An iminophenazine-derived coupling molecule for treating bacterial infection and its application

Abstract

The present invention discloses an iminophenazine-derived coupling compound, and stereoisomers, hydrates, deuterated products, esters, solvates, crystal forms, metabolites, pharmaceutically acceptable salts, and prodrugs thereof, having a structure shown in general formula I: The present invention also discloses a pharmaceutical composition, the above-mentioned iminophenazine-derived coupling compound, and stereoisomers, hydrates, deuterated products, esters, solvates, crystal forms, metabolites, pharmaceutically acceptable salts, and prodrugs thereof. The iminophenazine-derived coupling compound of the present invention, and stereoisomers, hydrates, deuterated products, esters, solvates, crystal forms, metabolites, pharmaceutically acceptable salts, and prodrugs thereof, or the above-mentioned pharmaceutical composition, can be used to treat or prevent microbial infections.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry and relates to an iminophenazine-derived conjugate molecule for treating bacterial infections and its applications. More specifically, the present invention relates to compounds of iminophenazine derivatives having antimicrobial activity, their pharmaceutical compositions, and their applications in the treatment and prevention of microbial infections. Background Art

[0002] Iminophenazine antibiotics can effectively treat mycobacterial infections such as leprosy and are often used in combination with other drugs such as rifampicin and dapsone. However, existing iminophenazine antibiotic compounds have less than ideal physicochemical properties and cause serious side effects, so they remain a potentially effective but relatively underdeveloped drug class.

[0003] Clofazimine (CFZ) was first introduced in the 1960s for the treatment of leprosy and is the only clinically approved iminophenazine antibiotic. A clinical trial conducted in Bangladesh in 2010 reported that the clofazimine-containing regimen could effectively treat multidrug-resistant Mycobacterium tuberculosis (MDR-TB) for 9 to 12 months. Therefore, the World Health Organization recommends CFZ as an important component of the new short-course regimen for multidrug-resistant tuberculosis.

[0004] Currently, various side effects including skin and mucosal pigmentation hinder the use of clofazimine in patients. In addition, the resistance of Mycobacterium leprae (the pathogen of leprosy) and Mycobacterium tuberculosis to clofazimine is increasing.

[0005] Multi-target conjugate antibiotics are an effective method to solve antibiotic resistance or to make multidrug-resistant bacteria sensitive. So far, no multi-target conjugate compounds having an iminophenazine pharmacophore or antibacterial activity have been reported. Saravanan et al. reported a compound that simultaneously contains the precursors of the antibiotic drugs rifampicin and clofazimine (Sci. Rep. 2021, 11, 1029 - 1035) and has antibacterial and cytotoxicity comparable to rifampicin. However, this molecule does not contain an iminophenazine pharmacophore, and the authors did not conduct a mechanism study to clarify whether the specific antibacterial activity related to the iminophenazine drug target was retained, so there is no evidence that this molecule has multi-target characteristics. Summary of the Invention

[0006] The object of the present invention is to provide an iminophenazine-derived conjugate molecule for treating bacterial infections, which is covalently linked to a linking group through the C-3 imine (3-isopropyliminocarbon) of the iminophenazine moiety, and the linking group is also covalently linked to other antibacterial therapeutic drugs or pharmacophores to form a conjugate molecule for solving the problem of iminophenazine resistance.

[0007] The object of the present invention is achieved by the following technical solutions:

[0008] An iminophenazine-derived coupling compound, and its stereoisomers, hydrates, deuterated compounds, esters, solvates, crystal forms, metabolites, pharmaceutically acceptable salts, prodrugs, having the structure shown in General Formula I:

[0009]

[0010] Wherein,

[0011] A is an antibacterial therapeutic agent or its pharmacophore covalently coupled through a linking group X;

[0012] X is 0 or a linking group selected from any one or any combination of 2-5 of the following groups:

[0013] 1) C1-C8 alkylene;

[0014] 2) C3-C8 cycloalkylene;

[0015] 3) Arylalkene;

[0016] 4) Arylene;

[0017] 5) Optionally unsaturated C3-C8 heterocycloalkylene containing 1-3 heteroatoms;

[0018] 6) —C(=O)—;

[0019] 7) —O—;

[0020] 8) —S(O)n—, n = 0, 1, or 2;

[0021] 9) —N(R 3 )—;

[0022] 10) ─C(R 4 )=C(R 5 )─;

[0023] 11) ─C=N—;

[0024] Wherein R 1 and R 2 are each independently selected from unsubstituted or substituted aryl, heteroaryl groups;

[0025] R 3 , R 4 and R 5 are each independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, aryl, heteroaryl or C3-C8 heterocycloalkyl; or, R 4 and R 5 are connected to each other to form a ring.

[0026] Preferably, wherein:

[0027] R 1 and R 2 are each independently selected from phenyl or a 5- or 6-membered aromatic heterocyclic group having at least one atom selected from N, O, S, or phenyl or the aromatic heterocyclic group is substituted with one or more substituents selected from halogen atoms, cyano group, hydroxy group, amino group, C1-C6 alkyloxy group, C1-C6 alkylamino group, C1-C6 haloalkyl group, C1-C6 haloalkyloxy group, C1-C6 haloalkylamino group, C2-C6 alkenyl group, C2-C6 haloalkenyl group, C2-C6 alkynyl group, C2-C6 haloalkynyl group, C2-C6 alkenylamino group, C2-C6 haloalkenylamino group, C2-C6 alkynylamino group, C2-C6 haloalkynylamino group, C2-C6 alkenyloxy group, C2-C6 haloalkenyloxy group, C2-C6 alkynyloxy group, C2-C6 haloalkynyloxy group;

[0028] More preferably, R 1 and R 2 are selected from

[0029] Preferably, wherein:

[0030] The left side of X is connected to the C-3 imine part of the iminophenazine molecule through a C-N or C-C bond, and the right side is connected to A through a C-N or C-C bond.

[0031] More preferably, wherein:

[0032] X is 0 or a linking group selected from any one or any combination of 2-5 of the following groups:

[0033] 1) C1-C8 alkylene;

[0034] 2) C3-C8 cycloalkyl;

[0035] 3) Arylalkene;

[0036] 4) Optionally unsaturated C3-C8 heterocyclic alkylene containing 1-3 heteroatoms;

[0037] 5) —C(=O)—;

[0038] 6) —O—;

[0039] 7) —N(R 3 )—;

[0040] R 3 is independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, aryl, heteroaryl or C3-C8 heterocycloalkyl.

[0041] Preferably, among them:

[0042] A is rifamycin, oxazolidinone, quinolone and its bioisosteres, nitroimidazole, macrolide, ethambutol, aminoglycoside antibiotics or their pharmacophores.

[0043] More preferably, among them: the iminophenazine-derived coupling compound, and its stereoisomers, hydrates, deuterated compounds, esters, solvates, crystal forms, metabolites, pharmaceutically acceptable salts, prodrugs, any one selected from the following compounds:

[0044] N,5-bis(4-chlorophenyl)-3-(((1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methyl)imino)-3,5-dihydrophenazin-2-amine;

[0045] 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl ((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)ethyl)carbamate;

[0046] (S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-6-yl 4-((((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)methyl)piperidine-1-carboxylate;

[0047] (S)-N,5-bis(4-chlorophenyl)-3-(((1-(4-(((2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-6-yl)oxy)methyl)benzyl)piperidin-4-yl)methyl)imino)-3,5-dihydrophenazin-2-amine;

[0048] 8-(3-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoline-3-carboxylic acid;

[0049] (R)-3-(4-(4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)methyl)piperidin-1-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one;

[0050] (S)-N-((3-(4-(4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)methyl)piperidin-1-yl)-3-fluorophenyl)-2-oxazolidin-5-yl)methyl)acetamide;

[0051] (R)-3-(4-(4-(2-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)ethyl)piperazin-1-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one;

[0052] (S)-N-((3-(4-(4-(2-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)ethyl)piperazin-1-yl)-3-fluorophenyl)-2-oxazolidin-5-yl)methyl)acetamide;

[0053] 4-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidine-1-carboxamide;

[0054] (2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methyl 4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino))phenazin-2(10H)-ylidene)amino)methyl)piperidine-1-carboxylate;

[0055] (R)-3-(3-fluoro-4-(4-(((3-((2-methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)methyl)piperidin-1-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one;

[0056] (R)-3-(3-fluoro-4-(4-(2-((3-((2-methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)ethyl)piperazin-1-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one;

[0057] 3-[[[4-[2-((3-((2-methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)ethyl]-1-piperazinyl]imino]methyl]rifamycin SV;

[0058] 2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)piperidine-1-carboxylate;

[0059] N,5-Bis(4-chlorophenyl)-3-((2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)imino)-3,5-dihydrophenazin-2-amine;

[0060] 2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)methyl)piperidine-1-carboxylate;

[0061] 8-(4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)methyl)piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinazoline-3-carboxylic acid;

[0062] N-(2-Methoxypyridin-3-yl)-3-((2-(5-methyl-2-nitro-1H-imidazol-1-yl)ethyl)imino)-5-(4-(trifluoromethoxy)phenyl)-3,5-dihydrophenazin-2-amine;

[0063] 1-Cyclopropyl-7-fluoro-8-(4-(((3-((2-methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)methyl)piperidin-1-yl)-9-methyl-4-oxo-4H-quinazoline-3-carboxylic acid;

[0064] 4-Deoxy-3,4-[2-spiro-[1-(2-((3-((2-methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)ethyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S.

[0065] The present invention also provides a pharmaceutical composition, which comprises the above-mentioned iminophenazine-derived conjugate compound, and its stereoisomers, hydrates, deuterated compounds, esters, solvates, crystal forms, metabolites, pharmaceutically acceptable salts, prodrugs.

[0066] Preferably, the components of the above-mentioned pharmaceutical composition further comprise at least one antibacterial agent. Such antibacterial agents can be currently available antibacterial agents.

[0067] The present invention also provides the use of the above-mentioned iminophenazine-derived coupling compound, its stereoisomers, hydrates, deuterated compounds, esters, solvates, crystal forms, metabolites, pharmaceutically acceptable salts, prodrugs, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating or preventing Staphylococcus aureus infection.

[0068] The beneficial effects of the present invention are as follows: The iminophenazine-derived coupling compound of the present invention, its stereoisomers, hydrates, deuterated compounds, esters, solvates, crystal forms, metabolites, pharmaceutically acceptable salts, prodrugs, or the above-mentioned pharmaceutical composition can be used for treating or preventing microbial infections. Detailed Embodiments

[0069] As used herein, terms and phrases have meanings and definitions known in the art. Some of the more commonly used phrases are described in more detail below.

[0070] The carbon atom content of various hydrocarbon-containing moieties is represented by a prefix indicating the minimum and maximum number of carbon atoms in the specified moiety, i.e., the prefix Ci-Cj represents the portion of integers from the integer "i" to the integer "j" carbon atoms. Thus, for example, C 1 -C 6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms.

[0071] As used herein, the term "alkyl" refers to a monovalent group of a saturated, straight-chain or branched-chain hydrocarbon group. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neopentyl, and n-hexyl. The alkyl groups of the present invention are optionally substituted. Preferred alkyl groups of the present invention have 1 to 8 carbons. The alkyl groups of the present invention can be optionally substituted.

[0072] As used herein, the term "alkenyl" refers to a monovalent group of an unsaturated, straight-chain or branched-chain hydrocarbon group having at least one C═C double bond. Examples of alkenyl groups include allyl or propenyl, butenyl, isobutenyl, pentenyl, etc. The alkenyl groups of the present invention can be optionally substituted.

[0073] As used herein, the term "alkynyl" refers to a monovalent group of an unsaturated, straight-chain or branched-chain hydrocarbon group having at least one C≡C triple bond. Examples of alkynyl groups include propargyl, butynyl, isobutynyl, pentynyl, etc. The alkynyl groups of the present invention are optionally substituted.

[0074] As used herein, the terms "alkylene", "alkenylene", or "alkynylene" refer to divalent groups of alkyl, alkenyl, or alkynyl groups as defined above. Examples of alkylene groups include methylene, ethylene, propylene, isopropylene, n-butylene, isobutylene, n-hexylene, etc. Examples of alkenylene groups include vinylene, propenylene, etc. Examples of alkynylene groups include acetylene, propyne, etc. The "alkylene", "alkenylene", or "alkynylene" of the present invention can be optionally substituted.

[0075] As used herein, the term "alkylamino" refers to an amino group (-NH 2 ), where one hydrogen atom is replaced by an alkyl group. Examples of alkylamino include methylamino, ethylamino, propylamino, and isopropylamino.

[0076] As used herein, the term "alkoxy" refers to an alkyl group as previously defined attached to an oxygen atom. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, pentyloxy, and n-hexyloxy. The alkoxy groups of the present invention may be optionally substituted.

[0077] As used herein, the term "aryl" refers to a monovalent group of a carbocyclic aromatic group, including phenyl, naphthyl, and anthryl. The aryl groups of the present invention may be optionally substituted.

[0078] As used herein, the term "arylene" refers to a divalent group of an aryl group as defined above, including phenylene. The arylene groups of the present invention may be optionally substituted.

[0079] As used herein, the term "cycloalkyl" refers to a monovalent group of a saturated carbocyclic group having three to eight carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl groups of the present invention may be optionally substituted.

[0080] As used herein, the term "cycloalkylene" refers to a divalent group of a saturated carbocyclic group having three to eight carbons. The cycloalkylene groups of the present invention may be optionally substituted.

[0081] As used herein, the term "halogen" or "halide" refers to fluorine, chlorine, bromine, and iodine atoms, and the term "halo" refers to -F, -Cl, -Br, and -I as substituents.

[0082] As used herein, the term "heteroaryl" refers to a cyclic aromatic group having five or six ring atoms, where at least one ring atom is selected from the group consisting of oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon. The heteroaryl groups of the present invention include those derived from furan, imidazole, isothiazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, thiazole, 1,3,4-thiadiazole, triazole, and tetrazole. The heteroaryl groups of the present invention may be optionally substituted.

[0083] As used herein, the term "heteroatom" refers to an oxygen, nitrogen, or sulfur atom.

[0084] As used herein, the term "heterocycloalkyl" refers to a non-aromatic five-, six-, seven- or eight-membered ring or bicyclic or tricyclic group having one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen. Each 5-membered ring has 0 to 1 double bonds, and each 6-membered ring has 0 to 2 double bonds. The nitrogen and sulfur heteroatoms are optionally oxidized, the nitrogen heteroatom can be optionally quaternized, and any of the above heterocycles can be fused to an aryl or heteroaryl ring. Representative heterocycloalkyls include, but are not limited to: pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, morpholinyl, isothiazolidinyl, and tetrahydrofuranyl. The heterocycloalkyl of the present invention is optionally substituted with one, two or three substituents independently selected from -F, -Cl, -OH, -NO 2 , -CN, -C(O)-alkyl, -C(O)-aryl, -C(O)-heteroaryl, -CO 2 -alkyl, -CO 2 -aryl, -CO 2 -heteroaryl, -C(O)NH 2 , -C(O)NH-alkyl, -C(O)NH-aryl, -C(O)NH-heteroaryl, -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-heteroaryl, -OC(O)NH2, -OC(O)NH-alkyl, -OC(O)NH-aryl, -OCONH-heteroaryl, -NHC(O)-alkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHCO 2 -alkyl, -NHCO 2 -aryl, -NHCO 2 -heteroaryl, -NHC(O)NH 2 , -NHC(O)NH-alkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -SO 2 -alkyl, -SO 2 -aryl, -SO 2 -heteroaryl, -SO 2 NH 2 , -SO 2 NH-alkyl, -SO 2 NH-aryl, -SO 2 NH-heteroaryl, -alkyl, -cycloalkyl, -cycloheteroalkyl, -CF 3 , -CH 2 OH, -CH 2 NH 2, -aryl, -heteroaryl, -benzyl, -benzyloxy, -aryloxy, -heteroaryloxy, -alkoxy, -methoxymethoxy, -methoxyethoxy, -amino, -benzylamino, -arylamino, -heteroarylamino, -alkylamino, -thio, -arylthio, -heteroarylthio, -benzylthio, -alkylthio or -methylthiomethyl.

[0085] As used herein, the term "heterocycloalkylene" refers to a divalent heterocycloalkyl as defined above. The heterocycloalkylene of the present invention may be optionally substituted.

[0086] As used herein, the term "hydroxy" refers to -OH.

[0087] As used herein, the term "substituted" means having one or more covalently linked substituents.

[0088] As used herein, the term "prodrug" refers to a prodrug of a compound of the present invention that is suitable for use in humans and animals, has acceptable toxicity, irritation, allergic reactions, etc., and is commensurate with a reasonable benefit-risk ratio and is effective for its intended use. As used herein, the term "prodrug" represents a compound that can be converted in vivo to the parent compound defined above.

[0089] As used herein, the term "salt" refers to those salts that are suitable for use in humans and animals, have acceptable toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well known in the art. Salts can be prepared by reacting the compounds of the present invention with an acid or a base (a pharmaceutically acceptable salt former), or can be prepared in situ during the final step of isolation. Examples of pharmaceutically acceptable salts are salts of acid groups formed with inorganic bases such as sodium hydroxide, sodium carbonate, sodium phosphate, etc. Examples of pharmaceutically acceptable salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydroboric acid, phosphoric acid, sulfuric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Other metal salts include lithium, potassium, calcium and magnesium. Additional pharmaceutically acceptable salts include ammonium cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

[0090] As used herein, the term "solvate" refers to a compound disclosed herein that associates with a solvent in molecular form, i.e., where the solvent is coordinated, and can be represented, for example, by the formula R·(solvent), where R is a compound disclosed herein. A given compound can form more than one solvate, including, for example, a monosolvate (R·solvent) or a polysolvate (R·n(solvent)), where n is an integer greater than 1, including, for example, a disolvate (R·2(solvent)), a trisolvate (R·3(solvent)), etc., or a hemisolvate, such as R·n / 2(solvent), R·n / 3(solvent), R·n / 4(solvent), etc., where n is an integer. Solvents herein include mixed solvents, such as methanol / water, and thus, a solvate can incorporate one or more solvents in the solvate.

[0091] As used herein, the term "deuterium-exchanged compound" refers to a compound in which one or more of the hydrogen atoms contained therein are replaced by deuterium atoms. Deuterated compounds can be prepared by a chemical reaction using deuterated oxides or by growing an organism (such as a bacterium) in a medium or plant containing heavy water, where the water source is replaced by heavy water.

[0092] As used herein, the term "pharmaceutically acceptable salt former" refers to an acid or a base that can react with a compound of the present invention to form a pharmaceutically acceptable salt. Examples of bases are inorganic bases such as sodium hydroxide, sodium carbonate or sodium phosphate, and organic bases such as pyridine, triethylamine or N,N-diisopropylmethylamine. Examples of acids are inorganic acids such as hydrochloric acid, hydroboric acid, phosphoric acid or sulfuric acid and organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid.

[0093] Compounds that have the same molecular formula but differ in the nature or sequence of the bonding of their atoms or the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers", while stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". A pair of enantiomers may arise when a compound has an asymmetric center, for example, a carbon atom attached to four different groups. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by the R and S sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as the (+) or (-)-isomer, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture". The compounds of the present invention may have one or more asymmetric centers; thus, such compounds can be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise stated, the description or naming of a particular compound in the specification and claims is intended to include the individual enantiomers and mixtures, racemic or otherwise.

[0094] "Pharmaceutically acceptable carrier" means a carrier that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic and has no adverse effects, biologically or otherwise, and includes carriers that can be used for veterinary use as well as for human pharmaceuticals. The "pharmaceutically acceptable carrier" used in the specification and claims includes one and more than one such carrier.

[0095] "Treatment" or "treating" of a disease includes: preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or is susceptible to the disease but has not yet experienced or exhibited the disease, inhibiting the disease, i.e., preventing or reducing the development of the disease or its clinical symptoms, or alleviating the disease, i.e., causing the regression of the disease or its clinical symptoms.

[0096] "Therapeutically effective amount" means the amount of a compound that is sufficient to achieve such treatment of a disease when administered to a mammal to treat the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated.

[0097] The compounds of the present invention are generally named according to the IUPAC or CAS naming system. Abbreviations well known to those of ordinary skill in the art may be used (e.g., "Ph" represents phenyl, "Me" represents methyl, "Et" represents ethyl, "h" represents hour or hours, "rt" represents room temperature).

[0098] The compounds of the preferred embodiments described herein can be better understood in conjunction with their synthetic schemes. The synthetic methods in Schemes A to B shown in Chemical Reaction Formulas 1-2 are for illustrative purposes and are not intended to limit the scope of the present invention. It will be apparent to those skilled in the art that the compounds of the present invention can be prepared by a variety of synthetic routes, including but not limited to substitution of appropriate reagents, solvents or catalysts, change of reaction sequence, and change of protecting groups.

[0099] Synthetic Scheme A of Chemical Reaction Formula 1

[0100]

[0101] Synthetic Scheme B of Chemical Reaction Formula 2

[0102]

[0103] The preferred embodiments described herein also include pharmaceutical compositions comprising a pharmaceutically effective amount of an iminophenazine-derived conjugate compound of Formula I, optionally in combination with other antibacterial agents, and a pharmaceutically acceptable carrier.

[0104] According to a method of treatment using the iminophenazine-derived conjugate compounds described herein, bacterial infections are treated or prevented in a patient, such as a human or an animal, by administering to the patient a therapeutically effective amount of the compound of the present invention.

[0105] A preferred embodiment of the compound of the present invention is the iminophenazine-derived conjugate compound of Formula I as determined above. On the one hand, the compounds of the present invention contain several asymmetric and geometric centers. In some cases, one or more of the asymmetric and geometric centers can be converted to their opposite configurations. These stereoisomers are within the scope of the present invention. The examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0106] The abbreviations used herein have meanings known to those skilled in the art. In particular, Ac represents acetyl, Boc represents tert-butoxycarbonyl, Bn represents benzyl, Cbz represents benzyloxycarbonyl, DCM represents dichloromethane, DMAP represents 4-N,N-dimethylaminopyridine, DMF represents N,N-dimethylformamide, DMSO represents dimethyl sulfoxide, EDCI represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, Et represents ethyl, EtOAc represents ethyl acetate, EtOH represents ethanol, HOBT represents 1-hydroxybenzotriazole, Me represents methyl, NCS represents N-chlorosuccinimide, NMM represents N-methylmorpholine, OMe represents methoxy, PE represents petroleum ether, PMB represents p-methoxybenzyl, Ph represents phenyl, Pr represents propyl, TEA represents triethylamine, TFA represents trifluoroacetic acid, THF represents tetrahydrofuran. The following abbreviations are also used: millimole (mmol), milliliter (mL), milligram (mg), microliter (μL), microgram (μg).

[0107] The following examples describe how to prepare various compounds and / or implement various methods of the present invention, and are to be construed as illustrative only and not limiting the foregoing disclosure in any way. Appropriate variations of the reagents and the methods of reaction conditions and techniques should be considered foreseeable to those skilled in the art.

[0108] Table 1 Summary of the names of the compounds in Examples 1-21

[0109]

[0110]

[0111]

[0112]

[0113]

[0114] Example 1

[0115] N,5-Bis(4-chlorophenyl)-3-(((1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methyl)imino)-3,5-dihydrophenazin-2-amine:

[0116]

[0117] Chemical reaction formula 1 shows the synthetic scheme for preparing this compound. Step 1: tert-Butyl ((1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methyl)carbamate. To a solution of tert-butyl (piperidin-4-ylmethyl)carbamate (0.215 g, 1.00 mmol) and potassium carbonate (0.276 g, 2.00 mmol) in acetonitrile (5 mL) was added 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl methanesulfonate (0.249 g, 1.00 mmol). The reaction mixture was stirred overnight at room temperature. The solution was poured into water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography to give the title product as a white solid (0.300 g, yield 82%). LC-MS (ESI): m / z = 386 (M+H) + .

[0118] Step 2: (1-(2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methanamine hydrochloride. To a solution of tert-butyl ((1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methyl)carbamate (0.300 g, 0.817 mmol) in dichloromethane (50 mL) was added a solution of hydrogen chloride in ethyl acetate (2.0 M, 4.0 mL, 8.0 mmol). The mixture was stirred overnight at room temperature. The solid was collected by filtration, washed with dichloromethane (15 mL) and dried in vacuo to give the title product as a white solid (0.218 g, 100%). LC-MS (ESI): m / z = 268 (M+H) + .

[0119] Step 3: N,5-Bis(4-chlorophenyl)-3-(((1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methyl)imino)-3,5-dihydrophenazin-2-amine. A solution of N,5-bis(4-chlorophenyl)-3-imino-3,5-dihydrophenazin-2-amine (0.086 g, 0.20 mmol), (1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methanamine hydrochloride (0.218 g, 0.817 mmol) and triethylamine (0.165 g, 1.63 mmol) in DMF (10 mL) was stirred overnight at 100 °C. The mixture was poured into water and extracted with DCM. The combined organic layers were washed three times with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title product as a black solid (0.030 g, 22%). 1 H NMR (400 MHz, CDCl 3)δ 11.4 - 10.20 (br m, 1H), 8.16 - 8.09 (m, 1H), 7.91 (s, 1H), 7.89 - 7.84 (m, 2H), 7.69 - 7.61 (m, 1H), 7.60 - 7.53 (m, 1H), 7.52 - 7.46 (m, 2H), 7.42 - 7.34 (m, 5H), 7.02 - 6.95 (m, 1H), 5.69 (s, 1H), 4.44 - 4.32 (m, 2H), 3.19 - 3.11 (m, 2H), 2.83 - 2.80 (m, 2H), 2.70 - 2.63 (m, 2H), 2.53 (s, 3H), 2.21 - 2.12 (m, 2H), 1.34 - 1.08 (m, 5H). LC-MS (ESI): m / z = 681 (M + H) + 。

[0120] Example 2

[0121] 2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl ((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)ethyl)carbamate:

[0122]

[0123] Chemical Reaction Scheme 2 shows the synthetic scheme for preparing this compound. Step 1: tert-Butyl (2-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)ethyl)carbamate. A solution of N,5-bis(4-chlorophenyl)-3-imino-3,5-dihydrophenazin-2-amine (0.200 g, 0.464 mmol) and tert-butyl (2-aminoethyl)carbamate (0.375 g, 2.32 mmol) in DMF (5 mL) was stirred at 100 °C overnight. The mixture was poured into water and extracted with DCM. The combined organic layers were washed with water 3 times and dried over anhydrous sodium sulfate.

[0124] Step 2: 3-((2-Aminoethyl)imino)-N,5-bis(4-chlorophenyl)-3,5-dihydrophenazin-2-amine hydrochloride. To a solution of tert-butyl (2-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)ethyl)carbamate (0.210 g, 0.365 mmol) in DCM (5 mL) was added a solution of hydrogen chloride in ethyl acetate (2.0 M, 1.5 mL, 3.0 mmol). The mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with dichloromethane (15 mL), and dried in vacuo to give the title product as a black solid (0.16 g, 100%). LC-MS (ESI): m / z = 474 (M + H)+ 。

[0125] Step 3: 2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl ((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)ethyl)carbamate. A solution of 3-((2-aminoethyl)imino)-N,5-bis(4-chlorophenyl)-3,5-dihydrophenazin-2-amine hydrochloride (0.080 g, 0.16 mmol), 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 1H-imidazole-1-carboxylate (0.090 g, 0.34 mmol) and triethylamine (0.035 g, 0.34 mmol) in dichloromethane (3 mL) was stirred overnight at room temperature. The solution was poured into water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography to give the title product as a black solid (0.022 g, yield 22%). 1 H NMR (400 MHz, CDCl 3 ) δ 10.25 (br, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.87 - 7.80 (m, 3H), 7.72 - 7.65 (m, 1H), 7.64 - 7.57 (m, 1H), 7.52 - 7.46 (m, 2H), 7.45 - 7.34 (m, 6H), 7.00 (d, J = 8.0 Hz, 1H), 5.77 (s, 1H), 4.53 - 4.47 (m, 2H), 4.41 - 4.35 (m, 2H), 3.66 - 3.58 (m, 2H), 3.22 - 3.16 (m, 2H), 2.48 (s, 3H). LC-MS (ESI): m / z = 671 (M + H) + 。

[0126] Example 3

[0127] (S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl 4-((((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)methyl)piperidine-1-carboxylate:

[0128]

[0129] The title compound was prepared using a similar method as described in Example 2, wherein N,5-bis(4-chlorophenyl)-3-((piperidin-4-ylmethyl)imino)-3,5-dihydrophenazine-2-amine hydrochloride and (S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl 1H-imidazole-1-carboxylate were used instead of 3-((2-aminoethyl)imino)-N,5-bis(4-chlorophenyl)-3,5-dihydrophenazine-2-amine hydrochloride and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 1H-imidazole-1-carboxylate. 1 H NMR(400MHz,CDCl 3 )δ11.20-11.08(br m,1H),8.16-8.11(m,1H),7.92-7.79(m,2H),7.70-7.63(m,1H),7.62-7.56(m,1H),7.50-7.34(m,8H),7.03-6.97(m,1H),5.71-5.63(m,1H),4.73-4.60(m,1H),4.47-4.41(m,1H),4.34-4.20(m,1H),4.19-4.12(m,1H),3.93-3.82(m,1H),3.19-3.10(m,2H),2.81-2.71(m,2H),2.36-2.11(m,2H),1.86-1.76(m,2H),1.30-1.23(m,3H). LC-MS(ESI):m / z=739(M+H) + 。

[0130] Example 4

[0131] (S)-N,5-bis(4-chlorophenyl)-3-(((1-(4-(((2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)oxy)methyl)benzyl)piperidin-4-yl)methyl)imino)-3,5-dihydrophenazine-2-amine:

[0132]

[0133] The title compound was prepared using a similar method as described in Example 2. N,5-Bis(4-chlorophenyl)-3-((piperidin-4-ylmethyl)imino)-3,5-dihydrophenazine-2-amine hydrochloride and (S)-6-(4-(chloromethyl)benzyloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine were used instead of 3-((2-aminoethyl)imino)-N,5-bis(4-chlorophenyl)-3,5-dihydrophenazine-2-amine hydrochloride and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 1H-imidazole-1-carboxylate. 1 H NMR(400MHz,CDCl 3 )δ10.27(br s,1H),8.11 - 8.05(m,1H),7.85 - 7.80(m,2H),7.63 - 7.50(m,2H),7.48 - 7.44(m,2H),7.40 - 7.33(m,8H),7.29 - 7.27(m,2H),6.97 - 6.89(m,1H),5.65(s,1H),4.74 - 4.69(m,1H),4.62 - 4.56(m,2H),4.37 - 4.31(m,1H),4.17 - 4.08(m,3H),3.73 - 3.63(m,2H),3.17 - 3.11(m,2H),3.05 - 2.95(m,2H),2.26 - 2.18(m,2H),1.86 - 1.76(m,3H),1.28 - 1.23(m,2H). LC-MS(ESI):m / z=815(M + H) + 。

[0134] Example 5

[0135] 8-(3-((10-(4-Chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinazoline-3-carboxylic acid:

[0136]

[0137] Step 1: Ethyl 8-(3-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoline-3-carboxylate. The title compound was prepared using a similar method as described in Example 2. Wherein N,5-bis(4-chlorophenyl)-3-(pyrrolidin-3-ylideneamino)-3,5-dihydrophenazin-2-amine hydrochloride and ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoline-3-carboxylate were used instead of 3-((2-aminoethyl)imino)-N,5-bis(4-chlorophenyl)-3,5-dihydrophenazin-2-amine hydrochloride and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 1H-imidazole-1-carboxylate. LC-MS (ESI): m / z = 787 (M+H) + .

[0138] Step 2: 8-(3-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoline-3-carboxylic acid. A solution of ethyl 8-(3-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoline-3-carboxylate (0.130 g, 0.165 mmol) in a mixture of THF (5 mL) and water (2 mL) was added with 1 M NaOH solution (0.50 mL, 0.50 mmol). The reaction mixture was stirred at room temperature for 3 hours, and 10% dilute hydrochloric acid was added, and a white solid was formed. The mixture was extracted with dichloromethane (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography to give the title product as a yellow solid (0.037 g, 29%). 1 H NMR (400 MHz, DMSO-d 6): δ 13.74 (s, 1H), 9.03 - 9.01 (m, 1H), 7.93 - 7.86 (m, 3H), 7.71 - 7.65 (m, 3H), 7.45 - 7.42 (m, 5H), 7.25 - 7.19 (m, 2H), 6.75 - 6.72 (m, 1H), 6.51 - 6.45 (m, 1H), 5.26 (s, 1H), 4.02 - 3.97 (m, 3H), 3.69 - 3.68 (m, 2H), 2.77 - 2.71 (m, 1H), 2.64 (s, 3H), 2.32 - 2.27 (m, 1H), 2.16 - 2.10 (m, 1H), 1.00 - 0.93 (m, 2H), 0.62 - 0.58 (m, 2H). LC-MS (ESI): m / z = 759 (M + H) + 。

[0139] Example 6

[0140] (R)-3-(4-(4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)methyl)piperidin-1-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one:

[0141]

[0142] The title compound was prepared using a similar method as described in Example 1. Wherein (R)-3-(4-(4-(aminomethyl)piperidin-1-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one was used instead of (1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methanamine hydrochloride. 1 H NMR (400 MHz, CDCl 3 ) δ 10.56 (s, 1H), 8.15 (d, J = 7.3 Hz, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.7 - 7.64 (m, 1H), 7.62 - 7.56 (m, 1H), 7.55 - 7.48 (m, 3H), 7.46 - 7.37 (m, 6H), 7.08 - 6.98 (m, 2H), 6.93 (t, J = 9.1 Hz, 1H), 4.77 - 4.70 (m, 1H), 4.03 - 3.90 (m, 4H), 3.76 (dd, J = 12.4, 4.1 Hz, 1H), 3.40 - 3.33 (m, 2H), 3.27 - 3.31 (m, 2H), 2.71 - 2.62 (m, 2H), 1.89 - 1.82 (m, 2H), 1.48 - 1.36 (m, 2H). LC-MS (ESI): m / z = 737.2 (M + H) + 。

[0143] Example 7

[0144] (S)-N-((3-(4-(4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)methyl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide

[0145]

[0146] The title compound was prepared using a similar method as described in Example 1, wherein (S)-N-((3-(4-(aminomethyl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide was used instead of (1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methanamine hydrochloride. 1 H NMR(400MHz,DMSO-d 6 ) δ 8.22 (t, J = 5.8 Hz, 2H), 8.03 - 7.95 (m, 2H), 7.82 - 7.74 (m, 2H), 7.58 - 7.51 (m, 3H), 7.48 - 7.43 (m, 6H), 7.20 - 7.15 (m, 2H), 7.08 (t, J = 9.4 Hz, 2H), 4.74 - 4.66 (m, 2H), 4.11 - 4.04 (m, 2H), 3.70 (dd, J = 9.1, 6.5 Hz, 2H), 3.42 - 3.38 (m, 2H), 3.19 - 3.15 (m, 1H), 2.63 - 2.53 (m, 2H), 1.83 (s, 3H), 1.70 - 1.62 (m, 1H), 1.42 - 1.33 (m, 2H), 1.28 - 1.23 (m, 2H). LC-MS(ESI): m / z = 778.2 (M + H) + .

[0147] Example 8

[0148] (R)-3-(4-(4-(2-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)ethyl)piperazin-1-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0149]

[0150] The title compound was prepared using a similar method as described in Example 1. Wherein (R)-3-(4-(4-(aminoethyl)piperazin-1-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one was used instead of (1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methanamine hydrochloride. 1 H NMR(400MHz,CDCl 3 )δ8.13-8.07(m,1H),7.84(d,J=8.4Hz,2H),7.67-7.59(m,1H),7.58-7.47(m,4H),7.47-7.34(m,7H),7.07(dd,J=8.8,2.0Hz,1H),6.97-6.87(m,2H),4.76-4.68(m,1H),4.00-3.93(m,3H),3.76(dd,J=12.6,4.0Hz,1H),3.54-3.43(m,3H),3.12-3.00(m,4H),2.87-2.78(m,2H),2.66-2.57(m,4H). LC-MS(ESI):m / z=752.2(M+H) + 。

[0151] Example 9

[0152] (S)-N-((3-(4-(4-(2-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)ethyl)piperazin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide:

[0153]

[0154] The title compound was prepared using a similar method as described in Example 1. Wherein (S)-N-((3-(4-(aminoethyl)piperazin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide was used instead of (1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methanamine hydrochloride. 1 H NMR(400MHz,DMSO-d 6)δ8.23(t, J = 5.7Hz, 1H), 7.98 - 7.91(m, 2H), 7.78 - 7.69(m, 1H), 7.54 - 7.46(m, 3H), 7.45 - 7.40(m, 2H), 7.21 - 7.16(m, 1H), 7.07(t, J = 9.3Hz, 1H), 4.75 - 4.67(m, 1H), 4.08(t, J = 9.0Hz, 1H), 3.71(dd, J = 9.0, 6.4Hz, 1H), 3.44 - 3.37(m, 4H), 3.31(m, 3H), 3.03 - 2.94(m, 4H), 2.69 - 2.56(m, 6H), 1.84(s, 3H). LC-MS(ESI): m / z = 793.2(M + H) + 。

[0155] Example 10

[0156] 4 - ((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidine-1-carboxamide:

[0157]

[0158] The title compound was prepared using a similar method as described in Example 2. Wherein N,5-bis(4-chlorophenyl)-3-(piperidin-4-ylideneamino)-3,5-dihydrophenazin-2-amine hydrochloride and N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)-1H-imidazole-1-carboxamide were used instead of 3-((2-aminoethyl)imino)-N,5-bis(4-chlorophenyl)-3,5-dihydrophenazin-2-amine hydrochloride and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 1H-imidazole-1-carboxylate. 1 H NMR(400MHz, DMSO-d 6)δ8.65(s,1H),8.02(s,1H),7.86(d,J=8.6Hz,2H),7.68-7.63(m,1H),7.60(d,J=8.6Hz,2H),7.49-7.41(m,4H),7.28-7.17(m,2H),6.76-6.68(m,2H),6.53-6.46(m,1H),5.16(s,1H),4.32(t,J=5.7Hz,2H),3.72-3.63(m,2H),3.41-3.34(m,2H),3.27-3.19(m,1H),2.86-2.75(m,2H),2.39(s,3H),1.55-1.45(m,2H),1.38-1.27(m,2H). LC-MS(ESI):m / z=710.6(M+H) + 。

[0159] Example 11

[0160] (2-Methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methyl 4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino))phenazin-2(10H)-ylidene)amino)methyl)piperidine-1-carboxylate:

[0161]

[0162] The title compound was prepared using a similar method as described in Example 2, wherein N,5-bis(4-chlorophenyl)-3-((piperidin-4-ylmethyl)imino)-3,5-dihydrophenazin-2-amine hydrochloride and (2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methyl 1H-imidazole-1-carboxylate were used instead of 3-((2-aminoethyl)imino)-N,5-bis(4-chlorophenyl)-3,5-dihydrophenazin-2-amine hydrochloride and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 1H-imidazole-1-carboxylate. 1 H NMR(400MHz,DMSO-d 6)δ 10.02 (s, 1H), 9.71 (s, 1H), 8.24 - 8.12 (m, 1H), 8.12 (s, 1H), 8.00 - 7.89 (m, 2H), 7.84 - 7.70 (m, 3H), 7.54 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.39 - 7.28 (m, 1H), 7.22 - 7.12 (m, 1H), 5.62 (s, 1H), 4.80 (dd, J = 11.6, 2.4 Hz, 1H), 4.58 (dd, J = 13.2, 2.4 Hz, 1H), 4.43 (d, J = 11.6 Hz, 1H), 4.17 (d, J = 13.2 Hz, 1H), 3.98 - 3.85 (m, 1H), 3.74 - 3.62 (m, 1H), 3.12 - 3.01 (m, 2H), 2.68 - 2.57 (m, 2H), 1.71 - 1.62 (m, 1H), 1.57 (s, 3H), 1.55 - 1.47 (m, 1H), 1.45 - 1.33 (m, 1H), 1.07 - 0.74 (m, 2H). LC-MS (ESI): m / z = 753 (M + H) + 。

[0163] Example 12

[0164] (R)-3-(3-Fluoro-4-(4-(((3-((2-Methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)methyl)piperidin-1-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one:

[0165]

[0166] The title compound was prepared using a similar method as described in Example 1, wherein (R)-3-(4-(4-(aminomethyl)piperidin-1-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one and 3-imino-N-(2-methoxypyridin-3-yl)-5-(4-(trifluoromethoxy)phenyl)-3,5-dihydrophenazin-2-amine were used instead of (1-(2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methanamine hydrochloride and N,5-bis(4-chlorophenyl)-3-imino-3,5-dihydrophenazin-2-amine. 1 H NMR (400 MHz, DMSO-d 6)δ10.17(s,1H),9.44(s,1H),8.23 - 8.16(m,2H),8.00 - 7.90(m,4H),7.83 - 7.73(m,3H),7.50(dd,J=14.8,2.4Hz,1H),7.22 - 7.13(m,3H),7.06(t,J=9.4Hz,1H),6.65(s,1H),5.69(s,1H),5.22(t,J=5.6Hz,1H),4.72 - 4.64(m,1H),4.04(t,J=9.0Hz,1H),3.92(s,3H),3.80(dd,J=8.9,6.2Hz,1H),3.70 - 3.63(m,1H),3.58 - 3.52(m,1H),3.32 - 3.24(m,2H),3.22 - 3.17(m,1H),2.60 - 2.50(m,2H),1.71 - 1.55(m,3H),1.40 - 1.27(m,2H). LC - MS(ESI):m / z=784(M + H) + 。

[0167] Example 13

[0168] (R)-3-(3 - fluoro - 4-(4-(2 - ((3 - ((2 - methoxypyridin - 3 - yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin - 2(10H)-ylidene)amino)ethyl)piperazin - 1 - yl)phenyl)-5-(hydroxymethyl)oxazolidin - 2 - one:

[0169]

[0170] The title compound was prepared using a similar method as described in Example 1, wherein (R)-3-(4-(4-(2 - aminoethyl)piperazin - 1 - yl)-3 - fluorophenyl)-5-(hydroxymethyl)oxazolidin - 2 - one and 3 - imino - N-(2 - methoxypyridin - 3 - yl)-5-(4-(trifluoromethoxy)phenyl)-3,5 - dihydrophenazin - 2 - amine were used instead of (1-(2-(2 - methyl - 5 - nitro - 1H - imidazol - 1 - yl)ethyl)piperidin - 4 - yl)methanamine hydrochloride and N,5 - bis(4 - chlorophenyl)-3 - imino - 3,5 - dihydrophenazin - 2 - amine. 1 H NMR(400MHz,DMSO - d 6) δ 8.87 (br s, 1H), 8.04 - 7.73 (m, 7H), 7.55 - 7.35 (m, 2H), 7.52 (dd, J = 15.0, 2.5 Hz, 1H), 7.22 - 7.17 (m, 1H), 7.12 (dd, J = 7.6, 5.0 Hz, 1H), 7.04 (t, J = 9.4 Hz, 1H), 6.92 - 6.60 (m, 1H), 6.83 (s, 1H), 5.19 (s, 1H), 4.72 - 4.65 (m, 1H), 4.04 (t, J = 9.0 Hz, 1H), 3.95 (s, 3H), 3.79 (dd, J = 8.8, 6.2 Hz, 1H), 3.70 - 3.63 (m, 1H), 3.58 - 3.52 (m, 1H), 3.40 - 3.32 (m, 2H), 3.00 - 2.93 (m, 3H), 2.68 - 2.54 (m, 5H). LC-MS (ESI): m / z = 799 (M + H) + 。

[0171] Example 14

[0172] 3 - [[[4 - [2 - ((3 - ((2 - methoxypyridin - 3 - yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin - 2(10H)-ylidene)amino)ethyl]-1 - piperazinyl]imino]methyl]rifamycin SV:

[0173]

[0174] Step 1: 3 - ((2-(4 - aminopiperazin - 1 - yl)ethyl)imino)-N-(2 - methoxypyridin - 3 - yl)-5-(4-(trifluoromethoxy)phenyl)-3,5 - dihydrophenazin - 2 - amine. To a solution of N-(2 - methoxypyridin - 3 - yl)-3 - ((2-(piperazin - 1 - yl)ethyl)imino)-5-(4-(trifluoromethoxy)phenyl)-3,5 - dihydrophenazin - 2 - amine (300 mg, 0.51 mmol) in acetone (2.5 mL) was added a solution of sodium hydroxide (480 mg, 12.0 mmol) in water (6 mL). The reaction mixture was cooled to 10 °C, and hydroxylamine - O - sulfate (288 mg, 2.55 mmol) was added in four portions under argon protection. The reaction mixture was stirred at 10 °C for 1 h to obtain a crude solution of the title compound, which was directly used in the next step.

[0175] Step 2: 3-[[[4-[2-((3-((2-Methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)ethyl]-1-piperazinyl]imino]methyl]rifamycin SV. A mixed solution of 3-formylrifamycin (333 mg, 0.46 mmol) in dichloromethane (2.5 mL) and acetone (1.5 mL) was cooled to 10 °C, and a mixture of methanol (2 mL), acetic acid (1.5 mL), and 15% aqueous L-(+)-ascorbic acid solution (0.5 mL) was added dropwise over 30 minutes. Then the crude product solution from Step 1 was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight, poured into water (10 mL), and extracted with dichloromethane (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate to methanol / dichloromethane 1 / 25) to give the title product as a yellow solid. 1 H NMR(400MHz,CDCl 3 )δ13.14(s,1H),12.01(s,1H),8.27(s,1H),8.18 - 8.03(m,1H),7.85 - 7.79(m,1H),7.76 - 7.64(m,2H),7.59 - 7.47(m,3H),7.01 - 6.95(m,1H),6.98 - 6.67(m,1H),6.59 - 6.50(m,1H),6.41 - 6.35(m,1H),6.25 - 6.18(m,1H),5.95 - 5.87(m,1H),5.14 - 5.07(m,1H),4.97 - 4.91(m,1H),4.15 - 4.08(m,1H),3.97(s,3H),3.78 - 3.72(m,1H),3.61 - 3.56(m,1H),3.50 - 3.37(m,4H),3.16 - 2.98(m,8H),2.95 - 2.86(m,2H),2.72 - 2.59(m,4H),2.38 - 2.30(m,1H),2.22(s,3H),2.09 - 2.03(m,8H),1.83 - 1.76(m,1H),1.79(s,3H),1.57 - 1.49(m,2H),1.38 - 1.32(m,2H),1.30 - 1.22(m,4H),1.00(d,J=6.8Hz,3H),0.84(d,J=6.8Hz,3H),0.59(d,J=6.7Hz,3H), - 0.30(d,J=6.8Hz,3H). LC-MS(ESI):m / z=1312(M + H) + 。

[0176] Example 15

[0177] 2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene))amino)piperidine-1-carboxylate:

[0178]

[0179] The title compound was prepared using a similar method as described in Example 2. Wherein N,5-bis(4-chlorophenyl)-3-(piperidin-4-ylideneamino)-3,5-dihydrophenazin-2-amine hydrochloride was used instead of 3-((2-aminoethyl)imino)-N,5-bis(4-chlorophenyl)-3,5-dihydrophenazin-2-amine hydrochloride. 1 H NMR(400MHz,DMSO-d 6 )δ9.53(s,1H),9.11(s,1H),8.14(s,1H),8.25 - 8.21(m,1H),8.05(s,1H),8.01 - 7.96(m,1H),7.84 - 7.77(m,3H),7.60 - 7.54(m,2H),7.49 - 7.44(m,2H),7.38(s,1H),7.25 - 7.18(m,1H),5.81(s,1H),4.63 - 4.58(m,2H),4.38 - 4.34(m,2H),3.96 - 3.64(m,2H),3.61 - 3.53(m,1H),3.05 - 2.99(m,1H),2.82 - 2.70(m,1H),2.46(s,3H),1.86 - 1.75(m,2H),1.60 - 1.49(m,2H). LC-MS(ESI):m / z=711(M + H) + 。

[0180] Example 16

[0181] N,5-Bis(4-chlorophenyl)-3-((2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)imino)-3,5-dihydrophenazin-2-amine:

[0182]

[0183] The title compound was prepared using a similar method as described in Example 1. Wherein 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethylamine was used instead of (1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methanamine hydrochloride. 1 H NMR(400MHz,CDCl 3) δ 7.90 (s, 1H), 7.86 - 7.72 (m, 3H), 7.39 - 7.29 (m, 9H), 7.10 - 6.91 (m, 1H), 6.74 - 6.48 (m, 1H), 4.63 (t, J = 6.0 Hz, 2H), 3.67 - 3.50 (m, 2H), 2.56 (s, 3H). LC-MS (ESI): m / z = 584 (M + H) + 。

[0184] Example 17

[0185] 2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)methyl)piperidine-1-carboxylate:

[0186]

[0187] The title compound was prepared using a similar method as described in Example 2, wherein N,5-bis(4-chlorophenyl)-3-((piperidin-4-ylmethyl)imino)-3,5-dihydrophenazin-2-amine hydrochloride was used instead of 3-((2-aminoethyl)imino)-N,5-bis(4-chlorophenyl)-3,5-dihydrophenazin-2-amine hydrochloride. 1 H NMR (400 MHz, CDCl 3 ) δ 11.07 (s, 1H), 10.53 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.98 (s, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.70 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.55 - 7.53 (m, 2H), 7.44 - 7.40 (m, 5H), 7.03 (t, J = 4 Hz, 1H), 5.73 (s, 1H), 4.67 - 4.62 (m, 2H), 4.45 (s, 1H), 4.19 - 4.16 (m, 1H), 3.91 - 3.89 (m, 1H), 3.18 - 3.17 (m, 2H), 2.78 (m, 2H), 2.51 (s, 3H), 2.24 (m, 1H), 1.79 (m, 2H), 1.09 (m, 2H). LC-MS (ESI): m / z = 725 (M + H) + 。

[0188] Example 18

[0189] 8-(4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)methyl)piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinazoline-3-carboxylic acid

[0190]

[0191] The title compound was prepared using a similar method as described in Example 5. N,5-Bis(4-chlorophenyl)-3-((piperidin-4-ylmethyl)imino)-3,5-dihydrophenazin-2-amine hydrochloride was used instead of N,5-bis(4-chlorophenyl)-3-(pyrrolidin-3-imino)-3,5-dihydrophenazin-2-amine hydrochloride. 1 H NMR(400MHz,DMSO-d 6 )δ13.87(s,1H),9.73(s,1H),9.37(s,1H),9.20(d,J=8.8Hz,1H),8.28-8.21(m,1H),8.05-7.97(m,3H),7.86-7.78(m,3H),7.59-7.53(m,2H),7.49-7.44(m,2H),7.43-7.38(m,1H),7.24-7.18(m,1H),5.81-5.74(m,1H),3.61-3.53(m,3H),2.76(s,3H),3.75-2.72(m,1H),2.44-2.37(m,2H),1.93-1.83(m,2H),1.74-1.66(m,2H),1.43-1.32(m,2H),1.05-0.96(m,2H),0.68-0.63(m,2H). LC-MS(ESI):m / z=787(M+H) + 。

[0192] Example 19

[0193] N-(2-Methoxypyridin-3-yl)-3-((2-(5-methyl-2-nitro-1H-imidazol-1-yl)ethyl)imino)-5-(4-(trifluoromethoxy)phenyl)-3,5-dihydrophenazin-2-amine

[0194]

[0195] The title compound was prepared using a similar method as described in Example 1. Where 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanamine and 3-imino-N-(2-methoxypyridin-3-yl)-5-(4-(trifluoromethoxy)phenyl)-3,5-dihydrophenazine-2-amine were used instead of (1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methanamine hydrochloride and N,5-bis(4-chlorophenyl)-3-imino-3,5-dihydrophenazine-2-amine. 1 H NMR(400MHz,DMSO-d 6 )δ8.46(s,1H),8.00(s,1H),7.95-7.85(m,2H),7.81-7.76(m,3H),7.73-7.63(m,3H),7.32-7.24(m,2H),7.13-7.07(m,1H),6.86(s,1H),6.49-6.43(m,1H),4.58-4.52(m,2H),3.98(s,3H),3.53–3.48(m,2H),2.46(s,3H). LC-MS(ESI):m / z=631(M+H) + 。

[0196] Example 20

[0197] 1-Cyclopropyl-7-fluoro-8-(4-(((3-((2-methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)methyl)piperidin-1-yl)-9-methyl-4-oxo-4H-quinazoline-3-carboxylic acid:

[0198] The title compound was prepared using a similar method as described in Example 18. Where N-(2-methoxypyridin-3-yl)-3-((piperidin-4-ylmethyl)imino)-5-(4-(trifluoromethoxy)phenyl)-3,5-dihydrophenazine-2-amine hydrochloride was used instead of N,5-bis(4-chlorophenyl)-3-((piperidin-4-ylmethyl)imino)-3,5-dihydrophenazine-2-amine hydrochloride. 1 HNMR(400MHz,CDCl 3)δ 13.86 (s, 1H), 9.18 (d, J = 9.0 Hz, 1H), 8.33 (s, 1H), 8.20 - 7.95 (m, 1H), 7.85 - 7.80 (m, 1H), 7.74 - 7.63 (m, 2H), 7.55 - 7.47 (m, 1H), 7.00 - 6.95 (m, 1H), 6.88 - 6.68 (m, 1H), 3.98 (s, 3H), 3.56 - 3.48 (m, 2H), 3.41 - 3.32 (m, 2H), 3.26 - 3.12 (m, 2H), 2.76 (s, 3H), 2.29 - 2.22 (m, 1H), 1.99 - 1.93 (m, 2H), 1.55 - 1.45 (m, 2H), 1.04 - 0.98 (m, 2H), 0.91 - 0.85 (m, 1H), 0.71 - 0.65 (m, 2H). LC-MS (ESI): m / z = 834 (M + H) + 。

[0199] Example 21

[0200] 4-Deoxy-3,4-[2-spiro-[1-(2-((3-((2-methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)ethyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S:

[0201]

[0202] Step 1: 3-((2-(1,4-Dioxo-8-azaspiro[4.5]dec-8-yl)ethyl)imino)-N-(2-methoxypyridin-3-yl)-5-(4-(trifluoromethoxy)phenyl)-3,5-dihydrophenazin-2-amine. The title compound was prepared using a similar method as described in Example 1. Wherein 2-(1,4-dioxo-8-azaspiro[4.5]dec-8-yl)ethylamine and 3-imino-N-(2-methoxypyridin-3-yl)-5-(4-(trifluoromethoxy)phenyl)-3,5-dihydrophenazin-2-amine were used instead of (1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methylamine hydrochloride and N,5-bis(4-chlorophenyl)-3-imino-3,5-dihydrophenazin-2-amine.

[0203] Step 2: 1-(2-((3-((2-Methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)ethyl)piperidin-4-one. A concentrated sulfuric acid solution of 3-((2-(1,4-dioxo-8-azaspiro[4.5]dec-8-yl)ethyl)imino)-N-(2-methoxypyridin-3-yl)-5-(4-(trifluoromethoxy)phenyl)-3,5-dihydrophenazin-2-amine was stirred at room temperature for 4 hours. The reaction mixture was quenched with ice water, neutralized to neutral with aqueous sodium carbonate solution, and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title product as a brown solid.

[0204] Step 3: 4-Deoxy-3,4-[2-spiro-[1-(2-((3-((2-methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)ethyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S. To a solution of 1-(2-((3-((2-methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)ethyl)piperidin-4-one (1.00 g, 1.66 mmol) in tetrahydrofuran (20 mL) was added 3-amino-4-deoxy-4-imino-rifamycin S (5.69 g, 1.83 mmol) and ammonium acetate (0.258 g, 3.34 mmol). The reaction mixture was stirred at room temperature for 12 hours, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to give the title product as a purple solid. 1 H NMR(400MHz,CDCl 3)δ14.66(s,1H),8.95(s,1H),8.22(s,1H),7.98 - 7.81(m,3H),7.69 - 7.60(m,2H),7.53 - 7.44(m,2H),6.98 - 6.86(m,2H),6.36(dd,J=15.2,10.4Hz,1H),6.24(d,J=10.4Hz,1H),6.13(d,J=12.4Hz,1H),6.00(dd,J=15.6,6.6Hz,1H),5.55 - 5.30(m,1H),5.11(dd,J=12.4,7.2Hz,1H),4.79 - 4.72(m,1H),4.00(s,3H),3.69 - 3.63(m,1H),3.63 - 3.58(m,1H),3.55 - 3.42(m,2H),3.33 - 3.28(m,1H),3.27 - 3.19(m,1H),3.16 - 2.90(m,8H),2.43 - 2.31(m,2H),2.32(s,3H),2.08 - 1.96(m,7H),1.79 - 1.68(m,6H),1.47 - 1.40(m,1H),1.29(s,12H),1.03(d,J=6.6Hz,3H),0.91 - 0.84(m,2H),0.83(d,J=6.6Hz,3H),0.59(d,J=6.4Hz,3H), - 0.08(d,J=6.8Hz,3H). LC - MS(ESI): m / z=1295(M + H) + 。

[0205] Those skilled in the art should readily understand that the disclosed invention is well suited to achieve the mentioned and inherent objectives. The linkers, pharmacophores and their functional equivalents, pharmaceutical compositions, treatments, methods, procedures and techniques described herein are presented as representatives of preferred embodiments and are not intended to limit the scope of the invention. Therefore, other uses within the spirit and principles of the said invention should be regarded as readily conceivable to those skilled in the art.

[0206] Experimental Example:

[0207] Biological Activity

[0208] Minimum Inhibitory Concentration Test

[0209] The minimum inhibitory concentration (MIC) was determined by broth microdilution method according to the recommendations of the Clinical and Laboratory Standards Institute (CLSI) with slight modification. Staphylococcus aureus ATCC 29213, originally from the American Type Culture Collection (ATCC), was used for the MIC determination of the compound. The bacterial inoculum in the test was approximately 5×10 5CFU per well. The MIC was defined as the minimum concentration after incubation at 37 °C for 18 - 20 hours without visible bacterial growth. The results are shown in Table 2 below.

[0210] Table 2. MIC (μg / mL) of iminophenazine-derived conjugate molecules and control drugs against Staphylococcus aureus ATCC 29213 strain

[0211]

[0212]

[0213] As can be seen from the above table, the anti-Staphylococcus aureus activity of this series of conjugate molecules is similar to or better than that of the clinically used antibiotics linezolid and vancomycin, basically reaching more than 2 times, showing a good antibacterial effect.

[0214] The above experimental results indicate that: the iminophenazine-derived conjugate compounds of the present invention, and their stereoisomers, hydrates, deuterated compounds, esters, solvates, crystal forms, metabolites, pharmaceutically acceptable salts, prodrugs, or the above pharmaceutical compositions, can be used for the treatment or prevention of microbial infections.

[0215] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and various modifications or changes based on them have been prompted to those skilled in the art, and these modifications or changes are included within the spirit and scope of the present application and the appended claims.

Claims

1. An iminophenazine-derived coupling compound selected from any one of the following compounds: N,5-bis(4-chlorophenyl)-3-(((1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)methyl)imino)-3,5-dihydrophenazin-2-amine; 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazine-2(10H)-ylidene)amino)ethyl)carbamate; (S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl 4-((((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazine-2(10H)-ylidene)amino)methyl)piperidine-1-carboxylate; (S)-N,5-bis(4-chlorophenyl)-3-(((1-(4-(((2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)oxy)methyl)benzyl)piperidin-4-yl)methyl)imino)-3,5-dihydrophenazin-2-amine; 8-(3-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazine-2(10H)-ylidene)amino)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolinazine-3-carboxylic acid; (R)-3-(4-(4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)methyl)piperidin-1-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one; (S)-N-((3-(4-(4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)methyl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide; (R)-3-(4-(4-(2-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)ethyl)piperazin-1-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one; (S)-N-((3-(4-(4-(2-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazin-2(10H)-ylidene)amino)ethyl)piperazin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide; 4-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazine-2(10H)-ylidene)amino)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)piperidine-1-carboxamide; (2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methyl 4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino))phenazine-2(10H)-ylidene)amino)methyl)piperidine-1-carboxylate; (R)-3-(3-fluoro-4-(4-(((3-((2-methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)methyl)piperidin-1-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one; (R)-3-(3-fluoro-4-(4-(2-((3-((2-methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)ethyl)piperazin-1-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one; 3-[[[4-[2-((3-((2-methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazine-2(10H)-ylidene)amino)ethyl]-1-piperazinyl]imino]methyl]rifamycin SV; 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazine-2(10H)-ylidene))amino)piperidine-1-carboxylate; N,5-bis(4-chlorophenyl)-3-((2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)imino)-3,5-dihydrophenazin-2-amine; 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazine-2(10H)-ylidene)amino)methyl)piperidine-1-carboxylate; 8-(4-(((10-(4-chlorophenyl)-3-((4-chlorophenyl)amino)phenazine-2(10H)-ylidene)amino)methyl)piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolinazine-3-carboxylic acid; N-(2-methoxypyridin-3-yl)-3-((2-(5-methyl-2-nitro-1H-imidazol-1-yl)ethyl)imino)-5-(4-(trifluoromethoxy)phenyl)-3,5-dihydrophenazin-2-amine; 1-cyclopropyl-7-fluoro-8-(4-(((3-((2-methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)methyl)piperidin-1-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 4-deoxy-3,4-[2-spiro-[1-(2-((3-((2-methoxypyridin-3-yl)amino)-10-(4-(trifluoromethoxy)phenyl)phenazin-2(10H)-ylidene)amino)ethyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S.

2. A pharmaceutical composition, the components of which include the iminophenazine derivative coupling compound according to claim 1.

3. The pharmaceutical composition according to claim 2, characterized in that The components of the pharmaceutical composition also include at least one antibacterial agent.

4. Use of the iminophenazine derivative coupling compound according to claim 1 in the preparation of a drug for treating or preventing Staphylococcus aureus infection.

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