ES2367338T3 - DERIVATIVES OF 1,2,3,4-TETRAHYDROPIRROLO [1,2-a] -PIRAZINA-6-CARBOXAMIDS AND 2,3,4,5-TETRAHYDROPIRROLO [1,2, -a] [1,4] -DIAZEPINO -7-CARBOXAMIDS, ITS PREPARATION AND ITS APPLICATION IN THERAPEUTICS. - Google Patents

Abstract

Compound that responds to formula (I) ** Formula ** in which: R1 represents a hydrogen atom, a (C1-C10) alkyl, cycloalkyl (C3-C7), (CH2) n-alkenyl (C1C6) group , (CH2) n-C1-C6 alkynyl, (C1-C6) alkyl-Z-C1-C6 alkyl, wherein Z represents a heteroatom chosen from O, N and S (O) m, or R1 represents a COOR group, S (O) mR, an aryl or an aralkyl; the groups being (C1-C10), cycloalkyl (C3-C7), (CH2) n-alkenyl (C1-C6), (CH2) n-alkynyl (C1-C6), alkyl (C1-C6) Z- alkyl groups (C1-C6), aryl or aralkyl optionally substituted with one or more groups selected from a halogen atom, a (C1-C6) alkyl group, (C3-C7) cycloalkyl, halo (C1-C6) alkyl, alkoxy ( C1-C6), haloalkoxy (C1-C6), NR7R8, nitro, cyano, OR, COOR, C (O) NR7R8 or S (O) mNR7R8, R2 represents one or more groups chosen from a hydrogen atom, an atom of halogen, a (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C8) alkenyl, (C1-C6) alkynyl or (C1-C6) -Z-(C1-C6) alkyl group, in the that Z represents a heteroatom chosen from O, N and S (O) m, or R2 represents a halo (C1-C6) alkyl, halo (C1-C6) alkoxy, hydroxy, (C1-C6) alkoxy group, nitro, cyano, amino, a group NR7R8, COOR, C (O) NR7R8, OC (O) -alkyl (C1-C6), S (O) m-NR7R8 or an aryl group, the aryl group being optionally substituted with one or more groups chosen among u n halogen atom, a (C1-C6) alkyl group, (C3-C7) cycloalkyl, halo (C1-C6) alkyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy, NR7R8, OR, nitro, cyano, COOR, C (O) NR7R8 or S (O) mNR7R8, R3 represents a trifluoromethyl group, R4 and R5 represent a hydrogen atom, or R4 and R5 form with the carbon atom to which a cycle is attached saturated containing 3 to 6 carbon atoms and optionally containing 0 to 1 heteroatom chosen from O, N or S, R6 represents a group selected from a hydrogen atom, a halogen atom, a (C1C6) alkyl group, cycloalkyl (C3-C7), cycloalkyl (C3-C7) -alkyl (C1-C6), nitro, amino, a group NR7R8, COOR, an aryl group, a group NR7 (SO2) R8 or C (O) NR7R8, R , R7 and R8 represent, independently of one another, one or more groups chosen from a hydrogen atom, a (C1-C6) alkyl, cycloalkyl (C3-C7), cycloalkyl (C3-C7) -alkyl (C1-C6) group ), an aryl or aryl (C1-C6) alkylene group, or R7 and R8 can form c on the atom to which a saturated, partially unsaturated or unsaturated cycle is attached, containing from 5 to 7 carbon atoms and optionally also containing a heteroatom chosen from O, N or S (O) m, W represents a methylene group or C (O), m represents an integer that can take the values 0, 1 or 2, n represents an integer that can take the values 1, 2, 3, 4, 5 or 6, p represents an integer that can take the values 2 or 3, the carbon to which the benzyl group substituted with R2 is attached has the absolute configuration S, the carbon to which the hydroxyl group is attached has the absolute configuration R, in the state of base or salt addition to an acid

Description

5

10

fifteen

twenty

25

30

35

40

Four. Five

The present invention relates to derivatives of 1,2,3,4-tetrahydropyrrolo- [1,2-a] -pyrazine-6-carboxamides and 2,3,4,5-tetrahydropyrrolo [1,2-a] [ 1,4] -diazepino-7-carboxamides, to its preparation and its application in therapeutics.

The presence of multiple senile plaques in brain tissue is one of the main histopathological alterations observed in Alzheimer's disease; These plaques are formed by deposition of fibrillar aggregates of a 4 kDa peptide (40-42 amino acids), called β-amyloid peptide (Aβ). The production and progressive accumulation of this peptide could play a crucial role in the onset and Alzheimer's disease progression, according to the hypothesis of an amyloid cascade (D. Selko et al. Nature 399A (1999) 23; S. Roggo et al. Top. Med. Chem 2 (2002) 359; A. Ghosh et al Curr. Med. Chem. 9 (2002) 1135).

The Aβ peptide comes from the APP protein (by its initials in English: Amyloid Precursor Protein), which can be cleaved by at least three different proteolytic activities: 1) cleavage in the Aβ region by an αsecretase activity (thus preventing the formation of Aβ) ; 2) cleavage at the N-terminal end of Aβ by a βsecretase activity: 3) cleavage at the C-terminal end of Aβ by a γ-secretase activity. Consecutive cleavage of the APP protein at the β and γ sites results in the formation of the Aβ peptide (M. Citron Nat. Rev. Neurosci. 5 (2004) 677685; D. Beher et al. Expert Opin. Invest. Drugs 14 (2005) 1385-1409).

There is therefore a real interest in finding compounds that inhibit the production of the Aβ peptide (T. B. Durham et al. Curr. Opin. Drug Disc. Dev. 9 (2006) 776-791).

WO 2004/094430, WO 2006/103088 and WO 2005/058915 describe hydroxyethylamine derivatives useful in the treatment of Alzheimer's disease.

EP 1 477 490 describes pyrrolopyrimidine derivatives useful as synthesis intermediates of compounds proposed for the treatment of Alzheimer's disease.

Now, it has been found that the compounds; 1,2,3,4 tetrahydropyrrolo- [1,2-a] -pyrazine-6-carboxamides and 2,3,4,5-tetrahydropyrrolo [1,2-a] [1,4] -diazepine- derivatives 7-carboxamides possess a strong inhibitory activity against β-secretase activity.

The present invention aims at compounds that respond to formula (I):

image 1

in which:

R1 represents a hydrogen atom, a (C1-C10) alkyl, cycloalkyl (C3-C7), (CH2) n-alkenyl (C1C6), (CH2) n-alkynyl (C1-C6), alkyl (C1-C6) group ) -Z-(C1-C6) alkyl, wherein Z represents a heteroatom chosen from O, N and S (O) m, or R1 represents a COOR, S (O) mR group, an aryl or an aralkyl; the groups being (C1-C10), cycloalkyl (C3-C7), (CH2) n-alkenyl (C1-C6), (CH2) n-alkynyl (C1-C6), alkyl (C1-C6) Z-alkyl groups (C1-C6), aryl or aralkyl optionally substituted with one or more groups selected from a halogen atom, a (C1-C6) alkyl group, (C3-C7) cycloalkyl, halo (C1-C6) alkyl, alkoxy ( C1-C6), haloalkoxy (C1-C6), NR7R8, nitro, cyano, OR, COOR, C (O) NR7R8 or S (O) mNR7R8,

R2 represents one or more groups chosen from a hydrogen atom, a halogen atom, a (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C6) alkenyl, (C1-C6) alkynyl or alkyl ( C1-C6) -Z-(C1-C6) alkyl, in which Z represents a heteroatom chosen from O, N and S (O) m, or R2 represents a halo-C1-C6 alkyl group, halo- (C1-C6) alkoxy, hydroxy, (C1-C6) alkoxy, nitro, cyano, amino, a group NR7R8, COOR, C (O) NR7R8, OC (O) -alkyl (C1-C6), S (O) m-NR7R8 or an aryl group, the aryl group being optionally substituted with one or more groups selected from a halogen atom, a (C1-C6) alkyl, cycloalkyl (C3-C7), halo-(C1-C6) alkyl group ), (C1-C6) alkoxy, halo (C1-C6) alkoxy, NR7R8, OR, nitro, cyano, COOR, C (O) NR7R8 or S (O) mNR7R8,

R3 represents a trifluoromethyl group, R4 and R5 represent a hydrogen atom, or R4 and R5 form a saturated cycle containing from 3 to 6 carbon atoms and optionally containing from 0 to 1 with the carbon atom heteroatom chosen from O, N or S,

R6 represents a group selected from a hydrogen atom, a halogen atom, a (C1C6) alkyl, cycloalkyl (C3-C7), cycloalkyl (C3-C7) -alkyl (C1-C6), nitro, amino, a group NR7R8, COOR, an aryl group, a group NR7 (SO2) R8 or C (O) NR7R8,

R, R7 and R8 represent, independently of one another, one or more groups chosen from a hydrogen atom, a (C1-C6) alkyl, cycloalkyl (C3-C7), cycloalkyl (C3-C7) -alkyl (C1-) group C6), an aryl or aryl (C1-C6) alkylene group, or R7 and R8 can form a saturated, partially unsaturated or unsaturated cycle with the atom to which they contain 5 to 7 carbon atoms and which optionally also contains a heteroatom chosen from O, N or S (O) m,

W represents a methylene group or C (O),

m represents an integer that can take the values 0, 1 or 2,

n represents an integer that can take the values 1, 2, 3, 4, 5 or 6,

p represents an integer that can take values 2 or 3,

the carbon to which the benzyl group substituted with R2 is attached has the absolute configuration S,

The carbon to which the hydroxyl group is attached has the absolute configuration R, in the base or salt state of addition to an acid.

The compounds of formula (I) may contain one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as mixtures thereof, including racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the state of bases or acid addition salts. Such addition salts form part of the invention.

These salts may be prepared with pharmaceutically acceptable acids, but salts of other acids useful, for example, for the purification or isolation of the compounds of formula (I) are also part of the invention.

Within the framework of the present invention, it is understood as:

 Ct-Cz, in which tyz can take the values of 1 to 10, a carbon chain or cycle that can have such carbon atoms, for example C1-C3 can characterize a carbon chain having 1 to 3 carbon atoms;

 a halogen atom: a fluorine, chlorine, bromine or iodine;

 an alkyl group: a saturated linear or branched aliphatic group. As examples, there may be mentioned the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, etc .;

 a cycloalkyl group: a cyclic alkyl group. As examples, there may be mentioned the cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc groups;

 an alkylene group: a saturated, linear or branched divalent aliphatic group. As an example, a C1-3 alkylene group represents a divalent carbon chain of 1 to 3 carbon atoms, linear or branched, such as a methylene (-CH2-), an ethylenyl (-CH2CH2-), a 1-methylethylenyl ( -CH (CH3) CH2-), a propylenyl (CH2CH2CH2-);

 a haloalkyl group: an alkyl group in which one or more hydrogen atoms have been replaced by a halogen atom; As examples, the groups CF3, CH2CF3, CHF2 or CCl3 can be mentioned;

 a haloalkoxy group: an alkoxy group in which one or more hydrogen atoms have been replaced by a halogen atom. As examples, the groups OCF3, OCHF2 or OCCl3 can be cited;

 an alkenyl group: a mono or polyunsaturated, linear or branched aliphatic group, comprising, for example, one or two ethylenic unsaturations;

 an alkynyl group: a mono or polyunsaturated, linear or branched aliphatic group, comprising for example one or two acetylenic unsaturations;



an alkoxy group: an -O-alkyl radical in which the alkyl group is as defined above;



an aryl group: a cyclic aromatic group comprising between 6 and 14 carbon atoms. As an example

of aryl group, one can cite phenyl or naphthyl;



the sulfur and nitrogen atoms may be present in the oxidized state (N-oxide, sulfoxide,

5

sulfone)



When p represents 2, the compounds respond to the following formula:

image 1

 When p represents 3, the compounds respond to the following formula:

image 1

In the different groups as defined above, the groups R1, R2, R3, R4, R5, R6, R, R7, R8, W

and p, when not defined, have the same definitions as those mentioned above. Among the compounds of formula (I) object of the invention, a first group of compounds is constituted by compounds for which:

W represents a methylene group. Among the compounds of formula (I) object of the invention, a second group of compounds is constituted by the compounds for which: W represents a group C (O). Among the compounds of formula (I) object of the invention, a third group of compounds is constituted by the compounds for which: 20 p represents 2. Among the compounds of formula (I) object of the invention, a fourth group of compounds it is constituted by the compounds for which: p represents 3. Among the compounds of formula (I) object of the invention, a fifth group of compounds is constituted by the 25 compounds for which: R6 represents a group chosen from an atom of hydrogen, a COOR group or a C (O) NR7R8 group. Among these subgroups of compounds of formula (I) object of the invention, a sixth subgroup of compounds is constituted by the compounds for which: R6 represents a group selected from a hydrogen atom, a COOH, COOMe group or a 30 C group (O) N (Et) 2. Among the compounds of formula (I) object of the invention, a seventh group of compounds is constituted by the compounds for which: W represents a methylene group or C (O),

p represents 2 or 3,

R1 represents a hydrogen atom, a (C1-C10), COOR or S (O) mR alkyl group, the (C1-C10) alkyl group being optionally substituted with one or more (C1-C6) alkyl groups,

R2 represents one or more groups chosen from a hydrogen atom or a halogen atom,

R4 and R5 represent a hydrogen atom or form with the carbon atom to which a cyclopropyl group is attached,

R6 represents a group chosen from a hydrogen atom, a COOR group or a C (O) NR7R8 group,

R, R7 and R8 represent, independently of one another, a hydrogen atom or one or more (C1-C6) alkyl groups.

Combinations of groups one to seven as defined above are also part of the invention.

Among the compounds of formula (I) object of the invention, the following compounds may be mentioned mainly:

 6 - {[(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -3,4 dihydropyrrolo [1,2 -a] pyrazine-2,8 (1H) -2-tert-butyl and 8-methyl dicarboxylate

 6 - {[(1S, 2R) -1-Benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -2- (tert-butoxycarbonyl) - 1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylic

 6 - {[(1S, 2R) -1-Benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} hydrochloride (2: 1) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylic

 6 - {[(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -8 (diethylcarbamoyl) -3, 4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -tert-butyl carboxylate

 6 - {(1S, 2R) -1-benzyl-2-hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropylamino] -propyl} -N-8, N-8-diethyl-1,2, 3,4-tetrahydropyrrolo [1,2-a] pyrazine-6,8-dicarboxamide and its hydrochloride (2: 1)

 6 - {(1S, 2R) -1-benzyl-2-hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropylamino] -propyl} -N-8, N-8-diethyl-2 (methylsulfonyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6,8-dicarboxamide

 N - [(1S, 2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] -1-oxo- 2- (1propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide and its hydrochloride (1: 1)

 N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] -1-oxo-2- (1-propylbutyl) ) 1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide and its hydrochloride (1: 1)

 N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- (1-propylbutyl-1,2, 3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide and its hydrochloride (1: 1)

 N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -2- (1-ethylpropyl) -1-oxo-1,2 , 3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide and its hydrochloride (1: 1).

 N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- (1-propylbutyl) -2.3 , 4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepino-7-carboxamide and its hydrochloride (1: 1).

A subject of the invention is also a process for preparing the compounds of the invention of formula (I).

In the following text, protective group Pg is understood as a group that allows, on the one hand, to protect a reactive function such as a hydroxy or an amine during a synthesis and, on the other hand, to regenerate the intact reactive function at the end of the synthesis. Examples of protective groups as well as protection and deprotection methods are provided in "Protective Groups in Organic Synthesis", Green et al., 2nd Edition (John Wiley & Sons, Inc., New York), 1991.

In the text that follows, a leaving group is understood as a group that can be easily cleaved from a molecule by breaking a heterolytic bond, leaving an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example. Such leaving groups are, for example, halogens or an activated hydroxy group such as a methanesulfonate, benzenesulfonate, p

5

10

fifteen

twenty

25

toluenesulfonate, triflate, acetate, etc. Examples of outgoing groups as well as references for their preparation are

provided in "Advances in Organic Chemistry", J. March, 3rd Edition, Wiley Interscience, 1985, p. 310-316. In the following schemes, the starting compounds and reagents, when their mode of preparation is not described, are commercially available or described in the literature, or they can be prepared according to the methods described therein or which are known by the skilled in the art.

The abbreviations and symbols used for the description of the synthesis procedures and for the description of the compounds are the following:

 BOC for tert-butoxycarboxylate,

 DCC for dicyclohexylcarbodiimide,

 DMF for dimethylformamide,

 EDCI for (1-ethyl-3,3-dimethylaminopropyl) carbodiimide,

 NMP for N-methyl-2-pyrrolidone,

 PyBOP for benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate,

 THF for tetrahydrofuran. According to the invention, the compounds of general formula (I) can be prepared according to the procedure illustrated by scheme 1 below.

image 1

The compound of the general formula (I) can be prepared by condensation of the amine function of a compound of the general formula (II) in which R2, R3, R4 and R5 are as defined in the general formula (I), on the carboxylic acid function of the compound of the general formula (III), in which p, R1 and R6 are as defined in the general formula (I). This reaction is operated in anhydrous medium, preferably inert (nitrogen or argon, for example) and using classic coupling agents of an acid function with an amine function, such as DCC, PyBOP, EDCl, in solvents such as dichloromethane, THF, ether or chloroform, at a temperature between 20 ° C and the reflux temperature of the solvent.

The compound of general formula (II), in which R2, R3, R4 and R5 are as defined in the general formula (I), can be prepared from the compound of general formula (IV), in which R2, R3, R4 and R5 are as defined in the general formula (I), by deprotection of the primary amine by the action of an acid (hydrochloric acid, for example) in solution in a solvent or a mixture of ether solvent (diethyl ether, for example) and / or chlorinated (dichloromethane, for example), according to the procedure illustrated by scheme 2 below.

image2

The compound of general formula (IV), in which R2, R3, R4 and R5 are as described above, can be prepared by reacting a benzylamine derivative of general formula (VI), in which R3, R4 and R5 are as defined in the general formula (I) with an oxirane of the general formula (V), in which R2 is as it has been

5

10

fifteen

twenty

25

30

defined in the general formula (I) operating in anhydrous medium, preferably inert (nitrogen or argon, for example), in a chlorinated solvent (dichloromethane, for example) and in the presence of a Lewis acid, such as scandium triflate.

The compounds of general formula (I) in which W represents C (O) and p represents 2, can be obtained by condensation of the amine function of the compound of general formula (II) on the carboxylic acid function of the compound of general formula (IIIa ), in which R1 and R6 are as described above.

The compounds of the general formula (IIIa) can be prepared according to the procedure of scheme 3 below, from the compound of the general formula (VII), in which R1 and R6 are as defined above, by reaction of the compound of the formula general (VII) with carbon monoxide (under pressure of 1 to 20 atmospheres), in the presence of acetate (potassium or sodium) ions and an alkaline iodide (sodium or potassium iodide, for example), in the presence of a Palladium catalyst (palladium acetate, for example), of a phosphine (triphenylphosphine, for example) in solution in an organic solvent (dimethylformamide, for example) and in the presence of water. The reaction takes place at a temperature between 20 ° C and the reflux of the solvent.

image 1

The halogenated derivative of general formula (VII), in which R1 and R6 are as defined above, can be prepared from the bicyclic derivative of general formula (VIII), by reaction with a halogenating agent such as N -bromosuccinimide in a chlorinated solvent (carbon tetrachloride, for example).

The bicyclic derivative of the general formula (VIII) can be prepared by aminolysis of the compound of the general formula

(IX) with an amine of the general formula R1NH2. This reaction is carried out in the presence or not of iodide ions (potassium or sodium iodide, for example) and in solution in an organic solvent (acetonitrile, dimethylformamide, ethanol, NMP, ether, THF, dioxane, toluene, for example), at a temperature between 20 ° C and the reflux temperature of the solvent. The aminated derivative obtained as an intermediate is cycled in the presence of a cyclising agent (trimethyl aluminum, for example) in solution in an organic solvent (toluene, for example) at a temperature between 20 ° C and the reflux temperature of the solvent.

The compound of the general formula (IX) can be prepared from the ethyl pyrrole-2-carboxylate derivative of the general formula (X), by a monoalkylation reaction, by the action of 1,2-dibromoethane. This alkylation is carried out with a base such as cesium carbonate, potassium carbonate, potassium phosphate, potassium t-butylate, soda, sodium hydride and in solvents such as ethanol, DMF, NMP, ether, THF, dioxane, acetonitrile , toluene, or by phase transfer in the presence of an agent such as tetrabutylammonium chloride in dichloromethane or dichloroethane in the presence of water or also in benzene.

The compounds of formula (I) in which W represents a methylene group and p represents 2, can be obtained by condensation of the amine function of the compound of general formula (II) on the carboxylic acid function of the compound of general formula (IIIb), according to the procedure in scheme 4 below.

image 1

Among the compounds of the general formula (IIIb), the compound of the formula (IIIb ') in which R 6 represents COOR, R being as defined above, is particularly interesting for the synthesis of the compounds of the formula (I).

This compound of formula (IIIb ') (2- (tert-butoxycarbonyl) -8- (methoxycarbonyl) -1,2,3,4-tetrahydropyrrolo [1,2a] pyrazine-6-carboxylic acid) can be synthesized according to the procedure of the following scheme 5, from 6-bromo3,4-dihydropyrrolo [1,2a] pyrazine2,8 (1H) -dicarboxylate of 2-tert-butyl and 8-methyl, under the same conditions as those used for the preparation of the compound of general formula (IIIa).

image 1

The 2-tert-butyl and 8-methyl 6-bromo-3,4-dihydropyrrolo [1,2a] pyrazine2,8 (1H) -dicarboxylate can be prepared by

10 a halogenation reaction of 3,4-dihydropyrrolo [1,2a] pyrazine-2,8- (1H)-2-tert-butyl and 8-methyl dicarboxylate, with a halogenating agent such as N-bromosuccinimide, in a chlorinated solvent (carbon tetrachloride, for example) at a temperature between 0 ° C and the reflux temperature of the solvent.

3,4-Dihydropyrrolo [1,2-a] pyrazine-2,8- (1 H) -2-tert-butyl and 8-methyl dicarboxylate can be prepared from 4- (tert-butoxycarbonyl) -1 -formylpiperazine-2-carboxylate sodium, by reaction with a mixture of tosyl chloride and

15 of methyl α-chloroacrylate in the presence of an organic base, such as triethylamine or pyridine, in a chlorinated solvent, such as dichloromethane or dichloroethane, at a temperature between 20 ° C and the reflux temperature of the solvent.

Sodium 4- (tert-butoxycarbonyl) -1-formylpiperazine-2-carboxylate can be prepared from commercial 2-methoxycarbonyl4-N-tert-butyl piperazine, by a formylation reaction with pentafluorophenyl formate (which is

20 prepares extemporaneously according to L. Kisfaludy et al. Synthesis (1987) 5, 510) operating in anhydrous medium, preferably inert (nitrogen or argon, for example), in a chlorinated organic solvent (dichloromethane, for example), at a temperature close to 20 ° C, followed by a salification reaction by action of a base such as soda, potassium carbonate, potassium tert-butylate, in solvents such as THF or dioxane, at a temperature close to 20 ° C.

The compounds of general formula (I) in which W represents a CO group and p represents 3, can be obtained by condensation of the amine function of the compound of general formula (II) on the carboxylic acid function of the compound of general formula (IIIc ), obtaining this according to the procedure of the following scheme 6.

image 1

The compounds of the general formula (IIIc) can be prepared by reacting the compound of the general formula (XII) 30 with carbon monoxide, in the presence of acetate (potassium or sodium) ions, and of an alkaline iodide (sodium iodide or potassium, for example) in the presence of a palladium catalyst (palladium acetate, for example), of a

phosphine (triphenylphosphine, for example) in solution in an organic solvent (dimethylformamide, for example) and in the presence of water. The reaction takes place at a temperature between 20 ° C and the reflux of the solvent.

The halogenated derivative of general formula (XII), in which R1 and R6 are as described above, can be prepared from a derivative of general formula (XI), by reaction with a halogenating agent such as N- Bromosuccinimide in a chlorinated solvent (carbon tetrachloride, for example).

The bicyclic derivative of the general formula (XI) can be prepared by aminolysis of the compound of the general formula (IX) with an amine of the general formula R1NH2. This reaction is carried out in the presence or not of iodide ions (potassium or sodium iodide, for example) and in solution in an organic solvent (acetonitrile, dimethylformamide, ethanol, NMP, ether, THF, dioxane, toluene, for example), at a temperature between 20 ° C and the reflux temperature of the solvent. The aminated derivative obtained as an intermediate is then cycled in the presence of a cyclising agent (trimethylaluminum, for example) in solution in an organic solvent (toluene, for example) at a temperature between 20 ° C and the reflux temperature of the solvent. The compound of general formula

(IX) can be prepared from the ethyl pyrrole-2-carboxylate derivative of the general formula (X), by a monoalkylation reaction, by the action of 1,3-dibromopropane. This alkylation is carried out with a base such as cesium carbonate, potassium carbonate, potassium phosphate, potassium t-butylate, soda, sodium hydride and in solvents such as ethanol, DMF, NMP, ether, THF, dioxane, acetonitrile , toluene, or by phase transfer in the presence of an agent such as tetrabutylammonium chloride in dichloromethane or dichloroethane in the presence of water, or also in benzene.

The products of formula (I) can be subjected, if desired and if necessary, to obtain the products of formula (I) or transformed into other products of formula (I), to one or more of the following transformation reactions, in any order:

a) an esterification or amidification reaction of the acid function,

b) a hydrolysis reaction of the acid function ester function,

c) a reaction of transforming the hydroxyl function into an alkoxy function,

d) an oxidation reaction of the alcohol function depending on aldehyde, ketone or acid,

e) an acid, aldehyde or ketone reduction function in alcohol function,

f) a reductive amination reaction of an aldehyde or ketone function,

g) an oxidation reaction of the alkenyl group based on aldehyde or ketone,

h) an oxidation reaction of a thioether in sulfone or sulfoxide,

i) an alkylation reaction of a sulfonamide,

j) a dehydration reaction of a hydroxyalkyl group in an alkenyl group,

k) a dehydrohalogenation reaction of a halogenated derivative,

l) a total or partial hydrogenation reaction of the alkenyl or alkynyl group in an alkenyl or alkyl group,

m) a catalytic coupling reaction of a halogenated derivative and an organometallic derivative, such

as stannic or boronic, to introduce an alkyl, alkenyl, alkynyl or aryl substituent, n) a protective reaction of reactive functions, o) an elimination reaction of the protective groups that may carry the protected reactive functions, p) a salification reaction with a mineral or organic acid or with a base to obtain the salt

correspondent, q) a doubling reaction of the racemic forms into enantiomers, where appropriate, said

products of formula (I) thus obtained in all possible racemic, enantiomeric and isomeric forms diastereoisomers, r) a reduction reaction of nitro derivatives in nitrous or amino derivatives, s) a mono- or di-alkylation reaction of an amine function, t) a sulfonylation reaction of a primary or secondary amine, u) an acylation reaction of an amine function.

The invention, according to another of its aspects, also has as its object the compounds of formulas (IIIa), (IIIb), (IIIb ') and (IIIc). These compounds are useful as synthesis intermediates of the compounds of formula (I).

The compounds of formula (I) can be purified by methods known to those skilled in the art, for example, by crystallization, chromatography or extraction.

The following examples describe the preparation of some compounds according to the invention. These examples only illustrate the present invention. The numbers of the compounds of the examples refer to those given in the following table, which illustrates the chemical structures and physical properties of some compounds according to the invention.

Proton nuclear magnetic resonance spectra (1 H NMR) were performed at 250 MHz, 300 MHz, 400 MHz or 500 MHz with Brüker devices (chemical shifts (δ in ppm) - in the dimethylsulfoxide solvent -d6 (DMSO-d6) referenced at 2.50 ppm at the temperature of 303K). The abbreviations used to characterize the signals are the following: s = singlet, m = multiplet, d = doublet, t = triplet, q = quadruplet.

The nomenclature of the compounds of the following examples has been established through the ACDLabs® version 10.0 software.

Example 1:

6 - {[(1S, 2R) -1-Benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -3,4-dihydropyrrolo [1,2-a ] pyrazine-2,8 (1H) -2-tert-butyl and 8-methyl dicarboxylate

The preparation of pentafluorophenyl formate is described in the literature (Lajos Kisfaludy et al., Synthesis 1987, 5, 510).

1.1: 1-tert-Butyl and 3-methyl 4-Formylpiperazine-1,3-dicarboxylate

10 g of 2-methoxycarbonyl-4-N-tert-butyl-piperazine are dissolved in 25 cm 3 of dichloromethane under an inert atmosphere at a temperature close to 20 ° C. The pentafluorophenyl formate solution obtained in the previous step is added dropwise at a temperature close to 20 ° C. Stirring is maintained 1h30 after finishing the addition. The reaction mixture is concentrated in the rotary evaporator under reduced pressure (5 kPa). The yellow-orange oil obtained is purified by flash chromatography on a silica cartridge (column: 700 g; particle size: 40-60 µM; flow rate: 80 cm3 / min; eluent: 30% cyclohexane-70% ethyl acetate). After concentrating the fractions under reduced pressure (5 kPa), 10.5 g of 1-tert-butyl and 3-methyl 4-formylpiperazine-1,3-dicarboxylate are obtained as a light yellow oil.

• NMR: for this lot, a 50% -50% split of rotamers with 1.38 (s, 4.5H) is observed; 1.39 (s, 4.5H); from 2.62 to 2.93 (m, 1.5H); 3.08 (m, 1 H); 3.26 (partially masked m, 0.5H); 3.64 (m partially masked, 0.5H); 3.68 (s, 1.5H); 3.69 (s, 1.5H); 3.90 (m, 1 H); 4.02 (m, 0.5H); 4.36 (broad d, J = 13.5 Hz, 0.5H); 4.42 (broad d, J = 13.5 Hz, 0.5H); 4.71 (broad d, J = 4.5 Hz, 0.5H); 4.89 (broad d, J = 4.5 Hz, 0.5H); 8.09 (s, 0.5H); 8.16 (s, 0.5H).

1.2: 4- (tert-Butoxycarbonyl) -1-formylpiperazine-2-carboxylate sodium

10.5 g of 1-tert-butyl and 3-methyl 4-formylpiperazine-1,3-dicarboxylate are dissolved in 200 cm 3 of dioxane at a temperature close to 20 ° C. 42 cm3 of a 1M soda solution are added and the reaction mixture is heated at reflux of the solvent for 1h30. The reaction mixture is concentrated in the rotary evaporator under reduced pressure (5 kPa). The beige solid residue obtained is triturated in ethyl acetate, filtered, washed and air dried. 10.5 g of sodium 4- (tert-butoxycarbonyl) -1-formylpiperazine-2-carboxylate are obtained in the form of an amorphous white solid.

 LC-MS-DAD-ELSD: 259 (+) = (M + H) (+)

 NMR: 8.08 (d, 1 H); 4.74 (d, 0.5H); 4.55 (m, 1 H); 4.39 (d, 0.5H); 4.00 (dd, 1 H); 3.62 (d, 0.5H); 3.43 (t, 0.5H); 3.00 (m, 3 H); 1.40 (s, 9H).

1.3: 3,4-dihydropyrrolo [1,2-a] pyrazine-2,8 (1H)-2-tert-butyl and 8-methyl dicarboxylate

10.5 g of sodium 4- (tert-butoxycarbonyl) -1-formylpiperazine-2-carboxylate are dissolved in 300 cm 3 of dichloroethane at a temperature close to 20 ° C. 8.5 g of tosyl chloride, 5.3 cm3 of methyl α-chloroacrylate and 12.6 cm3 of triethylamine are added. The reaction mixture is heated at reflux of the solvent for 1 h. The reaction mixture is cooled to a temperature close to 20 ° C. It is washed successively 2 times with 100 cm3 of water and 2 times with 100 cm3 of a saturated aqueous solution of sodium chloride. The aqueous phases are reextracted with dichloromethane. The organic phases are combined, dried on a phase separator filter and concentrated in the rotary evaporator under reduced pressure (5 kPa). The brown-orange oil obtained is purified by flash chromatography on a silica cartridge (column: 700 g; particle size: 40-60 µM; flow rate: 80 cm3 / min; eluent: cyclohexane 80% -ethyl acetate 20%). After concentrating the fractions under reduced pressure (5 kPa), 9.5 g of 3,4-dihydropyrrolo [1,2-a] pyrazine-2,8 (1 H) -dicarboxylate of 2-tert-butyl and of 8methyl in the form of a light yellow solid.



NMR (ppm): 6.77 (d, 1 H); 6.42 (d, 1 H); 4.73 (s, 2H); 3.98 (t, 2H); 3.72 (t, 2H); 3.70 (s, 3 H); 1.43 (s, 9H)



LC-MS-DAD-ELSD: 281 (+) = (M + H) (+)



PF: 100 ° C

1.4: 6-Bromo-3,4-dihydropyrrolo [1,2-a] pyrazine-2,8 (1H) -2-tert-butyl and 8-methyl dicarboxylate

9.5 g of 3,4-dihydropyrrolo [1,2-a] pyrazine-2,8 (1 H) -dicarboxylate of 2-tert-butyl and 8-methyl are dissolved in 1 dm 3 of carbon tetrachloride at a temperature close to 20 ° C. The reaction mixture is cooled to 4 ° C by means of an ice-water bath and 6 g of N-bromosuccinimide are added twice with an interval of 5 min. Stirring is maintained for 18 h during which the reaction medium is progressively raised to a temperature close to 20 ° C. 6 g of sodium hydrogen carbonate and 6 g of sodium sulfate dissolved in 150 cm3 of water are added to the reaction mixture (pH 9). The organic phase is washed successively with 150 cm3 of water and with 150 cm3 of a saturated aqueous solution of sodium chloride. The aqueous phases are reextracted with carbon tetrachloride. The organic phases are combined, dried on a phase separator filter and concentrated in the rotary evaporator under reduced pressure (5 kPa). The yellow oil obtained is triturated in cyclohexane. The brominated derivative that has precipitated is filtered and washed with cyclohexane. 8.6 g of 6-tert-butyl-6-bromo-3,4-dihydropyrrolo [1,2-a] pyrazine2,8 (1H) -dicarboxylate are obtained as a light yellow solid.

 NMR: 6.57 (s, 1 H); 4.72 (s, 2H); 3.88 (t, 2H); 3.76 (t, 2H); 3.71 (s, 3 H); 1.43 (s, 9H)

 LC-MS-DAD-ELSD: 359 (+) 79Br = (M + H) (+), 381 (+) 79Br = (M + Na) (+)

 PF: 109 ° C

1.5: 2- (tert-Butoxycarbonyl) -8- (methoxycarbonyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid

8.6 g of 6-tert-butyl and 8-methyl 6-bromo-3,4-dihydropyrrolo [1,2-a] pyrazine-2,8 (1 H) -dicarboxylate are dissolved in 320 cm 3 of dimethylformamide at a temperature close to 20 ° C. 9 g of potassium acetate and 4.2 g of potassium iodide are added and the reaction mixture is purged with carbon monoxide. Under an atmosphere of carbon monoxide, 20 cm3 of water are added as well as 538 mg of palladium acetate and 1.3 g of triphenylphosphine. The reaction mixture is bubbled with carbon monoxide and heated at 100 ° C for 6 h. It is concentrated in the rotary evaporator under reduced pressure (5 kPa). The solid residue obtained is taken up in 300 cm 3 of ethyl acetate and 220 cm 3 of soda are added, respectively 200 cm 3 of 1 M and 20 cm 3 of 5 M (pH 12). After filtering the palladium and decanting the filtrate, the acid is precipitated by adding 70 cm 3 of 5 M hydrochloric acid to the aqueous phase. The solid is filtered and air dried. 6.9 g of 2- (tert-butoxycarbonyl) -8- (methoxycarbonyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid are obtained as a white solid.

 NMR: 7.09 (s, 1 H); 4.79 (s, 2H); 4.32 (t, 2H); 3.73 (m, 5H); 1.44 (s, 9H)

 LC-MS-DAD-ELSD: 325 (+) = (M + H) (+); 225 (+) = (M + H) (+) t-BOC + H

 PF: 177 ° C

The preparation of 1- (3-trifluoromethyl-phenyl) -cyclopropylamine is described in the literature (Armin de Meijere et al, Organic Letters 2003, 5 (5), 753-755).

1.6: [(1S, 2R) -1-Benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] tert-butyl carbamate

4.6 g of 1- (3-trifluoromethyl-phenyl) -cyclopropylamine are dissolved in 12 cm 3 of dichloromethane at a temperature close to 20 ° C. 7.9 g of [S- (R, R)] - (-) - (1-oxyranyl-2-phenylethyl) tert-butyl carbamate and 2.3 g of scandium triflate are added. The reaction mixture is maintained with stirring at 20 ° C for 12 h. It is diluted in 100 cm3 of dichloromethane and washed successively 2 times with 15 cm3 of water, 20 cm3 of a saturated aqueous solution of sodium hydrogen carbonate and with 50 cm3 of a saturated aqueous solution of sodium chloride. The aqueous phases are extracted with dichloromethane, and the organic phases are combined, dried on a phase separator filter and concentrated on the rotary evaporator under reduced pressure (5 kPa). The white solid obtained is purified by flash chromatography on a silica cartridge (column: 600 g; particle size: 40-60 µM; flow rate: 80 cm3 / min; eluent: 80% diisopropyl ether - 20% ethyl acetate). 6.8 g of [(1S, 2R) -1-benzyl-2-hydroxy-3 ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] tert-butyl carbamate are obtained in the form of a white solid

 NMR: 7.64 (s, 1 H); 7.53 (m, 3 H); 7.23 (m, 2H). 7.15 (m, 3 H); 6.56 (d, 1 H); 6.12 (d, 1 H); 4.70 (d, 1 H); 3.51 (m, 1 H); 3.38 (m, 1 H); 3.18 (m, 1 H); 2.98 (dd, 1 H); 2.50 (m, 2 H); 1.21 (s, 9H); 0.98 (m, 4H)

 LC-MS-DAD-ELSD: 465 (+) = (M + H) (+)

 PF: 124 ° C

1.7: Hydrochloride (2: 1) of (2R, 3S) -3-amino-4-phenyl-1 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) butan-2-ol

6.8 g of [(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] tert-butyl carbamate are dissolved in 250 cm3 of dichloromethane at a temperature close to 20 ° C. 36.6 cm3 of a 4M hydrochloric acid solution in dioxane are added. The reaction mixture is maintained with stirring for 1h30 at a temperature close to 20 ° C. The reaction mixture is concentrated in the rotary evaporator under reduced pressure (5 kPa). The beige solid obtained is triturated in diisopropyl ether and filtered. 5.4 g of (2: 1) hydrochloride of (2R, 3S) 3-amino-4-phenyl-1 - {[(1- [3- (trifluoromethyl) phenyl] cyclopropyl} butan-2-ol are obtained.

 NMR: 1.16 (m, 1 H); 1.27 (m, 1 H); 1.60 (m, 2 H); 2.62 (m, 1 H); 2.85 (d, J = 7.0 Hz, 2H); 2.95 (m, 1 H); 3.52 (m, 1 H); 4.15 (m, 1 H); 6.17 (m, 1 H); 7.24 (m, 5H); 7.65 (t, J = 7.5 Hz, 1H); 7.77 (d, J = 7.5 Hz, 1H); 7.81 (d, J = 7.5 Hz, 1H); 7.94 (s, 1 H); 8.23 (broad m, 3H); 9.72 (extended m, 1H); 10.35 (extended m, 1H).

 LC-MS-DAD-ELSD: 409 (+) = (M + Formic Acid-H) (-); 365 (+) = (M +)

1.8: 6 - {[(1S, 2R) -1-Benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -3,4 dihydropyrrolo [1,2 -a] pyrazine-2,8 (1H) -2-tert-butyl and 8-methyl dicarboxylate

3.9 g of 2- (tert-butoxycarbonyl) -8- (methoxycarbonyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid and 5.4 g of hydrochloride (2 : 1) of (2R, 3S) -3-amino-4-phenyl-1 - ({1- [3 (trifluoromethyl) phenyl] cyclopropyl} amino) butan-2-ol in 270 cm3 of dichloromethane under an inert atmosphere at a temperature close to 20 ° C. 184 mg of hydroxybenzotriazole, 7.1 cm3 of N, N-diisopropylethylamine are added, followed by 3.1 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 166 mg of 4-dimethylaminopyridine. The reaction mixture is maintained with stirring for 3 hours at a temperature close to 20 ° C. The reaction mixture is washed successively with 50 cm 3 of water, twice with 50 cm 3 of a saturated aqueous solution of potassium hydrogen phosphate, again with 50 cm 3 of water and with 100 cm 3 of a saturated aqueous solution of sodium chloride. The aqueous phases are extracted with dichloromethane. The organic phases are combined, dried on a phase separator filter and concentrated in the rotary evaporator under reduced pressure (5 kPa). The beige meringue obtained is purified by reprecipitation in diisopropyl ether at a temperature close to 20 ° C. The precipitate is filtered, washed with diisopropyl ether and air dried. 6.8 g of 6 - {[(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3 (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -3.4 are obtained -dihydropyrrolo [1,2-a] pyrazine-2,8 (1H) -dicarboxylate of 2-tertbutyl and 8-methyl in the form of a white solid.

 NMR: 7.93 (d, 1 H); 7.72 (s, 1 H); 7.53 (m, 1 H); 7.46 (m, 2H); 7.18 (m, 4H); 7.13 (s, 1 H); 7.11 (m, 1 H); 4.80 (d, 1 H); 4.74 (c, 2H); 4.09 (m, 2 H); 4.01 (m, 1 H); 3.73 (s, 3 H); 3.62 (m, 2H); 3.50 (m, 1 H); 3.03 (dd, 1 H); 2.69 (dd, 1 H); 2.50 (m, 2 H); 1.42 (s, 9H); 0.80 (m, 4H)

 LC-MS-DAD-ELSD: 669 (-) = (M-H) (-); 671 (+) = (M + H) (+)

 PF: 136 ° C

Example 2:

6 - {[(1S, 2R) -1-Benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -2- (tert-butoxycarbonyl) -1, 2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylic

2 g of 6 - {[(1S, 2R) -1-benzyl-2-hydroxy-3 - ((1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -3,4 dihydropyrrolo [ 1,2-a] pyrazine-2,8 (1 H) -2-tert-butyl and 8-methyl dicarboxylate (prepared in Example 1.8) in 20 cm 3 of methanol at a temperature close to 20 ° C. They are added 6.8 cm 3 of 1 M soda and the reaction mixture is heated for 18 h at reflux of the solvent The methanol from the reaction mixture is evaporated under reduced pressure (5 kPa) and the aqueous residue obtained is acidified by the addition of 6 , 8 cm3 of 1 M hydrochloric acid. The gummy residue obtained is concentrated to dryness in the rotary evaporator and is taken up in ethyl acetate.The sodium chloride salts are filtered and the filtrate is concentrated in the rotary evaporator under reduced pressure ( 5 kPa) The beige meringue obtained is triturated in diisopropyl ether The solid obtained is filtered, washed with diisopropyl ether and air dried 1.8 g of 6 - {[(1S, 2R) acid are obtained. - 1-Benzyl-2-hydroxy-3 - ({1- [3 (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -2- (tert-butoxycarbonyl) -1,2,3,4-tetrahydropyrrolo [1, 2-a] pyrazine-8 carboxylic in the form of a white powder.

 NMR: from 0.87 to 1.06 (m, 4H); 1.42 (s, 9H); 2.46 (dd, J = 7.5 and 12.0 Hz, 1H); 2.55 (dd, J = 3.5 and 12.0 Hz, 1H); 2.69 (dd, J = 10.5 and 14.0 Hz, 1H); 3.04 (dd, J = 3.5 and 14.0 Hz, 1H); 3.49 (m, 1 H); 3.62 (m, 2H); from 3.96 to 4.15 (m, 3H); 4.73 (m, 2H); 4.80 (m, 1 H); 7.09 (s, 1 H); 7.11 (m, 1 H); 7.19 (m, 4H); 7.42 (m, 2H); 7.54 (m, 1 H); 7.61 (broad s, 1H); 7.92 (d, J = 9.0 Hz, 1H).

 LC-MS-DAD-ELSD: 655 (-) = (M-H) (-); 657 (+) = (M + H) (+)

 PF: 134.5 ° C

Example 3:

6 - {[(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -1-hydrochloride (2: 1) , 2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylic

200 mg of 6 - {[(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -2- ( tert-butoxycarbonyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylic acid (prepared as in example 2) in 5 cm 3 of dichloromethane at a temperature close to 20 ° C. 0.76 cm3 of a 4M hydrochloric acid solution in dioxane is added to the reaction mixture which is maintained with stirring for 18 h at a temperature close to 20 ° C. It is concentrated in the rotary evaporator under reduced pressure (5 kPa). The residue is triturated in diisopropyl ether, the solid is filtered, washed with diisopropyl ether and air dried. 194 mg of hydrochloride (2: 1) of 6 - {[(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3 (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] acid are obtained carbamoyl} -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylic acid in the form of a yellow solid.

 NMR: 1.19 (m, 1 H); 1.28 (m, 1 H); 1.58 (m, 2 H); 2.71 (m, 2 H); 2.94 (m, 1 H); 3.05 (dd, J = 3.0 and 14.0 Hz, 1H); 3.48 (m, 2 H); 3.85 (m, 1 H); 3.95 (m, 1 H); 4.32 (m, 2H); 4.50 (s, 2H); 5.80 (broad m, 1H); 7.11 (m, 1 H); 7.16 (s, 1 H); 7.18 (m, 4H); 7.60 (t, J = 7.5 Hz, 1H); 7.73 (d, J = 7.5 Hz, 1H); 7.84 (d, J = 7.5 Hz, 1H); 7.97 (s, 1 H); 8.13 (d, J = 9.0 Hz, 1H); from 9.26 to 10.0 (extended m, 4H); 12.4 (extended m, 1H).

 LC-MS-DAD-ELSD: 557 (+) = (M + H) (+)

 PF: 196 ° C

Example 4:

6 - {[(1S, 2R) -1-Benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -8 (diethylcarbamoyl) -3.4- dihydropyrrolo [1,2-a] pyrazine-2 (1H) tert-butyl carboxylate

0.6 g of 6 - {[(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -2 - (tert-butoxycarbonyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylic acid (prepared in example 2) and 0.094 cm 3 of diethylamine in 25 cm 3 of dichloromethane at a temperature close to 20 ° C 12 mg of hydroxybenzotriazole, 0.5 cm3 of N, N-diisopropylethylamine are added, followed by 210 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 11 mg of 4-dimethylaminopyridine. The reaction mixture is maintained with stirring for 18 h at a temperature close to 20 ° C. It is washed successively with 10 cm3 of a 1M hydrochloric acid solution, with 20 cm3 of water, with 10 cm3 of a saturated aqueous solution of sodium hydrogen carbonate and with 15 cm3 of a saturated aqueous solution of sodium chloride. The organic phase is dried on a phase separator filter and concentrated in the rotary evaporator under reduced pressure (5 kPa). The meringue obtained is purified by flash chromatography on a silica cartridge (column: 70 g; granulometry: 15-40 µM; flow rate: 30 cm3 / min; eluent: 20% cyclohexane-80% ethyl acetate). After concentrating the fractions under reduced pressure (5 kPa), 310 mg of 6 - {[(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1 [3- (trifluoromethyl) phenyl] cyclopropyl) are obtained } amino) propyl] carbamoyl} -8- (diethylcarbamoyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) tert-butyl carboxylate, as a white amorphous solid.

 NMR: from 0.89 to 1.06 (m, 4H); 1.12 (t, J = 7.0 Hz, 6H); 1.40 (s, 9H); 2.50 (masked m, 1H); 2.59 (m, 2 H); 2.70 (dd, J = 10.5 and 14.0 Hz, 1H); 3.03 (dd, J = 3.5 and 14.0 Hz, 1H); 3.40 (q, J = 7.0 Hz, 4H); 3.53 (m, 1 H); 3.60 (m, 2 H); 3.99 (m, 2H); 4.13 (m, 1 H); 4.58 (m, 2 H); 4.84 (d, J = 6.0 Hz, 1H); 6.75 (s, 1 H); 7.11 (m, 1 H); 7.19 (m, 4H); from 7.42 to 7.51 (m, 2H); 7.54 (d, J = 7.5 Hz, 1H); 7.63 (s, 1 H); 7.88 (d, J = 9.0 Hz, 1H).

 LC-MS-DAD-ELSD: 710 (-) = (M-H) (-); 712 (+) = (M + H) (+)

Example 5:

Hydrochloride (2: 1) of 6 - {(1S, 2R) -1-benzyl-2-hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropylamino] -propyl} -N-8, N8diethyl-1,2 , 3,4-tetrahydropyrrolo [1,2-a] pyrazine-6,8-dicarboxamide

200 mg of 6 - {[(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} 8- (diethylcarbamoyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) tert-butyl carboxylate (prepared as in example 4) in 5 cm 3 of dichloromethane at a temperature close to 20 ° C. 0.70 cm3 of a 4M hydrochloric acid solution in dioxane is added. The reaction mixture is maintained with stirring for 18 h at a temperature close to 20 ° C. It is concentrated in the rotary evaporator under reduced pressure (5 kPa). The residue is triturated in diisopropyl ether, the solid is filtered, washed with diisopropyl ether and air dried. 123 mg of hydrochloride (2: 1) of 6 - {(1S, 2R) -1-benzyl-2-hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropylamino] -propyl} -N-8 are obtained, N-8-diethyl-1,2,3,4 tetrahydropyrrolo [1,2-a] pyrazine-6,8-dicarboxamide, in the form of a yellow powder.

• NMR: from 1.10 to 1.35 (m, 8H); 1.60 (m, 2 H); from 2.61 to 2.81 (m, 2H); from 2.92 to 3.12 (m, 2H); from 3.25 to 3.58 (m partially masked, 6H); 4.90 (m, 2H); 4.22 (m, 1 H); from 4.30 to 4.43 (m, 3H); 5.89 (extended m, 1H); 6.90 (s, 1 H); 7.10 (t, J = 7.5 Hz, 1H); from 7.13 to 7.24 (m, 4H); 7.61 (t, J = 7.5 Hz, 1H); 7.77 (d, J = 7.5 Hz, 1H); 7.87 (d, J = 7.5 Hz, 1H); 8.00 (s, 1 H); 8.24 (d, J = 9.0 Hz, 1H); from 9.35 to 9.53 (extended m, 2H); 9.77 (extended m, 1H); 9.98 (extended m, 1H).

 LC-MS-DAD-ELSD: 612 (+) = (M + H) (+)

 PF: 143 ° C

Example 6:

6 - {(1S, 2R) -1-benzyl-2-hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropylamino] -propyl} -N-8, N-8-diethyl-2 (methylsulfonyl) -1 , 2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6,8-dicarboxamide

6.1: 6 - ({(1S) -1 - [(5R) -2-oxo-3- {1- [3- (trifluoromethyl) phenyl] cyclopropyl} -1,3-oxazolidin-5-yl] -2- phenylethyl} carbamoyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2,8 (1H)-2-tert-butyl and 8-methyl dicarboxylate

To a solution of 2 g of 1.8: 6 - {[(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3 (trifluoromethyl) phenyl] cyclopropyl} amino] propyl} carbamoyl} -3 , 4-dihydropyrrolo [1,2-a] pyrazine-2,8 (1H)-2-tert-butyl and 8-methyl dicarboxylate (prepared in Example 1.8) in 10 cm 3 of dichloromethane cooled to a temperature close to 0 ° C and under an inert atmosphere, 0.967 g of N, N'-carbonyldiimidazole are added and stirred allowing it to return to a temperature close to 25 ° C. Stirring is maintained for 48 H. 6 cm 3 of dichloromethane and 15 cm 3 of an aqueous solution of hydrochloric acid.The reaction mixture is extracted twice with 40 cm3 of dichloromethane.The organic phases are combined, dried and concentrated on the rotary evaporator under reduced pressure (5 kPa). The residual solid is purified by flash chromatography on silica (column: 200 g; particle size: 15-40 µM; flow rate: 90 cm3 / min .; eluent: 50% cyclohexane - 50% ethyl acetate). Fractions containing The expected product is concentrated to dryness with the rotary evaporator under reduced pressure (5 kPa). 1.46 g of 6 - ({(1S) -1 - [(5R) -2-oxo-3- {1- [3- (trifluoromethyl) phenyl] cyclopropyl} -1,3-oxazolidin-5- are obtained il] -2-phenylethyl} carbamoyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2,8 (1 H) -dicarboxylate of 2-tert-butyl and 8-methyl in the form of a white solid.

 PF: 106 ° C

 NMR 1.30 - 1.56 (m partially masked, 4 H) 1.46 (s, 9 H) 2.82 (dd, J = 14.0, 10.7 Hz, 1 H) 2.94 (d, J = 14.0, 3.6 Hz, 1 H) 3.60 (dd, J = 9.0, 6.4 Hz, 1 H) 3.68 (m, 2 H) 3.75 ( t, J = 9.0 Hz, 1 H) 3.79 (s, 3H) 4.13 4.29 (m, 2 H) 4.38 (m 1 H) 4.62 (m, 1 H) 4 , 79 (wide s, 2 H) 7.19 (m, 1 H) 7.27 (m, 5 H) 7.48 (wide s, 1 H) 7.52 - 7.66 (m, 3 H) 8.18 (d, J = 9.0 Hz, 1 H).

 LC-MS-DAD-ELSD: Tr (mn) = 2.44; MH + = 697+; Purity: 98%

6.2: 6 - ({(1S) -1 - [(5R) -2-oxo-3- {1- [3- (trifluoromethyl) phenyl] cyclopropyl} -1,3-oxazolidin-5-yl] -2- methyl phenylethyl} carbamoyl) 1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylate

1.3 g of 6 - ({(1S) -1 - [(5R) -2-oxo-3- {1- [3- (trifluoromethyl) phenyl] cyclopropyl} -1,3-oxazolidin-5- il] -2-phenylethyl} carbamoyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2,8 (1H) -dicarboxylate of 2-tert-butyl and 8-methyl in 5 cm3 of dichloromethane under an inert atmosphere a temperature close to 20 ° C and 5 cm3 of a 4M hydrochloric acid solution in dioxane is added in 10 min. The reaction mixture is stirred 15 h at a temperature close to 20 ° C and concentrated to dryness in the rotary evaporator under reduced pressure (5 kPa). The residual solid, light yellow, is collected with 15 cm 3 of diisopropyl ether and crushed. The solid is filtered, washed twice with 10 cm3 of diisopropyl ether and air dried to obtain 1.2 g of 6 - ({(1S) -1 - [(5R) -2-oxo-3- { 1- [3- (trifluoromethyl) phenyl] cyclopropyl} -1,3oxazolidin-5-yl] -2-phenylethyl} carbamoyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylate of methyl in the form of a white-cream dihydrochlorinated solid. This solid is used without any further purification in example 6.3.

• NMR: 1.28-1.45 (m, 3 H) 1.51 (m, 1 H) 2.78 (dd, J = 13.8, 10.5 Hz, 1 H) 2.90 ( dd, J = 13.8, 3.8 Hz, 1 H) 3.47 (m, 2 H) 3.59 (m, 1 H) 3.72 (t, J = 8.9 Hz, 1 H) 3.77 (s, 3 H) 4.24-4.48 (m, 3 H) 4.49 (s, 2 H) 4.61 (m, 1 H) 7.16 (m, 1 H) 7 , 24 (m, 4 H) 7.33 (s, 1 H) 7.44 (wide s, 1 H) 7.48-7.63 (m, 3 H) 8.24 (d, J = 9, 0 Hz, 1 H) 9.52 (extended m, 2 H)

 LC-MS-DAD-ELSD: Tr (mn) = 3.26; MH + = 597 +; MH- = 595 -; Purity: 98%

6.3: 2- (methylsulfonyl) -6 - ({(1S) -1 - [(5R) -2-oxo-3- {1- [3- (trifluoromethyl) phenyl] cyclopropyl} -1,3-oxazolidin-5 -yl] -2-phenylethyl} carbamoyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylate methyl

At a solution of 900 mg of 6 - ({(1S) -1 - [(5R) -2-oxo-3- {1- [3- (trifluoromethyl) phenyl] cyclopropyl} -1,3-oxazolidin-5- il] -2-phenylethyl} carbamoyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] methyl pyrazine-8-carboxylate, 0.5 cm3 of triethylamine and 30 cm3 of dichloromethane, is added, under an inert atmosphere , drop by drop in 5 min, a solution of 0.132 cm 3 of mesyl chloride in 2 cm 3 of dichloromethane. The reaction mixture is stirred 15 h at a temperature close to 20 ° C, 20 cm3 of water are added and the aqueous phase is brought to pH 2 by the addition of an aqueous solution of hydrochloric acid 1

N. The organic phase is decanted and separated and washed with 20 cm3 of water. It is dried over magnesium sulfate and concentrated to dryness in the rotary evaporator under reduced pressure (5 kPa). The 940 mg of solid obtained is purified by flash chromatography on silica (column: 100 g; particle size: 15-40 µM; flow rate: 30 cm3 / min .; eluent: 50% cyclohexane-50% ethyl acetate). Fractions containing the expected product are concentrated to dryness in the rotary evaporator under reduced pressure (5 kPa). The 713 mg of colorless solid obtained is collected with 30 cm3 of tetrahydrofuran. 3 cm3 of a 4N hydrochloric acid solution in tetrahydrofuran is added and left with stirring at a temperature close to 20 ° C for 1 h. The reaction mixture is concentrated to dryness in the rotary evaporator under reduced pressure (5 kPa). 704 mg of a solid are obtained in the form of a white meringue, which are crushed with 10 cm 3 of diisopropyl ether. The solid is filtered and air dried at a temperature close to 20 ° C. 596 mg of 2- (methylsulfonyl) -6 - ({(1S) -1 - [(5R) -2-oxo-3- {1- [3 (trifluoromethyl) phenyl] cyclopropyl} -1,3-oxazolidin are obtained -5-yl] -2-phenylethyl} carbamoyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylate in the form of a white solid with yellow highlights.

 PF: 104 ° C

 NMR (400 MHz) 1.26-1.55 (m, 4 H) 2.78 (dd, J = 13.7, 10.3 Hz, 1 H) 2.90 (dd, J = 13, 7, 3.9 Hz, 1 H) 3.02 (s, 3 H) 3.50 - 3.62 (m, 3 H) 3.72 (t, J = 8.8 Hz, 1 H) 3, 76 (s, 3 H) 4.18-4.41 (m, 3 H) 4.60 (m, 1 H) 4.63 (s, 2 H) 7.16 (m, 1 H) 7.25 (m, 4 H) 7.29 (s, 1 H) 7.44 (wide s, 1 H) 7.49-7.64 (m, 3 H) 8.20 (d, J = 9.3 Hz , 1 HOUR)

 LC-MS-DAD-ELSD: Tr (mn) = 4.42; (M + H) (+) = 675 (+); MH (-) = 673 (-); Purity: 98%

6.4: 2- (Methylsulfonyl) -6 - ({(1S) -1 - [(5R) -3- {1-methyl-1- [3- (trifluoromethyl) phenylethyl} -2-oxo-1,3- acid) oxazolidin-5-yl] -2-phenylethyl} carbamoyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylic

A mixture of 400 mg of 2- (methylsulfonyl) -6 - ({(1S) -1 - [(5R) -2-oxo-3- {1- [3- (trifluoromethyl) phenyl] cyclopropyl} -1,3oxazolidin -5-yl] -2-phenylethyl} carbamoyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylate of methyl, 10 cm 3 of methanol and 2 cm 3 of an aqueous solution of 1 N sodium hydroxide is heated for 3 h at a temperature close to reflux. The mixture is allowed to return to a temperature close to 20 ° C and the solvents are evaporated in the rotary evaporator under reduced pressure (5 kPa). The evaporation residue is collected with 10 cm3 of water and 10 cm3 of ethyl acetate. The organic phase is separated and the aqueous phase is acidified to pH -43-4 by a 1 N aqueous solution of hydrochloric acid. The aqueous phase is extracted with 10 cm3 of ethyl acetate. The organic phase is separated and washed successively with 10 cm3 of distilled water and 5 cm3 of a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvents are evaporated to dryness in the rotary evaporator under reduced pressure (5 kPa). 330 mg of 2- (methylsulfonyl) -6 - ({(1S) -1 - [(5R) 3- {1-methyl-1- [3- (trifluoromethyl) phenyl] ethyl} -2-oxo- acid are obtained 1,3-oxazolidin-5-yl] -2-phenylethyl} carbamoyl) -1,2,3,4-tetrahydropyrrolo [1,2a] pyrazine-8-carboxylic acid in the form of an orange-yellow solid.

 PF: 147 ° C

 NMR: 1.26 -1.53 (m, 4 H) 2.79 (dd, J = 13.9, 10.3 Hz, 1 H) 2.90 (dd, J = 13.9, 3 , 9 Hz, 1 H) 3.00 (s, 3 H) 3.52 (t, J = 5.6 Hz, 2 H) 3.57 (dd, J = 9.0, 6.1 Hz, 1 H) 3.71 (t, J = 9.0 Hz, 1 H) 4.15-4.40 (m, 3 H) 4.58 (m, 1 H) 4.63 (s, 2 H) 7 , 16 (m, 1 H) 7.21 (s, 1 H) 7.24. (m, 4 H) 7.45 (wide s, 1 H) 7.49-7.64 (m, 3 H) 8.13 (d, J = 8.8 Hz, 1 H) 12.25 (m extended, 1 H)

 LC-MS-DAD-ELSD: Tr (mn) = 4.14; (M + H) (+) = 661 (+); Purity: 98%

6.5: N-8, N-8-diethyl-2- (methylsulfonyl) -N-6 - {(1S) -1 - [(5R) -2-oxo-3- {1- [3- (trifluoromethyl) phenyl ] cyclopropyl} -1,3oxazolidin-5-yl] -2-phenylethyl} -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6,8-dicarboxamide

In a three-mouth flask, 5 cm 3 of dimethylformamide, 0.175 cm 3 of diethylamine and 0.05 cm 3 of diisopropylethylamine are successively introduced. A solution of 116 mg of 1- [bis (dimethylamino) methylene] hexafluorophosphate] -1H-1,2,3-triazolo [4,5-b] pyridinium-3-oxide (HATU) is added dropwise in 10 minutes and 125 mg of 2 (methylsulfonyl) -6 - ({(1S) -1 - [(5R) -3- {1-methyl-1- [3- (trifluoromethyl) phenyl] ethyl} -2-oxo- 1,3-oxazolidin-5-yl] -2-phenylethyl} carbamoyl) 1,2,3,4-tetrahydropyrrolo [1,2a] pyrazine-8-carboxylic acid in 10 cm 3 of dimethylformamide. The reaction mixture is stirred for 48 h at a temperature close to 20 ° C. 10 cm3 of ethyl acetate and 15 cm3 of a 0.1 N aqueous solution of hydrochloric acid are added to the reaction medium. The organic phase is separated and washed successively with 10 cm3 of water and 5 cm3 of a saturated aqueous solution of sodium chloride. Dry over sodium sulfate and concentrate on the rotary evaporator under reduced pressure (5 kPa). The residual solid obtained is purified by flash chromatography on silica (column: 25 g; particle size: 15-40 µM; flow rate: 10 cm3 / min .; eluent: 100% ethyl acetate). Fractions containing the expected product are concentrated to dryness in the rotary evaporator under reduced pressure (5 kPa). 100 mg of a solid are obtained which is collected and triturated with 3 cm 3 of diisopropyl ether which results in 93 mg of N-8, N-8-diethyl-2- (methylsulfonyl) -N-6 - {( 1S) -1 - [(5R) -2-oxo-3- {1- [3 (trifluoromethyl) phenyl] cyclopropyl} -1,3-oxazolidin-5-yl] -2-phenylethyl} -1,2,3 , 4-tetrahydropyrrolo [1,2-a] pyrazine-6,8-dicarboxamide in the form of a white solid with cream-colored reflections.

 PF: 109 ° C

 NMR: 1.16 (t, J = 7.1 Hz, 6 H) 1.28-1.54 (m, 4 H) 2.79 (dd, J = 13.7, 10.3 Hz, 1 H) 2.92 (dd, J = 13.7, 3.9 Hz, 1 H) 2.97 (s, 3 H) 3.36 - 3.62 (m, 7 H) 3.75 (t , J = 8.8 Hz, 1 H) 4.17-4.32 (m, 3 H) 4.46 (m, 2 H) 4.60 (m, 1 H) 6.87 (s, 1 H ) 7.16 (t, J = 7.5 Hz, 1 H) 7.19-7.30 (m, 4 H) 7.48 (wide s, 1 H) 7.50-7.66 (m, 3 H) 8.09 (d, J = 9.3 Hz, 1 H)

 LC-MS-DAD-ELSD: Tr (mn) = 5.08; (M + H) (+) = 716 (+); MH (-) = 714 (-); Purity: 98%

6.6: 6 - {(1S, 2R) -1-benzyl-2-hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropylamino] -propyl} -N-8, N-8-diethyl-2 (methylsulfonyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6,8-dicarboxamide

At a solution of 60 mg of N-8, N-8-diethyl-2- (methylsulfonyl) -N-6 - {(1S) -1 - [(5R) -2-oxo-3- {1- [3 (trifluoromethyl) phenyl] cyclopropyl} -1,3-oxazolidin-5-yl] -2-phenylethyl} -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6,8-dicarboxamide in 2 cm3 of isopropanol and 0.2 cm3 of methanol, 1 cm3 of a 30% aqueous solution of sodium hydroxide is added. The reaction mixture is heated for 2 h at a temperature close to that of reflux. The mixture is allowed to return to a temperature close to 20 ° C and the solvents are evaporated in the rotary evaporator under reduced pressure (5 kPa). The evaporation residue is collected with 5 cm3 of water and 5 cm3 of ethyl acetate. The organic phase is separated and the aqueous phase is acidified to pH -54-5 by a 1 N aqueous solution of hydrochloric acid. The aqueous phase is extracted with 10 cm3 of ethyl acetate. The organic phase is separated and washed successively 2 times with 5 cm 3 of distilled water and dried over magnesium sulfate. The organic phase is concentrated to dryness in the rotary evaporator under reduced pressure (5 kPa). The residual solid obtained (38 mg) is purified by flash chromatography on silica (column: 15 g; particle size: 15-40 µm; flow rate: 10 cm3 / min .; eluent: 100% ethyl acetate). Fractions containing the expected product are concentrated to dryness in the rotary evaporator under reduced pressure (5 kPa). 6 mg of 6 - {(1S, 2R) -1-benzyl-2-hydroxy-3- [1- (3trifluoromethylphenyl) -cyclopropylamino] -propyl} -N-8, N-8-diethyl-2- ( Methylsulfonyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6,8dicarboxamide in the form of a white solid.

• NMR: from 0.89 to 1.06 (m, 4H); 1.14 (t, J = 7.0 Hz, 6H); from 2.42 to 2.77 (m partially masked, 3H); 2.98 (s, 3 H); 3.02 (dd, J = 4.0 and 13.0 Hz, 1H); from 3.23 to 3.59 (m partially masked, 7H); 3.98 (m, 1 H); 4.10 (m, 1 H); 4.23 (m, 1 H); 4.45 (m, 2H); 4.87 (d, J = 5.0 Hz, 1H); 6.80 (s, 1 H); from 7.07 to 7.23 (m, 5H); from 7.42 to 7.58 (m, 3H); 7.64 (broad s, 1H); 7.91 (d, J = 8.5 Hz, 1H).

Example 7:

7.1: Base

6 - [(1S, 2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] -1-oxo-2- (1propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide

7.1.1: 1- (2-Bromoethyl) -1H-ethyl pyrrole-2-carboxylate

5 g of ethyl pyrrole-2-carboxylate, 15.5 cm3 of 1,2-dibromoethane, 21.5 cm3 of soda and 11.58 g of tetrabutylammonium bromide are stirred under an inert atmosphere for 20 h at a temperature close to 20 ° C. 100 cm3 of dichloromethane and 50 cm3 of water are added to the reaction medium. The aqueous phase is extracted 3 times with 20 cm 3 of dichloromethane. The organic phases are combined and washed with 50 cm 3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). The 29.5 g of transparent oil obtained are purified by flash chromatography on silica (column: 400 g; particle size: 15-40 µM; eluent: 100% dichloromethane). After concentrating the fractions under reduced pressure, 6.78 g of ethyl 1- (2-bromoethyl) -1H-pyrrol-2-carboxylate are obtained.

 LC-MS-DAD-ELSD: 246 (+) 79Br = (M + H) (+)

 NMR: 1.27 (t, J = 7.1 Hz, 3 H) 3.74 (t, J = 6.5 Hz, 2 H) 4.21 (q, J = 7.1 Hz, 2 H) 4.65 (t, J = 6.5 Hz, 2 H) 6.13 (dd, J = 3.9, 2.6 Hz, 1 H) 6.88 (dd, J = 3.9, 1.8 Hz, 1 H) 7.20 (dd, J = 2.6, 1.8 Hz, 1 H)

7.1.2: 1- {2 - [(1-propylbutyl) amino] ethyl} -1H-pyrrol-2-carboxylate ethyl

6.76 g of ethyl 1- (2-bromoethyl) -1H-pyrrole-2-carboxylate, 11.08 g of 4-heptylamine, 0.46 g of potassium iodide and 135 cm 3 of acetonitrile are stirred at 70 ° C under inert atmosphere for 20 h. The reaction mixture is brought to 30 ° C to concentrate on the rotary evaporator under reduced pressure (5 kPa). 200 cm3 of dichloromethane and 100 cm3 of water are added to the concentration residue. The phases are stirred 5 min and separated. The aqueous phase is extracted 3 times with 50 cm 3 of dichloromethane. The organic phases are combined, dried over magnesium sulfate and concentrated in the rotary evaporator under reduced pressure (5 kPa). The 10.8 g of brown oil obtained are purified by flash chromatography on silica (column: 450 g; particle size: 20-40 µm spherical; eluent: gradient cyclohexane 70% -ethyl acetate 30% to cyclohexane 50% -acetate 50% ethyl). After concentrating the fractions under reduced pressure, 4.31 g of ethyl 1- [2 - [(1-propylbutyl) amino] ethyl} -1H-pyrrol-2-carboxylate are obtained.

 SM-EI: 280 (+) = M (+)

• NMR: 0.82 (m, 6 H) 0.93-1.32 (m, 11 H) 2.36 (m, 1 H) 2.77 (t, J = 6.6 Hz, 2 H ) 4.19 (q, J = 7.1 Hz, 2 H) 4.29 (t, J = 6.6 Hz, 2 H) 6.07 (dd, J = 4.0, 2.5 Hz, 1 H) 6.83 (dd, J = 4.0, 1.8 Hz, 1 H) 7.12 (dd, J = 2.5, 1.8 Hz, 1 H)

7.1.3: 2- (1-propylbutyl) -3,4-dihydropyrrolo [1,2-a] pyrazin-1 (2H) -one

4.3 g of ethyl 1- {2 - [(1-propylbutyl) amino] ethyl} -1H-pyrrol-2-carboxylate are dissolved under an inert atmosphere, in 130 cm 3 of toluene at a temperature close to 20 ° C. 23 cm3 of toluene solution, 2 M trimethylaluminum, is poured onto the reaction mixture in 5 min. The reaction mixture is heated with stirring for 20 h at 110 ° C and then for 72 h at 20 ° C. It is poured onto an ice-water-ethyl acetate mixture. The suspension obtained is filtered through Celite 545. The aqueous phase is extracted 3 times with 75 cm 3 of ethyl acetate. The organic phases are combined, washed with 50 cm 3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). The 4.7 g of brown oil obtained are purified by flash chromatography on silica (column: 200 g; granulometry: 15-40 µM; eluent: 100% dichloromethane gradient to 80% dichloromethane -20% ethyl acetate). After concentrating the fractions under reduced pressure, 1.56 g of 2- (1-propylbutyl) -3,4-dihydropyrrolo [1,2-a] pyrazin-1 (2H) -one are obtained.

 SM-El: 234 (+) = M (+)

 NMR: 0.86 (t, J = 7.3 Hz, 6 H) 1.12-1.29 (m, 4 H) 1.39 (m, 2 H) 1.47 (m, 2 H ) 3.43 (m, 2 H) 4.10 (m, 2 H) 4.58 (m, 1 H) 6.12 (dd, J = 3.8, 2.5 Hz, 1 H) 6, 59 (dd, J = 3.8, 1.5 Hz, 1 H) 6.94 (dd, J = 2.5, 1.5 Hz, 1 H)

7.1.4: 6-Bromo-2- (1-propylbutyl) -3,4-dihydropyrrolo [1,2-a] pyrazin-1 (2H) -one

1.53 g of 2- (1-propylbutyl-dihydropyrrolo [1,2-a] pyrazin-1 (2 H) -one and 1.16 g of N-bromosuccinimide are dissolved in 153 cm 3 of carbon tetrachloride at a nearby temperature at 20 ° C. Stirring is maintained for 2 h 30. The reaction mixture is concentrated on the rotary evaporator under reduced pressure (5 kPa) The solid residue obtained is purified by flash chromatography on silica (column: 200 g; particle size: 15-40 µM; eluent: gradient 100% dichloromethane to 90% dichloromethane - 10% ethyl acetate) After concentrating the fractions under reduced pressure, 1.54 g of 6-bromo-2- (1-propylbutyl) is obtained -3,4-dihydropyrrolo [1,2-a] pyrazin-1 (2H) -one.

 NMR: 0.86 (t, J = 7.5 Hz, 6H); from 1.10 to 1.29 (m, 4H); from 1.32 to 1.54 (m, 4H); 3.48 (m, 2 H); 4.02 (m, 2H); 4.56 (m, 1 H); 6.30 (d, J = 4.0 Hz, 1H); 6.68 (d, J = 4.0 Hz, 1H).

 SM-EI: M (+). = 312 (+).

7.1.5: 1-Oxo-2- (1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid

In a three-mouth flask stirred and purged with carbon monoxide, 800 mg of 6-bromo-2- (1-propylbutyl) -3,4-dihydropyrrolo [1,2-a] are successively introduced at a temperature close to 20 ° C pyrazin-1 (2H) -one, 27 cm3 of dimethylformamide, 1.3 cm3 of water, 0.953 g of potassium acetate, 85 mg of potassium iodide, 230 mg of palladium acetate and 535 mg of triphenylphosphine. The reaction mixture is bubbled with carbon monoxide and heated at 100 ° C for 6 h. The reaction mixture is maintained at 100 ° C for 20 h and then cooled to 25 ° C to filter on a 45 µm millipore membrane. The filtrate is concentrated in the rotary evaporator under reduced pressure (5 kPa). The oily residue obtained is collected in 15 cm 3 of a water-ice mixture and 20 cm 3 of ethyl acetate. The pH is made alkaline with 5M soda (pH> 10). After decanting the filtrate, the aqueous phase is washed 3 times with 20 cm 3 of ethyl acetate. It is acidified with stirring with a 5M hydrochloric acid solution (pH = 1) and extracted 3 times with 20 cm3 of ethyl acetate. The organic phases are combined, washed with 10 cm 3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). The 1.2 g of orange oil obtained are purified by flash chromatography on silica (column: 90 g; particle size: 15-40 µM; eluent: gradient from 100% dichloromethane to 95% dichloromethane-5% methanol). After concentrating the fractions under reduced pressure, 0.69 g of 1-oxo-2- (1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid are obtained .

 SM-EI: 278 (+) = M (+) 261 (+) = M (+) - OH

 NMR: 86 (t, J = 7.2Hz, 6 H) 1.12-1.57 (m, 8 H) 3.49 (m, 2 H) 4.49 (m, 2 H) 4, 57 (m, 1 H) 6.66 (d, J = 4.0 Hz, 1 H) 6.81 (d, J = 4.0 Hz, 1 H) 12.78 (extended m, 1 H)

 7.1.6: [(1S, 2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] tert carbamate -butyl

To a solution of 0.794 g of 1- (3-trifluoromethyl-phenyl) -cyclopropylamine hydrochloride in 20 cm 3 of water, 4 cm 3 of 1 M soda are added at a temperature close to 20 ° C. This solution is stirred 15 min. 40 cm3 of dichloromethane are added and the mixture is stirred for 5 min. The aqueous phase is extracted with 30 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulfate and concentrated in the rotary evaporator under reduced pressure (5 kPa). 700 mg of 1- (3-trifluoromethyl-phenyl) -cyclopropylamine are obtained which are solubilized in 12 cm 3 of dichloromethane. To the solution is added 1 g of [(1S) -2- (3,5-difluorophenyl) -1-oxyran-2-ylethyl] tertbutyl carbamate and 0.329 g of scandium triflate. The light orange suspension is maintained with stirring at room temperature for 20 h. The reaction mixture is concentrated in the rotary evaporator under reduced pressure (5 kPa). The crude product obtained is purified by flash chromatography on silica (column: 200 g; particle size: 1540 µM; flow rate: 50 cm3 / min; eluent: 70% cyclohexane - 30% ethyl acetate). After concentrating the fractions under reduced pressure, 0.87 g of [(1S, 2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3 - ({1- [3 (trifluoromethyl) phenyl)] is obtained tert-butyl cyclopropyl} amino) propyl] carbamate in the form of a white solid.

 LC-MS-DAD-ELSD: 501 (+) = (M + H) (+); 445 (+) = (M + H) (+) - tBu + H

• NMR: 0.90 - 1.04 (m, 4 H) 1.22 (s, 9 H) 2.40 (m, 1 H) 2.46 - 2.62 (partially masked m, 2 H) 2.99 (dd, J = 14.1, 3.2 Hz, 1 H) 3.36 (m, 1 H) 3.52 (m, 1 H) 4.80 (d, J = 5.9 Hz , 1 H) 6.66 (d, J = 9.3 Hz, 1 H) 6.86 (m, 2 H) 6.99 (tt, J = 9.2, 2.4 Hz, 1 H) 7 , 48 -7.61 (m, 3 H) 7.65 (wide s, 1 H)

7.1.7: (1: 1) hydrochloride of (2R, 3S) -3-amino-4- (3,5-difluorophenyl) -1 - {[(1- [3 (trifluoromethyl) phenyl] cyclopropyl} butan- 2-ol

At a temperature of 20 ° C, 870 mg of [(1S, 2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3 - ({1- [3 (trifluoromethyl) phenyl] cyclopropyl} amino) ) tert-butyl propyl] carbamate in 20 cm 3 of dichloromethane. 17.38 cm3 of a 1M hydrochloric acid solution in ethyl ether is added to the reaction mixture which is maintained with stirring for 20 h at room temperature and concentrated on the rotary evaporator under reduced pressure (5 kPa). 0.82 g of hydrochloride (1: 1) of (2R, 3S) -3-amino-4- (3,5-difluorophenyl) -1 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) butan-2-ol in the form of white solid.

 LC-MS-DAD-ELSD: 401 (+) = (M + H) (+)

 NMR: For this lot, all signals are wide with: 1.13 - 1.37 (m, 2 H) 1.53 - 1.71 (m, 2 H) 2.71 (m, 1 H) 2.84 (dd, J = 14.3, 8.2 Hz, 1 H) 2.93 (dd, J = 14.3, 5.9 Hz, 1 H) 3.09 (m, 1 H) 3 , 57 (m, 1 H) 4.18 (m, 1 H) 6.19 (m, 1 H) 7.01 - 7.10 (m, 3 H) 7.65 (t, J = 7.8 Hz, 1 H) 7.77 (d, J = 7.8 Hz, 1 H) 7.87 (d, J = 7.8 Hz, 1 H) 7.98 (s, 1 H) 8.19 ( s, 3 H) 9.77 (m, 1 H) 10.23 (m, 1 H)

7.1.8: N - [(1S, 2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] -1- oxo-2 (1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide.

In an 80 mg suspension of 1-oxo-2- (1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid, 136 mg of hydrochloride (1: 1 ) of (2R, 3S) -3-amino-4- (3,5-difluorophenyl) -1 - ({1- [3 (trifluoromethyl) phenyl] cyclopropyl} amino) butan-2-ol, 6 mg of hydroxybenzotriazole, 69 mg of 1- (3dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 10 cm 3 of dichloromethane are poured 0.226 cm 3 of N, N-diisopropylethylamine at a temperature close to 20 ° C. The solution is maintained with stirring for 20 h at this temperature. 30 cm3 of dichloromethane and 15 cm3 of water are added to the reaction medium. The organic phase is washed with 10 cm 3 of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). The 310 mg of brown oil obtained are purified by flash chromatography on silica (column: 35 g; particle size: 20-40 µm spherical; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 116 mg of N - [(1S, 2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3 - ({1- [3 (trifluoromethyl) phenyl]) are obtained cyclopropyl} amino) propyl] -1-oxo-2- (1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide.

 LC-MS-DAD-ELSD: 661 (+) = (M + H) (+)

 NMR: 0.86 (t, J = 7.1 Hz, 3 H) 0.87 (t, J = 7.1 Hz, 3 H) 0.92 -1.54 (m, 12 H) 2 , 44 -2.72 (m partially masked, 3 H) 2.76 (dd, J = 13.9, 10.6 Hz, 1 H) 3.06 (dd, J = 13.9, 3.4 Hz , 1 H) 3.30 -3.42 (masked m, 2 H) 3.55 (m, 1 H) 4.08 (m, 1 H) 4.26 (m, 1 H) 4.35 (m , 1 H) 4.56 (m, 1 H) 4.98 (d, J = 6.0 Hz, 1 H) 6.62 (d, J = 4.1 Hz; 1 H) 6.77 (d , J = 4.1 Hz, 1 H) 6.94 (m, 2 H) 6.99 (tt, J = 9.2, 2.0 Hz, 1 H) 7.43-7.51 (m, 2 H) 7.55 (wide d, J = 7.6 Hz, 1 H) 7.66 (wide s, 1 H) 8.06 (d, J = 9.0 Hz, 1 H)

7.2: Hydrochloride (1: 1) salt of N - [(1S, 2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3 - ({1- [3 (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] -1-oxo-2- (1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6carboxamide

At a temperature close to 20 ° C, 112 mg of N - [(1S, 2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3 - ({1- [3 (trifluoromethyl) phenyl)] are dissolved cyclopropyl} amino) propyl] -1-oxo-2- (1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide in 1.5 cm 3 of ethyl ether. 0.43 cm3 of a 2M hydrochloric acid solution in ethyl ether is added while stirring under argon, at a temperature of 5 ° C. The reaction mixture precipitates. Stirring is maintained for 20 min and stops to remove the supernatant. 3 cm3 of ethyl ether is added again and removed. This operation is performed twice. The last suspension is concentrated under reduced pressure (5 kPa). 117 mg of hydrochloride (1: 1) of N - [(1 S, 2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl) are obtained } amino) propyl] -1oxo-2- (1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide as a white solid.

 PF: 183 ° C.

 NMR: 0.85 (t, J = 7.5 Hz, 3H); 0.87 (t, J = 7.5 Hz, 3H); from 1.12 to 1.65 (m, 12H); 2.72 (m, 1 H); 2.79 (m, 1 H); 2.98 (m, 1 H); 3.08 (dd, J = 3.0 and 14.0 Hz, 1H); 3.40 (partially masked m, 2H); 3.84 (m, 1 H); 3.98 (m, 1 H); 4.20 (m, 1 H); 4.35 (m, 1 H); 4.56 (m, 1 H); 5.83 (broad m, 1H); 6.62 (d, J = 4.0 Hz, 1H); 6.74 (d, J = 4.0 Hz, 1H); from 6.90 to 7.02 (m, 3H); 7.59 (t, J = 7.5 Hz, 1H); 7.71 (d, J = 7.5 Hz, 1H): 7.88 (d, J = 7.5 Hz, 1H); 7.97 (s, 1 H); 8.16 (d, J = 9.0 Hz, 1H); 9.35 (extended m, 1H); 9.62 (extended m, 1H).

 LC-MS-DAD-ELSD: 659 (-) = (M-H) (-); 661 (+) = (M + H) (+)

Example 8:

8.1: Base

N - [(1S, 2R) -1-Benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] -1-oxo-2- (1-propylbutyl) 1 , 2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide.

In a 50 mg suspension of 1-oxo-2- (1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid, 85 mg of (2R, hydrochloride) 3S) -3-amino-4-phenyl-1 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) butan-2-ol, 3.6 mg hydroxybenzotriazole, 43 mg hydrochloride 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide in 8 cm3 of dichloromethane is poured 0.185 cm3 of N, N-diisopropylethylamine at a temperature close to 20 ° C. The solution obtained is maintained with stirring for 20 h. 20 cm3 of dichloromethane and 10 cm3 of water are added to the reaction medium. The organic phase is washed with 10 cm 3 of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). The 170 mg of brown oil obtained are purified by flash chromatography on silica (column: 15 g; particle size: 20-40 µm spherical; eluent: gradient from 100% dichloromethane to 95% dichloromethane-5% methanol). After concentrating the fractions under reduced pressure, 90 mg of N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3 (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] - are obtained 1-oxo-2- (1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide.

 LC-MS-DAD-ELSD: 623 (-) = (M-H) (-); 669 (-) = (M + formic acid - H) (-) 625 (+) = (M + H) (+)

 NMR: 0.84 (t, J = 7.3 Hz, 3 H) 0.86 (t, J = 7.3 Hz, 3 H) 0.90 -1.54 (m, 12 H) 2 , 45 -2.60 (partially masked m, 2 H) 2.71 (dd, J = 13.9, 10.5 Hz, 1 H) 3.04 (dd, J = 13.9, 3.6 Hz , 1 H) 3.17 -3.47 (m partially masked, 3 H) 3.54 (m, 1 H) 4.03 (m, 1 H) 4.23 (m, 1 H) 4.33 ( m, 1 H) 4.54 (m, 1 H) 4.86 (d, J = 6.1 Hz, 1 H) 6.59 (d, J = 4.1 Hz, 1 H) 6.73 ( d, J = 4.1 Hz, 1 H) 7.12 (m, 1 H) 7.21 (m, 4 H) 7.42-7.59 (m, 3 H) 7.64 (wide s, 1 H) 8.01 (d, J = 9.0 Hz, 1 H).

8.2: Get out

N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] -1oxo-2- ((1: 2) hydrochloride 1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide

At a temperature close to 20 ° C, 85 mg of N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3 (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] is dissolved. -1-oxo-2- (1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6carboxamide in 1 cm3 of ethyl ether. 0.4 cm3 of a 2M hydrochloric acid solution in ethyl ether is added while stirring under argon, at a temperature of 5 ° C. The reaction mixture precipitates. Stirring is maintained for 15 min and stops to remove the supernatant. 3 cm3 of ethyl ether is added again and removed. This operation is performed 3 times. The last suspension is concentrated under reduced pressure (5 kPa). 87 mg of N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] - hydrochloride (1: 1) are obtained. 1-oxo-2- (1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2a] pyrazine-6-carboxamide as a white solid.

 PF: 176 ° C.

 NMR: 0.84 (t, J = 7.5 Hz, 3H); 0.87 (t, J = 7.5 Hz, 3H); from 1.11 to 1.62 (m, 12H); 2.74 (m, 2 H); 2.95 (m, 1 H); 3.09 (dd, J = 3.0 and 14.0 Hz, 1H); 3.38 (partially masked m, 2H); 3.83 (m, 1 H); 3.94 (m, 1 H); 4.17 (m, 1 H); 4.34 (m, 1 H); 4.55 (m, 1 H); 5.82 (very broad m, 1 H); 6.61 (d, J = 4.0 Hz, 1H); 6.72 (d, J = 4.0 Hz, 1H); 7.11 (m, 1 H); 7.20 (m, 4 H); 7.58 (t, J = 7.5 Hz, 1H); 7.71 (d, J = 7.5 Hz, 1H); 7.87 (d, J = 7.5 Hz, 1H); 7.96 (s, 1 H); 8.14 (d, J = 9.0 Hz, 1H); 9.33 (extended m, 1H); 9.61 (extended m, 1H).

 LC-MS-DAD-ELSD: 623 (-) = (M-H) (-); 625 (+) = (M + H) (+)

Example 9:

9.1: Base

N - [(1S, 2R) -1-Benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- (1-propylbutyl) -1,2,3 , 4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide.

9.1.1: [(1S, 2R) -1-Benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] tert-butyl carbamate

In a suspension under argon of 10 g of [S- (R, R)] - (-) - (1-oxyranyl-2-phenylethyl) carbamate of tert-butyl in 100 cm3 of 2-propanol is poured in 20 min 6.5 cm3 solution of 3- (trifluoromethyl) benzylamine in 20 cm3 of 2-propanol at a temperature close to 20 ° C. The reaction mixture is heated at a temperature of 65 ° C for 20 h. It is cooled to concentrate it in the rotary evaporator under reduced pressure (5 kPa). The 20 g of colorless oil obtained are purified by flash chromatography on silica (column: 400 g; particle size: 15-40 µM; flow rate: 20 cm3 / min; eluent: gradient from 100% dichloromethane to 95% dichloromethane-5% methanol in 140 min) After concentrating the fractions under reduced pressure, 11 g of tert-butyl [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3 (trifluoromethyl) benzyl] amino} propyl] carbamate are obtained of a white solid.

 LC-MS-DAD-ELSD: 439 (+) = (M + H) (+); 483 (-) M + Formic acid - H) (-)

 NMR: For this batch all signals are wide with: 1.22 (s, 9 H) 2.25 (m, 1 H) 2.38 -2.65 (partially masked m, 3 H) 2.99 (m, 1 H) 3.51-3.65 (m, 2 H) 3.80 (m, 2 H) 4.83 (d, J = 6.3 Hz, 1 H) 6.61 (d, J = 9.1 Hz, 1 H) 6.99-7.30 (m, 5 H) 7.48-7.80 (m, 4 H).

9.1.2: Hydrochloride (1: 1) of (2R, 3S) -3-amino-4-phenyl-1 - {[3- (trifluoromethyl) benzyl] amino} butan-2-ol

11.2 g of tert-butyl [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] carbamate are dissolved in 111 cm 3 of dichloromethane at a temperature close to 20 ° C. 63 cm3 of a 4M hydrochloric acid solution in dioxane is added at a temperature of 0 ° C. The reaction mixture precipitates. It is kept under stirring for 2 hours at 20 ° C. The precipitate is filtered, washed 4 times with 30 cm 3 of dichloromethane and 3 times 30 cm 3 of diisopropyl ether. The white solid obtained is dried in a desiccator for 2 days. 10.5 g of (2R, 3S) -3-amino-4-phenyl-1 - {[3- (trifluoromethyl) benzyl] amino} butan-2-ol hydrochloride are obtained.

 LC-MS-DAD-ELSD: 339 (+) = (M + H) (+)

• NMR: 2.79 -2.96 (m, 3 H) 3.13 (m, 1 H) 3.46-3.59 (partially masked m, 1 H) 4.16-4.30 (m , 3 H) 6.30 (m wide, 1 H) 7.21-7.36 (m, 5 H) 7.67 (t, J = 7.8 Hz, 1 H) 7.79 (d, J = 7.8 Hz, 1 H) 7.87 (d, J = 7.8 Hz, 1 H) 8.00 (s, 1 H) 8.21 (wide s, 3 H) 9.41 (wide m , 1 H) 9.72 (m wide, 1 H).

9.1.3: (2R, 3S) -3-amino-4-phenyl-1 - {[3- (trifluoromethyl) benzyl] amino} butan-2-ol

To a solution of 0.6 g of hydrochloride (1: 1) of (2R, 3S) -3-amino-4-phenyl-1 - {[3- (trifluoromethyl) benzyl] amino} butan-2-ol in 30 10 cm3 of dichloromethane are added 10 cm3 of water and 2.9 cm3 of 1 M soda at a temperature close to 20 ° C. The reaction mixture is maintained 1 hour with stirring. The organic phase is dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure (5 kPa). 360 mg of (2R, 3S) -3-amino-4-phenyl-1 - {[3 (trifluoromethyl) benzyl] amino} butan-2-ol are obtained in the form of a colorless oil that crystallizes.

• NMR: 1.67 (wide m, 3 H) 2.35 (dd, J = 12.5, 8.1 Hz, 1 H) 2.56 (dd, J = 11.9, 7.4 Hz , 1 H) 2.68 (dd, J = 12.0, 3.7 Hz, 1 H) 2.76-2.89 (m, 2 H) 3.38 (m partially masked, 1 H) 3, 80 (s, 2 H) 4.65 (wide s, 1 H) 7.11-7.22 (m, 3 H) 7.24-7.30 (m, 2 H) 7.52-7.61 (m, 2 H) 7.64 (broad d, J = 7.6 Hz, 1 H) 7.70 (wide s, 1 H)

 LC-MS-DAD-ELSD: Tr (mn) = 2.23; MH (+) = 339 (+); Purity: 95%

9.1.4: N - [(1S, 2R) -1-Benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- (1-propylbutyl) -1 , 2,3,4 tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide.

In a 230 mg suspension of 1-oxo-2- (1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid, 340 mg of (2R, hydrochloride) 3S) -3-amino-4-phenyl-1 - {[3- (trifluoromethyl) benzyl] amino} butan-2-ol, 17 mg of hydroxybenzotriazole, 198 mg of 1- (3-dimethylaminopropyl) hydrochloride -3- Ethylcarbodiimide in 23 cm3 of dichloromethane is poured 0.566 cm3 of N, N-diisopropylethylamine. The solution is maintained with stirring 24 h at 20 ° C. 15 cm3 of water are added to the reaction medium. The aqueous phase is extracted with 15 cm3 of dichloromethane. The organic phases are combined, washed with 10 cm 3 of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). The 840 mg of product obtained are purified by flash chromatography on silica (column: 35 g; granulometry: 20-40 µm spherical; eluent: gradient from 100% dichloromethane to 95% dichloromethane-5% methanol). After concentrating the fractions under reduced pressure, 237 mg of N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3 (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2 is obtained - (1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide in the form of a meringue.

 LC-MS-DAD-ELSD: 599 (+) = (M + H) (+)

 NMR: 0.84 (t, J = 7.3 Hz, 3 H) 0.85 (t, J = 7.3 Hz, 3 H) 1.10-1.28 (m, 4 H) 1 , 36 (m, 2 H) 1.46 (m, 2 H) 2.55 (m partially masked, 1 H) 2.65 (m, 1 H) 2.74 (dd, J = 13.8, 10 , 7 Hz, 1 H) 3.05 (dd, J = 13.7, 3.8 Hz, 1 H) 3.37 (t, J = 5.9 Hz, 2 H) 3.62 (m wide, 1 H) 3.80 (s, 2 H) 4.06 (m, 1 H) 4.21-4.39 (m, 2 H) 4.54 (m, 1 H) 4.97 (broad d, J = 5.0 Hz, 1 H) 6.58 (d, J = 4.0 Hz, 1 H) 6.72 (d, J = 4.0 Hz, 1 H) 7.12 (m, 1 H ) 7.21 (m, 4 H) 7.50 (t, J = 7.5 Hz, 1 H) 7.55 (d, J = 7.5 Hz, 1 H) 7.62 (d, J = 7.5 Hz, 1 H) 7.68 (s, 1 H) 8.10 (d, J = 9.0 Hz, 1 H).

9.2: Get out

N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- (1-propylbutyl) hydrochloride (1: 1) 1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide

At a temperature close to 20 ° C, 230 mg of N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3 (trifluoromethyl) benzyl] amino} propyl] -1-oxo- 2- (1-Propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide in 3 cm 3 of ethyl ether. 0.7 cm3 of a 4M hydrochloric acid solution in dioxane is added under stirring under argon at a temperature of 5 ° C. The reaction mixture precipitates. Stirring is maintained for 10 min and stops to remove the supernatant. 5 cm3 of ethyl ether are added again. This operation is performed 3 times. The last suspension is concentrated under reduced pressure (5 kPa). 218 mg of hydrochloride (1: 1) of N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- ( 1-propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6carboxamide as a beige solid.

 PF: 168 ° C.

 NMR: 0.84 (t, J = 7.5 Hz, 3H); 0.86 (t, J = 7.5 Hz, 3H); from 1.10 to 1.58 (m, 8H); 2.80 (dd, J = 11.0 and 14.0 Hz, 1H); 2.86 (m, 1 H); 3.09 (m, 1 H); 3.15 (dd, J = 3.5 and 14.0 Hz, 1H); 3.40 (partially masked m, 2H); 3.88 (m, 1 H); 4.00 (m, 1 H); from 4.22 to 4.42 (m, 4H); 4.55 (m, 1 H); 5.90 (extended m, 1H); 6.62 (d, J = 4.0 Hz, 1H); 6.82 (d, J = 4.0 Hz, 1H); 7.13 (m, 1 H); 7.23 (m, 4H); 7.65 (t, J = 7.5 Hz, 1H); 7.76 (d, J = 7.5 Hz, 1H); 7.86 (d, J = 7.5 Hz, 1H); 7.97 (s, 1 H); 8.22 (d, J = 9.0 Hz, 1H); 8.99 (extended m, 1H); 9.38 (extended m, 1H).

 LC-MS-DAD-ELSD: 597 (-) = (M-H) (-), 599 (+) = (M + H) (+)

Example 10:

10.1: Base

N - [(1S, 2R) -1-Benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -2- (1-ethylpropyl) -1-oxo-1,2,3 , 4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide.

10.1.1: 1- {2 - [(1-ethylpropyl) amino] ethyl} -1H-ethyl pyrrole-2-carboxylate

3.15 g of ethyl 1- (2-bromoethyl) -1H-pyrrol-2-carboxylate, 6 cm 3 of 3-pentylamine, 212 mg of potassium iodide and 63 cm 3 of acetonitrile are stirred at a temperature close to 20 ° C under an inert atmosphere for 72 h. The mixture is heated 7 h at 70 ° C and stirred 48 h at a temperature close to 20 ° C. The reaction mixture is concentrated in the rotary evaporator under reduced pressure (5 kPa). 80 cm3 of dichloromethane and 50 cm3 of water are added to the concentration residue. The phases are stirred 10 min and separated. The aqueous phase is extracted twice with 50 cm3 of dichloromethane. The organic phases are combined, washed with 40 cm 3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). The 2.85 g of the product obtained are purified by flash chromatography on silica (column: 200 g; granulometry: 15-40 µM; eluent: 50% cyclohexane-50% ethyl acetate). After concentrating the fractions under reduced pressure, 1.66 g of ethyl 1- [2 - [(1-ethylpropyl) amino] ethyl] -1H-pyrrol-2-carboxylate are obtained.

 NMR: 0.76 (t, J = 7.5 Hz, 6H); 1.26 (t, J = 7.5 Hz, 3H); 1.27 (partially masked m, 4H); 1.64 (m, 1 H); 2.25 (m, 1 H); 2.77 (t, J = 6.5 Hz, 2H); 4.19 (q, J = 7.5 Hz, 2H); 4.30 (t, J = 6.5 Hz, 2H); 6.08 (dd, J = 2.5 and 4.0 Hz, 1H); 6.83 (dd, J = 2.0 and 4.0 Hz, 1H); 7.13 (t, J = 2.5 Hz, 1H).

 SM-EI: M (+). = 252 (+) .; CI: (M + H) (+) = 253 (+)

10.1.2: 2- (1-Ethylpropyl) -3,4-dihydropyrrolo [1,2-a] pyrazin-1 (2H) -one

At a temperature close to 20 ° C, 1.6 g of ethyl 1- {2 - [(1-ethylpropyl) amino] ethyl} -1H-pyrrol-2-carboxylate are dissolved, under an inert atmosphere, in 60 cm3 of Toluene. 6.35 cm3 of toluene solution, 2M trimethylaluminum, is poured onto the reaction mixture in 5 min. The reaction mixture is heated under stirring for 18 h at 100 ° C and then cooled to 20 ° C. It is poured onto an ice-water-ethyl acetate mixture. The aqueous phase is extracted 3 times with 40 cm3 of ethyl acetate. The organic phases are combined, washed with 40 cm 3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). The crude product obtained (1.55 g) is purified by flash chromatography on silica (column: 70 g; granulometry: 15-40 µM; eluent: 50% cyclohexane-50% ethyl acetate). After concentrating the fractions under reduced pressure, 0.43 g of 2- (1-ethylpropyl) -3,4-dihydropyrrolo [1,2-a] pyrazin-1 (2H) -one is obtained.

 SM-El: 206 (+) = M (+)

 NMR: 0.94 (t, J = 7.5 Hz, 6 H) 1.39 - 1.56 (m, 4 H) 3.43 (m, 2 H) 4.12 (m, 2 H ) 4.36 (m, 1 H) 6.13 (dd, J = 3.8, 2.5 Hz, 1 H) 6.60 (dd, J = 3.8, 1.5 Hz, 1 H) 6.95 (dd, J = 2.5, 1.5 Hz, 1 H).

10.1.3: 6-Bromo-2- (1-ethylpropyl) -3,4-dihydropyrrolo [1,2-a] pyrazin-1 (2H) -one

At a temperature close to 20 ° C, 0.42 g of 2- (1-ethylpropyl) -3,4-dihydropyrrolo [1,2-a] pyrazin-1 (2H) -one is dissolved in 42 cm3 of tetrachloride of carbon. 363 mg of N-bromosuccinimide are added to the solution. Stirring is maintained 18 h at room temperature. The reaction mixture is concentrated in the rotary evaporator under reduced pressure (5 kPa). The solid residue obtained is purified by flash chromatography on silica (column: 90 g; granulometry: 15-40 µM; eluent: 90% dichloromethane - 10% ethyl acetate). After concentrating the fractions under reduced pressure, 0.5 g of 6-bromo-2- (1-ethylpropyl) -3,4-dihydropyrrolo [1,2-a] pyrazin-1 (2H) -one are obtained.

 SM-El: 284 (+) 79Br = M (+)

 NMR: 0.79 (t, J = 7.3 Hz, 6 H) 1.38 - 1.57 (m, 4 H) 3.49 (m, 2 H) 4.04 (m, 2 H ) 4.33 (m, 1 H) 6.31 (d, J = 3.9 Hz, 1 H) 6.69 (d, J = 3.9 Hz, 1 H)

10.1.4: 2- (1-ethylpropyl) -1-oxo-1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid

In a three-mouth flask stirred and purged with carbon monoxide, 490 mg of 6-bromo-2- (1-ethylpropyl) -3,4-dihydropyrrolo [1,2-a] are introduced successively at a temperature close to 20 ° C pyrazin-1 (2H) -one, 15 cm3 of dimethylformamide, 0.75 cm3 of water, 0.641 g of potassium acetate, 285 mg of potassium iodide, 39 mg of palladium acetate and 91 mg of triphenylphosphine. The reaction mixture is subjected to a carbon monoxide bubble and heated at 100 ° C for 6 h 30. The reaction mixture is cooled to 20 ° C and stirred for 20 h. The dimethylformamide is evaporated in the rotary evaporator under reduced pressure (5 kPa). The oily residue obtained is collected in 80 g of ice and 80 cm3 of ethyl acetate. The pH is made alkaline with 15 cm 3 of 1 M soda. After decanting, the aqueous phase is washed twice with 40 cm 3 of ethyl acetate. It is acidified with stirring with a solution of 5 M hydrochloric acid (pH = 1) and extracted 3 times with 40 cm 3 of ethyl acetate. The organic phases are combined, washed with 30 cm 3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). 0.31 g of 2 (1-ethylpropyl) -1-oxo-1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid are obtained.

 SM-El: 250 (+) = M (+)

 NMR: 0.80 (t, J = 7.4 Hz, 6 H) 1.35 - 1.60 (m, 4 H) 3.49 (m, 2 H) 4.35 (m, 1 H ) 4.51 (m, 2 H) 6.67 (d, J = 4.1 Hz, 1 H) 6.82 (d, J = 4.1 Hz, 1 H) 12.55 (extended m, 1 H)

10.1.5: N - [(1S, 2R) -1-Benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -2- (1-ethylpropyl) -1-oxo-1 , 2,3,4 tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide.

In a 150 mg suspension of 2- (1-ethylpropyl) -1-oxo-1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid, 247 mg of (2R, hydrochloride) 3S) -3-amino-4-phenyl-1 - {[3- (trifluoromethyl) benzyl] amino} butan-2-ol, 12.2 mg of hydroxybenzotriazole, 144 mg of 1- (3-dimethylaminopropyl) hydrochloride 3 -ethylcarbodiimide in 15 cm3 of dichloromethane, 0.410 cm3 of N, N-diisopropylethylamine is poured at a temperature close to 20 ° C. The solution is maintained with stirring 72 h. 30 cm3 of dichloromethane and 15 cm3 of water are added to the reaction medium. The aqueous phase is extracted with 15 cm3 of dichloromethane. The organic phases are combined, washed with 10 cm 3 of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). The 520 mg of product obtained are purified by flash chromatography on silica (column: 70 g; granulometry: 20-40 µm spherical; eluent: dichloromethane 95% -methanol 5% and then dichloromethane 90% -methanol 10%). After concentrating the fractions under reduced pressure, 163 mg of N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -2- ( 1-ethylpropyl) -1-oxo-1,2,3,4 tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide.

 LC-MS-DAD-ELSD: 571 (+) = (M + H) (+)

 NMR: 0.77 (wide t, J = 7.3 Hz, 6 H) 1.37 -1.56 (m, 4 H) 2.52 - 2.80 (m, 3 H) 3.05 (dd, J = 13.9, 3.6 Hz, 1 H) 3.37 (t, J = 6.0 Hz, 2 H) 3.62 (wide m, 1 H) 3.80 (s, 2 H) 4.07 (m, 1 H) 4.22 - 4.44 (m, 3 H) 4.96 (broad d, J = 4.8 Hz, 1 H) 6.58 (d, J = 4 , 1 Hz, 1 H) 6.72 (d, J = 4.1 Hz, 1 H) 7.12 (m, 1 H) 7.21 (m, 4 H) 7.45-7.58 (m , 2 H) 7.62 (d wide, J = 7.6 Hz, 1 H) 7.69 (wide s, 1 H) 8.09 (d, J = 8.7 Hz, 1 H)

10.2: Get out

N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -2- (1-ethylpropyl) -1oxo- hydrochloride (1: 1) 1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide

At a temperature close to 20 ° C, 155 mg of N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3 (trifluoromethyl) benzyl] amino} propyl] -2- (1) -ethylpropyl) -1-oxo-1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide in 1.5 cm 3 of ethyl ether. 0.5 cm3 of a 4M hydrochloric acid solution in dioxane is added under stirring under argon, at a temperature of 5 ° C. The reaction mixture precipitates. 5 cm3 of ethyl ether are added. Stirring is maintained for 10 min and stops to remove the supernatant. 2 cm3 of ethyl ether are added again and removed. This operation is performed 3 times. The last suspension is concentrated under reduced pressure (5 kPa). 162 mg of N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -2- (1-) hydrochloride are obtained ethylpropyl) -1oxo-1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide as a white solid.

 PF: 178 ° C.

 NMR: 0.77 (t, J = 7.5 Hz, 3H); 0.78 (t, J = 7.5 Hz, 3H); 1.47 (m, 4 H); 2.79 (dd, J = 11.0 and 14.0 Hz, 1H); 2.86 (m, 1 H); 3.10 (m, 1 H); 3.15 (dd, J = 3.0 and 14.0 Hz, 1H); 3.41 (partially masked m, 2H); 3.88 (m, 1 H); 4.01 (m, 1 H); from 4.22 to 4.44 (m, 5H); 5.90 (very widespread, 1H); 6.63 (d, J = 4.0 Hz, 1H); 6.82 (d, J = 4.0 Hz, 1H); 7.14 (m, 1 H); 7.23 (m, 4H); 7.65 (t, J = 7.5 Hz, 1H); 7.76 (d, J = 7.5 Hz, 1H); 7.85 (d, J = 7.5 Hz, 1H); 7.97 (s, 1 H); 8.21 (d, J = 9.0 Hz, 1H); 8.97 (extended m, 1 H); 9.33 (extended m, 1 H).

 LC-MS-DAD-ELSD: 569 (-) = (M-H) (-); 615 (-) = (M + Formic acid – H) (-) 571 (+) = (M + H) (+)

Example 11:

11.1: Base N - [(1S, 2R) -1-Benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- (1-propylbutyl) 2,3 , 4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepino-7-carboxamide

11.1.1: 1- (3-bromopropyl) -1H-ethyl pyrrole-2-carboxylate

5.15 g of ethyl pyrrole-2-carboxylate, 18 cm 3 of 1,3-dibromopropane, 22 cm 3 of concentrated soda and 11.93 g of tetrabutylammonium bromide are stirred under an inert atmosphere for 48 h at a temperature close to 20 ° C. 80 cm3 of dichloromethane and 80 cm3 of water are added to the reaction medium. The aqueous phase is extracted 3 times with 40 cm 3 of dichloromethane. The organic phases are combined, washed with 50 cm 3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). The 50 g of oil obtained are purified by flash chromatography on silica (column: 400 g; granulometry: 15-40 µM; eluent: 100% dichloromethane). After concentrating the fractions under reduced pressure, 9.8 g of ethyl 1- (3-bromopropyl) -1H-pyrrole-2-carboxylate are obtained.

 SM-EI: 259 (+) 79Br = M (+)

 1 H NMR (400 MHz, DMSO-d6) d ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.22 (m, 2 H) 3.40 (t, J = 6.7 Hz, 2 H) 4.21 (q, J = 7.1 Hz, 2 H) 4.38 (t, J = 6.7 Hz, 2 H) 6.12 (dd, J = 3.9, 2 , 5 Hz, 1 H) 6.87 (dd, J = 3.9, 2.0 Hz, 1 H) 7.14 (dd, J = 2.5, 2.0 Hz, 1 H).

11.1.2: 1- {3 - [(1-propylbutyl) amino] propyl} -1H-ethyl pyrrole-2-carboxylate

7 g of ethyl 1- (3-bromopropyl) -1H-pyrrole-2-carboxylate, 9.3 g of 4-aminoheptane, 4.46 g of potassium iodide and 140 cm 3 of acetonitrile are stirred under an inert atmosphere for 20 at 70 ° C and cooled to a temperature close to 20 ° C. The reaction mixture is concentrated in the rotary evaporator under reduced pressure (5 kPa). 100 cm3 of dichloromethane and 100 cm3 of water are added to the concentration residue. The aqueous phase is extracted 3 times with 50 cm 3 of dichloromethane. The organic phases are combined, washed with 40 cm 3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). The product obtained is purified by flash chromatography on silica (column: 400 g; particle size: 1540 µM; eluent: gradient heptane 75% -ethyl acetate 25% to 100% ethyl acetate). After concentrating the fractions under reduced pressure, 5.87 g of ethyl 1- {3 - [(1-propylbutyl) amino] propyl} -1H-pyrrol-2-carboxylate are obtained.

 SM-EI: 294 (+) = M (+) 251 (+) = M (+) - C3H7

 1 H NMR (300 MHz, DMSO-d6) d ppm 0.85 (t, J = 6.9 Hz, 6 H) 1.13 - 1.35 (m, 11 H) 1.76 (m, 2 H) 2.28 -2.44 (m, 3 H) 4.19 (q, J = 7.1 Hz, 2 H) 4.32 (t, J = 6.9 Hz, 2 H) 6.08 (dd, J = 2.5, 1.8 Hz, 1 H) 6.83 (dd, J = 3.9.1.8 Hz, 1 H) 7.10 (dd, J = 2.5, 1 , 9 Hz, 1 H)

11.1.3: 2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepin-1-one

At a temperature close to 20 ° C, 5.85 g of ethyl 1- {3 - [(1-propylbutyl) amino] propyl} -1H-pyrrol-2-carboxylate are dissolved under an inert atmosphere, in 150 cm3 of toluene . 29.8 cm3 of toluene solution, 2M of trimethylaluminum are poured onto the reaction mixture in 5 min. The reaction mixture is heated with stirring for 20 h at 100 ° C and cooled to a temperature close to 20 ° C. It is poured onto 200 g of ice and 100 cm3 of ethyl acetate. The suspension obtained is filtered through Celite 545. The aqueous phase is extracted 3 times with 40 cm 3 of ethyl acetate. The organic phases are combined, washed with 40 cm3 of water, 40 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). The 4.71 g of crude product obtained is purified by flash chromatography on silica (column: 200 g; granulometry: 15-40 µM; eluent: gradient from 100% dichloromethane to 80% dichloromethane - 20% ethyl acetate). After concentrating the fractions under reduced pressure, 2.97 g of 2- (1-propyl-butyl) -2,3,4,5-tetrahydro-pyrrolo [1,2-a] [1,4] diazepin-1 are obtained -one.

 SM-EI: 248 (+) = M (+) 249 (+) = (M + H) (+)

 1 H NMR (300 MHz, DMSO-d6) d ppm 0.88 (t, J = 7.3 Hz, 6 H) 1.13 - 1.34 (m, 4 H) 1.35 - 1.58 (m, 4 H) 1.98 (m, 2 H) 3.13 (t, J = 6.7 Hz, 2 H) 4.11 (t, J = 6.7 Hz, 2 H) 4.46 (m, 1 H) 6.02 (m, 1 H) 6.48 (m, 1 H) 6.88 (wide s, 1 H).

11.1.4: 7-Bromo-2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepin-1-one

At a temperature close to 20 ° C, 1.5 g of 2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2a] [1,4] diazepin-1 are dissolved -one in 120 cm3 of carbon tetrachloride. 1,075 g of N-bromosuccinimide are added to the solution. Stirring is maintained 3 h. The reaction mixture is concentrated in the rotary evaporator under reduced pressure (5 kPa). The solid residue obtained is purified by flash chromatography on silica (column: 200 g; granulometry: 15-40 µM; eluent: dichloromethane 90% -ethyl acetate 10%). After concentrating the fractions under reduced pressure, 1.92 g of 7-bromo-2- (1-propylbutyl) -2,3,4,5-tetrahydro-1 H -pyrrolo [1,2a] [1,4 ] diazepin-1-one.

 SM-EI: 326 (+) 79Br = M (+)

 1 H NMR (300 MHz, DMSO-d6) d ppm 0.88 (t, J = 7.2 Hz, 6 H) 1.12 - 1.33 (m, 4 H) 1.35 - 1.56 (m, 4 H) 1.97 (m, 2 H) 3.12 (t, J = 6.7 Hz, 2 H) 4.11 (t, J = 6.7 Hz, 2 H) 4.45 (m, 1 H) 6.23 (d, J = 3.9 Hz, 1 H) 6.56 (d, J = 3.9 Hz, 1 H).

11.1.5: 1-Oxo-2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepino-7-carboxylic acid

In a three-mouth flask stirred and purged with carbon monoxide, 1 g of 7-bromo-2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H- is introduced successively at a temperature close to 20 ° C pyrrolo [1,2-a] [1,4] diazepin-1-one, 25 cm3 of dimethylformamide, 2.5 cm3 of water, 1.14 g of potassium acetate, 102 mg of potassium iodide, 275 mg of palladium acetate and 640 mg of triphenylphosphine. The reaction mixture is subjected to a carbon monoxide bubble and heated at 100 ° C for 7 h. It is cooled to 20 ° C to filter through Celita 545. The filtrate is evaporated in the rotary evaporator under reduced pressure (5 kPa). The oily residue obtained is collected in 40 g of ice and 40 cm3 of ethyl acetate. The pH is brought to 10 with 5M soda. After decanting, the aqueous phase is washed 3 times with 40 cm3 of ethyl acetate and filtered through Celite 545. The filtrate is acidified with stirring with a solution of hydrochloric acid. M (pH = 1) and extracted 3 times with 40 cm3 of ethyl acetate. The organic phases are combined, washed with 30 cm 3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). The crude product obtained (1 g) is purified by flash chromatography on silica (column: 90 g; particle size: 15-40 µM; eluent: 95% dichloromethane-5% methanol). After concentrating the fractions under reduced pressure, 0.74 g of 1-oxo-2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [ 1,4] diazepino-7-carboxylic.

 SM-El: 292 (+) = M (+)

 1 H NMR (400 MHz, DMSO-d6) d ppm 0.88 (t, J = 7.2 Hz, 6 H) 1.25 (m, 4 H) 1.46 (m, 4 H) 1, 99 (m, 2H) 3.11 (t, J = 6.7 Hz, 2 H) 4.51 (m, 1 H) 4.62 (t, J = 6.7 Hz, 2 H) 6.47 (d, J = 4.1 Hz, 1 H) 6.79 (d, J = 4.1Hz, 1 H) 12.59 (extended m, 1 H)

1.1.6: N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- (1-propylbutyl) -2 , 3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepino-7-carboxamide

In a 200 mg suspension of 1-oxo-2- (1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepino-7-carboxylic acid, 281 mg of hydrochloride (1: 1) of (2R, 3S) -3-amino-4-phenyl-1 - {[3- (trifluoromethyl) benzyl] amino} -butan-2-ol, 14 mg of hydroxybenzotriazole, 164 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 25 cm 3 of dichloromethane, 0.468 cm 3 of N, N-diisopropylethylamine is poured at a temperature close to 20 ° C. The solution obtained is kept under stirring for 3 h 30 at 20 ° C under an inert atmosphere. 25 cm3 of dichloromethane and 15 cm3 of water are added to the reaction medium. The organic phase is washed with 20 cm 3 of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated on the rotary evaporator under reduced pressure (5 kPa). The product obtained is purified by flash chromatography on silica (column: 15 g; granulometry: 20-40 µm spherical; eluent: gradient dichloromethane 95% -methanol 5% to dichloromethane 90% -methanol 10%). After concentrating the fractions under reduced pressure, 206 mg of N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2 is obtained - (1-Propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2a] [1,4] diazepino-7-carboxamide.

 LC-MS-DAD-ELSD: 611 (-) = (M-H) (-); 657 (-) = (M + Formic Acid-H) (-); 613 (+) = (M + H) (+)

 1H NMR (400 MHz, DMSO-d6) d ppm 0.86 (t, J = 7.3 Hz, 3 H) 0.88 (t, J = 7.3 Hz, 3 H) 1.15 - 1.30 (m, 4H) 1.34

- 1.51 (m, 4 H) 1.86 (m, 2 H) 2.46 -2.77 (m partially masked, 3 H) 2.93 - 3.14 (m, 3 H) 3.61 (m, 1 H) 3.73-3.86 (m, 2 H) 4.03 (m, 1 H) 4.22 (m, 1 H) 4.35 (m, 1 H) 4.47 ( m, 1 H) 4.98 (d, J = 5.9 Hz, 1 H) 6.39 (d, J = 3.9 Hz, 1 H) 6.54 (d, J = 3.9 Hz, 1 H) 7.12 (m, 1 H) 7.21 (m, 4 H) 7.47 - 7.58 (m, 2 H) 7.62 (broad d, J = 7.5 Hz, 1 H ) 7.69 (wide s, 1 H) 8.08 (d, J = 9.0 Hz, 1 H)

11.2: Get out

N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- (1-propylbutyl) hydrochloride (1: 1) 2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepino-7-carboxamide

At a temperature close to 20 ° C, 200 mg of N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3 (trifluoromethyl) benzyl] amino} propyl] -1-oxo- 2- (1-Propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepino-7carboxamide in 2.5 cm3 of ethyl ether. 0.6 cm3 of a 4M hydrochloric acid solution in dioxane is added under stirring under argon at a temperature of 5 ° C. The reaction mixture precipitates partially. The suspension is concentrated under reduced pressure (5 kPa). 3 cm3 of ethyl ether are added. The suspension is stirred for 15 min, stirring is stopped and the supernatant is removed. This operation is performed twice. The last suspension is concentrated under reduced pressure (5 kPa). 183 mg of hydrochloride (1: 1) of N - [(1S, 2R) -1-benzyl-2-hydroxy3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- ( 1-propylbutyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepino-7carboxamide as a white solid.

 1 H NMR (400 MHz, DMSO-d6) d ppm 0.86 (t, J = 7.5 Hz, 3H); 0.88 (t, J = 7.5 Hz, 3H); from 1.15 to 1.30 (m, 4H); 1.44 (m, 4 H); 1.88 (m, 2 H); 2.77 (dd, J = 11.0 and 14.0 Hz, 1H); 2.87 (m, 1 H); from 2.96 to 3.17 (m, 4H); 3.87 (m, 1 H); 3.97 (m, 1 H); 4.17 (m, 1 H); 4.31 (m, 2H); from 4.41 to 4.53 (m, 2H); 5.92 (extended m, 1H); 6.44 (d, J = 4.0 Hz, 1H); 6.62 (d, J = 4.0 Hz, 1H); 7.14 (m, 1 H); 7.24 (m, 4H); 7.65 (t, J = 7.5 Hz, 1H); 7.76 (d, J = 7.5 Hz, 1H); 7.86 (d, J = 7.5 Hz, 1H); 7.96 (s, 1 H); 8.18 (d, J = 9.0 Hz, 1H); 8.97 (extended m, 1H); 9.32 (extended m, 1H).

 LC-MS-DAD-ELSD: 611 (-) = (M-H) (-); 657 (-) = (M + Formic Acid-H) (-); 613 (+) = (M + H) (+)

Table 1 below illustrates the chemical structures and physical properties of some examples of compounds according to the invention. In this table:

 PF (° C) represents the melting point of the compound in degrees Celsius,

 in the column "salt", "-" represents a compound in the form of a free base, while "HCl" represents a compound in the form of hydrochloride, the ratio in parentheses is the ratio (acid: base);

 R3 represents a trifluoromethyl group;

 Me and Et respectively represent the methyl and ethyl groups;

 «nd»: not determined.

The compounds described in this table have been prepared according to the methods described above.

Table 1:

 image 1

Compound

 R1 W ρ  R2 R4, R5 R6 PF (° C) Salt

one

BOC -CH2- 2 H -CH2CH2  8-COOMe 136 -

2

BOC -CH2-  2 H -CH2CH2  8-COOH 134.5 -

3

H -CH2- 2 H -CH2CH2  8-COOH 196 HCl (2: 1)

4

BOC -CH2- 2 H -CH2CH2  8-CON (Et) 2  nd (a)  -

5

H -CH2- 2 H -CH2CH2  8-CON (Et) 2  143 HCl (2: 1)

6

 MeSO2- -CH2- 2 H -CH2CH2  8-CON (Et) 2  nd (b)  -

7

(n-C3H7) 2CH C = O 2 3,5-diF -CH2CH2  H 183 HCl (1: 1)

8

(n-C3H7) 2CH- C = O 2 H -CH2CH2 H 176 HCl (1: 1)

9

(n-C3H7) 2CH C = O 2 H H H H 168 HCl (1: 1)

10

 Et2CH C = O 2 H H H H 178 HCl (1: 1)

eleven

 Et2CH C = O 3 H H H H nd (a)  HCl (1: 1)

(a) characterized by an NMR-1H spectrum and by liquid chromatography coupled to a mass spectrometer (b) characterized by an NMR-1H spectrum

The compounds according to the invention have been subject to pharmacological tests that allow their inhibitory effect against β-secretase activity to be determined.

The tests have consisted in measuring the in vitro inhibition of β-secretase activity by the compounds of the invention.

The measured β secretase activity corresponds to that of a purified recombinant form of human aspartyl protease BACE1 (the latter comprising a hexa-histidine tag at the C-terminal end) produced by expression in Drosophilic cells. The purified enzyme is conditioned in TRIS buffer (18 mM) at pH 7.5 containing NaCl (0.45 M), MnCl2 (0.9 mM), CaCl2 (0.9 mM), alpha D methylmanoside 10% glycerol and preserved at -80 ° C

10 until use.

BACE1 activity is measured after excision of a fluorogenic peptide substrate, called FS1, described in principle by Ermolieff et al. (2000, Biochemistry, 39, 12450-12456) and is based on the principle of resonance fluorescence energy transfer (FRET); FS1 peptide cleavage is measured by the increase in fluorescent signal emitted by the EDANS group (or 5 - [(2-aminoethyl) amino] -naphthalen-1-sulfonic acid).

The assay is carried out in a 96-well microplate to determine the inhibition of enzymatic activity by the products of the invention. The FS1 substrate is solubilized at a concentration of 1 mM in 100% dimethylsulfoxide (DMSO) and stored at -20 ° C until use. Dilutions of the products to be tested are prepared in DMSO from a 10 mM stock solution. The products of the invention, at the final concentrations of 0.003 to 10 µM, are incubated at 37 ° C with the substrate FS1 (final concentration 5 µM) and the purified enzyme (final concentration 10 nM), in sodium acetate buffer ( 0.1 M) pH 4.5 containing 0.02% CHAPS detergent and 200 mM NaCl for 45 minutes. The final percentage of DMSO does not exceed 7%. When the incubation is over, the fluorescence is measured in a spectrofluorimeter, at the excitation wavelengths of 355 nm and emission of 509 nm. For each concentration of product tested, the fluorescence signal is compared with the maximum signal obtained when the FS1 substrate has been incubated only with the enzyme.

The inhibitory activity of the products of the invention is evaluated by the measurement of IC50 (concentration of product that provides 50% inhibition of enzymatic activity) by means of a non-linear regression analysis (Xlfit computer application, IDBS ™).

The IC50s are between 0.1 and 5 µM.

For example, compounds 5, 7, 9 and 11 have shown an IC50 respectively of 0.31; 0.48; 0.37 and 1.40 µM.

It seems, therefore, that the compounds according to the invention have an inhibitory activity against β-secretase activity.

The compounds according to the invention can therefore be used for the preparation of medicaments, in particular medicaments inhibiting the production of Aβ.

Thus, according to another of its aspects, the object of the invention is medicaments comprising a compound of formula (I), or a salt of addition of the latter to a pharmaceutically acceptable acid, or also a hydrate or a solvate of the compound of formula ( I).

These drugs find their use in therapeutics, mainly in the treatment and prevention of diseases associated with the production of the Aβ peptide, among which neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, disease of Huntington, Creutzfeld-Jacob disease, Down syndrome, Lewy body dementia, senile dementia, fronto-temporal dementia, cerebral and systemic amyloidosis, light cognitive disorders, amyloid cerebral angiopathy, primary disorders and secondary memory, amyotrophic lateral sclerosis, multiple sclerosis, peripheral neuropathies, diabetic neuropathies, migraine, mood disorders, depression, anxiety, vascular disorders such as atherosclerosis, cerebrovascular ischemia , tumors and cell proliferation disorders.

These drugs find their use particularly in the treatment and prevention of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Down syndrome, dementia with Lewy bodies, senile dementia, fronto-temporal dementia, cerebral and systemic amyloidosis, mild cognitive disorders, amyloid cerebral angiopathy, primary and secondary memory disorders and cerebrovascular ischemia.

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, a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, among the usual excipients that 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 its salt, solvate or optional hydrate, can be administered in unit form of administration, mixed with classical pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.

Appropriate unit forms of administration comprise oral forms, such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal, inhalation, administration forms, topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.

As an example, a unit form of administration of a compound according to the invention in tablet form may comprise the following components:

Compound according to the invention

50.0 mg

Mannitol

223.75 mg

Croscarmellose sodium

6.0 mg

Cornstarch.

15.0 mg

Hydroxypropyl methylcellulose

 2.25 mg

Magnesium stearate

3.0 mg

A method of treating the pathologies indicated above is also described which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or of a pharmaceutically acceptable salt or hydrate or solvate.

5

10

fifteen

twenty

25

30

35

40

Claims (19)

1. Compound that responds to formula (I) image 1 in which: R1 represents a hydrogen atom, a (C1-C10) alkyl, cycloalkyl (C3-C7), (CH2) n-alkenyl (C1C6), (CH2) n-alkynyl (C1-C6), alkyl (C1-C6) group ) -Z-(C1-C6) alkyl, wherein Z represents a heteroatom chosen from O, N and S (O) m, or R1 represents a COOR, S (O) mR group, an aryl or an aralkyl; the groups being (C1-C10), cycloalkyl (C3-C7), (CH2) n-alkenyl (C1-C6), (CH2) n-alkynyl (C1-C6), alkyl (C1-C6) Z-alkyl groups (C1-C6), aryl or aralkyl optionally substituted with one or more groups selected from a halogen atom, a (C1-C6) alkyl group, (C3-C7) cycloalkyl, halo (C1-C6) alkyl, alkoxy ( C1-C6), haloalkoxy (C1-C6), NR7R8, nitro, cyano, OR, COOR, C (O) NR7R8 or S (O) mNR7R8, R2 represents one or more groups chosen from a hydrogen atom, a halogen atom, a (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C8) alkenyl, (C1-C6) alkynyl or alkyl ( C1-C6) -Z-(C1-C6) alkyl, in which Z represents a heteroatom chosen from O, N and S (O) m, or R2 represents a halo-C1-C6 alkyl group, halo- (C1-C6) alkoxy, hydroxy, (C1-C6) alkoxy, nitro, cyano, amino, a group NR7R8, COOR, C (O) NR7R8, OC (O) -alkyl (C1-C6), S (O) m-NR7R8 or an aryl group, the aryl group being optionally substituted with one or more groups selected from a halogen atom, a (C1-C6) alkyl, cycloalkyl (C3-C7), halo-(C1-C6) alkyl group ), (C1-C6) alkoxy, halo (C1-C6) alkoxy, NR7R8, OR, nitro, cyano, COOR, C (O) NR7R8 or S (O) mNR7R8, R3 represents a trifluoromethyl group, R4 and R5 represent a hydrogen atom, or R4 and R5 form a saturated cycle containing 3 to 6 carbon atoms and optionally containing 0 to 1 heteroatom chosen from O, N with the carbon atom or S, R6 represents a group selected from a hydrogen atom, a halogen atom, a (C1C6) alkyl, cycloalkyl (C3-C7), cycloalkyl (C3-C7) -alkyl (C1-C6), nitro, amino, a group NR7R8, COOR, an aryl group, a group NR7 (SO2) R8 or C (O) NR7R8, R, R7 and R8 represent, independently of one another, one or more groups chosen from a hydrogen atom, a (C1-C6) alkyl, cycloalkyl (C3-C7), cycloalkyl (C3-C7) -alkyl (C1-) group C6), an aryl or aryl (C1-C6) alkylene group, or R7 and R8 can form a saturated, partially unsaturated or unsaturated cycle with the atom to which they contain 5 to 7 carbon atoms and which optionally also contains a heteroatom chosen from O, N or S (O) m, W represents a methylene group or C (O), m represents an integer that can take the values 0, 1 or 2, n represents an integer that can take the values 1, 2, 3, 4, 5 or 6, p represents an integer that can take values 2 or 3, the carbon to which the benzyl group substituted with R2 is attached has the absolute configuration S, The carbon to which the hydroxyl group is attached has the absolute configuration R, in the base or salt state of addition to an acid.

2.

Compound of formula (I) according to claim 1, characterized in that W represents a methylene group, in the state of base or salt addition to an acid.

3.

Compound of formula (I) according to one of claims 1 to 2, characterized in that W represents a group C (O), in the state of base or salt addition to an acid.

Four.

Compound of formula (I) according to one of claims 1 to 3, characterized in that p represents 2, in the state of base or salt of addition to an acid.

5.

Compound of formula (I) according to one of claims 1 to 3, characterized in that p represents 3, in the state of base or salt of addition to an acid.

6.

Compound of formula (I) according to one of claims 1 to 5, characterized in that R6 represents a group selected from a hydrogen atom, a COOR group or a C (O) group NR7R8, in the state of base or salt addition to an acid

7.

Compound of formula (I) according to one of claims 1 to 6, characterized in that R6 represents a group selected from a hydrogen atom, a COOH, COOMe group or a C (O) N (Et) 2 group, in the base state or of acid addition salt,

8.

Compound of formula (I) according to one of claims 1 to 7, characterized in that W represents a methylene group or C (O), p represents 2 or 3, R1 represents a hydrogen atom, a (C1-C10) alkyl group, COOR or S (O) mR, the (C1-C10) alkyl group being

optionally substituted with one or more (C1-C6) alkyl groups, R2 represents one or more groups chosen from a hydrogen atom or a halogen atom, R4 and R5 represent a hydrogen atom or form with the carbon atom to which a group is attached cyclopropyl, R6 represents a group chosen from a hydrogen atom, a COOR group or a C (O) NR7R8 group, R, R7 and R8 represent, independently of one another, a hydrogen atom or one or more (C1) alkyl groups C6), in the base or salt state of addition to an acid. 9. Compound of formula (I) according to one of claims 1 to 8, characterized in that it is chosen from:

•

 6 - {[(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -3,4-dihydropyrrolo [1,2-a ] pyrazine-2,8 (1H) -2-tert-butyl and 8-methyl dicarboxylate

•

 6 - {[(1S, 2R) -1-Benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -2- (tert-butoxycarbonyl) -1, 2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylic

•

Hydrochloride (2: 1) of 6 - {[(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -1 , 2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxylic

•

 6 - {[(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] carbamoyl} -8 (diethylcarbamoyl) -3.4- dihydropyrrolo [1,2-a] pyrazine-2 (1H) tert-butyl carboxylate

•

 6 - {(1S, 2R) -1-benzyl-2-hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropylamino] -propyl} -N-8, N-8-diethyl-1,2,3, 4-tetrahydropyrrolo [1,2-a] pyrazine-6,8-dicarboxamide and its hydrochloride (2: 1)

•

 6 - {(1S, 2R) -1-benzyl-2-hydroxy-3- [1- (3-trifluoromethylphenyl) -cyclopropylamino] -propyl} -N-8, N-8-diethyl-2 (methylsulfonyl) -1 ', 2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6,8-dicarboxamide

•

N - [(1S, 2R) -1- (3,5-difluorobenzyl) -2-hydroxy-3 - ({1- [3- (trfluoromethyl) phenyl] cyclopropyl} amino) propyl] -1-oxo-2- (1propylbutyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide and its hydrochloride (1: 1)

•

N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - ({1- [3- (trifluoromethyl) phenyl] cyclopropyl} amino) propyl] -1-oxo-2- (1-propylbutyl) 1 , 2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide and its hydrochloride (1: 1)

•

N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- (1-propylbutyl) -1,2,3 , 4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide and its hydrochloride (1: 1)

•

N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -2- (1-ethylpropyl) -1-oxo-1,2,3 , 4-tetrahydropyrrolo [1,2-a] pyrazine-6-carboxamide and its hydrochloride (1: 1).

•

N - [(1S, 2R) -1-benzyl-2-hydroxy-3 - {[3- (trifluoromethyl) benzyl] amino} propyl] -1-oxo-2- (1-propylbutyl) -2,3,4 , 5-tetrahydro-1H-pyrrolo [1,2-a] [1,4] diazepino-7-carboxamide and its hydrochloride (1: 1).

10. Compound of formula (IIIa) image 1 5 10 fifteen twenty 25 30 35 wherein R1 and R6 are as defined in the general formula (I) according to claim 1. 11. Compound of formula (IIIb) image 1 wherein R1 and R6 are as defined in the general formula (I) according to claim 1.

12.

Compound according to claim 11, characterized in that the compound of formula (IIIb) is 2- (tert-butoxycarbonyl) -8- (methoxycarbonyl) -1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-6- carboxylic.

13.

Compound of formula (IIIc)

image 1 wherein R1 and R6 are as defined in the general formula (I) according to claim 1.

14.

Medication, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 9, or an addition salt of this compound, to a pharmaceutically acceptable acid.

fifteen.

Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, as well as at least one pharmaceutically acceptable excipient.

16.

Use of a compound of formula (I) according to any one of claims 1 to 9 for the preparation of a medicament for the treatment and prevention of Alzheimer's disease, Parkinson's disease, Huntington's disease, Creutzfeld's disease -Jacob, Down syndrome, dementia with Lewy bodies, senile dementia, fronto-temporal dementia, cerebral and systemic amyloidosis, light cognitive disorders, amyloid cerebral angiopathy, primary and secondary memory disorders, Amyotrophic lateral sclerosis, multiple sclerosis, peripheral neuropathies, diabetic neuropathies, migraine, mood disorders, depression, anxiety, vascular disorders such as atherosclerosis, cerebrovascular ischemia, tumors and disorders of cell proliferation.

17.

Use of a compound of formula (I) according to any one of claims 1 to 9 for the preparation of a medicament for the treatment and prevention of Alzheimer's disease, Parkinson's disease, Down's syndrome, dementia with bodies of Lewy, senile dementia, fronto-temporal dementia, cerebral and systemic amyloidosis, mild cognitive disorders, amyloid cerebral angiopathy, primary and secondary memory disorders and cerebrovascular ischemia.

18.

Compound of formula (I) according to any one of claims 1 to 9, in the base state, for the prevention or treatment of Alzheimer's disease, Parkinson's disease, Huntington's disease, Creutzfeld-Jacob's disease, Down syndrome, dementia with Lewy bodies, senile dementia, fronto-temporal dementia, cerebral and systemic amyloidosis, mild cognitive disorders, amyloid cerebral angiopathy, primary and secondary memory disorders, lateral sclerosis Amyotrophic, multiple sclerosis, peripheral neuropathies, diabetic neuropathies, migraine, mood disorders, depression, anxiety, vascular disorders such as atherosclerosis, cerebrovascular ischemia, tumors and proliferation disorders mobile.

19.

Compound of formula (I) according to any one of claims 1 to 9, in the base state, for the preparation of a medicament for the treatment and prevention of Alzheimer's disease, Parkinson's disease, Down's syndrome, Lewy body dementia, senile dementia, fronto-temporal dementia, cerebral and systemic amyloidosis, mild cognitive disorders, amyloid cerebral angiopathy, primary and secondary memory disorders and cerebrovascular ischemia.