A preparation method and use of aromatic iminothiazole compounds

Abstract

The present invention provides an aryliminothiazole compound represented by Formula I or a pharmaceutically acceptable salt thereof, as well as a preparation method and use thereof. These compounds or pharmaceutically acceptable salts thereof can simultaneously enhance the activity of polymyxin E against Gram-negative bacteria and daptomycin against Gram-positive bacteria, and can be used in the antibacterial treatment of pathogens that are insensitive to polymyxins. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry; specifically, the present invention relates to an antibacterial synergist capable of simultaneously enhancing the effects of polymyxin E against Gram-negative bacteria and daptomycin against Gram-positive bacteria, a preparation method of the compound salt and derivatives thereof, and uses thereof. Background Art

[0002] Since the advent of penicillin in the 1940s, a wide range of antibiotics have emerged, making significant contributions to human antimicrobial therapy. However, due to the increase in bacterial infections and the inappropriate use of antibiotics, clinically resistant strains have also emerged. The World Health Organization recently released a global priority list of drug-resistant bacterial pathogens. Bacterial pathogens are classified as urgent, high, and medium priority based on multiple criteria, including mortality, prevalence of resistance, and treatability. Among these, infections caused by multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) Gram-negative bacteria are particularly problematic. Among clinically isolated Gram-negative bacteria, the most common include Escherichia coli (E. coli), Klebsiella pneumoniae, Acinetobacter baumanii, and Pseudomonas aeruginosa. Treating infections caused by these superbugs is becoming an increasingly challenging issue.

[0003] Drug-resistant Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE), are the main pathogens of nosocomial bacterial infections, causing bloodstream infections, skin and soft tissue infections, pneumonia, and infective endocarditis. Nosocomial infections caused by drug-resistant bacteria increase the difficulty of clinical treatment and prevention of cross-infection.

[0004] In recent years, with the widespread use of broad-spectrum antibiotics and the increase in indwelling catheters, the incidence of Gram-positive cocci (GPC) infections has tended to increase, with a significant increase in the detection rate of MRSA.

[0005] Polymyxin has been used clinically since 1952 and has demonstrated excellent bactericidal efficacy against Gram-negative bacteria. However, its significant nephrotoxicity and neurotoxicity limited its use, and with the advent of newer carbapenem antibiotics, polymyxin was gradually discontinued from clinical use. However, with the emergence of antibiotic-resistant "superbugs," polymyxin has been revived as a 21st-century "last line of defense" against Gram-negative infections, particularly for infections with extensively drug-resistant Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa, as these bacteria are currently only susceptible to polymyxins.

[0006] Daptomycin (DAP) is a novel cyclic lipopeptide antibiotic that was originally isolated from Streptomyces roseosporus in the 1980s. Daptomycin can be used to treat skin infections, bacteremia, and endocardial infections caused by Gram-positive bacteria such as Staphylococcus aureus, methicillin-sensitive and -resistant bacteria (MSSA and MRSA), and several streptococci and enterococci. Daptomycin is one of the few polypeptide antibiotics that can be used systemically. Since its clinical introduction in 2003, it has become a first-line antibiotic for the treatment of serious infections caused by Gram-positive bacteria and an important option for the treatment of bacterial infections caused by multidrug-resistant Gram-positive bacteria. Daptomycin only needs to be used once daily to achieve the dosage standard. It also has an excellent safety profile and low bacterial resistance to it. It is currently recognized worldwide as the best alternative to currently used antibiotics such as vancomycin. Summary of the Invention

[0007] The object of the present invention is to provide a compound which has excellent synergistic function on polymyxin and daptomycin and excellent drugability.

[0008] In a first aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0009]

[0010] Where:

[0011] X represents a substituted or unsubstituted C 1-10 Alkylene (preferably substituted or unsubstituted C 1-6 alkylene), substituted or unsubstituted C 2-10 Alkenylene (preferably substituted or unsubstituted C 1-6 Alkenylene) or substituted or unsubstituted C 2-10 Alkyne group (preferably substituted or unsubstituted C 1-6 Alkynylidene), C(O), C(O)O,

[0012] Y represents no, substituted or unsubstituted C 1-10 Alkylene (preferably substituted or unsubstituted C 1-6 alkylene), substituted or unsubstituted C 2-10 Alkenylene (preferably substituted or unsubstituted C 1-6 alkenylene), substituted or unsubstituted C 2-10 Alkyne group (preferably substituted or unsubstituted C 1-6 Alkynylidene), substituted or unsubstituted C 3-7 Cycloalkylene, substituted or unsubstituted C 5-7cycloalkenylene, substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted 5- or 6-membered heterocyclylene, or substituted or unsubstituted 8- to 14-membered heteroaromatic bicyclic or tricyclic ring system;

[0013] M stands for None, or NR'R",

[0014] wherein R' and R" are each independently selected from H, substituted or unsubstituted C 1-6 Alkyl (e.g., alkenyl-substituted or alkynyl-substituted alkyl), substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, or substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 5-7 cycloalkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5- or 6-membered heterocyclyl, or substituted or unsubstituted 8- to 12-membered heteroaromatic bicyclic ring system.

[0015] In a preferred embodiment, the "substituted" refers to being substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C 1-6 Alkoxy, hydroxy, hydroxy C 1-6 Alkyl, hydroxyl C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Carboxyl, substituted or unsubstituted thiol, substituted or unsubstituted C 2-6 Ester group, substituted or unsubstituted C 1-6 Amide, substituted or unsubstituted C 6-10 Aryl.

[0016] In a preferred embodiment, the "substituted" refers to being substituted by one or more groups selected from the group consisting of: CH3-, HN=C(NH2)-NH-(CH2)3-, H2N-CO-CH2-, HOOC-CH2-, HS-CH2-, H2N-CO-(CH2)2-, HOOC-(CH2)2-, CH3-CH2-CH(CH3)-, (CH3)2CH-CH2-, H2N-(CH2)4-, CH3-S-(CH2)2-, Ph-CH2-, HO-CH2-, CH3-CH(OH)-, HO-Ph-CH2- (preferably HO-p-Ph-CH2-), (CH3)2CH-, -CH2-COOCH3, -CH2-COOCH2CH3, -(CH2)2-COOCH3, -(CH2)2-COOCH2CH3, -CH2-O-CH3, -CH2-O-CH2CH3, -CH(CH3)-O-CH3, -CH(CH3)-O-CH2CH3.

[0017] In a specific embodiment, X represents a substituted or unsubstituted C 1-10 Alkylene (preferably substituted or unsubstituted C 1-6 alkylene), substituted or unsubstituted C 2-10 Alkenylene (preferably substituted or unsubstituted C 1-6 Alkenylene) or substituted or unsubstituted C 2-10 Alkyne group (preferably substituted or unsubstituted C 1-6 alkynylene), C(O) or C(O)O;

[0018] Y represents a substituted or unsubstituted C 1-10 Alkylene (preferably substituted or unsubstituted C 1-6 alkylene), substituted or unsubstituted C 2-10 Alkenylene (preferably substituted or unsubstituted C 1-6 alkenylene), or substituted or unsubstituted C 2-10 Alkyne group (preferably substituted or unsubstituted C 1-6 alkynylene);

[0019] M stands for NR'R",

[0020] wherein R' and R" are as described above.

[0021] In a specific embodiment, X represents C(O) or C(O)O;

[0022] Y represents a substituted or unsubstituted C 1-10 Alkylene (preferably substituted or unsubstituted C 1-6 alkylene);

[0023] M stands for NR'R",

[0024] wherein R' and R" are as described above.

[0025] In a specific embodiment, the compound is represented by the following formula:

[0026]

[0027] Wherein, Y and M are as described above.

[0028] In a specific embodiment, when the compound is as shown in Formula IV, Y is a substituted or unsubstituted C 1-10 Alkylene (preferably substituted or unsubstituted C 1-6 alkylene), substituted or unsubstituted C 2-10 Alkenylene (preferably substituted or unsubstituted C 1-6 alkenylene), substituted or unsubstituted C 2-10 Alkyne group (preferably substituted or unsubstituted C 1-6 alkynylene);

[0029] M is -NH2, Preferably

[0030] When the compound is as shown in Formula IV, Y is substituted or unsubstituted C 1-10 Alkylene (preferably substituted or unsubstituted C 1-6 Alkylene); M is -NH2;

[0031] or,

[0032] When the compound is as shown in Formula V, Y is substituted or unsubstituted C 1-10 Alkylene (preferably substituted or unsubstituted C 1-6 alkylene), substituted or unsubstituted C 2-10 Alkenylene (preferably substituted or unsubstituted C 1-6 alkenylene), substituted or unsubstituted C 2-10 Alkyne group (preferably substituted or unsubstituted C 1-6 alkynylene);

[0033] M is -NH2, Preferably,

[0034] When the compound is as shown in Formula V, Y is substituted or unsubstituted C 1-10 Alkylene (preferably substituted or unsubstituted C 1-6 alkylene), M is -NH2.

[0035] In a specific embodiment, the pharmaceutically acceptable salt is a salt of the compound formed with a pharmaceutically acceptable inorganic acid or organic acid, or a salt formed with a base.

[0036] In a preferred embodiment, the inorganic acid includes (but is not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; the organic acid includes (but is not limited to): various natural and artificial amino acids, formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid (1,5), linaloic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid;

[0037] In a preferred embodiment, the pharmaceutically acceptable salt is a salt formed by the compound with hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, nitric acid, formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, succinic acid, or butenedioic acid.

[0038] In a preferred embodiment, the pharmaceutically acceptable salt is a salt formed by the compound and an appropriate inorganic or organic cation (base), including alkali metal salts, alkaline earth metal salts, amine salts and salts formed by nitrogen-containing organic bases. The alkali metal salts include but are not limited to sodium salts and potassium salts; the alkaline earth metal salts include but are not limited to metal elements such as beryllium (Be), magnesium (Me), calcium (Ca), strontium (Sr), barium (Ba), and radium (Ra); the nitrogen-containing organic bases include but are not limited to aliphatic amines (such as ethylenediamine, diethylamine, and ethanolamine), cyclic amines (such as morpholine, piperazine, and piperidine), aromatic amines, and alkaloids (such as ephedrine, amino acids, and theobromine).

[0039] In a specific embodiment,

[0040] When M is NR'R",

[0041] The inorganic acids include (but are not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid; preferred organic acids include (but are not limited to): various natural and artificial amino acids, formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid (1,5), linaloic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, and citric acid;

[0042] When M is When, the salt is a Na salt or a K salt.

[0043] In a second aspect, the present invention provides a compound of formula II,

[0044]

[0045] The compound is a salt formed with an inorganic acid or an organic acid or a salt formed with a base.

[0046] In a preferred embodiment, the inorganic acid includes (but is not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; the organic acid includes (but is not limited to): various natural and artificial amino acids, formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid (1,5), linaloic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid;

[0047] In a preferred embodiment, the pharmaceutically acceptable salt is a salt formed by the compound with hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, nitric acid, formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, succinic acid, or butenedioic acid.

[0048] In a third aspect, the present invention provides a pharmaceutical composition comprising the compound according to the first or second aspect or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable excipient.

[0049] In a preferred embodiment, the pharmaceutical composition is a polymyxin and / or daptomycin potentiator.

[0050] In a preferred embodiment, the polymyxin is colistin.

[0051] In a fourth aspect, the present invention provides a pharmaceutical composition comprising the compound of the first or second aspect or a pharmaceutically acceptable salt thereof, an optional pharmaceutically acceptable excipient and polymyxin and / or daptomycin (preferably polymyxin and daptomycin).

[0052] In a preferred embodiment, the polymyxin is colistin.

[0053] In a fifth aspect, the present invention provides use of the compound according to the first or second aspect or a pharmaceutically acceptable salt thereof in the preparation of a polymyxin and / or daptomycin (preferably polymyxin and daptomycin) synergist.

[0054] In a preferred embodiment, the polymyxin is colistin.

[0055] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 The bactericidal effect of I-31-enhanced polymyxin against Gram-negative bacteria was shown;

[0057] Figure 2 Shown are time-kill curves for 4 μg / ml I-31 potentiating daptomycin against Gram-positive bacteria. DETAILED DESCRIPTION

[0058] After extensive and in-depth research, the inventors unexpectedly discovered a series of derivatives of 4-(2,4-difluorophenyl)-N-(4-(trifluoromethyl)phenyl)thiazol-2-amine that exhibit potent synergistic antibiotic activity, such as colistin and / or daptomycin. These derivatives also exhibit excellent water solubility after salification, resulting in excellent drugability. This work led to the present invention.

[0059] definition

[0060] Unless otherwise defined, the technical and scientific terms used in the present invention have the same meaning as the general understanding of the common technology in the field to which the present invention belongs. For the sake of clarity, some terms used in this article are defined as follows.

[0061] The "subunit" mentioned herein refers to a compound formed by formally eliminating two monovalent or one divalent atoms or groups, and the remaining part is called a subunit.

[0062] For example, the term "C 1-10 "Alkylene" refers to a straight or branched chain alkylene group having 1 to 10 carbon atoms, such as methylene, ethylene, propylene and the like. Similarly, the term "C 2-10 "Alkenylene" refers to a straight or branched chain alkenylene group having 2 to 10 carbon atoms; the term "C 2-10 The term "alkynylene" refers to a straight-chain or branched alkynylene group having 2 to 10 carbon atoms.

[0063] As used herein, the term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms, such as methyl, ethyl, propyl, and the like. Similarly, as used herein, the term "alkenyl" refers to a straight or branched chain alkenyl group having the indicated number of carbon atoms; and the term "alkynyl" refers to a straight or branched chain alkynyl group having the indicated number of carbon atoms. In addition, those skilled in the art will understand that when an alkenyl or alkynyl substituent is referred to herein, it can refer to the case where the carbon forming the double or triple bond is directly attached to the main body of the compound, or it can refer to the case where the alkenyl or alkynyl substituent is attached to the main body of the compound through an alkylene chain; that is, the "compound main body -(CH2) n -C=C" or "compound main body -(CH2) n-C≡C", when the carbon forming the double bond or triple bond is directly connected to the main body of the compound, n is 0, and when the alkenyl or alkynyl substituent is connected to the main body of the compound through an alkylene chain, n is a positive integer greater than 0.

[0064] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0065] The term "C 1-6 The term "alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like.

[0066] The term "ring" or "ring system" refers to a carbocyclic or heterocyclic ring.

[0067] The term "aryl" refers to a monocyclic, bicyclic or condensed-ring aromatic hydrocarbon group. The aryl group may be substituted or unsubstituted. When an aryl group is preceded by a carbon atom number limit (such as C6-12), it means that the aryl group contains 6-12 carbon atoms. When the aryl group is bicyclic, at least one ring is an aromatic ring, and the other ring may be saturated or unsaturated, and may contain no or one or more heteroatoms, wherein the heteroatoms are selected from N, O, and S. Examples of aryl groups include (but are not limited to): phenyl, biphenyl, naphthyl, or similar groups (each carbon atom of which may be arbitrarily substituted). Unless otherwise specified, the aryl group herein is an aryl group containing 6-12 carbon atoms.

[0068] The term "heteroaryl" refers to a monocyclic, bicyclic, or fused-ring aromatic group having a specific number of ring carbon atoms (e.g., C4-10, which has 4-10 ring carbon atoms) and including at least one heteroatom selected from N, O, or S, which may be the same or different. Each ring atom may be substituted. The heteroaryl group may be a 5- to 15-membered aromatic ring group having 1-5 heteroatoms, each independently selected from N, O, or S. Examples of heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrrole, indazole, indole, furan, benzofuran, thiophene, or similar groups, as well as 8- to 12-membered heteroaromatic bicyclic ring systems, all of which may be substituted or unsubstituted. Unless otherwise specified, heteroaryl groups in the present invention are 5- to 15-membered heteroaryl groups.

[0069] The term "heterocyclyl" refers to a saturated or partially saturated monocyclic or fused ring substituent having a specific number of ring carbon atoms (e.g., C3-11 means having 3-11 ring carbon atoms) and including at least one heteroatom selected from N, O or S, which may be the same or different. The heterocyclyl may be a 3- to 15-membered heterocyclyl having 1-5 heteroatoms independently selected from N, O or S. Examples of heterocyclyls include (but are not limited to): nitrogen heterocyclyl, oxygen heterocyclyl, sulfur heterocyclyl, nitrogen oxygen heterocyclyl, nitrogen sulfur heterocyclyl, oxygen sulfur heterocyclyl, etc., and more preferably the heterocyclyls appearing in the embodiments of the present application. In the present invention, the heterocyclyl may be monocyclic, bicyclic or tricyclic (including cyclic, bridged or spirocyclic).

[0070] The term "heterocycle" refers to an atom in which at least one of the atoms forming the heterocycle skeleton is not carbon but is nitrogen, oxygen or sulfur. Typically, the heterocycle contains no more than 4 nitrogen atoms, no more than 2 oxygen atoms and / or no more than 2 sulfur atoms. Unless otherwise indicated, the heterocycle may be a saturated, partially unsaturated or fully unsaturated ring.

[0071] The term "ring system" refers to two or more rings fused together.

[0072] As used herein, the term "5-membered or 6-membered heterocyclyl" refers to a five-membered or six-membered ring containing one or more heteroatoms selected from nitrogen, oxygen or sulfur, for example, pyridyl, thiazolyl, isothiazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, pyrimidinyl, tetrahydrofuranyl, 4,5-dihydrothiazol-2-yl, 2-cyanoimino-4-oxo-1,3-thiazolidin-3-yl, 2-cyanoimino-4-oxo-1,3-thiazin-3-yl, oxazolyl, isoxazolyl, 1H-tetrazolyl, 1H-1,2,3-triazolyl, 4H-1,2,4- triazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl or tetrazolyl, and the like.

[0073] The term "heterocyclic ring system" refers to a ring system in which at least one ring of the ring system is a heterocycle.

[0074] The term "heteroaromatic ring system" refers to a system in which at least one ring in the ring system is aromatic.

[0075] As used herein, the term "8- to 12-membered heteroaromatic bicyclic ring system" or "8- to 14-membered heteroaromatic bicyclic or tricyclic ring system" may be selected from the group consisting of benzofuran, benzo[b]thiophene, indole, quinoline, isoquinoline, 1H-indazole, 1H-benzo[d]imidazole, benzo[d]thiazole, benzo[d]oxazole, benzo[d]isoxazole, benzo[d][1,2,3]thiadiazole, 2,3-dihydroimidazo[1,2-a]pyridine, quinazoline, quinoxaline, cinnoline, phthalazine, 1,8-naphthyridine, 4,5,6,7-tetrahydrobenzo[b]thiophene, benzo[b]thiophene-1,1- dioxane, 8H-indeno[2,1-b]thiophene, 7,8-dihydro-6H-cyclopenta[4,5]thieno[2,3-d]pyrimidine, 3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-one, spiro[indoline-3,2'-[1,3]dioxolane]-2-one, spiro[indoline-3,2'-[1,3]dioxane]-2-one, or indoline-2,3-dione.

[0076] The term "heterocyclylalkyl" refers to an alkyl group having a heterocyclyl substituent, that is, one or more hydrogen atoms on the alkyl group are replaced by one or more heterocyclylalkyl groups. When there are multiple heterocyclylalkyl groups, each heterocyclylalkyl group may be the same or different.

[0077] Unless otherwise specified, the groups described in the present invention may be substituted as long as the substitution meets the valence requirements. For example, the groups described in the present invention may be substituted by one or more groups selected from the following groups: halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 2-6 Alkynyl, C 2-6 Haloalkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxy, hydroxy C 1-4 Alkyl, hydroxyl C 1-4 Alkoxy.

[0078] Compounds of the present invention

[0079]

[0080] Previous research has synthesized the compound 4-(2,4-difluorophenyl)-N-(4-(trifluoromethyl)phenyl)thiazol-2-amine (KJ1311), which was found to have excellent antibacterial activity against antibiotics such as colistin. This compound can be used to treat a range of diseases associated with Acinetobacter baumannii and Klebsiella pneumoniae, effectively reducing the dosage of colistin and the risk of colistin toxicity during treatment. Furthermore, it can be used to treat Acinetobacter baumannii and Klebsiella pneumoniae that are insensitive to colistin or have weak antibacterial activity. However, this compound has poor water solubility, which limits its clinical use.

[0081] To this end, the inventors have structurally modified the compound to obtain a compound represented by Formula I or a pharmaceutically acceptable salt thereof. The compound represented by Formula I not only retains the activity of the original compound, but also significantly improves its water solubility after salt formation:

[0082]

[0083] Wherein, X, Y and M are as described above.

[0084] In a specific embodiment, the present invention provides the compounds shown in Table A below

[0085] Table A

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093] After the compound represented by Formula I forms a pharmaceutically acceptable salt, its water solubility is significantly improved, thereby having excellent drugability.

[0094] The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound of the present invention formed with a pharmaceutically acceptable inorganic acid or organic acid or a salt formed with a base, wherein the inorganic acid includes (but is not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; the organic acid includes (but is not limited to): various natural and artificial amino acids, formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid (1,5), asiatic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid; salts formed with appropriate inorganic or organic cations (bases), including alkali metal salts, alkaline earth metal salts, amine salts and salts formed with nitrogen-containing organic bases, the alkali metal salts including but not limited to sodium salts and potassium salts; the alkaline earth metal salts including but not limited to beryllium (Be), magnesium (Me), calcium (Ca), strontium (Sr), barium (Ba), radium (Ra) and other metal elements; the nitrogen-containing organic bases including but not limited to aliphatic amines (such as ethylenediamine, diethylamine, ethanolamine), cyclic amines (such as morpholine, piperazine, piperidine), aromatic amines, alkaloids (such as ephedrine, amino acids, theobromine).

[0095] The compound 4-(2,4-difluorophenyl)-N-(4-(trifluoromethyl)phenyl)thiazol-2-amine has excellent synergistic effects on polypeptide antibiotics, but its water solubility is poor. Therefore, the present invention also provides a pharmaceutically acceptable salt of this compound that, while retaining its activity, effectively improves its solubility in water, allowing it to be used to treat, prevent, and alleviate diseases associated with bacterial infections.

[0096] The pharmaceutically acceptable salt of the compound 4-(2,4-difluorophenyl)-N-(4-(trifluoromethyl)phenyl)thiazol-2-amine is shown in Formula II:

[0097]

[0098] The salt is a salt formed by the compound 4-(2,4-difluorophenyl)-N-(4-(trifluoromethyl)phenyl)thiazol-2-amine with an inorganic acid or an organic acid, or a salt formed with a base. The inorganic acid, organic acid or base is as described above.

[0099] In a preferred embodiment of the present invention, representative compounds of formula II are shown in Table B below:

[0100] Table B

[0101]

[0102]

[0103] Based on the teachings of the present invention, those skilled in the art will recognize that the compounds of the present invention can possess pharmaceutical activity; in other words, the compounds of the present invention can be applied to a subject as a drug. Therefore, those skilled in the art will also understand that, as a drug, the compounds of the present invention should naturally possess various inherent properties of a drug, such as therapeutic activity, toxicity, bioavailability, stability, half-life, and the like. Those skilled in the art can detect these properties using existing techniques, but due to space limitations, they will not be detailed here.

[0104] Pharmaceutical composition of the present invention

[0105] Because the compound of the present invention not only shows good synergistic effect on polymyxins, such as colistin, but also shows good synergistic effect on daptomycin. The compound of the present invention can also have excellent water solubility, so the compound of the present invention has excellent drugability. On this basis, the present invention provides a pharmaceutical composition, which is a synergist for polymyxin and / or daptomycin. In a specific embodiment, the pharmaceutical composition includes a compound of the present invention or a pharmaceutically acceptable salt thereof and an optional pharmaceutically acceptable excipient.

[0106] Based on the teachings of the present invention, it is contemplated that the compounds of the present invention may be combined directly with polymyxins and / or daptomycin to provide a drug for treating Gram-negative and / or Gram-positive infections. In such pharmaceutical compositions, a compound of the present invention or a pharmaceutically acceptable salt thereof, an optional pharmaceutically acceptable excipient, and polymyxins and / or daptomycin (preferably polymyxins and daptomycin) are included.

[0107] In a specific embodiment, the Gram-negative bacteria include but are not limited to Escherichia coli (E. coli), Klebsiella pneumoniae, Acinetobacter baumanii and Pseudomonas aeruginosa; the Gram-positive bacteria include but are not limited to Staphylococcus aureus, methicillin-sensitive Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MSSA and MRSA), as well as Streptococcus and Enterococcus.

[0108] The pharmaceutical compositions of the present invention can be formulated into dosage forms suitable for various routes of administration, including but not limited to forms formulated for parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, nasal or topical administration. The dosage is the amount of drug that effectively improves or eliminates one or more symptoms. For the treatment of a specific disease, an effective amount is an amount of drug sufficient to improve or alleviate in some way the symptoms associated with the disease. Such a dosage can be administered as a single dose or can be administered according to an effective treatment regimen. The dosage may cure the disease, but the administration is usually to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired symptom improvement. The dosage of the drug will be determined based on the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

[0109] The pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compound of the present invention. Among these mammals, the most important one is human.

[0110] The pharmaceutical preparations of the present invention can be manufactured in known manners. For example, they can be manufactured by conventional mixing, granulation, tableting, dissolution, or freeze-drying processes. For oral preparations, solid excipients and the active compound can be combined and the mixture can be optionally ground. After adding appropriate amounts of adjuvants, if desired or necessary, the granular mixture can be processed to obtain tablets or lozenge cores.

[0111] Suitable excipients include, in particular, fillers, for example, sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate; and binders, for example, starch pastes including corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone. If necessary, disintegrants may be added, such as the starches mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate. Auxiliary agents include, in particular, flow conditioners and lubricants, for example, silica, talc, stearates such as magnesium calcium stearate, stearic acid, or polyethylene glycol. If necessary, the tablet cores may be provided with a suitable coating resistant to gastric juices. For this purpose, a concentrated sugar solution may be used. This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. To prepare a coating resistant to gastric juices, suitable cellulose solutions, such as cellulose acetate phthalate or hydroxypropylmethylcellulose phthalate, can be used. Dyes or pigments can be added to the coating of tablets or lozenge cores, for example, for identification or to characterize the combination of active ingredient doses.

[0112] The methods of administration of the compounds or pharmaceutical compositions of the present invention include, but are not limited to, various methods known in the art, which can be determined based on the patient's actual situation. These methods include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, nasal, or topical administration.

[0113] Advantages of the present invention:

[0114] 1. The present invention structurally derivatizes existing antibacterial synergists. The resulting derivatives not only greatly enhance the synergistic activity of polymyxin E, but also significantly enhance the synergistic activity of daptomycin against Gram-positive bacteria.

[0115] 2. The water solubility of the antibacterial synergist of the present invention is significantly improved after salt formation, thereby having excellent drugability and practical application value;

[0116] 3. The antibacterial synergist of the present invention can be used to prepare a series of diseases related to Acinetobacter baumannii and Klebsiella pneumoniae, effectively reducing the dosage of polymyxin E and effectively reducing the risk of polymyxin E toxicity during the treatment process. It can also be used for the antibacterial treatment of Acinetobacter baumannii and Klebsiella pneumoniae that are insensitive to polymyxin E or have weak antibacterial activity; and

[0117] 4. The antibacterial synergist of the present invention can also be used to treat Gram-positive bacterial infections including methicillin-resistant Staphylococcus aureus (MRSA), sensitive Staphylococcus aureus (MSSA) and vancomycin-resistant Enterococcus (VRE), effectively reducing the dosage of daptomycin and reducing the risk of bacterial resistance to daptomycin.

[0118] The technical solutions of the present invention are further described below with reference to specific examples. However, the following examples do not constitute a limitation of the present invention. All various application methods adopted in accordance with the principles and technical means of the present invention are within the scope of the present invention. Experimental methods in the following examples, where specific conditions are not specified, are generally carried out under conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0119] Example 1. 2-(4-trifluoromethylphenylimino)-4-(2,4-difluorophenyl)thiazole hydrochloride

[0120]

[0121] Compound KJ1311 (0.178 g, 0.5 mmol) was added to a round-bottom flask and dissolved in 5 mL of ethanol. 3 mL of 35% hydrochloric acid was added and the mixture was reacted at 40°C until no precipitation occurred. After the reaction was completed, the mixture was cooled to room temperature, the solid was filtered, and washed with ethanol to obtain the pure compound.

[0122] White solid; yield 76%; melting point: 148.3-150.1℃.

[0123] 1 H NMR (400MHz, DMSO-d6): δ10.91(s,1H),8.18(td,J=8.8,6.8Hz,1H),7.94(d,J=8.6Hz,2 H),7.70(d,J=8.6Hz,2H),7.45-7.29(m,2H),7.22(td,J=8.6,2.6Hz,1H),6.20(s,1H); 13 C NMR (100MHz, DMSO-d6): δ161.8,161.3(dd,J=248.0,12.6Hz),159.6(dd,J =251.8,12.5Hz),143.9,142.9(d,J=2.4Hz),130.8(dd,J=9.5,4.8Hz),126.3(q,J=3.6H z),124.7(q,J=269.0Hz),121.0(q,J=32.2Hz),118.7(dd,J=11.6,3.8Hz),116.7,111.9 (dd,J=21.2,3.4Hz),108.3(d,J=14.4Hz),105.1(t,J=26.6Hz); 19 F NMR (376MHz, DMSO-d6): δ-59.9(s,3F),-108.9--109.9(m,1F),-110.1--110.9(m,1F).

[0124] Example 2. 2-(4-trifluoromethylphenylimino)-4-(2,4-difluorophenyl)thiazole methanesulfonate

[0125]

[0126] The synthesis steps and feed amounts are the same as those in Example 1. White solid; yield 79%; melting point: 166.9-168.3°C.

[0127] 1 H NMR (400MHz, DMSO-d6): δ10.76(s,1H),8.18(dd,J=16.0,8.8Hz,1H),7.92(d,J=8.6Hz,2H),7. 70(d,J=8.6Hz,2H),7.45-7.29(m,2H),7.22(td,J=8.4,2.2Hz,1H),6.51(s,1H),2.45(s,3H). 13C NMR (100MHz, DMSO-d6): δ161.8,161.3 (dd, J=246.3, 12.4Hz), 159.5(dd,J=250.7,12.3Hz),144.2,143.0(d,J=2.4Hz),130.8(dd,J=9.6,4.8Hz),126 .3(q,J=3.8Hz),124.6(q,J=269.5Hz),121.0(q,J=31.9Hz),118.7(dd,J=11.4,3.7Hz), 116.6, 111.9 (dd, J = 21.2, 3.4Hz), 108.2 (d, J = 14.5Hz), 104.5 (t, J = 26.4Hz). 19 F NMR (376MHz, DMSO-d6): δ-59.9(s,3F),-108.6--109.9(m,1F),-109.9--110.8(m,1F).

[0128] Example 3. 2-(4-trifluoromethylphenylimino)-4-(2,4-difluorophenyl)thiazole p-toluenesulfonate

[0129]

[0130] The synthesis steps and feed amounts are the same as those in Example 1. White solid; yield 68%; melting point: 196.5-199.1°C.

[0131] 1 H NMR (400MHz, DMSO-d6): δ10.75(s,1H),8.18(dd,J=15.8,8.8Hz,1H),7.92(d,J=8.6Hz,2H),7.70(d,J=8.6Hz, 2H),7.50(d,J=8.0Hz,2H),7.41-7.31(m,2H),7.21(td,J=8.6,2.3Hz,1H),7.13(d,J=8.0Hz,2H),2.30(s,3H). 13C NMR (100MHz, DMSO-d6): δ161.8,161.4(dd,J=247.4,12.6Hz),159.5(dd,J=250.7,12.3Hz),145.4,144 .2,143.0(d,J=2.4Hz),137.8,130.8(dd,J=9.6,4.8Hz),128.1,126.3(q,J=3.8Hz),125.5,124.6(q,J= 269.5Hz), 121.0 (q, J = 31.8Hz), 118.7 (dd, J = 11.4, 3.6Hz), 116.6, 111.9 (dd, J = 21.2, 3.4Hz), 108.2 (d, J = 14.5Hz), 104.5 (t, J = 26.5Hz), 20.7. 19 F NMR (376MHz, DMSO-d6): δ -59.9(s,3F),-108.7--109.9(m,1F),-110.0--110.8(m,1F).

[0132] Example 4. 2-(4-trifluoromethylphenylimino)-4-(2,4-difluorophenyl)thiazole sulfate

[0133]

[0134] The synthesis steps and feed amounts are the same as those in Example 1. White solid; yield 71%; melting point: 178.7-180.7°C.

[0135] 1 H NMR (400MHz, DMSO-d6): δ10.75(s,1H),8.18(dd,J=15.8,8.8Hz,1H),7.92(d,J=8 .6Hz,2H),7.70(d,J=8.6Hz,2H),7.45-7.29(m,2H),7.22(td,J=8.4,2.2Hz,1H). 13CNMR (100MHz, DMSO-d6): δ161.8,161.3(dd,J=247.5,12.3Hz),159.5(dd,J=251.9,12.4 Hz), 144.3, 143.0 (d, J = 2.4Hz), 130.8 (dd, J = 9.7, 4.6Hz), 126.3 (q, J = 3.6Hz), 124.6 (q, J =271.0Hz), 121.0 (q, J = 32.1Hz), 118.7 (dd, J = 11.4, 3.6Hz), 116.6, 111.9 (dd, J = 20.9, 3.4Hz), 108.2 (d, J = 14.5Hz), 104.5 (t, J = 26.3Hz). 19 F NMR (376MHz, DMSO-d6): δ-59.9(s, 3F),-109.1--110.0(m,1F),-110.2--111.1(m,1F).

[0136] Example 5. 2-(4-trifluoromethylphenylimino)-4-(2,4-difluorophenyl)thiazole nitrate

[0137]

[0138] The synthesis steps and feed amounts are the same as those in Example 1. Pale yellow solid; yield 65%; melting point: 103.1-106.0°C.

[0139] 1 H NMR (400MHz, DMSO-d6): δ10.75(s,1H),8.18(dd,J=15.8,8.8Hz,1H),7.92(d,J=8.6Hz, 2H),7.70(d,J=8.6Hz,2H),7.45-7.28(m,2H),7.22(dd,J=8.4,2.0Hz,1H),6.70(s,1H). 13 C NMR (100MHz, DMSO-d6): δ161.8, 161.3 (dd, J=247.3, 12.4Hz), 159.6 (dd,J=251.7,12.4Hz),144.2,142.9(d,J=2.6Hz),130.8(dd,J=9.4,4.7Hz),126.3(q,J=3.6Hz),124.6(q,J=271.2Hz),12 1.0(q,J=31.9Hz), 118.7(dd,J=11.4,3.7Hz), 116.6, 111.9(dd,J=21.2,3.4Hz), 108.2(d,J=14.5Hz), 104.5(t,J=26.4Hz).19 F NMR (376MHz, DMSO-d6): δ-59.9(s,3F),-109.6--110.0(m,1F),-110.6--110.9(m,1F).

[0140] Example 6. 2-amino-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)acetamide hydrochloride

[0141] Synthesis of the intermediate 2-(((tert-butoxycarbonyl)oxy)amino)-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)acetamide:

[0142]

[0143] To a 100ml round-bottom flask, add ((tert-butyloxycarbonyl)oxy)glycine (1.05g, 6mmol) and dissolve in 30ml of dichloromethane. Add HATU (2.85g, 7.5mmol) and DIPEA (0.967g, 7.5mmol) and stir for 1 hour. Add KJ1311 (1.78g, 5mmol) and react at room temperature for 20 hours. Add 30ml of water, separate the layers, and extract the aqueous phase three times with 20ml of dichloromethane. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and separate by column chromatography (eluent: n-heptane:EA, 15% EA) to obtain a white solid. Yield: 65%. White solid.

[0144] 1 H NMR (400MHz, DMSO): δ8.01(d,J=8.4Hz,1H),7.83(d,J=8.2Hz,2H),7.64(d,J=2.3Hz,2H),7.54(dd,J=15.8,8.8H z,1H),7.36-7.25(m,1H),7.18(t,J=5.8Hz,1H),7.09(td,J=8.4,2.3Hz,1H),3.62(d,J=5.8Hz,2H),1.38(s,9H). 19 F NMR (376MHz, DMSO-d6): δ-60.7(s,3F),-109.6--110.4(m,1F),-110.5--111.2(m,1F).

[0145] Target compound 2-amino-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)acetamide hydrochloride:

[0146]

[0147] In a 100 ml round-bottom flask, 2 M hydrochloric acid (2.85 ml, 5.7 mmol) was dissolved in 20 ml of ethyl acetate. KJ1311 (1,173 g, 2.28 mmol) was then dissolved in 10 ml of ethyl acetate and added dropwise to the hydrochloric acid solution. The mixture was stirred for 4 hours and the solvent was dried to obtain a white solid.

[0148] White solid, yield 60%, melting point: 354.1-356.7℃.

[0149] 1 H NMR (400MHz, MeOD): δ7.99(d,J=8.2Hz,2H),7.79(d,J=8.2Hz,2H), 7.71–7.54(m,2H),7.03–6.93(m,1H),6.92–6.81(m,1H),3.89(s,2H). 13 C NMR (100MHz, MeOD): δ170.8,163.6(dd,J CF =190.89,12.12Hz),161.3(dd,J CF =193.21,12.12Hz),160.7, 144.4(d, 4 J CF =1.01Hz),143.5,132.3(q, 2 J CF =32.32Hz),131.6(2C),131.6(dd,J CF =5.05 Hz),128.3(q, 3 J CF =4.04Hz,2C),125.3(q, 1 J CF =272.70Hz),119.9(dd,J CF =11.11,4.04Hz),114.1(d, 3 J CF =15.15Hz),112.4(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF =27.27Hz),35.4. 19 F NMR(376MHz, CDCl3): δ-62.61(s,3F),-99.80–-131.03(m,2F).HRMS(ESI):m / zcalcd for C 17 H 13 F5N3OS[M+H]+ :414.0699;found:414.0700.

[0150] Example 7. 3-Amino-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)propanamide hydrochloride

[0151]

[0152] Implementation plan is the same as Example 6

[0153] White solid, yield 68%, melting point: 358.7-366.9℃.

[0154] 1 H NMR (400MHz, MeOD): δ7.96(d,J=8.3Hz,2H),7.72(d,J=8.2Hz,2H), 7.68–7.58(m,1H),7.54(d,J=2.1Hz,1H),7.04–6.94(m,1H),6.92–6.84(m,1H),3.27(t,J=6.2Hz,2H),2.71(t,J=4.9Hz,2H). 13 C NMR(100MHz,MeOD): δ170.8,163.6(dd,J CF =190.89,12.12Hz),161.2(dd,J CF =193.21,12.12Hz),160.7,144.4(d, 4 J CF =1.01Hz),143.5, 132.3(q, 2 J CF =32.32Hz),131.6(2C),131.6(dd,J CF =5.05Hz),128.3(q, 3 J CF =4.04Hz,2C), 125.30(q, 1 J CF =272.70Hz),119.9(dd,J CF =11.11,4.04Hz),114.1(d, 3 J CF =15.15Hz), 112.4(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF=27.27Hz),36.3,34.2. 19 F NMR (376MHz, MeOD): δ-63.93 (s, 3F), -112.34 (dd, J=19.4, 9.1Hz, 1F), -112.65–-112.98 (m, 1F). HRMS (ESI): m / z calcd for C 18 H 15 F5N3OS[M+H] + :428.0856; found:428.0857.

[0155] Example 8. 4-amino-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)butanamide hydrochloride

[0156] Implementation plan is the same as Example 6

[0157] White solid, yield 62%, melting point: 372.2-378.2℃.

[0158] 1 H NMR (400MHz, DMSO): δ7.99(d,J=8.4Hz,2H),7.90(s,3H),7.83(d,J=8.2Hz,2H),7.62(d,J=2.2Hz,1H),7.51(dd,J=15.9,8.8H z,1H),7.36–7.26(m,1H),7.08(td,J=8.7,2.4Hz,1H),2.79(dd,J=12.4,6.5Hz,2H),2.35(t,J=6.9Hz,2H),1.92–1.80(m,2H). 13 C NMR(100MHz,MeOD): δ172.5,163.6(dd,J CF =190.89,12.12Hz),161.3(dd,J CF =193.21,12.12Hz),160.7,144.4(d, 4 J CF =1.01Hz),143.5,132.3(q, 2 J CF =32.32Hz),131.59(2C),131.6(dd,J CF =5.05Hz),128.2(q, 3 J CF =4.04Hz,2C),125.3(q, 1 JCF =272.70Hz),119.9(dd,J CF =11.11,4.04Hz),114.1(d, 3 J CF =15.15Hz),112.4(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF =27.27Hz),40.1,33.8,23.5. 19 F NMR (376MHz, DMSO): δ-60.85 (s, 3F), -110.44–-110.60 (m, 2F). HRMS (ESI): m / z calcd for C 19 H 17 F5N3OS[M+H] + :442.1012; found:442.1011.

[0159] Example 9. 5-amino-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)pentanamide hydrochloride

[0160]

[0161] Implementation plan is the same as Example 6

[0162] White solid, yield 65%, melting point: 377.5-379.8℃.

[0163] 1 H NMR (400MHz, MeOD): δ7.93(d,J=8.2Hz,2H),7.69(d,J=8.1Hz,2H),7.60(dd,J=15.8,8.6Hz,1H),7.44(d,J= 1.5Hz,1H),7.01–6.88(m,1H),6.88–6.74(m,1H),2.98–2.90(m,2H),2.41–2.33(m,2H),1.79–1.65(m,4H). 13 C NMR(100MHz,MeOD): δ 173.1,163.8(dd,J CF =190.89,12.12Hz),161.3(dd,J CF =193.21,12.12Hz),160.7,144.4(d, 4 J CF =1.01Hz),143.5,132.3(q, 2 JCF =32.32Hz),131.6(2C),131.7(dd,J CF =5.05Hz),128.2(q, 3 J CF =4.04Hz,2C),125.4(q, 1 J CF =272.70Hz),119.9(dd,J CF =11.11,4.04Hz),114.2(d, 3 J CF =15.15Hz),112.4(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF =26.26Hz),40.5,35.9,27.9, 22.5. 19 F NMR (376MHz, MeOD): δ-63.79 (s, 3F), -112.06 (dd, J=18.5, 9.2Hz, 1F), -112.58–-112.69 (m, 1F). HRMS (ESI): m / z calcd for C 20 H 19 F5N3OS[M+H] + :456.1169,found:456.1167.

[0164] Example 10. 6-amino-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)hexanamide hydrochloride

[0165]

[0166] Implementation plan is the same as Example 6

[0167] White solid, yield 50%, melting point: 382.4-385.3℃.

[0168] 1 H NMR (400MHz, MeOD): δ7.93(d,J=8.2Hz,2H),7.67(d,J=8.1Hz,2H), 7.65–7.55(m,1H),7.48(d,J=1.8Hz,1H),7.02–6.92(m,1H),6.90–6.81(m,1H),3.31(s, 1H), 2.91 (t, J=7.5Hz, 2H), 2.33 (t, J=7.1Hz, 2H), 1.77–1.58 (m, 4H), 1.43–1.33 (m, 2H).13 CNMR(100MHz,MeOD): δ173.4,163.8(dd,J CF =190.89,12.12Hz),161.3(dd,J CF = 193.21,12.12Hz),160.8,144.5(d, 4 J CF =1.01Hz),143.5,132.5(q, 2 J CF =32.32Hz),131.5 (2C),131.7(dd,J CF =5.05Hz),128.2(q, 3 J CF =4.04Hz,2C),125.4(q, 1 J CF =272.70Hz), 119.9(dd,J CF =11.11,4.04Hz),114.1(d, 3 J CF =15.15Hz),112.5(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF =26.26Hz),40.6,36.3,28.4,26.8,25.1. 19 F NMR (376MHz, MeOD): δ-63.93 (s, 3F), -112.34 (dd, J=19.4, 9.1Hz, 1F), -112.65–-112.98 (m, 1F). HRMS (ESI): m / z calcdfor C 21 H 21 F5N3OS[M+H] + :470.1327,found:470.1326.

[0169] Example 11. 7-amino-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)heptylamide hydrochloride

[0170]

[0171]

[0172] Implementation plan is the same as Example 6

[0173] White solid, yield 63%, melting point: 392.8-396.1℃.

[0174] 1 H NMR(400MHz,MeOD):δ7.93(d,J=8.3Hz,2H),7.73–7.65(m,2H),7.65–7.56(m,1H),7.49(d,J=2.5Hz,1H),6.97(ddd,J=11.6,9.0,2.5Hz,1H),6.86(td,J=8.2,2.3Hz, 1H),2.93–2.86(m,2H),2.31(t,J=7.3Hz,2H),1.65(M,4H),1.39–1.29(m,4H). 13 CNMR (100MHz,MeOD):δ173.4,163.8(dd,J CF =190.89,12.12Hz),161.3(dd,J CF =193.21,12.12 Hz),160.8,144.5(d, 4 J CF =1.01Hz),143.5,132.5(q, 2 J CF =32.32Hz),131.5(2C),131.7(dd, J CF =5.05Hz),128.2(q, 3 J CF =4.04Hz,2C),125.4(q, 1 J CF =272.70Hz),119.9(dd,J CF = 11.11,4.04Hz),114.1(d, 3 J CF =15.15Hz),112.5(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF = 26.26Hz),40.7,36.5,29.5,28.4,27.2,25.5. 19 F NMR(376MHz,MeOD):δ-63.96(s,3F), -112.35–-112.47(m,1F),-112.84–-112.95(m,1F).HRMS(ESI):m / z calcdfor C 22 H 23 F5N3OS [M+H] + :484.1482;found:484.1481.

[0175] Example 12. 8-amino-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)octanamide hydrochloride

[0176]

[0177]

[0178] Implementation plan is the same as Example 6

[0179] White solid, yield 67%, melting point: 395.3-399.2℃.

[0180] 1 H NMR (400MHz, DMSO): δ7.98(d,J=8.2Hz,2H),7.82(d,J=8.1Hz,2H),7.60(s,1H),7.57–7.46(m,1H),7.39–7.22(m,1H),7.14– 7.02(m,1H),6.81–6.69(m,1H),2.87(dd,J=12.7,6.4Hz,2H),2.21(t,J=7.2Hz,2H),1.59–1.50(m,2H),1.43–1.19(m,17H). 13 C NMR(100MHz,MeOD): δ173.4,163.8(dd,J CF =190.89,12.12Hz),161.3(dd,J CF =193.21,12.12Hz),160.8,144.5(d, 4 J CF =1.01Hz),143.5,132.5(q, 2 J CF =32.32Hz),131.5(2C),131.7(dd, J CF =5.05Hz),128.2(q, 3 J CF =4.04Hz,2C),125.4(q, 1 J CF =272.70Hz),119.9(dd,J CF = 11.11,4.04Hz),114.1(d, 3 J CF =15.15Hz),112.5(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF= 26.26Hz),40.8,36.5,35.1,29.87,28.48,27.27,25.63. 19 F NMR (376MHz, MeOD): δ-63.93 (s, 3F), -112.34 (dd, J=19.4, 9.1Hz, 1F), -112.65–-112.98 (m, 1F). HRMS (ESI): m / zcalcd for C 23 H 25 F5N3OS[M+H] + :498.1638; found:498.1639.

[0181] Example 13. 2-Guanidino-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)acetamide hydrochloride

[0182]

[0183] White solid, yield 60%, melting point: 354.1-356.7℃.

[0184] 1 H NMR (400MHz, MeOD): δ7.99(d,J=8.2Hz,2H),7.79(d,J=8.2Hz,2H), 7.71–7.54(m,2H),7.03–6.93(m,1H),6.92–6.81(m,1H),3.89(s,2H). 13 C NMR (100MHz, MeOD): δ170.8,163.6(dd,J CF =190.89,12.12Hz),161.3(dd,J CF =193.21,12.12Hz),160.7, 144.4(d, 4 J CF =1.01Hz),143.5,132.3(q, 2 J CF =32.32Hz),131.6(2C),131.6(dd,J CF =5.05 Hz),128.3(q, 3 J CF =4.04Hz,2C),125.3(q, 1 J CF =272.70Hz),119.9(dd,J CF =11.11,4.04Hz),114.1(d, 3 JCF =15.15Hz),112.4(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF =27.27Hz),35.4. 19 F NMR(376MHz, CDCl3): δ-62.61(s,3F),-99.80–-131.03(m,2F).HRMS(ESI):m / zcalcd for C 17 H 13 F5N3OS[M+H] + :456.0918; found:456.0917.

[0185] Example 14. 3-Guanidino-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)propanamide hydrochloride

[0186]

[0187] White solid, yield 68%, melting point: 358.7-366.9℃.

[0188] 1 H NMR (400MHz, MeOD): δ7.96(d,J=8.3Hz,2H),7.72(d,J=8.2Hz,2H), 7.68–7.58(m,1H),7.54(d,J=2.1Hz,1H),7.04–6.94(m,1H),6.92–6.84(m,1H),3.27(t,J=6.2Hz,2H),2.71(t,J=4.9Hz,2H). 13 C NMR(100MHz,MeOD): δ170.8,163.6(dd,J CF =190.89,12.12Hz),161.2(dd,J CF =193.21,12.12Hz),160.7,144.4(d, 4 J CF =1.01Hz),143.5, 132.3(q, 2 J CF =32.32Hz),131.6(2C),131.6(dd,J CF =5.05Hz),128.3(q, 3 J CF =4.04Hz,2C), 125.30(q, 1 J CF=272.70Hz),119.9(dd,J CF =11.11,4.04Hz),114.1(d, 3 J CF =15.15Hz),112.4 (dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF =27.27Hz),36.3,34.2. 19 F NMR(376MHz,MeOD): δ-63.93(s,3F),-112.34(dd,J=19.4,9.1Hz,1F),-112.65–-112.98(m,1F).HRMS(ESI):m / zcalcd for C 18 H 15 F5N3OS[M+H] + :470.0814; found:470.0857.

[0189] Example 15. 4-Guanidinyl-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)butanamide hydrochloride

[0190]

[0191] White solid, yield 62%, melting point: 372.2-378.2℃.

[0192] 1 H NMR (400MHz, DMSO): δ7.99(d,J=8.4Hz,2H),7.90(s,3H),7.83(d,J=8.2Hz,2H),7.62(d,J=2.2Hz,1H),7.51(dd,J=15.9,8.8H z,1H),7.36–7.26(m,1H),7.08(td,J=8.7,2.4Hz,1H),2.79(dd,J=12.4,6.5Hz,2H),2.35(t,J=6.9Hz,2H),1.92–1.80(m,2H). 13 C NMR(100MHz,MeOD): δ172.5,163.6(dd,J CF =190.89,12.12Hz),161.3(dd,J CF =193.21,12.12Hz),160.7,144.4(d, 4 J CF =1.01Hz),143.5,132.3(q,2 J CF =32.32Hz),131.59(2C),131.6(dd,J CF =5.05Hz),128.2(q, 3 J CF =4.04Hz,2C),125.3(q, 1 J CF =272.70Hz),119.9(dd,J CF =11.11,4.04Hz),114.1(d, 3 J CF =15.15Hz),112.4(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF =27.27Hz),40.1,33.8,23.5. 19 F NMR (376MHz, DMSO): δ-60.85 (s, 3F), -110.44-110.60 (m, 2F). HRMS (ESI): m / z calcd for C 19 H 17 F5N3OS[M+H] + :484.0918; found:484.0916.

[0193] Example 16. 5-Guanidinyl-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)pentanamide hydrochloride

[0194]

[0195] White solid, yield 65%, melting point: 377.5-379.8℃.

[0196] 1 H NMR (400MHz, MeOD): δ7.93(d,J=8.2Hz,2H),7.69(d,J=8.1Hz,2H),7.60(dd,J=15.8,8.6Hz,1H),7.44(d,J= 1.5Hz,1H),7.01–6.88(m,1H),6.88–6.74(m,1H),2.98–2.90(m,2H),2.41–2.33(m,2H),1.79–1.65(m,4H). 13 C NMR(100MHz,MeOD): δ 173.1,163.8(dd,J CF=190.89,12.12Hz),161.3(dd,J CF =193.21,12.12Hz),160.7,144.4(d, 4 J CF =1.01Hz),143.5,132.3(q, 2 J CF =32.32Hz),131.6(2C),131.7(dd,J CF =5.05Hz),128.2(q, 3 J CF =4.04Hz,2C),125.4(q, 1 J CF =272.70Hz),119.9(dd,J CF =11.11,4.04Hz),114.2(d, 3 J CF =15.15Hz),112.4(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF =26.26Hz),40.5,35.9,27.9, 22.5. 19 F NMR (376MHz, MeOD): δ-63.79 (s, 3F), -112.06 (dd, J=18.5, 9.2Hz, 1F), -112.58-112.69 (m, 1F). HRMS (ESI): m / z calcd for C 20 H 19 F5N3OS[M+H] + :498.0615;found:498.0613.

[0197] Example 17. 6-Guanidinyl-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)hexanamide hydrochloride

[0198]

[0199] White solid, yield 50%, melting point: 382.4-385.3℃.

[0200] 1H NMR(400MHz,MeOD):δ7.93(d,J=8.2Hz,2H),7.67(d,J=8.1Hz,2H), 7.65–7.55(m,1H),7.48(d,J=1.8Hz,1H),7.02–6.92(m,1H),6.90–6.81(m,1H),3.31(s,1H),2.91(t,J=7.5Hz,2H),2.33(t,J=7.1Hz,2H),1.77–1.58(m,4H),1.43–1.33(m,2H). 13 CNMR(100MHz,MeOD):δ173.4,163.8(dd,J CF =190.89,12.12Hz),161.3(dd,J CF = 193.21,12.12Hz),160.8,144.5(d, 4 J CF =1.01Hz),143.5,132.5(q, 2 J CF =32.32Hz),131.5 (2C),131.7(dd,J CF =5.05Hz),128.2(q, 3 J CF =4.04Hz,2C),125.4(q, 1 J CF =272.70Hz), 119.9(dd,J CF =11.11,4.04Hz),114.1(d, 3 J CF =15.15Hz),112.5(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF =26.26Hz),40.6,36.3,28.4,26.8,25.1. 19 F NMR(376MHz,MeOD):δ-63.93(s,3F),-112.34(dd,J=19.4,9.1Hz,1F),-112.65-112.98(m,1F).HRMS(ESI):m / z calcd forC 21 H 21 F5N3OS[M+H] + :512.0813;found:512.0815.

[0201] Example 18. 7-Guanidino-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)heptylamide hydrochloride

[0202]

[0203] White solid, yield 63%, melting point: 392.8-396.1℃.

[0204] 1 H NMR (400MHz, MeOD): δ7.93(d,J=8.3Hz,2H),7.73–7.65(m,2H),7.65–7.56(m,1H),7.49(d,J=2.5Hz,1H),6.97(ddd,J=11. 6,9.0,2.5Hz,1H),6.86(td,J=8.2,2.3Hz,1H),2.93–2.86(m,2H),2.31(t,J=7.3Hz,2H),1.65(M,4H),1.39–1.29(m,4H). 13 CNMR (100MHz, MeOD): δ173.4,163.8(dd,J CF =190.89,12.12Hz),161.3(dd,J CF =193.21,12.12 Hz),160.8,144.5(d, 4 J CF =1.01Hz),143.5,132.5(q, 2 J CF =32.32Hz),131.5(2C),131.7(dd, J CF =5.05Hz),128.2(q, 3 J CF =4.04Hz,2C),125.4(q, 1 J CF =272.70Hz),119.9(dd,J CF = 11.11,4.04Hz),114.1(d, 3 J CF =15.15Hz),112.5(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF = 26.26Hz),40.7,36.5,29.5,28.4,27.2,25.5. 19F NMR(376MHz,MeOD): δ-63.96(s,3F), -112.35–-112.47(m,1F),-112.84–-112.95(m,1F).HRMS(ESI):m / z calcdfor C 22 H 23 F5N3OS [M+H] + :526.0538;found:526.0536.

[0205] Example 19. 8-Guanidino-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)octanamide hydrochloride

[0206]

[0207] White solid, yield 67%, melting point: 395.3-399.2℃.

[0208] 1 H NMR (400MHz, DMSO): δ7.98(d,J=8.2Hz,2H),7.82(d,J=8.1Hz,2H),7.60(s,1H),7.57–7.46(m,1H),7.39–7.22(m,1H),7.14– 7.02(m,1H),6.81–6.69(m,1H),2.87(dd,J=12.7,6.4Hz,2H),2.21(t,J=7.2Hz,2H),1.59–1.50(m,2H),1.43–1.19(m,17H). 13 C NMR(100MHz,MeOD): δ173.4,163.8(dd,J CF =190.89,12.12Hz),161.3(dd,J CF =193.21,12.12Hz),160.8,144.5(d, 4 J CF =1.01Hz),143.5,132.5(q, 2 J CF =32.32Hz),131.5(2C),131.7(dd, J CF =5.05Hz),128.2(q, 3 J CF =4.04Hz,2C),125.4(q, 1 J CF =272.70Hz),119.9(dd,J CF= 11.11,4.04Hz),114.1(d, 3 J CF =15.15Hz),112.5(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF =26.26Hz),40.8,36.5,35.1,29.87,28.48,27.27,25.63. 19 F NMR (376MHz, MeOD): δ-63.93 (s, 3F), -112.34 (dd, J=19.4, 9.1Hz, 1F), -112.65-112.98 (m, 1F). HRMS (ESI): m / z calcdfor C 23 H 25 F5N3OS[M+H] + :540.0808;found:540.0806.

[0209] Example 20. 3-Amino-N-(4-(2,4-difluorophenyl)thiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)-4-methyl-2-butanamide hydrochloride

[0210]

[0211] Implementation plan is the same as Example 6

[0212] White solid, yield 9%, melting point: 461.6-463.1℃.

[0213] 1 H NMR (400MHz, MeOD): δ8.01(d,J=8.0Hz,2H),7.83(d,J=6.2Hz,2H),7.62(d,J=8.4Hz,2H),7. 08–6.79(m,2H),4.54–4.12(m,1H),2.68–2.55(m,1H),2.52–2.34(m,1H),2.21–1.99(m,2H). 13 C NMR(100MHz,MeOD): δ173.1,163.8(dd,J CF =190.89,12.12Hz),161.3(dd,J CF =193.21,12.12Hz),160.7,144.4(d, 4 J CF =1.01Hz),143.5,132.3(q, 2 J CF=32.32Hz),131.6(2C),131.7(dd,J CF =5.05Hz),128.2(q, 3 J CF =4.04Hz,2C),125.4(q, 1 J CF =272.70Hz),120.0(dd,J CF =11.11,4.04Hz),114.2(d, 3 J CF =15.15Hz),112.4(dd,J CF =21.21, 4.04Hz),105.0(t, 2 J CF =26.26Hz),50.4,34.8,30.5,14.8. 19 F NMR (376MHz, CDCl3): δ-62.58 (s, 3F), -110.65 (s, 2F). HRMS (ESI): m / z calcd for C 19 H 15 F5N3OS[M+H] + :488.0890; found:488.0891.

[0214] Example 21. N-(4-(2,4-difluorophenyl)thiazol-2-yl)-2-phenoxy-2-((pivaloyloxy)amino)-N-(4-(trifluoromethyl)phenyl)acetamide hydrochloride

[0215]

[0216]

[0217] Implementation plan is the same as Example 6

[0218] White solid, yield 8%, melting point: 452.2-458.3℃.

[0219] 1H NMR(400MHz,DMSO):δ8.04(t,J=8.5Hz,2H),7.89–7.71(m,2H),7.71–7.61(m,1H),7.53(dd,J=15.4,8.0Hz,1H),7.31(t,J=10.4Hz,1H),7.08(td,J=8.5,2.3Hz,1H),4.21–3.94(m,1H),3.49–3.39(m,1H),3.29(dd,J=8.0,5.0Hz,1H),2.23–1.61(m,4H),2.21–1.65(m,4H),1.38(d,J=14.7Hz,9H). 13 C NMR(100MHz,MeOD):δ172.1,163.8(dd, J CF =190.89,12.12Hz),161.3(dd,J CF =193.21,12.12Hz),160.7,144.4(d, 4 J CF =1.01Hz),143.5,132.3(q, 2 J CF =32.32Hz),131.6(2C),131.7(dd,J CF =5.05Hz),128.2(q, 3 J CF =4.04Hz,2C),125.4(q, 1 J CF =272.70Hz),119.9(dd,J CF =11.11,4.04Hz),114.2(d, 3 J CF =15.15Hz),112.4(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF =26.26Hz),69.6,56.3,35.8,27.8. 19 FNMR(376MHz,MeOD):δ-64.06(s,3F),-112.33(d,J=48.6Hz,1F),-112.42-112.77(m,1F).HRMS(ESI):m / z calcd for C 19 H 15 F5N3O2S[M+H] + :454.0934;found:454.1013.

[0220] Example 22. N-(4-(2,4-difluorophenyl)thiazol-2-yl)-2-phenoxy-2-((pivaloyloxy)amino)-N-(4-(trifluoromethyl)phenyl)acetamide hydrochloride

[0221]

[0222] Implementation plan is the same as Example 6

[0223] White solid, yield 8%, melting point: 452.2-458.3℃.

[0224] 1 H NMR (400MHz, MeOD): δ8.00(d,J=8.2Hz,2H),7.83(d,J=8.2Hz,2H),7.62(s,2H),6.96(dd,J=30.8,19.4Hz,2H),4.44(s,1H) ,3.48(dt,J=13.2,6.7Hz,1H),3.36(dd,J=11.7,6.6Hz,1H),3.33–3.29(m,1H),2.23–2.05(m,2H),2.00(d,J=10.6Hz,2H). 13 C NMR(100MHz,MeOD): δ172.1,163.8(dd,J CF =190.89,12.12Hz),161.3(dd,J CF =193.21,12.12Hz),160.7,144.4(d, 4 J CF =1.01Hz),143.5,132.3(q, 2 J CF =32.32Hz),131.6(2C),131.7(dd, J CF =5.05Hz),128.2(q, 3 J CF =4.04Hz,2C),125.4(q, 1 J CF =272.70Hz),119.9(dd,J CF = 11.11,4.04Hz),114.2(d, 3 J CF =15.15Hz),112.4(dd,J CF =21.21,4.04Hz),105.0(t, 2 J CF = 26.26Hz),69.6,56.3,35.8,27.9.19 F NMR (376MHz, MeOD): δ-64.06 (s, 3F), -112.33 (d, J= 48.6Hz, 1F), -112.42-112.77 (m, 1F). HRMS (ESI): m / z calcd for C 19 H 15 F5N3O2S[M+H] + :454.0934; found:454.1013.

[0225] Example 23. (((4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)amino)methyl)phosphonic acid sodium salt

[0226] Synthesis of the intermediate (((4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)amino)methyl)phosphonic acid diisopropyl ester

[0227]

[0228] Compound KJ1311 (1.78 g, 5 mmol) and 60% pure NaH (0.30 g, 7.5 mmol) were added to a three-necked flask and dissolved in 12 mL of DMF. The mixture was allowed to react under argon in an ice bath. After 60 min, diisopropyl bromomethylphosphonate (1.30 g, 5 mmol) was added. The reaction was heated to 80°C and monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the product was separated by column chromatography (eluent: n-hexane / ethyl acetate) to obtain a pure pale yellow solid in a 62% yield.

[0229] 1 H NMR (400MHz, DMSO-d6): δ8.12(td,J=8.8,7.0Hz,1H),7.87(d,J=8.8Hz,2H),7.82(d,J=8.8Hz,2H),7.42-7.30(m ,1H),7.26-7.15(m,2H),4.65(d,J=9.0Hz,2H),4.60-4.47(m,2H),1.15(d,J=6.4Hz,6H),1.03(d,J=6.0Hz,6H). 13C NMR (100MHz, DMSO-d6): δ167.1,161.3(d,J=235.2Hz), 159.5(d,J=251.6Hz), 147.6,142.8(d,J=1.8Hz), 130.7(dd,J=9.3,4.9Hz),126.8(q,J=3.5Hz),126.8(q,J=32.1Hz),126.2,124.0(q,J=27 1.9Hz), 118.6 (dd, J=11.5, 3.7Hz), 111.9 (dd, J=21.3, 3.4Hz), 108.2 (d, J=14.7Hz), 104.5 (t,J=26.3Hz),70.4,70.3,48.3(d,J=156.8Hz),23.7(d,J=3.5Hz),23.3(d,J=5.0Hz). 19 F NMR (376MHz, DMSO-d6): δ-60.7(s,3F),-109.6--110.4(m,1F),-110.5--111.2(m,1F).

[0230] Synthesis of target compounds

[0231] To a round-bottom flask, add the intermediate diisopropyl (((4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)amino)methyl)phosphonate (1.07 g, 2 mmol), dissolve in 20 mL of ethyl acetate, and add 70 drops of concentrated hydrochloric acid dropwise at 75°C. After completion of the reaction, follow the reaction by TLC. The mixture was cooled to room temperature, the solvent was removed by rotary evaporation, and 10 mL of CH2Cl2 was added. The mixture was sonicated for 5 minutes to remove impurities, yielding the pure target compound.

[0232] (((4-(2,4-Difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)amino)methyl)phosphonic acid

[0233]

[0234] White solid; yield 62%; melting point: 173.8-176.7℃.

[0235] 1 H NMR (400MHz, DMSO-d6): δ9.95 (s, 2H), 8.16-8.08 (m, 1H), 7.86 (d, J = 8.8Hz, 2H), 7 .82(d,J=8.8Hz,2H),7.41-7.30(m,1H),7.24-7.15(m,2H),4.42(d,J=9.6Hz,2H). 13C NMR (100MHz, DMSO-d6): δ167.3,161.3(dd,J=245.1,12.2Hz), 159.5(dd,J=249.0,11.8Hz), 148.2,142.8,131.0(dd,J=9.5,4.7Hz), 126.5(q,J=3.6Hz),126.0(q,J=31.6Hz),125.6,124.1(q,J=269.2Hz),118.7(dd,J=11.4,3.7Hz),111.8(d,J=20.9Hz),108.2(d,J= 13.6Hz), 104.4(t,J=26.1Hz), 50.2(d,J=151.2Hz). 19 F NMR(376MHz, DMSO-d6): δ -60.7(s,3F),-109.6--110.4(m,1F),-110.5--111.2(m,1F).HRMS(ESI):m / z calcdfor C 19 H 15 F5N3O2S[M+H] + :451.0305;found:451.0306.

[0236] (((4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)amino)methyl)phosphonic acid sodium salt:

[0237]

[0238] A white solid was obtained with a yield of 95%.

[0239] Example 24. Di-tert-butyl ((((4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)amino)methyl)phosphate sodium salt

[0240] Synthesis of intermediate di-tert-butyl ((((4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)amino)methyl) phosphate:

[0241]

[0242] Compound KJ1311 (0.356 g, 1 mmol) and 60% pure NaH (0.06 g, 2.5 mmol) were added to a 50 ml three-necked flask and dissolved in 10 mL of anhydrous DMF. The mixture was allowed to react under an ice bath and argon. After 60 min, di-tert-butyl (chloromethyl)phosphate (1.94 g, 5 mmol) and potassium iodide (0.167 g, 1 mmol) were added. The reaction was heated to 80°C and monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature. Under an ice bath, 30 ml of ice water and 30 ml of ethyl acetate were added. The organic phase was separated and washed five times with 20 ml of water. The aqueous phase was extracted three times with 20 ml of ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was separated by column chromatography (eluent: n-heptane / ethyl acetate) to obtain 58 mg of the pure product as a pale yellow solid in a 10% yield.

[0243] 1 H NMR (400MHz, DMSO-d6): δ7.78(d,2H),7.75(d,2H),7.68(s,1H),7.62(m,1H),7.25-7.40(m,1H),7.21(s,1H),4.42(d,2H),1.36(s,18H). 13 C NMR (100MHz, DMSO-d6): δ 163.5, 163.1 (dd, J = 245.1, 12.2Hz), 162.4, 162.3 (dd, J = 249.0, 11.8Hz), 159. 8,159.7(dd,J=9.5,4.7Hz),158.2(d,J=3.6Hz),157.0(d,J=31.6Hz),143.4(d,J=269.2Hz),143.1(dd, J=11.4,3.7Hz),131.4(d,J=20.9Hz),131.1(d,J=13.6Hz),130.8(s,J=26.1Hz),129.3(t ,J=151.2Hz),122.5(s,J=11.1Hz),117.1,117.0(d,J=20.9Hz),113.5,113.3(dd,J=11.4, 3.7Hz), 105.8(t,J=151.2Hz), 79.8(s,J=31.6Hz), 74.8(s,J=26.1Hz), 29.3(s,J=31.6Hz). 19 F NMR(376MHz, DMSO-d6): δ-60.9(s,3F),-109.5--110.3(m,1F),-110.6--111.3(m, 1F).HRMS(ESI):m / z calcd for C 19 H 15F5N3O2S[M+H] + :578.1403; found:578.1401.

[0244] Di-tert-butyl((((4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)amino)methyl)phosphonic acid:

[0245]

[0246] In a 25 ml round-bottom flask, the intermediate di-tert-butyl ((((4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)amino)methyl) phosphate (100 mg, 0.178 mmol) was added and dissolved in 10 ml of DCM. 1 ml of trifluoroacetic acid was added under ice bath. After stirring for half an hour, the mixture was reacted at room temperature for 8 hours. The solvent was then dried to give 82.8 mg of a white solid in a yield of 98%.

[0247] 1 H NMR (400MHz, DMSO-d6): 8.15-8.07(m,1H),7.84(d,J=8.8Hz,2H),7.81(d,J=8.8Hz,2H),7.40-7.29(m,1H),7.23-7.14(m,2H),4.40(d,J=9.6Hz,2H). 13 C NMR(100 MHz, DMSO-d6): δ168.4,161.9(dd,J=245.1,12.2Hz), 159.3(dd,J=249.0,11.8Hz), 148.3,142.9,130.8(dd,J=9.5,4.7Hz), 126.3(q,J= 3.6Hz), 126.2 (q, J = 31.6Hz), 125.4, 123.9 (q, J = 269.2Hz), 118.5 (dd, J = 11.4, 3.7Hz), 111.7 (d, J = 20.9Hz), 107.9 (d, J = 13.6Hz), 104.1 (t,J=26.1Hz),50.8(d,J=151.2Hz). 19 F NMR(376MHz, DMSO-d6): δ-60.7(s,3F), -109.6--110.4(m,1F),-110.5--111.2(m,1F).HRMS(ESI):m / z calcd for C 19 H 15 F5N3O2S[M+H] + :466.0243;found:466.0241.

[0248] Sodium di-tert-butyl((((4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)amino)methyl)phosphate

[0249]

[0250] White solid, yield 95%.

[0251] Example 25. 3-(Phosphonooxy)propyl(4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)carbamate sodium salt

[0252] Synthesis of the intermediate 3-chloropropyl(4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)carbamate

[0253] NAH (0.54 g, 22.4 mmol) was added to 30 ml of anhydrous THF. KJ1311 (2 g, 5.6 mmol) was previously dissolved in 10 ml of anhydrous THF and added dropwise under ice-bath. The mixture was stirred for 1 h. 3-Chloropropyl chloride (2.636 g, 16.8 mmol) and DMAP (68 mg, 0.56 mmol) were quickly added and reacted for four hours. The reaction was quenched by adding 40 ml of ice water under ice-bath. The layers were separated and the aqueous phase was extracted three times with 20 ml of dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was separated by column chromatography (eluent: n-heptane:EA, 13% EA) to obtain the intermediate in a yield of 71%.

[0254] 1 H NMR (400MHz, DMSO): δ7.92(d,J=8.5Hz,2H),7.77(d,J=8.3Hz,2H),7.64(d,J=2.1Hz,1H),7.55(dd,J=16.0,8.6Hz,1H) ,7.38-7.26(m,1H),7.09(ddd,J=9.3,7.1,2.6Hz,1H),4.32(t,J=6.1Hz,2H),3.52(t,J=6.5Hz,2H),2.04-1.95(m,2H).

[0255] Synthesis of the intermediate 3-((di-tert-butoxyphosphoryl)oxy)propyl(4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)carbamate

[0256]

[0257] 3-Chloropropyl(4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)carbamate (0.447 g, 1 mmol) was dissolved in 20 ml of DMF. KI (0.165 g, 1 mmol) and di-tert-butyl tetra-n-butylammonium phosphate (1.8 g, 4 mmol) were added and heated at 60°C for 48 h. The reaction solution was cooled to room temperature and transferred to a separatory funnel containing diethyl ether. The organic layer was washed five times with 20 ml of water, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated and separated by column chromatography (eluent: n-heptane:EA, 25% EA) to obtain the intermediate in a 45% yield.

[0258] 1 H NMR (400MHz, DMSO): δ7.89(d,J=8.5Hz,2H),7.76(d,J=8.3Hz,2H),7.64(d,J=1.8Hz,1H),7.55(dd,J=16.2,8.4Hz,1H),7.38-7. 25(m,1H),7.09(ddd,J=9.3,7.0,2.5Hz,1H),4.30(t,J=6.0Hz,2H),4.03(q,J=7.1Hz,2H),3.76(q,J=6.3Hz,2H),1.36(s,18H).

[0259] Synthesis of the intermediate 3-(phosphonooxy)propyl(4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)carbamate

[0260]

[0261] 3-((Di-tert-butoxyphosphoryl)oxy)propyl(4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)carbamate (325 mg, 0.5 mmol) was added to 10 ml of DCM, and trifluoroacetic acid (1.2 ml, 1.2 mmol) was added. The mixture was stirred at 0°C for 30 min and reacted at room temperature for 2 hours. The solvent was then dried to give a white solid in a yield of 93%.

[0262] 1 H NMR (400MHz, DMSO): δ7.90(d,J=8.3Hz,2H),7.76(d,J=8.2Hz,2H),7.63(s,1H),7.55(dd,J=16.2,8.3Hz,1H),7.32 (t,J=10.3Hz,1H),7.09(d,J=10.7Hz,1H),4.28(t,J=6.1Hz,2H),3.75(dd,J=12.8,6.2Hz,2H),2.02-1.69(m,2H).13 C NMR (125MHz, DMSO): δ163.4(d,J=8.6Hz), 163.2, 161.38(d,J=8.6Hz), 159.80(d,J=8.6Hz), 157.8(d,J=8.6Hz), 14 7.8,143.2,138.3,132.2,129.3,127.7(d,J=10.8Hz),124.7,122.6,117.1,114.7,113.5,105.9,63.3,62.8,30.3. 19 F NMR(376MHz, DMSO-d6): δ-60.9(s,3F), -109.5--110.3(m,1F),-110.6--111.3(m,1F).HRMS(ESI):m / z calcd for C 19 H 15 F5N3O2S[M+H] + :538.0403;found:538.0401.

[0263] Synthesis of the target compound 3-(phosphonooxy)propyl(4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)carbamate sodium salt:

[0264]

[0265] A white solid was obtained with a yield of 80%.

[0266] Example 26. (4-(2,4-Difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)carbamate, phosphonooxy)methyl sodium salt

[0267] Synthesis of intermediate chloromethyl (4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)carbamate:

[0268]

[0269] NAH (0.54 g, 22.4 mmol) was added to 30 ml of anhydrous THF. KJ1311 (2 g, 5.6 mmol) was previously dissolved in 10 ml of anhydrous THF and added dropwise under ice bath. The mixture was stirred for 1 h. Chloromethyl chloride (2.166 g, 16.8 mmol) and DMAP (68 mg, 0.56 mmol) were quickly added and reacted for four hours. The mixture was quenched by adding 40 ml of ice water under ice bath. The layers were separated and the aqueous phase was extracted three times with 20 ml of dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The intermediate was separated by column chromatography (eluent: n-heptane:EA, 13% EA) to obtain the intermediate in a yield of 65%.

[0270] 1 H NMR (400MHz, DMSO) δ7.92(d,J=8.5Hz,2H),7.77(d,J=8.3Hz,2H),7.64(d, J=2.1Hz,1H),7.55(dd,J=16.0,8.6Hz,1H),7.38-7.26(m,1H),7.09(ddd,J=9.3,7.1,2.6Hz,1H),4.45(s,J=6.1Hz,2H),.

[0271] Synthesis of the intermediate ((di-tert-butoxyphosphoryl)oxy)methyl(4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)carbamate:

[0272]

[0273] Dissolve chloromethyl (4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)carbamate (0.448 g, 1 mmol) in 20 ml of DMF, add KI (0.165 g, 1 mmol) and di-tert-butyl tetra-n-butylammonium phosphate (1.8 g, 4 mmol), and heat at 60°C for 48 h. Cool the reaction mixture to room temperature and transfer it to a separatory funnel containing diethyl ether. Wash the organic layer five times with 20 ml of water, then with saturated brine and dry over anhydrous sodium sulfate. The solvent is then evaporated and separated by column chromatography (eluent: n-heptane:EA, 25% EA) to obtain the intermediate in a 50% yield.

[0274] 1H NMR (400MHz, DMSO) δ7.89(d,J=8.5Hz,2H),7.76(d,J=8.3Hz,2H),7.64(d, J=1.8Hz,1H),7.55(dd,J=16.2,8.4Hz,1H),7.38-7.25(m,1H),7.09(ddd,J=9.3,7.0,2.5Hz,1H),4.39(s,J=6.0Hz,2H),1.38(s,18H).

[0275] Synthesis of the intermediate (4-(2,4-difluorophenyl)thiazol-2-yl)(phosphonooxy)methyl of 4-(trifluoromethyl)phenyl)carbamate:

[0276]

[0277] 3-((Di-tert-butoxyphosphoryl)oxy)propyl(4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)carbamate (200 mg, 0.3 mmol) was added to 10 ml of DCM, and trifluoroacetic acid (1.2 ml, 1.2 mmol) was added. The mixture was stirred at 0°C for 30 min and reacted at room temperature for 2 hours. The solvent was then dried to give a white solid in a yield of 93%.

[0278] 1 H NMR (400MHz, DMSO) δ7.90(d,J=8.3Hz,2H),7.76(d,J=8.2Hz,2H),7.63(s,1H),7.55(dd,J =16.2,8.3Hz,1H),7.32(t,J=10.3Hz,1H),7.09(d,J=10.7Hz,1H),4.36(s,J=6.1Hz,2H). 13 C NMR (100MHz, DMSO) δ163.4(d,J=8.6Hz),163.2(s),161.4(d,J=8.6Hz),159.8(d,J=8.6Hz),157.8(d,J=8.6Hz),14 7.8,143.2,138.3,132.2,129.3,127.7(d,J=10.8Hz),124.7,122.6,117.1,114.7,113.5,105.9,63.3,62.8,30.3. 19 F NMR(376MHz, DMSO-d6)δ-60.9(s,3F),-109.5--110.3(m,1F),-110.6--111.3(m,1F); HRMS(ESI):m / z calcd for C 19 H15 F5N3O2S[M+H] + :510.0128;found:510.0126.

[0279] Synthesis of the target compound (phosphonooxy)methyl 4-(2,4-difluorophenyl)thiazol-2-yl)(4-(trifluoromethyl)phenyl)carbamate:

[0280]

[0281] A white solid was obtained with a yield of 78%.

[0282] Example 27. Solubility test part:

[0283] To create a standard curve: Accurately weigh the standard sample and prepare a 100 ppm standard stock solution. Dissolve it by ultrasonication and dilute it sequentially to 80 ppm, 60 ppm, 40 ppm, and 20 ppm standard solutions. Analyze the prepared standard solutions by HPLC in ascending concentration order and plot a standard curve.

[0284] Preparation of saturated solution: Take 1.5 ml of ultrapure water or water: ethanol (1:1) mixed solution, add excess standard sample so that it cannot be completely dissolved, and shake in a constant temperature shaker at 25°C for 24 hours.

[0285] Test Method: HPLC analysis was performed using an Eclipse XDB-C18 column (5 μm, 250 mm × 4.6 mm) at 25°C. Flow rate: 1 mL min-1, detection wavelength: 302 nm, automated injection, 20 μL per injection. Mobile phases: A: acetonitrile, B: water. Elution: gradient elution: 70-100% A (0-10 min); 100% A (10-15 min). Sample run time: 15 min.

[0286] The test results are shown in Table C:

[0287] Table C. Water solubility of target compounds

[0288]

[0289]

[0290]

[0291]

[0292] The experimental results showed that the solubility of the compounds represented by Formula I in water was significantly improved. The solubility of compound I-34 in water reached 3.637 mg / mL, which is about 1000 times higher than the solubility of the original compound. The maximum solubility of compound I-55 (sodium phosphate salt) in water was 3.518 mg / mL, which is also about 1000 times higher than the solubility of the original compound. However, the solubility of the compound represented by Formula II in water did not improve significantly.

[0293] Example 28 Activity Test Part:

[0294] Experimental methods: The minimum inhibitory concentration (MIC) was determined by the microdilution broth method according to the CLSI-M07-A9 (Clinical & Laboratory Standards Institute M07-A9, Clinical and Laboratory Standards Institute - Aerobic Dilution Susceptibility Testing Method).

[0295] The bacteria to be tested are removed from the cryopreservation tube, streaked on a plate for initial activation and culture for about 16 to 20 hours, then a single colony is picked and inoculated into a liquid culture medium and cultured to the logarithmic growth phase. In a 96-well plate, the antibacterial drug (daptomycin and polymyxin E in this invention) is diluted in 100 μl of culture medium, and then 4 μg / ml of the test compound is added to each well. The overnight culture solution is diluted 1:1000 and added to the wells, 100 μl per well. The culture plate is placed at 37°C and cultured for 16 to 18 hours. The minimum inhibitory concentration (MIC) of the drug is determined by reference to the standard.

[0296] Experimental results:

[0297] 1. The results of the synergistic activity of the preferred compounds of formula (I) according to the present invention against polymyxin E against Gram-negative bacteria are shown in Table 1.

[0298] The synergistic factor of a compound is the MIC of polymyxin E measured when used alone divided by the MIC of polymyxin E measured after adding the test compound (at a concentration of 4 μg / ml). In the table, ATCC19606 is Acinetobacter baumannii, purchased from ATCC; ATCC13883 is Klebsiella pneumoniae; and ATCC27853 is Pseudomonas aeruginosa, purchased from ATCC.

[0299]

[0300] Table 1. Synergistic activity of compounds represented by formula I against Gram-negative bacteria

[0301]

[0302]

[0303]

[0304]

[0305] 2. The results of the synergistic activity of the pharmaceutically acceptable salts of the compound of formula (I) according to the present invention against daptomycin against Gram-positive bacteria are shown in Table 2.

[0306] The compound synergistic factor is the MIC of daptomycin alone divided by the MIC of daptomycin after the test compound (at a concentration of 4 μg / ml) is added. In the table, strain ATCC43300 is methicillin-resistant Staphylococcus aureus, purchased from ATCC; strain ATCC25923 is sensitive Staphylococcus aureus; strain ATCC29212 is Enterococcus faecalis, both purchased from ATCC; and strain ATCC51299 is vancomycin-resistant Enterococcus faecalis, also purchased from ATCC.

[0307] Table 2 Synergistic activity of preferred compounds of formula I against Gram-positive bacteria

[0308]

[0309]

[0310]

[0311] 3. The results of the synergistic activity of the compound of formula (II) according to the present invention against polymyxin E against Gram-negative bacteria are shown in Table 1.

[0312] The synergistic factor of a compound is the MIC of polymyxin E measured when used alone divided by the MIC of polymyxin E measured after adding the test compound (at a concentration of 4 μg / ml). In the table, ATCC19606 is Acinetobacter baumannii, purchased from ATCC; ATCC13883 is Klebsiella pneumoniae; and ATCC27853 is Pseudomonas aeruginosa, purchased from ATCC.

[0313]

[0314] Table 3. Synergistic activity of preferred compounds of formula II against Gram-negative bacteria

[0315]

[0316]

[0317]

[0318] 4. The compounds of the present invention have a synergistic effect on colistin and daptomycin, but the compounds of the present invention themselves do not have or have no significant antibacterial activity. Due to space limitations, Table 4 below lists only the test results of representative compounds of the present invention against Acinetobacter baumannii ACCT19606. The results show that the compounds of the present invention alone have no inhibitory effect on the test strain within the tested concentration range:

[0319] Table 4

[0320]

[0321] 5. The synergistic effect of compound I-31 on the bactericidal effect of polymyxin E against Gram-negative bacteria

[0322] The time-kill curve is a very intuitive and effective means of evaluating the bactericidal ability of antibiotics. While examining the bactericidal ability of antibiotics, it can also objectively reflect the bactericidal efficacy at each time point.

[0323] Experimental Method: Activated cultured bacteria were inoculated at a dilution of 1:1000 into a test tube containing 2 ml of liquid culture medium. The desired concentrations of antibiotics and potentiators were added to the test tubes. A test tube without any drug was used as a control group. Samples were taken at 0, 1, 2, 4, 8, and 24 hours. The sampled bacterial solution was diluted tenfold each time. 100 μl of the appropriate dilution was spread onto a pre-prepared culture medium plate and incubated in a 37°C incubator for 16-20 hours. The plates were then removed and viable bacteria were counted, using colony-forming units (CFU) as the standard. After three replicates, the logarithm of the colony count was plotted against the incubation time to generate a time-kill curve.

[0324] The experimental results are as follows Figure 1 As shown (Note: KJ and KJ1311AA in the figure are nicknames for I-31). In the figure, ATCC19606 strain is Acinetobacter baumannii, purchased from ATCC; ATCC13883 strain is Klebsiella pneumoniae, and ATCC27853 strain is Pseudomonas aeruginosa, purchased from ATCC.

[0325] Results showed that the combination of 1 μg / ml I-31 and 1 μg / ml PmE completely killed Acinetobacter baumannii within 8 hours, and prevented its re-growth within 24 hours. Higher I-31 concentrations enhanced PmE's bactericidal effect against Klebsiella pneumoniae and Pseudomonas aeruginosa.

[0326] 6. The synergistic effect of compound I-31 on the bactericidal effect of daptomycin against Gram-positive bacteria

[0327] The experimental method is the same as above.

[0328] The experimental results are as follows Figure 2 As shown (Note: KJ in the figure is another name for I-31). In the figure, ATCC43300 is a methicillin-resistant Staphylococcus aureus purchased from ATCC; ATCC25923 is a sensitive Staphylococcus aureus, ATCC29212 is an Enterococcus faecalis, both purchased from ATCC; and ATCC51299 is a vancomycin-resistant Enterococcus faecalis, also purchased from ATCC.

[0329] The results showed that 4 μg / ml of I-31 could enhance the bactericidal effect of daptomycin against Gram-positive bacteria.

[0330] 7. Compound I-31 enhances the MIC50 and MIC90 of polymyxin B against 98 carbapenem-resistant Acinetobacter baumannii strains

[0331] The experimental method was the same as 1. All experimental strains were provided by Huashan Hospital.

[0332] Table 5. MIC50 and MIC90 of 1 μg / ml I-31-potentiated polymyxin against 98 carbapenem-resistant Acinetobacter baumannii strains detected by broth microdilution method

[0333]

[0334] Table 6. MIC50 and MIC90 of 4 μg / ml I-31-potentiated polymyxin against 98 carbapenem-resistant Acinetobacter baumannii strains detected by broth microdilution assay

[0335]

[0336] From the results shown in Tables 5 and 6, it can be seen that 1 μg / ml of KJ1311AA has no obvious synergistic effect on the antibacterial efficacy of polymyxin E2 against 98 strains of carbapenem-resistant Acinetobacter baumannii, but the synergistic effect is obvious when the concentration is increased to 4 μ / ml, which proves that the synergistic effect of KJ1311AA on the antibacterial efficacy of polymyxin E2 against carbapenem-resistant Acinetobacter baumannii is concentration-related and dependent.

[0337] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, Where: X represents substituted or unsubstituted C 1-10 Alkylene, C(O) or C(O)O; Y represents no or substituted or unsubstituted C 1-10 alkylene; M stands for None, or NR'R", in, R' and R" are each independently selected from H, substituted or unsubstituted C 1-6 alkyl; The "substituted" refers to being substituted by one or more groups selected from the following groups: halogen, CH3-, HN=C(NH2)-NH-(CH2)3-, H2N-CO-CH2-, HOOC-CH2-, HS-CH2-, H2N-CO-(CH2)2-, HOOC-(CH2)2-, CH3-CH2-CH(CH3)-, (CH3)2CH-CH2-, H2N-(CH2)4-, CH3-S-(CH2)2-, Ph-CH2-, HO-CH2-, CH3-CH(OH)-, HO-Ph-CH2-, (CH3)2CH-, -CH2-COOCH3, -CH2-COOCH2CH3, -(CH2)2-COOCH3, -(CH2)2-COOCH2CH3, -CH2-O-CH3, -CH2-O-CH2CH3, -CH(CH3)-O-CH3, -CH(CH3)-O-CH2CH3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The substituted or unsubstituted C 1-10 Alkylene is a substituted or unsubstituted C 1-6 Alkylene.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein HO-Ph-CH2- is HO-p-Ph-CH2-.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X represents a substituted or unsubstituted C 1-10 Alkylene, C(O) or C(O)O; Y represents a substituted or unsubstituted C 1-10 alkylene; M stands for NR'R", wherein R' and R" are as described in claim 1.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein The substituted or unsubstituted C 1-10 Alkylene is a substituted or unsubstituted C 1-6 Alkylene.

6. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein X represents C(O) or C(O)O; Y represents a substituted or unsubstituted C 1-10 alkylene; M stands for NR'R", wherein R' and R" are as described in claim 1.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein The substituted or unsubstituted C 1-10 Alkylene is a substituted or unsubstituted C 1-6 Alkylene.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound is shown in the following formula: Wherein, Y and M are as described in claim 1.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein When the compound is as shown in Formula IV, Y is substituted or unsubstituted C 1-10 alkylene; M is -NH2, or, When the compound is as shown in Formula V, Y is substituted or unsubstituted C 1-10 alkylene; M is -NH2, 10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein The substituted or unsubstituted C 1-10 Alkylene is a substituted or unsubstituted C 1-6 Alkylene.

11. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein When the compound is as shown in Formula IV, Y is substituted or unsubstituted C 1-10 Alkylene; M is -NH2; or, When the compound is as shown in Formula V, Y is substituted or unsubstituted C 1-10 Alkylene, M is -NH2.

12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein The pharmaceutically acceptable salt is a salt formed by the compound and a pharmaceutically acceptable inorganic acid or organic acid, or a salt formed by a base.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein When M is NR'R", The inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid; the organic acid is selected from the group consisting of various natural and artificial amino acids, formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid, asiatic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, and citric acid; When M is When, the salt is a Na salt or a K salt.

14. A compound of formula I or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from compounds I-1 to I-111 shown in the following table:

15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable excipient.

16. The pharmaceutical composition according to claim 15, wherein The pharmaceutical composition is a daptomycin potentiator.

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, an optional pharmaceutically acceptable excipient, and daptomycin.

18. Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof in the preparation of a daptomycin enhancer.

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