N-acyl-(3-substituted)-(8-methyl)-5,6-dihydro-[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 or trifluoromethyl;

X 1 is S and X 2 is N, or X 1 is CH and X 2 is O;

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

represents an (R)-enantiomer or a racemate of the compound of Formula I;

the process comprising the following steps:

(a) reacting a compound of Formula (i)

wherein

PG represents a suitable protecting group;

stands for the (R)-enantiomer or for the racemate;

with a compound of Formula (ii)

wherein:

R 4 , X 1 , and X 2 are as defined above, and represents a single or a double bound 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, stands for the (R)-enantiomer or for the racemate, and represents a single or a double bound depending on X 1 and X 2 ;

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

wherein R 4 , X 1 and X 2 are as defined above, stands for the (R)-enantiomer or for the racemate, and represents a single or a double bound depending on X 1 and X 2 ;

(c) N-acylating compound of Formula (iv) with a compound of Formula (v)

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

to afford the compound of Formula I as defined above.

2. The process of claim 1 , wherein the compound of Formula I is 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 or trifluoromethyl;

X 1 is S and X 2 is N, or X 1 is CH and X 2 is O; and

represents a single or a double bound depending on X 1 and X 2 .

3. The process of claim 1 , wherein the compound of Formula I is 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 or trifluoromethyl;

X 1 is S and X 2 is N, or X 1 is CH and X 2 is O; and

represents a single or a double bound depending on X 1 and X 2 .

4. The process of 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;

R 4 is methyl or trifluoromethyl; and

represents an (R)-enantiomer or a racemate of the compound of Formula Ia.

5. The process of claim 4 , 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 or trifluoromethyl.

6. The process of 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 C1;

R 2′ is H or F;

R 3 is F or Cl;

R 4 is methyl or trifluoromethyl; and

represents an (R)-enantiomer or a racemate of the compound of Formula Ib.

7. The process of claim 6 , 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 or trifluoromethyl.

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

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

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

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

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

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

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

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

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

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

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

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

(R)-(8-methyl-3-(2-(trifluoromethyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(2,3,4,5-tetrafluorophenyl)methanone;

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

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

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

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

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

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

and pharmaceutically acceptable solvates thereof.

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

10. The process of claim 9 , wherein the protecting group PG is 2,4-dimethoxybenzyl (DMB).

11. The process of claim 1 , wherein the deprotection agent is trifluoroacetic acid (TFA).