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WO2018177218A1 - Preparing method for and uses of 3,5-disubstituted methylpyrazolo[1,5-a] pyrimidin-7-phenolate analogues and derivatives - Google Patents

Preparing method for and uses of 3,5-disubstituted methylpyrazolo[1,5-a] pyrimidin-7-phenolate analogues and derivatives Download PDF

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WO2018177218A1
WO2018177218A1 PCT/CN2018/080281 CN2018080281W WO2018177218A1 WO 2018177218 A1 WO2018177218 A1 WO 2018177218A1 CN 2018080281 W CN2018080281 W CN 2018080281W WO 2018177218 A1 WO2018177218 A1 WO 2018177218A1
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difluorophenyl
methylpyrazolo
pyrimidin
sodium
pyrimidine
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PCT/CN2018/080281
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French (fr)
Chinese (zh)
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徐利锋
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辽宁利锋科技开发有限公司
徐利锋
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • 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

Definitions

  • the present invention relates to 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs as antibacterial and antibiotic Discovery of fungal activity, medicinal chemistry research and preparation methods.
  • the invention also relates to the use of such compounds as medicaments for diseases such as antibacterial and antifungal agents.
  • the effective antibacterial drugs used may have drug-resistant strains, which are resistant to various antibacterial drugs, such as methicillin-resistant Staphylococcus aureus (called super bacteria). MRSA), vancomycin-resistant enterococci (VRE), etc.
  • super bacteria methicillin-resistant Staphylococcus aureus
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant enterococci
  • the spread of infection "super bacteria” has become a serious threat to human health, so the development of new antibacterial drugs that are active against resistant bacteria is already imminent.
  • the present invention has a 3-(2,4-difluorophenyl)-5-substituted structure of the compound represented by the structural formula I.
  • the patented inventions and articles on the antibacterial and antifungal biological activity of the 2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs have not been reported.
  • the object of the present invention is to provide a chemistry of a 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivative. Synthesis and preparation, having the following formulas and prodrugs, and providing their preparation, pharmacological activity test methods and pharmacologically active applications.
  • M + as defined by structural formula I is: Li + , K + , Na + , Ca + /2, Mg + /2, one of Cu + /2 and Fe + /2, which can pass through heterocyclic phenolic hydroxyl groups and various
  • the alkali and the alkali metal are reacted to form a salt, for example, an inorganic base such as metal Li, metal Na, metal K, sodium carbonate, sodium hydride, sodium hydroxide or potassium hydroxide, or an organic base to form a phenate or a double salt;
  • the atom is alkaline and can form a mineral acid salt, an organic acid salt or an acid by reacting with an acid such as hydrochloric acid, sulfuric acid, nitric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid or the like.
  • Double salt is: Li + , K + , Na + , Ca +
  • R of the formula I is H, an optionally substituted aryl ring group, an alicyclic group and/or an aromatic ring fused ring combination, which may be a substituent 1, 2, 3, 4, 5 in the formula II.
  • X of the formula II may be absent, may be the same or different substituents, and is optionally substituted hydrogen, halogen, hydroxy, thiol, cyano, carbonyl, substituted carbonyl, aldehyde, keto, nitro, carboxy , substituted carboxyl, carboxylate, secondary, tertiary, di, tri, tetra, penta or hexaalkyloxy, arylalkoxy, aryloxy, heteroaryloxy, alkane Thio group, decyl ester group, arylalkylthio group, arylthio group, heteroarylthio group, ester group, acyloxy group, phosphoric acidoxy group, sulfonic acidoxy group, aromatic oxy group, quaternary ammonium salt group, amide group, Sulfhydryl, fluorenyl, fluorenyl, nitrogen-containing aliphatic hydrocarbon group, nitrogen-containing aromatic hydrocarbon group, nitrogen-containing cyclo
  • Respiratory infections urinary tract infections, skin and soft tissue infections, sepsis, bone and joint infections, and abdominal, pelvic infections, hemolytic streptococcus, pneumococci, and Staphylococcus aureus infections caused by sensitive strains; Streptococcus viridans and Endocarditis caused by Enterococcus and gas gangrene, anaerobic infection, anthrax, syphilis, gonorrhea, etc.
  • the administration route of the pharmaceutical compound of the present invention includes: oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, sheath Administration is carried out intraluminally, intracranically, intranasally or topically.
  • the preparation method is characterized in that: the intermediate reaction is carried out by a cyclization reaction under the action of a catalyst, and an ethyl carbonyl compound containing various substituents is reacted with 4-(2,4-difluorophenyl) under the action of a catalyst.
  • the -3-methyl-1H-pyrazole-5-amine reacts to form a CN bond, completing the cyclization reaction.
  • the catalyst is one of a dehydrating agent, an organic acid and/or a mineral acid catalyst, and uses tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethyl B.
  • One of the amide, n-hexane, toluene and the like is a solvent, and the reaction temperature is controlled at -40 ° C to 180 ° C to form a key intermediate 2,3-(2,4-difluorophenyl)-2-methyl Pyrazolo[1,5-a]pyrimidin-7-phenol, the reaction formula is as follows:
  • 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs are prepared by: Under the action of a base, one of the following reagents (tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, etc.) is used as a solvent. The reaction temperature is controlled at -40 ° C to 180 ° C to form a phenate compound 3, the reaction formula is as follows:
  • the pharmaceutically acceptable salts of the compounds of the invention are also within the scope of the invention, the acid of which can be converted to a salt by reaction with a base such as sodium carbonate, sodium hydride, potassium hydroxide or the like.
  • a base such as sodium carbonate, sodium hydride, potassium hydroxide or the like.
  • the structure containing a nitrogen atom is basic and can be converted into a salt such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid or the like by reaction with an acid.
  • Prodrugs of the compounds of the invention are also within the scope of the invention.
  • the medicament of the present invention can be modified into a prodrug to increase its water solubility and molecular volume, and to reduce its toxicity.
  • Standard strains Bacillus cereus 2, Bacillus subtilis 168, Enterococcus faecalis 29212, Enterococcus faecalis F2518 (vre), Staphylococcus aureus 29231, Staphylococcus aureus 43300 (MRSA), Staphylococcus aureus 703 ( MRSA), Streptococcus pneumoniae 6303 (PRSP), Streptococcus pneumoniae M2, Streptococcus agalactia B group, Streptococcus pneumoniae 10351, Bacillus anthracis, Diphtheria, Clostridium perfringens, Oral Candida, Peel fungus.
  • Test sample Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8,
  • Sterilization The required experimental equipment and culture solution were autoclaved at 121 ° C for 30 min; sterile ultraviolet irradiation for 30 min.
  • Preparation of broth culture medium Accurately weigh 6 g of tryptic soy broth culture medium in a 500 ml beaker, add 200 ml of distilled water, fully dissolve by heating, transfer into a conical flask, add a cotton plug, and wrap the autoclave.
  • slant culture medium 3.8 g of tryptic soy agar was weighed into a 500 ml beaker, 100 ml of distilled water was added, dissolved sufficiently by heating, transferred into an Erlenmeyer flask, tampon added, and autoclaved by dressing. After a little cooling, it is divided into 7 tubes, about 10-15 ml per tube, tilted at an appropriate angle, and cooled for later use.
  • Bacterial amplification Open the ATCC 4300 sealed vial, take a small amount of bacterial powder block with a small ophthalmology clip after disinfection, transfer it into a 5 ml centrifuge tube, add 0.6 ml of tryptic soy broth medium, and mix well. The average was divided into 7 slant mediums, 80 ⁇ l/test tube, and evenly coated. It was placed in an incubator and cultured at 37 ° C for 24 hours.
  • Preparation of bacterial suspension and bacterial count The bacteria in the large test tube were washed with the culture solution and transferred into a sterile centrifuge tube. Mix well and prepare a bacterial suspension. A drop of the pipette was taken for bacterial density determination. Take a clean blood cell counting plate, cover a counting piece on the counting area, dilute the bacterial suspension with physiological saline for a certain multiple, and blow evenly. Pipette a little, from the sides of the intermediate plate of the counting plate. A drop (not too much) is dropped into the groove along the lower edge of the cover glass, so that the bacterial suspension fills the counting area with the surface tension of the liquid, so that bubbles are not generated. The plate was placed under a microscope for bacterial count. Count the total number of bacteria in 16 cells, and calculate the concentration of the bacteria using the following formula:
  • Bacterial density (pieces/ml) 16 small bacteria number ⁇ 10 4 ⁇ dilution factor
  • Preparation of the sample First, the drug to be tested is fully dissolved in a small amount of DMSO, and then the culture medium is formulated into a desired initial concentration, and sequentially diluted to each test gradient.
  • Preparation of bacterial solution According to the measurement result of the bacterial concentration, the bacterial suspension was diluted with a culture solution (TSB) to a bacterial solution having a concentration of 1.07 ⁇ 10 7 cf ⁇ / ml.
  • TBS culture solution
  • Dosing regimen The experiment was divided into positive control group, normal saline group, blank control group and each test group. Among them, there were 6 gradient wells in each test group, saline group and blank group. The positive control group was 7 gradient holes. 50 ⁇ l of the bacterial suspension, 30 ⁇ l of the culture solution, and 20 ⁇ l of each sample solution were sequentially added to each well.
  • the 96-well plate was added and placed in an incubator for cultivation.
  • the culture temperature was 37 ° C and the culture time was 24 hours.
  • the cultivation was completed in a clean bench to observe the growth of colonies in each group.
  • the bacterial liquid is clear, no turbidity, and the bottom of the well is aseptic.
  • the concentration is determined as the minimum inhibitory concentration (MIC) of the drug.
  • - represents MIC value ( ⁇ M) > 150 ⁇ g / mL
  • + represents MIC value ( ⁇ M) ⁇ 150 ⁇ g / / mL
  • ++ represents MIC value ( ⁇ M) ⁇ 100 ⁇ g / / mL
  • + + + represents MIC value ( ⁇ M) ⁇ 50 ⁇ g //mL.
  • Table 2 shows that the compounds of the examples of the present invention have excellent antibacterial activity.
  • Test sample Compound 3, Compound 5, Compound 9, Compound 10, Compound 30, Compound 1, Compound 2
  • Test animals Kunming healthy mice, weighing 19-21 g, male and female, are divided into groups, and other groups are used by single sex. They are provided by the Animal Center of the Institute of Materia Medica, Beijing Academy of Military Medical Sciences.
  • mice were randomly divided into a blank control group, a positive control group, and a test drug group, with 10 rats in each group, half male and half female.
  • the mouse body weight 0.2ml/10g abdominal cavity bacteria (MRSA-2152)
  • the bacterial concentration was 5.0 ⁇ 10 6 cfu/ml
  • the tail vein injection was administered, and after 6 hours, the second dose was administered.
  • the survival period of each group of animals was recorded, and the life extension rate of the positive control group and the sample group was calculated:
  • Life extension rate% (the number of days in the test group - the number of days in the blank group) / the number of days in the blank group ⁇ 100%
  • Compound 2 is compound 5 + ciprofloxacin, ratio 1:1

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
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Abstract

An object of the present invention is to provide: as an invention of an antibacterial and antifungal activity, 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a] pyrimidin-7-phenolate derivatives and analogues having the following general formula or prodrug, a preparation method and pharmacological activity test procedure therefor, and the pharmacological activity thereof; and a pharmaceutical chemical research and preparation method, and uses of the compounds as antibacterial and antifungal drugs. The definitions of R and M + in the general formula I are set forth in the description. The 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a] pyrimidin-7-phenolate derivatives and analogues of the formula I of the present application can be compatible with the other known antibacterial and antifungal drugs and drugs for treating bacterial infections with various complications, such as inflammation, viruses and immune system diseases.

Description

3,5-二取代甲基吡唑并[1,5-a]嘧啶-7-酚盐类似物和衍生物制备方法和用途Preparation method and use of 3,5-disubstituted methylpyrazolo[1,5-a]pyrimidin-7-phenolate analogs and derivatives 发明领域Field of invention
本发明涉及3-(2,4-二氟苯基)-5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物作为抗菌和抗真菌活性的发现，药物化学研究和制备方法。本发明还涉及该类化合物作为抗菌和抗真菌等疾病药物的应用。The present invention relates to 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs as antibacterial and antibiotic Discovery of fungal activity, medicinal chemistry research and preparation methods. The invention also relates to the use of such compounds as medicaments for diseases such as antibacterial and antifungal agents.
背景技术Background technique
由于大量抗菌药品滥用，所用有效的抗菌药物都有可能出现耐药菌株,对多种抗菌药物呈现耐药性,如产生了称之为“超级细菌”的甲氧西林耐药金黄色葡萄球菌(MRSA)，耐万古霉素肠球菌(VRE)等。感染“超级细菌”的蔓延已构成对人类健康的严重威胁，因此研发出新的对耐药菌具有活性的抗菌药已经是迫在眉睫。Due to the abuse of a large number of antibacterial drugs, the effective antibacterial drugs used may have drug-resistant strains, which are resistant to various antibacterial drugs, such as methicillin-resistant Staphylococcus aureus (called super bacteria). MRSA), vancomycin-resistant enterococci (VRE), etc. The spread of infection "super bacteria" has become a serious threat to human health, so the development of new antibacterial drugs that are active against resistant bacteria is already imminent.
检索全部文献，还没有发现有关3-(2,4-二氟苯基)-5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类具有抗菌和抗真菌活性用途的报道。其它不同结构，只是在结构母核具有相似性的化合物所发明的生物活性研究专利有：WO 2008062026、EP 2086947和US 20130252951，这些专利所发明化合物与本发明化合物结构不同，只是在母核结构具有相似性，其生物活性及应用适应症也是与本发明无关，它们都是用于抗炎治疗；US 20160022742所发明化合物与本发明化合物不同，只是在母核结构具有相似性，其生物活性及应用也是与本发明无关，是用于肝功能紊乱治疗。Search all the literatures and have not found any antibacterial and antibiotics related to 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate Reports on the use of fungal activity. Other biologically active research patents of different structures, such as compounds having similarities in the structural nucleus are: WO 2008062026, EP 2086947 and US 20130252951, the compounds of the invention are different in structure from the compounds of the present invention, but have a structure in the parent core. Similarity, its biological activity and application indications are also not related to the present invention, they are all used for anti-inflammatory treatment; the compound of the invention of US 20160022742 is different from the compound of the present invention, only has similarity in the structure of the mother nucleus, its biological activity and application. It is also irrelevant to the present invention and is used for the treatment of liver dysfunction.
综上所述，迄今为止检索全部文献，在化学结构、合成和治疗作用应用方面，本发明以结构通式I所表示的化合物结构3-(2,4-二氟苯基)-5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物、这些化合物的抗菌和抗真菌生物活性应用的专利发明和文章还没见报道。In summary, all the literatures have been searched to date, and in the application of chemical structure, synthesis and therapeutic effects, the present invention has a 3-(2,4-difluorophenyl)-5-substituted structure of the compound represented by the structural formula I. The patented inventions and articles on the antibacterial and antifungal biological activity of the 2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs have not been reported.
发明内容Summary of the invention
本发明的目的是提供一种3-(2,4-二氟苯基)-5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物的化学合成与制备，具有下列结通式及前药，并提供它们的制备、药理活性实验方法及药理活性应用。The object of the present invention is to provide a chemistry of a 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivative. Synthesis and preparation, having the following formulas and prodrugs, and providing their preparation, pharmacological activity test methods and pharmacologically active applications.
本发明的目的是这样实现的，其分子式结构如下：The object of the present invention is achieved in that the molecular formula is as follows:
Figure PCTCN2018080281-appb-000001
Figure PCTCN2018080281-appb-000001
其中结构式I所述的M +为：Li +、K +、Na +、Ca +/2,Mg +/2,Cu +/2和Fe +/2之一，可通过杂环酚羟基和各种碱及碱金属反应成盐，例如金属Li、金属Na、金属K、碳酸钠、氢化钠、氢氧化钠、氢氧化钾等无机碱、有机碱形成酚盐或复盐；结构式I所述含有氮原子具有碱性可通过和酸，如盐酸、硫酸、硝酸、富马酸、马来酸、琥珀酸、乙酸、柠檬酸、酒石酸、碳酸、磷酸、草酸等反应形成无机酸盐、有机酸盐或复盐。 Wherein M + as defined by structural formula I is: Li + , K + , Na + , Ca + /2, Mg + /2, one of Cu + /2 and Fe + /2, which can pass through heterocyclic phenolic hydroxyl groups and various The alkali and the alkali metal are reacted to form a salt, for example, an inorganic base such as metal Li, metal Na, metal K, sodium carbonate, sodium hydride, sodium hydroxide or potassium hydroxide, or an organic base to form a phenate or a double salt; The atom is alkaline and can form a mineral acid salt, an organic acid salt or an acid by reacting with an acid such as hydrochloric acid, sulfuric acid, nitric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid or the like. Double salt.
其中结构式I所述的3-(2,4-二氟苯基)--5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物，结构式I所述的R为H、任意取代的芳环基、脂环基和/或芳环与脂环稠合组合基，可为结构式II中取代基1、2、3、4、5、6、7、8和9之一，其中化学结构8和9芳环所稠脂环为三碳、四碳或五碳脂环。3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs of the formula I R of the formula I is H, an optionally substituted aryl ring group, an alicyclic group and/or an aromatic ring fused ring combination, which may be a substituent 1, 2, 3, 4, 5 in the formula II. One of 6, 7, 8, and 9, wherein the alicyclic ring of the chemical structure 8 and 9 aromatic rings is a three carbon, four carbon or five carbon alicyclic ring.
Figure PCTCN2018080281-appb-000002
Figure PCTCN2018080281-appb-000002
其中结构式II所述的X可不存在、可分别为相同或不相同取代基，为任意取代的氢、卤素、羟基、巯基、氰基、羰基、取代羰基、醛基、酮基、硝基、羧基、取代羧基、羧酸酯基、仲氨基、叔氨基、二碳、三碳、四碳、五碳或六碳烷基氧基、芳基烷氧基、芳氧基、杂芳氧基、烷硫基、巯酯基、芳基烷硫基、芳硫基、杂芳硫基、酯基、酰氧基、磷酸氧基、磺酸氧基、芳香氧基、季铵盐基、酰胺基、肼基、肟基、腙基、含氮脂肪烃基、含氮芳香烃基、含氮环基、含氮脂环基、含氮芳香环基、含氮芳杂环基、磷化物基、磷酸基、磷酸酯基、一碳、二碳、三碳、四碳或五碳烷基以及与这些取代基组合基。Wherein X of the formula II may be absent, may be the same or different substituents, and is optionally substituted hydrogen, halogen, hydroxy, thiol, cyano, carbonyl, substituted carbonyl, aldehyde, keto, nitro, carboxy , substituted carboxyl, carboxylate, secondary, tertiary, di, tri, tetra, penta or hexaalkyloxy, arylalkoxy, aryloxy, heteroaryloxy, alkane Thio group, decyl ester group, arylalkylthio group, arylthio group, heteroarylthio group, ester group, acyloxy group, phosphoric acidoxy group, sulfonic acidoxy group, aromatic oxy group, quaternary ammonium salt group, amide group, Sulfhydryl, fluorenyl, fluorenyl, nitrogen-containing aliphatic hydrocarbon group, nitrogen-containing aromatic hydrocarbon group, nitrogen-containing cyclic group, nitrogen-containing alicyclic group, nitrogen-containing aromatic ring group, nitrogen-containing aromatic heterocyclic group, phosphide group, phosphoric acid group, Phosphate groups, mono-, di-, tri-, tetra- or penta-alkyl groups and combinations with these substituents.
结构式I所述,3-(2,4-二氟苯基)-5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物，包括抗菌药理活性和作为抗菌药物的应用，抗真菌药理活性和作为抗真菌药物的应用，包括与其它已知的抗菌、抗真菌、抗炎和抗病毒及免疫药物配伍使用，还包括对细菌感染伴随的炎症和炎症疾病、真菌和真菌疾病、病毒和病毒性疾病以及免疫系统疾病等与细菌感染的并发症的治疗药物配伍使用、其单独或与已知的下述药物配合使用的给药剂量为0.02mg/kg-250mg/kg(静脉、肌肉注射、口服、局部用药等给药途径)；各种方法治疗和途径治疗，其中该细菌为革兰氏阳性菌：葡萄球菌、肺炎球菌、粪肠球菌、链球菌、牛链球菌，肺炎链球菌、消化链球菌、化脓肺炎链球菌、化脓肺炎链球菌、化脓性链球菌、无乳链球菌、 绿色链球菌、牛链球菌、无乳链球菌B、组绿色链球菌、白喉杆菌、破伤风杆菌、丹毒杆菌、炭疽杆菌、破伤风杆菌、蜡样芽孢杆菌、枯草芽胞杆菌、梭状芽孢杆菌、蜡样芽孢杆菌、枯草芽胞杆菌、炭疽杆菌、白喉杆菌、梭状芽孢杆菌、破伤风杆菌、产气荚膜杆菌、产气荚膜杆菌螺旋体、放线菌、结核菌，其中该细菌为革兰氏阳性耐药菌，耐甲氧西林葡萄球菌、耐万古霉素金葡菌、葡萄球菌属诱导型克林霉素耐药、耐万古霉素肠球菌、肠球菌高水平耐氨基糖苷类、耐青霉素肺炎链球菌、多重耐药鲍曼不动杆菌、耐药与多重耐药结核杆菌与结核分枝杆菌、链球菌、粪肠球菌、铜绿假单胞菌、大肠埃希氏菌及鮑氏不动桿菌等、耐药流感嗜血杆菌、耐药淋球菌、耐药脑膜炎奈瑟菌、耐药肠杆菌科细菌、耐药铜绿假单胞菌。3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs, including Antibacterial pharmacological activity and application as an antibacterial, antifungal pharmacological activity and as an antifungal drug, including compatibility with other known antibacterial, antifungal, anti-inflammatory and antiviral and immunological drugs, including bacterial infections Inflammatory and inflammatory diseases, fungal and fungal diseases, viral and viral diseases, and immune system diseases, etc., which are used in combination with therapeutic agents for complications of bacterial infection, alone or in combination with known drugs, are administered at a dose of 0.02mg/kg-250mg/kg (intravenous, intramuscular, oral, topical, etc.); various methods of treatment and route treatment, wherein the bacteria are Gram-positive bacteria: staphylococcus, pneumococcal, fecal Cocci, Streptococcus, Streptococcus bovis, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus mutans, Streptococcus bovis, Streptococcus agalactiae Group of green streptococci Diphtheria, tetanus, erysipelas, Bacillus anthracis, tetanus, Bacillus cereus, Bacillus subtilis, Clostridium, Bacillus cereus, Bacillus subtilis, Bacillus anthracis, diphtheria, Clostridium , tetanus bacillus, Clostridium perfringens, Clostridium perfringens, actinomycetes, tuberculosis, wherein the bacteria are Gram-positive bacteria, methicillin-resistant Staphylococcus, vancomycin-resistant Bacteria, Staphylococcus inducible clindamycin resistance, vancomycin-resistant Enterococcus, Enterococcus high-grade aminoglycosides, penicillin-resistant Streptococcus pneumoniae, multi-drug resistant Acinetobacter baumannii, drug resistance and multiple resistance Mycobacterium tuberculosis and Mycobacterium tuberculosis, Streptococcus, Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli and Acinetobacter baumannii, drug-resistant Haemophilus influenzae, drug-resistant gonococcal, drug-resistant meninges Neisseria faecalis, resistant Enterobacteriaceae, and resistant Pseudomonas aeruginosa.
所述结构式I，3-(2,4-二氟苯基)-5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物具体化合物结构见表1，实施例1至实施例33，但不局限于实施例：The specific compound of the formula I, 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs The structure is shown in Table 1, Embodiment 1 to Embodiment 33, but is not limited to the embodiment:
3-(2,4-二氟苯基)-2-甲基-5-(4-(三氟甲基)苯基)吡唑并[1,5-a]嘧啶-7-酚钠、5-(4-氰基苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(4-硝基苯基)吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-5-(4-甲氧基苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-5-(4-(二甲氨基)苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(4-酚钠基)-吡唑并[1,5-a]嘧啶-7-酚钠、5-(4-羧酸钠苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、5-(4-磺酸钠苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(4-氨磺酰基苯基)吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(4-苯氧基苯基)吡唑并[1,5-a]嘧啶-7-酚钠、5-(4-甲酰基苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3,5-双(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、5-(4-乙氧基苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(6-(三氟甲基)吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠、5-(6-氰基吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(6-硝基吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-5-(6-甲氧基吡啶-3-基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-5-(6-(二甲氨基)吡啶-3-基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-5-(6-酚钠吡啶-3-基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、5-(4-氰基苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钾、5-(6-羧酸钠吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(4-(三氟甲基)苯基)吡唑并[1,5-a]嘧啶-7-酚钾、3-(2,4-二氟苯基)-2-甲基-5-(4-硝基苯基)吡唑并[1,5-a]嘧啶-7-酚钾、3-(2,4-二氟苯基)-5-(4-(二甲氨基)苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钾、3-(2,4-二氟苯基)-2-甲基-5-(4-氨磺酰基苯基)吡唑并[1,5-a]嘧啶-7-酚钾、3-(2,4-二氟苯基)-2-甲基-5-(6-(三氟甲基)吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钾、5-(6-氰基吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钾、3-(2,4-二氟苯基)-2-甲基-5-(6-亚磺酸钠吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(6-氨磺酰基吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(6-苯氧基吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-5-(4-((2-(二甲氨基)乙基)氨基甲酰基)苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、5-(6-甲酰基吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、5-(6-乙酰氧基吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠。3-(2,4-difluorophenyl)-2-methyl-5-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-7-phenol sodium, 5 -(4-cyanophenyl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4 -difluorophenyl)-2-methyl-5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7-phenolate, 3-(2,4-difluorophenyl -5-(4-Methoxyphenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4-difluorophenyl)-5- (4-(Dimethylamino)phenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4-difluorophenyl)-2-methyl -5-(4-phenol sodium)-pyrazolo[1,5-a]pyrimidine-7-phenol sodium, 5-(4-carboxylate phenyl)-3-(2,4-difluorobenzene 2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 5-(4-sulfonic acid sodium phenyl)-3-(2,4-difluorophenyl)-2 -methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4-difluorophenyl)-2-methyl-5-(4-sulfamoylphenyl)pyridinium Zoxa[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4-difluorophenyl)-2-methyl-5-(4-phenoxyphenyl)pyrazolo[1 , 5-a] pyrimidine-7-phenol sodium, 5-(4-formylphenyl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a] Pyrimidine-7-phenol sodium, 3,5-bis(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenol , 5-(4-ethoxyphenyl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-( 2,4-Difluorophenyl)-2-methyl-5-(6-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-7-phenol sodium, 5 -(6-Cyanopyridin-3-yl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-( 2,4-difluorophenyl)-2-methyl-5-(6-nitropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-phenolate sodium, 3-(2, 4-difluorophenyl)-5-(6-methoxypyridin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate sodium, 3-(2,4 -difluorophenyl)-5-(6-(dimethylamino)pyridin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate sodium, 3-(2, 4-difluorophenyl)-5-(6-phenol sodium pyridin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 5-(4-cyano group Phenyl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol potassium, 5-(6-carboxylatepyridine-3- 3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4-difluorophenyl)- 2-methyl-5-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-phenol potassium, 3-(2,4-difluorophenyl)-2 -methyl-5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidine-7-phenol potassium, 3-(2,4-difluorobenzene -5-(4-(Dimethylamino)phenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol potassium, 3-(2,4-difluorophenyl)- 2-methyl-5-(4-sulfamoylphenyl)pyrazolo[1,5-a]pyrimidin-7-phenol potassium, 3-(2,4-difluorophenyl)-2-methyl -5-(6-(Trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-phenol potassium, 5-(6-cyanopyridin-3-yl)-3 -(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol potassium, 3-(2,4-difluorophenyl)-2-methyl -5-(6-Sodium sulfinate-pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-phenolate, 3-(2,4-difluorophenyl)-2-methyl -5-(6-sulfamoylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4-difluorophenyl)-2-methyl- 5-(6-phenoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4-difluorophenyl)-5-(4-( (2-(Dimethylamino)ethyl)carbamoyl)phenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 5-(6-formylpyridine-3 -yl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 5-(6-acetoxypyridine-3- Sodium (3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate.
结构式I所述的3-(2,4-二氟苯基)-5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物的药理活性和作为抗菌和抗真菌药物的应用，所述细菌和真菌等感染所造成的各种感染还包括对细菌感染伴随的炎症和炎症疾病、真菌和真菌疾病、病毒和病毒性疾病以及免疫系统疾病的并发症：甲氧西林敏感葡萄球菌、溶血性链球菌和肺炎链球菌所致的上、下呼吸道感染、皮肤软组织感染、尿路感染、败血症、心内膜炎等；亦可用于流感嗜血杆菌、奇异变形杆菌、大肠埃希菌敏感株所致的尿路感染以及肺炎，链球菌属、肺炎链球菌等革兰阳性球菌、以及流感嗜血杆菌、大肠埃希菌、奇异变形杆菌等中的敏感株所致的呼吸道感染、尿路感染、皮肤软组织感染、败血症、骨、关节感染和腹腔、盆腔感染，溶血性链球菌、肺炎球菌、敏感金葡菌等感染；草绿色链球菌和肠球菌所致心内膜炎以及气性坏疽、厌氧菌感染、炭疽、梅毒、淋病等。Pharmacology of 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs of formula I Activity and as an antibacterial and antifungal drug, various infections caused by infections such as bacteria and fungi include inflammation and inflammatory diseases accompanying bacterial infections, fungal and fungal diseases, viral and viral diseases, and immune system diseases. Complications: methicillin-sensitive staphylococcus, hemolytic streptococcus and upper and lower respiratory tract infections caused by S. pneumoniae, skin and soft tissue infections, urinary tract infections, sepsis, endocarditis, etc.; Urinary tract infections caused by bacilli, Proteus mirabilis, Escherichia coli sensitive strains, pneumonia, Gram-positive cocci, such as Streptococcus, Streptococcus pneumoniae, and Haemophilus influenzae, Escherichia coli, Proteus mirabilis, etc. Respiratory infections, urinary tract infections, skin and soft tissue infections, sepsis, bone and joint infections, and abdominal, pelvic infections, hemolytic streptococcus, pneumococci, and Staphylococcus aureus infections caused by sensitive strains; Streptococcus viridans and Endocarditis caused by Enterococcus and gas gangrene, anaerobic infection, anthrax, syphilis, gonorrhea, etc.
结构式I所述的3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物及其用途，其中该化合物与至少选自以下一种或其组合已知的抗菌剂、抗真菌剂、抗炎剂或该试剂的可药用盐或前药一起配伍或联合用药，但不局限于以下药物，其中，包括：β-内酰胺类：青霉素、普鲁卡因青霉素、苄星青霉素、甲氧西林、苯唑西林、氯唑西林、双氯西林钠、氨苄西林、阿莫西林、海他西林、羧苄西林、磺苄西林、替莫西林、呋苄西林、哌拉西林、阿洛西林、美洛西林、替卡西林、美西林、阿帕西林、阿扑西林、仑氨西林、氟氯西林、舒他西林、匹氨西林、酞氨西林、巴氨西林、卡茚西林、呋布西林、头孢曲松、头孢匹罗、头孢呋辛、头孢呋辛酯、头孢噻肟、头孢噻吩、头孢噻啶、头孢硫脒、头孢乙腈、头孢匹林、头孢唑林、头孢甲肟、头孢哌酮、头孢克洛、头孢唑肟、头孢他啶、头孢尼西、头孢地尼、头孢克肟、头孢拉宗、头孢匹胺、头孢咪唑、头孢特仑、头孢泊肟酯、头孢地秦、头孢替安、头孢他美、头孢唑南、头孢丙烯、头孢布烯、头孢吡肟、头孢氨苄、头孢拉定、头孢克罗、头孢曲秦、头孢羟氨苄、头孢孟多、头孢磺啶、头孢西丁、头孢美唑、头孢替坦、头孢米诺、拉氧头孢、头孢卡品酯、头孢唑兰、头孢替安、头孢雷特、头孢克定、头孢噻利、氯碳头孢、氟氧头孢，大环内酯类：地红霉素、罗红霉素、罗地霉素、克拉霉素、氟红霉素、阿奇霉素、罗他霉素、他克美司、红霉素、依托红霉素、克拉霉素、吉他霉素、麦白霉素、柱晶白霉素、麦迪霉素、阿奇霉素、交沙霉素、螺旋霉素、乙酰螺旋霉素，氨基糖苷类：奈替米星、阿司米星、阿贝卡星、异帕米星链霉素、卡拉霉素、庆大霉素、妥布霉素、阿米卡星、西索米星、新霉素、巴龙霉素、福提米星、小诺米星、异帕米星、地贝米星、达地米星、大观霉素、链霉素、卡那霉素、依替米星、地贝卡星，酰胺醇类：氯霉素、琥珀氯霉素、棕榈氯霉素、甲砜霉素，林可霉素、克林霉素、克林霉素磷酸酯，多肽多烯类：环孢素、替考拉宁、培洛霉素多粘菌素、多粘霉素、万古霉素、去甲万古霉素、杆菌肽、多粘菌素B、夫西地酸、米卡霉素，利福霉素类：利福布汀、利福喷汀、利福昔明、利福平、利福霉素、利福定，喹诺酮类药物：依诺沙星、托氟沙星、诺氟沙星、环丙沙星、洛美沙星、司氟沙星、培氟沙星、氟罗沙星、替马沙星、沙氟沙星、莫西沙星、特伐沙星、格帕沙星、氧氟沙星、左氧氟沙星、帕楚沙星、芦氟沙星、磺胺异恶唑、磺胺甲恶唑、磺胺嘧啶、磺胺醋酰钠、磺胺嘧啶银、甲氧苄啶、吡哌酸、呋喃妥因、呋喃唑酮，萘啶酸，氨氟沙星、加替沙星、帕珠沙星、曲氟沙星、酸莫西沙星，四环素类：四环素，甲烯土霉素，米诺环素，金霉素，强力霉素，土霉素、多西环素、美他环素、地美环素、胍甲环素，β-内酰胺酶抑制剂：克拉维酸、舒巴坦、三唑巴坦，碳青霉烯类抗生素：亚胺培南、西司他丁、帕尼培南、倍他米隆、美罗培南、头霉素，磺胺类：磺胺米隆、磺胺二甲嘧啶、磺胺二甲异嘧啶、磺胺苯吡唑、磺胺间甲氧嘧啶、碘胺对甲氧嘧啶、碘胺多辛、磺胺脒、磺胺嘧啶锌、磺胺林、琥珀磺胺噻唑、联磺甲氧苄啶、酞磺胺噻唑、硫霉素、克拉维酸、氨曲南、亚胺培南、法罗培南、西司他丁、舒巴坦、三唑巴坦、卡芦莫南、西索米星、氯霉素棕榈酸酯、磷霉素、SV、溴莫普林、奥替尼啶、乌洛托品、孟德立胺、次水杨酸铋、甲硝唑磷酸二钠、舒哌酮、新灭菌、甲 硝唑，阿柔比星、表柔比星、佐柔比星、吡柔比星、伊达比星、莫匹罗星、硝咪唑、替硝唑、吡哌酸、呋喃妥因，硝基呋喃类：呋喃唑酮、甲氧苄啶，甲基呋喃类：柳氮磺吡啶，抗真菌类：硫康唑、拉诺康唑、齐诺康唑、布康唑、氯康唑、硝酸芬替康唑、舍他康唑、奥昔康唑、联苯苄唑、氟康唑、伊曲康唑、沙康唑、克霉唑、益康唑、噻康唑、咪康唑、酮康唑、萘替芬、布替萘芬、环吡酮、阿莫罗芬、两性霉素B、球红霉素、氟胞嘧啶、特比奈芬、制霉菌素、灰黄霉素、克念菌素。3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs of the formula I, wherein The compound is compatible or combined with an antibacterial agent, an antifungal agent, an anti-inflammatory agent or a pharmaceutically acceptable salt or prodrug of the agent, which is at least one selected from the group consisting of, but not limited to, the following: Including: β-lactams: penicillin, procaine penicillin, benzathine penicillin, methicillin, oxacillin, cloxacillin, dicloxacillin sodium, ampicillin, amoxicillin, hetacillin, carboxybenzyl Xilin, sulfacillin, temocillin, furazocillin, piperacillin, azlocillin, mezlocillin, ticarcillin, mecillin, apacillin, apocillin, lenampicillin, flucloxacillin, sulphate Hecilin, piramacillin, acesulfamecil, bacilcillin, carbocillin, furbutacil, ceftriaxone, cefpirome, cefuroxime, cefuroxime axetil, cefotaxime, cefotaxime, cefotaxime , cefathiamidine, cefotaxime, cefpirin, cefazolin, cefmenoxime, cefoperazone, cephalosporin Clost, ceftizoxime, ceftazidime, cefonicid, cefdinir, cefixime, cefradine, cefpiramide, cefotaxime, ceftelem, cefpodoxime, cefodizime, cefotiam, cephalosporin Hemei, ceftizox, cefprozil, ceftibuten, cefepime, cephalexin, cefradine, cefaclor, ceftriaxone, cefadroxil, cefmenoxime, cefsulodin, cefoxitin, cefmetazole , cefotetan, cefminox, cephalosporin, cefaclor, cefotaxime, cefotiam, cefreat, cefixime, cefotaxime, cephalosporin, fluoxetine, macrolide Class: dirithromycin, roxithromycin, ropoxmycin, clarithromycin, erythromycin, azithromycin, rotamycin, tacrolimus, erythromycin, erythromycin, clarithromycin, Guitarmycin, melamycin, columnar leucomycin, medimycin, azithromycin, josamycin, spiramycin, acetylspiramycin, aminoglycosides: netilmicin, astem, A Bekaxing, isepamicin streptomycin, karamycin, gentamicin Tobramycin, amikacin, sisomicin, neomycin, paromomycin, formimicin, small nomimethine, isepamicin, dibemimethine, dardimethod, grand view Streptomycin, streptomycin, kanamycin, etimicin, dibekacin, amide alcohols: chloramphenicol, amber chloramphenicol, palm chloramphenicol, thiamphenicol, lincomycin, Clindamycin, clindamycin phosphate, polypeptide polyene: cyclosporine, teicoplanin, pilomycin polymyxin, polymyxin, vancomycin, norvancomycin, Bacitracin, polymyxin B, fusidic acid, micammycin, rifamycin: rifabutin, rifapentine, rifaximin, rifampicin, rifamycin, Fuding, quinolones: enoxacin, toloxacin, norfloxacin, ciprofloxacin, lomefloxacin, seroxacin, pefloxacin, fleroxacin, temafloxacin, sand Ofloxacin, moxifloxacin, tevafloxacin, gepafloxacin, ofloxacin, levofloxacin, pazufloxacin, rufloxacin, sulfisoxazole, sulfamethoxazole, sulfadiazine, sulfonamide Sodium sulfonate Trimethoprim, pipemidic acid, nitrofurantoin, furazolidone, nalidixic acid, amlodipine, gatifloxacin, pazufloxacin, troxafloxacin, moxifloxacin, tetracyclines: tetracycline, terpene , minocycline, chlortetracycline, doxycycline, oxytetracycline, doxycycline, metacycline, dimecycline, indomethacin, beta-lactamase inhibitor: Clavi Acid, sulbactam, tazobactam, carbapenem antibiotics: imipenem, cilastatin, panipenem, betamethepone, meropenem, cefomycin, sulfonamides: sulfamethicamine , sulfamethazine, sulfamethazine, sulfamethoxazole, sulfamonomethoxine, iodine-p-methoxypyrimidine, iodine, sulfaguanidine, zinc sulfadiazine, sulfamethamine, amber sulfathiazole, Trimethoprim, sulfamethoxazole, thienamycin, clavulanic acid, aztreonam, imipenem, faropenem, cilastatin, sulbactam, tazobactam, carumonam, Sisomicin, chloramphenicol palmitate, fosfomycin, SV, bromoprolin, octenidine, urotropine, montelide, sub-salicylic acid Bismuth, metronidazole disodium phosphate, sulpirone, new sterilization, metronidazole, arubicin, epirubicin, zorubicin, pirarubicin, idarubicin, mupirocin , nitroimidazole, tinidazole, pipemidic acid, nitrofurantoin, nitrofuran: furazolidone, trimethoprim, methylfuran: sulfasalazine, antifungal: thiconazole, lanoconazole, Qi Noconazole, butoconazole, chlorconazole, fenteconazole nitrate, sheraconazole, oxyxazole, bifonazole, fluconazole, itraconazole, saconazole, clotrimazole, Econazole, tioconazole, miconazole, ketoconazole, naftifine, butenafine, ciclopirox, amorolfine, amphotericin B, erythromycin, flucytosine, terbina Fen, nystatin, griseofulvin, and flunin.
结构式I所述的3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物，药理活性和作为抗菌和抗真菌药物的应用以及联合用药所述的其特征是：本发明药物化合物的给药途径包括：口服、非胃肠道、皮下、静脉内、肌内、腹膜内、透皮、颊、鞘内、颅内、鼻内或局部途径进行给药。3-(2,4-Difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs of the formula I, pharmacological activity and as an antibacterial And the use of the antifungal drug and the combination thereof are characterized in that the administration route of the pharmaceutical compound of the present invention includes: oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, sheath Administration is carried out intraluminally, intracranically, intranasally or topically.
具体实施方式detailed description
下面将通过实施例对本发明做进一步说明，但下述的实施例仅是本发明其中的举例而已，并不代表本发明所限定的权利范围，该权利范围以权利要求书为准。The invention is further illustrated by the following examples, but the following examples are merely examples of the invention and are not intended to limit the scope of the invention.
1.化学合成与制备1. Chemical synthesis and preparation
(1)重要中间体的制备(1) Preparation of important intermediates
结构式I所述的3-(2,4-二氟苯基)-5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物，它们的制备方法，其特征是：在催化剂的作用下进行环合反应制备中间体2，含有各种取代基的羰基乙酸乙酯化合物在催化剂作用下与4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺反应形成C-N键，完成环合反应。该催化剂为脱水剂、有机酸和/或无机酸催化剂之一，采用四氢呋喃、1,4-二氧六环、乙氰、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、正己烷、甲苯等其中一种为溶剂，反应温度控制在-40℃至180℃条件下，可形成关键中间体2，3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚，反应式如下：3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs of the formula I, The preparation method is characterized in that: the intermediate reaction is carried out by a cyclization reaction under the action of a catalyst, and an ethyl carbonyl compound containing various substituents is reacted with 4-(2,4-difluorophenyl) under the action of a catalyst. The -3-methyl-1H-pyrazole-5-amine reacts to form a CN bond, completing the cyclization reaction. The catalyst is one of a dehydrating agent, an organic acid and/or a mineral acid catalyst, and uses tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethyl B. One of the amide, n-hexane, toluene and the like is a solvent, and the reaction temperature is controlled at -40 ° C to 180 ° C to form a key intermediate 2,3-(2,4-difluorophenyl)-2-methyl Pyrazolo[1,5-a]pyrimidin-7-phenol, the reaction formula is as follows:
Figure PCTCN2018080281-appb-000003
Figure PCTCN2018080281-appb-000003
(2)酚盐的制备(2) Preparation of phenate
3-(2,4-二氟苯基)-5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物的制备方法为：在无机碱的作用下，采用下列其中一种试剂(四氢呋喃、1,4-二氧六环、乙氰、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺等)为溶剂，反应温度控制在-40℃至180℃条件下，可形成酚盐化合物3，反应式如下：3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs are prepared by: Under the action of a base, one of the following reagents (tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, etc.) is used as a solvent. The reaction temperature is controlled at -40 ° C to 180 ° C to form a phenate compound 3, the reaction formula is as follows:
Figure PCTCN2018080281-appb-000004
Figure PCTCN2018080281-appb-000004
本发明化合物的可药用盐也在本发明范围内，其酸可通过和碱反应成盐，例如碳酸钠、氢化钠、氢氧化钾等。含有氮原子结构具有碱性可通过和酸反应成盐如盐酸、富马酸、马来酸、琥珀酸、乙酸、柠檬酸、酒石酸、碳酸、磷酸、草酸等。The pharmaceutically acceptable salts of the compounds of the invention are also within the scope of the invention, the acid of which can be converted to a salt by reaction with a base such as sodium carbonate, sodium hydride, potassium hydroxide or the like. The structure containing a nitrogen atom is basic and can be converted into a salt such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid or the like by reaction with an acid.
本发明化合物的前药也在本发明范围内。可将本发明药物修饰成前药，增大其水溶性和分子体积，并可降低其毒性。Prodrugs of the compounds of the invention are also within the scope of the invention. The medicament of the present invention can be modified into a prodrug to increase its water solubility and molecular volume, and to reduce its toxicity.
2.合成与制备举例(实施例及其结构1-33见表1)2. Synthesis and preparation examples (Examples and structures 1-33 are shown in Table 1)
实施例1的制备 3-(2,4-二氟苯基)-2-甲基-5-(4-(三氟甲基)苯基)吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 1 3-(2,4-Difluorophenyl)-2-methyl-5-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-7 - sodium phenolate
(1)于100ml的茄形瓶，室温下依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-氧代-3-(4-(三氟甲基)苯基)丙酸乙酯0.260g，N,N-二甲基甲酰胺20ml，在氮气保护和搅拌下120℃反应5小时，TLC检测反应完全。冷却后过滤，用乙酸乙酯萃取三次(30ml×2)，饱和食盐水反洗两次(20ml×2)，无水硫酸钠干燥，减压回收溶剂得到粗产物，粗产物经柱层析获得粗品固体物进行硅胶柱层析，采用流动相CH 2Cl 2:CH 3OH不同比例浓度梯度洗脱，获得洗脱物经重结晶得关键中间体3-(2,4-二氟苯基)-2-甲基-5-(4-(三氟甲基)苯基)吡唑并[1,5-a]嘧啶-7-酚。红外光谱测定IR(KBr,cm -1)3246,2986,1612,1565,1478,1326,1171,1104,1064,1014；核磁共振光谱测定 1H NMR(DMSO-d 6)δ11.53(b,1H),7.75(d,J＝8.0,1H),7.72(d,J＝7.5,2H),7.68(d,J＝7.5,2H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 (1) In a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole-5-amine 0.209 g, 3-oxo-3- 0.260 g of ethyl (4-(trifluoromethyl)phenyl)propanoate and 20 ml of N,N-dimethylformamide were reacted at 120 ° C for 5 hours under nitrogen atmosphere and stirring, and the reaction was confirmed by TLC. After cooling, it was filtered, and extracted with EtOAc (3 mL) (EtOAc (EtOAc) The crude solid was subjected to silica gel column chromatography and eluted with different gradients of mobile phase CH 2 Cl 2 :CH 3 OH to obtain the key intermediate 3-(2,4-difluorophenyl). 2-Methyl-5-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-phenol. Infrared spectroscopy IR (KBr, cm -1 ) 3246, 2986, 1612, 1565, 1478, 1326, 1171, 1104, 1064, 1014; 1 H NMR (DMSO-d 6 ) δ 11.53 (b, 1H), 7.75 (d, J = 8.0, 1H), 7.72 (d, J = 7.5, 2H), 7.68 (d, J = 7.5, 2H), 7.07 (d, J = 8.0, 1H), 6.82 (s) , 1H), 6.74 (s, 1H), 2.06 (s, 3H).
(2)于100ml的茄形瓶，室温下依次加入3-(2,4-二氟苯基)-2-甲基-5-(4-(三氟甲基)苯基)吡唑并[1,5-a]嘧啶-7-酚钠0.427g，氢氧化钠0.40g，四氢呋喃和水(1：1)混合溶剂20ml，在氮气保护和搅拌下回流反应5小时，减压下回收容积，冷却后过滤，获得粗品固体物进行重结晶得目标产物,3-(2,4-二氟苯基)-2-甲基-5-(4-(三氟甲基)苯基)吡唑并[1,5-a]嘧啶-7-酚。红外光谱测定IR(KBr.cm-1):3659-2840,1612,1565,1517,1479,1419,1375,1326,1263,1173,1104,1063,1014,964,932,851,791；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.75(d,J＝8.0,1H),7.72(d,J＝7.5,2H),7.68(d,J＝7.5,2H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 (2) In a 100 ml eggplant-shaped flask, 3-(2,4-difluorophenyl)-2-methyl-5-(4-(trifluoromethyl)phenyl)pyrazole was added sequentially at room temperature [ 1,5-a] pyrimidine-7-phenol sodium 0.427 g, sodium hydroxide 0.40 g, tetrahydrofuran and water (1:1) mixed solvent 20 ml, refluxed under nitrogen for 5 hours under stirring, and the volume was recovered under reduced pressure. After cooling, it was filtered to obtain a crude solid which was recrystallized to give the desired product, 3-(2,4-difluorophenyl)-2-methyl-5-(4-(trifluoromethyl)phenyl)pyrazole. [1,5-a]pyrimidine-7-phenol. Infrared spectroscopy IR (KBr.cm-1): 3659-2840, 1612, 1565, 1517, 1479, 1419, 1375, 1326, 1263, 1173, 1104, 1063, 1014, 964, 932, 851, 791; NMR spectroscopy 1 H NMR ( DMSO-d 6 ) δ 7.75 (d, J = 8.0, 1H), 7.72 (d, J = 7.5, 2H), 7.68 (d, J = 7.5, 2H), 7.07 (d, J = 8.0, 1H) , 6.82 (s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例2的制备 5-(4-氰基苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 2 5-(4-Cyanophenyl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(4-氰基苯基)-3-氧代丙酸乙酯0.217g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3661-2840,2220,1610,1566,1479,1327,1175,1106, 1065,964；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.97(d,J＝7.5,2H),7.82(d,J＝7.5,2H),7.75(d,J＝8.0,1H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-Amine 0.209 g, 0.217 g of ethyl 3-(4-cyanophenyl)-3-oxopropanoate, the intermediate was obtained, and the title compound was obtained by further reacting with sodium hydroxide. Infrared spectroscopy IR (KBr.cm-1): 3661-2840, 2220, 1610, 1566, 1479, 1327, 1175, 1106, 1065, 964; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ 7.97 (d, J = 7.5, 2H), 7.82 (d, J = 7.5, 2H), 7.75 (d, J = 8.0, 1H), 7.07 (d, J = 8.0, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例3的制备 3-(2,4-二氟苯基)-2-甲基-5-(4-硝基苯基)吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 3 3-(2,4-Difluorophenyl)-2-methyl-5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7-phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(4-硝基苯基)-3-氧代丙酸乙酯0.237g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3664-2845,1614,1567,1481,1329,1250,1177,1106,1066,1016；核磁共振光谱测定 1H NMR(DMSO-d 6)δ8.32(d,J＝7.5,2H),8.05(d,J＝7.5,2H),7.75(d,J＝8.0,1H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g, 0.237 g of ethyl 3-(4-nitrophenyl)-3-oxopropanoate, obtained, the intermediate was obtained; Infrared spectroscopy IR (KBr.cm-1): 3664-2845,1614,1567,1481,1329,1250,1177,1106,1066,1016 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ8.32 (d, J = 7.5, 2H), 8.05 (d, J = 7.5, 2H), 7.75 (d, J = 8.0, 1H), 7.07 (d, J = 8.0, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例4的制备 3-(2,4-二氟苯基)-5-(4-甲氧基苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 4 3-(2,4-Difluorophenyl)-5-(4-methoxyphenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(4-甲氧基苯基)-3-氧代丙酸乙酯0.222g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3657-2838,1610,1563,1477,1324,1250,1171,1102,1061,962；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.75(d,J＝8.0,1H),7.55(d,J＝7.5,2H),7.07(m,3H),6.82(s,1H),6.74(s,1H),3.83(s,3H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. 5-09-amine 0.209 g, 0.222 g of ethyl 3-(4-methoxyphenyl)-3-oxopropanoate, the title compound was obtained. Infrared spectroscopy IR (KBr.cm-1): 3657-2838,1610,1563,1477,1324,1250,1171,1102,1061,962 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ7.75 (d, J = 8.0, 1H), 7.55 (d, J = 7.5, 2H), 7.07 (m, 3H), 6.82 (s, 1H), 6.74 (s, 1H), 3.83 (s, 3H), 2.06 (s, 3H).
实施例5的制备 3-(2,4-二氟苯基)-5-(4-(二甲氨基)苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 5 3-(2,4-Difluorophenyl)-5-(4-(dimethylamino)phenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7- Sodium phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(4-(二甲氨基)苯基)-3-氧代丙酸乙酯0.235g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3669-2837,1610,1562,1476,1340,1170,1100,1060,1011；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.75(d,J＝8.0,1H),7.61(d,J＝7.5,2H),7.07(d,J＝8.0,1H),6.85(d,J＝7.5,2H),6.82(s,1H),6.74(s,1H),3.06(s,6H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g, 0.235 g of ethyl 3-(4-(dimethylamino)phenyl)-3-oxopropanoate to obtain an intermediate; Infrared spectroscopy IR (KBr.cm-1): 3669-2837,1610,1562,1476,1340,1170,1100,1060,1011 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ7.75 (d , J = 8.0, 1H), 7.61 (d, J = 7.5, 2H), 7.07 (d, J = 8.0, 1H), 6.85 (d, J = 7.5, 2H), 6.82 (s, 1H), 6.74 ( s, 1H), 3.06 (s, 6H), 2.06 (s, 3H).
实施例6的制备 3-(2,4-二氟苯基)-2-甲基-5-(4-酚钠基)-吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 6 3-(2,4-Difluorophenyl)-2-methyl-5-(4-phenol sodium)-pyrazolo[1,5-a]pyrimidine-7-phenol sodium
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(4-羟基苯基)-3-氧代丙酸乙酯0.208g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3658-2841,1612,1564,1224,1172,1104,1061,1012,960；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.75(d,J＝8.0,1H),7.49(d,J＝7.5,2H),7.07(d,J＝8.0,1H),6.86(d,J＝7.5,2H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g, 0.28 g of ethyl 3-(4-hydroxyphenyl)-3-oxopropanoate was reacted to obtain an intermediate; and the reaction was continued with sodium hydroxide to give the aimed product. Infrared spectroscopy IR (KBr.cm-1): 3658-2841,1612,1564,1224,1172,1104,1061,1012,960 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ7.75 (d , J=8.0,1H), 7.49 (d, J=7.5, 2H), 7.07 (d, J=8.0, 1H), 6.86 (d, J=7.5, 2H), 6.82 (s, 1H), 6.74 ( s, 1H), 2.06 (s, 3H).
实施例7的制备 5-(4-羧酸钠苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 7 5-(4-Carboxylic phenyl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate sodium
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g 4-(3-乙氧基-3-氧代丙酰基)苯甲酸0.236g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3665-2810,1617,1600,1480,1326,1173,1104,1063,1014；核磁共振光谱测定 1H NMR(DMSO-d 6)δ8.10(d,J＝7.5,2H),8.0(d,J＝7.5,2H),7.75(d,J＝8.0,1H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g of 4-(3-ethoxy-3-oxopropanoyl)benzoic acid 0.236 g of the reaction gave an intermediate; and continued to react with sodium hydroxide to give the object product. Infrared spectroscopy IR (KBr.cm-1): 3665-2810,1617,1600,1480,1326,1173,1104,1063,1014 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ8.10 (d , J = 7.5, 2H), 8.0 (d, J = 7.5, 2H), 7.75 (d, J = 8.0, 1H), 7.07 (d, J = 8.0, 1H), 6.82 (s, 1H), 6.74 ( s, 1H), 2.06 (s, 3H).
实施例8的制备 5-(4-磺酸钠苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 8 5-(4-Sodium sulfonate phenyl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3- 甲基-1H-吡唑-5-胺0.209g，4-(3-乙氧基-3-氧代丙酰基)苯亚磺酸0.256g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3670-2810,1612,1565,1479,1326,1200,1104,1063,1014；核磁共振光谱测定 1H NMR(DMSO-d 6)δ8.01(d,J＝7.5,2H),7.75(d,J＝8.0,1H)，7.64(d,J＝7.5,2H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g, 4-(3-ethoxy-3-oxopropanoyl)benzenesulfinic acid 0.256 g to give an intermediate; continue to react with sodium hydroxide to give the desired product. Infrared spectroscopy IR (KBr.cm-1): 3670-2810,1612,1565,1479,1326,1200,1104,1063,1014 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ8.01 (d , J=7.5, 2H), 7.75 (d, J=8.0, 1H), 7.64 (d, J=7.5, 2H), 7.07 (d, J=8.0, 1H), 6.82 (s, 1H), 6.74 ( s, 1H), 2.06 (s, 3H).
实施例9的制备 3-(2,4-二氟苯基)-2-甲基-5-(4-氨磺酰基苯基)吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 9 3-(2,4-Difluorophenyl)-2-methyl-5-(4-sulfamoylphenyl)pyrazolo[1,5-a]pyrimidin-7-phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g 3-氧-3-(4-氨磺酰基苯基)丙酸乙酯0.271g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3665-2840,1612,1565,1479,1320,1173,1104,1063,1017；核磁共振光谱测定 1H NMR(DMSO-d 6)δ8.07(d,J＝7.5,2H),7.92(d,J＝7.5,2H),7.75(d,J＝8.0,1H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H),2.0(b,2H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g of 3-oxo-3-(4-sulfamoylphenyl)propanoic acid ethyl ester 0.271 g of the reaction gave an intermediate; and continued to react with sodium hydroxide to give the desired product. Infrared spectroscopy IR (KBr.cm-1): 3665-2840,1612,1565,1479,1320,1173,1104,1063,1017 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ8.07 (d , J=7.5, 2H), 7.92 (d, J=7.5, 2H), 7.75 (d, J=8.0, 1H), 7.07 (d, J=8.0, 1H), 6.82 (s, 1H), 6.74 ( s, 1H), 2.06 (s, 3H), 2.0 (b, 2H).
实施例10的制备 3-(2,4-二氟苯基)-2-甲基-5-(4-苯氧基苯基)吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 10 3-(2,4-Difluorophenyl)-2-methyl-5-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-氧-3-(4-苯氧基苯基)丙酸乙酯0.284g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3659-2840,1612,1565,1479,1326,1173,1104,1063,1014；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.60-7.07(m,11H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. 5-09-amine 0.209 g, ethyl 3-oxo-3-(4-phenoxyphenyl)propanoate, 0.284 g, gave an intermediate; and continued to react with sodium hydroxide to give the desired product. Infrared spectroscopy IR (KBr.cm-1): 3659-2840,1612,1565,1479,1326,1173,1104,1063,1014 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ7.60-7.07 (m, 11H), 6.82 (s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例11的制备 5-(4-甲酰基苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 11 5-(4-Formylphenyl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(4-氨甲酰基苯基)-3-氧代丙酸乙酯0.235g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3669-2840,1750,1565,1479,1326,1173,1104,1063,1014；核磁共振光谱测定 1H NMR(DMSO-d 6)δ8.09(d,J＝7.5,2H),7.97(d,J＝7.5,2H),7.75(d,J＝8.0,1H),7.50(b,2H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g, 0.235 g of ethyl 3-(4-carbamoylphenyl)-3-oxopropanoate to obtain an intermediate; the reaction was continued with sodium hydroxide to give the object product. Infrared spectroscopy IR (KBr.cm-1): 3669-2840,1750,1565,1479,1326,1173,1104,1063,1014 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ8.09 (d , J=7.5, 2H), 7.97 (d, J=7.5, 2H), 7.75 (d, J=8.0, 1H), 7.50 (b, 2H), 7.07 (d, J=8.0, 1H), 6.82 ( s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例12的制备 3,5-双(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 12 3,5-Bis(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(2,4-二氟苯基)-3-氧代丙酸乙酯0.228g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3669-2850,1622,1565,1481,1333,1104,1063；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.75(d,J＝7.5,2H),7.07(d,J＝7.5,2H),6.82(s,1H),6.74(s,2H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. 5-09-amine 0.209 g, 0.228 g of ethyl 3-(2,4-difluorophenyl)-3-oxopropanoate, obtained the intermediate, and the title compound was obtained by reacting with sodium hydroxide. Infrared spectroscopy IR (KBr.cm-1): 3669-2850,1622,1565,1481,1333,1104,1063 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ7.75 (d, J = 7.5 , 2H), 7.07 (d, J = 7.5, 2H), 6.82 (s, 1H), 6.74 (s, 2H), 2.06 (s, 3H).
实施例13的制备 5-(4-乙氧基苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 13 5-(4-Ethoxyphenyl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate sodium
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(4-乙酰氧基苯基)-3-氧代丙酸乙酯0.250g反应，获得中间体；继续和氢氧化钠反应获得目标产物红外光谱测定IR(KBr.cm-1):3652-2838,1750,1612,1565,1479,1326,1173,1106,1061,1014；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.83(d,J＝7.5,2H),7.75(d,J＝8.0,1H),7.15(d,J＝7.5,2H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.28(s,3H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g, ethyl 2-(4-acetoxyphenyl)-3-oxopropanoate 0.250 g to obtain an intermediate; continue to react with sodium hydroxide to obtain the desired product. Infrared spectrometry IR (KBr .cm-1): 3652-2838,1750,1612,1565,1479,1326,1173,1106,1061,1014; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ7.83 (d, J = 7.5 , 2H), 7.75 (d, J = 8.0, 1H), 7.15 (d, J = 7.5, 2H), 7.07 (d, J = 8.0, 1H), 6.82 (s, 1H), 6.74 (s, 1H) , 2.28 (s, 3H), 2.06 (s, 3H).
实施例14的制备 3-(2,4-二氟苯基)-2-甲基-5-(6-(三氟甲基)吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 14 3-(2,4-Difluorophenyl)-2-methyl-5-(6-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a] Pyrimidine-7-phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-氧-3-(6-(三氟甲基)吡啶-3-基)丙酸乙酯0.261g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3659-2840,1612,1565,1479,1326,1173,1104,1063,1018；核磁共振光谱测定 1H NMR(DMSO-d 6)δ8.58(s,1H),7.88(d,J＝7.5,1H),7.75(d,J＝8.0,1H),7.35(d,J＝7.5,1H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g, 0.261 g of ethyl 3-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate, the title compound was obtained. Infrared spectroscopy IR (KBr.cm-1): 3659-2840, 1612, 1565, 1479, 1326, 1173, 1104, 1063, 1018; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ 8.58 (s , 1H), 7.88 (d, J = 7.5, 1H), 7.75 (d, J = 8.0, 1H), 7.35 (d, J = 7.5, 1H), 7.07 (d, J = 8.0, 1H), 6.82 ( s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例15的制备 5-(6-氰基吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 15 5-(6-Cyanopyridin-3-yl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7- Sodium phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(6-氰基吡啶-3-基)-3-氧代丙酸乙酯0.218g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3651-2831,2240,1612,1565,1479,1326,1173,1104,1063,1017；核磁共振光谱测定 1H NMR(DMSO-d 6)δ9.20(s,1H),8.35(d,J＝7.5,1H),7.75(d,J＝8.0,1H),7.73(d,J＝7.5,1H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. 5-09-amine 0.209 g, 0.218 g of ethyl 3-(6-cyanopyridin-3-yl)-3-oxopropanoate, the title compound was obtained. Infrared spectroscopy IR (KBr.cm-1): 3651-2831, 2240, 1612, 1565, 1479, 1326, 1173, 1104, 1063, 1017; nuclear magnetic resonance spectrometry 1 H NMR (DMSO-d 6 ) δ 9.20 (s, 1H), 8.35 (d, J = 7.5, 1H), 7.75 (d, J = 8.0, 1H), 7.73 (d, J = 7.5, 1H), 7.07 (d, J = 8.0, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例16的制备 3-(2,4-二氟苯基)-2-甲基-5-(6-硝基吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 16 3-(2,4-Difluorophenyl)-2-methyl-5-(6-nitropyridin-3-yl)pyrazolo[1,5-a]pyrimidine-7- Sodium phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(6-硝基吡啶-3-基)-3-氧代丙酸乙酯0.238g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3651-2840,1612,1565,1479,1375,1326,1173,1104,1063,1017；核磁共振光谱测定 1H NMR(DMSO-d 6)δ9.07(s,1H),8.64(d,J＝7.5,1H),8.15(d,J＝7.5,1H),7.75(d,J＝8.0,1H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -09-amine 0.209 g, 0.238 g of ethyl 3-(6-nitropyridin-3-yl)-3-oxopropanoate, obtained the intermediate. Infrared spectroscopy IR (KBr.cm-1): 3651-2840, 1612, 1565, 1479, 1375, 1326, 1173, 1104, 1063, 1017; nuclear magnetic resonance spectrometry 1 H NMR (DMSO-d 6 ) δ 9.07 (s, 1H), 8.64 (d, J = 7.5, 1H), 8.15 (d, J = 7.5, 1H), 7.75 (d, J = 8.0, 1H), 7.07 (d, J = 8.0, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例17的制备 3-(2,4-二氟苯基)-5-(6-甲氧基吡啶-3-基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 17 3-(2,4-Difluorophenyl)-5-(6-methoxypyridin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine-7 - sodium phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(6-甲氧基吡啶-3-基)-3-氧代丙酸乙酯0.223g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3649-2840,1612,1565,1479,1326,1250,1173,1105,1066；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.97(d,J＝7.5,1H),7.91(s,1H),7.75(d,J＝8.0,1H)，7.07(d,J＝8.0,1H),6.88(s,1H),6.74(s,1H),6.60(d,J＝7.5,1H),3.80(s,3H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -09-amine 0.209 g, 0.223 g of ethyl 3-(6-methoxypyridin-3-yl)-3-oxopropanoate, the title compound was obtained. Infrared spectroscopy IR (KBr.cm-1): 3649-2840,1612,1565,1479,1326,1250,1173,1105,1066 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ7.97 (d , J = 7.5, 1H), 7.91 (s, 1H), 7.75 (d, J = 8.0, 1H), 7.07 (d, J = 8.0, 1H), 6.88 (s, 1H), 6.74 (s, 1H) , 6.60 (d, J = 7.5, 1H), 3.80 (s, 3H), 2.06 (s, 3H).
实施例18的制备 3-(2,4-二氟苯基)-5-(6-(二甲氨基)吡啶-3-基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 18 3-(2,4-Difluorophenyl)-5-(6-(dimethylamino)pyridin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine Sodium -7-phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(6-(二甲氨基)吡啶-3-基)-3-氧代丙酸乙酯0.236g反应，获得中间体；继续和氢氧化钠反应获得目标产物红外光谱测定IR(KBr.cm-1):3639-2850,1612,1565,1479,1326,1200,1104,1063,1021；核磁共振光谱测定 1H NMR(DMSO-d 6)δ8.33(s,1H),7.75(d,J＝8.0,1H),7.66(d,J＝7.5,1H),7.07(d,J＝8.0,1H),6.88(s,1H),6.76(d,J＝7.5,1H),6.74(s,1H),3.15(s,6H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g, ethyl 3-(6-(dimethylamino)pyridin-3-yl)-3-oxopropanoate 0.236 g to obtain an intermediate; continue to react with sodium hydroxide to obtain the desired product infrared Spectrometric determination IR (KBr.cm-1): 3639-2850, 1612, 1565, 1479, 1326, 1200, 1104, 1063, 1021; 1 H NMR (DMSO-d 6 ) δ 8.33 (s, 1H), 7.75 (d, J = 8.0, 1H), 7.66 (d, J = 7.5, 1H), 7.07 (d, J = 8.0, 1H), 6.88 (s, 1H), 6.76 (d, J = 7.5) , 1H), 6.74 (s, 1H), 3.15 (s, 6H), 2.06 (s, 3H).
实施例19的制备 3-(2,4-二氟苯基)-5-(6-酚钠吡啶-3-基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 19 3-(2,4-Difluorophenyl)-5-(6-phenol sodium pyridin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine-7- Sodium phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(6-羟基吡啶-3-基)-3-氧代丙酸乙酯0.209g反应，获得中间体；继续和氢氧化钠反应获得目标产物红外光谱测定IR(KBr.cm-1):3659-2840,1612,1565,1479,1326,1250,1173,1104, 1063,1014,964；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.97(d,J＝7.5,1H),7.91(s,1H),7.75(d,J＝8.0,1H),7.07(d,J＝8.0,1H),6.88(s,1H),6.74(s,1H),6.60(d,J＝7.5,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. 5-09-amine 0.209 g, ethyl 3-(6-hydroxypyridin-3-yl)-3-oxopropanoate 0.209 g to obtain an intermediate; continue to react with sodium hydroxide to obtain the target product by infrared spectrometry IR ( KBr.cm-1): 3659-2840,1612,1565,1479,1326,1250,1173,1104, 1063,1014,964 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ7.97 (d, J = 7.5, 1H), 7.91 (s, 1H), 7.75 (d, J = 8.0, 1H), 7.07 (d, J = 8.0, 1H), 6.88 (s, 1H), 6.74 (s, 1H), 6.60 (d, J = 7.5, 1H), 2.06 (s, 3H).
实施例20的制备 5-(4-氰基苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钾Preparation of Example 20 5-(4-Cyanophenyl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenol potassium
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(4-氰基苯基)-3-氧代丙酸乙酯0.217g反应，获得中间体；继续和氢氧化钾反应获得目标产物。红外光谱测定IR(KBr.cm-1):3661-2840,2220,1610,1566,1479,1327,1175,1106,1065,964；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.97(d,J＝7.5,2H),7.82(d,J＝7.5,2H),7.75(d,J＝8.0,1H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-Amine 0.209 g, 0.217 g of ethyl 3-(4-cyanophenyl)-3-oxopropanoate, the intermediate was obtained, and the title compound was obtained by further reacting with potassium hydroxide. Infrared spectroscopy IR (KBr.cm-1): 3661-2840,2220,1610,1566,1479,1327,1175,1106,1065,964 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ7.97 (d, J = 7.5, 2H), 7.82 (d, J = 7.5, 2H), 7.75 (d, J = 8.0, 1H), 7.07 (d, J = 8.0, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例21的制备 5-(6-羧酸钠吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 21 5-(6-carboxylatepyridin-3-yl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7 - sodium phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，5-(3-乙氧基-3-氧代丙酰基)吡啶羧酸0.237g反应，获得中间体；继续和氢氧化钠反应获得目标产物红外光谱测定IR(KBr.cm-1):3659-2840,1660,1565,1479,1326,1173,1104,1063,1020；核磁共振光谱测定 1H NMR(DMSO-d 6)δ9.23(s,1H),8.40(d,J＝7.5,1H),8.35(d,J＝7.5,1H),7.75(d,J＝8.0,1H),7.07(d,J＝8.0,1H),6.88(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g, 5-37-(3-ethoxy-3-oxopropanoyl)pyridinecarboxylic acid 0.237 g to obtain an intermediate; continue to react with sodium hydroxide to obtain the desired product IR spectrum (KBr. cm-1): 3659-2840,1660,1565,1479,1326,1173,1104,1063,1020; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ9.23 (s, 1H), 8.40 (d , J = 7.5, 1H), 8.35 (d, J = 7.5, 1H), 7.75 (d, J = 8.0, 1H), 7.07 (d, J = 8.0, 1H), 6.88 (s, 1H), 6.74 ( s, 1H), 2.06 (s, 3H).
实施例22的制备 3-(2,4-二氟苯基)-2-甲基-5-(4-(三氟甲基)苯基)吡唑并[1,5-a]嘧啶-7-酚钾Preparation of Example 22 3-(2,4-Difluorophenyl)-2-methyl-5-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7 -Phenol potassium
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入3-(2,4-二氟苯基)-2-甲基-5-(4-(三氟甲基)苯基)吡唑并[1,5-a]嘧啶-7-酚0.427g，氢氧化钾0.40g，反应5小时，获得中间体；继续和氢氧化钾反应获得目标产物,3-(2,4-二氟苯基)-2-甲基-5-(4-(三氟甲基)苯基)吡唑并[1,5-a]嘧啶-7-酚。红外光谱测定IR(KBr.cm-1):3659-2840,1612,1565,1479,1326,1173,1104,1063,1014,964,932,851,791；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.75(d,J＝8.0,1H),7.72(d,J＝7.5,2H),7.68(d,J＝7.5,2H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, 3-(2,4-difluorophenyl)-2-methyl-5-(4) was sequentially added to a 100 ml eggplant-shaped flask. -(Trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-phenol 0.427 g, potassium hydroxide 0.40 g, reacted for 5 hours to obtain an intermediate; continue to react with potassium hydroxide to obtain a target Product, 3-(2,4-difluorophenyl)-2-methyl-5-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-phenol. Infrared spectroscopy IR (KBr.cm-1): 3659-2840,1612,1565,1479,1326,1173,1104,1063,1014,964,932,851,791 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ7.75 (d, J = 8.0, 1H), 7.72 (d, J = 7.5, 2H), 7.68 (d, J = 7.5, 2H), 7.07 (d, J = 8.0, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例23的制备 3-(2,4-二氟苯基)-2-甲基-5-(4-硝基苯基)吡唑并[1,5-a]嘧啶-7-酚钾Preparation of Example 23 3-(2,4-Difluorophenyl)-2-methyl-5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7-phenol potassium
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(4-硝基苯基)-3-氧代丙酸乙酯0.237g反应，获得中间体；继续和氢氧化钾反应获得目标产物。红外光谱测定IR(KBr.cm-1):3664-2845,1614,1567,1481,1329,1250,1177,1106,1066,1016；核磁共振光谱测定 1H NMR(DMSO-d 6)δ8.32(d,J＝7.5,2H),8.05(d,J＝7.5,2H),7.75(d,J＝8.0,1H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g, 0.237 g of ethyl 3-(4-nitrophenyl)-3-oxopropanoate, obtained the intermediate. Infrared spectroscopy IR (KBr.cm-1): 3664-2845,1614,1567,1481,1329,1250,1177,1106,1066,1016 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ8.32 (d, J = 7.5, 2H), 8.05 (d, J = 7.5, 2H), 7.75 (d, J = 8.0, 1H), 7.07 (d, J = 8.0, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例24的制备 3-(2,4-二氟苯基)-5-(4-(二甲氨基)苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钾Preparation of Example 24 3-(2,4-Difluorophenyl)-5-(4-(dimethylamino)phenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7- Potassium phenol
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(4-(二甲氨基)苯基)-3-氧代丙酸乙酯0.235g反应，获得中间体；继续和氢氧化钾反应获得目标产物。红外光谱测定IR(KBr.cm-1):3656-2837,1610,1562,1476,1340,1170,1100,1060,1011；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.75(d,J＝8.0,1H),7.61(d,J＝7.5,2H),7.07(d,J＝8.0,1H),6.85(d,J＝7.5,2H),6.82(s,1H),6.74(s,1H),3.06(s,6H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g, 0.235 g of ethyl 3-(4-(dimethylamino)phenyl)-3-oxopropanoate, to give an intermediate; Infrared spectroscopy IR (KBr.cm-1): 3656-2837,1610,1562,1476,1340,1170,1100,1060,1011 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ7.75 (d , J = 8.0, 1H), 7.61 (d, J = 7.5, 2H), 7.07 (d, J = 8.0, 1H), 6.85 (d, J = 7.5, 2H), 6.82 (s, 1H), 6.74 ( s, 1H), 3.06 (s, 6H), 2.06 (s, 3H).
实施例25的制备 3-(2,4-二氟苯基)-2-甲基-5-(4-氨磺酰基苯基)吡唑并[1,5-a]嘧啶-7-酚钾Preparation of Example 25 3-(2,4-Difluorophenyl)-2-methyl-5-(4-sulfamoylphenyl)pyrazolo[1,5-a]pyrimidin-7-phenol potassium
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g 3-氧-3-(4-氨磺酰基苯基)丙酸乙酯0.271g反应，获得中间体；继续和氢氧化钾反应获得目标产物。红外光谱测定IR(KBr.cm-1):3665-2840,1612,1565,1479,1320,1173,1104,1063,1017；核磁共振光谱测定 1H NMR(DMSO-d 6)δ8.07(d,J＝7.5,2H),7.92(d,J＝7.5,2H),7.75(d,J＝8.0,1H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H),2.0(b,2H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-Amine 0.209 g of 3-oxo-3-(4-sulfamoylphenyl)propanoic acid ethyl ester 0.271 g was reacted to obtain an intermediate; and the reaction with potassium hydroxide was continued to obtain the objective product. Infrared spectroscopy IR (KBr.cm-1): 3665-2840,1612,1565,1479,1320,1173,1104,1063,1017 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ8.07 (d , J=7.5, 2H), 7.92 (d, J=7.5, 2H), 7.75 (d, J=8.0, 1H), 7.07 (d, J=8.0, 1H), 6.82 (s, 1H), 6.74 ( s, 1H), 2.06 (s, 3H), 2.0 (b, 2H).
实施例26的制备 3-(2,4-二氟苯基)-2-甲基-5-(6-(三氟甲基)吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钾Preparation of Example 26 3-(2,4-Difluorophenyl)-2-methyl-5-(6-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a] Pyrimidine-7-phenol potassium
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-氧-3-(6-(三氟甲基)吡啶-3-基)丙酸乙酯0.261g反应，获得中间体；继续和氢氧化钾反应获得目标产物。红外光谱测定IR(KBr.cm-1):3659-2840,1612,1565,1479,1326,1173,1104,1063,1018；核磁共振光谱测定 1H NMR(DMSO-d 6)δ8.58(s,1H),7.88(d,J＝7.5,1H),7.75(d,J＝8.0,1H),7.35(d,J＝7.5,1H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-Amine 0.209 g, 0.261 g of ethyl 3-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate, the title compound was obtained. Infrared spectroscopy IR (KBr.cm-1): 3659-2840, 1612, 1565, 1479, 1326, 1173, 1104, 1063, 1018; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ 8.58 (s , 1H), 7.88 (d, J = 7.5, 1H), 7.75 (d, J = 8.0, 1H), 7.35 (d, J = 7.5, 1H), 7.07 (d, J = 8.0, 1H), 6.82 ( s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例27的制备 5-(6-氰基吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钾Preparation of Example 27 5-(6-Cyanopyridin-3-yl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7- Potassium phenol
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(6-氰基吡啶-3-基)-3-氧代丙酸乙酯0.218g反应，获得中间体；继续和氢氧化钾反应获得目标产物。红外光谱测定IR(KBr.cm-1):3651-2831,2240,1612,1565,1479,1326,1173,1104,1063,1017；核磁共振光谱测定 1H NMR(DMSO-d 6)δ9.20(s,1H),8.35(d,J＝7.5,1H),7.75(d,J＝8.0,1H),7.73(d,J＝7.5,1H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -09-amine 0.209 g, 0.218 g of ethyl 3-(6-cyanopyridin-3-yl)-3-oxopropanoate, the title compound was obtained. Infrared spectroscopy IR (KBr.cm-1): 3651-2831, 2240, 1612, 1565, 1479, 1326, 1173, 1104, 1063, 1017; nuclear magnetic resonance spectrometry 1 H NMR (DMSO-d 6 ) δ 9.20 (s, 1H), 8.35 (d, J = 7.5, 1H), 7.75 (d, J = 8.0, 1H), 7.73 (d, J = 7.5, 1H), 7.07 (d, J = 8.0, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例28的制备 3-(2,4-二氟苯基)-2-甲基-5-(6-亚磺酸钠吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 28 3-(2,4-Difluorophenyl)-2-methyl-5-(sodium sulfinate-pyridin-3-yl)pyrazolo[1,5-a]pyrimidine- Sodium phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，5-(3-乙氧基-3-氧代丙酰基)吡啶-2-亚磺酸0.257g反应，获得中间体；继续和氢氧化钠反应获得目标产物红外光谱测定IR(KBr.cm-1):3666-2840,1612,1565,1479,1326,1253,1173,1104,1063,1016；核磁共振光谱测定 1H NMR(DMSO-d 6)δ8.19(d,J＝7.5,1H),7.83(d,J＝7.5,1H),7.75(d,J＝8.0,1H),7.07(d,J＝8.0,1H),6.88(s,1H),6.74(s,1H),2.06(s,3H),2.0(b,1H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g, 5-(3-ethoxy-3-oxopropanoyl)pyridine-2-sulfinic acid 0.257 g to obtain an intermediate; continue to react with sodium hydroxide to obtain the target product by infrared spectrometry IR (KBr.cm-1): 3666-2840,1612,1565,1479,1326,1253,1173,1104,1063,1016 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ8.19 (d, J = 7.5, 1H), 7.83 (d, J = 7.5, 1H), 7.75 (d, J = 8.0, 1H), 7.07 (d, J = 8.0, 1H), 6.88 (s, 1H), 6.74 (s) , 1H), 2.06 (s, 3H), 2.0 (b, 1H).
实施例29的制备 3-(2,4-二氟苯基)-2-甲基-5-(6-氨磺酰基吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 29 3-(2,4-Difluorophenyl)-2-methyl-5-(6-sulfamoylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-7 - sodium phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g 3-氧-3-(6-氨磺酰基吡啶-3-基)丙酸乙酯0.272g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3651-2840,1612,1565,1479,1330,1173,1063,1021；核磁共振光谱测定 1H NMR(DMSO-d 6)δ9.24(s,1H),8.42(d,J＝7.5,1H),7.75(d,J＝8.0,1H),7.57(d,J＝7.5,1H),7.07(d,J＝8.0,1H),6.88(s,1H),6.74(s,1H),2.06(s,3H),2.0(b,2H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-Amine 0.209 g of 3-oxo-3-(6-sulfamoylpyridin-3-yl)propanoic acid ethyl ester 0.272 g to give an intermediate; Infrared spectroscopy IR (KBr.cm-1): 3651-2840,1612,1565,1479,1330,1173,1063,1021 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ9.24 (s, 1H ), 8.42 (d, J = 7.5, 1H), 7.75 (d, J = 8.0, 1H), 7.57 (d, J = 7.5, 1H), 7.07 (d, J = 8.0, 1H), 6.88 (s, 1H), 6.74 (s, 1H), 2.06 (s, 3H), 2.0 (b, 2H).
实施例30的制备 3-(2,4-二氟苯基)-2-甲基-5-(6-苯氧基吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 30 3-(2,4-Difluorophenyl)-2-methyl-5-(6-phenoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-7 - sodium phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-氧-3-(6-苯氧基吡啶-3-基)丙酸乙酯0.285g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3639-2860,1612,1565,1479,1326,1255,1173,1104, 1063,1009；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.96-6.9(m,10H),6.88(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-Amine 0.209 g, ethyl 3-oxo-3-(6-phenoxypyridin-3-yl)propanoate, 0.285 g, gave an intermediate. Infrared spectroscopy IR (KBr.cm-1): 3639-2860,1612,1565,1479,1326,1255,1173,1104 , 1063,1009; nuclear magnetic resonance spectrometry 1 H NMR (DMSO-d 6 ) δ7.96 - 6.9 (m, 10H), 6.88 (s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例31的制备 3-(2,4-二氟苯基)-5-(4-((2-(二甲氨基)乙基)氨基甲酰基)苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 31 3-(2,4-Difluorophenyl)-5-(4-((2-(dimethylamino)ethyl)carbamoyl)phenyl)-2-methylpyrazole [1,5-a]pyrimidine-7-phenol sodium
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-(4-((2-(二甲氨基)乙基)氨基甲酰基)苯基)-3-氧代丙酸乙酯0.306g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3656-2837,1680,1640,1562,1476,1410,1340,1170,1100,1060,1011；核磁共振光谱测定 1H NMR(DMSO-d 6)δ8.09(d,J＝7.5,3H)7.97(d,J＝7.5,2H),7.75(d,J＝8.0,1H),7.07(d,J＝8.0,1H),6.82(s,1H),6.74(s,1H),3.60(t,J＝7.5,2H),2.57(t,J＝7.5,2H),2.26(s,6H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g, 3-(4-((2-(dimethylamino)ethyl)carbamoyl)phenyl)-3-oxopropanoic acid ethyl ester 0.306 g, The sodium hydroxide reaction gives the desired product. Infrared spectroscopy IR (KBr.cm-1): 3656-2837,1680,1640,1562,1476,1410,1340,1170,1100,1060,1011 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ8 .09(d,J=7.5,3H)7.97(d,J=7.5,2H),7.75(d,J=8.0,1H),7.07(d,J=8.0,1H),6.82(s,1H) , 6.74 (s, 1H), 3.60 (t, J = 7.5, 2H), 2.57 (t, J = 7.5, 2H), 2.26 (s, 6H), 2.06 (s, 3H).
实施例32的制备 5-(6-甲酰基吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 32 5-(6-Formylpyridin-3-yl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7- Sodium phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g，3-氧-3-(6-苯氧基吡啶-3-基)丙酸乙酯0.236g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3659-2840,1720,1565,1479,1326,1173,1104,1063,1021；核磁共振光谱测定 1H NMR(DMSO-d 6)δ9.11(s,1H),8.44(d,J＝7.5,1H),8.41(d,J＝7.5,1H),8.37(b,2H),7.75(d,J＝8.0,1H),7.07(d,J＝8.0,1H),6.88(s,1H),6.74(s,1H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-Amine 0.209 g, 0.236 g of ethyl 3-oxo-3-(6-phenoxypyridin-3-yl)propanoate, the title compound was obtained, and the title compound was obtained. Infrared spectroscopy IR (KBr.cm-1): 3659-2840, 1720, 1565, 1479, 1326, 1173, 1104, 1063, 1021; nuclear magnetic resonance spectroscopy 1 H NMR (DMSO-d 6 ) δ 9.11 (s , 1H), 8.44 (d, J = 7.5, 1H), 8.41 (d, J = 7.5, 1H), 8.37 (b, 2H), 7.75 (d, J = 8.0, 1H), 7.07 (d, J = 8.0, 1H), 6.88 (s, 1H), 6.74 (s, 1H), 2.06 (s, 3H).
实施例33的制备 5-(6-乙酰氧基吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠Preparation of Example 33 5-(6-acetoxypyridin-3-yl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7 - sodium phenolate
分别采用实施例1中的(1)和(2)相似的制备方法，于100ml的茄形瓶，依次加入4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺0.209g 3-(6-乙酰氧基吡啶-3-基)-3-氧代丙酸乙酯0.251g反应，获得中间体；继续和氢氧化钠反应获得目标产物。红外光谱测定IR(KBr.cm-1):3622-2830,1730,1565,1479,1326,1173,1104,1065；核磁共振光谱测定 1H NMR(DMSO-d 6)δ7.97(d,J＝7.5,1H),7.91(s,1H),7.75(d,J＝8.0,1H),7.07(d,J＝8.0,1H),6.88(s,1H),6.74(s,1H),6.60(d,J＝7.5,1H),2.28(s,3H),2.06(s,3H)。 Using a preparation method similar to (1) and (2) in Example 1, respectively, in a 100 ml eggplant-shaped flask, 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole was sequentially added. -5-amine 0.209 g of ethyl 3-(6-acetoxypyridin-3-yl)-3-oxopropanoate (0.251 g) was reacted to give an intermediate; Infrared spectroscopy IR (KBr.cm-1): 3622-2830,1730,1565,1479,1326,1173,1104,1065 ; NMR spectroscopy 1 H NMR (DMSO-d 6 ) δ7.97 (d, J = 7.5, 1H), 7.91 (s, 1H), 7.75 (d, J = 8.0, 1H), 7.07 (d, J = 8.0, 1H), 6.88 (s, 1H), 6.74 (s, 1H), 6.60 (d, J = 7.5, 1H), 2.28 (s, 3H), 2.06 (s, 3H).
表1 实施例化合物Table 1 Example compounds
Figure PCTCN2018080281-appb-000005
Figure PCTCN2018080281-appb-000005
Figure PCTCN2018080281-appb-000006
Figure PCTCN2018080281-appb-000006
Figure PCTCN2018080281-appb-000007
Figure PCTCN2018080281-appb-000007
Figure PCTCN2018080281-appb-000008
Figure PCTCN2018080281-appb-000008
Figure PCTCN2018080281-appb-000009
Figure PCTCN2018080281-appb-000009
Figure PCTCN2018080281-appb-000010
Figure PCTCN2018080281-appb-000010
实施例34 体外抗菌实验实例Example 34 Example of in vitro antibacterial experiment
注射剂制备实例Injection preparation example
称取0.50g化合物1，加入乙醇60ml，搅拌使溶解，溶解后加入60ml 1,2-丙二醇和10ml吐温80，搅拌混合均匀，加注射用水至总体积500ml，用0.22μm滤膜过滤，分装，100℃热压灭菌30min，检漏，全检，包装，即得5mg/5ml(氨瓶)，共100支。Weigh 0.50g of compound 1, add 60ml of ethanol, stir to dissolve, dissolve, add 60ml of 1,2-propanediol and 10ml of Tween 80, stir and mix evenly, add water for injection to the total volume of 500ml, filter with 0.22μm filter, divide Packed, 100 °C hot-press sterilization for 30min, leak detection, full inspection, packaging, that is, get 5mg/5ml (ammonia bottle), a total of 100.
材料与方法Materials and Methods
1.标准菌株：蜡样芽孢杆菌2、枯草芽胞杆菌168、粪肠球菌29212、粪肠球菌F2518(vre)、金黄色葡萄球菌29231、金黄色葡萄球菌43300(MRSA)、金黄色葡萄球菌703(MRSA)、肺炎链球菌6303(PRSP)、化脓肺炎链球菌M2、无乳链球菌B组、肺炎链球菌10351、炭疽杆菌Bacillus 1、白喉杆菌、产气荚膜杆菌、口腔念珠菌、皮真菌。1. Standard strains: Bacillus cereus 2, Bacillus subtilis 168, Enterococcus faecalis 29212, Enterococcus faecalis F2518 (vre), Staphylococcus aureus 29231, Staphylococcus aureus 43300 (MRSA), Staphylococcus aureus 703 ( MRSA), Streptococcus pneumoniae 6303 (PRSP), Streptococcus pneumoniae M2, Streptococcus agalactia B group, Streptococcus pneumoniae 10351, Bacillus anthracis, Diphtheria, Clostridium perfringens, Oral Candida, Peel fungus.
2.测试样品：化合物1、化合物2、化合物3、化合物4、化合物5、化合物6、化合物7、化合物8、2. Test sample: Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8,
化合物9、化合物10、化合物11、化合物12、化合物13、化合物14、化合物15、化合物16、化合物17、化合物18、化合物19、化合物20、化合物21、化合物22、化合物23、化合物24、化合物25、化合物26、化合物27、化合物28、化合物29、化合物30、化合物31、化合物32、化合物33Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, Compound 20, Compound 21, Compound 22, Compound 23, Compound 24, Compound 25 , Compound 26, Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32, Compound 33
3.方法3. Method
(1)灭菌：将所需实验器材及培养液经121℃、30min高压灭菌；无菌间紫外照射30min。(1) Sterilization: The required experimental equipment and culture solution were autoclaved at 121 ° C for 30 min; sterile ultraviolet irradiation for 30 min.
(2)细菌增菌(2) Bacterial enrichment
肉汤培养基制备：准确称取胰蛋白大豆肉汤培养基6g于500ml烧杯，加入200ml蒸馏水，加热充分溶解，移入三角烧瓶内，加棉塞，包扎高压灭菌即可。Preparation of broth culture medium: Accurately weigh 6 g of tryptic soy broth culture medium in a 500 ml beaker, add 200 ml of distilled water, fully dissolve by heating, transfer into a conical flask, add a cotton plug, and wrap the autoclave.
斜面培养基制备：称取胰蛋白大豆琼脂3.8g于500ml烧杯内，加入100ml蒸馏水，加热充分溶解，移入三角烧瓶内，加棉塞，包扎高压灭菌。稍冷却后，分装于7个试管内，每试管约10～15ml，倾斜适当角度，冷却备用。Preparation of slant culture medium: 3.8 g of tryptic soy agar was weighed into a 500 ml beaker, 100 ml of distilled water was added, dissolved sufficiently by heating, transferred into an Erlenmeyer flask, tampon added, and autoclaved by dressing. After a little cooling, it is divided into 7 tubes, about 10-15 ml per tube, tilted at an appropriate angle, and cooled for later use.
细菌扩增：打开ATCC 4300密封小瓶，用消毒后的小眼科镊夹取少量菌粉块，移入5ml离心管内，加胰蛋白大豆肉汤培养基0.6ml，混合均匀。平均分至7个斜面培养基内，既80μl/试管，涂布均匀。放入培养箱内，37℃培养24小时。Bacterial amplification: Open the ATCC 4300 sealed vial, take a small amount of bacterial powder block with a small ophthalmology clip after disinfection, transfer it into a 5 ml centrifuge tube, add 0.6 ml of tryptic soy broth medium, and mix well. The average was divided into 7 slant mediums, 80 μl/test tube, and evenly coated. It was placed in an incubator and cultured at 37 ° C for 24 hours.
菌悬液制备及细菌计数：用培养液将大试管内细菌洗下，移入无菌离心管中。混合均匀，制得菌悬液。移液枪取出一滴进行细菌密度测定。取洁净血细胞计数板一块，在计数区上盖上一块盖玻片，将所取的菌悬液用生理盐水稀释一定倍数，并吹打均匀，移液枪吸取少许，从计数板中间平台两侧的沟槽内沿盖玻片的下边缘滴入一滴(不宜过多)，让菌悬液利用液体的表面张力充满计数区，勿使气泡产生。将培养板置于显微镜下进行细菌计数。数出16小格的细菌总数，利用以下公式计算菌液浓度：Preparation of bacterial suspension and bacterial count: The bacteria in the large test tube were washed with the culture solution and transferred into a sterile centrifuge tube. Mix well and prepare a bacterial suspension. A drop of the pipette was taken for bacterial density determination. Take a clean blood cell counting plate, cover a counting piece on the counting area, dilute the bacterial suspension with physiological saline for a certain multiple, and blow evenly. Pipette a little, from the sides of the intermediate plate of the counting plate. A drop (not too much) is dropped into the groove along the lower edge of the cover glass, so that the bacterial suspension fills the counting area with the surface tension of the liquid, so that bubbles are not generated. The plate was placed under a microscope for bacterial count. Count the total number of bacteria in 16 cells, and calculate the concentration of the bacteria using the following formula:
细菌密度(个/ml)＝16小格细菌数×10 4×稀释倍数 Bacterial density (pieces/ml) = 16 small bacteria number × 10 4 × dilution factor
(3)96孔板接种(3) 96-well plate inoculation
样品的配制：首先将待测药物用少量DMSO充分溶解，然后用培养基配制成所需初始浓度，并依次稀释成各受试梯度。Preparation of the sample: First, the drug to be tested is fully dissolved in a small amount of DMSO, and then the culture medium is formulated into a desired initial concentration, and sequentially diluted to each test gradient.
菌液配制：根据菌浓度测定结果，将菌悬液用培养液(TSB)稀释成1.07×10 7cfμ/ml浓度的菌液。 Preparation of bacterial solution: According to the measurement result of the bacterial concentration, the bacterial suspension was diluted with a culture solution (TSB) to a bacterial solution having a concentration of 1.07 × 10 7 cf μ / ml.
加药方案：本实验分为阳性对照组、生理盐水组、空白对照组及各受试药组，其中各受试药组、生理盐水组、空白组均设6个梯度孔，阳性对照组为7个梯度孔。各孔分别依次加入50μl菌悬液、30μl培养液及20μl各样品溶液。Dosing regimen: The experiment was divided into positive control group, normal saline group, blank control group and each test group. Among them, there were 6 gradient wells in each test group, saline group and blank group. The positive control group was 7 gradient holes. 50 μl of the bacterial suspension, 30 μl of the culture solution, and 20 μl of each sample solution were sequentially added to each well.
培养及观察：加完样的96孔板置于恒温箱中培养。培养温度为37℃，培养时间为24小时。培养结束于超净台内观察各组菌落生长情况。菌液澄清、无浑浊、孔底部无菌落。浓度定为该药的最低抑菌浓度(MIC)。Culture and observation: The 96-well plate was added and placed in an incubator for cultivation. The culture temperature was 37 ° C and the culture time was 24 hours. The cultivation was completed in a clean bench to observe the growth of colonies in each group. The bacterial liquid is clear, no turbidity, and the bottom of the well is aseptic. The concentration is determined as the minimum inhibitory concentration (MIC) of the drug.
结果与结论Results and conclusions
采用微量稀释法以原液在96孔板的微孔稀释板逐孔稀释药液(第1～10孔),然后在第1～11孔加入50μL菌液,使第1～10孔中的药液浓度呈倍递减，第12孔加100μL培养基作空白对照。微孔稀释板震荡混合后，置垫有湿纱布的有盖瓷盘内37℃培养24小时，在有黑色背景的光源下观察结果。有菌生长呈球型、弥漫性浑浊或底部呈扣子样沉淀，无菌生长孔所含的最低药物浓度即为最低抑菌浓度。结果见表2。Dilute the drug solution (1st to 10th holes) by microdilution method in a microporous dilution plate of a 96-well plate, and then add 50 μL of the bacterial solution to the 1st to 11th holes to make the solution in the 1st to 10th holes. The concentration was reduced in multiples, and the 12th well was added with 100 μL of the medium as a blank control. After the microporous dilution plates were shaken and mixed, the cells were incubated at 37 ° C for 24 hours in a covered porcelain dish with wet gauze, and the results were observed under a light source with a black background. The bacteria grow in a spherical shape, diffuse turbidity or a button-like precipitate at the bottom. The minimum drug concentration contained in the sterile growth well is the minimum inhibitory concentration. The results are shown in Table 2.
表2 体外抗菌实验结果MIC值(μM)Table 2 MIC value (μM) of in vitro antibacterial test results
Figure PCTCN2018080281-appb-000011
Figure PCTCN2018080281-appb-000011
表2(续表) 体外抗菌实验结果MIC值(μM)Table 2 (continued) In vitro antibacterial test results MIC value (μM)
Figure PCTCN2018080281-appb-000012
Figure PCTCN2018080281-appb-000012
注：Note:
(1)细菌及真菌(带*为耐药菌)(1) Bacteria and fungi (with * for resistant bacteria)
1.蜡样芽孢杆菌2；2.枯草芽胞杆菌168；3.粪肠球菌29212；4*.粪肠球菌F2518(VRE)；5.金黄色葡萄球菌29231；6*.金黄色葡萄球菌43300(MRSA)；7*.金黄色葡萄球菌703(MRSA)；8*.肺炎链球菌6303(PRSP)；9.化脓肺炎链球菌M2；10.无乳链球菌B组；11.肺炎链球菌10351；12.炭疽杆菌Bacillus 1；13.白喉杆菌；14.产气荚膜杆菌；15.口腔念珠菌；16.皮真菌。1. Bacillus cereus 2; 2. Bacillus subtilis 168; 3. Enterococcus faecalis 29212; 4 *. Enterococcus faecalis F2518 (VRE); 5. Staphylococcus aureus 29231; 6 *. Staphylococcus aureus 43300 ( MRSA); 7*. Staphylococcus aureus 703 (MRSA); 8*. Streptococcus pneumoniae 6303 (PRSP); 9. Streptococcus pneumoniae M2; 10. Streptococcus agalactia B group; 11. Streptococcus pneumoniae 10351; 12. Bacillus anthracis Bacillus 1; 13. Diphtheria bacilli; 14. Clostridium perfringens; 15. Oral Candida; 16. Peel fungus.
(2)MIC值(μM)测定值(2) MIC value (μM) measured value
—代表MIC值(μM)>150μg/mL；+代表MIC值(μM)<150μg//mL；++代表MIC值(μM)<100μg//mL；+++代表MIC值(μM)<50μg//mL。- represents MIC value (μM) > 150 μg / mL; + represents MIC value (μM) < 150 μg / / mL; ++ represents MIC value (μM) < 100 μg / / mL; + + + represents MIC value (μM) < 50 μg //mL.
结论：in conclusion:
(1)表2显示本发明的实施例化合物具有很好的抗菌活性。特别值得注意的是实施例化合物2和3对于金黄色葡萄球耐药菌43300(MRSA)和金黄色葡萄球耐药菌703(MRSA)的MIC值(μM)分别是<50μg//mL。(1) Table 2 shows that the compounds of the examples of the present invention have excellent antibacterial activity. Of particular note is the MIC values (μM) of Example Compounds 2 and 3 for Staphylococcus aureus resistant strain 43300 (MRSA) and Staphylococcus aureus resistant 703 (MRSA), respectively, <50 μg//mL.
(2)化合物1,2,3,4,6,7,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,29,30,31,32和33分别对多种不同耐药菌，如粪肠球耐药菌F2518(VRE)、金黄色葡萄球耐药菌43300(MRSA)、金黄色葡萄球耐药菌703(MRSA)和肺炎链球耐药菌6303(PRSP)有抑制作用，其MIC值(μM)分别在<100μg//mL区间。(2) Compounds 1, 2, 3, 4, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27,29,30,31,32 and 33 respectively for a variety of different resistant bacteria, such as fecal enterotrophic bacteria F2518 (VRE), Staphylococcus aureus resistant strain 43300 (MRSA), golden yellow grape ball Drug-resistant bacteria 703 (MRSA) and pneumococcal resistance bacteria 6303 (PRSP) have inhibitory effects, and their MIC values (μM) are in the range of <100 μg//mL, respectively.
(3)化合物1,2,3,6,9,10,14,15,16,20,22,24,26,27和31对蜡样芽孢杆菌2、枯草芽胞杆菌168、粪肠球菌29212、粪肠球菌F2518(VRE)、金黄色葡萄球菌29231、金黄色葡萄球菌43300(MRSA)、金黄色葡萄球菌703(MRSA)、肺炎链球菌6303(PRSP)和化脓肺炎链球菌M2有效，MIC值(μM)分别在<100μg//mL区间。(3) Compounds 1, 2, 3, 6, 9, 10, 14, 15, 16, 20, 22, 24, 26, 27 and 31 against Bacillus cereus 2, Bacillus subtilis 168, Enterococcus faecalis 29212, Enterococcus faecalis F2518 (VRE), Staphylococcus aureus 29231, Staphylococcus aureus 43300 (MRSA), Staphylococcus aureus 703 (MRSA), Streptococcus pneumoniae 6303 (PRSP) and Streptococcus pneumoniae M2 are effective, MIC values ( μM) is in the <100 μg//mL interval.
(4)化合物1,5,6,9,13,14,16,17,21,22,23,24,25,26,27,28,29,30,31,32和33对口腔念珠菌有效，MIC值(μM)分别在<100μg//mL区间。(4) Compounds 1,5,6,9,13,14,16,17,21,22,23,24,25,26,27,28,29,30,31,32 and 33 are effective against oral Candida The MIC value (μM) was in the range of <100 μg//mL, respectively.
实施例35Example 35
体内抗菌实验实例In vivo antibacterial experiment example
1.材料Material
测试样品：化合物3、化合物5、化合物9、化合物10、化合物30，复方1，复方2Test sample: Compound 3, Compound 5, Compound 9, Compound 10, Compound 30, Compound 1, Compound 2
试验动物：昆明种健康小鼠,体重19～21g，雌雄各半分组，其它组单性别使用，由北京军事医学科学院药物研究所动物中心提供。Test animals: Kunming healthy mice, weighing 19-21 g, male and female, are divided into groups, and other groups are used by single sex. They are provided by the Animal Center of the Institute of Materia Medica, Beijing Academy of Military Medical Sciences.
菌株：金黄色葡萄球菌43300(MRSA)Strain: Staphylococcus aureus 43300 (MRSA)
2.方法2. Method
将小鼠随机分成空白对照组、阳性对照组、受试药品组，每组10只，雌雄各半。按小鼠体重0.2ml/10g腹腔接菌(MRSA-2152)，菌浓度为5.0×10 6cfu/ml，接菌后立即进行尾静脉注射给药，并于6小时后进行 第二次给药。观察30天，记录各组动物的存活期，计算阳性对照组及样品组的生命延长率： The mice were randomly divided into a blank control group, a positive control group, and a test drug group, with 10 rats in each group, half male and half female. According to the mouse body weight 0.2ml/10g abdominal cavity bacteria (MRSA-2152), the bacterial concentration was 5.0×10 6 cfu/ml, immediately after the inoculation, the tail vein injection was administered, and after 6 hours, the second dose was administered. . After 30 days of observation, the survival period of each group of animals was recorded, and the life extension rate of the positive control group and the sample group was calculated:
生命延长率％＝(受试组生存天数-空白组生存天数)/空白组生存天数×100％Life extension rate%=(the number of days in the test group - the number of days in the blank group) / the number of days in the blank group × 100%
3.结果与结论3. Results and conclusions
表3 动物的平均存活天数及生命延长率Table 3 Average survival days and life extension rate of animals
Figure PCTCN2018080281-appb-000013
Figure PCTCN2018080281-appb-000013
注：复方1为化合物30+环丙沙星，比例1:1Note: Compound 1 is compound 30 + ciprofloxacin, ratio 1:1
复方2为化合物5+环丙沙星，比例1:1Compound 2 is compound 5 + ciprofloxacin, ratio 1:1
体内试验表明，化合物3、化合物5、化合物9、化合物10、化合物30、复方1和复方2对耐药性金黄色葡萄球菌43300(MRSA)具有一定的抑制作用，给药时生命延长率均超过50％，复方与单方相比生命延长率明显提高，说明复方用药可以明显增强生命延长率。以上样品可以作为抗MRSA的进一步深入研究。In vivo tests showed that Compound 3, Compound 5, Compound 9, Compound 10, Compound 30, Compound 1 and Compound 2 had a certain inhibitory effect on drug-resistant Staphylococcus aureus 43300 (MRSA), and the life extension rate exceeded when administered. 50%, the life extension rate of the compound compared with the single side was significantly improved, indicating that the compound medication can significantly enhance the life extension rate. The above samples can be further studied as anti-MRSA.

Claims (9)

  1. 一种3-(2,4-二氟苯基)-5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物，其特征是：分子结构通式如下：A 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivative characterized by: molecular structure The formula is as follows:
    Figure PCTCN2018080281-appb-100001
    Figure PCTCN2018080281-appb-100001
    其中结构式I所述M +为：Li +、K +、Na +、Ca +/2,Mg +/2,Cu +/2和Fe +/2之一，可通过杂环酚羟基和各种碱及碱金属反应成盐，例如金属Li、金属Na、金属K、碳酸钠、氢化钠、氢氧化钠、氢氧化钾等无机碱、有机碱形成酚盐或复盐；结构式I所述含有氮原子具有碱性可通过和酸，如盐酸、硫酸、硝酸、富马酸、马来酸、琥珀酸、乙酸、柠檬酸、酒石酸、碳酸、磷酸、草酸等反应形成无机酸盐、有机酸盐或复盐。 Wherein M + in the formula I is: Li + , K + , Na + , Ca + / 2 , Mg + / 2 , Cu + / 2 and Fe + / 2 , which can pass through the heterocyclic phenolic hydroxyl group and various bases. And alkali metal reaction to form a salt, such as metal Li, metal Na, metal K, sodium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide and other inorganic bases, organic base to form a phenate or double salt; the formula I contains a nitrogen atom Alkaline can form inorganic acid salts, organic acid salts or complexes by reacting with acids such as hydrochloric acid, sulfuric acid, nitric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, etc. salt.
  2. 根据权利要求1所述的3-(2,4-二氟苯基)--5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物，结构式I所述的R为H、任意取代的芳环基、脂环基和/或芳环与脂环稠合组合基，可为结构式II中取代基1、2、3、4、5、6、7、8和9之一，其中化学结构8和9芳环所稠脂环为三碳、四碳或五碳脂环。The 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivative according to claim 1 and the like R, wherein R is H, an optionally substituted aryl ring group, an alicyclic group, and/or an aromatic ring fused combination, may be a substituent of formula II, 2, 3, 4, 5 One of 6, 7, 8, and 9, wherein the alicyclic ring of the chemical structure 8 and 9 aromatic rings is a three carbon, four carbon or five carbon alicyclic ring.
    Figure PCTCN2018080281-appb-100002
    Figure PCTCN2018080281-appb-100002
  3. 根据权利要求2所述的X可不存在、可分别为相同或不相同取代基，为任意取代的氢、卤素、羟基、巯基、氰基、羰基、取代羰基、醛基、酮基、硝基、羧基、取代羧基、羧酸酯基、仲氨基、叔氨基、二碳、三碳、四碳、五碳或六碳烷基氧基、芳基烷氧基、芳氧基、杂芳氧基、烷硫基、巯酯基、芳基烷硫基、芳硫基、杂芳硫基、酯基、酰氧基、磷酸氧基、磺酸氧基、芳香氧基、季铵盐基、酰胺基、肼基、肟基、腙基、含氮脂肪烃基、含氮芳香烃基、含氮环基、含氮脂环基、含氮芳香环基、含氮芳杂环基、磷化物基、磷酸基、磷酸酯基、一碳、二碳、三碳、四碳或五碳烷基以及与这些取代基组合基。The X may be absent, may be the same or different substituents according to claim 2, and may be an optionally substituted hydrogen, halogen, hydroxy, thiol, cyano, carbonyl, substituted carbonyl, aldehyde, keto, nitro, Carboxyl, substituted carboxy, carboxylate, secondary, tertiary, di, tri, tetra, penta or hexaalkyloxy, arylalkoxy, aryloxy, heteroaryloxy, Alkylthio, decyl ester, arylalkylthio, arylthio, heteroarylthio, ester, acyloxy, phosphooxy, sulfonateoxy, aryloxy, quaternary ammonium, amide , fluorenyl, fluorenyl, fluorenyl, nitrogen-containing aliphatic hydrocarbon group, nitrogen-containing aromatic hydrocarbon group, nitrogen-containing cyclic group, nitrogen-containing alicyclic group, nitrogen-containing aromatic ring group, nitrogen-containing aromatic heterocyclic group, phosphide group, phosphate group , phosphate groups, mono-, di-, tri-, tetra- or penta-alkyl groups and combinations with these substituents.
  4. 根据权利要求1所述结构式I，其特征是3-(2,4-二氟苯基)--5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物，包括抗菌药理活性和作为抗菌药物的应用，抗真菌药理活性和作为抗真菌药物的应用，包括与其它已知的抗菌、抗真菌、抗炎和抗病毒及免疫药物配伍使用，还包括对细菌感染伴随的炎症和炎症疾病、真菌和真菌疾病、病毒和病毒性疾病以及免疫系统疾病等与细菌感染的并发症的治疗 药物配伍使用、其单独或与已知的下述药物配合使用的给药剂量为0.02mg/kg-250mg/kg(静脉、肌肉注射、口服、局部用药等给药途径)；各种方法治疗和途径治疗，其中该细菌为革兰氏阳性菌：葡萄球菌、肺炎球菌、粪肠球菌、链球菌、牛链球菌，肺炎链球菌、消化链球菌、化脓肺炎链球菌、化脓肺炎链球菌、化脓性链球菌、无乳链球菌、绿色链球菌、牛链球菌、无乳链球菌B、组绿色链球菌、白喉杆菌、破伤风杆菌、丹毒杆菌、炭疽杆菌、破伤风杆菌、蜡样芽孢杆菌、枯草芽胞杆菌、梭状芽孢杆菌、蜡样芽孢杆菌、枯草芽胞杆菌、炭疽杆菌、白喉杆菌、梭状芽孢杆菌、破伤风杆菌、产气荚膜杆菌、产气荚膜杆菌螺旋体、放线菌、结核菌，其中该细菌为革兰氏阳性耐药菌，耐甲氧西林葡萄球菌、耐万古霉素金葡菌、葡萄球菌属诱导型克林霉素耐药、耐万古霉素肠球菌、肠球菌高水平耐氨基糖苷类、耐青霉素肺炎链球菌、多重耐药鲍曼不动杆菌、耐药与多重耐药结核杆菌与结核分枝杆菌、链球菌、粪肠球菌、铜绿假单胞菌、大肠埃希氏菌及鮑氏不动桿菌等、耐药流感嗜血杆菌、耐药淋球菌、耐药脑膜炎奈瑟菌、耐药肠杆菌科细菌、耐药铜绿假单胞菌。The structural formula I according to claim 1, characterized in that 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate Derivatives and analogues, including antibacterial pharmacological activities and applications as antibacterials, antifungal pharmacological activities and applications as antifungal agents, including compatibility with other known antibacterial, antifungal, anti-inflammatory and antiviral and immunological drugs Also used, in combination with inflammatory and inflammatory diseases associated with bacterial infections, fungal and fungal diseases, viral and viral diseases, and immune system diseases, in combination with therapeutic agents for complications of bacterial infection, either alone or with known The drug is administered in a dose of 0.02 mg/kg to 250 mg/kg (intravenous, intramuscular, oral, topical, etc.); various methods of treatment and route treatment, wherein the bacterium is a Gram-positive bacterium: Staphylococcus, pneumococcal, Enterococcus faecalis, Streptococcus, Streptococcus bovis, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus mutans, cattle Streptococcus, no Streptococcus B, group of Streptococcus mutans, diphtheria, tetanus, erysipe, anthrax, tetanus, Bacillus cereus, Bacillus subtilis, Clostridium, Bacillus cereus, Bacillus subtilis, anthrax Bacillus, diphtheria, Clostridium, tetanus, Clostridium perfringens, Clostridium perfringens, actinomycetes, tuberculosis, wherein the bacterium is Gram-positive, methicillin-resistant Staphylococcus, vancomycin-resistant Staphylococcus aureus, Staphylococcus-inducible clindamycin resistance, vancomycin-resistant Enterococcus, Enterococcus high-grade aminoglycoside-resistant, penicillin-resistant Streptococcus pneumoniae, multi-drug-resistant Bauman Acinetobacter, resistant and multi-drug resistant Mycobacterium tuberculosis and Mycobacterium tuberculosis, Streptococcus, Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli and Acinetobacter baumannii, Haemophilus influenzae , resistant gonococcus, resistant Neisseria meningitidis, resistant Enterobacteriaceae bacteria, resistant Pseudomonas aeruginosa.
  5. 根据权利要求1结构式I所述的3-(2,4-二氟苯基)--5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物的制备方法，其特征是：本发明所获得的化合物包括，但不局限于实施例：3-(2,4-Difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivative according to Claim 1 And a method for preparing an analog, characterized in that the compound obtained by the present invention includes, but is not limited to, the examples:
    3-(2,4-二氟苯基)-2-甲基-5-(4-(三氟甲基)苯基)吡唑并[1,5-a]嘧啶-7-酚钠、5-(4-氰基苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(4-硝基苯基)吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-5-(4-甲氧基苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-5-(4-(二甲氨基)苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(4-酚钠基)-吡唑并[1,5-a]嘧啶-7-酚钠、5-(4-羧酸钠苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、5-(4-磺酸钠苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(4-氨磺酰基苯基)吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(4-苯氧基苯基)吡唑并[1,5-a]嘧啶-7-酚钠、5-(4-甲酰基苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3,5-双(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、5-(4-乙氧基苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(6-(三氟甲基)吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠、5-(6-氰基吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(6-硝基吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-5-(6-甲氧基吡啶-3-基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-5-(6-(二甲氨基)吡啶-3-基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-5-(6-酚钠吡啶-3-基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、5-(4-氰基苯基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钾、5-(6-羧酸钠吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(4-(三氟甲基)苯基)吡唑并[1,5-a]嘧啶-7-酚钾、3-(2,4-二氟苯基)-2-甲基-5-(4-硝基苯基)吡唑并[1,5-a]嘧啶-7-酚钾、3-(2,4-二氟苯基)-5-(4-(二甲氨基)苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钾、3-(2,4-二氟苯基)-2-甲基-5-(4-氨磺酰基苯基)吡唑并[1,5-a]嘧啶-7-酚钾、3-(2,4-二氟苯基)-2-甲基-5-(6-(三氟甲基)吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钾、5-(6-氰基吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钾、3-(2,4-二氟苯基)-2-甲基-5-(6-亚磺酸钠吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(6-氨磺酰基吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟苯基)-2-甲基-5-(6-苯氧基吡啶-3-基)吡唑并[1,5-a]嘧啶-7-酚钠、3-(2,4-二氟 苯基)-5-(4-((2-(二甲氨基)乙基)氨基甲酰基)苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、5-(6-甲酰基吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠、5-(6-乙酰氧基吡啶-3-基)-3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚钠。3-(2,4-difluorophenyl)-2-methyl-5-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-7-phenol sodium, 5 -(4-cyanophenyl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4 -difluorophenyl)-2-methyl-5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7-phenolate, 3-(2,4-difluorophenyl -5-(4-Methoxyphenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4-difluorophenyl)-5- (4-(Dimethylamino)phenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4-difluorophenyl)-2-methyl -5-(4-phenol sodium)-pyrazolo[1,5-a]pyrimidine-7-phenol sodium, 5-(4-carboxylate phenyl)-3-(2,4-difluorobenzene 2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 5-(4-sulfonic acid sodium phenyl)-3-(2,4-difluorophenyl)-2 -methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4-difluorophenyl)-2-methyl-5-(4-sulfamoylphenyl)pyridinium Zoxa[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4-difluorophenyl)-2-methyl-5-(4-phenoxyphenyl)pyrazolo[1 , 5-a] pyrimidine-7-phenol sodium, 5-(4-formylphenyl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a] Pyrimidine-7-phenol sodium, 3,5-bis(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenol , 5-(4-ethoxyphenyl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-( 2,4-Difluorophenyl)-2-methyl-5-(6-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-7-phenol sodium, 5 -(6-Cyanopyridin-3-yl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-( 2,4-difluorophenyl)-2-methyl-5-(6-nitropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-phenolate sodium, 3-(2, 4-difluorophenyl)-5-(6-methoxypyridin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate sodium, 3-(2,4 -difluorophenyl)-5-(6-(dimethylamino)pyridin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate sodium, 3-(2, 4-difluorophenyl)-5-(6-phenol sodium pyridin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 5-(4-cyano group Phenyl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol potassium, 5-(6-carboxylatepyridine-3- 3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4-difluorophenyl)- 2-methyl-5-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-phenol potassium, 3-(2,4-difluorophenyl)-2 -methyl-5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidine-7-phenol potassium, 3-(2,4-difluorobenzene -5-(4-(Dimethylamino)phenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol potassium, 3-(2,4-difluorophenyl)- 2-methyl-5-(4-sulfamoylphenyl)pyrazolo[1,5-a]pyrimidin-7-phenol potassium, 3-(2,4-difluorophenyl)-2-methyl -5-(6-(Trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-phenol potassium, 5-(6-cyanopyridin-3-yl)-3 -(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol potassium, 3-(2,4-difluorophenyl)-2-methyl -5-(6-Sodium sulfinate-pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-phenolate, 3-(2,4-difluorophenyl)-2-methyl -5-(6-sulfamoylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4-difluorophenyl)-2-methyl- 5-(6-phenoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-7-phenol sodium, 3-(2,4-difluorophenyl)-5-(4-( (2-(Dimethylamino)ethyl)carbamoyl)phenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 5-(6-formylpyridine-3 -yl)-3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-phenol sodium, 5-(6-acetoxypyridine-3- Sodium (3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate.
  6. 根据权利要求1所述结构式I，3-(2,4-二氟苯基)--5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物，它们的制备方法，其特征是：在催化剂的作用下进行环合反应制备3-(2,4-二氟苯基)--5-取代-2-甲基吡唑并[1,5-a]嘧啶-7-酚，含有各种取代基的羰基乙酸乙酯化合物在催化剂作用下与4-(2,4-二氟苯基)-3-甲基-1H-吡唑-5-胺反应形成C-N键完成环合反应，该催化剂为脱水剂、有机酸和/或无机酸催化剂之一，采用四氢呋喃、1,4-二氧六环、乙氰、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、正己烷、甲苯等其中一种为溶剂，反应温度控制在-40℃至180℃条件下，可形成关键中间体3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚。The formula I, 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivative according to claim 1 And analogs, their preparation method, characterized in that a cyclone reaction is carried out under the action of a catalyst to prepare 3-(2,4-difluorophenyl)-5-substituted-2-methylpyrazole[1 , 5-a]pyrimidin-7-phenol, ethyl carbonylate compound containing various substituents under the action of a catalyst with 4-(2,4-difluorophenyl)-3-methyl-1H-pyrazole- The 5-amine reaction forms a CN bond to complete the cyclization reaction. The catalyst is one of a dehydrating agent, an organic acid and/or a mineral acid catalyst, and uses tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethyl One of the base carboxamide, N,N-dimethylacetamide, n-hexane, toluene and the like is a solvent, and the reaction temperature is controlled at -40 ° C to 180 ° C to form a key intermediate 3-(2,4- Difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenol.
  7. 根据权利要求4所述的3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物，其特征是：所述的3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物的药理活性和作为抗菌和抗真菌药物的应用，所述细菌和真菌等感染所造成的各种感染还包括对细菌感染伴随的炎症和炎症疾病、真菌和真菌疾病、病毒和病毒性疾病以及免疫系统疾病的并发症：甲氧西林敏感葡萄球菌、溶血性链球菌和肺炎链球菌所致的上、下呼吸道感染、皮肤软组织感染、尿路感染、败血症、心内膜炎等；亦可用于流感嗜血杆菌、奇异变形杆菌、大肠埃希菌敏感株所致的尿路感染以及肺炎，链球菌属、肺炎链球菌等革兰阳性球菌、以及流感嗜血杆菌、大肠埃希菌、奇异变形杆菌等中的敏感株所致的呼吸道感染、尿路感染、皮肤软组织感染、败血症、骨、关节感染和腹腔、盆腔感染，溶血性链球菌、肺炎球菌、敏感金葡菌等感染；草绿色链球菌和肠球菌所致心内膜炎以及气性坏疽、厌氧菌感染、炭疽、梅毒、淋病等。The 3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivative and analog according to claim 4, which is characterized in that : Pharmacological activity of the 3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs and as antibacterial and The use of antifungal drugs, the various infections caused by infections such as bacteria and fungi also include complications of inflammation and inflammatory diseases associated with bacterial infections, fungal and fungal diseases, viral and viral diseases, and diseases of the immune system: Upper and lower respiratory tract infections, skin and soft tissue infections, urinary tract infections, sepsis, endocarditis caused by oxycillin-sensitive Staphylococcus, hemolytic streptococcus and Streptococcus pneumoniae; also used for Haemophilus influenzae and Proteus mirabilis , urinary tract infections caused by Escherichia coli sensitive strains, and pneumonia, gram-positive cocci, such as Streptococcus, Streptococcus pneumoniae, and sensitive strains such as Haemophilus influenzae, Escherichia coli, and Proteus mirabilis Respiratory infections, urinary tract infections, skin and soft tissue infections, sepsis, bone and joint infections And abdominal, pelvic infection, hemolytic streptococcus, pneumococci, sensitive Staphylococcus aureus infection; endocarditis caused by Streptococcus viridans and enterococci and gas gangrene, anaerobic infection, anthrax, syphilis, gonorrhea, etc. .
  8. 根据权利要求4和5所述的3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物，其特征是：本发明所述的3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物及其用途，其中该化合物与至少选自以下一种或其组合已知的抗菌剂、抗真菌剂、抗炎剂或该试剂的可药用盐或前药一起配伍或联合用药，但不局限于以下药物，其中，包括：3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs according to claims 4 and 5, Characterized by the 3-(2,4-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and the analogues of the present invention and uses thereof Wherein the compound is compatible or combined with an antibacterial agent, an antifungal agent, an anti-inflammatory agent or a pharmaceutically acceptable salt or prodrug of at least one selected from the group consisting of: or a combination thereof, but is not limited to the following drugs Among them, including:
    β-内酰胺类：青霉素、普鲁卡因青霉素、苄星青霉素、甲氧西林、苯唑西林、氯唑西林、双氯西林钠、氨苄西林、阿莫西林、海他西林、羧苄西林、磺苄西林、替莫西林、呋苄西林、哌拉西林、阿洛西林、美洛西林、替卡西林、美西林、阿帕西林、阿扑西林、仑氨西林、氟氯西林、舒他西林、匹氨西林、酞氨西林、巴氨西林、卡茚西林、呋布西林、头孢曲松、头孢匹罗、头孢呋辛、头孢呋辛酯、头孢噻肟、头孢噻吩、头孢噻啶、头孢硫脒、头孢乙腈、头孢匹林、头孢唑林、头孢甲肟、头孢哌酮、头孢克洛、头孢唑肟、头孢他啶、头孢尼西、头孢地尼、头孢克肟、头孢拉宗、头孢匹胺、头孢咪唑、头孢特仑、头孢泊肟酯、头孢地秦、头孢替安、头孢他美、头孢唑南、头孢丙烯、头孢布烯、头孢吡肟、头孢氨苄、头孢拉定、头孢克罗、头孢曲秦、头孢羟氨苄、头孢孟多、头孢磺啶、头孢西丁、头孢美唑、头孢替坦、头孢米诺、拉氧头孢、头孢卡品酯、头孢唑兰、头孢替安、头孢雷特、头孢克定、头孢噻利、氯碳头孢、氟氧头孢，大环内酯类：地红霉素、罗红霉素、罗地霉素、克拉霉素、氟红霉素、阿奇霉素、罗他霉素、他克美司、红霉素、依托红霉素、克拉霉素、吉他霉素、麦白霉素、柱晶白霉素、麦迪霉素、阿奇霉素、交沙霉素、螺旋霉素、乙酰螺旋霉素，氨基糖苷类：奈替米星、阿司米星、阿贝卡星、异帕米星链霉素、卡拉霉素、庆大霉素、妥布霉素、阿米卡星、西索米星、新霉素、巴龙霉素、福提米星、小诺米星、异帕米星、地贝米星、达地米星、大观霉素、链霉素、卡那霉素、依替米星、地贝卡星，酰胺醇类：氯霉 素、琥珀氯霉素、棕榈氯霉素、甲砜霉素，林可霉素、克林霉素、克林霉素磷酸酯，多肽多烯类：环孢素、替考拉宁、培洛霉素多粘菌素、多粘霉素、万古霉素、去甲万古霉素、杆菌肽、多粘菌素B、夫西地酸、米卡霉素，利福霉素类：利福布汀、利福喷汀、利福昔明、利福平、利福霉素、利福定，喹诺酮类药物：依诺沙星、托氟沙星、诺氟沙星、环丙沙星、洛美沙星、司氟沙星、培氟沙星、氟罗沙星、替马沙星、沙氟沙星、莫西沙星、特伐沙星、格帕沙星、氧氟沙星、左氧氟沙星、帕楚沙星、芦氟沙星、磺胺异恶唑、磺胺甲恶唑、磺胺嘧啶、磺胺醋酰钠、磺胺嘧啶银、甲氧苄啶、吡哌酸、呋喃妥因、呋喃唑酮，萘啶酸，氨氟沙星、加替沙星、帕珠沙星、曲氟沙星、酸莫西沙星，四环素类：四环素，甲烯土霉素，米诺环素，金霉素，强力霉素，土霉素、多西环素、美他环素、地美环素、胍甲环素，β-内酰胺酶抑制剂：克拉维酸、舒巴坦、三唑巴坦，碳青霉烯类抗生素：亚胺培南、西司他丁、帕尼培南、倍他米隆、美罗培南、头霉素，磺胺类：磺胺米隆、磺胺二甲嘧啶、磺胺二甲异嘧啶、磺胺苯吡唑、磺胺间甲氧嘧啶、碘胺对甲氧嘧啶、碘胺多辛、磺胺脒、磺胺嘧啶锌、磺胺林、琥珀磺胺噻唑、联磺甲氧苄啶、酞磺胺噻唑、硫霉素、克拉维酸、氨曲南、亚胺培南、法罗培南、西司他丁、舒巴坦、三唑巴坦、卡芦莫南、西索米星、氯霉素棕榈酸酯、磷霉素、SV、溴莫普林、奥替尼啶、乌洛托品、孟德立胺、次水杨酸铋、甲硝唑磷酸二钠、舒哌酮、新灭菌、甲硝唑，阿柔比星、表柔比星、佐柔比星、吡柔比星、伊达比星、莫匹罗星、硝咪唑、替硝唑、吡哌酸、呋喃妥因，硝基呋喃类：呋喃唑酮、甲氧苄啶，甲基呋喃类：柳氮磺吡啶，抗真菌类：硫康唑、拉诺康唑、齐诺康唑、布康唑、氯康唑、硝酸芬替康唑、舍他康唑、奥昔康唑、联苯苄唑、氟康唑、伊曲康唑、沙康唑、克霉唑、益康唑、噻康唑、咪康唑、酮康唑、萘替芬、布替萘芬、环吡酮、阿莫罗芬、两性霉素B、球红霉素、氟胞嘧啶、特比奈芬、制霉菌素、灰黄霉素、克念菌素。--lactams: penicillin, procaine penicillin, benzathine penicillin, methicillin, oxacillin, cloxacillin, dicloxacillin sodium, ampicillin, amoxicillin, hetacillin, carbenicillin, Sulbenillin, temocillin, furazocillin, piperacillin, azlocillin, mezlocillin, ticarcillin, mecillin, apacillin, apocillin, lenampicillin, flucloxacillin, sulbaccillin , piramacillin, acesulfamecil, bacilcillin, carocycline, furbuterazine, ceftriaxone, cefpirome, cefuroxime, cefuroxime axetil, cefotaxime, cefotaxime, cefotaxime, cephalosporin Thiopurine, cefacid, cefpirin, cefazolin, cefmenoxime, cefoperazone, cefaclor, ceftizoxime, ceftazidime, cefonicid, cefdinir, cefixime, cefradine, cefpi Amine, cefmenoxime, ceftiram, cefpodoxime, cefdiprozil, cefotiam, cefetamet, ceftizox, cefprozil, ceftibuten, cefepime, cephalexin, cephradine, cefaclor, Ceftriaxone, cephalosporin Ampicillin, cefmenudene, cefsulodin, cefoxitin, cefmetazole, cefotetan, cefminox, cephalosporin, cefaclor, cefazolin, cefotiam, ceftriax, cefixime , cefotaxime, chlorocarbon cephalosporin, fluoxetine, macrolides: dirithromycin, roxithromycin, ropoxmycin, clarithromycin, fluoroerythromycin, azithromycin, rotamycin, Tacomus, erythromycin, erythromycin, clarithromycin, guitarmycin, melamycin, columnar leucomycin, medimycin, azithromycin, josamycin, spiramycin, acetylspira , aminoglycosides: netilmicin, astemizine, arbekacin, isepamicin streptomycin, caramycin, gentamicin, tobramycin, amikacin, cisplatin Michelin, neomycin, paromomycin, formimicin, small nomitellin, isepamicin, dibemimethine, dardimethine, spectinomycin, streptomycin, kanamycin, Etimicin, dibekacin, amide alcohols: chloramphenicol, amber chloramphenicol, palm chloramphenicol, thiamphenicol, lincomycin, clindamycin, gram Polyphosphates, polypeptide polyenes: cyclosporine, teicoplanin, polymycin, polymyxin, vancomycin, norvancomycin, bacitracin, polymyxin B, fusidic acid, micammycin, rifamycin: rifabutin, rifapentine, rifaximin, rifampicin, rifamycin, rifampicin, quinolones: Enoxacin, toloxacin, norfloxacin, ciprofloxacin, lomefloxacin, serfloxacin, pefloxacin, fleroxacin, temafloxacin, haloxacin, moxifloxacin , valvafloxacin, gepafloxacin, ofloxacin, levofloxacin, pazufloxacin, rufloxacin, sulfisoxazole, sulfamethoxazole, sulfadiazine, sodium sulfacetamide, silver sulfadiazine, Trimethoprim, pipemidic acid, nitrofurantoin, furazolidone, nalidixic acid, amlodipine, gatifloxacin, pazufloxacin, troxafloxacin, moxifloxacin, tetracyclines: tetracycline, terpene , minocycline, chlortetracycline, doxycycline, oxytetracycline, doxycycline, metacycline, dimecycline, indomethacin, beta-lactamase inhibitor Clavulanic acid, sulbactam, tazobactam, carbapenem antibiotics: imipenem, cilastatin, panipenem, betamethepone, meropenem, cephalosin, sulfonamides: Sulfametholone, sulfamethazine, sulfamethazine, sulfamethoxazole, sulfamonomethoxine, iodine-p-methoxypyrimidine, iodine, sulfaguanidine, zinc sulfadiazine, sulfamethamine, amber sulfonamide Thiazole, thiazolidine, sulfamethoxazole, thienamycin, clavulanic acid, aztreonam, imipenem, faropenem, cilastatin, sulbactam, tazobactam, carumimo South, sirmimycin, chloramphenicol palmitate, fosfomycin, SV, bromoprolin, octenidine, urotropine, montadylamine, bismuth subsalicylate, metronidazole phosphate disodium , sulpirone, new sterilization, metronidazole, arubicin, epirubicin, zorubicin, pirarubicin, idarubicin, mupirocin, nimidazole, tinidazole, Pipemidic acid, nitrofurantoin, nitrofuran: furazolidone, trimethoprim, methylfuran: sulfasalazine, antifungal: thiconazole, lanoconazole, Zinorconazole, butoconazole, cloconazole, fenteconazole nitrate, sheraconazole, oxconazole, bifonazole, fluconazole, itraconazole, saconazole, clotrimazole , econazole, tioconazole, miconazole, ketoconazole, naftifine, butenafine, ciclopirox, amorolfine, amphotericin B, erythromycin, flucytosine, special Bienfene, nystatin, griseofulvin, and flunin.
  9. 根据权利要求1、4和5所述的3-(2,4-二氟苯基)-2-甲基吡唑并[1,5-a]嘧啶-7-酚盐类衍生物和类似物，其特征是：本发明药物化合物的给药途径包括：口服、非胃肠道、皮下、静脉内、肌内、腹膜内、透皮、颊、鞘内、颅内、鼻内或局部途径进行给药。3-(2,4-Difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-phenolate derivatives and analogs according to claims 1, 4 and 5 , characterized in that the route of administration of the pharmaceutical compound of the present invention comprises: oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes. Dosing.
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