HK1143163B - 1-oxo-isoindoline-4-carboxamide and 1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide derivatives, preparation and therapeutic use thereof - Google Patents

Description

1-oxo-isoindoline-4-carboxamide and 1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide derivatives, preparation and therapeutic use thereof

The present invention relates to 1-oxo-isoindoline-4-carboxamide and 1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide derivatives, to their preparation and to their therapeutic use.

The presence of multiple senile plaques (multiple plaques) in brain tissue is one of the major histopathological lesions observed in alzheimer's disease; these plaques are formed by the deposition of fibrillar aggregates (agregatsfibrillaires) of the 4kDa peptide (40-42 amino acids) called amyloid β (Α β). According to the amyloid cascade (hypoth ase d' unecascade)) The production and progressive accumulation of this peptide plays a decisive role in the initiation and progression of Alzheimer's disease (D.Selko et al Nature399A(1999) 23; roggo et al Top. Med. chem2(2002) 359; ghosh et al curr.med.chem.9(2002)1135)。

A β peptide derived from APP protein (amyloid precursor protein), which can be cleaved by at least three different proteolytic activities: 1) by alpha-secretase activity at ACleavage (clevage) in the β region (thus preventing a β formation); 2) cleavage at the N-terminus of a β by β -secretase activity; 3) cleavage at the C-terminus of a β by γ -secretase activity. The sequential cleavage of APP protein at the β and γ sites results in the formation of a β peptide (m.citron, nat. rev. neurosci).5(2004) 677-; beer et al Expert opin invest drugs14(2005)1385-1409)。

There is therefore a real interest in finding compounds that inhibit the production of a β peptide (t.b. durham et al curr. opin. drug disc. dev.9(2006)776-791)。

It has now been found that the compounds 1-oxo-isoindoline-4-carboxamide and 1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide derivatives have strong inhibitory activity against β -secretase activity.

The object of the present invention is a compound corresponding to the general formula (I):

wherein:

r1 represents a hydrogen atom, or a hydrogen atom₁-C₁₀) Alkyl, (C)₃-C₇) Cycloalkyl group, (CH)₂)_n-(C₁-C₆) Alkenyl group, (CH)₂)_n-(C₁-C₆) Alkynyl, (C)₁-C₆) alkyl-Z- (C)₁-C₆) Alkyl, wherein Z represents a radical selected from O, N and S (O)_mOr R1 represents COOR, S (O)_mR, aryl or aralkyl; (C)₁-C₁₀) Alkyl, (C)₃-C₇) Cycloalkyl group, (CH)₂)_n-(C₁-C₆) Alkenyl group, (CH)₂)_n-(C₁-C₆) Alkynyl, (C)₁-C₆) alkyl-Z- (C)₁-C₆) Alkyl, wherein aryl or aralkyl is optionally substituted with one or more groups selected from: halogen atom, (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl, halo (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, halo (C)₁-C₆) Alkoxy, NR7R8, nitro, cyano, OR, COOR, CONR7R8, S (O)_mNR7R8, aryl optionally substituted with halogen atoms;

r2 represents one or more groups selected from: a hydrogen atom, a halogen atom, and (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₁-C₆) Alkenyl, (C)₁-C₆) Alkynyl, (C)₁-C₆) alkyl-Z- (C)₁-C₆) Alkyl, wherein Z represents a radical selected from O, N and S (O)_mOr R2 represents halo (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, halo (C)₁-C₆) Alkoxy, hydroxy, nitro, cyano, amino, NR7R8, COOR, CONR7R8, OCO (C)₁-C₆) Alkyl, S (O)_m-NR7R8, aryl, wherein aryl may be optionally substituted with one or more groups selected from: halogen atom, (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl, halo (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, halo (C)₁-C₆) Alkoxy, NR7R8, OR, nitro, cyano, COOR, CONR7R8, S (O)_mNR7R8；

R3 represents trifluoromethyl;

r4 and R5 represent a hydrogen atom, or R4 and R5 form, together with the carbon atoms that carry them, a saturated ring comprising from 3 to 6 carbon atoms and optionally from 0 to 1 heteroatom chosen from O, N or S;

r6 represents a group selected from: a hydrogen atom, a halogen atom, and (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₃-C₇) Cycloalkyl (C)₁-C₆) Alkyl, halo (C)₁-C₆) Alkyl, nitro, amino, NR7R8, COOR, NR7 (SO)₂) R8, c (o) NR7R8, aryl or heterocyclyl, said aryl and heterocyclyl being optionally substituted by one or more groups selected from: halogen atom, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy or cyano;

r, R7 and R8 represent, independently of one another, one or more groups selected from: hydrogen atom, (C)₁-C₆) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₃-C₇) Cycloalkyl (C)₁-C₆) Alkyl, aryl (C)₁-C₆) Alkylene, or R7 and R8 may form, together with the atoms which carry them, a saturated, partially unsaturated or unsaturated ring containing from 5 to 7 carbon atoms and optionally additionally containing a substituent selected from O, N or S (O)_mA heteroatom of (a);

x represents (C)₁-C₂) Alkylene, optionally with one or more (C)₁-C₆) Alkyl substitution;

m represents an integer which may take the value of O, 1 or 2, and n represents an integer which may take the value of 1,2,3,4, 5 or 6;

the carbon bearing the benzyl group substituted with R2 is in the S absolute configuration;

the carbon bearing the hydroxyl group is in the absolute R configuration,

the compounds of formula (I) may contain one or more asymmetric carbon atoms. They may therefore exist as enantiomers or diastereomers. These enantiomers, diastereomers and mixtures thereof, including racemic mixtures, form part of the present invention.

The compounds of formula (I) may be present in the form of a base or an addition salt with an acid. Such addition salts form part of the present invention.

These salts may be prepared using pharmaceutically acceptable acids, but salts of other acids which may be used, for example, in the purification or isolation of the compounds of formula (I) also form part of the invention.

In the context of the present invention, the following are understood:

-C_t-C_z(wherein t and z may take values of 1-10) carbon chains or rings which may have t-z carbon atoms, e.g. C₁-C₃Carbon chains having 1-3 carbon atoms can be characterized;

-a halogen atom: fluorine, chlorine, bromine or iodine;

-an alkyl group: a straight or branched chain saturated aliphatic group. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and the like;

-a cycloalkyl group: a cyclic alkyl group. For example, there may be mentioned cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;

-alkylene groups: a linear or branched saturated divalent aliphatic group. E.g. C_1-3Alkylene represents a linear or branched divalent carbon chain having 1 to3 carbon atoms, such as methylene (-CH)₂-) ethylene (-CH₂CH₂-, 1-methylethylidene (-CH (CH)₃)CH₂-) or propylene (-CH)₂CH₂CH₂-)；

-alkenyl: linear or branched mono-or polyunsaturated aliphatic groups, for example containing 1 or 2 ethylenic unsaturations;

-alkynyl: linear or branched mono-or polyunsaturated aliphatic groups, for example containing 1 or 2 acetylenic unsaturations;

-an alkoxy group: -O-alkyl, wherein alkyl is as previously defined;

-halo (C)₁-C₆) Alkyl groups: alkyl groups whose hydrogen atom or atoms have been substituted with halogen atoms. For example, CF may be mentioned₃、CH₂CF₃、CHF₂、CCl₃；

-halo (C)₁-C₆) Alkoxy groups: -O-alkyl, wherein alkyl is as previously defined and is substituted by oneOr a plurality of identical or different halogen atoms. By way of example, OCF may be mentioned₃、OCHF₂、OCCl₃；

The sulphur and nitrogen atoms may be present in the oxidised state (N-oxide, sulphoxide, sulphone).

-aryl: cyclic aryl groups containing 6 to 14 carbon atoms. Aryl, for example, phenyl or naphthyl;

-a heterocyclic group: an unsaturated, partially unsaturated monocyclic or polycyclic group having 4 to 10 carbon atoms and 1 to 4 heteroatoms selected from N, O and S. Examples of such heterocyclic groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine or triazine.

In the groups as defined below, the radicals R1, R2, R3, R4, R5, R6, R, R7 and R8, when they are not defined, have the same definitions as those described above.

Within the object of the present invention compounds of formula (I), a first group of compounds consists of the compounds for which:

x represents optionally one or more (C)₁-C₆) An alkyl-substituted methylene group.

Among the compounds of formula (I) object of the present invention, the second group of compounds consists of the compounds for which:

x represents optionally one or more (C)₁-C₆) Alkyl-substituted ethylene.

Among the compounds of formula (I) object of the present invention, the third group of compounds consists of the compounds for which:

r6 represents a group selected from: a hydrogen atom, a halogen atom, and (C)₁-C₆) Alkyl or halo (C)₁-C₆) Alkyl, NR7SO₂R8, aryl optionally substituted by cyano or R6 representsA heterocyclic ring.

In this subclass of compounds of formula (I) object of the present invention, the fourth group consists of the compounds for which:

r6 represents a group selected from: hydrogen, chlorine or fluorine atoms, methyl or trifluoromethyl, NMeSO₂Me, phenyl substituted with cyano, or R6 represents oxazole.

Among the compounds of formula (I) object of the present invention, the fifth group of compounds consists of the compounds for which:

r1 represents optionally substituted one or more (C)₁-C₆) Alkyl substituted (C)₁-C₁₀) Alkyl, aryl optionally substituted by a halogen atom, or R1 represents (C)₁-C₆) alkyl-O- (C)₁-C₆) Alkyl or aralkyl optionally substituted with a halogen atom;

r2 represents one or more groups selected from a hydrogen atom or a halogen atom;

r4 and R5 represent a hydrogen atom or form, together with the carbon atom bearing them, a cyclopropyl group;

r6 represents a group selected from: a hydrogen atom, a halogen atom, and (C)₁-C₆) Alkyl or halo (C)₁-C₆) Alkyl, NR7SO₂R8, aryl optionally substituted with cyano, or R6 represents a heterocycle;

r7 represents a hydrogen atom or (C)₁-C₆) An alkyl group; and

r8 represents (C)₁-C₆) An alkyl group.

Combinations of groups 1-5 as defined above are also part of the invention.

In the name of a compound, a dash "-" is a part of a word, and a dash "" is used only for breaks at the end of the line; it should be removed without interruption and should not be replaced with a normal stub or with a space.

Among the compounds of formula (I) object of the present invention, mention may be made in particular of the following compounds:

n- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -1-oxo-2- (1-propylbutyl) isoindoline-4-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-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

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-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

2-benzyl-N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -1-oxo-2-pentyl-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- (2-methoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- (2-ethoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- [1- (4-fluorophenyl) ethyl ] -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -6- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-3-methyl-4-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -6- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-4-carboxamide and its hydrochloride (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-trifluoromethyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- [ (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (2-oxazolyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-methyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-chloro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -l- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-fluoro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1).

Another subject of the invention is also a process for the preparation of the compounds of formula (I).

In the following, a protecting group Pg is understood to mean, on the one hand, a protection of the reactive function, such as a hydroxyl group or an amine, during the synthesis and, on the other hand, a regeneration of the intact reactive function at the end of the synthesis. Such protecting Groups and methods of protection and deprotection are given in "Protective Groups in organic Synthesis", Green et al, 2 nd edition (John Wiley & Sons Inc., New York) 1991.

In the following, "leaving group" is understood to be a group which can be easily cleaved from a molecule by heterolytic bond cleavage and which carries away an electron pair. Such a group can thus be easily replaced with another group, for example during a substitution reaction. Such leaving groups are, for example, halogen or activated hydroxy groups, such as methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, trifluoromethanesulfonyl, acetate and the like. Examples of leaving groups and references for their preparation are given in "Advances in Organic Chemistry", J.March, 3 rd edition, Wiley Interscience, 1985, p.310-.

In the schemes that follow, the starting compounds and reactants, when their methods of preparation are not described, are commercially available or described in the literature, or can be prepared according to the methods described herein or known to those skilled in the art.

Abbreviations and symbols used to describe the synthetic methods and to describe the compounds are as follows:

use of APP for polyphosphoric acid

BOC for tert-butoxyformates

-DCC for dicyclohexylcarbodiimide

DMF is used for dimethylformamide,

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

NMP for N-methyl-2-pyrrolidone,

PyBOP for benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate

THF was used for tetrahydrofuran.

According to the present invention, the compound of the general formula (I) can be prepared according to the method illustrated by the following scheme 1.

Scheme 1

According to scheme 1, the compounds of general formula (I) are prepared by condensing the amine function of the compounds of general formula (II) wherein R2, R3, R4 and R5 are as defined in general formula (I) with the carboxylic acid function of the compounds of general formula (III) wherein R1 and R6 are as defined in general formula (I). The reaction is carried out in a solvent (such as dichloromethane, THF, ether or chloroform) at a temperature between 20 ℃ and the reflux temperature of the solvent in a preferably inert anhydrous medium (such as nitrogen or argon) by using conventional reagents (such as DCC, PyBOP or EDAC) that couple the acid functional group with the amine functional group.

According to the process illustrated by scheme 2 below, the compounds of formula (II), in which R2, R3, R4 and R5 are as defined in formula (I), can be prepared from compounds of formula (IV), in which R2, R3, R4 and R5 are as defined in formula (I), by deprotecting the primary amine by the action of an acid (for example hydrochloric acid) dissolved in an ethereal (er) solvent (for example diethyl ether) and/or a chlorinated solvent (for example dichloromethane) or a mixture of solvents.

Scheme 2

Compounds of general formula (IV), wherein R2, R3, R4 and R5 are as described above, can be prepared by reacting a benzylamine derivative of general formula (VI), wherein R3, R4 and R5 are as defined in general formula (I), with an oxirane of general formula (V), wherein R2 is as defined in general formula (I), in a preferably inert anhydrous medium, such as nitrogen or argon, in a chlorine-containing solvent, such as dichloromethane, and in the presence of a lewis acid, such as scandium triflate.

Compounds of general formula (IIIa) wherein X represents methylene and R1 and R6 are as described above may be prepared according to the method described in scheme 3 below.

Scheme 3

The compounds of the formula (IIIa) can be prepared by reacting isoindolin-1-ones of the formula (VII) with carbon monoxide in the presence of (potassium or sodium) acetate ions, alkali metal iodides (e.g.sodium iodide or potassium iodide), palladium-containing catalysts (e.g.palladium acetate), phosphines (e.g.triphenylphosphine) (dissolved in organic solvents, for example dimethylformamide or dimethyl sulfoxide) and in the presence of water. The reaction is carried out similarly to d.milstein et al (j.am.chem.soc. (1989)8742) and t.w.ku et al (Tetrahedron Lett. (1997)3131) under carbon monoxide pressures of 1-100 atmospheres and at temperatures of 20-120 ℃.

Isoindolin-1-ones of formula (VII) can be prepared from halogen-containing derivatives of formula (VIII), wherein R1 and R6 are as previously defined, under the action of a mixture of carbon monoxide and air at atmospheric pressure. The reaction is carried out in solution in an organic solvent (e.g. toluene) in the presence of palladium (II) and copper (II) salts (e.g. palladium acetate and copper acetate) and at a temperature between 20 ℃ and the reflux temperature of the solvent, similarly to the working of k.

Halogen-containing compounds of formula (VIII) can be prepared from bromobenzaldehyde of formula (IX) by reacting said bromobenzaldehyde with a compound of formula R1-NH in a chlorine-containing organic solvent, such as dichloromethane, at a temperature between 0 ℃ and the reflux temperature of said solvent, by operating in a preferably inert anhydrous medium, such as nitrogen or argon, in the presence or absence of dehydrating agents, such as magnesium sulfate, sodium sulfate, molecular sieves₂The amine of (2) is reacted. The crude mixture is then subjected to a reducing agent (e.g., sodium borohydride or sodium cyanoborohydride) in an alcoholic solvent (e.g., methanol or ethanol).

Compounds of general formula (IIIb), wherein X represents ethylene and R1 and R6 are as defined in general formula (I), can be prepared according to the method described in scheme 4 below.

Scheme 4

The compound of formula (IIIb) can be prepared from the compound of formula (X) under the same conditions as used for the preparation of the compound of formula (IIIa).

Compounds of formula (X) in which R1 is a chain which does not contain an oxygen atom are obtained from carbamates of formula (XII) by Bischler-Napieralski type cyclisation of triflic anhydride analogously to the work of Y-C.Wang et al Synthesis 15(2002) 2187-90. The reaction is carried out in the presence of an organic base (e.g. 4-dimethylaminopyridine) in an organic solvent (e.g. dichloromethane) at a temperature between 0 ℃ and the reflux temperature of the solvent.

In the compound of the general formula (X) (wherein the substituent R1 is (C)₁-C₆) alkyl-O- (C)₁-C₆) Alkyl chain) the action of triflic anhydride gives compounds of general formula (XI) (wherein p represents an integer corresponding to 1,2, 4 or 4. These compounds of the general formula (XI) are prepared by reacting an alkyl halide R '-X (wherein R' represents (C)₁-C₆) Alkyl and X represents a halogen atom) (for example, methyl iodide or ethyl iodide) is converted into a compound of the general formula (X). The reaction is carried out as a solution in an organic solvent (e.g. dimethyl sulfoxide, acetonitrile or dimethylformamide) for example in the presence of a base (e.g. sodium hydroxide, potassium hydroxide or sodium hydride) at a temperature between 0 ℃ and the reflux temperature of the solvent.

Alternatively, the compound of general formula (X) may be obtained as described in scheme 5 below.

Scheme 5

The compound of formula (X) may be prepared by alkylation of a compound of formula (XVIII) (e.g. alkyl or aryl iodides) dissolved in an organic solvent (e.g. dimethylformamide, acetonitrile or dimethyl sulphoxide) in the presence of a base (e.g. sodium carbonate, potassium carbonate, sodium hydride, triethylamine or pyridine) at a temperature between 0 ℃ and the reflux temperature of the solvent.

The compound of formula (XVIII) may be prepared by cyclisation of a compound of formula (XIX) (e.g. the cyclisation agent is polyphosphoric acid). The reaction is carried out at a temperature of 50 ℃ to 200 ℃ in the absence of a solvent.

Compounds of formula (XIX) may be prepared from compounds of formula (XX) by treatment of chloroformates (e.g., methyl or ethyl chloroformates as indicated in scheme 4). The reaction is carried out as a solution in an organic solvent (e.g. tetrahydrofuran or toluene) in the presence of an organic base (e.g. triethylamine or pyridine) at a temperature between 0 ℃ and the reflux temperature of the solvent.

Compounds of formula (XIII) can be prepared in two steps according to scheme a, starting from the hydroxylated derivative of formula (XV). First, the alcohol (XV) is converted to a sulfonate derivative (e.g., a mesylate derivative as indicated in scheme 4). The reaction is carried out in the presence of a base (e.g. pyridine as indicated in scheme 4), in the form of a solution in an organic solvent (e.g. dichloromethane or dioxane), at a temperature between 0 ℃ and the reflux temperature of the solvent. The intermediate (XIV) is then reacted with a primary amine of the formula R1-NH 2. The reaction is carried out as a solution in an organic solvent (e.g. tetrahydrofuran, acetonitrile, dimethylformamide) in the presence of a base (e.g. sodium or potassium carbonate) at a temperature between 0 ℃ and the reflux temperature of the solvent.

Alternatively, according to scheme 4, route B, compounds of formula (XIII) can also be obtained by reaction of an amine of formula (XVI) with an aldehyde. The reaction may be carried out in an acidic solvent (e.g., acetic acid) in the presence of a reducing agent (e.g., sodium borohydride or cyanoborohydride) at a temperature of 0 ℃ to 100 ℃.

As a further alternative, according to scheme C, the compounds of formula (XIII) may also be prepared from the compounds of formula R1-NH₂In the presence of a reducing agent (e.g. acetic acid) dissolved in a carboxylic acid (e.g. acetic acid)Such as sodium borohydride or sodium triacetoxyborohydride). The reaction is preferably carried out under an inert atmosphere (e.g. argon or nitrogen) at a temperature between 0 ℃ and the reflux temperature of the solvent.

Compounds of general formula (IIIc) (in which X represents ethylene, R1 is as defined above and R6 is NR7SO₂The R8 group) can be prepared according to the methods described in scheme 6 below.

Scheme 6

Compounds of formula (IIIc) wherein R1, R7 and R8 are as previously defined can be prepared by the action of an aqueous solution of a base (e.g., alkali metal hydroxide or potassium carbonate) on a compound of formula (XXI) dissolved in an organic solvent (e.g., dioxane or methanol). The reaction is preferably carried out at a temperature of from 0 ℃ to 100 ℃.

Compounds of formula (XXI) wherein R1, R7 and R8 are as defined above can be prepared by the action of an alkyl halide of formula R7-X wherein X represents a halogen atom, on a compound of formula (XXII) dissolved in an organic solvent (e.g., dimethylformamide, acetonitrile, N-methylpyrrolidine) in the presence of a base (e.g., sodium hydride). The reaction is preferably carried out under an inert atmosphere (e.g. nitrogen or argon) at a temperature of from 0 ℃ to 100 ℃.

Compounds of formula (XXII) wherein R1, R7 and R8 are as previously defined may be prepared by reaction of a compound of formula R8-SO in the presence of a base such as triethylamine or pyridine₂The action of Cl-sulfonyl chloride on a compound of formula (XXIII) dissolved in a chlorine-containing organic solvent such as dichloromethane or chloroform. The reaction is preferably carried out under an inert atmosphere (e.g. nitrogen or argon) at a temperature of from 0 ℃ to 100 ℃.

The compounds of formula (XXIII) can be prepared by the action of a reducing agent (gaseous hydrogen at 1 to 10 atmospheres and in the presence of a catalyst such as, for example, palladium) on a compound of formula (XXIV) dissolved in an alcoholic solvent (for example methanol or ethanol). The reaction is preferably carried out at a temperature of from 0 ℃ to 50 ℃.

The compound of formula (XXIV) may be prepared by the action of concentrated nitric acid on a compound of formula (XXV) dissolved in concentrated sulphuric acid. The reaction is preferably carried out under an inert atmosphere (nitrogen or argon) at a temperature of from 10 ℃ to 20 ℃.

The compound of formula (XXV) may be prepared by reaction of a compound of formula (X) with carbon monoxide in the presence of an alcohol (e.g. methanol) and a palladium-based catalyst (e.g. [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride). The reaction is carried out analogously to the research work of j.r. scheffer et al (Synthesis (2001)1253) under carbon monoxide pressures of 1 to 100 atmospheres and at temperatures of 20 ℃ to 120 ℃.

Esters of the formula (XXI) can also be used for preparing compounds of the formula (I) after condensation with amine functions of the formula (II).

The compounds of formula (IIIa), (IIIb) and (IIIc) are useful as intermediates in the synthesis of the compounds of formula (I).

If desired and if necessary, the product of formula (I) may be subjected to one or more of the following conversion reactions in any order to obtain a product of formula (I) or converted to other products of formula (I):

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

b) the hydrolysis of the ester function to the acid function,

c) the reaction of the hydroxyl function to the alkoxy function,

d) oxidation of the alcohol function to an aldehyde, ketone or acid function,

e) reduction of the acid, aldehyde or ketone function to the alcohol function,

f) reductive amination of the aldehyde or ketone function,

g) the oxidation of an alkylene to an aldehyde or ketone function,

h) the oxidation of a thioether to a sulfone or sulfoxide,

i) the alkylation reaction of the sulfamide is carried out,

j) the reaction of dehydration of a hydroxyalkyl group to an alkenyl group,

k) the reaction for dehydrohalogenation of a halogen-containing derivative,

l) reaction of complete or partial hydrogenation of alkenyl or alkynyl groups to alkenyl or alkyl groups,

m) catalytic coupling of halogen-containing derivatives with organometallic derivatives, such as tin or boron derivatives, to introduce alkyl, alkenyl, alkynyl or aryl substituents,

n) a protection reaction of the reactive function,

o) elimination of the protective group which is carried by the protected reactive function,

p) salt formation using inorganic or organic acids or using bases to obtain the corresponding salts,

q) resolution of the racemic form into enantiomers, the product of formula (I) thus obtained optionally being in all possible racemic, enantiomeric or diastereomeric isomeric forms,

r) reduction of nitro derivatives to nitroso or amino derivatives,

s) mono-or dialkylation of amine functions,

t) sulfonylation of primary or secondary amines,

u) acylation of amine functions.

According to a further aspect of the invention, the object is also compounds of formulae (IIIa), (IIIb) and (IIIc). These compounds are useful as synthetic intermediates for compounds of formula (I).

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

In schemes 1-6, the starting compounds and reactants, when their manner of preparation is not described, are commercially available or described in the literature, or can be prepared according to the methods described herein or known to those skilled in the art.

The following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and serve only to illustrate the invention. The numbering of the exemplified compounds refers to the numbering given in the table below, in which the chemical structures and physical properties of some compounds according to the invention are illustrated.

Proton nuclear magnetic resonance (¹H NMR) spectra were taken at 250MHz, 300MHz, 400MHz or 500MHz on a Bru ker instrument (chemical shifts (. delta., ppm) -in dimethyl sulfoxide-d 6(DMSO-d6) solvent, reference 2.50ppm at 303K). Abbreviations used to characterize the signals are as follows: s is singlet, m is multiplet, d is doublet, t is triplet, q is quartet.

The nomenclature used for the Compounds illustrated belowVersion 10.0 software was created.

Example 1:

1.1: base N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -1-oxo-2- (1-propylbutyl) isoindoline-4-carboxamide 1.1.1: n- (2-bromobenzyl) hept-4-amine

6.25g of sodium sulfate and 5.07g of 4-aminoheptane are added at a temperature close to 20 ℃ to 7.4g of 2-bromobenzaldehyde at 80cm³In dichloromethane. After stirring for 2 hours, the reaction mixture was filtered through a cartridge (cartouche) and used 2 times for 10cm³With dichloromethane (g) as the eluentAnd (6) washing. The filtrate was concentrated under reduced pressure (5kPa) using a rotary evaporator. The obtained oil was dissolved in 80cm³In methanol. 0.757g of sodium borohydride was added in 3 portions. The reaction mixture was stirred at 20 ℃ for 1 hour, and then 0.757g of sodium borohydride was added. This operation was performed twice. After stirring at a temperature of 20 ℃ for 20 hours, the reaction mixture was concentrated using a rotary evaporator under reduced pressure (5 kPa). Dissolving the concentrated residue in 100cm³Dichloromethane and 50cm³In the water of (2). The organic phase is 2 times 50cm³The sodium chloride saturated aqueous solution was washed, dried over magnesium sulfate and concentrated under reduced pressure (5kPa) using a rotary evaporator. 10.8g of the colorless oil obtained are removed by applying 1dm of the solution to 150g of silica pieces (cut)³The mixture of 80% heptane/20% ethyl acetate was filtered for purification. After concentration of the fractions under reduced pressure, 9.75g of N- (2-bromobenzyl) hept-4-amine are obtained in the form of a colorless clear oil.

NMR: 0.84(t, J ═ 7.0Hz, 6H)1.21-1.43(m, 8H)1.74 (width S, 1H)2.43(m, 1H)3.73(S, 2H)7.17(td, J ═ 7.7, 1.8Hz, 1H)7.35(td, J ═ 7.7, 1.8Hz, 1H)7.53(dd, J ═ 7.7, 1.8Hz, 1H)7.56(dd, J ═ 7.7, 1.8Hz, 1H)

·MS-EI：283⁽⁺⁾(⁷⁹Br)＝M⁽⁺⁾；240⁽⁺⁾(⁷⁹Br)＝[283⁽⁺⁾-C₃H₉]

·MS-CI(NH₃)：284⁽⁺⁾(⁷⁹Br)＝(M+H)⁽⁺⁾

1.1.2: 4-bromo-2- (1-propylbutyl) isoindolin-1-one

In a three-necked flask, which was stirred and purged with carbon monoxide, at a temperature close to 20 ℃ was introduced at 70cm³2g N- (2-bromobenzyl) heptan-4-amine in toluene. To this solution were added 0.639g of copper acetate and 79mg of palladium acetate. Carbon monoxide bubbling as well as dry air bubbling were used. The reaction mixture was heated under reflux of the solvent for 9 hours 30 minutes. The reaction mixture is cooled, filtered over a pad of celite 545 (culot de celite 545) and then filtered over 210cm in length³And washing with ethyl acetate. The filtrate was concentrated under reduced pressure (5kPa) using a rotary evaporator. 3g of the resulting green oil were purified by flash chromatography on silica (column: 200 g; particle size: 15-40 μm; flow rate: 20 cm)³Per minute; eluent: gradient from 90% heptane/10% ethyl acetate to 100% ethyl acetate over 150 minutes). After concentration of the fractions under reduced pressure, 800mg of 4-bromo-2- (1-propylbutyl) isoindolin-1-one are obtained in the form of a colorless oil.

·NMR：0.86(t，J＝7.4Hz，6H)1.07-1.24(m，4H)1.43-1.76(m，4H)4.17-4.31(m，3H)7.47(t，J＝7.7Hz，1H)7.69(d，J＝7.7Hz，1H)7.81(d，J＝7.7Hz，1H)

·MS-EI：309⁽⁺⁾(⁷⁹Br)＝M⁽⁺⁾

1.1.3: 1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid

400mg of 4-bromo-2- (1-propylbutyl) isoindolin-1-one are introduced into a stirred, carbon monoxide-purged three-necked flask at a temperature of approximately 20 ℃ in succession³Dimethylformamide, 0.6cm³Water, 0.481g potassium acetate, 214mg potassium iodide, 29mg palladium acetate and 68mg triphenylphosphine. The reaction mixture was subjected to carbon monoxide bubbling and then heated at 100 ℃ for 6 hours. The reaction mixture was concentrated under reduced pressure (5kPa) using a rotary evaporator. The obtained beige solid was dissolved in 7.5cm³1M sodium hydroxide, 2g ice and 30cm³In ethyl acetate. After decantation, the aqueous phase took 20cm³And washing with ethyl acetate. Then, under stirring, it took 1.5cm³Acidified (pH 4) with 5M hydrochloric acid solution, and then diluted with 30cm³And (5) extracting with ethyl acetate. 5cm for organic phase³Washing with water, then washing with 5cm³The sodium chloride saturated aqueous solution was washed, dried over magnesium sulfate and concentrated under reduced pressure (5kPa) using a rotary evaporator. 295mg of beige solid obtained are 15cm³Trituration in diisopropyl ether, filtration and drying under vacuum. 264mg of 1-oxo-2- (1-propylbutyl) iso-butyl are obtained as a white solidIndoline-4-carboxylic acid.

·NMR：0.86(t，J＝7.4Hz，6H)1.10-1.24(m，4H)1.46-1.74(m，4H)4.26(m，1H)4.54(S，2H)，7.64(t，J＝7.7Hz，1H)7.90(d，J＝7.7Hz，1H)8.12(d，J＝7.7Hz，1H)，13.41(m，1H)

·MS-EI：275⁽⁺⁾＝M⁽⁺⁾；232⁽⁺⁾＝M⁽⁺⁾-C₃H₇

1.1.4: n- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid amide

Under an inert atmosphere, 136.4mg of 1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid are dissolved in 8cm at a temperature close to 20 ℃³In dichloromethane. To the solution was added 195mg of ((2R, 3S) -3-amino-4-phenyl-1- { [3- (trifluoromethyl) benzyl]Amino } but-2-ol hydrochloride (2: 1), 9.6mg of hydroxybenzotriazole, 108.7mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. Pouring 0.308cm into the reaction medium³N, N-diisopropylethylamine. Stirring was maintained at a temperature of 20 ℃ for 20 hours. Is divided into 10cm³Is added to the reaction medium. 10cm for organic phase³The sodium chloride saturated aqueous solution was washed, dried over magnesium sulfate and concentrated under reduced pressure (5kPa) using a rotary evaporator. The 310mg of beige gum obtained are purified by flash chromatography on silica (column: 15 g; particle size: 20-40 μm, spherical; flow rate: 20 cm)³Per minute; eluent: 95% dichloromethane/5% methanol). After concentrating the fractions under reduced pressure, 110mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] are obtained in the form of a beige foam (meringee)]Amino } propyl group]-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid amide.

1.2: the salt N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -1-oxo-2- (1-propylbutyl) isoindoline-4-carboxamide hydrochloride (1: 1)

In the proximity of110mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] at a temperature of 20 deg.C]Amino } propyl group]-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxamide dissolved in 8cm³In ether. Under argon, 0.5cm of the solution was added while stirring³4M hydrochloric acid solution in dioxane. The reaction mixture precipitated. The precipitate was filtered under a slight vacuum and 2 times 5cm³Washed with diethyl ether and then dried in a desiccator for 2 hours. 80mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] are obtained in the form of a white solid]Amino } propyl group]-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxamide hydrochloride (1: 1).

NMR: 0.83(t, J ═ 7.5Hz, 3H); 0.86(t, J ═ 7.5Hz, 3H); 1.03 to 1.20(m, 4H); 1.51(m, 4H); 2.81(m, 1H); 2.92(m, 1H); 3.18(m, 2H); 3.96(m, 1H); 4.09 to 4.25(m, 4H); 4.31(m, 2H); 5.95 (width m, 1H); 7.13(m, 1H); 7.23(m, 4H); 7.57(t, J ═ 7.5Hz, 1H)7.64(t, J ═ 7.5Hz, 1H); 7.73 to 7.88(m, 4H); 7.97 (width s, 1H); 8.53(d, J ═ 9.0Hz, 1H); 9.00 (width s, 1H); 9.34 (width s, 1H).

·MS-EI：595⁽⁺⁾＝M⁽⁺⁾；552⁽⁺⁾＝M⁽⁺⁾-C₃H₇

Example 2:

2.1: the 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-tetrahydroisoquinoline-5-carboxamide

2.1.1: n- [2- (2-bromophenyl) ethyl ] hept-4-amine

10g of 2-bromophenylethylamine and 5.71g of 4-heptanone were dissolved in 250cm at a temperature close to 20 deg.C³1, 2-dichloroethane. 14.84g of sodium triacetoxyborohydride and 2.9cm³Glacial acetic acid is added to the reaction medium. Stirring was maintained for 20 hours. Will be 300cm³1M sodium hydroxide is added to the reaction medium. The water phase is used for 3 times for 100cm³Is extracted with ethyl acetate. The organic phases were combined and used 4 times 100cm³Washing with water, then washing with 100cm³The sodium chloride saturated aqueous solution was washed, dried over magnesium sulfate and concentrated under reduced pressure (5kPa) using a rotary evaporator. The resulting yellow liquid was purified by flash chromatography on silica (column: 400 g; particle size: 20-40 μm, spherical; flow rate: 30 cm)³Per minute; eluent: gradient from 100% heptane to 70% ethyl acetate/30% heptane). After concentrating the fractions under reduced pressure, 17.33g N- [2- (2-bromophenyl) ethyl ] is obtained]Hept-4-amine.

·LC-MS-DAD-ELSD：298⁽⁺⁾(⁷⁹Br)＝(M+H)⁽⁺⁾

2.1.2: [2- (2-bromophenyl) ethyl ] (1-propylbutyl) carbamic acid methyl ester

Stirring 5.85g N- [2- (2-bromophenyl) ethyl ] at 0 ℃ under an inert atmosphere]Hept-4-amine at 60cm³Solution in anhydrous tetrahydrofuran. 2.76cm³Triethylamine was added to the reaction mixture and then introduced by syringe to 1.52cm in 10 minutes³Methyl chloroformate. The reaction mixture was kept under stirring at 0 ℃ for 1 hour and then at 20 ℃ for 3 hours. Adding 20cm³Saturated aqueous solution of ammonium chloride, then 100cm³And (3) ethyl acetate. The organic phase is used for 4 times and is 30cm³Is washed with water and then with 30cm of water³Washing with saturated aqueous solution of sodium chloride, drying over magnesium sulfate, filtering through (30g) silica pieces (particle size: 40-63 μm) with 50cm³Washed with ethyl acetate and concentrated under reduced pressure (5kPa) on a rotary evaporator. 6.4g of [2- (2-bromophenyl) ethyl ] are obtained in the form of a colorless oil](1-Propylbutyl) carbamic acid methyl ester.

NMR: 0.85(t, J ═ 7.4Hz, 6H)1.12-1.25(m, 4H)1.28-1.54(m, 4H)2.92(m, 2H)3.14(m, 2H)3.62(S, 1H)3.64(S, 2H)3.86 (width m, 0.34H)3.98 (width m, 0.66H)7.18(m, 1H)7.25-7.40(m, 2H)7.60(d, J ═ 7.7Hz, 1H)

·LC-MS-DAD-ELSD：356⁽⁺⁾(⁷⁹Br)＝(M+H)⁽⁺⁾

2.1.3: 5-bromo-2- (1-propylbutyl) -3, 4-dihydroisoquinolin-1 (2H) -one

5.8g of 2- (2-bromophenyl) ethyl are reacted at a temperature close to 20 ℃ under an inert atmosphere](1-Propylbutyl) carbamic acid methyl ester dissolved to 250cm³In dichloromethane. 5.43g of 4-dimethylaminopyridine were added to the reaction mixture. It is cooled to a temperature close to 0 ℃. Dissolving in 250cm³13cm in anhydrous dichloromethane³The triflic anhydride solution was poured into the reaction mixture over 45 minutes. The suspension was kept stirring at a temperature close to 20 ℃ for 20 hours. Will be 300cm³Is added to the reaction medium. Stirring was maintained for 30 minutes. The organic phase is 100cm³100cm of 20% aqueous acetic acid solution³Saturated aqueous solution of sodium carbonate and 100cm³Is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered through a silica plate (50g) (particle size: 40-63 μm) and dried over 500cm³The dichloromethane is flushed and concentrated under reduced pressure (5kPa) using a rotary evaporator. This gave 4.63g of 5-bromo-2- (1-propylbutyl) -3, 4-dihydroisoquinolin-1 (2H) -one in the form of a yellow oil.

·NMR：0.86(t，J＝7.3Hz，6H)1.12-1.30(m，4H)1.41(m，2H)1.51(m，2H)2.96(t，J＝6.6Hz，2H)3.36(t，J＝6.6Hz，2H)4.64(m，1H)7.31(t，J＝7.9Hz，1H)7.76(dd，J＝7.9，1.0Hz，1H)7.91(dd，J＝7.9，1.0Hz，1H)

·LC-MS-DAD-ELSD：324⁽⁺⁾(⁷⁹Br)＝(M+H)⁽⁺⁾

2.1.4: 1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

At a temperature close to 20 ℃, 350mg of 5-bromo-2- (1-propylbutyl) -3, 4-dihydroisoquinoline-1 (2H) -one and 15cm of hydrogen are introduced into a stirred and carbon monoxide purged three-necked flask³Dimethylformamide, 1.5cm³Water, 0.4g potassium acetate36mg of potassium iodide, 97mg of palladium acetate and 227mg of triphenylphosphine. The reaction mixture was subjected to carbon monoxide bubbling and then heated at 100 ℃ for 5 hours and 30 minutes. The reaction mixture was maintained at a temperature of 100 ℃ for 20 hours, and then cooled to 25 ℃ to be filtered through a 45 μm microporous membrane. The residue was used 2 times for 5cm³And 2 X5 cm of dimethylformamide³Washed with ethyl acetate. The filtrate was concentrated under reduced pressure (5kPa) using a rotary evaporator. Dissolving the obtained oily residue in 15cm³And 20cm of water/ice mixture³In ethyl acetate. The pH was basified with 5M sodium hydroxide (pH > 10). After decantation of the filtrate, the aqueous phase is used 3 times for 20cm³Washed with ethyl acetate. Then acidified with 5M hydrochloric acid solution (pH 1) under stirring, and then used 3 times 20cm³Is extracted with ethyl acetate. The organic phase was concentrated and then used for 10cm³Is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure (5kPa) with a rotary evaporator. 125mg of 1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid are obtained in the form of a pale yellow oil.

NMR: 0.87(t, J ═ 7.3Hz, 6H)1.12-1.31(m, 4H)1.40(m, 2H)1.52(m, 2H)3.17-3.42 (partially masked m, 4H)4.66(m, 1H)7.44(t, J ═ 7.8Hz, 1H)7.97(dd, J ═ 7.8, 1.2Hz, 1H)8.10(dd, J ═ 7.8, 1.2Hz, 1H)12.56 (unresolved m, 1H)

·LC-MS-DAD-ELSD：290⁽⁺⁾＝(M+H)⁽⁺⁾

The (2R, 3S) -3-amino-4-phenyl-1- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) butan-2-ol hydrochloride used in step 2.1.5 (2: 1) was prepared as follows. The preparation of 1- (3-trifluoromethylphenyl) cyclopropylamine is described in the literature (Armin de Meijere et al, Organic Letters 2003, 5(5), 753-one 755).

4.6g of 1- (3-trifluoromethylphenyl) cyclopropylamine are dissolved in 12cm at a temperature close to 20 DEG C³In dichloromethane. 7.9g of [ S- (R, R) are added]- (-) -1-Oxiranyl-2-phenylethyl) carbamic acid tert-butyl ester and 2.3g scandium trifluoromethanesulfonate. Reaction mixture in 2Stirring was maintained at a temperature of 0 ℃ for 12 hours. Then at 100cm³Diluted in dichloromethane and successively 2 times 15cm³Water, 20cm³Saturated aqueous solution of sodium bicarbonate and 50cm³Washing with saturated aqueous solution of sodium chloride. The aqueous phase is extracted with dichloromethane, the organic phases are combined, dried using phase separation filters (fitre phases) and concentrated using a rotary evaporator under reduced pressure (5 kPa). The white solid obtained was purified by flash chromatography on a silica column (column: 600 g; particle size: 40-60 μm; flow rate 80 cm)³Per minute; eluent: 80% diisopropyl ether/20% ethyl acetate). 6.8g of [ (1S, 2R) -1-benzyl-2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl) are obtained in the form of a white solid]Cyclopropyl } amino) propyl]Carbamic acid tert-butyl ester.

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

·LC-MS-DAD-ELSD：465⁽⁺⁾＝(M+H)⁽⁺⁾

Melting point: 124 deg.C

Then 6.8g of [ (1S, 2R) -1-benzyl-2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl) are reacted at a temperature close to 20 ℃]Cyclopropyl } amino) propyl]Carbamic acid tert-butyl ester dissolved in 250cm³In dichloromethane. Adding 36.6cm³4M hydrochloric acid solution in dioxane. The reaction mixture was kept stirring at a temperature close to 20 ℃ for 1 hour 30 minutes. The reaction mixture was concentrated under reduced pressure (5kPa) using a rotary evaporator. The beige solid obtained is triturated in diisopropyl ether and then filtered. 5.4g of (2R, 3S) -3-amino-4-phenyl-1- ({1- [3- (trifluoromethyl) phenyl)]Cyclopropyl } amino) but-2-ol hydrochloride (2: 1).

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

·LC-MS-DAD-ELSD：409^(-)Not (M + formic acid-H)^(-)；365⁽⁺⁾＝(M⁺)

2.1.5: n- [ (1S, 2R) -1-benzyl-2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

At a temperature close to 20 deg.C, the thickness of the film is 0.444cm³Pouring N, N-diisopropylethylamine into 125mg of 1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid, 170mg of (2R, 3S) -3-amino-4-phenyl-1- ({1- [3- (trifluoromethyl) phenyl ] ethyl methyl ether]Cyclopropyl } amino) but-2-ol hydrochloride (2: 1), 9mg of hydroxybenzotriazole and 104mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride at 15cm³Suspension in dichloromethane. Stirring of the solution was maintained for 24 hours. Mixing 15cm³Methylene chloride and 15cm³Water is added to the reaction medium. The water phase used was 15cm³Extraction was carried out with dichloromethane. Combining the organic phases, using 10cm³The sodium chloride saturated aqueous solution was washed, dried over magnesium sulfate and concentrated under reduced pressure (5kPa) using a rotary evaporator. 350mg of the oil obtained are purified by flash chromatography on silica (column: 50 g; particle size: 120-40 μm, spherical; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 79mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl)]Cyclopropyl } amino) propyl]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide.

NMR: 0.86(t, J ═ 7.3Hz, 3H)0.87(t, J ═ 7.3Hz, 3H)0.98(m, 2H), 1.04(m, 2H)1.12-1.25(m, 4H)1.32-1.55(m, 4H)2.28-2.45(m, 2H)2.46-2.68 (partially masked m, 3H)3.00(m, 2H)3.13(dd, J ═ 13.9, 3.7Hz, 1H)3.51 (width m, 1H)4.11(m, 1H)4.62(m, 1H)4.86 (width d, J ═ 5.5Hz, 1H)7.05(dd, J ═ 7.7, 1.2, 1H)7.11-7.34(m, 7.6H) (width d, J ═ 5.5Hz, 1H)7.05(dd, J ═ 7.7.7, 1.7, 1H), 7.9, 1H)4.9 (width H), 3.9, 1H)4.9 (dd, 1H).

·LC-MS-DAD-ELSD：634^(-)＝(M-H)^(-)；636⁽⁺⁾＝(M+H)⁽⁺⁾

2.2: salt N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

79mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl) methyl ] phenyl]Cyclopropyl } amino) propyl]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide in a solution of 1.2cm³In diethyl ether. Under argon at 5 deg.C, 0.4cm was added while stirring³2M hydrochloric acid solution in diethyl ether. The reaction mixture precipitated. Stirring was maintained for 20 minutes, and then stirring was terminated to remove the supernatant. Then 5cm of³Diethyl ether. This operation was performed twice. The final suspension was then concentrated under reduced pressure (5 kPa). 68mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl) are obtained in the form of a white solid]Cyclopropyl } amino) propyl]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: 0.86(t, J ═ 7.5Hz, 3H); 0.88(t, J ═ 7.5Hz, 3H); 1.11 to 1.64(m, 12H); 2.31(m, 2H); 2.59(dd, J ═ 11.5 and 14.0Hz, 1H); 2.81(m, 1H); 3.02(m, 3H); 3.15(dd, J ═ 3.0 and 14.0Hz, 1H); 3.80(m, 1H); 4.11(m, 1H); 4.63(m, 1H); 5.84 (width m, 1H); 6.97(d, J ═ 7.5Hz, 1H); 7.17 to 7.33(m, 6H); 7.68(t, J ═ 7.5Hz, 1H); 7.81(d, J ═ 7.5Hz, 1H); 7.90(d, J ═ 7.5Hz, 2H); 8.01(s, 1H); 8.20(d, J ═ 9.0Hz, 1H); 9.35 (broad unresolved m, 1H); 9.70 (broad unresolved m, 1H).

·LC-MS-DAD-ELSD：634^(-)＝(M-H)^(-)；636⁽⁺⁾＝(M+H)⁽⁺⁾

Melting point: 174 deg.C

Example 3:

3.1: the base 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-tetrahydroisoquinoline-5-carboxamide

(2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) but-2-ol hydrochloride (2: 1) was prepared as follows.

At a temperature close to 20 deg.C, 4cm³1M sodium hydroxide was added to 0.794g of 1- (3-trifluoromethylphenyl) cyclopropylamine hydrochloride at 20cm³In solution in water. The solution was stirred for 15 minutes. Adding 40cm³Dichloromethane and the mixture was stirred for 5 minutes. The aqueous phase used was 30cm³Extraction was carried out with dichloromethane. The organic phases were combined, dried over magnesium sulphate and concentrated using a rotary evaporator under reduced pressure (5 kPa). 700mg of 1- (3-trifluoromethylphenyl) cyclopropylamine are obtained, which is dissolved in 12cm³Dichloromethane. 1g of [ (1S) -2- (3, 5-difluorophenyl) -1-oxiran-2-ylethyl]Tert-butyl carbamate and 0.329g scandium triflate were added to the solution. The orange light suspension was kept stirring at ambient temperature for 20 hours. The reaction mixture was concentrated under reduced pressure (5kPa) using a rotary evaporator. The crude product obtained was purified by flash chromatography on silica (column: 200 g; particle size: 15-40 μm; flow rate: 50 cm)³Per minute; eluent: 70% cyclohexane/30% ethyl acetate). After concentrating the fractions under reduced pressure, 0.87g of [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl) in the form of a white solid was obtained]Cyclopropyl } amino) propyl]Carbamic acid tert-butyl ester.

NMR: 0.90-1.04(m, 4H)1.22(s, 9H)2.40(m, 1H)2.46-2.62 (partially masked m, 2H)2.99(dd, J ═ 14.1, 3.2Hz, 1H)3.36(m, 1H)3.52(m, 1H)4.80(d, J ═ 5.9Hz, 1H)6.66(d, J ═ 9.3Hz, 1H)6.86(m, 2H)6.99(tt, J ═ 9.2, 2.4Hz, 1H)7.48-7.61(m, 3H)7.65 (width s, 1H)

LC-MS-DAD-ELSD: 545(-) - (M + formic acid-H) (); 501⁽⁺⁾＝(M+H)⁽⁺⁾；445⁽⁺⁾＝(M+H)⁽⁺⁾-tBu+H

870mg of [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] at 20 ℃ C]Cyclopropyl } amino) propyl]Carbamic acid tert-butyl ester dissolved in 20cm³In dichloromethane. Will be 17.38cm³A1M hydrochloric acid solution in ether was added to the reaction mixture, which was kept stirring at ambient temperature for 20 hours, and then concentrated under reduced pressure (5kPa) using a rotary evaporator. 0.82g of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl ] is obtained in the form of a white solid]Cyclopropyl } amino) but-2-ol hydrochloride (1: 1).

·NMR：1.13-1.37(m，2H)1.53-1.71(m，2H)2.71(m，1H)2.84(dd，J＝14.3，8.2Hz，1H)2.93(dd，J＝14.3，5.9Hz，1H)3.09(m，1H)3.57(m，1H)4.18(m，1H)6.19(m，1H)7.01-7.10(m，3H)7.65(t，J＝7.8Hz，1H)7.77(d，J＝7.8Hz，1H)7.87(d，J＝7.8Hz，1H)7.98(s，1H)8.19(s，3H)9.77(m，1H)10.23(m，1H)

·LC-MS-DAD-ELSD：401⁽⁺⁾＝(M+H)⁽⁺⁾

At a temperature close to 20 deg.C, 0.217cm³N, N-diisopropylethylamine was poured into 150mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl]Cyclopropyl } amino) -but-2-ol hydrochloride (2: 1), 101mg of 1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid, 4mg of hydroxybenzotriazole and 76mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride at 6cm³Suspension in dichloromethane. The solution was kept stirring at a temperature close to 20 ℃ for 24 hours. Mixing 15cm³Is added to the reaction medium. 5cm for organic phase³Washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and spun using a spinnerThe evaporator was concentrated under reduced pressure (5 kPa). The product obtained is purified by flash chromatography on silica (column: 15 g; particle size: 120-40 μm, spherical; flow rate: 10 cm)³Per minute; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 140mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl) in the form of a colorless oil were obtained]-cyclopropyl } amino) propyl]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide.

3.2: the salt 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-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

40mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] was heated at a temperature close to 20 ℃]Cyclopropyl } amino) propyl]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide in 10cm³In diethyl ether. Under argon, 3cm of the solution was added while stirring³1M hydrochloric acid solution in diethyl ether. The reaction mixture precipitated. The precipitate was filtered through sintered glass, 3 times with 5cm³Washed with diethyl ether and then dried in a desiccator at 35c under vacuum for 2 hours. This gave 129mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] methyl) phenyl ] in the form of a white solid]Cyclopropyl } amino) propyl]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: for this batch, all signals are broad: 0.86(t, J ═ 7.5Hz, 3H); 0.87(t, J ═ 7.5Hz, 3H); 1.05 to 1.69(m, 12H); 2.38(m, 2H); 2.63(m, 1H); 2.79(m, 1H); 2.95 to 3.19(m, 4H); 3.81(m, 1H); 4.11(m, 1H); 4.64(m, 1H); 5.86(m, 1H); 6.95(m, 2H); 7.02(d, J ═ 7.5Hz, 1H); 7.07(t, J ═ 9.0Hz, 1H); 7.33(t, J ═ 7.5Hz, 1H); 7.67(t, J ═ 7.5Hz, 1H); 7.80(d, J ═ 7.5Hz, 1H); 7.90 (partially masked d, J ═ 7.5Hz, 1H); 7.93(d, J ═ 7.5Hz, 1H); 8.02(s, 1H); 8.26(d, J ═ 9.0Hz, 1H); 9.39(m, 1H); 9.81(m, 1H).

Melting point: 172 deg.C

Example 4:

4.1: the base N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

At a temperature close to 20 deg.C, under an inert atmosphere, 43mg of 1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid was dissolved in 2.5cm³In dichloromethane. 62mg of (2R, 3S) -3-amino-4-phenyl-1- { [3- (trifluoromethyl) benzyl]Amino } butan-2-ol hydrochloride (2: 1), 3mg hydroxybenzotriazole and 34mg 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added to the solution. Is measured at a distance of 0.124cm³N, N-diisopropylethylamine was poured onto the reaction medium. The medium is kept stirred for 20 hours at a temperature close to 20 ℃. Is divided into 10cm³Dichloromethane (2) was added to the reaction mixture, followed by addition of 10cm³The water of (2). After decantation, the organic phase took 5cm³The sodium chloride saturated aqueous solution was washed, dried over magnesium sulfate and concentrated under reduced pressure (5kPa) using a rotary evaporator. 100mg of the resulting colorless oil were purified by flash chromatography on silica (column: 7 g; particle size: 20-40 μm, spherical; flow rate: 20 cm)³Per minute; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 40mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] are obtained in the form of a colorless oil]Amino } propyl group]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide.

NMR: 0.88(t, J ═ 7.5Hz, 3H); 0.90(t, J ═ 7.5Hz, 3H); 1.17 to 1.29(m, 4H); 1.37 to 1.56(m, 4H); 2.46 to 2.60 (partially masked m, 2H); 2.62 to 2.78(m, 3H); 2.97 to3.18 (partially masked m, 3H); 3.67(m, 1H); 3.87(m, 2H); 4.22(m, 1H); 4.62(m, 1H); 4.70(m, 1H); 7.17(m, 2H); 7.22 to 7.30 (partially masked m, 5H); 7.52(t, J ═ 7.5Hz, 1H); 7.56(d, J ═ 7.5Hz, 1H); 7.64(d, J ═ 7.5Hz, 1H); 7.69(s, 1H); 7.91(m, 2H)

4.2: the salt N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

38mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] are reacted at a temperature close to 20 deg.C]Amino } propyl group]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide was dissolved in 8cm³Diethyl ether of (2). Under argon, 0.2cm of the solution was added while stirring³4M hydrochloric acid solution in dioxane. The reaction mixture precipitated. Stirring was stopped to remove the supernatant, and 5cm additional time was added³Diethyl ether. This operation was performed 3 times. The final suspension was concentrated under reduced pressure (5 kPa). 26mg of N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] are obtained in the form of a white solid]Amino } propyl group]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: 0.85(t, J ═ 7.5Hz, 3H); 0.89(t, J ═ 7.5Hz, 3H); 1.10 to 1.27(m, 4H); 1.32 to 1.57(m, 4H); 2.33(m, 2H); 2.62(m, 1H); 2.91(m, 1H); 3.03(m, 2H); 3.13(m, 1H); 3.21(m, 1H); 3.85(m, 1H); 4.17(m, 1H); 4.34 (width S, 2H); 4.63(m, 1H); 5.93 (width d, J ═ 6.0Hz, 1H); 7.15 to 7.36(m, 7H); 7.69(t, J ═ 7.5Hz, 1H); 7.80(d, J ═ 7.5Hz, 1H); 7.87(d, J ═ 7.5Hz, 1H); 7.91(d, J ═ 7.5Hz, 1H); 8.00(s, 1H); 8.27(d, J ═ 9.0Hz, 1H); 9.04 (broad unresolved m, 1H); 9.30 (Wide unresolved m, 1H)

·LC-MS-DAD-ELSD：608^(-)＝(M-H)^(-)；654^(-)Not (M + formic acid-H)^(-)；610⁽⁺⁾＝(M+H)⁽⁺⁾

Example 5:

5.1: the base 2-benzyl-N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide

5.1.1: methanesulfonic acid 2- (2-bromophenyl) ethyl ester

9.8g of 2- (2-bromophenyl) ethanol and 4.7cm were added at a temperature close to 20 deg.C³Pyridine is dissolved in 200cm under inert atmosphere³In dichloromethane. The reaction mixture was cooled to a temperature close to 0 ℃ and 4.55cm was added dropwise³Methanesulfonyl chloride. Stirring was maintained for 72 hours, and the medium was gradually re-warmed to a temperature close to 20 ℃ during stirring. Will be 100cm³To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate. Stirring was maintained for 10 minutes. The aqueous phase was extracted with dichloromethane. The organic phases are combined, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and then concentrated using a rotary evaporator under reduced pressure (5 kPa). 18g of the brown oil obtained are purified by flash chromatography on silica (column: 200 g; particle size: 15-40 μm; eluent: gradient from 100% dichloromethane to 90% dichloromethane/10% ethyl acetate).

After concentrating the fractions under reduced pressure, 12.9g of 2- (2-bromophenyl) ethyl methanesulfonate were obtained as a colorless oil.

·EI：m/z＝278⁺⁷⁹Br＝M⁺；m/z＝183(M-OSO₂CH₃)⁺；m/z＝169(m/z＝183-CH₂)⁺；m/z＝90(m/z＝169-Br)⁺.

5.1.2: n-benzyl-2- (2-bromophenyl) ethylamine

Under reflux of the solvent, 3.18g of 2- (2-bromophenyl) ethyl methanesulfonate, 6.2g of 1-phenylmethylamine, 7.87g of potassium carbonate and 65cm of³Tetrahydrofuran was stirred under an inert atmosphere for 16 hours. The reaction mixture was cooled to a temperature close to 20 ℃ and then placed on iceIn (1). Then adding 100cm³Ethyl acetate and 200cm³And (3) water. Stirring was maintained for 5 minutes. The aqueous phase was extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). 7.8g of the brown oil obtained are purified by flash chromatography on silica (column: 400 g; particle size: 15-40 μm; eluent: gradient from 100% dichloromethane to 90% dichloromethane/10% methanol). After concentration of the fractions under reduced pressure, 2.49g N-benzyl-2- (2-bromophenyl) ethylamine was obtained.

NMR: 2.21 (broad unresolved m, 1H)2.72(t, J ═ 7.6Hz, 2H)2.86(t, J ═ 7.6Hz, 2H)3.73(S, 2H)7.09-7.38(m, 8H)7.55 (broad d, J ═ 8.1Hz, 1H)

·LC-MS-DAD-ELSD：m/z＝290⁷⁹Br＝MH⁺；m/z＝198(M-CH₂Ph)⁺；m/z＝91＝(CH₂Ph)⁺

5.1.3: benzyl [2- (2-bromophenyl) ethyl ] carbamic acid methyl ester

2.48g N-benzyl-2- (2-bromophenyl) ethylamine was stirred at 50cm at 0 ℃ under an inert atmosphere³Solution in anhydrous tetrahydrofuran. 1.2cm in length³Triethylamine was added to the reaction mixture, which was then introduced into 0.67cm by syringe³Methyl chloroformate. The reaction mixture was kept stirring at 0 ℃ for 1 hour and then at a temperature close to 20 ℃ for 5 hours. The reaction mixture was poured onto a mixture comprising ice, ethyl acetate and water. Stirring was maintained for 10 minutes. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The brown oil obtained is purified by flash chromatography on silica (column: 200 g; particle size: 15-40 μm; eluent: 70% cyclohexane/30% ethyl acetate). After concentrating the fractions under reduced pressure, 2.51g of benzyl [2- (2-bromophenyl) ethyl ] are obtained in the form of an oil]Methyl carbamate.

NMR: 2.89(t, J ═ 7.6Hz, 2H)3.37(t, J ═ 7.6Hz, 2H)3.50-3.67 (broad unresolved m, 3H)4.39(S, 2H)7.11-7.39(m, 8H)7.57 (broad d, J ═ 8.1Hz, 1H)

·LC-MS-DAD-ELSD：m/z＝348⁷⁹Br＝MH⁺；m/z＝270＝(M-Ph)⁺；m/z＝91＝(CH₂Ph)⁺

·EI：m/z＝347⁷⁹Br＝M⁺；m/z＝268＝(M-Br)⁺；m/z＝178＝(m/z＝268-(CH₂Ph)⁺；m/z＝91＝(CH₂)Ph)⁺

5.1.4: 2-benzyl-5-bromo-3, 4-dihydroisoquinoline-1 (2H) -one

0.5g of benzyl [2- (2-bromophenyl) ethyl ] acetate are added at a temperature close to 20 ℃ under an inert atmosphere]Methyl carbamate dissolved in 20cm³In dichloromethane. 0.526g N, N-dimethylpyridin-4-amine was added and the reaction mixture was cooled to a temperature close to 0 ℃. Introduced dropwise at 1.2cm³Trifluoromethanesulfonic anhydride. The resulting suspension was stirred at a temperature close to 0 ℃ for 15 minutes and then for 4 hours 30 minutes while gradually increasing the temperature close to 20 ℃. Dichloromethane was added to the reaction mixture and a saturated aqueous solution of ammonium chloride was added. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over magnesium sulphate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The crude product obtained (1g) was purified by flash chromatography on silica (column: 90 g; particle size: 15-40 μm; eluent: gradient from 100% dichloromethane to 95% dichloromethane/5% ethyl acetate). After concentrating the fractions under reduced pressure, 0.22g of 2-benzyl-5-bromo-3, 4-dihydroisoquinolin-1 (2H) -one is obtained.

·NMR：3.01(t，J＝6.7Hz，2H)3.52(t，J＝6.7Hz，2H)4.71(S，2H)7.22-7.40(m，6H)7.79(dd，J＝7.8，1.4Hz，1H)7.98(dd，J＝7.8，1.4Hz，1H)

·ES：m/z＝316⁷⁹Br＝MH⁺；m/z＝238＝(M+H-Ph)⁺

5.1.5: 2-benzyl-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

At a temperature close to 20 ℃, 0.46g of 2-benzyl-5-bromo-3, 4-dihydroisoquinoline-1 (2H) -one and 18cm of hydrogen are introduced into a stirred and carbon monoxide purged three-necked flask³Dimethylformamide, 1.8cm³Water, 0.543g of potassium acetate, 48mg of potassium iodide, 131mg of palladium acetate and 305mg of triphenylphosphine. The reaction mixture was subjected to carbon monoxide bubbling and then heated at 100 ℃ for 6 hours. The reaction mixture was maintained at 100 ℃ for 20 hours under carbon monoxide overpressure, and then cooled to 25 ℃ to be filtered through a 45 μm microporous membrane. The residue was washed with ethyl acetate. The filtrate was concentrated under reduced pressure (5kPa) using a rotary evaporator. The resulting oily residue was dissolved in a mixture of ice and ethyl acetate. The pH was basified with 5M sodium hydroxide (pH > 10). After decanting the filtrate, the aqueous phase was washed with 2 times of ethyl acetate. Then, the mixture was acidified (pH 1) with a 5M hydrochloric acid solution under stirring, and then extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). 440mg of the crude product obtained are purified by flash chromatography on silica (particle size: 15-40 μm; eluent: 95% dichloromethane/5% methanol). After concentrating the fractions under reduced pressure, 315mg of 2-benzyl-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid was obtained in the form of yellow crystals.

·NMR：3.30(t，J＝6.5Hz，2H)3.47(t，J＝6.5Hz，2H)4.73(S，2H)7.25-7.39(m，5H)7.47(t，J＝7.8Hz，1H)8.00(dd，J＝7.8，1.5Hz，1H)8.15(dd，J＝7.8，1.5Hz，1H)

·ES：m/z＝282＝MH⁺

5.1.6: 2-benzyl-N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide

Stirring was carried out at a temperature close to 20 ℃ with 100mg of 2-benzyl-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid, 168mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl ] methyl) ethyl acetate]Cyclopropyl } amino) but-2-ol hydrochloride (2: 1), 7.2mg hydroxybenzotriazole, 85mg 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.243cm³N, N-diisopropylethylamine at 10cm³Solution in dichloromethane for 20 hours. Dichloromethane was added to the reaction medium. The organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). 400mg of the product obtained are purified by flash chromatography on silica (column: 50 g; particle size: 15-40 μm; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 103mg of 2-benzyl-N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl)]Cyclopropyl } amino) propyl]-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide.

NMR: 0.95(m, 2H)1.02(m, 2H)2.38-2.55 (partially masked m, 5H)3.11(dd, J ═ 13.7, 3.1Hz, 1H)3.28 (partially masked m, 2H)3.50(m, 1H)4.11(m, 1H)4.69(m, 2H)4.89(d, J ═ 5.9Hz, 1H)6.91(m, 2H)6.97(tt, J ═ 9.2, 2.2Hz, 1H)7.11(dd, J ═ 7.7, 1.2Hz, 1H)7.26-7.39(m, 6H)7.46(m, 2H)7.55(m, 1H)7.67 (width s, 1H)7.97(dd, J ═ 7, 1H)7.8, J ═ 1H) 7.7.9, 1H (d, 1H)7.9 Hz, 1H

·ES：m/z＝664＝MH⁺

5.2: the salt 2-benzyl-N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

100mg of 2-benzyl-N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] was reacted at a temperature close to 20 ℃]Cyclopropyl } amino) propyl]-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide dissolved in 2cm³In diethyl ether. Due to the fact thatThe material was crystallized and diethyl ether was removed under reduced pressure (5 kPa). The residue was hot dissolved in ethyl acetate and the resulting solution was cooled to a temperature close to 0 ℃ and added 0.7cm³2M hydrochloric acid solution in diethyl ether. Stirring was maintained for 15 minutes. The solution was then concentrated under reduced pressure (5 kPa). Adding 3cm³Diethyl ether. The reaction mixture precipitated. Stirring was stopped to remove the supernatant, and then additional ether was added. This operation was performed twice. The final suspension was then concentrated under reduced pressure (5 kPa). 94mg of 2-benzyl-N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a pale yellow solid]Cyclopropyl } amino) propyl]-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: 1.11-1.65(m, 4H); 2.30 to 3.40 (partially masked m, 8H); 3.78(m, 1H); 4.10(m, 1H); 4.65(d, J ═ 15.0Hz, 1H); 4.72(d, J ═ 15.0Hz, 1H); 5.81 (broad unresolved m, 1H); 6.81(m, 2H); 7.00(tt, J ═ 2.5and9.5hz, 1H); 7.05(dd, J ═ 1.5 and 7.5Hz, 1H); 7.29(m, 3H); 7.38(m, 3H); 7.61(t, J ═ 7.5Hz, 1H); 7.72 (width d, J ═ 7.5Hz, 1H); 7.85 (width d, J ═ 7.5Hz, 1H); 7.98 (masked dm, 1H); 7.99(dd, J ═ 1.5 and 7.5Hz, 1H); 8.28(d, J ═ 9.0Hz, 1H); 9.20 to 9.80 (broad unresolved m, 2H)

·ES：m/z＝663＝MH⁺

Melting point: 178 deg.C

Example 6

6.1: the base N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -1-oxo-2-pentyl-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide

6.1.1: n- [2- (2-bromophenyl) ethyl ] pentan-1-amine

7g of 2- (2-bromophenyl) ethyl methanesulfonate, 14.5 g of ethyl methanesulfonate were stirred at a temperature between 65 ℃ and 70 ℃ under an inert atmospherecm³1-Pentylamine, 17.33g of Potassium carbonate and 200cm³Tetrahydrofuran was used for 72 hours. The reaction mixture was raised to 30 ℃ to pour it into a mixture of water, ice and ethyl acetate. The phases were stirred for 5 minutes and then separated. The aqueous phase was extracted 3 times with ethyl acetate. The organic phases are combined, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). 6.6g of the oil obtained are purified by flash chromatography on silica (column: 200 g; particle size: 15-40 μm; eluent: gradient 95% dichloromethane/5% methanol to 90% dichloromethane/10% methanol). After concentrating the fractions under reduced pressure, 4.56g of N- [2- (2-bromophenyl) ethyl ] are obtained in the form of a white oil]Pentane-1-amine.

NMR: 0.86(t, J ═ 7.0Hz, 3H)1.21-1.32(m, 4H)1.41(m, 2H)2.55(t, J ═ 7.3Hz, 2H)2.74(m, 2H)2.84(m, 2H)3.14 (broad unresolved m, 1H)7.14(td, J ═ 7.7, 2.0Hz, 1H)7.22-7.39(m, 2H)7.56(dd, J ═ 7.7, 2.0Hz, 1H)

·ES：m/z＝270(⁷⁹Br)＝MH⁺

6.1.2: [2- (2-bromophenyl) ethyl ] pentylcarbamic acid methyl ester

4.51g N- [2- (2-bromophenyl) ethyl ] ethyl were stirred at 5 ℃ under an inert atmosphere]Pentane-1-amine at 120cm³Suspension in anhydrous tetrahydrofuran. 2.33cm³To the reaction mixture was added triethylamine, followed by 1.3cm³Methyl chloroformate of (1). Stirring was carried out at a temperature close to 20 ℃ for 20 hours, and then the mixture was poured into a mixture of water and ice. The phases were stirred for 5 minutes and then separated. The aqueous phase was extracted 3 times with ethyl acetate. The organic phases are combined, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). 6.33g of the oil obtained are purified by flash chromatography on silica (column: 200 g; particle size: 15-40 μm; eluent: 20% heptane/80% ethyl acetate). After concentrating the fractions under reduced pressure, 5.45g of [2- (2-bromobenzene) are obtained as a colorless oilYl) ethyl]Methyl amyl carbamate.

NMR: 0.85(t, J ═ 7.3Hz, 3H)1.18(m, 2H)1.27(m, 2H)1.43(m, 2H)2.91(m, 2H)3.11 (wide t, J ═ 7.6Hz, 2H)3.38(m, 2H)3.45-3.70 (wide unresolved m, 3H)7.17(m, 1H)7.32(m, 2H)7.59(d, J ═ 7.8Hz, 1H)

·ES：m/z＝328(⁷⁹Br)＝MH⁺；m/z＝258＝(M-C₅H₁₀)⁺；m/z＝226＝(m/z＝258-OCH₄)⁺；m/z＝183＝(m/z＝226-NHC0)⁺

6.1.3: 5-bromo-2-pentyl-3, 4-dihydroisoquinolin-1 (2H) -one

5.44g of [2- (2-bromophenyl) ethyl ] are introduced at a temperature close to 20 ℃ under an inert atmosphere]Methyl amyl carbamate dissolved in 200cm³In dichloromethane. 6.07g of 4-dimethylaminopyridine were added to the reaction mixture. It is cooled to a temperature near 0 ℃. The diameter of the tube is 13.94cm³Triflic anhydride was poured into the reaction mixture over 15 minutes. The suspension was kept stirring at a temperature close to 20 ℃ for 4 hours. Mixing dichloromethane and 50cm³To the reaction medium. The 4-dimethylaminopyridine was filtered. The filtrate was decanted and the aqueous phase was extracted with dichloromethane. The organic phases are combined, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The crude product obtained is purified by flash chromatography on silica (column: 200 g; particle size: 15-40 μm; eluent: 90% dichloromethane/10% ethyl acetate). After concentrating the fractions under reduced pressure, 4.14g of 5-bromo-2-pentyl-3, 4-dihydroisoquinolin-1 (2H) -one are obtained in the form of a colorless oil.

·NMR：0.87(t，J＝7.1Hz，3H)1.20-1.38(m，4H)1.55(m，2H)3.00(t，J＝6.7Hz，2H)3.45(t，J＝7.3Hz，2H)3.56(t，J＝6.7Hz，2H)7.30(t，J＝7.8Hz，1H)7.76(dd，J＝7.8，1.2Hz，1H)7.90(dd，J＝7.8，1.2Hz，1H)

·ES：m/z＝296(⁷⁹Br)＝MH⁺；m/z＝318＝MNaH⁺；m/z＝359＝MNaACNH⁺；m/z＝613＝(2MNaH⁺)

6.1.4: 1-oxo-2-pentyl-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

At a temperature close to 20 ℃, 500mg of 5-bromo-2-pentyl-3, 4-dihydroisoquinoline-1 (2H) -one and 18cm of hydrogen are introduced into a stirred and carbon monoxide purged three-necked flask³Dimethylformamide, 2cm³Water, 0.63g potassium acetate, 56mg potassium iodide, 152mg palladium acetate and 354mg triphenylphosphine. The reaction mixture was subjected to carbon monoxide bubbling and then heated at 100 ℃ for 6 hours and 30 minutes. The reaction mixture was kept at 100 ℃ for 20 hours, and then cooled to 25 ℃ to be filtered using a 45 μm microporous membrane. The filtrate was concentrated under reduced pressure (5kPa) using a rotary evaporator. The resulting residue was dissolved in a water/ice mixture and ethyl acetate. The pH was basified with 5M sodium hydroxide (pH > 10). After decantation, the aqueous phase was washed 3 times with ethyl acetate. The aqueous phase was acidified with 5M hydrochloric acid solution (pH 1) under stirring and then extracted 3 times with ethyl acetate. The organic phases are combined, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated using a rotary evaporator under reduced pressure (5 kPa). 430mg of 1-oxo-2-pentyl-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid are obtained in the form of a beige solid.

NMR: 0.87(t, J ═ 7.1Hz, 3H)1.19-1.39(m, 4H)1.56(m, 2H)3.30 (partially masked m, 2H)3.44-3.53(m, 4H)7.44(t, J ═ 7.8Hz, 1H)7.97(dd, J ═ 7.8, 1.5Hz, 1H)8.08(dd, J ═ 7.8, 1.5Hz, 1H)13.15 (unresolved m, 1H)

·ES：m/z＝262＝MH⁺；m/z＝523(2MH⁺)

6.1.5: n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -1-oxo-2-pentyl-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide

326mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl ] was reacted at a temperature close to 20 ℃]Cyclopropyl } amino) but-2-ol hydrochloride (2: 1), 180mg of 1-oxo-2-pentyl-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid, 14mg of hydroxybenzotriazole, 165mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.47cm³N, N-diisopropylethylamine at 18cm³The mixture was stirred in dichloromethane for 20 hours. Is divided into 10cm³Water and dichloromethane are added to the reaction medium. The suspension was filtered and washed with water followed by dichloromethane. The resulting solid was dissolved in ether, filtered, washed with ether and dried under vacuum at 20 ℃. 360mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white solid]Cyclopropyl } amino) propyl]-1-oxo-2-pentyl-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide.

NMR: 0.87(t, J ═ 7.1Hz, 3H)0.98(m, 2H)1.04(m, 2H)1.18-1.38(m, 4H)1.53(m, 2H)2.36-2.69 (partially masked m, 3H)3.13(dd, J ═ 14.2, 3.4Hz, 1H)3.31 (partially masked m, 6H)4.12(m, 1H)4.93(d, J ═ 5.9Hz, 1H)6.93(m, 2H)7.03(tt, J ═ 9.2, 2.0Hz, 1H)7.08 (wide d, J ═ 7.8Hz, 1H)7.31(t, J ═ 7.8Hz, 1H)7.46-7.65(m, 4H)7.69 (wide d, J ═ 7.8Hz, 1H)7.31(t, J ═ 7.8Hz, 1H)7.9, 1H, 7.9H, 1H, 7.9 (m, 4H) 7.9, 7.8H, J ═ 1H, 1H)7.9 (d, 1H)

·ES：m/z＝644＝MH⁺；m/z＝642＝MH^-；m/z＝688＝MHCOO^-

6.2: the salt N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -1-oxo-2-pentyl-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

Stirring at 6cm under inert atmosphere at a temperature close to 5 deg.C³360mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] in diethyl ether]Cyclopropyl } amino) propyl]-1-oxo-2-pentyl-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide. Adding 1.9cm³2M hydrochloric acid solution in diethyl ether. Under reduced pressure (5 kP)a) The solution was concentrated. Diethyl ether was added. The suspension was stirred and after stopping the stirring, the supernatant was removed. Further diethyl ether was added. This operation is performed a plurality of times. The final suspension was then concentrated under reduced pressure (51 kPa). 363mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white solid]Cyclopropyl } amino) propyl]-1-oxo-2-pentyl-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: 0.88(t, J ═ 7.0Hz, 3H); 1.18 to 1.40(m, 6H); 1.47 to 1.70(m, 4H); 2.30 to 2.82 (partially masked m, 4H); 3.02(m, 1H); 3.12(m, 1H); 3.20 to 3.60 (partially masked m, 4H); 3.83(m, 1H); 4.10(m, 1H); 5.87 (broad unresolved m, 1H); 6.95(m, 2H); 7.05(m, 2H); 7.32(t, J ═ 7.5Hz, 1H); 7.68(t, J ═ 7.5Hz, 1H); 7.81 (width d, J ═ 7.5Hz, 1H); 7.91 (width d, J ═ 7.5Hz, 2H); 8.03 (width s, 1H); 8.31(d, J ═ 8.5Hz, 1H); 9.44 (width m, 1H); 9.96 (Width m, 1H)

·ES：m/z＝644＝MH⁺；m/z＝1287＝(2MH⁺)

Melting point: 165 deg.C

Example 7:

7.1: the base N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- (2-methoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide

7.1.1: 2- (2-bromophenyl) -N- (2-ethoxyethyl) ethylamine

Under reflux of the solvent, 3.5g of 2- (2-bromophenyl) ethyl methanesulfonate, 5.59g of 2-ethoxyethylamine, 8.67g of potassium carbonate and 70cm of³Tetrahydrofuran was used for 48 hours. The heating was stopped and the reaction mixture was then filtered. The insoluble material was washed twice with ethyl acetate. The filtrate was concentrated under reduced pressure (5kPa) using a rotary evaporator. The obtained product is subjected to flash chromatographyThe separation was purified on silica (column: 330 g; particle size: 20-40 μm, spherical; eluent: gradient from 100% ethyl acetate to 90% ethyl acetate/10% methanol). After concentrating the fractions under reduced pressure, 2.45g of 2- (2-bromophenyl) -N- (2-ethoxyethyl) ethylamine were obtained in the form of a yellow oil.

NMR: 1.09(t, J ═ 7.1Hz, 3H)1.78 (broad unresolved m, 1H)2.68(t, J ═ 5.9Hz, 2H)2.74(m, 2H)2.82(m, 2H)3.37-3.44(m, 4H)7.14(td, J ═ 7.7, 2.0Hz, 1H)7.28-7.37(m, 2H)7.56(dd, J ═ 7.7, 2.0Hz, 1H)

·EI-MS：283m/z＝212＝(M-CH₂OC₂H₅)⁺；m/z＝183＝(m/z＝212-NHCH₂)⁺

·ES-MS：m/z＝272(⁷⁹Br)＝MH⁺；m/z＝226＝(M-OC₂H₅)⁺；m/z＝183＝(m/z＝226-NHC₂H₄)⁺

7.1.2: [2- (2-bromophenyl) ethyl ] (2-ethoxyethyl) carbamic acid methyl ester

2.45g of 2- (2-bromophenyl) -N- (2-ethoxyethyl) ethylamine and 1.4cm of³Triethylamine at 22cm³Solution in anhydrous tetrahydrofuran. 1.3cm in length³Methyl chloroformate at 4cm³A solution in tetrahydrofuran was poured into the reaction mixture. The mixture was then stirred at a temperature close to 20 ℃ for 20 hours. Adding 50cm³Saturated aqueous solution of ammonium chloride and 50cm³And (3) ethyl acetate. After decantation, the organic phase took 20cm³Then 20cm of water³Is washed twice with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered through a 30g silica bed (lit). The latter is 75cm³The ethyl acetate was washed twice. The filtrate was concentrated under reduced pressure (5kPa) using a rotary evaporator. 2.97g of [2- (2-bromophenyl) ethyl ] are obtained in the form of a yellow oil](2-ethoxyethyl) carbamic acid methyl ester.

NMR: 1.08(t, J ═ 7.1Hz, 3H)2.92(m, 2H)3.28 (partially masked m, 2H)3.34-3.63(m, 9H)7.17(m, 1H)7.26-7.39(m, 2H)7.59 (width d, J ═ 7.8Hz, 1H)

·ES-MS：m/z：330(⁷⁹Br)＝MH⁺；m/z：298＝(M-OCH₃)⁺；m/z：284＝(M-OC₂H₅)⁺

7.1.3: 5-bromo-2- (2-hydroxyethyl) -3, 4-dihydroisoquinolin-1 (2H) -one

1.5g of [2- (2-bromophenyl) ethyl ] are introduced at a temperature close to 20 ℃ under an inert atmosphere](2-ethoxyethyl) carbamic acid methyl ester dissolved in 140cm³In dichloromethane. 1.6g of 4-dimethylaminopyridine are added to the reaction mixture, which is cooled to a temperature of approximately 0 ℃. Mixing 3.7cm³Trifluoromethanesulfonic anhydride at 15cm³A solution in dichloromethane was poured into the reaction mixture over 30 minutes. The suspension was kept under stirring at 0 ℃ for 1 hour and then at a temperature close to 20 ℃ for 48 hours. Will be 100cm³To the reaction medium. Stirring was maintained at a temperature close to 20 ℃ for 1 hour. After decantation, the organic phase took 100cm³Is washed with a 20% aqueous solution of acetic acid and then with 150cm of water³Was washed with saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate and concentrated under reduced pressure (5kPa) using a rotary evaporator. The crude product obtained was purified by filtration over a 20g silica bed. The latter being 100cm³Washed with ethyl acetate. The filtrate was concentrated under reduced pressure (5kPa) using a rotary evaporator. 0.8g of 5-bromo-2- (2-hydroxyethyl) -3, 4-dihydroisoquinolin-1 (2H) -one is obtained in the form of a beige oil.

·NMR：3.01(t，J＝6.6Hz，2H)3.47-3.67(m，6H)4.74(t，J＝5.4Hz，1H)7.31(t，J＝7.8Hz，1H)7.76(dd，J＝7.8，1.1Hz，1H)7.90(dd，J＝7.8，1.1Hz，1H)

·ES-MS：m/z：270(⁷⁹Br)＝MH⁺；m/z：252＝(M-H₂O)⁺；m/z：292＝MNaH⁺

7.1.4: 5-bromo-2- (2-methoxyethyl) -3, 4-dihydroisoquinolin-1 (2H) -one

At a temperature close to 20 deg.C, under an inert atmosphere, 0.39g 5-bromo-2- (2-hydroxyethyl) -3, 4-dihydroisoquinoline-1 (2H) -one is dissolved in 3cm³In dimethyl sulfoxide. 105mg of finely ground potassium hydroxide were added. The reaction mixture was stirred at a temperature close to 20 ℃ for 30 minutes and then 0.108cm was introduced³Methyl iodide. Stirring was maintained at a temperature close to 20 ℃ for 20 hours. Adding 30cm³Water (2) and 30cm³Diethyl ether of (2). After decantation, the organic phase took 30cm³The sodium chloride saturated aqueous solution was washed, dried over magnesium sulfate, filtered and concentrated under reduced pressure (5kPa) using a rotary evaporator. 170mg of 5-bromo-2- (2-methoxyethyl) -3, 4-dihydroisoquinolin-1 (2H) -one are obtained in the form of a yellow oil.

·NMR：2.99(t，J＝6.8Hz，2H)3.26(s，3H)3.52(m，2H)3.59-3.66(m，4H)7.31(t，J＝7.8Hz，1H)7.77(dd，J＝7.9，1.2Hz，1H)7.90(dd，J＝7.9，1.2Hz，1H)

·ES-MS：m/z＝284(⁷⁹Br)＝MH⁺；m/z＝252(⁷⁹Br)＝(m/z＝284-CH₃OH)⁺；m/z＝306(⁷⁹Br)＝MNaH⁺

7.1.5: 2- (2-methoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

At a temperature close to 20 ℃, 165mg of 5-bromo-2- (2-methoxyethyl) -3, 4-dihydroisoquinolin-1 (2H) -one, 4cm were introduced into a stirred and carbon monoxide purged three-necked flask³Dimethylformamide, 0.27cm³Water, 0.217g potassium acetate, 96mg potassium iodide, 26mg palladium acetate and 61mg triphenylphosphine. The reaction mixture was subjected to carbon monoxide bubbling, then heated at a temperature of 100 ℃ for 4 hours, and then heated at a temperature close to 20 ℃ for 20 hours. The reaction mixture was filtered through a Cellite 545 plate, which was 10cm³Two-agentThe formamide is washed twice. The filtrate was concentrated under reduced pressure (5kPa) using a rotary evaporator. The obtained residue was dissolved in 20cm³Water, 2cm³5M sodium hydroxide and 10cm³In ethyl acetate. After decantation the aqueous phase used 10cm³And washing with diethyl ether. Acidification with 5M hydrochloric acid solution (pH 3-4) with stirring, followed by 15cm³Ethyl acetate and 10cm³And (4) extracting with dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated using a rotary evaporator under reduced pressure (5 kPa). This gave 107mg of 2- (2-methoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid as an orange powder.

NMR: 3.27(s, 3H)3.29(t, J ═ 6.6Hz, 2H)3.50-3.58(m, 4H)3.65(t, J ═ 5.7Hz, 2H)7.44(t, J ═ 7.8Hz, 1H)7.98(dd, J ═ 7.8, 1.5Hz, 1H)8.09(dd, J ═ 8.1, 1.2Hz, 1H)12.79 (unresolved m, 1H)

·ES-MS：m/z＝250＝MH⁺；m/z＝272MNaH⁺；m/z＝521＝(2MNaH⁺)

7.1.6: n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- (2-methoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide

At a temperature close to 20 deg.C, 0.28cm³N, N-diisopropylethylamine was poured into 242mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl]Cyclopropyl } amino) but-2-ol hydrochloride (2: 1), 104mg of 2- (2-methoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid, 8mg of hydroxybenzotriazole, 99mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride at 7cm³Suspension in dichloromethane. The reaction mixture was kept stirring at a temperature close to 20 ℃ for 20 hours. The resulting suspension was filtered and the precipitate was taken up in 5cm³Washed 3 times with diethyl ether and then dried under vacuum. 79mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white powder]Cyclopropyl } amino) propyl]-2- (2-methoxy)Ethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide.

NMR: 0.94-1.08(m, 4H)1.25 (broad unresolved m, 1H)2.34-2.83 (partially masked m, 5H)3.12(dd, J ═ 13.9, 3.7Hz, 1H)3.26(s, 3H)3.36(m, 2H)3.46-3.70(m, 5H)4.13(m, 1H)4.91(d, J ═ 6.4Hz, 1H)6.93(m, 2H)7.02(tt, J ═ 9.4, 2.2Hz, 1H)7.09(dd, J ═ 7.8, 1.0Hz, 1H)7.32(t, J ═ 7.8Hz, 1H)7.46-7.60(m, 3H)7.69(s, 1H)7.90 (J ═ 7.8, 1H)7.46-7.60(m, 3H)7.69(s, 1H)7.90 (J ═ 1H )7.8, 1H (dd, 1H)7.8, 1H) 1.17 (d

7.2: the salt N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- (2-methoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

79mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl) are introduced at a temperature close to 20 DEG C]Cyclopropyl } amino) propyl]-2- (2-methoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide in 2cm³In dioxane. Under argon, at a temperature of 20 ℃ and while stirring, 1cm of³4M hydrochloric acid solution in diethyl ether. The reaction mixture was concentrated under vacuum at 40 ℃.83 mg of N- [ (1S, 2R) -1-3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white powder]Cyclopropyl } amino) propyl]-2- (2-methoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: 1.20 to 1.68(m, 4H); 2.30 to 2.86 (partially masked m, 4H); 3.00(m, 1H); 3.12(m, 1H); 3.20 to 3.70 (partially masked m, 9H); 3.79(m, 1H); 4.12(m, 1H); 5.83(m, 1H); 6.93(m, 2H); 7.04(m, 2H); 7.33(t, J ═ 7.5Hz, 1H); 7.69 (width t, J ═ 7.5Hz, 1H); 7.81 (width d, J ═ 7.5Hz, 1H); 7.89 (width m, 1H); 7.92(d, J ═ 7.5Hz, 1H); 8.01 (width s, 1H); 8.26 (width d, J ═ 8.5Hz, 1H); 9.32 (width m, 1H); 9.49 (Width m, 1H)

·ES-MS：m/z：632＝MH⁺

Example 8:

8.1: the base N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- (2-ethoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide

8.1.1: 5-bromo-2- (2-ethoxyethyl) -3, 4-dihydroisoquinolin-1 (2H) -one

At a temperature close to 20 deg.C, under an inert atmosphere, 0.363g 5-bromo-2- (2-hydroxyethyl) -3, 4-dihydroisoquinoline-1 (2H) -one is dissolved in 3cm³In dimethyl sulfoxide. 98mg of finely ground potassium hydroxide was added. The reaction mixture was stirred at a temperature close to 20 ℃ for 30 minutes and then 0.131cm was introduced³And iodoethane. Stirring was maintained at a temperature close to 20 ℃ for 20 hours. Adding 50cm³And 80cm of water/ice mixture³Diethyl ether of (2). After decantation, the organic phase took 10cm³30cm of water³Was washed 3 times with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure (5kPa) using a rotary evaporator. 356mg of 5-bromo-2- (2-ethoxyethyl) -3, 4-dihydroisoquinolin-1 (2H) -one are obtained in the form of a colorless oil.

·NMR：1.09(t，J＝7.1Hz，3H)3.00(t，J＝6.6Hz，2H)3.45(q，J＝7.1Hz，2H)3.55(m，2H)3.62(m，4H)7.31(t，J＝7.8Hz，1H)7.77(dd，J＝7.8，1.2Hz，1H)7.90(dd，J＝7.8，1.2Hz，1H)

·ES-MS：m/z：298(⁷⁹Br)＝MH⁺；m/z：252(⁷⁹Br)＝(M-OC₂H₆)⁺；m/z：320(⁷⁹Br)＝MNaH⁺

·EI-MS：m/z：297(⁷⁹Br)＝M⁺；m/z：268(⁷⁹Br)＝(M-C₂H₅)⁺；m/z：251(⁷⁹Br)＝(m/z＝268-OH)⁺；m/z：238(⁷⁹Br)＝(m/z＝251-CH)⁺；m/z：159＝(m/z＝238-Br)⁺

8.1.2: 2- (2-ethoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

At a temperature close to 20 ℃, 350mg of 5-bromo-2- (2-ethoxyethyl) -3, 4-dihydroisoquinoline-1 (2H) -one and 9cm of hydrogen were introduced into a stirred and carbon monoxide purged three-necked flask³Dimethylformamide, 0.5cm³Water, 0.438g potassium acetate, 195mg potassium iodide, 53mg palladium acetate and 123mg triphenylphosphine. The reaction mixture was subjected to carbon monoxide bubbling, then heated at a temperature of 100 ℃ for 4 hours, and then heated at a temperature close to 20 ℃ for 20 hours. The reaction mixture was filtered through a Cellite 545 plate, which was used with 10cm³Two washes with dimethylformamide were performed. The filtrate was concentrated under reduced pressure (5kPa) using a rotary evaporator. The obtained residue was dissolved in 20cm³Water, 2cm³5M sodium hydroxide and 30cm³In ethyl acetate. After decantation, the aqueous phase used 10cm³And washing with diethyl ether. Then acidified with 5M hydrochloric acid solution (pH 4) under stirring and then with 20cm³The dichloromethane was extracted twice. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated using a rotary evaporator under reduced pressure (5 kPa). 114mg of 2- (2-ethoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid are obtained in the form of a beige powder.

NMR: 1.09(t, J ═ 7.1Hz, 3H)3.29(t, J ═ 6.6Hz, 2H)3.45(q, J ═ 7.1Hz, 2H)3.56(m, 4H)3.63(m, 2H)7.44(t, J ═ 7.8Hz, 1H)7.97(d, J ═ 7.8Hz, 1H)8.08(d, J ═ 7.8Hz, 1H)13.04 (unresolved m, 1H)

·ES-MS：m/z＝264＝MH⁺；m/z＝218＝(M-OC₂H₆)⁺；m/z＝286＝MNaH⁺

8.1.3: n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- (2-ethoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide

At a temperature close to 20 deg.C, 0.3cm³N, N-diisopropylethylamine was poured into 255mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl]Cyclopropyl } amino) but-2-ol hydrochloride (2: 1), 113.5mg of 2- (2-ethoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid, 9mg of hydroxybenzotriazole, 104mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride at 7.6cm³Suspension in dichloromethane. The reaction mixture was kept stirring at a temperature close to 20 ℃ for 20 hours. The resulting suspension was filtered and the precipitate was taken up in 5cm³Washing with dichloromethane once, using 5cm³Diisopropyl ether was washed twice and then dried under vacuum. 82mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white powder]Cyclopropyl } amino) propyl]-2- (2-ethoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide.

·LC-MS-DAD-ELSD：[M+H]⁺：m/z 646；[M+H]^-：m/z 644

8.2: the salt N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- (2-ethoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

82mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl) are stirred at a temperature close to 20 ℃ under argon]Cyclopropyl } amino) propyl]-2- (2-ethoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide and 1cm³2M hydrochloric acid solution in diethyl ether. The stirring was stopped and the ether was removed. The resulting paste was dried at 40 ℃ under vacuum. 86mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white powder]Cyclopropyl } amino) propyl]-2- (2-ethoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: 1.09(t, J ═ 7.0Hz, 3H); 1.20 to 1.40(m, 2H); 1.48 to 1.65(m, 2H); 2.30 to 2.85 (partially masked m, 4H); 2.97 to 3.72 (partially masked m, 10H); 3.80(m, 1H); 4.12(m, 1H); 5.84 (width m, 1H); 6.93(m, 2H); 7.03(m, 2H); 7.34(t, J ═ 7.5Hz, 1H); 7.69(t, J ═ 7.5Hz, 1H); 7.81 (width d, J ═ 7.5Hz, 1H); 7.89 (width d, J ═ 7.5Hz 1H); 7.92 (width d, J ═ 7.5Hz, 1H); 8.02 (width s, 1H); 8.29(d, J ═ 8.5Hz, 1H); 9.35 (width m, 1H); 9.60 (Width m, 1H)

·ES-MS：m/z：646＝MH⁺；m/z：668＝MNaH⁺

Example 9:

9.1: the base N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

9.1.1: 1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester

In a close to 20 degrees C temperature, in stirring and with carbon monoxide purge three-neck flask into the sequence of 10g 5-bromo-2- (1-propyl butyl) -3, 4-two hydrogen isoquinoline-1 (2H) -ketone, 65cm³Methanol and 130cm³Dimethylformamide (DMF). 1.354g of [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride was added to the reaction medium and 10.5cm were added³N, N-diisopropylethylamine was poured into the reaction mixture. It was subjected to carbon monoxide bubbling and then heated at a temperature of 70 ℃ for 20 hours. The reaction mixture was cooled to a temperature close to 0 ℃, purged with argon and poured into a container containing 300cm³0.5M aqueous hydrochloric acid solution and 1000cm³The mixture of ethyl acetate was then filtered through celite 545. After decanting the filtrate, the organic phase was used 5 times for 100cm³Is washed with water and then with 2 times 100cm³Is washed with a saturated aqueous solution of sodium chloride, which is dried over magnesium sulfateAnd concentrated under reduced pressure (5kPa) using a rotary evaporator. 12.5g of the product obtained are purified by flash chromatography on silica (column: 400 g; particle size: 15-40 μm; eluent: 50% heptane/50% ethyl acetate). After concentrating the fractions under reduced pressure, 8.8g of methyl 1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate were obtained in the form of a yellow oil.

·NMR：0.87(t，J＝7.1Hz，6H)1.13-1.30(m，4H)1.41(m，2H)1.51(m，2H)3.22(m，2H)3.30(m，2H)3.85(s，3H)4.66(m，1H)7.47(t，J＝7.8Hz，1H)7.98(dd，J＝7.8，1.5Hz，1H)8.13(dd，J＝7.8，1.5Hz，1H)

·EI：m/z＝303＝M⁺；m/z＝260＝(M-C₃H₇)⁺；m/z＝145＝(m/z＝260-COOCH₃CHC₃H₇)⁺

·ES：m/z＝304＝MH⁺；m/z＝326＝MNaH⁺；m/z＝367＝MACNH⁺；m/z＝629＝(2MNaH⁺)

9.1.2: 7-Nitro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester

At a temperature close to 20 ℃, under an inert atmosphere, 7.9g 1-oxo-2- (1-propyl butyl) -1,2,3, 4-four hydrogen isoquinoline-5-methyl formate dissolved in 60cm³Concentrated sulfuric acid (95%). The reaction mixture was cooled to a temperature close to 0 ℃ and then 12cm was introduced within 1 hour³Nitric acid. The temperature is maintained close to 0 ℃ for 3 hours and then 12cm is introduced again within 1 hour³Nitric acid. The reaction mixture was kept stirring at a temperature below 5 ℃ for 8 hours and then poured into a flask containing 100g of ice and 100cm³A mixture of water. 700cm for the aqueous phase³And (4) extracting with dichloromethane. After decantation, the organic phase took 2 times 100cm³Was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure (5kPa) using a rotary evaporator. 9g of the crude product obtained are passed through a tube at 50cm³By grinding in hot diisopropyl etherAnd (5) purifying. After filtration at a temperature close to 20 ℃ for 2 times 20cm³Washed with diisopropyl ether and dried under vacuum to give 8.6g of methyl 7-nitro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate in the form of beige crystals.

·NMR：4.66(tt，J＝10.0，4.9Hz，1H)8.69(d，J＝2.9Hz，1H)8.78(d，J＝2.9Hz，1H)

·ES：m/z：349＝MH⁺；m/z：390＝MACNH⁺(acetonitrile)；m/z：719＝(2MNaH⁺)；m/z：697＝2MH⁺

9.1.3: 7-amino-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester

At 25 degrees C, in 2 bar hydrogen in an autoclave make 8.6g 7-nitro-1-oxo-2- (1-propyl butyl) -1,2,3, 4-four hydrogen isoquinoline-5-methyl formate, 10cm³Methanol and 28mg of dry 10% palladium on carbon were stirred for 2 hours 20 minutes. The catalyst was filtered through a Cellite 545 plate and used 2 times 100cm³Is washed with methanol. The filtrate was then concentrated under reduced pressure (5 kPa). 7.7g in light green powder form of 7-amino-1-oxo-2- (1-propyl butyl) -1,2,3, 4-four hydrogen isoquinoline-5-methyl formate.

·NMR：0.86(t，J＝7.1Hz，6H)1.13-1.29(m，4H)1.38(m，2H)1.49(m，2H)3.01(t，J＝6.4Hz，2H)3.20(t，J＝6.4Hz，2H)3.80(s，3H)4.64(m，1H)5.39(S，2H)7.22(d，J＝2.9Hz，1H)7.38(d，J＝2.9Hz，1H)

·ES：m/z：319＝MH⁺；m/z：360＝MACNH⁺；m/z：659＝(2MNaH⁺)；m/z：637＝2MH⁺

9.1.4: 7- [ (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester

0.5g of 7-amino-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroiso-yl is reacted at a temperature close to 20 ℃ under an inert atmosphereQuinoline-5-carboxylic acid methyl ester dissolved in 5cm³In dichloromethane. Will be 0.142cm³Pyridine was poured into the reaction mixture and then cooled to a temperature close to 5 ℃. 0.122cm was introduced within 30 minutes³Methanesulfonyl chloride. Stirring was maintained for 20 hours while gradually re-warming to a temperature close to 20 ℃. Is measured by a distance of 20cm³And 5cm of a saturated aqueous solution of sodium hydrogencarbonate³To the reaction mixture. Stirring was maintained at a temperature close to 20 ℃ for 1 hour. The water phase used was 10cm³Extraction was carried out with dichloromethane. After decantation, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure (5kPa) using a rotary evaporator. The crude product obtained was passed through a tube at 10cm³Purification was carried out by trituration in hot diisopropyl ether. Filtering, and standing at a temperature close to 20 deg.C for 2 times of 5cm³Washed with diisopropyl ether and dried under vacuum to give 0.6g of 7- [ (methylsulfonyl) amino group in the form of pink crystals]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester.

NMR: 0.86(t, J ═ 7.1Hz, 6H)1.21(m, 4H)1.34-1.58(m, 4H)3.00(s, 3H)3.16(m, 2H)3.29 (masked m, 2H)3.85(s, 3H)4.62(m, 1H)7.86(s, 1H)8.00(s, 1H)9.99(s, 1H)

·ES：m/z：397＝MH⁺；m/z：816＝(2MNaH⁺)；m/z：793＝2MH⁺

9.1.5: 7- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester

1.4g of 7- [ (methylsulfonyl) amino group are reacted at a temperature close to 20 ℃ under an inert atmosphere]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester was dissolved in 18cm³In dimethylformamide. The solution was cooled to a temperature close to 0 ℃ and 141mg of sodium hydride (60% in oil) were added in 2 portions. The reaction mixture was stirred at a temperature close to 0 ℃ for 2 hours. Introducing 0.264cm³Then stirring is maintained for 20 hours while gradually increasing the temperature to approximately 20 fTemperature of deg.C. Is measured by a distance of 20cm³Frozen water and 50cm³Ethyl acetate was added to the reaction mixture. After decantation, the organic phase took 20cm³2M aqueous hydrochloric acid solution, 3 times 20cm³The water is then reused by 30cm³Washing with saturated aqueous solution of sodium chloride. It was then dried over magnesium sulfate, filtered and then concentrated under reduced pressure (5kPa) using a rotary evaporator. 1.187g of 7- [ methyl (methylsulfonyl) amino group are obtained in the form of beige crystals]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester.

·NMR：0.87(t，J＝7.3Hz，6H)1.14-1.31(m，4H)1.34-1.45(m，2H)1.49-1.60(m，2H)2.99(s，3H)3.21(t，J＝6.5Hz，2H)3.29(s，3H)3.33(t，J＝6.5Hz，2H)3.87(s，3H)4.66(m，1H)7.97(d，J＝2.6Hz，1H)8.13(d，J＝2.6Hz，1H)

·ES：m/z：411＝MH⁺；m/z：455＝(MHCOO^-)

9.1.6: 7- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

0.25g of 7- [ methyl (methylsulfonyl) amino group at a temperature close to 20 DEG C]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester dissolved in 5cm³In dioxane. Adding 1.52cm³1M aqueous sodium hydroxide solution and the reaction mixture was then heated to a temperature close to 60 ℃ for 1 hour. The dioxane contained in the reaction mixture was concentrated under reduced pressure (5kPa) using a rotary evaporator. Is measured by a distance of 20cm³Diethyl ether and 10cm³Water was added to the residue obtained. After decantation, the aqueous phase used 1.6cm³Is acidified with 1M aqueous hydrochloric acid. The water phase used was 20cm³Extraction was carried out with dichloromethane. After decantation, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure (5kPa) using a rotary evaporator. 0.233g of 7- [ methyl (methylsulfonyl) amino group is obtained in the form of a pale pink powder]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid.

NMR: 0.87(t, J ═ 7.3Hz, 6H)1.13-1.30(m, 4H)1.35-1.45(m, 2H)1.42-1.57(m, 2H)2.98(s, 3H)3.25(m, 4H)3.28(s, 3H)4.66(m, 1H)7.97(d, J ═ 2.6Hz, 1H)8.09(d, J ═ 2.6Hz, 1H)13.35 (broad unresolved m, 1H)

·ES：m/z＝397＝MH⁺；m/z＝419＝MNaH⁺；m/z＝815＝(2MNaH⁺)；m/z＝793＝2MH⁺

9.1.7: n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

At a temperature close to 20 deg.C, 0.4cm³N, N-diisopropylethylamine was poured into 233mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl]Cyclopropyl } amino) but-2-ol hydrochloride (2: 1), 278mg of 7- [ methyl (methylsulfonyl) amino]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid, 12mg hydroxybenzotriazole and 142mg 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride at 10cm³Suspension in dichloromethane. The solution was kept stirring at a temperature close to 20 ℃ for 20 hours. Is measured by a distance of 20cm³Is added to the reaction medium. After decantation, the organic phase is filtered through a 15g 40-63 μm silica plate. The silica piece was used 150cm for the first time³Washing with dichloromethane and then a second time with 150cm³A mixture of 50% ethyl acetate/50% dichloromethane was washed. The second filtrate was concentrated under reduced pressure (5kPa) using a rotary evaporator. 330mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white foam]Cyclopropyl } amino) propyl]-7- [ methyl (methylsulfonyl) amino]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide.

NMR: 0.86(t, J ═ 7.5Hz, 3H)0.87(t, J ═ 7.5Hz, 3H)0.94-1.09(m, 4H)1.20(m, 4H)1.33-1.56(m, 4H)2.45-2.54 (partially masked m, 3H)2.64(m, 2H)2.72 (broad, unresolved m, 1H)2.96(s, 3H)3.03-3.13(m, 3H)3.22(s, 3H)3.55(m, 1H)4.14(m, 1H)4.64(m, 1H)4.95(d, J ═ 5.8Hz, 1H)6.95(m, 2H)7.05(tt, J ═ 9.5, 1.9, 1H)7.18 (J ═ 7.5, J ═ 7.8H), 7.5H (J ═ 7.5, 1H) 7.59 (J ═ 7.8H), 7.5H) (J ═ 1.8Hz, 1H) 3H (m, 1H) 3.55(m, 1H)4.5 Hz, 1H)4.9, 1.8Hz, 7.8Hz, 7.1H) 7.5Hz, 7.1H, 7.9, 7.1H, 7.5H, 7.

·LC-MS-DAD-ELSD：[M+H]+m/z＝779；[M-H]-m/z＝777

9.2: the salt N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

330mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] was added at a temperature close to 20 ℃]Cyclopropyl } amino) propyl]-7- [ methyl (methylsulfonyl) amino]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide in 10cm³In diethyl ether. At a temperature of 20 ℃ under argon, 1cm of a solution was added with stirring³2M hydrochloric acid solution in diethyl ether. The reaction mixture precipitated. Filtering the solid with 5cm³Washed with ether and dried under vacuum at a temperature of 35 ℃ for 3 hours. 310mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white powder]Cyclopropyl } amino) propyl]-7- [ methyl (methylsulfonyl) amino]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: for this batch, all signals were broad: 0.88(m, 6H); 1.11 to 1.67(m, 12H); 2.35 to 3.40 (partially masked m, 8H); 2.99(s, 3H); 3.26(s, 3H); 3.83(m, 1H); 4.12(m, 1H); 4.65(m, 1H); 5.88(m, 1H); 6.97(d, J ═ 9.5Hz, 2H); 7.10(t, J ═ 9.5Hz, 1H); 7.22(d, J ═ 2.0Hz, 1H); 7.69(t, J ═ 8.0Hz, 1H); 7.80(d, J ═ 8.0Hz, 1H); 7.90(d, J ═ 8.0Hz, 1H); 7.92(d, J ═ 2.0Hz, 1H); 8.00(s, 1H); 8.39(d, J ═ 8.5Hz, 1H); 9.38 (width u undefined m, 1H); 9.69 (Wide unresolved m, 1H)

·ES：m/z＝779＝MH⁺；m/z＝778＝MH^-；m/z＝823＝(MHCOO^-)

Example 10:

10.1: the base N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- [1- (4-fluorophenyl) ethyl ] -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide

10.1.1: 1- (1-bromoethyl) -4-fluorobenzene

0.5g of 1- (4-fluorophenyl) ethanol is dissolved in 20cm at a temperature close to 20 ℃ under an inert atmosphere³Dichloromethane (2). 1.24cm of this reaction mixture was introduced in two portions³Pure bromo (trimethyl) silane. The latter is stirred for 48 hours at a temperature close to 20 ℃ and then washed with a saturated aqueous solution of sodium chloride, dried using a phase separation cartridge and concentrated under reduced pressure (5kPa) using a rotary evaporator. 700mg of the crude product obtained are purified by filtration through silica plates (eluent: 10% ethyl acetate/90% cyclohexane). After concentrating the fractions under reduced pressure, 439mg of 1- (1-bromoethyl) -4-fluorobenzene were obtained as a colorless thick oil.

·NMR：ppm：1.98(d，J＝6.8Hz，3H)5.53(q，J＝6.8Hz，1H)7.19(t，J＝8.8Hz，2H)7.56(dd，J＝8.8，5.4Hz，2H)

·EI：[M]⁺m/z＝202；[M-Br]⁺m/z＝123

10.1.2: [2- (2-bromophenyl) ethyl ] carbamic acid methyl ester

Stirring at a temperature close to 10 deg.C under inert atmosphere for 30cm³5g of 2- (2-bromophenyl) ethylamine and 10g of potassium carbonate in anhydrous tetrahydrofuran. 2.5cm in length³Methyl chlorocarbonate is 10cm³A solution in tetrahydrofuran was poured into the reaction mixture. Return to close toAfter a temperature of 20 ℃, the reaction mixture was heated in reflux of the solvent for 2 hours. The potassium carbonate was filtered and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure (5kPa) using a rotary evaporator. 3.43g of [2- (2-bromophenyl) ethyl ] are obtained in the form of a colorless thick oil]Methyl carbamate.

NMR: 2.85(t, J ═ 6.5Hz, 2H); 3.22(q, J ═ 6.5Hz, 2H); 3.51(s, 3H); 7.18(m, 1H); 7.22 (width t, J ═ 6.5Hz, 1H); 7.31(m, 2H); 7.59(d, J ═ 8.0Hz, 1H)

10.1.3: 5-bromo-3, 4-dihydroisoquinolin-1 (2H) -one

1.36g of methyl [2- (2-bromophenyl) ethyl ] carbamate and 5.2g of phosphoric acid are stirred at a temperature close to 150 ℃ under an inert atmosphere. The reaction mixture was cooled to a temperature close to 20 ℃ and then hydrolyzed by sonication with a mixture of water and ethyl acetate. After decantation, the organic phase is washed with a saturated aqueous solution of sodium bicarbonate, water, saturated aqueous solution of sodium chloride and then concentrated under reduced pressure (5kPa) using a rotary evaporator. 0.105g of 5-bromo-3, 4-dihydroisoquinolin-1 (2H) -one is obtained in the form of an amorphous beige solid.

NMR: 2.98(t, J ═ 6.5Hz, 2H); 3.40(dt, J ═ 3.5 and 6.5Hz, 2H); 7.30(t, J ═ 8.0Hz, 1H); 7.78 (width d, J ═ 8.0Hz, 1H); 7.89 (width d, J ═ 8.0Hz, 1H); 8.05 (Wide s, 1H)

10.1.4: 5-bromo-2- [1- (4-fluorophenyl) ethyl ] -3, 4-dihydroisoquinolin-1 (2H) -one

Under inert atmosphere at a temperature of approximately 20 deg.C, 0.15g is added to 5cm³5-bromo-3, 4-dihydroisoquinolin-1 (2H) -one in dimethylformamide was poured into a flask containing 31mg of sodium hydride (60% in oil) and 10cm³Dimethylformamide. Then 0.2g is added to 5cm³1- (1-bromoethyl) -4-fluorobenzene in dimethylformamide was poured into the reaction mixture. It was stirred for 20 hours at a temperature close to 20 ℃. Water and ethyl acetate were added to the reaction mixture. After decantation, the organic phase is saturated with sodium chlorideAnd the aqueous solution was washed, dried over magnesium sulfate, filtered and then concentrated under reduced pressure (5kPa) using a rotary evaporator. 325mg of the crude product obtained are purified by filtration over a silica plate (eluent: 20% ethyl acetate/80% cyclohexane). After concentrating the fractions under reduced pressure, 146mg of 5-bromo-2- [1- (4-fluorophenyl) ethyl in the form of a pale yellow thick oil are obtained]-3, 4-dihydroisoquinolin-1 (2H) -one.

·NMR：ppm：1.54(d，J＝7.3Hz，3H)2.85(m，1H)2.97(m，1H)3.10(m，1H)3.47(m，1H)5.92(q，J＝7.3Hz，1H)7.18(t，J＝8.8Hz，2H)7.33(t，J＝8.1Hz，1H)7.41(dd，J＝8.8，5.9Hz，2H)7.78(dd，J＝8.1，1.4Hz，1H)7.98(dd，J＝8.1，1.4Hz，1H)

·LC-MS-DAD-ELSD：[M+H]⁺m/z＝348

10.1.5: 2- [1- (4-fluorophenyl) ethyl ] -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

0.53g of 5-bromo-2- [1- (4-fluorophenyl) ethyl ] are introduced successively at a temperature of approximately 20 ℃ into a stirred three-necked flask which is purged with carbon monoxide]-3, 4-dihydroisoquinolin-1 (2H) -one, 12cm³Dimethylformamide, 0.7cm³Water, 0.570g potassium acetate, 253mg potassium iodide, 68mg palladium acetate and 160mg triphenylphosphine. The reaction mixture was subjected to carbon monoxide bubbling and then heated at 100 ℃ for 5 hours. The reaction mixture was cooled to 20 ℃ and stirred for 20 hours. The reaction mixture was again bubbled with carbon monoxide and then heated at a temperature of 100 ℃ for 3 hours. It was cooled to 20 ℃, filtered, rinsed with dimethylformamide and the filtrate was evaporated using a rotary evaporator under reduced pressure (5 kPa). The obtained residue was dissolved in 5cm³5M sodium hydroxide and ethyl acetate. After decantation, the organic phase is extracted with water. The aqueous phases were combined and used for 5cm³Acidification with 5M hydrochloric acid (pH 4-5) followed by extraction with ethyl acetate. The organic phase was washed with water, saturated aqueous solution with sodium chloride, dried over magnesium sulfate, filtered and then concentrated under reduced pressure (5kPa) using a rotary evaporator. 0.375g of 2- [1-, (in the form of a pale yellow thick oil) is obtained4-fluorophenyl) ethyl]-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid.

NMR: 1.54(d, J ═ 7.0Hz, 3H)3.02-3.44(m, 4H)5.94(q, J ═ 7.0Hz, 1H)7.18(t, J ═ 8.8Hz, 2H)7.41(dd, J ═ 8.8, 5.4Hz, 2H)7.46(t, J ═ 7.8Hz, 1H)7.98(dd, J ═ 7.8, 1.5Hz, 1H)8.15(dd, J ═ 7.8, 1.5Hz, 1H)12.85 (unresolved m, 1H)

·LC-MS-DAD-ELSD：[M+H]+m/z＝314；[M-H]-m/z＝312

10.1.6: n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- [1- (4-fluorophenyl) ethyl ] -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide

200mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl) are introduced at a temperature close to 20 ℃]Cyclopropyl } amino) but-2-ol hydrochloride (2: 1) and 0.221cm³N, N-diisopropylethylamine was added to 133mg of 2- [1- (4-fluorophenyl) ethyl ester]-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxylic acid at 20cm³Suspension in dichloromethane. 5.7mg of hydroxybenzotriazole, 5mg of dimethylaminopyridine and 97mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are added successively. The solution was kept under stirring at a temperature close to 20 ℃ for 6 hours. The reaction mixture was washed with water and then with a saturated aqueous solution of sodium chloride. It is dried using a phase separation cartridge (car separation de phase) and concentrated using a rotary evaporator under reduced pressure (5 kPa). 290mg of the product obtained are purified by flash chromatography on silica (column: 25 g; particle size: 15-40 μm; eluent: 20% cyclohexane/80% ethyl acetate). After concentrating the fractions under reduced pressure, 0.202g of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl) was obtained in the form of a whitish foam]Cyclopropyl } amino) propyl]-2- [1- (4-fluorophenyl) ethyl]-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide.

NMR: 1.19-1.39(m, 2H)1.49-1.68(m, 2H)1.51(d, J-7.1 Hz, 1.5H)1.53(d, J-7.1 Hz, 1.5H)2.19-3.28(m, 8H)3.82(m, 1H)4.07(m, 1H)5.85 (unresolved m, 1H)5.93(q, J-7.1 Hz, 1H)6.95-7.10(m, 4H)7.19(m, 2H)7.32-7.42(m, 3H)7.61(t, J-7.8 Hz, 0.5H)7.64(t, J-7.8 Hz, 0.5H)7.72(d, J-7.8, 7.8H) 7.8, 7.8H, 7H, 7.8H, 7H

·LC-MS-DAD-ELSD：[M+H]+m/z＝696；[M-H]-m/z＝694

10.2: the salt N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- [1- (4-fluorophenyl) ethyl ] -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

202mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] at a temperature close to 20 ℃]Cyclopropyl } amino) propyl]-2- [1- (4-fluorophenyl) ethyl]-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide is dissolved in a mixture comprising diethyl ether and a few drops of methanol. Adding 5cm³1M hydrochloric acid solution in diethyl ether. The reaction mixture was concentrated under reduced pressure (5kPa) using a rotary evaporator. The resulting solid was triturated in diisopropyl ether, filtered and dried. 206mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white amorphous solid]Cyclopropyl } amino) propyl]-2- [1- (4-fluorophenyl) ethyl]-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: for this batch, a 50%/50% mixture of isomers was obtained in the following observed ranges: 1.18 to 1.40(m, 2H); 1.48 to 1.68(m, 5H); 2.20 to 3.28(m, 8H); 3.81(m, 1H); 4.09(m, 1H); 5.83 (broad unresolved m, 1H); 5.93(q, J ═ 7.5Hz, 1H); 6.95 to 7.10(m, 4H); 7.19(t, J ═ 9.0Hz, 0.5H); 7.20(t, J ═ 9.0Hz, 0.5H); 7.30 to 7.42(m, 3H); 7.60(t, J ═ 7.6Hz, 0.5H); 7.65(t, J ═ 7.5Hz, 0.5H); 7.71(d, J ═ 7.5Hz, 0.5H); 7.75(d, J ═ 7.5Hz, 0.5H); 7.88(d, J ═ 7.5Hz, 0.5H); 7.90(d, J ═ 7.5Hz, 0.5H); 8.00(m, 2H); 8.27(d, J ═ 8.5Hz, 0.5H); 8.29(d, J ═ 8.5Hz, 0.5H); 9.40 (width m, 1H); 9.92 (Width m, 1H)

Melting point: 157 deg.C

Example 11:

11.1 base N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -6- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-3-methyl-4-carboxylic acid amide

11.1.1: 1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid methyl ester

3.481g of 4-bromo-2- (1-propylbutyl) isoindolin-1-one (prepared as in example 1.1.2) were dissolved in 40cm in a stirred three-necked flask purged with carbon monoxide³Methanol and 80cm³Anhydrous dimethylformamide. 3.908g N, N-diisopropylethylamine was added followed by 493mg of [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride. The reaction mixture was subjected to carbon monoxide sparging and heated at a temperature of approximately 70 ℃ for 6 hours 30 minutes. The reaction mixture was cooled to a temperature close to 0 ℃ and subsequently 180cm was added again³1M aqueous hydrogen chloride solution and 1000cm³And (3) ethyl acetate. The mixture was filtered through a pad of celite. Separating the organic phase and using successively 5X 100cm³Distilled water and 2X 100cm³Washing with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The red residual oil was purified by column chromatography (silica 60-particle size: 15-40 μm-200 g-eluent: 80% cyclohexane/20% ethyl acetate). The fractions were concentrated under reduced pressure (5 kPa). 1.92g of methyl 1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylate are obtained in the form of a yellow oil.

·NMR：0.86(t，J＝7.3Hz，6H)1.17(m，4H)1.49-1.70(m，4H)3.91(s，3H)4.27(m，1H)4.56(S，2H)7.67(t，J＝7.8Hz，1H)7.95(dd，J＝7.8，1.3Hz，1H)8.15(dd，J＝7.8，1.3Hz，1H)

·LC-MS-DAD-ELSD：[M+H]+m/z＝290；[2M+Na]+m/z＝601

11.1.2: 6-Nitro-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid methyl ester

In a three-necked flask, 1.92g of methyl 1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylate was dissolved in 20cm³In concentrated sulfuric acid. The reaction mixture was cooled to a temperature near 0 ℃. The reaction medium is introduced for 3cm while maintaining a temperature close to 0 ℃ within 30 minutes³Concentrated nitric acid (60% -density 1.38) which is then returned to a temperature of approximately 20 ℃. The mixture was stirred at this temperature for 12 hours and then added to 2.60cm³Concentrated nitric acid, stirring was maintained for 2 hours. While stirring, the reaction medium is poured into 30g of ice and 30cm³Mixture of distilled water, then 200cm³And (5) extracting with ethyl acetate. 2X 150cm for organic phase³The saturated solution of sodium chloride was washed, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual yellow oil was purified by column chromatography (silica 60-particle size: 15-40 μm-200 g-eluent: 80% cyclohexane/20% ethyl acetate). The fractions were concentrated under reduced pressure (5 kPa). 1.57g of a mixture comprising methyl 6-nitro-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylate were obtained, which was used in the next step without purification.

·NMR：0.87(t，J＝7.3Hz，6H)1.18(m，4H)1.50-1.74(m，4H)3.97(s，3H)4.28(m，1H)4.71(S，2H)8.54(d，J＝2.4Hz，1H)8.77(d，J＝2.4Hz，1H)

·LC-MS-DAD-ELSD：[M+H]+m/z＝335；[M-H]-m/z＝333

11.1.3: 6-amino-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid methyl ester

In an autoclave, 1.52g of 6-Nitro-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid methyl ester dissolved in 15cm³Methanol. Adding 100mg of suspension in 1cm³5% palladium on carbon in methanol. The autoclave was placed under a hydrogen pressure of 2 bar and the mixture was stirred for 5 minutes at a temperature close to 25 ℃. The reaction medium is filtered through a pad of celite. 2 x 10cm for diatomite³Methanol rinse, then the organic phase was concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual yellow oil was purified by column chromatography (silica 60-particle size: 15-40 μm-150 g-eluent: 60% cyclohexane/40% ethyl acetate). The fractions were concentrated under reduced pressure (5 kPa). 1.05g of methyl 6-amino-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylate in the form of a pale yellow solid are obtained.

·NMR：0.85(t，J＝7.3Hz，6H)1.15(m，4H)1.45-1.67(m，4H)3.85(s，3H)4.20(m，1H)4.32(S，2H)5.63(S，2H)7.06(d，J＝2.4Hz，1H)7.38(d，J＝2.4Hz，1H)

·LC-MS-DAD-ELSD：[M+H]+m/z＝305；[2M+H]+m/z＝609

Melting point 114 deg.C

11.1.4: 6- [ (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid methyl ester

In a three-necked flask, 500mg of 6-amino-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid methyl ester were dissolved in 5cm³Dichloromethane. 150 μ l of pyridine was added and the reaction mixture was cooled to a temperature near 0 ℃. 188mg of methanesulfonyl chloride were added over 15 minutes, and then the mixture was returned to a temperature of approximately 25 ℃ and stirred for 12 hours. Adding 5cm successively³Distilled water and 20cm³The solution was saturated with sodium chloride and allowed to stir at a temperature of approximately 25 ℃ for 1 hour. Adding 10cm³Dichloromethane. The organic phase was separated, dried and then concentrated using a rotary evaporator under reduced pressure (5 kPa). Residual yellow solid and 15cm³The hot diisopropyl ether was triturated with each other. The mixture is returned to a temperature of approximately 25 ℃. The remaining solid was filtered and then washed with 2X 5cm³Two different kinds ofAnd (4) rinsing with propyl ether. 574mg of 6- [ (methylsulfonyl) amino group are obtained in the form of a beige solid]-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid methyl ester.

NMR: 0.86(t, J ═ 7.3Hz, 6H)1.16(m, 4H)1.46-1.70(m, 4H)3.03(S, 3H)3.90(S, 3H)4.24(m, 1H)4.49(S, 2H)7.73(d, J ═ 2.4Hz, 1H)7.98(d, J ═ 2.4Hz, 1H)10.19 (broad unresolved m, 1H)

LC-MS-DAD-ELSD: [ M + H ] + M/z 383; [2M + H ] + M/z ═ 765 (peak base); [ M-H ] -M/z ═ 381

Melting point 173 deg.C

11.1.5: 6- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid methyl ester and 6- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-3-methyl-4-carboxylic acid methyl ester

In a three-necked flask, 500mg of 6- [ (methylsulfonyl) amino group]-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid methyl ester dissolved in 10cm³Anhydrous dimethylformamide and the reaction mixture was cooled to a temperature near 0 ℃.38 mg of sodium hydride suspension in oil are added and the reaction mixture is stirred for 2 hours at a temperature close to 0 ℃. 100 μ l of methyl iodide was added by syringe. It was returned to a temperature of approximately 25 ℃ and stirring was maintained for 12 hours. A further 38mg of sodium hydride suspension in oil were added. After stirring for 30 minutes, an additional 100. mu.l of methyl iodide was added at a temperature near 25 ℃. The medium is allowed to stir at a temperature of approximately 25 ℃ for 3 hours. Then 20cm of the solution was added³Distilled water and 20cm³And (3) ethyl acetate. Separating the organic phase, using 20cm successively³2N aqueous hydrogen chloride solution, 3 times 20cm³Distilled water and 20cm³The saturated solution of sodium chloride was washed, dried and then finally concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual yellow solid was purified by column chromatography (silica 60-particle size: 15-40 μm-70 g-eluent: 60% cyclohexane/40% ethyl acetate-45 cm)³In terms of minutes). To yield 170mg of 6- [ methyl (methylsulfonyl) amino group, respectively]-1-oxo-2- (1-propyl)Butyl) isoindoline-3-methyl-4-carboxylic acid methyl ester, fractions 15 to 23 and 27 to 42 were concentrated under reduced pressure (5 kPa):

·NMR：0.88(t，J＝7.3Hz，3H)0.89(t，J＝7.3Hz，3H)1.13-1.41(m，4H)1.45(d，J＝6.4Hz，3H)1.52-1.98(m，4H)3.00(s，3H)3.33(s，3H)3.86(m，1H)3.92(s，3H)4.92(q，J＝6.4Hz，1H)7.90(d，J＝2.4Hz，1H)8.07(d，J＝2.4Hz，1H)

LC-MS-DAD-ELSD: [ M + H ] + M/z ═ 411 (base peak); [2M + H ] + M/z 821

Melting point 174 deg.C

And 284mg of methyl 6- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylate:

melting point 183 ℃

11.1.6: 6- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-3-methyl-4-carboxylic acid

In a single-necked flask, 157mg of 6- [ methyl (methylsulfonyl) amino group obtained in example 11.1.5]-1-oxo-2- (1-propylbutyl) isoindoline-3-methyl-4-carboxylic acid methyl ester is separated by column chromatography and dissolved in 5cm³Dioxane and 0.956cm³1M sodium hydroxide solution. The reaction mixture was heated at a temperature of approximately 60 ℃ for 90 minutes. The reaction mixture was then concentrated to dryness under reduced pressure (5kPa) using a rotary evaporator. Dissolving the residual solid in 20cm³Diethyl ether and 10cm³Distilled water. The aqueous phase was separated and then used for 1.2cm³The acidification is carried out with 1M aqueous hydrogen chloride solution. Solids appeared. It is used for 2 times with 20cm³Is treated with dichloromethane. The organic phase is dried and then concentrated using a rotary evaporator under reduced pressure (5 kPa). 130mg of 6- [ methyl (methylsulfonyl) amino group are obtained in the form of a beige solid]-1-oxo-2- (1-propylbutyl) isoindoline-3-methyl-4-carboxylic acid.

NMR: 0.88(t, J ═ 7.2Hz, 3H)0.89(t, J ═ 7.2Hz, 3H)1.17-1.42(m, 4H)1.49(d, J ═ 6.4Hz, 3H)1.53-2.00(m, 4H)3.01(s, 3H)3.33 (masked s, 3H)3.88(m, 1H)4.93(q, J ═ 6.4Hz, 1H)7.85(d, J ═ 2.2Hz, 1H)8.06(d, J ═ 2.2Hz, 1H)13.7 (nonsingulated m, 1H)

·LC-MS-DAD-ELSD：[M+H]+m/z＝397；[M-H]-m/z＝395

Melting point 200 deg.C

11.1.7: n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -6- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-3-methyl-4-carboxamide

Under an argon atmosphere and at a temperature close to 20 ℃, 0.215cm³N, N-diisopropylethylamine, 4mg 4-dimethylaminopyridine, then 6mg 1-hydroxy-7-azabenzotriazole and 74mg1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to 122mg 6- [ methyl (methylsulfonyl) amino]-1-oxo-2- (1-propylbutyl) isoindoline-3-methyl-4-carboxylic acid and 1146mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [ 3-trifluoromethyl) phenyl]Cyclopropyl } amino) but-2-ol hydrochloride (2: 1) at 15cm³Solution in dichloromethane. The solution was kept under stirring at a temperature close to 20 ℃ for 15 hours under argon. The reaction medium is then concentrated under reduced pressure (5 kPa). The remaining solid was purified by flash chromatography on silica (column: 70 g; silica of the type SuperVarioPrep D40-Si60, particle size: 15-40 μm; eluent: 30% cyclohexane/70% ethyl acetate). After concentrating the fractions under reduced pressure, N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl) was obtained as a beige foam]Cyclopropyl } amino) propyl]-6- [ methyl (methylsulfonyl) amino]-1-oxo-2- (1-propylbutyl) isoindoline-3-methyl-4-carboxamide.

11.2 salt of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -6- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-3-methyl-4-carboxylic acid amide hydrochloride (1: 1)

The foam obtained in example 17.7 was dissolved in 10cm³In diethyl ether. Adding 3cm of the mixture at a temperature of approximately 20 ℃ with stirring³1N hydrochloric acid solution in diethyl ether, then 2cm³Methanol. The reaction mixture was concentrated to dryness under reduced pressure (5 kPa). The residue was taken up in a 5cm column³Is ground together, the solid formed is filtered and then dried at a temperature close to 20 ℃ under atmospheric pressure. 198mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] in the form of a white solid are obtained]Cyclopropyl } amino) propyl]-6- [ methyl (methylsulfonyl) amino]Hydrochloride of (E) -1-oxo-2- (1-propylbutyl) isoindoline-3-methyl-4-carboxamide hydrochloride (1: 1).

NMR: 0.82 to 0.91(m, 7.5H)0.97(d, J ═ 6.5Hz, 1.5H)1.09 to 1.91(m, 12H)2.58 to 2.87(m, 2H)2.98 to 3.17(m, 2H)3.02(s, 1.5H)3.05(s, 1.5H)3.31(s, 1.5H)3.36(s, 1.5H)3.78(m, 1H)3.94(m, 1H)4.14(m, 1H)4.64(q, J ═ 6.5Hz, 0.5H)4.70(q, J ═ 6.5Hz, 0.5H)5.93 (wide m, 1H)6.85 to 7.08(m, 3H)7.54(d, J ═ 2.5H) 0.81, 7.9H (m, 9H) 5H) 3.9, 9H (m, 9H) 4.9.9, 9H) 3.9 (m, 9H) 3.5H) 3.9, 9(m, 9H) 4.9, 9H) 3.9 (H) 3.5H) 3.9, 9H) 3.9 (H) 3.9, 9H) width (H) 3.9, 9H

·LC-MS-DAD-ELSD：[M+H]+m/z＝779

Melting point 193 ℃ C

Example 12:

12.1 base N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -6- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid amide

12.1.1: 6- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid

In a single-necked flask, 2 is placed67mg of 6- [ methyl (methylsulfonyl) amino ] obtained in example 17.1.5 (after separation by column chromatography)]-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid methyl ester dissolved in 7cm³Dioxane and 1.68cm³1M sodium hydroxide solution. The reaction mixture was heated at a temperature of approximately 60 ℃ for 90 minutes. The reaction mixture was then concentrated to dryness under reduced pressure (5kPa) using a rotary evaporator. Dissolving the residual solid in 20cm³Diethyl ether and 10cm³Distilled water. The aqueous phase was separated and then used for 1.8cm³The acidification is carried out with 1M aqueous hydrogen chloride solution. Solids appeared. It is used for 2 times with 20cm³Is treated with dichloromethane. The organic phase was dried and then concentrated under reduced pressure (5kPa) using a rotary evaporator. 257mg of 6- [ methyl (methylsulfonyl) amino are obtained in the form of a beige solid]-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid.

NMR: 0.88(t, J ═ 7.3Hz, 6H)1.19(m, 4H)1.46-1.73(m, 4H)3.01(S, 3H)3.25-3.45 (masked S, 3H)4.27(m, 1H)4.55(S, 2H)7.92(d, J ═ 2.2Hz, 1H)8.09(d, J ═ 2.2Hz, 1H)12.0-14.0 (very broad unresolved m, 1H)

·LC-MS-DAD-ELSD：[M+H]+m/z＝383；[M-H]-m/z＝381

Melting point 206 deg.C

12.1.2: under an argon atmosphere and at a temperature close to 20 ℃, 0.274cm³N, N-diisopropylethylamine, 5mg 4-dimethylaminopyridine, then 8mg 1-hydroxy-7-azabenzotriazole and 94mg 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to 150mg6- [ methyl (methylsulfonyl) amino]-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid and 185mg (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [ 3-trifluoromethyl) phenyl]Cyclopropyl } amino) but-2-ol hydrochloride (2: 1) at 19cm³In dichloromethane. The solution was kept under stirring at a temperature close to 20 ℃ for 15 hours under argon. The reaction medium is then concentrated under reduced pressure (5 kPa). The remaining solid was purified by flash chromatography on silica (column): 70g of a mixture; silica particle size of the type SuperVarioPrep D40-Si 60: 15-40 μm; eluent: 30% cyclohexane/70% ethyl acetate). After concentrating the fractions under reduced pressure, N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl) was obtained as a beige foam]Cyclopropyl } amino) propyl]-6- [ methyl (methylsulfonyl) amino]-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid amide.

12.2: salt N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -6- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-4-carboxylic acid amide hydrochloride (1: 1)

The solid obtained in 17.1 was dissolved in 10cm³Diethyl ether. Adding 4cm of the mixture at a temperature of approximately 20 ℃ while stirring³1N hydrochloric acid solution in diethyl ether, then 1cm³Methanol. Adding 2cm³The reaction mixture was then concentrated to dryness under reduced pressure (5kPa) using a rotary evaporator. Residue and 5cm³The diisopropyl ether is triturated together and the solid formed is filtered and then dried at a temperature of approximately 20 ℃ under atmospheric pressure. 203mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white solid]Cyclopropyl } amino) propyl]-6- [ methyl (methylsulfonyl) amino]-1-oxo-2- (1-propylbutyl) isoindoline-4-carboxamide hydrochloride (1: 1).

NMR: 0.85(t, J ═ 7.3Hz, 6H)1.06-1.65(m, 12H)2.74(m, 1H)2.87(dd, J ═ 14.2, 10.8Hz, 1H)3.00-3.15(m, 2H)3.04(S, 3H)3.34(S, 3H)3.96(m, 1H)4.11(m, 1H)4.22(m, 1H)4.24(S, 2H)5.91 (broad unresolved m, 1H)6.92-7.01(m, 3H)7.60(t, J ═ 7.9Hz, 1H)7.73(d, J ═ 7.9Hz, 1H)7.82(d, J ═ 2, 1H)7.89(d, J ═ 7.91, J ═ 7.9H) 7.9 (d, J ═ 7.9H) 7.97(d, 1H) 7.9H (1H) 7.9Hz, 1H)7.9 (d, 1H) 1H, 1H)5.9 (d, 1H) 5.91 (d, 1H)5.9 Hz, 1H)5.9 (d

·LC-MS-DAD-ELSD：[M+H]+m/z＝765；[M-H]-m/z＝763

Melting point 194 ℃ C

Example 13:

13.1 base N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) -phenyl ] -cyclopropyl } amino) propyl ] -7-trifluoromethyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

13.1.1: n- [2- (2-bromo-4-trifluoromethylphenyl) ethyl ] hept-4-amine

Is measured at a distance of 0.5cm³Triethylamine is added under inert atmosphere to 1g of 2-bromo-4-trifluoromethylphenethylamine hydrochloride at 25cm³In suspension in dichloroethane. After stirring for 30 minutes, 5cm were added at a temperature close to 20 deg.C³Water was distilled and stirring was continued for 30 minutes. The phases were separated and the organic phase was dried. To the resulting solution, 375mg of 4-heptanone and 970mg of sodium triacetoxyborohydride were added successively. The reaction mixture was stirred at a temperature close to 20 ℃ for 15 hours. Then 20cm³Is added to the reaction medium. The organic phase was clarified and separated from the aqueous phase and then used successively for 15cm³Distilled water and 15cm³Washing with saturated sodium chloride solution. The organic phase was dried and then concentrated using a rotary evaporator under reduced pressure (5 kPa).

1.16g of N- [2- (2-bromo-4-trifluoromethylphenyl) ethyl ] hept-4-amine are obtained in the form of a colorless oil.

NMR: 0.83(m, 6H)1.25(m, 8H)1.35 (width s, 1H)2.44(m, 1H)2.75(t, J ═ 7.3Hz, 2H)2.88(t, J ═ 7.3Hz, 2H)7.59(d, J ═ 8.1Hz, 1H)7.68(dd, J ═ 8.1, 2.0Hz, 1H)7.92(d, J ═ 2.0Hz, 1H)

·LC-MS-DAD-ELSD：[M+H]+m/z＝366

13.1.2: [2- (2-bromo-4-trifluoromethylphenyl) ethyl ] (1-propylbutyl) carbamic acid methyl ester

Stirring at a temperature of about 5 ℃ under an inert atmosphereStirring 770mg of N- [2- (2-bromo-4-trifluoromethylphenyl) ethyl]Hept-4-amine at 15cm³A solution in anhydrous tetrahydrofuran and 500mg of potassium carbonate. 0.19cm³Methyl chloroformate was introduced into the reaction mixture over 5 minutes. The reaction mixture was refluxed during 15 hours, the insoluble material was separated by filtration and the filtrate was concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual oil was purified by filtration through a silica pad using a mixture of 10% ethyl acetate and 90% cyclohexane as eluent. The organic phase is then concentrated to dryness under reduced pressure (5kPa) using a rotary evaporator to give 666mg of [2- (2-bromo-4-trifluoromethylphenyl) ethyl as a colorless oil](1-Propylbutyl) carbamic acid methyl ester.

·NMR：0.84(t，J＝7.3Hz，6H)1.17(m，4H)1.27-1.50(m，4H)3.02(m，2H)3.20(m，2H)3.63(s，3H)3.86(m，0.34H)3.96(m，0.66H)7.57(m，1H)7.72(d，J＝7.9Hz，1H)7.96(s，1H)

·LC-MS-DAD-ELSD：[M+H]+m/z＝424

13.1.3: 5-bromo-7-trifluoromethyl-2- (1-propylbutyl) -3, 4-dihydroisoquinolin-1 (2H) -one

660mg of [2- (2-bromo-4-trifluoromethylphenyl) ethyl group are introduced into a reaction vessel at a temperature close to 10 ℃ under an inert atmosphere](1-Propylbutyl) carbamic acid methyl ester dissolved in 15cm³In dichloromethane. 575mg of 4-dimethylaminopyridine are added to the reaction mixture. Will be 1.32cm³Trifluoromethanesulfonic anhydride at 2cm³The solution in anhydrous dichloromethane was poured into the reaction mixture over 5 minutes. The reaction mixture was kept under stirring at a temperature close to 20 ℃ for 15 hours. Is measured by a distance of 20cm³To the reaction medium. Stirring was maintained for 30 minutes, then 20cm was added³Methylene chloride was added to the mixture. The organic phase was decanted and then successively with 100cm³0.1M aqueous hydrochloric acid solution and 20cm³And washing with saturated aqueous solution of sodium bicarbonate. The organic phase was then dried and then concentrated using a rotary evaporator under reduced pressure (5 kPa). Then the remaining solid is passed overPurification was carried out by filtration over silica (silica 60-particle size 15-40 μm-eluent: 50% ethyl acetate/50% cyclohexane). The organic phase was concentrated under reduced pressure (5 kPa). 519mg of 5-bromo-7-trifluoromethyl-2- (1-propylbutyl) -3, 4-dihydro-isoquinolin-1 (2H) -one are obtained in the form of a yellow oil.

NMR: 0.87(t, J ═ 7.1Hz, 6H)1.15-1.34(m, 4H)1.42(m, 2H)1.53(m, 2H)3.05(t, J ═ 6.6Hz, 2H)3.42(t, J ═ 6.6Hz, 2H)4.64(m, 1H)8.15 (width s, 1H)8.17 (width s, 1H)

·LC-MS-DAD-ELSD：[M+H]+m/z＝392

13.1.4: 7-trifluoromethyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

At a temperature close to 20 ℃, in a stirred and carbon monoxide purged three-necked flask were introduced 500mg of 5-bromo-7-trifluoromethyl-2- (1-propylbutyl) -3, 4-dihydroisoquinolin-1 (2H) -one, followed by 16cm³Dimethylformamide, 0.8cm³Water, 482mg potassium acetate, 222mg potassium iodide, 28mg palladium acetate and 68mg triphenylphosphine. The reaction mixture was subjected to carbon monoxide bubbling and then heated at a temperature close to 100 ℃ for 6 hours. The reaction mixture was cooled to 25 ℃ and then concentrated under reduced pressure (5kPa) using a rotary evaporator. Dissolving the residue in 50cm³In ethyl acetate. The pH was basified with 1M sodium hydroxide (pH > 10). The two phases were clarified and separated. The aqueous phase was acidified with 5M hydrochloric acid solution (pH 2) and then 30cm with stirring³And (5) extracting with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). 336mg of 7-trifluoromethyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid are obtained in the form of a slightly white amorphous solid.

NMR: 0.87(t, J ═ 7.3Hz, 6H)1.15-1.31(m, 4H)1.41(m, 2H)1.53(m, 2H)3.36(broads, 4H)4.66(m, 1H)8.23(d, J ═ 2.2Hz, 1H)8.32(d, J ═ 2.2Hz, 1H)13.60 (broad unresolved m, 1H)

·LC-MS-DAD-ELSD：[M+H]+m/z＝358；[M-H]-m/z＝356

13.1.5: n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-trifluoromethyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

Under an argon atmosphere and at a temperature close to 20 ℃, 0.30cm³N, N-diisopropylethylamine, 5mg of 4-dimethylaminopyridine and 200mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [ 3-trifluoromethyl) phenyl]Cyclopropyl } amino) but-2-ol hydrochloride then 8.5mg of 1-hydroxy-7-azabenzotriazole and 100mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added to 150mg of 7-trifluoromethyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid at 20cm³In dichloromethane. The solution was kept stirring at a temperature close to 20 ℃ for 3 hours under argon. Then using 20cm successively³Distilled water and 20cm³The reaction medium is washed with a saturated aqueous solution of sodium chloride. The organic phase was decanted, dried and then concentrated under reduced pressure (5 kPa). The remaining solid was purified by flash chromatography on silica (column: 30 g; silica of the type SuperVarioPrep D40-S160, particle size: 15-40 μm; eluent: 90% cyclohexane/10% ethyl acetate). After concentrating the fractions under reduced pressure, 238mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) -phenyl) are obtained as a colorless oil]-cyclopropyl } amino) propyl]-7-trifluoromethyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide.

13.2 salts of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-trifluoromethyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride

The oil obtained in step 13.1 was then dissolved in 5cm³In diethyl ether. Adding 1cm of the mixture at a temperature of 20 ℃ while stirring³1N hydrochloric acid solution in diethyl ether, then 1cm³Methanol. The reaction mixture was concentrated to dryness under reduced pressure (5 kPa). Mixing the residue with 10cm³Is ground together, the solid formed is filtered and then dried at a temperature at atmospheric pressure close to 20 ℃. 249mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white solid]Cyclopropyl } amino) propyl]-7-fluoro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride.

NMR: 0.86(t, J ═ 7.3Hz3H)0.87(t, J ═ 7.3Hz, 3H)1.11-1.69(m, 12H)2.42-2.71 (partially masked m, 2H)2.80(m, 1H)3.03-3.35 (partially masked m, 5H)3.84(m, 1H)4.12(m, 1H)4.64(m, 1H)5.89 (wide d, J ═ 6.2Hz, 1H)6.98(m, 2H)7.09(tt, J ═ 9.5, 2.0Hz, 1H)7.41(d, J ═ 1.0Hz, 1H)7.66 (wide t, J ═ 7.9Hz, 1H)7.76 (wide d, J ═ 7.90H, J ═ 1.8H, 1H ═ 1H)7.66 (wide t, J ═ 7.9, 1H, 8H, 1H)7.9, 8 (wide, 8H, 1H) 1H, 8(m, 8H, 1H)7.9, 1H, 8, 1H)7.9, 8 (H, 1H, 8, 1H) 1H, 8, 1H) 1H

·LC-MS-DAD-ELSD：[M+H]+m/z＝740；[M-H]-m/z＝738

Melting point 196 ℃ C

Example 14:

14.1: the base N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- [ (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

14.1.1: 7- [ (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

0.51g of 7- [ (methylsulfonyl) amino group are reacted at a temperature close to 20 DEG C]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester dissolved in 10.5cm³In dioxane. Adding 3.2cm³1N aqueous sodium hydroxide solution, then at a temperature close to 60 deg.CThe reaction mixture was heated at temperature for 30 minutes. The dioxane contained in the reaction mixture was concentrated to dryness under reduced pressure (5 kPa). Is measured by a distance of 20cm³Diethyl ether and 20cm³Water was added to the residue obtained. After decantation, the aqueous phase used 2cm³Is acidified with 2N aqueous hydrochloric acid. 50cm in length³Methylene chloride was added to the mixture and stirred at a temperature close to 20 ℃ for 1 hour. Filtering the precipitate, and taking twice with 10cm³Then twice with 10cm of water³Washed with dichloromethane and dried under vacuum. 0.42g of 7- [ (methylsulfonyl) amino group in the form of a powder is obtained]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydro-isoquinoline-5-carboxylic acid.

NMR: 0.87(t, J ═ 7.5Hz, 6H); 1.12 to 1.30(m, 4H); 1.39(m, 2H); 1.51(m, 2H); 3.00(s, 3H); 3.19(m, 2H); 3.29 (partially masked m, 2H); 4.63(m, 1H); 7.87(d, J ═ 2.0Hz, 1H); 7.98(d, J ═ 2.0Hz, 1H); 9.94 (width s, 1H); 13.3 (broad unresolved m, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺：m/z 383；[M-H]^-：m/z 381；[2M-H]^-: m/z 763 (Kyoho)

14.1.2: n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- [ (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

64mg of 1-hydroxy-7-azabenzotriazole and then 90mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added to 185mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl ] methyl]Cyclopropyl } amino) but-2-ol hydrochloride (2: 1), 150mg of 7- [ (methylsulfonyl) amino]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid and 0.176cm³Triethylamine at 1.6cm³In anhydrous dimethylformamide. The solution was kept stirring at a temperature close to 20 ℃ for 24 hours. Is measured by a distance of 20cm³Water and 50cm³Ethyl acetate was added to the reaction medium. After decantation, the organic phase took 20cm³Saturated aqueous solution of ammonium chloride, 5 times 20cm³20cm of water³Was washed with saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa). Residual solution (about 3 cm)³) Filtration was carried out through 15g of a 40-63 μm silica plate. 75cm for silicon dioxide sheet³And washing with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure (5 kPa). 300mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [ 3-trifluoromethyl) -phenyl ] are obtained in the form of a directly salified white powder]Cyclopropyl } amino) propyl]-7- [ (methylsulfonyl) amino group]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide.

14.2: the salt N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- [ (methyl-sulfonyl) -amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

300mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl) are introduced at a temperature close to 20 ℃]Cyclopropyl } amino) propyl]-7- [ (methyl-sulfonyl) -amino]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide in 10cm³In diethyl ether. Adding 0.4cm of the mixture at a temperature of 20 ℃ while stirring³4N hydrochloric acid solution in dioxane. The reaction mixture precipitated. 3 times of 5cm for solid³Washed and dried under vacuum at a temperature of 50 ℃. 280mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white powder]Cyclopropyl } amino) propyl]-7- [ (methyl-sulfonyl) -amino]-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydro-isoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: 0.88(m, 6H); 1.11 to 1.69(m, 12H); 2.37(m, 2H); 2.63(m, 1H); 2.74(m, 1H); 3.00(s, 3H); 3.01 to 3.15(m, 4H); 3.88(m, 1H); 4.11(m, 1H); 4.63(m, 1H); 5.86 (width m, 1H); 6.93(m, 2H); 7.18(tt, J ═ 2.0 and 9.0Hz, 1H); 7.20(d, J ═ 2.5Hz, 1H); 7.68 (width t, J ═ 7.5Hz, 1H); 7.78(m, 2H); 7.90 (width d, J ═ 7.5Hz, 1H); 8.01 (width s, 1H); 8.39 (width d, J ═ 8.0Hz, 1H); 9.47 (width m, 1H); 9.87 (width m, 1H); 9.97(s, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺：m/z 765；[M-H]^-：m/z 763

Example 15:

n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (2-oxazolyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

15.1: 7-bromo-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester

1.26g of copper bromide was added to 0.87cm³N-butyl nitrite in 65cm³Acetonitrile, then, in 25 minutes, introduce 1.5g 7-amino-1-oxo-2- (1-propyl butyl) -1,2,3, 4-four hydrogen isoquinoline-5-methyl formate dissolved in 70cm³A solution of acetonitrile. Stirring was maintained at a temperature close to 20 ℃ for 4 hours. Will be 30cm³Is added to the reaction medium and the precipitate is filtered. It is used for 2 times with 20cm³And (3) washing with acetonitrile. The filtrate was concentrated to dryness under reduced pressure (5kPa) and then passed through 250cm³Ethyl acetate and 50cm³Dissolving the water. The organic phase is decanted, after 2 passages of 20cm³2N hydrochloric acid aqueous solution, then 50cm³Water and 50cm³Is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). The residual oil was dissolved in 5cm³Is purified by flash chromatography on silica (column: 200 g; particle size: 15-40 μm; eluent: 60% heptane/40% ethyl acetate). After concentrating the fractions under reduced pressure, 1.2g of methyl 7-bromo-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate was obtained in the form of a yellow oil.

NMR: 0.89(m, 6H); 1.10 to 1.70(m, 8H); 2.38 to 2.60 (partially masked m, 2H); 2.65(m, 1H); 2.81(m, 1H): 3.03 to 3.24(m, 4H); 3.30 to 3.60 (masked m, 2H); 3.89(m, 1H); 4.16(m, 1H); 4.68(m, 1H); 5.92 (broad unresolved m, 1H); 6.99(m, 2H); 7.10 (width t, J ═ 9.0Hz, 1H); 7.46(s, 1H); 7.68(t, J ═ 7.5Hz, 1H); 7.74(m, 2H); 7.92(d, J ═ 7.5Hz, 1H); 8.01 (width s, 1H); 8.29(s, 1H); 8.49(m, 2H); 9.42 (width m, 1H); 9.80 (Width m, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺: m/z 382 (base peak); [2M + Na ]]⁺：m/z 785

15.2: 7- (2-oxazolyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester

Under an argon atmosphere at a temperature close to 20 deg.C, 308mg tetrakis (triphenylphosphine) palladium and 3.2g 2- (tri-n-butylstannyl) oxazole were added to 0.8g 7-bromo-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester at 8cm³In solution in dioxane. The reaction medium is heated in a microwave oven to 145 ℃ for 15 minutes and then brought back to a temperature close to 20 ℃. The reaction medium is concentrated to dryness under reduced pressure (5 kPa). The residue passed 5cm³Dichloromethane was dissolved and purified by flash chromatography on silica (column: 110 g; BP-SUP type spherical silica, particle size: 20-40 μm; eluent: 90% heptane/10% ethyl acetate then 100% ethyl acetate). After concentrating the fraction under reduced pressure, 320mg of methyl 7- (2-oxazolyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate were obtained.

NMR: 0.89(t, J ═ 7.5Hz, 6H); 1.14 to 1.34(m, 4H); 1.41(m, 2H); 1.56(m, 2H); 3.25 to 3.40 (partially masked m, 4H); 3.91(s, 3H); 4.68(m, 1H); 7.43(s, 1H); 8.29(s, 1H); 8.53(d, J ═ 2.0Hz, 1H); 8.68(d, J ═ 2.0Hz, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺: m/z 371 (base peak); [2M + H ]]⁺：m/z 741；[2M+Na]⁺：m/z 763

The preparation of 2- (tri-n-butylstannyl) oxazole is described in international patent application WO 2006/099352.

15.3: 7- (2-oxazolyl ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

320mg of 7- (2-oxazolyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester was dissolved in 7cm at a temperature close to 20 deg.C³In dioxane. Adding 2.1cm³1N aqueous sodium hydroxide solution, and the reaction mixture was then heated at a temperature close to 60 ℃ for 30 minutes. The dioxane contained in the reaction mixture was concentrated to dryness under reduced pressure (5 kPa). 2.5cm in length³20cm of 1N hydrochloric acid aqueous solution³Methylene chloride and 20cm³Water was added to the residue obtained. After decantation, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). This gave 289mg of 7- (2-oxazolyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid in the form of a beige powder.

NMR: 0.89(t, J ═ 7.5Hz, 6H); 1.11 to 1.32(m, 4H); 1.41(m, 2H); 1.54(m, 2H); 3.22 to 3.39 (partially masked m, 4H); 4.69(m, 1H); 7.43(s, 1H); 8.28(s, 1H); 8.52(d, J ═ 2.0Hz, 1H); 8.62(d, J ═ 2.0Hz, 1H); 13.45 (Wide unresolved m, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺: m/z 357 (base peak); [2M + H ]]⁺：m/z 713；[M-H]^-: m/z 355 (base peak); [2M-H ]]^-：m/z 711

15.4: n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (2-oxazolyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

Under an argon atmosphere, the mixture was cooled to 0.19cm³Triethylamine and 201mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl)]Cyclopropyl } amino) but-2-ol hydrochloride 69mg of 1-hydroxy-7-azabenzotriazole and 97mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were then added to 150mg of 7- (2-oxazolyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid at 4cm³In anhydrous dimethylformamide. The solution was kept under stirring at a temperature close to 20 ℃ for 15 hours. 50cm in length³Water and 50cm³Ethyl acetate was added to the reaction medium. After decantation, the organic phase took 50cm³Saturated aqueous solution of ammonium chloride, 2 times 20cm³Water (d) and 20cm³Washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). Residual solution (about 3 cm)³) Filtration through a 15g 40-63 μm silica plate. 40cm for silicon dioxide sheet³Washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure (5 kPa). The obtained 255mg of white powder was dissolved in 10cm³Diethyl ether of (2). Adding 0.2cm of the mixture under stirring at 20 deg.C³4N hydrochloric acid solution in dioxane. The reaction mixture precipitated. Filtering the precipitate, and collecting the filtrate with a volume of 5cm for 2 times³Washed and dried under vacuum at a temperature of 35 ℃. 236mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of white crystals]Cyclopropyl } amino) propyl]-7- (2-oxazolyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride.

NMR: 0.89(m, 6H); 1.10 to 1.70(m, 8H); 2.38 to 2.60 (partially masked m, 2H); 2.65(m, 1H); 2.81(m, 1H); 3.03 to 3.24(m, 4H); 3.30 to 3.60 (masked m, 2H); 3.89(m, 1H); 4.16(m, 1H); 4.68(m, 1H); 5.92 (broad unresolved m, 1H); 6.99(m, 2H); 7.10 (width t, J ═ 9.0Hz, 1H); 7.46(s, 1H); 7.68(t, J ═ 7.5Hz, 1H); 7.74(m, 2H); 7.92(d, J ═ 7.5Hz, 1H); 8.01 (width s, 1H); 8.29(s, 1H); 8.49(m, 2H); 9.42 (width m, 1H); 9.80 (Width m, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺：m/z 739；[M-H]^-：m/z 737

Example 16:

16.1: the base N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

16.1.1: 7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester

At a temperature close to 20 deg.C, 147mg of sodium bicarbonate was added to 0.3g of methyl 7-bromo-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate at 9.4cm³Dioxane and 1.8cm³In solution in water. The reaction medium is then degassed under an argon atmosphere and 111mg of 3-cyanophenylboronic acid and 72mg of tetrakis (triphenylphosphine) palladium are then added. The mixture was heated to 150 ℃ for 4 minutes in a microwave oven, cooled to a temperature close to 20 ℃ and filtered. Drying the filtrate over anhydrous magnesium sulfate and then filtering; 1g of silica was added to the filtrate and the absorbed residue was purified by flash chromatography on silica (column: 15 g; spherical silica of BP-SUP type, particle size: 20-40 μm, eluent: 80% heptane/20% ethyl acetate then 60% heptane/40% ethyl acetate). After concentrating the fractions under reduced pressure, 103mg of methyl 7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate were obtained in the form of orange oil.

NMR: 0.89(t, J ═ 7.5Hz, 6H); 1.12 to 1.32(m, 4H); 1.41(m, 2H); 1.54(m, 2H); 3.27(t, J ═ 6.0Hz, 2H); 3.37(t, J ═ 6.0Hz, 2H); 3.90(s, 3H); 4.70(m, 1H); 7.70(t, J ═ 7.5Hz, 1H); 7.89 (width d, J ═ 7.5Hz, 1H); 8.09 (width d, J ═ 7.5Hz, 1H); 8.24 (width s, 1H); 8.29(d, J ═ 2.0Hz, 1H); 8.41(d, J ═ 2.0Hz, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺: m/z 405 (base peak); [2M + H ]]⁺：m/z 809

16.1.2: 7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

103mg of methyl 7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate were dissolved in 2cm at a temperature close to 20 deg.C³In dioxane. Adding 0.6cm³And then the reaction mixture was heated at a temperature close to 60c for 30 minutes. The mixture was then concentrated to dryness under reduced pressure (5kPa) over 20cm³Water (d) and 20cm³Dissolving the ethyl ether. Decanting the aqueous phase, using 0.4cm³Acidification with 2N aqueous hydrochloric acid and 20cm³The methylene chloride is dissolved. The organic phase was extracted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). 89mg of 7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid were obtained in the form of a white powder.

NMR: 0.89(t, J ═ 7.5Hz, 6H); 1.12 to 1.32(m, 4H); 1.41(m, 2H); 1.54(m, 2H); 3.21 to 3.40 (partially masked m, 4H); 4.70(m, 1H); 7.70(t, J ═ 7.5Hz, 1H); 7.88 (width d, J ═ 7.5Hz, 1H); 8.08 (width d, J ═ 7.5Hz, 1H); 8.22 (width s, 1H); 8.27(d, J ═ 2.0Hz, 1H); 8.38(d, J ═ 2.0Hz, 1H); 13.4 (Wide unresolved m, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺: m/z 391 (base peak); [2M + H ]]⁺：m/z 781；[M-H]^-: m/z 389 (base peak); [2M-H ]]^-：m/z 779

16.1.3: n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

Under argon atmosphere, the mixture is heated to 0.092cm³Triethylamine and 97mg of (2R, 3S) -3-amino-4- (3, 5-diFluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl]Cyclopropylamino) but-2-ol hydrochloride (2: 1), then 33mg of 1-hydroxy-7-azabenzotriazole and 47mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are added to 89mg of 7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid at 1cm³In anhydrous dimethylformamide. The solution was kept under stirring at a temperature close to 20 ℃ for 15 hours. 50cm in length³Water and 50cm³Ethyl acetate was added to the reaction medium. After decantation, the organic phase is used 3 times for 5cm³Then 5cm of water³Then using 20cm of saturated aqueous solution of ammonium chloride³Washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). Residue at 2cm³Diluted in dichloromethane and purified by flash chromatography on silica (column: 15 g; particle size: 15-40 μm; eluent: 20% heptane/80% ethyl acetate). After concentrating the fractions under reduced pressure, 119mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl) in the form of a white gum were obtained]-cyclopropyl } amino) propyl]-7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide.

·LC-MS-DAD-ELSD：[M+H]⁺：m/z 773；[M-H]^-: m/z 771 (base peak); [ M + HCO ]₂H-H]^-：m/z 817

16.2: the salt N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

119mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl)]Cyclopropyl } amino) propyl]-7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide was dissolved in 5cm³In diethyl ether. Stirring at 20 deg.C while adding 0.3cm³2N hydrochloric acid solution in diethyl ether. Precipitate formedFiltration was carried out and dried under vacuum at a temperature of 35 ℃.89 mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white powder]Cyclopropyl } amino) propyl]-7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: 0.89(m, 6H); 1.11 to 1.69(m, 12H); 2.42 to 2.60 (partially masked m, 2H); 2.69(m, 1H); 2.80(m, 1H); 3.03 to 3.24(m, 4H); 3.85(m, 1H); 4.13(m, 1H); 4.69(m, 1H); 5.89 (width m, 1H); 6.95 to 7.11(m, 3H); 7.49 (width s, 1H); 7.55 to 7.79(m, 3H); 7.90(m, 2H); 8.00(m, 2H); 8.13 (width s, 1H); 8.22 (width s, 1H); 8.43 (width d, J ═ 8.0Hz, 1H); 9.36 (width m, 1H); 9.72 (Width m, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺：m/z 773；[M-H]^-: m/z 771 (base peak); [ M + HCO ]₂H-H]^-：m/z 817

Example 17:

17.1: the base N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

17.1.1: 7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester

196mg of sodium bicarbonate was added to 0.4g of methyl 7-bromo-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate at 12.5cm at a temperature close to 20 deg.C³Dioxane and 2.5cm³A solution in water. The reaction medium is then degassed under an argon atmosphere and 147.5mg of 2-cyanophenylboronic acid and 96mg of tetrakis (triphenylphosphine) palladium are then added. The mixture was heated to 150 ℃ for 4 minutes in a microwave oven, cooled to a temperature close to 20 ℃ and filtered. The filtrate passed through a 20cm filter³2 ofMethyl chloride and 20cm³Dissolving the water. The organic phase was extracted, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa). Residual solution (about 3 cm)³) Purification was performed by flash chromatography on silica (column: 50g of the total weight of the mixture; BP-SUP type spherical silica, particle size: 20-40 μm; eluent 80% heptane/20% ethyl acetate then 60% heptane/40% ethyl acetate then 50% heptane/50% ethyl acetate). After concentrating the fractions under reduced pressure, 178mg of methyl 7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate was obtained as a colorless oil.

NMR: 0.89(t, J ═ 7.5Hz, 6H); 1.16 to 1.32(m, 4H); 1.42(m, 2H); 1.53(m, 2H); 3.25 to 3.35 (masked m, 2H); 3.39(m, 2H); 3.89(s, 3H); 4.68(m, 1H); 7.63(dt, J ═ 1.5 and 7.5Hz, 1H); 7.70 (width d, J ═ 7.5Hz, 1H); 7.83(dt, J ═ 1.5 and 7.5Hz, 1H); 8.00(dd, J ═ 1.5 and 7.5Hz, 1H); 8.27(d, J ═ 2.0Hz, 1H); 8.30(d, J ═ 2.0Hz, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺: m/z 405 (base peak); [ M + Na ]]⁺：m/z 427；[M+HCO₂H-H]^-：m/z 449

17.1.2: 7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

178mg of methyl 7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate were dissolved in 3.6cm at a temperature close to 20 deg.C³In dioxane. Adding 1.1cm³And then the reaction mixture was heated at a temperature close to 60c for 30 minutes. The mixture was then concentrated to dryness under reduced pressure (5kPa) and passed through 20cm³Water (d) and 20cm³Dissolving the ethyl ether. 5cm for the aqueous phase³Washing with diethyl ether, 2cm³Is acidified with a 2N aqueous hydrochloric acid solution and is brought to 10cm³The methylene chloride is dissolved. The organic phase was extracted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). 171mg of white foam are obtainedForm of 7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid.

NMR: 0.89(t, J ═ 7.5Hz, 6H); 1.16 to 1.32(m, 4H); 1.41(m, 2H); 1.54(m, 2H); 3.25 to 3.41 (partially masked m, 4H); 4.69(m, 1H); 7.63(dt, J ═ 1.5 and 7.5Hz, 1H); 7.70 (width d, J ═ 7.5Hz, 1H); 7.82(dt, J ═ 1.5 and 7.5Hz, 1H); 7.99 (width d, J ═ 7.5Hz, 1H); 8.16(d, J ═ 2.0Hz, 1H); 8.25(d, J ═ 2.0Hz, 1H); 13.4 (Wide unresolved m, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺：m/z 391；[M+Na]⁺: m/z 413 (Kyoho)

17.1.3: n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

Under an argon atmosphere, the mixture was heated to 0.198cm³Triethylamine and 207mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl)]Cyclopropyl } amino) but-2-ol hydrochloride, then 71mg of 1-hydroxy-7-azabenzotriazole and 100.5mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added to 171mg of 7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid at 2cm³In anhydrous dimethylformamide. The solution was kept stirring at a temperature close to 20 ℃ for 15 hours. 50cm in length³Water and 50cm³Ethyl acetate was added to the reaction medium. After decantation, the organic phase took 50cm³Saturated aqueous solution of ammonium chloride, 2 times 20cm³Then 20cm of water³Washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). Residual solution (about 3 cm)³) Purification was performed by flash chromatography on silica (column: 15g of the total weight of the mixture; BP-SUP type spherical silica, particle size: 20-40 μm; eluent: 50% heptane/50% ethyl acetate). After concentration of the fractions under reduced pressure, 268mg are obtained in the form of a white powderN- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl)]-cyclopropyl } -amino) propyl]-7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide.

·LC-MS-DAD-ELSD：[M+H]⁺: m/z 773; (basal peak); [2M + H ]]⁺：m/z 1545

17.2: the salt N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

268mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] methyl) are reacted under an argon atmosphere]Cyclopropyl } amino) propyl]-7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide was dissolved in 5cm³In diethyl ether. Adding 0.3cm of the mixture at 20 ℃ while stirring³4N hydrochloric acid solution in dioxane. The reaction mixture precipitated. The supernatant was aspirated under vacuum and the residue was taken up to 5cm³Washing with isopropyl ether; this operation was repeated three times and the residual medium was then dried under vacuum at a temperature of 50 ℃. 230mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white powder]Cyclopropyl } amino) propyl]-7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: 0.89(m, 6H); 1.11 to 1.69(m, 12H); 2.41 to 2.59 (partially masked m, 2H); 2.65(m, 1H); 2.79(m, 1H); 3.00 to 3.25(m, 4H); 3.82(m, 1H); 4.14(m, 1H); 4.68(m, 1H); 5.87 (width m, 1H); 6.97(m, 2H); 7.08 (width t, J ═ 9.0Hz, 1H); 7.30 (width s, 1H); 7.51 to 7.71(m, 4H); 7.84(m, 2H); 8.00(m, 2H); 8.12 (width s, 1H); 8.41 (width d, J ═ 8.0Hz, 1H); 9.37 (width m, 1H); 9.72 (Width m, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺：m/z 773；[M-H]^-: m/z 771 (base peak); [ M + H ]CO₂H-H]^-：m/z 817

Example 18:

18.1: the base N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-methyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

18.1.1: 7-methyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester

190mg of sodium bicarbonate is added to 0.385g of methyl 7-bromo-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate at a temperature of approximately 20 ℃ in 9.6cm³Dioxane, 2cm³Water and one drop of dimethylformamide. The reaction medium is then degassed under an argon atmosphere and 58mg of methylboronic acid and 93mg of tetrakis (triphenylphosphine) palladium are then added. The mixture was heated to 150 ℃ for 8 minutes in a microwave oven, cooled to a temperature close to 20 ℃, filtered and concentrated to dryness under reduced pressure (5 kPa). The filtrate used was 20cm³Dichloromethane and 10cm³Dissolving the water. The organic phase was extracted, washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa). Residual solution (about 4 cm)³) Purification was performed by flash chromatography on silica (column: 50g of the total weight of the mixture; BP-SUP type spherical silica, particle size: 20-40 μm; eluent: 80% heptane/20% ethyl acetate then 60% heptane/40% ethyl acetate then 100% ethyl acetate). After concentrating the fractions under reduced pressure, 35mg of methyl 7-methyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate was obtained as a colorless oil.

NMR: 0.86(t, J ═ 7.5Hz, 6H); 1.12 to 1.30(m, 4H); 1.39(m, 2H); 1.51(m, 2H); 2.38(s, 3H); 3.16(t, J ═ 6.0Hz, 2H); 3.22 to 3.34 (partially masked m, 2H); 3.83(s, 3H); 4.67(m, 1H); 7.81 (width s, 1H); 7.95 (Width s, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺: m/z 318 (base peak); [ M + Na + CH ]₃CN]⁺：m/z 381；[2M+Na]⁺：m/z 657

18.1.2: 7-methyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

At a temperature close to 20 deg.C, 33mg of methyl 7-methyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate was dissolved in 1cm³In dioxane. Adding 0.3cm³And then heating the reaction mixture at a temperature close to 60c for 1 hour. The mixture was then concentrated to dryness under reduced pressure (5kPa) over 10cm³Water and 15cm³Dissolving the ethyl ether. Decanting the aqueous phase, using 10cm³Washing with diethyl ether, using 0.3cm³Is acidified with a 2N aqueous hydrochloric acid solution and is brought to 10cm³The methylene chloride is dissolved. The organic phase was extracted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). 33.5mg of 7-methyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid are obtained in the form of a colorless varnish.

NMR: 0.87(t, J ═ 75Hz, 6H); 1.12 to 1.30(m, 4H); 1.39(m, 2H); 1.50(m, 2H); 2.37(s, 3H); 3.19(m, 2H); 3.27 (partially masked m, 2H); 4.67(m, 1H); 7.78 (width s, 1H); 7.89 (width s, 1H); 13.1 (Wide unresolved m, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺：m/z 304；[M-H]^-：m/z 302

18.1.3: n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-methyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

0.05cm in length³Triethylamine and 51mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl]-cyclopropyl } amino) but-2-ol hydrochloride (2: 1) and then 17mg of 1-hydroxy-7-azabenzeneBenzotriazole and 24mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added to 33mg of 7-methyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid at 0.5cm³In anhydrous dimethylformamide. The solution was kept stirring at a temperature close to 20 ℃ for 15 hours. Is measured by a distance of 20cm³Water and 30cm³Ethyl acetate was added to the reaction medium. After decantation, the organic phase took 20cm³Saturated aqueous solution of ammonium chloride, 5 times 20cm³Then 20cm of water³Washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). The residue was dissolved in 2cm³Is then purified by flash chromatography on silica (column: 15 g; spherical silica of the BP-SUP type, particle size: 20-40 μm; eluent: 60% heptane/40% ethyl acetate). After concentrating the fractions under reduced pressure, 68mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) -phenyl ] in the form of a colorless oil are obtained]-cyclopropyl } amino) propyl]-7-methyl-1-oxo-2- (1-propyl-butyl) -1,2,3, 4-tetrahydro-isoquinoline-5-carboxamide.

·LC-MS-DAD-ELSD：[M+H]⁺: m/z 686 (base peak); [2M + H ]]⁺：m/z 1371

18.2: the salt N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-methyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

Under an argon atmosphere, 68mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] methyl) phenyl]Cyclopropyl } amino) propyl]-7-methyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide was dissolved in 5cm³In diethyl ether. Adding 0.2cm of the mixture at 20 ℃ while stirring³4N hydrochloric acid solution in dioxane. The reaction mixture was concentrated to dryness under reduced pressure (5 kPa). 10cm for residue³Dissolving in diethyl ether, concentrating to dryness under reduced pressure (5kPa), and heating at 35 deg.C under vacuumDrying the mixture. 69mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a white powder]-cyclopropyl } amino) propyl]-7-methyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: 0.84(m, 6H); 1.10 to 1.70(m, 12H); 2.24 to 2.45 (partially masked m, 2H); 2.29(s, 3H); 2.61(m, 1H); 2.79(m, 1H); from2.98to3.18(m, 4H); 3.80(m, 1H); 4.09(m, 1H); 4.64(m, 1H); 5.87 (width m, 1H); 6.87 (width s, 1H); 6.96(m, 2H); 7.09 (width t, J ═ 9.0Hz, 1H); 7.68 (width t, J ═ 7.5Hz, 1H); 7.75 (width s, 1H); 7.79 (width d, J ═ 7.5Hz, 1H); 7.90 (width d, J ═ 7.5Hz, 1H); 8.02 (width s, 1H); 8.23 (width d, J ═ 8.0Hz, 1H); 9.36 (width m, 1H); 9.77 (Width m, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺：m/z 686

Example 19:

19.1: the base N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-chloro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

19.1.1: 7-chloro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester

316mg of copper chloride are added to 0.29cm at a temperature close to 20 deg.C³N-butyl nitrite in the range of 20cm³In solution in acetonitrile. The temperature of the reaction mixture is reduced to 0 ℃, then in 30 minutes time introduction of 0.5g 7-amino-1-oxo-2- (1-propyl butyl) -1,2,3, 4-four hydrogen isoquinoline-5-methyl formate dissolved in 20cm³Solution in acetonitrile. Stirring was maintained at a temperature close to 20 ℃ for 3 hours. Will be 30cm³Water was added to the reaction medium, followed by 50cm³Saturated aqueous solution of sodium bicarbonate and 100cm³And (3) ethyl acetate. Filtering the mixture andand the organic phase was decanted, using 100cm³100cm of water³1N aqueous hydrochloric acid solution and then 100cm³100cm of water³100cm of a saturated aqueous solution of sodium hydrogencarbonate³Water of (2) and 100cm³Is washed with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). The residual oil was dissolved in 3cm³Then purified by flash chromatography on silica (column: 50 g; spherical silica of the BP-SUP type, particle size: 20-40 μm; eluent: 60% heptane/40% ethyl acetate). After concentrating the fractions under reduced pressure, 243mg of methyl 7-chloro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate was obtained as a yellow oil.

NMR: 0.88(t, J ═ 7.5Hz, 6H); 1.11 to 1.30(m, 4H); 1.40(m, 2H); 1.52(m, 2H); 3.19(t, J ═ 6.0Hz, 2H); 3.32(t, J ═ 6.0Hz, 2H); 3.88(s, 3H); 4.62(m, 1H); 7.98(d, J ═ 2.0Hz, 1H); 8.08(d, J ═ 2.0Hz, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺: m/z 338 (base peak); [2M + Na ]]⁺：m/z 697

19.1.2: 7-chloro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

240mg of methyl 7-chloro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate were dissolved in 6cm at a temperature close to 20 deg.C³In dioxane. Adding 1.8cm³And then heating the reaction mixture at a temperature close to 60c for 1 hour. The mixture was then concentrated to dryness under reduced pressure (5kPa) over 10cm³And 10cm of diethyl ether³Dissolving the water. Decanting the aqueous phase, using 1cm³Is acidified with 2N aqueous hydrochloric acid. 10cm for reaction medium³The dichloromethane was washed twice. The organic liquids were combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). 215mg of 7-methyl-1-oxo-2- (1-propylbutyl) are obtained in the form of yellow crystals) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid, which is used directly in the following reaction.

19.1.3: n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-chloro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

Under an argon atmosphere and at a temperature close to 20 ℃, 0.25cm³Triethylamine and 263mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [3- (trifluoromethyl) phenyl]-cyclopropyl } amino) but-2-ol hydrochloride (2: 1), then 90mg of 1-hydroxy-7-azabenzotriazole and 127mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are added to 180mg of 7-chloro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid at 2.2cm³In anhydrous dimethylformamide. The solution was kept stirring under argon at a temperature close to 20 ℃ for 15 hours. The reaction medium is then added to 10cm³Water (d) and 20cm³In ethyl acetate. After decantation, the organic phase took 10cm³Saturated aqueous solution of ammonium chloride, 5 times 10cm³Then 10cm of water³Was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa). Residual solution (about 2 cm)³) Purification was performed by flash chromatography on silica (column: 15g of the total weight of the mixture; BP-SUP type spherical silica, particle size: 20-40 μm; eluent: 50% heptane/50% ethyl acetate). After concentrating the fractions under reduced pressure, 274mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) -phenyl ] in the form of a beige foam are obtained]-cyclopropyl } amino) propyl]-7-chloro-1-oxo-2- (1-propyl-butyl) -1,2,3, 4-tetrahydro-isoquinoline-5-carboxamide.

·LC-MS-DAD-ELSD：[M+H]⁺：m/z 706

19.2: the salt N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-chloro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

Under an argon atmosphere, 272mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] methyl) phenyl]Cyclopropyl } amino) propyl]-7-chloro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide was dissolved in 5cm³In diethyl ether. Adding 0.35cm of water at 20 deg.C while stirring³4N hydrochloric acid solution in dioxane. The reaction mixture was concentrated to dryness under reduced pressure (5 kPa). The residue was used 2 times for 10cm³The diisopropyl ether of (a) was dissolved, concentrated to dryness under reduced pressure (5kPa), and dried under vacuum at a temperature of 35 ℃. 277mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] are obtained in the form of a beige powder]-cyclopropyl } amino) propyl]-7-chloro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: 0.87(m, 6H); 1.10 to 1.71(m, 12H); 2.30(m, 1H); 2.46 (partially masked m, 1H); 2.61(m, 1H); 2.79(m, 1H); 3.00 to 3.20(m, 4H); 3.84(m, 1H); 4.10(m, 1H); 4.61(m, 1H); 5.88 (width m, 1H); 6.97(m, 2H); 7.08(tt, J ═ 2.0 and 9.0Hz, 1H); 7.15(d, J ═ 2.5Hz, 1H); 7.68(t, J ═ 7.5Hz, 1H); 7.78 (width d, J ═ 7.5Hz, 1H); 7.88(d, J ═ 2.5Hz, 1H); 7.91 (width d, J ═ 7.5Hz, 1H); 8.01 (width s, 1H); 8.42 (width d, J ═ 8.0Hz, 1H); 9.41 (broad unresolved m, 1H); 9.92 (Wide unresolved m, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺：m/z 706；[M+H]^-：m/z 704

Example 20:

20.1: the base N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-fluoro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

20.1.1: n- [2- (2-bromo-4-fluorophenyl) ethyl ] hept-4-amine

663. mu.l of triethylamine are added under an inert atmosphere to 1g of 2-bromo-4-fluorophenylethylamine hydrochloride at 25cm³Suspension in dichloromethane. After stirring at a temperature close to 20 ℃ for 30 minutes, 5cm were added³Water was distilled and stirring was maintained for 30 minutes. Adding 15cm³Water was distilled and the 2 phases were separated. The organic phase is used for three times for 10cm³Is washed with distilled water and then dried. 449mg of 4-heptanone and 1.166g of sodium triacetoxyborohydride are then added to the resulting solution. The reaction mixture was stirred at a temperature close to 20 ℃ for 15 hours. Then 20cm³Is added to the reaction medium. The organic phase was decanted and separated from the aqueous phase and then used successively for 15cm³Distilled water and 15cm³Washing with saturated sodium chloride solution. The organic phase was dried and then concentrated under reduced pressure (5kPa) using a rotary evaporator. 1.069g of N- [2- (2-bromo-4-fluoro-phenyl) -ethyl are obtained in the form of a colourless oil]-hept-4-amine.

NMR: ppm0.84(m, 6H)1.21-1.30(m, 8H)1.38 (width m, 1H)2.43(m, 1H)2.69(m, 2H)2.77(m, 2H)7.18(td, J ═ 8.5, 2.5Hz, 1H)7.40(dd, J ═ 8.5, 6.5Hz, 1H)7.51(dd, J ═ 8.5, 2.5Hz, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺：m/z＝316

20.1.2: [2- (2-bromo-4-fluorophenyl) ethyl ] (1-propylbutyl) carbamic acid methyl ester

1.045g N- [2- (2-bromo-4-fluorophenyl) ethyl ] ethyl is stirred at a temperature of approximately 20 ℃ under an inert atmosphere]Hept-4-amine at 15cm³A solution in anhydrous tetrahydrofuran and 502mg of potassium carbonate. 0.28cm was introduced within 10 minutes using a syringe³Methyl chloroformate. The reaction mixture was refluxed over a period of 30 hours, then filtered through celite and concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual oil was dissolved in 20cm³In dichloromethane. The organic phase is successively used by 10cm³Aqueous hydrochloric acid (pH 2) and then 3X 20cm³Is washed with distilled water. Is dried withThe organic phase is then concentrated to dryness under reduced pressure (5kPa) using a rotary evaporator. 10cm of residual oil³The diisopropyl ether of (a) was dissolved. The emerging solid was filtered and the filtrate was concentrated to dryness under reduced pressure (5kPa) using a rotary evaporator to give 778mg of [2- (2-bromo-4-fluorophenyl) ethyl group as a beige oil](1-Propylbutyl) carbamic acid methyl ester.

NMR: 0.86(t, J ═ 7.3Hz, 6H)1.13-1.54(m, 8H)2.92(m, 2H)3.16(m, 2H)3.63 (width S, 1H)3.65 (width S, 2H)3.88 (width m, 0.33H)3.99 (width m, 0.67H)7.25(td, J ═ 8.7, 2.7Hz, 1H)7.39 (width m, 1H)7.57(dd, J ═ 8.7, 2.7Hz, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺：m/z＝374

20.1.3: 5-bromo-7-fluoro-2- (1-propylbutyl) -3, 4-dihydroisoquinolin-1 (2H) -one

540mg of [2- (2-bromo-4-fluorophenyl) ethyl are reacted at a temperature close to 20 ℃ under an inert atmosphere](1-Propylbutyl) carbamic acid methyl ester dissolved in 40cm³In dichloromethane. 529mg of 4-dimethylaminopyridine were added to the reaction mixture. The latter cools it to a temperature near 0 ℃. 1.91cm in length³Trifluoromethanesulfonic anhydride at 15cm³The solution in anhydrous dichloromethane was poured into the reaction mixture over 30 minutes. The suspension was kept stirring at a temperature close to 20 ℃ for 15 hours. Is measured by a distance of 20cm³To the reaction medium. Stirring was maintained for 30 minutes, then 20cm was added³Methylene chloride was added to the mixture. The organic phase is decanted and then successively taken up by 100cm³0.1M aqueous hydrochloric acid solution and 20cm³And washing with saturated aqueous solution of sodium bicarbonate. Then, the organic phase was dried and then concentrated under reduced pressure (5kPa) using a rotary evaporator. The residual brown oil was then dissolved in ethyl acetate and purified by filtration through silica (silica 60-particle size 15-40 μm). The organic phase was concentrated under reduced pressure (5 kPa). 477mg of 5-bromo-7-fluoro-2- (1-propylbutyl) -3, 4-dihydro-isoquinolin-1 (2H) -one are obtained in the form of a dark orange oil.

·NMR：0.88(t，J＝7.3Hz，6H)1.13-1.33(m，4H)1.42(m，2H)1.53(m，2H)2.94(t，J＝6.7Hz，2H)3.38(t，J＝6.7Hz，2H)4.64(m，1H)7.67(dd，J＝8.9，2.7Hz，1H)7.80(dd，J＝8.9，2.7Hz，1H)

·LC-MS-DAD-ELSD：[M+H]⁺：m/z＝342

20.1.4: 7-fluoro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid

In a close to 20 ℃ temperature in stirring and using carbon monoxide purge three-neck flask into the 655mg, 5-bromo-7-fluoro-2- (1-propyl butyl) -3, 4-two hydrogen isoquinoline- (1(2H) -ketone, 25 cm)³Dimethylformamide, 2cm³Water, 723mg potassium acetate, 334mg potassium iodide, 43mg palladium acetate and 102mg triphenylphosphine. The reaction mixture was subjected to carbon monoxide bubbling and then heated at a temperature of 100 ℃ for 6 hours. The reaction mixture was cooled to 25 ℃ and then concentrated under reduced pressure (5kPa) using a rotary evaporator. The residue was dissolved in 50cm³In ethyl acetate. The pH was basified with 5M sodium hydroxide (pH > 10). The two phases were filtered through celite and then clarified and separated. The aqueous phase was acidified with 5M hydrochloric acid solution (pH 2) and then 30cm with stirring³And (5) extracting with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). 166mg of 7-fluoro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid are obtained in the form of a dark orange solid.

NMR: 0.87(t, J ═ 7.3Hz, 6H)1.12-1.30(m, 4H)1.40(m, 2H)1.52(m, 2H)3.22(m, 2H)3.31 (partially masked m, 2H)4.64(m, 1H)7.74(dd, J ═ 9.0, 2.9Hz, 1H)7.82(dd, J ═ 9.0, 2.9Hz, 1H)13.47 (unresolved m, 1H)

·LC-MS-DAD-ELSD：[M+H]⁺m/z＝308；[M-H]^-m/z＝306

Melting point: 142.8 deg.C

20.1.5: n- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-fluoro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide

Under an argon atmosphere and at a temperature close to 20 ℃, 0.35cm³N, N-diisopropylethylamine, 6mg of 4-dimethylaminopyridine and 235mg of (2R, 3S) -3-amino-4- (3, 5-difluorophenyl) -1- ({1- [ 3-trifluoromethyl) phenyl)]Cyclopropyl } amino) but-2-ol hydrochloride was added to 150mg of 7-fluoro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid at 20cm³Then 10mg of 1-hydroxy-7-azabenzotriazole and 119mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added. The solution was kept stirring under argon at a temperature close to 20 ℃ for 15 hours. The reaction medium is then concentrated under reduced pressure (5 kPa). The remaining solid was purified by flash chromatography on silica (column: 90 g; silica of the type SuperVarioPrep D40-Si60, particle size: 15-40 μm; eluent: 50% cyclohexane/50% ethyl acetate). After concentrating the fractions under reduced pressure, 1g of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) -phenyl ] in the form of a beige foam is obtained]-cyclopropyl } -amino) propyl]-7-fluoro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydro-isoquinoline-5-carboxamide.

20.2: the salt N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-fluoro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1)

The foam obtained in step 19.1.5 was dissolved in 10cm³In diethyl ether. Adding 4cm of the mixture at a temperature of 20 ℃ while stirring³1N hydrochloric acid solution in diethyl ether, then 1cm³Methanol. The reaction mixture was concentrated to dryness under reduced pressure (5 kPa). Residue to 10cm³Is ground together and the solid formed is filtered and then dried at a temperature of approximately 20c under atmospheric pressure.249mg of N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) -phenyl ] are obtained in the form of a white solid]Cyclopropyl } amino) propyl]-7-fluoro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1: 1).

NMR: 0.86(m, 6H); 0.93 to 1.09(m, 4H); 1.11 to 1.28(m, 4H); 1.32 to 1.56(m, 4H); 2.30 to 2.73 (partially masked m, 5H); 3.03 to 3.15(m, 4H); 3.54(m, 1H); 4.12(m, 1H); 4.61(m, 1H); 4.95(d, J ═ 6.0Hz, 1H); 6.93(m, 2H); 7.08(tt, J ═ 2.0 and 9.0Hz, 1H); 7.12(d, J ═ 2.5Hz, 1H); 7.52(m, 2H); 7.59(m, 1H); 7.69 (width s, 1H); 7.85(d, J ═ 2.5Hz, 1H); 8.29 (Width d, J ═ 8.0Hz, 1H)

LC-MS-DAD-ELSD [ M + H ] + M/z 690 (base peak); [2M + H ] + M/z ═ 1379

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

melting point (. degree.C.) represents the melting point of the compound (degree.C.);

in the column "salts", "represents the compound in free base form and" HCl "the compound in hydrochloride salt form, the ratio between brackets being (acid: base) ratio;

- "nd": indicates not measured;

-Me represents methyl;

-R3 represents trifluoromethyl.

The compounds described in the tables were prepared according to the methods described previously.

TABLE 1：

Compound (I)

R1

X

R2

R4，R5

R6

Salt (salt)

Melting Point (. degree.C.)

1

(n-C)3H7)2CH-

-CH2-

H-

H-，H-

H-

HCl(1∶1)

nd(a)

2

(n-C)3H7)2CH-

-CH2CH2-

H-

-CH2CH2-

H-

HCl(1∶1)

174

3

(n-C)3H7)2CH-

-CH2CH2-

3, 5-difluoro

-CH2CH2-

H-

HCl(1∶1)

172

4

(n-C)3H7)2CH-

-CH2CH2-

H-

H-，H-

H-

HCl(1∶1)

nd(a)

5

C6H5CH2-

-CH2CH2-

3, 5-difluoro

-CH2CH2-

H-

HCl(1∶1)

178

6

n-C5H11

-CH2CH2-

3, 5-difluoro

-CH2CH2-

H-

HCl(1∶1)

165

7

CH3OCH2CH2-

-CH2CH2-

3, 5-difluoro

-CH2CH2-

H-

HCl(1∶1)

nd(a)

8

CH3CH2OCH2CH2-

-CH2CH2-

3, 5-difluoro

-CH2CH2-

H-

HCl(1∶1)

nd(a)

9

(n-C)3H7)2CH-

-CH2CH2-

3, 5-difluoro

-CH2CH2-

7-NMeSO2Me

HCl(1∶1)

nd(a)

10

4-F-C6H4CH(Me)-

-CH2CH2-

3, 5-difluoro

-CH2CH2-

H-

HCl(1∶1)

157

11

(n-C)3H7)2CH-

-CH(CH3)-

3, 5-difluoro

-CH2CH2-

6-NMeSO2Me

HCl(1∶1)

193

12

(n-C)3H7)2CH-

-CH2-

3, 5-difluoro

-CH2CH2-

6-NMeSO2Me

HCl(1∶1)

194

13

(n-C)3H7)2CH-

-CH2CH2-

3, 5-difluoro

-CH2CH2-

7-CF3

HCl(1∶1)

196

14

(n-C)3H7)2CH-

-CH2CH2-

3, 5-difluoro

-CH2CH2-

7-NHSO2Me

HCl(1∶1)

nd(a)

15

(n-C)3H7)2CH-

-CH2CH2-

3, 5-difluoro

-CH2CH2-

7- (oxazol-5-yl)

HCl(1∶1)

nd(b)

16

(n-C)3H7)2CH-

-CH2CH2-

3, 5-difluoro

-CH2CH2-

7-[(3-CN)C6H5]

HCl(1∶1)

nd(b)

17

(n-C)3H7)2CH-

-CH2CH2-

3, 5-difluoro

-CH2CH2-

7-[(2-CN)C6H5]

HCl(1∶1)

nd(b)

18

(n-C)3H7)2CH-

-CH2CH2-

3, 5-difluoro

-CH2CH2-

7-Me

HCl(1∶1)

nd(b)

19

(n-C)3H7)2CH-

-CH2CH2-

3, 5-difluoro

-CH2CH2-

7-Cl

HCl(1∶1)

nd(b)

20

(n-C)3H7)2CH-

-CH2CH2-

3, 5-difluoro

-CH2CH2-

7-F

HCl(1∶1)

nd(b)

(a) By passing¹H NMR spectra and characterization by liquid chromatography in conjunction with a mass spectrometer

(b) By passing¹Characterization by H NMR Spectroscopy

The compounds according to the invention are intended as pharmacological test objects, which enable their inhibitory effect on the activity of beta-secretase to be determined.

The assay consists in measuring the in vitro inhibition of the beta-secretase activity by the compounds of the invention.

The measured beta-secretase activity corresponds to that produced by expression in Drosophila cellsPurified recombinant form of human BACE1 aspartyl-protease activity (the latter comprising a hexahistidine tag at the C-terminus). Purified enzyme contains NaCl (0.45M), MnCl₂(0.9mM)、CaCl₂(0.9mM), α -D-methyl mannoside and 10% glycerol in TRIS buffer pH7.5 (18mM) and stored at-80 ℃ until use.

BACE1 activity was measured according to cleavage of a fluorescent peptide substrate called FS1, which was first described by Ermolieff et al (2000, Biochemistry, 39, 12450-; cleavage of the FS1 peptide was measured as an increase in the fluorescence signal emitted by the EDANS (or 5- [ (2-aminoethyl) amino ] naphthalene-2-sulfonic acid) group.

Assays were performed in 96-well black microplates to determine inhibition of enzyme activity by the products of the invention. Substrate FS1 was dissolved in 100% dimethyl sulfoxide (DMSO) to a concentration of 1mM and stored at-20 ℃ until use. Dilutions of the product to be tested were prepared in DMSO using 10mM stock solutions. The product of the invention, at a final concentration of 0.003-10. mu.M, was incubated at 37 ℃ for 45 minutes in sodium acetate buffer (0.1M, pH4.5, containing 0.02% CHAPS detergent and 200mM NaCl) with substrate FS1 (final concentration of 5. mu.M) and purified enzyme (final concentration of 10nM) in the dark. The final percentage of DMSO does not exceed 7%. When the incubation was complete, fluorescence was measured in a spectrofluorimeter at an excitation wavelength of 355nm and an emission wavelength of 509 nm. For each concentration of test product, the fluorescent signal was compared to the maximum signal obtained when the substrate FS1 was incubated with enzyme only.

Nonlinear regression analysis (computer application software XIfit, IDBS) was then used by measuring CI50 (concentration of product giving 50% inhibition of enzyme activity)^TM) The products of the invention were evaluated for inhibitory activity.

CI₅₀Is 0.01-5. mu.M.

Preferred compounds according to the invention have an IC of 10nM to 500nM₅₀。

For example, compounds No.1, 9, 16 and 17 showed CI50 at 0.77. mu.M, 0.048. mu.M, 0.39. mu.M and 0.63. mu.M, respectively.

It is therefore apparent that the compounds according to the invention have inhibitory activity on the activity of β -secretase.

The compounds according to the invention can therefore be used for the preparation of medicaments, in particular medicaments which inhibit the production of a β.

Thus, according to another aspect of the invention, the object is a medicament comprising a compound of formula (I) or an addition salt of the latter with a pharmaceutically acceptable acid, or a hydrate or solvate of the compound of formula (I). .

These drugs can be used in therapeutics, in particular in the treatment and prevention of diseases associated with the production of A.beta.peptides, among which mention may be made of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Creutzfeld-Jakob disease, Down's syndrome (syndrome de Down), dementia with Lewy bodies, senile dementia, frontotemporal dementia, cerebral and systemic amyloidosisc é blale et sys mique), mild cognitive impairment, cerebral amyloid angiopathy, primary and secondary memory disorders, amyotrophic lateral sclerosis, multiple sclerosis, peripheral neuropathy, diabetic neuropathy, migraine, affective disorders, depression, anxiety, vascular diseases, such as atherosclerosis, cerebral vascular ischemia, tumors and cell proliferation disorders.

These medicaments are particularly useful for the treatment and prevention of neurodegenerative diseases such as alzheimer's disease, parkinson's disease, down's syndrome, dementia with lewy bodies, senile dementia, frontotemporal dementia, cerebral and systemic amyloidosis, mild cognitive impairment, cerebral amyloid angiopathy, primary and secondary memory disorders and cerebral vascular ischemia.

According to another aspect of the invention, it relates to a pharmaceutical composition comprising a compound according to the invention as active ingredient. These pharmaceutical compositions comprise an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate of said compound, and at least one pharmaceutically acceptable excipient. The excipients are selected from the usual excipients known to those skilled in the art according to the pharmaceutical form and the desired method of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its optional salt, solvate or hydrate thereof, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the disorders or diseases mentioned above.

Suitable unit administration forms include oral route forms (e.g. tablets, soft or hard capsules, powders, granules and oral solutions or suspensions), sublingual, buccal, intratracheal, intraocular, intranasal administration forms, administration forms by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical administration, the compounds according to the invention may be used in creams, gels, salves or lotions.

For example, a unit administration form (in the form of a tablet) of a compound according to the invention may comprise the following components:

compound according to the invention 50.0mg

Mannitol 223.75mg

Croscarmellose sodium 6.0mg

Corn starch 15.0mg

Hydroxypropyl methylcellulose 2.25mg

Magnesium stearate 3.0mg

According to another aspect of the present invention, it also relates to a method of treating the pathologies indicated above, which comprises administering to the patient an effective dose of a compound according to the present invention or of one of its pharmaceutically acceptable salts or of its hydrates or of its solvates.

Claims (20)

1. A compound corresponding to the general formula (I):

wherein:

r1 represents optionally substituted one or more (C)₁-C₆) Alkyl substituted (C)₁-C₁₀) Alkyl, aryl optionally substituted by a halogen atom, or R1 represents (C)₁-C₆) alkyl-O- (C)₁-C₆) Alkyl or aralkyl optionally substituted with a halogen atom;

r2 represents one or more groups selected from a hydrogen atom or a halogen atom;

r3 represents trifluoromethyl;

r4 and R5 represent a hydrogen atom or form, together with the carbon atom bearing them, a cyclopropyl group;

r6 represents a group selected from: a hydrogen atom, a halogen atom, and (C)₁-C₆) Alkyl, halo (C)₁-C₆) Alkyl, NR7SO₂R8, aryl optionally substituted with cyano, or R6 represents a heterocycle;

r7 represents a hydrogen atom or (C)₁-C₆) An alkyl group;

r8 represents (C)₁-C₆) An alkyl group;

x represents (C)₁-C₂) Alkylene, optionally with one or more (C)₁-C₆) Alkyl substitution;

the aryl group is a cyclic aryl group containing 6 to 14 carbon atoms; and is

Said heterocyclyl is an unsaturated, partially unsaturated monocyclic or polycyclic group having 4 to 10 carbon atoms and 1 to 4 heteroatoms selected from N, O and S;

the carbon bearing the benzyl group substituted with R2 is in the S absolute configuration;

the carbon bearing the hydroxyl group is in the absolute R configuration,

in the form of a base or of an addition salt with an acid.

2. A compound of formula (I) according to claim 1, characterized in that X represents optionally with one or more (C)₁-C₆) An alkyl-substituted methylene group in the form of a base or an addition salt with an acid.

3. A compound of formula (I) according to claim 1, characterized in that X represents optionally with one or more (C)₁-C₆) Alkyl-substituted ethylene, in the form of a base or of an addition salt with an acid.

4. A compound of formula (I) according to any one of claims 1 to3, characterized in that R6 represents a group selected from: hydrogen, chlorine or fluorine atoms, methyl or trifluoromethyl, NMeSO₂Me radicals, phenyl substituted by cyano, or R6 representsAnd (3) azole.

5. The compound of formula (I) according to claim 1, characterized in that it is selected from

N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -1-oxo-2- (1-propylbutyl) isoindoline-4-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-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

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-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1-benzyl-2-hydroxy-3- { [3- (trifluoromethyl) benzyl ] amino } propyl ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride (1: 1) & gt-

2-benzyl-N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -1-oxo-2-pentyl-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- (2-methoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- (2-ethoxyethyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -2- [1- (4-fluorophenyl) ethyl ] -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -6- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-3-methyl-4-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -6- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) isoindoline-4-carboxamide and its hydrochloride (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-trifluoromethyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- [ (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl)]Cyclopropyl } amino) propyl]-7-(2-Azolyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetra-ethylHydroisoquinoline-5-carboxamide hydrochloride (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-methyl-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-chloro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1)

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7-fluoro-1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1).

6. The compound of formula (I) according to claim 5, characterized in that it is selected from

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

7. The compound of formula (I) according to claim 5, characterized in that it is selected from

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- [ methyl (methylsulfonyl) amino ] -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1).

8. The compound of formula (I) according to claim 5, characterized in that it is selected from

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (3-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1).

9. The compound of formula (I) according to claim 5, characterized in that it is selected from

N- [ (1S, 2R) -1- (3, 5-difluorobenzyl) -2-hydroxy-3- ({1- [3- (trifluoromethyl) phenyl ] cyclopropyl } amino) propyl ] -7- (2-cyanophenyl) -1-oxo-2- (1-propylbutyl) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide and its hydrochloride salt (1: 1).

10. A compound of the formula (IIIa)

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

11. A compound of the general formula (IIIb),

wherein R1 is as defined in general formula (I) according to claim 1.

12. A compound of the formula (IIIc)

Wherein R1, R7 and R8 are as defined in general formula (I) according to claim 1.

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

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

15. The use of a compound of formula (I) according to any one of claims 1 to 9 for the preparation of a medicament for the prevention and treatment of any disease in which β -secretase activity is involved.

16. The use of a compound of formula (I) according to any one of claims 1 to 9 for the preparation of medicaments for the treatment and prevention of alzheimer's disease, parkinson's disease, huntington's disease, Creutzfeld-Jakob disease, down syndrome, dementia with lewy bodies, senile dementia, frontotemporal dementia, cerebral and systemic amyloidosis, mild cognitive impairment, primary and secondary memory disorders, amyotrophic lateral sclerosis, multiple sclerosis, peripheral neuropathy, diabetic neuropathy, migraine, affective disorders, vascular diseases and cell proliferation disorders.

17. Use according to claim 16, wherein the vascular disease is atherosclerosis, cerebral amyloid angiopathy or cerebral vascular ischemia.

18. The use according to claim 16, wherein the cell proliferative disorder is a tumor.

19. The use of a compound of formula (I) according to any one of claims 1 to 9 for the preparation of medicaments for the treatment and prophylaxis of depression or anxiety.

20. The 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 syndrome, dementia with lewy bodies, senile dementia, frontotemporal dementia, cerebral and systemic amyloidosis, mild cognitive impairment, cerebral amyloid angiopathy, primary and secondary memory disorders and cerebrovascular ischemia.