Rifamycin analogs and antibody-drug conjugates thereof

Abstract

The present disclosure relates to rifamycin analog compounds, intermediates and precursors thereof, and pharmaceutical compositions capable of inhibiting bacterial growth (e.g., Staphylococcus aureus growth) and treating bacterial infections (e.g., Staphylococcus aureus infections). The present disclosure also relates to antibody-drug conjugates of rifamycin analog compounds and antibodies and methods for inhibiting bacterial growth and treating bacterial infections with the antibody-drug conjugates, wherein the antibodies are, for example, antibodies specific to targets associated with infectious diseases such as membrane glycoprotein receptors (MSR1), wall teichoic acid (WTA), or protein A.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application Serial No. 62 / 783,506, filed on December 21, 2018, and U.S. Provisional Application Serial No. 62 / 844,860, filed on May 8, 2019, the contents of which are incorporated herein by reference in their entirety.

[0003] Areas of public content

[0004] The present disclosure relates to rifamycin analog compounds and pharmaceutical compositions capable of inhibiting bacterial growth and treating bacterial infections, as well as antibody-drug conjugates of rifamycin analog compounds and antibodies (e.g., antibodies specific for targets associated with infectious diseases), and methods of use thereof.

[0005] Sequence Listing

[0006] This application contains a sequence listing, which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy created on December 19, 2019 is named 250298_000145_SL.txt and is 409,310 bytes in size.

[0007] Background of the Disclosure

[0008] Staphylococcus aureus (S.aureus) is a Gram-positive, round bacterium that is a member of the Firmicutes phylum and is also a common member of the body's microflora, often found in the upper respiratory tract and on the skin. Staphylococcus aureus is typically catalase and nitrate reduction positive and is a facultative anaerobe that does not require oxygen for growth. Although Staphylococcus aureus is typically a symbiont of the human microflora, it may also become an opportunistic pathogen and is a common cause of skin infections including abscesses, respiratory infections such as sinusitis, and food poisoning. Pathogenic strains typically promote infection by producing virulence factors such as effective protein toxins and expressing cell surface proteins that bind to and inactivate antibodies.

[0009] It is estimated that 20% to 30% of the human population are chronic carriers of S. aureus, which can be found as part of the normal skin flora in the nares and as a normal inhabitant of the lower female genital tract. S. aureus can cause a range of diseases, ranging from minor skin infections such as papules, impetigo, furuncles, cellulitis, folliculitis, carbuncles, scalded skin syndrome, and abscesses, to life-threatening conditions such as pneumonia, meningitis, osteomyelitis, endocarditis, toxic shock syndrome, bacteremia, and sepsis. S. aureus remains one of the five most common causes of hospital-acquired infections and is often the cause of post-operative wound infections. Each year, approximately 500,000 patients in U.S. hospitals develop staphylococcal infections, primarily caused by S. aureus. In the United States, up to 50,000 deaths each year are associated with S. aureus infections. Schlecht LM et al., 2015, Microbiology, 161, 1, 168-181. Despite extensive research and development, no vaccine has been approved against S. aureus.

[0010] Initially, the treatment of choice for S. aureus infections was penicillin. When penicillin was first introduced in 1943, antibiotic resistance in S. aureus was uncommon. By 1950, 40% of hospital-acquired S. aureus isolates were penicillin-resistant; by 1960, this had risen to 80%. Chambers HF, 2001, Emerging Infectious Diseases, 7, 2, 178-82. Today, S. aureus has become resistant to many commonly used antibiotics.

[0011] Antibiotic-resistant strains of Staphylococcus aureus, such as the emergence of methicillin-resistant Staphylococcus aureus (MRSA), are a worldwide problem in clinical medicine. MRSA strains are most often found to be associated with institutions such as hospitals, but are becoming increasingly popular in community-acquired infections. MRSA is one of many very frightening Staphylococcus aureus strains that have become tolerant to most β-lactam antibiotics. In both hospital and community settings, MRSA infections are typically treated with non-β-lactam antibiotics, such as clindamycin (a type of lincomycin) and trimethoprim / sulfamethoxazole (also referred to as trimethoprim / sulfamethoxazole). Tolerance to these antibiotics has also led to the use of new broad-spectrum anti-Gram-positive antibiotics, such as linezolid, because it can be used as an oral medication. Glycopeptide antibiotics (vancomycin and teicoplanin) are currently the first-line treatment for the serious invasive infections caused by MRSA. These antibiotics have many problems, such as the need for intravenous administration (no oral formulation is available), toxicity, and the need to regularly monitor drug levels by blood tests. Furthermore, glycopeptide antibiotics do not penetrate well into infected tissue (a particular concern in infections of the brain and meninges, as well as endocarditis). Thus, there is a strong unmet need for new antibiotic treatments for S. aureus in general, and in addressing intracellular S. aureus infections in particular.

[0012] Rifamycins are a subclass of the ansamycin antibiotic family, a group of antibiotics that are naturally or artificially synthesized by the bacterium Amycolatopsis rifamycinica. Rifamycins are particularly effective against mycobacteria and are therefore used to treat tuberculosis, leprosy, and Mycobacterium avium complex (MAC) infections. The group of rifamycins includes the "classic" rifamycin drugs as well as the rifamycin analogs rifampicin (rifampin), rifabutin, rifapentine, rifalazil, and rifaximin. Rifamycin SV is sold under the trade name Aemcolo and is FDA-approved for the treatment of travelers' diarrhea in certain cases.

[0013] Rifamycin antibiotics inhibit bacterial RNA polymerase (RNAP) and have potent activity against Staphylococcus aureus. However, monotherapy with this class of antibiotics can lead to the selection of resistant populations during treatment. Therefore, rifamycin antibiotics can be used in combination with first-line antibiotics to improve outcomes, typically for infections involving prosthetic or foreign devices.

[0014] Macrophage scavenger receptor 1 (MSR1) is a single-pass, trimeric, type II transmembrane glycoprotein pattern recognition receptor that mediates the uptake of a range of negatively charged / polyanionic ligands, including modified low-density lipoprotein (LDL) (Krieger, M. 1994. Annu. Rev. Biochem. 63: 601-637; Platt, N. and S. Gordon. 2001. J Clin Invest. 108(5): 649-654) and advanced glycation end products of bovine serum albumin (AGE-BSA) ( et al. 1997. Biochem J. 322(Pt 2):567-573). The MSR1 receptor is involved in many macrophage-related physiological and pathological processes (including atherosclerosis, Alzheimer's disease, and host defense).

[0015] MSR1 expression was initially thought to be macrophage-specific. However, it has recently been shown to be present on different classes of dendritic cells (Herber et al. 2010. Nat. Med. 16(8): 880-886). In addition, MSR1 appears to be expressed in endothelial cells and smooth muscle cells. Before recycling back to the cell surface from the trans-Golgi apparatus, it is internalized through coated pits on the cell surface and releases its ligand at acidic pH (Doi et al. 1994. Journal of Biological Chemistry; Mori, T. 1994. Lab Invest). It promotes the transformation of monocyte-derived macrophages into foam cells, which is a key step in the progression of atherosclerosis.

[0016] Staphylococcus aureus is a facultative intracellular bacterium that can survive phagocytosis by macrophages and other cell types (Horn et al. 2018. Int. J. Med. Microbiol. 308(6):607-624; Jubrail et al. 2016. Cell Microbiol. 18(1):80-96; Mitchell et al. 2016. Microbiol. Spectr. 4(3)). In vivo imaging has demonstrated that macrophages can serve as a reservoir in which S. aureus replicates and then seed other organs during infection (Surewaard et al. 2016. J. Exp. Med. 213(7):1141-51). Most antibiotics do not penetrate cells (including macrophages) well, suggesting that intracellular S. aureus reservoirs can escape treatment with standard-of-care antibiotics (Lehar et al. 2015. Nature. 527(7578):323-8). However, a liposomal formulation of vancomycin increased the penetration of antibiotics into macrophages more effectively than standard-of-care vancomycin and reduced the organ burden of S. aureus (Surewaard et al. 2016. J. Exp. Med. 213(7): 1141-51). Taken together, these data suggest that delivering antibiotics to macrophages may be an effective approach to eliminate intracellular S. aureus reservoirs.

[0017] Teichoic acid is a phosphate-rich molecule found on many glycan binding proteins in the cell wall of most gram-positive bacteria (including Staphylococcus aureus). Teichoic acid and many other glycoproteins form a thick layer of multiple peptidoglycan sheaths around bacteria, not only stabilizing the cell membrane, but also providing many attachment sites for other molecules. Wall teichoic acid (" WTA ") is a type of teichoic acid, covalently attached to peptidoglycan and extending through the cell wall and reaching outside the cell wall. In glycan binding proteins, WTA can account for up to 60% of total cell wall quality. Therefore, it represents the highly expressed cell surface antigens of gram-positive bacteria (including Staphylococcus aureus).

[0018] Staphylococcus aureus also expresses many surface determinant antigens, including Staphylococcus aureus protein A (SpA) and the polysaccharide poly-N-acetylglucosamine (PNAG), iron-regulated surface determinant proteins IsdA, IsdB, IsdC, IsdE and IsdH, clumping factor proteins ClfA and ClfB, capsular polysaccharide types (CP) 5 and CP8, serine-aspartate repeat proteins SdrC, SdrD and SdrE, fibronectin binding proteins A and B (FnBpA, FnBpB), Cna (collagen binding protein) and SasG (Staphylococcus aureus surface protein G). These surface antigens play a role in host tissue colonization, evasion of host immune responses and bacterial fitness.

[0019] Therefore, the development of ADCs comprising rifamycin analogs will allow the rifamycin analogs to be delivered specifically to macrophages, or the rifamycin analogs to be bound to the bacterial surface. In addition, such ADCs can provide improved activity, improved bioavailability, and improved therapeutic windows for, for example, tolerant bacterial targets. Therefore, there is a continued need to use antibody-drug conjugates of rifamycin analogs to effectively treat antibiotic-tolerant bacteria.

[0020] Therefore, there is a strong unmet need for developing effective analogs of rifamycin to combat the growing problem of antibiotic-resistant bacteria (including antibiotic-resistant Staphylococcus aureus strains). MSR1 antibodies can provide means for specific targeted therapeutic molecules (such as rifamycin analogs) to minimize the undesirable side effects caused by systemic administration of such compounds and help these compounds to be internalized into macrophages. Alternatively, conjugation with antibodies targeting cell surface antigens (e.g., WTA, protein A) can improve the therapeutic effect of rifamycin analogs.

[0021] The foregoing discussion is presented merely to provide a better understanding of the nature of the problems faced in the art and should not be construed in any way as an admission of prior art, nor should citation of any reference herein be construed as an admission that such reference constitutes "prior art" to the present application.

[0022] Overview of the Disclosure

[0023] As discussed herein, there is a strong need to develop effective treatments for bacterial infections in general and Staphylococcus aureus infections in particular. The present disclosure addresses these and other needs by providing novel rifamycin analog compounds, intermediates and precursors thereof, antibody-drug conjugates, pharmaceutical compositions, and therapeutic methods based on such compounds and pharmaceutical compositions.

[0024] Various non-limiting aspects and embodiments are described below.

[0025] In one aspect, the present disclosure provides rifamycin analog compounds, intermediates or precursors thereof having the structure of Formula (A):

[0026]

[0027] or a pharmaceutically acceptable salt thereof, wherein:

[0028] X is selected from -O- and -NR*-;

[0029] Za and Zb are independently selected from hydrogen, -Cl, -Br, -OR1 and -R N ; Provided that at least one of Za or Zb is not hydrogen; wherein:

[0030] R1 is selected from hydrogen, R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[0031] R N Selected from:

[0032]

[0033] The symbols Represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: fluorenylmethoxycarbonyl (F MOC ) and tert-butyloxycarbonyl (Boc), or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0034] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[0035] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[0036] R b Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, and

[0037] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0038] In one aspect, the present disclosure provides rifamycin analog compounds having the structure of Formula (I):

[0039]

[0040] or a pharmaceutically acceptable salt thereof, wherein:

[0041] X is selected from -O- and -NR*-;

[0042] R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[0043] R N Selected from:

[0044]

[0045] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0046] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[0047] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[0048] R b Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b Optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*; and R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0049] In one aspect, the present disclosure provides rifamycin analog compounds having the structure of Formula (I'):

[0050]

[0051] or a pharmaceutically acceptable salt thereof, wherein:

[0052] X is selected from -O- and -NR*-;

[0053] R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[0054] R N Selected from:

[0055]

[0056] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0057] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[0058] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[0059] R b Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b Optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, and R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0060] In embodiments of the compounds of Formula (A), Formula (I), or Formula (I'), X is -O-; R1 is an aliphatic C1-C3 hydrocarbon; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; and R a It's hydrogen.

[0061] In an embodiment of the compound of Formula (A), Formula (I) or Formula (I'), X is -O-; R1 is a benzyl group; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; R a is hydrogen and R b It's hydrogen.

[0062] In embodiments of the compounds of Formula (A), Formula (I), or Formula (I'), X is -O-; R1 is an aliphatic C1-C8 hydrocarbon containing 1-8 heteroatoms selected from O and N; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; R a is hydrogen and R b It's hydrogen.

[0063] In embodiments of the compounds of Formula (A), (I), or (I'), X is -O-; R1 is an aliphatic C1-C8 hydrocarbon substituted with one or more of -NH2, -NHR*, -N(R*)2, R* is hydrogen or an aliphatic C1-C3 hydrocarbon; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; R a is hydrogen and R b It's hydrogen.

[0064] In embodiments of the compounds of Formula (A), Formula (I), or Formula (I'), X is -NCH3-; R1 is -OH; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; R a is hydrogen and R b It's hydrogen.

[0065] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (II):

[0066]

[0067] or a pharmaceutically acceptable salt thereof, wherein:

[0068] X is selected from -O- and -NR*-;

[0069] R a is selected from hydrogen, -Cl and -OR*;

[0070] R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, - O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O )-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, with the proviso that R1 is not an n-butyl group;

[0071] R N Selected from:

[0072]

[0073] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0074] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0075] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (II'):

[0076]

[0077] or a pharmaceutically acceptable salt thereof, wherein:

[0078] X is selected from -O- and -NR*-;

[0079] R a is selected from hydrogen and -OR*;

[0080] R1 is selected from RN , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, - O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O )-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, with the proviso that R1 is not an n-butyl group;

[0081] R N Selected from:

[0082]

[0083] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0084] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0085] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (III):

[0086]

[0087] or a pharmaceutically acceptable salt thereof, wherein:

[0088] R a is selected from hydrogen and -OR*;

[0089] R5 is selected from R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and combinations thereof, with the proviso that R5 is not an n-butyl group;

[0090] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; and

[0091] R N Selected from:

[0092]

[0093] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure.

[0094] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (III'):

[0095]

[0096] or a pharmaceutically acceptable salt thereof, wherein:

[0097] R a is selected from hydrogen and -OR*;

[0098] R5 is selected from R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and combinations thereof, with the proviso that R5 is not an n-butyl group;

[0099] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; and

[0100] R N Selected from:

[0101]

[0102] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure.

[0103] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (IV):

[0104]

[0105] or a pharmaceutically acceptable salt thereof, wherein:

[0106] R a is selected from hydrogen and -OR*;

[0107] R5 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and combinations thereof;

[0108] R N Selected from:

[0109]

[0110] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0111] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0112] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (IV'):

[0113]

[0114] or a pharmaceutically acceptable salt thereof, wherein:

[0115] R a is selected from hydrogen and -OR*;

[0116] R5 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and combinations thereof;

[0117] R N Selected from:

[0118]

[0119]

[0120] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0121] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0122] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (V):

[0123]

[0124] or a pharmaceutically acceptable salt thereof, wherein:

[0125] X is selected from -O- and -NR*-;

[0126] R a is selected from hydrogen and -OR*;

[0127] R6 is selected from R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R6 is optionally substituted with one or more of: -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and combinations thereof, with the proviso that R6 is not an n-butyl group;

[0128] R N Selected from:

[0129]

[0130] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0131] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0132] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (V'):

[0133]

[0134] or a pharmaceutically acceptable salt thereof, wherein:

[0135] X is selected from -O- and -NR*-;

[0136] R a is selected from hydrogen and -OR*;

[0137] R6 is selected from R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons, each of which further comprises 0-8 heteroatoms selected from halogen, O, N and S, and wherein R6 is optionally substituted with one or more of: -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and combinations thereof, with the proviso that R6 is not an n-butyl group;

[0138] R N Selected from:

[0139]

[0140] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0141] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0142] In another aspect, the present disclosure provides rifamycin analog compounds, intermediates or precursors thereof having the structure of Formula (B):

[0143]

[0144] or a pharmaceutically acceptable salt thereof, wherein:

[0145] X is selected from -O- and -NR*-;

[0146] R1 is selected from hydrogen, R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[0147] R N Selected from:

[0148]

[0149] The symbols Represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: fluorenylmethoxycarbonyl (F MOC ) and tert-butyloxycarbonyl (Boc), or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0150] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[0151] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[0152] R b Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, and

[0153] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0154] In another aspect, the present disclosure provides rifamycin analog compounds having the structure of Formula (B-1):

[0155]

[0156] or a pharmaceutically acceptable salt thereof, wherein:

[0157] X is selected from -O- and -NR*-;

[0158] R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, - O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O )-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, with the proviso that R1 is not an n-butyl group;

[0159] R N Selected from:

[0160]

[0161] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0162] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0163] In another aspect, the present disclosure provides rifamycin analog compounds having the structure of Formula (B-2):

[0164]

[0165] or a pharmaceutically acceptable salt thereof, wherein:

[0166] R N Selected from:

[0167]

[0168] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure.

[0169] In another aspect, the present disclosure provides rifamycin analog compounds having the structure of Formula (B-2):

[0170]

[0171] or a pharmaceutically acceptable salt thereof, wherein:

[0172] R N yes The symbols represents the point of attachment; and R′ and R″ are selected from hydrogen and C1-C6 aliphatic hydrocarbons.

[0173] In one embodiment, the rifamycin analog compound has a structure according to the following formula:

[0174]

[0175] or a pharmaceutically acceptable salt thereof.

[0176] In any of the preceding embodiments, a compound is provided wherein R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further comprises 0-3 heteroatoms selected from O and N, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, C 1-3 Alkoxy (C 1-3 alkoxide), -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -O-(C=O)-H, -O-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -Si(R*)3, -CF3, -O-CF3 and combinations thereof, with the proviso that R1 is not an n-butyl group and when X is -O-, R1 is not hydrogen.

[0177] In any of the preceding embodiments, a compound is provided wherein R1 is an aliphatic C1-C 20 Hydrocarbons and aromatic C1-C 20 Combination of hydrocarbons.

[0178] In any of the preceding embodiments, a compound is provided wherein R1 is an aliphatic C1-C 20 Hydrocarbons and heteroaromatic C1-C 20 Combination of hydrocarbons.

[0179] In an embodiment of any of the foregoing formulas, a compound is provided wherein R1 is selected from:

[0180]

[0181] In any of the foregoing embodiments, a compound is provided wherein R1 is an aliphatic C1-C2 substituted with one or more of -NH2, -NHR*, -N(R*)2, or -N(R*)-(C=O)-R*. 20 hydrocarbon.

[0182] In any of the preceding embodiments, a compound is provided wherein R1 is an aliphatic C1-C1-substituted with -NH-(C=O)-CH3 or -N(CH3)-(C=O)-CH3. 20 hydrocarbon.

[0183] In an embodiment of any of the foregoing formulas there is provided a compound wherein R a It's hydrogen.

[0184] In an embodiment of any of the foregoing formulas there is provided a compound wherein R a It is -OH.

[0185] In an embodiment of any of the foregoing formulas there is provided a compound wherein R a It is -Cl.

[0186] In an embodiment of any of the foregoing formulas there is provided a compound wherein R a is -OR*, and R* is selected from aliphatic C1-C 20Hydrocarbons, aromatic C1-C 20 Hydrocarbons and combinations thereof.

[0187] In an embodiment of any of the foregoing formulas there is provided a compound wherein R N Selected from:

[0188]

[0189] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure.

[0190] In an embodiment of any of the foregoing formulas there is provided a compound wherein R N Selected from:

[0191]

[0192] wherein R' is hydrogen, an aliphatic hydrocarbon or a protecting group, and wherein the symbol Indicates an attachment point.

[0193] In an embodiment of the compound of any of the foregoing formulae, a compound is provided wherein R* at each occurrence is independently selected from hydrogen, aliphatic C1-C6 hydrocarbons, aromatic C4-C6 hydrocarbons, and combinations thereof, optionally containing 1-3 heteroatoms selected from O, N, and combinations thereof.

[0194] In one embodiment, the rifamycin analog compounds of the present disclosure have a structure selected from the group consisting of:

[0195]

[0196]

[0197]

[0198]

[0199] or a pharmaceutically acceptable salt thereof.

[0200] In one embodiment, the rifamycin analog compounds of the present disclosure have a structure selected from the group consisting of:

[0201]

[0202] or a pharmaceutically acceptable salt thereof.

[0203] In one aspect, the present disclosure provides a method of making a rifamycin analog compound having the structure of Formula (V):

[0204]

[0205] Wherein: X is selected from -O- and -NR*-;

[0206] R6 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof,

[0207] R N Selected from:

[0208]

[0209] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0210] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0211] The method comprises the following steps:

[0212] (a) making rifamycin S having the following structure:

[0213] and a compound having the structure of formula (VI):

[0214] touch,

[0215] wherein X' is selected from -OH and -NHR*; and

[0216] (b) treating the product of step (a) with an oxidizing agent.

[0217] In one aspect, the present disclosure provides a method of making a rifamycin analog compound having the structure of Formula (V'):

[0218]

[0219] Wherein: X is selected from -O- and -NR*-;

[0220] R6 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof,

[0221] R N Selected from:

[0222]

[0223] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0224] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0225] The method comprises the following steps:

[0226] (a) making rifamycin S having the following structure:

[0227] and a compound having the structure of formula (VI'):

[0228] touch,

[0229] wherein X' is selected from -OH and -NHR*; and

[0230] (b) treating the product of step (a) with an oxidizing agent.

[0231] In one aspect, the present disclosure provides a method of making a compound having the structure:

[0232]

[0233] The method comprises the following steps:

[0234] (a) reacting rifamycin S with a compound having the structure of formula (VII):

[0235] touch,

[0236] Where PG is a protecting group;

[0237] (b) treating the product of step (a) with an oxidizing agent; and

[0238] (c) Removal of the protecting group PG.

[0239] In one embodiment, the compound of formula (VII) is prepared by removing the protecting group PG' from the compound of formula (VIII),

[0240]

[0241] The protecting groups PG and PG' may be the same as or different from each other.

[0242] In one embodiment, the compound of formula (VIII) is prepared by allowing a compound of formula (IX):

[0243] With a compound of formula (X): wherein the protecting groups PG and PG' may be the same as or different from each other.

[0244] In one aspect, the present disclosure provides a method of making a compound having the structure of Formula (XI):

[0245]

[0246] Wherein: R6 is selected from R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof, and wherein R6 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR *, -O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, - O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof;

[0247] R N Selected from:

[0248]

[0249] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0250] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0251] The method comprises making a compound having the structure of formula (XII):

[0252]

[0253] Contacting with an alcohol having the structure R6-OH.

[0254] In one aspect, the present disclosure provides a method of making a compound having the structure of Formula (XIII):

[0255]

[0256] Wherein: A is selected from a bond (A is absent) or an aliphatic C1-C 20 hydrocarbon;

[0257] R cy It is C3-C 14 Cycloaliphatic hydrocarbons further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof, and wherein R cy Optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR *, -O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O -(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof; and

[0258] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0259] The method comprises making a compound having the structure of formula (XII):

[0260]

[0261] With structure R cy-A-OH alcohol contact.

[0262] In one aspect, the present disclosure provides a method of making a compound having the structure of Formula (XIII'):

[0263]

[0264] Wherein: A is selected from a bond (A is absent) or an aliphatic C1-C 20 hydrocarbon;

[0265] R cy It is C3-C 14 Cycloaliphatic hydrocarbons further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof, and wherein R cy Optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR *, -O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O -(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof; and

[0266] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0267] The method comprises making a compound having the structure of formula (XII):

[0268]

[0269] With structure Rcy -A-OH alcohol contact.

[0270] In one aspect, the present disclosure provides a method of making a compound having the structure of Formula (XIV):

[0271]

[0272] wherein: Y is selected at each occurrence from -O- and -NR'R"-; n is independently an integer from 1 to 6 at each occurrence; and R', R" and R'" are each independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbon; the method comprises making a compound having a structure of formula (XII):

[0273]

[0274] With the structure R″R′NY-(CH2) n -Y-(CH2) n -OH alcohol contact.

[0275] In one aspect, the present disclosure provides a method of making a compound having the structure of Formula (XIV'):

[0276]

[0277] wherein: Y is selected at each occurrence from -O- and -NR'R"-; n is independently an integer from 1 to 6 at each occurrence; and R', R" and R'" are each independently selected from hydrogen and aliphatic C1-C 20 Hydrocarbon; the method comprises making a compound having a structure of formula (XII'):

[0278]

[0279] With the structure R″R′NY-(CH2) n -Y-(CH2) n -OH alcohol contact.

[0280] In one embodiment, the compound of formula (XII) is prepared by contacting rifamycin S with 2-amino-5-bromophenol and treating the product with an oxidizing agent.

[0281] In one embodiment, the compound of formula (XII') is prepared by contacting rifamycin S with 2-amino-4-bromophenol and treating the product with an oxidizing agent.

[0282] In one aspect, the present disclosure provides a pharmaceutical composition comprising any one or more compounds as described above, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0283] In another aspect, the present disclosure provides a pharmaceutical dosage form comprising any one or more compounds as described above, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as described above.

[0284] In another aspect, the present disclosure provides a method of preventing or inhibiting the growth of bacteria, comprising administering an effective amount of a rifamycin analog compound having a structure according to any one of Formula (A), Formula (B), Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), Formula (III'), Formula (IV), Formula (IV'), Formula (V), and Formula (V') as provided herein.

[0285] In one embodiment, the bacteria is a Gram-positive bacteria.

[0286] In one embodiment, the bacteria is a penicillin-resistant bacteria.

[0287] In one embodiment, the bacterium is Staphylococcus aureus.

[0288] In one embodiment, the bacteria is methicillin-resistant Staphylococcus aureus (MRSA).

[0289] In one embodiment, the bacteria is vancomycin-resistant Staphylococcus aureus (VRSA).

[0290] In one embodiment, the bacterium is methicillin-susceptible Staphylococcus aureus (MSSA).

[0291] In yet another aspect, the present disclosure provides a method of treating a bacterial infection in a subject in need of such treatment, comprising administering to the subject an effective amount of a rifamycin analog compound having a structure according to any one of Formula (A), (B), (I), (I'), (II), (III), (III'), (IV), (IV'), (V), or (V') as provided herein.

[0292] In one embodiment, the bacterial infection is a Gram-positive bacterial infection.

[0293] In one embodiment, the bacterial infection is a penicillin-resistant bacterial infection.

[0294] In one embodiment, the bacterial infection is a Staphylococcus aureus infection.

[0295] In one embodiment, the bacterial infection is a methicillin-resistant Staphylococcus aureus (MRSA) infection.

[0296] In one embodiment, the bacterial infection is a vancomycin-resistant Staphylococcus aureus (VRSA) infection.

[0297] In one embodiment, the bacterial infection is a methicillin-susceptible Staphylococcus aureus (MSSA) infection.

[0298] In one embodiment, the bacterial infection is an intracellular bacterial infection.

[0299] In one embodiment, the subject is a human.

[0300] In one embodiment, the method further comprises administering a second therapeutic agent.

[0301] In one embodiment, the second therapeutic agent is a second antibiotic.

[0302] In one embodiment, the second antibiotic is effective against Staphylococcus aureus.

[0303] In one embodiment, the second antibiotic is selected from the group consisting of an aminoglycoside, a beta-lactam, a macrolide, a cyclic peptide, a tetracycline, a fluoroquinoline, a fluoroquinolone, and an oxazolidinone.

[0304] In one embodiment, the second antibiotic is selected from clindamycin, novobiocin, retapamulin, daptomycin, sitafloxacin, teicoplanin, triclosan, napthyridone, radezolid, doxorubicin, ampicillin, vancomycin, imipenem, doripenem, gemcitabine, dalbavancin, and azithromycin.

[0305] In one embodiment, the compound is administered to the subject orally, topically, intranasally, intravenously, intramuscularly, or subcutaneously.

[0306] In another aspect, there is provided herein a kind of antibody-drug conjugate, the antibody-drug conjugate includes the antigen-binding fragment of antibody or antibody, and also includes rifamycin analog.In some embodiments of the antibody-drug conjugate of the present invention, antibody or the antigen-binding fragment of antibody is bound to the target related to infectious disease.The target related to infectious disease that can be used for present disclosure includes but is not limited to macrophage scavenger receptor 1 (MSR1), wall teichoic acid (WTA), Staphylococcus aureus antigen such as protein A, IsdA, IsdB, IsdC, IsdE, IsdH, ClfA, ClfB, CP5, CP8, SdrC, SdrD, SdrE, FnBpA, FnBpB, Can, polysaccharide poly-N-acetylglucosamine (PNAG) and SasG.

[0307] In some embodiments, the antibody or antigen-binding fragment of the antibody binds to MSR1. In some embodiments, the antibody or antigen-binding fragment of the antibody binds to WTA. In some embodiments, the antibody or antigen-binding fragment of the antibody binds to Protein A.

[0308] In another aspect, provided herein are antibody-drug conjugates comprising an antibody or antigen-binding fragment thereof that binds to a membrane glycoprotein receptor known as MSR1 and further comprising a rifamycin analog. The antibodies are particularly useful for targeting cells expressing MSR1, such as macrophages.

[0309] In another aspect, provided herein are antibody-drug conjugates comprising an antibody or antigen-binding fragment of an antibody and further comprising a rifamycin analog, the antibody or antigen-binding fragment of the antibody binding to wall teichoic acid (WTA).

[0310] In another aspect, provided herein are antibody-drug conjugates comprising an antibody or an antigen-binding fragment of an antibody and further comprising a rifamycin analog, the antibody or antigen-binding fragment of the antibody bound to Protein A.

[0311] In another aspect, there is provided herein a pharmaceutical composition comprising an antibody-drug conjugate and a pharmaceutically acceptable carrier, wherein the antibody-drug conjugate comprises a recombinant human antibody or a fragment thereof and further comprises a rifamycin analog. In some embodiments, the recombinant human antibody or its fragment specifically binds to a target associated with an infectious disease. In some embodiments, the recombinant human antibody or its fragment specifically binds to MSR1, WTA or protein A. In related aspects, the embodiment relates to a composition, which is a combination of an antibody-drug conjugate and a second therapeutic agent, and the antibody-drug conjugate comprises an antibody described herein and further comprises a rifamycin analog. In one embodiment, the second therapeutic agent is any agent advantageously combined with an antibody-drug conjugate comprising an antibody described herein. In one embodiment, the second therapeutic agent is an antibody-drug conjugate comprising an antibody conjugated to a second drug or a second therapeutic agent as described herein. Disclosed elsewhere herein are exemplary combination therapies, co-formulations and ADCs relating to antibodies.

[0312] Also provided herein are reactive linkers-payloads comprising rifamycin analogs, for example, compounds having structures according to any embodiment of the antibody-drug conjugates comprising antibodies, as provided herein, and according to formula (A), formula (B), formula (I), formula (I'), formula (II), formula (II'), formula (III), formula (III'), formula (IV), formula (IV'), formula (V), formula (V'), formula (B-1), and formula (B-2). Also provided herein are modified antibodies and modified antigen-binding fragments that can be used to prepare antibody-drug conjugates comprising rifamycin analogs. In some embodiments, the antibody or its antigen-binding fragment specifically binds to targets associated with infectious diseases. In some embodiments, the antibody or its antigen-binding fragment specifically binds to MSR1, WTA, or protein A.

[0313] Also provided herein is a method for preventing or inhibiting the growth of bacteria, the method comprising administering an effective amount of an antibody-drug conjugate (ADC), wherein the antibody-drug conjugate (ADC) comprises an antibody or its antigen-binding fragment and a rifamycin analog. In some embodiments, the antibody or its antigen-binding fragment specifically binds to the target associated with an infectious disease. In some embodiments, the antibody or its antigen-binding fragment specifically binds to MSR1, WTA or protein A.

[0314] Also provided herein is a method of treatment, comprising administering an effective amount of an ADC to a subject in need thereof, the ADC comprising an antibody or its antigen-binding fragment and a rifamycin analog. The method of treatment comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an ADC, the ADC comprising an antibody or its antigen-binding fragment and a rifamycin analog. The disorder treated is any disease or condition that is improved, ameliorated, inhibited or prevented by targeting targets associated with infectious diseases and / or by administering antibiotics. In some embodiments, the disease or condition is a proliferative disease, metabolic disease, inflammation, neurodegenerative disease or a disease, disorder or condition associated with glucocorticoid receptor signaling. In some such embodiments, the side effects associated with the administration of unconjugated rifamycin analogs are reduced. Provided herein are the uses of antibodies described herein, their antigen-binding portions or ADCs comprising antibodies or their antigen-binding fragments for treating any disease, disorder or condition described herein. In some embodiments, antibodies or their antigen-binding fragments specifically bind to targets associated with infectious diseases. In some embodiments, antibodies or their antigen-binding fragments specifically bind to MSR1, WTA or protein A.

[0315] Also provided herein are methods for treating, alleviating, or ameliorating a disease, disorder, or condition associated with a Staphylococcal infection, such as a Staphylococcus aureus infection, and / or for ameliorating at least one symptom associated with such a disease, disorder, or condition, comprising administering to a subject in need thereof a rifamycin analog or an ADC comprising an antibody or antigen-binding fragment thereof and a rifamycin analog. Such a disease, disorder, or condition can be cellulitis, bacteremia, dermonecrosis, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, furuncle, scalded skin syndrome, food poisoning, pneumonia, surgical infection, urinary tract infection, burn infection, meningitis, endocarditis, sepsis, toxic shock syndrome, or septic arthritis. In some embodiments, the subject has a prosthetic joint, and the rifamycin analogs disclosed herein or ADCs comprising antibodies or antigen-binding fragments thereof and rifamycin analogs are used to treat and / or prevent Staphylococcus aureus infection of tissues surrounding the prosthetic joint. In some embodiments, the subject has a catheter, and the rifamycin analogs disclosed herein or ADCs comprising antibodies or antigen-binding fragments thereof and rifamycin analogs are used to treat and / or prevent Staphylococcus aureus infection of the catheter and / or tissues surrounding the catheter. In some embodiments, the subject has a foreign body implanted, and the rifamycin analogs disclosed herein or ADCs comprising antibodies or antigen-binding fragments thereof and rifamycin analogs are used to treat and / or prevent Staphylococcus aureus infection of the foreign body and / or tissues surrounding the foreign body. In some embodiments, the subject suffers from mastitis, and the antibodies disclosed herein can be used to treat mastitis. The method of treatment comprises administering a therapeutically effective amount of a pharmaceutical composition to a subject in need thereof, the pharmaceutical composition comprising a rifamycin analog or an ADC comprising an antibody or antigen-binding fragment thereof and a rifamycin analog. In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to a target associated with an infectious disease. In some embodiments, the antibody or antigen-binding fragment thereof specifically binds MSR1, WTA, or Protein A.

[0316] In another aspect, the present disclosure provides an antibody-drug conjugate comprising an antibody or antigen-binding fragment thereof conjugated to a rifamycin analog compound of any embodiment of the present disclosure via a linker or through a linker-spacer.

[0317] In various embodiments, the antibody or its antigen-binding fragment binds to macrophage scavenger receptor 1 (MSR1). In various embodiments, the antibody or its antigen-binding fragment binds to wall teichoic acid (WTA). In various embodiments, the antibody or its antigen-binding fragment binds to Staphylococcus aureus protein A.

[0318] In one embodiment, the antibody or antigen-binding fragment thereof may comprise: (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence as listed in Table 9; and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence as listed in Table 9.

[0319] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof may comprise:

[0320] (i) a HCDR 1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 36, 52, 92, and 284;

[0321] (ii) a HCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 38, 54, 94, and 286;

[0322] (iii) a HCDR 3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 40, 56, 96, and 288;

[0323] (iv) a LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 44, 60, 100, and 292;

[0324] (v) a LCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 46, 62, 102, and 294; and

[0325] (vi) a LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 48, 64, 104, and 296.

[0326] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof may comprise: (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence as listed in Table 2A; and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence as listed in Table 2A.

[0327] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof may comprise:

[0328] (i) a HCDR 1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 470, 476, 482, and 488;

[0329] (ii) a HCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 471, 477, 483, and 489;

[0330] (iii) a HCDR 3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 472, 478, 484, and 490;

[0331] (iv) a LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 467, 473, 479, and 485;

[0332] (v) a LCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 468, 474, 480, and 486; and

[0333] (vi) a LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 469, 475, 481, and 487.

[0334] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof may comprise: (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence as listed in Table 2B; and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence as listed in Table 2B.

[0335] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof may comprise:

[0336] (i) a HCDR 1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 502, 508, 514, 520, 526, 532, 538, 544, 550, 556, 562, 568, and 574;

[0337] (ii) a HCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 503, 509, 515, 521, 527, 533, 539, 545, 551, 557, 563, 569, and 575;

[0338] (iii) a HCDR 3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 504, 510, 516, 522, 528, 534, 540, 546, 552, 558, 564, 570, 576, and 584;

[0339] (iv) a LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 499, 505, 511, 517, 523, 529, 535, 541, 547, 553, 559, 565, and 571;

[0340] (v) a LCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 500, 506, 512, 518, 524, 530, 536, 542, 548, 554, 560, 566, and 572; and

[0341] (vi) a LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 501, 507, 513, 519, 525, 531, 537, 543, 549, 555, 561, 567, and 573.

[0342] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises a V205C mutation (EU numbering) in the light chain.

[0343] In one embodiment, an anti-Protein A antibody or antigen-binding fragment thereof may comprise: (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence as set forth in Table 3A; and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence as set forth in Table 3A.

[0344] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof may comprise:

[0345] (i) a HCDR 1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 632, 652, and 672;

[0346] (ii) a HCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 634, 654, and 674;

[0347] (iii) a HCDR 3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 636, 656, and 676;

[0348] (iv) a LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 640, 660, and 680;

[0349] (v) a LCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 642 and 662; and

[0350] (vi) a LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 644, 664, and 683.

[0351] In some embodiments, the anti-Protein A antibody or antigen-binding fragment thereof comprises an H435R mutation and a Y436F mutation (EU numbering) in the heavy chain Fc.

[0352] In various embodiments, the antibody or antigen-binding fragment thereof comprises a C103S mutation in the light chain.

[0353] In various embodiments, the antibody or antigen-binding fragment thereof is conjugated to a Compound of the Disclosure at position 103 of the light chain.

[0354] In one embodiment, the linker or linker-spacer is selected from:

[0355]

[0356]

[0357] In another aspect, the present disclosure provides an antibody-drug conjugate having a structure according to Formula (XVIII):

[0358] in:

[0359] BA is an antibody or its antigen-binding fragment;

[0360] RG is a reactive group selected from maleimide, N-hydroxysuccinimide or succinimide;

[0361] SP is absent or is a spacer residue selected from the group consisting of: C 1-6 Alkyl, -NH-, -C(O)-, -CH2-CH2-C(O)-NH-, -(CH) u -C(O)-NH-, (-CH2-CH2-O) e 、-NH-CH2-CH2-(-O-CH2-CH2) e -C(O)-, -C(O)-(CH2) u -C(O)-, -C(O)-NH-(CH2) v-、-(CH) u -C(O)-NH-(CH2-CH2-O) e -(CH) u -C(O)-NH-, -(CH)2-C(O)-NH-(CH2-CH2-O)8-(CH)2-C(O)-NH-, and combinations thereof, wherein, independently at each occurrence, subscript e is an integer from 0 to 20, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8;

[0362] AA is a linker selected from the group consisting of valine-citrulline, citrulline-valine, valine-alanine, alanine-valine, valine-glycine, or glycine-valine;

[0363] B does not exist or in indicates the atom through which B is bonded to the adjacent group in the formula;

[0364] n is an integer from 1 to 30; and

[0365] PA is a rifamycin analog according to any embodiment of the present disclosure.

[0366] In one embodiment, yes

[0367]

[0368] In one embodiment, yes

[0369]

[0370] In one embodiment, yes

[0371]

[0372] in, Is a bond to the antibody or antigen-binding fragment thereof. In one aspect, the present disclosure provides an antibody-drug conjugate having a structure according to Formula (XIX):

[0373]

[0374] BA is an antibody or its antigen-binding fragment;

[0375] RG is selected from maleimide, N-hydroxysuccinimide or succinimide;

[0376] SP 1 and SP 2is independently absent or is a spacer selected from the group consisting of: C 1-6 Alkyl, -NH-, -C(O)-, -CH2-CH2-C(O)-NH- -(CH) u -C(O)-NH-, (-CH2-CH2-O) e 、-NH-CH2-CH2-(-O-CH2-CH2) e -C(O)-, -C(O)-(CH2) u -C(O)-, -C(O)-NH-(CH2) v - and combinations thereof, wherein subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8;

[0377] AA is a linker selected from the group consisting of valine-citrulline, citrulline-valine, valine-alanine, alanine-valine, valine-glycine, or glycine-valine;

[0378] PEG is a polyethylene glycol chain containing between 1 and 30 polyethylene glycol residues;

[0379] B does not exist or in indicates the atom through which B is bonded to the adjacent group in the formula;

[0380] n is an integer from 1 to 30;

[0381] m is an integer from 0 to 20;

[0382] And PA is a rifamycin analog according to any embodiment of the present disclosure.

[0383] In one embodiment, yes

[0384]

[0385] In one aspect, the present disclosure provides an antibody-drug conjugate comprising an antibody or antigen-binding fragment thereof conjugated to a rifamycin analog payload via a linker or through a linker-spacer, the rifamycin analog payload having the structure of Formula (XX):

[0386]

[0387] in:

[0388] X is selected from -O-, -S- and -NR*-;

[0389] Za is selected from -OR1 and -R N ;

[0390] R1 is selected from a bond, an aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR *, -O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, - O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof;

[0391] R N Selected from:

[0392]

[0393] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0394] R2, R3 and R4 are independently selected from hydrogen, linear, branched or cyclic aliphatic C1-C 20 hydrocarbon, or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[0395] R a independently selected at each occurrence from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[0396] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; and

[0397] wherein the group Za is bonded to a linker.

[0398] It is understood that the group R1 is either a bond (ie, R1 is absent); or a divalent group, ie, R1 is capable of bonding to the -O- group of the rifamycin analog and to the linker.

[0399] In one embodiment, -OR1 is -O- (ie, R1 is absent),

[0400] In one embodiment, X is -O-, and -OR1 comprises a tertiary amine. In some such embodiments, -OR1 is

[0401] In some embodiments, the antibody-drug conjugate comprising a linker-rifamycin analog payload comprises an ammonium salt having one or more counterions. Any pharmaceutically acceptable counterion may be suitable. For example, in embodiments of the present disclosure, a suitable counterion may be an anion selected from the group consisting of: - 、Cl - Br - , I - OH - 、 - BF4、CF3SO3 - , bisulfate, sulfate, dihydrogen phosphate, hydrogen phosphate or phosphate, NO3- PF6 - 、NO2 - , carboxylate, C e F f SO3 - (where e=2-10 and f=2e+1), acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, camsylate, carbonate, citrate, decanoate, edetate, esylate, fumarate, glucoheptanoate, gluconate, glutamate, glycolate, glycolamidophenylarsonic acid, hexanoate, hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate , malate, maleate, mandelate, methanesulfonate, methyl bromide, methylnitrate, mucate, napsylate, octanoate, oleate, pamoate, pantothenate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, tartrate, teoclate, toluenesulfonate, or triethyliodide.

[0402] In some embodiments, R a In some embodiments, R a It is -OH and is present in one occurrence.

[0403] In one aspect, the present disclosure provides an antibody or antigen-binding fragment thereof conjugated to a rifamycin analog via a linker or through a linker-spacer, the rifamycin analog having the structure of Formula (XXI):

[0404]

[0405] in:

[0406] X is selected from -O-, -S- and -NR*-;

[0407] R5 is selected from a bond; aliphatic C1-C 20 A hydrocarbon further comprising 0-8 heteroatoms selected from halogen, O, N and S; Wherein Y is C or N;

[0408] R2, R3 and R4 are independently selected from hydrogen, linear, branched or cyclic aliphatic C1-C 20 hydrocarbon, or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S; and

[0409] R 5c is a bond or an aliphatic C1-C8 hydrocarbon;

[0410] wherein the group R5 is bonded to the linking group.

[0411] It is understood that the group R5 is either a bond (ie, R5 is absent); or a divalent group, ie, R5 is capable of bonding to the -O- of the rifamycin and to the linker.

[0412] In one embodiment, -OR5 is -O- (ie, R5 is absent),

[0413] In one embodiment, X is O and -OR5 comprises a tertiary amine. In some such embodiments, -OR5 is

[0414] In one embodiment of any of the above, R2 is methyl, ethyl, propyl or isopropyl; R3 is a CH3-(C=O)-(acetyl) group, CH3CH2-(C=O)-, CH3CH2CH2-(C=O)- or (CH3)2CH-(C=O)-; and R4 is hydrogen.

[0415] In one embodiment of any of the above, R2 is methyl, R3 is acetyl, and R4 is hydrogen.

[0416] In one embodiment of any of the above, the compound is selected from the group consisting of:

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423] in is the bond to the linker.

[0424] In one aspect, the present disclosure provides an antibody-drug conjugate having the structure of Formula (XXII):

[0425]

[0426] in:

[0427] BA is an antibody or its antigen-binding fragment;

[0428] L is a linker;

[0429] SP is a spacer selected from the group consisting of: The symbols Represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: fluorenylmethoxycarbonyl (F MOC ) and tert-butyloxycarbonyl (Boc), or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0430] Y is C or N;

[0431] R' and R" are independently selected at each occurrence from hydrogen and C 1-6 alkyl; and

[0432] X is selected from -O-, -S- and -NR*-.

[0433] In one embodiment, the antibody is an anti-MSR1 antibody or an antigen-binding fragment thereof, comprising: (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence as listed in Table 9; and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence as listed in Table 9.

[0434] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof comprises:

[0435] (i) a HCDR 1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 36, 52, 92, and 284;

[0436] (ii) a HCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 38, 54, 94, and 286;

[0437] (iii) a HCDR 3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 40, 56, 96, and 288;

[0438] (iv) a LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 44, 60, 100, and 292;

[0439] (v) a LCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 46, 62, 102, and 294; and

[0440] (vi) a LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 48, 64, 104, and 296.

[0441] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof comprises:

[0442] (i) a HCDR 1 domain comprising the amino acid sequence of SEQ ID NO: 52;

[0443] (ii) a HCDR 2 domain comprising the amino acid sequence of SEQ ID NO: 54;

[0444] (iii) a HCDR 3 domain comprising the amino acid sequence of SEQ ID NO: 56;

[0445] (iv) a LCDR1 domain comprising the amino acid sequence of SEQ ID NO: 60;

[0446] (v) a LCDR 2 domain comprising the amino acid sequence of SEQ ID NO: 62; and

[0447] (vi) a LCDR3 domain comprising the amino acid sequence of SEQ ID NO: 64.

[0448] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof comprises an N297Q mutation.

[0449] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof may comprise: (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence as listed in Table 2A; and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence as listed in Table 2A.

[0450] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof may comprise:

[0451] (i) a HCDR 1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 470, 476, 482, and 488;

[0452] (ii) a HCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 471, 477, 483, and 489;

[0453] (iii) a HCDR 3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 472, 478, 484, and 490;

[0454] (iv) a LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 467, 473, 479, and 485;

[0455] (v) a LCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 468, 474, 480, and 486; and

[0456] (vi) a LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 469, 475, 481, and 487.

[0457] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof may comprise: (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence as listed in Table 2B; and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence as listed in Table 2B.

[0458] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof may comprise:

[0459] (i) a HCDR 1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 502, 508, 514, 520, 526, 532, 538, 544, 550, 556, 562, 568, and 574;

[0460] (ii) a HCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 503, 509, 515, 521, 527, 533, 539, 545, 551, 557, 563, 569, and 575;

[0461] (iii) a HCDR 3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 504, 510, 516, 522, 528, 534, 540, 546, 552, 558, 564, 570, 576, and 584;

[0462] (iv) a LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 499, 505, 511, 517, 523, 529, 535, 541, 547, 553, 559, 565, and 571;

[0463] (v) a LCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 500, 506, 512, 518, 524, 530, 536, 542, 548, 554, 560, 566, and 572; and

[0464] (vi) a LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 501, 507, 513, 519, 525, 531, 537, 543, 549, 555, 561, 567, and 573.

[0465] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises a V205C mutation (EU numbering) in the light chain.

[0466] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof is derived from antibody 4497 ​​described in U.S. Patent Application Publication No. 20140356375, which is incorporated herein by reference in its entirety. In one embodiment, the anti-WTA antibody is derived from antibody 4497 ​​and further comprises a V205C mutation in the light chain.

[0467] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof comprises HCDR 1-HCDR 2-HCDR 3-LCDR 1-LCDR2-LCDR 3 of SEQ ID Nos: 568-569-570-565-566-567.

[0468] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID NO: 586; and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) within the light chain variable region (LCVR) amino acid sequence of SEQ ID NO: 585.

[0469] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO: 586 and the LCVR amino acid sequence of SEQ ID NO: 585.

[0470] In some embodiments, the anti-WTA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 602 and a light chain amino acid sequence of SEQ ID NO: 587 or SEQ ID NO: 589. In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises a V205C mutation in the light chain.

[0471] In one embodiment, an anti-Protein A antibody or antigen-binding fragment thereof may comprise: (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence as set forth in Table 3A; and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence as set forth in Table 3A.

[0472] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof may comprise:

[0473] (i) a HCDR 1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 632, 652, and 672;

[0474] (ii) a HCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 634, 654, and 674;

[0475] (iii) a HCDR 3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 636, 656, and 676;

[0476] (iv) a LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 640, 660, and 680;

[0477] (v) a LCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 642 and 662; and

[0478] (vi) a LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 644, 664, and 683.

[0479] In some embodiments, the anti-Protein A antibody or antigen-binding fragment thereof comprises an H435R mutation and a Y436F mutation (EU numbering) in the heavy chain Fc.

[0480] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID NO: 630; and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) within the light chain variable region (LCVR) amino acid sequence of SEQ ID NO: 638. In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof comprises a set of six CDRs (HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) comprising SEQ ID NOs: 632-634-636-640-642-644.

[0481] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO:630 and the LCVR amino acid sequence of SEQ ID NO:638.

[0482] In one embodiment, the anti-Protein A antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 666 and a light chain amino acid sequence of SEQ ID NO: 668. In one embodiment, the anti-Protein A antibody further comprises an H435R mutation and a Y436F mutation in the heavy chain Fc (EU numbering). In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof is conjugated to a compound of the disclosure at position 103 of the light chain.

[0483] In various embodiments, the antibody or antigen-binding fragment thereof comprises a C103S mutation in the light chain.

[0484] In various embodiments, the antibody or antigen-binding fragment thereof is conjugated to a Compound of the Disclosure at position 103 of the light chain.

[0485] In one embodiment, L is a linker having the formula: in:

[0486] RG is selected from maleimide, N-hydroxysuccinimide or succinimide;

[0487] SP 1 and SP 2 is independently absent or is a spacer selected from the group consisting of C 1-6 Alkyl, -NH-, -C(O)-, -CH2-CH2-C(O)-NH-, -(CH) u -C(O)-NH-, (-CH2-CH2-O) e 、-NH-CH2-CH2-(-O-CH2-CH2)e -C(O)-, -C(O)-(CH2) u -C(O)-, -C(O)-NH-(CH2) v - and combinations thereof, wherein subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8;

[0488] AA 2-4 is a peptide unit comprising from 2 to 4 amino acids; and

[0489] PEG is a polyethylene glycol chain containing between 1 and 30 polyethylene glycol residues.

[0490] In one embodiment, AA 2-4 It is a dipeptide selected from the group consisting of valine-citrulline, citrulline-valine, valine-alanine, alanine-valine, valine-glycine, glycine-valine, or alanine-glycine, alanine-alanine.

[0491] In one embodiment, AA 2-4 It's valine-citrulline.

[0492] In one embodiment, SP is and R' and R" are each C 1-6 alkyl.

[0493] In one embodiment, SP is and R' and R" are each methyl.

[0494] In one embodiment, SP 1 and SP 2 Each is

[0495] In one embodiment, PEG comprises 8 polyethylene glycol units.

[0496] In one embodiment, BA is an antibody or an antigen-binding fragment thereof;

[0497] L is a linker having the formula: in:

[0498] RG is selected from maleimide or succinimide;

[0499] SP 1 and SP 2 Each is

[0500] AA 2-4 It is valine-citrulline;

[0501] PEG is a polyethylene glycol chain containing 8 polyethylene glycol residues;

[0502] SP is and R' and R" are each methyl; and

[0503] X is -O-.

[0504] In one embodiment, the antibody-drug conjugate has the following structure:

[0505]

[0506] wherein BA is an antibody or an antigen-binding fragment thereof.

[0507] In another aspect, the present disclosure provides an isolated antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof is conjugated directly or through a linker or linker-spacer to a payload having a structure selected from the group consisting of:

[0508]

[0509]

[0510]

[0511]

[0512]

[0513] In one embodiment, the payload has a structure selected from the group consisting of:

[0514]

[0515] In one embodiment, the payload is conjugated via a linker having the following structure:

[0516] in:

[0517] RG is selected from maleimide or succinimide;

[0518] SP 1 and SP 2 is independently absent or is a spacer selected from the group consisting of: C 1-6 Alkyl, -NH-, -C(O)-, -CH2-CH2-C(O)-NH-, -(CH) u -C(O)-NH-, (-CH2-CH2-O) e 、-NH-CH2-CH2-(-O-CH2-CH2)e -C(O)-, -C(O)-(CH2) u -C(O)-, -C(O)-NH-(CH2) v - and combinations thereof, wherein subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8;

[0519] AA 2-4 is a peptide unit comprising from 2 to 4 amino acids; and

[0520] PEG is a polyethylene glycol chain containing between 1 and 30 polyethylene glycol residues.

[0521] In one embodiment, AA 2-4 is a dipeptide selected from the group consisting of valine-citrulline, citrulline-valine, valine-alanine, alanine-valine, valine-glycine or glycine-valine.

[0522] In one embodiment, AA 2-4 It's valine-citrulline.

[0523] In one embodiment, SP is and R' and R" are each C 1-6 alkyl.

[0524] In one embodiment, SP is and R' and R" are each methyl.

[0525] In one embodiment, SP 1 and SP 2 Each is

[0526] In one embodiment, PEG comprises 8 polyethylene glycol units.

[0527] In one embodiment, the payload is conjugated via a linker having the following structure:

[0528]

[0529] In one embodiment, the payload is conjugated via a linker, and the linker-payload has the following structure:

[0530]

[0531] in It is a bond to an antibody or antigen-binding fragment thereof.

[0532] In one embodiment, the payload is conjugated via a linker, and the linker-payload has the following structure:

[0533]

[0534] in It is a bond to an antibody or antigen-binding fragment thereof.

[0535] In one embodiment, an antibody or antigen-binding fragment thereof that binds to macrophage scavenger receptor 1 (MSR1) comprises: (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence as listed in Table 9; and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence as listed in Table 9.

[0536] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof comprises:

[0537] (i) a HCDR 1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 36, 52, 92, and 284;

[0538] (ii) a HCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 38, 54, 94, and 286;

[0539] (iii) a HCDR 3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 40, 56, 96, and 288;

[0540] (iv) a LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 44, 60, 100, and 292;

[0541] (v) a LCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 46, 62, 102, and 294; and

[0542] (vi) a LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 48, 64, 104, and 296.

[0543] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof comprises:

[0544] (i) a HCDR 1 domain comprising the amino acid sequence of SEQ ID NO: 52;

[0545] (ii) a HCDR 2 domain comprising the amino acid sequence of SEQ ID NO: 54;

[0546] (iii) a HCDR 3 domain comprising the amino acid sequence of SEQ ID NO: 56;

[0547] (iv) a LCDR1 domain comprising the amino acid sequence of SEQ ID NO: 60;

[0548] (v) a LCDR 2 domain comprising the amino acid sequence of SEQ ID NO: 62; and

[0549] (vi) a LCDR3 domain comprising the amino acid sequence of SEQ ID NO: 64.

[0550] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof comprises an N297Q mutation.

[0551] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof may comprise: (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence as listed in Table 2A; and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence as listed in Table 2A.

[0552] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof may comprise:

[0553] (i) a HCDR 1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 470, 476, 482, and 488;

[0554] (ii) a HCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 471, 477, 483, and 489;

[0555] (iii) a HCDR 3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 472, 478, 484, and 490;

[0556] (iv) a LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 467, 473, 479, and 485;

[0557] (v) a LCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 468, 474, 480, and 486; and

[0558] (vi) a LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 469, 475, 481, and 487.

[0559] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof may comprise: (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence as listed in Table 2B; and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence as listed in Table 2B.

[0560] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof may comprise:

[0561] (i) a HCDR 1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 502, 508, 514, 520, 526, 532, 538, 544, 550, 556, 562, 568, and 574;

[0562] (ii) a HCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 503, 509, 515, 521, 527, 533, 539, 545, 551, 557, 563, 569, and 575;

[0563] (iii) a HCDR 3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 504, 510, 516, 522, 528, 534, 540, 546, 552, 558, 564, 570, 576, and 584;

[0564] (iv) a LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 499, 505, 511, 517, 523, 529, 535, 541, 547, 553, 559, 565, and 571;

[0565] (v) a LCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 500, 506, 512, 518, 524, 530, 536, 542, 548, 554, 560, 566, and 572; and

[0566] (vi) a LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 501, 507, 513, 519, 525, 531, 537, 543, 549, 555, 561, 567, and 573.

[0567] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises a V205C mutation (EU numbering) in the light chain.

[0568] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof is derived from antibody 4497 ​​described in U.S. Patent Application Publication No. 20140356375, which is incorporated herein by reference in its entirety. In one embodiment, the anti-WTA antibody is derived from antibody 4497 ​​and further comprises a V205C mutation in the light chain.

[0569] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof comprises HCDR 1-HCDR 2-HCDR 3-LCDR 1-LCDR2-LCDR 3 of SEQ ID Nos: 568-569-570-565-566-567.

[0570] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID NO: 586; and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) within the light chain variable region (LCVR) amino acid sequence of SEQ ID NO: 585.

[0571] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO: 586 and the LCVR amino acid sequence of SEQ ID NO: 585.

[0572] In some embodiments, the anti-WTA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 602 and a light chain amino acid sequence of SEQ ID NO: 587 or SEQ ID NO: 589. In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises a V205C mutation in the light chain.

[0573] In one embodiment, an anti-Protein A antibody or antigen-binding fragment thereof may comprise: (a) a complementarity determining region (CDR) of a heavy chain variable region (HCVR) comprising an amino acid sequence as set forth in Table 3A; and (b) a CDR of a light chain variable region (LCVR) comprising an amino acid sequence as set forth in Table 3A.

[0574] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof may comprise:

[0575] (i) a HCDR 1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 632, 652, and 672;

[0576] (ii) a HCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 634, 654, and 674;

[0577] (iii) a HCDR 3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 636, 656, and 676;

[0578] (iv) a LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 640, 660, and 680;

[0579] (v) a LCDR 2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 642 and 662; and

[0580] (vi) a LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 644, 664, and 683.

[0581] In some embodiments, the anti-Protein A antibody or antigen-binding fragment thereof comprises an H435R mutation and a Y436F mutation (EU numbering) in the heavy chain Fc.

[0582] In some embodiments, the anti-Protein A antibody or antigen-binding fragment thereof comprises an H435R mutation and a Y436F mutation (EU numbering) in the heavy chain Fc.

[0583] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID NO: 630; and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) within the light chain variable region (LCVR) amino acid sequence of SEQ ID NO: 638. In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof comprises a set of six CDRs (HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) comprising SEQ ID NOs: 632-634-636-640-642-644.

[0584] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof comprises the HCVR amino acid sequence of SEQ ID NO:630 and the LCVR amino acid sequence of SEQ ID NO:638.

[0585] In one embodiment, the anti-Protein A antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 666 and a light chain amino acid sequence of SEQ ID NO: 668. In one embodiment, the anti-Protein A antibody further comprises an H435R mutation and a Y436F mutation in the heavy chain Fc (EU numbering). In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof is conjugated to a compound of the disclosure at position 103 of the light chain.

[0586] In various embodiments, the antibody or antigen-binding fragment thereof comprises a C103S mutation in the light chain.

[0587] In various embodiments, the antibody or antigen-binding fragment thereof is conjugated to a Compound of the Disclosure at position 103 of the light chain.

[0588] In one aspect, the disclosure provides a method of preventing or inhibiting the growth of bacteria, the method comprising administering an effective amount of an antibody-drug conjugate as described herein.

[0589] In one embodiment, the bacteria is a Gram-positive bacteria.

[0590] In one embodiment, the bacteria is a penicillin-resistant bacteria.

[0591] In one embodiment, the bacterium is Staphylococcus aureus.

[0592] In one embodiment, the bacteria is selected from methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), and methicillin-susceptible Staphylococcus aureus (MSSA).

[0593] In one aspect, the present disclosure provides a method of treating a bacterial infection in a subject in need of such treatment, the method comprising administering to the subject an effective amount of an antibody-drug conjugate as described herein.

[0594] In one embodiment, the bacterial infection is a Gram-positive bacterial infection.

[0595] In one embodiment, the bacterial infection is a penicillin-resistant bacterial infection.

[0596] In one embodiment, the bacterial infection is a Staphylococcus aureus infection.

[0597] In one embodiment, the bacterial infection is selected from the group consisting of a methicillin-resistant Staphylococcus aureus (MRSA) infection, a vancomycin-resistant Staphylococcus aureus (VRSA) infection, and a methicillin-susceptible Staphylococcus aureus (MSSA) infection.

[0598] In one embodiment, the bacterial infection is an intracellular bacterial infection.

[0599] In one embodiment, the subject is a human.

[0600] In one embodiment, the method further comprises administering a second therapeutic agent.

[0601] In one embodiment, the second therapeutic agent is a second antibiotic.

[0602] In one embodiment, the second antibiotic is effective against Staphylococcus aureus.

[0603] In one embodiment, the second antibiotic is selected from the group consisting of an aminoglycoside, a beta-lactam, a macrolide, a cyclic peptide, a tetracycline, a fluoroquinoline, a fluoroquinolone, and an oxazolidinone.

[0604] In one embodiment, the second antibiotic is selected from the group consisting of clindamycin, novobiocin, retapamulin, daptomycin, sitafloxacin, teicoplanin, triclosan, naphthyridone, redezolid, doxorubicin, ampicillin, vancomycin, imipenem, doripenem, gemcitabine, dalbavancin, and azithromycin.

[0605] In one embodiment, the antibody-drug conjugate is administered to a subject orally, topically, intranasally, intravenously, intramuscularly, or subcutaneously.

[0606] In yet another aspect, the present disclosure provides a method of preventing or treating cellulitis, bacteremia, skin necrosis, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, furuncle, scalded skin syndrome, food poisoning, pneumonia, surgical infection, urinary tract infection, burn infection, meningitis, endocarditis, sepsis, toxic shock syndrome, septic arthritis, mastitis, infection associated with a prosthetic joint, infection associated with a catheter, or infection associated with an implant in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound, antibody-drug conjugate, or pharmaceutical composition as described herein.

[0607] These and other aspects of the present disclosure will become apparent to those skilled in the art after reading the following detailed description of the disclosure, including the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0609] Figure 1 is a graph of the results of a Staphylococcus aureus growth inhibition assay performed with rifamycin analogs according to the present disclosure.

[0610] Figure 2 is a bar graph of the results of a Staphylococcus aureus intracellular killing assay performed with rifamycin analogs according to the present disclosure.

[0611] Figure 3is a graph of the results of a Staphylococcus aureus intracellular killing assay performed with rifamycin analogs according to the present disclosure.

[0612] Figure 4 is a schematic diagram of the four-day Staphylococcus aureus infection model.

[0613] Figure 5 is a graph of colony forming units of anti-S. aureus ADCs according to the present disclosure in an intracellular killing assay using THP cells.

[0614] Figure 6 Depicted are the average S. aureus kidney burden of mice treated with an isotype control at 2 mg / kg and an anti-WTA Ab-antibiotic ncADC (antibody-drug conjugate) according to the present disclosure in combination with vancomycin.

[0615] Figure 7 Depicted are the average S. aureus kidney burdens of mice treated with an isotype control at 2 mg / kg in combination with vancomycin and an anti-Protein A Ab-antibiotic ncADC according to the present disclosure.

[0616] Figure 8 Depicted are the average S. aureus kidney burdens of mice treated with an isotype control at 5 mg / kg in combination with vancomycin and an anti-WTA Ab-antibiotic ncADC according to the present disclosure. Detailed Description of the Invention

[0618] Detailed embodiments of the present disclosure are disclosed herein; however, it should be understood that the disclosed embodiments are merely illustrative of the present disclosure that can be embodied in various forms. Furthermore, each example provided in conjunction with the various embodiments of the present disclosure is intended to be illustrative rather than limiting. Therefore, the specific structural and functional details disclosed herein should not be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously utilize the present disclosure.

[0619] definition

[0620] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0621] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes one or more methods, and / or steps of the type described herein and / or which will become apparent to those skilled in the art upon reading this disclosure.

[0622] The terms "treat" or "treatment" of a state, disorder, or condition include: (1) preventing, delaying, or reducing the appearance and / or likelihood of occurrence of at least one clinical or subclinical symptom of the state, disorder, or condition developing in a subject who may be suffering from or susceptible to the state, disorder, or condition but who does not yet experience or exhibit clinical or subclinical symptoms of the state, disorder, or condition; or (2) inhibiting the state, disorder, or condition, i.e., arresting, reducing, or delaying the development of the disease or a recurrence thereof, or at least one clinical or subclinical symptom thereof; or (3) ameliorating the disease, i.e., causing regression of the state, disorder, or condition, or at least one of its clinical or subclinical symptoms. The benefit to the subject being treated is statistically significant or at least perceptible to the patient or to the physician.

[0623] As used herein, "subject" or "patient" or "individual" or "animal" refers to humans, veterinary animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.), and experimental animal models of disease (e.g., mice, rats). In one embodiment, the subject is a human.

[0624] As used herein, the term "effective," as applied to dosage or amount, refers to an amount of a compound or pharmaceutical composition sufficient to produce the desired activity upon administration to a subject in need thereof. Note that when a combination of active ingredients is administered, an effective amount of the combination may or may not include the amount of each ingredient that would be effective if administered alone. The exact amount required will vary from subject to subject depending on the species, the age and general condition of the subject, the severity of the condition being treated, the specific drug or drugs used, the mode of administration, and the like.

[0625] The phrase "pharmaceutically acceptable," as used in connection with the compositions of the present disclosure, refers to the molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce adverse reactions when administered to mammals (e.g., humans). Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

[0626] As used herein, the phrase "therapeutically effective amount" refers to an amount that produces the desired effect when administered. The exact amount will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0627] Ranges may be expressed herein as from "about" or "approximately" one particular value and / or to "about" or "approximately" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value.

[0628] “Comprising” or “containing” or “including” means that at least the named compound, element, particle or method step is present in the composition or article or method, but does not exclude the presence of other compounds, materials, particles or method steps, even if such other compounds, materials, particles or method steps have the same function as the named compounds, materials, particles or method steps.

[0629] The compounds of the present disclosure include compounds generally described herein and are further illustrated by the categories, subclasses and species disclosed herein. As used herein, unless otherwise indicated, the following definitions should apply. For the purposes of the present disclosure, chemical elements are determined according to the periodic table of the elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th edition, editors: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the full contents of which are incorporated herein by reference. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Greene's Protective Groups in Organic Synthesis, 4th edition, John Wiley & Sons: New York, 2006.

[0630] The term "hydrocarbon" is used herein to include hydrocarbon groups (also referred to as "groups") containing carbon and hydrogen, and also includes derivatives thereof in which one or more carbons are replaced by any heteroatoms such as oxygen, nitrogen, sulfur and phosphorus. The hydrocarbons of the present disclosure are optionally substituted by oxygen-containing groups, nitrogen-containing groups, sulfur-containing groups and phosphorus-containing groups or halogens without limitation. The term hydrocarbon includes linear, branched, cyclic or polycyclic aliphatic groups as well as aromatic groups and heteroaromatic groups, as discussed in more detail below.

[0631] The term "optionally substituted" has the same meaning as where the substituted element "also contains 0-n" optional elements, where n is an integer, typically from 0 to 20, or from 0 to 10, or from 1 to 3. For example, when an aliphatic hydrocarbon optionally contains one or more heteroatoms, it would have the same meaning as where the aliphatic hydrocarbon also contains 0 to 20 heteroatoms.

[0632] As used herein, the term "aliphatic" or "aliphatic group" means a straight (i.e., non-branched), branched, substituted, or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic, bicyclic, or tricyclic hydrocarbon (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single point of attachment to the rest of the molecule, and combinations thereof. In some embodiments, aliphatic groups include a combination (hybrid) of straight-chain aliphatic hydrocarbons and cyclic aliphatic hydrocarbons. In some embodiments, aliphatic groups include a combination of straight-chain aliphatic hydrocarbons and cyclic aliphatic hydrocarbons. Unless otherwise specified, aliphatic groups contain 1-30 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-20 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In still other embodiments, aliphatic groups comprise 1-6 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups comprise 1, 2, 3 or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups and combinations / mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Simple aliphatic hydrocarbons include methyl, ethyl, propyl, butyl, tert-butyl, n-butyl, pentyl, etc.

[0633] As used herein, the terms "alicyclic ring," "cycloaliphatic," "carbocycle," "alicyclic," or "cycloaliphatic" refer to saturated or partially unsaturated cycloaliphatic monocyclic, bicyclic, or polycyclic ring structures having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as defined above and described herein. Alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, the cycloalkyl group has 3 to 6 carbon atoms. Alicyclic ring structures also include alicyclic rings fused to one or more aromatic or non-aromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, with the radical or point of attachment being on the aliphatic ring. In some embodiments, the alicyclic group is bicyclic. In some embodiments, the carbocyclic group is tricyclic. In some embodiments, aliphatic cyclic group is polycyclic.In some embodiments, aliphatic polycyclic group is spirocyclic structure, and it presents the twisted structure (ring system) of two or more rings, and wherein 2 or 3 rings are connected together by a common atom.In another embodiment, aliphatic polycyclic group is fused bicyclic structure, and wherein two rings share two adjacent atoms, i.e., rings share a covalent bond, i.e., so-called bridgehead atoms directly connect (such as α- thujene (α-thujene) and decalin).In some embodiments, aliphatic polycyclic structure is the bicyclic structure of bridge connection, wherein, for example, two rings share three or more atoms, and two bridgehead atoms are separated by the bridge comprising at least one atom.For example, norbornane, also known as bicyclo [2.2.1] heptane, can be considered as a pair of cyclopentane rings, and each ring shares three of five carbon atoms. In some embodiments, an "aliphatic ring" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon, or C6-C8 hydrocarbon, that is fully saturated or contains one or more units of unsaturation but is not aromatic, and has a single point of attachment to the rest of the molecule. 12 Bicyclic hydrocarbons; C9-C12-C16-C18-C19-C19-C18 ... 16 Tricyclic hydrocarbons.

[0634] As used herein, the term "alkyl" has ordinary meaning in the art and can include saturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, a straight chain alkyl group or a branched chain alkyl group has about 1 to 20 carbon atoms in its backbone (e.g., a straight chain is C1-C1 20 , the branch chain is C2-C 20), and optionally, about 1 to 10 carbon atoms or about 1 to 6 carbon atoms. In some embodiments, the cycloalkyl ring has from about 3 to 10 carbon atoms in its ring structure, wherein such ring is monocyclic or bicyclic, or alternatively has about 5, 6 or 7 carbons in the ring structure. In some embodiments, the alkyl group can be a lower alkyl group, wherein the lower alkyl group contains 1 to 4 carbon atoms (e.g., a straight chain lower alkyl is C1-C4).

[0635] As used herein, the term "alkenyl" refers to an alkyl group as defined herein having one or more double bonds.

[0636] As used herein, the term "alkynyl" refers to a hydrocarbyl group as defined herein having one or more triple bonds.

[0637] The term "heteroalkyl" has ordinary meaning in the art and refers to an alkyl group as described herein in which one or more carbon atoms are replaced by a heteroatom, such as halogen, oxygen, nitrogen, sulfur, etc. Examples of heteroalkyl groups include, but are not limited to, alkoxy, poly(ethylene glycol), alkyl-substituted amino, tetrahydrofuranyl, piperidinyl, morpholinyl, and the like.

[0638] As used herein, "aromatic" refers to a monocyclic or polycyclic aromatic ring or heteroaromatic ring, which may have from 5 to 20 ring atoms and optionally may have from 1 to 20 heteroatom substituents. In some embodiments, the aromatic group may optionally have from 1 to 10 heteroatom substituents. In some embodiments, the aromatic group may optionally have from 1 to 5 heteroatom substituents. In some embodiments, the aromatic group is a monocyclic or polycyclic aromatic ring, such as cyclopentadienyl, phenyl, naphthyl or anthracenyl. In some embodiments, the aromatic group is a monocyclic or polycyclic aromatic ring with from 5 to 10 ring atoms. In some embodiments, the aromatic group is a monocyclic aromatic ring containing from 5 to 6 carbon atoms, such as phenyl and cyclopentadienyl. In a specific embodiment, the aromatic group is a phenyl group.

[0639] The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkyloxy" or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracenyl, and the like, which may carry one or more substituents. The scope of the term "aryl" as used herein also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0640] The terms "heteroaromatic," "heteroaryl," and "heteroar-," used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having from 5 to 10 ring atoms, and in some embodiments, 5, 6, 9, or 10 ring atoms (i.e., monocyclic or bicyclic). In some embodiments, such rings have 6, 10, or 14 pi electrons shared in the cyclic array; and from 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of a basic nitrogen. Heteroaromatic hydrocarbon or heteroaryl groups include but are not limited to thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. In some embodiments, heteroaryl is a heterobiaryl group, such as bipyridyl etc. As used herein, the terms "heteroaryl" and "heteroaromatic" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the group or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and pyrido [2,3-b] -1, 4-oxazin-3 (4H) -one. The heteroaryl group can be monocyclic, bicyclic, tricyclic, tetracyclic and / or polycyclic. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which includes optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0641] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic group," and "heterocycle" are used interchangeably and refer to stable 5- to 7-membered monocyclic heterocyclic moieties or 7-10-membered bicyclic heterocyclic moieties that are saturated or partially unsaturated and have, in addition to carbon atoms, one or more, preferably 1 to 4 heteroatoms, as defined above. The term "nitrogen," when used in reference to a ring atom of a heterocycle, includes substituted nitrogens.

[0642] The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine, oxazolidinyl ... Oxaza oxazepinyl, thiazepinyl The terms "heterocycle", "heterocyclyl", "heterocyclic ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic group" are used interchangeably herein and also include groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. The heterocyclic group can be monocyclic, bicyclic, tricyclic, tetracyclic and / or polycyclic in addition. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclic radical, wherein the alkyl and heterocyclic moieties are independently and optionally substituted.

[0643] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double or triple bond. The term "partially unsaturated" is intended to include rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0644] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen in a heterocycle).

[0645] As used herein, the term "unsaturated" means that the moiety has one or more unsaturated units. The term "halogen" means F, Cl, Br or I; the term "halide" refers to a halogen group or substituent, i.e., -F, -Cl, -Br or -I. As used herein, "haloalkyl" refers to an alkyl group as defined above wherein the alkyl group includes at least one substituent selected from halogen, such as fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Examples of haloalkyl groups include, but are not limited to, -CF3, -CH2CF3, -CCl2F and -CCl3.

[0646] As used herein, term " blocking group " refers to the group introduced into molecule by the chemical modification of functional group such as amino or alcohol, to obtain chemoselectivity in subsequent chemical reaction. In a non-limiting embodiment, blocking group can include 1- chloroethyl carbonyl (ACE), acetyl, benzyl (Bn), benzyloxycarbonyl (CBz), formyl, methylcarbonyl, trifluoroacetyl, tert-butyloxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). In another non-limiting embodiment, blocking group includes benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl (Ac), benzoyl (bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP) group, tosyl (Ts), Troc (trichloroethyl chloroformate), sulfonamides such as Nosyl and Nps. In further non-limiting embodiments, protecting groups include β-methoxyethoxymethyl ether (MEM), dimethoxytrityl, [bis-(4-methoxyphenyl)phenylmethyl] (DMT), methoxymethyl ether (MOM), methoxytrityl [(4-methoxyphenyl)diphenylmethyl] (MMT), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), tetrahydrofuran (THF), trityl (triphenylmethyl, Tr), silyl ether (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsiloxymethyl (TOM) and triisopropylsilyl (TIPS) ether, TBDMS and TOM; methyl ether and ethoxyethyl ether (EE).

[0647] As used herein, the term "O-amino acid" or "HO-amino acid" refers to an amino acid in which the native amino group at the N-terminus of the amino acid or amino acid sequence is replaced by an oxygen group or a hydroxyl group, respectively. For example, "O-XXXX" or "HO-XXXX" is intended to refer to an amino acid sequence (XXXX) in which the native amino group at the N-terminus is replaced by an oxygen group or a hydroxyl group, respectively (e.g., wherein each R is an amino acid side chain). Similarly, the term "O-amino acid residue" or "HO-amino acid residue" refers to a chemical moiety that remains in a compound after a chemical reaction. For example, "O-amino acid residue" or "HO-amino acid residue" refers to the product of amide coupling or peptide coupling of an O-amino acid or HO-amino acid with a suitable coupling partner; wherein, for example, following amide coupling or peptide coupling of the O-amino acid or HO-amino acid, a water molecule is expelled, resulting in the product having the O-amino acid residue or HO-amino acid residue incorporated therein.

[0648] The nomenclature of amino acids or amino acid residues, without specifying their stereochemistry, is intended to include the L-form of the amino acid, the D-form of the amino acid, or racemic mixtures thereof.

[0649] As described herein, the compounds of the present disclosure may include "optionally substituted" moieties. Typically, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of a specified moiety are replaced by suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituent may be the same or different at each position. The combination of substituents contemplated by the present disclosure is preferably one that results in the formation of stable compounds or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow its production, detection, and in certain embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0650] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds herein are within the scope of the present disclosure.

[0651] Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0652] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing a hydrogen atom with deuterium or tritium, or with 11 C- or 13 C- or 14 C-rich carbon replaces carbon, or with 17 O- or 18 O-enriched oxygen replaces oxygen, or with 15 Compounds having the structures herein where an N-enriched nitrogen replaces the nitrogen are within the scope of this disclosure.

[0653] It should also be understood that reference to one or more method steps does not exclude the presence of additional method steps or intermediate method steps between those steps that are explicitly identified. Similarly, it should also be understood that reference to one or more components in an apparatus or system does not exclude the presence of additional components or intermediate components between those components that are explicitly identified.

[0654] Unless otherwise indicated, all crystalline forms of the compounds of the present disclosure and their salts are also within the scope of the present disclosure. The compounds of the present disclosure can be isolated in various amorphous and crystalline polymorphic forms, including but not limited to amorphous and crystalline polymorphic forms that are anhydrous, hydrated, unsolvated, or solvated. Examples of hydrates include hemihydrates, monohydrates, dihydrates, and the like. In some embodiments, the compounds of the present disclosure are anhydrous and unsolvated. "Anhydrous" means that the crystalline form of the compound does not substantially contain bound water in the crystal lattice structure, i.e., the compound does not form crystalline hydrates.

[0655] As used herein, "crystalline form" is intended to refer to a certain lattice configuration of a crystalline material. Different crystalline forms (polymorphic forms) of the same substance typically have different lattices (e.g., unit cells) due to the different physical properties unique to each crystalline form. In some cases, different lattice configurations have different water or solvent contents. Different lattices can be identified by solid-state characterization methods such as by X-ray powder diffraction (PXRD). Other characterization methods, such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), solid-state NMR, etc., also help identify the crystalline form and help determine stability and solvent / water content.

[0656] Crystalline forms of substances include both solvated (e.g., hydrated) and non-solvated (e.g., anhydrous) forms. A hydrated form is a crystalline form that contains water in the crystal lattice. A hydrated form can be a stoichiometric hydrate, wherein water is present in the crystal lattice at a certain water / molecule ratio, such as a hemihydrate, a monohydrate, a dihydrate, etc. A hydrated form can also be a non-stoichiometric form, wherein the water content is variable and depends on external conditions, such as humidity.

[0657] In some embodiments, the compounds of the present disclosure are substantially isolated. "Substantially isolated" means that a particular compound is at least partially separated from impurities. For example, in some embodiments, the compounds of the present disclosure contain less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2.5%, less than about 1%, or less than about 0.5% impurities. Impurities generally include anything that is not a substantially isolated compound, including, for example, other crystalline forms and other substances.

[0658] As used herein, the term "antibiotic" (abx or Abx) includes any molecule that specifically inhibits the growth of microorganisms (such as bacteria) or kills microorganisms, but is non-lethal to the host at the concentrations and dosing intervals applied. In specific aspects, the antibiotic is non-toxic to the host at the applied concentrations and dosing intervals. Antibiotics effective against bacteria can be broadly divided into bactericidal (i.e., directly killing) or bacteriostatic (i.e., preventing division). Antibacterial antibiotics can be further subdivided into narrow spectrum or broad spectrum. Broad-spectrum antibiotics are effective antibiotics for a wide range of bacteria, including both gram-positive and gram-negative bacteria, compared to narrow-spectrum antibiotics that are effective for smaller ranges or specific bacterial families.Examples of antibiotics include: aminoglycosides, such as amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin, ansamycins, such as geldanamycin, herbimycin, carbacephems, such as loracarbef, carbapenems, such as ertapenum, doripenem, imipenem / cilastatin, meropenem, cephalosporins (first generation), such as cefadroxil, cefazolin, cephalothin, cephalexin, cephalosporins (second generation), such as cefuroxil, cefazolin, cephalothin, cephalexin cefoperazone, cefadroxil, cefoxitin, cefprozil, cefuroxime, cephalosporins (third generation), such as cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cephalosporins (fourth generation), such as cefepime, cephalosporins (fifth generation), such as ceftobiprole, glycopeptides, such as teicoplanin, vancomycin, macrolides, such as azithromycin, clarithromycin, dirithromycin, erythromycin, spiririnomycin, troleandomycin, telithromycin, spectinomycin, monobactams, such as axtreonam, penicillins, such as amoxicillin, ampicillin penicillin, axlocilin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin, piperacillin, ticarcillin, antibiotic polypeptides such as bacitracin, colistin, polymyxin B, quinolones such as ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trofloxacin, sulfonamides such as mafenide, sulfazosulfonamide, sulfacetamide, sulfamethizole, sulfonamide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim- trimethoprim-sulfamethoxazole (TMP-SMX), tetracyclines such as demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, and other drugs such as arspenamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platamicin, pyrazinamide, quinupristin / dalfopristin, rifampin / rifampicin, or timidazole.

[0659] The term "methicillin-resistant Staphylococcus aureus" (MRSA), alternatively referred to as multidrug-resistant Staphylococcus aureus or oxacillin-resistant Staphylococcus aureus (ORSA), refers to any strain of Staphylococcus aureus that is resistant to β-lactam antibiotics, which include penicillins (e.g., methicillin, dicloxacillin, nafcillin, oxacillin, etc.) and cephalosporins. "Methicillin-susceptible Staphylococcus aureus" (MSSA) refers to any strain of Staphylococcus aureus that is sensitive to β-lactam antibiotics.

[0660] The term "minimum inhibitory concentration" ("MIC") refers to the lowest concentration of an antimicrobial agent that will inhibit visible growth of a microorganism after overnight incubation. Assays for determining the MIC are known. One method is described in the Examples below.

[0661] The drug-antibody ratio (DAR) is the average number of drugs conjugated to an antibody or antigen-binding fragment, which plays an important role in the efficacy, effectiveness, and pharmacokinetics of an ADC. In various embodiments, the DAR is 1, 2, 3, 4, 5, 6, 7, or 8 drug molecules per antibody. In some embodiments, the DAR is from 1 to 8. In some embodiments, the DAR is from 1 to 6. In certain embodiments, the DAR is from 2 to 4. In some cases, the DAR is from 2 to 3. In some cases, the DAR is from 0.5 to 3.5. In some embodiments, the DAR is about 1, or about 1.5, or about 2, or about 2.5, or about 3, or about 3.5.

[0662] As used herein, the expressions "MSR1," "hMSR1," and the like refer to a human single-pass, trimeric type II transmembrane glycoprotein pattern recognition receptor comprising (i) the amino acid sequence set forth in NCBI Accession No. NP_002436.1, (ii) the amino acid sequence set forth in NCBI Accession No. NP_619729.1, and / or (iii) the amino acid sequence set forth in NCBI Accession No. NP_619730.1, which represent various types and isoforms of class A macrophage scavenger receptors. The expression "MSR1" includes both monomeric and multimeric MSR1 molecules. As used herein, the expression "monomeric human MSR1" means an MSR1 protein or portion thereof that does not contain or have any multimerization domain and that, under normal conditions, exists as a single MSR1 molecule without direct physical association with another MSR1 molecule. An exemplary monomeric MSR1 molecule is the molecule referred to herein as "His-hMSR1," which comprises the amino acid sequence of SEQ ID NO: 393 (see, eg, Example 25 herein).

[0663] All references to proteins, polypeptides, and protein fragments herein are intended to refer to the human version of the respective protein, polypeptide, or protein fragment, unless expressly designated as being from a non-human species. Thus, the expression "MSR1" is intended to refer to human MSR1, unless designated as being from a non-human species, e.g., "mouse MSR1," "monkey MSR1," etc.

[0664] As used herein, the expression "cell surface expressed MSR1" means one or more MSR1 proteins or extracellular domains thereof that are expressed on the surface of cells in vitro or in vivo such that at least a portion of the MSR1 protein is exposed on the extracellular side of the cell membrane and is accessible to the antigen-binding portion of an antibody. "Cell surface expressed MSR1" may include or consist of MSR1 proteins expressed on the surface of cells that normally express MSR1 protein. Alternatively, "cell surface expressed MSR1" may include or consist of MSR1 proteins expressed on the surface of cells that do not normally express human MSR1 on their cell surfaces but have been artificially engineered to express MSR1 on their surface.

[0665] As used herein, the phrase "anti-MSR1 antibody" includes monovalent antibodies with a single specificity, as well as bispecific antibodies comprising a first arm that binds MSR1 and a second arm that binds a second (target) antigen, wherein the anti-MSR1 arm comprises any HCVR / LCVR or CDR sequence as listed in Table 9 herein. The phrase "anti-MSR1 antibody" also includes antibody-drug conjugates (ADCs) comprising an anti-MSR1 antibody, or an antigen-binding portion thereof, conjugated to a drug or therapeutic agent. The phrase "anti-MSR1 antibody" also includes antibody-radionuclide conjugates (ARCs) comprising an anti-MSR1 antibody, or an antigen-binding portion thereof, conjugated to a radionuclide.

[0666] The term "wall teichoic acid" (WTA) refers to an anionic sugar-containing polymer of the C6 hydroxyl group of the N-acetyl muramic acid sugar covalently attached to the peptidoglycan via a phosphodiester bond. Although the precise chemical structure can vary between organisms, in some embodiments, WTA is a repeating unit of a 1,5-phosphodiester bond with D-ribitol and D-alanyl ester at the 2 position and a ribitol teichoic acid with a glycosyl substituent at the 4 position. The glycosyl group can be an N-acetylglucosamine group α (alpha) or β (beta) as present in Staphylococcus aureus. The hydroxyl group on the alditol / sugar alcohol phosphate repeating unit can be replaced by a cationic D-alanine ester and a monosaccharide such as N-acetylglucosamine. The hydroxyl substituent can include D-alanyl and α (alpha) or β (beta) GlcNHAc. In a specific embodiment, WTA includes a compound of the formula:

[0667]

[0668] Wherein the wavy line indicates the attachment site of the repeating linker unit or polyglycan-P or peptidoglycan, wherein X is D-alanyl or -H; and Y is α(alpha)-GlcNHAc or β(beta)-GlcNHAc.

[0669]

[0670] As used herein, the term "anti-WTA antibody" refers to any antibody that binds to wall teichoic acid (WTA) (whether it is WTA α or WTA β). The term "anti-wall teichoic acid α antibody" or "anti-WTA α antibody" or "anti-αWTA" or "anti-αGlcNac WTA antibody" is used interchangeably to refer to antibodies that specifically bind to WTA α. Similarly, the term "anti-wall teichoic acid β antibody" or "anti-WTA β antibody" or "anti-βWTA" or "anti-βGlcNac WTA antibody" is used interchangeably to refer to antibodies that specifically bind to WTA β. The term "anti-WTA antibody" includes monovalent antibodies with single specificity, and a bispecific antibody comprising a first arm that binds to WTA (whether it is WTA α or WTA β) and a second arm that binds to a second (target) antigen, wherein the anti-WTA arm includes any HCVR / LCVR or CDR sequence listed in Table 2A and Table 2B herein. The expression "anti-WTA antibody" also includes an antibody-drug conjugate (ADC) comprising an anti-WTA antibody, or an antigen-binding portion thereof, conjugated to a drug or therapeutic agent.

[0671] As used herein, the term "antibody" means any antigen binding molecule or molecular complex comprising at least one complementary determining region (CDR) that specifically binds to a specific antigen (e.g., MSR1, WTA, or protein A) or interacts with a specific antigen. The term "antibody" includes immunoglobulin molecules, which include four polypeptide chains, two heavy (H) chains, and two light (L) chains, interconnected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain includes a heavy chain variable region (abbreviated herein as HCVR or V H ) and heavy chain constant region. The heavy chain constant region consists of three domains, C H 1. C H 2 and C H 3. Each light chain includes a light chain variable region (abbreviated herein as LCVR or V L ) and the light chain constant region. The light chain constant region consists of a domain (C L 1). V H and V L The V domains can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). H and V L It comprises three CDRs and four FRs arranged from amino terminus to carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments, the FRs of the antibody (or its antigen-binding portion) may be identical to human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a juxtaposition analysis of two or more CDRs.

[0672] As used herein, the term "antibody" also includes the antigen-binding fragment of a complete antibody molecule. As used herein, the term "antigen-binding portion thereof," "antigen-binding fragment" of an antibody, etc., include any naturally occurring, enzymatically obtainable, synthetic or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. The antigen-binding fragment of an antibody can use any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering technology, including manipulation and expression of DNA encoding antibody variable domains and optional constant domains, for example, derived from a complete antibody molecule. Such DNA is known and / or easily obtained from, for example, commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. Chemically or by using molecular biology techniques, DNA can be sequenced and manipulated, for example, to arrange one or more variable domains and / or constant domains into suitable configurations, or to introduce codons, produce cysteine ​​residues, modify, add or delete amino acids, etc.

[0673] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) the smallest recognition unit consisting of amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity-determining region (CDR) such as a CDR3 peptide) or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed by the expression "antigen-binding fragment" as used herein.

[0674] Antigen-binding fragments of antibodies will generally include at least one variable domain. A variable domain can be of any size or amino acid composition and will generally include at least one CDR adjacent to or within a framework having one or more framework sequences. L Domain-associated V H In the antigen-binding fragment of the structural domain, V H and V L The domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer and comprise V H -V H 、V H -V L or V L -V LAlternatively, the antigen-binding fragment of an antibody may comprise a monomer V H or V L domain.

[0675] In certain embodiments, the antigen-binding fragment of an antibody may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found in the antigen-binding fragments of an antibody of the present disclosure include: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) V H -C H 2-C H 3; (vii) V H -C L ;(viii)V L -C H 1; (ix) V L -C H 2;(x)V L -C H 3; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C L. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other, or may be linked by a complete or partial hinge or linker region. The hinge region may be composed of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which results in a flexible or semi-flexible connection between adjacent variable and / or constant domains in a single polypeptide molecule. In addition, the antigen-binding fragments of the antibodies of the present disclosure may comprise the above-listed non-covalently associated with each other and / or (e.g., via disulfide bonds) with one or more monomeric V domains. H or V L Any configuration of variable and constant domains in non-covalently associated homodimers or heterodimers (or other multimers).

[0676] As with complete antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will generally comprise at least two different variable domains, each of which is capable of specifically binding to a separate antigen or a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be adapted for use in the context of antigen-binding fragments of the antibodies of the present disclosure using conventional techniques available in the art.

[0677] The antibodies of the present disclosure can act by complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC). "Complement-dependent cytotoxicity" (CDC) refers to the lysis of cells expressing antigens by antibodies of the present disclosure in the presence of complement. "Antibody-dependent cell-mediated cytotoxicity" (ADCC) refers to a cell-mediated reaction in which non-specific cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages) expressing Fc receptors (FcRs) recognize the antibodies bound on target cells and thereby cause the lysis of target cells. CDC and ADCC can be measured using assays well known in the art and available. (See, e.g., U.S. Patent Nos. 5,500,362 and 5,821,337, and Clynes et al. (1998) Proc. Natl. Acad. Sci. (USA) 95: 652-656). The constant region of an antibody is important in the ability of an antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of an antibody can be selected based on whether the antibody is desired to mediate cytotoxicity.

[0678] In certain embodiments, antibodies disclosed herein are human antibodies. As used herein, the term "human antibody" is intended to include antibodies with variable regions and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the present disclosure may include amino acid residues (e.g., mutations introduced in vitro or in vivo by random or site-specific mutagenesis) that are not encoded by human germline immunoglobulin sequences, such as in CDR and particularly in CDR3. However, as used herein, the term "human antibody" is not intended to include antibodies in which the CDR sequences derived from the germline of another mammalian species (such as a mouse) have been grafted onto human framework sequences.

[0679] In some embodiments, the antibodies disclosed herein can be recombinant human antibodies. As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, produced or separated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells (further described below), antibodies separated from recombinant combinatorial human antibody libraries (further described below), antibodies separated from animals (e.g., mice) transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20: 6287-6295) or antibodies prepared, expressed, produced or separated by any other means involving human immunoglobulin gene sequences and other DNA sequences splicing. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when using animals transgenic for human Ig sequences, in vivo somatic mutagenesis), and therefore the V H Area and V L The amino acid sequence of the region is such that, although derived from and identical to the human germline V H and V L Sequences are related, but may not naturally occur in the human antibody germline repertoire in vivo.

[0680] Human antibodies can exist in two forms, which are related to hinge heterogeneity. In one form, the immunoglobulin molecule comprises a stable four-chain construct of about 150kDa-160kDa, in which the dimer is held together by an interchain heavy chain disulfide bond. In the second form, the dimer is not connected via an interchain disulfide bond and forms a molecule (half antibody) of about 75kDa-80kDa comprising a covalently coupled light chain and a heavy chain. Even after affinity purification, these forms are extremely difficult to separate.

[0681] The frequency of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the occurrence of the second form (Angal et al. (1993) Molecular Immunology 30:105) to the level typically observed with the human IgG1 hinge. The embodiments disclosed herein include substitutions in the hinge region, C H 2 or C H Antibodies with one or more mutations in region 3 may be desirable, for example, in production to increase the yield of the desired antibody form.

[0682] The antibodies disclosed herein can be isolated antibodies. As used herein, "isolated antibody" means an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally occurs or is naturally produced, is an "isolated antibody" for the purposes of this disclosure. Isolated antibodies also include in situ antibodies in recombinant cells. An isolated antibody is an antibody that has been subjected to at least one purification or separation step. According to certain embodiments, the isolated antibody may be substantially free of other cellular material and / or chemicals.

[0683] The antibodies disclosed herein may comprise one or more amino acid substitutions, insertions and / or deletions in the framework regions and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be easily determined by comparing the amino acid sequences disclosed herein with germline sequences that can be obtained, for example, from public antibody sequence databases. Embodiments include antibodies and antigen-binding fragments thereof derived from any amino acid sequence disclosed herein, wherein one or more amino acid mutations in the framework regions and / or CDR regions are mutated to the corresponding residues of the germline sequence from which the antibodies were derived, or mutated to the corresponding residues of another human germline sequence, or mutated to the conservative amino acid substitutions of the corresponding germline residues (such sequence changes are collectively referred to herein as "germline mutations"). One of ordinary skill in the art can easily produce many antibodies and antigen-binding fragments comprising one or more individual germline mutations or combinations thereof, starting from the heavy and light chain variable region sequences disclosed herein. In certain embodiments, in V H and / or V LIn another embodiment, all framework and / or CDR residues in the domain are mutated back to the residues found in the original germline sequence of the derived antibody.In other embodiments, only certain residues are mutated back to the original germline sequence, for example, only the residues of the mutation found in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only the residues of the mutation found in CDR1, CDR2 or CDR3.In other embodiments, one or more mutations in the framework and / or CDR residues are mutated into the corresponding residues of different germline sequences (that is, germline sequences different from the germline sequences of the initial derived antibody).In addition, the antibody of the present disclosure can be included in any combination of two or more germline mutations in the framework and / or CDR regions, for example, wherein some individual residues are mutated into the corresponding residues of specific germline sequences, and some other residues different from the original germline sequence are retained or mutated into the corresponding residues of different germline sequences. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, e.g., improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as appropriate), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are included in the embodiments disclosed herein.

[0684] Embodiments also include antibodies comprising variants of any HCVR, LCVR and / or CDR amino acid sequences disclosed herein with one or more conservative substitutions. For example, embodiments include anti-MSR1 antibodies comprising HCVR, LCVR and / or CDR amino acid sequences relative to any HCVR, LCVR and / or CDR amino acid sequences listed in Table 9 herein, with, for example, 10 or less, 8 or less, 6 or less, 4 or less, etc., conservative amino acid substitutions of HCVR, LCVR and / or CDR amino acid sequences. As another example, embodiments include anti-WTA antibodies comprising HCVR, LCVR and / or CDR amino acid sequences relative to any HCVR, LCVR and / or CDR amino acid sequences listed in Table 2A or Table 2B herein, with, for example, 10 or less, 8 or less, 6 or less, 4 or less, etc., conservative amino acid substitutions of HCVR, LCVR and / or CDR amino acid sequences. As yet another example, embodiments include anti-Protein A antibodies comprising HCVR, LCVR and / or CDR amino acid sequences having, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc., conservative amino acid substitutions relative to any of the HCVR, LCVR and / or CDR amino acid sequences listed in Table 3A herein.

[0685] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule and is called a paratope. A single antigen can have more than one epitope. Therefore, different antibodies can bind to different regions on the antigen and can have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are produced by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. A linear epitope is an epitope produced by adjacent amino acid residues in a polypeptide chain. In some cases, an epitope can include part of a sugar, a phosphoryl group, or a sulfonyl group on the antigen.

[0686] The term "substantial identity" or "substantially identical," when referring to a nucleic acid or fragment thereof, indicates that when optimally aligned with appropriate nucleotide insertions or deletions of another nucleic acid (or its complementary strand), there is at least about 95%, and more preferably at least about 96%, 97%, 98% or 99% nucleotide base identity in the nucleotide sequence as measured by any well-known sequence identity algorithm, such as FASTA, BLAST or GAP, as discussed below. A nucleic acid molecule that is substantially identical to a reference nucleic acid molecule can, in some cases, encode a polypeptide comprising an amino acid sequence that is identical or substantially similar to a polypeptide encoded by the reference nucleic acid molecule.

[0687] When applied to polypeptides, the term "substantially similar" or "substantially similar" means that two peptide sequences share at least 95% sequence identity, even more preferably at least 98% or 99% sequence identity, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights. Preferably, residue positions that are not identical differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is replaced by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). Typically, conservative amino acid substitutions will not significantly alter the functional properties of the protein. In the case where two or more amino acid sequences differ from each other by conservative substitutions, the percentage of sequence identity or similarity can be adjusted upward to correct for the conservative nature of the substitution. Means for making such adjustments are well known to those skilled in the art. See, for example, Pearson (1994) Methods Mol.Biol.24:307-331. Examples of amino acid groups having side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; (2) aliphatic-hydroxy side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartic acid and glutamic acid, and (7) sulfur-containing side chains: cysteine ​​and methionine. Preferred conservative amino acid substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine. Alternatively, a conservative substitution is any change that has a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256:1443-1445. A "moderately conservative" substitution is any change that has a non-negative value in the PAM250 log-likelihood matrix.

[0688] The sequence similarity of polypeptide, also referred to as sequence identity, is usually measured using sequence analysis software. Protein analysis software uses the metric of similarity assigned to various substitutions, deletions and other modifications (including conservative amino acid substitutions) to match similar sequences. For example, GCG software includes programs such as GAP and BESTFIT, which can be used together with default parameters to determine sequence homology or sequence identity between closely related polypeptides (such as homologous polypeptides from organisms of different species) or between wild-type proteins and mutants thereof. See, for example, GCG version 6.1. Peptide sequences can also be compared using default parameters or recommended parameters using FASTA (the program in GCG version 6.1). FASTA (such as FASTA2 and FASTA3) provides comparison and sequence identity percentage of the best overlapping region between query sequence and search sequence (Pearson (2000) the same). When the sequence of the present disclosure is compared with a database comprising a large number of sequences from different organisms, another preferred algorithm is computer program BLAST, particularly BLASTP or TBLASTN, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-402.

[0689] As used herein, "O-PEG n " refers to a monovalent moiety attached via a terminal oxygen atom, wherein n is from 1 to 100. For example, when n is 1, then O-PEGn is -O-CH2CH2OH; when n is 2, then O-PEGn is -O-CH2CH2O-CH2CH2OH; and when n is 3, then O-PEGn is -O-CH2CH2O-CH2CH2O-CH2CH2OH.

[0690] As used herein, "binding agent" refers to any molecule, such as a protein or antibody, that is capable of specifically binding to a given binding partner (eg, an antigen).

[0691] As used herein, "linker" refers to a divalent, trivalent, or multivalent moiety that covalently attaches a binding agent to one or more compounds described herein (eg, a payload compound and a hydrophilic group as described herein).

[0692] As used herein, a "reactive group" or RG refers to a moiety that contains in its structure a moiety that is capable of reacting with another chemical moiety and forming a covalent bond, such as a moiety that reacts with an antibody at its cysteine ​​or lysine residues. Illustrative reactive groups for use in the present disclosure include, but are not limited to, those that include maleimide, succinimide, N-hydroxysuccinimide (NHS), a terminal primary amine, a haloacetyl group, an isothiocyanate, a thiol, an alcohol, a ketone, an aldehyde, an acid, an ester, a hydrazine, and an aniline. RG also includes a moiety having the following structure:

[0693]

[0694] wherein X is -O- or -NH- and LG is a leaving group, such as Br.

[0695] As used herein, "amide synthesis conditions" refers to reaction conditions suitable for achieving amide formation, for example, by the reaction of a carboxylic acid, an activated carboxylic acid, or an acid halide with an amine. In some instances, amide synthesis conditions refer to reaction conditions suitable for achieving amide bond formation between a carboxylic acid and an amine. In some of these instances, the carboxylic acid is first converted to an activated carboxylic acid before the activated carboxylic acid reacts with the amine to form the amide. Suitable conditions for achieving amide formation include, but are not limited to, those for achieving the reaction between a carboxylic acid and an amine using reagents including, but not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl Uranium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate hexafluorophosphate (CIP), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), and carbonyldiimidazole (CDI).

[0696] In some instances, before the carboxylic acid esters of activation are treated with amines to form amido bonds, carboxylic acid is first converted into activated carboxylic acid esters. In certain embodiments, carboxylic acid is treated with a reagent. This reagent activates carboxylic acid by deprotonating the carboxylic acid, and then forms a product complex with the deprotonated carboxylic acid due to the nucleophilic attack of the deprotonated carboxylic acid on the protonated reagent. Compared with the carboxylic acid before activation, the activated carboxylic acid esters of some carboxylic acid are more susceptible to amine nucleophilic attack subsequently. This causes amido bonds to form. Therefore, carboxylic acid is described as activated. Exemplary reagents include DCC and DIC.

[0697] As used herein, "taurine" refers to an agent or group in Indicates the atom through which taurine is bonded to the adjacent group in the formula.

[0698] Compounds of the Disclosure

[0699] In accordance with the foregoing and other objects, the present disclosure provides rifamycin analog compounds, precursors and intermediates thereof, pharmaceutical compositions, and methods for inhibiting bacterial growth and / or treating bacterial infection in a subject in need thereof.

[0700] In one aspect, the present disclosure provides a rifamycin analog compound having the structure of Formula (A) or a precursor thereof:

[0701]

[0702] or a pharmaceutically acceptable salt thereof, wherein:

[0703] X is selected from -O- and -NR*-;

[0704] Za and Zb are independently selected from hydrogen, -Cl, -Br, -OR1 and -R N ; Provided that at least one of Za or Zb is not hydrogen; wherein:

[0705] R1 is selected from hydrogen, R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3+ , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[0706] R N Selected from:

[0707]

[0708] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and for example F MOC and a protecting group of Boc, or wherein R' and R" together form an aliphatic cyclic structure, such as an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0709] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[0710] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[0711] R bSelected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, and

[0712] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0713] In one aspect, the present disclosure provides rifamycin analog compounds having the structure of Formula (I):

[0714]

[0715] or a pharmaceutically acceptable salt thereof, wherein:

[0716] X is selected from -O- and -NR*-;

[0717] R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[0718] R N Selected from:

[0719]

[0720] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0721] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[0722] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[0723] R bSelected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, and

[0724] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0725] In one aspect, the present disclosure provides rifamycin analog compounds having the structure of Formula (I'):

[0726]

[0727] or a pharmaceutically acceptable salt thereof, wherein:

[0728] X is selected from -O- and -NR*-;

[0729] R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[0730] R N Selected from:

[0731]

[0732] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0733] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[0734] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[0735] R bSelected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, and

[0736] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0737] In embodiments of the compounds of Formula (A), Formula (I), or Formula (I'), X is -O-; R1 is an aliphatic C1-C3 hydrocarbon; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; and R a It's hydrogen.

[0738] In an embodiment of the compound of Formula (A), Formula (I) or Formula (I'), X is -O-; R1 is a benzyl group; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; R a is hydrogen and R b It's hydrogen.

[0739] In embodiments of the compounds of Formula (A), Formula (I), or Formula (I'), X is -O-; R1 is an aliphatic C1-C8 hydrocarbon containing 1-8 heteroatoms selected from O and N; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; R a is hydrogen and R b It's hydrogen.

[0740] In embodiments of the compounds of Formula (A), (I), or (I'), X is -O-; R1 is an aliphatic C1-C8 hydrocarbon substituted with one or more of -NH2, -NHR*, -N(R*)2, R* is H or an aliphatic C1-C3 hydrocarbon; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; R a is hydrogen and R b It's hydrogen.

[0741] In embodiments of the compounds of Formula (A), Formula (I), or Formula (I'), X is -NCH3-; R1 is -OH; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; R a is hydrogen and R b It's hydrogen.

[0742] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (II):

[0743]

[0744] or a pharmaceutically acceptable salt thereof, wherein:

[0745] X is selected from -O- and -NR*-;

[0746] R a is selected from hydrogen, -Cl and -OR*;

[0747] R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, - O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O )-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, with the proviso that R1 is not an n-butyl group;

[0748] R NSelected from:

[0749]

[0750] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0751] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0752] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (II'):

[0753]

[0754] or a pharmaceutically acceptable salt thereof, wherein:

[0755] X is selected from -O- and -NR*-;

[0756] R a is selected from hydrogen and -OR*;

[0757] R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, - O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O )-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, with the proviso that R1 is not an n-butyl group;

[0758] R N Selected from:

[0759]

[0760] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0761] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0762] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (III):

[0763]

[0764] or a pharmaceutically acceptable salt thereof, wherein:

[0765] R a is selected from hydrogen and -OR*;

[0766] R5 is selected from R N 、Aliphatic C1-C 20Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and combinations thereof, with the proviso that R5 is not an n-butyl group;

[0767] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; and

[0768] R N Selected from:

[0769]

[0770]

[0771] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure.

[0772] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (III'):

[0773]

[0774] or a pharmaceutically acceptable salt thereof, wherein:

[0775] R a is selected from hydrogen and -OR*;

[0776] R5 is selected from R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and combinations thereof, with the proviso that R5 is not an n-butyl group;

[0777] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof; and

[0778] R N Selected from:

[0779]

[0780] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure.

[0781] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (IV):

[0782]

[0783] or a pharmaceutically acceptable salt thereof, wherein:

[0784] R a is selected from hydrogen and -OR*;

[0785] R5 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and combinations thereof;

[0786] R N Selected from:

[0787]

[0788] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0789] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0790] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (IV'):

[0791]

[0792] or a pharmaceutically acceptable salt thereof, wherein:

[0793] R a is selected from hydrogen and -OR*;

[0794] R5 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and combinations thereof;

[0795] R N Selected from:

[0796]

[0797]

[0798] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0799] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0800] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (V):

[0801]

[0802] or a pharmaceutically acceptable salt thereof, wherein:

[0803] X is selected from -O- and -NR*-;

[0804] R a is selected from hydrogen and -OR*;

[0805] R6 is selected from R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R6 is optionally substituted with one or more of: -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, and combinations thereof, with the proviso that R6 is not an n-butyl group;

[0806] R N Selected from:

[0807]

[0808] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0809] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0810] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of Formula (V'):

[0811]

[0812] or a pharmaceutically acceptable salt thereof, wherein:

[0813] X is selected from -O- and -NR*-;

[0814] R a is selected from hydrogen and -OR*;

[0815] R6 is selected from R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20hydrocarbons, each of which further comprises 0-8 heteroatoms selected from halogen, O, N and S, and wherein R6 is optionally substituted with one or more of: -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and combinations thereof, with the proviso that R6 is not an n-butyl group;

[0816] R N Selected from:

[0817]

[0818] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0819] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0820] In another aspect, the present disclosure provides rifamycin analog compounds, intermediates or precursors thereof having the structure of Formula (B):

[0821]

[0822] or a pharmaceutically acceptable salt thereof, wherein:

[0823] X is selected from -O- and -NR*-;

[0824] R1 is selected from hydrogen, R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[0825] R N Selected from:

[0826]

[0827] The symbols Represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: fluorenylmethoxycarbonyl (F MOC ) and tert-butyloxycarbonyl (Boc), or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0828] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[0829] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[0830] R b Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, and

[0831] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0832] In another aspect, the present disclosure provides rifamycin analog compounds having the structure of Formula (B-1):

[0833]

[0834] or a pharmaceutically acceptable salt thereof, wherein:

[0835] X is selected from -O- and -NR*-;

[0836] R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3+ , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, - O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O )-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, with the proviso that R1 is not an n-butyl group;

[0837] R N Selected from:

[0838]

[0839] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0840] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0841] In another aspect, the present disclosure provides rifamycin analog compounds having the structure of Formula (B-2):

[0842]

[0843] or a pharmaceutically acceptable salt thereof, wherein:

[0844] R N Selected from:

[0845]

[0846] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure.

[0847] In another aspect, the present disclosure provides rifamycin analog compounds having the structure of Formula (B-2):

[0848]

[0849] or a pharmaceutically acceptable salt thereof, wherein:

[0850] R N yes The symbols represents the point of attachment; and R′ and R″ are selected from hydrogen and C1-C6 aliphatic hydrocarbons.

[0851] In one embodiment, the rifamycin analog compound has a structure according to the following formula:

[0852]

[0853] or a pharmaceutically acceptable salt thereof.

[0854] In any of the preceding embodiments, a compound is provided wherein R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further comprises 0-3 heteroatoms selected from O and N, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, C 1-3 Alkoxy, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -O-(C=O)-H, -O-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When is hydrogen, R1 is not hydrogen.

[0855] In any of the preceding embodiments, a compound is provided wherein R1 is an aliphatic C1-C 20 Hydrocarbons and aromatic C1-C 20 Combination of hydrocarbons.

[0856] In any of the preceding embodiments, a compound is provided wherein R1 is an aliphatic C1-C 20 Hydrocarbons and heteroaromatic C1-C 20 Combination of hydrocarbons.

[0857] In an embodiment of any of the foregoing formulas, a compound is provided wherein R1 is selected from:

[0858]

[0859] In any of the foregoing embodiments, a compound is provided wherein R1 is an aliphatic C1-C2 substituted with one or more of -NH2, -NHR*, -N(R*)2, or -N(R*)-(C=O)-R*. 20 hydrocarbon.

[0860] In any of the preceding embodiments, a compound is provided wherein R1 is an aliphatic C1-C1-substituted with -NH-(C=O)-CH3 or -N(CH3)-(C=O)-CH3. 20 hydrocarbon.

[0861] In an embodiment of any of the foregoing formulas there is provided a compound wherein R a It's hydrogen.

[0862] In an embodiment of any of the foregoing formulas there is provided a compound wherein R a It is -OH.

[0863] In an embodiment of any of the foregoing formulas there is provided a compound wherein R a It is -Cl.

[0864] In an embodiment of any of the foregoing formulas there is provided a compound wherein R a is -OR*, and R* is selected from aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons and combinations thereof.

[0865] In an embodiment of any of the foregoing formulas there is provided a compound wherein R N Selected from:

[0866]

[0867]

[0868] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure.

[0869] In an embodiment of any of the foregoing formulas there is provided a compound wherein R N Selected from:

[0870]

[0871] wherein R' is hydrogen, an aliphatic hydrocarbon or a protecting group, and wherein the symbol In an embodiment of any of the foregoing formulae, a compound is provided wherein R* is independently selected at each occurrence from hydrogen; an aliphatic C1-C6 hydrocarbon; an aromatic C6-C7 hydrocarbon, and combinations thereof, further comprising 0-3 heteroatoms selected from O and N, and combinations thereof; an aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O and N and combinations thereof.

[0872] Some exemplary non-limiting embodiments of rifamycin analog compounds according to the present disclosure are shown in Table 1 below:

[0873] Table 1: Selected Rifamycin Analogs According to the Disclosure

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885] In one embodiment, the rifamycin analog compounds of the present disclosure have a structure selected from the group consisting of:

[0886]

[0887]

[0888] or a pharmaceutically acceptable salt thereof.

[0889] In one aspect, the compounds of the present disclosure have the structure of Formula (IA):

[0890]

[0891] in:

[0892] X is selected from -O-, -S- and -NR*-;

[0893] R1 is selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C5-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbon, aromatic C6-C 20 Hydrocarbon, heteroaryl C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR *, -O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, - O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof,

[0894] R2, R3 and R4 are independently selected from hydrogen, linear, branched or cyclic aliphatic C1-C 20 hydrocarbon, or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[0895] R a independently selected at each occurrence from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a and R b optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[0896] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C5-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbon, aromatic C6-C 20 Hydrocarbon, heteroaryl C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0897] In one embodiment, X is -O-; R1 is an aliphatic C1-C3 hydrocarbon; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; and R a It's hydrogen.

[0898] In one embodiment, X is -O-; R1 is a benzyl group; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; and R a It's hydrogen.

[0899] In one embodiment, X is -O-; R1 is an aliphatic C1-C8 hydrocarbon containing 1-8 heteroatoms selected from halogen, O, N and S; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; and R a It's hydrogen.

[0900] In one embodiment, X is -O-; R1 is an aliphatic C1-C8 hydrocarbon substituted with one or more of -NH2, -NHR*, -N(R*)2; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; and R a It's hydrogen.

[0901] In one embodiment, X is -NCH3-; R1 is -OH; R2 is a methyl group; R3 is Ac(-(C=O)-CH3); R4 is hydrogen; and R a It's hydrogen.

[0902] The present disclosure also includes salts of the compounds described herein. As used herein, "salt" refers to a derivative of a disclosed compound, wherein the parent compound is modified by converting an existing acid moiety or base moiety into its salt form. Examples of salts include, but are not limited to, basic residues such as inorganic acid (e.g., HCl, HBr, H2SO4) salts or organic acid (e.g., acetic acid, benzoic acid, trifluoroacetic acid) salts of amines; acidic residues such as alkali metal (e.g., Li, Na, K, Mg, Ca) salts or organic (e.g., trialkylammonium) salts of carboxylic acids; and the like. The salts of the present application can be synthesized by conventional chemical methods from parent compounds comprising a basic moiety or an acidic moiety. Typically, such salts can be prepared by reacting the free acid form or free base form of these compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent or in a mixture of the two. In some embodiments, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (ACN) can be used.

[0903] The present application also includes pharmaceutically acceptable salts of the compounds described herein. "Pharmaceutically acceptable salts" include a subset of the above-mentioned "salts", which are conventional non-toxic salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Berge, SM et al., Journal of Pharmaceutical Science, 1977, 66, 1, 1-19. The term "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment.

[0904] The preparation of compound can include the protection and deprotection of various chemical groups.The selection of protection and deprotection demand and suitable blocking group can be easily determined by those skilled in the art.The chemistry (chemistry) of blocking group can be for example found in Wuts and Greene, Greene Protective Groups in Organic Synthesis, the 4th edition, John Wiley & Sons:New York, 2006.In a kind of non-limiting embodiments, blocking group can include 1-chloroethyl carbonyl (ACE), acetyl, benzyl (Bn), benzyloxycarbonyl (CBz), formyl, methyl carbonyl, trifluoroacetyl, tert-butyloxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc).

[0905] The rifamycin analog compounds depicted herein include all isomeric (e.g., enantiomers, diastereomers, and geometric (or conformational)) forms of the compounds; for example, the R and S configurations of each asymmetric center, (Z) double bond isomers and (E) double bond isomers, and (Z) conformational isomers and (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the invention as well as enantiomers, diastereomers, and geometric (or conformational) mixtures are within the scope of the present disclosure. All tautomeric forms of the compounds presented herein are also within the scope of the present disclosure.

[0906] The rifamycin analog compounds described herein also include all compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except for the replacement of hydrogen with deuterium or tritium, or with 11 C- or 13 C- or 14C-enriched carbon instead of carbon, or with 17 O- or 18 O-enriched oxygen replaces oxygen, or uses 15 Compounds having the present structures except for the substitution of an N-enriched nitrogen for the nitrogen are within the scope of this disclosure.

[0907] The crystalline forms of the compounds of the present disclosure and their salts are also within the scope of the present disclosure. The compounds of the present disclosure can be isolated in various amorphous forms and crystalline polymorphic forms, including but not limited to anhydrous, hydrated, non-solvated or solvated amorphous forms and crystalline polymorphic forms. Exemplary hydrates include hemihydrates, monohydrates, dihydrates, etc. In some embodiments, the compounds of the present disclosure are anhydrous and non-solvated. "Anhydrous" means that the crystalline form of the compound is substantially free of bound water in the lattice structure, i.e., the compound does not form a crystalline hydrate.

[0908] Manufacturing method

[0909] In one aspect, the present disclosure provides a method of making a rifamycin analog compound having the structure of Formula (V):

[0910]

[0911] Wherein: X is selected from -O- and -NR*-;

[0912] R6 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof,

[0913] R N Selected from:

[0914]

[0915] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0916] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0917] The method comprises the following steps:

[0918] (a) making rifamycin S having the following structure:

[0919] and a compound having the structure of formula (VI):

[0920] touch,

[0921] wherein X' is selected from -OH and -NHR*; and

[0922] (b) treating the product of step (a) with an oxidizing agent.

[0923] In one aspect, the present disclosure provides a method of making a rifamycin analog compound having the structure of Formula (V'):

[0924]

[0925] Wherein: X is selected from -O- and -NR*-;

[0926] R6 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof,

[0927] R N Selected from:

[0928]

[0929]

[0930] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0931] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0932] The method comprises the following steps:

[0933] (a) making rifamycin S having the following structure:

[0934] and a compound having the structure of formula (VI'):

[0935] touch,

[0936] wherein X' is selected from -OH and -NHR*; and

[0937] (b) treating the product of step (a) with an oxidizing agent.

[0938] In one aspect, the present disclosure provides a method of making a compound having the structure:

[0939]

[0940] The method comprises the following steps:

[0941] (a) reacting rifamycin S with a compound having the structure of formula (VII):

[0942] touch,

[0943] Where PG is a protecting group;

[0944] (b) treating the product of step (a) with an oxidizing agent; and

[0945] (c) Removal of the protecting group PG.

[0946] In one embodiment, the compound of formula (VII) is prepared by removing the protecting group PG' from the compound of formula (VIII),

[0947]

[0948] The protecting groups PG and PG' may be the same as or different from each other.

[0949] In one embodiment, the compound of formula (VIII) is prepared by allowing a compound of formula (IX):

[0950] With a compound of formula (X): wherein the protecting groups PG and PG' may be the same as or different from each other.

[0951] In one aspect, the present disclosure provides a method of making a compound having the structure of Formula (XI):

[0952]

[0953] Wherein: R6 is selected from R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof, and wherein R6 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR *, -O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, - O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof;

[0954] R N Selected from:

[0955]

[0956] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOCand Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0957] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0958] The method comprises making a compound having the structure of formula (XII):

[0959]

[0960] Contacting with an alcohol having the structure R6-OH.

[0961] In one aspect, the present disclosure provides a method of making a compound having the structure of Formula (XI'):

[0962]

[0963] Wherein: R6 is selected from R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof, and wherein R6 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR *, -O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, - O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof;

[0964] R N Selected from:

[0965]

[0966]

[0967] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0968] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0969] The method comprises making a compound having the structure of formula (XII'):

[0970]

[0971] Contacting with an alcohol having the structure R6-OH.

[0972] In one aspect, the present disclosure provides a method of making a compound having the structure of Formula (XIII):

[0973]

[0974] Wherein: A is selected from a bond (A is absent) or an aliphatic C1-C 20 hydrocarbon;

[0975] R cy It is C3-C 14 Cycloaliphatic hydrocarbons further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof, and wherein R cy Optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR *, -O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O -(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof; and

[0976] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0977] The method comprises making a compound having the structure of formula (XII):

[0978]

[0979] With structure R cy -A-OH alcohol contact.

[0980] In one aspect, the present disclosure provides a method of making a compound having the structure of Formula (XIII'):

[0981]

[0982] Wherein: A is selected from a bond (A is absent) or an aliphatic C1-C 20 hydrocarbon;

[0983] R cy It is C3-C 14 Cycloaliphatic hydrocarbons further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof, and wherein R cy Optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR *, -O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O -(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof; and

[0984] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0985] The method comprises making a compound having the structure of formula (XII'):

[0986]

[0987] With structure R cy -A-OH alcohol contact.

[0988] In one aspect, the present disclosure provides a method of making a compound having the structure of Formula (XIV):

[0989]

[0990] wherein: Y is selected at each occurrence from -O- and -NR'R"-; n is independently an integer from 1 to 6 at each occurrence; and R', R" and R'" are each independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbon; the method comprises making a compound having a structure of formula (XII):

[0991]

[0992] With the structure R"R′NY-(CH2) n -Y-(CH2) n -OH alcohol contact.

[0993] In one aspect, the present disclosure provides a method of making a compound having the structure of Formula (XIV'):

[0994]

[0995] wherein: Y is selected at each occurrence from -O- and -NR'R"-; n is independently an integer from 1 to 6 at each occurrence; and R', R" and R'" are each independently selected from hydrogen and aliphatic C1-C 20 Hydrocarbon; the method comprises making a compound having a structure of formula (XII'):

[0996]

[0997] With the structure R"R′NY-(CH2) n -Y-(CH2) n -OH alcohol contact.

[0998] In one embodiment, the compound of formula (XII) is prepared by contacting rifamycin S with 2-amino-5-bromophenol and treating the product with an oxidizing agent.

[0999] In one embodiment, the compound of formula (XII') is prepared by contacting rifamycin S with 2-amino-4-bromophenol and treating the product with an oxidizing agent.

[1000] Pharmaceutical compositions and dosage forms

[1001] The present disclosure also provides pharmaceutical compositions comprising the compounds described herein. When used as a drug, the compounds of the present disclosure can be administered in the form of a pharmaceutical composition, which is a combination of a compound of the present disclosure and a pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by a variety of routes. Such pharmaceutical compositions can be administered systemically. The term "systemic" as used herein includes parenteral, topical, transdermal, oral, by inhalation / pulmonary, rectal, nasal, buccal and sublingual administration. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intracranial and intraperitoneal administration. In some embodiments, the compound is administered orally, topically, intranasally, intravenously, intramuscularly or subcutaneously in a therapeutically effective amount to treat bacterial infections (e.g., Staphylococcus aureus infections).

[1002] Pharmaceutical compositions comprising compounds of the present disclosure can be prepared in combination with one or more pharmaceutically acceptable carriers. In preparing the compositions of the present disclosure, the active ingredient is typically mixed with an excipient, diluted with the excipient, or encapsulated in such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When an excipient is used as a diluent, it can be a solid material, semisolid material, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[1003] In some embodiments, the pharmaceutical composition of the present disclosure is in liquid form. By way of non-limiting example, liquid form includes emulsions, solutions, suspensions, syrups, slurries, dispersions, colloids, etc. In some embodiments, the pharmaceutical composition described herein is in liquid form, semi-solid form or solid (e.g., powder) form. In specific embodiments, the pharmaceutical composition described herein is in semi-solid form, such as gel, gel matrix, cream, paste or similar form. In some embodiments, the semi-solid form includes a liquid vehicle. In some embodiments, the pharmaceutical composition of the present disclosure is a solid dosage form, such as a tablet, granules, sachets or powders. Also provided is a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the form of a dissolving tablet, dissolving wafer, capsule or gel capsule. In certain embodiments, the solid dosage form described herein includes a solid vehicle (e.g., as used in a tablet) and / or a gaseous vehicle (e.g., as used in a DPI).

[1004] In some embodiments, the composition is in a unit dosage formulation for oral, intranasal, intravenous, or other administration to a patient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[1005] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it should be understood that the amount of compound actually administered will generally be determined by a physician based on the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[1006] In some embodiments, a composition or unit dosage form described herein is administered as an emulsion, solution, suspension, syrup, slurry, dispersion, colloid, dissolving tablet, dissolving wafer, capsule, gel capsule, semi-solid form of gel, solid form of gel, gel matrix, cream, paste, tablet, granules, sachet, powder, or the like. In certain aspects, about 0.000001 mg to about 2000 mg, about 0.00001 mg to about 1000 mg, or about 0.0001 mg to about 750 mg, about 0.001 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.1 mg to about 100 mg, about 0.5 mg to about 75 mg, about 1 mg to about 50 mg, about 2 mg to about 40 mg, about 5 mg to about 20 mg, or about 7.5 mg to about 15 mg of a compound of Formula (I), or a compound having a structure according to any embodiment of Formula (A), (B), (I), (I'), (II), (III), (III'), (IV), (IV'), (V), or (V') as provided herein, is administered to a subject per day or per dose.

[1007] In some embodiments, a compound of the present disclosure is present in a composition or unit dose of a composition described herein in an amount from about 0.01 mg to about 10 mg (e.g., about 0.1 mg-10 mg, about 0.25 mg-5 mg, about 0.25 mg-2.5 mg, about 1 mg-2 mg, or about 2 mg-3 mg, about 0.5 mg to about 2 mg, about 1 mg to about 2 mg, about 1 mg, or about 2 mg). In some embodiments, the amount of compound administered daily or in a unit dose is between about 0.5 mg and about 3 mg, between about 0.5 mg and about 4 mg, or between about 0.35 mg and about 4 mg. In other embodiments, the amount of compound present in a unit dose or administered daily is between about 1 mg and about 3 mg, or between about 1 mg and about 2 mg, or between about 2 mg and about 3 mg.

[1008] In certain aspects, about 0.05 mg to about 50 mg, about 0.25 mg to about 20 mg, about 0.25 mg to about 15 mg, about 0.25 mg to about 10 mg, or about 0.25 mg to about 5 mg (e.g., about 0.1 mg to about 5 mg, about 0.25 mg to about 2.5 mg, about 0.3 mg to about 2 mg, about 0.5 mg to about 1 mg, about 0.7 mg to about 1.5 mg, about 0.375 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, or about 2 mg) of the compound is administered to the patient per day or dose.

[1009] In some embodiments, the compound is present in a unit dose in an amount between about 5 mg and about 500 mg. In some embodiments, the amount of the compound administered daily or in a unit dose is between about 5 mg and about 300 mg. In other embodiments, the amount of the compound present in a unit dose or administered daily is between about 5 mg and about 250 mg, or between about 5 mg and about 200 mg, or between about 5 mg and about 150 mg, between about 5 mg and about 100 mg, or between about 5 mg and about 50 mg.

[1010] When preparing the formulation, the active compound can be ground to provide a suitable particle size before being combined with the other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by grinding to provide a substantially uniform distribution in the formulation, such as about 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose. The formulation may additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and propylhydroxy-benzoate; sweeteners and flavorings. The compositions of the present disclosure can be formulated using procedures known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to the patient.

[1011] In order to prepare solid composition such as tablet, main active ingredient is mixed with pharmaceutical excipient to form the solid preformulation composition of the homogeneous mixture of the compound containing Formula I.When these preformulation compositions are referred to as homogeneous, active component is usually evenly dispersed in the whole composition so that composition can be easily subdivided into equally effective unit dosage forms such as tablet, pill and capsule.Then this solid preformulation is subdivided into the unit dosage form of above-mentioned type, comprises for example the active component of the application from 0.000001mg to about 2000mg.

[1012] The tablet or pill containing the compound of formula I can be coated or otherwise compounded, to provide the dosage form with extended effect advantage.For example, tablet or pill can comprise inner dosage component and outer dosage component, and the latter is the form being encapsulated on the former.Two kinds of components can be separated by enteric layer, and enteric layer is in order to resist the decomposition in the stomach and allows the complete passage of inner component into the duodenum or delayed release.Multiple materials can be used for such enteric layer or coating, and such material comprises the acid of a large amount of polymerization and the mixture of the acid of polymerization and the such material of for example shellac, cetyl alcohol and cellulose acetate.

[1013] Liquid forms into which the compounds and compositions of the present application can be incorporated for oral administration or administration by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[1014] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered via an oral route or nasal respiratory route for local or systemic action. The composition can be atomized using an inert gas. The atomized solution can be inhaled directly from the atomizing device, or the atomizing device can be attached to a face mask tent or intermittent positive pressure breathing machine. The solution, suspension or powder composition can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[1015] The composition administered to the patient may be in the form of the above-mentioned pharmaceutical composition. These compositions may be sterilized by conventional sterilization techniques or may be aseptically filtered. The aqueous solution may be packaged for use as is, or lyophilized, and the lyophilized product combined with a sterile aqueous carrier prior to administration. The pH of the composite product will generally be between 3 and 11, more preferably from 5 to 9. It will be understood that the use of some of the aforementioned excipients, carriers, or stabilizers will result in the formation of a pharmaceutical salt.

[1016] The therapeutic dose of a compound of the present disclosure can vary according to, for example, the specific use being treated, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of a compound of the present disclosure in a pharmaceutical composition can vary according to many factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. The dosage may depend on variables such as the type and degree of progression of the disease or disorder, the overall health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose can be inferred from a dose-response curve derived from an in vitro model test system or an animal model test system.

[1017] The present application also includes a pharmaceutical kit that can be used, for example, to treat a bacterial infection (e.g., a Staphylococcus aureus infection), the pharmaceutical kit comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. If desired, such a kit may also include one or more of various conventional pharmaceutical kit components, such as, for example, a container with one or more pharmaceutically acceptable carriers, an additional container, etc., which will be readily apparent to those skilled in the art. The kit may also include instructions (as an insert or as a label) indicating the amount of the component to be administered, administration instructions, and / or instructions for mixing the components.

[1018] The delivery device is important not only for delivering the compounds of the present disclosure, but also for providing a suitable storage environment. This will include protection from microbial contamination and chemical degradation. The device and formulation should be compatible to avoid potential leaching or adsorption. The delivery device (or its packaging) can optionally be provided with a label and / or instructions for use indicating that the composition should be used intranasally.

[1019] How to use

[1020] In another aspect, the present disclosure provides a method of preventing or inhibiting the growth of bacteria, the method comprising administering an effective amount of a compound having the structure of Formula (A):

[1021]

[1022] or a pharmaceutically acceptable salt thereof, wherein:

[1023] X is selected from -O-, -S- and -NR*-;

[1024] Za and Zb are independently selected from hydrogen, -Cl, -Br, -OR1 and -R N ; Provided that at least one of Za or Zb is not hydrogen; wherein:

[1025] R1 is selected from hydrogen, R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20hydrocarbons, and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3+, -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O-(C=O)-H, -O-(C=O)-R*, -S -(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, with the proviso that R1 is not an n-butyl group and when X is -O- and Ra is hydrogen, R1 is not hydrogen;

[1026] R N Selected from:

[1027]

[1028] The symbols represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and for example F MOC and a protecting group of Boc, or wherein R' and R" together form an aliphatic cyclic structure, such as an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1029] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1030] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[1031] R b Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, and

[1032] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1033] In another aspect, the present disclosure provides a method of preventing or inhibiting the growth of bacteria, the method comprising administering an effective amount of a compound having the structure of Formula (I):

[1034]

[1035] or a pharmaceutically acceptable salt thereof, wherein:

[1036] X is selected from -O- and -NR*-;

[1037] R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[1038] R N Selected from:

[1039]

[1040] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1041] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1042] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[1043] R bSelected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*; and

[1044] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1045] In another aspect, the present disclosure provides a method of preventing or inhibiting the growth of bacteria, the method comprising administering an effective amount of a compound having the structure of Formula (I'):

[1046]

[1047] or a pharmaceutically acceptable salt thereof, wherein:

[1048] X is selected from -O- and -NR*-;

[1049] R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[1050] R N Selected from:

[1051]

[1052] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1053] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1054] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[1055] R bSelected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, and

[1056] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1057] In another aspect, the present disclosure provides a method of preventing or inhibiting the growth of bacteria, the method comprising administering an effective amount of a compound having the structure of Formula (B):

[1058]

[1059] or a pharmaceutically acceptable salt thereof, wherein:

[1060] X is selected from -O- and -NR*-;

[1061] R1 is selected from hydrogen, R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[1062] R N Selected from:

[1063]

[1064] The symbols Represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: fluorenylmethoxycarbonyl (F MOC ) and tert-butyloxycarbonyl (Boc), or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1065] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1066] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[1067] R bSelected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, and

[1068] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1069] In another aspect, the present disclosure provides a method of preventing or inhibiting the growth of bacteria, comprising administering an effective amount of a rifamycin analog compound having a structure according to any one of Formula (IA)-C, (II)-C, (III)-III', (IV)-IV', (V)-V', (B-1), and (B-2) as provided herein. In one embodiment, the bacteria is a Gram-positive bacteria.

[1070] In one embodiment, the bacteria is a penicillin-resistant bacteria.

[1071] In one embodiment, the bacterium is Staphylococcus aureus.

[1072] In one embodiment, the bacterium is a resistant Staphylococcus aureus strain selected from MRSA and VRSA.

[1073] In one embodiment, the bacteria is methicillin-resistant Staphylococcus aureus (MRSA).

[1074] In one embodiment, the bacteria is vancomycin-resistant Staphylococcus aureus (VRSA).

[1075] In one embodiment, the bacterium is methicillin-susceptible Staphylococcus aureus (MSSA).

[1076] In yet another aspect, the present disclosure provides a method of treating a bacterial infection in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound having the structure of Formula (A):

[1077]

[1078] or a pharmaceutically acceptable salt thereof, wherein:

[1079] X is selected from -O-, -S- and -NR*-;

[1080] Za and Zb are independently selected from hydrogen, -Cl, -Br, -OR1 and -R N ; Provided that at least one of Za or Zb is not hydrogen; wherein:

[1081] R1 is selected from hydrogen, R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[1082] R N Selected from:

[1083]

[1084] in represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOCand Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1085] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1086] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[1087] R b Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, and

[1088] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1089] In another aspect, the present disclosure provides a method of treating a bacterial infection in a subject in need thereof, comprising administering an effective amount of a compound having the structure of Formula (I):

[1090]

[1091] or a pharmaceutically acceptable salt thereof, wherein:

[1092] X is selected from -O- and -NR*-;

[1093] R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[1094] R N Selected from:

[1095]

[1096] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1097] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1098] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[1099] R b Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*; and

[1100] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1101] In another aspect, the present disclosure provides a method of treating a bacterial infection in a subject in need thereof, comprising administering an effective amount of a compound having the structure of Formula (I'):

[1102]

[1103] or a pharmaceutically acceptable salt thereof, wherein:

[1104] X is selected from -O- and -NR*-;

[1105] R1 is selected from R N , hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[1106] R N Selected from:

[1107]

[1108] The symbols represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1109] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1110] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[1111] R b Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, and

[1112] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1113] In yet another aspect, the present disclosure provides a method of treating a bacterial infection in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound having the structure of Formula (B):

[1114]

[1115] or a pharmaceutically acceptable salt thereof, wherein:

[1116] X is selected from -O- and -NR*-;

[1117] R1 is selected from hydrogen, R N 、Aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, and when X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[1118] R N Selected from:

[1119]

[1120] The symbols Represents the point of attachment; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: fluorenylmethoxycarbonyl (F MOC ) and tert-butyloxycarbonyl (Boc), or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1121] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1122] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[1123] R bSelected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, and

[1124] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1125] In another aspect, the present disclosure provides a method of treating a bacterial infection in a subject in need of such treatment, comprising administering an effective amount of a rifamycin analog compound having a structure according to any one of Formula (IA)-C, (II)-C, (III)-III', (IV)-IV', (V)-V', (B-1), and (B-2) as provided herein. In one embodiment, the bacterial infection is a Gram-positive bacterial infection.

[1126] In one embodiment, the bacterial infection is a penicillin-resistant bacterial infection.

[1127] In one embodiment, the bacterial infection is a Staphylococcus aureus infection.

[1128] In one embodiment, the bacterial infection is an intracellular bacterial infection.

[1129] In one embodiment, the subject is a human.

[1130] In one embodiment, the method further comprises administering a second therapeutic agent.

[1131] In one embodiment, the second therapeutic agent is a second antibiotic.

[1132] In one embodiment, the second antibiotic is effective against Staphylococcus aureus.

[1133] In one embodiment, the second antibiotic is selected from the group consisting of an aminoglycoside, a beta-lactam, a macrolide, a cyclic peptide, a tetracycline, a fluoroquinoline, a fluoroquinolone, and an oxazolidinone.

[1134] In one embodiment, the second antibiotic is selected from the group consisting of clindamycin, novobiocin, retapamulin, daptomycin, sitafloxacin, teicoplanin, triclosan, naphthyridone, redezolid, doxorubicin, ampicillin, vancomycin, imipenem, doripenem, gemcitabine, dalbavancin, and azithromycin.

[1135] In one embodiment, the compound is administered to the subject orally, topically, intranasally, intravenously, intramuscularly, or subcutaneously.

[1136] In another aspect, the present disclosure provides a method of preventing or inhibiting the growth of bacteria, the method comprising administering an effective amount of a compound having the structure of Formula (I):

[1137]

[1138] in:

[1139] X is selected from -O-, -S- and -NR*-;

[1140] R1 is selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C5-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, -O- (C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O)-NHN H2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, provided that R1 is not an n-butyl group, wherein when X is -O- and R aWhen it is hydrogen, R1 is not hydrogen;

[1141] R2, R3 and R4 are independently selected from hydrogen, linear, branched or cyclic aliphatic C1-C 20 hydrocarbon, or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1142] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[1143] R b is a hydrogen atom at each occurrence; and

[1144] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof;

[1145] or a pharmaceutically acceptable salt thereof.

[1146] In yet another aspect, the present disclosure provides a method of treating a bacterial infection in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound having the structure of Formula (I'):

[1147]

[1148] in:

[1149] X is selected from -O-, -S- and -NR*-;

[1150] R1 is selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20Hydrocarbons and combinations thereof, each of which further comprises 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -ON(R*)2, -N(R*)-OR*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-SR*, - O-(C=O)-H, -O-(C=O)-R*, -S-(C=O)-R*, -(C=O)-NH2, -(C=O)-N(R*)2, -(C=O)-NHNH2, -O-(C=O )-NHNH2, -(C=S)-NH2, -(C=S)-N(R*)2, -N(R*)-CHO, -N(R*)-(C=O)-R*, -SCN, -NCS, -NSO, -SSR*, -SO2R*, -SO2-N(R*)2, -S(=O)-OR*, -S(=O)-R*, -Si(R*)3, -CF3, -O-CF3, and combinations thereof, with the proviso that R1 is not an n-butyl group;

[1151] Where X is -O- and R a When it is hydrogen, R1 is not hydrogen;

[1152] R2, R3 and R4 are independently selected from hydrogen, linear, branched or cyclic aliphatic C1-C 20 hydrocarbon, or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1153] R a Selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbon, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[1154] R b is a hydrogen atom at each occurrence; and

[1155] R* is independently selected at each occurrence from hydrogen, aliphatic C1-C 20Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof;

[1156] or a pharmaceutically acceptable salt thereof.

[1157] In one aspect, the present disclosure provides a method of preventing or inhibiting the growth of bacteria, comprising administering an effective amount of a rifamycin analog compound of the present disclosure, or a pharmaceutical composition comprising a rifamycin analog compound of the present disclosure, or a pharmaceutical dosage form comprising a rifamycin analog compound of the present disclosure.

[1158] In another aspect, the present disclosure provides a method for treating a bacterial infection in a subject in need of corresponding treatment, comprising administering to the subject an effective amount of a rifamycin analog compound of the present disclosure, or a pharmaceutical composition comprising a rifamycin analog compound of the present disclosure, or a pharmaceutical dosage form comprising a rifamycin analog compound of the present disclosure.

[1159] In one embodiment, the compound, composition, or dosage form is administered to the subject orally, topically, intranasally, intravenously, intramuscularly, or subcutaneously.

[1160] Anti-MSR1 antibodies suitable for ADC

[1161] The antibody-drug conjugates described herein can comprise a full-length anti-MSR1 antibody (e.g., an IgG1 or IgG4 antibody), or can comprise only the antigen-binding portion (e.g., a Fab, F(ab')2, or scFv fragment), and can be modified to affect function, e.g., to eliminate residual effector function (Reddy et al., 2000, J. Immunol. 164:1925-1933).

[1162] Embodiments of the antibody-drug conjugates described herein can include the anti-MSR1 antibodies listed in Tables 9 and 10. Table 9 lists the amino acid sequence identifiers of the heavy chain variable region (HCVR), light chain variable region (LCVR), heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), and light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) of exemplary anti-MSR1 antibodies. Table 10 lists the nucleic acid sequence identifiers of the HCVR, LCVR, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of exemplary anti-MSR1 antibodies.

[1163] Suitable antibodies or antigen-binding fragments thereof for use in the antibody-drug conjugates described herein include antibodies or antigen-binding fragments thereof that specifically bind MSR1 and comprise a HCVR comprising an amino acid sequence selected from any HCVR amino acid sequence listed in Table 9, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[1164] Another suitable antibody or antigen-binding fragment thereof that specifically binds to MSR1 comprises a LCVR comprising an amino acid sequence selected from any of the LCVR amino acid sequences listed in Table 9, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[1165] Additional suitable antibodies or antigen-binding fragments thereof that specifically bind to MSR1 comprise a HCVR and LCVR amino acid sequence pair (HCVR / LCVR) comprising any of the HCVR amino acid sequences listed in Table 9 paired with any of the LCVR amino acid sequences listed in Table 9. Certain embodiments relate to antibody-drug conjugates comprising an antibody or antigen-binding fragment thereof comprising a HCVR / LCVR amino acid sequence pair comprised in any of the exemplary anti-MSR1 antibodies listed in Table 9. In some embodiments, the HCVR / LCVR amino acid sequence pair is selected from the group consisting of: 2 / 10, 23 / 42, 50 / 58, 90 / 98, and 282 / 290.

[1166] Suitable antibodies or antigen-binding fragments thereof for use in the antibody-drug conjugates described herein include antibodies or antigen-binding fragments thereof that specifically bind to MSR1 and comprise a heavy chain CDR1 (HCDR1) comprising an amino acid sequence selected from any HCDR1 amino acid sequence listed in Table 9, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[1167] Additional suitable antibodies or antigen-binding fragments thereof that specifically bind to MSR1 comprise a heavy chain CDR2 (HCDR2) comprising an amino acid sequence selected from any HCDR2 amino acid sequence listed in Table 9, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[1168] Another suitable antibody or antigen-binding fragment thereof that specifically binds to MSR1 comprises a heavy chain CDR3 (HCDR3) comprising an amino acid sequence selected from any HCDR3 amino acid sequence listed in Table 9, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[1169] Suitable antibodies or antigen-binding fragments thereof for use in the antibody-drug conjugates described herein include antibodies or antigen-binding fragments thereof that specifically bind to MSR1 and comprise a light chain CDR1 (LCDR1) comprising an amino acid sequence selected from any LCDR1 amino acid sequence listed in Table 9, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[1170] Another suitable antibody or antigen-binding fragment thereof that specifically binds to MSR1 comprises a light chain CDR2 (LCDR2) comprising an amino acid sequence selected from any LCDR2 amino acid sequence listed in Table 9, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[1171] Another suitable antibody or antigen-binding fragment thereof that specifically binds to MSR1 comprises a light chain CDR3 (LCDR3) comprising an amino acid sequence selected from any LCDR3 amino acid sequence listed in Table 9, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[1172] Additional suitable antibodies or antigen-binding fragments thereof that specifically bind to MSR1 comprise a HCDR3 and LCDR3 amino acid sequence pair (HCDR3 / LCDR3) comprising any of the HCDR3 amino acid sequences listed in Table 9 paired with any of the LCDR3 amino acid sequences listed in Table 9. Certain embodiments relate to antibodies or antigen-binding fragments thereof comprising a HCDR3 / LCDR3 amino acid sequence pair comprised in any of the exemplary anti-MSR1 antibodies listed in Table 9. In some embodiments, the HCDR3 / LCDR3 amino acid sequence pair is selected from the group consisting of: 8 / 16, 40 / 48, 56 / 64, 96 / 104, and 288 / 296.

[1173] Suitable antibodies or antigen-binding fragments thereof for use in the antibody-drug conjugates described herein include antibodies or antigen-binding fragments thereof that specifically bind to MSR1 and comprise a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained in any of the exemplary anti-MSR1 antibodies listed in Table 9. In certain embodiments, the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence set is selected from the group consisting of: 4-6-8-12-14-16; 36-38-40-44-46-48; 52-54-56-60-62-64; 92-94-96-100-102-104; and 284-286-288-292-294-296.

[1174] In related embodiments, suitable antibodies or antigen-binding fragments thereof that specifically bind to MSR1 comprise a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained in a HCVR / LCVR amino acid sequence pair as defined by any of the exemplary anti-MSR1 antibodies listed in Table 9. For example, the present disclosure includes suitable antibodies or antigen-binding fragments thereof that specifically bind to MSR1 and comprise a HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence set contained in a HCVR / LCVR amino acid sequence pair selected from the group consisting of 2 / 10, 23 / 42, 50 / 58, 90 / 98, and 282 / 290. Methods and techniques for identifying CDRs in HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs in the specific HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general, the Kabat definition is based on sequence variability, the Chothia definition is based on the position of the structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, for example, Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Public databases can also be used to identify CDR sequences in antibodies.

[1175] Also provided herein are nucleic acid molecules encoding anti-MSR1 antibodies or portions thereof for use in preparing the antibody-drug conjugates described herein. For example, provided herein are nucleic acid molecules encoding any of the HCVR amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule can comprise a polynucleotide sequence selected from any of the HCVR nucleic acid sequences listed in Table 10, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[1176] Also provided herein are nucleic acid molecules encoding any of the LCVR amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule can comprise a polynucleotide sequence selected from any of the LCVR nucleic acid sequences listed in Table 10, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[1177] Also provided herein are nucleic acid molecules encoding any of the HCDR1 amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule can comprise a polynucleotide sequence selected from any of the HCDR1 nucleic acid sequences listed in Table 10, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[1178] Also provided herein are nucleic acid molecules encoding any of the HCDR2 amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule can comprise a polynucleotide sequence selected from any of the HCDR2 nucleic acid sequences listed in Table 10, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[1179] Also provided herein are nucleic acid molecules encoding any of the HCDR3 amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule can comprise a polynucleotide sequence selected from any of the HCDR3 nucleic acid sequences listed in Table 10, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[1180] Also provided herein are nucleic acid molecules encoding any of the LCDR1 amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule can comprise a polynucleotide sequence selected from any of the LCDR1 nucleic acid sequences listed in Table 10, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[1181] Also provided herein are nucleic acid molecules encoding any of the LCDR2 amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule can comprise a polynucleotide sequence selected from any of the LCDR2 nucleic acid sequences listed in Table 10, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[1182] Also provided herein are nucleic acid molecules encoding any of the LCDR3 amino acid sequences listed in Table 9; in certain embodiments, the nucleic acid molecule can comprise a polynucleotide sequence selected from any of the LCDR3 nucleic acid sequences listed in Table 10, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

[1183] Also provided herein are nucleic acid molecules encoding HCVRs, wherein the HCVR can comprise a set of three CDRs (ie, HCDR1-HCDR2-HCDR3), wherein the HCDR1-HCDR2-HCDR3 amino acid sequence set is as defined by any of the exemplary anti-MSR1 antibodies listed in Table 9.

[1184] Also provided herein are nucleic acid molecules encoding LCVRs, wherein the LCVR can comprise a set of three CDRs (ie, LCDR1-LCDR2-LCDR3), wherein the LCDR1-LCDR2-LCDR3 amino acid sequence set is as defined by any of the exemplary anti-MSR1 antibodies listed in Table 9.

[1185] Also provided herein are nucleic acid molecules encoding both a HCVR and a LCVR, wherein the HCVR may comprise an amino acid sequence of any HCVR amino acid sequence listed in Table 9, and wherein the LCVR may comprise an amino acid sequence of any LCVR amino acid sequence listed in Table 9. In certain embodiments, the nucleic acid molecule may comprise a polynucleotide sequence selected from any HCVR nucleic acid sequence listed in Table 10, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto; and a polynucleotide sequence selected from any LCVR nucleic acid sequence listed in Table 10, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto. In certain embodiments according to this aspect of the disclosure, the nucleic acid molecule encodes both a HCVR and a LCVR, wherein both the HCVR and the LCVR are derived from the same anti-MSR1 antibody listed in Table 9.

[1186] Also provided herein are recombinant expression vectors capable of expressing polypeptides comprising the heavy or light chain variable regions of anti-MSR1 antibodies useful in preparing the antibody-drug conjugates described herein. For example, embodiments include recombinant expression vectors comprising any of the nucleic acid molecules mentioned above, i.e., nucleic acid molecules encoding any of the HCVR, LCVR, and / or CDR sequences listed in Table 9. Also within the scope of the present disclosure are host cells into which such vectors have been introduced, as well as methods for producing antibodies or portions thereof for use in preparing the antibody-drug conjugates described herein by culturing the host cells under conditions that allow the production of antibodies or antibody fragments and recovering the antibodies and antibody fragments thus produced.

[1187] Suitable anti-MSR1 antibodies for use in the antibody-drug conjugates described herein include those with modified glycosylation patterns. In some embodiments, modification to remove undesirable glycosylation sites may be useful, or to remove antibodies lacking fucose moieties present on oligosaccharide chains, for example, to increase antibody-dependent cellular cytotoxicity (ADCC) function (see Shield et al. (2002) JBC 277:26733). In other applications, modification of galactosylation may be performed to modify complement-dependent cytotoxicity (CDC).

[1188] According to certain embodiments, an antibody-drug conjugate according to the present disclosure comprises an anti-MSR1 antibody comprising an Fc domain comprising one or more mutations that enhance or reduce binding of the antibody to an FcRn receptor, e.g., at acidic pH compared to neutral pH. For example, provided herein are antibody-drug conjugates comprising an anti-MSR1 antibody comprising an Fc domain comprising one or more mutations that enhance or reduce binding of the antibody to an FcRn receptor, e.g., at acidic pH compared to neutral pH. H 2 or C HMutations in region 3, wherein the mutation increases the affinity of the Fc domain for FcRn in an acidic environment (e.g., in an endosome at a pH range of about 5.5 to about 6.0). Such mutations can result in an increase in the serum half-life of the antibody when administered to an animal. Non-limiting examples of such Fc modifications include, e.g., modifications at position 250 (e.g., E or Q); positions 250 and 428 (e.g., L or F); modifications at positions 252 (e.g., L / Y / F / W or T), 254 (e.g., S or T), and 256 (e.g., S / R / Q / E / D or T); or modifications at positions 428 and / or 433 (e.g., H / L / R / S / P / Q or K) and / or 434 (e.g., H / F or Y); or modifications at positions 250 and / or 428; or modifications at positions 307 or 308 (e.g., 308F, V308F) and 434. In one embodiment, modifications can include 428L (e.g., M428L) and 434S (e.g., N434S) modifications; 428L, 259I (e.g., V259I) and 308F (e.g., V308F) modifications; 433K (e.g., H433K) and 434 (e.g., 434Y) modifications; 252, 254 and 256 (e.g., 252Y, 254T and 256E) modifications; 250Q and 428L modifications (e.g., T250Q and M428L); and 307 and / or 308 modifications (e.g., 308F or 308P).

[1189] For example, embodiments include antibody-drug conjugates comprising an anti-MSR1 antibody comprising an Fc domain comprising one or more pairs or groups of mutations selected from the group consisting of: 250Q and 248L (e.g., T250Q and M248L); 252Y, 254T, and 256E (e.g., M252Y, S254T, and T256E); 428L and 434S (e.g., M428L and N434S); and 433K and 434F (e.g., H433K and N434F). All possible combinations of the foregoing Fc domain mutations and other mutations within the antibody variable domains disclosed herein are contemplated as being within the scope of the present disclosure.

[1190] Biological properties of anti-MSR1 antibodies

[1191] Embodiments include antibody-drug conjugates comprising a rifamycin analog and an antibody and antigen-binding fragments thereof that bind to human MSR1 with high affinity. For example, the present disclosure includes an antibody-drug conjugate comprising an anti-MSR1 antibody that has a K of less than about 10 nM at 25° C. or 37° C. as measured by surface plasmon resonance (e.g., using an assay format as defined in Example 25 herein, or a substantially similar assay).D Binds to the extracellular domain of human MSR1 expressed with an N-terminal nonahistidine tag (SEQ ID NO: 688) (e.g., His9-hMSR1). According to certain embodiments, an antibody-drug conjugate is provided comprising an anti-MSR1 antibody having an OD of less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 3 nM, less than about 4 nM, less than about 5 nM, less than about 6 nM, less than about 7 nM, less than about 8 nM, less than about 9 nM, less than about 10 ... 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, or less than about 10 pM. D In some embodiments, the antibody-drug conjugate comprises an anti-MSR1 antibody disclosed herein having a K of less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, or less than about 20 pM at 25°C as measured by surface plasmon resonance (e.g., using an assay format as defined in Example 25 herein, or a substantially similar assay). D Binds human MSR1.

[1192] Embodiments also include antibody-drug conjugates comprising antibodies and antigen-binding fragments thereof that bind to monkey MSR1 with high affinity. For example, disclosed herein are antibody-drug conjugates comprising an anti-MSR1 antibody having a K of less than about 20 nM at 25° C. or 37° C. as measured by surface plasmon resonance (e.g., using an assay format as defined in Example 25 herein, or a substantially similar assay). DBinds to the extracellular domain of monkey MSR1 expressed with an N-terminal myc-myc-hexahistidine tag ("hexahistidine" is disclosed as SEQ ID NO: 689) (e.g., HMM-mfMSR1). According to certain embodiments, an antibody-drug conjugate is provided comprising an anti-MSR1 antibody that has an antibody-drug conjugate at 37°C of less than about 20 nM, less than about 18 nM, less than about 15 nM, less than about 12 nM, less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 6 nM, less than about 8 nM, less than about 9 nM, less than about 10 nM, less than about 15 nM, less than about 12 ...5 nM, less than about 12 nM, less than about 15 nM, less than about 12 nM, less than about 15 nM, less than about 15 nM, less than about 12 nM, less than about 15 nM, less than about 15 nM, less than about 15 nM, less than about 15 nM, less than about 15 nM, less than about 15 nM, less than about 1 A K of about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, or less than about 10 pM D In some embodiments, an antibody-drug conjugate comprising an anti-MSR1 antibody disclosed herein has a binding affinity of less than about 12 nM, less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, or less than about 10 nM at 25°C as measured by surface plasmon resonance (e.g., using an assay format as defined in Example 25 herein, or a substantially similar assay). less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, or less than about 20 pM D Binds monkey MSR1.

[1193] The present disclosure also includes antibody-drug conjugates comprising antibodies and antigen-binding fragments thereof that bind to the extracellular domain of human MSR1 expressed with an N-terminal nine-histidine tag (SEQ ID NO: 688) (e.g., His9-hMSR1) with a dissociation half-life (t1 / 2) of greater than about 5 minutes at 25°C or 37°C as measured by surface plasmon resonance (e.g., using an assay format as defined in Example 25 herein, or a substantially similar assay). According to certain embodiments, an antibody-drug conjugate is provided comprising an anti-MSR1 antibody that binds to human MSR1 with a t1 / 2 of greater than about 4 minutes, greater than about 5 minutes, greater than about 6 minutes, greater than about 8 minutes, greater than about 10 minutes, greater than about 12 minutes, greater than about 14 minutes, greater than about 16 minutes, greater than about 18 minutes, greater than about 20 minutes, greater than about 30 minutes, greater than about 40 minutes, greater than about 50 minutes, greater than about 60 minutes, greater than about 70 minutes, greater than about 80 minutes, greater than about 90 minutes, greater than about 120 minutes, greater than about 150 minutes, greater than about 180 minutes, greater than about 210 minutes, greater than about 240 minutes, or longer at 37°C as measured by surface plasmon resonance (e.g., using an assay format as defined in Example 25 herein, or a substantially similar assay).

[1194] Embodiments also include antibody-drug conjugates comprising antibodies and antigen-binding fragments thereof that can bind with high affinity to the extracellular domain of monkey MSR1 expressed with an N-terminal myc-myc-hexahistidine tag ("hexahistidine" is disclosed as SEQ ID NO: 689) (e.g., HMM-mfMSR1). For example, the present disclosure includes antibody-drug conjugates comprising an anti-MSR1 antibody that has a K of less than about 20 nM at 25° C. or 37° C. as measured by surface plasmon resonance (e.g., using an assay format as defined in Example 25 herein, or a substantially similar assay). DAccording to certain embodiments, an antibody-drug conjugate is provided comprising an anti-MSR1 antibody having an HMM-mfMSR1 antibody concentration of less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, or less than about 6 nM at 37°C as measured by surface plasmon resonance (e.g., using an assay format as defined in Example 25 herein, or a substantially similar assay). A K of less than about 100 pM, less than about 200 pM, less than about 150 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 150 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, or less than about 50 pM D In some embodiments, an anti-MSR1 antibody disclosed herein has a K of less than about 12 nM, less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 150 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, or less than about 50 pM at 25°C as measured by surface plasmon resonance (e.g., using an assay format as defined in Example 25 herein, or a substantially similar assay). D Combined with HMM-mfMSR1.

[1195] Embodiments also include antibody-drug conjugates comprising antibodies and antigen-binding fragments thereof that bind to the extracellular domain of monkey MSR1 expressed with an N-terminal myc-myc-hexahistidine tag ("hexahistidine" disclosed as SEQ ID NO: 689) (e.g., HMM-mfMSR1) with a dissociation half-life (t1 / 2) of greater than about 55 minutes at 25°C or 37°C as measured by surface plasmon resonance (e.g., using an assay format as defined in Example 25 herein, or a substantially similar assay). According to certain embodiments, an antibody-drug conjugate is provided comprising an anti-MSR1 antibody that binds to dimeric human MSR1 at 37°C with a t1 / 2 of greater than about 1 minute, greater than about 2 minutes, greater than about 3 minutes, greater than about 4 minutes, greater than about 5 minutes, greater than about 6 minutes, greater than about 8 minutes, greater than about 10 minutes, greater than about 12 minutes, greater than about 14 minutes, greater than about 16 minutes, greater than about 18 minutes, greater than about 20 minutes, greater than about 30 minutes, greater than about 40 minutes, greater than about 50 minutes, greater than about 60 minutes, greater than about 70 minutes, greater than about 80 minutes, greater than about 90 minutes, greater than about 120 minutes, greater than about 150 minutes, greater than about 180 minutes, greater than about 210 minutes, or longer as measured by surface plasmon resonance (e.g., using an assay format as defined in Example 25 herein, or a substantially similar assay).

[1196] Embodiments al...

Claims

1. An antibody-drug conjugate comprising an antibody or an antigen-binding fragment thereof, wherein the antibody or the antigen-binding fragment thereof is conjugated to a rifamycin analog via a linker or through a linker-spacer, wherein the rifamycin analog has the structure of formula (XXI): in: X is selected from -O-, -S- and -NR*-; R5 is selected from a bond; aliphatic C1-C 20 A hydrocarbon further comprising 0-8 heteroatoms selected from halogen, O, N and S; ;or , wherein Y is C or N; R2, R3 and R4 are independently selected from hydrogen, linear, branched or cyclic aliphatic C1-C 20 A hydrocarbon, or -(C=O)-R*, each of which further comprises 0-8 heteroatoms selected from halogen, O, N and S; R* at each occurrence is independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C5-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbon, cycloaliphatic C3-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof; and R 5c is a bond or an aliphatic C1-C8 hydrocarbon; wherein the group R5 is bonded to the linking group.

2. The antibody-drug conjugate according to claim 1, wherein -OR5 is -O-, , , , , or ; or where -R5 is , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

3. The antibody-drug conjugate of claim 1, wherein X is O and -OR5 comprises a tertiary amine.

4. The antibody-drug conjugate according to claim 1, wherein -OR5 is or .

5. The antibody-drug conjugate of claim 1, wherein R2 is methyl, ethyl, propyl or isopropyl; R3 is CH3(C=O)-, CH3CH2(C=O)-, CH3CH2CH2(C=O)- or (CH3)2CH-(C=O)-; and R4 is hydrogen.

6. The antibody-drug conjugate of claim 1, wherein R2 is methyl; R3 is acetyl; and R4 is hydrogen.

7. An antibody-drug conjugate comprising an antibody or an antigen-binding fragment thereof conjugated to a compound selected from the group consisting of: and , in is a bond to the linker, and when the compound comprises an ammonium salt, the counterion is an anion selected from the group consisting of: F - , Cl - Br - ,I - OH - , - BF4、CF3SO3 − , hydrogen sulfate, sulfate, dihydrogen phosphate, hydrogen phosphate or phosphate, NO3 - PF6 - 、NO2 - , carboxylate, C where e=2-10 and f=2e+1 e F f SO3 - , acetate, aspartate, benzenesulfonate, benzoate, benzenesulfonate, bicarbonate, bitartrate, camphorsulfonate, carbonate, citrate, decanoate, edetate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, glycolate, glycolamidophenylarsonic acid, hexanoate, hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methylnitrate, mucate, naphthenate, octanoate, oleate, pamoate, pantothenate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, tartrate, theocrolate, toluenesulfonate, or triethyl iodide.

8. An antibody-drug conjugate having the structure of formula (XXII): ， in: BA is an antibody or an antigen-binding fragment thereof; L is a A linker, wherein RG is selected from maleimide, N-hydroxysuccinimide or succinimide; SP 1 and SP 2 is independently absent or is a spacer selected from the group consisting of: , C 1-6 Alkyl, -NH-, -C(O)-, -CH2-CH2-C(O)-NH-, -(CH) u -C(O)-NH-, (-CH2-CH2-O) e 、-NH-CH2-CH2-(-O-CH2-CH2) e -C(O)- , -C(O)-(CH2) u -C(O)- , -C(O)-NH-(CH2) v - and combinations thereof, wherein subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8; AA 2-4 is a dipeptide selected from the group consisting of valine-citrulline, citrulline-valine, valine-alanine, alanine-valine, valine-glycine or glycine-valine; and PEG is a polyethylene glycol chain containing between 1 and 30 polyethylene glycol residues; SP is a spacer selected from the group consisting of: , , , , , , , , , and ; Y is C or N; where the symbol represents the point of attachment; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from fluorenylmethoxycarbonyl (Fmoc) and tert-butyloxycarbonyl (Boc), or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; or wherein With structure: or ； X is selected from -O-, -S- and -NR*, and R* at each occurrence is independently selected from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C5-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbon, cycloaliphatic C3-C 20 Hydrocarbon, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

9. The antibody-drug conjugate according to claim 8, wherein AA 2-4 It's valine-citrulline.

10. The antibody-drug conjugate of claim 8, wherein SP is , and R' and R" are each C 1-6 alkyl.

11. The antibody-drug conjugate of claim 10, wherein SP is , and R' and R" are each methyl.

12. The antibody-drug conjugate according to claim 8, wherein SP 1 and SP 2 Each is .

13. The antibody-drug conjugate of claim 8, wherein PEG comprises 8 polyethylene glycol units.

14. The antibody-drug conjugate of claim 8, wherein the antibody-drug conjugate has a structure selected from the group consisting of: 、 and ， wherein BA is an antibody or an antigen-binding fragment thereof.

15. The antibody-drug conjugate of any one of claims 1-14, wherein the antibody or antigen-binding fragment thereof binds to a target associated with an infectious disease.

16. Use of the antibody-drug conjugate according to any one of claims 1 to 15 in the preparation of a medicament for preventing or inhibiting the growth of bacteria.

17. Use of an antibody-drug conjugate according to any one of claims 1 to 15 in the preparation of a medicament for treating a bacterial infection in a subject in need of corresponding treatment.

18. Use of an antibody-drug conjugate according to any one of claims 1 to 15 in the preparation of a medicament for preventing or treating cellulitis, bacteremia, skin necrosis, eye infection, osteomyelitis, impetigo, furuncle, scalded skin syndrome, food poisoning, pneumonia, surgical infection, urinary tract infection, burn infection, meningitis, endocarditis, sepsis, toxic shock syndrome, septic arthritis, mastitis or an implant-related infection in a subject.

19. Use according to claim 18, wherein the eye infection is selected from eyelid infection and neonatal conjunctivitis.

20. The use according to claim 18, wherein the implant-related infection is selected from the group consisting of a prosthetic joint-related infection and a catheter-related infection.

21. A pharmaceutical composition comprising the antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier.

22. A pharmaceutical dosage form comprising the antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15.

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