Compounds
A compound of Formula (I), or a salt thereof, compositions comprising the compound, processes for its preparation and its use in therapy, for example in the treatment of parasitic diseases such as Chagas disease, Human African Trypanosomiasis (HAT), Animal African trypanosomiasis (AAT) and leishmaniasis, particularly visceral leishmaniasis (VL).
1. A compound of Formula (I), or a salt thereof,
wherein
A 1 is CH;
A 2 is selected from CR 13 and N;
R 1 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 7 heterocycloalkyl, phenyl, C 5 -C 6 heteroaryl, C 1 -C 6 alkoxy, —OC 3 -C 7 cycloalkyl and NR 10a R 10b ; wherein C 3 -C 7 cycloalkyl, C 4 -C 7 heterocycloalkyl, phenyl, C 5 -C 6 heteroaryl and —OC 3 -C 7 cycloalkyl are optionally substituted with one to three groups independently selected from hydroxy, methoxy, C 1 -C 3 alkyl and halo;
L 1 is a linker group selected from —C(O)— and —S(O) n —, wherein n represents 1 to 2;
R 3 is selected from hydrogen, halo, methyl, methoxy and cyano;
R 4 is selected from hydrogen, halo, methyl, methoxy and cyano;
R 2 is selected from hydrogen, halo, Ar, Cy, X, NR 5a R 5b and —C(O)—R 15 ;
Ar is selected from phenyl and C 5 -C 6 heteroaryl, each of which is optionally substituted with one to three groups independently selected from halo and -L 2 -R 7 ;
L 2 is a linker group selected from a bond, —(CH 2 ) m —, —O(CH 2 ) m —, —C 2 -C 4 alkenyl-, —OC 2 -C 4 alkenyl-, —(CH 2 ) p —NH—(CH 2 ) q —, and —(CH 2 ) p C(O)—(CH 2 ) q —; wherein m represents 1 to 4 and p and q independently represent 0 to 4;
R 7 is selected from hydrogen; hydroxy; NR 8a R 8b ; C 4 -C 7 heterocycloalkyl optionally substituted with one or two C 1 -C 3 alkyl groups; C 3 -C 7 cycloalkyl; C 1 -C 6 alkoxy optionally substituted with one NR 14a R 14b group; and phenyl optionally substituted with one to three groups independently selected from halo, methoxy and methyl;
Cy is selected from C 3 -C 7 cycloalkyl, C 4 -C 7 heterocycloalkyl, C 5 -C 7 cycloalkenyl and C 5 -C 7 heterocycloalkenyl, each of which is optionally substituted with one to three groups independently selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 4 -C 7 heterocycloalkyl, NR 11a R 11b , ═O, —C(O)—R 15 and —C(O)O—R 15 ;
X is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 1 -C 6 alkoxy, each of which is optionally substituted with one to three groups independently selected from hydroxy, methoxy, halo, NR 13a R 13b and C 4 -C 7 heterocycloalkyl, wherein C 4 -C 7 heterocycloalkyl is optionally substituted with one to three C 1 -C 3 alkyl groups;
R 5a is selected from hydrogen; C 1 -C 6 alkyl optionally substituted with one group selected from Ar and Cy; —C(O)—R 9 ; —C(O)—OR 9 ; and —SO 2 —R 9 ;
R 5b is selected from hydrogen and C 1 -C 3 alkyl;
R 8a and R 8b are independently selected from hydrogen and C 1 -C 3 alkyl;
R 9 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 7 heterocycloalkyl, phenyl and C 5 -C 6 heteroaryl;
R 10a and R 10b are independently selected from hydrogen and C 1 -C 3 alkyl;
R 11a and R 11b are independently selected from hydrogen and C 1 -C 3 alkyl;
R 12 is selected from hydrogen, halo and methyl;
R 13 is selected from hydrogen, C 1 -C 3 alkyl, —C(O)—C 4 -C 7 heterocycloalkyl, —C(O)—C 1 -C 3 alkyl and —C(O)—C 3 -C 7 cycloalkyl;
R 13a and R 13b are independently selected from hydrogen and C 1 -C 3 alkyl;
R 14a and R 14b are independently selected from hydrogen and C 1 -C 3 alkyl; and
R 15 is selected from C 1 -C 6 alkyl, Ar, C 3 -C 7 cycloalkyl and C 4 -C 7 heterocycloalkyl.
2. A compound according to claim 1 , wherein R 1 is C 4 -C 7 heterocycloalkyl optionally substituted with one C 1 -C 3 alkyl or with one or two halo.
3. A compound according to claim 1 , wherein L 1 is —C(O)—.
4. A compound according to claim 1 , wherein R 2 is selected from hydrogen, halo, Ar, Cy, and X.
5. A compound according to claim 1 , wherein R 2 is Cy and Cy is optionally substituted C 4 -C 7 heterocycloalkyl.
6. A compound according to claim 1 , wherein R 3 is hydrogen or halo and R 4 is hydrogen, halo, or methyl.
7. A compound of Formula (I) according to claim 1 , which is
8. A compound of Formula (IA), or a salt thereof,
wherein
A 1 is CH;
A 2 is selected from CR 13 and N;
R 1 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 7 heterocycloalkyl, phenyl, C 5 -C 6 heteroaryl, C 1 -C 6 alkoxy, —OC 3 -C 7 cycloalkyl and NR 10a R 10b ; wherein C 3 -C 7 cycloalkyl, C 4 -C 7 heterocycloalkyl, phenyl, C 5 -C 6 heteroaryl and —OC 3 -C 7 cycloalkyl are optionally substituted with one to three groups selected from hydroxy, methoxy, C 1 -C 3 alkyl and halo;
L 1 is a linker group selected from —C(O)— and —S(O) n —; wherein n represents 1 to 2;
R 3 is selected from hydrogen, halo, methyl, methoxy and cyano;
R 4 is selected from hydrogen, halo, methyl, methoxy and cyano;
R 2 is selected from hydrogen, halo, Ar, Cy, X and NR 5a R 5b ;
Ar is selected from phenyl and C 5 -C 6 heteroaryl, each of which is optionally substituted with one to three groups independently selected from NR 6a R 6b and -L 2 -R 7 ;
L 2 is a linker group selected from a bond, —(CH 2 ) m —, —O(CH 2 ) m —, —C 2 -C 4 alkenyl- and —OC 2 -C 4 alkenyl-; wherein m represents 1 to 4;
R 7 is selected from hydrogen, C 4 -C 7 heterocycloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, hydroxy and NR 8a R 8b ;
Cy is selected from C 3 -C 7 cycloalkyl, C 4 -C 7 heterocycloalkyl, C 5 -C 7 cycloalkenyl and C 5 -C 7 heterocycloalkenyl, each of which is optionally substituted with one to three groups independently selected from C 1 -C 3 alkyl, C 4 -C 7 heterocycloalkyl and NR 11a R 11b ;
X is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 1 -C 6 alkoxy, each of which is optionally substituted with one to three groups independently selected from hydroxy, methoxy, halo and C 4 -C 7 heterocycloalkyl, wherein C 4 -C 7 heterocycloalkyl is optionally substituted with one to three C 1 -C 3 alkyl groups;
R 5a is selected from hydrogen, C 1 -C 6 alkyl, —C(O)—R 9 , —C(O)—OR 9 and —SO 2 —R 9 ;
R 5b is selected from hydrogen and C 1 -C 3 alkyl;
R 6a and R 6b are independently selected from hydrogen and C 1 -C 3 alkyl;
R 8a and R 8b are independently selected from hydrogen and C 1 -C 6 alkyl;
R 9 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 7 heterocycloalkyl, phenyl and C 5 -C 6 heteroaryl;
R 10a and R 10b are independently selected from hydrogen and C 1 -C 3 alkyl;
R 11a and R 11b are independently selected from hydrogen and C 1 -C 3 alkyl;
R 12 is selected from hydrogen, halo and methyl; and
R 13 is selected from hydrogen and C 1 -C 3 alkyl.
9. A compound of Formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising (a) a compound of Formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier.
11. A combination comprising (a) a compound of Formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, and (b) at least one additional therapeutic agent.
12. A method of treatment of a parasitic disease selected from Chagas disease, Human African Trypanosomiasis, Animal African trypanosomiasis and leishmaniasis, which method comprises administering to a mammal in need thereof, a therapeutically effective amount of a compound of Formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof.
13. The method of treatment according to claim 12 , wherein the mammal is a human.
14. The method of treatment according to claim 12 , wherein the leishmaniasis is visceral leishmaniasis.
15. A compound of Formula (IA) according to claim 8 , or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising (a) a compound of Formula (IA) according to claim 8 , or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier.
17. A combination comprising (a) a compound of Formula (IA) according to claim 8 , or a pharmaceutically acceptable salt thereof, and (b) at least one additional therapeutic agent.
18. A method of treatment of a parasitic disease selected from Chagas disease, Human African Trypanosomiasis, Animal African trypanosomiasis and leishmaniasis, which method comprises administering to a mammal in need thereof, a therapeutically effective amount of a compound of Formula (IA) according to claim 8 , or a pharmaceutically acceptable salt thereof.
19. The method of treatment according to claim 18 , wherein the mammal is a human.
20. The method of treatment according to claim 18 , wherein the leishmaniasis is visceral leishmaniasis.
21. The combination of claim 11 , wherein the at least one additional therapeutic agent is selected from the group consisting of an anti-leishmaniasis agent, an anti-parasitic agent, an anti-AIDS agent, an anti-HIV agent, and an anti-TB agent.
22. The combination of claim 17 , wherein the at least one additional therapeutic agent is selected from the group consisting of an anti-leishmaniasis agent, an anti-parasitic agent, an anti-AIDS agent, an anti-HIV agent, and an anti-TB agent.
23. The combination of claim 11 , wherein the at least one additional therapeutic agent is an anti-leishmaniasis agent selected from the group consisting miltefosine, paromomycin, sodium stibugluconate, meglumine antimoniate, amphotericin B deoxycholate, and liposomal amphotericin B.
24. The combination of claim 17 , wherein the at least one additional therapeutic agent is an anti-leishmaniasis agent selected from the group consisting miltefosine, paromomycin, sodium stibugluconate, meglumine antimoniate, amphotericin B deoxycholate, and liposomal amphotericin B.