FIELD

The present disclosure is directed to novel aminoglycoside compounds useful as therapeutic or prophylactic agents and methods for their preparation.

BACKGROUND

The rapid spread of antibiotic resistance in pathogenic bacteria has prompted a continuing search for new agents capable of antibacterial activity. Aminoglycosides (AGs) are highly potent, broad-spectrum antibiotics with many desirable properties for the treatment of life threatening infections. Examples of aminoglycosides include tobramycin, gentamicin, and amikacin. Aminoglycoside antibiotics have long been known to bind RNA in a fashion that leads to misreading of the genetic code. They exert their antibacterial effects by binding to specific target sites in the bacterial ribosome. For the structurally related antibiotics neamine, ribostamycin, neomycin B, and paromomycin, the binding site has been localized to the A-site of the prokaryotic 16S ribosomal decoding region RNA (see Moazed, D.; Noller, H. F., Nature, 1987, 327, 389). Binding of aminoglycosides to this RNA target interferes with the fidelity of mRNA translation and results in miscoding and truncation, leading ultimately to bacterial cell death (see Alper, P. B.; Hendrix, M.; Sears, P.; Wong, C., J. Am. Chem. Soc., 1998, 120, 1965). For example, misreading of the code during translation of integral membrane proteins is thought to produce abnormal proteins that compromise the barrier properties of the bacterial membrane.

Over time, resistance to AGs has emerged clinically. AG resistance (AG-R) can be categorized mechanistically into three types: (1) AG-modifying enzymes (AMEs); (2) target modifying enzymes called ribosomal methyltransferases (RMTs); and (3) reduction of intracellular AG concentrations, primarily mediated by the overexpression of efflux pumps. At present, the most significant contribution to AG-R amongst clinical isolates is conferred by AMEs, which are diverse and widely distributed in both developed and developing nations. RMTs, while less common than AMEs inEnterobacteriaceaeandP. aeruginosa, are a serious threat because they modify the 16S rRNA AG binding site and prevent AG target engagement, conferring high-level resistance to all clinically available AGs. Alarmingly, approximately 30% of isolates from a contemporaryAcinetobacterspp. panel (n=80) contain RMTs. As an additional concern, AME and RMT genes are tyl)ically located on plasmids or transposons together with genes encoding resistance to other classes of antibacterials, which leads to multidrug resistant isolates.

In addition, prolonged clinical use of aminoglycosides can lead to adverse events in the kidney (nephrotoxicity) and ear (ototoxicity). These are cumulative processes, with the likelihood of observing toxicity increasing with treatment duration. The nephrotoxicity potential of AGs limits the dose and the length of treatment, making it challenging to achieve the systemic exposures required for efficacy againstP. aeruginosaandA. baumanniiinfections. The origin of this toxicity is assumed to result from a combination of different factors and mechanisms such as interactions with phospholipids, inhibition of phospholipases and the formation of free radicals.

For the foregoing reasons, while progress has been made in this field there is a need for new chemical entities that possess antibacterial activity and reduced toxicity with a sufficient therapeutic window (TW) to enable high-dose, long duration treatment for the most difficult to treat Gram-negative infections, such asP. aeruginosaandA. baumannii, and/or which are refractory to the common RMTs. Further, in order to accelerate the drug discovery process, new methods for synthesizing aminoglycoside antibiotics are needed to provide an array of compounds that are potentially new drugs for the treatment of bacterial infections. New methods for synthesizing aminoglycoside antibiotics are also needed to facilitate their production and reduce associated costs. The present disclosure fulfills these needs and provides further related advantages.

BRIEF SUMMARY

The present disclosure relates to aminoglycoside compounds, having antibacterial activity, including stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof, and to uses thereof in, for example, treatment of medical conditions associated with a pathogenic microorganism, which are also referred to herein as “bacterial infections.”

One aspect of the disclosure relates to a compound of formula (IV):


or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein as valence and stability permit,

R1is —OR9or —NR10R11, wherein R9, R10, and R11are independently H or C1-C6alkyl, wherein the C1-C6alkyl is unsubstituted or substituted with one or more —OH;

R2and R3are 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, —SR12, —SO2R13, —OSF2NR14R15, —NR14R15, and —OR16, andwherein each R12, R13, R14, R15, and R16is independently H or alkyl, or

R1and R2, 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, —SR17, —SO2R18, —NR19R20, and —OR21, andwherein each R17, R18, R19, R20, and R21is independently H or alkyl, or

R2and R3, 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, —SR22, —SO2R23, —NR24R25, and —OR26, andwherein each R22, R23, R24, R25, and R26is independently H or alkyl; R4is H or absent;



R5and R6are independently H, —OR27, —NR28R29,halogen, or alkyl, wherein each R27, R28, and R29is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR30, —NR31R32, —SR33, and —SO2R34, and

wherein each R30, R31, R32, R33, and R34is independently H or alkyl,

R5aand R6aare, independently, absent or independently H, —OR53, —NR54R55, halogen, or alkyl, wherein each R53, R54, and R55is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR56, —NR57R58, —SR59, and —SO2R60, andwherein each R56, R57, R58, R59, and R60is independently H or alkyl, or

R5and R5aform an oxo group, or

R6and R6aform an oxo group;

R7is H or C1-C3alkyl;

R8is H, C1-C6alkyl, an amino protecting group, or

wherein Q1is NH, O, or S,n is an integer from 0 to 4,R35is H or C1-C3alkyl,each R36and R37is independently H, alkyl, halogen, or —OH, andR38is H, alkyl, or —C(═NH)NR39R40, wherein R39and R40are independently H orC1-C3alkyl, orR35and R38, together with the atoms to which they are attached, form a heterocycloalkyl group comprising at least one N;

R41is H, —CN, —CONH2or C1-C3alkyl, wherein the C1-C3alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —OH, —OC(O)CH3, —NH2, —CN, —CONH2, and halogen;

R42R43are, independently H, —OH, —OR45, —NR46R47, or halogen,wherein each R45, R46, and R47is independently H, alkyl, —CONH2, or —COCH3,wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R44and R44aare, independently H, halogen, —OH, C1-C3alkoxy, or —OC(O)CH3;

X1is H, NH2, OH, or halogen:

R51a, R51b, and R51care, independently, H, OH, or —OR51d,wherein each R51dis, independently. alkyl or —COCH3, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R52aand R52bare independently H, OH, or —OR52c,wherein each R52cis, independently, alkyl or —COCH3, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;wherein if R2and R3are both H and R5is —OR27or R5ais —OR53, then R6is not —OR27,wherein if R2and R3are both H and R5is —OR27or R5ais —OR53, then R6ais not —OR53,wherein if R2and R3are both H, then at least one of R41, R42, R43, R44, or R44ais not H, andwherein if R2and R3are both H and one of R44and R44ais —OH, then at least one of R41, R42, or R43is not H.

In some embodiments, the compound of formula (IV) is of formula (IV-X):


or a pharmaceutically acceptable salt, solvate, or tautomer thereof.

In some embodiments, the compound of formula (IV) is of formula (IVa):


or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein as valence and stability permit,

R1is —OR9or —NR10R11,wherein R9, R10,and R11are independently H or C1-C6alkyl, wherein the C1-C6alkyl is unsubstituted or substituted with one or more —OH;

R2and R3are 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, —SR12, —SO2R13, —OSF2NR14R15, —NR14R15, and —OR16, andwherein each R12, R13, R14, R15, and R16is independently H or alkyl, or

R1and R2, 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, —SR17, —SO2R18, —NR19R20,and —OR21, andwherein each R17, R18, R19, R20, and R21is independently H or alkyl, or

R2and R3, 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, —SR22, —SO2R23, —NR24R25, and —OR26,wherein each R22, R23, R24, R25, and R26is independently H or alkyl, andwherein at least one of R2and R3is other than H;

R4is H or absent;



R5and R6are independently H, —OR27, —NR28R29,halogen, or alkyl, wherein each R27, R28, and R29is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR30, —NR31R32, —SR33, and —SO2R34, and

wherein each R30, R31, R32, R33, and R34is independently H or alkyl,

R5aand R6aare, independently, absent or independently H, —OR53, —NR54R55, halogen, or alkyl, wherein each R53, R54, and R55is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR56, —NR57R58, —SR59, and —SO2R60, andwherein each R56, R57, R58, R59, and R60is independently H or alkyl, or

R5and R5aform an oxo group, or

R6and R6aform an oxo group;

R7is H or C1-C3alkyl;

R8is H, C1-C6alkyl, an amino protecting group, or

wherein Q1is NH, O, or S,n is an integer from 0 to 4,R35is H or C1-C3alkyl,each R36and R37is independently H, alkyl, halogen, or —OH, andR38is H, alkyl, or —C(═NH)NR39R40, wherein R39and R40are independently H or C1-C3alkyl, orR35and R38, together with the atoms to which they are attached, form a heterocycloalkyl group comprising at least one N;

R41is H, —CN, —CONH2or C1-C3alkyl, wherein the C1-C3alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —OH, —OC(O)CH3, —NH2, —CN, —CONH2, and halogen;

R42and R43are, independently H, —OH, —OR45, —NR46R47, or halogen,wherein each R45, R46, and R47is independently H, alkyl, —CONH2, or —COCH3,wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R44and R44aare, independently H, halogen, —OH, C1-C3alkoxy, or —OC(O)CH3;

X1is H, NH2, OH, or halogen;

R51a, R51b, and R51care, independently, H, OH, or —OR51d,wherein each R51dis, independently, alkyl or —COCH3, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R52aand R52bare independently H, OH, or —OR52c,wherein each R52cis, independently, alkyl or —COCH3, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

In some embodiments, the compound of formula (IVa) is of formula (IVa-X):


or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

In some embodiments, the compound of formula (IV) is of formula (V):


or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein as valence and stability permit,

R1is —OR9or —NR10R11,wherein R9, R10, and R11are independently H or C1-C6alkyl, wherein the C1-C6alkyl is unsubstituted or substituted with one or more —OH;

R2and R3are 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, —SR12, —SO2R13, —OSF2NR14R15, —NR14R15, and —OR16, andwherein each R12, R13, R11, R15, and R16is independently H or alkyl, or

R1and R2, 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, —SR17, —SO2R18, —NR19R20,and —OR21, andwherein each R17, R18, R19, R20, and R21is independently H or alkyl, or R2and R3, 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, —SR22, —SO2R23, —NR24R25, and —OR26, andwherein each R22, R23, R24, R25, and R26is independently H or alkyl; R4is H or absent;



R5and R6are independently H, —OR27, —NR28R29,halogen, or alkyl, wherein each R27, R28, and R29is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR30, —NR31R32, —SR33, and —SO2R34, and

wherein each R30, R31, R32, R33, and R34is independently H or alkyl,

R5aand R6aare, independently, absent or independently H, —OR53, —NR54R55, halogen, or alkyl, wherein each R53, R54, and R55is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR56, —NR57R58, —SR59, and —SO2R60, andwherein each R56, R57, R58, R59, and R60is independently H or alkyl, or

R5and R5aform an oxo group, or

R6and R6aform an oxo group,

wherein if R5is —OR27or R5ais —OR53, then R6is not —OR27, and

wherein if R5is —OR27or R5ais —OR53, then R6ais not —OR53;

R7is H or C1-C3alkyl;

R8is H, C1-C6alkyl, an amino protecting group, or

wherein Q1is NH, O, or S,n is an integer from 0 to 4,R35is H or C1-C3alkyl,each R36and R37is independently H, alkyl, halogen, or —OH, andR38is H, alkyl, or —C(═NH)NR39R40, wherein R39and R40are independently H or C1-C3alkyl, orR35and R38, together with the atoms to which they are attached, form a heterocycloalkyl group comprising at least one N;

R41is H, —CN, —CONH2or C1-C3alkyl, wherein the C1-C3alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —OH, —OC(O)CH3, —NH2, —CN, —CONH2, and halogen;

R42and R43are, independently H, —OH, —OR45, —NR46R47, or halogen,wherein each R45, R46, and R47is independently H, alkyl, —CONH2, or —COCH3,wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R44and R44aare, independently H, OH, halogen, C1-C3alkoxy, or —OC(O)CH3, wherein when R44or R44ais OH, then R41is not H;

X1is H, NH2, OH, or halogen;

R51a, R51b, and R51care, independently, H, OH, or —OR51d,wherein each R51dis, independently, alkyl or —COCH3, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R52aand R52bare independently H, OH, or —OR52c,

wherein each R52cis, independently, alkyl or —COCH3, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

In some embodiments, the compound of formula (V) is of formula (V-X):


or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

In some embodiments, the compound of formula (IV) is of formula (VI):


or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein as valence and stability permit,

R1is —OR9or —NR10R11,wherein R9, R10,and R11are independently H or C1-C6alkyl, wherein the C1-C6alkyl is unsubstituted or substituted with one or more —OH;

R2and R3are 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, —SR12, —SO2R13, —OSF2NR14R15, —NR14R15, and —OR16, andwherein each R12, R13, R14, R15, and R16is independently H or alkyl, or

R1and R2, 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, —SR17, —SO2R18, —NR19R20,and —OR21, andwherein each R17, R18, R19, R20, and R21is independently H or alkyl, or

R2and R3, 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, —SR22, —SO2R23, —NR24R25, and —OR26, andwherein each R22, R23, R24, R25, and R26is independently H or alkyl, and R4is H or absent;



R5and R6are independently H, —OR27, —NR28R29,halogen, or alkyl, wherein each R27, R28, and R29is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR30, —NR31R32, —SR33, and —SO2R34, and

wherein each R30, R31, R32, R33, and R34is independently H or alkyl,

R5aand R6aare, independently, absent or independently H, —OR53, —NR54R55, halogen, or alkyl, wherein each R53, R54, and R55is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR56, —NR57R58, —SR59, and —SO2R60, andwherein each R56, R57, R58, R59, and R60is independently H or alkyl, or

R5and R5aform an oxo group, or

R6and R6aform an oxo group,

wherein if R5is —OR27or R5ais —OR53, then R6is not —OR27, and

wherein if R5is —OR27or R5ais —OR53, then R6ais not —OR53;

R7is H or C1-C3alkyl;

R8is H, C1-C6alkyl, an amino protecting group, or

wherein Q1is NH, O, or S,n is an integer from 0 to 4,R35is H or C1-C3alkyl,each R36and R37is independently H, alkyl, halogen, or —OH, andR38is H, alkyl, or —C(═NH)NR39R40, wherein R39and R40are independently H or C1-C3alkyl, orR35and R38, together with the atoms to which they are attached, form a heterocycloalkyl group comprising at least one N;

R41is H, —CN, —CONH2or C1-C3alkyl, wherein the C1-C3alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —OH, —OC(O)CH3, —NH2, —CN, —CONH2, and halogen;

R42and R43are, is independently H, —OH, —OR45, —NR46R47, or halogen,wherein each R45, R46, and R47is independently H, alkyl, —CONH2, or —COCH3,wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, andwherein at least one of R42and R43is other than H;

R44and R44aare, independently H, halogen, —OH, C1-C3alkoxy, or —OC(O)CH3;

X1is H, NH2, OH, or halogen;

R51a, R51b, and R51care, independently, H, OH, or —OR51d,wherein each R51dis, independently, alkyl or —COCH3, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R52aand R52bare independently H, OH, or —OR52c,wherein each R52cis, independently, alkyl or —COCH3, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

In some embodiments, the compound of formula (VI) is of formula (VI-X):


or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

Another aspect of the disclosure relates to a compound of formula (VIIa):


or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein as valence and stability permit,

R1is —OR9or —NR10R11,wherein R9, R10, and R11are independently H or C1-C6alkyl, wherein the C1-C6alkyl is unsubstituted or substituted with one or more —OH;

R2and R3are 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, —SR12, —SO2R13, —OSF2NR14R15, —NR14R15, and —OR16, andwherein each R12, R13, R14, R15, and R16is independently H or alkyl, or

R1and R2, 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, —SR17, —SO2R18, —NR19R20,and —OR21, and

1wherein each R17, R18, R19, R20, and R21is independently H or alkyl, or

R2and R3, 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, —SR22, —SO2R23, —NR24R25, and —OR26, andwherein each R22, R23, R24, R25, and R26is independently H or alkyl; R4is H;

R5is H, —OR27, —NR28R29, halogen, or alkyl, wherein each R27, R28, and R29is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR30, —NR31R32, —SR33, and —SO2R34, and

wherein each R30, R31, R32, R33, and R34is independently H or alkyl,

R6is H, NR28R29, F, Br, I, or alkyl, wherein each R28and R29is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR30, —NR31R32, —SR33, and —SO2R34, and

wherein each R30, R31, R32, R33, and R34is independently H or alkyl,

R5ais H, —OR53, —NR54R55, halogen, or alkyl, wherein each R53, R54, and R55is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR56, —NR57R58, —SR59, and —SO2R60, andwherein each R56, R57, R58, R59, and R60is independently H or alkyl,

R6ais H, NR54R55, F, Br, I, or alkyl, wherein each R54and R55is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR56, —NR57R58, —SR59, and —SO2R60, andwherein each R56, R57, R58, R59, and R60is independently H or alkyl;

R7is H or C1-C3alkyl;

R8is H, C1-C6alkyl, an amino protecting group, or

wherein Q1is NH, O, or S,n is an integer from 0 to 4,R35is H or C1-C3alkyl,each R36and R37is independently H, alkyl, halogen, or —OH, andR38is H, alkyl, or —C(═NH)NR39R40, wherein R39and R40are independently H or C1-C3alkyl, orR35and R38, together with the atoms to which they are attached, form a heterocycloalkyl group comprising at least one N;

R41is H, —CN, —CONH2or C1-C3alkyl, wherein the C1-C3alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —OH, —OC(O)CH3, —NH2, —CN, —CONH2, and halogen;

R42and R43are, independently H, —OH, —OR45, —NR46R47, or halogen,wherein each R45, R46and R47is independently H, alkyl, —CONH2, or —COCH3,wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R44and R44aare, independently H, halogen, —OH, C1-C3alkoxy, or —OC(O)CH3;

X1is H, NH2, OH, or halogen;

R51a, R51b, and R51care, independently, H, OH, or —OR51d,wherein each R51dis, independently, alkyl or —COCH3, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R52aand R52bare independently H, OH, or —OR52c,wherein each R52cis, independently, alkyl or —COCH3, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

wherein if R5is —OR27or R5ais —OR53, then at least one of R6and R6aare other than H,

wherein if each of R5, R5a, R6, and R6aare H, then R1is not —OR9, wherein R9is H, and

wherein if each of R5, R5a, R6, and R6aare H and R1is —NR10R11, then R8is not



In some embodiments, the compound of formula (VIIa) is of formula (VIIa-X):



or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

One aspect of the disclosure relates to a compound of formula (VIIb):


or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein as valence and stability permit,

R1is —OR9or —NR10R11,wherein R9, R10, and R11are independently H or C1-C6alkyl, wherein the C1-C6alkyl is unsubstituted or substituted with one or more —OH;

R2and R3are 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, —SR12,

—SO2R13, —OSF2NR14R15, —NR14R15, and —OR16, andwherein each R12, R13, R14, R15, and R16is independently H or alkyl, or

R1and R2, 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, —SR17, —SO2R18, —NR19R20,and —OR21, andwherein each R17, R18, R19, R20, and R21is independently H or alkyl, or

R2and R3, 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, —SR22, —SO2R23, —NR24R25, and —OR26, andwherein each R22, R23, R24, R25, and R26is independently H or alkyl; R4is H;

R5is H, NR28R29, F, Br, I, or alkyl, wherein each R28and R29is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR30, —NR31R32, —SR33, and —SO2R34, and

wherein each R30, R31, R32, R33, and R34is independently H or alkyl,

R6is H, —OR27, —NR28R29, halogen, or alkyl, wherein each R27, R28, and R29is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR30, —NR31R32, —SR33, and —SO2R34, and

wherein each R30, R31, R32, R33, and R34is independently H or alkyl,

R5ais H, NR54R55, F, Br, I, or alkyl, wherein each R54and R55is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR56, —NR57R58, —SR59, and —SO2R60, andwherein each R56, R57, R58, R59, and R69is independently H or alkyl,

R6ais H, —OR53, —NR54R55, halogen, or alkyl, wherein each R53, R54, and R55is independently H or C1-C6alkyl,wherein the alkyl or C1-C6alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR56, —NR57R58, —SR59, and —SO2R60, andwherein each R56, R57, R58, R59, and R60is independently H or alkyl; R7is H or C1-C3alkyl;

R8is H, C1-C6alkyl, an amino protecting group, or

wherein Q1is NH, O, or S,n is an integer from 0 to 4,R35is H or C1-C3alkyl,each R36and R37is independently H, alkyl, halogen, or —OH, andR38is H, alkyl, or —C(═NH)NR39R49, wherein R39and R40are independently H or C1-C3alkyl, orR35and R38, together with the atoms to which they are attached, form a heterocycloalkyl group comprising at least one N;

R41is H, —CN, —CONH2or C1-C3alkyl, wherein the C1-C3alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —OH, —OC(O)CH3, —NH2, —CN, —CONH2, and halogen;

R42and R43are, independently H, —OH, —OR45, —NR46R47, or halogen,wherein each R45, R46and R47is independently H, alkyl, —CONH2, or —COCH3,wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R44and R44aare, independently H, halogen, —OH, C1-C3alkoxy, or —OC(O)CH3;

X1is H, NH2, OH, or halogen;

R51a, R51b, and R51care, independently, H, OH, or —OR51d,wherein each R51dis, independently, alkyl or —COCH3, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R52aand R52bare independently H, OH, or —OR52c,wherein each R52cis, independently, alkyl or —COCH3, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

wherein if R6is —OR27or R11ais —OR53, then at least one of R5and R5aare other than H,

wherein if R5is NR28R29or R5ais NR54R55, then R1is not —OR9, wherein R9is H,

wherein if each of R5, R5a, R6, and R6aare H, then R1is not —OR9, wherein R9is H, and

wherein if each of R5, R5a, R6, and R6aare H and R1is —NR10R11,then R8is not



In some embodiments, the compound of formula (VIIb) is of formula (VIIb-X):


or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

In some embodiments, the compound of formula (IV) is of formula (II):


or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein as valence and stability permit,

R1is —OR9or —NR10R11,wherein R9, R10, and R11are independently H or C1-C6alkyl, wherein the alkyl is unsubstituted or substituted with one or more —OH;

R2and R3are independently selected from the group consisting of H, alkyl, cycloalkyl, and 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, —SR12, —SO2R13, —NR14R15, and —OR16, andwherein each R12, R13, R14, R15, and R16is independently H or alkyl; or

R1and R2, 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, —SO2R18, —NR19R20,and —OR21, andwherein each R17, R18, R19, R20, and R21is independently H or alkyl; or

R2and R3, 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, —SR22, —SO2R23, —NR24R25, and —OR26, andwherein each R22, R23, R24, R25, and R26is independently H or alkyl; and wherein at least one of R2and R3is other than H;

R4is H or absent;



R5and R6are independently selected from the group consisting of H, —OR27, —NR28R29, halogen, and alkyl, wherein each R27, R28, and R29is independently H or C1-C6alkyl,wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR30, —NR31R32,—SR33, and —SO2R34; andwherein each R30, R31, R32, R33, and R34is independently H or alkyl;

R7is H or C1-C3alkyl;

R8is H or

wherein n is an integer from 0 to 4,R35is H or C1-C3alkyl;each R36and R37is independently selected from the group consisting of H, alkyl, halogen, and —OH, andR38is H, alkyl, or —C(═NH)NR39R49, wherein R39and R40are independently H or C1-C3alkyl; orR35and R38, together with the atoms to which they are attached, form a heterocycloalkyl group comprising at least one N;

R41is H, C1-C3alkyl, wherein the alkyl is unsubstituted or substituted by —OH or halogen;

R42and R43are, independently H, —OH, or halogen; and R44is H, halogen, —OH, or C1-C3alkoxy.

In some embodiments, the compound of formula (II) is of formula (II-A):



In some embodiments, the compound of formula (IV) is of formula (I):


or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein as valence and stability permit,

R1is —OR9or —NR10R11,wherein R9, R10, and R11are independently H or C1-C6alkyl, wherein the alkyl is unsubstituted or substituted with one or more —OH;

R2and R3are independently selected from the group consisting of H, alkyl, cycloalkyl, and 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, —SR12, —SO2R13, —NR14R15, and —OR16, andwherein each R12, R13, R14, R15, and R16is independently H or alkyl; or

R1and R2, 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, —SR17, —SO2R18, —NR19R20, and —OR21, andwherein each R17, R18, R19, R20, and R21is independently H or alkyl; or

R2and R3, 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, —SR22, —SO2R23, —NR24R25, and —OR26, andwherein each R22, R23, R24, R25, and R26is independently H or alkyl; and wherein at least one of R2and R3is other than H;

R4is H or absent;



R5and R6are independently selected from the group consisting of H, —OR27, —NR28R29, halogen, and alkyl, wherein each R27, R28, and R29is independently H or C1-C6alkyl,wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, —OR30, —NR31R32, —SR33, and —SO2R34; andwherein each R30, R31, R32, R33, and R34is independently H or alkyl;

R7is H or C1-C3alkyl;

R8is H or

wherein n is an integer from 0 to 4,R35is H or C1-C3alkyl;each R36and R37is independently selected from the group consisting of H, alkyl, halogen, and —OH, andR38is H, alkyl, or —C(═NH)NR39R40, wherein R39and R40are independently H or C1-C3alkyl; orR35and R38, together with the atoms to which they are attached, form a heterocycloalkyl group comprising at least one N.

In some embodiments, the compound of formula (I) is of formula (I-A):



One aspect of the disclosure relates to a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

Another aspect of the disclosure relates to a method for treating a bacterial infection in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

One aspect of the disclosure relates to a method for treating a bacterial infection in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.

Another aspect of the disclosure relates to use of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in the manufacture of a medicament for treating a bacterial infection in a subject in need thereof.

One aspect of the disclosure relates to use of a pharmaceutical composition disclosed herein in the manufacture of a medicament for treating a bacterial infection in a subject in need thereof.

Another aspect of the disclosure relates to a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, for use in a method of treating a bacterial infection in a subject in need thereof.

One aspect of the disclosure relates to a pharmaceutical composition disclosed herein for use in a method of treating a bacterial infection in a subject in need thereof.

In some embodiments of any of the foregoing or following, the bacterial infection is a Gram-negative bacterial infection.

In some embodiments of any of the foregoing or following, the bacterial infection is infection of aStaphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria, Baccillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella, Francisella, Yersinia, Corynebacterium, Moraxella, orEnterococcusspecies.

