NOVEL INDOLIZINE DERIVATIVES, AND PREPARATION AND
THERAPEUTIC USE THEREOF
The subject of the present invention is novel
indolizine derivatives, the process for preparing same
and the therapeutic use thereof.
Atrial fibrillation (AF) is the most common arrhythmia
and is associated with a high morbidity including heart
failure and heart attacks. It is often encountered in
patients exhibiting a cardiac pathological condition
such as hypertension, or coronary artery disease or
heart valve disease. The most significant consequences
of AF are heart failure, with a 5-fold increase in the
risk of heart attack and twice the risk of mortality
(Duray G.Z., Ehrlich J.R., Hohnloser S.H., Dronedarone:
a novel antiarrhythmic agent for the treatment of
atrial fibrillation. Curr. Opin. Cardiol. 2010; 25: 53-
58). Because of the aging of the population, the number
of adults exhibiting AFs is likely to increase over the
coming decades.
AF is characterized by the coexistence of numerous
activation waves in the atrial myocardium. The
mechanism of their initiation and of their persistence
has been the subject of a great deal of discussion over
the past few years. Because any form of tachyarrhythmia
induces frequency-dependent remodeling, the coexistence
of multiple reentry foci could represent the common
mechanism responsible for the persistence of AFs
associated with various pathological causes. According
to the "leading circle" theory, the maintenance of
reentries depends on the wavelength of the circuit
which is the result of the conduction rate multiplied
by the effective refractory period (ERP) within the
circuit. The longer the wavelength, the fewer the
possible number of AF circuits in the atrium and the
higher the probability that the reentry circuits will
be simultaneously interrupted. Thus, any medicament

which prolongs the atrial ERP should have
antiarrhythmic properties (Ehrlich J.R., Nattel S.
Novel approaches for pharmacological management of
atrial fibrillation. Drugs 2009; 69: 757-774).
FR 2341578 and EP 471609 describe indolizine
derivatives which have notable pharmacological
properties, in particular antiarrhythmic properties,
since these derivatives have proven to be capable of
suppressing or preventing atrial rhythm disorders. Most
compounds described have electrophysiological
properties of classes 1, 2, 3 and 4 of the Vaughan-
Williams classification, which confer, in addition to
their antiarrhythmic properties, noncompetitive anti-α-
and -β-adrenergic, anti-hypertensive and bradycardic
properties. These properties make the compounds in
question very useful in the treatment of certain
pathological syndromes of the cardiovascular system, in
particular in the treatment of angina pectoris, of
hypertension, or of ventricular or supraventricular
arrhythmia. Likewise, these compounds are used in the
treatment of heart failure, or of myocardial infarction
which may or may not be complicated by heart failure,
or for the prevention of post-infarction mortality.
Nevertheless, these compounds have the drawback of
being insoluble or sparingly soluble in water.
Amiodarone, which is an auricular and ventricular
antiarrhythmic that is active orally and intravenously,
is a water-insoluble molecule; the injectable solution
therefore contains solvents such as polysorbate 80 and
benzyl alcohol. These solvents induce hypotensive and
negative inotropic effects in the patient. The
injectable solution also causes local venous
intolerance, which is avoided by recommending a central
injection in a specialized hospital environment.

Dronedarone, a benzofuran derivative, which does not
contain iodine in its chemical structure unlike
amiodarone, is also an auricular and ventricular
antiarrhythmic which is active orally and
intravenously.
In the context of the invention, antiarrhythmics which
are active orally, of indolizine type, capable of
blocking several ion channels like dronedarone but
without its limitations and drawbacks, have now been
discovered. The biggest disadvantage of dronedarone is
its contraindication in patients with heart failure. It
is probable that these effects are linked to the
blockage of sodium channels (Lalevee N., Nargeot J.,
Barrere-Lemaire S., Gautier P., Richard S. Effects of
amiodarone and Dronedarone on voltage-dependent sodium
current in human cardiomyocytes. J. Cardiovasc.
Electrophysiol. 2003; 14:885-890) and calcium channels
(Gautier P., Guillemare E., Marion A., Bertrand J.P.,
Tourneur Y. , Nisato D. Electrophysiologic
characterization of Dronedarone in guinea pig
ventricular cells. J. Cardiovasc. Pharmacol. 2003; 41:
191-202) causing negative inotropy in animals and
probably also in

patients. Consequently, the new compounds will have to
be free of any negative inotropy effect in animals
(pigs, for example). Furthermore, compared with
amiodarone or with dronedarone, our compounds offer
better metabolic stability and a stability in water
that is sufficient for an injectable form.
A subject of the present invention is compounds
corresponding to formula (I):

R2 represents a hydrogen atom, a (C1-C6) alkyl group, a
benzyl group or a CH2-CF3 group;

R3 represents a hydrogen atom, a (C1-C6) alkyl group or
a benzyl group;
R4 represents a hydrogen atom or a (C1-C4) alkyl group;
R5 represents a hydrogen atom or a (C1-C5) alkyl group;
R6 represents a nitrile group or a heteroaryl group
comprising from 1 to 4 heteroatoms chosen from a
nitrogen atom and an oxygen atom, this heteroaryl group
being optionally substituted with a (C1-C6) alkyl group;
R7 represents a hydrogen atom or a linear, branched or
cyclic (C1-C6) alkyl group;
R8 represents a hydroxyl group or a cyano group;
X represents a bond or an oxygen atom;
Am represents:
either

or
— (CH2) t—CR19R20NR17-R18
R16 represents a hydrogen atom or a (C1-C6) alkyl group;
R17 represents a hydrogen atom or a (C1-C6) alkyl group;

R18 represents a branched or cyclic (C1-C6) alkyl group;
R19 and R20 represent a hydrogen atom or a (C1-C6) alkyl
group, or form a (C3-C6) spiroalkyl group;
m represents an integer equal to 0 or 1;
n represents an integer equal to 1 or 2;
r represents an integer equal to 1 or 2;
s represents an integer equal to 1 or 2;
t represents an integer between 2 and 4.
The compounds of formula (I) can comprise one or more
asymmetric carbon atoms. They can therefore exist in
the form of enantiomers or of diastereoisomers. These
enantiomers and diastereoisomers, and also mixtures
thereof, including racemic mixtures, form part of the
invention.
The compounds of formula (I) can exist in the form of
bases or in a form salified with acids or bases, in
particular pharmaceutically acceptable acids or bases.
Such addition salts form part of the invention.
These salts are advantageously prepared with
pharmaceutically acceptable acids, but the salts of
other acids useful, for example, for purifying or
isolating the compounds of formula (I) also form part
of the invention.
In the context of the present invention, and unless
otherwise mentioned in the text:

the term "a halogen atom" is intended to mean: a
fluorine, a chlorine, a bromine or an iodine;
the term "an alkyl group" is intended to mean: a
linear, branched or cyclic saturated aliphatic group.
By way of examples, mention may be made of methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
pentyl, etc. groups;
the term "a spiroalkyl group" is intended to mean:
a bicycle of which the rings are connected via a single
atom. The rings may be of identical or different length
or nature;
the term "a haloalkyl group" is intended to mean:
an alkyl group of which one or more hydrogen atoms has
(have) been substituted with a halogen atom;
the term "an aryl group" is intended to mean: a
cyclic aromatic group comprising between 6 and 10
carbon atoms. By way of examples of aryl groups,
mention may be made of a phenyl, benzyl or naphthyl;
the term "a heteroaryl group" is intended to mean:
a cyclic aromatic group comprising 2, 3, 4 or 5 carbon
atoms and comprising from 1 to 4 heteroatoms chosen
from a nitrogen atom and an oxygen atom, independently
of one another, so as to be identical or different,
when there are 2 of them, or independently of one
another, so as to be identical or different, when there
are 3 of them. Mention may be made of pyridyl, furanyl
and pyrrolyle groups;
the term "a hydroxyl group" is intended to mean:
an -OH group.

Among the compounds of formula (I) which are subjects
of the invention, mention may in particular be made of
the following compounds:
- compound No. 2: (S)-l-{2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}-pyrrolidine-2-
carboxylic acid methyl ester;
- compound No. 3: (R)-l-{2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}pyrrolidine-2-
carboxylic acid methyl ester;
- compound No. 4: 2-Butyl-3-[4-(3-dibutylaminoprop-
yl)benzoyl]indolizine-7-carboxylic acid ethyl (2-
methoxyethyl)amide;
- compound No. 5: ({2-Butyl-3-[4-(3-
dibutylaminopropyl)benzoyl]indolizine-7-
carbonyl}ethylamino)acetic acid methyl ester;
- compound No. 6: ({2-Butyl-3-[4-(3-
dibuty1aminopropy1)benz oy1]indo1i z ine- 7 -
carbonyl}ethylamino)acetic acid;
- compound No. 7: 3-({2-Butyl-3-[4-(3-
dibuty1aminopropy1)benz oy1]indo1i z ine-7-
carbonyl}ethylamino)propionic acid;
- compound No. 8: ({3-[4- (3-
Cyclopentylaminopropy1)benzoyl]-2-ethylindolizine-7-
carbonyl}isopropylamino)acetic acid methyl ester;
- compound No. 9: 2-Butyl-3-[4-(3-
dibutylaminopropyl)benzoyl]indolizine-7-carboxylic acid
ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;

- compound No. 10: 2-Butyl-3-[4-(3-
dibutylaminopropyl)benzoyl]indolizine-7-carboxylic acid
ethyl(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)amide;
- compound No. 11: 2-Butyl-3-[4-(3-
dibutylamine-propyl)benzoyl] indolizine-7-carboxylic acid
ethyl(lH-tetrazole-5-ylmethyl)amide;
- compound No. 12: {[2-Butyl-3-(4-piperidin-4-ylbenzo-
yl)indolizine-7-carbonyl]isopropylamino}acetic acid
methyl ester;
- compound No. 13: 4-{2-Butyl-3-[4-(3-dibutylamino-
propyl) benzoyl] indolizine-7-carbonyl}piperazine-2-one;
- compound No. 14: ({3-[4-(4-
Cyclopentylaminobutyl)benzoyl]-2-ethylindolizine-7-
carbonyl}isopropylamino)acetic acid methyl ester;
- compound No. 15: [ (3-{4-[3-(1-
Aminocyclopentyl)propyl]benzoyl}-2-ethylindolizine-7-
carbonyl)isopropylamino]acetic acid methyl ester;
- compound No. 16: [(2-Ethyl-3-(4-[3-(1-
methylaminocyclopentyl)propyl]benzoyl}indolizine-7-
carbonyl)isopropylamino]acetic acid methyl ester;
- compound No. 17: 3-[4-(3-tert-
Butylaminopropyl)benzoyl]-2-ethylindolizine-7-
carboxylic acid ethyl(2-methyl-2H-tetrazol-5-
ylmethyl)amide;
- compound No. 18: 3-[4-(3-tert-Butylamino-3-
methylbutyl)benzoyl]-2-ethylindolizine-7-carboxylic
acid ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;

- compound No. 19: ({3-[4-(3-Cyclopentylamino-3-
methylbutyl)benzoyl]-2-ethylindolizine-7-
carbonyl}isopropylamino)acetic acid methyl ester;
- compound No. 20: 2-Ethyl-3- [4- ( (S) -3-ethylamino-4-
methylpentyl)benzoyl]indolizine-7-carboxylic acid
ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 21: 2-Butyl-3-[4-(3-
dibutylaminopropyl)benzoyl]indolizine-7-carboxylic acid
benzyl(2-methoxyethyl)amide;
- compound No. 22: 2-Butyl-3-[4-(3-
dibutylaminopropyl)benzoyl]indolizine-7-carboxylic acid
isopropyl(2-methoxyethyl)amide;
- compound No. 23: 2-Butyl-3-[4-(3-
dibutylaminopropyl)benzoyl]indolizine-7-carboxylic acid
ethyl(2-isopropoxyethyl)amide;
- compound No. 24: 2-Butyl-3-[4-(3-
dibutylaminopropyl)benzoyl]indolizine-7-carboxylic acid
(2-ethoxyethyl)isopropylamide;
- compound No. 25: 2-Butyl-3-[4-(3-
dibutylaminopropyl)benzoyl]indolizine-7-carboxylic acid
(2-methoxyethyl)(2,2,2-trifluoroethyl)amide;
- compound No. 26: ({2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indoliz ine-7-carbonyl}ethylamino)acet i c
acid ethyl ester;
- compound No. 27: ({2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}ethylamino)acetic
acid isopropyl ester;

- compound No. 28: ({2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}isopropyl-
amino)acetic acid methyl ester;
- compound No. 29: ({3-[4-(3-dibutylamino-
propyl) benzoyl]-2-ethylindolizine-7-
carbonyl}isopropylamino)acetic acid methyl ester;
- compound No. 30: ({3-[4-(3-Butylaminopropyl)benzoyl]-
2-ethylindolizine-7-carbonyl}isopropylamino)acetic acid
methyl ester;
- compound No. 31: ({3-[4-(3-tert-
Butylaminopropyl)benzoyl]-2-ethylindolizine-7-
carbonyl}isopropylamino)acetic acid methyl ester;
- compound No. 32: ({2-Ethyl-3-[4-(3-
i s opropylaminopropy1)benz oy1]indolizine-7-
carbonyl}isopropylamino)acetic acid methyl ester;
- compound No. 33: ({3-[4-(3-
Cyc1opentylaminopropy1)benzoyl]-2-ethylindolizine-7-
carbonyl}ethylamino)acetic acid ethyl ester;
- compound No. 34: ({3-[4-(3-Cyclopentylamino-
propyl ) benzoyl ] -2-isopropylindolizine-7-
carbonyl}isopropylamino)acetic acid methyl ester;
- compound No. 35: ({3-[4-(3-
Cyclohexylaminopropyl)benzoyl]-2-ethylindolizine-7-
carbonyl}isopropylamino)acetic acid methyl ester;
- compound No. 36: [(3-{4-[3(2,2-Dimethylpropyl-
amino)propyl]benzoyl}-2-ethylindolizine-7-
carbonyl)isopropylamino]acetic acid methyl ester;

- compound No. 37: 3-[4-(3-
Cyclopentylaminopropyl)benzoyl]-2-ethylindolizine-7-
carboxylic acid (2-ethoxyethyl)ethylamide;
- compound No. 38: 4-{3-[4-(3-tert-
Butylaminopropyl)benzoyl]-2-ethylindolizine-7-
carbonyl}piperazin-2-one;
- compound No. 39: 2-Ethyl-3-{4-[3-(1-
methylcyclopentylamino)propyl]benzoyl}indolizine-7-
carboxylic acid ethyl(2-methyl-2H-tetrazol-5-yl-
methyl)amide;
- compound No. 40: 3-[4-(3-tert-
Butylaminopropyl)benzoyl]-2-ethylindolizine-7-
carboxylic acid ethyl(2-ethyl-2H-tetrazol-5-yl-
methy1)amide;
- compound No. 41: 3-[4-(3-tert-Butylaminopropyl)benzo-
yl] indolizine-7-carboxylic acid ethyl(2-methyl-2H-
tetrazol-5-ylmethyl)amide;
- compound No. 42: 3-[4-(3-tert-Butylaminopropyl)benzo-
yl] -2 -cyclobutylindolizine-7 -carboxylic acid ethyl(2-
methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 43: 2-Ethyl-3-[4-(3-ethylamino-4,4-
dimethylpentyl)benzoyl]indolizine-7-carboxylic acid
ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 44: 3-[4-(3-tert-Butylaminopropyl)benzo-
yl] -2-ethylindolizine-7-carboxylic acid ethyl (1-me thyl-
1H-pyrazol-3-ylmethyl)amide;
- compound No. 45: 3-[4-(3-tert-Butylaminopropyl)benzo-
yl] -2 -ethylindolizine-7 -carboxylic acid ethyl (1-methyl-
1H-pyrazol-4-ylmethyl)amide;

- compound No. 46: 3-[4-(3-tert-Butylaminopropyl)benzo-
yl] -2-ethylindolizine-7-carboxylic acid ethyl(5-
methylisoxazol-3-ylmethyl)amide;
- compound No. 47: (R)-l-{3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-
carbonyl>pyrrolidine-3-carbonitrile,•
- compound No. 48: {3-[4-(3-tert-Butylamino-
propyl)benzoyl-2-ethylindolizin-7-yl}-((S)-3-
hydroxypyrrolidin-1-yl)methanone;
- compound No. 49: 3-[4-(3-tert-
Butylaminopropyl)benzoyl]-2-ethylindolizine-7-
carboxylic acid 2-methyl-2H-tetrazol-5-ylmethyl ester;
- compound No. 50: (S)-l-{3-[4-(3-tert-
Butylaminopropyl)benzoyl]-2-ethylindolizine-7-
carbonyl}-2-methylpyrrolidine-2-carboxylic acid methyl
ester;
- compound No. 51: 3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-carboxylic acid
(R)-2-methoxy-1-methylethyl ester;
- compound No. 52: 3-[4-(3-tert-
Butylaminopropyl)benzoyl]-2-ethylindolizine-7-
carboxylic acid (R)-5-oxopyrrolidin-3-yl ester;
- compound No. 53: l-{3-[4-(3-
Cyclopentylaminopropyl)benzoyl]-2-ethylindolizine-7-
carbonyl}[1,4]diazepam-5-one;
- compound No. 54: [(3-{4-[3-(tert-
Butylmethylamino)propyl]benzoyl}-2-ethylindolizine-7-
carbonyl)isopropylamino]acetic acid methyl ester;

- compound No. 55: [(2-Ethyl-3-{4-[3-
(ethylisopropylamino)propyl]benzoyl}indolizine-7-
carbonyl)isopropylamino]acetic acid methyl ester;
- compound No. 56: ({3-[4-(3-Dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}isopropyl-
amino)acetic acid methyl ester;
- compound No. 57: ({3-[4-(3-
Dibutylaminopropyl)benzoyl]indolizine-7-
carbonyl}isopropylamino)acetic acid;
- compound No. 58: ({2-Butyl-3-[4-(3-
dibutylaminopropyl)benzoyl]indolizine-7-
carbonyl}isopropylamino)acetic acid isopropyl ester;
- compound No. 59: 2-Butyl-3-(4-piperidin-4-
ylbenzoyl)indolizine-7-carboxylic acid diethylamide;
- compound No. 60: ({2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}isopropyl-
amino)acetic cid ethyl ester;
- compound No. 61: ({3-[4-(3-Dipropylamino-
propyl)benzoyl]-2-ethylindolizine-7-
carbonyl}isopropylamino)acetic acid methyl ester;
- compound No. 62: [(2-Butyl-3-{4-[3-
(butylethylamino)propyl]benzoyl}indoli zine-7-
carbonyl)isopropylamino]acetic acid methyl ester;
- compound No. 63: ({2-Butyl-3-[4-(3-dibutylamino-
propyl) benzoyl] indolizine-7-carbonyl}isobutyl~
amino)acetic acid methyl ester;

- compound No. 64: ({2-Butyl-3-[4-(l-methylpiperidin-4-
yl)benzoyl]indolizine-7-carbonyl}isopropylamino)acetic
acid;
- compound No. 65: {[2-Ethyl-3-(4-piperidin-4-yl-
benzoyl)indolizine-7-carbonyl]isopropylamino}acetic
acid methyl ester;
- compound No. 66: 2-Butyl-3-(4-piperidin-4-yl-
benzoyl)indolizine-7-carboxylic acid diethylamide;
- compound No. 67: ({2-Butyl-3-[4-(piperidin-4-
yloxy)benzoyl]indolizine-7-carbonyl}isopropyl-
amino)acetic acid methyl ester;
- compound No. 68: ({2-Butyl-3-[4-((S)-piperidin-3-
yloxy)benzoyl]indolizine-7-carbonyl}isopropyl-
amino)acetic acid methyl ester;
- compound No. 69: (S)-2-({2-Butyl-3-[4-(3-
dibutylaminopropyl)benzoyl]indolizine-7-carbonyl}ethyl-
amino)propionic acid methyl ester;
- compound No. 70: 2-Butyl-3-[4-(3-
dibutylaminopropyl)benzoyl]indolizine-7-carboxylic. acid
benzylethylamide;
- compound No. 71: 2-Butyl-3-[4-(3-butylamino-
propyl)benzoyl]indolizine-7-carboxylic acid ethyl(2-
methoxyethyl) amide;.
- compound No. 72: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carboxylic acid (2-
isopropoxyethyl)isopropylamide;

- compound No. 73: [(2-Butyl-3-{4-[3-((3R,5S)-3,5-
dimethylpiperidin-1-yl)propyl]benzoyl}indoli zine-7-
carbonyl)isopropylamino]acetic acid methyl ester;
- compound No. 74: (Benzyl-{2-butyl-3-[4-(3-dibutyl-
aminopropyl)benzoyl]indolizine-7-carbonyl}amino)acetic
acid methyl ester;
- compound No. 75: ({2-Butyl-3-[4-(3-diethylamino-
propyl) benzoyl] indolizine-7-
carbonyl}isopropylamino)acetic acid;
- compound No. 76: ({3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-
carbonyl}isopropylamino)acetic acid;
- compound No. 77: 3- [4- (3-Cyclopentyl-
aminopropyl)benzoyl] -2-ethylindolizine-7-carboxylic
acid ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 78: 3-[4-(3-tert-Butylaminopropyl)benzo-
yl] -2-methylindolizine-7-carboxylic acid ethyl(2-
methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 79: [(2-Ethyl-3-{4-[3-(1-isopropylamino-
cyclopentyl)propyl]benzoyl}indolizine-7-carbon-
yl) isopropylamino] acetic acid methyl ester;
- compound No. 80: 2-Butyl-3-(4-piperidin-4-
ylbenzoyl)indolizine-7-carboxylic acid ethyl(3-methyl-
[1,2,4]oxadizol-5-ylmethyl)amide;
- compound No. 81: ({2-Butyl-3-[4-( (R)-piperidin-3-
yloxy)benzoyl]indolizine-7-carbonyl}isopropyl-
amino) acetic acid methyl ester;
in the form of a base or of an addition salt with an acid.

Among the compounds of formula (I) which are subjects
of the invention, one group of compounds consists of
the following compounds:
- compound No. 3: (R)-l-{2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carbonylpyrrolidine-2-
carboxylic acid methyl ester;
- compound No. 4: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carboxylic acid ethyl(2-
methoxyethyl)amide;
- compound No. 5: ({2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}ethylamino)acetic
acid methyl ester;
- compound No. 8: ({3-[4-(3-Cyclopentylamino-
propyl) benzoyl] 2-ethylindolizine-7-carbon-
yl}isopropylamino)acetic acid methyl ester;
- compound No. 9: 2-Butyl-3-[4-(3-dibutylamino-
propyl) benzoyl] indolizine-7-carboxylic acid ethyl(2-
methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 10: 2-Butyl-3-[4-(3-
dibutylaminopropyl)benzoyl]indolizine-7-carboxylic acid
ethyl(3-methyl[1,2,4]oxadizol-5-ylmethyl)amide;
- compound No. 13: 4-{2-Butyl-3-[4-(3-dibutylamino-
propyl ) benzoyl ] indolizine-7-carbonyl}piperazin-2-one;
- compound No. 16: [(2-Ethyl-3-{4-[3-(1-
methylaminocyclopentyl)propyl]benzoyl}indolizine-7-
carbonyl)isopropylamino]acetic acid methyl ester;

- compound No. 17: 3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-carboxylic acid
ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 18: 3-[4-(3-tert-Butylamino-3-methyl-
butyl)benzoyl]-2-ethylindolizine-7-carboxylic acid
ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 22: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl] indolizine-7-carboxylic acid
isopropyl (2-methoxyethyl)amide;
- compound No. 23: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carboxylic acid ethyl(2-
isopropoxyethy1)amide ;
- compound No. 24: 2-Butyl-3- [4- (3-dibutylaminoprop-
yl) benzoyl ] indolizine-7-carboxylic acid (2-ethoxy-
ethyl)isopropylamide;
- compound No. 28: ({2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}isopropyl-
amino)acetic acid methyl ester;
- compound No. 29: ({3-[4-(3-Dibutylamino-
propyl ) benzoyl ] -2-ethylindolizine-7-carbonyl}iso-
propylamino)acetic acid methyl ester;
- compound No. 30: ({3-[4-(3-Butylaminopropyl)benzoyl]-
2-ethylindolizine-7-carbonyl}isopropylamino)acetic acid
methyl ester;
- compound No. 31: ({3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-carbonyl}iso-
propylamino)acetic acid methyl ester;

- compound No. 35 : ({3- [4- (3-Cyclohexylamino-
propyl) benzoyl]-2-ethylindolizine-7-
carbonyl}isopropylamino)acetic acid methyl ester;
- compound No. 40: 3- [4- (3-tert-Butylaminopropyl)benzo-
yl ]-2-ethylindolizine-7-carboxylic acid ethyl(2-ethyl-
2H-tetrazol-5-ylmethyl)amide;
- compound No. 42: 3- [4- (3-tert-Butylaminopropyl) benzo-
yl] -2-cyclobutylindolizine-7-carboxylic acid ethyl(2-
methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 43: 2-Ethyl-3-[4-(3-ethylamino-4,4-di-
methylpentyl)benzoyl]indolizine-7-carboxylic acid
ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 53: l-{3-[4-(3-Cyclopentylaminoprop-
yl)benzoyl]-2-ethylindolizine-7-carbonyl}[1,4]diazepam-
5-one;
- compound No. 55: [(2-Ethyl-3-{4-[3-(ethylisopropyl-
amino)propyl]benzoyl}indolizine-7-carbonyl)isopropyl-
amino]acetic acid methyl ester;
- compound No. 58: ({3-[4-(3-Dibutylamino-
propyl)benzoyl]-2-ethylindolizine-7-carbonyl}ethyl-
amino)acetic acid isopropyl ester;
- compound No. 62: [(2-Butyl-3-{4-[3-
(butylethylamino)propyl]benzoyl}indolizine-7-
carbonyl)isopropylamino]acetic acid methyl ester;
- compound No. 63: ({2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}isobutyl-
amino)acetic acid methyl ester;

- compound No. 64: ({2-Butyl-3-[4-(l-methylpiperidin-4-
yl)benzoyl]indolizine-7-carbonyl}isopropylamino)acetic
acid
- compound No. 65: {[2-Ethyl-3-(4-piperidin-4-ylbenzo-
yl)indolizine-7-carbonyl]isopropylamino}acetic acid
methyl ester;
- compound No. 69: (S)-2-({2-Butyl-3-[4-(3-dibutyl-
aminopropyl) benzoyl] indolizine-7-carbonyl}ethyl-
amino)propionic acid methyl ester;
- compound No. 75: ({2-Butyl-3-[4-(3-diethylamino-
propyl) benzoyl] indolizine-7-carbonyl}isopropyl-
amino)acetic acid;
- compound No. 77: 3-[4-(3-Cyclopentylaminoprop-
yl)benzoyl]-2-ethylindolizine-7-carboxylic acid
ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 78: 3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-methylindolizine-7-carboxylic acid
ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
in the form of a base or of an addition salt with an
acid.
In the subsequent text, the term "protective group"
(Pg) is intended to mean a group which 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
intact reactive function at the end of synthesis.
Examples of protective groups and also of methods of
protection and deprotection are given in "Protective
Groups in Organic Synthesis", Green et al. , 3rd edition
(John Wiley & Sons, Inc., New York).

In the text which follows, the term "Leaving group"
(Lg) is intended to mean a group which can be readily
cleaved from a molecule by breaking a heterolytic bond,
with the departure of a pair of electrons. This group
can thus be readily replaced with another group in a
substitution reaction, for example. Such leaving groups
are, for example, halogens or an activated hydroxyl
group such as a mesyl, tosyl, triflate, acetyl, etc.
Examples of leaving groups and also references for the
preparation thereof are given in "Advances in Organic
Chemistry", J. March, 3rd edition, Wiley Interscience,
p. 310-316.
In accordance with the invention, it is possible to
prepare the compounds of formula (I) with Ri, R7, X and
Am having the same meaning as previously according to
the process which follows, illustrated in schemes 1, 2,
3, 4 and 5.
In schemes 1, 2, 3, 4 and 5, the starting compounds and
the reagents, when the method for preparing same is not
described, are commercially available or described in
the literature, or else can be prepared according to
methods which are described therein and which are known
to those skilled in the art.
The indolizine nucleus (VIII, scheme 1) is prepared
according to the Chichibabin process via the
quaternization of the pyridine (XI) (with R = an alkyl
group such as isopropyl) with an oc-haloketone
derivative (X) such as l-bromohexan-2-one (Y = Br, step
ii) , in a solvent such as butan-2-one brought to
reflux, followed by a cyclization reaction (step iii)
in the presence of a base such as sodium carbonate, in
a protic solvent such as isopropanol brought to reflux.

A Friedel-Crafts reaction for acylation of position 3
with an acid chloride (VII) where Y represents a
halogen atom (step iv) gives, after heating, the ketone
derivative (VI). Alternatively, in step (iv'), the
acylation can be carried out with an acid chloride
(VII') with X-Am bearing an amine function which is
masked in an amide or formate group, and which is
unmasked at the end of synthesis so as to give the
compound (I) , or again used in a second protective
group compatible with the saponification conditions of
step (vi) and freed again after the final step (vii).
In a step (v) , the condensation of the amine Am-H (V)
with the halogenated derivative (VI), where Y
represents a halogen atom, in the presence of a base
such as potassium carbonate and of a catalytic amount
of potassium iodide (KI) , in a solvent such as
acetonitrile brought to reflux, gives the amine (IV)
which corresponds to a compound of the formula (I)
wherein Ri represents OR when R = R12 = a (Ci-C6)alkyl
group such as an isopropyl group.
The saponification (step vi) of the ester (IV) with
sodium hydroxide in a solvent such as dioxane, followed
by the activation (step vii) of the corresponding
carboxylic acid (III) (which corresponds to a compound
of formula (I) wherein Ri represents O-R12 with R12 = H)
with a coupling agent such as O-benzotriazolyl-
N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU),
in the presence of the amine derivative or alcohol
derivative Ri-H (II) and of a base such as
N,N-diisopropylethylamine (DIEA) , in an aprotic solvent
such as dichloromethane (DCM), gives the compounds of
general formula (I) in accordance with the present
invention.

Alternatively, as described in scheme 2, the X-Am chain
can be introduced using a Sonogashira reaction between
an alkyne derivative (V) and a halogenated derivative
(VI) , prepared as described in scheme 1, where Z
represents a halogen, preferably an iodine atom. Thus,
in step (ii) , the coupling is carried out in the
presence of an organic base such as DIEA and of a
catalytic amount of copper (I) such as Cul or CuBr, and
of palladium such as PdCl2(PPh3) in a polar solvent such
as acetonitrile heated to 50°C. In step (iii) , the
triple bond of the alkyne derivative (IV) is then
totally reduced under a hydrogen atmosphere or with a
hydrogen-transferring agent such as ammonium formate,
in the presence of a catalytic amount of palladium-on-
carbon (Pd-C) in a protic solvent such as ethanol or
methanol. Finally, as described in scheme 1, the ester
(III) is subjected to a saponification-peptide coupling
sequence (steps iv and v) to give the compound I. The
various substituents, when their definition is not
specified, are as defined in general formula (I).
Alternatively, as described in scheme 3, the
Sonogashira coupling can be carried out with an alkyne
derivative functionalized with a precursor of amine
function such as a carboxylic acid function which is
masked in a hydrogenolyzable benzyl ester group so as
to guarantee effective orthogonal deprotection in the
presence of the second ester function with R as
previously described. Thus, in step (ii), the triple
bond and the benzyl ester (R13 = OBn) of the
Sonogashira product are concomitantly reduced under a
hydrogen atmosphere or with a hydrogen-transferring
agent, such as ammonium formate, in the presence of a
catalytic amount of palladium-on-carbon (Pd-C) in a
protic solvent such as ethanol or methanol. The
carboxylic acid function (VII) thus freed is converted,
in step (iii) according to a Curtius rearrangement,

into a tert-butyl carbamate function (V) in the
presence of diphenylphosphoryl azide (DPPA) in tert-
butyl alcohol and of a catalytic amount of copper (I)
such as CuCl. The derivative (V) in steps (iv) and (v)
is subjected, as described in scheme 1, to a
saponification-peptide coupling sequence so as to give
the compound (III) .
Finally, the tert-butyl carbamate function (III) can be
either acidolyzed with trifluoroacetic acid or hydrogen
chloride in step (vii) so as to result in the compound
(I) with R17 = H, or, in step (vi) , before the
acidolysis step, treated with an inorganic base such as
sodium hydride (NaH) in the presence of an alkyl halide
R17X, with X representing a bromium or iodine atom, in
a polar aprotic solvent such as dimethylformamide (DMF)
and give the alkylated carbamate derivative (II).
The various substituents, when their definition is not
specified, are as defined in general formula (I).
Alternatively, as described in scheme 4, the X-Am
chain, with X representing an oxygen atom and Am
functionalized with a protected amine function such as
a tert-butyl carbamate, which guarantees good stability
during the step of saponification of the ester function
with R as described previously, is introduced using a
Buchwald reaction so as to create a carbon-oxygen bond.
Thus, in step (i) , the coupling between the derivative
(VI) , with Z representing a halogen atom such as an
iodine atom and HXAm (V) is carried out in the presence
of an inorganic base such as cesium carbonate (CS2CO3)
and of a catalytic amount of a ligand of
phenanthrolidine type and of copper (I), such as Cul,
in an apolar solvent such as toluene heated at reflux.
The ether (IV) in step (iii) is converted into the
derivative (II) according to a saponification-peptide

coupling sequence as described in scheme 1. Finally,
the tert-butyl carbamate group is acidolyzed either
with trifluoroacetic acid or with hydrogen chloride in
an aprotic solvent such as methylene chloride (CH2CI2)
or ethyl acetate (EtOAC) so as to give the derivative
I.
Alternatively, as described in scheme 5, the XAm chain
can be introduced using a Wittig reaction. In step (i),
the acylation reaction between the indolizine (VIII)
and the acid chloride (IX) , with X representing a
halogen atom such as a

chlorine atom, in the presence of an organic base such
as lutidine and of pyridine in catalytic amounts in an
aprotic solvent such as chlorobenzene heated at reflux,
gives the compound (VII). In step (ii) , according to
the Arbuzov conditions, the benzyl halide derivative
(VII) treated in an excess of phosphite derivative (V)
such as ethyl phosphite heated at reflux, is converted
into the phosphonate (VI). A Wittig reaction in step
(iii) between the ester (VI) and a chiral
a-aminoaldehyde derivative (IV), prepared from the
a-amino acid parent compound of which the amine
function is protected with a tert-butyl carbamate group
for a final deprotection in an aprotic acidic medium,
and from an inorganic base such as NaH, in an aprotic
solvent such as THF, gives the alkene (III). In step
(v) , the alkene is converted, according to a
hydrogenation-saponification-peptide coupling-
acidolysis sequence, as described in scheme 2, into the
derivative (I). The various substituents, when their
definition is not specified, are as defined in general
formula (I).
RECTIFIED SHEET (RULE 91) ISA/EP

A subject of the invention, according to another of its
aspects, is also the compounds of formula (VI)

wherein:
- R7 is as defined in claim 1;
- R represents a (C1-C4) alkyl group;
- R' represents a (C1-C4) alkyl group;
- P represents a phosphorus atom; in the form of a base
or of an addition salt with an acid, as described in
synthesis scheme 5. These compounds are useful as
synthesis intermediates for the compounds of formula
(I) •
The following abbreviations and molecular formulae are
used:
anh. anhydrous
EtOAc ethyl acetate
DCM dichloromethane
DCE dichloroethane
DIEA N,N-diisopropylethylamine
DIPA diisopropylamine
DIAD diisopropyl azodicarboxylate
DPPA diphenylphosphoryl azide
DMF dimethyl formamide
EDCI N-ethyl-N'-(3-dimethylamino-
propyl)carbodiimide * HCl
HMPA hexamethylphosphoramide
HOBt 1-hydroxybenzotriazole
HPLC high performance liquid chromatography
LC/MS liquid chromatography/mass spectrometry
RECTIFIED SHEET (RULE 91) ISA/EP

NMP N-methylmorpholine
Pd-C palladium-on-carbon
TBTU N-[(lH-benzotriazol-1-
yloxy)(dimethylamino)methylidiene]-N-
methylmethanaminium tetrafluoroborate
TEA triethylamine
THF tetrahydrofuran
AT ambient temperature
TFA trifluoroacetic acid
DIAD 1,1'-(azodicarbonyl)dipiperidine
RECTIFIED SHEET (RULE 91) ISA/EP

DME dimethoxyethane
DMF dimethylformamide
DMSO dimethyl sulfoxide
The following examples illustrate the preparation of
some compounds in accordance with the invention. The
numbers of the compounds exemplified refer back to
those of the table given later on which illustrates the
chemical structures and the physical properties of some
compounds according to the invention.
The melting points were measured with a "Biichi melting
point B-545" instrument.
The optical rotations were measured with a "Perkin .
Elmer 343" instrument.
The mass spectra are obtained under the following LC/MS
coupling conditions:
Conditions A:
Column: Kromasil 50 x 2.1 mm, 6.5 \iia
Eluents: A = CH3CN/TFA (0.05%)
B = H2O/CH3CN/TFA (1000 : 3 : 0.5)

Conditions B:
Column: Acquity BEH C18 (50 x 2.1 mm, 1.7 pm)
Eluents: A = H20/TFA (0.05%)
B = CH3CN/TFA (0.035%)


The retention time is denoted Tr.
- The proton magnetic resonance spectra (1H NMR), as
described below, are recorded at 400 MHz in DMSO-d6,
using the DMSO-d5 peak as reference (8 = 2.5 ppm) . The
chemical shifts 8 are expressed in parts by million
(ppm). The signals observed are expressed as follows:
s = singlet; d = doublet; t = triplet; bs = unresolved
peak or broad singlet; H = proton (for the rotamers, BM
and Hjn are denoted with reference to the major and minor
isomers M and m respectively).
Example 1: Synthesis of the intermediate 1-methylethyl
2 -butyl -3-({4-[3-( dibutylamino) propyl ] phenyl} carbon-
yl)indolizine-7-carboxylate
1.1 1-methylethyl 2-methylpyridine-4-carboxylate
A mixture of 11.9 g (55.7 mmol) of 1-methylethyl 2-
chloro-6-methylpyridine-4-carboxylate and 1.2 g of
palladium-on-activated carbon at 10% in 150 ml of iPrOH
is stirred for 24 h at ambient temperature under 4 bar
of hydrogen. The term "ambient temperature" is intended
to mean a temperature between 5 and 25°C. The reaction
mixture is filtered and the filtrate is concentrated
under reduced pressure. The residue obtained is then
taken up with 200 ml of water, neutralized at 0°C using
Na2C03, and then extracted with 3 X 200 ml of DCM. The
organic phases are combined, dried over sodium sulfate,
filtered, and then concentrated under reduced pressure.

The residue is purified by silica column
chromatography, elution being carried out with an
EtOAc/cyclohexane gradient of 0 to 30% with respect to
EtOAc. After concentration under reduced pressure,
38.05 g of 1-methylethyl 2-methylpyridine-4-carboxylate
are obtained in the form of a colorless oil.
Yield = 70%.
1.2 2-Methyl-4-[(1-methylethoxy)carbonylj-1-(2-
oxohexyDpyridinium bromide
A mixture of 9.88 g (55.13 mmol) of 1-methylethyl 2-
methylpyridine-4-carboxylate and 14.88 g (82.69 mmol)
of l-bromohexan-2-one in 3 0 ml of but an-2-one is
refluxed for 24 h. The reaction mixture is allowed to
return to ambient temperature, and the resulting
precipitate is filtered off and then washed
successively with butan-2-one and pentane. 16.4 g of 2-
methyl-4-[(1-methylethoxy)carbonyl]-1-(2-oxo-
hexyl)pyridinium bromide are thus obtained in the form
of a whitish powder which is used as it is in the next
step.
Yield = 82%.
1.3 1-Methylethyl 2-butylindolizine-7-carboxylate
A mixture of .16.4 g (45.52 mmol) of 2-methyl-4-[(1-
methylethoxy) carbonyl] -1- (2-oxohexyl)pyridinium bromide
and 14.17 g (136.52 mmol) of Na2C03 in 200 ml of iPrOH
is refluxed for 1 h 30. The reaction mixture is then
concentrated under reduced pressure, and then taken up
with 2 00 ml of water and extracted with 3 x 150 ml of
DCM. The organic phases are combined, dried over the
sodium sulfate, filtered, and then concentrated under
reduced pressure. The residue obtained is purified by
silica column chromatography, elution being carried out
with DCM. After concentration under reduced pressure,

8.24 g of 1-methylethyl 2-butylindolizine-7-carboxylate
are obtained in the form of a yellow solid.
Yield = 70%.
1.4 1-methylethyl 2-butyl-3-{[4-(3-chloropropyl)phen-
yl] carbonyl}indolizine-7-carboxylate
8.24 g (31.77 mmol) of 1-methylethyl 2-butylindolizine-
7-carboxylate and 6.89 g (31.77 mmol) of 4-(3-
chloropropyl)benzoyl chloride are stirred for 4 h 30 at
85°C. At ambient temperature, the reaction mixture is
taken up with 2 00 ml of water, neutralized with Na2C03
and then extracted with 3 x 150 ml of ether. The
organic phases are combined, dried over Na2S04,
filtered, and then concentrated under reduced pressure.
The residue obtained is chromatographed on a silica
column, elution being carried out with an
EtOAc/cyclohexane gradient of 0 to 10% with respect to
EtOAc. After concentration under reduced pressure,
12.4 g of 1-methylethyl 2-butyl-3-{[4-(3-chloro-
propyl)phenyl]carbonyl}indolizine-7-carboxylate are
obtained in the form of a yellow solid.
Yield = 89%.
1.5 1-Methylethyl 2-butyl-3-({4-[3-(dibutylamino)prop-
yl ]phenyl}carbonyl)indolizine-7-carbxoylate
hydrochloride
A mixture of 12.4 g (28.18 mmol) of 1-methylethyl 2-
butyl-3-{[4-(3-chloropropyl)phenyl]carbonyl}indolizine-
7-carboxylate, 5.46 g (42.27 mmol) of di-n-butylamine,
11.69 g (84.55 mmol) of K2C03 and 4.68 g (28.18 mmol) of
KI in 350 ml of CH3CN is refluxed for 3 days. The
reaction mixture is then concentrated under reduced
pressure, taken up with 200 ml of water and then
extracted with 3 x 200 ml of EtOAc. The organic phases
are combined, dried over Na2S04, filtered, and then

concentrated under reduced pressure. The residue
obtained is chromatographed on a silica column, elution
being carried out with an EtOAc/cyclohexane gradient of
0 to 40% with respect to EtOAc. After concentration
under reduced pressure, 12.7 g of 1-methylethyl 2-
butyl-3-({4-[3-(dibutylamino)propyl]phenyl}carbon-
yl)indolizine-7-carboxylate are obtained in the form of
a yellow oil.
Yield = 85%.
The hydrochloride is prepared by taking up the base
with a 0. IN solution of hydrochloric acid in iPrOH
(1.1 eq.) which is then concentrated under reduced
pressure, and the residue obtained is chromatographed
on RP18 reverse phase, elution being carried out with a
CH3CN/H20 (0.01N HCl) gradient of 0 to 100% with respect
to CH3CN, and then lyophilized.
Mp (°C) = hygroscopic gum
LC/MS: M = C34H48N203 = 532; M+H = 533; Tr 13.0 min
(conditions A).
XH NMR (ppm, d6-DMSO, 400 MHz) :
10.30-10.15 (bs, 1H); 9.30 (d, 1H); 8.30 (s, 1H); 7.60
(d, 2H) ; 7.45 (d, 2H) ; 7.30 (d, 1H) ; 6.85 (s, 1H) ;
5.25-5.10 (bs, 1H) ; 3.15-2.95 (bs, 6H) ; 2.85-2.70 (t,
2H) ; 2.40-2.25 (t, 2H) 2.15-1.95 (bs, 2H) 1.70-1.55
(bs, 4H), 1.50-1.30 (bs, 12H); 1.10-1.00 (bs, 2H); 0.95
(t, 6H) 0.70 (6, 3H).
Example 2; compound No. 2: methyl {S)-l-{ [2-butyl-3-
({4- [3- (dibutylamino)propyl]phenyl}carbonyl) indolizin-
7-yl]carbonyl}prolinate hydrochloride
2.1 2-Butyl-3-({4-[3-(dibutylamino)propyl]phen-
yl} carbonyl) indolizine-7-carboxylic acid
A mixture of 12.7 g (23.84 mmol) of 1-methylethyl 2-
butyl-3- ( {4- [3- (dibutylamino)propyl]phenyl}carbon-

yl)indolizine-7-carboxylate and 1.91 g (47.68 mmol) of
NaOH in 100 ml of dioxane and 20 ml of water is stirred
for 3 days at ambient temperature. The reaction mixture
is then neutralized with a 2N aqueous solution of
hydrochloric acid, and concentrated under reduced
pressure, and the resulting precipitate is filtered
off, and washed with ice-cold water and then with
ether. After drying under reduced pressure, 11.4 g of
2-butyl-3-({4-[3-dibutylamino)propyl]phenyl}carbon-
yl)indolizine-7-carboxylic acid are obtained in the
form of a yellow solid.
Yield = 97%.
2.2 Methyl (S) -l-{[2-butyl-3-({4-[3-(dibutyl-
amino )propyl]phenyl}carbonyl)indoli z in-7-
yl]carbonyl}prolinate hydrochloride
1.0 g (3.06 mmol) of TBTU is added, in small amounts,
at 0°C, under argon, to a solution of 1.5 g (3.06 mmol)
of 2-butyl-3({4-[3-(dibutylamino)propyl]phenyl}carbon-
yl) indol izine- 7- carboxylic acid, 0.51 g (3.06 mmol) of
methyl (S) -prolinate and 1.07 ml (6.11 mmol) of DIEA in
3 0 ml of DCM. The reaction mixture is allowed to return
slowly to ambient temperature and the stirring is
continued for 18 h. The reaction mixture is taken up
with 150 ml of DCM, washed successively with 2 x 75 ml
of a saturated solution of NaHC03, 2 x 75 ml of water
and 75 ml of brine, dried over Na2S04 and filtered, and
the filtrate is then treated with 1 ml of a 4N solution
of hydrogen chloride in dioxane and then concentrated
under reduced pressure. The residue obtained is
chromatographed on RP18 reverse phase, elution being
carried out with a CH3CN/H20 (0.01N HCl) gradient of 0
to 100% with respect to CH3CN. After concentration under
reduced pressure and lyophilization, 1.33 g of methyl
(5)-l-{[2-butyl-3-({4-[3-(dibutylamino)propyl]phen-
yl} carbonyl) indolizin-7-yl]carbonyl}prolinate

hydrochloride are obtained.
Yield = 68%.
Mp (°C): hygroscopic gum
[a]D20 = -22 (c = 0.1; MeOH)
LC/MS: M = C37H5iN304 = 601; M+H = 602; Tr = 9.0 min
(conditions A).
1H NMR (ppm, d6-DMSO, 400 MHz, 2 conformers M/m 8:2):
10.10-10.00 (bs, 1H); 9.35 (d, 1H); 7.90 (s, 1HM) ; 7.70
(S, 1H,„) ; 7.60 (d, 2H) ; 7.40 (d, 2H) ; 7.05 (d, 1HM) ;
6.85 (d, lHm) ; 6.70 (s, 1HM) ; 6.65 (s, lHm) ; 4.70-4.60
(bs, lHm) ; 4.60-4.50 (bs, 1HM) ; 3.80-3.45 (bs, 5H) ;
3.15-2.95 (bs, 6H); 2.80-2.70 (bs, 2H); 2.40-2.20 (bs,
3H) ; 2.10-1.85 (bs, 5H) ; 1.70-1.55 (bs, 4H) ; 1.45-1.25
(bs, 6H) ; 1.10-0.95 ( bs, 2H) ; 0.90 (t, 6H) ; 0.70 (t,
3H) .
Example 3: compound No. 3: methyl (R) -l-{[2-butyl-2-3-
({4- [3- (dibutylamino)propyl]phenyl}carbonyl) indolizin-
7-yl]carbonyl}prolinate hydrochloride
The process is carried out in the same way as in
example 2.2. Thus, starting from 1.50 g (3.06 mmol) of
2-butyl-3-({4- [3-(dibutylamino)propyl]phenyl}carbon-
yl ) indolizine-7-carboxylic acid and 0.50 g (3.06 mmol)
of methyl {R) -prolinate, 1.20 g of methyl (J?)-l-{[2-
butyl-3-({4-[3-(dibutylamino)propyl]phenyl}carbon-
yl ) indolizin-7-yl]carbonyl}prolinate hydrochloride are
obtained after a reverse phase on RP18, elution being
carried out with a CH3CH/H20 (0.01N HCl) gradient of 0
to 100% with respect to CH3CN, and lyophilization.
Yield = 65%.
Mp (°C): hygroscopic gum
[a]D20 = +22 (c = 0.1; MeOH)
LC/MS: M = C37H5iN304 = 6.01; M+H = 602; Tr = 9.0 min
(conditions A).
1H NMR (ppm, d6-DMSO, 400 MHz, 2 conformers M/m 85:15) :
9.90-9.75 (bs, 1H) ; 9.35 (d, 1H) ; 7.90 (s, 1HM) ; 7.70

(s, lHm) ; 7.60 (d, 2H) ; 7.45 (d, 2H) ; 7.05 (d, 1HM) ;
6.90 (d, lHm) ; 6.75 (s, 1HM) ; 6.65 (s, lHm) ; 4.75-4.65
(bs, 1HJ ; 4.60-4.50 (bs, 1HM) ; 3.80-3.50 (bs, 5H) ;
3.15-2.95 (bs, 6H) ; 2.85-2.70 (bs, 2H); 2.40-2.20 (bs,
3H) ; 2.10-1.80 (bs, 5H) ; 1.70-1.50 (bs, 4H) ; 1.45-1.25
(bs, 6H) ; 1.10-0.95 (bs, 2H) ; 0.90 (t, 6H) ; 0.70 (t,
3H) .
Example 4 : compound No. 4: 2-butyl-3-({4-[3-
(dibutylamino)propyl]phenyl}carbonyl)-W-ethyl-N- (2-
methoxyethyl)indolizine-7-carboxamide hydrochloride
The process is carried out in the same way as in
example 2.2. Thus, starting from 1.0 g (2.04 mmol) of
2-butyl-3-({4-[3-(dibutylamino)propyl]phenyl}carbon-
yl) indolizine-7 -carboxylic acid and 0.36 g (2.55 mmol)
of i\7-ethyl-2-methoxyethanamine, 0.75 g of 2-butyl-3-
({4-[3-(dibutylamino)propyl]phenyl}carbonyl)-i\7-ethyl-IV-
(2-methoxyethyl)indolizine-7-carboxamide hydrochloride
are obtained in the form of a hygroscopic yellow foam
after an RP18 reverse phase and lyophilization.
Yield =.60%.
Mp (°C): hygroscopic gum
LC/MS: M = C36H53N3O3 = 575; M+H = 576; Tr = 9.6 min
(conditions A)
^■H NMR (ppm, d6-DMS0, 400 MHz) :
10.00 (si, 1H) ; 9.40 (d, 1H) ; 7.70 (s, 1H) ; 7.60 (d,
2H) ; 7.45 (d, 2H) ; 6.90 (d, 1H) ; 6.65 (s, lH) ; 3.70-
3.15 (bs, 8H) ; 3.15-2.95 (bs, 6H); 2.80-2.70 (bs, 2H) ;
2.30-2.20 (bs, 2H); 2.10-1.95 (bs, 2H) ; 1.70-1.55 (bs,
4H) ; 1.40-1.25 (bs, 6H) ; 1.20-0.95 (bs, 6H) ; 0.90 (t,
6H) ; 0.70 (t, 3H) .
Example 5; compound No. 5: methyl N-{[2-butyl-3-({4-[3-
(dibutylamino)propyl]phenyl}carbonyl)indoli zin-7-
yl]carbonyl}-W-ethylglycinate hydrochloride

5.1 methyl N-ethylglycinate hydrochloride
3 ml (40.72 mmol) of thionyl chloride are added
dropwise, at 0°C, to a solution of 2.1 g (20.36 mmol)
of N-ethylglycine in 40 ml of MeOH. The reaction
mixture is allowed to return to ambient temperature and
then, after stirring for 4 h, the reaction mixture is
concentrated under reduced pressure. The residue
obtained is solidified from ether, filtered and washed
successively with ether and pentane. 3 g of methyl
N-ethylglycinate hydrochloride are obtained in the form
of a white solid which is used as it is in the next
step.
Yield = 95%.
5.2 Methyl N-{[2-butyl-3-({4-[3-(dibutylamino)prop-
yl ]phenyl}carbonyl)indolizin-7-yl]carbonyl}-N-
ethylglycinate hydrochloride
The process is carried out in the same way as in
example 2.2. Thus, starting from 2.0 g (4.08 mmol) of
2-butyl-3-({4-[3-(dibutylamino)propyl]phenyl}carbon-
yl )indolizine-7-carboxylic acid and 0.78 g (5.09 mmol)
of N-ethylglycinate hydrochloride, 0.77 g of methyl N-
{[2-butyl-3-({4-[3-
(dibutylamino)propyl]phenyl}carbonyl)indoli zin-7-
yl] carbonyl }-i\7-ethylglycinate hydrochloride is obtained
in the form of a hygroscopic yellow foam, after an RP18
reverse phase, elution being carried out with a
CH3CN/H20 (0.01N HCl) gradient of 0 to 30% with respect
to CH3CN, and lyophilization.
Yield = 30%.
Mp (°C): hygroscopic gum
LC/MS: M = C36H51N3O4 = 589; M+H = 590; Tr = 9.30 min
(conditions A)
1H NMR (ppm, d6-DMS0, 400 MHz, 2 conformers) :
10.15-10.00 (bs, 1H); 9.45-9.35 (bs, 1H); 7.75-7.65

(bs, 1H) ; 7.60 (d, 2H) ; 7.45 (d, 2H) ; 7.00-6.85 (bs,
1H) ; 6.75-6.65 (bs, 1H) ; 4.25 (s, 2H) ; 3.80-3.65 (bs,
3H); 3.55-3.35 (bs, 3H) ; 3.15-2.95 (bs, 6H) ; 2.85-2.70
(t, 2H) ; 2.30-2.20 (t, 2H) ; 2.10-1.95 (bs, 2H) ; 1.70-
1.55 (bs, 4H) ; 1.45-1.25 (bs, 6H) ; 1.20-1.10 (t, 2H) ;
1.10-1.00 (bs, 2H); 0.95 (t, 6H); 0.70 (t, 3H).
Example 6: compound No. 6: N-{[2-butyl-3-({4-[3-(dibut-
yl amino)propyl]phenyl}carbonyl)indolizin-7-
ylJcarbonyD-N-ethylglycine hydrochloride
3.0 ml (3.0 mmol) of a IN aqueous solution of sodium
hydroxide are added, at 0°C, to a solution of 1.6 g
(2.71 mmol) of methyl N-{[2-butyl-3-({4-[3-
(dibutylamino)propyl]phenyl}carbonyl)indoli zin-7-
yl] carbonyl}-i\7-ethylglycinate, and then the reaction
mixture is allowed to return to ambient temperature and
the stirring is continued for 24 h. The reaction
mixture is treated with 1.0 ml of a 4N solution of
hydrogen chloride in dioxane, concentrated under
reduced pressure, and then chromatographed on RP18
reverse phase, elution being carried out with a
CH3CH/H20 (0.01N HCl) gradient of 0 to 3 0% with respect
to CH3CN. After concentration under reduced pressure and
lyophilization, 0.78 g of 2V-{ [2-butyl-3- ({4- [3-
(dibutylamino)propyl]phenyl}carbonyl)indolizin-7-
yl] carbonyl }-.W-ethylglycine hydrochloride is obtained
in the form of a hygroscopic yellow foam.
Yield = 41%.
Mp (°C): hygroscopic yellow foam
LC/MS: M = C35H49N3O4 = 575; M+H = 57 6; Tr = 8.6 mins
(conditions A)
XH NMR (ppm, d6-DMSO, 400 MHz):
9.45-9.30 (bs, 1H) ; 7.75-7.55 (bs, 3H) ; 7.4 (d, 2H) ;
6.95-6.80 (bs, 1H) ; 6.75-6.60 (bs, 1H) ; 4.20-4.05 (bs,
2H) ; 3.60-3.20 (bs, 2H) ; 3.15-2.95 (bs, 6H) ; 2.85-2.70
(t, 2H) ; 2.30-2.20 (t, 2H); 2.10-1.95 (bs, 2H); 1.70-

1.55 (bs, 4H); 1.45-1.25 (bs, 6H); 1.20-0.90 (bs, 11H);
0.70 (t, 3H).
Example 7; compound No. 7: 3-({2-butyl-3[4-(3-
dibutylaminopropyl) benzoyl ] indolizine-7-
carbonyl}ethylamino)propionic acid hydrochloride
7.1 Methyl N-{[2-butyl-3-({4-[3-(dibutylamino)prop-
yl ]phenyl}carbonyl)indolizin-7-yl]carbonyl}-N- ethyl-ft-
alaninate hydrochloride
The process is carried out in the same way as in
example 2.2. Thus, starting from 2.0 g (4.08 mmol) of
2-butyl-3-({4-[3-(dibutylamino)propyl]phenyl}carbonyl)-
2\/V2V-diethylindolizine-7-carboxamide acid and 0.54 g
(4.08 mmol) of methyl N-ethyl-(3-alaninate, 2.2 g of
methyl N-{[2-butyl-3-({4-[3-(dibutylamino)propyl]phen-
yl}carbonyl) indolizin-7-yl] carbonyl}-iV-ethyl-p-
alaninate hydrochloride are obtained.
Yield = 89%.
MP (°C): hygroscopic yellow foam
LC/MS: M = C37H53N3O4 = 603; M+H = 604; Tr = 1.18 min
(conditions B)
XH NMR (ppm, d6-DMSO, 400 MHz) :
9.40 (d, 1H) ; 7.65 (s, 1H) ; 7.60 (d, 2H) ; 7.45 (d, 2H) ;
6.90 (d, 1H) , 6.65 (s, 1H); 3.80-3.20 (bs, 7H) ; 3.15-3.00
(bs, 6H) ; 2.80-2.70 (bs, 2H); 2.70-2.60 (t, 2H); 2.30-2.20
(t, 2H); 2.10-1.95 (bs, 2H) 1.70-1.55 (bs, 4H) ; 1.45-1.25
(bs, 6H) ; 1.20-0.90 (bs, 11H); 0.70 (t, 3H) .
7.2 3-({2-Butyl-3-[4-(3-dibutylaminopropyl)benzo-
yl] indolizine-7-carbonyDethylamino) propionic acid
hydrochloride
The process is carried out in the same way as in
example 6. Thus, starting from 1.1 g (1.82 mmol) of
methyl N-{[2-butyl-3-({4-[3-(dibutylamino)propyl]phen-
yl} carbonyl) indolizin-7-yl]carbonyl}-N- ethyl-p-

alaninate, 0.91 g of 3-({2-butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}ethylamino)pro-
pionic acid hydrochloride is obtained in the form of a
hygroscopic foam.
Yield = 85%.
Mp (°C): hygroscopic foam
LC/MS: M = C36H51N3O4 = 589; M+H = 590; Tr = 1.09 min
(conditions B)
^■H NMR (ppm, d6-DMSO, 400 MHz) :
9.40 (d, 1H) ; 7.65 (s, 1H) ; 7.60 (d, 2H) ; 7.45 (d, 2H) ;
6.90 (d, 1H), 6.65 (s, 1H); 3.80-3.20 (bs, 4H) ; 3.15-3.00
(bs, 6H) ; 2.80-2.70 (bs, 2H); 2.70-2.60 (t, 2H); 2.30-2.20
(t, 2H) ; 2.10-1.95 (bs, 2H) 1.70-1.55 (bs, 4H); 1.45-1.25
(bs, 6H); 1.20-0.90 (bs, 11H); 0.70 (t, 3H).
Example 8; compound No. 8: methyl N-{ [3- ({4- [3-
(cyclopentylamino) propyl ] phenyl} carbonyl) -2 -
ethylindolizin-7-yl]carbonyl}-W-propane-2-ylglycinate
hydrochloride
8.1 2-Methyl-l-(2-oxopropyl)-4-[(propan-2-
yloxy)carbonyl]pyridinium bromide
The process is carried out in the same way as in
example 1.2. Thus, starting from 39.0 g (217.61 mmol)
of 1-methylethyl 2-methylpyridine-4-carboxylate and
49.29 g (326.42 mmol) of 1-bromobutanone in 120 ml of
butan-2-one, 66.15 g of 2-methyl-l-(2-oxopropyl)-4-
[(propan-2-yloxy)carbonyl]pyridinium bromide are
obtained in the form of a pale yellow powder which is
used as it is in the next step.
Yield = 96%.
8.2 Propan-2-yl 2-ethylindolizine-7-carboxylate
The process is carried out in the same way as in
example 1.3. Thus, starting from 66.15 g (209 mmol) of

2-methyl-l-(2-oxopropyl)-4-[(propan-2-yloxy)carbon-
yl ]pyridinium bromide and 6.5 g (627.62 mmol) of Na2C03
in 700 ml of iPrOH, 40 g of propan-2-yl 2-
ethylindolizine-7-carboxylate are obtained in the form
of a pale yellow solid.
Yield = 83%.
8.3 Propan-2-yl 3-{[4-(3-chloropropyl)phenyl]carbon-
yl}-2-ethylindolizine-7-carboxylate
The process is carried out in the same way as in
example 1.4. Thus, starting from 10.0 g (43.24 mmol) of
propan-2-yl 2-ethylindolizine-7-carboxylate and 25.03 g
(51.88 mmol) of 4-(3-chloropropyl)benzoyl chloride,
17.6 g of propan-2-yl 3-{[4-(3-chloropropyl)phen-
yl] carbonyl}-2-ethylindolizine-7-carboxylate are
obtained in the form of a yellowish oil which
crystallizes slowly.
Yield = 98%.
8.4 Propan-2-yl 3-[(4-{3-[(tert-butoxycarbonyl)(cyclo-
pentyl)amino]propyl}phenyl)carbonyl]-2-ethylindolizine-
7-carboxylate
In a sealed tube, a mixture of 4.0 g (9.71 mmol) of
propan-2-yl 3-{[4-(3-chloropropyl)phenyl]carbonyl} -2-
ethylindolizine-7-carboxylate, 1.65 g (19.42 mmol) of
eye lop en tyl amine and 1.69 g (10.2 mmol) of KI in 30 ml
of a 2:1 CH3CN/DMF mixture is heated for 18 h at 105°C.
The reaction mixture is then concentrated under reduced
pressure, and then taken up with 200 ml of DCM, washed
successively with 2 x 300 ml of water and 100 ml of
brine, dried over Na2S04, filtered, and concentrated
under reduced pressure. 2.08 g of a yellow powder are
thus obtained, and taken up with 25 ml of DCM, and then
1.28 g (5.90 mmol) of Boc20 and 0.46 g (4.52 mmol) of
TEA are added at 0°C. After stirring for 18 h at

ambient temperature (AT), the reaction mixture is taken
up with 200 ml of DCM, washed successively with 100 ml
of water and 100 ml of brine, then dried over MgS04,
filtered, and concentrated under reduced pressure. The
residue obtained is purified by silica gel
chromatography, elution being carried out with a
DCM/MeOH gradient of 0 to 5% with respect to MeOH.
After concentration under reduced pressure, 2.37 g of
propan-2-yl 3-[(4-{3-[(tert-butoxycarbonyl)(cyclo-
pentyl)amino]propyl}phenyl)carbonyl]-2-ethylindolizine-
7-carboxylate are obtained in the form of a yellow gum.
Yield = 43%.
8.5 3-[(4-{3-[(tert-Butoxycarbony1)(cyclopent-
yl)amino]propyl}phenyl)carbonyl]-2-ethylindolizine-7-
carboxylic acid
8.5 ml of a IN aqueous NaOH solution are added
dropwise, at AT, to a solution of 2.37 g (4.23 mmol) of
propan-2-yl 3-[(4-{3-[(tert-butoxycarbonyl)(cyclopent-
yl)amino]propyl}phenyl)carbonyl]2-ethylindolizine-7-
carboxylate in 10 ml of dioxane and the stirring is
continued for 72 h. The reaction mixture is cooled to
0°C, treated by adding, dropwise, 10 ml of a IN aqueous
HC1 solution and then extracted with 2 x 200 ml of DCM.
The organic phases are combined, washed with 100 ml of
brine, dried over Na2S04/ filtered, and then
concentrated under reduced pressure. 2.29 g of 3-[(4-
{3-[(tert-butoxycarbonyl)(cyclopentyl)amino]prop-
yl} phenyl) carbonyl] ~2-ethylindolizine-7-carboxylic acid
are thus obtained in the form of a yellow solid which
is used as it is in the next step.
Yield = 100%.
8.6 Methyl N-({3-[(4-{3-[(tert-butoxycarbonyl)(cyclo-
pentyl) amino]propyl}phenyl)carbonyl]-2-ethylindolizin-
7 -yl} carbonyl) -AT-propan-2 -ylglycinate

With the exception of the salification step, the
process is carried out in the same way as in
example 2.2. Thus, starting from 2.29 g (4.42 mmol) of
3-[(4-{3-[(tert-butoxycarbonyl)(cyclopentyl)amino]prop-
yl }phenyl )carbonyl]-2-ethylindolizine-7-carboxylic
acid, 0.96 g (5.74 mmol) of methyl I\T-propan-2-
ylglycinate hydrochloride, 1.71 g (13.25 mmol) of DIEA
and 2.13 g (6.62 mmol) of TBTU in 2 0 ml of DCM, 2.0 g
of methyl N-({3-[(4-{3-[(tert-butoxycarbonyl)(cyclo-
pentyl) amino]propyl}phenyl)carbonyl]-2-ethylindolizin-
7-yl}carbonyl)-W-propan-2-ylglycinate are obtained in
the form of a yellow foam, after purification on a
silica column, elution being carried out with an
EtOAc/cyclohexane gradient of 0 to 40% of EtOAc.
Yield = 72%.
8.7 Methyl i\f-{[3-({4-[3- (cyclopentylamino) propyl] phen-
yl } carbonyl) -2-ethylindolizine-7-yl ] carbonyl} -iV-propan-
2-ylglycinate hydrochloride
A 2N solution of hydrogen chloride in Et20 is added
dropwise, at 0°C, to a solution of 2.0 g (3.06 mmol) of
methyl N- ({3-[(4-{3-[(tert-butoxycarbonyl) (cyclopent-
yl) amino]propyl}phenyl)carbonyl]-2-ethylindolizin-7-
yl} carbonyl)-iV-propan-2-ylglycinate in 2 0 ml of DCM and
then the reaction mixture is allowed to return to AT.
After stirring for 24 h, the reaction mixture is
concentrated under reduced pressure and the residue
obtained is triturated from Et20, filtered through a
sintered glass funnel and washed with Et20 and then
dried under reduced pressure. 1.72 g of methyl N-{[3-
({4-[3-(cyclopentylamino)propyl]phenyl}carbonyl)-2-
ethylindolizine-7-yl] carbonyl}-I\7-propan-2-ylglycinate
hydrochloride are thus obtained in the form of a yellow
powder.
Yield = 96%.
Mp (°C): 228

LC/MS: M = C32H41N3O4 = 531; M+H = 532; Tr = 1.09 min
(conditions B).
XH NMR (ppm, d6-DMSO, 400 MHz) :
9.60-9.50 (bs, 1H) ; 8.70-8.50 (bs, 1H) ; 7.70 (s, 1H) ;
7.60 (d, 2H); 7.40 (d, 2H); 6.90 (d, 1H); 6.70 (s, 1H);
4.20-4.00 (bs,. 3H) ; 3.75-3.65 (bs, 3H) ; 3.50-3.40 (bs,
1H) ; 3.00-2.90 (t, 2H) ; 2.90-2.80 (t, 2H) ; 2.30-2.20
(bs, 2H); 2.10-1.95 (bs, 4H); 1.80-1.70 (bs, 2H); 1.70-
1.50 (bs, 4H); 1.20-1.05 (bs, 6H); 1.00 (t, 3H).
Example 9: compound No. 9: 2-butyl-3-({4-[3-
(dibutylamino) propyl] phenyl }carbonyl) -N-ethyl-N- [ (2-
methyl-2Jir-tetrazol-5-yl)methyl] indolizine-7-carboxamide
hydrochloride
9.1 tert-Butyl {2- [ (2-cyanoethyl) amino] -2-oxoeth-
yl)ethylcarbamate
11.31 g (59.04 mmol) of EDCI are added, at 0°C and in
small amounts, to a mixture of 10.0 g (49.2 mmol) of N-
(tert-buytoxycarbonyl) -I\7-ethylglycine, 6.89 g
(98.41 mmol) of 3-aminopropanenitrile and 7.53 g
(49.2 0 mmol) of HOBT in 230 ml of an 8:2 DCM/THF
mixture, and then the reaction mixture is allowed to
return slowly to AT and the stirring is continued for
18 h. The reaction mixture is washed successively with
2 x 100 ml of water and 2 x 100 ml of a saturated
solution of K2C03, dried over MgS04, filtered, and then
concentrated under reduced pressure. 11.0 g of tert-
butyl {2-[(2-cyanoethyl)amino]-2-oxoethyl}ethylcarba-
mate are thus obtained in the form of a white solid
which is used as it is in the next step.
Yield = 88%
9.2 fcert-butyl { [1- (2-cyanoethyl) -lH-tetrazol-5-
yl]methyl}ethylcarbamate

12.32 g (47.00 mmol) of PPh3 and then 9.36 ml (70.50 mmol)
of trimethylsilyl azide are added under argon, in small
amounts, to a mixture of 6.0 g (23.50 mmol) of tert-butyl
{2-[(2-cyanoethyl)amino]-2-oxoethyl}ethylcarbamate and
9.5 g (47.00 mmol) of DIAD in 48 ml of anh. THF. After
stirring at AT for 48 h, the reaction mixture is taken up
with 250 ml of EtOAc, washed successively with 2 x 100 ml
of water and 2 x 100 ml of brine, dried over MgS04,
filtered, and then concentrated under reduced pressure.
The residue obtained is purified by silica gel column
chromatography, elution being carried out with an
EtOAc/cyclohexane gradient of 0 to 40% with respect to
EtOAc. After concentration under reduced pressure, 3.2 g
of tert-butyl {[1- (2-cyanoethyl) -lH-tetrazol-5-
yl] methyl} ethyl carbamate are obtained in the form of a
reddish oil.
Yield = 48%.
9.3 tert-Butyl ethyl (lff-tetrazol-5-ylmethyl) carbamate
A mixture of 3.3 g (11.77 mmol) of tert-butyl { [1-(2-
cyanoethyl)-lff-tetrazol-5-yl]methyl}ethylcarbamate and
17.7 ml of a IN aqueous NaOH solution in 24.0 ml of THF
is stirred for 3 days at AT. The reaction mixture is
then cooled to 0°C, neutralized by adding, dropwise,
17.7 ml of a IN aqueous HCl solution and then extracted
with 2 x 150 ml of DCM after addition of 40 ml of
brine. The organic phases are combined, washed with
50 ml of brine, dried over Na2S04, filtered, and then
concentrated under reduced pressure. 2.76 g of tert-
butyl ethyl(lH-tetrazol-5-ylmethyl)carbamate are then
obtained in the form of a colorless oil which is used
as it is in the next step.
Yield = 51%.
9.4 tert-Butyl ethyl [ (2-methyl-2ff-tetrazol-5-yl)meth-
yl]carbamate

0.517 g (12.92 rnmol) of NaH at 60% in oil is added in
small amounts, at 0°C, under argon, to a solution of 2.67
g (11.75 rnmol) of tert-butyl ethyl(lff-tetrazol-5-
ylmethyl)carbamate in 10.7 ml of anh. DMF. After stirring
for 30 minutes at 0°C, 0.73 ml (11.75 rnmol) of iodomethane
is added dropwise and the stirring is continued for 18 h
at AT. The reaction mixture is taken up with .150 ml of
EtOAc, washed successively with 2 x 100 ml of water and
100 ml of brine, dried over Na2S04, filtered, and then
concentrated under reduced pressure. The residue obtained
is purified by silica column chromatography, elution being
carried out with an EtOAc/cyclohexane gradient of 0 to 40%
with respect to EtOAc. After concentration under reduced
pressure, 0.95 g of tert-butyl ethyl[(2-methyl-2H-
tetrazol-5-yl)methyl]carbamate and 0.76 g of tert-butyl
ethyl [■(2-methyl-2H-tetrazol-5-yl)methyl] carbamate are
isolated in the form of colorless oils.
Yield =60%.
9.5 N- [ (2-methyl-2ff-tetrazol-5-yl)methyl] ethanamine
hydrochloride
6 ml of a 2N solution of hydrogen chloride in Et20 are
added to a solution of 0.95 g (3.17 rnmol) of tert-butyl
ethyl [ (l-methyl-lH-tetrazol-5-yl)methyl] carbamate in
6 ml of DCM and the stirring is continued for 18 h at
AT. The reaction mixture is then concentrated under
reduced pressure, triturated from Et20, filtered, and
dried under reduced pressure. 0.395 g of N-[(2-methyl-
2H-tetrazol-5-yl)methyl]ethanamine hydrochloride is
thus obtained in the form of a white solid which is
used as it is in the next step.
Yield = 56%.

9.6 2-Butyl-3-({4-[3-(dibutylamino)propyl]phen-
yl } carbonyl ) -N- ethyl-N-[(2-methyl-2ff-tetrazol-5-
yl)methyl]indolizine-7-carboxide hydrochloride
The process is carried out in the same way as in
example 2.2. Thus, starting from 0.93 g (1.90 mmol) of
2-butyl-3-({4-[3-(dibutylamino)propyl]phenyl}carbon-
yl )indolizine-7-carboxylic acid, 0.36 g (2.0 mmol) of
N-[(1-methyl-Iff-tetrazol-5-yl)methyl]ethanamine
hydrochloride, 0.74 g (5.70 mmol) of DIEA and 0.92 g
(2.85 mmol) of TBTU in 9.5 ml of DCM, 0.91 g of 2-
butyl-3-({4-[3-(dibutylamino)propyl]phenyl}carbonyl)-N-
eth.yl-.W- [ (2-methyl-2ff-tetrazol-5-yl)methyl] indolizine-
7-carboxamide hydrochloride is obtained in the form of
a hygroscopic white powder.
Yield = 73%.
LC/MS: M = C36H51N7O2 = 613; M+H = 614; Tr = 1.16 min
(conditions B)
XH NMR (ppm, de-DMSO, 400 MHz) :
10.40-10.30 (bs, 1H); 9.40 (d, 1H); 7.80-7.70 (bs, 1H) ;
7.60 (d, 2H) ; 7.50 (d, 2H) ; 7.00-6.90 (bs, 1H) ; 7.70
(s, 1H) ; 5.00-4.80 (bs, 2H) ; 4.40 (s, 3H) ; 3.55-3.40
(bs, 2H) ; 3.15-3.00 (bs, 6H); 2.80-2.70 (t, 2H) ; 2.30-
2.20 (t, 2H) ; 2.10-1.95 (bs, 2H) ; 1.70-1.60 (bs, 4H) ;
1.45-1.25 (bs, 6H) ; 1.20-1.10 (t, 2H) ; 1.10-1.00 (bs,
2H); 1.00 (t, 6H); 0.70 (t, 3H).
Example 10: compound No. 10; 2-butyl-3- ( {4- [3-
(dibutyl amino) propyl ] phenyl} carbonyl) -Jff-ethyl -N- [ (3 -
methyl-l/2/4-oxodiazol-5-yl)methyl]indolizine-7-
carboxamide hydrochloride
10.1 tert-Butyl ethyl[(3-methyl-l,2,4-oxadizol-5-yl)-
methyl]carbamate
1.9 g (29.92 mmol) of NaH at 60% in oil are added in
small amounts, at 0°C under argon, to a mixture of

1.3 g (17.149 mmol) of N'-hydroxyethanimidamide and 3 g
of powdered 3A molecular sieve in 184 ml of anh. THF.
After stirring for 1 h at AT, a solution of 2.0 g
(9.21. mmol) of methyl N- (tert-butoxycarbony1) -N-
ethylglycinate in 30 ml of anh. THF is added and then
the reaction mixture is refluxed for 18 h. The mixture
is then filtered, concentrated under reduced pressure,
taken up with 200 ml of DCM, washed successively with
2 X 100 ml of water and 100 ml of brine, dried over
Na2S04, filtered, and then again concentrated under
reduced pressure. The residue obtained is purified by
silica column chromatography, elution being carried out
with an EtOAc/cyclohexane mixture of 0 to 40% with
respect to EtOAc. After concentration under reduced
pressure, 1.65 g of tert-butyl ethyl[(3-methyl-l,2,4-
oxadiazol-5-yl)methyl]carbamate are obtained in the
form of a colorless oil.
Yield = 74%.
10.2 N-[(3-Methyl-l,2,4-oxadiazol-5-
yl)methyl]ethanamine hydrochloride
The process is carried out in the same way as in
example 9.5. Thus, starting from 1.65 g (6.85 mmol) of
tert-butyl ethyl[(3-methyl-l,2,4-oxadiazol-5-yl)meth-
yl] carbamate, 1.05 g of N-[(3-methyl-i,2,4-oxadiazol-5-
yl)methyl]ethanamine hydrochloride are obtained in the
form of a white powder.
Yield = 86%.
10.3 2-Butyl-3-({4-[3-
(dibutylamino) propyl ] phenyl} carbonyl) -N-ethyl -N- [ (3 -
methyl-1,2,4-oxadiazol-5-yl)methyl]indolizine-7-
carboxamide hydrochloride
The process is carried out in the same way as in
example 2.2. Thus, starting from 0.52 g (2.91 mmol) of

N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]ethanamine
hydrochloride, 1.3 g (2.65 mmol) of 2-butyl-3-({4-[3-
(dibutylamino)propyl]phenyl}carbonyl)indolizine-7-
carboxylic acid and 1.03 g (3.97 mmol) of TBTU in
1.4 ml of DCM, 1.04 g of 2-butyl-3- ({4- [3-
(dibutylamino)propyl]phenyl}carbonyl)-N-ethyl-N- [(3-
methyl-1,2,4-oxadiazol-5-yl)methyl]indolizine-7-
carboxamide hydrochloride are obtained in the form of a
gum.
Yield = 58%.
LC/MS: M = C37H53N5O3 = 613; M+H = 614; Tr = 1.18 min
(conditions B)
XH NMR (ppm,d6-DMS0, 400 MHz) :
10.35-10.20 (bs, 1H) ; 9.4 (d, 1H) ; 7.75 (s, 1H) ; 7.60
(d, 2H); 7.40 (d, 2H); 6.95 (d, 1H); 6.70 (s, 1H); 4.90
(s, 2H); 3.60-3.45 (bs, 2H); 3.15-3.00 (bs, 6H); 2.85-
2.75 (t, 2H) ; 2.40 (s, 3H) ; 2.30-2.20 (t, 2H) ; 2.10-
1.95 (bs, 2H) ; 1.7-1.55 (bs, 4H) ; 1.40-1.25 (bs, 6H) ;
1.20 (t, 3H) ; 1.10-0.95 (bs, 2H) ; 0.90 (t, 6H) ; 0.70
(t, 3H).
Example 11; compound No. lit 2-butyl-3-({4-[3-(dibutyl-
amino)propyl]phenyl}carbonyl) -N-etiiyl-N~ (lJET-tetrazol-5-
ylmethyl) indolizine-7-carboxamide hydrochloride
11.1 3-{5-[(Ethylamino)methyl]-lff-tetrazol-1-
yl}propanenitrile hydrochloride
The process is carried out in the same way as in
example 9.5. Thus, starting from 3.02 g (11.42 mmol) of
tert-butyl {[1-(2-cyanoethyl)-Iff-tetrazol-5-yl]methyl}-
ethylcarbamate, 1.83 g of 3-{5-[(ethylamino)methyl]-lff-
tetrazol-l-yl}propanenitrile hydrochloride are obtained
in the form of a white powder.
Yield = 74%.

11.2 2-Butyl-JV-{ [l-(2-cyanoethyl)-lH-tetrazol-5-
yl]methyl}-3-({4-[3-(dibutylamino)propyl]phen-
yl }carbonyl) -iV-ethylindolizine-7-carboxamide
With the exception of the salification step, the
process is carried out in the same way as in
example 2.2. Thus, starting from 2.0 g (4.08 mmol) of
2-butyl-3- ({4- [3- (dibutylamino) propyl] phenyl-} carbon -
yl)indolizine-7-carboxylic acid, 0.97 g (4.48 mmol) of
3-{5-[(ethylamino)methyl]-lH-tetrazol-1-
yl}propanenitrile hydrochloride, 1.58 g (12.23 mmol) of
DIEA and 1.97 g (6.11 mmol) of TBTU in 20 ml of DCM and
with purification on a silica column, elution being
carried out with a DCM/MeOH gradient of 0 to 5% with
respect to MeOH, after concentration under reduced
pressure, 1.35 g of 2-butyl-i\M [1- (2-cyanoethyl) -1H-
tetrazol-5-yl]methyl}-3-({4-[3-
(dibutylamino) propyl] phenyl}carbonyl) -IV-ethyl-
indolizine-7-carboxamide are obtained in the form of a
yellow foam.
Yield = 50%.
11.3 2-Butyl-3-({4-[3-
(dibutylamino) propyl ] phenyl} carbonyl) -iV-ethyl-AT- (1H-
tetrazol-5-ylmethyl)indolizine-7-carboxamide
hydrochloride
A mixture of 1.32 g (2.02 mmol) of 2-butyl-i\T-{ [1- (2-
cyanoethyl)-lff-tetrazol-5-yl]methyl}-3 -({4-[3-(dibutyl-
amino ) propyl] phenyl}carbonyl) -iV-ethylindolizine-7-
carboxamide in 5 ml of THF and 4 ml of a IN aqueous
NaOH solution is stirred for 18 h at AT. The reaction
mixture is then neutralized with 4 ml of a IN aqueous
HC1 solution, the THF is evaporated off, and then the
resulting product is extracted with 2 x 50 ml of DCM.
The organic phases are combined, washed successively
with 50 ml of water and 50 ml of brine, dried over

Na2S04, filtered, treated with 2 ml of a 2N solution of
hydrogen chloride in Et20, and then concentrated under
reduced pressure. The residue obtained is triturated
from ether, filtered, and then dried under vacuum.
1.19 g of 2-butyl-3-({4-[3-(dibutylamino)propyl]phen-
yl }carbonyl) -N-ethyl-N- (lH-tetrazol-5-ylmeth-
yl)indolizine-7-carboxamide hydrochloride are thus
obtained in the form of a hygroscopic foam.
Yield = 92%.
LC/MS: M = C35H49N7O2 = 599; M+H = 600; Tr = 3.82 min
(conditions B)
1H NMR (ppm, d6-DMSO, 400 MHz): 10.70-10.50 (bs, 1H) ;
9.40 (d, 1H); 7.80 (s, 1H); 7.55 (d, 2H); 7.40 (d, 2H);
7.00 (d, 1H) ; 6.65 (s, 1H) ; 4.45 (s, 2H) ; 3.55-3.40
(bs, 2H); 3.10-2.95 (bs, 6H); 2.80-2.70 (t, 2H); 2.30-
2.20 (bs, 2H); 2.10-2.00 (bs, 2H); 1.70-1.60 (bs, 4H) ;
1.40-1.25 (bs, 6H) ; 1.15 (t, 3H) ; 1.05-0.95 (bs, 2H) ;
0.90 (t, 6H); 0.65 (t, 3H).
Example 12; compound No. 12: methyl N- [(2-butyl-3-{E4-
(piperidin-4-yl)phenyl]carbonyl}indolizin-7-
yDcarbonyl] -W-propan-2-ylglycinate hydrochloride
12.1 4-[1-(Trifluoroacetyl)piperidin-4-yl]benzoic acid
20.34 ml (146.16 mmol) of TFAA are added dropwise to a
solution of 10.0 g (48.72 mmol) of 4-(piperidin-4-
yl) benzoic acid in 490 ml of THF. After stirring for
1 h at AT, the reaction mixture is concentrated under
reduced pressure, taken up with 500 ml of EtOAc, washed
successively with 200 ml of water and 200 ml of brine,
dried over MgS04, filtered, and then again concentrated
under reduced pressure. The residue obtained is then
triturated from pentane, filtered, and then dried under
reduced pressure. 11.24 g of 4-[1-(trifluoro-
acetyl )piperidin-4-yl] benzoic acid are thus obtained in
the form of a whitish solid which is used as it is in

the next step.
Yield = 77%.
12.2 4-[1-(Trifluoroacetyl)piperidin-4-yl]benzoyl
chloride
In a sealed tube, a mixture of 11.2 g (37.18 mmol) of
4-[1-(trifluoroacetyl)piperidin-4-yl]benzoic acid in
35 ml (483 mmol) of thionyl chloride is heated to 70°C
in the presence of a drop of DMF. After 5 h at 70°C,
the reaction mixture is then concentrated under reduced
pressure. 11.82 g of 4-[1-(trifluoroacetyl)piperidin-4-
yl) benzoyl chloride are thus obtained in the form of a
whitish solid which is used as it is in the next step.
Yield = 100%.
12.3 Propan-2-yl 2-butyl-3- ({4- [1-(trifluoroacet-
yl)piperidin-4-yl3phenyl}carbonyl)indolizine-7-
carboxylate
A solution of 9.65 g (37.19 mmol) of 1-methylethyl 2-
butylindolizine-7-carboxylate and of 4.8 g (37.19 mmol)
of DIEA is added dropwise to a solution of 11.89 g
(37.19 mmol) of 4-[1-(trifluoroacetyl)piperidin-4-
yl] benzoyl chloride in 41 ml of THF and then the
mixture is heated for 5 h at 85°C. At AT, the reaction
mixture is concentrated under reduced pressure, taken
up with 400 ml of EtOAc, washed successively with
200 ml of water and 200 ml of brine, dried over Na2S04,
filtered, and then again concentrated under reduced
pressure. The residue obtained is purified by silica
column chromatography, elution being carried out with a
cyclohexane/EtOAc mixture of 0 to 3 0% with respect to
EtOAc. After concentration under reduced pressure,
7.19 g of propan-2-yl 2-butyl-3-({4-[1-
(trifluoroacetyl)piperidin-4-yl]phenyl}carbon-
yl)indolizine-7-carboxylate are obtained in the form of

a whitish solid with a purity, determined by LC/MS, of
90%.
Yield = 31%.
12.4 3-({4-[1-(tert-Butoxycarbonyl)piperidin-4-
yl]phenyl}carbonyl)-2-butylindolizine-7-carboxylic acid
A mixture of 7.19 g (13.25 mmol) of propan-2-yl 2-
butyl-3-({4-[1-(trifluoroacetyl)piperidin-4-
yl]phenyl}carbonyl)indolizine-7-carboxylate and 4.58 g
(33.13 mmol) of K2C03 in 270 ml of MeOH is stirred for
2 h at AT. The reaction mixture is then concentrated
under reduced pressure, taken up with 200 ml of water,
and washed with 2 x 100 ml of DCM, and then the
precipitate thus obtained in the aqueous phase is
filtered off, washed with Et20 and dried under reduced
pressure. 1.6 g of a yellow solid are thus obtained,
and placed in solution in 12 ml of a 2:1 0. 5N aqueous
NaOH/dioxane mixture to which 0.95 g (4.36 mmol) of
Boc20 is added. After stirring for 4 h at AT, the
reaction mixture is cooled to 0°C, neutralized with
3 0 ml of a 0.2N aqueous HC1 solution and then extracted
with 2 X 150 ml of DCM. The organic phases are
combined, washed with 50 ml of brine, dried over Na2S04,
filtered and then concentrated under reduced pressure.
2.29 g of 3-({4-[1-(tert-butoxycarbonyl)piperidin-4-
yl]phenyl}carbonyl)-2-butylindolizine-7-carboxylic acid
are thus obtained in the form of an amorphous powder
which is used as it is in the next step.
Yield = 34%.
12.5 tert-Butyl 4-[4-({2-butyl-7-[(2-methoxy-2-oxoeth-
yl)(propan-2-yl)carbamoyl]indolizin-3-
yl}carbonyl)phenyl]piperidine-1-carboxylate
With the exception of the salification step, the
process is carried out in the same way as in

example 2.2. Thus, starting from 2.29 g (4.54 mmol) of
3- ({4- [l-fcert-butoxycarbonyl)piperidin-4-yl]phen-
yl}carbonyl)-2-butylindolizine-7-carboxylic acid,
0.84 g (5.0 mmol) of methyl .W-propan-2-ylglycinate
hydrochloride, 1.76 g (13.63 mmol) of DIEA and 2.19 g
(6.81 mmol) of TBTU in 22 ml of DCM, 1.99 g of tert-
butyl 4-[4-({2-butyl-7-[(2-methoxy-2-oxoethyl)(propan-
2-yl)carbamoyl]indolizin-3-yl}carbonyl)phen-
yl ]piperidine-l-carboxylate are obtained in the form of
a white foam.
Yield = 67%.
12.6 Methyl N-[ (2-butyl-3-{ [4-(piperidin-4-yl)phen-
yl] carbonyl}indolizin-7-yl) carbonyl] -JV-propan-2-
ylglycinate hydrochloride
3 ml of a 4N solution of hydrogen chloride in dioxane
are added to a solution of 1.99 g (3.22 mmol) of tert-
butyl 4-[4-({2-butyl-7-[(2-methoxy-2-oxoethyl)(propan-
2-yl)carbamoyl]indolizin-3-yl}carbonyl)phen-
yl ]piperidine-l-carboxylate in 7 ml of DCM. After
stirring for 8 h at AT, the reaction mixture is
concentrated under reduced pressure, and the residue
obtained is triturated from Et20, filtered, and then
concentrated under reduced pressure. 1.4 g of methyl N-
[(2-butyl-3-{[4-(piperidin-4-yl)phenyl]carbon-
yl }indolizin-7-yl) carbonyl] -JV-propan-2-ylglycinate
hydrochloride are thus obtained.
Yield = 79%.
Mp (°C): 123
LC/MS: M = C31H39N3O4 = 517; M+H = 518; Tr = 0.99 min
(conditions B)
XH NMR (ppm, d6-DMSO, 400 MHz) :
9.50 (d, 1H) ; 8.90-8.70 (bs, 2H) ; 7.65 (s, 1H) ; 7.60
(d, 2H); 7.40 (d, 1H); 6.90 (d, 1H); 6.65 (s, 1H); 4.10
(s, 2H) ; 4.10-3.95 (bs, 1H) ; 3.70 (s, 3H) ; 3.45-3.35
(bs, 2H); 3.10-2.90 (bs, 3H); 2.25-2.15 (bs, 2H); 2.05-

1.80 (bs, 4H) ; 1.40-1.25 (bs, 2H) ; 1.25-1.10 (bs, 6H) ;
1.10-0.90 (bs, 2H); 0.65 (t, 3H).
Example 13; compound No. 13: 4-{[2-butyl-3-({4-[3-
(dibutylamino) propyl ] phenyl} carbony 1) indol i z in- 7 -
yl]carbonyl}piperazin-2-one hydrochloride
The process is carried out in the same way as in
example 2.2. Thus, starting from 1.0 g (2.04 mmol) of
3-({4-[1-(tert-butoxycarbonyl)piperidin-4-
yl]phenyl}carbonyl)-2-butylindolizine-7-carboxylic
acid, 0.25 g (2.45 mmol) of piperazin-2-one, 0.66 g
(5.1 mmol) of DIEA and 0.98 g (3.06 mmol) of TBTU in
10 ml of DCM, 0.88 g of 4-{ [2-butyl-3- ({4- [3-
(dibutylamino) propyl]phenyl}carbonyl) indolizin-7-
yl]carbonyl}piperazin-2-one hydrochloride is obtained
in the form of a yellow solid, after purification on a
silica column, elution being carried out with a
MeOH/DCM gradient of 0 to 10% with respect to MeOH,
followed by a salification step.
Yield = 75%.
Mp (°C): 162
LC/MS: M = C35H48N4O3 = 572; M+H = 573; Tr = 1.01 min
(conditions B)
XH NMR (ppm, d6-DMSO, 400 MHz) :
9.50-9.35 (bs, 2H) ; 8.15 (s, 1H) ; 7.80 (s, 1H) ; 7.60
(d, 2H); 7.45 (d, 2H); 7.00 (d, 1H); 6.70 (s, 1H); 4.10
(s, 2H); 3.80-3.60 (bs, 2H); 3.15-3.00 (bs, 6H); 2.80-
2.70 (t, 2H) ; 2.30-2.20 (t, 2H) ; 2.05-1.90 (bs, 2H) ;
1.70-1.55 (bs, 4H) ; 1.50-1.25 (bs, 6H) ; 1.10-1.00 (bs,
2H); 0.95 (t, 6H); 0.65 (t, 3H).
Example 14; compound No. 14: methyl N-{[3-({4-[4-
(cyclopentylamino)butyl]phenyl}carbonyl)-2-ethyl-
indolizin-7 -yl ] carbonyl} -W-propan-2 -ylglycinate
hydrochloride

14.1 Propan-2-yl 3-{[4-(4-chlorobutyl)phenyl]carbonyl}-
2-ethylindolizine-7-carboxylate
Except for the addition of DIEA, the process is carried
out in the same way as in example 1.4. Thus, starting
from 4.7 g (20.32 mmol) of propan-2-yl 2-ethyl-
indolizine-7-carboxylate, 5.1 g (20.92 mmol) of 4-(4-
chlorobutyl)benzoyl chloride and 2.63 g (20.32 mmol) of
DIEA in 20 ml of anh. THF, 6.15 g of propan-2-yl 3-{[4-
(4-chlorobutyl)phenyl]carbonyl}-2-ethylindoli zine-7-
carboxylate are obtained in the form of an orangey-
colored gum.
Yield = 71%.
14.2 Propan-2-yl 3-({4-[4-(cyclopentylamino)butyl]phen-
yl }carbonyl) -2-ethylindolizine-7-carboxylate
The process is carried out in the same way as in
example 8.4. Thus, starting from 6.15 g (14.11 mmol) of
propan-2-yl 3-{ [4-(4-chlorobutyl)phenyl]carbonyl}-2-
ethylindolizine-7-carboxylate, 4.92 g (57.75 mmol) of
cyclopentylamine and 2.52 g (15.16 mmol) of KI in 3 5 ml
of CH3CN, 6.66 g of propan-2-yl 3-({4-[4-(cyclo-
pentylamino) butyl] phenyl} carbonyl) -2-ethylindolizine-7-
carboxylate are obtained in the form of a yellow
powder.
Yield = 97%.
14.3 Propan-2-yl 3-[(4-{4-[(tert-butoxycarbonyl)(cyclo-
pentyl)amino]butyl}phenyl)carbonyl]-2-ethylindolizine-
7-carboxylate
A mixture of 6.66 g (14.03 mmol) of propan-2-yl 3-({4-
[4-(cyclopentylamino)butyl]phenyl}carbonyl)-2-
ethylindolizine-7-carboxylate, 3.67 g (16.84 mmol) of
Boc20 and 1.42 g (14.03 mmol) of TEA in 60 ml of DCM is
stirred for 18 h at AT. The mixture is then washed

successively with 50 ml of water and 50 ml of brine,
dried over Na2S04, filtered, and then concentrated under
reduced pressure. The residue obtained is purified by
silica column chromatography, elution being carried out
with an EtOAc/cyclohexane mixture of 0 to 3 0% with
respect to EtOAc. After concentration under reduced
pressure, 7.15 g of propan-2-yl 3-[(4-{4-[(tert-
butoxycarbonyl)(eye1opentyl)amino]butyl}phenyl)carbon-
yl]-2-ethylindolizine-7-carboxylate are obtained in the
form of an orangey-colored oil.
Yield = 89%.
14.4 3-[((4-{4-[[(fcert-Butoxycarbonyl)(cyclo-
pentyl)amino]butyl}phenyl)carbonyi]-2-ethylindolizine-
7-carboxylic acid
The process is carried out in the same way as in
example 8.5. Thus, starting from 7.15 g (12.44 mol) of
propan-2-yl 3-[(4-{4-[(tert-butoxycarbonyi)(cyclopent-
yl)amino]butyl}phenyl)carbonyi]-2-ethylindolizine-7-
carboxylate, 6.016 g of 3-[(4-{4-[(tert-butoxy-
carbonyi)(cyclopentyl)amino]butyl}phenyl)carbonyi]-2-
ethylindolizine-7-carboxylic acid are obtained in the
form of a yellow powder.
Yield = 91%.
14.5 Methyl N-({3-[(4-{4-[(tert-butoxycarbonyl)(cyclo-
pentyl) amino]butyl}phenyl)carbonyi]-2-ethylindolizine-
7-yl} carbonyi) -i\T-propan-2-ylglycinate
The process is carried out in the same way as in
example 8.6. Thus, starting from 1.1 g (2.07 mol) of 3-
[(4-{4-[(tert-butoxycarbonyi)(cyclopentyl)amino]but-
yl} phenyl) carbonyi]-2-ethylindolizine-7-carboxylic
acid, 0.52 g (3.10 mmol) of methyl N-propan-2-
ylglycinate hydrochloride, 0.80 g (6.20 mmol) of DIEA
and 0.99 g (3.10 mmol) of TBTU, 1.3 g of methyl N-{{3-

[(4-{4-[(tert-butoxycarbonyl)(cyclopent-
yl)amino]butyl}phenyl)carbonyl]-2-ethylindolizine-7-
yl}carbonyl) -iV-propan-2-ylglycinate are obtained in the
form of a yellow gum.
Yield = 97%.
14.6 Methyl N-{[3-({4-[4-(cyclopentylamino)butyl]phen-
yl } carbonyl) - 2 - ethyl indol i z in-7 -yl ] carbonyl} -iV-propan-
2-ylglycinate hydrochloride
The process is carried out in the same way as in
example 8.7. Thus, starting from 1.3 g (2.01 mmol) of
methyl N- ({3-[(4-{4-[(tert-butoxycarbonyl) (cyclo-
pentyl)amino]butyl}phenyl)carbonyl]-2-ethyiindolizine-
7-yl}carbonyl)-iV-propan-2-ylglycinate, 1.03 g of methyl
-ZV-{[3-({4-[4- (cyclopentylamino) butyl] phenyl} carbonyl) -
2-ethylindolizin-7-yl] carbonyl }-JV-propan-2-ylglycinate
hydrochloride are obtained in the form of a yellow
foam.
Yield = 88%.
Mp (°C): 154
LC/MS: M = C33H43N3O4 = 545; M+H = 545; Tr = 1.13 min
(conditions B)
XH NMR (ppm, d6-DMSO, 400 MHz) :
9.45-9.35 (bs, 1H) ; 8.75-8.60 (bs, 2H) ; 7.65 (s, 1H) ;
7.55 (d,.2H); 7.40 (d, 2H); 6.90 (d, 1H); 6.70 (s, 1H);
4.10 (s, 2H); 4.10-3.95 (bs, 1H) ; 3.70 (s, 3H) ; 3.50-
3.35 (bs, 1H) ; 2.95-2.85 (t, 2H) ; 2.75-2.65 (t, 2H) ;
2.30-2.20 (bs, 2H); 2.00-1.85 (bs, 2H); 1.70-1.45 (bs,
10H); 1.15 (d, 6H); 1.05 (t, 3H).
Example 15; compound No. 15: methyl N-{[3-({4-[3-(1-
aminocyclopentyl)propyl]phenyl}carbonyl)-2-
ethylindolizine-7-yl]carbonyl}-W-propan-2-ylglycinate
hydrochloride
15.1 Benzyl 1-(prop-2-yn-l-yl)cyclopentanecarboxylate

36.72 ml (58.75 mmol) of a 1.6 M solution of n-BuLi in
n-hexane and 34.07 ml of HMPA are added dropwise, at
-40°C under argon, to a solution of 8.30 ml
(58.75 mmol) of DIPA in 100 ml of anh. THF. After
stirring for 15 min at -40°C, the reaction mixture is
cooled to -78°C and then a solution of 10.0 g
(48.96 mmol) of benzyl cyclopentanecarboxylate is added
dropwise. After stirring for 15 min at -78°C, 21.81 ml
(195.82 mmol) of an 80% w/v solution of propargyl
bromide in toluene are added dropwise. The reaction
mixture is then left to return slowly to AT and, after
1 h, it is treated with 200 ml of a saturated aqueous
solution of ammonium chloride and then extracted with
2 x 200 ml of EtOAc. The organic phases are combined,
washed with 100 ml of brine, dried over MgS04, filtered,
and then concentrated under reduced pressure. The
residue obtained is purified by silica column
chromatography, elution being carried out with an
EtOAc/cyclohexane gradient of 0 to 3 0% with respect to
EtOAc. After concentration under reduced pressure,
9.1 g of benzyl 1-(prop-2-yn-l-yl)cyclopentane-
carboxylate are obtained in the form of an orangey-
colored oil.
Yield = 77%.
15.2 Propan-2-yl 2-ethyl-3- [ (4-iodophenyl) carbon-
yl]indolizine-7-carboxylate
The process is carried out in the same way as in
example 14.1. Thus, starting from 22.0 g (95.12 mmol)
of propan-2-yl 2-ethylindolizine-7-carboxylate, 25.3 5 g
(95.12 mmol) of 4-iodobenzyl chloride and 12.3 0 g
(95.12 mmol) of DIEA in 100 ml of THF, 34.3 g of
propan-2-yl 2-ethyl-3-[(4-iodophenyl)carbon-
yl]indolizine-7-carboxylate are obtained in the form of
a yellow solid.
Yield = 78%.

15.3 Propan-2-yl 3-{ [4- (3-{l- [ (benzyloxy) carbon-
yl]cyclopentyl}prop-l-yn-l-yl)phenyl]carbonyl}-2-ethyl-
indolizine-7-carboxylate
A mixture of 12.60 g (27.31 mmol) of propan-2-yl 2-
ethyl-3-[(4-iodophenyl)carbonyl]indolizine-7-
carboxylate, 9.93 g (40.97 mmol) of benzyl l-(prop-2-
yn-l-yl)cyclopentanecarboxylate, 3.53 g (27.31 mmol) of
DIEA and 0.31 g (1.64 mmol) of Cul in 54 ml of CH3CN is
stirred for 15 min at AT under argon, and then 0.77 g
(1.09 mmol) of PdCl2 (PPh3) is added and the reaction
mixture is then heated to 5 h at 50°C. At AT, the
mixture is taken up with 3 00 ml of EtOAc, washed
successively with 2 x 100 ml of water and 100 ml of
brine, dried over MgS04, filtered, and then concentrated
under reduced pressure. The residue obtained is
purified by silica column chromatography, elution being
carried out with an EtOAc/eyelohexane gradient of 0 to
10% with respect to EtOAc. After concentration under
reduced pressure, 10.5 g of propan-2-yl 3-{[4-(3-{l-
[(benzyloxy)carbonyl]eye1opentyl}prop-1-yn-l-
yl)phenyl]carbonyl}-2-ethylindolizine-7-carboxylate are
obtained in the form of an approximately 80% pure brown
oil which is used as it is in the next step.
Yield = 54% (corrected).
15.4 l-{3-[4-({2-Ethyl-7-[(propan-2-yloxy)carbon-
yl ]indolizine-3-yl}carbonyl)phenyl 3 propyl}cyclopentane
carboxylic acid
A mixture of 5.0 g (6.2 mmol corrected) of propan-2-yl
3-{[4-3-{l-[(benzyloxy)carbonyl]cyclopentyl}prop-l-yn-
1-y1)phenyl]carbonyl}-2-ethylindoli z ine-7-carboxylat e,
9.47 g (150 mmol) of ammonium formate and 0.6 g of 10%
Pd-C in 50 ml of a 9:1 MeOH/dioxane mixture is heated
under argon for 9 h at 90°C. The reaction mixture is
then concentrated under reduced pressure, taken up with

3 00 ml of DCM, washed successively with 2 x 100 ml of
water and 100 ml of brine, dried over MgS04, filtered,
and then concentrated under reduced pressure. The
residue obtained is purified by silica column
chromatography, elution being carried out with an
MeOH/DCM gradient of 0 to 5% with respect to MeOH.
After concentration under reduced pressure, 3 g of 1-
{3-[4-({2-ethyl-7-[(propan-2-yloxy)carbonyl]indolizin-
3-yl}carbonyl)phenyl]propyl}cyclopentanecarboxylic acid
are obtained in the form of a yellow solid.
Yield =70%.
15.5 Propan-2-yl 3-{[4-(3-{l-[ (tert-butoxycarbon-
yl) amino] eye 1 opentyl}propyl)phenyl] carbonyl}-2-
ethylindolizine-7-carboxylate
2.83 ml (3.61 mmol) of DPPA are added dropwise, at AT,
to a solution of 5.36 g (10.95 mmol) of l-{3-[4-({2-
ethyl-7-[(propan-2-yloxy)carbonyl]indolizin-3-
yl}carbonyl)phenyl]propyl}cyclopentanecarboxylic acid
and 2.22 g (21.90 mmol) TEA in toluene. After stirring
for 3 h at. AT, the reaction mixture is taken up with
200 ml of EtOAc, washed successively with 2 x 50 ml of
water and 50 ml of brine, dried over MgS04, filtered,
and then concentrated under reduced pressure. In a
sealed tube, a solution of the residue obtained and
0.1 g (1 mmol) of CuCl in 50 ml of anh. t-BuOH is
heated for 18 h at 115°C. The reaction mixture is
concentrated under reduced pressure and then purified
by silica column chromatography, elution being carried
out with an EtOAc/cyclohexane gradient of 0 to 15% with
respect to EtOAc. After concentration under reduced
pressure, 4.0 g of propan-2-yl 3-{[4-(3-{l-[(terfc-
butoxycarbonyl) amino ] eye 1 openty 1}propyl) phen-
yl] carbonyl}-2-ethylindolizine-7-carboxylate are
obtained in the form of a yellow oil.
Yield = 65%.

15.6 3-{[4-(3-{l-[(tert-Butoxycarbonyl)amino]cyclopent-
yl}propyl)phenyl]carbonyl}-2-ethylindolizine-7-
carboxylic acid

The process is carried out in the same way as in
example 8.5. Thus, starting from 0.50 g (0.9 mmol) of
propan-2-yl 3-{[4-(3-{l-[(tert-butoxycarbonyl)amino] -
cyclopentyl}propyl)phenyl]carbonyl}-2-ethylindolizine-
7-carboxylate, 0.48 g of 3-{[4-(3-{1-[(tert-butoxy-
carbonyl) amino]cyclopentyl}propyl)phenyl]carbonyl}-2-
ethylindolizine-7-carboxylic acid is obtained in the
form of a yellow foam.
Yield = 100%.
15.7 Methyl I\7-[(3-{[4-(3-{l-[( tert-butoxycarbon-
yl) amino]cyclopentyl}propyl)phenyl]carbonyl}-2-
ethylindolizine-7-yl) carbonyl] -.ZV-propan-2-ylglycinate
The process is carried out in the same way as in
example 8.6. Thus, starting from 0.48 g (0.94 mmol) of
3-{[4-(3-{l-[(tert-butoxycarbonyl)amino]cyclo-
pentyl }propyl )phenyl]carbonyl}-2-ethylindolizine-7-
yl)carboxylic acid, methyl N-propan-2-ylglycinate
hydrochloride, 0.36 g (2.81 mmol) of DIEA and 0.45 g
(1.40 mmol) of TBTU, 0.43 g of methyl N- [ (3-{ [4- (3-{l-
[(tert-butoxycarbonyl)amino]cyclo-
pentyl} propyl) phenyl] carbonyl}-2-ethylindolizine-7-
yl) carbonyl] -i\f-propan-2-ylglycinate is obtained in the
form of a yellow foam.
Yield = 74%.
15.8 Methyl iV-{[3-({4-[3-(1 -aminocyclopentyl)prop-
yl 3 phenyl}carbonyl)-2-ethylindolizin-7-yl]carbonyl}-N-
propan-2-ylglycinate hydrochloride
The process is carried out in the same way as in
example 8.7. Thus, starting from 0.435 g (0.69 mol) of
methyl IV-[(3-{[4-(3-{l-[ (tert-butoxycarbon-
yl) amino]cyclopentyl}propyl)phenyl]carbonyl}-2-
ethylindolizine-7-yl) carbonyl] -IV-propan-2-ylglycinate,
0.272 g of methyl N-{ [3- ( {4- [3- (1-aminocyclo-
pentyl)propyl]phenyl}carbonyl)-2-ethylindolizin-7-
RECTIFIED SHEET (RULE 91) ISA/EP

yl] carbonyl}-2\r-propan-2-ylglycinate hydrochloride is
obtained in the form of a yellow powder.
Yield = 69%.
Mp (°C): 176
LC/MS: M = C32H41N3O4 = 531; M+H = 532; Tr = 1.13 min
(conditions B)
^•H NMR (ppm, d6-DMSO, 400 MHz) :
9.40 (d, 1H) ; 7.95-7.80 (bs, 3H) ; 7.65 (s, 1H) ; 7.55
(d, 2H); 7.40 (d, 2H); 6.90 (d, 1H); 6.70 (s, 1H); 4.10
(s, 2H) ; 4.05-3.95 (bs, 1H) ; 3.75 (s, 3H) ; 2.80-2.70
(t, 2H); 2.30-2.20 (bs, 2H); 1.80-1.50 (bs, 12H); 1.15
(d, 6H); 1.00 (t, 3H).
RECTIFIED SHEET (RULE 91) ISA/EP

Example 16; compound No. 16: methyl N-{ {2-ethyl-3- [ (4-
{3-[l-
(methylamino) cyclopentyl ] propyl }phenyl) carbonyl ] indoliz
in-7-yl}carbonyl) -W-propan-2-ylglycinate hydrochloride
16.1 3-{[4-(3-{l-[(tert-Butoxycarbonyl)(meth-
yl) amino]cyclopentyl}propyl)phenyl]carbonyl}-2-ethyl-
indolizine-7-carboxylic acid
140 mg (3.43 mmol) of NaH at 60% in oil are added in
small amounts, at AT under argon, to a solution of
970 mg (1.73 mmol) of propan-2-yl 3-{[4-(3-{l-[(tert-
butoxycarbonyl) amino] cyclopentyl}propyl)phenyl] carbonyl
}-2-ethylindolizine-7-carboxylate in 5 ml of anh. DMF.
After 15 min, 220 \il (3.43 mmol) of iodomethane are
added dropwise at AT and the stirring is continued for
18 h. The reaction mixture is then treated with 50 ml
of a saturated aqueous NH4C1 solution, and then
extracted with 2 x 100 ml of ether. The organic phases
are combined, washed successively with 2 x 50 ml of
water and 50 ml of brine, dried over Na2S04, filtered,
and then concentrated under reduced pressure. The
residue obtained is taken up with 10 ml of dioxane and
then 4 ml of a IN aqueous NaOH solution are added
dropwise at AT. After stirring for 18 h, the reaction
mixture is cooled to 0° and then neutralized with 4 mi
of a IN aqueous . HCl solution and extracted with
2 x 100 ml of EtOAc. The organic phases are combined,
washed successively with 2 x 50 ml of water and 50 ml
of brine, dried over Na2S04, filtered, and then
concentrated under reduced pressure. The residue
obtained is chromatographed on a silica gel column,
elution being carried out with a DCM/MeOH gradient of 0
to 2 0% with respect to MeOH. After concentration under
reduced pressure, 733 mg of 3-{[4-(3-{l-[(tert-
butoxycarbonyl) (methyl) amino] cyclopentyl}prop-
yl) phenyl ] carbonyl} -2-ethylindolizine-7-carboxylic acid

are obtained in the form of an orangey-colored solid
which is used as it is in the next step.
Yield = 77%.
16.2 Methyl Jf-[(3-{[4-(3-{!-[( ter t-but oxycarbon-
yl) (methyl)amino]cyclopentyl}propyl)phenyl]carbonyl}-2 -
ethylindolizin-7-yl) carbonyl] -iy-propan-2-ylglycinate
With the exception of the final salification step, the
process is carried out in the same way as in
example 2.2. Thus, starting from 1.1 g (2.08 mmol) of
3-{[4-(3-{l-[(tert-butoxycarbonyl)(methyl)amino]cyclo-
pentyl }propyl) phenyl] carbonyl} -2 -ethylindolizine- 7-
carboxylic acid and 0.7 g (4.17 mmol) of methyl N-
propan-2-ylglycinate hydrochloride,

1.07 g of methyl N-[(3-{[4-(3-{l-[(tert-butoxycarbon-
yl)(methyl)amino]cyclopentyl}propyl)phenyl]carbonyl}-2-
ethylindolizin-7-yl)carbonyl]-IV-propan-2-ylglycinate
are obtained in the form of a yellow foam, after
chromatography on a silica gel column, elution being
carried out with a cyclohexane/EtOAc gradient of 0 to
50% with respect to EtOAc.
Yield = 80%.
16.3 Methyl N- ({2-ethyl-3-[(4-{3-[1-(methylamino)cyclo-
pentyl] propyl} phenyl) carbonyl]indolizin-7-yl}carbonyl)-
■Rr-propan-2-ylglycinate hydrochloride
The process is carried out in the same way as in
example 11.3.
Thus, starting from 1.68 g (2.60 mmol) of methyl JV-[(3-
{[4-(3-{l-[(tert-butoxycarbonyl)(methyl)amino]cyclo-
pentyl} propyl) phenyl] carbonyl}-2-ethylindolizin-7-
yl) carbonyl]-iV-propan-2-ylglycinate, of methyl N-({2-
ethyl-3-[(4-{3-[1-(methylamino)cyclopentyl]propyl}phen-
yl) carbonyl] indolizin-7-yl}carbonyl) -JV-propan-2-yl-
glycinate hydrochloride is obtained in the form of a
yellow powder, after chromatography on an RP18 reverse
phase column, elution being carried out with a CH3CN/H20
(0.01N HC1) gradient of 0 to 3 0% with respect to CH3CN.
Yield = 45%.
Mp (°C): 149.5
LC/MS: M = C33H43N3O4 = 545; M+H = 546; Tr = 1.13 min
(conditions B)
XH NMR (ppm, d8-DMS0, 400 MHz, T = 60°C)
9.40 (d, 1H) ; 8.70-8.60 (bs, 2H) ; 7.65 (s, 1H) ; 7.55
(d, 2H) ; 7.40 (d, 2H) ; 6.85 (d, 1H) ; 6.70 (s, 1H) ;
4.15-4.05 (bs, 3H) ; 3.70 (s, 3H) ; 2.75 (t, 2H) ; 2.50-
2.40 (bs, 3H); 2.30-2.20 (bs, 2H); 1.90-1.50 (bs, 12H) ;
1.15 (d, 6H); 1.00 (t, 3H).
RECTIFIED SHEET (RULE 91) ISA/EP

Example 17; compound No. 17: 3-({4-[3-(tert-butyl-
amino) propyl ] phenyl} carbonyl) -N, 2 -diethyl-N- [ (2 -methyl-
2ff-tetrazol-5-yl)methyl]indolizine-7-carboxamide
hydrochloride
17.1 Propan-2-yl 3-({4-[3-(tert-butylamino)propyl 3 phen-
yl} carbonyl)-2-ethylindolizine-7-carboxylate
In a sealed tube, a mixture of 2.35 g (5.7 mmol) of
propan-2-yl 3-{[4-(4-chlorobutyl)phenyl]carbonyl}-2-
ethylindolizine-7-carboxylate, 2.4 ml (22.8 mmol) of
tert-butylamine and 0.99 g (5.9 mmol) of KI in 12 ml of
CH3CN is

heated for 48 h at 105°C. The reaction mixture is taken
up with 100 ml of EtOAc, washed successively with
2 x 30 ml of water and 3 0 ml of brine, dried over
Na2S04, filtered, and then concentrated under reduced
pressure. The residue obtained is solidified from
ether, filtered and washed with ether. 3.53 g of
propan-2-yl 3-({4-[3-(tert-butylamino)propyl 3phen-
yl}carbonyl)-2-ethylindolizine-7-carboxylate are thus
obtained in the form of a yellow powder which is used
as it is in the next step.
Yield = 70%.
17.2 3-({4- [3- (tert-Butylamino)propyl 3 phenyl}carbonyl)-
2-ethylindolizine-7-carboxylic acid
16 ml of a IN aqueous NaOH solution are added, dropwise
at AT, to a solution of 3.53 g (7.9 mmol) of propan-2-
yl 3-({4-[3-(tert- butyl amino) propyl ] phenyl} carbony 1) - 2 -
ethylindolizine-7-carboxylate in 16 ml of a 2:1:1
dioxane/MeOH/THF mixture and the stirring is continued
for 18 h. The mixture is cooled to 0°C and then 16 ml
of a IN aqueous HCl solution are added dropwise. The
resulting precipitate is then filtered off, washed with
water and then dried under reduced pressure. 3.1 g of
3-({4-[3-(tert-butylamino) propyl]phenyl}carbonyl)-2-
ethylindolizine-7-carboxylic acid are thus obtained in
the form of a yellow powder which is used as it is in
the next step.
Yield = 99%.
17.3 3-({4- [3- (tert-Butylamino)propyl3phenyl}carbonyl)-
N, 2-diethyl-N- [ (2-methyl-2if-tetrazol-5-
yl)methyl]indolizine-7-carboxamide hydrochloride
The process is carried out in the same way as in
example 2.2. Thus, starting from 0.8 g (1.97 mmol) of
3-({4-[3-(tert-butylamino)propyl 3 phenyl}carbonyl)-2-
ethylindolizine-7-carboxylic acid and 0.3 6 g

(2.56 mmol) of N- [ (2-methyl-2fJ-tetrazol-5-yl)meth-
yl]ethaneamine hydrochloride, 0.9 g are obtained, after
silica column chromatography, elution being carried out
with a DCM/MeOH gradient of 0 to 10% with respect to
MeOH, and taken up with 5 ml of DCM, and then the
resulting product is cooled to 0°C, 1.7 0 ml of a 2N
solution of hydrogen chloride in ether are added and
the resulting mixture is left to return slowly to AT.
The precipitate obtained is filtered off, washed with
ether, and then dried under reduced pressure. 0.88 g of
3- ({4-[3-(tert-butylamino)propyl]phenyl}carbonyl)-N, 2-
diethyl-N- [(2-methyl-2ff-tetrazol-5-yl)meth-
yl]indolizine-7-carboxamide hydrochloride is thus
obtained in the form of a white powder.
Yield = 84%.
Mp (°C): 175
LC/MS: M = C30H39N7O2 = 529; M+H = 530; Tr = 1.04 min
(conditions B)
XH NMR (ppm, d6-DMSO, 400 MHz):
9.50 (d, 1H) ; 9.00-8.80 (bs, 2H); 7.80-7.65 (bs, 1H) ;
7.55 (d, 2H) ; 7.40 (d, 2H) ; 6.95-6.85 (bs, 1H) ; 6.70-
6.60 (bs, 1H) ; 4.95-4.80 (bs, 2H) ; 4.35 (s, 3H) ; 3.50-
3.35 (bs, 2H); 2.95-2.70 (bs, 4H); 2.30-2.15 (bs, 2H) ;
2.10-1.95 (t, 2H); 1.25 (s, 9H); 1.20-0.95 (bs, 6H) .
Example 18; compound No. 18: 3-({4-[3-(tert-butyl-
amino )-3-methylbutyl]phenyl}carbonyl)-N, 2-diethyl-N-
[(2-methyl-2ff-tetrazol-5-yl)methyl]indolizine-7-
carboxamide hydrochloride
18.1 Propan-2-yl 3- ({4- [3- (tert-butylamino) -3-
methylbut-1-yn-l-yl]phenyl}carbonyl)-2-ethylindolizine-
7-carboxylate
The process is carried out in the same way as in
example 15.3. Thus, starting from 2.2 g (4.77 mmol) of
propan-2-yl 2-ethyl-3- [ (4-
iodophenyl)carbonyl]indolizine-7-carboxylate and

1.27 ml (7.15 mmol) of I\7-tert-butyl-2-methylbut-3-yn-2-
amine, 2.5 g of 3-({4-[3-(tert-butylamino)-3-methylbut-
1-yn-l-yl]phenyl}carbonyl)-2-ethylindolizine-7-
carboxylate are obtained in the form of an oil, after
silica column chromatography, elution being carried out
with a cyclohexane/EtOAc gradient of 0 to 40% with
respect to EtOAc.
Yield = 100%.
18.2 Propan-2-yl 3- ({4- [3- (tert-butylamino) -3-
methylbutyl]phenyl}carbonyl)-2-ethylindolizine-7-
carboxylate
A mixture of 2.5 g (5.29 mmol) of propan-2-yl 3-({4-[3-
(tert-butylamino)-3-methylbut-l-yn-l-
yl]phenyl}carbonyl)-2-ethylindolizine-7-carboxylate and
1.7 g of 10% Pd-C in 20 ml of a 1:1 EtOAc/EtOH mixture
is stirred for 1 h under 3 bar of hydrogen. The
reaction medium is subsequently filtered and then
concentrated under reduced pressure. The residue
obtained is chromatographed on a silica column, elution
being carried out with a

cyclohexane/EtOAc gradient of 0 to 40% with respect to
EtOAc. After concentration under reduced pressure,
1.17 g of propan-2-yl 3-({4-[3-(tert-butylamino)-3-
methylbutyl]phenyl}carbonyl)-2-ethylindolizine-7-
carboxylate are obtained in the form of an orangey-
colored gum.
Yield = 46%.
18.3 3-({4-[3-(tert-Butylamino)-3-
methylbutyl] phenyl }carbonyl) -N, 2-diethyl-AT- [ (2-methyl-
2JJ-tetrazol-5-yl)methyl] indolizine-7-carboxamide
hydrochloride
By applying a saponification-peptide coupling sequence
as described in examples 17.2 and 17.4 respectively,
and starting from 0.79 g (1.81 mmol) of propan-2-yl 3-
({4-[3-(tert-butylamino)-3-
methylbutyl]phenyl}carbonyl)-2-ethylindolizine-7-
carboxylate, and after a final trituration in ether,
0.52 g of 3-({4-[3-(tert-butylamino)-3-
methylbutyl]phenyl}carbonyl)-N,2-diethyl-N-[(2-methyl-
2H-1etrazol-5-yl)methyl]indoli z ine-7-carboxamide
hydrochloride is obtained in the form of a green
powder.
Yield = 48%.
Mp (°C): 122
LC/MS: M = C32H43N7O2 = 557; M+H = 558; Tr = 1.05 min
(conditions B)
XH. NMR (ppm, d6-DMSO, 400 MHz) :
9.45-9.30 (bs, 1H) ; 8.30-8.10 (bs, 2H) 7 7.80-7.65 (bs,
1H) ; 7.55 (d, 2H) ; 7.40 (d, 2H) ; 7.00-6.85 (bs, 1H) ;
7.65 (s, 1H); 5.00-4.80 (bs, 2H); 4.35 (s, 3H);
3.60-3.30 (bs, 2H) ; 2.80-2.70 (bs, 2H) ; 2.25-2.15 (bs,
2H); 2.15-2.05 (bs, 2H); 1.55-1.40 (bs, 15H); 1.20-1.05
(bs, 3H) ; 1.05-0.95 (bs, 3H) .

Example 19; compound No. 19: methyl N-{ [3- ({4- [3-
(cyclopentylamino)-3-methylbutyl]phenyl}carbonyl) - 2 -
ethylindolizin-7-yl]carbonyl}-tf-prqpan-2-ylglycinate
hydrochloride
19.1 Propan-2-yl 3-{ [4- (3-amino-3-methylbut-l-yn-l-
yl)phenyl]carbonyl}-2-ethylindolizine-7-carboxylate
The process is carried out in the same way as in
example 15.3. Thus, starting from 6.0 g (13.01 mmol) of
propan-2-yl 2-ethyl-3-[(4-iodophenyl)carbonyl]-
indolizine-7-carboxylate and 1.68 ml (15.61 mmol) of 2-
methylbut-3-yn-2-amine, 5.15 g of propan-2-yl 3-{[4-(3-
amino-3-methylbut-1-yn-l-yl)phenyl]carbonyl} -2 -
ethylindolizine-7-carboxylate are obtained in the form
of a yellow solid, after silica column chromatography,
elution being carried out with a DCM/MeOH gradient of 0
to 10% with respect to MeOH.
Yield = 95%.
19.2 Propan-2-yl 3- ({4- [3- (cyclopentylamino) -3-
methylbut-1-yn-1-yl]phenyl}carbonyl)-2-ethylindoli zine-
7-carboxylate
A solution of 5.15 g (12.36 mmol) of propan-2-yl 3-{[4-
(3-amino-3-methylbut-1-yn-l-yl)phenyl]carbonyl}-2 -
ethylindolizine-7-carboxylate and 2.19 ml (24.7 mmol)
of cyclopentanone in 25 ml of DCE is stirred for 2 h at
AT and then 0.71 ml (12.3 6 mmol) of AcOH and 3.14 g
(14.84 mmol) of NaBH(OAc)3 are successively added.
After stirring for 24 h at AT, the reaction mixture is
treated with 20 ml of a saturated aqueous NaHC03
solution and then extracted with 2 x 50 ml of EtOAc.
The organic phases are combined, dried over Na2SC>4,
filtered, and then concentrated under reduced pressure.
The residue obtained is chroma tographed on a silica
column, elution being carried out with a DCM/MeOH

gradient of 0 to 5% with respect to MeOH. After
concentration under reduced pressure, 5.99 g of propan-
2-yl 3-({4-[3-(eye1opentylamino)-3-methylbut-l-yn-l-
yl]phenyl}carbonyl)-2-ethylindolizine-7-carboxylate are
obtained in the form of a brown-green solid which is
used as it is in the next step.
Yield = 100%.
19.3 Methyl N-{ [3-({4-[3- (eye 1 open tyl amino) -3-
methybutyl]phenyl}carbonyl)-2-ethylindolizine-7-
yl ] carbonyl} -.Ar-propan-2 -ylglycinate hydrochloride
By applying a reduction-saponification-peptide coupling
sequence, as described in examples 18.3, 17.2 and 8.6
respectively, and starting from 1.60 g (3.58 mmol) of
propan-2-yl 3-({4-[3-(cyclopentylamino)-3-methylbut-l-
yn-l-yl]phenyl}carbonyl)-2-ethylindolizine-7-
carboxylate, 1.58 g of methyl N-{[3-({4- [3-
(cyclopentylamino)-3-methybutyl]phenyl}carbonyl)-2-
ethylindolizine-7-yl] carbonyl}-i\7-propan-2-ylglycinate
hydrochloride are obtained in the form of a yellow
powder.
Yield = 79%.
Mp (°C): 245
LC/MS: M = C34H45N3O4 = 559; M+H = 560; Tr = 1.18 min
(conditions B)
1H MMR (ppm, d6-DMSO, 400 MHz) :

9.50-9.35 (bs, 1H); 8.60-8.40 (bs, 2H); 7.65 (s, 1H) ;
7.60 (d, 2H); 7.40 (d, 2H); 6.90 (d, 1H); 6.70 (s, 1H);
4.15 (s, 2H); 4.10-4.00 (bs, 1H) ; 3.80-3.60 (bs, 4H) ;
2.80-2.70 (bs, 2H); 2.30-2.20 (bs, 2H); 2.10-1.90 (bs,
4H) ; 1.80-1.70 (bs, 4H) ; 1.70-1.50 (bs, 2H) ; 1.40 (s,
6H); 1.10 (d, 6H); 1.00 (t, 3H).
Example 20; compound No. 20: (R,S)-.W, 2-diethyl-3-( {4-
[ 3 - (ethylamino) -4 -methylpentyl ] phenyl} carbonyl) -N- [ (2 -
methyl-2ff-tetrazol-5-yl)methyl]indolizine-7-carboxamide
hydrochloride
20.1 Propan-2-yl 3-{[4-(chloromethyl)phenyl]carbonyl}-
2-ethylindolizine-7-carboxylate
10.61 g (56.14 mmol) of 4-(chloromethyl)benzoyl
chloride are added to a solution of 8.66 g (37.43 mmol)
of propan-2-yl 2-ethylindolizine-7-carboxylate, 8.69 ml
(74.86 mmol) of lutidine and 0.61 ml (7.49 mmol) of
pyridine in 75 ml of chlorobenzene and then the mixture
is refluxed for 2 h. The reaction mixture is then taken
up with 300 ml of EtOAc, washed successively with
2 x 150 ml of water and 150 ml of brine, dried over
Na2S04, filtered, and then concentrated under reduced
pressure. The residue obtained is chromatographed on a
silica gel column, elution being carried out with a
cyclohexane/EtOAc gradient of 0 to 10% with respect to
EtOAc. After concentration under reduced pressure,
10.44 g of propan-2-yl 3-{[4-
(chloromethyl)phenyl]carbonyl}-2-ethylindoli z ine-7-
carboxylate are obtained in the form of a yellow solid.
Yield = 72%.
20.2 Propan-2-yl 3- ({4- [ (diethoxyphosphoryl)methyl] -
phenyl}carbonyl)-2-ethylindolizine-7-carboxylate
A mixture of 15.0 g (39.08 mmol) of propan-2-yl 3-{[4-
(chloromethyl)phenyl]carbonyl}-2-ethylindoli zine-7-

carboxylate and 26.80 ml of triethyl phosphite is
refluxed for 3 h. The excess triethyl phosphite is
evaporated off under reduced pressure. The residue
obtained is taken up with 500 ml of EtOAc, washed
successively with 2 x 200 ml of water and 100 ml of
brine, dried over Na2S04, filtered, and then
concentrated under reduced pressure. The residue
obtained is chromatographed on a silica column, elution
being carried out with a cyclohexane/EtOAc gradient of
0 to 100%. After concentration under reduced pressure,
12.8 g of propan-2-yl 3-({4-
[(diethoxyphosphoryl)methyl]phenyl}carbonyl)-2-
ethylindolizine-7-carboxylate are obtained in the form
of a brown oil which is used as it is in the next step.
Yield = 68%.
20.3 N2- (tert-butoxycarbonyl) -N2-ethyl-JV-methoxy-JV-
methyl-D,L-valinamide
1.66 g (41.37 mmol) of NaH at 60% in oil are added in
small amounts, at 0°C, under argon, to a solution of
7.18 g (27.58 mmol) of N2- (tert-butoxycarbonyl) -N-
methoxy-2\7-methyl-D, L-valinamide in 92 ml of anh. NMP.
After 15 min at 0°C, 4.41 ml (55.16 mmol) of iodoethane
are added dropwise, then the reaction mixture is
allowed to return slowly to AT and the stirring is
continued for 18 h. The residue obtained is
chromatographed on a silica column, elution being
carried out with a cyclohexane/EtOAc gradient of 0 to
40% with respect to EtOAc. After concentration under
reduced pressure, 6.25 g of N2-(tert-butoxycarbonyl)-N2-
ethyl-iV-methoxy-iV-methyl-D, L-valinamide are obtained in
the form of a colorless oil.
Yield = 79%.
20.4 tert-Butyl (R,S)-ethyl[3-methyl-1-oxobutan-2-
yl]carbamate

3.64 ml (3.64 mmol) of a IN solution of LiAlH4 in THF
are added dropwise, under argon, at -78°C, to a
solution of 1.0 g (3.47 mmol) of itf2-(ter-t-
butoxycarbonyl) -N2-ethyl -N-methoxy-iV-methyl-D, L-
valinamide in 11 ml of anh. THF. After stirring for
10 min, the reaction mixture is stirred at 0°C for
10 min, diluted with 40 ml of ether, and treated
successively with ~2 g of ammonium chloride added in
small amounts and water added dropwise until two liquid
phases are obtained. The supernatant is then removed,
washed successively with 2 0 ml of a IN aqueous HC1
solution and 2 0 ml of brine, dried over Na2S04,
filtered, and then concentrated under reduced pressure.
After concentration under reduced pressure, 1.17 g of
tert-butyl (R,S)-ethyl[3-methyl-l-oxobutan-2-
yl] carbamate are obtained in the form of a colorless
oil which is used as it is in the next step.
Yield = 100%.
20.5 Propan-2-yl (R,S)-3-[(4-{(l£)-3-[ (tert-
butoxycarbonyl)(ethyl)amino]-4-methylpent-l-en-l-
yl}phenyl)carbonyl]-2-ethylindolizine-7-carboxylate
0.15 g (3.64 mmol) of NaH at 50% in oil is added in
small amounts, under argon, at 0°C, to a solution of
1.7 g (3.50 mmol) of propan-2-yl 3-({4-
t(diethoxyphosphoryl)methyl]phenyl}carbonyl)-2-
ethylindolizine-7-carboxylate in 10 ml of anh. THF.
After 30 min at 0°C, the reaction mixture is cooled to
-78°C and then a solution of 1.17 g (3.47 mmol) of
tert-butyl (R,S)-ethyl[3-methyl-l-oxobutan-2-
yl]carbamate in 5 ml of anh. THF is added dropwise. The
reaction mixture is allowed to return slowly to AT and
the stirring is continued for 18 h. The reaction
mixture is then again cooled to 0°C, treated with 3 0 ml
of a saturated aqueous NH4C1 solution and then
extracted with 3 x 7 0 ml of EtOAc. The organic phases
are combined, washed successively with 50 ml of a IN

aqueous HCl solution, 50 ml of water and 50 ml of
brine, dried over Na2SC>4, filtered, and then
concentrated under reduced pressure. The residue
obtained is chromatographed on a silica column, elution
being carried out with a cyclohexane/EtOAc gradient of
0 to 3 0% with respect to EtOAc and then with a DCM/MeOH
gradient of 0 to 10% with respect to MeOH. After
concentration under reduced pressure, 1.32 g of propan-
2-yl (R,S)-3-[(4-{(IE)-3-[(tert-butoxycarbony1)(ethyl)-
amino]-4-methylpent-l-en-l-yl}phenyl)carbonyl]-2-
ethylindolizine-7-carboxylate are obtained in the form
of an orangey-colored gum.
Yield = 68%.
20.6 (R,S)-3-[(4-{(lE)-3-[(tert-Butoxycarbonyl)(ethyl)-
amino]-4-methylpent-l-en-l-yl}phenyl)carbonyl]-2-
ethylindolizine-7-carboxylic acid
7.1 ml (7.1 mmol) of a IN aqueous NaOH solution are
added dropwise, at 0°C, to a solution of 1.98 g
(3.53 mmol) of propan-2-yl (R,S)-3-[(4-{(IE)-3-[(tert-
butoxycarbonyl)(ethyl)amino]-4-methylpent-l-en-l-
yl}phenyl)carbonyl]-2-ethylindolizine-7-carboxylate in
22 ml of a 10:1 THF/MeOH mixture and then the reaction
mixture is allowed to return slowly to AT. After
stirring for 18 h, the reaction mixture is cooled to
0°C, neutralized with 7.1 ml of a IN HCl solution and
extracted with 3 x 70 ml of a 95:5 DCM/iPrOH mixture.
The organic phases are combined, washed with 50 ml of
brine, dried over Na2S04, filtered, and then
concentrated under reduced pressure. 2.19 g of (R,S)-3-
[ (4-{ (l.E)-3-[ (tert-butoxycarbonyl) (ethyl)amino]-4-
methylpent-l-en-l-yl}phenyl)carbonyl]-2-
ethylindolizine-7-carboxylic acid are thus obtained in
the form of a yellow powder which is used as it is in
the next step.
Yield = 94%.

20.7 tert-Butyl (R,S)-ethyl [ (lE)-l-{4-[ (2-ethyl-7-
{ethyl[(2-methyl-2ff-tetrazol-5-yl)methyl]carbamoyl}-
indolizin-3-yl)carbonyl]phenyl}-4-methylpent-l-en-3-
yl]carbamate
The process is carried out in the same way as in
example 2.2. Thus, starting from 1.25 g (2.41 mmol) of
(R,S)-3-[(4-{(IE)-3-[(tert-butoxycarbonyl)(ethyl)-
amino]-4-methylpent-l-en-l-yl}phenyl)carbonyl)-2-
ethylindolizine-7-carboxylic acid and 0.47 g
(2.65 mmol) of N- [ (2-methyl-2H-tetrazol-5-
yl)methyl]ethanamine hydrochloride, 1.4 g of tert-butyl
(R,S)-ethyl[(lE)-l-{4-[(2-ethyl-7-{ethyl[(2-methyl-2ff-
tetrazol-5-yl)methyl]carbamoyl}indolizin-3-
yl)carbonyl]phenyl}-4-methylpent-l-en-3-yl]carbamate
are obtained in the form of a yellow foam, after silica
column chromatography, elution being carried out with a
cyclohexane/EtOAc gradient of 0 to 100% of EtOAc.
Yield = 91%.
20.8 tert-Butyl (R,S)-ethyl[1-{4-[(2-ethyl-7-{ethyl[(2-
methyl-2ff-tetrazol-5-yl)methyl]carbamoyl}indolizine-3-
yl)carbonyl]phenyl}-4-methylpentan-3-yl]carbamate
A mixture of 1.4 g (2.19 mmol) of tert-butyl (R,S)-
ethyl[(l£)-l-{4-[(2-ethyl-7-{ethyl[(2-methyl-2ff-
tetrazol-5-yl)methyl]carbamoyl}indolizin-3-
yl)carbonyl]phenyl}-4-methylpent-l-en-3 -yl]carbamate
and 0.14 g of Pd-C at 10% in 30 ml of MeOH is stirred
for 3 h under 5 bar of hydrogen. The reaction mixture
is subsequently filtered and then concentrated under
reduced pressure. The residue obtained is
chromatographed on a silica column, elution being
carried out with a DCM/MeOH gradient of 0 to 10% with
respect to MeOH. After concentration under reduced
pressure, 1.12 g of tert-butyl (R, S) -ethyl[l-{4-[ (2-
ethyl-7-{ethyl[(2-methyl-2ff-tetrazol-5-yl)methyl]

carbamoyl}indolizine-3-yl)carbonyl]phenyl} -4-
methylpentan-3-yl]carbamate are obtained in the form of
a yellow foam.
Yield = 81%.
20.9 (R,S)-i\7, 2-Diethyl-3-({4-[3-(ethylamino)-4-
methylpentyl3phenyl}carbonyl)-N- [(2-methyl-2ff-tetrazol-
5-yl)methyl 3 indolizine-7-carboxamide hydrochloride
The process is carried out in the same way as in
example 8.7. Thus, starting from 1.12 g (1.78 mmol) of
tert-butyl (R,S)-ethyl[l-{4-[(2-ethyl-7-{ethyl[(2-
methyl-2if-tetrazol-5-yl) methyl] carbamoyl}indolizine-3-
yl)carbonyl]phenyl}-4-methylpentan-3-yl]carbamate,
0.77 g of (R,S)-N, 2-Diethyl-3-({4-[3-(ethylamino)-4-
methylpentyl]phenyl}carbonyl)-N- [(2-methyl-2ff-tetrazol-
5-yl)methyl]indolizine-7-carboxamide hydrochloride is
obtained in the form of a greenish powder.
Yield = 93%.
Mp (°C): 100
[a]D20 = +4.2 (c = 0.19; MeOH)
LC/MS: M = C31H41N7O2 = 543; M+H = 544; Tr = 1.05 min
(conditions B)
XH NMR (ppm, d6-DMSO, 400 MHz) :
9.45-9.35 (bs, 1H) ; 8.80-8.60 (bs, 1H) ; 8.30-8.10 (bs,
1H) ; 7.80-7.70 (bs, 1H) ; 7.55 (d, 2H) ; 7.45 (d, 2H) ;
7.00-6.90 (bs, 1H) ; 6.75-6.85 (bs, 1H) ; 5.00-4.80 (bs,
2H); 4.40 (s, 3H); 3.50-3.35 (bs, 2H); 3.15-2.75 (bs,
5H); 2.30-2.15 (bs, 2H) ; 2.15-2.00 (bs, 1H) ; 2.00-1.80
(bs, 2H); 1.35-0.80 (bs, 15H).
Example 21: compound No. 81: methyl N-{[2-butyl-3-({4-
[(3K)-piperidin-3-yloxy]phenyl}carbonyl)indoli2in-7-
yl]carbonyl}-£r-propan-2-ylglycinate hydrochloride
21.1 Propan-2-yl 2-butyl-3- [ (4-iodophenyl) carbonyl ]-
indolizine-7-carboxylate

The process is carried out in the same way as in
example 14.1. Thus, starting from 3 0.0 g (115.68 mmol)
of propan-2-yl 2-butylindolizine-7-carboxylate and
3 0.8 g (115.68 mmol) of 4-iodobenzoyl chloride and
14.84 g (114.82 mmol) of DIEA, 42.81 g of propan-2-yl
2-butyl-3- [ (4-iodophenyl)carbonyl]indolizine-7-
carboxylate are obtained in the form of a yellow solid,
after silica column chromatography, elution being
carried out with a cyclohexane/EtOAc gradient of 0 to
2 0% with respect to EtOAc.
Yield = 76%.
21.2 3-[ (4-{ [ (3R) -1-(tert-Butoxycarbonyl)piperidin-3-
yl]oxy}phenyl)carbonyl]-2-butylindolizine-7-carboxylate
A mixture of 8.0 g (16.35 mmol) of propan-2-yl 2-butyl -
3-[(4-iodophenyl)carbonyl]indolizine-7-carboxylate,
6.0 g (29.81 mmol) of tert-butyl (3J?)-3-
hydroxypiperidine-1-carboxylate, 8.0 g (24.55 mmol) of
Cs2C03, 0.5 g (2.77 mmol) of 1,10-phenan thro line and
0.25 g (1.31 mmol) of Cul in 20 ml of anh. toluene is
refluxed for 18 h under argon. The reaction mixture is
then

taken up with 200 ml of EtOAc, washed successively with
100 ml of water and 50 ml of brine, dried over Na2S04,
filtered, and then concentrated under reduced pressure.
The residue obtained is chromatographed on a silica
column, elution being carried out with a
cyclohexane/EtOAc gradient of 0 to 40% with respect to
EtOAc. After concentration under reduced pressure,
2.45 g of (3R)-1-(tert-butoxycarbonyl)piperidin-3-yl 3-
[(4-{[(3H)-l-(tert-butoxycarbonyl)piperidin-3-
yl]oxy}phenyl)carbonyl]-2-butylindolizine-7-carboxylate
are obtained in the form of a yellow powder.
Yield = 21%.
21.3 3- [ (4-{ [ (31?) -1- (tert-Butoxycarbonyl)piperidin-3-
yl]oxy}phenyl)carbonyl]-2-butylindolizine-7-carboxylic
acid
The process is carried out in the same way as in
example 8.5. Thus, starting from 2.54 g (3.48 mmol) of
(31?)-1-(tert-butoxycarbonyl) piperidin-3-yl 3-[ (4-
{ [ (3i?) -1- (tert-butoxycarbonyl)piperidin-3-
yl]oxy}phenyl)carbonyl]-2-butylindolizine-7-
carboxylate, 0.65 g of 3- [ (4- { [ (31?) -1- (tert-
butoxycarbonyl)piperidin-3-yl]oxy}phenyl)carbonyl]-2-
butylindolizine-7-carboxylic acid is obtained in the
form of a yellow foam.
Yield = 36%.
21.4 tert-Butyl (3i?) -3- [4- ( {2-butyl-7- [ (2-methoxy-2-
oxoethyl)(propan-2-yl)carbamoyl]indolizin-3-
yl}carbonyl)phenoxy]piperidine-1-carboxylate
The process is carried out in the same way as in
example 2.2. Thus, starting from 0.65 g (1.25 mmol) of
3- [ (4- { [ (3i?) -1- (tert-butoxycarbonyl)piperidin-3-
yl]oxy}phenyl)carbonyl]-2-butylindoli z ine-7-carboxyli c
acid, 0.31 g (1.87 mmol) of methyl N-propan-2-
ylglycinate hydrochloride, 0.48 g (3.75 mmol) of DIEA

and 0.60 g (1.87 mmol) of TBTU, 0.62 g of tert-butyl
(3J?)-3-[4- ({2-butyl-7-[ (2-methoxy-2-oxoethyl) (propan-2-
yl)carbamoyl]indolizin-3-yl}carbonyl)phenoxy]-
piperidine-1-carboxylate is obtained in the form of a
yellow gum, after silica column chromatography, elution
being carried out with a DCM/MeOH gradient of 0 to 10%
with respect to MeOH.
Yield = 78%.
21.5 Methyl N-{ [2-butyl-3- ( {4- [ (3R) -piperidin-3-
yloxy]phenyl}carbonyl)indolizin-7-yl]carbonyl}-N-
propan-2-ylglycinate hydrochloride
The process is carried out in the same way as in
example 8.7. Thus, starting from 0.61 g (0.97 mmol) of
tert-butyl (3J?) -3- [4- ({2-butyl-7- [ (2-methoxy-2-
oxoethyl)(propan-2-yl)carbamoyl]indolizin-3-
yl}carbonyl)phenoxy]piperidine-l-carboxylate, 0.55 g of
methyl N-{[2-butyl-3-({4-[(3R)-piperidin-3-
yloxy]phenyl}carbonyl)indoli zin-7-yl]carbonyl}-N-
propan-2-ylglycinate hydrochloride is obtained in the
form of a yellow powder.
Yield = 100%.
Mp (°C): 141.5
[a]D20 = -2.6 (c = 0.205; MeOH)
LC/MS:' M = C31H39N3O5 = 533; M+H = 534; Tr = 1.09 min
(conditions B)
XH NMR (ppm, d6-DMSO, 400 MHz) :
9.35-9.25 (bs, 1H) ; 9.15-8.85 (bs, 2H) ; 7.70-7.65 (bs,
3H) ; 7.20 (d, 2H) ; 6.90-6.80 (bs, 1H) ; 6.65 (s, 1H) ;
4.95-4.85 (bs, 1H) ; 4.15 (s, 2H) ; 4.15-4.00 (bs, 1H) ;
3.75-3.60 (bs, 3H) ; 3.40-3.15 (bs, 2H) ; 3.15-3.05 (bs,
2H); 2.40-2.25 (bs, 2H); 2.00-1.80 (bs, 3H); 1.80-1.65
(bs, 1H); 1.50-1.35 (bs, 2H), 1.25-0.95 (bs, 8H); 0.80
(t, 3H).

The table which follows illustrates the chemical
structures and the physical properties of some examples
of compounds according to the invention:

The evaluation of the solubility of the compounds of the invention is carried out at pH > 4 (using a
phosphate buffer, pH = 6.01) by HPLC using an H2O/CH3CN/CH3SO3H gradient, relative to a reference
sample (a dilute solution of the product to be evaluated which serves as an internal control). The
solubility S results are expressed in mg/ml. Generally, the compounds of the present invention have
a solubility S > 4 mg/ml at pH > 4. Among them, mention may be made of the solubilities of the
following compounds in the table below:

Effect of the compounds on left atrial fibrillation
The effect of the compounds of the invention on atrial
refraction and on the induction of brief episodes of
atrial fibrillation/flutter caused by premature atrial
beats of the left atrium was studied in pigs of the
German Landrace strain, anesthetized with pentobarbital
and subjected to a thoractomy (Knobloch et al.
Electrophysiological and antiarrhythmic effects of the
novel IKur channel blockers, S9947 and S20951, on left
vs. right pig atrium in vivo in comparison with the IKr
blockers dofetilide, azimilide, d,I-sotalol and
ibutilide", Naunyn-Schmiedeberg's Arch Pharmacol 2002,
366: 482-487). Left atrial vulnerability in this pig
model is also a valid parameter for testing the
efficacy of atrial antiarrhythmic compounds and has
demonstrated its predictiveness in humans (Knobloch et
al.).
Method
The animals were premedicated with 2 ml of
intramuscular (i.m.) Rompun® 2% and 2 ml of
ZoletillOO®, and anesthetized with 5 ml of Narcoren®
(pentobarbital, 160 mg/ml = 25-30 mg/kg i.v.) injected
as an intravenous (i.v.) bolus, followed by a
continuous intravenous drip of pentobarbital at 12-
17 mg/kg/h. The heart was exposed after left
thoracotomy supported by a pericardial cradle. The
animals are ventilated by respiratory assistance
(air/oxygen). The analysis of blood gases (p02; pC02)
was carried out at regular intervals in order to check
the oxygen supply provided by the respirator and to
maintain a p02 > 100 mmHg and a pC02 < 35 mmHg.

To record the hemodynamic parameters, electronic
catheters of Millar PC 350 type are implanted in the
left femoral artery (BPs/d: abbreviation for blood
pressure systolic/diastolic), the pulmonary artery and
in the left ventricular via the right carotid artery
(LVP, LVEDP and HR: abbreviations for left ventricular
pressure, left ventricular end-diastolic pressure and
heart rate, respectively).
The bipolar surface ECGs (electrocardiograms) were
recorded by means of lead II or III needle electrodes
implanted subcutaneously.
A monophasic action potential electrode is placed in
the right atrium via a venous approach, and another on
the epicardium of the left atrium in order to measure
the atrial refraction.
The electrophysiological data are continuously recorded
and stored on the hard disk of a computer via an online
acquisition and analysis system (Hem Notocord
Evolution, Croissy-sur-Seine, France).
The left and right atrial refractions are measured
according to the S1-S2 incrementation protocol with
base cycle lengths of 240, 300 and 400 ms before and ■
after administration of the vehicle or of the test
compound at regular intervals (15, 30, 60, 90,
120 min).
The episodes of brief atrial fibrillations which
frequently follow the premature beat S2 are noted and
compared with the base recording (left atrial
vulnerability: maximum 45 min before and after the
injection of the test compound).

The evaluation of the QT interval was carried out
during right atrial pacing, the rate of which was
increased by 10 beats per minute compared with the
sinus rate for the first 15 minutes after the
administration so as to avoid having to correct the
duration of the QT interval and the monophasic action
potential (MAP) relative to the heart rate. For this
purpose, a stimulating electrode is placed on the
proximal part of the left atrium. This procedure makes
it possible to distinguish the compounds which affect
the ventricular repolarization (prolonged QT interval
is an undesirable effect, since it promotes ventricular
arrhythmias).
The electrophysiological recording (ECG and MAP) makes
it possible to identify the standard side effects which
are often related to the blockage of potassium, sodium
and calcium channels in the heart (prolonged QT,
atrioventicular block, delayed conduction) . Hemodynamic
monitoring makes it possible to distinguish the adverse
effects relating to inappropriate blockage of potassium
channels [increase in arterial pressure (AP) and in
pulmonary pressure (PP)], and of sodium and calcium
channels (negative inotropic effects, drop in arterial
pressure).
Results:
The compound of the invention is evaluated on 2 to 4
pigs at 3 mg/kg i.v., bolus or as a drip for 15 min,
and with 3 pacing rates (150, 200 and 250 bpm) . The
results obtained are expressed as % increase in right
and left atrial refractory periods (LAERP and RAERP,
respectively), and as % decrease in left atrial
vulnerability (episodes of atrial fibrillation induced
by S2, LAV) relative to the base line, and the duration
of action is expressed in hours (h). Compounds No. 2 to

81 of the invention, which prolong the LAERP by at
least 20%, inhibit the LAV by at least 60%, prolong the
QTc by a maximum of 5 ms and induce a negative
inotropic effect of a maximum of 20% or an increase in
AP or in PP of a maximum of 5 mmHg.
It therefore appears that the compounds according to
the invention have an advantageous pharmacological
activity, in particular antiarrhythmic properties.
The compounds according to the invention can therefore
be used for preparing medicaments, in particular
antiarrhythmic medicaments.
Thus, according to another of its aspects, a subject of
the invention is medicaments which comprise a compound
of formula (I) , or an addition salt thereof with a
pharmaceutically acceptable acid of the compound of
formula (I).
These medicaments are of therapeutic use in particular
in the treatment and prevention of atrial and
ventricular arrhythmias: atrial tachyarrhythmia, atrial
fibrillation, atrial flutter, atrial tachycardia,
ventricular tachyarrhythmia, ventricular extrasystoles,
ventricular tachycardia, ventricular flutter and
fibrillation; of angina pectoris, of hypertension, of
cerebral circulatory insufficiency, of heart failure,
of myocardium infarction which may or may not be
complicated by heart failure, or the prevention of
post-infarction mortality, or of stroke.
Thus, according to another of its aspects, a subject of
the invention is the use for a compound of formula (I)
for preparing a medicament intended for the treatment
of pathological syndromes of the cardiovascular system.

According to another of its aspects, the present
invention relates to pharmaceutical compositions
comprising, as active ingredient, a compound according
to the invention. These pharmaceutical compositions
contain an effective dose of at least one compound
according to the invention, or a pharmaceutically
acceptable salt of said compound, and also at least one
pharmaceutically acceptable excipient.
Said excipients are chosen, according to the
pharmaceutical form and the method of administration
desired, from the usual excipients which are known to
those skilled in the art.
In the pharmaceutical compositions of the present
invention for oral, sublingual, subcutaneous,
intramuscular, intravenous, topical, local,
intratracheal, intranasal, transdermal or rectal
administration, the active ingredient of formula (I)
above, or salt thereof, can be administered in a unit
administration form, as a mixture with conventional
pharmaceutical excipients, to animals and to human
beings for the treatment of the above disorders or
diseases.
The suitable unit administration forms include oral
administration forms, such as tablets, soft or hard
capsules, powders, granules and oral solutions or
suspensions, sublingual, buccal, intratracheal,
intraocular and intranasal administration forms, forms
for administration by inhalation, topical, transdermal,
subcutaneous, intramuscular or intravenous
administration forms, rectal administration forms, and
implants. For topical application, the compounds
according to the invention can be used in creams, gels,
ointments or lotions.

By way of example, a unit administration form of a
compound according to the invention in tablet form can
comprise the following constituents:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Sodium croscaramellose 6.0 mg
Corn starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
There may be specific cases where higher or lower
dosages are appropriate; such dosages do not part from
the context of the invention. According to the usual
practice, the dosage appropriate for each patient is
determined by the physician according to the method of
administration and the weight and response of said
patient.
According to another of its aspects, the present
invention also relates to a method for treating the
pathological conditions indicated above, which
comprises the administration, to a patient, of an
effective dose of a compound according to the
invention, or a pharmaceutically acceptable salt
thereof.

1. A compound corresponding to formula (I)

wherein
R1 represents:

R3 represents a hydrogen atom, a (C1-C6) alkyl
group or a benzyl group;
R4 represents a hydrogen atom or a (C1-C4) alkyl
group;
R5 represents a hydrogen atom or a (C1-C5) alkyl
group;
R6 represents a nitrile group or a heteroaryl
group comprising from 1 to 4 heteroatoms chosen
from a nitrogen atom and an oxygen atom, this
heteroaryl group being optionally substituted with
a (C1-C6) alkyl group;
R7 represents a hydrogen atom or a linear,
branched or cyclic (C1-C6) alkyl group;
R8 represents a hydroxyl group or a cyano group;
X represents a bond or an oxygen atom;
Am represents:
either

or
- (CH2) t-CR19R20NR17-R18

R16 represents a hydrogen atom or a (C1-C6) alkyl
group;
R17 represents a hydrogen atom or a (C1-C6) alkyl
group;
R18 represents a branched or cyclic (C1-C6) alkyl
group;
R19 and R20 represent a hydrogen atom or a (C1-C6)
alkyl group, or form a (C3-C6) spiroalkyl group;
m represents an integer equal to 0 or 1;
n represents an integer equal to 1 or 2;
r represents an integer equal to 1 or 2;
s represents an integer equal to 1 or 2;
t represents an integer between 2 and 4;
in the form of a base or an addition salt with an
acid.
The compound of formula (I) as claimed in claim 1,
chosen from:
- compound No. 2: (S)-1-{2-Butyl-3-[4-(3-dibutyl-
aminopropyl)benzoyl]indolizine-7-carbonyl}-
pyrrolidine-2-carboxylic acid methyl ester;
- compound No. 3: (R)-l-{2-Butyl-3-[4-(3-dibutyl-
aminopropyl)benzoyl]indolizine-7-car-
bonyl}pyrrolidine-2-carboxylic acid methyl ester;
- compound No. 4: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carboxylic acid ethyl
(2-methoxyethyl)amide;

- compound No. 5: ({2-Butyl-3-[4-(3-dibutyl-
aminopropyl)benzoyl]indolizine-7-carbonyl}ethyl-
amino)acetic acid methyl ester;
- compound No. 6: ({2-Butyl-3-[4-(3-dibutyl-
aminopropyl)benzoyl]indolizine-7-carbonyl}ethyl-
amino)acetic acid;
- compound No. 7: 3-({2-Butyl-3-[4-(3-dibutyl-
aminopropyl)benzoyl]indoli z ine-7-carbonyl}ethyl-
amino)propionic acid;
- compound No. 8: ({3-[4-(3-Cyclopentylaminoprop-
yl)benzoyl]-2-ethylindolizine-7-
carbonyl}isopropylamino)acetic acid methyl ester;
- compound No. 9: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carboxylic acid eth-
yl (2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 10: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carboxylic acid eth-
yl (3-methyl-[1,2,4]oxadiazol-5-ylmethyl)amide;
- compound No. 11: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carboxylic acid eth-
yl (lH-tetrazole-5-ylmethyl)amide;
- compound No. 12: {[2-Butyl-3-(4-piperidin-4-
ylbenzoyl)indolizine-7-carbonyl]isopropyl-
amino}acetic acid methyl ester;
- compound No. 13: 4-{2-Butyl-3-[4-(3-dibutyl-
aminopropyl)benzoyl]indolizine-7-
carbonyl}piperazine-2-one;

- compound No. 14: ({3-[4-(4-Cyclopentylamino-
butyl)benzoyl]-2-ethylindolizine-7-carbon-
yl}isopropylamino)acetic acid methyl ester;
- compound No. 15: [(3-{4-[3-(1-Aminocyclo-
pentyl)propyl]benzoyl}-2-ethylindolizine-7-
carbonyl)isopropylamino]acetic acid methyl ester;
- compound No. 16: [(2-Ethyl-3-{4-[3-(1-methyl-
aminocyclopentyl)propyl]benzoyl}indolizine-7-
carbonyl)isopropylamino]acetic acid methyl ester;
- compound No. 17: 3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-carboxylic
acid ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 18: 3-[4-(3-tert-Butylamino-3-
methylbutyl)benzoyl]-2-ethylindolizine-7-
carboxylic acid ethyl(2-methyl-2H-tetrazol-5-
ylmethyl) amide ;
- compound No. 19: ({3-[4-(3-Cyclopentylamino-3-
methylbutyl)benzoyl]-2-ethylindolizine-7-
carbonyl}isopropylamino)acetic acid methyl ester;
- compound No. 20: 2-Ethyl-3-[4-((S)-3-ethylamino-
4-methylpentyl)benzoyl]indolizine-7-carboxylic
acid ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 21: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carboxylic acid
benzyl(2-methoxyethyl)amide;
- compound No. 22: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carboxylic acid
isopropyl(2-methoxyethyl)amide;

- compound No. 23: 2-Butyl-3-[4-(3-dibutylamino-
propyl ) benzoyl ] indolizine-7-carboxylic acid
ethyl(2-isopropoxyethyl)amide;
- compound No. 24: 2-Butyl-3-[4-(3-dibutylamino-
propyl) benzoyl]indolizine-7-carboxylic acid (2-
ethoxyethyl)isopropylamide;
- compound No. 25: 2-Butyl-3-[4-(3-
dibutylaminopropyl)benzoyl]indolizine-7-carboxylic
acid (2-methoxyethyl)(2,2,2-trifluoroethyl)amide;
- compound No. 26: ({2-Butyl-3-[4-(3-dibutylamino-
propyl ) benzoyl ] indolizine-7-carbonyl}ethyl-
amino)acetic acid ethyl ester;
- compound No. 27: ({2-Butyl-3-[4-(3-dibutylamino-
propyl) benzoyl] indolizine-7-carbonyl}ethyl-
amino)acetic acid isopropyl ester;
- compound No. 28: ({2-Butyl-3-[4-(3-dibutylamino-
propyl )benzoyl]indolizine-7-carbonyl}is opropy1-
amino)acetic acid methyl ester;
- compound No. 29: ({3-[4-(3-dibutylamino-
propyl ) benzoyl ] -2-ethylindolizine-7-carbon-
yl}isopropylamino)acetic acid methyl ester;
- compound No. 30: ({3-[4-(3-Butylamino-
propyl ) benzoyl ] -2-ethylindolizine-7-carbon-
yl}isopropylamino)acetic acid methyl ester;
- compound No. 31: ( {3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-carbon-
yl}isopropylamino)acetic acid methyl ester;

- compound No. 32: ({2-Ethyl-3-[4-(3-
isopropylaminopropyl)benzoyl]indolizine-7-
carbonyl}isopropylamino)acetic acid methyl ester;
- compound No. 33: ({3-[4-(3-Cyclopentylamino-
propyl)benzoyl]-2-ethylindolizine-7-carbon-
yl}ethylamino)acetic acid ethyl ester;
- compound No. 34: ({3-[4-(3-Cyclopentylamino-
propyl ) benzoyl ] -2-isopropylindolizine-7-carbon-
yl}isopropylamino)acetic acid methyl ester;
- compound No. 35: ({3-[4-(3-Cyclohexylamino-
propyl)benzoyl]-2-ethylindolizine-7-carbon-
yl}isopropylamino)acetic acid methyl ester;
- compound No. 36: [(3-{4-[3(2,2-Dimethylpropyl-
amino) propyl ]benzoyl}-2-ethylindolizine-7-carbon-
yl)isopropylamino]acetic acid methyl ester;
- compound No. 37: 3-[4-(3-Cyclopentylamino-
propyl)benzoyl]-2-ethylindolizine-7-carboxylic
acid (2-ethoxyethyl)ethylamide;
- compound No. 38: 4-{3-[4-(3-tert-Butylamino-
propy1)benzoyl]-2-ethylindolizine-7-carbon-
yl}piperazin-2-one;
- compound No. 39: 2-Ethyl-3-{4-[3-(1-methyl-
cyclopentylamino) propyl ]benzoyl}indolizine-7-
carboxylic acid ethyl(2-methyl-2H-tetrazol-5-yl-
methyl)amide;
- compound No. 40: 3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-carboxylic
acid ethyl(2-ethyl-2H-tetrazol-5-ylmethyl)amide;

- compound No. 41: 3-[4-(3-tert-Butylamino-
propyl)benzoyl]indolizine-7-carboxylic acid
ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 42: 3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-cyclobutylindolizine-7-
carboxylic acid ethyl(2-methyl-2H-tetrazol-5-
ylmethyl)amide;
- compound No. 43: 2-Ethyl-3-[4-(3-ethylamino-4,4-
dimethylpentyl)benzoyl]indolizine-7-carboxylic
acid ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 44: 3-[4-(3-tert-Butylaminoprop-
yl)benzoyl]-2-ethylindolizine-7-carboxylic acid
ethyl(1-methyl-lH-pyrazol-3-ylmethyl)amide;
- compound No. 45: 3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-carboxylic
acid ethyl(l-methyl-lH-pyrazol-4-ylmethyl)amide;
- compound No. 46: 3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-carboxylic
acid ethyl(5-methylisoxazol-3-ylmethyl)amide;
- compound No. 47: (R)-l-{3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-carbon-
yl}pyrrolidine-3-carbonitrile,•
- compound No. 48: {3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizin-7-yl}-((S)-3-
hydroxypyrrolidin-1-yl)methanone;
- compound No. 49: 3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-carboxylic
acid 2-methyl-2H-tetrazol-5-ylmethyl ester;

- compound No. 50: (S)-l-{3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-carbonyl}-2-
methylpyrrolidine-2-carboxylic acid methyl ester;
- compound No. 51: 3-[4-(3-tert-Butylamino-
propyl ) benzoyl ] -2-ethylindolizine-7-carboxylic
acid (R)-2-methoxy-1-methylethyl ester;
- compound No. 52: 3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-carboxylic
acid (R)-5-oxopyrrolidin-3-yl ester;
- compound No. 53: 2-{3-[4-(3-Cyclopentylamino-
propyl)benzoyl]-2-ethylindolizine-7-carbon-
yl}[1,4] diazepam-5-one;
- compound No. 54: [(3-{4-[3-(tert-Butylmethyl-
amino)propyl]benzoyl}-2-ethylindolizine-7-carbon-
yl)isopropylamino]acetic acid methyl ester;
- compound No. 55: [(2-Ethyl-3-{4-[3-(ethyliso-
propylamino)propyl]benzoyl}indolizine-7-
carbonyl)isopropylamino]acetic acid methyl ester;
- compound No. 56: ({3-[4-(3-Dibutylamino-
propyl ) benzoyl ] indolizine-7-carbonyl}isopropyl-
amino) acetic acid methyl ester;
- compound No. 57: ({3-[4-(3-Dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}isopropyl-
amino) acetic acid;
- compound No. 58: ({2-Butyl-3-[4-(3-dibutyl-
aminopropyl)benzoyl]indolizine-7-carbonyl}iso-
propylamino) acetic acid isopropyl ester;

- compound No. 59: 2-Butyl-3-(4-piperidin-4-
ylbenzoyl)indolizine-7-carboxylic acid diethyl-
amide;
- compound No. 60: ({2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}isopropyl-
amino)acetic cid ethyl ester;
- compound No. 61: ({3-[4-(3-Dipropylamino-
propyl)benzoyl]-2-ethylindolizine-7-carbonyl}iso-
propylamino)acetic acid methyl ester;
- compound No. 62: [(2-Butyl-3-{4-[3-(butylethyl-
amino)propyl]benzoyl}indolizine-7-carbonyl)iso-
propylamino]acetic acid methyl ester;
- compound No. 63: ({2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indoli zine-7-carbonyl}i sobutyl-
amino)acetic acid methyl ester;
- compound No. 64: ({2-Butyl-3-[4-(1-methyl-
piperidin-4-yl)benzoyl]indolizine-7-
carbonyl}isopropylamino)acetic acid;
- compound No. 65: {[2-Ethyl-3-(4-piperidin-4-yl-
benzoyl)indolizine-7-carbonyl]isopropyl-
amino}acetic acid methyl ester;
- compound No. 66: 2-Butyl-3-(4-piperidin-4-yl-
benzoyl)indolizine-7-carboxylic acid diethylamide;
- compound No. 67: ({2-Butyl-3-[4-(piperidin-4-
yloxy)benzoyl]indolizine-7-carbonyl}isopropyl-
amino)acetic acid methyl ester;

- compound No. 68: ({2-Butyl-3-[4-((S)-piperidin-
3-yloxy)benzoyl]indolizine-7-carbonyl}isopropyl-
amino)acetic acid methyl ester;
- compound No, 69: (S)-2-({2-Butyl-3-[4-(3-
dibutylaminopropyl) benzoyl]indolizine-7-carbon-
yl}ethylamino)propionic acid methyl ester;
- compound No. 70: 2-Butyl-3-[4-(3-dibutyl-
aminopropyl)benzoyl]indolizine-7-carboxylic acid
benzylethylamide;
- compound No. 71: 2-Butyl-3-[4-(3-butylamino-
propyl) benzoyl] indolizine-7-carboxylic acid
ethyl (2-methoxyethyl) amide ;
- compound No. 72: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carboxylic acid (2-
isopropoxyethyl) isopropylamide;
- compound No. 73: [(2-Butyl-3-{4-[3-((3R,5S)-3,5-
dimethylpiperidin-1-yl)propyl]benzoyl}indolizine-
7-carbonyl) isopropylamino] acetic acid methyl
ester;
- compound No. 74: (Benzyl-{2-butyl-3-[4-(3-
dibutylaminopropyl)benzoyl] indolizine-7-
carbonyl}amino)acetic acid methyl ester;
- compound No. 75: ({2-Butyl-3-[4-(3-diethylamino-
propyl)benzoyl]indolizine-7-carbonyl}isopropyl-
amino) acetic acid;
- compound No. 76: ({3-[4-(3-tert-Butylamino-
propyl ) benzoyl] -2-ethylindolizine-7-carbonyl}iso-
propylamino) acetic acid;

- compound No. 77: 3-[4- (3-Cyclopentylamino-
propyl)benzoyl]-2-ethylindolizine-7-carboxylic
acid ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 78: 3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-methylindolizine-7-carboxylic
acid ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 79: [(2-Ethyl-3-{4-[3-(1-
isopropylaminocyclopentyl)propyl]benzo-
yl }indolizine- 7- carbonyl) isopropylamino)acetic
acid methyl ester;
- compound No. 80: 2-Butyl-3-(4-piperidin-4-
ylbenzoyl)indolizine-7-carboxylic acid ethyl(3-
methyl-[1,2,4]oxadiazol-5-ylmethyl)amide;
- compound No. 81: ({2-Butyl-3-[4-((R)-piperidin-
3-yloxy)benzoyl]indolizine-7-carbonyl}isopropyl-
amino) acetic acid methyl ester;
in the form of a base or of an addition salt with
an acid.
The compound of formula (I) as claimed in either
of claims 1 and 2, chosen from:
- compound No. 3: (R)-1-{2-Butyl-3-[4-(3-dibutyl-
aminopropyl)benzoyl]indolizine-7-
carbonyl}pyrrolidine-2-carboxylic acid methyl
ester;
- compound No♦ 4: 2-Butyl-3-[4-(3-dibutylamino-
propyl) benzoyl] indolizine-7-carboxylic acid
ethyl(2-methoxyethyl)amide;

- compound No. 5: ({2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}ethyl-
amino)acetic acid methyl ester;
- compound No. 8: ({3-[4-(3-Cyclopentylamino-
propyl) benzoyl] 2-ethylindolizine-7-carbon-
yl}isopropylamino)acetic acid methyl ester;
- compound No. 9: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carboxylic acid
ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 10: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carboxylic acid
ethyl(3-methyl[1,2,4]oxadiazol-5-ylmethyl)amide;
- compound No. 13: 4-{2-Butyl-3-[4-(3-dibutyl-
aminopropyl)benzoyl]indolizine-7-carbon-
yl}piperazin-2-one;
- compound No. 16: [(2-Ethyl-3-{4-[3-(1-
methylaminocyclopentyl)propyl]benzoyl}indolizine-
7-carbonyl)isopropylamino]acetic acid methyl
ester;
- compound No. 17: 3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-carboxylic
acid ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 18: 3-[4-(3-tert-Butylamino-3-
methylbutyl)benzoyl]-2-ethylindolizine-7-
carboxylic acid ethyl(2-methyl-2H-tetrazol-5-
ylmethyl)amide;
- compound No. 22: 2-Butyl-3-[4-(3-dibutylamino-
propyl) benzoyl] indolizine-7-carboxylic acid
isopropyl(2-methoxyethyl)amide;

- compound No, 23: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carboxylic acid
ethyl(2-isopropoxyethyl)amide;
- compound No. 24: 2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carboxylic acid (2-
ethoxyethyl)isopropylamide;
- compound No. 28: ({2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}isopropyl-
amino)acetic acid methyl ester;
- compound No. 29: ({3-[4-(3-Dibutylamino-
propyl)benzoyl]-2-ethylindolizine-7-carbonyl}iso-
propylamino)acetic acid methyl ester;
- compound No. 30: ({3-[4-(3-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-
carbonyl}isopropylamino)acetic acid methyl ester;
- compound No. 31: ({3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-ethylindolizine-7-carbonyl}iso-
propylamino)acetic acid methyl ester;
- compound No. 35: ({3- [4- (3-Cyclohexylamino-
propyl)benzoyl]-2-ethylindolizine-7-carbon-
yl}isopropylamino)acetic acid methyl ester;
- compound No. 40: 3-[4-(3-tert-
Butylaminopropyl)benzoyl]-2-ethylindolizine-7-
carboxylic acid ethyl(2-ethyl-2H-tetrazol-5-
ylmethyl)amide;
- compound No. 42: 3-[4-(3-tert-Butylamino-
propyl)benzoyl-2-cyclobutylindolizine-7-carboxylic
acid ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;

- compound No. 43: 2-Ethyl-3-[4-(3-ethylamino-4,4-
dimethylpentyl)benzoyl]indolizine-7-carboxylic
acid ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 53: l-{3-[4-(3-Cyclopentylamino-
propyl)benzoyl]-2-ethylindolizine-7-carbon-
yl}[1,4]diazepam-5-one;
- compound No. 55: [(2-Ethyl-3-{4-[3-(ethyliso-
propylamino)propyl]benzoyl}indolizine-7-
carbonyl)isopropylamino]acetic acid methyl ester;
- compound No. 58: ({3-[4-(3-Dibutylamino-
propyl)benzoyl]-2-ethylindolizine-7-carbon-
yl}ethylamino)acetic acid isopropyl ester;
- compound No. 62: [(2-Butyl-3-{4-[3-(butyl-'
ethylamino)propyl]benzoyl}indolizine-7-
carbonyl)isopropylamino]acetic acid methyl ester;
- compound No. 63: ({2-Butyl-3-[4-(3-dibutylamino-
propyl)benzoyl]indolizine-7-carbonyl}isobutyl-
amino)acetic acid methyl ester;
- compound No. 64: ({2-Butyl-3-[4-(1-methyl-
piperidin-4-yl)benzoyl]indolizine-7-carbon-
yl}isopropylamino)acetic acid;
- compound No. 65: {[2-Ethyl-3-(4-piperidin-4-
ylbenzoyl)indolizine-7-carbonyl]isopropyl-
amino}acetic acid methyl ester;
- compound No. 69: (S)-2-({2-Butyl-3-[4-(3-
dibutylaminopropyl)benzoyl]indolizine-7-
carbonyl}ethylamino)propionic acid methyl ester;

- compound No. 75: ({2-Butyl-3-[4-(3-diethylamino-
propyl)benzoyl]indolizine-7-carbonyl}isopropyl-
amino)acetic acid;
- compound No. 77: 3-[4-(3-Cyclopentylaminoprop-
yl)benzoyl]-2-ethylindolizine-7-carboxylic acid
ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
- compound No. 78: 3-[4-(3-tert-Butylamino-
propyl)benzoyl]-2-methylindolizine-7-carboxylic
acid ethyl(2-methyl-2H-tetrazol-5-ylmethyl)amide;
in the form of a base or of an addition salt with
an acid.
4. A compound of formula (VI):

wherein:
- R7 is as defined in claim 1;
- R represents a (C1-C4) alkyl group;
- R' represents a (C1-C4) alkyl group;
- P represents a phosphorus atom;
in the form of a base or of an addition salt with
an acid.
5. A medicament, characterized in that it comprises a
compound of formula (I) as claimed in any one of
claims 1 to 3, or an addition salt of this
compound with a pharmaceutically acceptable acid
of the compound of formula (I).

6. The compound of general formula (I) as defined in
any one of claims 1 to 3, for use thereof as a
medicament.
7. The compound of general formula (I) as defined in
any one of claims 1 to 3, for preparing a
medicament intended for the prevention or
treatment of atrial and ventricular arrhythmias:
atrial tachyarrhythmia, atrial fibrillation,
atrial flutter, atrial tachycardia, ventricular
tachyarrhythmia, ventricular extrasystoles,
ventricular tachycardia, ventricular flutter and
fibrillation; of angina pectoris, of hypertension,
of cerebral circulatory insufficiency, of heart
failure, of myocardium infarction which may or may
not be complicated by heart failure, or the
prevention of post-infarction mortality, or of
stroke.
8. A pharmaceutical composition, characterized in
that it comprises a compound of formula (I) as
claimed in any one of claims 1 to 3, or a
pharmaceutically acceptable salt, and also at
least one pharmaceutically acceptable excipient.
9. The use of a compound of formula (I) as claimed in
any one of claims 1 to 3, for preparing a
medicament intended for the treatment of
pathological syndromes of the cardiovascular
system.
10. The use of a compound of formula (I) as claimed in
any one of claims 1 to 3, for preparing a
medicament intended for the prevention or
treatment of. atrial and ventricular arrhythmias:
atrial tachyarrhythmia, atrial fibrillation,

atrial flutter, atrial tachycardia, ventricular
tachyarrhythmia, ventricular extrasystoles,
ventricular tachycardia, ventricular flutter and
fibrillation; of angina pectoris, .of hypertension,
of cerebral circulatory insufficiency, of heart
failure, of myocardium infarction which may or may
not be complicated by heart failure, or the
prevention of post-infarction mortality, or of
stroke.