Aminoglycosides and uses thereof
Provided herein are aminoglycoside compounds, such as compounds of formula (I), (II), (III), (IV), (IVa), (V), (VI), (VIIa), or (VIIb) or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers of any of the foregoing, useful as therapeutic or prophylactic agents. Also provided herein are methods for their preparation. The compounds may be useful in treating a bacterial infection in a subject, for example a Gram-negative bacterial infection.
1. A compound of formula (IV):
or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein as valence and stability permit,
R 1 is —OR 9 or —NR 10 R 11 , wherein R 9 , R 10 , and R 11 are independently H or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is unsubstituted or substituted with one or more —OH;
R 2 and R 3 are independently H, alkyl, cycloalkyl, or aryl,
wherein the alkyl, cycloalkyl, or aryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, aryl, —SR 12 , —SO 2 R 13 , —OSF 2 NR 14 R 15 , NR 14 R 15, and —OR 16 , and
wherein each R 12 , R 13 , R 14 , R 15 , and R 16 is independently H or alkyl, or
R 1 and R 2 , together with the atom to which they are attached, form a heterocycloalkyl group comprising at least one heteroatom selected from the group consisting of N and O,
wherein the heterocycloalkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, —SR 17 , —SO 2 R 18 , —NR 19 R 20, and —OR 21 , and
wherein each R 17 , R 18 , R 19 , R 20 , R 21 is independently H or alkyl, or
R 2 and R 3 , together with the atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group,
wherein the cycloalkyl group or heterocycloalkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, —SR 22 , —SO 2 R 23 , —NR 24 R 25, and —OR 26 , and
wherein each R 22 , R 23 , R 24 , R 25 , R 26 is independently H or alkyl;
R 4 is H or absent;
R 5 and R 6 are independently H, —OR 27 , —NR 28 R 29, halogen, or alkyl, wherein each R 27 , R 28, and R 29 is independently H or C 1 -C 6 alkyl,
wherein the alkyl or C 1 -C 6 alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR 30 , —NR 31 R 32, SR 33 , and —SO 2 R 34 , and
wherein each R 30 , R 31 , R 32 , R 33 and R 34 is independently H or alkyl;
R 5a and R 6a are, independently, absent or H, —OR 53 , —NR 54 R 55 , halogen, or alkyl, wherein each R 53 , R 54 , and R 55 is independently H or C 1 -C 6 alkyl,
wherein the alkyl or C 1 -C 6 alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR 56 , —NR 57 R 58 , —SR 59 , and —SO 2 R 60 , and
wherein each R 56 , R 57 , R 58 , R 59 , and R 60 is independently H or alkyl,
R 7 is H or C 1 -C 3 alkyl;
R 8 is H, C 1 -C 6 alkyl, an amino protecting group, or
wherein Q 1 is NH, O, or S,
n is an integer from 0 to 4,
R 35 is H or C 1 -C 3 alkyl,
each R 36 and R 37 is independently H, alkyl, halogen, or —OH, and
R 38 is H, alkyl, or —C(═NH)NR 39 R 40 , wherein R 39 and R 40 are independently H or C 1 -C 3 alkyl, or
R 35 and R 38 , together with the atoms to which they are attached, form a heterocycloalkyl group comprising at least one N;
R 41 is H, —CN, —CONH 2 or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —OH, —OC(O)CH 3 , —NH 2 , —CN, —CONH 2 , and halogen;
R 42 and R 43 are, independently H, —OH, —OR 45 , —NR 46 R 47, or halogen,
wherein each R 45 , R 46 , and R 47 is independently H, alkyl, —CONH 2 , or —COCH 3 ,
wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH 2 , —OH, —NH 2 , —COCH 3 , aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R 44 and R 44a are, independently H, halogen, —OH, C 1 -C 3 alkoxy, or —OC(O)CH 3 ;
X 1 is H, NH 2 , OH, or halogen;
R 51a , R 51b , and R 51c are, independently, H, OH, or —OR 51d ,
wherein each R 51d is, independently, alkyl or —COCH 3 , wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH 2 , —OH, —NH 2 , —COCH 3 , aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R 52a and R 52b are independently H, OH, or —OR 52c ,
wherein each R 52c is, independently, alkyl or —COCH 3 , wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH 2 , —OH, —NH 2 , —COCH 3 , aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
wherein if R 2 and R 3 are both H and R 5 is —OR 27 or R 5a is —OR 53 , then R 6 is not —OR 27 ,
wherein if R 2 and R 3 are both H and R 5 is —OR 27 or R 5a is —OR 53 , then R 6a is not —OR 53 ,
wherein if R 2 and R 3 are both H, then at least one of R 41 , R 42 , R 43 , R 44 or R 44a is not H, and
wherein if R 2 and R 3 are both H and one of R 44 and R 44a is —OH, then at least one of R 41 , R 42 , or R 43 is not H.
2. The compound of claim 1 , wherein the compound is of formula (IV-X):
3. The compound of claim 1 , wherein at least one of R 2 and R 3 is other than H.
4. The compound of claim 1 , wherein:
R 4 is absent; and
5. The compound of claim 4 , wherein R 5 is H, halogen, or —OH.
6. The compound of claim 1 , wherein:
R 4 is H; and
7. The compound of claim 6 , wherein R 5 is H, halogen, or —OH.
8. The compound of claim 7 , wherein Ring A has the structure:
9. A compound of formula (IV):
or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein as valence and stability permit,
R 1 is —OR 9 or —NR 10 R 11 , wherein R 9 , R 10 , and R 11 are independently H or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is unsubstituted or substituted with one or more —OH;
R 2 and R 3 are independently H, alkyl, cycloalkyl, or aryl,
wherein the alkyl, cycloalkyl, or aryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, aryl, —SR 12 , —SO 2 R 13 , —OSF 2 NR 14 R 15 , NR 14 R 15, and —OR 16 , and
wherein each R 12 , R 13 , R 14 , R 15 , and R 16 is independently H or alkyl, or
R 1 and R 2 , together with the atom to which they are attached, form a heterocycloalkyl group comprising at least one heteroatom selected from the group consisting of N and O,
wherein the heterocycloalkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, —SR 17 , —SO 2 R 18 , —NR 19 R 20, and —OR 21 , and
wherein each R 17 , R 18 , R 19 , R 20 , R 21 is independently H or alkyl, or R 2 and R 3 , together with the atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group,
wherein the cycloalkyl group or heterocycloalkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, —SR 22 , —SO 2 R 23 , —NR 24 R 25, and —OR 26 , and
wherein each R 22 , R 23 , R 24 , R 25 , R 26 is independently H or alkyl; R 4 is H or absent;
R 5 and R 6 are independently H, —OR 27 , —NR 28 R 29, halogen, or alkyl, wherein each R 27 , R 28, and R 29 is independently H or C 1 -C 6 alkyl, wherein the alkyl or C 1 -C 6 alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR 30 , —NR 31 R 32, SR 33 , and—SO 2 R 34 , and wherein each R 30 , R 31 , R 32 , R 33 , and R 34 is independently H or alkyl;
R 5a and R 6a are, independently, absent or H, —OR 53 , —NR 54 R 55 , halogen, or alkyl, wherein each R 53 , R 54 , and R 55 is independently H or C 1 -C 6 alkyl, wherein the alkyl or C 1 -C 6 alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR 56 , —NR 57 R 58 , —SR 59 , and —SO 2 R 60 , and wherein each R 56 , R 57 , R 58 , R 59 , and R 60 is independently H or alkyl; or
R 5 and R 5a form an oxo group; or
R 6 and R 6a form an oxo group;
with the proviso that if R 5 is —OR 27 or R 5a is —OR 53 , then R 6 is not —OR 27 and R 6a is not —OR 53 ;
R 7 is H or C 1 -C 3 alkyl;
R 8 is H, C 1 -C 6 alkyl, an amino protecting group, or
wherein Q 1 is NH, O, or S,
n is an integer from 0 to 4,
R 35 is H or C 1 -C 3 alkyl,
each R 36 and R 37 is independently H, alkyl, halogen, or —OH, and
R 38 is H, alkyl, or —C(═NH)NR 39 R 40 , wherein R 39 and R 40 are independently H or C 1 -C 3 alkyl, or
R 35 and R 38 , together with the atoms to which they are attached, form a heterocycloalkyl group comprising at least one N;
R 41 is H, —CN, —CONH 2 or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —OH, —OC(O)CH 3 , —NH 2 , —CN, —CONH 2 , and halogen;
R 42 and R 43 are, independently H, —OH, —OR 45 , —NR 46 R 47, or halogen,
wherein each R 45 , R 46 , and R 47 is independently H, alkyl, —CONH 2 , or —COCH 3 ,
wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH 2 , —OH, —NH 2 , —COCH 3 , aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R 44 and R 44a are, independently H, halogen, —OH, C 1 -C 3 alkoxy, or —OC(O)CH 3 ;
X 1 is H, NH 2 , OH, or halogen;
R 51a , R 51b , and R 51c are, independently, H, OH, or —OR 51d ,
wherein each R 51d is, independently, alkyl or —COCH 3 , wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH 2 , —OH, —NH 2 , —COCH 3 , aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R 52a and R 52b are independently H, OH, or —OR 52c ,
wherein each R 52c is, independently, alkyl or —COCH 3 , wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH 2 , —OH, —NH 2 , —COCH 3 , aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and
with the proviso that:
if R 2 and R 3 are both H, then at least one of R 41 , R 42 , R 43 , R 44, or R 44a is not H; and
if R 2 and R 3 are both H and one of R 44 and R 44a is —OH, then at least one of R 41 , R 42 , or R 43 is not H.
10. The compound of claim 9 , wherein the compound is of formula (IVa-X):
11. The compound of claim 9 , wherein R 5 and R 5a are independently selected from the group consisting of H, F, and OH.
12. The compound of claim 9 , wherein R 6 and R 6a are independently selected from the group consisting of H, F, and OH.
13. The compound of claim 9 , wherein Ring A is selected from the group consisting of:
14. The compound of claim 9 , wherein Ring A is selected from the group consisting of: