Gyrase inhibitors
View Patent ↗Novel gyrase inhibitors and related compositions and methods are useful for impeding bacterial growth. Compounds of Formula I are disclosed: wherein Y is N or CH; Z is N or CR 5 ; R 5 is H, a substituted or unsubstituted hydrocarbyl residue (1-3C) containing 0-2 heteroatoms selected from O, S and N, or is an inorganic residue; L is O, S, NR 7 , or CR 8 R 9 ; R 7 is H or C 1-3 alkyl; R 8 and R 9 are each independently H or C 1-3 alkyl; R 2 is H, a hydrocarbyl residue (1-40C) containing 0-10 heteroatoms selected from O, S and N optionally substituted with an inorganic residue; R 4 is H, an inorganic residue, or a hydrocarbyl residue (1-30C) containing 0-12 heteroatoms selected from O, S and N and containing 0-10 inorganic residues, wherein R 5 and R 4 together may join to form a fused ring; and R 6 is selected from the group consisting of H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, halo C 1-5 alkyl, halo C 2-5 alkenyl, halo C 2-5 alkynyl, C 1-5 hydroxyalkyl, C 1-5 alkyl chloride, C 2-5 alkenyl chloride, and C 2-5 alkynyl chloride; or a pharmaceutically-acceptable salt, ester, or prodrug thereof.
1. A compound having the structure of Formula I,
wherein
Y is N;
Z is CR 5 ;
L is O, S, NR 7 , SO 2 or CR 8 R 9 ;
R 7 is H or C 1-3 alkyl;
R 8 and R 9 are each independently H or C 1-3 alkyl;
R 2 is H, Cl, COOCH 2 CH 3 , CH 3 , CH 2 CH 3 , or a hydrocarbyl residue (1-40C) containing 0-10 heteroatoms selected from O, S and N optionally substituted with an inorganic residue, wherein the hydrocarbyl residue comprises at least one aryl or heteroaryl moiety;
R 4 is H, an inorganic residue, or a hydrocarbyl residue (1-30C) containing 0-12 heteroatoms selected from O, S and N and containing 0-10 inorganic residues, optionally wherein R 5 and R 4 together join to form a fused ring;
R 6 is CH 3 or —CH 2 CH 3 ; and
R 5 is methyl, C(O)CH 3 , C(O)NH 2 , CH 2 OH, CF 3 , CN, CHF 2 , CHO, halogen;
or a pharmaceutically-acceptable salt, or ester thereof.
2. A compound having the structure of Formula I,
Y is N;
Z is CR 5 ;
R 5 is H, a substituted or unsubstituted hydrocarbyl residue (1-3C) containing 0-2 heteroatoms selected from O, S and N, or is an inorganic residue;
L is O, S, NR 7 , SO 2 or CR 8 R 9 ;
R 7 is H or C 1-3 alkyl;
R 8 and R 9 are each independently H or C 1-3 alkyl;
R 2 is H, Cl, COOCH 2 CH 3 , CH 3 , CH 2 CH 3 , or a hydrocarbyl residue (1-40C) containing 0-10 heteroatoms selected from O, S and N optionally substituted with an inorganic residue, wherein the hydrocarbyl residue comprises at least one aryl or heteroaryl moiety;
R 4 is H, an inorganic residue, or a hydrocarbyl residue (1-30C) containing 0-12 heteroatoms selected from O, S and N and containing 0-10 inorganic residues, optionally wherein R 5 and R 4 together join to form a fused ring; and
R 6 is —CH 3 or —CH 2 CH 3 ;
or a pharmaceutically-acceptable salt, or ester thereof,
wherein the at least one aryl or a heteraryl moiety of R 2 is directly linked to L.
3. The compound of claim 1 , wherein R 6 is ethyl.
4. The compound of claim 1 , having the structure of Formula II
wherein X is halogen;
R 4 is an amine-substituted heteroalicyclic ring; and
Q is N or N + —O − .
5. The compound of claim 4 ,
wherein X is Cl or Br;
wherein R 4 is a 4-7 membered heteroalicyclic ring containing an N heteroatom; and
wherein the 4-7 membered heteroalicyclic ring is substituted with NH 2 .
6. The compound of claim 4 ,
wherein X is Cl;
wherein R 4 is a 5-6 membered heteroalicyclic ring having one N heteroatom in the backbone of the ring;
wherein the N heteroatom is directly linked to the remainder of the compound; and
wherein the 5-6 membered heteroalicyclic ring is substituted with one NH 2 substituent.
7. The compound of claim 1 , wherein
R 4 is
8. The compound of claim 1 which is
9. The compound of claim 1 which is
10. The compound of claim 1 which is