5-OXO-5,8-DIHYDROPYRIDO[2.3-d]PYRlMIDINE DERIVATIVES
AS CAMKII KINASE INHIBITORS FOR TREATING CARDIOVASCULAR DISEASES
The present invention relates to 5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine
derivatives, to their preparation and to their therapeutic use.
Calcium is a key element of intracellular signalling leading to varied
responses, for example at the cardiac and cerebral level. Calcium also has an
essential role as a second messenger in various intracellular processes such as
apoptosis, regulation of the cell cycle, gene expression, hormonal signalling and the
cellular response to oxidative stress. To induce these biological responses, calcium
uses a ubiquitous intracellular receptor, calmodulin. The calcium-calmodulin complex
can then bind to and activate especially the "Ca2+/calmodulin-dependent protein
kinases" (CaMKs), which are serine/threonine protein kinases.
CaMKII is a member of the family of CaMKs, of which four known isoforms (a,
ß, ? and d) are distributed in various tissue types. Thus, CaMKIfct and CaMKIIß are
mainly localized in the brain and skeletal muscle, whereas CaMKIIy and CaMKIId
are expressed in numerous tissues and organs including the heart, the lungs and the
kidneys.
Recently, the four isoforms of CaMKII (a, ß, ? and d) were crystallized with
relatively unselective competitive ATP inhibitors (Rellos et al. Plosbiology 2010, 8,
e1000426). As expected, the four structures are very similar on account of the very
high sequence homology of the four isoforms of CaMKII, in particular as regards the
ATP binding pocket. On the basis of these data, it may be considered that an
inhibitor that binds to the ATP binding pocket of the d isoform is also an inhibitor of
the a, ß, and ? isoforms.
Many indications supporting the deleterious role of CaMKII in the
development of heart pathologies have been reported in the literature:
- the increase in expression and activity of CaMKII d has been demonstrated
in experimental models of cardiac hypertrophy and in cardiac insufficiency in man
(Hagemann et al., Mol. Cell. Biochem. 2001, 220:69-76; Boknik et al., Cardiovasc.
Res. 2001, 51:717-728; Hempel et al., Basic Res. Cardiol. 2002;97 Suppl. 1:196-101;
Colomer et al., Mol. Endocrinol. 2003, 17:183-192; Zhang et al., Circ. Res. 2003,
92:912-919; Currie et al., FEBS Lett. 1999, 459:244-248; Hoch et al., Circ. Res.
1999, 84:713-721; Kirchhefer et al., Cardiovasc. Res. 1999, 42:254-261);
- the development of cardiac hypertrophy and cardiac insufficiency has been
established in transgenic mice that overexpress CaMKII d in the heart (Zhang et al.,
Circ. Res. 2003, 92:912-919; Zhang et al., J. Biol. Chem. 2002, 277:1261-1267;
Maieretal., Circ. Res. 2003, 92:904-911);
- the protection of mice against myocardial infarction, cardiac arrhythmia,
cardiac hypertrophy and cardiac insufficiency by inhibition of CaMKII has been
demonstrated by means of an inhibitor of the CaMKII activation of small molecule
type (KN-93 inhibitor), a peptide inhibitor of the CaMKII pseudo-substrate (AC3-1) or
by means of mice bearing a deletion of the CaMKIIS gene (Zhang et al., Nat. Med.
2005, 11:379-380; Yang et al., Am. J. Physiol. Heart Circ. Physiol. 2006, 291:H3065-
H3075; Vila-Petroff et al., Cardiovasc. Res. 2007, 73:689-98; Wu et al., Circulation
2002, 106:1288-1293; Khoo et al., Circulation 2006, 114:1352-1359; Backs et al.,
Proc. Natl Acad. Sci. 2009, 106:2342-2347, Ling et al., J. Clin. Invest. 2009,
119:1230-40). These indications confirm the potential use of CaMKII inhibitors for
preventing and/or treating myocardial infarction, cardiac arrhythmia, cardiac
hypertrophy and cardiac insufficiency.
It has moreover been demonstrated that the extinction of CaMKIId leads to
an 80% reduction of formation of neo-intima in a model of carotid cuff lesion in rats
(House et al., Arterioscler. Thromb. Vasc. Biol. 2008, 28:441-7), indicating that
CaMKII inhibitors might also be used for treating restenosis.
What is more, CaMKII contributes towards the proliferation of hepatic stellate
cells (Soliman et al., Cell Calcium 2009, 45, 284-292) and also towards the
proliferation of cardiac fibroblasts and the production of extracellular matrix by these
cells (Zhang et al., J. Cardiovasc. Pharmacol. 2010, 55:96-105).
These indications make CaMKII a new therapeutic target in the treatment of
fibrotic diseases including hepatic fibrosis, cardiac fibrosis, pancreatic fibrosis, renal
fibrosis, pulmonary fibrosis, cutaneous fibrosis, intestinal fibrosis and ocular fibrosis.
It has also been recently suggested that CaMKII is involved in the apoptosis
of endothelial cells induced by stress of the endoplasmic reticulum or of neuronal
cells induced with 6-hydroxydopamine, which may be important events, respectively,
in atherosclerosis and Parkinson's disease (Timmins et al., J. Clin. Invest. 2009, 119:
2925-2941). Moreover, in a model of acute renal insufficiency induced by a systemic
stress of the endoplasmic reticulum in mice, a reduction in the apoptosis of the
tubular epithelial cells and preservation of the renal function were observed in the
case of CaMKIIy KO mice (Timmins et al., J. Clin. Invest. 2009, 119:2925-2941),
suggesting a possible use of a CaMKII inhibitor in the treatment of renal pathologies,
in particular acute renal insufficiency.
Moreover, a neuroprotective effect by a peptide inhibitor of the "autonomous"
activity of CaMKII, in this instance CN21, has recently been reported (Vest et al. J.
Biol. Chem. 2010, 285: 20675-20682). This type of CaMKII inhibition may offer a
new therapeutic approach for neuroprotection after a stroke.
Furthermore, in a murine model of pain of inflammatory origin, it has been
shown that inhibition of the activity of CaMKII with trifluoperazine allows dose-
dependent reversion of allodynia of mechanical origin and hyperalgia of thermal
origin (Luo et al. J. Pharm. Exp. Ther. 2008 325: 267-275). These results suggest
that CaMKII inhibitors might make it possible to treat chronic pain.
It has also been reported that CaMKII inhibitors, in particular SMP-114,
enable inhibition of the expression of HIF-1a and the significant inhibition of VEGF
production in macrophages (Westra et al. BMC Musculoskeletal Disorders 2010,
11:61-72). In this case, the inhibitory activity of CaMKII might be partly responsible
for the anti-arthritic effect of SMP-114, and, more generally, it might be thought that a
CaMKII inhibitor might make it possible to treat rheumatoid arthritis.
A certain number of competitive CaMKII inhibitors are well known in the
literature, for instance KN-93 and the peptide AIP (autocamtide-2-related inhibitory
peptide). Isoxazole derivatives have also been described as CaMKII inhibitors (EP
1 815 867) and, more recently, peptides such as CN21 have been disclosed as
inhibitors of the autonomous activity of CaMKII (WO 2009/042 906).
Other competitive inhibitors of aryl-indolyl maleimide type (Levy et al. Bioorg.
Med. Chem. Letters 2008, 18:2390-2394, 2395-2398 and 2399-2403) have been
described in the literature. Non-competitive inhibitors bearing a pyrimidine unit are
also known (Mavunkel et al. Bioorg. Med. Chem. Letters 2008, 18:2404-2408).
One subject of the present invention is novel compounds that are CaMKII
inhibitors, corresponding to formula (I):

in which:
> A represents CH or C(alkyl);
> X represents CH, C(alkyl) or N;
> R1, R2, R3 and R4, which may be identical or different, represent,
independently of each other:
• a hydrogen atom;
• a linear, branched or cyclic alkyl, optionally substituted with one or more of
the following:
o halogen atoms;
o -OR9;
o -NR9R'9:
o -CN;
o -C(O)OR9;
o -C(O)NR9R9.;
o -S(O)pR10:
o -S(O)2NR9R'9;
in which R9, R'9, R10 and p are as defined below
• a group -S(O)pR10 in which p and R10 are as defined below;
• a group -OR10 in which R10 is as defined below;
• a halogen atom;
• a group -N(R11)C(O)R12, in which
(i) R11 and R12 represent, independently of each other, a
hydrogen atom or a linear, branched or cyclic alkyl, optionally
substituted with one or more substituents chosen from halogen atoms,
groups -OR9 and groups -NR9R'9, or
(ii) R11 and R12 form, together with the atoms to which they are
attached, a heterocycloalkyl, so as to form a lactam;
• a group -N(R14)-CH2-C(O)NR15R9, in which R14 and R15 form, together with
the atoms to which they are attached, a heterocycloalkyl, so as to form a
piperazinone and in which R9 is as defined below;
• a group -C(O)NR16R17 with R16 and R17 forming, together with the nitrogen
atom to which they are attached, a heterocycloalkyl
• a group -T-U, in which:
¦ T represents:
o a single bond,
o a linear or branched alkylene group;
o a group -C(O)-,
o a group -S(O)p- in which p is as defined below, or
o a group -0-(CH2)n- in which n is as defined below,
with U representing a heterocycle comprising one or more
heteroatoms chosen from N, O and S(O)p, in which p is as defined
below, the said heterocycle being saturated, unsaturated or aromatic,
optionally mono- or di- or polysubstituted with one, two or several
substituents chosen from:
? groups -OR7, in which R7is as defined beiow,
? halogen atoms,
? groups -C(O)R7 in which R7 is as defined below,
? linear, branched or cyclic alkyls, optionally substituted
with one or more substituents chosen from halogen atoms,
groups -OR10. groups -NR9R'9 and the group -CN, in which
R9, R'9 and R10are as defined below; and
? saturated, unsaturated or aromatic heterocycles,
optionally substituted with one or more substituents
chosen from halogen atoms, groups -OR9, groups -NR9R'9
and alkyl groups, the said alkyl groups being optionally
substituted with one or more halogen atoms;
it being understood that when U is a heterocycloalkyl group
comprising at least one nitrogen atom, the said substituent is
advantageously chosen from:
? groups -C(O)R7 in which R7 is as defined below; and
? linear, branched or cyclic alkyls, optionally substituted
with one or more substituents chosen from halogen atoms,
groups -OR-10, groups -NR9R'9and the group -CN, in which
R9, R'9 and R10 are as defined below;
and the said substituent being advantageously borne by the said
nitrogen atom, or
¦ T represents:
o a group -C(O)-;
o a group -S(O)2-; or
o a group -O-(C2-C3)alkylene-;
with U representing a group -NR9R'9in which R9 and R'9 are as
defined below; or
¦ T represents:
o a group -C(O)-; or
o a group -O-(C2-C3)alkylene-;
when U represents a group -OR9, in which R9 is as defined below; or
¦ T represents:
o a linear or branched alkylene group; or
o a group -O-(C2-C3)alkylene;
with U representing a group -NR8R9 in which R9 and R8 are as
defined below;
or alternatively two adjacent groups chosen from R1, R2, R3 and R4 are linked
and form, with the two carbons that bear them, a saturated, unsaturated or
aromatic heterocycle, optionally substituted with one or more linear, branched or
cyclic alkyl groups, the said alkyl groups being optionally substituted with one or
more substituents chosen from halogen atoms, groups -OR10, and groups
-NR9R'9, in which R9, R'9 and R10are as defined below,
the said heterocycle being fused with the aromatic ring,
> R5 represents:
• a linear or branched alkyl, optionally substituted with one or more
substituents chosen from halogen atoms, groups -OR9, groups -NR9R'9, the
group -CN, groups -C(O)NR9R9', groups -S(O)pR10 and cycloalkyl groups
optionally substituted with a group -NR9R'9, in which R9, R'9, R10and p are
as defined below,
• a cycloalkyl group, optionally substituted with a group -NR9R'9, in which R9
and R'9 are as defined below,
• an alkoxy group -OR9, in which R9 is as defined below,
• an aryt optionally substituted with one or more substituents chosen from
groups (C1-C3)alkyl, halogen atoms and groups -O-(C1-C3)alkyl, or
• a group -(CH2)t-R13, in which R13 and t are as defined below,
> R6 represents a hydrogen atom or a linear, branched or cyclic alkyl,
and in which:
> R7 represents a hydrogen atom or a linear, branched or cyclic alkyl, optionally
substituted with one or more of the following substituents chosen from halogen
atoms, groups -OR9 and groups -NR9R'9with R9and R'9as defined above;
> R8 represents a heteroaryl group, advantageously a pyridine;
> R9 and R'9 represent, independently of each other, a hydrogen atom or a linear,
branched or cyclic alkyl;
> R10 represents a hydrogen atom or a linear, branched or cyclic alkyl optionally
substituted with one or more halogen atoms,
> R13 represents a heteroaryl or a heterocycloalkyl optionally substituted with one
or more substituents chosen from linear, branched or cyclic alkyls, it being
understood that when the said heterocycloalkyl comprises at least one nitrogen
atom, this atom may optionally bear the said substituent,
> t represents 1 or 2,
> n represents 0, 1, 2 or 3, and
> p represents 0, 1 or 2,
in the form of acid, base or addition salt with an acid or a base, and also in the form
of hydrate or solvate.
The compounds of formula (I) may comprise one or more asymmetric carbon
atoms. They may thus exist in the form of enantiomers or diastereoisomers. These
enantiomers and diastereoisomers, and also mixtures thereof, including racemic
mixtures, form part of the invention.
The compounds of formula (I) may exist in the form of bases or acid-addition
salts. Such addition salts form part of the invention.
These salts may be prepared with pharmaceutically acceptable acids, but the
salts of other acids that are useful, for example, for purifying or isolating the
compounds of formula (I) also form part of the invention.
The compounds of formula (I) may also exist in the form of hydrates or
solvates, i.e. in the form of associations or combinations with one or more water
molecules or with a solvent. Such hydrates and solvates also form part of the
invention.
In the context of the present invention, and unless otherwise mentioned in the
text, the following definitions apply:
> a halogen atom: a fluorine, chlorine, bromine or iodine atom;
> an alkvl group: a linear or branched, saturated aliphatic group, which may
comprise 1, 2, 3, 4, 5 or 6 carbon atoms (abbreviated as -(C1-C6)alkyl). By way of
example, the following groups may be mentioned: (i) as group -Clalkyl, the methyl
group, (ii) as group -C2alkyl, the ethyl group, (iii) as group -C3alkyl, the propyl or
isopropyl group, (iv) as group -C4a!kyl, the butyl, isobutyl or tert-butyl group, (v) as
group -C5alkyl, the pentyl or isopentyl group;
> an alkvlene group: a linear or branched, saturated, divalent alkyl group as
defined previously, which may comprise 1, 2, 3, 4 or 5 carbon atoms (abbreviated as
-(C1-C5)alkylene-). Examples that may be mentioned include the methylene (or
-CH2-), ethylene (or -CH2-CH2-) or propylene (-CH2-CH2-CH2- or -C(CH3)r)
radicals;
> a cycloalkvl group: a cyclic alkyl group that may comprise 3, 4, 5 or 6 carbon
atoms, also abbreviated as -(C3-C6)cycloalkyl and in which all the carbon atoms are
engaged in the ring. Examples that may be mentioned include cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl groups;
> an alkoxy group: a radical -O-alkyl in which the alkyl group is as defined
previously. Examples that may be mentioned include the groups -O-(C1-C5)alkyl or
-(C1-C5)alkoxy, and in particular, (i) as group -O-dalkyl, the group -Omethyl, (ii) as
group -O-C2alkyl, the group -Oethyl, (iii) as group -O-C3alkyl, the group -Opropyl or
-Oisopropyl, (iv) as group -O-C4alkyl, the group -Obutyl, -Oisobutyl or -Otert-butyl,
(v) as group -O-C5alkyl, the group -Opentyl, -Oisopentyl or -Oneopentyl;
> an arvl group: a monocyclic or bicyclic aromatic group comprising between 5
and 10 carbon atoms and advantageously between 5 and 6 carbon atoms. Examples
of aryl groups that may be mentioned include the phenyl group and the naphthyl
group;
> a heterocyclyl group: a 3- to 10-membered monocyclic or bicyclic group
comprising one or more heteroatoms chosen from O, N and S.
The said heterocycle may be saturated or partially unsaturated and may
comprise one or more double bonds, ft is then referred to as a heterocycloalkyl
group. Examples of non-aromatic or heterocycloalkyl heterocycles that may be
mentioned include lactams, piperazinone, epoxyethyl, oxiranyl, aziridinyl,
tetrahydrofuryl, dioxolanyl, pyrrolidinyl, piperidyl, pyrazolidinyl, imidazolidinyl,
tetrahydrothiophenyl, dithiolanyl, thiazolidinyl, tetrahydropyranyl, dioxanyl,
morpholinyl, piperidyl, piperazinyl, tetrahydrothiopyranyl, dithianyl, thiomorpholinyl,
dihydrofuryl, 2-imidazolinyl, 2,3-pyrrolinyl, pyrazolinyl, dihydrothiophenyl,
dihydropyranyl, pyranyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrimidinyl and
dihydrothiopyranyl, and corresponding groups derived from fusion with a phenyl
nucleus, and more particularly morpholinyl, dioxalanyl, benzothiazolidinyl, pyrrolidinyl
and benzopyrrolidinyl rings.
Advantageously, a heterocycloalkyl is an optionally bridged cyclic alkyl group
comprising 4, 5, 6 or 7 carbon atoms and comprising 1, 2 or 3 heteroatoms chosen
from oxygen, nitrogen and sulfur, for instance piperidyl, piperazinyl, pyrrolidinyl,
hexamethyleneimino, morpholinyl and 1,1-dioxydotetrahydrothienyl groups.
The said heterocycle may also be aromatic and 5- to 10-membered, and may
then represent a heteroaryl group.
Heteroaryls that may especially be mentioned include the following
representative groups: benzimidazolyl, benzothiazolyl, furyl, imidazolyl, indolyl,
indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl,
pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3, 4-thiadiazolyl,
thiazolyl, thienyl and triazolyl.
Advantageously, a heteroaryl group is a cyclic aromatic group comprising 2,
3, 4 or 5 carbon atoms and comprising 1, 2 or 3 heteroatoms, which may be chosen
from a nitrogen atom, an oxygen atom and a sulfur atom, independently of each
other, so as to be identical or different, when there are two of them, or independently
of each other, so as to be identical or different, when there are three of them.
Examples that may especially be mentioned include pyridyl, pyrrolyl and furyl
groups.
When the heterocycle is substituted, the substituent(s) may be on one or
more carbon atoms included in the said heterocycle and/or, where appropriate, on
the heteroatom(s) of the said heterocycle. When the heterocycle comprises several
substituents, they may be borne on different atoms or, where appropriate, on the
same atom;
> a protecting group Pg: a group that makes it possible, firstly, to protect a
reactive function such as a hydroxyl or an amine during a synthesis, and, secondly,
to regenerate the intact reactive function at the end of the synthesis. Examples of
protecting groups and of protection and deprotection methods are given in
"Protective Groups in Organic Synthesis", Greene et al., 2nd Edition (John Wiley &
Sons, Inc., New York);
> a leaving group: a group that can be readily cleaved from a molecule by
breaking a heterolytic bond, with loss of an electron pair. This group may thus be
readily replaced with 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, etc.
Examples of leaving groups and references for preparing them are given in
"Advances in Organic Chemistry", J. March, 3rd Edition, Wiley Interscience, pp. 310-
316.
Among the compounds of formula (I) that are subjects of the invention, a first
group of compounds is formed by the compounds for which:
A represents CH or C(CH3), advantageously A represents CH;
and/or
X represents CH or N, advantageously X represents CH;
and/or
R1, R2, R3 and R4, which may be identical or different, represent, independently
of each other:
• a hydrogen atom;
• a linear, branched or cyclic alkyl, optionally substituted with one or more of
the following:
o halogen atoms;
o -OR9;
O -NR9R'9;
o -CN;
o -C(O)OR9;
o -C(O)NR9R9';
o -S(O)pRi0:
o -S(O)2NR9R'9;
• a group -S(O)pR10;
• a group -OR10;
• a halogen atom;
• a group-N(R11)C(O)R12,
• a group -N(R14)-CH2-C(O)NR15R9, in which R14 and R15 form, together with
the atoms to which they are attached, a heterocycloalkyl, so as to form a
piperazinone and in which R9 is as defined below;
• a group -C(O)NR16R17 with R16 and R17 forming, together with the nitrogen
atom to which they are attached, a heterocycloalkyl, so as to form
advantageously a piperidyl or a pyrrolidinyl,
• a group -T-U, in which:
¦ T represents:
o a single bond,
o a linear or branched alkylene group;
o a group -C(O)-,
o a group -S(O)p- in which p is as defined below, or
o a group -O-(CH2)n- in which n is as defined below,
with U representing a heterocycle comprising one or more
heteroatoms chosen from N, O and S(O)p, in which p is as defined
below, the said heterocycle being saturated, unsaturated or aromatic,
optionally mono- or di- or polysubstituted with one, two or several
substituents chosen from:
? groups -OR7,
? halogen atoms,
? groups -C(O)R7,
? linear, branched or cyclic alkyls, optionally substituted
with one or more substituents chosen from halogen atoms,
groups -OR10, groups -NR9R'9and the group -CN;
? saturated, unsaturated or aromatic heterocycles,
optionally substituted with one or more substituents
chosen from halogen atoms, groups -OR9, groups -NR9R'9
and alkyl groups, the said alkyl groups being optionally
substituted with one or more halogen atoms;
it being understood that when U is a heterocycloalkyl group
comprising at least one nitrogen atom, the said substituent is
advantageously chosen from:
? a group -C(O)R7; and
? linear, branched or cyclic alkyls, optionally substituted
with one or more substituents chosen from halogen atoms,
groups -OR10, groups -NR9R'9and the group -CN;
and the said substituent being advantageously borne by the said
nitrogen atom, or
¦ T represents:
o a group -C(O)-;
o a group -S(O)2-; or
o a group -O-(C2-C3)alkylene-;
with U representing a group ~NR9R'9;
or
¦ T represents:
o a group -C(O)-; or
o a group -O-(C2-C3)alkylene-;
with U representing a group -OR9;
or
¦ T represents:
o a linear or branched alkylene group; or
o a group -O-(C2-C3)alkylene-;
with U representing a group -NR8R9;
or alternatively two adjacent groups chosen from R1, R2, R3 and R4 are linked
and form, with the two carbons that bear them, a saturated, unsaturated or
aromatic heterocycle, optionally substituted with one or more linear, branched or
cyclic alkyl groups, the said alkyl groups being optionally substituted with one or
more substituents chosen from halogen atoms, groups -OR10, and groups
-NR9R9,
and/or
R5 represents:
• a linear or branched alkyl, optionally substituted with one or more
substituents chosen from halogen atoms, groups -OR9, groups -NR9R'9 the
group -CN, groups -C(O)NR9R9', groups -S(O)pR10 and cycloalkyl groups
optionally substituted with a group -NR9R'9,
• a cycloalkyl group, optionally substituted with a group -NR9R'9,
• an alkoxy group -OR9,
• an aryl optionally substituted with one or more substituents chosen from
groups (C1-C3)alkyl, halogen atoms and groups -O-(C1-C3)alkyl, or
• a group-(CH2)t-R13,
advantageously R5 represents (i) a linear or branched alkyl, optionally substituted
with one or more substituents chosen from halogen atoms, groups -OR9, groups
-NR9R'9and cycloalkyl groups, (ii) a cycloalkyl group (iii), an aryl optionally
substituted with one or more substituents chosen from groups (C1-C3)alkyl,
halogen atoms and groups -O-(C1-C3)alkyl, or (iv) a group -(CH2)t-R13.
and/or
R6 represents a hydrogen atom or a linear, branched or cyclic alkyl,
advantageously R6 represents a hydrogen atom,
and/or
R7 represents a hydrogen atom or a linear, branched or cyclic alkyl, optionally
substituted with one or more substituents chosen from halogen atoms, groups
-OR9 and groups -NR9R'9;
and/or
R8 represents a heteroaryl group, advantageously a pyridine;
and/or
R9 and R'9 represent, independently of each other, a hydrogen atom or a linear,
branched or cyclic alkyl;
and/or
R10 represents a hydrogen atom or a linear, branched or cyclic alkyl optionally
substituted with one or more halogen atoms,
and/or
R11 and R12 represent, independently of each other, a hydrogen atom or a linear,
branched or cyclic alkyl, optionally substituted with one or more substituents chosen
from halogen atoms, groups -OR9 and groups -NR9R'9, or R11 and R12 form, together
with the atoms to which they are attached, a heterocycloalkyl, so as to form a lactam;
and/or
R13 represents a heteroaryl or a heterocycloalkyl optionally substituted with one
or more substituents chosen from linear, branched or cyclic alkyls, it being
understood that when the said heterocycloalkyl comprises at least one nitrogen
atom, this atom may optionally bear the said substituent, advantageously R13 is a
tetrahydrofuryl,
and/or
t represents 1 or 2,
and/or
n represents 0, 1, 2 or 3,
and/or
p represents 0, 1 or 2
and/or
in the form of acid, base or addition salt with an acid or a base, and also in the form
of hydrate or solvate.
Among the compounds of formula (I) that are subjects of the invention, a
second group of compounds is formed by the compounds for which:
> A represents CH,
> X represents CH, C(alkyl) or N, advantageously X represents CH,
> R1, R2, R3 and R4, which may be identical or different, represent,
independently of each other:
o a hydrogen atom,
o a linear, branched or cyclic alkyl, optionally substituted with one or
more of the following halogen atoms, a group -OR9 or -NR9R'g, in
which R9 and R'9 represent, independently of each other, a hydrogen
atom or a linear, branched or cyclic alkyl,
o a group -S(O)pR10 or a group -OR10, in which R10 represents a
hydrogen atom or a linear, branched or cyclic alkyl optionally
substituted with one or more halogen atoms, and p represents 0, 1 or
2,
o a halogen atom,
o a group -N(R-11)C(O)R12, in which R11 and R12 represent,
independently of each other, a hydrogen atom or a linear, branched or
cyclic alkyl or R11 and R12 form, together with the atoms to which they
are attached, a heterocycloalkyl, so as to form a lactam;
o a group -T-U, in which
¦ T represents:
• a single bond,
• a linear or branched alkylene group,
• a group -C(O)-,
• a group -S(O)p, in which p represents 0, 1 or 2,
• a group -O-(CH2)n- in which n represents 0, 1, 2 or 3,
and U represents a heterocycle comprising one or more
heteroatoms chosen from N, O and S(O)p in which p represents 0,
1 or 2, the said heterocycle being of the formula:

in which
• * represents the position of attachment of U to T;
• M1 represents a C or N atom;
• M2 and M3, which may be identical or different, represent a C, N or O atom
or S(O)p in which p = 0, 1 or 2;
• M4 represents a C, C(=O), N, O or S(O)p atom in which p = 0, 1 or 2;
each of the Mi, which may be identical or different, represent a C, C(=O), N,
O or S(O)p atom in which p = 0, 1 or 2;
• i=O, 1,2 or 3;
it being understood that each of the M1' M2, M3, M4 or Mi may be optionally
substituted if a valency is available and/or the adjacent M1' M2, M3, M4 or Mi
may be attached via a double bond, where appropriate;
the said heterocycle U being saturated, unsaturated or aromatic, optionally
mono- or di- or polysubstituted with one, two or several substituents chosen from:
o groups -OR7, in which R7 represents a hydrogen atom or a linear,
branched or cyclic alkyl,
o halogen atoms,
o groups -COR7 in which R7 represents a hydrogen atom or a linear,
branched or cyclic alkyl,
o linear, branched or cyclic alkyls, advantageously a methyl, an ethyl or
a cyclopropyl, optionally substituted with one or more halogen atoms,
o saturated, unsaturated or aromatic heterocycles, especially a
heterocycle comprising an N, advantageously a morpholinyl, a
pyrrolidinyl or a piperidyl, optionally substituted with one or more
groups chosen from halogen atoms and alkyl groups optionally
substituted with one or more halogen atoms;
or alternatively two adjacent groups from among R1, R2, R3 and R4 are linked and
form, with the two carbons that bear them, a saturated, unsaturated or aromatic
heterocycle, optionally substituted with one or more linear, branched or cyclic
alkyl groups, the said alkyl groups being optionally substituted with at least one
group chosen from groups -NR9R'9, in which R9 and R'9 represent, independently
of each other, a hydrogen atom or an alkyl group,
the said heterocycle being fused with the aromatic ring,
> R5 represents (i) a linear or branched alkyl, optionally substituted with one or
more substituents chosen from halogen atoms, cycloalkyl groups, groups
-NRgR'g, in which Rg and R'9 represent, independently of each other, a
hydrogen atom or an alkyl group and groups -OR9, in which R9 represents a
hydrogen atom or an alkyl group, (ii) an aryl optionally substituted with one or
more substituents chosen from groups (C1-C3)alkyl, halogen atoms and
groups -O-(C1-C3)alkyl, and
> R6 represents a hydrogen atom or a linear, branched or cyclic alkyl,
in the form of acid, base or addition salt with an acid or a base, and also in the form
of hydrate or solvate.
Among the compounds of formula (I) that are subjects of the invention,
another group of compounds is formed by the compounds corresponding to formula
(I') below:

in which:
> R1 represents:
• a hydrogen atom,
• a linear, branched or cyclic alkyl, optionally substituted with one or
more of the following substituents chosen from halogen atoms, groups
-NR9R'9, in which R9 and R'9 represent, independently of each other, a
hydrogen atom or an alkyl group, advantageously a methyl,
• -OR10, in which R10 represents a hydrogen atom or a linear, branched
or cyclic alkyl optionally substituted with one or more halogen atoms,
• a halogen atom,
• a group -T-U, in which
T represents:
o a single bond,
o an alkylene group, advantageously a group -(CH2)1-3-,
o a group -C(O)-,
o a group -O-(CH2)n in which n represents 0, 1, 2 or 3,
and U represents a saturated, unsaturated or aromatic heterocycle,
optionally mono- or disubstituted with a substituent, advantageously
chosen from:
o halogen atoms,
o groups -COR7 in which R7 represents a hydrogen atom or
a linear, branched or cyclic alkyl, advantageously a methyl,
o linear, branched or cyclic alkyls, advantageously a methyl,
an ethyl or a cyclopropyl, the said alkyl being optionally
substituted with one or more halogens,
o heterocycles, advantageously saturated, comprising a
nitrogen atom, advantageously a morpholinyl, a pyrrolidinyl
or a piperidyl, the said heterocycle being optionally
substituted with one or more groups chosen from halogen
atoms;
>R2, R3 and R4, which may be identical or different, independently represent:
o a hydrogen atom,
o a linear, branched or cyclic alkyl, optionally substituted with one or
more of the following substituents chosen from halogen atoms and
groups -NR9R'9, in which R9 and R'9 represent, independently of
each other, a hydrogen atom or an alkyl, advantageously a methyl,
o a group -OR10, in which R10 represents a hydrogen atom or an alkyl
optionally substituted with one or more halogen atoms,
o a halogen,
o a group -T-U with T representing a bond and U a morpholinyl, or
>R1 and R2 are linked and form, with the two carbon atoms that bear them, a
heterocycle chosen from a piperidine, a thiazole, a tetrahydrofuran and a
dioxane, the said heterocycle being optionally substituted with a linear, branched
or cyclic alkyl optionally substituted with -NR9R'9, in which R9 and R'9 represent,
independently of each other, a hydrogen atom or a methyl,
the said heterocycle being fused with the aromatic ring,
> R5 represents (i) a linear or branched alkyl comprising from 1 to 5 carbon
atoms, advantageously an ethyl, optionally substituted with one or more
substituents chosen from halogen atoms advantageously a fluorine atom or a
group -OH, (ii) an aryl optionally substituted with one or more substituents
chosen from groups (C1-C3)alkyf, advantageously a methyl group, halogen
atoms, advantageously a fluorine atom and groups -O-(C1-C3)alkyl
advantageously a group methoxy,
in the form of acid, base or addition salt with an acid or a base, and also in the form
of hydrate or solvate.
Among the compounds of formula (I) or (I') above, mention may be made of
the compounds for which:
> A represents CH; and/or
> X represents CH; and/or
> R1, R2, R3 and R4 do not all represent a hydrogen atom; and/or
> R1 is other than a hydrogen atom; and/or
> R5 represents (i) a linear or branched alkyl advantageously an ethyl, (ii) an
aryl optionally substituted with one or more substituents chosen from groups
(C1-C3)alkyl, advantageously a methyl group, halogen atoms,
advantageously a fluorine atom; and/or
> U represents a saturated, unsaturated or aromatic heterocycle, optionally
mono- or disubstituted, comprising at least one nitrogen atom and/or one
oxygen atom, and/or
> U represents a saturated heterocycle comprising at least one nitrogen atom;
and/or
> U represents a heterocycle chosen from:
o an azetidinyl, advantageously an azetidin-1-yl or an azetidin-3-yl;
o a pyrrolidinyl, advantageously a pyrrolidin-1-yl or a pyrrolidin-3-yl;
o an oxopyrrolidinyl, advantageously a 2-oxopyrrolidin-1-yl;
o a piperidyl, advantageously a piperid-1-yl, a piperid-2-yl or a piperid-4-
yl, particularly advantageously a piperid-1-yl or a piperid-4-yl;
o a 1,2,3,6-tetrahydropyridyl, advantageously a 1,2,3,6-tetrahydropyrid-
4-yl;
o a pyridyl, advantageously a pyrid-2-yl;
o a piperazinyl, advantageously a piperazin-1-yl;
o a diazepanyl, advantageously a diazepan-1 -yl;
o a morpholinyl, advantageously a morpholin-4-yl or a morpholin-3-yl,
especially a 4-(R)-1-morpholin-3-yl, particularly advantageously a
morpholin-4-yl;
o a 1,1 -dioxo-1 lambda6-thiomorpholin-4-yl.
Among the compounds of formula (I) that are subjects of the invention,
mention may be made especially of the following compounds in the order of the
compounds of the table below:
7-Amino-8-ethyl-2-(4-hydroxyphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-2-(benzothiazol-6-ylamino)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-2-[4-(cyclopropanecarbonylmethylamino)phenylamino]-8-ethyl-5-oxo-5,8-
dihydropyndo[2,3-djpyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(4-methylpiperazine-1-carbonyl)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-(4-cyclopentyloxyphenylamino)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-[4-(4-pyrrolidin-1-ylpiperrd-1-yl)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethy!-5-oxo-2-[4-(4-pyrrolidin-1-ylpiperid-1-yl)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyi-5-oxo-2-[4-(4-pyrrolidin-1-ylpiperid~1-yl)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-cyclopentyl-2-(4-morpholin-4-ylphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-[4-(piperidine-1-sulfonyi)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6-is carboxamide;
2-[4-(4-Acetylpiperazin-1-yl)phenylamino]-7-amino-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(4-morpho!in-4-ylben2ylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(quinolin-3-ylamino)-5,8-dihydropyrido[2,3-d]pyrimidine-6-
carboxylamide;
7-Amino-8-ethyl-5-oxo-2-[4-(3-piperid-1-ylpropoxy)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(3,4,5,6-tetrahydro-2H-[1,2']bipyridyl-5'-ylamino)-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-[4-(2-oxopyrrolidin-1-yl)phenylamino]-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(quinolin-6-ylamino)-5,8-dihydropyrido[2,3-d]pyrimidine-6-
carboxamide;
7-Amino-8-ethyl-2-(3-morpholin-4-ylphenyiamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-2-(2,3-dihydrobenzo[1,4]dioxin-6-ylamino)-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(3-fluoro-4-hydroxyphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(3-methylsulfanylphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Am!no-8-ethyl-2-(4-morpholin-4-ylphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(4-morpholin-4-ylphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(4-morpholin-4-ylphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(2-fluorophenylamino)-5-oxo-5,8-dihydropyridot2,3-d]pyrimidine-6-
carboxamide;
7-Arnrno-2-[4-(4,4-difluoro[1,4']bipiperidyl-1'-yl)-2-methoxyphenylamino]-8-ethyl-5-
oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6~carboxamide
7-Amino-8-ethyl-2-[2-methoxy-4-(4-trifluoromethyl[1,4']bipiperidyl-1'-yl)phenylamino]-
5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{4-[4-(3,3-difluoropyrrolidin-1-yl)piperid-1-yl]-2-methoxyphenyiamino}-8-
ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-fluoro-6-methoxyphenylamino]-5-oxo-
5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxarriide;
7-Amino-2-[4-(1-cyclopropylpiperid-4-yl)-2-methoxyphenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-(2-dimethylaminomethylchroman-6-ylamino)-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-[5-chloro-4-(4-cyclopropylpiperazin-1-yl)-2-methoxyphenyiamino]-8-ethyl-
5-0X0-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[2-methoxy-4-{4-morpholin-4-ylpiperid-1-yl)phenylamino]-5-oxo-
5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxyamide;
7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-difluoromethoxyphenylamino]-8-ethyl-5-
oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-methoxyphenylamino]-8-ethyl-5-oxo-
5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-5-
oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-[2-chloro-4-(4-ethylpiperazin-1-yl)phenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-y!)-3-trifluoromethylphenylamino3-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-{4-morpholin-4-ylmethylphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8~ethyl-5-oxo-2-{4-[4-(3,3,3-trifluoropropyl)piperazin-1-yl]phenylamino}-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-t4-(4-ethylpipera2in-1-yl)-3-fluorophenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
6-(4-Morpholin-4-ylphenylamino)-9-oxo-1,3,4,9-tetrahydro-2H-1,4a,5,7-tetraaza-
phenanthrene-10-carboxamide;
7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-methoxyphenyiamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(1-methylpiperid-4-ylmethoxy)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)phenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrtmidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-{4-ethylpiperazin-1-yl)-2-methylphenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(4-ethyl[1,4]diazepan-1-yl)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
8-(4-Morpholin-4-ylphenylamino)-5-oxo-1,2,3,5-tetrahydro-3,7,9,9b-tetraaza-
cyclopenta[a]naphthalene-4-carboxamide;
7-Amino-8-ethyl-5-oxo-2-{4-[2-(3-trifluoromethylpiperid-1-yl)ethyl]phenylamino}-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(3-morpholin-4-ylpropyl)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-{4-[1-(2,2,2-trifluoroethyl)piperid-4-yl]phenylamino}-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(4-(S)-1-morpholin-3-ylmethylphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-isobutyl-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-{4-[2-{3-fluoroazetidin-1-yl)ethyl]phenylamino}-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5-oxo-8-propyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(2-hydroxyethyl)phenylamino]-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-amino-8-ethyt-2-(4-hydroethylphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-{4-[2-(1,1 -dioxo-1 lambda6-thiomorpholin-4-yl)ethyl]phenylamino}-8-ethyl-
5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-{4-[2-(4-methyl-3-oxopiperazin-1-yl)ethyl]phenylamino}-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-{4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethy)-5-oxo-2-{4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-(4-dirnethylaminomethylphenylamino)-5-oxo-8-(2,2,2-tnfluoroethyl)-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-[3-chloro-4-(4-pyrrolidin-1-ylpiperid-1-yl)phenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-[3-chloro-4-(4-pyrrolidin-1-ylpiperid-1-yl)phenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(4-pyrid-2-ylmethylphenylamino)-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-2-{4-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]phenylamino}-8-ethyl~5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(4-pyrrolidin-3-ylphenylamino)-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(4-pyrrolidin-3-ylphenylamino)-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-[4-(2-piperid-1-ylethyl)phenylamino]-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5-oxo-8-(2,2,2-trifluoroethyl)-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{4-[2-(4,4-difluoropiperid-1-yl)ethyl]phenylamino}-8-ethyl-5-oxo-5,8-
dihydropyridoE2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(1-methylpyrrolidin-3-yl)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-{4-[2-(3,3-difluoropipend-1-yl)ethyl]phenylamino}-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-(3-methoxy-propyl)-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(1-methylpiperid-3-yi)pheny!amino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-(4-dimethylaminomethylphenylamino)-8-isopropyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-(4-dimethylaminomethylphenylamino)-8-isopropyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(4-piperid-3-ylphenylamino)-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-{1,2,3,4-tetrahydroisoquinolin-7-ylamino)-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(1-methylpiperid-4-yloxy)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(2-morpholin-4-ylethoxy)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-(3-dimethylaminomethylphenylamino)-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-[4-(4-pyrrolidin-1-ylpiperid-1-yl)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-[4-(piperid-4-yloxy)phenylamino]-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-(3-aminopropyl)-2-(4-morpholin-4-ylphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-(4-dimethylaminomethylphenylamino)-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(1-ethyipiperid-4-yl)phenylamino3-5-oxo-5,8-dihydropyndo[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(4-piperid-4-ylphenylamino)-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-2-[3-chloro-4-(4-ethylpiperazin-1-yl)phenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-[3-methoxy-4-(3-piperid-1-ylpropoxy)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyf-5-oxo-2-{4-[2-(4-trifluoromethylpiperid-1-yl)ethyl]phenylamino}-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{4-[2-(cis-2,6-dimethylmorpholin-4-yl)ethyl]phenylamino}-8-ethyl-5-oxo-
5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-(4-diethylaminomethylphenylamino)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide
7-Amino-2-(4-dimethylaminomethylphenylamino)-8-(3-methoxy-propyl)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-fluorophenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{4-[1-(2-cyanoethyl)piperid-4-yl]phenylamino}-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-{4-[1-(3-fluoropropyl)piperid-4-yl]phenylamino}-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid amide
7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-3-methylphenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-ethylphenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
(+)-7-Amino-2-trans-[4-(2-dimethylaminocyclopropyl)phenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)-5-fluoro-2-methoxyphenylamino]-8-ethyl-
5-oxo-5,8-dihydropyrido[2,3-d]pyrirnidine-6-carboxamide
7-Amino-2-[4-(4-cyclopropylpipera2in-1-yl)-3-fluoro-2-methoxyphenylamino]-8-ethyl-
5~oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-ethoxyphenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyi-5-oxo-2-(4-propylphenylamino)-5,8-dihydropyrido[2,3-d]pyrimidine-
6-carboxamide
7-Amino-8-ethyl-5-oxo-2-(4-propoxyphenylamino)-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-(6-methoxypyrid-3-ylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-(4-fluorophenylamino)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-
carboxamide
7-Amino-8-ethyl-2-(4-methoxyphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide
7-Amino-2-(ben20[1,3]dioxol-5-ylamino)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-5-oxo-2-(4-piperid-1-ylphenylamino)-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide
8-Ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylarnino}-7-
methylamino-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-isobutyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-
yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-cyclopropylmethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-
yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(2-methoxyethyl)-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-
yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-5-oxo-8-
(tetrahydrofuran-2-ylmethyl)-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-5-oxo-2-{4-[1-(3,3,3-trifluoropropyl)a2etidin-3-yl]phenylamino}-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{5-fluoro-2-methoxy-4-[1-{3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-
8-isobutyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-5-oxo-2-[4-(1,2,3,6-tetrahydropyrid-4-yl)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-(2-methoxy-4-piperid-4-ylphenylamino)-5-oxo-8-phenyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(2-hydroxyethyl)-2-(2-methoxy-4-piperid-4-yiphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-5-oxo-8-
thiazol-2-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-5-oxo-8-
thiazol-5-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(2-hydroxy-2-methylpropyl)-2-(2-methoxy-4-piperid-4-ylphenylamino)-5-
oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
8-(2-Acetylaminoethyl)-7-amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-
yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(2-aminoethyl)-2-{4-morpholin-4-ylphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-(4-morpholin-4-ylphenylamino)-5-oxo-8-pyrrolidin-3-ylmethyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino~8-ethyl-2-[4-{4-ethylpiperazin-1-yl)-2-hydroxyphenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-(4-morpholin-4-ylphenylamino)-5-oxo-8-piperid-4-ylmethyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-(2-methoxy-4-morpholin-4-ylphenylamino)-5-oxo-8-pyrrolidin-3-ylmethy!-
5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-(2-methoxy-4-piperid-4-ylphenylamino)-4-methyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-5-oxo-8-
thiophen-2-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-isobutyl-2-[2-methoxy-4-(4-morpholin-4-ylpiperid-1-yl)phenylamino]-5-
oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-(4-morpholin-4-ylphenylamino)-5-oxo-8-pyrrolidin-2-ylmethyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)-1,2,3,6-tetrahydropyrid-4-
yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[4-(4-ethylpiperazin-1-yl)-2-methoxyphenylamino]-8-(2-hydroxy-2-
methylpropyl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-{3,3,3-
trifluoropropyl)piperid-4-yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimicline-6-
carboxamide
7-Amino-8-(2-hydroxy-2-methylpropyl)-2-[4-(4-ethylpiperid-1-yl)-2-
methoxyphenylamino]-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[4-(1-cyclopropylpiperid-4-yl)-2-methoxyphenylamino]-8-(2-hydroxy-2-
methylpropyl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(2-methoxyethyl)piperid-4-
yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[2-methoxy-4-(1-methylpiperid-4-yl)phenylamino]-5-oxo-8-phenyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(3-fluorophenyl)-2-[2-methoxy-4-piperid-4-ylphenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(4-fluorophenyl)-2-[2-methoxy-4-piperid-4-ylphenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[2-methoxy-4-piperid-4-ylphenylamino]-5-oxo-8-m-tolyl-5,8-
dihydropyrido[2,3~d]pyrimidine-6-carboxamide
7-Amino-2-[2-methoxy-4-piperid-4-ylphenylamino]-5-oxo-8-p-tolyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(3-methoxyphenyl)-2-(2-methoxy-4-piperid-4-yfphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[2-methoxy-4-(2-pyrrolidin-1-ylethyl)phenylamino]-5-oxo-8-phenyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(4-fluorophenyl)-2-[2-methoxy-4-(1-methylpiperid-4-yi)phenylamino]-5-
oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[2-methoxy-4-(1-rnethylpiperid-4-yl)phenylamino]-5-oxo-8-m-tolyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-5-oxo-8-
phenyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[4-(4-ethylpiperazin-1-yl)-2-methoxyphenylamino]-5-oxo-8-phenyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
in the form of base or of acid-addition salt, and also in the form of hydrate or solvate.
Combinations of the groups of compounds according to the invention also
form part of the invention as an embodiment.
In accordance with the invention, the compounds of general formula (I) may
be prepared according to the process that follows.
According to a first embodiment, the process according to the invention
includes the step of nucleophilic substitution of a compound of formula (IX)

by means of a primary amine of formula (A):

in which R1, R2, R3, R4 and R5 are as defined in the general formula (I). This process
leads to the formation of a compound of formula (I), in particular of formula (I").
In accordance with Scheme 1 below, ethyl 4-chloro-2-methylthiopyridine-5-
carboxylate (II with A = CH) (prepared according to Todd et al., J. Amer. Chem. Soc.
(1943), 65, 350-354; Pesson, M., Eur. J. Med. Chem. (1974), 9(6), 585-590;
Shadbolt, R., J. Chem. Soc. (1967), 13, 1172-1178) or ethyl 4-chloro-6-methyl-2-
methylthiopyridine-5-carboxylate (II with A = C-Me) (prepared according to the
method described in WO 2005/105 801) is reacted with an amine of formula R5-NH2
(in which R5 is as defined previously in relation to formula (I) according to the
invention) in an organic solvent such as THF or dioxane, and in the presence of an
organic base, for example triethylamine, at room temperature, according to the
method described by D. Boschelli et al. in J. Med. Chem. (1998), 41, 4365-4377, to
give an ethyl 4-amino-2-methylthiopyridine-5-carboxylate derivative of formula (III).
Scheme 1
The ester group of the 4-aminopyrimidine derivative of formula (III) is then
hydrolysed with sodium or potassium or lithium hydroxide, at a temperature of
between 20 and 100°C, to give the corresponding carboxylic acid of formula (IV).
The carboxylic acid group is then activated via methods known to those skilled in the
art, such as its conversion into acid chloride using thionyl chloride, or
advantageously its conversion into the acid fluoride of formula (V) by reacting it with
an excess of cyanuric fluoride (C3N3F3) in an inert solvent such as dichloromethane,
in the presence of an organic base such as pyridine or, advantageously,
triethylamine. For further details regarding this reaction, reference may be made to
Synthesis 1973,487.
The acid fluoride of formula (V) thus obtained is condensed with
cyanoacetamide of formula (VI), in the presence of a strong base such as sodium
hydride (NaH) in a polar solvent, advantageously DMF, at ordinary temperature. If 2
equivalents of NaH are added, a ß-keto cyanoacetamide of formula (VII) may be
obtained, which is cyclized to a pyrido[2,3-d]pyrimidine derivative of formula (VIII) by
heating in a polar solvent such as DMF, DMSO or n-butanol, at a temperature above
100°C. On the other hand, if the acid fluoride of formula (V) is placed in contact with
cyanoacetamide of formula (VI) in the presence of 2 equivalents of sodium hydride,
in a first stage, and a third equivalent is then added after the in situ formation of the
ß-keto cyanoacetamide, then the compound of formula (V) is cyclized directly to the
pyrido[2,3-d]pyrimidine derivative of formula (Vlll). The methylsulfanyl group of the
compounds of formula (VIII) is then oxidized ([Ox] symbol in Scheme 1) to the
corresponding sulfoxide (n = 1) and sulfone (n = 2) derivatives by reaction with
oxidizing agents such as m-perchlorobenzoic acid, hydrogen peroxide, sodium
perborate and potassium hydrogen sulfate or trans-2-phenylsulfonyl-3-
phenyloxaziridine, as described, for example, by D. Boschelli et al. in J. Med. Chem.
(1998), 41, 4365-4377 and in the international PCT patent application published
under the number WO 96/34867. The sulfone and sulfoxide mixture of formula (IX)
reacts with a primary amine via aromatic nucleophilic substitution in a polar solvent
such as DMF, DMSO or NMP, at a temperature of between 75 and 150°C, to give
the compounds of formula (I"), which is a subgroup of the compounds of formula (I)
with A representing -CH= and R6 representing a hydrogen atom, which are subjects
of the present invention. It is understood that, in the process described in Scheme 1,
the groups R1, R2, R3, R4 or R5 may comprise one or more temporary protecting
groups.
According to another embodiment, the process according to the invention
includes the step of reacting a compound of general formula (XIV) or (XV):

and a compound of general formula (A);

in which R1' R2, R3, R4, R5 and R6 are defined as in the general formula (I), via a
nucleophilic substitution reaction or a coupling reaction of Buchwald/Hartwig type
catalysed with a palladium complex. This process leads to the formation of a
compound of formula (I), in particular of formulae (I") and (I'").

In accordance with Scheme 2, uracil-5-carboxylic acid (X) is reacted with
phosphorus oxychloride in the presence of N,N-diethylaniline according to the
method of V.H. Smith and B.E. Christensen (J. Am. Chem. Soc. 1955, 20, 829) to
give 2,4-dichloro-5-pyrimidinecarboxylic acid (XI). It is advantageously possible to
use directly commercial 2,4-dichloro-5-pyrimidinecarboxylic acid chloride, which is
subjected to a controlled hydrolysis. The chlorine atom in position 4 of the
intermediate (XI) is selectively substituted with an amine of formula R5-NH2 (in which
R5 is as defined previously in relation to formula (I) according to the invention) in an
organic solvent such as THF or dioxane, and in the presence of an organic base, for
example triethylamine, at room temperature, to give a 4-amino-2-chloropyrimidine-5-
carboxylic acid derivative of formula (XII). The carboxylic acid group is then activated
via methods known to those skilled in the art, such as its conversion into acid
chloride using thionyl chloride, or advantageously by converting it into acid fluoride of
formula (XIII) by reacting it with an excess of cyanuric fluoride in an inert solvent
such as dichloromethane, in the presence of an organic base, such as triethylamine.
The acid fluoride of formula (XIII) thus obtained is condensed with
cyanoacetamide of formula (VI), in the presence of an excess of a strong base such
as sodium hydride (NaH) in a polar solvent, advantageously DMF, at ordinary
temperature. In the presence of 2 equivalents of sodium hydride and then addition of
a third equivalent after in situ formation of the (3-keto cyanoacetamide, the compound
of formula (XIII) is converted directly at ordinary temperature into the pyrido[2,3-
d]pyrimidine derivative of formula (XIV). The chloro intermediate (XIV) may react
directly with a primary or secondary amine by aromatic nucleophilic substitution or by
Buchwald/Hartwig coupling catalysed with a metal such as palladium, at a
temperature of between 75 and 150°C, optionally in a microwave machine, to give
the compounds of formula (I"), which is a subgroup of the compounds of formula (I)
that are subjects of the present invention, in which R6 represents a hydrogen atom
and A represents -CH=. The chloro intermediate (XIV) may be alkylated beforehand
on the exocyclic amino group to give (XV) in the presence of a base such as sodium
hydride or potassium tert-butoxide and of an alkylating agent, advantageously an
alkyl iodide, in a polar solvent such as DMF, to give finally the compounds of formula
(I"'), which is a subgroup of the compounds of formula (I) that are subjects of the
present invention with R6 ?H and as defined above and A representing -CH=. It is
understood that, in the process described in Scheme 2, the groups R1, R2, R3, R4, R5
or R6 may comprise one or more temporary protecting groups.
In Schemes 1 and 2, the starting compounds and the reagents, when their
preparation method is not described, are commercially available or described in the
literature, or else may be prepared according to methods that are described therein
or that are known to those skilled in the art.
According to another of its aspects, a subject of the invention is also the
compounds of formulae (VII), (VIII), (IX) and (XV) with R6 not being a hydrogen atom,
the said compounds being defined in the synthetic Schemes 1 and 2. These
compounds are useful as synthetic intermediates for the compounds of formula (I).
The examples that follow describe the preparation of certain compounds in
accordance with the invention. These examples are not limiting, and serve merely to
illustrate the present invention. The numbers of the compounds presented as
examples refer to those given in the table hereinbelow, which illustrates the chemical
structures and physical properties of a number of compounds according to the
invention.
The following abbreviations and empirical formulae are used:
CH2CI2 dichloromethane
HPLC high-performance liquid chromatography
LC/MS liquid chromatography/mass spectrometry
d doublet
DMF dimethylformamide
DMSO dimethyl sulfoxide
dppf diphenylphosphinoferrocene
Et3N triethylamine
h hour(s)
HCI hydrochloric acid
MHz MegaHertz
m multiplet or unresolved complex
min minute(s)
MeOH methanol
MgSO4 magnesium sulfate
NaCI sodium chloride
NaHCO3 sodium hydrogen carbonate
NaOH sodium hydroxide
Na2SO4 sodium sulfate
NH4CI ammonium chloride
NH4OH ammonium hydroxide
NMP N-methylpyrrolidinone
ppm parts per million
s singlet
t triplet
THF tetrahydrofuran
Example 1: 7-Amino-8-ethyl-2-[(4-hydroxyphenyl)amino]-5-oxo-5,8-dihydro-
pyrido[2,3-d]pyrimidine-6-carboxamide
1.1: Ethyl 4-ethylamino-2-methylthiO'5-pyrimidinecarboxylate
To a solution of 15.0 g (64.0 mmol) of ethyl 4-chloro-2-methylthio-5-
pyrimidinecarboxylate and 195 ml_ (1.39 mol) of triethylamine in 226 ml_ of THF are
added 14.6 mL of aqueous 70% ethylamine solution. The mixture is stirred at room
temperature for 2 hours. After diluting in water, the resulting mixture is extracted with
ethyl acetate and the organic phase is dried over MgS04. The product is purified by
chromatography on silica gel, eluting with a cyclohexane/EtOAc mixture (8/15).
13.7 g of expected product are obtained in the form of a colourless oil. Yield = 89%.
1.2: 4-Ethylamino-2-methylthio 5-pyrimidinecarboxylic acid
A mixture containing 6.33 g (26.0 mmol) of ethyl 4-ethylamino-2-methylthio-5-
pyrimidinecarboxylate, 65 mL (65.0 mmol) of 1N NaOH and 60 mL of ethanol is
refluxed for 1 hour. The ethanol is evaporated off under reduced pressure and the
residue is diluted in 100 mL of water. 65 mL of aqueous 1N HCI solution are added
and the white precipitate formed is drained by suction. The solid is rinsed with water
and dried under vacuum. 5.1 g of expected product are obtained in the form of a
white solid. Melting point = 188°C. Yield = 92%.
1.3:4-Ethylamino-2-methylthio-5-pyrimidinecarboxylic acid fluoride
To a solution containing 3.0 g (14.0 mmol) of 4-ethylamino-2-methylthio-5-
pyrimidinecarboxylic acid and 2.1 mL (15.0 mmol) of triethylamine in 50 mL of
CH2CI2 are added 2.3 mL (28.0 mmol) of cyanuric fluoride. The mixture is stirred for
3 hours and the solution is diluted with 250 mL of CH2CI2 and 75 mL of ice-cold
water. After separation of the phases by settling, the organic phase is washed with
75 mL of ice-cold water and dried over MgSO4. The solvent is then evaporated off
under reduced pressure. 3.0 g of expected product are obtained in the form of a
greenish gum. The yield is quantitative.
1.4: 7-AminO'8-ethyl-2-(methylthio)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-
carboxamide
To a solution of 1.18 g (14.0 mmol) of cyanoacetamide in 20 mL of anhydrous DMF,
cooled to 0-5°C, are added 1.12 g (28 mmol) of 60% NaH. After the addition, the
mixture is stirred for 10 minutes at room temperature and then cooled again in an
ice-water bath, and the solution of the acid fluoride (14.0 mmol) prepared in step 1.3
in 30 mL of anhydrous DMF is added. The reaction mixture is stirred at room
temperature for 30 minutes, and 0.56 g (14.0 mmol) of 60% NaH is added. The
mixture is stirred for 1 hour at room temperature, and 100 ml_ of water are then
added. The precipitate is separated out by filtration, rinsed with water, drained by
suction and then dried in an oven. 2.85 g of the expected product are obtained in the
form of a yellow solid. Yield = 73%.
1.5: 7-Amino-8-ethyl-2-(methylsulfonyl)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6~carboxamide
To a solution of 0.60 g (2.15 mmol) of the compound obtained in step 1.4 in 20 mL of
N-methylpyrrolidinone are added 1.08 g (4.83 mmol) of mefa-chloroperbenzoic acid.
The mixture is stirred at room temperature for 24 hours and then evaporated to
dryness. The solid residue is taken up in aqueous NaHC03 solution and then filtered
off. The solid is drained by suction and then dried in an oven. 0.4 g of the expected
product is obtained in the form of a pale yellow solid. Yield = 60%.
1.6: 7-Amino-8-ethyl-2-[(4-hydroxyphenyl)amino]-5-oxo-5,8-dihydropyrido-
[2,3-d]pyrimidine-6-carboxamide
To a solution of 0.40 g (1.29 mmol) of the product obtained in step 1.5 in 4 mL of
anhydrous DMSO is added 0.160 g (1.47 mmol) of 4-aminophenol. The reaction
mixture is heated at 110°C overnight and then evaporated to dryness. The solid
residue is purified by chromatography on silica gel, eluting with a
dichlorornethane/methanol gradient (100/0 to 90/10). 0.090 g of the expected
product is obtained in the form of an off-white solid. Yield = 20%. m.p. > 260°C.
M+H+=341.
1H NMR (DMSO-d6; 400 MHz): d 11.70 (broad s, 1H); 9.85 (s, 1H); 8.89 (s, 1H); 7.95
(broad s, 1H); 7.48 (d, 2H); 7.72 (d, 2H); 4.29 (q, 2H); 1.20 (t, 3H).
Example 2: 7-Amino-8-ethvl-2-r4-(4-methvlpiperazine-1 -carbonyl)phenvlaminol-
5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
2.1 (4-Methylpiperazin-1-yl)(4-nitrophenyl)methanone
A mixture of 2.0 g of 4-nitrobenzoic acid (11.97 mmol), 10.42 mL of
diisopropylethylamine (59.84 mmol) and 1.46 mL of 1-methylpiperazine
(13.16 mmol) in 40 mL of DMF is cooled to 2-5°C on an ice bath. 11.53 g
(35.9 mmol) of O-benzotriazolyltetramethylisouronium tetrafluoroborate (TBTU,
CAS No. = 125700-67-6) are then added portionwise and the mixture is stirred at
temperature overnight. The reaction mixture is diluted with dichloromethane and
saturated aqueous NaCI solution. After separation of the phases by settling, the
aqueous phase is extracted with dichloromethane. The organic phases are
combined, dried over Na2SO4, filtered and concentrated under vacuum. The oily
residue containing insoluble material is drained by suction and then rinsed with
dichloromethane and a small amount of methanol. 1.67 g of the expected product
are obtained in the form of a pale pink solid, which is used as obtained without
further purification. Yield = 56%.
2.2: (4-Aminophenyl)(4-methylpiperazin-1-yl)methanone
To 1.67 g (6.70 mmol) of the product prepared in step 2.1 partially dissolved in
50 mL of methanol are added, under an inert atmosphere, 71 mg of 10% palladium-
on-charcoal. The reaction mixture is stirred at room temperature under 3 bar of
hydrogen for 2 hours 30 minutes and then filtered through Celite. After evaporating
to dryness, 1.5 g of the expected product are obtained in the form of an orange oil,
which is used as obtained in the following step. Quantitative yield.
2.3: 2,4-Dichloro-5-pyrimidinecarboxylic acid
- Method A:
To 10.0 g (64.06 mmol) of uracil-5-carboxylic acid (Aldrich Chemical Company)
partially dissolved in 20 mL of DMF are added, under cold conditions, 59.7 mL
(0.64 mol) of phosphorus oxychloride and 10.3 mL (64.7 mmol) of N,N-diethylaniline,
and the mixture is then heated at 90°C for 2 hours 40 minutes. After cooling to room
temperature and evaporating off half the excess POCI3, the medium is poured onto
ice and then extracted with ether. The ether phases are combined, dried over
sodium sulfate, filtered and concentrated under vacuum. 8.1 g (41.97 mmol) of 2,4-
dichloro-5-pyrimidinecarboxylic acid are obtained in a yield of 65%.
- Method B:
To a solution of 9 g (42.8 mmol) of 2,4-dichloro-5-pyrimidinecarboxylic acid chloride
(Manchester Organics Limited) in 60 mL of ether are added 10 mL of water and the
reaction mixture is stirred vigorously at 35°C for 1 hour. After addition of ether and
separation of the phases by settling, the organic phase is dried over Na2SO4, filtered
and concentrated under vacuum. 7.7 g of a colourless oil that solidifies rapidly in air,
and which is used immediately in the following step, are obtained. Yield = 93%.
2.4:2-Chloro-4-(ethylamino)pyrimidinecarboxylic acid
8.1 g (41.97 mmol) of 2,4-dichloro-5-pyrimidinecarboxylic acid are dissolved in
84 mL of THF in the presence of 81.3 mL (0.923 mol) of triethylamine. 3.4 ml_ of
aqueous 70% ethylamine (41.97 mmol) are added and the mixture is stirred at room
temperature for 1 hour 45 minutes. After evaporating off the solvents, the residue is
taken up in water and aqueous 1N HCI solution is added slowly to pH 2. The
precipitate is isolated by filtration, washed with water and then with an ether/pentane
mixture, and dried under vacuum. 7.2 g of a solid very predominantly containing 2-
chloro-4-(ethylamino)pyrimidinecarboxylic acid are obtained and are used as
obtained in the following step.
2.5: 2-Chloro-4-(ethylamino)pyrimidinecarboxylic acid fluoride
To a solution containing 7.0 g (34.72 mmol) of acid prepared in step 2.4 and 5.32 mL
(38.19 mmol) of triethylamine in 98 mL of dichloromethane are added 5.89 mL
(69.79 mmol) of cyanuric fluoride. The mixture is stirred for 3 hours and the solution
is diluted with 590 mL of CH2CI2 and 190 mL of ice-cold aqueous NaHCO3. The
organic phase is washed twice with 190 mL of ice-cold aqueous NaHCO3 and dried
over MgSO4. The solvent is then evaporated off under reduced pressure. 7.0 g of
expected product are obtained in the form of a red oil that solidifies slowly, and that
is used as obtained in the following step. Quantitative yield.
2.6: 7-Amino-2-chloro-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-
carboxamide
To a solution, cooled to 2-5°C on an ice bath, of 6.29 g (74.78 mmol) of
cyanoacetamide in 140 mL of anhydrous DMF are added portionwise 5.98 g
(149.55 mmol) of 60% sodium hydride. The mixture is stirred for 15 minutes at 2-5°C
and this suspension is then added rapidly to the solution of 14.5 g (71.22 mmol) of
the acid fluoride prepared in step 2.5 in 155 mL of anhydrous DMF, precooled to 2-
5°C on an ice bath. The mixture is stirred overnight at room temperature and then
cooled to 2-5°C, and 2.99 g (74.78 mmol) of 60% sodium hydride are added
portionwise. The medium is stirred for 4 hours at room temperature, ice is then
added slowly to destroy the excess hydride, and the reaction medium is poured into
an ice-water mixture. The resulting mixture is acidified by adding aqueous 0.1 N HCI
solution. The precipitate formed is isolated by filtration, rinsed with water and then
dried in an oven, followed by rinsing with pentane. 14.0 g of expected product are
finally obtained in the form of a pale orange solid. Yield = 73.4%.
2.7: 7-Amino-8-ethyf-2-[4-(4-methylpiperazine-1-carbonyl)phenylamino]-5-
oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
A mixture of 0.3 g (1.12 mmol) of the product prepared in step 2.6 and 491 mg
(2.24 mmol) of the product prepared in step 2.2 in 6 mL of NMP is placed in a 10 mL
microwave tube. The sealed tube is placed in a microwave oven (CEM machine,
Discover model) and the mixture is heated under pressure at 120°C for 60 minutes
at a power of 75 W, and then cooled to room temperature. 15 mL of water and then
5 mL of saturated aqueous NaHCO3 are added and the precipitate formed is drained
by suction and then dried in an oven. The crude solid is purified by chromatography
on a column of silica, eluting with a dichloromethane/methanol gradient (100/0 to
90/10). 0.055 g of the expected product is obtained in the form of an orange powder,
m.p. = 281°C.%. M+H+ = 451. Yield = 11%.
1H NMR (DMSO-d6, 400 MHz): d 11.8 (broad s, 1H); 10.3 (s, 1H); 10.2 (d, 1H); 9.0
(s, 1H); 8.0 (broad s, 1H); 7.8 (d, 2H); 7.40 (d, 2H); 7.2 (d, 1H); 4.4 (q, 2H); 3.5 (m,
4H); 3.30 (s, 3H); 2.30 (m, 4H); 1.3 (t, 3H).
Example 3: 7-Amino-8-cyclopentyl-2-(4-morpholin-4-ylphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
3.1: 2-Chloro-4-(cyclopentylamino)pyrimidinecarboxylic acid
A suspension of 10 g (51.82 mmol) of 2,4-dichloro-5-pyrimidinecarboxylic acid in
100 mL of THF is cooled on an ice bath to 2-5°C, and a solution of 5.12 mL
(51.82 mmol) of cyclopentylamine and 21.67 mL (155.45 mmol) of triethylamine in
40 mL of THF is added dropwise. The mixture is stirred at room temperature for
2 hours. The THF is evaporated off and the residue is then diluted with water. The
resulting mixture is acidified with aqueous 1N HCI solution to pH 2 and then
extracted twice with dichloromethane. The organic phases are combined, dried over
Na2SO4, filtered and concentrated under vacuum. The solid recovered is triturated in
ether, drained by suction and dried in an oven. 5.28 g of the expected product are
obtained in the form of a beige-coloured solid, which is used as obtained in the
following step. Yield = 42%.
3.2: 2-Chloro-4-(cyclopentylamino)pyrimidinecarboxylic acid fluoride
To a suspension of 5.24 {21.68 mmol) of the product prepared in step 3.1 in 140 ml_
of dichloromethane are added 3.02 ml_ (21.68 mmol) of triethylamine and then
2.75 ml_ (35.52 mmol) of cyanuric fluoride. The mixture is stirred at room
temperature for 4 hours and the solution is diluted with 150 ml_ of dichloromethane.
The organic phase is washed three times with 200 ml_ of ice-cold aqueous NaHCO3,
dried over MgSO4, filtered and concentrated under vacuum. 5.2 g of the expected
product are obtained in the form of an orange solid. Yield = 98%.
3.3: 7-Amino-2-chloro-8-cyclopentyl-5-oxo-5,8-dihydropyrido[2,3-d]pyri-
midine-6-carboxamide
To a solution, cooled to 2-5°C on an ice bath, of 1.88 g (22.41 mmol) of
cyanoacetamide in 20 ml_ of anhydrous DMF are added portionwise 1.8 g
(44.82 mmol) of 60% sodium hydride. The mixture is stirred for 15 minutes at 2-5°C,
and this suspension is then added rapidly to a solution of 5.2 g (21.34 mmol) of the
acid fluoride prepared in step 3.2 in 20 ml_ of anhydrous DMF precooled to 2-5°C.
The mixture is stirred overnight at room temperature and then cooled to 2-5°C on an
ice bath, and 0.90 g (22.41 mmol) of 60% sodium hydride is added portionwise. The
reaction mixture is stirred for 3 hours at room temperature and then poured into a
mixture of ice, 100 ml_ of water and 150 ml_ of aqueous 1N HCI. The yellow
precipitate formed is isolated by filtration, rinsed with water and then dried in an
oven, after which it is rinsed with pentane. 5.4 g of a mixture containing the expected
cyclized product and the non-cyclized product are finally obtained in the form of an
orange powder. The mixture is purified by chromatography on a column of silica,
eluting with a dichloromethane/methanol gradient (99/1 to 96/4). 0.6 g of the
expected product is finally obtained in the form of a pale yellow solid. Yield = 9%.
3.4: 7-Amino-8-cyclopentyl-2-(4-morpholin~4-ylphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
A mixture of 184 mg (0.60 mmol) of the product prepared in step 3.3 and 0.266 g
(1.49 mmol) of N-(4-aminophenyl)morpholine (Lancaster) in 6 mL of NMP is placed
in a 10 mL microwave tube. The sealed tube is placed in the microwave oven (CEM
machine, Discover model) and the mixture is heated under pressure at 90°C for 1
hour at a power of 100 W and then cooled to room temperature. 20 mL of water and
then 5 mL of saturated aqueous NaHCO3 are added and the precipitate formed is
drained by suction and dried in an oven. The crude solid is purified by
chromatography on a column of silica, eluting with a dichloromethane/methanof
gradient (98/2 to 95/5). 0.065 g of the expected product is obtained in the form of a
beige-cofoured powder. Yield = 24%. m.p. = 265°C. M+H+ = 450.
1H NMR (DMSO-d6, 400 MHz): d 11.5-12.5 (very broad s, 1H); 10.4 (d, 1H); 9.6 (s,
1H); 8.9 (s, 1H); 7.4 (d, 2H); 7.1 (d, 1H); 6.9 (d, 2H), 5.0 (m, 1H); 3.7 (m, 4H); 3.0 (m,
4H); 2.2-2.5 (m, 2H); 1.3-1.9 (m, 6H)
Example 4: 7-Amino-8-ethyl-2-(2-methoxy-4-piperid-4-ylphenylamino)-5-oxo-
5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
4.1:4-Bromo-2-methoxy-1-nitrobenzene
18.4 g (83.64 mmol) of 2-fluoro-4-bromonitrobenzene (Aldrich) are almost fully
dissolved in 300 mL of anhydrous methanol. 19.9 mL (106.22 mmol) of a 30%
solution of sodium methoxide in methanol are added dropwise and the mixture is
stirred overnight at room temperature. The methanol is evaporated off under reduced
pressure, the medium is taken up in ethyl acetate and water, and the aqueous phase
is then acidified by adding aqueous 1N HCI. After separation of the phases by
settling, the organic phase is washed with saturated aqueous NaCI, dried over
Na2SO4, filtered and concentrated under vacuum. 17.4 g of the expected product are
obtained in the form of a yellow solid. Yield = 89.7%.
4.2: tert-Butyl 4-(3-methoxy-4-nitrophenyl)-3,6-dihydro-2H-pyridine-1-
carboxylate
Argon is bubbled for 10 minutes into a mixture of 4.64 g (20.0 mmol) of the product
prepared in step 4.1, 6.25 g (20.2 mmol) of 3,6-dihydro-2H-pyridine-1-N-Boc-4-
boronic acid pinacol ester (Frontier Scientific) and 8.29 g (60.0 mmol) of potassium
carbonate in 125 mL of anhydrous DMF. 0.98 g (1.2 mmol) of PdCI2dppf-CH2CI2 is
added and the mixture is heated under argon at 90°C for 3 hours. The resulting
mixture is diluted with ethyl acetate and washed twice with water and once with
saturated aqueous NaCI. The organic phase is dried over Na2SO4, filtered and
concentrated under vacuum. The crude solid obtained is purified by chromatography
on a column of silica, eluting with a cyclohexane/ethyl acetate gradient (75/25 to
70/30). 6.02 g of a pale yellow solid are obtained, and are triturated in cyclohexane
and then drained by suction and dried in an oven. 5.89 g of the expected product are
finally recovered in the form of a white solid. Yield = 88%.
4.3: tert-Butyl 4-(4-amino-3-methoxyphenyl)piperidine- 1-carboxylate
4.27 g (12.77 mmol) of the product prepared in step 4.2 in 130 ml_ of an ethyl
acetate/ethanol mixture (v/v = 1/1) are placed in a hydrogenation autoclave, and
0.54 g of 10% palladium-on-charcoal is added, under an inert atmosphere. The
mixture is stirred under a hydrogen pressure of 3 bar at room temperature. After
filtration through thin glass fibre paper and evaporation under reduced pressure,
3.87 g of the expected product are obtained in the form of a pink solid, which is used
as obtained in the following step. Yield = 99%.
4.4: tert-Butyl 4-[4-(7-amino-6-carbamoyl-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidin-2-ylamino)-3-methoxyphenyl]piperidine-1-carboxylate
A mixture of 0.45 g (1.63 mmol) of the product prepared in step 2.6 and 1.00 g
(3.25 mmol) of the product prepared in step 4.3 in 3 ml_ of NMP is placed in a round-
bottomed flask. The suspension is heated at 110°C for 3 hours. 30 mL of water and
then 5 mL of saturated aqueous NaHCO3 are added and the precipitate formed is
drained by suction and then dried in an oven. The crude solid is purified by
chromatography on a column of silica, eluting with a dichloromethane/methanol
gradient (100/0 to 93/7). 0.52 g of the expected product is obtained in the form of a
beige-coloured powder. Yield = 59.5%.
4.5: 7-Amino-8-ethyl-2-(2-methoxy-4-piperid-4-ylphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
0.51 g (0.95 mmol) of the product prepared in step 4.4 is suspended in 10 mL of a
dichloromethane/methanol mixture (v/v = 8/2), and 3.55 mL (14.20 mmol) of a 4N
solution of hydrogen chloride in dioxane are added. The mixture is stirred at room
temperature overnight, and ether is added. The solid is drained by suction, rinsed
with pentane and dried in an oven. 0.48 g the expected product is obtained in the
form of a beige-coloured solid, which is used as obtained in the following step. Yield
(dihydrochloride) = 99.1%. m.p. = 117°C. M+H+= 408.
1HNMR(DMSO-d6; 400 MHz): d 11.8 (broads, 1H); 10, 4 (very broad s, <1H); 10.2
(s, 1H); 9.0 (s, 1H); 8.9 (broad s, 1H); 8.1 (broad s, 1H); 7.8 (d, 1H); 7.2 (d, 1H); 4.3
(q, 2H); 3.4 (m, 2H), 3.0 (m, 2H); 2.8 (m, 1H); 1.9 (m, 4H); 1.3 (t, 3H).
Example 5: 7-Amino-8-ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-
yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-N-methylcarbox-
amide hydrochloride
5.1: 7-Amino-8-ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]-
phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-N-methylcarboxamide
0.47 g (0.92 mmol) of the hydrochloride prepared in step 4.5 is suspended in 7.8 mL
of a dichloromethane/glacial acetic acid mixture (v/v = 5/1) and sodium 3,3,3-
trifluoropropionaldehyde (Alfa Aesar) and then sodium triacetoxyborohydride are
added portionwise. The reaction mixture is stirred for 2.5 hours and then poured into
50 mL of aqueous NaHCO3. A solid is isolated by filtration, and is purified by
chromatography on a column of silica, eluting with a dichloromethane/methanof
gradient (100/0 to 90/10). After triturating in ether, 0.25 g of the expected product is
finally obtained in the form of a beige-coloured solid. Yield = 50.9%.
5.2: 7-Amino-8-ethyl'2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid'4-yl]-
phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-N-methylcarboxamide
hydrochloride
0.19 g (0.36 mmol) of the product prepared in step 4.6 is dissolved in 4 mL of a
dichloromethane/methanol mixture (v/v = 4/1), and 1.09 mL (109 mmol) of 1.0 M
hydrogen chloride in ether are added. The suspension is stirred for 5 minutes and
then diluted with ether, and the precipitate is drained by suction, rinsed with ether
and with pentane, and dried under vacuum. 0.22 g of the expected product is
obtained in the form of an ochre-coloured powder. Yield (dihydrochloride) = 96.5%.
m.p. = 199°C. M+H+=534.
1H NMR (DMSO-d6; 400 MHz): d 11.8 (broad s, 1H); 11.2 (very broad s, <1H); 10.3
(broad s, 1H); 9.0 (s, 1H); 8.8 (s, 1H); 8.1 (broad s, 1H); 7.9 (d, 1H); 7.2 (very broad
s, <1H); 7.0 (s, 1H); 6.9 (d, 1H); 4.3 (q, 2H); 3.9 (s, 3H); 3.6 (m, 2H), 3.4 (m, 2H);
3.0-3.2 (m, 2H); 2.9 (m, 1H); 2.0 (m, 4H); 1.3 (t, 3H).
Example 6: 7-Amino-2-f4-(1-cvclopropylpiperid-4-vl)-2-methoxvphenvlamino1-8-
ethyl -5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
6.1: 7-Amino-2-[4-(1-cyclopropylpiperid-4-yl)-2-methoxyphenylamino]-8-ethyl-
5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
The hydrochloride prepared in step 4.5 is converted into the base form by treatment
with aqueous 1N NaOH followed by filtration and drying in an oven. 0.44 g
(1.0 mmol) of this product is suspended in 10 mL of anhydrous methanol. 0.57 mL
(10.0 mmol) of glacial acetic acid, 3 A molecular sieves predried under vacuum,
0.9 mL (4.5 mmol) of (l-ethoxycyclopropoxy)trimethylsilane and 0.188 g (3.0 mmol)
of sodium cyanoborohydride are added. The mixture is heated for 1 hour at 80°C,
and 2 mL of tetrahydrofuran and a further 0.45 mL (2.25 mmol) of (1-
ethoxycyclopropoxy)trimethylsilane are added. The reaction mixture is heated for
20 hours at 80°C and is then allowed to cool to room temperature and evaporated to
dryness. The residue obtained is purified by chromatography on a column of silica,
eluting with a dichloromethane/methanol gradient (96/4 to 90/10). After triturating in
an ether/isopropanol mixture (v/v ~ 3/1) and then in ethyl acetate/isopropanol,
0,126 g of the expected product is finally obtained in the form of a white solid. Yield =
26%.
6.2: 7-Amino-2-[4-(1-cyclopropylpiperid-4-yl)-2-methoxyphenylamino]-8-ethyl-
5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
To a suspension of 0.126 g (0.26 mmol) of the product prepared in step 7.1 in
2.6 mL of methanol is added 0.79 mL (0.79 mmol) of 1.0 M hydrochloric ether. The
mixture is stirred for 5 minutes at room temperature and then diluted with ether. The
precipitate is drained by suction, rinsed with ether and with pentane, and dried under
vacuum. 0.133 g of the expected product is obtained in the form of a beige-coloured
solid. Yield (dihydrochloride) = 92%. m.p. = 226-228°C. M+H+= 478.
1H NMR (DMSO-de, 400 MHz): d 11.8 (broad s, 1H); 10.6 (broad s, -0.5H); 10.4
(broad s, -1.5H); 9.0 (s, 1H); 8.8 (s, 1H); 8.1 (broad s, 1H); 7.9 (d, 1H); 7.2 (very
broad s, <1H); 7.0 (s, 1H); 6.9 (d, 1H); 4.3 (q, 2H); 3.9 (S, 3H); 3.6 (m, 2H); 2.8-3.4
(m, 4H); 2.0-2.2 (m, 2H); 1.30 (t, 3H); 1.20 (m, 2H); 0.80 (m; 2H)
Example 7: 7-Amino-8-ethyl-2-(3-morpholin-4-ylphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
A mixture of 0.25 g (0.93 mmol) of the product prepared in step 2.6 and 0.33 g
(1.87 mmol) of 3-morpholin-4-ylphenylamine in 4 ml_ of NMP is placed in a 10 mL
microwave tube. The sealed tube is placed in the microwave oven (CEM machine,
Discover model) and the mixture is heated under pressure at 90°C for 30 minutes at
120°C, for 1 hour at a power of 100 W, and is then cooled to room temperature.
20 mL of water and then 5 mL of saturated aqueous NaHCO3 are added and the
precipitate formed is drained by suction and then dried in an oven. The crude solid is
triturated in methanol, drained by suction, rinsed with ether and with pentane, and
dried under vacuum. 0.16 g of the expected product is finally obtained in the form of
a beige-coloured powder. Yield = 41.8%. m.p. = 195°C. M+H+= 410.
1HNMR(DMSO-d6, 400 MHz): d 11.8 (broads, 1H); 10.3 (d, 1H); 10.0 (broads, 1H);
8.9 (s, 1H); 8.0 (very broad s, < 1H); 7.3 (m, 2H); 7.1-7.3 (m, 3H); 6.6 (d, 1H), 4.4 (q,
2H); 3.7 (m, 4H); 3.1 (m, 4H); 1.2 (t, 3H)
Example 8: 2-[4-(4-Acetylpiperazin-1-yl)phenylamino]-7-amino-8-ethyl-5-oxo-
5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
8.1: 1-[4-(4-Nitrophenyl)piperazin-1-yl]ethanone
A solution of 5.0 g (35.44 mmol) of 1-fluoro-4-nitrobenzene and 4.99 g (38.98 mmol)
of N-acetylpiperazine in 50 mL of acetonitrile is heated at 60°C for 15 hours. The
resulting mixture is diluted with water and with ethyl acetate. After separation of the
phases by settling and extraction of the aqueous phase with ethyl acetate, the
organic phases are combined, dried over Na2SO4, filtered and concentrated under
vacuum. 7.7 g of the expected product are obtained in the form of a yellow solid,
which is used as obtained in the following step. Yield = 88.8%.
8.2: 1-[4-(4-Aminophenyl)piperazin- 1-yl]ethanone
3.0 g (12.04 mmol) of the product prepared in step 8.1 in 40 mL of ethyl acetate are
placed in a hydrogenation autoclave, and 0.15 g of 10% palladium-on-charcoal are
added, under an inert atmosphere. The mixture is stirred at a hydrogen pressure of
5 bar at room temperature. After filtering through Celite and evaporating under
reduced pressure, 1.6 g of the expected product are obtained in the form of a beige-
coloured solid, which is used as obtained in the following step. Yield = 61%.
8.3: 2-[4-(4-AcetyIpiperazin-1-yl)phenylamino]-7-amino-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6~carboxamide
A mixture of 0.30 g (1.12 mmol) of the product prepared in step 2.6 and 0.49 g
(2.24 mmol) of the product prepared in step 8.2 in 5 mL of NMP is placed in a 10 mL
microwave tube. The sealed tube is placed in a microwave oven (CEM machine,
Discover model) and the mixture is heated under pressure at 90°C for 30 minutes at
a power of 100 W, and then cooled to room temperature. 20 mL of water and then
5 mL of saturated aqueous NaHCO3 are added, and the precipitate formed is drained
by suction and then dried in an oven. The crude solid is triturated in methanol,
drained by suction, rinsed with ether and with pentane, and dried under vacuum.
0.30 g of the expected product is finally obtained in the form of a beige-coloured
powder. Yield = 60%. m.p. = 179X. M+H+= 548.
1H NMR (DMSO-de, 400 MHz): d 11.7 (very broad s, <1H); 10.4 (d, 1H), 9.9 (s, 1H);
8.9 (s, 1H); 8.0 (very broad s, <1H); 7.6 (d, 2H); 7.1 (d, 1H); 6.9 (d, 2H); 4.4 (q, 2H);
3.6 (m, 4H); 3.1 (m, 4H); 2.0 (s, 3H); 1.3 (t, 3H)
Example 9: 7-Amino-2-[4-(cyclopropanecarbonylmethylamino)phenylamino)-8-
ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
9.1: Methyl-(4-nitrophenyl)cyclopropanecarboxamide
To a solution of 2.0 g (13.14 mmol) of /V-methyl-4-nitroaniline (Aldrich) and 1.59 mL
(19.72 mmol) of pyridine in 15 mL of tetrahydrofuran are added slowly 1.43 mL
(15.77 mmol) of cyclopropanoyl chloride. The mixture is refluxed for 2 hours and
evaporated to dryness. The residue is taken up in an ethyl acetate/water mixture and
the organic phase is then dried over Na2SO4, filtered and concentrated under
vacuum. The expected product is obtained in the form of a yellow oil, which is used
as obtained in the following step.
9.2: Methyl-(4-aminophenyl) cyclopropanecarboxamide
To a suspension of 3.56 g (54.49 mmol) of zinc powder in 15 mL of concentrated
aqueous 33% NH4OH solution are added 1.2 g (5.45 mmol) of the product prepared
in step 9.1 dissolved in 15 mL of tetrahydrofuran. The mixture is stirred for 1 hour at
room temperature, the zinc is then separated out by filtration and the mixture is
extracted with ether. The organic phases are combined, dried over Na2SO4, filtered
and concentrated under vacuum. The oily residue is purified by chromatography on a
column of silica, eluting with a cyclohexane/ethyl acetate gradient (70/30 to 60/40).
3 g of the expected product are obtained in the form of a yellow oil. Quantitative
yield.
9.3: 7-Amino~2-[4-(cyclopropanecarbonylmethylamino)phenylamino]-8-ethyl-
5-0X0-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
A mixture of 0.30 g (1.12 mmol) of the product prepared in step 2.6 and 0.43 g
(2.24 mmol) of the product prepared in step 9.2 in 4.5 ml_ of NMP is heated at 90°C
for 3 hours. After addition of water, no precipitate forms. The mixture is left for
48 hours at room temperature, and the precipitate formed is drained by suction. After
triturating in dichloromethane, 0.17 g of the expected product is obtained in solid
form. m.p. = 248°C. M+H+= 422. Yield = 36%
1H NMR (DMSO-d6, 400 MHz): d 11.8 (very broad s, <1H); 10.2-10.4 (m, 2H), 9.0 (s,
1H); 8.0 (very broad s, <1H); 7.8 (d, 2H); 7.4 (d, 1H); 7.2 (d, 1H); 4.3 (q, 2H); 3.1 (s,
3H); 1.4 (m, 1H); 1.2 (t, 3H); 0.8 (m, 2H); 0.6 (m, 2H)
Example 10: 7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-fluoro-6-methoxy-
phenylamino]-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
hydrochloride
10.1: 1.5-Difluoro-3-methoxy-2-nitrobenzene
To a solution of 2.45 g (14.0 mmol) of 1,3,5-thfluoro-2-nitrobenzene in acetone are
successively added 2.9 g (21.0 mmol) of K2CO3 powder and 3.5 ml_ (56.0 mmol) of
methyl iodide. The reaction mixture is heated at 50°C for 2 hours and then filtered
and evaporated to dryness. The residue is taken up in ethyl acetate and washed with
water and with saturated aqueous NaCI solution. The organic phase is dried over
Na2SO4, filtered and concentrated under vacuum. 2.52 g of the expected product are
recovered in the form of a yellow solid, which is used as obtained in the following
step. Yield = 95%.
10.2:tert-Butyl 4-(3-fluoro-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate
To a solution of 2.48 g (13.1 mmol) of the product prepared in step 10.1 in 26 mL of
acetonitrile are added 2.43 g (13.1 mmol) of tert-butyl piperazinecarboxylate and
3.36 mL (19.65 mmol) of diisopropylethylamine. The reaction mixture is heated at
90°C for 20 hours. It is diluted with ethyl acetate and washed with water and then
with saturated aqueous NaCI solution. The crude solid is purified by chromatography
on a column of silica, eluting with a cyclohexane/ethyl acetate gradient (85/15 to
50/50). A 3.25 g fraction predominantly containing the regioisomer tert-butyl 4-(5-
fluoro-3-methoxy-2-nitrophenyl)piperazine-1-carboxylicate is isolated. An impure
secondary fraction is purified again on a column of silica, eluting with a
dichloromethane/ethyl acetate gradient (96/4 to 94/6). 0.985 g of expected product is
finally obtained in the form of a yellow solid. Yield = 21%.
10.3: tert-Butyl 4-(4-amino-3-fluoro-5-methoxyphenyl)piperazine-1-
carboxylate
0.975 g (2.74 mmol) of the product prepared in step 9.2 in 55 ml_ of an ethyl
acetate/ethanol mixture (v/v = 1/1) is placed in a hydrogenation autoclave, and
0.14 g of 10% palladium-on-charcoal is added, under an inert atmosphere. The
mixture is stirred at a hydrogen pressure of 3 bar at room temperature for 4 hours.
After filtering through thin glass fibre paper and evaporating under reduced pressure,
0.88 g of the expected product is obtained in the form of a violet solid, which is used
as obtained in the following step. Yield = 99%.
10.4: tert-Butyl 4-[4-(7-amino-6-carbamoyl-8-ethyl-5-oxo-5,8-dihydro-
pyrido[2,3-d]pyrimidin-2-ylamino)-3-fluoro-5-methoxyphenyl]piperazine-1-carboxylate
A mixture of 0.36 g (1.35 mmol) of the product prepared in step 2.6 and 0.88 g
(2.70 mmol) of the product prepared in step 10.3 in 3 ml_ of NMP is placed in a
round-bottomed flask. The suspension is heated at 100°C for 5.5 hours. 50 mL of
water and then 5 mL of saturated aqueous NaHCO3 are added and the precipitate
formed is drained by suction and dried in an oven. The crude solid is purified by
chromatography on a column of silica, eluting with a dichloromethane/methanol
gradient (100/0 to 96/4). 0.149 g of the expected product is obtained in the form of a
violet solid. Yield = 20%.
10.5: 7-Amino-8~ethyl-2-(2-fluoro~6-methoxy-4-piperazin-1-ylphenylamino)~5-
oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
0.14 g (0.23 mmol) of the product prepared in step 10.4 is suspended in 4 mL of
methanol, and 1.15 mL (4.61 mmol) of a 4N solution of hydrogen chloride in dioxane
are added. The mixture is stirred at room temperature overnight, and ether is added.
The solid is drained by suction, rinsed with pentane and dried in an oven. 0.10 g of
the expected product is obtained in the form of a grey powder, which is used as
obtained in the following step. Yield (dihydrochloride) = 95%,
10.6: 7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-fluoro-6-methoxyphenyI-
amino]~5-oxo-5,8-dihydropyrido[2,3-d]pyrirnidine~6-carboxamide
0.1 g (0.23 mmol) of the hydrochloride prepared in step 10.5 is suspended in 3 mL of
1,2-dichloroethane, and 0.13 mL (0.72 mmol) of diisopropylethylamine, 0.04 mL
(1.2 mmol) of acetaldehyde and then 0.10 g (0.48 mmol) of sodium
triacetoxyborohydride are added portionwise. The mixture is stirred for 2 hours, and
poured into 0.25 N sodium hydroxide solution, and dichloromethane is added. After
separation of the phases by settling, the aqueous phase is extracted with
dichloromethane and the organic phases are combined, dried over Na2SO4, filtered
and concentrated under vacuum. A light-brown solid is recovered, which is purified
by chromatography on a column of silica, eluting with a dichloromethane/methanol
gradient (95/5 to 90/10). 0.085 g of the expected product is obtained in the form of a
glassy yellow solid. Yield = 73%.
10.7: 7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-fluoro-6-methoxyphenyl-
amino]-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
To a solution of 0.08 g (0.18 mmol) of the product prepared in step 10.6 in 5 mL of
methanol is added 0.53 mL (0.53 mmol) of 1.0 M hydrochloric ether. The mixture is
stirred for 30 minutes at room temperature and then diluted with ether. The
precipitate is drained by suction, rinsed with ether and with pentane, and dried under
vacuum. 0.133 g of the expected product is obtained in the form of a beige-coloured
solid. Yield (dihydrochloride) = 77%. m.p. > 260°C. M+hf = 485.
1H NMR (DMSO-de, 400 MHz): d 11.8 (broad s, 1H); 11.0 (broad s, 1H), 9.1 (broad s,
1H); 8.9 (broad s, 1H); 8.0 (broad s, 1H), 6.8-7.4 (very broad s, < 1H); 6.45 (d, 1H);
6.4 (s, 1H); 3.5-4.4 (s + m, 9H); 3.0-3.3 (m, 6H); 1.3 (t, 3H); 1.0-1.3 (m, 3H)
Example 11: 7-Amino-8-(3-aminopropyl)-2-(4-morpholin-4-ylphenylamino)-5-
oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
11.1: 4-(3-tert-Butoxycarbonylaminopropylamino)-2-chloropyrimidine-5-
carboxylic acid
A solution of 2.21 g (11.45 mmot) of 2,4-dichloro-5-pyrimidinecarboxylic acid
prepared in step 2.3 (method B) in 20 mL of anhydrous THF is cooled to 2-5°C on an
ice bath. A solution of 4.79 mL (34.35 mmol) of triethylamine and 2 g (11.48 mmol) of
tert-butyl (3-aminopropyl)carbamate in 15 mL of anhydrous THF is then added
dropwise. The reaction mixture is stirred at room temperature for 30 minutes. Ethyl
acetate is added and the organic phase is washed with aqueous 1N HCI and with
water. The organic phases are combined, dried over sodium sulfate, filtered and
concentrated under vacuum. 3.35 g of the expected product are obtained in the form
of a yellow solid. Yield = 88.6%.
11.2: tert-Butyl [3-(2-chloro-5-fluorocarbonylpyrimidin-4-ylamino)propyl]-
carbamate
To a suspension of 4.91 g (14.85 mmol) of the product prepared in step 11.1 in
75 mL of dichloromethane are added 2.07 g (14.85 mmol) of triethylamine and then
1.88 mL (22.28 mmol) of cyanuric fluoride. The mixture is stirred at room
temperature for 2 hours and the solution is diluted with 100 mL of dichloromethane.
The organic phase is washed three times with 100 mL of ice-cold aqueous NaHCO3,
dried over MgSO4, filtered and concentrated under vacuum. 4.56 g of the expected
product are obtained, and are used directly in the following step. Yield = 98%.
11.3: tert-Butyl [3-(7-amino-6-carbamoyl-2-chloro-5-oxo-5H-pyrido[2,3-
d]pyrimidin-8-yl)propyl]carbamate
To a solution, cooled to 2-5°C on an ice bath, of 1.21 g (14.39 mmol) of
cyanoacetamide in 20 mL of anhydrous DMF are added portionwise 1.73 g
(43.17 mmol) of 60% sodium hydride. The mixture is stirred for 15 minutes at 2-5°C,
and this suspension is then added rapidly to the solution of 4.56 g (13.70 mmol) of
the acid fluoride prepared in step 11.2 in 30 mL of anhydrous DMF, precooled to 2-
5°C on an ice bath. The mixture is stirred overnight at room temperature and then
cooled to 2-5°C, and a further 0.22 g of 60% sodium hydride is added. The medium
is stirred overnight at room temperature, and ice is then added slowly to destroy the
excess hydride, and the reaction mixture is poured into an ice-water mixture. The
resulting mixture is acidified by adding aqueous 1 N HCI solution. The precipitate
formed is isolated by filtration, rinsed with water and then dried. The expected
product is obtained in the form of an orange solid, which is used as obtained in the
following step. Yield = 64%.
11.4: tert-Butyl {3-[7-amino-6-carbamoyl-2-(4-morpholin-4-yfphenylamino)-5-
oxo-5H-pyrido[2,3-dpyrimidin~8-yl]propyl}carbamate
A mixture of 0.60 g (1.51 mmol) of the product prepared in step 11.3 and 0.53 g
(3.02 mmol) of 4-morpholin-4-ylphenylamine in 6.5 ml_ of NMP is placed in a 10 mL
microwave tube. The sealed tube is placed in the microwave oven (CEM machine,
Discovery model) and the mixture is heated under pressure at 120°C for 60 minutes
at a power of 75 W, and then cooled to room temperature. 15 mL of water and then
5 mL of saturated aqueous NaHCO3 are added and the precipitate formed is drained
by suction and then dried in an oven. The crude solid is triturated in methanol,
drained by suction and dried in an oven under vacuum. 0.159 g of the expected
product is obtained in solid form. Yield = 20%.
11.5: 7-Amino-8-(3-aminopropyl)-2-(4-morpholin-4-ylphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
0.16 g (0.30 mmol) of the product prepared in step 11.4 is suspended in 4 mL of
anhydrous dioxane, and 0.74 mL (2.95 mmol) of a 4N solution of hydrogen chloride
in dioxane is added. The mixture is stirred at room temperature for 5 hours, and
ether is added. The solid is drained by suction, rinsed with pentane and dried in an
oven. 0.14 g of the expected product is obtained in the form of a white powder. Yield
(dihydrochloride) = quantitative, m.p. = 250°C. M+H+ = 439.
1H NMR (DMSO-d6, 400 MHz): d 11.9 (broad s, 1H); 10.2-10.4 (very broad s, <1H);
10.2 (s, 1H); 9.0 (s, 1H); 8.4 (broad s, 1H); 8.2 (d, 2H); 7.7 (d, 2H); 7.4 (broad s, 1H);
7.1-7.5 (very broad s, <1H); 4.4 (m, 2H); 3.9 (m, 4H); 3.3 (m, 4H); 2.9 (m, 2H); 2.1
(m, 2H)
Example 12: 7-Amino-8-ethyl-2-[4-(2-hydroxyethyl)phenylamino>5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
A mixture of 2.1 g (7.89 mmol) of the product prepared in step 2.6 and 2.17 g
(15.79 mmol) of 2-(4-aminophenyl)ethanol in 10 mL of NMP is heated at 100°C for
3 hours in a sealed tube. The hot reaction mixture is poured into a mixture of 125 mL
of water and 25 ml_ of saturated aqueous NaHCO3. The precipitate formed is drained
by suction, rinsed with water and then dried in an oven under vacuum. After
triturating in ether, 2.5 g of the expected product are obtained in the form of a light-
brown solid. Yield = 89.2%.
An analytically pure sample is obtained by triturating 0.2 g of the preceding solid in a
minimum amount of methanol, draining by suction, rinsing with ether and drying with
a vacuum pump. 0.15 g of the pure expected product is thus recovered in the form of
a beige-coloured powder,
m.p. = 289°C. M+H+=369.
1H NMR (DMSO-d6; 400 MHz): d 11.8 (broad s, 1H); 10.4 (d, 1H); 10.1 (broad s,
1H); 9.0 (s, 1H); 8.0 (broad s, 1H); 7.7 (d, 2H); 7.2 (d, 2H); 4.6 (t, 1H); 4.4 (m, 2H);
3.6 (m, 2H), 2.7 (m, 2H); 1.3 (t, 3H).
Example 13: 7-Amino^^thyl-5-oxo-2-[4^2-piperid-1-ylethyl)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
13.1: Ethyl 2-[4-(7'amino-6-carbamoyt-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidin-2-ylamino)phenyl]methanesulfonate
To a suspension of 1.0 g (2.71 mmol) of the product of Example 12 in 50 mL of
tetrahydrofuran cooled to 2-5°C on an ice-water bath are added 1.51 mL
(10.86 mmol) of triethylamine, followed by dropwise addition of 0.84 mL
(10.86 mmol) of methanesulfonyl chloride. The reaction mixture is heated at 50°C for
2 hours. It is poured into water and ethyl acetate is added. The organic phase is
washed with aqueous 0.5 N HCI and with saturated aqueous NaCI and then dried
over Na2SO4, filtered and concentrated under vacuum. 0.94 g of the expected
product is obtained in the form of a brown solid, in a sufficient purity to perform the
following step.
13.2: 7-Amino-8-ethyl-5-oxo-2'[4-(2-piperid-1-ylethyl)phenylamino]-5,8-
dihydropyrido[2,3~d]pyrimidine-6-carboxamide hydrochloride
1.1 g (2.46 mmol) of the product prepared in step 13.1 and 1.17 mL (11.83 mmol) of
piperidine are placed in a round-bottomed flask. The mixture is heated at 60°C for
2 hours and then concentrated. The residue is purified by chromatography on a
column of silica, eluting with a dichloromethane/methanol gradient (100/0 to 90/10).
0.12 g (0.28 mmol) of the expected product is obtained in base form, which is salified
by treating with 0.55 ml_ (0.55 mmol) of 1 M hydrochloric ether in methanol, m.p. =
216°C. M+H+=436.
1H NMR (DMSO-d6l 400 MHz): d 11.8 (broad s, 1H); 10.4 (broad s, -1H); 10.2 (s,
1H); 9.0 (s, 1H); 8.1 (broad s, 1H); 7.7 (d, 2H); 7.1-7.3 (very broad s, < 1H); 4.4 (q,
2H); 3.5 (m, 2H); 3.2 (m, 2H); 3.1 (m, 2H); 2.9 (m, 2H); 1.7-1.9 (m, 5H); 1.4 (m, 1H),
1.3 (t, 3H)
Example 14: 7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-difluoromethoxy-
phenylamino]-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
hydrochloride
14.1: 2-Difluoromethoxy-4-fluoro~1-nitrobenzene
To a solution of 3.14 g (20.0 mmol) 5-fluoro-2-nitrophenol in 36 mL of DMF are
added 6.1 g (40.0 mmol) of sodium chlorodifluoroacetate and 3.31 g (24.0 mmol) of
powdered sodium carbonate. The reaction mixture is heated at 100°C for 4 hours
30 minutes and is then allowed to cool to room temperature. Aqueous 4N HCI
solution is added and the mixture is stirred at room temperature for 2 hours. The
resulting mixture is diluted with 100 mL of water and 100 mL of ether. The aqueous
phase is extracted with ether and the organic phases are then combined, washed
with aqueous 1N NaOH solution and then with saturated aqueous NaCI, dried over
Na2SO4, filtered and concentrated under vacuum. 3.68 g of the expected product are
obtained in the form of a yellow oil, which is used as obtained in the following step.
Yield = 89%.
14.2: 1-Cyclopropyl-4-(3-difluoromethoxy-4-nitrophenyl)piperazine
To 2.07 g (10.0 mmol) of the product prepared in step 14.1 in 30 mL of acetonitrile
are added 5.99 mL (35.0 mmol) of diispropylethylamine and then 2.09 g (10.5 mmol)
of finely ground N-cyclopropylpiperazine (supplier). The reaction mixture is heated at
100°C for 1 hour 30 minutes, cooled and concentrated under vacuum. The residue is
taken up in 75 mL of ethyl acetate and washed with saturated aqueous NaHCO3
solution and with saturated aqueous NaCI solution. The organic phase is dried over
Na2SO4, filtered and concentrated under vacuum. After triturating in cyclohexane, the
solid is drained by suction and dried in an oven under vacuum. 2.33 g of the
expected product are obtained in the form of a yellow solid, which is used as
obtained in the following step. Yield = 74.5%.
14.3 4-(4-Cyclopropylpiperazin~ 1-yl)-2-difluoromethoxyphenylamine
2.32 g (7.4 mmol) of the product prepared in step 14.2 in 50 mL of an ethyl
acetate/ethanol mixture (v/v =1/1) are placed in a hydrogenation autoclave, and
0.196 g of 10% palladium-on-charcoal is added, under an inert atmosphere..The
mixture is stirred under a hydrogen pressure of 2.5 bar at room temperature for
1 hour 45 minutes. After filtering through thin glass fibre paper and evaporating
under reduced pressure, 2.09 g of the expected product are obtained in the form of a
beige-coloured solid, which is used as obtained in the following step. Quantitative
yield.
14.4: 7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-difluoromethoxyphenyl-
amino]-8~ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine~6-carboxamide
A mixture of 0.44 g (1.65 mmol) of the product prepared in step 2.6 and 0.93 g
(3.3 mmol) of the product prepared in step 14.3 in 3 mL of NMP is placed in a round-
bottomed flask. The solution is heated at 100°C for 18 hours. 50 mL of water and
then 5 mL of saturated aqueous NaHCO3 are added and the precipitate formed is
drained by suction and then dried in an oven. The crude solid is purified by
chromatography on a column of silica, eluting with a dichloromethane/methanol
gradient (100/0 to 90/10). 0.117 g of the expected product is finally obtained in the
form of a yellow solid. Yield = 12%.
14.5: 7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-difluoromethoxyphenyl-
amino]-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
hydrochloride
0.11 g (0.21 mmol) of the product prepared in step 14.4 is suspended in 3 mL of
anhydrous dioxane and 0.63 mL (0.63 mmol) of a 1M solution of hydrogen chloride
in ether is added. The mixture is diluted with ether and the solid is then drained by
suction, rinsed with pentane and dried in an oven. 0.11 g of the expected product is
obtained in the form of a yellow powder. Yield (dihydrochloride) = 87%. m.p. = 204-
206°C. M+H+=515.
1H NMR (DMSO-d6, 400 MHz): d 11.8 (broad s, 1H); 11.0 (broad s, 1H); 10.1-10.6
(very broad s, <1H); 9.2 (s, 1H); 8.9 (s, 1H); 8.0 (broad s, 1H); 7.6 (d, 2H); 7.1 (t,
1H); 7.0 (d, 1H); 6.9 (s, 1H); 4.3 (m, 2H); 3.9 (m, 2H); 3.6 (m, 2H); 3.4 (m, 2H); 3.2
(m, 2H); 3.0 (m, 1H); 1.1-1.3 (m, 5H); 0.8 (m, 2H)
Example 15: (+)-7-Amino-2-[4-(trans-2-dimethylaminocyclopropyl)phenyl-
amino]-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
hydrochloride
15.1: (±j-trans-2-(4-Nitrophenyl)cyciopropanecarboxylic acid
20.3 g (125.0 mmol) of (±)-trans-2-phenyl-cyclopropanecarboxylic acid (Aldrich) are
added portionwise to 150 ml_ of concentrated 70% nitric acid solution. The mixture is
stirred for 2 hours at room temperature, and the formation of a fine white powder in
the reaction medium is observed. The mixture is cooled to 10°C, and the solid is
drained by suction, rinsed four times with 40 mL of water and then dried in an oven.
The solid is partially dissolved in 700 mL of xylene at 160°C and is allowed to cool to
room temperature. The solid is drained by suction, rinsed with xylene and then with
pentane, and dried in an oven under vacuum. 12.6 g of an off-white solid containing
a 90/10 mixture of the expected product and of the ortho-nitro regioisomer are
obtained. The mixture is used as obtained in the following step. Yield = 48%.
15.2: tert-Butyl (±j-[trans-2-(4-nitrophenyl)cyclopropyl]carbamate
To a suspension of 12.4 g (60.0 mmol) of the mixture prepared in step 15.1 in
150 mL of tert-butanol are added 9.2 mL (66.0 mmol) of Et3N, followed by dropwise
addition of 14.2 mL (66 mmol) of diphenylphosphoryl azide. The reaction mixture is
heated at 95°C for 4 hours 30 minutes and then allowed to cool to room temperature.
The resulting mixture is diluted with 300 mL of ethyl acetate and the organic phase is
washed with 150 mL of saturated aqueous NaHCO3 and then with saturated
aqueous NaCI. After evaporation, the solid residue is taken up in 50 mL of ethyl
acetate and 100 mL of cyclohexane, and is heated until dissolution is complete. The
solution is cooled to room temperature, and the precipitate is drained by suction and
rinsed with cyclohexane and with pentane. The pink solid is almost totally dissolved
in 150 mL of CH2CI2 and then filtered through silica, eluting with CH2CI2, followed by
a dichloromethane/ethyl acetate mixture (1/4). The filtrate is evaporated to give
7.12 g of the expected product in the form of a light-brown solid. Yield = 42.5%.
15.3: tert-Butyl (±j-[trans~2-(4-aminophenyl)cyciopropyl]carbamate
1.39 g (5.0 mmol) of the product prepared in step 15.2 are dissolved in 25 mL of hot
ethyl acetate. After cooling to room temperature, 25 mL of absolute ethanol and
0.057 g (0.25 mmol) of platinum (IV) oxide are successively added. The reaction
mixture is placed under a hydrogen pressure of 2.75 bar for 2 hours, and is filtered
through thin glass fibre paper. The filtrate is concentrated under vacuum and purified
by chromatography on a column of silica, eluting with a cyclohexane/ethyl acetate
gradient (from 70/30 to 55/45). 1.05 g of the expected product are obtained. Yield =
85%.
15.4: tert-Butyi (±)-{trans-2-[4-(7-amino-6-carbamoyl-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl]cyclopropyl}carbamate
A mixture of 0.87 g (3.5 mmol) of the product prepared in step 2.6 and 0.47 g
(1.75 mmol) of the product prepared in step 15.3 in 3 mL of NMP is placed in a
round-bottomed flask. The solution is heated at 100°C for 18 hours. 50 mL of water
and then 5 mL of saturated aqueous NaHCO3 are added and the precipitate formed
is drained by suction and then dried in an oven. The crude solid is purified by
chromatography on a column of silica, eluting with a dichloromethane/methanol
gradient (98/2 to 92.5/7.5). 0.46 g of the expected product is finally obtained in the
form of an orange solid. Yield = 55%.
15,5: (±j-7-Amino-2-[4-(tran$~2-aminocyclopropyl)phenylamino]-8~ethyl-5-oxo-
5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
To a suspension of 0.46 g (0.96 mmol) of the product prepared in step 15.4 in 20 mL
of a dichloromethane/methanol mixture (1/1) are added 4.8 mL (19.2 mmol) of 4N
hydrogen chloride in dioxane. The mixture is stirred for 5 hours at room temperature
and then diluted with ether, and the solid is drained by suction, rinsed with ether and
dried in an oven under vacuum. 0.48 g of a dark violet solid is obtained, and is used
as obtained in the following step. Yield (dihydrochloride) = quantitative.
15.6: (±)J-Amino-2-[4-(trans-2-dimethylaminocyclopropyl)phenylamino]-8-
ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
To a suspension of 0.19 g (0.43 mmol) of the product prepared in step 15.5 in
5.4 mL of acetonitrile are added 0.22 mL (1.29 mmol) of diisopropylethylamine and
0.64 mL (8.58 mmol) of 70% formalin. After stirring for 3 minutes, 0.13 g (2.14 mmol)
of sodium cyanoborohydride is added and the mixture is stirred for 3 hours at room
temperature. The reaction mixture is concentrated and then taken up in 6 mL of
water and 3 mL of aqueous 35% NaOH. The solid is drained by suction and dried in
an oven under vacuum. It is purified by chromatography on a column of silica, eluting
with a dichloromethane/methanol mixture (98/2 to 85/15) containing traces of
concentrated aqueous NH4OH. 0.054 g of the expected product is obtained. Yield =
31%.
15.7: (±)J-Amino-2-[4'(trans-2-dimethylaminocyclopropyl)phenylamino]-8-
ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
To a solution of 0.05 g (0.13 mmol) of the product prepared in step 15.6 in 2.5 mL of
methanol is added 0.20 mL (0.4 mmol) of 2.0 M hydrochloric ether. The mixture is
stirred for 5 minutes at room temperature and then evaporated to dryness. The
residue is purified by preparative HPLC. The fraction corresponding to the expected
pure product is evaporated to dryness under then taken up in methanol. Ether is
added and the solid is drained by suction and dried in an oven under vacuum.
0.031 g of the expected product is obtained. Yield (dihydrochloride) = 49%. m.p. =
208-210°C (decomposition). M+H+ = 408.
1H NMR (DMSO-de, 400 MHz): d 11.8 (broad s, 1H); 10.7 (broad s, 1H); 10.1-10.4
(very broad s, <1H); 10.2 (s, 1H); 9.0 (s, 1H); 8.1 (broad s, 1H), 7.7 (d, 1H); 6.45 (d,
1H); 7.2 (d, 1H); 4.4 (m, 2H); 3.1 (m, 1H); 2.9 (d, 3H); 2.85 (d, 3H); 2.7 (m, 1H); 1.7
(m, 1H); 1,2-1.4 (m + t,4H)
Example 16: 8-Ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-
yl]phenylamino}-7-methylamino-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-
carboxamide hydrochloride
16,1:4-(3-Methoxy-4-nitrophenyl)-1,2,3,6-tetrahydropyridine hydrochloride
A solution of 10.0 g (29.91 mmol) of the product prepared in step 4.2 in 120 mL of
dichloromethane is cooled to 2-5°C on an ice-water bath, and 60 mL of a 4N solution
of HCI in dioxane (Aldrich) are then added slowly over 1 hour. The reaction mixture
is stirred at room temperature overnight. The solid formed is drained by suction,
rinsed with ether and then dried in an oven. 7.6 g of the expected product are
recovered in the form of a beige-coloured solid. Yield = 94%.
16.2: 4-(3-Methoxy-4-nitrophenyl)-1~(3,3,3-trifluoropropyl)-1,2,3,6-tetrahydro-
pyridine
A solution of 6.6 g (24.38 mmol) of the hydrochloride prepared in step 16.1 in
110 mL of dichloromethane is cooled in an ice-water bath. 14 ml_ (243.8 mmol) of
glacial acetic acid, 8.19 g (73.14 mmol) of 3,3,3-trifluoropropionaldehyde and 12.9 g
(60.95 mmol) of sodium triacetoxyborohydride are successively added portionwise.
The mixture is stirred at room temperature for 3 hours and then diluted with
dichloromethane, water and aqueous 1N NaOH solution. The aqueous phase is
extracted with dichloromethane and the organic phases are combined, dried over
Na2SO4, filtered and concentrated under vacuum. 8.4 g of a yellow oil very
predominantly containing the expected product are recovered, and are used as
obtained in the following step. Quantitative crude yield.
16.3:2-Methoxy-4-[1-(3,3,3-trifluoropropyl)piperid~4-yl]phenylamine
1.65 g (5.0 mmol) of the product prepared in step 16.2 are placed in 120 mL of an
ethanol/acetic acid mixture (v/v = 1/1) in a hydrogenation autoclave, and 0.150 g of
platinum (IV) oxide is added, under an inert atmosphere. The mixture is stirred under
a hydrogen pressure of 4 bar at room temperature for 4 hours. After filtering through
thin glass fibre paper and evaporating to dryness under reduced pressure, the oily
residue is taken up in chloroform and washed with aqueous 1N NaOH solution. The
organic phase is dried over Na2SO4, filtered and concentrated under vacuum. 1.5 g
of the expected product are obtained in the form of a brown oil, which is used as
obtained in the following step. Crude yield = quantitative.
16,4: 2-Chloro-8-ethyl-7-methylamino-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide
A suspension of 2 g (7.47 mmol) of the product prepared in step 2.6 in 40 mL of
anhydrous NMP is cooled on an ice-water bath, and 0.45 g (11.21 mmol) of 60%
sodium hydride is added in a single portion. The mixture is stirred with cooling until
the evolution of gas has ceased, and then for 10 minutes at room temperature. The
solution is cooled on an ice-water bath and a solution of 0.56 mL (8.97 mmol) of
methyl iodide in 5 mL of anhydrous NMP is added dropwise. The mixture is allowed
to warm slowly to room temperature, and is stirred for 24 hours. Ice is added, and
the reaction mixture is then poured into water. The resulting mixture is acidified to pH
1 by adding aqueous 1N HCI solution. The resulting mixture is left for 48 hours at
room temperature, and ethyl acetate is added. This mixture is stirred vigorously for
1 hour. After separation of the phases by settling, the organic phase is dried over
Na2SO4, filtered and concentrated under vacuum. The yellow solid obtained is
triturated in ether, drained by suction, rinsed with pentane and dried in an oven
under vacuum. 0.7 g of a 90/10 mixture (LC/MS) of the expected product and of the
starting material is obtained in the form of a yellow solid, which is used as obtained
in the following step.
16.5: 8-Ethyl-2-{2-methoxy-4-[1-(3,3,3-trifiuoropropyl)piperid-4-yl]phenyl-
amino}-7-methylamino~5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
To a suspension of 0.5 g (1.77 mmol) of the product prepared in step 16.4 in 5 ml_ of
anhydrous DMF are added 1.07 g (3.55 mmol) of the product prepared in step 16.3,
and the reaction mixture is heated at 100°C for 4 hours. It is evaporated to dryness
and the residue is purified by chromatography on a column of silica, eluting with a
dichloromethane/methanol gradient (100/0 to 95/5). After triturating in methanol,
0.08 g of the expected product is obtained in the form of a white solid.
16.6: 8-Ethyl-2-{2-methoxy-4-[1-(3,3,3-triftuoropropyl)piperid-4'yl]phenyl-
amino}-7-methylamino-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
hydrochloride
To a solution of 0.08 g (0.15 mmol) of the product prepared in step 16.5 in 6 mL of a
dichloromethane/methanol mixture (v/v = 1/1) is added 0.44 mL (0.44 mmol) of a 1M
solution of hydrochloric ether. The mixture is stirred for 1 hour at room temperature,
and ether is then added. The solid is drained by suction, rinsed with pentane and
dried in an oven under vacuum. 0.09 g of the expected product is finally obtained in
the form of a yellow solid. Yield (dihydrochloride) = 99%. M+H+ = 548.
1H NMR (DMSO-d6; 400 MHz): d 11.75 (broad s, 1H); 11.1 (broad s, 1H); 10.9
(broad s, 1H); 8.9 (s, 1H); 8.8 (s, 1H); 8.05 (broad s, 1H); 7.9 (d, 1H); 7.0 (s, 1H);
6.85(d, 1H); 4.3 (q, 2H); 3.85 (s, 3H); 3.65 (m, 2H), 3.35 (m, 2H); 2.9-3.2 (m, 4H); 2.8
(m, 1H); 2.75 (s, 3H), 2.0 (m, 4H); 1.2 (t, 3H).
Example 17: 7-Amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(3,3,3-
trifluoropropyl)piperid-4-yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyri-
midine-6-carboxamide hydrochloride
17.1: 2-Chforo-4-(2-hydroxy-2-methylpropylamino)pyrimidine-5-carboxylic
acid
A suspension of 19.9 g (86.73 mmol) of 2,4-dichloro-5-pyrimidinecarboxylic acid in
155 mL of THF is cooled on an ice bath to 2-5°C, and a solution of 8.5 g
(95.40 mmol) of 1-amino-2-methyl-2-propanol and 36.3 mL (260.19 mmol) of
triethylamine in 60 mL of THF is added dropwise. The mixture is stirred at room
temperature overnight. Ethyl acetate and water are added. After separation of the
phases by settling, the aqueous phase is acidified with aqueous 1N HCI solution to
pH 2. The precipitate is isolated by filtration to give 12.6 g of the expected product in
the form of a pale yellow solid, which is used as obtained in the following step. Yield
= 59%.
17.2: 2-Chloro-4-(2-hydroxy-2~methylpropylamino)pyrimidine-5-carboxylic
acid fluoride
To a solution containing 12.64 g (51.45 mmol) of the acid prepared in step 17.1 and
7.89 mL (56.60 mmol) of triethylamine in 250 mL of dichloromethane are added
6.51 mL (77.18 mmol) of cyanuric fluoride. The mixture is stirred at room
temperature overnight and the solution is diluted with 590 mL of CH2CI2 and 190 mL
of ice-cold aqueous NaHCO3. The organic phase is washed twice with 250 mL of ice-
cold aqueous NaHCO3 and dried over MgSO4. The solvent is then evaporated off
under reduced pressure. 12.3 g of the expected product are obtained in the form of a
yellow oil that solidifies slowly, and which is used as obtained in the following step.
Yield = 96%.
17.3: 7-Amino-2-chloro-8-(2-hydroxy-2-methylpropyl)-5-oxo-5,8-dihydro-
pyrido[2,3-d]pyrimidine-6-carboxamide
To a solution, cooled to 2-5°C on an ice bath, of 4,4 g (52.36 mmol) of
cyanoacetamide in 70 mL of anhydrous DMF are added portionwise 4.19 g
(104.72 mmol) of 60% sodium hydride. The mixture is stirred for 15 minutes at 2-
5°C, and this suspension is then added rapidly to a solution of 12.35 g (49.87 mmol)
of the acid fluoride prepared in step 17.2 in 70 mL of anhydrous DMF, precooled to
2-5°C. The mixture is stirred overnight at room temperature and is then cooled to 2-
5°C on an ice bath, and 2.09 g (52.36 mmol) of 60% sodium hydride are added
portionwise. The reaction mixture is stirred for 3 hours at room temperature and then
poured into a mixture of ice, 100 mL of water and 150 mL of aqueous 1N HCI. The
yellow precipitate formed is isolated by filtration, rinsed with water and then dried in
an oven. After triturating in methanol and drying in an oven, 8.84 g of the expected
product are finally obtained in the form of a yellow solid. Yield = 57%.
17.4: 7-Amino-8-(2-hydroxy-2-methylpropyi)-2-{2-methoxy-4-[1-(3,3,3-
trifluoropropyl)piperid-4-yl]pheny!amino}~5-oxo-5,8'dihydropyrido[2,3-d]pyrimidine-6-
carboxamide
To a suspension of 0.82 g (2.62 mmol) of the product prepared in step 17.3 in
6.4 mL of anhydrous NMP are added 1.59 g (5.25 mmol) of the product prepared in
step 16.3, and the reaction mixture is heated at 110°C for 1.5 hours. It is evaporated
to dryness and the residue is purified by chromatography on a column of silica,
eluting with a dichloromethane/methanol gradient (100/0 to 95/5) containing traces of
concentrated aqueous NH4OH. 0.70 g of the expected product is obtained in the
form of a white solid. Yield = 46%.
17.5: 7-Amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(3,3f3-
trifluoropropyl)piperid~4-yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]py
carboxamide hydrochloride
A solution of 0.70 g (1.22 mmol) of the product prepared in step 17.4 in 17 mL of
methanol is cooled on an ice bath, and 0.91 mL (3.65 mmol) of a 4N solution of
hydrogen chloride in dioxane is added. The mixture is stirred for 30 minutes at room
temperature and is then poured into ether. The solid is drained by suction, rinsed
with pentane and dried in an oven under vacuum. 0.64 g of the expected product is
finally obtained in the form of a white solid. Yield (dihydrochloride) = 91%. m.p.>
260°C. M+H+=578
1H NMR (DMSO-d6 + D20; 400 MHz): d.9 (s, 1H); 7.6 (d, 1H); 6.95 (s, 1H); 6.85 (d,
1H); 4.8 (very broad s, 1H); 3.8 (s, 3H); 3.6 (m, 2H), 3.4 (m, 2H); 3.1 (m, 1H); 2.8-
2.95 (m, 3H); 2.05 (m, 2H); 1.95 (m, 2H);1.1 (very broad s, 6H).
Example 18: 7-Amino-2-[4-(4-ethylpipera2in-1-yl)-2-methoxyphenylamino]-8-(2-
hydroxy-2-methylpropyl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carbox-
amide hydrochloride
18.1:1-Ethyl-4-(3-methoxy-4-nitrophenyl)piperazine
A mixture of 3.42 g (20 mmol) of 4-fluoro-2-methoxy-1-nitrobenzene, 2.67 mL
(21 mmol) of 1-ethylpiperazine and 5.14 ml_ (30 mmol) of diisopropylethylamine in
25 mL of acetonitrile is heated for 2.5 hours at 85°C and then for 1 hour at 95°C, and
is then stirred overnight while allowing to return to room temperature. The acetonitrile
is evaporated off and the residue is then taken up in 50 mL of ether and 25 mL of
water. The aqueous phase is extracted with ether. The organic phases are
combined, dried over Na2SO4, filtered and concentrated under vacuum. The oil
obtained is triturated in an ether/cyclohexane mixture (1/1) and the precipitate is
isolated by filtration, rinsed with pentane and dried in an oven. 4.1 g of the expected
product are finally obtained. Yield = 77%.
18.2:4~(4-Ethylpiperazin-1-yl)-2-methoxyphenylamine
4,05 g (15.27 mmol) of the product prepared in step 18.1 in 25 mL of an ethyl
acetate/ethanol mixture (v/v = 1/1) are placed in a hydrogenation autoclave, and
0.32 g of 10% palladium-on-charcoal is added, under an inert atmosphere. The
mixture is stirred under a hydrogen pressure of 2.5 bar at room temperature for
2 hours. After filtering through thin glass fibre paper and evaporating under reduced
pressure, 3.51 g of the expected product are obtained in the form of a violet solid,
which is used as obtained in the following step. Yield = 98%.
18.3: 7-Amino-2-[4-(4-ethylpiperazin-1 -yl)-2-methoxyphenylamino]-8-(2-
hydroxy-2-methylpropyl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
To a suspension of 1.0 g (3.21 mmol) of the product prepared in step 17.3 in 5 mL of
anhydrous NMP are added 1.51 g (6.42 mmol) of the product prepared in step 18.2,
and the reaction mixture is heated at 100°C for 2 hours. It is allowed to cool to room
temperature and is then diluted with aqueous NaHCO3 solution. The mixture is
stirred overnight and the precipitate is isolated by filtration and then dried in an oven.
The residue is purified by chromatography on a column of silica, eluting with a
dichloromethane/methanol gradient (100/0 to 95/5) containing traces of concentrated
aqueous NH4OH. After a final trituration in methanol and drying in an oven, 0.46 g of
the expected product is obtained. Yield = 28%.
18.4: 7-Amino-2-[4-(4-ethylpiperazin-1~yl)-2-methoxyphenylarninoJ-8-(2-
hydroxy-2-methylpropyl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
hydrochloride
A solution of 0.46 g (0.9 mmol) of the product prepared in step 18.3 in 13 mL of
methanol is cooled on an ice bath, and 0.67 mL (2.69 mmol) of a 4N solution of
hydrogen chloride in dioxane is added. The mixture is stirred for 30 minutes at room
temperature and is then poured into ether. The solid is drained by suction, rinsed
with pentane and dried in an oven under vacuum. 0.47 g of the expected product is
finally obtained in the form of a yellow solid. Yield (dihydrochloride) = 90%. m.p. =
222°C (decomposition). M+H+= 511.
1H NMR(DMSO-d6> 400 MHz): d 11.5 (broads, 1H); 10.9 (broads, 1H); 9.1 (broads,
1H); 8.9 (broads, 1H); 8.4 (broad s, 1H); 7.45 (d, 1H);6.75(d, lH);6.6(dd, 1H); 4.8
(very broad s, 1H); 3.70-4.20 (s + m, 9H); 3.0-3.3 (m, 6H); 1.3 (t, 3H); 1.05 (very
broad s, 6H).
Example 19: 7-Amino-2-[4-(4-ethylpiperid-1-yl)-2-methoxyphenylamino]-8-(2-
hydroxy-2-methylpropyl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-
carboxamide hydrochloride
19.1: tert-Butyl 4-[4-(7-amino-6-carbamoyl-8-(2-hydroxy-2-methylpropyl)-5-
oxo~5,8-dihydropyrido[2,3-d]pyrimidin-2-yiamino)-3-methoxyphenyl]piperidine-1-
carboxylate
A mixture of 2.0 g (6.42 mmol) of the product prepared in step 17.3 and 2.95 g
(9.62 mmol) of the product prepared in step 4.3 in 18 mL of NMP is placed in a
round-bottomed flask. The suspension is heated at 110°C for 2 hours. 30 mL of
water and then 5 mL of saturated aqueous NaHCO3 are added and the precipitate
formed is drained by suction and then dried in an oven. The crude solid is triturated
in methanol and then dried in an oven. 2.38 g of the expected product are obtained
in the form of a pink solid, which is used as obtained in the following step. Yield =
64%.
19.2: 7-Amino-8-(2-hydroxy-2-methylpropyl)-2-(2-methoxy-4-piperid-4-yl-
phenylamino)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
A suspension of 2.28 g (3.92 mmol) of the product prepared in step 19.1 in 70 ml_ of
dichloromethane is cooled on an ice-water bath, and 9.8 mL (39.20 mmol) of a 4N
solution of hydrogen chloride in dioxane are added slowly. The mixture is stirred at
room temperature for 1 hour, and ether is added. The solid is drained by suction,
rinsed with pentane and dried in an oven. 2.2 g of the expected product are obtained
in the form of a beige-coloured solid, which is used as obtained in the following step.
Yield (dihydrochloride) = quantitative.
19.3: 7'Amino-8-(2-hydroxy-2-methylpropyl)-2-[4-(4-ethylpiperJd-1-yl)-2-
methoxyphenylamino]-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
0.6 g (1.08 mmol) of the hydrochloride prepared in step 19.2 is suspended in 14 mL
of 1,2-dichloroethane, and 0.56 mL (3.25 mmol) of diisopropylethylamine, 0.30 mL
(5.41 mmol) of acetaldehyde and then, portionwise, 0.46 g (2.16 mmol) of sodium
triacetoxyborohydride are added. The mixture is stirred for 2 hours and is poured into
0.25 N sodium hydroxide solution, and dichloromethane is added. After separation of
the phases by settling, the aqueous phase is extracted with dichloromethane and the
organic phases are combined, dried over Na2SO4, filtered and concentrated under
vacuum. 0.58 g of a light-brown solid is recovered, and is purified by
chromatography on a column of silica, eluting with a dichloromethane/methanol
gradient (95/5 to 90/10). 0.26 g of the expected product is obtained in the form of a
yellow solid. Yield = 47%.
19.4: 7-Amino-8-(2-hydroxy-2-methylpropyl)-2-[4-(4-ethylpiperid~1-yl)-2-
methoxyphenylamino]-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxarnide
hydrochloride
To a solution of 0.25 g (0.50 mmol) of the product prepared in step 19.3 in 10 mL of
a dichloromethane/methanol mixture (4/1) are added 2 mL (2 mmol) of 1.0 M
hydrochloric ether. The mixture is stirred for 10 minutes at room temperature and is
then diluted with ether. The precipitate is drained by suction, rinsed with ether and
with pentane, and dried under vacuum. 0.28 g of the expected product is obtained in
the form of a yellow solid. Yield (dihydrochloride) = 96%. m.p. = 200°C
(decomposition). M+H+= 510.
1H NMR (DMSO-d6, 400 MHz): d 11.5 (broad s, 1H); 10.4 (broad s, 1H); 9.1 (s, 1H);
8.95 (s, 1H); 8.45 (broad s, 1H); 7.6 (d, 1H); 7.0 (s, 1H); 6.85 (d, 1H); 4.8 (broad s,
2H); 3.85 (s, 3H); 3.6 (m, 2H); 3.1 (m, 2H); 3.05 (m, 2H); 2.85 (m, 1H); 2.1-2.2 (m,
4H); 1.3 (t, 3H); 1.1 (very broad s, 6H).
Example 20: 7-Amino-2-(2-methoxy-4-piperid-4-ylphenylamino)-5-oxo-8-phenyl-
5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
20.1: Ethyl 2~methylsulfanyl-4-phenyiamino-5-pyrimidinecarboxylate
To a solution of 5.0 g (21.49 mmol) of ethyl 4-chloro-2-methylsulfanyl-5~
pyrimidinecarboxylate and 4.9 mL (53.72 mmol) of aniline in 75 mL of THF are
added 7.49 mL (53.72 mmol) of triethylamine. The mixture is stirred at room
temperature overnight. After evaporating off the THF, aqueous 1N HCI solution is
added and the mixture is extracted with ethyl acetate. The organic phase is washed
with saturated aqueous NaHCO3 solution and then with NaCI solution. The organic
phase is dried over MgSO4. After filtering, the filtrate is concentrated to give 3.99 g of
the expected product in the form of a beige-coloured solid, which is used as obtained
in the following step. Yield = 64%.
20.2: 2~Methylsulfanyl-4-phenylamino-5-pyrimidinecarboxylic acid
A mixture containing 3.98 g (13.75 mmol) of the product prepared in step 20.1,
34.4 mL (34.4 mmol) of 1N NaOH and 35 mL of ethanol is stirred at room
temperature overnight. The ethanol is evaporated off under reduced pressure and
the residue is diluted in 100 mL of water. 65 mL of aqueous 1N HCI solution are
added and the precipitate formed is drained by suction. The solid is rinsed with water
and dried under vacuum. 2.88 g of the expected product are obtained in the form of
a beige-coloured solid. Yield = 92%.
20.3:2-Methylsulfanyl-4'phenylamino-5-pyrimidinecarboxylic acid fluoride
To a solution containing 2.88 g (11.02 mmol) of the product prepared in step 20.2
and 2.1 mL (15.0 mmol) of triethylamine in 55 mL of CH2CI2 are added 1.40 mL
(16.53 mmol) of cyanuric fluoride. The mixture is stirred at room temperature
overnight and washed twice with 50 mL of ice-cold aqueous NaHCO3 solution. The
organic phase is washed with 75 mL of ice-cold water and dried over MgSO4. The
solvent is then evaporated off under reduced pressure. 3.0 g of the expected product
are obtained in the form of a yellow solid. The yield is quantitative.
20.4: 7-Amino-2-methylsulfanyl-5-oxo-8-phenyl-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide
To a solution of 1.0 g (11.96 mmol) of cyanoacetamide in 17 mL of anhydrous DMF,
cooled to 0-5°C, is added 0.96 g (23.93 mmol) of 60% NaH. After the addition, the
mixture is stirred for 10 minutes at room temperature and then cooled again on an
ice-water bath, and a solution of 3.0 g the acid fluoride (11.39 mmol) prepared in
step 20.3 in 17 mL of anhydrous DMF is added. The reaction mixture is stirred at
room temperature overnight. The reaction mixture is cooled on an ice-water bath,
and 0.48 g (11.96 mmol) of 60% NaH is added. The reaction mixture is stirred for
5 hours at room temperature and then poured into ice-cold aqueous 0.5 N HCI
solution. The precipitate formed is isolated by filtration, rinsed with water, drained by
suction and then dried in an oven. 3.44 g of a yellow solid mainly composed of the
expected product in non-cyclized form are obtained.
The solid obtained above is taken up in 50 mL of n-butanol and the solution is
refluxed overnight. After cooling to room temperature, the precipitate is isolated by
filtration and dried in an oven. 1.69 g of the expected product are obtained in the
form of a yellow solid. Yield = 45%.
20.5: 7-Amino-2-methanesulfonyl-5-oxo-8-phenyl~5,8-dihydropyhdo[2,3-
d]pyrimidine-6~carboxamide and 7-amino~2-methanesulfinyl-5-oxo-8-phenyi-5,8-
dihydropyrido[2,3~d]pyrimidine-6-carboxamide
To a suspension of 1.69 g (5.16 mmol) of the compound obtained in step 20.4 in
100 mL of chloroform are added 3.18 g (12.91 mmol) of mete-chloroperbenzoic acid.
The mixture is stirred at room temperature for 24 hours, and 0.44 g (2.58 mmol) of
mete-chloroperbenzoic acid is added. This mixture is stirred for 24 hours and the
insoluble material is then separated out by filtration. The filtrate is concentrated
under vacuum and then triturated in methanol and dried in an oven. 1.12 g of a pale
yellow solid composed of a mixture of the expected sulfone and sulfoxide (about
80/20 by 1H NMR) are obtained.
20.6 tert-Butyl 4-[4-(7-amino-6-carbamoyt-5-oxo-8-phenyl-5,8-dihydro-
pyrido[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl]piperidine-1-carboxylate
0.4 g (1.11 mmol) of the mixture of sulfone and sulfoxide obtained in step 20.5 and
0.51 g (1.67 mmol) of the product prepared in step 16.3 are heated at 110°C for
6 hours in 5 mL of NMP. Water is added and the solid is isolated by filtration and
then dried in an oven. The 0.42 g of solid residue is purified by chromatography on a
column of silica, eluting with a dichloromethane/methanol gradient (100/0 to 97/3).
0.16 g of expected product is obtained in the form of a light-brown solid. Yield = 46%.
20.7: 7-Amino-2-(2-methoxy-4-piperid-4-ylphenylamino)-5-oxo-8~phenyl-5,8-
dihydropyrido[2,3-d]pyrimidine'6-carboxamide hydrochloride
A solution of 0.15 g (0.26 mmol) of the product prepared in step 20.6 in 4 mL of
CH2CI2 is cooled on an ice bath, and 0.99 mL (3.94 mmol) of a 4N solution of
hydrogen chloride in dioxane is added. The mixture is stirred for 30 minutes at room
temperature and then poured into ether. The solid is drained by suction, rinsed with
pentane and dried in an oven under vacuum. 0.136 g of a pale pink solid is obtained,
and is purified on a reverse phase to give, finally, 0.1 g of the expected product in
the form of a yellow solid. Yield (dihydrochloride) = 68%. m.p. = 228°C
(decomposition). M+H+ = 487.
1H NMR (DMSO-de, 400 MHz): d 11.3 (broad s, 1H); 10.25 (broad s, 1H); 8.9-9.0 (s
+ m, 2H); 8.8 (m, 1H); 8.3 (s, 1H); 7.7 (m, 3H); 7.5 (m, 2H); 7.25 (broad s, 1H); 7.15
(m, 1H); 6.8 (s, 1H); 6.7 (broad s, 1H); 6.3 (m, 1H); 3.95 (s, 3H); 3.4 (m, 2H); 3.0 (m,
2H); 2.75 (m, 1H); 1.75-1.95 (m, 4H).
Example 21: 7-Amino-2-[4-(1-cyclopropylpiperid-4-yl)-2-methoxyphenylamino]-
8-(2-hydroxy-2-methylpropyl)-5-oxo-5,8-dihydropyrrdo[2,3-d]pyrimidine-6-
carboxamide hydrochloride
21.1: 7-Amino-2-[4-(1-cyclopropylpiperid-4-yl)-2-methoxyphenylamino]-8-(2-
hydroxy-2-methyIpropyI)-5-oxo-5,8-dihydropyrido[2,3~d]pynmidine-6-carboxamide
To a solution of 0.46 g (0.83 mmol) of the hydrochloride prepared in step 20.7 in
14 mL of anhydrous methanol are successively added 0.42 mL (2.48 mmol) of
diisopropylethylamine, 0.47 mL (8.26 mmol) of acetic acid, finely ground 3 A
molecular sieves predried in a vacuum oven at 60°C overnight, 0.75 mL (3.72 mmol)
of (l-ethoxycyclopropoxy)trimethylsilane and 0.16 g {2.48 mmol) of sodium
cyanoborohydride. The mixture is heated at 80CC overnight, and is evaporated to
dryness. The residue obtained is purified by chromatography on a column of silica,
eluting with a dichloromethane/methanol gradient (96/4 to 90/10). 0.16 g of the
expected product is finally obtained in the form of a white solid. Yield = 37%.
21.2: 7-Amino-2-[4-(1-cyclopropylpiperid-4-yl)-2-methoxyphenylamino]-8-(2-hydroxy-
2-methylpropyl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
hydrochloride
To a suspension of 0.137 g (0.26 mmol) of the product prepared in step 21.1
in 5 mL of CH2CI2 are added 1.05 mL (1.05 mmol) of 1.0 M hydrochloric ether. The
mixture is stirred for 5 minutes at room temperature and then diluted with ether. The
precipitate is drained by suction, rinsed with ether and with pentane, and dried under
vacuum. 0.12 g of the expected product is obtained in the form of a yellow solid.
Yield (dihydrochloride) = 77%. m.p. = 206°C (decomposition). M+H+= 568
1H NMR (DMSO-d6l 400 MHz): d 11,5 (broad s, 1H); 10.7 (broad s, <1H); 10.6 (m,
1H); 9.1 (s, 1H); 8.9 (s, 1H); 8.4 (broad s, 1H); 7.6 (d, 1H); 7.0 (s, 1H); 6.85 (d, 1H);
4.8 (broad s, 2H); 3.8 (s, 3H); 3.6 (m, 2H); 3.2-3.4 (m, 3H); 3.05 (m, 1H); 2.8 (m, 2H);
2.15 (m, 2H); 1.95 (m, 2H); 1.15 (m, 2H); 1.0 (very broad s, 6H); 0.8 (m, 2H).
Example 22: 7-Amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(2-
methoxyethyl)piperid-4-yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide hydrochloride
22.7: 7-Amino-2-{4-[1-(2-chloroethyi)piperid-4-yl]-2-methoxyphenylamino}-8-
(2-hydroxy-2-methylpropyl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6'Carboxamide
To a suspension of 0.60 g (1.08 mmol) of the hydrochloride prepared in step 20.7 in
15 mL of anhydrous dichloroethane are successively added 0.56 mL (3.25 mmol) of
diisopropylethylamine, 0.4 mL (5.41 mmol) of methoxyacetaldehyde (batch received
from the company TCI Fine Chemicals) and 0.46 g of sodium triacetoxyborohydride.
The mixture is stirred at room temperature for 2 hours and then diluted with 15 mL of
a water/aqueous 1N NaOH mixture (2/1). The resulting mixture is stirred for
10 minutes and then diluted with ethyl acetate. The organic phase is dried over
MgSO4, filtered and concentrated under vacuum. 0.41 g of a yellow solid
corresponding to 7-amino-2-{4-[1-(2-chloroethyl)piperid-4-yl]-2-methoxyphenyl-
amino}-8-(2-hydroxy-2-methylpropyl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-
carboxamide, and not to the 7-amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-
[1-(2-methoxyethyl)piperid-4-yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide initially expected, is obtained. Yield = 69%.
22.2: 7-Amino-8~(2'hydroxy-2-methylpropyiy2-{2-methoxy-4-[1~(2~methoxy-
ethyl)piperid-4-yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-
carboxamide
To a suspension of 0.29 g (0.54 mmol) of the product prepared in step 22.1 in 9 mL
of anhydrous methanol is added 0.37 g (2.68 mmol) of K2CO3, and the mixture is
refluxed for 1 hour. It is evaporated to dryness and the residue is taken up in water
and CH2CI2. The organic phase is dried over MgSO4) filtered and concentrated under
vacuum. The crude product is purified by chromatography on a column of silica,
eluting with a dichloromethane/methanol gradient (90/10). After triturating in
methanol, 0.22 g of the expected product is finally obtained in the form of a yellow
solid. Yield = 78%.
22.3: 7-Amino-8-(2-hydroxy-2-methylpropyl)~2-{2-methoxy-4-[1~(2-methoxy-
ethyl)piperid~4-yl]phenylamino}-5-oxo-5,8~dihydropyrido[2,3-d]pyrimidine~6~carbox^
amide
To a suspension of 0.22 g (0.41 mmol) of the product prepared in step 22.2 in 8 mL
of a CH2CI2/methanol mixture (4/1) are added 1.63 mL (1.63 mmol) of 1.0 M
hydrochloric ether. The mixture is stirred for 5 minutes at room temperature and is
then diluted with ether. The precipitate is drained by suction, rinsed with ether and
with pentane, and dried under vacuum. 0.23 of the expected product is obtained in
the form of a pale yellow solid. Yield (dihydrochloride) = 92%. m.p. = 170°C
(decomposition). M+H+= 540
1H NMR (DMSO-d6, 400 MHz): d 11.5 (broad s, 1H); 10.35 (broad s, 1H); 10.6 (m,
1H); 9.05 (s, 1H); 8.9 (s, 1H); 8.4 (broad s, 1H); 7.6 (d, 1H); 7.0 (s, 1H); 6.8 (d, 1H);
4.75 (broad s, 2H); 3.7-3.85 (m + s, 5H); 3.6 (m, 2H); 3.2-3.4 (m + s, 5H); 3.1 (m,
2H); 2.85 (m, 1H); 2.15 (m, 2H); 2,0 (m, 2H); 1.0 (very broad s, 6H).
Example 23: 7-Amino-2-[2-methoxy-4-(1-methylpiperid-4-yl)phenylamino]-5-
oxo-8-phenyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
23.1: 7-Amino-2-[2-methoxy-4-(1-methylpiperid-4-yl)phenylamino]-5-oxo-8-
phenyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
0.2 g (0.55 mmol) of the mixture of the sulfone and sulfoxide obtained in step 20.5
and 0.24 g (1.11 mmol) of 2-methoxy-4-(1-methylpiperid-4-yl)phenylamine (prepared
according to the method described in patent WO-09/024 824) are heated at 110°C
for 6 hours in 5 mL of NMP. The mixture is evaporated to dryness under vacuum and
the residue is purified by chromatography on a column of silica, eluting with a
dichloromethane/methanol gradient (100/0 to 95/5) containing traces of concentrated
aqueous NH4OH. 0.096 g of the expected product is obtained in the form of a beige-
coloured solid. Yield = 35%.
23.2: 7-Amino-2-[2-methoxy-4-(1-methylpiperid-4-yl)phenylamino]-5-oxo-8-
phenyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
A solution of 0.065 g (0.13 mmol) of the product prepared in step 23.1 in 3 mL of
CH2CI2 is cooled on an ice bath, and 0.39 mL (0.39 mmol) of a 1M solution of
hydrogen chloride in ether is added. The mixture is stirred for 10 minutes at room
temperature and then poured into ether. The solid is drained by suction, rinsed with
pentane and dried in an oven under vacuum. 0.059 g of the expected compound is
obtained. Yield (dihydrochloride) = 80%. m.p. = 256°C (decomposition). M+H+= 500
1H NMR (DMSO-d6, 400 MHz): d 11.3 (broad s, 1H); 10.25 (broad s, 1H); 9.0 (s, 1H);
8.35 (s, 1H); 7.7 (m, 3H); 7.5 (m, 2H); 7.25 (broad s, 1H); 7.15 (m, 1H); 6.8 (s, 1H);
6.7 (broad s, 1H); 6.3 (m, 1H); 3.8 (s, 3H); 3.45 (m, 2H); 3.0 (m, 2H); 2.8 (d, 3H); 2.7
(m, 1H); 1.85-2.05 (m,4H).
Example 24: 7-Amino-2-[2-methoxy-4-(2-pyrrolidin-1-ylethyl)phenylamino]-5-
oxo-8-phenyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
24.1: 2-Methoxy-1-nitro-4-vinylbenzene
4.32 g (31.31 mmol) of potassium trifluorovinylborate and 3.12 mL (22.37 mmol) of
triethylamine are added to a mixture of 5.19 g (22.37 mmol) of the product prepared
in step 4.1 in 56 mL of n-propanol, under argon, and argon is bubbled through for
10 minutes. 0.36 g (0.45 mmol) of PdCI2dppf-CH2CI2 is added and the mixture is
heated under argon at 100°C for 3 hours. After cooling to room temperature, the
reaction mixture is concentrated to dryness and then taken up in a
dichloromethane/water mixture. After separation of the phases by settling, the
organic phase is washed twice with water and once with saturated aqueous NaCI.
The organic phase is dried over Na2SO4, filtered and concentrated under vacuum.
The residue obtained is purified by chromatography on a column of silica, eluting
with a cyclohexane/ethyl acetate gradient (95/5 to 70/30). 3.1 g of the expected
product are obtained in the form of a brown oil, which is used as obtained in the
following step. Yield = 77%.
24.2: 1-[2-(3-Methoxy-4-nitrophenyl)ethylJpyrro!idine
3.07 g (17.17 mmol) of the product prepared in step 24.1 and 7.13 ml_ (85.84 ml_) of
pyrrolidine in 60 mL of anhydrous methanol are placed in a sealed tube. The mixture
is heated under pressure at 100°C for 4 hours. After cooling to room temperature, it
is evaporated to dryness. The residue obtained is purified by chromatography on a
column of silica, eluting with a dichloromethane/methanol gradient (100/0 to 90/10).
3.22 g of the expected product are obtained in the form of a yellow solid. Yield =
75%.
24.3: 2-Methoxy-4-(2-pyrrolidin-1-ylethyl)phenylamine
0.41 g of palladium-on-charcoal and 4.1 g (64.32 mmol) of ammonium formate are
added to a solution of 3.2 g (12.86 mmol) of the product prepared in step 24.2 in
120 mL of methanol, under argon, and the mixture is refluxed for 2 hours. After
filtration, the filtrate is concentrated to dryness to give 2.6 g of the expected product
in the form of a light-brown solid, which is used as obtained in the following step.
Yield = 92%.
24.4: 7-Amino-2-[2-methoxy-4-(2-pyrrolidin-1-ylethyl)phenylamino]-5-oxo-8-
phenyI-5,8-dihydropyrido[2,3-d]pyhmidine-6-carboxamide
0.2 g (0.55 mmol) of the mixture of sulfone and sulfoxide obtained in step 20.5 and
0.24 g (1.11 mmol) of the aniline prepared in step 24.3 are heated at 110°C for
6 hours in 5 mL of NMP. The mixture is evaporated to dryness under vacuum and
the residue is purified by chromatography on a column of silica, eluting with a
dichloromethane/methanol gradient (100/0 to 90/10) containing traces of
concentrated aqueous NH4OH. 0.07 g of the expected product is obtained in the
form of a glassy yellow solid. Yield = 25%.
24.5: 7-Amino-2-[2-methoxy-4-(2-pyrrolidin-1-ylethyl)phenylamino]-5-oxo-8-
phenyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide hydrochloride
A solution of 0.07 g (0.14 mmol) of the product prepared in step 24.4 in 3 ml_ of
methanol is cooled on an ice bath, and 0.42 mL (0.42 mmol) of a 1M solution of
hydrogen chloride in ether is added. The mixture is stirred for 10 minutes at room
temperature and ether is then added. The solid is drained by suction, rinsed with
pentane and dried in an oven under vacuum. 0.075 g of the expected compound is
obtained. Yield (dihydrochloride) = 93%.
M+H+=500
1H NMR (DMSO-d6 + D2O, 400 MHz, T = 130°C): 9.0 (s, 1H); 7.7 (m, 3H); 7.4 (m,
2H); 7.25 (d, 1H); 6.85 (s, 1H); 6.4 (d, 1H); 3.8 (s, 3H); 3.1-3.5 (m, 6H); 2.9 (m, 2H);
2.0 (m, 4H).
Table 1 beiow illustrates the chemical structures and physical properties of a number
of compounds of formula (I) according to the invention. In this table:
> Me and Et represent, respectively, methy! and ethyl groups,
> the "LC/UV/MS" column indicates, successively, the high-performance liquid
chromatography analytical method used (A, B, C or D) and detailed below, the
retention time (abbreviated as tr) of the compound, expressed in minutes, and the
MH+ peak identified by mass spectrometry.
Method A:
Column: Kromasil C18, 50 x 2.1 mm, 3.5 urn
Solvent A: H2O/ACN/TFA (1000/30/0.5); solvent B: ACN/TFA (1000/0.5); flow rate =
0.5 mL/min
Gradient: 100/0 (0 min) to 0/100 (12 min) to 0/100 (15 min)
Detection: 220 nM
Ionization: ESI+
Method B:
Column: Gemini, 50 x 3 mm, 3 µm
Solvent A: H2O + 0.1% HCO2H; solvent B: ACN + 0.1% HCO2H; flow rate = 1 mL/min
Gradient: 95/5 (0 min) to 0/100 (5.5 min) to 0/100 (7.5 min)
Detection: 220 nM
Ionization: ESI+
Method C:
Column: Kromasil C18, 50x2.1 mm, 3.5 µm
Solvent A: CH3CO2NH4 5 mM; solvent B; ACN; flow rate = 0.5 mL/min
Gradient: 100/0 (0 min) to 0/100 (13 min) to 0/100 (16 min)
Detection; 220 nM
Ionization: ESI+
Method D;
Column: Acquity BEH C18, 50x2.1 mm; 1.7 µm
Solvent A: H2O + 0.05% TFA; solvent B: ACN + 0.035% TFA; flow rate = 1 mL/min
Gradient: TO: 98% A; T1.6 to T2.1 min: 100% B; T2.5 to T3 min: 98% A
Detection: 220 nM
Ionization: ESI+
> in the "Form" column,"-" indicates that the compound is in free base form, while
"HCI" indicates that the compound is in hydrochloride form,
> in the "Compounds" column, "RAC" indicates that the compound is in the form of
a racemic mixture,
> "?" means that the data are not available.
The compounds according to the invention underwent pharmacological trials
to determine their inhibitory effect on CaMKII, on the 5 isoform.
The tests consisted in measuring the in vitro activity of the compounds of the
invention on CaMKIIS.
The compounds according to the invention were tested in vitro for their
capacity to inhibit the kinase function of calcium/calmodulin-dependent protein
kinase II delta (CaMKIIS). CaMKIIo" is an intracellular serine/threonine kinase. It has
an enzymatic domain that is capable of using ATP to autophosphorylate. Its kinase
function allows it to use ATP to phosphorylate its substrates on the serines and/or
threonines. Several enzymatic and cellular tests are used to evaluate the activity of
the products with respect to the kinase function of CaMKIIS.
The kinase activity of CaMKIIo" is evaluated by means of a radioactive test on
the recombinant CaMKII6 enzyme. The amount of ATP-y33P incorporated into the
specific substrate Autocamtide-2 during its phosphorylation by CaMKIIS is
measured. The effect of the products is quantified by the concentration of product
that inhibits the total activity of CaMKII5 by 50% (50% inhibitory concentration =
IC50). For the determination of the IC50 values, the product is diluted in 100% of
DMSO to obtain a 10 mM stock solution. The concentration range tested during the
radioactive test ranges from 3 to 10 000 nM with a final concentration in the test of
1% DMSO. This concentration range may, for the most powerful compounds, be
extended to 0.1 nM. On the day of the operation, 5 pi of the compounds are
deposited in each well of a 96-well plate at 10 times the concentration of that to be
tested. Each concentration is tested in duplicate on the same plate. The negative
controls (0% activity) and positive controls (100% activity) receive 5 uL of 10%
DMSO solution. A reaction premix containing the 1X kinase buffer and an ATP-
MgCI2 mixture is prepared. Extemporaneously, a mixture containing the substrate
Autocamtide-2 (100 uM) with calmodulin and calcium, and the solution of enzyme
CaMKIIS, is added to the premix. 45 uL of this mixture are immediately deposited per
well. The final concentrations in the 50 uL final volume are as follows: compound 1X,
0.37 nM of CaMKIIS (Invitrogen reference PV3373), 10 uM of ATP (1 uCi per well),
100 uM of Autocamtide-2, 8 ug/mL 0f calmodulin, 15 mM MgCI2, 400 uM CaCI2,
10 mM ^-glycerophosphate, and 1% of DMSO. Two negative controls are prepared
on each plate, a first without enzyme CaMKIIS, and a second without substrate
Autocamtide-2; these two elements are replaced with water. The plate is then
incubated for two hours at 37°C with gentle shaking. The reaction is stopped by
adding 20 uL per well of H3PO4 solution. The 50 uL of each well are transferred onto
a Whatman P81 filter. After rinsing twice with H3PO4 (150 ul/well per wash), followed
by two rinses with 150 uLof H20, 50 uL of scintillant are added per well. The amount
of phosphorylated substrate is detected by means of a liquid scintillation counter.
The inhibitory activity toward CaMKIIS is given by the concentration that
inhibits 50% of the activity of CaMKIIS. The IC50 values are generally between 10 pM
and 10"5 uM. In the table below, the IC50 values measured for several compounds (I)
of the invention are presented as examples.
It is thus seen that the compounds according to the invention have inhibitory
activity on CaMKIIS.
The compounds according to the invention may thus be used for the
preparation of medicaments that inhibit CaMKIi and in particular medicaments that
inhibit CaMKI 16.
Thus, according to another of its aspects, a subject of the invention is
medicaments that comprise a compound of formula (I), or an addition salt thereof
with a pharmaceutically acceptable acid, or alternatively a hydrate or a solvate of the
compound of formula (I).
These medicaments find their use in therapy, especially in the treatment
and/or prevention of pathologies in which CaMKII is involved, and in particular in
which CaMKII5 is involved.
According to another of its aspects, the present invention also relates to the
use of a compound of formula (I) for the preparation of a medicament for preventing
and/or treating cardiovascular pathologies including myocardial infarction, ventricular
hypertrophy, myocardial fibrosis, cardiac insufficiency, cardiac arrhythmia and
restenosis, and also pathologies associated with the development of fibrosis,
including hepatic, pancreatic, renal, pulmonary, cutaneous, intestinal and ocular
fibrosis. A compound of formula (I) may also be used in the treatment and/or
prevention of other renal pathologies, such as acute renal insufficiency, and also in
the treatment of atherosclerosis, rheumatoid arthritis, Parkinson's disease and
strokes.
According to another of its aspects, the present invention relates to
pharmaceutical compositions comprising, as active principle, a compound according
to the invention. These pharmaceutical compositions contain an effective dose of at
least one compound according to the invention, or a pharmaceutically acceptable
salt, a hydrate or a solvate of the said compound, and also at least one
pharmaceutical^ acceptable excipient.
The said excipients are chosen, according to the pharmaceutical form and
the desired mode of administration, from the usual excipients known to those skilled
in the art.
In the pharmaceutical compositions of the present invention for oral,
sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal,
intranasal, transdermal or rectal administration, the active principle of formula (I)
above, or the possible salt, solvate or hydrate thereof, may be administered in unit
administration form, as a mixture with standard pharmaceutical excipients, to man
and animals for the prophylaxis or treatment of the above disorders or diseases.
The appropriate unit administration forms include oral forms such as tablets,
soft or hard gel capsules, powders, granules and oral solutions or suspensions,
sublingual, buccal, intratracheal, intraocular, intranasal or inhalation administration
forms, topical, transdermal, subcutaneous, intramuscular or intravenous
administration forms, rectal administration forms 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 administration form 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
Sodium croscarmellose 6.0 mg
Cornstarch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
There may be particular cases in which higher or lower dosages are
appropriate; such dosages are not outside the scope of the invention. According to
the usual practice, the dosage that is appropriate for each patient is determined by
the doctor according to the mode of administration, and the weight and response of
the said patient.
According to another of its aspects, the present invention also relates to a
method for treating and/or preventing the pathologies indicated above, which
comprises the administration to a patient of an effective dose of a compound
according to the invention, or a pharmaceutically acceptable salt or hydrate or
solvate thereof.
WE CLAIM:
received by the International Bureau on 10 June 2011 (10.06.2011)
1. Compound corresponding to the general formula (I)

in which:
> A represents CH or C(alkyl);
> X represents CH, C(alkyl) or N;
> R1, R2, R3 and R4, which may be identical or different, represent,
independently of each other:
• a hydrogen atom;
• a linear, branched or cyclic alkyl, optionally substituted with one or more of
the following:
o halogen atoms;
o -OR9;
o -NR9R'9;
o -CN;
o -C(O)OR9;
o -C(O)NR9R9';
o -S(O)pR10;
o -S(O)2NR9R'9;
in which R9, R'9, R10 and p are as defined below
• a group -S(O)pR10 in which p and R10 are as defined below;
• a group -OR10in which R10 is as defined below;
• a halogen atom;
• a group -N(R11)C(O)R12, in which
(v) R11 and R12 represent, independently of each other, a
hydrogen atom or a linear, branched or cyclic alkyl, optionally
substituted with one or more substituents chosen from halogen atoms,
groups -OR9 and groups -NR9R'9, or
(vi) R11 and R12 form, together with the atoms to which they are
attached, a heterocycloalkyl, so as to form a lactam;
• a group -N(R14)-CH2-C(O)NR15R9, in which R14 and R15 form, together with
the atoms to which they are attached, a heterocycloalkyl, so as to form a
piperazinone and in which R9 is as defined below;
• a group -C(O)NR16R17 with R16 and R17 form, together with the nitrogen
atom to which they are attached, a heterocycloalkyl,
• a group -T-U, in which:
¦ T represents;
o a single bond,
o a linear or branched alkylene group;
o a group -C(O)-,
o a group -S(O)p- in which p is as defined below, or
o a group -O-(CH2)n- in which n is as defined below,
with U representing a heterocycle comprising one or more
heteroatoms chosen from N, O and S(O)p, in which p is as defined
below, the said heterocycle being saturated, unsaturated or aromatic,
optionally mono- or di- or polysubstituted with one, two or several
substituents chosen from;
? groups -OR7l in which R7is as defined below,
? halogen atoms,
? groups -C(O)R7 in which R7 is as defined below,
?> linear, branched or cyclic alkyls, optionally substituted
with one or more substituents chosen from halogen atoms,
groups -OR10, groups -NR9R'9and the group -CN, in which
R9, R'9 and R10 are as defined below; and
? saturated, unsaturated or aromatic heterocycles,
optionally substituted with one or more substituents
chosen from halogen atoms, groups -ORg, groups ~NRgR'9
and groups alkyl, the said alkyl groups being optionally
substituted with one or more halogen atoms; or
" T represents:
o a group -C(O)-;
o a group -S(O)2-; or
o a group -O-(C2-C3)alkylene-;
with U representing a group -NR9R'9in which R9 and R'9 are as
defined below; or
¦ T represents:
o a group -C(O)-; or
o a group -O-(C2-C3)alkylene-;
with U representing a group -OR9, in which R9 is as defined below; or
¦ T represents;
o a linear or branched alkylene group; or
o a group -O-(C2-C3)alkylene-;
with U representing a group -NR8R9 in which R9 and Ra are as
defined below;
or alternatively two adjacent groups chosen from R1' R2, R3 and R4 are linked and
form, with the two carbons that bear them, a saturated, unsaturated or aromatic
heterocycle, optionally substituted with one or more linear, branched or cyclic
alkyl groups, the said alkyl groups being optionally substituted with one or more
substituents chosen from halogen atoms, groups -OR10, and groups -NR9R'9, in
which R9, R'9 and R10are as defined below,
the said heterocycle being fused with the aromatic ring,
> R5 represents:
• a linear or branched alkyl, optionally substituted with one or more
substituents chosen from halogen atoms, groups -OR9, groups -NR9R'9, the
group -CN, groups -C(O)NR9R9., groups -S(O)pR10 and cycloalkyl groups
optionally substituted with a group -NR9R'9, in which R9, R'9, R10 and p are
as defined below,
• a cycloalkyl group, optionally substituted with a group -NR9R'9, in which R9
and R'9 are as defined below,
• an alkoxy group -OR9, in which R9 is as defined below,
• an aryl optionally substituted with one or more substituents chosen from
groups (C1-C3)alkyl, halogen atoms and groups -O-(C1-C3)alkyl, or
• a group -(CH2)t-R13, in which R13and t are as defined below,
> R6 represents a hydrogen atom or a linear, branched or cyclic alkyl,
and in which:
> R7 represents a hydrogen atom or a linear, branched or cyclic alkyl, optionally
substituted with one or more of the following substituents chosen from halogen
atoms, groups -OR9 and groups -NR9R'9with R9and R'9as defined above;
> R8 represents a heteroaryl group;
> R9 and R'9 represent, independently of each other, a hydrogen atom or a linear,
branched or cyclic alkyl;
> R10 represents a hydrogen atom or a linear, branched or cyclic alkyl optionally
substituted with one or more halogen atoms,
> R13 represents a heteroaryl or a heterocycloalkyl optionally substituted with one
or more substituents chosen from linear, branched or cyclic alkyls, it being
understood that when the said heterocycloalkyl comprises at least one nitrogen
atom, this atom may optionally bear the said substituent,
> t represents 1 or 2,
> n represents 0, 1, 2 or 3, and
> p represents 0, 1 or 2,
in the form of acid, base or addition salt with an acid or a base, and also in the form
of hydrate or solvate.
2. Compound according to Claim 1, characterized in that:
A represents CH or C(CH3);
and/or
X represents CH or N.
3. Compound according to Claim 1 or 2, characterized in that:
> A represents CH,
> X represents CH, C(alkyl) or N,
> R1, R2, R3 and R4, which may be identical or different, represent,
independently of each other:
o a hydrogen atom,
o a linear, branched or cyclic alkyl, optionally substituted with one or
more of the following halogen atoms, a group -OR9 or -NR9R9, in
which R9 and R'9 represent, independently of each other, a hydrogen
atom or a linear, branched or cyclic alkyl,
o a group -S(O)pR10 or a group -OR10, in which R10 represents a
hydrogen atom or a linear, branched or cyclic alkyl optionally
substituted with one or more halogen atoms, and p represents 0, 1 or
2,
o a halogen atom,
o a group -N(R11)C(O)R12, in which R11 and R12 represent,
independently of each other, a hydrogen atom or a linear, branched or
cyclic alkyl or R11 and R12 form, together with the atoms to which they
are attached, a heterocycloalkyl, so as to form a lactam;
o a group -T-U, in which
¦ T represents:
• a single bond,
• a linear or branched alkylene group,
• a group -C(O)-,
• a group -S(O)p, in which p represents 0, 1 or 2,
• A group -O-(CH2)n- in which n represents 0, 1, 2 or 3,
and U represents a heterocycle comprising one or more
heteroatoms chosen from N, O and S(O)p in which p represents 0,
1 or 2, the said heterocycle being of the formula:

in which
• * represents the position of attachment of U to T;
• M1 represents a C or N atom;
• M2 and M3, which may be identical or different, represent a C, N or O atom
or S(O)p in which p = 0, 1 or 2;
• M4 represents a C, C(=O), N, O or S(O)p atom in which p = 0, 1 or 2;
each of the Mi, which may be identical or different, represent a C, C(=O), N,
O or S(O)p atom in which p = 0, 1 or 2;
• i=O, 1,2 or 3;
it being understood that each of the M1, M2, M3, M4 or Mi may be optionally
substituted if a valency is available and/or the adjacent M1, M2, M3, M4 or Mi
may be attached via a double bond, where appropriate;
the said heterocycle U being saturated, unsaturated or aromatic, optionally
mono- or di- or polysubstituted with one, two or several substituents chosen from:
o groups -OR7, in which R7 represents a hydrogen atom or a linear,
branched or cyclic alkyl,
o halogen atoms,
o groups -COR7 in which R7 represents a hydrogen atom or a linear,
branched or cyclic alkyl,
o linear, branched or cyclic alkyls, optionally substituted with one or
more halogen atoms,
o saturated, unsaturated or aromatic heterocycles, especially a
heterocycle comprising an N, optionally substituted with one or more
groups chosen from halogen atoms and groups alkyl optionally
substituted with one or more halogen atoms;
or alternatively two adjacent groups from among R1, R2, R3 and R4 are linked and
form, with the two carbons that bear them, a saturated, unsaturated or aromatic
heterocycle, optionally substituted with one or more linear, branched or cyclic
alkyl groups, the said alkyl groups being optionally substituted with at least one
group chosen from groups -NR9R'9, in which R9 and R'9 represent, independently
of each other, a hydrogen atom or an alkyl group,
the said heterocycle being fused with the aromatic ring.
4. Compound according to any one of Claims 1 to 3, characterized in that it
corresponds to formula (I') below:

in which:
> R1 represents:
• a hydrogen atom,
• a linear, branched or cyclic alkyl, optionally substituted with one or
more of the following substituents chosen from halogen atoms, groups
-NR9R'9, in which R9 and R'9 represent, independently of each other, a
hydrogen atom or an alkyl group,
• -OR10, in which R10 represents a hydrogen atom or a linear, branched
or cyclic alkyl optionally substituted with one or more halogen atoms,
• a halogen atom,
• a group -T-U, in which
T represents:
oa single bond,
oan alkylene group,
oa group-C(O)-,
o a group -O-(CH2)n in which n represents 0, 1, 2 or 3,
o and U represents a saturated, unsaturated or aromatic
heterocycle, optionally mono- or disubstituted with a
substituent,
>R2, R3 and R4, which may be identical or different, independently represent:
o a hydrogen atom,
o a linear, branched or cyclic alkyl, optionally substituted with one or
more of the following substituents chosen from halogen atoms and
groups -NR9R'9, in which R9 and R'9 represent, independently of
each other, a hydrogen atom or an alkyl,
o a group -OR10, in which R10 represents a hydrogen atom or an alkyl
optionally substituted with one or more halogen atoms,
o a halogen,
o a group -T-U with T representing a bond and U a morpholinyl, or
>R1 and R2 are linked and form, with the two carbon atoms that bear them, a
heterocycle chosen from a piperidine, a thiazole, a tetrahydrofuran and a
dioxane, the said heterocycle being optionally substituted with a linear, branched
or cyclic alkyl optionally substituted with -NR9R'9, in which R9 and R'9 represent,
independently of each other, a hydrogen atom or a methyl,
the said heterocycle being fused with the aromatic ring,
> R5 represents (i) a finear, branched or cyclic alkyl comprising from 1 to 5
carbon atoms, optionally substituted with one or more substituents chosen from
halogen atoms or a group -OH, (ii) an aryl optionally substituted with one or
more substituents chosen from groups (C1-C3)alkyl, halogen atoms and
groups-O-(C1-C3)alkyl;
in the form of acid, base or addition salt with an acid or a base, and also in the form
of hydrate or solvate.
5. Compound according to any one of Claims 1 to 4, characterized in that
> A represents CH; and/or
> X represents CH; and/or
> R1 is other than a hydrogen atom; and/or
> R5 represents a linear, branched or cyclic alkyl; and/or
> U represents a saturated, unsaturated or aromatic heterocycle, optionally
mono- or disubstituted, comprising at least one nitrogen atom and/or one
oxygen atom, and/or
> U represents a saturated heterocycle comprising at least one nitrogen atom;
and/or
> U represents a heterocycle chosen from:
o an azetidinyl;
o a pyrrolidinyl;
o an oxopyrrolidinyl;
o a piperidyl;
o a 1,2,3,6-tetrahydropyridyl;
o a pyridyl;
o a piperazinyl;
o a diazepanyl;
o a morpholinyl;
o a 1,1-dioxo-1lambda6-thiomorpholin-4-yl.
6. Compound according to any one of the preceding claims, characterized in
that R1 is chosen from:
7. Compound according to any one of the preceding claims, characterized in
that A and X represent CH.
8. Compound according to any one of the preceding claims, characterized in
that U represents a saturated heterocycle comprising at least one nitrogen atom.
9. Compound according to any one of the preceding claims, characterized in
that it is chosen from:
7-Amino-8-ethyl-2-(4-hydroxyphenylamino)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-
6-carboxamide;
7-Amino-2-(benzothiazof-6-ylamino)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-2-[4-(cyclopropanecarbonylmethylamino)phenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-dJpyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(4-methylpiperazine-1-carbonyl)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7~Amino-2-(4-cyclopentyloxyphenylamino)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxarnide;
7-Amino-8-ethyl-5-oxo-2-[4-(4-pyrrolidin-1-ylpiperid-1-yl)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-[4-(4-pyrrolidin-1-ylpiperid-1-yl)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-[4-(4-pyrrolidin-1-ylpiperid-1-yl)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-cyclopentyl-2-(4-morpholin-4-ylphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxb-2-[4-(piperidine-1-sulfonyl)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
2-[4-(4-Acetylpiperazin-1-yl)phenylamino]-7-amino-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(4-morpholin-4-ylbenzylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(quinolin-3-yiamino)-5,8-dihydropyrido[2,3-d]pyrimidine-6-
carboxylamide;
7-Amino-8-ethyl-5-oxo-2-[4-(3-piperid-1-ylpropoxy)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(3,4,5,6-tetrahydro-2H-[1,2']bipyridyl-5'-ylamino)-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-[4-(2-oxopyrrolidin-1-yl)phenylamino]-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(quinolin-6-y!amino)-5,8-dihydropyrido[2T3-d]pyrimidine-6-
carboxamide;
7-Amino-8-ethy!-2-(3-morpholin-4-ylphenylamino)-5-oxo-5I8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-2-(2,3-dihydrobenzo[1,4]dioxin-6-ylamino)-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(3-fluoro-4-hydroxyphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6~carboxamide;
7-Amino-8-ethyl-2-(3-methylsulfanylphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(4-morpholin-4-ylphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(4-morpholin-4-ylphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(4-morpholin-4-ylphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(2-fluorophenylamino)-5-oxo-5,8-dihydropyrido[2,3-d]pyrirnidine-6-
carboxamide;
7-Amino-2-[4-(4,4-difluoro[1,4']bipiperidyl-1'-yl)-2-methoxyphenylamino]-8-ethyl-5-
oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-[2-methoxy-4-(4-trifluoromethylE1,4']bipiperidyl-1'-yl)phenylamino]-
5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{4-[4-(3,3-difluoropyrrolidin-1-yl)piperid-1-yl]-2-methoxyphenyiamino}-8-
ethyl-5-oxo-518-dihydropyrido[2I3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-fluoro-6-methoxyphenylamino]-5-oxo-
5,8-dihydropyrido[2,3-d3pyrimidine-6-carboxamide;
7-Amino-2-[4-(1-cyclopropylpiperid-4-yl)-2-methoxyphenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-(2-dimethylaminomethylchroman-6-ylamino)-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-[5-chloro-4-(4-cyclopropylpipera2in-1-yl)-2-methoxyphenylamino]-8-ethyl-
5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[2-methoxy-4-(4-morpholin-4-ylpiperid-1-yi)phenylamino]-5-oxo-
5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxyamide;
7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-difluoromethoxyphenylamino]-8-ethyl-5-
oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-[4-(4-cyclopropylpiperazin-1-yi)-2-methoxyphenylamino]-8-ethyl-5-oxo-
5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyf)piperid-4-yl]phenylamino}-5-
oxo-5,8-dihydropyrido[2,3-d3pyrimidine-6-carboxamide;
7-Amino-2-[2-chloro-4-(4-ethylpiperazin-1-yl)phenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-3-trifluoromethylphenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d3pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(4-morpholin-4-ylmethylphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-{4-[4-(3,3,3-trifluoropropyl)piperazin-1-yl]phenylamino}-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-3-fluorophenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
6-(4-Morpholin-4-ylphenylamino)-9-oxo-1,3,4,9-tetrahydro-2H-1,4a,5,7-tetraaza-
phenanthrene-10-carboxamide;
7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-methoxyphenyiamino]-5-oxo-5,8-
dihydropyrido[2,3-d3pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(1-methylpiperid-4-ylmethoxy)phenylamino3-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)phenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-t4-(4-ethylpiperazin-1-yl)-2-methylphenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(4-ethyl[1,4]diazepan-1-yl)phenylamino3-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
8-(4-Morpholin-4-ylphenylamino)-5-oxo-1,2,3,5-tetrahydro-3,7,9,9b-tetraaza-
cyclopenta[a]naphthalene-4-carboxamide;
7-Amino-8-ethyl-5-oxo-2-{4-[2-(3-trifluoromethylpiperid-1-yl)ethyl]phenylamino}-5,8-
dihydropyrido[2,3-d]pyrimidtne-6-carboxamide;
7-Amino-8-ethyl-2-[4-(3-morpholin-4-ylpropyl)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-{4-[1-(2,2,2-trifluoroethyl)piperid-4-yl]phenylamino}-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(4-{S)-1-morpholin-3-ylmethylphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-isobutyl-2-[4-(2-morpholin-4-ylethyl)phenyiamino]-5-oxo-5,8-
dihydropyridot2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-{4-[2-(3-fluoroazetidin-1-yl)ethyl]phenylamino}-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5-oxo-8-propyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(2-hydroxyethyl)phenylamino]-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-amino-8-ethyl-2-(4-hydroethylphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-{4-[2-(1,1 -dioxo-1 lambda6-thiomorpholin-4-yl)ethyl]phenylamino}-8-ethyl-
5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-{4-[2-(4-methyl-3-oxopiperazin-1-yl)ethyl]phenylamino}-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-{4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-{4-[1-(3,3,3-trifluoropropyl)piperid-4-yf]phenylamino}-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-(4-dimethylaminomethylphenylamino)-5-oxo-8-(2,2,2-trifluoroethyl)-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-[3-chloro-4-(4-pyrrolidin-1-ylpiperid-1-yl)phenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrtdo[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-[3-chloro-4-(4-pyrrolidin-1-ylpiperid-1-yl)phenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(4-pyrid-2-ylmethylphenylamino)-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-2-{4-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]phenylamino}-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(4-pyrrolidin-3-ylphenylamino)-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(4-pyrrolidin-3-ylphenylamino)-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-t4-{2-piperid-1-ylethyl)phenylamino]-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5-oxo-8-(2,2,2-trifluoroethyl)-5,8-
dihydropyrido[2,3-d3pyrimidine-6-carboxamide
7-Amino-2-{4-[2-(4,4-difluoropiperid-1-yl)ethyl]phenylamino}-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(1-methylpyrrolidin-3-yl)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-{4-[2-(3,3-difluoropiperid-1-yl)ethyl]phenylamino}-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-(3-methoxy-propyl)-2-[4-(2-morpholin-4-ylethyl)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-E4-(1-methylpiperid-3-yl)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimicline-6-carboxamide;
7-Amino-2-(4-dimethylaminomethylphenylamino)-8-isopropyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-{4-dimethylarninomethylphenylamino)-8-isopropyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(4-piperid-3-yiphenylamino)-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino}-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(1-methylpiperid-4-yloxy)phenylamino3-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(2-morpholin-4-ylethoxy)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-(3-dimethylaminomethylphenylamino)-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-[4-(4-pyrrolidin-1-ylpiperid-1-yl)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6~carboxamide;
7-Amino-8-ethyl-5-oxo-2-[4-(piperid-4-yloxy)phenylamino]-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-(3-aminopropyl)-2-{4-morpholin-4-ylphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(2-morpholin-4-ylethyl}phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-2-(4-dimethylaminomethylphenylamino)-8-ethyi-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-2-[4-(1-ethylpiperid-4-yl)phenylamino]-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide;
7-Amino-8-ethyl-5-oxo-2-(4-piperid-4-ylphenylamino)-5,8-dihydropyridoE2,3-
d]pyrimidine-6-carboxamide;
7-Amino-2-[3-chloro-4-(4-ethylpiperazin-1-yl)phenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrirnidine-6-carboxamide
7-Amino-8-ethyl-2-[3-methoxy-4-(3-piperid-1-ylpropoxy)phenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-5-oxo-2-{4-[2-(4-trifIuoromethyipiperid-1-yl)ethyl]phenylamino}-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{4-[2-(cis-2,6-dimethylmorpholin-4-yl)ethyf]phenylamino}-8-ethyl-5-oxo-
5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-(4-diethylaminomethylphenylamino)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide
7-Amino-2-(4-dimethylaminornethylphenylamino)-8-(3-methoxy-propyl)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-fluorophenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{4-[1-{2-cyanoethyl)piperid-4-yl]phenylamino}-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-{4-[1-(3-fluoropropyl)piperid-4-yl]phenylamino}-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid amide
7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-3-methylphenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-ethylphenyiamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
(±)-7-Amino-2-trans-[4-(2-dimethylaminocyclopropyl)phenyiamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[4-(4-cyciopropylpiperazin-1-yl)-5-fluoro-2-methoxyphenylamino]-8-ethyl-
5-0X0-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[4-(4-cyclopropyfpiperazin-1-yl)-3-fluoro-2-methoxyphenylamino]-8-ethyl-
5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[4-(4-cyclopropylpiperazin-1-yl)-2-ethoxyphenylamino]-8-ethyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-5-oxo-2-(4-propylphenylamino)-5,8-dihydropyrido[2,3-d]pyrimidine-
6-carboxamide
7-Amino-8-ethyl-5-oxo-2-(4-propoxyphenylamino)-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-(6-methoxypyrid-3-ylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-(4-fluorophenylamino)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-
carboxamide
7~Amino-8-ethyl-2-(4-methoxyphenylamino)-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide
7-Amino-2-(benzo[1,3]dioxol-5-ylamino)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-5-oxo-2-(4-piperid-1-ylphenylamino)-5,8-dihydropyrido[2,3-
d]pyrimidine-6-carboxamide
8-Ethyl-2-{2-methoxy-4-[1-{3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-7-
methylamino-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-isobutyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-
yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-cyclopropylmethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-
yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(2-methoxyethyl)-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-
yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d3pyrimidine-6-carboxamide
7-Amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-5-oxo-8-
(tetrahydrofuran-2-ylmethyl)-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-5-oxo-2-{4-[1-(3,3,3-trifluoropropyl)azetidin-3-yi]phenyiamino}-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{5-fluoro-2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-
8-isobutyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-5-oxo-2-[4-(1,2,3,6-tetrahydropyrid-4-yl)phenylamino]-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-(2-methoxy-4-piperid-4-ylphenylamino)-5-oxo-8-phenyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(2-hydroxyethyl)-2-(2-methoxy-4-piperid-4-ylphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-5-oxo-8-
thiazol-2-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-5-oxo-8-
thiazol-5-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(2-hydroxy-2-methylpropyl)-2-(2-methoxy-4-piperid-4-ylphenylamino)-5-
oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
8-(2-Acetytaminoethy!)-7-amino-2-{2-methoxy-4-[1-{3,3,3-trifluoropropyl)piperid-4-
yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(2-aminoethyl)-2-(4-morpholin-4-ylphenylamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-(4-morphoiin-4-ylphenylamino)-5-oxo-8-pyrrolidin-3-ylmethyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-[4-(4-ethylpiperazin-1-yl)-2-hydroxyphenytamino3-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-(4-morpholin-4-ylphenylamino)-5-oxo-8-piperid-4-ylmethyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-(2-methoxy-4-morpholin-4-ylphenylamino)-5-oxo-8-pyrrolidin-3-ylmethyl-
5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-(2-methoxy-4-piperid-4-ylphenylamino)-4-methyl-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-5-oxo-8-
thiophen-2-ylmethyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-isobutyl-2-[2-methoxy-4-(4-morpholin-4-ylpiperid-1-yl)phenylamino]-5-
oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-(4-morpholin-4-yiphenylamino)-5-oxo-8-pyrrolidin-2-ylmethyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-ethyl-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)-1,2,3,6-tetrahydropyrid-4-
yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[4-(4-ethylpiperazin-1-yl)-2-methoxyphenylamino]-8-(2-hydroxy-2-
methylpropyl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(3,3,3-
trifluoropropyl)piperid-4-yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d3pyrimidine-6-
carboxamide
7-Amino-8-(2-hydroxy-2-methylpropyl)-2-[4-(4-ethylpiperid-1-yl)-2-
methoxyphenylamino]-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[4-(1-cyclopropylpiperid-4-yl)-2-methoxyphenylamino]-8-(2-hydroxy-2-
methylpropyl)-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(2-hydroxy-2-methylpropyl)-2-{2-methoxy-4-[1-(2-methoxyethyl)piperid-4-
yl]phenylamino}-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[2-methoxy-4-(1-methylpiperid-4-yl)phenylamino]-5-oxo-8-phenyl-5,8-
dihydropyrido[2,3-d3pyrimidine-6-carboxamide
7-Amino-8-(3-fluorophenyl)-2-[2-methoxy-4-piperid-4-ylphenylamino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(4-fluorophenyl)-2-[2-methoxy-4-piperid-4-ylpheny!amino]-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[2-methoxy-4-piperid-4-ylphenyiamino]-5-oxo-8-m-tolyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[2-methoxy-4-piperid-4-y!phenylaminoj-5-oxo-8-p-tolyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(3-methoxyphenyl)-2-(2-methoxy-4-piperid-4-ylphenyiamino)-5-oxo-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[2-methoxy-4-(2-pyrrolidin-1-ylethy!)phenyiamino]-5-oxo-8-phenyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-8-(4-fiuorophenyl)-2-[2-methoxy-4~(1-methylpiperid-4-yl)phenylamino]-5-
oxo-5,8-dihydropyridoE2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[2-methoxy-4-(1-methylpiperid-4-yl)phenylamino]-5-oxo-8-m-tolyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-{2-methoxy-4-[1-(3,3,3-trifluoropropyl)piperid-4-yl]phenylamino}-5-oxo-8-
phenyl-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
7-Amino-2-[4-(4-ethylpiperazin-1-yl)-2-methoxyphenylamino]-5-oxo-8-phenyl-5,8-
dihydropyrido[2,3-d]pyrimidine-6-carboxamide
in the form of base or of acid-addition salt, and also in the form of hydrate or solvate.
10. Process for preparing a compound of formula (I) according to any one of
Claims 1 to 9, characterized in that it comprises the reaction of a compound of
formula (IX)

with a primary amine of formula (A):

in which R1' R2, R3, R4and R5 are defined according to any one of Claims 1 to 9 and
t represents 1 or 2.
11. Process for preparing a compound of formula (t) according to any one of
Claims 1 to 9, characterized in that it comprises the reaction of a compound of
general formula (XIV) or (XV):

with a compound of general formula (A):

in which R1' R2, R3, R4, R5 and R6 are defined according to any one of Claims 1 to 9.
12. Compound of formula (VII):

13. Compound of formula (VIII):

in which R5 is defined according to any one of Claims 1 to 8.
14. Compound of formula (IX):

in which R5 is defined according to any one of Claims 1 to 8 and t represents 1 or 2.
15. Compound of formula (XV):

in which R5 and R6 are defined according to any one of Claims 1 to 8 and R6 is other
than H.
16. Medicament, characterized in that it comprises a compound of formula (I)
according to any one of Claims 1 to 9, or an addition salt of this compound with a
pharmaceutically acceptable acid, or alternatively a hydrate or a solvate of the
compound of formula (I).
17. Pharmaceutical composition, characterized in that it comprises a compound
of formula (I) according to any one of Claims 1 to 9, or a pharmaceutically
acceptable salt, a hydrate or a solvate of this compound, and also at least one
pharmaceutically acceptable excipient.
18. Compound of formula (I) according to any one of Claims 1 to 9, for its use in
treating and/or preventing any pathology in which the kinase CaMKII is involved.
19. Compound according to Claim 18, for its use in the treatment and/or
prevention of cardiovascular pathologies including myocardial infarction, ventricular
hypertrophy, myocardial fibrosis, cardiac insufficiency, cardiac arrhythmia and
restenosis, and also vascular pathologies associated with an endothelial dysfunction,
including atherosclerosis, and also pathologies associated with the development of
fibrosis, including hepatic, pancreatic, renal, pulmonary, cutaneous, intestinal and
ocular fibrosis, kidney transplantation, liver transplantation, and also acute
pathologies including acute renal insufficiency, acute pulmonary insufficiency and
acute hepatic insufficiency, and also pathologies associated with neuronal death or
degeneration, including strokes and Parkinson's disease, and also pathologies of
inflammatory origin, such as chronic pain and rheumatoid arthritis.