ARYLSULFONAMIDE PYR1DINE-PYR1DINONE DERIVATIVES. PREPARATION OF
SAME, AND THERAPEUTIC USE THEREOF
The present invention relates to pyridino-pyridinone derivatives substituted at the 7-
position with an arylsulfonamide, to their preparation and to their therapeutic application
as inhibitors of protein kinases such as p70S6 (S6K1) and/or of PDGFR-TK (platelet
derived growth factors), or of other kinases.
1) Protein kinase p70S6K:
I. p70 S6Kinase or S6K1: overview, structure, activation
The ribosomal p70 S6 Kinase (S6K1, formerly p70S6K) is a serine/threonine kinase (of
the AGC kinase family) of the PI3-kinase/mTOR pathway among the first described as
activated by insulin and many growth factors. This kinase participates in the regulation of
two cellular processes: protein synthesis and cell growth (proliferation and size of the
cells), via its main substrate, the ribosomal protein S6 of the 40S subunit. (Avruch J.
2001). Cloned in 1991 by Grove et al, two isoforms, resulting from an alternative splicing
of the mRNA, encode 2 protein sequences: p85 S6K (a-l, 525 amino acids) and p70S6K
(a-ll, 502 amino acids) have been identified. The latter isoform is mainly located in the
cytosoi while the a-l isoform is nuclear (presence of a nuclear localization site on the N-
terminal extension of 23 amino acids). S6K1 is expressed ubiquitously.
S6K1 exhibits 70% amino acid homology with S6K2 (formerly p70 beta S6 kinase), also
activated by mTOR, in which 7 phosphorylation sites (serine or threonine) are conserved.
The structure of S6K1 comprises four modules: a noncatalytic domain at the N-terminal
end (I), a central catalytic domain (II), an extension of the kinase domain (III) and finally
an auto-inhibitory domain at the C-terminal end (IV). The activation of this kinase
requires sequential phosphorylation in 4 stages of serine or threonine sites located on
various domains which will modify its overall conformation, allowing it to acquire its
enzyme activity (Pollen N. 1997, Dennis JBC1998).
II. S6K1 in the PI3K/ mTOR signaling pathway
The upstream signaling of S6K1 results from the activation of many membrane G Protein
Coupled Receptors (GPCRs), which control cell growth, proliferation and differentiation.
After binding of ligands such as growth factors (for example PDGF, EGF), nutrients or
hormones (for example amino acids, glucose or insulin), the activation of their receptors
results in the recruitment of PI3-Kinase, triggering a phosphorylation cascade via PDK1
which phosphorylates Akt, activating mTOR (via TSC1/2 and Rheb) which finally
activates S6K1, one of the two main effectors of mTOR. Finally, the pro-apoptotic protein
BAD is phosphorylated at S136 by S6K1 which inactivates and improves cell survival
(Harada er al. PNAS 2001).
More recently, chaperonin containing TCP1, CCT, was reported as substrate for S6K1
and plays a role in the folding of neosynthesized proteins such as actin, tubulin and
several cell cycle proteins, also suggesting a role for S6K1 in cell cycle regulation (Abe et
at. JBC2009).
III. Applications of S6K1 inhibitors
By virtue of its regulatory activity on cell growth and protein synthesis, S6K1 is involved in
many physiopathological processes. S6K1 inhibitors can therefore find applications in
many therapeutic domains: cardiovascular diseases such as heart failure following
myocardial hypertrophy, atherosclerosis and restenosis following excessive proliferation
of the smooth muscle cells of the arteries or kidney failure. Metabolic disorders and in
particular diabetes and obesity represent other possible therapeutic applications for S6K1
inhibitors. Fibrotic diseases, such as hepatic, pancreatic, pulmonary, cardiac and
perivascular fibrosis, resulting from excessive synthesis of extracellular matrix and
excessive proliferation of fibroblasts, stellar cells or smooth muscle cells, regulated inter
alia by the activity of S6K1, also constitute therapeutic indications for these inhibitors.
Finally, any tumors with deregulations of the PI3K/Akt/mTOR pathway could benefit from
treatment with S6K1 inhibitors.
IV. Role of S6K1 in the cardiovascular system
Hypertrophy of the cardiomyocytes due to an excessive protein synthesis is one of the
key mechanisms involved in the development of myocardial hypertrophy which results in
heart failure. The mTOR/S6K1 signaling pathway is one of the main systems for
regulating cell growth by regulating protein synthesis and cell proliferation. Numerous
studies in vivo have shown the therapeutic potential of inhibitors of this pathway,
including rapamycin, inhibitor of mTOR (mTORCI complex) which blocks the activation
of S6K1. Rapamycin reduces cardiac hypertrophy following a cardiac overload by
constriction of the aorta in mice and rats (Gao et al. Hypertension 2006, Boluyt M. et al.
Cardiovasc. Drug Therap. 2004, Shioi et al. Circulation 2003). Rapamycin reduces the
hypertrophy of the left ventricle, preserves the contractile function and reduces cardiac
fibrosis (reduction of collagen) by a mechanism involving the mTOR/S6K1 pathway since
the phosphorylation of the ribosomal protein S6 and elF4E is inhibited (Gao J
Hypertension 2006).
The involvement of the mTOR/S6K1 pathway in the hyperplasia of the smooth muscle
cells of the artery is demonstrated by the inhibitory role of rapamycin in the growth of the
smooth muscle cells of the artery in vitro and has been used in the prevention of
restenosis of the coronary artery after transluminal angioplasty using stents coated with
rapamycin (Moses et al. N Engl. J. Med. 2003) or after systemic injection (ORAR Trial,
Rodriguez et al. J. Invasive cardiol. 2003). In particular, in diabetic patients, a clinical
study has shown that stents impregnated with rapamycin significantly reduce the risks of
restenosis after coronary angioplasty (SIRIUS Substudy, Moussa et al. Circulation 2004).
The compounds of the present invention could therefore have an application in the
prevention of restenosis and atherosclerosis.
V. Role of S6K1 in the fibrosis process
Excessive tissue repair following chronic lesions/stimuli resulting in an excessive
synthesis of extracellular matrix and excessive differentiation of the fibroblasts into
myofibroblasts characterizes the fibrosis process which occurs in numerous tissues. By
virtue of its regulatory activity on protein synthesis and cell growth, S6K1 is highly
involved in fibrosis; the inhibitors of the present invention may therefore find applications
in fibrosis of the liver, the pancreas, the skin, the lung, the heart or the kidney.
The role of S6K1 in liver fibrosis and in particular in the process of activation of hepatic
stellar cells (for a review cf Parsons J. Gastro. Hepatol. 2007) has been demonstrated in
experiments in vivo in the liver fibrosis model in rats by ligation of the bile duct or the
inhibition of mTOR by rapamycin reduces the activation of S6K1, reduces fibrosis and
improves portal hypertension, a functional effect accompanied by a reduction in the
mRNA of TGFß, CTGF, PDGFß as well as a reduction in the phosphorylated S6K1
(Biecker et al. JPET 2005). In another model of fibrosis of the liver induced in rats by
carbon tetrachloride, rapamycin reduces collagen deposits and transglutaminase activity
in vivo and completely blocks the proliferation of stellar cells which is induced by PDGFß
(Zhu et a/. Gastroenterology 1999). in 2 models of liver fibrosis induced by ligation of the
bile duct (BDL) or by injection of dimethylnitrosamine (DMN), a kinetic study ex vivo of
the activity of ERK1/2 and of S6K1 has shown that the activity of this kinase precedes the
activation and proliferation of the hepatic stellar cells, the S6K1 activity peak being 6
hours in the DMN model and 72 hours in the BDL mode! (Svegliati-Baroni et al. J.
Hepatol. 2003). In vitro, the activation of stellar cells by PDGFb and IGF-1 involves S6K1
and rapamycin inhibits the proliferation of the stellar cells and the activation of S6K1
(Bridle et al. JLCM 2006). This inhibitor has also proved capable of blocking the
overexpression of MMP13, of collagen I and the activation of S6K1 in stellar cells
activated byTGFß (Lechuga era/. J. AJPGLP 2004).
At the level of skin fibrosis, a high expression of S6K1 has been demonstrated in keloid
scars. Rapamycin reduces collagen, fibronectin, actin a (a-SMA) (Ong et al Exp.
Dermatol. 2007).
At the level of lung fibrosis, rapamycin prevents the initiation and progression of lung
fibrosis in a transgenic mouse model overexpressing TGFct in the lung. Furthermore, this
inhibitor blocks the phosphorylation of S6K1 induced by TGFct and the depositions of
collagen in the lung (Korfhagen et af. Am. J. resp. Cell Mol. Biol. 2009).
VI. Oncology:
Inhibitors of P70S6K have applications in oncology, in particular in:
- breast cancer, where the amplified and overexpressed S6K1 gene is present in
7.5-10.2% primary breast cancers (Barlund et ai 2000, Wu er ai 2000, Couch er ai
1999); this overexpression is associated with a poor prognosis independent of the
amplification of HER2 (Barlund et ai 2000).
- liver cancer (hepatocarcinoma, HCC): overexpression of S6K1 reported by Sahin et al
(2004).
- glioblastoma (Riemenschneider et al. 2006)
- thyroid cancer (Miyakawa et al. 2003)
- ovarian and cervical cancers (Wong et ai 2000). S6K1 promotes the process of
transition of epithelial cells to mesenchymal cells (EMT) in ovarian cancer cells (Pon et ai
Cancer Res. 2008).
2) PDGF-R receptor tyrosine kinases:
The PDGF-R receptors are members of the class III family of receptor tyrosine kinases
(RTK). The binding of ligands to RTKs induces dimerization of the receptors, the
activation of their tyrosine kinase portion which leads to the transphosphoryiation of the
tyrosine residues (Weiss & Schlessinger, 1998).
The binding of ligands to these RTKs induces dimerization of the receptors, the activation
of their tyrosine kinase portion which leads to the transphosphorylation of the tyrosine
residues (Weiss & Schlessinger, 1998). These phosphorylated residues thus serve as
anchoring point for the intracellular signaling proteins which in fine cause various cellular
responses: maintenance, division, proliferation, differentiation, or else cell migration.
(Claesson-Welsh, 1994).
Two isoforms of PDGF receptors have been identified, the PDGF-Ralpha chain and the
PDGF-Rbeta chain, which, following the attachment of their ligands, homo- or
heterodimerize and induce intracellular signaling. The PDGF receptors are mainly
expressed by cells of mesenchymal origin and are found in particular on the fibroblasts,
the smooth muscle cells, the pericytes and the glial cells (Ross et al., 1986, Heldin,
1992).
"Platelet Derived Growth Factor", PDGF, a protein having a molecular weight of about
30 000 daltons, is mainly secreted by the platelets, secondarily by the endothelium, the
vascular smooth muscles and the monocytes. It is formed of two polypeptide chains
linked to each other by disulfide bonds forming either homodimers or heterodimers. Four
genes (7p22, 22q13, 4q31 and 11q22) have been described as encoding 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 a review, Yu et al, 2003). A binding specificity
exists, including in particular PDGF-AA for the alpha isoform of the receptor, PDGF-D for
the BB form, and PDGF-C for the alpha and alpha/beta forms. The PDGF ligands are
potent mitogens, but are also involved in the phenomena of cell migration, survival,
apoptosis and transformation.
The inhibitors of the PDGF-R alpha, beta function are involved in various therapeutic
fields. Among the physiopathological phenomena in which these receptors may be
involved are cancers with or without metastases targeting tumor cells and/or (vascular,
fibroblast) cells of the tumor environment, fibroses and vascular diseases:
Advantageously, AML (acute myeloid leukemia)-type blast ceils can also overexpress
other receptors with kinase activity such as c-kit or else PDGF-R.
Mveloproliferative/dysplastic syndromes
Quite frequently, cytogenetic abnormalities following chromosomal translocations have
been reported in myeloproliferative syndromes. These rearrangements generate
deregulated fusion proteins with tyrosine kinase activity which are involved in the
proliferation of myeloid blast cells.
- Fusion proteins with PDGF-R beta kinase activity
Fusion proteins with PDGF-R beta kinase activity consist of the intracellular portion of
PDGF-R-beta and, on the other hand, of an N-ter domain of another protein (in general a
transcription factor). The following have been reported in particular in chronic
myelomonocytic leukemias (CMML): Rab5/PDGF-Rbeta, H4-PDGF-Rbeta, HIP1-PDGF-
RB or else Tel/PDGF-R beta. The latter is the most widely represented. It is derived from
the translocation t(5;12)(q31;p12) and encodes a fusion protein consisting of the N-
terminal part of the transcription factor Tel and of 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 hematopoietic cells on several occasions and in
particular in detail in the article by M. Carrol et a!., (PNAS, 1996, 93, 14845-14850). In
vivo, this fusion protein leads to a myeloid cell hyperproliferation (Ritchie et al., 1999).
Furthermore, in animals and in the clinical setting in humans, it has been shown that
inhibitors of tyrosine kinase activity inhibit the proliferation of blast cells and make it
possible to check the ieukemogenesis process.
- Fusion proteins with PDGF-R alpha kinase activity
Two fusion proteins involving PDGF-R alpha have been reported: bcr-PDGF-Ralpha
which is present in an atypical chronic myeloid leukemia (CML) and F1P1L1-PDGF-
Ralpha which is found in a subpopulation of leukemias, CELs "eosinophilic leukemias",
derived from a hypereosinophilic syndrome (Griffin et ai., 2003). This fusion protein bears
a 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 positive FIP1L1-PDGF-R alpha cells and recently an inhibitory compound got the
indication for HES/CEL.
Thus, inhibiting the kinase activity of PDGF-Ralpha and beta as the compounds of the
invention do has proved to be of therapeutic interest for AMLs.
A. Solid cancers
Inhibitors of the tyrosine kinase activity of PDGF-R alpha and beta receptors may be of
interest for solid cancers either by directly targeting the tumor cell which by autocriny or
paracriny is sensitive to the PDGF-R TK inhibiting activity, or by targeting the cells of the
environment by destabilizing the network in order to promote the association with other
therapeutic agents. Examples of solid cancers are Ewing's sarcoma, gastrointestinal
stromal tumors (GIST), dermatofibrosarcomas, gliomas, glyobiastomas, hemangiomas
as well as desmoid tumors. The compounds of the invention are of interest for the
treatment of such solid cancers.
B. Targeting PDGF-RTK in the tumor environment
Angiogenesis
The cells of the tumor environment form an integral part of the development of the
cancer whether in the case of a primary or secondary tumor (metastases). Among the
cells of the environment which express PDGF-R and for which the role of this receptor
has been demonstrated are the mural cells of the vessels, that is to say the pericytes and
the smooth muscle cells but also the activated fibroblasts.
Angiogenesis is a process for generating new capillary vessels from pre-existing vessels
or by mobilization and differentiation of bone marrow cells. Thus, both uncontrolled
proliferation of the endothelial cells and a mobilization of angioblasts from the bone
marrow are observed in the tumor neovascularization process. 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 the
mural cells such as the pericytes and the smooth muscle cells participate in the
stabilization of the newly-formed vessels. The invalidation of PDGF-R beta causes a
deficiency in the pericytes in mice and leads to the death of the animals at the end of
gestation due to microhemorrhages and edemas (Hellstrdm et al, 1999, Hellstrom et al,
2001). In an elegant study of transplantation, the expression of PDGF-R-beta by the
pericytes has been shown to be necessary for their recruitment at the level of the tumor
vessels via the retention of PDGF-B by the endothelial cells but also by the PDGF-B
secreted by the tumor cells (Abramsson et al, 2003). In the Rip1Tag2 transgenic model
of pancreatic tumor, Song et al. have also shown the expression of PDGF-R beta on the
perivascular progenitors in the marrow derived from bone marrow, progenitors which
differentiate into mature pericytes around the tumor.
The importance of blocking the activity of PDGF-R on the tumor pericytes has been
demonstrated by the use of an inhibitor of the tyrosine kinase activity of PDGF-R in
animal models {transgenic model of pancreatic tumor and implantation of glioma tumor),
and the effect on tumor growth turns out to be profound in combination with an inhibitor
of the kinase activity of VEGF-R (Bergers et al., 2003). Literature data (Cao et af, 2002,
Fons et al., 2004) have demonstrated the intervention of PDGF-R alpha and PDGF-C in
angiogenesis and in the differentiation of the endothelial progenitors into cells of the
pericyte type and smooth muscle cells.
In the light of these various studies, it is apparent that the compounds of the invention
are of interest for the treatment of solid cancers by their effect on the cells of the
environment and this being in combination with other therapeutic agents such as
cytotoxic agents or inhibitors of angiogenesis.
Activated fibroblasts
PDGF-R is abundant in the tumor stroma and is found on the activated fibroblasts
(myofibroblasts). It has been shown in two studies that the combination of inhibitors or
antagonists of PDGF-R with cytotoxic agents leads to a reduction in the microdensity of
the vessels in ovarian cancers (Apte et al., 2004) and in pancreatic cancers (Hwang et
al., 2003). PDGF-R beta regulates the pressure of the interstitial tissue of the tumor
(Heuchel et al., 1999) and the co-administration of inhibitors of PDGF-R and
chemotherapeutic agents improves their delivery in tumor cells by reducing the
intratumor pressure (Griffon-Etienne, 1999). Finally, in a murine model, the
administration of an inhibitor of the kinase activity of PDGF-R improves the consumption
of chemotherapeutic agents by the tumor and thus increases their efficacy (Griffon-
Etienne, 1999; Pietras et al., 2002; Pietras et al., 2003). The activated fibroblasts present
in the tumor stroma therefore represent a novel therapeutic target in oncology (for a
review see Bouzin & Feron, 2007).
Metastases
Several studies show that the PDGF-R and PDGF-ligand pair is involved in the
development of metastases, certainly by their action on angiogenesis and metastatization
by the blood circulation, but also by a direct effect on lymphangiogenesis and therefore
the metastases disseminated by the lymphatic vessels. One review documents in
particular the direct role of PDGF-BB in lymphangiogenesis and lymphatic metastases
(Cao et al., 2005). However, the majority of the studies involve the expression of PDGF-
R in the environment of the metastases which promote the establishment and
development of secondary tumors. The example most frequently reported is the
development of bone metastases, of prostate cancer.
In the light of these various studies, it is apparent that the compounds of the invention
are of interest for the treatment of solid cancers by their effect on the cells of the
environment and this being in combination with other therapeutic agents such as
cytotoxic agents or inhibitors of angiogenesis.
C. Fibroses
Fibroses are often the cause of a primary event such as a cancer, radiotherapy
treatment, hepatitis, alcoholemia. The implication of PDGF is clearly demonstrated in
pulmonary fibrosis (including asbestosis), renal fibrosis (glomerulonephritis), medullar
fibrosis (often associated with megakaryocyte leukemias), induced by radiotherapy as
well as hepatic and pancreatic fibroses (linked to alcoholemia or to hepatitis) (for a review
see JC Bonner, 2004). An overexpression of PDGF has been in particular clearly shown
and results in in vivo models with inhibitors of the PDGF-R TK activity have also been
reported. Among these studies, that of Einter et a!., (2002) has shown that PDGF-CC is a
potent inducer of renal fibrosis. The authors tested the efficacy of a neutralizing antibody
in a model of unilateral urethra ligation, where fibrosis develops particularly rapidly. They
observed a very marked antifibrosing effect with a reduction in the accumulation of
myofibroblasts, a reduction in the accumulation of extracellular matrix and a reduction in
collagen IV deposits. Another study carried out in a model of pulmonary fibrosis induced
by bleomycin in mice has shown the efficacy of an inhibitor of the TK activity of PDGF-R
on the prevention of fibrosis by inhibition of the proliferation of mesenchymal cells (Aono
et al., 2005). In a model of fibrosis induced by asbestos, a PDGF-R TK inhibitor 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 shown the involvement of PDGF-R in hepatic fibrosis. It has
been clearly shown that PDGFBB and DD possess profibrogenic characteristics on
hepatic stellate cells (Rovida et al., 2008; Borkham-Kamphorst et al., 2007). In vivo, a
PDGF-R TK inhibitor is capable of reducing early fibrogenesis in a model of bile duct
ligation in rats (Neef et al., 2006).
Accordingly, in the light of the literature data, the compounds of the invention appear to
be of therapeutic interest for various types of fibrosis.
D. Vascular diseases: atherosclerosis & restenosis, arteriosclerosis
The proliferation and migration of vascular smooth muscle cells contribute to intimal
hypertrophy of the arteries and thus plays a major role in atherosclerosis and in
restenosis following angioplasty and endoarterectomy. It has been clearly demonstrated
in vitro and in vivo in animal models that PDGF is involved in these phenomena. In vivo,
an increase in the expression of PDGF in a "vein graft" model in pigs has been shown in
particular. Furthermore, it has also been shown that an inhibitor of the TK activity of
PDGF-R substantially reduced the size of the lesions of the thoracic and abdominal
artery in diabetic mice ApoE-KO (animals treated with streptozotocin). Another study has
shown that the inhibition of the signaling induced by PDGF (antisense TK or PDGF A)
leads to a reduction in the formation of the neointima 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 linked to the proliferation of vascular
smooth muscle cells such as atherosclerosis, restenosis post-angioplasty or following the
fitting of endovascular prostheses (stents) or during aortocoronary bypass.
The compounds of the invention, by virtue of their inhibitory activity on the TK activity of
PDGF-R, have proved advantageous for treating these vascular diseases.
E. Others
Other pathologies appear to be possible indications for the compounds of the invention
including idiopathic pulmonary arterial hypertension (PAH). PAH characterized by a high
and continuous increase in pressure in the pulmonary artery leads to right ventricular
failure and often the death of the patient. It is associated with the increase in the
proliferation and migration of the smooth muscle cells of the pulmonary vessels.
Schermuly et al. (2005) have shown that the inhibition of the tyrosine kinase activity of
the PDGF receptors considerably improves the progression of the disease. For that, they
used inter alia an experimental pulmonary arterial hypertension model in rats, obtained
by the administration of monocrotaline for 28 days. All the treated rats survived whereas
50% of them died in the untreated control group.
The subject of the present invention is compounds corresponding to the formula (I):

in which
• n represents 0, 1, 2 or 3;
• n' represents 0, 1, 2, 3 or 4;
• R1 represents an alkyl group;
• R2 represents:
(i) a cycloalkyl group,
(ii) an alkyl group, or
(iii) an alkoxy group,
said cycloalkyl, alkyl or alkoxy groups being optionally substituted with one or
more halogen atoms;
• R3 represents:
(i) a hydrogen atom, or
(ii) a -C(O)alkyl group;
• Ar represents a 5- or 6-membered aryl or heteroaryl ring in which Y, Z, V and W:
(a) represent, independently of each other,
(i) a =CH- group,
(ii) a =C(R5)- group in which R5 represents:
o an alkyl group,
o a halogen atom, or
o an alkoxy group,
(iii) a heteroatom chosen from the nitrogen atom, the sulfur atom and
the oxygen atom,
(b) at most one among Y, Z, V and W being optionally absent,
it being understood that, when Ar represents a heteroaryl chosen from pyrrolyl,
imidazolyl, pyrazolyl and triazolyls, at least one of the nitrogen atoms of said heteroaryl
may be optionally substituted with a group R6 chosen from an alkyl group,
• R4 represents a group chosen from:
o an alkyl group;
o an alkoxyalkyl group,
o a group -NRR' with R and R', which may be identical or different,
representing, independently of each other, a hydrogen atom, an alkyi group or
a -(C3-C6)cycloalkyl group,
o a cycloalkyl group,
o an alkenyl group,
o an aryl group, said aryl groups being optionally substituted with at least one
halogen atom, and/or with at least one group chosen from a -(C1-C5)alkyl,
haioalkyl, nitriie, haloaikyloxy, alkoxy, nitro group and the groups -NRR' with
R and R', which may be identical or different, representing, independently of
each other, a hydrogen atom or a group chosen from alkyl groups and
-(C3-C6)cycloafkyl groups,
o a heteroaryl group, said groups comprising at least one heteroatom chosen
from the nitrogen or sulfur atom, said heteroaryl groups being optionally
substituted with at least one group chosen from alkyl groups and a
heterocycloalkyl group comprising at least one heteroatom chosen from the
nitrogen and oxygen atoms;
it being understood that, when a heteroaryl group is chosen from
pyrrolyl, imidazolyl, pyrazolyl and triazolyls, at least one of the nitrogen atoms
of said heteroaryl may be substituted with a group R6 chosen from an alkyl
group,
o a heterocycloalkyl group comprising at least one heteroatom chosen from the
nitrogen, sulfur, and oxygen atoms and being optionally substituted with at
least one substituent chosen from (i) halogen atoms, (ii) haioalkyl groups,
(iii) alkyl groups, advantageously linear or branched ~(C1-C4)alkyl groups, and
(iv) cycloalkyl groups,
it being understood that when the heterocycloalkyl groups are
chosen from pyrrolinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolinyl,
pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl and thiomorphoiinyl, at least
one of the nitrogen atoms of said heterocycloalkyl may be optionally
substituted with a group R6 chosen from an alkyl group,
in the form of an acid, a base or an addition salt with an acid or a base.
The compounds of formula (i) may contain one or more asymmetric carbon atoms. They
may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers,
diastereoisomers, and mixtures thereof, including racemic mixtures, form part of the
invention.
For example, when R4 represents a heterocycle, the absolute configuration of a carbon
substituted on said heterocycie may be R or S.
The compounds of formula (I) may exist in the form of bases or addition salts with acids.
Such addition salts form part of the invention.
These salts may be prepared with pharmaceutically acceptable acids, but the salts of
other acids useful, for example, for the purification or isolation of the compounds of
formula (I), also form part of the invention.
The compounds of formula (I) may also exist in the form of solvates or hydrates, namely
in the form of associations or combinations with one or more molecules of solvent or
water, in crystalline or amorphous form. Such solvates and hydrates also form part of the
invention.
The subject of the invention is also a method for preparing a compound of formula (I)
according to the invention, characterized in that a compound of formula (lXa):

is reacted with a compound of formula (VII), in the presence of a coupling catalyst and a
base as defined below,

where R1, R2, R3, R4, n, n\ V, W, Y, Z and Ar are as defined above, X represents a
leaving group defined below, advantageously X represents a halogen, more
advantageously still X represents a chlorine atom and M is as defined above.
According to another aspect, the subject of the invention is also a method for preparing a
compound of formula (I) according to the invention, characterized in that a compound of
formula (IXb)

is reacted with a compound of formula (VIII),

where R1, R2, R3, R4, n, n', V, W, Y, Z and Ar are as defined above, X represents a
leaving group defined below, advantageously X represents a halogen, more
advantageously still X represents a bromine or iodine atom and M is as defined above.
In the context of the present invention, unless otherwise stated in the text, there is
understood by:
- a halogen atom: a fluorine, chlorine, bromine or iodine atom;
- a heteroatom: a nitrogen, oxygen or sulfur atom;
- an alkyl group: a linear or branched saturated aliphatic group which may
contain 1, 2, 3, 4, 5 or 6 carbon atoms (abbreviated -(C1-C6)alkyl). Advantageously, this
is a -(C1-C4)alkyl group. By way of examples, there may be mentioned as (i) -Clalkyl
group, the methyl group, as (ii) -C2alkyl group, the ethyl group, as (iii) -C3alkyl group, the
propyl, isopropyl group, as (iv) -C4alkyl group, the butyl, isobutyl, tert-butyl group, as
(v) -C5alkyl group, the pentyl, isopentyl group, as (vi) ~C6alkyl group, the hexyl group;
- an alkylene group: a linear or branched saturated divalent alkyl group as
previously defined, which may contain 1, 2, 3, 4, 5 or 6 carbon atoms (abbreviated
-(C1-C6)alkylene). By way of example, there may be mentioned the methylene (or
-CH2-), ethylene (or-CH2-CH2-), propylene (-CH2-CH2-CH2-) radicals;
- an alkenyl group: an aliphatic group comprising at least 2 carbon atoms and
being mono- or polyunsaturated. Advantageously, this is a C2-C10 group comprising at
least one C=C double bond, more advantageously still a C2-C6 group comprising at least
one C=C double bond;
- a cycloalkyl group: a cyclic alky! group which may contain 3, 4, 5, 6, 7, 8, 9 or
10 carbon atoms, also abbreviated -(C3-C10)cycloalkyl. Advantageously, this is a
-(C3-C5)cycloalkyl group. By way of examples, there may be mentioned the cyclopropyl,
methylcyclopropyl, cyclobutyl, cyclopentyi, cyclohexyl, cycloheptyl, adamantyl and
pentalene groups;
- an alkoxy or alkyloxy group: an -O-alkyl radical where the alkyl group is as
previously defined. By way of examples, there may be mentioned the -O-(C1-C5)a!kyl or
-(C1-C5)a!koxy groups, and in particular as (i) -O-C1 alkyl group, the -Omethyl group, as
(ii) -O-C2alkyl group, the -Oethyi group, as (iii) -O-C3alkyl group, the -Opropyl,
-Oisopropyl group, as (iv) -O-C4alkyl group, the -Obutyl, -Oisobutyl, -Otert-butyl group,
as (v) -O-C5alkyl group, the -Opentyl, -Oisopentyl group;
- an aikoxyalkyl group: a radical of formula -alkylene-O-alkyl, where the alkyl and
alkylene groups, comprising the same number of carbons or not comprising the same
number of carbons, are as previously defined. By way of examples, there may be
mentioned the groups -(C1-C6)alkylene-O-(C1-C6)alkyl, with -(C1-C6)a!kylene- and
-(C1-C6)alkyl as defined above;
- a haloalkyl group: an alkyl group as defined above substituted with 1, 2, 3, 4 or
5 halogen atoms, as previously defined. There may be mentioned for example the
groups -halo(C1-C5)alkyi, with (C1-C5)aikyl as defined above, and in particular the
thfluoromethyi group (abbreviated -CF3);
- a haloalkyloxy group: a haloalkyl-O- group where the haloalkyl group is as
defined above;
- an aryl group: a cyclic aromatic group comprising 6, 7, 8, 9 or 10 carbon
atoms. By way of examples of aryl groups, there may be mentioned the phenyl group
(abbreviated Ph) or a naphthyl group;
- an arylalkyl group: an aryl group, as defined above, substituted with at least
one alkyl group, as defined above. Advantageously, this refers to -alkyl-aryl radicals.
There may be mentioned, for example, benzyl, that is to say the -CH2-Ph radical;
- an aryloxy group: a radical of formula -O-aryl, where the aryl group is as
previously defined;
- a heteroaryl group: a cyclic aromatic group comprising 2, 3, 4 or 5 carbon
atoms and comprising 1 to 3 heteroatoms, which may be chosen from the nitrogen atom,
the oxygen atom and the sulfur atom, independently of each other, so as to be identical
or different, when they are 2 in number or independently of each other, so as to be
identical or different, when they are 3 in number. There may be mentioned, for example,
the pyridinyl, pyrrolyl, pyrazolyi, furanyl, pyrazinyl, pyrimidyl, imidazolyl, thiophenyl,
thiazolyl, 1, 2, 3-triazolyl and 1, 2, 4-triazolyl groups;
- a heterocycloalkyl: an optionally bridged cyclic alkyl group comprising 5, 6 or 7
carbon atoms and comprising 1, 2 or 3 heteroatoms which may be chosen,
independently of each other, so as to be identical or different, when they are 2 in number
or independently of each other, so as to be identical or different, when they are 3 in
number, from the nitrogen atom, the oxygen atom or the sulfur atom. There may be
mentioned in particular piperidinyl, piperazinyl, pyrrolidinyl, hexamethyieneimino,
tetrahydrofuranyl, morpholinyl, 1,1-dioxydotetrahydrothienyl groups;
- a protecting group Pg: a group which makes it possible, on the one hand, to
protect a reactive functional group such as a hydroxy! or an amine during a synthesis
and, on the other hand, to regenerate the reactive functional group intact at the end of
the synthesis. Examples of protecting groups and methods of protection and deprotection
are given in "Protective Groups in Organic Synthesis", Green et al., 2nd Edition (John
Wiley & Sons, Inc., New York), 1991;
- a leaving group: a group which may be readily cleaved from a molecule by
breaking a heterolytic bond, with the departure of an electron pair. This group may thus
be easily replaced by another group during a substitution reaction, for example. Such
leaving groups are, for example, halogens or an activated hydroxyl group such as a
methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, and the like.
Examples of leaving groups and references for their preparation are given in "Advances
in Organic Chemistry", J. March, 3rd Edition, Wiley Interscience, 1985, p. 310-316;
- a coupling catalyst: a complex of metals such as palladium and nickel which
are generally used in a catalytic quantity allowing the formation of carbon-carbon bonds
from halogenated derivatives and organometallic compounds derived from tin (via a
"Stille coupling"), from magnesium (via a "Corriu-Kumada coupling"), from boron (via a
"Suzuki coupling"), from zinc (via a "Negishi coupling"), and the like. Examples of such
coupling catalysts are described in "Palladium reagents and catalysts - Innovations in
organic synthesis", J. Tsuji. (John Wiley & Sons, Inc., Chichester), 1995.
Among the compounds of formula (I) which are the subject of the invention, there may be
mentioned a group of compounds in which:
• n represents 0, 1, 2 or 3;
and/or
• n' represents 0, 1, 2, 3 or 4;
and/or
• R1 represents an alkyl group, advantageously a -(C1 -C6)alkyl group, more
advantageously a -(C1-C4)alkyl group;
and/or
• R2 represents:
o a cycloalkyl group, advantageously a -(C3-C10)cycloalkyl group, more
advantageously still a -(C3-C5)cycloalkyl group,
o an alkyl group, advantageously a -(C1-C6)alkyl group, more
advantageously still a -(C1-C4)alkyl group, or
o an alkoxy group, advantageously a -O-(C1-C6)alkyl group, more
advantageously still a -O-(C1-C4)a!kyl group,
said cycloalkyl, alkyl or alkoxy groups being optionally substituted with one or
more halogen atoms, advantageously with one or more fluorine atoms;
advantageously R2 represents an alkyl group;
and/or
• R3 represents:
o a hydrogen atom, or
(C1-C6)alkyl
o a -C(O)alkyl group, advantageously a group
(C1-C4)alkyl
more advantageously stiil a group ;
advantageously R3 represents a hydrogen atom;
and/or
• Ar represents a 5- or 6-membered aryl or heteroaryl ring,
and/or
• Y, Z, V and W:
a) represent, independently of each other,
i) a =CH- group,
ii) a =C(R5)- group in which R5 represents:
• an alkyl group, advantageously a -(C1-C6)alkyl group, more
advantageously stiil a -(C1-C4)alkyl group,
• a halogen atom, advantageously chosen from the fluorine
atom or the chlorine atom, or
• an alkoxy group, advantageously a -O-(C1-C6)alkyl group,
more advantageously still a -O-(C1-C4)a!kyl group,
iii) a heteroatom chosen from the nitrogen atom, the suifur atom and
the oxygen atom, and/or
b) at most one among Y, Z, V and W is optionally absent,
it being understood that when Y, Z, V and W are contained in a heteroaryl chosen from
pyrrolyl, imidazolyl, pyrazolyl and triazolyls, at least one of the nitrogen atoms of said
heteroaryl may be optionally substituted with a group R6,
and/or
• R4 represents a group chosen from:
o the alkyl groups, advantageously a- (C1-C6)alkyl group, more advantageously
still a -(C1-C4)alkyl group;
o the alkoxyalkyl groups,
o the groups -NRR',
o the cycloalkyl groups, advantageously the -(C3-C5)cycloa!kyl groups,
o the alkenyl groups, advantageously the C2-C10 groups comprising at least
one C=C double bond, more advantageously still the C2-C6 groups
comprising at least one C=C double bond,
o the aryl groups, advantageously the aryl groups comprising 6 carbon atoms,
said aryl groups being optionally substituted with at least one halogen atom,
advantageously chosen from the fluorine and chlorine atoms, and/or with at
least one group chosen from the -(C1-C5)alkyl, haioalkyl, nitrile, haloalkyloxy,
alkoxy and nitro groups and the groups -NRR',
o the heteroaryl groups, advantageously the 5- or 6-membered heteroaryl
groups comprising at least one heteroatom chosen from the nitrogen or sulfur
atom, said heteroaryl groups being optionally substituted with at least one
group chosen from the alkyl groups, advantageously a -(C1-C4)alkyl group
and the heterocycloalkyi groups comprising at least one heteroatom chosen
from the nitrogen and oxygen atoms; advantageously said heterocycloalkyi
group is morpholinyl;
(i) it being understood that when said heteroaryl groups are chosen
from pyrrolyl, imidazolyi, pyrazolyl and triazolyis, at least one of the
nitrogen atoms of said heteroaryl may be optionally substituted with
a group R6,
(ii) advantageously said heteroaryl groups are chosen from the pyridinyl
and imidazoiyl groups,
o the heterocycloalkyi groups comprising at least one heteroatom chosen from
the nitrogen, sulfur and oxygen atoms and being optionally substituted with at
least one substituent chosen from (i) the halogen atoms, advantageously
chosen from the fluorine and chlorine atoms, (ii) the haioalkyl groups,
advantageously the fluoro(C1-C4)alkyl groups substituted with 1, 2, 3, 4 or 5
fluorine atoms, (iii) the alkyl groups, advantageously the linear or branched
-(C1-C4)alkyl groups, and (iv) the cycloalkyl groups, advantageously the
-(C3-C5)cycloalkyl groups,
it being understood that when the heterocycloalkyl groups are
chosen from pyrrolinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazoiinyl,
pyrazolidinyl, piperidinyl, morphoiinyl, piperazinyl and thiomorpholinyl, at least
one of the nitrogen atoms of said heterocycloalkyl may be optionally
substituted with a group R6,
and/or
• R5 represents:
o an alkyl group, advantageously a -(C1-C6)alkyl group, more advantageously still
a-(C1-C4)alkylgroup,
o a halogen atom, advantageously chosen from the fluorine atom and the chforine
atom, or
o an alkoxy group, advantageously a -O-(C1-C6)alkyl group, more
advantageously still a -O-(C1-C4)alkyl group,
and/or
• R6 represents a group chosen from an alkyl group, advantageously a -{C1-C6)alkyl
group, more advantageously still a -(C1-C4)alkyl group,
and/or
• R and R', which may be identical or different, representing, independently of each
other, a hydrogen atom, an alkyl group or a -(C3-C6)cycloalkyl group,
in the form of an acid, a base or an addition salt with an acid or a base.
Among the compounds of formula (I) which are the subject of the invention, there may be
mentioned a group of compounds in which:
R1 represents a -(C1-C4)alkyl group,
and/or
R2 represents a -(C1-C4)alkyl group,
and/or
n' represents 1,
and/or
R3 represents a hydrogen atom,
and/or
Ar represents a phenyl,
and/or
said compounds are in the form of a base or of addition salts with an acid,
advantageously hydrochloric acid.
Among the compounds of formula (I) which are the subject of the invention, there may be
mentioned a group of compounds in which:
R4 represents a group chosen from:
o the alkyl groups, advantageously a -(C1-C6)alkyl group, more advantageously
still a -(C1-C4)alkyl group;
o the groups -NRR', with R and R\ which may be identical or different,
representing, independently Of each other, a hydrogen atom, an alkyl group or
a -(C3-C6)cycloalkyl group,
o the alkenyl groups, advantageously the C2-C10 groups comprising at least
one C=C double bond, more advantageously still the C2-C6 groups
comprising at least one C=C double bond,
o the aryl groups, advantageously the aryl groups comprising 6 carbon atoms,
said aryl groups being optionally substituted with at least one halogen atom,
advantageously chosen from the fluorine and chlorine atoms, and/or with at
least one group chosen from alkoxy groups and the groups -NRR', with R and
R' as defined above,
o the heteroaryl groups, advantageously the 5- or 6-membered heteroaryl
groups comprising at least one heteroatom chosen from the nitrogen atom,
said heteroaryl groups being optionally substituted with at least one group
chosen from alkyl groups, advantageously a -(C1-C4)alkyl group, and
heterocycloalkyl groups comprising at least one heteroatom chosen from the
nitrogen and oxygen atoms; advantageously said heterocycloalkyl group is
morpholinyl;
it being understood that when said heteroaryl groups are chosen from pyrrolyl, imidazoiyl,
pyrazolyl and triazolyls, at least one of the nitrogen atoms of said heteroaryl may be
optionally substituted with a group R6, with R6 representing a group chosen from an alkyl
group, advantageously a -(C1-C6)alkyl group, more advantageously still a -(C1-C4)alkyl
group.
Among the compounds of formula (I) which are the subject of the invention, there may be
mentioned a group of compounds in which R4 represents a group chosen from the
phenyl, pyridinyl and imidazoiyl groups.
Among the compounds of formula (I) which are the subject of the invention, there may be
mentioned a group of compounds in which Y, 2, V and W each represents a =CH group
and/or a =C(R5)- group, with R5 representing a chlorine or fluorine atom, Y, Z, V and W
thus being in an optionally substituted phenyl group.
Among the compounds of formula (I) which are the subject of the invention, the following
compounds may be mentioned in particular:
2-amino-1-ethyl-7-(3-fluoro-4-{[(pyridin-3-ylmethyl)sulfonyl]amino}phenyl)-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 1)
2-amino-1-ethyl-7-(3-fluoro-4-{[(3-fluorophenyl)sulfonyl]amino}phenyl)-N-methyl-
4-0x0-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 2)
2-amino-7-{4-[(ethenylsulfonyl)amino]-3-fluorophenyl}-1-ethyl-N-methyl-4-oxo-1,4-
dihydro-1,8-naphthyridine-3-carboxamide (compound No. 3)
2-amino-7-[4-({[2-(dimethylamino)ethyl]su!fonyl}amino)-3-fluorophenyl]-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 4)
2-amino-7-(4-{[(3-aminobenzyl)sulfonyl]amino}-3-fluorophenyl)-1-ethyl-N-methyl-
4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 5)
2-amino-1-ethyl-7-(3-fluoro-4-{[(1-methyl-1H-imidazo!-4-yl)sulfonyl]amino}phenyI)-
N-methyl-4-oxo-1,4^dihydro-1,8-naphthyridine-3-carboxamide (compound No. 6)
2-amino-7-{4-[(butylsulfonyl)amino]-3-fluorophenyl}-l-ethyl-N-methyl-4-oxo-1,4-
dihydro-1,8-naphthyridine-3-carboxamide (compound No. 7)
2-amino-7-(3-chloro-4-{[(2,3-dichlorophenyl)sulfonyl]amino}phenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 8)
2-amino-7-(4-{[(2,5-dichlorophenyl)sulfonyi]amino}-3-fluoropheny!)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 9)
2-amino-1-ethyl-N-methyI-4-oxo-7-{4-[(pyridin-3-ylsulfonyl)amino]phenyl}-1,4-
dihydro-1,8-naphthyridine-3-carboxamide (compound No. 10)
2-amino-7-(4-{[(2,6-dichlorophenyl)su!fonyl]amino}-3-fiuorophenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 11)
2-amino-7-(2-chloro-4-{[(2,5-dichlorophenyl)sulfonyl]amino}phenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 12)
2-amino-7-(2-chloro-4-{[(2,3-dichlorophenyl)sulfonyl3amino}phenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 13)
2-amino-7-(4-{[(2,3-dichlorophenyl)sulfonyi]amino}-2-fluorophenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 14)
2-amino-7-(4-{[(2,3-dichiorophenyl)sulfonyl3amino}-3-methylphenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 15)
2-amino-1-ethyl-N-methyl-7-{4-[(methyisulfonyl)amino]phenyl}-4-oxo-1l4-dihydro-
1,8-naphthyridine-3-carboxamide (compound No. 16)
2-amino-7-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}phenyl)-1-ethyl-N-methyf-4-oxo-
1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 17)
2-amino-7-(4-{[(2,3-dichlorophenyl)sulfonyi]amino}-3-fiuorophenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 18)
2-amino-7-(4-{[(2-chIorophenyl)suifonyl]amino}phenyl)-1-ethyl-N-methyl-4-oxo-
1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 19)
2-amino-1-ethyl-7-(3-fluoro-4-{[(2-fluorophenyi)sulfonyl3amino}phenyl)-N-methyI-4-
oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 20)
2-amino-7-(4-{[(4-chlorophenyl)sulfonyl]amino}-3-fluorophenyi)-1-ethyl-N-methyl-
4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 21)
2-amino-7-(4-{[(3-chlorophenyl)sulfonyl]amino]-3-fiuorophenyl)-1-ethyl-N-methyl-
4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 22)
2-amino-7-(4-{[(3,4-difluorophenyl)sulfonyI]amino}-3-fluorophenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 23)
2-amino-1-ethyl-7-(3-fluoro-4-{[(4-fluorophenyi)sulfonyl]amino}phenyl)-N-methyl-4-
oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 24)
2-amino-1-ethyl-7-(3-fiuoro-4-{[(3-methoxyphenyl)sulfonyl]amino}phenyl)-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 25)
2-amino-1-ethyl-7-[3-ftuoro-4-({[6-(morpholin-4-yl)pyridin-3-
yi]sulfonyl}amino)phenyl]-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
(compound No. 26)
2-amino-1-ethyl-7-(3-fluoro-4-{[(pyridin-2-ylmethyl)sulfonyI]amino}phenyl)-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound No. 27).
It should be noted that the above compounds were named in the IUPAC nomenclature
with the aid of the software ACDLABS 10.0 ACD/name (Advanced Chemistry
Development).
In accordance with the invention, the compounds of the general formula (I) may be
prepared according to the following method.
According to scheme 1, a 2,6-dihalonicotinic acid of formula (II), where X and X'
represent, independently of each other, a halogen atom advantageously chosen from the
F, CI and Br atoms, advantageously X and X' represent a chlorine atom, is mono-
substituted at the 2 position with an amine of formula R2-(CH2)n'-NH2 in which R2 and n'
are as previously defined in relation to the compounds of formula (I), which are the
subject of the invention. This reaction may take place at room temperature, or at a
temperature of'50°C to 100°C, with conventional or microwave heating and in a protic
solvent such as an alcohol, for example ethanol, n-butano!, tert-butanoi or water. The
acid (III), obtained from step (i), is then activated to a derivative of formula (IV).
This derivative (IV) may either be in the form of an acid fluoride with A = F by the action
of cyanuryl fluoride at room temperature, in the presence of a base such as triethyiamine
or pyridine and in a solvent such as dichloromethane or THF, as described by G. OLAH
et al. in Synthesis (1973), 487, or in the form of an imidazolide with A = imidazoly! by the
action of carbodiimidazole in a solvent such as DMF or THF or by other methods known
to 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 acid fluoride (compound of formula (IV) with A = F, X = halogen, advantageously
X = CI and with n' and R2 as defined above) or the imidazolide (compound of formula
(IV) with A = imidazolyl, X = halogen, advantageously X = CI and with n' and R2 as
defined above) of formula (IV) obtained at the end of step (ii) are very reactive but stable.
They may then be reacted with an N-substituted cyanoacetamide of formula (V)
according to the methods A or B described below.
According to the method A, two equivalents of a base such as sodium hydride or
potassium tert-butoxide are used for step (iv) for condensation of the N-substituted
cyanoacetamide derivative (V), with a compound of formula (IV); after leaving overnight
at room temperature, a ß-ketocyanoacetamide of formula (VI) is obtained, which is then
cyclized to a pyridinopyridinone of formula (VII) in which X = halogen, advantageously
X = CI and R1, R2, n' are as defined above by heating to a temperature between 90 and
125°C in a polar solvent such as n-butanol, DMSO or DMF.
The method B is similar to method A for the condensation step (iv) but a third equivalent
of the based used is added to the reaction mixture, and the compound of formula (VI)
formed undergoes cyclization in situ, at room temperature, to directly give the
pyridinopyridinone compound of formula (Vll) in which X = halogen, advantageously X =
CI and R1, R2, n' are as defined above.
The N-alkylcyanoacetamides of formula (V) are prepared according to step (iii) by
reacting ethyl cyanoacetate with an excess of amine of formula R1-NH2 (where R1 is as
previously defined in relation to the compounds of formula (I) which are the subject of the
invention) in a solvent such as THF or ethanol, at a temperature ranging from room
temperature to the reflux temperature of the solvent.
To obtain the compounds of formula (I) which are the subject of the present invention,
two methods can be used starting with the halogenated intermediate of formula (VII)
previously described.
According to the route 1 represented in scheme 2, the intermediate (VII) in which X
represents a leaving group, advantageously a halogen atom, advantageously an atom
chosen from F, CI and Br, more advantageously still a CI atom, and in which n', R1 and
R2 are as defined above in accordance with the invention, is used in step (vi) in a
SUZUKI coupling reaction with a boronic acid or a boronic ester of bispinacol (IXa) in
which n, R3, R4, V, W, Y and Z are as previously defined in relation to the compounds of
formula (I) which are the subject of the invention, M being as defined in scheme 2 and it
being understood that the ring (Ar), defined above in accordance with the invention,
should comprise 5 or 6 members. This reaction (vi) is carried out in the presence of a
catalyst such as a complex of palladium (at the oxidation state (O) or (II)) such as for
example Pd(PPh3)4, PdCI2(PPh3)2, Pd2dba3, Xphos or PdCI2(dppf), in a nonprotic or protic
polar solvent such as DME, ethanol, DMF, dioxane, or mixtures of these solvents, in the
presence of a base such as cesium carbonate, aqueous sodium hydrogen carbonate, or
K3PO4, with conventional heating between 80 and 120°C or else under the action of
microwave heating between 130 and 170°C.
For the production of the compounds of formula (I) which are the subject of the present
invention, a second route may be used starting with the halogenated intermediate of
formula (VII): this route 2 is described in scheme 2. The halogenated intermediate of
formula (VII), as previously defined, may be converted to a boronic acid of formula (VIII),
in which M is as defined in scheme 2 and R1, R2, n' is as defined above in accordance
with the invention, according to step (vii), by reaction with bis(pinacolato)diborane in the
presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) and potassium
acetate or potassium carbonate in a polar solvent such as DMSO, DMF, DME or dioxane,
at a temperature between 50 and 100°C, according to the methodology described by
ISHIYAMA, T. et al. in J. Org. Chem., 1995, 60, 7508-7510 and GIROUX, A. et al. in Tet.
Lett., 1997, 38, 3841-3844. In the following step (viii), said boronic acid compound (VIII)
is used in a Suzuki type reaction, with a halogenated aromatic compound of formula
(IXb) in which X represents a leaving group, advantageously a halogen atom,
advantageously X is chosen from bromine and iodine atoms and where R3, R4, V, W, Y
and Z are as previously defined in relation to the compounds of formula (I) which are the
subject of the invention, it being understood that the aryi or heteroaryl ring (Ar) should
comprise 5 or 6 members.
While the modes of preparation, starting compounds, reagents, such as the compounds
of formula (IX), used in schemes 1 and 2 are not described, they are commercially
available or eise they may be prepared according to methods which are described in the
literature or which are known to a person skilled in the art.
If necessary, some reactive functional groups present in the groups, such as for example
in the groups R1, R2, R3 and R4, in particular in the groups R5 and/or R6, in accordance
with the invention, may be protected during these reactions by means of protecting
groups, as described in "Protective Groups in Organic Synthesis", Green et al, 2nd
Edition (John Wiley & Sons, Inc., New York).
The subject of the invention, according to another of its aspects, is also the compounds
of formulae (VII), (VIII), (IXa) and (IXb). These compounds are useful as intermediates
for the synthesis of the compounds of formula (I).
The following examples illustrate the preparation of some compounds in accordance with
the invention. These examples are not limiting and merely illustrate the present invention.
The numbers for the compounds exemplified refer to those given in the table below,
which illustrates the chemical structures and the physical properties of a few of the
compounds according to the invention.
The following abbreviations and empirical formulae are used:
AcOEt ethyl acetate
DCM dichloromethane
°C degrees Celsius
DME dimethoxyethane
DMF dimethylformamide
DMSO dimethylsulfoxide
h hour(s)
HCI hydrochloric acid
NaHCO3 sodium hydrogen carbonate
Na2SO4 sodium sulfate
NaCI sodium chloride
NaOH sodium hydroxide
Na2SO4 sodium sulfate
min. minutes
ml milliliter
P2O5 diphosphorus pentoxide
THF tetrahydrofuran
The analytical conditions for the examples described below and the table below are as
follows:
> LC/UV/MS coupling conditions:
• Conditions A:
Instrument (Micromass): HPLC chain: Gilson, mass spectrometer ZMD (Micromass).
LC/UV
Column: XTerra C18 3.5 µm (4.6 x 50 mm) (Waters), Column temp. :25°C,
UV detection: 220 nm.
Gradient: 15 minutes
Eluents: A: H2O + HCOOH 0.1% / B: CH3CN + HCOOH 0.1%, Flow rate: 1 ml/min.
Gradient: 0 to 15 min from 5 to 95% B.
• Conditions B:
Instrument (Micromass): HPLC chain: Waters, mass spectrometer platform II
(Micromass).
LC/UV
Column: XTerra MSC18 3.5 µm (4.6 x 150 mm) (Waters), Column temp.: 20°C,
UV detection: 220 nm.
Gradient: 11 minutes
Eluents: A: CH3COONH4 5mM + CH3CN 3% / B: CH3CN, Flow rate: 0.5 ml/min.
Gradient: 0 to 8 min from 10 to 90% B; 8 to 11 min 90% B.
> MS
Ionization mode: Electrospray positive mode ESI+, Mass range: 90-1500 amu or APCI+
> NMR
The 1H NMR spectra were obtained using NMR spectrometers Bruker 200 or 400 MHz in
CDCI3 or DMSO-d6, using the peak for CHCI3 or DMSO-d5 as reference. The chemical
shifts 5 are expressed in part per million (ppm). The signals observed are expressed as
follows: s = singlet; d = doublet; t = triplet; m = unresolved complex or broad singlet;
H = proton.
> Melting point
Melting points below 260°C were measured with a Koffier stage apparatus and melting
points greater than 260°C were measured with a Buchi B-545 apparatus.
Example 1: 2-amino-7-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}phenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
1.1: 6-chloro-2-fethvlamino)pyridine-3-carboxvlic acid:
A solution of 18.0 g (84.4 mmol) of 2,6-dichloronicotinic acid in 180 ml (3.45 mol)
of a 70% ethylamine solution in water is heated at 50°C for 10 hours. The excess amine
is then evaporated under reduced pressure, and then a 10% aqueous acetic acid solution
is added until precipitation of the product is obtained. The beige solid is drained, rinsed
with cold water and dried in an oven. 10.5 g of the expected product are obtained.
Yield = 62%. Melting point: 158-160°C. MH+: 201.1 (tr: 7.7 min, condition A).
1.2: 6-chloro-2-(ethvlamino)pyridine-3-carbonvl fluoride
To a suspension of 10.5 g (52.3 mmol) of the compound obtained at the end of
step 1.1 in dichloromethane (250 ml), 4.2 ml (52.3 mmol) of pyridine and 8.4 ml
(99.6 mmol) of cyanuric fluoride are successively added. 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 cold water (60 ml). The organic phase is
dried over Na2SO4 and then concentrated under reduced pressure. 10.44g of product
are obtained, in the form of an orange-colored oil. Yield = 99%. The product is used
without purification in the next step.
1.3: 2-cvano-N-methvlacetamide
To 10.9 g (353.6 mmol) of a solution of methylamine in THF cooled to 0°C, 20 g
(176.8 mmol) of ethyl cyanoacetate are added dropwise and then the reaction mixture is
stirred at room temperature overnight. The solvents are evaporated under reduced
pressure and the product is purified by recrystallization from toluene. 16.8 g of product
are obtained, in the form of a beige solid. Yield = 96%. Melting point = 99°C.
> According to Method A of scheme 1 above (steps 1.4 and 1.5 below)
1.4: 3-r6-chloro-2-(ethvlamino)pyridin-3-yn-2-cyano-3-hvdroxy-N-methylprop-2-
enamide
To a solution, cooled to 0-5°C, of 9.80 g (100 mmol) of the compound obtained at
the end of step 1.3, in 100 ml of anhydrous DMF, 3.98 g (100 mmol) of 60% sodium
hydride in mineral oil are added in small quantities. At the end of the emission of
hydrogen, the mixture is stirred for 10 minutes at room temperature and then cooled
again to 0-5°C. A solution of 10.1 g (49.8 mmol) of the compound obtained at the end of
step 1.2, in 60 ml of DMF, is added and the mixture is stirred at room temperature
overnight and then 2.85 ml (49.8 mmol) of acetic acid are added. The DMF is evaporated
under reduced pressure and then the residue is taken up in water and the product is
extracted twice with a dichioromethane:methanol mixture in proportions of 95 to 5, and
then once with an ethyl acetate:THF mixture (2:1). The combined organic phases are
dried over MgSO4, and then the solvents are evaporated under reduced pressure. 19.0 g
of product are obtained which are used as they are in the next step.
1.5: 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxamide
A solution of 19.0 g (49.8 mmol) of the crude product obtained at the end of step
1.4 in 600 ml of n-butanol Is heated for 48 hours at 110°C. The solvent is evaporated
under reduced pressure and the solid obtained is triturated in methanol. The solid is then
filtered and dried in an oven. 7.9 g of the expected product are obtained in the form of a
pale yellow solid. Yield = 57%. Melting point: 283-286°C. MH+: 281.2 (tr= 6.99 min,
condition A)
> According to Method B of scheme 1 above (step 1.6 below instead of the
previous steps 1.4 and 1.5)
1.6: 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxamide
To a solution cooled to 0-5°C of 0.48 g (4.9 mmol) of the compound obtained at
the end of step 1.3, in anhydrous DMF (7 ml), 0.4 g (9.95 mmol) of 60% sodium hydride
in mineral oil are added in small portions. The mixture is stirred at this temperature for
10 minutes and then a solution of 1.0 g (4.93 mmol) of the compound obtained at the end
of step 1.2 in anhydrous DMF (5 ml) is added. The reaction mixture is stirred overnight at
room temperature and then 0.2 g (4.9 mmol) of 60% sodium hydride is added in small
portions. The stirring is continued at this temperature for 30 minutes and then 0.56 ml
(9.8 mmol) of acetic acid is added, followed by 60 ml of water and the solid is filtered,
rinsed with water and then dried in an oven. 1.30 g of the expected product is obtained.
Yield = 94%. Melting point: 283-284°C. MH+: 281.2 (tr= 6.99 min, condition A)
1.7: r7-amino-8-ethyl-6-(rnethylcarbamoyl)-5-oxo-5,8-dihydro-1,8-naphthyridin-2-
yl]boronic acid
A suspension of 8 g (0.03 mol) of the compound obtained at the end of step 1.5
or 1.6 (depending on whether method A or B was used), 8.0 g (0.03 mol) of
bis(pinacolato)diborane and 8.5 g (0.08 mol) of potassium acetate in DMSO (130 ml), is
degassed with argon for 15 minutes. 1.4g (1.7 mmol) of [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complexed with dichloromethane
(1:1), is added and the mixture is heated at 80°C for 30 minutes, under argon, and then
cooled and diluted with 1.1 I of water and acidified to pH = 4 by the addition of acetic acid
(50 ml). The mixture is filtered and the black precipitate is washed with water (40 ml) and
then with ether (60 ml). The black residue is taken up in 575 ml of an NaOH solution (1N)
and the mixture is filtered on celite 545. The filtrate is acidified with 60 ml of acetic acid
and the precipitate is filtered, washed with water and with ether and then dried in an
oven. 6.85 g of product are obtained in the form of a white powder. Yield = 83%. Melting
point: 335°C. MH+: 291.2 (tr= 5.3 min, condition A)
1H NMR(250 MHZ, DMSO-d6), d (ppm): 11.69 (s, 1H); 11.12 (q, 1H, 4.67 Hz); 8.47 (s,
2H); 8.44 (d, 1H, 7.7 Hz); 7.9 (s, 1H); 7.75 (d, 1H, 7.7 Hz); 4.72 (m, 2H); 2.8 (d, 3H,
4.67 Hz); 1.22 (t, 3H, 6.9 Hz).
1.8: 2-amino-7-(4-{[(2,3-dichlorophenyl)sulfonynamino)phenyl)-1 -ethyl-N-methyl-4-
oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
1.8.1: 2,3-dichloro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]
benzenesulfonamide
To a solution of 1.1 g (5 mmoi) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)aniline in 10 ml of pyridine, 1.23 g (5 mmol) of 2,3-dichlorobenzenesulfonyl chloride is
added in portions and the mixture is kept stirred for 15 h at room temperature. The
solvent is evaporated and the residue is taken up in 20 ml of ethyl acetate, washed with
1N HCI and then with water and with a saturated aqueous sodium chloride solution. The
organic phase is dried over Na2SO4 and evaporated to dryness. 2.1 g of the compound
are obtained in the form of dark red crystals. Yield = 100%. Melting point: 235°C
1H NMR (400 MHz; CDCI3): d (ppm): 1.2 (s; 12H; 7.0 (br s; 1H); 7.05 (d; 2H;
8 Hz); 7.2 (t; 1H; 8 Hz); 7.55 (d; 1H; 8 Hz); 7.6 (d; 2H; 8 Hz); 7.9 (d; 1h; 8 Hz).
1.8.2: 2-amino-7-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}phenyl)-1-ethyl-N-methyl-
4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
280 mg (1 mmol) of chloronaphthyridine obtained in 1.6 and 450 mg (1.05 mmol)
of the boronate obtained in the preceding step are dissolved in 12 ml of DME and 3 ml of
ethanol. 8 ml of a saturated aqueous NaHCO3 solution are added and then argon is
bubbled through for 10 minutes. 85 mg (0.073 mmol) of
tetrakis(triphenylphosphine)palladium(O) are then added and the reaction medium is
heated to 90°C under an argon atmosphere. After 3 h, the medium is filtered in the hot
state, the precipitate obtained after cooling is filtered, washed with water and then with
ethanol and finally with ethyl ether. The solid obtained is recrystallized from ethanol and
dried in an oven. 205 mg of product are obtained in the form of a pale yellow powder.
Yield = 37%. Melting point = 210°C
NMR (200 MHz; DMSO-d6): d(ppm): 1.2 (t; 3H; 7 Hz); 2,8 (d; 3H; 4.5 Hz); 4.55 (q;
2H; 7 Hz); 7.2 (d; 2H; 8 Hz); 7.55 (t; 1H; 8 Hz); 7.7-7.9 (m; 4H); 8.1-8.2 (m; 3H); 8.4 (d;
1H;8Hz); 11.1 (q; 1H;4.5Hz); 11.65 (brs; 1H)
LCMS: MH+: 546 (tr: 6.58 min, condition B).
Example 2: 2-amino-7-(4-{[(2,3-dichlorophenyl)sulfonyl3amino}-3-fluorophenyl)-1-
ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
> According to Method A of scheme 1 above:
2.1: 2-fluoro-4-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-vl)aniline
5.0 g (21.1 mmol) of 2-fluoro-4-iodoaniline and 5.89 g (23.2 mmoi) of
bis(pinacolato)diborane are dissolved in 130 mi of DMSO. 6.21 g (63.3 mmol) of
potassium actetate are added and argon is bubbled through for 10 min. 1.21 g
(1.50 mmol) of [1,1,-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complexed
with dichloromethane (1:1), is added and the mixture is heated at 85°C for 4.5 hours,
under argon, and then cooled and diluted with 500 ml of water. The mixture is extracted
with ethyl acetate (3 X 200 ml), the organic phases are washed with water, dried over
Na2SO4 and then evaporated to dryness. The crude product is purified by
chromatography on silica (eluent: cyclohexane/ethyl acetate 90/10). 3.73 g of product are
obtained in the form of a white powder. Yield = 75%. Melting point: 112°C.
1H NMR (400 MHz; CDCI3): d(ppm): 1.2 (s; 12H); 3.8 (br s; 2H); 6.55 (t; 1H;
7 Hz); 7.25-7.35 (m; 2H).
2.2:2,3-dichloro-N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3.2-dioxaborolan-2-yl)-
phenyl]benzenesulfonamide
Under an inert atmosphere, 1.24 g of 2,3-dichlorobenzenesulfonyl chloride is
added in portions to a solution of 1.0 g (4.22 mmol) of the compound obtained at the end
of step 2.1, in 40 ml of anhydrous pyridine, and then the reaction mixture is kept stirred
for 18 hours. The solvent is evaporated and the residue is taken up in 20 ml of ethyl
acetate, washed with 1N HCI and then with water and with a saturated aqueous sodium
chloride solution. The organic phase is dried over Na2SO4 and evaporated to dryness and
the residue is recrystallized from cyciohexane. 1.13 g of product is obtained in the form of
white crystals. Yield: 60%. MH+: 445 (tr: 8.43 min, condition A).
2.3: 2-amino-7-(4-{[(2.3-dichlorophenyl)sulfonvnamino}-3-fluorophenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
1.13 g (2.53 mmol) of the compound obtained at the end of step 2.2 and 0.65 g
(2.32 mmol) of chloronaphthyridine obtained in 1.6 are dissolved in 18 ml of
dimethoxyethane and 7 ml of ethanol. 16 ml of a saturated aqueous NaHCO3 solution are
added and argon is bubbled through for 10 minutes. 0.134 g (0.12 mM) of
tetrakis(triphenylphosphine)palladium(O) is added and the reaction medium is heated at
100°C under argon for 4 h and is then filtered and the residue obtained after evaporation
of the filtrate is triturated in water. The precipitate is filtered, washed with water and dried,
and then purified by chromatography on silica, eluting with a gradient of methanol in
dichloromethane. 740 mg of product are obtained in the form of a white powder. Yield:
57%. Melting point: 333°C
NMR (200 MHz; DMSOd6):d (ppm): 1.2 (t; 3H; 7 Hz); 2.7 (s; 3H); 4.5 (q; 2H;
7 Hz); 7.35 (t; 1H; 8 Hz); 7.5 (t; 1H; 8 Hz); 7.8-8.0 (m; 6H); 8.45 (d; 1H; 8 Hz); 10.8 (s;
1H); 11.1 (q; 1H;4.5 Hz); 11.7 (br s; 1H).
LCMS: MH+: 563.9 (tr: 7.544 min, condition A)
> According to Method B of scheme 1 above:
2.4: 2,3-dichloro-N-(2-fiuoro-4-iodophenvl)benzenesulfonamide
To a solution of 2-fluoro-5-iodoaniline (2.8 g; 11.8 mmol) in 30 ml of anhydrous
pyridine, 2.96 g (11.8 mmol) of 2,3-dichlorobenzenesulfonyl chloride are added in
portions and the mixture is kept stirred for 24 hours at 20°C. The pyridine is evaporated,
the residue is taken up in 50 ml of ethyl acetate and washed with water and then with a
saturated aqueous NaCI solution. The organic phase is dried over Na2SO4 and then
evaporated to dryness. The product is recrystallized from cyclohexane. 4.51 g of product
are obtained in the form of a white powder. Yield: 86%; LCMS: (M-H)": 444 (tr: 7.90 min,
condition A).
2.5: 2-amino-7-(4-{[(2.3-dichlorophenyl)sulfonvnamino)-3-fluorophenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1.8-naphthyridine-3-carboxamide
To a solution of 1.0 g (2.24 mmol) of the compound obtained at the end of step
2.4 and 1.0 g (3.45 mmol) of boronic acid obtained at the end of step 1.7 in 16 ml of
DMF, 4.5 ml of a saturated aqueous NaHCO3 solution are added and argon is bubbled
through for 10 min. 144 mg (0.16 mmol) of tris(dibenzylideneacetone)dipalladium(O) are
then added and the mixture is heated at 85°C for 5 hours. The reaction medium is filtered
in the hot state and then the filtrate is evaporated to dryness and the residue is triturated
in water (20 ml). The precipitate is filtered, washed with water and then dried in an oven
under vacuum. The crude product is purified by chromatography on silica. 504 mg of
product are obtained in the form of a white powder. Yield: 40%. NMR and LCMS are
identical to those for the compound obtained by method A.
Example 3: 2-amino-7-f4-{[(2,5-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1-
ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide:
3.1: 2,5-dichloro-N-(2-fluoro-4-iodophenyl)benzenesulfonamide
Prepared according to the method described in 2.4 (method B) from 2.0 g (8.44 mmol) of
2-fluoro-4-iodoaniline and 2.11 g (8.44 mmol) of 2,5-dichlorobenzenesulfonyl chioride in
21 ml of pyridine.
3.20 g of product are obtained in the form of a white powder. Yield: 85%.
LCMS: (M-H): 444 (tr: 7.88 min, condition A).
3.2: 2-aminO-7-(4-|[(2,5-dichiorophenvl)sulfonvllamino)-3-fluorophenyl)-1-ethyl
-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
Prepared according to the method described in 2.d (method B) from 1.24 g (2.78 mmol)
of the product obtained from step 3.1 and 1.24 g (4.28 mmol) of the boronic acid
obtained from step 1.7.
610 mg of product are obtained in the form of a white powder. Yield: 39%. Melting
point: 230°C
1H NMR (200 MHZ, DMSO-d6): d(ppm): 1.3 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.55
(q; 2H; 7Hz); 7.40 (t; 1H; 8Hz); 7.75 (s; 2H); 7.85-8.2 (m; 5H); 8.50 (d; 1H; 8Hz); 10.85
(s;1H); 11.05 (q;1H; 4.5Hz); 11.7 (br s; 1H).
LCMS: MH+: 564 (tr: 7.32 min, condition A).
Example 4: 2-amino-1-ethyl-N-methyl-7-{4-[(methylsulfonyl)amino]phenyl}-4-oxo-
1,4-dihydro-1,8-naphthyridine-3-carboxamide
4.1: {4-f(methylsulfonyl)amino]phenyl}boronic acid
A suspension of 1.0 g (5.77 mmol) of 4-aminobenzeneboronic acid hydrochloride
in 10 ml of a saturated aqueous NaHCO3 solution is cooled on ice and 2 ml (25.8 mmol)
of methanesulfonyl chloride are added and the pH is adjusted to 7.2 by adding about
10 ml of a saturated aqueous NaHCO3 solution and the mixture is kept stirred for 2 h at
5°C. 1 ml of methanesulfonyl chloride and 5 ml of a saturated aqueous NaHCO3 solution
are added. The temperature of the medium is allowed to rise to 20°C and 3N HCI is
added to pH=2 and then the whole is evaporated to dryness. 20 ml of water are added.
The precipitate is filtered, washed with a minimum of water and then with ethyl ether. The
product is dried in an oven under vacuum at 40°C. 0.45 g of white powder is obtained
which is used without further purification.
4.2: 2-amino-1-ethvl-N-methyl-7-{4-ffrnethylsulfonyl)amino]phenyl}-4-oxo-1.4-
dihydro-1,8-naphthyridine-3-carboxamide
0.33 g (1.16 mmol) of chloronaphthyridine obtained at the end of step 1.6 is
dissolved in 16 ml of dimethoyethane and 8 ml of ethanol and nitrogen is bubbled
through. The boronic acid obtained at the end of the preceding step as well as 8 ml of a
saturated aqueous NaHCO3 solution are added. 67 mg (0.06 mmol) of
tetrakis(triphenylphosphine)pal!adium(O) are introduced and the medium is heated at
110°C for 3 h. After cooling, the mixture is filtered on paper and the filtrate is
concentrated to dryness. The residue is taken up in water and the precipitate obtained is
filtered, washed with water and dried in an oven under vacuum over P205 and then
purified by chromatography on silica (eluent: CH2Cl2/MeOH: 95/5). 450 mg of product are
obtained in the form of a powder. Yield: (93%). Melting point: >300°C
1H NMR (200 MHZ, DMSO-d6): d(ppm): 1.3 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 3.1 (s;
3H); 4.6 (q; 2H; 7Hz); 7.3 (d; 2H; 8Hz); 7.9 (d; 1H; 8Hz); 8.2 (d; 2H; 8Hz); 8.50 (d; 1H;
8Hz); 10.1 (s; 1H); 11.1 (q; 1H;4.5Hz); 11.7 (brs; 1H).
MH+: 416 (tr: 5.05 min, condition B).
Example 5: 2-amino-1-ethvl-7-(3-fluoro-4-ir(pvridin-3-
ylmethyl)sulfonyl]amino}phenyl)-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxamide hydrochloride
5.1: N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3.2-dioxaborolan-2-yl)phenyl1-1-fpyridin
-3-yl)methanesulfonamide
Under an inert atmosphere, 0.493 g (1.30 mmol) of pyridin-3-yimethanesulfonyl
chloride trifluoromethanesulfonate is introduced in portions into a solution of 0.28 g
(1.18 mmol) of the compound obtained at the end of step 2.1, in 12 mi of anhydrous
pyridine, and the reaction medium is kept stirred for 18 hours. 0.1 equivalent of sulfonyl
chloride is added and the mixture is kept stirred for 24 hours. The pyridine is completely
evaporated (two expulsions with toluene). The residue is redissolved in ethyl acetate,
washed with water and then dried over Na2SO4 and concentrated to dryness. The solid
obtained is recrystallized from cyclohexane. 330 mg of a white powder are isolated.
Yield: 75%. Melting point: 206°C.
1H NMR (400 MHz; DMSO-d6): d(ppm): 1.15 (s; 12H); 4.d (s; 2H); 7.2-7.3 (m; 4H);
7.6 (d; 1H; 8Hz); 8.35-8.45 (m; 2H); 9.8 (s; 1H).
5.2: 2-amino-1-ethyl-7-(3-fiuoro-4-([pyridin-3-ylmethyl)sulfonynamino)phenyl)-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthvridlne-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.300 g (0.76 mmol) of the compound obtained in the preceding step and
0.195 g (0.69 mmo!) of chloronaphthyridine obtained from step 1.6. 200 mg of product
are obtained in the form of a white powder. Yield: 56%
1H NMR(400 MHZ, DMSO-d6): d(ppm): 1.2 (t; 3H; 7Hz); 2.7 (d; 3H; 4.5Hz); 4.5
(m; 4H); 7.3 (m; 1H); 7.4 (t; 1H; 8Hz); 7.7 (d; 1H; 8Hz); 7.8-8.0 (m; 3H); 8.3d (m; 3H);
9.9d (s; 1H); 11.0 (q; 1H;4.5Hz); 11.6 (br s; 1H).
5.3:2-amino-1-ethvi-7-(3-fluoro-4-fr(pyridin-3-vlmethyl)
sulfonyl]amino}phenyl)-N-methvl-4-oxo-1,4-dihydro-1.8-naphthyridine-3-carboxamide
hydrochloride
To a suspension of 0.200 g (0.39 mmol) of product obtained from the preceding step in
10 ml of dichloromethane, 0.2 ml of a 2N HCI solution in ethyl ether is added dropwise.
The mixture is kept stirred for 10 minutes at 20°C and the precipitate is filtered, washed
with ethyl ether and dried in an oven under vacuum. 202 mg of product are obtained in
the form of a white powder. Yield: 94%. Melting point: 220-223°C.
1H NMR(200 MHZ, DMSO-d6): d(ppm): 1.3 (t; 3H; 7Hz); 2.8 (s; 3H); 4.6 (m; 2H);
4.8 (s; 2H); 7.55 (t; 1H; 8Hz); 7.65 (t; 1H; 8Hz); 7.9-8.2 (m; 4H); 8.5 (d; 1H; 8Hz); 8.7 (m;
2H); 10.1 (s; 1H); 11.1 (s; 1H); 11.7 (brs; 1H).
LCMS: MH+:511 (tr: 5, 68 min; condition A).
Example 6: 2-amino-1-ethyi-7-(3-fluoro-4-{[(3-fluorophenyl)sulfonyl]amino}
phenyl)-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
6.1: 3-fluoro-N-r2-fluoro-4-f4,4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)phenyl]
benzenesulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 0.5 g (2.11 mmol) of the compound obtained from step 2.1 and 0.635 g
(3.16 mmol) of 3-fluorobenzenesulfonyl chloride. 0.524 g of product is obtained in the
form of a white powder. Yield: 63%
1H NMR(400 MHZ, DMSO-d6): d(ppm):1.25 (s; 12H); 7.3-7.5 (m; 3H); 7.6-7.9 (m;
4H); 10.55 (s; 1H).
6.2: 2-amino-1-ethvl-7-(3-fluoro-4-{[(3-fluorophenyl)sulfonynamino)phenyl)-N-
methyl-4-oxo-1,4-dihvdro-1.8-naphthyridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.496 g (1.25 mmol) of the compound obtained from the preceding step and
0.320 g (1.14 mmol) of chloronaphthyridine obtained from step 1.6. 0.287 g of product is
obtained in the form of a beige powder. Yield: 49%. Melting point: 256°C
1H NMR (200 MHZ, DMSO-d6): d(ppm): 1.3 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.55
(q; 2H; 7Hz); 7.4 (t; 1H; 8Hz); 7.5-7.7 (m; 4H); 7.9-8.1 (m; 4H); 8.d (d; 1H; 8Hz); 10.6 (s;
1H); 11.1 (q; 1H; 4.5Hz); 11.7 (brs; 1H).
LCMS: MH+:514 (tr: 7.38 min; condition B).
Example 7: 2-amino-1-ethyl-7-(3-fluoro-4-{[(3-methoxvphenyl)sulfonyl]amino}
phenyl)-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
7.1: N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-
methoxybenzenesulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 0.5 g (2.11 mmol) of the compound obtained from step 2.1 and 0.674 g
(3.16 mmol) of 3-methoxybenzenesulfonyl chloride. 0.454 g of product is obtained in the
form of a white powder. Yield: 53%
1H NMR (400 MHZ, DMSO-d6): d(ppm): 1.25 (s; 12H); 3.8 (s; 3H); 7.2 (d; 1H;
8Hz); 7.25-7.4 (m; 5H); 7.6 (t; 1H; 8Hz); 10.4 (s; 1H).
7.2: 2-amino-1-ethyl-7-(3-fluoro-4-{[(3-methoxvDhenyl)sulfonyllamino}phenyl)-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.447 g (1.1 mmol) of the compound obtained from the preceding step and
0.280 g (1.0 mmol) of chloronaphthyridine obtained from step 1.6. 0.19 g of product is
obtained in the form of a white powder. Yield: 36%. Melting point: >260°C.
1H NMR (200 MHZ, DMSO-d6): d(ppm): 1.25 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.55
(q; 2H; 7Hz); 7.2 (d; 1H; 8Hz); 7.3-7.5 (m; 4H); 7.8-8.0 (m; 4H); 8.5 (d; 1H; 8Hz); 10.4 (s;
1H); 11.1 (q; 1H;4.5Hz); 11.7 (brs; 1H).
LCMS: MH+: 526 (tr: 7.56 min; condition B).
Example 8: 2-amino-1-ethvl-7-(3-fluoro-4-{[4-fluorophenyl)sulfonvllamino}
phenyl)-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide:
8.1:4-fluoro-N-r2-fluoro-4-(4,4,5,5-tetramethyl-1,3.2-dioxaborolan-2-
yl)phenyl]benzenesulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 0.6 g (2.53 mmol) of the compound obtained from step 2.1 and 0.739 g
(3.80 mmol) of 4-fiuorobenzenesulfonyl chloride. 0.736 g of product is obtained in the
form of a white powder. Yield: 53%
1H NMR (400 MHZ, DMSO-d6): d(ppm): 1.1 (s; 12H); 7.0-7.25 (m; 5H); 7.65 (m; 2H);
10.25 (s; 1H).
8.2: 2-amino-1-ethyl-7-(-3-fiuoro-4-{[(4-fluorophenyl)sulfonyl]amino}phenyl)-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.542 g (1.37 mmol) of the compound obtained from the preceding step and
0.350 g (1.25 mmol) of chloronaphthyridine obtained from step 1.6. 0.186 g of product is
obtained in the form of a white powder. Yield: 29%. Melting point: >260°C.
1H NMR (200 MHZ,DMSO-d6): d (ppm): 1.3 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.55
(q;2H;7Hz); 7.3-7.45 (m; 3H); 7.8-8.1 (m; 6H); 8.5 (d; 1H; 8Hz); 10.45 (s; 1H); 11.1 (q;
1H;4.5Hz); 11.7(brs; 1H).
LCMS: MH+: 514 (tr: 7.47 min; condition B).
Example 9: 2-amino-7-(4-{[(3-chlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1-ethyl-
N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
9.1: 3-chloro-N-[2-fluoro-4-(4.4,5,5-tetramethyl-1,3.2-dioxaborolan-2-yl)phenyl]
benzenesulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 0.5 g (2.11 mmol) of the compound obtained from step 2.1 and 0.579 g
(2.74 mmol) of 3-chlorobenzenesulfonyi chloride. 0.408 g of product is obtained in the
form of a white powder. Yield: 47%
1H NMR (400 MHZ, DMSO-d6): d(ppm): 1.3 (s; 12H); 7.3-7.5 (m; 3H); 7.6-7.9 (m;
4H); 10.6 (s; 1H).
9.2: 2-amino-7-(4-{[(3-chiorophenyl)sulfonvnamino)-3-fluorophenyl)-1-ethyl-N-
methvl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.408 g (0.99 mmol) of the compound obtained from the preceding step and
0.253 g (0.90 mmol) of chloronaphthyridine obtained from step 1.6. 0.402 g of product is
obtained in the form of a yellow powder. Yield: 84%. Melting point: >260°C.
1H NMR (200 MHZ, DMSO-d6): d(ppm): 1.3 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.55
(q; 2H; 7Hz); 7,2 (t; 1H; 8Hz); 7.3-7.4 (m; 2H); 7.55-8.0 (m; 6H); 8.3d (d; 1H; 8Hz); 10.45
(s; 1H); 11.1 (q; 1H;4.5Hz); 11.6 (brs; 1H).
LCMS: MH+: 530 (tr: 7.69 min; condition B).
ExanTgleJO: 2-aminO"1-ethyl-7-(3-fluoro-4-{[(2-fluorophenyl)sulfonyl]amino}
phenyl)-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
10.1:2-fluoro-N-f2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yi)
phenyllbenzenesulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 0.5 g (2.11 mmol) of the compound obtained from step 2.1 and 0.451 g
(2.32 mmol) of 2-fluorobenzenesulfonyl chloride. 0.528 g of product is obtained in the
form of a pinkish powder. Yield: 63%.
1H NMR (400 MHZ, DMSO-d6): d(ppm): 1.2 (s; 12H); 7.25-7.d (m; 5H); 7.7-7.8 (m;
2H); 11.65 (s; 1H).
10.2: 2-amino-1-ethvl-7-(r3-fluoro-4-ir(2-fluorophenvl)sulfonvl]amino)phenv0-N-
methyl-4-oxo-1,4-dihvdro-1,8-naphthyridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.528 g (1.34 mmol) of the compound obtained from the preceding step and
0.341 g (1.21 mmol) of chloronaphthyridine obtained from step 1.6. 0.097 g of product is
obtained in the form of a pale yellow powder. Yield: 16%. Melting point: >260°C.
1H NMR (200 MHZ, DMSO-d6): d (ppm): 1.2d (t; 3H; 7Hz); 2.8 (s; 3H); 4.d (q; 2H;
7Hz); 7.2-7.45(m; 3H); 7.7-8.0 (m; 6H); 8.d (d; 1H;8Hz); 10.6d (s; 1H); 11.1 (q; 1H;
4.5Hz); 11.7 (brs; 1H).
LCMS: MH+: 514 (tr: 7.25 min; condition B).
Example 11: 2-amino-7-(4-{[(2,6-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1-
ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
11.1: 2.6-dichloro-N-f2-fluoro-4-iodophenyl)benzenesulfonamide
This product was prepared according to the protocol described in paragraph 2.4 (method
B) from 2.8 g (11.81 mmo!) of 2-fluoro-4-iodoaniline and 2.99 g (11.81 mmol) of 2,6-
dichlorobenzenesuifonyl chloride. 4.43 g of product are obtained in the form of a yellow
powder. Yield: 84%.
LCMS: MH+: 446 (tr: 7.55 min; condition A).
11.2: 2-amino-7-f4-irf2,6-dichlorophenv0sulfonvnamino>-3-fiuorophenyl)-1 -ethyl-
N-methvl-4-oxo-1,4-dihydro-1.8-naphthyridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.d (method
B) from 2.0 g (4.48 mmol) of the compound obtained from the preceding step and 2.0 g
(6.89 mmol) of the boronic acid obtained from step 1.7. 0.700 g of product is obtained in
the form of a white powder. Yield: 28%. Melting point: 321 °C.
1H NMR (200 MHZ, DMSO-d6): d (ppm): 1.3 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.55
(q; 2H; 7Hz); 7.35 (t; 1H; 8Hz); 7.45-7.7 (m; 3H); 7.8-8.2 (m; 4H); 8.5 (d; 1H; 8Hz); 10.9
(s; 1H); 11.1 (q; 1H;4.5Hz); 11.7 (brs; 1H).
LCMS: MH+: 564 (tr: 14.33 min; condition A).
Example 12: 2-amino-7-(2-chloro-4-(rf2.3-dichlorophenyl)sulfonvnamino>
phenyl)-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
12.1: 3-chloro-4-(4,4,5.5-tetramethvl-1,3,2-dioxaborolan-2-vQaniiine
This product was prepared according to the protocol described in paragraph 2.1 (method
A) from 3.0 g (11.84 mmol) of 3-chloro-4-iodoaniline and 3.31 g (13.0 mmol) of
bis(pinacolato)diborane. 1.51 g of product are isolated in the form of a white solid.
Yield: 50%
1H NMR (400 MHz; CDCI3): 8(ppm): 1.4 (s; 12H); 3.9d (br s; 2H); 6.55 (d; 1H;
8Hz); 6.7 (s;1H); 7.6 (d; 1H; 8Hz).
12.2:2,3-dichloro-N-r3-chloro-4-f4.4,5,5-tetramethvl-1,3,2-dioxaborolan-2-
vQphenvnbenzenesulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 0.6 g (2.37 mmol) of the compound obtained from the preceding step and
0.593 g (2.37 mmol) of 2,3-dichlorobenzenesulfonyl chloride. 0.944 g of product is
obtained in the form of a light beige powder. Yield: 86%.
1H NMR (400 MHZ, DMSO-d6): S(ppm): 1.2 (s; 12H);7.0(d; 1H;8Hz);7.1 (s; 1H);
7.d (d; 1H;8Hz);7.6(t; 1H; 8Hz); 7.9d (d; 1H; 8Hz); 8.10 (d; 1H; 8Hz); 11.25(s; 1H).
12.3: 2-amino-7-f2-chloro-4-{f(2,3-dichlorophenvl)sulfonvnamino)phenvl)-1-ethvl-
N-methvl-4-oxo-1.4-dihvdro-1,8-naphthvridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.943 g (2.04 mmol) of the compound obtained from the preceding step and
0.515 g (1.84 mmol) of chloronaphthyridine obtained from step 1.6. 0.630 g of product is
obtained in the form of a beige powder. Yield: 53%. Melting point: 239°C.
1H NMR (200 MHZ, DMSO-d6): 8(ppm): 1.2 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.d (q; 2H;
7Hz); 7.1-7.3 (m; 2H); 7.5-7.8 (m; 4H); 8.0 (s; 1H); 8.1 (d; 1H; 2Hz); 8.d (d; 1H; 8Hz);
11.0d (q; 1H; 4.5Hz); 11.3 (s; 1H) 11.7 (br s; 1H).
LCMS: MH+: 580 (tr: 7.74 min; condition A).
Example 13: 2-amino-7-(4-{[(4-chlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1-
ethyl-N-methyi-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
13.1:4-chloro-N-r2-fluoro-4-f4,4.5.5-tetramethvl-1,3,2-dioxaborolan~2-yl)
phenyllbenzenesulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 0.5 g (2.11 mmoi) of the compound obtained from step 2.1 and 0.468 g
(2.15 mmol) of 4-chIorobenzenesulfonyl chloride. 0.645 g of product is obtained in the
form of a pink powder. Yieid: 75%. Melting point: 196°C.
1H NMR (400 MHZ, DMSO-d6): S(ppm): 1.3 (s; 12H); 7.35-7.4d (m; 2H); 7.50 (d; 1H;
8Hz); 7.7 (d; 2H; 8Hz); 7.8 (d; 2H; 8Hz); 10.5d (s; 1H).
13.2 : 2-amino-7-(4-{r('4-chlorophenvl)sulfonvnamino)-3-fluorophenvl)-1-ethvl-N-
methvl-4-oxo-1,4-dihvdro-1,8-naphthyridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.613 g (1.49 mmol) of the compound obtained from the preceding step and
0.380 g (1.35 mmol) of chloronaphthyridine obtained from step 1.6. 0.407 g of product is
obtained in the form of a yellow powder. Yield: 57%. Melting point: >260°C.
1H NMR (200 MHZ, DMSO-d6): S(ppm): 1.3 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.55 (q; 2H;
7Hz); 7.4 (t; 1H; 8Hz); 7.7 (d; 2H; 8Hz); 7.8 (d; 2H; 8Hz); 7.8-8.1 (m; 4H); 8.d (d; 1H;
8Hz); 10.5d (s; 1H); 11.1 (q; 1H;4.5Hz); 11.7(brs; 1H).
LCMS: MH+: 530 (tr: 7.91 min; condition A).
Example 14: 2-amino-7-(4-{[(3,4-difluorophenyl)sulfonyl]amino}-3-fluorophenyl)-1-
ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
14.1:3,4-difluoro-N-f2-fluoro-4-(4,4,5,5-tetramethvl-1,3,2-dioxaborolan-2-
vDphenvllbenzenesulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 0.4 g (169 mmol) of the compound obtained from step 2.1 and 0.518 g
(2.36 mmol) of 3,4-difluorobenzenesulfonyl chloride. 0.437 g of product is obtained in the
form of a white powder. Yield: 63%. Melting point: 114°C.
1H NMR (400 MHZ, DMSO-d6): S(ppm): 1.2 (s; 12H); 7.2 (m; 2H); 7.3 (d;1H; 8Hz); 7.5-
7.6d (m; 2H); 7.7 (t; 1H; 8Hz); 10.4 (s; 1H).
14.2: 2-amino-7-(4-fr(3.4-difluorophenvl)sulfonvllamino>-3-fiuorophenyl)-1-ethyl-N-
methvl-4-oxo-1.4-dihydro-1,8-naphthvridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.400 g (0.97 mmoi) of the compound obtained from the preceding step and
0.259 g (0.92 mmol) of chloronaphthyridine obtained from step 1.6. 0.228 g of product is
obtained in the form of a white powder. Yield: 46%. Melting point: >260°C.
1H NMR (200 MHZ, DMSO-d6): d(ppm): 1.3 (t; 3H; 7Hz); 2.8 (s; 3H); 4.55 (q; 2H; 7Hz);
7.4 (t; 1H;8Hz); 7.5-7.7 (m;2H); 7.8-8.1 (m; 5H); 8.d (d; 1H; 8Hz); 10.6 (s; 1H); 11.0d (q;
1H; 4.5Hz); 11.7 (brs; 1H).
LCMS: MH+: 532 260°C.
1H NMR (200 MHZ, DMSO-d6): S(ppm): 1.2d (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 3.5-
3.8 (m; 8H); 4.55 (q; 2H; 7Hz); 6.90 (d; 1H; 8Hz); 7.d (t; 1H; 8Hz); 7.8 (dd; 1H; 8Hz and
2Hz); 7.85-8.1 (m; 4H); 8.4 (d; 1H; 2Hz); 8.d (d; 1H; 8Hz); 10.3 (s; 1H); 11.1 (q; 1H;
4.5Hz); 11.7 (brs; 1H).
LCMS: MH+: 582 (tr: 7.07 min; condition B).
Example 16: 2-amino-1-ethyl-7-(3-fluoro-4-{[(pyridin-2"ylmethyl)sulfonyl]amino}-
phenyl)-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
hydrochloride
16.1: N42-fluoro-4-(4,4,5,5-tetramethvl-1,3.2-dioxaborolan-2-vl)phenvn-1-(pyridin-
2-vl)methanesulfonamide
This product was prepared according to the protocol described in paragraph 5.1 from
0.28 g (1.18 mmol) of the compound obtained from step 2.1 and 0.493 g (1.30 mmol) of
pyridin-2-ylmethanesulfonyl chloride trifluoromethanesulfonate. 0.441 g of product is
obtained in the form of a white powder. Yield: 95%. Melting point: 152°C.
1H NMR (400 MHZ, DMSO-d6): d(ppm): 1.3 (s; 12H); 4.7 (s; 2H); 7.35-7.4d (m;
4H); 7.d (d; 1H; 8Hz); 7.8 (t; 1H; 8Hz); 8.5d (d; 1H; 2Hz); 9.9d (s;1H).
16.2: 2-amino-1-ethvl-7-f3-fluoro-4-frfpyridin-2-vlmethvhsulfonvnamino)
phenvl)-N~methvl-4-oxo-1,4-dihydro-1,8-naphthvridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.400 g (1.02 mmol) of the compound obtained from the preceding step and
0.260 g (0.93 mmol) of chloronaphthyridine obtained from step 1.6. 0.204 g of product is
obtained in the form of a yellow powder. Yield: 43%.
1H NMR (400 MHZ, DMSO-d6): d(ppm): 1.3 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.6
(q; 2H; 7Hz); 4.7 (s; 2H); 7.35 (m; 1H); 7.d (d; 1H; 8Hz); 7.6 (t; 1H; 8Hz); 7.8 (t; 1H; 8Hz);
7.95-8.1 (m; 4H); 8.5d (m; 2H); 9.9d (s; 1H); 11.1 (q; 1H; 4.5Hz); 11.7 (brs; 1H).
16.3: 2-amino-1-ethvl-7-f3-fluoro-4-(FfPVhdin~2-ylmethvl)sulfonvl1amino)phenvl)-N-
methvl-4-oxo-1,4-dihvdro-1.8-naphthvridine-3-carboxarnide hydrochloride
The product obtained from the preceding reaction (0.204 g-0.4 mmol) is salified
according to the protocol used in paragraph 5.3 using 0.2 ml of a 2N HCI solution in
ether. 0.202 g of product is isolated in the form of a yellow powder. Yield: 92%; Melting
point: 260°C.
^ NMR (200 MHZ, DMSO-d6): 8 (ppm): 1.3 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.6
(m; 2H); 4.7d (s; 2H); 7.4 (m; 1H); 7.55 (t; 1H; 8Hz); 7.8d (t; 1H; 8Hz); 7.9-8.1 (m; 5H);
8.55(m;2H); 10.0 (s; 1H); 11.1 (q; 1H;4.5Hz); 11.7 (brs; 1H).
LCMS: MH+: 511 (tr: 6.33 min; condition A).
Example 17: 2-amino-7'{4-[(ethenylsulfonyl)amino]-3-fluorophenyl}-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
17.1: N-r2-fluoro-4-f4,4,5,5-tetramethvi-1.3,2-dioxaborolan-2-vl)phenyl1
ethenesulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 0.5 g (2.11 mmol) of the compound obtained from step 2.1 and 0.425 g
(2.53 mmol) of 2-chloroethanesulfonyl chloride. 0.390 g of product is obtained in the form
of a pinkish oil. Yield: 56%.
1H NMR (400 MHZ, DMSO-d6): d(ppm): 1.4 (s; 12H); 6.2 (m; 2H); 7.0 (m; 1H);
7.5-7.7 (m; 3H); 10.2 (s; 1H).
17.2: 2-amino-7-(4-rfethenvlsulfonvl)amino1-3-fluorophenvl>-1-ethvl-N-methvl-4'
oxo-1,4-dihvdro-1,8-naphthvridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.390 g (1.2 mmol) of the compound obtained in the preceding step and 0.280 g
(1.0 mmol) of chioronaphthyridine obtained from step 1.6. 0.095 g of product is obtained
in the form of a white powder. Yield: 21 %. Melting point: >260°C.
1H NMR (200 MHZ, DMSO-d6): d(ppm): 1.3 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.6
(q; 2H; 7Hz); 6.0d (d; 1H; 12Hz); 6.1 (d; 1H; 16Hz); 6.8d (dd; 1H; 12 and 16Hz); 7.d (t;
1H;8Hz); 7.8-8.2 (m;5H); 8.d (d; 1H;8Hz);10.1 (s; 1H); 11.0 (q; 1H;4.5Hz); 11.7(brs;
1H).
LCMS: MH+: 446 (tr: 6.75 min; condition A).
Example 18: 2-amino-7-[4-({[2-(dimethylamino)ethyl]sulfonyl}amino)-3-fluoro-
phenyl]-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
hydrochloride
18.1: 2-fdimethvlamino)-N-r2-fluoro-4-f4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-
vDphenvllethanesulfonamide
To a solution of 0.23 g (0.7 mmol) of the product obtained from step 17.1 in 7 ml of
toluene, 0.35 ml of 2N dimethylamine solution in THF is added dropwise and the stirring
is maintained for 3 hours at 20°C. The reaction medium is evaporated to dryness and the
residue is taken up in 20 ml of ethyl acetate, washed with 20 ml of water and then dried
over Na2SO4 and concentrated to dryness. 0.261 g of product is isolated in the form of a
white wax. Yield: 100%.
1H NMR (400 MHZ, DMSO-d6): S(ppm): 1.3 (s; 12H); 2.2d (s; 6H); 2.8 (m; 2H);
3.3d (m; 2H); 7.4 (d; 1H; 8Hz); 7.d (m; 2H).
LCMS: MH+: 373 (tr: 5.29 min; condition A)
18.2: 2-amino-7-r4-fir2-fdimethvlamino)ethvnsulfonyl>aminoV3-fluorophenvn-1-
ethvl-N~methvt-4-oxo-1,4-dihvdro-1,8-naphthvridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.261 g (0.70 mmol) of the compound obtained in the preceding step and
0.179 g (0.64 mmol) of chloronaphthyridine obtained from step 1.6. 0.200 g of product is
obtained in the form of a yellow powder. Yield: 64%.
LCMS: MH+: 491 (tr: 5.22 min; condition A).
18.3: 2-amino-7-r4-ffr2-(dimethvlamino)ethvnsulfonvl>amino)-3-fluorophenvI1-1-
ethvl-N-methyl-4-oxo-1,4-dihvdro-1,8-naphthyrldine-3-carboxamide hydrochloride
The product obtained from the preceding reaction (0.200 g-0.41 mmol) is salified
according to the protocol used in paragraph 5.3 using 0.2 ml of a 2N HCI solution in
ether. 0.055 g of product is isolated in the form of a yellow powder. Yield: 25%; Melting
point: 268-270°C.
1H NMR (200 MHZ, DMSO-d6): 8(ppm): 1.3 (t; 3H; 7Hz); 2.2d (s; 6H); 2.8 (m; 5H);
3.3 (m; 2H); 4.6 (m; 2H); 7.55 (t; 1H; 8Hz); 7.8-8.1 (m; 4H); 8.d (d; 1H; 8Hz); 11.0d (m;
1H); 11.7(brs; 1H).
LCMS: MH+: 491 (tr: 4.99 min; condition A).
Example 19: 2-amino-1-ethyl-7-(3-fluoro-4-{[(1-methyl-1H-imidazol-4-y0sulfonyl]-
amino}phenyl)-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
hydrochloride
19.1: N-r2-fluoro-4-(4,4.5,5-tetramethyl-1,3.2-dioxaboroian-2-yl)phenylI-1-methyl-
1 H-imidazole-4-sulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 0.5 g (2.11 mmol) of the compound obtained in step 2.1 and 0.481 g (2.53 mmol)
of 1-methyl-1H-imidazole-4-sulfonyi chloride. 0.574 g of product is obtained in the form of
a white powder. Yield: 71%. Melting point: 230°C.
1H NMR(400 MHZ, DMSO~d6): d(ppm): 1.1 (s; 12H); 3.4(s; 3H); 7.05 (s; 1H); 7.1
(s; 1H);7.1 (s; 1H); 7.55 (m; 2H); 9.9 (s; 1H).
19.2:2-amino-1-ethyl-7-(3-fluoro-4-irf1-methyl-1H-imidazol-4-yl)sulfonvn
amino>phenylVN-methyl-4-oxo-1,4-dihydro-1.8-naphthyhdine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.574 g (1.50 rnmol) of the compound obtained from the preceding step and
0.384 g (1.37 rnmol) of chloronaphthyridine obtained from step 1.6. 0.202 g of product is
obtained in the form of a yellow powder. Yield: 30%.
LCMS: MH+: 500 (tr: 6.01 min; condition A).
19.3: 2-amino-1-ethvl-7-(3-fluoro-4-(ff1-methvl-1H-imidazol-4-vl)suifonvl]amino)-
phenvl)-N-methvl-4oxo-1.4-dihydro-1.8-naphthyridine-3-carboxamide hydrochloride
The product obtained from the preceding reaction (0.200 g-0.40 mmol) is salified
according to the protocol used in paragraph 5.3 using 0.2 ml of a 2N HCI solution in
ether. 0.178 g of product is isolated in the form of a white powder. Yield: 82%; Melting
point: >300°C.
1H NMR(200 MHZ, DMSO-d6): S(ppm): 1.3d (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 3.7
(s; 3H); 4.6 (m; 2H); 7.6d (t; 1H; 8Hz); 7.8 (s; 1H); 7.8d (s; 1H); 7.9-8.1 (m; 4H); 8.d (d;
1H;8Hz); 10.25(s; 1H); 11.1 (q; 1H;4.5Hz); 11.7(brs; 1H).
LCMS: MH+: 500 (tr: 6.06 min; condition A).
Example 20: 2-amino-7-{4-[(butylsulfonyl)amino]-3-fluorophenyl}-1-ethyI-N-methyl-
4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
20.1: N-f2-fluoro-4-f4.4.5.5-tetramethvi-1,3.2-dioxaborolan-2-vnphenvnbutane-1-
sulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 0.400 g (1.69 mmol) of the compound obtained from step 2.1 and 0.31 mi
(2.36 mmol) of butane-1-sulfonyl chloride. 0.652 g of product is obtained in the form of an
orange-colored oil. Yield: 100%.
1H NMR (400 MHZ, DMSO-d6): d (ppm): 0.8 (t; 3H; 7Hz); 1.3 (s; 12H); 1.4 (m;
2H); 1.7 (m; 2H); 3.1d (m; 2H); 7.4 (d; 1H; 8Hz); 7.d (s; 2H); 9.8 (s; 1H).
20.2: 2-amino-7-(4-f(butylsulfonyl)amino1-3-fiuorophenvll-1-ethvl-N-methvi-4-oxo-
1,4-dihydro-1,8-naphthvridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.636 g (1.34 mmol) of the compound obtained from the preceding step and
0.326 g (1.16 mmol) of chloronaphthyridine obtained from step 1.6. 0.200 g of product is
obtained in the form of a white powder. Yield: 36%. Melting point: 165-167°C.
1H NMR (200 MHZ, DMSO-d6): d(ppm): 0.9 (t; 3H; 7Hz); 1.2-1.4 (m; 5H); 1.7d (m;
2H); 2.8 (d; 3H; 4.5Hz); 3.2 (m; 2H); 4.6 (m; 2H); 7.6d (t; 1H; 8Hz); 7.8-8.2 (m; 4H); 8.5
(d; 1H;8Hz);9.9(s; 1H); 11.0 (q; 1H; 4.5Hz); 11.7 (br s; 1H).
LCMS: MH+: 476 (tr: 7.43 min ; condition A).
Example 21: 2-amino-7-{4-{[{3-aminobenzyI)sulfonyl]amino}-3-fluorophenyl)-1-
ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide hydrochloride
21.1: N-r2-fluoro-4-f4,4,5,54etramethvl-1,3,2-dioxaborolan-2-vl)phenvn-1-(3-
nitrophenvQmethanesulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 0.400 g (1.69 mmol) of the compound obtained from step 2.1 and 0.502 g
(2.02 mmol) of (3-nitrophenyl)methanesulfonyl chloride. 0.584 g of product is obtained in
the form of a beige powder. Yield: 80%. Melting point: 178°C.
1H NMR (400 MHZ, DMSO-d6): 8(ppm): 1.3 (s; 12H); 4.8 (s; 2H); 7.3-7.4d (m; 3H);
7.6d (m; 1H);7.8(m; 1H); 8.2 (m; 2H); 10.0 (s; 1H).
21.2: 1-(3-aminophenvl)-N-r2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
vDphenvllmethanesulfonamide
0.58 g (1.33 mmol) of the product obtained in the preceding step is dissolved in 6 ml of
ethyl acetate and 1.38 g (6.65 mmol) of tin(ll) chloride dihydrate is added at 20°C. The
reaction medium is kept stirring for 15 hours and 0.276 g of tin(ll) chloride dihydrate is
added. The reaction medium is heated at 80°C for 3 hours and left for 15 hours at 20°C.
This solution was slowly poured over an aqueous NaHCO3 solution (4.18 g in 34 ml of
water) and the insoluble matter is filtered. The filtrate is extracted with 3x100 ml of ethyl
acetate, washed with water and then dried over Na2SO4 and evaporated to dryness.
0.42 g of product is obtained in the form of a white wax. Yield: 78%.
1H NMR (400 MHZ, DMSO-d6): 8 (ppm): 1.3 (s; 12H); 4.3d (s; 2H); 5.1d (s; 2H);
6.d (m; 1H); 6.6 (m; 2H); 7.0 (m; 1H); 7.4 (m; 3H); 9.9 (s; 1H).
21.3: 2-amino-7-(4-{rf3-aminobenzvl)sulfonvnamino>-3-fluorophenyl)-1 -ethyl-N-
methvl-4-oxo-1,4-dihvdro-1,8-naphthvridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.414 g (1.02 mmol) of the compound obtained from the preceding step and
0.260 g (0.93 mmol) of chloronaphthyridine obtained in step 1.6. 0.160 g of product is
obtained in the form of a yellow powder. Yield: 33%.
LCMS: MH+: 52d (tr: 6.11 min; condition A).
21.4: 2-amino-7-(4-{r(3-aminobenzvl)sulfonvnamino)-3-fluorophenvl)-1-ethyl-N-
methvl-4-oxo-1,4-dihydro-1.8-naphthyridine-3-carboxamide hydrochloride
The product obtained from the preceding reaction (0.160 g -0.31 mmol) is salified
according to the protocol used in paragraph 5.3 using 0.15 ml of a 2N HCI solution in
ether. 0.100 g of product is isolated in the form of a beige powder: Yield: 58%; Melting
point: >260°C.
1H NMR (200 MHZ, DMSO-d6): d(ppm): 1.3 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.4 (s;
2H); 4.6 (m; 2H); 6.6-6.8 (m; 3H); 7.05 (t; 1H; 8Hz); 7.d (t; 1H; 8Hz); 7.9-8.1 (m; 4H); 8.5
(d; 1H;8Hz);9.9(s; 1H); 11.1 (q; 1H;4.5Hz); 11.7 (brs; 1H).
LCMS: MH+: 52d (tr: 6.02 min; condition A).
Example 22: 2-amino-7-(4-{[(2-chlorophenyl)sulfonyl]amino}phenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
22.1: 2-chloro-N-f4-(4.4,5,5-tetramethyl-1,3,2-dioxaborolan-2-vnphenyl1
benzenesulfonamide
This product was prepared according to the protocol described in paragraph 1.8-A from
0.660 g (3.01 mmol) of 4-(4,4I5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 0.635 g
(3.01 mmol) of 2-chlorobenzenesulfonyl chloride. 1.13 g of product is obtained in the
form of a dark red powder. Yield: 96%. Melting point: 198°C.
1H NMR (400 MHZ, DMSO-d6): d (ppm); 1.2d (s; 12H); 7.2 (d; 2H; 8Hz); 7.4 (m;
1H); 7.d (m; 2H); 7.6 (d; 1H;8Hz);8.1 (d; 1H;8Hz).
22.2: 2-amino-7-(44rf2-chlorophenvl)sulfonvnamino)phenvl)-1-ethvl-N-methyi-4-
oxo-1,4-dihvdro-1.8-naphthvridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.413 g (1.05 mmol) of the compound obtained from the preceding step and
0.280 g (1.0 mmol) of chloronaphthyridine obtained from step 1.6. 0.180 g of product is
obtained in the form of a white powder. Yield: 35%. Melting point: >260°C.
1H NMR (200 MHZ, DMSO-d6): d (ppm): 1.8d (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.55
(m; 2H); 7.2 (d; 2H; 8Hz); 7.4-7.7 (m; 3H); 7.8 (d; 1H; 8Hz); 7.8-8.2 (m; 3H); 7.9 (s; 1H);
8.4d (d; 1H;8Hz); 10.9 (s;1H); 11.0d (q; 1H;4.5Hz); 11.7 (brs; 1H).
LCMS: MH+: 512 (tr: 6.12 min; condition B).
Example 23: 2-amino-7-(3-chlorc~4-W2.3-dichlorophenvhsulfonvl1arnino)
phenyl)-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
23.1: 2-chloro-4-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-vl)aniline
This product was prepared according to the protocol described in paragraph 2.1 (method
A) from 5.0 g (24.22 mmol) of 4-bromo-2-chloroaniiine and 6.76 g (26.64 mmol) of
bis(pinacolato)diborane. 3.14 g of product are obtained in the form of a brown oil used in
the next step without further purification.
23.2:2,3-dichlorO"N-[2-chioro-4-(4,4.5.5-tetramethvl-1,3,2-dioxaboroian-2-yl)
phenyllbenzenesulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 1.5 g (5.92 mmol) of the compound obtained from the preceding step and 2.18 g
(8.87 mmol) of 2,3-dichlorobenzenesulfonyl chloride, 1.57 g of product are obtained in
the form of a beige powder. Yield: 57%. Melting point: 156°C.
23.3: (S-chloro^-ir^.SdichlorophenvnsulfonvllaminoyphenvOboronicacid
0.3 g (6.09 mmoi) of the product obtained from the preceding step is dissolved in 100 ml
of anhydrous dichloromethane and this solution is cooled to -78°C. 20.0 ml of a 1M boron
trichloride solution in dichloromethane are added dropwise and the reaction medium is
kept at -78°C for 3 hours and then for 15 hours at 20°C. At 0°C, 11 ml of methanol are
added and the reaction medium is then evaporated to dryness. The residue is taken up in
20 ml of dichloromethane and extracted with a 0.5N sodium hydroxide solution and then
the aqueous phase is acidified to pH=1 by addition of 1N HCI. The precipitate formed is
filtered, washed with a little water and dried in an oven under vacuum over P2O5. 1.03 g
of product is obtained in the form of a white powder. Yield: 42%. Melting point: 90°C.
1H NMR (400 MHZ, DMSO-d6): S(ppm): 7.4 (d; 1H; 8H2); 7.55 (t; 1H; 8Hz); 7.8 (d;
1H;8Hz);7.95(s; 1H);8.0(d; 1H;8Hz);8.1 (d; 1H; 8Hz); 8.3 (s; 2H); 10.6 (s; 1H).
23.4: 2-amino-7-f3-chloro-4-lf('2,3dichlorophenvl)sulfonvnamino)phenvl)-1-ethvi-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthvridine~3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 1.02 g (2.68 mmoi) of the compound obtained from the preceding step and
0.565 g (2.24 mmol) of chloronaphthyridine obtained from step 1.6. 0.698 g of product is
obtained in the form of a light yeliow powder. Yield: 54%. Melting point: 311 °C.
1H NMR (400 MHZ, DMSO-d6): S(ppm): 1.3 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.55 (q; 2H;
7Hz); 7.4d (d; 1H; 8Hz); 7.55 (t; 1H; 8Hz); 7.9 (d; 1H; 8Hz); 7.9d (m; 2H); 8.0 (s; 1H);
8.1d (d; 1H;8Hz);8.25(s; 1H);8.5(d; 1H; 8Hz); 10.6d (s;1H); 11.0d (q; 1H; 4.5Hz);11.7
(brs; 1H).
LCMS: MH+: 582 (tr: 8.58 min; condition A).
Example 24: 2-amino-7-(4-{[(2,3-dichlorophenyl)suIfonyl]amino}-2-fluorophenyl)-1-
ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
24.1: 3-fluoro-4-f4.4.5.5-tetramethyl-1,3.2-dioxaborolan-2-vnaniline
This product was prepared according to the protocol described in paragraph 2.1 (method
A) from 5.0 g (26.3 mmol) of 4-bromo-3-fluoroaniline and 7.34 g (28.9 mmol) of
bis(pinacolato)diborane. 2.45 g of product are obtained in the form of a brown oil which is
used in the next step without further purification.
24.2:2,3-dichforo-N-r3-fluoro-4-f4,4,5,5-tetramethy!-1,3l2-dioxaborolan-2-vl)
phenvUbenzenesulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 2.5 g (15.4 mmol) of the compound obtained from the preceding step and 3.88 g
(15.8 mmol) of 2,3-dichlorobenzenesulfonyl chloride. 2.67 g of product are obtained in
the form of a beige powder. Yield: 57%.
1H NMR (400 MHz; CDCI3): S(ppm): 1.2 (s; 12H); 6.7d (d; 1H; 7Hz); 6.8 (d; 1H;
12Hz); 7.1 (s; 1H); 7.2d (t; 1H; 7Hz); 7.d (t; 1H; 7Hz); 7.55 (d; 1H; 7Hz); 7.9 (d; 1H; 7Hz).
24.3: 2-amino-7-f4-(rf2.3-dichlorophenvhsulfonvnamino)-2-fluorophenvl)-1-ethyl-
N-methvl-4-oxo-1,4-dihydro-1.8-naphthvhdine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 2.6 g (5.82 mmol) of the compound obtained in the preceding step and 1.36 g
(4.84 mmof) of chloronaphthyridine obtained from step 1.6. 1.89 g of product are
obtained in the form of a light yellow powder. Yield: 69%. Melting point: 340°C.
1H NMR (200 MHZ, DMSO-d6): S(ppm): 1.2 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.5
(q; 2H; 7Hz); 7.05 (d; 1H; 12Hz); 7.1 (d; 1H; 7Hz); 7.6 (d; 1H; 7Hz); 7.6d (d; 1H; 7Hz);
7.8-8.2 (m;4H); 8.1d (d; 1H; 7Hz); 8.4d (d; 1H; 7Hz); 11.0 (q; 1H;4.5Hz); 11.4 (s; 1H);
11.7 (brs; 1H).
LCMS: MH+: 564 (tr: 8.18 min; condition A).
Example 25: 2-amino-7-f4-ir(2,3-dichlorophenvl)sulfonvnamino}-3-methvlphenyl)
-1 -ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
25.1: 2-methyl-4-(4.4,5,5-tetramethyH .S^-dioxaborolan^-yPaniline
This product was prepared according to the protocol described in paragraph 2.1 (method
A) from 5.0 g (26.8 mmol) of 4-bromo-2-methylaniline and 7.5 g (29.5 mmol) of
bis(pinacolato)diborane. 0.992 g of product is obtained which is used in the next step
without further purification.
1H NMR (400 MHz; CDCI3): d(ppm); 1.4 (s; 12H); 2.2d (s; 3H); 3.9 (s; 2H); 6.7 (d; 1H;
7Hz); 7.55 (m; 2H).
25.2:2,3-dichloro-N-r2-methyl-4-f4,4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)
phenvllbenzenesulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 1.35 g (5.79 mmol) of the compound obtained from the preceding step and
2.13 g (8.67 mmol) of 2,3-dichlorobenzenesulfonyl chloride. 2.1 g of product are obtained
in the form of a beige powder. Yield: 82%.
1H NMR (400 MHz; CDCI3): S(ppm): 1.2 (s; 12H); 3.1d (s; 3H); 6.8 (s; 1H); 7.1 (d;
1H;7Hz);7.15(t; 1H; 7Hz); 7.35 (d; 1H; 7Hz); 7.4d (s; 1H);7.50(d; 1H; 7Hz); 7.9 (d; 1H;
7Hz).
25.3: 2-amino-7-(4-{F(2,3-dichIorophenvi)suJfonvnamino|-3-methvlphenvi)-1-ethyl-
N-methvl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.700 g (1.58 mmol) of the compound obtained from the preceding step and
0.370 g (1.32 mmol) of chioronaphthyridine obtained from step 1.6. 0.224 g of product is
obtained in the form of a powder. Yield: 30%. Melting point: 299°C.
1H NMR (200 MHZ, DMSO-d6): 8(ppm): 1.2d (t; 3H; 7Hz); 2.25 {s; 3H); 2.8 (d; 3H;
4.5Hz); 4.55 (q; 2H; 7Hz); 7.1 (d; 1H; 8Hz); 7.d (t; 1H; 8Hz); 7.7-8.1 (m; 6H); 8.d (d; 1H;
8Hz); 10.2 (s; 1H);11.05(q; 1H;4.5Hz); 11.7 (brs; 1H).
LCMS: MH+: 560 (tr: 8.36 min; condition A).
Example 26: 2-amino-7-(2-chloro-4-fr(2,5-dichlorophenvl)sulfonvnamino>phenyl)
-1-ethyl-N-methyl-4-oxo-1,4^dihydro-1,8-naphthyridine-3-carboxamide
26.1: 2,5-dichloro-N-F3-chloro-4-(4,4,5.5-tetramethyl-1,3.2-dioxaborolan-2-vl)
phenvllbenzenesulfonamide
This product was prepared according to the protocol described in paragraph 2.2 (method
A) from 0.500 g (1.97 mmol) of the compound obtained from step 12.1 and 0.484 g
(1.97 mmol) of 2,5-dichlorobenzenesulfonyl chloride. 0.704 g of product is obtained in the
form of a beige powder. Yield: 77%.
1H NMR (400 MHz; CDCI3): S(ppm): 1.2d (s; 12H); 7.0-7.1d (m; 2H); 7.50 (d; 1H;
8Hz);7.65(d; 1H; 8Hz); 7.80 (d; 1H;8Hz);8.1 (s; 1H); 11.2 (s; 1H).
26.2: 2-amino-7-(2-chloro-4-(r(2.5-dichJorophenvl)sulfonvl1amino)phenvn-1-ethyl-
N-methyl-4-oxo-1,4-dihydro-1.8-naphthyridine-3-carboxamide
This product was prepared according to the protocol described in paragraph 2.3 (method
A) from 0.703 g (1.52 mmol) of the compound obtained from the preceding step and
0.388 g (1.38 mmol) of chioronaphthyridine obtained from step 1.6. 0.224 g of product is
obtained in the form of a white powder. Yield: 28%. Melting point: 323°C.
1H NMR (200 MHZ, DMSO-d6): d (ppm): 1.2 (t; 3H; 7Hz); 2.8 (d; 3H; 4.5Hz); 4.5
(q; 2H; 7Hz); 7.1-7.3 (m; 2H); 7.5-7.8 (m; 4H); 8.0 (s; 1H); 8.1 (s; 1H);
8.d (d; 1H; 8Hz);
11.0 (q; 1H;4.5Hz); 11.3 (s; 1H); 11.7 (brs; 1H).
LCMS: MH+: 580 (tr: 5.15 min; condition A).
The following table 1 illustrates compounds of formula (I) - according to the
invention for which R1 and R2 represent a methyl (abbreviated Me), n' represents 1; R3
represents a hydrogen atom and Ar represents phenyl, these compounds are called
below compounds of formula (I*).
In this table:
In the column "Form", "-" means that the relevant compound is in the form of a free
base, whereas "HO" means that the relevant compound is in the form of a
hydrochloride salt.
- The symbol "?" means that the data are not available.
The compounds according to the invention were the subject of pharmacological trials
which make it possible to determine their inhibitory effect on protein kinases.
By way of example, their inhibitory effects on the p70S6 serine/threonine kinase and/or
PDGF-R tyrosine kinase activity were measured in vitro in biochemical tests.
The inhibitory activity on the PDGF receptor kinases is given by the concentration which
inhibits 50% of the proliferation activity of Baf3 tel/PDGF cells respectively. The inhibitory
activity on p70S6 kinase is given by the concentration which inhibits 50% of the
phosphorylation of the peptide substrate derived from the S6 ribosomai protein
(AKRRRLSSLRA, Upstate).
Measurement of the inhibition of the PDGF beta receptor (PDGF-RS) tyrosine
kinase activity (Baf-3 tel/PDGFRß):
This test consists in evaluating the effects of the compounds on the PDGF beta receptor
tyrosine kinase activity.
The inhibitory effect of the compounds according to the invention toward the PDGF-R
receptor tyrosine kinase activity was evaluated on the hematopoietic murine celf line
BaF/3 transfected with a plasmid encoding the fusion protein Tel/PDGF-R beta. This
fusion protein is found in chronic myelomonocytic myeloid leukemias (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 therefore
leads to the constitutive activity of the PDGF-R beta kinase domain. This BaF3 Tel/PDGF
line has been described in the literature several times and in particular in detail in the
article by CARROLL, M. etal., PNAS.1996, 93, 14845-14850, CARROLL, M. et al, Blood
2002,99, 14845-14850.
The BaF3 Tel/PDGF cells are washed with phosphate buffer and inoculated in 96-welI
plates, at the density of 5 x 104 cells/ml (100 ml per well), in RPMI 1640 containing 10%
FCS, in the presence or absence of the compounds to be tested. After 72 h of
incubation, the viable cells are quantified by measuring the cellular ATP using the kit
CellTiter-Glo® (Promega, Cat G7571). The cells are treated according to the instructions
given by the kit supplier and the luminescence is measured with the aid of a Luminoskan
(Ascent, Labsystem) with the following parameters: measurement: single; integration
time: 1000 ms, lag time: 5 s.
It is thus apparent that the compounds according to the invention have an inhibitory
activity on the PDGF-R beta tyrosine kinase activity. This activity is given by the
concentration which inhibits 50% of the proliferation of the Baf3 tel/PDGF ceils (IC50).
The IC50 values for the compounds according to the invention are less than 10.0 µM.
For example, compounds No. 2, 18, 20 and 24 show an IC50 of 36, 12, 280 and 24 nM
respectively in the test for measuring the inhibitory activity of the PDGF receptor tyrosine
kinase.
Measurement of the inhibition of the p70S6 kinase activity:
The active mutant recombinant S6K1 (1-421, T412E) (ref. 14-333, Upstate USA, Inc.
Charlottesville VA) (specific activity 298 U/mg) is incubated (20mU/10µl) with 8
concentrations of inhibitors solubiiized at 1 mM in DMSO in the presence of the peptide
substrate obtained from the S6 ribosomal protein (AKRRRLSSLRA, Upstate) (50 µM
final) and of a cold ATP mixture (100 µM) and 1 uCi/well of [?-33]ATP (NEN,
Courtaboeuf, France). The enzyme reaction is carried out in a final volume of 50 pi in a
96-well filter plate (Multiscreen TM-PH opaque plate with Phospho-Celfulose cat #
MAPHNOB, Millipore) previously soaked with 100 µl 1M Tris buffer pH 7.4 by adding the
reagents of the S6 Kinase Assay kit (# 17-136, Upstate) in the following order:
10 µl of 5% DMSO or various inhibitors at a 5X concentration
30 µl of reaction mixture containing the ADBI buffer (# 20-108 Upstate, composed of
20 mM MOPS pH 7.2, 25 mM beta-glycerol phosphate, 5 mM EGTA, 1 mM sodium
orthovanadate, 1 mM dithiothreitol), S6K1 (20 mU) and 250 µlM peptide substrate
[AKRRRLSSLRA] in ADBI buffer (# 20-122, Upstate). The reaction is started by adding
10 µl of cold ATP/33yATP mixture (1 µCi/50 µl as 500 µM ATP in ADBI buffer, 75 mM
MgCI2) and then incubated for 20 minutes at 30°C before being stopped by adding 20 µl
of 7.5% phosphoric acid. The reaction mixture is filtered by aspiration under vacuum
(Vacuum manifold, Millipore), the wells are rinsed twice with 200 µl of 7.5% phosphoric
acid (2 minutes) and then twice with 200 µl of distilled H2O (2 minutes). After drying the
plate, 25 µl/well of scintillant (Optiphase Super Mix, Waliac) are added and the
radioactivity is detected with the Micro-Beta scintillation reader (Waliac). A negative
control (all the reagents without peptide substrate) is prepared in order to determine the
nonspecific binding of 33yATP to the phosphocelluiose filter which is subtracted from the
experimental results.
It is thus apparent that the compounds of the invention have an inhibitory activity on the
p70S6 kinase activity. This activity is given by the concentration which inhibits 50% of the
phosphorylation of the peptide substrate derived from the S6 ribosomal protein
(AKRRRLSSLRA, Upstate). The IC50 values for the compounds according to the
invention are less than 10.0 µM.
For example, compounds No. 8, 9, 14 and 18 showed an IC50 of 412, 240, 224 and
132 nM respectively in the test for measuring the inhibitory activity of the p70S6 kinase.
The compounds according to the invention are therefore inhibitors of protein kinases, in
particular PDGF tyrosine kinases receptor and, for some of them, also of p70S6 kinase.
The compounds according to the invention may therefore be used for the preparation of
medicaments intended for the treatment and/or prevention of diseases linked to the
activity of protein kinases, in particular of medicaments inhibiting protein kinases.
These are protein kinase-inhibiting medicaments, in particular medicaments inhibiting
PDGF-R receptor tyrosine kinase and optionally p70S6 kinase.
Thus, according to another of its aspects, the subject of the invention is medicaments
which comprise a compound of formula (I), or an addition salt of the latter with a
pharmaceutically acceptable acid, or else a solvate of the compound of formula (I).
These medicaments find their use in therapy, in particular in the treatment and/or
prevention of diseases linked to the activity of protein kinases and in particular
proliferative diseases such as cancers, for example cancers of the lung (NSCLC), of the
bones, of the pancreas, of the skin, Kaposi's syndrome, intraocular melanomas, cancers
of the breast, of the uterus, of the cervix, of the ovaries, of the endometrium, of the
vagina, of the vulva, of the urethra, of the penis, of the prostate, fallopian tube
carcinomas, cancers such as GISTs and of the anal region, of the rectum, of the small
intestine, of the colon, of the stomach, of the esophagus, of the endocrine, thyroid,
parathyroid or adrenal glands, soft tissue sarcomas, Ewing's sarcomas, ostesarcomas,
dermatofibrosarcoma and other fibrosarcomas, cancers of the bladder or of the kidney,
neoplasms of the centra! nervous system, vertebral column and desmoid tumors, brain
stem gliomas and glioblastomas, pituitary adenomas and metastases thereof, chronic or
acute leukemias, lymphocytic lymphomas, Hodgkin's disease and myeloproliferative
syndromes, and myelodysplastic syndromes.
Another aspect of the invention comprises a combination of at least one compound
according to the invention with at least one chemotherapeutic agent.
Indeed, the compounds of the present invention may be used alone or as a mixture with
at least one chemotherapeutic agent which may be chosen from cytotoxic agents and/or
antiangiogenic agents. For example, the antiangiogenic agents may be a compound
inhibiting VEGF-R kinase activity 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 chemotherapeutic agents
mentioned above and/or radiation are another subject of the present invention.
The chemotherapeutic agents mentioned above and/or the radiations may be
administered simultaneously, separately or sequentially. The treatment will be adapted by
the practitioner according to the patient to be treated.
These medicaments also find use in therapy, in nonmalignant proliferative diseases such
as for example restenosis, atherosclerosis, thrombosis, heart failure, cardiac
hypertrophy, pulmonary arterial hypertension, fibrosis, diabetic nephropathy,
glomerulonephritis, chronic pyelonephritis, hemangiomas, autoimmune diseases such as
psoriasis, sclerodermatitis, immunosuppression (graft rejection for example).
According to another of its aspects, the present invention relates to pharmaceutical
compositions comprising, as active ingredient, a compound according to the invention.
These pharmaceutical compositions contain an effective dose of at least one compound
according to the invention, or a pharmaceutically acceptable salt of the latter, or else a
solvate of said compound, and at least one pharmaceutically acceptable excipient.
Said excipients are chosen according to the pharmaceutical dosage form and the desired
mode of administration, from the customary excipients which are known to 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 ingredient of formula (I) above, or its optional salt or
solvate, may be administered in unit form for administration, as a mixture with
conventional pharmaceutical excipients, to animals and to humans for the prophylaxis or
treatment and/or the prevention of the above disorders or diseases.
The appropriate unit forms for administration comprise the forms for oral administration,
such as tablets, soft or hard gelatin capsules, powders, granules and oral solutions or
suspensions, forms for sublingual, buccal, intratracheal, intraocular or intranasal
administration or for administration by inhalation, the forms for topical, transdermal,
subcutaneous, intramuscular or intravenous administration, the forms for rectal
administration and implants. For topical application, the compounds according to the
invention may be used in creams, gels, ointments or lotions.
By way of example, a unit form for administration of a compound according to the
invention in tablet form may comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Croscarmellose sodium 6.0 mg
Comstarch 15.0 mg
Hydroxypropylmethylceliulose 2.25 mg
Magnesium stearate 3.0 mg
The present invention, according to another of its aspects, also relates to a method for
the treatment and/or prevention of the pathologies indicated above which comprises the
administration, to a patient, of an effective dose of a compound according to the
invention or one of its pharmaceutically acceptable salts or solvates.
The present invention, according to another of its aspects, also relates to the use of a
compound-of formula (I) for the preparation of a medicament intended for the treatment
and/or prevention of diseases linked to the activity of protein kinases, for the treatment
and/or prevention of proliferative diseases such as cancers, chronic or acute leukemias,
lymphocytic lymphomas, Hodgkin's disease, and myeloproliferative syndromes, and
myelodysplastic syndromes, for the treatment and/or prevention of proliferative diseases
such as solid tumor cancers, for example cancers of the lung (NSCLC), of the bones, of
the pancreas, of the skin, Kaposi's syndrome, intraocular melanomas, cancers of the
breast, of the uterus, of the cervix, of the ovaries, of the endometrium, of the vagina, of
the vulva, of the urethra, of the penis, of the prostate, fallopian tube carcinomas, cancers
such as GISTs and of the anal region, of the rectum, of the small intestine, of the colon,
of the stomach, of the esophagus, of the endocrine, thyroid, parathyroid or adrenal
glands, soft tissue sarcomas, Ewing's sarcomas, ostesarcomas, dermatofibrosarcoma
and other fibrosarcomas, cancers of the bladder or of the kidney, neoplasms of the
central nervous system, vertebral column and desmoid tumors, brain stem gliomas and
glioblastomas, pituitary adenomas and metastases thereof, chronic or acute leukemias,
lymphocytic lymphomas, Hodgkin's disease and myeloproliferative syndromes, and
myelodysplastic syndromes, or for the treatment and/or prevention of nonmalignant
proliferative diseases such as restenosis, atherosclerosis, thrombosis, heart failure,
cardiac hypertrophy, pulmonary arterial hypertension, fibrosis, diabetic nephropathy,
glomerulonephritis, chronic pyelonephritis, hemangiomas, autoimmune diseases such as
psoriasis, sclerodermatitis, immunosuppression.
CLAIMS
1. A compound corresponding to the formula (I):

in which
• n represents 0, 1, 2 or 3;
• n' represents 0, 1, 2, 3 or 4;
• R1 represents an alkyl group;
• R2 represents:
(i) a cycloaikyl group,
(ii) an afkyl group, or
(iii) an alkoxy group,
said cycloaikyl, alkyl or alkoxy groups being optionally substituted with one or
more halogen atoms;
• R3 represents:
i) a hydrogen atom, or
ii) a -C(O)alkyl group;
• Ar represents a 5- or 6-membered aryl or heteroaryl ring in which Y, Z, V and W:
(a) represent, independently of each other,
(i) a =CH- group,
(ii) a =C(R5)- group in which R5 represents:
o an alkyl group,
o a halogen atom, or
o an alkoxy group,
(iii) a heteroatom chosen from the nitrogen atom, the sulfur atom and
the oxygen atom,
(b) at most one among Y, Z, V and W being optionally absent,
it being understood that, when Ar represents a heteroaryl chosen from pyrrolyl,
imidazolyl, pyrazolyi and triazolyis, at least one of the nitrogen atoms of said heteroaryl
may be optionally substituted with a group R6 chosen from an alkyl group,
• R4 represents a group chosen from:
o an alkyl group,
o an alkoxyalkyl group,
o a group -NRR' with R and R', which may be identical or different,
representing, independently of each other, a hydrogen atom, an alkyl group or
a -(C3-C6)cycloalkyl group,
o a cycloalkyl group,
o an alkeny! group,
o an aryl group, said group being optionally substituted with at least one
halogen atom, and/or with at least one group chosen from a -(C1-C5)alkyl,
haloalkyl, nitrile, haloalkyloxy, alkoxy, nitro group and the groups -NRR' with
R and R', which may be identical or different, representing, independently of
each other, a hydrogen atom or a group chosen from alkyl groups and
-(C3-C6)cycloalkyl groups,
o a heteroaryl group, said group comprising at least one heteroatom chosen
from the nitrogen or sulfur atom, said heteroaryi groups being optionally
substituted with at least one group chosen from alkyl groups and
heterocycloalkyl groups comprising at least one heteroatom chosen from the
nitrogen and oxygen atoms;
it being understood that, when the heteroaryi group is chosen from
pyrrolyl, imidazoiyl, pyrazolyl and triazolyls, at least one of the nitrogen atoms
of said heteroaryi may be optionally substituted with a group R6 chosen from
an alkyl group,
o a heterocycloalkyl group comprising at least one heteroatom chosen from the
nitrogen, sulfur and oxygen atoms and being optionally substituted with at
least one substituent chosen from (i) halogen atoms, (ii) haloalkyl groups, (iii)
linear or branched alkyl groups, and (iv) cycloalkyl groups,
it being understood that when the heterocycloalkyl groups are
chosen from pyrrolinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolinyl,
pyrazolidinyl, piperidinyl, morpholinyl, piperazinyi and thiomorpholinyl, at least
one of the nitrogen atoms of said heterocycloalkyl may be optionally
substituted with a group R6 chosen from an alkyl group,
in the form of an acid, a base or an addition salt with an acid or a base.
2. The compound of formula (I) as claimed in claim 1, characterized in that:
R1 represents a -(C1-C4)alkyl group,
said compounds are in the form of a base or addition salts with an acid.
3. The compound of formula (I) as claimed in one of claims 1 and 2, characterized in
that:
R2 represents a -(C1-C4)alkyl group,
said compounds are in the form of a base or addition salts with an acid.
4. The compound of formula (I) as claimed in any one of claims 1 to 3, characterized in
that:
n' represents 1,
said compounds are in the form of a base or addition salts with an acid.
5. The compound of formula (I) as claimed in any one of claims 1 to 4, characterized in
that:
R3 represents a hydrogen atom,
said compounds are in the form of a base or addition salts with an acid.
6. The compound of formula (I) as claimed in any one of claims 1 to 5, characterized in
that:
Ar represents a phenyl,
said compounds are in the form of a base or addition salts with an acid.
7. The compound of formula (I) as claimed in any one of claims 1 to 6, characterized in
that:
R4 represents a group chosen from:
o an alkyi group;
o a group -NRR', with R and R', which may be identical or different,
representing, independently of each other, a hydrogen atom, an alkyl group or
a -(C3-C6)cycloalkyl group,
o an alkenyl group,
o an aryl group, said group being optionally substituted with at least one
halogen atom, and/or with at least one group chosen from alkoxy groups and
the groups -NRR', with R and R' as defined above,
o a heteroaryl group, said heteroaryl group being optionally substituted with at
least one group chosen from alkyl groups and heterocycloalkyl groups
comprising at least one heteroatom chosen from the nitrogen and oxygen
atoms;
it being understood that, when said heteroaryl group is chosen from
pyrrolyl, imidazoiyl, pyrazolyl and triazotyls, at least one of the nitrogen atoms of said
heteroaryl may be optionally substituted with a group R6, with R6 representing a
group chosen from an alkyl group.
8. The compound of formula (I) as claimed in any one of claims 1 to 7, characterized in
that R4 represents a group chosen from phenyl, pyridinyl and imidazoly! groups.
9. The compound of formula (I) as claimed in any one of claims 1 to 8, characterized in
that Y, Z, V and W each represents a =CH group and/or a =C(R5)- group, with R5
representing a chlorine or fluorine atom, Y, Z, V and W being thus in an optionally
substituted phenyl group.
10. The compound of formula (I) as claimed in any one of claims 1 to 9, chosen from the
following compounds:
2-amino-1-ethy!-7-(3-fluoro-4-{[(pyridin-3-ylmethyl)sulfonyl]amino}phenyl)-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-1-ethyl-7-(3-fluoro-4-{[{3-fluorophenyl)suIfonyl]amino}phenyl)-N-methyl-
4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-7-{4-[(ethenylsulfonyl )amino]-3-fluorophenyl}-1-ethyl-N-methyl-4-oxo-1,4-
dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-7-[4-({[2-(dimethylamino)ethyl3sulfonyl}amino)-3-fluorophenyi]-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-7-(4-{[(3-aminobenzyl)sulfonyl]amino}-3-fluorophenyl)-1-ethy!-N-methyl-
4-oxo-l ,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-1-ethyl-7-(3-fluoro-4-{[(1-methyl-1H-imidazo!-4-yl)sulfonyl]amino}phenyl)-
N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-7-{4-[(butylsulfonyl)amino]-3-fluorophenyl}-1-ethyl-N-methyl-4-oxo-1,4-
dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-7-(3-chloro-4-{[(2,3-dichlorophenyl)sulfonyl]amino}phenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-7-(4-{[(2,5-dichlorophenyl)sulfonyl]amino}-3-fIuorophenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-1-ethyl-N-methyl-4-oxo-7-{4-[(pyridin-3-ylsulfonyl)amino]phenyl}-1)4-
dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-7-(4-{[(2,6-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-7-(2-chloro-4-{[(2,5-dichlorophenyl)sulfonyl]amino}phenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-7-(2-chloro-4-{[(2,3-dichlorophenyl)sulfonyl]amino}phenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-7-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-2-fluorophenyl)-1-ethyl-N-
methyl-4~oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-7-(4-{[(2,3-dichloropher>yl)sulfonyl]amino}-3-methylphenyl)-1-ethyI-N-
methyl-4-oxo-1,4-dihydro-1,8~naphthyridine-3-carboxamide;
2-amino-1-ethyl-N-methyl-7-{4-[(methylsulfonyi)amino]phenyl}-4-oxo-1,4-dihydro-
1,8-naphthyridine-3-carboxamide;
2-amino-7-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}phenyl)-1-ethyl-N-methyl-4-oxo-
1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino~7-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-l-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-7-(4-{[(2-chlorophenyl)sulfonyl]amino}phenyl)-1-ethyl-N-methyl-4-oxo-
1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-1-ethyl-7-(3-fluoro-4-{[(2-fluorophenyl)sulfonyl]amino}phenyl)-N-methyl-4-
oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-7-(4-{[(4-chlorophenyl)sulfonyl3amino}-3-fluorophenyl)-1-ethyl-N-methyl-
4-oxo-l ,4-dihydro-1,8~naphthyridine-3-carboxamide;
2-amino-7-(4-{[(3-chlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1-ethyl-N-methyl-
4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-7-(4-{[(3,4-difiuorophenyl)sulfonyl]amino}-3-fluorophenyl)-1-ethyl-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-1-ethyi-7-(3-fluoro-4-{[(4-fluorophenyl)sulfony!]amino}phenyl)-N-methyl-4-
oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-1-ethyl-7-(3-fluoro-4-{[(3-methoxyphenyI)sulfonyl]amino}phenyl)-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-1-ethyl-7-[3-fluoro-4-({[6-(morpholin-4-yl)pyridin-3-
yl]sulfonyl}amino)phenyl]-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide;
2-amino-1-ethyi-7-(3-fiuoro-4-{[(pyridin-2-ylmethyl)suIfonyl]amino}phenyl)-N-
methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide.
11. A method for preparing a compound of formula (I) as claimed in any one of claims 1
to 10, characterized in that a compound of formula (IXa):

is reacted with a compound of formula (VII), in the presence of a coupling catalyst and a
base,

where R1, R2, R3, R4, n, n\ V, W, Y, Z and Ar are as defined in claim 1, X represents a
leaving group and M is as defined above.
12. A method for preparing a compound of formula (I) as claimed in any one of claims 1
to 10, characterized in that a compound of formula (IXb)

is reacted with a compound of formula (VIII),

where R1, R2, R3, R4, n, n', V, W, Y, Z and Ar are as defined in claim 1, X represents a
leaving group and M is as defined above.
13. A compound of formula (VIII):

where R1, R2, n' are as defined in claim 1 and M is as defined above.
14. A medicament, characterized in that it comprises a compound of formula (I) as
claimed in any one of claims 1 to 10, or an addition salt of this compound with a
pharmaceutically acceptable acid, or else a solvate of the compound of formula (I).
15. A pharmaceutical composition, characterized in that it comprises a compound of
formula (I) as claimed in any one of claims 1 to 10, or a pharmaceutically acceptable salt,
or a solvate of this compound, and at least one pharmaceutically acceptable excipient.
16. The compound of formula (I) as claimed in any one of claims 1 to 10, for its use in the
treatment and/or prevention of diseases linked to the activity of protein kinases.
17. The compound of formula (I) as claimed in any one of claims 1 to 10, for its use in the
treatment and/or prevention of proliferative diseases such as cancers, chronic or acute
leukemias, lymphocytic lymphomas, Hodgkin's disease, and myeloproliferative
syndromes, and myelodysplastic syndromes.
18. The compound of formula (I) as claimed in any one of claims 1 to 10, for its use in the
treatment and/or prevention of proliferative diseases such as solid tumor cancers, for
example cancers of the lung (NSCLC), of the bones, of the pancreas, of the skin,
Kaposi's syndrome, intraocular melanomas, cancers of the breast, of the uterus, of the
cervix, of the ovaries, of the endometrium, of the vagina, of the vulva, of the urethra, of
the penis, of the prostate, fallopian tube carcinomas, cancers such as GISTs and of the
anal region, of the rectum, of the small intestine, of the colon, of the stomach, of the
esophagus, of the endocrine, thyroid, parathyroid or adrenal glands, soft tissue
sarcomas, Ewing's sarcomas, ostesarcomas, dermatofibrosarcoma and other
fibrosarcomas, cancers of the bladder or of the kidney, neoplasms of the central nervous
system, vertebral column and desmoid tumors, brain stem gliomas and glioblastomas,
pituitary adenomas and metastases thereof, chronic or acute leukemias, lymphocytic
lymphomas, Hodgkin's disease and myeloproliferative syndromes, and myelodysplastic
syndromes.
19. The compound of formula (I) as claimed in any one of claims 1 to 10, for its use in the
treatment and/or prevention of nonmalignant proliferative diseases such as restenosis,
atherosclerosis, thrombosis, heart failure, cardiac hypertrophy, pulmonary arterial
hypertension, fibrosis, diabetic nephropathy, glomerulonephritis, chronic pyelonephritis,
hemangiomas, autoimmune diseases such as psoriasis, sclerodermatitis,
immunosuppression.
20. A combination of at least one compound of formula (I) as claimed in any one of
claims 1 to 10 with at least one chemotherapeutic agent.

ABSTRACT

The invention relates to pyridine-pyridinone derivatives general formula (I):

in which R1, R2, R3, R4, n, n', V, W, Y, Z, Ar are as defined in the
description, and to their methods of preparation and their therapeutic applications.