Substituted [1,2,4]triazolo[4,3-a]pyrazines as selective NK-3 receptor antagonists

1. A process for manufacturing a compound of Formula I,

wherein:

R 1 is H, F or methyl;

R 1′ is H;

R 2 is H, F, Cl or methoxy;

R 2′ is H or F;

R 3 is H, F, Cl, methyl, trifluoromethyl or cyano;

R 4 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl;

R 5 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, or fluoromethyl;

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

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

stands for the (R)-enantiomer or for the racemate of the compound of Formula I;

said process comprising the following steps:

a) reacting a compound of Formula (i)

wherein:

PG represents a suitable protecting group selected from the group consisting of 2,4-dimethoxybenzyl, 4-methoxybenzyl, tert-butoxycarbonyl, allyl, diphenyl-phosphinamide and 2-trimethylsilylethanesulfonyl;

R 4′ is R 4 as defined above or —CH 2 CO 2 -alkyl; and

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

with a compound of Formula (ii)

wherein:

R 5′ is R 5 as defined above, H or 1-((tert-butyldiphenylsilyl)oxy)ethyl;

X 1 and X 2 are as defined above; and

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′ , R 5′ , 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 bond depending on X 1 and X 2 ;

b) deprotecting the compound of Formula (iii) to afford a compound of Formula (iv)

wherein:

R 4′ , R 5′ , 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 bond depending on X 1 and X 2 ;

c) when R 5′ is H, introducing a trifluoromethyl or difluoromethyl group by direct C—H trifluoromethylation or difluoromethylation, to afford a compound of Formula (v)

wherein:

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

R 5 is trifluoromethyl or difluoromethyl,

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

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

d) when R 5′ is not H, N-acylating a compound of Formula (iv) or N-acylating a 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;

leading to a compound of Formula (vii)

wherein:

R 1 , R 1′ , R 2 , R 2′ , R 3 , R 4′ , X 1 and X 2 are as defined above,

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

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

R 5″ is R 5 as defined above or 1-((tert-butyldiphenylsilyl)oxy)ethyl; and

optionally e′) when R 4′ is —CH 2 CO 2 -alkyl, (i) a step of reduction optionally followed by (ii) methyl ether formation

to afford a compound of Formula I.

2. The process according to claim 1 , wherein the process is for manufacturing a compound of Formula I′ or Formula I″:

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

4. The process according to claim 1 , wherein the process is for manufacturing a compound of Formula Ia′ or Formula Ia″:

5. The process according to claim 1 , wherein the process is for manufacturing a compound of Formula Ia-1:

6. The process according to claim 1 , wherein the process is for manufacturing a compound of Formula Ia-2:

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

8. The process according to claim 1 , wherein the process is for manufacturing a compound of Formula Ib:

wherein:

R 3 is F; and

R 5 is methyl, ethyl, trifluoromethyl, difluoromethyl, or fluoromethyl.

9. The process according to claim 1 , wherein the process is for manufacturing a compound of Formula Ib′:

wherein:

R 3 is F; and

R 5 is methyl, ethyl, trifluoromethyl, difluoromethyl, or fluoromethyl.

10. The process according to claim 1 , wherein the process for manufacturing a compound of Formula Ic:

wherein:

R 4 is methyl, ethyl, n-propyl or hydroxyethyl; and

R 5 is methyl, ethyl or trifluoromethyl.

11. The process according to claim 1 , wherein the process is for manufacturing a compound of Formula Ic′:

wherein:

R 4 is methyl, ethyl, n-propyl or hydroxyethyl; and

R 5 is methyl, ethyl or trifluoromethyl.

12. The process according to claim 1 , wherein the process is for manufacturing a compound selected from the group consisting of:

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

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

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

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

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

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

(R)-(8-methyl-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;

(R)-(8-methyl-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;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(R)-4-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)benzonitrile;

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

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

(8-methyl-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;

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

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

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

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

13. The process according to claim 1 , wherein the process is for manufacturing a compound selected from the group consisting of:

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

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

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

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

14. The process according to claim 1 , wherein the process is for manufacturing (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone.

15. A process for manufacturing a compound of Formula I,

wherein:

R 1 is H, F, or methyl;

R 1′ is H;

R 2 is H, F, Cl, or methoxy;

R 2′ is H or F;

R 3 is H, F, Cl, methyl, trifluoromethyl, or cyano;

R 4 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl, or fluoromethyl;

R 5 is 1-fluoroethyl, 1,1-difluoroethyl, or 2,2,2-trifluoroethyl;

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

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

stands for the (R)-enantiomer or for the racemate of the compound of Formula I;

said process comprising the following steps:

a) reacting a compound of Formula (i)

wherein:

PG represents a suitable protecting group selected from the group consisting of 2,4-dimethoxybenzyl, 4-methoxybenzyl, tert-butoxycarbonyl, allyl, diphenyl-phosphinamide, and 2-trimethylsilylethanesulfonyl;

R 4′ is R 4 as defined above or —CH 2 CO 2 -alkyl; and

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

with a compound of Formula (ii)

wherein:

R 5′ is R 5 as defined above, H, or 1-((tert-butyldiphenylsilyl)oxy)ethyl;

X 1 and X 2 are as defined above; and

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′ , R 5′ , 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 bond depending on X 1 and X 2 ;

b) deprotecting the compound of Formula (iii) to afford a compound of Formula (iv)

wherein:

R 4′ , R 5′ , 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 bond depending on X 1 and X 2 ;

c) when R 5′ is H, introducing a trifluoromethyl or difluoromethyl group by direct C—H trifluoromethylation or difluoromethylation, to afford a compound of Formula (v)

wherein:

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

R 5 is trifluoromethyl or difluoromethyl,

stands for the (R)-enantiomer or for the racemate, and

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

d) when R 5′ is not H, N-acylating a compound of Formula (iv) wherein R 5′ or N-acylating a 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;

leading to a compound of Formula (vii)

wherein:

R 1 , R 1′ , R 2 , R 2′ , R 3 , R 4′ , X 1 , and X 2 are as defined above,

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

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

R 5″ is R 5 as defined above or 1-((tert-butyldiphenylsilyl)oxy)ethyl;

optionally e′) when R 4′ is —CH 2 CO 2 -alkyl, (i) a step of reduction, optionally followed by (ii) methyl ether formation; and

optionally e″) when R 5″ is 1-((tert-butyldiphenylsilyl)oxy)ethyl, (i) alcohol deprotection followed by fluorination to afford a 1-fluoroethyl R 5 group; or (ii) alcohol deprotection, followed by an oxidation step and a subsequent fluorination step to afford a 1,1-difluoroethyl R 5 group;

to afford a compound of Formula I.

16. The process according to claim 15 , wherein the process is for manufacturing a compound of Formula I′ or Formula I″:

17. The process according to claim 15 , wherein the process is for manufacturing a compound of Formula Ib:

wherein R 3 is F.

18. The process according to claim 15 , wherein the process is for manufacturing a compound of Formula Ib′:

wherein R 3 is F.

19. The process according to claim 15 , wherein the process is for manufacturing a compound selected from the group consisting of:

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

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

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