9H-PYRROLO[2,3-B:5,4-C'1DIPYRIDINE AZACARBOLINE DERIVATIVES-
PREPARATION THEREOF AND THERAPEUTIC USE THEREOF
The present invention relates to 9H-pyrrolo [2,3-b:5,4-c']dipyridine α-aza-β-carboline
derivatives, to their preparation and to their therapeutic use. The α-aza-β-carbolines
are defined by the 1,7-diazacarbazole or 8-aza-β-carboline derivatives; in the French
IUPAC nomenclature (use of ACD/Name 12.00), the name of this tricyclic unit is 9H-
pyrrolo[2,3-b:5,4-c']dipyridine.
The present invention is directed towards compounds that act on protein kinases, for
instance: CHK1, CDK1, CDK2, dyrk2, Flt3, GSK3 beta, MNK2, PDGFR beta, PI3K,
PIM1, PIM2, PIM3, PLK, TrkB, all of which are involved in the development of
cancers. More particularly, the present invention is directed towards compounds that
act on a target known as Pirn, which is involved in the development of cancers.
The Pirn kinases, including 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 via which the Pirn kinases can increase the
survival of cancer cells and promote the development of cancer proceeds via
modulation of the activity of BAD, a key regulator of apoptosis. The Pirn kinases are
mutually highly homogeneous and display similar oncogenic behaviour.
Clinical reports underline the importance of the role of the Pirn kinases in the
development of human cancers:
The Pirn kinases, in particular Pim-1 and Pim-2, have been found to be abnormally
expressed in a large number of malignant haematological diseases. Amson et al.
report the overexpression of Pim-1 in acute myeloid leukaemia and acute lymphoid
leukaemia, and that the overexpression of Pim-1 appears to result from an untoward
activation in various leukaemias (Proc. Natl. Acad. Sci., Vol. 86., 8857-8861 (1989)).
Studies have demonstrated the overexpression of Pim-1 in primitive and metastatic
lymphoma of the CNS, an aggressive form of non-Hodgkin lymphoma (Rubenstein et
al., Blood, Vol. 107, No. 9, 3716-3723 (2006)). Huttmann et al. have also discovered
an overexpression of Pim-2 in chronic B-cell lymphocytic leukaemia and suggest that
upregulation of Pim-2 may be associated with a more aggressive development of the

disease (Leukemia, 20, 1774-1782 (2006)). An abnormal expression of Pim-1 and of
Pim-2 has been associated with 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, p.341-346 (2001)) and in standard and
nodular Hodgkin lymphoma with a lymphocytic predominance (Liso et al., Blood, Vol.
108, No. 3, 1013-1020 (2006)).
Many studies have also linked an abnormal expression of the Pirn kinases to various
non-haematological human cancers (prostate, pancreas, head and neck, etc.) and
their presence is often associated with a more aggressive phenotype. For example,
Pim-1 and Pim-2 have both 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 the case of patients suffering from a prostate carcinoma and in high-
grade intraepithelial prostate neoplasia (precancerous lesions) (The Prostate, (60)
367-371 (2004)), whereas Dai et al. suggest that the overexpression of Pim-2 in
prostate cancer is associated with more aggressive clinical characteristics (The
Prostate, 65:276-286 (2005)). Xie et al. have discovered that the 44 kDa Pim-1 (Pim-
1L) was significantly upregulated in samples of human prostate tumour, and indicate
that Pim-1 L has an anti-apoptotic effect on human prostate cancer cells in response
to chemotherapeutic drugs (Oncogene, 25, 70-78 (2006)).
Pim-2 is linked to perineural invasion (PNI), during which the cancer cells become
wound around nerves, which is often found in certain cancers such as prostate
cancer, pancreatic cancer, cancer of the bile ducts and cancer of the 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 murine hepatocarcinomas and human
pancreatic cancer tissues (Cancer Res. 66 (13), 6741-6747 (2006)). An aberrant
expression of Pim-3 has also been observed in gastric adenoma and the metastatic
sites of gastric carcinoma (Zheng et al., J. Cancer Res. Clin. Oncol., 134:481-488
(2008)).
Together, these reports suggest that Pirn kinase inhibitors are useful for treating
cancer, especially leukaemias, lymphomas, myelomas and various solid tumours,
especially cancers of the head and neck, bowel cancer, prostate cancer, pancreatic

cancer, liver cancer and oral cancer, for example. Insofar as cancer remains a
disease for which the existing treatments are insufficient, it is manifestly necessary to
identify novel Pirn kinase inhibitors that are effective for treating cancer.
Among the patent applications claiming compounds of the azacarboline class, which
is the subject of our invention, mention may be made of the following documents:
Patent application WO 2007/044 779 describes 9H-pyrrolo[2,3-b:5,4-c']dipyridines or
α-aza-β-carbolines of the following general formula, which is partially restricted,
relative to the application as published:

in which - Z5, Z4 and Z3 may represent C and
- Z and Z2 may also represent C,
- Z1 may finally represent C or N and
- R2 may represent a carbon bond or an alkylene radical, each
possibly being substituted with several possibilities, including heteroaryloxy,
heteroaryl(C1-C5)alkyl, heteroaryls and heterobicycloaryls.
The preparation process and all the examples of this application are limited to
derivatives substituted in positions 2 and 8 and optionally in position 5.
Patent EP 1 209 158 claims compounds having the following formula:


in which B6, B7, B8, B9 may represent C or N, but R7 never represents a heteroaryl.
The activity of the compounds of this invention is particularly directed towards the
treatment of heart problems.
The present invention relates to compounds of general formula (I) below:

in which
- Z2, Z3, Z4, which may be identical or different, represent CH, CRa, CRs or N;
- R3 is chosen from:

1. H;
2. halogen (F, CI, Br, I);
3. -CF3,-CHF2;
4. -OH
5. alkoxy in which the alkyl part is optionally mono-, di- or trisubstituted;
6. -NH2, -NH(alkyl), -N(alkyl)2 in which the alkyl part is optionally mono-, di-
or trisubstituted;
7. -C(O)Oalkyl optionally mono-, di- or trisubstituted;
8. -CONH(alkyl), CON(alkyl)2 in which the alkyl part is optionally mono-, di-
or trisubstituted;
9. linear, branched or cyclic C1-C10 alkyl optionally comprising a heteroatom
and optionally mono-, di- or trisubstituted;
10. aryl or heteroaryl optionally mono-, di- or trisubstituted;

- R6 being a heteroaryl (5- or 6-membered with 1 to 4 heteroatoms chosen from N, S
and 0) linked to the azacarboline unit either via a C or via an N belonging to R6, R6
being optionally mono- or polysubstituted;
- Ra being necessarily chosen from:

1. -CONH2,
2. -CONHalkyl, CONHcycloalkyl optionally mono-, di- or trisubstituted;
3. -CONHheterocycloalkyl optionally mono-, di- or trisubstituted;
4. -CON(alkyl)2 optionally mono-, di- or trisubstituted;
5. -CON(alkyl)(heterocycloalkyl) optionally mono-, di- or trisubstituted;
6. -CONHN(alkyl)2 in which the alkyl part is optionally mono-, di- or
trisubstituted;
7. -C(O)heterocycloalkyl, the heterocycloalkyl radical containing at least one
nitrogen atom linked to C(O); and being optionally mono-, di- or
trisubstituted;
- Rs being chosen from the following groups:
1. H;
2. F; CI; Br; I
3. -OH;
4. linear or branched -O-(C1-C10)alkyl optionally mono- or polysubstituted;
5. -NH2;
6. -N(alkyl(C1-C10) or cycloalkyl(C3-C7))2, each group being optionally mono-
or polysubstituted;
7. -NHC(O)R3a;
8. -N(alkyl(C1-C10)C(O)R3a;
9. -NHS(O2)R3a;
10. -N(alkyl(C1-C10)S(O2)R3a;
11.-CO2R3a;
12. -SR3a; -S(O)R3a;-S(O2)R3a
Ra and Rs possibly forming a 4- to 7-membered ring substituted with an oxo radical,
comprising at least one nitrogen atom and optionally another heteroatom chosen
from N, O and S and optionally substituted with one or more radicals chosen from
oxo, F, CI, Br, I, CF3, CHF2, alkyl, OH, Oalkyl, NO2, NH2, NHAlk and N(Alk)2
radicals;

R3a being chosen from:
1. F; CI; Br; I
2. -CF3;
3. linear or branched C1-C10 alkyl
4. -C3-C7 cycloalkyl;
5. -C2-C6 alkenyl;
6. -C2-C6 alkynyl;
7. -OH;

8. linear or branched (C1-C10) or cyclic (C3-C7) -O-alkyl;
9. heterocycloalkyl (C3-C7);

10. -NH2;
11. -NH-(alkyl(C1-C10) or cycloalkyl(C3-C7));
12. -N(alkyl(C1-C10) or cycloalkyl(C3-C7))2;

13. -NH-(alkyl(C1-C10) or heterocycloalkyl (C3-C7));
14. -N(alkyl(C1-C10) or heterocycloalkyl (C3-C7))2;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and organic
acids or with mineral and organic bases of the said products of formula (I).
The products of formula (I) according to the present invention are such that the ring
hereinbelow:

bears only one substituent Ra and only one substituent Rs as defined above, Ra and
Rs being linked to the carbon chain units or to Z2, Z3 or Z4 when they represent a
carbon chain unit.
One subject of the present invention is thus the compounds as defined above,
characterized in that the possible substituents of R3, R6 and Ra are chosen from the
groups R2a, R2b and R2c chosen, independently of each other, from:
1. F;

2. CI;
3. Br;
4. I;
5. -CF3;-CHF2
6. linear or branched C1-C10 alkyl optionally mono- or polysubstituted;
7. -C3-C7 cycloalkyl optionally mono- or polysubstituted;
8. -OH;
9. linear or branched -0-(C1-C10)alkyl optionally mono- or polysubstituted;
10.-O-cycloalkyl (C3-C7) optionally mono- or polysubstituted;
11 .-O-aryl optionally mono- or polysubstituted;
12. aryl optionally mono- or polysubstituted;
13. heteroaryl optionally mono- or polysubstituted;
14.heterocycloalkyl optionally mono- or polysubstituted;
15.-NO2;
I6.-NH2;
17.-NH-(alkyl(C1-C10) or cycloalkyl(C3-C7) or heterocycloalkyl), each group
optionally mono- or polysubstituted;
18.-N(alkyl(C1-C10) or cycloalkyl(C3-C7))2, each group being optionally mono-
or polysubstituted;
19. -NHaryl or NH heteroaryl optionally mono- or polysubstituted
20. -NHC(O)substituted;
21.-N(alkyl(C1-C10)C(O)substituted;
22.-NHS(O2)substituted;
23.-N(alkyl(C1-C10)S(O2)substituted;
24.-CO2substituted;
25. -Ssubstituted;
26.-S(O2)substituted;
27.-S(O) substituted;
28. oxo (double bond O);
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and organic
acids or with mineral and organic bases of the said products of formula (I).

One subject of the present invention is thus the compounds as defined above,
characterized in that the optional substituents of all the substituted groups and of the
groups Rs, R2a, R2b and R2c or the groups are chosen from:
1. F; CI; Br; I
2. -CF3;
3. linear or branched C1-C10 alkyl
4. -C3-C7 cycloalkyl;
5. -C2-C6 alkenyl;
6. -C2-C6 alkynyl;
7. -OH;
8. linear or branched (C1-C10) or cyclic (C3-C7) -O-alkyl;
9. heterocycloalkyl (C3-C7);
10.-NH2;
11 .-NH-(alkyl(C1-C10) or cycloalkyl(C3-C7));
12.-N(alkyl(C1-C10) or cycloalkyl(C3-C7))2;
13.-NH-(alkyl(C1-C10) or heterocycloalkyl (C3-C7));
14.-N(alkyl(C1-C10) or heterocycloalkyl (C3-C7))2;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and organic
acids or with mineral and organic bases of the said products of formula (I).
One subject of the present invention is thus the compounds of general formula (I) as
defined above, in which
- Z2, Z3, Z4, which may be identical or different, represent CH, CRa, CRs or N;
- R3 is chosen from:

1. H;
2. halogen (F, CI, Br, I);
3. -CF3, -CHF2;
4. -OH
5. alkoxy in which the alkyl part is optionally mono-, di- or trisubstituted with
R2a, R2b, R2c;

6. -NH2, -NH(alkyl), -N(alkyl)2 in which the alkyl part is optionally mono-, di-
or trisubstituted with R2a, R2b, R2c;
7. -C(O)Oalkyl optionally mono-, di- or trisubstituted with R2a, R2b, R2c;
8. -CONH(alkyl), CON(alkyl)2 in which the alkyl part is optionally mono-, di-
or trisubstituted with R2a, R2b, R2c;
9. linear, branched or cyclic C1-C10 alkyl optionally comprising a heteroatom
and optionally mono-, di- or trisubstituted with R2a, R2b, R2c;
10. aryl or heteroaryl optionally mono-, di- or trisubstituted with R2a, R2b,
R2c;
- R6 being a heteroaryl (5- or 6-membered with 1 to 4 heteroatoms chosen
from N, S and O) linked to the azacarboline unit either via a C or via an N belonging
to R6, R6 being optionally mono- or polysubstituted with R2a, R2b, R2c;
- Ra necessarily being:
1. -CONH2,
2. -CONHalkyl, CONHcycloalkyl optionally mono-, di- or trisubstituted with
R2a, R2b, R2c;
3. -CONHheterocycloalkyl optionally mono-, di- or trisubstituted with R2a,
R2b, R2c;
4. -CON(alkyl)2 optionally mono-, di- or trisubstituted with R2a, R2b, R2c;
5. -CON(alkyl)(heterocycloalkyl) optionally mono-, di- or trisubstituted with
R2a, R2b, R2c;
6. -CONHN(alkyl)2 in which the alkyl part is optionally mono-, di- or
trisubstituted with R2a, R2b, R2c;
7. -C(O)heterocycloalkyl, the heterocycloalkyl radical containing at least
one nitrogen atom linked to C(O); and being optionally mono-, di- or
trisubstituted;
- Rs being chosen from the following groups:
1. H;
2. F; CI; Br; I
3. -OH;
4. linear or branched -0-(C1-C10)alkyl optionally mono- or polysubstituted
with identical or different groups R3a;
5. -NH2;

6. -N(alkyl(C1-C10) or cycloalkyl(C3-C7))2, each group being optionally
mono- or polysubstituted with identical or different groups R3a;
7. -NHC(O)R3a;
8. -N(alkyl(C1-C10)C(O)R3a;
9. -NHS(O2)R3a;
10. -N(alkyl(C1-C10)S(O2)R3a;
11. -CO2R3a;
12. -SR3a; -S(O)R3a; -S(O2)R3a
Ra and Rs may optionally form a 5- to 6-membered ring substituted with an oxo
radical and comprising at least one nitrogen atom and optionally substituted with one
or more radicals chosen from oxo, F, CI, Br, I, CF3, CHF2, alkyl, OH, Oalkyl, NO2,
NH2, NHAlk and N(Alk)2 radicals;
The groups R2a, R2b or R2c are chosen, independently of each other, from:
1. F;
2. CI;
3. Br;
4. I;
5. -CF3;-CHF2
6. linear or branched C1-C10 alkyl optionally mono- or polysubstituted with
identical or different groups R3a;
7. -C3-C7 cycloalkyl optionally mono- or polysubstituted with identical or
different groups R3a;
8. -OH;
9. linear or branched -0-(C1-C10)alkyl optionally mono- or polysubstituted
with identical or different groups R3a;
10.-O-cycloalkyl (C3-C7) optionally mono- or polysubstituted with identical or
different groups R3a;
11 .-O-aryl optionally mono- or polysubstituted with different groups R3a;
12. aryl optionally mono- or polysubstituted with identical or different groups
R3a;
13. heteroaryl optionally mono- or polysubstituted with identical or different
groups R3a;

14. heterocycloalkyl optionally mono- or polysubstituted with identical or
different groups R3a;
15.-NO2
I6.-NH2;
17.-NH-(alkyl(C1-C10) or cycloalkyl(C3-C7) or heterocycloalkyl), each group
optionally mono- or polysubstituted with identical or different groups R3a;
18.-N(alkyl(C3-C10) or cycloalkyl(C3-C7))2, each group being optionally mono-
or polysubstituted with identical or different groups R3a;
19. NHaryl or NH heteroaryl optionally mono- or polysubstituted with identical
or different groups R3a
20. NHC(O)R3a;
21. N(alkyl(C1-C10)C(O)R3a;
22. NHS(O2)R3a;
23. N(alkyl(C1-C10)S(O2)R3a;
24. CO2R3a;
25. SR3a; S(O)R3a; S(O2)R3a;
26. N(alkyl(C1-C10) or cycloalkyl (C3-C7))2, each group being optionally mono-
or polysubstituted with identical or different groups R3a;
27. oxo (C3ouble bond O);
The possible substituents of the groups R2a, R2b and R2c or the groups R3a are
chosen from:
2. F; CI; Br; I
3. -CF3;
4. linear or branched C1-C10 alkyl
5. -C3-C7 cycloalkyl;
6. -C2-C6 alkenyl;
7. -C2-C6 alkynyl;
8. -OH;
9. linear or branched (C1-C10) or cyclic (C3-C7) -O-alkyl;
10. heterocycloalkyl (C3-C7);
11. -NH2;

12. -NH-(alkyl(C1-C10) or cycloalkyl(C3-C7));
13. -N(alkyl(C1-C10) or cycloalkyl(C3-C7))2;
14. -NH-(alkyl(C1-C10) or heterocycloalkyl (C3-C7));
15. -N(alkyl(C1-C10) or heterocycloalkyl (C3-C7))2.
In the context of the present invention, positions 2 and 8 should not be substituted, in
contrast with the prior art documents.
The substituents Ra and Rs as defined above are, respectively, and without
preference, linked to any of the carbons of the ring below:
in which Z2, Z3 and Z4 have the meanings indicated above.
A subject of the present invention is particularly the products of formula I belonging
to formula la:
in which Z2 represents CH, Z4 represents -C-Ra and R3, R6, Ra and Rs have any
of the meanings given above and Z3 represents CH or N,
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and organic
acids or with mineral and organic bases of the said products of formula (I).
A subject of the present invention is particularly the products of formula I belonging
to formula lb:


in which Rs represents a hydrogen atom, Z2 and Z3 represent CH, Z4 represents
-C-Ra and R3, R6 and Ra have any of the meanings given above, the said products
of formula (I) being in any possible racemic, enantiomeric or diastereoisomeric
isomer form, and also the addition salts with mineral and organic acids or with
mineral and organic bases of the said products of formula (I).
A subject of the present invention is particularly the products of formula I belonging
to formula Ic:
in which Rs represents a hydrogen atom, Z2 and Z3 represent CH, Z4 represents
-C-Ra, R6 represents a pyridyl radical optionally mono- or polysubstituted with one
or more identical or different radicals Rp chosen from F, CI, Br, I, CF3, CHF2, alkyl,
OH, Oalkyl, NO2, NH2, NHAlk and N(Alk)2 radicals and R3 and Ra have any of the
meanings given above, the said products of formula (I) being in any possible
racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts
with mineral and organic acids or with mineral and organic bases of the said
products of formula (I).
A subject of the present invention is particularly the products of formula I belonging
to formula Id:


in which Rs represents a hydrogen atom, Z2 and Z3 represent CH, Z4 represents
-C-Ra, R6 represents a pyrazolyl radical optionally mono- or polysubstituted with one
or more identical or different radicals Rp chosen from F, CI, Br, I, CF3, CHF2, alkyl,
OH, Oalkyl, NO2, NH2, NHAlk and N(Alk)2 radicals and R3 and Ra have any of the
meanings given above, the said products of formula (I) being in any possible
racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts
with mineral and organic acids or with mineral and organic bases of the said
products of formula (I).
The following terms used herein above or hereinbelow have the following meanings:
- Alkyl, alkyl(C3-C10) or C1-C10 alkyl means any linear or branched, saturated carbon
chain of 1 to 10 carbons.
- Aryl means phenyl or naphthyl.
- Heteroaryl means any 5- or 6-membered aromatic monocycle containing at least
one heteroatom (N, O, S), especially: pyridine, pyrimidine, imidazole, pyrazole,
triazole, thiophene, furan, thiazole, oxazole, etc., and also aromatic bicyclic systems
containing at least one heteroatom (N, O, S), especially indole, benzimidazole,
azaindole, benzofuran, benzothiophene, quinoline, tetrazole
- Heterocycloalkyl means any non-aromatic monocycle or bicycle (spiro or non-spiro)
containing at least one heteroatom (N, O, S in the different possible oxidation states)
with or without unsaturation, especially: morpholine, piperazine, piperidine, pyrroli-
dine, 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]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, and especially hexahydropyrrolo[3,4-b]pyrrole, 2,7-
diazaspiro[4,4]nonane and octahydropyrrolo[3,4-c]pyridine.
- Cycloalkyl(C3-C7) means any non-aromatic ring formed solely from carbon atoms,
especially cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane; but
also possibly bearing an unsaturation, for example cyclopentene, cyclohexene,
cycloheptene or bicyclo[2.2.1]heptane.
- C1-C10 alkylhydroxy means any linear or branched, saturated carbon chain of 1 to
10 carbons bearing at least one hydroxyl group (OH).
- C1-C10 alkoxy means any linear or branched, saturated carbon chain of 1 to 10
carbons bearing at least one ether function (C-O-C).
- C1-C10 alkylamino means any linear or branched, saturated carbon chain of 1 to 10
carbons bearing at least one amine (primary, secondary or tertiary) function.
A subject of the present invention is especially the products of formula (I) as defined
above, the names of which are as follows:
- 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(1H-tetrazol-5-yl-
methyl)benzamide
[(3R)-3-(dimethylamino)pyrrolidin-1-yl]{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]phenyl}methanone
- {4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]phenyl}[(3aS,6aS)-
5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]methanone
- N-[2-(acetylamino)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-
4-yl]benzamide
- 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[3-(2-oxopyrroli-
din-1-yl)propyl]benzamide
4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(phenyl-
amino)ethyl]benzamide
N-[(1-ethylpyrrolidin-2-yl)methyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide

- N-[3-(dimethylamino)-2,2-dimethylpropyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]benzamide
N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]benzamide
- N-(1-ethylpiperidin-3-yl)-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-
4-yl]benzamide
4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(2-methyl-
piperidin-1-yl)ethyl]benzamide
4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(1-methyl-
azetidin-3-yl)benzamide
[3-(dimethylamino)piperidin-1-yl]{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]phenyl}methanone
- 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-methyl-2-(pyr-
rolidin-1-yl)propyl]benzamide
N-[3-(dimethylamino)propyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]-N-methylbenzamide
- N-[2-(azepan-1-yl)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-
4-yl]benzamide
4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(1-methyl-
piperidin-4-yl)ethyl]benzamide
4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-[(methyl-
sulfonyl)amino]ethyl}benzamide
- 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(pyrrolidin-1-
yl)propyl]benzamide
4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-methyl-N-[(1-
methylpiperidin-2-yl)methyl]benzamide
- 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(1-methy!pyr-
rolidin-2-yl)ethyl]benzamide
N-[2-(dipropan-2-ylamino)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
- N-[2-(dimethylamino)ethyl]-N-ethyl-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
- N-[1-(dimethylamino)propan-2-yl]-4-t3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide

[(3S)-3-(dimethylamino)pyrrolidin-1-yl]{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]phenyl}methanone
4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-methyl-N-(1-
methylpyrrolidin-3-yl)benzamide
N-[2-(diethylamino)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]-N-methylbenzamide
{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]phenyl}[4-(2-
methoxyethyl)piperazin-1-yl]methanone
4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[(3-methyl-1H-
pyrazol-4-yl)methyl]benzamide
- {4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]phenyl}(2-methyl-
octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)methanone
N-[4-(dimethylamino)butyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyrid in-4-yl) be nza m ide
- 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(1H-imidazol-2-
ylmethyl)benzamide
- {4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]phenyl}(7-methyl-
2,7-diazaspiro[4.4]non-2-yl)methanone
- 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(pyridin-2-yl-
amino)ethyl]benzamide
N-ethyl-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[(1-
methylpyrrolidin-3-yl)methyl]benzamide
- 1,3'-bipyrrolidin-1 '-yl{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-
yl]phenyl}methanone
4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-methyl-N-(1-
methyIpiperidin-4-yl)benzamide
- 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[(2-hydroxypyri-
din-4-yl)methyl]benzamide
- N-[2-(ethylamino)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-
4-yl]benzamide
4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(methyl-
amino)ethyl]benzamide
N-[(1-aminocyclopropyl)methyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide

- N-(3-amino-2,2-difluoropropyl)-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]benzamide
N-(2-amino-3,3,3-trifluoro-2-methylpropyl)-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridin-4-yl]benzamide
N-[(1R,2R)-2-aminocyclohexyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
- N-[(1S,2S)-2-aminocyclohexyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]benzamide
N-[(1S,2S)-2-aminocyclopentyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
N-[(1R,2R)-2-aminocyclopentyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
- 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(4-
methylpiperazin-1-yl)benzamide
- 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(1-
methylpiperidin-4-yl)benzamide
- 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-
[(3R)-3-hydroxypyrrolidin-1-yl]ethyl}benzamide
- 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-
[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}benzamide
- 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(2-
hydroxyethyl)benzamide
- N-[(1S,2S)-2-aminocyclohexyl]-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- N-[(1S,2S)-2-(diethylamino)cyclohexyl]-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- N-[(1S,2S)-2-(ethylamino)cyclohexylH-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benz-
amide
- 4-[6-(5-chloro-1-methyl-1H-pyrazol-4-yl)-3-fluoro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-
yl]-N-(4-methylpiperazin-1-yl)benzamide
- 4-[6-(5-chloro-1-methyl-1H-pyrazol-4-yl)-3-fluoro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-
yl]-N-(1-methylpiperidin-4-yl)benzamide

- N-[2-(dimethylamino)ethyl]-4-[3-(2-methoxyethoxy)-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]benzamide
N-[2-(dimethylamino)ethyl]-5-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]pyridine-2-carboxamide
- N-[2-(dimethylamino)ethy[]-2-fluoro-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide.
A subject of the present invention is also the products of formula (I) as defined
above, the names of which are as follows:
- N-(2-aminoethyl)-4-[3-(2-methoxyethoxy)-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- N-(2-aminoethyl)-4-[6-(1-methyl-1H-pyrazol-4-yl)-3-(oxetan-3-yloxy)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]benzamide
- N-[(1 S,2S)-2-aminocyclopentyl]-4-[3-(2-methoxyethoxy)-6-(1-methyl-1 H-pyrazol-4-
yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
N-[(1S,2S)-2-(ethylamino)cyclopentyl]-4-[3-(2-methoxyethoxy)-6-(1-methyl-1H-
pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- 4-[6-(1-ethyl-1H-pyrazol-4-yl)-3-methoxy-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(2R)-pyrrolidin-2-ylmethyl]benzamide
N-[(1 S,2S)-2-(cyclopropylamino)cyclohexyl]-4-[3-fluoro-6-(1 -methyl-1 H-pyrazol-4-
yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
N-[(1 S,2S)-2-aminocyclohexyl]-4-[3-methoxy-6-(1-methyl-1 H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yi]benzamide
- 4-[6-(1-methyl-1H-pyrazol-4-yl)-3-(oxetan-3-yloxy)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-
4-yl]-N-[(2R)-pyrrolidin-2-ylmethyl]benzamide
- 4-t3-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(2S)-pyrrolidin-2-ylmethyl]benzamide
4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{[(2R,3R)-3-
hydroxypyrrolidin-2-yl]methyl}benzamide
N-[(3R,4R)-4-aminotetrahydrofuran-3-yl]-4-[3-(2-methoxyethoxy)-6-(pyridin-3-yl)-
9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- N-[(1 R,2R)-2-(ethylamino)cyclohexyl]-4-[3-methoxy-6-(1-methyl-1 H-pyrazol-4-yl)-
9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- N-{[(2R,3R,4S)-3,4-dihydroxypyrrolidin-2-yl]methyl}-4-[3-methoxy-6-(1-methyl-1H-
pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide

N-[(1 S,2S)-2-hydroxycyclohexyl]-4-[3-methoxy-6-(1-methyl-1 H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- N-({4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-
phenyl}carbonyl)-p-D-galactopyranosylamine
- N-[(3R,4R)-4-aminotetrahydrofuran-3-yl]-4-[3-fluoro-6-(1 -methyl-1 H-pyrazol-4-yl)-
9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
N-[(1S,2R,3S,4S)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl]-4-[3-fluoro-6-(1-
methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolot2,3-b:5,4-c']dipyridin-4-yl]-N-
[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(1S,2S)-2-hydroxycyclopentyl]benzamide
N-[(1 R)-7-azaspiro[3.5]non-1-yl]-4-[3-f!uoro-6-(1-methyl-1 H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
N-[(1 S)-7-azaspiro[3.5]non-1-yl]-4-[3-fluoro-6-(1-methyl-1 H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(1S,2S)-2-hydroxycyclohexyl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(3S,4S)-4-hydroxypyrrolidin-3-yl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yi]-N-
[(3R,4R)-4-hydroxypyrrolidin-3-yl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(3S,4R)-4-hydroxypyrrolidin-3-yl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(3R,4S)-4-hydroxypyrrolidin-3-yl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(3R,4R)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(3R,4S)-4-hydroxy-1,1-dioxidotetrahydrothiophen-3-yl]benzamide
- 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-
[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]ethyl}benzamide
- 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-
[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]ethyl}benzamide

4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(1S,3R)-3-hydroxycyclopentyl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(1R,3R)-3-hydroxycyclopentyl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(1S,3S)-3-hydroxycyclopentyl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(1R, 3S)-3-hyd roxycyclo pe nty I] benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(1S,2R)-2-(hydroxymethyl)cyclopentyl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(1S,2R)-2-(hydroxymethyl)-1-methylcyclopentyl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(2S,3R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(2R,3S)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]benzamide
- 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-
[(2R)-2-(hydroxymethyl) pi peridin-1 -yi]ethyl}benzamide
- 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-
t(2S)-2-(hydroxymethyl)piperidin-1-yl]ethyl}benzamide
- 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-
t(3S)-3-(hydroxymethyl)piperidin-1-yl]ethyl}benzamide
- 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-
[(3R)-3-(hydroxymethyl)piperidin-1-yl]ethyl}benzamide
- 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-
[(3S)-3-hydroxypiperidin-1-yl]ethyl}benzamide
- 4-[3-fluora-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-
[(3R)-3-hydroxypiperidin-1-yl]ethyl}benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(1S,2S)-2-(hydroxymethyl)cyclohexyl] benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(1R,2R)-2-(hydroxymethyl)cyclohexyl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(2R,3R)-3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]benzamide

N-[(1 R,3R)-5-azaspiro[2.4]hept-1-yl]-4-[3-fluoro-6-(1-methyl-1 H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']clipyriclin-4-yl]ben2amide
N-[(1 R,3S)-5-azaspiro[2.4]hept-1-yl]-4-[3-fluoro-6-(1-methyl-1 H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
N-[(1S,3R)-5-azaspiro[2.4]hept-1-yl]-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
N-[(1S,3S)-5-azaspiro[2.4]hept-1-yl]-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
N-[(1 R,3R)-5-azaspiro[2.5]oct-1-yl]-4-[3-fluoro-6-(1-methyl-1 H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
N-[(1 R,3S)-5-azaspiro[2.5]oct-1-yl]-4-[3-fluoro-6-(1-methyl-1 H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
N-[(1S,3R)-5-azaspiro[2.5]oct-1-yl]-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
N-[(1S,3S)-5-azaspiro[2.5]oct-1-yl]-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(2S)-pyrrolidin-2-ylmethyl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c,]dipyridin-4-yl]-N-
[(2R)-pyrrolidin-2-ylmethyl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(3R)-pyrrolidin-3-ylmethyl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(3S)-pyrrolidin-3-ylmethyl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(2S)-piperidin-2-ylmethyl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(2R)-piperidin-2-ylmethyl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(3R)-piperidin-3-ylmethyl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
[(3S)-piperidin-3-ylmethyl]benzamide
- 3,4-dihydro-1,8-naphthyridin-1(2H)-yl{4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]phenyl}methanone

. i-({4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolot2,3-b:5,4-c']dipyridin-4-yl]-
phenyl}carbonyl)-2,3-dihydro-1,8-naphthyridin-4(1 H)-one
{4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-
phenyl}(octahydroquinoxalin-1(2H)-yl)methanone
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
(1,3-thiazol-2-ylmethyl)benzamide
N-[(5-cyano-1,3-thiazol-2-yl)methyl]-4-[3-fluoro-6-(1-methyl-1 H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[1-
(1,3-thiazol-2-yl)ethyl]benzamide
{4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-
phenyl}[2-(1,3-thiazol-2-yl)piperidin-1-yl]methanone
{4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-
phenyl}[2-(1,3-thiazol-2-yl)pyrrolidin-1-yl]methanone
- [(3S)-3-aminopiperidin-1-yl]{4-[3-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridin-4-yl]phenyl}methanone
- [(3R,4R)-3-amino-4-hydroxypiperidin-1-yl]{4-[3-methoxy-6-(1-methyl-1H-pyrazol-4-
yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]phenyl}methanone
- N-[(3R,4R)-4-hydroxypiperidin-3-yl]-4-[3-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- N-[(3S,4S)-4-hydroxypiperidin-3-yl]-4-t3-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- N-[(3R,4S)-4-hydroxypiperidin-3-yl]-4-t3-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- N-[(3S,4R)-4-hydroxypiperidin-3-yl]-4-[3-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- N-[(3S,5R)-5-hydroxypiperidin-3-yl]-4-[3-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
N-[(1S,2S)-2-aminocyclopentyl]-4-[6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]benzamide
- N-[(1S,2S)-2-(ethylamino)cyclopentyl]-4-[3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
4-[6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[(2S)-pyrrolidin-2-yl-
methyl]benzamide

N-[(1 S,2S)-2-aminocyclohexyl]-4-[6-(1 -methyl-1 H-pyrazol-4-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]benzamide
4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yi]-N-
[(3S,4S)-4-hydroxypiperidin-3-yl]benzamide
N-{2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}-4-[3-'Tiethyl-6-(pyridin-3-yl)-9H-pyrrolo-
[2,3-b: 5,4-c']d i py ridi n-4-y I] benzamide
2-(3-aminopropyl)-5-[3-fluoro-6-(1 -methyl-1 H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]-2,3-dihydro-1H-isoindol-1-one.
The compounds of formula (I) may comprise one or more asymmetric carbons. They
may thus exist in the form of enantiomers or diastereoisomers. These enantiomers
and diastereoisomers, and also mixtures thereof, including racemic mixtures, form
part of the invention.
The compounds of formula (I) may comprise one or more stereochemistries of E/Z
type on double bonds or of cis/trans type on non-aromatic rings. These various
stereoisomers, and also mixtures thereof, form part of the invention.
The compounds of formula (I) may exist in the form of bases or of acid-addition salts.
Such addition salts form part of the invention.
These salts may be prepared with pharmaceutically acceptable acids (P. Stahl, C.
Wermuth; Handbook of Pharmaceutical Salts; Wiley Ed.), but the salts of other acids
that are useful, for example, for purifying or isolating the compounds of formula (I)
also form part of the invention.
The compounds of formula (I) may comprise one or more isotopes of the atoms
described above, especially deuterium D, tritium T, 11C, 13C, 14C, 150, 15N, 18F, 123l, 12"l
and 136l. These compounds, irrespective of their isotopic composition, form part of the
invention.
All the synthetic intermediates not described in the literature, which lead to the
production of the compounds belonging to the general formula, also form part of the
invention.

The strategy for the synthesis of the tricyclic nucleus is based on two coupling
reactions; a carbon-carbon bond is first created between two suitably selected
pyridines, leading to the intermediate of formula Bn, and the formation of an
intramolecular carbon-nitrogen bond then leads to the 9H-pyrrolo[2,3-b:5,4-c']di-
pyridine unit (intermediate of formula Cn, see scheme 1 below).
A subject of the present invention is also any synthetic process known to those
skilled in the art allowing the preparation of the products of formula (I) as defined
above.

A subject of the present invention is especially a process for synthesizing the
products of formula (la) as defined above, described hereinbelow in Scheme 1.


The operating conditions for obtaining the products of formula la as defined above,
starting from the intermediates of formulae An, Bn and Cn in which X, M, R, R4 and
PG have the definitions given in the general scheme as defined above, are
described hereinbelow.
For example, the process for preparing the compounds bearing a (3'-pyridinyl) group
in position 6 according to the invention consists, in a first step, in preparing 5-chloro-
4-(trimethylstannyl)-2,3'-bipyridine A1 from 2-(3'-pyridyl)-5-chloropyridine (Journal of
the Chemical Society, Perkin Transactions 1, 2002, (16), 1847-1849) (Scheme 2):

In a second step, Stille coupling is performed with a 2-amino-3-(bromo or iodo)pyridine
derivative optionally substituted in position 5 (intermediate B1, Scheme 3):

One subject of the present invention is thus especially a process for synthesizing the
products of formula (Ic) as defined above, described in Scheme 7.
The boronic reagent, bearing the carboxamido function, may also be prepared
before condensation as for a commercial derivative.
The process for preparing the compounds bearing a (1'-methyl-1'H-pyrazol-4'-yl) unit
in position 6 according to the invention consists in a first step in preparing the
intermediate A2 (Scheme 8):

In a second step, Stille coupling is performed (A2→B2) with a 2-amino-3-(bromo or
iodo)pyridine derivative optionally substituted in position 4 or 5, followed by an
intramolecular aryl amination reaction (B2→C7), catalysed either with a palladium
complex, or with copper (I) iodide (Scheme 9):

One subject of the present invention is thus especially a process for synthesizing the
products of formula (IC7) as defined above, described in Scheme 11.
An alternative synthesis for obtaining compounds Id bearing the (1'-methyl-1'H-
pyrazol-4'-yl) group was also used. The first step involves preparation of 2,5-
dichloro-4-(trimethylstannyl)pyridine A3 via a method analogous to that described
hereinabove. The Stille coupling (A3→B3) with a 2-amino-3-(bromo or iodo)pyridine
derivative substituted in position 5 is, in this case, followed by an intramolecular aryl
amination reaction (B3→C12), catalysed with a copper salt in oxidation state (I) or (II)


The end of the synthesis first involves two consecutive chemoselective couplings of
Suzuki type (C15→C16→C17). After saponification of the ester, the final amide D2 is
formed via conventional carboxylic acid-activating methods (Scheme 14). The
intermediates of C5 type and the products of formula (I) of formula Ic are also

One subject of the present invention is thus especially a process for synthesizing the
products of formula (IC7) as defined above, described in Scheme 14.
Introduction of an alkoxy group into position 3 (intermediate C18) is performed using
the derivative 3-bromo-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine obtained via
the action of dibromine in acetic acid on 6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridine. For example, a methoxy or ethoxymethoxy unit may be introduced in the


The following steps, namely the introduction of the iodine atom into position 4 and
the formation of the phenylcarboxamido chain, are identical to those described
hereinabove (C18→C2→C3→C6→lcwith R3 = alkoxy).
A subject of the present invention is also, as medicaments, the products of formula
(I) as defined above, and also the prodrugs thereof, the said products of formula (I)
being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and
also the pharmaceutically acceptable addition salts with mineral and organic acids or
with mineral and organic bases of the said products of formula (I).
A subject of the present invention is especially, as medicaments, the products of
formula (I) as defined above, the names of which are as follows:
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(1H-tetrazol-5-yl-
methyhbenzamide
-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]phenyl}methanone
-{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]phenyl}[(3aS,6aS)-
5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]rnethanone
-N-[2-(acetylamino)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-
4-yl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolot2,3-b:5,4-c']dipyridin-4-yl]-N-[3-(2-oxopyrroli-
din-1-yl)propyl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(phenyl-
amino)ethyl]benzamide
-N-[(1-ethylpyrrolidin-2-yl)methyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
-N-[3-(dimethylamino)-2,2-dimethylpropyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]benzamide
-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]benzamide
- N-(1-ethylpiperidin-3-yl)-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-
4-yl]benzamide

-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(2-methyl-
piperidin-1-yl)ethyl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(1-methyl-
azetidin-3-yl)benzamide
-[3-(dimethylamino)piperidin-1-yl]{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]phenyl}methanone
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-methyl-2-(pyr-
rolidin-1-yl)propyl]benzamide
-N-[3-(dimethylamino)propyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]-N-methylbenzamide
-N-[2-(azepan-1-yl)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin
4-yl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(1-methyl-
piperidin-4-yl)ethyl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-[(methyl-
sulfonyl)amino]ethyl}benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(pyrrolidin-1-
yl)propyl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-methyl-N-[(1-
methylpiperidin-2-yl)methyl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(1-methylpyr-
rolidin-2-yl)ethyl]benzamide
-N-[2-(dipropan-2-ylamino)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
-N-[2-(dimethylamino)ethyl]-N-ethyl-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4
c']dipyridin-4-yl]benzamide
-N-[1-(dimethylamino)propan-2-yl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']d i py rid i n-4-yl] benzamide
-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]phenyl}methanone

-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-methyl-N-(1-
methylpyrrolidin-3-yl)benzamide
-N-[2-(diethylamino)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]-N-methylbenzamide
-{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]phenyl}[4-(2-
methoxyethyl)piperazin-1-yl]methanone
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[(3-methyl-1H-
pyrazol-4-y I) methyl] benza mide
-{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]phenyl}(2-methyl-
octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)methanone
-N-[4-(dimethylamino)butyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(1H-imidazol-2-
ylmethyl)benzamide
-{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]phenyl}(7-methyl-
2,7-diazaspiro[4.4]non-2-yl)methanone
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(pyridin-2-yl-
amino)ethyl]benzamide
-N-ethyl-4-t3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[(1-
methylpyrrolidin-3-yl)methyl]benzamide
-1,3'-bipyrrolidin-1 '-yl{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-
yl]phenyl}methanone
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-methyl-N-(1-
methylpiperidin-4-yl)benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[(2-hydroxypyri-
din-4-yl)methyl]benzamide
-N-[2-(ethylamino)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-
4-yl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(methyl-
amino)ethyl]benzamide

- N-t(1-aminocyclopropyl)methyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
-N-(3-amino-2,2-difluoropropyl)-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]benzamide
-N-(2-amino-3,3,3-trifluoro-2-methylpropyl)-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridin-4-yl]benzamide
-N-[(1R,2R)-2-aminocyclohexyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
-N-[(1S,2S)-2-aminocyclohexyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]benzamide
-N-[(1S,2S)-2-aminocyclopentyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
-N-[(1R,2R)-2-aminocyclopentyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(4-
methylpiperazin-1-yl)benzamide
-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(1-
methylpiperidin-4-yl)benzamide
-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-
[(3R)-3-hydroxypyrrolidin-1-yl]ethyl}benzamide
-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-
[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}benzamide
-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(2-
hydroxyethyl)benzamide
-N-[(1S,2S)-2-aminocyclohexyl]-4-[3-fluoro-6-(1-rriethyl-1H-pyrazol-4-yi)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridin-4-yl]benzamide
-N-[(1S,2S)-2-(diethylamino)cyclohexyl]-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- N-[(1 S,2S)-2-(ethylamino)cyclohexyl]-4-[3-fluoro-6-(1-methyl-1 H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide

-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benz-
amide
-4-[6-(5-chloro-1-methyl-1H-pyrazol-4-yl)-3-fluoro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-
yl]-N-(4-methylpiperazin-1-yl)benzamide
-4-[6-(5-chloro-1-methyl-1H-pyrazol-4-yl)-3-fluoro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-
yl]-N-(1-methylpiperidin-4-yl)benzamide
-N-[2-(dimethylamino)ethyl]-4-[3-(2-methoxyethoxy)-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]benzamide
-N-[2-(dimethylamino)ethyl]-5-[3-fluoro-6-(pyridin-3-yl)-9H-pyirolo[2,3-b:5,4-c']di-
pyridin-4-yl]pyridine-2-carboxamide
-N-[2-(dimethylamino)ethyl]-2-fluoro-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the pharmaceutical^ acceptable addition
salts with mineral and organic acids or with mineral and organic bases of the said
products of formula (I).
A subject of the present invention is also pharmaceutical compositions containing, as
active principle, a compound according to any one of the preceding claims and also
at least one pharmaceutically compatible excipient.
A subject of the present invention is also the pharmaceutical compositions according
to the preceding claim, used for treating 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 the said compound, and also 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 known to those skilled in
the art.

In the pharmaceutical compositions of the present invention for oral, sublingual,
subcutaneous, intramuscular or intravenous administration, the active principle of
formula (I) above, or its salt, may be administered in unit administration form, as a
mixture with standard pharmaceutical excipients, to man and animals for the
treatment of the above disorders or diseases.
The appropriate unit administration forms include oral-route forms such as tablets,
soft or hard gel capsules, powders, granules and oral solutions or suspensions, and
sublingual, buccal, subcutaneous, intramuscular or intravenous administration forms.
These medicaments find their use in therapeutics, especially in the treatment of
cancers sensitive to deregulation of the Pirn kinases.
The Pirn kinase inhibitors that are subjects of the present invention are useful for
treating cancer. Insofar as cancer remains a disease for which the existing
treatments are insufficient, it is manifestly necessary to identify novel Pirn kinase
inhibitors that are effective for treating cancer.
According to another of its aspects, the present invention also relates to a method for
treating the pathologies indicated above, which comprises the administration, to a
patient, of an effective dose of a compound according to the invention, or a
pharmaceutical^ acceptable salt thereof.
The examples that follow describe the preparation of certain compounds in
accordance with the invention. These examples are not limiting, and serve merely to
illustrate the present invention. The numbers of the presented compounds refer to
those given in the table hereinbelow, which illustrates the chemical structures and
the physical properties of a number of 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 synthetic
intermediates for obtaining the said products of formula I, as defined below:
Examples 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
37, 38, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,

64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85,
86, 87, 88, 89, 90, 91, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 112,
113 and 120 constitute the products of formula I.
Compounds A1, A2 and A3 constitute synthetic intermediates of formula An

in which X, M and R have the definitions indicated in the general scheme.
Examples 1, 29, 39, 92 and 114 constitute synthetic intermediates of formula Bn

in which R and R4 have the definitions indicated in the general scheme.
Examples 2, 3, 4, 5, 6, 8, 18, 30, 31, 32, 33, 34, 35, 36, 40, 41, 42, 43, 93, 94, 95,
96, 97, 98, 110, 111, 115, 116, 117, 118 and 119 constitute synthetic intermediates
of formula Cn

in which R, R3, R4 and PG have the definitions indicated in the general scheme.
Thus X, M, R, R3, R4 and PG represent the definitions indicated in the preparation of
the examples according io the present invention and especially hereinbelow:


One subject of the present invention is thus especially, as novel industrial products,
the synthetic intermediates of the products of formula (I) described in the general
scheme and in Schemes 1 to 15 above.
One subject of the present invention is thus, as novel industrial products, the
synthetic intermediates of formulae An, Bn and Cn as defined in the general scheme
hereinabove and hereinbelow.
One subject of the present invention is thus especially, as novel industrial products,
the synthetic intermediates of the products of formula An described in the scheme
above.
One subject of the present invention is thus especially, as novel industrial products,
the synthetic intermediates of the products of formula Bn described in the scheme
above.
One subject of the present invention is thus especially, as novel industrial products,
the synthetic intermediates of the products of formula Cn described in the scheme
above.
GENERAL INFORMATION:
Abbreviations:
1H NMR: proton nuclear magnetic resonance
DAD: wavelength-scanning detector
DCM: dichloromethane
DME: 1,2-dimethoxyethane
DMF: dimethylformamide
DMSO: dimethyl sulfoxide

ELSD. light-scattering detector
HATU: 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
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
THF: tetrahydrofuran
Tr: retention time
► All the reactions are performed with anhydrous solvents from the Acros Organics
AcroSeal range. The solvents used for the extractions and the chromatographies are
obtained from SDS. The microwave reactions are performed in a Biotage or CEM
machine. The purifications on silica gel are performed using VWR-Merck silica
cartridges (silica gel 60 15-40 urn). The 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 Ci8) with suitable eluents.
► LC-MS-DAD-ELSD analysis: 2 possible experimental conditions:
O LC-MS-DAD-ELSD analysis: MS = Waters ZQ; electrospray mode +/-; mass
range m/z = 100-1200; LC = Agilent HP 1100; LC column = XBridge 18 C Waters 3.0
x 50 mm -2.5 urn; LC oven = 60°C; flow rate = 1.1 ml/min.
Eluents: A = water + 0.1% formic acid; B = acetonitrile, with the following gradient:

© LC-MS-DAD-ELSD analysis: MS = Platform II Waters Micromass; electrospray
+/-; mass range m/z = 100-1100; LC Alliance 2695 Waters; XTerra 18C Waters
column 4.6 mm x 75 mm - 2.5 urn; LC oven = 60°C; flow rate = 1.0 ml/min.
Eluents: A = water + 0.1% formic acid; B = acetonitrile, with the following gradient:

A mixture of 15 ml of diisopropylamine and 40 ml of tetrahydrofuran is cooled to
-74°C, followed by addition of 64 ml of 1.6 N n-butyllithium in hexane over
20 minutes, while keeping the temperature below -70°C. 16.2 g of 2-(3'-pyridyl)-5-
chloropyridine prepared according to the reference Journal of the Chemical Society,
Perkin Transactions 1, 2002, 16, 1847-1849, dissolved in 170 ml of tetrahydrofuran,
are added to the reaction mixture, while still keeping the temperature below -70°C.
The mixture is stirred at -74°C for 1 hour 30 minutes, followed by gradual addition of
19.47 g of trimethyltin chloride dissolved in 100 ml of tetrahydrofuran, while keeping
the temperature below -70°C. The reaction mixture is stirred for a further 1 hour at a
temperature below -72°C, followed by addition of 100 ml of water. The mixture,
warmed to room temperature, is poured into 300 ml of water and 100 ml of saturated
aqueous potassium hydrogen carbonate solution and then extracted with twice
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 and then with 2 N ammoniacal methanol, followed by
chromatography on a column of silica, eluting with a 100/0 to 50/50 heptane/ethyl
acetate mixture to give 19.22 g of 5-chloro-4-(trimethylstannyl)-2,3'-bipyridine A1 in
the form of a beige-coloured powder.
UPLC-MS-DAD-ELSD: Tr (min) = 4.29; [M+H]t: m/z 355; purity: 98%
1H NMR (400 MHz, DMSO-dB): ppm 0.45 (s, 9 H) 7.52 (C3d, J = 7.6, 5.1 Hz, 1 H)
7.94 (C3, J = 1.0 Hz, 1 H) 8.40 (C3t, J = 7.9, 2.1 Hz, 1 H) 8.63 (s, 1 H) 8.64 - 8.66 (m,
1 H) 9.22 (C3, J =2.4 Hz, 1 H)
Example 1: 5'-chloro-5"-fluoro-3,2':4',3"-terpyridin-2"-amine


A mixture of 10 g of 2-amino-3-bromo-5-fluoropyridine, 19.2 g of 5-chloro-4-
(trimethylstannyl)-2,3'-bipyridine A1, 4.24 g of tetrakis(triphenylphosphine)-
palladium(O) and 2.095 g of copper (I) iodide in 120 ml of 1,4-dioxane is refluxed for
18 hours. The reaction medium is treated with aqueous 10% sodium hydrogen
carbonate solution and then diluted with ethyl acetate. After separation of the phases
by settling, the aqueous phase is extracted twice with ethyl acetate. The combined
organic phases are dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure. The residue is taken up in a mixture of
dichloromethane and methanol, and is then filtered by suction to give 11.67 g of 5'-
chloro-5"-fluoro-3,2':4',3"-terpyridin-2"-amine in the form of a beige-coloured solid.
The filtrate is concentrated under reduced pressure and then taken up in
dichloromethane, and silica is added. After concentrating under reduced pressure,
the deposit is purified by chromatography on a column of silica, eluting with a 98/2 to
90/10 dichloromethane/methanol mixture to give 1.98 g of 5'-chloro-5"-fluoro-
3,2':4',3"-terpyridin-2"-amine in the form of a beige-coloured solid.
UPLC-MS-DAD-ELSD: Tr (min) = 2.71; [M+H]+: m/z 301; purity: 95%
1H NMR (400 MHz, DMSO-d6): ppm: 5.78 (s, 2 H) 7.47 (C3d, J = 8.8, 2.9 Hz, 1 H)
7.55 (br. s., 1 H) 8.06(s, 1 H) 8.12 (s, 1 H) 8.49 (C3, J = 7.8 Hz, 1 H) 8.68 (br. s., 1 H)
8.84 (s, 1 H) 9.35 (br. s., 1 H)


are placed in a 100 ml reactor under an argon atmosphere and stirred for 10 minutes
at 40°C.
11.6 g of 5'-chloro-5"-fluoro-3,2':4',3"-terpyridin-2"-amine in 160 ml of anhydrous
1,4-dioxane are placed in a 500 ml reactor under argon and the solution prepared
previously is added, followed by addition of 5.97 g of potassium tert-butoxide. The
reaction mixture is refluxed for 18 hours. The mixture is diluted with a 71/29
dichloromethane/methanol mixture and is then filtered under vacuum. After
concentrating under reduced pressure, the deposit is purified by chromatography on
a column of silica, eluting with a 98/2 to 92/8 dichloromethane/methanol mixture to
give 6.5 g of 3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine in the form of
a brown solid.
UPLC-MS-DAD-ELSD: Tr (min) = 0.42; [M+H]+: m/z 265; [M-H]- m/z 263; purity: 98%
1H NMR (400 MHz, DMSO-d6): ppm 7.54 (C3dd, J = 8.0, 4.7, 0.7 Hz, 1 H) 8.48 (C3t, J
= 7.8, 2.0 Hz, 1 H) 8.60 (C3d, J = 4.6, 1.5 Hz, 1 H) 8.65 (s, 1 H) 8.65 - 8.68 (m, 1 H)
8.90 (C3, J = 1.2 Hz, 1 H) 9.05 (C3, J = 1.2 Hz. 1 H) 9.34 (C3, J = 1.5 Hz, 1 H) 12.39 (br.
s., 1 H)
Example 3: 3-fluoro-9-[(4-methylphenyl)sulfonyl]-6-(pyridin-3-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridine

3.20 g of 3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine in 80 ml of
dimethylformamide and 0.847g of 60% sodium hydride in oil are placed in a 250 ml
reactor under argon. After stirring for 3 hours at room temperature, 4.61 g of para-
toluenesulfonyl chloride dissolved in 20 ml of dimethylformamide are added. The
reaction medium is stirred for 3 hours at room temperature and then treated with
aqueous 10% sodium hydrogen carbonate solution and diluted with ethyl acetate.
After separation of the phases by settling, the aqueous phase is extracted twice with
ethyl acetate. The combined organic phases are washed with water and then dried

over anhydrous magnesium sulfate, filtered and concentrated under reduced
pressure. The residue is purified by chromatography on a column of silica, eluting
with a 100/0 to 95/5 dichloromethane/methanol mixture to give 4.75 g of 3-fluoro-9-
[(4-methylphenyl)sulfonyl]-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine.
UPLC-MS-DAD-ELSD: Tr (min) = 0.90; [M+H]t: m/z 419; purity: 98%
1H NMR (400 MHz, DMSO-d6) ppm: 2.32 (s, 3 H) 7.39 (C3, J = 8.1 Hz, 2 H) 7.59 (C3d,
J = 8.1, 4.6 Hz, 1 H) 8.03 (C3, J = 8.6 Hz, 2 H) 8.51 (C3t, J = 8.0, 2.0 Hz, 1 H) 8.67 (C3d,
J = 4.8, 1.6 Hz, 1 H) 8.73 (C3d, J = 8.3, 2.9 Hz, 1 H) 8.78 (C3d, J = 2.9, 1.2 Hz, 1 H)
8.98 (C3, J = 0.5 Hz, 1 H) 9.36 (C3, J = 1.7 Hz, 1 H) 9.70 (C3, J = 0.7 Hz, 1 H)
Example 4: 3-fluoro-9-[(4-methylphenyl)sulfonyl]-6-(pyridin-3-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridine

0.43 ml of diisopropylamine in 10 ml of tetrahydrofuran is placed in a round-bottomed
flask. After stirring and cooling to-78°C, 1.15 ml of 2.5 N n-butyllithium in hexane are
added. The reaction mixture is stirred for 15 minutes at -78°C, followed by addition of
0.800 g of 3-fluoro-9-[(4-methylphenyl)sulfonyl]-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c'Jdipyridine in 50 ml of tetrahydrofuran. After stirring for 2 hours at -78°C, 0.776 g of
iodine in 5 ml of tetrahydrofuran is added. After stirring for 1 hour, the reaction
mixture is poured into 150 ml of aqueous 10% ammonium chloride solution and
50 ml of water, and extracted twice with 150 ml of ethyl acetate. The organic phases
are washed with aqueous 5% sodium thiosulfate solution, dried over sodium sulfate,
filtered and concentrated to dryness under reduced pressure. 1.03 g of 3-fluoro-4-
iodo-9-[(4-methylphenyl)sulfonyl]-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine
are obtained.
UPLC-MS-DAD-ELSD: Tr (min) = 1.05; [M+H]* m/z 545; purity: 66%

1H NMR (400 MHz, DMSO-d6) ppm: 2.33 (s, 3 H) 7.40 (C3, J = 8.1 Hz, 2 H) 7.60 (C3d,
J = 7.8, 4.6 Hz, 1 H) 8.05 (C3, J = 8.3 Hz, 2 H) 8.47 (C3t, J= 7.9, 2.0 Hz, 1 H) 8.65 (s,
1 H)8.69(C3d,J = 4.8,1.6 Hz, 1 H)9.19(s, 1H) 9.29 (C3, J= 2.0 Hz, 1 H) 9.79 (s, 1 H)
Example 5: methyl 4-{3-fluoro-9-[(4-methylphenyl)sulfonyl]-6-(pyridin-3-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl}benzoate

800 mg of 3-fluoro-4-iodo-9-[(4-methylphenyl)sulfonyl]-6-(pyridin-3-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridine, 847 mg of 4-methoxycarbonylphenylboronic acid pinacol
ester, 170 mg of tetrakis(triphenylphosphine)palladium(O), 718 mg of caesium
carbonate in 12 ml of 1,4-dioxane and 3 ml of water are placed in a reactor, and the
tube is sealed and subjected to microwave irradiation at 120°C for 1 hour. 3 ml of
methanol and 100 ml of water are added to the reaction medium and the resulting
mixture is then extracted with five times 150 ml of ethyl acetate. The organic phases
are combined, dried over sodium sulfate, filtered and concentrated to dryness under
reduced pressure. The residue is purified by chromatography on a column of silica,
eluting with a 100/0 to 97/3 dichloromethane/methanol mixture to give 793 mg of
methyl 4-{3-fluoro-9-[(4-methylphenyl)sulfonyl]-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl}benzoate.
UPLC-MS-DAD-ELSD: Tr (min) = 1.10; [M+H]+: m/z 553; purity: 40%
1H NMR (400 MHz, DMSO-d6) ppm: 2.35 (s, 3 H) 3.95 (s, 3 H) 7.44 (C3, J = 7.8 Hz,
2 H) 7.47 - 7.52 (m, 2 H) 7.87 (C3, J = 7.8 Hz, 2 H) 8.12 (C3, J = 8.3 Hz, 2 H) 8.13 -
8.17 (m, 1 H) 8.26 (C3, J = 8.3 Hz, 2 H) 8.59 (C3d, J = 4.9, 1.5 Hz, 1 H) 8.86 (C3, J =
2.4 Hz, 1 H) 8.89 (C3, J = 1.5 Hz, 1 H) 9.77 (s, 1 H)
Example 6: 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-
benzoic acid


790 mg of methyl 4-{3-fluoro-9-[(4-methylphenyl)sulfonyl]-6-(pyridin-3-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridin-4-yl}benzoate in 10 ml of methanol and 20 ml of
tetrahydrofuran and then 479 mg of lithium hydroxide dissolved in 15 ml of water are
placed in a round-bottomed flask. The reaction mixture is stirred for 2 hours at room
temperature, followed by addition of 30 ml of water and 10 ml of aqueous 2 M
hydrochloric acid solution. The precipitate is filtered off by suction and dried under
vacuum to give 340 mg of 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]benzoic acid.
UPLC-MS-DAD-ELSD: Tr (min) = 0.56; [M+H]+: m/z 385; [M-H]": m/z 383; purity: 95%
1H NMR (400 MHz, DMSO-d6) ppm: 7.48 (C3d, J = 7.6, 4.9 Hz, 1 H) 7.68 (s, 1 H)
7.91 (C3, J = 8.1 Hz, 2 H) 8.17 (C3, J = 8.1 Hz, 1 H) 8.27 (C3, J = 8.3 Hz, 2 H) 8.54 (C3, J
= 4.4 Hz, 1 H) 8.78 (C3, J = 2.2 Hz, 1 H) 8.92 (s, 1H) 9.09 (s, 1 H) 12.65 (s, 1 H) 13.24
(br. s.,1H)
Example 7: 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-
(4-methylpiperazin-1-yl)benzamide

A mixture of 150 mg of 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-
yl]benzoic acid and 928 mg of thionyl chloride in a round-bottomed flask is refluxed
for 12 hours and then evaporated under reduced pressure. 450 mg of 1-amino-4-
methylpiperazine dissolved in 5 ml of dichloromethane are added to the residue.

After stirring for 1 hour at room temperature, the reaction mixture is evaporated
under reduced pressure, and the residue is taken up in dichloromethane and 150 g
of silica are added. The deposit is concentrated under reduced pressure and is then
purified by chromatography on a column of silica, eluting with a 98/2 to 90/10
dichloromethane/methanol mixture to give 34 mg of 4-[3-fluoro-6-(pyridin-3-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(4-methylpiperazin-1-yl)benzamide.
UPLC-MS-DAD-ELSD: Tr (min) = 0.38; [M+H]+: m/z 482; [M-H]": m/z 480; purity: 98%
1H NMR (400 MHz, DMSO-d6) ppm: 2.21 (s, 3 H) 2.41 - 2.48 (m, 4 H) 2.96 (t, J =
4.6 Hz, 4 H) 7.46 (C3d, J = 8.1, 4.6 Hz, 1 H) 7.67 (s, 1 H) 7.85 (C3, J = 8.3 Hz, 2 H)
8.10 (C3, J = 8.3 Hz, 2 H) 8.12-8.16 (m, 1 H) 8.54 (C3d, J = 4.6, 1.2 Hz, 1 H) 8.77 (C3, J
= 2.4 Hz, 1 H) 8.92 (C3, J = 2.0 Hz, 1 H) 9.09 (s, 1 H) 9.63 (s, 1 H) 12.62 (br. s., 1 H)
Example 8: 3-fluoro-4-iodo-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine

2.2 g of 3-fluoro-4-iodo-9-[(4-methylphenyl)sulfonyl]-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridine in 50 ml of methanol and 100 ml of tetrahydrofuran and then 2.1 g
of lithium hydroxide dissolved in 100 ml of water are placed in a round-bottomed
flask. The reaction mixture is stirred for 3 hours at room temperature, followed by
addition of 200 ml of water and aqueous 2 M hydrochloric acid solution to pH 6. The
precipitate is filtered off by suction and dried under vacuum to give 1.16 g of 3-fluoro-
4-iodo-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine.
UPLC-MS-DAD-ELSD: Tr (min) = 2.91; [M+H]+: m/z 391; [M-H]": m/z 389; purity: 98%
1H NMR (400 MHz, DMSO-d6): ppm 7.56 (C3d, J = 8.1, 4.6 Hz, 1 H) 8.43 (C3t, J = 7.8,
2.0 Hz, 1 H) 8.56 (s, 1 H) 8.62 (C3d, J = 4.6, 1.2 Hz, 1 H) 9.09 (s, 1 H) 9.11 (s, 1 H)
9.27 (C3, J = 2.0 Hz, 1 H) 12.63 (br. s., 1 H)
Example 9: N-[2-(dimethylamino)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridin-4-yl]benzamide


1.1 g of 3-fluoro-4-iodo-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine, 1.9 g N-(2-
dimethylaminoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide,
326 mg of tetrakis(triphenylphosphine)palladium(O), 1.84 g of caesium carbonate in
15 ml of 1,4-dioxane and 2.5 ml of water are placed in a 20 ml reactor, and the tube
is sealed and subjected to microwave irradiation for 1 hour at 130°C. The reaction
mixture is filtered and then poured into 100 ml of water and 250 ml of ethyl acetate
with vigorous stirring. After separation of the phases by settling, the aqueous phase
is extracted with 100 ml of ethyl acetate and the combined organic phases are dried
over magnesium sulfate, filtered and then evaporated under reduced pressure. The
residue is purified by chromatography on a column of silica, eluting with a 100/0/0 to
90/10/0.2 dichloromethane/methanol/28% aqueous ammonia mixture; the product is
suspended in 15 ml of ethyl acetate. After vigorous stirring for 16 hours at room
temperature, the solid is filtered off by vacuum suction to give 1.02 g of N-[2-
(dimethylamino)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-
yl]benzamide.
UPLC-MS-DAD-ELSD: Tr (min) = 0.41; [M+H]*: 455 m/z; [M-H]": 453 m/z; purity: 95%
1H NMR (400 MHz, DMSO-d6): ppm 2.22 (s, 6 H) 2.45 - 2.49 (m, 2 H) 3.44 (q, J =
6.5 Hz, 2 H) 7.46 (C3d, J = 7.8, 4.6 Hz, 1 H) 7.68 (s, 1 H) 7.87 (C3, J = 8.1 Hz, 2 H)
8.11 -8.15(m, 1 H) 8.16 (C3, J = 8.1 Hz, 2 H) 8.54 (C3d, J = 4.6, 1.5 Hz, 1 H) 8.61 (t, J
= 5.6 Hz, 1 H) 8.77 (C3, J = 2.4 Hz, 1 H) 8.91 (C3, J = 2.0 Hz, 1 H) 9.08 (s, 1 H) 12.61
(br. s., 1 H)
Example 10: N-[3-(dimethylamino)propyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide


In a manner similar to that of Example 9, Example 10 is obtained starting with
150 mg of 3-fluoro-4-iodo-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine and
383 mg of N-(3-dimethylaminopropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzamide.
UPLC-MS-DAD-ELSD: Tr (min) = 2.21; [M+H]+: m/z 469; [M-H]": m/z 467; purity: 98%
1H NMR (400 MHz, DMSO-d6): ppm 1.72 (quint., J = 7.1 Hz, 2 H) 2.16 (s, 6 H) 2.31
(t, J = 7.1 Hz, 2 H) 3.35 - 3.41 (m, 2 H) 7.46 (C3d, J = 7.9, 4.8 Hz, 1 H) 7.68 (C3, J =
1.1 Hz, 1 H) 7.87 (C3, J = 7.9 Hz, 2 H) 8.12 -8.15 (m, 1 H) 8.16 (C3, J = 8.3 Hz, 2 H)
8.53 (C3d, J = 4.6, 1.5 Hz, 1 H) 8.73 - 8.77 (m, 1 H) 8.77 (C3, J = 2.4 Hz, 1 H) 8.91 (C3, J
= 1.8 Hz, 1 H) 9.09 (C3, J= 0.9 Hz, 1 H) 12.62 (br. s., 1 H)
Examples 11 to 17
General procedure for Examples 11 to 17:

0.2 mmol of 3-fluoro-4-iodo-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine,
0.4 mmol of boronic reagent in 2 ml of 1,4-dioxane, 0.4 mmol of caesium carbonate
in 0.5 ml of water, and 0.02 mmol of tetrakis(triphenylphosphine)palladium(O) in
0.5 ml of dimethylformamide are placed in a reactor under argon, and the tube is
sealed and stirred at 110°C for 18 hours. After cooling, the reaction mixture is diluted

with 6 ml of 1,4-dioxane, 2 ml of methanol and 0.1 ml of trifluoroacetic acid and then
treated with 150 mg of resin of propanethiol type grafted onto silica, for 4 hours at
room temperature. The reaction mixture is filtered and then washed twice with a 4/1
1,4-dioxane/methanol mixture. After evaporating under reduced pressure, the
residue is dissolved in 2 ml of dimethylformamide and 0.1 ml of trifluoroacetic acid,
filtered off and then purified by preparative HPLC.

A mixture of 100 mg of 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-
yl]benzoic acid and 12 ml of thionyl chloride is heated at 70°C for 20 hours. The
reaction mixture is concentrated to dryness under reduced pressure to give 105 mg
of 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzoyl chloride in
the form of a yellow powder. The product is characterized by addition of methanol to
give the corresponding ester.
Examples 19 to 28
General procedure for Examples 19 to 28:


A mixture of 105 mg of 4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-
yl]benzoyl chloride, 10 equivalents of amine (cf. Table 2) and 10 ml of
dichloromethane is stirred at room temperature for 20 hours and the reaction mixture
is then concentrated to dryness under reduced pressure. The residue is taken up in
300 ml of water and 300 ml of ethyl acetate. After separation of the phases by
settling, the aqueous phase is extracted with 100 ml of ethyl acetate and the organic
phases are then combined and concentrated under reduced pressure.
The amides are detailed in Table 2 (yield between 10% and 79% depending on the
reagent).

A mixture of 10 g of 5-chloro-2-methoxypyridine and 220 ml of tetrahydrofuran is
cooled to -78°C, followed by gradual addition of a solution freshly prepared from
14.1 ml of 2,2,6,6-tetramethylpiperidine in 50 ml of tetrahydrofuran and 36.4 ml of
2.3 N n-butyllithium in hexane. After stirring for 4 hours at -78°C, 17.3 g of
trimethyltin chloride dissolved in 30 ml of tetrahydrofuran are added to the reaction
mixture. The reaction mixture is stirred at room temperature for 18 hours and then
treated with 200 ml of water and 200 ml of aqueous 10% ammonium chloride
solution and extracted with 500 ml and then 200 ml of ethyl acetate. The combined
organic phases are dried over magnesium sulfate, filtered and then concentrated to
dryness under reduced pressure. The residue is purified by chromatography on a
column of silica, eluting with dichloromethane to give 17.7 g of 5-chloro-2-methoxy-4-
(trimethylstannyl)pyridine A2 in the form of a colourless oil.
UPLC-MS-DAD-ELSD: Tr (min) = 1.24; [M+H]+: m/z 308; purity: 98%
1H NMR (400 MHz, DMSO-d6): ppm 0.16 (t, J = 29.6 Hz, 9 H) 3.62 (s, 3 H) 6.61 (t,
J = 20.5 Hz, 1 H) 7.90 (t, J = 8.3 Hz, 1 H)

A mixture of 13.2 g of 5-chloro-2-methoxy-4-(trimethylstannyl)pyridine, 7.5 g of 2-
amino-3-bromo-5-fluoropyridine, 3.1 g of tetrakis(triphenylphosphine)palladium(O)
and 1.6 g of copper iodide in 100 ml of 1,4-dioxane is refluxed for 18 hours. The
reaction mixture is hydrolysed with a mixture of 200 ml of aqueous 10% sodium
hydrogen carbonate solution and 100 ml of water and is then extracted with twice
200 ml of ethyl acetate. The combined organic phases are dried over magnesium

sulfate, filtered and then concentrated to dryness under reduced pressure. The
residue is purified by trituration in 120 ml of ethyl acetate to give 8.7 g of 5'-chloro-5-
fluoro-2'-methoxy-3,4'-bipyridin-2-amine in the form of a colourless oil.
UPLC-MS-DAD-ELSD: Tr (min) = 0.94; [M+H]+; m/z 253; purity: 72%
1H NMR (400 MHz, DMSO-d6): ppm 3.89 (s, 3 H) 5.65 (s, 2 H) 6.86 (s, 1 H) 7.33
(C3d, J= 8.7, 3.1 Hz, 1H) 8.01 (C3, J= 2.9 Hz, 1 H) 8.32 (s, 1 H)
Example 30: 3-fluoro-6-methoxy-9H-pyrrolo[2,3-b:5,4-c']dipyridine

1.12 g of (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphos-
phine and 0.40 g of palladium (II) acetate in 15 ml of anhydrous 1,2-
dimethoxyethane are placed in a dry tube under an argon atmosphere and stirred for
10 minutes at 40°C.
6.38 g of 5'-chloro-5-fluoro-2'-methoxy-3,4'-bipyridin-2-amine in 80 ml of anhydrous
1,2-dimethoxyethane are placed in a 250 ml reactor under argon, and the solution
prepared previously is added, followed by addition of 5.64 g of potassium tert-
butoxide. The reaction mixture is refluxed for 18 hours, followed by addition of a
further 3 ml of freshly prepared catalyst solution of the same concentration and
1.41 g of potassium tert-butoxide. After refluxing for 6 hours, 10 ml of methanol and
300 ml of ethyl acetate are added to the reaction mixture. The organic phase is
washed with 200 ml of aqueous 5% sodium hydrogen carbonate solution and then
dried over magnesium sulfate, filtered and concentrated to dryness under reduced
pressure. The residue is purified by trituration in 100 ml of ethyl acetate to give
2.23 g of 3-fluoro-6-methoxy-9H-pyrrolo[2,3-b:5,4-c']dipyridine.
UPLC-MS-DAD-ELSD: Tr (min) = 0.58; [M+H]+: m/z 218; purity: 98%
1H NMR (400 MHz, DMSO-d6): ppm 3.91 (s, 3 H) 7.58 (s, 1 H) 8.49 (s, 1 H) 8.54 -
8.61 (m, 2H)11.85(br. s., 1 H)

Example 31: 3-fluoro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-6-ol

600 mg of 3-fluoro-6-methoxy-9H-pyrrolo[2,3-b:5,4-c']dipyridine in 3 ml of acetic acid
and 2 ml of aqueous 37% hydrochloric acid solution are placed in a reactor, and the
tube is sealed and subjected to microwave irradiation for 30 minutes at 130°C. The
reaction mixture is filtered by vacuum suction and then washed with ethyl ether to
give 755 mg of 3-fluoro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-6-ol in the form of a yellow
solid.
UPLC-MS-DAD-ELSD (LS): Tr (min) = 0.45; [M+H]+: m/z 204; purity: 91%
1H NMR (400 MHz, DMSO-d6): ppm 5.47 (br. s., 1 H) 7.92 (s, 1 H) 8.52 (s, 1 H)
8.75 (C3d, J = 2.7, 1.7Hz, 1 H) 8.87 (C3d, J = 8.7, 2.8 Hz, 1 H) 12.52 (s, 1 H)

A mixture of 755 mg of 3-fluoro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-6-ol in 15 ml of
pyridine and 4.32 ml of anhydrous trifluoromethanesulfonic acid is stirred at room
temperature for 30 minutes. The reaction mixture is diluted with 100 ml of ethyl
acetate and washed with 100 ml of saturated aqueous sodium bicarbonate solution.
After separation of the phases by settling, the aqueous phase is extracted with
100 ml of ethyl acetate and the organic phases are then combined, dried over
magnesium sulfate, filtered and then concentrated under vacuum to give 978 mg of
3-fluoro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-6-yl trifluoromethanesulfonate in the form of
a brown solid.

UPLC-MS-DAD-ELSD: Tr (min) = 4.22; [M+H]+ m/z 336; [M-H]": m/z 334; purity: 98%
1H NMR (400 MHz, DMSO-C7) ppm 8.41 (C3, J = 0.7 Hz, 1 H) 8.71 - 8.78 (m, 3 H)
12.69 (br. s., 1 H)

960 mg of 3-fluoro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-6-yl trifluoromethanesulfonate,
43.7 mg of 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(ll), 372 mg of 1-
methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and 1.17 g of
caesium carbonate in 10 ml of 1,4-dioxane and 2.5 ml of water are placed in a
reactor, and the tube is sealed and subjected to microwave irradiation at 125°C for
1 hour. The reaction mixture is diluted with 50 ml of ethyl acetate and washed with
50 ml of water. After separation of the phases by settling, the aqueous phase is
extracted with 100 ml of ethyl acetate and the organic phases are then combined,
dried over magnesium sulfate, filtered and then concentrated under vacuum. The
residue is purified by chromatography on a column of silica, eluting with ethyl acetate
to give 168 mg of 3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridine in the form of a yellow solid.
UPLC-MS-DAD-ELSD: Tr (min) = 2.24; [M+H]+: m/z 268; [M-H]": m/z 266; purity: 98%
1H NMR (400 MHz, DMSO-d6): ppm 3.91 (s, 3 H) 7.96 (C3, J = 0.5 Hz, 1 H) 8.19 (s,
1 H) 8.41 (C3, J = 1.0 Hz, 1 H) 8.55 (C3d, J = 8.8, 2.9 Hz, 1 H) 8.59 - 8.61 (m, 1 H) 8.86
(C3, J =1.2 Hz, 1 H) 12.14 (br. S., 1 H)
Example 34: 3-fluoro-9-[(4-methylphenyl)sulfonyl]-6-(1-methyl-1H-pyrazol-4-yl)-
9H-pyrrolo[2,3-b:5,4-c']dipyridine


168 mg of 3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine in
10 ml of dimethylformamide are placed in a 100 ml round-bottomed flask under
argon and 11 mg of sodium hydride are added. The reaction mixture is stirred for
3 hours at room temperature, followed by addition of 240 mg of para-toluenesulfonyl
chloride. The reaction mixture is stirred for 45 minutes at room temperature and is
then poured into a mixture of water and sodium hydrogen carbonate solution: a white
precipitate appears. After stirring, it is filtered off by vacuum suction and then
washed with diethyl ether. The white solid obtained is purified by chromatography on
a column of silica, eluting with ethyl acetate, to give 225 mg of 3-fluoro-9-[(4-
methylphenyl)sulfonyl]-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine
in the form of a white solid.
UPLC-MS-DAD-ELSD (LS): Tr (min) = 1.26; [M+H]+ m/z 422.26; purity: 93%

A mixture of 53 ul of 2,2,6,6-tetramethylpiperidine and 2 ml of tetrahydrofuran is
cooled to -78°C, followed by addition of 100 ul of 2.7 N n-butyllithium in hexane. After
15 minutes, 75 mg of 3-fluoro-9-[(4-methylphenyl)sulfonyl]-6-(1-methyl-1H-pyrazol-4-
yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine dissolved in 5 ml of tetrahydrofuran are added
to the reaction mixture and the resulting mixture is stirred at -78°C for 1 hour,

followed by addition of 72 mg of iodine dissolved in 2 ml of tetrahydrofuran. The
reaction mixture is poured into a mixture of water and saturated aqueous ammonium
chloride solution and then extracted with ethyl acetate. The organic phase is washed
with aqueous sodium thiosulfate solution, dried over magnesium sulfate, filtered and
then concentrated to dryness under reduced pressure. The residue is purified by
chromatography on a column of silica, eluting with ethyl acetate, to give 60 mg of 3-
fluoro-4-iodo-9-[(4-methylphenyl)sulfonyl]-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridine in the form of a yellow solid.
UPLC-MS-DAD-ELSD (LS): Tr (min) = 1.37; [M+H]+: m/z 548; purity: 71%
Example 36: 3-fIuoro-4-iodo-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-
c']di pyridine

60 mg of 3-fluoro-4-iodo-9-[(4-methylphenyl)sulfonyl]-6-(1-methyl-1H-pyrazol-4-yl)-
9H-pyrrolo[2,3-b:5,4-c']dipyridine in 5 ml of methanol and 5 ml of tetrahydrofuran are
placed in a round-bottomed flask and 60 mg of lithium hydroxide are then added.
The reaction mixture is stirred for 18 hours at room temperature, followed by addition
of a small amount of water and a few ml of aqueous ammonium chloride solution.
The precipitate is filtered off by suction, washed with water, with ethyl acetate and
with diethyl ether and then dried under vacuum to give 25 mg of 3-fluoro-4-iodo-6-(1-
methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine.
1H NMR (400 MHz, DMSO-d6): ppm 3.94 (s, 3 H) 8.03 (s, 1 H) 8.34 (s, 1 H) 8.59 (s,
1 H) 8.83 (s, 1 H) 8.99 (s, 1 H) 12.73 (br. s., 1 H)
Example 37: N-[3-(dimethylamino)ethyl]-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-
yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide


55 mg of 3-fluoro-4-iodo-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridine, 16 mg of tetrakis(triphenylphosphine)palladium(O), 134 mg of N-(2-
dimethylaminoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide,
68 mg of caesium carbonate in 2 ml of 1,4-dioxane and 500 ul of water are placed in
a reactor, and the tube is sealed and subjected to microwave irradiation at 120°C for
1 hour. The reaction mixture is diluted with ethyl acetate and water, and the yellow
precipitate formed is then filtered off by vacuum suction and washed with ethyl
acetate, water and diethyl ether to give 45 mg N-[3-(dimethylamino)ethyl]-4-[3-fluoro-
6-(1-methyl-1 H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide in the
form of a yellow solid.
UPLC-MS-DAD-ELSD: Tr (min) = 0.38; [M+H]+: m/z 458; [M-H]": m/z 456; purity:
98%
1H NMR (400 MHz, DMSO-d6): 5 ppm 2.23 (s, 6 H) 2.46 - 2.49 (m, 2 H) 3.45 (q, J =
6.6 Hz, 2 H) 3.85 (s, 3 H) 7.29 (C3, J = 1.2 Hz, 1 H) 7.54 (C3, J = 0.7 Hz, 1 H) 7.82 (C3, J
= 7.8 Hz, 2 H) 7.92 (s, 1 H) 8.14 (C3, J = 8.3 Hz, 2 H) 8.61 (t, J = 5.5 Hz, 1 H) 8.71 (C3,
J = 2.4 Hz, 1 H) 8.89 (C3, J =1.0 Hz, 1 H) 12.36 (br. s., 1 H)
Example 38: N-[2-(dimethylamino)propyl]-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-
yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide


In a manner similar to that of Example 37, starting with 55 mg of product of Example
36, 35 mg of N-[2-(dimethylamino)propyl]-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-
9H-pyrrolo[2,3-b:5,4-c']dipyhdin~4-yl]benzamide are obtained in the form of a pale
yellow solid.
UPLC-MS-DAD-ELSD: Tr (min) = 0.39; [M+H]+: m/z 472; purity: 95%
1H NMR (400 MHz, DMSO-3-b:5,4-c']dipyridin-4-yl]benzoyl chloride 18
(1 eq.) is suspended in dichloromethane (50 mL per 1 mmol of 18). 5 to 10
equivalents of diamine E are dissolved in dichloromethane (same volume used as for
placing 18 in suspension) in a dry round-bottomed flask under an argon atmosphere.
The suspension of 18 is then added to the solution containing E with stirring at room
temperature. The mixture is stirred for 2 to 20 hours. Methanol is then added until the
precipitate disappears, and silica (10 mg per 1 mg of 18) is then added. The solvents
are evaporated off under reduced pressure and the product is recovered by
chromatography on silica gel (eluent: CH2CI2/MeOH or CH2CI2/2N NH3 in MeOH:
gradient from 100/0 to 85/15).
Examples 83 to 86 obtained via this method are described in Table 4.



Examples 87 to 91
Synthesis of 1-aminomethylcyclopropylamine:
The synthesis of 1-aminomethylcyclopropylamine is performed via hydrogenation as
described in J. Org. Chem. 1992, 57(22), 6071-6075.
Synthesis of 2,2-difluoropropan-1,3-diamine:

45 ml of ammoniacal methanol (7N) are added to 5 g (25 mmol) of ethyl
difluoromalonate at 0°C in a 250 mL three-necked flask. The mixture is stirred until it
has warmed to room temperature, and is then left stirring overnight. The
difluoromalonadiamide is recovered by evaporating the mixture under reduced
pressure (3.35 g; 95% yielC7). 500 mg of this residue are placed in a microwave tube,
and 17 mL of a boron hydride/tetrahydrofuran solution (1 M Bhb/THF in THF) are
then added slowly at 0°C. After warming to room temperature, the mixture is left
stirring until the evolution of gas has ceased. The tube is sealed and then heated by
microwave for 30 minutes at 120°C. 5 ml of methanol are then added to the reaction

medium, cooled beforehand to 0°C. The solvents are evaporated off under reduced
pressure. The residue is taken up in 20 ml of methanol and then evaporated to
dryness, this operation being repeated twice. 291 mg of 2,2-difluoropropan-1,3-
diamine are obtained and are used in the following step without further purification.
Synthesis of 2-trifluoromethylpropan-1,2-diamine:
2-Trifluoromethylpropan-1,2-diamine is prepared racemically by following the
synthesis described in J. Org. Chem. 2006, 71(18), 7075-7079. To obtain the
racemic compound, the optically pure a-methylbenzylamine used in the publication is
simply replaced with benzylamine in the first step of the process. The rest of the
synthesis proceeds in accordance with the publication.
General procedure for Examples B7 to 91:

1.2 mmol (10 eq.) of amine D are dissolved in 0.5 ml of anhydrous pyridine (addition
of triethylamine if the amine E is in hydrochloride form) in a dry round-bottomed flask
under an argon atmosphere. 4-[3-Fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]benzoyl chloride 18 (50 mg, 0.124 mmol, 1 eq.) is dissolved in 1 ml of
pyridine. This solution is then added to the solution containing D with stirring at room
temperature. The mixture is left stirring for between 30 minutes and 2 hours, and if
the reaction is incomplete after 2 hours, it may also be heated for 30 minutes by
microwave at 140°C. The pyridine is then evaporated off under reduced pressure.
The residue is dissolved in a CH2CI2/MeOH mixture and 500 mg of silica are added.
The solvents are evaporated off under reduced pressure and the product is
recovered by chromatography on silica gel (eluent: CH2CI2/MeOH or CH2CI2/2N NH3
in MeOH: gradient from 100/0 to 85/15).
Examples 87 to 91 obtained via this method are described in Table 5.

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, while 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 hour 30 minutes 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 ammonium chloride solution and 350 ml of water. The suspension is
extracted with three times 500 mL of ethyl acetate. The organic solution is separated
out by settling, dried over magnesium sulfate and then concentrated to dryness on a
rotary evaporator to give 27 g of a mobile oil, which is purified by chromatography on
silica (200 g), eluent: 97.5/2.5 cyclohexane/ethyl acetate by volume. 12.46 g (59%)
of 2,5-dichloro-4-trimethylstannylpyridine A3 are obtained in the form of a white
powder.
The reaction is performed in four runs of about 1.5 g in a 20 mL reactor of Biotage
vial type and a Biotage microwave oven.

A suspension of 1.5 g of 5-fluoro-3-iodo-2-aminopyridine (6.3 mmol), 2.15 g
(6.93 mmol) of 2,5-dichloro-4-trimethylstannylpyridine, 0.25 g (1.32 mmol) of copper
(I) chloride and 0.515 g (O.44 mmol) of tetrakis(triphenylphosphine)palladium(O) in
15 ml of dioxane and 0.1 ml of dimethylformamide is heated at 120°C for 1 hour
20 minutes by microwave.
The four crude reaction products are then combined and diluted in 80 mL of ethyl
acetate, and washed with 90 mL of saturated sodium bicarbonate solution and then
with 90 ml of water. After drying over magnesium sulfate, the organic phase is
concentrated on a rotary evaporator and then purified by chromatography on silica
(90 g), eluent: 9/1 and then 8/2 cyclohexane/ethyl acetate by volume to give 4.22 g
(68%) of 2',5'-dichloro-5-fluoro[3,4']bipyridinyl-2-ylamine 92 in the form of a pale
yellow powder.
UPLC-MS-DAD-ELSD: Tr(min) = 3.35; [M+H]+: m/z 299.06 and 301.08
Example 93: 6-chloro-3-fluoro-9H-pyrrolo[2,3-b:5,4-c']dipyiidine

A suspension of 4.2 g (16.27 mmol) of 2',5'-dichloro-5-fluoro[3,4']bipyridinyl-2-yl-
amine, 7 g (48.81 mmol) of potassium carbonate and 0.62 g (3.25 mmol) copper
iodide in 100 ml of dimethyl sulfoxide is heated on an oil bath at 170°C for 3 hours
30 minutes. The reaction mixture is then stirred in 300 g of ice and 250 ml of 28%
aqueous ammonia solution for 1 hour, and then extracted with five times 300 mL of
ethyl acetate. The organic phases are combined, dried over magnesium sulfate and
concentrated to dryness on a rotary evaporator to give an ochre-coloured solid,
which is triturated in 80 mL of ethyl ether. The suspension is filtered, drained by
suction and dried to give 1.75 g (49%) of 6-chloro-3-fluoro-9H-dipyrido[2,3-b:4',3'-
d]pyrrole 93 in the form of an ochre-coloured powder.
UPLC-MS-DAD-ELSD: Tr (min) = 0.73; [M+H]+: m/z 257.95 and 259.93
Example 94: 6-chloro-3-fluoro-9-[(4-methylphenyl)sulfonyl]-9H-pyrrolo[2,3-
b:5,4-c']dipyridine


6-Chloro-3-fluoro-9H-dipyrido[2,3-b:4',3'-d]pyrrole 93 (800 mg, 3.6 mmol) is
dissolved in 20 ml of DMF in a dry one-necked flask under argon (gentle heating to
35°C may be necessary in certain cases for complete dissolution). Sodium hydride
(245 mg, 6.1 mmol, 1.7 eq.) is added in a single portion, and the reaction mixture is
then stirred under an inert atmosphere for 3 hours. Tosyl chloride dissolved in 2 ml of
DMF is then added (addition time of about two minutes). After one hour, the reaction
medium is poured into a mixture of aqueous 10% NaHCCb solution (50 ml_) and
water (30 ml_). The precipitate is filtered off and then drained by suction with 50 ml of
water. After drying (overnight), the precipitate is purified by chromatography on silica
gel (no need for slurrying on silica, since the product is sufficiently soluble in
dichloromethane: 70 g Si02, CH2CI2/EtOAc: 100/0 to 90/10). 1.02 g (75%) of 6-
chloro-3-fluoro-9-(toluene-4-sulfonyl)dipyrido[2,3-b:4',3'-d]pyrrole 94 are obtained.
UPLC-MS-DAD-ELSD: Tr (min) = 1.10; [M+H]+: m/z 375.99 and 377.95

To a solution of 0.37 ml_ (2.6 mmol) of diisopropylamine in 6 ml of tetrahydrofuran is
added under an argon atmosphere, dropwise over about two minutes at -78°C, 1 ml
(2.5 mmol) of a solution of butyllithium (2.5 M) in hexane. After stirring for 30 minutes
at -78°C, a solution of 94 (620 mg, 1.6 mmol) in 25 ml of THF is then added slowly
(total addition time of about 10 minutes). After 3 hours at -78°C, a solution of diiodine
(670 mg) in 2 ml of THF is then added rapidly. After stirring for 30 minutes at -78°C,

the reaction medium is poured into a mixture of ethyl acetate (150 ml_) and half-
saturated aqueous ammonium chloride solution (50 ml of saturated aq. NH4CI +
50 ml of water). The phases are separated and the organic phase is then washed
with aqueous 5% sodium thiosulfate solution. The organic phase is dried over
MgS04, filtered and evaporated under reduced pressure. 615 mg (74%) of 6-chloro-
3-fluoro-4-iodo-9-(toluene-4-sulfonyl)dipyrido[2,3-b:4',3'-d]pyrrole 95 are obtained.
UPLC-MS-DAD-ELSD: Tr (min) = 1.19; [M+H]+: m/z 501.89 and 503.85

6-Chloro-3-fluoro-4-iodo-9-(toluene-4-sulfonyl)dipyrido[2,3-b:4',3'-d]pyrrole 95
(615 mg, 1.2 mmol) is dissolved in 40 ml of THF and 15 ml of MeOH. Aqueous
lithium hydroxide monohydrate solution (503 mg, 12 mmol in 20 ml of water) is then
added rapidly. After stirring for 2 hours, 80 ml of water are added and the medium is
then acidified by addition of aqueous 1N hydrochloric acid solution (about 12 ml_) to
pH 4. The precipitate is filtered off on a porosity 4 sinter funnel, drained by suction
with 20 ml of water and then dried (overnight). 415 mg (97%) of 6-chloro-3-fluoro-4-
iodo-9H-dipyrido[2,3-b:4',3'-d]pyrrole 96 are obtained.
UPLC-MS-DAD-ELSD: Tr (min) = 0.93; [M+H]+ m/z 347.91 and 349.90

625 mg of 6-chloro-3-fluoro-4-iodo-9H-dipyrido[2,3-b:4',3'-d]pyrrole 96, 1.415 g of 4-
methoxycarbonylphenylboronic acid pinacol ester, 208 mg of tetrakis(triphenyl-
nhnsnhinetoalladiumfOV 1.76 a of caesium carbonate in 40 ml of 1,4-dioxane and

8 ml of water are placed in a three-necked flask, and the mixture is then refluxed for
18-20 hours. 4 ml of aqueous 1N sodium hydroxide solution are added to the
reaction medium, and the resulting mixture is refluxed for a further one hour. After
cooling, the reaction medium is poured into a mixture of water and ethyl acetate with
vigorous stirring. The phases are separated and the pH of the aqueous phase is then
brought to 4 by adding aqueous hydrochloric acid solution. The precipitate that forms
during this acidification is filtered off, drained by suction and dried under vacuum.
540 mg (88%) of 4-[3-fluoro-6-chloro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzoic
acid 97 are thus obtained.
UPLC-MS-DAD-ELSD: Tr (min) = 0.73; [M-HT/m/z 340.08 and 342.02
Example 98: 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]benzoic acid

440 mg of 4-[3-fluoro-6-chloro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzoic acid 97,
148 mg of tetrakis(triphenylphosphine)palladium(O), 804 mg of 1-methyl-4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 1.26 g of caesium carbonate in
25 ml of 1,4-dioxane and 5 ml of water are placed in a 50 mL microwave reactor, and
the tube is sealed and then subjected to microwave irradiation at 140°C for 2 hours.
The reaction mixture is diluted with 50 ml of ethyl acetate and washed with 50 ml of
water. After separation of the phases by settling, the aqueous phase is extracted
with 100 ml of ethyl acetate and the organic phases are then combined, dried over
magnesium sulfate, filtered and then concentrated under vacuum. The residue is
purified by chromatography on a column of silica (eluent: 100/0 to 95/5
CH2CI2/MeOH). 321 mg (64%) of 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridin-4-yl]benzoic acid 98 are obtained in the form of a yellow solid.
UPLC-MS-DAD-ELSD: Tr(min) = 0.55; [M+H]+: m/z 388.14 and [M-H]m/z 386.20

Examples 99 to 105
General procedure for Examples 99 to 105:

A mixture of 100 mg of 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzoic acid and 12 ml of thionyl chloride is refluxed for 2 hours. The
reaction mixture is concentrated to dryness under reduced pressure to give 105 mg
of 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-
benzoyl chloride in the form of a yellow powder.
The 4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-
benzoyl chloride (1 eq.) is suspended in dichloromethane (50 ml_ per 1 mmol of acyl
chloride). 5 to 10 equivalents of the amine D are dissolved in dichloromethane (same
volume used as for placing 18 in suspension) in a dry round-bottomed flask under an
argon atmosphere. The suspension is then added to the solution containing D with
stirring at room temperature. The mixture is left stirring for between 2 and 20 hours.
Methanol is then added until the precipitate disappears, and silica (10 mg per 1 mg
of 98 used in the reaction) is then added. The solvents are evaporated off under
reduced pressure and the product is recovered by chromatography on silica gel
(eluent: CH2CI2/MeOH or CH2Cl2/2N NH3 in MeOH: gradient from 100/0 to 85/15).
Examples 99 to 105 obtained via this method are described in Table 6.

The 4-[3-fluoro-6-(5-chloro-1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yI]benzoyl chloride (1 eq.) is suspended in dichloromethane (50 mL per
1 mmol of acyl chloride). 5 to 10 equivalents of the amine D are dissolved in
dichloromethane (same volume used as for placing 18 in suspension) in a dry round-
bottomed flask under an argon atmosphere. The suspension is then added to the
solution containing D with stirring at room temperature. The mixture is stirred for
2 hours. Methanol is then added until the precipitate disappears, and silica (10 mg
per 1 mg of 98 used in the reaction) is then added. The solvents are evaporated off
under reduced pressure and the product is recovered by chromatography on silica
gel (eluent: CH2CI2/MeOH or CH2CI2/2N NH3 in MeOH: gradient from 100/0 to 85/15).
Examples 106 and 107 obtained via this method are described in Table 7.



13 mg of N-[(1S,2S)-2-aminocyclohexyl]-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide 105 are dissolved in 2.5 ml of methanol
and 0.1 mL of glacial acetic acid in a dry tube under an argon atmosphere.
Acetaldehyde is then introduced via a syringe (35 uL of a freshly prepared 1M
methanolic solution of acetaldehyde). The mixture is stirred for 5 minutes and
sodium cyanoborohydride is then added in a single portion. After 1 hour 30 minutes,
the mono-reaction product 108 is predominant; when the reaction is left stirring
overnight, the diethylamino derivative 109 is then predominant. In both cases, the
reaction is hydrolysed with aqueous 5% sodium bicarbonate solution and then
extracted with 40 mL of ethyl acetate. After separating the phases, the organic phase
is dried over MgSO*, filtered and evaporated. The residue is purified by
chromatography on silica gel (5 g of silica, eluent: CH2CI2/2N NH3 in MeOH: 100/0 to
98/2). In each case, 10 mg of compounds 108 and 109 are obtained.
Examples 108 and 109 obtained via this method are described in Table 8.



250 mg of 3-fluoro-4-iodo-9-[(4-methylphenyl)sulfonyl]-6-(pyridin-3-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridine 4, 3 equivalents of the appropriate pinacol boronate, 53 mg of
tetrakis(triphenylphosphine)palladium(O), 300 mg of caesium carbonate and 68 mg
of copper (I) chloride are suspended in 4.5 ml of DMF in a 5 mL microwave tube, and
the tube is sealed and subjected to microwave irradiation at 120°C for 1 hour. The
reaction medium is hydrolysed with 100 ml of water and the resulting mixture is then
extracted with twice 250 ml of ethyl acetate. The organic phases are combined, dried
over sodium sulfate, filtered and concentrated to dryness under reduced pressure.
The residue is then taken up in a mixture of tetrahydrofuran (2.5 mL) and methanol
(2.5 mL), and 2.5 mL of aqueous 2N lithium hydroxide solution are then added. After

total disappearance of the starting material, water is added to the reaction medium
and the pH is brought to 4 by adding aqueous hydrochloric acid solution. The
precipitate formed is isolated by filtration, rinsed with distilled water, drained by
suction and then dried under vacuum.
138 mg (74%) of 110 are thus obtained.
UPLC-MS-DAD-ELSD: Tr (min) = 0.57; [M+H]+: m/z 386.12
144 mg (69%) of 111 are thus obtained.
UPLC-MS-DAD-ELSD: Tr (min) = 0.69; [M+H]+: m/z 403.11
Examples 112 and 113:

0.35 mmol of the appropriate acid (110 or 111) is suspended in 10 ml of thionyl
chloride, and the mixture is then refluxed overnight. The reaction mixture is
concentrated to dryness under reduced pressure. The residue is suspended in 5 ml
of dichloromethane, and 3.5 mmol (10 eq.) of N,N-dimethylethylenediamine are then
added. After stirring overnight at room temperature, methanol is added until the
precipitate disappears, and silica (1 to 2 g) is then added. The solvents are
evaporated off under reduced pressure and the product is recovered by
chromatography on silica gel (eluent: CH2CI2/2N NH3 in MeOH: gradient from 100/0
to 90/10).
Examples 112 and 113 obtained via this method are described in Table 9.


2.90 g (13.8 mmol) of 2-aimino-3-iodopyridine and 4.7 g (13.2 mmol) of 5-chloro-4-
(trimethylstannyl)-2,3'-bipyridine A1 are placed in 250 mL three-necked flask, and
1.07 g (7% mol) of tetrakis(triphenylphosphine)palladium(O) and 531 nig copper
iodide(l) are added in a single portion, along with 80 ml of 1,4-dioxane. The mixture
is refluxed for 18 hours. After cooling, the reaction medium is treated with aqueous
10% sodium hydrogen carbonate solution and then diluted with ethyl acetate. After
separation of the phases by settling, the aqueous phase is extracted twice with ethyl
acetate. The combined organic phases are dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure. The residue is taken up in a

mixture of dichloromethane and methanol, and is then filtered by suction to give
1.9 g (51%) of 5'-chloro-3,2':4',3"-terpyridin-2"-amine 114 in the form of a pale
beige-coloured solid, which is used in the following step without further purification.
237 mg of (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphos-
phine and 85 mg of palladium (II) acetate are dissolved in 4 ml of anhydrous 1,4-
dioxane in a dry 25 ml round-bottomed flask under an argon atmosphere, and the
mixture is stirred for 10 minutes at 40°C.
1.8 g of 5'-chloro-3,2':4',3"-terpyridin-2"-amine are dissolved in 30 ml of anhydrous
1,4-dioxane with 1.12 g of potassium tert-butoxide in a 100 ml reactor under argon,
and the catalyst solution prepared previously is then added. The reaction mixture is
refluxed for 18 hours. After concentrating under reduced pressure, the product is
purified by chromatography on a column of silica (eluent: 98/2 to 92/8 CH2CI2/MeOH)
to give 1.06 g (68%) of 6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine in the form
of a light brown solid.
1H NMR (400 MHz, DMSO-d6) 6 ppm: 7.35 (C3d, J = 8.0, 4.5 Hz, 1 H) 7.53 (C3d, J =
8.5, 4.5 Hz, 1 H) 8.51 (C3t, J = 8.5, 1.5 Hz, 1 H) 8.59 (C3d, J = 4.5, 1.5 Hz, 1 H) 8.62
(C3d, J = 4.5, 1.5 Hz, 1 H) 8.72 (C3d, J = 8.0, 1.5 Hz, 1 H) 8.91 (C3, J = 1.0 Hz, 1 H) 9.03
(C3, J =1.0 Hz, 1 H) 9.37 (C3, J =1.5 Hz, 1 H) 12.3 (broad m, 1 H)
LC-MS-DAD-ELSD: [M+Hf m/z 247
Example 116: 3-bromo-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine

360 mg of 115, 15 ml_ of acetic acid and 10 ml of dimethylformamide are placed in a
round-bottomed flask. After stirring, 0.3 ml of bromine is added dropwise. After
stirring for 3 hours at room temperature, the precipitate is filtered off and then rinsed
with aqueous sodium thiosulfate solution and water. After drying, 463 mg (97%) of 3-
bromo-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine 116 are obtained.

1H NMR (400 MHz, DMSO-d6) 8 ppm: 7.54 (C3d, J = 8.0, 4.9 Hz, 1 H) 8.47 (C3t, J =
8.0, 2.0 Hz, 1 H) 8.60 (C3d, J = 4.9, 2.0 Hz, 1 H) 8.69 (C3, J = 2.4 Hz, 1 H) 8.93 (s, 1 H)
9.00 (C3, J = 2.4 Hz, 1 H) 9.05 (s, 1 H) 9.34 (C3, J = 2.0 Hz, 1 H) 12.55 (broad m, 1 H)
Example 117: 3-(2-methoxyethoxy)-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridine

180 mg of 3-bromo-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine 116 and 169 mg
copper(l) iodide are dissolved in 4.1 ml of a 21% solution of sodium methoxyethoxide
in methoxyethanol and 0.4 ml of dimethylformamide in a 5 mL microwave tube, and
the tube is sealed and then subjected to microwave irradiation for 45 minutes at
120°C. After cooling, the reaction medium is poured into a mixture of 50 ml of ethyl
acetate and aqueous ammonium chloride solution with vigorous stirring. After
separation of the phases by settling, the organic phase is dried over sodium sulfate,
filtered and concentrated to dryness. The residue is purified by chromatography on a
column of silica (eluent: 100/0 to 95/5 CH2CI2/MeOH) to give 132 mg (74%) of 3-(2-
methoxyethoxy)-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine 117.
1H NMR (400 MHz, DMSO-d6) 8 ppm 3.36 (s, 3 H) 3.76 (t, J = 4.9 Hz, 2 H) 4.27 (t, J
= A A Hz, 2 H) 7.53 (C3d, J = 7.9, 4.8 Hz, 1 H) 8.39 - 8.41 (m, 2 H) 8.48 (C3t, J = 8.0,
2.0 Hz, 1 H) 8.58 (C3d, J = 4.6, 1.7 Hz, 1 H) 8.87 (C3, J = 1.0 Hz, 1 H) 8.99 (C3, J =
1.0 Hz, 1 H) 9.34 (C3, J = 2.2 Hz, 1 H) 12.11 (br. s., 1 H).
LC-MS-DAD-ELSD: Tr (min) = 2.31; [M+H]+: m/z 321; [M-H]"; m/z 319.
Example 118: 3-(2-methoxyethoxy)-9-[(4-methylphenyl)sulfonyl]-6-(pyridin-3-
yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridine


117 (70 mg, 0.22 mmol) is dissolved in 2 ml of DMF in a dry one-necked flask under
argon. Sodium hydride (15 mg, 1.7 eq.) is added in a single portion, and the reaction
mixture is then stirred under an inert atmosphere for 3 hours. Tosyl chloride
dissolved in 0.5 ml of DMF is then added (addition time of about two minutes). After
one hour, the reaction medium is poured into a mixture of aqueous 10% NaHCO3
solution (50 mL) and water (50 mL) and extracted with twice 100 mL of ethyl acetate.
After drying the combined organic phases over MgSO*, they are filtered and then
evaporated under reduced pressure. The residue is purified by chromatography on
silica gel (25 g of Si02, 100/0 to 95/5 CH2CI2/MeOH). 77 mg (72%) of 6-chloro-3-(2-
methoxyethoxy)-9-(toluene-4-sulfonyl)dipyrido[2,3-b:4',3'-d]pyrrole 118 are obtained.
UPLC-MS-DAD-ELSD: Tr(min) = 1.18; [M+H]+: m/z 475.33
Example 119: 4-iodo-3-(2-methoxyethoxy)-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridine

A solution of 34 uL (O.24 mmol) of diisopropylamine in 1 ml of tetrahydrofuran is
stirred under an argon atmosphere at -78°C. 0.1 ml (2.4 mmol) of a solution of
butyllithium (2.4 M) in hexane is added slowly dropwise over about two minutes.
After stirring for 30 minutes at -78°C, a solution of 118 (77 mg, 0.16 mmol) in 3 ml of
THF is then added slowly (total addition time of about 10 minutes). After 3 hours at
-78°C, a solution of diiodine (66 mg) in 0.5 ml of THF is added rapidly. After stirring

for 30 minutes at -78°C, the reaction medium is poured into a mixture of ethyl
acetate (50 mL) and half-saturated aqueous ammonium chloride solution (30 ml of
saturated aqueous NH4CI + 30 mL of water). The phases are separated and the
organic phase is then washed with aqueous 5% sodium thiosulfate solution. The
organic phase is dried over MgS04, filtered and evaporated under reduced pressure.
89 mg (91%) of 6-chloro-3-(2-methoxyethoxy)-4-iodo-9-(toluene-4-sulfonyl)di-
pyrido[2,3-b:4',3'-d]pyrrole are obtained. The product is used in the following step
without further purification.
6-Chloro-3-(2-methoxyethoxy)-4-iodo-9-(toluene-4-sulfonyl)dipyrido[2,3-b:4',3'-
d]pyrrole (85 mg, 0.14 mmol) is dissolved in 1.5 ml of THF and 1.5 ml of MeOH.
Aqueous lithium hydroxide monohydrate solution (61 mg, 2.55 mmol in 1.5 ml of
water) is then added rapidly. After stirring for 2 hours, 10 ml of water are added and
the medium is then acidified by addition of aqueous hydrochloric acid solution to pH
4. The precipitate is filtered off on a porosity 4 sinter funnel, drained by suction with
5 ml of water and then dried overnight under vacuum. 40 mg (97%) of 6-chloro-3-(2-
methoxyethoxy)-4-iodo-9H-dipyrido[2,3-b:4',3'-d]pyrrole 119 are obtained.
UPLC-MS-DAD-ELSD: Tr (min) = 0.85; [M+H]+ m/z 447.00

40 mg of 119, 57 mg N-(2-dimethylaminoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzamide, 10 mg of tetrakis(triphenylphosphine)palladium(O) and
58 mg of caesium carbonate are suspended in 0.5 ml of 1,4-dioxane and 0.1 ml of
water in a 2 mL microwave reactor, and the tube is sealed and then subjected to
microwave irradiation for 1 hour at 130°C. The reaction mixture is filtered and then
poured into 25 ml of water and 50 ml of ethyl acetate with vigorous stirring. After
separation of the phases by settling, the aqueous phase is extracted with 30 ml of
ethyl acetate and the combined organic phases are dried over magnesium sulfate,

filtered and then evaporated under reduced pressure. The residue is purified by
chromatography on a column of silica (eluent:100/0 to 90/10 CH2CI2/2N NH3 in
MeOH) to give 30 mg of N-[2-(dimethylamino)ethyl]-4-[3-(2-methoxyethoxy)-6-
(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide.
UPLC-MS-DAD-ELSD: Tr (min) = 0.39; [M+H]* m/z 511.25
Example 121: Pharmaceutical composition
Tablets corresponding to the following formula were prepared:
Product of Example 44 0.2 g
Excipient for a finished tablet weighing 1 g
(C3etails of the excipient: lactose, talc, starch, magnesium stearate).
Example 122: Pharmaceutical composition
Tablets corresponding to the following formula were prepared:
Product of Example 87 0.2 g
Excipient for a finished tablet weighing 1 g
(C3etails of the excipient: lactose, talc, starch, magnesium stearate).
Examples 44 and 87 are taken as examples of pharmaceutical preparation, this
preparation possibly being performed, if desired, with other products illustrated in the
present patent application.
in vitro biochemical test procedures
The pharmacological properties of the compounds of the invention may be confirmed
by a certain number of pharmacological assays. The pharmacological assay
examples that follow were performed with compounds according to the invention.
Example 1
TR-FRET assay
In order to determine the inhibition of Pirn kinase activity, the compounds of the
invention are tested in accordance with a routinely-used in-vitro TR-FRET assay
("Time Resolved-Fluorescence Resonance Energy Transfer"). The TR-FRET assay
is based on the detection of phosphorylation of the specific residue Ser112 in the

Bad protein, which was found to be a natural substrate of the Pirn kinases in cells.
For the assay, the following reagents are used:
Pirn kinase - full-length human recombinant His6-labelled Pim-1, Pim-2 or Pim-3
protein (prepared according to J. Mol. Biol. (2005) 348, 183-193);
Bad - full-length human recombinant His6-labelled Bad protein (prepared according
to J. Mol. Biol. (2005) 348, 183-193);
a-His6-APC - mouse monoclonal antibody conjugated to allophycocyanine
SureLight™ directed against the His6 label (Perkin-Elmer, No. AD0059H, Waltham,
Massachusetts, United States);
a-P~Bad-Eu - mouse monoclonal antibody (Cell Signaling Technology #9296B,
Danvers, Massachusetts, United States) directed against phosphoBad (Ser112)
(7E11) labelled on request by Perkin-Elmer with the reagent LANCE™ Eu-W1024.
The assay is based on the LANCE™ technology from Perkin-Elmer: the Eu-labelled
antibody binds to phospho-Ser112 and generates a TR-FRET signal by interaction
with the APC-labelled antibody directed against His6, bound to the His6 label of Bad.
The TR-FRET signal is detected using a SpectraMax M5 plate reader (Molecular
Devices) with the following settings: hex = 340 nm, A.em1 = 615 nm, ?iem2 = 665 nm.
The ratio of the fluorescence signal at 665 nm to the fluorescence signal at 615 nm
is used as the signal reading for the IC50 (calculations based on the 4-parameter
logistic model). The assay is performed in 384-well format; the liquid manipulations
are performed using a Beckmann 3000 liquid manipulation station. The test
compounds are tested at 10 concentration points in duplicate; the highest
concentration of compound is typically equal to 30 uM. The ATP concentration is
equal to 40 uM.
Example 2
Cell viability assay
The representative compounds of the invention are also screened as regards their
effects on cell proliferation and viability, using a variety of tumoral cell lines of human
source, representative of different pathological indications. These cell lines include:
Models of haematological cancers:
TF-1 (acute myelogenic leukaemia; AML M6 at the time of diagnosis);

KG-1 (AML; erythroleukaemia evolving into ANIL);
KG-1a (AML; subclone derived from immature KG-1);
EOL-1 (AML; eosinophilic leukaemia);
PL-21 (AML; M3);
ML-2 (AML; T-NHL evolving into T-ALL evolving into AML M4);
HL-60 (AML, M3);
Kasumi-1 (AML);
GDM-1 (AML);
K-562 (CML - chronic myelogenic leukaemia; blastic crisis);
JURL-MK1 (CML; blastic crisis);
DND-41 (T-ALL - T-cell acute lymphoblastic leukaemia);
Jurkat (T-ALL); NALM-6 (B-ALL B-cell ALL);
CEM (ALL; lymphosarcoma evolving into ALL);
Jeko-1 (B-NHL - B-cell non-Hodgkin lymphoma; lymphoma with coat
cells derived from a large-cell variant in leukaemic transformation);
WSU-DLCL2 (B-NHL; diffuse lymphoma with large B cells);
RL (B-NHL; undifferentiated diffuse);
OC1-Ly10 (B-NHL);
DoHH-2 (B-NHL);
RPMI-8226 (MM - multiple myelomas);
JVM-2 (B-CLL- B-cell chronic lymphocytic leukaemia); and
JVM-3 (B-CLL).
Models of solid tumours:
HCT-116 (bowel cancer);
HT-29 (bowel cancer);
HC-15 (bowel cancer);
H460 (lung cancer; non-small-cell lung cancer);
A375 (melanoma);
B16F10 (melanoma);
MDA-A1 (breast cancer);
MDA-MB231 (breast cancer);
MDA-MB231adr (breast cancer);
PANC-1 (pancreatic cancer); and
PC-3 (prostate cancer).

In order to measure the viability, the tumour cells are incubated in 96-well or 384-well
format for 48, 72 or 96 hours, preferably 72 hours, with a compound of the invention
at dilutions of a factor 3, with, in general, nine doses in total, the highest dose being
equal to 10 uM or 30 uM. The cell viability is evaluated by adding CellTiter-Blue®
(Promega, Madison, Wisconsin, United States) for 4 hours and endpoint readings
are taken using a SpectraMax Genmini EM plate reader (Molecular Devices,
Sunnyvale, California, United States). The CellTiter-Blue® cell viability assay
measures the ability of the cells in culture to reduce resazurin to resorufin, the
intensity of the fluorescence signal being directly proportional to the number of live
cells. The EC50 represents the concentration of compound that leads to a 50%
reduction of the viability/proliferative expansion of the cells.
Example 3
The activity of the molecules is evaluated on the JEKO or DND-41 cell line by
measuring the level of phosphorylation of Bad and the total Bad content, via the
ELISA technique.
The JEKO or DND-41 cells are resuspended at a concentration of 500 000 cells per
ml. The cells are then diluted in RPMI-1640 medium containing 20% foetal calf
serum. 225 ul of cells are placed in a plate. Serial dilutions of the molecules are then
performed (8 points, three-fold dilution, range started at 10 mM). Each dilution point
is then diluted to 1/100 in medium. Next, 25 ul of each of the concentrations are
added to the cells and then incubated for 3 hours at 37°C.
100 ul of the cells are transferred into a plate treated with poly- D-Lysine. The plate
is then incubated for 5-10 minutes at 37°C and then centrifuged for 5 minutes at
1500 rpm. A volume of 100 ul of 8% fixing solution (solution of formaldehyde in PBS
buffer) is added to each of the wells. After covering with a self-adhesive film and a
lid, the plate is incubated for 20 minutes at room temperature and then stored at 4°C
overnight.
Next, the liquid is removed and two successive washes are performed with washing
buffer. 100 pi of quenching buffer are added, followed by incubating for 15 minutes at
room temperature. After washing, 100 ul of quenching buffer are added, followed by

incubation for 1 hour at room temperature. After washing, 50 ul of primary antibody
diluted to 1/250 for pBAD (Cell Signaling Cat# 5284) and to 1/500 for Bad (MBL Cat#
591) are added to each of the plates. Each plate is incubated for 2 hours at room
temperature. After two washes, 50 ul of secondary antibody (diluted to 1/16) are
added to the pBAD plate (tebu-bio ref: FE-021) and 50 ul of the HRP-conjugated IgG
secondary antibody (Santa Cruz Cat # SC-2004; diluted to 1/1000) are added to the
Bad plate. Incubation for 1 hour at room temperature is performed. Four washes with
the washing solution are performed, followed by three washes with PBS. Finally,
100 ul of the developing solution are added, followed by incubation for 10 minutes.
Finally, 100 ul of the quenching solution are added, before reading at 450 nm.
BIOCHEMICAL RESULTS
The biochemical results are expressed according to the following classification:
Class A: IC50 less than 100 nM
Class B: IC50 between 100 nM and 1000 nM (or 1 uM)
Class C: IC50 between 1 uM and 5 uM
Class D: IC50 greater than 5 uM

CLAIMS
1. Compounds of general formula (I) below:

in which
- Z2, Z3, Z4, which may be identical or different, represent CH, CRa, CRs or N;
- R3 is chosen from:

11. H;
12. halogen (F, CI, Br, I);
13.CF3, CHF2;

14. OH
15. alkoxy in which the alkyl part is optionally mono-, di- or trisubstituted;
16. NH2, NH(alkyl), N(alkyl)2 in which the alkyl part is optionally mono-, di- or
trisubstituted;
17. C(O)Oalkyl optionally mono-, di- or trisubstituted;
18.CONH(alkyl), CON(alkyl)2 in which the alkyl part is optionally mono-, di- or
trisubstituted;
19. linear, branched or cyclic C1-C10 alkyl optionally comprising a heteroatom
and optionally mono-, di- or trisubstituted;
20. aryl or heteroaryl optionally mono-, di- or trisubstituted;

- R6 being a heteroaryl (5- or 6-membered with 1 to 4 heteroatoms chosen from N, S
and O) linked to the azacarboline unit either via a C or via an N belonging to R6, R6
being optionally mono- or polysubstituted;
- Ra necessarily being chosen from:

8. COIMH2,
9. CONHalkyl, CONHcycloalkyl optionally mono-, di- ortrisubstituted;
10. CONHheterocycloalkyl optionally mono-, di- ortrisubstituted;
11. CON(alkyl)2 optionally mono-, di- or trisubstituted;
12. CON(alkyl)(heterocycloalkyl) optionally mono-, di- ortrisubstituted;
13.CONHN(alkyl)2 in which the alkyl part is optionally mono-, di- or
trisubstituted;
14. C(O)heterocycloalkyl, the heterocycloalkyl radical containing at least one
nitrogen atom linked to C(O); and being optionally mono-, di- or
trisubstituted;
- Rs being chosen from the following groups:
13. H;
14. F; CI; Br; I
15. OH;
16. linear or branched O-alkyl(C1-C10) optionally mono- or polysubstituted;
17.NH2;
18.N(alkyl(C1-C10) or cycloalkyl(C3-C7))2, each group being optionally mono-
or polysubstituted;
19. NHC(O)R3a;
20. N(alkyl(C1-C10)C(O)R3a;
21.NHS(O2)R3a;

22. N(alkyl(C1-C10)S(O2)R3a;
23. CO2R3a;
24. SR3a; S(O)R3a;S(O2)R3a
Ra and Rs possibly forming a 4- to 7-membered ring substituted with an oxo radical,
comprising at least one nitrogen atom and optionally another heteroatom chosen
from N, O and S and optionally substituted with one or more radicals chosen from
oxo, F, CI, Br, I, CF3, CHF2, alkyl, OH, Oalkyl, NO2, NH2, NHAlk and N(Alk)2
radicals;

R3a being chosen from:
1.F;CI;Br; I
2. CF3;
3. linear, branched or cyclic C1-C10
4. C3-C7 cycloalkyl;
5. C2-C6 alkenyl;
6. C2-C6 alkynyl;
7. OH;
8. linear or branched (C1-C10) or cyclic (C3-C7) O-alkyl;
9. heterocycloalkyl (C3-C7);

10. NH2;
11. NH-(alkyl(C1-C10) or cycloalkyl(C3-C7));
12. N(alkyl(C1-C10) or cycloalkyl(C3-C7))2;
13. NH-(alkyl(C1-C10) or heterocycloalkyl (C3-C7));
14. N(alkyl(C1-C10) or heterocycloalkyl (C3-C7))2;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and organic
acids or with mineral and organic bases of the said products of formula (I).
2. Compounds according to Claim 1, characterized in that the possible
substituents of R3, R6 and Ra are chosen from the groups R2a, R2b and R2c
chosen, independently of each other, from:
1. F;
2. CI;
3. Br;
4. I;
5. CF3;CHF2
6. linear or branched C1-C10 alkyl optionally mono- or polysubstituted;
7. C3-C7 cycloalkyl optionally mono- or polysubstituted;
8. OH;
9. linear or branched O-alkyl(C1-C10) optionally mono- or polysubstituted;
10.O-cycloalkyl (C3-C7) optionally mono- or polysubstituted;
11.O-aryl optionally mono- or polysubstituted;

12. aryl optionally mono- or polysubstituted;
13. heteroaryl optionally mono- or polysubstituted;
14.heterocycloalkyl optionally mono- or polysubstituted;
15.NO2;
16.NH2;
17. NH-(alkyl(C1-C10) or cycloalkyl(C1-C10) or heterocycloalkyl), each group
optionally mono- or polysubstituted;
18.N(alkyl(C1-C10) or cycloalkyl(C3-C7))2, each group being optionally mono-
or polysubstituted;
19. NHaryl or NH heteroaryl optionally mono- or polysubstituted
20. NHC(O)substituted;
21. N(alkyl(C1-C10)C(O)substituted;
22.NHS(O2)substituted;
23.N(alkyl(C1-C10)S(O2)substituted;
24.CO2substituted;
25. Ssubstituted;
26.S(O2)substituted;
27. S(O) substituted;
28. oxo (C3ouble bond 0);
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and organic
acids or with mineral and organic bases of the said products of formula (I).
3. Compounds according to Claim 2, characterized in that the optional
substituents of all the substituted groups and of the groups Rs, R2a, R2b and R2c or
the groups are chosen from:
15. F; CI; Br; I
I6.CF3;
17. linear or branched C1-C10 alkyl
18.C3-C7cycloalkyl;
19.C2-C6alkenyl;
20.C2-C6alkynyl;

21. OH;
22. linear or branched (C1-C10) or cyclic (C3-C7) O-alkyl;
23.heterocycloalkyl (C3-C7);

24. NH2;
25. NH-(alkyl(C1-C10) or cycloalkyl(C3-C7));
26. N(alkyl(C1-C10) or cycloalkyl(C3-C7))2;
27. NH-(alkyl(C1-C10) or heterocycloalkyl (C3-C7));
28. N(alkyl(C1-C10) or heterocycloalkyl (C3-C7))2;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and organic
acids or with mineral and organic bases of the said products of formula (I).
4. Compounds according to the preceding claims, characterized in that
- Z2, Z3, Z,, which may be identical or different, represent CH, CRa, CRs or N;
- R3 is chosen from:
1-H
2- halogen (F, CI, Br, I);
3- CF3, CHF2;
4-OH

5- alkoxy in which the alkyl part is optionally mono-, di- or trisubstituted with
R2a, R2b, R2c;
6- NH2l NH(alkyl), N(alkyl)2 in which the alkyl part is optionally mono-, di- or
trisubstituted with R2a, R2b, R2c;
7- C(O)Oalkyl optionally mono-, di- or trisubstituted with R2a, R2b, R2c;
8- CONH(alkyl), CON(alkyl)2 in which the alkyl part is optionally mono-, di- or
trisubstituted with R2a, R2b, R2c;
9- linear, branched or cyclic C1-C,0 alkyl optionally comprising a heteroatom
and optionally mono-, di- or trisubstituted with R2a, R2b, R2c;
10- aryl or heteroaryl optionally mono-, di- or trisubstituted with R2a, R2b, R2c;
- R6 being a heteroaryl (5- or 6-membered with 1 to 4 heteroatoms chosen from N, S
and O) linked to the azacarboline unit either via a C or via an N belonging to R6, R6
being optionally mono- or polysubstituted with R2a, R2b, R2c;

- Ra necessarily being:
1.CONH2,
2. CONHalkyl, CONHcycloalkyl optionally mono-, di- or trisubstituted with R2a,
R2b, R2c;
3. CONHheterocycloalkyl optionally mono-, di- or trisubstituted with R2a, R2b,
R2c;
4. CON(alkyl)2 optionally mono-, di- or trisubstituted with R2a, R2b, R2c;
5. CON(alkyl)(heterocycloalkyl) optionally mono-, di- or trisubstituted with
R2a, R2b, R2c;
6. CONHN(alkyl)2 in which the alkyl part is optionally mono-, di- or trisubstituted
with R2a, R2b, R2c;
7. C(O)heterocycloalkyl, the heterocycloalkyl radical containing at least one
nitrogen atom linked to C(O); and being optionally mono-, di- or trisubstituted;
- Rs being chosen from the following groups:
1.H;
2. F; CI; Br; I
3. OH;
4. linear or branched O-alkyl(C1-C10) optionally mono- or polysubstituted with
identical or different groups R3a;
5. NH2;
6. N(alkyl(C1-C10) or cycloalkyl(C3-C7))2, each group being optionally mono- or
polysubstituted with identical or different groups R3a;
7. NHC(O)R3a;
8. N(alkyl(C1-C10)C(O)R3a;
9. NHS(O2)R3a;

10. N(alkyl(C1-C10)S(O2)R3a;
11. CO2R3a;
12. SR3a; S(O)R3a;S(O2)R3a
Ra and Rs possibly forming a 5- to 6-membered ring substituted with an oxo radical,
comprising at least one nitrogen atom and optionally substituted with one or more
radicals chosen from oxo, F, CI, Br, I, CF3, CHF2, alkyl, OH, Oalkyl, NO2, NH2,
NHAlk and N(Alk)2 radicals;
the groups R2a, R2b or R2c are chosen, independently of each other, from:
1 F

2. CI;
3. Br;
4.1;
5. CF3; CHF2
6. linear or branched C1-C10 alkyl optionally mono- or polysubstituted with
identical or different groups R3a;
7. C3-C7 cycloalkyl optionally mono- or polysubstituted with identical or different
groups R3a;
8. OH;
9. linear or branched O-alkyl(C1-C10) optionally mono- or polysubstituted with
identical or different groups R3a;
10. O-cycloalkyl (C3-C7) optionally mono- or polysubstituted with identical or
different groups R3a;
11. O-aryl optionally mono- or polysubstituted with different groups R3a;

12. aryl optionally mono- or polysubstituted with identical or different groups
R3a;
13. heteroaryl optionally mono- or polysubstituted with identical or different
groups R3a;
14. heterocycloalkyl optionally mono- or polysubstituted with identical or
different groups R3a;
15. NO2
16. NH2;
17. NH-(alkyl(C1-C10) or cycloalkyl(C3-C7) or heterocycloalkyl), each group
optionally mono- or polysubstituted with identical or different groups R3a;
18. N(alkyl(C1-C10) or cycloalkyl(C3-C7))2, each group being optionally mono- or
polysubstituted with identical or different groups R3a;
19 NHaryl or NH heteroaryl optionally mono- or polysubstituted with identical or
different groups R3a
20. NHC(O)R3a;
21.N(alkyl(C1-C10)C(O)R3a;
22. NHS(O2)R3a;
23. N(alkyl(C1-C10)S(O2)R3a;
24. CO2R3a;
25. SR3a; S(O)R3a; S(O2)R3a;

26. N(alkyl(C1-C10) or cycloalkyl(C3-C7))2, each group being optionally mono-
or polysubstituted with identical or different groups R3a;
27. oxo (C3ouble bond O);
the possible substituents of the groups R2a, R2b and R2c in which the groups R3a
are chosen from:
1. F; CI; Br; I
2. CF3;
3. linear or branched C1-C10 alkyl
4. C3-C7 cycloalkyl;
5. C2-C6 alkenyl;
6. C2-C6 alkynyl;
7. OH;
8. linear or branched (C1-C10) or cyclic (C3-C7) O-alkyl;
9. heterocycloalkyl (C3-C7);

10. NH2;
11. NH-(alkyl(C1-C10) or cycloalkyl(C3-C7));
12. N(alkyl(C1-C10) or cycloalkyl(C3-C7))2;
13. NH-(alkyl(C1-C10) or heterocycloalkyl (C3-C7));
14. N(alkyl(C1-C10) or heterocycloalkyl (C3-C7))2;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and organic
acids or with mineral and organic bases of the said products of formula (I).
5. Products of formula (I) as defined in any one of the preceding claims, belonging
to formula la:
in which Z2 represents CH, Z3 represents CH or N, Z4 represents -C-Ra and R3,
R6, Ra and Rs have the meanings indicated in any one of the preceding claims,

the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and organic
acids or with mineral and organic bases of the said products of formula (I).
6. Products of formula (I) as defined in any one of the preceding claims, belonging
to formula lb:
in which Rs represents a hydrogen atom, Z2 and Z3 represent CH, Z4 represents
-C-Ra and R3, R6 and Ra have the meanings indicated in any one of the preceding
claims,
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and organic
acids or with mineral and organic bases of the said products of formula (I).
7. Products of formula (I) as defined in any one of the preceding claims, belonging
to formula Ic:
in which Rs represents a hydrogen atom, Z2 and Z3 represent CH, Z4 represents
-C-Ra, R6 represents a pyridyl radical optionally mono- or polysubstituted with one
or more identical or different radicals Rp chosen from F, CI, Br, I, CF3, CHF2, alkyl,
OH, Oalkyl, NO2, NH2, NHAlk and N(Alk)2 radicals and R3 and Ra have the
meanings indicated in any one of the preceding claims,

the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and organic
acids or with mineral and organic bases of the said products of formula (I).
8. Products of formula (I) as defined in any one of the preceding claims, belonging
to formula Id:
in which Rs represents a hydrogen atom, Z2 and Z3 represent CH, Z4 represents
-C-Ra, R6 represents a pyrazolyl radical optionally mono- or polysubstituted with one
or more identical or different radicals Rp chosen from F, CI, Br, I, CF3, CHF2, alkyl,
OH, Oalkyl, NO2, NH2, NHAlk and N(Alk)2 radicals and R3 and Ra have the
meanings indicated in any one of the preceding claims,
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and organic
acids or with mineral and organic bases of the said products of formula (I).
9. Products of formula (I) as defined in any one of the preceding claims, the
names of which are as follows:
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolot2,3-b:5,4-c']dipyridin-4-yl]-N-(1H-tetrazol-5-yl-
methyl)benzamide
-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]phenyr}methanone
-{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]phenyl}[(3aS,6aS)-
5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]methanone
-N-[2-(acetylamino)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-
4-yl]benzamide

-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[3-(2-oxopyrroli-
din-1-yl)propyl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(phenyl-
amino)ethyl]benzamide
-N-[(1-ethylpyrrolidin-2-yl)methyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyrid in-4-yl] benzamide
-N-[3-(dimethylamino)-2,2-dimethylpropyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]benzamide
-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]benzamide
-N-(1-ethylpiperidin-3-yl)-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-
4-yl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(2-methyl-
piperidin-1-yl)ethyl]benzamide
-4-[3-fiuoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(1-methyl-
azetidin-3-yl)benzamide
-[3-(dimethylamino)piperidin-1-yl]{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]phenyl}methanone
-4-[3-fIuoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-methyl-2-(pyr-
rolidin-1-yl)propyl]benzamide
-N-[3-(dimethylamino)propyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]-N-methylbenzamide
-N-[2-(azepan-1-yl)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-
4-yl]benzamide
-4-[3-fIuoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(1-methyl-
piperidin-4-yl)ethyl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-[(methyl-
sulfonyl)amino]ethyl}benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(pyrrolidin-1-
yl) propyl] benzam ide

-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-methyl-N-[(1-
methylpiperidin-2-yl)methyl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(1-methylpyr-
rolidin-2-yl)ethyl]benzamide
-N-[2-(dipropan-2-ylamino)ethy[]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
-N-[2-(dimethylamino)elhyl]-N-ethyl-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
-N-[1-(dimethylamino)propan-2-yl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]phenyl}methanone
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-methyl-N-(1-
methylpyrrolidin-3-yl)benzamide
-N-[2-(diethylamino)ethyl]-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]-N-methylbenzamide
-{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]phenyl}[4-(2-
methoxyethyl)piperazin-1-yl]methanone
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b-.5,4-c']dipyridin-4-yl]-N-[(3-methyl-1H-
pyrazol-4-yl)methyl]benzamide
-{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]phenyl}(2-methyl-
octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)methanone
- N-[4-(dimethylamino)butyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(1H-imidazol-2-
ylmethyi)benzamide
-{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]phenyl}(7-methyl-
2l7-diazaspiro[4.4]non-2-yl)methanone
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolot2,3-b:5,4-c']dipyridin-4-yl]-N-[2-(pyridin-2-yl-
amino)ethyl]benzamide

-N-ethyl-4-[3-fIuoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-[(1-
methylpyrrolidin-3-yl)methyl]benzamide
-1.3'-bipyrrolidin-1 '-yl{4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-
yl]phenyl}methanone
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-methyl-N-(1-
methylpiperidin-4-yl)benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yI]-N-[(2-hydroxypyri-
din-4-yl)methyl]benzamide
-N-[2-(ethylamino)ethyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-
4-yl]benzamide
-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-t2-(methyl-
amino)ethyl]benzamide
- N-[(1-aminocyclopropyl)methyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
-N-(3-amino-2,2-difluoropropyl)-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]benzamide
-N-(2-amino-3,3,3-trifluoro-2-methylpropyl)-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridin-4-yl]benzamide
-N-[(1R,2R)-2-aminocyclohexyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
-N-[(1S,2S)-2-aminocyclohexyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]benzamide
-N-[(1S,2S)-2-aminocyclopentyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
-N-[(1R,2R)-2-aminocyclopentyl]-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(4-
methylpiperazin-1-yl)benzamide
-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(1-
methylpiperidin-4-yl)benzamide

-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-
[(3R)-3-hydroxypyrrolidin-1-yl]ethyl}benzamide
-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-{2-
[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}benzamide
-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]-N-(2-
hydroxyethyl)benzamide
-N-[(1S,2S)-2-aminocyclohexyl]-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo-
[2,3-b:5,4-c']dipyridin-4-yl]benzamide
- N-[(1 S,2S)-2-(diethylamino)cyclohexyl]-4-[3-fluoro-6-(1-methyl-1 H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
-N-[(1S,2S)-2-(ethylamino)cyclohexyl]-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-
pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide
-4-[3-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benz-
amide
-4-[6-(5-chloro-1-methyl-1H-pyrazol-4-yl)-3-fluoro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-
yl]-N-(4-methylpiperazin-1-yl)benzamide
-4-[6-(5-chloro-1-methyl-1H-pyrazol-4-yl)-3-fluoro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-
yl]-N-(1-methylpiperidin-4-yl)benzamide
-N-[2-(dimethylamino)ethyl]-4-[3-(2-methoxyethoxy)-6-(pyridin-3-yl)-9H-pyrrolo[2,3-
b:5,4-c']dipyridin-4-yl]benzamide
-N-[2-(dimethylamino)ethyl]-5-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']di-
pyridin-4-yl]pyridine-2-carboxamide
-N-[2-(dimethylamino)ethyl]-2-fluoro-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-
c']dipyridin-4-yl]benzamide
10. Process for preparing the products of formula (I) as defined in the preceding
claims, characterized by the general scheme below:


in which the substituents R3, R6; Z2, Z3, Z4 Ra and Rs have the meanings indicated
for the products of formula (I) in any one of the preceding claims.
11. As medicaments, the products of formula (I) as defined in Claims 1 to 9, and
also the prodrugs thereof, the said products of formula (I) being in any possible
racemic, enantiomeric or diastereoisomeric isomer form, and also the
pharmaceutically acceptable addition salts with mineral and organic acids or with
mineral and organic bases of the said products of formula (I).
12. Pharmaceutical compositions containing as active principle a compound
according to any one of the preceding claims, and also at least one pharmaceutically
compatible excipient.
13. Pharmaceutical compositions according to the preceding claim, used for
treating cancer.
14. As novel industrial products, the synthetic intermediates of formulae An, Bn
and Cn as defined in the general scheme of Claim 10 and hereinbelow:

The invention relates to novel 9H-pyrrolo[2,3-b: 5,4-c'] dipyridine azacarbolines of formula (I), Where: Z2, Z3,
and Z4 are CH, CRa, CRs, or N; R3 is H, Hal; CF3, CHF2; OH, alkoxy; NH2, NH (alkyl), N(alkyl)2; C(O)O alkyl; CONH(alkyl),
CON(alkyl)2; C1-C10 alkyl; aryl; heteroaryl; R6 is heteroaryl; Ra is CONH2, CONH alkyl, CONH cycloalkyl; CONH
heterocycloalicyl; CON(alkyl)2; CON(alkyl)(heterocycloalkyl); CONHN(alkyl)2; C(O)heterocycloalkyl; Rs is H; Hal, OH; O-
alkyl(Cl-Cl0); NH2; N(alkyl(Cl-C10) or cycloalkyl(C3-C7))2; NHC(O)R3a; N(alkyl(Cl-C10)C(O)R3a; NHS(O2)R3a;
N(alkyI(C1-C10)S(O2)R3a; CO2R3a; SR3a; S(O)R3a; S(C2)R3a; Ra and Rs optionally form a cycle; R3a is selected from among
Hal, CF3, C1-C10 alkyl; C3-C7 cycloalkyl; C2-C6 alkenyl; C2-C6 alkynyl; OH; O-alkyl(Cl-C10); (C3-C7), heterocycloalkyl
(C3-C7); NH2; NH-(alkyl(Cl-C10) or cycloalkyl(C3-C7)); N(alkyl(Cl-C10) or cycloalkyl(C3-C7})2; NH-(alkyl(C1-C10) or
heterocycloalkyl(C3-C7)); N(alkyl(C1-C10) or heterocycloalkyl(C3-C7))2, as well as to the isomers and salts of said substances
of formula (I) and to the therapeutic use thereof for treating cancer.