N-acyl-(3-substituted)-5,6,7,8-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

1. A process of manufacturing a compound of Formula I:

or a pharmaceutically acceptable solvate thereof, wherein:

R 1 is H or F;

R 1′ is H;

R 2 is H, F or Cl;

R 2′ is H or F;

R 3 is F or Cl;

R 4 is methyl, trifluoromethyl, difluoromethyl or fluoromethyl;

X 1 is N and X 2 is S; or X 1 is S and X 2 is N; and

represents a single or a double bond depending on X 1 and X 2 ;

comprising the following steps:

a) reacting a compound of Formula (i)

wherein:

PG represents a suitable protecting group;

with a compound of Formula (ii)

wherein:

R 4′ is R 4 as defined above or H;

X 1 and X 2 are as defined above;

represents a single or a double bond depending on X 1 and X 2 ;

so as to obtain a compound of Formula (iii)

wherein PG, R 4′ , X 1 and X 2 are as defined above and

represents a single or a double bond depending on X 1 and X 2 ;

b) deprotecting compound of Formula (iii) with a suitable deprotection agent to afford compound of Formula (iv)

wherein R 4′ , X 1 and X 2 are as defined above and

represents a single or a double bond depending on X 1 and X 2 ;

c) when R 4′ is H, a trifluoromethyl or difluoromethyl group is introduced by direct C—H trifluoro- or difluoromethylation, leading to compound of Formula (v)

wherein X 1 and X 2 are as defined above and R 4 is trifluoromethyl, or difluoromethyl and represents a single or a double bond depending on X 1 and X 2 ;

d) N-acylating compound of Formula (iv) wherein R 4′ is not H or compound of Formula (v) with a compound of Formula (vi)

wherein R 1 , R 1′ , R 2 , R 2′ and R 3 are as defined above;

to afford compound of Formula I as defined above.

2. The process according to claim 1 , wherein the compound of Formula I is a compound of Formula Ia:

or a pharmaceutically acceptable solvate thereof, wherein:

R 1 is H or F;

R 1′ is H;

R 2 is H, F or Cl;

R 2′ is H or F;

R 3 is F or Cl; and

R 4 is methyl, trifluoromethyl, difluoromethyl or fluoromethyl.

3. The process according to claim 1 , wherein the compound of Formula I is a compound of Formula Ia-1:

or a pharmaceutically acceptable solvate thereof, wherein:

R 3 is F or Cl; and

R 4 is methyl, trifluoromethyl, difluoromethyl or fluoromethyl.

4. The process according to claim 1 , wherein the compound of Formula I is a compound of Formula Ia-2:

or a pharmaceutically acceptable solvate thereof, wherein:

R 1 is H or F;

R 1′ is H;

R 2 is H, F or Cl;

R 2′ is H or F; and

R 3 is F or Cl.

5. The process according to claim 1 , wherein the compound of Formula I is a compound of Formula Ib:

or a pharmaceutically acceptable solvate thereof, wherein:

R 1 is H or F;

R 1′ is H;

R 2 is H, F or Cl;

R 2′ is H or F;

R 3 is F or Cl; and

R 4 is methyl, trifluoromethyl, difluoromethyl or fluoromethyl.

6. The process according to claim 1 , wherein the compound of Formula I is selected from the group consisting of:

(4-fluorophenyl)(3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;

(4-chlorophenyl)(3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;

(4-chloro-3-fluorophenyl)(3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;

(3-chloro-4-fluorophenyl)(3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;

(3,4-difluorophenyl)(3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;

(3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(3,4,5-trifluorophenyl)methanone;

(3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(2,3,4-trifluorophenyl)methanone;

and a pharmaceutically acceptable solvate thereof.

7. The process according to claim 1 , wherein protecting group is selected from the group consisting of 2,4-dimethoxybenzyl (DMB), 4-methoxybenzyl (PMB), and tert-butoxycarbonyl (Boc).

8. The process according to claim 7 , wherein protecting group is tert-butoxycarbonyl (Boc).

9. The process according to claim 1 , wherein the deprotection agent is trifluoroacetic acid (TFA).