Compounds for the treatment of parasitic infections

1. A compound according to Formula (I) or a pharmaceutically acceptable salt thereof:

wherein

R 1 is hydrogen, fluoro or methyl, wherein

when R 1 is hydrogen, R 2 is fluoro, methyl, hydroxyl or amino,

when R 1 is fluoro, R 2 is fluoro, and

when R 1 is methyl, R 2 is methyl or hydroxyl;

R 3 is hydrogen or fluoro;

R 4 is fluoro, chloro, cyano or methoxy;

n is 1 or 2; and

Het is imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole or tetrazole, wherein each Het is optionally substituted by C 1 -C 4 alkyl, cyano or —C(O)NH 2 .

2. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is hydrogen.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is hydroxyl or amino.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is hydrogen.

5. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein n is 1.

6. Thesompound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 4 is at the para position.

7. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 4 is fluoro or chloro.

8. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is defined according to Formula Ib:

9. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is defined according to Formula (Id):

10. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Het is selected from one of the following groups, where * represents the point of attachment:

11. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Het is selected from one of the following groups, where * represents the point of attachment:

12. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Het is tetrazole.

13. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is selected from the group consisting of:

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-(2-methyl-3-(1H-tetrazol-1-yl) propoxy)phenyl)methanone;

(R)-(4-(2,2-dimethyl-3-(1H-tetrazol-1-yl)propoxy)phenyl)(3-(4-fluorophenyl)pyrrolidin-1-yl)methanone;

(4-(2-fluoro-3-(1H-tetrazol-1-yl)propoxy)phenyl)((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)methanone;

(R)-(4-(2,2-difluoro-3-(1H-tetrazol-1-yl)propoxy)phenyl)(3-(4-fluorophenyl)-pyrrolidin-1-yl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(1H-tetrazol-1-yl) propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((S)-2-hydroxy-3-(1H-tetrazol-1-yl) propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(2H-tetrazol-2-yl) propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((S)-2-hydroxy-3-(2H-tetrazol-2-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-(2-hydroxy-2-methyl-3-(2H-tetrazol-2-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-(2-hydroxy-2-methyl-3-(1H-tetrazol- 1-yl)propoxy)phenyl)methanone;

(4-((R)-2-fluoro-3-(2H-tetrazol-2-yl)propoxy)phenyl)((R)-3-(4-fluorophenyl) pyrrolidin-1-yl)methanone);

(4-((S)-2-fluoro-3 -(2H-tetrazol-2-yl)propoxy)phenyl)((R)-3-(4-fluorophenyl) pyrrolidin-1-yl)methanone);

((S)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(2H-tetrazol-2-yl)propoxy)phenyl)methanone;

((S)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((S)-2-hydroxy-3-(2H-tetrazol-2-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(2H-1,2,3-triazol-2-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(1H-1,2,3-triazol-1-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(4H-1,2,4-triazol-4-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(1H-pyrazol-1-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4- ((R)-2-hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(5-methyl-1H-tetrazol-1-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4- ((R)-2-hydroxy-3-(5 -methyl-2H-tetrazol-2-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(2-methyl-2H-tetrazol-5-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(1-methyl-1H-tetrazol-5-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(1H-tetrazol-5-yl)propoxy)phenyl)methanone;

(2-fluoro-4-((R)-2-hydroxy-3-(1H-tetrazol -1-yl)propoxy)phenyl)((R)-3-(4-fluorophenyl)pyrrolidin--yl)methanone;

(2-fluoro-4-((R)-2-hydroxy-3-(2H-tetrazol -2-yl)propoxy)phenyl)((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)methanone;

((R)-3-(4-chlorophenyl)pyrrolidin-1-yl)(4- ((R)-2-hydroxy-3-(1H-tetrazol-1-yl)propoxy)phenyl)methanone;

((R)-3-(4-chlorophenyl)pyrrolidin-1-yl)(4- ((R)-2-hydroxy-3-(2H-tetrazol-2-yl)propoxy)phenyl)methanone;

((R)-3-(4-chlorophenyl)pyrrolidin-1-yl) (4-((R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy)phenyl)methanone;

((R)-3-(4-chlorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(2H-1,2,3-triazol-2-yl)propoxy)phenyl)methanone;

((R)-3-(4-chlorophenyl)pyrrolidin-1-yl)(4- ((R)-2-hydroxy-3-(1H-1,2,3-triazol-1-yl)propoxy)phenyl)methanone;

((R)-3-(4-chlorophenyl)pyrrolidin-1-yl) (2-fluoro-4-((R)-2-hydroxy-3-(1H-tetrazol-1-yl)propoxy)phenyl)methanone;

((R)-3-(4-chlorophenyl)pyrrolidin-1-yl) (2-fluoro-4-((R)-2-hydroxy-3-(2H-tetrazol-2-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-(2-hydroxy-3-(thiazol-4-yl)propoxy)phenyl)methanone;

((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-(2-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)propoxy)phenyl)methanone;

2-((R)-3-(4-((R)-3-(4-fluorophenyl)pyrrolidine-1-carbonyl)phenoxy)-2-hydroxypropyl)-2H-tetrazole-5-carboxamide;

2-((R)-3-(4-((R)-3-(4-fluorophenyl)pyrrolidine-1-carbonyl)phenoxy)-2-hydroxypropyl)-2H-tetrazole-5-carbonitrile;

(3-(2-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(2H-tetrazol-2-yl)propoxy)phenyl)methanone;

(3-(3-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(2H-tetrazol-2-yl)propoxy)phenyl)methanone;

(3-(2,4-difluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(2H-tetrazol-2-yl)propoxy)phenyl)methanone;

4-(1-(4-((R)-2-hydroxy-3-(2H-tetrazol-2-yl)propoxy)benzoyl) pyrrolidin-3-yl)benzonitrile;

(4-((R)-2-hydroxy-3-(2H-tetrazol-2-yl)propoxy)phenyl)(3-(4-methoxyphenyl)pyrrolidin-1-yl)methanone;

(4-((R)-2-amino-3-(2H-tetrazol-2-yl)propoxy)phenyl)((R)-3-(4-fluorophenyl) pyrrolidin-1-yl)methanone;

(4-((R)-2-amino-3-(1H-tetrazol-1-yl)propoxy)phenyl)((R)-3-(4-fluorophenyl) pyrrolidin-1-yl)methanone;

(4-((R)-2-amino-3-(1H-tetrazol-1-yl) propoxy)phenyl)((R)-3-(4-chlorophenyl) pyrrolidin-1-yl)methanone;

(4-((R)-2-amino-3-(2H-tetrazol-2-yl) propoxy)phenyl)((R)-3-(4-chlorophenyl) pyrrolidin-1-yl)methanone;

(4-((S)-2-amino-3-(2H-tetrazol-2-yl) propoxy)phenyl)((R)-3-(4-fluorophenyl) pyrrolidin-1-yl)methanone;

(4-((R)-2-amino-3-(2H-tetrazol-2-yl) propoxy)phenyl)((S)-3-(4-fluorophenyl) pyrrolidin-1-yl)methanone;

(4-((S)-2-amino-3-(2H-tetrazol-2-yl) propoxy)phenyl)((S)-3-(4-fluorophenyl) pyrrolidin-1-yl)methanone;

(4-((R)-2-amino-3-(2H-1,2,3-triazol-2-yl) propoxy)phenyl)((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)methanone;

(4-((R)-2-amino-3-(1H-1,2,3-triazol-1-yl) propoxy)phenyl)((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)methanone;

(4-((R)-2-amino-3-(1H-pyrazol-1-yl) propoxy)phenyl)((R)-3-(4-fluorophenyl) pyrrolidin-1-yl)methanone; and

(4-((R)-2-amino-3-(2H-tetrazol-2-yl)propoxy)-2-fluorophenyl)((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)methanone.

14. A pharmaceutical composition comprising (a) a compound or pharmaceutically acceptable salt thereof according to claim 1 ; and (b) a pharmaceutically acceptable excipient.

15. A method for the treatment of a parasitic protozoal infection in a human in need thereof, comprising administering to the human a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the parasitic protozoal infection is a Plasmodium falciparum infection.

16. The method according to claim 15 , wherein the parasitic protozoal infection is malaria.

17. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is ((R)-3-(4-fluorophenyl)pyrrolidin-1-yl)(4-((R)-2-hydroxy-3-(2-H-tetrazol-2-yl) propoxy)phenyl)methanone.

18. A compound which is

or a pharmaceutically acceptable salt thereof.

19. A method for the treatment of a parasitic protozoal infection in a human in need thereof, comprising administering to the human a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 18 , wherein the parasitic protozoal infection is malaria.