocarboline of step 3, 325 mg of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2). -yl) -1H-pyrazole and 515 mg of cesium carbonate in 3.8 ml of dioxane under argon then 181 mg of tetrakistriphenylphosphine palladium and 0.7 ml of water are added. The tube is sealed and heated under microwave irradiation at 130 ° C. for 1 h. After the reaction medium has been cooled to room temperature, 90 mg of tetrakistriphenylphosphine palladium is added and heated again under microwave irradiation at 140 ° C. for 1.5 h. The reaction medium cooled at room temperature is then poured into 30 ml of water and extracted with 3 × 30 ml AcOEt. The organic solution is dried over magnesium sulfate, filtered and concentrated. This gives 520 mg of a rust oil. Purification on a Merck EVF D22 25 g Si60 15-40 μηη cartridge using CH ₂ Cl ₂ eluent (5 column volumes) and then a CH ₂ Cl ₂ / MeOH 100/0 to 90/10 gradient makes it possible to obtain 10 mg of 6-methoxy-3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carboline as an orange-yellow solid. LC / MS (method B)

Tr (min) = 2.56;

 [M + H] +: m / z 279; [M-H] -: m / z 277

Example 14 6- (difluoromethoxy) -3- (pyridin-3-yl) -9H-beta-carboline

 In a 5 ml vial biotage, 238 mg of 2-bromo-4-difluoromethoxyaniline, 371 mg of 5-chloro-4-trimethylstannanyl- [2,3 '] bipyridinyl derivative (step 1 of example 10), are placed. 38 mg of copper iodide (I) and 152 mg of cesium fluoride in 4 ml of DMF. It is homogenized under argon and then 70 mg of bis (triphenylphosphine) palladium (II) dichloride are added. The suspension is then subjected to microwave irradiation at 100 ° C. for 1.5 h. The reaction medium is cooled to room temperature and then poured into 15 ml of water and extracted with 2 × 20 ml AcOEt. The combined organic phases are dried over magnesium sulphate, filtered and concentrated to give 740 mg of a brown oil. Purification on a Biotage SNAP KP-SIL silica cartridge 50 g of 40-63 μηη silica using n-heptane / AcOEt 8/2 eluent (4 column volumes) and then a n-heptane / AcOEt gradient 8/2 to 5 / 5 (6 column volumes) then n-heptane / AcOEt 5/5 to 2/8, 40 ml / min gives 128 mg of expected product as a gray solid.

LC / MS (method A)

 Tr (min) = 1, 12

 [M + H] +: m / z 348

2nd step:

In a 5 ml vial biotage, 70 mg of the product of step 1, 56 mg of potassium carbonate and 53 mg of copper (II) acetylacetonate in 2 ml of DMSO are placed and then the pale blue suspension obtained under microwaves at 140 ° C. for 2 h The reaction medium is then cooled to room temperature, diluted with 25 ml AcOEt and poured into 20 ml of saturated aqueous ammonium chloride solution, the mixture is filtered through celite and, after decantation, the mixture is filtered off. aqueous phase is extracted with 25 ml AcOEt The combined organic phases are washed with 2 times 25 ml of water, dried over magnesium sulphate, filtered and concentrated Biotage SNAP Silica cartridge purification KP-SIL 10 g of silica 40 -63 μηη using as eluent CH ₂ Cl ₂ (5 column volumes) then a gradient CH ₂ Cl ₂ / MeOH, 100/0 to 95/5 (5 column volumes), CH ₂ Cl ₂ / MeOH, 95 / 5 (5 column volumes) then a gradient CH ₂ Cl ₂ / MeOH, 95/5 to 90/10 (5 volumes of co). lonne), 15 ml / min, gives 35 mg of 6 (difluoromethoxy) -3- (pyridin-3-yl) -9H-beta-carboline as an off-white solid.

 LC / MS (method A)

 Tr (min) = 0.66;

 [M + H] +: m / z 312; [M-H] -: m / z 310

Example 15: 6- (difluoromethoxy) -3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carboline:

 In a 5 ml biotage, 238 mg of 2-bromo-4-difluoromethoxyaniline, 373 mg of 2,5-dichloro-4-trimethylstannylpyridine (step 1 of example 10) and 38 mg of copper iodide are placed. (l) in 4 ml of dioxane. The mixture is homogenized under argon and then 16 mg of tetrakistriphenylphosphine palladium is added. The suspension is then subjected to microwave irradiation at 140 ° C. for 3 hours. Once cooled to room temperature, the reaction medium is poured into 15 ml of water and extracted with 2 × 20 ml AcOEt. The combined organic phases are dried over magnesium sulphate, filtered and concentrated to give 584 mg of a rust oil. Purification on a Biotage SNAP KP-SIL silica cartridge 100 g of silica 40-63 μηη using as eluent an n-heptane / AcOEt mixture 9/1 (5 column volumes) then a n-heptane / AcOEt gradient 9/1 to 8/2 (4 column volumes) then n-heptane / AcOEt 8/2, 40 ml / min, gives 50 mg of expected structure in the form of a yellow solid which is used as it is in the next step .

 LC / MS (method A)

Tr (min) = 1.38;

[M + H] +: m / z 305

2nd step:

 In a 5 ml vial biotage, 136 mg of the aniline from step 1, 62 mg of potassium carbonate and 58 mg of copper (II) acetylacetonate in 2.2 ml of DMSO are added and the suspension is irradiated. blue thus obtained under microwave at 140 ° C for 2 h.

The reaction medium cooled at room temperature is poured into 20 ml of saturated aqueous ammonium chloride solution and 20 ml AcOEt. The mixture is filtered on celite. After decantation, the aqueous phase is extracted with 20 ml AcOEt. The combined organic phases are washed with twice 30 ml of water, dried over magnesium sulfate, filtered and concentrated. 72 mg of an ocher yellow solid are obtained. Purification on Merck silica cartridge 5 g SI60 15-40 μηη using as eluent CH ₂ Cl ₂ (5 column volumes) then a gradient CH ₂ Cl ₂ / MeOH 100/0 to 95/5 (10 column volumes) , 18 ml / min, makes it possible to obtain 31 mg of expected product in the form of a beige solid

LC / MS (method A)

 Tr (min) = 1.31;

 [M + H] +: m / z 269 (Cl Cl)

 Step 3:

In a 2 ml vial biotage, the chlorocarboline of step 2, 54 mg of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) is placed. -1 H-pyrazole and 96 mg of cesium carbonate in 0.90 ml of dioxane under argon and then 34 mg of tetrakistnphenylphosphine palladium and 0.16 ml of water, sealed the tube and heated under microwave irradiation at 130 ° C for 1 h. 30 mg of boronate, 17 mg of tetrakistnphenylphosphine palladium and 0.1 ml of dioxane are added and then again heated under microwave irradiation at 130 ° C. for 1 hour. The reaction medium is poured into 15 ml of water and extracted with 3 × 15 ml AcOEt. The combined organic phases are dried over magnesium sulfate, filtered and concentrated. 45 mg of a rusty ocher oil which is purified on a Biotage SNAP KP-SIL silica cartridge are obtained 2.5 g of 40-63 μηη silica with CH 2 Cl 2 eluent (5 column volumes) and then a CH 2 Cl 2 / MeOH gradient, 100 / 0 to 95/5 (10 column volumes), then CH2Cl2 / MeOH, 95/5, 8 ml / min. 18 mg of 6- (difluoromethoxy) -3- (1-methyl-1H-pyrazol-4-yl) -9H-beta- carboline are obtained in the form of an oily yellow solid.

LC / MS (method A)

 Tr (min) = 0.57;

 [M + H] +: m / z 315; [M-H] -: m / z 313

Example 16: N, N-diethyl-2- (4-r3- (1-methyl-1H-pyrazol-4-yl) -9H-beta-carbolin-6-yl-H-pyrazol-1-dimethanamine

Step 1

 In a sealed vial are placed dichloropyridine (3.23 g, 21.8 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - 1 H-pyrazole (5 g, 24 mmol), cesium carbonate (14.17 g, 43.6 mmol) as well as DME (60 ml) and water (6 ml). To this mixture is added tetrakistriphenylphosphine palladium. (126 mg, 0.1 mmol). The reaction medium is heated at 100 ° C. overnight. The reaction medium is diluted with ethyl acetate (50 ml). A saturated aqueous solution of ammonium chloride (50 ml) is then added. The aqueous phase is then separated and extracted twice with ethyl acetate (20 ml). The organic phases are then combined and dried over magnesium sulfate. The solvent is then evaporated to give 5 g of residue which is purified by chromatography eluting with pure ethyl acetate to obtain 3.6 g of desired product.

LC-MS (method E)

Tr (min) = 2.49

[M + H] +: m / z = 194

2nd step

 The lithium diisopropylamide solution is freshly prepared: to a solution of diisopropylamine (0.95 ml, 6.7 mmol) in THF (10 ml), cooled to -40 ° C., a solution of nBuLi (4.2 ml, 6.7 mmol). The solution is stirred for 30 minutes at -40 ° C.

In another flask, the product of step 1 (1 g, 5.18 mmol) in THF (20 ml) is diluted. The solution of trimethylsilyl chloride (5.18 ml, 5.18 mmol) in THF is then added under nitrogen. The reaction medium is cooled to -70 ° C. At this temperature is added the solution of lithium diisopropyl amide previously prepared. The mixture is stirred at -70 ° C for 30 to 45 minutes. After 45 minutes at -70 ° C., 1.3 additional equivalents of lithium diisopropylamide are then added, again at -70 ° C. The reaction is stirred at -70 ° C for 30 minutes and then the 1 M trimethyltinane chloride solution in THF (6.7 ml, 6.7 mmol) is added. The reaction medium is then stirred for 30 minutes at -70 ° C. The reaction medium is treated with the addition of water and then allowed to rise to room temperature. The mixture is then extracted with AcOEt. The organic phase is dried over magnesium sulphate, and the final product is purified by flash chromatography using as eluent heptane / AcOEt 95/5 for 20 minutes then passage with heptane / AcOEt 80/20 over 10 minutes then heptane / AcOEt 80/20 for 30 minutes to give 650 mg of desired product.

LC-MS (method E)

Tr (min) = 6.24

[M + 2H] +: m / z = 430

Step 3

In a sealed tube are mixed the product of step 2 (200 mg, 0.47 mmol), 4-bromo-2-iodo-phenylamine (139 mg, 0.47 mmol), tetrakistriphenylphosphine palladium (27 mg, 0.023 mmol), cesium fluoride (143 mg, 0.94 mmol), copper iodide (18 mg, 0.094 mmol) and DMF (5 ml). The whole is heated at 120 ° C in the microwave oven for 1 hour. The reaction medium is filtered on celite then the solvent is evaporated. The residue obtained is purified directly by flash chromatography using AcOEt 100% for 20 minutes then AcOEt / iPrOH / NH ₄ OH, 95/5/1 for 20 minutes to give 170 mg of the desired product.

 LC-MS (method E)

Tr (min) = 3.30

[M + H] +: m / z = 365

Step 4

In a sealed tube is placed the product of step 3 (138 mg, 0.38 mmol), followed by potassium carbonate (158 mg, 1.10 mmol), copper iodide (15 mg, 0.08 mmol) and DMSO (5 ml). The reaction mixture is heated at 170 ° C for two hours using the microwave oven. The reaction mixture is filtered through celite and the filtrate is purified directly by flash chromatography using 100% DCM for 10 minutes then DCM / MeOH / NH ₄ OH-85/15/1 for 30 minutes to give 63 mg of desired product. .

LC-MS (method E)

Tr (min) = 2.44

 [M + H] +: m / z = 327

To 109 mg of sodium hydride (50% in oil) in 0.5 ml of DMF under argon at a temperature in the region of 25 ° C. is added 4- (4,4,5,5-tetramethyl) -1,3 , 2-dioxaborolan-2-yl) -1H-pyrazole (200 mg) in 1.2 ml of DMF and, at the end of the evolution of gas, 2-bromo-N, N-diethylethylamine hydrobromide (269 mg) dissolved in 1.5 ml of DMF. The reaction medium is stirred for 1 h at a temperature in the region of 25 ° C. and then treated with 5 ml of water and extracted with 5 times 10 ml of ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulfate, filtered and concentrated to give 235 mg of the desired product as a colorless crude oil used in the next step. Step 6

 In a sealed tube are placed the product of step 4 (63 mg, 0.19 mmol), the boronic ester prepared in step 5 (57 mg, 0.19 mmol), tetrakistriphenylphosphine palladium (11 mg, 0.009 mmol) , cesium carbonate (126 mg, 0.39 mmol), DME (5 ml) followed by water (0.5 ml). The reaction mixture is heated at 100 ° C using the microwave oven for two hours. Boronic ester (45 mg, 0.15 mmol) is added and the reaction medium is heated at 100 ° C. for an additional hour. The reaction medium is filtered on celite, diluted in a mixture of ethyl acetate and methanol, and then washed with water. The organic phase is then dried over magnesium sulfate and the solvent is evaporated.

The final product is purified by flash chromatography using DCM / MeOH / NH ₄ OH, 95/5/1 for 10 minutes and then DCM / MeOH / NH ₄ OH, 90/10/1 for 20 minutes. 17 mg of final product are obtained.

LC-MS (method E)

Tr (min) = 1.79

 [M + H] +: m / z = 414

Example 17: 3-Im-methyl-1H-pyrazol-4-yl) -6- (4-piperidin-1-yl) propoxyphenyl) -9H-

Dans un tube scellé sont places le produit de l'étape 4 de l'exemple 16 (34 mg, 0.10 mmol), l'ester pinacolique de l'acide boronique commercial (38 mg, 0.1 1 mmol), le tetrakistriphenylphosphine palladium (12 mg, 0.001 mmol), le carbonate de césium (65 mg, 0.20 mmol), le DME (5 ml) suivi de l'eau (0.5 ml). Le mélange réactionnel est chauffé à 100 °C à l'aide du four à micro-onde pendant une heure. On rajoute du catalyseur (12 mg, 0.001 mmol) et le milieu réactionnel est chauffé à 100 °C pendant une heure supplémentaire. Le milieu réactionnel est filtré sur célite, dilué dans un mélange d'acétate d'éthyle et de méthanol, puis lavé avec de l'eau. La phase organique est ensuite séchée sur sulfate de magnésium et le solvent est évaporé. Le produit final est purifié par chromatographie flash utilisant DCM/iPrOH/NH₄OH, 90/10/1 pendant 10 minutes puis DCM/iPrOH/NH₄OH, 80/20/1 pendant 20 minutes pour obtenir 10 mg de produit final.

In a sealed tube are placed the product of Step 4 of Example 16 (34 mg, 0.10 mmol), pinacolic ester of commercial boronic acid (38 mg, 0.1 mmol), tetrakistriphenylphosphine palladium (12 mg, 0.10 mmol), mg, 0.001 mmol), cesium carbonate (65 mg, 0.20 mmol), DME (5 ml) followed by water (0.5 ml). The reaction mixture is heated at 100 ° C using the microwave oven for one hour. Catalyst (12 mg, 0.001 mmol) is added and the reaction mixture is heated at 100 ° C. for an additional hour. The reaction medium is filtered on celite, diluted in a mixture of ethyl acetate and methanol, and then washed with water. The organic phase is then dried over magnesium sulfate and the solvent is evaporated. The final product is purified by flash chromatography using DCM / iPrOH / NH ₄ OH, 90/10/1 for 10 minutes and then DCM / iPrOH / NH ₄ OH, 80/20/1 for 20 minutes to obtain 10 mg of final product.

LC-MS (method E):

Tr (min) = 2.13

[M + H] +: m / z = 466

Example 18: N, N-Diethyl-2- [4- (3-pyridin-3-yl) -9H-beta-carbolin-6-yl-1H-pyrazol-1-tethanamine

 Step 1

Five sealed tubes are mixed with the product of Step 1 of Example 10 (1.00 g, 2.84 mmol), 4-bromo-2-iodo-phenylamine (846 mg, 2.84 mmol), tetrakistriphenylphosphine palladium ( 164 mg, 0.14 mmol), cesium fluoride (860 mg, 5.66 mmol), copper iodide (108 mg, 0.57 mmol) and then DMF (20 ml). The whole is heated at 120 ° C in the microwave oven for 1 hour. The reaction medium is filtered on celite then the solvent is evaporated. The residue obtained is purified directly by flash chromatography using 100% AcOEt for 20 minutes then AcOEt / iPrOH / NH ₄ OH, 95/5/1 for 20 minutes to obtain 1.6 g of desired product.

LC-MS (method E): Tr (min) = 3.07

[M + 2H] +: m / z

 In a sealed tube is placed the product of step 1 (1.70 g, 4.75 mmol), followed by potassium carbonate (1.97 g, 14.25 mmol), copper iodide (181 mg, 0.95 mmol) and DMSO (20 ml). The reaction mixture is then heated at 170 ° C for two hours using the microwave oven. The reaction mixture is filtered through Celite and the filtrate is purified directly by flash chromatography using 100% ethyl acetate for 10 minutes then AcOEt / iPrOH 95/5 for 30 minutes to obtain 540 mg of desired product.

LC-MS (method E)

Tr (min) = 2.64

[M + H] +: m / z = 324

 Step 3

In a sealed tube are placed the product of step 2 (100 mg, 0.31 mmol), the boronic ester prepared in step 5 of Example 16 (91 mg, 0.31 mmol), tetrakistriphenylphosphine palladium. (18 mg, 0.015 mmol), cesium carbonate (200 mg, 0.61 mmol), DME (5 mL) followed by water (0.5 mL). The reaction mixture is heated at 100 ° C using the microwave oven for two hours. Boronic ester (45 mg, 0.15 mmol) is added and the reaction medium is heated to 100 ° C. for an extra hour. The reaction medium is filtered on celite, diluted with a mixture of ethyl acetate and methanol, and then washed with water. The organic phase is then dried over magnesium sulfate and the solvent is evaporated. The final product is purified by flash chromatography using AcOEt / iPrOH / NH ₄ OH, 95/5/1 for 10 minutes and then AcO Et / i PrO H / NH ₄ 0 H, 90/10/1 for 20 minutes then AcOEt / iPrOH. / NH ₄ OH, 70/30/1 for 20 minutes.

 As the product is still on silica gel, the solvent is changed to

DCM / MeOH / NH ₄ OH, 90/10/1 to obtain 53 mg of final product.

 LC-MS (method E):

Tr (min) = 1.83

[M + H] +: m / z = 41

Example 19: 6- {4-r3- (piperidin-1-yl) propoxy] phenyl) -3- (pyridin-3-yl) -9H-beta-carboline

 In a sealed tube are placed the product of step 2 of Example 18 (100 mg,

0.31 mmol), pinacolic ester of commercial boronic acid (106 mg, 0.31 mmol), tetrakistriphenylphosphine palladium. (18 mg, 0.015 mmol), cesium carbonate (200 mg, 0.61 mmol), DME (5 mL) followed by water (0.5 mL). The reaction mixture is heated at 100 ° C using the microwave oven for one hour. Catalyst (18 mg, 0.015 mmol) is added and the reaction mixture is heated at 100 ° C. for an additional hour. The reaction medium is filtered on celite, diluted in a mixture of ethyl acetate and methanol, and then washed with water. The organic phase is then dried over magnesium sulfate and the solvent is evaporated. The final product is purified by flash chromatography using DCM / iPrOH / NH ₄ OH- 90/10/1 for 10 minutes and then DCM / iPrOH / NH ₄ OH-50/50/1 for 20 minutes to obtain 20 mg of final product.

LC-MS (method E):

Tr (min) = 2.17

 [M + H] +: m / z = 463

 The preparations of the pharmaceutical compositions as defined above could be carried out with any of the products of formula (I) according to the present invention: such pharmaceutical compositions form part of the present invention.

In Vitro Biochemical Testing Procedures

 The pharmacological properties of the compounds of the invention can be confirmed by a number of pharmacological assays. The following examples of pharmacological assays were carried out with compounds according to the invention.

Example 1

 TR-FRET dosage

In order to determine the inhibition of the activity of Pim kinases, the compounds of the invention are tested according to a TR-FRET assay ("Time Resolved-Fluorescence Resonance Energy Transfer", fluorescence energy transfer by resonance in time. resolved) in vitro used routinely. The TR-FRET assay is based on the detection of phosphorylation of the Ser1 12 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:

 Pim-kinase Pim-1 protein, Pim-2 or Hisim-tagged recombinant full-length human 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);

oc-His6-APC - SureLight ™ allophycocyanin-conjugated mouse monoclonal antibody directed against the His6 tag (Perkin Elmer, No. AD0059H, Waltham, Mass., USA); α-Ρ-Bad-Eu - mouse monoclonal antibody (Cell Signaling Technology # 9296B, Danvers, Mass., USA) against phosphoBad (Ser1 12) (7E1 1) labeled on demand by Perkin Elmer with LANCE ™ reagent Eu-W1024. The assay is based on PerkinElmer's LANCE ™ technology: the Eu-labeled antibody binds to phospho-SerI 12 and generates a TR-FRET signal by interaction with PCA-labeled His6 antibody bound to His6 tag of Bad. The TR-FRET signal is detected using a SpectraMax M5 plate reader (Molecular Devices) with the following settings: λβχ = 340 nm, λβηηΐ = 615 nm, λβηι2 = 665 nm. The fluorescence signal ratio at 665 nm on fluorescence signal at 615 nm is used as the signal reading for Cl ₅₀ (calculations based on the 4-parameter logistic model). The assay is implemented in a 384-well format; the handling of liquids are carried out using a station of

handling of Beckman 3000 fluids. Test compounds are tested at 10 concentration points in duplicate; the highest compound concentration is typically 30 μΜ. The concentration of ATP is equal to 40 μΜ.

BIOCHEMICAL RESULTS

 The biochemical results are expressed according to the following classification:

Class A: IC50 less than 1000 nM (or 1 μΜ)

Class B: IC50 between 1 μΜ and 5 μΜ

Class C: IC50 greater than 5μΜ

Example No. IC50 Pim1

 Ex1 A

 Ex2 B

 Ex3 B

 Ex4 B

 Ex5 B

 Ex6 B

 Ex7 C

 Ex8 C

 Ex9 C

 Ex10 C

 Ex11 C

Ex12 C Ex13 B

Ex14 B

Ex15 B

Ex16 A

Ex17 A

Ex18 A

Ex19 A

Claims

CLAIMS 1 - Products of general formula (I) following: (I) in which - Z3 represents a heteroaryl radical consisting of 5 or 6 members with 1 to 4 heteroatoms chosen from N, S or O linked to the carboline unit either by a C or by an N belonging to Z3, Z3 being optionally mono or poly substituted; - Z6 is chosen from: 1. H; 2. halogen 3. -OH 4. alkoxy whose alkyl part is optionally mono, di or tri substituted;; 5. -Y-alkyl (Y = S, SO, S02) linear or branched optionally mono, di or tri substituted; 6. -X-aryl (X = O, S, SO, S02) optionally mono, di or tri substituted; 7. -X-heteroaryl (X = O, S, SO, S02, heteroaryl of 5 or 6 members with 1 to 4 heteroatoms chosen from N, S or O linked to X either by a C or an N) optionally mono, di or substituted sort; 8. -NH2, 9. -NH(alkyl), -N(alkyl)2 linear(s), branched(s) or cyclic(s) of which the alkyl part is optionally mono, di or tri substituted; 10. -NH(aryl) in which the aryl part is optionally mono, di or tri substituted; 1 1 . -NH (heteroaryl) whose heteroaryl part (5 or 6-membered heteroaryl with 1 to 4 heteroatoms chosen from N, S or O linked to the atom of nitrogen either by a C or by an N) is optionally mono, di or tri substituted^ 12. -N(alkyl)(aryl) whose alkyl (linear, branched or cyclic) and aryl parts are optionally mono, di or tri substituted; 13. -N(alkyl)(heteroaryl) whose alkyl parts (linear, branched or cyclic) and heteroaryl (5- or 6-membered heteroaryl with 1 to 4 heteroatoms chosen from N, S or O linked to the nitrogen atom either by a C or an N) are optionally mono, di or tri substituted; 14. -C(0)OH 15. -C(0)O linear, branched or cyclic alkyl optionally mono, di or tri substituted; 16. -C(0)Oaryl optionally mono, di or tri substituted; 17. -C(0)Oheteroaryl (5- or 6-membered heteroaryl with 1 to 4 heteroatoms chosen from N, S or O linked to oxygen by a C atom) optionally mono, di or tri substituted; 18. -CONH2 19. -CO-heterocycloalkyl mono, di or tri substituted 20. -CONH(alkyl),CON(alkyl) ₂ linear(s), branched(s) or cyclic(s) of which the alkyl part is optionally mono, di or tri substituted; 21. -CON(alkyl)(aryl), linear, branched or cyclic alkyl whose alkyl and aryl parts are optionally mono, di or tri substituted; 22. -CON(alkyl)(heteroaryl), linear, branched or cyclic alkyl and 5- or 6-membered heteroaryl with 1 to 4 heteroatoms chosen from N, S or O linked to the nitrogen atom either by a C or by an N) whose alkyl and hetroaryl parts are optionally mono, di or tri substituted; 23. -C1 -C10 linear, branched or cyclic alkyl optionally comprising a heteroatom and optionally mono, di or tri substituted 24. aryl optionally mono, di or tri substituted 25. heteroaryl (5 or 6 members with 1 to 4 heteroatoms chosen from N, S or O) linked to the carboline unit either by a C or by an N belonging to Z6, Z6 being optionally mono or poly substituted; 26. heterocycloalkyl optionally mono or poly substituted; 27. -C2-C6 alkenyl optionally mono or disubstituted; 28. -C2-C6 optionally substituted alkynyl; said products of formula (I) being in all possible isomeric, racemic, enantiomeric and diastereomeric forms, as well as the addition salts with mineral and organic acids or with the mineral and organic bases of said products of formula (I) . 2- Products of general formula (I) as defined in claim 1 in which the possible substituents of Z3, i.e. the groups R2a, R2b, R2c, R2d or R2e, are chosen independently of one another from: 1. F; 2. Cl; 3.Br; 4.I; 5. -C-I-C-IO linear or branched alkyl optionally mono or poly substituted (R3a,R3b,R3c); 6. -C3-C7 cycloalkyl optionally mono or poly substituted (R3a,R3b,R3c), 7. -OH; 8. -O-alkyl (CrCio) linear, or branched optionally mono or poly substituted (R3a,R3b,R3c); 9. -Y-alkyl (Y = S, SO, S02) linear or branched optionally mono, di or tri substituted (R3a,R3b,R3c); 10. -O-cycloalkyl (C ₃ -C ₇ ) optionally mono or poly substituted (R3a,R3b,R3c); 1 1 . -O-aryl optionally mono or poly substituted (R3a,R3b,R3c); 12. aryl optionally mono or poly substituted (R3a,R3b,R3c); 13. heteroaryl (5 or 6 members with 1 to 4 heteroatoms chosen from N, S or O) linked either by a C or by an N) optionally mono or poly substituted (R3a, R3b, R3c); 14. heterocycloalkyl optionally mono or poly substituted (R3a,R3b,R3c); 15. -N0 ₂ ; 1 6. -NH2; 17. -NH-(alkyl (CrCio) or cycloalkyl (C ₃ -C ₇ ) or heterocycloalkyl) each group optionally mono or poly substituted (R3a,R3b,R3c); 18. -N(alkyl(d-Cio) or cycloalkyl(C ₃ -C ₇ ))2 each group being optionally mono or poly substituted (R3a,R3b,R3c); 19. -NHaryl or NH heteroaryl optionally mono or poly substituted 20. -NHC(0)substituted (R3a,R3b,R3c); 21. -N(alkyl(C Cio)C(0)substituted (R3a,R3b,R3c); 22. -NHS(0 ₂ )substituted (R3a,R3b,R3c); 23. -N(alkyl(C Cio)S(0 ₂ )substituted (R3a,R3b,R3c); 24. -C0 ₂ substituted (R3a,R3b,R3c); 25. -Ssubstituted (R3a,R3b,R3c); 26. -S(0 ₂ )substituted (R3a,R3b,R3c); 27. -S(O) substituted (R3a,R3b,R3c); 28. oxo (O double bond); 29. -C2-C6 alkenyl optionally mono or disubstituted (R3a,R3b); 30. -C2-C6 optionally substituted alkynyl ((R3a); the groups R3a, R3b, R3c, i.e. the substituents of the groups R2a, R2b, R2c, R2d or R2e, are chosen independently of one another from: I. F; 2. Cl; 3.Br; 4.I; 5. -C-I-C-IO linear or branched alkyl optionally mono or poly substituted by R4a, R4b, R4c; 6. -C3-C7 cycloalkyl optionally mono or poly substituted by R4a, R4b, R4c; 7. -OH; 8. -O-alkyl (CrCio) linear or branched optionally mono or poly substituted by R4a, R4b, R4c; 9. -Y-alkyl (Y = S, SO, S02) linear or branched optionally mono, di or tri substituted with R4a, R4b, R4c; 10. -O-cycloalkyl (C ₃ -C ₇ ) optionally mono or poly substituted by R4a, R4b, R4c; II. -O-aryl optionally mono or poly substituted with R4a, R4b, R4c; 12. aryl optionally mono or poly substituted with R4a, R4b, R4c; 13. heteroaryl optionally mono or poly substituted with R4a, R4b, R4c; 14. heterocycloalkyl optionally mono or poly substituted with R4a, R4b, R4c; 15. -N0 ₂ ; 16. -NH ₂ ; 17. -NH-(alkyl (CrCio) or cycloalkyl (C ₃ -C ₇ ) or heterocycloalkyl) each group optionally mono or poly substituted by R4a, R4b, R4c; 18. -N(alkyl(d-Cio) or cycloalkyl(C ₃ -C ₇ ))2 each group being optionally mono or poly substituted by R4a, R4b, R4c; 19. -NHaryl or NH heteroaryl optionally mono or poly substituted with R4a, R4b, R4c; 20. -NHC(O) substituted with R4a, R4b, R4c; 21. -N(alkyl(C Cio)C(0) substituted by R4a, R4b, R4c; 22. -NHS(0 ₂ ) substituted by R4a, R4b, R4c; 23. -N(alkyl(C Cio)S(0 ₂ )substituted by R4a, R4b, R4c; 24. -C0 ₂ substituted by R4a, R4b, R4c;

26. -CONH(alkyl), CON(alkyl) ₂ linear(s), branched(s) or cyclic(s) whose alkyl part is optionally mono, di or tri substituted by R4a, R4b, R4c; 27. -C(0)heterocycloalkyl optionally mono, di or tri substituted with R4a, R4b, R4c; 28. -S substituted by R4a, R4b, R4c; 29. -S(0 ₂ ) substituted by R4a, R4b, R4c; 30. -S(O) substituted with R4a, R4b, R4c; 31. oxo (O double bond); 32. -C ₂ -C ₆ alkenyl optionally mono or poly substituted with R4a, R4b, R4c; 33. -C ₂ -C ₆ alkynyl optionally mono or poly substituted with R4a, R4b, R4c; the groups R4a, R4b, R4c, i.e. the substituents of the groups R3a, R3b and R3c, are chosen independently of one another from: 2. Cl; 3.Br; 4.I; 5. -CF ₃ ; -CHF ₂ 6. -C ₁ -C ₁ 0 linear or branched alkyl; 7. -C ₃ -C ₇ cycloalkyl; 8. -OH; 9. -O-alkyl (CrCio) linear or branched; 10. -Y-alkyl (Y = S, SO, S02) linear or branched; 1 1 . -O-cycloalkyl (C ₃ -C ₇ ); 12. -0-aryl; 13. aryl; 14. heteroaryl; 15. heterocycloalkyl;

18. -NH-(alkyl (CrCio) or cycloalkyl (C ₃ -C ₇ ) or heterocycloalkyl); 19. -N(alkyl(CC ₁₀ ) or cycloalkyl(C ₃ -C ₇ )) ₂ ; 20. -NHaryl or NH heteroaryl; 21. -NHS(0 ₂ )alkyl; 22. -N(alkyl(C Cio)S(0 ₂ )alkyl; 23. -C0 ₂ alkyl; 24. -CONH ₂ 25. -CONH(alkyl), CON(alkyl) ₂ linear(s), branched(s) or cyclic(s); 26. -C(0)heterocycloalkyl; 27. -S-alkyl; 28. -S(0 ₂ )alkyl; 29. -S(0)alkyl; 30. oxo (O double bond); 31. -C ₂ -C ₆ linear or branched alkenyl; 32. -C ₂ -C ₆ linear or branched alkynyl; said products of formula (I) being in all possible isomeric, racemic, enantiomeric and diastereomeric forms, as well as the addition salts with mineral and organic acids or with the mineral and organic bases of said products of formula (I). 3 - Products of general formula (I) as defined in claim 1 in which the possible substituents of Z6, i.e. the groups R2a, R2b, R2c, R2d or R2e, are chosen independently of one another from: 1. F; 2. Cl; 3.Br; 4.I; 5. -C-I-C-IO linear or branched alkyl optionally mono or poly substituted (R3a,R3b,R3c); 6. -C3-C7 cycloalkyl optionally mono or poly substituted (R3a,R3b,R3c), 7. -OH; 8. -O-alkyl (CrCio) linear, or branched optionally mono or poly substituted (R3a,R3b,R3c); 9. -Y-alkyl (Y = S, SO, S02) linear or branched optionally mono, di or tri substituted (R3a,R3b,R3c); 10. -O-cycloalkyl (C ₃ -C ₇ ) optionally mono or poly substituted (R3a,R3b,R3c); 1 1 . -O-aryl optionally mono or poly substituted (R3a,R3b,R3c); 12. aryl optionally mono or poly substituted (R3a,R3b,R3c); 13. heteroaryl (5 or 6 members with 1 to 4 heteroatoms chosen from N, S or O) linked either by a C or by an N) optionally mono or poly substituted (R3a, R3b, R3c); 14. heterocycloalkyl optionally mono or poly substituted (R3a, R3b, R3c); 15. -N0 ₂ ;

17. -NH-(alkyl (CrCio) or cycloalkyl (C ₃ -C ₇ ) or heterocycloalkyl) each group optionally mono or poly substituted (R3a,R3b,R3c); 18. -N(alkyl(d-Cio) or cycloalkyl(C ₃ -C ₇ ))2 each group being optionally mono or poly substituted (R3a,R3b,R3c); 19. -NHaryl or NH heteroaryl optionally mono or poly substituted 20. -NHC(0)substituted (R3a,R3b,R3c); 21. -N(alkyl(C Cio)C(0)substituted (R3a,R3b,R3c); 22. -NHS(0 ₂ )substituted (R3a,R3b,R3c); 23. -N(alkyl(C Cio)S(0 ₂ )substituted (R3a,R3b,R3c); 24. -C0 ₂ substituted (R3a,R3b,R3c); 25. -Ssubstituted (R3a,R3b,R3c); 26. -S(0 ₂ )substituted (R3a,R3b,R3c); 27. -S(O) substituted (R3a,R3b,R3c); 28. oxo (O double bond); 29. -C2-C6 alkenyl optionally mono or disubstituted (R3a,R3b); 30. -C2-C6 optionally substituted alkynyl ((R3a); the groups R3a, R3b, R3c, i.e. the substituents of the groups R2a, R2b, R2c, R2d or R2e, are chosen independently of one another from: 1. F; 2. Cl; 3.Br; 4.I; 5. -C-I-C-IO linear or branched alkyl optionally mono or poly substituted by R4a, R4b, R4c; 6. -C3-C7 cycloalkyl optionally mono or poly substituted with R4a, R4b, R4c; 7. -OH; 8. -O-alkyl (CrCio) linear or branched optionally mono or poly substituted by R4a, R4b, R4c; 9. -Y-alkyl (Y = S, SO, S02) linear or branched optionally mono, di or tri substituted with R4a, R4b, R4c; 10. -O-cycloalkyl (C ₃ -C ₇ ) optionally mono or poly substituted by R4a, R4b, R4c; 1 1 . -O-aryl optionally mono or poly substituted with R4a, R4b, R4c; 12. aryl optionally mono or poly substituted with R4a, R4b, R4c; 13. heteroaryl optionally mono or poly substituted with R4a, R4b, R4c; 14. heterocycloalkyl optionally mono or poly substituted with R4a, R4b, R4c; 15. -N0 ₂ ;

17. -NH-(alkyl (CrCio) or cycloalkyl (C ₃ -C ₇ ) or heterocycloalkyl) each group optionally mono or poly substituted by R4a, R4b, R4c; 18. -N(alkyl(d-Cio) or cycloalkyl(C ₃ -C ₇ ))2 each group being optionally mono or poly substituted by R4a, R4b, R4c; 19. -NHaryl or NH heteroaryl optionally mono or poly substituted with R4a, R4b, R4c; 20. -NHC(O) substituted with R4a, R4b, R4c; 21. -N(alkyl(C Cio)C(0) substituted by R4a, R4b, R4c; 22. -NHS(0 ₂ ) substituted by R4a, R4b, R4c; 23. -N(alkyl(C Cio)S(0 ₂ )substituted by R4a, R4b, R4c; 24. -C0 ₂ substituted by R4a, R4b, R4c;

26. -CONH(alkyl), CON(alkyl) ₂ linear(s), branched(s) or cyclic(s) whose alkyl part is optionally mono, di or tri substituted by R4a, R4b, R4c; 27. -C(0)heterocycloalkyl optionally mono, di or tri substituted with R4a, R4b, R4c; 28. -S substituted by R4a, R4b, R4c; 29. -S(0 ₂ ) substituted by R4a, R4b, R4c; 30. -S(O) substituted with R4a, R4b, R4c; 31. oxo (O double bond); 32. -C ₂ -C ₆ alkenyl optionally mono or poly substituted with R4a, R4b, R4c; 33. -C ₂ -C ₆ alkynyl optionally mono or poly substituted with R4a, R4b, R4c; the groups R4a, R4b, R4c, i.e. the substituents of the groups R3a, R3b and R3c, are chosen independently of one another from: 1. F; 2. Cl; 3.Br; 4.I; 5. -CF ₃ ; -CHF ₂ 6. -C ₁ -C ₁ 0 linear or branched alkyl; 7. -C ₃ -C ₇ cycloalkyl; 8. -OH; 9. -O-alkyl (CrCio) linear or branched; 10. -Y-alkyl (Y = S, SO, S02) linear or branched; 1 1 . -O-cycloalkyl (C ₃ -C ₇ ); 12. -0-aryl; 13. aryl; 14. heteroaryl; 15. heterocycloalkyl;

18. -NH-(alkyl (CrCio) or cycloalkyl (C ₃ -C ₇ ) or heterocycloalkyl); 19. -N(alkyl(C Cio) or cycloalkyl(C ₃ -C ₇ )) ₂ ; 20. -NHaryl or NH heteroaryl; 21. -NHS(0 ₂ )alkyl; 22. -N(alkyl(CrCio)S(0 ₂ )alkyl; 23. -C0 ₂ alkyl; 24. -CONH ₂ 25. -CONH(alkyl), CON(alkyl) ₂ linear(s), branched(s) or cyclic(s); 26. -C(0)heterocycloalkyl; 27. -S-alkyl; 28. -S(0 ₂ )alkyl; 29. -S(0)alkyl; 30. oxo (O double bond); 31. -C ₂ -C ₆ linear or branched alkenyl; 32. -C ₂ -C ₆ linear or branched alkynyl; said products of formula (I) being in all possible isomeric, racemic, enantiomeric and diastereomeric forms, as well as the addition salts with mineral and organic acids or with the mineral and organic bases of said products of formula (I) . 4 - Products of general formula (I) as defined in any one of the preceding claims in which - Z3 represents a heteroaryl radical of 5 or 6 members with 1 to 4 heteroatoms chosen from N, S or O linked to the carboline unit either by a C or by an N belonging to Z3, Z3 being optionally mono or poly substituted by R2a, R2b , R2c, R2d, R2e, identical or different; - Z6 is chosen from: 1. H; 2. halogen; 3. -OH 4. alkoxy whose alkyl part is optionally mono, di or tri substituted with R2a, R2b, R2c, identical or different; 5. -Y-alkyl (Y = S, SO, S02) linear or branched optionally mono, di or tri substituted with R2a, R2b, R2c, identical or different; 6. -X-aryl (X = O, S, SO, S02) optionally mono, di or tri substituted with R2a, R2b, R2c, identical or different; 7. -X-heteroaryl (X = O, S, SO, S02, heteroaryl of 5 or 6 members with 1 to 4 heteroatoms chosen from N, S or O linked to X either by a C or an N) optionally mono, di or sort substituted by R2a, R2b, R2c, identical or different; 8. -NH2, 9. -NH(alkyl), -N(alkyl) ₂ linear(s), branched(s) or cyclic(s) whose alkyl part is optionally mono, di or tri substituted by R2a, R2b, R2c, identical or different ; 10. -NH(aryl) whose aryl part is optionally mono, di or tri substituted with R2a, R2b, R2c, identical or different; 1 1 . -NH (heteroaryl) whose heteroaryl part (heteroaryl of 5 or 6 members with 1 to 4 heteroatoms chosen from N, S or O linked to the nitrogen atom either by a C or by an N) is optionally mono, di or sort substituted by R2a, R2b, R2c, identical or different; 12. -N(alkyl)(aryl) whose alkyl (linear, branched or cyclic) and aryl parts are optionally mono, di or tri substituted by R2a, R2b, R2c, identical or different; 13. -N(alkyl)(heteroaryl) whose alkyl parts (linear, branched or cyclic) and heteroaryl (5- or 6-membered heteroaryl with 1 to 4 heteroatoms chosen from N, S or O linked to the nitrogen atom either by a C or an N) are optionally mono, di or tri substituted with R2a, R2b, R2c, identical or different; 14. -C(0)OH 15. -C(0)O linear, branched or cyclic alkyl optionally mono, di or tri substituted with R2a, R2b, R2c, identical or different; 16. -C(0)Oaryl optionally mono, di or tri substituted with R2a, R2b, R2c, identical or different; 17. -C(0)Oheteroaryl (5- or 6-membered heteroaryl with 1 to 4 heteroatoms chosen from N, S or O linked to oxygen by a C atom) optionally mono, di or tri substituted by R2a, R2b, R2c, identical or different; 18. -CONH2 19. -CO-heterocycloalkyl mono, di or tri substituted 20. -CONH(alkyl),CON(alkyl) ₂ linear(s), branched(s) or cyclic(s) whose alkyl part is optionally mono, di or tri substituted by R2a, R2b, R2c, identical or different; 21. -CON(alkyl)(aryl), linear, branched or cyclic alkyl whose alkyl and aryl parts are optionally mono, di or tri substituted with R2a, R2b, R2c, identical or different; 22. -CON(alkyl)(heteroaryl), linear, branched or cyclic alkyl and 5- or 6-membered heteroaryl with 1 to 4 heteroatoms chosen from N, S or O linked to the nitrogen atom either by a C or by an N) whose alkyl and hetroaryl parts are optionally mono, di or tri substituted with R2a, R2b, R2c, identical or different; 23. -C-I-C-IO linear, branched or cyclic alkyl optionally comprising a heteroatom and optionally mono, di or tri substituted by R2a, R2b, R2c, identical or different; 24. aryl optionally mono, di or tri substituted with R2a, R2b, R2c, identical or different; 25. heteroaryl (5 or 6 members with 1 to 4 heteroatoms chosen from N, S or O) linked to the carboline unit either by a C or by an N belonging to Z6, Z6 being optionally mono or poly substituted by R2a, R2b, R2c, R2d, R2e identical or different; 26. heterocycloalkyl optionally mono or poly substituted with R2a, R2b, R2c, identical or different; 27. -C2-C6 alkenyl optionally mono or disubstituted by R2a, R2b, identical or different; 28. -C2-C6 alkynyl optionally substituted with R2a; the groups R2a, R2b, R2c, R2d or R2e are chosen independently of each other from: 1. F; 2. Cl; 3.Br; 4.I; 5. -C-I-C-IO linear or branched alkyl optionally mono or poly substituted by R3a, R3b, R3c, identical or different 6. -C ₃ -C ₇ cycloalkyl optionally mono or poly substituted by R3a, R3b, R3c, identical or different, 7. -OH; 8. -O-alkyl (CrCio) linear, or branched optionally mono or poly substituted with R3a, R3b, R3c, identical or different; 9. -Y-alkyl (Y = S, SO, S02) linear or branched optionally mono, di or tri substituted with R3a, R3b, R3c, identical or different; 10. -O-cycloalkyl (C ₃ -C ₇ ) optionally mono or poly substituted with R3a, R3b, R3c, identical or different; 1 1 . -0-aryl optionally mono or poly substituted with R3a, R3b, R3c, identical or different; 12. aryl optionally mono or poly substituted with R3a, R3b, R3c, identical or different; 13. heteroaryl consisting of 5 or 6 members with 1 to 4 heteroatoms chosen from N, S or O linked either by a C or by an N) optionally mono or poly substituted by R3a, R3b, R3c, identical or different; 14. heterocycloalkyl optionally mono or poly substituted with R3a, R3b, R3c, identical or different; 15. -N0 ₂ ; 16. -NH ₂ ; 17. -NH-(alkyl (CrCio) or cycloalkyl (C ₃ -C ₇ ) or heterocycloalkyl) each group optionally mono or poly substituted by R3a, R3b, R3c, identical or different; 18. -N(alkyl(d-Cio) or cycloalkyl(C ₃ -C ₇ ))2 each group being optionally mono or poly substituted by R3a, R3b, R3c, identical or different; 19. -NHaryl or NH heteroaryl optionally mono or poly substituted by R3a, R3b, R3c, identical or different 20. -NHC(0) substituted by R3a, R3b, R3c, identical or different; 21. -N(alkyl(C Cio)C(0)substituted by R3a, R3b, R3c, identical or different; 22. -NHS(0 ₂ ) substituted by R3a, R3b, R3c, identical or different; 23. -N(alkyl(C Cio)S(0 ₂ )substituted by R3a, R3b, R3c, identical or different; 24. -C0 ₂ substituted by R3a, R3b, R3c, identical or different; 25. -Ssubstituted by R3a, R3b, R3c, identical or different; 26. -S(0 ₂ ) substituted by R3a, R3b, R3c, identical or different; 27. -S(O) substituted by R3a, R3b, R3c, identical or different; 28. oxo (O double bond); 29. -C2-C6 alkenyl optionally mono or disubstituted by identical or different R3a, R3b; 30. -C2-C6 alkynyl optionally substituted with R3a; the groups R3a, R3b, R3c, i.e. the substituents of the groups R2a, R2b, R2c, R2d or R2e, are chosen independently of one another from: 1. F; 2. Cl; 3.Br; 4.I; 5. -C-I-C-IO linear or branched alkyl optionally mono or poly substituted by R4a, R4b, R4c; 6. -C3-C7 cycloalkyl optionally mono or poly substituted with R4a, R4b, R4c; 7. -OH; 8. -O-alkyl (CrCio) linear or branched optionally mono or poly substituted by R4a, R4b, R4c; 9. -Y-alkyl (Y = S, SO, S02) linear or branched optionally mono, di or tri substituted with R4a, R4b, R4c; 10. -O-cycloalkyl (C ₃ -C ₇ ) optionally mono or poly substituted by R4a, R4b, R4c; 1 1 . -O-aryl optionally mono or poly substituted with R4a, R4b, R4c; 12. aryl optionally mono or poly substituted with R4a, R4b, R4c; 13. heteroaryl optionally mono or poly substituted with R4a, R4b, R4c; 14. heterocycloalkyl optionally mono or poly substituted by R4a, R4b, R4c; 15. -N0 ₂ ; 16. -NH ₂ ; 17. -NH-(alkyl (CrCio) or cycloalkyl (C ₃ -C ₇ ) or heterocycloalkyl) each group optionally mono or poly substituted by R4a, R4b, R4c; 18. -N(alkyl(d-Cio) or cycloalkyl(C ₃ -C ₇ ))2 each group being optionally mono or poly substituted by R4a, R4b, R4c; 19. -NHaryl or NH heteroaryl optionally mono or poly substituted with R4a, R4b, R4c; 20. -NHC(O) substituted with R4a, R4b, R4c; 21. -N(alkyl(C Cio)C(0) substituted by R4a, R4b, R4c; 22. -NHS(0 ₂ ) substituted by R4a, R4b, R4c; 23. -N(alkyl(C Cio)S(0 ₂ )substituted by R4a, R4b, R4c; 24. -C0 ₂ substituted by R4a, R4b, R4c;

26. -CONH(alkyl), CON(alkyl) ₂ linear(s), branched(s) or cyclic(s) whose alkyl part is optionally mono, di or tri substituted by R4a, R4b, R4c; 27. -C(0)heterocycloalkyl optionally mono, di or tri substituted with R4a, R4b, R4c; 28. -S substituted by R4a, R4b, R4c; 29. -S(0 ₂ ) substituted by R4a, R4b, R4c; 30. -S(O) substituted with R4a, R4b, R4c; 31. oxo (O double bond); 32. -C ₂ -C ₆ alkenyl optionally mono or poly substituted with R4a, R4b, R4c; 33. -C ₂ -C ₆ alkynyl optionally mono or poly substituted with R4a, R4b, R4c; the groups R4a, R4b, R4c, i.e. the substituents of the groups R3a, R3b and R3c, are chosen independently of one another from: 1. F; 2. Cl; 3.Br; 4.I; 5. -CF ₃ ; -CHF ₂ 6. -C ₁ -C ₁ 0 linear or branched alkyl; 7. -C ₃ -C ₇ cycloalkyl; 8. -OH; 9. -0-alkyl (Ci-Cio) linear or branched; 10. -Y-alkyl (Y = S, SO, S02) linear or branched; 1 1 . -O-cycloalkyl (C3-C7); 12. -0-aryl; 13. aryl; 14. heteroaryl; 15. heterocycloalkyl;

18. -NH-((C Cio) alkyl or (C ₃ -C ₇ ) cycloalkyl or heterocycloalkyl); 19. -N(alkyl(C Cio) or cycloalkyl(C ₃ -C ₇ ))2; 20. -NHaryl or NH heteroaryl; 21. -NHS(0 ₂ )alkyl; 22. -N(alkyl(C Cio)S(0 ₂ )alkyl; 23. -C0 ₂ alkyl; 24. -CONH ₂ 25. -CONH(alkyl), CON(alkyl) ₂ linear(s), branched(s) or cyclic(s); 26. -C(0)heterocycloalkyl; 27. -S-alkyl; 28. -S(0 ₂ )alkyl; 29. -S(0)alkyl; 30. oxo (O double bond); 31. -C ₂ -C ₆ linear or branched alkenyl; 32. -C ₂ -C ₆ linear or branched alkynyl; said products of formula (I) being in all possible isomeric, racemic, enantiomeric and diastereomeric forms, as well as the addition salts with mineral and organic acids or with the mineral and organic bases of said products of formula (I) . 5 - Products of formula (I) as defined in any one of the preceding claims whose names follow: - 6-methoxy-3-(pyridin-3-yl)-9H-beta-carboline - 3-(pyridin-3-yl)-9H-beta-carboline - 6-bromo-3-(pyridin-3-yl)-9H-beta-carboline - Methyl 3-(pyridin-3-yl)-9H-beta-carboline-6-carboxylate - 6-methoxy-3-(5-methoxypyridin-3-yl)-9H-beta-carboline - 5-(6-methoxy-9H-beta-carbolin-3-yl)pyridin-2-amine - 3-(pyrimidin-5-yl)-9H-beta-carboline - 6-methoxy-3-(6-methoxypyridin-3-yl)-9H-beta-carboline - 6-methoxy-3-[6-(methylsulfanyl)pyridin-3-yl]-9H-beta-carboline - 3-(pyridin-3-yl)-6-(trifluoromethyl)-9H-beta-carboline - 3-(pyridin-3-yl)-6-(trifluoromethoxy)-9H-beta-carboline - 6-fluoro-3-(pyridin-3-yl)-9H-beta-carboline -N,N-diethyl-2-{4-[3-(pyridin-3-yl)-9H-beta-carbolin-6-yl]-1 H-pyrazol-1 - yl}ethanamine - N,N-diethyl-2-{4-[3-(1 -methyl-1 H-pyrazol-4-yl)-9H-beta-carbolin-6-yl]-1 H-pyrazol- 1 -yl} ethanamine - 6-{4-[3-(piperidin-1 -yl)propoxy]phenyl}-3-(pyridin-3-yl)-9H-beta-carboline 3-(1-methyl-1H-pyrazol-4-yl)-6-{4-[3-(piperidin-1-yl)propoxy]phenyl}-9H-beta-carboline - 6-(difluoromethoxy)-3-(pyridin-3-yl)-9H-beta-carboline - 6-(difluoromethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-beta-carboline - 6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-beta-carboline 6 - Process for preparing the products of formula (I) as defined in the preceding claims, characterized by the general diagram below:

in which the substituents Z3 and Z6 have the meanings indicated for the products of formula (I) in any one of the preceding claims, the possibly reactive functions of Z3 and Z6 being optionally protected by known protective groups. 7- As medications, the products of formula (I) as defined in claims 1 to 4 as well as their prodrugs, said products of formula (I) being in all possible racemic isomeric, enantiomeric and diastereomeric forms, as well as as the addition salts with mineral and organic acids or with pharmaceutically acceptable mineral and organic bases of said products of formula (I). 8- As medicines, the products of formula (I) as defined in claims 1 to 4 whose names follow: - 6-methoxy-3-(pyridin-3-yl)-9H-beta-carboline - 3-(pyridin-3-yl)-9H-beta-carboline - 6-bromo-3-(pyridin-3-yl)-9H-beta-carboline - Methyl 3-(pyridin-3-yl)-9H-beta-carboline-6-carboxylate - 6-methoxy-3-(5-methoxypyridin-3-yl)-9H-beta-carboline - 5-(6-methoxy-9H-beta-carbolin-3-yl)pyridin-2-amine - 3-(pyrimidin-5-yl)-9H-beta-carboline - 6-methoxy-3-(6-methoxypyridin-3-yl)-9H-beta-carboline - 6-methoxy-3-[6-(methylsulfanyl)pyridin-3-yl]-9H-beta-carboline - 3-(pyridin-3-yl)-6-(trifluoromethyl)-9H-beta-carboline - 3-(pyridin-3-yl)-6-(trifluoromethoxy)-9H-beta-carboline - 6-fluoro-3-(pyridin-3-yl)-9H-beta-carboline N,N-diethyl-2-{4-[3-(pyndin-3-yl)-9H-beta-carbolin-6-yl]-1 H-pyrazol-1 - yl}ethanamine - N,N-diethyl-2-{4-[3-(1 -methyl-1 H-pyrazol-4-yl)-9H-beta-carbolin-6-yl]-1 H-pyrazol- 1 -yl} ethanamine - 6-{4-[3-(piperidin-1 -yl)propoxy]phenyl}-3-(pyridin-3-yl)-9H-beta-carboline 3-(1-methyl-1H-pyrazol-4-yl)-6-{4-[3-(piperidin-1-yl)propoxy]phenyl}-9H-beta-carboline - 6-(difluoromethoxy)-3-(pyridin-3-yl)-9H-beta-carboline - 6-(difluoromethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-beta-carboline - 6-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-beta-carboline 9 - Pharmaceutical compositions containing as active principle, a compound according to any one of the preceding claims as well as at least one pharmaceutically compatible excipient. 10 - Pharmaceutical compositions according to the preceding claim used for the treatment of cancer. 11 - As new industrial products, the synthesis intermediates of formula (XIV) as defined in the general diagram of claim 6 and

in which the substituents Z3 and Z6 have the meanings indicated for the products of formula (I) in any one of the preceding claims, the possibly reactive functions of Z3 and Z6 being optionally protected by known protective groups.