Rifamycin analogs and antibody-drug conjugates thereof

Abstract

The present disclosure relates to rifamycin analogs and antibody-drug conjugates thereof. The present disclosure relates to rifamycin analogue 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 analogue compounds and antibodies specific for example to targets associated with infectious diseases, such as membrane glycoprotein receptor (MSR1), wall teichoic acid (WTA) or Protein A, and methods of using the antibody-drug conjugates to inhibit bacterial growth and treat bacterial infections.

Description

[0001] This application is a divisional application of the application with the filing date of December 20, 2019, application number 201980085251.5, and invention title "Rifamycin Analogues and Antibody-Drug Conjugates Thereof".

[0002] Cross-reference to related applications

[0003] This application claims the priority of 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.

[0004] Field of the disclosure

[0005] The present disclosure relates to rifamycin analogue compounds and pharmaceutical compositions capable of inhibiting bacterial growth and treating bacterial infections, as well as antibody-drug conjugates of rifamycin analogue compounds and antibodies (such as antibodies specific for targets related to infectious diseases), and methods of using the same.

[0006] Sequence listing

[0007] This application contains a sequence listing, which has been electronically submitted in ASCII format and is incorporated herein 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.

[0008] Background of the present disclosure

[0009] Staphylococcus aureus (S. aureus) is a Gram-positive, round bacterium, a member of the phylum Firmicutes, and also a common member of the body's microbiota, often found in the upper respiratory tract and on the skin. S. aureus is typically catalase and nitrate reductase positive and is a facultative anaerobe that can grow without oxygen. Although S. aureus is typically a symbiont of the human microbiota, it can 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 potent protein toxins and expressing cell surface proteins that bind to and inactivate antibodies.

[0010] It is estimated that 20% to 30% of the human population are long-term carriers of Staphylococcus aureus, which can be found as part of the normal skin flora in the nostrils and as a normal inhabitant of the lower genital tract in women. Staphylococcus aureus can cause a range of diseases, from mild skin infections such as papules, impetigo, boils, cellulitis, folliculitis, carbuncles, scalded skin syndrome, and abscesses, to life-threatening diseases such as pneumonia, meningitis, osteomyelitis, endocarditis, toxic shock syndrome, bacteremia, and sepsis. Staphylococcus 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 US hospitals develop staphylococcal infections, mainly caused by Staphylococcus aureus. In the United States, up to 50,000 deaths each year are associated with Staphylococcus aureus infections. Schlecht LM et al., 2015, Microbiology, 161, 1, 168 - 181. Despite extensive research and development, no vaccine against Staphylococcus aureus has been approved yet.

[0011] Initially, the treatment option for Staphylococcus aureus infections was penicillin. When penicillin was first introduced in 1943, antibiotic tolerance in Staphylococcus aureus was not common. By 1950, 40% of hospital Staphylococcus aureus isolates were penicillin-tolerant; by 1960, this had risen to 80%. Chambers HF, 2001, Emerging Infectious Diseases, 7, 2, 178 - 82. Today, Staphylococcus aureus has become tolerant to many commonly used antibiotics.

[0012] The emergence of antibiotic-tolerant strains of Staphylococcus aureus, such as methicillin-resistant Staphylococcus aureus (MRSA), is a worldwide problem in clinical medicine. MRSA strains are most commonly found associated with institutions such as hospitals, but are becoming increasingly prevalent in community-acquired infections. MRSA is one of many very feared strains of Staphylococcus aureus 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 lincosamide) and trimethoprim / sulfamethoxazole (also known as co-trimoxazole). Tolerance to these antibiotics has also led to the use of new broad-spectrum anti-Gram-positive antibiotics, such as linezolid, as it is available as an oral drug. The first-line treatment for severe invasive infections caused by MRSA is currently glycopeptide antibiotics (vancomycin and teicoplanin). 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 through blood tests. In addition, glycopeptide antibiotics do not penetrate well into infected tissues (which is a particular concern for infections of the brain and meninges and endocarditis). Therefore, there is a strong unmet need for new antibiotic treatments for Staphylococcus aureus in general, and particularly in addressing intracellular Staphylococcus aureus infections.

[0013] Rifamycins are a subclass of the ansamycin antibiotic family, a group of antibiotics that are either naturally synthesized by the bacterium Amycolatopsis rifamycinica or synthetically produced. 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 analogues rifampicin (or rifampin), rifabutin, rifapentine, rifalazil, and rifaximin. Rifamycin SV is sold under the trade name Aemcolo and is FDA-approved for the treatment of traveler's diarrhea in certain cases.

[0014] Rifamycin-class antibiotics inhibit bacterial RNA polymerase (RNAP) and have effective activity against Staphylococcus aureus. However, monotherapy with this class of antibiotics may lead to the selection of tolerant populations during treatment. Therefore, rifamycin antibiotics can be used in combination with first-line antibiotics to improve the prognosis, typically in infections involving prosthetics or foreign devices.

[0015] 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 the uptake of 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.

[0016] 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. It is internalized via clathrin-coated pits on the cell surface and releases its ligand at acidic pH before recycling back to the cell surface from the trans-Golgi (Doi et al. 1994. Journal of Biological Chemistry; Mori, T. 1994. Lab Invest). It promotes the transformation of monocyte-derived macrophages into foam cells, a key step in the progression of atherosclerosis.

[0017] 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 reservoirs in which S. aureus replicates and then seeds 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, liposomal formulations of vancomycin increase antibiotic penetration into macrophages more effectively than standard-of-care vancomycin and reduce the organ burden of S. aureus (Surewaard et al. 2016. J. Exp. Med. 213(7):1141-51). Collectively, these data suggest that delivery of antibiotics to macrophages may be an effective means of eliminating intracellular S. aureus reservoirs.

[0018] Teichoic acids are phosphate-rich molecules found on many glycan-binding proteins within the cell walls of most Gram-positive bacteria, including S. aureus. Teichoic acids, along with many other glycoproteins, form a thick layer of multiple peptidoglycan sheaths around the bacterium, which not only stabilizes the cell membrane but also provides numerous attachment sites for other molecules. Wall teichoic acid (“WTA”) is a type of teichoic acid that is covalently attached to peptidoglycan and extends through the cell wall and out of the cell wall. Among glycan-binding proteins, WTA can account for up to 60% of the total cell wall mass. Thus, it represents a highly expressed cell surface antigen of Gram-positive bacteria, including S. aureus.

[0019] Staphylococcus aureus also expresses many surface determinant antigens, including Staphylococcus aureus protein A (SpA) and 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-aspartic acid 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 colonization of host tissues, evasion of the host immune response, and bacterial fitness.

[0020] Accordingly, the development of ADCs comprising rifamycin analogs will allow for the target-specific delivery of rifamycin analogs into macrophages or the tethering of rifamycin analogs to the bacterial surface. Additionally, such ADCs can provide improved activity against, for example, antibiotic-tolerant bacterial targets, improved bioavailability, and an improved therapeutic window. Accordingly, there is a continuing need for antibody-drug conjugates using rifamycin analogs to effectively treat antibiotic-tolerant bacteria.

[0021] Accordingly, there is a strong unmet need for the development of effective analogs of rifamycin to combat the growing problem of antibiotic-tolerant bacteria, including antibiotic-tolerant Staphylococcus aureus strains. The MSR1 antibody can provide a means for specifically targeting therapeutic molecules, such as rifamycin analogs, to minimize the undesirable side effects caused by systemic administration of such compounds and to facilitate the internalization of these compounds into macrophages. Optionally, conjugation with antibodies that target cell surface antigens (e.g., WTA, protein A) can improve the therapeutic efficacy of rifamycin analogs.

[0022] The foregoing discussion is presented only to provide a better understanding of the nature of the problems faced in the art and should not in any way be construed as an admission of prior art, nor should the citation of any references herein be construed as an admission that such references constitute "prior art" for this application.

[0023] Overview of the Disclosure

[0024] As discussed herein, there is a strong need for the development of 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 methods of treatment based on such compounds and pharmaceutical compositions.

[0025] The following describes various non-limiting aspects and embodiments.

[0026] In one aspect, the present disclosure provides a rifamycin analogue compound, an intermediate or a precursor thereof having a structure of formula (A):

[0027]

[0028] or a pharmaceutically acceptable salt thereof, wherein:

[0029] X is selected from -O- and -NR*;

[0030] 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:

[0031] R1 is selected from hydrogen, R N , aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group, and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[0032] R N is selected from:

[0033]

[0034] wherein the symbol represents an attachment point; 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-butoxycarbonyl (Boc), or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure;

[0035] R2, R3, and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S;

[0036] R a is 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 hydrocarbons, which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R a is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[0037] R b is selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and aliphatic C1-C 20 hydrocarbons, which further contains 0-3 heteroatoms selected from halogen, O, and S, and wherein R b is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, and

[0038] R* is independently selected, each time it appears, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

[0039] In one aspect, the present disclosure provides a rifamycin analogue compound having a structure of formula (I):

[0040]

[0041] or a pharmaceutically acceptable salt thereof, wherein:

[0042] X is selected from -O- and -NR*;

[0043] R1 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group, and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[0044] R N is selected from:

[0045]

[0046] wherein 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: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0047] R2, R3, and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S;

[0048] R a is 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 hydrocarbons, which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R a is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[0049] R b is selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and aliphatic C1-C 20 hydrocarbons, which further contains 0-3 heteroatoms selected from halogen, O, and S, and wherein R b is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*; and R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

[0050] In one aspect, the present disclosure provides a rifamycin analog compound having a structure of formula (I’):

[0051]

[0052] or a pharmaceutically acceptable salt thereof, wherein:

[0053] X is selected from -O- and -NR*-;

[0054] 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 Hydrocarbons, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[0055] R N is selected from:

[0056]

[0057] wherein the symbol represents an attachment point; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0058] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S;

[0059] R a is 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 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[0060] R b is 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 the following: -F, -Cl, -Br, -I, -OH, -OR*, and R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0061] In an embodiment of the compound 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 is hydrogen.

[0062] 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 is hydrogen.

[0063] In an embodiment of the compound 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 is hydrogen.

[0064] In an embodiment of the compound of formula (A), formula (I) or formula (I’), X is -O-; R1 is an aliphatic C1-C8 hydrocarbon substituted by one or more of -NH2, -NHR*, -N(R*)2, where 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 is hydrogen.

[0065] In an embodiment of the compound 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 is hydrogen.

[0066] In one embodiment, the rifamycin analogue compound of the present disclosure has the structure of formula (II):

[0067]

[0068] or a pharmaceutically acceptable salt thereof, wherein:

[0069] X is selected from -O- and -NR*-;

[0070] R a is selected from hydrogen, -Cl and -OR*;

[0071] R1 is selected from R N 、hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group;

[0072] R N Selected from:

[0073]

[0074] wherein the symbol represents an attachment point; and R’, R” and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from: F MOC and Boc, or wherein R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0075] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, and further comprising 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0076] In one embodiment, the rifamycin analogue compound of the present disclosure has the structure of formula (II’):

[0077]

[0078] or a pharmaceutically acceptable salt thereof, wherein:

[0079] X is selected from -O- and -NR*-;

[0080] R a is selected from hydrogen and -OR*;

[0081] 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group;

[0082] R N is selected from:

[0083]

[0084] wherein the symbol represents an attachment point; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0085] R* is independently selected, each time it appears, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20Hydrocarbons and their combinations, which also contain 0-8 heteroatoms selected from halogen, O, N, and S and their combinations.

[0086] In one embodiment, the rifamycin analogue compound of the present disclosure has the structure of formula (III):

[0087]

[0088] Or a pharmaceutically acceptable salt thereof, wherein:

[0089] R a Is selected from hydrogen and -OR*;

[0090] 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and their combinations, each of which also contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of the following: -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 their combinations, provided that R5 is not a n-butyl group;

[0091] R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and their combinations, which also contains 0-8 heteroatoms selected from halogen, O, N, and S and their combinations; and

[0092] R N Is selected from:

[0093]

[0094]

[0095] Wherein the symbol Represents an attachment point; and R’, R” and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from the following: F MOCand Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure.

[0096] In one embodiment, the rifamycin analog compounds of the present disclosure have the structure of formula (III'):

[0097]

[0098] or a pharmaceutically acceptable salt thereof, wherein:

[0099] R a is selected from hydrogen and -OR*;

[0100] R5 is selected from R N 、aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of the following: -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, provided that R5 is not a n-butyl group;

[0101] R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof; and

[0102] R N is selected from:

[0103]

[0104] wherein 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 the following: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure.

[0105] In one embodiment, the rifamycin analog compound of the present disclosure has the structure of formula (IV):

[0106]

[0107] or a pharmaceutically acceptable salt thereof, wherein:

[0108] R a is selected from hydrogen and -OR*;

[0109] R5 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of the following: -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;

[0110] R N is selected from:

[0111]

[0112] wherein 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: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure; and

[0113] R* is independently selected, each time it appears, from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

[0114] In one embodiment, the rifamycin analog compound of the present disclosure has the structure of formula (IV'):

[0115]

[0116] or a pharmaceutically acceptable salt thereof, wherein:

[0117] R a is selected from hydrogen and -OR*;

[0118] R5 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of the following: -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;

[0119] R N is selected from:

[0120]

[0121]

[0122] wherein the symbol represents a point of attachment; and R', R", and R''' are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups selected from: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure; and

[0123] R* is independently selected, each time it appears, from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

[0124] In one embodiment, the rifamycin analog compound of the present disclosure has the structure of formula (V):

[0125]

[0126] or a pharmaceutically acceptable salt thereof, wherein:

[0127] X is selected from -O- and -NR*;

[0128] R a is selected from hydrogen and -OR*;

[0129] R6 is selected from R N , aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R6 is optionally substituted by one or more of the following: -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and combinations thereof, provided that R6 is not a n-butyl group;

[0130] R N is selected from:

[0131]

[0132] wherein 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: F MOC and Boc, or wherein R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0133] R* is independently selected, each time it appears, from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

[0134] In one embodiment, the rifamycin analog compound of the present disclosure has the structure of formula (V’):

[0135]

[0136] or a pharmaceutically acceptable salt thereof, wherein:

[0137] X is selected from -O- and -NR*;

[0138] R a is selected from hydrogen and -OR*;

[0139] 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R6 is optionally substituted by one or more of the following: -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + 、-N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and combinations thereof, provided that R6 is not a n-butyl group;

[0140] R N is selected from:

[0141]

[0142] wherein the symbol represents the attachment point; and R’, R”, and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups selected from: F MOC and Boc, or wherein R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure; and

[0143] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

[0144] In another aspect, the present disclosure provides a rifamycin analog compound, an intermediate, or a precursor having the structure of formula (B):

[0145]

[0146] or a pharmaceutically acceptable salt thereof, wherein:

[0147] X is selected from -O- and -NR*;

[0148] 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group, and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[0149] R N is selected from:

[0150]

[0151] wherein the symbol represents the attachment point; 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-butoxycarbonyl (Boc), or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0152] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20Hydrocarbons and -(C=O)-R*, each of which further contains 0 - 8 heteroatoms selected from halogen, O, N, and S;

[0153] 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 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[0154] 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 the following: -F, -Cl, -Br, -I, -OH, -OR*, and

[0155] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, which further contains 0 - 8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

[0156] In another aspect, the present disclosure provides a rifamycin analog compound having a structure of formula (B-1):

[0157]

[0158] or a pharmaceutically acceptable salt thereof, wherein:

[0159] X is selected from -O- and -NR*-;

[0160] R1 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C20 Hydrocarbons and combinations thereof, each of which further contains 0 - 8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + 、-N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group;

[0161] R N Selected from:

[0162]

[0163] wherein the symbol represents an attachment point; and R', R" and R'" are selected from hydrogen, C1 - C6 aliphatic hydrocarbons and protecting groups selected from: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0164] 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 hydrocarbons, heterocyclic C1 - C 20 hydrocarbons and combinations thereof, which further contains 0 - 8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

[0165] In another aspect, the present disclosure provides a rifamycin analogue compound having a structure of formula (B - 2):

[0166]

[0167] or a pharmaceutically acceptable salt thereof, wherein:

[0168] R N is selected from:

[0169]

[0170] wherein the symbol represents an attachment point; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure.

[0171] In another aspect, the present disclosure provides a rifamycin analogue compound having a structure of formula (B-2):

[0172]

[0173] or a pharmaceutically acceptable salt thereof, wherein:

[0174] R N is wherein the symbol represents an attachment point; and R' and R" are selected from hydrogen and C1-C6 aliphatic hydrocarbons.

[0175] In one embodiment, the rifamycin analogue compound has a structure according to the following formula:

[0176]

[0177] or a pharmaceutically acceptable salt thereof.

[0178] In an embodiment of any of the foregoing formulas, 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further contains 0-3 heteroatoms selected from O and N, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, C 1-3 alkoxide (C 1-3 alkoxide), -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -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 a n-butyl group and when X is -O-, R1 is not hydrogen.

[0179] In an embodiment of any of the foregoing formulas, a compound is provided wherein R1 is an aliphatic C1-C 20 hydrocarbon and an aromatic C1-C 20 hydrocarbon combination.

[0180] In an embodiment of any of the foregoing formulas, a compound is provided wherein R1 is an aliphatic C1-C 20 hydrocarbon and a heteroaromatic C1-C 20 hydrocarbon combination.

[0181] In an embodiment of any of the foregoing formulas, a compound is provided wherein R1 is selected from:

[0182]

[0183] In an embodiment of any of the foregoing formulas, a compound is provided wherein R1 is an aliphatic C1-C hydrocarbon substituted with one or more of -NH2, -NHR*, -N(R*)2, or -N(R*)-(C=O)-R*. 20 hydrocarbon.

[0184] In an embodiment of any of the foregoing formulas, a compound is provided wherein R1 is an aliphatic C1-C hydrocarbon substituted with -NH-(C=O)-CH3 or -N(CH3)-(C=O)-CH3. 20 hydrocarbon.

[0185] In an embodiment of any of the foregoing formulas, a compound is provided wherein R a is hydrogen.

[0186] In an embodiment of any of the foregoing formulas, a compound is provided wherein R a is -OH.

[0187] In an embodiment of any of the foregoing formulas, a compound is provided wherein R a is -Cl.

[0188] In an embodiment of any of the foregoing formulas, a compound is provided wherein R a is -OR*, and R* is selected from aliphatic C1-C 20Hydrocarbons, aromatic C1-C 20 Hydrocarbons and combinations thereof.

[0189] In an embodiment of any of the foregoing formulas, a compound is provided wherein R N is selected from:

[0190]

[0191]

[0192] wherein the symbol represents an attachment point; and R', R", and R''' are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups selected from: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure.

[0193] In an embodiment of any of the foregoing formulas, a compound is provided wherein R N is selected from:

[0194]

[0195] wherein R' is hydrogen, an aliphatic hydrocarbon, or a protecting group, and wherein the symbol represents an attachment point.

[0196] In an embodiment of the compound of any of the foregoing formulas, a compound is provided wherein R* is independently selected, at each occurrence, from hydrogen, aliphatic C1-C6 hydrocarbons, aromatic C4-C6 hydrocarbons, and combinations thereof, which optionally contain 1-3 heteroatoms selected from O, N, and combinations thereof.

[0197] In one embodiment, the rifamycin analog compound of the present disclosure has a structure selected from the group consisting of:

[0198]

[0199]

[0200]

[0201]

[0202] or a pharmaceutically acceptable salt thereof.

[0203] In one embodiment, the rifamycin analog compound of the present disclosure has a structure selected from the group consisting of:

[0204]

[0205] or a pharmaceutically acceptable salt thereof.

[0206] In one aspect, the present disclosure provides a method for making a rifamycin analog compound having the structure of formula (V):

[0207]

[0208] wherein: X is selected from -O- and -NR*;

[0209] R6 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof,

[0210] R N is selected from:

[0211]

[0212] 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: F MOC and Boc, or where R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0213] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, and it further contains 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0214] the method comprising the steps of:

[0215] (a) contacting rifamycin S having the following structure:

[0216] with a compound having the structure of formula (VI):

[0217] contacting,

[0218] where X’ is selected from -OH and -NHR*; and

[0219] (b) Treat the product of step (a) with an oxidizing agent.

[0220] In one aspect, the present disclosure provides a method for manufacturing a rifamycin analog compound having a structure of formula (V’):

[0221]

[0222] wherein: X is selected from -O- and -NR*;

[0223] R6 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof,

[0224] R N is selected from:

[0225]

[0226] where the symbol represents the attachment point; and R’, R” and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from: F MOC and Boc, or where R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0227] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, and it further contains 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0228] The method includes the following steps:

[0229] (a) Contact rifamycin S having the following structure:

[0230] with a compound having a structure of formula (VI’):

[0231] to contact,

[0232] wherein X’ is selected from -OH and -NHR*; and

[0233] (b) Treat the product of step (a) with an oxidizing agent.

[0234] In one aspect, the present disclosure provides a method for manufacturing a compound having the following structure:

[0235]

[0236] The method comprises the following steps:

[0237] (a) Contact rifamycin S with a compound having the structure of formula (VII):

[0238] contact,

[0239] wherein PG is a protecting group;

[0240] (b) Treat the product of step (a) with an oxidizing agent; and

[0241] (c) Remove the protecting group PG.

[0242] In one embodiment, the compound of formula (VII) is prepared by removing the protecting group PG' from the compound of formula (VIII),

[0243]

[0244] wherein the protecting groups PG and PG' may be the same or different from each other.

[0245] In one embodiment, the compound of formula (VIII) is prepared by contacting a compound of formula (IX):

[0246] with a compound of formula (X): contact, wherein the protecting groups PG and PG' may be the same or different from each other.

[0247] In one aspect, the present disclosure provides a method for manufacturing a compound having the structure of formula (XI):

[0248]

[0249] wherein: R6 is selected from R N , aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20Hydrocarbons and combinations thereof, which also contain 0-8 heteroatoms selected from halogens, O, N, and S and combinations thereof, and wherein R6 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + ,-N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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;

[0250] R N Selected from:

[0251]

[0252] wherein the symbol represents an attachment point; 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

[0253] R* is independently selected, each time it appears, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which also contain 0-8 heteroatoms selected from halogens, O, N, and S and combinations thereof,

[0254] The method comprises contacting a compound having a structure of formula (XII):

[0255]

[0256] with an alcohol having the structure R6-OH.

[0257] In one aspect, the present disclosure provides a method for making a compound having the structure of formula (XIII):

[0258]

[0259] wherein: A is selected from a bond (A is absent) or an aliphatic C1-C 20 hydrocarbon;

[0260] R cy is a C3-C 14 cycloaliphatic hydrocarbon which further comprises 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof, and wherein R cy is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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

[0261] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, which further comprises 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof,

[0262] The method comprises reacting a compound having the structure of formula (XII):

[0263]

[0264] with a compound having the structure R cyContact with an alcohol of -A-OH.

[0265] In one aspect, the present disclosure provides a method for making a compound having the structure of formula (XIII’):

[0266]

[0267] Wherein: A is selected from a bond (A is absent) or an aliphatic C1-C 20 hydrocarbon;

[0268] R cy is a C3-C 14 cycloaliphatic hydrocarbon which further comprises 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof, and wherein R cy is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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

[0269] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, which further comprises 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof,

[0270] The method comprises contacting a compound having the structure of formula (XII):

[0271]

[0272] with a structure Rcy Contact with an alcohol of -A-OH.

[0273] In one aspect, the present disclosure provides a method for making a compound having the structure of formula (XIV):

[0274]

[0275] Wherein: Y is independently selected from -O- and -NR’R” each time it appears; n is independently an integer from 1 to 6 each time it appears; and R’, R” and R”’ are each independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon; the method comprising contacting a compound having the structure of formula (XII):

[0276]

[0277] with an alcohol having the structure R″R′N-Y-(CH2) n -Y-(CH2) n -OH.

[0278] In one aspect, the present disclosure provides a method for making a compound having the structure of formula (XIV’):

[0279]

[0280] Wherein: Y is independently selected from -O- and -NR’R” each time it appears; n is independently an integer from 1 to 6 each time it appears; and R’, R” and R”’ are each independently selected from hydrogen and aliphatic C1-C 20 hydrocarbon; the method comprising contacting a compound having the structure of formula (XII’):

[0281]

[0282] with an alcohol having the structure R″R′N-Y-(CH2) n -Y-(CH2) n -OH.

[0283] 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.

[0284] 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.

[0285] In one aspect, the present disclosure provides a pharmaceutical composition comprising any one or more of the compounds described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0286] In another aspect, the present disclosure provides a pharmaceutical dosage form comprising any one or more of the compounds described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above.

[0287] 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 rifamycin analogue 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), formula (V’) as provided herein.

[0288] In one embodiment, the bacteria are Gram-positive bacteria.

[0289] In one embodiment, the bacteria are penicillin-resistant bacteria.

[0290] In one embodiment, the bacteria are Staphylococcus aureus.

[0291] In one embodiment, the bacteria are methicillin-resistant Staphylococcus aureus (MRSA).

[0292] In one embodiment, the bacteria are vancomycin-resistant Staphylococcus aureus (VRSA).

[0293] In one embodiment, the bacteria are methicillin-susceptible Staphylococcus aureus (MSSA).

[0294] 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 rifamycin analogue 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), formula (V’) as provided herein.

[0295] In one embodiment, the bacterial infection is a Gram-positive bacterial infection.

[0296] In one embodiment, the bacterial infection is a penicillin-resistant bacterial infection.

[0297] In one embodiment, the bacterial infection is a Staphylococcus aureus infection.

[0298] In one embodiment, the bacterial infection is a methicillin-resistant Staphylococcus aureus (MRSA) infection.

[0299] In one embodiment, the bacterial infection is a vancomycin-resistant Staphylococcus aureus (VRSA) infection.

[0300] In one embodiment, wherein the bacterial infection is a methicillin-susceptible Staphylococcus aureus (MSSA) infection.

[0301] In one embodiment, the bacterial infection is an intracellular bacterial infection.

[0302] In one embodiment, the subject is human.

[0303] In one embodiment, the method further comprises administering a second therapeutic agent.

[0304] In one embodiment, the second therapeutic agent is a second antibiotic.

[0305] In one embodiment, the second antibiotic is effective against Staphylococcus aureus.

[0306] In one embodiment, the second antibiotic is selected from aminoglycosides, β-lactams, macrolides, cyclic peptides, tetracyclines, fluoroquinolines, fluoroquinolones, and oxazolidinones.

[0307] 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.

[0308] In one embodiment, the compound is administered to the subject orally, topically, intranasally, intravenously, intramuscularly, or subcutaneously.

[0309] In another aspect, provided herein is an antibody-drug conjugate that comprises an antibody or an antigen-binding fragment of an antibody and further comprises a rifamycin analogue. In some embodiments of the antibody-drug conjugates of the present invention, the antibody or an antigen-binding fragment of the antibody binds to a target associated with an infectious disease. Targets associated with infectious diseases that can be used in the present disclosure include, but are not limited to, macrophage scavenger receptor 1 (MSR1), wall teichoic acid (WTA), Staphylococcus aureus antigens 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.

[0310] In some embodiments, the antibody or an antigen-binding fragment of the antibody binds to MSR1. In some embodiments, the antibody or an antigen-binding fragment of the antibody binds to WTA. In some embodiments, the antibody or an antigen-binding fragment of the antibody binds to protein A.

[0311] In another aspect, provided herein is an antibody-drug conjugate that comprises an antibody or an antigen-binding fragment of an antibody and further comprises a rifamycin analogue, wherein the antibody or an antigen-binding fragment of the antibody binds to a membrane glycoprotein receptor called MSR1. The antibody can be particularly used to target cells expressing MSR1, such as macrophages.

[0312] In another aspect, provided herein is an antibody-drug conjugate that comprises an antibody or an antigen-binding fragment of an antibody and further comprises a rifamycin analogue, wherein the antibody or an antigen-binding fragment of the antibody binds to wall teichoic acid (WTA).

[0313] In another aspect, provided herein is an antibody-drug conjugate that comprises an antibody or an antigen-binding fragment of an antibody and further comprises a rifamycin analogue, wherein the antibody or an antigen-binding fragment of the antibody binds to protein A.

[0314] In another aspect, the present disclosure provides 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 a fragment thereof specifically binds to a target associated with an infectious disease. In some embodiments, the recombinant human antibody or a fragment thereof specifically binds to MSR1, WTA, or protein A. In a related aspect, embodiments relate to a composition that is a combination of an antibody-drug conjugate and a second therapeutic agent, wherein 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 that is advantageously combined with an antibody-drug conjugate comprising an antibody described herein. In one embodiment, the second therapeutic agent is an antibody-drug conjugate that comprises an antibody described herein conjugated to a second drug or second therapeutic agent. Exemplary combination therapies, co-formulations, and ADCs involving antibodies are disclosed elsewhere herein.

[0315] The present disclosure also provides reactive linker-payloads comprising a rifamycin analog, e.g., compounds having a structure according to any embodiment of 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), Formula (B-2) as provided herein that can be used to prepare antibody-drug conjugates comprising an antibody. The present disclosure also provides modified antibodies and modified antigen-binding fragments that can be used to prepare antibody-drug conjugates comprising a rifamycin analog. In some embodiments, the antibody or an antigen-binding fragment thereof specifically binds to a target associated with an infectious disease. In some embodiments, the antibody or an antigen-binding fragment thereof specifically binds to MSR1, WTA, or protein A.

[0316] The present disclosure also provides a method of preventing or inhibiting the growth of bacteria, the method comprising administering an effective amount of an antibody-drug conjugate (ADC) comprising an antibody or an antigen-binding fragment thereof and a rifamycin analog. In some embodiments, the antibody or an antigen-binding fragment thereof specifically binds to a target associated with an infectious disease. In some embodiments, the antibody or an antigen-binding fragment thereof specifically binds to MSR1, WTA, or protein A.

[0317] The present invention also provides a treatment method, which includes administering an effective amount of an ADC to a subject in need thereof, wherein the ADC comprises an antibody or an antigen-binding fragment thereof and a rifamycin analogue. The treatment method includes administering a therapeutically effective amount of a pharmaceutical composition comprising the ADC to a subject, wherein the ADC comprises an antibody or an antigen-binding fragment thereof and a rifamycin analogue. The disorder to be treated is any disease or condition that is recovered (improve), ameliorated, inhibited or prevented by targeting a target related to an infectious disease and / or by administering an antibiotic agent. In some embodiments, the disease or condition is a proliferative disease, a metabolic disease, an inflammation, a neurodegenerative disease or a disease, disorder or condition related to glucocorticoid receptor signaling. In some such embodiments, the side effects associated with administering an unconjugated rifamycin analogue are reduced. The present invention provides the use of the antibodies, antigen-binding portions thereof or ADCs comprising an antibody or an antigen-binding fragment thereof described herein for treating any disease, disorder or condition described herein. In some embodiments, the antibody or an antigen-binding fragment thereof specifically binds to a target related to an infectious disease. In some embodiments, the antibody or an antigen-binding fragment thereof specifically binds to MSR1, WTA or protein A.

[0318] The present invention also provides a treatment method for treating, attenuating or improving a disease, disorder or condition associated with a staphylococcal infection such as Staphylococcus aureus infection and / or for improving at least one symptom associated with such a disease, disorder or condition, the treatment method comprising administering to a subject in need thereof a rifamycin analogue or an ADC comprising an antibody or an antigen-binding fragment thereof and a rifamycin analogue. Such a disease, disorder or condition may be cellulitis, bacteremia, dermonecrosis, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, boil, scalded skin syndrome, food poisoning, pneumonia, surgical site 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 analogue or the ADC comprising an antibody or an antigen-binding fragment thereof and a rifamycin analogue disclosed herein is used for treating and / or preventing Staphylococcus aureus infection of the tissue around the prosthetic joint. In some embodiments, the subject has a catheter, and the rifamycin analogue or the ADC comprising an antibody or an antigen-binding fragment thereof and a rifamycin analogue disclosed herein is used for treating and / or preventing Staphylococcus aureus infection of the catheter and / or the tissue around the catheter. In some embodiments, the subject has a foreign body implanted, and the rifamycin analogue or the ADC comprising an antibody or an antigen-binding fragment thereof and a rifamycin analogue disclosed herein is used for treating and / or preventing Staphylococcus aureus infection of the foreign body and / or the tissue around the foreign body. In some embodiments, the subject has mastitis, and the antibody disclosed herein can be used for treating mastitis. The treatment method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a rifamycin analogue or an ADC comprising an antibody or an antigen-binding fragment thereof and a rifamycin analogue. In some embodiments, the antibody or an antigen-binding fragment thereof specifically binds to a target associated with an infectious disease. In some embodiments, the antibody or an antigen-binding fragment thereof specifically binds to MSR1, WTA or protein A.

[0319] In another aspect, the present disclosure provides an antibody-drug conjugate comprising an antibody or an antigen-binding fragment thereof, which is conjugated to a rifamycin analogue compound of any embodiment of the present disclosure via a linker or through a linker-spacer.

[0320] 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.

[0321] In one embodiment, the antibody or its antigen-binding fragment can comprise: (a) complementarity-determining regions (CDRs) of the heavy-chain variable region (HCVR) that include the amino acid sequences listed in Table 9; and (b) CDRs of the light-chain variable region (LCVR) that include the amino acid sequences listed in Table 9.

[0322] In one embodiment, the anti-MSR1 antibody or its antigen-binding fragment can comprise:

[0323] (i) An HCDR1 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 36, 52, 92, and 284;

[0324] (ii) An HCDR2 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 38, 54, 94, and 286;

[0325] (iii) An HCDR3 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 40, 56, 96, and 288;

[0326] (iv) An LCDR1 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 44, 60, 100, and 292;

[0327] (v) An LCDR2 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 46, 62, 102, and 294; and

[0328] (vi) An LCDR3 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 48, 64, 104, and 296.

[0329] In one embodiment, the anti-WTA antibody or its antigen-binding fragment can comprise: (a) complementarity-determining regions (CDRs) of the heavy-chain variable region (HCVR) that include the amino acid sequences listed in Table 2A; and (b) CDRs of the light-chain variable region (LCVR) that include the amino acid sequences listed in Table 2A.

[0330] In one embodiment, the anti-WTA antibody or its antigen-binding fragment can comprise:

[0331] (i) An HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 470, 476, 482, and 488;

[0332] (ii) An HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 471, 477, 483, and 489;

[0333] (iii) An HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 472, 478, 484, and 490;

[0334] (iv) An LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 467, 473, 479, and 485;

[0335] (v) An LCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 468, 474, 480, and 486; and

[0336] (vi) An LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 469, 475, 481, and 487.

[0337] In one embodiment, an anti-WTA antibody or an antigen-binding fragment thereof may comprise: (a) complementarity-determining regions (CDRs) of a heavy-chain variable region (HCVR) comprising the amino acid sequences listed in Table 2B; and (b) CDRs of a light-chain variable region (LCVR) comprising the amino acid sequences listed in Table 2B.

[0338] In one embodiment, an anti-WTA antibody or an antigen-binding fragment thereof may comprise:

[0339] (i) An HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 502, 508, 514, 520, 526, 532, 538, 544, 550, 556, 562, 568, and 574;

[0340] (ii) An HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 503, 509, 515, 521, 527, 533, 539, 545, 551, 557, 563, 569, and 575;

[0341] (iii) An HCDR3 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 504, 510, 516, 522, 528, 534, 540, 546, 552, 558, 564, 570, 576 and 584;

[0342] (iv) An LCDR1 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 499, 505, 511, 517, 523, 529, 535, 541, 547, 553, 559, 565 and 571;

[0343] (v) An LCDR2 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 500, 506, 512, 518, 524, 530, 536, 542, 548, 554, 560, 566 and 572; and

[0344] (vi) An LCDR3 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 501, 507, 513, 519, 525, 531, 537, 543, 549, 555, 561, 567 and 573.

[0345] In some embodiments, the anti-WTA antibody or an antigen-binding fragment thereof comprises a V205C mutation (EU numbering) in the light chain.

[0346] In one embodiment, the anti-Protein A antibody or an antigen-binding fragment thereof may comprise: (a) complementarity-determining regions (CDRs) of the heavy chain variable region (HCVR), which comprise the amino acid sequences listed in Table 3A; and (b) CDRs of the light chain variable region (LCVR), which comprise the amino acid sequences listed in Table 3A.

[0347] In one embodiment, the anti-Protein A antibody or an antigen-binding fragment thereof may comprise:

[0348] (i) An HCDR1 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 632, 652 and 672;

[0349] (ii) An HCDR2 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 634, 654 and 674;

[0350] (iii) An HCDR3 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 636, 656 and 676;

[0351] (iv) The LCDR1 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 640, 660, and 680;

[0352] (v) The LCDR2 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 642 and 662; and

[0353] (vi) The LCDR3 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 644, 664, and 683.

[0354] In some embodiments, the anti-Protein A antibody or antigen-binding fragment thereof comprises the H435R mutation and the Y436F mutation (EU numbering) in the heavy chain Fc.

[0355] In various embodiments, the antibody or antigen-binding fragment thereof comprises the C103S mutation in the light chain.

[0356] In various embodiments, the antibody or antigen-binding fragment thereof is conjugated to a compound of the present disclosure at position 103 of the light chain.

[0357] In one embodiment, the linker or linker-spacer is selected from:

[0358]

[0359]

[0360] In another aspect, the present disclosure provides an antibody-drug conjugate having a structure according to formula (XVIII):

[0361] Wherein:

[0362] BA is an antibody or antigen-binding fragment thereof;

[0363] RG is a reactive group selected from maleimide, N-hydroxysuccinimide, or succinimide;

[0364] 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, where in each occurrence independently, 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;

[0365] AA is a linking group selected from: valine-citrulline, citrulline-valine, valine-alanine, alanine-valine, valine-glycine or glycine-valine;

[0366] B is absent or is where indicates the atom through which B is bonded to the adjacent group in the formula;

[0367] n is an integer from 1 to 30; and

[0368] PA is a rifamycin analogue according to any embodiment of the present disclosure.

[0369] In one embodiment, is

[0370]

[0371] In one embodiment, is

[0372]

[0373] In one embodiment, is

[0374]

[0375] where, is a bond to an antibody or an antigen-binding fragment thereof. In one aspect, the present disclosure provides an antibody-drug conjugate having a structure according to formula (XIX):

[0376] where:

[0377] BA is an antibody or an antigen-binding fragment thereof;

[0378] RG is selected from maleimide, N-hydroxysuccinimide or succinimide;

[0379] SP 1 and SP 2Independently absent or a spacer group selected from the group consisting of: C 1-6 alkyl, -NH-, -C(O)-, -(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;

[0380] AA is a linking group selected from: valine-citrulline, citrulline-valine, valine-alanine, alanine-valine, valine-glycine or glycine-valine;

[0381] PEG is a polyethylene glycol chain comprising from 1 to 30 polyethylene glycol residues;

[0382] B is absent or wherein indicates the atom through which B is bonded to the adjacent group in the formula;

[0383] n is an integer from 1 to 30;

[0384] m is an integer from 0 to 20;

[0385] and PA is a rifamycin analogue according to any embodiment of the present disclosure.

[0386] In one embodiment, is

[0387]

[0388] In one aspect, the present disclosure provides an antibody-drug conjugate comprising an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof being conjugated to a rifamycin analogue payload via a linker or a linker-spacer, the rifamycin analogue payload having a structure of formula (XX):

[0389]

[0390] wherein:

[0391] X is selected from -O-, -S- and -NR*;

[0392] Za is selected from -OR1 and -RN ;

[0393] R1 is selected from a bond, an aliphatic C1-C 20 hydrocarbon, an aromatic C1-C 20 hydrocarbon, a heteroaromatic C1-C 20 hydrocarbon, a cycloaliphatic C1-C 20 hydrocarbon, a heterocycle C1-C 20 hydrocarbon, and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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;

[0394] R N is selected from:

[0395]

[0396] wherein the symbol represents an attachment point; 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;

[0397] R2, R3, and R4 are independently selected from hydrogen, a straight-chain, branched-chain, 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;

[0398] R aindependently selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 at each occurrence + 、-(C=O)-R*, -CHO, -CO2H, -CO2R*, -SR*, -SO2R* and aliphatic C1-C 20 hydrocarbons, which also contain 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[0399] R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which also contain 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof; and

[0400] wherein the group Za is bonded to a linker.

[0401] It should be understood that the group R1 is a bond (i.e., R1 is absent); or is a divalent group, i.e., R1 can be bonded to the -O- of the rifamycin analogue and to the linker.

[0402] In one embodiment, -OR1 is -O- (i.e., R1 is absent),

[0403] In one embodiment, X is -O-, and -OR1 includes a tertiary amine. In some such embodiments, -OR1 is

[0404] In some embodiments, the antibody-drug conjugate comprising a linker-rifamycin analogue payload includes an ammonium salt having one or more counterions. Any pharmaceutically acceptable counterion can be suitable. For example, in embodiments of the present disclosure, suitable counterions can be anions selected from the following: F - 、Cl - 、Br - 、I - 、OH - 、 - BF4, CF3SO3 - 、hydrogen sulfate, 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, caprate, edetate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, p - hydroxyacetylarsanilate, caproate, hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, mucate, napsylate, caprylate, oleate, pamoate, pantothenate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, tartrate, teoclate, tosylate or triethyliodide.

[0405] In some embodiments, R a is absent. In some embodiments, R a is - OH and is present in one occurrence.

[0406] In one aspect, the present disclosure provides an antibody or an antigen - binding fragment thereof, which is conjugated to a rifamycin analogue via a linker or by a linker - spacer, and the rifamycin analogue has a structure of formula (XXI):

[0407]

[0408] Wherein:

[0409] X is selected from - O -, - S - and - NR* -;

[0410] R5 is selected from a bond; an aliphatic C1 - C 20 hydrocarbon, which further contains 0 - 8 heteroatoms selected from halogen, O, N and S; where Y is C or N;

[0411] R2, R3 and R4 are independently selected from hydrogen, linear, branched or cyclic aliphatic C1 - C20 a hydrocarbon, or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from the group consisting of halogen, O, N, and S; and

[0412] R 5c is a bond or an aliphatic C1-C8 hydrocarbon;

[0413] wherein the group R5 is bonded to the linker.

[0414] It should be understood that the group R5 is a bond (i.e., R5 is absent); or a divalent group, i.e., R5 is capable of bonding to the -O- of rifamycin and to the linker.

[0415] In one embodiment, -OR5 is -O- (i.e., R5 is absent),

[0416] In one embodiment, X is O, and -OR5 includes a tertiary amine. In some such embodiments, -OR5 is

[0417] In any one of the above embodiments, 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.

[0418] In any one of the above embodiments, R2 is methyl, R3 is acetyl, and R4 is hydrogen.

[0419] In any one of the above embodiments, the compound is selected from the group consisting of:

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426] wherein is a bond to the linker.

[0427] In one aspect, the present disclosure provides an antibody-drug conjugate having a structure of formula (XXII):

[0428]

[0429] Wherein:

[0430] BA is an antibody or an antigen-binding fragment thereof;

[0431] L is a linker;

[0432] SP is a spacer selected from the following: Wherein the symbol represents an attachment point; and R', R", and R''' are independently selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups selected from the following: fluorenylmethyloxycarbonyl (F MOC ), and tert-butoxycarbonyl (Boc), or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure;

[0433] Y is C or N;

[0434] R' and R" are independently selected from hydrogen and C 1-6 alkyl each time they appear; and

[0435] X is selected from -O-, -S-, and -NR*-.

[0436] In one embodiment, the antibody is an anti-MSR1 antibody or an antigen-binding fragment thereof, comprising: (a) complementarity-determining regions (CDRs) of the heavy-chain variable region (HCVR) that include the amino acid sequences listed in Table 9; and (b) CDRs of the light-chain variable region (LCVR) that include the amino acid sequences listed in Table 9.

[0437] In one embodiment, the anti-MSR1 antibody or an antigen-binding fragment thereof comprises:

[0438] (i) an HCDR1 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 36, 52, 92, and 284;

[0439] (ii) an HCDR2 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 38, 54, 94, and 286;

[0440] (iii) an HCDR3 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 40, 56, 96, and 288;

[0441] (iv) an LCDR1 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 44, 60, 100, and 292;

[0442] (v) The LCDR2 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 14, 46, 62, 102, and 294; and

[0443] (vi) The LCDR3 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 16, 48, 64, 104, and 296.

[0444] In one embodiment, the anti-MSR1 antibody or an antigen-binding fragment thereof comprises:

[0445] (i) The HCDR1 domain, which comprises the amino acid sequence of SEQ ID NO: 52;

[0446] (ii) The HCDR2 domain, which comprises the amino acid sequence of SEQ ID NO: 54;

[0447] (iii) The HCDR3 domain, which comprises the amino acid sequence of SEQ ID NO: 56;

[0448] (iv) The LCDR1 domain, which comprises the amino acid sequence of SEQ ID NO: 60;

[0449] (v) The LCDR2 domain, which comprises the amino acid sequence of SEQ ID NO: 62; and

[0450] (vi) The LCDR3 domain, which comprises the amino acid sequence of SEQ ID NO: 64.

[0451] In one embodiment, the anti-MSR1 antibody or an antigen-binding fragment thereof comprises the N297Q mutation.

[0452] In one embodiment, the anti-WTA antibody or an antigen-binding fragment thereof may comprise: (a) the complementarity-determining regions (CDRs) of the heavy chain variable region (HCVR), which comprise the amino acid sequences listed in Table 2A; and (b) the CDRs of the light chain variable region (LCVR), which comprise the amino acid sequences listed in Table 2A.

[0453] In one embodiment, the anti-WTA antibody or an antigen-binding fragment thereof may comprise:

[0454] (i) The HCDR1 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 470, 476, 482, and 488;

[0455] (ii) The HCDR2 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 471, 477, 483, and 489;

[0456] (iii) An HCDR3 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 472, 478, 484, and 490;

[0457] (iv) An LCDR1 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 467, 473, 479, and 485;

[0458] (v) An LCDR2 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 468, 474, 480, and 486; and

[0459] (vi) An LCDR3 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 469, 475, 481, and 487.

[0460] In one embodiment, an anti-WTA antibody or an antigen-binding fragment thereof may comprise: (a) complementarity determining regions (CDRs) of a heavy chain variable region (HCVR), which comprise the amino acid sequences listed in Table 2B; and (b) CDRs of a light chain variable region (LCVR), which comprise the amino acid sequences listed in Table 2B.

[0461] In one embodiment, an anti-WTA antibody or an antigen-binding fragment thereof may comprise:

[0462] (i) An HCDR1 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 502, 508, 514, 520, 526, 532, 538, 544, 550, 556, 562, 568, and 574;

[0463] (ii) An HCDR2 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 503, 509, 515, 521, 527, 533, 539, 545, 551, 557, 563, 569, and 575;

[0464] (iii) An HCDR3 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 504, 510, 516, 522, 528, 534, 540, 546, 552, 558, 564, 570, 576, and 584;

[0465] (iv) An LCDR1 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 499, 505, 511, 517, 523, 529, 535, 541, 547, 553, 559, 565, and 571;

[0466] (v) An LCDR2 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 500, 506, 512, 518, 524, 530, 536, 542, 548, 554, 560, 566, and 572; and

[0467] (vi) An LCDR3 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 501, 507, 513, 519, 525, 531, 537, 543, 549, 555, 561, 567, and 573.

[0468] In some embodiments, the anti-WTA antibody or its antigen-binding fragment comprises a V205C mutation (EU numbering) in the light chain.

[0469] In one embodiment, the anti-WTA antibody or its antigen-binding fragment is derived from antibody 4497 described in U.S. Patent Application Publication 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.

[0470] In one embodiment, the anti-WTA antibody or its antigen-binding fragment comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 of SEQ ID No: 568-569-570-565-566-567.

[0471] In some embodiments, the anti-WTA antibody or its antigen-binding fragment comprises three heavy-chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) within the heavy-chain variable region (HCVR) amino acid sequence 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 SEQ ID NO: 585.

[0472] In some embodiments, the anti-WTA antibody or its antigen-binding fragment comprises the HCVR amino acid sequence of SEQ ID NO: 586 and the LCVR amino acid sequence of SEQ ID NO: 585.

[0473] In some embodiments, the anti-WTA antibody comprises the heavy-chain amino acid sequence of SEQ ID NO: 602 and the light-chain amino acid sequence of SEQ ID NO: 587 or SEQ ID NO: 589. In some embodiments, the anti-WTA antibody or its antigen-binding fragment comprises a V205C mutation in the light chain.

[0474] In one embodiment, the anti-Protein A antibody or an antigen-binding fragment thereof can comprise: (a) complementarity-determining regions (CDRs) of the heavy-chain variable region (HCVR) that include the amino acid sequences listed in Table 3A; and (b) CDRs of the light-chain variable region (LCVR) that include the amino acid sequences listed in Table 3A.

[0475] In one embodiment, the anti-Protein A antibody or an antigen-binding fragment thereof can comprise:

[0476] (i) an HCDR1 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 632, 652, and 672;

[0477] (ii) an HCDR2 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 634, 654, and 674;

[0478] (iii) an HCDR3 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 636, 656, and 676;

[0479] (iv) an LCDR1 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 640, 660, and 680;

[0480] (v) an LCDR2 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 642 and 662; and

[0481] (vi) an LCDR3 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 644, 664, and 683.

[0482] In some embodiments, the anti-Protein A antibody or an antigen-binding fragment thereof comprises the H435R and Y436F mutations (EU numbering) in the heavy-chain Fc.

[0483] In one embodiment, the anti-Protein A antibody or an 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 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 SEQ ID NO: 638. In one embodiment, the anti-Protein A antibody or an antigen-binding fragment thereof comprises a set of six CDRs (HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) that includes SEQ ID NO: 632-634-636-640-642-644.

[0484] 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.

[0485] In one embodiment, the anti-Protein A antibody comprises the heavy chain amino acid sequence of SEQ ID NO: 666 and the light chain amino acid sequence of SEQ ID NO: 668. In one embodiment, the anti-Protein A antibody further comprises the H435R mutation and the Y436F mutation (EU numbering) in the heavy chain Fc. In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof is conjugated to a compound of the present disclosure at light chain position 103.

[0486] In various embodiments, the antibody or antigen-binding fragment thereof comprises the C103S mutation in the light chain.

[0487] In various embodiments, the antibody or antigen-binding fragment thereof is conjugated to a compound of the present disclosure at position 103 of the light chain.

[0488] In one embodiment, L is a linker having the following formula: Wherein:

[0489] RG is selected from maleimide, N-hydroxysuccinimide or succinimide;

[0490] SP 1 and SP 2 are independently absent or are 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;

[0491] AA 2-4 is a peptide unit comprising from 2 to 4 amino acids; and

[0492] PEG is a polyethylene glycol chain comprising from 1 to 30 polyethylene glycol residues.

[0493] In one embodiment, AA2-4 is a dipeptide selected from: valine-citrulline, citrulline-valine, valine-alanine, alanine-valine, valine-glycine, glycine-valine, or alanine-glycine, alanine-alanine.

[0494] In one embodiment, AA 2-4 is valine-citrulline.

[0495] In one embodiment, SP is and R’ and R” are each C 1-6 alkyl.

[0496] In one embodiment, SP is and R’ and R” are each methyl.

[0497] In one embodiment, SP 1 and SP 2 are each

[0498] In one embodiment, PEG comprises 8 polyethylene glycol units.

[0499] In one embodiment, BA is an antibody or an antigen-binding fragment thereof;

[0500] L is a linker having the following formula: wherein:

[0501] RG is selected from maleimide or succinimide;

[0502] SP 1 and SP 2 are each

[0503] AA 2-4 is valine-citrulline;

[0504] PEG is a polyethylene glycol chain comprising 8 polyethylene glycol residues;

[0505] SP is and R’ and R” are each methyl; and

[0506] X is -O-.

[0507] In one embodiment, the antibody-drug conjugate has the following structure:

[0508]

[0509] where BA is an antibody or an antigen-binding fragment thereof.

[0510] In another aspect, the present disclosure provides an isolated antibody or an antigen-binding fragment thereof, wherein the antibody or the antigen-binding fragment is directly or conjugated to a payload via a linker or a linker-spacer conjugate, and the payload has a structure selected from the group consisting of:

[0511]

[0512]

[0513]

[0514]

[0515]

[0516] In one embodiment, the payload has a structure selected from:

[0517]

[0518] In one embodiment, the payload is conjugated via a linker having the following structure:

[0519] wherein:

[0520] RG is selected from maleimide or succinimide;

[0521] SP 1 and SP 2 are independently absent or are 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, where 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;

[0522] AA 2-4 is a peptide unit comprising from 2 to 4 amino acids; and

[0523] PEG is a polyethylene glycol chain comprising from 1 to 30 polyethylene glycol residues.

[0524] In one embodiment, AA 2-4 is a dipeptide selected from: valine-citrulline, citrulline-valine, valine-alanine, alanine-valine, valine-glycine, or glycine-valine.

[0525] In one embodiment, AA 2-4 is valine-citrulline.

[0526] In one embodiment, SP is and R’ and R” are each C 1-6 alkyl.

[0527] In one embodiment, SP is and R’ and R” are each methyl.

[0528] In one embodiment, SP 1 and SP 2 are each

[0529] In one embodiment, the PEG comprises 8 polyethylene glycol units.

[0530] In one embodiment, the payload is conjugated via a linker having the following structure:

[0531]

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

[0533]

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

[0535] In one embodiment, the payload is conjugated via a linker-linker payload having the following structure:

[0536]

[0537] wherein is a bond to an antibody or an antigen-binding fragment thereof.

[0538] In one embodiment, an antibody or an antigen-binding fragment thereof that binds to macrophage scavenger receptor 1 (MSR1) comprises: (a) complementarity determining regions (CDRs) of the heavy chain variable region (HCVR) that include the amino acid sequences listed in Table 9; and (b) CDRs of the light chain variable region (LCVR) that include the amino acid sequences listed in Table 9.

[0539] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof comprises:

[0540] (i) An HCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 36, 52, 92, and 284;

[0541] (ii) An HCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 38, 54, 94, and 286;

[0542] (iii) An HCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 40, 56, 96, and 288;

[0543] (iv) An LCDR1 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 44, 60, 100, and 292;

[0544] (v) An LCDR2 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 46, 62, 102, and 294; and

[0545] (vi) An LCDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 48, 64, 104, and 296.

[0546] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof comprises:

[0547] (i) An HCDR1 domain comprising the amino acid sequence of SEQ ID NO: 52;

[0548] (ii) An HCDR2 domain comprising the amino acid sequence of SEQ ID NO: 54;

[0549] (iii) An HCDR3 domain comprising the amino acid sequence of SEQ ID NO: 56;

[0550] (iv) An LCDR1 domain comprising the amino acid sequence of SEQ ID NO: 60;

[0551] (v) An LCDR2 domain comprising the amino acid sequence of SEQ ID NO: 62; and

[0552] (vi) An LCDR3 domain comprising the amino acid sequence of SEQ ID NO: 64.

[0553] In one embodiment, the anti-MSR1 antibody or antigen-binding fragment thereof comprises the N297Q mutation.

[0554] In one embodiment, an anti-WTA antibody or an antigen-binding fragment thereof can comprise: (a) complementarity-determining regions (CDRs) of a heavy-chain variable region (HCVR) that include the amino acid sequences listed in Table 2A; and (b) CDRs of a light-chain variable region (LCVR) that include the amino acid sequences listed in Table 2A.

[0555] In one embodiment, an anti-WTA antibody or an antigen-binding fragment thereof can comprise:

[0556] (i) an HCDR1 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 470, 476, 482, and 488;

[0557] (ii) an HCDR2 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 471, 477, 483, and 489;

[0558] (iii) an HCDR3 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 472, 478, 484, and 490;

[0559] (iv) an LCDR1 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 467, 473, 479, and 485;

[0560] (v) an LCDR2 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 468, 474, 480, and 486; and

[0561] (vi) an LCDR3 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 469, 475, 481, and 487.

[0562] In one embodiment, an anti-WTA antibody or an antigen-binding fragment thereof can comprise: (a) complementarity-determining regions (CDRs) of a heavy-chain variable region (HCVR) that include the amino acid sequences listed in Table 2B; and (b) CDRs of a light-chain variable region (LCVR) that include the amino acid sequences listed in Table 2B.

[0563] In one embodiment, an anti-WTA antibody or an antigen-binding fragment thereof can comprise:

[0564] (i) an HCDR1 domain that includes 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;

[0565] (ii) An HCDR2 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;

[0566] (iii) An HCDR3 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;

[0567] (iv) An 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;

[0568] (v) An LCDR2 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

[0569] (vi) An 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.

[0570] In some embodiments, the anti-WTA antibody or antigen-binding fragment thereof comprises a V205C mutation (EU numbering) in the light chain.

[0571] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof is derived from antibody 4497 described in U.S. Patent Application Publication 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.

[0572] In one embodiment, the anti-WTA antibody or antigen-binding fragment thereof comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 of SEQ ID No: 568-569-570-565-566-567.

[0573] 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 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 SEQ ID NO: 585.

[0574] 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.

[0575] In some embodiments, the anti-WTA antibody comprises the heavy-chain amino acid sequence of SEQ ID NO: 602 and the 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.

[0576] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof may comprise: (a) complementarity-determining regions (CDRs) of the heavy-chain variable region (HCVR) that include the amino acid sequences listed in Table 3A; and (b) CDRs of the light-chain variable region (LCVR) that include the amino acid sequences listed in Table 3A.

[0577] In one embodiment, the anti-Protein A antibody or antigen-binding fragment thereof may comprise:

[0578] (i) an HCDR 1 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 632, 652, and 672;

[0579] (ii) an HCDR 2 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 634, 654, and 674;

[0580] (iii) an HCDR 3 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 636, 656, and 676;

[0581] (iv) an LCDR1 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 640, 660, and 680;

[0582] (v) an LCDR 2 domain that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 642 and 662; and

[0583] (vi) The LCDR3 domain, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 644, 664, and 683.

[0584] In some embodiments, the anti-Protein A antibody or an antigen-binding fragment thereof comprises the H435R mutation and the Y436F mutation (EU numbering) in the heavy-chain Fc.

[0585] In some embodiments, the anti-Protein A antibody or an antigen-binding fragment thereof comprises the H435R mutation and the Y436F mutation (EU numbering) in the heavy-chain Fc.

[0586] In one embodiment, the anti-Protein A antibody or an 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 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 SEQ ID NO: 638. In one embodiment, the anti-Protein A antibody or an antigen-binding fragment thereof comprises a set of six CDRs (HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3), which comprises SEQ ID NO: 632-634-636-640-642-644.

[0587] In one embodiment, the anti-Protein A antibody or an 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.

[0588] In one embodiment, the anti-Protein A antibody comprises the heavy-chain amino acid sequence of SEQ ID NO: 666 and the light-chain amino acid sequence of SEQ ID NO: 668. In one embodiment, the anti-Protein A antibody further comprises the H435R mutation and the Y436F mutation (EU numbering) in the heavy-chain Fc. In one embodiment, the anti-Protein A antibody or an antigen-binding fragment thereof is conjugated to a compound of the present disclosure at light-chain position 103.

[0589] In various embodiments, the antibody or an antigen-binding fragment thereof comprises the C103S mutation in the light chain.

[0590] In various embodiments, the antibody or an antigen-binding fragment thereof is conjugated to a compound of the present disclosure at position 103 of the light chain.

[0591] In one aspect, the present disclosure provides a method for preventing or inhibiting the growth of bacteria, the method comprising administering an effective amount of an antibody-drug conjugate as described herein.

[0592] In one embodiment, the bacterium is a Gram-positive bacterium.

[0593] In one embodiment, the bacterium is a penicillin-resistant bacterium.

[0594] In one embodiment, the bacterium is Staphylococcus aureus.

[0595] In one embodiment, the bacterium is selected from methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), and methicillin-susceptible Staphylococcus aureus (MSSA).

[0596] In one aspect, the present disclosure provides a method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject an effective amount of an antibody-drug conjugate as described herein.

[0597] In one embodiment, the bacterial infection is a Gram-positive bacterial infection.

[0598] In one embodiment, the bacterial infection is a penicillin-resistant bacterial infection.

[0599] In one embodiment, the bacterial infection is a Staphylococcus aureus infection.

[0600] In one embodiment, the bacterial infection is selected from methicillin-resistant Staphylococcus aureus (MRSA) infection, vancomycin-resistant Staphylococcus aureus (VRSA) infection, and methicillin-susceptible Staphylococcus aureus (MSSA) infection.

[0601] In one embodiment, the bacterial infection is an intracellular bacterial infection.

[0602] In one embodiment, the subject is human.

[0603] In one embodiment, the method further comprises administering a second therapeutic agent.

[0604] In one embodiment, the second therapeutic agent is a second antibiotic.

[0605] In one embodiment, the second antibiotic is effective against Staphylococcus aureus.

[0606] In one embodiment, the second antibiotic is selected from aminoglycosides, β-lactams, macrolides, cyclic peptides, tetracyclines, fluoroquinolines, fluoroquinolones, and oxazolidinones.

[0607] In one embodiment, the second antibiotic is selected from clindamycin, novobiocin, retapamulin, daptomycin, sitafloxacin, teicoplanin, triclosan, nalidixic acid, ridinilazole, doxorubicin, ampicillin, vancomycin, imipenem, doripenem, gemcitabine, dalbavancin, and azithromycin.

[0608] In one embodiment, the antibody-drug conjugate is administered to a subject orally, topically, intranasally, intravenously, intramuscularly, or subcutaneously.

[0609] 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, boil, scalded skin syndrome, food poisoning, pneumonia, surgical site 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 an effective therapeutically amount of a compound, antibody-drug conjugate, or pharmaceutical composition as described herein.

[0610] 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

[0611] Figure 1 is a graph of the results of a Staphylococcus aureus growth inhibition assay performed with a rifamycin analog according to the present disclosure.

[0612] Figure 2 is a bar graph of the results of an intracellular killing assay of Staphylococcus aureus performed with a rifamycin analog according to the present disclosure.

[0613] Figure 3 is a graph of the results of an intracellular killing assay of Staphylococcus aureus performed with a rifamycin analog according to the present disclosure.

[0614] Figure 4 is a schematic diagram of a four-day Staphylococcus aureus infection model.

[0615] Figure 5 is a graph of colony forming units of an anti-Staphylococcus aureus ADC according to the present disclosure in an intracellular killing assay using THP cells.

[0616] Figure 6 depicts the mean Staphylococcus aureus renal burden of mice treated with: an isotype control at 2 mg / kg in combination with vancomycin and an anti-WTAAb-antibiotic ncADC (antibody-drug conjugate) according to the present disclosure.

[0617] Figure 7Depict the mean Staphylococcus aureus renal burden in mice treated with: isotype control at 2 mg / kg in combination with vancomycin and anti-protein A Ab-antibiotic ncADC according to the present disclosure.

[0618] Figure 8 Depict the mean Staphylococcus aureus renal burden in mice treated with: isotype control at 5 mg / kg in combination with vancomycin and anti-WT A Ab-antibiotic ncADC according to the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0619] Detailed embodiments of the present disclosure are disclosed herein; however, it should be understood that the disclosed embodiments merely illustrate the present disclosure which can be embodied in various forms. In addition, each example given in connection with the various embodiments of the present disclosure is intended to be illustrative, not restrictive. Thus, the specific structural and functional details disclosed herein should not be construed as restrictive, but merely as a representative basis for teaching those skilled in the art to utilize the present disclosure differently.

[0620] Definition

[0621] Unless otherwise defined, 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.

[0622] As used in this specification and the appended claims, unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" include plural referents. Thus, for example, reference to "a method" includes one or more methods, and / or steps of the type described herein, and / or those that will become apparent to those skilled in the art upon reading this disclosure.

[0623] The term "treat" or "treatment" with respect to a condition, disorder, or disease includes: (1) preventing, delaying, or reducing the likelihood of the occurrence and / or development of at least one clinical or subclinical symptom of the condition, disorder, or disease in a subject who may be predisposed to or susceptible to the condition, disorder, or disease but has not yet experienced or manifested the clinical or subclinical symptoms of the condition, disorder, or disease; or (2) inhibiting the condition, disorder, or disease, i.e., preventing, reducing, or delaying the development of the disease or its recurrence or at least one of its clinical or subclinical symptoms; or (3) alleviating the disease, i.e., causing the regression of at least one of the condition, disorder, or disease or 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.

[0624] 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 diseases (e.g., mice, rats). In one embodiment, the subject is a human.

[0625] As used herein, the term "effective" in relation to a dose or amount means an amount of a compound or pharmaceutical composition sufficient to produce a desired activity upon administration to a subject in need thereof. Note that when combinations of active ingredients are administered, the effective amount of the combination may or may not include the amounts 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 particular drug or drugs used, the mode of administration, and the like.

[0626] The phrase "pharmaceutically acceptable" as used in connection with the compositions of the present disclosure refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and generally produce no adverse reactions when administered to a mammal (e.g., a human). Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeias for use in mammals and more particularly in humans.

[0627] The phrase "therapeutically effective amount" as used herein means an amount that produces a desired effect upon administration. The exact amount will depend on the purpose of the treatment and will be determined by those skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0628] 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.

[0629] "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 compound, material, particle, or method step.

[0630] The compounds of the present disclosure include the compounds generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present disclosure, chemical elements are determined according to the Periodic Table, CAS version, Handbook of Chemistry and Physics, 75th Edition. In addition, 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, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated 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.

[0631] 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 heteroatom such as oxygen, nitrogen, sulfur, and phosphorus. The hydrocarbons of the present disclosure are optionally substituted with oxygen-containing groups, nitrogen-containing groups, sulfur-containing groups, and phosphorus-containing groups or halogens, without limitation. The term hydrocarbon includes straight-chain, branched-chain, cyclic, or polycyclic aliphatic groups as well as aromatic groups and heteroaromatic groups, as discussed in more detail below.

[0632] The term “optionally substituted” has the same meaning as “also contains 0 - n” optional elements in which the element being substituted, where n is an integer, typically from 0 - 20, or from 0 - 10, or from 1 - 3. For example, when an aliphatic hydrocarbon optionally contains one or more heteroatoms, it will have the same meaning as when the aliphatic hydrocarbon also contains 0 - 20 heteroatoms.

[0633] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched), branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic, bicyclic or tricyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic and has a single point of attachment to the remainder of the molecule (also referred to herein as a "carbocycle", "alicyclic" or "cycloalkyl"), and combinations thereof. In some embodiments, the aliphatic group includes a combination (mixture) of a straight-chain aliphatic hydrocarbon and a cyclic aliphatic hydrocarbon. In some embodiments, the aliphatic group includes a combination of a straight-chain aliphatic hydrocarbon and a cyclic aliphatic hydrocarbon. Unless otherwise specified, the aliphatic group contains 1 to 30 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 20 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 10 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains 1 to 6 aliphatic carbon atoms, and in yet other embodiments, the aliphatic group contains 1, 2, 3 or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, straight-chain 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 and the like.

[0634] As used herein, the terms "aliphatic ring", "cycloaliphatic", "carbocyclic", "alicyclic", or "cycloaliphatic" refer to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring structures having from 3 to 14 members as described herein, 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 has 3 to 6 carbons. The aliphatic ring structure also includes an aliphatic ring fused to one or more aromatic or non-aromatic rings (such as decahydronaphthyl or tetrahydronaphthyl), wherein the group or point of attachment is on the aliphatic ring. In some embodiments, the aliphatic cyclic group is bicyclic. In some embodiments, the carbocyclic group is tricyclic. In some embodiments, the aliphatic cyclic group is polycyclic. In some embodiments, the aliphatic polycyclic group is a spiro structure that exhibits a distorted structure (ring system) of two or more rings, wherein two or three rings are joined together by a common atom. In another embodiment, the aliphatic polycyclic group is a fused bicyclic structure, wherein two rings share two adjacent atoms, i.e., the rings share a covalent bond, i.e., the so-called bridgehead atoms are directly connected (e.g., α-thujene and decalin). In some embodiments, the aliphatic polycyclic structure is a bridged bicyclic structure, wherein, for example, two rings share three or more atoms, and the two bridgehead atoms are separated by a bridge containing at least one atom. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be considered a pair of cyclopentane rings, each ring sharing three of the five carbon atoms. In some embodiments, "aliphatic ring" (or "carbocyclic" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon that is completely saturated or contains one or more unsaturated units but is not aromatic and has a single point of attachment to the rest of the molecule, or a C9-C 12 bicyclic hydrocarbon; or a completely saturated or containing one or more unsaturated units but not aromatic C9-C having a single point of attachment to the rest of the molecule 16 tricyclic hydrocarbon.

[0635] As used herein, the term "alkyl" has its 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, the straight-chain alkyl or branched-chain alkyl has from about 1 to 20 carbon atoms in its backbone (e.g., straight-chain is C1-C 20 and branched-chain is C2-C 20), and optionally, from about 1 to 10 carbon atoms or from 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 a ring is monocyclic or bicyclic, or optionally 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).

[0636] As used herein, the term "alkenyl" refers to a hydrocarbyl group having one or more double bonds as defined herein (alkyl group).

[0637] As used herein, the term "alkynyl" refers to a hydrocarbyl group having one or more triple bonds as defined herein.

[0638] The term "heteroalkyl" has its ordinary meaning in the art and refers to an alkyl group in which one or more carbon atoms are replaced by heteroatoms (e.g., halogen, oxygen, nitrogen, sulfur, etc.) as described herein. Examples of heteroalkyl groups include, but are not limited to, alkoxy, poly(ethylene glycol), alkyl-substituted amino, tetrahydrofuranyl, piperidinyl, morpholinyl, etc.

[0639] As used herein, "aromatic" refers to a monocyclic or polycyclic aromatic or heteroaromatic ring that can have from 5 to 20 ring atoms and optionally can have from 1 to 20 heteroatom substituents. In some embodiments, the aromatic group can optionally have from 1 to 10 heteroatom substituents. In some embodiments, the aromatic group can 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 having 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 particular embodiment, the aromatic group is a phenyl group.

[0640] The term "aryl", used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", 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" may 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, anthryl, etc., which may be substituted with one or more substituents. The scope of the term "aryl" as used herein also includes groups in which the aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimido, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc.

[0641] The terms "heteroaromatic hydrocarbon", "heteroaryl(heteroaryl)", and "heteroar-(heteroar-)" when used alone or as part of a larger moiety such as "heteroalkyl" or "heteroalkoxy" 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 π electrons shared in a cyclic array; and in addition to carbon atoms, have from 1 to 5 heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of 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, the heteroaryl is a heteroaryl group such as bipyridyl. As used herein, the terms "heteroaryl" and "heteroar" also include groups in which the heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings, where the group or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic, bicyclic, tricyclic, tetracyclic, and / or otherwise polycyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which includes optionally substituted rings. The term "heteroalkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are independently optionally substituted.

[0642] As used herein, the terms "heterocycle", "heterocyclic group", "heterocyclic moiety", and "heterocycle" are used interchangeably and refer to a stable 5- to 7-membered monocyclic heterocyclic moiety or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and, in addition to carbon atoms, has one or more, preferably 1 to 4, heteroatoms as defined above. When referring to the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen.

[0643] The heterocycle can be attached to its side group at any heteroatom or carbon atom, resulting in a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrroline, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diaza yl, oxaaza yl (oxazepinyl), thiaza yl (thiazepinyl), morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclic group", "heterocyclic ring", "heterocyclic moiety", "heterocyclic portion", 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 cycloaliphatic rings, such as dihydroindolyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. The heterocyclic group can be monocyclic, bicyclic, tricyclic, tetracyclic, and / or otherwise polycyclic. The term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl and heterocyclic moieties are independently optionally substituted.

[0644] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double bond 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.

[0645] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of any basic nitrogen; or a replaceable nitrogen in a heterocycle).

[0646] As used herein, the term "unsaturated" means a moiety having 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 as defined above in which the alkyl includes at least one substituent selected from halogen (e.g., fluorine (F), chlorine (Cl), bromine (Br), or iodine (I)). Examples of haloalkyls include, but are not limited to, -CF3, -CH2CF3, -CCl2F, and -CCl3.

[0647] As used herein, the term "protecting group" refers to a group introduced into a molecule through chemical modification of a functional group such as an amino group or an alcohol, in order to achieve chemoselectivity in subsequent chemical reactions. In one non-limiting embodiment, the protecting group may include 1-chloroethylcarbonyl (ACE), acetyl, benzyl (Bn), benzyloxycarbonyl (CBz), formyl, methylcarbonyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), and fluorenylmethoxycarbonyl (Fmoc). In another non-limiting embodiment, the protecting group includes benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butoxycarbonyl (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 a further non-limiting embodiment, the protecting group includes 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), triisopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ether, TBDMS and TOM; methyl ether and ethoxyethyl ether (EE).

[0648] As used herein, the term "O-amino acid" or "HO-amino acid" refers to an amino acid in which the natural 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 natural amino group at the N-terminus is replaced by an oxygen group or a hydroxyl group, respectively (e.g., where each R is an amino acid side chain). Similarly, the term "O-amino acid residue" or "HO-amino acid residue" refers to the chemical moiety remaining in a compound after a chemical reaction. For example, an "O-amino acid residue" or "HO-amino acid residue" refers to the product of an amide coupling or peptide coupling of an O-amino acid or HO-amino acid with a suitable coupling partner; where, for example, after the amide coupling or peptide coupling of an O-amino acid or HO-amino acid, a water molecule is expelled, resulting in a product having an O-amino acid residue or HO-amino acid residue incorporated therein.

[0649] The naming of an amino acid or amino acid residue is intended to include the L-form of the amino acid, the D-form of the amino acid, or a racemic mixture thereof, without specifying its stereochemistry.

[0650] As described herein, the compounds of the present disclosure may contain "optionally substituted" moieties. Generally, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. 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 the designated group, the substituent may be the same or different at each position. Combinations of substituents contemplated by the present disclosure are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that permit its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0651] Unless otherwise stated, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations at each asymmetric center, the (Z) and (E) double bond isomers, and the (Z) and (E) conformational isomers. Accordingly, individual stereoisomers of the compounds herein, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures, are within the scope of the present disclosure.

[0652] Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0653] In addition, unless otherwise stated, the structures depicted herein are also intended 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 replacing carbon with 11 C- or 13 C- or 14 C-enriched carbon, or replacing oxygen with 17 O- or 18 O-enriched oxygen, or replacing nitrogen with 15 N-enriched nitrogen, compounds having the structures herein are within the scope of the present disclosure.

[0654] It should also be understood that the recitation of one or more method steps does not preclude the presence of additional method steps or intermediate method steps between those expressly recited. Similarly, it should also be understood that the recitation of one or more components in a device or system does not preclude the presence of additional components or intermediate components between those expressly recited.

[0655] Unless otherwise indicated, all crystalline forms of the compounds and their salts of the present disclosure 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, non-solvated or solvated. Examples of 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 substantially does not contain bound water in the lattice structure, i.e., the compound does not form a crystalline hydrate.

[0656] As used herein, "crystalline form" is intended to refer to a particular lattice configuration of a crystalline substance. Different crystalline forms (polymorphic forms) of the same substance typically have different lattices (e.g., unit cells), which is attributed 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 to identify the crystalline form and to determine stability and solvent / water content.

[0657] The crystalline forms of a substance include both solvated (e.g., hydrated) and non-solvated (e.g., anhydrous) forms. Hydrated forms are crystalline forms that contain water in the lattice. Hydrated forms can be stoichiometric hydrates, where water is present in the lattice in a certain water / molecule ratio, such as hemihydrates, monohydrates, dihydrates, etc. Hydrated forms can also be non-stoichiometric, where the water content is variable and depends on external conditions such as humidity.

[0658] 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 the substantially isolated compound, including, for example, other crystalline forms and other substances.

[0659] As used herein, the term "antibiotic" (abx or Abx) includes any molecule that specifically inhibits the growth of or kills microorganisms, such as bacteria, but is non-lethal to the host at the concentrations administered and dosing intervals. In specific aspects, the antibiotic is non-toxic to the host at the administered concentration and dosing interval. Antibiotics effective against bacteria can be broadly classified as bactericidal (i.e., directly kill) or bacteriostatic (i.e., prevent division). Bactericidal antibiotics can be further subdivided into narrow-spectrum or broad-spectrum. Compared to narrow-spectrum antibiotics, which are effective against a smaller range or specific bacterial families, broad-spectrum antibiotics are antibiotics that are effective against a wide range of bacteria, including both Gram-positive and Gram-negative bacteria.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 ertapenem, doripenem, imipenem / cilastatin, meropenem; cephalosporins (first generation) such as cefadroxil, cefazolin, cefalotin, cephalexin; cephalosporins (second generation) such as cefaclor, cefoxitin, cefprozil, cefuroxime; cephalosporins (third generation) such as cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, cefizoxime, 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, roxithromycin, oleandomycin, telithromycin, spectinomycin; monobactams such as aztreonam; penicillins such as amoxicillin, ampicillin, azlocillin, 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, trovafloxacin; sulfonamides such as mafenide, sulfanilamide, sulfacetamide, sulfamethizole, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim-sulfamethoxazole (TMP-SMX); tetracyclines such as demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline; and other agents such as arsphenamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinupristin / dalfopristin, rifampin / rifampicin or tinidazole.

[0660] The term "methicillin-resistant Staphylococcus aureus" (MRSA), optionally referred to as multi-drug 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 (such as methicillin, dicloxacillin, nafcillin, oxacillin, etc.) and cephalosporins. "Methicillin-susceptible Staphylococcus aureus" (MSSA) refers to any strain of Staphylococcus aureus that is susceptible to β-lactam antibiotics.

[0661] The term "minimum inhibitory concentration" ("MIC") refers to the lowest concentration of an antimicrobial agent that will inhibit the visible growth of a microorganism after overnight incubation. Assays for determining MIC are known. One method is described in the Examples below.

[0662] The drug-antibody ratio (DAR) is the average number of drugs conjugated to an antibody or antigen-binding fragment and has an important role in the efficacy, potency, 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 certain 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.

[0663] As used herein, the expressions “MSR1,” “hMSR1,” etc. refer to the human single-pass, trimeric type II transmembrane glycoprotein pattern recognition receptor, which includes (i) the amino acid sequence set forth in NCBI accession number NP_002436.1, (ii) the amino acid sequence set forth in NCBI accession number NP_619729.1, and / or (iii) the amino acid sequence set forth in NCBI accession number NP_619730.1, which represent various types and isotypes of class A macrophage scavenger receptors. The expression “MSR1” includes both monomeric MSR1 molecules and multimeric MSR1 molecules. As used herein, the expression “monomeric human MSR1” means an MSR1 protein or a portion thereof that does not contain or have any domains for multimerization and that exists as a single MSR1 molecule under normal conditions and has no direct physical connection to another MSR1 molecule. An exemplary monomeric MSR1 molecule is the molecule referred to herein as “His-hMSR1,” which includes the amino acid sequence of SEQ ID NO: 393 (see, e.g., Example 25 herein).

[0664] All references herein to proteins, polypeptides, and protein fragments are intended to refer to the human versions of the respective proteins, polypeptides, or protein fragments, unless expressly designated as being from a non-human species. Thus, the expression “MSR1” means human MSR1, unless designated as being from a non-human species, e.g., “mouse MSR1,” “monkey MSR1,” etc.

[0665] 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 a cell in vitro or in vivo such that at least a portion of the MSR1 protein is exposed to the extracellular side of the cell membrane and is accessible to the antigen-binding portion of an antibody. “Cell surface-expressed MSR1” can include an MSR1 protein expressed on the surface of a cell that normally expresses the MSR1 protein or that consists of such an MSR1 protein. Alternatively, “cell surface-expressed MSR1” can include an MSR1 protein expressed on the surface of a cell that does not normally express human MSR1 on its surface but has been engineered to express MSR1 on its surface or that consists of such an MSR1 protein.

[0666] As used herein, the expression "anti-MSR1 antibody" includes monovalent antibodies having 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 of the HCVR / LCVR or CDR sequences listed in Table 9 herein. The expression "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 expression "anti-MSR1 antibody" also includes antibody-radionuclide conjugates (ARCs) comprising an anti-MSR1 antibody or an antigen-binding portion thereof conjugated to a radionuclide.

[0667] The term "wall teichoic acid" (WTA) refers to an anionic sugar-containing polymer covalently attached via a phosphodiester bond to the C6 hydroxyl of N-acetylmuramic acid sugars of peptidoglycan. While the exact chemical structure can vary between organisms, in some embodiments, WTA is ribitol teichoic acid having a repeating unit of 1,5-phosphodiester bonds with D-ribitol and D-alanyl esters at the 2-position and a glycosyl substituent at the 4-position. The glycosyl group can be N-acetylglucosaminyl α(alpha) or β(beta) as present in Staphylococcus aureus. Hydroxyl groups on the alditol / sugar alcohol phosphate repeating unit can be substituted with cationic D-alanine esters and monosaccharides such as N-acetylglucosamine. Hydroxyl substituents can include D-alanyl and α(alpha) or β(beta) GlcNHAc. In one specific embodiment, WTA comprises a compound of the formula:

[0668]

[0669] where the wavy line indicates the attachment site of the repeating linkage unit or glycanol-P or peptidoglycan, where X is D-alanyl or -H; and Y is α(alpha)-GlcNHAc or β(beta)-GlcNHAc.

[0670]

[0671] As used herein, the term "anti-WTA antibody" refers to any antibody that binds wall teichoic acid (WTA), whether WTAα or WTAβ. The terms "anti-wall teichoic acid α antibody" or "anti-WTAα antibody" or "anti-αWTA" or "anti-αGlcNac WTA antibody" are used interchangeably to refer to an antibody that specifically binds WTAα. Similarly, the terms "anti-wall teichoic acid β antibody" or "anti-WTAβ antibody" or "anti-βWTA" or "anti-βGlcNac WTA antibody" are used interchangeably to refer to an antibody that specifically binds WTAβ. The expression "anti-WTA antibody" includes monovalent antibodies having a single specificity, as well as bispecific antibodies comprising a first arm that binds WTA, whether WTAα or WTAβ, and a second arm that binds a second (target) antigen, wherein the anti-WTA arm comprises any HCVR / LCVR or CDR sequence listed in Tables 2A and 2B herein. The expression "anti-WTA antibody" also includes antibody-drug conjugates (ADCs) comprising an anti-WTA antibody or an antigen-binding portion thereof conjugated to a drug or therapeutic agent.

[0672] As used herein, the term "antibody" means any antigen-binding molecule or molecular complex that comprises at least one complementarity determining region (CDR) that specifically binds or interacts with a particular antigen (e.g., MSR1, WTA, or protein A). The term "antibody" includes immunoglobulin molecules that comprise four polypeptide chains interconnected by disulfide bonds, two heavy (H) chains and two light (L) chains, and their multimers (e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V H ) and a heavy chain constant region. The heavy chain constant region comprises three domains, C H 1, C H 2, and C H 3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L ) and a light chain constant region. The light chain constant region comprises one domain (C L 1). The V H and V L regions may be further subdivided into hypervariable regions known as complementarity determining regions (CDRs), which are interspersed with more conserved regions known as framework regions (FRs). Each V H and V L comprises 3 CDRs and 4 FRs arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments, the FRs of the antibody (or its antigen-binding portion) may be the same as the human germline sequence, or may be naturally or artificially modified. Amino acid consensus sequences may be defined based on the juxtaposed analysis of two or more CDRs.

[0673] As used herein, the term "antibody" also includes antigen-binding fragments of whole antibody molecules. As used herein, terms such as "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc. include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody can be derived from whole antibody molecules using any suitable standard techniques, such as proteolytic digestion or recombinant genetic engineering techniques, including manipulation and expression of DNA encoding the variable domains and optionally the constant domains of the antibody, e.g., by cleaving from the whole antibody molecule. Such DNA is known and / or readily obtainable from, for example, commercial sources, DNA libraries (including, e.g., phage antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated chemically or by using molecular biological techniques, e.g., to arrange one or more variable domains and / or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

[0674] 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) minimal recognition units consisting of amino acid residues of hypervariable regions of mimetic antibodies (e.g., isolated complementarity determining regions (CDRs) such as CDR3 peptides) or constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetra-bodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also included within the expression "antigen-binding fragment" as used herein.

[0675] Antigen-binding fragments of an antibody generally will include at least one variable domain. The variable domain can be of any size or amino acid composition and generally will include at least one CDR adjacent to or within a framework having one or more framework sequences. In antigen-binding fragments having a V L domain associated with a V H domain, the V H and V L domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer and contain V H -V H 、V H -V L or V L -V LDimer. Optionally, the antigen-binding fragment of the antibody may comprise a monomeric V H or V L domain.

[0676] In certain embodiments, the antigen-binding fragment of the 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 the antibodies 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 the variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains can be directly connected to each other or can be connected by a full or partial hinge region or linker region. The hinge region can consist 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. Additionally, antigen-binding fragments of the antibodies of the present disclosure can comprise any of the variable and constant domain configurations listed above that are non-covalently associated with each other and / or (e.g., via disulfide bonds) non-covalently associated with one or more monomeric V H or V L homodimers or heterodimers (or other multimers) of domain configurations that are non-covalently associated with the domain.

[0677] Like the intact antibody molecule, the antigen-binding fragment can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies will generally comprise at least two different variable domains, where each variable domain is capable of specifically binding a separate antigen or different epitopes on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be adapted for use in the case of antigen-binding fragments of the antibodies of the present disclosure using conventional techniques available in the art.

[0678] The antibodies of the present disclosure can act via complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC). "Complement-dependent cytotoxicity" (CDC) refers to the lysis of cells expressing an antigen by the 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 expressing Fc receptors (FcR) (e.g., natural killer (NK) cells, neutrophils, and macrophages) recognize an antibody bound to a target cell and thereby cause lysis of the target cell. CDC and ADCC can be measured using assays well known and available in the art. (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 the antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of the antibody can be selected based on whether the antibody is required to mediate cytotoxicity.

[0679] In certain embodiments, the antibodies disclosed herein are human antibodies. As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the present disclosure may include amino acid residues that are not encoded by human germline immunoglobulin sequences, such as in the CDRs and particularly in CDR3 (e.g., mutations introduced in vitro by random or site-specific mutagenesis or in vivo by somatic mutation). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0680] 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 isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant combinatorial human antibody library (described further below), antibodies isolated from an animal transgenic for human immunoglobulin genes (e.g., a mouse) (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, produced, or isolated by any other means that involve splicing of human immunoglobulin gene sequences with other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subject to in vitro mutagenesis (or, when using an animal transgenic for human Ig sequences, in vivo somatic mutagenesis), and thus the amino acid sequences of the V H region and the V L region are such sequences that, while derived from and related to human germline V H and V L sequences, may not naturally exist in the in vivo human antibody germline repertoire.

[0681] Human antibodies can exist in two forms that are related to hinge heterogeneity. In one form, the immunoglobulin molecule comprises a stable four-chain construct of about 150 kDa - 160 kDa, in which the dimers are held together by interchain heavy chain disulfide bonds. In the second form, the dimers are not linked by interchain disulfide bonds and form a molecule of about 75 kDa - 80 kDa (half-antibody) that comprises covalently coupled light and heavy chains. These forms are extremely difficult to separate, even after affinity purification.

[0682] The frequency of occurrence of the second form among the 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 levels typically observed using the human IgG1 hinge. Embodiments disclosed herein include antibodies having one or more mutations in the hinge region, C H 2 or C H 3 region, which can be desirable, for example, in production to increase the yield of the desired antibody form.

[0683] 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 the tissue or cells in which the antibody naturally occurs or is naturally produced, is an "isolated antibody" for the purposes of this disclosure. Isolated antibodies also include antibodies in situ in recombinant cells. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, the isolated antibody can be substantially free of other cellular material and / or chemicals.

[0684] Compared to the corresponding germline sequences from which the antibodies are derived, the antibodies disclosed herein can contain 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. Such mutations can be readily determined by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. Embodiments include antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework regions and / or CDR regions are mutated to the corresponding residues of the germline sequence of the derived antibody, or to the corresponding residues of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue (such sequence variations are collectively referred to herein as "germline mutations"). One of ordinary skill in the art, starting from the heavy and light chain variable region sequences disclosed herein, can readily produce many antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof. In certain embodiments, in V H and / or V LAll framework and / or CDR residues within 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, e.g., only the mutated residues found in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only the mutated residues found in CDR1, CDR2, or CDR3. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residues of a different germline sequence (i.e., a germline sequence different from the germline sequence of the originally derived antibody). Additionally, the antibodies of the present disclosure can contain any combination of two or more germline mutations within the framework region and / or CDR region, e.g., where certain individual residues are mutated to the corresponding residues of a specific germline sequence while certain other residues different from the original germline sequence are retained or mutated to the corresponding residues of a different germline sequence. Once obtained, the one or more desired properties of the antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested, 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.

[0685] Embodiments also include antibodies comprising variants of any HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, embodiments include anti-MSR1 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 9 herein. As another example, embodiments include anti-WTA 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 2A or Table 2B herein. 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.

[0686] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule, which is called a paratope. A single antigen can have more than one epitope. Thus, 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 generated by amino acids that are spatially juxtaposed from different segments of a linear polypeptide chain. Linear epitopes are epitopes generated by adjacent amino acid residues in a polypeptide chain. In some cases, an epitope can include a portion of a sugar, a phosphoryl group, or a sulfonyl group on the antigen.

[0687] The term "substantially identical" or "substantially the same", when referring to a nucleic acid or a fragment thereof, indicates that there is at least about 95%, and more preferably at least about 96%, 97%, 98% or 99% nucleotide sequence identity of nucleotide bases when optimally aligned with appropriate nucleotide insertions or deletions to another nucleic acid (or its complementary strand), 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 that contains an amino acid sequence that is the same as or substantially similar to the polypeptide encoded by the reference nucleic acid molecule.

[0688] When applied to polypeptides, the terms "substantially similar" or "substantially similarity" mean that two peptide sequences share at least 95% sequence identity, even more preferably at least 98% or 99% sequence identity when optimally aligned using default gap weights, such as by the programs GAP or BESTFIT. Preferably, the non-identical residue positions 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). Generally, conservative amino acid substitutions will not significantly alter the functional properties of the protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or similarity can be adjusted upward to correct for the conservative nature of the substitution. Means for making such an adjustment are well known to those of skill in the art. See, e.g., Pearson (1994) Methods Mol. Biol. 24:307-331. Examples of groups of amino acids having side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; (2) aliphatic-hydroxyl 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 having 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 having a non-negative value in the PAM250 log-likelihood matrix.

[0689] The sequence similarity of polypeptides, also known as sequence identity, is typically measured using sequence analysis software. Protein analysis software uses measures of similarity assigned to various substitutions, deletions, and other modifications, including conservative amino acid substitutions, to match similar sequences. For example, the GCG software contains programs such as GAP and BESTFIT, which can be used 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 a wild-type protein and its mutants. See, e.g., GCG version 6.1. Polypeptide sequences can also be compared using FASTA (a program in GCG version 6.1) with default or recommended parameters. FASTA (e.g., FASTA2 and FASTA3) provides an alignment of the best overlapping regions between a query sequence and a search sequence and the percentage of sequence identity (Pearson (2000) supra). When comparing the sequences of the present disclosure to a database containing a large number of sequences from different organisms, another preferred algorithm is the 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.

[0690] As used herein, "O-PEG n " refers to a monovalent moiety attached via a terminal oxygen atom, where n ranges 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.

[0691] 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 (e.g., an antigen).

[0692] As used herein, "linker" refers to a divalent, trivalent, or multivalent moiety that covalently links a binding agent to one or more compounds described herein (e.g., a payload compound and a hydrophilic group as described herein).

[0693] As used herein, "reactive group" or RG refers to a moiety that contains, within its structure, a moiety 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. Exemplary reactive groups for use in the present disclosure include, but are not limited to, those groups that include maleimide, succinimide, N-hydroxysuccinimide (NHS), terminal primary amines, haloacetyl groups, isothiocyanates, thiols, alcohols, ketones, aldehydes, acids, esters, hydrazines, and anilines. RG also includes moieties having the following structures:

[0694]

[0695] wherein X is -O- or -NH- and LG is a leaving group, such as Br.

[0696] 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 acyl halide with an amine. In some instances, amide synthesis conditions refer to reaction conditions suitable for achieving the formation of an amide bond between a carboxylic acid and an amine. In some of these instances, the carboxylic acid is first converted to an activated carboxylic acid prior to the reaction of the activated carboxylic acid with an amine to form an amide. Suitable conditions for achieving amide formation include, but are not limited to, those that utilize reagents to effect the reaction between a carboxylic acid and an amine, the 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′-tetramethyluronium 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 (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).

[0697] In some instances, prior to treating an activated carboxylic acid ester with an amine to form an amide bond, the carboxylic acid is first converted to an activated carboxylic acid ester. In certain embodiments, the carboxylic acid is treated with a reagent. The reagent activates the carboxylic acid by deprotonating the carboxylic acid and then forms a product complex with the deprotonated carboxylic acid due to a nucleophilic attack of the deprotonated carboxylic acid on the protonated reagent. The activated carboxylic acid ester of certain carboxylic acids is then more susceptible to nucleophilic attack by an amine compared to the carboxylic acid prior to activation. This results in the formation of an amide bond. Accordingly, the carboxylic acid is described as being activated. Exemplary reagents include DCC and DIC.

[0698] As used herein, "taurine" refers to a reagent or a group wherein indicates the atom through which taurine is bonded to an adjacent group in the formula.

[0699] Compounds of the present disclosure

[0700] 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 infections in a subject in need of such treatment.

[0701] In one aspect, the present disclosure provides a rifamycin analog compound having the structure of formula (A) or a precursor thereof:

[0702]

[0703] or a pharmaceutically acceptable salt thereof, wherein:

[0704] X is selected from -O- and -NR*;

[0705] 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:

[0706] R1 is selected from hydrogen, R N , aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon 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 the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3+ ,-N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group, and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[0707] R N is selected from:

[0708]

[0709] where the symbol represents an attachment point; and R’, R” and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups such as F MOC and Boc, or where R’ and R” together form an aliphatic cyclic structure, such as an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0710] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[0711] R a is 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 hydrocarbons, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and where R a is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[0712] R bSelected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, and

[0713] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0714] In one aspect, the present disclosure provides rifamycin analogue compounds having a structure of formula (I):

[0715]

[0716] or a pharmaceutically acceptable salt thereof, wherein:

[0717] X is selected from -O- and -NR*-;

[0718] 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[0719] R N is selected from:

[0720]

[0721] where the symbol represents an attachment point; and R’, R” and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including: F MOC and Boc, or where R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0722] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[0723] R a is 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 hydrocarbons, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and where R a is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[0724] R bSelected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, and

[0725] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0726] In one aspect, the present disclosure provides rifamycin analogue compounds having a structure of formula (I'):

[0727]

[0728] or a pharmaceutically acceptable salt thereof, wherein:

[0729] X is selected from -O- and -NR*-;

[0730] 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group, and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[0731] R N is selected from:

[0732]

[0733] where the symbol represents an attachment point; and R’, R” and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including: F MOC and Boc, or where R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0734] 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;

[0735] R a is 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 where R a is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[0736] R bSelected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbons, which also contain 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, and

[0737] R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which also contain 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0738] In an embodiment of the compound 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 is hydrogen.

[0739] 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 is hydrogen.

[0740] In an embodiment of the compound 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 is hydrogen.

[0741] In an embodiment of the compound of formula (A), formula (I) or formula (I'), X is -O-; R1 is an aliphatic C1-C8 hydrocarbon substituted with one or more of -NH2, -NHR*, -N(R*)2, where 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 is hydrogen.

[0742] In an embodiment of the compound 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 is hydrogen.

[0743] In one embodiment, the rifamycin analog compound of the present disclosure has the structure of formula (II):

[0744]

[0745] or a pharmaceutically acceptable salt thereof, wherein:

[0746] X is selected from -O- and -NR*;

[0747] R a is selected from hydrogen, -Cl and -OR*;

[0748] R1 is selected from R N 、hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + 、-N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group;

[0749] R NSelected from:

[0750]

[0751] wherein the symbol represents an attachment point; and R’, R” and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including: F MOC and Boc, or wherein R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0752] R* is independently selected, each time it appears, from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, and it further contains 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0753] In one embodiment, the rifamycin analogue compound of the present disclosure has the structure of formula (II’):

[0754]

[0755] or a pharmaceutically acceptable salt thereof, wherein:

[0756] X is selected from -O- and -NR*-;

[0757] R a is selected from hydrogen and -OR*;

[0758] R1 is selected from R N 、hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group;

[0759] R N Selected from:

[0760]

[0761] wherein the symbol represents an attachment point; and R’, R” and R”’ are independently selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups including: F MOC and Boc, or wherein R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure; and

[0762] 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, and further comprising 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0763] In one embodiment, the rifamycin analog compound of the present disclosure has the structure of formula (III):

[0764]

[0765] or a pharmaceutically acceptable salt thereof, wherein:

[0766] R a is selected from hydrogen and -OR*;

[0767] R5 is selected from R N , aliphatic C1-C 20Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of the following: -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, provided that R5 is not a n-butyl group;

[0768] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof; and

[0769] R N is selected from:

[0770]

[0771]

[0772] wherein the symbol represents an attachment point; and R', R", and R''' are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups including: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure.

[0773] In one embodiment, the rifamycin analog compound of the present disclosure has the structure of formula (III'):

[0774]

[0775] or a pharmaceutically acceptable salt thereof, wherein:

[0776] R a is selected from hydrogen and -OR*;

[0777] R5 is selected from R N , aliphatic C1-C 20 Hydrocarbons, aromatic C1-C20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of the following: -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, provided that R5 is not a n-butyl group;

[0778] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof; and

[0779] R N is selected from:

[0780]

[0781] wherein the symbol represents an attachment point; and R', R", and R''' are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups including: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure.

[0782] In one embodiment, the rifamycin analog compound of the present disclosure has the structure of formula (IV):

[0783]

[0784] or a pharmaceutically acceptable salt thereof, wherein:

[0785] R a is selected from hydrogen and -OR*;

[0786] 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 Hydrocarbons, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of the following: -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;

[0787] R N Selected from:

[0788]

[0789] wherein the symbol represents an attachment point; and R', R", and R''' are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups including: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure; and

[0790] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

[0791] In one embodiment, the rifamycin analog compound of the present disclosure has the structure of formula (IV'):

[0792]

[0793] or a pharmaceutically acceptable salt thereof, wherein:

[0794] R a is selected from hydrogen and -OR*;

[0795] 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 hydrocarbons, heterocyclic C1-C 20Hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted by one or more of the following: -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;

[0796] R N selected from:

[0797]

[0798]

[0799] wherein the symbol represents an attachment point; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0800] R* is independently selected, each time it appears, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0801] In one embodiment, the rifamycin analog compound of the present disclosure has the structure of formula (V):

[0802]

[0803] or a pharmaceutically acceptable salt thereof, wherein:

[0804] X is selected from -O- and -NR*-;

[0805] R a is selected from hydrogen and -OR*;

[0806] 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 hydrocarbons, heterocyclic C1-C20 Hydrocarbons and combinations thereof, each of which further contains 0 - 8 heteroatoms selected from halogen, O, N, and S, and wherein R6 is optionally substituted with one or more of the following: -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R* and combinations thereof, provided that R6 is not a n-butyl group;

[0807] R N Selected from:

[0808]

[0809] wherein the symbol represents an attachment point; and R’, R” and R”’ are selected from hydrogen, C1 - C6 aliphatic hydrocarbons and protecting groups including: F MOC and Boc, or wherein R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0810] R* is independently selected, each time it appears, from hydrogen, aliphatic C1 - C 20 hydrocarbons, aromatic C1 - C 20 hydrocarbons, heteroaromatic C1 - C 20 hydrocarbons, cycloaliphatic C1 - C 20 hydrocarbons, heterocyclic C1 - C 20 hydrocarbons and combinations thereof, which further contains 0 - 8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

[0811] In one embodiment, the rifamycin analogue compound of the present disclosure has the structure of formula (V’):

[0812]

[0813] or a pharmaceutically acceptable salt thereof, wherein:

[0814] X is selected from -O- and -NR*-;

[0815] R a is selected from hydrogen and -OR*;

[0816] R6 is selected from R N , aliphatic C1 - C 20 , aromatic C1 - C 20 , heteroaromatic C1 - C 20 , cycloaliphatic C1 - C 20 , heterocyclic C1 - C 20Hydrocarbons, each of which also contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R6 is optionally substituted with one or more of the following: -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and combinations thereof, provided that R6 is not a n-butyl group;

[0817] R N is selected from:

[0818]

[0819] wherein the symbol represents an attachment point; and R', R", and R''' are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups including: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure; and

[0820] R* is independently selected, each time it appears, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, and it also contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

[0821] In another aspect, the present disclosure provides a rifamycin analogue compound, an intermediate or a precursor thereof having a structure of formula (B):

[0822]

[0823] or a pharmaceutically acceptable salt thereof, wherein:

[0824] X is selected from -O- and -NR*-;

[0825] 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 hydrocarbons, heterocyclic C1-C 20Hydrocarbons and combinations thereof, each of which further contains 0 - 8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + 、-N(R*)-OH、-O-N(R*)2、-N(R*)-O-R*、-CN、-NC、-(C=O)-R*、-CHO、-CO2H、-CO2R*、-(C=O)-S-R*、-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, provided that R1 is not a n-butyl group and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[0826] R N is selected from:

[0827]

[0828] wherein the symbol represents an attachment point; and R’, R” and R”’ are selected from hydrogen, C1 - C6 aliphatic hydrocarbons and protecting groups selected from the following: fluorenylmethyloxycarbonyl (F MOC ) and tert-butoxycarbonyl (Boc), or wherein R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[0829] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1 - C 20 hydrocarbons and -(C=O)-R*, each of which further contains 0 - 8 heteroatoms selected from halogen, O, N, and S;

[0830] R a is 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 also contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[0831] R b is selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which also contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, and

[0832] R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, which also contain 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[0833] In another aspect, the present disclosure provides a rifamycin analog compound having a structure of formula (B-1):

[0834]

[0835] or a pharmaceutically acceptable salt thereof, wherein:

[0836] X is selected from -O- and -NR*-;

[0837] R1 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which also contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3+ 、 -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group;

[0838] R N is selected from:

[0839]

[0840] where the symbol represents an attachment point; and R’, R”, and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups selected from: F MOC and Boc, or where R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure; and

[0841] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, and further comprising 0-8 heteroatoms selected from halogen, O, N, and S, and combinations thereof.

[0842] In another aspect, the present disclosure provides a rifamycin analogue compound having a structure of formula (B-2):

[0843]

[0844] or a pharmaceutically acceptable salt thereof, wherein:

[0845] R N is selected from:

[0846]

[0847] wherein the symbol represents an attachment point; and R', R", and R''' are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups selected from: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure.

[0848] In another aspect, the present disclosure provides a rifamycin analog compound having a structure of formula (B-2):

[0849]

[0850] or a pharmaceutically acceptable salt thereof, wherein:

[0851] R N is wherein the symbol represents an attachment point; and R' and R" are selected from hydrogen and C1-C6 aliphatic hydrocarbons.

[0852] In one embodiment, the rifamycin analog compound has a structure according to the following formula:

[0853]

[0854] or a pharmaceutically acceptable salt thereof.

[0855] In an embodiment of any of the foregoing formulas, 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, each of which further contains 0-3 heteroatoms selected from O and N, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, C 1-3 alkoxy, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -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 a n-butyl group, and when X is -O- and R a is hydrogen, R1 is not hydrogen.

[0856] In an embodiment of any of the foregoing formulas, a compound is provided, wherein R1 is a combination of aliphatic C1-C 20 hydrocarbons and aromatic C1-C 20 hydrocarbons.

[0857] In an embodiment of any of the foregoing formulas, a compound is provided, wherein R1 is a combination of aliphatic C1-C 20 hydrocarbons and heteroaromatic C1-C 20 hydrocarbons.

[0858] In an embodiment of any of the foregoing formulas, a compound is provided, wherein R1 is selected from:

[0859]

[0860] In an embodiment of any of the foregoing formulas, a compound is provided, wherein R1 is an aliphatic C1-C hydrocarbon substituted with one or more of -NH2, -NHR*, -N(R*)2, or -N(R*)-(C=O)-R*. 20 hydrocarbon.

[0861] In an embodiment of any of the foregoing formulas, a compound is provided, wherein R1 is an aliphatic C1-C hydrocarbon substituted with -NH-(C=O)-CH3 or -N(CH3)-(C=O)-CH3. 20 hydrocarbon.

[0862] In an embodiment of any of the foregoing formulas, a compound is provided, wherein R a is hydrogen.

[0863] In an embodiment of any of the foregoing formulas, a compound is provided, wherein R a is -OH.

[0864] In an embodiment of any of the foregoing formulas, a compound is provided, wherein R a is -Cl.

[0865] In an embodiment of any of the foregoing formulas, a compound is provided, wherein R a is -OR*, and R* is selected from aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, and combinations thereof.

[0866] In an embodiment of any of the foregoing formulas, a compound is provided, wherein R N is selected from:

[0867]

[0868]

[0869] wherein the symbol represents an attachment point; and R', R", and R''' are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups including: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure.

[0870] In an embodiment of any of the foregoing formulas, there is provided a compound wherein R N is selected from:

[0871]

[0872] wherein R' is hydrogen, an aliphatic hydrocarbon, or a protecting group, and wherein the symbol represents an attachment point.

[0873] In an embodiment of any of the foregoing formulas, there is provided a compound wherein R* is independently selected, each occurrence, from hydrogen; aliphatic C1-C6 hydrocarbons; aromatic C6-C7 hydrocarbons and combinations thereof, which further contain 0-3 heteroatoms selected from O and N and combinations thereof; aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, and N and combinations thereof.

[0874] Some exemplary non-limiting embodiments of the rifamycin analogue compounds according to the present disclosure are shown in Table 1 below:

[0875] Table 1: Selection of rifamycin analogues according to the present disclosure

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887] In one embodiment, the rifamycin analog compounds of the present disclosure have a structure selected from the group consisting of:

[0888]

[0889]

[0890] or a pharmaceutically acceptable salt thereof.

[0891] In one aspect, the compounds of the present disclosure have a structure of formula (IA):

[0892]

[0893] wherein:

[0894] X is selected from -O-, -S-, and -NR*;

[0895] R1 is selected from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C5-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, aryl C6-C 20 hydrocarbon, heteroaryl C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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,

[0896] 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;

[0897] R a is independently 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 and R b are optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[0898] R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C5-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, aryl C6-C 20 hydrocarbon, heteroaryl C1-C 20 hydrocarbon, and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N, S, and combinations thereof.

[0899] In one embodiment, X is -O-; R1 is aliphatic C1-C3 hydrocarbon; R2 is a methyl group; R3 is Ac (-(C=O)-CH3); R4 is hydrogen; and R a is hydrogen.

[0900] 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 is hydrogen.

[0901] 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 is hydrogen.

[0902] 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 is hydrogen.

[0903] 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 is hydrogen.

[0904] The present disclosure also includes salts of the compounds described herein. As used herein, "salt" refers to a derivative of the disclosed compound in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of salts include, but are not limited to: inorganic acid (e.g., HCl, HBr, H2SO4) salts or organic acid (e.g., acetic acid, benzoic acid, trifluoroacetic acid) salts of basic residues such as amines; alkali metal (e.g., Li, Na, K, Mg, Ca) salts or organic (e.g., trialkylammonium) salts of acidic residues such as carboxylic acids; and the like. The salts of the present application can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base forms 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 both. In some embodiments, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (ACN) can be used.

[0905] This 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 formed, for example, from non-toxic inorganic or organic acids. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Berge, S.M. et al., Journal of Pharmaceutical Science, 1977, 66, 1, 1-19. The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications and are commensurate with a reasonable benefit / risk ratio.

[0906] The preparation of the compounds may include the protection and deprotection of various chemical groups. The need for protection and deprotection and the choice of suitable protecting groups can be readily determined by those skilled in the art. 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. In one non-limiting embodiment, the protecting groups may include 1-chloroethylcarbonyl (ACE), acetyl, benzyl (Bn), benzyloxycarbonyl (CBz), formyl, methylcarbonyl, trifluoroacetyl, tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc).

[0907] The rifamycin analogue compounds depicted herein include all isomeric (e.g., enantiomeric, diastereomeric and geometric (or conformational)) forms of the compounds; for example, the R configuration and the S configuration at each asymmetric center, the (Z) double bond isomers and the (E) double bond isomers, and the (Z) conformational isomers and the (E) conformational isomers. Accordingly, the single stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the compounds of the invention are within the scope of this disclosure. All tautomeric forms of the compounds presented herein are also within the scope of this disclosure.

[0908] The rifamycin analogue compounds described herein also include all compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium, or with 11 C- or 13 C- or 14C-enriched carbon in place of carbon, or 17 O- or 18 O-enriched oxygen in place of oxygen, or 15 N-enriched nitrogen in place of nitrogen, compounds having the structure of the present invention are within the scope of the present disclosure.

[0909] 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 hemihydrate, monohydrate, dihydrate, 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 crystal lattice structure, i.e., the compound does not form a crystalline hydrate.

[0910] Manufacturing method

[0911] In one aspect, the present disclosure provides a method for manufacturing a rifamycin analogue compound having the structure of formula (V):

[0912]

[0913] Wherein: X is selected from -O- and -NR*;

[0914] R6 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof,

[0915] R N is selected from:

[0916]

[0917] Where the symbol represents the attachment point; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including: F MOC and Boc, or where R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0918] R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, which further comprise 0-8 heteroatoms selected from the group consisting of halogen, O, N, and S and combinations thereof,

[0919] The method comprises the following steps:

[0920] (a) Contacting rifamycin S having the following structure:

[0921] with a compound having the structure of formula (VI):

[0922] Contacting,

[0923] wherein X’ is selected from -OH and -NHR*; and

[0924] (b) Treating the product of step (a) with an oxidizing agent.

[0925] In one aspect, the present disclosure provides a method for manufacturing a rifamycin analogue compound having the structure of formula (V’):

[0926]

[0927] wherein: X is selected from -O- and -NR*-;

[0928] 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof,

[0929] R N is selected from:

[0930]

[0931]

[0932] where the symbol represents the point of attachment; and R’, R” and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including: F MOC and Boc, or where R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0933] R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, and it further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof,

[0934] The method comprises the following steps:

[0935] (a) Subjecting rifamycin S having the following structure:

[0936] to contact with a compound having the structure of formula (VI’):

[0937] wherein X’ is selected from -OH and -NHR*; and

[0938]

[0939] (b) Treating the product of step (a) with an oxidizing agent.

[0940] In one aspect, the present disclosure provides a method for manufacturing a compound having the following structure:

[0941]

[0942] The method comprises the following steps:

[0943] (a) Subjecting rifamycin S to contact with a compound having the structure of formula (VII):

[0944] wherein PG is a protecting group;

[0945]

[0946] (b) Treating the product of step (a) with an oxidizing agent; and

[0947] (c) Removing the protecting group PG.

[0948] In one embodiment, the compound of formula (VII) is prepared by removing the protecting group PG’ from the compound of formula (VIII),

[0949]

[0950] wherein the protecting groups PG and PG’ may be the same or different from each other.

[0951] In one embodiment, the compound of formula (VIII) is prepared by subjecting the compound of formula (IX):​​

[0952] by contacting with a compound of formula (X): wherein the protecting groups PG and PG’ may be the same or different from each other.

[0953] In one aspect, the present disclosure provides a method for making a compound having the structure of formula (XI):

[0954]

[0955] 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which also contain 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof, and wherein R6 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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;

[0956] R N is selected from:

[0957]

[0958] where the symbol represents an attachment point; and R’, R” and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including: F MOCand Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0959] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, and it further contains 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0960] The method includes contacting a compound having a structure of formula (XII):

[0961]

[0962] with an alcohol having the structure R6-OH.

[0963] In one aspect, the present disclosure provides a method for manufacturing a compound having a structure of formula (XI'):

[0964]

[0965] wherein: R6 is selected from R N 、aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, and it further contains 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof, and wherein R6 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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;

[0966] R N Selected from:

[0967]

[0968]

[0969] wherein the symbol represents an attachment point; and R’, R” and R”’ are independently selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including: F MOC and Boc, or wherein R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; and

[0970] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which also contain 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0971] The method comprises contacting a compound having a structure of formula (XII’):

[0972]

[0973] with an alcohol having the structure R6-OH.

[0974] In one aspect, the present disclosure provides a method for manufacturing a compound having a structure of formula (XIII):

[0975]

[0976] Wherein: A is selected from a bond (A is absent) or an aliphatic C1-C 20 hydrocarbon;

[0977] R cy is a C3-C 14 cycloaliphatic hydrocarbon which further comprises 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof, and wherein R cy is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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

[0978] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, which further comprises 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0979] The method comprises contacting a compound having a structure of formula (XII):

[0980]

[0981] with an alcohol having the structure R cy -A-OH.

[0982] In one aspect, the present disclosure provides a method of making a compound having a structure of formula (XIII'):

[0983]

[0984] Wherein: A is selected from a bond (where A is absent) or an aliphatic C1-C 20 hydrocarbon;

[0985] R cy is a C3-C 14 cycloaliphatic hydrocarbon which further contains 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof, and wherein R cy is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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

[0986] R* is independently selected, each occurrence, from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof,

[0987] The method comprises contacting a compound having a structure of formula (XII’):

[0988]

[0989] with an alcohol having the structure R cy -A-OH.

[0990] In one aspect, the present disclosure provides a method for manufacturing a compound having a structure of formula (XIV):

[0991]

[0992] Wherein: Y is independently selected from -O- and -NR'R" each time it appears; n is independently an integer from 1 to 6 each time it appears; and R', R", and R''' are each independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon; the method comprises contacting a compound having the structure of formula (XII):

[0993]

[0994] with an alcohol having the structure R″R′N-Y-(CH2) n -Y-(CH2) n -OH.

[0995] In one aspect, the present disclosure provides a method for making a compound having the structure of formula (XIV'):

[0996]

[0997] Wherein: Y is independently selected from -O- and -NR'R" each time it appears; n is independently an integer from 1 to 6 each time it appears; and R', R", and R''' are each independently selected from hydrogen and aliphatic C1-C 20 hydrocarbon; the method comprises contacting a compound having the structure of formula (XII'):

[0998]

[0999] with an alcohol having the structure R″R′N-Y-(CH2) n -Y-(CH2) n -OH.

[1000] 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.

[1001] 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.

[1002] Pharmaceutical Compositions and Dosage Forms

[1003] The present disclosure also provides pharmaceutical compositions comprising the compounds described herein. When used as a medicine, the compounds of the present disclosure can be administered in the form of a pharmaceutical composition, which is a combination of the compounds of the present disclosure and a pharmaceutically acceptable carrier. These compositions can be prepared in a manner well-known in the pharmaceutical art and can be administered by a variety of routes. Such pharmaceutical compositions can be administered systemically. As used herein, the term "systemically" includes parenteral, topical, transdermal, oral, by inhalation / lung, rectal, nasal, buccal and sublingual administration. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intracranial and intraperitoneal administration. In some embodiments, the compounds are administered orally, topically, nasally, intravenously, intramuscularly or subcutaneously in a therapeutically effective amount to treat a bacterial infection (e.g., Staphylococcus aureus infection).

[1004] Pharmaceutical compositions comprising the 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 usually admixed with an excipient, diluted by the excipient or enclosed within a carrier such as, for example, a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, carrier or medium for the active ingredient. Accordingly, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments 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.

[1005] In some embodiments, the pharmaceutical compositions of the present disclosure are in liquid form. By way of non-limiting example, liquid forms include emulsions, solutions, suspensions, syrups, slurries, dispersions, colloids, etc. In some embodiments, the pharmaceutical compositions described herein are in liquid form, semi-solid form or solid (e.g., powder) form. In certain embodiments, the pharmaceutical compositions described herein are in semi-solid form, such as gels, gel matrices, creams, pastes or similar forms. In some embodiments, the semi-solid form includes a liquid vehicle. In some embodiments, the pharmaceutical compositions of the present disclosure are solid dosage forms, such as tablets, granules, sachets or powders. Also provided are pharmaceutical compositions that include the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the form of dissolving tablets, dissolving wafers, capsules or gel capsules. In certain embodiments, the solid dosage forms described herein include a solid vehicle (e.g., as used in tablets) and / or a gaseous vehicle (e.g., as used in DPIs).

[1006] In some embodiments, the composition is in unit dosage form for oral, intranasal, intravenous or other administration to a patient. The term "unit dosage form" refers to a physically discrete unit suitable as a single dose for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.

[1007] 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 the compound actually administered will generally be determined by the physician in view of 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.

[1008] In some embodiments, the compositions or unit dosage forms described herein are administered as emulsions, solutions, suspensions, syrups, slurries, dispersions, colloids, soluble tablets, soluble cachets, capsules, gelatin capsules, gels in semi-solid form, gels in solid form, gel matrices, creams, pastes, tablets, granules, sachets, powders or similar forms. In certain aspects, the compound of formula (I) or a compound having a structure according to any embodiment of formula (A), formula (B), formula (I), formula (I'), formula (II), formula (II'), formula (III), formula (III'), formula (IV), formula (IV'), formula (V), formula (V') as provided herein is administered to an individual at 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 per day or per dose.

[1009] In some embodiments, the compounds of the present disclosure are present in the compositions or unit dose compositions 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 the compound administered daily or in 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 the 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.

[1010] In certain aspects, a compound from 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) is administered per day or per dose to a patient.

[1011] 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 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.

[1012] In the preparation of a formulation, the active compound may be milled to provide a suitable particle size before being combined with other ingredients. If the active compound is substantially insoluble, it may be milled to a particle size less than 200 mesh. If the active compound is substantially water-soluble, the particle size may be adjusted by milling 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, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may additionally include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propylhydroxy-benzoate; sweetening and flavoring agents. The compositions of the present disclosure may be formulated by procedures known in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient.

[1013] To prepare solid compositions such as tablets, the major active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition that contains a homogeneous mixture of the compound of formula I. When these preformulation compositions are referred to as homogeneous, the active ingredient is generally uniformly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. The solid preformulation is then subdivided into unit dosage forms of the above types, containing, for example, from 0.000001 mg to about 2000 mg of the active ingredient of the present application.

[1014] Tablets or pills containing the compound of formula I may be coated or otherwise compounded to provide a dosage form with the advantage of extended action. For example, a tablet or pill may contain an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be released therein in a delayed manner. A variety of materials may be used for such enteric layers or coatings, such materials including a large number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[1015] Liquid forms in which the compounds and compositions of the present application may 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.

[1016] Compositions for inhalation or insufflation include solutions, suspensions, and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for topical or systemic action. The compositions may be nebulized using an inert gas. The nebulized solution may be inhaled directly from the nebulizer device, or the nebulizer device may be attached to a face masks tent or an intermittent positive pressure ventilator. The solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[1017] The compositions administered to a patient may be in the form of the pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The aqueous solutions may be packaged for use as such or lyophilized, and the lyophilized product is combined with a sterile aqueous carrier prior to administration. The pH of the complex product will generally be between 3 and 11, more preferably from 5 to 9. It should be understood that the use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of drug salts.

[1018] The therapeutic dose of the compounds of the present disclosure may vary depending on, for example, the particular use for which treatment is carried out, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present disclosure in the pharmaceutical composition may vary depending on many factors, including the dose, chemical characteristics (e.g., hydrophobicity), and route of administration. The dose may depend on variables such as the type and degree of progression of the disease or disorder, the overall health status of the particular patient, the relative biological potency of the selected compound, the formulation of the excipients, and its route of administration. The effective dose may be extrapolated from dose-response curves derived from in vitro model test systems or animal model test systems.

[1019] 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 includes one or more containers containing a pharmaceutical composition that includes a therapeutically effective amount of a compound of the present disclosure. If desired, such a kit may also contain one or more of the various conventional pharmaceutical kit components, such as, for example, a container having one or more pharmaceutically acceptable carriers, additional containers, 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 components to be administered, administration guidelines, and / or guidelines for mixing the components.

[1020] Delivery devices are 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 the formulation should be compatible to avoid potential leaching or adsorption. The delivery device (or its packaging) may optionally be provided with a label and / or instructions for use indicating that the composition should be used intranasally.

[1021] Method of Use

[1022] 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):

[1023]

[1024] or a pharmaceutically acceptable salt thereof, wherein:

[1025] X is selected from -O-, -S- and -NR*;

[1026] 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:

[1027] R1 is selected from hydrogen, R N , aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group, and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[1028] R N is selected from:

[1029]

[1030] where the symbol represents an attachment point; and R’, R” and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups such as F MOC and Boc, or where R’ and R” together form an aliphatic cyclic structure, such as an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1031] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1032] R a is 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 hydrocarbons, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and where R a is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[1033] 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 the following: -F, -Cl, -Br, -I, -OH, -OR*, and

[1034] R* is independently selected, each time it appears, from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1035] In another aspect, the present disclosure provides a method for preventing or inhibiting the growth of bacteria, the method comprising administering an effective amount of a compound having the structure of formula (I):

[1036]

[1037] or a pharmaceutically acceptable salt thereof, wherein:

[1038] X is selected from -O- and -NR*-;

[1039] R1 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[1040] R N is selected from:

[1041]

[1042] wherein the symbol represents an attachment point; and R’, R” and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including: F MOC and Boc, or wherein R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1043] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1044] R a is 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 hydrocarbons, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[1045] R bSelected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*; and

[1046] R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1047] In another aspect, the present disclosure provides a method for preventing or inhibiting the growth of bacteria, the method comprising administering an effective amount of a compound having the structure of formula (I’):

[1048]

[1049] or a pharmaceutically acceptable salt thereof, wherein:

[1050] X is selected from -O- and -NR*-;

[1051] 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group, and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[1052] R N is selected from:

[1053]

[1054] where the symbol represents an attachment point; and R’, R” and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including: F MOC and Boc, or where R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1055] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1056] R a is 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 hydrocarbons, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and where R a is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[1057] R bSelected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbons, which also contain 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, and

[1058] R* is independently selected, each time it appears, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which also contain 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1059] In another aspect, the present disclosure provides a method for preventing or inhibiting the growth of bacteria, the method comprising administering an effective amount of a compound having the structure of formula (B):

[1060]

[1061] or a pharmaceutically acceptable salt thereof, wherein:

[1062] X is selected from -O- and -NR*-;

[1063] 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which also contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group, and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[1064] R N is selected from:

[1065]

[1066] where the symbol represents an attachment point; and R’, R” and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from: fluorenylmethoxycarbonyl (F MOC ), and tert-butoxycarbonyl (Boc), or where R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1067] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1068] R a is 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 hydrocarbons, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and where R a is optionally substituted with one or more of: -F, -Cl, -Br, -I, -OH, -OR*;

[1069] R bSelected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbons, which also contain 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, and

[1070] R* is independently selected, each time it appears, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which also contain 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1071] 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 rifamycin analogue compound having a structure according to any one of formula (IA), formula (II), formula (II’), formula (III), formula (III’), formula (IV), formula (IV’), formula (V), formula (V’), formula (B-1) and formula (B-2) as provided herein. In one embodiment, the bacteria are Gram-positive bacteria.

[1072] In one embodiment, the bacteria are penicillin-resistant bacteria.

[1073] In one embodiment, the bacteria are Staphylococcus aureus.

[1074] In one embodiment, the bacteria are Staphylococcus aureus strains selected from MRSA and VRSA.

[1075] In one embodiment, the bacteria are methicillin-resistant Staphylococcus aureus (MRSA).

[1076] In one embodiment, the bacteria are vancomycin-resistant Staphylococcus aureus (VRSA).

[1077] In one embodiment, the bacteria are methicillin-susceptible Staphylococcus aureus (MSSA).

[1078] 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 a structure of formula (A):

[1079]

[1080] or a pharmaceutically acceptable salt thereof, wherein:

[1081] X is selected from -O-, -S-, and -NR*;

[1082] 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:

[1083] R1 is selected from hydrogen, R N , aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group, and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[1084] R N is selected from:

[1085]

[1086] wherein represents the point of attachment; and R', R", and R''' are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups including: F MOCand Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1087] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1088] R a is 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 hydrocarbons, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R a is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[1089] R b is selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbons, which further contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, and

[1090] R* is independently selected, each time it appears, from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1091] In 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 an effective amount of a compound having the structure of formula (I):

[1092]

[1093] or a pharmaceutically acceptable salt thereof, wherein:

[1094] X is selected from -O- and -NR*-;

[1095] 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group, and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[1096] R N is selected from:

[1097]

[1098] wherein the symbol represents an attachment point; and R', R" and R'" are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1099] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S;

[1100] 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 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[1101] 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 the following: -F, -Cl, -Br, -I, -OH, -OR*; and

[1102] R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1103] In another aspect, the present disclosure provides a method for treating a bacterial infection in a subject in need of such treatment, the method comprising administering an effective amount of a compound having the structure of formula (I’):

[1104]

[1105] or a pharmaceutically acceptable salt thereof, wherein:

[1106] X is selected from -O- and -NR*-;

[1107] R1 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20Hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + ,-N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[1108] R N is selected from:

[1109]

[1110] wherein the symbol represents an attachment point; and R', R" and R"' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups including: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1111] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S;

[1112] R a is 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 20A hydrocarbon, which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S, and wherein R a is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[1113] R b is selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R*, and aliphatic C1-C 20 A hydrocarbon, which further contains 0 to 3 heteroatoms selected from halogen, O, and S, and wherein R b is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, and

[1114] R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

[1115] In yet another aspect, the present disclosure provides a method for 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):

[1116]

[1117] or a pharmaceutically acceptable salt thereof, wherein:

[1118] X is selected from -O- and -NR*-;

[1119] R1 is selected from hydrogen, R N , aliphatic C1-C 20 hydrocarbon, aromatic C1-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0 to 8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 +, -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group, and when X is -O- and R a is hydrogen, R1 is not hydrogen;

[1120] R N is selected from:

[1121]

[1122] where the symbol denotes an attachment point; and R’, R” and R”’ are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from: fluorenylmethyloxycarbonyl (F MOC ), and tert-butoxycarbonyl (Boc), or where R’ and R” together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure;

[1123] R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S;

[1124] R a is 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 hydrocarbons, which further contains 0-8 heteroatoms selected from halogen, O, N and S, and where R a is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[1125] R bSelected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbons, which further contain 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, and

[1126] R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, which further contain 0-8 heteroatoms selected from halogen, O, N and S and combinations thereof.

[1127] In 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 an effective amount of a rifamycin analog compound having a structure according to any one of Formula (IA), Formula (II), Formula (II’), Formula (III), Formula (III’), Formula (IV), Formula (IV’), Formula (V), Formula (V’), Formula (B-1) and Formula (B-2) as provided herein. In one embodiment, the bacterial infection is a Gram-positive bacterial infection.

[1128] In one embodiment, the bacterial infection is a penicillin-resistant bacterial infection.

[1129] In one embodiment, the bacterial infection is a Staphylococcus aureus infection.

[1130] In one embodiment, the bacterial infection is an intracellular bacterial infection.

[1131] In one embodiment, the subject is human.

[1132] In one embodiment, the method further comprises administering a second therapeutic agent.

[1133] In one embodiment, the second therapeutic agent is a second antibiotic.

[1134] In one embodiment, the second antibiotic is effective against Staphylococcus aureus.

[1135] In one embodiment, the second antibiotic is selected from aminoglycosides, β-lactams, macrolides, cyclic peptides, tetracyclines, fluoroquinolines, fluoroquinolones and oxazolidinones.

[1136] In one embodiment, the second antibiotic is selected from clindamycin, novobiocin, retapamulin, daptomycin, sitafloxacin, teicoplanin, triclosan, nalidixic acid, ridzolamide, doxorubicin, ampicillin, vancomycin, imipenem, doripenem, gemcitabine, dalbavancin, and azithromycin.

[1137] In one embodiment, the compound is administered to a subject orally, topically, intranasally, intravenously, intramuscularly, or subcutaneously.

[1138] 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):

[1139]

[1140] wherein:

[1141] X is selected from -O-, -S-, and -NR*;

[1142] R1 is selected from hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C5-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon 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 the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C═O)-R*, -CHO, -CO2H, -CO2R*, -(C═O)-S-R*, -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, provided that R1 is not a n-butyl group, where when X is -O- and R aWhen it is hydrogen, R1 is not hydrogen;

[1143] R2, R3, and R4 are independently selected from hydrogen, straight-chain, branched-chain, or cyclic aliphatic C1-C 20 hydrocarbons, or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S;

[1144] R a is 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 hydrocarbons, which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R a is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[1145] R b is a hydrogen atom each time it appears; and

[1146] R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons, and combinations thereof, which further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof;

[1147] or a pharmaceutically acceptable salt thereof.

[1148] In yet another aspect, the present disclosure provides a method for 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’):

[1149]

[1150] wherein:

[1151] X is selected from -O-, -S-, and -NR*-;

[1152] R1 is selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20Hydrocarbons and combinations thereof, each of which further contains 0 - 8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + 、-N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group;

[1153] wherein when X is -O- and R a is hydrogen, R1 is not hydrogen;

[1154] R2, R3, and R4 are independently selected from hydrogen, straight-chain, branched-chain, or cyclic aliphatic C1-C 20 hydrocarbons, or -(C=O)-R*, each of which further contains 0 - 8 heteroatoms selected from halogen, O, N, and S;

[1155] R a is 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 hydrocarbons, which further contains 0 - 8 heteroatoms selected from halogen, O, N, and S, and wherein R a is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*;

[1156] R b is a hydrogen atom each time it appears; and

[1157] R* is independently selected from hydrogen, aliphatic C1-C 20Hydrocarbons, aromatic C1-C 20 Hydrocarbons, heteroaromatic C1-C 20 Hydrocarbons, cycloaliphatic C1-C 20 Hydrocarbons, heterocyclic C1-C 20 Hydrocarbons and combinations thereof, which further contain 0-8 heteroatoms selected from the group consisting of halogen, O, N, and S and combinations thereof;

[1158] or a pharmaceutically acceptable salt thereof.

[1159] In one aspect, the present disclosure provides a method for preventing or inhibiting the growth of bacteria, the method 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.

[1160] In another aspect, the present disclosure provides a method for treating a bacterial infection in a subject in need of such treatment, the method 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.

[1161] In one embodiment, the compound, composition, or dosage form is administered to the subject orally, topically, intranasally, intravenously, intramuscularly, or subcutaneously.

[1162] Anti-MSR1 antibody suitable for ADC

[1163] The antibody-drug conjugates described herein may comprise a full-length anti-MSR1 antibody (e.g., an IgG1 or IgG4 antibody), or may comprise only the antigen-binding portion (e.g., Fab, F(ab’)2, or scFv fragments), and may be modified to affect function, e.g., to eliminate residual effector function (Reddy et al., 2000, J. Immunol. 164:1925-1933).

[1164] Embodiments of the antibody-drug conjugates described herein may 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.

[1165] Suitable antibodies or antigen-binding fragments thereof for the antibody-drug conjugates described herein include antibodies or antigen-binding fragments thereof that specifically bind to MSR1 and comprise a HCVR that comprises an amino acid sequence selected from any of the HCVR amino acid sequences listed in Table 9, or an amino acid sequence of a substantially similar sequence thereto having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.

[1166] Additional suitable antibodies or antigen-binding fragments thereof that specifically bind to MSR1 comprise a LCVR that comprises an amino acid sequence selected from any of the LCVR amino acid sequences listed in Table 9, or an amino acid sequence of a substantially similar sequence thereto having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.

[1167] Additional suitable antibodies or antigen-binding fragments thereof that specifically bind to MSR1 comprise a pair of HCVR and LCVR amino acid sequences (HCVR / LCVR) that comprises any HCVR amino acid sequence listed in Table 9 paired with any LCVR amino acid sequence listed in Table 9. Certain embodiments relate to antibody-drug conjugates comprising an antibody or antigen-binding fragment thereof that comprises 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.

[1168] Suitable antibodies or antigen-binding fragments thereof for 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) that comprises an amino acid sequence selected from any of the HCDR1 amino acid sequences listed in Table 9, or an amino acid sequence of a substantially similar sequence thereto having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.

[1169] Additional suitable antibodies or antigen-binding fragments thereof that specifically bind to MSR1 comprise a heavy chain CDR2 (HCDR2) that comprises an amino acid sequence selected from any of the HCDR2 amino acid sequences listed in Table 9, or an amino acid sequence of a substantially similar sequence thereto having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.

[1170] Additional suitable antibodies or antigen-binding fragments thereof that specifically bind to MSR1 comprise a heavy chain CDR3 (HCDR3) that comprises an amino acid sequence selected from any of the HCDR3 amino acid sequences listed in Table 9, or an amino acid sequence of a substantially similar sequence thereto having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[1171] 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) that comprises an amino acid sequence selected from any of the LCDR1 amino acid sequences listed in Table 9, or an amino acid sequence of a substantially similar sequence thereto 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 light chain CDR2 (LCDR2) that comprises an amino acid sequence selected from any of the LCDR2 amino acid sequences listed in Table 9, or an amino acid sequence of a substantially similar sequence thereto having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[1173] Additional suitable antibodies or antigen-binding fragments thereof that specifically bind to MSR1 comprise a light chain CDR3 (LCDR3) that comprises an amino acid sequence selected from any of the LCDR3 amino acid sequences listed in Table 9, or an amino acid sequence of a substantially similar sequence thereto having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[1174] Additional suitable antibodies or antigen-binding fragments thereof that specifically bind to MSR1 comprise a pair of HCDR3 and LCDR3 amino acid sequences (HCDR3 / LCDR3) that comprises any HCDR3 amino acid sequence paired with any LCDR3 amino acid sequence listed in Table 9. Certain embodiments relate to antibodies or antigen-binding fragments thereof that comprise the HCDR3 / LCDR3 amino acid sequence pair contained 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.

[1175] Suitable antibodies or antigen-binding fragments thereof for the antibody-drug conjugates described herein include antibodies or antigen-binding fragments thereof that specifically bind to MSR1 and contain 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 set of HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequences 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.

[1176] In related embodiments, suitable antibodies or antigen-binding fragments thereof that specifically bind to MSR1 contain a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained in an HCVR / LCVR amino acid sequence pair 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 contain the set of HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequences contained in an 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 the 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. Generally, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia methods. See, e.g., 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.

[1177] The present disclosure also provides nucleic acid molecules encoding an anti-MSR1 antibody or a portion thereof, which anti-MSR1 antibody or a portion thereof is used for preparing the antibody-drug conjugates described herein. For example, the present disclosure provides 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.

[1178] The present disclosure also provides 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.

[1179] The present disclosure also provides 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.

[1180] The present disclosure also provides 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.

[1181] The present disclosure also provides 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.

[1182] The present disclosure also provides 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.

[1183] The present disclosure also provides 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 thereto having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[1184] The present disclosure also provides 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 thereto having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[1185] The present disclosure also provides nucleic acid molecules encoding HCVR, wherein HCVR can comprise a set of three CDRs (i.e., HCDR1-HCDR2-HCDR3), wherein the HCDR1-HCDR2-HCDR3 amino acid sequence set is defined by any of the exemplary anti-MSR1 antibodies listed in Table 9.

[1186] The present disclosure also provides nucleic acid molecules encoding LCVR, wherein LCVR can comprise a set of three CDRs (i.e., LCDR1-LCDR2-LCDR3), wherein the LCDR1-LCDR2-LCDR3 amino acid sequence set is defined by any of the exemplary anti-MSR1 antibodies listed in Table 9.

[1187] The present disclosure also provides nucleic acid molecules encoding both HCVR and LCVR, wherein HCVR can comprise the amino acid sequence of any of the HCVR amino acid sequences listed in Table 9, and wherein LCVR can comprise the amino acid sequence of 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 HCVR nucleic acid sequences listed in Table 10, or a substantially similar sequence thereto having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; and a polynucleotide sequence selected from any of the LCVR nucleic acid sequences listed in Table 10, or a substantially similar sequence thereto having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In certain embodiments of this aspect of the present disclosure, the nucleic acid molecule encodes HCVR and LCVR, wherein both HCVR and LCVR are derived from the same anti-MSR1 antibody listed in Table 9.

[1188] The present invention also provides recombinant expression vectors capable of expressing polypeptides comprising the heavy or light chain variable regions of an anti-MSR1 antibody, which anti-MSR1 antibody is used for 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, and methods of producing an antibody or a portion thereof for use in preparing the antibody-drug conjugates described herein by culturing the host cells under conditions permitting the production of the antibody or antibody fragment and recovering the antibody and antibody fragment so produced.

[1189] Suitable anti-MSR1 antibodies for the antibody-drug conjugates described herein include those having a modified glycosylation pattern. In some embodiments, it may be useful to modify to remove undesired glycosylation sites, or to remove antibodies lacking fucose moieties present on the oligosaccharide chain, e.g., to increase antibody-dependent cell cytotoxicity (ADCC) function (see Shield et al. (2002) JBC 277:26733). In other applications, modifications of galactosylation can be made to modify complement-dependent cytotoxicity (CDC).

[1190] According to certain embodiments, the antibody-drug conjugates according to the present disclosure comprise an anti-MSR1 antibody comprising an Fc domain containing one or more mutations, such as mutations that enhance or reduce the binding of the antibody to the FcRn receptor at acidic pH compared to neutral pH. For example, provided herein are antibody-drug conjugates comprising an anti-MSR1 antibody comprising at C of the Fc domain H 2 or C HMutations in Region 3, where the mutations increase the affinity of the Fc domain for FcRn in an acidic environment (e.g., in endosomes with a pH range of about 5.5 to about 6.0). When administered to an animal, such mutations can result in an increased serum half-life of the antibody. Non-limiting examples of such Fc modifications include, for example, modifications at position 250 (e.g., E or Q); positions 250 and 428 (e.g., L or F); 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, the 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).

[1191] For example, embodiments include antibody-drug conjugates comprising an anti-MSR1 antibody, the anti-MSR1 antibody comprising an Fc domain containing one or more pairs of mutations 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 expected to be within the scope of this disclosure.

[1192] Biological properties of the anti-MSR1 antibody

[1193] Embodiments include antibody-drug conjugates that comprise a rifamycin analogue and an antibody and antigen-binding fragments thereof that bind human MSR1 with high affinity. For example, the present disclosure includes antibody-drug conjugates comprising an anti-MSR1 antibody that has a K measured at 25 °C or 37 °C of less than about 10 nM as measured by surface plasmon resonance (e.g., using the assay format defined in Example 25 herein, or a substantially similar assay).D In combination with the extracellular domain of human MSR1 (SEQ ID NO: 688) expressed with an N-terminal nonahistidine tag (e.g., His9-hMSR1). According to certain embodiments, provided are antibody-drug conjugates comprising an anti-MSR1 antibody that has a K 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 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 as measured by surface plasmon resonance at 37 °C (e.g., using the assay format defined in Example 25 herein, or a substantially similar assay). D Binds to human MSR1. In some embodiments, the antibody-drug conjugate comprises an anti-MSR1 antibody disclosed herein that has 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 as measured by surface plasmon resonance at 25 °C (e.g., using the assay format defined in Example 25 herein, or a substantially similar assay). D Binds to human MSR1.

[1194] Embodiments also include antibody-drug conjugates that comprise an antibody and antigen-binding fragments thereof that bind to cynomolgus MSR1 with high affinity. For example, disclosed herein are antibody-drug conjugates comprising an anti-MSR1 antibody that has a K of less than about 20 nM as measured by surface plasmon resonance at 25 °C or 37 °C (e.g., using the assay format defined in Example 25 herein, or a substantially similar assay). DIn combination with the extracellular domain of simian 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, provided are antibody-drug conjugates comprising an anti-MSR1 antibody that has a K 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 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 as measured by surface plasmon resonance at 37°C (e.g., using the assay format defined in Example 25 herein, or a substantially similar assay). D Binds to simian MSR1. In some embodiments, the antibody-drug conjugate comprising the 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 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 as measured by surface plasmon resonance at 25°C (e.g., using the assay format defined in Example 25 herein, or a substantially similar assay). D Binds to simian MSR1.

[1195] The present disclosure also includes antibody-drug conjugates comprising an antibody and antigen-binding fragments thereof that bind to the extracellular domain of human MSR1 (SEQ ID NO: 688) expressed with an N-terminal nine histidine tag (e.g., His9-hMSR1) with a dissociation half-life (t1 / 2) of greater than about 5 minutes as measured by surface plasmon resonance at 25°C or 37°C (e.g., using the assay format defined in Example 25 herein, or substantially similar assays). According to certain embodiments, provided are antibody-drug conjugates 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 as measured by surface plasmon resonance at 37°C (e.g., using the assay format defined in Example 25 herein, or substantially similar assays).

[1196] Embodiments also include antibody-drug conjugates comprising an antibody and antigen-binding fragments thereof that can bind with high affinity to the extracellular domain of cynomolgus 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 the assay format defined in Example 25 herein, or substantially similar assays). DIn combination with HMM-mfMSR1. According to certain embodiments, there are provided antibody-drug conjugates comprising an anti-MSR1 antibody that binds to HMM-mfMSR1 with a K 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, 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 as measured by surface plasmon resonance at 37°C (e.g., using the assay format defined in Example 25 herein or a substantially similar assay). D In combination with HMM-mfMSR1. In some embodiments, the anti-MSR1 antibodies disclosed herein bind to HMM-mfMSR1 with 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 as measured by sur...

Claims

1. A compound having a structure of formula (A), or a pharmaceutically acceptable salt thereof, wherein: X is selected from -O- and -NR*-. 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: 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 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group and when X is -O- and R a is hydrogen, R1 is not hydrogen; R N Selected from: wherein the symbol represents an attachment point; and R', R", and R''' are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups selected from the following: fluorenylmethyloxycarbonyl (F MOC ) and tert-butoxycarbonyl (Boc), or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure; R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons and -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S; 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 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*; R b selected from hydrogen, -F, -Cl, -Br, -I, -OH, -OR*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and aliphatic C1-C 20 hydrocarbon, which also contains 0-3 heteroatoms selected from halogen, O and S, and wherein R b is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, and R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C1-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, and further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

2. The compound according to claim 1, having a structure according to formula (I) or a pharmaceutically acceptable salt thereof, wherein: X is selected from -O- and -NR*-. R1 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C5-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group and that when X is -O- and R a is hydrogen, R1 is not hydrogen; R N Selected from: wherein the symbol represents an attachment point; and R', R" and R''' are selected from hydrogen, C1-C6 aliphatic hydrocarbons and protecting groups selected from: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic or aliphatic polycyclic structure; R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S; 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 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*; 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 the following: -F, -Cl, -Br, -I, -OH, -OR*, and R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C5-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, and further comprises 0 to 8 heteroatoms selected from halogen, O, N and S and combinations thereof.

3. The compound according to claim 1, having a structure according to formula (I') or a pharmaceutically acceptable salt thereof, wherein: X is selected from -O- and -NR*-. R1 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C5-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group and when X is -O- and R a is hydrogen, R1 is not hydrogen; R N Selected from: wherein the symbol represents an attachment point; and R', R", and R''' are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups selected from: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure; R2, R3 and R4 are independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons or -(C=O)-R*, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S; 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 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*; 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 the following: -F, -Cl, -Br, -I, -OH, -OR*, and R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C5-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, and it further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

4. The compound according to claim 1 or 2, having a structure of formula (II) or a pharmaceutically acceptable salt thereof, wherein: X is selected from -O- and -NR*-. R a selected from hydrogen, -Cl and -OR*; R1 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C5-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group; R N Selected from: wherein the symbol represents an attachment point; and R', R", and R''' are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups selected from: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure; and R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C5-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, and further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

5. The compound according to claim 1 or 3, having a structure according to formula (II') wherein: X is selected from -O- and -NR*-. R a selected from hydrogen, -Cl, and -OR*; R1 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C5-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R1 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NO, -NO2, -NO3, -O-NO, -N3, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-OH, -O-N(R*)2, -N(R*)-O-R*, -CN, -NC, -(C=O)-R*, -CHO, -CO2H, -CO2R*, -(C=O)-S-R*, -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, provided that R1 is not a n-butyl group; R N is selected from: wherein the symbol represents an attachment point; and R', R", and R''' are selected from hydrogen, C1-C6 aliphatic hydrocarbons, and protecting groups selected from: F MOC and Boc, or wherein R' and R" together form an aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic structure; and R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C5-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, and it further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

6. The compound according to claim 1, 2 or 4, having a structure according to formula (III) or a pharmaceutically acceptable salt thereof, wherein: R a selected from hydrogen and -OR*; R5 is selected from R N , aliphatic C1-C 20 hydrocarbon, aromatic C5-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R* and combinations thereof, provided that R5 is not a n-butyl group; R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C5-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, and it further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof; and R N Selected from: wherein the symbol represents an attachment point; 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.

7. The compound according to claim 1, 3 or 5, having a structure according to formula (III') or a pharmaceutically acceptable salt thereof, wherein: R a selected from hydrogen and -OR*; R5 is selected from R N , aliphatic C1-C 20 hydrocarbon, aromatic C5-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted by one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R* and combinations thereof, provided that R5 is not a n-butyl group; R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C5-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, and it further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof; and R N Selected from: wherein the symbol represents an attachment point; 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.

8. The compound according to claim 1, 2 or 4, having a structure according to formula (IV) or a pharmaceutically acceptable salt thereof, wherein: R a selected from hydrogen and -OR*; R5 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C6-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R* and combinations thereof; R N Selected from: wherein the symbol represents an attachment point; 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 R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C5-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, and it further contains 0 to 8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

9. The compound according to claim 1, 3 or 5, having a structure according to formula (IV') or a pharmaceutically acceptable salt thereof, wherein: R a selected from hydrogen and -OR*; R5 is selected from R N , hydrogen, aliphatic C1-C 20 hydrocarbon, aromatic C6-C 20 hydrocarbon, heteroaromatic C1-C 20 hydrocarbon, cycloaliphatic C1-C 20 hydrocarbon, heterocyclic C1-C 20 hydrocarbon and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R5 is optionally substituted with one or more of the following: -F, -Cl, -Br, -I, -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -(C=O)-R*, -CHO, -CO2H, -CO2R* and combinations thereof; R N Selected from: and wherein the symbol represents an attachment point; 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 R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C5-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, and it further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

10. The compound according to claim 1, 2 or 4, having a structure according to formula (V) or a pharmaceutically acceptable salt thereof, wherein: X is selected from -O- and -NR*-. R a selected from hydrogen and -OR*; R6 is selected from R N , aliphatic C1-C 20 hydrocarbons, aromatic C5-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, each of which further contains 0-8 heteroatoms selected from halogen, O, N, and S, and wherein R6 is optionally substituted by one or more of the following: -OH, -OR*, -NH2, -NHR*, -N(R*)2, -N(R*)3 + , -N(R*)-(C=O)-R*, -(C=O)-R*, -CHO, -CO2H, -CO2R* and combinations thereof, provided that R6 is not a n-butyl group; R N Selected from: and wherein the symbol represents an attachment point; 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 R* is independently selected from hydrogen, aliphatic C1-C 20 hydrocarbons, aromatic C5-C 20 hydrocarbons, heteroaromatic C1-C 20 hydrocarbons, cycloaliphatic C1-C 20 hydrocarbons, heterocyclic C1-C 20 hydrocarbons and combinations thereof, and it further contains 0-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

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