CN112279845B - Aryl or heteroaryl substituted thiadiazoles compounds and antibacterial application thereof - Google Patents

Aryl or heteroaryl substituted thiadiazoles compounds and antibacterial application thereof Download PDF

Info

Publication number
CN112279845B
CN112279845B CN201910672950.1A CN201910672950A CN112279845B CN 112279845 B CN112279845 B CN 112279845B CN 201910672950 A CN201910672950 A CN 201910672950A CN 112279845 B CN112279845 B CN 112279845B
Authority
CN
China
Prior art keywords
thiadiazol
ethyl
quinolone
hydroxy
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201910672950.1A
Other languages
Chinese (zh)
Other versions
CN112279845A (en
Inventor
吴松
夏杰
薛文杰
张驰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Materia Medica of CAMS
Original Assignee
Institute of Materia Medica of CAMS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute of Materia Medica of CAMS filed Critical Institute of Materia Medica of CAMS
Priority to CN201910672950.1A priority Critical patent/CN112279845B/en
Publication of CN112279845A publication Critical patent/CN112279845A/en
Application granted granted Critical
Publication of CN112279845B publication Critical patent/CN112279845B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention belongs to the technical field of medicines, and particularly relates to aryl or heteroaryl substituted thiadiazole compounds, a preparation method and application thereof as antibacterial medicines. The compound is shown as a formula (1), wherein Ar represents substituted or unsubstituted aryl or heteroaryl. The aryl or heteroaryl substituted thiadiazole compound is a new structural compound, has a strong inhibition effect on gram-positive bacteria and mycoplasma including staphylococcus aureus, staphylococcus epidermidis, enterococcus, clostridium difficile and the like, particularly drug-resistant gram-positive bacteria (MRSA, MRSE, VRE), has a certain inhibition effect on macrolide drug-resistant mycoplasma pneumoniae, has a good protection effect on systemic infection mice caused by MRSA intraperitoneal injection, and is worthy of further research and development.

Description

Aryl or heteroaryl substituted thiadiazoles compounds and antibacterial application thereof
Technical Field
The invention belongs to the technical field of antibacterial medicines, and particularly relates to aryl or heteroaryl substituted thiadiazole compounds, a preparation method and application thereof as an antibacterial medicine.
Background
Abuse or unreasonable use of antibiotics has prompted the continued emergence of pathogenic microorganisms such as drug resistant bacteria or mycoplasma, resulting in the loss of efficacy of currently available antimicrobial agents. The world health organization identified antibiotic resistance as one of the global health threats in 2001. In recent years, the development of antibacterial drugs is slowed down, few antibacterial drugs are marketed, and the problem of antibiotic resistance is more serious. Therefore, the development of antibacterial drugs with new structure types or new action mechanisms has important clinical significance and application value for solving the problem of antibiotic resistance.
Among the drug resistant gram positive bacteria, methicillin-resistant staphylococcus aureus (MRSA), methicillin-resistant surface staphylococcus (MRSE) and vancomycin-resistant enterococci (VRE) are most common. For mycoplasma pneumoniae, the most interesting is the resistant strain to macrolide antibiotics. The development of novel antibiotics against the above resistant pathogenic microorganisms is a current hotspot.
The compound belongs to aryl or heteroaryl substituted thiadiazole compounds, and is a compound with a new structure because the 5-position of 1,3, 4-thiadiazole is substituted by aryl or heteroaryl. The compound related to the patent has strong gram-positive bacteria resistance activity and broad antibacterial spectrum. The representative compound has certain inhibitory activity on standard and clinical separation of drug-resistant staphylococcus aureus, staphylococcus epidermidis, enterococcus faecalis and enterococcus faecium strains, the minimum inhibitory concentration (minimum inhibitory concentration, MIC) is 0.03-32 mug/mL, and the representative compound also has certain inhibitory activity on macrolide drug-resistant mycoplasma pneumoniae, and the gastric administration has better protection effect on mice infected by MRSA intraperitoneal injection, and half of the effective dose (ED 50 ) The value reached 1.70mg/kg. Therefore, the compounds of this patent have further value for development as clinical antibacterial agents.
Disclosure of Invention
The invention solves the technical problem of overcoming the defect of insufficient drug resistant bacteria resistant drugs in the prior art and provides aryl or heteroaryl substituted thiadiazole compounds, a preparation method and application thereof as antibacterial drugs.
In order to solve the technical problems of the invention, the invention provides the following technical scheme:
in a first aspect, there is provided an aryl or heteroaryl substituted thiadiazole compound, which is a compound of formula (1):
wherein:
ar represents a substituted or unsubstituted aryl or heteroaryl group, the substituents being selected from halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, halo C 1-8 Alkyl, halogenated C 2-8 Alkenyl, halo C 2-8 Alkynyl, C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH) 2 ) m OR 5 、(CH 2 ) m SR 5 、(CH 2 ) m NR 5 R 6 、(CH 2 ) m C(O)R 5 、(CH 2 ) m C(O)OR 5 、(CH 2 ) m OC(O)R 5 、(CH 2 ) m C(O)NR 5 R 6 、(CH 2 ) m NR 6 C(O)R 5 、(CH 2 ) m S(O) 2 R 5 、(CH 2 ) m S(O) 2 NR 5 R 6 、(CH 2 ) m NR 6 S(O) 2 R 5 One or more of (a) and (b);
R 1 each independently selected from hydrogen, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, halo C 1-8 Alkyl, halogenated C 2-8 Alkenyl, halo C 2-8 Alkynyl, C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH) 2 ) m OR 5 、(CH 2 ) m SR 5 、(CH 2 ) m NR 5 R 6 、(CH 2 ) m C(O)R 5 、(CH 2 ) m C(O)OR 5 、(CH 2 ) m OC(O)R 5 、(CH 2 ) m C(O)NR 5 R 6 、(CH 2 ) m NR 6 C(O)R 5 、(CH 2 ) m S(O) 2 R 5 、(CH 2 ) m S(O) 2 NR 5 R 6 、(CH 2 ) m NR 6 S(O) 2 R 5 Etc.;
R 2 、R 3 、R 4 each independently selected from hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, halo C 1-8 Alkyl, halogenated C 2-8 Alkenyl, halo C 2-8 Alkynyl, C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH) 2 ) m OR 5 、(CH 2 ) m SR 5 、(CH 2 ) m NR 5 R 6 、(CH 2 ) m C(O)R 5 、(CH 2 ) m C(O)OR 5 、(CH 2 ) m OC(O)R 5 、(CH 2 ) m C(O)NR 5 R 6 、(CH 2 ) m NR 6 C(O)R 5 、(CH 2 ) m S(O) 2 R 5 、(CH 2 ) m S(O) 2 NR 5 R 6 、(CH 2 ) m NR 6 S(O) 2 R 5 Etc.; each R is 5 And R is 6 Each independently is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, halo C 1-8 Alkyl, halogenated C 2-8 Alkenyl, halo C 2-8 Alkynyl, C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, or the like;
or R is 5 And R is 6 Together with the nitrogen atom to which it is attached, form a 3-to 9-membered ring optionally having 0-3 additional heteroatoms each independently selected from N, O or S;
n is 0, 1, 2, 3 or 4;
each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10;
unless otherwise indicated, aryl groups as described above contain 6 to 16 carbon atoms; heteroaryl is a 5-to 15-membered heteroaryl; and heterocyclyl is a 3-to 12-membered heterocyclyl; heteroaryl or heterocyclyl contains one or more heteroatoms selected from N, O or S.
Preferably, the halogen is selected from fluorine, chlorine, bromine, iodine; the halo represents monohalo at any substitution position, polyhalo of the same or different halogen atoms; the C is 1-8 The alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, linear or branched pentyl, linear or branched hexyl, linear or branched heptyl, linear or branched octyl; aryl is selected from phenyl, naphthyl, anthryl, phenanthryl or pyrenyl; heteroaryl is selected from furan, thiophene, oxazole, thiazole, isoxazole, oxadiazole, thiadiazole, pyrrole, pyrazole, imidazole Pyridine, pyrimidine, pyrazine, pyridazine, phthalazine, quinoline, isoquinoline, pteridine, purine, indole, isoindole, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl or benzophthalazinyl.
Preferably, said R 2 、R 3 、R 4 Each independently selected from hydrogen or C 1-8 An alkyl group.
Further, the aryl group is preferably phenyl or naphthyl, more preferably phenyl; heteroaryl groups are preferably pyridine, thiophene, furan, thiazole, quinoline, indole.
Preferably, the aryl or heteroaryl substituted thiadiazole compounds provided by the invention are:
n- (5-phenyl-1, 3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J1)
N- (5- (4-chlorophenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J2)
N- (5- (4-bromophenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J3)
N- (5- (3-fluorophenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J4)
N- (5- (2-fluorophenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J5)
N- (5- (4-methylphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J6)
N- (5- (3-methylphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J7)
N- (5- (4-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J8)
N- (5- (3-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J9)
N- (5- (2-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J10)
N- (5- (3-ethoxyphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J11)
N- (5- (2-ethoxyphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J12)
N- (5- (4-Difluoromethoxyphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J13)
N- (5- (4-dimethylaminophenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J14)
N- (5- (4-methylsulfonylphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J15)
N- (5- (2, 4-difluorophenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J16)
N- (5- (2-chloro-4-nitrophenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J17)
N- (5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J18)
N- (5- (pyridin-3-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J19)
N- (5- (pyridin-4-yl) -1,3, 4-thiadiazol-3-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J20)
N- (5- (thiophen-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J21)
N- (5- (furan-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J22)
N- (5- (thiazol-4-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J23)
N- (5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J24)
N- (5- (1-methyl-1H-pyrazol-3-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J25)
N- (5- (quinolin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J26)
N- (5- (1-methyl-1H-indol-6-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J27)
N- (5- (6-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J28)
N- (5- (5-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J29)
N- (5- (4-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J30)
N- (5- (3-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J31)
N- (5- (4-methoxypyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J32)
N- (5- (6-Fluoropyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J33)
N- (5- (5-Fluoropyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J34)
N- (5- (3-Fluoropyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J35)
N- (5- (5-bromopyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J36)
N- (5- (5-trifluoromethylpyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J37)
N- (5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-6-fluoro-4-hydroxy-2-quinolone-3-carboxamide (J38)
N- (5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-7-chloro-4-hydroxy-2-quinolone-3-carboxamide (J39)
N- (5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-8-chloro-4-hydroxy-2-quinolone-3-carboxamide (J40)
N- (5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-6-methyl-4-hydroxy-2-quinolone-3-carboxamide (J41)
N- (5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-6-methoxy-4-hydroxy-2-quinolone-3-carboxamide (J42)
In a second aspect, the present invention provides a process for the preparation of a compound of formula (1), comprising the steps of:
namely, reacting the intermediate (a) with the intermediate (d) to prepare the compound (1);
wherein Ar and R 1 、R 2 、R 3 、R 4 Is defined as before.
Preferably, the above reaction is carried out in the presence of a basic catalyst and a condensing agent.
Further, the basic catalyst is selected from inorganic or organic bases; the inorganic base is at least one selected from alkali metal hydroxide, alkaline earth metal hydroxide and alkali metal carbonate; the organic base is selected from at least one of primary amino group, secondary amino group, tertiary amino group and quaternary ammonium base in the molecule, preferably triethylamine, pyridine, diethylamine, diisopropylamine, pyridine, N-diisopropylethylamine, N-methylpiperidine and N-methylmorpholine; the condensing agent is selected from 1, 3-dicyclohexylcarbodiimide, N, N ' -diisopropylcarbodiimide, benzotriazol-N, N, N ', N ' -tetramethylurea hexafluorophosphate, and a carbowax condensing agent, preferably a carbowax condensing agent.
On the basis, the invention also provides a preparation method of the intermediate (a), which comprises the following steps:
the reaction is carried out in an organic solvent selected from trifluoroacetic acid, concentrated sulfuric acid, trifluoromethanesulfonic acid, preferably trifluoroacetic acid; wherein Ar and R4 are defined as above.
On the basis, the invention also provides a preparation method of the intermediate (d), which comprises the following steps:
(1) Converting intermediate (b) to intermediate (c), wherein, when R 3 In the case of H, the intermediate (b) is reacted with diethyl malonate to obtain an intermediate (c), when R 3 When selected from other groups than H as defined above, intermediate (b) is reacted with diethyl malonate and then with X-R 3 Obtaining an intermediate (c) through reaction, wherein X is I or Br;
(2) Converting intermediate (c) into intermediate (d) under alkaline conditions provided by sodium hydroxide, strong potassium oxide or lithium hydroxide, preferably lithium hydroxide;
wherein R is 1 、R 2 、R 3 The definition of n is as described above.
Further, a more specific example of one of the above reaction conditions is given by way of illustration only and not limiting the inventive content and scope of protection of the present invention in any way:
(1) 1 equivalent of Ar-CN is dissolved in trifluoroacetic acid, then 0.9 to 1.5 equivalent of thiosemicarbazide is added, stirring reaction is carried out at the temperature of 40 to 80 ℃, after the reaction is finished, the reaction solution is poured into ice water, the pH value is regulated to 11 to 12, and solids are separated out, thus obtaining an intermediate (a);
(2) 1 equivalent of N, N-dimethylformamide solution of substituted isatoic anhydride is added with 0.9-1.5 equivalent of N, N-diisopropylethylamine, and 0.9-1.5 equivalent of iodo R is added dropwise 2 (e.g. C 1-8 Alkane) at 25-60 ℃ and pouring the reaction liquid into ice water to separate out solid, thus obtaining an intermediate (b);
(3) Dissolving the intermediate (b) in an organic solvent (such as N, N-dimethylformamide, acetonitrile and the like), sequentially adding 0.9-1.5 equivalent of diethyl malonate and sodium hydride for reaction at 50-90 ℃, quenching with ice water after the reaction is finished, adjusting the pH to 4-5, and separating out solids to obtain an intermediate (c);
(4) Dissolving the intermediate (c) in an organic solvent (such as ethanol, acetonitrile, chloroform and the like), dropwise adding 2-10 times of 5% -20% lithium hydroxide aqueous solution, heating at 25-60 ℃ for reaction, adjusting pH to 4-5 after the reaction is finished, and separating out solids to obtain an intermediate (d);
(5) Dissolving an equal amount of the intermediate (a) and the intermediate (d) in ethanol, acetonitrile, chloroform or N, N-dimethylformamide, sequentially adding 0.9-2.0 equivalents of N, N-diisopropylethylamine and 0.9-2.0 equivalents of a Kate condensing agent, stirring overnight at 10-50 ℃, pouring the reaction liquid into ice water, and precipitating a solid to obtain the compound (1).
In a third aspect, the present invention provides an antibacterial use of the aryl or heteroaryl substituted thiadiazoles or use in the preparation of an antibacterial agent.
Preferably, the antibacterial use is for the treatment and prevention of infectious diseases of humans or animals caused by pathogenic microorganisms such as bacteria, mycoplasma, chlamydia, rickettsia, spirochetes, fungi, etc.
Further preferably, the bacteria are staphylococcus aureus, staphylococcus epidermidis, enterococcus faecalis, enterococcus faecium, clostridium difficile, escherichia coli, pseudomonas aeruginosa, klebsiella pneumoniae and the like, the mycoplasma is mycoplasma pneumoniae, ureaplasma urealyticum, mycoplasma hominis, mycoplasma genitalium and the like, and the chlamydia is chlamydia pneumoniae, chlamydia psittaci, chlamydia trachomatis, chlamydia bovis and the like.
Further preferably, the staphylococcus aureus comprises methicillin-sensitive staphylococcus aureus and methicillin-resistant staphylococcus aureus, the staphylococcus epidermidis comprises methicillin-sensitive staphylococcus epidermidis and methicillin-resistant staphylococcus epidermidis, the enterococcus faecalis and enterococcus faecium comprise vancomycin-sensitive enterococcus faecium and enterococcus faecium, vancomycin-resistant enterococcus faecalis and enterococcus faecium, and the mycoplasma is selected from drug-sensitive mycoplasma pneumoniae or drug-resistant mycoplasma pneumoniae.
In a fourth aspect, the present invention provides an antibacterial pharmaceutical composition comprising an aryl or heteroaryl substituted thiadiazole compound as described above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
Further, the carrier includes excipients, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. which are conventional in the pharmaceutical field.
Preferably, the pharmaceutical administration form is an injection, a tablet, a pill, a capsule, a suspension, an emulsion or an ointment, and the administration route is selected from intravenous or intramuscular injection, oral administration, transdermal administration, mucosal administration, rectal administration, vaginal administration and the like.
Compared with the prior art, the invention has the following beneficial effects:
the aryl or heteroaryl substituted thiadiazole compounds are antibacterial drugs with new structures, and experiments prove that the series of compounds are effective to various drug-resistant bacteria, have broad-spectrum activity against gram-positive bacteria, and particularly have strong inhibition effects on methicillin-resistant staphylococcus aureus (MRSA), methicillin-resistant staphylococcus epidermidis (MRSE) and vancomycin-resistant enterococci (VRE), and have certain inhibition activity on macrolide-resistant mycoplasma pneumoniae. The in vivo animal experiments prove that the series of compounds have good protection effect on mice infected by the system caused by the intraperitoneal injection of MRSA. Because the structure type is different from clinical antibacterial drugs, the antibacterial drug-resistant composition is expected to solve the problem of bacterial drug resistance, and has the value of intensive research and the potential of clinical application.
Detailed Description
The invention will be further illustrated with reference to the following specific examples, which are intended to illustrate the invention, but not to limit it. The experimental methods used in the examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are those which are commercially available unless otherwise specified.
1. Preparation and detection of Compounds
Example 1: preparation and detection of Compound J1
To a 100mL eggplant-shaped bottle was added benzonitrile (1.03 g,10 mmol), dissolved with 10mL of trifluoroacetic acid (TFA) and stirred for 5 minutes, then thiosemicarbazide (1.00 g,11 mmol) was added in portions, 10mL of trifluoroacetic acid was further added, and the mixed solution was reacted at 70℃for 8 hours. The reaction was monitored by thin layer chromatography and heating was stopped and allowed to cool naturally after the consumption of benzonitrile. Then, the reaction solution was poured into ice water, and the pH was adjusted to 11-12 with 1 equivalent concentration of sodium hydroxide solution, and a large amount of yellow precipitate was observed to be precipitated. Suction filtration is carried out, and a filter cake is washed by water (150 mL) and suction filtered to obtain a crude product. Recrystallization from 95% ethanol gave 1.21g (yield: 67.9%).
To a solution of 10g (61.3 mmol) of isatoic anhydride in N, N-Dimethylformamide (DMF) was added 12.8mL (73.6 mmol) of diisopropylethylamine, and 9.6g (73.6 mmol) of iodoethane was added dropwise and reacted overnight at 45 ℃. After the reaction is monitored by thin layer chromatography, the reaction solution is poured into ice water to precipitate solid, the solid is washed with water, filtered by suction, and dried to obtain 8.1g (yield: 67.5%) of intermediate 1-ethyl-2H-benzo [1,3] oxazine-2, 4-dione.
1.96g (10 mmol) of 1-ethyl-2H-benzo [1,3] oxazine-2, 4-dione are dissolved in N, N-dimethylformamide, diethyl malonate and sodium hydride are added in sequence in an amount of 1.2 times the equivalent, and the mixture is reacted at 80℃for 6 hours. After the reaction is monitored by thin layer chromatography, the solution is quenched by ice water, the pH value of 2mol/L hydrochloric acid solution is adjusted to 4-5, solid is precipitated, water washing, suction filtration and drying are carried out, and 0.83g (yield: 31.8%) of intermediate 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid ethyl ester is obtained.
0.5g (1.9 mmol) of ethyl 1-ethyl-4-hydroxy-2-quinolone-3-carboxylate was dissolved in absolute ethanol, and 5 times of 10% aqueous lithium hydroxide solution was added dropwise thereto, followed by heating at 50℃for reaction for 10 hours. After the reaction is monitored by a thin layer chromatography, adding 2mol/L hydrochloric acid solution to adjust the pH to 4-5, precipitating solid, washing with water, filtering, and drying to obtain 0.21g (yield: 47.4%) of intermediate 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid.
1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid (256.3 mg,1.1 mmol) and N, N-dimethylformamide (10 mL) were sequentially added to a 50mL eggplant-shaped bottle, and dissolved with stirring. Then, N-diisopropylethylamine (DIPEA, 349.3. Mu.L, 2 mmol) as an acid application agent and benzotriazole-1-oxo tris (dimethylamino) phosphonium hexafluorophosphate (BOP, 884.6mg,2 mmol) as a condensing agent were added, respectively, and the mixture was stirred at room temperature for 20 minutes. Next, 5-phenyl-1, 3, 4-thiadiazol-2-amine (177.2 mg,1 mmol) was added, and the reaction was allowed to react overnight at room temperature. The progress of the reaction was monitored by thin layer chromatography. When the 5-phenyl-1, 3, 4-thiadiazole-2-amine was consumed, the reaction solution was poured into 50mL of water, and a white precipitate was precipitated. And (5) carrying out suction filtration, drying, stirring, washing and pulping a filter cake with a small amount of absolute ethyl alcohol, and carrying out suction filtration again to obtain a crude product. Purification by silica gel column chromatography gave 82.6mg of the target product N- (5-phenyl-1, 3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J1).
Off-white solid, yield 24.7%. ESI-MS (m/z): 393.08[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.24(s,1H),8.02(s,2H),7.91(s,1H),7.78(s,1H),7.59(s,3H),7.47(s,1H),4.42(s,2H),1.31(s,3H).
Example 2: preparation and detection of Compound J2
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazole-2-amine mentioned in example 1, starting from 4-chlorobenzonitrile, giving intermediate 5- (4-chlorophenyl) -1,3, 4-thiadiazole-2-amine (yield: 77.2%).
The synthesis was the same as the preparation of the final product J1 mentioned in example 1 starting from 5- (4-chlorophenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid to give N- (5- (4-chlorophenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J2).
Pale yellow solid, yield 31.5%. ESI-MS (m/z): 428.12[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ7.80(d,J＝8.2Hz,2H),7.55(d,J＝8.3Hz,3H),7.50(s,3H),4.27(dd,J＝19.5,12.3Hz,2H),1.22(t,J＝7.1Hz,3H).
Example 3: preparation and detection of Compound J3
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazole-2-amine mentioned in example 1, starting from 4-bromoxynil, giving intermediate 5- (4-bromophenyl) -1,3, 4-thiadiazole-2-amine (yield: 55.3%).
The synthesis was the same as the preparation of end product J1 mentioned in example 1 starting from 5- (4-bromophenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid to give N- (5- (4-bromophenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J3).
Off-white solid, yield 19.2%. ESI-MS (m/z): 472.31[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ7.73(d,J＝8.5Hz,2H),7.69(d,J＝8.4Hz,3H),7.51(s,3H),4.30(p,J＝6.8Hz,2H),1.23(t,J＝7.1Hz,3H).
Example 4: preparation and detection of Compound J4
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazole-2-amine mentioned in example 1, starting from 3-fluorobenzonitrile, giving intermediate 5- (3-fluorophenyl) -1,3, 4-thiadiazole-2-amine (yield: 49.2%).
The synthesis was the same as the preparation of the final product J1 mentioned in example 1 starting from 5- (3-fluorophenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid to give N- (5- (3-fluorophenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J4).
Off-white solid, yield 30.1%. ESI-MS (m/z): 411.06[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ7.92-7.87(m,1H),7.80-7.73(m,1H),7.62(d,J＝8.4Hz,2H),7.54(s,2H),7.31(t,J＝8.8Hz,2H),4.29(q,J＝7.0Hz,2H),1.23(t,J＝7.1Hz,3H).。
Example 5: preparation and detection of Compound J5
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazole-2-amine mentioned in example 1, starting from 2-fluorobenzonitrile, giving intermediate 5- (2-fluorophenyl) -1,3, 4-thiadiazole-2-amine (yield: 49.2%).
The synthesis was the same as the preparation of end product J1 mentioned in example 1 starting from 5- (2-fluorophenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid to give N- (5- (2-fluorophenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J5).
Pale yellow solid, yield 41.1%. ESI-MS (m/z): 411.31[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.28(dd,J＝8.4,4.3Hz,1H),8.11(t,J＝7.7Hz,1H),7.92-7.85(m,1H),7.80-7.72(m,1H),7.51(d,J＝16.4Hz,4H),7.43-7.34(m,3H),4.29(q,J＝7.1Hz,2H),1.22(t,J＝7.1Hz,3H).
Example 6: preparation and detection of Compound J6
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazole-2-amine mentioned in example 1, starting from 4-methylbenzonitrile, giving intermediate 5- (4-methylphenyl) -1,3, 4-thiadiazole-2-amine (yield: 75.3%).
The synthesis was the same as the preparation of the final product J1 mentioned in example 1 starting from 5- (4-methylphenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid to give N- (5- (4-methylphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J6).
White solid, yield 27.4%. ESI-MS (m/z): 407.19[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ7.90(t,J＝8.8Hz,1H),7.81-7.73(m,1H),7.66(d,J＝7.9Hz,2H),7.37(s,2H),7.30(d,J＝7.9Hz,2H),4.30(p,J＝7.2,6.4Hz,2H),2.37(s,3H),1.23(t,J＝7.1Hz,3H).
Example 7: preparation and detection of Compound J7
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazole-2-amine mentioned in example 1, starting from 3-methylbenzonitrile, giving intermediate 5- (3-methylphenyl) -1,3, 4-thiadiazole-2-amine (yield: 49.2%).
The synthesis was the same as the preparation of end product J1 mentioned in example 1 starting from 5- (3-methylphenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid to give N- (5- (3-methylphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J7).
Brown gray solid, yield 28.4%. ESI-MS (m/z): 407.09[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ7.60(s,1H),7.57(d,J＝7.8Hz,1H),7.37(t,J＝7.7Hz,1H),7.27(d,J＝7.7Hz,1H),4.29(q,J＝7.2Hz,2H),2.38(s,3H),1.24-1.20(m,3H).
Example 8: preparation and detection of Compound J8
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazole-2-amine mentioned in example 1, starting from 4-methoxybenzonitrile, giving intermediate 5- (4-methoxyphenyl) -1,3, 4-thiadiazole-2-amine (yield: 75.3%).
The synthesis was carried out in the same manner as the preparation of the final product J1 mentioned in example 1, starting from 5- (4-methoxyphenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, giving N- (5- (4-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J8).
White solid, yield 31.2%. ESI-MS (m/z): 423.43[ M)+H] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.28(dd,J＝8.2,4.1Hz,1H),7.94-7.85(m,1H),7.80-7.74(m,1H),7.72(s,2H),7.31(s,2H),7.05(d,J＝8.5Hz,2H),4.29(q,J＝7.1Hz,2H),3.84(s,3H),1.27-1.22(m,3H).
Example 9: preparation and detection of Compound J9
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazole-2-amine mentioned in example 1, starting from 3-methoxybenzonitrile, giving intermediate 5- (3-methoxyphenyl) -1,3, 4-thiadiazole-2-amine (yield: 49.2%).
The synthesis was carried out in the same manner as the preparation of the final product J1 mentioned in example 1, starting from 5- (3-methoxyphenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, giving N- (5- (3-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J9).
Off-white solid, yield 14.4%. ESI-MS (m/z): 423.21[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.28(dd,J＝8.3,3.9Hz,1H),7.94-7.86(m,1H),7.81-7.72(m,1H),7.41(t,J＝7.9Hz,2H),7.35-7.29(m,3H),7.04(dd,J＝8.2,2.5Hz,2H),4.29(q,J＝7.1Hz,2H),3.85(s,3H),1.23(t,J＝7.1Hz,3H).
Example 10: preparation and detection of Compound J10
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazole-2-amine mentioned in example 1, starting from 2-methoxybenzonitrile, giving intermediate 5- (2-methoxyphenyl) -1,3, 4-thiadiazole-2-amine (yield: 49.2%).
The synthesis was carried out in the same manner as the preparation of the final product J1 mentioned in example 1, starting from 5- (2-methoxyphenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, giving N- (5- (2-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J10).
Off-white solid, yield 37.3%. ESI-MS (m/z): 423.11[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.28(dd,J＝8.3,3.7Hz,1H),8.12(d,J＝7.8Hz,1H),7.93-7.86(m,1H),7.81-7.72(m,1H),7.50(t,J＝7.5Hz,1H),7.45(t,J＝7.9Hz,1H),7.22(d,J＝8.7Hz,1H),7.09(t,J＝7.6Hz,1H),4.29(q,J＝7.0Hz,1H),3.96(s,3H),1.23(t,J＝7.1Hz,3H).
Example 11: preparation and detection of Compound J11
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazol-2-amine mentioned in example 1, starting from 3-ethoxybenzonitrile, giving intermediate 5- (3-ethoxyphenyl) -1,3, 4-thiadiazol-2-amine (yield: 49.2%).
The synthesis was the same as the preparation of end product J1 mentioned in example 1 starting from 5- (3-ethoxyphenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid to give N- (5- (3-ethoxyphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J11).
Pale yellow solid, yield 33.1%. ESI-MS (m/z): 437.25[ M+H ]] + , 1 H NMR(500MHz,DMSO-d 6 )δ7.45(s,2H),7.39(t,J＝7.9Hz,2H),7.30(d,J＝7.1Hz,2H),7.04-6.99(m,2H),4.29(q,J＝7.1Hz,2H),4.11(q,J＝7.0Hz,2H),1.37(t,J＝7.0Hz,3H),1.27-1.14(m,3H).
Example 12: preparation and detection of Compound J12
The procedure was as described for the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazole-2-amine from 2-ethoxybenzonitrile as starting material in example 1, giving intermediate 5- (2-ethoxyphenyl) -1,3, 4-thiadiazole-2-amine (yield: 49.2%).
The synthesis was the same as the preparation of end product J1 mentioned in example 1 starting from 5- (2-ethoxyphenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid to give N- (5- (2-ethoxyphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J12).
Yellow solid, yield 54.1%. ESI-MS (m/z): 437.23[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.15(d,J＝7.7Hz,1H),7.43(t,J＝7.9Hz,1H),7.20(d,J＝4.4Hz,3H),7.07(d,J＝7.7Hz,1H),4.32-4.27(m,2H),4.24(q,J＝7.0Hz,2H),1.49(t,J＝6.9Hz,3H),1.23(t,J＝7.1Hz,3H).
Example 13: preparation and detection of Compound J13
The synthesis was carried out in the same manner as the preparation of 5-phenyl-1, 3, 4-thiadiazole-2-amine as an intermediate mentioned in example 1, starting from 4-difluoromethoxy-benzonitrile, to give 5- (4-difluoromethoxy-phenyl) -1,3, 4-thiadiazole-2-amine as an intermediate (yield: 61.8%).
The procedure was followed, starting from 5- (4-difluoromethoxyphenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (4-difluoromethoxyphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J13) in the same manner as in the preparation of final product J1 mentioned in example 1.
Yellow solid, yield 19.9%. ESI-MS (m/z): 459.14[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.24(dd,J＝14.7,7.3Hz,1H),7.89-7.81(m,1H),7.71(d,J＝8.4Hz,1H),7.60(dd,J＝13.2,7.6Hz,1H),7.51-7.39(m,2H),7.37-7.29(m,2H),7.19(d,J＝12.4Hz,1H),4.26(dd,J＝15.6,7.9Hz,2H),1.23-1.17(m,3H).
Example 14: preparation and detection of Compound J14
The synthesis procedure was identical to that described in example 1, starting from 4-dimethylaminobenzonitrile, for the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazol-2-amine, giving intermediate 5- (4-dimethylaminophenyl) -1,3, 4-thiadiazol-2-amine (yield: 92.2%).
The synthesis was carried out in the same manner as the preparation of the final product J1 mentioned in example 1, starting from 5- (4-dimethylaminophenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid to give N- (5- (4-dimethylaminophenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J14).
Brown solid, yield 16.1%. ESI-MS (m/z): 436.09[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ7.57(d,J＝8.5Hz,2H),7.18(s,3H),6.77(d,J＝8.5Hz,3H),4.27(tt,J＝23.3,17.0,12.1Hz,2H),2.98(s,6H),1.21(dt,J＝14.3,7.2Hz,3H).
Example 15: preparation and detection of Compound J15
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazole-2-amine mentioned in example 1, starting from p-methanesulfonyl-benzonitrile, giving intermediate 5- (4-methanesulfonylphenyl) -1,3, 4-thiadiazole-2-amine (yield: 41.3%).
The procedure was followed, starting from 5- (4-methanesulfonylphenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (4-methanesulfonylphenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J15) as described in example 1 for the preparation of final product J1.
Pale yellow solid was found to be 16.6% in yield. ESI-MS (m/z): 471.35[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.31-8.26(m,1H),8.11(d,J＝8.0Hz,2H),7.92-7.86(m,1H),7.72(s,2H),7.43-7.39(m,2H),4.40(dd,J＝14.1,7.2Hz,3H),4.29(q,J＝7.4Hz,2H),1.27(t,J＝7.1Hz,3H).
Example 16: preparation and detection of Compound J16
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazol-2-amine mentioned in example 1, starting from 2, 4-difluorobenzonitrile, giving intermediate 5- (2, 4-difluorophenyl) -1,3, 4-thiadiazol-2-amine (yield: 49.2%).
The procedure was followed, starting from 5- (2, 4-difluorophenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (2, 4-difluorophenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J16) as described in example 1 for the preparation of final product J1.
White solid, yield 31.4%. ESI-MS (m/z): 393.09[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.23(dd,J＝23.3,11.9Hz,2H),7.56(t,J＝7.6Hz,1H),7.48(q,J＝10.3,8.8Hz,1H),7.37(d,J＝8.4Hz,1H),7.28(d,J＝8.6Hz,1H),7.15(t,J＝7.9Hz,1H),4.23(q,J＝7.9,7.2Hz,2H),1.20(s,3H).
Example 17: preparation and detection of Compound J17
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazole-2-amine mentioned in example 1, starting from 2-chloro-4-nitronitrile, giving intermediate 5- (2-chloro-4-nitrophenyl) -1,3, 4-thiadiazole-2-amine (yield: 61.8%).
The procedure was followed, starting from 5- (2-chloro-4-nitrophenyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (2-chloro-4-nitro-phenyl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J17) as described in example 1 for the preparation of final product J1.
Yellow solid, yield 25.1%. ESI-MS (m/z): 472.15[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.46(s,2H),8.39(d,J＝8.9Hz,1H),8.29(d,J＝8.6Hz,2H),7.78(s,2H),4.26(q,J＝7.6Hz,2H),1.23-1.17(m,3H).
Example 18: preparation and detection of Compound J18
The procedure was identical to that described in example 1, starting from 2-cyanopyridine, to give intermediate 5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-amine (yield: 72.9%).
The synthesis was carried out in the same manner as the preparation of the final product J1 mentioned in example 1, starting from 5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, giving N- (5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J18).
White solid, yield 21.1%. ESI-MS (m/z): 393.09[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.72-8.59(m,1H),8.28(dd,J＝8.3,4.0Hz,1H),8.23-8.12(m,1H),8.09-7.96(m,1H),7.89(t,J＝9.1Hz,1H),7.76(dd,J＝24.3,8.3Hz,1H),7.62(dd,J＝16.6,8.4Hz,1H),7.49(q,J＝7.3Hz,1H),4.36-4.19(m,2H),1.24(t,J＝6.9Hz,3H).
Example 19: preparation and detection of Compound J19
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazol-2-amine mentioned in example 1, starting from 3-cyanopyridine, to give intermediate 5- (pyridin-3-yl) -1,3, 4-thiadiazol-2-amine (yield: 72.9%).
The synthesis was carried out in the same manner as the preparation of the final product J1 mentioned in example 1, starting from 5- (pyridin-3-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, giving N- (5- (pyridin-3-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J19).
The white solid was found to be 23.3% yield. ESI-MS (m/z): 393.09[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.28(dd,J＝8.5,4.5Hz,1H),8.07(d,J＝7.9Hz,1H),7.93-7.85(m,1H),7.76(dd,J＝23.3,8.3Hz,1H),7.66-7.58(m,1H),7.51(q,J＝8.1,7.6Hz,1H),7.39-7.31(m,1H),7.16-7.07(m,1H),4.29(q,J＝6.9Hz,2H),1.22(t,J＝7.3Hz,3H).
Example 20: preparation and detection of Compound J20
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazol-2-amine mentioned in example 1, starting from 4-cyanopyridine, to give intermediate 5- (pyridin-4-yl) -1,3, 4-thiadiazol-2-amine (yield: 63.2%).
The synthesis was carried out in the same manner as the preparation of the final product J1 mentioned in example 1, starting from 5- (pyridin-4-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, giving N- (5- (pyridin-4-yl) -1,3, 4-thiadiazol-3-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J20).
Brown solid, yield 26.2%. ESI-MS (m/z): 393.09[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.28(dd,J＝8.2,4.6Hz,1H),8.08(s,1H),7.93-7.86(m,1H),7.81-7.72(m,1H),7.64(t,J＝7.8Hz,1H),7.51(t,J＝7.6Hz,1H),7.33(s,1H),7.14(s,1H),4.30(q,J＝7.1Hz,2H),1.23(t,J＝7.1Hz,3H).
Example 21: preparation and detection of Compound J21
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazol-2-amine mentioned in example 1, starting from 2-cyanothiophene, to give intermediate 5- (thiophen-2-yl) -1,3, 4-thiadiazol-2-amine (yield: 83.8%).
The synthesis was carried out in the same manner as the preparation of the final product J1 mentioned in example 1, starting from 5- (thiophen-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, giving N- (5- (thiophen-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J21).
White solid, yield 19.4%. ESI-MS (m/z): 399.05[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.28(dd,J＝8.4,3.7Hz,1H),7.90(t,J＝9.3Hz,1H),7.75(dd,J＝15.8,8.2Hz,1H),7.68-7.61(m,1H),7.50(t,J＝7.7Hz,1H),7.44(d,J＝4.9Hz,1H),4.29(q,J＝7.3Hz,2H),1.23(t,J＝7.1Hz,3H).
Example 22: preparation and detection of Compound J22
The procedure was as described for the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazol-2-amine, as described in example 1, starting from 2-cyanofuran, to give intermediate 5- (furan-2-yl) -1,3, 4-thiadiazol-2-amine (yield: 63.2%).
The synthesis was carried out in the same manner as the preparation of the final product J1 mentioned in example 1, starting from 5- (furan-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, giving N- (5- (furan-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J22).
White solid, yield 20.1%. ESI-MS (m/z): 383.07[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.33-8.21(m,1H),7.93-7.86(m,1H),7.78(d,J＝8.8Hz,1H),7.75-7.71(m,1H),7.63(t,J＝7.8Hz,1H),7.50(t,J＝7.6Hz,1H),4.29(q,J＝7.1Hz,2H),1.22(t,J＝7.1Hz,3H).
Example 23: preparation and detection of Compound J23
The procedure was identical to that described in example 1, starting from 4-cyanothiazole, to give intermediate 5- (thiazol-4-yl) -1,3, 4-thiadiazol-2-amine (yield: 51.3%).
The synthesis was carried out in the same manner as the preparation of the final product J1 mentioned in example 1, starting from 5- (thiazol-4-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, giving N- (5- (thiazol-4-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J23).
Yellow solid, yield 10.2%. ESI-MS (m/z): 400.35[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.15(s,1H),7.48(s,2H),7.38-7.10(m,3H),4.30(s,2H),1.32-1.16(m,3H).
Example 24: preparation and detection of Compound J24
The procedure was identical to that described in example 1, starting from 2-cyanothiazole, to give intermediate 5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-amine (yield: 61.8%).
The procedure was followed, starting from 5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J24) as described in example 1 for the preparation of final product J1.
Yellow solid, yield 14.9%. ESI-MS (m/z): 400.18[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.21(d,J＝8.0Hz,1H),8.01(d,J＝27.5Hz,1H),7.94(d,J＝3.1Hz,1H),7.58(d,J＝8.1Hz,1H),7.39(d,J＝8.4Hz,1H),7.16(t,J＝7.5Hz,1H),4.23(q,J＝7.5Hz,2H),1.22(t,J＝7.0Hz,3H).
Example 25: preparation and detection of Compound J25
The synthesis was identical to the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazol-2-amine mentioned in example 1, starting from 1-methyl-3-cyanopyrazole, yielding intermediate 5- (1-methyl-1H-pyrazol-3-yl) -1,3, 4-thiadiazol-2-amine (yield: 41.3%).
The synthesis was carried out in the same manner as the preparation of the final product J1 mentioned in example 1 starting from 5- (1-methyl-1H-pyrazol-3-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid to give N- (5- (1-methyl-1H-pyrazol-3-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J25).
Pale green solid, yield 8.2%. ESI-MS (m/z): 397.16[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.06(d,J＝7.8Hz,2H),7.45(t,J＝7.8Hz,1H),7.33(d,J＝8.4Hz,1H),7.11(t,J＝7.5Hz,2H),4.26(s,3H),4.20(q,J＝6.9Hz,2H),1.18(t,J＝7.1Hz,3H).
Example 26: preparation and detection of Compound J26
The procedure was as described for the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazole-2-amine, as described in example 1, starting from 2-cyanoquinoline to give intermediate 5- (2-quinolinyl) -1,3, 4-thiadiazole-2-amine (yield: 31.1%).
The synthesis was carried out in the same manner as the preparation of the final product J1 mentioned in example 1 starting from 5- (2-quinolinyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid to give N- (5- (quinolin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J26).
Brown gray solid, yield 3.12%. ESI-MS (m/z): 444.21[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ9.46(s,1H),8.48(t,J＝10.9Hz,2H),8.04(t,J＝7.9Hz,2H),7.82(d,J＝7.9Hz,2H),7.71(s,2H),7.66(t,J＝7.9Hz,2H),4.24(q,J＝6.7Hz,2H),1.19(t,J＝6.7Hz,3H).
Example 27: preparation and detection of Compound J27
The procedure was as described for the preparation of intermediate 5-phenyl-1, 3, 4-thiadiazole-2-amine, as described in example 1, starting from 1-methyl-1H-indole-6-carbonitrile, to give intermediate 5- (1-methyl-1H-indol-6-yl) -1,3, 4-thiadiazole-2-amine (yield: 30.2%).
The procedure was followed, starting from 5- (2-quinolinyl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (1-methyl-1H-indol-6-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J27) as described in example 1.
Yellow solid, yield 21.1%. ESI-MS (m/z): 446.31[ M+H ]] + , 1 H NMR(500MHz,DMSO-d 6 )δ8.24(t,J＝9.7Hz,1H),8.11(s,1H),7.73-7.66(m,1H),7.57(s,2H),7.40(t,J＝14.1Hz,2H),7.05-7.12(m,2H),4.38-4.11(m,2H),3.36(s,3H),1.21(s,3H).
Example 28: preparation and detection of Compound J28
The procedure was as described for the preparation of intermediate 5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-amine, as mentioned in example 1, starting from 6-methyl-2-cyanopyridine, to give intermediate 5- (4-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-amine (yield: 10.8%).
The procedure was followed, starting from 5- (6-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (6-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J28) as described in example 1 for the preparation of final product J1.
Brown solid, yield 9.6%. ESI-MS (m/z): 408.27[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ7.98(s,1H),7.88(d,J＝7.9Hz,1H),7.81(t,J＝7.8Hz,1H),7.51(s,2H),7.45(s,1H),7.30(d,J＝7.5Hz,1H),4.28(d,J＝17.4Hz,1H),2.76(s,3H),1.27-1.12(m,3H).
Example 29: preparation and detection of Compound J29
The procedure was as described for the preparation of intermediate 5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-amine, as mentioned in example 1, starting from 5-methyl-2-cyanopyridine, to give intermediate 5- (5-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-amine (yield: 45.1%).
The procedure was followed, starting from 5- (5-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (5-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J29) as described in example 1 for the preparation of final product J1.
Brown solid, yield 12.9%. ESI-MS (m/z): 408.39[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.22(d,J＝7.9Hz,1H),8.08(d,J＝9.0Hz,1H),7.97(d,J＝12.7Hz,1H),7.77(s,1H),7.56(d,J＝8.0Hz,1H),7.38(d,J＝8.4Hz,1H),7.15(s,1H),4.26-4.22(m,2H),2.37(s,3H),1.19(m,3H).
Example 30: preparation and detection of Compound J30
The procedure was as described for the preparation of intermediate 5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-amine, as mentioned in example 1, starting from 4-methyl-2-cyanopyridine, to give intermediate 5- (4-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-amine (yield: 19.1%).
The procedure was followed, starting from 5- (3-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (4-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J30) as described in example 1 for the preparation of final product J1.
The yield of grey solid was 15.7%. ESI-MS (m/z): 408.71[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.07(s,1H),7.45(s,2H),7.33(s,2H),7.12(s,2H),4.24(s,2H),2.44(s,3H),1.19(s,3H).
Example 31: preparation and detection of Compound J31
The procedure was as described for the preparation of intermediate 5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-amine, as mentioned in example 1, starting from 3-methyl-2-cyanopyridine, to give intermediate 5- (3-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-amine (yield: 19.1%).
The procedure was followed, starting from 5- (3-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (3-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J31) as described in example 1 for the preparation of final product J1.
Off-white solid was obtained in 12.6% yield. ESI-MS (m/z): 408.31[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.06(d,J＝7.8Hz,2H),7.45(d,J＝7.6Hz,2H),7.32(s,1H),7.10(s,2H),4.23(s,2H),1.51(s,3H),1.19(s,3H).
Example 32: preparation and detection of Compound J32
The procedure was as described for the preparation of intermediate 5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-amine, as mentioned in example 1, starting from 4-methoxy-2-cyanopyridine, to give intermediate 5- (4-methoxypyridin-2-yl) -1,3, 4-thiadiazol-2-amine (yield: 21.4%).
The procedure was followed, starting from 5- (4-methoxypyridin-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (4-methoxypyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J32) as described in example 1.
The yield of grey solid was 9.1%. ESI-MS (m/z): 424.19[ M+H ]] + , 1 H NMR(500MHz,DMSO-d 6 )δ8.37(d,J＝5.8Hz,1H),8.05(d,J＝7.9Hz,1H),7.69(s,1H),7.43(d,J＝7.9Hz,1H),7.32(d,J＝8.5Hz,1H),7.10(t,J＝7.6Hz,1H),6.84(s,1H),4.28-4.17(m,2H),3.92(s,3H),1.20(t,J＝7.4Hz,3H).
Example 33: preparation and detection of Compound J33
The procedure was as described for the preparation of intermediate 5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-amine, as mentioned in example 1, starting from 6-fluoro-2-cyanopyridine, to give intermediate 5- (6-fluoropyridin-2-yl) -1,3, 4-thiadiazol-2-amine (yield: 18.3%).
The procedure was followed, starting from 5- (6-fluoropyridin-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (6-fluoropyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J33) as preparation of final product J1 mentioned in example 1.
Brown solid, yield 8.1%. ESI-MS (m/z): 412.44[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.13(q,J＝7.8Hz,2H),8.01(dd,J＝7.6,2.2Hz,1H),7.68(s,2H),7.24(d,J＝8.1Hz,2H),4.24(m,2H),1.27-1.15(m,3H).
Example 34: preparation and detection of Compound J34
The procedure was as described for the preparation of intermediate 5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-amine, as mentioned in example 1, starting from 5-fluoro-2-cyanopyridine, to give intermediate 5- (5-fluoropyridin-2-yl) -1,3, 4-thiadiazol-2-amine (yield: 18.3%).
The procedure was followed, starting from 5- (5-fluoropyridin-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (5-fluoropyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J34) as described in example 1 for the preparation of final product J1.
Brown solid, yield 7.3%. ESI-MS (m/z): 412.24[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.52(s,1H),8.21(d,J＝7.7Hz,1H),7.96(d,J＝13.5Hz,1H),7.61-7.56(m,2H),7.38(d,J＝8.3Hz,1H),7.15(s,1H),4.38-4.09(m,2H),1.21(s,3H).
Example 35: preparation and detection of Compound J35
The procedure was as described for the preparation of intermediate 5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-amine, as mentioned in example 1, starting from 3-fluoro-2-cyanopyridine, to give intermediate 5- (3-fluoropyridin-2-yl) -1,3, 4-thiadiazol-2-amine (yield: 35.1%).
The procedure was followed, starting from 5- (3-fluoropyridin-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (3-fluoropyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J35) in the same manner as for the preparation of final product J1 mentioned in example 1.
Brown solid, yield 12.4%. ESI-MS (m/z): 412.24[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.52(s,1H),8.21(d,J＝7.7Hz,1H),7.96(d,J＝13.5Hz,1H),7.61-7.56(m,2H),7.38(d,J＝8.3Hz,1H),7.15(s,1H),4.38-4.09(m,2H),1.21(s,3H).
Example 36: preparation and detection of Compound J36
The synthesis was identical to the preparation of intermediate 5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-amine mentioned in example 1 starting from 5-bromo-2-cyanopyridine, giving intermediate 5- (5-bromopyridin-2-yl) -1,3, 4-thiadiazol-2-amine (yield: 20.1%).
The procedure was followed, starting from 5- (5-bromopyridin-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (5-bromopyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J36) in the same manner as for the preparation of final product J1 mentioned in example 1.
Brown solid, yield 7.7%. ESI-MS (m/z): 472.19[ M+H ]] + .ESI-MS(m/z):472.19[M+H] + , 1 H NMR(500MHz,DMSO-d 6 )δ8.78(s,2H),8.12(m,3H),7.66(s,2H),4.24(s,2H),1.24(s,3H).
Example 37: preparation and detection of Compound J37
The procedure was as described for the preparation of intermediate 5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-amine, as mentioned in example 1, starting from 5-trifluoromethyl-2-cyanopyridine, to give intermediate 5- (5-trifluoromethylpyridin-2-yl) -1,3, 4-thiadiazol-2-amine (yield: 20.1%).
The procedure was followed, starting from 5- (5-trifluoromethylpyridin-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid, to give N- (5- (5-trifluoromethylpyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J37) in the same manner as in the preparation of final product J1 mentioned in example 1.
Off-white solid was obtained in 4.2% yield. ESI-MS (m/z): 462.28[ M+H ]] + , 1 H NMR(500MHz,DMSO-d 6 )δ9.02(s,1H),8.38(s,1H),8.20(s,1H),7.78(s,1H),7.57(s,1H),7.38(s,1H),7.14(s,1H),4.27-4.20(m,2H),1.21(s,3H).
Example 38: preparation and detection of Compound J38
The synthesis was the same as the preparation of intermediate 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid mentioned in example 1 using 6-fluoroisatoic anhydride as starting material, yielding intermediate 1-ethyl-4-hydroxy-6-fluoro-2-quinolone-3-carboxylic acid (yield: 50.2%).
The procedure was followed, starting from 5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-6-fluoro-2-quinolone-3-carboxylic acid, to give N- (5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-6-fluoro-4-hydroxy-2-quinolone-3-carboxamide (J38) in the same manner as for the preparation of final product J1 mentioned in example 1.
Yellow solid, yield 16.9%. ESI-MS (m/z): 418.12[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.28(d,J＝8.4Hz,1H),8.08(dd,J＝9.0,2.9Hz,1H),7.92(d,J＝8.4Hz,1H),7.74(d,J＝8.0Hz,1H),7.63(t,J＝7.7Hz,1H),4.29(q,J＝7.1Hz,2H),1.22(t,J＝7.0Hz,3H).
Example 39: preparation and detection of Compound J39
The synthesis was identical to the preparation of intermediate 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid mentioned in example 1, starting from 7-chloroisatoic anhydride, giving intermediate 1-ethyl-4-hydroxy-7-chloro-2-quinolone-3-carboxylic acid (yield: 50.2%).
The procedure was followed, starting from 5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-7-chloro-2-quinolone-3-carboxylic acid, to give N- (5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-7-chloro-4-hydroxy-2-quinolone-3-carboxamide (J39) in the same manner as in the preparation of final product J1 mentioned in example 1.
Yellow solid, yield 30.7%. ESI-MS (m/z): 434.18[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.27(d,J＝7.4Hz,1H),7.99(d,J＝6.9Hz,1H),7.95-7.90(m,1H),7.82-7.71(m,1H),7.62(t,J＝7.7Hz,1H),4.27(q,J＝6.9Hz,2H),1.21(t,J＝6.9Hz,3H).
Example 40: preparation and detection of Compound J40
The synthesis was identical to the preparation of the intermediate 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid mentioned in example 1, starting from 8-chloroindigotic anhydride, giving the intermediate 1-ethyl-4-hydroxy-8-chloro-2-quinolone-3-carboxylic acid (yield: 50.2%).
The procedure was followed, starting from 5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-8-chloro-2-quinolone-3-carboxylic acid, to give N- (5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-8-chloro-4-hydroxy-2-quinolone-3-carboxamide (J40) in the same manner as for the preparation of final product J1 mentioned in example 1.
Brown solid, yield 19.6%. ESI-MS (m/z): 434.28[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.27(dd,J＝8.5,4.3Hz,1H),8.04(d,J＝8.8Hz,1H),7.89(q,J＝8.1Hz,1H),7.77-7.72(m,1H),7.54(d,J＝8.6Hz,1H),4.28(q,J＝7.0Hz,2H),1.20(t,J＝7.1Hz,3H).
Example 41: preparation and detection of Compound J41
The synthesis was identical to the preparation of intermediate 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid mentioned in example 1, starting from 6-methylisatoic anhydride, giving intermediate 1-ethyl-4-hydroxy-6-methyl-2-quinolone-3-carboxylic acid (yield: 50.2%).
The procedure was followed, starting from 5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-6-methyl-2-quinolone-3-carboxylic acid, to give N- (5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-6-methyl-4-hydroxy-2-quinolone-3-carboxamide (J41) in the same manner as for the preparation of final product J1 mentioned in example 1.
Pale yellow solid, yield 10.4%. ESI-MS (m/z): 414.15[ M+H ]] + . 1 H NMR(500MHz,DMSO-d 6 )δ8.28(d,J＝8.3Hz,1H),7.90(d,J＝8.3Hz,1H),7.75(d,J＝7.5Hz,1H),7.69(s,1H),7.63(t,J＝7.9Hz,1H),4.26(q,J＝7.4Hz,2H),2.51(s,3H),1.22(d,J＝7.4Hz,3H).
Example 42: preparation and detection of Compound J42
The synthesis was identical to the preparation of intermediate 1-ethyl-4-hydroxy-2-quinolone-3-carboxylic acid mentioned in example 1, starting from 6-methoxyisatoic anhydride, giving intermediate 1-ethyl-4-hydroxy-6-methoxy-2-quinolone-3-carboxylic acid (yield: 50.2%).
The procedure was followed, starting from 5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-amine and 1-ethyl-4-hydroxy-6-methoxy-2-quinolone-3-carboxylic acid, to give N- (5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-6-methoxy-4-hydroxy-2-quinolone-3-carboxamide (J42) as described in example 1 for the preparation of final product J1.
Brown solid, yield 13.1%. ESI-MS (m/z): 430.23[ M+H ]] + , 1 H NMR(500MHz,DMSO-d 6 )δ8.03-7.86(m,1H),7.79-7.61(m,2H),7.52(s,1H),7.31(d,J＝20.7Hz,1H),4.29-4.26(m,2H),3.83(s,3H),1.19(s,3H).
2. Determination of antibacterial Activity
Experimental example 1: activity assay of Compounds against Staphylococcus aureus Standard Strain ATCC 29213
1. Preparation of test bacterial liquid
The standard strain of Staphylococcus aureus ATCC 29213 was inoculated into 20mL of tryptone soy broth and cultured in an incubator at 37℃for 12 hours with shaking at a speed of 200 rpm. When the clarified medium became turbid, it was shown that the bacteria proliferated significantly and grew vigorously. At this time, the bacterial liquid is diluted in a new tryptic soy broth medium to have an OD600 value of between 0.3 and 0.5, and is again diluted 10 times with the new tryptic soy broth medium 5 The double is used as a test bacterial liquid.
2. Determination of minimum inhibitory concentration
Taking a clean and sterile 96-well cell culture plate, adding 200 mu L of prepared test bacterial liquid into each well of a first row, and adding 100 mu L of test bacterial liquid into each well of a second row to twelve rows. 4 μl of pre-prepared 5mg/ml DMSO solution of the test sample was added to each well of column 1 (each sample was repeated three times), and a positive control group (i.e. 4 μl of levofloxacin at the same concentration) and a blank control group (i.e. no drug addition) were additionally provided. Starting from the first row of wells, 100. Mu.L of sample from the first row of wells was sequentially added to the next row of wells in an 8-fold micropipette for 2-fold gradient dilution, and a total of 12 different concentrations of compound solutions were set, 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39, 0.20, 0.10, 0.05. Mu.g/mL. The 96-well cell culture plate was placed in a 37℃incubator, and after culturing for 18 hours, the growth of Staphylococcus aureus in each well of the 96-well plate was observed. For each compound, the concentration of the compound corresponding to the well in which the bacteria were growing was not seen, i.e. the lowest inhibitory concentration (Minimal Inhibitory Concentration, MIC) of the compound.
3. The activity of the compounds against Staphylococcus aureus standard strain ATCC29213 is shown in Table 1.
Experimental example 2: antibacterial spectrum determination of compounds against gram-positive bacteria
1. Strain class
Clinical isolates collected in ATCC standard strain or Sichuan area include 12 strains of Staphylococcus aureus (methicillin resistant Staphylococcus aureus: MRSA15-1, MRSA15-2, MRSA15-3, MRSA15-6, MRSA15-7, MRSA15-8, MRSA15-9, methicillin sensitive Staphylococcus aureus: MSSA15-1, vancomycin sensitive Staphylococcus aureus: ATCC25923, vancomycin moderately sensitive Staphylococcus aureus: ATCC700699, ATCC 700788), 5 strains of Staphylococcus epidermidis (methicillin resistant Staphylococcus epidermidis: MRSE15-1, MRSE15-2, MRSE15-3, methicillin sensitive Staphylococcus epidermidis: MSSE15-3, MSSE 15-4), 6 strains of enterococcus faecalis (vancomycin sensitive enterococcus: EFA15-1, EFA15-2, EF29212, vancomycin resistant enterococcus: ATCC 3545, ATCC 35 700802 5), vancomycin resistant enterococcus (ATCC 51575), vancomycin resistant enterococcus (ATCC 15-84-42).
2. Culture medium and culture conditions
Staphylococci: MH broth was incubated at 35-37℃for 18-24h for observations.
Other species: conventional MH broth was incubated at 35-37℃for 18-24h for observations.
MH broth formulation: 1% of peptone, 0.3% of beef powder and 0.5% of NaCl.
3. Test method
(1) The method is based on
The procedure for antimicrobial susceptibility testing using the american society of clinical and laboratory standards (Clinical and Laboratory Standards Institute, CLSI) [ Methods for Dilution Antimicrobial Succeptibility Tests for Bacteria That Grow Aerobically; approved Standard-Eleventh Edition, M07-A11,2018) the MIC values of each test sample for the strain tested were determined by the microcyst dilution method recommended.
(2) The specific operation steps are as follows
100. Mu.L of each of the sample solutions of different concentrations was aspirated into wells 1 to 12 of a sterilized 96-well polystyrene plate, so that the final concentrations of the drugs were 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03. Mu.g/mL, respectively (specific concentration ranges were calculated based on the amounts of the drugs). Then 100. Mu.L of the test bacterial liquid (200. Mu.L per well) was added to each well, and the final concentration of the bacterial liquid was about 10 5 CFU/mL. Sealing, culturing in 35-37deg.C incubator for 18-24 hr, and judging the result. The MIC of the test sample was taken as the lowest drug concentration that completely inhibited bacterial growth in the well. A blank bacteria control without any sample and a vehicle control with DMSO were also established.
4. The antibacterial spectrum of the compounds against gram-positive bacteria is shown in table 2.
Experimental example 3: determination of anti-clostridium difficile Activity of Compounds
1. Strain class
Clostridium difficile standard strain ATCC9689 or a clinically isolated strain 18-2 collected in Guangzhou.
2. Culture medium and culture conditions
Brookfield broth was cultured at 37℃for 48 hours in anaerobic conditions.
The formula of the culture medium comprises: 5% (V/V) defibrinated sheep blood, hemin (5 mg/L) and vitamin K1 (1 mg/L).
3. Test method
(1) The method is based on
MIC values of the test samples for the tested strains were determined using agar dilution as recommended by the american society for Clinical and Laboratory Standards (CLSI) antimicrobial susceptibility testing protocol (M11-A8, 2012).
(2) The specific operation steps are as follows
Reinforced broths agar medium was prepared, autoclaved and equilibrated in a 60 ℃ water bath. The DMSO solutions of the samples with different concentrations which are diluted by 2 times are respectively added into the reinforced Brucella broth agar, and are fully and uniformly mixed to prepare 12 concentration gradient test liquid medicines within the range of 320-0.15 mug/mL. Then, 1mL of each test reagent was added to 9mL of agar medium, and 12 concentration drug agar plates in the range of 32-0.015. Mu.g/mL were prepared. Subsequently, 1-2. Mu.l of the bacterial suspension was pipetted into the surface of a drug-containing agar plate using a multi-point inoculator, the inoculum size being about 10 per point 5 CFU, forming plaque with a diameter of 5-8 mm. After inoculation, the cells are placed in an anaerobic environment and incubated for 48 hours at 35 ℃. Bacterial growth was then observed, and the MIC of the test sample was determined at the concentration corresponding to the drug-containing agar plates where no bacterial growth was observed.
4. The activity of the compounds against clostridium difficile is shown in table 3.
Experimental example 4: determination of the anti-mycoplasma pneumoniae Activity of Compounds
1. Strain class
Mycoplasma pneumoniae clinical isolates MP19 and MP standard strain ATCC29342 (M129 strain) in Yunnan region.
2. Test method
In a sterile test tube, liquid culture medium is adopted to prepare liquid medicine with four concentrations of 5, 10, 20 and 40 mug/mL according to a double dilution method. Then, an equal amount of the bacterial liquid (mass concentration 10) 5 CFU/mL), and culturing at 37℃for 18-24 hours. Meanwhile, acetylspiramycin is used as a positive control, and a culture medium control and a strain control are used. The drug activity was judged by observing the change in color of the medium, the control color of the medium was red, and the control color of the strain was yellow. The experiment was repeated twice.
3. The activity of the compounds against mycoplasma pneumoniae is shown in table 4.
Experimental example 5: in vivo protection experiment of systemic infection mice caused by intraperitoneal injection of compound J24 to MRSA
1. Strain class
Compound-sensitive clinical isolate of MRSA strain MRSA15-1
2. Test method
(1) Determination of minimum lethal microbial load
Healthy KM mice weighing about 18-22 g (male and female halves) were randomly divided into 4 groups (5 per group). 4 MRSA15-1 bacterial solutions with different dilution concentrations are sucked, and are respectively injected into mice of corresponding groups intraperitoneally, wherein the injection volume is 25mL/kg. The mice were observed 7-14 days after infection and the number of deaths recorded. The minimum bacterial load resulting in 100% death of mice is the minimum lethal load, which is the infectious bacterial load of the in vivo protection test.
(2) In vivo protection test
Healthy KM mice (male and female halves) weighing about 18-22 g were taken and randomly grouped. Test drug J24 and positive drug linezolid were each in 4 dose groups (8 each). On the day of infection, the minimum lethal dose of MRSA15-1 was intraperitoneally injected into mice, and a model of systemic infection caused by intraperitoneal injection of MRSA15-1 was established. The doses were given by gavage once (co-preventive twice) 6h and 12h before infection, and once (co-2 times) 0h and 6h after infection. Following dosing, mice were observed and recorded for mortality. The half-dose ED50 and 95% confidence limit are calculated according to Bliss method by using DAS1.0 software of Sun Ruiyuan and other main codes according to the death number of mice after continuous observation for 7-14 days. In addition, an infection control group (8, i.e., a normal saline solution of the same volume is administered by lavage at a set time point), a test drug toxicity control group (5, i.e., a normal saline solution of the same volume is administered by intraabdominal injection at a set time point without bacteria), a blank control group (5, i.e., a normal saline solution of the same volume is administered by intragastric injection at a set time point without bacteria), and a normal saline solution of the same volume is administered by intragastric injection at a set time point.
3. The results of the in vivo protection experiments of the compound on mice infected with the system caused by intraperitoneal injection of MRSA are shown in Table 5.
(1) Test agent J24, 40, 20, 10 and 5mg/kg, positive agent linezolid, 20, 10, 5 and 2.5mg/kg;
(2) Test agent J24:9, 3, 1 and 0.3mg/kg, positive agent linezolid 9, 3, 1 and 0.3mg/kg.
TABLE 1 minimum inhibitory concentration of Compounds against Staphylococcus aureus Standard strain ATCC 29213
Table 2. Minimum inhibitory concentrations MIC (μg/mL) of representative compounds for different strains of gram-positive bacteria.
TABLE 3 minimum inhibitory concentration MIC of compounds for Clostridium difficile clinical isolates and standard strains (. Mu.g/mL).
Table 4. Minimum inhibitory concentration MIC (μg/mL) of representative compounds for clinical isolates or standard strains of Mycoplasma pneumoniae.
TABLE 5 in vivo experimental results of J24 administration by intragastric administration to mice on model of systemic infection with Staphylococcus aureus MRSA15-1
Dose set (1)
Dose set (2)

Claims (13)

1. A compound represented by the formula (1) or a pharmaceutically acceptable salt thereof,
wherein:
ar represents a substituted or unsubstituted heteroaryl group, said substituents being selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 One or more of alkynyl groups;
R 1 independently selected from hydrogen;
R 2 selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl;
the C is 1-8 The alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, linear or branched pentyl, linear or branched hexyl, linear or branched heptyl, linear or branched octyl;
R 3 、R 4 each independently selected from hydrogen;
heteroaryl is selected from pyridine, furan, thiazole;
wherein n is 1.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
n- (5- (pyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J18)
N- (5- (furan-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J22)
N- (5- (thiazol-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J24)
N- (5- (5-methylpyridin-2-yl) -1,3, 4-thiadiazol-2-yl) -1-ethyl-4-hydroxy-2-quinolone-3-carboxamide (J29).
3. A process for the preparation of a compound as claimed in claim 1, comprising the steps of:
namely, reacting the intermediate (a) with the intermediate (d) to prepare the compound (1) according to claim 1;
wherein Ar and R 1 、R 2 、R 3 、R 4 N is as defined in claim 1.
4. The production process according to claim 3, wherein the reaction is carried out in the presence of a basic catalyst and a condensing agent.
5. The process according to claim 4, wherein the basic catalyst is selected from inorganic or organic bases; the inorganic base is at least one selected from alkali metal hydroxide, alkaline earth metal hydroxide and alkali metal carbonate; the organic base is selected from triethylamine, pyridine, diethylamine, diisopropylamine, pyridine, N-diisopropylethylamine, N-methylpiperidine and N-methylmorpholine; the condensing agent is selected from 1, 3-dicyclohexylcarbodiimide, N, N ' -diisopropylcarbodiimide, benzotriazole-N, N, N ', N ' -tetramethylurea hexafluorophosphate and a catter condensing agent.
6. The process according to claim 5, wherein the intermediate (a) is prepared by the following process:
wherein Ar, R 4 Is as defined in claim 1.
7. The process according to claim 6, wherein the reaction for producing the intermediate (a) occurs in an organic solvent selected from the group consisting of trifluoroacetic acid, concentrated sulfuric acid, and trifluoromethanesulfonic acid.
8. A process according to claim 3, characterized in that the intermediate (d) is prepared by the following method:
(1) Converting intermediate (b) to intermediate (c), wherein, when R 3 When H is H, reacting the intermediate (b) with diethyl malonate to obtain an intermediate (c);
(2) Converting intermediate (c) to intermediate (d) under alkaline conditions provided by sodium hydroxide, potassium hydroxide or lithium hydroxide;
wherein R is 1 、R 2 、R 3 N is as defined in claim 1.
9. A pharmaceutical composition comprising a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier.
10. The pharmaceutical composition according to claim 9, wherein said pharmaceutical composition is selected from the group consisting of injections, tablets, pills, capsules, suspensions, emulsions or ointments, and the route of administration is selected from the group consisting of intravenous or intramuscular injection, oral administration, transdermal administration, mucosal administration, rectal administration, vaginal administration.
11. Use of a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, for the manufacture of an antibacterial, antimycotic medicament.
12. The use according to claim 11, characterized in that the bacteria are staphylococcus aureus, staphylococcus epidermidis, enterococcus faecalis, enterococcus faecium, clostridium difficile, escherichia coli, pseudomonas aeruginosa, klebsiella pneumoniae, and the mycoplasma is mycoplasma pneumoniae, ureaplasma urealyticum, mycoplasma hominis, mycoplasma genitalium.
13. The use according to claim 12, characterized in that said staphylococcus aureus is methicillin-sensitive staphylococcus aureus, methicillin-resistant staphylococcus aureus, said staphylococcus epidermidis is methicillin-sensitive staphylococcus epidermidis, methicillin-resistant staphylococcus epidermidis, said enterococcus faecium and enterococcus faecium are vancomycin-sensitive enterococcus faecium and enterococcus faecium, vancomycin-resistant enterococcus faecium and enterococcus faecium, said mycoplasma is selected from drug-sensitive mycoplasma pneumoniae or drug-resistant mycoplasma pneumoniae.
CN201910672950.1A 2019-07-24 2019-07-24 Aryl or heteroaryl substituted thiadiazoles compounds and antibacterial application thereof Active CN112279845B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910672950.1A CN112279845B (en) 2019-07-24 2019-07-24 Aryl or heteroaryl substituted thiadiazoles compounds and antibacterial application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910672950.1A CN112279845B (en) 2019-07-24 2019-07-24 Aryl or heteroaryl substituted thiadiazoles compounds and antibacterial application thereof

Publications (2)

Publication Number Publication Date
CN112279845A CN112279845A (en) 2021-01-29
CN112279845B true CN112279845B (en) 2023-07-28

Family

ID=74419018

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910672950.1A Active CN112279845B (en) 2019-07-24 2019-07-24 Aryl or heteroaryl substituted thiadiazoles compounds and antibacterial application thereof

Country Status (1)

Country Link
CN (1) CN112279845B (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013106641A1 (en) * 2012-01-13 2013-07-18 Bristol-Myers Squibb Company Thiazolyl- or thiadiazolyl-substituted pyridyl compounds useful as kinase inhibitors
CN103864776A (en) * 2014-03-19 2014-06-18 山东省医学科学院药物研究所 Tegafur derivative containing 1,3,4-thiadiazole heterocyclic ring and amide group
CN109678883A (en) * 2018-10-31 2019-04-26 河南大学 The preparation and application of double-fluoquinolone thiadiazoles ureas N- acetyl norfloxacin derivatives
KR20190067546A (en) * 2017-12-07 2019-06-17 한국화학연구원 Pharmaceutical composition for prevention or treatment of pneumonia comprising dihydroquinoline carboxamide derivative or pharmacurically acceptable salt thereof as an active ingredient
CN110041306A (en) * 2018-01-15 2019-07-23 中国医学科学院药物研究所 4- hydroxyl -2- quinolone-nitrogen-(4- quinazolinone) -3- carboxamides derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013106641A1 (en) * 2012-01-13 2013-07-18 Bristol-Myers Squibb Company Thiazolyl- or thiadiazolyl-substituted pyridyl compounds useful as kinase inhibitors
CN103864776A (en) * 2014-03-19 2014-06-18 山东省医学科学院药物研究所 Tegafur derivative containing 1,3,4-thiadiazole heterocyclic ring and amide group
KR20190067546A (en) * 2017-12-07 2019-06-17 한국화학연구원 Pharmaceutical composition for prevention or treatment of pneumonia comprising dihydroquinoline carboxamide derivative or pharmacurically acceptable salt thereof as an active ingredient
CN110041306A (en) * 2018-01-15 2019-07-23 中国医学科学院药物研究所 4- hydroxyl -2- quinolone-nitrogen-(4- quinazolinone) -3- carboxamides derivatives
CN109678883A (en) * 2018-10-31 2019-04-26 河南大学 The preparation and application of double-fluoquinolone thiadiazoles ureas N- acetyl norfloxacin derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Natural product-inspired rational design, synthesis and biological evaluation of 2,3-dihydropyrano[2,3-f]chromen-4(8H)-one based hybrids as potential mitochondrial apoptosis inducers";Palaniappan Sakthivel et al.;《European Journal of Medicinal Chemistry》;20160627;第122卷;第302-318页 *

Also Published As

Publication number Publication date
CN112279845A (en) 2021-01-29

Similar Documents

Publication Publication Date Title
US8299065B2 (en) Antibacterial condensed thiazoles
EP1737459B1 (en) Imidazopyridine and imidazopyrimidine derivatives as antibacterial agents
US20100311766A1 (en) Antibacterial compositions
KR20010014030A (en) Quinoline-indole antimicrobial agents, uses and compositions related thereto
CN102827155B (en) Oxazolidinone compounds and application of oxazolidinone compound in preparation of antibiotic medicine
RU2527769C2 (en) 5-hydroxymethyloxazolin-2-one derivatives for treating bacterial intestinal diseases
CN107325093B (en) Synthesis and application of thiourea compound with antibacterial activity
WO2018177218A1 (en) Preparing method for and uses of 3,5-disubstituted methylpyrazolo[1,5-a] pyrimidin-7-phenolate analogues and derivatives
CN110041306B (en) 4-hydroxy-2-quinolone-N- (4-quinazolinone) -3-carboxamide derivatives
CA2405532A1 (en) Pyridoarylphenyl oxazolidinone antibacterials, and related compositions and methods
CN112279845B (en) Aryl or heteroaryl substituted thiadiazoles compounds and antibacterial application thereof
Glinka et al. Relationships between structure, antibacterial activity, serum stability, pharmacokinetics and efficacy in 3-(heteroarylthio) cephems. Discovery of RWJ-333441 (MC-04,546)
Youssif et al. Synthesis and biological evaluation of some novel 1, 2, 3-triazol-N-arylidene Acetohydrazide incorporating benzimidazole ring moiety as potential antimicrobial agents
US6498146B1 (en) Erythromycin derivatives
CN106146559B (en) A kind of preparation method of Oxazolidinone derivative
CN104910177B (en) Aminomethyl triazole-substituted tricyclic fluoroquinolone carboxylic acid derivative and preparation method and application thereof
JP3796612B2 (en) Antibacterial agent
CN110878061B (en) 2-aryl substituted benzoxazoline compound and synthesis method and application thereof
US20080139574A1 (en) Novel quinoline derivatives
CN102329315A (en) Fluoro methoxyimino-substituted nalidixic carboxylic acid compound and preparation method thereof
CA2270124C (en) 9a,11b-dehydro derivatives of 9-oxime-3-keto-6-0-methylerythromycin
CN103755724B (en) Penicillin derivative and uses thereof
CN116102478A (en) Preparation method of 1, 4-dicarbonyl thiosemicarbazide compound and anti-infection application
WO2006018682A2 (en) Oxazolidinone derivatives as antimicrobials
CN104817537A (en) 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolones carboxylic acid derivative, method for preparing same and application of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolones carboxylic acid derivative

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant