NOVEL CHIRAL N-ACYL-5,6,7(8-SUBSTITUTED)-TETRAHYDRO-[1,2,4]TRIAZOLO[4,3-a]PYRAZINES AS SELECTIVE NK-3 RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITION, METHODS FOR USE IN NK-3 RECEPTOR MEDIATED DISORDERS AND CHIRAL SYNTHESIS THEREOF

A compound of Formula I:

• and pharmaceutically acceptable solvates thereof, wherein
• Ar1 is unsubstituted thiophen-2-yl, unsubstituted phenyl, or 4-fluorophenyl;
• R1 is H or methyl;
• Ar2 is of general Formula (i), (ii) or (iii):
• wherein
• R2 is linear or branched C1-C4 alkyl, C1-C2 haloalkyl, linear or branched C2-C3 alkenyl, C3-C4 cycloalkyl or di(C1-C2 alkyl)amino;
• X1 is N or C—R6 wherein R6 is H, fluoro or C1-C2 alkyl;
• X2 is O or S;
• X3 is N, or X3 is CH under the condition that X1 is N and X2 is N—R7 wherein R7 is linear or branched C1-C3 alkyl or cyclopropyl;
• R3 is linear or branched C1-C4 alkyl or C3-C4 cycloalky;
• X4 is N or C—R8 wherein R8 is H or C1-C2 alkyl;
• X5 is O or S;
• X6 is N, or X6 is CH under the condition that X4 is N and X5 is N—R9 wherein R9 is linear or branched C1-C3 alkyl or cyclopropyl;
• R4 is halo, cyano, methyl, or hydroxyl;
• R5 is H or halo;
• with the condition that when Ar2 is of Formula (iii), then R1 is methyl;
• and
• the compound of Formula I is not
• (3-(2-isobutylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;
• [1,1′-biphenyl]-4-yl(8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;
• (8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone.

Process of preparing 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine compound of Formula II

• or a salt or solvate thereof, wherein
• R1′ is linear or branched C1-C4 alkyl or C3-C4 cycloalkyl, each of said alkyl or cycloalkyl groups, groups being optionally substituted by one or more group(s) selected from halo or esters;
• and
• Ar2 is a 5- to 6-membered aryl or heteroaryl group, each of the aryl, or heteroaryl groups being optionally substituted by one or more group(s) selected from halo, alkyl, haloalkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, alkoxy, alkylamino, carbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, arylsulfonylalkyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, fused to the aryl or heteroaryl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituent(s) selected from halo, alkyl, haloalkyl, alkoxy, haloalkoxy;
• said process comprising the following steps:
• a) reacting a compound of Formula A
• wherein
• R1′ is as defined in respect of Formula II;
• with a reagent resulting in a N-sp3 protective 3) on the amine nitrogen of compound of Formula A,
• in the presence of a reducing agent to obtain a compound of Formula C
• b) converting the compound of Formula C a tri(C1-C2 alkyl) oxonium salt so as to obtain a compound of Formula D
• wherein R1′ is as defined with respect to Formula II, PG is as defined with respect to Formula C, and R10 is C1-C2 alkyl,
• in the presence of a base;
• c) reacting the compound of Formula D with a compound of Formula E
• or a salt or solvate thereof, wherein
• Ar2′ is as defined with respect to Formula II;
• so as to obtain a compound of Formula F
• wherein R1′ is as defined with respect to Formula II, PG is as defined with respect to Formula C, and Ar2′ is as defined with respect to Formula E;
• and
• d) deprotecting the compound of Formula F with a suitable deprotection reagent to afford the compound of Formula II or a salt or solvate thereof.

A compound of Formula D

• or a salt or solvate thereof;
• wherein
• R1′ is linear or branched C1-C4 alkyl or C3-C4 cycloalkyl, each of said alkyl or cycloakyl groups, groups being optionally substituted by one or more group(s) selected from halo or esters;
• PG is a N-sp3 protective oup;
• and
• R10 is C1-C2 alkyl.

A compound of Formula III

• or salts or solvates thereof, wherein
• R1′ is linear or branched C1-C4 alkyl or C3-C4 cycloalkyl, each of said alkyl or cycloakyl groups, groups being optionally substituted by one or more group(s) selected from halo or esters;
• Ar2′ is a 5- to 6-membered aryl or heteroaryl group, each of the aryl, or heteroaryl groups being optionally substituted by one or more group(s) selected from halo, alkyl, haloalkyl, cycloalkyl, heteroalkyl;
• heterocyclyl, aryl, heteroaryl, hydroxyl, alkoxy, alkylamino, carbamoyl, alkyl carbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkyl sulfonyl, arylsulfonylalkyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or fused to the aryl or heteroaryl group may be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of said substituents being optionally substituted by one or more further substituent(s) selected from halo, alkyl, haloalkyl, alkoxy, haloalkoxy;
• and
• R11 is H or an N-sp3 protective group;
• with the proviso that the compound of Formula III is not
• (R)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-phenylthiazole hydrochloride,
• (R)-8-methyl-3-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine dihydrochloride salt,
• (R)-2-(4-chlorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole hydrochloride salt,
• (R)-2-(4-fluorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole hydrochloride salt,
• (S)-8-methyl-3-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine,
• (S)-2-(4-fluorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole,
• (S)-4-(4-(8-meth-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)morpholine.