Rifamycin derivatives for the treatment of diseases

Abstract

The present disclosure relates to compounds and pharmaceutical compositions comprising same for the treatment, amelioration, and / or prevention of disease. In some embodiments, the disease is a bacterial infection. In some embodiments, the infection is caused by Acinetobacter spp., Clostridium spp., Enterococcus spp., Hemophilus spp., Legionella spp., Mycobacterium spp. (tuberculous and nontuberculous mycobacteria), Neisseria spp., Staphylococcus spp., Streptococcus spp., Listeria monocytogenes, Moraxella catarrhalis, Bacillus spp., Bacteroides spp., or any of the following: spp., Gardnerella vaginalis, Lactobacillus spp., Mobiluncus spp., Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis, and / or Toxoplasma gondii. Preferably, the bacterial infection is caused by a bacterium belonging to the genus Staphylococcus aureus (S. aureus), A. baumannii (A. baumannii), E. faecium (E. faecalis), Staphylococcus epidermidis (S. epidermidis), Streptococcus pneumoniae (S. pneumoniae), Group A hemolytic streptococcus (S. pyogenes), Haemophilus influenzae (H. influenzae), M. abscessus (M. abscessus), M. tuberculosis (M. tuberculosis) and / or M. smegmatis (M.smegmatis), even more preferably the bacterial infection is caused by one or more bacteria belonging to the genus Acinetobacter, even more preferably by A. baumannii, even more preferably by A. baumannii having one or more resistance mechanisms to rifamycins, such as rifabutin and / or rifampicin.

Description

[Technical field]

[0001] The present disclosure relates to compounds and pharmaceutical compositions comprising same for the treatment, amelioration, and / or prevention of disease. In some embodiments, the disease is a bacterial infection. In some embodiments, the bacteria is selected from the group consisting of Acinetobacter spp., Clostridium spp., Enterococcus spp., Hemophilus spp., Legionella spp., Mycobacterium spp., Neisseria spp., Staphylococcus spp., Streptococcus spp., Listeria monocytogenes, Moraxella catarrhalis, Bacillus spp., Bacteroides spp., Gardnerella vaginalis, and the like. vaginalis, Lactobacillus spp., Mobiluncus spp., Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis, and / or Toxoplasma gondii. In some embodiments, the infection is caused by a bacterium of the genus Acinetobacter. [Background technology]

[0002] Rifamycins, such as rifabutin, are active against Clostridium spp., Enterococcus spp., Haemophilus spp., Legionella spp., Mycobacterium spp. (tuberculous and nontuberculous mycobacteria), Neisseria spp., Staphylococcus spp., Streptococcus spp., Listeria monocytogenes, Moraxella catarrhalis, Bacillus spp., Bacteroides spp., Gardnerella vaginalis, and other bacteria of the genera ... Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus spp., Enterococcus It is a known antibiotic with activity against a broad spectrum of pathogens, including Bacillus vaginalis, Lactobacillus spp., Mobiluncus spp., Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis, and / or Toxoplasma gondii (Kunin, Clin. Infect. Dis., 1996; Farr and Mandell, Med. Clin. North. Am., 1982; Thornsberry et al., Rev. Infect. Dis., 1983; Hoover et al., Diagn. Microbiol. Infect. Dis., 1993; Kerry et al., Diagn. Microbiol. Infect. Dis., 1994; Kerry et al., Diagn. Microbiol. Infect. Dis., 1994). al., J. Antimicrob. Chemother., 1975).

[0003] Rifabutin has recently been shown to have potent in vitro and in vivo activity against Mycobacterium abscessus (Aziz et al., Antimicrob. Agents Chemother., 2017; Dick et al., Antimicrob. Agents Chemother., 2020) and Acinetobacter baumannii (Luna et al., Nat. Microbiol., 2020; Trebosc et al., Drug Discov. Today, 2021; Trebosc et al., J. Antimicrob. Chemother., 2020). However, pathogens such as A. baumannii can exhibit reduced susceptibility to rifabutin through mechanisms such as mutations in the RNA polymerase β-subunit (RpoB) gene (Trebosc et al., J. Antimicrob. Chemother., 2020). al., J. Antimicrob. Chemother., 2020). Thus, there is a need for more effective rifamycins for the treatment of bacterial infections, such as those caused by bacteria of the genus Acinetobacter. Summary of the Invention

[0004] In a first aspect, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt, tautomer, solvate, hydrate, enantiomer or diastereomer thereof: [ka] During the ceremony, X 1 But -CR 1 R 1A - and X 2 but independently, in each occurrence, -CR 2 R 2A -, -NR 2B -, -O-, and a chemical bond; X 3but independently, in each occurrence, -CR 3 R 3A -, -NR 3B -, -O-, and a chemical bond; X 4 But -CR 4 R 4A - and X 5 but independently, in each occurrence, -CR 5 R 5A -, -NR 5B -, -O-, and a chemical bond; X 6 but independently, in each occurrence, -CR 6 R 6A -, -NR 6B -, -O-, and a chemical bond; R 51 is independently, at each occurrence, selected from: -H, -C1-C6 alkyl, and -C3-C8 cycloalkyl; R 1 , R 1A , R 2 , R 2A , R 3 , R 3A , R 4 , R 4A , R 5 , R 5A , R 6 , and R 6A is independently, at each occurrence, selected from: -H, -C1-C6 alkyl, and -C1-C6 alkoxy; R 2B , R 3B , R 5B , and R 6B is independently, at each occurrence, selected from: -H, and -C1-C6 alkyl; or R 1 , R 1A , R 2 , R 2A , R 2B , R 3 , R 3A , R 3B , R 4 , R 4A , R 5 , R 5A , R 5B, R 6 , R 6A , R 6B , and R 51 together with the atom to which they are attached, R 1 , R 1A , R 2 , R 2A , R 2B , R 3 , R 3A , R 3B , R 4 , R 4A , R 5 , R 5A , R 5B , R 6 , R 6A , R 6B , and R 51 can independently combine with any other member of to form a first bridged C4-C8 cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or heterocycloalkyl optionally substituted by one or more -C1-C6 alkyl or -C1-C6 alkoxy; R 1 , R 1A , R 2 , R 2A , R 2B , R 3 , R 3A , R 3B , R 4 , R 4A , R 5 , R 5A , R 5B , R 6 , R 6A , and R 6B taken together to form the first bridged cycloalkyl ring, or the first bridged heterocycloalkyl ring, the first bridged cycloalkyl, or the first bridged heterocycloalkyl, independently, is R 51 together with -C1-C6 alkyl, -C1-C6 alkoxy, and However, R 1 , R 1A , R2 , R 2A , R 2B , R 3 , R 3A , R 3B , R 4 , R 4A , R 5 , R 5A , R 5B , R 6 , R 6A , R 6B , and R 51 at least two of X are taken together to form a bridged cycloalkyl or heterocycloalkyl; or 2 , X 3 , X 5 , and X 6 is a chemical bond.

[0005] In one aspect, the invention provides a pharmaceutical composition comprising at least one compound described herein, or a pharma- ceutically acceptable salt, tautomer, solvate, or hydrate thereof, and a pharma- ceutically acceptable excipient.

[0006] In one aspect, the present invention provides a method for the treatment of a disease, preferably an infection, more preferably a bacterial infection, in a subject, more preferably an infection of the genus Acinetobacter spp., Clostridium spp., Enterococcus spp., Haemophilus spp., Legionella spp., Mycobacterium spp. (tuberculous and non-tuberculous mycobacteria), Neisseria spp., Staphylococcus spp., Streptococcus spp., Listeria monocytogenes, Moraxella catarrhalis, Bacillus spp. spp., Bacteroides spp., Gardnerella vaginalis, Lactobacillus spp., Mobiluncus spp., Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis, and / or Toxoplasma gondii. gondii, more preferably caused by bacteria belonging to the group S. aureus, A. baumannii, E. faecium, E. faecalis, S. epidermidis, S. pneumoniae, S. pyogenes, H. influenzae, M. abscessus, M. tuberculosis, and / or M. smegmatis.In one embodiment, a compound or pharmaceutical composition as described herein is provided for use in a method of preventing and treating a bacterial infection caused by one or more bacteria belonging to the genus Acinetobacter, even more preferably A. baumannii, even more preferably A. baumannii having one or more resistance mechanisms to a rifamycin, such as rifabutin and / or rifampicin.

[0007] The compounds of the present invention are novel rifamycin derivatives that contain a novel modified spiro-imidazole moiety. Antibiotics of the rifamycin class (e.g. Clostridium spp., Enterococcus spp., Haemophilus spp., Legionella spp., Mycobacterium spp. (tuberculous and nontuberculous mycobacteria), Neisseria spp., Staphylococcus spp., Streptococcus spp., Listeria monocytogenes, Moraxella catarrhalis, Bacillus spp., Bacteroides spp., Gardnerella vaginalis, In addition to exhibiting broad antibacterial activity profiles against A. vaginalis, Lactobacillus spp., Mobiluncus spp., Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis, and / or Toxoplasma gondii, the compounds of the present invention further exhibit enhanced antibacterial activity against strains of the genus Acinetobacter. In particular, the compounds of the present invention have shown activity against strains of A. baumannii that have one or more resistance mechanisms to rifamycins, such as rifampicin and / or rifabutin. Further features and advantages of the compounds of the present invention are described in the detailed description below. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 shows the overlay of the ROESY and HSQC spectra of compound 13B. [Diagram 2] FIG. 2 shows the stereochemical attributes of the tropane moiety of compound 13B. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present disclosure relates to a method for treating bacterial infections, preferably Acinetobacter spp., Clostridium spp., Enterococcus spp., Hemophilus spp., Legionella spp., Mycobacterium spp. (tuberculous and nontuberculous mycobacteria), Neisseria spp., Staphylococcus spp., Streptococcus spp., Listeria monocytogenes, Moraxella catarrhalis, Bacillus spp., Bacteroides ... spp., Gardnerella vaginalis, Lactobacillus spp., Mobiluncus spp., Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis, and / or Toxoplasma gondii. gondii, more preferably Staphylococcus aureus (S. aureus), A. baumannii (A. baumannii), E. faecium (E. faecalis), Staphylococcus epidermidis (S. epidermidis), Streptococcus pneumoniae (S. pneumoniae), Group A hemolytic streptococcus (S. pyogenes), Haemophilus influenzae (H. influenzae), M. abscessus (M. abscessus), M. tuberculosis (M. tuberculosis), and / or M. smegmatis (M.The present invention provides novel rifamycin derivatives containing novel modified spiro-imidazole moieties that are effective in treating bacterial infections caused by A. smegmatis, even more preferably caused by one or more bacteria belonging to the genus Acinetobacter, even more preferably caused by A. baumannii, even more preferably caused by A. baumannii having one or more resistance mechanisms to rifamycins, such as rifabutin and / or rifampicin.

[0010] Details of this technology are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0011] definition 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 invention belongs.

[0012] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0013] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0014] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be attached to other substituents (e.g., a heteroatom or an alkoxy group). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., purely hydrocarbon). Alternatively, the same optionally substituted alkyl group can have a substituent other than hydrogen. For example, it can be attached at any point along the chain, for example, to an alkoxy group or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety can potentially contain other functional groups, but does not necessarily have additional functional groups.

[0015] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon. A C1-C6 alkyl group contains 1 to 6 carbon atoms. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.

[0016] The term "alkylene" or "alkylenyl" as used herein refers to a biradical of a straight or branched hydrocarbon chain derived from an alkyl, as defined herein, in which one hydrogen of said alkyl is broken to produce a secondary radical of said alkylene. Examples of alkylene are, by way of example, -CH-, -CH-CH-, -CH(CH)-, -CH-CH-CH-, -CH(CH)-CH-, or -CH(CHCH)-.

[0017] The term "cycloalkyl" means a monocyclic saturated carbocyclic ring containing 3 to 8 carbon atoms. A C3-C6 cycloalkyl contains 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, and cyclooctanyl.

[0018] The term "heterocyclyl" or "heterocycloalkyl" or "heterocycle" refers to a 3-8 membered ring containing carbon and heteroatoms taken from oxygen, nitrogen, sulfur, and / or phosphorus (preferably oxygen and nitrogen), where the ring does not contain delocalized π electrons (aromaticity) shared between ring carbons or heteroatoms. In preferred embodiments, the heterocycloalkyl ring is fully saturated. Heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxanyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl. In some embodiments, a heterocyclyl or heterocycloalkyl ring is bridged, eg, formed together with the atom or substituent to which it is attached, into a bicyclic or tricyclic ring.

[0019] "C1-C6 alkoxy" as used herein refers to a substituted hydroxyl of formula (-OR') where R' is an optionally substituted C1-C6 alkyl as defined herein and the oxygen moiety is directly attached to the parent molecule, and thus the term "C1-C6 alkoxy" as used herein refers to straight or branched chain C1-C6 alkoxy, which may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight or branched chain pentoxy, straight or branched chain hexyloxy. Preferred alkoxy is C1-C4 alkoxy, and C1-C3 alkoxy.

[0020] The term "pharmaceutical acceptable salt" as used herein refers to a salt that has the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic or organic acids known to those skilled in the art (P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor); Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition, March 2011, Wiley-VCH, ISBN: 978-3-90639-051-2). Representative "pharmaceutically acceptable salts" of the compounds of the present invention include, for example, acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavularate, dihydrochloride, edetate, edisylate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, hydroiodide, sethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mannose, tetrahydrofuran ... For example, water soluble and water insoluble salts include deltaate, mesylate, methyl bromide, methyl nitrate, methyl bromide, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methylene-bis-2-hydroxy-3-naphthoate, ainbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, acetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theocrate, tosylate, triethiodide, and valerate salts.

[0021] The term "stereoisomers" refers to a set of compounds that have the same number and kinds of atoms and share the same bond connectivity between those atoms, but differ in three-dimensional structure. The term "stereoisomer" refers to any member of this set of compounds.

[0022] The term "diastereomer" refers to a set of stereoisomers that are not superimposable by rotation around a single bond. For example, compounds containing cis- and trans-double bonds, endo- and exo-substitution on a bicyclic ring system, and multiple stereocenters with different relative configurations are considered to be diastereomers. The term "diastereomer" refers to any member of this series of compounds. In some examples presented, the synthetic route may produce a single diastereomer, or a mixture of diastereomers. In such cases, all possible diastereomers are contemplated by the present invention.

[0023] The term "enantiomer" refers to a pair of stereoisomers of a compound that are non-superimposable mirror images of one another. The term "enantiomer" refers to a single member of the pair of stereoisomers. The term "racemic" refers to a 1:1 mixture of a pair of enantiomers.

[0024] The term "tautomers" refers to a set of compounds that have the same number and type of atoms but differ in bond connectivity and are in equilibrium with each other. A "tautomer" is a single member of this series of compounds. Typically, a single tautomer is depicted, but it is understood that this single structure is meant to represent all possible tautomers that may exist. An example includes enol-ketone tautomerism. When a ketone is depicted, it is understood that both the enol form and the ketone form are part of the disclosure.

[0025] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. For the purposes of this disclosure, such a solvent does not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are typically referred to as "hydrates". Hydrates include compositions that contain stoichiometric amounts of water and compositions that contain variable amounts of water.

[0026] An "effective amount" when used in reference to a compound is an amount effective to treat or prevent a disease of interest as described herein.

[0027] The term "carrier" as used in this disclosure encompasses excipients and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in the transfer or transport of a pharmaceutical agent from one organ or part of the body to another organ or part of the body of a subject.

[0028] The term "treating" with respect to a subject refers to improving at least one symptom of the subject's disorder. Treatment includes curing, ameliorating, or at least partially alleviating the disorder.

[0029] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise specified.

[0030] The terms "administer," "administering," or "administration" as used in this disclosure refer to either administering a disclosed compound, or a pharma- ceutically acceptable salt of a disclosed compound, or a composition comprising same, directly to a subject.

[0031] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate such as a monkey, chimpanzee, baboon, or rhesus monkey, preferably a human.

[0032] Compounds of the Invention In a first aspect, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt, tautomer, solvate, hydrate, enantiomer or diastereomer thereof: [ka] During the ceremony, X 1 But -CR 1 R 1A - and X 2 but independently, in each occurrence, -CR 2 R 2A -, -NR 2B -, -O-, and a chemical bond; X 3 but independently, in each occurrence, -CR 3 R 3A -, -NR 3B -, -O-, and a chemical bond; X 4 But -CR 4 R 4A - and X 5 but independently, in each occurrence, -CR 5 R 5A -, -NR 5B -, -O-, and a chemical bond; X 6 but independently, in each occurrence, -CR 6 R 6A -, -NR 6B -, -O-, and a chemical bond; R 51 is independently, at each occurrence, selected from: -H, -C1-C6 alkyl, and -C3-C8 cycloalkyl; R 1 , R 1A , R 2 , R 2A , R 3 , R 3A , R 4 , R 4A , R 5 , R 5A , R6 , and R 6A is independently, at each occurrence, selected from: -H, -C1-C6 alkyl, and -C1-C6 alkoxy; R 2B , R 3B , R 5B , and R 6B is independently, at each occurrence, selected from: -H, and -C1-C6 alkyl; or R 1 , R 1A , R 2 , R 2A , R 2B , R 3 , R 3A , R 3B , R 4 , R 4A , R 5 , R 5A , R 5B , R 6 , R 6A , R 6B , and R 51 together with the atom to which they are attached, R 1 , R 1A , R 2 , R 2A , R 2B , R 3 , R 3A , R 3B , R 4 , R 4A , R 5 , R 5A , R 5B , R 6 , R 6A , R 6B , and R 51 can independently combine with any other member of to form a first bridged C4-C8 cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or heterocycloalkyl optionally substituted by one or more -C1-C6 alkyl or -C1-C6 alkoxy; R 1 , R 1A , R 2 , R 2A , R 2B , R 3 , R3A , R 3B , R 4 , R 4A , R 5 , R 5A , R 5B , R 6 , R 6A , and R 6B taken together to form the first bridged cycloalkyl ring, or the first bridged heterocycloalkyl ring, the first bridged cycloalkyl, or the first bridged heterocycloalkyl, independently, is R 51 together with -C1-C6 alkyl, -C1-C6 alkoxy, and However, R 1 , R 1A , R 2 , R 2A , R 2B , R 3 , R 3A , R 3B , R 4 , R 4A , R 5 , R 5A , R 5B , R 6 , R 6A , R 6B , and R 51 at least two of X are taken together to form a bridged cycloalkyl or heterocycloalkyl; or 2 , X 3 , X 5 , and X 6 is a chemical bond.

[0033] In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and N.R. 51 are linked to form an azepane, the azepane optionally further comprising a bridged C4-C8 cycloalkyl, or a bridged 5-8 membered heterocycloalkyl, or X1 , X 2 , X 3 , X 4 , X 5 , X 6 , and N.R. 51 are linked to form a piperidine, which further comprises a bridged C4-C8 cycloalkyl, or a bridged 5-8 membered heterocycloalkyl.

[0034] In some embodiments, X 1 But -CR 1 R 1A - and X 2 but independently, in each occurrence, -CR 2 R 2A -, -NR 2B -, and -O-; X 3 but independently, in each occurrence, -CR 3 R 3A -, -NR 3B -, -O-, and a chemical bond; X 4 But -CR 4 R 4A - and X 5 but independently, in each occurrence, -CR 5 R 5A -, -NR 5B -, and -O-; X 6 but independently, in each occurrence, -CR 6 R 6A -, -NR 6B -, -O-, and a chemical bond; R 51 is independently, at each occurrence, selected from: -H, -C1-C6 alkyl, and -C3-C8 cycloalkyl; R 1 , R 1A , R 2 , R 2A , R 3 , R 3A , R 4 , R 4A , R 5 , R 5A , R6 , and R 6A is independently, at each occurrence, selected from: -H, -C1-C6 alkyl, and -C1-C6 alkoxy; R 2B , R 3B , R 5B , and R 6B is independently, at each occurrence, selected from: -H, and -C1-C6 alkyl; or R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 51 together with the atom to which they are attached, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6A , and R 51 can independently combine with any other member of to form a first bridged C4-C8 cycloalkyl ring, or a bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C6 alkyl or -C1-C6 alkoxy; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 and R 51 together with a second bridged 5-7 membered heterocycloalkyl, said second bridged heterocycloalkyl optionally substituted by one or more -C1-C6 alkyl, or -C1-C6 alkoxy; However, R 1 , R 2 , R 3 , R 4 , R 5, R 6 , and R 51 at least two of X are linked to form a bridged cycloalkyl or heterocycloalkyl; or 1 , X 2 , X 3 , X 4 , X 5 , and X 6 provided that not more than one of the following is a chemical bond.

[0035] In some embodiments, X 1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 3 But independently, in each occurrence, CR 3 R 3A , and a chemical bond; X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and X 6 But independently, in each occurrence, CR 6 R 6A and a chemical bond; R 1 , R 1A , R 2 , R 2A , R 3 , R 3A , R 4 , R 4A , R 5 , R 5A , R 6 , and R 6A is independently, at each occurrence, selected from -H, -C1-C6 alkyl, and -C1-C6 alkoxy; R 51 is independently, at each occurrence, selected from: -H, -C1-C6 alkyl, and -C3-C8 cycloalkyl; or R 1 , R 2 , and R 3 together with the carbon atom to which they are attached, R 4 , R5 , R 6 , and R 51 can be independently bonded to either of R to form a bridged C4-C8 cycloalkyl ring or a bridged 5-8 membered heterocycloalkyl ring, or R 4 , R 5 , R 6 together with the carbon atom to which they are attached, independently represent R 51 together with -C1-C6 alkyl, -C1-C6 alkoxy, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 and R 51 together to form a second bridged 5-7 membered heterocycloalkyl, each of which is optionally substituted by one or more -C1-C6 alkyl or -C1-C6 alkoxy; However, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 51 at least two of X are linked to form a bridged cycloalkyl or heterocycloalkyl; or 3 , and X 6 provided that not more than one of the following is a chemical bond.

[0036] In some embodiments, X 1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 3But independently, in each occurrence, CR 3 R 3A , and a chemical bond; X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and X 6 But independently, in each occurrence, CR 6 R 6A and a chemical bond; R 1 , R 1A , R 2 , R 2A , R 3 , R 3A , R 4 , R 4A , R 5 , R 5A , R 6 , and R 6A is independently, at each occurrence, selected from: -H, -C1-C6 alkyl, and -C1-C6 alkoxy; R 51 is independently, at each occurrence, selected from: -H, -C1-C6 alkyl, and -C3-C8 cycloalkyl; or R 1 , R 2 , and R 3 together with the carbon atom to which they are attached, R 4 , R 5 , R 6 , and R 51 can be independently bonded to either of R to form a bridged C4-C8 cycloalkyl ring or a bridged 5-8 membered heterocycloalkyl ring, or R 4 , R 5 , R 6 together with the carbon atom to which they are attached, independently represent R 51 together with may form a bridged C4-C8 cycloalkyl ring, or a bridged 5-8 membered heterocycloalkyl ring, each cycloalkyl or heterocycloalkyl optionally substituted by one or more -C1-C6 alkyl or -C1-C6 alkoxy; R1 , R 2 , and R 3 Either of the following is true: 4 , R 5 , and R 6 and R 51 together to form a second bridged 5-7 membered heterocycloalkyl, each bridged cycloalkyl or heterocycloalkyl optionally substituted by one or more -C1-C6 alkyl or -C1-C6 alkoxy; However, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 51 at least two of X are linked to form a bridged cycloalkyl or heterocycloalkyl; or 3 , and X 6 provided that not more than one of the following is a chemical bond.

[0037] In some embodiments, X 1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 3 But independently, in each occurrence, CR 3 R 3A , and a chemical bond; X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and X 6 But independently, in each occurrence, CR 6 R 6A and a chemical bond; R 1 , R 1A , R 2 , R 2A , R3 , R 3A , R 4 , R 4A , R 5 , R 5A , R 6 , and R 6A is independently, at each occurrence, selected from -H, -C1-C4 alkyl, and -C1-C4 alkoxy, preferably -H, C1-C3 alkyl, and C1-C3 alkoxy, more preferably -H, C1-C2 alkyl, and -C2 alkoxy, and even more preferably -H; R 51 is independently, at each occurrence, selected from: -H, -C1-C4 alkyl, and -C3-C6 cycloalkyl; or R 1 , R 2 , and R 3 together with the carbon atom to which they are attached, R 4 , R 5 , R 6 , and R 51 can be independently bonded to either of R to form a bridged C4-C8 cycloalkyl ring or a bridged 5-8 membered heterocycloalkyl ring, or R 4 , R 5 , and R 6 together with the carbon atom to which they are attached, independently represent R 51 and together with R can form a bridged C4-C8 cycloalkyl ring, or a bridged 5-8 membered heterocycloalkyl ring, or R 4 , R 5 , R 6 together with the carbon atom to which they are attached, independently represent R 51 together with each other to form a bridged C4-C8 cycloalkyl ring, or a bridged 5-8 membered heterocycloalkyl ring, said cycloalkyl or heterocycloalkyl being optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably one or more -C1-C3 alkyl or -C1-C3 alkoxy; R 1, R 2 , and R 3 Either of the following is true: 4 , R 5 , and R 6 and R 51 together to form a second bridged 5-7 membered heterocycloalkyl, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; However, (i) R 1 and R 4 are linked to form a first bridged cycloalkyl or heterocycloalkyl, and X 3 and X 6 is a chemical bond, and (ii) R 2 and R 5 are linked to form a first bridged cycloalkyl or heterocycloalkyl, and X 3 and X 6 is a chemical bond, and (iii) R 1 and R 4 One of them is R 51 together with X form a first bridged cycloalkyl or heterocycloalkyl ring, and X 3 and X 6 is a chemical bond, or (iv) X 3 and X 6 is a chemical bond.

[0038] In some embodiments, X 1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 3 But independently, in each occurrence, CR 3 R 3A, and a chemical bond; X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and X 6 But independently, in each occurrence, CR 6 R 6A and a chemical bond; R 1 , R 1A , R 2 , R 2A , R 3 , R 3A , R 4 , R 4A , R 5 , R 5A , R 6 , and R 6A is independently, at each occurrence, selected from -H, -C1-C4 alkyl, and -C1-C4 alkoxy, preferably -H, C1-C3 alkyl, and C1-C3 alkoxy, more preferably -H, C1-C2 alkyl, and -C2 alkoxy, and even more preferably -H; R 51 is independently, at each occurrence, selected from: -H, -C1-C4 alkyl, and -C3-C6 cycloalkyl; or R 1 , R 2 , and R 3 together with the carbon atom to which they are attached, R 4 , R 5 , R 6 , and R 51 can be independently bonded to either of R to form a bridged C4-C8 cycloalkyl ring or a bridged 5-8 membered heterocycloalkyl ring, or R 4 , R 5 , and R 6 together with the carbon atom to which they are attached, independently represent R 51together with each other to form a bridged C4-C8 cycloalkyl ring, or a bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally being substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably one or more -C1-C3 alkyl and -C1-C3 alkoxy, more preferably one or more C1-C3 alkyl and -C1-C3 alkoxy; R 1 , R 2 , and R 3 Either of the following is true: 4 , R 5 , and R 6 and R 51 together to form a second bridged 5-7 membered heterocycloalkyl, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; However, (i) R 1 and R 4 are linked to form a bridged cycloalkyl or heterocycloalkyl, and X 3 and X 6 is a chemical bond, and (ii) R 2 and R 5 are linked to form a bridged cycloalkyl or heterocycloalkyl, and X 3 and X 6 is a chemical bond, or (iii) X 3 and X 6 is a chemical bond.

[0039] In some embodiments, X 1 But, CR 1 R 1A and X 2 But, CR2 R 2A and X 3 But independently, in each occurrence, CR 3 R 3A , and a chemical bond; X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and X 6 But independently, in each occurrence, CR 6 R 6A and a chemical bond, (i)R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or is -H, and R 1 and R 4 combine to form a first bridged C4-C8 cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (ii)R 1A , R 1 , R 2A , R 4A , R 4 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or is -H, and R 2 and R 5combine to form a first bridged C4-C8 cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (iii)R 1A , R 2 , R 2A , R 4 , R 4A , R 5 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or is -H, and R 1 and R 51 are linked to form a 5-8 membered heterocycloalkyl ring, said bridged heterocycloalkyl being optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (iv) R 1 , R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or is -H, and R 4 and R 51 are linked to form a 5-8 membered heterocycloalkyl ring, said bridged heterocycloalkyl being optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; R 1 and R4 , or R 2 and R 5 When R 51 together with -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or -C1-C2 alkoxy, to form a second bridged 5-7 membered heterocycloalkyl, each bridged cycloalkyl or heterocycloalkyl optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or -C1-C2 alkoxy, or (v) X 3 and X 6 is a chemical bond, and optionally, R 1 , R 2 , R 4 , R 5 Either of these and R 3 or R 6 the remainder can be linked to form a bridged C4-C8 cycloalkyl, or a bridged 5-8 membered heterocycloalkyl.

[0040] In some embodiments, X 1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 3 But independently, in each occurrence, CR 3 R 3A , and a chemical bond; X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and X 6 But independently, in each occurrence, CR 6 R 6A and a chemical bond, (i)R 1A , R 2 , R 2A , R 4A, R 5 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or is -H, and R 1 and R 4 combine to form a first bridged C4-C8 cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (ii)R 1A , R 1 , R 2A , R 4A , R 4 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or is -H, and R 2 and R 5 combine to form a first bridged C4-C8 cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (iii)R 1A , R 2 , R 2A , R 4 , R 4A , R 5 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or is -H, and R 1 and R 51are linked to form a 5-8 membered heterocycloalkyl ring, said bridged heterocycloalkyl being optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (iv) R 1 , R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or is -H, and R 4 and R 51 are linked to form a 5-8 membered heterocycloalkyl ring, said bridged heterocycloalkyl being optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; R 1 and R 4 , or R 2 and R 5 When R 51 together with -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or -C1-C2 alkoxy, to form a second bridged 5-7 membered heterocycloalkyl, each bridged cycloalkyl or heterocycloalkyl optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or -C1-C2 alkoxy, or (v) X 3 and X 6 Exactly one of these is a chemical bond.

[0041] In some embodiments, X1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 3 But independently, in each occurrence, CR 3 R 3A and a chemical bond, preferably X 3 is a chemical bond, and R 3 and R 3A does not exist and X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and X 6 But independently, in each occurrence, CR 6 R 6A and a chemical bond, preferably X 6 is a chemical bond, and R 6 and R 6A is not present, and in the formula (i)R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or -H, preferably R 3 , R 3A , R 6 , and R 6A But it doesn't exist, R 1 and R 4 combine to form a first bridged C4-C8 cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (ii)R 1A , R1 , R 2A , R 4A , R 4 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or -H, preferably R 3 , R 3A , R 6 , and R 6A But it doesn't exist, R 2 and R 5 combine to form a first bridged C4-C8 cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (iii)R 1A , R 2 , R 2A , R 4 , R 4A , R 5 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or -H, preferably R 3 , R 3A , R 6 , and R 6A But it doesn't exist, R 1 and R 51 are linked to form a 5-8 membered heterocycloalkyl ring, said bridged heterocycloalkyl being optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (iv) R 1 , R 1A , R 2 , R 2A , R4A , R 5 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or -H, preferably R 3 , R 3A , R 6 , and R 6A But it doesn't exist, R 4 and R 51 are linked to form a 5-8 membered heterocycloalkyl ring, said bridged heterocycloalkyl being optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; R 1 and R 4 , or R 2 and R 5 When R 51 together with -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or -C1-C2 alkoxy, to form a second bridged 5-7 membered heterocycloalkyl, each bridged cycloalkyl or heterocycloalkyl optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or -C1-C2 alkoxy, or (v) X 3 and X 6 is a chemical bond, and optionally, R 1 , R 2 , R 4 , R 5 Either of these and R 3 or R 6 the remainder can be linked to form a bridged C4-C8 cycloalkyl, or a bridged 5-8 membered heterocycloalkyl.

[0042] In some embodiments, X1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 3 But independently, in each occurrence, CR 3 R 3A and a chemical bond, preferably X 3 is a chemical bond, and R 3 and R 3A But it doesn't exist, X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and X 6 But independently, in each occurrence, CR 6 R 6A and a chemical bond, preferably X 6 is a chemical bond, and R 6 and R 6A is not present, and in the formula (i)R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or -H, preferably R 3 , R 3A , R 6 , and R 6A But it doesn't exist, R 1 and R 4 combine to form a first bridged C4-C8 cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (ii)R 1A , R1 , R 2A , R 4A , R 4 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or -H, preferably R 3 , R 3A , R 6 , and R 6A But it doesn't exist, R 2 and R 5 combine to form a first bridged C4-C8 cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (iii)R 1A , R 2 , R 2A , R 4 , R 4A , R 5 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or -H, preferably R 3 , R 3A , R 6 , and R 6A But it doesn't exist, R 1 and R 51 are linked to form a 5-8 membered heterocycloalkyl ring, said bridged heterocycloalkyl being optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (iv) R 1 , R 1A , R 2 , R 2A , R4A , R 5 , and R 5A is -H and R 3 , R 3A , R 6 , and R 6A is absent or -H, preferably R 3 , R 3A , R 6 , and R 6A But it doesn't exist, R 4 and R 51 are linked to form a 5-8 membered heterocycloalkyl ring, said bridged heterocycloalkyl being optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; R 1 and R 4 , or R 2 and R 5 When R 51 together with -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or -C1-C2 alkoxy, to form a second bridged 5-7 membered heterocycloalkyl, each bridged cycloalkyl or heterocycloalkyl optionally substituted by one or more -C1-C4 alkyl or -C1-C4 alkoxy, preferably -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or -C1-C2 alkoxy, or (v) X 3 and X 6 Exactly one of these is a chemical bond.

[0043] In some embodiments, X 1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 4 But, CR 4 R 4A and X 5But, CR 5 R 5A and (i)X 3 and X 6 However, both are chemical bonds, and R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 1 and R 4 combine to form a first bridged C4-C8 cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; or (ii) X 3 and X 6 However, both are chemical bonds, and R 1A , R 1 , R 2A , R 4A , R 4 , and R 5A is -H and R 2 and R 5 combine to form a first bridged C4-C8 cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; or (iii)X 3 and X 6 However, both are chemical bonds, and R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 4 and R 51are linked to form a 5-8 membered heterocycloalkyl ring, said bridged heterocycloalkyl being optionally substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; R 1 and R 4 , or R 2 and R 5 When R 51 together with -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or -C1-C2 alkoxy, to form a second bridged 5-7 membered heterocycloalkyl, optionally substituted by one or more -C1-C3 alkyl or -C1-C2 alkoxy, or (iv) X 3 and X 6 is a chemical bond, and optionally, R 1 , R 2 , R 4 , R 5 Either of these and R 3 or R 6 the remainder can be linked to form a bridged C4-C8 cycloalkyl, or a bridged 5-8 membered heterocycloalkyl.

[0044] In some embodiments, X 1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and (i)X 3 and X 6 However, both are chemical bonds, and R 1A , R 2 , R 2A , R4A , R 5 , and R 5A is -H and R 1 and R 4 combine to form a first bridged C4-C8 cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; or (ii) X 3 and X 6 However, both are chemical bonds, and R 1A , R 1 , R 2A , R 4A , R 4 , and R 5A is -H and R 2 and R 5 combine to form a first bridged C4-C8 cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; or (iii)X 3 and X 6 However, both are chemical bonds, and R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 1 and R 4 One of them is R 51と linked together to form a 5-8 membered heterocycloalkyl ring, said bridged heterocycloalkyl being optionally substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; R 1 and R 4 , or R 2 and R 5When R 51 and may be joined to form a second bridged 5-7 membered heterocycloalkyl, the second bridged heterocycloalkyl optionally being substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; or (iv) X 3 and X 6 Exactly one of these is a chemical bond.

[0045] In some embodiments, X 1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and (i)X 3 and X 6 However, both are chemical bonds, and R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 1 and R 4 are joined to form a first bridged C4-C6 cycloalkyl ring, or a first bridged 5-7 membered heterocycloalkyl ring, the heterocycloalkyl ring containing one or more atoms selected from O and N, preferably one or two atoms selected from O and N, more preferably exactly one atom selected from O and N, each bridged cycloalkyl or bridged heterocycloalkyl optionally being substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (ii) X3 and X 6 However, both are chemical bonds, and R 1A , R 1 , R 2A , R 4A , R 4 , and R 5A is -H and R 2 and R 5 are joined to form a first bridged C5-C7 cycloalkyl ring, or a first bridged 5-7 membered heterocycloalkyl ring, the heterocycloalkyl ring containing one or more atoms selected from O and N, preferably one or two atoms selected from O and N, more preferably exactly one atom selected from O and N, each bridged cycloalkyl or bridged heterocycloalkyl optionally being substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (iii)X 3 and X 6 However, both are chemical bonds, and R 1A , R 1 , R 2A , R 4 , R 4A , R 5 , and R 5A is -H and R 1 and R 4 One of them is R 51 and combine with each other to form a 5-7 membered heterocycloalkyl ring, said heterocycloalkyl ring containing one or more atoms selected from O and N, preferably one or two atoms selected from O and N, more preferably exactly one atom selected from O and N, said bridged heterocycloalkyl optionally being substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; R 1 and R 4 , or R 2 and R 5When R 51 together with -C1-C2 alkyl or -C1-C2 alkoxy, or (iv) X 3 and X 6 is a chemical bond, and optionally, R 1 , R 2 , R 4 , R 5 Either of these and R 3 or R 6 the remainder can be linked to form a bridged C4-C8 cycloalkyl, or a bridged 5-8 membered heterocycloalkyl.

[0046] In some embodiments, X 1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and (i)X 3 and X 6 However, both are chemical bonds, and R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 1 and R 4are joined to form a first bridged C4-C6 cycloalkyl ring, or a first bridged 5-7 membered heterocycloalkyl ring, the heterocycloalkyl ring containing one or more atoms selected from O and N, preferably one or two atoms selected from O and N, more preferably exactly one atom selected from O and N, each bridged cycloalkyl or bridged heterocycloalkyl optionally being substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (ii) X 3 and X 6 However, both are chemical bonds, and R 1A , R 1 , R 2A , R 4A , R 4 , and R 5A is -H and R 2 and R 5 are joined to form a first bridged C5-C7 cycloalkyl ring, or a first bridged 5-7 membered heterocycloalkyl ring, the heterocycloalkyl ring containing one or more atoms selected from O and N, preferably one or two atoms selected from O and N, more preferably exactly one atom selected from O and N, each bridged cycloalkyl or bridged heterocycloalkyl optionally being substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (iii)X 3 and X 6 However, both are chemical bonds, and R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 1 and R 4 One of them is R 51and combine with each other to form a 5-7 membered heterocycloalkyl ring, said heterocycloalkyl ring containing one or more atoms selected from O and N, preferably one or two atoms selected from O and N, and the bridged heterocycloalkyl is optionally substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; R 1 and R 4 , or R 2 and R 5 When R 51 taken together can form a second bridged 5-7 membered heterocycloalkyl, the second bridged heterocycloalkyl containing one or more atoms selected from O and N, preferably one or two atoms selected from O and N, optionally substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy, or (iv) X 3 and X 6 Exactly one of these is a chemical bond.

[0047] In some embodiments, X 1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and (i)X 3 and X 6 However, both are chemical bonds, and R 1A , R 2 , R 2A , R 4A , R 5 , and R 5Ais -H and R 1 and R 4 join to form a bridged cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl ring, each cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl ring optionally substituted by one or more -C1-C3 alkyl, or -C1-C3 alkoxy, more preferably -C1-C2 alkyl, or C1-C2 alkoxy; or (ii) X 3 and X 6 However, both are chemical bonds, and R 1A , R 1 , R 2A , R 4A , R 4 , and R 5A is -H and R 2 and R 5 join to form a first bridged cyclohexyl or cyclopentyl ring, each cyclohexyl or heteropentyl optionally substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; or (iii)X 3 and X 6 However, both are chemical bonds, and R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 1 and R 4 One of them is R 51 combines with to form a bridged pyrrolidinyl, piperidinyl, or oxazinanyl, preferably a bridged pyrrolidinyl, piperidinyl, or 1,4 oxazinanyl, each pyrrolidinyl, piperidinyl, or oxazinanyl optionally substituted by one or more -C1-C3 alkyl, or -C1-C3 alkoxy, more preferably -C1-C2 alkyl, or C1-C2 alkoxy; R 1 and R 4 , or R 2 and R 5When R is linked to form a first bridged cyclohexyl or piperidinyl, the first bridged cyclohexyl or piperidinyl is independently 51 together to form a second bridged piperidinyl or 1,3-diazinanyl, the second bridged piperidinyl or 1,3-diazinanyl optionally being substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; or (iv) X 3 and X 6 is a chemical bond, and optionally, R 1 , R 2 , R 4 , R 5 Either of these and R 3 or R 6 the remainder can be linked to form a bridged C4-C8 cycloalkyl, or a bridged 5-8 membered heterocycloalkyl.

[0048] In some embodiments, X 1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and (i)X 3 and X 6 However, both are chemical bonds, and R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 1 and R 4join to form a bridged cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl ring, each cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl ring optionally substituted by one or more -C1-C3 alkyl, or -C1-C3 alkoxy, more preferably -C1-C2 alkyl, or C1-C2 alkoxy; or (ii) X 3 and X 6 However, both are chemical bonds, and R 1A , R 1 , R 2A , R 4A , R 4 , and R 5A is -H and R 2 and R 5 join to form a first bridged cyclohexyl or cycloheptyl ring, each cyclohexyl or cycloheptyl optionally substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; or (iii)X 3 and X 6 However, both are chemical bonds, and R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 1 and R 4 One of them is R 51 combines with to form a bridged pyrrolidinyl, piperidinyl, or oxazinanyl, preferably a bridged pyrrolidinyl, piperidinyl, or 1,4 oxazinanyl, each pyrrolidinyl, piperidinyl, or oxazinanyl optionally substituted by one or more -C1-C3 alkyl, or -C1-C3 alkoxy, more preferably -C1-C2 alkyl, or C1-C2 alkoxy; R 1 and R 4 , or R 2 and R 5When R is linked to form a first bridged cyclohexyl or piperidinyl, the first bridged cyclohexyl or piperidinyl is independently 51 together to form a second bridged piperidinyl or 1,3-diazinanyl, the second bridged piperidinyl or 1,3-diazinanyl optionally being substituted by one or more -C1-C3 alkyl or -C1-C3 alkoxy, more preferably -C1-C2 alkyl or C1-C2 alkoxy; or (iv) X 3 and X 6 Exactly one of these is a chemical bond.

[0049] In some embodiments, X 1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and (i)X 3 and X 6 However, both are chemical bonds, and R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 1 and R 4 join to form a first bridged cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl ring, each cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl ring optionally substituted by one or more -C1-C3 alkyl, preferably one or two -C1-C2 alkyl; or (ii) X 3 and X 6 However, both are chemical bonds, and R 1A , R 1 , R 2A , R 4A , R 4, and R 5A is -H and R 2 and R 5 are linked to form a first bridged cyclohexyl or cycloheptyl ring, each cyclohexyl or cycloheptyl optionally substituted by one or more -C1-C3 alkyl, preferably one or two -C1-C2 alkyl; or (iii)X 3 and X 6 However, both are chemical bonds, and R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 1 and R 4 One of them is R 51 to form a bridged pyrrolidinyl, piperidinyl, or oxazinanyl, preferably a bridged pyrrolidinyl, piperidinyl, or 1,4 oxazinanyl, each pyrrolidinyl, piperidinyl, or oxazinanyl optionally substituted by one or more -C1-C3 alkyl, preferably one or two -C1-C2 alkyl; R 1 and R 4 , or R 2 and R 5 When R is linked to form a first bridged cyclohexyl or piperidinyl, the first bridged cyclohexyl or piperidinyl is independently 51 together to form a second bridged piperidinyl or 1,3-diazinanyl, the second bridged piperidinyl or 1,3-diazinanyl optionally being substituted by one or more -C1-C3 alkyl, preferably one or two -C1-C2 alkyl; or (iv) X 3 and X 6 is a chemical bond, and optionally, R 1 , R 2 , R 4 , R 5 Either of these and R 3 or R 6the remainder can be linked to form a bridged C4-C8 cycloalkyl, or a bridged 5-8 membered heterocycloalkyl.

[0050] In some embodiments, X 1 But, CR 1 R 1A and X 2 But, CR 2 R 2A and X 4 But, CR 4 R 4A and X 5 But, CR 5 R 5A and (i)X 3 and X 6 However, both are chemical bonds, and R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 1 and R 4 join to form a first bridged cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl ring, each cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl ring optionally substituted by one or more -C1-C3 alkyl, preferably one or two -C1-C2 alkyl; or (ii) X 3 and X 6 However, both are chemical bonds, and R 1A , R 1 , R 2A , R 4A , R 4 , and R 5A is -H and R 2 and R 5 are linked to form a first bridged cyclohexyl or cycloheptyl ring, each cyclohexyl or cycloheptyl optionally substituted by one or more -C1-C3 alkyl, preferably one or two -C1-C2 alkyl; or (iii)X 3 and X 6 However, both are chemical bonds, and R1A , R 2 , R 2A , R 4A , R 5 , and R 5A is -H and R 1 and R 4 One of them is R 51 to form a bridged pyrrolidinyl, piperidinyl, or oxazinanyl, preferably a bridged pyrrolidinyl, piperidinyl, or 1,4 oxazinanyl, each pyrrolidinyl, piperidinyl, or oxazinanyl preferably optionally substituted by one or more -C1-C3 alkyl, preferably one or two -C1-C2 alkyl; R 1 and R 4 , or R 2 and R 5 When R is linked to form a first bridged cyclohexyl or piperidinyl, the first bridged cyclohexyl or piperidinyl is independently 51 together to form a second bridged piperidinyl or 1,3-diazinanyl, the second bridged piperidinyl or 1,3-diazinanyl optionally being substituted by one or more -C1-C3 alkyl, preferably one or two -C1-C2 alkyl; or (iv) X 3 and X 6 Exactly one of these is a chemical bond.

[0051] In some embodiments, R 51 is selected from -H, -C1-C4 alkyl, and -C5-C6 cycloalkyl.

[0052] In some embodiments, R 51 is selected from --H, methyl, ethyl, propyl, and tert-butyl.

[0053] In some embodiments, X 3 and X 6 Exactly one of these is a chemical bond.

[0054] In some embodiments, X2 , X 3 , X 5 , and X 6 Exactly one of these is a chemical bond.

[0055] In some embodiments, X 3 , and X 6 Exactly one of the X's is a chemical bond. 1 , X 2 , X 4 , and X 5 However, each 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , C.R. 5 R 5A It is.

[0056] In some embodiments, X 3 is a chemical bond, and R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0057] In some embodiments, X 3 is a chemical bond, and X 1 , X 2 , X 4 , X 5 , and X 6 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , C.R. 5 R 5A , and C.R. 6 R 6A where R 1 , R 1A , R 2 , R 2A , R 4 , R 4A , R 5 , R 5A , R 6 , and R 6Aare each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0058] In some embodiments, X 3 is a chemical bond, and X 1 , X 2 , X 4 , X 5 , and X 6 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , C.R. 5 R 5A , and C.R. 6 R 6A where R 2 and R 6 are linked to form a bridged -C5-C8 cycloalkyl, preferably a bridged -C7-C8 cycloalkyl, R 1 , R 1A , R 2A , R 4 , R 4A , R 5 , R 5A , and R 6A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0059] In some embodiments, X 3 is a chemical bond, and X 1 , X 2 , X 4 , X 5 , and X 6 However, each CR 1 R 1A , C.R. 2 R 2A, C.R. 4 R 4A , C.R. 5 R 5A , and C.R. 6 R 6A where R 2 and R 5 are linked to form a bridged -C5-C8 cycloalkyl, preferably a bridged -C6-C7 cycloalkyl, R 1 , R 1A , R 2A , R 4 , R 4A , R 5A , R 6 , and R 6A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0060] In some embodiments, X 3 is a chemical bond, and X 1 , X 2 , X 4 , X 5 , and X 6 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , C.R. 5 R 5A , and C.R. 6 R 6A where R 2 and R 4 are linked to form a bridged -C5-C8 cycloalkyl, preferably a bridged -C5-C6 cycloalkyl, R 1 , R 1A , R 2A , R 4A , R 5 , R 5A , R 6 , and R 6Aare each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0061] In some embodiments, X 3 is a chemical bond, and X 1 , X 2 , X 4 , X 5 , and X 6 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , C.R. 5 R 5A , and C.R. 6 R 6A where R 1 and R 6 are linked to form a bridged -C5-C8 cycloalkyl, preferably a bridged -C6-C7 cycloalkyl, R 1A , R 2 , R 2A , R 4 , R 4A , R 5 , R 5A , and R 6A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0062] In some embodiments, X 3 is a chemical bond, and X 1 , X 2 , X 4 , X 5 , and X 6 However, each CR 1 R 1A , C.R. 2 R 2A, C.R. 4 R 4A , C.R. 5 R 5A , and C.R. 6 R 6A where R 1 and R 5 are linked to form a bridged -C5-C8 cycloalkyl, preferably a bridged -C5-C6 cycloalkyl, R 1A , R 2 , R 2A , R 4 , R 4A , R 5A , R 6 , and R 6A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0063] In some embodiments, X 3 is a chemical bond, and X 1 , X 2 , X 4 , X 5 , and X 6 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , C.R. 5 R 5A , and C.R. 6 R 6A where R 1 and R 4 are linked to form a bridged -C5 to C8 cycloalkyl, preferably a bridged -C5 cycloalkyl, R 1A , R 2 , R 2A , R 4A , R 5 , R 5A , R 6 , and R 6Aare each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0064] In some embodiments, X 6 is a chemical bond, and R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0065] In some embodiments, X 6 is a chemical bond, and X 1 , X 2 , X 3 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 3 R 3A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 , R 1A , R 2 , R 2A , R 3 , R 3A , R 4 , R 4A , R 5 , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0066] In some embodiments, X 6 is a chemical bond, and X 1 , X 2 , X3 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 3 R 3A , C.R. 4 R 4A , and C.R. 5 R 5A where R 3 and R 5 are linked to form a bridged -C5-C8 cycloalkyl, preferably a bridged -C7-C8 cycloalkyl, R 1 , R 1A , R 2 , R 2A , R 3A , R 4 , R 4A , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0067] In some embodiments, X 6 is a chemical bond, and X 1 , X 2 , X 3 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 3 R 3A , C.R. 4 R 4A , and C.R. 5 R 5A where R 2 and R 5 are linked to form a bridged -C5-C8 cycloalkyl, preferably a bridged -C6-C7 cycloalkyl, R 1 , R 1A , R 2A , R 3 , R3A , R 4 , R 4A , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0068] In some embodiments, X 6 is a chemical bond, and X 1 , X 2 , X 3 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 3 R 3A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 5 are linked to form a bridged -C5-C8 cycloalkyl, preferably a bridged -C5-C6 cycloalkyl, R 1A , R 2 , R 2A , R 3 , R 3A , R 4 , R 4A , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0069] In some embodiments, X 6 is a chemical bond, and X 1 , X 2 , X 3 , X 4 , and X 5However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 3 R 3A , C.R. 4 R 4A , and C.R. 5 R 5A where R 3 and R 4 are linked to form a bridged -C5-C8 cycloalkyl, preferably a bridged -C6-C7 cycloalkyl, R 1 , R 1A , R 2 , R 2A , R 3A , R 4A , R 5 , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0070] In some embodiments, X 6 is a chemical bond, and X 1 , X 2 , X 3 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 3 R 3A , C.R. 4 R 4A , and C.R. 5 R 5A where R 2 and R 4 are linked to form a bridged -C5-C8 cycloalkyl, preferably a bridged -C5-C6 cycloalkyl, R 1 , R 1A , R 2A , R 3 , R 3A , R 4A , R 5 , and R5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0071] In some embodiments, X 6 is a chemical bond, and X 1 , X 2 , X 3 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 3 R 3A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4 are linked to form a bridged -C5 to C8 cycloalkyl, preferably a bridged -C5 cycloalkyl, R 1A , R 2 , R 2A , R 3 , R 3A , R 4A , R 5 , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C3 alkyl, more preferably -H or -C1 to C2 alkyl.

[0072] In some embodiments, X 3 and X 6 But both are chemical bonds.

[0073] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A It is.

[0074] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4 are linked to form a bridged -C4-C8 cycloalkyl, preferably C4-C6 cycloalkyl, more preferably C5-C6 cycloalkyl, R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H, -C1 to C6 alkyl, or -C3 to C8 cycloalkyl, preferably -H, -C1 to C4 alkyl, or -C5 to C6 cycloalkyl, and more preferably -H, -C1 to C2 alkyl, or -C5 to C6 cycloalkyl.

[0075] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4 are linked together to form a bridged C4-C8 cycloalkyl, preferably C4-C6 cycloalkyl, more preferably C5-C6 cycloalkyl, R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H, -C1 to C6 alkyl, preferably -H, or -C1 to C4 alkyl.

[0076] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4 are linked to form a bridged C5-C8 heterocycloalkyl, preferably a C6 heterocycloalkyl, said bridged heterocycloalkyl optionally being further joined to one or more -C1-C6 alkyl, preferably -C 1~ C3 is replaced by R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C4 alkyl, more preferably -H or -C1 to C3 alkyl.

[0077] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4 are linked to form a bridged C5-C8 heterocycloalkyl, preferably a bridged C6 heterocycloalkyl, said heterocycloalkyl containing one or more heteroatoms selected from O and N, preferably one or two heteroatoms selected from O and N, more preferably one heteroatom selected from O and N, and optionally substituted by one or more -C1-C6 alkyl, preferably -C1-C3 alkyl; R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C4 alkyl, more preferably -H or -C1 to C3 alkyl.

[0078] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A, C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4 are linked to form a bridged piperidine, said piperidine being optionally substituted at N with -C1-C6 alkyl, preferably -C1-C3 alkyl; R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H or -C1 to C6 alkyl, preferably -H or -C1 to C4 alkyl, more preferably -H or -C1 to C3 alkyl.

[0079] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4 are linked together to form a bridged C4-C8 cycloalkyl or a bridged C4-C8 heterocycloalkyl, preferably a C4-C6 cycloalkyl or a C4-C6 heterocycloalkyl, R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 But R1 and R 4 or a C4-C6 alkyl formed by

[0080] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4 are combined to form a bridged cyclohexane or cyclopentane, R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -C1 to -C2 alkylene, preferably -C1 alkylene, R 1 and R 4 The cyclohexane or cyclopentane is connected to a bridge formed by

[0081] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4are combined to form a bridged piperidine or pyrrolidine, R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -C1 to -C2 alkylene, preferably -C1 alkylene, R 1 and R 4 The compound is connected to a bridged piperidine, or pyrrolidine, formed by

[0082] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 2 and R 5 are linked together to form a bridged C4-C8 cycloalkyl or C6-C7 cycloalkyl, R 1 , R 1A , R 2A , R 4 , R 4A , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is -H, -C1 to C6 alkyl, or -C3 to C8 cycloalkyl, preferably -H, -C1 to C4 alkyl, or -C5 to C6 cycloalkyl, and most preferably -H, -C1 to C3 alkyl, or -C5 to C6 cycloalkyl.

[0083] In some embodiments, X 3 and X 6However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 2 and R 5 are linked to form a bridged C7 cycloalkyl, R 1 , R 1A , R 2A , R 4 , R 4A , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 But, it is -H.

[0084] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 2 and R 5 are linked to form a bridged C7 cycloalkyl, R 1 , R 1A , R 2A , R 4 , R 4A , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is methyl.

[0085] In some embodiments, X3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 2 and R 5 are linked to form a bridged C7 cycloalkyl, R 1 , R 1A , R 2A , R 4 , R 4A , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 isopropyl.

[0086] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 2 and R 5 are linked to form a bridged C7 cycloalkyl, R 1 , R 1A , R 2A , R 4 , R 4A , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is propyl.

[0087] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 2 and R 5 are linked to form a bridged C7 cycloalkyl, R 1 , R 1A , R 2A , R 4 , R 4A , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is cyclopentyl.

[0088] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 2 and R 5 are linked to form a bridged C6 cycloalkyl, R 1 , R 1A , R 2A , R 4 , R 4A , and R 5A are each -H or -C1-C6 alkyl, preferably -H or -C1-C2 alkyl, more preferably -H; R 51 is methyl.

[0089] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4 One of them combines to form R 51 together form a bridged C4-C8 cycloalkyl or 4-8 membered heterocycloalkyl, preferably a C5-C6 cycloalkyl or 5-6 membered heterocycloalkyl, R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A are each -H or -C1 to C6 alkyl, preferably -H or -C1 to C2 alkyl, more preferably -H.

[0090] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4 One of them combines to form R 51 together form a bridged C4-C8 cycloalkyl, preferably C5-C6 cycloalkyl, R 1A , R 2 , R 2A , R4A , R 5 , and R 5A are each -H or -C1 to C6 alkyl, preferably -H or -C1 to C2 alkyl, more preferably -H.

[0091] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4 One of them combines to form R 51 together form a bridged 4- to 8-membered heterocycloalkyl, preferably a 5- to 6-membered heterocycloalkyl, R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A are each -H or -C1 to C6 alkyl, preferably -H or -C1 to C2 alkyl, more preferably -H.

[0092] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4 One of them combines to form R 51together form a bridged 4-8 membered heterocycloalkyl, preferably a 5-6 membered heterocycloalkyl, said heterocycloalkyl containing one or more heteroatoms selected from O and N, preferably one or two heteroatoms selected from O and N, more preferably one heteroatom selected from O and N; R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A are each -H or -C1 to C6 alkyl, preferably -H or -C1 to C2 alkyl, more preferably -H.

[0093] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A , C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4 are linked together to form a bridged 1,3 oxazine ring, and R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A are each -H or -C1 to C6 alkyl, preferably -H or -C1 to C2 alkyl, more preferably -H.

[0094] In some embodiments, X 3 and X 6 However, both are chemical bonds, and X 1 , X 2 , X 4 , and X 5 However, each CR 1 R 1A , C.R. 2 R 2A, C.R. 4 R 4A , and C.R. 5 R 5A where R 1 and R 4 One of them is R 51 and form a bridged 1,4 oxazine ring, R 1A , R 2 , R 2A , R 4A , R 5 , and R 5A are each -H or -C1 to C6 alkyl, preferably -H or -C1 to C2 alkyl, more preferably -H.

[0095] In some embodiments, the compound is of formula IA, IB, IC, ID, or IE: [ka] During the ceremony, R A1 , R A2 , R A4 , and R A5 are each independently -H or -C1-C4 alkyl; X A is independently selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2NHCH2-, or -CH2N(C1-C4 alkyl)CH2; R A51 is independently -H or -C1-C4 alkyl; or X A and R A51 together with the atom to which they are attached form a 5- to 6-membered heterocycloalkyl; [ka] During the ceremony, R B1 , R B2 , R B4 , and R B5 are each independently -H or -C1-C4 alkyl; X B is independently selected from -CH-, and -CHCH-; R B51 is independently -H or -C1-C4 alkyl; [ka] During the ceremony, R C1 , R C2 , R C4 , and R C5 are each independently -H or -C1-C4 alkyl; X c is independently selected from -CH2CH2-, -CH2CH2CH2-, -OCH2CH2-, and -NHCH2CH2-; [ka] During the ceremony, R D1 , R D2 , R D4 , and R D5 are each independently -H or -C1-C4 alkyl; X D is independently selected from -CH2CH2-, -CH2CH2CH2-, -OCH2CH2-, and -NHCH2CH2-; [ka] During the ceremony, R E1 , R E2 , and R E4 are each -H or C1-C4 alkyl; or R E3 and R E5 is H or is joined to form a bridged cyclooctane, and R E51 is -H or -C1 to C4 alkyl.

[0096] In some embodiments, the compound is of formula IA. In some embodiments, the compound is of formula IB. In some embodiments, the compound is of formula IC. In some embodiments, the compound is of formula ID. In some embodiments, the compound is of formula IE.

[0097] In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and N.R. 51は , forming any structure selected from the following: [ka] [ka]

[0098] In some embodiments, the compound is selected from the group consisting of: [ka] [ka] [ka] [ka]

[0099] In some embodiments, the compound is selected from the group consisting of: [ka]

[0100] In some embodiments, the compound is: [ka]

[0101] In some embodiments, the compound is: [ka]

[0102] In some embodiments, the compound is: [ka]

[0103] In some embodiments, the compound is: [ka]

[0104] In some embodiments, the compound is: [ka] .

[0105] In some embodiments, the compound is: [ka]

[0106] In some embodiments, the compound is: [ka]

[0107] In some embodiments, the compound is: [ka]

[0108] In some embodiments, the compound is: [ka]

[0109] In some embodiments, the compound is: [ka]

[0110] In some embodiments, the compound is: [ka]

[0111] In some embodiments, the compound is: [ka]

[0112] In some embodiments, the compound is: [ka]

[0113] In some embodiments, the compound is: [ka]

[0114] In some embodiments, the compound is: [ka]

[0115] In some embodiments, the compound is: [ka]

[0116] In some embodiments, the compound is Compound 1A.

[0117] In some embodiments, the compound is Compound 1B.

[0118] In some embodiments, the compound is compound 2A.

[0119] In some embodiments, the compound is compound 2B.

[0120] In some embodiments, the compound is compound 3A.

[0121] In some embodiments, the compound is compound 3B.

[0122] In some embodiments, the compound is Compound 4.

[0123] In some embodiments, the compound is compound 5A.

[0124] In some embodiments, the compound is compound 5B.

[0125] In some embodiments, the compound is compound 6A.

[0126] In some embodiments, the compound is compound 6B.

[0127] In some embodiments, the compound is compound 7A.

[0128] In some embodiments, the compound is compound 7B.

[0129] In some embodiments, the compound is compound 8A.

[0130] In some embodiments, the compound is compound 8B.

[0131] In some embodiments, the compound is compound 8C.

[0132] In some embodiments, the compound is compound 8D.

[0133] In some embodiments, the compound is compound 9A.

[0134] In some embodiments, the compound is compound 9B.

[0135] In some embodiments, the compound is compound 10A.

[0136] In some embodiments, the compound is compound 10B.

[0137] In some embodiments, the compound is compound 11A.

[0138] In some embodiments, the compound is compound 11B.

[0139] In some embodiments, the compound is compound 12A.

[0140] In some embodiments, the compound is compound 12B.

[0141] In some embodiments, the compound is compound 13A.

[0142] In some embodiments, the compound is compound 13B.

[0143] In some embodiments, the compound is compound 14A.

[0144] In some embodiments, the compound is compound 14B.

[0145] In some embodiments, the compound is compound 15A.

[0146] In some embodiments, the compound is compound 15B.

[0147] In some embodiments, the compound is compound 16A.

[0148] In some embodiments, the compound is compound 16B.

[0149] In some embodiments, the compound is compound 17.

[0150] In some embodiments, the compound is compound 18.

[0151] In some embodiments, the compound is compound 19.

[0152] In some embodiments, the compound is compound 20A.

[0153] In some embodiments, the compound is compound 20B.

[0154] Methods for synthesizing the disclosed compounds The compounds of the present disclosure can be prepared by methods known in the art of organic synthesis, as illustrated in part by the following synthetic schemes and examples, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as would be understood by one skilled in the art. Methods include, but are not limited to, those described below. Starting materials are commercially available or made by known procedures reported in the literature, or as exemplified.

[0155] In the schemes and examples described below, it is fully understood that protective groups for functional or reactive groups are used where necessary according to general principles of chemistry. Protective groups are manipulated according to standard methods of organic synthesis (TW Greene and PG M Huts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selected processes, as well as reaction conditions and the order of their execution, shall be consistent with the preparation of the compounds of the present disclosure.

[0156] Those skilled in the art will recognize whether a stereocenter exists in the compound of formula I. Thus, the present disclosure includes both possible stereoisomers (unless specified in the synthesis), including not only the racemates but also the individual enantiomers and / or diastereomers. If a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material can be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-lnterscience, 1994).

[0157] Scheme 1. General synthesis of rifamycin spiro-imidazole tropinone derivatives [ka] A general method for preparing compounds of formula (I) is outlined in Scheme 1. To a suspension of ammonium acetate (2.5 eq.) and zinc (2.5 eq.) in THF was added 3-amino-4-deoxy-4-imino-rifamycin S (1 eq.), ketone (2.5 eq.), and acetic acid (20 eq.). The resulting mixture was stirred at room temperature or at elevated temperature and monitored by LC / MS. Upon completion, the mixture was filtered and evaporated. The desired compound was tested for antibacterial activity without further purification or purified by flash chromatography and tested for antibacterial activity.

[0158] Methods of Use of the Disclosed Compounds The compounds of the present invention are rifamycin derivatives that contain a modified spiro-imidazole moiety at the 3,4-imino-amino position and exhibit broad-spectrum antibacterial activity characteristic of the rifamycin class. Furthermore, the compounds of the present invention unexpectedly exhibit enhanced antibacterial activity against bacteria of the genus Acinetobacter.

[0159] Without wishing to be bound by theory, compounds of the rifamycin class other than rifabutin are generally not active against infections caused by A. baumannii. Surprisingly, the compounds described herein have demonstrated activity against A. baumannii that is comparable to or better than that exhibited by rifabutin. Also surprisingly, the compounds described herein have demonstrated better antibacterial activity than rifabutin in A. baumannii strains that have mutations in the RNA polymerase (RpoB) gene.

[0160] As shown in Example 3, Tables 2 and 3A and 3B, the compounds of the present invention are effective in inhibiting the growth of a broad range of bacteria, including S. aureus, A. baumannii, E. faecium, E. faecalis, S. epidermidis, S. pneumoniae, S. pyogenes, H. influenzae, M. abscessus, M. tuberculosis, and / or M. smegmatis. Additionally, as shown in Tables 4 and 5, compounds of the invention were effective in inhibiting the growth of strains of A. baumannii that have a mutation in the RpoB gene that results in reduced activity of rifamycin, such as rifampicin and / or rifabutin. For example, Table 4 demonstrates that compounds of the invention exhibited several-fold increased activity compared to rifabutin and rifampicin against A. baumannii strains that have a H535L mutation in the RpoB gene. Table 5 provides further examples where compounds of the invention exhibited several-fold increased activity against A. baumannii strains with reduced rifabutin and / or rifampicin activity.

[0161] In one aspect, the invention provides a compound or pharmaceutical composition as described herein for use as a medicament.In one aspect, the invention provides a compound or pharmaceutical composition as described herein for use in a method for preventing or treating a disease, preferably an infection, more preferably a bacterial infection, in a subject.

[0162] In some embodiments, the present invention provides a method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition of the present invention, hi some embodiments, the disease being treated is an infection, more preferably a bacterial infection.

[0163] In some embodiments, the present invention provides the use of a compound or pharmaceutical composition of the present invention in the manufacture of a medicament for treating or preventing a disease in a subject in need thereof, hi some embodiments, the disease being treated is an infection, more preferably a bacterial infection.

[0164] Thus, in some embodiments, the compounds of the invention are used to inhibit bacterial infections. In some embodiments, the infection is caused by Acinetobacter spp., Clostridium spp., Enterococcus spp., Hemophilus spp., Legionella spp., Mycobacterium spp. (tuberculous and nontuberculous mycobacteria), Neisseria spp., Staphylococcus spp., Streptococcus spp., Listeria monocytogenes, Moraxella catarrhalis, Bacillus spp., Bacteroides spp., and / or other pathogenic bacteria. It is caused by bacteria belonging to the genera Lactobacillus spp., Gardnerella vaginalis, Lactobacillus spp., Mobiluncus spp., Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis, and / or Toxoplasma gondii.

[0165] Most preferably, the bacterial infection is caused by S. aureus, A. baumannii, E. faecium, E. faecalis, S. epidermidis, S. pneumoniae, S. pyogenes, H. influenzae, M. abscessus, M. tuberculosis, and / or M. smegmatis. Even more preferably, the bacterial infection is caused by one or more bacteria belonging to the genus Acinetobacter. Even more preferably, the bacterial infection is caused by A. baumannii. Even more preferably, the bacterial infection is caused by A. baumannii having one or more mechanisms of resistance to rifamycins, such as rifabutin and / or rifampicin.

[0166] In some preferred embodiments, the compounds of the present invention are used to treat bacterial infections caused by bacterial strains that have one or more resistance genes or mechanisms to currently available antibiotics (e.g., rifampicin and / or rifabutin). In some preferred embodiments, the infection is caused by bacteria of the A. baumannii species, which has a mutation in the RNA polymerase B (RpoB) gene, preferably a mutation that confers reduced activity of antibiotics, preferably antibiotics of the rifamycin class, more preferably rifabutin and / or rifampicin. In some preferred embodiments, the RpoB mutation is selected from I581M, H535Q, S521T, S583L, N527D, H535C, H535L, L542F, H535N, and combinations thereof. In some preferred embodiments, the mutation in RpoB is H535L.

[0167] Pharmaceutical Compositions In one aspect, the present invention provides a pharmaceutical composition comprising at least one compound according to any one of the preceding claims, or a pharma- ceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharma- ceutically acceptable excipient.

[0168] Exemplary pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the present disclosure and a pharma- ceutically acceptable carrier, such as, for example, a) a diluent, such as purified water, triglyceride oil, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, such as EPA or DHA, or esters or triglycerides thereof, or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) a lubricant, such as silica, talcum, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium ... For tablets, c) binders, for example magnesium aluminium silicate, starch paste, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural or synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired, d) disintegrants, for example starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures, e) absorbents, colouring agents, flavourings and sweeteners, f) emulsifiers or dispersing agents, for example Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS, or other acceptable emulsifiers, and / or g) agents that enhance absorption of the compound, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

[0169] Liquid, particularly injectable compositions can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed compounds are dissolved or mixed in a pharma- ceutically acceptable solvent, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins, such as albumin, chylomicron particles, or serum proteins, can be used to solubilize the disclosed compounds.

[0170] In some embodiments, the disclosed compounds are also formulated as suppositories prepared from fatty emulsions or suspensions. Polyalkylene glycols, such as propylene glycol, are used as the carrier.

[0171] In some embodiments, the disclosed compounds are administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, including cholesterol, stearylamine, or phosphatidylcholine.In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to form a lipid layer that encapsulates the drug, as described in U.S. Patent No. 5,262,564.

[0172] Injectable parenteral dosages are generally used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for solution or suspension in liquid prior to injection.

[0173] Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention and a pharma- ceutically acceptable carrier, which may further comprise an excipient, diluent, or surfactant.

[0174] The compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the pharmaceutical compositions can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the disclosed compounds by weight or volume.

[0175] Dosage regimens utilizing the disclosed compounds are selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient: the severity of the condition being treated, the route of administration, the renal or hepatic function of the patient, and the particular disclosed compound being used. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition.

[0176] When used for the indicated effects, the effective dosage of the disclosed compounds ranges from about 0.5 mg to about 5000 mg of the compound, as needed to treat the condition. Compositions for in vivo or in vitro use may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compounds, or a range of amounts from one amount to another in the dosage listing. In one embodiment, the composition is in the form of a scoreable tablet.

[0177] The compounds and pharmaceutical compositions of the present invention can be administered by any suitable route, depending on the nature of the disease or disorder to be treated, for example orally (as syrups, tablets, capsules, lozenges, controlled release formulations, fast dissolving formulations, lozenges, etc.), topically (as creams, ointments, lotions, nasal sprays or aerosols, etc.), by injection (subcutaneous, intradermal, intramuscular, intravenous, etc.), or by inhalation (as a dry powder, solution, dispersion, etc.).

[0178] Equivalent While the present technology has been described in conjunction with the specific embodiments outlined above, many alternatives, modifications, and other variations thereof will be apparent to those skilled in the art, and all such alternatives, modifications, and variations are intended to fall within the spirit and scope of the present disclosure.

[0179] example The present invention will be described by the following non-limiting examples. Specific embodiments of the present invention are described below, but those skilled in the art will understand that various changes and modifications can be made. References to preparations made in the same manner as other preparations or by general methods of other preparations may include variations in routine parameters such as slight changes in time, temperature, processing conditions, amounts of reagents, etc. These embodiments for the synthesis of derivatives are within the scope of the present invention.

[0180] Abbreviation The following list provides definitions of certain abbreviations and symbols used herein. It will be understood that the list is not exhaustive, but that the meanings of abbreviations and symbols not defined below herein will be readily apparent to one of ordinary skill in the art. In describing the present invention, the elements are identified according to the Periodic Table of the Elements. [Table 1]

[0181] Analysis method Unless otherwise specified, the purity and identity of intermediates or example compounds were assessed by HLPC-MS, as described below.

[0182] HPLC analysis: Reaction monitoring and compound purity determination were performed by liquid chromatography / mass spectrometry (LC / MS). The HPLC system was a Waters 2695 LC equipped with a photodiode array detector Waters 996, and an XBridge C18 column (particle size 3.5 μm, dimensions 50 mm×4.6 mm). The mobile phases were: phase A (HO / ammonium formate, pH 3.75), and phase B (CHCN+5% HO / ammonium formate, pH 3.75), and the compounds were eluted according to the following method. [Table 2]

[0183] Mass Spectroscopy: The mass spectrometer was a Waters Alliance Micromass ZQ 2000 using electrospray ionization (polarity: negative, positive). Percent purity of compounds was determined by reversed-phase HPLC using UV detection (254 nm). Structures were confirmed by MS using electrospray ionization positive ion (ESI+) method and reported as M+H, referring to the protonated molecular ion.

[0184] NMR analysis: NMR spectra were recorded on a Bruker 500 MHz spectrometer equipped with a TXI probe. Chemical shifts are given in parts per million (ppm). One-dimensional (1D) 1 H and 13 The assignment was made using the C spectrum, and two-dimensional (2D) HSQC, HMBC and COSY spectra. Confirmation of the stereochemistry was achieved by ROESY experiments.

[0185] Compound synthesis: All starting materials were purchased from commercial sources or prepared according to published procedures. Chemical reagents were purchased from commercial sources and used without further purification. The starting material 3-amino-4-deoxy-4-imino-rifamycin S was purchased from a commercial source.

[0186] Unless otherwise stated, flash column chromatography purification was performed on prepacked columns (Grace Resolv® flash cartridges from Grace® or FlashPure from BUCHI) using a PuriFlash430 system from Interchim. The mobile phase used was CH3Cl / NH3 in MeOH (1N) from 100 / 0 to 95 / 5. Preparative thin layer chromatography (TLC) was performed on glass plates (20x20 cm) of silica gel (silica gel 60, 1 mm or 2 mm thick, MACHEREY-NAGEL, with fluorescent indicator UV254). The mobile phase used was cyclohexane / DCM / MeOH (3 / 6 / 1).

[0187] Antibacterial activity: In the following examples where the corresponding starting ketones do not exhibit an axis of symmetry, the condensation reaction may result in the formation of multiple (e.g., two or four) diastereoisomeric isomers of the 3,4-spiro-rifamycin derivatives. The antibacterial activity of the diastereoisomeric compounds was tested either as a mixture (e.g., "A+B") or the isomers were separated by preparative TLC or flash chromatography and tested separately.

[0188] Example 1: Synthesis and isolation of compounds 13A and 13B [ka] To a suspension of ammonium acetate (136 mg, 1.76 mmol, 2.5 equiv.) and zinc (115 mg, 1.76 mmol, 2.5 equiv.) in THF (5 mL) was added 3-amino-4-imino-rifamycin S (500 mg, 0.70 mmol, 1 equiv.), acetic acid (807 μL, 14.10 mmol, 20 equiv.), and tropinone hydrochloride hydrate (245 mg, 1.76 mmol, 2.5 equiv.). The reaction was stirred at 40° C. After 1 h, the mixture was filtered over sintered glass and the THF was evaporated. The resulting oil was dissolved in EtOAc (50 mL) and washed with aqueous HCl (0.5 N, 3×50 mL), saturated NaHCO3 solution (3×50 mL), and brine (50 mL). The organic layer was dried over MgSO4 and evaporated in vacuum. The resulting solid was purified by flash chromatography (CH3Cl / NH3:100 / 0 to 94 / 6 in MeOH (1N)) to give two products, 13A (72 mg, yield = 12.3%, purity (254 nm) = 99%) as a purple solid, and 13B (28 mg, yield = 4.7%, purity (254 nm) = 99%) as a purple solid.

[0189] The compounds shown in Table 1 were prepared according to Example 1. The compounds contain a 3,4 spiro-rifamycin core as shown in the general structure below and the substitution pattern shown in Table 1. [ka] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0190] Example 2: Stereochemical elution of compounds 13A and 13B Structural characterization of the novel rifabutin analogs 13A and 13B was achieved using 1D and 2D NMR spectroscopic experiments by analysis of their HSQC and HMBC spectra. The atomic numbering is shown in the following structure: [ka]

[0191] 1D Experiments: 1 H NMR and 13 C NMR Compound 13A 11H NMR (500 MHz, CDCl3): -0.04 (d, J = 7.08 Hz, 3H), 0.60 (d, J = 6.95 Hz, 3H), 0.82 (d, J = 7.06 Hz, 3H), 1.02 (d, J = 7.06 Hz, 3H), 1.32 - 1.39 (m, 2H), 1.60 (d, J = 13.86 Hz, 1H), 1.73 - 1.76 (m, 4H), 1.83 (m, 1H), 1.99 (s, 3H), 2.01 (s, 3H), 2.20 - 2.25 (m, 2H), 2.32 (s, 3H), 2.36 (m, 1H), 2.51 (s, 3H), 2.67 (m, 2H), 2.76 (m, 2H), 2.99 (d, J = 9.94 Hz, 1H), 3.08 (s, 3H), 3.31 (dd, J = 7.90 Hz, J = 2.76 Hz, 1H), 3.36 (bs, 1H), 3.43 - 3.47 (m, 2H), 3.54 (bs, 1H), 3.64 (d, J = 9.94 Hz, 1H), 4.73 (d, J = 10.73 Hz, 1H), 5.20 (dd, J = 12.69 Hz, J = 7.97 Hz, 1H), 5.94 (dd, J = 15.69 Hz, J = 6.50 Hz, 1H), 6.18 (d, J = 12.56 Hz, 1H), 6.21 (d, J = 10.35 Hz, 1H), 6.31 (dd, J = 15.64 Hz, J = 10.18 Hz, 1H), 8.09 (s, 1H), 14.75 (s, 1H) (chemical shift in ppm). 13C NMR (500 MHz, CDCl3): 7.7, 8.9, 11.3, 11.4, 17.4, 20.4, 21.2, 22.0, 25.3, 25.5, 27.8, 33.1, 37.6, 37.8, 38.6, 39.2, 39.6, 39.8, 56.9, 70.6, 72.5, 73.0, 81.2, 91.0, 104.6, 107.3, 108.9, 111.8, 114.9, 115.7, 124.3, 124.9, 131.4, 133.2, 140.7, 141.3, 144.5, 155.5, 168.2, 168.3, 171.5, 172.1, 181.6, 193.2 (chemical shifts in ppm). Compound 13B 11H NMR (500 MHz, CDCl3): -0.15 (d, J = 7.09 Hz, 3H), 0.53 (d, J = 6.94 Hz, 3H), 0.77 (d, J = 6.94 Hz, 3H), 0.96 (d, J = 7.01 Hz, 3H), 1.18 (m, 1H), 1.38 (m, 1H), 1.47 (d, J = 14.65 Hz, 1H), 1.66 - 1.70 (m, 5H), 1.95 (s, 3H), 1.99 (s, 3H), 2.02 (m, 1H), 2.14 (m, 1H), 2.25 (s, 3H), 2.32 - 2.38 (m, 3H), 2.62 (s, 3H), 2.93 (d, J = 9.90 Hz, 1H), 2.99 - 3.05 (m, 6H), 3.31 (dd, J = 6.99 Hz, J = 2.1 Hz, 1H), 3.53 - 3.61 (m, 4H), 4.68 (d, J = 10.49 Hz, 1H), 5.05 (dd, J = 12.43 Hz, J = 7.22 Hz, 1H), 5.94 (dd, J = 15.93 Hz, J = 6.77 Hz, 1H), 6.07 (d, J = 12.62 Hz, 1H), 6.18 (d, J = 10.49 Hz, 1H), 6.29 (dd, J = 15.73 Hz, J = 10.48 Hz, 1H), 8.16 (s, 1H), 9.70 (s, 1H), 14.56 (s, 1H) (chemical shift in ppm). 13C NMR (500 MHz, CDCl3): 7.6, 8.8, 10.8, 11.2, 17.4, 20.2, 21.0, 21.8, 25.4, 25.6, 33.0, 35.9, 36.8, 37.5, 37.7, 37.9, 56.9, 58.6, 58.7, 73.0, 73.1, 76.8, 80.4, 92.0, 104.3, 107.2, 109.0, 111.5, 114.5, 116.0, 123.9, 124.6, 131.3, 132.8, 141.0, 142.2, 144.0, 155.2, 168.1, 168.9, 171.4, 172.2, 180.9,192.5 (chemical shifts in ppm).

[0192] 2D Experiment-ROESY NMR (Compound 13B) The stereochemistry of the diastereoisomers was assigned by examining the ROESY spectra. The ROESY analysis shows correlations between NH-3 and H-7', H-8', H-2', and H-6'. For the minor isomer 13B, the proposed placement of the ethylenic bridge was supported by NOESY correlation peaks between the amine proton NH-3 and the protons H-7' and H-8' of the ethylenic portion of the tropane moiety, as shown in FIG. 1. This observation leads to the conclusion that compound 13B is a diastereomer with the ethylenic portion oriented toward NH-3, as shown in FIG. 2.

[0193] Example 3: Antibacterial activity The in vitro antibacterial activity of the compounds of the present disclosure was determined according to the following protocol.

[0194] MIC values ​​were determined by broth microdilution method according to CLSI guidelines. Unless otherwise stated, MICs against Acinetobacter baumannii were performed in RPMI medium supplemented with 10% FCS. MICs against Streptococcus pneumoniae and Group A hemolytic streptococci were performed in cation-adjusted Mueller-Hinton broth supplemented with 5% lake horse blood. MICs against Hemophilus influenzae were performed in Haemophilus test medium broth. MICs against Mycobacterium abscessus, Mycobacterium tuberculosis, and Mycobacterium smegmatis were performed in Middlebrook 7H9 broth supplemented with Middlebrook ADC growth supplement. All other MICs were performed in standard cation-adjusted Mueller-Hinton broth.

[0195] The following procedure applies to all species tested, except for M. tuberculosis and M. smegmatis. From overnight culture plates, cells were resuspended in 0.9% (w / v) saline and bacterial inocula were added at 5×10 5 CFU / mL were prepared. Appropriate volumes of 10 mg / mL compound solution were dispensed directly into 96-well assay plates using a digital dispenser to generate a two-fold dilution series with final concentrations ranging from 32 to 0.002 μg / mL. 100 μL of bacterial suspension was finally added to the compound. Plates were covered and incubated at 35°C for 20 h without shaking. All experiments included antibiotics as quality controls. MICs were determined visually as the lowest concentration of compound that prevented visible growth of bacteria, and plates were scanned for documentation.

[0196] Inocula were prepared from exponentially growing cultures and incubated at OD of 0.02 and 0.002 for M. tuberculosis and M. smegmatis, respectively. 600 Similar procedures were used for M. tuberculosis and M. smegmatis, except that the incubation time was set at 1 min. MICs were determined as 90% growth inhibition using a GFP reporter after 5 days of incubation for M. tuberculosis and using the BacTiter-Glo kit (Promega) after 20 h incubation for M. smegmatis.

[0197] The results are reported in the table below. [Table 4]

[0198] Compounds 3B, 7A, 8 (A+B+C+D), 12B, 13B, 16 (A+B), 18, and 20B were tested against other representative species: Enterococcus faecium (strain NCTC 12204), Enterococcus faecalis (strain ATCC 51575), Staphylococcus epidermidis (strain ATCC 12228), S. pneumoniae (strain ATCC 49619), S. pyogenes (strain IHMA 1117021), H. influenzae (strain ATCC 49247), M. abscessus (strain ATCC 49261), and ... 19977), M. tuberculosis (H37Rv ATCC 27294), and M. smegmatis (ATCC 700084). The results are shown in Tables 3A and 3B. [Table 5] [Table 6]

[0199] The same compounds were tested against a representative A. baumannii clinical isolate carrying a mutation in RpoB known to result in reduced rifabutin activity (Trebosc et al. J. Antimicrob. Chemother. 2020;75(12):3552-3562). The results are shown in Table 4. [Table 7]

[0200] The in vitro activity of compounds 3B, 12B, and 13B was further tested against all known A. baumannii clinical isolates harboring RpoB mutations (n=20) from a collection of 353 A. baumannii strains. The results are shown in Table 5. [Table 8]

Claims

1. A compound of formula I, 【Chemistry 1】 During the ceremony, X １ But -CR １ R １Ａ - and X ２ is independently, at each occurrence, -CR ２ R ２Ａ --, --NR ２Ｂ is selected from -, -O-, and a chemical bond; X ３ is independently, at each occurrence, -CR ３ R ３Ａ --, --NR ３Ｂ is selected from -, -O-, and a chemical bond; X ４ But -CR ４ R ４Ａ - and X ５ is independently, at each occurrence, -CR ５ R ５Ａ --, --NR ５Ｂ is selected from -, -O-, and a chemical bond; X ６ is independently, at each occurrence, -CR ６ R ６Ａ --, --NR ６Ｂ is selected from -, -O-, and a chemical bond; R ５１ is independently, at each occurrence, -H, -C １ ~C ６ Alkyl, and -C ３ ~C ８ cycloalkyl; R １ , R １Ａ , R ２ , R ２Ａ , R ３ , R ３Ａ , R ４ , R ４Ａ , R ５ , R ５Ａ , R ６ , and R ６Ａ is independently, at each occurrence, -H, -C １ ~C ６ Alkyl, and -C １ ~C ６ alkoxy; R ２Ｂ , R ３Ｂ , R ５Ｂ , and R ６Ｂ is independently, at each occurrence, -H, and -C １ ~C ６ alkyl; or R １ , R １Ａ , R ２ , R ２Ａ , R ２Ｂ , R ３ , R ３Ａ , R ３Ｂ , R ４ , R ４Ａ , R ５ , R ５Ａ , R ５Ｂ , R ６ , R ６Ａ , R ６Ｂ , and R ５１ together with the atom to which they are attached, R １ , R １Ａ , R ２ , R ２Ａ , R ２Ｂ , R ３ , R ３Ａ , R ３Ｂ , R ４ , R ４Ａ , R ５ , R ５Ａ , R ５Ｂ , R ６ , R ６Ａ , R ６Ｂ , and R ５１ and a first bridge C ４ ~C ８ A cycloalkyl ring or a first bridged 5-8 membered heterocycloalkyl ring can be formed, each bridged cycloalkyl or bridged heterocycloalkyl optionally having one or more -C １ ~C ６ Alkyl, or -C １ ~C ６ substituted by alkoxy, R １ , R １Ａ , R ２ , R ２Ａ , R ２Ｂ , R ３ , R ３Ａ , R ３Ｂ , R ４ , R ４Ａ , R ５ , R ５Ａ , R ５Ｂ , R ６ , R ６Ａ , and R ６Ｂ when either of R ５１ and a second bridged 5-7 membered heterocycloalkyl may be joined to form a second bridged 5-7 membered heterocycloalkyl, said second bridged heterocycloalkyl optionally comprising one or more —C １ ~C ６ Alkyl, or -C １ ~C ６ substituted by alkoxy, However, R １ , R １Ａ , R ２ , R ２Ａ , R ２Ｂ , R ３ , R ３Ａ , R ３Ｂ , R ４ , R ４Ａ , R ５ , R ５Ａ , R ５Ｂ , R ６ , R ６Ａ , R ６Ｂ , and R ５１ at least two of X are linked to form a bridged cycloalkyl or heterocycloalkyl; or ２ , X ３ , X ５ , and X ６ is a chemical bond, or a pharma- ceutically acceptable salt, tautomer, solvate, hydrate, enantiomer, or diastereomer thereof.

2. X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and N.R. ５１ are linked to form an azepane, the azepane optionally being cross-linked by C ４ ~C ８ further comprising a cycloalkyl, or a bridged 5-8 membered heterocycloalkyl; or X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and N.R. ５１ is bonded to form a crosslink C ４ ~C ８ cycloalkyl, or a bridged 5-8 membered heterocycloalkyl, forming a piperidine; The compound of claim 1.

3. A compound according to claim 1 or 2, During the ceremony, X １ But, CR １ R １Ａ and X ２ But, CR ２ R ２Ａ and X ３ independently, in each occurrence, CR ３ R ３Ａ and a chemical bond; X ４ But, CR ４ R ４Ａ and X ５ But, CR ５ R ５Ａ and X ６ independently, in each occurrence, CR ６ R ６Ａ and a chemical bond; R １ , R １Ａ , R ２ , R ２Ａ , R ３ , R ３Ａ , R ４ , R ４Ａ , R ５ , R ５Ａ , R ６ , and R ６Ａ is independently, at each occurrence, -H, -C １ ~C ６ Alkyl, and -C １ ~C ６ alkoxy; R ５１ is independently, at each occurrence, -H, -C １ ~C ６ Alkyl, and -C ３ ~C ８ cycloalkyl; or R １ , R ２ , and R ３ together with the carbon atom to which they are attached, R ４ , R ５ , R ６ , and R ５１ Independently bonded to any one of the crosslinks C ４ ~C ８ A cycloalkyl ring or a bridged 5- to 8-membered heterocycloalkyl ring can be formed, or R ４ , R ５ , and R ６ together with the carbon atom to which they are attached, R ５１ and independently combine with each other to form a bridged 5-8 membered heterocycloalkyl ring, said heterocycloalkyl optionally having one or more -C １ ~C ６ Alkyl, or -C １ ~C ６ substituted by alkoxy, R １ , R ２ , R ３ , R ４ , R ５ , and R ６ are joined to form a first bridged cycloalkyl ring, or a first bridged heterocycloalkyl ring, the first bridged cycloalkyl or the first bridged heterocycloalkyl independently being ５１ and a second bridged 5-7 membered heterocycloalkyl, each of which may optionally include one or more -C １ ~C ６ Alkyl, or -C １ ~C ６ substituted by alkoxy, However, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ５１ at least two of X are linked to form a bridged cycloalkyl or heterocycloalkyl; or ３ , and X ６ is a chemical bond.

4. A compound according to any one of claims 1 to 3, comprising the formula: X １ But, CR １ R １Ａ And X ２ But, CR ２ R ２Ａ And X ３ independently, in each occurrence, CR ３ R ３Ａ 、 and a chemical bond; X ４ But, CR ４ R ４Ａ And X ５ But, CR ５ R ５Ａ And X ６ independently, in each occurrence, CR ６ R ６Ａ and a chemical bond; (i) R １Ａ , R ２ , R ２Ａ , R ４Ａ , R ５ , and R ５Ａ is -H, and R ３ , R ３Ａ , R ６ , and R ６Ａ is absent or is —H, and R １ and R ４ is bonded to the first crosslink C ４ ~C ８ cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally having one or more -C １ ~C ４ Alkyl, or -C １ ~C ４ Alkoxy, preferably -C １ ~C ３ Alkyl, or -C １ ~C ３ Alkoxy, more preferably -C １ ~C ２ Alkyl, or C １ ~C ２ substituted by alkoxy, or (ii) R １Ａ , R １ , R ２Ａ , R ４Ａ , R ４ , and R ５Ａ is -H, and R ３ , R ３Ａ , R ６ , and R ６Ａ is absent or is —H, and R ２ and R ５ is bonded to the first crosslink C ４ ~C ８ cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally having one or more -C １ ~C ４ Alkyl, or -C １ ~C ４ Alkoxy, preferably -C １ ~C ３ Alkyl, or -C １ ~C ３ Alkoxy, more preferably -C １ ~C ２ Alkyl, or C １ ~C ２ substituted by alkoxy, or (iii) R １Ａ , R ２ , R ２Ａ , R ４ , R ４Ａ , R ５ , and R ５Ａ is -H, and R ３ , R ３Ａ , R ６ , and R ６Ａ is absent or is —H, and R １ and R ５１ are linked to form a bridged 5-8 membered heterocycloalkyl ring, said bridged heterocycloalkyl optionally containing one or more -C １ ~C ４ Alkyl, or -C １ ~C ４ Alkoxy, preferably -C １ ~C ３ Alkyl, or -C １ ~C ３ Alkoxy, more preferably -C １ ~C ２ Alkyl, or C １ ~C ２ substituted by alkoxy, or (iv) R １ , R １Ａ , R ２ , R ２Ａ , R ４Ａ , R ５ , and R ５Ａ is -H, and R ３ , R ３Ａ , R ６ , and R ６Ａ is absent or is —H, and R ４ and R ５１ are linked to form a bridged 5-8 membered heterocycloalkyl ring, said bridged heterocycloalkyl optionally containing one or more -C １ ~C ４ Alkyl, or -C １ ~C ４ Alkoxy, preferably -C １ ~C ３ Alkyl, or -C １ ~C ３ Alkoxy, more preferably -C １ ~C ２ Alkyl, or C １ ~C ２ substituted by alkoxy, R １ and R ４ , or R ２ and R ５ when combine to form a first bridged cycloalkyl ring or a first bridged heterocycloalkyl ring, the first bridged cycloalkyl or the first bridged heterocycloalkyl can independently be selected from R ５１ and a second bridged 5-7 membered heterocycloalkyl, each bridged cycloalkyl or heterocycloalkyl may optionally have one or more -C １ ~C ４ Alkyl, or -C １ ~C ４ Alkoxy, preferably -C １ ~C ３ Alkyl, or -C １ ~C ３ Alkoxy, more preferably -C １ ~C ２ Alkyl, or C １ ~C ２ substituted by alkoxy, or (v) X ３ and X ６ is a chemical bond, compound.

5. A compound according to any one of claims 1 to 4, comprising the formula: X １ But, CR １ R １Ａ And X ２ But, CR ２ R ２Ａ And X ４ But, CR ４ R ４Ａ And X ５ But, CR ５ R ５Ａ and (i) X ３ and X ６ are both chemical bonds, and R １Ａ , R ２ , R ２Ａ , R ４Ａ , R ５ , and R ５Ａ is -H, and R １ and R ４ is bonded to the first crosslink C ４ ~C ８ cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally having one or more -C １ ~C ３ Alkyl, or -C １ ~C ３ Alkoxy, preferably -C １ ~C ２ Alkyl, or C １ ~C ２ substituted by alkoxy, or (ii) X ３ and X ６ are both chemical bonds, and R １Ａ , R １ , R ２Ａ , R ４Ａ , R ４ , and R ５Ａ is -H, and R ２ and R ５ is bonded to the first crosslink C ４ ~C ８ cycloalkyl ring, or a first bridged 5-8 membered heterocycloalkyl ring, each bridged cycloalkyl or bridged heterocycloalkyl optionally having one or more -C １ ~C ３ Alkyl, or -C １ ~C ３ Alkoxy, preferably -C １ ~C ２ Alkyl, or C １ ~C ２ substituted by alkoxy, or (iii) X ３ and X ６ are both chemical bonds, and R １Ａ , R ２ , R ２Ａ , R ４Ａ , R ５ , and R ５Ａ is -H, and R １ and R ４ One of them is R ５１ and combine to form a bridged 5-8 membered heterocycloalkyl ring, said bridged heterocycloalkyl optionally containing one or more -C １ ~C ３ Alkyl, or -C １ ~C ３ Alkoxy, preferably -C １ ~C ２ Alkyl, or C １ ~C ２ substituted by alkoxy, R １ and R ４ , or R ２ and R ５ when combine to form a first bridged cycloalkyl ring or a first bridged heterocycloalkyl ring, the first bridged cycloalkyl or the first bridged heterocycloalkyl can independently be selected from R ５１ and a second bridged 5-7 membered heterocycloalkyl may be joined to form a second bridged 5-7 membered heterocycloalkyl, said second bridged heterocycloalkyl optionally comprising one or more —C １ ~C ３ Alkyl, or -C １ ~C ３ Alkoxy, preferably -C １ ~C ２ Alkyl, or C １ ~C ２ substituted by alkoxy, or (iv) X ３ and X ６ is a chemical bond, compound.

6. A compound according to any one of claims 1 to 5, comprising the formula: X １ But, CR １ R １Ａ And X ２ But, CR ２ R ２Ａ And X ４ But, CR ４ R ４Ａ And X ５ But, CR ５ R ５Ａ and (i) X ３ and X ６ are both chemical bonds, and R １Ａ , R ２ , R ２Ａ , R ４Ａ , R ５ , and R ５Ａ is -H, and R １ and R ４ are linked to form a first bridged cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl ring, each cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl ring optionally containing one or more -C １ ~C ３ Alkyl, preferably one or two -C １ ~C ２ substituted by alkyl, or (ii) X ３ and X ６ are both chemical bonds, and R １Ａ , R １ , R ２Ａ , R ４Ａ , R ４ , and R ５Ａ is -H, and R ２ and R ５ are linked to form a first bridged cyclohexyl or cycloheptyl ring, each cyclohexyl or cycloheptyl optionally having one or more -C １ ~C ３ Alkyl, preferably one or two -C １ ~C ２ substituted by alkyl, or (iii) X ３ and X ６ are both chemical bonds, and R １Ａ , R ２ , R ２Ａ , R ４Ａ , R ５ , and R ５Ａ is -H, and R １ and R ４ One of them is R ５１ to form a bridged pyrrolidinyl, piperidinyl, or oxazinanyl, each pyrrolidinyl, piperidinyl, or oxazinanyl optionally having one or more -C １ ~C ３ Alkyl, preferably one or two -C １ ~C ２ is substituted by alkyl, R １ and R ４ , or R ２ and R ５ are linked to form a first bridged cyclohexyl or piperidinyl, the first bridged cyclohexyl or piperidinyl is independently selected from R ５１ to form a second bridged piperidinyl or 1,3-diazinanyl, said second bridged piperidinyl or 1,3-diazinanyl optionally comprising one or more -C １ ~C ３ Alkyl, preferably one or two -C １ ~C ２ substituted by alkyl, or (iv) X ３ and X ６ is a chemical bond, compound.

7. R ５１ But -H, -C １ ~C ４ Alkyl, and -C ５ ~C ６ The compound according to any one of claims 1 to 6, wherein the aryl group is selected from cycloalkyl.

8. X ３ and X ６ The compound according to any one of claims 1 to 7, wherein exactly one of is a chemical bond.

9. X ３ and X ６ The compound according to any one of claims 1 to 8, wherein both are chemical bonds.

10. 2. The compound of claim 1 , wherein the compound is of formula IA, IB, IC, ID, or IE, 【Chemistry 2】 During the ceremony, R Ａ１ , R Ａ２ , R Ａ４ , and R Ａ５ are each independently -H or -C １ ~C ４ is alkyl, X Ａ But -CH ２ --, --CH ２ CH ２ --, --CH ２ CH ２ CH ２ --, --CH ２ OCH ２ --, --CH ２ N.H.C.H. ２ - or -CH ２ N (C １ ~C ４ alkyl)CH ２ are independently selected from R Ａ５１ are independently -H or -C １ ~C ４ is alkyl, or X Ａ and R Ａ５１ together with the atom to which they are attached, combine to form a 5-6 membered heterocycloalkyl; 【Chemistry 3】 During the ceremony, R Ｂ１ , R Ｂ２ , R Ｂ４ , and R Ｂ５ are each independently -H or -C １ ~C ４ is alkyl, X Ｂ But -CH ２ - and -CH ２ CH ２ - are independently selected from R Ｂ５１ are independently -H or -C １ ~C ４ is alkyl, 【Chemistry 4】 During the ceremony, R Ｃ１ , R Ｃ２ , R Ｃ４ , and R Ｃ５ are each independently -H or -C １ ~C ４ is alkyl, X ｃ But -CH ２ CH ２ --, --CH ２ CH ２ CH ２ --, --OCH ２ CH ２ -, and -NHCH ２ CH ２ - independently selected from 【Chemistry 5】 During the ceremony, R Ｄ１ , R Ｄ２ , R Ｄ４ , and R Ｄ５ are each independently -H or -C １ ~C ４ is alkyl, X Ｄ But -CH ２ CH ２ --, --CH ２ CH ２ CH ２ --, --OCH ２ CH ２ -, and -NHCH ２ CH ２ - independently selected from 【Chemistry 6】 During the ceremony, R Ｅ１ , R Ｅ２ , and R Ｅ４ Each of them is -H or C １ ~C ４ is alkyl, or R Ｅ３ and R Ｅ５ is —H or is joined to form a bridged cyclooctane; and R Ｅ５１ is -H or -C １ ~C ４ is alkyl, compound.

11. X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and N.R. ５１ The compound of claim 1 , wherein: 【Chemistry 7-1】 【Chemistry 7-2】

12. Selected from the group consisting of: 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 【Chemistry 8-4】 Preferably, selected from the group consisting of: 【Chemistry 9】 The compound of claim 1.

13. 13. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt, tautomer, solvate, or hydrate thereof, and a pharma- ceutically acceptable excipient.

14. 14. A compound according to any of claims 1 to 12 or a pharmaceutical composition according to claim 13 for use as a medicament, preferably for use in a method for the prevention or treatment of a disease in a subject, said disease being an infectious disease, preferably said disease being a bacterial infection.

15. 15. A compound or pharmaceutical composition for use according to claim 14, wherein the disease is a bacterial infection, the bacterial infection being caused by Acinetobacter spp., Clostridium spp., Enterococcus spp., Hemophilus spp., Legionella spp., Mycobacterium spp. (tuberculous and nontuberculous mycobacteria), Neisseria spp., Staphylococcus spp., Streptococcus spp., or other species of bacteria. spp.), Listeria monocytogenes, Moraxella catarrhalis, Bacillus spp., Bacteroides spp., Gardnerella vaginalis, Lactobacillus spp., Mobiluncus spp., Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis trachomatis, and / or Toxoplasma gondiigondii, more preferably a bacterial infection caused by S. aureus, A. baumannii, E. faecium, E. faecalis, S. epidermidis, S. pneumoniae, S. pyogenes, H. influenzae, M. abscessus, M. tuberculosis, and / or M. smegmatis, preferably said bacterial infection is caused by one or more bacteria belonging to the genus Acinetobacter, even more preferably a bacterial infection caused by A. baumannii, and even more preferably, a compound or pharmaceutical composition caused by A. baumannii having one or more mechanisms of resistance to a rifamycin, such as rifabutin and / or rifampicin.

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