ISOXAZOLE BETA-LACTAMASE INHIBITORS
β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.
1 .- 50 . (canceled)
51 . A pharmaceutical composition comprising aztreonam or a pharmaceutically acceptable salt thereof and a compound of Formula (A-I) or a pharmaceutically acceptable salt thereof:
wherein
R* is selected from
and
R 1 * is selected from:
a.
wherein R 2 * is selected from
R 3 * is selected from hydrogen, (C 1 -C 3 )-alkyl, aminoalkyl, aminocycloalkyl, hydroxyalkyl,
each of R 4 *, R 5 *, R 6 * and R 7 * is independently selected from hydrogen, (C 1 -C 6 )-alkyl, aminoalkyl, aminocycloalkyl, and hydroxyalkyl, provided that at least one of R 4 *, R 5 *, R 6 * and R 7 * is hydrogen,
n is selected from 1, 2, 3 and 4, and
m is selected from 1, 2 and 3;
b.
wherein R 8 is selected from —NH(C 1 -C 3 )-alkyl and
wherein each of R 4 *, R 5 *, R 6 * and R 7 * is as described previously;
c.
wherein Z is selected from CR 9 R 10 and NR 11 ,
each of R 9 and R 10 is independently selected from H, NH 2 , —NH(C 1 -C 3 )-alkyl and
wherein each of R 4 *, R 5 *, R 6 * and R 7 * is as described previously,
alternatively, R 9 and R 10 together with the carbon to which they are attached, form a cycloalkyl or heterocyclyl ring containing 4-6 ring members,
R 11 is selected from H and
each of R 12 , R 13 and R 14 is independently selected from hydrogen, (C 1 -C 6 )-alkyl, amino alkyl, aminocycloalkyl, and hydroxyalkyl, provided that at least one of R 12 , R 13 and R 14 is hydrogen,
R 15 is selected from NH 2 and
wherein each of R 4 *, R 5 *, R 6 * and R 7 * is as described previously,
each of p* and q* is independently selected from 0, 1, 2 and 3,
T is selected from NH and O,
t is selected from 0, 1, 2, 3, and 4, and
each of r and y is independently selected from 0 and 1;
d.
wherein R 16 is selected from NH 2 , —NH(C 1 -C 3 )-alkyl and
wherein each of R 4 *, R 5 *, R 6 * and R 7 * is as described previously,
s is selected from 0 and 1, and,
v is selected from 0, 1, 2, and 3;
e.
wherein R 18 is selected from NH 2 and
wherein each of R 4 *, R 5 *, R 6 * and R 7 * is as described previously,
R 17 is selected from amino and hydroxyl, and
w is selected from 0 and 1;
f.
wherein M is selected from NR 19 , CR 20 R 21 and O,
wherein R 19 is selected from H and
where each of R 12 , R 13 and R 14 is as described previously,
each of R 20 and R 21 is independently selected from H, NH 2 and
wherein each of R 4 *, R 5 *, R 6 * and R 7 * is as described previously, and
u is selected from 0, 1 and 2; and
g.
52 . The pharmaceutical composition according to claim 51 , wherein the compound of Formula A-I has the stereochemistry specified in Formula A-II
or a pharmaceutically acceptable salt thereof.
53 . The pharmaceutical composition according to claim 52 , wherein the compound, or a pharmaceutically acceptable salt thereof is selected from
54 . The pharmaceutical composition according to claim 52 , wherein R 1 * is selected from
55 . The pharmaceutical composition according to claim 54 , wherein the compound is selected from
56 . The pharmaceutical composition according to claim 55 , wherein the compound or a pharmaceutically acceptable salt thereof has the Formula
57 . The pharmaceutical composition compound according to claim 55 , wherein the compound or a pharmaceutically acceptable salt thereof has the Formula
58 . A pharmaceutical composition comprising meropenem or a pharmaceutically acceptable salt thereof and a compound of Formula (A-I) or a pharmaceutically acceptable salt thereof:
wherein
R* is selected from
and
R 1 * is selected from:
a.
wherein R 2 * is selected from
R 3 * is selected from hydrogen, (C 1 -C 3 )-alkyl, aminoalkyl, aminocycloalkyl, hydroxyalkyl,
each of R 4 *, R 5 *, R 6 * and R 7 * is independently selected from hydrogen, (C 1 -C 6 )-alkyl, aminoalkyl, aminocycloalkyl, and hydroxyalkyl, provided that at least one of R 4 *, R 5 *, R 6 * and R 7 * is hydrogen,
n is selected from 1, 2, 3 and 4, and
m is selected from 1, 2 and 3;
b.
wherein R 8 is selected from —NH(C 1 -C 3 )-alkyl and
wherein each of R 4 *, R 5 *, R 6 * and R 7 * is as described previously;
c.
wherein Z is selected from CR 9 R 10 and NR 11 ,
each of R 9 and R 10 is independently selected from H, NH 2 , —NH(C 1 -C 3 )-alkyl and
wherein each of R 4 *, R 5 *, R 6 * and R 7 * is as described previously,
alternatively, R 9 and R 10 together with the carbon to which they are attached, form a cycloalkyl or heterocyclyl ring containing 4-6 ring members,
R 11 is selected from H and
each of R 12 , R 13 and R 14 is independently selected from hydrogen, (C 1 -C 6 )-alkyl, amino alkyl, aminocycloalkyl, and hydroxyalkyl, provided that at least one of R 12 , R 13 and R 14 is hydrogen,
R 15 is selected from NH 2 and
wherein each of R 4 *, R 5 *, R 6 * and R 7 * is as described previously,
each of p* and q* is independently selected from 0, 1, 2 and 3,
T is selected from NH and O,
t is selected from 0, 1, 2, 3, and 4, and
each of r and y is independently selected from 0 and 1;
d.
wherein R 16 is selected from NH 2 , —NH(C 1 -C 3 )-alkyl and
wherein each of R 4 *, R 5 *, R 6 * and R 7 * is as described previously,
s is selected from 0 and 1, and,
v is selected from 0, 1, 2, and 3;
e.
wherein R 18 is selected from NH 2 and
wherein each of R 4 *, R 5 *, R 6 * and R 7 * is as described previously,
R 17 is selected from amino and hydroxyl, and
w is selected from 0 and 1;
f.
wherein M is selected from NR 19 , CR 20 R 21 and O,
wherein R 19 is selected from H and
where each of R 12 , R 13 and R 14 is as described previously,
each of R 20 and R 21 is independently selected from H, NH 2 and
wherein each of R 4 *, R 5 *, R 6 * and R 7 * is as described previously, and
u is selected from 0, 1 and 2; and
g.
59 . The pharmaceutical composition according to claim 58 , wherein the compound of Formula A-I has the stereochemistry specified in Formula A-II
or a pharmaceutically acceptable salt thereof.
60 . The pharmaceutical composition according to claim 59 , wherein the compound, or a pharmaceutically acceptable salt thereof is selected from
61 . The pharmaceutical composition according to claim 58 , wherein R 1 * is selected from
62 . The pharmaceutical composition according to claim 60 , wherein the compound is selected from
63 . The pharmaceutical composition according to claim 62 , wherein the compound or a pharmaceutically acceptable salt thereof has the Formula