OA16268A

OA16268A - 3,4-dihydropyrrolo[1,2-A]pyrazine-2,8(1H)dicarboxamide derivatives, preparation thereof and therapeutic use thereof.

Info

Publication number: OA16268A
Application number: OA1201200506
Authority: OA
Inventors: Sylvain Cote-Des-Combes; Jacques Froissant; Jean-François Gibert; Frank Marguet; Christophe Pacaud; Frédéric Puech; Antoine Ravet
Original assignee: Sanofi
Priority date: 2010-06-03
Filing date: 2011-06-01
Publication date: 2015-04-24

Abstract

Compounds corresponding to the general formula (I) in which R2 represents a group C1-10alkyl, C3-10-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkyl-C3-7-cycloalkyl, C3-7-cycloalkyl-C3-7cycloalkyl, C1-6-alkylthio-C-1-10-alkyl, C1-6-alkoxyC1-10-alkyl, hydroxy-C1-10-alkyl, hydroxy-C1-6-alkylC3-7-cycloalkyl-C1-6-alkyl, hydroxy-C3-10-cycloalkyl, C1-10-fluoroalkyl or C3-10-fluorocycloalkyl; an optionally substituted heterocyclic group; a group C1-10-alkyl substituted with an optionally substituted heterocyclic group; Xe represents a group chosen from hydrogen, fluorine, chlorine and bromine atoms or a group C1-6-alkyl, C3-7cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6fluoroalkyl or cyano; and R7 represents an aryl group such as phenyl or naphthyl, optionally substituted with one or more substituents, in the form of the base or of an acid-addition salt. Therapeutic use.

Description

The présent invention relates to 3,4-dihydropyrrolo[l,2-

a]pyrazine-2,8 (lJï)-dicarboxamide dérivatives, to a process for preparing them and to their therapeutic use, in the treatment or prévention of dîseases involving casein kinase 1 epsilon and/or casein kinase 1 delta.

The technical problem according to the présent invention is that of obtaining novel compounds

CKlepsilon and/or CKldelta, so as that inhibit the enzymes to modify the circadian rhythm, and linked to the which may circadian be useful rhythm.

One subject of the corresponding for treating disorders présent invention is to the general formula (I) :

(I) compounds in which

R₂ represents:

a group

Ci-io-alkyl, C₃_7-cycloalkyl-Ci-₆-alkyl, Ci_₆alkylthio-C-i-io-alkyl, Ci-g-alkoxy-Ch-io-alkyl, hydroxy-Οχ-ιοalkyl, hydroxy-Ci-6~alkyl-C3-7-cycloalkyl-Ci_6-alkyl,

Ci-io-fluoroalkyl, Ci-i₀-alkyl-oxyimino-Ci-i₀-alkyl,

- a group C₃_io-cycloalkyl, C₃-i₀-f luorocycloalkyl, hydroxyC₃-i₀-cycloalkyl,

- a group C₃-7-cycloalkyl which may be substituted with one or two groups independently chosen from Ci_₆-alkyl, C3-7cycloalkyl, hydroxyl, Ci-i₀-fluoroalkyl and Ci_i₀-alkyloxyimino,

- a heterocyclic group comprising from 3 to 8 carbon atoms and at least one heteroatom chosen from nitrogen, oxygen, sulfur and the oxide or dioxide form of sulfur, this heterocyclic group possibly being substituted with one or more groups from among hydroxyl, Ci_₆-alkyl, hydroxy-Ci_₆alkyl, Ci-6~fluoroalkyl,

- a group Ci_i₀-alkyl substituted with a heterocyclic group comprising from 3 to 8 carbon atoms and at least one heteroatom chosen from nitrogen, oxygen, sulfur and the oxide or dioxide form of sulfur, this heterocyclic group possibly being substituted with one or more groups from among hydroxyl, Ci_₆-alkyl, hydroxy-Ci-6-alkyl,

Ci-6- f luoroalkyl ;

X₆ represents a hydrogen, fluorine, chlorine or bromine atom or a group Ci-₆-alkyl, C₃_7-cycloalkyl, C₃_₇-cycloalkylCi-6-alkyl, Ci_₆-fluoroalkyl or cyano;

R₇ represents a phenyl group or a naphthyl group, optionally substituted with one or more substituents X₇₍ which may be identical or different, chosen independently;

X₇ represents:

a halogen atom chosen from fluorine, chlorine and bromine atoms, or a group chosen from:

hydroxyl,

Ci-e-alkyl, C₃_₇-cycloalkyl, C₃-₇-cycloalkyl-Ci-₆-alkyl, hydroxy-Ci-g-alkyl, hydroxy-C₃_7-cycloalkyl, hydroxyC₃-7-cycloalkyl-Ci-₆-alkyl,

Ci-₆-alkoxy, C₃-₇-cycloalkoxy, C₃-₇-cycloalkyl-Ci_₆alkoxy,

- Ci-e-alkylthio, C₃_7~cycloalkylthio, C₃-₇-cycloalkyl-Ci_₆alkylthio,

- aryl, aryl-Ci-₆-alkyl,

- aryloxy, aryl-Ci-g-alkoxy,

Ci-g-f luoroalkyl, C₃_₇-f luorocycloalkyl, C₃_₇f luorocycloalkyl-Ci-₆-alkyl,

- Ci-6~fluoroalkoxy, C₃_7-fluorocycloalkoxy,

C₃-₇-f luorocycloalkyl-Ci-e-alkoxy,

- cyano, cyano-Ci-₆-alkyl, cyano-Ci_₆-alkoxy,

- NR_aR_b, NR_cCOR_d, NR_cSO₂R_d, NR_cSO₂NR_aR_b, CONR_aR_b, CON (OR_C) R_d,

- a heteroaryl group, the aryl or heteroaryl groups being optionally substituted with one or more substituents chosen from fluorine, chlorine and bromine atoms or a group Ci-s-alkyl, C₃_7~cycloalkyl, Ci^₆-alkoxy, Ci_₆-f luoroalkyl, Ci_6~fluoroalkoxy or cyano,

R_a and R_b represent, independently of each other, a hydrogen atom or a group Ci_₆-alkyl, C₃_7-cycloalkyl or C₃-₇cycloalkyl-Ci-g-alkyl, or alternatively they form with the atom that bears them a ring chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine and piperazine, this ring being optionally substituted with one or more groups Ci-₆-alkyl,

R_c and R_d represent, independently of each other, a hydrogen atom or a group Ci_₆-alkyl, C₃-7-cycloalkyl or C3-7cycloalkyl-Ci-g-alkyl.

Among the compounds of general formula (I), a first subgroup of compounds is formed by the compounds of general formula (I) for which:

R₂ represents:

- a group Ci_i₀-alkyl, C₃-i₀-cycloalkyl, C₃_7~cycloalkyl-

Ci-6-alkyl, Ci-₆-alkyl-C₃-7-cycloalkyl, C₃-7-cycloalkyl-C₃_₇cycloalkyl, Ci_₆-alkylthio-C-i_io-alkyl, Ci-₆-alkoxy-Ci-i₀alkyl, hydroxy-Ci_i₀-alkyl·, hydroxy-Ci_₆-alkyl-C₃-₇cycloalkyl-Ci-g-alkyl, hydroxy-C₃-₁₀-cycloalkyl,

Ci-10-f luoroalkyl, C₃-i₀-f luorocycloalkyl,

K

- a heterocyclic group comprising from 3 to 8 carbon atoms and at least one heteroatom chosen from nitrogen, oxygen, sulfur and the oxide or dioxide form of sulfur, this heterocyclic group possibly being substituted with one or more groups from among hydroxyl, Ci-₆-alkyl, hydroxy-Ci-6-alkyl, Ci-g-f luoroalkyl,

- a group Ci-i₀-alkyl substituted with a heterocyclic group comprising from 3 to 8 carbon atoms and at least one heteroatom chosen from nitrogen, oxygen, sulfur and the oxide or dioxide form of sulfur, this heterocyclic group possibly being substituted with one or more groups from among hydroxyl, Ci_₆-alkyl, hydroxy-Ci__e-alkyl,

Ci-₆-f luoroalkyl;

X₆ represents a hydrogen, fluorine, chlorine or bromine atom or a group Ci_₆-alkyl, C₃_7-cycloalkyl, C₃-₇-cycloalkylCi-e-alkyl, Ci-₆-f luoroalkyl or cyano;

R₇ represents a phenyl group or a naphthyl group, optionally substituted with one or more substituents X₇, which may be identical or different, chosen independently;

X₇ represents:

- a halogen atom chosen from fluorine, chlorine and bromine atoms, or a group chosen from:

- hydroxyl,

- Ci-g-alkyl, C₃_₇-cycloal kyl, C₃_₇-cycloalkyl-Ci_6-alkyl, hydroxy-Ci-6-alkyl, hydroxy-C₃_₇-cycloalkyl, hydroxyC3-7-cycloalkyl~Ci-6-alkyl,

Ci-₆-alkoxy, C₃_₇-cycloalkoxy, C₃-₇-cycloalkyl-Ci-₆alkoxy,

- Ci-₆-alkylthio, C₃-₇-cycloalkylthio, C₃-₇-cycloalkyl-Ci_₆alkylthio,

- aryl, aryl-C₃__ë-alkyl,

- aryloxy, aryl-Cx-g-alkoxy,

V

Ci-₆-f luoroalkyl, C₃-₇-fluorocycloalkyl, C₃_₇f luorocycloalkyl-Ci-₆-alkyl,

- Ci-e-fluoroalkoxy, C₃_₇-f luorocycloalkoxy, C₃-₇-fluorocycloalkyl-Ci_₆-alkoxy,

- cyano, cyano-Ci-₆-alkyl, cyano-Ci_₆-alkoxy,

- NR_aR_b, NR_cCOR_d, NR_cSO₂R_d, NR_cSO₂NR_aR_b, CONR_aR_b, CON(OR_c)R_d,

- a heteroaryl group, the aryl or heteroaryl groups being optionally substituted with one or more substituents chosen from fluorine, chlorine and bromine atoms or a group Ci-e-alkyl, C₃-₇-cycloalkyl, Ci_₆-alkoxy, Ci_₆-f luoroalkyl, Ci_₆-fluoroalkoxy or cyano,

R_a and R_b represent, independently of each other, a hydrogen atom or a group Ci-₆-alkyl, C₃_₇-cycloalkyl or C₃_₇cycloalkyl-Ci-e-alkyl, or alternatively they form with the atom that bears them a ring chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine and piperazine, this ring being optionally substituted with one or more groups Ci-g-alkyl,

R_c and R_d represent, independently of each other, a hydrogen atom or a group Ci_₆-alkyl, C₃_₇-cycloalkyl or C₃-₇cycloalkyl-Ci-e-alkyl.

Among the compounds of general formula (I), a second subgroup of compounds is formed by compounds for which R₂represents:

- a group Ci-io-alkyl, C₃_₇-cycloalkyl-Ci_₆-alkyl, Ci_₆-alkoxy-

Ci-iQ-alkyl, hydroxy-Ci_i₀-al kyl, hydroxy-Ci-₆-alkyl-C₃_₇cycloalkyl-Ci-6-alkyl, Ci_i₀~fluoroalkyl,

- a group C₃-i₀-cycloalkyl, C₃~i₀-f luorocycloalkyl, hydroxyC₃-io-cycloalkyl,

- a group C₃_₇-cycloalkyl which may be substituted with one or two groups independently chosen from Ci_₆-alkyl, C₃_₇-

6L

-6cycloalkyl, hydroxyl, Ci_i₀-f luoroalkyl and Ci-io-alkyloxyimino,

- a heterocyclic group comprising from 3 to 8 carbon atoms and at least one heteroatom chosen from oxygen or a sulfur atom in dioxide form, this heterocyclic group possibly being substituted with one or more groups Ci-e-alkyl,

- a group C₁_i₀-alkyl substituted with a heterocyclic group comprising from 3 to 8 carbon atoms and at least one oxygen heteroatom, this heterocyclic group possibly being substituted with one or more groups Ci-₆-alkyl;

and X₆ and R₇ are as defined in the general formula (I).

Among the compounds of general formula (I), a third subgroup of compounds is formed by compounds for which R₂ represents:

- a group Ci-io-alkyl, C₃_io~cycloal kyl, C₃-₇-cycloalkyl-Ci_6“ alkyl, C₃-₇-cycloalkyl-C₃_₇-cycloalkyl, Ci-₆-alkoxy-Ci-i₀-alkyl, hydroxy-Ci-io-alkyl, hydroxy-Ci-6-alkyl-C₃_₇-cycloalkyl-Ci-₆alkyl, hydroxy-C₃-i₀~cycloalkyl·, Ci-io-f luoroalkyl, C₃^i₀fluorocycloalkyl,

- a heterocyclic group comprising from 3 to 8 carbon atoms and at least one heteroatom chosen from an oxygen atom or a sulfur atom in dioxide form;

and X₆ and R₇ are as defined in the general formula (I).

Among the compounds of general formula (I), a fourth subgroup of compounds is formed by compounds for which R₂represents:

- a group Ci-i₀-alkyl, C₃-i₀-cycloalkyl, C₃_₇-cycloalkyl-Ci-₆alkyl, C₃-7-cycloalkyl-C₃-₇-cycloal kyl, Ci-₆-alkoxy-Ci-i₀-alkyl, hydroxy-Ci-i₀-alkyl, hydroxy-Ci_6^-alkyl-C₃-₇-cycloalkyl-Ci-6alkyl, hydroxy-C₃_i₀-cycloal kyl, Ci_i₀-f luoroalkyl, C₃-iqfluorocycloalkyl;

and X₆ and R₇ are as defined in the general formula (I).

ii L

Among the compounds of general formula (I), a fifth subgroup of compounds is formed by compounds for which R₂ represents:

and X₆ and R₇ are as defined in the general formula (I).

Among the compounds of general formula (I), a sixth subgroup of compounds is formed by compounds for which R₂ represents a group chosen from:

- cyclo-propyl

- iso-propyl

- ïso-butyl

- tert-butyl

- cyclo-propylmethyl

- 3-methyl-butyl

- 2,2-dimethyl-propyl

- 2-ethyl-butyl

- 3,3-dimethyl-butyl

- cyclo-hexyl

- cyclo-hexylmethyl

- 1,1'-bi(cyclo-propyl)-1-yl

- 2,4,4-trimethylpentan-2-yl

- bicyclo[2.2.1]hept-2-yl

- hexahydro-2,5-methanopentalen-3a(1H)-yl or

- tricyclo [ 3.3.1. O³'⁷] non-3-yl

- adamantan-l-yl or

- tricyclo [3.3.1.1³'⁷] dec-l-yl

- 2,2,2-trifluoro-ethyl

- (2S)-1,1,1-trifluoropropan-2-yl

- (S) -2,2,2-trifluoro-l-methyl-ethyl

- 3,3,3-trifluoro-propyl

- 1,1,1-trifluoro-2-methylpropan-2-yl

- 2,2,2-trifluoro-1,1-dimethyl-ethyl

- 4,4,4-trifluoro-butyl

*

- 4 , 4-dif luoro-cyclo-’hexyl

- 4-hydroxy-cyclo-hexyl

- 4-tert-butoxyimino-cyclohexyl

- 4-methoxyimino-cyclohexyl

- 4-hydroxy-4-methyl-cyclohexyl

- 4-hydroxy-4-trifluoromethyl-cyclohexyl

- 3-hydroxy-2,2-dimethyl-propyl

- [1-(hydroxymethyl)cyclo-propyl]methyl

- l-methoxy-2-methylpropan-2-yl

- tetrahydro-2Jï-pyran-4-yl

- 2,2-dimethyl-tetrahydro-2/f-pyran-4-yl

- 2,6-dimethyl-tetrahydro-2if-pyran-4-yl

- oxetan-3-yl

- 3-methyl-oxetan-3-ylmethyl

- tetrahydro-furan-3-yl

- 1,l-dioxydotetrahydrothiophen-3-yl

- 1,l-dioxydotetrahydro-2H-thiopyran-4-yl, and X₆ and R₇ are as defined in the general formula (I).

Among the compounds of general formula (I), a seventh subgroup of compounds is formed by compounds for which R₂represents a group chosen from:

- cyclo-propyl

- iso-propyl

- iso-butyl

- tert-butyl

- cyclo-propylmethyl

- 3-methyl-butyl

- 2,2-dimethyl-propyl

- 2-ethyl-butyl

- 3,3-dimethyl-butyl

- cyclo-hexyl

- cycio-hexylmethyl

- 1,1' -bi(cyclo-propyl)-1-yl

- 2,4,4-trimethylpentan-2-yl ’Œ16268

- bicyclo[2.2.1]hept-2-yl

- hexahydro-2,5-methanopentalen-3a(1H)-yl or

- tricyclo [3.3.1. O³'⁷ ] non-3-yl

- adamantan-l-yl or

- tricyclo [3.3.1.1³’⁷] dec-l-yl

- 2,2,2-trifluoro-ethyl

- (2S) -1,1,l-trifluoropropan-2-yl

- 3,3,3-trifluoro-propyl

- 1,1,1-trifluoro-2-methylpropan-2-yl

- 4,4,4-trifluoro-butyl

- 4,4-difluoro-cyclo-hexyl

- 4-hydroxy-cyclo-hexyl

- 3-hydroxy-2,2-dimethyl-propyl

- [1-(hydroxymethyl)cyclo-propyl]methyl

- l-methoxy-2-methylpropan-2-yl

- tetrahydro-2R-pyran-4-yl

- oxetan-3-yl

- tetrahydro-furan-3-yl

- 1,l-dioxydotetrahydrothiophen-3-yl

- 1, l-dioxydotetrahydro-2H-thiopyran-4-yl, and X₆ and R₇ are as defined in the general formula (I).

Among the compounds of general formula (I), an eighth subgroup of compounds is formed by compounds for which X₆25 represents a hydrogen, fluorine, chlorine or bromine atom or a group Ci_₆-alkyl, C3-₇-cycloalkyl or cyano; and R₂ and R₇are as defined in the general formula (I).

Among the compounds of general formula (I), a ninth subgroup 30 of compounds is formed by compounds for which X₆ represents a hydrogen, fluorine, chlorine or bromine atom or the cyano group; and R₂ and R₇ are as defined in the general formula (I) · ί 6268

-ιοAmong the compounds of general formula (I), a tenth subgroup of compounds is formed by compounds for which X₆ represents a hydrogen atom or a group Ci_₆-alkyl or C₃-₇-cycloalkyl ; and R₂ and R₇ are as defined in the general formula (I).

Among the compounds of general formula (I), an eleventh subgroup of compounds is formed by compounds for which X₅represents a fluorine, chlorine or bromine atom or a methyl, cyclopropyl or cyano group; and R₂ and R₇ are as defined in the general formula (I).

Among the compounds of general formula (I), a twelfth subgroup of compounds is formed by compounds for which R₇represents a phenyl group optionally substituted with one or more substituents X₇, which may be identical or different, chosen independently from:

- a fluorine or chlorine atom or a group chosen from

- Ci-₆-alkyl, C3_₇-cycloalkyl,

- Ci-6-alkoxy, C₃-₇-cycloalkyl-Ci_₆-alkoxy,

- Ci-6-alkylthio,

- aryl,

- aryloxy, aryl-Ci^₆-alkoxy,

- Ci-6 fluoroalkyl,

- Ci-e fluoroalkoxy,

- cyano, cyano-Ci-₆-alkoxy,

- NR_aR_b, NR_cSO₂R_d, NR_cSO₂NR_aR_b, CONR_aR_b, CON(OR_c)R_d, heteroaryl chosen from oxadiazolyl and pyrazolyl groups, optionally substituted with a group Ci-₆-alkyl, the aryl group being optionally substituted with a fluorine atom,

R_a and R_b represent, independently of each other, a hydrogen atom or a group C₁_₆-alkyl, C₃_₇-cycloalkyl, or alternatively they form with the atom that bears them a ring chosen from pyrrolidine and morpholine,

-11 R_c and R<j represent, independently of each other, a hydrogen atom or a group Ci_₆-alkyl;

and R₂ and X₆ are as defined in the general formula (I).

Among the compounds of general formula (I), a thirteenth subgroup of compounds is formed by compounds for which R₇represents a phenyl group optionally substituted with one or more substituents X₇, which may be îdentical or different, chosen independently from:

- a fluorine or chlorine atom,

- methyl or isopropyl, cyclo-hexyl,

- methoxy, butoxy, cyclo-propylmethoxy,

- methylsulfanyl,

- phenyl,

- phenoxy,

- benzyloxy, 4-fluorobenzyloxy,

- trifluoromethyl,

- trifluoromethoxy,

- cyano, cyanomethoxy,

- 4-dimethylamino, morpholin-4-yl, methanesulfonylamino, (dimethylsulfamoyl)amino, dimethylcarbamoyl, cyclo-propylcarbamoyl, pyrrolidine-1-carbonyl, methoxy-methyl-carbamoyl, and

- 5-methyl-[1.3.4]oxadiazol-2-yl, pyrazol-l-yl;

and R₂ and X₆ are as defined in the general formula (I).

Among the compounds of general formula (I), a fourteenth subgroup of compounds is formed by compounds for which R₇represents a naphthyl group optionally substituted with one or more substituents X₇, which may be îdentical or different, independently chosen as described above for the compounds of general formula (I), and R₂ and X₆ are as defined in the general formula (I).

Among the compounds of general formula (I), a fifteenth subgroup of compounds is formed by compounds for which R₇

U

-12represents an unsubstituted naphthyl group, and R₂ and X₆are as defined in the general formula (I).

Among the compounds of general formula (I), a sixteenth subgroup of compounds is formed by the compounds of general formula (I) in which both R₂ and/or R₇ and/or X₆ and/or X₇are as defined in the above subgroups.

Among the compounds of general formula (I), a seventeenth subgroup of compounds is formed by the compounds of general formula (I) for which:

R₂ represents:

- a group Ci-i₀-alkyl, C₃-₇-cycloalkyl-Ci-₆-alkyl·, Ci_₆-alkoxyCi-io-alkyl, hydroxy-Ci-i₀-alkyl, hydroxy-Ci-_Ê-alkyl-C₃-₇cycloalkyl-C₁_₆-alkyl, Ci_i₀-fluoroalkyl,

- a group C₃_io-cycloal kyl, C₃_io-fluorocycloalkyl, hydroxyC₃_io-cycloalkyl,

- a group C₃_₇-cycloalkyl which may be substituted with one or two groups independently chosen from Ci-6-alkyl, C₃_₇cycloalkyl, hydroxyl, Ci_i₀-f luoroalkyl and Ci_i₀-alkyloxyimino,

- a heterocyclic group comprising from 3 to 8 carbon atoms and at least one heteroatom chosen from oxygen or a sulfur atom in dioxide form, this heterocyclic group possibly being substituted with one or more groups Ci_₆-alkyl,

- a group Ci^io-alkyl substituted with a heterocyclic group comprising from 3 to 8 carbon atoms and at least one oxygen heteroatom, this heterocyclic group possibly being substituted with one or more groups Ci_₆-alkyl,

R₇ represents a phenyl group optionally substituted with one or more substituents X₇, which may be identical or different, chosen independently from:

- a fluorine or chlorine atom or a group chosen from

- Ci-6-alkyl, C3_₇-cycloalkyl,

- Ci_₆-alkoxy, C₃_7-cycloalkyl-Ci-₆-alkoxy,

- Ci-₆-alkylthio,

- aryl,

- aryloxy, aryl-Ci_₆-alkoxy,

- Ci-6 fluoroalkyl,

- Ci-s fluoroalkoxy,

- cyano, cyano-Ci-g-alkoxy,

- NR_aR_b, NR_cSO₂R_d, NR_cSO₂NR_aR_b, CONR_aR_b, CON(OR_c)R_d, heteroaryl chosen from oxadiazolyl and pyrazolyl groups, optionally substituted with a group Ci_₆-alkyl, the aryl group being optionally substituted with a fluorine atom,

R_a and R_b represent, independently of each other, a hydrogen atom or a group Ci_₆-alkyl, C₃_7-cycloalkyl, or alternatively they form with the atom that bears them a ring chosen from pyrrolidine and morpholine,

R_c and R_d represent, independently of each other, a hydrogen atom or a group Ci-₆~alkyl.

Among the compounds of general formula (I), an eighteenth subgroup of compounds is formed by the compounds of general formula (I) for which:

R₂ represents:

- a group Ci_i₀-alkyl, C₃_i₀-cycloalkyl, C₃-7-cycloalkyl-Ci-6alkyl, C3-7-cycloalkyl-C₃-7-cycloalkyl, Ci_₆-alkoxy-Ci-io-alkyl, hydroxy-Ci-io-alkyl, hydroxy-Ci-₆-alkyl-C3-7-cycloalkyl-Ci-₆alkyl, hydroxy-C₃-io-cycloalkyl, Ci-i₀-f luoroalkyl, C₃-i₀- fluorocycloalkyl,

X₆ represents a hydrogen, fluorine, chlorine or bromine atom or a group Ci_₆-alkyl, C₃_7-cycloalkyl or cyano;

VïU

-14R₇ represents a phenyl group optionally substituted with one or more substituents X₇, which may be identical or different, chosen independently from:

- a fluorine or chlorine atom or a group chosen from

- Ci-6-alkyl, C₃-₇-cycloalkyl,

- Ci-s-alkoxy, C₃_₇-cycloalkyl-Ci-₆-alkoxy,

- Ci-e-alkylthio,

- aryl,

- aryloxy, aryl-Ci-₆-alkoxy,

- Ci_6 fluoroalkyl,

- Ci-s fluoroalkoxy,

- cyano, cyano-Ci-g-alkoxy,

R_a and R_b represent, independently of each other, a hydrogen atom or a group Cx-^-alkyl, C₃_₇-cycloalkyl, or alternatively they form with the atom that bears them a ring chosen from pyrrolidine and morpholine,

R_c and R_d represent, independently of each other, a hydrogen atom or a group Ci-6-alkyl.

Among the compounds of general formula (I), a nineteenth subgroup of compounds is formed by the compounds of general formula (I) for which:

R₂ represents:

a group Ci_i₀-alkyl, C₃-₇-cycloalkyl-Ci_₆-alkyl, Ci-ealkylthio-C-i^io-alkyl, Ci_₆-alkoxy-Ci-i₀-alkyl, hydroxy-Ci-i₀alkyl, hydroxy-Ci-₆-alkyl-C₃-₇-cycloalkyl-Ci-₆-alkyl,

Ci-io-fluoroalkyl, Ci-io-alkyl-oxyimino-Ci_i₀-alkyl,

- a group C₃_i₀-cycloalkyl, C₃_io-f luorocycloalkyl, hydroxyC₃_i₀-cycloalkyl,

Vit16268

- a group C3-₇-cycloalkyl which may be substituted with one or two groups independently chosen from Ci_₆-alkyl, C₃_₇cycloalkyl, hydroxyl, Ci_i₀-f luoroalkyl and Ci-i₀-alkyloxyimino,

- a heterocyclic group comprising from 3 to 8 carbon atoms and at least one heteroatom chosen from nitrogen, oxygen, sulfur and the oxide or dioxide form of sulfur, this heterocyclic group possibly being substituted with one or more groups from among hydroxyl, Ci-g-alkyl, hydroxy-Ci-galkyl and Ci~₆-f luoroalkyl, this heterocyclic group being chosen from oxetanyl, tet rahydrofuryl, tetrahydro-2i£pyranyl, oxepanyl, thietanyl, tetrahydrothiophenyl, tetrahydro-2H-thiopyranyl, thiepanyl, 1,1-dioxydothietanyl,

1,1-dioxydotetrahydrothiophenyl, 1, l-dioxydotetrahydro-277thiopyranyl and 1,1-dioxydothiepanyl;

- a group Ci-i₀-alkyl substituted with a heterocyclic group comprising from 3 to 8 carbon atoms and at least one heteroatom chosen from nitrogen, oxygen, sulfur and the oxide or dioxide form of sulfur, this heterocyclic group possibly being substituted with one or more groups from among hydroxyl, Ci~₆-alkyl, hydroxy-Ci-₆-alkyl,

Ci-6-fluoroalkyl, this heterocyclic group being chosen from oxetanyl, tetrahydrofuryl, tetrahydro-2/ï-pyranyl·, oxepanyl, thietanyl, tetrahydrothiophenyl, tetrahydro-2/i-thiopyranyl, thiepanyl, 1,1-dioxydothietanyl, 1,1dioxydotetrahydrothiophenyl, 1, l-dioxydotetrahydro-2iZthiopyranyl and 1,1-dioxydothiepanyl;

X₆ represents a hydrogen, fluorine, chlorine or bromine atom or a group Ci_₆-alkyl, C₃-₇-cycloalkyl, C₃_₇-cycloalkylCi-₆-alkyl, Ci_₆-fluoroalkyl or cyano;

R₇ represents a phenyl group or a naphthyl group, optionally substituted with one or more substituents X_7/ which may be identical or different, chosen independently;

-16X₇ represents:

- hydroxyl,

- Ci-₆-alkyl, C₃_7-cycloal kyl, C₃-7-cycloalkyl-Ci_₆-alkyl, hydroxy-Ci-6-alkyl, hydroxy-C₃-7-cycloalkyl, hydroxyC₃-7-cycloalkyl-Ci-₆-alkyl,

Ci-₆-alkoxy, C₃_7-cycloalkoxy, C₃-7-cycloalkyl-Ci_₆alkoxy,

- Ci-₆-alkylthio, C₃-₇-cycloalkylthio, C₃_7-cycloalkyl-Ci-₆alkylthio,

- aryl, aryl-Ci__É-alkyl,

- aryloxy, aryl-Ci~₆-alkoxy,

Ci_₆-f luoroalkyl, C₃-₇-f luorocycloalkyl, C3-7f luorocycloal kyl-Ci-e-alkyl,

- Ci-6~fluoroalkoxy, C₃-₇-fluorocycloalkoxy,

C₃_7-f luorocycloalkyl-Ci-g-alkoxy,

- cyano, cyano-Ci_₆-alkyl, cyano-Ci-₆-alkoxy,

- NR_aR_b, NR_cCOR_d, NR_cSO₂R_d, NR_cSO₂NR_aR_b, CONR_aR_b, CON(OR_c)R_d,

- a heteroaryl group, the aryl or heteroaryl groups being optionally substituted with one or more substituents chosen from fluorine, chlorine and bromine atoms or a group Ci-e-alkyl, C₃^₇-cycloalkyl, Ci~₆-alkoxy, Ci-g-f luoroalkyl, Ci_₆-fluoroalkoxy or cyano, the aryl group being chosen from phenyl and naphthyl, and the heteroaryl group being chosen from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl;

R_a and R_b represent, independently of each other, a hydrogen atom or a group Ci_₆-alkyl, C₃-7~cycloalkyl or C3-7

-17cycloalkyl-Ci-g-alkyl, or alternatively they form with the atom that bears them a ring chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine and piperazine, this ring being optionally substituted with one or more groups Ci-g-alkyl,

R_c and Rd represent, independently of each other, a hydrogen atom or a group Ci_₆-alkyl, C₃-7-cycloalkyl or C3-7cycloalkyl-Ci-e-alkyl.

Among the compounds of general formula (I), the following compounds may be mentioned (IUPAC nomenclature generated with the ACD Name software):

1. N²-tert-butyl-7-phenyl-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1 H) -dicarboxamide,

2. J^-tert-butyl-ï-(4-methoxyphenyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(lHj-dicarboxamide,

3. H²-tert-butyl-6-methyl-7-phenyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H) -dicarboxamide , fi^-tert-butyl-?-(4-methoxyphenyl)-6-methyl-3,4- dihydropyrrolo[1,2-a]pyrazine-2,8(1H}-dicarboxamide, . N²-tert-butyl-6-methyl-7-(4-phenoxyphenyl)-3,4- dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide,

6, A^-ë-di-cyclo-propyl-?-(4-methoxyphenyl)-3,4- dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide, . 6-cyclo-propyl-7-phenyl-.N²- (ïso-propyl) -3,4- dihydropyrrolo [ 1,2-a] pyrazine-2,8(1#) -dicarboxamide, . 6-cyclo-propyl-7-(4-methoxyphenyl)-N²-(iso-propyl)-

3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide, . 6-cyclo-propyl-7-phenyl-.N²- ( ïso-butyl) -3,4- dihydropyrrolo[1,2-a]pyrazine-2,8(1#)-dicarboxamide, . W²-tert-butyl-6-cyclo-propyl-7-phenyl-3,4- dihydropyrrolo[1,2-a]pyrazine-2,8(1#)-dicarboxamide,

11, N²-tert-butyl-6-cyclo-propyl-7-(3-methylphenyl)-3, 4- dihydropyrrolo[1,2-a]pyrazine-2,8(1#) -dicarboxamide,

12. N²-tert-butyl-6-cycJo-propyl-7-(4-methylphenyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8 ( IH)-dicarboxamide,

13. i/-tert-butyl-6-cyclo-propyl-7“[4-(isopropyl)phenyl] - 3,4-dihydropyrrolo [1,2-a] pyrazine-2,8 ( IH) dicarboxamide, . N²-tert-buty 1-7- (4-cyclo-hexylphenyl) -6-cyclo-propyl-

3,4-dihydropyrrolo[1,2-a]pyrazine-2,8 (IH)-dicarboxamide, . 7-(biphenyl-4-yl)-N²-tert-butyl-6-cyclo-propy1-3,4- dihydropyrrolo[1,2-a]pyrazine-2,8(IH) -dicarboxamide,

16. N²-tert-butyl-6-cyclo-propyl-7-[3- (trifluoromethyl)phenyl]-3,4-dihydropyrrolo[1,2-

a] pyrazine-2,8(1/7) -dicarboxamide,

17. N²-tert-butyl-6-cyclo-propyl-7-[3(dimethylcarbamoyl)phenyl]-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(IH) -dicarboxamide, . W²-tert-butyl-6-cyclo-propyl-7- [4 - ( cyclo- propylcarbamoyl)phenyl]-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(IH)-dicarboxamide, . N²-tert-butyl-6-cyclo-propy1-7-[4-(pyrrolidin-1- ylcarbonyl)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 (IH) -dicarboxamide, . N²-tert-butyl-6-cyclo-propyl-7-{4- [methoxy(methyl)carbamoyl]phenyl}-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(IH) -dicarboxamide,

21. N²-tert-butyl-7-(3-cyanophenyl)-6-cyclo-propyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide,

22. i)²-ter t-but y 1-7-(4-cyanophenyl)-6-cyclo-propyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide, . N²-tert-buty1-6-cyclo-propy1-7-[4-(5-methyl-l,3,4oxadiazol-2-yl)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 (IH) -dicarboxamide,

24. W²-tert-butyl-6-cyclo-propyl-7-[4- (trifluoromethyl)phenyl]-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(IH)-dicarboxamide,

C16268

25. N²-tert-butyl-6-cyclo-propyl-7-(naphthalen-2-yl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(177)-dicarboxamide,

26. TV²-tert-butyl-6-cyclo-propyl-7- { 3[(dimethylsulfamoyl)amino]phenyl}-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8 (127) -dicarboxamide, . A/²-tert-butyl-6-cyclo-propyl-7-[3-(lH-pyrazol-1- yl)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazine-2, 8 ( 177) dicarboxamide, . TV²-tert-butyl-6-cycio-propyl-7-[4- (dimethylamino)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazine2,8(177) -dicarboxamide,

29. N²-tert-butyl-6-cyclo-propyl-7-{4- [(methylsuifonyl)amino]phenyl}-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1H)-dicarboxamide,

30. TV²-tert-butyl-6-cycl o-propyl-7- [4- (morpholin-4- yl) phenyl] -3,4-dihydropyrrolo [1, 2-a] pyrazine-2,8 (177) dicarboxamide,

31. TV²- tert-butyl-6-cyclo-propy 1-7- [4 - (177-pyrazol-lyl)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8 ( 177) dicarboxamide,

32. A^-tert-butyl-ô-cyclo-propyl-V-(3-methoxyphenyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8 ( 177)-dicarboxamide,

33. N²-tert-butyl-6-cyclo-propyl-7-[3-(cyclopropylmethoxy)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 ( 177) -dicarboxamide, . 7-[3-(benzyloxy)phenyl]-T^-tert-butyl-6-cyclo-propyl-

3, 4-dihydropyrrolo [ 1,2-a] pyrazine-2,8 ( 177) -dicarboxamide,

35. TV²-tert-butyl-6-cyclo-propyl-7- [3(trifluoromethoxy)phenyl]-3,4-dihydropyrrolo[1,2—

a] pyrazine-2,8 ( 177) -dicarboxamide, . 2J²-tert-butyl-6-cyclo-propyl-7-[4-(methoxy)phenyl]-

3,4-dihydropyrrolo [1,2-a ] pyrazine-2,8 ( 177) -dicarboxamide, . 7^-tert-butyl-6-cycIo-propyl-7-[4-(cyclopropylmethoxy)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazine2,8 ¢12/) -dicarboxamide, . 7-(4-butoxyphenyl)-Z^-tert-butyl-6-cyclo-propyl-3,4- dihydropyrrolo[1,2-a]pyrazine-2,8 (1H) -dicarboxamide, . ï/-tert-butyl-6-cyc/o-propyl-7-(4-phenoxyphenyl)-3 ,4- dihydropyrrolo[1,2-a]pyrazine-2,8(1H) -dicarboxamide, . 7-[4-(benzyloxy)phenyl]-N²-tert-buty1-6-cyclo-propyl-

3, 4-dihydropyrrolo [1,2-a] pyrazine-2,8(1/1) -dicarboxamide,

41. N²-tert-butyl-6-cyc/o-propyl-7-{4-[(4 — fluorobenzyl)oxy]phenyl}-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1//) -dicarboxamide,

42. N²-tert-butyl-7-{3-chloro-4-[(4fluorobenzyl)oxy]phenyl}-6-cyc2o-propyl~3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide, . A^-tert-butyl-7-[4-(cyanomethoxy)phenyl]-6-cyclopropyl-3,4-dihydropyrrolo[l,2-a]pyrazine-2,8(1H)dicarboxamide,

44. N²-tert-butyl-6-cyclo-propyl-7-[4- (trifluoromethoxy)phenyl]-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1H) -dicarboxamide,

45. fJ²-tert-butyl-6-cyclo-propyl-7- ( 2-fluorophenyl) -3,4dihydropyrrolo [ 1,2-a] pyrazine-2,8(1/1) -dicarboxamide, . A^-tert-butyl-ô-cyclo-propyl-?-( 3-fluorophenyl)-3,4dihydropyrrolo [ 1,2-a] pyrazine-2,8(1//) -dicarboxamide, . AJ²-tert-butyl-6-cyc_Zo-propyl-7- ( 4-fluorophenyl ) -3, 4- dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide, . W²-tert-butyl-6-cyclo-propyl-7-[4- (methylsulfanyl)phenyl]-3,4-dihydropyrrolo[1,2-

a] pyrazine-2,8(1//) -dicarboxamide,

9 . N²-cyclo-hexyl-6-cyclo-propyl-7-phenyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide, . N²-(cyclo-hexylmethyl)-6-cycIo-propyl-7-phenyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide,

51. bf- [1,1' -bi ( cyclo-propyl ) -1-yl] -6-cyc_Zo-propyl-7- (4methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1Æ)dicarboxamide,

52.	6-cyclo-propyl-7-phenyl-Î^-(2,4,4-trimethylpentan-2-

yl) -3, 4-dihydropyrrolo [ 1,2-a]pyrazine-2,8(12/)dicarboxamide,

53.	6-cyclo-propyl-N²-(hexahydro-2,5-methanopentalen-

3a(IH) -yl)-7-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(IH) -dicarboxamide.

54.	N²-(adamantan-l-yl)-6-cyclo-propyl-7-phenyl-3,4-

dihydropyrrolo[1,2-a]pyrazine-2,8(IH) -dicarboxamide,

55.	N²-(adamantan-l-yl)-6-cyclo-propyl-7-(4-

methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IH)dicarboxamide,

56.	6-cyclo-propyl-7-(4-methoxyphenyl)-rf-(tetrahydro-2H-

pyran-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2, 8 ( IH) dicarboxamide,

57.	6-cyclo-propyl-N²- (l-methoxy-2-methylpropan-2-yl) -7-

(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 (IH) -dicarboxamide,

58.	N²-tert-butyl-6-fluoro-7-phenyl-3,4-

dihydropyrrolo[1,2-a]pyrazine-2,8(IH) -dicarboxamide,

59.	e-chloro-zZ-iso-butyl-V-phenyl-S,4 -

dihydropyrrolo[1,2-a]pyrazine-2,8(IH) -dicarboxamide,

60.	N²-tert-butyl-ô-chloro-V-phenyl-S, 4-

dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide,

61.	N²-tert-butyl-6-chloro-7-(3-methylphenyl)-3,4-

dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide,

62.	A^-tert-butyl-ô-chloro-?-(3-methoxyphenyl)-3,4-

dihydropyrrolo[1,2-a]pyrazine-2,8(IH) -dicarboxamide,

63. N²-tert-butyl-6-chloro-7-[3(trifluoromethoxy)phenyl]-3,4-dihydropyrrolo[1,2a]pyrazine-2,8(IH) -dicarboxamide,

64.	7\^-tert-butyl-6-chloro-7- (4-methoxyphenyl) -3,4-

dihydropyrrolo[1,2-a]pyrazine-2,8(IH) -dicarboxamide,

65.	A^-tert-butyl-6-chloro-7-(3-cyanophenyl)-3,4-

dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide,

66. A^-tert-butyl-ë-chloro-l-[3-(trifluoromethyl)phenyl]-

3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H) -dicarboxamide,

67. A^-tert-butyl-e-chloro-V-(3-fluorophenyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide, . 6-chloro-W³-(cyclo-propylmethyl)-7-phenyl-3,4dihydropyrrolo[ 1,2-a]pyrazine-2, 8 ( 1H) -dicarboxamide,

69. ô-chloro-Λ^-(3-methylbutyl)-7-phenyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1/7) -dicarboxamide, . 6-chloro-N²-(2, 2-dimethylpropyl)-7-phenyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide,

71. 6-chloro-A^- (2-ethylbutyl) -7-phenyl-3, 4dihydropyrrolo[1,2-a]pyrazine-2,8 (127) -dicarboxamide,

72. 6-chloro-N²- (3,3-dimethylbutyl) -7-phenyl-3,4dihydropyrrolo [ 1,2-a] pyrazine-2,8 (1H) -dicarboxamide,

73. 6-chloro-7-(3-fluorophenyl)-ff-(3-hydroxy-2,2dimethylpropyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8(1H) -dicarboxamide,

74. 6-chloro-N²-(3-hydroxy-2,2-dimethylpropyl)-7-(3trifluoromethyl-phenyl)-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1/7)-dicarboxamide,

75. 6-chloro-7-(3-fluorophenyl)-N²-([1(hydroxymethyl)cyclo-propyl]methyl}-3,4- dihydropyrrolo [ 1,2-a] pyrazine-2, 8(1/7) -dicarboxamide,

76. 6-chloro-7-phenyl-Z^-(2,2,2-trifluoroethyl)-3,4dihydropyrrolo [ 1,2-a] pyrazine-2,8(1/7) -dicarboxamide,

77. 6-chloro-7- (3-fluorophenyl) -TV²- (2,2,2trifluoroethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 (127) -dicarboxamide,

78. 6-chloro-7-(3-fluorophenyl)-N²-[(23)-1,1,1trifluoropropan-2-yl]-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 (1/7) -dicarboxamide,

79. 6-chloro-7- (3-fluorophenyl) -TV²- (1,1, 1-trifluoro-2methylpropan-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine2,8 (127) -dicarboxamide, . 6-chloro-7-(3-fluorophenyl)-N²-(3,3,3trifluoropropyl)-3, 4-dihydropyrrolo[1,2-a]pyrazine2,8(IH)-dicarboxamide,

81. 6-chloro-7-(3-fluorophenyl)-/^-(4,4,4trifluorobutyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 (1/1) -dicarboxamide,

82. G-chloro-A^-cyclo-hexyl-l-phenyl-S,4dihydropyrrolo [ 1,2-a] pyrazine-2,8 (1/7) -dicarboxamide,

83. trans-6-chloro-(3-fluorophenyl)-W²-(-[(4-hydroxycyclo-hexyl) -3, 4-dihydropyrrolo[1,2-a] pyrazine-2,8 (117) dicarboxamide, . trans-6-chloro- (3-fluorophenyl) -Λ7²- (- [ (4-hydroxy-4methyl-cyclo-hexyl)-3,4-dihydropyrrolo[1,2-a]pyrazine2,8(IH)-dicarboxamide,

85. trans-6-chloro-(3-fluorophenyl)-N²-(-[(4-hydroxy-4trifluoromethyl-cyclo-hexyl)-3,4-dihydropyrrolo[1,2—

a] pyrazine-2,8(1/7) -dicarboxamide,

86. trans-6-chloro-(3-fluorophenyl)-N²-(-[(4methoxyimino-cyclohexyl)-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1H)-dicarboxamide, . trans-6-chloro-(3-fluorophenyl)-N²-(-[(4-tertbutyloxyimino-cyclohexyl)-3,4-dihydropyrrolo[1,2-

a] pyrazine-2,8 ( 117) -dicarboxamide,

8 . N²-(bicyclo[2.2.1]hept-2-yl)-6-chloro-7-phenyl-3,4dihydropyrrolo[l, 2-a]pyrazine-2,8 (1/7) -dicarboxamide,

89. 6-chloro-W²-(4,4-difluoro-cyclo-hexyl)-7-(3f luorophenyl) -3, 4-dihydropyrrolo [ 1,2-a] pyrazine-2,8 (1/7) dicarboxamide, . 6-chloro-7-(3-fluorophenyl)-rf-(oxetan-3-yl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide,

91. 6-chloro-7-(3-fluorophenyl)-N²-(3-methyl-oxetan-3ylmethyl) -3, 4-dihydropyrrolo [1,2-a] pyrazine-2,8 (117) dicarboxamide, . G-chloro-7-phenyl-N²-(tetrahydrofuran-3-yl)-3,4dihydropyrrolo [1,2-a] pyrazine-2,8 ( 1/7) -dicarboxamide,

-2493. G-chloro-ï-phenyl-N²- (tetrahydro-227-pyran-4-yl) -3,4dihydropyrrolo[1,2-a]pyrazine-2,8(127) -dicarboxamide, . 6-chloro-7-(3-methylphenyl)-N²-(tetrahydro-227-pyran-

4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(127) dicarboxamide,

95. 6-chloro-7-(3-cyanophenyl)-W²-(tetrahydro-2//-pyran-4- yl) -3, 4-dihydropyrrolo [1,2-a ] pyrazine-2,8 (127) dicarboxamide,

96. 6-chloro-JV²- ( tetrahydro-227-pyran-4-yl) —7—[3 — (trifluoromethyl)phenyl]-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1H)-dicarboxamide, . 6-chloro-N²- (tetrahydro-22/-pyran-4-yl) -7- [3- (trifluoromethoxy)phenyl]-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1H) -dicarboxamide, . 6-chloro-7- (3-fluorophenyl) -2V²- ( tetrahydro-2/f-pyran-

4-yl) -3, 4-dihydropyrrolo [1,2-a ] pyrazine-2,8(12/)dicarboxamide,

99. 6-chloro-7-(3-fluorophenyl)-N²-(2,2-dimethyltetrahydro-2J/-pyran-4-yl) -3,4-dihydropyrrolo [1,2-

a]pyrazine-2,8 ( 12/) -dicarboxamide,

100. cïs-6-chloro-N²- (2,6-dimethyl-tetrahydro-21f-pyran-4yl)-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 (177) - dicarboxamide,

101. 6-chloro-N²- (1, l-dioxydotetrahydrothiophen-3-yl) -7phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)dicarboxamide,

102 . 6-chloro-ZV²- ( 1, l-dioxydotetrahydrothiophen-3-yl ) -7- (3-fluorophenyl)-3,4-dihydropyrrolo[ 1,2-a]pyrazine-

2,8 ( 127) -dicarboxamide,

103 . 6-chloro-TJ²- (1, l-dioxydotetrahydro-22/-thiopyran-4yl)-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 (127) -dicarboxamide,

104 . 6-bromo-7- (3-fluorophenyl ) -Λ/²-tert-butyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide,

105. 6-cyano-7-(3—fluorophenyl)-N²-(tert-butyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide,

106. 6-cyano-7-(3-fluorophenyl)-if-((2S)-1,1,1trifluoropropan-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine2,8(1H)-dicarboxamide,

107. 6-cyano-7-(3-fluorophenyl)-N²-{1,1,l-trifluoro-2methylpropan-2-yl)-3, 4-dihydropyrrolo[1,2-a]pyrazine-

2,8(1H)-dicarboxamide,

108 . 6-cyano-7-(3-fluorophenyl)-if-(4,4,4-trifluoro- butyl) -3, 4-dihydropyrrolo[ 1,2-alpyrazine-2,8 (1/7) dicarboxamide,

109 . 6-cyano-7-(3-fluorophenyl)-N²-(tetrahydro-2/7-pyran-

4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1/7) dicarboxamide,

110 . 6-cyano-if-(4,4-difluoro-cyclohexyl)-7-(3- f luorophenyl ) -3, 4-dihydropyrrolo [ 1,2-a ] pyrazine-2,8 ( 1/7) dicarboxamide.

The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.

Some of the compounds of formula (I) may exist in the form of bases or of acid-addition salts. Such addition salts form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for purification or isolation of the compounds of formula (I) also form part of the invention.

In the context of the invention, the following définitions apply:

ViL·16268

-26C_t-z where t and z may take values from 1 to 7, carbonbased chain possibly containing from t to z carbon atoms, for example Ci_₇ a carbon-based chain which may contain from 1 to 7 carbon atoms;

alkyl, a linear or branched saturated aliphatic group; for example a group Ci-s-alkyl represents a linear or branched carbon-based chain of 1 to 6 carbon atoms, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl;

cycloalkyl, a fused, bridged or spiro cyclic or polycyclic alkyl group, for example it may be a group from among:

o C3_it)-cycloal kyl representing a cyclic carbon-based group of 3 to 10 carbon atoms, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, o fused bicyclic C4-i₀-cycloalkyl representing a fused bicyclic carbon-based group of 4 to 10 carbon atoms, such as a bicyclo[1.1.0]butane, bicyclo[3.1.0]hexane group, bicyclo[3.2.0]heptane or bicyclo[3.3.0]octane, o bridged bicyclic C₅_io-cycloalkyl representing a bridged bicyclic carbon-based group of 5 to 10 carbon atoms, such as a bicyclo[1.1.l]pentane or a bicyclo[2.2.1]heptane, o spiro bicyclic C₅-io-cycloalkyl representing a spiro bicyclic carbon-based group of 5 to 10 carbon atoms, such as a spiro[2.2]pentane or a spiro[4,4]nonane, o tricyclic C4_i₀-cycloalkyl representing a tricyclic carbon-based group of 4 to 10 carbon atoms, such as a tricyclo [1.1.0. O²*⁴] butane, a tricyclo[3.3.3 . O³'⁷] nonane or a tricyclo (3.3.3.1^3-7] decane;

hydroxyl, a group -OH;

Vi L16268

-27hydroxyalkyl, an alkyl group in which a hydrogen atom has been replaced with a hydroxyl group;

alkyloxy, a group -O-alkyl;

alkylthio, a group ~S-alkyl;

fluoroalkyl, an alkyl group in which one or more hydrogen atoms hâve been replaced with a fluorine atom;

fluoroalkyloxy, an alkyloxy group in which one or more hydrogen atoms hâve been replaced with a fluorine atom;

fluorocycloalkyl, a cycloalkyl group in which one or more hydrogen atoms hâve been replaced with a fluorine atom;

a heterocyclic group, a saturated carbon-based cyclic group comprising at least one heteroatom such as oxygen or sulfur or the oxide or dioxide forms thereof, for example a group from among oxetanyl, tetrahydrofuryl, tetrahydro-2.H-pyranyl, oxepanyl, thietanyl, tetrahydrothiophenyl, tetrahydro-2H-thiopyranyl, thiepanyl, 1,1-dioxydothietanyl, 1,1dioxydotetrahydrothiophenyl, 1, l-dioxydotetrahydro-2Jithiopyranyl heteroaryl, and 1,1-dioxydothiepanyl;

an aromatic carbon-based cyclic group comprising at least one heteroatom such as nitrogen, oxygen or sulfur, for pyridyl, pyrimidinyl, example a group pyridazinyl, from among pyrazinyl, triazinyl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, oxadiazolyl.

pyrazolyl, thiadiazolyl, isoxazolyl, triazolyl and tetrazolyl;

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

aryl, a monocyclic or comprising between 6 and 10 phenyl or naphthyl group;

bicyclic aromatic group carbon atoms, for example a aryloxy, a group -O-aryl.

-28For the purposes of the présent invention, it should be noted that the terms ranging from ... to ... and between ... and ... mean that the limits are also included.

In accordance with the invention, the compounds of general formula (I) may be prepared according to the general process described in Scheme 1 below:

SCHEME 1

O ^R^n^o^{R illb)}

H

(II) <θ)

N

*6 (D

Thus, another subject of the invention is directed towards a process for preparing compounds of formula (I) according to the invention, comprising the step that consists in reacting a 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide dérivative, which is a compound of formula (II) below:

in which R₇ and Xe are as defined previously in the general formula (I) defined above,

- with a compound of formula

-29ο

R_?\ Jk -R ² N O ^H (Ilb) in which R₂ is as defined previously in the general formula (I) defined above and R represents a group such as phenyl, pentafluorophenyl or 4-nitrophenyl, in an aprotic solvent such as acetonitrile and in the presence of a minerai base such as sodium carbonate;

or alternatîvely

- with a cornpound of formula

(Ha) in which R₂ is as defined previously in the general formula (I) defined above, in an aprotic solvent such as dichloromethane and optionally in the presence of an organic amine such as triethylamine.

The compounds of general formula (I) according to the process described in may also be prepared

Scheme 2 below.

SCHEME 2

Thus, yet another subject of the invention is directed towards a process for preparing the compounds of formula (I) according to the invention, comprising the step that consists in hydrating the nitrite function of a 1,2,3,4tetrahydropyrrolo[1,2-a]pyrazine dérivative of general formula (III ) ,

L·16268

(III) in which R₂, Xg and R₇ are as defined previously and G_arepresents a nitrile group. This transformation may be performed, for example, in the presence of aqueous hydrogen peroxide solution and a base such as sodium hydroxide.

Still as illustrated in Scheme 2, the 3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide dérivatives of general formula (I) in which R₂, Xè and R₇ are as defined above may also be prepared from a 1,2,3,4tetrahydropyrrolo[1,2-a]pyrazine dérivative of general formula (III), in which R₂, X₆ and R₇ are as defined above and G₈ represents an alkyl carboxylate group, preferentially a methyl or ethyl carboxylate. The 3,4-dihydropyrrolo[l,2-

a]pyrazine-2, 8(17/)-dicarboxamide dérivatives of general formula (I) as defined above are then prepared by saponification of the alkyl carboxylate group of the dérivative of general formula (III) to the corresponding carboxylic acid, followed by amidation of this carboxylic acid function. This amidation may be performed, for example, by activation of the acid using a coupling agent such as carbonyldiimidazole in dichloromethane and treatment of the activated acid using aqueous ammonia.

The compounds of general formula (I) may also be prepared according to the process described in Scheme 3 below.

SCHEME 3 m-r₇ (IVa)

*6 (I)

Thus, another subject of the invention is directed towards a process for preparing compounds of formula (I) according to the invention, comprising the step that consists in reacting a 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-2-carboxamide derivative of general formula (IV)

in which R₂ and Xê are as defined above and G₇ represents a chlorine, bromine or iodine atom, preferentially a bromine atom, via metallo-catalysed coupling, such as the Suzuki reaction with a derivative of general formula M-R₇ (IVa) in which R₇ is as defined above and M represents a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5tetramethyl-1,3,3,2-dioxaborolan-2-yl group. This réaction may be performed, for example, in the presence of caesium carbonate or sodium carbonate, and 1,1'bis(diphenylphosphino)ferrocenedichloropalladium (II) in a mixture of tetrahydrofuran and water.

More specifically, the 3,4-dihydropyrrolo[l,2-a]pyrazine2,8(1H)-dicarboxamide dérivatives of general formula (I) in which R₂ and R₇ are as defined above and Xe represents a hydrogen atom may also be prepared from a 3,4dihydropyrrolo [1,2-a]pyrazine-2,8 ( 1 Jf) -dicarboxamide h C16268

-32dérivative of general formula (I) in which R₂ and R₇ are as defined above and X_e represents a chlorine atom. This transformation may be performed, for example, via a hydrogénation reaction in the presence of a catalyst such as palladium-on-charcoal.

Préparation of the precursors (II)

The 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide dérivatives of general formula (II) as defined above and for which X₆ represents a group Ci-₆-alkyl, C₃_₇-cycloalkyl, C₃_₇cycloalkyl-Ci-₆-alkyl or Ci_₆-fluoroalkyl may be prepared in 5 steps (Scheme 4) starting with a piperazine-1,3dicarboxylate dérivative of general formula (IX) in which X₆represents a group Ci_₆-alkyl, C₃-₇-cycloalkyl, C₃_₇cycloalkyl-Ci-₆-alkyl or Ci_₆-fluoroalkyl and PG represents an acid-labile protecting group for the amine function such as a tert-butyloxycarbonyl.

According to the method described in document WO 03/024967, treatment of the sodium or potassium sait of a piperazine-

1,3-dicarboxylate dérivative of general formula (IX) using a tosyl chloride followed by treatment with 2chloroacrylonitrile and an organic base such as triethylamîne in a solvent such as dichloromethane leads to a 8-cyano-3, 4-dihydro-127-pyrrolo [1,2-a]pyrazine dérivative of general formula (VIII) in which X₆ and PG are as defined above.

These dérivatives of general formula (VIII) are then transformed into

8-carbamoyl-3,4-dihydro-lR-pyrrolo[1,2-

a]pyrazine dérivatives of general formula (VII) in which X₆and PG are as defined above, by treatment with aqueous hydrogen peroxide solution and a minerai base such as aqueous sodium hydroxide in a solvent such as methanol.

The 8-carbamoyl-3,4-dihydro-lH-pyrrolo[1,2-a]pyrazine dérivatives of general formula (VII) as defined above are then transformed into dérivatives of general formula (VI) in which X₆ and PG are as defined above and G₇ represents a 5 chlorine, bromine or iodine atom, more particularly bromine, by regioselective halogénation. In the case of bromine, this halogénation is performed, for example, by treatment with Nbromosuccinimide in a solvent such as dichlorométhane.

SCHEME 4

The dérivatives of general formula (VI) as defined above are transformed into dérivatives of general formula (V) in which

-34X₆ and PG are as defined above and R? is as defined in the general formula (I) by metallo-catalysed coupling, for example by Suzuki reaction with a dérivative of general formula (IVa) as defined previously. This reaction may be performed, for example in the presence of caesium carbonate and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) in a mixture of tetrahydrofuran and water.

The compound of general formula (II) is then obtained from the 8-carbamoyl-3,4-dihydro-lH-pyrrolo[1,2-a] dérivative of general formula (V) by removal of the protecting group PG, for example by treatment with trimethylsilyl chloride in a solvent such as methanol when PG represents tertbutyloxycarbonyl.

The 1,2,3,4-tetrahydropyrrolo[1,2~a]pyrazine-8-carboxamide dérivatives of general formula (II) as defined above in which X₆ represents a chlorine atom may be prepared in 6 steps (Scheme 5) starting with a piperazine-1,3dicarboxylate dérivative of general formula (XV) in which PG represents an acid-labile protecting group for the amine function such as a tert-butyloxycarbonyl.

SCHEME 5

R—Μ (IVa)

Xs (X)

*6 (H)

According to the method described in document WO 03/024 967, treatment with the sodium or potassium sait of a piperazine5 1,3~dicarboxylate dérivative of general formula by treatment tosyl chloride followed chloroacrylonitrile and an organic base (XV) using with such

2as

-36triethylamine in a solvent such as dichloromethane leads to a 8-cyano-3,4-dihydro-lH-pyrrolo[1,2-a]pyrazine dérivative of general formula (XIV) in which PG is as defined above.

These 8-cyano-3,4-dihydro-lH-pyrrolo[1,2-a]pyrazine dérivatives of general formula (XIV) as defined above are then transformed into 8-carbamoyl-3,4-dihydro-l/7pyrrolo[1,2-a]pyrazine dérivatives of general formula (XIII) in which PG is as defined above by treatment with aqueous hydrogen peroxide solution and a minerai base such as aqueous sodium hydroxide in a solvent such as methanol.

The dérivatives of general formula (XIII) as defined above are then transformed into 6-chloro-8-carbamoyl-3,4-dihydroΙΗ-pyrrolo[1,2-a]pyrazine dérivatives of general formula (XII) in which PG is as defined above and X₆ represents a chlorine atom by regioselective chlorination. This halogénation is performed, for example, by treatment with Nchlorosuccinimide in a solvent such as dichloromethane.

The dérivatives of general formula (XII) as defined above are then transformed into 7-bromo-6-chloro-8-carbamoyl-3,4dihydro-lH-pyrrolo[1,2-a]pyrazine dérivatives of general formula (XI) in which GP, X₅ and G₇ are as defined above by regioselective bromination. This halogénation is performed, for example, by treatment with 7J-bromosuccinimide in a solvent mixture such as dichloromethane and ethyl acetate.

The dérivatives of general formula (XI) as defined above are transformed into 6-chloro-8-carbamoyl-3,4-dihydro-lHpyrrolo[1,2-a]pyrazine dérivatives of general formula (X) in which PG is as defined above and R₇ is as defined in the general formula, by metallo-catalysed coupling, for example by Suzuki reaction with a dérivative of general formula (IVa) as defined previously. This reaction may be performed,

-37for example, in the presence of caesium carbonate and 1,1'bis(diphenylphosphino)ferrocenedichloropalladium (II) in a mixture of tetrahydrofuran and water.

The compound of general formula (II) for which X₆ represents a chlorine atom is then obtained from dérivatives of general

formula	(X)	by	removal of	the protecting	group PG,	for
example	by	treatment with	trimethylsilyl	chloride	in a
solvent	such	as	methanol or	by treatment with an acid	such

as trifluoroacetic acid in a solvent such as dichloromethane when PG represents a tert-butyloxycarbonyl group.

The 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide dérivatives of general formula (II) as defined above and for which X₆ represents a fluorine or chlorine atom may be prepared in 6 steps starting with a pyrrole dérivative of general formula (XX) for which R₇ is as defined above and G_erepresents a nitrile group or an alkyl carboxylate group, preferentially a methyl or ethyl carboxylate (Scheme 6).

The pyrrole dérivatives of general formula (XX) are thus regioselectively halogenated in position 6 by treatment with N-chlorosuccinimide in a solvent such as tetrahydrofuran or using l-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane (SelectFluor) in a solvent such as acetonitrile to give a dérivative of general formula (IXX) for which R₇ and G_e are as defined above and X₆ represents a fluorine or chlorine atom.

X

(XX)

(XVIII)

The pyrrole dérivatives of general formula (IXX) are then alkylated using aminoethyl dérivatives of general formula (IXXb) for which X constitutes a leaving group, for example a chlorine atom and PG constitutes an acid-labile protecting group such as tert-butyloxycarbonyl, to give a pyrrole 10 dérivative of general formula (XVIII) for which X₆

-39represent s a fluorine or chlorine atom, R₇ and Gg are as defined above and PG constitutes an acid-labile protecting group such as tert-butyloxycarbonyl. This alkylation reaction is performed, for example, in the presence of a minerai base such as sodium hydroxide and a phase-transfer catalyst such as tetrabutylammonium hydrogen sulfate, and in a solvent such as acetonitrile.

The pyrrole dérivatives of general formula (XVIII) are treated in acidic medium in the presence of formaldéhyde or paraformaldéhyde to give, after deprotection of the protecting group PG and cyclization, the 1,2,3,4tetrahydropyrrolo[1,2-a]pyrazine dérivatives of general formula (XVII) for which X₆ represents a fluorine or chlorine atom, while R? and Gg are as defined above. This step is performed, for example, using aqueous hydrochloric acid solution and formaldéhyde or paraformaldéhyde.

A subject of the présent invention relates to a process for preparing compounds of formula (XVII) for which X₆represents a fluorine or chlorine atom, while R₇ is as defined previously in the general formula (I), and Gg represents a nitrile group or an alkyl carboxylate group, such as a methyl or ethyl carboxylate, comprising the step that consists in reacting a pyrrole dérivative, which is a cornpound of formula (XVIII) with an acidic solution, for example an aqueous hydrochloric acid solution, and formaldéhyde or paraformaldéhyde, to give the 1,2,3,4tetrahydropyrrolo[1,2-a]pyrazine dérivatives of general formula (XVII) in which X₆ represents a fluorine or chlorine atom, while R₇ is as defined previously in the general formula (I), and Gg represents a nitrile group or an alkyl carboxylate group, such as a methyl or ethyl carboxylate.

K

-40The 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine dérivatives of general formula (XVII) are then protected as 1,2,3,4tetrahydropyrrolo[1,2-a]pyrazine dérivatives of general formula (XVI) for which Xg represents a fluorine or chlorine atom, while R₇ and Gg are as defined above and PG represents an acid-labile protecting group, for example tertbutyloxycarbonyl, The reaction is then performed by treatment with di-tert-butyl dicarbonate in a solvent such as dichloromethane.

Depending on the nature of the group G₈, the process may be performed according to one of the alternatives described below,

The 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine dérivatives of general formula (XVI), for which Xg represents a fluorine or chlorine atom, while R₇ and PG are as defined above and G₈represents a nitrile group, are transformed into 8carbamoyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine dérivatives of general formula (X) for which X₆ represents a fluorine or chlorine atom, while R₇ and PG are as defined above by hydration of the nitrile function. This transformation may be performed, for example, in the presence of aqueous hydrogen peroxide solution and a base such as sodium hydroxide.

The 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine dérivatives of general formula (XVI), for which Xg represents a fluorine or chlorine atom, while R₇ and PG are as defined above and G₈represents an alkyl carboxylate group, are transformed into 8-carbamoyl-l,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine dérivatives of general formula (X) as defined above, in two steps. Thus, the 3, 4-dîhydropyrrolo [ 1,2-a ] pyrazine-2,8 ( 1/7) dicarboxamide dérivatives of general formula (XVI) as defined above are saponified using a base to the

-41 corresponding carboxylic acid of general formula (XVIb) for which X₆ represents a fluorine or chlorine atom, while R₇and PG are as defined above. This reaction is performed, for example, by treatment with potassium, sodium or lithium hydroxide, preferentially lithium hydroxide, in a mixture of solvents such as water, methanol and tetrahydrofuran.

The transformation of the carboxylic acid dérivatives of general formula (XVIb) into 8-carbamoyl-l,2,3,4tetrahydropyrrolo[1,2-a]pyrazine dérivatives of general formula (X), for which Χς represents a fluorine or chlorine atom, while R₇ and PG are as defined above, may be performed by amidation of the carboxylic acid funetion. This amidation may be performed, for example, by activating the acid with a coupling agent such as carbonyldiimidazole in tetrahydrofuran, and then treatment of the formed activating acid using aqueous ammonia in a solvent such as dimethy1formamide.

The compound of general formula (II) is then obtained from dérivatives of general formula (X) according to the protocol described above.

Alternatively, and still according to Scheme 6, tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide the 1,2,3,4dérivatives of general formula (II) as defined above and for which X_s represents a bromine atom or a cyano group, may be prepared in 5 steps starting with a pyrrole dérivative of general formula (XVI) for which

R₇ is as defined above, X₆ represents a hydrogen atom, G₈ represents an alkyl carboxylate group, preferentially a methyl or ethyl carboxylate and PG constitutes an acid-labile protecting group such as tert-butyloxycarbonyl.

-42These pyrrole dérivatives of general formula (XVI) for which

Xs represents a hydrogen atom are thus regioselectively brominated or cyanated in position 6, respectively, by treatment with

N-bromosuccinimide in a solvent such as tetrahydrofuran or using chlorosulfonyl isocyanate in mixture of solvents such as dichloromethane and dimethylformamide to give the corresponding derivative of general formula (XVI) for which

R 7 r Gg and PG are as defined above and Xg represents a bromine atom or a cyano group.

The compounds of general formula (II) for which X₆represents a bromine atom or a cyano group, are then obtained according to the protocol described above starting with the derivative of general formula (XVI), after step of saponification to the corresponding carboxylic acid, activation of the carboxylic acid using a coupling agent such as carbonyldiimidazole and then treatment of the activated form with aqueous ammonia and removal of the protecting group PG using an acid.

The pyrrole dérivatives of general formula (XVI) for which R7 is as defined above, Χβ represents a hydrogen atom, Gg represents an alkyl carboxylate group and PG constitutes an acid-labile protecting group such as tert-butyloxycarbonyl may be prepared from the corresponding pyrrole derivative of general formula (XVI) for which R₇ is as defined above, X_srepresents a chlorine or bromine atom, G₈ represents an alkyl carboxylate group and PG constitutes an acid-labile protecting group such as tert-butyloxycarbonyl. This transformation may be performed, for example, via a hydrogénation reaction in the presence of a catalyst such as palladium-on-charcoal.

AC

-43Préparation of the precursors (III)

The 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine dérivatives of general formula (III), in which R₂, Xgx and R₇ are as defined above and G_a represents a nitrile group or an alkyl carboxylate group, may be prepared in two steps starting with dérivatives of general formula (XVI), in which X₆ and Rv are as defined above, Gg represents a nitrile or alkyl carboxylate group and PG represents an acid-labile protecting group such as a tert-butyloxycarbonyl.

Thus, the dérivatives of general formula (XXI) in which X₆and R? are as defined above and Gg represents a nitrile or alkyl carboxylate group are then obtained from dérivatives of general formula (XVI) by removal of the protecting group PG, for example, by treatment with trimethylsilyl chloride in a solvent such as methanol or by treatment with an acid such as trif luoroacet ic acid in a solvent such as dichloromethane. The dérivatives of general formula (III) as defined above may then be prepared from dérivatives of general formula (XXI) as defined above:

either by treatment with an isocyanate dérivative of general formula (lia) in which R₂ is as defined previously, in an aprotic solvent such as dichloromethane and optionally in the presence of an organic amine such as triethylamine, - or by treatment with a carbamate dérivative of general formula (Ilb) in which R₂ is as defined previously and R represents a group such as phenyl, pentafluorophenyl or 4nitrophenyl, in an aprotic solvent such as acetonitrile and in the presence of a minerai base such as sodium carbonate.

-44SCHEME 7

(llb) (Ha)

Préparation of the precursors (IV)

The 1,2,3,4-tetrahydropyrrolo[1 general formula (IV), in which above, may be prepared in dérivatives of general formula as defined above, and PG protecting group such as a tert,2-a]pyrazine dérivatives of R₂, Xe and G₇ are as defined two steps starting with (VI), in which X₆ and G₇ are represents an acid-labile -butyloxycarbonyl.

Thus, the dérivatives of general formula (XXII), in which X₆ and G₇ are as defined above, are then obtained from dérivatives of general formula (VI) by removal of the protecting group PG, for example by treatment with trimethylsilyl chloride in a solvent such as méthanol or by treatment with an acid such as trifluoroacetic acid in a solvent such as dichloromethane.

The dérivatives of general formula (IV) as defined above may then be prepared from dérivatives of general formula (XXII) as defined above:

- either by treatment with an isocyanate dérivative of general formula (lia) in which R₂ is as defined previously,

K

-45in an aprotic solvent such as dichloromethane and optionally in the presence of an organic amine such as triethylamine,

- or by treatment with a carbamate dérivative of general formula (Ilb) in which R₂ is as defined previously and R represents a group such as phenyl, pentafluorophenyl or 4nitrophenyl, in an aprotic solvent such as acetonitrile and in the presence of a minerai base such as sodium carbonate.

SCHEME 8

(VI)

*6 (IV)

Isocyanate dérivatives of general formula (lia)

The isocyanate dérivatives of general formula (Ha), in which R₂ is as defined, are either commercially available, or prepared according to methods known to those skilled in the art.

Carbamate dérivatives of general formula (IIb)

The carbamate dérivatives of general formula (Ilb), in which

R₂ is as defined previously and R represents a group such as

SC

-46phenyl, pentafluorophenyl or 4-nitrophenyl, are prepared from the corresponding amine R₂NH₂ by reaction with the corresponding chloroformate according to methods known to those skilled in the art.

Leaving groups

In the text hereinabove, the term leaving group means a group that can be readily cleaved from a molécule by breaking a heterolytic bond, with loss of an électron pair. This group may, for example, thus be readily replaced with another group during a substitution reaction. Such leaving groups are, for exemple, halogens or an activated hydroxyl group such as a mesyl, tosyl, triflate, acetyl, etc. Examples of leaving groups and references for preparing them are given in Advances in Organic Chemistry, J. March, 3^rdEdition, Wiley Interscience, pp. 310-316.

Protecting groups

For the compounds of general formula (I) as defined above and in the case where group R₂ comprises a hydroxyl function, this function may optionally be protected during the synthesis with a protecting group, for example a tertbutyldiphenylsilyl. This protecting group is removed at the end of the synthesis. Examples of hydroxyl-function protecting groups and references for preparing them and removing them are given in Greene's Protective Groups in Organic Synthesis (Fourth Edition), Peter G.M. Wuts, Theodora W. Green, John Wiley & Sons, Inc.

The examples that follow describe the préparation of certain compounds in accordance with the invention. These examples are not limiting, and serve merely to illustrate the invention. The numbers for the compounds given as examples refer to those given in Table 1 below, which illustrate the chemical structures and physical properties, respectively, fi

-47of a number of compounds according to the invention.

Example 1 (compound 80):

6-Chloro-7-(3-fluorophenyl)-tf (4,4,4-trifluorobutyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 (1H) -dicarboxamide

Cl

Step 1.1. 4-Nitrophenyl 4,4,4-trifluorobutylcarbamate

To a solution of 0.35 g (2.75 mmol) of 4,4,4-trifluorobutylamine (CAS 819-46-5) in 20 ml of dichloromethane, cooled to -15°C, is added dropwise 1.00 g (4.96 mmol) of 4nitrophenyl chloroformate (CAS 7693-46-1) dissolved in 15 ml of dichloromethane, while maintaining the température at -15°C. 0.48 ml (2.75 mmol) of diisopropylethylamine in 10 ml of dichloromethane still at -15°C is then added. Stirring is continued at -15°C for 45 minutes, and the température of the mixture is then allowed to return to 0°C over 30 minutes. 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out by settling and dried over sodium sulfate, and the solvent is partially evaporated off under reduced pressure to a volume of about 8 ml. This solution is chromatographed on a column of 40 g of silica gel, eluting with a mixture of 20% cyclohexane in dichloromethane, to

-48give 0.76 g of 4-nitrophenyl 4,4,4-trifluorobutylcarbamate in the form of a white solid.

m.p.: 118-120°C ^XH NMR (CDC1₃) δ: 8.20 (d, 2H) ; 7.25 (d, 2H) ; 5.15 (broad s, 1H) ; 3.3 (m, 2H); 2.15 (m, 2H); 1.8 (m, 2H) ppm.

Step 1.2. (E) and (Z) 3-(3-Fluorophenyl)-2-propenenitrile (CAS 82344-56-7 and 115665-80-0)

A mixture of 35.0 g (411 mmol) of cyanoacetic acid (CAS 37209-8 ) and 56.2 g (453 mmol ) of 3-fluorobenzaldéhyde [CAS 456-48-4) in a mixture of 400 ml of toluene and 220 ml of pyridine is refluxed for 22 hours using Dean-Stark apparatus to remove the water formed during the reaction. The solvent is then removed under reduced pressure and the residue is co-evaporated 3 times with toluene. The residue is then taken up in ethyl acetate and the organic phase is washed successively with aqueous IN sodium hydroxide solution, aqueous IN hydrochloric acid solution and then with saturated sodium chioride solution. The organic phase is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown oil, which is chromatographed on a column of silica gel, eluting with toluene, to give 48.5 g a mixture of (E) and (Z) 3—(3— fluorophenyl)-2-propenenitrile in a ratio of (7/3) ¹H NMR (CDC1₃) δ: 7.55-7.00 (m, 5H); 5.85 and 5.55 (d and d, 1H) ppm.

Step 1.3.______4-(3-Fluorophenyl)-lH-pyrrole-3-carbonitrile (CAS 87388-09-8)

To a suspension of 19.8 g (494 mmol) of sodium hydride at 60% in oil in 350 ml of anhydrous tetrahydrofuran is added dropwise a mixture of 48.5 g (330 mmol) of the mixture of (Z) and (E) 3-(3-fluorophenyl)-2-propenenitrile in a ratio of (7/3) and 64.4 g (330 mmol) of tosylmethyl isooyanide (CAS 36635-61-7) dissolved in 250 ml of tetrahydrofuran, while maintaining the température of the reaction medium at about 25°C. The mixture is then stirred for 1 hour at room température and is then poured into ice-water. The reaction product is then extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown solid, which is dissolved in 350 ml of hot chloroform and purified by chromatography on a column of 600 g of silica gel, eluting with dichloromethane and then with a mixture of 1% methanol in dichloromethane, to give 41.5 g of 4-(3-

fluorophenyl) -lJ7-pyrrole-3-	carbonitrile	in	the form of a
beige-coloured solid after	triturating	in	dichloromethane,
filtering off and drying.
m.p.: 140-142°C
NMR (DMSO-de) δ: 12.0	(broad s,	1H) ;	7.75 (s, 1H);
7.55-7.00 (m, 4H); 7.10 (m.	1H) ppm.

Step 1.4.______5-Chloro-4- (3-fluorophenyl) -lH-pyrrole-3carbonitrile

-50To a solution of 41,0 g (220 mmol) of 4-(3-fluorophenyl)-1Hpyrrole-3-carbonitrile in 400 ml of tetrahydrofuran are added portionwise 33.0 g (242 mmol) of 77-chlorosuccinimide (CAS 128-09-6) and the mixture is then stirred for 24 hours at reflux. After cooling, 200 ml of water containing 5 g of sodium thiosulfate are added and, after stirring for 5 minutes, the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give

45.5 g of 5-chloro-4-(3-fluorophenyl)-lH-pyrrole-3carbonitrile in the form of a whitish powder after triturating in 200 ml of dichloromethane, filtering off and drying.

m.p.: 158-161°C ¹H NMR (DMSO-d₆) δ: 12.9 (broad s, 1H) ; 7.85 (s, 1H) ; 7.55 (m, 1H); 7.35 (m, 2H); 7.25 (m, 1H) ppm.

Step 1.5. tert-Butyl__________{ 2- [2-chloro-4-cyano-3- (3fluorophenyl)-IH-pyrrol-l-yl]ethyl}carbamate

To a solution of 39.5 g (179 mmol) of 5-chloro-4-(3fluorophenyl)-lH-pyrrole-3-carbonitrile in

450 ml of acetonitrile are added 14.3 g (358 mmol) of powdered sodium hydroxide and 2.43 g (7.1 mmol) of tetrabutylammonium hydrogen sulfate, and the mixture is stirred vigorously for minutes, 48.1 g (214 mmol) of tert-butyl (2-bromoethyl)carbamate (CAS 39684-80-5) are then added and the mixture is then stirred for 17 hours at reflux. After cooling, the solvent is evaporated off under reduced pressure, and the residue is taken up in ethyl acetate. The organic phase is then washed with saturated sodium chloride solution and «L

-51 dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give 47.3 g of tert-butyl {2-[2chloro-4-cyano-3- (3-fluorophenyl ) -1/f-pyrrol-l-yl ] ethyl} carbamate in the form of a beige-coloured powder after triturating in 150 ml of diisopropyl ether, filtering off and drying.

m.p.: 97-99°C ^TH NMR (DMSO-d₆) δ: 7.85 (s, IH); 7.60 (m, IH); 7.35 (m, IH) ;

7.30 (m, 2H); 7.0 (broad t, IH); 4.10 (m, 2H); 3.30 (m, 2H);

1.40 (s, 9H) ppm.

Step 1.6.______6-Chloro-7-(3-fluorophenyl)-1,2,3,4tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile

To a solution of 47.3 g (130 mmol) of tert-butyl (2-[2chloro-4-cyano-3- (3-f luorophenyl) -lff-pyrrol-l-yl] ethyl} carbamate in 85 ml of éthanol are added slowly 488 ml (1465 mmol) of aqueous 3N hydrochloric acid solution. Setting to a solid is rapidly observed, and the medium then becomes clear. After 45 minutes, 5.56 g (48.1 mmol) of paraformaldéhyde are added and heating is continued at 70°C for 2 hours 30 minutes. After cooling, the reaction medium is poured slowly into ice-cold aqueous 4N sodium hydroxide solution. The product is extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown oil, which is chromatographed on a column of 300 g of silica gel, eluting with a mixture of 1 to 2% methanol in dichloromethane, to give 21.0 g of 6-chloro-7-(3fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carbonitrile in the form of a beige-coloured powder after

U

-52triturating in 150 ml of diisopropyl ether, at reflux, chilling, filtering off and drying.

m.p.: 104-106°C ^TH NMR (DMS0-d₆) δ: 7.55 (m, IH) ; 7.35 (m, IH) ; 7.30 (m, IH);

7.25 (m, IH) ; 4.00 (s, 2H) ; 3.80 (t, 2H); 3.15 (t, 2H); 1.70 (broad s, IH) ppm.

Step 1.7.______Z7-tert-Butyl-6-chloro-8-cyano-7- (3fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1K) carboxamide

To a solution of 21.0 g (76.0 mmol) of 6-chloro-7-(3fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carbonitrile in 200 ml of dichloromethane are added slowly

18.2 g (83.6 mmol) of di-tert-butyl dicarbonate (CAS 2442499-5) dissolved in about 100 ml of dichloromethane. After stirring for 45 minutes at room température, the solvent is evaporated off under reduced pressure to give a brown oil, which is crystallized from 100 ml of diisopropyl ether to give 26.3 g of N-tert-butyl-6-chloro-8-cyano-7-(3fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(IH)carboxamide in the form of a beige-coloured powder after filtering off and drying.

m.p.: 144-116°C ^XH NMR (DMSO-dg) δ: 7.58 (m, IH) ; 7.38 (m, IH) ; 7.32 (m, IH) ;

7.26 (m, IH); 4.70 (s, 2H); 4.05 (t, 2H); 3.85 (t, 2H); 1.50 (s, 9H) ppm.

Step 1.8.______tert-butyl 8-carbamoyl-6-chloro-7- (3-fluoro phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(IH) -carboxylate

To a solution of 26.6 g (70.8 mmol) of N- tert-butyl-6chloro-8-cyano-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-

a]pyrazine-2(IH) -carboxamide in 270 ml of methanol and dimethyl sulfoxide (3:2) are added 6.15 ml (74.3 mmol) of aqueous 35% sodium hydroxide solution and then 12.4 ml (142 mmol) of 35-volumes aqueous hydrogen peroxide solution in 4 fractions every 30 minutes. After reaction for 18 hours at 60°C, the mixture is cooled, partially concentrated under reduced pressure and taken up in ethyl acetate. The solution is washed with aqueous 5% sodium thiosulfate solution and then with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give an orangecoloured solid, which is crystallized from about 200 ml of acetonitrile to give 19.8 g of tert-butyl 8-carbamoyl-6chloro-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2~a]pyrazine2 ( IH) -carboxylate in the form of a whitish powder after filtering off and drying.

After evaporating off the solvent under reduced pressure and purifying by chromatography of the crystallization mother liquors on a column of 80 g of silica gel, élut ion with a mixture of 4% methanol in dichlorométhane gives 2.35 g of addîtional product after crystallizing from acetonitrile, filtering off and drying.

m.p. : 189-192°C ³Η NMR (DMSO-de) δ: 7.55 (m, IH) ; 7.2 (m, 3H) ; 7.1 (broad s, IH); 6.2 (broad s, IH); 4.80 (s, 2H); 4.00 (t, 2H); 3.85 (t, 2H); 1.50 (s, 9H) ppm.

-54Step 1.9._____6-Chloro-7-(3-fluorophenyl)-1,2,3,4tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide

To a solution of 22.0 g (70.8 mmol) of tert-butyl 8carbamoyl-6-chloro-7-(3-fluorophenyl)-3,4-dihydropyrrolo-

[1,2-a]pyrazine-	-2(1/7)	-carboxylate	in	130	ml	of
dichloromethane	are	added slowly	128 ml	(1680	mmol)	of
trifluoroacetic	acid.
After stirring	for 1	hour at room	température, the solvent

is evaporated off under reduced pressure, the residue is taken up in aqueous 3N hydrochloric acid solution and the aqueous phase is washed with ethyl acetate. The aqueous phase is basified by addition of aqueous ammonia and the product is extracted with chloroform. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue is triturated while hot from 80 ml of hot acetonitrile. After cooling, 15.4 g of 6-chloro-7-(3fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carboxamide are isolated in the form of a whitish powder after separating out by filtration and drying under reduced pressure.

m.p.: 226-228°C ¹H NMR (DMSO-d₆) δ: 7.55 (m, IH); 7.15 (m, 3H); 6.9 (broad s, IH) ; 6.2 (broad s, IH); 4.00 (s, 2H); 3.85 (t, 2H); 3.10 (t, 2H) ppm.

Step 1.10. 6-Chloro-7- (3-fluorophenyl) -W²- (4,4,4-trifluorobutyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8 ( IH) dicarboxamide

A suspension of 0.165 (0.56 mmol) of 6-chloro-7-(3fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carboxamide, 0.197 g (0.67 mmol) of 4-nitrophenyl 4,4,4trifluorobutylcarbamate and 0.155 g (1.12 mmol) of sodium carbonate in 3 ml of acetonitrile is heated at 65 °C for 1 hour 30 minutes. After cooling, the mixture is poured into aqueous IN sodium hydroxide solution and the product is extracted with dichloromethane. After drying over sodium sulfate and filtering, the solvent is evaporated off under reduced pressure and the residue is purifîed by chromatography on a column of 24 g of silica gel, eluting with a mixture of 3% méthanol in dichloromethane, to give 0.192 g of 6-chloro-7-(3-fluorophenyl)-N²-((4,4,4-trifluorobutyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IH)dicarboxamide in the form of a white powder after crystallization from 8 ml of acetonitrile, filtering off and drying under reduced pressure.

m.p.: 100-117°C

NMR (DMSO-de) S: 7.50 (m, IH) ; 7.2 (m, 3H) ; 7.05 (broad s, IH) ; 6.90 (t, IH) ; 6.20 (broad s, 1H) ; 4.7 5 (s, 2H) ; 3.90 (m, 2H) ; 3.80 (m, 2H) ; 3.15 (m, 2H) ; 2.3 (m, 2H) ; 1.70 (m, 2H) ppm.

Example 2 (compound 78): 6-Chloro-7-(3-fluorophenyl)-N²(1,1,1-trif luoro-2-Tnethylpropan-2-yl ) -3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide

Step 2.1. 4-Nitrophenyl 1,1,1-trifluoro-2-methylpropan-2ylcarbamate

To a solution of 0.35 g (2.75 mmol) of 1,1,1-trifluoro-2methylpropan-2-ylamine (CAS 812-18-0) in 20 ml of dichloromethane, cooled to -15°C, is added dropwise 1.00 g (4.96 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1) dissolved in 15 ml of dichloromethane, while maintaining the température at -15°C. 0.48 ml (2.75 mmol) of diisopropylethylamine in 10 ml of dichloromethane is then added, still at -15°C. Stirring is continued at -15°C for 2 hours, and the température of the mixture is then allowed to return to 0°C over 1 hour. 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out by settling and dried over sodium sulfate, and the solvent is partially evaporated off under reduced pressure to a volume of about 8 ml. This solution is chromatographed on a column of 40 g of silica gel, eluting with a mixture of 20% cyclohexane in dichloromethane, to give 0.21 g of 4-nitrophenyl 1,1,1trifluoro-2-methylpropan-2-ylcarbamate in the form of a white solid.

m.p.: 77-80°C ¹H NMR (CDC13) δ: 8.30 (d, 2H) ; 7.35 (d, 2H) ; 5.25 (broad s,

1H); 1.65 (s, 6H) ppm.

-57Step 2,2 6-Chloro-7-( 3-f luorophenyl )-Λ7²-( 1,1, l-trifluoro-2methylpropan-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine2,8(1/7)-dicarboxamide

A suspension of 0.165 (0.56 mmol) of 6-chloro-7-(3 fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carboxamide, 0.197 g (0.67 mmol) of 4-nitrophenyl 1,1,1trifluoro-2-methylpropan-2-ylcarbamate and 0.155 g (1.12 mmol) of sodium carbonate in 3 ml of acetonitrile is heated at 65°C for 1 hour 30 minutes. After cooling, the mixture is poured into aqueous IN sodium hydroxide solution and the product is extracted with dichloromethane.

After drying over sodium sulfate and filtering, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of 2 4 g of silica gel, eluting with a mixture of 3% methanol in dichloromethane, to give 0.125 g of 6-chloro-7-(3fluorophenyl)-if-(1,1, l-trifluoro-2-methylpropan-2-yl)-3,4 dihydropyrrolo[1,2-a]pyrazine-2,8(1/7) -dicarboxamide in the form of a white powder after crystallization from 4 ml of acetonitrile, filtering off and drying under reduced pressure.

m.p.: 183-187°C

NMR (DMSO-dg) δ: 7.50 (m, 1H) ; 7.2 (m, 3H) ; 7.05 (broad s,

1H) ; 6.65 (s, 1H) ; 6.25 (broad s, 1H) ; 4.70 (s, 2H) ; 3.95 (m, 2H); 3.80 (m, 2H); 1.50 (s, 6H) ppm.

Example 3 (compound 73) : 6-Chloro (3-f luorophenyl) -if- (3hydroxy-2,2-dimethylpropyl)-3,4-dihydropyrrolo[1,2a ] pyrazine-2,8(1/7) -dicarboxamide

H

-583-(tert-Butyldiphenylsilanoxy)-2,2-dimethyl-

Step 3.1.

propylamine

To a solution at 0°C of 0.500 g (4.85 mmol) of 3-amino-2,2dimethylpropanol (CAS 26734-09-8) in 12 ml of dichloromethane are added 0.059 g (0.48 mmol) of dimethylaminopyridine and 1.35 ml (9.7 mmol) of triethylamine. 1.60 g (5.82 mmol) of tert-butyldiphenylsilyl chloride dissolved in 5 ml of dichloromethane are then added dropwise. The mixture is stirred for 30 minutes at 0°C and then for 2 hours at room température. 20 ml of water are then added. The organic phase is separated out by settling, washed with water and then with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give an oil, which is chromatographed on a column of aminopropyl silica gel, eluting with a mixture of 0 to 10% méthanol in dichloromethane, to give 1.20 g of 3-(tert-butyldiphenylsilanoxy)-2,2-dimethylpropylamine in the form of a colourless oil.

NMR (CDC1₃) δ: 7.70 (m, 4H) ; 7.45 (m, 6H) ; 3.40 (s, 2H) ;

2.65 (s, 2H); 1.5 (broad s, 2H); 1.10 (s, 9H); 0.90 (s, 4H) ppm.

Ή

-59Step 3.2.______4-Nitrophenyl 3-(tert-butyldiphenylsilanoxy)-

2,2-dimethylpropylcarbamate

To a solution, at 0°C, of 0.120 g (3.51 mmol) of 3-(tertbutyldiphenylsilanoxy)-2,2-dimethylpropylamine in 25 ml of dichloromethane are added dropwise 1.42 g (7.03 mmol) of 4nitrophenyl chloroformate (CAS 7693-46-1) dissolved in 5 ml of dichloromethane. 0.63 ml (3.5 mmol) of diisopropylethylamine is then added. Stirring is continued at 0°C for 45 minutes, and the température of the mixture is then allowed to return to 0°C over 1 hour, 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out on a hydrophobie filter cartridge and the solvent is partially evaporated off under reduced pressure to a volume of about 8 ml. This solution is chromatographed on a column of silica gel, eluting with a mixture of 5 to 40% ethyl acetate in cyclohexane, to give 0.21 g of 4-nitrophenyl 3-(tertbutyldiphenylsilanoxy )-2,2-dimethylpropylcarbamate in the form of an oil.

³Η NMR (CDC1₃) δ: 8.28 (d, 2H) ; 7.73 (m, 4H) ; 7.5 (m, 6H) ;

7.34 (d, 2H) ; 5.9 (broad s, 1H); 3.50 (s, 2H); 2.29 (d, 2H);

1.16 (s, 9H); 1.00 (s, 4H) ppm.

V

Step 3.3 N²-(3-(tert-Butyldiphenylsilanoxy)-2,2-dimethylpropyl)-6-chloro-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1#)-dicarboxamide

A suspension of 0.250 (0.85 mmol) of 6-chloro-7-(3fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carboxamide, 0.518 g (1.02 mmol) of 4-nitrophenyl 3-(tertbutyldiphenylsilanoxy)-2,2-dimethylpropylcarbamate and

0.235 g (1.70 mmol) of sodium carbonate in 3 ml of acetonitrile is heated at 65°C for 1 hour 30 minutes. After cooling, the mixture is poured into aqueous IN sodium hydroxide solution and the product is extracted with dichloromethane. After drying over sodium sulfate and filtering, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of 35 to 65% ethyl acetate in cyclohexane, to give 0,44 g of /^-^-(tertbutyldiphenylsilanoxy)-2,2-dimethylpropyl)-6-chloro-7-(3fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IH)dicarboxamide in the form of a pale yellow foam.

^XH NMR (DMSO-d₆) Ô: 7.59 (m, 4H) ; 7.3 (m, 7H) ; 7.1 (m, 3H) ;

5.20 (broad s, 2H); 4.8 (broad t, IH); 6.25 (broad s, IH);

3.80 (m, 4H); 4.70 (s, 2H); 3.34 (s, 2H); 3.21 (d, 2H); 1.01 (s, 9H); 0.85 (s, 6H) ppm.

Step 3.4._______6-Chloro ( 3-fluorophenyl ) -N²- ( 3-hydroxy-2,2dimethylpropyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IH)dicarboxamide

-61 ^ΗΠ λ' h₃c ch₃

N H

To a solution at 0°C of 0.44 g (0.65 mmol) of TV²-( 3-( tertbutyldiphenylsilanoxy)-2,2-dimethylpropyl)-6-chloro-7-(3f luorophenyl ) -3, 4-dihydropyrrolo [ 1,2-a ] pyrazine-2,8(17/)dicarboxamide in 1.3 ml of tetrahydrofuran is added 0.73 ml (0.73 mmol) of a IM solution of tetrabutylammonium fluoride in tetrahydrofuran. The mixture is stirred for 30 minutes at 0°C and then for 4 hours at room température, and is then diluted with 20 ml of dichloromethane. The solution is washed with aqueous ammonia solution and the organic phase is separated out on a hydrophobie cartridge and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of 2 to 5% méthanol in dichloromethane, to give 0.095 g of 6-chloro-(3-fluorophenyl)-AÎ-(-[(3-hydroxy-2,2dimethylpropyl ) -3,4-dihydropyrrolo [1,2-a] pyrazine-2,8(17/)dicarboxamide in the form of a white solid after recrystallizing from acetonitrile and drying.

m.p.: 205-207°C ⁷H NMR (DMSO-dg) Ô: 7.48 (m, 1H) ; 7.2 (m, 4H) ; 6.86 (broad t, 1H) ; 6.9 (broad s, 1H); 4.75 (s, 2H); 4.65 (t, 1H); 3.92 (m, 2H) ; 3.84 (m, 2H) ; 3.06 (d, 2H); 2.97 (d, 2H); 0.79 (s, 6H) ppm.

Exemple 4 (compound 60) : TV²- ( tert-Butyl) -6-chloro-7-phenyl-

3, 4-dihydropyrrolo [ 1,2-a ] pyrazine-2,8 (17?) -dicarboxamide

Cl

-62Step 4.1.______4-Phenyl-l#-pyrrole-3-carbonitrile________(CAS 40167-37-1) (Organic Reactions. Vol. 57, Edited by Larry E. Overman et al. 2001 Organic Reactions, Inc. published by

John Wiley & Sons)

To a suspension of 53.7 g (464 mmol) of potassium tertbutoxide in 500 ml of anhydrous tetrahydrofuran is added dropwise a mixture of 48.5 g (330 mmol) of the mixture of 50.0 g (387 mmol) of cinnamonitrile (CAS 1885-38-7) and

75.6 g (387 mmol) of tosylmethyl isocyanide (CAS 36635-61-7) dissolved in 500 ml of tetrahydrofuran, while maintaining the température of the reaction, medium at about 25°C. The mixture is then stirred for 1 hour 30 minutes at room température and is then poured into saturated sodium chloride solution. The reaction product is then extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown solid, which is dissolved in

350 ml of hot chloroform gel, eluting with and purified by chromatography dichloromethane, to give 44.3 on silica of 4phenyl-l#-pyrrole-3-carbonitrile in after triturating the form of beigecoloured powder in diisopropyl ether, filtering off and drying.

^ςΗ NMR (CDC1₃) δ:

7.7-7.6 (m, 2H); 7.5-7.3 (m, 3H); 7.00 (t,

1H) ppm.

-63To a solution of 44.3 g (263 mmol) of 4-phenyl-lH-pyrrole-3carbonitrile (CAS 40167-37-1) in 600 ml of tetrahydrofuran are added portionwise 35.8 g (268 mmo1) o f Nohlorosuccinimide (CAS 128-09-6) and the mixture is then stirred for 48 hours at reflux. After cooling, the reaction medium is concentrated under reduced pressure and the residue is then taken up in water. The reaction product is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown solid, which is triturated in diisopropyl ether and then isolated by filtration. The filtrate is concentrated under reduced pressure and the solid residue obtained is triturated in diisopropyl ether and then isolated by filtration. The two batches of solid are combined to give 51.7 g of 5-chloro-4-phenyl-lü-pyrrole-

3-carbonitrile in the form of a beige-coloured powder after drying.

m.p.: 140-142°C ³Η NMR (CDCI3) δ: 7.65-7.55 (m, 2H) ; 7.5-7.3 (m, 3H) ; 7.30 (d, 1H) ppm.

Step 4.3.______tert-Butyl {2- [2-chloro-4-cyano-3-phenyl-lffpyrrol-l-yl]ethyl}carbamate

To a solution of 51.6 g (254 mmol) of 5-chloro-4-phenyl-l.fipyrrole-3-carbonitrile in 400 ml of acetonitrile are added

20.4 g (509 mmol) of finely ground sodium hydroxide and

3.46 g (10.2 mmol) of tetrabutylammonium hydrogen sulfate, and the mixture is stirred vigorously for a few minutes, followed by adding 68.5 g (255 mmol) of tert-butyl (2-bromo ethyl)carbamate (CAS 39684-80-5), and the mixture is then stirred for 4 hours at reflux. [After cooling, the solvent is evaporated off under reduced pressure, the residue is taken up in water and the product is extracted with ethyl acetate.] The organic phase is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 67.9 g of tert-butyl (2-[2-chloro-4-cyano-

3-phenyl-lH-pyrrol-l-yl]ethyl}carbamate in the form of a white powder after recrystallizing from acetonitrile, filtering off and drying.

m.p. : 114-116°C ²Η NMR (CDC1₃) δ: 7.6-7.55 (m, 2H) ; 7.5-7.3 (m, 1H) ; 7.20 (s, 1H); 4.65 (broad s, 1H); 4.15 (broad t, 2H); 3.45 (m, 2H);

1.46 (s, 9H) ppm.

Step 4.4.______6-Chloro-7-phenyl-l, 2,3,4 - tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrite

To a suspension of 66.9 g (193 mmol) of tert-butyl {2—[2 — chloro-4-cyano-3-phenyl-lH-pyrrol-l-yl]ethyl}carbamate in 150 ml of éthanol are added slowly 688 ml (2670 mmol) of aqueous 4N hydrochloric acid solution and the mixture is heated to 90°C. Evolution of gas is rapidly observed, and after 1 hour, the medium is clear. 6.44 g (71.5 mmol) of paraformaldéhyde are then added and heating is continued for a further 4 hours. After cooling, the reaction medium is basified slowly by adding aqueous ammonia, the product is extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a yellow solid, which is triturated in acetonitrile and then isolated by filtration. The

filtrate is concentrated under reduced pressure and the solid residue obtained is triturated in acetonitrile and then isolated by filtration. The two batches of solid are combined to give 30.6 g of 6-chloro-7-phenyl-l,2,3,4tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile in the form of a beige-coloured powder after drying.

m.p.: 128-130°C ³Η NMR (CDC1₃) δ: 7.6 (m, 2H) ; 7.5-7.3 (m, 6H) ; 4.20 (s, 2H) ;

3.90 (t, 2H); 3.35 (t, 2H) ; 1.7 (bs, 1H) ppm.

Step 4.5.______Ai-tert-But yl-6-chloro-8-cyano-7-phenyl-3,4 dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide

To a solution of 34 g (119 mmol) of M-tert-buty1-6-chloro-8cyano-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(lff)carboxamide in 300 ml of dichloromethane are added 16.3 ml (143 mmol) of tert-butyl isocyanate (CAS1609-86-5). After stirring for 4 hours at room température, the solvent is evaporated off under reduced pressure to give an orangecoloured solid, which is crystallized from acetonitrile to give 40.0 g of N-tert-butyl-6-chloro-8-cyano-7-phenyl-3,4-

dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide in the	form
of a yellow powder after	filtering off	and	drying.
m.p.: 174-176°C
²H NMR (CDC1₃) δ: 7.6 (m,	2H) ; 7.5-7.3	(m,	3H); 4.35	(s,	2H) ;
4.4 (broad s, 1H) ; 4.0	(m, 2H) ; 3.9	(m,	2H); 1.4	(s,	9H)
ppm.

Step 4.6. A/²- ( tert-Butyl) -6-chloro-7-phenyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(lff)-dicarboxamide

To a solution at 65 °C of 40.0 g (112 mmol) of N-tert butyl-6-chIoro-8-cyano-7-phenyl-3,4-dihydropyrrolo[1,2-

a]pyrazine-2 ( 1 Ef)-carboxamide in 400 ml dimethyl suifoxide (3:2) are added 10.1 aqueous 35% sodium hydroxide solution

of	méthanol
ml	(118	mmol)
and	then	19.8

and of ml (21.8 mmol) of 35-volumes aqueous hydrogen peroxide solution in 4 fractions every 15 minutes. After reaction for minutes at 65°C, the mixture is cooled, partially concentrated under reduced pressure and taken up in dichloromethane. The organic phase is washed with water and is then dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give a yellow solid, which is crystallized from acetonitrile and then recrystallized from acetonitrile, to give 25.2 g of W² (tert-butyl)-6-chloro-7-phenyl-3,4-dihydropyrrolo[1,2-

a] pyrazine-2,8 (lff)-dicarboxamide in the form of a white powder after filtering off and drying.

m.p.: 197-199°C ³H NMR (DMSO-dg) δ: 7.45 (m, 2H); 7.35 (m, 3H); 7.0 (broad s,

1H) ; 6.15 (s, 1H) ; 5.85 (broad s, 1H) ; 4.70 (s, 2H) ; 3.90 (m, 2H); 3.80 (m, 2H); 1.30 (s, 9H) ppm.

Exemple 5 (compound 89) : 6-Chloro-7-(3-cyanophenyl)-JÎ (tetrahydro-2H-pyran-4-yl)-3, 4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1H)-dicarboxamide

H

-67Step 5.1. 4-Nitrophenyl tetrahydro-2H-pyran-4-ylcarbamate

To a solution of 5.00 g (36.3 mmol) of tetrahydro-2H-pyran-

4-yl-amine hydrochloride (CAS 38041-19-9) in 300 ml of dichloromethane, cooled to -15°C are added portionwise

13.2 g (65.4 mmol) of 4-nitrophenyl chloroformate (CAS 769346-1} and then 12.7 ml (72.7 mmol) of diisopropylethylamine. Stirring is continued at -0°C for 2 hours, and 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out by settling and dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column 80 g of silica gel, eluting with a mixture of 20% acetone in dichloromethane, to give 8.26 g of 4-nitrophenyl tetrahydro-2H-pyran-4-ylcarbamate in the form of a white powder.

m.p.: 174-176°C ^ςΗ NMR (CDC1₃) δ: 8.25 (d, 2H) ; 7.35 (d, 2H) ; 5.10 (broad d, 1H) ; 4.05 (m d, 2H) ; 3.85 (m, 1H) ; 3.50 (t d, 2H) ; 2.0 (m, 2H); 1.60 (m, 2H) ppm.

Step 5.2,______Methyl_____ 4- ( 3-cyanophenyl ) -lH-pyrrole-3 carboxylate

To a suspension of butoxide at 60% tetrahydrofuran, is

12.0 g (107 mmol) in oil, in 100 added dropwise a of potassium tertml of anhydrous mixture of 13.3 g

-68(71.1 mmol) of methyl (E)-3-(3-cyanophenyl)acrylate (CAS 193151-10-9) and 13.9 g (71.1 mmol) of tosylmethyl isocyanide (CAS 36635-61-7) dissolved in 100 ml of tetrahydrofuran, while maintaining the température of the reaction medium at about 25°C. The mixture is then stirred for 2 hours at room température, and is then partially concentrated under reduced pressure. This solution is then poured into ice-water and the reaction product is then extracted with dichloromethane. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown solid, which is triturated in chloroform to give 10.8 g of methyl 4-(3-cyanophenyl)-1Hpyrrole-3-carboxylate in the form of a beige-coloured solid after cooling, filtering off and drying.

m. p. : 181-183°C ²H NMR (CDC1₃) 5: 8.6 (broad s, IH) ; 7.70-7.80 (m, 2H) ;

7.40-7.60 (m, 3H); 6.85 (t, IH); 3.75 (s, 3H) ppm.

Step 5.3. Methyl 5-chloro-4-(3-cyanophenyl)-lH-pyrrole-

3-carboxylate

To a solution of 16.5 g (72.9 mmol) of methyl 4-(3-cyanophenyl)-lH-pyrrole-3-carboxylate in 150 ml of tetrahydrofuran are added portionwise 9.93 g (74.4 mmol) of N-chlorosuccinimide (CAS 128-09-6) and the mixture is then stirred for 6 hours at reflux. After cooling, 250 ml of water are added and the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced

-69pressure to give 17.1 g of methyl 5-chloro-4-(3cyanophenyl)-ltt-pyrrole-3-carboxylate in the form of a beige-coloured powder after recrystallizing from acetonitrile, filtering off and drying.

m.p.: 194-196°C ^ΧΗ NMR (CDC1₃) δ: 8.6 (broad s, 1H) ; 7.7-7.6 (m, 3H) ; 7.50 (m, 1H) ; 7.45 (d, 1H); 3.73 (s, 3H) ppm.

Step 5.4. Methyl 1-(2-tert-butoxycarbonylaminoethyl)-5chloro-4-(3-cyanophenyl)-lH-pyrrole-3-carboxylate

To a solution of 9.38 g (36.0 mmol) of methyl 5-chloro-4-(3 cyano-phenyl)-lH-pyrrole-3-carboxylate in 60 ml of acetonitrile are added 2.88 g (72.0 mmol) of powdered sodium hydroxide and 0.49 g (1.4 mmol) of tetrabutylammonium hydrogen sulfate, and the mixture is stirred vigorously for a few minutes, followed by adding 9.68 g (43.2 mmol) of tert-butyl (2-bromoethyl)carbamate (CAS 39684-80-5), and the mixture is then stirred for 6 hours at reflux, After cooling, the mixture is taken up in 250 ml of water and the product is extracted with ethyl acetate. The organic phase is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give an orangecoloured oil, which is purified by chromatography on a column of 150 g of silica gel, eluting with a mixture of 2% méthanol in dichloromethane, to give 13.5 g of methyl 1—(2— tert-butyloxycarbonylaminoethyl)-5-chloro-4-(3-cyanophenyl)lJ7-pyrrole-3-carboxylate in the form of a yellow oil.

-70^ΣΗ NMR (CDC1₃) δ: 7.60-7.75 (m, 3Η) ; 7.50 (d, 1H) ; 7.37 (s,

1H) ; 4.68 (broad s, 1H) ; 4.15 (m, 2H) ; 3.71 (s, 3H) ; 3.47 (q, 2H); 1.46 (s, 9H) ppm.

Step 5.5. Methyl 1-(2-aminoethyl)-5-chloro-4-(3-cyano-

To a solution of 13.5 g (33.4 mmol) of methyl l-(2-tertbutyloxycarbonylaminoethyl) -5-chloro-4- (3-cyanophenyl) -1/7pyrrole-3-carboxylate in 50 ml of methanol are added 80 ml (320 mmol) of 4N hydrochloric acid and the mixture is heated vigorously at 60°C for 2 hours. 150 ml of water are then added and the solution is basified by adding agueous ammonia. The product is extracted with dichloromethane, the organic phase is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a yellow oil, which is purified by chromatography on a column of 80 g of silica gel, eluting with a mixture of 0.3% aqueous ammonia and 3% methanol in dichloromethane, to give

8.4 g of methyl 1-(2-aminoethyl)-5-chloro-4-(3-cyanophenyl)lH-pyrrole-3-carboxylate in the form of a white powder after crystallizing, triturating in diisopropyl ether, filtering off and drying.

m.p.: 111-113°C ²H NMR (CDCI3) δ: 7.80-7.4 (m, 5H) ; 4.09 (t, 2H) ; 3.70 (s,

3H); 3.12 (t, 2H); 1.4 (broad s, 2H) ppm.

Step 5.6.______Methyl____6-chloro-7- (3-cyanophenyl) -1,2,3,4 tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate

To a solution of 8.41 g (27.7 mmol) of methyl 1-(2-aminoethyl)-5-chloro-4-( 3-cyanophenyl)-lH-pyrrole-3-carboxylate in 20 ml of methanol are added 8 4 ml (34 0 mmol) of aqueous 4N hydrochloric acid solution. The formation of a white precipitate is rapidly observed and the medium then becomes clear, while the mixture is heated to 90°C and 0.92 g (10 mmol) of paraformaldéhyde is added. Heating is continued at 90°C for 4 hours. After cooling, the reaction medium is poured into 200 ml of water and the solution is basified by adding aqueous ammonia. The product is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give an orange-coloured oil, which is chromatographed on a column of 80 g of silica gel, eluting with a mixture of 2% methanol in dichloromethane, to give 7.1 g of methyl 6-chloro-7-(3cyanophenyl)-1,2,3,4-tetrahydropyrrolo[1,2~a]pyrazine-8carboxylate in the form of a yellow oil.

^ZH NMR (CDC1₃) δ: 7.65-7.40 (m, 4H) ; 4.35 (s, 2H) ; 3.90 (t, 2H); 3.65 (s, 3H); 3.35 (t, 2H) ppm.

Step 5.7.______2-tert-Butyl______8-methyl______6-chloro-7- (3cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H) -

-72To a solution of 7.10 g (22.5 mmol) of methyl 6-chloro-7-(3cyanophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carboxylate in 50 ml of dichloromethane are added slowly

5.40 g (24.7 mmol) of di-tert-butyl dicarbonate (CAS 2442499-5) dissolved in about 20 ml of dichloromethane. After stirring for 1 hour at room température, the solvent is evaporated off under reduced pressure to give a yellow oil, which is purified by chromatography on a column of 80 g of silica gel, eluting with a mixture of 20% ethyl acetate in cyclohexane to give 7.5 g of 2-tert-butyl 8-methyl 6chloro-7-(3-cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 ( 1E)-dicarboxylate in the form of a transparent oil that crystallizes from methanol.

m.p.: 154-156°C ²H NMR (CDC1₃) δ: 7.65-7.40 (m, 4H) ; 4.90 (s, 2H) ; 3.9 (2m, 4H); 3.70 (s, 3H); 1.50 (s, 9H) ppm.

Step 5.8.______2-(tert-Butoxycarbonyl)-6-chloro-7-(3cyanophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carboxylic acid

To a suspension of 5.50 g (13.2 mmol) of 2-tert-butyl 8methyl 6-chloro-7-(3-cyanophenyl)-3,4-dihydropyrrolo[1,2-

a] pyrazine-2,8 (lif)-dicarboxylate in 60 ml of a mixture of methanol, water and tetrahydrofuran (1:1:2) is added 0.38 g (15.9 mmol) of lithium hydroxide, and the mixture is heated at 60°C for 18 hours. The mixture is then taken up in 100 ml of dichloromethane and 100 ml of water, and is then acidified by addition of aqueous IN sulfurie acid. The organic phase is separated out and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give a yellow solid, which is purified by chromatography on a column of 80 g of silica gel, eluting with a mixture of 2% methanol in dichloromethane, to give

3.35 g of 2-(tert-butyloxycarbonyl)-6-chloro-7-(3- cyanophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carboxylic acid in the form of a white powder after triturating in acetonitrile, filtering off and drying.

m.p.: 208-210°C *H NMR (DMSO-de) δ: 12.1 (broad s, 1H) ; 7.8-7.5 (m, 4H) ; 4.80 (s, 2H); 3.95 (m, 2H); 3.80 (m, 2H); 1.45 (s, 9H) ppm.

Step 5.9.______tert-Butyl 6-chloro-7- (3-cyanophenyl) -8- (1H imidazol-l-ylcarbonyl)-3,4-dihydropyrrolo[1,2-a]pyrazine2 (1#) -carboxylate

To a solution of 3.1 g (7.71 mmol) of 2-(tertbutyloxycarbonyl)-6-chloro-7-(3-cyanophenyl)-1,2,3,4tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid in 20 ml of tetrahydrofuran are added 1.38 g (8.49 mmol) of carbonyldiimidazole (CAS 530-62-1). After reaction for 2 hours at 60°C, the mixture is cooled and concentrated under reduced pressure. The residue is taken up in 60 ml of water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a yellow oil, which is purified by chromatography on a column of 80 g of silica gel, eluting with a mixture of 2% methanol in dichloromethane, to give 3.38 g of tert-butyl 6-chloro-7-(3cyanophenyl)-8-(l#-imidazol-l-ylcarbonyl)-3,4V16268

-74dihydropyrrolo [1,2-a] pyrazine-2 (177)-carboxylate in the form of a colourless oil.

³H NMR (COC1₃) δ: 7.60 (m, IH) ; 7.5 (m, 2H) ; 7.30 (m, 2H) ;

7.2 (m, IH) ; 6.80 (m, 1H); 4.80 (s, 2H); 4.05 (t, 2H); 3.95 (m, 2H); 1.50 (s, 9H) ppm.

Step 5.10._____tert-Butyl_________8-carbamoyl-6-chloro-7- (3cyanophenyl) -3, 4-dihydropyrrolo [1,2-a] pyrazine-2 (177) -

To a solution of 3.28 g (7.26 mmol) of tert-butyl 6chloro-7- (3-cyanophenyl) - 8- ( 177-imidazol-l-ylcarbonyl) -3,4dihydropyrrolo [1,2-a] pyrazine-2 ( 177)-carboxylate in 4 ml of dimethylformamide in an autoclave are added 6 ml of 33% aqueous ammonia. The mixture is stirred for 3 hours at 110°C and, after cooling, is then poured into 80 ml of water and the solid is separated out by filtration. The solid is taken up in dichloromethane, the solution is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 2.9 g of tert-butyl 8-carbamoyl-6chloro-7-(3-cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine2 ( 177)-carboxylate after drying.

m.p. : 206-208°C ^ςΗ NMR (DMSO-dg) δ: 7.85-7.75 (m, IH) ; 7.70 (m, IH) ;

7.65-7.60 (m, 2H); 7.1 (broad s, IH) ; 6.45 (broad s, IH) ;

4.70 (s, 2H); 3.95 (m, 2H); 3.8 (m, 2H); 1.45 (s, 9H) ppm.

Step 5.11. 6-Chloro-7-(3-cyanophenyl)-1,2,3,4-tetrahydropyrrolo [1,2-a]pyrazine-8-carboxamide

TO

To a solution of 2.90 g (7.23 mmol) of tert-butyl 8carbamoyl-6-chloro-7-( 3-cyanophenyl)-3,4-dihydropyrrolo[1,2-

a]pyrazine-2(IH)-carboxylate in 7 ml of dichloromethane are added slowly 7 ml (72 mmol) of trifluoroacetic acid. After stirring for 1 hour at room température, the solvent is evaporated off under reduced pressure, the residue is taken up in water and the aqueous phase is basified by addition of aqueous ammonia. The white solid formed is separated out by filtration, rinsed with water and triturated in acetonitrile to give 1.7 g of 6-chloro-7-(3-cyanophenyl)-l,2,3,4tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide in the form of a white powder after separating out by filtration and drying under reduced pressure.

m.p.: 151-153°C

NMR (DMSO-d₆) δ: 7.80-7.65 (m, IH); 7.65 (m, IH); 7.6-7.5 (m, 2H); 7.0 (broad s, IH); 6.5 (broad s, IH); 4.00 (s, 2H);

3.75 (t, 2H) ; 3.10 (t, 2H) ppm.

Step 5.12._____6-Chloro-7-(3-cyanophenyl)-N²-(tetrahydro-2Hpyran-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IH) dicarboxamide

Cl

A suspension of 0.67 g (2.23 mmol) of 6-chloro-7-(3cyanophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carboxamide, 0.712 g (2.67 mmol) of 4-nitrophenyl tetrahydro-2H-pyran-4-ylcarbamate and 0.616 g (1.12 mmol) of

IA L

-76potassium carbonate in 10 ml of acetonitrile is heated at 65°C for 1 hour 30 minutes. After cooling, the mixture is concentrated under reduced pressure, the residue is diluted with dichloromethane and the solution is washed with aqueous IN sodium hydroxide solution. The organic phase is washed with water, dried over sodium sulfate and filtered, and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of 2 to 5% methanol in dichloromethane, to give 0.79 g of 6-chloro-7-(3cyanophenyl) -N²- (tetrahydro-227-pyran-4-yl) -3,4dihydropyrrolo [1,2-a ] pyrazine-2,8 ( 127) -dicarboxamide in the form of a whitish powder after recrystallizing from 100 ml of éthanol, filtering off and drying under reduced pressure, m.p.: 236-238°C ²H NMR (DMSO-de) ô: 7.80 (m, 1H) ; 7.70 (m, 1H) ; 7.65 (, 2H) ; 7.05 (broad s, 1H); 6.65 (d, 1H); 6.50 (broad s, 1H); 4.75 (s, 2H) ; 3.95-3.75 (m, 6H); 3.70 (m, 1H); 3.45 (m, 2H); 1.70 (m, 2H); 1.50 (m, 2H) ppm.

Exemple 6 (compound 58) : TV²- ( tert-Butyl) -6-fluoro-7-phenyl3, 4-dihydropyrrolo [1,2-a] pyrazine-2,8 (127) -dicarboxamide

-77To a solution of 9.50 g (56.5 mmol) of 4-phenyl-lH-pyrrole-

3- carbonitrile (CAS 40167-37-1) in 300 ml of acetonitrile are added portionwise 24.0 g (67.8 mmol) of 1-chloromethyl-

4- fluoro-l, 4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SelectFluor - CAS 140681-55-6), with a certain amount of exothermicity being observed. The mixture is stirred for 18 hours at 60°C. After cooling, the reaction medium is concentrated under reduced pressure and the residue is then taken up in 500 ml of ethyl acetate. The solution is washed twice with 250 ml of water and then with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown oil, which is chromatographed on a column of silica gel, eluting with a mixture of 15% ethyl acetate in cyclohexane, to give

3.75 g of 5-fluoro-4-phenyl-lH-pyrrole-3-carbonitrile in the form of a red oil after drying, which product is used as obtained for the rest of the synthesis.

¹H NMR (CDC13) δ: 8.7 (broad s, IH) ; 7.7-7.3 (m, 5H) ; 6.95 (m, IH) ppm.

Step 6.2.______tert-Butyl {2- [4-cyano-2-fluoro-3-phenyl-lHpyrrol-l-yl]ethyl)carbamate

H_:H.

To a solution of 3.75 g (20.1 mmol) of 5-fluoro-4-phenyl-lHpyrrole-3-carbonitrile in 101 ml of acetonitrile are added

1.6 g (40 mmol) of finely ground sodium hydroxide and 0.27 g (0.81 mmol) of tetrabutylammonium hydrogen sulfate, and the mixture is stirred vigorously for a few minutes, followed by adding 5.42 g (24.2 mmol) of tert-butyl (2-bromoethyl)carbamate (CAS 39684-80-5), and the mixture is then stirred for 18 hours at 90°C. After cooling, the solvent is evaporated off under reduced pressure and the residue is taken up in twice 125 ml of water. The product is extracted with ethyl acetate. The organic phase is then washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of 15 to 50% ethyl acetate in cyclohexane, to give 2.5 g of 5-fluoro-

4-phenyl-lH-pyrrole-3-carbonitrile in the form of a brown oil.

^TH NMR (CDC1₃) δ: 7.65 (d, 2H) ; 7.55 {t, 2H) ; 7.30 (d, 1H) ;

4.7 (broad s, 1H) ; 4.05 (m, 2H); 3.45 (m, 2H); 1.46 (s, 9H) ppm.

Step 6.3.______6-Fluoro-7-phenyl-l·, 2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile

To a suspension of 2.50 g (7.59 mmol) of tert-butyl {2—[2— fluoro-4-cyano-3-phenyl-lH-pyrrol-l-yl]ethyl}carbamate in 5 ml of éthanol are added slowly 25 ml (100 mmol) of aqueous 4N hydrochloric acid solution and 0.25 g (2.8 mmol) of paraformaldéhyde. The mixture is heated at 90°C for a further 2 hours. After cooling, the reaction medium is basified slowly by adding aqueous ammonia and the product is extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The black oil obtained is purified by chromatography on a column of silica gel, eluting with a mixture of 2 to 5% methanol in dichloromethane, to give 0.75 g of 6-fluoro-7-phenyl-l,2,3,4-tetrahydropyrrolo[1,216268

a] pyrazine-8-carbonitrile in the form of a brown oil after drying.

³H NMR (CDC1₃) δ: 7.7 (m, IH); 7.5-7.3 (m, 4H); 4.20 (s, 2H) ;

3.90 (t, 2H); 3.30 (t, 2H) ; 1.8 (bs, IH) ppm.

Step 6.4.______N-tert-Buty1-8-cyano-6-fluoro-7-pheny1-3,4dihydropyrrolo[1,2-a]pyrazine-2(IH)-carboxamide

To a solution cooled to 0°C of 0.75 g (3.1 mmol) of 6fluoro-7-phenyl-l,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carbonitrile in 50 ml of dichloromethane are added 1.4 ml (10 mmol) of triethylamine and then 0.37 g (3.7 mmol) of tert-butyl isocyanate (CAS1609-86-5) dropwise. After stirring for 2 hours at room température, the medium is poured into water, the organic phase is separated out and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give a solid in the form of a green foam, which is purified by chromatography on a column of silica gel, eluting with a mixture of 20 to 50% ethyl acetate in cyclohexane, to give 0.36 g of N-tert-buty 1-8cyano-6-fluoro-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine2 (17f)-carboxamide in the form of an orange-coloured gummy solid.

-¹}] NMR (CDC1₃) δ: 7.65 (m, 2H) ; 7.45 (m, 2H) ; 7.35 (m, IH) ;

4.65 (s, 2H) ; 4.5 (broad s, IH) ; 3.95 (m, 2H) ; 1.4 (s, 9H) ppm.

Step 6.5.__N²- ( tert-Butyl) -6-fluoro-7-phenyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IH) -dicarboxamide «

To a solution of 0.360 g (1.06 mmol) of N-tert-butyl-6fluoro-8-cyano-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine- ( 1H) -carboxamide in 4,2 ml of méthanol is added 0,1 ml (1.1 mmol) of aqueous 35% sodium hydroxide solution and then 0.28 ml (3.2 mmol) of 35-volumes aqueous hydrogen peroxide solution. After stirring for 2 hours at 60°C, a further 0.05 ml (0.5 mmol) of 35-volumes aqueous hydrogen peroxide solution is added and the mixture is stirred for 16 hours at 60°C. After cooling, 0.25 g of sodium thiosulfate dissolved in 0.5 ml of water is added and the heterogeneous mixture is diluted with 75 ml of ethyl acetate. The organic phase is separated out, washed twice with 25 ml of water and then with 25 ml of saturated aqueous sodium chloride solution, after which it is dried over sodium sulfate. The solvent is evaporated off under reduced pressure to give a yellow oil, which is purified by chromatography on a column of silica gel, eluting with a mixture of 2 to 6% méthanol in dichloromethane, to give 0.06 g of 6-fluoro-7-phenyl-W²( tert-butyl) -3, 4-dihydropyrrolo [1, 2-a] pyrazine-2,8(11/)dicarboxamide in the form of a solid after triturating in diisopropyl ether, filtering off and drying.

m.p.: 213-215°C ¹H NMR (CDCI3) δ: 7.4 (m, 5H); 7.05 (bs, 1H); 6.15 (bs and s, 2H); 4.70 (s, 2H); 3.90 (m, 2H); 3.75 (m, 2H); 1.30 (s, 9H) ppm.

Example 7 (compound 60) : AT²-tert-Buty 1 -6-chlo ro-7-pheny1-

3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide ο

ct

The synthesis of this compound is also described in Example

4.

Step 7.1.: tert-Butyl 8-cyano-3,4-dihydropyrrolo[1,2-

a]pyrazine-2(1H)-carboxylate

To a solution under nitrogen of 28.7 g (102 mmol) of sodium

4-(tert-butyloxycarbonyl)-l-formylpiperazine-2-carboxylate (CAS 1108698-36-7) in 1 1 of dichloromethane are added

21.5 g (113 mmol) of p-toluenesulfonyl chloride. After stirring for 40 minutes, 8.2 ml (102 mmol) of 2chloroacrylonitrile are added. After stirring for 40 minutes, 32.8 ml (235 mmol) of triethylamîne are added dropwise and the mixture is stirred overnight at room température, and then refluxed for 1 hour. The solution is then cooled to room température. 150 ml of water are added. The organic phase is separated out by settling, washed twice with 100 ml of water, dried over sodium sulfate and fîltered, and concentrated under reduced pressure. The residue obtained is chromatographed on a column of silica gel, eluting with a mixture of 0 to 10% ethyl acetate in dichloromethane, to give 17.5 g of tert-butyl 8-cyano-3,4dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in the form of a white solid after dissolving in a mixture of cyclohexane and dichloromethane and then precipitating by slow concentration and drying under reduced pressure.

m.p.: 97°C

-82^ςΗ NMR (CDC1₃) δ: 6.60 (d, 1H) ; 6.45 (d, 1H) ; 4.75 (s, 2H) ;

4.0 (m, 2H) ; 3.9 (m, 2H); 1.55 (s, 9H) ppm.

Step 7.2. tert-Butyl 8-carboxylate-3,4-dihydropyrrolo[1,2—

a]pyrazine-2(1H)-carboxylate

To a solution of 26.7 g (108 mmol) of tert-butyl 8-cyanoin

3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H) -carboxylate

490	ml of	methanol	are	added	80 ml (864 mmol)
concentrated	aqueous	32%	sodium	hydroxide and 4.0
(41	mmol) of	aqueous	35%	hydrogen	peroxide solution.

of g

The reaction medium is heated at 55°C for 2 hours. 4 times 4.0 g (41 mmol) of aqueous 35% hydrogen peroxide solution are then added every 2 hours and heating is then continued at 55°C for 18 hours. The medium is then treated with an aqueous solution of 30 g (190 mmol) of sodium thiosulfate in 250 ml of water and the reaction mixture is stirred for 1 hour and then partially concentrated under reduced pressure. The product is extracted with 350 ml and then twice 100 ml of dichloromethane, and the organic phases are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in a mixture of dichloromethane and ethyl acetate and then precipitated by slow concentration to give 21.1 g of tert-butyl 8-carbamoyl-

3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in the form of a white solid after drying in an oven at 60°C under reduced pressure.

m.p.: 181°C ^TH NMR (CDC1₃) Ô: 6.55 (d, 1H) ; 6.30 (d, 1H) ; 5.5 (bs, 2H) ;

4.95 (s, 2H); 4.0 (m, 2H); 3.85 (m, 2H); 1.50 (s, 9H) ppm.

«C

-83Step_____7.3.:______tert-Butyl______8-carbamoyl-6-chloro-3, 4 dihydropyrrolo[1,2-a]pyrazine-2(IH)-carboxylate

To a solution under nitrogen of 21.1 g (79.6 mmol) of tertbutyl 8-carbamoyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(IH) carboxylate in 600 ml of dichloromethane, cooled to -40°C, is added dropwise a solution of 10.6 g (79.6 mmol) of Nchlorosuccinimide in 200 ml of dichloromethane over about 40 minutes. Stirring is continued for 6 hours at a température of -40°C, 150 ml of water are then added and the reaction medium is allowed to warm to room température. The product is isolated by filtration and is washed with water to give 17.5 g of tert-butyl 8-carbamoyl-6-chloro-3,4dihydropyrrolo[1,2-a]pyrazine-2(IH}-carboxylate in the form of a whitish solid after drying under reduced pressure at 40°C in the presence of phosphorus pentoxide.

m.p. = 223-225°C ¹H NMR (DMSO) δ: 7.35 (broad s, 1H) ; 6.85 (broad s, IH) ;

6.75 (s, IH); 4.75 (s, 2H); 3.85 (m, 2H); 3.75 (m, 2H); 1.45 (s, 9H) ppm.

Step 7.4.____tert-Butyl 7-bromo-8-carbamoyl-6-chloro-3,4 dihydropyrrolo[1,2-a]pyrazine-2(IH) -carboxylate

To a solution of 10.5 g (35.1 mmol) of tert-butyl 8carbamoyl-6-chloro-3, 4-dihydropyrrolo [ 1, 2-a] pyrazine-2 (IH') carboxylate in 1 1 of a mixture of 50% ethyl acetate in

-84dichlorométhane precooled to 0°C is added slowly a solution of 6.90 g (38.6 mmol) of N-bromosuccinimide in 200 ml of dichlorométhane. The reaction is stirred for 5 hours at 0°C and then for 12 hours while allowing the température to return to room température. 300 ml of water are then added, the organic phase is separated out by settling and the aqueous phase is then washed with twice 2 00 ml of ethyl acetate. The organic phases are combined and partially concentrated under reduced pressure. The solution is taken up in 60 ml of water and the organic solvents are removed by évaporation under reduced pressure. The insoluble matter suspended in water is isolated by filtration, washed with water and then dried under reduced pressure in the presence of phosphorus pentoxide. The residue obtained is chromatographed on a column of silica gel, eluting with a mixture of 5 to 50% ethyl acetate in dichlorométhane, to give 5.0 g of tert-butyl 7-bromo-8-carbamoyl-6-chloro-3,4dihydropyrrolo[1,2-a]pyrazine-2(IH)-carboxylate in the form of a white solid after triturating in ethyl acetate and drying at 60°C under reduced pressure.

m.p.: 214-216°C ²H NMR (CDC1₃) δ: 6.7 (broad s, IH); 5.5 (broad s, IH); 5.00 (s, 2H); 3.9 (m, 4H); 1.50 (s, 9H) ppm.

Step 7.5. tert-Butyl 8-carbamoyl-6-chloro-7-phenyl-3,4dihydropyrrolo[1,2-a]pyrazine-2(IH) -carboxylate

Cl

To a solution under nitrogen of 3.78 g (9.98 mmol) of tertbutyl 7-bromo-8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2-

a]pyrazine-2(IH)-carboxylate in 160 ml of tetrahydrofuran rtc.

are added	1.34	g	(11.0	mmol)	of	benzeneboronic acid (CAS 98-
80-6), 8	ml	of	water, 9.	76	g	(30.0 mmol) of caesium
carbonate	and	0.	98 g	(1.20	mmol )	of a complex of 1,1'-

bis(diphenylphosphino)ferrocenedichloropalladium (II) and dichloromethane (PdC12(dppf) ·0Η₂012 - CAS 95464-05-4). The mixture is stirred for 6 hours at 100°C and then for 15 hours at 80°C, then cooled to room température and filtered through Celite™. The Celite is rinsed with 100 ml of ethyl acetate and 30 ml of water are added to the combined filtrâtes. The organic phase is separated out by settling, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is chromatographed on a column of silica gel, eluting with a mixture of 5 to 50% ethyl acetate in dichloromethane, to give 1.50 g of tert-butyl 8-carbamoyl-6-chloro-7-phenyl-3,4dihydropyrrolo[1,2-a]pyrazine-2(IH)-carboxylate in the form of a white solid after recrystallization from ethyl acetate and drying at 60°C under reduced pressure.

m.p.: 178-180°C

NMR (CDC1₃) δ: 7.4-7.25 (m, 5H) ; 5.1 (broad s, 2H) ; 4.9 (s, 2H); 3.85 (m, 4H); 1.45 (s, 9H) ppm.

Step 7.6. 8-Carbamoyl-6-chloro-7-phenyl-l,2,3,4-dihydropyr rolo [1,2-a]pyrazine hydrochloride

To a solution cooled to about 0°C of 5.99 g (15.9 mmol ) of tert-butyl 8-carbamoyl-6-chloro-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(IH) -carboxylate in 50 ml of dichloromethane and 200 ml of methanol are added portionwise

12.6 g (116 mmol) of chlorotrimethylsilane. The mixture is stirred for 16 hours at room température and the reaction medium is then concentrated under reduced pressure and coevaporated twice with ethyl acetate. The residue is crystallized from ethyl acetate to give 4.88 g of 8carbamoyl-6-chloro-7-phenyl-l,2,3,4-dihydropyrrolo[1,2ajpyrazine hydrochloride in the form of a white solid after drying at 60°C under reduced pressure.

m.p.: 227-230°C (décomposition) ³H NMR (DMSO) δ: 9.5 (broad s, 2H) ; 7.55 - 7.30 (m, 5H) ;

7.20 (broad s, 1H); 4.55 (s, 2H); 4.15 (m, 2H); 3.65 (m, 2H) ppm.

Step 7.7. JJ^-tert-Butyl-ô-chloro-î-phenyl-S, 4-dihydropyrrolo [ 1, 2-a] pyrazine-2,8(1H) -dicarboxamide

To a solution under nitrogen and cooled to about 0°C of

2.06 g (6.6 mmol) of 8-carbamoyl-6-chloro-7-phenyl-l,2,3,4 dihydropyrrolo[1,2-a]pyrazine hydrochloride in 60 ml of dichloromethane are added 2.76 ml (19.8 mmol) of triethylamine, and then 0.90 ml (7.92 mmol) of tert-butyl isocyanate. The solution is stirred for 4 hours at room température and 20 ml of water are then added. The organic phase is separated out by settling, washed twice with 20 ml of water, dried over sodium sulfate and filtered, and concentrated under reduced pressure. The residue is chromatographed on a column of silica gel, eluting with a mixture of 5 to 50% ethyl acetate in dichloromethane, and the product obtained is recrystallized from ethyl acetate, to give 0.46 g of N^-tert-butyl-ô-chloro-l-phenyl-S,4 dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the

form of a white solid after drying at

60°C under reduced pressure.

m.p.: 192 - 195°C ³H NMR (DMSO) δ: 7.45 (m, 2H) ; 7.35 (m, 3H) ; 7.0 (broad s,

Example 8 (compound 1 ) : N²--tert--Buty 1-7-pheny 1-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H) -dicarboxamide

A mixture of 0.866 g (2.31 mmol) of N²-tert-butyl“6chloro-7-phenyl-3, 4-dihydropyrrolo [ 1,2-a] pyrazine-2,8(12/) — dicarboxamide, 6.0 g (95 mmol) of ammonium formate and 0.20 g (0.09 mmol) of 10% palladiura-on-charcoal containing 50% water in 50 ml of methanol is refluxed for 6 hours. After cooling, the mixture is filtered through Celite and the Celite is rinsed with dichloromethane. The filtrate is then concentrated under reduced pressure and the residue is taken up in dichloromethane. The solution is washed with water, dried over sodium sulfate and then concentrated under reduced pressure. The product is then purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of 95 to 50% ethyl acetate in dichloromethane, to give 0.31 g of N²-tert-butyl-7-phenyl-

3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a white solid after crystallizing from diethyl ether and drying.

m.p.: 156-158°C ²H NMR (DMSO-dg) δ:

1H); 6.55 (s, 1H);

2H); 3.95 (m, 2H);

7.4 (m, 4H); 7.25

6.2 (broad s, 1H);

3.70 (m, 2H) ; 1.33 (m, 1H); 6.9 (broad s,

6.05 (s, 1H); 4.70 (s, (s, 9H) ppm.

-88Example 9 (compound €5) : ΔΖ²-tort--Buty 1-6-ch 1oro-7- (3cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)dicarboxamide

Step 9.1.______tert-Butyl 8-carbamoyl-6-chloro-7- (3-cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H) -carboxylate

CI

To a solution under nitrogen of 6.50 g (17.2 mmol) of tertbutyl 7-bromo-8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2—

a]pyrazine-2(1H) -carboxylate in 200 ml of tetrahydrofuran are added 2.52 g (17.2 mmol) of 3-cyanophenylboronic acid (CAS 150255-96-2), 10 ml of water, 16.8 g (52.4 mmol) of caesium carbonate and 1.68 g (2.06 mmol) of a complex of 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) and dichloromethane (PdCl₂(dppf) -CH2C12 - CAS 95464-05-4). The mixture is stirred for 6 hours at 100°C and then for 15 hours at 80°C, then cooled to room température and filtered through Celite™. The Celite is rinsed with 200 ml of ethyl acetate and 30 ml of water are added to the combined filtrâtes. The organic phase is separated out by settling, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is chromatographed on a column of silica gel, eluting with a mixture of 2 to 50% ethyl acetate in dichloromethane, to give 3.69 g of tert-butyl 8-carbamoyl-6-chloro-7-(3cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2 ( 1H) carboxylate in the form of a white solid after

-89recrystallization from ethyl acetate and drying at 60°C under reduced pressure.

m.p.: 209-210°C ¹H NMR (CDCI3) δ: 7.8-7.55 (m, 4H) ; 5.1 (broad s, 2H) ; 5.00 (s, 2H) ; 3.95 (m, 4H) ; 1.55 (s, 9H) ppm.

Step 9.2. 8-Carbamoyl-6-chloro-7-(3-cyanophenyl)-1,2,3, 4dihydropyrrolo[ 1,2-a]pyrazine hydrochloride

HCl

To a solution cooled to about 0°C of 2.12 g (5.29 mmol) of tert-butyl 8-carbamoyl-6-chloro-7-(3-cyanophenyl)-3, 4dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in a mixture of 50 ml of dichloromethane and 150 ml of methanol are added portionwise 2.75 g (31.7 mmol) of chlorotrimethylsilane. The mixture is stirred for 18 hours at room température and the reaction medium is then concentrated under reduced pressure and co-evaporated twice with ethyl acetate. The residue is isolated after concentration under reduced pressure by filtering off and rinsing with ether, to give 1.78 g of 8carbamoyl-ë-chloro-7-(3-cyanophenyl)-1,2,3,4-dihydropyrrolo[1,2-a]pyrazine hydrochloride in the form of a white solid. m.p.: 254-256°C ²H NMR (DMSO) Ô: 9.9 (broad s, 2H) ; 7.80 (m, 1H) ; 7.70 (s,

1H) ; 7.60 (d, 2H) ; 7.20 (broad s, 1H) ; 6.5 (broad s, 1H) ;

4.45 (s, 2H); 4.15 (m, 2H); 3.50 (m, 2H) ppm.

Step 9.3. N²-tert-Butyl-6-chloro-7-(3-cyanophenyl)-3,4 dihydropyrrolo[1,2-a]pyrazine-2,8(7/7)-dicarboxamide

-90under nitrogen and cooled to about 0°C, of

To a solution,

1.11 g {3.29 mmol) of 8-carbamoyl-6-chloro-7-(3-cyano phenyl)-1,2,3,4-dihydropyrrolo[1,2-a]pyrazine hydrochloride and 1.15 ml (8.23 mmol ) of triethylamîne in 40 ml of dichloromethane is added 0.45 ml (3.95 mmo1) of tert-butyl isocyanate.

The solution is stirred for 3 hours at room température and ml of water are then added.

The organic phase is separated out by settling, washed with saturated aqueous IN hydrochloric acid solution, dried over sodium sulfate and fîltered, and concentrated under reduced pressure. The residue is chromatographed on a column of silica gel, eluting with a mixture of 10 to 50% methanol in dichloromethane, and the product obtained is recrystallized from ethyl acetate, to give 0.97 g of N^-tert-butyl-ôchloro-7-(3-cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 (1H) -dicarboxamide in the form of a white solid after drying.

m.p.: 192 - 195°C

NMR (DMSO)	δ: 7.80	(d,	1H); 7.45	(s, 1H) ; 7.65 (m, 2H) ;
7.1 (broad s,	1H) ; 6.5	(s,	1H) ; 6.15	(broad s, 1H);	4.65 (s,
2H); 3.90 (m,	2H); 3.80	(m,	2H); 1.30	(s, 9H) ppm.

Example 10 (compound 64): JV²-tert-Butyl-6-chloro-7-(4methoxyphenyl) -3, 4-dihydropyrrolo [1,2-a ] pyrazine-2,8(1//)dicarboxamide

Ct

-91 Step 10.1._____tert-Butyl 8-carbamoyl-6-chloro-7- (4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(IH) -carboxylate

Cl

To a mixture under nitrogen of 4.00 g (10.6 mmol) of tertbutyl 7-bromo-8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2-

a]pyrazine-2(IH)-carboxylate under N₂ with the bromo dérivative of pyrrolo[1,2-a]pyrazine, 1.77 g (11.6 mmol) of

4-methoxyphenylboronic acid and 10.3 g (31.7 mmol) of caesium carbonate in a mixture of 80 ml of tetrahydrofuran and 4 ml of water is added 0.863 g (1.06 mmol) of 1,1'bis(diphenylphosphino)ferrocenedichloropalladium (II) (CAS 72287-26-4). The mixture is heated at 100°C for 20 hours and, after cooling, the medium is then diluted with ethyl acetate and filtered through Celite. The filtrate is washed with water, the organic phase is dried over sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on a column of 40 g of silica gel, eluting with 5 to 100% ethyl acetate in dichloromethane, to give

3.35 g of tert-butyl 8-carbamoyl-6-chloro-7-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(IH) -carboxylate after crystalli zation from ethyl acetate and drying.

m.p.: 188.5 °C ^XH NMR (CDC1₃) Ô: 7.35 (d, 2H) ; 7.05 (d, 2H) ; 5.3 (broad s, IH) ; 5.2 (broad s, IH); 5.00 (s, 2H); 3.95 (m, 4H); 3.90 (s, 3H); 1.55 (s, 9H) ppm.

Step 10.2._____8-Carbamoyl-6-chloro-7- (4-methoxyphenyl) -

1,2,3,4-dihydropyrrolo[1,2-a]pyrazine hydrochloride

Vi ο

HCl

Cl

Λ ch₃

To a solution of 3.35 g (8.25 mmol) of tert-butyl 8carbamoyl-6-chloro-7-(4-methoxyphenyl)-3,4-dihydropyrrolo[l,2-a]pyrazine-2(1H) -carboxylate in 100 ml of methanol are added 6.29 ml (5.38 mmol) of chlorotrimethylsilane. After stirring for 19 hours, the solvent is evaporated off under reduced pressure and the évaporation residue is coevaporated several times with ethyl acetate to give 2.75 g of 8-carbamoyl-6-chloro-7-(4-methoxyphenyl)-1,2,3,4-dihydropyrrolo[1,2-a]pyrazine hydrochloride isolated by filtration, rinsing with ether and drying. The product is used as obtained in the rest of the synthesis.

Step 10.3._____N²-tert -Butyl- 6-chloro-7- ( 4-methoxyphenyl ) -

3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H) -dicarboxamide

O,

H.

<3

CH₃

Cl

To a solution, under nitrogen and at 0°C, of 1.55 g (4.53 mmol) of 8-carbamoyl-6-chloro-7-(4-methoxyphenyl)-

1,2,3,4-dihydropyrrolo[1,2-a]pyrazine hydrochloride in 70 ml of dichloromethane are added 1.89 ml (13.7 mmol) of triethylamine and 0.62 ml (5.44 mmol) of tert-butyl isocyanate. The mixture is stirred for three hours while allowing the température to return to room température, and water and 30 ml of dichloromethane are then added. The organic phase is separated out, washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on 40 g of silica gel, eluting with a mixture of 20 to 50% ethyl acetate in dichloromethane, to give 0.48 g of N^-tert-butyl-G-chloro-V(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)dicarboxamide in the form of a pale yellow solid after crystallizing from ethyl acetate and drying.

m.p.: 168-170°C ³H NMR (DMSO-dg) δ: 7.25 {d, 2H) ; 7.00 (d and broad s, 3H) ; 6.15 (s, 2H) ; 5.70 (broad s, 1H); 4.70 (s, 2H); 3.9 (m, 2H);

3.85 (s, 3H); 3.80 (m, 2H); 3.75 (m, 2H); 1.30 (s, 9H) ppm.

Example 11 (compound 2) : T^-tert-Butyl·-?-(4-methoxyphenyl)-

3,4-dihydropyrrolo[ 1,2-a]pyrazine-2,8(1H) -dicarboxamide

CH₃

A mixture of 1.20 g (2.96 mmol) of Af²-tert-butyl-6-chloro-7( 4-methoxyphenyl ) -3,4-dihydropyrrolo [ 1,2-a] pyrazine-2,8(1/1)dicarboxamide, 6.0 g (95 mmol) of ammonium formate and 0.22 g (0.10 mmol) of 10% palladium-on-charcoal containing 50% water in 80 ml of méthanol is refluxed for 6 hours. After cooling, the mixture is filtered through Celite and the Celite is rinsed with méthanol and dichloromethane. The filtrate is then concentrated under reduced pressure and the residue is taken up in dichloromethane. The solution is washed with water, dried over sodium sulfate and then concentrated under reduced pressure. The product is then purified by chromatography on a column of 70 g of silica gel, eluting with a mixture of 20 to 50% ethyl acetate in dichloromethane, to give 0.64 g of N²-tert-butyl-7-(4methoxyphenyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2, 8 ( IH) dicarboxamide in the form of a white solid after crystallizing from ethyl acetate and drying.

m.p.: 197-198°C

-94NMR (DMSO-dg) δ: 7.30 (d, 2H) ; 6.95 (d, 2H) ; 6.85 (broad s, 1H); 6.15 (s, 2H); 6.70 (s, 1H); 5.95 (broad s, 1H); 4.70 (s, 2H); 3.95 (m, 2H); 3.80 (s, 3H); 3.70 (m, 2H); 1.30 (s, 9H) ppm.

Exemple 12 (compound 36) : N²-tert-Butyl-6-cyclopropyl-7-(4methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)dicarboxamide

Step 12.1._____1-tert-Butyl 3-methyl 4-cyclopropanecarbonylpiperazine-1,3-dicarboxylate

O

To a solution cooled to 0°C of 10.0 g (35.6 mmol) of 1-tertbutyl 3-methyl piperazine-1,3-dicarboxylate hydrochloride (CAS 129799-08-2) in 350 ml of dichloromethane are added 11.0 ml (79.1 mmol) of triethylamine and then, over 35 minutes, 3.6 ml (40 mmol) of cyclopropylcarbonyl chloride dissolved in 50 ml of dichloromethane. The medium is stirred from 0°C to room température over 4 hours 30 minutes and is then washed with twice 40 ml of water and dried over sodium sulfate. The solvent is evaporated off under reduced pressure and the residue is chromatographed on a column of 90 g of silica gel, eluting with a mixture of 5 to 50% ethyl acetate in dichloromethane, to give 11.5 g 1-tert-butyl 3methyl 4-cyclopropanecarbonylpiperazine-l,3-dicarboxylate in the form of a viscous oil.

-95³Η NMR (DMSO-d₆ - 110°C) δ: 5.6 (m, 1H) ; 4.95 (broad d, 1H) ;

4.70 (m, 1H) ; 4.45 (m, 1H) ; 4.30 (s, 3H); 4.05 (s, 1H); 3.85 (dd, 1H); 3.60 (broad t, 1H) ; 2.5 (m, 1H); 2.0 (s, 9H); 1.4 (m, 4H) ppm.

Step 12.2. Sodium 1-tert-butyl 4-cyclopropanecarbonylpiperazine-1,3-dicarboxylate

O

To a solution of 11.5 g (36.8 mmol) of 1-tert-butyl 3-methyl

4-cyclopropanecarbonylpiperazine-l,3-dicarboxylate in

127.5 ml of methanol are added 1.77 g of sodium hydroxide dissolved in 22.5 ml of water. The mixture is stirred for 24 hours and the reaction medium is then concentrated under reduced pressure and the residue co-evaporated with toluene, to give 12.6 g of sodium 1-tert-butyl 4-cyclopropanecarbonylpiperazine-1,3-dicarboxylate in the form of a white powder after drying, and is used as obtained in the rest of the synthesis.

²H NMR (DMSO-de - 110°C) Ô: 4.50 (m, 1H); 4.35 (dd, 1H); 3.95 (m, 1H) ; 3.70 (m, 1H) ; 3.35 (broad s, 1H) ; 3.10 (m, 1H) ;

2.95 (m, 1H); 1.80 (m, 1H); 1.40 (s, 9H); 0.85-0.55 (m, 4H) ppm.

Step 12.3._____tert-Butyl 8-cyano-6-cyclopropyl-3,4-dihydrolff-pyrrolo[1,2-a]pyrazine-2~carboxylate (CAS 502933-77-9; WO 2003/024 967)

-96To a solution of 57.4 g (179 mmol) of sodium 1-tert-butyl 4cyclopropanecarbonylpiperazine-1,3-dicarboxylate in 900 ml of dichlorométhane are added 35.9 g (188 mmol) of tosyl chloride. After stirring for 20 minutes, 14.3 ml of chloroacrylonitrile (CAS 920-37-6) are added. After a further 20 minutes, 52.7 ml of triethylamine are added, while évolution of gas is observed at the start of the addition. Stirring is continued for 18 hours, and the solution is then washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on a column of 330 g of silica gel, eluting with a mixture of 80 to 0% cyclohexane, 20 to 95% dichlorométhane and 0 to 5% ethyl acetate, to give 10 g of an oil predominantly containing tert-butyl 8-cyano-6-cyclopropyl-3,4-dihydro-lH-pyrrolo[1,2-a]pyrazine-2-carboxylate (CAS 502933-77-9; WO 2003/024 967) and in minor amount tertbutyl 7-cyano-6-cyclopropyl-3,4-dihydro-l/f-pyrrolo [1,2-

a]pyrazine-2-carboxylate.

²H NMR (CDC1₃) Ô: 6.00 and 5.95 (s and s, 1H); 4.65 and 4.45 (s and s, 2H); 3.95 and 3.80 (m and m, 4H); 1.6 (m, IH); 1.4 (s, 9H); 1.1-0.75 (m, 3H); 0.55 (m, IH) ppm.

Step 12.4,_____tert-Butyl ____8-carbamoyl-6-cyclopropyl-3,4dihydro-lH-pyrrolo[1,2-a]pyrazine-2-carboxylate

To a solution of 9.8 g (34.1 mmol) of tert-butyl 8-cyano-6cyclopropyl-3,4-dihydro-lH-pyrrolo[1,2-a]pyrazine-2carboxylate (CAS 502933-77-9; WO 2003/024 967) and tertbutyl 7-cyano-6-cyclopropyl-3, 4-dihydro-lÎf-pyrrolo [1,2 —

a]pyrazine-2-carboxylate (502933-78-0; WO 2003/024 967) obtained during step 10.3. in 200 ml of methanol are added

8.6 ml (290 mmol) of aqueous 35 wt% sodium hydroxide and 8.0 ml (93 mmol) of 35% aqueous hydrogen peroxide solution four times every 2 hours, while the mixture is maintained at 45 °C. After 18 hours at this same température, the mixture is cooled and treated with 10.7 g (68 mmol) of sodium thiosulfate and 50 ml of water and then stirred for 1 hour. The solvent is partially concentrated and the reaction product is extracted with ethyl acetate. The organic phases are dried over sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on a column of 80 g of silica gel, eluting with a mixture of 5 to 50% ethyl acetate in dichloromethane, to give 2.82 g of tert-butyl 7carbamoyl-6-cyclopropyl-3,4-dihydro-lH-pyrrolo[1,2-

a]pyrazine-2-carboxylate and 4.82 g of tert-butyl 8carbamoyl-6-cyclopropyl-3,4-dihydro-lH-pyrrolo[1,2-

a]pyrazine-2-carboxylate after crystallizing from ethyl acetate and drying.

NMR (CDC1₃) δ: 5.95 (s, 1H); 5.45 (broad s, 2H); 4.95 [s, 2H) ; 4.05 (m, 2H); 3.90 (m, 2H); 1.7 (m, 1H) ; 1.50 (s, 9H);

0.90 (m, 2H); 0.60 (m, 2H) ppm.

Step

12.5.

tert-Butyl 7-bromo-8-carbamoyl-6-cyclopropyl-

3,4-dihydro~lE-pyrrolo[1,2-a]pyrazine-2-carboxylate

To a solution of 12.8 g (41.9 mmol) of tert-butyl 8-cyano-6cyclopropyl-3,4-dihydro-lH-pyrrolo[1,2-a]pyrazine-2carboxylate (CAS 502933-77-9; WO 2003/024 967) in 350 ml of dichloromethane cooled to between -30 and -35 °C are added portionwise 8.36 g (47.0 mmol) of N-bromosuccinimide (CAS 128-08-5) . After stirring for 1 hour at this same hL

-98température, water is added and the mixture is stirred until it has returned to room température. The organic phase is separated out and the solvent is evaporated off under reduced pressure. The solid residue is triturated in water, isolated by filtration, rinsed with water and dried in air. The solid is then purified by chromatography on a column of silica gel, eluting with a mixture of 10 to 50% ethyl acetate in dichloromethane, to give 11.8 g of tert-butyl 7bromo-8-carbamoyl-6-cyclopropyl-3, 4-dihydro-127-pyrrolo [1,2-

a]pyrazine-2-carboxylate in the form of a white solid after

crystallizing	from	a	minimum amount	of	ethyl acetate,
rinsing with diethyl	ether and drying.
m.p.: 162.1°C
^ςΗ NMR (CDC1₃)	Ô : 6	.85	(broad s, IH);	5.40	(broad s, IH);
5.00 (s, 2H) ;	4.05	(m,	2H) ; 3.90 (m,	2H) ;	1.55 (m and s,
10H) ; 1.10 (m,	2H) ;	0.85	(m, 2H) ppm.

Step 12.6._____tert-Butyl____8-carbamoyl-6-cyclopropyl-7- (4methoxyphenyl ) -3,4-dihydro-lH^,-pyrrolo [ 1,2-a ] pyrazine-2carboxylate

To a mixture of 3.00 g (7.81 mmol) of tert-butyl 7-bromo-8cyano-6-cyclopropyl-3,4-dihydro-lH-pyrrolo[1,2-a]pyrazine-2carboxylate, 1.54 g (10.2 mmol) of 4-methoxyphenylboronic acid (CAS 5720-07-0) and 7.63 g (23.4 mmol) of caesium carbonate in a mixture of 80 ml of tetrahydrofuran and 4 ml of water under argon is added 0.64 g (0.78 mmol) of 1,1'bis(diphenylphosphino)ferrocenedichloropalladium (II) (CAS 72287-26-4), and the mixture is heated at 100°C for 20 hours. After cooling, the mixture is diluted with ethyl acetate and filtered through Celite, the organic phase is ύ L·

-99washed with water, dried over sodium sulfate and filtered, and the solution is concentrated under reduced pressure. The residue is chromatographed on a column of 40 g of silica gel, eluting with a mixture of 20 to 50% ethyl acetate in dichloromethane, to give 1.51 g of tert-butyl 8-cyano-6cyclopropyl-7-(4-methoxyphenyl)-3,4-dihydro-lH-pyrrolo[1,2-

a]pyrazine-2-carboxylate in the form of a white solid after crystallizing from a minimum amount of ethyl acetate, rinsing with diethyl ether and drying.

m.p.: 181-182°C ^XH NMR (DMSO-dg) δ: 7.20 (d, 1H) ; 7.00 (d, 2H) ; 6.75 (broad s, 1H); 5.25 (broad s, 1H); 4.80 (s, 2H); 4.00 (m, 2H); 3.80 (m and s, 5H); 1.65 (m, 1H); 1.5 (s, 9H) ; 0.60 (m, 2H); 0.15 (m, 2H) ppm.

Step 12.7._____8-Carbamoyl-6-cyclopropyl-7- ( 4-methoxyphenyl)-1,2,3,4-dihydropyrrolo[1,2-a]pyrazine hydrochloride

To a solution of 1.47 g (3.57 mmol) of tert-butyl 8-cyano-6cyclopropyl-7-(4-methoxyphenyl)-3,4-dihydro-lH-pyrrolo[1,2-

a] pyrazine-2-carboxylate in 60 ml of methanol are added

2.7 ml (21 mmol) of trimethylsilyl chloride. After stirring for 20 hours, the solvent is evaporated off under reduced pressure and the residue is co-evaporated several times with ethyl acetate, to give 1.1 g of 8-carbamoyl-6-cyclopropyl-7-(4-methoxyphenyl)-1,2,3,4-dihydropyrrolo[1,2-

a]pyrazine hydrochloride in the form of a white solid after crystallizing from a minimum amount of ethyl acetate and drying. It is then used as obtained in the rest of the synthesîs.

m.p.: 267-271°C

-100*H NMR (DMSO-d₆) δ: 9.9 (broad s, 2H); 7.10 (d, IH); 6.90 (d, 2H) ; 6.80 (broad s, IH) ; 5.15 (broad s, IH) ; 4.35 (s, 2H) ;

4.10 (m, 2H); 3.80 (s, 3H) ; 3.50 (m, 2H); 1.55 (m, IH) ; 0.55 (m, 2H); 0.00 (m, 2H) ppm.

Step 12,8._____A^-tert-Butyl-6-cyclopropyl-7- (4-methoxyphenyl) -3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IH} dicarboxamide

To a solution of 0.25 g (0.72 mmol) of 8-carbamoyl-6-cyclopropyl-7-(4-methoxyphenyl)-1,2,3,4-dihydropyrrolo[1,2-

a]pyrazine hydrochloride in 30 ml of dichloromethane is added 0.25 ml (1.8 mmol) of triethylamine and then, at 0°C, 0.10 ml (0.86 mmol) of tert-butyl isocyanate. After stirring for 3 hours at 0°C, dichloromethane and water are added and the organic phase is then separated out, washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on a column of 12 g of silica gel, eluting with a mixture of 20 to 50% ethyl acetate in dichloromethane, to give 0.22 g of N²-tertbutyl-6-cyclopropyl-7-(4-methoxyphenyl)-3,4-dihydropyrrolo[ 1,2-a]pyrazine-2,8(IH) -dicarboxamide in the form of a white solid after crystallization from a minimum amount of ethyl acetate, rinsing with diethyl ether and drying.

m.p.: 177-179°C ^XH NMR (DMSO-dg) Ô: 7.10 (d, 2H) ; 6.90 (d, 2H) ; 6.60 (broad s, IH); 5.95 (s, IH); 5.20 (broad s, IH); 4.60 (s, 2H); 3.85 (m, 2H); 3.70 (s, 3H); 3.65 (m, 2H); 1.55 (m, IH); 1.20 (s, 9H); 0.55 (m, 2H); 0.05 (m, 2H) ppm.

bC

- 101 Example 13 (compound 36): N² -1 er t -Bu t y 1 - 6 - c y c 1 op r op y 1 - 7 (4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H) dicarboxamide

The synthesis of this compound has already been described in Example 12 via an alternative procedure.

Step 13.1._____7-Bromo-6-cyclopropyl-3,4-dihydropyrrolo[1,2-

a]pyrazine hydrochloride

To a solution under nitrogen of 6.34 g (16.5 mmol) of tertbutyl 7-bromo-8-carbamoyl-6-cyclopropyl-3,4-dihydro-lffpyrrolo[1,2-a]pyrazine-2-carboxylate in 120 ml of méthanol are added 10.5 ml of trimethylsilyl chloride. After reaction for 18 hours, the medium is concentrated under reduced pressure, the residue is taken up in toluene and the solvent is evaporated off under reduced pressure. 5.4 g of 7bromo-6-cyclopropyl-3,4-dihydropyrrolo[1,2-a]pyrazine hydrochloride are thus obtained in the form of a yellow powder.

m.p.: 240-241°C ¹H NMR (DMSO-dg) δ: 9.8 (broad s, 2H) ; 7.35 (broad s, 1H) ;

6.75 (broad s, 1H) ; 4.45 (s, 2H) ; 4.20 (τη, 2H) ; 3.55 (m, 2H) ; 1.65 (m, 1H); 1.00 (m, 2H); 0.70 (m, 2H) ppm.

Step 13.2.____ JJ^-tert-Butyl-Z-bromo-e-cyclopropyl-S, 4 dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide

-102-

To a mixture of 5.2 g (16.5 mmol) of 7-bromo-6-cyclopropyl-

3,4-dihydropyrrolo[1,2-a]pyrazine hydrochloride and 6.90 ml (49.5 ml) of triethylamine in 200 ml of dichloromethane at 0°C are added 2.1 ml (18 mmol) of tert-butyl isocyanate. After stirring for 2 hours, 50 ml of water are added and the product is extracted with dichloromethane. The organic phase is separated out, washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on a column of 70 g of silica gel, eluting with a mixture of 5 to 50% ethyl acetate in dichloromethane, to give 4.5 g of N²-tert-butyl-7-bromo-6cyclopropyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IH) dicarboxamide in the form of a white solid after crystallizing from a minimum amount of ethyl acetate, rinsing with diethyl ether and drying.

m.p.: 204-208°C ^XH NMR (DMSO-ds) δ: 6.95 (broad s, IH) ; 6.45 (broad s, IH) ;

5.85 (s, IH); 4.45 (s, 2H); 3.75 (m, 2H); 3.45 (m, 2H); 1.40 (m, IH); 1.15 (s, 9H); 0.75 (m, 2H); 0.50 (m, 2H) ppm.

Step 13.3._____N^-tert-Butyl-6-cyclopropyl-7- (4-methoxyphenyl)-3, 4-dihydropyrrolo[1,2-a]pyrazine-2,8 ( IH) dicarboxamide

To a mixture under nitrogen of 0.750 g (1.96 mmol) of N² tert-butyl-7-bromo-6-cyclopropyl-3,4-dihydropyrrolo[1,216268

-103-

a]pyrazine-2,8(1H) -dicarboxamide, 0.446 g (2.94 mmol) of 4methoxyphenylboronic acid (CAS 5720-07-0) and 5.8 ml (12 mmol) of aqueous 2M caesium carbonate solution in a mixture of 15 ml of toluene and 15 ml of éthanol under argon is added 0.64 g (0.78 mmol) of tetrakis(triphenylphosphine)palladium (CAS 14221-01-3), and the mixture is heated at 100°C for 17 hours. After cooling, the mixture is filtered through Celite and the filtrate concentrated under reduced pressure. The residue is then taken up in dichloromethane, the organic phase is washed with water, dried over sodium sulfate and filtered, and the solution is concentrated under reduced pressure. The residue is chromatographed on a column of 15 g of silica gel, eluting with a mixture of 10 to 100% ethyl acetate in dichloromethane, to give 0.19 g of N²-tert-butyl-6-cyclopropyl-7-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-

a] pyrazine-2,8 ( 1H)-dicarboxamide in the form of a white solid after crystallizing from a minimum amount of ethyl acetate, rinsing with diethyl ether and drying, and is identical to the compound obtained according to the procedure of Example 12.

Example 14 (compound 16) : A^-tert-Butyl-ô-cyclopropyl-V-( 3trifluoromethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine2,8(1H) -dicarboxamide

H.

F

To a mixture of 57.0 mg (0.300 mmol) of (3trifluoromethylphenyl)boronic acid and 76.7 mg (0.200 mmol) of A^-tert-butyl-ï-bromo-G-cyclopropyl-S,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H}-dicarboxamide in a reaction tube are

-104added 2 ml of tetrahydrofuran degassed beforehand under argon for 15 minutes and 63.6 mg (0.60 mmol) of disodium carbonate dissolved in 1 ml of water. The tube is then purged with argon, and about 16 mg (0.02 mmol) of a complex of 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) and dichloromethane (PdC12(dppf) -CH₂C12 - CAS 95464-054) suspended in 2 ml of tetrahydrofuran degassed beforehand under argon are added. The tube is then stirred at 70°C for 20 hours, the mixture is cooled and the solvent is evaporated off under reduced pressure. The residue is taken up in 5 ml of tetrahydrofuran and 100 mg of propanethiolgrafted silica (Si-Thiol, Biotage) are added. The mixture is stirred for 4 hours at room température and the grafted silica is separated out by filtration on a Celite cartridge, the Celite is washed twice with 1 ml of tetrahydrofuran and the filtrate is concentrated under reduced pressure. The residue is then purified by SPC purification, to give 0.017 g of ?7²-tert-butyl-6-cyclopropyl-7-(3-trifluoromethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IH) -dicarboxamide.

^ςΗ NMR (DMSO-de) ô: 7.60 (d, 3H) ; 6.90 (broad s, IH) ; 6.20 (broad s, IH) ; 6.10 (s, IH) ; 4.65 (s, 2H) ; 3.95 (m, 2H) ;

3.70 (m, 2H); 1.80 (m, IH); 1.30 (s, 9H); 0.7 (m, 2H); 0.00 (m, 2H) ppm.

Example 15 (compound 82): trans-6-Chloro(3-fluorophenyl)-N²(-[(4-hydroxycyclohexyl)-3,4-dihydropyrrolo[1,2-a]pyrazine2,8(IH) -dicarboxamide

-105To a solution of 0.480 g (4.17 mmol) of trans-4-aminocyclohexanol (CAS27489-62-9) in 10 ml of dichloromethane is added 0.84 g (4.17 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1), followed by addition of 1.36 g (2.52 mmol) of diisopropylethylamine. After 1 hour at room température, the solvent is stripped off by évaporation under reduced pressure and the residue is suspended in 21 ml of ethyl acetate. 1.00 g (3.42 mmol) of 6-chloro-7-(3-fluorophenyl)- l, 2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide and

0.90 g (0.70 mmol) of diisopropylethylamine are then added and the mixture is stirred for 30 minutes at reflux, to give a homogeneous solution. After cooling, the solvent is stripped off by évaporation under reduced pressure, the residue is then taken up in ethyl acetate and the solution is washed with aqueous sodium hydrogen carbonate solution and then with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. The residue is purified by two successive chromatographies on a column of silica gel, eluting with a mixture of 2 to 10% methanol in dichloromethane, to give 0.37 g of trans-6-chloro-(3—fluorophenyl)-N²-(-[(4-hydroxycyclohexyl)-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1H)-dicarboxamide in the form of a solid after recrystallizing from a mixture of methanol and diisopropyl ether and drying.

m. p.: 251-253°C *Η NMR (DMSO-dg) Ô: 7.45 (m, IH) ; 7.15 (m, 3H) ; 7.05 (bs,

IH) ; 6.50 (d, IH); 6.2 (broad s, IH); 4.80 (s, 2H); 4.45 (d, IH) ; 3.85 (m, 2H) ; 3.80 (m, 2H) ; 3.5 (m, 2H) ; 1.8 (m, 4H) ;

1.2 (m, 4H) ppm.

Example 16 (compound 96) : 6 - B r om o - -1 e r t - b u t y 1 - 7 - ( 3 fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IH)dicarboxamide

Vît

-106-

Step 16.1._____Ethyl_______ 4- ( 3-fluorophenyl) -lH-pyrrole-3carboxylate

To a suspension of 38.3 g (341 mmol) of potassium tertbutoxide at 60% in oil in 500 ml of anhydrous tetrahydrofuran is added dropwise a mixture of 55.2 g (284 mmol) of ethyl (E)-3-(3-fluorophenyl)acrylate (CAS 166250-00-6) and 55.5 g (284 mmol) of tosylmethyl isocyanide (CAS 36635-61-7) dissolved in 500 ml of tetrahydrofuran, while maintaining the température of the reaction medium at about 25°C. The mixture is then stirred for 1 hour 30 minutes at room température. The mixture is then poured into saturated aqueous solution and the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give a brown solid, which is chromatographed on a column of silica gel, eluting with dichloromethane, to give 40.7 g of ethyl 4-(3-fluorophenyl)lH-pyrrole-3-carboxylate, in the form of a white powder

after triturating in diisopropyl ether, filtering	off	and
drying.
m.p. : 120-122°C
³H NMR (CDC1₃) δ: 8.55 (broad s, 1H); 7.50 (d, 1H);	7.3	(m,
3H); 7.00 (m, 1H); 6.80 (d, 1H); 4.25 (q, 2H); 1.30	(t.	3H)

ppm.

-107Step 16.2._____Ethyl 5-bromo-4- (3-fluorophenyl) -lR-pyrrole-

3-carboxylate

Br

To a solution of 38.3 g (164 mmol) of ethyl 4-(3-fluorophenyl )-lH-pyrrole-3-carboxylate in 380 ml of tetrahydrofuran are added, over 30 minutes, 32.1 g (181 mmol) of W-bromosuccinimide (CAS 128-08-5), and the mixture is then stirred for 3 hours at reflux. After cooling, 200 ml of aqueous 5% sodium thiosulfate solution are added and the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give 17.1 g of ethyl 5-bromo-4-(3-fluorophenyl)-l#-pyrrole-

3-carboxylate in the form of a white powder after recrystallizing from diisopropyl ether, filtering off and drying.

m.p. : 114-117°C ¹H NMR (CDC1₃) δ: 8.55 (broad s, 1H) ; 7.50 (s, 1H) ; 7.35 (m, 1H); 7.20 (m, 1H); 7.05 (m, 1H); 4.20 (q, 2H); 1.20 (t, 3H) ppm.

Step 16.3.

Ethyl 1-(2-tert-butoxycarbonylaminoethyl)-5bromo-4-(3-fluorophenyl)-l#-pyrrole-3-carboxylate

CH, O ^H3^C4 X ³ H

F

- 108To a solution of 39.6 g (127 mmol) of ethyl 5-bromo-4-(3fluorophenyl)-lH-pyrrole-3-carboxylate in 275 ml of acetonitrile are added 10.1 g (253 mmol) of powdered sodium hydroxide and 1.7 g (5.1 mmol) of tetrabutylammonium hydrogen sulfate, and the mixture is stirred vigorously for a few minutes, followed by adding 34.1 g (152 mmol) of (2tert-butyl bromoethyl)carbamate (CAS 39684-80-5), and the mixture is then stirred for 17 hours at reflux. After cooling, the solvent is evaporated off under reduced pressure and the residue is taken up in ethyl acetate. The solution is washed with saturated aqueous sodium chloride solution, the organic phase is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give a brown oil, which is crystallized from diisopropyl ether, to give 43 g of ethyl l-(2-tertbutoxycarbonylaminoethyl) -5-bromo-4- (3-fluorophenyl) -1Hpyrrole-3-carboxylate in the form of a beige-coloured powder after filtering off and drying.

m.p.: 108-110°C ³H NMR (CDC1₃) 5: 7.50 (s, 1H) ; 7.35 (m, 1H) ; 7.15 (m, 1H) ;

7.10 (m, 1H) ; 7.05 (m, 1H) ; 4.70 (broad s, 2H) ; 4.15 (m, 4H); 3.50 (m, 2H); 1.50 (s, 9H); 1.2 (t, 3H) ppm.

Step 16.4._____Ethyl_____6-chloro-7- (3-fluorophenyl) -1,2,3,4tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate

HN

Cl

To a solution of 38.4 g (84.3 mmol) of ethyl l-(2-tertbutoxycarbonylaminoethyl)-5-bromo-4-(3-fluorophenyl)-1Hpyrrole-3-carboxylate in 80 ml of éthanol are added slowly 271 ml (949 mmol) of aqueous 3.5N hydrochloric acid 'fit16268

-109 solution. The formation of a observed and then, after 45 clear, while the mixture is white precipitate is rapidly minutes, the medium becomes heated to 70°C, and 3.00 g (31.2 mmol) of paraformaldéhyde are added. Heating is continued at 70°C for 1 hour. After cooling, the reaction medium is poured into a mixture of ice and aqueous 4N sodium hydroxide solution, The product is extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give a brown oil, which is chromatographed on a column of 330 g of silica gel, eluting with a mixture of 3% méthanol in dichloromethane, to give 14.3 g of ethyl 6 chloro-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-

a]pyrazine-8-carboxylate after crystallizing from 50 ml of diisopropyl ether.

m.p.: 96-98°C ^XH NMR (DMSO-dg) Ô: 7.40 (m, IH) ; 7.1 (m, 3H) ; 4.10 (s, 2H) ;

4.05 (q, 2H); 3.80 (t, 2H); 3.15 (t, 2H); 2.8 (broad s, IH);

1.1 (t, 3H) ppm.

Step 16.5.

2-terf-Butyl

8-ethyl

6-chloro-7-(3fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IH)dicarboxylate

To a solution of 12.7 q (34.7 mmol) of ethyl 6-chloro-7-(3 fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carboxylate in 150 ml of dichloromethane are added slowly

7.95 g (36.4 mmol) of di-tert-butyl dicarbonate (CAS 24424

99-5) dissolved in dichloromethane. After stirring for minutes at room température, the solvent is evaporated

-110off under reduced pressure, to give an orange-coloured oil, which is purified by chromatography on a column of 220 g of silica gel, eluting with a mixture of 15% ethyl acetate in cyclohexane, to give 17.0 g of 2-tert-butyl 8-ethyl 6chloro-7-(3-fluorophenyl)-3,4-dihydropyrrolo[l,2-a]pyrazine2,8(1H)-dicarboxylate in the form of a pale yellow oil, which is crystallized from 60 ml of hexane, to give 14.2 g of a beige-coloured powder.

m.p.: 84-86°C ²Η NMR (DMSO-dg) δ: 7.45 (m, 1H) ; 7.15 {m, 3H) ; 4.80 (s, 2H) ; 4.05 (q, 2H); 3.95 (m, 2H); 3.80 (m, 2H) ; 1.50 (s, 9H); 1.10 (t, 3H) ppm.

Step 16.6.__2-tert-Butyl 8-ethyl 7-( 3-fluorophenyl)-3,4dihydropyrrolo [ 1,2-a ] pyrazine-2,8 ( 1/f) -dicarboxylate

A mixture of 6.00 g (14.2 mmol) of 2-tert-butyl 8-ethyl 6chloro-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine2,8(1H)-dicarboxylate, 13.4 g (212 mmol) of ammonium formate (CAS 540-69-2) and 0.6 g of 10% palladium-on-charcoal containing 50% water in 50 ml of methanol is stirred at reflux for 45 minutes. After cooling, the mixture is filtered through a Büchner funnel and the filtrate is concentrated under reduced pressure. The residue is taken up in ethyl acetate, the solution is washed with aqueous 2N sodium hydroxide solution and then dried over sodium sulfate, and the solvent is evaporated off under reduced pressure, to give 5.5 g of 2-tert-butyl 8-ethyl 7-(3fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IR) dicarboxylate in the form of a yellow oil.

bc

-111 ^yH NMR (DMSO-de) δ: 7.35 (m, 1H) ; 7.20 (m, 2H) ; 7.05 (m, 1H) ;

7.00 (s, 1H) ; 4.80 (s, 2H); 4.05 (q, 2H); 4.00 (m, 2H); 3.85 (m, 2H); 1.45 (s, 9H); 1.20 (t, 3H) ppm.

Step 16.7._____2-tert-Butyl_____8-ethyl 6-bromo-7-(3fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H) dicarboxylate

To a solution of 2.00 g (5.15 mmol) of ethyl 7—(3— fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carboxylate in 12 ml of tetrahydrofuran are added portionwise 1.01 g (5.66 mmol) of N-bromosuccinimide (CAS 128-08-5) over 30 minutes. After stirring for 1 hour at room température, the mixture is poured into water and the product is extracted with ethyl acetate. The solution is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give 2.4 g of 2-tert-butyl 8ethyl 6-bromo-7-(3—fluorophenyl)-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1H)-dicarboxylate in the form of a yellow oil.

²H NMR (DMSO-d₆) δ: 7.50 (m, 1H) ; 7.15 (m, 1H) ; 7.05 (m, 2H) ;

4.80 (s, 2H) ; 4.05 (m, 2H); 3.95 (m, 2H); 3.80 (m, 2H); 1.45 (s, 9H); 1.05 (t, 3H) ppm.

Step 16.9._____2-(tert-Butoxycarbonyl)-6-bromo-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carboxylic acid

-112 -

To a suspension of 2.41 g (5.16 mmol) of 2-tert-butyl 8ethyl 6-bromo-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1H)-dicarboxylate in 18 ml of éthanol are added 10.3 ml (10.3 mmol) of IN sodium hydroxide solution and the mixture is heated at 70°C for 2 days. The mixture is then taken up in dichloromethane and acidified by addition of 25 ml of aqueous IN sulfuric acid. The organic phase is separated out and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure, to give a yellow solid, which is purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of 4% methanol in dichloromethane, to give 1.65 g of 2-(tert-butyloxycarbonyl)-6-bromo-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo [ 1,2-a ] pyrazine-8-carboxylic acid in the form of a pale yellow powder.

m.p.: 199-201°C ¹H NMR (DMSO-dg) δ: 12.0 (broad s, 1H) ; 7.4 (m, 1H) 7.1 (m, 3H); 4.80 (s, 2H); 3.95 (m, 2H); 3.80 (m, 2H); 1.45 (s, 9H) ppm.

Step 16.10.____tert-Butyl 6-bromo-7- (3-fluorophenyl) -8- ( 1Himidazol-l-ylcarbonyl)-3,4-dihydropyrrolo[1,2-a]pyrazine2(1#) -carboxy la te

Br

To a solution of 1.87 g (4.27 mmol) of 2-(tertbutyloxycarbonyl)-6-bromo-7-(3-fluorophenyl)-1,2,3,4

-113tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid in 10 ml of tetrahydrofuran is added 0.831 g (5.12 mmol) of carbonyldiimidazole (CAS 530-62-1). After reaction for 1 hour at 50°C, the mixture is cooled and taken up in water, and the product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give a yellow oil, which crystallizes from 25 ml of diisopropyl ether, to give

l. 82 g tert-butyl 6-bromo-7-(3-fluorophenyl)-8-(lH-imidazol-

1-ylcarbonyl) -3, 4-dihydropyrrolo [ 1,2-a] pyrazine-2 ( 1/7) carboxylate in the form of a beige-coloured powder.

m. p.: 168-169°C ^TH NMR (DMSO-d_e) Ô: 7.75 (s, 1H); 7.35 (s, 1H); 7.25 (m, 1H) ; 7.0 (m, 3H); 6.75 (s, 1H); 4.70 (s, 2H); 4.05 (m, 2H); 3.85 (m, 2H); 1.45 (s, 9H) ppm.

Step 16.11, tert-Butyl 8-carbamoyl-6-bromo-7-(3-fluorophenyl) -3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H) -carboxylate

Br

To 1.79 g (3.66 mmol) of tert-butyl 6-bromo-7-(3fluorophenyl) -8- (1/7-imidazol-l-ylcarbonyl) -3,4-dihydropyrrolo [ 1, 2-a] pyrazine-2 ( 177)-carboxylate in an autoclave are added 30 ml of 33% aqueous ammonia. The mixture is stirred for 5 hours 30 minutes at 90°C and, after cooling, is then poured into water, to give 1.26 g of tert-butyl 8carbamoyl-6-bromo-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2a ] pyrazine-2 ( 1/7)-carboxylate after drying over potassium hydroxide.

m.p.: 168-174°C

-114 ³H NMR (DMSO-de) δ: 7.50 (m, IH) ; 7.20 (m, 3H) ; 7.05 (broad s, IH); 6.00 (broad s, IH); 4.75 (s, 2H); 3.95 (m, 2H); 3.80 (m, 2H); 1.45 (s, 9H) ppm.

Step 16.12. 6-Bromo-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide

HN

Br

To a solution of 1.24 g (2.83 mmol) of tert-butyl 8carbamoyl-6-bromo-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-

a]pyrazine-2(IH)-carboxylate in 10 ml of dichloromethane are added slowly 2.8 ml (28 mmol) of trifluoroacetic acid. After stirring for 1 hour at room température, the solvent is evaporated off under reduced pressure, the residue is taken up in water and the aqueous phase is basified by addition of aqueous ammonia. The solid formed is separated out by filtration and rinsed with water, to give 0.92 g of 6bromo-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-

a]pyrazine-8-carboxamide in the form of a beige-coloured powder after drying under reduced pressure in the presence of potassium hydroxide.

m.p.: 216-218°C ^XH NMR (DMSO-d₆) Ô: 7.35 (m, IH) ; 7.05 (m, 3H) ; 6.80 (broad s, IH); 6.00 (broad s, IH); 3.95 (s, 2H); 3.65 (t, 2H); 3.00 (t, 2H) ppm.

Step 16.13.____6-Bromo-A/²- ( tert-butyl )-7-( 3-fluorophenyl ) -

3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IH) -dicarboxamide

-115-

To a suspension of 0.24 g {0.71 mmol) of 6-bromo-7- (3fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carboxamide is added 0.30 ml (2.13 mmol) of triethylamine and then, at 0°C, 0.10 ml (0.85 mmol) of tert-butyl isocyanate. After reaction for 1 hour at room température, the mixture is treated with aqueous IN sodium hydroxide solution and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of 4% méthanol in dichloromethane, to give 0.16 g of 6-bromo-7-(3fluorophenyl)-ff-(tert-butyl)-3, 4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1H)-dicarboxamide in the form of a powder after recrystallization from 10 ml of acetonitrile, filtering and drying under reduced pressure.

m.p.: 184-189°C ³H NMR (DMSO-de) Ô: 7.45 (m, 1H) ; 7.15 (m, 3H) ; 7.00 (broad s, 1H) ; 6.15 (broad s and s, 2H); 4.80 (s, 2H); 3.90 (m,

2H); 3.75 (m, 2H); 1.30 (m, 9H) ppm.

Example 17 (compound 97): W²-(tert-Butyl)-6-cyano-7-(3f luorophenyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2,8 (1/f) dicarboxamide

-116Step 17.1. 2-tert-Butyl 8-ethyl 6-cyano-7-(3-fluorophenyl)-

3,4-dihydropyrrolo[1,2-a]pyrazine-2,8 (1H)-dicarboxylate

To a solution, under argon and cooled to 10 °C, of 2.52 g (6.49 mmol) of 2-tert-butyl 8-ethyl 7-(3-fluorophenyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(17/)-dicarboxylate in 20 ml of dichloromethane is added dropwise 0.62 ml (7.14 mmol) of chlorosuifonyl isocyanate (CAS 1189-71-5) and the mixture is left stirring at 0°C for 1 hour. 3.3 ml (65 mmol) of dimethylformamide are then added dropwise to the mixture, cooled to -10°C. After stirring for 5 hours at room température, the mixture is poured into 60 ml of aqueous IN sodium hydroxide solution and the product is extracted with dichloromethane. The solution is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give a yellow oil, which is chromatographed on a column of 80 g of silica gel, eluting with a mixture of 20% ethyl acetate in cyclohexane, to give 1.24 g of 2-tert-butyl 8ethyl 6-cyano-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8 (1JZ)-dicarboxylate in the form of a white powder after crystallizing from diisopropyl ether, filtering off and drying.

m.p.: 129-131°C ⁷H NMR (DMSO-dg) δ: 7.6-7.2 (m, 4H) ; 4.84 (s, 2H) ; 4.2 (m, 2H); 4.10 (q, 2H); 3.83 (m, 2H); 1.45 (s, 9H); 1.10 (t, 3H) ppm.

-117Step 17.2._____2-(tert-Butoxycarbonyl)-6-cyano-7-(3-fluorophenyl )-1,2,3,4-tetrahydropyrrolo[1, 2-a]pyrazine-8carboxylic acid

To a suspension of 1.24 g (3.00 mmol ) of 2- tert-butyl 8ethyl 6-cyano-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2—

a]pyrazine-2,8 ( 1H) - dicarboxylate in 15 ml of a mixture of éthanol, water and tetrahydrofuran (1:1:1) is added 0.086 g (3.6 mmol) of lithium hydroxide, and the mixture is heated at 60°C for 1 day. The mixture is then taken up in 60 ml of dichloromethane and is acidified by addition of aqueous IN sulfuric acid. The organic phase is separated out and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give a solid, which is triturated in acetonitrile to give 1.07 g of 2-{tert-butyloxycarbonyl)-6cyano-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-

a]pyrazine-8-carboxylie acid in the form of a white powder. m.p.: > 210°C ³H NMR (DMSO-de) δ: 12.5 (broad s, 1H); 7.45 (m, 1H) 7.25 (m, 3H) ; 4.83 (s, 2H); 4.12 (m, 2H); 3.82 (m, 2H); 1.45 (s, 9H) ppm.

Step 17.3.______tert-Butyl 6-cyano-7-(3-fluorophenyl)-8-(ltfimidazol-l-ylcarbonyl)-3,4-dihydropyrrolo[1,2-a]pyrazine (1H) -carboxylate

-118-

To a solution of 1.21 g (3.14 mmol) of 2-(tertbutyloxycarbonyl)-6-cyano-7-(3-fluorophenyl)-1,2,3,4tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid in 10 ml of tetrahydrofuran is added 0.560 g (3.45 mmol) of carbonyldiimidazole (CAS 530-62-1). After reaction for 1 hour 30 minutes at 60°C, the mixture is cooled and taken up in water, and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give a yellow oil, which is chromatographed on a column of 24 g of silica gel, eluting with a mixture of 3% methanol in dichloromethane, to give 1.35 g of tert-butyl 6-cyano-7-(3fluorophenyl)-8-(lH-imidazol-1-ylcarbonyl)-3,4-dihydropyrrolo [1,2-a] pyrazine-2 ( 1/7)-carboxylate in the form of a white f oam.

^XH NMR (DMSO-de) Ô: 7.64 (s, IH) ; 7.3-6.9 (m, 5H) ; 6.84 (m, IH); 4.90 (s, 2H); 4.23 (m, 2H); 4.00 (m, 2H); 1.51 (s, 9H) ppm.

Step_____17.4.______tert-Butyl______8-carbamoyl-6-cyano-7- (3fluorophenyl) - 3, 4-dihydropyrrolo [ 1,2-a] pyrazine-2 ( 1/7) carboxylate

-119 Το 1.35 g ¢3.10 mmol) of tert-butyl 6-cyano-7-(3fluorophenyl)-8-(IH-imidazol-l-ylcarbonyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in an autoclave are added 10 ml of 30% aqueous ammonia. The mixture is stirred for 1 hour at 50°C and, after cooling, is poured into 60 ml of water, to give 1.05 g of tert-butyl 8-carbamoyl-6cyano-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine2 (lif)-carboxylate after drying over potassium hydroxide. m.p.: 208-210°C ^ΧΗ NMR (CDC13) δ: 7.6-7.1 (m, 4H); 5.20 (broad s, 2H) ; 5.00 (s, 2H); 4.14 (m, 2H); 3.93 {m, 2H); 1.52 (s, 9H) ppm.

Step 17.5. 6-Cyano-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide

To a solution of 1.05 g (2.73 mmol) of tert-butyl 8carbamoyl-6-cyano-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-

a] pyrazine-2 {1JZ) -carboxylate in 10 ml of dichloromethane are added slowly 2.7 ml (27 mmol) of trifluoroacetic acid. After stirring for 1 hour at room température, the solvent is evaporated off under reduced pressure, the residue is taken up in water and the aqueous phase is basified by addition of aqueous ammonia. The solid formed is separated out by filtration and rinsed with water, to give 0.71 g of 6cyano-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-

a]pyrazine-8-carboxamide in the form of a white powder after drying under reduced pressure.

m.p.: 195°C (décomposition) ¹H NMR (DMSO-dg) δ: 7.5 (m, 1H) ; 7.25 (m, 3H) ; 6.80 (broad s, 1H); 4.02 (s, 2H); 3.96 (t, 2H); 3.10 (t, 2H) ppm.

H

-120Step 17.6._____Λ/²- ( tert-Butyl) -6-cyano-7- (3-fluorophenyl) -

3, 4-dihydropyrrolo [1,2-a] pyrazine-2,8(1#) -dicarboxamide

H.

To a suspension of 0.50 g (0.53 mmol) of 6-cyano-7-(3fluorophenyl)-1,2,3,4-tetrahydropyrrolo[ 1,2-a]pyrazine-8carboxamide is added 0.07 ml (0.6 mmol) of tert-butyl isocyanate. After reaction for 2 hours at room température, the solvent is evaporated off under reduced pressure and the solid residue is recrystallized from acetonitrile, to give 0.16 g of 6-cyano-7-(3-f luorophenyl)-TV²-( tert-butyl )-3,4dihydropyrrolo11,2-a]pyrazine-2,8(IH)-dicarboxamide in the form of a white powder after filtering off and drying under reduced pressure.

m.p.: > 217°C ³H NMR (DMSO-d₆) δ: 7.6 and 7.3 (m and m, 4H) ; 6.95 (broad s, IH); 6.25 (s, IH); 4.75 (s, 2H); 4.10 (m, 2H); 3.85 (m, 2H); 1.33 (m, 9H) ppm.

Example 18 (compound 86): 6-Chloro-7-(3-f luorophenyl)-A/²-[4[ (1,1-dimethylethoxy)imino]cyclohexyl]-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IH) -dicarboxamide

Step 18.1. 4-Nitrophenyl [4-[(1,1-dimethylethoxy)imino]cyclohexyl]carbamate

-121 To a suspension of 1.15 g (5.16 mmol) of [4—[(1,1— dimethylethoxy)imino]cyclohexyl]amine hydrochloride (CAS 701249-71-0} in 30 ml of dichloromethane cooled to about 0°C are added 1.15 g (5.68 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1). 1.58 ml (11.4 mmol) of diisopropylethylamine are then added portionwise. Stirring is continued at 0°C for 2 hours and the mixture is then allowed to warm to room température and is stirred for a further 2 hours. The solvent is then partially evaporated off under reduced pressure to a volume of about 8 ml. This solution is chromatographed on a column of 4 0 g of silica gel, éluting with a dichloromethane/ethyl acetate mixture (100/0 to 50/50), to give 1.19 g of 4-nitrophenyl [4—[ (1, 1 — dimethylethoxy)imino]cyclohexyl]carbamate in the form of a white solid.

m.p.: 132.4°C

NMR (CDC1₃) δ: 8.20 (d, 2H) ; 7.25 (d, 2H) ; 4.95 (broad s, IH) ; 3.75 (broad s, IH) ; 3.15 (m, IH) ; 2.45 (m, IH) ; 2.25-

1.90 (m, 4H); 1.55-1.30 (m, 4H); 1.20 (s, 9H) ppm.

Step 18.2._____6-Chloro-7-(3-fluorophenyl)-ff-[4-[(1,1 dimethylethoxy)imino]cyclohexyl]-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(IH)-dicarboxamide

A suspension of 0.27 (0.82 mmol) of 6-chloro-7-(3fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8carboxamide hydrochloride, 0.37 g (1.06 mmol) of 4nitrophenyl [4-[(1,1-dimethylethoxy)imino]cyclohexyl]carbamate and 0.33 g (2.45 mmol) of sodium carbonate in 30 ml of acetonitrile is heated at 60°C for 3 hours. After

-122cooling, the mixture is poured into water and the product is extracted with dichloromethane. After drying over sodium sulfate and filtration, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of dichloromethane/ethyl acetate (60/40 to 20/80), to give 0.18 g of 6-chloro-7-(3-fluorophenyl)-A?²-[4[(1,1-dimethylethoxy)imino]cyclohexyl]-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1#)-dicarboxamide in the form of a yellowish powder, after evaporating the fractions down to a small volume of solvent, filtering off the crystallized product, washing with ethyl acetate and drying under reduced pressure.

m.p.: 195-198°C

²Η NMR (DMSO-dg) Ô: 7.45 (m, 1H); 7.2 (m,	3H); 7.05	(broad s,
ih:	) ; 6.55 (d,	1H)	; 6.20 (broad	s, 1H) ;	4.70 (s,	2H); 3.90
(m	, 2H) ; 3.75	(m,	2H+1H); 3.00	(m, 1H) ;	2.30 (m,	1H) ; 2.15

(m, 1H); 2.00-1.80 (m, 3H); 1.50-1.25 (m, 2H); 1.20 (s, 9H) ppm.

Table 1 below illustrâtes the chemical structures and the physical properties of a number of compounds according to the invention.

In this table :

- the m.p. °C column gives the melting points of the products in degrees Celsius. N.D means that the melting point is not determined,

- the m/z column gives the molecular ion (M+H⁺) or (M-H“) observed on analysis of the products by LC-MS.

Λ.	LJ	fo	J—¹	K O
tert-butyl	tert-butyl	CT (B h rt 1 tr c CT 1—·	rr CD H CT 1 σ b rt *< 1-·	£
methyl	methyl	tr 0. H O tQ Φ b	hydrogen	£
4-methoxy- phenyl	Ό ρω P t-·	4-methoxy- phenyl	phenyl	JO «q
				3 $ 3
384.477	354.451	370.45	340.425	¹
-—· LJ S œ + Cn X +	— ω K + en X +	^; 371 (M+H⁺)	to Ξ ω + <o π >	8 x N
I—¹σι 1 h-¹ 0Ί	h-¹CO -J i h-¹CO	197-198	156-158	B ? « Q

T.'Z.

124

12	11	10	co	co	-J	Ch	CD
tert-butyl	tert-butyl	tert-butyl	μto O 1 σ c rt k—¹	μto O 1 TJ hf O TJ t-·	μ. to O TJ ht O TJ I—·	O Q kO 1 TJ ht O TJ ·< h-·	tert-butyl
n Q l·O 1 TJ H O TJ t—¹	o ·< Q kO 1 TJ M O TJ < t-·	o c O k-. o 1 TJ h! O TJ I-*	O O k- O TJ O TJ I-*	O ·< O kO 1 TJ ht O TJ !-	3 Ω O TJ ht O TJ 1—·	s O h-i O TJ ht O TJ »< 1—'	3 (D etX t-¹
4-methylphenyl	3-methylphenyl	TJ X (D t> h->	Ό tr fD y <->	4-methoxy- phenyl	TJ tr n> t» ·< 1—¹	4-methoxy- phenyl	: 4-phenoxyphenyl
1.22 (A)	> ’ — h-¹ Cn				K> O * k£>
394.516	CO kP kU en H¹Ch	to co O œ kP	Cü CO O CO VP	CO ÎÛ Ch CD CO	CO Ch ΟΊ o> bJ	CO CP kU k£> -J K>	kU Ch CD kCh 00
-—· co 2 ^p 4- cji :x +	Gü Z w + tn X +	ω Z œ + H* X +	co S co + H rc +	Gü Z + -J X +	GJ Z OT + -J X +	395 (M+H⁺)	J? Z + -J X +
		N) bD GJ t bD ro CH	h* --j uj * M -J en	ro 1—‘ ro i bD H* LH		bD co H* 1 bJ to	bD O -J 1 bD O

125

Μ	I—¹	H»	I-¹		1—‘	H¹	h-¹
ο	cd	CO	-J	en	en	rU	CO
rt	rt	rt	rt	rt	rt	rt	rt
φ	Φ	Φ	Φ	(B	Φ	n>	Φ
Η	H	h	•Ί	h	H	H	h
rt	rt	rt	rt	n-	rt	et	rt
I	t	\|	1	1	t	i	l
σ	tr	tr	tr	tr	σ	σ	tr
e	c	c	c	c	c	c	c
rt	rt	rt	et	rt	r+	rt	rt
'C	^l<	*<	“<	><	k<
H	f—·	M	H*	1—¹	w	M	\|—¹
Ο	b	o	b	b	0	n	,0
*<	‘C	*c	‘c	*<
η	b	Cl	b	b	b	b	b
	μ-	μ-J	μ-j	S~j	K-»	l·-	h-.
ο	o	o	o	o	o	o	O
TS	Ό	Ή	TS	T5	TS	TS	TS
H	H	H\|	H	H	n	H	H
Ο	O	o	O	O	o	O	O
Ό	Ό	TS	TS	TS	Ό	Ό	TS
		‘C	·<	<	<	ec	ec
I—¹	t—¹	1—*	1-*	H*	I—¹	J—¹	h-¹
TS Ω 3	Ό H ¢.	στι 4?	TS Ω w	5 co	tr	X u?	TS 4?
X φ <ο ι	X i Ti t	Φ H \|	tr i*> t	ro i	H*	ro i	X 1
φ n r+ --	Φ Ω *<	3 ο n	φ k Q.	rt rt	Ό	x b	O H-
ss σ χ 3	ss a> k	Ο TS ‘C	s tr h-	x n	tr	ec k;	Π ω
< Φ < φ	H bj	ki Q	< w 3	1< H-	ro	ι-- n	!< o
W 3 Η ft	h σ o	t-¹ 1—’	H* 3 Φ	1—’ l-h	SS	i r?	t—¹ TS
b i b	O V	ι η o	O rt-	( 1—¹	k<	TS O	n
< o	n h*	Ό £U t	*< tr	TS C	1—¹	X 1	o
I—¹ X	*< P·	X K		tr o	1	Φ	Ό
— I<	j-j _H.	Φ 1	! H	Φ H		b	·<
I I	— b	b	I	SS O	l	ec	h-¹
	1 Φ	t:		k: i		w	l
	¹				M
—. I—1	—. t—¹	—. h-*	— 1—¹	— H»	n. 1—¹	1—¹	. 4—¹
> ·	> ·	> ·	>	> *	> ·	> ·	> ·
ro	FO	— \|_l	— [U	ro	*-- o	— N>	— î—¹
O	en			CO	CD	CD	M
					►U	rU	kCi
CTi	-j	en	tn	Æx	en	en	ru
’-J	•o	CO	H¹	GO	en	ro	M
*	*	•	«	•	V	♦	V
CJi	en	<_n	en		Ch	en	en
O)	o	-J	en	GO	00	co	Ό
	en	to	œ	en	-J
		π	4s		H—. Æh	. Æ>	. rU
2 σ>	2 -J	2 en	2 tn	2	2 en	2 σ>	2 ro
+ 00	+ œ	+	+ FO	+ u>	+ -J	+ ω	+ ω
x	X	SC	SC	X	X	x	X
+	+	+	+	4-	+	+	+

tK

126

kj	KJ	KJ	KJ	KJ	KJ	KJ	KJ
oo	-J	o>	CB	►to	CO	M	TO
η	rr	et	et	rr	rt	rr	rt
(h	ffi	(D	CD	CD	CD	CD	CD
h	h	3	3	3	3	3	3
rt	rr	rr	et	et	CT	n-	CT
tr	tr	e>-	t>-	tr	tr	σ	tr
c	c	c	c	c	a	c	c
et	et	rt	rt	rr	rt-	rr	et
3:	3:	3	3	3	3	3	3
TO	i-*	TO	TO	H*	TO	TO	TO
Ω	O	Q	n	Q	Q	Ω	Ό
·<	3:	3;	3:	•c	3:	3:	3;
n	O	Ω	o	O	Ω	o	o
h-	TO	TO	TO	TO	TO	r-	M
O	O	O	o	o	o	o	O
TJ	TJ	TJ	TJ	TJ	TJ	TJ	TJ
M	3	n	3	3	3	3	3
O	O	O	o	O	O	o	O
TJ	TJ	TJ	TJ	TJ	TJ	TJ	TJ
3.		3	3	3	3	3	3
TO	1—*	to	b-*	TO	TO	TO	TO
w os	·< UJ	¢) ω GJ	3 3	£3 *K-	TJ £L —. J=·	TJ	TJ GJ
3 i	h—¹ 1	3 C i	f—¹ W	(D 1	3 p- h l	P* 1	rr i
h- CL	1 TJ	H- 1—· —·	TJ	rr rt	CD W · —	CD O	φ n
3 H-	TJ <	3 H, ~	3*	3* H	3 N GJ en	3	3 <<
0 s	rr n	o îu a	et	3	3 0- 1	3 W	3 w
1 (D	CD w	— 3 H-	3*	1—¹ Hl	TO TO 4^ £2	H 3	h-* 3
TJ rr	rt n	TJ O 3	d>	t 1—¹	1 — CD	O	o
rr rr	3 O	rr>< Φ	1—·	TJ C	M O rt	1	I
(D »<	H· H·	(D H tt	n>	rr o	i x rr
3 H·	1	3 — rr	3	(D K	3 û> 3
3: i	TO	3 1 3	1	3 O	1— 1 i—
TO	1	h-¹ 3*	KJ	3 1	—' 1
		1	1	TO	1
TO	—- TO	n. TO	h-¹	— TO	— o	— TO	--- H*
> '	> ·	> ·	> ·	w ·	> -	> ·	> ·
—- f_l	— KJ	— KJ	' KJ	— TO	— CD	— KJ	—· KJ
O	CO	TO	«U	TO	CH	œ	en
•toi	4^	CH	►to		•to	4^	►to
M	►to.	O	CO	►to	ΟΊ	o	O
ÜJ	σ>	KJ	O	00	KJ	en	(-Π
•	*	•		•	•	•	•
CJi	tn	σ>	LH		en	►to	►to
CH	Cn	UJ	»to	00	en	kD	CD
00	ro	TO	k£>	tn	TO	UJ	CD
- ttoi	—	_Λ CFI	rto	—	— *to		rto
Ξ ro	K	Ξ o	Ξ GJ	:<	:< o₂	Ξ o	2 O
	+ -J	+ ω	+ 1—¹	+ CD	+ GJ	+ en	+ en
X	X	X	X	X	X	X	X
+	4-	4-	t	+	+	+	+

127

ω	CO	to	GO	CO	LO	tü	N>
CH	tn	JS	CO	K>	W	O	kD
CT	n-	rt	rt	rt	rt	CT	ΓΤ
w	(D	(b	(0	(D	(D	(D	Φ
h	te	te	h	h	h	te	te
rt	et	rt	rt	CT	CT	CT	CT
tr	tr	σ	σ	ÏT	tr	σ	tr
c	g	c	G	c	G	G	G
rt	et	rt	rt	ΓΤ	rt	rt	r+
MC	MC	MC	MC	MC	m;	MC	MC
H*	H*	W	W	K	1—¹	H'	1—*
Q	Ω	Ω	Ω	o	o	0	Ω
Mc	MC	MC	Μς	MC	•c	MC	Mc
O	Ω	Ω	o	O	o	Ω	Ω
h-	K·	K»	k·	K	K	1—i	M
O	O	O	o	o	o	o	O
Ό	Ti	TJ	TJ	’d	TJ	TJ	TJ
te	if	n	te	K	H	te	H
O	O	O	O	O	O	O	O
TJ	TJ	TJ	TJ	TJ	TJ	TJ	TJ
mc	mc	m:	MC	MC	MC	MC	MC
K	H*	1—*	H·	t_*		1—»	H*
Tl -Γ-	TJ 3 w	TJ gj	t Ό ω	TJ UJ	MC Λ.	Js JS	te te
tr i	tr ro i	tr i	TJ te l	tr 2	H- 1	1 1	tr o i
(D 3	(D et r+	φ σ	tr ο o	o> 3	1 TJ	^k< 3	(D 3 3
3 (D	□ tr h	3 CD	(D TJ M-	Π (D	TJ MC	1-· o	3 MC (D
mc <+	MC O H-	MC 3	3 MC O	MC rt	tr κ	1 te	m: H rt
f-* 3*	t-- X Ht	H* N	·< H G	t- tr	(D B»	T) TJ	h- îd tr
O	MC H>	MC	H· 3 O	o	5 N	tr tr	3 w
x	1 c	M	(D 1	X	MC O	ro o	H- 3
MC	O	O	rt	m;	H' H-	3 h-	3 (D
	ht	X	tr	I	I	MC H-	ο ω
	O	MC	o		1—‘	F-¹ 3	I G
	t	I	X		I	1	H*
			<				r
. h-¹	--·- H*		— w	_Λ h-*	I-¹	—. I-¹	— l·-¹
> ’	> ·		> -	X	> ·	> ·	> ·
*“ h-¹	H¹		- i—¹	kO	- 1—¹	' I-¹	— H⁴
kd	-J		tn	-J	CO	ΓΟ	œ
		JS	JS	Js	JS	JS	Js
h-¹	en	00	Cn	l·—¹	JS	CH	-U
O	>>	en	o	o	en	en	to
	*	•	•		»	-	•
Ln	Js	CH	en	en	en	en	en
l·-¹	CO	t—¹	CO	F-¹	en	<£>	(D
<J1	Cn	GO		en	M	Js	en
— Js	~ Js	Js	JS	_Λ JS	Js	. js	— js
S ►--*	2 GY	2 œ	2 en	S ·—¹	2 s	2 <Ti	Ξ <1
+ h-*	4- Gn	+ -I	+ >-*	+ H*	t* ’-J	+ ot	+
te	te	x	X	X	X	X	X
4-	+	+	+	4-	T	+	+

l->		H*
-J		en
’-J		CH
I—¹		H»
-J		Ui
kD		cp

«iL

128

4^	GO	42	JS I—¹	4^ o	39	38	37
tert-butyl	rt (D H (Τ- Ι tr c rt· f—	rt Φ »Ί rt 1 σ c et 1—’	CT Φ h rt 1 σ c rt H	CT rt H CT ! tr c et H*	πω H rt 1 σ c rt'C	et (D h rt 1 σ c rt ‘C p—1	CT (D H ct ! σ c rt M
o o h--¹O 1 Ό n o ό ·< 1—¹	£ Ω t—t o t Ό H O Ό »< h-¹	s Q t— O 1 Ό M o Ό t—	£ Q t— O 1 *Ü ht O Ό ·<	n n ΓΟ 1 Ό ht O Ό l·-·	Ω h-« O 1 Ό ht O ·< 1—¹	£ Ω G-j o 1 Ό H O Ό ·< 1—	Ω t— O 1 Ό ht O Ό ·< h-¹
4-trifluoromethoxyphenyl	O u? x t < Ω 1 ‘C •o t» tr '.> rt) o 3 3 < (D t-¹ rt- 7	3-chloro-4(4-fluorobenzyloxy)phenyl	4-(4-fluorobenzyloxy)phenyl	4-benzyloxy- phenyl	4-phenoxy- phenyl	4-butoxyphenyl	1 TJ Λ- Ό ht 1 tr ο ω rt> Ό 4; 3 »< Ω 1— . ι-^3ο rt) 1 rt 3* O X ‘C
1—¹> ’ - H⁴o	h‘ M tû	F-¹00 · <n kO	1—¹m » *— Js ko		. f—* > · - w J—¹	1—¹> · <— 1—¹ dS	I-* > · 1—¹ -J
464.485	4^ GO Cn CH ΓΟ CB	en GO CO O 00	CD O 4S <Ti O Gü	Js CO en en H* GO	4s -J ΓΌ tn 00 en	JS en N> CD kP Cn	Cn O en 00
— j? S σ> + σι SC +	—. 4? S ω + en s: +	<_n g ω + 10 X +	- (Jl S o + en X +	g œ + -j K +	g -J + ω LC +	— J? g en + ω LC +	— Ξ en + t-* te +
				ΓΌ o Gû K) o en	h-¹ Cn -J 1 l~> en kD

129

CH	<J1	m	Xi	Xi	Xi	Xi	Xi
ro	I—¹	o	eo	00	-J	OY	en
< rt ro	TS i-¹	O	Ω	rt	et	et	rt
H h	H '	*<	*<	CD	CD	CD	CD
H- bU	O h-¹	o	O	h	h		Ht
3	TJ -	1—	I-j	Ct	Ct	rt	CT
Ο	‘C 1	o	o	1	1	1	1
<T 1	tr	1	1	σ	tr	tr	tr
tr	— P-	tr	tr	a	ri	ri	ri
	î	cd	CD	rt	rt	rt	rt
1—¹	•-¹ O	>:	X		<	·<	·<
TJ	1 «C	c	*<	H*	\|—’	1—	l·-’
CD	'C Q	H»	J—¹
O	H* K-·
rt	O	(D
β>	t	ΓΙ’
3		tr
1		·<
ΓΌ [		I-¹
O	O	o	o	o	o	o	o
·<				‘C
Ω	O	o	o	o	o	Ω	o
h-J	k-J	k-J	1—*	k-i	k-J	h->
O	O	o	o	o	o	O	O
Ό	TJ	TJ	TJ	TJ	TJ	TJ	TJ
K	H	H	bi	H	H	r<	M
O	O	O	O	O	O	O	o
Ό	TJ	TJ	TJ	TJ	TJ	TJ	TJ
*<	*<	<<	*<		*<	<	c
M	I-*	h-»	I—¹	w	1—¹	h-¹	H·
TJ	TJ 4»	TJ	TJ	Ft] 4i	TJ 4»	TJ ω	TJ N>
zr	tr i	tr	tr	(D 1	tr i	tr i	tr i
(D	cd 3	cd	ro	ri 3	CD rt>	CD Hi	CD Hi
n	Π (D	n	ri	*< (D	ri 1—¹	ri J-	ri J—¹
k:	< et-		*<	1-· rf	< ri	‘C C	c
H·	h· tr	\|—’	1—¹	i tr	H· O	1- o	l·-¹ o
	o			TJ ^k<	K	H	ht
	>:			tr h*	o	O	O
				CD U>	\|	1	1
				ri ri
				*< »-
				1—¹ 1
— W		_Λ Lü	— u>	_Λ F-*		— 1—¹	H¹
a ·		Q ·	Q ·	>		> -	> ·
— -J		CH	u>	1—¹		' N>	' N>
Xi		Xi	Xi	-J		to	W
Xi	Xi	Xi	Xi	Xi	CO	ω	ω
LJ	lj	to	o	K)	ko	ko	ko
OY		o	OY	CY	00	00	00
«	•	«	•	«	•	-	-
<J1	Cn	en	Ln	en	Xi	Xi	Xi
<£>	LJ	en	ΓΌ	CO	-J	-J	’-J
σγ	-J	Xi	-J	N>	kO	(D	(£>
Xi		_Λ Xi	. Xi	— Ji	— GJ	— LJ	— CO
K ω	K ω	K N>	S o	S CO	K tD	s: >x>	K «>
+ -j	+ CJ1	+ H*	+ -J	+	+ kD	+ 10	+ >0
	te	X	te	te	te	te	te
+	+	+	+	+	4-	4-	4-

	h-¹				M
	-J				ΓΌ
	Ln				O
	ί—i				ΓΟ
	--J				ro
	-J				CO

h¹16268

130

<Γι	Cn	en	en	CH	cn	en	en
Ο	to	00	-J	CT	en	js	LU
π-	μ.	rt	3	73 rt	Q)	û>	ω B sr
CD	en	CD	CD 1	< CD	n-	tx	pi CD CD
Η	O	h	rt 3	H rt	Q)	ω	— rt x
rt		CT	sr cd	P> rt	5	3	h· sr pi
!	σ	1	>< er	Si W	Q)	£L>	Pl X
cr	c	σ	i- sr	1 sr	Si	ΰ	— SI <
c	et-	c	73 O	*<	rt	rt	1 O X
et	K	rt	H X	1 Q.	Q)	CD	< TJ h
'C	l·-¹	*<	O ‘C	< H	Si	Si	H Π) O
		l·-	73 1	1—’ O	r	C	si 1
			ÛJ N)	1	w	1-¹	r+ M
			y i	N)	1	1	ÛI '
			1	X	e<		h-¹ en
			ΓΌ		J-»	l·-*	CD 1
			1				a
			e<				1
			i—*
O	O	l-h	n	O	Ω	O	n
X		W		*<	*<	·<
	H*	d	n	n	n	O	n
O	O	O	l*	h-J		t-	M
H	H	K	O	O	O	O	0
O	O	O	1	1	1	\|	1
			TJ	73	73	73	TJ
			K		H	13	K
			O	O	O	O	O
			TJ	73	73	TJ	TJ
				x:	«<	<	ec
			I—¹	M	M	I—¹	J—¹
73	73	TJ	73 -t?	73 ·«?	73	73	73 4?
X	X	x	sr i	sr i	X 1	sr	X I
(D	CD	CD	CD 3	CD 3	CD 3	CD	CD 3
□	S>	n	SJ CD	□ (D	Si CD	S>	S> CD
	*<	'C	< et	k: rt	x: rt	e<	*< X
M	M	»-*	e-¹ ST	m sr	i- sr	H*	i—¹ X
			o	O	O		O
			X	X	X		X
			k: I	1	x:		s:
						— CO
						σ -
						—' en

LU	Lû	U)	JS		Js	JS	JS
-J	-J	cn	Js	ω	CO	cn	-J
Js		00	O	CO	CO	00	JS
«	•	«		•	•	-	V
CO	00	js	Cn	en	στ	CTi	στ
-J	-J	h-¹	J=?	ro	N>	O	o
		en	M	cn	CO	eu	NJ
eu	— eu	— GU	—- JS	~ JS	JS	JS	_Λ Js
Ξ -i	K -~J	K en	S	K ω	K CO	Z en	Z -J
4- en	1 eu	+ ID	+ 1—¹	+ ID	+ CD	+ CD	+ en
X	SC	SC	X	X	X	X	X
+	1	+	+	+	+	4-	+

I-¹ l·-¹	N>	M	t—¹	h-¹	K>		NJ
to to	t—‘	l—i	στ	-J	NJ		H¹
N) -J	h-¹	eu	œ	στ	JS		στ
1 i	1	1	1	1	1		1
I—¹ *—¹	ΓΟ	N>	I-*	1—‘	NJ		K»
to to	H¹	i-¹	-J	-J	NJ		J—¹
UT tD	eu	Cn	O	--J	στ		to
Μ- X-
*

131

m	en	en	en	en	en	en	<n
CO	--j	en	tn	JS	co	ro	h¹
O	CT	n-	rr	Γ+	CT	rt	et
	CD	CD	CD	CD	(D	(D	CD
n	h	h	h	•Ί	H	H	h
l-	CT	et	rt	CT	rr	rt	et
0	I	1	1	1	1	l	\|
I	tr	O'	σ	σ	tr	σ	σ
TJ	£	c	c	i	c	c	p
ri	et	c+	et	rt	et	et	et
O	<	^l<	c<		<	c<
Ό	H*	1—’	H*	M	M	1—¹	H*


B
(D
et
rt
c<
H*
n	Ω	n	n	o	o	o	Ω
rt	rt	y	tr	tr	tr	tr	rt
h-*	l—¹	H*	W	1—¹	H*	1—’	1—*
O	o	O	o	o	o	o	o
et	Ci	H	Ci	ri	H	Ci	H
O	O	O	O	O	O	O	O
TJ	TJ GJ	3 <jj	TJ ω	TJ J?	τι 3 ω	TJ ÜÜ	TJ DJ
rt	tr i	CD 1	tr i	ET i	rt (D i	tr i	rt 1
ro	CD l-t)	ft et	CD o	CD 3	en rt rr	CD 3	CD 3
rs	Π l·-	rt n	El *<	rt ro	t> rt et	t) (D	t> (D
	< C	H-	< fl>	·< rt	*< O H-	^l< rr	^k< rr
l·-*	O	H Ct>	C—· rt	»- tr	1 ‘ X H,	>- rt	I-- rt
	ht	1 t-·	O	o	*< l·-»	0	·<
	O	Ό C	1	x	1 c	X	H·
	i	tr o			o	·<	1
		CD H		I	ri	I
		tJ O			O
		“< 1			1
		H»

CO	co	Æs	LO	4S		Js	ω
-J	kD		kO	O	en	O	00
fo	N>	N>	k£>	4s	œ	*is	co
•	«	e	•	•	•	•	V
00	CO	00	CO	00	co	00	co
en	tn	en	00	ko	<n	kO	kO
»u		-j		en	en	<n	en
—- co	co	— us	Us			.—. JS	—- co
K -·	Ξ co	:< o?	Ξ o	Ξ o	en	Ξ o	3 oo
I w	+ ω	I M	+ o	+ en	1 -*J	+ tr	+ CD
tC	te	X	te	te	te	te	te
r	+	1	+	+	1	+	+

M		l·-¹	1—¹	I—¹		N>	l·-*
O	kO	k£>	kP	en	œ	O	k£>
en	en	en	M	CD	en	en	en
N>	w	t—¹	F-¹	h-¹	1—>	N>	h-*
O	CD	k£>	CO	’-j	CD	O	kD
-J	00	CO	CB	o	00	ko	-j

132

-J	-J	-J	--J	-J	-J	-J	en
en	CD	*U	Lü	KJ	P¹	o	ko
(D to	o '	CL ω	CL U>	u>	M	M	ω
et	*< K¹	P- 1	H- 1	-	1	X	i
tr to	O 1	3 tr	3 tr	U)	Φ	NJ	B
c	F	Φ *<	Φ <	1	et	i	Φ
M ho	O tr	rt CL	rt Q.	CL	tr	CL	et
\|	l	tr k	tr h	H-	ce	H-	tr
ri-	ό a	ce o	ce o	3	w	3	ce
	N F	F X	F X	CD	1	m	P
H-	O O	l c<	t k:	et	tr	rt	l
l-t)	T5 X	TS 1	Ό 1	tr	c	tr	tr
I—'	c<	t-! tO	Μ ΓΟ	ce	et	ce	c
c	F 3	O '	o -	F		M	et
O	— (D	Ό to	X) to	1	1-*	1
M	3 c+	< t	ce l	σ		Ό	1—¹
O	(D tT	P—¹	H*	c		H
\|	r+ »<			rt		O
	tr f			ce		Ό
	ce —			H¹		<
	Μ 1					1—’
n	Ω	o	o	o	o	o	o
cr	tT	tr	ΖΓ	tr	tr	tr	tr
F	M	M	M	1—'	w	P¹	F
O	O	o	o	o	o	o	O
M	K	K	K	H	rs	H	N
O	O	o	o	O	O	O	0
Ό	Ό ω	3 ω	*O ω	Ό	ü	Ό	Ό
tr	tr t	Φ 1	tr i	tr	tr	tr	tr
o	Φ H»	rt et	Φ Hl	Φ	φ	φ	φ
d	3 F	tr t-l	t) F	3	3	□	3
<	ce G	u< p-	ce E	ce	ce		ce
H·	F O	F Hl	F O	1—¹	H-	P	P·
	H	1 I-¹	H
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O	O	ro	ΓΌ	N>	NJ	CO	00
«		•	•	-		«	•
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CO	-j	eo	CO	ro	ro	<£>	kO
en		GJ	<Ti	Lü	w	en	en
			. *i=>		. kU	— Gü	π ω
Z o	Z to	-J	Z to	Z o	Z O	Z a»	Z œ
+ h*	+ F	ω	+ ω	1 F	1 I-¹	r	+ LO
X	tC		te	te	te	te	te
+	+		+	1	1	1	4-

N)	ΓΟ	H¹	hJ	I—¹	K¹	rxj	P*
W	O	00	o	00	-J	N)	Cn
O		LD	CD	kj	I—¹		»c=*
M	ΓΟ	W	ΓΟ	I—¹	P*	N)	P
h-¹	O	OO	o	00	-J	KJ	en
Où	ΟΊ	-J	-J		u>	en	en

133

00	oo	00	CO	00	-J	-J	-J
	Cü	N>	h-¹	o	k£>	CO	-J
3 n-	x 4?	O	x 4?	TJ GJ	5	'-c et ~	<D M
ο h	Φ 1	*<	C '	H '	(T> '	1—¹ H bJ	r+
rt- tu	x x	O	rt J?	Ο ω	rt h*	H- 01	X M
n a	u< u<	b-J	·< ,	TJ	x '	Hi —	!< ,
*< «	H· Q.	O	1— 4?	>< u>	< H*	k-* 1	b-* bO
H I	H	1	1	1—' 1	H· 1	G H*	\|
I d^	O	a*	rr	rt	Ό rt	O '	rt
O I	X	ro	H	H	H H	H H*	H
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O <	I	*<	Hi	H,	TJ Hl	TJ H*	H,
H· CL	n	H	F¹	F·	[V F»	H 1	F
O i-s	À;		c	G	a c	O	c
a* o	n		O	O	1 o	TJ	o
Φ x	k-J		H	H	bJ hj	û>	N
X *<	O		O	O	f o	a	O
*< I	i		1	I	< 1	l	1
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Ω	Ω	Ω	Ω	Ω	Ω	Ω	Ω
X	a	a·	a^-	x	a*	X	X
F*	1—'	1—’	H	M	w	F	F
O	O	O	O	o	o	o	0
F	a	H	H	K	H	H	M
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134

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135

100	LD LD	86	97	96	LD Cn	94	93
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136

108	107	106	105	104	103	102	101
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o [V a o	cyano	o EU □ o	cyano	tr H o 3 o	chloro	chloro	chloro
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437.395	437.395	423.368	383.425	437.31	468.935	454.908	436,918
438	438	424	LU 2 œ -h +	:< ω + -~-i rc +	Ξ o; + rc +	455 (M+H⁺)	λ Ξ U) + -~J π +
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137

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138

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(C) The LC/MS spectre were recorded using a YMC-Pack Jsphere H80 2.4 x 33 mm; 4 pm) reverse-phase column, using a gradient of water containing 0.05% trifluoroacetic acid and acetonitrile

139

Biological examples

The capacity of the compounds of the invention to inhibit the phosphorylation of casein by casein kinase 1 epsilon and/or delta may be evaluated according to the procedures described in document US 2005/0 131 012.

Test A: Inhibitory activity on CK1 epsilon measured by assay on an ATP-³³P filter plate

The effect of the compounds on inhibition of the phosphorylation of casein by the enzyme casein kinase 1 epsilon (CK1 epsilon) is measured, using a casein assay via filtration of ATP-³³P in vitro.

Casein kinase 1 epsilon (0.58 mg/ml) is obtained via fermentation and purification processes performed according to methods that are well known to those skilled in the art, or may also be obtained from Invitrogen Corporation™ (human CK1 epsilon).

The compounds are tested at five different concentrations so as to generate IC₅₀ values, i.e. the concentration at which a compound is capable of inhibiting the enzymatic activity by 50%, or alternatively the percentage of inhibition at a concentration of 10 micromolar.

U-bottomed Falcon plates are prepared by placing 5 pL of solutions of the compounds according to the invention at concentrations of 10, 1, 0.1, 0.01 or 0.001 pM in different wells. The solutions of the compounds according to the invention at these various concentrations are prepared by diluting in a test buffer (Tris 50 mM pH 7.5, MgCl₂ 10 M, DTT 2 mM and EGTA 1 mM) a stock solution in DMSO at a concentration of 10 mM. Next, 5 pL of dephosphorylated casein are added to a final concentration of 0.2 pg/pL, 20

140 pL of CK1 epsilon to a final concentration of 3 ng/pL, and 20 pL of ATP-³³P to a final concentration of 0.02 pCi/pL mixed with coid ATP (10 pM final - approximately 2*10⁶ CPM per well) . The final total test volume per well is equal to 50 pL.

The U-bottomed Falcon® test plate mentioned above is vortexed, and then incubated at room température for 2 hours. After 2 hours the reaction is stopped by adding an ice-cold solution of 65 pL of coid ATP (2 mM) prepared in test buffer.

100 pL of the reaction mixture are then transferred from the U-bottomed Falcon® plate into Millipore® MAPH filter plates, preimpregnated with 25 pL of ice-cold 100% TCA.

The Millipore MAPH filter plates are agitated gently and are left to stand at room température for at least 30 minutes to precipitate the proteins.

After 30 minutes, the filter plates are sequentially washed and filtered with 2x150 pL of 20% TCA, 2*150 pL of 10% TCA and 2*150 pL of 5% TCA (6 washes in total per plate/900 pL per well).

The plates are left to dry overnight at room température. Next, 40 pL of Microscint-20 Packard® scintillation liquid are added per well and the plates are closed in a leaktight manner. The radiation emitted by each well is then measured for 2 minutes in a TopCount NXT Packard® scintillation counter, in which the values of CPM/well are measured.

The percentâge inhibition of the capacity of the enzyme to phosphorylate the substrate (casein) is determined for each concentration of test cornpound. These inhibition data

141 expressed as percentages are used to calculate the IC₅₀value for each compound compared with the controls.

The kinetic studies determined the K_M value for ΆΤΡ as being 5 21 μΜ in this test System.

Table 2 below gives the IC50 values or the IC50 inhibition ranges (resuit of several experiments) for the phosphorylation of Casein Kinase 1 Epsilon for a number of compounds according to the invention.

Table 2

No.	CK1 epsilon IC_5D (nM)	No.	CK1 epsilon IC₅o (»H)	No.	CK1 epsilon IC₅₀ (nM)
1	12-35	38	152	75	4-5
2	<1	39	4-36	76	10-27
3	5-104	40	38	77	2-8
4	1-3	41	42	78	3-3
5	34-78	42	16	79	1-4
6	28-57	43	24	80	2-16
7	42	44	33	81	2-16
8	221-273	45	12	82	1-7
9	49	46	5-11	83	2-4
10	15-77	47	45-146	84	1
11	3-6	48	1-2	85	2
12	12-12	49	17-28	86	<1
13	450-1000	50	25	87	<1
14	136-1090	51	40	88	3-5
15	2-4	52	45	89	1-3
16	19-57	53	7	90	6-7
17	958	54	6-6	91	4
18	963	55	3-5	92	11-13
19	587	56	26-38	93	21-28
20	620	57	36	94	2-18
21	26-46	58	5-28	95	6

142

22	25	59	8-13	96	19
23	65	60	1-12	97	122
24	84	61	1-8	98	2-16
25	33	62	1-4	99	4
26	521	63	29	100	>1
27	23	64	1-5	101	9-24
28	4	65	1-2	102	4-11
29	532	66	3-6	103	7-14
30	331	67	1-5	104	<1
31	5-29	68	10	105	<1-1
32	1-7	69	5	106	2
33	847	70	4	107	<1
34	315	71	4	108	4
35	25	72	1-17	109	9
36	46-75	73	1-11	110	<1
37	62	74	6

Under these conditions, the compounds of the invention that

are the	most	active	hâve	IC₅₀	values	(concentrations that
inhibit	50%	of the	enzymatic	activity	of casein kinase 1
5 epsilon)	of	between	1 nM	and	1 μΜ, and more particularly
between	1 nM	and 100	nM.

Test B:

Inhibitory actîvity on

CK1 delta measured by FRET

The capacity of the compounds of the invention to inhibit the phosphorylation of casein by the casein kinases 1 epsilon and delta may be evaluated using an FRET (Fluorescence with the aid

Résonance Energy of the Z'Lyte™

Transfer) fluorescence test kinase assay kit (reference

PV3670;

Invitrogen Corporation™) according to the manufactureras instructions.

The casein kinases 1 used are obtained from

Invitrogen

Corporation (human CK1 epsilon PV3500 and human CK1 delta

PV3665).

V

143

A peptide substrate labelled at both ends with a fluorophore-donating group (coumarin) and a fluorophoreaccepting group (fluorescein) constituting an FRET System is dephosphorylated in the presence of ATP by casein kinase 1 epsilon or delta in the presence of increasing concentrations of compounds of the invention.

The mixture is treated with a site-specific protease that specifically cleaves the substrate peptide to form two fluorescent fragments having a large fluorescence émission ratio.

The fluorescence observed is thus related to the capacity of the products of the invention to inhibât the phosphorylation of the substrate peptide by casein kinase 1 epsilon or casein kinase 1 delta.

The compounds of the invention are dissolved at different concentrations starting with a 10 mM stock solution in DMSO diluted in a buffer containing 50 mM HEPS, pH 7.5, 1 mM EGTA, 0.01% Brij-35, 10 mM MgCl₂ for casein kinase 1 epsilon and supplemented with Trizma Base (50 mM) , pH 8.0 and NaN₃(0.01% final) for casein kinase 1 delta.

The phosphorylation of the substrate peptide SER/THR 11 obtained from Invitrogen Corporation™ is performed at a final concentration of 2 pM. The ATP concentration is 4 times the K_M, this value being 2 μΜ for casein kinase 1 epsilon and 4 pM for casein kinase 1 delta.

The emitted fluorescence is measured at wavelengths of 445 and 520 nm (excitation at 400 nm).

144

Table 3 below gives the IC50 values for the inhibition of phosphorylation of casein kinase 1 delta for a number of compounds according to the invention.

Table 3

Cornpound	CK1 delta IC₅₀ (nM)
10	31

Under these conditions, the compounds of the invention that are the most active hâve IC50 values (concentration that inhibits 50% of the enzymatic activity of casein kinase 1 delta) of between 1 nM and 1 pM, and more particularly between 1 nM and 100 nM.

It is thus seen that the compounds according to the invention hâve inhibitory activity on the enzyme casein kinase 1 epsilon or casein kinase 1 delta.

Test C: Experimental protocol for circadian cell assay Mperl-luc Rat-1 (P2C4) fibroblast cultures were prepared by dividing the cultures every 3-4 days (about 10-20% of confluence) on 150 cm² degassed polystyrène tissue culture flasks (Falcon® # 35-5001) and maintained in growth medium [EMEM (Cellgro #10-010-CV); 10% foetal bovine sérum (FBS;

Gibco #16000-044); and 50 I.U./mL of penicillin-streptomycin (Cellgro #30~001-Cl)] at 37°C and under 5% CO₂.

Cells obtained from Rat-1 fibroblast cultures at 30-50% of confluence as described above were co-transfected with vectors containing the sélection marker for résistance to zeocin for a stable transfection and a luciferase reporter gene directed by the promoter mPer-1. After 24 to 48 hours, the cultures were divided on 96-well plates and maintained in growth medium supplemented with 50-100 pg/mL of zeocin (Invitrogen® #45-0430) for 10-14 days. The zeocin-resistant 'QL·'

145 stable transfectants were evaluated for expression of the reporter by adding to the growth medium luciferin 100 μΜ (Promega® #E1603®) and by assaying the luciferase actîvity on a TopCount® scintillation counter (Packard model #C384V00). The Rat-1 cell clones expressing both zeocin résistance and luciferase actîvity directed by mPerl were serum-shock-synchronized with 50% horse sérum [HS (Gibco® #16050-122)] and the actîvity of the circadian reporter was evaluated. The P2C4 clone of fibroblasts Mperl-luc Rat-1 was selected to test the compound.

The Mperl-luc Rat-1 (P2C4) fibroblasts at 40-50% of confluence obtained according to the protocol described above were plated out onto 96-well opaque tissue culture plates (Perkin Elmer® #6005680). The cultures are maintained in growth medium supplemented with 100 pg/mL of zeocin (Invitrogen #45-0430) until they reached 100% of confluence (48-72 hours). The cultures were then synchronized with 100 pL of synchronization medium [EMEM (Cellgro #10-010-CV); 100

I.U./mL of penicillin-streptomycin (Cellgro #30-001-Cl); 50% HS (Gibco #16050-122}] for 2 hours at 37°C and under 5% CO₂. After synchronization, the cultures were rinsed with 100 pL of EMEM (Cellgro #10-010-CV) for 10 minutes at room température. After rinsing, the medium was replaced with 300 pL of CO₂-independent medium [CO₂I (Gibco #18045-088); L-glutamine 2 mM (Cellgro #25-005-Cl); 100 U.I./mL of penicillin-streptomycin (Cellgro #30-001-C1); luciferin 100 pM (Promega #E 1603)]. The compounds of the invention tested for the circadian effects were added to CO₂-independent medium in DMSO at 0.3% (final concentration). The cultures were immediately closed in a leaktight manner with TopSealA® film (Packard #6005185) and transferred for the luciferase actîvity measurement.

146

After synchronization, the test plates were maintained at 37°C in a tissue culture oven (Forma Scientific Model #3914). The in vivo luciferase activity was estimated by measuring the relative light émission on a TopCount scintillation counter (Packard model #C384V00).

The period analysis was performed either by determining the interval between the relative light émission minima over several days or by Fourier transform. The two methods produced a virtually identical period estimation on a range of circadian periods. The power is given in EC Delta (t+lh), which is presented as the effective micromolar concentration that induce a 1-hour prolongation of the period. The data were analysed by adjusting a hyperbolic curve to the data expressed as change of period (y-axis) as a function of the concentration of the test compound (x-axis) in the XLfit™ software and the EC Delta (t+lh) was interpolated from this curve.

Table 4 below gives the EC Delta (t + lh) or the EC Delta (t+lh) ranges (results from several experiments) for a number of compounds according to the invention.

Table 4

Compound	CE Delta (t+lh) (nM)
3	8
25	26
54	15
60	3-20

Under these conditions, the compounds of the invention that are the most active hâve EC Delta (t+lh) values (effective micromolar concentration that induced a 1-hour prolongation of the period) of between 1 nM and 2 μΜ, and more particularly between 1 nM and 500 nM.

147

By inhibiting the enzymes CKlepsilon and/or CKldelta, the compounds that are the subject of the invention modulate the circadian periodicity, and may be useful for treating circadian rhythm disorders.

The compounds according to the invention may especially be used for the préparation of a médicament for preventing or treating sleep disorders; circadian rhythm disorders, especially such as those caused by jetlag, shift work, delayed sleep-phase syndrome and advanced sleep-phase syndrome.

According to one of its aspects, the invention relates to a compound of formula (I) in base form or in the form of an addition sait with a pharmaceutically acceptable acid, for preventing or treating sleeping disorders; circadian rhythm disorders, especially such as those caused by jetlag, shift work, delayed sleep-phase syndrome and advanced sleep-phase syndrome.

Among the sleep disorders that are especially distinguished are primary sleep disorders such as dyssomnia (for example primary insomnia), parasomnia, hypersomnia (for example excessive somnolence), narcolepsy, sleep disorders related to sleep apnoea, sleep disorders related to the circadian rhythm and other unspecified dyssomnias, sleep disorders associated with medical/psychiatric disorders, for instance Alzheimer's disease.

The compounds that are the subject of the invention also cause a circadian phase shift and such a property may be useful in the context of a potential monotherapy or combination therapy that is clinically effective in the case

TU

148 of mood disorders and/or in âge- and/or ageing-related circadian-phase movement disorders.

According to one of its aspects, the invention relates to a compound of formula (I) in base form or in the form of an addition sait with a pharmaceutically acceptable acid, in the context of a potential monotherapy or combination therapy that is clinically effective in the case of mood disorders and/or in âge- and/or ageing-related circadianphase movement disorders.

Among the mood disorders that are especially distinguished are dépressive disorders (unipolar dépréssion), bipolar disorders, mood disorders caused by a general medical complaint and also mood disorders induced by pharmacological substances.

Among the bipolar disorders that are especially distinguished are bipolar I disorders and bipolar II disorders, especially including seasonal affective disorders.

The compounds that are the subject of the invention, which modulate the circadian periodicity, may be useful in the treatment of anxiety and dépressive disorders caused in particular by an impairment in the sécrétion of CRF.

Among the dépressive disorders that are especially distinguished are major dépressive disorders, dysthymie disorders and other unspecified dépressive disorders.

According to one of its aspects, the invention relates to a compound of formula (I) in base form or in the form of an addition sait with a pharmaceutically acceptable acid, for

149 treating anxiety and dépressive disorders due in particular to impairment of CRF sécrétion.

The compounds that are the subject of the invention, which modulate the circadian periodicity, may be useful for preparing a médicament for treating diseases related to dependency on abuse substances such as cocaine, morphine, nicotine, éthanol and cannabis.

According to one of its aspects, the invention relates to a compound of formula (I) in base form or in the form of an addition sait with a pharmaceutically acceptable acid, for treating diseases related to dependency on abuse substances such as cocaine, morphine, nicotine, éthanol and cannabis.

By inhibiting casein kinase 1 epsilon and/or casein kinase 1 delta, the compounds according to the invention may be used for preparing médicaments, especially for preparing a médicament for preventing or treating diseases related to hyperphosphorylation of the tau protein, especially Alzheimer's disease.

According to one of its aspects, the invention relates to a compound of formula (I) in base form or in the form of an addition sait with a pharmaceutically acceptable acid, for preventing or treating diseases related to hyperphosphorylation of the tau protein, especially Alzheimer's disease.

By inhibiting casein kinase 1 epsilon and/or casein kinase 1 delta, the compounds according to the invention may also be used for preparing médicaments, especially for preparing a médicament for preventing or treating neuropathie pain.

fie *

150

According to one of its aspects _f the invention relates to a compound of formula (I) in base form or in the form of an addition sait with a pharmaceutically acceptable acid, for preventing or treating neuropathie pain.

The compounds according to the invention may also be used for the préparation of médicaments, especially for the préparation of a médicament for preventing or treating inflammatory diseases, especially such as inflammatory diseases of the central nervous System, for instance multiple sclerosis, encephalitis, myelitis and encephalomyelitis, and other inflammatory diseases, for instance vascular pathologies, atherosclerosis, joint inflammation, arthrosis and rheumatoid arthritis.

According to one of its aspects, the invention relates to a compound of formula (I) in base form or in the form of an addition sait with a pharmaceutically acceptable acid, for preventing and/or treating inflammatory diseases, especially those indicated above.

The compounds according to the invention in base form or in the form of an addition sait with a pharmaceutically acceptable acid may thus be used for the préparation of médicaments, in particular médicaments that are useful for treating or preventing diseases related to casein kinase 1 epsilon and/or casein kinase 1 delta.

According to one of its aspects, the invention relates to a compound of formula (I) in base form or in the form of an addition sait with a pharmaceutically acceptable acid, for preventing for treating diseases related to casein kinase 1 epsilon and/or casein kinase 1 delta.

n.

151

According to one of its aspects, the invention relates to a cornpound of formula (I) in base form or in the form of an addition sait with a pharmaceutically acceptable acid, for its use as a médicament.

According to one of its aspects, the invention relates to a médicament comprising a cornpound of formula (I) in base form or in the form of an addition sait with a pharmaceutically acceptable acid.

Thus, according to another of its aspects, a subject of the invention is médicaments comprising a cornpound of formula ( I ) , or an addition sait thereof with a pharmaceutically acceptable acid, or alternatîvely a hydrate or solvaté of 15 the cornpound of formula (I).

According to another of its aspects, the présent invention relates to pharmaceutical compositions comprising, as active principle, a cornpound according to the invention in base 20 form or in the form of an addition sait with a pharmaceutically acceptable acid, and optionally one or more pharmaceutically acceptable excipients. These pharmaceutical compositions thus contain an effective dose of at least one cornpound according to the invention or a pharmaceutically 25 acceptable sait, a hydrate or solvaté of the said cornpound, and also optionally at least one pharmaceutically acceptable excipient.

The said excipients are chosen, according to the 30 pharmaceutical form and the desired mode of administration, from the usual excipients known to those skilled in the art.

In the pharmaceutical compositions of the présent invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, rie,·

152 transdermal or rectal administration, the active principle of formula (I) above, or the possible sait, solvaté or hydrate thereof, may be administered in unit administration form, as a mixture with standard pharmaceutical excipients, to man and animais for the prophylaxis or treatment of the above disorders or diseases.

The appropriate unit administration forms include oral-route forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, inhalation forms, 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 créants, gels, ointments or lotions.

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

Compound according to the invention 50.0 mg

Mannitol 223.75 mg

Croscarmellose sodium 6.0 mg

Corn starch 15.0 mg

Hydroxypropylmethylcellulose 2.25 mg

Magnésium stéarate 3.0 mg

Via the oral route, the dose of active principle administered per day may range from 0.1 to 20 mg/kg, in one or more dosage intakes.

There may be particular cases in which higher or lower dosages are appropriate; such dosages are not outside the context of the invention. According to the usual practice,

153 the dosage that is appropriate to each patient is determined by the practitioner according to the mode of administration and the weight and response of the said patient.

According to another of its aspects, the présent invention also relates to a method for preventing and/or treating the pathologies indicated above, which comprises the administration to a patient of an effective dose of a compound according to the invention, or a pharmaceutically 10 acceptable sait or hydrate or solvaté thereof.

2 NOV. 2012

kBINET CAZENAV ropriété 500VAOU

Camero

154

Claims

1. Compounds corresponding to the general formula (I)

Claims in which

R₂ represents:

a group Cx_x₀-alkyl, C₃-₇-cycloalkyI-Ci__e-alkyl, Ci-₆alkylthio-C-i-iQ-alkyl, Ci-₆-alkoxy-Ci^i₀-alkyl, hydroxy-Ci_i₀alkyl, hydroxy-Cx-e-alkyl-Ca-T-cycloalkyl-Cx-g-alkyl,

Ci-io-f luoroalkyl, Ci_io-alkyl-oxyimino-Ci_io-alkyl,

- a group C3_xo-cycloal kyl, C₃_io-fluorocycloalkyl, hydroxyC₃-iQ-cycloalkyl,

- a group C₃_7-cycloalkyl which may be substituted with one or two groups independently chosen from Ci_₆~alkyl, C₃_₇cycloalkyl, hydroxyl, Cx_₁₀-f luoroalkyl and Ci-x₀-alkyl~ oxyimino,

- a heterocyclic group comprising from 3 to 8 carbon atoms and at least one heteroatom chosen from nitrogen, oxygen, sulfur and the oxide or dioxide form of sulfur, this heterocyclic group possibly being substituted with one or more groups from among hydroxyl, Cx_₆-alkyl, hydroxy-Ci_₆alkyl, Ci-₆-f luoroalkyl,

- a group Ci-iQ-aikyl substituted with a heterocyclic group comprising from 3 to 8 carbon atoms and at least one heteroatom chosen from nitrogen, oxygen, sulfur and the oxide or dioxide form of sulfur, this heterocyclic group possibly being substituted with one or more groups from among hydroxyl, Cx-₆-alkyl, hydroxy-Cx_₆-alkyl,

Cx-₆-f luoroalkyl;

155

Xg represents a hydrogen, fluorine, chlorine or bromine atom or a group Ci-g-alkyl, C3_7-cycloalkyl, C₃_₇-cycloalkylCi-g-alkyl, Ci-g-fluoroalkyl or cyano;

X₇ represents:

- hydroxyl,

- Ci-e-alkyl, C₃_₇-cycloalkyl, C₃_₇-cycloalkyl-Ci_₆-alkyl, hydroxy-Ci-₆-alkyl, hydroxy-C₃-₇-cycloalkyl, hydroxyC₃-7-cycloalkyl-Ci-6-alkyl,

Ci-₆-alkoxy, C₃_7-cycloalkoxy, C₃-₇-cycloalkyl-Ci_₆alkoxy,

- Ci-e-alkylthio, C₃-₇-cycloalkylthio, C₃-7-cycloalkyl-Ci_₆alkylthio,

- aryl, aryl-Ci-g-alkyl,

- aryloxy, aryl-Ci-g-alkoxy,

Ci-e-f luoroalkyl, C₃_₇-f luorocycloalkyl, C₃_₇f luorocy cl oalkyl-C ι-g-alkyl,

- Ci-6~fluoroalkoxy, C₃-₇-f luorocycloalkoxy,

C₃-₇-f luorocycloalkyl-Cx-ç-alkoxy,

- cyano, cyano-Ci-g-alkyl, cyano-Ci-g-alkoxy,

- NR_aR_b, NR_cCOR_d, NR_cSO₂Rd, NR_cSO₂NR_aR_b, CONR_aR_b, CON(OR_c)R_d,

- a heteroaryl group, the aryl or heteroaryl groups being optionally substituted with one or more substituents chosen from fluorine, chlorine and bromine atoms or a group Ci-e-alkyl, C₃_₇-cycloalkyl, Ci_₆-alkoxy, Ci_₆-f luoroalkyl, Cj-g—fluoroalkoxy or cyano,

156

R_a and R_b represent, independently of each other, a hydrogen atom or a group Ci_₆-alkyl, C₃-₇-cycloalkyl or C₃-₇cycloalkyl-Ci-₆-alkyl, or alternatively they form with the atom that bears them a ring chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine and piperazine, this ring being optionally substituted with one or more groups Cx-g-alkyl,

R_c and R_d represent, independently of each other, a hydrogen atom or a group Ci-₆-alkyl, C₃_7-cycloalkyl or C₃_₇cycloalkyl-Ci-e-alkyl;

in the form of the base or of an acid-addition sait.

2. Compounds of formula (I) according to Claim 1, characterized in that

R₂ represents:

- a group Ci_i₀-alkyl, C3-₇-cycloalkyl-C₁-₆-alkyl, Ci-₆-alkoxy-

Ci-io^-alkyl, hydroxy-Ci-i₀-alkyl, hydroxy-Ci-s-alkyl-C₃-₇cycloalkyl-Ci-e-alkyl, Ci_₁₀-f luoroal kyl,

- a group C₃-io-cycloalkyl, C₃_io-fluorocycloalkyl, hydroxyC₃-i₀-cycloalkyl,

- a group C₃-₇-cycloalkyl which may be substituted with one or two groups independently chosen from Ci-6-alkyl, C₃_₇cycloalkyl, hydroxyl, Ci_io-f luoroal kyl and Ci-io^-alkyloxyimino,

- a heterocyclic group comprising from 3 to 8 carbon atoms and at least one heteroatom chosen from oxygen or a sulfur atom in dioxide form, this heterocyclic group possibly being substituted with one or more groups Ci-₆-alkyl,

- a group Ci-i₀-alkyl substituted with a heterocyclic group comprising from 3 to 8 carbon atoms and at least one oxygen heteroatom, this heterocyclic group possibly being substituted with one or more groups Ci-e-alkyl,

157

- a fluorine or chlorine atom or a group chosen from

- Ci_₆-alkyl, C₃_₇-cycloalkyl,

- Ci-₆-alkoxy, C₃-₇-cycloalkyl-Ci-₆-alkoxy,

- Ci-g-alkylthio,

- aryl,

- aryloxy, aryl-Ci-e-alkoxy,

- Ci_₆ fluoroalkyl,

- Ci-6 fluoroalkoxy,

- cyano, cyano-Ci_₆-alkoxy,

- NR_aR_b, NR_cSO₂Rd, NR_cSO₂NR_aR_b, CONR_aR_b, CON(OR_c)Rd, heteroaryl chosen from oxadiazolyl and pyrazolyl groups, optionally substituted with a group Ci-6-alkyl, the aryl group being optionally substituted with a fluorine atom,

R_a and R_b represent, independently of each other, a hydrogen atom or a group Ci_₆-alkyl, C₃-₇-cycloalkyl, or alternatively they form with the atom that bears them a ring chosen from pyrrolidine and morpholine,

R_c and Rj represent, independently of each other, a hydrogen atom or a group Ci_₆-alkyl.

3. Compound of formula (I), characterized in that it is chosen from:

2V²-tert-buty1-7-pheny1-3,4-dihydropyrrolo[1,2-a]pyrazine2,8(IH) -dicarboxamide,

N²-tert-butyl-7-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2a ] pyrazine-2,8(1/7) -dicarboxamide,

2\^-tert-butyl-6-methyl-7-phenyl-3,4-dihydropyrrolo[1,2a ] pyrazine-2, 8 ( 177) -dicarboxamide

2V²-tert-buty 1-7- (4-methoxyphenyl) -6-methyl-3,4dihydropyrrolo [ 1,2-a] pyrazine-2,8 (17/) -dicarboxamide,

Ht

158 ίί-tert-butyl-6-methyl-7-(4-phenoxyphenyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide,

Z^-ô-di-cyclo-propyl-7-(4-methoxyphenyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IH) -dicarboxamide,

5 6-cyclo-propyl-7-phenyl-_JN²- (iso-propyl) -3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide, 6-cyclo-propyl-7-(4-methoxyphenyl)-hf-(iso-propyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide,

6- cyclo-propyl-7-phenyl-.N²- ( iso-butyl )-3,4-

10 dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide,

W²- tert-butyl-6-cydo-propyl-7-phenyl-3,4dihydropyrrolo [1,2-a] pyrazine-2,8 (IH) -dicarboxamide, A^-tert-butyl-ô-cyclo-propyl-?-(3-methylphenyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide,

15 î/-tert-butyl-6-cyclo-propyl-7-(4-methylphenyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide, A^-tert-butyl-6-cyclo-propyl-7-[4-(iso-propyl)phenyl]-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IH) -dicarboxamide, A^-tert-butyl-/-(4-cyclo-hexylphenyl)-6-cyclo-propyl-3,420 dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide,

7- (biphenyl-4-yl)-7^-tert-butyl-6-cyclo-propyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IH) -dicarboxamide, A^-tert-butyl-6-cycIo-propyl-7-[3-(trifluoromethyl)phenyl]-

3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(IH)-dicarboxamide,

25 W²-tert-butyl-6-cyclo-propyl-7-[3- (dimethylcarbamoyl)phenyl]-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(IH) -dicarboxamide,

Λ7²- tert-butyl-6-cyclo-propyl-7- [ 4- ( cyclopropylcarbamoyl)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazine30 2,8(IH) -dicarboxamide, l^-tert-butyl-6-cyclo-propyl-7-[4-(pyrrolidin-1ylcarbonyl)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazine2,8(IH)-dicarboxamide,

159

TV²-tert-butyl-6-cyclo-propyl-7-{4 [methoxy[methyl)carbamoyl]phenyl} -3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1H)-dicarboxamide,

EÎ-tert-butyl-7-(3-cyanophenyl)-6-cyclo-propyl-3,45 dihydropyrrolo [ 1,2-a] pyrazine-2,8 ( 177) -dicarboxamide, TV²- tert-buty 1-7- ( 4-cyanophenyl ) -6-cyclo-propyl-3,4dihydropyrrolo [1,2-a] pyrazine-2,8 (1/7) -dicarboxamide, if-tert-butyl-6-cyclo-propy1-7-[4-(5-methyl-1.3,4-oxadiazol-

2-yl) phenyl ] -3, 4-dihydropyrrolo [ 1,2-a] pyrazine-2,8 (177) -

10 dicarboxamide, if-tert-butyl-6-cyclo-propy1-7-[4 -(trifluoromethyl)phenyl]-

3,4-dihydropyrrolo [1,2-a] pyrazine-2,8 (1/7) -dicarboxamide, 7\f-tert-butyl-6-cyclo-propyl-7-(naphthalen-2-yl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide,

15 if-tert-butyl-6-cyclo-propy1-7-{ 3[(dimethylsulfamoyl)amino]phenyl}-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1H)-dicarboxamide,

TV²-tert-butyl-6-cyclo-propyl-7- [ 3- (1/7-pyrazol-l-yl) phenyl] -

3, 4-dihydropyrrolo [ 1,2-a] pyrazine-2,8 (1/7) -dicarboxamide,

20 if -tert-butyl-6-cyclo-propyl-7-[4-(dimethylamino)phenyl]-

3, 4-dihydropyrrolo [1,2-a] pyrazine-2,8 (1/7) -dicarboxamide, TV²- tert-butyl-6-cycIo-propyl-7- { 4- [(methylsulfonyl)amino]phenyl}-3,4-dihydropyrrolo[1,2-

a] pyrazine-2,8 (1/7) -dicarboxamide,

25 7\f-tert-butyl-6-cyclo-propyl-7-[4-(morpholin-4-yl)phenyl]-

3, 4-dihydropyrrolo [1,2-a] pyrazine-2,8 ( 1/7) -dicarboxamide, if-tert-butyl-6-cyclo-propy1-7- [ 4 - ( lH-pyrazol-l-yl ) phenyl ] 3, 4-dihydropyrrolo [ 1,2-a] pyrazine-2,8(1/7) -dicarboxamide, if-tert-butyl-6-cyclo-propy1-7- ( 3-methoxyphenyl) -3,4-

30 dihydropyrrolo [1,2-a] pyrazine-2,8 (1/7) -dicarboxamide, if-tert-butyl-6-cydo-propyl-7- [3- (cyclopropylmethoxy)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 (1/7) -dicarboxamide,

7-[3-(benzyloxy)phenyl]-if-tert-butyl-6-cyclo-propyl-3,435 dihydropyrrolo [ 1,2-a ] pyrazine-2,8 ( 1/7) -dicarboxamide,

160

A/²-terfc-butyl-6-cyclo-propyl-7-[3-( trifluoromethoxy)phenyl]-

3.4- dihydropyrrolo[1,2-a]pyrazine-2,8(1H) -dicarboxamide, tert-butyl-6-cyclo-propyl-7-[4-(methoxy)phenyl]-3,4- dihydropyrrolo [1,2-a] pyrazine-2,8 ( IB) -dicarboxamide,

5 A^-tert-butyl-6-cyclo-propyl-7-[4-(cyclopropylmethoxy)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazine2,8(1H)-dicarboxamide,

7-(4~butoxyphenyl)-N²-tert-butyl-6-cyclo-propy1-3,4 dihydropyrrolo[1,2-a]pyrazine-2,8( IB)-dicarboxamide,

10 A^-tert-butyl-ô-cyclo-propyl-?-(4-phenoxyphenyl)-3, 4dihydropyrrolo [ 1,2-a ] pyrazine-2,8 ( IB) -dicarboxamide, 7-[4-(benzyloxy)phenyl]-N²-tert-butyl-6-cyclo-propyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide, A^-tert-butyl-ë-cyclo-propyl-?-]4-[(415 fluorobenzyl)oxy]phenyl}-3,4-dihydropyrrolo[1,2-a]pyrazine2,8(1/1) -dicarboxamide,

N²- tert-buty 1-7 - { 3-chloro-4- { ( 4 - f luorobenzyl ) oxy] phenyl} -6cyclo-propyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1K)dicarboxamide,

20 AT²-tert-butyl-7- [4- (cyanomethoxy) phenyl] -6-cyclo-propyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IB)-dicarboxamide,

A/² - tert-butyl-6-cyclo-propy 1-7- [ 4- (trif luoromethoxy) phenyl ] -

3.4- dihydropyrrolo[1,2-a]pyrazine-2,8 ( IB) -dicarboxamide, A^-tert-butyl-6-cyclo-propyl-7-(2-fluorophenyl)-3,4-

25 dihydropyrrolo[1,2-a]pyrazine-2,8(IB)-dicarboxamide, A^-tert-butyl-G-cyclo-propyl-?-(3-fluorophenyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IB)-dicarboxamide, A^-tert-butyl-6-cycIo-propyl-7-(4-fluorophenyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(IB)-dicarboxamide,

30 A/²- tert-butyl-6-cycl o-propy 1-7- [4 - (methylsuifany 1 ) phenyl ] -

3.4- dihydropyrrolo[1,2-a]pyrazine-2,8(IB)-dicarboxamide, A^-cyclo-hexyl-G-cyclo-propyl-l-phenyl-S,4- dihydropyrrolo[1,2-a]pyrazine-2,8(IB)-dicarboxamide,

N²-(cyclo-hexylmethyl)-6-cyclo-propyl-7-phenyl-3,435 dihydropyrrolo[1,2-a]pyrazine-2,8(IB)-dicarboxamide,

L·

161

N²-[1,1-bi(cyclo-propyl)-1-yl]-6-cyclo-propyl-7- (4methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1/7) dicarboxamide,

6-cycio-propyl-7-phenyl-A^-(2,4,4-trimethylpentan-2-yl)-3,45 dihydropyrrolo[1,2-a]pyrazine-2,8(1H) -dicarboxamide, 6-cyclo-propyl-N²- (hexahydro-2,5-methanopentalen-3a ( lHj yl)-7-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine2,8(1/7)-dicarboxamide,

TV²-(adamantan-l-yl)-6-cycio-propyl-7-phenyl-3,410 dihydropyrrolo[1,2-a]pyrazine-2, 8(1H)-dicarboxamide,

TV²-(adamantan-l-yl)-6-cyclo-propyl-7-(4-methoxyphenyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide, 6-cyclo-propyl-7- (4-methoxyphenyl) -rf- (tetrahydro-2/7-pyran-

4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-

15 dicarboxamide,

6-cyclo-propyl-TV²- (l-methoxy-2-methylpropan-2-yl) -7- (4methoxyphenyl) -3, 4-dihydropyrrolo [1,2-a] pyrazine-2,8 ( 1/7) dicarboxamide,

A^-tert-butyl-6-fluoro-7-phenyl-3,4-dihydropyrrolo[1,220 a] pyrazine-2,8 (1/7) -dicarboxamide,

6-chloro-7\^-iso-butyl-7-phenyl-3, 4-dihydropyrrolo [1,2a ] pyrazine-2,8(1/7) -dicarboxamide,

N²-tert-butyl-6-chloro-7-phenyl·-3,4-dihydropyrrolo[1,2a ] pyrazine-2,8(1/7) -dicarboxamide,

25 Z^-tert-butyl-ô-chloro-?-(3-methylphenyl)-3,4dihydropyrrolo [1,2-a ] pyrazine-2,8 ( 1/7) -dicarboxamide,

TV²- tert-butyl-6-chloro-7-(3-methoxyphenyl)-3,4dihydropyrrolo [1, 2-a] pyrazine-2,8 (1/7) -dicarboxamide,

TV²-tert-butyl-6~chloro-7-[3-(trifluoromethoxy)phenyl]-3,430 dihydropyrrolo [1,2-a ] pyrazine-2,8 (1/7) -dicarboxamide, 2/-tert-butyl-6-chloro-7-(4-methoxyphenyl)-3,4dihydropyrrolo [1,2-a] pyrazine-2,8 (1/7) -dicarboxamide,

N²-tert-butyl-6-chloro-7-(3-cyanophenyl)-3,4dihydropyrrolo [1,2-a ] pyrazine-2,8 ( 1/7) -dicarboxamide,

Ve

162

W²-tert-butyl-6-chloro-7-[3-(trifluoromethyl)phenyl]-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1#)-dicarboxamide, ?/-tert-butyl-6-chloro-7-(3-fluorophenyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide,

5 6-chloro-#²-(cyclo-propylmethyl)-7-phenyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1#)-dicarboxamide,

6-chloro-#²- ( 3-methylbutyl) -7-phenyl-3,4 -dihydropyrrolo [1,2-

a]pyrazine-2,8(1H) -dicarboxamide,

6-ch1orο-N²-¢2,2-dimethylpropyl)-7-phenyl-3,410 dihydropyrrolo[1,2-a]pyrazine-2,8(1#)-dicarboxamide,

6-chloro-W²-(2-ethylbutyl)-7-phenyl-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8(1#)-dicarboxamide,

6-chloro-#²-(3.3-dimethylbutyl)-7-phenyl-3,4dihydropyrrolo [1,2-a] pyrazine-2,8 ( 1#) -dicarboxamide,

15 6-chloro-7-(3-fluorophenyl)-N²-(3-hydroxy-2, 2dimethylpropyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1#) dicarboxamide,

6-chloro-#²- (3-hydroxy-2,2-dimethylpropyl) -7- (3trifluoromethyl-phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine20 2,8(1#)-dicarboxamide,

6-chloro-7-(3-fluorophenyl)-Λ^-( [1-(hydroxymethyl) cyclopropyl]methyl}— 3,4-dihydropyrrolo[1,2-a]pyrazine-2,8 (1#) dicarboxamide, ë-chloro-7-phenyl-W²-(2,2,2-trifluoroethyl)-3,425 dihydropyrrolo[1,2-a]pyrazine-2,8(1#) -dicarboxamide,

6-chloro-7-(3-fluorophenyl)-if-(2,2,2-trifluoroethyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide, 6-chloro-7-(3-fluorophenyl)-W²-[(2S)-1,1,1-trifluoropropan-

2-yl]-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1#)-

30 dicarboxamide,

6-chloro-7-(3-fluorophenyl)-W²-(1,1,1-trifluoro-2methylpropan-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine2,8(1#) - dicarboxamide,

6-chloro-7-(3-fluorophenyl)-W²-(3,3, 3~trifluoropropyl)-3,435 dihydropyrrolo[1,2-a]pyrazine-2,8(1#) -dicarboxamide,

163

6-ch1or0-7-(3-fluorophenyl)-N²-(4,4,4-trifluorobutyl)-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide, 6-chloro-A^-cycIo-hexyl-7-phenyl-3, 4-dihydropyrrolo [1,2-

a]pyrazine-2,8(1H)-dicarboxamide

5 trans-6-chloro-(3-fluorophenyl)-ftf-(-[(4-hydroxy-cyclohexyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2,8(1//) — dicarboxamide, trans-6-chloro-(3-fluorophenyl)-if-(-[(4-hydroxy-4-methylcyclo-hexyl ) -3,4-dihydropyrrolo [ 1,2-a ] pyrazine-2,8(1//)10 dicarboxamide, trans-6-chloro-(3-fluorophenyl)-N²-(-[(4-hydroxy-4trifluoromethyl-cyclo-hexyl)-3,4-dihydropyrrolo[1,2-

a]pyrazine-2,8 (1/7) -dicarboxamide, trans-6-chloro-(3-fluorophenyl)-N²-(-[(4-methoxyimino-

15 cyclohexyl) -3, 4-dihydropyrrolo [ 1,2-a] pyrazine-2,8(1//)dicarboxamide, trans-6-chloro-(3-fluorophenyl)-N²-(-[(4-tert-butyloxyiminocyclohexyl) - 3,4-dihydropyrrolo [ 1,2-a ] pyrazine-2,8(1/7)dicarboxamide,

20 N²-[bicyclo[2.2.1]hept-2-yl)-6-chloro-7-phenyl-3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1/7) -dicarboxamide, 6-chloro-N²- ( 4 , 4-difluoro-cyclo-hexyl )-7-( 3-f luorophenyl ) -

3.4- dihydropyrrolo[1,2-a]pyrazine-2,8(1 H) -dicarboxamide, 6-chloro-7-(3-fluorophenyl)-N²-(oxetan-3-yl)-3,4-

25 dihydropyrrolo [ 1,2-a] pyrazine-2,8(1/7) -dicarboxamide, 6-chloro-7-(3-fluorophenyl)-N²-(3-methyl-oxetan-3-ylmethyl)-

3.4- dihydropyrrolo [1,2-a] pyrazine-2,8 ( 1/7) -dicarboxamide,

5- chloro-Z-phenyl-N²-(tetrahydrofuran-3-yl)-3,4dihydropyrrolo [ 1,2-a] pyrazine-2,8(1/7) -dicarboxamide,

30 ë-chloro-Z-phenyl-N²- (tetrahydro-2/7-pyran-4-yl) -3,4dihydropyrrolo [ 1,2-a] pyrazine-2,8(1/7) -dicarboxamide,

6- chloro-7- (3-methylphenyl) -W²- (tetrahydro-2I/-pyran-4-yl) -

3,4-dihydropyrrolo [ 1,2-a ] pyrazine-2,8(1/7) -dicarboxamide, 6-chloro-7- (3-cyanophenyl) -N²- (tetrahydro-2//-pyran-4-yl) -

35 3,4-dihydropyrrolo [1,2-a] pyrazine-2,8 (1/7) -dicarboxamide,

164

6-chloro-A?²- (tetrahydro-277-pyran-4-yl) —7—[3— (trifluoromethyl)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazine2,8(1H) -dicarboxamide,

6-chloro-N²- (tetrahydro-277-pyran-4-yl) -7- [35 (trifluoromethoxy)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 (1/7) -dicarboxamide,

6-ch1or0-7-(3-fluorophenyl)-N²-(tetrahydro-2H-pyran-4-yl)-

3,4-dihydropyrrolo [1,2-a]pyrazine-2,8 (1/7) -dicarboxamide, 6-chloro-7- (3-f luorophenyl) -ff- (2,2-dimethyl-tetrahydro-2/7-

10 pyran-4-yl) -3, 4-dihydropyrrolo [ 1,2-a] pyrazine-2,8(1/7)dicarboxamide, cis-G-chloro-ÏV²- ( 2.6-dimethyl-tetrahydro-2/7-pyran-4-yl ) -7(3-fluorophenyl) -3,4-dihydropyrrolo [1,2-a] pyrazine-2,8 ( 1/1) dicarboxamide,

15 Ê-chloro-TT²- (1, l-dioxydotetrahydrothiophen-3-yl) -7-phenyl-

3,4-dihydropyrrolo [1,2-a] pyrazine-2,8 ( 1/7) -dicarboxamide, 6-chloro-TJ²- (1, l-dioxydotetrahydrothiophen-3-yl) -7- (3f luorophenyl) -3, 4-dihydropyrrolo [1,2-a] pyrazine-2,8 (1/7) dicarboxamide,

20 6-ch 1 oro-N²- ( 1, l-dioxydotetrahydro-2J7-thiopyran-4-yl ) -7- ( 3fluorophenyl) -3, 4-dihydropyrrolo [ 1,2-a] pyrazine-2,8 ( 1/7) dicarboxamide,

6-bromo-7-(3-fluorophenyl)-A^-tert-butyl-S,4dihydropyrrolo [1, 2-a] pyrazine-2,8 (1/7) -dicarboxamide,

25 6-cyano-7- (3-f luorophenyl) -Λ²- ( tert-butyl) -3,4dihydropyrrolo[1,2-a]pyrazine-2,8(1H) -dicarboxamide, 6-cyano-7-(3-fluorophenyl)-N²-((2S)-1,1,1-trifluoropropan-2yl) - 3,4-dihydropyrrolo [1,2-a] pyrazine-2,8(1/7) -dicarboxamide, 6-cyano-7-(3-fluorophenyl)-N²-(1,1,1-trifluoro-230 methylpropan-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-

2,8 ( 1/7) -dicarboxamide,

6-cyano-7-(3-fluorophenyl)-N²-(4,4,4-trifluoro-butyl)-3,4dihydropyrrolo [ 1,2-a ] pyrazine-2,8 ( 1/7) -dicarboxamide, 6-cyano-7- ( 3-f luorophenyl ) -N*- (tetrahydro-2/7-pyran-4-yl ) 35 3, 4-dihydropyrrolo [1,2-a] pyrazine-2,8 ( 1/7) -dicarboxamide,

165

6-cyano-N²-¢4,4-difluoro-cyclohexyl)-7-(3-fluorophenyl)-3,4dihydropyrrolo [1,2-a] pyrazine-2,8 (lli) -dicarboxamide.

4. Process for preparing compounds of formula (I) according to any one of Claims 1 to 3, comprising the step that consîsts in reacting a 1,2,3,4-tetrahydropyrrolo[1,2-

a]pyrazine-8-carboxamide dérivative.

which is a compound of formula (II) below:

in which R₇ and Xg are as defined in the general formula (I) defined in Claim 1, with a compound of formula (Ilb) in which R₂ is as defined in the general formula (I) defined in Claim 1 and R represents a group such as phenyl, pentafluorophenyl or 4-nitrophenyl, in an aprotic solvent such as acetonitrile and in the presence of a minerai base such as sodium carbonate, ο

or alternatively with a compound of formula ^N (Ha) in which R₂ is as defined in the general formula (I) defined in Claim 1, in an aprotic solvent such as dichloromethane and optionally in the presence of an organic amine such as triethylamine.

5. Process for preparing compounds of formula (XVII), comprising the step that consîsts in reacting a pyrrole dérivative, which is a compound of formula (XVIII) below:

VT16268

166 (XVIII) with an acidic solution, for example an aqueous hydrochloric acid solution, and formaldéhyde or paraformaldéhyde, to give the 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine dérivatives of general formula (XVII)

GP^

HN ^l6 (XVII) in which Xé represents a fluorine or chlorine atom, while R7 is as defined according to either of Claims 1 and 2, and Gg represents a nitrile group or an alkyl carboxylate group, such as a methyl or ethyl carboxylate.

6. Médicament comprising a compound of formula (I) according to any one of Claims 1 to 3, in the form of the base or of an addition sait with a pharmaceutically acceptable acid.

7. Pharmaceutical composition contaîning at least one compound of formula (I) according to any one of Claims 1 to 3, in the form of the base or of an addition sait with a pharmaceutically acceptable acid, and optionally one or more pharmaceutically acceptable excipients.

8. Use of a compound of formula (I) according to any one of Claims 1 to 3, in the form of the base or of an addition sait with a pharmaceutically acceptable acid, for the préparation of a médicament for preventing and/or treating sleep disorders and circadian rhythm disorders.

167

9. Use of a compound of formula (I) according to any one of Claims 1 to 3, in the form of the base or of an addition sait with a pharmaceutically acceptable acid, for the préparation of a médicament for preventing or treating

5 inflammatory diseases, especially such as inflammatory diseases of the central nervous system, for instance multiple sclerosis, encephalitis, myelitis and encephalomyelitis and other inflammatory diseases, for instance vascular pathologies, atherosclerosis, joint

10 inflammation, arthrosis and rheumatoid arthritis.

167 pages