DERIVATIVES OF N-[(1H-PYRAZOL-1-YL)ARYL]-1H-INDOLE OR 1H-
INDAZOLE-3-CARBOXAMIDE, PREPARATION THEREOF AND
APPLICATIONS THEREOF IN THERAPEUTICS
The present invention relates to novel derivatives of N-[(1H-pyrazol-1-
yl)aryl]-1H-indole or 1H-indazole-3-carboxamide, preparation thereof and
application thereof in therapeutics.
The compounds according to the present invention are reversible
antagonists of the P2Y12 purinergic receptor. These compounds are antiplatelet
drugs, exerting a powerful antithrombotic effect. They can be used for treating
and preventing cardiovascular disorders such as thromboembolic diseases or
restenoses.
In the industrialized world, medical complications associated with
occurrence of a thrombosis represent one of the main causes of mortality.
Some examples of pathologies associated with the development of a
thrombosis include acute myocardial infarction, unstable angina and chronic
stable angina, transient ischemic attacks, cerebrovascular accidents, peripheral
vascular disease, pre-eclampsia and eclampsia, deep vein thrombosis,
embolisms (cerebral, pulmonary, coronary, renal etc.), disseminated
intravascular coagulation, or thrombotic thrombocytopenic purpura. There are
also risks of thrombotic and restenotic complications during and following
invasive surgery, such as angioplasty, carotid endarterectomy, aortocoronary
bypass graft, or placement of stents or of endovascular prostheses.
Arterial thromboses can occur following a lesion of a vessel wall or rupture
of an atherosclerotic plaque. Platelets play an essential role in the formation of
these thromboses. Platelets can be activated either by mediators released in
the bloodstream by circulating cells or by damaged endothelial cells present
along the vessel wall, or by thrombogenic molecules of the subendothelial
matrix - such as collagen - exposed during vascular lesions. Moreover, platelets
can also be activated in conditions of blood flow with high shear stress as is
observed in stenotic vessels. After activation, the circulating platelets adhere
and accumulate at the vascular lesion, forming a thrombus. During this process,
the thrombi generated can be sufficiently voluminous for the blood flow in the
vessel to be blocked partially or completely.
In the veins, thrombi can also form where there is stasis or slow blood flow.
Owing to their nature, these venous thrombi can produce emboli which move
through the vascular system. These emboli can then block the blood flow in
vessels that are more remote, such as pulmonary or coronary arteries.
Numerous studies have demonstrated that adenosine 5'-diphosphate (ADP)
is a major mediator of platelet activation and aggregation, playing a crucial role
in initiation and progression of thrombus formation (Maffrand et al., Thromb.
Haemostas. (1988) 59, 225-230; Herbert et al., Arterioscl. Thromb. (1993) 13,
1171-1179).
ADP is released into the circulation by damaged red blood cells and the
endothelial cells of the atherosclerotic wall, and more specifically is secreted by
the activated platelets where ADP is stored in the dense granules at very high
concentration. ADP-induced platelet aggregation is triggered by its binding to
two specific purinergic receptors, expressed on the cell membrane of human
platelets: P2Y1 and P2Y12. The P2Y1 receptor, coupled with stimulation of
PLCB via Gaq, is responsible for mobilization of the internal stores of calcium,
the change in shape of the platelets, and transient aggregation on ADP. The
P2Y12 receptor, coupled with inhibition of adenylcyclase via Gai2 and with
activation of PI-3 kinase, is responsible for amplification of the responses and
stabilization of aggregation (Gachet, Thromb. Haemost. (2001) 86, 222-232;
Andre et al., J. Clin. Invest. (2003) 112, 398-406). The use of P2Y1-/-
transgenic mice (Gachet et al., J Clin Invest (1999) 104, 1731-1737; Gachet et
al., Circulation (2001) 103, 718-723; Gachet et al., Haematology (2002) 87, 23)
and P2Y12-/- (Conley et al., Nature (2001) 409, 202-207) demonstrated the
importance of these two receptors in the development of thromboses in vivo. In
humans, genetic defects for P2Y12 have been described as being associated
with a hemorrhagic phenotype and with pronounced deterioration of ADP-
induced platelet aggregation (Kanakura et al., J Thromb Haemost. (2005) 3,
2315-2323).
The use of clopidogrel in human clinical practice has supplied proof that
blocking of the P2Y12 receptor by an antagonist represents a key therapeutic
strategy in the treatment of cardiovascular diseases. Clopidogrel is a prodrug of
the thienopyridine family, whose active metabolite binds covalently to the
P2Y12 receptor, leading to irreversible inhibition of platelet activity in vivo. (Savi
et al., Biochem Biophys Res Commun (2001) 283, 379-383; Savi et al., Proc
Natl Acad Sci (2006) 103, 11069-11074). This molecule had initially shown its
efficacy in several clinical trials, reducing the risk of cardiovascular accidents in
patients at risk ("A randomised, blinded, trial of clopidogrel versus aspirin in
patients at risk of ischaemic events (CAPRIE)" CAPRIE steering committee
Lancet (1996) 348, 1329-1339; "The Clopidogrel in Unstable Angina to Prevent
Recurrent Events (CURE). Effects of Clopidogrel in Addition to Aspirin in
Patients with Acute Coronary Syndromes without ST-Segment Elevation" CURE
steering committee N Engl J Med (2001) 345, 7, 494-502).
Synthetic antagonists of the P2Y12 receptor that display antiplatelet and
antithrombotic activity have been described. Nevertheless, there is still a need
for new antagonists possessing better properties, notably the need for
reversible antagonists with a better benefit/risk ratio.
The present invention relates to compounds corresponding to formula (I):

in which:
- A represents a divalent aromatic radical selected from:

- X represents a -CH- group or a nitrogen atom;
- R1 represents a (C1-C4)alkyl or a (C1-C4)alkoxy;
- R2 represents a group Alk;
- R3 represents a hydroxyl or a group -NR7R8;
- R4 represents a hydrogen atom, a halogen atom, a cyano, a phenyl, a group
Alk, a group OAlk or a group -NR9R10;
- R5 represents a hydrogen atom, a halogen atom or a group Alk;
- R6 represents a hydrogen atom, a halogen atom, a cyano, a group
-COOAlk or a -CONH2 group;
- R7 represents a hydrogen atom or a (C1-C4)alkyl;
- R8 represents:
a) a hydrogen atom;
b) a (C1-C4)alkyl, unsubstituted or substituted with:
(i) a hydroxyl;
(ii) a group OAlk;
(iii) a group -NR9R10;
(iv) a (C3-C6)heterocycloalkyl, unsubstituted or substituted with a (C1-
C4)alkyl or with a group -COOAlk;
(v) a heteroaryl, unsubstituted or substituted with a (C1-C4)alkyl;
c) a (C3-C7)cycloalkyl;
d) a (C3-C6)heterocycloalkyl, unsubstituted or substituted with a (C1-C4)alkyl,
a group -COOAlk or with one or two oxo groups;
e) a group -SO2Alk;
- or else R7 and R8, together with the nitrogen atom to which they are attached,
constitute a heterocycle, saturated or unsaturated, mono- or polycyclic,
condensed or bridged, comprising 4 to 10 ring members and which can
contain one, two or three other nitrogen atoms or another heteroatom
selected from an oxygen atom or a sulfur atom; said heterocycle being
unsubstituted or substituted once, twice or three times with substituents
selected independently from:
a) a halogen atom;
b) a hydroxyl;
c)agroup-OR11;
d) an oxo;
e) a group -NR9R10;
f) a group -NR12COR13;
g) a group -NR12COOR13;
h) a group -COR13;
i) a group -COOR13;
j) a group -CONR14R15;
k) a (C3-C7)cycloalkyl, unsubstituted or substituted with a hydroxyl or with a
(C1-C4)alkyl;
I) a (C3-C6)heterocycloalkyl, unsubstituted or substituted with one or two oxo
groups;
m) a phenyl, unsubstituted or substituted one or more times with substituents
selected independently from a halogen atom, a group Alk or a group OAlk;
n) a pyridinyl;
o) a (C1-C4)alkyl, unsubstituted or substituted one or more times with
substituents selected independently from:
(i) a halogen atom;
(ii) a hydroxyl;
(iii)agroup-OR11;
(iv) a group -NR9R10;
(v) a group -NR12COR13;
(vi) a group -COOR13;
(vii) a group -CONR14R15;
(viii) a group -SO2Alk;
(ix) a (C3-C7)cycloalkyl;
(x) a (C3-C6)heterocycloalkyl;
(xi) a phenyl, unsubstituted or substituted one or more times with
substituents selected independently from a halogen atom, a group Alk or a
group OAlk;
(xii) a heteroaryl, unsubstituted or substituted with a (C1-C4)alkyl;
- R9 and R10 represent, each independently, a hydrogen atom or a (C1-
C4)alkyl;
- R11 represents a group Alk, a (C1-C4)alkylene-OH or a (C1-C4)alkylene-OAIk;
- R12 represents a hydrogen atom or a (C1-C4)alkyl;
- R13 represents a (C1-C4)alkyl;
- R14 and R15 represent, each independently, a hydrogen atom, a (C1-C4)alkyl
or a (C3-C7)cycloalkyl;
- or else R14 and R15, together with the nitrogen atom to which they are
attached, constitute a heterocyclic radical selected from: azetidin-1-yl,
pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl or piperazin-1-yl;
- Alk represents a (C1-C4)alkyl, unsubstituted or substituted one or more times
with a fluorine atom.
The compounds of formula (I) can have one or more asymmetric carbon
atoms. They can therefore exist in the form of enantiomers or diastereoisomers.
These enantiomers, diastereoisomers as well as mixtures thereof, including the
racemic mixtures, form part of the invention.
The compounds of formula (I) can exist in the form of bases or salified by
acids or by bases, notably pharmaceutically acceptable acids or bases. Said
salts of addition form part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable
acids or bases, but salts of other acids or bases that can be used, for example,
for purification or isolation of the compounds of formula (I), also form part of the
invention.
Halogen atom means a bromine, chlorine, fluorine or iodine atom.
(C1-C4)alkyl means a linear or branched alkyl radical with one to four carbon
atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl radical.
(C1-C4)alkylene means a divalent radical with one to four carbon atoms
such as the methylene, ethylene, trimethylene or tetramethylene radical.
(C1-C4)alkoxy means a linear or branched alkoxy radical with one to four
carbon atoms, such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec-butoxy, tert-butoxy radical.
(C3-C7)cycloalkyl means a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl carbon-containing radical.
(C3-C6)heterocycloalkyl means a saturated monocyclic ring, comprising 3 to
6 ring members and one or more heteroatoms such as nitrogen, oxygen or
sulfur atoms. As examples, a heterocycloalkyl can be an aziridine, an azetidine,
a pyrrolidine, a morpholine, a piperazine, a piperidine, an imidazolidine, a
pyrazolidine, a thiomorpholine, an oxetane, a tetrahydrofuran, a tetrahydro-2H-
pyran, a tetrahydrothiophene.
Heteroaryl means an aromatic monocyclic system comprising 5 to 6 ring
members, and comprising one or more heteroatoms such as nitrogen, oxygen
or sulfur atoms. The nitrogen atoms can be in the form of N-oxides. As
examples of monocyclic heteroaryls we may mention thiazole, thiadiazole,
thiophene, imidazole, triazole, tetrazole, pyridine, furan, oxazole, isoxazole,
oxadiazole, pyrrole, pyrazole, pyrimidine, pyridazine and pyrazine.
Saturated or unsaturated, mono- or polycyclic, condensed or bridged
heterocycle, comprising 4 to 10 ring members, means a heterocycloalkyl such
as for example an aziridine, an azetidine, a pyrrolidine, a piperidine, a
piperazine, a morpholine, a thiomorpholine, as well as, for example, the
following heterocycles: an octahydro-2H-pyrido[1,2-a]pyrazine, a 5,6,7,8-
tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, a 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine,
an octahydropyrrolo[1,2-a]pyrazine, a 1,4-diazepane, a 5,6,7,8-
tetrahydroimidazo[1,2-a]pyrazine, a 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-
c]pyridine, a 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole, a 6,7-dihydro-5H-
pyrrolo[3,4-b]pyridine, a 3,8-diazabicyclo[3.2.1]octane, a 4,5,6,7-tetrahydro-1H-
imidazo[4,5-c]pyridine, a 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine, a 2,5-
diazabicyclo[2.2.2]octane, a 2,5-diazabicyclo[2.2.1]heptane, an
octahydropyrrolo[3,4-b]pyrrole, an octahydropyrrolo[3,4-c]pyrrole, an octahydro-
2H-pyrazino[1,2-a]pyrazine.
According to the present invention, a distinction is made between:
- the compounds of formula (I) in which R3 represents a hydroxyl (reference
IA) and the other substituents A, X, R1, R2, R4 and R5 are as defined for a
compound of formula (I);
- the compounds of formula (I) in which R3 represents a group -NR7R8
(reference IB) and the other substituents A, X, R1, R2, R4, R5, R7 and R8 are
as defined for a compound of formula (I);
in the form of a base or of salts of addition with acids or bases.
According to the present invention, we may mention the compounds of
formula (I) in which:
- A represents a divalent aromatic radical selected from:

- X represents a -CH- group or a nitrogen atom;
- R1 represents a methyl, ethyl, n-propyl radical or an ethoxy radical;
- R2 represents a methyl radical;
- R3 represents a hydroxyl or a group -NR7R8;
- R4 represents a hydrogen atom, a bromine, chlorine or fluorine atom, a
cyano, a phenyl, a methyl radical, a trifluoromethyl radical, a methoxy radical
or a dimethylamino group;
- R5 represents a hydrogen atom, a bromine, chlorine or fluorine atom or a
methyl radical;
- R6 represents a hydrogen atom, a bromine atom, a cyano, a
methoxycarbonyl group or a -CONH2 group;
- R7 represents a hydrogen atom or a methyl radical;
- R8 represents:
a) a hydrogen atom;
b) a methyl radical, a 2-hydroxyethyl, a 3-hydroxypropyl, a 2-methoxyethyl, a
2-(methylamino)ethyl, a 2-(dimethylamino)ethyl, a 2-
(dimethylamino)propyl, a 2-(dimethylamino)-1-methylethyl, a 2-
(dimethylamino)-2-methylpropyl, a 3-(dimethylamino)propyl, a (1-
methylpiperidin-3-yl)methyl, a tetrahydrofuran-3-ylmethyl, a tetrahydro-2H-
pyran-4-ylmethyl, a 2-furylmethyl, a (3-methyl-1H-1,2,4-triazol-5-yl)methyl,
1-(1H-tetrazol-5-yl)ethyl, a 2-(1H-pyrrol-1-yl)ethyl, a 2-(1H-imidazol-1-
yl)ethyl;
c) a cyclopropyl;
d) a 1,1-dioxidotetrahydro-3-thienyl, a pyrrolidin-3-yl, a 1-methylpyrrolidin-3-
yl, a 1-(tert-butoxycarbonyl)pyrrolidin-3-yl, a piperidin-3-yl, a 1-
methylpiperidin-3-yl, a 1-(tert-butoxycarbonyl)piperidin-3-yl, a 1-
methylpiperidin-4-yl;
e) a methylsulfonyl group;
- or else R7 and R8, together with the nitrogen atom to which they are
attached, constitute a heterocycle selected from: an azetidine, a pyrrolidine, a
piperidine, a piperazine, a morpholine, a thiomorpholine, an octahydro-2H-
pyrido[1,2-a]pyrazine, a 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, a 2,3-
dihydro-1H-pyrrolo[3,4-c]pyridine, an octahydropyrrolo[1,2-a]pyrazine, a 1,4-
diazepane, a 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, a 4,5,6,7-tetrahydro-1H-
pyrazolo[4,3-c]pyridine, a 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole, a 6,7-
dihydro-5H-pyrroio[3,4-b]pyridine, a 3,8-diazabicyclo[3.2.1]octane, a 4,5,6,7-
tetrahydro-1 H-imidazo[4,5-c]pyridine, a 4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-
cjpyridine, a 2,5-diazabicyclo[2.2.2]octane, a 2,5-diazabicyclo[2.2.1]heptane, an
octahydropyrrolo[3,4-b]pyrrole, an octahydropyrrolo[3,4-c]pyrrole, an octahydro-
2H-pyrazino[1,2-a]pyrazine; said heterocycle being unsubstituted or substituted
once, twice or three times with substituents selected independently from:
a) a fluorine atom;
b) a hydroxyl;
c) a methoxy radical, a 2-hydroxyethoxy, a 2-methoxyethoxy;
d) an oxo;
e) an amino group, a methylamino, a dimethylamino;
f) an acetamido group;
g) a (tert-butoxycarbonyl)amino group, a (tert-butoxycarbonyl)(methyl)amino;
h) an acetyl group;
i) a methoxycarbonyl group, a tert-butoxycarbonyl;
j) a dimethylcarbamoyl group, a cyclopropylcarbamoyl, a
cyclobutylcarbamoyl;
k) a cyclopropyl, a cyclobutyl, a 2-hydroxycyclopentyl radical;
I) an oxetan-3-yl, a 1,1-dioxidotetrahydro-3-thienyl, a piperidin-1-yl, a
morpholin-4-yl radical;
m) a 4-fluorophenyl;
n) a pyridin-2-yl;
o) a methyl radical, an ethyl, an n-propyl, an isopropyl, an n-butyl, a
trifluoromethyl, a 2-fluoroethyl, a 2,2-difluoroethyl, a 2,2,2-trifluoroethyl, a
3,3,3-trifluoropropyl, a 3,3,3-trifluoro-2-hydroxypropyl, a hydroxymethyl, a
2-hydroxyethyl, a 2-hydroxy-1,1-dimethylethyl, a methoxymethyl, a 2-
methoxyethyl, a 2-methoxy-1-methylethyl, a 2-methoxy-1,1-dimethylethyl,
a 2-ethoxyethyl, a 2-(trifluoromethoxy)ethyl, a 2-(2-hydroxyethoxy)ethyl, a
2-(2-methoxyethoxy)ethyl, a 2-(dimethylamino)ethyl, a 2-acetamidoethyl, a
2-[acetyl(methyl)amino]ethyl, a 2-methoxy-2-oxoethyl, a 2-ethoxy-2-
oxoethyl, a 3-ethoxy-3-oxopropyl, a 2-amino-2-oxoethyl, a 2-
(methylamino)-2-oxoethyl, a 2-(isopropylamino)-2-oxoethyl, a 2-
(dimethylamino)-2-oxoethyl, a 2-(cyclopropylamino)-2-oxoethyl, a 2-oxo-2-
pyrrolidin-1-ylethyl, a 2-(methylsulfonyl)ethyl, a cyclopropylmethyl, a
pyrrolidin-1-ylmethyl, a tetrahydrofuran-2-ylmethyl, a 2-thienylmethyl, a 4-
chlorobenzyl, a 4-fluorobenzyl, a 2-methoxybenzyl, a 3-fluoro-4-
methoxybenzyl, a pyridin-4-ylmethyl, a (5-methyl-1,2,4-oxadiazol-3-
yl)methyl, a (5-methylisoxazol-3-yl)methyl;
in the form of a base or of salts of addition with acids or bases.
According to the present invention, we may mention compounds of formula
(I) in which:
- A represents a divalent aromatic radical selected from:

- X represents a -CH- group;
- R1 represents an n-propyl radical;
- R2 represents a methyl radical;
- R3 represents a hydroxyl or a group -NR7R8;
- R4 represents a chlorine atom;
- R5 represents a hydrogen atom;
- R7 represents a hydrogen atom or a methyl radical;
- R8 represents:
b) a methyl radical, a 2-hydroxyethyl, a 3-hydroxypropyl, a 2-methoxyethyl, a
2-(dimethylamino)ethyl, a 2-(dimethylamino)propyl, a 2-(dimethylamino)-2-
methylpropyl, a 3-(dimethylamino)propyl, a tetrahydrofuran-3-ylmethyl, a
tetrahydro-2H-pyran-4-ylmethyl, a 2-furylmethyl, a (3-methyl-1H-1,2,4-
triazol-5-yl)methyl, 1-(1H-tetrazol-5-yl)ethyl, a 2-(1H-pyrrol-1-yl)ethyl;
c) a cyclopropyl;
d) a 1-methylpyrrolidin-3-yl, a 1-(tert-butoxycarbonyl)piperidin-3-yl, a 1-
methylpiperidin-4-yl;
- or else R7 and Rs, together with the nitrogen atom to which they are attached,
constitute a heterocycle selected from: an azetidine, a pyrrolidine, a piperidine,
a piperazine, a morpholine, a thiomorpholine, an octahydro-2H-pyrido[1,2-
a]pyrazine, a 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, a 2,3-dihydro-1H-
pyrrolo[3,4-c]pyridine, an octahydropyrrolo[1,2-a]pyrazine, a 1,4-diazepane;
said heterocycle being unsubstituted or substituted once, twice or three times
with substituents selected independently from:
b) a hydroxyl;
c) a methoxy radical;
d) an oxo;
h) an acetyl group;
i) a methoxycarbonyl group;
j) a dimethylcarbamoyl group;
k) a cyclobutyl radical;
I) a 1,1-dioxidotetrahydro-3-thienyl, a piperidin-1-yl, a morpholin-4-yl;
m) a 4-fluorophenyl;
o) a methyl radical, an ethyl, an n-propyl, an isopropyl, an n-butyl, a
trifluoromethyl, a 3,3,3-trifluoropropyl, a hydroxymethyl, a 2-hydroxyethyl,
a methoxymethyl, a 2-methoxyethyl, a 2-ethoxyethyl, a 2-
(trifluoromethoxy)ethyl, a 2-(dimethylamino)ethyl, a 2-methoxy-2-oxoethyl,
a 2-ethoxy-2-oxoethyl, a 2-(isopropylamino)-2-oxoethyl, a 2-
(dimethylamino)-2-oxoethyl, a 2-(cyclopropylamino)-2-oxoethyl, a 2-oxo-2-
pyrrolidin-1-ylethyl, a tetrahydrofuran-2-ylmethyl, a 4-fluorobenzyl, a 3-
fluoro-4-methoxybenzyl, a pyridin-4-ylmethyl, a (5-methyl-1,2,4-oxadiazol-
3-yl)methyl;
in the form of a base or of salts of addition with acids or bases.
According to the present invention, we may mention compounds of formula
(I) in which:
- A represents a divalent aromatic radical:

- X represents a -CH- group or a nitrogen atom;
- R1 represents a methyl, ethyl, n-propyl radical or an ethoxy radical;
- R2 represents a methyl radical;
- R3 represents a hydroxyl or a group -NR7R8;
- R4 represents a hydrogen atom, a bromine, chlorine or fluorine atom, a
cyano, a phenyl, a methyl radical, a trifluoromethyl radical, a methoxy radical
or a dimethylamino group;
- R5 represents a hydrogen atom, a bromine, chlorine or fluorine atom or a
methyl radical;
- R6 represents a hydrogen atom, a bromine atom, a cyano, a
methoxycarbonyl group or a -CONH2 group;
- R7 represents a hydrogen atom or a methyl radical;
- R8 represents:
b) a methyl radical, a 2-hydroxyethyl, a 2-methoxyethyl, a 2-
(methylamino)ethyl, a 2-(dimethylamino)ethyl, a 2-(dimethylamino)-1-
methylethyl, a (1-methylpiperidin-3-yl)methyl, a 2-(1H-imidazol-1-yl)ethyl;
d) a 1,1-dioxidotetrahydro-3-thienyl, a pyrrolidin-3-yl, a 1-methylpyrrolidin-3-
yl, a 1-(tert-butoxycarbonyl)pyrrolidin-3-yl, a piperidin-3-yl, a 1-
methylpiperidin-3-yl, a 1-(tert-butoxycarbonyl)piperidin-3-yl;
e) a methylsulfonyl group;
- or else R7 and R8, together with the nitrogen atom to which they are
attached, constitute a heterocycle selected from: an azetidine, a pyrrolidine, a
piperidine, a piperazine, a morpholine, a 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-
a]pyrazine, an octahydropyrrolo[1,2-a]pyrazine, a 1,4-diazepane, a 5,6,7,8-
tetrahydroimidazo[1,2-a]pyrazine, a 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-
c]pyridine, a 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole, a 6,7-dihydro-5H-
pyrrolo[3,4-b]pyridine, a 3,8-diazabicyclo[3.2.1]octane, a 4,5,6,7-tetrahydro-1H-
imidazo[4,5-c]pyridine, a 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine, a 2,5-
diazabicyclo[2.2.2]octane, a 2,5-diazabicyclo[2.2.1]heptane, an
octahydropyrrolo[3,4-b]pyrrole, an octahydropyrrolo[3,4-c]pyrrole, an octahydro-
2H-pyrazino[1,2-a]pyrazine; said heterocycle being unsubstituted or substituted
once, twice or three times with substituents selected independently from:
a) a fluorine atom;
b) a hydroxyI;
c) a 2-hydroxyethoxy, a 2-methoxyethoxy;
d) an oxo;
e) an amino group, a methylamino, a dimethylamino;
f) an acetamido group;
g) a (tert-butoxycarbonyl)amino group, a (tert-butoxycarbonyl)(methyl)amino
group;
i) a methoxycarbonyl group, a tert-butoxycarbonyl;
j) a cyclopropylcarbamoyl group, a cyclobutylcarbamoyl;
k) a cyclopropyl, a cyclobutyl, a 2-hydroxycyclopentyl radical;
I) an oxetan-3-yl, a morpholin-4-yl;
n) a pyridin-2-yl;
o) a methyl radical, an ethyl, an n-propyl, an isopropyl, an n-butyl, a
trifluoromethyl, a 2-fluoroethyl, a 2,2-difluoroethyl, a 2,2,2-trifluoroethyl, a
3,3,3-trifluoro-2-hydroxypropyl, a hydroxymethyl, a 2-hydroxyethyl, a 2-
hydroxy-1,1-dimethylethyl, a methoxymethyl, a 2-methoxyethyl, a 2-
methoxy-1-methylethyl, a 2-methoxy-1,1-dimethylethyl, a 2-ethoxyethyl, a
2-(trifluoromethoxy)ethyl, a 2-(2-hydroxyethoxy)ethyl, a 2-(2-
methoxyethoxy)ethyl, a 2-(dimethylamino)ethyl, a 2-acetamidoethyl, a 2-
[acetyl(methyl)amino]ethyl, a 2-ethoxy-2-oxoethyl, a 3-ethoxy-3-oxopropyl,
a 2-amino-2-oxoethyl, a 2-(methylamino)-2-oxoethyl, a 2-(dimethylamino)-
2-oxoethyl, a 2-oxo-2-pyrrolidin-1-ylethyl, a 2-(methylsulfonyl)ethyl, a
cyclopropylmethyl, a pyrrolidin-1-ylmethyl, a 2-thienylmethyl, a 4-
chlorobenzyl, a 4-fluorobenzyl, a 2-methoxybenzyl, a (5-methylisoxazol-3-
yl)methyl;
in the form of a base or of salts of addition with acids or bases.
According to the present invention, we may mention compounds of formula
(I) in which:
- A represents a divalent aromatic radical selected from:

- X represents a -CH- group;
- R1 represents an n-propyl radical;
- R2 represents a methyl radical;
- R3 represents a hydroxyl or a group -NR7R8 selected from:

- R4 represents a chlorine atom;
- R5 represents a hydrogen atom; in the form of a base or of salts of addition
with acids or bases.
According to the present invention, we may mention compounds of formula
(I) in which:
- A represents a divalent aromatic radical:

- X represents a -CH- group or a nitrogen atom;
- R1 represents a methyl, ethyl, n-propyl radical or an ethoxy radical;
- R2 represents a methyl radical;
- R3 represents a hydroxyl or a group -NR7R8 selected from:

- R4 represents a hydrogen atom, a bromine, chlorine or fluorine atom, a
cyano, a phenyl, a methyl radical, a trifluoromethyl radical, a methoxy radical
or a dimethylamino group;
- R5 represents a hydrogen atom, a bromine, chlorine or fluorine atom or a
methyl radical;
R6 represents a hydrogen atom, a bromine atom, a cyano, a
methoxycarbonyl group or a -CONH2 group; in the form of a base or of salts
of addition with acids or bases.
According to the present invention, we may mention compounds of formula
(I) in which:
- A represents a divalent aromatic radical selected from:

- X represents a -CH- group;
- R1 represents an n-propyl radical;
- R2 represents a methyl radical;
- R3 represents a hydroxyl or a group -NR7R8 selected from:

- R4 represents a chlorine atom;
- R5 represents a hydrogen atom;
in the form of a base or of salts of addition with acids or bases.
According to the present invention, we may mention compounds of formula
(I) in which:
- A represents a divalent aromatic radical:

- X represents a -CH- group or a nitrogen atom;
- R1 represents a methyl, ethyl, n-propyl radical or an ethoxy radical;
- R2 represents a methyl radical;
- R3 represents a hydroxyl or a group -NR7R8 selected from:

- R4 represents a hydrogen atom, a bromine, chlorine or fluorine atom, a
cyano, a phenyl, a methyl radical, a trifluoromethyl radical, a methoxy radical
or a dimethylamino group;
- R5 represents a hydrogen atom, a bromine, chlorine or fluorine atom or a
methyl radical;
- R6 represents a hydrogen atom, a bromine atom, a cyano, a
methoxycarbonyl group or a -CONH2 group;
in the form of a base or of salts of addition with acids or bases.
Among the compounds of formula (I) according to the invention, we may notably
mention the following compounds:
- (3-{[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]carbamoyl}-5-methyl-1 H-
indol-1-yl)acetic acid;
- (3-{[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]carbamoyl}-5,6-dimethyl
-1H-indol-1-yl)acetic acid;
(3-{[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]carbamoyl}-5-
chloro-1 H-indol-1-yl)acetic acid;
- N-[5-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyrazin-2-yl]-5-chloro-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-[4-(2-
methoxyethyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-oxo-
2-[4-(3,3,3-trifluoropropyl)piperazin-1-yl]ethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-
(methylamino)-2-oxoethyl]-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -(2-
morpholin-4-yl-2-oxoethyl)-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-
(dimethylamino)-2-oxoethyl]-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-
[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-(4-
ethylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-(4-
propylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-[(2-
methoxyethyl)(methyl)amino]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-oxo-
2-[4-(tetrahydrofuran-2-ylmethyl)piperazin-1-yl]ethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-(5,6-
dihydro[1,2,4]triazolo[4,3-a]pyrazin-7 (8H)-yl)-2-oxoethyl]-1 H-indole-3-
carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-(4-
cyclobutylpiperazin-1-yl)-2-oxoethyl]-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -(2-{4-
[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]piperazin-1 -yl}-2-oxoethyl)-1 H-indole-3-
carboxamide;
- {4-[(3-{[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]carbamoyl}-5-
chloro-1 H-indol-1-yl)acetyl]piperazin-1-yl}methyl acetate;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-
[cyclopropyl(methyl)amino]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-[4-(4-
fluorobenzyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
. N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-[4-(2-
ethoxyethyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-[4-(2-
hydroxyethyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -(2-{[2-
(dimethylamino)ethyl](methyl)amino}-2-oxoethyl)-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-(4-
methyl-1,4-diazepan-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -[2-(8-methyl-9-
oxooctahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)-2-oxoethyl]-1H-indole-3-
carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)-2-cyanophenyl]-5-chloro-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-(4-
fluorobenzyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
-N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-(2-
methoxyethyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-1 -{2-[4-(2-
methoxyethyl)piperazin-1-yl]-2-oxoethyl}-5-methyl-1H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-(2-
methoxy-1 -methylethyl)piperazin-1 -yl]-2-oxoethyl}-1 H-indole-3-carboxamide;
. N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-methyl-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-6-fluoro-1 -{2-[4-
(2-methoxyethyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-methoxy-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-methyl-3-
(methylcarbamoyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5,6-dimethyl-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-methyl-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indazole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-methyl-1 -(2-oxo-2-
piperazin-1 -ylethyl)-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-6-fluoro-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -(2-{4-[(5-
methylisoxazol-3-yl)methyl]piperazin-1-yl}-2-oxoethyl)-1H-indole-3-
carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-methyl-1 -(2-morpholin-
4-yl-2-oxoethyl)-1H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -(2-oxo-2-
piperazin-1 -ylethyl)-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-(2-
methoxy-1,1 -dimethylethyl)piperazin-1 -yl]-2-oxoethyl}-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-(2-
hydroxy-1,1 -dimethylethyl)piperazin-1 -yl]-2-oxoethyl}-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -[2-(8-methyl-
3,8-diazabicyclo[3.2.1]oct-3-yl)-2-oxoethyl]-1H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-1 -[2-(4-methylpiperazin-
1 -yl)-2-oxoethyl]-5-(trifluoromethyl)-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -[2-oxo-2-(9-
oxooctahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)ethyl]-1H-indole-3-carboxamide;
in the form of a base or salt of addition with an acid or a base.
Hereinafter, protective group Pg means a group that makes it possible, on
the one hand, to protect a reactive function such as a hydroxyl or an amine
during a synthesis and, on the other hand, to regenerate the reactive function
intact at the end of synthesis. Examples of protective groups as well as of
methods of protection and of deprotection are given in "Protective Groups in
Organic Synthesis", Greene et al., 4th Edition, John Wiley & Sons, Inc., New
York, 2007.
Leaving group means, hereinafter, a group that can be easily cleaved from
a molecule by rupture of a heterolytic bond, with departure of an electron pair.
This group can thus easily be replaced with another group during a substitution
reaction, for example. Said leaving groups are, for example, the halogens or an
activated hydroxyl group such as a methanesulfonate, benzenesulfonate, p-
toluenesulfonate, triflate, acetate, etc. Examples of leaving groups as well as
references for their preparation are given in "Advanced Organic Chemistry",
M.B. Smith and J. March, 6th Edition, Wiley Interscience, 2007, p. 496-501.
According to the invention, the compounds of formula (I) in which R3 = -OH
(compound IA) can be prepared by a method that is characterized in that:
a compound of formula (II):

in which A, X, R1, R2, R4 and R5 are as defined for a compound of formula
(I) and Z represents a (C1-C4) alkyl, are hydrolyzed, in an acid or basic
medium.
Optionally, the compound of formula (I) is transformed to one of its salts
with mineral or organic bases.
The reaction is carried out in an acid medium by the action of a strong acid,
for example hydrochloric acid or sulfuric acid, in a solvent such as for example
dioxane or water and at a temperature between -10°C and 110°C.
The reaction is carried out in a basic medium by the action of an alkaline
base, for example potassium hydroxide, lithium hydroxide or sodium hydroxide,
in a solvent such as for example dioxane, tetrahydrofuran, water, methanol,
ethanol or a mixture of these solvents and at a temperature between -10°C and
the reflux temperature of the solvent.
According to the invention, the compounds of formula (I) in which R3 =
-NR7R8 (compound IB) can be prepared by a method that is characterized in
that:
a compound of formula (IA):

in which A, X, R1, R2, R4 and R5 are as defined for a compound of formula
(I), is reacted with an amine of formula (III):
HNR7R8 (III)
in which R7 and R8 are as defined for a compound of formula (I).
Optionally, the compound of formula (I) is transformed into one of its salts
with mineral or organic acids.
The reaction is carried out in the presence of a base, for example
triethylamine, 4-dimethylaminopyridine, N-methylmorpholine, N-ethylmorpholine
or pyridine and in the presence of a coupling agent, for example bis(2-oxo-1,3-
oxazolidin-3-yl)phosphinic chloride, isobutyl chloroformate, 1,1'-
carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride, 2-cyano-2-(hydroxyimino)ethyl acetate. The solvent used is, for
example, dichloromethane, 1,2-dichloroethane or N,N-dimethylformamide. The
reaction temperature is between -10°C and the reflux temperature of the
solvent.
In particular, certain compounds of formula (I) can be prepared from other
compounds of formula (I).
The compounds of formula (I) thus obtained can be separated subsequently
from the reaction mixture and purified by classical methods, for example by
crystallization or silica gel column chromatography.
The compounds of formula (I) thus obtained are isolated in the form of free
base or of salt, by classical techniques.
The compounds of formula (II) can be prepared by reaction of an acid or of
an activated functional derivative of said acid of formula:

in which X, R4 and R5 are as defined for a compound of formula (I) and Z
represents a (C«|-C4)alkyl, with a compound of formula:
in which A, R1 and R2 are as defined for a compound of formula (I).
When a compound of formula (V) is treated with the acid of formula (IV)
itself, this is carried out in the presence of a coupling agent used in peptide
chemistry such as 1,3-dicyclohexylcarbodiimide or benzotriazol-1-yl-
oxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-
oxytris(pyrrolidino)phosphonium hexafluorophosphate or 2-(1H-benzotriazol-1-
yl)-1,1,3,3-tetramethyluronium tetrafluoroborate or 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride, in the presence of a base such as
triethylamine, N,N-diisopropylethylamine or 4-dimethylaminopyridine, in a
solvent such as dichloromethane, 1,2-dichloroethane, N-N-dimethylformamide
or tetrahydrofuran at a temperature between -10°C and the reflux temperature
of the solvent.
As the activated functional derivative of acid (IV), it is possible to use the
acid chloride, the anhydride, a mixed anhydride, a C1-C4 alkyl ester in which
the alkyl is linear or branched, an activated ester, for example the p-nitrophenyl
ester.
Thus, for example, the chloride of the acid obtained by reaction of thionyl
chloride or of oxalyl chloride on the acid of formula (IV) can be reacted with the
compound of formula (V), in a solvent, such as a chlorinated solvent
(dichloromethane, 1,2-dichloroethane, chloroform for example), an ether
(tetrahydrofuran, dioxane for example), an amide (N,N-dimethylformamide for
example) or pyridine, under an inert atmosphere, at a temperature between 0°C
and the reflux temperature of the solvent, in the presence of a tertiary amine
such as triethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine
or 1,8-diazabicyclo[5.4.0]undec-7-ene.
The compounds of formula (II) can also be prepared by reacting a
compound of formula:

in which A, X, R1, R2, R4 and R5 are as defined for a compound of formula
(I), with a compound of formula:
in which Y represents a leaving group such as a halogen atom, a
methanesulfonate, a benzenesulfonate, a p-toluene sulfonate or a triflate and Z
represents a (C1-C4)alkyl.
The reaction is carried out in the presence of a base such as for example
sodium carbonate or potassium carbonate, in a solvent such as for example
N,N-dimethylformamide and at a temperature between -20°C and the reflux
temperature of the solvent.
In particular, certain compounds of formula (II) can be prepared from other
compounds of formula (II).
Thus, for example, starting from the compounds of formula (II) in which R4
= Br, it is possible to prepare the compounds of formula (II):
- in which R4 = phenyl, by reaction with phenylboronic acid in the presence
of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0);
- in which R4 = -NR9R10, by reaction with an amine HNR9R10 in the presence
of a copper(l) catalyst such as copper(l) iodide;
- in which R4= CN, by reaction with zinc(ll) cyanide and in the presence of a
catalyst such as tetrakis(triphenylphosphine)palladium(0).
Startina from the compounds of formula (II) in which:
(triphenylphosphine)palladium(O).
The compounds of formula (III) are known, are commercially available or
are prepared by methods known by a person skilled in the art, for example
those described in WO 95/18105.
The compounds of formula (IV) are prepared by reacting a compound of
formula:

in which X, R4 and R5 are as defined for a compound of formula (I), with a
compound of formula (VII):

in which Y represents a leaving group such as a halogen atom, a
methanesulfonate, a benzenesulfonate, a p-toluenesulfonate or a triflate and Z
represents a (C1-C4)alkyl.
The reaction is carried out in the presence of two equivalents of a strong
base, for example sodium hydride, in a solvent, for example N,N-
dimethylformamide and at a temperature between -30°C and the reflux
temperature of the solvent.
The compounds of formula (V) are prepared by reacting a compound of
formula:

in which R1 and R2 are as defined for a compound of formula (I), with a
compound of formula:
in which A is as defined for a compound of formula (I) and Y represents a
leaving group such as a halogen atom, a methanesulfonate, a benzene
sulfonate, a p-toluenesulfonate, a triflate or an acetate.
The reaction is carried out in the presence of a base, for example
potassium carbonate or cesium carbonate, mixed with proline. The reaction is
carried out in the presence of a metallic agent, for example copper iodide, in a
solvent such as dimethylsulfoxide, dioxane or tetrahydrofuran for example, and
at a temperature between 0°C and 150°C.
The compounds of formula (V) can also be prepared by reduction of a
compound of formula:
in which R1 and R2 are as defined for a compound of formula (I).
The reduction reaction can be carried out, for example, in the presence of a
metal such as iron(O), zinc or tin with an acid such as acetic acid for example, in
a solvent, for example methanol, ethanol, water or a mixture of these solvents
and at a temperature between 0°C and the reflux temperature of the solvent. A
reduction can also be carried out under hydrogen pressure in the presence of a
catalyst such as palladium for example.
The compounds of formula (V) in which R1 represents a (C1-C4)alkyl can
also be prepared by acid hydrolysis of a compound of formula:

in which A and R2 are as defined for a compound of formula (I), Z represents a
(C1-C4) alkyl, R'1 represents a hydrogen atom or a (C1-C3) alkyl and R
represents a tert-butoxycarbonyl or a hydrogen atom.
The reaction is effected by the action of a strong acid, for example
hydrochloric acid in a solvent such as water and at a temperature between
room temperature and the reflux temperature of the reaction mixture.
In particular, certain compounds of formula (V) can be prepared from other
compounds of formula (V).
Thus, for example, starting from the compounds of formula (V) in which A
represents an unsubstituted phenyl, the compounds of formula (V) can be
prepared in which:

Starting from these compounds of formula (V, R6 = Br) thus obtained, the
compounds of formula (V) are prepared in which:
Starting from these compounds of formula (V, R6 = CN) thus obtained, by
basic hydrolysis, the compounds of formula (V) are prepared in which:

Starting from these compounds of formula (V, R6 = COOH) thus obtained,
the compounds of formula (V) are prepared, by alkylation, in which:

The compounds of formula (VI) can be prepared according to SCHEME I
below, in which A, X, R1, R2, R4 and R5 are as defined for a compound of
formula (I), and Pg represents an N-protective group, preferably an acetyl
group.

In step a1 of SCHEME I, the nitrogen atom of the compounds of formula
(VIII) is protected selectively by means of an acylating agent.
In step b1, the acid or a functional derivative of said acid of formula (XIII) is
reacted with a compound of formula (V) to obtain the compound of formula
(XIV). The reaction is carried out according to the methods described above, by
reaction of a compound of formula (IV) with the compound of formula (V).
In step c1, the compound of formula (XIV) thus obtained is deprotected by
the classical methods.
In particular, certain compounds of formula (VI) can be prepared from other
compounds of formula (VI). Thus, for example, starting from compounds of
formula (VI) in which R4 = Br, the compounds of formula (VI) can be prepared in
which R4 = CI by reaction with nickel(ll) chloride by the classical methods.
The compounds of formula (VII) are known, are commercially available or
can be prepared by known methods.
The compounds of formula (VIII) in which X = -CH- can be prepared
according to an adaptation of the method described in Journal of Fluorine
Chemistry (1977) 10, 437-445 and illustrated in SCHEME II below in which R4
and R5 are as defined for a compound of formula (I).
In step a2 of SCHEME II, a compound of formula (XV) is reacted with
trifluoroacetic anhydride, in a solvent such as for example diethyl ether and at a
temperature less than or equal to 0°C.
In step b2, the compound of formula (XVI) thus obtained is hydrolyzed by
the action of a strong base such as for example sodium hydroxide or potassium
hydroxide. The reaction is carried out in a solvent, for example water or ethanol
and at a temperature between room temperature and the reflux temperature of
the solvent.
The compounds of formula (VIII) in which X = -CH- can also be prepared
according to an adaptation of the method described in Synthesis (1990) 215-
218 and illustrated in SCHEME III below in which R4 and R5 are as defined for
a compound of formula (I) and Hal represents a halogen atom, preferably
bromine or iodine.

In step a3 of SCHEME III, a compound of formula (XVII) is reacted with
benzyl acrylate, in the presence of 1,4-benzoquinone, lithium chloride and
palladium acetate. The reaction is carried out in a solvent, for example
tetrahydrofuran and at a temperature between 0°C and the reflux temperature
of the solvent.
In step b3, the compound of formula (XVIII) thus obtained is cyclized in the
presence of a base such as for example triethylamine or 1,4-
diazabicyclo[2.2.2]octane and in the presence of a palladium complex such as
for example palladium acetate. The reaction is carried out in a solvent, for
example N,N-dimethylformamide and at a temperature between room
temperature and 130°C.
In step c3, the compound of formula (XIX) thus obtained is debenzylated
according to known methods (Protective Groups in Organic Synthesis, Greene
et al., 4th Edition, John Wiley & Sons, Inc., New York, 2007) to give the
expected acid of formula (VIII).
The compounds of formula (VIII) in which X = N can be prepared by the
method described in Synthetic Communications (2005) 35 (20), 2681-2684 and
illustrated in SCHEME IV below in which R4 and R5 are as defined for a
compound of formula (I).

The compounds of formula (IX) in which R1 = (C1-C4)alkyl can be prepared
according to SCHEME V below in which R2 is as defined for a compound of
formula (I), Pg represents a protective group, preferably a trityl group.

In step as of SCHEME V, the nitrogen atom of the compound of formula
(IX) is protected, in particular by a trityl group, then the intermediate obtained is
hydrolyzed in a basic medium.
In step b5, the compound of formula (XXI) thus obtained is reacted with N-
methoxymethanamine, in the presence of a coupling agent such as for example
bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride and in the presence of a base
such as for example 4-dimethylaminopyridine. The reaction is carried out in a
solvent, for example dichloromethane and at a temperature between 0°C and
room temperature.
The compound of formula (XXII) thus obtained is reacted in step C5 with an
organometallic compound such as a (C1-C4)alkylmagnesium halide, in a
solvent such as diethyl ether or tetrahydrofuran and at a temperature between
-70°C and room temperature.
The compound of formula (XXIII) thus obtained is deprotected in step ds by
the classical methods (Protective Groups in Organic Synthesis, Greene et al.,
4th Edition, John Wiley & Sons, Inc., New York, 2007).
The compounds of formula (IX) in which R1 = (C1-C4)alkyl can also be
prepared according to SCHEME VI below in which R2 is as defined for a
compound of formula (I), Pg represents a protective group, preferably a trityl
group, Z represents a (C1-C4)alkyl and R'1 represents a hydrogen atom or a
(C1-C3)alkyl.

In step as of SCHEME VI, the compound of formula (XXI) is reacted with
1,1'-carbonyldiimidazole then, without isolating, the intermediate thus obtained
is treated with a magnesium salt of a hemi-ester of malonic acid according to
the method described in Angew. Chem. Int. Ed. Engl/(1979) 18 (1), 72-74.
In step b6, the compound of formula (XXIV) thus obtained is alkylated by
reaction of a (C1-C3)alkyl halide, mesylate or tosylate, in the presence of a
strong base such as for example sodium hydride, in a solvent, for example
tetrahydrofuran and at a temperature between 0°C and room temperature.
In step C6, the compound of formula (XXV) thus obtained is hydrolyzed in
an acid medium. The reaction is effected by the action of a strong acid such as
for example hydrochloric acid, in a solvent such as water and at a temperature
between room temperature and 105°C. The spontaneous decarboxylation that
ensues is able to generate the compound of formula (IX).
The compounds of formula (IX) in which R1 = (C1-C4)alkoxy are known, are
commercially available or are prepared according to known methods (Synlett
(2004) 4, 703-707).
The compounds of formula (X) are known, are commercially available or are
prepared according to known methods (Tetrahedron (1988) 44 (10), 2977-2983;
J. Org. Chem. (2008) 73 (23), 9326-9333).
The compounds of formula (XI) in which R1 = (C1-C4)alkyl are prepared
according to SCHEME VII below in which A and R2 are as defined for a
compound of formula (I), Z represents a (C1-C4)alkyl and R'1 represents a
hydrogen atom or a (C1-C3)alkyl.

Steps a7, b7 and c7 of SCHEME VII are carried out according to the same
protocols as those described for steps a6, b6 and c6 of SCHEME VI.
The compounds of formula (XII) can also be prepared according to
SCHEME VIII below in which A and R2 are as defined for a compound of
formula (I), Z represents a (C1-C4)alkyl, R'1 represents a hydrogen atom or a
(C1-C3)alkyl, Y represents a leaving group as defined previously and Boc
represents a tert-butoxycarbonyl.

In step as of SCHEME VIII, the compound of formula (XXIX) is reacted with
4-methoxybenzylamine in a solvent such as dioxane and at the reflux
temperature of the solvent.
In step b8, the compound of formula (XXX) thus obtained is hydrolyzed in a
basic medium, with a base such as potassium hydroxide to give the acid of
formula (XXXI).
In step C8, the compound of formula (XXXI) is protected by a group Boc, in
the presence of bases such as triethylamine or 4-dimethylaminopyridine in a
solvent such as DMF.
Steps d8 and eg are carried out according to the same protocols as those
described for steps a6 and b6 of SCHEME VI.
The compounds of formula (XV), (XVII), (XX) are known, are commercially
available or can be prepared by known methods.
The compounds of formula (XXVI) are known, are commercially available or
are prepared according to methods described in EP 1 176 140.
The compounds of formula (XXIX) in which A represents a pyridazinyl
radical are prepared according to the method described in J. Heterocyclic
Chem. (2009) 46, 584-590.
According to another of its aspects, the invention also relates to novel
compounds of formula (II). These compounds are useful as synthesis
intermediate for the compounds of formula (I).
Thus, the invention relates to compounds of formula:

in which:
- A represents a divalent aromatic radical selected from:

- X represents a -CH- group or a nitrogen atom;
- R1 represents a (C1-C4)alkyl or a (C1-C4)alkoxy;
- R2 represents a group Alk;
- R4 represents a hydrogen atom, a halogen atom, a cyano, a phenyl, a group
Alk, a group OAlk or a group -NR9R10;
- R5 represents a hydrogen atom, a halogen atom or a group Alk;
- R6 represents a hydrogen atom, a halogen atom, a cyano, a group
-COOAlk or a -CONH2 group;
- R9 and R10 represent, each independently, a hydrogen atom or a (C1-
C4)alkyl;
- Z represents a (C1-C4)alkyl;
- Alk represents a (C1-C4)alkyl, unsubstituted or substituted one or more
times with a fluorine atom.
According to another of its aspects, the invention also relates to the use of
compounds of formula (I), as they are or in radiolabeled form as
pharmacological tools in humans or in animals, for the detection and labeling of
the P2Y12 purinergic receptor.
The following examples describe the preparation of some compounds
according to the invention. These examples are not limiting and are only
intended to illustrate the present invention. The numbers of compounds in the
examples refer to those given in TABLES X to XV below, which illustrate the
chemical structures and physical properties of some compounds according to
the invention.
The following abbreviations are used in the preparations and in the
examples:
Me: methyl
Et: ethyl
n-Pr: n-propyl
Ph: phenyl
ether: diethyl ether
iso ether: diisopropyl ether
DMSO: dimethylsulfoxide
DMF: N,N-dimethylformamide
THF: tetrahydrofuran
DCM: dichloromethane
EtOAc: ethyl acetate
DMAP: 4-dimethylaminopyridine
DIPEA: diisopropylethylamine
HOAT: 1 -hydroxy-7-azabenzotriazole
HOBT: 1-hydroxybenzotriazole
TFA: trifluoroacetic acid
BOP: benzotriazol-1 -yloxytris(dimethylamino)phosphonium
hexafluorophosphate
BOP-CI: bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride
EDC: 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
NaOH: sodium hydroxide
KOH: potassium hydroxide
HCI: hydrochloric acid
NaBH4: sodium borohydride
NaHCO3: sodium hydrogen carbonate
NaH: sodium hydride
Na2SO4: sodium sulfate
1N or 2N hydrochloric ether: 1N or 2N solution of hydrochloric acid in diethyl
ether
1N (or 2N) HCI in ether: 1N (or 2N) solution of hydrochloric acid in diethyl
ether
4N HCI in dioxane: 4N solution of hydrochloric acid in dioxane
m.p.: melting point
RT: room temperature
b.p.: boiling point
HPLC: high-performance liquid chromatography
Brine: saturated solution of sodium chloride in water.
The proton nuclear magnetic resonance spectra (1H NMR) are recorded on
Bruker spectrometers (250 and 400 MHz) in DMSO-d6. The chemical shifts d
are expressed in parts per million (ppm). The following abbreviations are used
for interpreting the spectra: s: singlet, d: doublet, t: triplet, q: quadruplet: m:
massive, mt: multiplet, bs: broad singlet, dd: doublet of doublets, br: broad
peak.
The compounds according to the invention are analyzed by coupled HPLC-
UV-MS (liquid chromatography/UV detection/mass spectroscopy).
The equipment used is composed of a chromatographic chain equipped
with a diode array detector and a quadrupole mass spectrometer. The
molecular peak (MH+) and the retention time (tR) in minutes are measured.
Method A: WatersXBridge C18, 4.6 x 50 mm, 2.5µm
Solvent A: water + 0.05% TFA
Solvent B: MeCN + 0.05% TFA
1.3 ml/min; 40°C; Waters LCT classic TOF-MS

The mass spectra are recorded in positive electrospray mode (ESI), in order
to observe the ions resulting from protonation of analyzed compounds (MH+), or
from the formation of adducts with other cations such as Na+, K+, etc.
PREPARATIONS
1. Preparations of the compounds of formula (XVI).
Preparation 1.1
1 -(5-Bromo-1H-indol-3-yl)-2,2,2-trifluoroethanone.
(XVI): R4 = Br; R5 = H.
A solution of 21.3 ml of trifluoroacetic anhydride in 70 ml of ether is added
dropwise to a solution of 20 g of 5-bromoindole in 250 ml of ether cooled to
-5°C. It is stirred for 2 hours at -5°C. The precipitate formed is drained and is
washed with ether. 24.5 g of the expected compound is obtained in the form of
a white powder.
m.p. = 254°C
1H NMR: DMSO-d6 (250 MHz): d (ppm): 7.50 (1H, d); 7.58 (1H, d); 8.31
(1H, s); 8.55 (1H, s); 12.85 (1H, br).
Following the procedure described in preparation 1.1, the 3-
trifluoroacetylindoles of formula (XVI) presented in TABLE I below are prepared:

2. Preparations of the compounds of formula (VIII: X = CH).
Preparation 2.1
5-Bromo-1 H-indole-3-carboxylic acid
(VIII): X = CH; R4 = Br; R5 = H.
24 g of the compound obtained in Preparation 1.1 is added to a solution of
46.1 g of potassium hydroxide in 25 ml of water, and is heated for 4 hours under
reflux. The reaction mixture is cooled and is washed with ether. The aqueous
phase is cooled to 5°C and is then neutralized with a solution of phosphate
buffer preloaded with 35% hydrochloric acid. The precipitate formed is drained
and is washed with water. 15.6 g of the expected compound is obtained in the
form of a white powder.
m.p. = 234°C.
1H NMR: DMSO-d6 (250 MHz): d (ppm): 7.32 (1H, d); 7.46 (1H, d); 8.06
(1H, s); 8.14 (1H, s); 12.00 (2H, br).
Following the procedure described in preparation 2.1, the 3-carboxyindoles
of formula (VIII: X = CH) presented in TABLE II below are prepared:
TABLE II

Preparation 2.6
5,6-Dimethyl-1 H-indole-3-carboxylic acid.
(VIII): X = CH; R4 = Me; R5 = Me.
Step 1: 3-[(2-lodo-4,5-dimethylphenyl)amino]benzyl acrylate (XVIII).
60.8 g of lithium chloride is added to a solution of 15.5 g of [1,4]-
benzoquinone in 350 ml of THF, and it is degassed with nitrogen. 3.2 g of
palladium acetate and 23.7 g of benzyl acrylate are added and it is degassed
with nitrogen for about 30 minutes. Then a solution of 35.1 g of 2-iodo-4,5-
dimethylaniline (prepared according to J. Med. Chem 2001, 44, 3856-3871) in
150 ml of THF is added and it is stirred overnight. It is filtered and the filtrate is
evaporated. The solid residue thus obtained is triturated with ether. It is filtered,
the filtrate is washed with a solution of NaOH 0.5N and then with water and with
brine. It is evaporated and then the solid residue is purified by silica gel
chromatography, eluting with a cyclohexane/EtOAc mixture (8/2; v/v). 57.6 g of
the expected compound is obtained in the form of a white powder.
1H NMR: DMSO-d6 (250 MHz): d (ppm): 2.14 (3H, s); 2.19 (3H, s); 4.93 (1H,
d); 5.18 (2H, s); 7.23 (1H, s); 7.30-7.45 (5H, m); 7.59 (1H, s); 7.72 (1H, dd);
10.05 (1H,d).
Following the same procedure, the compound of formula (XVIII) shown
below is prepared:
Step 2: Benzyl 5,6-dimethyl-1H-indole-3-carboxylate (XIX).
8.60 g of 1,4-diazabicyclo[2.2.2]octane is added to a solution of 25.5 g of
the compound obtained in step 1 in 120 ml of DMF. It is degassed with nitrogen,
then 0.703 g of palladium acetate is added and the reaction mixture is heated at
120°C for 7 hours. EtOAc is added, then it is washed with water and with brine,
dried over Na2SO4 and evaporated. After trituration of the solid residue with iso
ether, 12.3 g of the expected compound is obtained in the form of a beige
powder.
1H NMR: DMSO-d6 (250 MHz): d (ppm): 2.29 (3H, s); 2.30 (3H, s); 5.32 (2H,
s); 7.24 (1H, s); 7.30-7.50 (5H, m); 7.76 (1H, s); 7.98 (1H, d); 11.70 (1H, br).
Following the same procedure, the compound of formula (XIX) presented
below is DreDared:
Step 3: 5,6-Dimethyl-1H-indole-3-carboxylic acid.
0.54 g of Pd/C 10% and 16.9 g of ammonium formate are added to a
solution of 5 g of the compound obtained in step 2 in 120 ml of MeOH. It is
heated under reflux for 2 hours. It is filtered on talc and the filtrate is
evaporated.
The solid residue is extracted with EtOAc. It is washed with 0.1 N HCI
solution, dried over Na2SO4 and evaporated to dryness. 2.87 g of the expected
compound is obtained in the form of a white powder.
1H NMR: DMSO-d6 (250 MHz): d (ppm): 2.31 (6H, s); 7.23 (1H, s); 7.77 (1H,
s); 7.85 (1H, s); 11.50 (1H, br); 11.80 (1H, br).
Following the same procedure, the compound of formula (VIII: X = CH)
presented below is obtained:
The 3-carboxyindazoles (compounds of formula VIII, X=N) are synthesized
from commercial isatine according to the method described in Synthetic
Communications (2005), 2681-2684.
3. Preparations of the compounds of formula (IV).
Preparation 3.1
5-Chloro-1 -(2-methoxy-2-oxoethyl)-1 H-indole-3-carboxylic acid.
(IV): X = CH; R4 = CI; R5 = H; Z = Me.
110 ml of a solution containing 10 g of 5-chloro-1 H-indole-3-carboxylic acid
(commercial) in DMF is added dropwise to a mixture of 4.50 g of NaH (60% in
oil) in 400 ml of DMF at -10°C. After it returns to RT, it is stirred for 1 hour. The
reaction mixture is cooled to -20°C. 4.86 ml of methyl bromoacetate is added
dropwise, it is returned to RT for a period of 5 hours and is stirred for 15 hours.
The reaction mixture is added to 1L of EtOAc/1N HCI mixture, the organic
phase is collected and the aqueous phase is extracted with EtOAc. The organic
phases are combined, washed with water and with brine, then dried over
Na2SO4 and evaporated to dryness. 8.9 g of the expected compound is
obtained in the form of a white powder.
1H NMR: DMSO-d6 (250 MHz): d (ppm): 3.70 (3H, s); 7.26 (1H, d); 7.57
(1H, d); 7.98 (1H, s); 8.12 (1H, s); 12.3 (1H, br).
Following the procedure described in preparation 3.1, the compounds of
formula (IV) in which X = CH and Z = Me, presented in TABLE III below, are
prepared:

4. Preparations of the compounds of formula (XIII).
Preparation 4.1
1-Acetyl-5-chloro-6-fluoro-1 H-indole-3-carboxylic acid.
(XIII): X = CH; R4 = CI; R5 = F; Pg = -COMe.
A solution of 4.4 g of the compound from Preparation 2.5 in 100 ml of DCM
is cooled to 0°C, 6.28 ml of triethylamine and 0.51 g of DMAP are added and
then, dropwise, 1.47 ml of acetyl chloride and it is stirred for 3 hours. The
reaction mixture is washed with 1N HCI solution and then with water, with
saturated NaCI solution, the organic phase is dried over Na2SO4 and the solvent
is evaporated under vacuum. 4.82 g of the expected compound is obtained in
the form of white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 2.74: s: 3H; 8.13: d: 1H; 8.25: d:
1H; 8.52: s:1H; 13.10: br:1H.
Following the procedure described in preparation 4.1, the compounds of
formula (XIII) in which Pg = -COMe, presented in TABLE IV below, are
prepared:
TABLE IV
5. Preparations of the compounds of formula (IX).
Preparation 5.1
1 -(5-Methyl-1 H-pyrazol-4-yl)butan-1 -one.
(IX): R-| = n-Pr; R2 = Me.
Step 1: 3-methyl-1-trityl-1H-pyrazole-4-carboxylic acid (XXI).
8.46 g of potassium carbonate and 15.8 g of chloride trityl are added to a
solution of 6.60 g of methyl 5-methyl-1H-pyrazole-4-carboxylate in 50 ml of
DMF. After 5 days at RT, EtOAc is added, it is washed with water, with brine,
dried over Na2SO4 and evaporated to dryness. The oily residue thus obtained is
dissolved in 100 ml of EtOH/water mixture (50/50; v/v), 9.95 g of potassium
hydroxide is added and it is heated under reflux for 6 hours. The reaction
mixture is filtered while hot, the filtrate is concentrated and acidified with 1N HCI
solution. The precipitate that formed is drained, dried under vacuum and then
washed with EtOAc/iso ether mixture (50/50; v/v) and dried under vacuum.
9.70 g of the expected compound is obtained in the form of a white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 2.33 (3H, s); 7.03-7.09 (6H, m);
7.34-7.43 (9H, m); 7.61 (1H,s).
Step 2: N-methoxy-N,3-dimethyl-1-trityl-1H-pyrazole-4-carboxamide (XXII).
10.3 g of DMAP and 10.3 g of BOP-CI are added to a solution of 9.70 g of
the compound obtained in the preceding step, in 100 ml of DCM. Then 3.85 g of
N-methoxymethanamine hydrochloride is added in portions and stirred for 1
hour at RT. The reaction mixture is concentrated under vacuum, the residue is
extracted with EtOAc, it is washed with water, with brine, dried over Na2SO4 and
then evaporated to dryness. It is triturated with iso ether, filtered and dried in a
vacuum stove. 10.4 g of the expected compound is obtained in the form of a
white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 2.34 (3H, s); 3.13 (3H, s); 3.39 (3H,
s); 7.05-7.15 (6H, m); 7.33-7.44 (9H, m); 7.71 (1H, s).
Step 3:1-(3-methyl-1-trityl-1H-pyrazol-4-yl)butan-1-one (XXIII).
32.7 ml of a 2M solution of n-propylmagnesium chloride in ether is added
dropwise to a solution of 10.4 g of the compound obtained in the preceding
step, in 130 ml of THF at -30°C. It is returned to RT and then stirred for 4 hours.
The reaction mixture is cooled to -30°C and then 50 ml of water is added
(dropwise at first). It is returned to RT, 250 ml of 1N HCI solution is added and
then it is extracted with EtOAc. It is washed with water, with brine, dried over
Na2SO4 and then evaporated to dryness. It is triturated in iso ether, filtered and
dried in a vacuum stove. 8.4 g of the expected compound is obtained in the
form of a white powder.
1H NMR: DMSO-d6 (400 MHz):d (ppm): 0.84 (3H, t); 1.52 (2H, sext); 2.34
(3H, s); 2.62 (2H, t); 7.04-7.12 (6H, m); 7.33-7.45 (9H, m); 7.93 (1H, s).
Step 4:1-(5-methyl-1H-pyrazol-4-yl)butan-1-one.
A suspension of 8.4 g of the compound obtained in the preceding step, in
50 ml of 4N HCI in dioxane is stirred for 6 hours. It is evaporated to dryness,
triturated with iso ether, filtered and dried in a vacuum stove. 3.1 g of the
expected compound is obtained in the form of a colorless gum.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.90 (3H, t); 1.58 (2H, sext); 2.39
(3H,s);2.71 (2H, t); 8.15 (1H, s).
6. Preparations of the compounds of formula (V).
Preparation 6.1
1 -[1 -(5-Aminopyrazin-2-yl)-5-methyl-1 H-pyrazol-4-yl]butan-1 -one.

A mixture of 0.60 g of the compound from Preparation 5.1, 1.37 g of 5-
bromo-pyrazin-2-ylamine (X), 1.36 g of potassium carbonate, 0.38 g of proline
and 0.23 g of copper(l) iodide in 15 ml of DMSO is heated at 130°C for 20
hours. 100 ml of water is added and it is extracted with DCM. The organic
phase is washed with a saturated solution of sodium bicarbonate and then with
brine, dried over Na2SO4 and evaporated to dryness. It is purified by silica gel
chromatography, eluting with a gradient of DCM/EtOAc mixture from (80/20;
v/v) to (40/60; v/v). 0.17 g of the expected compound is obtained in the form of
powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.93 (3H, t); 1.62 (2H, sext); 2.55
(3H, s); 2.80 (2H, t); 6.86 (2H, br); 7.80 (1H, s); 8.19-8.22 (2H, m).
Preparation 6.2
1 -[1 -(6-Aminopyridazin-3-yl)-5-methyl-1 H-pyrazol-4-yl]butan-1 -one.

Step 1:1-[6-(4-methoxybenzylamino)-pyridazin-3-yl]-5-methyl-1H-pyrazole-
4-ethyl carboxylate (XXX).
0.31 ml of 4-methoxybenzylamine is added to a solution of 0.30 g of ethyl 1-
(6-chloropyridazin-3-yl)-5-methyl-1H-pyrazole-4-carboxylate (synthesized by the
method described in J. Heterocyclic Chem. 2009, 46, 584-590) in 2 ml of
dioxane, then it is heated at 130°C for 2 hours. It is evaporated to dryness,
triturated with water, the precipitate is drained and dried under vacuum. The
precipitate is taken up in iso ether, drained and dried under vacuum. 0.30 g of
the expected product is obtained in the form of powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 1.30 (3H, t); 2.69 (3H, s); 3.74 (3H,
s); 4.26 (2H, q); 4.55 (2H, d); 6.91 (2H, d); 7.09 (1H, d); 7.32 (2H, d); 7.62 (1H,
d); 7.67 (1H,t); 8.03 (1H,s).
Step 2:1 -[6-(4-Methoxybenzylamino)-pyridazin-3-yl]-5-methyl-1 H-pyrazole-
4-carboxylic acid (XXXI).
A solution of 5 g of the compound obtained in the preceding step in 50 ml of
EtOH is added to a solution of 3.82 g of KOH in 50 ml of water. It is heated at
80°C for 2 hours. It is evaporated to dryness and then the residue is taken up in
100 ml of water. 68 ml of 1N HCI solution is added dropwise, with stirring. The
precipitate that formed is drained, it is washed with water and then dried in a
vacuum stove. 4.5 g of the expected compound is obtained in the form of a
white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 2.71 (3H, s); 3.75 (3H, s); 4.57 (2H,
s); 6.93 (2H, d); 7.30-7.37 (3H, m); 7.81 (1H, d); 8.04 (1H, s); 8.42 (1H, br).
Step 3:1 -{6-[(tert-Butoxycarbonyl)-(4-methoxybenzyl)-amino]-pyridazin-3-
yl}-5-methyl-1H-pyrazole-4-carboxylic acid (XXXII).
0.17 g of DMAP, 2.32 ml of triethylamine and 3 g of di-tert-butyl bicarbonate
are added to a solution of 1.87 g of the compound from the preceding step in
22 ml of DMF, then it is stirred for 20 hours at RT. 0.47 g of potassium
hydroxide in solution in 10 ml of water is added, then it is stirred for 20 hours.
500 ml of water is added and it is washed with ether. The aqueous phase is
buffered with phosphate buffer preloaded with 1N hydrochloric acid. The
precipitate that formed is drained, it is washed with water and dried in a vacuum
stove at 50°C. 1.35 g of the expected compound is obtained in the form of
powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 1.43 (9H, s); 2.83 (3H, s); 3.71 (3H,
s); 5.19 (2H, br); 6.88 (1H, d); 7.25 (1H, d); 8.05-8.21 (3H, m); 12.7 (1H, br).
Step 4: Ethyl 3-(1-{6-[(tert-butoxycarbonyl)-(4-
methoxybenzyl)amino]pyridazin-3-yl}-5-methyl-1H-pyrazol-4-yl)-3-oxo-
propanoate (XXXIII).
0.53 g of 1,1'-carbonyldiimidazole is added to a solution of 1.1 g of the
compound obtained in the preceding step in 17 ml of THF, and it is stirred for 20
hours at RT. 0.82 g of magnesium bis(3-ethoxy-3-oxopropanoate) is added and
it is stirred at 55°C for 20 hours. 50 ml of EtOAc is added, it is washed with 0.1
N soda, with brine, dried over Na2SO4 and evaporated to dryness. It is purified
by silica gel chromatography, eluting with DCM and then eluting with
DCM/MeOH mixture (95/5; v/v). 1.18 g of the expected compound is obtained in
the form of a white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 1.21 (3H, t); 1.43 (9H, s); 2.82 (3H,
s); 3.72 (3H, s); 4.04 (2H, s); 4.13 (2H, q); 5.19 (2H, s); 6.88 (2H, d); 7.25 (2H,
d); 8.09 (1H, d); 8.22 (1H, d); 8.41 (1H, s).
Step 5: Ethyl 2-{1-[6-(4-methoxybenzylamino)-pyridazin-3-yl]-5-methyl-1 H-
pyrazole-4-carbonyl}butanoate(XII).
1.25 g of potassium carbonate, 0.98 g of tetrabutylammonium bromide and
0.44 ml of iodoethane are added to a solution of 1.15 g of the compound
obtained in the preceding step in 23 ml of THF, then it is stirred at 55°C for 20
hours. After it returns to RT, 150 ml of EtOAc is added, it is washed with water,
with brine, dried over Na2SO4 and evaporated to dryness. It is purified by silica
gel chromatography, eluting with DCM/MeOH mixture (97/3; v/v). 1.18 g of the
expected compound is obtained in the form of a white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.92 (3H, t); 1.15 (3H, t); 1.43 (9H,
s); 1.88 (2H, quint); 2.82 (3H, s); 3.72 (3H, s); 4.10 (2H, q); 4.28 (1H, t); 5.19
(2H, s); 6.88 (2H, d); 7.25 (2H, d); 8.09 (1H, d); 8.22 (1H, d); 8.49 (1H, s).
Step 6:1 -[1 -(6-Amino-pyridazin-3-yl)-5-methyl-1 H-pyrazol-4-yl]butan-1 -one.
1.18 g of the compound from the preceding step in 5 ml of 6N HCI is heated
under reflux for 6 hours. After it returns to RT, 50 ml of water is added, it is
washed with EtOAc, and then the aqueous phase is evaporated to dryness.
50 ml of 0.2N NaOH solution is added and it is extracted with EtOAc. The
organic phase is washed with brine, dried over Na2SO4 and evaporated to
dryness. 0.42 g of the expected compound is obtained in the form of a white
powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.93 (3H, t); 1.62 (2H, sext); 2.65
(3H, s); 2.82 (2H, t); 6.76 (2H, br); 7.00 (1H, d); 7.59 (1H, d); 8.27 (1H, s).
Preparation 6.3
1 -[1 -(4-Aminophenyl)-5-methyl-1 H-pyrazol-4-yl]butan-1 -one.

Step 1: Ethyl 3-[5-Methyl-1-(4-nitrophenyl)-1 H-pyrazol-4-yl]-3-
oxopropanoate (XXVII).
2.95 g of 1,1'-carbonyldiimidazole is added to a solution of 3 g of 5-methyl-
1-(4-nitrophenyl)-1H-pyrazole-4-carboxylic acid (XXVI) in 120 ml of THF, and
stirred for 20 hours at RT. 5.2 g of magnesium bis (3-ethoxy-3-oxopropanoate)
(synthesized according to the method described in Angew. Chem. Int. Ed. Engl.,
1979, 18, 72-74) is added and it is heated at 45°C for 16 hours. The reaction
mixture is concentrated under vacuum, the residue is extracted with EtOAc, the
organic phase is washed with a saturated solution of Na2CO3, with water, dried
over MgSO4 and the solvent is evaporated under vacuum. The residue is
chromatographed on silica gel, eluting with DCM and then with DCM/EtOH
mixture (99.5/0.5; v/v). 2.82 g of the expected compound is obtained.
1H NMR: CDCI3 (250 MHz): d (ppm): 1.28 (3H, t); 2.70 (3H, s); 3.88 (2H,
s); 4.26 (2H, q); 7.70 (2H, d); 8.09 (1H, s); 8.42 (2H, d).
Step 2: Ethyl 2-{[5-Methyl-1-(4-nitrophenyl)-1 H-pyrazol-4-
yl]carbonyl}butanoate (XXVIII).
A solution of 2.44 g of the compound from the preceding step in 25 ml of
THF is cooled to 0°C, 0.34 g of NaH (60% in oil) is added in portions and stirred
for 30 minutes. Then 0.92 ml of iodoethane is added and stirred for 24 hours at
RT. Water is added slowly, then the reaction mixture is concentrated under
vacuum. The residue is extracted with DCM, the organic phase is washed with
water, dried over MgSO4 and the solvent is evaporated under vacuum. The
residue is chromatographed on silica gel, eluting with EtOAc/cyclohexane
mixture (gradient from 10 to 20% of EtOAc). 2.19 g of the expected compound
is obtained.
1H NMR: CDCl3 (250 MHz):d (ppm): 1.02 (3H, t); 1.28 (3H, t); 2.06 (3H, m);
2.72 (3H, s); 3.97 (1H, t); 4.23 (2H, q); 7.70 (2H, d); 8.18 (1H, s); 8.42 (2H, d).
Step 3:1-[5-Methyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl]butan-1-one (XI).
2.4 g of the compound from the preceding step in 58 ml of an aqueous
solution of HCI at 37% is heated at 105°C for 2 hours. The reaction mixture is
cooled to 0°C, 60 ml of 35% NaOH is added slowly, it is extracted with EtOAc,
the organic phase is washed with water, dried over MgSO4 and the solvent is
evaporated under vacuum. 1.8 g of the expected compound is obtained.
1H NMR: CDCl3 (250 MHz):d (ppm): 1.02 (3H, t); 1.78 (2H, m); 2.75 (3H, s);
2.85 (2H, t); 7.70 (2H, d); 8.10 (1H, s); 8.42 (2H, d).
Step 4:1 -[1 -(4-Aminophenyl)-5-methyl-1 H-pyrazol-4-yl]butan-1 -one.
450 ml of EtOH is poured onto 5 g of palladium/charcoal under a controlled
argon stream. Then a suspension of 48.7 g of the compound from the preceding
step in 50 ml of EtOH is added, and then 181 ml of cyclohexene and it is heated
under reflux for 4 hours. After cooling to RT, the reaction mixture is filtered on
Celite®, it is washed with EtOAc and the filtrate is concentrated under vacuum.
The residue is taken up in petroleum ether, the precipitate that formed is
drained, it is washed with petroleum ether and dried under vacuum at 50°C.
41.3 g of the expected compound is obtained.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.93 (3H, t); 1.60 (2H, m); 2.41
(3H, s); 2.77 (2H, t); 5.6 (2H, br); 6.66 (2H, d); 7.10 (2H, d); 8.14 (1H, s).
Preparation 6.4
1 .[1 -(4-Aminophenyl)-5-methyl-1 H-pyrazol-4-yl]propane-1 -one.

Step 1: Ethyl 2-methyl-3-[5-methyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl]-3-oxo-
propanoate.
0.07 g of NaH (60% in oil) is added slowly in small portions to 0.50 g of the
compound obtained in step 1 of Preparation 6.3 in 5 ml of THF at 0°C. It is
stirred for 30 minutes and then 0.15 ml of iodomethane is added. After 24 h at
RT, water is added slowly and the THF is evaporated. The residue is extracted
with DCM and the organic phase is washed with water, dried over Na2SO4 and
evaporated to dryness. The residue is recrystallized from cyclohexane,
obtaining 0.5 g of a yellow solid.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 1.16 (3H, t); 1.32 (1H, d); 2.61 (3H,
s); 4.09 (2H, q); 4.44 (1H, q); 7.90 (2H, d); 8.38-8.44 (3H, m).
Step 2:1 -[5-Methyl-1 -(4-nitrophenyl)-1 H-pyrazol-4-yl]propane-1 -one.
0.5 g of the compound obtained in the preceding step in 13 ml of 35% HCI
is heated at 105°C for 2 hours. It is cooled to 0°C and 14 ml of 35% NaOH is
added slowly. It is extracted with EtOAc, washed with water, with brine, dried
over Na2SO4 and evaporated to dryness. The residue is chromatographed on
silica gel, eluting with EtOAc/cyclohexane mixture (gradient from 0 to 20% of
EtOAc). 0.39 g of a beige solid is obtained.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 1.08 (3H, t); 2.62 (3H, s); 2.89 (2H,
q); 7.88 (2H, d); 8.36-8.43 (3H, m).
Step 3:1 -[1 -(4-Aminophenyl)-5-methyl-1 H-pyrazol-4-yl]propane-1 -one.
0.5 g of the compound from the preceding step is dissolved in 20 ml of
EtOAc/MeOH mixture (50/50; v/v). It is reduced using the H-Cube continuous
hydrogenation apparatus (Cartridge Pd 10%, Mode Full H2, 50°C, flow
1 ml/min). It is concentrated to dryness, the solid residue is taken up in iso
ether, the precipitate that formed is drained and 0.25 g of a white powder is
obtained.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 1.07 (3H, t); 2.42 (3H, s); 2.82 (2H,
q); 5.44 (2H, br); 6.64 (2H, d); 7.07 (2H,d); 8.12 (1H, s).
Preparation 6.5
1 -[1 -(4-Aminophenyl)-5-methyl-1 H-pyrazol-4-yl]ethanone.

2 ml of acetic acid and 0.64 g of iron(0) are added to 0.94 g of 1 -[5-methyl-
1-(4-nitrophenyl)-1H-pyrazol-4-yl]ethanone (Journal of Chemical Research,
Synopses (1986), (5), 166-7) in 60 ml of EtOH/water mixture (65/35; v/v). It is
heated at 75°C for 2 hours. It is concentrated, filtered on Celite®, the filtrate is
neutralized with saturated Na2CO3 and it is extracted with DCM. The organic
phase is washed with water, with brine, it is dried over Na2SO4 and evaporated.
0.70 g of yellow powder is obtained.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 2.41 (3H, s); 5.47 (2H, br); 6.65
(2H, d); 7.08 (2H,d); 8.12(1 H,s).
Preparation 6.6
1 -(4-Aminophenyl)-5-methyl-1 H-pyrazole-4-ethyl carboxylate.

0.1 g of ethyl 5-methyl-1-(4-nitrophenyl)-1 H-pyrazole-4-carboxylate
(Russian Journal of Organic Chemistry English (2000) 36, 2, 191-194) is
dissolved in 20 ml of EtOAc/MeOH mixture (50/50; v/v). It is reduced using the
continuous hydrogenation apparatus (Cartridge Pd 10%, Mode Full H2, 50°C,
flow 1 ml/min). It is concentrated to dryness, the solid residue is taken up in iso
ether and the precipitate that formed is drained. 0.08 g of a white powder is
obtained.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 1.41 (3H, t); 4.35 (2H, q); 6.74 (2H,
d); 7.20 (2H,d); 8.03 (1H, s).
Preparation 6.7
1 -[1 -(4-Amino-3-bromophenyl)-5-methyl-1 H-pyrazol-4-yl]butan-1 -one.

2.2 g of N-bromosuccinimide is added to 3g of the compound from
Preparation 6.3 in 50 ml of acetonitrile, then heated under reflux for 1 hour.
After it returns to RT, 1N NaHCO3 solution is added, it is extracted with EtOAc,
washed with water, with brine, dried over Na2SO4 and evaporated to dryness.
The residue is taken up in petroleum ether, and the precipitate that formed is
drained, obtaining 3.5 g of a beige powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.92 (3H, t); 1.62 (2H, sext); 2.44
(3H, s); 2.78 (2H, t); 5.69 (2H, br); 6.89 (1H, d); 7.19 (1H, d); 7.49 (1H, s); 8.17
(1H,s).
Preparation 6.8
2-Amino-5-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)benzonitrile.

0.44 g of zinc cyanide and 0.18 g of Tetrakis(triphenylphosphine)palladium
are added to 1 g of the compound from Preparation 6.7 in 20 ml of DMF in a
sealed tube, and it is heated at 100°C for 7 hours. The reaction mixture is
poured into saturated solution of NaHCO3 and extracted with EtOAc. It is
washed with water, with brine, dried over Na2SO4 and evaporated to dryness.
The residue is taken up in iso ether and the precipitate that formed is drained,
obtaining 0.71 g of a white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.92 (3H, t); 1.61 (2H, sext); 2.44
(3H, s); 2.78 (2H, t); 6.45 (2H, br); 6.90 (1H, d); 7.42 (1H, d); 7.58 (1H, s); 8.19
(1H,s).
Preparation 6.9
Methyl 2-amino-5-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)benzoate.

Step 1: 2-Amino-5-(4-butyryl-5-methyl-1H-pyrazol-1-yl)benzoic acid.
17 ml of 2N NaOH is added to 1.5 g of the compound from Preparation 6.8
and it is heated at 100°C for 8 hours. Water is added, it is washed with DCM
and then acidified with 2N HCI. The precipitate is drained, it is washed with
water and dried in a vacuum stove. 1.4 g of the expected compound is obtained
in the form of a white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.93 (3H, t); 1.62 (2H, sext); 2.44
(3H, s); 2.78 (2H, t); 6.88 (1H, d); 7.33 (1H, d); 7.69 (1H, s); 8.17 (1H, s).
Step 2: Methyl 2-amino-5-(4-butyryl-5-methyl-pyrazol-1-yl)-benzoate.
0.38 g of potassium bicarbonate and then 0.24 ml of methyl iodide are
added to 1 g of the compound from the preceding step in 20 ml of DMF. After 3
hours at RT, water is added and it is extracted with EtOAc. The organic phase
is washed with water, with brine, dried over Na2SO4 and evaporated to dryness,
obtaining 0.89 g of a beige powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.93 (3H, t); 1.62 (2H, sext); 2.44
(3H, s); 2.78 (2H, t); 3.80 (3H, s); 6.91 (1H, d); 6.97 (2H, br); 7.38 (1H, d); 7.72
(1H, s);8.17(1H, s).
Preparation 6.10
2-Amino-5-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)benzamide.

2.2 ml of 2N NaOH is added to 0.2 g of the compound from Preparation 6.8
in 5 ml of dioxane, then it is heated at 100°C for 20h. After it returns to RT,
water is added and it is extracted with DCM. It is dried over Na2SO4 and
evaporated to dryness. It is purified by silica gel chromatography, eluting with
DCM/MeOH mixture (up to 95/5; v/v). 0.14 g of a white powder is obtained.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.93 (3H, t); 1.62 (2H, sext); 2.44
(3H, s); 2.78 (2H, t); 6.81 (1H, d); 6.98 (2H, br); 7.18 (1H, br); 7.24 (1H, d); 7.65
(1H, s); 7.81 (1H,br); 8.16 (1H,s).
7. Preparations of the compounds of formula (III).
Preparation 7.1
1 -(1 -Methoxypropan-2-yl)piperazine dihydrochloride

Step 1: tert-Butyl 4-(1-methoxy-1-oxopropan-2-yl)piperazine-1-carboxylate.
2.97 g of potassium carbonate and 1.97 g of methyl 2-bromopropanoate are
added to a solution of 2 g of tert-butyl piperazine-1-carboxylate in 36 ml of DMF,
and then it is heated at 60°C for 1 hour. After it returns to RT, 150 ml of EtOAc
is added, it is washed with water, with brine, dried over Na2SO4 and then
evaporated to dryness. 2.8 g of the expected compound is obtained in the form
of a colorless oil.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 1.18 (3H, d); 1.39 (9H, s); 2.49
(4H, m); 3.26 (4H, m); 3.37 (1H, q); 3.62 (3H, s).
Step 2: 2-[4-(tert-Butoxycarbonyl)piperazin-1-yl]propanoic acid.
6.33 ml of a solution of 2N NaOH is added to a solution of 2.3 g of the
compound obtained in the preceding step in 30 ml of MeOH, and it is stirred for
20 hours. The reaction mixture is added to a solution of ammonium chloride and
then evaporated to dryness. The solid residue is taken up in DCM/MeOH
mixture (9/1; v/v), filtered and the filtrate evaporated. The residue is taken up in
ether and drained. 1.2 g of the expected compound is obtained in the form of a
white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 1.17 (3H, d); 1.39 (9H, s); 2.50 (m,
4H); 3.22-3.32 (m, 5H); 7.25 (1H, br).
Step 3: tert-Butyl 4-(1-hydroxypropan-2-yl)piperazine-1-carboxylate.
1.10 g of 1,1'-carbonyldimidazole is added to a solution of 1.35 g of the
compound obtained in the preceding step, in 15 ml of THF, and it is stirred for
30 minutes. In addition, a solution of 0.33 g of NaBH4 in 6 ml of water is
prepared at 0°C and is added dropwise to the initial solution of activated ester,
previously cooled to -5°C. 30 ml of water is added and it is extracted with
EtOAc. It is washed with brine, dried over Na2SO4 and evaporated to dryness. It
is purified by silica gel chromatography, eluting with DCM/MeOH mixture
(gradient from 2 to 5% of MeOH). 1 g of the expected compound is obtained in
the form of a colorless oil.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.90 (3H, d); 1.39 (9H, s); 2.42 (m,
4H); 2.57 (1H, q); 3.22-3.45 (m, 6H); 4.24 (1H, t).
Step 4: tert-Butyl 4-(1-methoxypropan-2-yl)piperazine-1-carboxylate.
A solution of 0.49 g of the compound obtained in the preceding step in 5 ml
of THF is added to a suspension of 0.17 g of NaH (60% in oil) in 5 ml of THF at
0°C, and it is stirred for 30 minutes. 0.27 ml of iodomethane is added at 0°C,
and stirred for 20 hours. 10 ml of EtOAc is added, it is washed with water, with
brine, dried over Na2SO4 and evaporated to dryness. It is purified by silica gel
chromatography, eluting with DCM/MeOH mixture (97/3; v/v). 0.41 g of the
expected compound is obtained in the form of a colorless oil.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.93 (3H, d); 1.39 (9H, s); 2.42 (m,
4H); 2.70 (1H, q); 3.17-3.48 (m, 11H).
Step 5:1-(1-Methoxypropan-2-yl)piperazine dihydrochloride.
3.88 ml of a solution of 4N hydrochloric acid in dioxane is added to a
solution of 0.40 g of the compound obtained in the preceding step in 7 ml of
DCM. After 2 hours at RT, it is evaporated to dryness, taken up in acetone and
filtered. 0.34 g of the expected compound is obtained in the form of a white
powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 1.30 (3H, d); 3.31 (3H, s); 3.40-
4.00 (m, 11H); 9.75 (2H, br); 11.75 (1H, br).
Preparation 7.2
Oxetan-3-ylpiperazine.
2.6 g of 3-oxetanone, 1.0 g of sodium cyanoborohydride and 0.16 ml of
acetic acid are added to a solution of 2.0 g of benzyl piperazine-1-carboxylate in
20 ml of acetonitrile and then stirred for 16 hours at RT. The reaction mixture is
diluted with water and filtered through a Chem Elut® cartridge, eluting with
DCM. The combined organic phases are dried over MgSO4 and the solvent is
evaporated under vacuum. The residue is purified by preparative HPLC and
1.7 g of a white solid is obtained. 0.5 g of this solid is dissolved in 20 ml of
EtOH, 0.2 g of Pd/C at 10% is added and the mixture is stirred under a
hydrogen atmosphere (4 bar) for 3 hours. The reaction mixture is filtered on
Celite® and the filtrate is concentrated under vacuum. The expected compound
is obtained.
Preparation 7.3
N-Methyl-N-[2-(piperazin-1-yl)ethyl]acetamide ditrifluoroacetate.
0.341 g of 60% NaH in oil is added to a solution of 0.748 g of N-
methylacetamide in 80 ml of THF and stirred for 10 minutes at RT. Then 2 g of
tert-butyl 4-(2-bromoethyl)piperazinecarboxylate is added and stirred for 16
hours at RT. Water is added to the reaction mixture, it is decanted and the
organic solvent is evaporated under vacuum. The residue is dissolved in DCM,
filtered through a Chem Elut® cartridge, eluting with DCM and the solvents are
evaporated under vacuum. The residue is purified by preparative HPLC and a
white solid is obtained. The solid is dissolved in 5 ml of DCM, 1.2 ml of TFA is
added and it is stirred for 16 hours at RT. The reaction mixture is diluted by
adding 100 ml of toluene and the solvents are concentrated under vacuum.
1.5 g of the expected compound is obtained.
Preparation 7.4
(1S,4S)-2-(2-Methoxyethyl)-2,5-diazabicyclo[2.2.1]heptane
ditrifluoroacetate.
2 ml of DIPEA and 0.52 ml of 1-bromo-2-methoxyethane are added to a
solution of 1.0 g of tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-
carboxylate hydrochloride in 10 ml of EtOH and heated under reflux for 16
hours. After cooling to RT, the reaction mixture is diluted by adding water and
filtered through a Chem Elut® cartridge, eluting with DCM. The combined
organic phases are dried over MgSO4 and the solvent is evaporated under
vacuum. The residue is dissolved in 10 ml of DCM, 15 ml of TFA is added and
stirred for 2 hours at RT. 100 ml of toluene is added and the solvents are
concentrated under vacuum. 1.45 g of the expected compound is obtained.
Preparation 7.5
(2R)-2-(Cyclobutylcarbamoyl)-1-methylpiperazine ditrifluoroacetate.
0.39 ml of a solution of formaldehyde at 37% in water, 0.32 g of sodium
cyanoborohydride and 0.994 ml of acetic acid are added to a solution of 1 g of
tert-butyl (3R)-piperazine-1,3-dicarboxylate in 26 ml of MeOH and stirred for 3
hours at RT. The reaction mixture is diluted by adding a saturated solution of
K2CO3, extracted with DCM, the organic phase is dried over MgSO4 and the
solvent is evaporated under vacuum. The residue is dissolved in 4 ml of DMF,
0.19 g of HOAT, 0.267 g of EDC and 0.1 g of cyclobutylamine are added and it
is stirred for 16 hours at RT. The reaction mixture is diluted by adding a
saturated solution of NaHCO3, extracted with DCM, the organic phase is dried
over MgSO4 and the solvent is evaporated under vacuum. The residue is
purified by preparative HPLC, the fractions containing the product are
concentrated under vacuum and lyophilized, obtaining 0.31 g of a white solid.
The solid is dissolved in 2 ml of DCM, 2.5 ml of TFA is added and stirred for 4
hours at RT. It is diluted by adding 100 ml of toluene and the solvents are
concentrated under vacuum. 0.94 g of the expected compound is obtained.
Preparation 7.6
1,1,1 -Trifluoro-3-(piperazin-1 -yl)propan-2-ol.
Step 1: Benzyl 4-(3,3,3-trifluoro-2-hydroxypropyl)piperazine-1-carboxylate.
0.47 ml of 1,1,1-trifluoro-2,3-epoxypropane is added to a solution of 1 g of
benzyl piperazine-1 -carboxylate in 100 ml of N-methylpyrrolidine and it is
heated at 80°C for 12 hours. 0.05 ml of 1,1,1-trifluoro-2,3-epoxypropane is
added and it is heated at 80°C for 48 hours. The reaction mixture is extracted
with DCM, the organic phase is washed with a 4% solution of LiCI in water, it is
dried over MgSO4 and the solvent is evaporated under vacuum. The residue is
purified by preparative HPLC and 1.7 g of the expected compound is obtained.
Step 2:1,1,1-Trifluoro-3-(piperazin-1-yl)propan-2-ol.
0.15 g of Pd/C at 10% is added, under an argon atmosphere, to a solution
of 1.7 g of the compound from the preceding step in 50 ml of EtOH and it is
stirred for 16 hours under a hydrogen atmosphere (3 bar). The reaction mixture
is filtered on Celite®, it is washed with EtOH and the filtrate is concentrated
under vacuum. 1.2 g of the expected compound is obtained.
Preparation 7.7
1-(2-Methoxyethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine.
Step 1: Benzyl 1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate.
A mixture of 2.0 g of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine
dihydrochloride, 2.36 g of NaHCO3 and 2.45 g of N-
(benzyloxycarbonyloxy)succinimide in 80 ml of dioxane/water mixture (50/50;
v/v) is stirred for 16 hours at RT. The reaction mixture is extracted with EtOAc,
the organic phase is washed with a saturated solution of NaHCO3, with 0.1 M
HCI solution, with saturated NaCI solution, it is dried and the solvent is
evaporated under vacuum. The residue is chromatographed on silica gel,
eluting with DCM/MeOH mixture. 1.9 g of the expected compound is obtained.
Step 2: Benzyl 1-(2-methoxyethyl)-1,4,6,7-tetrahydro-5H-imidazo[4,5-
c]pyridine-5-carboxylate.
3.6 ml of 6N NaOH, 0.051 g of tetrabutylammonium bromide and 0.308 g of
1-bromo-2-methoxyethane are added to a solution of 0.475 g of the compound
from the preceding step in 20 ml of toluene and 5 ml of DCM and it is stirred for
12 hours at RT. 0.308 g of 1-bromo-2-methoxyethane and 0.05 g of
tetrabutylammonium iodide are added and stirred for 36 hours at RT. The
reaction mixture is concentrated under vacuum, the residue is extracted with
DCM, the organic phase is washed with water, it is dried and the solvent is
evaporated under vacuum. The product thus obtained is purified by preparative
HPLC and 0.24 g of the expected compound is obtained.
Step 3:1 -(2-Methoxyethyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridine.
0.025 g of Pd/C at 10% is added under argon to a solution of 0.25 g of the
compound from the preceding step in 50 ml of EtOH and stirred for 16 hours
under a hydrogen atmosphere (1 bar). It is filtered on Celite®, washed with
EtOH and the filtrate is concentrated under vacuum. 0.115 g of the expected
compound is obtained.
Preparation 7.8
Trans-2-(piperazin-1-yl)cyclopentanol.
Step 1: Benzyl 4-(trans-2-hydroxycyclopentyl)piperazine-1-carboxylate.
A solution of 0.524 g of benzyl piperazine-1-carboxylate is cooled to 0°C,
0.2 g of 1,2-epoxycyclopentane is added and it is heated at 80°C for four days.
The reaction mixture is concentrated under vacuum and the residue is purified
by silica gel chromatography, eluting with EtOAc/MeOH mixture. 0.32 g of the
expected compound is obtained.
Step 2: Trans-2-(piperazin-1-yl)cyclopentanol.
0.025 g of Pd/C at 10% is added under argon to a solution of 0.32 g of the
compound from the preceding step in 50 ml of EtOH and it is stirred for 16
hours under a hydrogen atmosphere (3 bar). The reaction mixture is filtered on
Celite, it is washed with EtOH and the filtrate is concentrated under vacuum.
0.19 g of the expected compound is obtained.
Preparation 7.9
2-(Pyrrolidin-3-yloxy)ethanol.
Step 1: Benzyl 3-(2-benzyloxyethoxy)pyrrolidine-1-carboxylate.
A solution of 1.29 g of benzyl 3-hydroxypyrrolidine-1-carboxylate in 80 ml of
THF is cooled to 0°C, 0.245 g of 60% NaH in oil is added and then 1.26 g of [(2-
bromoethoxy)methyl]benzene and 0.108 g of tetrabutylammonium iodide and it
is heated at 80°C for 3 hours. 0.28 g of NaH and 0.40 g of [(2-
bromoethoxy)methyl]benzene are added and it is heated at 80°C for 2 hours.
The reaction mixture is concentrated under vacuum, the residue is extracted
with DCM, the organic phase is washed with 0.1M HCI solution, with a saturated
solution of NaHCO3, it is dried and the solvent is evaporated under vacuum.
The product thus obtained is purified by preparative HPLC and 0.46 g of the
expected compound is obtained.
Step 2: 2-(Pyrrolidin-3-yloxy)ethanol.
0.05 g of Pd/C at 10% is added, under argon, to a solution of 0.459 g of the
compound from the preceding step in 35 ml of EtOH and it is stirred for 16
hours under a hydrogen atmosphere (3 bar). The reaction mixture is filtered on
Celite, it is washed with EtOH and the filtrate is concentrated under vacuum.
0.205 g of the expected compound is obtained.
Preparation 7.10
(2S,4R)-2-(Cyclobutylcarbamoyl)-4-hydroxypyrrolidine trifluoroacetate.
Step 1: tert-Butyl (2S,4R)-2-(cyclobutylcarbamoyl)-4-hydroxypyrrolidine-1-
carboxylate.
1.17 g of HOAT, 1.66 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride and 0.615 g of cyclobutylamine are added to a solution of 2.0 g of
(4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline in 20 ml of DMF. 1.5 ml of a
saturated solution of NaHCO3 is added and the reaction mixture is filtered on a
Chem Elut® cartridge, eluting with DCM. The solvents are concentrated under
vacuum and the residue is purified by filtration on silica gel, eluting with EtOAc.
1.22 g of the expected compound is obtained.
Step 2: (2S,4R)-2-(cyclobutylcarbamoyl)-4-hydroxypyrrolidine
trifluoroacetate.
3.2 ml of TFA is added to a solution of 1.22 g of the compound from the
preceding step in 31 ml of DCM and it is stirred for 12 hours at RT. It is
concentrated under vacuum, the residue is taken up in toluene and the solvent
is evaporated under vacuum. 1.51 g of the expected compound is obtained.
Preparation 7.11
2-(Methoxymethyl)-1 -methylpiperazine ditrifluoroacetate.
Step 1: tert-Butyl 3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate.
0.303 g of sodium acetate, 0.375 g of formaldehyde and 0.218 g of sodium
cyanoborohydride are added to a solution of 0.5 g of tert-butyl 3-
(hydroxymethyl)piperazine-l-carboxylate in 50 ml of MeOH and stirred for 1
hour at RT. A saturated solution of NaHCO3 is added, it is extracted with DCM,
the organic phase is dried over Na2SO4 and the solvent is evaporated under
vacuum. The residue is chromatographed on silica gel, eluting with DCM/MeOH
mixture. 0.31 g of the expected compound is obtained.
Step 2: tert-Butyl 3-(methoxymethyl)-4-methylpiperazine-1-carboxylate.
A solution of 0.125 g of the compound from the preceding step in 12 ml of
DMF is cooled to 0°C, 0.024 g of NaH (60% in oil) and 0.092 g of iodomethane
are added and it is stirred for 16 hours at RT. Water is added to the reaction
mixture, it is extracted with DCM, the organic phase is dried over Na2SO4 and
the solvent is evaporated under vacuum. 0.122 g of the expected compound is
obtained.
Step 3: 2-(Methoxymethyl)-1-methylpiperazine ditrifluoroacetate.
0.4 ml of TFA is added to a solution of 0.122 g of the compound from the
preceding step in 5 ml of DCM and stirred for 12 hours at RT. It is concentrated
under vacuum, the residue is taken up in toluene and the solvent is evaporated
under vacuum. 0.14 g of the expected compound is obtained.
Preparation 7.12
3-Methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine.
Step 1: Benzyl 3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate.
A mixture of 2.0 g of 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine
dihydrochloride, 2.36 g of NaHCO3 and 2.45 g of N-
(benzyloxycarbonyloxy)succinimide in 80 ml of dioxane/water mixture (50/50;
v/v) is stirred for 16 hours at RT. The reaction mixture is extracted with EtOAc,
the organic phase is washed with a saturated solution of NaHCO3, with a 0.1 M
solution of HCI, with saturated NaCI solution, it is dried over Na2SO4 and the
solvent is evaporated under vacuum. The residue is purified by silica gel
chromatography, eluting with DCM/MeOH mixture. 1.9 g of the expected
compound is obtained.
Step 2: Benzyl 3-methyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-
carboxylate.
3.6 ml of 6N NaOH, 0.051 g of tetrabutylammonium bromide and 0.313 g of
iodomethane are added to a solution of 0.475 g of the compound from the
preceding step in 20 ml of toluene and 5 ml of DCM and stirred for 12 hours at
RT. The reaction mixture is concentrated under vacuum, the residue is
extracted with DCM, the organic phase is washed with water, it is dried and the
solvent is evaporated under vacuum. The residue is purified by preparative
HPLC. 0.32 g of the expected compound is obtained.
Step 3: 3-Methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine.
0.025 g of Pd/C at 10% is added, under argon, to a solution of 0.3 g of the
compound from the preceding step in 50 ml of EtOH and stirred for 16 hours
under a hydrogen atmosphere (1 bar). The reaction mixture is filtered on
Celite®, it is washed with EtOH and the filtrate is concentrated under vacuum.
0.166 g of the expected compound is obtained in the form of oil.
8. Preparations of the compounds of formula (VI).
Preparation 8.1
N-[4-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-6-methyl-1 H-indole-3-
carboxamide.

Step 1:1-acetyl-N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1-yl)phenyl]-6-methyl-
1 H-indole-3-carboxamide (XIV).
A mixture of 1.03 g of the compound from Preparation 4.2 in 20 ml of DCM
is cooled to 0°C, 0.81 g of the compound from Preparation 6.3, 0.62 g of DMAP
and then 0.97 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
are added and stirred for 2 hours, allowing the temperature to return to RT.
100 ml of EtOAc is added, the organic phase is washed with 1N HCI solution,
with a solution of 1N NaOH, with water, with saturated NaCI solution, dried over
Na2SO4 and the solvent is evaporated under vacuum. The residue is taken up in
iso ether, the precipitate that formed is drained and dried under vacuum. 1.39 g
of the expected compound is obtained.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.95 (3H, t); 1.65 (2H, m); 2.47-
2.52 (6H); 2.77 (3H, s); 2.83 (2H, t); 7.24 (1H, d); 7.55 (2H, d); 7.95 (2H, d);
8.13 (1H, d); 8.24 (2H, d); 8.75 (1H, s); 10.30 (1H, s).
Following the procedure described in step 1, the compounds of formula
(XIV) presented in TABLE V below are prepared:
Step 2: N-[4-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-6-methyl-1 H-
indole-3-carboxamide.
1.5 g of K2CO3 is added to a solution of 1.15 g of the compound from step 1
in 40 ml of MeOH/THF mixture (50/50; v/v) and stirred for 4 hours at RT. The
reaction mixture is concentrated under vacuum, the residue is taken up in
EtOAc/water mixture, the organic phase is washed with water, with saturated
NaCI solution, dried over Na2SO4 and the solvent is evaporated under vacuum.
The residue is taken up in iso ether and the precipitate that formed is drained.
0.9 g of the expected compound is obtained.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.95 : t: 3H; 1.65 : m : 2H; 2.42 : s
: 3H; 2.50 : s : 3H; 2.82 : t: 2H; 7.00 : d : 1H; 7.27 : s : 1H; 7.47 : d : 2H; 7.95 : d
: 2H; 8.07 : d : 1H; 8.24 : s : 1H; 8.25 : s : 1H; 9.90 : s : 1H; 11.60 : s : 1H.
Following the procedure described in step 2, the compounds of formula (VI)
presented in TABLE VI below are prepared:
Preparation 8.7
N-[4-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-6-methyl-1 H-
indole-3-carboxamide.

0.5 g of nickel(ll) chloride is added to a solution of 1 g of the compound
from Preparation 8.4 in 6 ml of DMF and it is heated in a microwave for 30
minutes at 200°C. After cooling to RT, 60 ml of water is added, it is extracted
with EtOAc, the organic phase is washed with saturated NaCI solution, dried
over Na2SO4 and the solvent is evaporated under vacuum. The residue is taken
up in acetone/iso ether mixture (50/50; v/v) and the precipitate that formed is
drained. 0.66 g of the expected compound is obtained.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.47
(3H, s); 2.52 (3H, s); 2.82 (2H, t); 7.46-7.51 (3H, m); 7.94 (2H, d); 8.19 (1H, s);
8.24 (1H, s); 8.34 (1H, s); 9.95 (1H, s); 11.80 (1H, br).
9. Preparations of the compounds of formula (II).
Preparation 9.1
Methyl (3-{[5-(4-butyryl-5-methyl-1H-pyrazol-1 -yl)pyrazin-2-yl]carbamoyl}-5-
chloro-1H-indol-1-yl)acetate.

Step 1: Methyl [5-chloro-3-(chlorocarbonyl)-1H-indol-1-yl] acetate.
6.6 ml of thionyl chloride and a few drops of DMF are added to a solution of
6.00 g of the compound from Preparation 3.1 in 200 ml of DCM. After 3h under
reflux, it is evaporated to dryness and the solid residue is triturated with 80 ml of
DCM. The precipitate formed is filtered, and washed with DCM, obtaining 4.5 g
of a white powder.
Step 2: Methyl (3-{[5-(4-butyryl-5-methyl-1H-pyrazol-1-yl)pyrazin-2-
yl]carbamoyl}-5-chloro-1 H-indol-1 -yl)acetate.
0.16 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.26 g of the compound
from step 1 are added to 0.17 g of the compound from Preparation 6.1 in 10 ml
of 1,2-dichloroethane, then it is heated at 80°C for 2 hours. After it returns to
RT, the reaction mixture is washed with water and then with brine and dried
over Na2SO4. It is evaporated and then the solid residue is purified by silica gel
chromatography, eluting with DCM/MeOH mixture (gradient from 1 to 2% of
MeOH). The solid residue is triturated with iso ether and then filtered, obtaining
0.14 g of a yellow powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.63 (2H, m); 2.78
(3H, s); 2.86 (2H, t); 3.73 (3H, s); 5.32 (2H, s); 7.31 (1H, d); 7.61 (1H, d); 8.25
(1H, s); 8.36 (1H, s); 8.62 (1H, s); 8.86 (1H, s); 9.42 (1H, s); 11.15 (1H, s).
Preparation 9.2
Methyl (3-{[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]carbamoyl}-
5-chloro-1 H-indol-1 -yl)acetate.

A solution of 0.35 g of the compound from Preparation 6.2 and 0.59 g of
DMAP is stirred for 30 minutes in the presence of 1 g of molecular sieve 4A in
20 ml of 1,2-dichloroethane. 0.92 g of the compound obtained in step 1 of
Preparation 9.1 is added, then it is heated at 80°C for 6 hours. After it returns to
RT, the molecular sieve is removed by filtration, the reaction mixture is washed
with water and then with brine and dried over Na2SO4. It is evaporated and then
the solid residue is purified by silica gel chromatography, eluting with
DCM/MeOH mixture (gradient from 0 to 5% of MeOH), obtaining 0.51 g of a
white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.82
(3H, s); 2.87 (2H, t); 3.73 (3H, s); 5.33 (2H, s); 7.32 (1H, d); 7.62 (1H, d); 8.13
(1H, d); 8.23 (1H, s); 8.41 (1H, s); 8.65 (1H, s); 8.71 (1H, d); 11.42 (1H, s).
Preparation 9.3
Methyl (3-{[4-(4-butyryl-5-methyl-1H-pyrazol-1 -yl)phenyl]carbamoyl}-5-
chloro-6-fluoro-1H-indol-1-yl)acetate.

A solution of 1.25 g of the compound from Preparation 8.5 in 15 ml of DMF
is cooled to 0°C, 0.47 g of K2CO3 and then 0.49 g of methyl bromoacetate are
added and it is stirred for 3 hours at RT. 50 ml of EtOAc and 100 ml of water are
added, it is decanted, the organic phase is washed with water and with
saturated NaCI solution, dried over Na2SO4 and the solvent is evaporated under
vacuum. 1.38 g of a white powder is obtained.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.51
(3H, s); 2.81 (2H, t); 3.73 (3H, s); 5.32 (2H, s); 7.50 (2H, d); 7.78 (1H, d); 7.94
(2H, d); 8.24 (1H, s); 8.30 (1H, d); 8.35 (1H, s); 10.20 (1H, s).
Following the procedure described in Preparation 9.3, the compounds of
formula (II) presented in TABLE VII below are prepared:
Preparation 9.10
Methyl (3-{[4-(4-butyryl-5-methyl-1H-pyrazol-1 -yl)phenyl]carbamoyl}-5-
chloro-1 H-indol-1 -yl)acetate.

2.17 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,
2.61 g of DMAP and 2.67 g of the compound from Preparation 6.3 are added to
a solution of 2.70 g of the compound from Preparation 3.1 in 50 ml of 1,2-
dichloroethane and it is stirred for 20 hours at RT. The reaction mixture is
washed with 1N HCI solution, with a saturated NaHCO3 solution, and with
water, the organic phase is dried over Na2SO4 and the solvent is evaporated
under vacuum. The residue is taken up in acetone and the precipitate that
formed is drained. 3.35 g of the expected compound is obtained.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.62 (2H, m); 2.50
(3H, s); 2.82 (2H, t); 3.73 (3H, s); 5.34 (2H, s); 7.29 (1H, d); 7.50 (2H, d); 7.60
(1H, d); 7.94 (2H, d); 8.21 (1H, s); 8.24 (1H, s); 8.35 (1H, s); 10.20 (1H, s).
Following the procedure described in Preparation 9.10, the compounds of
formula (II) presented in TABLE VIII below are prepared:
Preparation 9.20
Methyl (3-[[2-bromo-4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)-
phenyl]carbamoyl]-5-chloro-1 H-indol-1 -yl)acetate.

0.63 ml of pyridine and then 1 g of the compound from Preparation 6.7 are
added to 1.33 g of the compound from step 1 of Preparation 9.1 in 25 ml of 1,2-
dichloroethane. The reaction mixture is placed in a microwave apparatus at
80°C for 30 min (300 W). After it returns to RT, 50 ml of water is added and it is
extracted with DCM. The combined organic phases are washed with saturated
sodium bicarbonate, with water and with brine, dried over sodium sulfate and
evaporated to dryness. The product is triturated in acetone and then filtered,
obtaining 0.89 g of a white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.58
(3H, s); 2.83 (2H, t); 3.73 (3H, s); 5.34 (2H, s); 7.29 (1H, d); 7.57-7.63 (2H, m);
7.86 (1H, d); 7.93 (1H, d); 8.18 (1H, s); 8.30 (1H, s); 8.34 (1H, s); 9.69 (1H, s).
Following the procedure described in Preparation 9.20, the compounds of
formula (II) presented in TABLE IX below are prepared:

Preparation 9.23
Methyl 3-{[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]carbamoyl}-5-
phenyl-1 H-indol-1 -yl)acetate.

0.18 g of phenylboronic acid, and 0.36 g of K3PO4.2H2O are added to 0.60
of the compound from Preparation 9.17 in 10 ml of dioxane. The reaction
mixture is degassed with argon, then 0.06 g of
tetrakis(triphenylphosphine)palladium(0) is added and it is heated under reflux
for 5 hours. 50 ml of EtOAc and 50 ml of water are added, the organic phase is
recovered, and then the aqueous phase is extracted two more times. The
organic phases are combined, washed with water and then with brine and dried
over Na2SO4. After evaporation, the solid residue is purified by silica gel
chromatography, eluting with DCM/MeOH mixture up to (98/2; v/v). 0.39 g of a
white powder is obtained.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.96 (3H, t); 1.65 (2H, m); 2.54
(3H, s); 2.83 (2H, t); 3.75 (3H, s); 5.37 (2H, s); 7.33-7.75 (9H, m); 7.99 (2H, d);
8.25 (1H, s); 8.33 (1H, s); 8.48 (1H, s); 10.20 (1H, s).
Preparation 9.24
Methyl [3-{[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)-phenyl]carbamoyl}-5-
(dimethylamino)-1H-indol-1 -yl]acetate.

0.26 g of proline and 0.21 g of copper(l) iodide are added to 1 g of the
compound from Preparation 9.17 in 7 ml of DMSO in a screw-top tube. The
reaction mixture is degassed with nitrogen, then 7 ml of a 2M solution of
dimethylamine in THF is added. The tube is closed and it is heated at 120°C for
7 hours. The reaction mixture is poured into water and is extracted with EtOAc,
the organic phase is dried over Na2SO4 and evaporated. The solid residue is
purified by silica gel chromatography, eluting with DCM/MeOH mixture up to
(95/5; v/v). 0.11 g of powder is obtained.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.52
(3H, s); 2.83 (2H, t); 2.91 (6H, s); 3.71 (3H, s); 5.22 (2H, s); 6.88 (1H, d); 7.34
(1H, d); 7.47 (2H, d); 7.56 (1H, s); 7.95 (2H, d); 8.16 (1H, s); 8.24 (1H, s); 9.95
(1H,s).
Preparation 9.25
Methyl (3-{[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)-phenyl]carbamoyl}-5-
cyano-1 H-indol-1 -yl)acetate.

In a screw-top tube, 3 g of the compound from Preparation 9.17 is dissolved
in 40 ml of DMF. The reaction mixture is degassed with argon, then 0.79 g of
zinc(ll) cyanide and 0.32 g of tetrakis(triphenylphosphine)palladium(0) are
added. The tube is closed and then it is heated at 100°C for 7 hours. The
reaction mixture is poured into a dilute solution of sodium bicarbonate, ensuring
that at the end of addition the pH of the solution is basic. It is extracted with
EtOAc, the organic phase is dried over Na2SO4 and evaporated. The solid
residue is triturated in MeOH and then filtered, obtaining 2.2 g of white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.52
(3H, s); 2.82 (2H, t); 3.73 (3H, s); 5.42 (2H, s); 7.52 (2H, d); 7.66 (1H, d); 7.80
(1H, d); 7.95 (2H, d); 8.25 (1H, s); 8.46 (1H, s); 8.61 (1H, s); 10.25 (1H, s).
Preparation 9.26
Methyl (3-{[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)-2-cyano-
phenyl]carbamoyl}-5-chloro-1 H-indol-1 -yl)acetate.

In a screw-top tube, 0.78 g of the compound from Preparation 9.21 is dissolved
in 15 ml of DMF. The reaction mixture is degassed with argon, then 0.21 g of
zinc(ll) cyanide and 0.08 g of tetrakis(triphenylphosphine)palladium(0) are
added. The tube is closed and then it is heated at 100°C for 6 hours. The
reaction mixture is poured into a dilute solution of sodium bicarbonate, ensuring
that at the end of addition the pH of the solution is basic. It is extracted with
EtOAc, washed with water, with brine, dried over Na2SO4 and evaporated. The
solid residue is triturated in iso ether and then filtered. The solid residue is
purified by silica gel chromatography, eluting with DCM/MeOH mixture up to
(95/5; v/v). 0.59 g of white powder is obtained.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.59
(3H, s); 2.83 (2H, t); 3.73 (3H, s); 5.37 (2H, s); 7.32 (1H, d); 7.64 (1H, d); 7.80
(1H, d); 7.91 (1H, d); 8.11 (1H, s); 8.17 (1H, s); 8.33 (2H, d); 10.40 (1H, s).
EXAMPLES
EXAMPLE 1: Compound No. 1
Sodium (3-{[5-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyrazin-2-yl]carbamoyl}-
5-chloro-1 H-indol-1 -yl)acetate.
0.80 ml of an aqueous solution of 1N NaOH is added to 0.14 g of the
compound from Preparation 9.1 in 6 ml of MeOH/dioxane mixture (50/50; v/v),
and it is stirred for 3h. The reaction mixture is evaporated to dryness. The solid
residue is triturated with water and then drained, obtaining 0.10 g of a white
powder.
EXAMPLE 2: Compound No. 2
(3-{[6-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]carbamoyl}-5-
chloro-1 H-indol-1-yl)acetic acid.
5.30 ml of an aqueous solution of 1N NaOH is added to 2.20 g of the
compound from Preparation 9.2 in 42 ml of dioxane, and it is stirred for 2h. The
reaction mixture is evaporated to dryness. The solid residue is redissolved in
30 ml of water and then acidified with 7 ml of 1N HCI solution. The precipitate
that formed is drained, it is washed with water, obtaining 2.07 g of a beige
powder.
EXAMPLE 3: Compound No. 3, (3-{[4-(4-butyryl-5-methyl-1H-pyrazol-1-
yl)phenyl]carbamoyl}-5-chloro-1 H-indol-1 -yl)acetic acid.
32.9 ml of an aqueous solution of 2N NaOH is added to 16.2 g of the
compound from Preparation 9.11 in 60 ml of MeOH/dioxane mixture (50/50;
v/v), and it is stirred for 2 hours. The reaction mixture is acidified with 1N HCI
solution and then it is extracted with EtOAc. The combined organic phases are
washed with brine, dried over Na2SO4 and then evaporated. The solid residue is
triturated with acetone/iso ether mixture (50/50; v/v) and then filtered, obtaining
11 g of a white powder. The precipitate formed during concentration of the
filtrate gives an additional 2.95 g, i.e. 13.95 g in total.
EXAMPLE 4: Compound No. 4
Sodium (3-{[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]carbamoyl}-5-
chloro-6-methyl-1 H-indol-1 -yl)acetate.
0.22 ml of an aqueous solution of 1N NaOH is added to 0.11 g of
Preparation 9.8 in 5 ml of MeOH/dioxane mixture (50/50; v/v), and then
evaporated to dryness. The solid residue is redissolved in a minimum of
acetone (about 1 ml) and it is added dropwise to 10 ml of pentane. The
precipitate formed is filtered, and dried in a vacuum stove, obtaining 0.082 g of
a white powder.
Following the procedures described in Examples 1 to 4, the compounds of
Formula (I) presented in TABLE X below are prepared:
In this table:
- Me represents a methyl radical;
- Et represents an ethyl radical;
- nPr represents an n-propyl radical;
- Ph represents a phenyl radical;
- Na represents a compound in the form of sodium salt.
EXAMPLE 5: Compound No. 25
(3-{[4-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)-2-
(methoxycarbonyl)phenyl]carbamoyl}-5-chloro-1 H-indol-1-yl)acetic acid.
0.03 g of lithium hydroxide is added to 0.71 g of the compound from
Preparation 9.22 in 20 ml of THF, and it is stirred for 2 hours. It is evaporated to
dryness, the solid residue is triturated with DCM and then drained. The
precipitate is taken up in water, acidified with 0.175 mg of KHSO4, the
precipitate that formed is drained, it is washed with water and dried under
vacuum, obtaining 0.47 g of a beige powder.
Following the procedure described in Example 5, the compounds of formula
(I) represented in TABLE XI below are prepared:
N-[5-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)pyrazin-2-yl]-5-chloro-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide hydrochloride.
0.055 g of 1-methylpiperazine (commercial) and 0.086 g of BOP-CI are
added successively to 0.10 g of the compound from Example 1 in 5 ml of DCM.
The medium is heterogeneous. 2 ml of DMF is added and the homogeneous
reaction mixture is stirred overnight. It is evaporated to dryness, 1M NaHCO3
solution is added and it is extracted with DCM. The combined organic phases
are washed with water, with brine, dried over Na2SO4 and then evaporated
under vacuum. The oily residue thus obtained is purified by silica gel
chromatography, eluting with DCM/MeOH mixture (gradient from 1 to 10% of
MeOH), obtaining 0.08 g of a white powder. It is redissolved in 6 ml of
DCM/acetone mixture (50/50; v/v) and then 0.09 ml of 2N ethyl chloride solution
is added. It is evaporated to dryness, triturated with acetone, drained and then
dried in a vacuum stove at 60°C, obtaining 0.06 g of a white powder.
EXAMPLE 7: Compound No. 28
N-[6-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide hydrochloride.
1.66 g of 1-methylpiperazine (commercial), 2.18 g of pyridine and 4.30 g of
BOP-CI are added successively to 2.65 g of the compound from Example 2 in
80 ml of DMF. It is stirred for 48 h, then the reaction mixture is poured into a
mixture of EtOAc and saturated NaHCO3 solution. The precipitate formed is
filtered and washed with iso ether. The filtrate is transferred to a separating
funnel and the organic phase is washed with water, with brine and then dried
over Na2SO4. The organic phase is concentrated partially and the precipitate
formed is filtered. The two precipitates are combined, and dried in a vacuum
stove, obtaining 2.68 g of a white powder. It is suspended in 200 ml of MeOH,
then 6.6 ml of 1N HCI solution in ether is added and it is stirred for 1 h. The
precipitate that formed is drained, it is washed with iso ether and then dried in a
vacuum stove at 40°C, obtaining 2.29 g of a light yellow powder.
EXAMPLE 8: Compound No. 29
N-[6-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-[4-(2-
methoxyethyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide
hydrochloride.
0.14 g of DMAP, 0.10 g of 1-(2-methoxyethyl)piperazine, and 0.17 g of
BOP-CI are added successively to 0.11 g of the compound from Example 2 in
10 ml of DMF. It is stirred overnight, then the reaction mixture is poured into a
mixture of EtOAc and saturated NaHCO3 solution. The organic phase is
washed with water, with brine, dried over Na2SO4 and then evaporated to
dryness. The solid residue thus obtained is purified by silica gel
chromatography, eluting with DCM/MeOH mixture (gradient from 2 to 5% of
MeOH). The purified product is redissolved in 5 ml of DCM/acetone mixture
(50/50; v/v) and then 0.12 ml of 2N ethyl chloride solution is added. It is
concentrated partially. A precipitate slowly forms. It is drained, washed with
acetone and then with pentane and dried in a vacuum stove at 60°C, obtaining
0.11 g of a light yellow powder.
EXAMPLE 9: Compound No. 30
N-[6-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -(2-oxo-2-
{4-[2-(trifluoromethoxy)ethyl]piperazin-1-yl}ethyl)-1H-indole-3-carboxamide
hydrochloride
0.11 g of DMAP, 0.08 g of 1-[2-(trifluoromethoxy)ethyl]piperazine, 0.13 ml of
pyridine and 0.24 g of BOP-CI are added successively to 0.15 g of the
compound from Example 2 in 20 ml of DMF, and it is stirred at RT overnight.
EtOAc is added, it is washed with water, with brine, dried over Na2SO4 and then
evaporated to dryness. The solid residue thus obtained is purified by silica gel
column chromatography, eluting with a mixture of DCM and methanol (gradient
from 1 to 10% of methanol), obtaining 0.08 g of powder. The purified product is
redissolved in 4 ml of a mixture (1:1) of methanol and acetone, then 0.15 ml of
2N ethyl chloride solution is added. It is poured into 30 ml of iso ether, the
precipitate that formed is drained and dried in a vacuum stove at 60°C,
obtaining 0.06 g of a white powder.
EXAMPLE 10: Compound No. 31
N-[6-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-oxo-2-
[4-(3,3,3-trifluoropropyl)piperazin-1-yl]ethyl}-1H-indole-3-carboxamide
hydrochloride
0.13 g of 1-(3,3,3-trifluoropropyl)piperazine, 0.04 g of DMAP and 0.13 g of
BOP-CI are added successively to 0.16 g of the compound from Example 2 in
5 ml of DCM, and it is stirred at RT for 48 h. The reaction mixture is evaporated
to dryness, and the solid residue is triturated with a 1M solution of NaHCO3.
The precipitate is filtered and is washed with water, obtaining 0.085 g of a white
powder. It is redissolved in 4 ml of a mixture (1:1) of DCM and acetone and then
0.28 ml of 1N HCI solution in ether is added. The precipitate that formed is
drained, and dried in a vacuum stove at 60°C, obtaining 0.08 g of a white
powder.
Following the procedure described in Examples 6 to 10, the compounds of
formula (I) presented in TABLE XII below are prepared:
In this table:
- in the column "Salt", "-" represents a compound in the form of free base,
whereas "HCI" represents a compound in the form of hydrochloride, "TFA"
represents a compound in the form of trifluoroacetate;
- Me represents a methyl radical;
- Et represents an ethyl radical;
- nPr represents an n-propyl radical.
The NMR analyses for certain compounds are given below:
Compound 27:
1H NMR: DMSO-d6 (400 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.70-
4.50 (16H, m); 5.38 (2H, br); 7.29 (1H, d); 7.57 (1H, d); 8.25 (1H, s); 8.36 (1H,
s); 8.57 (1H, s); 8.85 (1H, s); 9.42 (1H, d); 11.10 (1H, s); 11.15 (1H, br).
Compound 28 :
1H NMR: DMSO-d6 (400 MHz):d (ppm): 0.95 (3H, t); 1.65 (2H, m); 2.80-2.89
(8H, m); 2.93-3.25 (3H, m); 3.41-4.08 (3H, m); 4.20 (1H, d); 4.39 (1H, d); 5.35
(1H, d); 5.50 (1H, d); 7.30 (1H, d); 7.59 (1H, d); 8.14 (1H, d); 8.24 (1H, s); 8.41
(1H, s); 8.58 (1H, s); 8.71 (1H, d); 10.97 (1H, br); 11.38 (1H, s).
Compound 29 :
1H NMR: DMSO-d6 (400 MHz):d (ppm): 0.95 (3H, t); 1.65 (2H, m); 2.82 (3H, s);
2.87 (2H, t); 2.98-3.29 (3H, m); 3.35 (3H, s); 3.36-3.42 (2H, m); 3.50-3.88
(5H, m); 4.19 (1H, d); 4.37 (1H, d); 5.36 (1H, d); 5.50 (1H, d); 7.30 (1H, d); 7.58
(1H, d); 8.14 (1H, d); 8.24 (1H, s); 8.41 (1H, s); 8.58 (1H, s); 8.71 (1H, d); 10.56
(1H, br); 11.38(1 H,s),
Compound 30 :
1H NMR: DMSO-d6 (500 MHz):d (ppm): 0.95 (3H,t); 1.65 (2H,m); 2.82 (3H, s);
2.86 (2H,t); 3.11-3.80 (9H,m); 3.95-4.80 (3H,m); 5.20-5.65 (2H,m); 7.30 (1H,d);
7.57 (1H,d); 8.13 (1H,d); 8.24 (1H, s); 8.41 (1H, s); 8.59 (1H, s); 8.70 (1H,d).
Compound 31 :
1H NMR: DMSO-d6 (400 MHz):d (ppm): 0.95: t: 3H; 1.65: m: 2H; 2.82: s:
3H; 2.86: t: 2H; 3.00-3.90: m: 9H; 3.95-4.70: m: 3H; 5.25-5.55: m: 2H; 7.30: d:
1H; 7.57: d: 1H; 8.13: d: 1H; 8.24: s: 1H; 8.41: s: 1H; 8.59: s: 1H; 8.70: d: 1H.
EXAMPLE 11: Compound No. 105
N-[4-(4-Butyryl-5-methyl-1H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-(2-
methoxyethyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide
hydrochloride.
1.28 g of 1-(2-methoxyethyl)piperazine and 1.40 g of BOP-CI are added
successively to 1.70 g of compound No. 3 in 35 ml of DCM. It is stirred at RT for
20 hours. The reaction mixture is evaporated to dryness, a dilute solution of
NaHCO3 is added and it is extracted with EtOAc. The organic phase is washed
with water, with brine, dried over Na2SO4 and evaporated to dryness. It is
triturated in iso ether and then drained. The product is dissolved in 5 ml of
DCM/acetone mixture (50/50; v/v) and then 5 ml of 1N HCI solution in ether is
added. The hydrochloride is precipitated with 10 ml of ether and then drained,
obtaining 1.96 g of a white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.63 (2H, m); 2.52
(3H, s); 2.82 (2H, t); 2.97-3.29 (3H, m); 3.35-3.41 (5H, m); 3.50-3.78 (5H, m);
4.18 (1H, d); 4.37 (1H, d); 5.36 (1H, d); 5.51 (1H, d); 7.27 (1H, d); 7.49 (2H, d);
7.57 (1H, d); 7.97 (2H, d); 8.22 (1H, s); 8.25 (1H, s); 8.34 (1H, s); 10.22 (1H, s);
10.81 (1H, br).
m.p. =218°C.
Following the procedure described in Example 11 and starting from the
corresponding compounds of formula (IA), the compounds of formula (I)
presented in TABLE XIII below are prepared:
In this table:
- in the column "Salt", "Base" represents a compound in the form of free base,
whereas "HCI" represents a compound in the form of hydrochloride, "TFA"
represents a compound in the form of trifluoroacetate;
- Me represents a methyl radical;
- Et represents an ethyl radical;
- nPr represents an n-propyl radical.
Compounds Nos. 223 to 241 of formula (I) bearing a tert-butyloxycarbonyl
protective group on one of the nitrogen atoms do not display the required
pharmacological activity. These are intermediates that can be used for
preparing the compounds of formula (I) Nos. 242 to 260.
The NMR analyses for certain compounds are given below:
Compound 106:
1H NMR: DMSO-d6 (250 MHz): d (ppm): 0.94 (3H, t); 1.63 (2H, m); 2.33
(6H, s); 2.52 (3H, s); 2.81 (2H, t); 2.89 (3H, s); 3.14 (3H, s); 5.22 (2H, s); 7.25
(1H, s); 7.47 (2H, d); 7.93-7.99 (3H, m); 8.09 (1H, s); 8.24 (1H, s); 9.97 (1H, s).
Compound 107:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.63 (2H, m); 2.33
(6H, s); 2.52 (3H, s); 2.78-2.84 (5H, m); 2.91-3.24 (3H, m); 3.39-3.75 (3H, m);
4.11-4.45 (2H, m); 5.20-5.45 (2H, m); 7.27 (1H, s); 7.47 (2H, d); 7.95-8.01
(3H, m); 8.12 (1H, s); 8.25 (1H, s); 10.06 (1H, s); 11.18 (1H, br).
Compound 114:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.43
(3H, s); 2.52 (3H, s); 2.78-2.81 (5H, m); 2.93-3.24 (3H, m); 3.41-3.64 (3H, m);
4.15-4.46 (2H, m); 5.29 (1H, d); 5.43 (1H, d); 7.06 (1H, d); 7.37 (1H, d); 7.48
(2H, d); 7.97 (2H, d); 8.02 (1H, s); 8.17 (1H, s); 8.24 (1H, s); 10.06 (1H, s);
10.60 (1H,br).
Compound 115 :
1H NMR: DMSO-d6 (250 MHz): d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.52
(3H, s); 2.78-2.89 (5H, m); 2.93-3.24 (3H, m); 3.39-3.69 (3H, m); 4.20 (1H, s);
4.39 (1H, s); 5.35 (1H, d); 5.50 (1H, d); 7.28 (1H, d); 7.49 (2H, d); 7.56 (1H, d);
7.96 (2H, d); 8.22 (1H, s); 8.25 (1H, s); 8.31 (1H, s); 10.21 (1H, s); 10.95 (1H,
br).
Compound 119:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.43
(3H, s); 2.52 (3H, s); 2.82 (2H, t); 2.97-3.28 (3H, m); 3.34 (3H, s); 3.35-3.41
(2H, m); 3.50-3.77 (6H, m); 4.20 (1H, d); 4.38 (1H, d); 5.29 (1H, d); 5.42 (1H, d);
7.06 (1H, d); 7.39 (1H, d); 7.48 (2H, d); 7.98 (2H, d); 8.03 (1H, s); 8.20 (1H, s);
8.24 (1H,s); 10.08 (1H,s); 10.80 (1H, br).
Compound 128:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.43
(3H, s); 2.52 (3H, s); 2.82 (2H, t); 3.48-3.70 (8H, m); 5.31 (2H, s); 7.06 (1H, d);
7.37 (1H, d); 7.48 (2H, d); 7.97 (2H, d); 8.02 (1H, s); 8.20 (1H, s); 8.24 (1H, s);
10.01 (1H,s).
Compound 136:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.52
(3H, s); 2.78-3.25 (8H, m); 3.40-3.68 (3H, m); 3.80 (3H, s); 4.13-4.49 (2H, m);
5.28 (1H, d); 5.43 (1H, d); 6.87 (1H, d); 7.40 (1H, d); 7.48 (2H, d); 7.74 (1H, s);
7.97 (2H, d); 8.20 (1H, s); 8.25 (1H, s); 10.07 (1H, s); 10.70 (1H, br).
Compound 137:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.11 (2H, d); 1.34 (1H,
d); 1.63 (2H, m); 1.90-2.20 (2H, m); 2.44 (3H, s); 2.52 (3H, s); 2.82 (2H, t); 3.10-
4.55 (10H, m); 5.15-5.60 (2H, m); 7.07 (1H, d); 7.37-7.48 (3H, m); 7.98-8.03
(3H, m); 8.18-8.25 (2H, m); 10.05 (1H, s); 10.30-11.50 (1H, m).
Compound 142:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H,t); 1.64 (2H,m); 2.52 (3H,
s); 2.82 (2H,t); 3.01-3.77 (8H,m); 4.13-4.48 (2H,m); 4.81-5.03 (2H,m); 5.36
(1H,d); 5.51 (1H,d); 7.28 (1H,d); 7.50 (2H,d); 7.56 (1H,d); 7.96 (2H,d); 8.21 (1H,
s); 8.25 (1H, s); 8.30 (1H, s); 10.20 (1H, s); 10.90 (1H, br).
Compound 145:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.52
(3H, s); 2.82 (2H, t); 3.06 (1H, m); 3.10-3.78 (14H, m); 3.86 (2H, m); 4.19 (1H,
d); 4.37 (1H, d); 5.36 (1H, d); 5.51 (1H, d); 7.27 (1H, d); 7.49 (2H, d); 7.58 (1H,
d); 7.98 (2H, d); 8.22 (1H, s); 8.25 (1H, s); 8.36 (1H, s); 10.24 (1H, s); 11.03
(1H,br).
Compound 146:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.63 (2H, m); 2.52
(3H, s); 2.82 (2H, t); 2.98-3.31 (5H, m); 3.52-3.86 (5H, m); 4.15-4.42 (2H, m);
5.37 (1H, d); 5.50 (1H, d); 7.28 (1H, d); 7.49 (2H, d); 7.57 (1H, d); 7.97 (2H, d);
8.22 (1H, s); 8.25 (1H, s); 8.34 (1H, s); 10.22 (1H, s); 10.53 (1H, br).
Compound 147:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.43
(3H, s); 2.52 (3H, s); 2.81 (2H, t); 2.90-3.70 (6H, m); 4.21 (2H, d); 4.40 (2H, s);
5.27 (1H, d); 5.41 (1H, d); 7.05 (1H, d); 7.31-7.39 (3H, m); 7.47 (2H, d); 7.66
(1H, d); 7.96 (2H, d); 8.02 (1H, s); 8.15 (1H, s); 8.24 (1H, s); 10.04 (1H, s);
10.90 (1H, br).
Compound 148:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.63 (2H, m); 2.52
(3H, s); 2.82 (2H, t); 2.88-4.70 (15H, m); 5.39 (1H, br); 5.49 (1H, br); 7.28 (1H,
d); 7.49 (2H, d); 7.57 (1H, d); 7.97 (2H, d); 8.22 (1H, s); 8.25 (1H, s); 8.36 (1H,
s); 10.20 (1H,s); 11.64 (1H, br).
Compound 154:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.52
(3H, s); 2.82 (2H, t); 2.95 (6H, d); 3.01-3.29 (3H, m); 3.47-3.80 (3H, m); 4.10-
4.46 (4H, m); 5.38 (1H, s); 5.49 (1H, s); 7.28 (1H, d); 7.50 (2H, d); 7.56 (1H, d);
7.96 (2H, d); 8.22 (1H, s); 8.25 (1H, s); 8.31 (1H, s); 10.09-10.24 (2H, m).
Compound 157:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.63 (2H, m); 2.52
(3H, s); 2.80-3.70 (11H, m); 4.15 (1H, br); 4.39 (1H, br); 5.33 (1H, br); 5.48 (1H,
br); 7.50 (2H, d); 7.73 (1H, d); 7.96 (2H, d); 8.25 (1H, s); 8.30 (1H, d); 8.34 (1H,
s); 10.25 (1H, s);10.95(1 H, br).
Compound 158:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.63 (2H, m); 2.52
(3H, s); 2.82 (2H, t); 2.91-3.84 (13H, m); 4.15 (1H, d); 4.37 (1H, d); 5.33 (1H, d);
5.49 (1H, d); 7.49 (2H, d); 7.74 (1H, d); 7.98 (2H, d); 8.25 (1H, s); 8.31 (1H, d);
8.34 (1H, s); 10.29 (1H, s); 11.02 (1H, br).
Compound 159:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.29 (3H, d); 1.35 (3H,
d); 1.64 (2H, m); 2.52 (3H, s); 2.69-2.85 (3H, m); 3.11-3.68 (3H, m); 4.15 (1H,
d); 4.42 (1H, d); 5.35 (1H, d); 5.54 (1H, d); 7.27 (1H, d); 7.49 (2H, d); 7.58 (1H,
d); 7.98 (2H, d); 8.21 (1H, s); 8.24 (1H, s); 8.34 (1H, s); 9.22-9.46 (1H, m); 9.60-
9.79 (1H, m);10.22(1H, br).
Compound 165:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.52
(3H, s); 2.82 (2H, t); 2.90-3.23 (3H, m); 3.44-3.73 (2H, m); 4.19 (1H, d); 4.41
(3H, s); 5.34 (1H, d); 5.49 (1H, d); 7.27 (1H, d); 7.36 (2H, t); 7.49 (2H, d); 7.55
(1H,d); 7.68 (2H, s); 7.96 (2H, d); 8.21 (1H, s); 8.25 (1H, s); 8.30 (1H, s); 10.19
(1H, s);11.08(1 H, br).
Compound 166:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.48
(3H, s); 2.52 (3H, s); 2.82 (2H, t); 2.88-3.35 (4H, m); 3.63-4.78 (6H, m); 5.39
(1H, s); 5.44 (1H, s); 6.61 (1H, s); 7.27 (1H, d); 7.49 (2H, d); 7.56 (1H, d); 7.97
(2H, d); 8.21 (1H, s); 10.20 (1H, s); 11.83 (1H, br).
Compound 177:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.34 (2H, d); 1.56 (1H,
d); 1.63 (2H,m); 2.52 (3H, s); 2.77-2.87 (6H, m); 3.13 (1H, br); 3.35-3.74
(3H, m); 4.11 (0.6H, d); 4.41 (0.39H, d); 4.59 (0.39H, br); 4.74 (0.61 H, br); 5.22-
5.65 (2H, m); 7.28 (1H, d); 7.45-7.58 (3H, m); 7.97 (2H, d); 8.20-8.35 (3H, m);
10.21 (1H, s); 10.68 (1H,br).
Compound 179:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.33 (3H, d); 1.64
(2H, m); 2.52 (3H, s); 2.82 (2H, t); 3.00-3.79 (12H, m); 4.18 (1H, d); 4.42 (1H,
d); 5.36 (1H, d); 5.49 (1H, d); 7.28 (1H, d); 7.49 (2H, d); 7.58 (1H, d); 7.97 (2H,
d); 8.21 (1H, s); 8.24 (1H, s); 8.38 (1H, s); 10.21 (1H, s); 10.62 (1H, br).
Compound 180:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.38 (6H, s); 1.63
(2H, m); 2.52 (3H, s); 2.81 (2H, t); 2.96-3.09 (1H, m); 3.19-3.30 (2H, m); 3.37
(3H, s); 3.47-3.61 (4H, m); 3.72-3.84 (1H, m); 4.16 (1H, d); 4.42 (1H, d); 5.37
(1H, d); 5.47 (1H, d); 7.27 (1H, d); 7.49 (2H, d); 7.59 (1H, d); 7.98 (2H, d); 8.22
(1H, s); 8.24 (1H, s); 8.35 (1H, s); 10.22 (1H, s); 10.44 (1H, br).
Compound 181:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.33 (6H, s); 1.63
(2H, m); 2.52 (3H, s); 2.81 (2H, t); 2.97-3.10 (1H, m); 3.20-3.30 (2H, m); 3.50-
3.64 (4H, m); 3.73-3.84 (1H, m); 4.18 (1H, d); 4.43 (1H, d); 5.38 (1H, d); 5.48
(1H, d); 5.80 (1H, br); 7.27 (1H, d); 7.49 (2H, d); 7.59 (1H, d); 7.98 (2H, d); 8.22
(1H, s); 8.24 (1H, s); 8.36 (1H, s); 10.13 (1H, br); 10.24 (1H, s).
Compound 192:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 1.88-
2.30 (4H, m); 2.52 (3H, s); 2.76-2.85 (5H, m); 3.08 (1H, t); 3.36-3.57 (3H, m);
4.65 (1H, s); 4.72 (1H, s); 5.31 (1H, d); 5.42 (1H, d); 7.29 (1H, d); 7.49 (2H, d);
7.60 (1H, d); 7.97 (2H, d); 8.22 (1H, s); 8.25 (1H, s); 8.36 (1H, s); 10.15 (1H,
br); 10.19 (1H,s).
Compound 196:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.95 (3H, t); 1.64 (2H, m); 1.76
(1H, m); 1.91 (1H, m); 2.24 (1H, m); 2.55 (3H, s); 2.85 (2H, t); 2.88 (1H, m);
2.95 (2H, m); 3.27 (3H, s); 3.42-3.72 (5H, m); 3.89-4.07 (1H, br); 4.23 (1H, br);
4.48 (1H, br); 5.50 (2H, br); 7.34 (1H, br); 7.56 (2H, d); 7.63 (1H, d); 8.02 (2H,
d); 8.28 (1H, d); 8.32 (1H, s); 8.35 (1H, s); 10.23 (2H, s Br).
Compound 199:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.52
(3H, s); 2.82 (2H, t); 2.98-4.48 (10H, m); 5.38 (1H, s); 5.46 (1H, s); 7.28 (1H, d);
7.49 (2H, d); 7.56 (1H, d); 7.74 (1H, s); 7.97 (2H, d); 8.02 (1H, s); 8.21 (1H, s);
8.24(1H,s);8.31 (1H, s); 10.20 (1H, s); 10.31 (1H, br).
Compound 200:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.53
(3H, s); 2.82 (2H, t); 2.89 (1.65H, s); 3.18 (1.35H, s); 3.26 (1.35H, s); 3.41
(1.65H, s); 3.47 (2H, m); 3.64 (2H, m); 5.34 (2H, s); 7.27 (1H, m); 7.43 (0.55H,
d); 7.49 (2H, d); 7.54 (0.45H, d); 7.96 (2H, d); 8.21 (1H, s); 8.24 (1H, s); 8.30
(1H,s); 10.11 (0.55H,s); 10.13 (0.45H,S).
Compound 203:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.53
(3H, s); 2.79-3.25 (8H, m); 3.40-3.69 (3H, m); 4.10-4.50 (2H, m); 5.43 (1H, d);
5.58 (1H, d); 7.50 (2H, d); 7.57 (1H, d); 7.75 (1H, d); 7.98 (2H, d); 8.25 (1H, s);
8.41 (1H, s); 8.59 (1H, s); 10.29 (1H, s); 10.49 (1H, br).
Compound 209:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.93 (3H, t); 1.63 (2H, m); 2.52
(3H, s); 2.82 (2H, t); 3.05-3.75 (11H, m); 4.32 (1H, br); 4.83 (1H, br); 5.49 (2H,
br); 7.33 (1H, d); 7.55 (2H, d); 7.61 (1H, d); 8.01 (2H, d); 8.27 (1H, d); 8.31 (1H,
s); 8.36 (1H, s); 10.23 (1H, s); 10.68 (1H, br).
Compound 212: TLC.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.53
(3H, s); 2.55-4.20 (13H, m); 5.20-5.60 (2H, m); 7.26 (1H, d); 7.45-7.55 (3H, m);
7.96 (2H, d); 8.22 (1H, s); 8.24 (1H, s); 8.32 (1H, s); 10.15 (1H, s).
Compound 219:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.23
(3H, s); 2.30 (2H, m); 2.44 (2H, m); 2.58 (3H, s); 2.84 (2H, t); 3.48 (2H, m); 3.59
(2H, m); 5.40 (2H, s); 7.28 (1H, d); 7.56 (1H, d); 7.81 (1H, d); 7.90 (1H, d); 8.11
(1H, s); 8.16 (1H, s); 8.28 (1H, s); 8.32 (1H, s); 10.37 (1H, s).
Compound 221:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.95 (3H, t); 1.64 (2H, m); 2.24
(3H, s); 2.32 (2H, m); 2.45 (2H, m); 2.55 (3H, s); 2.83 (2H, t); 3.48 (2H, m); 3.58
(2H, m); 5.43 (2H, s); 7.30 (1H, d); 7.56 (1H, d); 7.85 (1H, d); 8.08 (1H, s); 8.12
(1H, s); 8.22 (1H, s); 8.29 (1H, s); 8.76 (1H, d); 11.25 (1H, s).
EXAMPLE 12: Compound No. 242:
N-[4-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-methyl-1 -[2-(3-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide hydrochloride.
8.19 ml of a solution of 4N HCI in dioxane is added to 1.05 g of compound
No. 224 in 20 ml of EtOAc/MeOH mixture (50/50; v/v). After 20 hours at RT, the
precipitate is filtered, triturated with acetone and then filtered, obtaining 0.77 g
of the expected compound.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.22-1.39 (3H, m);
1.64 (2H, m); 2.43 (3H, s); 2.52 (3H, s); 2.81 (2H, t); 2.85-3.75 (5H, m); 4.02-
4.39 (2H, m); 5.22-5.50 (2H, m); 7.06 (1H, d); 7.40 (1H, d); 7.48 (2H, d); 7.99
(2H, d); 8.03 (1H, s); 8.22 (1H, s); 8.24 (1H, s); 9.44-9.74 (2H, m); 10.09 (1H, s).
MH+ = 541; tR = 6.33 min (Method G).
m.p. = 223°C.
Following the procedure described in Example 12 and starting from the N-
protected compounds No. 224 to 241, the compounds of formula (I) presented
in TABLE XIV below are prepared:
In this table:
- in the column "Salt", "-" represents a compound in the form of free base,
whereas "HCI" represents a compound in the form of hydrochloride, "TFA"
represents a compound in the form of trifluoroacetate;
- Me represents a methyl radical;
The NMR analyses for certain compounds are given below:
Compound 256:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.63 (2H, m); 2.52
(3H, s); 2.82 (2H, t); 3.11 (2H, br); 3.27 (2H, br); 3.64-3.84 (4H, m); 5.42 (2H, s);
7.27 (1H, d); 7.49 (2H, d); 7.58 (1H, d); 7.97 (2H, d); 8.21 (1H, s); 8.25 (1H, s);
8.33 (1H, s); 9.32 (2H, br); 10.21 (1H, s).
Compound 259:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 1.86-
2.17 (4H, m); 2.52 (3H, s); 2.82 (2H, t); 3.10 (1H, d); 3.67 (1H, d); 3.92 (1H, d);
4.02-4.20 (3H, m); 5.30 (2H, d); 5.58 (2H, d); 7.28 (1H, d); 7.49 (2H, d); 7.56
(1H, d); 7.96 (2H, d); 8.21 (1H, s); 8.25 (1H, s); 8.33 (1H, s); 9.18 (2H, br);
10.16 (1H,s).
EXAMPLE 13: Compound No. 261
N-[4-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-(2-
methoxyethyl)-3,5-dimethylpiperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide
hydrochloride
0.12 g of potassium carbonate, 0.13 g of sodium iodide and then 0.080 ml
of 1-bromo-2-methoxyethane are added to 0.4 g of compound No. 159 in 5 ml
of DMF. The reaction mixture is placed in a microwave apparatus at 160°C for
40 min (300 W). After it returns to RT, it is poured into 50 ml of water and
extracted with EtOAc. The combined organic phases are washed with water,
dried over Na2SO4 and evaporated to dryness. The solid residue is purified by
silica gel chromatography, eluting with DCM/MeOH mixture (gradient from 3 to
5% of MeOH), obtaining 0.12 g of powder. The product is dissolved in 4 ml of
DCM/MeOH mixture (1/1; v/v) and then 0.38 ml of 1M HCI solution in ether is
added. The hydrochloride is precipitated with 10 ml of ether and then filtered,
obtaining 0.103 g of a white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.36 (3H, d); 1.43 (3H,
d); 1.63 (2H, m); 2.52 (3H, s); 2.81 (2H, t); 3.05 (1H, t); 3.35 (3H, s); 3.38-3.77
(7H, m); 4.19 (1H, d); 4.41 (1H, d); 5.33 (1H, d); 5.55 (1H, d); 7.28 (1H, d); 7.49
(2H, d); 7.58 (1H, d); 7.97 (2H, d); 8.22 (1H, s); 8.24 (1H, s); 8.34 (1H, s); 10.21
(1H, s); 10.97 (1H,br),
MH+ = 633; tR = 6.25 min (Method G).
m.p. = 187°C.
EXAMPLE 14: Compound No. 262
N-[4-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -[2-oxo-2-
(3,4,5-trimethylpiperazin-1-yl)ethyl]-1H-indole-3-carboxamide hydrochloride.
0.12 g of potassium carbonate, and then 0.053 ml of iodomethane, are
added to 0.4 g of compound No. 159 in 5 ml of DMF. After 20 h at RT, water is
added and it is extracted with EtOAc. The organic phase is washed with water,
dried over Na2SO4 and then evaporated to dryness. The solid residue is purified
by silica gel chromatography, eluting with DCM/MeOH mixture (95/5; v/v),
obtaining 0.17 g of powder. The product is dissolved in 5 ml of acetone, then
1 ml of 1M HCI solution in ether is added. The hydrochloride is precipitated with
10 ml of diethyl ether and then filtered, obtaining 0.095 g of a white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.38 (3H, d); 1.45
(3H, d); 1.63 (2H, m); 2.52 (3H, s); 2.79-2.85 (5H, m); 2.97 (1H, t); 3.22-3.52
(3H, m); 4.21 (1H, d); 4.41 (1H, d); 5.33 (1H, d); 5.55 (1H, d); 7.28 (1H, d); 7.49
(2H, d); 7.57 (1H, d); 7.97 (2H, d); 8.22 (1H, s); 8.25 (1H, s); 8.33 (1H, s); 10.21
(1H, s); 10.85 (1H,br),
MH+ = 589; tR = 6.12 min (Method G).
m.p. =217°C.
Following the procedure described in Example 14, the compounds of
formula (I) presented in TABLE XV below are prepared:
In this table:
- in the column "Salt", "Base" represents a compound in the form of free base,
whereas "HCI" represents a compound in the form of hydrochloride, "TFA"
represents a compound in the form of trifluoroacetate;
- Me represents a methyl radical;
The NMR analyses for certain compounds are given below:
Compound 263 :
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.36 (3H, d); 1.58-1.68
(5H, m); 2.43 (3H, s); 2.52 (3H, s); 2.82 (2H, t); 2.88 (3H, s); 3.06-3.30 (2H, m);
3.42-3.59 (2H, m); 4.56-4.75 (2H, m); 5.18 (1H, d); 5.56 (1H, d); 7.07 (1H, d);
7.31 (1H, d); 7.48 (2H, d); 7.98 (2H, d); 8.03 (1H, s); 8.25 (2H, s); 10.07 (1H, s);
10.56 (1H,br).
Compound 268 :
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.43
(3H, s); 2.52 (3H, s); 2.82 (2H, t); 2.89 (3H, s); 3.00-4.50 (9H, m); 5.20-5.52
(2H, m); 5.70 (1H, br); 7.06 (1H, d); 7.38 (1H, d); 7.48 (2H, d); 7.97 (2H, d); 7.99
(1H, s); 8.03 (1H, s); 8.21 (1H, s); 10.00-10.30 (2H, m).
Compound 269:
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.37 (3H, d); 1.63
(2H, m); 2.43 (3H, s); 2.52 (3H, s); 2.74-2.85 (5H, m); 2.89-4.46 (7H, m); 5.22-
5.53 (2H, m); 7.06 (1H, d); 7.38 (1H, d); 7.48 (2H, d); 7.98 (2H, d); 8.03 (1H, s);
8.19 (1H, s); 8.25 (1H, s); 10.08 (1H, s); 11.01 (0.8H, br); 11.19 (0.2H, br).
EXAMPLE 15: Compound No. 270
Methyl 4-[(3-{[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]carbamoyl}-5-
chloro-1 H-indol-1 -yl)acetyl]-1 -methylpiperazine-2-carboxylate.
0.62 ml of formaldehyde in solution at 37% in water is added to 0.5 g of
compound No. 212 in 1 ml of formic acid at 50°C, and it is heated at 70°C for
1.5 h. The reaction mixture is added to 15 ml of a saturated solution of sodium
bicarbonate. The precipitate formed is filtered, it is washed with water and then
dried in a vacuum stove at 50°C, obtaining 0.49 g of a white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.65 (2H, m); 2.20-
2.45 (4H, m); 2.52 (3H, s); 2.82 (2H, t); 3.06-3.35 (2H, m); 3.40-3.85 (7H, m);
5.10-5.50 (2H, m); 7.27 (1H, d); 7.48-7.52 (3H, m); 7.95 (2H, d); 8.21 (1H, s);
8.24 (1H, s); 8.29 (1H, s); 10.15 (1H, s).
MH+ = 619; tR = 7.41 min (Method G)
EXAMPLE 16: Compound No. 271
4-[(3-{[4-(4-Butyryl-5-methyl-1H-pyrazol-1-yl)phenyl]carbamoyl}-5-chloro-
1 H-indol-1 -yl)acetyl]-1-methylpiperazine-2-carboxylic acid.
0.89 ml of 1N soda solution is added to 0.49 g of compound No. 270 in
5 ml of methanol, and it is stirred for 18 h. It is evaporated to dryness, the solid
residue is taken up in water and then 2 ml of 1N HCI is added dropwise. The
precipitate formed is filtered, it is washed with water and then dried in a vacuum
stove at 50°C, obtaining 0.40 g of a white powder. 1H NMR: DMSO-d6 +
trifluoroacetic acid (250 MHz):d (ppm): 0.93 (3H, t); 1.64 (2H, m); 2.51 (3H, s);
2.80 (2H, t); 2.99 (3H, s); 3.10-4.60 (7H, m); 5.30-5.60 (2H, m); 7.26 (1H, d);
7.48 (2H, d); 7.52 (1H, d); 7.96 (2H, d); 8.21 (1H, s); 8.22 (1H, s); 8.27 (1H, s).
MH+ = 605; tR = 6.79 min (Method G)
EXAMPLE 17: Compound No. 272
N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-methyl-
3-(methylcarbamoyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide
29 µL of N-methylmorpholine and then 25 µL of ethyl chloroformate are
added to 0.20 g of compound No. 271 in 2 ml of THF at -10°C, and it is stirred
for 2 h, maintaining the temperature at -10°C. After adding 159 uL of 2M
methylamine solution in THF, it is allowed to return slowly to RT and then it is
stirred for 15 h. The reaction mixture is evaporated and then the solid residue is
purified by silica gel chromatography, eluting with DCM/MeOH mixture (gradient
from 0 to 10% of MeOH). The product is dissolved in 5 ml of acetone/MeOH
mixture (1/1: v/v). Then 0.4 ml of 1M HCI solution in ether is added. It is
evaporated to dryness, the solid residue is triturated with acetone, it is washed
with MeOH and dried under vacuum, obtaining 0.090 g of a white powder.
1H NMR: DMSO-d6 + trifluoroacetic acid (250 MHz):d (ppm): 0.94 (3H,
t); 1.64 (2H, m); 2.52 (3H, s); 2.69 (2H, s); 2.77-2.87 (6H, m); 2.89-4.70 (7H, m);
5.25-5.67 (2H, m); 7.28 (1H, d); 7.45-7.59 (3H, m); 7.96 (2H, d); 8.23 (2H, s);
8.30 (1H,d).
MH+ = 618; tR = 6.63 min (Method G)
m.p. = 274°C.
Inhibition of platelet aggregation in vitro (rat blood): 0.21 uM
EXAMPLE 18: Compound No. 273
N-[4-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -[2-oxo-2-(9-
oxooctahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)ethyl]-1H-indole-3-carboxamide
hydrochloride
0.34 g of tert-butyl (2-oxoethyl)carbamate, 0.177 g of sodium
cyanoborohydride and then 0.5 ml of acetic acid are added to 1 g of compound
No. 212 in suspension in 15 ml of MeOH. After stirring at RT for 20 h, it is
evaporated to dryness and then the raw reaction product is purified by silica gel
chromatography, eluting with DCM/MeOH mixture (gradient from 0 to 5% of
methanol). The powder obtained is dissolved in 2 ml of trifluoroacetic acid and
then it is stirred at RT for 4 h. The reaction mixture is poured into 30 ml of 2N
soda solution. The heterogeneous medium is stirred for 15 min and then
extracted with EtOAc. The organic phase is washed with water, with brine and
then evaporated to dryness. The solid residue is purified by silica gel
chromatography, eluting with DCM/MeOH mixture (gradient from 2 to 10% of
methanol). The product is dissolved in 5 ml of acetone/MeOH mixture (1/1: v/v)
and then 1 ml of 2N HCI solution in ether is added. It is evaporated to dryness,
recrystallized from acetone while hot and filtered, obtaining 0.38 g of a white
powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.52
(3H, s); 2.80 (2H, t); 3.20-4.90 (11H, m); 5.20-5.65 (2H, m); 7.20-7.35 (1H, m);
7.49 (2H, d); 7.56 (1H, d); 7.96 (2H, d); 8.22 (1H, s); 8.23 (1H, s); 8.28 (1H, s).
MH+ = 616; tR = 7.74 min (Method G)
m.p. = 230°C.
Inhibition of platelet aggregation in vitro (rat blood): 0.29 uM
EXAMPLE 19: Compound No. 274 SAR164737
N-[4-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -[2-(8-methyl-
9-oxooctahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)-2-oxoethyl]-1H-indole-3-
carboxamide hydrochloride.
0.23 g of tert-butyl methyl(2-oxoethyl)carbamate, 0.082 g of sodium
cyanoborohydride and then 0.4 ml of acetic acid are added to 0.79 g of
compound No. 212 in suspension in 15 ml of MeOH. After stirring at RT for
20 h, it is evaporated to dryness and then the raw reaction product is purified by
silica gel chromatography, eluting with DCM/MeOH mixture (gradient from 0 to
5% of methanol). The powder obtained is dissolved in 2 ml of trifluoroacetic acid
and then it is stirred at RT for 4 h. The reaction mixture is poured into 30 ml of
2N soda solution. The heterogeneous medium is stirred for 15 min and then
extracted with EtOAc. The organic phase is washed with water, with brine and
then evaporated to dryness. The solid residue is purified by silica gel column
chromatography, eluting with DCM/MeOH mixture (gradient from 2 to 10% of
methanol). The product is triturated with iso ether and then filtered, obtaining
0.48 g of a white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.64 (2H, m); 2.07-
3.54 (18H, m); 3.97 (0.5H, d); 4.16 (0.5H, d); 4.25 (0.5H, d); 4.72 (0.5H, d);
5.27-5.56 (2H, m); 7.22-7.29 (1H, m); 7.49 (2H, d); 7.52-7.61 (1H, m); 7.95 (2H,
d); 8.19-8.22 (1H, m); 8.24 (1H, s); 8.27-8.31 (1H, m).
MH+ = 630; tR = 7.96 min (Method G)
m.p. = 220°C.
Inhibition of platelet aggregation in vitro (rat blood): 0.10 µM
EXAMPLE 20: Compound No. 275
2-{4-[(3-{[4-(4-Butyryl-5-methyl-1H-pyrazol-1-yl)phenyl]carbamoyl}-5-
chloro-1 H-indol-1-yl)acetyl]piperazin-1-yl}ethyl acetate hydrochloride
0.27 ml of triethylamine and then 0.14 ml of acetyl chloride are added to
0.40 g of compound No. 146 in 5 ml of DCM at 0°C. After stirring at RT for 1 h,
the reaction mixture is washed with water, with brine and then dried over
Na2SO4 and evaporated to dryness. The solid residue is purified by silica gel
column chromatography, eluting with DCM/MeOH mixture (gradient from 4 to
10% of MeOH). The product is dissolved in 2 ml of acetone/MeOH mixture (1/1:
v/v), 1.5 ml of 1N HCI solution in ether is added and then it is poured into 15 ml
of ether. The precipitate formed is filtered, obtaining 0.32 g of a white powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.63 (2H, m); 2.10
(3H, s); 2.52 (3H, s); 2.82 (2H, t); 3.02-3.32 (3H, m); 3.45-3.75 (5H, m); 4.15-
4.45 (4H, m); 5.36 (1H, d); 5.50 (1H, d); 7.28 (1H, d); 7.49 (2H, d); 7.57 (1H, d);
7.98 (2H, d); 8.22 (1H, s); 8.25 (1H, s); 8.32 (1H, s); 10.15 (1H, s); 11.10 (1H,
br).
MH+ = 633; tR = 6.26 min (Method G)
m.p. = 160°C.
Inhibition of platelet aggregation in vitro (rat blood): 0.20 uM
EXAMPLE 21: Compound No. 276
N-[4-(4-Butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-oxo-2-[4-
(2-oxopropyl)piperazin-1 -yl]ethyl}-1 H-indole-3-carboxamide hydrochloride
0.21 g of K2CO3 and then 0.057 ml of chloroacetone are added to 0.25 g
of compound No. 256 in 11 ml of DMF. After stirring at RT for 48 h, 100 ml of
EtOAc is added, it is washed with water, with brine, dried over Na2SO4 and then
evaporated to dryness. The solid residue is purified by silica gel column
chromatography, eluting with DCM/MeOH mixture (gradient from 0 to 5% of
MeOH). The product is dissolved in 1 ml of DCM, 0.5 ml of 1N HCI solution in
ether is added and then it is poured into 15 ml of ether. The precipitate formed
is filtered, obtaining 0.073 g of a beige powder.
1H NMR: DMSO-d6 (250 MHz):d (ppm): 0.94 (3H, t); 1.63 (2H, m); 2.23
(3H, s); 2.52 (3H, s); 2.82 (2H, t); 2.93-4.64 (10H, m); 5.38 (1H, br); 5.47 (1H,
br); 7.28 (1H, d); 7.50 (2H, d); 7.57 (1H, d); 7.97 (2H, d); 8.22 (1H, s); 8.25 (1H,
s); 8.33 (1H, s); 10.21 (1H, s); 10.50 (1H, br).
MH+ = 603; tR = 6.11 min (Method G)
m.p. = 248°C.
Inhibition of platelet aggregation in vitro (rat blood): 0.22 uM
The compounds according to the invention were submitted to
pharmacological tests.
Inhibition of platelet aggregation in vitro (human blood)
The blood is taken from healthy volunteers, using 20-ml syringes containing
2 ml of buffered sodium citrate. The blood is transferred to polypropylene tubes,
and centrifuged for 5 minutes (100g) at room temperature (without using the
brake of the centrifuge). The supernatant platelet-rich plasma (PRP) is then
removed, diluted, and the platelets are counted before it is used in aggregation
measurements.
The measurements of platelet aggregation are performed at 37°C in glass
tubes (Chrono-Log - Kordia aggregometer). 4ul of the test compound (solution
100 times more concentrated than the required final concentration, in DMSO) is
mixed with 392ul of fresh PRP, and incubated for 1 minute with stirring. Then
4ul of a solution of ADP at 250uM is added to the mixture. The measurements
of aggregation are monitored for 6 to 8 minutes, stirring continuously, by
recording the variations of optical density according to the method of G.V.R.
BORN (Born Nature (1962) 194, 927).
The results are calculated using the aggregation amplitude expressed as
height, and are expressed as percentage inhibition.
The compounds according to the invention have CI50 (of inhibition of
platelet aggregation) between 0.1 and 2 uM.
Inhibition of platelet aggregation in vitro (rat blood)
The blood is taken from male rats of the Sprague-Dawley strain, weighing
250-300g. The sample is taken on sodium citrate at 3.8% (1 volume to 9
volumes of blood) by puncture of the abdominal aorta after anesthetizing the
animal with pentobarbital sodium.
The platelet-rich plasma (PRP) is obtained by centrifugation of the blood at
300g for 5 minutes, and the measurements of platelet aggregation are
performed as described above.
The results are calculated using the area under the curve of absorbance
measured for 6 minutes, and expressed as percentage inhibition.
The compounds according to the invention for which R3 = NR7R8 have
CI50 values (of inhibition of platelet aggregation) between 0.02 and 1.5 µM.
The compounds according to the invention for which R3 = OH have CI50
values (of inhibition of platelet aggregation) > 1.5 µM.
The results obtained for each compound are shown in tables X to XV
Inhibition of platelet aggregation ex vivo (rat blood)
Male rats of the Sprague-Dawley strain, weighing 250-300g, are used at a
rate of 6 animals per batch. Each test compound is diluted in a solution of
glucose-containing water (glucose 5%) containing 5% of cremophore and 3% of
glycofurol.
The compounds according to the invention are administered by stomach
tube (10 ml/kg at 1 mg/ml) two hours before taking the sample or by infusion
(Xml/kg at Xmg/ml) two hours before taking the sample.
The sample is taken on sodium citrate at 3.8% (1 volume to 9 volumes of
blood) by puncture of the abdominal aorta after anesthetizing the animal with
pentobarbital sodium.
The platelet-rich plasma (PRP) is obtained by centrifugation of the blood at
300g for 5 minutes, and the measurements of platelet aggregation are
performed as described above.
The results are calculated using the area under the curve of absorbance
measured for 6 minutes, and expressed as percentage (%) of inhibition.
TABLE XVI below shows the results obtained for compounds 11, 28,
29, 105, 107, 115, 119, 133, 142, 145, 147, 166, 170, 177, 179, 180, 219,
262, 274 and 276:
The compounds of the present invention are notably active principles
compatible with their use as medicinal products and/or pharmaceutical
compositions.
According to one of these aspects, the present invention relates to the use
of a compound of formula (I) or a pharmaceutically acceptable salt thereof for
preparing medicinal products intended for preventing or treating any human
pathology and/or for veterinary use. Thus, the compounds according to the
invention can be used in humans or in animals (notably in mammals including
but not limited to dogs, cats, horses, cattle, sheep) for the prevention or
treatment of diseases involving the P2Y12 receptor.
They are therefore indicated as inhibitors of platelet activation, aggregation
and degranulation, as promoters of platelet disaggregation, and as
antithrombotic agents. They are also indicated in the treatment or prevention of
unstable angina, of percutaneous transluminal coronary angioplasty (PTCA), of
myocardial infarction, of peri-thromboiysis, of thrombotic arterial complications
of atherosclerosis such as embolic or thrombotic cerebrovascular accidents,
transient ischemic attacks, peripheral vascular disease, myocardial infarction
with or without thrombolysis, arterial complications of atherosclerosis due to
surgical interventions such as angioplasty, endarterectomy, placement of
stents, coronary vascular and other grafts, thrombotic complications of surgery
or mechanical damage such as recovery of tissues after accidental or surgical
trauma, reconstructive surgery (including skin and muscle flaps), disseminated
intravascular coagulation, thrombotic thrombocytopenic purpura, hemolytic and
uremic syndrome, thrombotic complications of septicemia, respiratory distress
syndrome, antiphospholipid syndrome, heparin-induced thrombocytopenia and
pre-eclampsia/eclampsia; or venous thromboses such as deep vein thrombosis,
venoocclusive disease, hematological conditions such as myelo-proliferative
disease (including thrombocythemia), sickle-cell anemia; or in the prevention of
platelet activation induced mechanically in vivo, such as during cardiopulmonary
bypass and extracorporeal oxygenation (prevention of micro-
thromboembolisms), in the prevention of platelet activation induced
mechanically in vitro (use in the storage of blood products - for example, platelet
concentrates - use during shunts such as renal dialysis and plasmapheresis),
thrombosis secondary to vascular lesion / inflammation such as angiitis,
arteritis, glomerulonephritis, inflammatory bowel disease, and organ graft
rejection, conditions such as migraine, Raynaud phenomenon, conditions in
which platelets can contribute to the underlying inflammatory disease process in
the vessel wall such as formation / progression of atheromatous plaques,
stenosis / restenosis, and in other inflammatory diseases such as asthma, in
which platelets and platelet-derived factors are involved in the immunological
disease process.
The use of the compounds according to the invention for the prevention
and/or treatment of the aforementioned diseases, as well as for preparing
medicinal products intended for treating these diseases, forms an integral part
of the invention.
The compounds of formula (I) above, or a pharmaceutically acceptable salt
thereof, can be used at daily doses from 0.01 to 100 mg per kilogram of body
weight of the mammal to be treated, preferably at daily doses from 0.1 to
50 mg/kg. In humans, the dose can vary preferably from 0.1 to 4000 mg per
day, more particularly from 0.5 to 1000 mg depending on the age of the subject
to be treated or the type of treatment: prophylactic or curative.
Thus, according to another of its aspects, the present invention relates to
pharmaceutical compositions containing, as active principle, a compound of
formula (I), or a pharmaceutically acceptable salt thereof, as well as one or
more pharmaceutically acceptable excipients.
In the pharmaceutical compositions of the present invention for
administration by the oral, sublingual, inhaled, subcutaneous, intramuscular,
intravenous, topical, local, intratracheal, intranasal, transdermal, local or rectal
route, the active principles can be administered in unit dosage forms, mixed
with conventional pharmaceutical carriers, to animals and to human beings.
The appropriate unit dosage forms comprise oral dosage forms such as
tablets, soft or hard capsules, powders, granules, oral solutions or suspensions,
forms for administration by the sublingual, buccal, intratracheal, intraocular,
intranasal route, by inhalation, aerosols, topical and transdermal dosage forms,
implants, forms for subcutaneous, intramuscular, and intravenous
administration and forms for rectal administration.
For topical administration, the compounds according to the invention can be
used in creams, ointments, gels, or lotions.
As an example, a unit dosage form of a compound according to the
invention in tablet form can comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Croscarmellose sodium 6.0 mg
Maize starch 15.0 mg
Hydroxypropyl-methylcellulose 2.25 mg
Magnesium stearate 3.0 mg
By the oral route, the dose of active principle administered per day can
reach 0.01 to 100mg/kg, in one or more individual doses, preferably 0.02 to
50 mg/kg.
There may be special cases in which higher or lower dosages are
appropriate; such dosages fall within the scope of the invention. According to
the usual practice, the appropriate dosage for each patient is determined by the
doctor depending on the method of administration, and the weight and response
of said patient.
The present invention, according to another of its aspects, also relates to a
method of treatment of the aforementioned disorders that comprises the
administration, to a patient, of an effective dose of a compound according to the
invention, or of a pharmaceutically acceptable salt thereof.
The compounds according to the invention can also be used for preparing
compositions for veterinary use.
CLAIMS
1. Compound corresponding to formula (I):
in which:
-A represents a divalent aromatic radical selected from:
- X represents a -CH- group or a nitrogen atom;
- R1 represents a (C1-C4)alkyl or a (C1-C4)alkoxy;
- R2 represents a group Alk;
- R3 represents a hydroxyl or a group -NR7R8;
- R4 represents a hydrogen atom, a halogen atom, a cyano, a phenyl, a
group Alk, a group OAlk or a group -NR9R10;
- R5 represents a hydrogen atom, a halogen atom or a group Alk;
- R6 represents a hydrogen atom, a halogen atom, a cyano, a group
-COOAlk or a -CONH2 group;
- R7 represents a hydrogen atom or a (C1-C4)alkyl;
- R8 represents:
a) a hydrogen atom;
b) a (C1-C4)alkyl, unsubstituted or substituted with:
(i) a hydroxyl;
(ii) a group OAlk;
(iii) a group -NR9R10;
(iv) a (C3-C6)heterocycloalkyl, unsubstituted or substituted with a (C1-
C4)alkyl or with a group -COOAlk;
(v) a heteroaryl, unsubstituted or substituted with a (C1-C4)alkyl;
c) a (C3-C7)cycloalkyl;
d) a (C3-C6)heterocycloalkyl, unsubstituted or substituted with a (C1-
C4)alkyl, a group -COOAlk or with one or two oxo groups;
e) a group -SO2Alk;
- or else R7 and R8, together with the nitrogen atom to which they are
attached, constitute a heterocycle, saturated or unsaturated, mono- or
polycyclic, condensed or bridged, comprising 4 to 10 ring members and that
can contain one, two or three other nitrogen atoms or another heteroatom
selected from an oxygen atom or a sulfur atom; said heterocycle being
unsubstituted or substituted once, twice or three times with substituents
selected independently from:
a) a halogen atom;
b) a hydroxyl;
c)a group-OR11;
d) an oxo;
e) a group -NR9R10;
f) a group -NR12COR13;
g) a group -NR12COOR13;
h) a group -COR13;
i) a group -COOR13;
j) a group -CONR14R15;
k) a (C3-C7)cycloalkyl, unsubstituted or substituted with a hydroxyl or with a
(C1-C4)alkyl;
I) a (C3-C6)heterocycloalkyl, unsubstituted or substituted with one or two oxo
groups;
m) a phenyl, unsubstituted or substituted one or more times with
substituents selected independently from a halogen atom, a group Alk or a
group OAlk;
n) a pyridinyl;
o) a (C1-C4)alkyl, unsubstituted or substituted one or more times with
substituents selected independently from:
(i) a halogen atom;
(ii) a hydroxyl;
(iii)a group -ORn;
(iv) a group -NR9R10;
(v) a group -NR12COR13;
(vi) a group -COOR13;
(vii) a group -CONR14R15;
(viii) a group -SO2Alk;
(ix) a (C3-C7)cycloalkyl;
(x) a (C3-C6)heterocycloalkyl;
(xi) a phenyl, unsubstituted or substituted one or more times with
substituents selected independently from a halogen atom, a group Alk or a
group OAlk;
(xii) a heteroaryl, unsubstituted or substituted with a (C1-C4)alkyl;
- R9 and R10 represent, each independently, a hydrogen atom or a (C1-
C4)alkyl;
- R11 represents a group Alk, a -(C1-C4)alkylene-OH or a -(C1-C4)alkylene-
OAlk;
- R12 represents a hydrogen atom or a (C1-C4)alkyl;
- R13 represents a (C1-C4)alkyl;
- R14 and R15 represent, each independently, a hydrogen atom, a (C1-
C4)alkyl or a (C3-C7)cycloalkyl;
- or else R14 and R15, together with the nitrogen atom to which they are
attached, constitute a heterocyclic radical selected from: azetidin-1-yl,
pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl or piperazin-1-yl;
- Alk represents a (C1-C4)alkyl, unsubstituted or substituted one or more
times with a fluorine atom;
in the form of a base or salt of addition with an acid or a base.
2. Compound of formula (I) according to Claim 1, characterized in that R3
represents a hydroxyl (reference IA) and the other substituents A, X, R1, R2,
R4 and R5 are as defined for a compound of formula (I) in Claim 1;
in the form of a base or salt of addition with an acid or a base.
3. Compound of formula (I) according to Claim 1, characterized in that R3
represents a group -NR7R8 (reference IB) and the other substituents A, X,
R1, R2, R4, R5, R7 and R8 are as defined for a compound of formula (I) in
Claim 1;
in the form of a base or salt of addition with an acid or a base.
4. Compound of formula (I) according to Claim 1, characterized in that:
-A represents a divalent aromatic radical selected from:
- X represents a -CH- group or a nitrogen atom;
- R1 represents a methyl, ethyl, n-propyl radical or an ethoxy radical;
- R2 represents a methyl radical;
- R3 represents a hydroxyl or a group -NR7R8;
- R4 represents a hydrogen atom, a bromine, chlorine or fluorine atom, a
cyano, a phenyl, a methyl radical, a trifluoromethyl radical, a methoxy
radical or a dimethylamino group;
- R5 represents a hydrogen atom, a bromine, chlorine or fluorine atom or a
methyl radical;
- R6 represents a hydrogen atom, a bromine atom, a cyano, a
methoxycarbonyl group or a -CONH2 group;
- R7 represents a hydrogen atom or a methyl radical;
- R8 represents:
a) a hydrogen atom;
b) a methyl radical, a 2-hydroxyethyl, a 3-hydroxypropyl, a 2-methoxyethyl,
a 2-(methylamino)ethyl, a 2-(dimethylamino)ethyl, a 2-
(dimethylamino)propyl, a 2-(dimethylamino)-1-methylethyl, a 2-
(dimethylamino)-2-methylpropyl, a 3-(dimethylamino)propyl, a (1-
methylpiperidin-3-yl)methyl, a tetrahydrofuran-3-ylmethyl, a tetrahydro-2H-
pyran-4-ylmethyl, a 2-furylmethyl, a (3-methyl-1H-1,2,4-triazol-5-yl)methyl,
1-(1H-tetrazol-5-yl)ethyl, a 2-(1H-pyrrol-1-yl)ethyl, a 2-(1H-imidazol-1-
yl)ethyl;
c) a cyclopropyl;
d) a 1,1-dioxidotetrahydro-3-thienyl, a pyrrolidin-3-yl, a 1-methylpyrrolidin-3-
yl, a 1-(tert-butoxycarbonyl)pyrrolidin-3-yl, a piperidin-3-yl, a 1-
methylpiperidin-3-yl, a 1-(tert-butoxycarbonyl)piperidin-3-yl, a 1-
methylpiperidin-4-yl;
e) a methylsulfonyl group;
- or else R7 and Rs, together with the nitrogen atom to which they are
attached, constitute a heterocycle selected from: an azetidine, a pyrrolidine,
a piperidine, a piperazine, a morpholine, a thiomorpholine, an octahydro-
2H-pyrido[1,2-a]pyrazine, a 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine,
a 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine, an octahydropyrrolo[1,2-a]pyrazine,
a 1,4-diazepane, a 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, a 4,5,6,7-
tetrahydro-1H-pyrazolo[4,3-c]pyridine, a 1,4,5,6-tetrahydropyrrolo[3,4-
c]pyrazole, a 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, a 3,8-
diazabicyclo[3.2.1]octane, a 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, a
4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine, a 2,5-
diazabicyclo[2.2.2]octane, a 2,5-diazabicyclo[2.2.1]heptane, an
octahydropyrrolo[3,4-b]pyrrole, an octahydropyrrolo[3,4-c]pyrrole, an
octahydro-2H-pyrazino[1,2-a]pyrazine; said heterocycle being unsubstituted
or substituted once, twice or three times with substituents selected
independently from:
a) a fluorine atom;
b) a hydroxyl;
c) a methoxy radical, a 2-hydroxyethoxy, a 2-methoxyethoxy;
d) an oxo;
e) an amino group, a methylamino, a dimethylamino;
f) an acetamido group;
g) a (tert-butoxycarbonyl)amino group, a (tert-butoxycarbonyl)(methyl)amino
group;
h) an acetyl group;
i) a methoxycarbonyl group, a tert-butoxycarbonyl group;
j) a dimethylcarbamoyl group, a cyclopropylcarbamoyl, a
cyclobutylcarbamoyl;
k) a cyclopropyl, a cyclobutyl, a 2-hydroxycyclopentyl radical;
I) an oxetan-3-yl, a 1,1-dioxidotetrahydro-3-thienyl, a piperidin-1-yl, a
morpholin-4-yl;
m) a 4-fluorophenyl;
n) a pyridin-2-yl;
o) a methyl radical, an ethyl, an n-propyl, an isopropyl, an n-butyl, a
trifluoromethyl, a 2-fluoroethyl, a 2,2-difluoroethyl, a 2,2,2-trifluoroethyl, a
3,3,3-trifluoropropyl, a 3,3,3-trifluoro-2-hydroxypropyl, a hydroxymethyl, a 2-
hydroxyethyl, a 2-hydroxy-1,1-dimethylethyl, a methoxymethyl, a 2-
methoxyethyl, a 2-methoxy-1-methylethyl, a 2-methoxy-1,1-dimethylethyl, a
2-ethoxyethyl, a 2-(trifluoromethoxy)ethyl, a 2-(2-hydroxyethoxy)ethyl, a 2-
(2-methoxyethoxy)ethyl, a 2-(dimethylamino)ethyl, a 2-acetamidoethyl, a 2-
[acetyl(methyl)amino]ethyl, a 2-methoxy-2-oxoethyl, a 2-ethoxy-2-oxoethyl,
a 3-ethoxy-3-oxopropyl, a 2-amino-2-oxoethyl, a 2-(methylamino)-2-
oxoethyl, a 2-(isopropylamino)-2-oxoethyl, a 2-(dimethylamino)-2-oxoethyl,
a 2-(cyclopropylamino)-2-oxoethyl, a 2-oxo-2-pyrrolidin-1-ylethyl, a 2-
(methylsulfonyl)ethyl, a cyclopropylmethyl, a pyrrolidin-1-ylmethyl, a
tetrahydrofuran-2-ylmethyl, a 2-thienylmethyl, a 4-chlorobenzyl, a 4-
fluorobenzyl, a 2-methoxybenzyl, a 3-fluoro-4-methoxybenzyl, a pyridin-4-
ylmethyl, a (5-methyl-1,2,4-oxadiazol-3-yl)methyl, a (5-methylisoxazol-3-
yl)methyl;
in the form of a base or salt of addition with an acid or a base.
5. Compound of formula (I) according to Claim 1, characterized in that:
- A represents a divalent aromatic radical selected from:

- X represents a -CH- group;
- R1 represents an n-propyl radical;
- R2 represents a methyl radical;
- R3 represents a hydroxyl or a group -NR7R8;
- R4 represents a chlorine atom;
- R5 represents a hydrogen atom;
- R7 represents a hydrogen atom or a methyl radical;
- R8 represents:
b) a methyl radical, a 2-hydroxyethyl, a 3-hydroxypropyl, a 2-methoxyethyl,
a 2-(dimethylamino)ethyl, a 2-(dimethylamino)propyl, a 2-(dimethylamino)-
2-methylpropyl, a 3-(dimethylamino)propyl, a tetrahydrofuran-3-ylmethyl, a
tetrahydro-2H-pyran-4-ylmethyl, a 2-furylmethyl, a (3-methyl-1H-1,2,4-
triazol-5-yl)methyl, 1-(1H-tetrazol-5-yl)ethyl, a 2-(1H-pyrrol-1-yl)ethyl;
c) a cyclopropyl;
d) a 1-methylpyrrolidin-3-yl, a 1-(tert-butoxycarbonyl)piperidin-3-yl, a 1-
methylpiperidin-4-yl;
- or else R7 and R8, together with the nitrogen atom to which they are
attached, constitute a heterocycle selected from: an azetidine, a pyrrolidine,
a piperidine, a piperazine, a morpholine, a thiomorpholine, an octahydro-
2H-pyrido[1,2-a]pyrazine, a 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine,
a 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine, an octahydropyrrolo[1,2-a]pyrazine,
a 1,4-diazepane; said heterocycle being unsubstituted or substituted once,
twice or three times with substituents selected independently from:
b) a hydroxyl;
c) a methoxy radical;
d) an oxo;
h) an acetyl group;
i) a methoxycarbonyl group;
j) a dimethylcarbamoyl group;
k) a cyclobutyl radical;
I) a 1,1-dioxidotetrahydro-3-thienyl, a piperidin-1-yl, a morpholin-4-yl;
m) a 4-fluorophenyl;
0) a methyl radical, an ethyl, an n-propyl, an isopropyl, an n-butyl, a
trifluoromethyl, a 3,3,3-trifluoropropyl, a hydroxymethyl, a 2-hydroxyethyl, a
methoxymethyl, a 2-methoxyethyl, a 2-ethoxyethyl, a 2-
(trifluoromethoxy)ethyl, a 2-(dimethylamino)ethyl, a 2-methoxy-2-oxoethyl, a
2-ethoxy-2-oxoethyl, a 2-(isopropylamino)-2-oxoethyl, a 2-(dimethylamino)-
2-oxoethyl, a 2-(cyclopropylamino)-2-oxoethyl, a 2-oxo-2-pyrrolidin-1-
ylethyl, a tetrahydrofuran-2-ylmethyl, a 4-fluorobenzyl, a 3-fluoro-4-
methoxybenzyl, a pyridin-4-ylmethyl, a (5-methyl-1,2,4-oxadiazol-3-
yl)methyl,;
in the form of a base or salt of addition with an acid or a base.
6. Compound of formula (I) according to Claim 1, characterized in that:
- A represents a divalent aromatic radical:

- X represents a -CH- group or a nitrogen atom;
- R1 represents a methyl, ethyl, n-propyl radical or an ethoxy radical;
- R2 represents a methyl radical;
- R3 represents a hydroxyl or a group -NR7R8;
- R4 represents a hydrogen atom, a bromine, chlorine or fluorine atom, a
cyano, a phenyl, a methyl radical, a trifluoromethyl radical, a methoxy
radical or a dimethylamino group;
- R5 represents a hydrogen atom, a bromine, chlorine or fluorine atom or a
methyl radical;
- R6 represents a hydrogen atom, a bromine atom, a cyano, a
methoxycarbonyl group or a -CONH2 group;
- R7 represents a hydrogen atom or a methyl radical;
- R8 represents:
b) a methyl radical, a 2-hydroxyethyl, a 2-methoxyethyl, a 2-
(methylamino)ethyl, a 2-(dimethylamino)ethyl, a 2-(dimethylamino)-1-
methylethyl, a (1-methylpiperidin-3-yl)methyl, a 2-(1H-imidazol-1-yl)ethyl;
d) a 1,1-dioxidotetrahydro-3-thienyl, a pyrrolidin-3-yl, a 1-methylpyrrolidin-3-
yl, a 1-(tert-butoxycarbonyl)pyrrolidin-3-yl, a piperidin-3-yl, a 1-
methylpiperidin-3-yl, a 1-(tert-butoxycarbonyl)piperidin-3-yl;
e) a methylsulfonyl group;
- or else R7 and R8, together with the nitrogen atom to which they are
attached, constitute a heterocycle selected from: an azetidine, a pyrrolidine,
a piperidine, a piperazine, a morpholine, a 5,6,7,8-
tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, an octahydropyrrolo[1,2-a]pyrazine,
a 1,4-diazepane, a 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, a 4,5,6,7-
tetrahydro-1H-pyrazolo[4,3-c]pyridine, a 1,4,5,6-tetrahydropyrrolo[3,4-
c]pyrazole, a 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, a 3,8-
diazabicyclo[3.2.1]octane, a 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, a
4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine, a 2,5-
diazabicyclo[2.2.2]octane, a 2,5-diazabicyclo[2.2.1]heptane, an
octahydropyrrolo[3,4-b]pyrrole, an octahydropyrrolo[3,4-c]pyrrole, an
octahydro-2H-pyrazino[1,2-a]pyrazine; said heterocycle being unsubstituted
or substituted once, twice or three times with substituents selected
independently from:
a) a fluorine atom;
b) a hydroxyl;
c) a 2-hydroxyethoxy, a 2-methoxyethoxy;
d) an oxo;
e) an amino group, a methylamino, a dimethylamino;
f) an acetamido group;
g) a (tert-butoxycarbonyl)amino group, a (tert-butoxycarbonyl)(methyl)amino
group;
i) a methoxycarbonyl group, a tert-butoxycarbonyl;
j) a group, a cyclopropylcarbamoyl, a cyclobutylcarbamoyl;
k) a cyclopropyl, a cyclobutyl, a 2-hydroxycyclopentyl radical;
I) an oxetan-3-yl, a morpholin-4-yl;
n) a pyridin-2-yl;
o) a methyl radical, an ethyl, an n-propyl, an isopropyl, an n-butyl, a
trifluoromethyl, a 2-fluoroethyl, a 2,2-difluoroethyl, a 2,2,2-trifluoroethyl, a
3,3,3-trifluoro-2-hydroxypropyl, a hydroxymethyl, a 2-hydroxyethyl, a 2-
hydroxy-1,1-dimethylethyl, a methoxymethyl, a 2-methoxyethyl, a 2-
methoxy-1-methylethyl, a 2-methoxy-1,1-dimethylethyl, a 2-ethoxyethyl, a 2-
(trifluoromethoxy)ethyl, a 2-(2-hydroxyethoxy)ethyl, a 2-(2-
methoxyethoxy)ethyl, a 2-(dimethylamino)ethyl, a 2-acetamidoethyl, a 2-
[acetyl(methyl)amino]ethyl, a 2-ethoxy-2-oxoethyl, a 3-ethoxy-3-oxopropyl,
a 2-amino-2-oxoethyl, a 2-(methylamino)-2-oxoethyl, a 2-(dimethylamino)-2-
oxoethyl, a 2-oxo-2-pyrrolidin-1-ylethyl, a 2-(methylsulfonyl)ethyl, a
cyclopropylmethyl, a pyrrolidin-1-ylmethyl, a 2-thienylmethyl, a 4-
chlorobenzyl, a 4-fluorobenzyl, a 2-methoxybenzyl, a (5-methylisoxazol-3-
yl)methyl;
in the form of a base or salt of addition with an acid or a base.
7. Compound of formula (I) according to Claim 1, characterized in that:
- A represents a divalent aromatic radical selected from:

- X represents a -CH- group;
- R1 represents an n-propyl radical;
- R2 represents a methyl radical;
- R3 represents a hydroxyl or a group -NR7R8 selected from:
- R4 represents a chlorine atom;
- R5 represents a hydrogen atom;
in the form of a base or salt of addition with an acid or a base.
8. Compound of formula (I) according to Claim 1, characterized in that:
- A represents a divalent aromatic radical:

- X represents a -CH- group or a nitrogen atom;
- R1 represents a methyl, ethyl, n-propyl radical or an ethoxy radical;
- R2 represents a methyl radical;
- R3 represents a hydroxyl or a group -NR7R8 selected from:
- R4 represents a hydrogen atom, a bromine, chlorine or fluorine atom, a
cyano, a phenyl, a methyl radical, a trifluoromethyl radical, a methoxy
radical or a dimethylamino group;
- R5 represents a hydrogen atom, a bromine, chlorine or fluorine atom or a
methyl radical;
- R6 represents a hydrogen atom, a bromine atom, a cyano, a
methoxycarbonyl group or a -CONH2 group;
in the form of a base or salt of addition with an acid or a base.
9. Compound of formula (I) according to Claim 1, characterized in that:
- A represents a divalent aromatic radical selected from:
- X represents a -CH- group;
- R1 represents an n-propyl radical;
- R2 represents a methyl radical;
- R3 represents a hydroxyl or a group -NR7R8 selected from :

- R4 represents a chlorine atom;
- R5 represents a hydrogen atom;
in the form of a base or salt of addition with an acid or a base.
10. Compound of formula (I) according to Claim 1, characterized in that:
- A represents a divalent aromatic radical:

- X represents a -CH- group or a nitrogen atom;
- R1 represents a methyl, ethyl, n-propyl radical or an ethoxy radical;
- R2 represents a methyl radical;
- R3 represents a hydroxyl or a group -NR7R8 selected from:

- R4 represents a hydrogen atom, a bromine, chlorine or fluorine atom, a
cyano, a phenyl, a methyl radical, a trifluoromethyl radical, a methoxy
radical or a dimethylamino group;
- R5 represents a hydrogen atom, a bromine, chlorine or fluorine atom or a
methyl radical;
- R6 represents a hydrogen atom, a bromine atom, a cyano, a
methoxycarbonyl group or a -CONH2 group;
in the form of a base or salt of addition with an acid or a base.
11. Compound of formula (I) according to Claim 1 selected from:
- (3-{[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]carbamoyl}-5-methyl-1 H-
indol-1-yl)acetic acid;
- (3-{[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]carbamoyl}-5,6-dimethyl
-1H-indol-1-yl)acetic acid;
- (3-{[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]carbamoyl}-5-
chloro-1 H-indol-1-yl)acetic acid;
- N-[5-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyrazin-2-yl]-5-chloro-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-[4-(2-
methoxyethyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-oxo-
2-[4-(3,3,3-trifluoropropyl)piperazin-1-yl]ethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-
(methylamino)-2-oxoethyl]-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -(2-
morpholin-4-yl-2-oxoethyl)-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-
(dimethylamino)-2-oxoethyl]-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-
[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-2-oxoethyl}-1H-indole-3-
carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-(4-
ethylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-(4-
propylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-[(2-
methoxyethyl)(methyl)amino]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-oxo-
2-[4-(tetrahydrofuran-2-ylmethyl)piperazin-1-yl]ethyl}-1H-indole-3-
carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-(5,6-
dihydro[1,2,4]triazolo[4,3-a]-pyrazin-7 (8H)-yl)-2-oxoethyl]-1 H-indole-3-
carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-(4-
cyclobutylpiperazin-1-yl)-2-oxoethyl]-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1-yl)pyridazin-3-yl]-5-chloro-1 -(2-{4-
[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]piperazin-1 -yl}-2-oxoethyl)-1 H-indole-
3-carboxamide;
- {4-[(3-{[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]carbamoyl}-5-
chloro-1 H-indol-1 -yl)acetyl]piperazin-1 -yl}methyl acetate;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-
[cyclopropyl(methyl)amino]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-[4-(4-
fluorobenzyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-[4-(2-
ethoxyethyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -{2-[4-(2-
hydroxyethyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -(2-{[2-
(dimethylamino)ethyl](methyl)amino}-2-oxoethyl)-1H-indole-3-carboxamide;
- N-[6-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)pyridazin-3-yl]-5-chloro-1 -[2-(4-
methyl-1,4-diazepan-1-yl)-2-oxoethyl]-1H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -[2-(8-methyl-9-
oxooctahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)-2-oxoethyl]-1H-indole-3-
carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)-2-cyanophenyl]-5-chloro-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-(4-
fluorobenzyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-(2-
methoxyethyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-1 -{2-[4-(2-
methoxyethyl)piperazin-1-yl]-2-oxoethyl}-5-methyl-1H-indole-3-
carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-(2-
methoxy-1 -methylethyl)piperazin-1 -yl]-2-oxoethyl}-1 H-indole-3-
carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-methyl-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-6-fluoro-1 -{2-[4-
(2-methoxyethyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-methoxy-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-methyl-3-
(methylcarbamoyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5,6-dimethyl-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-methyl-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indazole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-methyl-1 -(2-oxo-2-
piperazin-1 -ylethyl)-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-6-fluoro-1 -[2-(4-
methylpiperazin-1 -yl)-2-oxoethyl]-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -(2-{4-[(5-
methylisoxazol-3-yl)methyl]piperazin-1-yl}-2-oxoethyl)-1H-indole-3-
carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-methyl-1 -(2-morpholin-
4-yl-2-oxoethyl)-1H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -(2-oxo-2-
piperazin-1 -ylethyl)-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-(2-
methoxy-1,1-dimethylethyl)piperazin-1-yl]-2-oxoethyl}-1H-indole-3-
carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -{2-[4-(2-
hydroxy-1,1 -dimethylethyl)piperazin-1 -yl]-2-oxoethyl}-1 H-indole-3-
carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -[2-(8-methyl-
3,8-diazabicyclo[3.2.1]oct-3-yl)-2-oxoethyl]-1H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-1 -[2-(4-methylpiperazin-
1 -yl)-2-oxoethyl]-5-(trifluoromethyl)-1 H-indole-3-carboxamide;
- N-[4-(4-butyryl-5-methyl-1 H-pyrazol-1 -yl)phenyl]-5-chloro-1 -[2-oxo-2-(9-
oxooctahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)ethyl]-1H-indole-3-
carboxamide;
in the form of a base or salt of addition with an acid or a base.
12. Method of preparation of compounds of formula (I) according to Claim 1 in
which R3 = -OH (compound IA), characterized in that:
a compound of formula (II):

in which A, X, R1, R2, R4 and R5 are as defined for a compound of formula
(I) in Claim 1 and Z represents a (C1-C4) alkyl, is hydrolyzed in an acid or
basic medium.
13. Method of preparation of the compounds of formula (I) according to Claim 1
in which R3 = -NR7R8 (compound IB), characterized in that:
a compound of formula (IA):

in which A, X, R1, R2, R4 and R5 are as defined for a compound of formula
(I) in Claim 1, is reacted with an amine of formula (III):
HNR7R8 (III)
in which R7 and R8 are as defined for a compound of formula (I) in Claim 1
14. Compound of formula:

in which:
- A represents a divalent aromatic radical selected from:

- X represents a -CH- group or a nitrogen atom;
- R1 represents a (C1-C4)alkyl or a (C1-C4)alkoxy;
- R2 represents a group Alk;
- R4 represents a hydrogen atom, a halogen atom, a cyano, a phenyl, a
group Alk, a group OAlk or a group -NR9R10;
- R5 represents a hydrogen atom, a halogen atom or a group Alk;
- R6 represents a hydrogen atom, a halogen atom, a cyano, a group
-COOAlk or a -CONH2 group;
- R9 and R10 represent, each independently, a hydrogen atom or a (C1-
C4)alkyl;
- Z represents a (C1-C4)alkyl;
- Alk represents a (C1-C4)alkyl, unsubstituted or substituted one or more
times with a fluorine atom.
15. Medicinal product, characterized in that it contains a compound of formula
(I) according to any one of Claims 1 to 11, or a pharmaceutically acceptable
salt of the compound of formula (I).
16. Pharmaceutical composition, characterized in that it comprises a compound
of formula (I) according to any one of Claims 1 to 11, a pharmaceutically
acceptable salt of said compound, as well as at least one pharmaceutically
acceptable excipient.
17. Compound of formula (I) according to any one of Claims 1 to 11 for the
treatment and prevention of unstable angina, percutaneous transluminal
coronary angioplasty (PTCA), of myocardial infarction, thrombotic arterial
complications of atherosclerosis such as embolic or thrombotic
cerebrovascular accidents, transient ischemic attacks, peripheral vascular
disease, arterial complications of atherosclerosis due to surgical
interventions such as angioplasty, endarterectomy, placement of stents,
coronary vascular grafts, thrombotic complications of surgery or of
mechanical damage such as recovery of tissues after accidental or surgical
trauma, reconstructive surgery (including skin and muscle flaps), thrombotic
thrombocytopenic purpura, antiphospholipid syndrome, heparin-induced
thrombocytopenia and pre-eclampsia/eclampsia; or venous thromboses
such as deep vein thrombosis, venoocclusive disease; or in the prevention
of platelet activation induced mechanically in vivo, such as during
cardiopulmonary bypass and extracorporeal oxygenation (prevention of
micro-thromboembolisms), in the prevention of platelet activation induced
mechanically in vitro (use in the storage of blood products (platelet
concentrates), use during shunts such as renal dialysis and
plasmapheresis), thrombosis secondary to a vascular lesion / inflammation
such as angiitis, arteritis, glomerulonephritis, and organ graft rejection,
conditions in which platelets can contribute to the process of the underlying
inflammatory disease in the vessel wall such as formation / progression of
atheromatous plaques, stenosis / restenosis.

The present invention relates to compounds corresponding to formula (I):

in which:
- A represents a divalent aromatic radical;
- X represents a -CH- group or a nitrogen atom;
- R1 represents a (C1-C4)alkyl or a (C1-C4)alkoxy;
- R2 represents a group Alk;
- R3 represents a hydroxyl or a group -NR7R8;
- R4 represents a hydrogen atom, a halogen atom, a cyano, a phenyl, a group
Alk, a group OAlk or a group -NR9R10;
- R5 represents a hydrogen atom, a halogen atom or a group Alk;
- R6 represents a hydrogen atom, a halogen atom, a cyano, a group
-COOAlk or a -CONH2 group.
Method of preparation and application in therapeutics.