US patent application 16/642,879 — Aminoglycosides and uses thereof

›CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 62/551,107, filed Aug. 28, 2017; U.S. Provisional Application No. 62/563,025, filed Sep. 25, 2017; and U.S. Provisional Application No. 62/652,161, filed Apr. 3, 2018, the entireties of which are incorporated herein by reference.

›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 in Enterobacteriaceae and P. 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 contemporary Acinetobacter spp. 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 against P. aeruginosa and A. baumannii infections. 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 as P. aeruginosa and A. 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 · 1 of 7

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,

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 2R 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 2R 18 , —NR 19 R 20 , and —OR 21 , and wherein each R 17 , R 18 , R 19 , R 20 , and 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 , and 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 2R 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 independently 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 2R 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;

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 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.

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,

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 2R 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

›BRIEF SUMMARY · 2 of 7

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 , and 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 , wherein each R 22 , R 23 , R 24 , R 25 , and R 26 is independently H or alkyl, and wherein at least one of R 2 and R 3 is other than H;

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 independently 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;

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.

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,

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 11 , 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 , and 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 , and 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,

›BRIEF SUMMARY · 3 of 7

R 5a and R 6a are, independently, absent or independently 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,

wherein if R 5 is —OR 27 or R 5a is —OR 53 , then R 6 is not —OR 27 , and

wherein if R 5 is —OR 27 or R 5a is —OR 53 , then 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, OH, halogen, C 1 -C 3 alkoxy, or —OC(O)CH 3 , wherein when R 44 or R 44a is OH, then R 41 is not H;

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.

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,

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 , and 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 , and R 26 is independently H or alkyl, and 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 independently 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,

wherein if R 5 is —OR 27 or R 5a is —OR 53 , then R 6 is not —OR 27 , and

wherein if R 5 is —OR 27 or R 5a is —OR 53 , then 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;

›BRIEF SUMMARY · 4 of 7

R 42 and R 43 are, is 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, and wherein at least one of R 42 and R 43 is other than H;

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.

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,

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

1 wherein each R 17 , R 18 , R 19 , R 20 , and 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 , and R 26 is independently H or alkyl; R 4 is H;

R 5 is 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 6 is H, NR 28 R 29 , F, Br, I, or alkyl, wherein each 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 is 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 6a is H, NR 54 R 55 , F, Br, I, or alkyl, wherein each 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;

›BRIEF SUMMARY · 5 of 7

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 5 is —OR 27 or R 5a is —OR 53 , then at least one of R 6 and R 6a are other than H,

wherein if each of R 5 , R 5a , R 6 , and R 6a are H, then R 1 is not —OR 9 , wherein R 9 is H, and

wherein if each of R 5 , R 5a , R 6 , and R 6a are H and R 1 is —NR 10 R 11 , then R 8 is 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,

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 , and 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 , and R 26 is independently H or alkyl; R 4 is H;

R 5 is H, NR 28 R 29 , F, Br, I, or alkyl, wherein each 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 6 is 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 is H, NR 54 R 55 , F, Br, I, or alkyl, wherein each 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 69 is independently H or alkyl,

R 6a is 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 49 , 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 6 is —OR 27 or R 11a is —OR 53 , then at least one of R 5 and R 5a are other than H,

wherein if R 5 is NR 28 R 29 or R 5a is NR 54 R 55 , then R 1 is not —OR 9 , wherein R 9 is H,

›BRIEF SUMMARY · 6 of 7

wherein if each of R 5 , R 5a , R 6 , and R 6a are H, then R 1 is not —OR 9 , wherein R 9 is H, and

wherein if each of R 5 , R 5a , R 6 , and R 6a are H and R 1 is —NR 10 R 11 ,then R 8 is 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,

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 alkyl is unsubstituted or substituted with one or more —OH;

R 2 and R 3 are 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, —SR 12 , —SO 2 R 13 , —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, —SO 2 R 18 , —NR 19 R 20, and —OR 21 , and wherein each R 17 , R 18 , R 19 , R 20 , and 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 , and R 26 is independently H or alkyl; and wherein at least one of R 2 and R 3 is other than H;

R 4 is H or absent;

R 5 and R 6 are independently selected from the group consisting of H, —OR 27 , —NR 28 R 29 , halogen, and alkyl, wherein each R 27 , R 28 , and R 29 is independently H or C 1 -C 6 alkyl,

wherein the 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 7 is H or C 1 -C 3 alkyl;

R 8 is H or

wherein 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 selected from the group consisting of H, alkyl, halogen, and —OH, and

R 38 is H, alkyl, or —C(═NH)NR 39 R 49 , 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, C 1 -C 3 alkyl, wherein the alkyl is unsubstituted or substituted by —OH or halogen;

R 42 and R 43 are, independently H, —OH, or halogen; and R 44 is H, halogen, —OH, or C 1 -C 3 alkoxy.

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,

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 alkyl is unsubstituted or substituted with one or more —OH;

R 2 and R 3 are 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, —SR 12 , —SO 2 R 13 , —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 , and 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 , and R 26 is independently H or alkyl; and wherein at least one of R 2 and R 3 is other than H;

R 4 is H or absent;

R 5 and R 6 are independently selected from the group consisting of H, —OR 27 , —NR 28 R 29 , halogen, and alkyl, wherein each R 27 , R 28 , and R 29 is independently H or C 1 -C 6 alkyl,

wherein the 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 7 is H or C 1 -C 3 alkyl;

R 8 is H or

wherein 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 selected from the group consisting of H, alkyl, halogen, and —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.

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.

›BRIEF SUMMARY · 7 of 7

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 a Staphylococcus, 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 , or Enterococcus species.

›DESCRIPTION OF THE FIGURES

FIG. 1 shows various possible, but not limiting, substituents on the compounds of the present disclosure.

›DETAILED DESCRIPTION · 1 of 47

The present disclosure provides antibacterial aminoglycoside compounds, including stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising said compounds, or stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof. The compounds and pharmaceutical compositions of the disclosure may be useful for treating bacterial infections as well as medical conditions associated therewith. The compounds and pharmaceutical compositions of the disclosure may also be useful for treating difficult-to-treat resistance mechanisms as well as multidrug resistant (MDR) bacterial infections.

This disclosure also features methods of and uses for treating a bacterial infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof The compounds and pharmaceutical compositions of the present disclosure may be useful for treating a variety of bacterial infections including, but not limited to, bacterial infections caused by Staphylococcus sp., Lactobacillus sp., Streptococcus sp., Sarcina sp., Escherichia sp., Enterobacter sp., Klebsiella sp., Pseudomonas sp., Acinetobacter sp., Mycobacterium sp., Proteus sp., Campylobacter sp., Citrobacter sp., Nisseria sp., Baccillus sp., Bacteroides sp., Peptococcus sp., Clostridium sp., Salmonella sp., Shigella sp., Serratia sp., Haemophilus sp., Brucella sp., Francisella sp., Yersinia sp., Corynebacterium sp., Moraxella sp., or Enterococcus sp.

The compounds and pharmaceutical compositions of the present disclosure may be useful for treating a variety of bacterial infections including, but not limited to, bacterial infections caused by Escherichia coli, Klebsiella sp., Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter sp., Enterobacter cloacae, Enterobacter aerogenes, Citrobacter sp., Citrobacter freundii, Citrobacter koseri, Proteus mirabilis, Bacillus anthraces, P. aeruginosa, A. baumannii, Proteus vulgaris , or Yersinia pestis.

In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful for treating a bacterial infection caused by Gram-negative bacteria. In certain such embodiments, the Gram-negative bacteria may include, but are not limited to, Escherichia sp., Enterobacter sp., Klebsiella sp., Pseudomonas sp., Acinetobacter sp., Proteus sp., Campylobacter sp., Citrobacter sp., Nisseria sp., Bacteroides sp., Salmonella sp., Shigella sp., Serratia sp., Haemophilus sp., Brucella sp., Francisella sp., Yersinia sp., or Moraxella sp.

In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful for treating a bacterial infection caused by Gram-positive bacteria. In certain such embodiments, the Gram-positive bacteria may include, but are not limited to, Staphylococcus sp., Lactobacillus sp., Streptococcus sp., Sarcina sp., Baccillus sp., Peptococcus sp., Clostridium sp., Corynebacterium sp., or Enterococcus sp.

In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful for treating a bacterial infection caused by Methicillin-resistant Staphylococcus aureus (MRSA).

In some embodiments, the compounds or pharmaceutical compositions disclosed herein are also useful for treating bacterial infections caused by Enterobacteriaceae.

In some embodiments, the compounds or pharmaceutical compositions disclosed herein are also useful for treating bacterial infections caused by KPC-producing carbapenem-resistant Enterobacteriaceae (CRE).

In some embodiments, the compounds or pharmaceutical compositions of the disclosure may be useful for treating bacterial infections caused by multidrug resistant (MDR) bacteria.

The following description sets forth numerous exemplary configurations, methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the disclosure may be practiced without these details.

Unless the context requires otherwise, throughout the present specification and claims, as used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

The articles “a” and “an” as used in this disclosure may refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” may mean one element or more than one element.

The term “and/or” as used in this disclosure may mean either “and” or “or” unless indicated otherwise.

“Amino” refers to —NH 2 .

“Hydroxy” or “hydroxyl” refers to —OH.

The term “oxo” as used herein refers to an “═O” group. It can also be abbreviated herein as C(O) or as C═O.

“Alkyl” refers to a saturated straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (C 1 -C 12 alkyl); one to eight carbon atoms (C 1 -C 8 alkyl); one to six carbon atoms (C 1 -C 6 alkyl), e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, or 2-methylhexyl; or one to three carbon atoms (C 1 -C 3 alkyl). An alkyl group can be unsubstituted or substituted.

›DETAILED DESCRIPTION · 2 of 47

“Cycloalkyl” refers to a single saturated all carbon ring having 3 to 20 carbon atoms (i.e., C 3 -C 20 cycloalkyl), for example from 3 to 15 carbon atoms, for example, from 3 to 12 carbon atoms. In certain embodiments, the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contains a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated. “Cycloalkyl” includes ring systems where the cycloalkyl ring, as defined herein, is fused with one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a cycloalkyl ring, and, in such instances, the number of carbon atoms recited continues to designate the number of carbons in the cycloalkyl ring containing the point of attachment. Examples of cycloalkyl groups include cyclohexyl, and cycloheptyl.

“Heteroaryl,” as used herein, refers to a monocyclic or polycyclic group comprising at least one aromatic ring, wherein the aromatic ring comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S. The heteroaryl group may comprise 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms, where ring atoms refer to the sum of carbon and heteroatoms in the one or more rings (e.g., be a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered heteroaryl). In some embodiments, heteroaryl includes groups with an aromatic ring that comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S, (e.g., pyridinyl, pyrazinyl, furanyl, thiophenyl). In certain embodiments, heteroaryl includes polycyclic groups with an aromatic ring comprising at least one ring heteroatom, fused to a non-aromatic hydrocarbon ring (e.g., 5,6,7,8-tetrahydroquinolinyl; 4,5,6,7-tetrahydroisobenzofuranyl). In some embodiments, heteroaryl includes polycyclic groups with an aromatic ring comprising at least one ring heteroatom fused to an aromatic hydrocarbon ring (e.g., quinolinyl, quinoxalinyl, benzothiazolyl). In still further embodiments, heteroaryl includes polycyclic groups with two fused aromatic rings, wherein each ring comprises at least one ring heteroatom (e.g., naphthyridinyl). Heteroaryl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each ring heteroatom is independently selected from the group consisting of N, O, and S. In one example, a heteroaryl has 3 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independently selected from N, O, and S. Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl, and pyrazolyl.

“Aryl” refers to cyclic, aromatic hydrocarbon group that has 1 to 3 aromatic rings, including monocyclic or bicyclic groups. Where the aryl group has two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point. An aryl group with two fused rings may include an unsaturated or partially saturated ring fused with a fully saturated ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenalenyl, indanyl, indenyl, and tetrahydronaphthalenyl. Unless stated otherwise specifically in the specification, an aryl group may be substituted or unsubstituted.

“Heterocycloalkyl” refers to non-aromatic, monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur. The heterocycloakyl group may be saturated or unsaturated, and may comprise 3, 4, 5, 6, 7, or more ring atoms. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, and tropanyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be substituted or unsubstituted.

“Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo.

The term “substituted” used herein means a group wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in a hydroxyl group; and a nitrogen atom in an amino group. Combinations of substituents envisioned by the present disclosure are typically those that result in the formation of stable or chemically feasible compounds.

As used herein, the term “unsubstituted” may mean that the specified group bears no substituents beyond the moiety recited (e.g., where valency satisfied by hydrogen).

“Stable compound” and “stable structure” may indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

Compounds of Disclosed Formulae: Compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (V), Formula (VI), Formula (VIIa), and Formula (VIIb)

Provided herein are compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IVa), Formula (V), Formula (VI), Formula (VIIa), and Formula (VIIb).

Provided herein are compounds of formula (IV):

and pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers 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 , and R 21 is independently H or alkyl, or

›DETAILED DESCRIPTION · 3 of 47

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 , and 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 independently 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;

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.

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

or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 1 , R 2 , R 3 , R 4 ,

R 7 , R 8 , R 41 , R 42 , R 43 , R 44 , R 44a , X 1 , R 51a , R 51b , R 51c , R 52a , and R 52b are as defined for formula (IV) herein.

In one aspect, the compound of formula (IV) is a compound of formula (I), including formula (I-A), formula (I-Ai), formula (I-Aii), formula (I-B), formula (I-Bi), and formula (I-Bii), and formula (II), or formula (II-A), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer of any of the foregoing, as disclosed herein.

In one aspect, the compound of formula (IV) is a compound of formula (IV-X); formula (IVa), including formula (IVa-X); formula (V), including formula (V-X); or formula (VI), including formula (VI-X), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer of any of the foregoing, as disclosed herein.

In some embodiments of formula (IV), including formula (IV-X), R 1 is —NR 10 R 11 , wherein R 10 and R 11 are independently H or C 1 -C 6 alkyl, wherein the alkyl is unsubstituted or substituted with one or more —OH. In certain embodiments, R 10 and R 11 are independently H, methyl, or hydroxyethyl. In certain embodiments, R 10 and R 11 are both H.

In some embodiments of formula (IV), including formula (IV-X), R 1 is OR 9 , wherein R 9 is H or C 1 -C 6 alkyl, wherein the alkyl is unsubstituted or substituted with one or more —OH. In certain embodiments, R 9 is H, methyl, or hydroxyethyl. In certain embodiments, R 9 is H.

In some embodiments of formula (IV), including formula (IV-X), R 2 and R 3 are independently selected from the group consisting of H, alkyl, cycloalkyl, and aryl. In some embodiments, at least one of R 2 and R 3 is other than H. In certain embodiments, one of R 2 and R 3 is H.

In some embodiments of formula (IV), including formula (IV-X), R 2 is alkyl, cyclopropyl, or phenyl; wherein the alkyl is unsubstituted or substituted with one, two, or three substituents selected from the group consisting of —NH 2 , —OH, F, —CN, and —S(O) 2 CH 3 . In some embodiments, R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. In other embodiments, R 2 is substituted methyl, substituted ethyl, substituted propyl, substituted butyl, substituted pentyl, substituted hexyl, substituted cyclopropyl, substituted cyclobutyl, substituted cyclopentyl, substituted cyclohexyl, or substituted phenyl, wherein the one or more substituents are independently selected from the group consisting of halogen, cyano, aryl, —SR 12 , —SO 2 R 13 , —NR 14 R 15 , and —OR 16 . In some embodiments, the one or more substituents are independently selected from the group consisting of halogen, cyano, aryl, —SO 2 R 13 , —NR 14 R 15 , and —OR 16 . For example, in certain embodiments, the one or more substituents are independently selected from the group consisting of F, Cl, B, I, cyano, —SO 2 CH 3 , —NH 2 , and —OH. In still other embodiments, R 2 is methyl; methyl substituted with one or two F; methyl substituted with —SO 2 CH 3 ; methyl substituted with —NH 2 ; methyl substituted with —OH; ethyl; cyclopropyl; or phenyl. In some embodiments, R 2 is H or unsubstituted methyl.

›DETAILED DESCRIPTION · 4 of 47

In some embodiments of formula (IV), including formula (IV-X), R 3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. In other embodiments, R 3 is substituted methyl, substituted ethyl, substituted propyl, substituted butyl, substituted pentyl, substituted hexyl, substituted cyclopropyl, substituted cyclobutyl, substituted cyclopentyl, substituted cyclohexyl, or substituted phenyl, wherein the one or more substituents are independently selected from the group consisting of halogen, cyano, aryl, —SR 12 , —SO 2 R 13 , —NR 14 R 15 , and —OR 16 . In some embodiments, the one or more substituents are independently selected from the group consisting of halogen, cyano, aryl, —SO 2 R 13 , —NR 14 R 15 , and —OR 16 . For example, in certain embodiments, the one or more substituents are independently selected from the group consisting of F, Cl, B, I, cyano, —SO 2 CH 3 , —NH 2 , and —OH. In still other embodiments, R 3 is methyl; methyl substituted with one or two F; methyl substituted with —SO 2 CH 3 ; methyl substituted with —NH 2 ; methyl substituted with —OH; ethyl; cyclopropyl; or phenyl. In certain embodiments, R 3 is H or unsubstituted methyl.

In some embodiments of formula (IV), including formula (IV-X), R 2 and R 3 , together with the atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group. In some embodiments, the cycloalkyl group or heterocycloalkyl group may be 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 , wherein each R 22 R 23 , R 24 , R 25 , and R 26 may be independently H or alkyl. In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a cyclopropyl or oxetanyl. In certain embodiments, R 2 and R 3 together with the atom to which they are attached form a cyclopropyl.

In some embodiments of formula (IV), including formula (IV-X), R 4 is H or absent.

In some embodiments of formula (IV), including formula (IV-X), R 5 and R 6 are H and R 5a and R 6a are independently absent or H.

In some embodiments of formula (IV), including formula (IV-X), both R 5 and R 6 are H.

In some embodiments of formula (IV), including formula (IV-X), both R 5a and R 6a are H.

In some embodiments of formula (IV), including formula (IV-X), R 5 is H or —OH. In some embodiments of formula (IV), including formula (IV-X), R 5 is —OH. In some embodiments of formula (IV), including formula (IV-X), R 5 is H.

In some embodiments of formula (IV), including formula (IV-X), R 5a is H or —OH. In some embodiments of formula (IV), including formula (IV-X), R 5a is —OH. In some embodiments of formula (IV), including formula (IV-X), R 5a is H.

In some embodiments of formula (IV), including formula (IV-X), R 6 is H or —OH. In some embodiments of formula (IV), including formula (IV-X), R 6 is —OH. In some embodiments of formula (IV), including formula (IV-X), R 6 is H.

In some embodiments of formula (IV), including formula (IV-X), R 6a is H or —OH. In some embodiments of formula (IV), including formula (IV-X), R 6a is —OH. In some embodiments of formula (IV), including formula (IV-X), R 6a is H.

In some embodiments of formula (IV), including formula (IV-X), R 5 is H, halogen, or —OH. In certain such embodiments, R 5 is halogen. In certain such embodiments, R 5 is F.

In some embodiments of formula (IV), including formula (IV-X), R 5a is H, halogen, or —OH. In certain such embodiments, R 5a is halogen. In certain such embodiments, R 5a is F.

In some embodiments of formula (IV), including formula (IV-X), R 6 is H, halogen, or —OH. In certain such embodiments, R 6 is halogen. In certain such embodiments, R 6 is F.

In some embodiments of formula (IV), including formula (IV-X), R 6a is H, halogen, or —OH. In certain such embodiments, R 6a is halogen. In certain such embodiments, R 6a is F.

In some embodiments of formula (IV), including formula (IV-X), R 5 is —OR 27 or —NR 28 R 29 , wherein R 27 , R 28 , and R 29 are independently H or C 1 -C 6 alkyl, such as C 1 -C 4 alkyl.

In some embodiments of formula (IV), including formula (IV-X), R 5a is —OR 27 or —NR 28 R 29 , wherein R 27 , R 28 , and R 29 are independently H or C 1 -C 6 alkyl, such as C 1 -C 4 alkyl.

In some embodiments of formula (IV), including formula (IV-X), R 6 is —OR 27 or —NR 28 R 29 , wherein R 27 , R 28 , and R 29 are independently H or C 1 -C 6 alkyl, such as C 1 -C 4 alkyl.

In some embodiments of formula (IV), including formula (IV-X), R 6a is —OR 27 or —NR 28 R 29 , wherein R 27 , R 28 , and R 29 are independently H or C 1 -C 6 alkyl, such as C 1 -C 4 alkyl.

In some embodiments of formula (IV), including formula (IV-X), R 4 is H.

In some embodiments of formula (IV), including formula (IV-X), X 1 is NH 2 . In some embodiments of formula (IV), including formula (IV-X), X 1 is OH. In some embodiments of formula (IV), including formula (IV-X), X 1 is halogen. In some embodiments of formula (IV), including formula (IV-X), X 1 is F. In some embodiments of formula (IV), including formula (IV -X), X 1 is Cl. In some embodiments of formula (IV), including formula (IV-X), X 1 is Br. In some embodiments of formula (IV), including formula (IV-X), X 1 is I.

In some embodiments of formula (IV), including formula (IV-X), R 41 is H.

In some embodiments of formula (IV), including formula (IV-X), one of R 42 and R 43 is —OH. In some embodiments of formula (IV), including formula (IV-X), one of R 42 and R 43 is halogen. In some embodiments of formula (IV), including formula (IV-X), one of R 42 and R 43 is H. In some embodiments of formula (IV), including formula (IV-X), one of R 42 and R 43 is —NR 46 R 47 . In some embodiments of formula (IV), including formula (IV-X), one of R 42 and R 43 is —F. In some embodiments of formula (IV), including formula (IV-X), R 42 is —F and R 43 is —F. In some embodiments of formula (IV), including formula (IV-X), one of R 42 and R 43 is —OH. In some embodiments of formula (IV), including formula (IV-X), one of R 42 and R 43 is —OR 45 .

›DETAILED DESCRIPTION · 5 of 47

In some embodiments of formula (IV), including formula (IV-X), R 42 and R 43 are H.

In some embodiments of formula (IV), including formula (IV-X), one of R 44 and R 44a is —OH. In some embodiments of formula (IV), including formula (IV-X), one of R 44 and R 44a is —OCH 3 . In some embodiments of formula (IV), including formula (IV-X), one of R 44 and R 44a is —F. In some embodiments of formula (IV), including formula (IV-X), R 44 and R 44a are —F. In some embodiments of formula (IV), including formula (IV-X), R 44 and R 44a are H. In some embodiments of formula (IV), including formula (IV-X), one of R 44 and R 44a is H. In some embodiments of formula (IV), including formula (IV-X), R 44 and R 44a are, independently H, halogen, C 1 -C 3 alkoxy, or —OC(O)CH 3 .

In some embodiments of formula (IV), including formula (IV-X), R 51a , R 51b , and R 51c are, independently, H, OH, or —OR 51d . In some embodiments of formula (IV), including formula (IV-X), one of R 51a , R 51b , and R 51c is —OH. In some embodiments of formula (IV), including formula (IV-X), one of R 51a , R 51b , and R 51c is —OR 51d . In some embodiments of formula (IV), including formula (IV-X), R 51a is —OH and R 51b and R 51c are H. In some embodiments of formula (IV), including formula (IV-X), R 51a is —OR 51d and R 51b and R 51c are H.

In some embodiments of formula (IV), including formula (IV-X), R 52a and R 52b are independently H, OH, or —OR 52c . In some embodiments of formula (IV), including formula (IV-X), R 52a and R 52b are —OH. In some embodiments of formula (IV), including formula (IV-X), one of R 52a and R 52b is —OR 52c . In some embodiments of formula (IV), including formula (IV-X), one of R 52a and R 52b is —OH. In some embodiments of formula (IV), including formula (IV-X), R 52a is H and R 52b is —OR 52c . In some embodiments of formula (IV), including formula (IV-X), R 52a is H and R 52b is —OH.

In some embodiments of formula (IV), including formula (IV-X), R 7 is H. In other embodiments, R 7 is C 1 -C 3 alkyl, for example C 1 -alkyl, C 2 -alkyl, or C 3 -alkyl. In some embodiments, R 8 is H. In some embodiments of formula (IV), including formula (IV-X), R 7 is H and R 8 is H.

In some embodiments of formula (IV), including formula (IV-X), R 8 is C 1 -C 6 alkyl, for example C 1 -alkyl, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 -alkyl, or C 6 -alkyl.

In some embodiments of formula (IV), including formula (IV-X), R 8 is

wherein Q 1 is NH, O, or S. In certain embodiments, Q 1 is NH. In certain embodiments, Q 1 is O. In certain embodiments, Q 1 is S. In certain embodiments, wherein when n is one, then R 36 and R 37 are not halo.

In some embodiments of formula (IV), including formula (IV-X), n is an integer from 0 to 4, from 0 to 3, from 0 to 2, from 1 to 4, from 2 to 4, or from 1 to 3. In certain embodiments, n is 0, or n is 1, or n is 2, or n is 3, or n is 4.

In Formula (IV), the ring substituted by R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , R 6 , R 6a , and X 1 may also be referred to as Ring A, as shown below. The ring substituted R 7 , R 8 , R 41 , R 42 , R 43 , R 44 , and R 44a may also referred to as Ring B, as shown below. Ring C is also used to refer to the moiety connected to Ring B through —O— moiety, as shown below. Ring D is also used to refer to the moiety connected to Ring C through —O— moiety, as shown below.

In some embodiments of the compound of Formula (IV), Ring A is selected from

In some embodiments of the compound of

Formula (IV), Ring A is selected from

In some embodiments of the compound of Formula (IV), Ring A is selected from

In some embodiments of the compound of Formula (IV), Ring B is selected from

In some embodiments of the compound of Formula (IV), Ring B is