PYRIDIN0-PYRID1N0NE DERIVATIVES, PREPARATION AND THERAPEUTIC USE
THEREOF
The present invention relates to derivatives of pyridino-pyridinones substituted (i)
in position 3 with an imidazole, itself substituted with a group R1 and substituted (ii) in
position 7 with an aryl or heteroaryl, itself substituted optimally with a motif of the type
-[C(R3)(R4)]m-CO-N(R5)(R6), to the preparation thereof and to the application thereof in
therapeutics as inhibitors of kinase activity of receptors for PDGF (platelet derived
growth factors) ligands and optionally of receptors for the FLT3 (fms-like tyrosine kinase
receptor) ligand.
The FLT3 and PDGF-R receptors are members of class III of the family of tyrosine
kinase receptors (TKR), which also includes the stem cell factor receptor (c-kit) and M-
CSF receptor (c-fms). They are characterized by an extracellular domain composed of 5
immunoglobulin-like domains containing the ligand binding region, a transmembrane
domain, and an intracellular moiety composed of a juxtamembrane domain, a kinase
domain split in two by an insert domain (split domain) (Ullrich & Schlessinger, 1990).
The fixation of ligands on the TKR induces dimerization of the receptors, and activation
of their tyrosine kinase moiety which leads to transphosphorylation of tyrosine residues
(Weiss & Schlessinger, 1998). These phosphorylated residues thus serve as a point of
anchorage for the intracellular signalling proteins which in fine cause various cellular
responses: maintenance, division, proliferation, differentiation, or even cellular migration.
(Claesson-Welsh, 1994).
The gene coding for FLT3 is located on chromosome 13q12 (Rosnet et al., 1992) and
codes for the FLT3 protein (CD135 antigen) expressed specifically by the
haematopoietic cells and more particularly the immature cells such as haematopoietic
stem cells and myeloid and lymphoid multipotent progenitors and its expression
disappears in the course of haematopoietic differentiation. Its ligand, the FLT3 Ligand,
induces dimerization of the receptor, followed by autophosphorylation of the intracellular
moiety of the receptor which leads to activation of the signalling cascade. The effects of
activation of the receptor by its ligand are the survival and expansion of the multipotent
progenitors.
Two isoforms of receptors to the PDGFs have been identified, the chain PDGF-Ralpha
and the chain PDGF-Rbeta, which following fixation of their ligands are homo- or
heterodimerized and induce intracellular signalling. The receptors to the PDGFs are
essentially expressed by the cells of mesenchymatous origin and are notably found on
fibroblasts, smooth muscle cells, pericytes and glial cells (Ross et al., 1986, Heldin,
1992).
Platelet Derived Growth Factor, PDGF, a protein with a molecular weight of about
30 000 dalton, is secreted essentially by the platelets, and secondarily by the
endothelium, vascular smooth muscles and monocytes. It is formed from two
polypeptide chains joined together by disulphide bridges forming either homodimers, or
heterodimers. Four genes (7p22, 22q13, 4q31 and 11q22) have been described as
coding for 4 different polypeptide chains (A, B, C and D), which once dimerized give five
biologically active ligands PDGF-AA, BB, CC, DD and AB (for review, Yu et al., 2003).
There is specificity of binding, including notably PDGF-AA for the alpha isoform of the
receptor, PDGF-D for the BB form, and PDGF-C for the alpha and alpha/beta form. The
PDGF ligands are potent mitogens, but are also involved in phenomena of migration,
survival, apoptosis and cellular transformation.
Inhibitors of the PDGF-R alpha, beta and FLT3 function are involved in various
therapeutic areas. The physiopathological phenomena in which these receptors may be
involved include liquid cancers or leukaemias, solid cancers with or without metastases
targeting tumour ceils and/or cells of the tumour environment (vascular, fibroblastic),
fibroses and vascular diseases:
A. Liquid cancers
The leukaemias are of various types and affect either the myeloid compartment or the
lymphoid compartment.
Expression of FLT3 in leukaemic cells derived from acute myeloid leukaemias (AML) is
of the order of 100% of cases, and FLT3 thus contributes to stimulation of survival and
proliferation of leukaemic cells (Carow et al., 1996; Drexler et al., 1996, Stacchini et al.,
1996).
Moreover, FLT3 is the site of activating mutations in 22 to 30% of adult AMLs and 11 %
of childhood AMLs. Most often it involves in-tandem duplications (ITD) in the
transmembrane region of the receptor (more particularly exons 14 and 15). These
mutations conserve the reading frame and their size can vary between 18 and 111 base
pairs. More rarely in about 7% of AMLs, a point mutation is found on the D835 residue
located in the kinase domain. In the majority of cases, the FLT3 ITD forms have a
greater risk of relapse and are markers of low survival prognosis. These two types of
mutations lead to constitutive activity of the kinase domain independent of stimulation by
the ligand and have been shown to transform haematopoietic cells in vitro and in vivo
(Mizuki et al., 2000; Tse et al., 2000). Kelly et al., (2002) gave an elegant demonstration,
in a model of bone marrow reconstitution in the mouse, that FLT3 ITD causes a
myeloproliferative syndrome.
The advantage of using inhibitors of tyrosine kinase activity has been reported both in
vitro and in vivo by several teams, and recently in the model of bone marrow
reconstitution FLT3 ITD, such an inhibitor was shown to be capable of inducing
regression of the tumour and of increasing the survival rate of the animals (Ofarrel,
2003).
Moreover, recent data demonstrate the advantage of combining said inhibitors with
cytotoxic agents such as daunorubicin (Levis et al., 2004).
Interestingly, blast cells of the AML type can also overexpress other receptors with
kinase activity such as c-kit or even PDGF-R.
Myeloproliferative/dvsplastic syndromes
Quite frequently, cytogenetic abnormalities resulting from chromosomal translocations
have been reported in myeloproliferative syndromes. These rearrangements generate
deregulated fusion proteins with tyrosine kinase activity involved in the proliferation of
myeloid blast cells.
-fusion proteins with kinase activity PDGF-R beta
The fusion proteins with kinase activity PDGF-R beta are constituted of the intracellular
moiety of PDGF-R-beta and in addition a domain N-ter of another protein (generally a
transcription factor). The following have been reported notably in chronic
myelomonocytic leukaemias (CMML): Rab5/PDGF-Rbeta, H4-PDGF-Rbeta, HIP1-
PDGF-RB or Tel/PDGF-R beta. The latter is the most represented. It is derived from the
translocation t(5; 12)(q31; p12) and codes for a fusion protein constituted of the N-
terminal part of the transcription factor Tel and the C-terminal part of PDGF-Rbeta. An
oligomerization domain present in the Tel part leads to a dimerized form of the fusion
protein and to the constitutive activity of the kinase domain. This protein has been
shown in vitro to be capable of transforming haematopoietic cells on many occasions
and notably in detail in the article by M. Carrol et al. (PNAS, 1996, 93, 14845-14850). In
vivo, this fusion protein leads to a hyperproliferation syndrome of the myeloid cells
(Ritchie et al., 1999).
Moreover, in animals, and in clinical practice in humans, it has been shown that
inhibitors of tyrosine kinase activity inhibit the proliferation of blast cells and can halt the
process of leukaemogenesis.
-fusion proteins with kinase activity PDGF-R alpha
Two fusion proteins involving PDGF-R alpha have been reported: bcr-PDGF-Ralpha
present in an atypical chronic myeloid leukaemia (CML) and FIP1L1-PDGF-Ralpha
found in a subpopulation of leukaemias, the LEC "eosinophilic leukaemias", arising from
a hyper-eosinophilia syndrome (Griffin et al., 2003). This fusion protein bears
constitutive activity of the kinase domain of PDGF-R alpha and is responsible for the
anarchic proliferation of these cells.
Inhibitors of the kinase activity of PDGF-R alpha have shown efficacy on the
proliferation of FIP1L1-PDGF-R alpha positive cells and recently an inhibitor compound
has received the indication for HES/CEL.
Thus, inhibiting the kinase activity of PDGF-Ralpha and beta and the FLT3wt and
FLT3ITD activity, as is done by the compounds of the invention, proves to be of
therapeutic interest for AMLs.
Apart from AMLs and myeloproliferative syndromes, other leukaemias can be interesting
for targeting with such inhibitors, including B-ALL and T-ALL (acute lymphoid-B or
lymphoid-T leukaemias), where FLT3 is also expressed. Moreover, by virtue of normal
expression of FLT3 on haematopoietic stem cells and the demonstration of its
expression on leukaemic stem cells, inhibitors of the kinase activity of FLT3 might prove
beneficial in all leukaemias (including the CMLs) where the role of leukaemic stem cells
in relapse where resistance is involved.
B. Solid cancers
Inhibitors of the tyrosine kinase activity of the PDGF-R alpha and beta receptors may be
of interest for solid cancers either by directly targeting the tumour cell, which through an
autocrine or paracrine mechanism is sensitive to the TK inhibitory activity of PDGF-R, or
by targeting cells in the surroundings by destabilizing the network for promoting
combination with other therapeutic agents.
-Examples of solid cancers in which the target is the tumour cell
* Soft cancer: Ewing sarcoma
Ewing sarcoma is a form of bone cancer which mainly affects children and young adults
(the average age is 13 years). It covers 10% of primary bone tumours and the risk of
metastasis is high. It is a rare tumour affecting 2 to 3 persons per million inhabitants per
year. The tumour cells are characterized by a chromosomal translocation t(11; 22)
coding for the fusion protein EWS/FLI1.
The cells responsible are those of the mesenchyma, which express the PDGF-R-beta
receptor which induces the motility and growth of the Ewing sarcoma cells under
stimulation by PDGF-BB (Uren et al., 2003). Moreover, Zwerner and May (2001) have
demonstrated expression of PDGF-C by the Ewing sarcoma cells.
These same cells also express the receptor TKR c-kit and it has been shown that an
inhibitor of the kinase activity of PDGF-R and c-kit is capable of inhibiting tumour growth
of Ewing sarcoma lines in a mouse model of xenograft (Merchant et al., 2002).
* Tumour of connective tissue (GIST, dermatofibrosarcoma)
- GISTs (gastrointestinal stromal tumours)
Fletcher's group (2004) considered the 15% of GISTs in which KIT is neither mutated
nor overexpressed (KIT-wt). These authors observed strong overexpression of the
PDGF-R alpha receptor. This situation is encountered in about a third of these GIST
KIT-wt. As for mutations of PDGFRA, the authors observe them (35%) in cases where
KIT is normal. Mutated PDGFRAs have high tyrosine kinase activity and are constitutive
and affect aspartic acid in position 842. In the same way as for Ewing sarcomas, two
inhibitors of the kinase activity of c-kit and PDGF-R have shown efficacy in vitro and in
vivo on the proliferation of PDGF-Ralpha mutated cells (Le Tourneau et al., 2007;
Corless et al., 2005).
- dermatofibrosarcomas (of Darier and Ferrand or protuberans or
DFSP)
Darier and Ferrand dermatofibrosarcoma (or DFSP) is a skin tumour with fusiform cells
of intermediate malignity characterized by slow progression with a major risk of
recurrence in the case of insufficient exeresis. A genetic abnormality present in 95% of
cases was discovered in 1990, notably with identification of the translocation of
chromosomes 17 and 22 t(17-22)(q22; q13) which leads to fusion of genes COL1A1 and
PDGF B and a large amount of PDGFB overexpresses its tyrosine kinase receptor,
PDGFR. Inhibiting the kinase activity of PDGF-R is a promising therapy since this leads
in vitro to inhibition of proliferation and apoptosis of tumour cells and in vivo this permits
reduction of tumour growth in models of tumour grafting in immunodeficient mice
(Sjoblom T et al., 2001). Moreover, clinical studies have demonstrated the efficacy
(complete or total remission) of such a molecule in DFSPs (for review see McArthur,
2007).
* Gliomas and Glioblastomas:
Glioblastoma is the commonest brain tumour and the most aggressive with a median
survival of around 1 year. PDGFs and their receptors (alpha and beta) are frequently
expressed in gliomas. The possibility exists that an autocrine/paracrine loop may
contribute to the pathogenicity of these tumours. The PDGF-R-alpha receptor is
expressed preferentially in the cells of the tumour, whereas the PDGF-beta receptor is
expressed preferentially in the vascular endothelial cells of the tumour. Blocking the
kinase activity of PDGF-R has demonstrated its efficacy 1) in vitro by reducing the
number of colonies on soft agar and inhibiting the proliferation of cell lines 2) on
reduction of tumour growth in models of grafts in the nude mouse 3) in combination with
irradiation in models of intracranial grafts of cells of glioblastoma lines (Oerbel et al.,
2006; Geng et al., 2005, Strawn et al., 1994, Chin et al., 1997).
Thus, the compounds of the invention are of interest for Ewing sarcomas, GISTs,
dermatofibrosarcomas but also desmoid tumours, haemangiomas and other
fibrosarcomas for which data on expression of PDGF-R are available.
C. Targeting PDGF-R in the tumour environment
Angioaenesis
The cells in the environment around the tumour form an integral part of the development
of cancer whether in the case of a primary tumour or secondary tumour (metastases).
Among the cells in the environment that express PDGF-R and for which the role of this
receptor has been demonstrated, we find the mural cells of vessels, i.e. pericytes and
smooth muscle cells but also activated fibroblasts.
Angiogenesis is a process of generation of new capillary vessels from preexisting
vessels or by mobilization and differentiation of bone marrow cells. Thus, both
uncontrolled proliferation of endothelial cells and mobilization of angioblasts from bone
marrow are observed in processes of neovascularization of tumours. It has been shown
in vitro and in vivo that several growth factors stimulate endothelial proliferation such as
VEGF and FGFs. In addition to these mechanisms, it has also been demonstrated that
mural cells such as pericytes and smooth muscle cells contribute to stabilization of
newly formed vessels. Invalidation of PDGF-R beta causes a deficit of pericytes in the
mouse and leads to death of the animals at the end of gestation due to micro-
haemorrhages and oedemas (Hellstrom et al., 1999, Hellstrom et al., 2001). In an
elegant study of transplantation, expression of PDGF-R-beta by pericytes was shown to
be necessary for their recruitment in tumour vessels by retention of PDGF-B by the
endothelial cells but also by the PDGF-B secreted by the tumour cells (Abramsson et al.,
2003). In the transgenic model Rip1Tag2 of pancreatic tumour, Song et al. also
demonstrated expression of PDGF-R beta on the perivascular progenitors in the marrow
derived from bone marrow, and these progenitors differentiate into mature pericytes
around the tumour.
The advantage of blocking the activity of PDGF-R on the tumour pericytes was
demonstrated by using the inhibitor of the tyrosine kinase activity of PDGF-R in animal
models (transgenic model of tumour of the pancreas and implantation of glioma
tumour), and the effect on tumour growth proves to be considerable in combination with
an inhibitor of the kinase activity of VEGF-R (Bergers et al., 2003). Data in the literature
(Cao et al., 2002, Fons et al., 2004) demonstrated the involvement of PDGF-R alpha
and of PDGF-C in angiogenesis and in the differentiation of endothelial progenitors to
cells such as pericytes and smooth muscle cells.
Activated fibroblasts
PDGF-R is abundant in the tumoral stroma and is found on activated fibroblasts
(myofibroblasts). It was shown in two studies that the combination of inhibitors or
antagonists of PDGF-R with cytotoxic agents leads to a decrease in the microdensity of
the vessels of ovarian cancers (Apte et al., 2004) and of pancreatic cancers (Hwang et
al., 2003). PDGF-R beta regulates the pressure of the interstitial tissue of the tumour
(Heuchel et al., 1999) and the co-administration of inhibitors of PDGF-R and
chemotherapeutic agents improves their delivery into the tumour cells by reducing the
intratumoral pressure (Griffon-Etienne, 1999). Finally in a murine model, administration
of an inhibitor of the kinase activity of PDGF-R improves the consumption of
chemotherapeutic agents by the tumour and thus increases their efficacy (Griffon-
Etienne, 1999; Pietras et al., 2002; Pietras et al., 2003). These effects are most
probably the effect of the TAFs (tumour-associated fibroblasts), also called CAFs
(carcinoma-associated fibroblasts), activated fibroblasts present around the tumour
which express PDGF-R, as illustrated by the recent works of Hwang et al., (2008), Kain
et al. (2008), Pietras et al. (2008) in in-vivo models of pancreatic cancer and of cervical
carcinogenesis. Stimulation by the PDGF ligand produced by the tumour cells stimulates
the fibroblasts that produce the extracellular matrix and thus increase the interstitial
tension. Furthermore, reducing this tension can facilitate delivery of drugs into the
tumour and thus increase their efficacy. The activated fibroblasts present in the tumoral
stroma therefore represent a novel therapeutic target in oncology (for review see Bouzin
& Feron, 2007).
Metastases
Several works indicate that the PDGF-R and PDGF-ligand couple is involved in the
development of metastases, probably by their action on angiogenesis and
metastasization by the blood circulation, but also by a direct effect on
lymphangiogenesis and therefore the metastases that are spread by the lymphatic
vessels. A review notably documents the direct role of PDGF-BB in lymphangiogenesis
and lymphatic metastases (Cao et al., 2005). However, most works implicate expression
of PDGF-R in the environment of the metastases which promote the establishment and
development of secondary tumours. The example most frequently reported is the
development of bone metastases.
* Example of prostate cancer:
Bone is frequently the site of metastases. 85 to 100% of patients who die from prostate
cancer have bone metastases. Chemotherapy improves survival without progression
and overall survival but because of the extreme heterogeneity of bone metastases in
one and the same patient, chemotherapy does not provide a cure. It was shown using a
model of immunodeficient mice that PDGF-BB plays an important role in the
development of osteoblastic bone metastases in vivo (Yu et al., 2003). As for PDGF-DD,
it speeds up the growth of prostate tumour cells and increases their interaction with the
cells of the stroma. Expression of the PDGF alpha and beta receptor has been
demonstrated respectively in 62 and 75% of prostate cancers. Moreover, an
immunohistochemical study showed that the prostatic tumour and its metastases
expressed PDGF-R (Hwang et al., 2003). Kim et al., (2003) showed that PDGF-R is
expressed on bone metastases and on the vascular endothelial cells dependent on the
metastases. An inhibitor of tyrosine kinase of PDGF-R combined with a cytotoxic agent
substantially reduces bone metastases of prostate cancer in a murine model (Uehara et
al., 2003). Moreover, this same combination leads to apoptosis of tumour cells, of
vascular endothelial cells and inhibition of the growth of tumour cells in bone. Blocking of
these receptors and of their signalling pathways in bone constitutes a novel therapeutic
approach (Hwang et al., 2003; Uehara et al., 2003). In humans, clinical trials have
shown the benefit offered by the combination of inhibitor of PDGF-R and of cytotoxic
agent in patients with hormone-resistant prostate cancers with bone metastases. A
decrease of the marker (prostate-specific antigen) PSA > 50% was in fact observed in
38% of patients. The mean duration of PSA response was 8 months and the survival
time without progression was 11 months.
Based on these various works, it appears that the compounds of the invention are of
interest for the treatment of solid cancers by their effect on the surrounding cells, in
combination with other therapeutic agents such as cytotoxic agents or inhibitors of
angiogenesis.
D. Fibroses
Fibroses are often the cause of a primary event such as a cancer, treatment by
radiotherapy, hepatitis, alcoholaemia. Involvement of PDGF is clearly demonstrated in
pulmonary fibrosis (including asbestosis), renal fibrosis (glomerulonephritis), marrow
fibrosis (often associated with megakaryocytic leukaemias), induced by radiotherapy as
well as hepatic and pancreatic fibrosis (connected with alcoholaemia or with hepatitis)
(for review see JC Bonner, 2004). Overexpression of PDGF was notably clearly shown,
and results in in-vivo models with inhibitors of TK activity of PDGF-R have also been
reported. Among these studies, that of Einter et al., (2002) showed that PDGF-CC is a
potent inducer of renal fibrosis. The authors tested the efficacy of a neutralizing antibody
in a model of unilateral urethral ligature, in which fibrosis develops particularly rapidly.
They observed a very pronounced antifibrotic effect with a reduction in accumulation of
myofibroblasts, a reduction in accumulation of extracellular matrix and a reduction in
deposits of collagen IV. Another study conducted in a model of bleomycin-induced
pulmonary fibrosis in the mouse showed the efficacy of an inhibitor of the TK activity of
PDGF-R on prevention of fibrosis by inhibition of proliferation of mesenchymal cells
(Aono et al., 2005). In a model of asbestos-induced fibrosis, an inhibitor of PDGF-R TK
reduced the progression of fibrosis in the pulmonary parenchyma and the deposition of
collagen (Vuorinen K, Gao F, Oury TD, Kinnula VL, Myllarniemi M. Imatinib mesylate
inhibits fibrogenesis in asbestos-induced interstitial pneumonia. Exp Lung Res. 2007
Sep; 33(7):357-73). Several teams have demonstrated involvement of PDGF-R in
hepatic fibrosis. It has been clearly demonstrated that PDGFBB and DD possess pro-
fibrogenic characteristics on hepatic stellate cells (Rovida et al., 2008; Borkham-
Kamphorst et al., 2007). In vivo, an inhibitor of PDGF-R TK is capable of reducing early
fibrogenesis in a model of ligature of the biliary duct in the rat (Neef et al., 2006).
Thus, in view of the data in the literature, the compounds of the invention appear to be
of therapeutic interest for various types of fibrosis.
E. Vascular diseases: atherosclerosis and restenosis, arteriosclerosis
The proliferation and migration of vascular smooth muscle cells contribute to intimal
hypertrophy of the arteries and thus play a predominant role in atherosclerosis and in
restenosis after angioplasty and endarterectomy. It was clearly demonstrated in vitro
and in vivo in animal models that PDGF is involved in these phenomena. In vivo, it was
notably shown that there is increased expression of PDGF in a vein graft model in the
pig. Moreover, it was also shown that an inhibitor of the TK activity of PDGF-R
consistently reduced the size of lesions of the thoracic and abdominal artery of ApoE-
KO diabetic mice (animals treated with streptozotocin). Another study showed that
inhibition of signalling induced by PDGF (TK or PDGF A antisense) leads to a decrease
in neointima formation in "balloon injury" and "coronary artery restenosis" models.
(Deguchi J, 1999, Ferns et al., 1991, Sirois et al., 1997, Lindner et al., 1995)
Thus, inhibitors of the tyrosine kinase activity of PDGF-R, such as the compounds of the
present invention, represent a therapy of choice, either alone, or in combination with
compounds that are antagonists of other growth factors involved in these pathologies
such as FGF, in the treatment of pathologies connected with proliferation of vascular
smooth muscle cells such as atherosclerosis, post-angioplasty restenosis or following
placement of endovascular prostheses (stents) or during aorto-coronary bypasses.
By virtue of their inhibitory activity on the TK activity of PDGF-R, the compounds of the
invention appear to be of interest for treating these vascular diseases.
F. Others
Other pathologies appear to be possible indications for the compounds of the invention,
including idiopathic pulmonary arterial hypertension (PAH). PAH, characterized by a
significant and sustained increase in pressure in the pulmonary artery, leads to right
ventricular heart failure and often to patient death. It is associated with increase in the
proliferation and migration of smooth muscle cells of the pulmonary vessels. Schermuly
et al., (2005) showed that inhibition of the tyrosine kinase activity of the PDGF receptors
greatly improves the progression of the disease. For this, among other things they used
a model of experimental pulmonary arterial hypertension in the rat, obtained by
administration of monocrotaline for 28 days. All the treated rats survived, whereas 50%
of those in the untreated control group died.
The compounds of the invention might also be of therapeutic interest in pathologies of
the eye. On the one hand, they might contribute to prevention of post-operative fibrosis
in the case of cicatricial lesions of the cornea and of keratoconus. This could be
explained by their action on proliferation of myofibroblasts as reported recently by Kaur
et al., (2009). Moreover, they might also promote neovascular regression for pathologies
such as ARMD (age-related macular degeneration). This was in fact demonstrated by
several teams in experimental models, including notably Jo et al.; Dell et al., in 2006.
The present invention relates to derivatives of pyridino-pyridinones substituted (i)
in position 3 with an imidazole itself substituted with a group R1 and substituted (ii) in
position 7 with an aryl or heteroaryl, itself substituted optimally with a motif of the type
-[C(R3)(R4)]m-CO-N(R5)(R6). The present invention also relates to the preparation of
said compounds and application thereof in therapeutics as inhibitors of the kinase
activity of receptors for PDGF (platelet derived growth factors) ligands and optionally of
receptors for the FLT3 (fms-like tyrosine kinase receptor) ligand.
The present invention relates to compounds corresponding to formula (I):

in which,
R1 represents a hydrogen atom or a (C1-C4)alkyl group;
R2 represents a group -(CH2)n—B where:
• n'=0, 1, 2, 3 or 4; and
• B represents (i) a (C3-C5)cycloalkyl group or a (C1-C4)alkyl group, said
group being optionally substituted with one or more fluorine atoms, or (ii)
a (C1-C4)alkoxy group;
Y, Z, V and W represent, independently of one another:
• a -CH- group,
• a carbon atom optionally substituted with a group R7, said group R7
representing a (C1-C4)alkyl group or a halogen atom,
• a heteroatom such as a nitrogen atom, a sulphur atom or an oxygen
atom, or
• no atom,
it being understood that the ring in which V, W, Y and Z are comprised is a ring
comprising 5 or 6 ring members, it being understood that the dotted lines in said ring
indicate that the resultant ring is an aromatic ring and it being understood that said ring
comprises 0, 1 or 2 heteroatoms;
R3 and R4 represent, independently of one another, groups that may be identical
or different, R3 and R4 being selected from:
• a hydrogen atom; and
• a linear (C1-C4)alkyl group;
or R3 and R4 form, together with the carbon to which they are bound, a (C3-C5)
cycloalkyl group;
m is an integer equal to 1, 2, 3 or 4;
R5 represents a hydrogen atom or a (C1-C4)alkyl group;
R6 represents a group -(CH2)n-L in which:
• n=0, 1,2 or 3, and
• L is a group selected from the following groups:
o an aryl comprising 6 carbon atoms;
o a heteroaryl comprising between 5 and 6 ring members and
comprising at least one heteroatom selected from nitrogen, oxygen
and sulphur;
o a saturated heterocycle comprising 5, 6 or 7 ring members and
comprising at least one heteroatom selected from nitrogen and
oxygen, said heterocycle being optionally a lactam;
said aryl, heteroaryl or heterocyclic group being optionally substituted
with at least one substituent selected from (i) linear or branched (C1-
C4)alkyl groups, (ii) (C3-C5)cycloalkyl groups, (iii) halogen atoms, (iv)
aryls and (v) benzyl;
it being understood that when L is a heteroaryl or a heterocycle, said
heteroaryl or heterocycle comprising at least one nitrogen atom, the latter
can optionally be substituted with said substituent;
or R5 and R6 form, together with the nitrogen atom to which they are bound, a
heterocyclic group, optionally substituted with at least
• a heteroaryl, or
• a (C1-C3)alkyl group, which can itself be substituted with a heterocycle
comprising 5 or 6 atoms and comprising at least one heteroatom
selected from nitrogen and oxygen, it being understood that when it is a
heterocycle comprising at least one nitrogen atom, the latter can
optionally be substituted;
said compound of formula (I), its enantiomers and diastereoisomers, including mixtures
thereof, being in the form of a base or a salt of addition to an acid, for example such as
trifluoroacetic acid (TFA) or hydrochloric acid and/or in the form of solvate.
The compounds of formula (I) can comprise one or more asymmetric carbon
atoms. They can therefore exist in the form of enantiomers or of diastereoisomers.
These enantiomers, diastereoisomers, as well as mixtures thereof, including racemic
mixtures, form part of the invention. For example, when L represents a heterocycle, the
absolute configuration of a carbon substituted on said heterocycle can be R or S, or
when R3 is different from R4.
The compounds of formula (I) can exist in the form of bases or of salts of addition to an
acid or to acids. Said salts of addition form part of the invention. These salts can be
prepared with pharmaceutically acceptable acids, but salts of other acids that may be
used for example for purification or isolation of the compounds of formula (I) also form
part of the invention.
The compounds of formula (I) can also exist in the form of solvates, namely in the form
of associations or of combinations with one or more molecules of solvent. Said solvates
also form part of the invention.
Within the scope of the present invention, the following definitions are used:
> alkyl group: a saturated aliphatic group comprising 1 to 7 carbon atoms
(advantageously, a saturated aliphatic group comprising 1 to 4 carbon atoms and
abbreviated to (C1-C4)alkyl) and being linear or, when the alkyl chain comprises at least
3 carbon atoms, possibly being branched or cyclic. As examples, we may mention
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methyl-cyclopropyl, pentyl, 2,2-
dimethylpropyl, hexyl and heptyl groups, as well as the cycloalkyl groups defined below;
> cycloalkyl group: a cyclic alkyl group comprising 3 to 7 carbon atoms
(advantageously from 3 to 5 carbon atoms) and in which all the carbon atoms are
inserted in the ring. We may mention the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
and cycloheptyl groups;
> alkoxy group: an -O-alkyl group, where the alkyl group is as defined
above;
> halogen atom: a fluorine, a chlorine, a bromine or an iodine atom;
> haloalkyl group: a group comprising an alkyl group as defined above in
which one or more hydrogen atoms have been substituted with one or more halogen
atoms as defined above; thus, the term fluoroalkyl is used when the halogen in question
is fluorine,
> heteroatom: a nitrogen, oxygen or sulphur atom;
> aryl group: a monocyclic aromatic group comprising 6 ring members, for
example a phenyl group;
> heteroaryl group: a monocyclic aromatic group comprising between 5 and
7 ring members including between 1 and 3 heteroatoms as defined previously. As
examples, we may mention the pyridine, pyrazine, pyrimidine, imidazole, pyrrole,
pyrazole, thiophene, thiazole, isothiazole, thiadiazole, oxazole and isoxazole groups;
> heterocyclic group: a cyclic alkyl group comprising between 5 and 7 ring
members including one or more heteroatoms as defined previously. As examples, we
may mention the pyrrolidine, morpholine, piperidine, piperazine and tetrahydrofuran
groups.
The aforementioned groups can be substituted, knowing moreover that in the case
of heteroaryl or heterocyclic groups comprising at least one nitrogen atom, substitution
can take place on this nitrogen atom when such a substitution proves chemically
possible.
Among the compounds of formula (I) according to the invention, we may mention
compounds for which:
R5 represents a hydrogen atom or a methyl, or R5 and R6 form, together with
the nitrogen atom to which they are bound, a heterocyclic group, optionally
substituted with at least
• a heteroaryl, advantageously a pyridine; or
• a (C1-C3)alkyl group, which can itself be substituted with a heterocycle
comprising 5 or 6 atoms and comprising at least one heteroatom
selected from nitrogen and oxygen, advantageously it is a Clalkyl group,
itself substituted with a heterocycle comprising 5 atoms including a
nitrogen atom;
and/or
m is equal to 0, 1 or 3,
and/or
R3 and R4 represent, independently of one another, groups that may be
identical or different, R3 and R4 being selected from:
o a hydrogen atom, and
o a methyl,
and/or
Y, Z, V and W represent, independently of one another:
o a -CH- group;
o a carbon atom substituted with a group R7, said group R7 representing a
(C1-C4)alkyl group or a fluorine atom; or
o a heteroatom such as a nitrogen atom, a sulphur atom or an oxygen
atom, advantageously a nitrogen atom,
and/or
R1 represents a hydrogen atom or a methyl,
and/or
R2 represents a group -(CH2)n-B where:
o n'=0, 1 or 3; and/or
o B represents (i) a (C3-C5)cycloalkyl group, (ii) a (C1-C4)alkyl group or (iii)
a (C1-C4)alkoxy group,
and/or
the compounds of formula (I) in the form of a base or of a salt of addition to an acid
such as hydrochloric acid or trifluoroacetic acid.
Among the compounds of formula (I) according to the invention, a first subgroup
of compounds consists of compounds for which:
R6 represents a group -(CH2)n-L in which:
• n=0, 1, 2 or 3, and
• L is a group selected from the following groups:
o a heteroaryl comprising 5 ring members and comprising (i) 2
heteroatoms selected, independently of one another, from nitrogen, oxygen
and sulphur, or (ii) 3 heteroatoms selected, independently of one another,
from nitrogen and sulphur,
o a heteroaryl comprising 6 ring members and comprising 1 or 2
heteroatom(s),
o a heterocycle comprising 5 ring members and comprising a
heteroatom selected from nitrogen and oxygen, said heterocycle being
optionally a lactam, and
o a heterocycle comprising 6 ring members and comprising 2
heteroatoms selected from nitrogen and oxygen,
said heteroaryl group or heterocycle being optionally substituted with at least one
substituent selected from (i) linear or branched (C1-C4)alkyl groups, (ii) (C3-C5)cycloalkyl
groups, (iii) halogen atoms, (iv) aryls and (v) benzyl,
it being understood that when L is a heteroaryl or a heterocycle, said heteroaryl
or heterocycle comprising at least one nitrogen atom, the latter can optionally be
substituted with said substituent.
Among the compounds of formula (I) according to the invention, a second subgroup
of compounds consists of compounds for which L is:
• a heteroaryl comprising 6 ring members selected from pyridine, pyrazine,
pyridazine and pyrimidine, or
• an aryl such as phenyl, or
• a heteroaryl comprising 5 ring members selected from thiazole, imidazole,
pyrazole, isoxazole and 1,3,4-thiadiazole, or
• a saturated heterocycle comprising 5 ring members selected from pyrrolidine,
tetrahydrofuran and 2-oxo-pyrrolidine, or
• a saturated heterocycle comprising 6.ring members selected from morpholine,
piperazine and piperidine,
said aryl, heteroaryl or heterocyclic group being optionally substituted with at least
one substituent selected from (i) linear or branched (C1-C4)alkyl groups, (ii) (C3-
C5)cycloalkyl groups and (iii) aryls,
it being understood that when L is a heteroaryl or a heterocycle, said heteroaryl or
heterocycle comprising at least one nitrogen atom, the latter can optionally be
substituted with said substituent.
Among the compounds of formula (I) according to the invention, a third subgroup of
compounds consists of compounds for which L is selected from:
• pyridine, optionally substituted with at least one linear or branched (C1-C4)alkyl
group,
• morpholine, optionally substituted with at least (i) a (C3-C5)cycloalkyl group or (ii)
a linear or branched (C1-C4)alkyl group,
• a pyrrolidine, optionally substituted with at least (i) a linear or branched (C1-
C4)alkyl group, or (ii) a benzyl,
• a thiazole, optionally substituted with at least (i) a linear or branched (C1-C4)alkyl
group, or (ii) a chlorine atom,
• an imidazole, optionally substituted with at least one linear or branched (C1-
C4)alkyl group,
• a gamma-lactam,
• a 1,3,4-thiadiazole, optionally substituted with at least (i) a linear or branched
(d-d)alkyl group, or (ii) a (C3-C5)cycloalkyl group,
• an isoxazole, optionally substituted with at least one linear or branched (C1-
C4)alkyl group,
• a pyrazole, optionally substituted with at least one linear or branched (C1-C4)alkyl
group,
• a pyrazine,
• an isothiazole, optionally substituted with at least one linear or branched (C1-
C4)alkyl group,
• a phenyl,
• a tetrahydrofuran,
it being understood that when L is a heteroaryl or a heterocycle, said heteroaryl or
heterocycle comprising at least one nitrogen atom, the latter can optionally be
substituted.
Among the compounds of formula (I) according to the invention, we may notably
mention the following compounds:
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-pyridin-2-yl-acetamide (compound 1)
2-{6-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-pyridin-3-yl}-N-pyridin-2-yl-acetamide (compound 2)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(4-cyclopropyl-morpholin-3-ylmethyl)-acetamide (compound 3)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(4-isopropyl-morpholin-3-ylmethyl)-acetamide (compound 4)
2-Amino-1-ethyl-3-(1H-imidazol-2-yl)-7-{4-[2-oxo-2-((S)-2-pyrrolidin-1-ylmethyl-
pyrrolidin-1 -yl)-ethyl]-phenyl}-1 H-[1,8]naphthyridin-4-one (compound 5)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yi]-phenyl}-N-(2-pyridin-4-yl-ethyl)-acetamide (compound 6)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-methyl-N-(2-pyridin-4-yl-ethyl)-acetamide (compound 7)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(5-methyl-thiazol-2-yl)-acetamide (compound 8)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-3-methyl-phenyl}-N-(1-ethyl-pyrrolidin-2-ylmethyl)-acetamide (compound 9)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(6-methyl-pyridin-3-yl)-acetamide (compound 10)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-acetamide (compound 11)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-thiazol-2-ylmethyl-acetamide (compound 12)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(5-oxo-pyrrolidin-2-ylmethyl)-acetamide (compound 13)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(5-methyl-[1,3,4]thiadiazol-2-yl)-acetamide (compound 14)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazoi-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-[1,3,4]thiadiazol-2-yl-acetamide (compound 15)
2-{4-[7-Amino-8-ethyi-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(3-methyl-isoxazol-5-yl)-acetamide (compound 16)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-[2-(1 -methyl-pyrrolidin-2-yl)-ethyl]-acetamide (compound 17)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(4-methyl-thiazol-2-yl)-acetamide (compound 18)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-pyridin-4-ylmethyl-acetamide (compound 19)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-acetamide (compound 20)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(2-pyridin-3-yl-ethyl)-acetamide (compound 21)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-acetamide (compound 22)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-y!)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(1 -methyl-1 H-imidazol-4-ylmethyl)-acetamide (compound 23)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-pyrazin-2-yl-acetamide (compound 24)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(2-pyridin-2-yl-ethyl)-acetamide (compound 25)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(5-chloro-thiazol-2-yl)-acetamide (compound 26)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(3,4-dimethyl-isoxazol-5-yl)-acetamide (compound 27)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(2-methyl-pyridin-4-yl)-acetamide (compound 28)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-pyrazin-2-ylmethyl-acetamide (compound 29)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acetamide (compound 30)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(tetrahydro-furan-2-ylmethyl)-acetamide (compound 31)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(3-methyl-pyridin-2-yl)-acetamide (compound 32)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
ylj-phenyl}-N-(4-methyl-pyridin-2-yl)-acetamide (compound 33)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(4,6-dimethyl-pyridin-2-yl)-acetamide (compound 34)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(6-methyl-pyridin-2-yl)-acetamide (compound 35)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-pyridin-3-ylmethyl-acetamide (compound 36)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(2-ethyl-2H-pyrazol-3-yl)-acetamide (compound 37)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(3-methyl-isothiazol-5-yl)-acetamide (compound 38)
2-Amino-1 -ethyl-3-(1 H-imidazol-2-yl)-7-{4-[2-oxo-2-(2-pyridin-3-yl-pyrrolidin-1 -yl)-
ethyl]-phenyl}-1H-[1,8]naphthyridin-4-one (compound 39)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(1 -benzyl-pyrrolidin-3-yl)-acetamide (compound 40)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-[(S)-1 -(tetrahydro-furan-2-yl)methyl]-acetamide (compound 41)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(4-methy!-pyridin-3-yl)-acetamide (compound 42)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(4-ethyl-pyridin-2-yl)-acetamide (compound 43)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-ethyl-N-pyridin-4-ylmethyl-acetamide (compound 44)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(6-ethyl-pyridin-2-yl)-acetamide (compound 45)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-benzyl-acetamide (compound 46)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-pyridin-4-ylmethyl-propionamide (compound 47)
4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-yl]-
N-pyridin-4-ylmethyl-benzamide (compound 48)
4-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-pyridin-4-ylmethyl-butyramide (compound 49)
2-{4-[7-Amino-8-ethyl-6-(4-methyl-1H-imidazol-2-yl)-5-oxo-5,8-dihydro-
[1,8]naphthyridin-2-yl]-phenyl}-N-pyridin-4-ylmethyl-acetamide (compound 50)
2-{4-[7-Amino-8-cyclopropylmethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-
[1,8]naphthyridin-2-yl]-phenyl}-N-pyridin-4-ylmethyl-acetamide (compound 51)
2-{4-[7-Amino-8-cyclopentyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-
[1,8]naphthyridin-2-yl]-phenyl}-N-pyridin-4-ylmethyl-acetamide (compound 52)
2-{5-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-pyridin-2-yl}-N-pyridin-4-ylmethyl-acetamide (compound 53)
2-{4-[7-Amino-6-(1H-imidazol-2-yl)-8-(3-methoxy-propyl)-5-oxo-5,8-dihydro-
[1,8]naphthyridin-2-yl]-phenyl}-N-pyridin-4-ylmethyl-acetamide (compound 54)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-phenyl}-N-(3-pheny!-propyl)-acetamide (compound 55)
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yl]-2-fluoro-phenyl}-N-(1 -ethyl-pyrrolidin-2-ylmethyl)-acetamide (compound 56)
It should be noted that the above compounds were named in IUPAC
nomenclature using the Autonom software.
Hereinafter, protecting group, denoted by Pg, means a group that makes it
possible, on the one hand, to protect a reactive function such as a hydroxy or an amine
during a synthesis and, on the other hand, to regenerate the intact reactive function at
the end of synthesis. Examples of protecting groups as well as methods of protection
and deprotection are given, for example, in "Protective Groups in Organic Synthesis",
Green et al., 2nd Edition (John Wiley & Sons, Inc., New York), 1991.
Leaving group means, hereinafter, a group that can be easily cleaved from a molecule
by rupture of a heterolytic bond, with departure of an electron pair. This group can thus
be replaced easily with another group during a substitution reaction, for example. Said
leaving groups are, for example, halogens or an activated hydroxyl group such as a
methanesulphonate, benzenesulphonate, p-toluenesulphonate, triflate, acetate, etc.
Examples of leaving groups as well as references for their preparation are given in
"Advances in Organic Chemistry", J. March, 3rd Edition, Wiley Interscience, 1985, p.
310-316.
According to the invention, the compounds of general formula (I) can be prepared
according to the method described in the following schemes 1, 2 and 3.

According to scheme 1, in stage (i), a 2,6-dihalogeno-nicotinic acid of formula (II)
is mono-substituted in position 2 with an amine of formula R2-NH2 (where R2 is as
defined previously with reference to the compounds of formula (I)), at room temperature,
or at a temperature from 50°C to 100°C, with conventional heating or microwave heating
and in a protic solvent such as an alcohol, for example ethanol, n-butanol, fert-butanol or
water. The acid (III), resulting from stage (i), is then activated to a derivative of formula
(IV), following stage (ii) either in the form of acid fluoride by the action of cyanuryl
fluoride at room temperature, in the presence of a base such as triethylamine or pyridine
and in an aprotic solvent such as dichloromethane or THF, as described by G. OLAH et
al., in Synthesis (1973), 487, or in the form of imidazolide by the action of
carbodiimidazole in a polar aprotic solvent such as DMF or THF or by other methods
known by a person skilled in the art, such as those described by MUKAIYAMA and
TANAKA in Chem. Lett. (1976), 303 or by ISHIKAWA and SASAKI in Chem. Lett.
(1976), 1407.
The cyanoacetylimidazoles of formula (V) are prepared in two stages from an
imidazole-2-carboxaldehyde unsubstituted or substituted in position (4,5) of the
imidazole. In stage (iii) the free nitrogen of the imidazole-2-carboxaldehyde is protected
by a protecting group, designated Pg in scheme 1, for example such as a SEM, Boc or
trityl group, in conventional working conditions known by a person skilled in the art
"Protective Groups in Organic Synthesis", Green et al., 2nd Edition (John Wiley & Sons,
Inc., New York). If applicable, the two isomers t and Ttof the protected imidazole are
obtained and used without distinction in the subsequent reactions. The protected
imidazole-2-carboxaldehyde is then transformed in stage (iv) to cyanoacetylimidazole of
formula (V) by reaction of the aldehyde function with the anion of TOSMIC, formed by
adding potassium tert-butylate to anhydrous DME at low temperature (-50°C), followed
by ring opening of the anionic intermediate formed, 4-tosyl-2-oxazoline, then the
reaction mixture is heated under reflux in the presence of methanol to permit formation
of the acetylnitrile function following the method described by Van Leusen A. et al.
{Synthetic Comm,. 10(5) 1980, 399-403).
The acid fluoride or the imidazolide of formula (IV) obtained at the end of stage
(ii), very reactive but stable, is then reacted, in stage (v), with a cyanoacetylimidazole of
formula (V), unsubstituted or substituted in position (4,5), in the presence of one
equivalent of a base such as sodium hydride or potassium tert-butoxide, in a polar
aprotic solvent such as THF or DMF, at a temperature from -5°C to room temperature,
then a second equivalent of the base used is added and the compound of formula (VI)
that formed is cyclized in situ, at room temperature, to give the pyridino-pyridinone
compound of formula (VII), following stage (vi).
The halogenated intermediate of formula (VII) can then be transformed to the
pyridino[2,3-b]pyridinone-7-stannous derivative of formula (VIII), by reacting it, in stage
(vii), with a hexaalkyldistannous compound, where the alkyl can be either a butyl or a
methyl, in the presence of a complex of palladium (in oxidation state (0) or (II)) for
example such as Pd(PPh3)4, PdCI2(PPh3)2, and optionally with addition of a ligand such
as triphenyl arsine, trifurylphosphine in a polar or nonpolar solvent such as dioxane,
THF, DMF or a nonpolar solvent such as toluene at a temperature between 50 and
110°C according to the methodology described by Stille JK et al., (JACS, 1987, 109,
813).
To obtain the compounds of formula (I) according to the present invention, two
methods can be used starting from the halogenated intermediate of formula (VII),
according to method 1 described in scheme 2, or starting from the stannous compound
of formula (VIII), according to method 2 described in scheme 3.
Following method 1 described in scheme 2, the intermediate (VII) is used in stage
(viii) in a Suzuki coupling reaction with a boronic acid
[formula (IXa) with M= -B(OH)2] or a boronic ester of pinacol [formula (lXa) with Pg being
a protecting group as defined previously, M=B(OC(CH3)2)2] where m, R1, R2, R3, R4, V,
W, Y and Z are as defined previously with reference to the compounds of formula (I)
according to the invention, it being understood that the ring must comprise between 5
and 6 ring members, and G is either a (CrC4)alkoxy group such as OEt or a motif
-NR5R6, where R5 and R6 are as defined for the compound of formula (I). These
compounds (IXa) are either commercial or are prepared from the corresponding
halogenated derivatives according to the method of Miyaura et al. (Chem Rev 1995, 95,
2457).
This reaction (viii) is carried out in the presence of a complex of palladium (in
oxidation state (0) or (II)) for example such as Pd(PPh3)„, PdCI2(PPh3)2, Pd2dba3, Xphos
or PdCl2(dppf), in a protic or aprotic polar solvent such as DME, ethanol, DMF, dioxane,
or mixtures of these solvents, in the presence of a base such as caesium carbonate,
aqueous sodium hydrogen carbonate, or K3P04, heating conventionally between 80 and
120°C or by microwave heating between 130 and 170°C.
In the case when G is a motif NR5R6, where R5 and R6 are as defined for the
compound of formula (I), it is route 1 that is followed, leading to compound (X), which
after a conventional stage of deprotection, for example in the presence of an acid such
as HCI (4N) in dioxane or trifluoroacetic acid in a solvent such as ethanol or
dichloromethane, at a temperature between -5°C and 60°C, gives the compound of
formula (I) according to the invention.
In the case when G is a (CVC^alkoxy group such as OEt, it is route 2 that is
followed, the compound (XI), obtained by Suzuki coupling in stage (viii), is saponified in
stage (ix) in the presence of LiOH or NaOH, in a mixture of protic solvent such as water,
methanol or ethanol and of aprotic solvent such as THF or DMF, at room temperature or
by heating to a temperature between 50 and 100°C, to give compound (XII). The latter is
then used in a peptide coupling reaction with the amine HNR5R6, where R5 and R6 are
as defined for the compound of formula (I), in stage (x), in the presence of a coupling
agent such as BTUT, BTUH or CDI and a base, for example diisopropylethylamine or
NaHC03, in an aprotic solvent such as dichloromethane, THF or DMF or by other
methods known by a person skilled in the art, such as those described in "Principles of
Peptide Synthesis", 2nd Ed 1993 M Bodanszky, Springer Laboratory, to give the
compound of formula (XIII), which after a conventional stage of deprotection, as
described previously, gives the compound of formula (I) according to the invention.
According to method 2 described in scheme 3, compound (VIII) is used in a Stille
coupling reaction with a halogenated derivative of formula (lXb) where Pg, m, R1, R2,
R3, R4, V, W, Y and Z are as defined previously with reference to the compounds of
formula (I) according to the invention, it being understood that the ring must comprise
between 5 and 6 ring members, X is a halogen atom and G is either a (C1-C4)alkoxy
group such as OEt or a motif -NR5R6, where R5 and R6 are as defined for the
compound of formula (I). This reaction (xi) is carried out in the presence of a complex of
palladium (in oxidation state (0) or (II)) for example such as Pd(PPh3)4, PdCI2(PPh3)2 or
Pd2(dba)3 and optionally with addition of a ligand such as triphenyl arsine,
trifurylphosphine or triphenylphosphine in a polar aprotic solvent such as DMF, dioxane
or THF with heating to a temperature between 50 and 120°C.
In the case when group G, on compound (IXb), is a motif NR5R6, where R5 and
R6 are as defined for the compound of formula (I), it is route 1 that leads to formation of
compound (X), which after a conventional stage of deprotection, as described
previously, gives the compound of formula (I) according to the invention.
In the case when G is a (C1-C4)alkoxy group such as OEt, it is route 2 that is
followed, and compound (XI) is obtained by the Stille coupling of stage (xi), and the
subsequent stages, (xii), (xiii) and of deprotection to give respectively the compounds of
formula (XII) and (XIII) and (I) according to the invention, are identical respectively to
stages (ix), (x) and of deprotection described previously.
If necessary, certain reactive functions located on group R5, R6, R7 or R2 can be
protected in the course of these couplings by protecting groups, as described in
"Protective Groups in Organic Synthesis", Green et al., 2nd Edition.
In schemes 1, 2, 3, the starting compounds and the reagents, when their manner of
preparation is not described, are commercially available or are described in the
literature, or else can be prepared according to methods that are described in the
literature or that are known by a person skilled in the art.
According to another of its aspects, the invention also relates to the compounds of
formulae (VII), (VIII), (XI). These compounds are useful as synthesis intermediates of
the compounds of formula (I).
The following examples illustrate the preparation of certain compounds according
to the invention. These examples are not limiting and their only purpose is to illustrate
the present invention. The numbers of the compounds in the examples refer to those
given in the following table, which presents the chemical structures and physical
properties of some compounds according to the invention.
The following abbreviations and empirical formulae are used:
EtOAc Ethyl acetate
CDI Carbonyldiimidazole
DCM Dichloromethane
°C degree Celsius
DME Dimethoxyethane
DMF Dimethylformamide
DMSO Dimethyl sulphoxide
EDC.HCI N-[3-(dimethylamino)propyl-N'-ethyl carbodiimide hydrochloride
BTUH 0-(-benzotria2ol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate.
h Hour(s)
HCI Hydrochloric acid
LiOH Lithium hydroxide
Na2CO3 Sodium carbonate
NH4CI Ammonium chloride
NaHCO3 Sodium hydrogen carbonate
Na2So4 Sodium sulphate
NaCI Sodium chloride
NaOH Sodium hydroxide
NH4OH Ammonium hydroxide
Na2SO4 Sodium sulphate
min. minutes
ml millilitre
P2O5 diphosphorus pentoxide
SEM 2-Trimethylsilanyl-ethoxymethyl
BTUT N-[(1H-benzotriazol-1-yloxy)(dimethylamino) methylidene]-N-
methylmethanaminium tetrafluoroborate
TFA Trifluoroacetic acid
THF Tetrahydrofuran
RT Room temperature
Tr retention time
TOSMIC Toulenesulphonylmethyl isocyanide
Xphos 2-Dicyclohexylphosphinol-2\4',6'-triisopropylbiphenyl
Equipment used:
> Microwave apparatus: Biotage, initiator
> Analysis conditions:
LC/UV/MS coupling conditions:
Instrument (Agilent): HPLC chain: Series 1100, Mass spectrometer MSD SL (Agilent),
Software: Chemstation version B.01.03 from Agilent
LC/UV
Column: Symmetry C18 3.5 urn (2.1 x 50 mm) (Waters), Column temp.: 25°C,
Post run: 5 min UV Detection: 220 nm. Injection volume: 2 pi of a solution at 0.5 mg/ml
Condition 1: pH 3 gradient 15 minutes
Eluents: A: H20 + 0.005% TFA / B: CH3CN + 0.005% TFA, Flow: 0.4 ml/min. Gradient: 0
to 10 min 0 to 100% B and from 10 to 15 min 100 B%
Condition 2: pH 3 gradient 30 minutes
Column: Symmetry C18 3.5 urn (2.1 x 50 mm) (Waters), Column temp.: 25°C, Eluents:
A: H20 + 0.005% TFA / B: CH3CN + 0.005% TFA, Flow: 0.4 ml/min. Gradient: 0 to 30
min 0 to 100% B and from 30 to 35 min 100 B%
Post run: 6 min. UV Detection: 220 nm. Injection volume: 2 ul of a solution at 0.5 mg/ml
Condition 3: pH 7 gradient 20 minutes
Column: X terra MS C18 3.5 urn (2.1X50 mm), Column temp.: 20°C Eluents: A H2O +
AcNH4 (5 nM) + 3% CH3CN / B: CH3CN. Gradient 0 to 20 min 0 to 100% of B. UV
Detection: 210 nm.
Condition GC CI/CH4+): ionization CI/CH4 +, 30 minutes
Column: Agilent HP-5MS 30 m x 250 urn film 0.25 urn thick. Temperature 250°C, Carrier
gas: Helium, constant flow 1.4 ml/min
MS:
ionization mode: Electrospray positive mode ESI+, mass range: 90-1500 uma
Spray Chamber Gas temp.: 350°C Drying gas (N2): 10.0 l/min Neb. pressure: 30 psig
Vcap: 4000 V
The 1H NMR spectra were obtained using NMR spectrometers Bruker 250, 300
or 400 MHz in DMSO-d6, using the peak of DMSO-d5 as reference. The chemical shifts
S are expressed in parts per million (ppm). The signals observed are expressed as
follows: s = singlet; d = doublet; t = triplet; m = multiplet or large singlet; H = proton.
The melting points below 260°C were measured with a Kofler bench and melting
points above 260°C were measured with a Buchi B-545 instrument.
The rotating powers were measured on a polarimeter of the type: Polarimeter
Perkin-Elmer, energy 55uA.
Example 1: 2-{6-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-
[1,8]naphthyridin-2-yl]-pyridin-3-yl}-N-pyridin-2-yl-acetamide (compound 2)
1.1 / 6-Chloro-2-(ethvlamino)pvridine-3-carboxylic acid
A solution of 18.0 g (84.4 mmol) of 2,6-dichloronicotinic acid in 180 ml (3.45 mol)
of a 70% solution of ethylamine in water is heated at 50°C for 10 hours. The excess
amine is then evaporated under reduced pressure, then a 10% aqueous solution of
acetic acid is added until the product is precipitated. The beige solid is filtered, rinsed
with cold water and stove-dried. 10.5 g of the expected product is obtained. Yield =
62%. Melting point: 158-160X. MH+: 201.1 (Tr: 7.7 min, condition 1).
1.2 / 6-Chloro-2-(ethvlamino)pvridine-3-carboxylic fluoride
4.2 ml (52.3 mmol) of pyridine and 8.4 ml (99.6 mmol) of cyanuric fluoride are
added successively to a suspension of 10.5 g (52.3 mmol) of the compound obtained at
the end of stage 1.1 in dichloromethane (250 ml). The mixture is stirred for 3 hours at
room temperature and then filtered. The solid is rinsed with dichloromethane (100 ml)
and the filtrate is washed twice with ice water (60 ml). The organic phase is dried over
Na2SO4 and then concentrated under reduced pressure. 10.44 g of product is obtained,
in the form of an orange oil. Yield = 99%. The product is used without purification in the
next stage.
1.3 / [1 -(2-Trimethvlsilanyl-ethoxvmethvl)-1 H-imidazol-2-vn-acetonitrile
Under inert atmosphere, 0.91 g (4.6 mmol) of TOSMIC in solution in anhydrous
DME (4 ml) is added to 0.96 g (8.6 mmol) of potassium tert-butylate in suspension in
4 ml of anhydrous DME at -35°C. The reaction mixture is cooled to -50°C then 1 g
(4.4 mmol) of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde (Whitten
JP, JOC 1986, 51 (10) 1891-1894) in solution in 4 ml of anhydrous DME is added
dropwise, keeping the temperature below -45°C. The reaction mixture is stirred at this
temperature for 30 min, then 11 ml of methanol is added, and the mixture is heated at
80°C for 15 minutes. The solvents are concentrated under reduced pressure, and the
residue is taken up in a water/acetic acid mixture (13 ml / 0.5 ml), the aqueous phase is
extracted with dichloromethane (3 X 100 ml), the organic phases are then washed with a
saturated solution of NaHC03, then dried over Na2SO4. After filtration, the filtrate is
concentrated under reduced pressure and the residue is purified by filtration on basic
alumina (eluent: A/B = DCM/AcEt 0 to 50% of B), 0.71 g of compound is thus obtained
in the form of a yellowish orange oil. Yield = 67%. MH+: 238 (Tr: 6.9 min, condition 1).
1H NMR (300MHz, DMSO-d6), d (ppm): 7.31 (d, 1H); 6.89 (d, 1H); 5.34 (s, 2H); 4.19 (s,
2H); 3.46 (dd, 2H); 0.87 (dd, 2H); 0 (s, 9H).
1.4 / 2-Amino-7-chloro-1-ethyl-3-ri-(2-trimethvlsilanvl-ethoxvmethvl)-1 H-imidazol-
2-vl1-1 H-f 1,81naphthvridin-4-one
Under inert atmosphere, 2.4 g (20.5 mmol) of potassium tert-butylate is added in
portions to 4.9 g (20.5 mmol) of the compound obtained at the end of stage 1.3, in
solution in anhydrous THF (50 ml) cooled to 0°C. After 45 minutes of stirring at room
temperature, the reaction mixture is cooled to 0°C, and 4.2 g (20.5 mmol) of the
compound obtained at the end of stage 1.2, in solution in anhydrous THF (20 ml), is
added dropwise. The mixture is stirred at room temperature for one hour, then 3.5 g
(30.8 mmol) of potassium tert-butylate is added and it is stirred for a further 2 hours.
500 ml of a saturated solution of ammonium chloride is added, and the medium is
acidified to pH=4 by adding a solution (1N) of HCI. The aqueous phase is extracted with
ethyl acetate (2x 500 ml). The organic phases are washed with a saturated solution of
sodium chloride, dried over Na2SO4, filtered and concentrated under reduced pressure.
The residue is purified by silica gel flash chromatography (eluent: A/B = DCM/Methanol,
from 0 to 5% of B). 6.1 g of compound is thus obtained in the form of a brown solid.
Yield = 70%. Melting point = 90°C MH+: 419 (Tr: 6.6 min, condition 1).
1H NMR (300MHz, DMSO-d6), d (ppm): 8.47 (d, 1H); 7:67 (s, 2H); 7.44 (d, 1H); 7.33 (d,
1H); 7.1 (d, 1H); 5.27 (s, 2H); 4.4d (q, 2H); 3.22 (dd, 2H); 1.28 (t, 3H); 0.63 (dd, 2H);
-0.2 (s, 9H).
1.5 / 2-Amino-1 -ethyl-3-H -(2-trimethvlsilanvl-ethoxvmethyl)-1 H-imidazol-2-yll-7-
trimethylstannanvl-1 H-[1,81naphthvridin-4-one
In a sealed tube, a solution of 2 g of the compound obtained at the end of stage
1.4 in 12 ml of dioxane is degassed with argon for 15 minutes, then 2.05 g (6.2 mmol) of
hexamethylditin, 0.16 g (0.50 mmol) of triphenylarsine and 0.54 g (0.75 mmol) of
bis(triphenylphosphine)dichloropalladium II are added successively under argon, then
the tube is closed. The reaction mixture is heated for 4.5 h at 85°C, then concentrated
under reduced pressure. The residue is purified directly on nitrile-grafted silica (eluent:
A/B = (heptane/DCM 1/1)/AcEt from 0 to 100% of B), 2 g of compound is obtained in the
form of a brown powder. Yield= 76%. Melting point = 76°C. MH+: 550 (Tr: 7.2 min,
condition 1).
1H NMR (400MHz, DMSO-d6), d (ppm): 8.28 (d, 1H, 7.5 Hz); 7.56 (d, 1H, 7.5 Hz); 7.53
(s, 2H); 7.32 (d, 1H, 1.3 Hz); 7.1(d, 1H, 1.3 Hz); 5.26 (s, 2H); 4.59 (q, 2H, 6.9 Hz); 3.18
(dd, 2H, 8.2- 8.04 Hz); 1.29 (t, 3H, 6.9 Hz); 0.6 (dd, 2H, 8.2- 8.04 Hz); 0 36 (t, 9H, 28
Hz); 0 (s, 9H).
1.6 /2-(6-Chloro-pvridin-3-vl)-N-pyridin-2-yl-acetamide
Under inert atmosphere, 6.2 g (38.5 mmol) of N,N-carbodiimidazole is added to a
suspension of 6 g (35 mmol) of 2-chloropyridylacetic acid in anhydrous THF (90 ml) at
room temperature. The reaction mixture is stirred at this temperature for 2 hours, then
5.4 g (57.7 mmol) of 2-aminopyridine is added and the mixture is heated for 2 hours
under reflux. 200 ml of dichloromethane is added to the reaction mixture, cooled
beforehand to room temperature, the organic phase thus obtained is washed with a
saturated solution of ammonium chloride, then with an aqueous solution of soda (1N),
dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is
purified by silica gel flash chromatography (eluent: A/B = dichloromethane / ethyl
acetate 0% to 70% of B). 5.6 g of compound is obtained in the form of a white powder.
Yield 65%. Melting point: 130°C. MH+: 248 (Tr: 5.6 min, condition 1).
1H NMR (400MHz, DMSO-d6), d (ppm): 10.81 (s, 1H); 8.3d (d, 1H, 2.3 Hz); 8.33 (ddd,
1H, 0.9-1.9-4.9 Hz); 8.03 (d, 1H, 8.2 Hz); 7.82 (dd, 1H, 2.5-8.2Hz); 7.77 (ddd, 1H, 1.9-
7.3, 8.2 Hz); 7.49 (d, 1H, 8.2Hz); 7.11 (ddd, 1H, 0.9-4.9-7.3Hz); 3.81 (s, 2H).
1.7 / 2-(6-{7-Amino-8-ethvl-5-oxo-6-n-(2-trimethvlsilanvl-ethoxvmethyl)-1H-
imidazol-2-vn-5,8-dihvdro-[1,8lnaphthyridin-2-yl}-pyridin-3-vl)-N-pyridin-2-vl-acetamide
A solution of 0.365 g (1.5 mmol) of the compound obtained at the end of stage
1.6 and of 1.2 g (2.2 mmol) of the compound obtained at the end of stage 1.5 in
anhydrous dioxane (7 ml) is degassed with argon for 10 minutes, then 0.170 g
(0.23 mmol) of palladium II dichlorodi(triphenylphosphine) and 0.05 g (0.16 mmol) of
triphenylarsine are added, the tube is sealed and the reaction mixture is heated at
100°C for 18 hours. The reaction mixture is diluted with 100 ml of dichloromethane, then
the organic phase is washed with a 10% aqueous ammonia solution, dried over Na2SO4,
filtered and concentrated under reduced pressure. The residue is purified by silica gel
flash chromatography (eluent: A/B = dichloromethane/methanol from 0% to 10% of B).
0.32 g of compound is obtained, in the form of a yellow powder. Yield: 37%. MH+: 597
(Tr: 6.1 min, condition 1)
1.8 / 2-{6-r7-Amino-8-ethvl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihvdro-
n,81naphthvridin-2-vn-pvridin-3-vl>-N-pyridin-2-vl-acetamide hydrochloride (compound 2)
Under inert atmosphere, 1 ml of trifluoroacetic acid in solution in 0.5 ml of
dichloromethane is added dropwise to a suspension of 0.2 g (0.34 mmol) of the
compound obtained at the end of stage 1.7 in suspension in dichloromethane (1 ml),
cooled to 0°C. The reaction mixture is stirred at this temperature for 10 minutes, then at
room temperature for 5 hours, then at 10°C overnight. The mixture is then poured into a
solution of Na2C03 (2N) (6 ml), previously cooled, the yellow precipitate formed is
filtered and rinsed with water, then dried under vacuum over P205. The solid is purified
by silica gel flash chromatography (eluent: A/B =dichloromethane/(methanol/1%
NH4OH), from 0% to 10% of B). 0.14 g of compound is obtained in the form of a yellow
powder. Yield 87%. 0.1 ml of a concentrated HCI solution (35%) is added dropwise to
0.14 g (0.3 mmol) of this compound in suspension in methanol, the mixture is then
stirred at room temperature for 45 minutes, then concentrated under reduced pressure.
The solid is triturated in diethyl ether, filtered and dried under vacuum over P205. 0.15 g
of hydrochloride compound is thus obtained in the form of beige powder. Yield: 86%.
Melting point= 200°C. MH+ 467.2 (Tr: 5.49 min, condition 1)
1H NMR (400MHz, DMSO-d6), d (ppm): 11.47 (s, 1H); 8.76 (d, 1H, 1.9Hz); 8.59 (d, 1H, 8
Hz); 8.52 (d, 1H, 8.2 Hz); 8.39 (d, 1H, 8 Hz); 8.36 (m, 1H); 8.08 (dd, 1H, 2-8.3 Hz); 8.03
(d, 1H, 8.3 Hz); 7.92 (m, 1H); 7.82 (s broad, 1H+ 1 HCI); 7.66 (s, 2H); 7.22 (m, 1H); 5.52
(s, 2 H+ 2 HCI); 4.7d (m, 2H); 4.0 (s, 2H); 1.37 (t, 3H, 6.85Hz).
Example 2: 2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-
[1,8]naphthyridin-2-yl]-phenyl}-N-(4-cyclopropyl-morpholin-3-ylmethyl)-acetamide
(compound 3)
2.1 / ethyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenvnacetate
A mixture of 9.5 g (33 mmol) of (4-iodo-phenyl)-ethyl acetate and of 9.2 g
(36 mmol) of bispinacolatodiborane in solution in anhydrous dimethylsulphoxide (65 ml)
is degassed with argon for 15 minutes, then 28 g (98 mmol) of potassium acetate and
1.34 g (1.6 mmol) of palladium dichloro(phosphinoferrocene) are added and the reaction
mixture is heated at 55°C for 1.5 h under argon. The reaction mixture is diluted with
220 ml of ethyl acetate, then the organic phase is washed three times with water
(200 ml), then dried over Na2SO4, and concentrated under reduced pressure. 11 g of
compound is obtained in the form of a brown oil, but is used as it is in the next stage.
MH+: 291.2 (Tr: 9.4 min, condition 1)
2.2 / (4-{7-Amino-8-ethvl-5-oxo-6-ri-(2-trimethvlsiianyl-ethoxvmethvl)-1 H-
imidazol-2-vn-5,8-dihvdro-[1,8lnaphthvridin-2-vl>-phenvlVaceticacid
In a tube, a suspension of 0.7 g (2.4 mmol) of the compound obtained at the end
of stage 2.1, 0.5 g (1.2 mmol) of the compound obtained at the end of stage 1.4 and
3.3 ml of a saturated solution of hydrogen carbonate in 7 ml of a mixture of DME/ethanol
(2/1), is degassed with argon for 10 minutes, then 0.08 g (0.07 mmol) of palladium
tetrakistriphenylphosphine is added and the tube is sealed. The reaction mixture is
heated at 170°C for 15 minutes in a microwave (Biotage initiator). The reaction mixture
is then taken up in water, and acidified by adding 1N HCI solution. The solid is collected
by filtration, rinsed with water and then dried over P205 under vacuum. 0.87 g of product
is obtained in the form of a mixture of acid and ester. This mixture is used directly in the
next stage.
0.1 g (2.4 mmol) of lithium hydroxide monohydrate is added to 0.87 g of the
mixture of acid and ester obtained at the end of the preceding stage, in suspension in a
solvent mixture THF/water/methanol (1/1/1). The reaction mixture is heated at 70°C for
5 hours. 3.5 ml of water is added to the reaction mixture cooled to room temperature,
followed by addition of HCI solution (1N) to pH 1. The solid is collected by filtration,
rinsed with dichloromethane, then dried over P205 under vacuum. 0.4 g of product is
thus isolated, without any other purification, in the form of grey powder. Yield: 62% for
the two stages. Melting point: 220°C. MH+: 467.2 (Tr: 5.49 min, condition 1).
1H NMR (400MHz, DMSO-d6), 8 (ppm): 14.42 (s, 1H); 12.46 (s, 1H); 8.46 (d, 1H, 7.2
Hz); 8.19 (d, 2H, 7.2 Hz); 8.02 (d, 1H, 7.2 Hz); 7.89 (s, 1H); 7.83 (s, 1H); 7.58 (s, 2H);
7.47 (d, 2H, 7.2 Hz); 5.3d (s, 2H); 4.68 (m, 2H); 3.7(s, 2H); 3 42 (m, 2H); 1.37(m, 3H);
0.77 (m,2H);-0.11(8, 9H).
2.3/4-Cvclopropvl-morpholine-3-carboxamide
2.9 g of molecular sieve 3A, 4.3 g (72 mmol) of acetic acid, 7.6 g (43.2 mmol) of
2(1-ethoxy-cyclopropyl)oxy]trimethylsilane and 4.4 g (31.7 mmol) of sodium
cyanoborohydride are added successively to 1.2 g (7.2 mmol) of morpholine-3-
carboxylic acid amide hydrochloride (WO2005026156 Hennequin L.F.A. et al.) in
solution in methanol (36 ml). The reaction mixture is heated at 70°C for 3.5 hours, then
cooled to room temperature and filtered. The filtrate is concentrated under reduced
pressure, then the residue is taken up in dichloromethane (200 ml) and washed 3 times
with an aqueous solution of NaOH (1N) (100 ml). The organic phase is dried over
Na2SO4, filtered and then concentrated under reduced pressure. 0.58 g of product is
obtained, in the form of a white powder. Yield 47%. Melting point 116°C. MH+: 171 (Tr:
1.03 min, condition 2).
1H NMR (250MHz, DMSO-d6), d (ppm):7.33 (s, 1H); 6.98 (s, 1H); 3.67-3.43 (m broad,
4H); 2.97 (dd, 2H, 7.3 - 3.6 Hz); 2.3d (ddd, 1H, 11.7-8.3-3.4 Hz); 1.89(ddd, 1H, 10.3-
6.6- 3.6 Hz); 0.56-0.22 (m broad, 4H).
2.4/ 1-(4-cyclopropvlmorpholin-3-yl)methanamine hydrochloride
Under inert atmosphere, 13.6 ml (13.6 mmol) of a solution (1N) of triborohydride
complexed with tetrahydrofuran in THF is added dropwise to a solution of 0.58 g
(3.4 mmol) of the compound obtained at the end of stage 2.3, in anhydrous THF, cooled
to 0°C. The reaction mixture is heated at 70°C for 3h. 15 ml of a solution (1N) of HCI is
added to the reaction mixture cooled to room temperature, after 30 min of stirring the
aqueous phase is decanted and extracted twice with ether (15 ml) then basified by
adding soda solution (1N). The aqueous phase is then extracted with ethyl acetate 4
times (20 ml) and with dichloromethane 4 times (20 ml). The combined organic phases
are dried over Na2SO4, filtered and concentrated under reduced pressure. The residue
is taken up in methanol (4 ml) and 3.4 ml of a solution of HCI (1N) in ether is added, the
solution is stirred for 30 minutes then 5 ml of ether is added, the solid formed is
collected by filtration and dried under vacuum over P2O5. 0.51 g of product is obtained,
in the form of a white powder. Yield 78%. MH+: 157 (Tr: 0.4 min, condition 2).
1H NMR (400MHz, DMSO-d6), d (ppm): 11.67(s, 1H); 8.07 (m, 2H); 4.09 (m, 1H); 3.94
(m, 1H); 3.74 (m, 2H); 3.54 (m, 2H); 3.36 (m, 1H); 3.2 (m, 1H); 2.99 (m, 1H); 1.2d (m,
1H); 1.09-0.72 (m,4H).
2.5/ 2-f4-r7-amino-8-ethvl-5-oxo-6-(1 -ff2-(trimethvlsilvl)ethoxv1methylM H-
imidazol-2-vl)-5,8-dihvdro-118-naphthvridin-2-yllphenvl)-N-f(4-cvclopropylmorpholin-3-
vQmethvnacetamide
Under inert atmosphere, 0.4 ml (2.3 mmol) of diisopropyl ethyl amine is added to
0.4 g (0.8 mmol) of the compound obtained at the end of stage 2.2, in suspension in
DMF (8 ml); after dissolution, the reaction mixture is cooled to 0°C then a solution, in
DMF (2 ml), of 0.18 g (0.94 mmol) of the compound obtained at the end of stage 2.4
and of 0.2 ml (1.2 mmol) of diisopropyl ethyl amine is added, followed by addition of
0.275 g (0.86 mmol) of BTUT. The reaction mixture is stirred at room temperature for 3
hours, then concentrated to dryness. The residue is purified directly by silica gel flash
chromatography (eluent: A/B = dichloromethane/methanol (1% NH40H) gradient from 0
to 10% of B). 0.34 g of product is obtained in the form of a yellow powder. Yield: 65%.
Melting point: 116°C.
MH+: 657 (Tr: 5.51 min, condition 1)
2.6/ 2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-vl)-5-oxo-5.8-dihydro-
[1,81naphthvridin-2-vll-phenyl)-N-(4-cvclopropvl-morpholin-3-vlmethvl)-acetamide
hydrochloride (compound 3)
1.4 ml (19 mmol) of trifluoroacetic acid in solution in 0.4 ml of dichloromethane is
added dropwise to 0.3 g (0.47 mmol) of the compound obtained at the end of stage 2.5,
in solution in 0.4 ml dichloromethane, cooled to -10°C, then the reaction mixture is
stirred at 5°C overnight and then poured into a solution of Na2C03 (2M) (10 mi) in the
cold (ice bath). The yellow precipitate formed is collected by filtration and rinsed with
water, and then dried over P205 under vacuum. The 0.18 g of solid is taken up in 2 ml of
methanol and 70 ul of a 36% solution of HCI is added, the mixture is stirred for one hour
at room temperature, then concentrated under vacuum. The residue is purified by flash
chromatography on a C8 reverse phase column (eluent: water HCI {H11000). 0.034 g of
product is obtained in the form of a yellow powder. Yield = 16%. Melting point: 210°C.
MH+: 528.2 (Tr: 4.78 min, condition 1).
1H NMR (400MHz, DMSO-d6), d (ppm): 11.29 (s, 1H); 8.52 (d, 1H, 8.2 Hz); 8.48 (s, 1H
exchangeable); 8.18 (d, 2H + 1H exchangeable, 8.3 Hz); 7.99 (d, 1H + 1H
exchangeable, 8.2 Hz); 7.54 (s, 2H); 7.48 (d, 2H, 8.3 Hz); 4.7 (q broad, 2H, 7 Hz); 3.91
(m, 3H); 3.73 (m, 1H); 3.58 (s, 3H); 3.47 (m, 2H); 3.34 (m, 2H); 2.93 (m, 1H); 1.36 (t,
3H, 7Hz); 1.2d (m, 1H); 0.9d (m, 2H); 0.81 (m, 1H).
Example 3: 2-{4-[7-Amino-8-ethyl-6-(1 H-imidazol-2-yl)-5-oxo-5,8-dihydro-
[1,8]naphthyridin-2-yl]-phenyl}-N-pyridin-4-ylmethyl-propionamide (compound 47)
3.1/ ethyl 2-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-vl)phenyflpropanoate
Same procedure as that described in example 2, stage 2.1, starting from 0.6 g
(2 mmol) of ethyl 2-(4-iodophenyl)propanoate in solution in anhydrous DMSO (4 ml),
0.57 g (2.2 mmol) of bispinacolatodiborane, 1.7 g (6 mmol) of potassium acetate and
83 mg (0.1 mmol) of palladium dichloro(phosphinoferrocene). 0.9 g of compound is
obtained in the form of a brown oil, used as it is in the next stage. MH+: 30d (Tr: 9.9 min,
condition 1)
3.2/ 2-(4-r7-amino-8-ethvl-5-oxo-6-(1-{r2-(trimethvlsilvl)ethoxv1methvlV1H-
imidazol-2-vl)-5,8-dihvdro-1,8-naphthyridin-2-vnphenvl>propanoic acid
Same procedure as that described in example 2, stage 2.2, starting from 0.57 g
(1.4 mmol) of the compound obtained at the end of stage 3.1, 0.82 g (2.7 mmol) of the
compound obtained at the end of stage 1.4, 94 mg (0.08 mmol) of palladium
tetrakistriphenylphosphine, 4 ml of a saturated solution of hydrogen carbonate in a
mixture of DME/ethanol (2/1) (7 ml), 1.1 g of product is obtained in the form of a mixture
of acid and ester. This mixture is used directly in the next stage, in the presence of
0.16 g (3.8 mmol) of lithium hydroxide monohydrate suspension in a solvent mixture
THF/water/methanol (1/1/1) (10 ml). 0.4 g of product is obtained in the form of brown
powder. Yield: 39% for the two stages. Melting point: 248°C. MH+ 534.1 (Tr: 6.5 min,
condition 1)
3.3/ 2-{4-r7-amino-8-ethvl-5-oxo-6-(1-{r2-(trimethvlsilvl)ethoxv1methvlV1H-
imidazol-2-yl)-5,8-dihydro-1,8-naphthyridin-2-yllphenylVN-(pyridin-4-
ylmethvDpropanamide
Same procedure as that described in example 2, stage 2.5, starting from 0.3 g
(0.56 mmol) of the compound obtained at the end of stage 3.2, 0.25 g (2.25 mmol) of 1-
(pyridin-4-yl)methanamine, 0.36 g (1.1 mmol) of BTUT and 0.14 g (1.1 mmol) of
diisopropylethylamine in anhydrous DMF (5 ml), 0.29 g of product is obtained in the form
of yellow powder. Yield: 82%. Melting point: 140°C. MH+: 624 (Tr: 5.66 min, condition 1).
3.4/ 2-f4-r7-Amino-8-ethyl-6-(1H-imidazol-2-vlV5-oxo-5.8-clihvclro-
f1,81naphthyridin-2-vll-phenylVN-pyridin-4-vlmethvl-propionamide (compound 47)
Same procedure as that described in example 2, stage 2.6, starting from 0.26 g
(0.42 mmol) of the compound obtained at the end of stage 3.3 in solution in 1.2 ml of
dichloromethane, 1.3 ml (17 mmol) of trifluoroacetic acid in solution in 0.5 ml of
dichloromethane. 0.051 g of product is obtained in the form of a yellow powder. Yield =
24%. Melting point: 186°C. MH+: 494.2 (Tr: 5.05 min, condition 1).
1H NMR (400MHz, DMSO-d6), d (ppm): 13.20 (s, 1H); 11.51 (s, 1H); 8.62 (m, 2H); 8.45
(dd, 2H, 4.5, 1.5 Hz); 8.29 (d, 2H, 8.2 Hz); 8.02 (s broad, 1H exchangeable); 7.97 (d,
1H, 8.2 Hz); 7.53 (d, 2H, 8.2 Hz); 7.16 (m, 3H); 7.04 (m, 1H); 4.72 (m, 2H); 4.29 (d, 2H,
6 Hz); 3.81 (q, 1H, 7 Hz); 1.4d (d, 3H, 7.1 Hz); 1.38 (t, 3H, 7 Hz).
Example 4: 4-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-
[1,8]naphthyridin-2-yl]-phenyl}-N-pyridin-4-ylmethyl-butyramide (compound 49)
4.1/ 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenvnbutanoic acid
Same procedure as that described in example 2, stage 2.1, starting from 0.3 g
(1 mmol) of 4-(4-iodophenyl)butanoic acid in solution in anhydrous DMSO (2 ml), 0.29 g
(1.1 mmol) of bispinacolatodiborane, 0.3 g (3.1 mmol) of potassium acetate and 42 mg
(0.05 mmol) of palladium dichloro(phosphinoferrocene). 0.21 g of compound is obtained
in the form of a brown oil, used as it is in the next stage. MH+: 291 (Tr. 8.35 min,
condition 1)
4.2/ 4-r4-(7-amino-8-ethvl-5-oxo-6-{1-r2-(trimethvlsilvl)ethoxvl-1H-imidazol-2-yl>-
5,8-dihydro-1,8-naphthyridin-2-vl)phenynbutanoic acid
Same procedure as that described in example 2, stage 2.2, from 0.17 g
(0.57 mmol) of the compound obtained at the end of stage 4.1, 0.18 g (0.44 mmol) of
the compound obtained at the end of stage 1.4, 25 mg (0.02 mmol) of palladium
tetrakistriphenylphosphine, 1.2 ml of a saturated solution of hydrogen carbonate in a
mixture of DME/ethanol (2/1) (3 ml), 0.25 g of product is obtained in the form of a brown
oil used as it is in the next stage. MH+: 548 (Tr: 6.5 min, condition 1)
4.3/ 4-r4-(7-amino-8-ethvl-5-oxo-6-{1-f2-(trimethvlsilyl)ethoxv1-1H-imidazol-2-vl)-
5,8-dihvdro-1,8-naphthvridin-2-vnphenvll-N-(pvridin-4-vlmethv1)butanamide
Same procedure as that described in example 2, stage 2.5, starting from 0.5 g
(0.46 mmol) of the compound obtained at the end of stage 4.2, 0.2 g (1.8 mmol) of 1-
(pyridin-4-yl)methanamine, 0.3 g (0.9 mmol) of BTUT and 0.12 g (0.9 mmol) of
diisopropylethylamine in anhydrous DMF (5 ml), 0.1 g of product is obtained in the form
of beige powder. Yield: 34%. Melting point: 223°C. MH+: 638 (Tr: 5.75 min, condition 1).
4.4/ 4-{447-Amino-8-ethvl-6-(1H-imidazol-2-vl)-5-oxo-5,8-dihydro-
[1,81naphthyridin-2-yll-phenyl}-N-pyridin-4-ylmethyl-butvramide (compound 49)
Same procedure as that described in example 2, stage 2.6, starting from 0.095 g
(0.15 mmol) of the compound obtained at the end of stage 4.3 in solution in 0.5 ml of
dichloromethane, 0.44 ml (6 mmol) of trifluoroacetic acid in solution in 0.3 ml of
dichloromethane. 0.045 g of product is obtained in the form of a yellow powder. Yield =
60%. Melting point: 240°C. MH+: 508.2 (Tr: 4.97 min, condition 1).
1H NMR (400MHz, DMSO-d6), d (ppm): 13.21 (s, 1H); 11.48 (s, 1H); 8.61 (d, 1H, 8 Hz);
8.49 (d, 2H, 4.5 Hz); 8.44 (t, 1H, 6 Hz); 8.4d (s broad, 1H exchangeable); 8.17 (d, 2H,
8.1 Hz); 7.97 (d, 1H, 8.1 Hz); 7.39 (t, 2H, 8.1 Hz); 7.24 (d, 1H, 4.8Hz); 7.1d (s, 1H); 7.03
(s, 1H); 4.72 (m, 2H); 4.30 (d, 2H, 5.8 Hz); 3.81 (q, 1H, 7 Hz); 2.68 (t, 2H, 7.5 Hz); 2.24
(t, 2H, 7.3 Hz); 1.92 (m, 2H); 1.38 (t, 3H, 7 Hz).
Example 5: 2-{4-[7-Amino-8-ethyl-6-(4-methyl-1 H-imidazol-2-yl)-5-oxo-5,8-
dihydro-[1,8]naphthyridin-2-yl]-phenyl}-N-pyridin-4-ylmethyl-acetamide
(compound 50)
5.1/[1-(2-Trimethvlsilanvl-ethoxymethvl)-1H-(4-methyl-1H-imidazol-2-
vDacetonitrile
Same procedure as that described in example 1, stage 1.3, starting from 4.6 g
(19 mmol) of [1-(2-Trimethylsilanyl-ethoxymethyl)-1H-(4-methyl-1H-imidazol-2-
yl)carbaldehyde, 4 g (20.3 mmol) of TOSMIC and 4.3 g of potassium tert-butylate in
solution in anhydrous DME (32 ml). 2.2 g of compound is obtained in the form of a
yellow oil as 70/30 mixture of x and 7t regioisomers (Yield 45%. MH+: 252 (Tr: 6.38 and
6.55 min, condition 1)
5.2/ 2-amino-7-chloro-1-ethvl-3-(4-rriethvl-1-(f2-(trimethvlsilvl)ethoxv1methvl>-1H-
imidazol-2-yl)-1,8-naphthyridin-4(1 H)-one
Same procedure as that described in example 1, stage 1.4, starting from 1 g
(4 mmol) of the compound obtained at the end of stage 5.1, 0.8 g (4 mmol) of the
compound obtained at the end of stage 1.2 and 1.15 g (10 mmol) of potassium tert-
butylate in solution in anhydrous THF (13 ml). 0.42 g of product is obtained in the form
of a beige powder. Yield 24%. Melting point: 120°C. MH+: 43d (Tr: 10.5 and 10.6 min,
condition 1)
5.3/ (4-r7-amino-8-ethvl-6-(4-methvl-1-{r2-(trimethvlsilvl)ethoxvlmethvl>-1H-
imidazol-2-vl)-5-oxo-5,8-dihvdro-1,8-naphthvridin-2-vnphenyl>aceticacid
Same procedure as that described in example 2, stage 2.2, starting from 0.42 g
(1 mmol) of the compound obtained at the end of stage 5.2, 0.84 g (2.9 mmol) of the
compound obtained at the end of stage 2.1, 67 mg (0.06 mmol) of palladium
tetrakistriphenylphosphine, 1.2 ml of a saturated solution of hydrogen carbonate in a
solvent mixture DME/EtOH (2/1) (7 ml). 0.69 g of product is obtained in the form of a
mixture of acid and ester. This mixture is used directly in the next stage, in the presence
of 0.12 g (3 mmol) of lithium hydroxide monohydrate suspension in a solvent mixture
THF/water/methanol (1/1/1) (7 ml). 0.67 g of product is obtained in the form of brown
powder used without purification. MH+: 534 (Tr: 4.38 min, condition 1).
5.4/ 2-{4-r7-amino-8-ethyl-6-(4-methvl-1-fr2-(trimethvlsilvl)ethoxv1methvlV1H-
imidazol-2-vl)-5-oxo-5,8-dihvdro-1,8-naphthvridin-2-vnphenvl>-N-(pvridin-4-
ylmethvDacetamide
Same procedure as that described in example 2, stage 2.5, starting from 0.67 g
(1.2 mmol) of the compound obtained at the end of stage 5.3, 0.55 g (5 mmol) of 1-
(pyridin-4-yl)methanamine, 0.8 g (2.5 mmol) of BTUT and 0.32 g (2.4 mmol) of
diisopropylethylamine in anhydrous DMF (12 ml), 0.22 g of product is obtained in the
form of yellow powder. Yield: 28%. MH+: 624 (Tr: 5.6 min, condition 1).
5.5/ 2-(4-f7-Amino-8-ethvl-6-(4-methvl-1H-imidazol-2-vn-5-oxo-5,8-dihydro-
f1,8lnaphthvridin-2-vl1-phenvl)-N-pvridin-4-vlmethvl-acetamide salt of TFA (compound
50)
Same procedure as that described in example 2, stage 2.6, starting from 0.22 g
(0.36 mmol) of the compound obtained at the end of stage 5.4 in solution in 0.5 ml of
dichloromethane, 1.6 ml (14 mmol) of trifluoroacetic acid in solution in 0.5 ml of
dichloromethane, purification by HPLC. 0.124 g of product, in the form of salt of
trifluoroacetic acid, is obtained in the form of a yellow powder. Yield = 60%. Melting
point: 144°C. MH+: 494 (Tr: 4.54 min, condition 1).
1H NMR (400MHz, DMSO-d6), d (ppm): 8.83 (t, 1H, 5.9 Hz); 8.68 (d, 2H, 5.2 Hz); 8.52
(d, 1H, 8.1 Hz); 8.19 (d, 2H, 8.3 Hz); 8.09 (s broad, 1H exchangeable); 8.0 (d, 1H, 8.2
Hz); 7.6 (d, 2H, 5.9 Hz); 7.d (d, 2H, 8.3 Hz); 7.2 (s, 1H); 4.7 (m, 2H); 5.4-4 (s broad, 2H
exchangeable); 4.46 (d, 2H, 6 Hz); 3.66 (s, 2H); 2.3 (s, 3H); 1.4 (t, 3H, 7 Hz)
Example 6: 2-{4-[7-Amino-8-cyclopropylmethyl-6-(1 H-imidazol-2-yl)-5-oxo-
5,8-dihydro-[1,8]naphthyridin-2-yl]-phenyl}-N-pyridin-4-ylmethyl-acetamide
(compound 51)
6.1/ 6-chloro-2-[(cvclopropvlmethvl)amino]pyridine-3-carboxylic acid
In a sealable tube, 3 g (42 mmol) of cyclopropylmethylamine is added to 3 g
(14 mmol) of 2,6-dichloronitinic acid in solution in terf-butanol (14 ml), the tube is sealed
and heated at 170°C for 30 minutes in a Biotage Initiator microwave. The reaction
mixture is cooled to room temperature, diluted in dichloromethane (100 ml) and washed
with a 10% aqueous solution of acetic acid (12 ml). The organic phase is dried over
Na2SO4, filtered, concentrated and dried under vacuum. 3.4 g of product is obtained in
the form of an orange oil. Yield is quantitative. MH+: 227 (Tr: 4.54 min, condition 1)
6.2 /6-chloro-2-f(cvclopropvlmethvl)amino1pyridine-3-carbonvl fluoride
Same procedure as that described in example 1, stage 1.2, starting from 0.43 g
(2 mmol) of the compound obtained at the end of stage 6.1 in solution in 4 ml of
dichloromethane, 0.52 g (3.8 mmol) of cyanuric fluoride, and 0.4 g (3.8 mmol) of
triethylamine. The product, obtained in the form of a green oil, is used without
purification in the next stage.
6.3/ 2-amino-7-chloro-1-(cvclopropylmethvl)-3-(Hr2-
(trimethvlsilvl)ethoxv1methyl)-1 H-imidazol-2-yl)-1,8-naphthvridin-4(1 H)-one
Same procedure as that described in example 1, stage 1.4, starting from 0.43 g
(2 mmol) of the compound obtained at the end of stage 6.2, 0.5 g (2 mmol) of the
compound obtained at the end of stage 1.3 in solution in 6 ml of anhydrous THF and
0.55 g (5 mmol) of potassium tert-butylate and 0.4 g (3.8 mmol) of triethylamine. 0.5 g of
product is obtained in the form of a brown powder. Yield = 60%. Melting point: 70°C.
MH+: 447 (Tr: 6.68 min, condition 1).
6.4/ (4-f7-am ino-8-(cvclopropylmethvl)-5-oxo-6-( 1 -([2-
(trimethylsilyl)ethoxv1methvl)-1H-imidazol-2-vl)-5,8-dihvdro-1,8-naphthyridin-2-
yllphenvDacetic acid
Same procedure as that described in example 2, stage 2.2, starting from 0.44 g
(1 mmol) of the compound obtained at the end of stage 6.3, 1 g (3.5 mmol) of the
compound obtained at the end of stage 2.1, 70 mg (0.06 mmol) of palladium
tetrakistriphenylphosphine, 2.8 ml of a saturated solution of hydrogen carbonate in a
solvent mixture DME/EtOH (2/1) (8 ml). 0.8 g of product is obtained in the form of a
mixture of acid and ester. This mixture is used directly in the next stage, in the presence
of 0.15 g (3.6 mmol) of lithium hydroxide monohydrate in suspension in a solvent
mixture THF/water/methanol (1/1/1) (9 ml). 0.91 g of product is obtained in the form of
brown powder, used without purification in the next stage. MH+: 546 (Tr: 4.39 min,
condition 1).
6.5/ 2-{4-f7-amino-8-(cvclopropylmethvl)-5-oxo-6-(1-{f2-
(trimethvlsilvl)ethoxv1methvl>-1H-imidazol-2-vl)-5,8-dihvdro-1,8-naphthvridin-2-yllphenvlV
N-(pvridin-4-ylmethvl)acetamide
Same procedure as that described in example 2, stage 2.5, starting from 0.9 g
(1.7 mmol) of the compound obtained at the end of stage 6.4, 0.73 g (6.7 mmol) of 1-
(pyridin-4-yl)methanamine, 1.1 g (3.3 mmol) of BTUT and 0.43 g (3.3 mmol) of
diisopropylethylamine in anhydrous DMF (17 ml), 0.3 g of product is obtained in the form
of beige powder. Yield: 28%. Melting point: 114°C. MH+: 63d (Tr: 5.6 min, condition 1).
6.6/ 2-(4-r7-Amino-8-cvclopropvlmethyl-6-(1H-imidazol-2-vl)-5-oxo-5,8-dihvdro-
n,81naphthvridin-2-yll-phenvl)-N-pvridin-4-vlmethyl-acetamide salt of TFA (compound
51)
Same procedure as that described in example 2, stage 2.6, starting from 0.28 g
(0.45 mmol) of the compound obtained at the end of stage 6.5 in solution in 1.5 ml of
dichloromethane, 1.3 ml (18 mmol) of trifluoroacetic acid in solution in 0.8 ml of
dichloromethane. 0.2 g of product is obtained in the form of a yellow powder. Yield =
60%. Melting point: 118°C. MH+: 506 (Tr: 4.96 min, condition 1).
1H NMR (400MHz, DMSO-d6), S (ppm): 8.8d (t, 1H, 5.7 Hz); 8.7 (d, 2H, 5.8 Hz); 8.58 (s
broad, 1H exchangeable); 8.56 (d, 1H, 8.1 Hz); 8.16 (d, 2H, 8.1 Hz); 8.0 (d, 1H, 8.2 Hz);
7.64 (d, 2H, 5.8 Hz); 7.50 (d, 2H, 8.2 Hz); 7.4 (s, 2H); 4.7 (m, 2H); 5.4-4.0 (s broad, 2H
exchangeable); 4.50 (d, 2H, 5.8 Hz); 3.67 (s, 2H); 1.4 (m, 1H); 0.6 (m, 2H); 0.d (m, 2H).
Example 7: 2-{5-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-
[1,8]naphthyridin-2-yl]-pyridin-2-yl}-N-pyridin-4-ylmethyl-acetamide (compound
53)
7.1/2-(5-bromopvridin-2-vl)-N-(pyridin-4-vlmethvl)acetamide
Same procedure as that described in example 2, stage 2.5, starting from 0.33 g
(1.5 mmol) of (5-bromo-pyridin-2-yl)-acetic acid (a synthesis of which is described in
Tetrahedron, 1997, 53(24) 8257-8268 Gurnos J. et al.), 0.67 g (6.1 mmol) of 1-(pyridin-
4-yl)methanamine, 1 g (3 mmol) of BTUT and 0.4 g (3 mmol) of diisopropylethylamine in
anhydrous DMF (15 ml), 0.59 g of product is obtained in the form of beige powder, used
without purification in the next stage. MH+: 307 (Tr: 2.92 min, condition 1).
7.2/ 2-{5-r7-amino-8-ethvl-5-oxo-6-(1-fr2-(trimethvlsilvl)ethoxv1methvl)-1H-
imidazol-2-vl)-5,8-dihydro-1,8-naphthvridin-2-ynpvridin-2-vl>-N-(pvridin-4-
ylmethvDacetamide
Same procedure as that described in example 1, stage 1.7, starting from 0.58 g
(1.9 mmol) of the compound obtained at the end of stage 7.1, 1.2 g (2.3 mmol) of the
compound obtained at the end of stage 1.5, 220 mg (0.3 mmol) of palladium II
dichlorodi(triphenylphosphine) and 65 mg (0.21 mmol) of triphenylarsine in solution in
9 ml of anhydrous dioxane. 0.38 g of compound is obtained, in the form of a yellow
powder. Yield: 32%. MH+: 611 (Tr: 5.43 min, condition 1).
7.3/ 2-(5-r7-Amino-8-ethvl-6-(1H-imidazol-2-vl)-5-oxo-5.8-dihvdro-
F1,81naphthvridin-2-vn-pvridin-2-vl)-N-pyridin-4-vlmethvl-acetamide (compound 53)
Same procedure as that described in example 1, stage 1.8, starting from 0.36 g
(0.6 mmol) of the compound obtained at the end of stage 7.2 in solution in 1.8 ml of
dichloromethane, 1.8 ml (24 mmol) of trifluoroacetic acid in solution in 1ml of
dichloromethane. 0.314 g of product is obtained in the form of a yellow powder. Yield =
78%. Melting point: 120°C. MH+: 481 (Tr: 4.32 min, condition 1).
1H NMR (400MHz, DMSO-d6), d (ppm): 9.38 (d, 1H, 2.3 Hz); 8.93 (t, 1H, 6 Hz); 8.77 (d,
2H, 6.3 Hz); 8.68 (s broad, 1H exchangeable); 8.62 (d, 1H, 8Hz); 8.57 (dd, 1H, 8.2, 2.4
Hz); 8.1 (d, 1H, 8 Hz); 7.77 (d, 2H, 6 Hz); 7.60 (d, 1H, 8.2Hz); 7.41 (s, 2H); 4.71 (m,
2H); 5.4-4 (s broad, 2H exchangeable); 4.54 (d, 2H, 6 Hz); 3.90 (s, 2H); 1.38 (t, 3H, 7
Hz).
Example 8: 2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-
[1,8]naphthyridin-2-yl]-2-fluoro-phenyl}-N-(1-ethyl-pyrrolidin-2-ylmethyl)-
acetamide (compound 56)
8.1/ (4-bromo-2-fluorophenyl)acetic acid
0.09 g of lithium hydoxide monohydrate is added to 0.37 g (1.4 mmol) of ethyl
ester of (4-bromo-2-fluorophenyl)acetic acid in solution in 8 ml of a solvent mixture
THF/methanol/water (1/1/1), and the reaction mixture is stirred for 3h at room
temperature. The reaction mixture is acidified with 1N HCI solution, then extracted with
dichloromethane (20 ml). The organic phases are combined, dried over Na2SO4, filtered
and concentrated under reduced pressure. 0.3 g of product is obtained in the form of
gum and is used without purification in the next stage. Yield 91%.
8.2/ (4-bromo-2-fluorophenvl)acetyl chloride
0.3 g (2.4mmol) of oxalyl chloride is added to 0.28 g (1.2mmol) of the
compound obtained at the end of stage 8.1 in solution in 7 ml of 1,2-dichloroethane. The
reaction mixture is stirred at room temperature for 1.5 h and then concentrated under
reduced pressure. 0.322 g of compound is obtained in the form of an oil and is used
without purification in the next stage.
8.3/2-(4-bromo-2-fluorophenvl)-N-f(1-ethvlpvrrolidin-2-vl)methvllacetamide
0.15 g (1.2mmol) of 1-(1-ethylpyrrolidin-2-yl)methanamine is added to 0.3 g
(1.2 mmol) of the compound obtained at the end of stage 8.2 in solution in 8 ml of
dichloromethane cooled by an ice bath and under inert atmosphere, and it is stirred for a
further 4h. The reaction mixture is diluted with 20 ml of dichloromethane and washed
with 20 ml of water, then the organic phase is dried over Na2SO4, filtered and
concentrated under reduced pressure. The residue is then purified by silica gel flash
chromatography (eluent: A/B = dichloromethane/methanol (1% NH40H) gradient from 0
to 10% of B). 0.2 g of product is obtained in the form of a beige powder. Yield: 50%.
MH+ 343 (Tr: 4.94 min, condition 1).
8.4/ 2-{4-r7-amino-8-ethvl-5-oxo-6-(1-(r2-(trimethvlsilvnethoxv1methvlV1H-
imidazol-2-vl)-5,8-dihvdro-1,8-naphthvridin-2-vl1-2-fluorophenvl)-N-r(1-ethvlpyrrolidin-2-
vDmethvllacetamide
Same procedure as that described in example 1, stage 1.7, starting from 0.074 g
(0.22 mmol) of the compound obtained at the end of stage 8.3, 0.15 g (0.3 mmol) of the
compound obtained at the end of stage 1.5, 24 mg (0.03 mmol) of palladium II
dichlorodi(triphenylphosphine) and 8 mg (0.02 mmol) of triphenylarsine in solution in
1 ml of anhydrous dioxane. 0.063 g of compound is obtained, in the form of a yellow
powder. Yield: 45%. MH+: 648 (Tr: 5.31 min, condition 1).
8.5/ 2-(4-r7-Amino-8-ethyl-6-(1H-imidazol-2-vn-5-oxo-5,8-dihvdro-
n,81naphthvridin-2-vn-2-fluoro-phenvl>-N-(1-ethvl-pyrrolidin-2-vlmethyn-acetamide
(compound 56)
Same procedure as that described in example 2, stage 2.6, starting from 0.055 g
(0.08 mmol) of the compound obtained at the end of stage 8.4 in solution in 0.25 ml of
dichloromethane, 0.25 ml (3.4 mmol) of trifluoroacetic acid in solution in 0.1 ml of
dichloromethane. 0.017 g of product is obtained in the form of a yellow powder. Yield =
39%. Melting point: 100°C. MH+: 518.3 (Tr: 4.71 min, condition 1).
1H NMR (400MHz, DMSO-d6), d (ppm): 9.1d (s, 1H); 8.62 (d, 1H, 8.1 Hz); 8.50 (t, 1H,
5.7 Hz); 8.07-8.0 (m, 3H); 7.54 (t, 1H, 8Hz); 7.24 (s, 2H); 4.70 (m, 2H); 3.92-3.32 (m, 6H
+ 3H exchangeable); 3.08 (m, 2H); 2.13 (m, 1H); 1.97 (m, 1H); 1.86 (m, 1H); 1.74 (m,
1H); 1.38 (t, 3H, 7 Hz); 1.22 (t, 3H, 7.2Hz).
Compounds 1,4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,
48 and 55 were synthesized following the synthesis route described in example 2;
compound 9 following the synthesis route described in example 1, and compounds 52
and 54 were synthesized following the synthesis route described in example 6.
The following table presents chemical structures and physical properties of some
examples of the compounds according to the invention.
In this table:
- in the "salt" column:
• " -" represents a compound in the form of free base, whereas
• "HCI" or "TFA" signify, respectively, a compound in the form of
hydrochloride or of salt of trifluoroacetic acid.
- Me, Et, represent methyl and ethyl groups respectively.
Pharmacological tests were conducted on the compounds according to the invention
to determine their inhibitory effect on protein with tyrosine kinase activity.
As an example, their inhibitory effects on the tyrosine kinase activity of PDGF-R
and/or Flt-3 were measured in vitro in cellular models.
The inhibitory activity with respect to PDGF or Flt-3 receptors is given by the
concentration that inhibits 50% of the proliferation activity of cells Baf3 tel/PDGF or
MV4-11, respectively.
Measurement of inhibition of the tyrosine kinase activity of the receptor
to PDGF beta (PDGF-RB) (Baf-3 tel/PDGFRB):
This test consists of evaluating the effects of the compounds on the tyrosine
kinase activity of the PDGF beta receptor.
The inhibitory effect of the compounds according to the invention on the
tyrosine kinase activity of the PDGF-R receptor was evaluated on the murine
haematopoietic cell line BaF/3 transfected with a plasmid coding for the fusion protein
Tel/PDGF-R beta. This fusion protein is found in chronic myeloid myelomonocytic
leukaemias (CMML). It comprises the N-terminal part of the transcription factor Tel
and the transmembrane and intracellular part of the PDGF-R beta receptor. This
fusion protein is present in dimerized form (presence of an oligomerization domain in
the N-terminal part of Tel) and accordingly leads to the constitutive activity of the
kinase domain of PDGF-R beta. This line BaF3 Tel/PDGF has been described several
times in the literature and notably in detail in the article of M CARROLL et al., PNAS,
1996, 93, 14845-14850, M CARROLL et al., Blood 2002, 99, 14845-14850.
The BaF3 Tel/PDGF cells are washed with phosphate buffer and seeded in 96-
well plates, at a density of 5.104 cells/ml (100 ml per well), in RPMI 1640 containing
10% of FCS, in the presence or absence of the test compounds. After incubation for
72 h, the viable cells are quantified by measurement of cellular ATP using the
CellTiter-Glo® kit (Promega, Cat G7571). The cells are treated according to the
instructions given by the supplier of the kit and the luminescence is measured with a
Luminoskan (Ascent, Labsystem) with the following parameters: measurement: single;
integration time: 1000 ms, lag time: 5 s.
It thus appears that the compounds according to the invention have an inhibitory
activity on the tyrosine kinase activity of PDGF-R beta. This activity is given by the
concentration that inhibits 50% of the proliferation of Baf3 tel/PDGF cells (IC50). The
IC50 values of the compounds according to the invention are below 1.0 jaM.
For example, compounds No. 2, 8, 9, 10, 14, 20, 27, 43, 50, 51, 52, 55 showed
an IC50 of 7.9, 2, 9.8, 2.5, 2.4, 8, 2, 1.4, 6.6, 8.9, 13.6, 5.9 nM respectively in the test
for measuring the tyrosine kinase activity of the PDGF receptor.
In addition to their properties of inhibition of PDGF-R tyrosine kinase, it also
appears that compounds according to the invention display properties of inhibition of
the tyrosine kinase activity of the Flt-3 receptor, as described below.
Measurement of inhibition of the tyrosine kinase activity of the Flt-3
receptor
The inhibitory effect of the compounds according to the invention on the
tyrosine kinase activity of the Flt-3 receptor was evaluated on the MV4-11 cell line, a
line established from a leukaemia of the AML type and bearing a constitutively active
mutant Flt3ITD. The inhibitory activity is correlated with inhibition of cell growth,
according to the protocols described by SPIEKERMANN, K. et al., Blood, 2003, 101.,
(4) 1494-1504 and O'FARRELL, A.-M. et al., Blood, 2003, 101, (9) 3597-3605.
The MV4-11 cells are washed with PBS buffer and seeded in 96-well plates, at
a density of 1.105 cells/ml (100 µl per well), in RPMI 1640 containing 10% of FCS, in
the presence or absence of the test compounds. After incubation for 72 h, viable cells
are quantified by measurement of cellular ATP using the CellTiter-Glo® kit (Promega,
Cat G7571). The cells are treated according to the instructions given by the supplier of
the kit and the luminescence is measured using a Luminoskan (Ascent, Labsystem)
with the following parameters: measurement: single; integration time: 1000 ms, lag
time: 5 s.
The inhibitory activity with respect to the Flt-3 receptor is given by the
concentration that inhibits 50% of the proliferation of the MV4-11 cells. It thus appears
that the compounds according to the invention have an inhibitory activity on the
tyrosine kinase activity of the Flt-3 receptor with IC50 values below 1.0 p.M.
For example, compounds No. 8, 20, 26, 27, 32, 42, 43, 50 showed an IC50 of 52, 26,
95, 30, 69, 84, 19, 115 nM respectively, in the test for measuring the tyrosine kinase
activity of the Flt-3 receptor.
The compounds according to the invention are therefore inhibitors of protein
kinases, notably of the tyrosine kinase receptors PDGF alpha and beta and, for some
of them, also of the Flt-3 tyrosine kinase receptor.
Thus, according to one of the objects of the present invention, the compounds
of formula (I) display very interesting activity of inhibition of phosphorylation of the
kinase domain of the PDGF-R beta receptor in BaF3 Tel/PDGF cells, induced by the
inhibitory activity of the product present in the plasma of the treated animals.
The compounds according to the invention are therefore inhibitors of protein
kinases, notably of the tyrosine kinase receptors PDGF alpha and beta and, for some
of them, also of the Flt-3 tyrosine kinase receptor.
The compounds according to the invention can therefore be used for preparing
medicinal products, in particular medicinal products that are inhibitors of protein
kinases.
The medicinal products are inhibitors of protein kinase, notably medicinal
products that are inhibitors of the PDGF-R tyrosine kinase receptor and optionally of
the Flt-3 tyrosine kinase receptor.
Thus, according to another of its aspects, the invention relates to medicinal
products that comprise a compound of formula (I), or a salt of addition of the latter to a
pharmaceutically acceptable acid, or a solvate of the compound of formula (I).
These medicinal products find application in therapeutics, notably in the
treatment of diseases associated with the activity of protein kinases and notably
proliferative diseases such as cancers with liquid tumours, chronic or acute
leukaemias, lymphocytic lymphomas, Hodgkin's disease, myeloproliferative
syndromes and myelodysplastic syndromes.
These medicinal products also find application in therapeutics in the treatment
of proliferative diseases such as cancers with solid tumours comprising lung cancers
(NSCLC), cancers of bone, pancreas, skin, Kaposi syndrome, intraocular melanomas,
cancers associated with the sexual organs comprising cancer of the breast, uterus,
cervix, ovary, endometrium, vagina, vulva, urethra, penis, prostate, carcinomas of the
fallopian tubes, cancers of the gastrointestinal stromal tumour type (abbreviation:
GIST) comprising cancers of the anal region, rectum, small intestine, colon, stomach,
oesophagus, cancers of endocrine glands, thyroid, parathyroid or adrenal glands, soft
tissue sarcomas, Ewing sarcomas, osteosarcomas, dermatofibrosarcomas and other
fibrosarcomas, cancers of the bladder or kidney, neoplasms of the central nervous
system, tumours of the vertebral column and desmoids, gliomas of the brainstem and
glioblastomas, pituitary adenomas and metastases thereof.
Another aspect of the invention comprises a combination between at least one
compound according to the invention and at least one chemotherapy agent.
In fact, the compounds of the present invention can be used alone or mixed
with at least one chemotherapy agent, which can be selected from cytotoxic agents
and/or antiangiogens. For example, the antiangiogenic agents can be a compound
that inhibits the kinase activity of VEGF-R or a compound that is an antagonist of a
growth factor.
It is also possible to combine the compounds according to the invention with a
radiation treatment.
The combinations of the compounds of the invention with the aforementioned
chemotherapeutic agents and/or radiation are another subject of the present
invention.
The aforementioned chemotherapeutic agents and/or radiation can be
administered simultaneously, separately or sequentially. The treatment will be adapted
by the practitioner according to the patient to be treated.
These medicinal products also find application in therapeutics, in the treatment of non-
malignant proliferative diseases such as restenosis, atherosclerosis, thrombosis, heart
failure, cardiac hypertrophy, pulmonary arterial hypertension, fibrosis, diabetic
nephropathy, glomerulonephritis, chronic pyelonephritis, haemangiomas, auto-
immune diseases such as psoriasis, sclerodermatitis, immunosuppression (transplant
rejection for example), pathologies associated with the eye such as post-operative
fibrosis or age-related macular degeneration.
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 latter, or a solvate of said compound, as well as at least one pharmaceutically
acceptable excipient.
Said excipients are selected depending on the pharmaceutical form and
desired method of administration, from the usual excipients that are known by a
person skilled in the art.
In the pharmaceutical compositions of the present invention for oral,
sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal,
transdermal or rectal administration, the active principle of formula (I) above, or
optionally a salt or solvate thereof, can be administered in the unit dosage form, mixed
with conventional pharmaceutical excipients, to animals and to human beings for
prophylaxis or treatment of the aforementioned disorders or diseases.
The appropriate unit dosage forms comprise the forms for administration by
the oral route, such as tablets, soft or hard capsules, powders, granules and oral
solutions or suspensions, forms for sublingual, buccal, intratracheal, intraocular,
intranasal administration, administration by inhalation, forms for topical, transdermal,
subcutaneous, intramuscular or intravenous administration, forms for rectal
administration and implants. For topical application, the compounds according to the
invention can be used in creams, gels, ointments or lotions.
As an example, a unit dosage form of a compound according to the invention
in tablet form can comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Croscarmellose sodium 6.0 mg
Maize starch 15.0 mg
Hydroxypropyl methylcellulose 2.25 mg
Magnesium stearate 3.0 mg
According to another of its aspects, the present invention also relates to a
method of treatment of the aforementioned pathologies comprising the administration,
to a patient, of an effective dose of a compound according to the invention or one of
its pharmaceutically acceptable salts or solvates.
CLAIMS
1. Compound corresponding to formula (I):

in which,
R1 represents a hydrogen atom or a (C1-C4)alkyl group;
R2 represents a group -(CH2)n-B where:
• n'=0, 1, 2, 3 or 4; and
• B represents (i) a (C3-C5)cycloalkyl group or a (C1-C4)alkyl group, said
group being optionally substituted with one or more fluorine atoms, or
(ii) a (C1-C4)alkoxy group;
Y, Z, V and W represent, independently of one another:
• a -CH- group,
• a carbon atom optionally substituted with a group R7, said group R7
representing a (C1-C4)alkyl group or a halogen atom,
• a heteroatom such as a nitrogen atom, a sulphur atom or an oxygen
atom, or
• no atom,
it being understood that the ring in which V, W, Y and Z are comprised is a ring
comprising 5 or 6 ring members, it being understood that the dotted lines in said ring
indicate that the resultant ring is an aromatic ring and it being understood that said
ring comprises 0, 1 or 2 heteroatoms;
R3 and R4 represent, independently of one another, groups that may be
identical or different, R3 and R4 being selected from:
• a hydrogen atom; and
• a linear (C1-C4)alkyl group;
or R3 and R4 form, together with the carbon to which they are bound, a (C3-
C5)cycloalkyi group;
m is an integer equal to 1, 2, 3 or 4;
R5 represents a hydrogen atom or a (C1-C4)alkyl group;
R6 represents a group -(CH2)n-L in which:
• n=0, 1, 2 or 3, and
• L is a group selected from the following groups:
o an aryl comprising 6 carbon atoms;
o a heteroaryl comprising between 5 and 6 ring members and
comprising at least one heteroatom selected from nitrogen, oxygen
and sulphur;
o a saturated heterocycle comprising 5, 6 or 7 ring members and
comprising at least one heteroatom selected from nitrogen and
oxygen, said heterocycle being optionally a lactam;
said aryl, heteroaryl or heterocyclic group being optionally
substituted with at least one substituent selected from (i) linear or
branched (C1-C4)alkyl groups, (ii) (C3-C5)cycloalkyl groups, (iii)
halogen atoms, (iv) aryls and (v) benzyl;
it being understood that when L is a heteroaryl or a heterocycle, said
heteroaryl or heterocycle comprising at least one nitrogen atom, the latter
can optionally be substituted with said substituent;
or R5 and R6 form, together with the nitrogen atom to which they are bound, a
heterocyclic group, optionally substituted with at least
• a heteroaryl, or
• a (C1-C3)alkyl group, which can itself be substituted with a heterocycle
comprising 5 or 6 atoms and comprising at least one heteroatom
selected from nitrogen and oxygen, it being understood that when it is a
heterocycle comprising at least one nitrogen atom, the latter can
optionally be substituted;
said compound of formula (I), its enantiomers and diastereoisomers, including
mixtures thereof, being in the form of a base or a salt of acid addition and/or in the
form of solvate.
2. Compound according to the preceding claim, characterized in that R6
represents a group -(CH2)n-L in which:
• n=0, 1, 2 or 3, and
• L is a group selected from the following groups:
o a heteroaryl comprising 5 ring members and comprising (i) 2
heteroatoms selected, independently of one another, from nitrogen,
oxygen and sulphur, or (ii) 3 heteroatoms selected, independently of one
another, from nitrogen and sulphur,
o a heteroaryl comprising 6 ring members and comprising 1 or 2
heteroatom(s),
o a heterocycle comprising 5 ring members and comprising a
heteroatom selected from nitrogen and oxygen, said heterocycle being
optionally a lactam, and
o a heterocycle comprising 6 ring members and comprising 2
heteroatoms selected from nitrogen and oxygen,
said heteroaryl group or heterocycle being optionally substituted with at least
one substituent selected from (i) linear or branched (C1-C4)alkyl groups, (ii) (C3-
C5)cycloalkyl groups, (iii) halogen atoms, (iv) aryls and (v) benzyl,
it being understood that when L is a heteroaryl or a heterocycle, said
heteroaryl or heterocycle comprising at least one nitrogen atom, the latter can
optionally be substituted with said substituent.
3. Compound according to any one of the preceding claims, characterized in that
L is:
• a heteroaryl comprising 6 ring members selected from pyridine, pyrazine,
pyridazine, pyrimidine;
• an aryl such as phenyl, or
• a heteroaryl comprising 5 ring members selected from thiazole, imidazole,
pyrazole, isoxazole and 1,3,4-thiadiazole, or
• a saturated heterocycle comprising 5 ring members selected from pyrrolidine,
tetrahydrofuran and 2-oxo-pyrrolidine or
• a saturated heterocycle comprising 6 ring members selected from morpholine,
piperazine, piperidine,
said aryl, heteroaryl or heterocyclic group being optionally substituted with at least
one substituent selected from (i) linear or branched (C1-C4)aikyl groups, (ii) (C3-
C5)cycloalkyl groups and (iii) aryls,
it being understood that when L is a heteroaryl or a heterocycle, said heteroaryl or
heterocycle comprising at least one nitrogen atom, the latter can optionally be
substituted with said substituent.
4. Compound according to any one of the preceding claims, characterized in that
L is selected from:
• pyridine, optionally substituted with at least one linear or branched (C1-C4)alkyl
group,
• morpholine, optionally substituted with at least (i) a (C3-C5)cycloalkyl group or
(ii) a linear or branched (C1-C4)alkyl group,
• a pyrrolidine, optionally substituted with at least (i) a linear or branched (C1-
C4)alkyl group, or (ii) a benzyl,
• a thiazole, optionally substituted with at least (i) a linear or branched (C1-
C4)alkyl group, or (ii) a chlorine atom,
• an imidazole, optionally substituted with at least one linear or branched (C1-
C4)alkyl group,
• a 2-oxo-pyrrolidine,
• a 1,3,4-thiadiazole, optionally substituted with at least (i) a linear or branched
(C1-C4)alkyl group, or (ii) a (C3-C5)cycloalkyl group,
• an isoxazole, optionally substituted with at least one linear or branched (C1-
C4)alkyl group,
• a pyrazole, optionally substituted with at least one linear or branched (C1-
C4)alkyl group,
• a pyrazine,
• an isothiazole, optionally substituted with at least one linear or branched (C1-
C4)alkyl group,
• a phenyl,
• a tetrahydrofuran,
it being understood that when L is a heteroaryl or a heterocycle, said heteroaryl or
heterocycle comprising at least one nitrogen atom, the latter can optionally be
substituted.
5. Compound according to any one of the preceding claims, characterized in that R5
represents a hydrogen atom or a methyl.
6. Compound according to any one of the preceding claims, characterized in that:
• m is equal to 1 or 3, and/or
• R3 and R4 represent, independently of one another, groups that may
be identical or different, R3 and R4 being selected from:
oa hydrogen atom, and
oa methyl.
7. Compound according to any one of the preceding claims, characterized in that Y, Z,
V and W represent, independently of one another:
• a group -CH-;
• a carbon atom substituted with a group R7, said group R7
representing a (C1-C4)alkyl group or a fluorine atom; or
• a heteroatom such as a nitrogen atom, a sulphur atom or an oxygen
atom, advantageously a nitrogen atom.
8. Compound according to any one of the preceding claims, characterized in that R1
represents a hydrogen atom or a methyl.
9. Compound according to any one of the preceding claims, characterized in that R2
represents a group -(CH2)n-B where:
o n'=0, 1 or 3; and/or
o B represents (i) a (C3-C5)cyc!oalkyl group, (ii) a (C1-C4)alkyl group or
(iii) a (C1-C4)alkoxy group.
10. Compound according to any one of Claims 1 and 6 to 9, characterized in that R5
and R6 form, together with the nitrogen atom to which they are bound, a heterocyclic
group, optionally substituted with at least
• a heteroaryl, advantageously a pyridine; or
• a (C1-C4)alkyl group, which can itself be substituted with a heterocycle
comprising 5 or 6 atoms and comprising at least one heteroatom
selected from nitrogen and oxygen, advantageously it is a Clalkyl
group, itself substituted with a heterocycle comprising 5 atoms
including a nitrogen atom.
11. Compound according to any one of the preceding claims, characterized in that it is
in the form of a base or a salt of addition to an acid such as hydrochloric acid or
trifluoroacetic acid.
12. Compound according to any one of the preceding claims, characterized in that it
is:
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-pyridin-2-yl-acetamide (compound 1);
2-{6-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-pyridin-3-yl}-N-pyridin-2-yl-acetamide (compound 2);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(4-cyclopropyl-morpholin-3-ylmethyl)-acetamide (compound 3);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(4-isopropyl-morpholin-3-ylmethyl)-acetamide (compound 4);
2-Amino-1 -ethyl-3-(1 H-imidazol-2-yl)-7-{4-[2-oxo-2-((S)-2-pyrrolidin-1 -ylmethyl-
pyrrolidin-1-yl)-ethyl]-phenyl}-1H-[1,8]naphthyridin-4-one (compound 5);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(2-pyridin-4-yl-ethyl)-acetamide (compound 6);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-methyl-N-(2-pyridin-4-yl-ethyl)-acetamide (compound 7);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(5-methyl-thiazol-2-yl)-acetamide (compound 8);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-3-methyl-phenyl}-N-(1 -ethyl-pyrrolidin-2-ylmethyl)-acetamide (compound 9);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-clihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(6-methyl-pyridin-3-yl)-acetamide (compound 10);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(1,3-dimethyl-1 H-pyrazol-4-ylmethyl)-acetamide (compound 11);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-thiazol-2-ylmethyl-acetamide (compound 12);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyi}-N-(5-oxo-pyrrolidin-2-ylmethyl)-acetamide (compound 13);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(5-methyl-[1,3,4]thiadiazol-2-yl)-acetamide (compound 14);
2-{4-[7-Amino-8-ethy!-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-[1,3,4]thiadiazol-2-yl-acetamide (compound 15);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(3-methyl-isoxazol-5-yl)-acetamide (compound 16);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl)-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-acetamide (compound 17);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(4-methyl-thiazol-2-yl)-acetamide (compound 18);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-pyridin-4-ylmethyl-acetamide (compound 19);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-acetamide (compound 20);
2-{4-[7-Amino-8-ethyi-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(2-pyridin-3-yl-ethyl)-acetamide (compound 21);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(2,5-dimethy!-2H-pyrazol-3-ylmethyl)-acetamide (compound 22);
2-{4-[7-Amino-8-ethy!-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(1 -methyl-1 H-imidazol-4-ylmethy!)-acetamide (compound 23);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazo!-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-pyrazin-2-yi-acetamide (compound 24);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl)-N-(2-pyridin-2-yl-ethyl)-acetamide (compound 25);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(5-chloro-thiazol-2-yl)-acetamide (compound 26);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-clihyclro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(3,4-dimethyl-isoxazol-5-yl)-acetamide (compound 27);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(2-methyl-pyridin-4-yl)-acetamide (compound 28);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-pyrazin-2-ylmethyl-acetamide (compound 29);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acetamide (compound 30);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyi}-N-(tetrahydro-furan-2-ylmethyl)-acetamide (compound 31);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yi]-phenyl}-N-(3-methyl-pyridin-2-yl)-acetamide (compound 32);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(4-methyl-pyridin-2-yl)-acetamide (compound 33);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(4,6-dimethyl-pyridin-2-yl)-acetamide (compound 34);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yi]-phenyl}-N-(6-methyl-pyridin-2-yl)-acetamide (compound 35);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-pyridin-3-ylmethyl-acetamide (compound 36);
2-{4-[7-Amino-8-ethy!-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1l8]naphthyridin-
2-yl]-phenyl}-N-(2-ethyl-2H-pyrazol-3-yl)-acetamide (compound 37);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(3-methyl-isothiazol-5-yl)-acetamide (compound 38);
2-Amino-1 -ethy!-3-(1 H-imidazol-2-yi)-7-{4-[2-oxo-2-(2-pyridin-3-yl-pyrrolidin-1 -
yl)-ethyl]-phenyl}-1H-[1,8]naphthyridin-4-one (compound 39);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazoi-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(1 -benzyl-pyrrolidin-3-yl)-acetamide (compound 40);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-y!)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-t(S)-1-(tetrahydro-furan-2-yl)methy!]-acetamide (compound 41);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(4-methyl-pyridin-3-yl)-acetamide (compound 42);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(4-ethyl-pyhdin-2-yl)-acetamide (compound 43);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-ethyi-N-pyridin-4-ylmethyl-acetamide (compound 44);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(6-ethyl-pyridin-2-yl)-acetamide (compound 45);
2-{4-[7-Amino-8-ethyi-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-benzy!-acetamide (compound 46);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-pyridin-4-ylmethyl-propionamide (compound 47);
4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-
yi]-N-pyridin-4-ylmethyl-benzamide (compound 48);
4-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-pyridin-4-ylmethyl-butyramide (compound 49);
2-{4-[7-Amino-8-ethyl-6-(4-methyl-1H-imidazol-2-yi)-5-oxo-5,8-dihydro-
[1,8]naphthyridin-2-yl]-phenyl}-N-pyridin-4-ylmethyl-acetamide (compound 50);
2-{4-[7-Amino-8-cyclopropylmethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-
[1,8]naphthyridin-2-yl]-phenyl}-N-pyridin-4-ylmethyl-acetamide (compound 51);
2-{4-[7-Amino-8-cyclopentyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-
[1,8]naphthyridin-2-yl]-phenyl}-N-pyridin-4-ylmethyl-acetamide (compound 52);
2-{5-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-pyridin-2-yl}-N-pyridin-4-ylmethyl-acetamide (compound 53);
2-{4-[7-Amino-6-(1H-imidazol-2-yl)-8-(3-methoxy-propyl)-5-oxo-5,8-dihydro-
[1,8]naphthyridin-2-yl]-phenyl}-N-pyridin-4-ylmethy!-acetamide (compound 54);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-phenyl}-N-(3-phenyl-propyl)-acetamide (compound 55);
2-{4-[7-Amino-8-ethyl-6-(1H-imidazol-2-yl)-5-oxo-5,8-dihydro-[1,8]naphthyridin-
2-yl]-2-fiuoro-phenyl}-N-(1 -ethyl-pyrrolidin-2-ylmethyl)-acetamide (compound 56).
13. Process for preparing a compound of formula (I) according to any one of Claims 1
to 12, characterized in that (i) a compound of the following formula (VII):

in which Pg represents a protecting group and X represents a halogen atom,
is reacted according to a Suzuki coupling reaction with (ii) a boronic acid or a boronic
ester of pinacol of formula (IXa):

in which G represents a group -NR5R6 or G represents a group
-OEt;
in order to obtain respectively (iii) a compound of the following formula (X):

in which G represents a group -NR5R6 and Pg is as defined previously;
or (iv) a compound of the following formula (XI):

in which G represents a group -OEt and Pg is as defined previously;
it being understood that m, R1, R2, R3, R4, R5, R6, V, W, Y and Z are as defined in
Claim 1.
14. Process for preparing a compound of formula (I) according to any one of Claims 1
to 12, characterized in that (i) a compound of formula (VIII):

in which Pg represents a protecting group;
is reacted according to a Stille coupling reaction with (ii) an aryl or heteroaryl halide of
the following formula (IXb):

in which G represents a group -OEt or G represents a group
-NR5R6 and X represents a halogen atom;
in order to obtain (iii) a compound of the following formula (X):

for which G represents a group -NR5R6 and Pg is as defined previously;
or (iv) a compound (XI) of the following formula:

for which G represents a group -OEt,
it being understood that m, R1, R2, R3, R4, R5, R6, V, W, Y and Z are as defined in
Claim 1.
15. Process for preparing a compound of formula (I) according to one of Claims 13 or
14, characterized in that the compound (XI) for which G represents a group -OEt then
undergoes a stage of saponification and then a stage of peptide coupling with the
amine HNR5R6, giving the compound (XIII) of the following formula:

it being understood that Pg represents a protecting group and that m, R1, R2, R3, R4,
R5, R6, V, W, Y and Z are as defined in Claim 1.
16. Medicinal product, characterized in that it comprises a compound of formula (I)
according to any one of Claims 1 to 12, or a salt of addition of this compound to a
pharmaceutically acceptable acid, or a solvate of the compound of formula (I).
17. Pharmaceutical composition, characterized in that it comprises a compound of
formula (l) according to any one of Claims 1 to 12, or a pharmaceutically acceptable
salt, a solvate of this compound, as well as at least one pharmaceutically acceptable
excipient.
18. Use of a compound of formula (I) according to any one of Claims 1 to 12 for
preparing a medicinal product intended for treating diseases linked to the activity of
protein kinases, said compound of formula (I) inhibiting the tyrosine kinase activity of
PDGF-R, in particular PDGF-R beta, in Baf3 tel/PDGF ceils and/or inhibiting the
tyrosine kinase activity of Flt-3 in MV4-11 cells.
19. Use of a compound of formula (l) according to any one of Claims 1 to 12 for
preparing a medicinal product intended for the treatment of proliferative diseases such
as cancers with liquid tumours, chronic or acute leukaemias, lymphocytic lymphomas,
Hodgkin's disease, myeloproliferative syndromes and myelodysplastic syndromes.
20. Use of a compound of formula (I) according to any one of Claims 1 to 12 for
preparing a medicinal product intended for the treatment of proliferative diseases such
as cancers with solid tumours comprising lung cancers (NSCLC), cancers of bone,
pancreas, skin, Kaposi syndrome, intraocular melanomas, cancers associated with
sexual organs comprising cancer of the breast, uterus, cervix, ovary, endometrium,
vagina, vulva, urethra, penis, prostate, carcinomas of the fallopian tubes, cancers of
the gastrointestinal stromal tumour type (abbreviation: GIST) comprising cancers of
the anal region, rectum, small intestine, colon, stomach, oesophagus, cancers of
endocrine glands, thyroid, parathyroid or adrenal glands, soft tissue sarcomas, Ewing
sarcomas, osteosarcomas, dermatofibrosarcomas and other fibrosarcomas, cancers
of the bladder or kidney, neoplasms of the central nervous system, tumours of the
vertebral column and desmoids, gliomas of the brainstem and glioblastomas, pituitary
adenomas and metastases thereof.
21. Use of a compound of formula (I) according to any one of Claims 1 to 12 for
preparing a medicinal product intended for the treatment of non-malignant proliferative
diseases such as restenosis, atherosclerosis, thrombosis, heart failure, cardiac
hypertrophy, pulmonary arterial hypertension, fibrosis, diabetic nephropathy,
glomerulonephritis, chronic pyelonephritis, haemangiomas, auto-immune diseases
such as psoriasis, sclerodermatitis, immunosuppression, pathologies of the eye such
as post-operative fibrosis and age-related macular degeneration.
22. Compound of formula (l) according to any one of Claims 1 to 12 for preparing a
medicinal product intended for the treatment of proliferative diseases such as cancers
with liquid tumours, chronic or acute leukaemias, lymphocytic lymphomas, Hodgkin's
disease, myeloproliferative syndromes and myelodysplastic syndromes.
23. Compound of formula (1) according to any one of Claims 1 to 12 for preparing a
medicinal product intended for the treatment of proliferative diseases such as cancers
with solid tumours comprising lung cancers (NSCLC), cancers of bone, pancreas,
skin, Kaposi syndrome, intraocular melanomas, cancers associated with sexual
organs comprising cancer of the breast, uterus, cervix, ovary, endometrium, vagina,
vulva, urethra, penis, prostate, carcinomas of the fallopian tubes, cancers of the
gastrointestinal stromal tumour type (abbreviation: GIST) comprising cancers of the
anal region, rectum, small intestine, colon, stomach, oesophagus, cancers of
endocrine glands, thyroid, parathyroid or adrenal glands, soft tissue sarcomas, Ewing
sarcomas, osteosarcomas, dermatofibrosarcomas and other fibrosarcomas, cancers
of the bladder or kidney, neoplasms of the central nervous system, tumours of the
vertebral column and desmoids, gliomas of the brainstem and glioblastomas, pituitary
adenomas and metastases thereof.
24. Compound of formula (I) according to any one of Claims 1 to 12 for preparing a
medicinal product intended for the treatment of non-malignant proliferative diseases
such as restenosis, atherosclerosis, thrombosis, heart failure, cardiac hypertrophy,
pulmonary arterial hypertension, fibrosis, diabetic nephropathy, glomerulonephritis,
chronic pyelonephritis, haemangiomas, auto-immune diseases such as psoriasis,
sclerodermatitis, immunosuppression, pathologies associated with the eye such as
post-operative fibrosis or age-related macular degeneration.
25. Combination of at least one compound of formula (I) according to any one of
Claims 1 to 12 with at least one chemotherapy agent.

ABSTRACT

The invention relates (i) to pyridine-pyridinone derivatives with the formula (I): where R1 is a hydrogen atom or a
(C1-C4)alkyl group; R2 is a (CH2)n-B group, in which n' = 0, 1, 2, 3 or 4 and B is a (C3-C5)cycloalkyl group, a (C1-C4)alkyl
group or a (C1-C4)alkoxy group; Y, Z, V and W are, independently from one another, a -CH- group, a carbon atom, a heteroatom
or no atom, with the understanding that the cycle, which includes V, W, Y and Z, is a cycle including 5 or 6 members, with the
understanding that the dotted lines in said cycle indicate that the resulting cycle is an aromatic cycle and with the understanding
that said cycle includes 0, 1 or 2 heteroatoms; R3 and R4 are, independently from one another, identical or different groups
selected among a hydrogen atom and a straight (C1-C4)alkyl group, or form a (C3-C5)cycloalkyl group together with the carbon
to which the former are bonded; m is an integer equal to 1, 2, 3 or 4; R5 is a hydrogen atom or a (C1-C4)alkyl group; R6 is a
(CH2)n-L group where n = 0, 1, 2 or 3, and L is a group selected among aryls with 6 carbon atoms, heteroaryls having 5 or 6
members, the saturated heterocycles including 5, 6 or 7 members or forming a heterocycle group together with the nitrogen atom
to which the former are linked. The invention also relates (ii) to the preparation of said derivatives, and (iii) to the therapeutic use
thereof as inhibitors of kinase activity in receptors having PDGF ligands and/or receptors with the FLT3 ligand.