Macrocyclic integrase inhibitors
View Patent ↗Compound having formula I and pharmaceutically acceptable salts or solvates thereof, their pharmaceutical formulations and use as HIV inhibitors.
1. A compound having formula I
or a stereochemically isomeric form thereof, wherein,
R 1 is F or Cl;
R 2 is H, F or Cl;
R 3 is C 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, cyclopropyl or tetrahydrofuranyl;
R 4 is hydrogen or methyl;
J is —N(R 5 )—SO 2 —, —C(═O)—N(R 5 )—, —N(R 5 )—,
wherein the dashed line denotes the point of attachment to the pyridazinone ring;
K is —(CHR 6 ) p —, *-(CH 2 ) q —CH═CH—CH 2 — or *-(CH 2 ) q —CH≡CH—CH 2 — wherein * denotes to point of attachment to the J moiety;
L is —O—, —O—CH 2 -* or —N(R 5 )—C(═O)-* wherein * denotes the point of attachment to the phenyl ring; and,
R 5 is hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl;
each R 6 independently is hydrogen or C 1-3 alkyl;
p is 3, 4, 5 or 6;
q is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein R 1 is F and R 2 is H.
3. A compound according to claim 2 wherein R 3 is ethyl, isopropyl or cyclopropyl.
4. A compound according to claim 3 wherein R 4 is methyl.
5. A compound according to claim 4 wherein J is —N(R 5 )—SO 2 — or
6. A compound according to claim 5 wherein K is —(CHR 6 ) p — wherein p is 3, 4, 5 or 6 and each R 6 is independently H or CH 3 .
7. A compound according to claim 5 wherein K is *-(CH 2 ) q —CH═CH—CH 2 — wherein q is 2 or 3.
8. A compound according to claim 6 wherein R 5 is methyl, ethyl or cyclopropyl.
9. A compound according to claim 8 wherein L is —O— or —O—CH 2 —.
10. A compound according to claim 9 wherein the -JKL- linking chain is 8 to 11 atoms long.
11. A pharmaceutical composition comprising an anti-virally effective amount of a compound of formula I as defined in claim and a carrier.
12. A pharmaceutical composition according to claim 11 , further comprising at least one additional anti-retroviral compound.
13. A compound according to claim 7 wherein R5 is methyl, ethyl or cyclopropyl.
14. A compound according to claim 13 wherein L is —O— or —O—CH 2 —.
15. A compound according to claim 14 wherein the -JKL- linking chain is 8 to 11 atoms long.
16. A method of treating HIV infection comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 11 .
17. A method of treating HIV infection comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 12 .