IP Library Granted Patent US 8,889,688
Granted Patent B2
US 8,889,688 · App. 13/519,938 · Granted Nov 18, 2014

Piperazines as antimalarial agents

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Quick Facts
Patent No.
US 8,889,688
App. No.
13/519,938
Granted
Nov 18, 2014
Kind
B2
Abstract

The invention relates to novel piperazine derivatives and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including pharmaceutical compositions containing one or more of those compounds and their use as medicaments for the treatment or prevention of protozoal infections, such as especially malaria.

Claims (142)

1. A compound of the formula I:

wherein

X is CH or N;

R 1 represents —NO 2 , —N(CH 3 ) 2 , or —NCH 3 (CH 2 CH 2 OH); and

R 2 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyano, halogen, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl, acetyl, or acetylamino; or

X is CH, R 1 is hydrogen, and R 2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, methylsulfonyl, acetylamino, or methoxycarbonyl; or

X is CH, R 1 is cyano, and R 2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl, or acetylamino; or

X is CH, R 1 is chloro, and R 2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, difluoromethoxy, methylsulfonyl, or acetylamino; or

X is CH, R 1 is methoxy or isopropoxy, and R 2 is trifluoromethyl; or

X is CH, R 1 is methylsulfonyl or ethylsulfonyl, and R 2 is trifluoromethyl, ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, or difluoromethoxy;

or a salt of such a compound.

2. The compound according to claim 1 , wherein

X is CH or N;

R 1 represents —NO 2 , —N(CH 3 ) 2 , or —NCH 3 (CH 2 CH 2 OH); and

R 2 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyano, halogen, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl, acetyl, or acetylamino; or

X is CH, R 1 is hydrogen, and R 2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, methylsulfonyl, acetylamino, or methoxycarbonyl; or

X is CH, R 1 is cyano, and R 2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl, or acetylamino; or

X is CH, R 1 is chloro, and R 2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, difluoromethoxy, methylsulfonyl, or acetylamino; or

X is CH, R 1 is methoxy or isopropoxy, and R 2 is trifluoromethyl;

or a salt of such a compound.

3. The compound according to claim 1 , wherein

X is CH or N;

R 1 represents —NO 2 , —N(CH 3 ) 2 , or —NCH 3 (CH 2 CH 2 OH); and

R 2 represents ethyl, isopropyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl, or acetylamino; or

X is CH, R 1 is hydrogen, and R 2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, methylsulfonyl, acetylamino, or methoxycarbonyl; or

X is CH, R 1 is cyano, and R 2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl, or acetylamino; or

X is CH, R 1 is chloro, and R 2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, isopropoxy, difluoromethoxy, methylsulfonyl, or acetylamino; or

X is CH, R 1 is methoxy or isopropoxy, and R 2 is trifluoromethyl;

or a salt of such a compound.

4. The compound according to claim 1 , wherein

R 1 represents —NO 2 , —N(CH 3 ) 2 , or —NCH 3 (CH 2 CH 2 OH); and

R 2 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyano, halogen, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl, acetyl, or acetylamino;

or a salt of such a compound.

5. The compound according to claim 1 , wherein

R 1 represents —NO 2 , —N(CH 3 ) 2 , or —NCH 3 (CH 2 CH 2 OH); and

R 2 represents ethyl, isopropyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethoxy, methylsulfonyl, or acetylamino;

or a salt of such a compound.

6. The compound according to claim 4 , wherein X is CH, or a salt of such a compound.

7. The compound according to claim 4 , wherein X is N, or a salt of such a compound.

8. The A compound according to claim 4 , wherein R 1 represents —NO 2 , or a salt of such a compound.

9. The compound according to claim 4 , wherein R 1 represents —N(CH 3 ) 2 , or a salt of such a compound.

10. The compound according to claim 4 , wherein R 1 represents —NCH 3 (CH 2 CH 2 OH), or a salt of such a compound.

11. The compound according to claim 4 , wherein R 2 is ethyl, isopropyl, tert-butyl, ethoxy, n-propoxy, or isopropoxy, or a salt of such a compound.

12. The compound according to claim 11 , wherein R 2 is isopropoxy, or a salt of such a compound.

13. The compound according to claim 4 , wherein R 2 is trifluoromethyl, difluoromethoxy, methylsulfonyl, or acetylamino, or a salt of such a compound.

14. The compound according to claim 4 , wherein R 2 is methoxy, or a salt of such a compound.

15. The compound according to claim 4 , wherein R 2 is hydrogen, methyl, n-propyl, cyano, halogen, or acetyl, or a salt of such a compound.

16. The compound according to claim 1 , selected from the group consisting of:

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(6-methoxy-pyridin-3-yl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(6-ethoxy-pyridin-3-yl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-ethoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-methanesulfonyl-phenyl)-acrylamide,

(S)-3-(4-Acetylamino-phenyl)-N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-propoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-isopropoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-ethyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-difluoromethoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-isopropyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(6-methoxy-pyridin-3-yl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(6-ethoxy-pyridin-3-yl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(4-ethoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(4-methanesulfonyl-phenyl)-acrylamide,

(S)-3-(4-Acetylamino-phenyl)-N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(4-propoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(4-isopropoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(4-ethyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(4-difluoromethoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(4-isopropyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(4-tert-butyl-phenyl)-acrylamide, and

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-nitro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide,

or salts of these compounds.

17. The compound according to claim 1 , selected from the group consisting of:

(S)—N-[4-(4-Acetyl-piperazin-1-yl)benzyl]-N-{1-(4-(4-(dimethylamino)benzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl}cinnamamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)benzyl]-N-{1-[4-(4-(dimethylamino)benzyl)piperazin-1-yl]-1-oxo-3-phenylpropan-2-yl}-3-(p-tolyl)acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)benzyl]-N-{1-(4-(4-(dimethylamino)benzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl}-3-(4-propylphenyl)acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)benzyl]-N-{1-(4-(4-(dimethylamino)benzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl}-3-(4-methoxyphenyl)acrylamide,

(S)-3-(4-Acetyl-phenyl)-N-[4-(4-acetyl-piperazin-1-yl)benzyl]-N-{1-(4-(4-(dimethylamino)benzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl}acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)benzyl]-3-(4-cyanophenyl)-N-{1-(4-(4-(dimethylamino)benzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl}acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)benzyl]-N-{1-(4-(4-(dimethylamino)benzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl}-3-(4-fluorophenyl)acrylamide, and

(S)—N-[4-(4-Acetyl-piperazin-1-yl)benzyl]-3-(4-chlorophenyl)-N-{1-(4-(4-(dimethylamino)benzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl}acrylamide, or salts of these compounds.

18. The compound according to claim 1 , selected from the group consisting of:

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-3-(4-ethyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-3-(4-tert-butyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-3-(4-ethoxy-phenyl)-acrylamide,

(S)-4-(2-{[4-(4-Acetyl-piperazin-1-yl)-benzyl]-[1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-carbamoyl}-vinyl)-benzoic acid methyl ester,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-3-(4-methanesulfonyl-phenyl)-acrylamide,

(S)-3-(4-Acetylamino-phenyl)-N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-3-(4-propoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-3-(4-isopropoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-3-(4-isopropyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-ethoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-methanesulfonyl-phenyl)-acrylamide,

(S)-3-(4-Acetylamino-phenyl)-N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-propoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-isopropoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-ethyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-difluoromethoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-isopropyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-trifluoromethoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-chloro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-ethoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-chloro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-methanesulfonyl-phenyl)-acrylamide,

(S)-3-(4-Acetylamino-phenyl)-N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-chloro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-chloro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-propoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-chloro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-isopropoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-chloro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-ethyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-chloro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-difluoromethoxy-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-chloro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-isopropyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-chloro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-methoxy-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide, and

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-isopropoxy-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide, or salts of these compounds.

19. The compound according to claim 1 , selected from the group consisting of:

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-(methylsulfonyl)-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-isopropoxyphenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-(methylsulfonyl)-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-(methylsulfonyl)-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-propoxyphenyl)-acrylamide,

(S)—N-(4-(4-acetylpiperazin-1-yl)benzyl)-N-(1-(4-(4-(methylsulfonyl)benzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)-3-(4-(trifluoromethyl)phenyl)acrylamide,

(S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-(ethylsulfonyl)-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-propoxyphenyl)-acrylamide, and

(S)—N-(4-(4-acetylpiperazin-1-yl)benzyl)-N-(1-(4-(4-(ethylsulfonyl)benzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)-3-(4-(trifluoromethyl)phenyl)acrylamide,

or salts of these compounds.

20. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier material.

21. A method for the treatment of malaria comprising administering to a subject a pharmaceutically active amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

22. A compound according to claim 1 , which is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide, or a salt thereof.

23. A compound according to claim 1 , which is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-propoxy-phenyl)-acrylamide, or a salt thereof.

24. A compound according to claim 1 , which is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide, or a salt thereof.

25. A compound according to claim 1 , which is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-(methylsulfonyl)-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide, or a salt thereof.

26. A compound according to claim 1 , which is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(4-tert-butyl-phenyl)-acrylamide, or a salt thereof.

27. The pharmaceutical composition according to claim 20 , wherein the compound is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide, or a pharmaceutically acceptable salt thereof.

28. The pharmaceutical composition according to claim 20 , wherein the compound is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-propoxy-phenyl)-acrylamide, or a pharmaceutically acceptable salt thereof.

29. The pharmaceutical composition according to claim 20 , wherein the compound is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide, or a pharmaceutically acceptable salt thereof.

30. The pharmaceutical composition according to claim 20 , wherein the compound is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-(methylsulfonyl)-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide, or a pharmaceutically acceptable salt thereof.

31. The pharmaceutical composition according to claim 20 , wherein the compound is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(4-tert-butyl-phenyl)-acrylamide, or a pharmaceutically acceptable salt thereof.

32. The method according to claim 21 , wherein the compound is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide, or a pharmaceutically acceptable salt thereof.

33. The method according to claim 21 , wherein the compound is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-propoxy-phenyl)-acrylamide, or a pharmaceutically acceptable salt thereof.

34. The method according to claim 21 , wherein the compound is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-cyano-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide, or a pharmaceutically acceptable salt thereof.

35. The method according to claim 21 , wherein the compound is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-{1-benzyl-2-[4-(4-(methylsulfonyl)-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3-(4-tert-butyl-phenyl)-acrylamide, or a pharmaceutically acceptable salt thereof.

36. The method according to claim 21 , wherein the compound is (S)—N-[4-(4-acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-piperazin-1-yl)-2-oxo-ethyl]-3-(4-tert-butyl-phenyl)-acrylamide, or a pharmaceutically acceptable salt thereof.

Assignments (3)
CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE ADDRESS PREVIOUSLY RECORDED AT REEL: 042464 FRAME: 0407. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Jun 28, 2017
From: ACTELION PHARMACEUTICALS LTD
To: IDORSIA PHARMACEUTICALS LTD
Reel/Frame 043017/0022 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 13, 2017
From: ACTELION PHARMACEUTICALS LTD
To: IDORSIA PHARMACEUTICALS LTD
Reel/Frame 042464/0407 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 27, 2012
From: AISSAOUI, HAMED; BOSS, CHRISTOPH; CORMINBOEUF, OLIVIER; HEIDMANN, BIBIA; SIEGRIST, ROMAIN
To: ACTELION PHARMACEUTICALS LTD.
Reel/Frame 028849/0066 →