Novel phenylquinolone compounds with antibacterial and anticancer functions and their preparation method

Abstract

The present invention discloses novel phenylquinolone compounds with antibacterial and anticancer functions and methods for preparing the same, which belong to the pharmaceutical technical field. The present invention provides phenylquinolone compounds represented by formula (I) or pharmaceutically acceptable salts, stereoisomers, deuterated compounds, or prodrugs thereof, which have antibacterial and anticancer activities. The present invention also provides antibacterial compositions containing one or more compounds of formula (I) or their salts. The present invention further includes methods for treating and preventing bacterial infections and tumor cell proliferation by administering multiple effective doses of a compound of formula (I) or its salt. JPEG2026506307000107.jpg46128

Description

[Technical Field]

[0001] The present invention belongs to the field of medical technology, and particularly relates to novel phenylquinolone compounds with antibacterial and anticancer functions and their preparation. [Background technology]

[0002] The antibacterial industry has grown rapidly since the discovery of the first antibiotic, penicillin, but bacterial resistance resulting from antibiotic misuse poses one of the most serious threats to global public health.

[0003] Approximately 30% of patients infected with drug-resistant Staphylococcus aureus (MRSA) ultimately die, a higher mortality rate than that of HIV. Carbapenem-resistant Gram-negative superbacteria are listed as "high-priority" pathogens, including Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter. High-priority pathogens are primarily S. aureus and Enterococci resistant to vancomycin or fluoroquinolones. These multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria are widely isolated and often lack susceptibility to multiple antibiotics. This not only poses serious food safety concerns but also has been reported to have a significant impact on the efficacy of anti-infective treatments for disease. Currently, resistance of Escherichia coli and Klebsiella pneumoniae to the fluoroquinolone antibiotic ciprofloxacin can reach 92.9% and 79.4%, respectively.

[0004] Furthermore, because cancer has a very high mortality rate, there is an urgent clinical need to provide antibiotics that are effective against drug-resistant bacteria and suitable for cancer patients. Summary of the Invention

[0005] General Formula Description The present invention relates to a phenylquinolone compound represented by formula (I). [ka] [In the formula, A1 is a nitrogen atom N or CR a where R a is a hydrogen atom, a halogen atom (F, Cl, Br, I), C1-C3 alkyl, C1-C2 alkoxy, amino (-NH2), nitro, or R1 and R a are joined to form a 6-membered heterocycle which is unsubstituted or optionally substituted with short chain alkyl (C1-4 alkyl), A2 is absent or is methylene -CH2-, alkenyl -CH=CH-, aminyl -NH- or oxygen atom -O-, and R4-A2- is R4- when A2 is absent; R1 is a hydrogen atom, cyano, C1-C2 short chain alkyl substituted with 0 or 2 halogen atom(s), C3-C6 cycloalkyl substituted with 0 or 1 halogen atom, phenyl substituted with 1 or 2 halogen atom(s), or 2-pyridinyl substituted with 1 to 3 substituent(s) selected from halogen atoms or amino (—NH2), or a are joined to form a 6-membered heterocycle which is unsubstituted or optionally substituted with short chain alkyl (C1-4 alkyl), R2 is hydroxy, C1-C2 alkoxy, or -NR b R c where R b , R c are each independently selected from a hydrogen atom, a C1-C2 alkyl, or a hydroxy, provided that they are not both hydroxy; R3 is halogen, nitro or C1-C2 alkoxy; R4 is substituted or unsubstituted aryl, the substitutions being mono- to tetra-substituted, including one or more combinations of ortho, meta, and para substitutions, and the substituents are selected from halogen-X (F, Cl, Br, I), nitro-NO2, cyano-CN, hydroxylaminyl-NH-OH, C1-C3 alkoxy substituted with 0-3 halogen atoms(s), C1-C9 alkyl substituted with 0-3 halogen atoms(s), sulfinyl-SO-R d , aminylsulfinyl-SO-NR e R e ', sulfonyl-SO2-R f , aminylsulfonyl-SO2-NR g R g ', methyliminosulfinyl-S(=O)(=NR h )CH3, sulfenyl-SR i , Aminyl-NR j R j ', carbamoyl-CO-NR k R k ', hydrazinyl-NH-NR l R l ', diazenyl-N=NR m R m ' is selected from where R d is C1-C9 straight or branched alkyl, C3-C6 cycloalkyl, halo C1-C9 alkyl, C1-C9 alkyl substituted with hydroxy, C1-C9 alkyl substituted with amino (-NH2), -SR d C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, morpholine, piperazine, piperidine, or d ' is selected from R d ', R d " are each independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, or a haloC1-C9 alkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom (N, O, S) at any position, if normal valence allows; R e , R e' are each independently a hydrogen atom, a C1-C9 straight or branched chain alkyl, a C3-C6 cycloalkyl, a halo C1-C9 alkyl, a C1-C9 alkyl substituted with hydroxy, a C1-C9 alkyl substituted with amino (-NH2), -SR e is selected from C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, C1-C5 acyl (H or C1-C4 alkyl)-C(=O)-, haloC2-C5 acyl, or C2-C5 alkoxycarbonyl substituted with R e '' is a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, or a haloC1-C9 alkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom (N, O, S) at any position, as long as normal valences permit; R f is C1-C9 straight or branched alkyl, C3-C6 cycloalkyl, halo C1-C9 alkyl, C1-C9 alkyl substituted with hydroxy, C1-C9 alkyl substituted with amino (-NH2), -SR f C1-C9 alkyl substituted with ''; morpholine; piperazine; piperidine; OR f ' is selected from R f ', R f " are each independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, or a haloC1-C9 alkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; R g , R g ' are each independently a hydrogen atom, a C1-C25 straight or branched chain alkyl containing 0-10 unsaturated bonds (a plurality of unsaturated bonds are possible), a C3-C6 cycloalkyl, a halo C1-C9 alkyl, a C1-C9 alkyl substituted with hydroxy, a C1-C9 alkyl substituted with amino (-NH2), -SR gis selected from C1-C9 alkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl (H or C1-C4 alkyl)-C(=O)-, haloC2-C5 acyl, or C2-C5 alkoxycarbonyl substituted with R g '' is a hydrogen atom, a C1-C9 straight or branched alkyl, and a C atom at any position in the carbon chain of the alkyl may be replaced by a heteroatom as long as normal valence allows, or -NR g R g 'teeth, [ka] and R h is selected from a hydrogen atom, a C1-C9 straight or branched alkyl containing 0 to 10 unsaturated bonds, a C3-C6 cycloalkyl, a haloC1-C9 alkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, a C1-C5 acyl (H or C1-C4 alkyl)-C(=O)-, a haloC2-C5 acyl, or a C2-C5 alkoxycarbonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; R i is a hydrogen atom, C1-C9 straight or branched alkyl, C3-C6 cycloalkyl, halo C1-C9 alkyl, C1-C9 alkyl substituted with hydroxy, C1-C5 acyl, halo C2-C5 acyl, -NR i 'R i '' is selected from R i ', R i each independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, a haloC1-C9 alkyl, a C1-C5 acyl (H or C1-C4 alkyl)-C(=O)-, a haloC2-C5 acyl, or a C2-C5 alkoxycarbonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valence allows; R j , R jeach ' is independently selected from a hydrogen atom, a C-C25 straight or branched alkyl having 0 to 10 unsaturated bonds, a C3 to C6 cycloalkyl, a haloC1 to C9 alkyl, a C2 to C9 alkenyl, a C2 to C9 alkynyl, a C1 to C25 acyl (H, a C2 to C9 alkenyl, or a C1 to C24 alkyl having 0 to 10 unsaturated bonds)-C(=O)-, a haloC2 to C5 acyl, a C1 to C3 alkoxycarbonyl, a C1 to C25 alkylsulfonyl, or a C2 to C25 alkenylsulfonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; R k , R k each ' is independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, a haloC1-C9 alkyl, a C1-C9 alkyl substituted with hydroxy, a C2-C9 alkenyl, a C2-C9 alkynyl, hydroxy, a C1-C5 acyl (H or C1-C4 alkyl)-C(=O)-, a haloC2-C5 acyl, a C2-C5 alkoxycarbonyl, or a C1-C9 alkylsulfonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valence permits; R l , R l each ' is independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, a haloC1-C9 alkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, a hydroxy, a C1-C5 acyl (H or C1-C4 alkyl)-C(=O)-, a haloC2-C5 acyl, or a C2-C5 alkoxycarbonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valence permits; R m , R meach ' is independently selected from a hydrogen atom, phenyl, C1-C9 straight or branched alkyl, C3-C6 cycloalkyl, haloC1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, hydroxy, C1-C5 acyl (H or C1-C4 alkyl)-C(=O)-, haloC2-C5 acyl, or C2-C5 alkoxycarbonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valence permits; The aryl is phenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, [ka] Select from or a pharmaceutically acceptable salt, stereoisomer, deuterated product, or prodrug thereof.

[0006] In one embodiment of the present invention, at least one substituent on the aryl in R4 is sulfinyl-SO-R d , aminylsulfinyl-SO-NR e R e ', sulfonyl-SO2-R f , aminylsulfonyl-SO2-NR g R g ', methyliminosulfinyl-S(=O)(=NR h )CH3, Aminyl-NR j R j ', hydrazinyl-NH-NR l R l ', diazenyl-N=NR m R m ', where R j is a hydrogen atom, and R j ' is halo C2-C5 acyl, C1-C25 alkylsulfonyl.

[0007] In one embodiment of the present invention, at least one substituent on the aryl in R4 is sulfinyl-SO-R d , aminylsulfinyl-SO-NR e R e', sulfonyl-SO2-R f , aminylsulfonyl-SO2-NR g R g ', methyliminosulfinyl-S(=O)(=NR h )CH3, Aminyl-NR j R j ', hydrazinyl-NH-NR l R l ', diazenyl-N=NR m R m ', where R j , R j Each ' is independently selected from a hydrogen atom, halo C2-C5 acyl, and C1-C25 alkylsulfonyl; R j , R j ' are both not H.

[0008] In one embodiment of the present invention, R4 is a monosubstituted aryl and the substituent is sulfinyl-SO-R d , aminylsulfinyl-SO-NR e R e ', sulfonyl-SO2-R f , aminylsulfonyl-SO2-NR g R g ', methyliminosulfinyl-S(=O)(=NR h )CH3, Aminyl-NR j R j ', hydrazinyl-NH-NR l R l ', diazenyl-N=NR m R m ' is selected from Alternatively, R4 is aryl substituted with 2 to 4 substituents, at least one of which is sulfinyl-SO-R d , aminylsulfinyl-SO-NR e R e ', sulfonyl-SO2-R f , aminylsulfonyl-SO2-NR g R g ', methyliminosulfinyl-S(=O)(=NR h )CH3, Aminyl-NR j R j', hydrazinyl-NH-NR l R l ', diazenyl-N=NR m R m ' is selected from where R j , R j Each ' is independently selected from a hydrogen atom, halo C2-C5 acyl, and C1-C25 alkylsulfonyl; R j , R j ' are both not H.

[0009] In one embodiment of the present invention, for R4, aryl is 4-pyridinyl or [ka] and at least one substituent on the aryl is carbamoyl-CO-NR k R k ' is.

[0010] In one embodiment of the present invention, R4 is specifically (1) Phenyl of Formula II: [ka] [wherein R5 is a hydrogen atom, a halogen atom, or sulfinyl-SO-R d , aminylsulfinyl-SO-NR e R e ', sulfonyl-SO2-R f , aminylsulfonyl-SO2-NR g R g ', methyliminosulfinyl-S(=O)(=NR h )CH3, Aminyl-NR j R j ', hydrazinyl-NH-NR l R l ', diazenyl-N=NR m R m ' and R6, R7, and R8 are each independently (a) a hydrogen atom, (b) a halogen atom, (c) nitro, (d) cyano; (e) hydroxylaminyl, (f) C1-C3 alkoxy substituted with 0 to 3 halogen atoms (may be multiple); (g) C1-C9 alkyl substituted with 0-3 halogen atoms(s); (h) Sulfinyl, which is selected from C1-C9 linear or branched alkyl, C3-C6 cycloalkyl, C1-C9 haloalkyl, C1-C9 alkyl substituted with hydroxy, C1-C9 alkyl substituted with amino (—NH2), -SR d C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, morpholine, piperazine, piperidine, or OR substituted with d ' and optionally replaced by R d ', R d each independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, or a C1-C9 haloalkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; sulfinyl; (i) Aminylsulfinyl, which is selected from the group consisting of a hydrogen atom, a C1-C9 linear or branched alkyl, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C1-C9 alkyl substituted with hydroxy, a C1-C9 alkyl substituted with amino (—NH2), and —SR e optionally substituted with C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 haloacyl, or C2-C5 alkoxycarbonyl substituted with R e aminylsulfinyl, wherein '' is a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, or a haloC1-C9 alkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; (j) Sulfonyl, which is selected from C1-C9 linear or branched alkyl, C3-C6 cycloalkyl, C1-C9 haloalkyl, C1-C9 alkyl substituted with hydroxy, C1-C9 alkyl substituted with amino (-NH2), -SR f C1-C9 alkyl substituted with ''; morpholine; piperazine; piperidine; or OR f ' and optionally replaced by R f ', R f '' are each independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, or a C1-C9 haloalkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; sulfonyl; (k) Aminylsulfonyl, which is selected from the group consisting of a hydrogen atom, a C1-C25 straight or branched alkyl having 0 to 10 unsaturated bonds (a plurality of unsaturated bonds), a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C1-C9 alkyl substituted with hydroxy, a C1-C9 alkyl substituted with amino (-NH2), -SR g optionally substituted with C1-C9 alkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 haloacyl, or C2-C5 alkoxycarbonyl substituted with R g '' is a hydrogen atom, a C1-C9 straight or branched alkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valence allows, or -NR g R g 'but, [ka] aminylsulfonyl, (l) methyliminosulfinyl, which is optionally substituted with a hydrogen atom, a C1-C9 straight or branched alkyl containing 0 to 10 unsaturated bonds, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, a C1-C5 acyl, a C2-C5 haloacyl, or a C2-C5 alkoxycarbonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; (m) sulfenyl, which is selected from the group consisting of a hydrogen atom, a C1-C9 linear or branched alkyl, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C1-C9 alkyl substituted with hydroxy, a C1-C5 acyl, a C2-C5 haloacyl, and -NR i 'R i Optionally replaced by '' and R i ', R i each independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C1-C5 acyl, a C2-C5 haloacyl, or a C2-C5 alkoxycarbonyl, in which a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; sulfenyl; (n) aminyl optionally substituted with a hydrogen atom, a C1-C25 straight or branched alkyl containing 0-10 unsaturated bond(s), a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, a C1-C25 acyl (H, a C2-C9 alkenyl, or a C1-C24 alkyl containing 0-10 unsaturated bond(s))-C(=O)-, a C2-C5 haloacyl, a C1-C3 alkoxycarbonyl, a C1-C25 alkylsulfonyl, or a C2-C25 alkenylsulfonyl; (o) carbamoyl, which is optionally substituted with a hydrogen atom, a C1-C9 straight-chain or branched-chain alkyl, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, hydroxy, a C1-C5 acyl, a C2-C5 haloacyl, a C2-C5 alkoxycarbonyl, or a C1-C9 alkylsulfonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; (p) hydrazinyl, (q) diazenyl, Select from (2) 2-pyridinyl substituted with one or two substituent(s) selected from the following: (a) a hydrogen atom, (b) a halogen atom, (c) hydroxylaminyl, (d) sulfonyl, which is selected from C1-C9 linear or branched alkyl, C3-C6 cycloalkyl, C1-C9 haloalkyl, C1-C9 alkyl substituted with hydroxy, C1-C9 alkyl substituted with amino (—NH2), -SR f C1-C9 alkyl substituted with ''; morpholine; piperazine; piperidine; or OR f ' and optionally replaced by R f ', R f '' are each independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, or a C1-C9 haloalkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; sulfonyl; (e) Aminylsulfonyl, which is selected from the group consisting of a hydrogen atom, a C1-C25 straight or branched alkyl having 0 to 10 unsaturated bonds, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C1-C9 alkyl substituted with hydroxy, a C1-C9 alkyl substituted with amino (-NH2), and -SR goptionally substituted with C1-C9 alkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 haloacyl, or C2-C5 alkoxycarbonyl substituted with R g '' is a hydrogen atom, a C1-C9 straight or branched alkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valence allows, or -NR g R g 'but, [ka] aminylsulfonyl, (f) methyliminosulfinyl, which is optionally substituted with a hydrogen atom, a C1-C9 straight or branched alkyl containing 0 to 10 unsaturated bonds, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, a C1-C5 acyl, a C2-C5 haloacyl, or a C2-C5 alkoxycarbonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; (g) Sulfenyl is selected from the group consisting of a hydrogen atom, a C1-C9 linear or branched alkyl, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C1-C9 alkyl substituted with hydroxy, a C1-C5 acyl, a C2-C5 haloacyl, and -NR i 'R i Optionally replaced by '' and R i ', R i each independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C1-C5 acyl, a C2-C5 haloacyl, or a C2-C5 alkoxycarbonyl, in which a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; sulfenyl; (h) aminyl optionally substituted with a hydrogen atom, a C1-C25 straight or branched alkyl containing 0-10 unsaturated bond(s), a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, a C1-C25 acyl (H, a C2-C9 alkenyl, or a C1-C24 alkyl containing 0-10 unsaturated bond(s))-C(=O)-, a C2-C5 haloacyl, a C1-C3 alkoxycarbonyl, a C1-C25 alkylsulfonyl, or a C2-C25 alkenylsulfonyl; (i) carbamoyl, which is optionally substituted with a hydrogen atom, a C1-C9 straight-chain or branched-chain alkyl, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, hydroxy, a C1-C5 acyl, a C2-C5 haloacyl, a C2-C5 alkoxycarbonyl, or a C1-C9 alkylsulfonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; (j) hydrazinyl, (k) diazenyl, Alternatively, at least one of the substituents is sulfinyl-SO-R d , aminylsulfinyl-SO-NR e R e ', sulfonyl-SO2-R f , aminylsulfonyl-SO2-NR g R g ', methyliminosulfinyl-S(=O)(=NR h )CH3, Aminyl-NR j R j ', hydrazinyl-NH-NR l R l ', diazenyl-N=NR m R m ' is selected from, (3) 3-pyridinyl substituted with one or two substituent(s) selected from the following: (a) a hydrogen atom, (b) a halogen atom, (c) hydroxylaminyl, (h) Sulfinyl, which is selected from C1-C9 linear or branched alkyl, C3-C6 cycloalkyl, C1-C9 haloalkyl, C1-C9 alkyl substituted with hydroxy, C1-C9 alkyl substituted with amino (—NH2), -SR d C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, morpholine, piperazine, piperidine, or OR substituted with d ' and optionally replaced by R d ', R d each independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, or a C1-C9 haloalkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; sulfinyl; (i) Aminylsulfinyl, which is selected from the group consisting of a hydrogen atom, a C1-C9 linear or branched alkyl, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C1-C9 alkyl substituted with hydroxy, a C1-C9 alkyl substituted with amino (—NH2), and —SR e optionally substituted with C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 haloacyl, or C2-C5 alkoxycarbonyl substituted with R e aminylsulfinyl, wherein '' is a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, or a haloC1-C9 alkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; (d) sulfonyl, which is selected from C1-C9 linear or branched alkyl, C3-C6 cycloalkyl, C1-C9 haloalkyl, C1-C9 alkyl substituted with hydroxy, C1-C9 alkyl substituted with amino (—NH2), -SR f C1-C9 alkyl substituted with ''; morpholine; piperazine; piperidine; or OR f ' and optionally replaced by R f ', R f'' are each independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, or a C1-C9 haloalkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; sulfonyl; (e) Aminylsulfonyl, which is selected from the group consisting of a hydrogen atom, a C1-C25 straight or branched alkyl having 0 to 10 unsaturated bonds, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C1-C9 alkyl substituted with hydroxy, a C1-C9 alkyl substituted with amino (-NH2), and -SR g optionally substituted with C1-C9 alkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl, C2-C5 haloacyl, or C2-C5 alkoxycarbonyl substituted with R g '' is a hydrogen atom, a C1-C9 straight or branched alkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valence allows, or -NR g R g 'but, [ka] aminylsulfonyl, (f) methyliminosulfinyl, which is optionally substituted with a hydrogen atom, a C1-C9 straight or branched alkyl containing 0 to 10 unsaturated bonds, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, a C1-C5 acyl, a C2-C5 haloacyl, or a C2-C5 alkoxycarbonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; (k) Sulfenyl is a hydrogen atom, a C1-C9 linear or branched alkyl, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C1-C9 alkyl substituted with hydroxy, a C1-C5 acyl, a C2-C5 haloacyl, or -NR i 'R iOptionally replaced by '' and R i ', R i each independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C1-C5 acyl, a C2-C5 haloacyl, or a C2-C5 alkoxycarbonyl, in which a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; sulfenyl; (h) aminyl optionally substituted with a hydrogen atom, a C1-C25 straight or branched alkyl containing 0-10 unsaturated bond(s), a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, a C1-C25 acyl (H, a C2-C9 alkenyl, or a C1-C24 alkyl containing 0-10 unsaturated bond(s))-C(=O)-, a C2-C5 haloacyl, a C1-C3 alkoxycarbonyl, a C1-C25 alkylsulfonyl, or a C2-C25 alkenylsulfonyl; (i) carbamoyl, which is optionally substituted with a hydrogen atom, a C1-C9 straight-chain or branched-chain alkyl, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, hydroxy, a C1-C5 acyl, a C2-C5 haloacyl, a C2-C5 alkoxycarbonyl, or a C1-C9 alkylsulfonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; (j) hydrazinyl, (k) diazenyl, Alternatively, at least one of the substituents is sulfinyl-SO-R d , aminylsulfinyl-SO-NR e R e ', sulfonyl-SO2-R f , aminylsulfonyl-SO2-NR g R g ', methyliminosulfinyl-S(=O)(=NR h )CH3, Aminyl-NR j R j ', hydrazinyl-NH-NRl R l ', diazenyl-N=NR m R m ' is selected from, (4) 4-pyridinyl substituted with one or two substituent(s) selected from the following: (a) a hydrogen atom, (b) a halogen atom, (c) hydroxylaminyl, (h) aminyl optionally substituted with C1-C25 alkyl, C3-C6 cycloalkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 alkynyl, C1-C25 acyl (H, C2-C9 alkenyl, or C1-C24 alkyl containing 0-10 unsaturated bond(s))-C(=O)-, C2-C5 haloacyl, C1-C3 alkoxycarbonyl, C1-C25 alkylsulfonyl, or C2-C25 alkenylsulfonyl; (i) carbamoyl, which is optionally substituted with a hydrogen atom, a C1-C9 straight-chain or branched-chain alkyl, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, hydroxy, a C1-C5 acyl, a C2-C5 haloacyl, a C2-C5 alkoxycarbonyl, or a C1-C9 alkylsulfonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; (j) hydrazinyl, (k) diazenyl, Alternatively, at least one of the substituents is sulfinyl-SO-R d , aminylsulfinyl-SO-NR e R e ', sulfonyl-SO2-R f , aminylsulfonyl-SO2-NR g R g ', methyliminosulfinyl-S(=O)(=NR h )CH3, Aminyl-NR j R j ', hydrazinyl-NH-NR l R l ', diazenyl-N=NR mR m ' is selected from, (5) a group of the formula: [ka] [Wherein R9 is (a) a hydrogen atom, (b) a halogen atom, (c) hydroxylaminyl, (h) aminyl optionally substituted with a hydrogen atom, a C1-C25 straight or branched alkyl containing 0-10 unsaturated bond(s), a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, a C1-C25 acyl (H, a C2-C9 alkenyl, or a C1-C24 alkyl containing 0-10 unsaturated bond(s))-C(=O)-, a C2-C5 haloacyl, a C1-C3 alkoxycarbonyl, a C1-C25 alkylsulfonyl, or a C2-C25 alkenylsulfonyl; (i) carbamoyl, which is optionally substituted with a hydrogen atom, a C1-C9 straight-chain or branched-chain alkyl, a C3-C6 cycloalkyl, a C1-C9 haloalkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, hydroxy, a C1-C5 acyl, a C2-C5 haloacyl, a C2-C5 alkoxycarbonyl, or a C1-C9 alkylsulfonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; (j) hydrazinyl, (k) diazenyl, is selected from Alternatively, at least one of the substituents is sulfinyl-SO-R d , aminylsulfinyl-SO-NR e R e ', sulfonyl-SO2-R f , aminylsulfonyl-SO2-NR g R g ', methyliminosulfinyl-S(=O)(=NR h )CH3, Aminyl-NR j R j ', hydrazinyl-NH-NRl R l ', diazenyl-N=NR m R m 'Selected from], (6) Triazinyl: [ka] (7) a group of the formula: [ka] is selected from.

[0011] In one embodiment of the present invention, the C3-C6 cycloalkyl in R4 may further be selected from C4-C5 heterocycloalkyl, specifically, for example: [ka] is.

[0012] In one embodiment of the present invention, the number of heteroatom(s) in the 6-membered heterocycle is 1 to 4, and the heteroatom(s) is one or more of N, O, and S. Specifically, the 6-membered heterocycle is [ka] wherein Z is O or S, and R n , R n are each independently selected from C1-C4 alkyl, halogen.

[0013] In one embodiment of the present invention, the unsaturated bonds comprise carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0014] In one embodiment of the present invention, C2-C9 alkenyl refers to C2-C9 alkenyl containing 1-5 unsaturated double bond(s), for example, (H, or C1-C7 alkyl containing 0-4 unsaturated double bond(s))-CH=CH-.

[0015] In one embodiment of the present invention, C2-C25 alkenyl refers to C2-C25 alkenyl containing 1-10 unsaturated double bond(s), for example, (H, or C1-C23 alkyl containing 0-9 unsaturated double bond(s))-CH=CH-.

[0016] In one embodiment of the present invention, C2-C9 alkynyl refers to C2-C9 alkynyl containing 1-3 unsaturated bond(s), such as (H, or C1-C7 alkyl containing 0-2 unsaturated bond(s)). [ka] The unsaturated bonds include carbon-carbon double bonds and / or carbon-carbon triple bonds.

[0017] In one embodiment of the present invention, C1-C5 acyl refers to (H or C1-C4 alkyl)-C(=O)-.

[0018] In one embodiment of the present invention, halo C2-C5 acyl refers to (halo C1-C4 alkyl)-C(=O)-.

[0019] In one embodiment of the present invention, C2-C5 alkoxycarbonyl refers to (C2-C5 alkyl)-OC(=O)-.

[0020] In one embodiment of the present invention, C1-C25 acyl refers to (H or C1-C24 alkyl containing 0-10 unsaturated double bond(s))-C(=O)-.

[0021] In one embodiment of the present invention, C1-C25 alkylsulfonyl refers to (C1-C25 alkyl containing 0-10 unsaturated bond(s))-SO2-.

[0022] In one embodiment of the present invention, C2-C25 alkenylsulfonyl refers to (C2-C25 alkenyl containing 1 to 10 unsaturated double bond(s))-SO2-.

[0023] In one embodiment of the present invention, the phenylquinolone compound is [ka] [ka] [ka] Further includes:

[0024] In one embodiment of the invention, the pharmaceutically acceptable salt comprises an inorganic salt or an organic salt, wherein the inorganic salt comprises sodium salt, potassium salt, magnesium salt, hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, acid phosphate, and the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, hydroxyacetate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, and ascorbate.

[0025] The present invention further provides an antibacterial agent comprising the above phenylquinolone compound or a pharmaceutically acceptable salt thereof.

[0026] The present invention further provides an antibacterial medicament comprising the above phenylquinolone compound or a pharmaceutically acceptable salt thereof.

[0027] The present invention further provides an anticancer drug comprising the above phenylquinolone compound or a pharmaceutically acceptable salt thereof.

[0028] In one embodiment of the present invention, the medicament further comprises one or more of the following pharmaceutical excipients: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmolality modifiers, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-binding agents, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, anti-foaming agents, thickeners, inclusion agents, humectants, flocculating and anti-flocculating agents, filter aids, and release retardants.

[0029] In one embodiment of the present invention, the medicament further comprises a pharmaceutical carrier selected from microcapsules, microspheres, nanoparticles, and liposomes.

[0030] In one embodiment of the present invention, the dosage forms of the pharmaceutical include injections, lyophilized powders for injection, suspensions, implants, suppositories, capsules, tablets, pills, and oral liquids.

[0031] In one embodiment of the present invention, cancers treated with the anticancer medicaments include cervical cancer, Burkitt's lymphoma, acute T-lymphoblastic leukemia, non-small cell lung cancer, gastric cancer, colon cancer, pancreatic cancer, liver cancer, malignant melanoma, prostate cancer, ovarian adenocarcinoma, glioma, breast cancer, osteosarcoma, and ductal carcinoma.

[0032] Beneficial Effects: The phenylquinolone compounds of the present invention, or pharmaceutically acceptable salts, stereoisomers, deuterated derivatives, or prodrugs thereof, have excellent antibacterial and anticancer activities. The present invention provides novel antibiotic drugs and treatment methods that are effective against drug-resistant bacteria and suitable for cancer patients. [Brief explanation of the drawings]

[0033] [Figure 1] 1 is a line graph showing the results of drug resistance testing of Example 34, ciprofloxacin, and vancomycin tested against Staphylococcus aureus ATCC 43300 subtype.

[0034] [Figure 2] Photographs of mouse skin infections are shown, illustrating the effects of the tested examples on the animal infection model: (A) saline group, (B) low concentration group (4 μg / mL), (C) medium concentration group (400 μg / mL), and (D) high concentration group (40,000 μg / mL).

[0035] [Figure 3] Figure 1 shows histograms of the effects of the tested drugs on kidney (left) and liver (right) weights. After the experiment, it was found that the related drug molecules had no significant effect on kidney and liver weights, indicating the good safety of the related molecules and the effects of the tested examples on the liver and kidneys of the animals.

[0036] [Figure 4] 1 is a histogram of bacterial colony count analysis of the liver (left) and kidney (right) in an animal model of systemic blood infection, showing the effect of the tested examples on colony counts in the liver and kidney of animals.

[0037] Detailed embodiment In addition to the compounds of formula (I) described above, the present invention further includes compounds of formula (I) in which variables (eg, A1, A2, R1, R2, etc.) have definitions other than those defined above.

[0038] [ka] A1 variable group: The present invention provides a compound of formula (I) and a salt thereof, wherein A1 is a N atom or CR a It includes the group.

[0039] In certain embodiments, R1 and A1 are joined to form a 6-membered heterocycle optionally substituted with a short chain alkyl.

[0040] A2 variable group: The present invention includes compounds of formula (I) and salts thereof, wherein A2 is absent, -CH2-, -CH=CH-, -O-, or -NH-.

[0041] R1 variable group: The present invention includes compounds of formula (I) and salts thereof, wherein R1 is hydrogen or R1 is C1-C3 alkyl or C3-C6 cycloalkyl, each of which is substituted with 0-3 halogen(s).

[0042] In certain embodiments, R1 is phenyl substituted with 0-2 halogen(s), or R1 is 2-pyridinyl substituted with 0-3 substituent(s) independently selected from halogen and amino (—NH2).

[0043] R2 variable group: The present invention includes compounds of formula (I) and salts thereof, wherein R2 is hydroxy, alkoxy, or amide optionally substituted with short chain alkyl or hydroxy. Examples of such compounds include compounds of formula (V) and compounds of formula (VI) [ka] These include, but are not limited to: The variables A1, A2, R shown in formula (V) and formula (VI) a , R1, R3, R4 and R5 are as defined herein for those variables. 10 is a hydrogen atom or a C1-C2 alkyl, and R 11 is a hydrogen atom, C1-C2 alkyl or hydroxy.

[0044] R3 variable group: The present invention includes compounds of formula (I) and salts thereof, wherein R3 is halogen, nitro, or alkoxy.

[0045] R4 variable group: The variable R4 shown in formula (I) is as defined herein for a variable.

[0046] In one embodiment, the present invention includes compounds of formula (I), wherein A and R are joined to form a 6-membered heterocycle optionally substituted with alkyl. Examples of such compounds include compounds of formula (VII) and compounds of formula (VIII):

[0047] [ka] wherein Z is O or S, and R n is selected from C1-C4 alkyl and halogen.

[0048] As used herein, "halogen" refers to F, Cl, Br and I atoms.

[0049] As used herein, "heteroatom" means N, O, and S atoms.

[0050] As used herein, "alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms (multiple). For example, "C1-C9 alkyl" includes straight or branched alkyl having 1, 2, 3 to 8 or 9 carbon atoms (multiple). For alkyl, a C atom in the carbon chain may be replaced by a heteroatom at any position, provided that normal valence permits. Examples of alkyl include, but are not limited to, methyl, ethyl, isopropyl, and tert-butyl.

[0051] As used herein, "cycloalkyl" refers to a saturated non-aromatic hydrocarbon cyclic group having 3 to 6 carbon atoms (or carbon atoms). For cycloalkyl, a C atom in the carbon chain may be replaced by a heteroatom at any position, as long as normal valences permit. Examples of cycloalkyl include, but are not limited to, cyclopropyl, 2-fluorocyclopropyl, cyclobutyl, adamantanyl, etc. Cycloalkyl may contain multiple spirocyclic or bridged rings. Cycloalkyl may be mono-, di-, tri-, tetra-, or penta-substituted at any position, as long as normal valences permit.

[0052] As used herein, "alkenyl" refers to a straight-chain, branched-chain, or cyclic non-aromatic hydrocarbon group having one or more C-C double bonds and 2 to 25 carbon atoms. Up to four C-C double bonds may be present in these groups. For alkenyl, a C atom in the carbon chain may be replaced by a heteroatom at any position, provided that normal valences permit. For example, a "C2-C7" alkenyl is defined as an alkenyl having 2 to 7 carbon atoms. Examples of alkenyl include, but are not limited to, vinyl, allyl, hexenyl, cyclopentadienyl, and the like. The straight-chain, branched, or cyclic portion of an alkenyl may contain double bonds and may be mono-, di-, tri-, tetra-, or penta-substituted at any position, provided that normal valences permit.

[0053] As used herein, "alkynyl" refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon triple bond. For example, "C2-C9 alkynyl" means an alkynyl containing 2 to 9 carbon atoms. For alkynyl, a carbon atom in the carbon chain may be replaced by a heteroatom at any position, as permitted by normal valences. Examples of alkynyl include, but are not limited to, ethynyl, 2-propargyl, and 2-butynyl. The straight or branched chain portion of alkynyl may be mono-, di-, tri-, tetra-, or penta-substituted at any position, as permitted by normal valences.

[0054] As used herein, "alkoxy" refers to an -O-alkyl containing a specified number of C atoms. For example, a C alkoxy is -OCH CH . Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, t-butoxy, n-pentyloxy, s-pentyloxy, n-heptyloxy, and n-octyloxy.

[0055] As used herein, "acyl" refers to a group bonded via a carbonyl bridge connected to a hydrogen, amino, hydroxylamine, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, or heterocycle. Examples of acyl include, but are not limited to, hydrogen (e.g., acetaldehyde group), alkyloyl (e.g., acetyl), alkenyloyl (e.g., acryloyl), alkynyl (e.g., ethynyl), cycloalkylcarbonyl (e.g., cyclopentylcarbonyl), aryloyl (e.g., benzoyl), alkoxycarbonyl (e.g., methoxycarbonyl), aryloxycarbonyl, and heterocyclylcarbonyl (e.g., epoxypropyl).

[0056] As used herein, "aryl" may be mono-, di-, tri-, tetra-, or penta-substituted at any position, where normal valences permit.

[0057] As used herein, "haloalkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group containing 1 to 6 carbon atoms, in which a C atom in the carbon chain can be substituted with a halogen atom at any position, as long as normal valences permit. Examples of haloalkyl include, but are not limited to, chloroethyl and trifluoromethyl.

[0058] The compound of formula (I) or its salt has excellent activity against both Gram-positive and Gram-negative bacteria and can be used to treat a wide range of endogenous or exogenous bacterial infections. The compound of formula (I) or its salt can inhibit the proliferation of tumor cells and is suitable for treating infections in cancer patients.

[0059] The compounds described may have various tautomeric forms, and the invention is not limited to a particular tautomer, but includes all tautomers.

[0060] Atoms in the compounds of formula (I) may have corresponding isotopes. The present invention includes compounds containing all isotopes. Isotopes include atoms having the same atomic number but different atomic masses, including hydrogen isotopes deuterium and tritium, and carbon isotopes. 11 C. 13 C and 14 Includes, but is not limited to, C.

[0061] In the present invention, the "salt" of a compound includes inorganic and organic acid salts and base salts. The salt of a compound can be synthesized by selecting an appropriate base or acid depending on the acidic or basic moiety of the compound itself. Generally, the method for preparing a salt is to react a free acid form of the compound with an appropriate base (e.g., sodium hydroxide, magnesium ethoxide, etc.), or a free base form of the compound with an appropriate acid (e.g., hydrochloric acid, acetic acid, etc.) to obtain the corresponding salt. Such reactions are usually carried out in an organic solvent or water, or in a mixture of an organic solvent and water. The salt of a compound also includes solvate compounds.

[0062] Compound preparation: All non-aqueous reactions were carried out using oven-dried glassware under dry argon. Reaction progress was monitored using thin-layer chromatography on glass plates coated with general reagent silica gel 60. Flash column chromatography was performed on general reagent silica gel. Mass spectra of compounds were recorded using an Agilent G7115A liquid-phase mass spectrometer. NMR spectra were recorded at ambient temperature using a Bruker Avance 400 spectrometer. 1 Chemical shifts of 1 H are reported in parts per million (δ) relative to external tetramethylsilane and were referenced to the signals of residual protons in the deuterated solvent.

[0063] In the preparation of the compounds of the present invention, different synthetic routes are applied: Compounds of formula (I) can be synthesized by the following synthetic process:

[0064] Reaction Scheme 1: [ka] [In the formula, R 10 is a short chain alkyl].

[0065] The synthesis is carried out by Suzuki reaction of intermediate 1 and intermediate 2 in a solvent such as DMF, DMSO, THF, dichloromethane, or acetonitrile in the presence of a base such as K2CO3, Na2CO3, or Cs2CO3, and a palladium catalyst such as 1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II), palladium(II) chloride, or palladium(II) acetate. This reaction can be carried out under atmospheric pressure in an inert gas environment (including nitrogen, argon, etc.). This reaction is typically carried out at room temperature to about 150°C for about 16 to 24 hours.

[0066] Reaction Scheme 2: [ka] The compound of general formula (B) can be prepared by hydrolyzing compound (A). Hydrolysis of compound (1) can be carried out under conventional hydrolysis reaction conditions, for example, in a solvent containing an alcohol such as dichloromethane or methanol, DMF, DMSO, or THF, in the presence of a basic compound such as LiOH, NaOH, or KOH. This reaction is usually carried out at room temperature to about 60°C for about 0.1 to 24 hours.

[0067] Reaction Scheme 3: [ka] Compounds of formula (C) can be synthesized by the condensation reaction of compounds of formula (B). Compounds of formula (B) can be reacted with the corresponding amine in the presence of a condensing agent (e.g., DMAP, HATU, etc.) in a solvent such as dichloromethane, DMF, or THF. This reaction is typically carried out at room temperature for approximately 3 to 12 hours.

[0068] Reaction Scheme 4: [ka] Intermediate 2 can be prepared by reacting compound (D) with bis(pinacolato)diboron compound (E) in the presence of a palladium catalyst and a base in a typical inert solvent. This reaction is carried out under normal pressure in an inert gas environment containing nitrogen, argon, etc. This reaction can usually be carried out at room temperature to about 150°C for about 16 to 24 hours.

[0069] Reaction Scheme 5: [ka] [In the formula, R 12 is a hydrogen atom or a halogen].

[0070] The compound of formula (F) can be synthesized by reacting intermediate 3 and intermediate 1 via the Buchwald reaction, Kumada reaction, Negishi reaction, or Ullmann reaction in a solvent such as DMF, DMSO, THF, or toluene in the presence of a base such as K2CO3, Na2CO3, or Cs2CO3, and in the presence of a copper catalyst such as CuI or Cu(I) or a palladium catalyst such as 1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II), palladium(II) chloride, or palladium(II) acetate. This reaction can be carried out under atmospheric pressure in an inert gas environment containing nitrogen, argon, or the like. This reaction is typically carried out at room temperature to about 100-150°C for about 16-24 hours.

[0071] Specific preparation of related intermediates: Preparation of intermediate compound 7: [ka] Preparation of 2,4,5-trifluoro-3-methoxybenzoyl chloride (2) [ka] To 2,4,5-trifluoro-3-methoxybenzoic acid (1) (30.0 g, 145.5 mmol) was added a solution of SOCl (180 mL) and stirred for 3 h at 85° C. After cooling to room temperature, the solvent was removed by evaporation and dried under vacuum to give a pale yellow oil (32.0 g, 142.5 mmol, 97.9% yield), which was used directly in the next step without further purification.

[0072] Preparation of ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propionate (3) [ka] To a solution of potassium 3-ethoxy-3-oxopropionate (2) (48.5 g, 284.9 mmol) in EA (300 mL) was added MgCl (33.9 g, 356.1 mmol). The mixture was stirred at room temperature for 30 min under nitrogen protection. Trimethylamine (28.8 g, 284.6 mmol) was then added to the mixture and stirred at room temperature for another 30 min. 2,4,5-trifluoro-3-methoxybenzoyl chloride (32.0 g, 142.5 mmol) was added dropwise to the mixture and stirred at 85 °C for 2 h. After cooling to room temperature, water (150 mL) was added to the mixture and it was acidified with HCl (2 M) to pH 1-2. The mixture was extracted with EA (200 mL). The organic layer was dried over NaSO and filtered. The solvent was removed under reduced pressure to give the crude product (58.0 g) as a brown oil.

[0073] Preparation of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (4) [ka] To a solution of ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propionate (3) (58.0 g, 210.0 mmol) in AcO (64.3 g, 630.0 mmol), triethoxymethane (46.6 g, 314.4 mmol) was added and stirred at 100 °C for 2 hours. The solvent was removed under reduced pressure to give a residue. The residue was dissolved in DMSO (400 ml), cyclopropylamine (14.4 g, 252.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. KCO (43.4 g, 314.8 mmol) was then added to the mixture and stirred at 100 °C for an additional hour. After cooling to room temperature, water (500 mL) was added to the mixture and stirred for 10 minutes. The suspension was filtered, and the filtrate was removed. The solid obtained by filtration was washed with water (50 mL) and dried in vacuo to give the target product as a white solid (21.0 g, 65.0 mmol, 45.6% yield over two steps).

[0074] Preparation of ethyl 7-azido-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (5) [ka] To a solution of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (4) (10.0 g, 30.9 mmol) in DMF (50 mL) was added NaN (4.02 g, 61.8 mmol) and stirred at 70 °C for 36 h. After the reaction was completed and cooled to room temperature, the mixture was filtered through Celite. The filtrate was added to water (50 mL) and extracted with EA (70 mL × 3). The organic phase was washed with water (50 mL × 3) and brine (50 mL × 3), dried over Na SO , filtered, and concentrated under reduced pressure to give the crude product as a brown solid (5.6 g).

[0075] Preparation of ethyl 7-amino-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (6): [ka] To a solution of ethyl 7-azido-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (5) (5.6 g, crude product) in THF / MeOH (50 mL / 10 mL), Pd / C (2.8 g, 10 wt%) was added, the mixture was charged with hydrogen three times, and stirred under hydrogen (balloon) at room temperature for 4 h. The reaction was filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1 to 20 / 1) to give a white solid (3.8 g, 11.86 mmol, 38.3% yield over two steps).

[0076] Preparation of ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (7): [ka] To a solution of ethyl 7-amino-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (6) (3.80 g, 11.86 mmol) in ACN (50 mL) was added tert-butyl alcohol (1.84 g, 17.84 mmol) and CuBr (5.30 g, 23.73 mmol), and the mixture was stirred at 70 °C for 2 h. After cooling to room temperature, the mixture was diluted with saturated NH Cl solution (25 mL) and extracted with EA (50 mL × 3). The organic layer was washed with brine (30 mL × 3), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was dissolved in DCM / MTBE (10 mL / 610 ml) and stirred at room temperature for 10 min. The suspension was filtered, and the filtrate was removed. The solid obtained by filtration was dried in vacuo to give the target product as a yellow solid (2.0 g, 5.21 mmol, 43.9%).

[0077] ESI-MS calculated value: 383.02, MS observed value: 386.1 [M+H] + .

[0078] 1 H NMR(400MHz,MeOD)δ8.77(s,1H),7.92(d,J=8.5Hz,1H),4.33(q,J=7.1Hz,2H),4.1 2(m,1H),3.94(s,3H),1.37(t,J=7.1Hz,3H),1.26-1.16(m,2H),1.09-0.99(m,2H).

[0079] Preparation of intermediate compound 10: [ka] Preparation of 2-amino-5-bromobenzulfonamide (9) [ka] To a mixture of 2-aminobenzulfonamide (7) (1 g, 5.81 mmol) in AcOH (20 mL) was added Br (928 mg, 5.81 mmol) at room temperature and stirred for 2 hours at room temperature. The reaction mixture was diluted with water (50 mL). The product was precipitated by the addition of water. The precipitated solid was collected by filtration and washed with water to give the title product as a white solid (910 mg, 3.62 mmol, 62.4%).

[0080] ESI-MS calculated value: 249.94, MS observed value: 251.0 [M+H] + .

[0081] 1 H NMR (400MHz, DMSO-d6) δ7.64-7.61 (m, 1H), 7.41-7.35 (m, 3H), 6.78 (d, J = 8.8Hz, 1H), 6.01 (s, 2H).

[0082] Preparation of 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bensulfonamide (10) [ka] A mixture of 2-amino-5-bromobenzulfonamide (8) (800 mg, 3.18 mmol), Pin2B2 (1.62 g, 6.37 mmol), Pd(dppf)Cl2 (233 mg, 0.32 mmol), potassium acetate (938 mg, 9.56 mmol), and 1,4-dioxane (20 mL) was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 1:1) to give the title product (760 mg, 2.54 mmol, 80.15% yield) as a white oil.

[0083] ESI-MS calculated value: 298.12, MS observed value: 299.0 [M+H] + .

[0084] Preparation of intermediate compound 12: [ka] Preparation of N-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (12) [ka] To a mixture of 4-bromo-N-(2-hydroxyethyl)benzenesulfonamide (11) (1 g, 3.57 mmol) in 1,4-dioxane (10 mL), B2Pin2 (1.2 g, 4.28 mmol), KOAc (1.05 g, 10.71 mmol), and Pd(dppf)Cl2 (259.04 mg, 356.97 mmol) were added at room temperature. The mixture was then heated to 90 °C and stirred for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 20:1) to afford the title product (582 mg, 312.24 mmol, 58.2%) as a brown solid.

[0085] ESI-MS calculated value: 327.20, MS observed value: 327.9 [M+H] + .

[0086] Following the same preparative route as above and using similar starting materials as substitutes, a series of derivatives were obtained.

[0087] Preparation of intermediate compound 14: [ka] Preparation of ethyl 7-(4-amino-3-cyanophenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (13) [ka] A mixture of ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (200 mg, 561.57 μmol), 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (205.62 mg, 842.35 μmol), Pd(dtbpf)Cl (36.26 mg, 56.16 μmol), and KPO (357.6 mg, 1.68 mmol) in 1,4-dioxane (5 mL) and HO (1 mL) was stirred at 90° C. under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with DCM:MeOH=20:1 to give the product as a white solid (130 mg, 561.57 μmol, 54.93%). ESI-MS calculated: 421.14, MS found: 422.0 [M+H] + .

[0088] Preparation of 7-(4-amino-3-cyanophenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (14) [ka] A mixture of ethyl 7-(4-amino-3-cyanophenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (130 mg, 308.47 μmol) and LiOH (29.55 mg, 1.23 μmol) in THF (3 mL) and HO (1 mL) was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (0.1% NH—HO, HO) to give the product as a white solid (22.73 mg, 308.47 μmol, 18.73%).

[0089] ESI-MS calculated value: 393.11, MS observed value: 394.1 [M+H] + .

[0090] A series of derivatives can be obtained by the same preparative route as above, substituting analogous starting materials.

[0091] The pharmaceutically acceptable salts that form part of this invention can be prepared in a manner known in the art by treating a compound of formula I with an appropriate acid or base in an appropriate solvent.

[0092] The present invention is further illustrated by the following examples, which illustrate some of the preferred embodiments of the invention. These examples are provided as representative examples only and should not be construed as limiting the scope of the invention in any way.

[0093] Example 1: Preparation of ethyl 7-(4-amino-3-sulfonylphenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate The synthetic route is as follows: [ka] Specific preparation process: 2-amino-5-(4,4,5,5,6-fluoro-8-methoxy-4-oxo-1,4-dioxabenzofuran-2-yl bensulfonamide (10) (311 mg, 1.04 mmol), ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (7) (200 mg, 0.522 mmol), Pd(dppf)Cl (38 mg, 0.05 mmol), KPO (333 mg, 10.57 mmol). A mixture of 1,4-dioxane / HO (4:1) (10 mL) was stirred at 90 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated aqueous sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA 1:0 to 1:9 gradient) to give a yellow solid (70 mg, 0.15 mmol, 28.23% yield).

[0094] MS calculated: 475.12, MS observed: 476.0 [M+H] + .

[0095] Example 2: 7-(4-amino-3-sulfonylphenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid The synthetic route is as follows: [ka] Specific preparation process: Ethyl 7-(4-amino-3-sulfonylphenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (70 mg, 0.15 mmol) (Example 1) was added to a 2:1 mixture of THF and HO (5 mL), and LiOH (35 mg, 1.47 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and diluted with water (20 mL). The mixture was adjusted to pH 4-5 with citric acid and extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC [water (0.1% FA)] to give the final product (18.96 mg, 0.042 mmol, 28.27%) as a yellow solid.

[0096] MS calculated: 447.09, MS observed: 448.0 [M+H] + .

[0097] 1 H NMR(400MHz,DMSO-d6)δ14.72(s,1H),8.79(s,1H),7.94-7.82(m,1H),7.75(s,1H),7.48-7.32 (m,3H),6.97(d,J=8.5Hz,1H),6.22(s,2H),4.29-4.12(m,1H),3.43(s,3H),1.22-1.08(m,4H).

[0098] Example 3: 1-Cyclopropyl-6-fluoro-7-(3-nitro-4-sulfamoylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1 and 2 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 448.05, MS observed: 448.1 [M+H] + .

[0099] 1 H NMR(400MHz,DMSO-d6)δ14.73(s,1H),8.81(s,1H),8.51(d,J=6.4Hz,1H),8.37(s ,1H),8.22(d,J=11.2Hz,3H),8.01(s,2H),4.08-3.75(m,1H),1.37-1.21(m,4H).

[0100] Example 4: 8-chloro-1-cyclopropyl-6-fluoro-7-(3-nitro-4-sulfamoylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1 and 2 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 482.01, MS observed: 482.1 [M+H] + .

[0101] 1 H NMR(400MHz,DMSO-d6)δ14.11(s,1H),8.93(s,1H),8.27-8.17(m,3H),8.02 (d,J=8.2Hz,3H),4.44-4.34(m,1H),1.24-1.19(m,2H),1.16-1.08(m,2H).

[0102] Example 5: Ethyl 1-cyclopropyl-6-fluoro-7-(4-(N-(2-hydroxyethyl)aminosulfonyl)phenyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate The synthetic route is as follows: [ka] To a mixture of N-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzolsulfonamide (12) (146 mg, 312.24 μmol) in 1,4-dioxane (3 mL) and HO (1 mL), ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (7) (100 mg, 260.28 μmol), KPO (165.74 mg, 780.84 μmol), and Pd(dtbpf)Cl (16.81 mg, 26.03 μmol) were added at room temperature. The mixture was then heated to 90° C. and stirred for 16 hours. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with a gradient of DCM:MeOH 1:0 to 20:1 to give the product as a brown solid (66 mg, 130.81 μmol, 35.18%).

[0103] MS calculated: 504.53, MS observed: 505.1 [M+H] + .

[0104] 1 H NMR(400MHz,DMSO-d6)δ8.58(s,1H),7.96(d,J=8.3Hz,2H),7.86-7.68(m,3H),4.72(t,J=5.6Hz,1H),4.25(q,J=7.1Hz) ,2H),4.05(dt,J=6.4,2.5Hz,1H),3.47-3.23(m,5H),2.88(t,J=6.1Hz,2H),1.29(t,J=7.1Hz,3H),1.36-1.03(m,7H).

[0105] Example 6: 1-Cyclopropyl-6-fluoro-7-(4-(N-(2-hydroxyethyl)aminosulfonyl)phenyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid The synthetic route is as follows: [ka] To a solution of ethyl 1-cyclopropyl-6-fluoro-7-(4-(N-(2-hydroxyethyl)aminosulfonyl)phenyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (66 mg, 130.81 μmol) in THF (3 mL) was added HO (1 mL) and LiOH (12.53 mg, 523.26 μmol). The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the pH was adjusted to neutral. After dilution with DCM (10 mL), the reaction solution was washed with water (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product as a white solid (22 mg, 46.17 μmol, 35.30%).

[0106] MS calculated: 476.11, MS observed: 477.2 [M+H] + .

[0107] 1 H NMR(400MHz,DMSO-d6)δ14.61(s,1H),8.82(s,1H),7.98(dd,J=8.7,4.7Hz,3H),7.77(dd,J=13.3,6.9Hz,3 H),4.72(t,J=5.2Hz,1H),4.28-4.17(m,1H),3.44-3.36(m,5H),2.88(q,J=6.0Hz,2H),1.23-1.12(m,4H).

[0108] Example 7: 7-(4-(N-(2-chloroethyl)aminosulfonyl)phenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [ka] To a solution of 1-cyclopropyl-6-fluoro-7-(4-(N-(2-hydroxyethyl)aminosulfonyl)phenyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 6) (22 mg, 130.81 μmol) in THF (3 mL) was added HO (1 mL) and SOCl (5 mL) at room temperature. After completion of the reaction was confirmed by MS, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (0.1% FA, HO) to give the product as a white solid (13.70 mg, 36.37 μmol, 78.77%).

[0109] MS calculated: 494.07, MS observed: 495.1 [M+H] + .

[0110] 1 H NMR(400MHz,DMSO-d6)δ14.63(s,1H),8.82(s,1H),8.16(d,J=10.6Hz,1H),7.98(d,J=11.1Hz,3H),7.80(d,J =7.9Hz,2H),4.21(q,J=5.8Hz,1H),3.61(t,J=6.1Hz,2H),3.39(s,3H),3.21-3.17(m,2H),1.20-1.13(m,4H).

[0111] Example 8: 7-(3-cyano-4-(2,2,2-trifluoroacetamido)phenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [ka] To 7-(4-amino-3-cyanophenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (14) (35 mg, 88.97 μmol) in DCM (3 mL) was added 2,2,2-trifluoroacetic anhydride (28.03 mg, 133.46 μmol) and triethanolamine (13.51 mg, 133.46 μmol) at room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (0.1% FA, HO) to give the product as a white solid (17.35 mg, 88.97 μmol, 39.85%).

[0112] MS calculated: 489.09, MS observed: 489.8 [M+H] + .

[0113] 1 H NMR(400MHz,DMSO-d6)δ14.60(s,1H),11.94(s,1H),8.82(s,1H),8.21(s,1H),8.06-7 .91(m,2H),7.81(d,J=8.4Hz,1H),4.33-4.10(m,1H),3.43(s,3H),1.27-1.09(m,4H).

[0114] Example 9: 7-(3-cyano-4-(N-(tetrahydro-2H-pyran-4-yl)sulfamoyl)phenyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 511.12, MS observed: 512.3 [M+H] + .

[0115] 1H NMR(400MHz,DMSO-d6)δ14.72(s,1H),8.81(s,2H),8.57-8.36(m,3H),8.31-8.14(m,3H), 4.01-3.69(m,3H),3.49-3.40(m,2H),2.67(s,1H),1.74-1.44(m,4H),1.38-1.17(m,4H).

[0116] Example 10: 7-(3-cyano-4-(N-cyclohexylaminosulfonyl)phenyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 539.15, MS observed: 540.3 [M+H] + .

[0117] 1 H NMR(400MHz,DMSO-d6)δ14.85(s,1H),8.71(s,1H),8.12-7.85(m,4H),7.71(dt,J=7.4,1.7 Hz, 1H), 7.26 (d, J=12.1Hz, 1H), 4.13-3.80 (m, 4H), 3.36-3.15 (m, 1H), 1.75-0.88 (m, 14H).

[0118] Example 11: 7-(4-amino-3-sulfonylphenyl)-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 462.06, MS observed: 463.0 [M+H] + .

[0119] 1 H NMR(400MHz,MeOD)δ8.99(s,1H),8.42(d,J=8.5Hz,1H),7.68(s,1H),7.25(d,J=8.7Hz,1H),6.93(d,J=8.2Hz,1H),3.90- 3.77(m,1H),1.21-1.08(m,4H).

[0120] Example 12: 7-(3,5-dimethyl-4-(piperidin-1-ylsulfonyl)phenyl)-1-ethyl-6-nitro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 514.15, MS observed: 515.2 [M+H] + .

[0121] 1 H NMR(400MHz,DMSO-d6)δ14.03(s,1H),9.34(s,1H),9.26(s,1H),7.56(s,2H),4.6 7(q,J=7.0Hz,2H),3.14(s,4H),2.66(s,6H),1.54(s,6H),1.45(t,J=7.1Hz,3H).

[0122] Example 13: 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-4-oxo-7-(4-pyrrolidin-1-ylsulfonyl)phenyl)-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 578.06, MS observed: 579.0 [M+H] + .

[0123] 1 H NMR(400MHz,MeOD)δ8.63(s,1H),8.25(d,J=9.0Hz,1H),7.98-7.93(m,2H), 7.60-7.56(m,2H),7.56-7.52(m,1H),3.29-3.26(m,4H),1.79-1.73(m,4H).

[0124] Example 14: 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-4-oxo-7-(4-(pyrrolidin-1-ylsulfonyl)phenyl)-1,4-dihydroquinoline-3-carboxamide By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 577.08, MS observed: 578.0 [M+H] + .

[0125] 1 H NMR(400MHz,DMSO-d6)δ11.03-9.91(m,2H),8.56-8.33(m,1H),8.00-7.86(m,3H),7.77- 7.67(m,1H),7.65-7.42(m,2H),6.42-6.20(m,2H),3.21-3.15(m,4H),1.69-1.62(m,4H).

[0126] Example 15: 7-(4-(N-(2-chloroethyl)sulfamoyl)phenyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 464.06, MS observed: 465.2 [M+H] +.

[0127] 1 H NMR(400MHz,DMSO-d6)δ14.76(s,1H),8.81(s,1H),8.44(d,J=6.4Hz,1H),8.18(dd,J=8.0,5.1Hz,2H),7.99(q,J=8.5Hz,4H),4.03 -3.93(m,1H),3.63(t,J=6.1Hz,2H),3.17(q,J=6.0Hz,2H),1.39-1.28(m,2H),1.29-1.21(m,2H).

[0128] Example 16: 1-Cyclopropyl-6-fluoro-7-(4-(N-(2-hydroxyethyl)aminosulfonyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 446.09, MS observed: 447.2 [M+H] + .

[0129] 1 H NMR(400MHz,DMSO)δ14.78(s,1H),8.80(s,1H),8.44(d,J=6.4Hz,1H),8.18(dd,J=10.3,2.0Hz,1H),8.04-7.91(m,4H), 7.80(t,J=5.9Hz,1H),4.73(s,1H),4.05-3.84(m,1H),3.43(t,J=6.3Hz,2H),2.87(q,J=6.2Hz,2H),1.38-1.21(m,4H).

[0130] Example 17: 6-Fluoro-1-(4-fluorophenyl)-7-(4-(N-heptylsulfamoyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 554.17, MS observed: 555.2 [M+H] + .

[0131] Example 18: 1-Cyclopropyl-6-fluoro-7-(4-(N-(2-hydroxyethyl)aminosulfonyl)phenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 447.09, MS observed: 448.2 [M+H] + .

[0132] 1 H NMR(400MHz,DMSO-d6)δ14.78(s,1H),8.80(s,1H),7.93-7.47(m,6H),4.73(s,1H), 4.05-3.84(m,1H),3.43(t,J=6.3Hz,2H),2.87(q,J=6.2Hz,2H),1.34-1.20(m,4H).

[0133] Example 19: 1-Cyclopropyl-6-fluoro-4-oxo-7-(6-(propylsulfonamido)pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 445.11, MS observed: 446.3 [M+H] + .

[0134] 1 H NMR(400MHz,DMSO-d6)δ15.08-14.64(m,1H),11.92-10.78(m,1H),8.78(s,1H),8.58(t, J=6.2Hz,1H),8.41(t,J=6.3Hz,1H),8.21(s,1H),8.18-8.10(m,1H),8.09-8.02(m,1H), 7.07(d,J=8.8Hz,1H),3.95(ddd,J=11.3,7.2,3.8Hz,1H),3.43(dd,J=13.2,4.9Hz,2H), 1.81-1.68(m,2H),1.34(dd,J=7.4,5.2Hz,2H),1.25-1.23(m,2H),0.99(t,J=7.4Hz,3H).

[0135] Example 20: 8-chloro-1-cyclopropyl-6-fluoro-4-oxo-7-(6-(N-pentylaminosulfonyl)pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 507.10, MS observed: 507.9 [M+H] + .

[0136] 1 H NMR(400MHz,DMSO-d6)δ14.19(s,1H),8.94(s,1H),8.87(s,1H),8.27(dd,J=8.0,1.8Hz,1H),8.22(d,J=8.6Hz,1H) ,8.15(d,J=8.1Hz,1H),8.00(t,J=5.8Hz,1H),4.42-4.38(m,1H),2.97(dd,J=13.1,6.7Hz,2H),1.62-0.79(m,13H).

[0137] Example 21: 1-Cyclopropyl-6-fluoro-4-oxo-7-(6-(N-(2,2,2-trichloroacetyl)sulfamoyl)pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 546.96, MS observed: 549.8 [M+H] + .

[0138] 1 H NMR(400MHz,DMSO-d6)δ8.95(s,1H),8.81(s,1H),8.51(d,J=6.4Hz,1H),8.34(d,J=8.3Hz,1H),8.2 1(d,J=10.2Hz,1H),8.08(d,J=8.2Hz,1H),4.03-3.92(m,1H),1.39-1.33(m,2H),1.27-1.19(m,2H).

[0139] Example 22: 1-Cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-(4-(N-pentylaminosulfonyl)phenyl)-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 502.16, MS observed: 503.3 [M+H] + .

[0140] 1H NMR(400MHz,DMSO-d6)δ14.64(s,1H),8.82(s,1H),7.97(d,J=8.4Hz,3H),7.79(d,J=7.9Hz,2H) ,7.74(t,J=5.8Hz,1H),4.26-4.15(m,1H),3.38(s,3H),2.85-2.78(m,2H),1.63-0.76(m,13H).

[0141] Example 23: Ethyl 1-ethyl-7-(4-(N-heptylsulfamoyl)-3,5-dimethylphenyl)-6-nitro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 572.23, MS observed: 573.2 [M+H] + .

[0142] 1 H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.98(s,1H),7.69(t,J=5.7Hz,1H),7.47(s,2H),4.52(q,J=7.0Hz,2H),4.28(q,J=7.1Hz,2H) ,2.84(dd,J=12.9,6.6Hz,2H),2.66(s,6H),1.40(t,J=7.1Hz,3H),1.31(t,J=7.1Hz,5H),1.24-1.14(m,8H),0.81(t,J=7.0Hz,3H).

[0143] Example 24: 6-Fluoro-1-(5-fluoropyridin-2-yl)-7-(4-(N-heptylsulfamoyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 555.16, MS observed: 556.2 [M+H] + .

[0144] 1 H NMR(400MHz,DMSO-d6)δ14.52(s,1H),9.01(s,1H),8.74(d,J=2.8Hz,1H),8.26(d,J=10.2 Hz,1H),8.16(td,J=8.4,2.7Hz,1H),8.05(dd,J=8.8,3.9Hz,1H),7.88(d,J=8.3Hz,2H),7 .75(d,J=7.8Hz,2H),7.69(t,J=5.8Hz,1H),7.56(d,J=6.2Hz,1H),2.76(dd,J=13.0,6.6H z,2H),1.35(dd,J=13.0,6.1Hz,2H),1.21(dd,J=16.9,9.4Hz,8H),0.81(t,J=6.9Hz,3H).

[0145] Example 25: 6-Fluoro-1-(2-fluoroethyl)-7-(4-(N-heptylsulfamoyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 506.17, MS observed: 507.2 [M+H] + .

[0146] 1 H NMR(400MHz,DMSO-d6)δ14.81(s,1H),9.03(s,1H),8.25(s,1H),8.19(d,J=10.2Hz,1H),7.95(s,4H),7.73(t,J=5.6Hz,1H),5.05( d,J=26.9Hz,2H),4.93(s,1H),4.81(s,1H),2.79(q,J=6.6Hz,2H),1.39(q,J=6.4Hz,2H),1.28-1.14(m,8H),0.83(t,J=6.9Hz,3H).

[0147] Example 26: 1-Cyclopropyl-7-(4-(N-heptylsulfamoyl)phenyl)-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 527.17, MS observed: 528.2 [M+H] + .

[0148] 1 H NMR(400MHz,DMSO-d6)δ14.30(s,1H),8.92(s,1H),8.86(s,1H),8.32(s,1H),7.93(d,J=8.4Hz,2H),7.79-7.69(m,3H),3.9 2(s,1H),2.81(dd,J=13.0,6.8Hz,2H),1.38(d,J=6.8Hz,2H),1.33-1.28(m,2H),1.26-1.19(m,10H),0.84(t,J=6.9Hz,3H).

[0149] Example 27: 7-(4-(N-(6-aminohexyl)sulfamoyl)-3,5-dimethylphenyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 529.20, MS observed: 530.3 [M+H] + .

[0150] 1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.38(d,J=26.7Hz,3H),8.11(s,1H),7.56(s, 3H), 4.05-3.85(m, 1H), 2.82(s, 2H), 2.70(s, 8H), 1.48-1.30(m, 6H), 1.21(s, 6H).

[0151] Example 28: Ethyl 7-(4-(N-(6-aminohexyl)sulfamoyl)-3,5-dimethylphenyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 557.24, MS observed: 558.7 [M+H] + .

[0152] 1 H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.18(d,J=6.4Hz,1H),7.99(d,J=10.6Hz,1H) ,7.64(dd,J=13.3,7.4Hz,3H),7.54(s,2H),4.24(q,J=7.1Hz,2H),3.81-3.74(m,1H ),2.82(dd,J=13.0,6.6Hz,2H),2.77-2.72(m,2H),2.70(s,6H),1.47(dd,J=14.2, 7.6Hz, 2H), 1.40 (dd, J=13.6, 6.6Hz, 2H), 1.32-1.21 (m, 9H), 1.14 (t, J=7.7Hz, 2H).

[0153] Example 29: 1-Cyclopropyl-6-fluoro-7-(4-(N-(6-hydroxyhexyl)sulfamoyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 502.16, MS observed: 503.3 [M+H] + .

[0154] 1 H NMR(400MHz,DMSO-d6)δ14.75(s,1H),8.80(s,1H),8.43(d,J=6.1Hz,1H),8.18(d,J=10.2Hz,1H),8.03-7.91 (m,4H),7.74(t,J=5.6Hz,1H),4.30(s,1H),3.97(s,1H),3.34(s,2H),2.91-2.70(m,2H),1.43-1.18(m,12H).

[0155] Example 30: 1-Cyclopropyl-6-fluoro-7-(4(N(5(methylthio)pentyl)sulfamoyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 518.13, MS observed: 519.3 [M+H] + .

[0156] 1 H NMR(400MHz,DMSO-d6)δ14.78(s,1H),8.81(s,1H),8.44(d,J=6.4Hz,1H),8.19(d,J=10.3Hz,1H),8.00-7.94(m,4H),7 .76(t,J=5.8Hz,1H),4.00-3.94(m,1H),2.82(d,J=6.4Hz,2H),2.40(t,J=7.2Hz,2H),2.00(s,3H),1.65-1.09(m,10H).

[0157] Example 31: 1-Cyclopropyl-6-fluoro-7-(5-(N-heptylsulfamoyl)pyridin-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1 and 2 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 501.17, MS observed: 502.2 [M+H] + .

[0158] 1 H NMR(400MHz,DMSO-d6)δ14.71(s,1H),9.15(d,J=2.0Hz,1H),8.86(d,J=6.4Hz,1H),8.82(s,1H),8.39(dd,J=8.0Hz,2.0Hz,1H),8.22(d,J=10.8Hz,2 H),7.97(t,J=5.6Hz,1H),4.02-3.90(m,1H),2.87(q,J=6.8Hz,2H),1.43- 1.37(m,2H),1.35-1.29(m,2H),1.26-1.17(m,10H),0.82(t,J=7.2Hz,3H).

[0159] Example 32: 7-(3-carbamoyl-4-(N-heptylsulfamoyl)phenyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 543.18, MS observed: 544.2 [M+H] + .

[0160] 1H NMR(400MHz,DMSO)δ14.75(s,1H),8.81(s,1H),8.48(s,1H),8.34(s,1H),8.20(d,J=10.5Hz,1H),8.07-8.00(m,2H),7.93(d,J=12.1Hz,2H),6.9 7(t,J=6.0Hz,1H),4.00-3.94(m,1H),2.89(q,J=6.5Hz,2H),1.43-1.38( m,2H),1.34(d,J=5.7Hz,2H),1.25-1.15(m,10H),0.81(t,J=6.8Hz,3H).

[0161] Example 33: 7-(3-amino-4-(N-heptylsulfonyl)phenyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 515.19, MS observed: 516.3 [M+H] + .

[0162] 1 H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.34(d,J=5.6Hz,1H),8.14(d,J=10.4Hz,1H),7.66(d,J=8.0Hz,2H),7.18(s,1H),6.94(d,J =8.0Hz,1H),6.17(s,2H),4.00-3.90(m,1H),2.78(t,J=6.8Hz,2H),1.43-1.30(m,4H),1.27-1.13(m,10H),0.81(t,J=6.8Hz,3H).

[0163] Example 34: 8-chloro-1-cyclopropyl-6-fluoro-4-oxo-7-(6-(N-(4,4,4-trifluorobutyl)sulfamoyl)pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 547.06, MS observed: 548.0 [M+H] + .

[0164] 1 H NMR(400MHz,DMSO-d6)δ14.15(s,1H),8.93(s,1H),8.88(d,J=2.0Hz,1H),8.29(dd,J=8.1,2.1Hz,1H),8.22(d,J=8.6Hz,1H),8.19- 8.13(m,2H),4.45-4.36(m,1H),3.12(t,J=6.7Hz,2H),2.32-2.22(m,2H),1.67-1.59(m,2H),1.24-1.19(m,2H),1.18-1.12(m,2H).

[0165] Example 35: 1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-nitro-4-(2,2,2-trifluoroacetamido)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid By referring to the preparation processes of Examples 1-8 and using similar starting materials as substitutes, the target compounds having the following structures were obtained. [ka] MS calculated: 509.08, MS observed: 509.8 [M+H] + .

[0166] 1 H NMR(400MHz,DMSO-d6)δ14.61(s,1H),11.91(s,1H),8.82(s,1H),8.26(s,1H),7.99( d,J=9.1Hz,2H),7.86(d,J=8.3Hz,1H),4.27-4.14(m,1H),3.46(s,3H),1.17(s,4H).

[0167] Following a similar process, the present invention also synthesized a series of compounds having the following structures:

[0168] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] In vitro antibacterial activity assay The method used to demonstrate the activity of the compounds in this example is to record the minimum inhibitory concentration (MIC) of the compounds against bacteria. The specific experimental method is as follows: 1. Bacterial fluid cultured from a single colony was collected and diluted 1:1000 into autoclaved CAMHB broth and mixed well.

[0169] 2. The prepared drug solution was filtered through a sterile 0.22 μm syringe filter and placed into a sterile EP tube for later use.

[0170] 3. Take a 96-well plate and add 20 μL of drug solution (400 μg / mL) to each well of the first column of the 96-well plate. Then add 180 μL of diluted bacterial solution and mix well (perform 3 replicate columns for each drug).

[0171] The same process was carried out for the hydrochloride salt drug.

[0172] 4. 100 μL of diluted bacterial solution was added to each well of the remaining 11 columns of the 96-well plate. The same drug was used as above.

[0173] 5. Serial dilution: 100 μL of liquid was taken from column 1 and transferred to column 2, mixed well, then 100 μL of liquid was taken from column 2 and transferred to column 3, mixed well, and so on, until serial dilution was achieved up to the last column (column 12). After mixing column 12 well, the 100 μL of liquid was discarded. The drug concentration in each well was decreased stepwise by 2-fold (the concentration in the first well was 40 μg / mL).

[0174] 6. Blank CAMHB broth without added bacterial solution was added to three blank wells in a 96-well plate as a negative control.

[0175] 7. The diluted bacterial solution was added to three blank wells in a 96-well plate as a positive control.

[0176] 8. Incubated at 37°C for 16 hours.

[0177] 9. Reading the results: The minimum inhibitory concentration is the lowest drug concentration at which no bacterial growth is visible to the naked eye and no turbidity is observed.

[0178] Specific antibacterial results are shown in Tables 1, 2, and 3.

[0179] [Table 2]

[0180] [Table 3]

[0181] [Table 4] Additionally, as further described herein, the methods and antimicrobial compounds disclosed herein can be used to inhibit the growth of multiple types of bacteria, including, but not limited to, in some instances, Gram-positive bacteria such as Staphylococcus aureus and Enterococcus faecalis, and Gram-negative bacteria such as Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and combinations thereof.

[0182] The antibacterial compounds and methods disclosed herein may have a variety of advantageous properties and uses. For example, in some embodiments, the antibacterial compounds disclosed herein have excellent activity against Gram-positive bacteria. In some embodiments, the antibacterial compounds disclosed herein have inhibitory activity against both Gram-positive and Gram-negative bacteria. In some embodiments, the antibacterial compounds disclosed herein have anti-cancer activity and antibacterial activity. In some embodiments, the antibacterial compounds disclosed herein are not susceptible to drug resistance.

[0183] Testing bacterial resistance to compounds This example provides a bacterial resistance test to compounds, and the specific experimental method is as follows:

[0184] 1. Drug Preparation: Using a methicillin-resistant Staphylococcus aureus (MRSA) strain with an MIC of 0.5 μg / mL as an example, six gradient concentrations of tylosin were prepared sequentially: 20 μg / mL, 10 μg / mL, 8 μg / mL, 4 μg / mL, 2 μg / mL, and 1 μg / mL. Of the six final concentrations of drug diluted into the wells, some were higher than the original MIC of the bacteria, and some were lower than the original MIC of the bacteria.

[0185] 2. Preparation of bacterial solution: 10 mL of culture medium was taken using a pipette and added to a sterile plate, and then 100 μL of the above-mentioned subcultured bacterial solution was added and mixed well for later use.

[0186] 3. The diluted bacterial solution was pipetted into a 96-well plate, with 180 μL per well, three wells per group, for a total of six groups. 20 μL of drug solution was added to each well (note: the pipette tip must be replaced each time a drug is added), resulting in final drug concentrations of 2 μg / mL, 1 μg / mL, 0.8 μg / mL, 0.4 μg / mL, 0.2 μg / mL, and 0.1 μg / mL, respectively. Wells containing 200 μL of diluted bacterial solution served as positive controls, and wells containing 200 μL of culture medium served as negative controls. The 96-well plate was secured around the perimeter with medical tape, placed in a shaker, and incubated at 37°C for 24 hours. The well with the lowest drug concentration with no bacterial growth was designated the MIC well for the induced strain.

[0187] 4. Each time the MIC of the induced strain changed, 50 μL of the bacterial solution in the well was taken and added to 5 mL of culture medium, and then tylosin was added to reach the final drug concentration of the MIC. The strain was then subcultured and stored in 50% sterilized glycerol as needed. Furthermore, depending on the change in the MIC of the induced strain, the drug concentration of the six groups was increased appropriately until the MIC reached 128 μg / mL. The bacterial solution in the well was then taken and the above steps (2) and (3) were repeated for the next induction.

[0188] In this experiment, a drug resistance test was conducted on Example 34, and the positive control was selected from commercially available drugs ciprofloxacin (CIP) and vancomycin (VAN). The test subject was Staphylococcus aureus (S. aureus). The specific results are shown in Figure 1.

[0189] As shown in the figure, for Staphylococcus aureus ATCC 43300, Example 34 had a superior initial MIC to the marketed drugs ciprofloxacin and vancomycin. Subsequent incubations revealed rapid bacterial resistance to ciprofloxacin. Over the course of a 21-day experiment, the MIC for ciprofloxacin reached 128 μg / mL, the MIC for vancomycin reached 4 μg / mL, and the MIC for Example 34 was found to be only 2 μg / mL at the end of the experiment.

[0190] In vitro anticancer activity test The anti-cancer activity of the compounds was tested using an in vitro cancer cell test. The specific test method is as follows. 1. Cell recovery and culture method: The cryovial was first removed from the liquid nitrogen container and immersed directly in 37°C warm water, with occasional shaking to thaw as quickly as possible. The cryovial was then transferred to a clean bench and the lid was opened. The cell suspension was transferred to a centrifuge tube using a rubber-tipped dropper, and 10 times more culture medium was added. The mixture was mixed well and centrifuged at 50 g for 5 minutes. The supernatant was then discarded, and complete culture medium containing 10% fetal bovine serum was added to resuspend the cells. The cells were counted, the cell density was adjusted, and the cells were seeded into culture bottles. The culture bottle was placed in a cell culture incubator at 5% CO2 and 37°C. The complete culture medium was replaced once the next day, and the culture was continued.

[0191] 2. Cell Passage Method: Adherent cells in the logarithmic growth phase were placed on a clean bench, the original culture medium was discarded, and the cells were washed three times with 1x PBS. An appropriate amount of 0.25% trypsin digestion solution was added to moisten the cells, and then the trypsin solution was aspirated. The cells were placed in a cell culture incubator at 5% CO2 and 37°C for the appropriate time for digestion, and observed under a microscope. When 90% of the cells had become rounded, they were immediately transferred to a clean bench and complete culture medium was added to terminate the digestion. The cells were then detached to single cells by pipetting up and down using a rubber-tipped syringe. The cells were counted and the cell density was adjusted. The cells were seeded into appropriate culture bottles or dishes, sufficient complete culture medium was added, and the cells were placed in a cell culture incubator at 5% CO2 and 37°C for static culture.

[0192] For logarithmic growth phase suspension cells, the original culture medium was directly centrifuged at 50 g for 5 minutes, the supernatant was discarded, and the cells were washed once with PBS and centrifuged. After discarding the supernatant, complete culture medium was added and the cells were dispersed using a rubber tip dropper. The cells were counted and the cell density was adjusted. The cells were seeded into appropriate culture bottles or dishes, sufficient complete culture medium was added, and the cells were cultured in a cell culture incubator at 5% CO2 and 37°C.

[0193] 3. Cell proliferation assay: Cells in good logarithmic growth phase were harvested and seeded in appropriate amounts into 96-well plates according to the cell passage method. Each well contained 180 μL of complete medium. After cell proliferation recovered and the cell count reached 5,000 ± 500 cells per well, drugs were added for treatment.

[0194] After drug treatment during the experimental period, MTT solution at a final concentration of 0.5 mg / mL was added to each well and placed in a cell culture incubator at 5% CO2 and 37°C to allow the MTT to fully react with the cells. After 4 hours, the solution in the 96-well plate was discarded, 100 μL of DMSO was added, and the plate was shaken to dissolve the formazan precipitated at the bottom. The absorbance value of the sample was detected at a wavelength of 570 nm using a microplate reader. Cell viability was calculated as follows: Survival rate = Sample group A ÷ Control group A × 100% 4. Cell imaging: Cells in good logarithmic growth phase were harvested and seeded in appropriate amounts into a 96-well plate according to the cell passage method. Each well contained 180 μL of complete medium. After cell growth recovered and the cell count in each well reached 5,000 ± 500 cells, drugs were added for treatment.

[0195] After drug treatment during the experimental period, the cells were photographed under a biological microscope.

[0196] Hela cells are artificial cultured cells with unlimited proliferation capacity. They have existed for 68 years since their creation until 2019. In the medical field, Hela cells are widely used in tumor research, biological experiments, and cell culture, and have become a very important tool in medical research.

[0197] Table 4 lists some compounds that have inhibitory effects on both bacteria and cancer cells. In the table, the inhibitory effect on cancer cells indicates the average growth inhibition rate (%) of cancer cells at a dose of 40 μM.

[0198] [Table 5] Furthermore, the inhibitory effects of related molecules on other different types of cancer cells were also tested, and all of them showed strong activity. The cells also include human Burkitt's lymphoma cells Raji, human acute T-lymphoblastic leukemia cells Jurkat, human acute myeloid leukemia cells MOLM-13, human acute monocytic leukemia cells THP-1, human non-small cell lung carcinoma cells A549, human gastric carcinoma cells MGC-803, human renal carcinoma cells OS-RC-2, human colon carcinoma cells HCT 116, human pancreatic carcinoma cells PNAC-1, human liver carcinoma cells HepG2, human liver carcinoma cells BLE-7402, human malignant melanoma cells A375, human epidermoid carcinoma cells A431, human prostate carcinoma cells PC-3, human bladder transitional cell carcinoma T24, human ovarian adenocarcinoma cells SK-OV-3, human glioma cells SNB-19, human breast carcinoma cells MCF-7, human osteosarcoma cells U2-OS, human breast carcinoma cells MFM223, and human ductal carcinoma cells T-47D. 50 is the concentration showing 50% inhibition. The lower the concentration showing 50% inhibition, the more sensitive the inhibitor. In this experiment, an in vitro antitumor cell test was performed on Example 34, and the positive control was the commercially available drug sunitinib.

[0199] Table 5 shows the IC of Example 34, Example 135, sunitinib, ciprofloxacin, Reference Compound 1 and Reference Compound 2 against different cancer cell lines. 50 The assay results are shown.

[0200] The present invention provides phenylquinolone compounds that have antibacterial activity and also exhibit excellent anticancer activity. In this specification, reference compound 1 disclosed in Chinese Patent Application Publication No. 103764631A and reference compound 2 disclosed in Chinese Patent Application Publication No. 109422726A of Otsuka Pharmaceutical Co., Ltd. are used as references.

[0201] [ka]

[0202] [Table 6] Testing antibacterial and drug resistance effects in animal models Testing Procedure: Kunming mice (20±2 g) were anesthetized with chloral hydrate, shaved, and then injected with 50 μL of 4 × 10 7 CFU / mL of methicillin-resistant Staphylococcus aureus was subcutaneously injected. One day later, 100 μL of Example 34 at 0.02 mg / kg, 2 mg / kg, and 200 mg / kg was subcutaneously injected, respectively, and 100 μL of saline was injected in the control group. The drugs were administered for four consecutive days, and on the fifth day, the mice were euthanized and the abscess area was measured.

[0203] Test Results: Mice in the control group showed extensive necrosis of skin tissue (Figure 2). Compared with the control group, 0.02 mg / kg and 2 mg / kg of Example 29 reduced the necrotic area by 78.09% and 81.21%, respectively (Figure 2). When administered at a high concentration of 200 mg / kg, certain bleeding symptoms appeared on the body surface at the subcutaneous injection site.

[0204] When the concentrations of Example 34 were 4 μg / mL and 400 μg / mL (equivalent to 0.02 mg / kg, 200 mg / kg), Example 29 showed good antibacterial effects.

[0205] Testing an animal model of systemic bloodstream infection Testing Procedure: (1) Specific pathogen-free mice were divided into six groups of five mice each: blank group, model group, low-dose treatment group (0.25 mg / kg), medium-dose treatment group (1 mg / kg), high-dose treatment group (4 mg / kg), and positive drug group (ciprofloxacin hydrochloride, administered orally at 4 mg / kg by gavage).

[0206] (2) Use sterile phosphate-buffered saline (PBS) to prepare 1 x 10 cells for later use. 7A bacterial suspension of Staphylococcus aureus ATCC43300 CFU / mL was prepared. The drug dose required for each group of mice was calculated, and the solution of Example 34 and the vehicle for oral gavage (400 μL or 200 μL of Tween® 80 was mixed with Example 34, and the mixture was ground in an agate mortar until transparent, followed by the addition of 0.5% sodium carboxymethylcellulose solution to achieve the required concentration and volume of the test drug) were prepared for later use.

[0207] (3) Except for the blank group, 100 μL of the bacterial suspension prepared in step 2 was injected into the tail vein of each mouse.

[0208] (4) Two hours after the challenge, the drug prepared in step 2 was administered by oral gavage to each group, 3 times a day at 8-hour intervals, 200 μL each time. The drug solvent was administered by oral gavage to the mice in the model and blank groups.

[0209] (5) Eight hours after the last administration, the mice were euthanized by cervical dislocation, disinfected with 75% alcohol, and then autopsied under aseptic conditions. The kidneys and livers were collected, observed, photographed, and their weights were recorded.

[0210] (6) The kidneys and livers were placed in a sterile glass grinder, and a volume of sterile PBS equivalent to 10 times the weight of the organs was added. The pulverized solution was removed, serially diluted 10-fold, and plated onto TSA solid culture medium. After incubation at 37°C for 16 hours, the colonies were counted. The number of colonies in the organs was calculated to evaluate the therapeutic effect.

[0211] Test Results: (1) Analysis of changes in the weight of related organs After dissection of the mice, it was found that the liver and kidney weights of the mice in each experimental group had no significant changes compared with the negative control group (Figure 3).

[0212] (2) Number of colonies in organs The analysis showed that Example 34 of the present invention exhibited highly significant antibacterial effects in the liver and kidney compared with the positive drug ciprofloxacin. At 1 mg / kg, there was a statistically significant difference between the drug and the control group. At 4 mg / kg, the drug of the present invention showed a significant difference and demonstrated good antibacterial effects, while the effects of the negative control and positive control ciprofloxacin were not clear (Figure 4).

Claims

1. A phenylquinolone compound represented by formula (I) 【Chemistry 1】 [In the formula, A １ is a nitrogen atom N or CR ａ where R ａ is a hydrogen atom, a halogen atom, C1-C3 alkyl, C1-C2 alkoxy, amino, nitro, or R １ and R ａ are joined to form a 6-membered heterocycle which is unsubstituted or optionally substituted with short chain alkyl; R ４ -A ２ - is A ２ If there is no ４ - and R １ is a hydrogen atom, cyano, C1-C2 short chain alkyl substituted with 0 or 2 halogen atom(s), C3-C6 cycloalkyl substituted with 0 or 1 halogen atom, phenyl substituted with 1 or 2 halogen atom(s), or 2-pyridinyl substituted with 1 to 3 substituent(s) selected from halogen or amino; or R １ and R ａ are joined to form a 6-membered heterocycle which is unsubstituted or optionally substituted with short chain alkyl; R ２ is hydroxy, C1-C2 alkoxy, or —NR ｂ R ｃ where R ｂ , R ｃ are each independently selected from a hydrogen atom, a C1-C2 alkyl, or a hydroxy, and are not both hydroxy; R ３ is halogen, nitro or C1-C2 alkoxy, R ４ is selected from substituted aryl, the substitutions being mono- to tetra-substituted, including one or more combinations of ortho, meta, and para substitutions, and the substituents are halogen, nitro-NO ２ , cyano-CN, hydroxylaminyl-NH—OH, C1-C3 alkoxy substituted with 0-3 halogen atom(s), C1-C9 alkyl substituted with 0-3 halogen atom(s), sulfinyl-SO—R ｄ , aminylsulfinyl-SO-NR ｅ R ｅ ', sulfonyl-SO ２ -R ｆ , aminylsulfonyl-SO ２ -NR ｇ R ｇ ', methyliminosulfinyl-S(=O)(=NR ｈ ) CH ３ , sulfenyl-S-R ｉ , aminyl-NR ｊ R ｊ ', carbamoyl-CO-NR ｋ R ｋ ', hydrazinyl-NH-NR ｌ R ｌ ', diazenyl-N=NR ｍ R ｍ ', wherein at least one substituent is selected from sulfinyl-SO-R ｄ , aminylsulfinyl-SO-NR ｅ R ｅ ', sulfonyl-SO ２ -R ｆ , aminylsulfonyl-SO ２ -NR ｇ R ｇ ', methyliminosulfinyl-S(=O)(=NR ｈ ) CH ３ , aminyl-NR ｊ R ｊ ', hydrazinyl-NH-NR ｌ R ｌ ', diazenyl-N=NR ｍ R ｍ ' is selected from Here, R ｄ is C1-C9 straight or branched alkyl, C3-C6 cycloalkyl, haloC1-C9 alkyl, C1-C9 alkyl substituted with hydroxy, C1-C9 alkyl substituted with amino, -SR ｄ C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, morpholine, piperazine, piperidine, OR ｄ ', and R ｄ ', R ｄ " are each independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, or a haloC1-C9 alkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; R ｅ , R ｅ ' are each independently a hydrogen atom, a C1-C9 straight or branched chain alkyl, a C3-C6 cycloalkyl, a halo C1-C9 alkyl, a C1-C9 alkyl substituted with hydroxy, a C1-C9 alkyl substituted with amino, -SR ｅ is selected from C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, C1-C5 acyl (H or C1-C4 alkyl)-C(=O)-, haloC2-C5 acyl, or C2-C5 alkoxycarbonyl substituted with R ｅ '' is a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, or a haloC1-C9 alkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; R ｆ is C1-C9 straight or branched alkyl, C3-C6 cycloalkyl, haloC1-C9 alkyl, C1-C9 alkyl substituted with hydroxy, C1-C9 alkyl substituted with amino, -SR ｆ C1-C9 alkyl substituted with ''; morpholine, piperazine, piperidine, OR ｆ ', and R ｆ ', R ｆ " are each independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, or a haloC1-C9 alkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; R ｇ , R ｇ ' are each independently a hydrogen atom, a C1-C25 straight or branched chain alkyl containing 0 to 10 unsaturated bonds, a C3-C6 cycloalkyl, a haloC1-C9 alkyl, a C1-C9 alkyl substituted with hydroxy, a C1-C9 alkyl substituted with amino, -SR ｇ is selected from C1-C9 alkyl, C2-C25 alkenyl, C2-C9 alkynyl, C1-C5 acyl (H or C1-C4 alkyl)-C(=O)-, haloC2-C5 acyl, or C2-C5 alkoxycarbonyl substituted with R ｇ '' is a hydrogen atom, a C1-C9 straight or branched alkyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit, or -NR ｇ R ｇ 'teeth, 【Chemistry 2】 and R ｈ is selected from a hydrogen atom, a C1-C9 straight or branched alkyl containing 0 to 10 unsaturated bonds, a C3-C6 cycloalkyl, a haloC1-C9 alkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, a C1-C5 acyl (H or C1-C4 alkyl)-C(=O)-, a haloC2-C5 acyl, or a C2-C5 alkoxycarbonyl, and a C atom in the carbon chain of said alkyl may be replaced by a heteroatom at any position, provided that normal valences permit; R ｉ represents a hydrogen atom, C1-C9 straight or branched alkyl, C3-C6 cycloalkyl, halo C1-C9 alkyl, C1-C9 alkyl substituted with hydroxy, C1-C5 acyl, halo C2-C5 acyl, -NR ｉ 'R ｉ '', and R ｉ ', R ｉ " are each independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, a haloC1-C9 alkyl, a C1-C5 acyl (H or C1-C4 alkyl)-C(=O)-, a haloC2-C5 acyl, or a C2-C5 alkoxycarbonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; R ｊ is a hydrogen atom, and R ｊ ' is halo C2-C5 acyl or C1-C25 alkylsulfonyl; R ｋ , R ｋ each ' is independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, a haloC1-C9 alkyl, a C1-C9 alkyl substituted with hydroxy, a C2-C9 alkenyl, a C2-C9 alkynyl, hydroxy, a C1-C5 acyl (H or C1-C4 alkyl)-C(=O)-, a haloC2-C5 acyl, a C2-C5 alkoxycarbonyl, or a C1-C9 alkylsulfonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; R ｌ , R ｌ each ' is independently selected from a hydrogen atom, a C1-C9 straight or branched alkyl, a C3-C6 cycloalkyl, a haloC1-C9 alkyl, a C2-C9 alkenyl, a C2-C9 alkynyl, a hydroxy, a C1-C5 acyl (H or C1-C4 alkyl)-C(=O)-, a haloC2-C5 acyl, or a C2-C5 alkoxycarbonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; R ｍ , R ｍ each ' is independently selected from a hydrogen atom, phenyl, C1-C9 straight or branched alkyl, C3-C6 cycloalkyl, haloC1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, hydroxy, C1-C5 acyl (H or C1-C4 alkyl)-C(=O)-, haloC2-C5 acyl, or C2-C5 alkoxycarbonyl, and a C atom in the carbon chain of the alkyl may be replaced by a heteroatom at any position, as long as normal valences permit; The aryl may be phenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 【Transformation 3】 Selected from or a pharmaceutically acceptable salt, stereoisomer, deuterated product, or prodrug thereof.

2. The R ４ wherein C3-C6 cycloalkyl is C4-C5 heterocycloalkyl, in particular 【Chemistry 4】 2. The phenylquinolone compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, deuterated product, or prodrug thereof, selected from:

3. The phenylquinolone compound is ４ wherein aryl is 4-pyridinyl or 【Transformation 5】 2. The phenylquinolone compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, deuterated product, or prodrug thereof, further comprising:

4. The phenylquinolone compound is 【Transformation 6】 【Transformation 7】 【Transformation 8】 2. The phenylquinolone compound of claim 1, wherein:

5. 2. The phenylquinolone compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, deuterated salt, or prodrug thereof, wherein the pharmaceutically acceptable salt comprises an inorganic salt or an organic salt, and the inorganic salt comprises sodium salt, potassium salt, magnesium salt, hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, or acid phosphate, and the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, hydroxyacetate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, and ascorbate.

6. 10. Use of the phenylquinolone compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, deuterated product, or prodrug thereof in the manufacture of an antibacterial or anticancer drug.

7. An antibacterial agent comprising the phenylquinolone compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, deuterated product, or prodrug thereof.

8. An antibacterial medicament comprising the phenylquinolone compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, deuterated product, or prodrug thereof.

9. An anti-cancer medicament comprising the phenylquinolone compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, deuterated product, or prodrug thereof.

10. 10. The medicament of claim 8 or 9, characterized in that the medicament further comprises one or more of the following pharmaceutical excipient(s): propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmolality regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-binding agents, penetration enhancers, pH adjusters, buffers, plasticizers, foaming agents, anti-foaming agents, thickening agents, encapsulating agents, humectants, flocculating and anti-flocculating agents, filter aids, and release retardants.

11. The pharmaceutical according to claim 8 or 9, characterized in that the pharmaceutical further comprises a pharmaceutical carrier selected from microcapsules, microspheres, nanoparticles, and liposomes.

12. The pharmaceutical composition of claim 9, wherein the cancer comprises cervical cancer, Burkitt's lymphoma, acute T-lymphoblastic leukemia, non-small cell lung cancer, gastric cancer, colon cancer, pancreatic cancer, liver cancer, malignant melanoma, prostate cancer, ovarian adenocarcinoma, glioma, breast cancer, osteosarcoma, and ductal carcinoma.

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