Antimalarial agents
Methods of treating malaria comprising administration of compounds of Formula (I′) or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the variables are as defined herein. It also provides uses of the compounds of Formula (I), as defined herein, for inhibiting plasmepsin X, plasmepsin IX or plasmepsin X and IX activity, for treating a Plasmodium infection, and for treating malaria. Also provided are methods of treatment further comprising administration of one or more additional anti-malarial compounds.
1. A compound having the structural Formula (I′):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH 2 , O, S, SO, SO 2 or NH;
Y is CR 9 or N, wherein when Y is N, Z is CR 11 and V is CR 10 ;
V is CR 10 or N, wherein when V is N, Z is CR 11 and Y is CR 9 ;
Z is CR 11 or N, wherein when Z is N, V is CR 10 and Y is CR 9 ;
R 1 is a heterocycloalkyl, C 3 -C 12 cycloalkyl, aryl, or C 1 -C 6 alkylaryl or when taken with R 2 and the nitrogen to which they are bonded, forms a nitrogen-containing ring, wherein the heterocycloalkyl, C 3 -C 12 cycloalkyl, aryl, C 1 -C 6 alkylaryl or nitrogen-containing ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1 -C 6 alkylN(R 7 )(R 8 );
R 2 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl or C 1 -C 6 alkylOH or when taken with R 1 , and the nitrogen to which they are bonded, forms a nitrogen-containing ring, wherein the nitrogen-containing ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1 -C 6 alkylN(R 7 )(R 8 );
R 3 is hydrogen, halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), or C 1 -C 6 alkylN(R 7 )(R 8 ), or when taken with R 4 forms a C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl;
R 4 is hydrogen, halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), or C 1 -C 6 alkylN(R 7 )(R 8 ), or when taken with R 3 forms a C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl;
R 5 is hydrogen, halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 ), or when taken with R 6 forms a C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl;
R 6 is hydrogen, halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 ), or when taken with R 5 forms a C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl;
R 7 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, or C 1 -C 6 alkylOH;
R 8 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, or C 1 -C 6 alkylOH;
R 9 is hydrogen, halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 );
R 10 is hydrogen, halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 );
R 11 is hydrogen, halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 );
R 12 is hydrogen, halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 ); and
m is 0, 1 or 2.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1 and X is O.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1 and X is CH 2 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0 and X is O.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1 and X is SO 2 .
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
and wherein R 1 is unsubstituted or substituted with 1 to 5 substituents independently selected from the group halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1 -C 6 alkylN(R 7 )(R 8 );
R 7 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl or C 1 -C 6 alkylOH; and
R 8 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl or C 1 -C 6 alkylOH.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:
and wherein R 1 is unsubstituted or substituted with 1 to 5 substituents independently selected from the group halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl and C 1 -C 6 alkylOH.
8. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:
and wherein R 1 is unsubstituted or substituted with 1 to 5 substituents independently selected from the group halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, NH 2 , and C 1 -C 6 alkylOH.
9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is taken with R 2 and the nitrogen to which they are bonded, to form a nitrogen-containing ring.
11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the nitrogen-containing ring is:
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, C 1 -C 6 alkylOC 1 -C 6 alkyl or C 1 -C 6 alkyl or when taken with R 4 forms a C 3 -C 6 heterocycloalkyl.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen or C 1 -C 6 alkyl, or when taken with R 4 forms a C 3 -C 6 heterocycloalkyl.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen or C 1 -C 6 alkyl.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen or C 1 -C 6 alkyl.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently selected from the group hydrogen, halogen, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkylalkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkyl, CON(C 1 -C 6 alkyl) 2 , and C 1 -C 6 alkylN(R 7 )(R 8 )
R 7 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, COC 1 -C 6 alkyl or COOC 1 -C 6 alkyl;
R 8 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, COC 1 -C 6 alkyl or COOC 1 -C 6 alkyl.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2, and R 12 is selected from hydrogen, halogen, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkylalkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, and C 1 -C 6 alkyl.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CH.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is CH.
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is CH.
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is N; and Y and V are both CH.
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is N; and Y and Z are both CH.
23. A compound selected from the group:
or a pharmaceutically acceptable salt thereof.
24. A compound selected from
25. A compound selected from
or a pharmaceutically acceptable salt thereof.
26. A compound having the formula
or a pharmaceutically acceptable salt thereof.
27. A compound having the formula
or a pharmaceutically acceptable salt thereof.
28. A compound having the formula
or a pharmaceutically acceptable salt thereof.
29. The compound according to claim 24 , which is:
30. The compound according to claim 24 , which is:
31. The compound according to claim 24 , which is:
32. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
33. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
34. A pharmaceutical composition comprising a compound of claim 26 , and a pharmaceutically acceptable carrier.
35. The pharmaceutical composition according to claim 34 , further comprising one or more additional agents selected from anti-malarial agents artemether, lumefantrine, dihydroartemisinin, piperaquine, pyronaridine, artesunate, amodiaquine, mefloquine, sulfadoxine, pyrimethamine, lumefantrine, quinine, chloroquine, atovaquone, and proguanil.
36. The pharmaceutical composition according to claim 35 , wherein the one or more additional agent is pyronaridine and/or artesunate.
37. A pharmaceutical composition comprising a compound of claim 27 , and a pharmaceutically acceptable carrier.
38. The pharmaceutical composition according to claim 37 , further comprising one or more additional agents selected from the anti-malarial agents artemether, lumefantrine, dihydroartemisinin, piperaquine, pyronaridine, artesunate, amodiaquine, mefloquine, sulfadoxine, pyrimethamine, lumefantrine, quinine, chloroquine, atovaquone, and proguanil, and a pharmaceutically acceptable carrier.
39. The pharmaceutical composition according to claim 38 , wherein the one or more additional agent is pyronaridine and/or artesunate.
40. A pharmaceutical composition comprising a compound of claim 28 , and a pharmaceutically acceptable carrier.
41. The pharmaceutical composition according to claim 40 , further comprising one or more additional agents selected from the antimalarial agents artemether, lumefantrine, dihydroartemisinin, piperaquine, pyronaridine, artesunate, amodiaquine, mefloquine, sulfadoxine, pyrimethamine, lumefantrine, quinine, chloroquine, atovaquone, and proguanil, and a pharmaceutically acceptable carrier.
42. The pharmaceutical composition according to claim 41 , wherein the one or more additional agent is pyronaridine and/or artesunate.
43. A method for treating a Plasmodium infection, or for treating malaria, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
44. A method for treating malaria, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
45. A method for dual inhibition of plasmepsin IX and plasmepsin X which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
46. A method for treating a Plasmodium infection, or for treating malaria, comprising administration to a subject in need thereof of a an effective amount of compound of claim 1 , or a pharmaceutically acceptable salt thereof, and an effective amount of one or more additional anti-malarial agents.
47. The method for treating a Plasmodium infection, or for treating malaria, in a subject in need thereof comprising administration of an effective amount of a compound of claim 26 to said subject.
48. A method for treating malaria, in a subject in need thereof comprising administration of an effective amount of a compound of claim 29 to said subject.
49. A method for treating a Plasmodium infection, or for treating malaria, in a subject in need thereof comprising administration to said subject an effective amount of the compound of claim 27 and an effective amount of one or more additional agents, wherein the one or more additional agents is an anti-malarial agent.
50. A method for treating malaria, in a subject in need thereof comprising administration to said subject an effective amount of the compound of claim 30 and an effective amount of one or more additional agents, wherein the one or more additional agents is an anti-malarial agent.
51. A method for treating a Plasmodium infection, or for treating malaria, in a subject in need threof comprising administration to said subject an effective amount of the compound of claim 28 and an effective amount of one or more additional agents, wherein the one or more additional agents is an anti-malarial agent.
52. A method for treating malaria, in a subject in need threof comprising administration to said subject an effective amount of the compound of claim 31 and an effective amount of one or more additional agents, wherein the one or more additional agents is an anti-malarial agent.