WO2020019289A1 - 新型罗丹明染料及其在抗致病菌中的应用 - Google Patents

新型罗丹明染料及其在抗致病菌中的应用 Download PDF

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WO2020019289A1
WO2020019289A1 PCT/CN2018/097386 CN2018097386W WO2020019289A1 WO 2020019289 A1 WO2020019289 A1 WO 2020019289A1 CN 2018097386 W CN2018097386 W CN 2018097386W WO 2020019289 A1 WO2020019289 A1 WO 2020019289A1
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optionally substituted
alkyl
compound
nmr
cdcl
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PCT/CN2018/097386
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French (fr)
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杨有军
陈代杰
钱旭红
罗潇
邵雷
董晓景
钱鎏佳
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华东理工大学
上海医药工业研究院
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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the field of biomedicine, in particular to a new rhodamine dye and its application in resisting pathogenic bacteria.
  • Antibiotics are weapons developed by humans in the last century to fight bacterial infections. In just a few decades from the 1930s to the 1970s, more than 20 classes of antibiotics with the same structure and mechanism of action were found. Their widespread use has saved the lives of a large number of patients. Therefore, antibiotics are hailed as one of the greatest inventions in medical history.
  • the two main development methods of new antibiotics include structurally derivatizing known antibiotics to develop metoto drugs and screening new chemical spaces to discover new types of antibiotics.
  • metoto drugs of existing drugs are also more likely to cause bacterial resistance, so the final way out is still to find a chemical space that is expected to discover new antibiotics, further screening to find active leaders, and drug development.
  • the first aspect herein provides compounds represented by Formula A, including compounds of Formulas BI, BII, BIII, BIV, BV, BVI, BVII, BVIII, BIX, and CI-CXIII.
  • a second aspect herein provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of the compounds of Formula A and a pharmaceutically acceptable carrier; and optionally a known antibacterial agent.
  • a third aspect of the present invention provides the use of a compound represented by the general formula A for antibacterial or enhancing the antibacterial activity of a known antibacterial drug, including the preparation of an antibacterial drug or the preparation of a drug for enhancing the antibacterial activity of a known antibacterial drug.
  • a fourth aspect of the present invention provides an antibacterial method comprising administering to a subject in need thereof any one or more compounds represented by Formula A of the present invention.
  • a fifth aspect of the present invention provides a method for improving the antibacterial activity of an antibacterial agent, which comprises administering one or more compounds represented by Formula A or a pharmaceutical composition thereof before, at the same time or after administration of the antibacterial agent.
  • a sixth aspect of the present invention provides a method for preparing a compound of the general formula A.
  • Figure 1 Bactericidal curves of compounds CXIIIo, vancomycin, linezolid, and tigecycline against methicillin-resistant Staphylococcus aureus (ATCC43300) in early logarithmic growth.
  • Figure 2 The bactericidal curve of compounds CXIIIo and tigecycline against Acinetobacter baumannii (ATCC19606) at an early logarithmic growth stage.
  • Figure 3 Bactericidal curves of compounds CXIIIo, vancomycin and linezolid against vancomycin-resistant Enterococcus faecalis (ATCC51299) at an early logarithmic growth stage.
  • Figure 4 Methicillin-resistant Staphylococcus aureus (ATCC43300) induced resistance to CXIIIo.
  • Figure 5 A methicillin-sensitive strain of Staphylococcus aureus (ATCC25923) to induce resistance to CXIIIo.
  • the present invention synthesizes a rhodamine dye library with structural diversity. After screening with different bacterial models, it was found that the compounds in the compound library had bactericidal effects on Gram-positive bacteria (including drug-resistant bacteria) and Gram-negative bacteria, and it was also found that some molecules in the compound library could enhance drug resistance The susceptibility of bacteria to ⁇ -lactam antibiotics. It has been reported in the literature that rhodamine modified antimicrobial peptides or rhodamine modified spermine with antibacterial activity have certain antibacterial activity. In these documents, rhodamine dyes as a control compound have not been found to have antibacterial activity per se. Therefore, the present invention is the first time that it is clearly confirmed that the reasonably substituted rhodamine dye can have strong bactericidal, bacteriostatic and antibacterial synergistic activities.
  • alkyl generally refers to an alkyl group having less than 10 carbon atoms, that is, a C1-C10 alkyl group, such as a C1-6 alkyl group or a C1-4 alkyl group.
  • an alkyl group can be a linear or linear alkyl group.
  • Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl, and octyl.
  • the alkyl group may be substituted.
  • the number of substituents may be 1, 2, 3, or 4, and the substituent may include, but is not limited to, a bridged cycloalkane group (such as adamantyl), a hydroxyl group, an alkoxy group, and optionally Substituted aryl, carboxyl, optionally substituted aralkyl, halogen, nitro, and the like.
  • alkenyl refers to a linear or branched C2-C10 alkenyl group, and usually contains at least one double bond in the chain.
  • the carbon chain length of an alkenyl group can be 2-6 carbon atoms.
  • Typical alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.
  • the alkenyl group may be substituted.
  • the number of substituents may be 1, 2, 3 or 4, and the substituents may include, but are not limited to, carboxyl, halogen, hydroxyl, alkoxy, nitro, optionally substituted aryl And optionally substituted the following groups:
  • alkoxy refers to an oxy group substituted with an alkyl group as described herein, such as a C1-C10 alkoxy group, a C1-C6 alkoxy group, or a C1-C4 alkoxy group.
  • the alkyl group in the alkoxy group may be optionally substituted as described above.
  • alkylmercapto refers to a thiol substituted with an alkyl group as described herein, i.e., alkyl-S-, such as C1-C6 alkyl-S-.
  • alkyl-S- such as C1-C6 alkyl-S-.
  • the alkyl group in the alkyl mercapto group may be optionally substituted as described above.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • aryl refers to a monocyclic, bicyclic, or polycyclic aromatic group.
  • the aryl group may include a C6-C14 aryl group, or a C6-C10 aryl group.
  • Typical aryl groups include phenyl, naphthyl, phenanthryl, anthryl, indenyl, fluorenyl, fluorenyl, and perylene (fluorenyl).
  • the aryl group may be substituted.
  • the number of substituents may be 1, 2, 3, 4 or 5, and the substituents may include, but are not limited to, halogen, hydroxyl, nitro, carboxyl, C1-C6 alkoxy, C1 -C6 alkoxycarbonyl, optionally substituted aryldiazo, alkylthiol, alkoxy, (CO) 3 Cr-, -SO 3 , -SO 2 Cl, optionally substituted C1-C6 alkyl, C1-C6 aldehyde, mercapto, NR a R b , optionally substituted aryl, PPh 2 , cyano, tert-butyldimethylsilyl-O-(-OTBS), bridged cycloalkane or lower :
  • heteroaryl refers to a group containing 5 to 14 ring atoms and having 6, 10 or 14 ⁇ electrons in common on the ring system.
  • the ring atoms contained in heteroaryl groups are carbon atoms and 1-3 heteroatoms optional from oxygen, nitrogen and sulfur.
  • heteroaryl groups include, but are not limited to, thienyl, benzo [d] isothiazol-3-yl, benzo [b] thienyl, naphtho [2,3-b] thienyl, thienyl, furanyl , Pyranyl, isobenzofuranyl, chromenyl, oxanthene, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (including but not limited to 2-pyridyl, 3-pyridyl, and 4- (Pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinazinyl, isoquinoline Base, quinolinyl, phthalazinyl, naphthyridinyl, quin
  • heteroaryl may be optionally substituted.
  • the number of substituents on the heteroaryl group can be 1, 2, 3, or 4 and can be selected from C1-C6 alkyl, NR a R b , halogen, carboxyl, C1-C6 alkoxy, nitrate Group, aryl-substituted C1-C6 alkyl (such as trityl), optionally substituted biphenyl-C1-C6 alkyl, hydroxyl group, and the like.
  • R a and R b are each independently selected from: H, C1-C6 alkyl and C1-C6 acyl.
  • carbocyclic groups include saturated or partially saturated carbocyclic groups.
  • Saturated carbocyclic groups include cycloalkyl and bridged cycloalkane groups, such as C3-8 cycloalkyl, bicyclic hydrocarbon group, tricyclic hydrocarbon group, and tetracyclic hydrocarbon group.
  • Typical cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Typical bridged cycloalkane groups are adamantyl.
  • Partially saturated carbocyclic groups can be cycloalkenyl, such as C3-8 cycloalkenyl, such as cyclopentenyl, cycloheptenyl, and cyclooctenyl.
  • heterocycle or heterocyclyl refers to a saturated or partially saturated 3-7 membered monocyclic ring, or a 7 to 10 membered bicyclic ring system, or a polycyclic ring system, which consists of carbon atoms and optionally 1 from O, N, and S. -4 heteroatoms, including the fusion of any heterocycle and a benzene ring as defined above in a bicyclic system.
  • saturated or partially saturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, and dihydroindane Indyl, isoindolyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetranoyl, tetramoyl and the following groups:
  • Heterocyclyl can be optionally substituted with 1, 2, 3 or 4 substituents selected from: optionally substituted C1-C6 alkyl, C1-C6 cycloalkyl, halogen, NR a R b , optionally Piperazinyl, hydroxyl and carboxyl groups substituted by 1-3 C1-C6 alkyl groups.
  • aryl, heteroaryl, carbocyclyl, and heterocyclyl may be selected by one or more (e.g., 1, 2, 3, or 4) Substituted from the following groups: halogen, hydroxy, carboxyl, amino, nitro, cyano, C1-6 amido, C1-6 acyloxy, C1-6 alkoxy, aryloxy, alkylthio , C1-6 alkyl, C6-10 aryl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl (C2-6) alkenyl, C6-10 Aryl (C2-6) alkynyl, saturated and unsaturated heterocyclic or heteroaryl, methylenedioxy, C1-6 haloalkyl, C6-10aryl (C1-6) alkyl, C1 -6Hydroxyalkyl, ureido, mercapto, azide,
  • alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl may be selected from one or more (e.g. 1, 2, 3 or 4) selected from the following Substituent group substitution: halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-6 amido, C1-6 acyloxy, C1-6 alkoxy, aryloxy, alkylthio, C1 -6 alkyl, C6-10 aryl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl (C2-6) alkenyl, C6-10 aryl (C2-6) alkynyl, saturated and unsaturated heterocyclic or heteroaryl, methylenedioxy, C1-6 haloalkyl, C6-10 aryl (C1-6) alkyl, C1-6 Hydroxyalkyl, ureido, mercapto, azide
  • alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, carbonyl, carbocyclic and heterocyclic rings may be substituted by one or more (e.g.
  • a substituent selected from the group consisting of halogen, hydroxy, carboxy, amino, nitro, cyano, C1-6 amido, C1-6 acyloxy, C1-6 alkoxy Aryl, aryloxy, alkylthio, C1-6 alkyl, C6-10 aryl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl (C2- 6) Alkenyl, C6-10 aryl (C2-6) alkynyl, saturated and unsaturated heterocyclic or heteroaryl.
  • C1-C6 acyl refers to C1-C5 alkyl-C (O)-, such as acetyl.
  • the invention provides compounds of formula A:
  • X - is an anion constituting the salt include, but are not limited to, F -, Cl -, Br - , I -, OAc -, HSO 4 -, H 2 PO 4 -, ClO 4 -, F 3 CCOO -, CH 3 SO 3 -, CF 3 SO 3 - , BF 4 -, PF 6 -, citrate, and NO 3 -;
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from H, halogen, and C1-C6 alkyl;
  • R 5 , R 6 , R 7 , R 8 are each independently selected from H and C1-C6 alkyl
  • R 5 and R 7 may form an optionally substituted 5 or 6 membered nitrogen-containing heterocyclic ring with the N to which they are attached, and / or R 6 and R 8 may form an optionally substituted 5 or 6 with the N to which they are attached
  • a 6-membered nitrogen-containing heterocyclic ring wherein said 5 or 6-membered nitrogen-containing heterocyclic ring optionally contains an epoxy atom; or R 3 and R 7 together with the atoms to which they are each attached form a 6-membered nitrogen-containing heterocyclic ring, and / Or R 4 and R 8 together with the atoms to which they are attached form a 6-membered nitrogen-containing heterocyclic ring;
  • R 1 and R 5 may form an optionally substituted 6-membered nitrogen-containing heterocyclic ring with the atom to which they are attached
  • R 3 and R 7 may form an optionally substituted 6-membered nitrogen-containing heterocyclic ring with the atom to which they are attached
  • / or R 2 and R 6 may form an optionally substituted 6-membered nitrogen-containing heterocyclic ring with the atom to which they are attached
  • R 4 and R 8 may form an optionally substituted 6-membered nitrogen-containing heterocyclic ring with the atom to which they are attached Heterocyclic
  • R 9 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted C2-C6 alkenyl.
  • the substituent of the optionally substituted group is as defined in the first part of the foregoing, or is a substituent at a corresponding position in any specific structural formula below.
  • R 1 and R 2 are each independently H.
  • R 3 and R 4 are each independently H or C1-C6 alkyl.
  • R 5 , R 6 , R 7 , R 8 are each independently selected from H and C1-C6 alkyl.
  • R 5 and R 7 form an optionally substituted 5 or 6 membered nitrogen-containing heterocyclic ring (such as pyrrolidin or piperidinyl) with the N to which they are attached
  • / or R 6 and R 8 May form an optionally substituted 5 or 6-membered nitrogen-containing heterocyclic ring (such as pyrrolidinyl or piperidinyl) with the N to which they are attached
  • the 5 or 6-membered nitrogen-containing heterocyclic ring optionally contains an epoxy atom (Such as morpholinyl).
  • R 1 and R 2 are each independently H, and R 5 and R 6 are each independently H or C1-C6 alkyl; R 3 and R 7 together with the atoms to which they are attached form a 6-membered A nitrogen heterocyclic ring and R 4 and R 8 together with the atoms to which they are attached form a 6-membered nitrogen-containing heterocyclic ring.
  • R 9 is selected from: C1-C6 alkyl, optionally substituted with adamantyl or phenyl, said adamantyl is optionally substituted with 1 to 3 selected from hydroxyl, C1-C6 alkoxy And C1-C6 alkyl substituents, the phenyl is optionally substituted with 1 to 3 substituents selected from hydroxyl and C1-C6 alkoxy; phenyl is optionally substituted with 1 to 3 selected from The nitro, halogen, C1-C6 alkyl, phenyldiazyl or naphthyldiazyl substituent is substituted, wherein the phenyldiazyl or naphthyldiazo group is optionally selected from 1 to 3 Substituted from halogen and NR a R b substituents; 1,3-benzodioxolyl optionally substituted with nitro.
  • R 1 and R 2 are each independently H; R 3 and R 4 are each independently H or C1-C6 alkyl; R 5 , R 6 , R 7 , R 8 are each Independently selected from H and C1-C6 alkyl, or R 5 and R 7 and the N to which they are attached form an optionally substituted 5 or 6 membered nitrogen-containing heterocyclic ring (such as pyrrolidinyl or piperidinyl), and / or R 6 and R 8 may form an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic ring (such as pyrrolidinyl or piperidinyl) with N to which they are attached; wherein the 5- or 6-membered nitrogen-containing heterocyclic ring is optionally Ground contains epoxy atoms (such as morpholinyl), or R 3 and R 7 form a 6-membered nitrogen-containing heterocyclic ring together with the atoms to which they are attached and R 4 and R 8 form a 6-membered
  • compounds of Formula A do not include the following compounds: Compounds BIb, BIf, BIg, BIIb, BIIe, BIIf, BIIIa, BIIIc, BIIIf, BIIIg, BIIIk, BVIa, BVIIIb, BIXa-BIXe, CIa- CIe, CIg, CIk, CIu, and CXIIIb.
  • R 9 is selected from optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • X - selected from, but not limited to, F -, Cl -, Br - , I -, OAc -, HSO 4 -, H 2 PO 4 -, ClO 4 -, F 3 CCOO -, CH 3 SO 3 -, CF 3 SO 3 ⁇ , BF 4 ⁇ , PF 6 ⁇ , citrate and NO 3 ⁇ .
  • the optionally substituted C1-C6 alkyl is a C1-C6 alkyl optionally substituted with adamantyl.
  • the optionally substituted aryl is optionally selected from 1 to 3 selected from C1-C6 alkyl, halogen, hydroxyl, nitro, carboxyl, C1-C6 alkoxycarbonyl, benzene A phenyl group substituted with a diazonium group and a C1-C6 alkylthio group.
  • the optionally substituted heteroaryl is a C1-C6 alkyl optionally substituted with 1 to 3 selected from C1-C6 alkyl, hydroxyl, triphenylmethyl, and phenyl , Halogen and carboxy substituted heteroaryl.
  • the heteroaryl group is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, or pyrrolyl.
  • R 9 in Formula BI is selected from C1-C6 alkyl optionally substituted with adamantyl and optionally from 1 to 3 selected from halogen, nitro, C1-C6 alkoxy Phenyl substituted with carbonyl, phenyldiazo and C1-C6 alkylthio. In certain embodiments, R 9 is adamantyl substituted C1-C6 alkyl.
  • Compounds of formula BI are useful for inhibiting resistant bacteria, such as methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii sensitive strains.
  • compounds of Formula BI do not include compounds BIb, BIf, and BIg.
  • the structure of the compound of Formula A is represented by Formula BII:
  • R 9 is selected from optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • X - selected from, but not limited to, F -, Cl -, Br - , I -, OAc -, HSO 4 -, H 2 PO 4 -, ClO 4 -, F 3 CCOO -, CH 3 SO 3 -, CF 3 SO 3 ⁇ , BF 4 ⁇ , PF 6 ⁇ , citrate and NO 3 ⁇ .
  • the optionally substituted C1-C6 alkyl is a C1-C6 alkyl optionally substituted with adamantyl.
  • the optionally substituted aryl is optionally selected from 1 to 3 selected from C1-C6 alkyl, halogen, hydroxyl, nitro, carboxyl, C1-C6 alkoxycarbonyl, benzene A phenyl group substituted with a diazonium group and a C1-C6 alkylthio group.
  • the optionally substituted heteroaryl is a C1-C6 alkyl optionally substituted with 1 to 3 selected from C1-C6 alkyl, hydroxyl, triphenylmethyl, and phenyl , Halogen and carboxy substituted heteroaryl.
  • the heteroaryl group is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, or pyrrolyl.
  • R 9 in formula BII is selected from C1-C6 alkyl optionally substituted with adamantyl and optionally substituted with 1 to 3 selected from nitro and phenyldiazo. Substituted phenyl. In certain embodiments, R 9 is adamantyl substituted C1-C6 alkyl.
  • Compounds of formula BII are useful for inhibiting resistant bacteria, such as methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii sensitive strains.
  • compounds of general formula BII do not include compounds BIIb, BIIe, and BIIf.
  • R 9 is selected from optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • X - selected from, but not limited to, F -, Cl -, Br - , I -, OAc -, HSO 4 -, H 2 PO 4 -, ClO 4 -, F 3 CCOO -, CH 3 SO 3 -, CF 3 SO 3 ⁇ , BF 4 ⁇ , PF 6 ⁇ , citrate and NO 3 ⁇ .
  • the optionally substituted C1-C6 alkyl is optionally substituted with adamantyl or hydroxy.
  • the optionally substituted aryl is optionally substituted by 1 to 3 selected from C1-C6 alkyl, halogen, hydroxyl, nitro, carboxyl, C1-C6 alkyl, C1-C6 Substituted phenyl for alkoxycarbonyl, phenyldiazo, -Cr (CO) 3 and C1-C6 alkylthio.
  • the optionally substituted heteroaryl is a C1-C6 alkyl optionally substituted with 1 to 3 selected from C1-C6 alkyl, hydroxyl, triphenylmethyl, and phenyl , Halogen and carboxy substituted heteroaryl.
  • the heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, or pyrrolyl.
  • R 9 in Formula BIII is selected from C1-C6 alkyl optionally substituted with adamantyl and optionally from 1 to 3 selected from nitro and C1-C6 alkoxy Substituted phenyl. In certain embodiments, R 9 is adamantyl substituted C1-C6 alkyl.
  • Compounds of formula BIII are useful for inhibiting resistant bacteria, such as methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii sensitive strains.
  • R 9 in Formula BIII is pyridyl optionally substituted with 1 to 3 C1-C6 alkyl.
  • R 9 is pyridyl substituted with 1 C1-C6 alkyl, and the substituent is on the N atom.
  • the compound of formula BIII has an antibacterial synergistic effect and can enhance the antibacterial effect of other antibacterial compounds, for example, can enhance the antibacterial activity of antibacterial drugs against methicillin-resistant Staphylococcus aureus.
  • compounds of Formula BIII do not include compounds BIIIa, BIIIc, BIIIf, BIIIg, and BIIIk.
  • R 9 is selected from an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocyclic group, and an optionally substituted C2-C6 alkenyl group;
  • X - selected from, but not limited to, F -, Cl -, Br - , I -, OAc -, HSO 4 -, H 2 PO 4 -, ClO 4 -, F 3 CCOO -, CH 3 SO 3 -, CF 3 SO 3 ⁇ , BF 4 ⁇ , PF 6 ⁇ , citrate and NO 3 ⁇ .
  • the substituents of the optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted C2-C6 alkenyl are as previously described in the first part Or as described below for the corresponding group of formula CI-CXIII.
  • compounds of Formula BIV do not include compounds CIa-CIe, CIg, CIk, CIu, and CXIIIb.
  • the structure of the compound of Formula A is represented by Formula BV:
  • R 9 is selected from optionally substituted aryl and optionally substituted C1-C6 alkyl
  • X - selected from, but not limited to, F -, Cl -, Br - , I -, OAc -, HSO 4 -, H 2 PO 4 -, ClO 4 -, F 3 CCOO -, CH 3 SO 3 -, CF 3 SO 3 ⁇ , BF 4 ⁇ , PF 6 ⁇ , citrate and NO 3 ⁇ .
  • the optionally substituted C1-C6 alkyl is optionally substituted with adamantyl.
  • the optionally substituted aryl is optionally selected from 1 to 3 selected from C1-C6 alkyl, halogen, hydroxyl, nitro, carboxyl, C1-C6 alkoxycarbonyl, benzene A phenyl group substituted with a diazonium group and a C1-C6 alkylthio group.
  • R 9 is selected from phenyl and adamantyl-substituted C1-C6 alkyl.
  • Compounds of formula BV are useful for inhibiting resistant bacteria, such as methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii sensitive strains.
  • R 9 is selected from optionally substituted aryl and optionally substituted C1-C6 alkyl
  • X - selected from, but not limited to, F -, Cl -, Br - , I -, OAc -, HSO 4 -, H 2 PO 4 -, ClO 4 -, F 3 CCOO -, CH 3 SO 3 -, CF 3 SO 3 ⁇ , BF 4 ⁇ , PF 6 ⁇ , citrate and NO 3 ⁇ .
  • the optionally substituted C1-C6 alkyl is optionally substituted with adamantyl.
  • the optionally substituted aryl is optionally selected from 1 to 3 selected from C1-C6 alkyl, halogen, hydroxyl, nitro, carboxyl, C1-C6 alkoxycarbonyl, benzene A phenyl group substituted with a diazonium group and a C1-C6 alkylthio group.
  • R 9 in formula BVI is selected from adamantyl-substituted C1-C6 alkyl.
  • Compounds of formula BVI are useful for inhibiting resistant bacteria, such as methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii sensitive strains.
  • compounds of general formula BVI do not include compound BVIa.
  • R 9 is selected from optionally substituted aryl and optionally substituted C1-C6 alkyl
  • X - selected from, but not limited to, F -, Cl -, Br - , I -, OAc -, HSO 4 -, H 2 PO 4 -, ClO 4 -, F 3 CCOO -, CH 3 SO 3 -, CF 3 SO 3 ⁇ , BF 4 ⁇ , PF 6 ⁇ , citrate and NO 3 ⁇ .
  • the optionally substituted C1-C6 alkyl is optionally substituted with adamantyl.
  • the optionally substituted aryl is optionally selected from 1 to 3 selected from C1-C6 alkyl, halogen, hydroxyl, nitro, carboxyl, C1-C6 alkoxycarbonyl, benzene A phenyl group substituted with a diazonium group and a C1-C6 alkylthio group.
  • R 9 in formula BVII is selected from phenyl and adamantyl substituted C1-C6 alkyl.
  • Compounds of formula BVII are useful for inhibiting resistant bacteria, such as methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii sensitive strains.
  • the structure of the compound of Formula A is represented by Formula BVIII:
  • R 5 and R 6 are each independently selected from H and C1-C6 alkyl
  • R 9 is selected from optionally substituted aryl and optionally substituted C1-C6 alkyl.
  • X - selected from, but not limited to, F -, Cl -, Br - , I -, OAc -, HSO 4 -, H 2 PO 4 -, ClO 4 -, F 3 CCOO -, CH 3 SO 3 -, CF 3 SO 3 ⁇ , BF 4 ⁇ , PF 6 ⁇ , citrate and NO 3 ⁇ .
  • the optionally substituted C1-C6 alkyl is optionally substituted with adamantyl.
  • the optionally substituted aryl is optionally selected from 1 to 3 selected from C1-C6 alkyl, halogen, hydroxyl, nitro, carboxyl, C1-C6 alkoxycarbonyl, benzene A phenyl group substituted with a diazonium group and a C1-C6 alkylthio group.
  • R 9 in formula BVIII is selected from adamantyl-substituted C1-C6 alkyl.
  • Compounds of formula BVIII are useful for inhibiting resistant bacteria, such as methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii sensitive strains.
  • compounds of formula BVIII do not include compound BVIIIb.
  • R 9 is selected from optionally substituted aryl
  • X - selected from, but not limited to, F -, Cl -, Br - , I -, OAc -, HSO 4 -, H 2 PO 4 -, ClO 4 -, F 3 CCOO -, CH 3 SO 3 -, CF 3 SO 3 ⁇ , BF 4 ⁇ , PF 6 ⁇ , citrate and NO 3 ⁇ .
  • the optionally substituted aryl is optionally substituted by 1 to 3 selected from C1-C6 alkyl, halogen, hydroxyl, nitro, carboxyl, C1-C6 alkoxycarbonyl,- SO 3 or -SO 2 Cl substituted phenyl.
  • R 9 is phenyl.
  • compounds of formula BIX can be used to inhibit drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii sensitive strains.
  • R 9 is carboxy, C1-C6 alkoxycarbonyl, -SO 3 or -SO 2 Cl substituted phenyl.
  • the compound of Formula IX has an antibacterial synergistic effect and can enhance the antibacterial effect of other antibacterial compounds, for example, can enhance the antibacterial activity of antibacterial drugs against methicillin-resistant Staphylococcus aureus.
  • compounds of the general formula BIX do not include compounds BIXa-BIXe.
  • R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from H, nitro, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, carboxyl, halogen, hydroxyl, thiol, C1- C6 alkylmercapto, NR a R b , optionally substituted aryl, diphenylphosphino, and optionally substituted aryldiazo and C1-C6 acyl, wherein R a and R b are independently selected from H, C1 -C6 alkyl and C1-C6 acyl; or two or more of R 10 , R 11 , R 12 , R 13 and R 14 may form an optionally substituted naphthyl, together with the phenyl group to which they are attached, Anthracenyl, quinolinyl, perylene (fluorenyl), benzimidazolyl, or 1,3-benzodioxolyl;
  • Y is selected from O, S, or NR 19 ;
  • R 16 , R 17 , R 18 , R 20 , R 21 , R 22 , R 24 and R 25 are each independently selected from H and C1-C6 alkyl; or, Y is formed together with R 25 and the Y-containing ring
  • Optional substituted structure :
  • R 19 is selected from H and optionally substituted C1-C6 alkyl, such as phenyl substituted C1-C6 alkyl, such as trityl or benzyl;
  • R 27 and R 28 are each independently selected from H and C1-C6 alkyl
  • R 30 , R 31 , R 32 and R 33 are each independently selected from H, halogen and C1-C6 alkyl;
  • R 34 , R 35 , R 36 and R 37 are each independently selected from H, halogen and C1-C6 alkyl;
  • R 38 , R 39 and R 40 are each independently selected from H, halogen and C1-C6 alkyl
  • R 41 , R 42 and R 43 are each independently selected from H, halogen and C1-C6 alkyl;
  • R 44 , R 45 and R 46 are each independently selected from H, halogen, carboxyl and C1-C6 alkyl;
  • R 47 , R 48 and R 49 are each independently selected from H, halogen and C1-C6 alkyl
  • R 50 , R 51 and R 52 are each independently selected from H, carboxyl, optionally substituted aryl, or optionally substituted the following groups:
  • R 50 , R 51 and R 52 together with the C atom to which they are attached form the following optionally substituted groups:
  • the substituent is selected from C1-C6 alkyl, NR a R b , halogen, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl substituted piperazinyl; wherein R a and R b are each independently selected From H and C1-C6 alkyl;
  • R 53 , R 54 and R 55 are each independently selected from H, optionally substituted C1-C6 alkyl, carboxyl; or any two of R 53 , R 54 and R 55 together with the C to which they are attached form an optional Substituted C3-C8 cycloalkyl or optionally substituted the following groups:
  • the substituent is selected from the group consisting of hydroxyl, carboxyl, optionally substituted C1-C6 alkyl, NR a R b , C1-C6 alkoxy, C2-C6 alkenyl, optionally substituted by hydroxy, C1-C6 alkoxy or C1-C6 alkyl substituted adamantyl, optionally substituted aralkyl (e.g. phenyl-C1-C6 optionally substituted with hydroxy, C1-C6 alkoxy, NR a R b , nitro or cyano Alkyl); wherein R a and R b are each independently selected from H and C1-C6 alkyl;
  • X - selected from, but not limited to, F -, Cl -, Br - , I -, OAc -, HSO 4 -, H 2 PO 4 -, ClO 4 -, F 3 CCOO -, CH 3 SO 3 -, CF 3 SO 3 ⁇ , BF 4 ⁇ , PF 6 ⁇ , citrate or NO 3 ⁇ .
  • R 10 and R 14 are each independently selected from the group consisting of: H, C1-C6 acyl, halogen, hydroxyl, thiol, C1-C6 alkylthiol, amino, optionally substituted aryl, di Phenylphosphino, C1-C6 alkoxy and optionally substituted aryldiazo;
  • R 11 and R 13 are each independently selected from: H, C1-C6 alkoxy and halogen;
  • R 12 is selected from H, optionally Substituted aryl, and optionally substituted aryldiazo.
  • two or more of R 10 , R 11 , R 12 , R 13 and R 14 may form an optionally substituted anthracenyl together with the phenyl group to which they are attached, Quinolinyl, perylene (fluorenyl) and benzimidazolyl.
  • compounds of formula CI can be used to inhibit resistant bacteria, such as methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii sensitive strains.
  • R 10 and R 14 are each independently selected from: H, C1-C6 alkyl optionally substituted with hydroxy, NR a R b, and optionally substituted phenyl (such as optionally Phenyl substituted with hydroxy or OTBS); R 11 -R 13 are each H; wherein Ra and R b are independently selected from H and C1-C6 acyl, preferably NRaRb is -NH (C1-C6 acyl).
  • the compound of formula CI has an antibacterial synergistic effect and can enhance the antibacterial effect of other antibacterial compounds, for example, can enhance the antibacterial activity of antibacterial drugs against methicillin-resistant Staphylococcus aureus.
  • Y is selected from O, S, or N; R 16 is selected from H or C1-C6 alkyl; R 17 is selected from H or C1-C6 alkyl; R 18 is selected from H or C1-C6 alkyl. In certain embodiments, R 16 is selected from H or C1-C6 alkyl; R 17 is selected from H; R 18 is selected from H or C1-C6 alkyl.
  • Formula CIII, Y is selected from O, S or NR 19; R 19 is selected from C1-C6 alkyl; R 20, R 21 and R 22 each is H.
  • Formula CIII, Y is selected from NR 19; R 19 is selected from C1-C6 alkyl; R 20, R 21 and R 22 each is H.
  • Such compounds can have antibacterial synergistic effects and can enhance the antibacterial effects of other antibacterial compounds, for example, can enhance the antibacterial activity of antibacterial drugs against methicillin-resistant Staphylococcus aureus.
  • Y is selected from S or NR 19 ;
  • R 19 is selected from triphenylmethyl;
  • R 24 is selected from H or C1-C6 alkyl; and
  • R 25 is selected from H.
  • Y is selected from NR 19; R 19 is selected from phenyl-substituted C1-C6 alkyl; R 27 and R 28 are each independently H.
  • R 30 -R 33 are each independently H.
  • R 34 and R 37 are each independently C1-C6 alkyl or halogen; R 35 and R 36 are each independently H.
  • R 38 is selected from halogens, R 39 is H, and R 40 is C1-C6 alkyl.
  • R 41 and R 42 are each independently H, and R 43 is selected from halogens.
  • R 44 is selected from H or carboxy; R 45 is selected from H or halogen; R 46 is selected from H.
  • R 47 is selected from H, halogen, and C1-C6 alkyl; R 48 and R 49 are each independently H. In certain embodiments, R 47 is selected from H, F, and C1-C6 alkyl; R 48 and R 49 are each independently H.
  • R 47 is selected from halogen and C1-C6 alkyl; R 48 and R 49 are each independently H.
  • Such compounds can have antibacterial synergistic effects and can enhance the antibacterial effects of other antibacterial compounds, for example, can enhance the antibacterial activity of antibacterial drugs against methicillin-resistant Staphylococcus aureus.
  • R 50 is H
  • one of R 51 and R 52 is H
  • the other is selected from the group consisting of 1 to 3 selected from C1-C6 alkyl, halogen, hydroxyl, C1-C6 alkoxy substituted phenyl or the following:
  • R 50 , R 51 and R 52 together with the C atom to which they are attached are optionally selected from 1 to 3 selected from C1-C6 alkyl, NR a R b , halogen, hydroxyl, C1-C6 alkoxy, And C1-C6 alkyl substituted piperazinyl substituents substituted with the following groups:
  • R 50 is H
  • one of R 51 and R 52 is H
  • the other is selected from carboxyl or phenyl: or R 50 , R 51 and R 52 are attached to them.
  • the C atoms together form the following groups optionally substituted with 1 to 3 substituents selected from C1-C6 alkyl, halogen, and C1-C6 alkyl substituted piperazinyl groups:
  • These compounds can have antibacterial synergistic effects and can enhance the antibacterial effect of other antibacterial compounds, for example, can enhance the antibacterial activity of antibacterial drugs against methicillin-resistant Staphylococcus aureus.
  • R 53 , R 54 and R 55 are all H, or any two of them are H, and the other is selected from the group consisting of carboxyl or C1-C6 alkyl, wherein the C1-C6 alkyl Group is optionally substituted by hydroxy, carboxyl, optionally substituted by 1 to 3 substituents selected from hydroxy, C1-C6 alkoxy, and C1-C6 alkyl, optionally substituted by 1 to 3 selected from hydroxyl , Cyano, NR a R b and C1-C6 alkoxy substituted phenyl substituted; or one of R 53 , R 54 and R 55 is H, and the remaining two are formed with the C to which they are attached C3-C8 cycloalkyl optionally substituted with 1 to 4 substituents selected from carboxyl, C1-C6 alkyl and C2-C6 alkenyl or optionally 1 to 3 selected from carboxy and C1-C6 alkyl
  • the C1-C6 alkyl Group
  • R 53 , R 54 and R 55 are all H, or any two of them are H, and the other is selected from the group consisting of carboxyl or C1-C6 alkyl, wherein the C1-C6 alkyl Is optionally substituted with phenyl selected from carboxy and optionally substituted with 1 to 3 substituents selected from hydroxy, cyano, and C1-C6 alkoxy; or one of R 53 , R 54 and R 55 is H , The remaining two together with the C to which they are attached form a C3-C8 cycloalkyl group optionally substituted with 1 to 4 substituents selected from a carboxyl group and a C1-C6 alkyl group or the following groups optionally substituted with a carboxyl group:
  • These compounds can have antibacterial synergistic effects and can enhance the antibacterial effect of other antibacterial compounds, for example, can enhance the antibacterial activity of antibacterial drugs against methicillin-resistant Staphylococcus aureus.
  • those compounds in which R 9 is a C1-C6 alkyl group substituted with a phenyl group substituted with 1 to 3 substituents selected from a hydroxyl group, a C1-C6 alkoxy group and a cyano group have The antibacterial synergistic effect can be combined with enhancing the antibacterial effect of other antibacterial compounds, for example, it can enhance the antibacterial activity of antibacterial drugs against methicillin-resistant Staphylococcus aureus.
  • the compound of the general formula A herein (including the compounds of the general formulae described herein) is a compound having antibacterial activity and / or antibacterial synergistic activity, and it is particularly preferred that the MIC value in Table 1 is 16 ⁇ g / ml and / or FICI Those compounds having a value of 1 or less, preferably 0.5 or less.
  • the compounds herein can exist as stereoisomers, including optical isomers. Included herein are all stereoisomers and racemic mixtures of such stereoisomers, as well as individual enantiomers that can be separated according to methods well known to those skilled in the art.
  • specific compounds of the general formulae of the invention may be selected from the following compounds:
  • prodrugs of the aforementioned compounds include simple esters of compounds containing carboxylic acids (such as esters obtained by condensation with C1-4 alcohols according to methods known in the art); esters of compounds containing hydroxyl groups (such as according to methods known in the art An ester obtained by condensation with a C1-4 carboxylic acid, a C3-6 diacid or its anhydride such as succinic anhydride and fumaric anhydride); an imine of an amino-containing compound (e.g., with C1-4 according to methods known in the art Imines obtained by condensation of aldehydes or ketones); carbamates of compounds containing amino groups, such as Leu et al. (J. Med. Chem.
  • the substituted 3-aminophenol (2eq) and the substituted aldehyde compound (1eq) were added to a round-bottom flask containing 30 ml of methanesulfonic acid, and heated to reflux for 8 hours.
  • the reaction solution was poured on a TLC plate to monitor the completion of the reaction.
  • a solid precipitated Into ice water, a solid precipitated.
  • the Buchner funnel was used for filtration, and the solid was collected and dissolved in a round bottom flask with 50 ml of dichloromethane.
  • a dichloromethane solution of DDQ (1 eq) was added, and the reaction was stirred at room temperature for half an hour.
  • the reaction solution was extracted three times with water and dichloromethane.
  • the prepared dibromoanisole compound (1eq) and 50 ml of anhydrous tetrahydrofuran were placed in a 100 ml round-bottomed flask and protected by argon.
  • the round bottom flask was placed in a Dewar flask.
  • To the reaction solution was added 1 ml of a sodium bicarbonate solution, and the mixture was extracted three times with water and dichloromethane.
  • R 1 -R 9 and X - are as defined in any one of the foregoing embodiments.
  • a method of preparing a compound of Formula A herein comprising performing a dibromoanisole and a carbonyl compound represented by the following formula in the presence of an organic solvent and an alkyl lithium reagent Reaction to prepare a compound of formula A:
  • R 1 to R 9 are as defined in any of the foregoing embodiments; LG is a leaving group, and may be selected from halogens such as Cl or Br, cyano, C1-C6 alkoxy, and C1-C6 alkyl-COO. -Wait.
  • Organic solvents suitable for the methods described herein may be ether solvents such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, and 1,4-dioxane.
  • the organic solvent may be n-hexane or the like.
  • the alkyl lithium reagents suitable for the methods described herein are generally C1-C6 alkyl lithium reagents, including but not limited to n-butyllithium, t-butyllithium, and sec-butyllithium. The above reaction can be carried out between minus 78 ° C and 0 ° C. Generally, the molar ratio of the dibromoanisole compound to the alkyllithium reagent is between 1: 2-3.
  • the reaction time can be determined according to the actual reaction conditions. After completion of the reaction, it can be separated and purified by a conventional method. For example, a sodium hydroxide solution can be added to the reaction solution, followed by extraction with water and a dichloromethane system, and the organic phase is dried over anhydrous magnesium sulfate.
  • the eluent for column chromatography may be dichloromethane: methanol.
  • the prepared dibromoanisole compound and an appropriate amount of an organic solvent are placed in a round bottom flask, and protected by an inert gas (such as argon). After the temperature is lowered to -78 ° C, an alkyl lithium reagent is added, and an organic solvent solution of a carbonyl compound is added after about 10 to 20 minutes, and a reaction is performed for a period of time to prepare a compound of the general formula A.
  • an inert gas such as argon
  • the compounds disclosed herein can be made into the form of a composition, especially a pharmaceutical composition.
  • a pharmaceutical composition may contain one or more compounds disclosed herein and a pharmaceutically acceptable carrier.
  • the amount of a compound herein in a pharmaceutical composition is a therapeutically or prophylactically effective amount.
  • An effective amount is an amount of a component sufficient to produce the desired response.
  • the specific effective amount depends on a variety of factors, such as the specific condition to be treated, the patient's physical condition (such as the patient's weight, age, or gender), the duration of the treatment, other concurrent treatments, and the specific formulation used.
  • An effective amount also means that at that amount, the compound is less toxic or negative than the positive effect it brings.
  • pharmaceutically acceptable carriers are generally safe, non-toxic, and may broadly include any known substance used in the pharmaceutical industry for the preparation of pharmaceutical compositions, such as fillers, diluents, coagulants, adhesives, Lubricants, glidants, stabilizers, colorants, wetting agents, disintegrants, etc.
  • a carrier suitable for delivering the compounds herein the method of administration of the pharmaceutical composition needs to be considered, and those skilled in the art are familiar with this technology. Therefore, the pharmaceutical composition of the present invention can be prepared into different dosage forms, such as tablets and capsules suitable for oral administration, injections suitable for parenteral administration, and external preparations such as oils, creams, emulsions and salves. Wait.
  • compositions can be prepared according to known pharmaceutical procedures, such as Remington's Pharmaceutical Sciences (17th edition, edited by Alfonoso R. Gennaro, Mack Publishing Company, Easton) , Pennsylvania (1985)).
  • the compound when the compound is prepared into an oral tablet, a concentration of 40% -80% (w / w) is required, and each tablet can contain 0.5-2g of the compound of the present invention, and starch, magnesium carbonate, silica, etc. can be used as an auxiliary .
  • the daily dose for adults can be 1 to 2 g / day, and for children it can be 20 to 40 mg / kg / day.
  • a 10% glucose solution is used as a solvent, and the injection is slowly diluted.
  • a concentration of 1% to 5% can be used, and polyethylene glycol 400 and polyethylene glycol 3350 can be used as auxiliary materials.
  • the pharmaceutical compositions herein may also contain one or more known antibacterial drugs, such as one or more of the following A known antibacterial drug.
  • compositions of the invention contain compounds CXIIIt and CXIIIt2. In certain embodiments, the composition is a solution.
  • the compounds herein can be used for antibacterial, especially various Gram-positive and Gram-negative bacteria related to human health, including but not limited to bactericidal and bacteriostatic.
  • the compounds herein can also be used for antibacterial synergism.
  • antibacterial synergism means that the compounds herein can enhance the antibacterial activity of known antibacterials.
  • certain compounds of the present invention are particularly useful for antibacterial enhancement.
  • provided herein is the use of rhodamine dyes to inhibit or kill Gram-positive and Gram-negative bacteria, or to enhance the antibacterial activity of known antibacterials.
  • ESKAPE Vancomycin-resistant Enterococcus faecium
  • Methicillin-resistant Staphylococcus aureus Carbapenem Klebsiella pneumoniae
  • Acinetobacter baumanii Pseudomonas aeruginosa
  • S. aureus can cause a wide range of human infections. The most common are skin and soft tissue infections; infections in these areas manifest as folliculitis, boils, scabies, sores, mastitis, wound infections, and Staphylococcus scalded skin syndrome. More serious infections include bacteremia, pneumonia, endocarditis, bone and joint infections, and toxic shock syndrome. Staphylococcus aureus can also cause an outbreak of food poisoning. The diversity of S. aureus also extends to its host range, including livestock, horses, goats, sheep, cattle, rabbits, pigs and poultry.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • MRSA can gain resistance to a variety of alternative antibiotics, including vancomycin, which is considered the last line of defense for a severe MRSA infection, as well as for relatively newer drugs such as linezolid and davidin. Toxomycin has also developed resistance. In order to ensure effective treatment, the development of new anti-MRSA antibiotics has become an urgent issue.
  • Enterococcus is known as a pathogen of infective endocarditis, and has now become one of the main pathogens causing nosocomial infections. Recently, it has attracted more attention due to its multi-drug resistance.
  • Common infections caused by Enterococcus are: urinary system infection, bacteremia, infective endocarditis, abdominal infection, biliary infection, and wound infection. Enterococci can also cause neonatal meningitis and adult central nervous system infections (especially patients with a history of central nervous surgery and intrathecal chemotherapy); Enterococci can also cause infections of the liver and biliary tract after liver transplantation. Less common infections are osteomyelitis and lower respiratory infections. There are 17 species of Enterococcus.
  • Streptococcus pneumoniae is one of the main pathogens of community-acquired infections. It is also a common pathogen of pyogenic meningitis, pleurisy, peritonitis, otitis media, and sinusitis. The main problem in clinical treatment focuses on the increase of resistant strains. Therefore, the development of new antibiotics against Streptococcus pneumoniae has become an urgent issue.
  • Staphylococcus epidermidis (staphylococcus epidermidis) is one of the normal flora colonized on human skin and mucous membranes, and usually has a low pathogenicity.
  • Acinetobacter baumannii is an opportunistic bacterium that is widely present in hospitals, accounting for 2-10% of hospital Gram-negative infections, with a mortality rate of 35-100%. In intensive care units worldwide, infections are as high as 20%. Because Acinetobacter baumannii is resistant to most of the antibiotics currently in clinical use, it is also called “methicillin-resistant Staphylococcus aureus (MRSA) gold Gram-negative bacteria. In 2012, China Acinetobacter baumannii is listed as the most important "super bacteria" at present. In 2013, the United States ranked it as one of the most serious super bacteria. Therefore, the development of new antibiotics against A. baumannii has become urgent. problem.
  • MRSA methicillin-resistant Staphylococcus aureus
  • Klebsiella pneumoniae is a gram-negative bacillus and is one of the conditional pathogens. It is often parasitic in the human respiratory tract and intestines. When the body's immunity is reduced, it can easily cause lower respiratory tract and urinary tract infections. Important cause of road infection. In recent years, with the widespread use of broad-spectrum antibiotics, the resistance of Klebsiella pneumoniae has also increased year by year, which has brought difficulties to clinical treatment. Therefore, the development of new antibiotics against Klebsiella pneumoniae has become an urgent issue.
  • bacteria include, but are not limited to: Staphylococcus aureus, such as methicillin-resistant Staphylococcus aureus; vancomycin-resistant Enterococcus faecalis; carbapenem-resistant Klebsiella pneumoniae; pantoea Multi-drug resistant Pseudomonas aeruginosa; Multi-drug resistant Enterobacteriaceae; Vancomycin-resistant Enterococcus faecium; Streptococcus pneumoniae; Methicillin-sensitive Staphylococcus epidermidis; Streptococcus pyogenes; Klebsiella pneumoniae (ESBL +); Klebsiella pneumoniae (ESBL-); Klebsiella pneumoniae-resistant; Escherichia coli (ESBL +); Klebsiella pneumoniae (ESBL-); Klebsiella pneumoniae-resistant; Escherichia coli (ESBL +); Klebsiella pneumoniae (ESBL-); Klebs
  • the compounds or pharmaceutical compositions herein can be used to treat various diseases and / or symptoms caused by these bacteria.
  • the compounds herein can be used for synergistic effects of a variety of known antibacterial compounds including, but not limited to, beta-lactam antibiotics such as cefaclor, cefepime, penicillin sodium, ampicillin, sulbactam And oxacillin; quinolones such as levofloxacin; aminoglycosides such as amikacin and gentamicin; and glycopeptides such as vancomycin. It is particularly preferred that the compounds herein have a synergistic effect on beta-lactam antibiotics.
  • an antibacterial method comprising administering to a subject in need thereof an antibacterially effective amount of one or more compounds described herein, or a pharmaceutical composition thereof, or comprising one or more compounds described herein and Pharmaceutical composition of one or more known antibacterial compounds.
  • the method of administration may be conventional in the art, including, but not limited to, oral, injection or other suitable modes of administration.
  • the compound was prepared by the general preparation procedure 1.
  • the compound was a purple-red solid with a yield of 33%.
  • the compound was prepared by using the general preparation process 1.
  • the compound was a reddish solid with a yield of 24%.
  • the compound was prepared by using the general preparation procedure 1.
  • the compound was a reddish solid with a yield of 27%.
  • the compound was prepared by the general preparation procedure 1.
  • the compound was a reddish solid with a yield of 25%.
  • the compound was prepared by using the general preparation process 1.
  • the compound was a reddish solid with a yield of 23%.
  • the compound was prepared by using the general preparation procedure 1.
  • the compound was a reddish solid with a yield of 27%.
  • the compound was prepared by using the general preparation process 1.
  • the compound was a reddish solid with a yield of 24%.
  • the compound was prepared by using the general preparation process 1.
  • the compound was a reddish solid with a yield of 35%.
  • the compound was prepared by using the general preparation procedure 1.
  • the compound was a reddish solid with a yield of 26%.
  • the compound was prepared by using the general preparation procedure 1.
  • the compound was a reddish solid with a yield of 22%.
  • the compound was prepared by the general preparation procedure 1.
  • the compound was a purple-red solid with a yield of 19%.
  • the compound was prepared by using the general preparation process 1.
  • the compound was a reddish solid with a yield of 23%.
  • the compound was prepared by the general preparation procedure 1.
  • the compound was a purple-red solid with a yield of 33%.
  • the compound was prepared by using the general preparation procedure 1.
  • the compound was a reddish solid with a yield of 27%.
  • the compound was prepared by the general preparation procedure 1.
  • the compound was a reddish solid with a yield of 25%.
  • the compound was prepared by the general preparation procedure 1.
  • the compound was a purple-red solid with a yield of 31%.
  • the compound was prepared by the general preparation procedure 1.
  • the compound was a reddish solid with a yield of 29%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 78%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 75%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 71%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 65%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 63%.
  • the compound was prepared by the general preparation process two, and the compound was a purple-red solid with a yield of 80%.
  • the compound was prepared by the general preparation procedure II, and the compound was a purple-red solid with a yield of 82%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 78%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 73%.
  • the compound was prepared by the general preparation procedure II, and the compound was a purple-red solid with a yield of 50%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 75%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 71%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 65%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 70%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 65%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 60%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 68%.
  • the compound was prepared by the general preparation procedure 1.
  • the compound was a purple-red solid with a yield of 37%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish-red solid with a yield of 69%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 73%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 78%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish solid with a yield of 84%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 73%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish-red solid with a yield of 69%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish solid with a yield of 84%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 70%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 61%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish-yellow solid with a yield of 53%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 68%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish solid with a yield of 85%.
  • the compound was prepared by the general preparation procedure II, and the compound was a purple-red solid with a yield of 81%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 72%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish solid with a yield of 85%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish solid with a yield of 57%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish solid with a yield of 57%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 71%.
  • the compound was prepared by the general preparation process two, and the compound was a reddish solid with a yield of 45%.
  • the compound was prepared by the general preparation process two, and the compound was a reddish solid with a yield of 55%.
  • the compound was prepared by the general preparation procedure II, and the compound was a reddish-yellow solid with a yield of 74%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 65%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish solid with a yield of 57%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 68%.
  • the compound was prepared by the general preparation procedure II, and the compound was a purple-red solid with a yield of 81%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 75%.
  • the compound was prepared by the general preparation procedure II, and the compound was a reddish-yellow solid with a yield of 74%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish solid with a yield of 84%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 83%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 72%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 75%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 68%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish solid with a yield of 84%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 83%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 67%.
  • the compound was prepared by the general preparation procedure II, and the compound was a purple-red solid with a yield of 82%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 77%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish-red solid with a yield of 69%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 48%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 39%.
  • the compound was prepared by the general preparation procedure II, and the compound was a purple-red solid with a yield of 50%.
  • the compound was prepared by the general preparation procedure II, and the compound was a reddish solid with a yield of 21%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 41%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 83%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish-yellow solid with a yield of 54%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 51%.
  • the compound was prepared by the general preparation process two, and the compound was a reddish solid with a yield of 42%.
  • the compound was prepared by the general preparation process two, and the compound was a reddish-yellow solid with a yield of 46%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish solid with a yield of 36%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 43%.
  • the compound was prepared by the general preparation procedure II, and the compound was a reddish solid with a yield of 44%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 31%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 41%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 39%.
  • the compound was prepared by the general preparation procedure II, and the compound was a reddish solid with a yield of 37%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 41%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 63%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 68%.
  • the compound was prepared by the general preparation procedure II, and the compound was a reddish-yellow solid with a yield of 35%.
  • the compound was prepared by the general preparation process two, and the compound was a reddish-yellow solid with a yield of 46%.
  • the compound was prepared by the general preparation procedure II, and the compound was a reddish-yellow solid with a yield of 35%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 34%.
  • the compound was prepared by the general preparation process two, and the compound was a reddish solid with a yield of 30%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 47%.
  • the compound was prepared by the general preparation procedure II, and the compound was a reddish solid with a yield of 44%.
  • the compound was prepared by the general preparation process two, and the compound was a reddish solid with a yield of 42%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 83%.
  • the compound was prepared by the general preparation procedure II, and the compound was a purple-red solid with a yield of 81%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish solid with a yield of 84%.
  • the compound was prepared by the general preparation process two, and the compound was a purple-red solid with a yield of 80%.
  • the compound was prepared by the general preparation process two, and the compound was a reddish solid with a yield of 59%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 71%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 68%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 83%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 70%.
  • the compound was prepared by the general preparation procedure II, and the compound was a purple-red solid with a yield of 82%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 61%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish solid with a yield of 79%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 77%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 67%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish solid with a yield of 57%.
  • the compound was prepared by the general preparation process two, and the compound was a reddish solid with a yield of 55%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish-yellow solid with a yield of 53%.
  • the compound was prepared by the general preparation procedure II, and the compound was a purple-red solid with a yield of 56%.
  • the compound was prepared by the general preparation scheme two, and the compound was a reddish solid with a yield of 51%.
  • the compound was prepared by the general preparation process two, and the compound was a reddish solid with a yield of 59%.
  • the compound was prepared by the general preparation scheme two, and the compound was a purple-red solid with a yield of 75%.
  • the compound was prepared by the general preparation procedure two, and the compound was a reddish-red solid with a yield of 69%.
  • the growth method was used to prepare a standardized inoculum equivalent to 0.5 Meyer units, and then diluted 1: 150 with MHB medium to obtain the initial bacterial solution for the experiment, and inoculated within 15min for the determination of the drug MIC experiment.
  • the CAMHB inoculation tube without drugs was used as a positive control, and the culture without inoculation was used as a negative control, so that the final bacterial solution concentration of each tube was about 0.25-0.5 ⁇ 10 6 CFU / ml. After the culture was placed at 37 ° C for 16h-20h, the growth of bacteria was observed, and the minimum inhibitory concentration (MICs) of the drug alone was determined.
  • the evaluation criteria of the antibacterial activity of the compound MIC> 64 ⁇ g / ml, the compound has no antibacterial activity; 16 ⁇ g / ml ⁇ MIC ⁇ 64 ⁇ g / ml, the compound has weak antibacterial activity; MIC ⁇ 16 ⁇ g / ml, the compound has strong antibacterial activity.
  • the final bacteria concentration of the culture solution was about 0.25-0.5 ⁇ 10 6 CFU / ml. After the culture was placed at 37 ° C for 16h-20h, the growth of bacteria was observed, and the MICs of oxacillin in each combination drug were determined.
  • FIC index (FICI) MIC when A drug is combined, MIC when A drug is tested alone, MIC when B drug is combined, MIC when B drug is tested alone, where the judgment criteria are: FICI ⁇ 0.5, synergism; 0.5 ⁇ FICI ⁇ 1, superimposed, 1.0 ⁇ FICI ⁇ 2.0, irrelevant; FICI> 2.0, antagonism.
  • the microdilution method was used to prepare antibacterial drugs at multiple dilutions in accordance with the CLSI M07-A9 standard, and the minimum antibacterial activity (MICs) of CXIIIo was determined.
  • the growth method was used to prepare a standardized inoculum equivalent to 0.5 Meyer's units, and then diluted 1: 150 with MHB medium to obtain the initial bacterial solution for the experiment, and inoculated within 15min for the determination of the drug MIC experiment.
  • the CAMHB inoculation tube without drugs was used as a positive control, and the culture without inoculation was used as a negative control, so that the final bacterial solution concentration of each tube was about 0.25-0.5 ⁇ 10 6 CFU / ml. After the culture was placed at 37 ° C for 16h-20h, the growth of bacteria was observed, and the minimum inhibitory concentration (MICs) of the drug alone was determined.
  • ATCC43300 (37 ° C, 12h) cultured overnight was inoculated 1:20 in 20 ml of MHB liquid medium.
  • Quantitative sampling was performed at 0h, 2h, 4h, 8h, 16h, and 24h.
  • the removed bacterial solution was sequentially diluted 10 times, and 100 ⁇ l of a suitable dilution multiple of the dilution solution was coated on a counting medium plate, and each dilution multiple was coated with 2-3 parallel plates, and cultured at 36 ° C ⁇ 1 ° C at constant temperature.
  • Inverted culture in the box for 16-20 hours count the colonies, and express them in colony forming units (CFU).
  • CFU colony forming units
  • Figure 1 shows that the bactericidal effect of CXIIIo on methicillin-resistant Staphylococcus aureus at the same concentration or lower is better than the clinical drugs vancomycin, linezolid, and tigecycline.
  • ATCC19606 (Acinetobacter baumannii) 1: 1000 cultured overnight (37 ° C, 220 rpm, 16h) was inoculated into the bacterial liquid of LB liquid culture medium as the initial bacterial liquid. Add 2.5 times, 5 times, 10 times MIC of CXIIIo compound and 10 times MIC of tigecycline to the prepared initial bacterial solution, and use blank control groups without any drugs at 0h, 1h, and 2h, respectively. , 4h, 8h, 24h quantitative sampling.
  • the removed bacterial solution was sequentially diluted 10 times, and 100 ⁇ l of a suitable dilution multiple of the dilution solution was coated on a counting medium plate, and each dilution multiple was coated with 2-3 parallel plates, and cultured at 36 ° C ⁇ 1 ° C at constant temperature.
  • Inverted culture in the box for 16-20 hours count the colonies, and express them in colony forming units (CFU).
  • CFU colony forming units
  • Figure 2 shows that the bactericidal effect of Acinetobacter baumannii is better than that of tigecycline at an equal multiple MIC concentration (10 * MIC) of CXIIIo.
  • ATCC51299 37 ° C, 12h cultured overnight was inoculated 1:20 in 20ml BHI (4 ⁇ g / ml vancomycin) liquid culture medium, and the bacterial solution was cultured at 37 ° C and 225rpm for 2h as the initial bacterial solution.
  • the removed bacterial solution was sequentially diluted 10 times, and 100 ⁇ l of a suitable dilution multiple of the dilution solution was coated on a counting medium plate, and each dilution multiple was coated with 2-3 parallel plates, and cultured at 36 ° C ⁇ 1 ° C at constant temperature Inverted culture in the box for 16-20 hours, count the colonies, and express them in Colony-Forming Units (CFU).
  • CFU Colony-Forming Units
  • Figure 3 shows that the bactericidal effect of CXIIIo against enterococcus faecalis at equal multiples of MIC concentration (10 * MIC) or lower (2.5MIC or 5MIC) is better than vancomycin and linezolid. .
  • the induced concentrations of Levofloxacin, Vancomycin, and 68 # compounds were induced from 0.25MIC.
  • the induced concentration was 0.25MIC on the first day and 220rmp was cultured at 37 °C for 24h. , 1MIC, 2MIC, 4MIC. Incubate at 37 ° C for 24 h. Induction was performed with OD 600 > 1.8 and cfu / ml> 10 9 as the middle concentration on the third day.
  • the inoculation amount was 1: 100 and repeated for 25 days.
  • Methicillin-resistant Staphylococcus aureus did not develop resistance to CXIIIo within 25 days.
  • the antibiotics selected were Levofloxacin, Vancomycin, Tetracycline, Gentamycin, and Erythromycin as controls.
  • the induced concentrations of CXIIIo and control antibiotics were induced from 0.25MIC.
  • the induced concentration was 0.25MIC, 220rmp, and cultured at 37 ° C for 24h on the first day.
  • the concentration gradient was 0.25MIC, 0.5MIC, 1MIC, 2MIC, 4MIC on the second day.
  • Incubate at 37 ° C for 24 h.
  • Induction was performed with OD 600 > 1.8 and cfu / ml> 10 9 as the middle concentration on the third day.
  • the inoculation amount was 1: 100 and repeated for 25 days.
  • Methicillin-sensitive strain S. aureus (ATCC25923) did not develop resistance to CXIIIo within 25 days.
  • the relationship between the concentration of rhodamine dye compound with better synergistic activity and synergistic activity was further determined.
  • the microdilution method was used to fix the final concentration of different rhodamine dye compounds to 4 ⁇ g / ml, 2 ⁇ g / ml, 1 ⁇ g / ml, 0.5 ⁇ g / ml, and then the M07-A9 procedure was used to sequentially multiply the antibiotics to be tested in the combined drug Specific dilution.
  • the culture solution containing oxacillin or a single rhodamine dye compound is used as a positive control, and the culture without inoculation of bacteria is used as a negative control, so that the final bacteria concentration of the culture solution is about 0.25-0.5 ⁇ 10 6 CFU / ml.
  • the culture was placed at 37 ° C and cultured for 16h-20h, the growth of bacteria was observed, and the MICs of antibiotics in each combination drug were interpreted.
  • FIC index (FICI) MIC when A drug is combined, MIC when A drug is tested alone, MIC when B drug is combined, MIC when B drug is tested alone, where the judgment criteria are: FICI ⁇ 0.5, synergism; 0.5 ⁇ FICI ⁇ 1, superimposed, 1.0 ⁇ FICI ⁇ 2.0, irrelevant; FICI> 2.0, antagonism.
  • Rhodamine dyes can still be found in the chemical structure space of antibacterial synergistically active compounds.
  • the final concentrations of CXIIIt were fixed to 4 ⁇ g / ml, 2 ⁇ g / ml, 1 ⁇ g / ml, 0.5 ⁇ g / ml, and then the antibiotics to be tested in the combined drug were diluted in multiple ratios in accordance with the M07-A9 operation steps.
  • Single antibiotics including ⁇ -lactam antibiotics: cefaclor, cefepime, penicillin sodium, ampicillin and sulbactam and oxacillin; quinolones: levofloxacin; aminoglycosides: amikacin, gentamicin Glycopeptides: vancomycin, etc.
  • CXIIIt medium was used as a positive control, and the culture without inoculation was used as a negative control, so that the final bacteria concentration in the culture solution was about 0.25-0.5 ⁇ 10 6 CFU / ml.
  • the culture was placed at 37 ° C and cultured for 16h-20h, the growth of bacteria was observed, and the MICs of antibiotics in each combination drug were interpreted.
  • FIC index (FICI) MIC when A drug is combined, MIC when A drug is tested alone, MIC when B drug is combined, MIC when B drug is tested alone, where the judgment criteria are: FICI ⁇ 0.5, synergism; 0.5 ⁇ FICI ⁇ 1, superimposed, 1.0 ⁇ FICI ⁇ 2.0, irrelevant; FICI> 2.0, antagonism.

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Abstract

本发明涉及新型罗丹明染料及其在抗致病菌中的应用。具体而言，本发明涉及下式 A 所示的化合物，式中，X- 和 R1-R9 如文中所述。本发明的新型罗丹明染料对革兰氏阳性菌和革兰氏阴性菌有抑菌、杀菌作用和抗菌增效作用。

Description

新型罗丹明染料及其在抗致病菌中的应用 技术领域
本发明涉及生物医药领域，特别是涉及新型罗丹明染料及其在抗致病菌中的应用。
背景技术
抗生素是上世纪人类开发出来对抗细菌感染的武器。从上世纪30年代到70年代短短几十年里，共发现超过20大类结构和作用机制都相同的抗生素。它们的广泛使用挽救了大量病患的生命。因此，抗生素被誉为医学史上最伟大的发明之一。
进入上世纪80年代，由于抗生素发现难度逐渐增加，回报也相对较低，主要大制药公司均已退出或极大缩减其抗生素部门，因此新抗生素开发已经大大放缓。同时，由于抗生素在临床及养殖业的滥用及无序排放，细菌已经对临床上主要使用的各类抗生素产生抗药性。在世界不同国家，受耐药菌感染致病而无药可治的病例层出不穷。据统计，2013年，在美国有超过两百万耐药菌感染病例，其中超过23、000人最终死于细菌感染。据总部在伦敦的Wellcome Trust估计，到2050年，中国每年因耐药菌导致的死亡人数可能会超过百万。针对细菌抗药性这一重大公共卫生安全问题，世界卫生组织于2015年推出全球行动计划对抗细菌耐药，并于2016年10月5日在联合国大会通过。世界主要国家也都制定了对抗细菌抗药的行动计划。主要措施包括严格规范抗生素使用，减少向环境排放并同时鼓励高校及制药企业加快新型抗生素的开发。
新型抗生素的两条主要开发方法包括对已知抗生素进行结构衍生开发me too类药物和对新型化学空间进行筛选发现全新抗生素种类。一般而言，对于已有药物的me too类药物也较易引发细菌抗性，因此最终的出路仍然是寻找有望发现新型抗生素的化学空间，进一步筛选发现活性先导，并进行药物开发。
发明内容
本文第一方面提供通式A所示的化合物，包括通式BI、BII、BIII、BIV、BV、BVI、BVII、BVIII、BIX以及CI-CXIII的化合物。
本文第二方面提供含有通式A所示化合物的一种或多种和药学上可接受的载体的药物组合物；和任选的已知抗菌药。
本文第三方面提供通式A所示化合物在抗菌或增强已知抗菌药抗菌活性中的应用， 包括用于制备抗菌药，或用于制备用来增强已知抗菌药的抗菌活性的药物。
本文第四方面提供一种抗菌方法，包括给予需要的对象本发明通式A所示的任意一种或多种化合物。
本文第五方面提供一种提高抗菌药抗菌活性的方法，包括在给予抗菌药之前、同时或之后给予一种或多种通式A所示的化合物或其药物组合物。
本发明第六方面提供了一种制备通式A化合物的方法。
附图说明
图1：化合物CXIIIo、万古霉素、利萘唑胺、替加环素对处于对数生长早期的耐甲氧西林金黄色葡萄球菌(ATCC43300)的杀菌曲线。
图2：化合物CXIIIo、替加环素对处于对数生长早期的鲍氏不动杆菌(ATCC19606)的杀菌曲线。
图3：化合物CXIIIo、万古霉素、利萘唑胺对处于对数生长早期的抗万古霉素粪肠球菌(ATCC51299)的杀菌曲线。
图4：耐甲氧西林金黄色葡萄球菌(ATCC43300)对CXIIIo的诱导耐药实验。
图5：甲氧西林敏感株金黄色葡萄球菌(ATCC25923)对CXIIIo的诱导耐药实验。
具体实施方式
应理解，在本发明范围内中，本发明上下文所述的各技术特征(包括实施例中具体描述的技术特征)之间都可以互相组合，从而构成新的技术方案。这些技术方案也包括在本发明的范围之内。
基于本发明人开发的一条新型罗丹明染料合成路线，本发明合成了一个具有结构多样性的罗丹明染料库。利用不同细菌模型筛选后发现，该化合物库中的化合物对革兰氏阳性菌(含耐药菌)和革兰氏阴性菌有杀菌效果，同时也发现该化合物库中的部分分子能够增强耐药菌对β-内酰胺类抗生素的敏感性。曾有文献报到，罗丹明修饰的抗菌肽或者罗丹明修饰的具有抗菌活性的精胺有一定抗菌活性。在这些文献中，作为对照化合物的罗丹明染料本身没有被发现有抗菌活性。所以，本发明是首次明确证实合理取代的罗丹明染料可以具有强杀菌、抑菌及抗菌增效活性。
一、术语和定义
本文中，烷基通常指碳原子数在10以内的烷基，即C1-C10烷基，例如C1-6烷基或C1-4烷基。本文所用的烷基可以是直链或直链烷基。典型的烷基包括甲基、乙基、丙基、 异丙基、丁基、仲丁基、叔丁基、3-戊基、己基和辛基。本文中，烷基可被取代。当指明烷基可被取代时，取代基的数量可以是1、2、3或4个，取代基可包括但不限于桥环烷烃基(如金刚烷基)、羟基、烷氧基、任选取代的芳基、羧基、任选取代的芳烷基、卤素和硝基等。
本文中，烯基指直链或支链的C2-C10烯基，通常链中至少含有一个双键。烯基的碳链长度可以为2－6个碳原子。典型的烯基包括乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基和2-丁烯基等。本文中，烯基可被取代。当指明烯基可被取代时，取代基的数量可以是1、2、3或4个，取代基可包括但不限于羧基、卤素、羟基、烷氧基、硝基、任选取代的芳基和任选取代的以下基团：
Figure PCTCN2018097386-appb-000001
本文中，烷氧基指被本文所述烷基取代的氧基，例如C1-C10烷氧基、C1-C6烷氧基或C1-C4烷氧基。烷氧基中的烷基可如前文所述被任意取代。
本文中，烷巯基指被本文所述烷基取代的巯基，即烷基-S-，如C1-C6烷基-S-。烷巯基中的烷基可如前文所述被任意取代。
本文中，卤素包括氟、氯、溴和碘。
本文中，芳基指单环、双环或多环芳族基团，例如，芳基可包括C6-C14芳基，或C6-C10芳基。典型芳基包括苯基、萘基、菲基、蒽基、茚基、薁基、茀基和二萘嵌苯基(苝基)。本文中，芳基可被取代。当指明芳基可被取代时，取代基的数量可以是1、2、3、4或5个，取代基可包括但不限于卤素、羟基、硝基、羧基、C1-C6烷氧基、C1-C6烷氧基羰基、任选取代的芳基重氮基、烷巯基、烷氧基、(CO) 3Cr-、-SO 3、-SO 2Cl、任选取代的C1-C6烷基、C1-C6醛基、巯基、NR aR b、任选取代的芳基、PPh 2、氰基、叔丁基二甲基硅基-O-(-OTBS)、桥环烷烃基或以下基团：
Figure PCTCN2018097386-appb-000002
Figure PCTCN2018097386-appb-000003
本文中，所用杂芳基指含有5－14个环原子，并且有6个，10个或14个π电子在环体系上共用的基团，通常，杂芳基所含环原子是碳原子和从氧、氮、硫中任选的1－3个杂原子。杂芳基的例子包括但不限于噻吩基、苯并[d]异噻唑-3-基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻蒽基、呋喃基、吡喃基、异苯并呋喃基、色烯基、夹氧蒽基、、吡咯基、咪唑基、吡唑基、吡啶基(包括但不限于2-吡啶基、3-吡啶基和4-吡啶基)、吡嗪基、嘧啶基、哒嗪基、吲嗪基、异吲哚基、3H-吲哚基、吲哚基、吲唑基、嘌呤基、4H-喹嗪基、异喹啉基、喹啉基、酞嗪基、萘啶基、喹唑啉基、噌啉基、蝶啶基、咔唑基、β-咔啉基、菲啶基、吖啶基、萘嵌间二氮(杂)苯基、菲咯啉基、吩嗪基、异噻唑基、吩噻嗪基、异恶唑基、呋咱基、吩恶嗪基、1,4-二氢喹喔啉-2,3-二酮、7-氨基异香豆素、吡啶并[1,2-a]嘧啶-4-酮、四氢化五员[c]吡唑-3-基、吡唑[1,5-a]嘧啶基、吡咯并吡啶基如吡咯[2,3-b]吡啶基、苯并异恶唑基如1,2-苯并异恶唑-3-基、苯并咪唑基、2-羟吲哚基、噻重氮基、1,3-苯并二氧戊环基和2-氧代苯并咪唑基。本文中，杂芳基可任选地被取代。当被取代时，杂芳基上的取代基数量可以是1、2、3或4个，可选自C1-C6烷基、NR aR b、卤素、羧基、C1-C6烷氧基、硝基、芳基取代的C1-C6烷基(如三苯甲基)、任选取代的联苯基-C1-C6烷基和羟基等。
本文中，除非另有说明，R a和R b各自独立选自：H、C1-C6烷基和C1-C6酰基。
本文中，碳环基包括饱和的或部分饱和的碳环基团。饱和的碳环基团包括环烷基和桥环烷烃基，如C3-8环烷基、二环烃基、三环烃基、四环烃基。典型的环烷基包括环丙基、环丁基、环戊基、环己基和环庚基。典型的桥环烷烃基如金刚烷基。部分饱和的碳环基团是可以是环烯基，如C3-8环烯基，例如环戊烯基、环庚烯基和环辛烯基。
本文中，杂环或杂环基指饱和或部分饱和的3－7元单环，或7－10元双环体系，或多环体系，它由碳原子和从O、N、S中任选1－4个杂原子组成，包括双环体系中上述定义的任意杂环与苯环的融合。饱和或部分饱和杂环基团的例子包括但不限于四氢呋喃基、四氢吡喃基、吡喃基，哌啶基、哌嗪基、吡咯烷基、咪唑烷基、咪唑啉基、二氢吲哚基、异二氢吲哚基、奎宁环基、吗啉基、异色满基、色满基、吡唑烷基、吡唑啉基、tetronoyl、tetramoyl以及以下基团：
Figure PCTCN2018097386-appb-000004
杂环基可任选地被1、2、3或4个选自以下的取代基取代：任选取代的C1-C6烷基、C1-C6环烷基、卤素、NR aR b、任选被1－3个C1-C6烷基取代的哌嗪基、羟基和羧基等。
除上述特别指出的取代基外，通常本文中，当被取代时，芳基、杂芳基、碳环基和杂环基可被一个或多个(例如1、2、3或4个)选自以下基团的取代基取代：卤素、羟基、羧基、氨基、硝基、氰基、C1-6酰氨基、C1-6酰氧基、C1-6烷氧基、芳氧基、烷硫基、C1-6烷基、C6-10芳基、C3-8环烷基、C2-6链烯基、C2-6炔基、C6-10芳基(C2-6)链烯基、C6-10芳基(C2-6)炔基、饱和和不饱和的杂环基或杂芳基、亚甲基二氧基、C1-6卤代烷基、C6-10芳基(C1-6)烷基、C1-6羟烷基、脲基、巯基、叠氮基、羰基、二(C1-10烷基)氨基、烷磺酰基、氨磺酰基、二烷基氨磺酰基和烷基亚磺酰基等。其中取代基本身也可被任意取代。
本文中，当被取代时，烷基、烷氧基、烷硫基、链烯基、炔基、环烷基、可被一个或多个(例如1、2、3或4个)选自以下基团的取代基取代：卤素、羟基、羧基、氨基、硝基、氰基、C1-6酰氨基、C1-6酰氧基、C1-6烷氧基、芳氧基、烷硫基、C1-6烷基、C6-10芳基、C3-8环烷基、C2-6链烯基、C2-6炔基、C6-10芳基(C2-6)链烯基、C6-10芳基(C2-6)炔基、饱和和不饱和的杂环基或杂芳基、亚甲基二氧基、C1-6卤代烷基、C6-10芳基(C1-6)烷基、C1-6羟烷基、脲基、巯基、叠氮基、羰基、二(C1-10烷基)氨基、烷磺酰基、氨磺酰基、二烷基氨磺酰基和烷基亚磺酰基等。其中取代基本身也可被任意取代。
在优选的实施方案中，当被取代时，烷基、烷氧基、烷硫基、链烯基、炔基、环烷基、羰基、碳环和杂环可被一个或多个(例如1、2、3或4个)选自以下基团的取代基取代：卤素、羟基、羧基、氨基、硝基、氰基、C1-6酰氨基、C1-6酰氧基、C1-6烷氧基、芳氧基、烷硫基、C1-6烷基、C6-10芳基、C3-8环烷基、C2-6链烯基、C2-6炔基、C6-10芳基(C2-6)链烯基、C6-10芳基(C2-6)炔基、饱和和不饱和的杂环基或杂芳基。
本文中，C1-C6酰基指C1-C5烷基-C(O)-，例如乙酰基。
除非另有说明，文中涉及的其它术语的含义为本领域惯常理解的含义。
二、化合物
本发明提供下式A的化合物：
Figure PCTCN2018097386-appb-000005
式中，
X －为可构成盐的阴离子，包括但不限于F -、Cl -、Br -、I -、OAc -、HSO 4 -、H 2PO 4 -、ClO 4 -、F 3CCOO -、CH 3SO 3 -、CF 3SO 3 -、BF 4 －、PF 6 －、柠檬酸根和NO 3 -；
R 1、R 2、R 3、R 4各自独立选自H、卤素和C1-C6烷基；
R 5、R 6、R 7、R 8各自独立选自H和C1-C6烷基；
其中，R 5和R 7可与它们所连接的N形成任选取代的5或6元含氮杂环，和/或R 6和R 8可与它们所连接的N形成任选取代的5或6元含氮杂环；其中，所述5或6元含氮杂环任选地含有环氧原子；或R 3与R 7与它们各自所连接的原子一起形成6元含氮杂环，和/或R 4与R 8与它们各自所连接的原子一起形成6元含氮杂环；
其中，R 1和R 5可与它们所连接的原子形成任选取代的6元含氮杂环，同时R 3和R 7可与它们所连接的原子形成任选取代的6元含氮杂环，和/或R 2和R 6可与它们所连接的原子形成任选取代的6元含氮杂环，同时R 4和R 8可与它们所连接的原子形成任选取代的6元含氮杂环；
R 9选自H，任选取代的C1-C6烷基，任选取代的芳基，任选取代的杂芳基，任选取代的杂环基，和任选取代的C2-C6烯基。
在某些实施方案中，上述被任选取代的基团的取代基如前文第一部分所定义，或为下文针对任一具体结构式中对应位置上的取代基。
在某些实施方案中，R 1和R 2各自独立为H。
在某些实施方案中，R 3和R 4各自独立为H或C1-C6烷基。
在某些实施方案中，R 5、R 6、R 7、R 8各自独立选自H和C1-C6烷基。
在某些实施方案中，R 5和R 7与它们所连接的N形成任选取代的5或6元含氮杂环(如吡咯烷基或哌啶基)，和/或R 6和R 8可与它们所连接的N形成任选取代的5或6元含氮杂环(如吡咯烷基或哌啶基)；其中，所述5或6元含氮杂环任选地含有环氧原子(如吗啉基)。
在某些实施方案中，R 1和R 2各自独立为H，R 5和R 6各自独立为H或C1-C6烷基；R 3与R 7与它们各自所连接的原子一起形成6元含氮杂环且R 4与R 8与它们各自所连接的原子一起形成6元含氮杂环。
在某些实施方案中，R 9选自：C1-C6烷基，任选被金刚烷基或苯基取代，所述金刚 烷基任选被1～3个选自羟基、C1-C6烷氧基和C1-C6烷基的取代基取代，所述苯基任选被1～3个选自羟基和C1-C6烷氧基的取代基取代；苯基，任选被1～3个选自硝基、卤素、C1-C6烷基、苯基重氮基或萘基重氮基的取代基取代，其中，所述苯基重氮基或萘基重氮基任选被1～3个选自卤素和NR aR b的取代基取代；任选被硝基取代的1,3-苯并二氧戊环基。
在某些实施方案中，R 1和R 2各自独立为H或C1-C6烷基；R 3和R 4各自独立为H或C1-C6烷基；R 9选自：C1-C6烷基，任选被金刚烷基或苯基取代，所述金刚烷基任选被1～3个选自羟基、C1-C6烷氧基和C1-C6烷基的取代基取代，所述苯基任选被1～3个选自羟基和C1-C6烷氧基的取代基取代；苯基，任选被1～3个选自硝基、卤素、C1-C6烷基、苯基重氮基或萘基重氮基的取代基取代，其中，所述苯基重氮基或萘基重氮基任选被1～3个选自卤素和NR aR b的取代基取代；任选被硝基取代的1,3-苯并二氧戊环基。
在某些实施方案中，通式A中，R 1和R 2各自独立为H；R 3和R 4各自独立为H或C1-C6烷基；R 5、R 6、R 7、R 8各自独立选自H和C1-C6烷基，或R 5和R 7与它们所连接的N形成任选取代的5或6元含氮杂环(如吡咯烷基或哌啶基)，和/或R 6和R 8可与它们所连接的N形成任选取代的5或6元含氮杂环(如吡咯烷基或哌啶基)；其中，所述5或6元含氮杂环任选地含有环氧原子(如吗啉基)，或R 3与R 7与它们各自所连接的原子一起形成6元含氮杂环且R 4与R 8与它们各自所连接的原子一起形成6元含氮杂环；和R 9选自：C1-C6烷基，任选被金刚烷基或苯基取代，所述金刚烷基任选被1～3个选自羟基、C1-C6烷氧基和C1-C6烷基的取代基取代，所述苯基任选被1～3个选自羟基和C1-C6烷氧基的取代基取代；苯基，任选被1～3个选自硝基、卤素、C1-C6烷基、苯基重氮基或萘基重氮基的取代基取代，其中，所述苯基重氮基或萘基重氮基任选被1～3个选自卤素和NR aR b的取代基取代；任选被硝基取代的1,3-苯并二氧戊环基。
在某些实施方案中，通式A的化合物不包括以下化合物：化合物BIb、BIf、BIg、BIIb、BIIe、BIIf、BIIIa、BIIIc、BIIIf、BIIIg、BIIIk、BVIa、BVIIIb、BIXa-BIXe、CIa-CIe、CIg、CIk、CIu和CXIIIb。
在某些实施方案中，通式A化合物的结构如下式BI所示：
Figure PCTCN2018097386-appb-000006
式中，
R 9选自任选取代的C1-C6烷基，任选取代的芳基和任选取代的杂芳基；
X -可选自但不限于F -、Cl -、Br -、I -、OAc -、HSO 4 -、H 2PO 4 -、ClO 4 -、F 3CCOO -、CH 3SO 3 -、CF 3SO 3 -、BF 4 －、PF 6 －、柠檬酸根和NO 3 -。
在某些实施方案中，所述任选取代的C1-C6烷基为任选地被金刚烷基取代的C1-C6烷基。在某些实施方案中，所述任选取代的芳基为任选地被1～3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷氧基羰基、苯基重氮基和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中，所述任选取代的杂芳基为任选地被1～3个选自C1-C6烷基、羟基、三苯基甲基、苯基取代的C1-C6烷基、卤素和羧基取代的杂芳基。优选地，所述杂芳基为吡啶基、嘧啶基、吡嗪基、哒嗪基、噁唑基、噻唑基、咪唑基、呋喃基、噻吩基或吡咯基。在某些实施方案中，式BI中的R 9选自任选地被金刚烷基取代的C1-C6烷基和任选地被1～3个选自卤素、硝基、C1-C6烷氧基羰基、苯基重氮基和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中，R 9为金刚烷基取代的C1-C6烷基。
式BI的化合物可用于抑制耐药菌，例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中，通式BI的化合物不包括化合物BIb、BIf和BIg。
在某些实施方案中，通式A化合物的结构如下式BII所示：
Figure PCTCN2018097386-appb-000007
式中，
R 9选自任选取代的C1-C6烷基，任选取代的芳基和任选取代的杂芳基；
X -可选自但不限于F -、Cl -、Br -、I -、OAc -、HSO 4 -、H 2PO 4 -、ClO 4 -、F 3CCOO -、CH 3SO 3 -、CF 3SO 3 -、BF 4 －、PF 6 －、柠檬酸根和NO 3 -。
在某些实施方案中，所述任选取代的C1-C6烷基为任选地被金刚烷基取代的C1-C6烷基。在某些实施方案中，所述任选取代的芳基为任选地被1～3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷氧基羰基、苯基重氮基和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中，所述任选取代的杂芳基为任选地被1～3个选自C1-C6烷基、羟基、三苯基甲基、苯基取代的C1-C6烷基、卤素和羧基取代的杂芳基。优选地，所述杂芳基为吡啶基、嘧啶基、吡嗪基、哒嗪基、噁唑基、噻唑基、咪唑基、呋喃基、噻吩基或吡咯基。在某些实施方案中，式BII中的R 9选自任选地被金刚烷基取代的C1-C6烷基和任选地被1～3个选自硝基和苯基重氮基的取代基取代的苯基。在某些实施方案中，R 9为金刚烷基取代的C1-C6烷基。
式BII的化合物可用于抑制耐药菌，例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中，通式BII的化合物不包括化合物BIIb、BIIe和BIIf。
在某些实施方案中，通式A化合物的结构如下式BIII所示：
Figure PCTCN2018097386-appb-000008
式中，
R 9选自任选取代的C1-C6烷基，任选取代的芳基和任选取代的杂芳基；
X -可选自但不限于F -、Cl -、Br -、I -、OAc -、HSO 4 -、H 2PO 4 -、ClO 4 -、F 3CCOO -、CH 3SO 3 -、CF 3SO 3 -、BF 4 －、PF 6 －、柠檬酸根和NO 3 -。
在某些实施方案中，所述任选取代的C1-C6烷基任选地被金刚烷基或羟基取代的C1-C6烷基。在某些实施方案中，所述任选取代的芳基为任选地被1～3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷基、C1-C6烷氧基羰基、苯基重氮基、-Cr(CO) 3和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中，所述任选取代的杂芳基为任选地被1～3个选自C1-C6烷基、羟基、三苯基甲基、苯基取代的C1-C6烷基、卤素和羧基取代的杂芳基。优选地，所述杂芳基为吡啶基、嘧啶基、吡嗪基、哒嗪基、噁唑基、噻唑基、咪唑基、呋喃基、噻吩基或吡咯基。在某些实施方案中，式BIII中的R 9选自任选地被金刚烷基取代的C1-C6烷基和任选地被1～3个选自硝基和C1-C6烷氧基的取代基取代的苯基。在某些实施方案中，R 9为金刚烷基取代的C1-C6烷基。式BIII的化合物可用于抑制耐药菌，例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中，式BIII中的R 9为任选地被1～3个C1-C6烷基取代的吡啶基。优选的，在某些实施方案中，R 9为被1个C1-C6烷基取代的吡啶基，其取代基在N原子上。在这些实施方案中，式BIII化合物具有抗菌增效作用，可与增强其它抗菌化合物的抗菌效果，例如，可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
在某些实施方案中，通式BIII的化合物不包括化合物BIIIa、BIIIc、BIIIf、BIIIg和BIIIk。
在某些实施方案中，通式A化合物的结构如下式BIV所示：
Figure PCTCN2018097386-appb-000009
Figure PCTCN2018097386-appb-000010
式中，
R 9选自任选取代的芳基，任选取代的杂芳基，任选取代的杂环基，和任选取代的C2-C6烯基；
X -可选自但不限于F -、Cl -、Br -、I -、OAc -、HSO 4 -、H 2PO 4 -、ClO 4 -、F 3CCOO -、CH 3SO 3 -、CF 3SO 3 -、BF 4 －、PF 6 －、柠檬酸根和NO 3 -。
在某些实施方案中，所述任选取代的芳基，任选取代的杂芳基，任选取代的杂环基，和任选取代的C2-C6烯基的取代基如前文第一部分所述，或如下文式CI-CXIII对应的基团所述。
在某些实施方案中，通式BIV的化合物不包括化合物CIa-CIe、CIg、CIk、CIu和CXIIIb。
在某些实施方案中，通式A化合物的结构如下式BV所示：
Figure PCTCN2018097386-appb-000011
式中，
R 9选自任选取代的芳基和任选取代的C1-C6烷基；
X -可选自但不限于F -、Cl -、Br -、I -、OAc -、HSO 4 -、H 2PO 4 -、ClO 4 -、F 3CCOO -、CH 3SO 3 -、CF 3SO 3 -、BF 4 －、PF 6 －、柠檬酸根和NO 3 -。
在某些实施方案中，所述任选取代的C1-C6烷基任选地被金刚烷基取代的C1-C6烷基。在某些实施方案中，所述任选取代的芳基为任选地被1～3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷氧基羰基、苯基重氮基和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中，式BV中，R 9选自苯基和金刚烷基取代的C1-C6烷基。
式BV的化合物可用于抑制耐药菌，例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中，通式A化合物的结构如下式BVI所示：
Figure PCTCN2018097386-appb-000012
式中，
R 9选自任选取代的芳基和任选取代的C1-C6烷基；
X -可选自但不限于F -、Cl -、Br -、I -、OAc -、HSO 4 -、H 2PO 4 -、ClO 4 -、F 3CCOO -、CH 3SO 3 -、 CF 3SO 3 -、BF 4 －、PF 6 －、柠檬酸根和NO 3 -。
在某些实施方案中，所述任选取代的C1-C6烷基任选地被金刚烷基取代的C1-C6烷基。在某些实施方案中，所述任选取代的芳基为任选地被1～3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷氧基羰基、苯基重氮基和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中，式BVI中R 9选自金刚烷基取代的C1-C6烷基。
式BVI的化合物可用于抑制耐药菌，例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中，通式BVI的化合物不包括化合物BVIa。
在某些实施方案中，通式A化合物的结构如下式BVII所示：
Figure PCTCN2018097386-appb-000013
式中，
R 9选自任选取代的芳基和任选取代的C1-C6烷基；
X -可选自但不限于F -、Cl -、Br -、I -、OAc -、HSO 4 -、H 2PO 4 -、ClO 4 -、F 3CCOO -、CH 3SO 3 -、CF 3SO 3 -、BF 4 －、PF 6 －、柠檬酸根和NO 3 -。
在某些实施方案中，所述任选取代的C1-C6烷基任选地被金刚烷基取代的C1-C6烷基。在某些实施方案中，所述任选取代的芳基为任选地被1～3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷氧基羰基、苯基重氮基和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中，式BVII中R 9选自苯基和金刚烷基取代的C1-C6烷基。
式BVII的化合物可用于抑制耐药菌，例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中，通式A化合物的结构如下式BVIII所示：
Figure PCTCN2018097386-appb-000014
式中，
R 5和R 6各自独立选自H和C1-C6烷基；
R 9选自任选取代的芳基和任选取代的C1-C6烷基；和
X -可选自但不限于F -、Cl -、Br -、I -、OAc -、HSO 4 -、H 2PO 4 -、ClO 4 -、F 3CCOO -、CH 3SO 3 -、 CF 3SO 3 -、BF 4 －、PF 6 －、柠檬酸根和NO 3 -。
在某些实施方案中，所述任选取代的C1-C6烷基任选地被金刚烷基取代的C1-C6烷基。在某些实施方案中，所述任选取代的芳基为任选地被1～3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷氧基羰基、苯基重氮基和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中，式BVIII中R 9选自金刚烷基取代的C1-C6烷基。
式BVIII的化合物可用于抑制耐药菌，例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中，通式BVIII化合物不包括化合物BVIIIb。
在某些实施方案中，通式A化合物的结构如下式BIX所示：
Figure PCTCN2018097386-appb-000015
式中，
R 9选自任选取代的芳基；和
X -可选自但不限于F -、Cl -、Br -、I -、OAc -、HSO 4 -、H 2PO 4 -、ClO 4 -、F 3CCOO -、CH 3SO 3 -、CF 3SO 3 -、BF 4 －、PF 6 －、柠檬酸根和NO 3 -。
在某些实施方案中，所述任选取代的芳基为任选地被1～3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷氧基羰基、-SO 3或-SO 2Cl取代的苯基。
在某些实施方案中，式BIX中，R 9为苯基。在这些实施方案中，式BIX的化合物可用于抑制耐药菌，例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中，式BIX中，R 9为羧基、C1-C6烷氧基羰基、-SO 3或-SO 2Cl取代的苯基。在这些实施方案中，式IX的化合物具有抗菌增效作用，可与增强其它抗菌化合物的抗菌效果，例如，可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
在某些实施方案中，通式BIX化合物不包括化合物BIXa-BIXe。
在某些实施方案中，通式A化合物的结构如下式CI到CXIII中任一所示：
Figure PCTCN2018097386-appb-000016
Figure PCTCN2018097386-appb-000017
式中，
R 10、R 11、R 12、R 13和R 14各自独立选自H，硝基，任选取代的C1-C6烷基，C1-C6烷氧基，羧基，卤素，羟基，巯基，C1-C6烷巯基，NR aR b，任选取代的芳基，二苯磷基，和任选取代的芳基重氮基和C1-C6酰基，其中，R a和R b独立选自H、C1-C6烷基和C1-C6酰基；或者R 10、R 11、R 12、R 13和R 14中的两个或两个以上可与它们所连接的苯基一起形成任选取代的萘基、蒽基、喹啉基、二萘嵌苯基(苝基)、苯并咪唑基或1,3-苯并二氧戊环基；
Y选自O、S、或NR 19；
R 16、R 17、R 18、R 20、R 21、R 22、R 24和R 25各自独立选自H和C1-C6烷基；或者，Y与R 25及所述含Y的环一同形成任选取代的下式结构：
Figure PCTCN2018097386-appb-000018
R 19选自H和任选取代的C1-C6烷基，如苯基取代的C1-C6烷基，如三苯甲基或苄基；
R 27、R 28各自独立选自H和C1-C6烷基；
R 30、R 31、R 32和R 33各自独立选自H，卤素和C1-C6烷基；
R 34、R 35、R 36和R 37各自独立选自H，卤素和C1-C6烷基；
R 38、R 39和R 40各自独立选自H，卤素和C1-C6烷基；
R 41、R 42和R 43各自独立选自H，卤素和C1-C6烷基；
R 44、R 45和R 46各自独立选自H，卤素，羧基和C1-C6烷基；
R 47、R 48和R 49各自独立选自H，卤素和C1-C6烷基；
R 50、R 51和R 52各自独立选自H，羧基，任选取代的芳基，或任选取代的以下基团：
Figure PCTCN2018097386-appb-000019
或者，R 50、R 51和R 52与它们所连接的C原子一起形成任选取代的以下基团：
Figure PCTCN2018097386-appb-000020
其中，取代基选自C1-C6烷基、NR aR b、卤素、羟基、C1-C6烷氧基、和C1-C6烷基取代的哌嗪基；其中，R a和R b各自独立选自H和C1-C6烷基；
R 53、R 54和R 55各自独立选自H，任选取代的C1-C6烷基，羧基；或者R 53、R 54和R 55中的任意两个与它们所连接的C一起形成任选取代的C3-C8环烷基或任选取代的以下基团：
Figure PCTCN2018097386-appb-000021
其中，取代基选自羟基，羧基，任选取代的C1-C6烷基，NR aR b，C1-C6烷氧基，C2-C6烯基，任选被羟基、C1-C6烷氧基或C1-C6烷基取代的金刚烷基，任选取代的芳烷基(如任选被羟基、C1-C6烷氧基、NR aR b、硝基或氰基取代的苯基-C1-C6烷基)；其中，R a和R b各自独立选自H和C1-C6烷基；
X -可选自但不限于F -、Cl -、Br -、I -、OAc -、HSO 4 -、H 2PO 4 -、ClO 4 -、F 3CCOO -、CH 3SO 3 -、CF 3SO 3 -、BF 4 －、PF 6 －、柠檬酸根或NO 3 -。
在某些实施方案中，式CI中，R 10和R 14各自独立选自：H、C1-C6酰基、卤素、羟基、巯基、C1-C6烷巯基、氨基、任选取代的芳基、二苯磷基、C1-C6烷氧基和任选取代的芳基重氮基；R 11和R 13各自独立选自：H、C1-C6烷氧基和卤素；R 12选自H、任选取代的芳基、和任选取代的芳基重氮基。在某些实施方案中，式CI中，R 10、R 11、R 12、R 13和R 14中的两个或两个以上可与它们所连接的苯基一起形成任选取代的蒽基、喹啉基、二 萘嵌苯基(苝基)和苯并咪唑基。在这些实施方案中，式CI的化合物可用于抑制耐药菌，例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中，式CI中，R 10和R 14各自独立选自：H、任选被羟基取代的C1-C6烷基、NR aR b和任选取代的苯基(如任选被羟基或OTBS取代的苯基)；R 11-R 13各自为H；其中，R a和R b独立选自H和C1-C6酰基，优选NRaRb为-NH(C1-C6酰基)。在这些实施方案中，式CI的化合物具有抗菌增效作用，可与增强其它抗菌化合物的抗菌效果，例如，可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
在某些实施方案中，式CII中，Y选自O、S或N；R 16选自H或C1-C6烷基；R 17选自H或C1-C6烷基；R 18选自H或C1-C6烷基。在某些实施方案中，R 16选自H或C1-C6烷基；R 17选自H；R 18选自H或C1-C6烷基。
在某些实施方案中，式CIII中，Y选自O、S或NR 19；R 19选自C1-C6烷基；R 20、R 21和R 22各自为H。
在某些实施方案中，式CIII中，Y选自NR 19；R 19选自C1-C6烷基；R 20、R 21和R 22各自为H。这类化合物可具有抗菌增效作用，可与增强其它抗菌化合物的抗菌效果，例如，可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
在某些实施方案中，式CIV中，Y选自S或NR 19；R 19选自三苯基甲基；R 24选自H或C1-C6烷基；R 25选自H。
在某些实施方式中，式CV中，Y选自NR 19；R 19选自苯基取代的C1-C6烷基；R 27和R 28各自独立为H。
在某些实施方案中，式CVI中，R 30-R 33各自独立为H。
在某些实施方案中，式CVII中，R 34和R 37各自独立为C1-C6烷基或卤素；R 35和R 36各自独立为H。
在某些实施方案中，式CVIII中，R 38选自卤素，R 39为H，R 40为C1-C6烷基。
在某些实施方案中，式CIX中，R 41和R 42各自独立为H，R 43选自卤素。
在某些实施方案中，式CX中，R 44选自H或羧基；R 45选自H或卤素；R 46选自H。
在某些实施方案中，式CXI中，R 47选自H、卤素和C1-C6烷基；R 48和R 49各自独立为H。在某些实施方案中，R 47选自H、F和C1-C6烷基；R 48和R 49各自独立为H。
在某些实施方案中，式CXI中，R 47选自卤素和C1-C6烷基；R 48和R 49各自独立为H。这类化合物可具有抗菌增效作用，可与增强其它抗菌化合物的抗菌效果，例如，可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
在某些实施方案中，式CXII中，R 50为H，R 51和R 52中，一个为H，另一个选自任选被1～3个选自C1-C6烷基、卤素、羟基、C1-C6烷氧基的取代基取代的苯基或以下基 团：
Figure PCTCN2018097386-appb-000022
或者，R 50、R 51和R 52与它们所连接的C原子一起形成任选被1～3个选自C1-C6烷基、NR aR b、卤素、羟基、C1-C6烷氧基、和C1-C6烷基取代的哌嗪基的取代基取代的以下基团：
Figure PCTCN2018097386-appb-000023
在某些实施方案中，式CXII中，R 50为H，R 51和R 52中，一个为H，另一个选自羧基或苯基：或R 50、R 51和R 52与它们所连接的C原子一起形成任选被1～3个选自C1-C6烷基、卤素和C1-C6烷基取代的哌嗪基的取代基取代的以下基团：
Figure PCTCN2018097386-appb-000024
这些化合物可具有抗菌增效作用，可与增强其它抗菌化合物的抗菌效果，例如，可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
在某些实施方案中，式CXIII中，R 53、R 54和R 55都为H，或其中任意两个为H，另一个选自：羧基或C1-C6烷基，其中该C1-C6烷基任选被羟基，羧基，任选被1～3个选自羟基、C1-C6烷氧基和C1-C6烷基的取代基取代的金刚烷基，任选被1～3个选自羟基、氰基、NR aR b和C1-C6烷氧基的取代基取代的苯基取代；或者R 53、R 54和R 55中的一个为H，余下两个与它们所连接的C一起形成任选被1～4个选自羧基、C1-C6烷基和C2-C6烯基的取代基取代的C3-C8环烷基或任选被1～3个选自羧基和C1-C6烷基的取代基取代的以下基团：
Figure PCTCN2018097386-appb-000025
在某些实施方案中，式CXIII中，R 53、R 54和R 55都为H，或其中任意两个为H，另 一个选自：羧基或C1-C6烷基，其中该C1-C6烷基任选被选自羧基和任选被1～3个选自羟基、氰基和C1-C6烷氧基的取代基取代的苯基取代；或者R 53、R 54和R 55中一个为H，余下两个与它们所连接的C一起形成任选被1～4个选自羧基和C1-C6烷基的取代基取代的C3-C8环烷基或任选被羧基取代的以下基团：
Figure PCTCN2018097386-appb-000026
这些化合物可具有抗菌增效作用，可与增强其它抗菌化合物的抗菌效果，例如，可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
尤其是，在本发明的化合物中，那些R 9为被1～3个选自羟基、C1-C6烷氧基和氰基的取代基取代的苯基取代的C1-C6烷基的化合物特别具有抗菌增效作用，可与增强其它抗菌化合物的抗菌效果，例如，可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
优选地，本文通式A化合物(包括本文所述的各通式的化合物)为具有抗菌活性和/或抗菌增效活性的化合物，尤其优选表1中MIC值小于等于16μg/ml和/或FICI值小于等于1、优选小于等于0.5的那些化合物。
本文的化合物可以作为立体异构体，包括旋光异构体存在。本文包括所有立体异构体和这样的立体异构体的外消旋混合物，以及可以根据本领域技术人员众所周知的方法分离出来的单独的对映体。
在某些实施方案中，本发明各通式的具体化合物可选自以下化合物：
Figure PCTCN2018097386-appb-000027
Figure PCTCN2018097386-appb-000028
Figure PCTCN2018097386-appb-000029
Figure PCTCN2018097386-appb-000030
Figure PCTCN2018097386-appb-000031
Figure PCTCN2018097386-appb-000032
Figure PCTCN2018097386-appb-000033
Figure PCTCN2018097386-appb-000034
Figure PCTCN2018097386-appb-000035
Figure PCTCN2018097386-appb-000036
本文还包括上述化合物的前药。本文前药的实施例包括含有羧酸的化合物的简单酯(例如依据本领域已知方法通过与C1-4醇缩合而获得的酯)；含有羟基的化合物的酯(例如依据本领域已知方法通过与C1-4羧酸、C3-6二酸或其酸酐例如琥珀酸酐和富马酸酐缩合而获得的酯)；含有氨基的化合物的亚胺(例如依据本领域已知方法通过与C1-4醛或酮缩合而获得的亚胺)；含有氨基的化合物的氨基甲酸酯，例如Leu等人(J.Med.Chem.1999,42:3623-3628)和Greenwald等人(J.Med.Chem.1999,42:3657-3667)描述的那些酯；含有醇的化合物的醛缩醇或酮缩醇(例如依据本领域已知方法通过与氯甲基甲基醚或氯甲基乙基醚缩合而获得的那些缩醇)。
三、化合物的制备
可采用以下通用制备流程一和二来制备本发明通式A化合物。
通用制备流程一：
Figure PCTCN2018097386-appb-000037
将取代的3-氨基苯酚(2eq)与取代醛基化合物(1eq)加入装有30毫升甲磺酸的圆底烧瓶中，加热至回流反应8小时，TLC点板监测反应完全后将反应液倒入冰水中，有固体析出。布氏漏斗过滤，收集固体，用50毫升二氯甲烷溶解在圆底烧瓶中，加入DDQ(1eq)的二氯甲烷溶液，常温搅拌反应半个小时。反应液用水和二氯甲烷体系萃取三次，取有机相并用无水硫酸镁干燥，过滤后收集滤液后旋干，通过柱层析(洗脱剂：二氯甲烷：甲醇＝25:1，v/v)分离得到为紫红色固体产物，产率10％-40％。
通用制备流程二：
Figure PCTCN2018097386-appb-000038
将制备好的二溴苯甲醚化合物(1eq)和50毫升无水四氢呋喃置于100毫升的圆底 烧瓶中，氩气保护。圆底烧瓶置于杜瓦瓶中，倒入乙酸乙酯没至瓶颈，用液氮降温至零下78摄氏度，用针管加入正丁基锂试剂(2eq)，15分钟后加入羰基化合物的无水四氢呋喃溶液，反应一个小时。往反应液中加入1毫升碳酸氢钠溶液，用水和二氯甲烷体系萃取三次，取有机相并用无水硫酸镁干燥，过滤后收集滤液后旋干，通过柱层析(洗脱剂：二氯甲烷：甲醇＝25:1，v/v)分离得到为紫红色固体产物，产率30％-95％。
上述两个通用制备流程中，R 1-R 9及X -如前文任一实施方案所定义。
在某些实施方案中，本文提供一种制备本文通式A化合物的方法，所述方法包括使下式所示的二溴苯甲醚和羰基化合物在有机溶剂和烷基锂试剂的存在下进行反应，从而制备得到式A化合物：
Figure PCTCN2018097386-appb-000039
式中，R 1-R 9如前文任一实施方案所定义；LG为离去基团，可选自卤素如Cl或Br，氰基，C1-C6烷氧基和C1-C6烷基-COO-等。
适用于本文所述方法的有机溶剂可以是醚类溶剂，如四氢呋喃、乙醚、甲基叔丁基醚和1,4-二氧六环。有机溶剂还可以是正己烷等。适用于本文所述方法的烷基锂试剂通常为C1-C6烷基锂试剂，包括但不限于正丁基锂、叔丁基锂和仲丁基锂等。上述反应可在零下78℃到0℃之间进行。通常，二溴苯甲醚化合物与烷基锂试剂的摩尔比在1：2－3之间。
反应时间可根据实际反应条件确定。反应结束后，可采用常规的方法进行分离纯化。例如，可向反应液中加入氢氧化钠溶液，之后用水和二氯甲烷体系萃取，有机相用无水硫酸镁干燥。柱层析的洗脱剂可以是二氯甲烷：甲醇。
在某些实施方案中，将制备好的二溴苯甲醚化合物和适量有机溶剂置于圆底烧瓶中，惰性气体(如氩气)保护。降温至零下78摄氏度后加入烷基锂试剂，约10到20分钟后加入羰基化合物的有机溶剂溶液，反应一段时间，即可制备得到通式A化合物。
四、组合物
本文所公开的化合物可被制成组合物的形式，尤其是药物组合物的形式。药物组合物可含有本文所公开的一种或多种化合物和药学上可接受的载体。通常，药物组合物中，本文化合物的含量为治疗或预防有效量。有效量指某成分的用量足以产生所期望的反应。具体的有效量取决于多种因素，如待治疗的具体病症、患者的身体条件(如患者体重、年龄或性别)、治疗持续时间、同时进行的其它疗法以及所用的具体配方等。有效量也指在该用量下，化合物的毒性或负面效果不及于其所带来的正面疗效。
本文中，药学上可接受的载体通常是安全、无毒的，且广义上可包括制药产业中用于 制备药物组合物的任何已知物质，如填充剂、稀释剂、凝结剂、黏合剂、润滑剂、助流剂、稳定剂、着色剂、润湿剂、崩解剂等。在选择适用于投递本文化合物的载体时，主要需考虑该药物组合物的给药方式，本领域技术人员熟知此项技术。因此，可将本发明的药物组合物制备成不同的剂型，例如适合口服给药的片剂、胶囊等，适合肠外给药的注射剂，以及外用制剂如油剂、霜剂、乳液剂和药膏等。
可根据已知的药学程序来制备上述药物组合物，譬如《雷明顿制药科学》(Remington’s Pharmaceutical Sciences)(第17版，Alfonoso R.Gennaro编，麦克出版公司(Mack Publishing Company)，伊斯顿，宾夕法尼亚(1985))一书中有详细的记载。
例如，当将化合物制备成口服片剂时，要求浓度为40％-80％(w/w)，每片可含0.5-2g的本发明化合物，可以淀粉、碳酸镁、二氧化硅等为辅料。当将化合物制备成注射剂时，成人的日剂量可为1～2g/日，儿童可为20～40mg/kg/日，以例如10％葡萄糖溶液为溶剂，稀释后缓慢注射。当将化合物制备成外用制剂比如药膏时，可采用1％-5％的浓度，可以聚乙二醇400和聚乙二醇3350等为辅料。
本文化合物具有抗菌增效的作用。因此，在某些实施方案中，本文的药物组合物中除含有一种或多种本发明化合物以外，还可含有一种或多种已知的抗菌药物，如下文所述的一种或多种已知的抗菌药物。
在某些实施方案中，本发明的组合物含有化合物CXIIIt和CXIIIt2。在某些实施方案中，该组合物是溶液。
五、方法和应用
本文的化合物可用于抗菌，尤其是与人类健康相关的各类革兰氏阳性菌和革兰氏阴性菌，包括但不限于杀菌、抑菌。本文的化合物还可用于抗菌增效。本文中，“抗菌增效”指本文的化合物能增强已知抗菌药的抗菌活性。尤其是，如前文所述，本发明的某些化合物特别可用于抗菌增效。在某些实施方案中，本文提供罗丹明染料在抑制或杀灭革兰氏阳性菌和革兰氏阴性菌中的应用，或在增强已知抗菌药的抗菌活性中的应用。
目前，世界范围内广泛传播和扩散的“超级细菌”主要：ESKAPE，即万古霉素耐药粪肠球菌(Enterococcus faecium)、甲氧西林耐药金黄色葡萄球菌(Staphylococcus aureus)、碳青霉烯耐药肺炎克雷伯菌(Klebsiella pneumoniae)、泛耐药鲍曼不动杆菌(Acinetobacter baumanii)、多药耐药铜绿假单胞菌(Pseudomonas aeruginosa)、以及多药耐药肠杆菌(Enterobacter species)，严重威胁着人类的生命健康。
金黄色葡萄球菌可引起广泛的人类感染。最常见的是皮肤和软组织感染；在这些部位的感染表现为毛囊炎、疖、痈、疮、乳腺炎、伤口感染、金黄色葡萄球菌烫伤样皮肤综合 症。更严重的感染，包括菌血症、肺炎、心内膜炎、骨关节感染和中毒性休克综合征。金黄色葡萄球菌也可导致食物中毒的爆发。金黄色葡萄球菌的多样性也延伸到其宿主范围，包括家畜、马、山羊、绵羊、牛、兔、猪和家禽。各种感染已在这些物种中报道，但与人类经济最相关的是奶牛和其他反刍动物的乳腺炎感染，养殖兔子的致死性全身感染，以及家禽的禽掌感染(溃疡性掌皮炎)。耐甲氧西林金黄色葡萄球菌(MRSA)是目前最常见的社区和医院获得性感染病原菌之一。MRSA感染导致日益增加的发病率、死亡率，恶性侵染、多重耐药性和医院感染的爆发，成为主要的公共健康问题之一。当前临床上用于MRSA治疗的抗生素主要是万古霉素、替考拉宁、利奈唑胺等。然而，MRSA可以获得抗多种替代抗生素耐药性，其中包括万古霉素，万古霉素被认为是一个严重的MRSA感染的最后一道防线的，同样对于相对较新的药物如利奈唑胺和达托霉素也出现了抗药性。为了保证有效的治疗，开发新型的抗MRSA的抗生素已经成为了一个迫切问题。
肠球菌作为感染性心内膜炎的致病菌为人们所知，目前已成为引起院内感染的主要致病菌之一，近来因其多重耐药特性而引起更多的关注。肠球菌引起的常见感染有：泌尿系统感染、菌血症、感染性心内膜炎、腹腔感染、胆道感染以及伤口感染。肠球菌还可以引起新生儿脑膜炎，成人中枢神经系统的感染(特别是有中枢神经手术史及鞘内化疗的患者)；肠球菌还可引起肝脏移植术后肝脏及胆道的感染。较少见的感染有骨髓炎和下呼吸道感染。肠球菌属共有17个种，临床上多数的感染是由于粪肠球菌和屎肠球菌引起，其中80％的感染是由粪肠球菌引起，但屎肠球菌更易出现多重耐药特别是对万古霉素的耐药，其引起的感染比例在不断上升。肠球菌对于传统的抗生素的耐药性正在上升，并且随着耐万古霉素肠球菌的快速播散使得肠球菌感染治疗极为困难。为了保证有效的治疗，开发新型的抗VRE的抗生素已经成为了一个迫切问题。
肺炎链球菌是社区获得性感染的主要病原菌之一。同时也是化脓性脑膜炎、胸膜炎、腹膜炎以及中耳炎、鼻窦炎等等的常见致病菌。临床治疗中的主要难题集中在耐药菌株的增加。因此开发新型的抗肺炎链球菌的抗生素已经成为了一个迫切问题。表皮葡萄球菌(表葡菌)是人体皮肤和黏膜上定居的正常菌群之一，通常情况下致病力很低。近几年来，随着留置静脉导管等侵袭性操作的增多，表葡菌已成为医院感染的重要致病菌。同时，目前，临床分离的表葡菌耐药现象非常严重。因此发展新的抗菌药物已经成为了一个迫切问题。
鲍曼不动杆菌是一种广泛存在于医院的机会致病菌，占医院革兰氏阴性菌感染的2-10％，死亡率高达35-100％。在世界范围内的重症监护病房中，感染高达20％。由于鲍曼不动杆菌对目前临床应用的绝大多数抗生素具有耐药性，因而也被称之为“甲氧西林耐药金黄色葡萄球菌(MRSA)金的革兰阴性菌。2012年，我国将鲍曼不动杆菌列为目前 最重要的“超级细菌”。2013年，美国将其列为最为严重的超级细菌之一。因此开发新型的抗鲍曼不动杆菌的抗生素已经成为了一个迫切问题。
肺炎克雷伯菌是革兰阴性杆菌属，是条件致病菌之一，常寄生于人体呼吸道和肠道，当机体免疫力降低时，易引起下呼吸道及尿路感染，是下呼吸道及尿路感染的重要病原。近年来，随着广谱抗生索的广泛使用，肺炎克雷伯菌的耐药性也逐年升高，给临床的治疗带来了困难。因此开发新型的抗肺炎克雷伯菌的抗生素已经成为了一个迫切问题。
本文化合物对以上各类菌有良好的抗菌、杀菌及增效活性，因此可以用于以上临床易感染菌及临床耐药菌感染的有效治疗。具体而言，这类菌包括但不限于：金黄色葡萄球菌，如甲氧西林耐药金黄色葡萄球菌；万古霉素耐药粪肠球菌；碳青霉烯耐药肺炎克雷伯菌；泛耐药鲍曼不动杆菌；多药耐药铜绿假单胞菌；多药耐药肠杆菌；抗万古霉素屎肠球菌；肺炎链球菌；甲氧西林敏感表皮葡萄球菌；化脓性链球菌；肺炎克雷伯菌(ESBL+)；肺炎克雷伯菌(ESBL-)；抗碳青霉烯肺炎克雷伯菌；大肠埃细菌(ESBL+)；大肠埃细菌(ESBL-)；和痢疾桿菌。本文化合物或药物组合物可用于治疗由这些菌导致的各种疾病和/或症状。本文的化合物可用于已知各种抗菌化合物的协同增效作用，这些已知抗菌化合物包括但不限于β内酰胺类抗生素，如头孢克洛、头孢吡肟、青霉素钠、氨苄西林、舒巴坦和苯唑西林；喹诺酮类，如左氧氟沙星；氨基糖苷类，如阿米卡星和庆大霉素；和糖肽类，如万古霉素等。尤其优选的是，本文化合物对β内酰胺类抗生素具有协同增效作用。
因此，本文也提供本文前文各实施方案所述的通式A化合物在制备抗菌药或制备用于增加已知抗菌化合物的抗菌效果的药物中的用途。本文还提供一种抗菌方法，所述方法包括给予需要的对象抗菌有效量的本文所述的一种或多种化合物，或其药物组合物，或含有本文所述的一种或多种化合物以及一种或多种已知抗菌化合物的药物组合物。给予的方法可以是本领域常规的方法，包括但不限于口服、注射或其它合适的给药方式。
下列实施例是举例说明，而不是限制本发明的方法和制剂。实施例中所采用的方法和材料，除非另有说明，否则均为本领域常规的方法和材料。其他对于本领域技术人员来说是显而易见的，和在临床治疗中通常会遇到的对各种条件和参数的适当修改和改进，都在本发明的精神和范围内。
制备例
实施例1：BIa的制备
Figure PCTCN2018097386-appb-000040
利用通用制备流程一制备，化合物为紫红色固体，产率33％。
1H NMR(400MHz,CDCl 3):δ8.08(d,J＝8.3Hz,2H),7.07(dd,J＝8.3Hz,1.2Hz,2H),6.65(d,J＝1.2Hz,2H),2.99(s,3H). 13C NMR(101MHz,CDCl 3):δ157.3,155.4,130.1,114.0,113.87,95.0,15.0.ESI-HRMS calculated for C 14H 13N 2O[M] +225.1023,found 225.1025。
实施例2：BIc的制备
Figure PCTCN2018097386-appb-000041
利用通用制备流程一制备，化合物为紫红色固体，产率24％。
1H NMR(400MHz,CDCl 3):δ7.77(d,J＝7.8Hz,1H),7.54(t,J＝7.0Hz,1H),7.45(t,J＝7.2Hz,1H),7.21(d,J＝7.8Hz,1H),7.01(d,J＝9.1Hz,2H),6.92(d,J＝8.9Hz,2H),6.80(s,2H)； 13C NMR(101MHz,CDCl 3)δ160.1,157.8,157.5,134.6,134.2,133.8,131.6,130.3,128.5,123.0,114.9,113.0,96.1；ESI-MS(m/z):[M] +calcd.for C 19H 14BrN 2O,365.0285；found 365.0283。
实施例3：BId的制备
Figure PCTCN2018097386-appb-000042
利用通用制备流程一制备，化合物为紫红色固体，产率27％。
1H NMR(400MHz,CD 3OD):δ7.45(t,J＝7.2Hz,1H),7.33(d,J＝9.5Hz,2H),7.21(dd,J＝7.2Hz,1.4Hz,1H),7.17-7.15(m,2H),7.02(dd,J＝9.6Hz,1.9Hz,2H),6.91(d,J＝2.1Hz,2H). 13C NMR(101MHz,CDCl 3)δ158.0,155.4,155.1,133.5,132.6,131.2,131.1,130.8,130.6,128.4,114.1,113.3,96.1.ESI-MS(m/z):[M] +calcd.for C 19H 15N 2O 2,303.1129；found 303.1130。
实施例4：BIe的制备
Figure PCTCN2018097386-appb-000043
利用通用制备流程一制备，化合物为紫红色固体，产率25％。
1H NMR(400MHz,CDCl 3):δ8.40(d,J＝8.2Hz,1H),8.02(t,J＝7.5Hz,1H),7.81(t,J＝7.5Hz,1H),7.46(d,J＝7.5Hz,1H),7.03(d,J＝9.4Hz,2H),6.96(dd,J＝9.4Hz,1.7Hz,2H),6.71(d,J＝1.8Hz,2H)； 13C NMR(101MHz,CDCl 3)δ158.0,156.7,155.2,148.8,135.7,131.2,131.0,130.7,129.3,128.4,127.8,125.2,114.9,112.2,96.1.ESI-HRMS(m/z):[M] +calcd.for C 19H 14N 3O 3,332.1030；found 332.1031。
实施例5：BIh的制备
Figure PCTCN2018097386-appb-000044
利用通用制备流程一制备，化合物为紫红色固体，产率23％。
1H NMR(400MHz,CDCl 3):δ8.17(d,J＝8.2Hz,2H),8.02(dd,J＝8.1Hz,1.8Hz,2H),7.61-7.53(m,5H),7.43(d,J＝9.4Hz,2H),6.93(dd,J＝9.5Hz,2.2Hz,2H),6.88(d,J＝2.1Hz,2H)； 13C NMR(101MHz,CDCl 3)δ158.1,156.3,155.7,153.6,152.6,134.2,132.0,131.9,130.6,129.4,123.4,123.3,114.5,113.3,96.9.ESI-HRMS(m/z):[M] +calcd.for C 25H 19N 4O,391.1554；found 391.1555。
实施例6：BIi的制备
Figure PCTCN2018097386-appb-000045
利用通用制备流程一制备，化合物为紫红色固体，产率27％。
1H NMR(400MHz,CDCl 3):δ8.81(d,J＝8.0Hz,1H),8.67(s,1H),7.89(d,J＝7.7Hz,1H),7.61(m,1H),7.22(d,J＝9.1Hz,2H),6.99(dd,J＝9.5Hz,1.9Hz,2H),6.77(d,J＝2.0 Hz,2H)； 13C NMR(101MHz,CDCl 3):δ158.2,156.8,154.1,152.6,149.9,137.5,132.5,128.1,125.1,114.0,112.5,97.3.ESI-MS(m/z):[M] +calcd.for C 18H 14N 3O,288.1132；found 288.1134。
实施例7：BIj的制备
Figure PCTCN2018097386-appb-000046
利用通用制备流程一制备，化合物为紫红色固体，产率24％。
1H NMR(400MHz,CDCl 3):δ7.81(d,J＝3.9Hz,1H),7.70(d,J＝9.1Hz,2H),7.33(s,2H),7.02(d,J＝9.1Hz,2H),6.82(s,2H)； 13C NMR(101MHz,CDCl 3)δ158.0,156.5,150.7,132.8,132.5,131.8,130.1,129.4,114.6,114.0,96.9.ESI-MS(m/z):[M] +calcd.for C 17H 13N 2OS,293.0744；found 293.0745。
实施例8：BIk的制备
Figure PCTCN2018097386-appb-000047
利用通用制备流程一制备，化合物为紫红色固体，产率35％。
1H NMR(400MHz,CDCl 3):δ7.84(d,J＝9.4Hz,2H),6.91(dd,J＝9.5Hz,2H),6.59(d,J＝1.8Hz,2H),3.05(s,2H),1.81(s,3H),1.51-1.41(m,12H). 13C NMR(101MHz,CDCl 3):δ158.1,157.3,155.6,131.3,114.6,113.8,96.1,44.2,40.8,38.2,36.3,28.9.EI-HRMS(m/z):[M] +calcd.for C 24H 27N 2O,359.2118；found 359.2119。
实施例9：BIl的制备
Figure PCTCN2018097386-appb-000048
利用通用制备流程一制备，化合物为紫红色固体，产率26％。
1H NMR(400MHz,CDCl 3):δ7.60-7.53(m,2H),7.34(t,J＝7.0Hz,1H),7.14-7.12(m,3H),6.86(d,J＝9.4Hz,2H),6.80(s,2H),2.84(t,J＝7.6Hz,2H),1.49-1.43(m,2H), 1.26-1.20(m,2H),0.80(t,J＝7.3Hz,3H)； 13C NMR(101MHz,CDCl 3):δ158.6,156.1,155.2,136.9,131.7,131.5,130.4,129.5,128.5,125.7,115.1,114.6,96.2,33.6,30.0,21.9,13.9；ESI-MS(m/z):[M] +calcd.for C 23H 23N 2OS,375.1526；found 375.1525。
实施例10：BIIa的制备
Figure PCTCN2018097386-appb-000049
利用通用制备流程一制备，化合物为紫红色固体，产率22％。
1H NMR(400MHz,CDCl 3):δ6.99(s,2H),6.89(s,2H),3.52(q,J＝7.1Hz,4H),2.98(s,3H),2.10(s,6H),1.33(t,J＝7.0Hz,6H). 13C NMR(101MHz,CDCl 3):δ158.5,156.1,134.2,116.4,113.7,95.6,46.1,15.1,14.6,13.2；ESI-MS(m/z):[M] +calcd.for C 20H 25N 2O,309.1962；found 309.1963。
实施例11：BIIc的制备
Figure PCTCN2018097386-appb-000050
利用通用制备流程一制备，化合物为紫红色固体，产率19％。
1H NMR(400MHz,CDCl 3):δ7.93(d,J＝8.0Hz,1H),7.62(t,J＝7.0Hz,1H),7.53(t,J＝7.2Hz,1H),7.23(d,J＝8.0Hz,1H),δ6.97(s,2H),6.83(s,2H),3.48(q,J＝7.2Hz,4H),2.09(s,6H),1.32(t,J＝7.0Hz,6H)； 13C NMR(101MHz,CDCl 3)δ159.0,156.8,156.5,134.7,134.2,132.8,131.6,130.8,128.1,123.2,114.7,113.3,96.8,46.5,14.2,12.9；ESI-MS(m/z):[M] +calcd.for C 25H 26FN 2O,389.2024；found 389.2023。
实施例12：BIId的制备
Figure PCTCN2018097386-appb-000051
利用通用制备流程一制备，化合物为紫红色固体，产率23％。
1H NMR(400MHz,CDCl 3):δ8.32(d,J＝7.4Hz,1H),8.11(t,J＝7.5Hz,1H),7.88(t,J＝7.5Hz,1H),7.41(d,J＝7.5Hz,1H),δ6.92(s,2H),6.85(s,2H),3.63(q,J＝7.0Hz,4H), 2.02(s,6H),1.25(t,J＝7.0Hz,6H)； 13C NMR(101MHz,CDCl 3)δ157.7,155.3,154.6,147.3,136.1,133.9,131.6,130.4,129.8,128.2,127.3,125.1,114.9,112.1,96.8,46.2,13.5,12.9.ESI-HRMS(m/z):[M] +calcd.for C 25H 26N 3O 3,416.1969；found 416.1969。
实施例13：BIIg的制备
Figure PCTCN2018097386-appb-000052
利用通用制备流程一制备，化合物为紫红色固体，产率33％。
1H NMR(400MHz,CDCl 3):δ8.21(d,J＝8.3Hz,2H),8.02(dd,J＝8.1Hz,1.8Hz,2H),7.62-7.56(m,5H),δ6.88(s,2H),6.73(s,2H),3.65(q,J＝7.1Hz,4H),2.07(s,6H),1.33(t,J＝7.0Hz,6H)； 13C NMR(101MHz,CDCl 3)δ158.7,156.7,155.8,153.4,152.2,135.2,133.0,131.9,130.6,129.8,124.4,123.1,115.5,113.3,96.9,46.2,13.1,12.8.ESI-HRMS(m/z):[M] +calcd.for C 31H 31N 4O,475.2493；found 475.2495。
实施例14：BIIh的制备
Figure PCTCN2018097386-appb-000053
利用通用制备流程一制备，化合物为紫红色固体，产率27％。
1H NMR(400MHz,CDCl 3):δ8.62(d,J＝7.0Hz,2H),7.85(d,J＝7.0Hz,2H),6.97(s,2H),6.87(s,2H),3.64(q,J＝7.0Hz,4H),2.03(s,6H),1.31(t,J＝7.0Hz,6H)； 13C NMR(101MHz,CDCl 3):δ158.2,156.8,154.1,152.6,149.9,138.5,132.5,128.9,124.9,115.8,114.5,97.1,46.4,13.6,12.8.ESI-MS(m/z):[M] +calcd.for C 24H 26N 3O,372.2071；found 372.2072。
实施例15：BIIi的制备
Figure PCTCN2018097386-appb-000054
利用通用制备流程一制备，化合物为紫红色固体，产率25％。
1H NMR(400MHz,CDCl 3):δ7.77(d,J＝3.9Hz,1H),7.53(m,1H),7.33(d,J＝3.9Hz,1H),6.98(s,2H),6.80(s,2H),3.64(q,J＝6.8Hz,4H),2.04(s,6H),1.35(t,J＝6.8Hz,6H)； 13C NMR(101MHz,CDCl 3)δ157.8,155.3,152.1,134.2,132.1,131.4,130.2,128.8,114.3,113.9,95.6,46.3,13.4,12.8.ESI-MS(m/z):[M] +calcd.for C 23H 25N 2OS,377.1683；found 377.1684。
实施例16：BIIj的制备
Figure PCTCN2018097386-appb-000055
利用通用制备流程一制备，化合物为紫红色固体，产率31％。
1H NMR(400MHz,CDCl 3):δ6.86(s,2H),6.67(s,2H),3.52(q,J＝7.0Hz,4H),3.06(s,2H),2.05(s,6H),1.81(s,3H),1.51-1.41(m,12H),1.26(t,J＝7.1Hz,6H). 13C NMR(101MHz,CDCl 3):δ157.8,157.0,155.3,131.9,114.6,113.0,97.6,45.5,43.4,42.8,37.1,36.1,28.6,13.6,12.6.EI-HRMS(m/z):[M] +calcd.for C 30H 39N 2O,443.3062；found 443.3061。
实施例17：BIIk的制备
Figure PCTCN2018097386-appb-000056
利用通用制备流程一制备，化合物为紫红色固体，产率29％。
1H NMR(400MHz,CDCl 3):δ7.58-7.50(m,2H),7.36(t,J＝7.1Hz,1H),7.01-6.99(m,3H),6.83(d,J＝9.6Hz,2H),3.60(q,J＝7.3Hz,4H),2.82(t,J＝7.4Hz,2H),2.02(s,6H),1.49-1.43(m,2H),1.27(t,J＝7.2Hz,6H),1.28-1.21(m,2H),0.81(t,J＝7.1Hz,3H)； 13C NMR(101MHz,CDCl 3):δ158.4,156.1,155.6,137.7,133.8,131.6,130.1,129.9,128.3,125.8,116.1,114.3,96.2,46.1,33.1,30.8,21.9,13.6,13.0,12.6；ESI-MS(m/z):[M] +calcd.for C 29H 35N 2OS,459.2470；found 459.2469。
实施例18：BIIIb的制备
Figure PCTCN2018097386-appb-000057
利用通用制备流程二制备，化合物为紫红色固体，产率78％。
1H NMR(400MHz,CDCl 3):δ8.16(d,J＝8.8Hz,2H),7.13(dd,J＝9.0Hz,1.7Hz,2H),6.80(d,J＝1.7Hz,2H),3.80(t,J＝5Hz,2H),3.61-3.58(m,2H),3.31(s,12H),1.95-1.92(m,2H)； 13C NMR(101MHz,CDCl 3)δ161.7,158.6,156.4,132.6,114.8,114.2,96.8,79.5,78.0,75.8,62.3,38.9,34.9,25.4；ESI-MS(m/z):[M] +calcd.for C 20H 25N 2O 2,325.1916；found 325.1915。
实施例19：BIIId的制备
Figure PCTCN2018097386-appb-000058
利用通用制备流程二制备，化合物为紫红色固体，产率75％。
1H NMR(400MHz,CDCl 3):δ7.78(d,J＝7.9Hz,1H),7.59(t,J＝7.0Hz,1H),7.59(t,J＝7.1Hz,1H),7.24(d,J＝7.9Hz,1H),7.17(d,J＝8.8Hz,2H),6.91(d,J＝8.9Hz,2H),6.82(s,2H),3.28(s,12H)； 13C NMR(101MHz,CDCl 3)δ157.8,155.3,155.2,135.6,134.2,132.8,131.9,131.8,129.0,122.1,116.7,115.3,97.8,38.2；ESI-MS(m/z):[M] +calcd.for C 23H 22ClN 2O,377.1421；found 377.1422。
实施例20：BIIIe的制备
Figure PCTCN2018097386-appb-000059
利用通用制备流程二制备，化合物为紫红色固体，产率71％。
1H NMR(400MHz,CDCl 3):δ8.38(d,J＝8.1Hz,1H),8.11(t,J＝7.6Hz,1H),7.88(t,J＝7.6Hz,1H),7.50(d,J＝7.6Hz,1H),7.11(d,J＝9.5Hz,2H),6.98(dd,J＝9.5Hz,1.8Hz,2H),6.82(d,J＝1.8Hz,2H),3.31(s,12H)； 13C NMR(101MHz,CDCl 3)δ157.7,155.8,153.9,147.3,136.0,132.9,132.7,131.6,129.9,128.9,128.5,125.2,115.9,113.8,96.5,39.1.ESI-HRMS(m/z):[M] +calcd.for C 23H 22N 3O 3,388.1661；found 388.1662。
实施例21：BIIIh的制备
Figure PCTCN2018097386-appb-000060
利用通用制备流程二制备，化合物为紫红色固体，产率65％。
1H NMR(400MHz,CDCl 3):δ8.19(d,J＝8.2Hz,2H),8.01(dd,J＝8.1Hz,1.8Hz,2H),7.62-7.58(m,5H),7.42(d,J＝9.5Hz,2H),6.97(dd,J＝9.5Hz,2.2Hz,2H),6.90(d,J＝2.2Hz,2H),3.30(s,12H)； 13C NMR(101MHz,CDCl 3)δ158.2,157.3,156.7,154.6,152.9,133.2,132.4,131.3,130.4,129.0,124.4,123.2,115.5,113.7,96.9,40.1.ESI-HRMS(m/z):[M] +calcd.for C 29H 27N 4O,447.2185；found 447.2185。
实施例22：BIIIi的制备
Figure PCTCN2018097386-appb-000061
利用通用制备流程二制备，化合物为紫红色固体，产率63％。
1H NMR(400MHz,CDCl 3):δ8.76(d,J＝3.9Hz,1H),8.58(s,1H),7.83(d,J＝3.9Hz,1H),7.67(m,1H),7.24(d,J＝9.0Hz,2H),6.93(dd,J＝9.3Hz,1.9Hz,2H),6.85(d,J＝2.0Hz,2H),4.28(s,3H),3.29(s,12H)； 13C NMR(101MHz,CDCl 3):δ157.6,156.8,153.7,152.6,149.8,137.7,130.5,127.2,125.1,115.6,114.5,97.1,39.8,38.3.ESI-MS(m/z):1/2[M] 2+calcd.for C 27H 33N 3O,207.6310；found 207.6309。
实施例23：BIIIj的制备
Figure PCTCN2018097386-appb-000062
利用通用制备流程二制备，化合物为紫红色固体，产率80％。
1H NMR(400MHz,CDCl3)δ8.10(d,J＝8.1Hz,1H),7.99(d,J＝8.2Hz,1H),7.62(t,J＝7.1Hz,1H),7.59(d,J＝7.7Hz,1H),7.48(t,J＝8.0Hz,1H),7.37(d,J＝8.9Hz,1H),7.05(d,J＝8.8Hz,2H),6.95(d,J＝1.9Hz,2H),6.84(dd,J＝8.8,2.0Hz,2H),3.26(s,12H)； 13C NMR(101MHz,CDCl 3):δ158.3,153.1,151.8,138.2,135.3,132.9,129.8,129.3,128.5,128.1,126.8,126.4,126.2,121.7,112.6,108.5,96.4,40.0；EI-HRMS(m/z):[M] +calcd.for C 27H 25N 2O,393.1967；found 393.1966。
实施例24：BIIIl的制备
Figure PCTCN2018097386-appb-000063
利用通用制备流程二制备，化合物为紫红色固体，产率82％。
1H NMR(400MHz,CDCl 3):δ7.91(d,J＝8.9Hz,2H),6.91(dd,J＝9.2Hz,2H),6.66(d,J＝1.9Hz,2H),3.27(s,12H),3.02(s,2H),1.88(s,3H),1.52-1.43(m,12H). 13C NMR(101MHz,CDCl 3):δ158.0,157.2,155.8,131.9,115.3,114.2,96.1,43.5,40.8,39.5,37.2,36.1,28.6.EI-HRMS(m/z):[M] +calcd.for C 28H 35N 2O,415.2749；found 415.2750。
实施例25：BIIIm的制备
Figure PCTCN2018097386-appb-000064
利用通用制备流程二制备，化合物为紫红色固体，产率78％。
1H NMR(400MHz,CDCl 3):δ7.58(d,J＝7.1Hz,1H),7.48(t,J＝7.1Hz,1H),7.33(t,J＝7.1Hz,1H),7.18-7.16(m,3H),6.85(d,J＝9.6Hz,2H),6.80(s,2H),3.27(s,12H),2.83(t,J＝7.4Hz,2H),1.48-1.43(m,2H),1.29-1.24(m,2H),0.77(t,J＝7.3Hz,3H)； 13C NMR(101MHz,CDCl 3):δ158.1,157.1,155.2,137.2,132.9,132.6,130.3,129.1,128.7,125.2,114.4,113.5,97.0,40.2,33.1,30.8,22.0,13.9,；ESI-MS(m/z):[M] +calcd.for C 27H 31N 2OS,431.2157；found 431.2155。
实施例26：BIIIn的制备
Figure PCTCN2018097386-appb-000065
利用通用制备流程二制备，化合物为紫红色固体，产率73％。
1H NMR(400MHz,CD 3Cl):δ7.52(t,J＝7.2Hz,1H),7.39(d,J＝9.3Hz,2H),7.21(dd,J＝7.2Hz,1.4Hz,1H),7.09(d,J＝9.6Hz,2H),7.05(dd,J＝9.6Hz,2.1Hz,2H),6.93(d,J＝2.1Hz,2H),4.05(q,J＝7.1Hz,2H),3.30(s,12H),1.34(t,J＝7.0Hz,3H)； 13C NMR(101MHz,CDCl 3)δ157.8,155.4,155.2,134.1,133.2,131.7,131.5,130.3,130.2,128.7,114.5,113.6,96.5,65.1,46.3,39.8,14.7.ESI-MS(m/z):[M] +calcd.for C 25H 27N 2O 2,387.2073；found 387.2074。
实施例27：BIIIo的制备
Figure PCTCN2018097386-appb-000066
利用通用制备流程二制备，化合物为紫红色固体，产率50％。
1H NMR(400MHz,CDCl 3):δ7.45(d,J＝8.8Hz,2H),6.60(d,J＝8.7Hz,2H),6.38(s,2H),5.55(d,J＝6.5Hz,2H),5.33-5.31(m,1H),5.03(t,J＝6.4Hz,2H),3.33(s,12H)； 13C NMR(101MHz,CDCl 3)δ153.3,153.2,148.9,148.7,128.7,108.3,108.0,97.4,94.4,88.9,40.2；ESI-MS(m/z):[M] +calcd.for C 26H 23CrN 2O 4,479.1063；found 479.1062。
实施例28：BVa的制备
Figure PCTCN2018097386-appb-000067
利用通用制备流程二制备，化合物为紫红色固体，产率75％。
1H NMR(400MHz,CDCl 3):δ7.50-7.45(m,3H),7.27(d,J＝7.5Hz,2H),7.16(d,J＝9.5Hz,2H),6.95(dd,J＝9.5,2.2Hz,2H),6.84(d,J＝2.2Hz,2H),3.34(t,J＝6.6Hz,8H),2.01(t,J＝6.6Hz,8H)； 13C NMR(101MHz,CDCl 3)δ159.3,159.1,156.4,137.2,133.4,132.4,131.9,131.2,130.1,127.3,116.6,114.7,97.9,50.1,19.6；ESI-MS(m/z):[M] +calcd.for C 27H 27N 2O,395.2123；found 395.2124。
实施例29：BVb的制备
Figure PCTCN2018097386-appb-000068
利用通用制备流程二制备，化合物为紫红色固体，产率71％。
1H NMR(400MHz,CDCl 3):δ7.85(d,J＝9.2Hz,2H),6.95(dd,J＝9.1Hz,2H),6.63(d,J＝2.0Hz,2H),3.41(t,J＝7.0Hz,8H),3.06(s,2H),2.06(t,J＝7.0Hz,8H),1.85(s,3H),1.51-1.43(m,12H). 13C NMR(101MHz,CDCl 3):δ157.6,156.9,155.0,130.9,114.4,113.3,95.6,50.2,43.7,41.3,37.8,36.3,29.0,19.5.EI-HRMS(m/z):[M] +calcd.for C 32H 39N 2O,467.3062；found 467.3063。
实施例30：BVIb的制备
Figure PCTCN2018097386-appb-000069
利用通用制备流程二制备，化合物为紫红色固体，产率65％。
1H NMR(400MHz,CDCl 3):δ7.88-7.76(m,3H),7.36-7.26(m,3H),7.15(d,J＝9.5Hz,2H),6.99(d,J＝9.5Hz,2H),3.67-3.65(m,8H),1.71-1.66(m,12H). 13C NMR(101MHz,CDCl 3):δ158.0,156.2,155.0,138.0,131.5,131.0,130.9,114.9,113.1,97.3,96.7,49.1,25.8,24.0.EI-HRMS(m/z):[M] +calcd.for C 29H 30FN 2O,441.2342；found 441.2345。
实施例31：BVIc的制备
Figure PCTCN2018097386-appb-000070
利用通用制备流程二制备，化合物为紫红色固体，产率70％。
1H NMR(400MHz,CDCl 3)δ8.01(d,J＝9.6Hz,2H),7.22(dd,J＝9.6,2.2Hz,2H),6.77(d,J＝2.2Hz,2H),3.66-3.63(m,8H),3.06(s,2H),1.82(s,3H),1.72-1.67(m,12H),1.52-1.40(m,12H)； 13C NMR(125MHz,CDCl3)δ157.7,156.4,156.3,130.1,114.8,114.0, 96.8,48.8,43.5,40.6,37.1,36.0,28.6,25.8,12.8；EI-HRMS(m/z):[M] +calcd.for C 34H 43N 2O,495.3375；found 495.3376。
实施例32：BVIIa的制备
Figure PCTCN2018097386-appb-000071
利用通用制备流程二制备，化合物为紫红色固体，产率65％。
1H NMR(400MHz,CDCl 3):δ7.63-7.62(m,3H),7.30-7.23(m,4H),6.92(dd,J＝8.0Hz,1.6Hz,2H),6.89(d,J＝1.6Hz,2H),3.87-3.85(m,8H),3.79-3.77(m,8H). 13C NMR(101MHz,CDCl 3)δ160.2,157.5,155.9,155.5,137.2,134.5,132.8,132.6,131.1,131.0,130.4,114.5,96.3,67.4,48.2.EI-HRMS(m/z):[M] +calcd.for C 27H 27N 2O 3,427.2022；found 427.2021。
实施例33：BVIIb的制备
Figure PCTCN2018097386-appb-000072
利用通用制备流程二制备，化合物为紫红色固体，产率60％。
1H NMR(400MHz,CD 3OD):δ7.42-7.36(m,3H),7.31(d,J＝9.5Hz,2H),7.18-7.15(m,2H),7.10(dd,J＝9.6Hz,2.1Hz,2H),6.95(d,J＝2.0Hz,2H),3.89-3.84(m,8H),3.72-3.68(m,8H). 13C NMR(101MHz,CDCl 3)δ160.0,158.5,158.2,155.0,137.2,133.8,133.0,131.9,131.2,128.9,115.7,114.5,97.3,68.0,48.5.EI-HRMS(m/z):[M] +calcd.for C 27H 27N 2O 4,443.1971；found 443.1970。
实施例34：BVIIc的制备
Figure PCTCN2018097386-appb-000073
利用通用制备流程二制备，化合物为紫红色固体，产率68％。
1H NMR(400MHz,CDCl 3)δ8.04(d,J＝9.5Hz,2H),7.29(dd,J＝9.5,2.1Hz,2H), 6.74(d,J＝2.2Hz,2H),3.86-3.81(m,8H),3.66-3.63(m,8H),3.03(s,2H),1.87(s,3H),1.52-1.44(m,12H)； 13C NMR(125MHz,CDCl3)δ157.6,156.1,156.0,131.1,115.8,115.0,97.8,49.0,44.2,40,9,37.0,36.1,28.3,19.8；EI-HRMS(m/z):[M] +calcd.for C 32H 39N 2O 3,499.2961；found 499.2963。
实施例35：BVIIIa的制备
Figure PCTCN2018097386-appb-000074
利用通用制备流程一制备，化合物为紫红色固体，产率37％。
1H NMR(400MHz,CDCl 3)δ7.60-7.56(m,3H),7.33-7.29(m,2H),6.71(s,2H),6.65(s,2H),3.44(t,J＝7.0Hz,4H),1.98-1.95(m,4H),2.69(t,J＝7.0Hz,4H)； 13C NMR(125MHz,CDCl 3)δ160.2,157.5,155.9,155.5,137.6,134.2,132.3,132.1,131.7,131.4,130.9,115.5,96.3,43.2,27.2,18.7；EI-HRMS(m/z):[M] +calcd.for C 25H 22N 2O,366.1732；found 366.1733。
实施例36：BVIIIc的制备
Figure PCTCN2018097386-appb-000075
利用通用制备流程二制备，化合物为紫红色固体，产率69％。
1H NMR(400MHz,CDCl 3)δ6.69(s,2H),6.58(s,2H),3.42(t,J＝7.0Hz,4H),1.97-1.93(m,4H),3.03(s,2H),3.01(s,6H),2.67(t,J＝7.0Hz,4H),1.53-1.43(m,12H),1.80(s,3H)； 13C NMR(125MHz,CDCl 3)δ157.7,157.0,155.0,130.9,114.9,114.3,96.6,45.7,43.5,40.8,37.2,36.1,28.6,27.0,18.2；EI-HRMS(m/z):[M] +calcd.for C 32H 39N 2O,467.3062；found 467.3065。
实施例37：CIf的制备。
Figure PCTCN2018097386-appb-000076
利用通用制备流程二制备，化合物为紫红色固体，产率73％。
1H NMR(400MHz,CDCl 3):δ7.79(d,J＝7.9Hz,1H),7.57(t,J＝7.0Hz,1H),7.49(t,J＝7.2Hz,1H),7.27(d,J＝7.9Hz,1H),7.11(d,J＝9.1Hz,2H),6.94(d,J＝8.9Hz,2H),6.84(s,2H),3.65(q,J＝7.2Hz,8H),1.32(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3)δ158.1,155.8,155.5,133.6,133.2,131.8,131.6,130.8,128.1,122.2,114.7,113.3,96.8,46.5,12.8；ESI-MS(m/z):[M] +calcd.for C 27H 30BrN 2O,477.1542；found 477.1548。
实施例38：CIh的制备
Figure PCTCN2018097386-appb-000077
利用通用制备流程二制备，化合物为紫红色固体，产率78％。
1H NMR(400MHz,CD 3OD):δ7.80(t,J＝8.0Hz,1H),7.62(t,J＝7.7Hz,1H),7.49(t,J＝7.7Hz,1H),7.20(d,J＝7.4Hz,1H),7.08(d,J＝9.5Hz,2H),6.87(dd,J＝9.5Hz,1.8Hz,2H),6.76(d,J＝1.8Hz,2H),4.79(s,1H),3.60(q,J＝7.4Hz,8H),1.27(t,J＝7.0Hz,12H). 13C NMR(101MHz,CDCl 3)δ157.9,155.7,155.0,133.3,132.8,131.7,131.2,130.5,130.0,128.1,114.5,113.6,96.5,46.3,12.7.ESI-MS(m/z):[M] +calcd.For C 27H 31N 2OS,431.2157；found 431.2157。
实施例39：CIi的制备
Figure PCTCN2018097386-appb-000078
利用通用制备流程二制备，化合物为紫红色固体，产率89％
1H NMR(400MHz,CDCl 3):δ7.57-7.49(m,2H),7.36(t,J＝7.1Hz,1H),7.14-7.12(m,3H),6.83(d,J＝9.6Hz,2H),6.78(s,2H),3.59(q,J＝7.4Hz,8H),2.81(t,J＝7.4Hz,2H),1.49-1.41(m,2H),1.30(t,J＝7.2Hz,12H),1.28-1.21(m,2H),0.79(t,J＝7.3Hz,3H)； 13C NMR(101MHz,CDCl 3):δ158.0,156.6,155.7,136.7,131.8,131.6,130.7,12965,128.1,125.8,114.1,113.6,96.5,46.2,33.1,30.8,21.9,13.6,12.6；ESI-MS(m/z):[M] +calcd.forC 31H 39N 2OS,487.2783；found 487.2782。
实施例40：CIj的制备
Figure PCTCN2018097386-appb-000079
利用通用制备流程二制备，化合物为紫红色固体，产率84％。
1H NMR(400MHz,CDCl3):δ10.85(s,1H),7.86(d,J＝8.0Hz,1H),7.56(d,J＝8.0Hz,1H),7.52(d,J＝9.4Hz,2H),7.30(t,J＝7.5Hz,1H),7.14(d,J＝7.5Hz,1H),6.88(d,J＝8.2Hz,2H),6.70(s,2H),3.59-3.52(m,8H),1.93(s,3H),1.28(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl3):δ170.8,158.4,158.1,155.4,137.0,133.3,131.1,130.2,127.5,127.0,125.1,113.9,113.5,96.0,45.9,29.8,23.4,12.7；ESI-MS(m/z):[M] +calcd.for C 29H 34N 3O 2,456.2651；found 456.2653。
实施例41：CIl的制备
Figure PCTCN2018097386-appb-000080
利用通用制备流程二制备，化合物为紫红色固体，产率73％。
1H NMR(400MHz,CDCl 3):δ7.69(t,J＝7.6Hz,1H),7.61(d,J＝7.4Hz,1H),7.57(t,J＝7.6Hz,1H),7.29(d,J＝7.5Hz,1H),7.26(d,J＝9.5Hz,2H),7.14-7.13(m,3H),7.07-7.06(m,2H),6.85(dd,J＝9.5Hz,2.2Hz,2H),6.76(d,J＝2.2Hz,2H),3.62(q,J＝7.1Hz,8H),1.31(t,J＝7.1Hz,12H)； 13C NMR(101MHz,CDCl 3)δ157.8,157.8,155.6,141.9,139.6,132.1,131.0,130.8,130.6,130.4,128.6,128.5,127.9,127.8,114.2,113.8,96.6,46.3,12.8.；ESI-MS(m/z):[M] +calcd.for C 33H 35N 2O,475.2749；found 475.2750。
实施例42：CIm的制备
Figure PCTCN2018097386-appb-000081
利用通用制备流程二制备，化合物为紫红色固体，产率69％。
1H NMR(400MHz,CDCl 3):δ7.59(t,J＝5.0Hz,2H),7.39(d,J＝6.6Hz,1H),7.30-7.26(m,7H),7.11(t,J＝7.3Hz,4H),6.88(d,J＝9.4Hz,2H),6.79(s,2H),6.61(d,J＝9.1Hz,2H),3.64(q,J＝6.4Hz,8H),1.33(t,J＝6.5Hz,12H)；13C NMR(101MHz,CDCl 3)δ157.7,157.6, 157.5,155.5,138.2,137.9,137.8,137.7,135.3,135.2,134.5,134.0,133.8,131.9,130.3,129.7,129.3,129.3,129.2,128.8,128.7,114.2,114.2,113.7,96.4,46.3,12.8.ESI-HRMS(m/z):[M] +calcd.for C 39H 40N 2OP,583.2878；found583.2878。
实施例43：CIn的制备
Figure PCTCN2018097386-appb-000082
利用通用制备流程二制备，化合物为紫红色固体，产率84％。
1H NMR(400MHz,CDCl 3):δ7.49(d,J＝7.4Hz,1H),7.37(t,J＝7.3Hz,1H),7.33(t,J＝7.3Hz,1H),7.01(d,J＝6.4Hz,1H),6.93(d,J＝7.5Hz,1H),6.68(d,J＝8.8Hz,1H),6.42-6.35(m,4H),6.27(s,1H),3.53(s,3H),3.38-3.32(m,8H),1.19-1.14(m,12H). 13C NMR(101MHz,CDCl 3)δ157.2,155.9,154.5,137.3,134.5,132.8,132.5,131.1,131.0,130.4,114.5,113.7,96.3,70.1,58.9,46.5,12.7.ESI-HRMS(m/z):[M+H] +calcd.for C 28H 31N 2O 2,427.2386；found427.2383。
实施例44：CIo的制备
Figure PCTCN2018097386-appb-000083
利用通用制备流程二制备，化合物为紫红色固体，产率68％
1H NMR(400MHz,CDCl 3):δ7.27-7.20(m,4H),6.93(d,J＝8.8Hz,2H),6.87-6.82(m,7H),6.74-6.73(m,3H),6.94-6.68(m,2H),6.63(t,J＝7.6Hz,2H),6.44(dd,J＝8.8Hz,1.8Hz,2H),6.05(d,J＝7.3Hz,2H),6.03(d,J＝1.8Hz,2H),3.36-3.29(m,8H),1.15(t,J＝7.0Hz,12H)；13C NMR(101MHz,CDCl 3)δ169.1,152.6,152.4,149.0,148.2,143.0,139.4,138.8,138.7,137.6,136.0,135.7,131.4,130.6,130.6,129.5,128.8,127.3,127.1,126.9,126.6,126.3,125.9,125.9,122.0,108.2,106.3,98.0,44.7,12.6.ESI-HRMS(m/z):[M+H] +calcd.for C 52H 47N 2O 3,747.3587；found 747.3588。
实施例45：CIp的制备
Figure PCTCN2018097386-appb-000084
利用通用制备流程二制备，化合物为紫红色固体，产率70％。
1H NMR(400MHz,CDCl 3):δ8.68(s,1H),7.83(d,J＝7.7Hz,1H),7.74(d,J＝7.5Hz,1H),7.53(s,1H),7.46(t,J＝7.5Hz,1H),7.33(t,J＝7.4Hz,1H),7.13(d,J＝7.5Hz,1H),6.96(t,J＝7.3Hz,1H),6.87(d,J＝9.5Hz,2H),6.71(t,J＝7.4Hz,1H),6.55(s,1H),6.54(d,J＝7.5Hz,2H),3.62-3.46(m,8H),1.38-1.06(m,12H)；13C NMR(101MHz,CDCl3)δ173.3,159.9,157.7,154.9,143.4,142.3,137.2,132.8,130.3,130.1,129.9,129.7,128.8,127.1,126.4,126.2,114.4,95.5,45.8,12.7.ESI-HRMS(m/z):[M] +calcd.for C 34H 35N 2O 3,519.2648；found519.2651。
实施例46：CIr的制备
Figure PCTCN2018097386-appb-000085
利用通用制备流程二制备，化合物为紫红色固体，产率61％。
1H NMR(400MHz,CDCl 3):δ7.97(d,J＝8.0Hz,4H),7.55(d,J＝8.0Hz,4H),7.49(d,J＝9.6Hz,4H),6.96(dd,J＝9.5Hz,1.6Hz,4H),6.79(d,J＝1.5Hz,4H),3.63(q,J＝7.0Hz,16H),1.32(t,J＝7.0Hz,24H)；13C NMR(101MHz,CDCl 3):δ158.1,157.2,155.7,142.1,132.5,131.5,130.5,128.1,114.7,113.4,96.5,46.4,12.9.ESI-MS(m/z):1/2[M] 2+calcd.for C 27H 30N 2O,398.2358；found 398.2358。
实施例47：CIs的制备
Figure PCTCN2018097386-appb-000086
利用通用制备流程二制备，化合物为紫红色固体，产率53％。
1H NMR(400MHz,CDCl 3):δ8.06(s,3H),8.02(d,J＝7.9Hz,6H),7.54(d,J＝7.9Hz,6H),7.50(d,J＝9.6Hz,6H),6.99(dd,J＝9.5Hz,1.3Hz,6H),6.77(d,J＝1.2Hz,6H),3.60(q,J＝7.0Hz,24H),1.29(t,J＝6.9Hz,36H)；13C NMR(101MHz,CDCl 3)δ158.0,157.1,155.6,142.9,141.7,132.3,131.1,130.4,128.1,126.2,114.5,113.3,96.3,46.1,12.6.ESI-HRMS(m/z):1/3[M] 3+calcd.for C 87H 93N 6O 3,423.2436；found 423.2438。
实施例48：CIt的制备
Figure PCTCN2018097386-appb-000087
利用通用制备流程二制备，化合物为紫红色固体，产率68％。
1H NMR(400MHz,CDCl 3):δ7.77(d,J＝7.9Hz,1H),7.67(d,J＝8.5Hz,1H),7.29(t,J＝7.5Hz,1H),7.08(t,J＝7.5Hz,1H),7.02(d,J＝8.8Hz,2H),6.87(d,J＝7.7Hz,1H),6.51(dd,J＝8.5Hz,2.2Hz,1H),6.41(d,J＝2.4Hz,2H),6.30-6.27(m,3H),3.33(q,J＝7.0Hz,8H),1.15(t,J＝7.0Hz,12H),0.93(s,9H),0.14(s,6H)； 13C NMR(101MHz,CDCl 3)δ157.2,153.9,151.8,148.9,137.4,130.7,130.2,129.3,127.6,126.9,123.3,120.4,115.6,113.6,111.8,110.0,107.7,97.5,44.5,25.8,18.3,12.8,-4.3.ESI-MS(m/z):[M+H] +calcd.for C 39H 49N 2O 3Si,621.3512；found 621.3515。
实施例49：CIv的制备
Figure PCTCN2018097386-appb-000088
利用通用制备流程二制备，化合物为紫红色固体，产率85％。
1H NMR(400MHz,CDCl 3):δ8.55(d,J＝7.0Hz,1H),8.20(d,J＝8.2Hz,1H),7.89(d,J＝8.2Hz,1H),7.72(t,J＝7.8Hz,1H),7.49(t,J＝8.2Hz,1H),7.22(d,J＝7.2Hz,1H),6.71(d,J＝8.9Hz,2H),6.43(d,J＝2.5Hz,2H),6.27(dd,J＝8.9Hz,2.5Hz,2H),3.33(q,J＝7.0Hz,8H),1.15(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3):δ163.5,151.9,149.1,136.6,133.5,131.8,129.9,129.4,128.6,128.2,126.9,126.8,126.2,121.1,111.4,108.1,97.4,44.5,12.6；EI-HRMS(m/z):[M+H] +calcd.for C 32H 33N 2O 3,493.2491；found 493.2491。
实施例50：CIw的制备
Figure PCTCN2018097386-appb-000089
利用通用制备流程二制备，化合物为紫红色固体，产率81％。
1H NMR(400MHz,CDCl 3):δ8.72(s,1H),8.15(d,J＝8.5Hz,2H),7.52(d,J＝7.0Hz,2H),7.41-7.34(m,4H),7.02(d,J＝2.0Hz,2H),6.76(dd,J＝9.5Hz,1.6Hz,2H),6.67(dd,J＝9.5Hz,2.1Hz,2H),3.63(q,J＝7.0Hz,8H),1.30(t,J＝7.0Hz,12H)；13C NMR(101MHz,CDCl 3)δ158.0,156.3,155.9,131.9,131.0,130.0,129.9,129.1,127.7,126.0,125.0,115.2,114.5,96.9,46.4,12.8.ESI-MS(m/z):[M] +calcd.for C 35H 35N 2O,499.2749；found 499.2751。
实施例51：CIx的制备
Figure PCTCN2018097386-appb-000090
利用通用制备流程二制备，化合物为紫红色固体，产率72％。
1H NMR(400MHz,CDCl 3):δ9.04(s,1H),8.60(s,1H),8.39(s,1H),8.04(s,1H),7.98(s,1H),7.77(s,1H),7.52(s,2H),7.17(d,J＝8.4Hz,2H),6.66(s,4H),3.50(q,J＝7.8Hz,8H),1.23(t,J＝7.8Hz,12H)；13C NMR(101MHz,CDCl 3)δ157.6,154.8,133.6,133.4,132.7,132.0,130.9,130.5,129.4,128.8,128.7,128.3,127.0,126.8,126.60,114.0,113.3,96.1,45.9,12.7.ESI-HRMS(m/z):[M+H] +calcd.for C 36H 35N 2O 3,543.2648；found.543.2651。
实施例52：CIy的制备
Figure PCTCN2018097386-appb-000091
利用通用制备流程二制备，化合物为紫红色固体，产率85％。
1H NMR(400MHz,CDCl 3):δ9.06(d,J＝3.1Hz,1H),8.38(d,J＝8.1Hz,1H),8.32(d,J＝8.1Hz,1H),7.97(s,1H),7.66(d,J＝8.0Hz,1H),7.58(m,1H),7.33(d,J＝9.4Hz,2H),6.92(d,J＝9.6Hz,2H),6.87(s,2H),3.65(q,J＝6.9Hz,8H),1.32(t,J＝6.9Hz,12H)； 13C NMR(101MHz,CDCl 3):δ13C NMR(101MHz,CDCl3)δ158.1,156.3,155.7,152.4,148.4,137.0,132.1,130.4,130.1,129.9,129.7,128.1,122.8,114.5,113.5,96.7,46.4,12.8.ESI-MS(m/z):[M] +calcd.for C 30H 32N 3O,450.2545；found 450.2548。
实施例53：CIz的制备
Figure PCTCN2018097386-appb-000092
利用通用制备流程二制备，化合物为紫红色固体，产率57％。
1H NMR(400MHz,CDCl 3):δ8.59(d,J＝7.7Hz,1H),8.49(d,J＝7.7Hz,1H),8.44(d,J＝7.7Hz,1H),8.36(d,J＝7.6Hz,1H),7.59-7.48(m,4H),7.32-7.25(m,6H),6.90-6.88(m,8H),3.66(q,J＝6.4Hz,16H),1.35(t,J＝6.4Hz,24H)；13C NMR(101MHz,CDCl 3)δ158.0,156.3,155.8,133.1,132.8,132.7,132.0,131.3,130.9,129.8,129.3,128.7,128.5,128.3,126.0,125.5,122.3,122.0,120.8,120.5,114.4,114.1,96.5,46.2,12.6,ESI-HRMS(m/z):1/2[M] 2+calcd.for C 62H 62N 4O 2,894.4873；found 447.2434。
实施例54：CIaa的制备
Figure PCTCN2018097386-appb-000093
利用通用制备流程二制备，化合物为紫红色固体，产率57％。
1H NMR(400MHz,CDCl 3):δ7.77(d,J＝6.9Hz,1H),7.65(t,J＝7.6Hz,1H),7.56-7.50(m,3H),7.41-7.40(m,2H),7.29-7.19(m,5H),7.01(d,J＝7.9Hz,2H),6.88(d,J＝7.9Hz,2H),6.83(d,J＝9.4Hz,2H),6.70(s,2H),5.34(s,2H),3.85(s,3H),3.58(q,J＝8.0Hz,8H),2.72-2.68(m,5H),1.68-1.62(m,2H),1.27(t,J＝7.8Hz,12H),0.87(t,J＝7.2Hz,3H)； 13C NMR(101MHz,CDCl 3)δ157.5,157.4,156.5,155.4,154.5,140.9,139.1,136.6,135.8,135.2,131.8,130.9,130.6,130.3,130.1,129.3,128.8,127.8,126.6,123.8,123.6,122.6,122.4,119.2,114.2,113.6,109.8,108.6,96.3,46.7,46.1,32.1,29.6,21.4,16.8,13.9,12.6.ESI-HRMS(m/z):[M] +calcd.for C 53H 55N 6O +,791.4437；found 791.4438。
实施例55：CIab的制备
Figure PCTCN2018097386-appb-000094
利用通用制备流程二制备，化合物为紫红色固体，产率71％。
1H NMR(400MHz,CDCl 3):δ8.11(s,1H),8.09(d,J＝8.6Hz,1H),7.96(d,J＝8.5Hz,1H),7.87(s,2H),7.61(s,1H),7.57(d,J＝8.3Hz,1H),7.45(d,J＝8.3Hz,1H),7.41(d,J＝9.5Hz,2H),7.00(d,J＝8.4Hz,1H),6.85(d,J＝9.7Hz,2H),6.82(s,2H),3.88(s,3H),3.60(q,J＝6.7Hz,8H),2.17(s,6H),2.08(s,3H),1.77(s,6H),1.30(t,J＝6.8Hz,12H)；13C NMR(101MHz,CDCl 3)δ159.1,158.1,157.6,155.6,141.2,139.2,134.3,132.4,132.4,131.5,129.4,129.0,128.9,128.8,127.5,126.8,126.0,125.9,124.9,114.3,113.5,112.3,96.7,55.3,46.3,40.7,37.3,37.2,29.2,12.8.ESI-HRMS(m/z):[M] +calcd.for C 48H 53N 2O 2 +,689.4107；found 689.4106。
实施例56：CIac的制备
Figure PCTCN2018097386-appb-000095
利用通用制备流程二制备，化合物为紫红色固体，产率45％。
1H NMR(400MHz,CDCl 3):δ6.82(d,J＝7.8Hz,1H),6.67(d,J＝8.7Hz,1H),6.33(s,2H),6.29(s,1H),6.28(d,J＝8.5Hz,1H),6.17(d,J＝5.2Hz,1H),5.90(d,J＝9.9Hz,2H),3.75(s,3H),3.70(s,3H),3.64(s,1H),3.35-3.27(m,8H),3.06(s,3H),2.67-2.60(m,3H),2.54(s,3H),1.34-1.25(m,2H),1.17-1.10(m,14H)； 13C NMR(101MHz,CDCl3)δ152.9,152.1,151.5,148.5,148.3,143.4,141.1,134.4,130.8,128.7,118.0,113.1,108.1,107.3,102.8,100.74,98.1,97.6,70.7,62.4,59.7,59.0,56.2,44.5,12.8.ESI-HRMS(m/z):[M] +calcd.for C 42H 49N 3O 7,707.3571；found 707.3571。
实施例57：CIad的制备
Figure PCTCN2018097386-appb-000096
利用通用制备流程二制备，化合物为紫红色固体，产率55％。
1H NMR(400MHz,CDCl 3):δ7.78(d,J＝7.9Hz,1H),7.68-7.63(m,2H),7.42(t,J＝7.6Hz,1H),7.32-7.26(m,2H),7.15(t,J＝8.0Hz,2H),6.92(d,J＝9.5Hz,2H),6.83(d,J＝7.5Hz,1H),6.76(s,2H),6.68(d,J＝9.4Hz,2H),6.46(d,J＝8.0Hz,2H),4.72-4.66(m,4H),3.56-3.51(m,8H),1.46(t,J＝7.1Hz,3H),1.16(t,J＝7.2Hz,12H)； 13C NMR(101MHz,CDCl 3)δ158.3,157.0,155.1,153.3,143.4,141.2,136.8,136.4,133.7,133.3,131.5,130.5,129.6,128.5,127.8,125.2,122.9,121.7,119.5,118.6,114.2,114.0,113.9,109.9,96.0,66.9,46.0,45.8,14.4,12.3.ESI-HRMS(m/z):[M] +calcd.for C 44H 44N 5O 2 +,674.3495；found674.3494。
实施例58：CIae的制备
Figure PCTCN2018097386-appb-000097
利用通用制备流程二制备，化合物为紫红色固体，产率74％。
1H NMR(400MHz,CDCl 3):δ8.36(d,J＝8.2Hz,1H),8.01(t,J＝7.4Hz,1H),7.86(t,J＝7.4Hz,1H),7.46(d,J＝7.4Hz,1H),7.01(d,J＝9.5Hz,2H),6.92(dd,J＝9.5Hz,1.7Hz,2H),6.77(d,J＝1.7Hz,2H),3.61(q,J＝7.0Hz,8H),1.28(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3)δ157.8,155.7,154.2,147.8,135.1,131.9,131.7,130.6,129.0,128.2,127.5,125.5,114.9,112.8,96.5,46.3,12.7.ESI-HRMS(m/z):[M] +calcd.for C 27H 30N 3O 3,444.2287；found 444.2285。
实施例59：CIaf的制备
Figure PCTCN2018097386-appb-000098
利用通用制备流程二制备，化合物为紫红色固体，产率65％。
1H NMR(400MHz,CDCl 3):δ8.05(s,1H),7.31(s,1H),6.92(dd,J＝9.5Hz,1.7Hz,2H),6.77(d,J＝1.7Hz,2H),3.63(q,J＝7.0Hz,8H),1.30(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3)δ157.3,155.9,146.8,135.6,132.9,130.6,129.0,128.4,127.7,125.3,114.9,111.8,101.2,96.8,46.3,12.8.ESI-HRMS(m/z):[M] +calcd.for C 28H 30N 3O 5,488.2185；found 488.2186。
实施例60：CIag的制备
Figure PCTCN2018097386-appb-000099
利用通用制备流程二制备，化合物为紫红色固体，产率57％。
1H NMR(400MHz,CDCl 3):δ8.06(d,J＝8.2Hz,1H),7.65(d,J＝8.2Hz,1H),7.55(s,1H),7.08(d,J＝9.4Hz,2H),6.88(dd,J＝9.4Hz,1.9Hz,2H),6.72(d,J＝1.9Hz,2H),3.59(q,J＝7.0Hz,8H),1.25(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3)δ158.0,155.9,155.2,147.6,134.9,131.8,130.3,129.5,127.1,125.1,114.9,113.8,96.5,46.1,12.6. ESI-HRMS(m/z):[M] +calcd.for C 27H 29ClN 3O 3,478.1897；found 478.1898。
实施例61：CIah的制备
Figure PCTCN2018097386-appb-000100
利用通用制备流程二制备，化合物为紫红色固体，产率68％。
1H NMR(400MHz,CDCl 3):δ8.00(d,J＝8.2Hz,1H),7.45(s,1H),7.34(d,J＝8.2Hz,1H),7.10(d,J＝9.3Hz,2H),6.78(dd,J＝9.2Hz,1.9Hz,2H),6.71(d,J＝2.1Hz,2H),3.59(q,J＝7.0Hz,8H),1.25(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3)δ158.2,155.9,154.5,147.6,134.9,131.8,131.3,129.5,127.5,123.1,114.7,113.1,96.2,46.2,21.7,12.8.ESI-HRMS(m/z):[M] +calcd.for C 28H 32N 3O 3,458.2444；found 458.2446。
实施例62：CIai的制备
Figure PCTCN2018097386-appb-000101
利用通用制备流程二制备，化合物为紫红色固体，产率81％。
1H NMR(400MHz,CDCl 3):δ7.98(d,J＝8.1Hz,1H),7.68(t,J＝7.6Hz,1H),7.55(t,J＝7.3Hz,1H),7.35(d,J＝9.1Hz,2H),7.31(d,J＝7.4Hz,1H),7.23(d,J＝9.5Hz,2H),6.88(d,J＝2.2Hz,2H),6.77(dd,J＝9.5Hz,2.2Hz,2H),6.53(d,J＝9.2Hz,2H),3.61(q,J＝7.0Hz,8H),3.36(q,J＝7.1Hz,4H),1.30(t,J＝7.0Hz,12H),1.14(t,J＝7.1Hz,6H)；13C NMR(101MHz,CDCl 3)δ158.4,157.8,155.5,151.2,150.8,142.8,132.4,131.2,130.1,129.7,129.0,125.9,117.9,114.3,113.9,110.9,96.5,46.2,44.8,12.8,12.7.ESI-HRMS(m/z):[M] +calcd.for C 37H 44N 5O,574.3546；found 574.3549。
实施例63：CIaj的制备
Figure PCTCN2018097386-appb-000102
利用通用制备流程二制备，化合物为紫红色固体，产率75％。
1H NMR(400MHz,CDCl 3):δ7.97(d,J＝8.1Hz,1H),7.70(t,J＝7.6Hz,1H),7.58(t,J＝7.3Hz,1H),7.32(s,1H),7.30(d,J＝7.4Hz,1H),7.23(d,J＝9.4Hz,1H),7.15(d,J＝9.4Hz,1H),6.88(d,J＝2.1Hz,2H),6.77(dd,J＝9.2Hz,2.1Hz,2H),6.53(d,J＝9.2Hz,2H),3.60(q,J＝7.0Hz,8H),3.34(q,J＝7.1Hz,4H),1.31(t,J＝7.0Hz,12H),1.13(t,J＝7.1Hz,6H)； 13C NMR(101MHz,CDCl 3)δ158.6,157.7,156.5,152.2,151.8,142.0,134.4,132.2,130.4,129.8,129.3,126.9,117.0,114.3,113.3,110.1,96.5,46.5,45.4,12.8,12.6.ESI-HRMS(m/z):[M] +calcd.for C 37H 43ClN 5O,608.3156；found 608.3157。
实施例64：CIak的制备
Figure PCTCN2018097386-appb-000103
利用通用制备流程二制备，化合物为紫红色固体，产率74％。
1H NMR(400MHz,CDCl 3):δ7.98(d,J＝8.1Hz,1H),7.68(d,J＝8.1Hz,1H),7.335(d,J＝9.1Hz,2H),7.30(s,1H),7.21(d,J＝9.1Hz,2H),6.85(d,J＝2.2Hz,2H),6.67(dd,J＝9.0Hz,2.2Hz,2H),6.57(d,J＝9.0Hz,2H),3.60(q,J＝7.0Hz,8H),3.35(q,J＝7.1Hz,4H),2.30(s,3H),1.31(t,J＝7.0Hz,12H),1.15(t,J＝7.1Hz,6H)； 13C NMR(101MHz,CDCl 3)δ158.2,157.9,155.1,152.2,151.8,143.7,132.5,131.7,130.8,129.3,129.0,126.9,118.9,114.0,113.9,111.0,96.5,46.4,44.7,21.3,12.8,12.6.ESI-HRMS(m/z):[M] +calcd.for C 38H 46N 5O,588.3702；found 588.3704。
实施例65：CIal的制备
Figure PCTCN2018097386-appb-000104
利用通用制备流程二制备，化合物为紫红色固体，产率84％。
1H NMR(400MHz,CDCl 3):δ8.14(d,J＝8.3Hz,2H),7.99(dd,J＝8.1Hz,1.8Hz,2H),7.59-7.52(m,5H),7.39(d,J＝9.5Hz,2H),6.95(dd,J＝9.6Hz,2.2Hz,2H),6.90(d,J＝2.2Hz,2H),3.67(q,J＝7.1Hz,8H),1.34(t,J＝7.0Hz,12H)；13C NMR(101MHz,CDCl 3) δ158.1,156.3,155.7,153.6,152.6,134.2,132.0,131.9,130.6,129.4,123.4,123.3,114.5,113.3,96.9,46.4,12.8.ESI-HRMS(m/z):[M] +calcd.for C 33H 35N 4O,503.2811；found503.2808。
实施例66：CIam的制备
Figure PCTCN2018097386-appb-000105
利用通用制备流程二制备，化合物为紫红色固体，产率83％。
1H NMR(400MHz,CDCl 3):δ8.15(d,J＝8.3Hz,2H),7.97(dd,J＝8.1Hz,1.8Hz,2H),7.57-7.50(m,4H),7.39(d,J＝9.5Hz,2H),6.91(dd,J＝9.6Hz,1.9Hz,2H),6.87(d,J＝1.9Hz,2H),3.62(q,J＝7.0Hz,8H),3.33(q,J＝7.1Hz,4H),1.31(t,J＝7.0Hz,12H),1.16(t,J＝7.1Hz,6H)； 13C NMR(101MHz,CDCl 3)δ158.0,157.5,155.7,151.5,150.7,142.3,132.6,131.7,130.7,129.3,129.2,126.3,118.9,114.9,113.0,110.9,96.5,46.1,44.5,12.9,12.5.ESI-HRMS(m/z):[M] +calcd.for C 37H 44N 5O,574.3546；found 574.3549。
实施例67：CIan的制备
Figure PCTCN2018097386-appb-000106
利用通用制备流程二制备，化合物为紫红色固体，产率72％。
1H NMR(400MHz,CDCl 3):δ7.95-7.91(m,3H),7.39(d,J＝9.4Hz,2H),7.26-7.19(m,2H),6.93-6.90(m,4H),6.73(d,J＝9.2Hz,2H),3.67(q,J＝7.1Hz,8H),3.48(q,J＝7.0Hz,4H),1.33(t,J＝7.1Hz,12H),1.23(t,J＝7.0Hz,6H)； 13C NMR(101MHz,CDCl 3)δ158.1,155.7,155.0,151.3,143.8,142.7,131.7,126.6,125.9,125.9,118.9,118.3,118.1,114.5,113.0,111.2,97.0,46.4,45.0,12.8,12.8.ESI-HRMS(m/z):[M] +calcd.for C 37H 43FN 5O,592.3452； found 592.3450。
实施例68：CIao的制备
Figure PCTCN2018097386-appb-000107
利用通用制备流程二制备，化合物为紫红色固体，产率75％。
1H NMR(400MHz,CDCl 3):δ7.90(d,J＝9.2Hz,2H),7.84-7.82(m,2H),7.25-7.19(m,3H),6.94(d,J＝2.1Hz,2H),6.86(dd,J＝9.6Hz,2.1Hz,2H),6.75(d,J＝9.5Hz,2H),3.67(q,J＝7.1Hz,8H),3.48(q,J＝7.1Hz,4H),2.13(s,3H),1.34(t,J＝7.0Hz,12H),1.24(t,J＝7.0Hz,6H)； 13C NMR(101MHz,CDCl 3)δ158.1,157.4,155.8,154.6,143.2,137.1,132.0,131.7,129.9,126.0,124.1,120.2,114.3,113.6,111.2,97.0,46.4,44.9,20.0,12.8.ESI-HRMS(m/z):[M] +calcd.for C 38H 46N 5O,588.3702；found 588.3701。
实施例69：CIap的制备
Figure PCTCN2018097386-appb-000108
利用通用制备流程二制备，化合物为紫红色固体，产率68％。
1H NMR(400MHz,CDCl 3):δ8.20-8.13(m,3H),7.84-7.82(m,3H),7.45-7.39(m,3H),6.90(d,J＝2.0Hz,2H),6.82(dd,J＝9.6Hz,2.0Hz,2H),6.71(d,J＝9.5Hz,2H),3.67(q,J＝7.1Hz,8H),2.86(s,6H),2.13(s,3H),1.34(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3)δ158.1,157.4,156.8,156.2,155.8,154.6,143.2,137.1,132.0,131.7,130.1,129.9,126.0,124.1,120.2,114.3,113.6,111.2,110.3,97.0,46.6,44.7,20.0,12.6.ESI-HRMS(m/z):[M] +calcd.for C 38H 46N 5O,610.3546；found 610.3545。
实施例70：CIIa的制备
Figure PCTCN2018097386-appb-000109
利用通用制备流程二制备，化合物为紫红色固体，产率84％。
1H NMR(400MHz,CDCl 3):δ8.00(d,J＝9.7Hz,2H),7.93(s,1H),7.16(d,J＝2.9Hz,1H),7.04(d,J＝9.5Hz,2H),6.84(s,1H),6.77(s,2H),3.65(q,J＝7.0Hz,8H),1.33(t,J＝7.0Hz,12H)；13C NMR(101MHz,CDCl 3)δ158.1,155.3,147.4,145.8,143.0,132.1,120.5,114.5,113.4,111.6,96.7,46.3,12.8.ESI-MS(m/z):[M] +calcd.for C 25H 29N 2O 2,389.2229；found 389.2230。
实施例71：CIIb的制备
Figure PCTCN2018097386-appb-000110
利用通用制备流程二制备，化合物为紫红色固体，产率83％。
1H NMR(400MHz,CDCl 3):δ7.76(d,J＝3.8Hz,1H),7.67(d,J＝9.5Hz,2H),7.34(s,2H),6.98(d,J＝9.3Hz,2H),6.80(s,2H),3.65(q,J＝6.8Hz,8H),1.32(t,J＝6.8Hz,12H)；13C NMR(101MHz,CDCl 3)δ157.8,155.5,150.1,132.2,132.1,131.0,130.6,128.4,114.4,113.8,96.6,46.3,12.8.ESI-MS(m/z):[M] +calcd.for C 25H 29N 2OS,405.2001；found 405.2000。
实施例72：CIIc的制备
Figure PCTCN2018097386-appb-000111
利用通用制备流程二制备，化合物为紫红色固体，产率67％。
1H NMR(400MHz,CDCl 3):δ8.00(d,J＝9.7Hz,2H),7.04(d,J＝9.5Hz,2H),6.84(s,1H),6.79(s,2H),3.89(s,3H),3.64(q,J＝7.0Hz,8H),2.19(s,3H),2.12(s,3H),1.33(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3)δ158.0,155.3,147.5,145.2,143.8,132.1,120.5,114.5,96.7,46.3,33.4,14.1,13.2,12.8.ESI-MS(m/z):[M] +calcd.for C 28H 36N 3O,430.2858；found 430.2859。
实施例73：CIIIa的制备
Figure PCTCN2018097386-appb-000112
利用通用制备流程二制备，化合物为紫红色固体，产率82％。
1H NMR(400MHz,CDCl 3):δ8.15(s,1H),7.25(d,J＝3.0Hz,1H),7.18(d,J＝9.4Hz,2H),7.04(d,J＝9.5Hz,2H),6.80(d,J＝3.0Hz,1H),6.77(s,2H),3.63(q,J＝7.0Hz,8H),1.32(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3)δ158.3,156.3,147.8,145.2,143.1,132.3,120.9,114.2,114.4,112.6,96.1,46.6,12.8.ESI-MS(m/z):[M] +calcd.for C 25H 29N 2O 2,389.2229；found 389.2227。
实施例74：CIIIb的制备
Figure PCTCN2018097386-appb-000113
利用通用制备流程二制备，化合物为紫红色固体，产率77％。
1H NMR(400MHz,CDCl 3):δ7.73(d,J＝9.5Hz,1H),7.67(s,1H),7.65(d,J＝9.5Hz,2H),7.22(d,J＝9.5Hz,1H),6.99(d,J＝9.3Hz,2H),6.84(s,2H),3.64(q,J＝6.8Hz,8H),1.34(t,J＝6.8Hz,12H)； 13C NMR(101MHz,CDCl 3)δ157.2,156.5,151.1,132.5,132.0,131.6,130.7,128.5,114.9,113.2,96.4,46.1,12.8.ESI-MS(m/z):[M] +calcd.for C 25H 29N 2OS,405.2001；found 405.2003。
实施例75：CIIIc的制备
Figure PCTCN2018097386-appb-000114
利用通用制备流程二制备，化合物为紫红色固体，产率69％。
1H NMR(400MHz,CDCl 3):δ7.33-7.24(m,7H),7.65(d,J＝9.5Hz,2H),7.12(S,1H),6.99(d,J＝9.4Hz,2H),6.84(s,2H),3.64(q,J＝6.8Hz,8H),1.34(t,J＝6.8Hz,12H)； 13C NMR(101MHz,CDCl 3)δ157.1,156.5,155.2,154.6,151.9,151.1,132.5,132.0,131.6,130.7,128.5,127.4,126.6,114.9,113.2,96.4,56.4,46.1,12.8.ESI-MS(m/z):[M] +calcd.for C 32H 36N 3O,478.2858；found 478.2858。
实施例76：CIVa的制备
Figure PCTCN2018097386-appb-000115
利用通用制备流程二制备，化合物为紫红色固体，产率48％。
1H NMR(400MHz,CDCl 3):δ8.74(s,1H),8.26(s,1H),8.02(d,J＝9.2Hz,2H),7.07(d,J＝8.7Hz,2H),6.78(s,2H),3.64(q,J＝7.0Hz,8H),1.34(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3)δ158.1,155.6,152.4,143.3,132.1,129.4,114.7,112.8,96.6,46.3,12.9.ESI-HRMS(m/z):[M] +calcd.for C 24H 28N 3O 2,390.2182；found 390.2181。
实施例77：CIVb的制备
Figure PCTCN2018097386-appb-000116
利用通用制备流程二制备，化合物为紫红色固体，产率39％。
1H NMR(400MHz,CDCl 3):δ7.78(s,1H),7.72(d,J＝9.3Hz,2H),6.98(d,J＝9.1Hz,2H),6.73(s,2H),3.62(q,J＝6.8Hz,8H),2.82(s,3H),1.29(t,J＝6.8Hz,12H)；13C NMR(101MHz,CDCl 3)δ168.0,158.1,155.5,149.3,145.2,132.3,125.1,114.5,113.1,96.4,46.2,29.7,19.4,12.8.ESI-HRMS(m/z):[M] +calcd.for C 25H 30N 3OS +,420.2110；found 420.2106。
实施例78：CIVc的制备
Figure PCTCN2018097386-appb-000117
利用通用制备流程二制备，化合物为紫红色固体，产率50％。
1H NMR(400MHz,CDCl 3):δ7.99(d,J＝9.6Hz,2H),7.80(s,1H),7.42-7.41(m,9H),7.30(s,1H),7.22-7.20(m,6H),6.88(dd,J＝9.6Hz,1.8Hz,2H),6.73(d,J＝1.9Hz,2H),3.88(s,3H),3.63(q,J＝7.0Hz,8H),1.31(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3)δ158.2,155.3,148.7,141.7,141.1,141.0,132.5,129.7,128.9,128.7,127.5,114.0,112.6,96.6,46.2,12.9.ESI-HRMS(m/z):[M] +calcd.for C 43H 43N 4O,631.3437；found 631.3438。
实施例79：CIVd的制备
Figure PCTCN2018097386-appb-000118
利用通用制备流程二制备，化合物为紫红色固体，产率21％。
1H NMR(400MHz,CDCl 3):δ8.19(s,1H),7.91(d,J＝7.8Hz,1H),7.78(d,J＝7.8Hz,1H),7.74(dd,J＝8.4Hz,2.2Hz,1H),7.65-7.62(m,1H),7.43-7.35(m,2H),6.90(d,J＝9.9Hz,1H),6.79(s,2H),3.72-3.55(m,10H),2.93(s,3H),1.34(t,J＝7.0Hz,12H)；13C NMR(101MHz,CDCl3)δ165.7,163.0,161.0,147.8,137.2,132.9,132.6,131.2,131.1,129.2,128.6,128.6,124.8,124.8,120.5,120.3,119.5,119.3,116.4,113.7,96.5,70.7,46.4,46.1,43.6,36.4,12.8.ESI-HRMS(m/z):[M] +calcd.for C 33H 35FN 5O 2 +,552.2775；found 552.2777。
实施例80：CVa的制备
Figure PCTCN2018097386-appb-000119
利用通用制备流程二制备，化合物为紫红色固体，产率41％。
1H NMR(400MHz,CDCl 3):δ8.10(s,1H),7.30(d,J＝9.6Hz,2H),7.09-7.02(m,4H),6.98(d,J＝9.5Hz,1H),6.89(s,1H),6.77-6.74(m,3H),6.56(dd,J＝9.3Hz,1.5Hz,1H),5.01(q,J＝6.8Hz,1H),3.69(q,J＝7.0Hz,4H),3.60(q,J＝7.0Hz,4H),1.86(d,J＝6.9Hz,3H),1.36(t,J＝7.0Hz,6H),1.30(t,J＝7.0Hz,6H)；13C NMR(101MHz,CDCl 3)δ157.7,157.6,155.8,155.6,144.7,140.5,131.4,130.8,129.0,128.4,125.8,115.0,114.2,113.9,113.8,97.0,96.8,57.0,46.4,22.4,12.8.ESI-HRMS(m/z):[M] +calcd.for C 32H 37N 4O +,493.2967；found 493.2968。
实施例81：CVIa的制备
Figure PCTCN2018097386-appb-000120
利用通用制备流程二制备，化合物为紫红色固体，产率83％。
1H NMR(400MHz,CDCl 3):δ8.86(d,J＝4.0Hz,1H),8.61(s,1H),7.85(d,J＝7.6Hz,1H),7.66(m,1H),7.27(d,J＝9.0Hz,2H),6.97(dd,J＝9.5Hz,1.9Hz,2H),6.87(d,J＝2.0Hz,2H),3.66(q,J＝7.0Hz,8H),1.33(t,J＝7.0Hz,12H)；13C NMR(101MHz,CDCl 3):δ157.9,155.8,153.1,151.6,149.2,137.5,131.5,128.3,124.1,114.8,113.5,96.9,46.4,12.8.ESI-MS(m/z):[M] +calcd.for C 26H 30N 3O,400.2389；found 400.2389。
实施例82：CVIb的制备
Figure PCTCN2018097386-appb-000121
利用通用制备流程二制备，化合物为紫红色固体，产率54％。
1H NMR(400MHz,CDCl 3):δ8.80(s,1H),7.94(d,J＝7.6Hz,1H),7.35(m,1H),7.29(d,J＝9.0Hz,2H),6.87(dd,J＝9.0Hz,1.9Hz,2H),6.82(d,J＝2.0Hz,2H),3.65(q,J＝7.1Hz,8H),1.33(t,J＝7.1Hz,12H)； 13C NMR(101MHz,CDCl 3):δ157.8,155.7,153.4,151.5,149.6,137.2,131.3,128.5,124.2,114.9,113.2,97.0,46.6,12.8.ESI-MS(m/z):[M] +calcd.for C 26H 29N 3O,434.1999；found 434.1998。
实施例83：CVIc的制备
Figure PCTCN2018097386-appb-000122
利用通用制备流程二制备，化合物为紫红色固体，产率51％。
1H NMR(400MHz,CDCl 3):δ8.65(s,1H),7.88(d,J＝7.6Hz,1H),7.30(m,1H),7.19(d,J＝9.0Hz,2H),6.83(dd,J＝9.0Hz,1.9Hz,2H),6.77(d,J＝2.0Hz,2H),3.63(q,J＝7.1Hz,8H),1.32(t,J＝7.1Hz,12H)； 13C NMR(101MHz,CDCl 3):δ157.1,155.3,153.8,151.2,149.9,137.5,131.7,128.6,124.7,114.0,113.1,96.5,46.3,23.9,12.8.ESI-MS(m/z):[M] +calcd.for C 27H 32N 3O,414.2545；found 414.2546。
实施例84：CVIIa的制备
Figure PCTCN2018097386-appb-000123
利用通用制备流程二制备，化合物为紫红色固体，产率42％。
1H NMR(400MHz,CDCl 3):δ8.39(d,J＝4.0Hz,1H),7.41(s,1H),7.31(d,J＝4.0Hz,1H),7.20(d,J＝9.0Hz,2H),6.82(dd,J＝9.0Hz,1.9Hz,2H),6.71(d,J＝2.0Hz,2H),3.64(q,J＝7.1Hz,8H),1.31(t,J＝7.1Hz,12H)； 13C NMR(101MHz,CDCl 3):δ156.9,155.5,153.9,151.3,149.7,138.5,135.7,128.7,124.9,115.0,113.7,96.8,46.2,12.8.ESI-MS(m/z):[M] +calcd.for C 26H 29FN 3O,418.2295；found 418.2296。
实施例85：CVIIb的制备
Figure PCTCN2018097386-appb-000124
利用通用制备流程二制备，化合物为紫红色固体，产率46％。
1H NMR(400MHz,CDCl 3):δ8.60(m,1H),7.63(m,1H),7.41(s,1H),7.15(d,J＝9.0Hz,2H),6.84(dd,J＝9.0Hz,1.9Hz,2H),6.65(d,J＝2.0Hz,2H),3.62(q,J＝7.1Hz,8H),2.51(s,3H),1.31(t,J＝7.1Hz,12H)； 13C NMR(101MHz,CDCl 3):δ159.7,156.5,154.9,152.3,149.5,137.5,136.7,127.7,125.9,116.0,114.7,96.8,46.4,24.3,12.8.ESI-MS(m/z):[M] +calcd.for C 26H 29FN 3O,418.2295；found 418.2296。
实施例86：CVIIIa的制备
Figure PCTCN2018097386-appb-000125
利用通用制备流程二制备，化合物为紫红色固体，产率36％。
1H NMR(400MHz,CDCl 3):δ9.24(s,1H),7.25(d,J＝9.1Hz,2H),7.01(d,J＝9.1Hz,2H),6.87(s,2H),3.67(q,J＝7.0Hz,8H),2.42(s,3H),1.33(t,J＝6.7Hz,12H)； 13C NMR(101MHz,CDCl 3)δ160.9,157.9,156.8,156.5,148.7,130.2,129.3,115.7,114.5,97.6,46.8,19.5,12.9.ESI-HRMS(m/z):[M] +calcd.for C 26H 30FN 4O,433.2404；found 433.2406。
实施例87：CIXa的制备
Figure PCTCN2018097386-appb-000126
利用通用制备流程二制备，化合物为紫红色固体，产率43％。
1H NMR(400MHz,CDCl 3):δ8.58(d,J＝8.7Hz,1H),7.28(d,J＝8.4Hz,1H),7.33(d,J＝9.5Hz,2H),6.95(dd,J＝9.6Hz,1.8Hz,2H),6.78(d,J＝1.8Hz,2H),3.63(q,J＝7.0Hz,8H),1.34(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3)δ158.4,158.2,155.8,154.2,150.0,133.3,131.8,130.6,115.0,113.2,100.1,96.6,77.5,12.8.ESI-HRMS(m/z):[M] +calcd.for C 25H 28ClN 4O,435.1952；found 435.1953。
实施例88：CXa的制备
Figure PCTCN2018097386-appb-000127
利用通用制备流程二制备，化合物为紫红色固体，产率44％。
1H NMR(400MHz,CDCl 3):δ8.94(s,1H),8.70(s,1H),7.16(s,2H),6.76(s,2H),6.68(s,2H),3.53(q,J＝8.0Hz,8H),1.25(t,J＝6.6Hz,12H)； 13C NMR(101MHz,CDCl 3)δ157.9,157.9,154.9,131.9,131.8,113.9,113.8,112.6,112.5,96.3,46.0,12.8.ESI-HRMS(m/z):[M+H] +calcd.for C 26H 29N 4O 3,445.2240；found445.2242。
实施例89：CXb的制备
Figure PCTCN2018097386-appb-000128
利用通用制备流程二制备，化合物为紫红色固体，产率31％。
1H NMR(400MHz,CDCl 3):δ8.98(s,1H),8.79(s,1H),7.19(s,2H),6.76(s,2H),6.66(s,2H),3.51(q,J＝8.0Hz,8H),1.33(t,J＝6.6Hz,12H)； 13C NMR(101MHz,CDCl 3)δ159.4,159.1,154.5,131.4,131.0,113.5,112.8,112.3,112.0,96.6,46.0,12.8.ESI-HRMS(m/z):[M] +calcd.for C 25H 28FN 4O 3,419.2247；found 419.2245。
实施例90：CXIa的制备
Figure PCTCN2018097386-appb-000129
利用通用制备流程二制备，化合物为紫红色固体，产率41％。
1H NMR(400MHz,CDCl 3):δ9.48(s,1H),8.85(s,2H),7.21(d,J＝9.2Hz,2H),7.01(d,J＝9.4Hz,2H),6.97(s,2H),3.67(q,J＝7.0Hz,8H),1.34(t,J＝6.7Hz,12H)；13C NMR(101MHz,CDCl3)δ160.1,157.8,156.9,156.0,148.5,130.7,115.2,113.5,97.5,46.6,12.9.ESI-HRMS(m/z):[M] +calcd.for C 25H 29N 4O,401.2341；found 401.2342。
实施例91：CXIb的制备
Figure PCTCN2018097386-appb-000130
利用通用制备流程二制备，化合物为紫红色固体，产率39％。
1H NMR(400MHz,CDCl 3):δ8.86(s,2H),7.27(d,J＝9.3Hz,2H),7.04(d,J＝9.3Hz,2H),6.99(s,2H),3.65(q,J＝7.0Hz,8H),1.33(t,J＝6.7Hz,12H)； 13C NMR(101MHz,CDCl3)δ160.5,158.8,156.4,156.1,148.8,130.9,116.2,114.5,97.1,46.5,12.8.ESI-HRMS(m/z):[M] +calcd.for C 25H 28ClN 4O,435.1952；found 435.1953。
实施例92：CXIc的制备
Figure PCTCN2018097386-appb-000131
利用通用制备流程二制备，化合物为紫红色固体，产率37％。
1H NMR(400MHz,CDCl 3):δ8.89(s,2H),7.17(d,J＝9.2Hz,2H),7.01(d,J＝9.2Hz,2H),6.98(s,2H),3.65(q,J＝7.0Hz,8H),1.32(t,J＝6.9Hz,12H)； 13C NMR(101MHz,CDCl3)δ160.0,157.5,156.1,155.8,147.5,132.7,116.2,114.5,97.8,46.7,12.8.ESI-HRMS(m/z):[M] +calcd.for C 25H 28FN 4O,419.2247；found 419.2246。
实施例93：CXId的制备
Figure PCTCN2018097386-appb-000132
利用通用制备流程二制备，化合物为紫红色固体，产率41％。
1H NMR(400MHz,CDCl 3):δ8.80(s,2H),7.15(d,J＝9.3Hz,2H),6.97(d,J＝9.3Hz,2H),6.88(s,2H),3.63(q,J＝7.0Hz,8H),2.18(s,3H),1.33(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl3)δ159.5,157.8,156.6,155.0,148.5,132.3,116.1,115.5,97.3,46.7,21.5,12.8.ESI-HRMS(m/z):[M] +calcd.for C 26H 31N 4O,415.2498；found 415.2499。
实施例94：CXIIa的制备
Figure PCTCN2018097386-appb-000133
利用通用制备流程二制备，化合物为紫红色固体，产率63％。
1H NMR(400MHz,CDCl 3):δ7.28(d,J＝5.4Hz,1H),7.99(d,J＝8.8Hz,2H),6.44(dd,J＝8.8Hz,1.9Hz,2H),6.39(d,J＝1.9Hz,2H),6.29(d,J＝5.4Hz,1H),3.36(t,J＝7.0Hz,8H),1.17(q,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3):δ173.2,157.8,152.8,149.7,128.2,120.4,108.0,102.5,98.2,44.6,12.6.ESI-HRMS(m/z):[M+H] +calcd.for C 24H 29N 2O 3,393.2178；found 393.2176。
实施例95：CXIIb的制备
Figure PCTCN2018097386-appb-000134
利用通用制备流程二制备，化合物为紫红色固体，产率68％。
1H NMR(400MHz,CDCl 3):δ7.80(d,J＝9.4Hz,1H),7.46(d,J＝7.8Hz,1H),7.27(d,J＝7.5Hz,1H),7.08-7.02(m,3H),6.91(s,1H),6.85(t,J＝7.6Hz,1H),6.75(d,J＝8.9Hz,1H),6.33(d,J＝8.4Hz,1H),4.69(s,1H),3.73(q,J＝7.0Hz,4H),3.59(q,J＝7.2Hz,4H),3.15-3.11(m,1H),2.99-2.87(m,3H),2.77(d,J＝16.6Hz,2H),2.18-2.12(m,2H),2.01-1.94(m,2H),1.87(d,J＝13.6Hz,1H),1.64(d,J＝12.7Hz,1H),1.50(t,J＝13.6Hz,12H),1.37(t, J＝7.0Hz,6H),1.28(t,J＝7.1Hz,6H),1.01(t,J＝7.0Hz,3H)； 13C NMR(101MHz,CDCl 3):δ158.3,157.6,156.2,155.7,148.2,133.6,131.4,130.0,128.7,126.6,123.6,123.5,121.2,119.2,115.3,114.9,113.7,112.7,110.9,109.5,97.6,97.0,56.0,51.8,46.6,46.3,45.3,38.9,30.0,27.4,19.9,16.4,12.8,9.0.ESI-MS(m/z):[M] +calcd.for C 40H 47N 4O,599.3750；found 599.3751。
实施例96：CXIIc的制备
Figure PCTCN2018097386-appb-000135
利用通用制备流程二制备，化合物为紫红色固体，产率35％。
1H NMR(400MHz,CDCl 3):δ8.03(d,J＝9.4Hz,2H),7.91(s,1H),7.34(d,J＝9.0Hz,1H),7.04(s,1H),6.81(dd,J＝9.6Hz,1.6Hz,2H),6.54(d,J＝1.9Hz,2H),6.24(d,J＝9.0Hz,1H),3.53(q,J＝7.0Hz,8H),3.46(q,J＝7.1Hz,4H),1.30(t,J＝7.0Hz,12H),1.24(t,J＝7.1Hz,12H)； 13C NMR(101MHz,CDCl 3)δ161.5,156.68,153.7,130.6,112.2,112.0,111.3,105.5,96.4,45.5,45.1,13.1,12.8.；ESI-MS(m/z):[M] +calcd.for C 34H 40N 3O 3,538.3070；found 538.3072。
实施例97：CXIId的制备
Figure PCTCN2018097386-appb-000136
利用通用制备流程二制备，化合物为紫红色固体，产率46％。
1H NMR(400MHz,CDCl 3):δ8.60(s,1H),7.84(d,J＝9.3Hz,1H),7.61(d,J＝12.4Hz,1H),7.84(d,J＝9.5Hz,1H),6.92(d,J＝8.8Hz,1H),6.79(dd,J＝9.5Hz,2.2Hz,1H),6.10(dd,J＝5.3Hz,2.3Hz,2H),5.61(s,1H),4.47(s,2H),3.58-3.48(m,8H),3.46-3.38(m,4H),2.69(s,4H),2.44(s,3H),1.53(d,J＝6.0Hz,3H),1.27-1.22(m,12H)； 13C NMR(101MHz,CDCl 3)δ173.4,173.4,158.2,157.9,156.9,155.6,155.1,154.4,154.1,142.8,140.2,140.1, 133.3,132.4,131.2,131.1,125.1,122.0,121.9,114.6,114.3,114.1,113.4,111.7,104.7,104.5,95.8,95.7,68.9,55.4,54.0,49.9,49.9,45.9,45.8,45.8,18.9,12.6.ESI-HRMS(m/z):[M] +calcd.for C 38H 45FN 5O 3 +,638.3506；found638.3502。
实施例98：CXIIe的制备
Figure PCTCN2018097386-appb-000137
利用通用制备流程二制备，化合物为紫红色固体，产率35％。
1H NMR(400MHz,CDCl 3):δ8.00(d,J＝9.6Hz,2H),7.60(d,J＝16.2Hz,1H),7.55-7.45(m,5H),7.25(d,J＝8.0Hz,2H),7.20(d,J＝16.2Hz,1H),7.02(dd,J＝9.6Hz,2.2Hz,2H),6.71(d,J＝2.2Hz,2H),3.63(q,J＝7.1Hz,8H),1.32(t,J＝7.1Hz,12H)； 13C NMR(101MHz,CDCl 3)δ157.6,155.2,154.4,144.8,141.5,132.7,130.3,130.1,127.1,117.4,114.2,112.5,96.2,46.1,12.6；ESI-MS(m/z):[M] +calcd.for C 29H 33N 2O,425.2593；found 425.2594。
实施例99：CXIIf的制备
Figure PCTCN2018097386-appb-000138
利用通用制备流程二制备，化合物为紫红色固体，产率34％。
1H NMR(400MHz,CDCl 3):δ8.00(d,J＝9.6Hz,2H),7.63(d,J＝16.2Hz,1H),7.59(d,J＝8.0Hz,2H),7.25(d,J＝8.0Hz,2H),7.15(d,J＝16.2Hz,1H),7.02(dd,J＝9.6Hz,2.2Hz,2H),6.71(d,J＝2.2Hz,2H),3.62(q,J＝7.1Hz,8H),2.38(s,3H),1.31(t,J＝7.1Hz,12H)；13C NMR(101MHz,CDCl 3)δ157.7,155.3,154.1,145.0,141.2,132.4,130.9,130.0,128.1,117.7,114.0,112.2,96.5,46.1,21.6,12.8；ESI-MS(m/z):[M] +calcd.for C 30H 35N 2O,439.2749；found 439.2749。
实施例100：CXIIg的制备
Figure PCTCN2018097386-appb-000139
利用通用制备流程二制备，化合物为紫红色固体，产率30％。
1H NMR(400MHz,CDCl 3):δ8.12(d,J＝9.6Hz,2H),7.86-7.79(m,3H),7.18-7.14(m,3H),7.07(dd,J＝9.6Hz,2.5Hz,2H),6.74(d,J＝2.5Hz,2H),3.64(q,J＝7.1Hz,8H),1.33(t,J＝7.1Hz,12H)；13C NMR(101MHz,CDCl 3)δ157.8,155.5,154.4,143.6,131.4,130.5,130.4,116.6,116.3,114.2,112.5,96.6,46.2,12.8；ESI-MS(m/z):[M] +calcd.for C 29H 32FN 2O,443.2499；found 443.2495。
实施例101：CXIIh的制备
Figure PCTCN2018097386-appb-000140
利用通用制备流程二制备，化合物为紫红色固体，产率47％。
1H NMR(400MHz,CDCl 3):δ7.82(d,J＝9.6Hz,2H),7.77(d,J＝16.2Hz,1H),7.63(d,J＝8.2Hz,1H),7.37(d,J＝16.2Hz,1H),7.36(d,J＝8.2Hz,1H),7.12(t,J＝7.6Hz,1H),6.75(dd,J＝9.6Hz,1.8Hz,2H),6.73(t,J＝7.6Hz,1H),6.55(d,J＝1.8Hz,2H),3.50(q,J＝7.0Hz,8H),1.23(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3)δ158.6,157.3,155.1,154.8,143.6,131.9,130.8,129.2,122.1,119.1,118.3,118.1,113.4,111.7,96.3,45.9,12.7.ESI-HRMS(m/z):[M] +calcd.forC 29H 33N 2O 2,441.2542；found 441.2542。
实施例102：CXIIi的制备
Figure PCTCN2018097386-appb-000141
利用通用制备流程二制备，化合物为紫红色固体，产率44％。
1H NMR(400MHz,CDCl 3):δ8.02(d,J＝9.5Hz,2H),7.92(d,J＝15.8Hz,1H),7.57(d, J＝15.8Hz,1H),7.35(d,J＝2.0Hz,1H),7.30(d,J＝8.7Hz,1H),6.86(dd,J＝9.6Hz,1.9Hz,2H),6.61(d,J＝1.9Hz,2H),6.39(dd,J＝8.7Hz,2.0Hz,1H),3.86(s,3H),3.57(q,J＝7.1Hz,8H),1.31(t,J＝7.1Hz,12H)；13C NMR(101MHz,CDCl 3)δ164.0,161.8,157.5,154.7,146.0,131.2,130.9,115.9,115.5,113.1,111.8,108.4,101.8,96.3,55.9,45.8,12.8；ESI-MS(m/z):[M] +calcd.for C 30H 35N 2O 3,471.2648；found 471.2646。
实施例103：CXIIj的制备
Figure PCTCN2018097386-appb-000142
利用通用制备流程二制备，化合物为紫红色固体，产率42％。
1H NMR(400MHz,CDCl 3):δ7.97(d,J＝9.5Hz,2H),7.78(t,J＝16.2Hz,1H),7.52-7.45(m,3H),6.90(d,J＝9.5Hz,2H),6.66(d,J＝11.4Hz,1H),6.65(s,2H),4.13(s,3H),3.54(q,J＝7.0Hz,8H),3.36(q,J＝7.1Hz,4H),1.30(t,J＝7.0Hz,12H),1.25(t,J＝7.0Hz,6H)；13C NMR(101MHz,CDCl 3)δ157.5,155.0,154.8,147.6,146.0,144.8,142.6,133.3,131.1,122.4,120.6,118.4,114.4,113.7,112.0,107.1,96.3,61.1,45.9,12.8.ESI-HRMS(m/z):[M] +calcd.for C 32H 35N 2O 4 +,511.2597；found 511.2594。
实施例104：CXIIIc的制备
Figure PCTCN2018097386-appb-000143
利用通用制备流程二制备，化合物为紫红色固体，产率83％。
1H NMR(400MHz,CDCl 3):δ8.19(d,J＝9.5Hz,2H),7.03(dd,J＝9.5Hz,1.7Hz,2H),6.71(d,J＝1.7Hz,2H),3.80(t,J＝5Hz,2H),3.59-3.52(m,10H),1.99-1.92(m,10H),1.27(t,J＝7.1Hz,12H)； 13C NMR(101MHz,CDCl 3)δ162.7,157.6,155.4,130.6,114.2,113.2,95.8,77.5,77.2,76.8,60.8,45.9,34.9,25.4,12.7；ESI-MS(m/z):[M] +calcd.for C 24H 33N 2O 2,381.2542；found381.2542。
实施例105：CXIIId的制备
Figure PCTCN2018097386-appb-000144
利用通用制备流程二制备，化合物为紫红色固体，产率81％。
1H NMR(400MHz,CDCl 3):δ8.22(d,J＝9.4Hz,2H),7.03(d,J＝9.4Hz,2H),6.64(s,2H),3.72(t,J＝7.4Hz,2H),3.60(q,J＝7.0Hz,8H),3.01(t,J＝7.4Hz,2H),1.32(q,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3):δ159.8,157.7,155.5,130.5,114.4,113.2,96.0,46.0,36.6,24.2,12.7；EI-HRMS(m/z):[M] +calcd.for C 24H 31N 2O 3,395.2335；found 395.2333。
实施例106：CXIIIe的制备
Figure PCTCN2018097386-appb-000145
利用通用制备流程二制备，化合物为紫红色固体，产率84％。
1H NMR(400MHz,CDCl 3):δ7.54(d,J＝8.8Hz,1H),7.25(d,J＝7.4Hz,1H),6.50(dd,J＝8.8Hz,2.5Hz,1H),6.45(dd,J＝8.7Hz,2.5Hz,1H),6.40(d,J＝2.5Hz,1H),6.37(d,J＝2.5Hz,1H),6.31(dd,J＝5.8Hz,1.4Hz,1H),6.19(dd,J＝5.8Hz,1.4Hz,1H),4.86(s,1H),4.69(t,J＝8.8Hz,1H),4.31(d,J＝1.0Hz,1H),4.19(dd,J＝8.8Hz,4.9Hz,1H),3.39-3.31(m,8H),2.91-2.86(m,1H),2.33(d,J＝7.7Hz,1H),1.17(t,J＝6.9Hz,6H),1.16(t,J＝6.9Hz,6H)； 13C NMR(101MHz,CDCl 3)δ152.3,151.0,148.3,147.9,137.7,136.8,129.1,125.8,119.2,112.1,107.9,107.5,98.6,98.2,82.7,80.7,79.9,73.8,62.0,47.9,44.5,12.7,12.6.ESI-HRMS(m/z):[M+H] +calcd.for C 28H 34N 2O 3,447.2648；found447.2648。
实施例107：CXIIIf和CXIIIg的制备
Figure PCTCN2018097386-appb-000146
利用通用制备流程二制备，化合物为紫红色固体，产率80％。
1H NMR(400MHz,CDCl 3):δ7.56(d,J＝8.9Hz,1H),7.23(d,J＝7.4Hz,1H),6.56(dd,J＝8.8Hz,2.3Hz,1H),6.45(dd,J＝8.7Hz,2.3Hz,1H),6.40(d,J＝2.3Hz,1H),6.37(d,J＝2.3Hz,1H),6.33(dd,J＝5.8Hz,1.4Hz,1H),6.21(dd,J＝5.8Hz,1.4Hz,1H),4.91(s,1H), 4.71(t,J＝8.8Hz,1H),4.41(d,J＝1.0Hz,1H),4.27(dd,J＝8.8Hz,4.9Hz,1H),3.37-3.32(m,8H),1.17(t,J＝7.0Hz,6H),1.16(t,J＝7.0Hz,6H)； 13C NMR(101MHz,CDCl 3)δ156.3,153.0,149.3,148.9,138.7,137.8,129.9,125.2,119.7,112.6,108.0,107.6,98.2,98.1,83.7,80.4,79.9,74.5,62.3,47.9,12.8,12.7.ESI-HRMS(m/z):[M+H] +calcd.for C 28H 32N 2O 4,461.2440；found 461.2441。
实施例108：CXIIIh的制备
Figure PCTCN2018097386-appb-000147
利用通用制备流程二制备，化合物为紫红色固体，产率59％。
1H NMR(400MHz,CDCl 3):δ7.02(d,J＝9.2Hz,2H),6.93(d,J＝8.1Hz,1H),6.39-6.37(m,4H),6.33(d,J＝1.5Hz,1H),6.24(dd,J＝8.1Hz,1.5Hz,1H),513.84(s,3H),3.34(q,J＝7.0Hz,8H),2.68(s,3H),2.65(t,J＝6.1Hz,2H),2.03(t,J＝6.1Hz,2H),1.18(t,J＝7.0Hz,12H)；13C NMR(101MHz,CDCl3)δ159.6,152.5,148.1,128.6,127.8,116.3,115.0,107.2,99.7,98.5,97.6,77.5,77.2,76.8,58.6,55.4,44.5,41.5,35.4,23.9,12.8；ESI-MS(m/z):[M] +calcd.forC 31H 40N 3O 2,486.3121；found 486.3121。
实施例109：CXIIIi和CXIIIj的制备
Figure PCTCN2018097386-appb-000148
利用通用制备流程二制备，化合物为紫红色固体，产率71％。
1H NMR(400MHz,CDCl 3):δ8.38(s,.1H),7.82(s,1H),6.95(d,J＝9.0Hz,2H),6.62(s,2H),3.57(q,J＝7.0Hz,8H),2.80(d,J＝6.2Hz,1H),2.23(d,J＝6.2Hz,1H),1.60(s,3H),1.29(t,J＝7.0Hz,12H)；13C NMR(101MHz,CDCl 3)δ174.4,159.5,157.8,155.3,131.8,115.3,113.9,95.8,46.0,38.6,30.9,26.8,24.2,20.3,12.7.ESI-HRMS(m/z):[M+H] +calcd.forC 27H 35N 2O 3,435.2648；found435.2648。
实施例110：CXIIIk和CXIIIl的制备
Figure PCTCN2018097386-appb-000149
利用通用制备流程二制备，化合物为紫红色固体，产率68％。
1H NMR(400MHz,CDCl 3):δ7.38(d,J＝7.2Hz,1H),7.25(d,J＝8.8Hz,1H),7.16(t,J＝7.4Hz,1H),7.12-7.06(m,2H),7.01-6.93(m,3H),6.89(d,J＝7.3Hz,1H),6.55(d,J＝2.1Hz,1H),6.44(d,J＝8.8Hz,1H),6.43(s,1H),6.39(dd,J＝8.8Hz,2.2Hz,1H),6.34(dd,J＝8.7Hz,2.3Hz,1H),4.78(d,J＝4.2Hz,1H),3.86(d,J＝1.8Hz,1H),3.62(dd,J＝9.7Hz,4.2Hz,1H),3.44(q,J＝7.0Hz,4H),3.31(q,J＝7.0Hz,4H),2.69(dd,J＝9.7Hz,1.9Hz,1H),1.25(t,J＝7.0Hz,6H),1.12(t,J＝7.0Hz,6H)； 13C NMR(101MHz,CDCl 3):δ176.7,153.1,151.6,149.0,148.5,145.1,142.0,141.9,138.5,128.7,128.5,126.6,126.3,126.0,125.6,125.1,124.3,123.3,123.2,116.8,108.6,107.3,106.4,99.2,98.7,82.2,57.0,47.8,46.1,45.5,44.7,44.6,12.8,12.6.EI-HRMS(m/z):[M+H] +calcd.forC 38H 39N 2O 3,571.2961；found 571.2966。
实施例111：CXIIIm的制备
Figure PCTCN2018097386-appb-000150
利用通用制备流程二制备，化合物为紫红色固体，产率83％。
1H NMR(400MHz,CDCl 3):δ7.93(s,2H),6.97(s,2H),6.69(s,2H),5.13(d,J＝8.4Hz,1H),3.63(q,J＝8.0Hz,8H),1.96(d,J＝6.2Hz,1H),1.85-1.77(m,7H),1.39(s,3H),1.31(t,J＝7.8Hz,12H),0.80(s,3H)；13C NMR(101MHz,CDCl 3)δ158.8,155.4,136.8,131.0,121.2,115.3,113.8,96.2,46.1,33.2,32.2,29.7,26.4,26.0,24.2,21.5,18.6,12.8.ESI-HRMS(m/z):[M] +calcd.for C 26H 29N 4O 3 +,445.3219；found445.3220。
实施例112：CXIIIn的制备
Figure PCTCN2018097386-appb-000151
利用通用制备流程二制备，化合物为紫红色固体，产率70％。
1H NMR(400MHz,CDCl 3):δ8.11(d,J＝9.9Hz,1H),8.02(d,J＝9.7Hz,1H),7.11(d,J＝9.0Hz,1H),6.95(d,J＝8.7Hz,1H),6.67(dd,J＝6.2Hz,1.4Hz,2H),4.39(t,J＝8.3Hz,1H),3.61(q,J＝7.8Hz,8H),2.98-2.90(m,1H),2.33(s,2H),1.88-1.85(m,1H),1.45(s,3H),1.31(t,J＝7.0Hz,12H),1.20(s,3H),0.81(s,3H)； 13C NMR(101MHz,CDCl 3)δ162.4,157.8,157.3,155.3,154.6,132.2,130.8,115.4,114.6,113.8,113.0,96.2,57.1,51.2,48.1,46.1,46.0,35.0,30.1,25.6,25.2,20.8,12.9.ESI-HRMS(m/z):[M] +calcd.for C 30H 41N 2O 3 +,477.3117；found477.3120。
实施例113：CXIIIo的制备
Figure PCTCN2018097386-appb-000152
利用通用制备流程二制备，化合物为紫红色固体，产率82％。
1H NMR(400MHz,CDCl 3):δ7.87(d,J＝9.6Hz,2H),6.96(d,J＝9.5Hz,2H),6.57(d,J＝1.0Hz,2H),3.53(q,J＝7.0Hz,8H),3.05(s,2H),1.81(s,3H),1.51-1.41(m,12H),1.21(t,J＝7.1Hz,12H). 13C NMR(101MHz,CDCl 3):δ157.6,156.9,155.0,130.9,114.4,113.3,95.6,45.7,43.5,40.8,37.2,36.1,28.6,12.5.EI-HRMS(m/z):[M] +calcd.For C 32H 43N 2O,471.3375；found 471.3376。
实施例114：CXIIIp的制备
Figure PCTCN2018097386-appb-000153
利用通用制备流程二制备，化合物为紫红色固体，产率61％。
1H NMR(400MHz,CDCl 3):δ8.02(d,J＝9.6Hz,2H),7.05(d,J＝9.5Hz,2H),6.64(s,2H),3.59(q,J＝7.0Hz,8H),3.24(s,2H),2.10(s,3H),1.60(s,6H),1.45-1.42(m,6H),1.30(t,J＝7.1Hz,12H). 13C NMR(101MHz,CDCl 3):δ157.8,157.3,155.4,131.4,114.9,113.8,95.9,68.3,50.7,45.9,43.9,42.7,40.3,40.1,35.2,30.9,29.7,23.2,12.7.EI-HRMS(m/z):[M] +calcd.for C 32H 43N 2O 2,487.3325；found 487.3327。
实施例115：CXIIIq的制备
Figure PCTCN2018097386-appb-000154
利用通用制备流程二制备，化合物为紫红色固体，产率79％。
1H NMR(400MHz,CDCl 3):δ7.97(d,J＝9.4Hz,2H),7.00(d,J＝9.4Hz,2H),6.66(s,2H),3.96(s,3H),3.58(q,J＝7.1Hz,8H),3.26(s,2H),2.12(s,3H),1.61(s,6H),1.43-1.40(m,6H),1.30(t,J＝7.1Hz,12H). 13C NMR(101MHz,CDCl 3):δ157.7,157.2,156.4,134.4,112.9,111.8,95.6,64.3,52.7,46.9,43.3,42.4,40.3,40.0,36.2,30.7,29.4,23.2,19.8,12.7.EI-HRMS(m/z):[M] +calcd.for C 33H 45N 2O 2,501.3481；found 501.3482。
实施例116：CXIIIr的制备
Figure PCTCN2018097386-appb-000155
利用通用制备流程二制备，化合物为紫红色固体，产率77％。
1H NMR(400MHz,CDCl 3):δ7.95(d,J＝9.4Hz,2H),7.04(d,J＝9.4Hz,2.2Hz,2H),6.70(d,J＝2.2Hz,2H),3.96(s,3H),3.64(q,J＝7.1Hz,8H),3.18(s,2H),2.00(m,1H),1.34-1.31(m,14H),1.22-1.19(m,8H),1.09-1.00(m,2H),0.73(s,6H). 13C NMR(101MHz,CDCl 3):δ157.9,157.4,155.4,131.2,114.8,113.6,96.1,50.7,50.2,46.1,42.6,42.3,40.6,39.1,31.9,30.5,29.9,12.8.EI-HRMS(m/z):[M] +calcd.for C 33H 45N 2O 2,499.3688；found 499.3687。
实施例117：CXIIIs的制备
Figure PCTCN2018097386-appb-000156
利用通用制备流程二制备，化合物为紫红色固体，产率67％。
1H NMR(400MHz,CDCl 3):δ7.32(dd,J＝8.8Hz,1.9Hz,1H),7.20-7.16(m,3H),7.04(dd,J＝8.8Hz,1.9Hz,1H),6.97(t,J＝8.9Hz,1H),6.43(d,J＝2.1Hz,2H),6.36(dd,J＝8.8Hz,2.1Hz,2H),3.37-3.28(m,8H),2.11(s,2H),1.17(s,6H),1.14(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3)δ155.1,152.7,148.2,131.5,127.5,127.0,126.6,120.7,117.4,116.4, 107.5,99.0,72.9,52.2,44.6,32.1,31.3,12.7；ESI-MS(m/z):[M] +calcd.for C 31H 39N 2O 2,471.3012；found 471.3010。
实施例118：CXIIIt的制备
Figure PCTCN2018097386-appb-000157
利用通用制备流程二制备，化合物为紫红色固体，产率57％。
1H NMR(400MHz,CDCl 3):δ7.18(d,J＝8.7Hz,2H),6.95(d,J＝8.8Hz,1H),6.85(d,J＝2.9Hz,1H),6.76(dd,J＝8.8Hz,2.9Hz,1H),6.42(d,J＝2.1Hz,2H),6.36(dd,J＝8.7Hz,2.1Hz,2H),3.82(s,3H),3.32(q,J＝7.0Hz,8H),2.13(s,2H),1.18(s,6H),1.14(t,J＝7.0Hz,12H)； 13C NMR(101MHz,CDCl 3)δ153.7,152.7,149.2,148.2,132.7,126.7,118.0,116.3,112.8,112.0,107.4,98.9,72.7,55.9,52.1,44.6,31.9,31.8,12.7；ESI-MS(m/z):[M] +calcd.for C 32H 41N 2O 3,501.3117；found 501.3115。
实施例119：CXIIIu的制备
Figure PCTCN2018097386-appb-000158
利用通用制备流程二制备，化合物为紫红色固体，产率55％。
1H NMR(400MHz,CDCl 3):δ7.24(d,J＝8.9Hz,2H),6.93(d,J＝8.7Hz,1H),6.70(s,1H),6.67(d,J＝8.8Hz,1H),6.41(s,2H),6.37(d,J＝8.9Hz,2H),3.31-3.27(m,12H),2.10(s,2H),1.17-1.12(m,24H)； 13C NMR(101MHz,CDCl 3)δ152.7,148.1,147.1,142.8,131.8,126.8,117.7,116.8,114.4,112.6,107.5,99.0,72.2,52.4,45.5,44.6,32.0,31.6,12.8,12.7.；ESI-MS(m/z):[M] +calcd.forC 35H 48N 3O 2,542.3747；found 542.3743。
实施例120：CXIIIv的制备
Figure PCTCN2018097386-appb-000159
利用通用制备流程二制备，化合物为紫红色固体，产率53％。
1H NMR(400MHz,CDCl 3):δ8.28(d,J＝2.7Hz,1H),8.09(d,J＝9.0Hz,2.7Hz,1H),7.12-7.10(m,3H),6.46(d,J＝2.5Hz,2H),6.39(dd,J＝9.0Hz,2.5Hz,2H),3.34(q,J＝7.1Hz,12H),2.21(s,2H),1.28(s,6H),1.17(t,J＝7.1Hz,12H)； 13C NMR(101MHz,CDCl 3)δ161.0,152.7,148.5,141.6,132.4,126.2,123.7,123.7,118.0,114.6,107.4,98.8,51.2,44.5,31.9,31.8,12.6；ESI-MS(m/z):[M] +calcd.forC 31H 38N 3O 4,516.2862；found 516.2864。
实施例121：CXIIIw的制备
Figure PCTCN2018097386-appb-000160
利用通用制备流程二制备，化合物为紫红色固体，产率56％。
1H NMR(400MHz,CDCl 3):δ7.22(d,J＝8.9Hz,2H),6.96(d,J＝8.7Hz,1H),6.57(d,J＝8.8Hz,1H),6.50(s,1H),6.46(s,2H),6.39(d,J＝8.9Hz,2H),3.30-3.26(m,12H),2.10(s,2H),1.18-1.13(m,24H)； 13C NMR(101MHz,CDCl 3)δ153.7,148.7,147.3,142.9,131.5,126.3,117.9,115.8,115.4,112.6,108.5,99.2,72.1,52.4,45.7,44.0,32.4,31.2,12.8,12.7.；ESI-MS(m/z):[M] +calcd.forC 35H 48N 3O 2,542.3747；found 542.3746。
实施例122：CXIIIx的制备
Figure PCTCN2018097386-appb-000161
利用通用制备流程二制备，化合物为紫红色固体，产率51％。
1H NMR(400MHz,CDCl 3):δ8.16(d,J＝2.5Hz,1H),8.00(d,J＝9.0Hz,2.5Hz,1H),7.05-7.01(m,3H),6.48(d,J＝2.5Hz,2H),6.29(dd,J＝9.0Hz,2.5Hz,2H),3.34(q,J＝7.1Hz,12H),2.19(s,2H),1.27(s,6H),1.17(t,J＝7.1Hz,12H)； 13C NMR(101MHz,CDCl 3) δ160.5,152.2,148.3,142.6,132.9,126.0,124.7,122.7,118.0,115.6,106.4,97.8,51.4,44.6,32.2,31.5,12.8；ESI-MS(m/z):[M] +calcd.forC 32H 38N 3O 2,496.2964；found 496.2965。
实施例123：CXIIIy的制备
Figure PCTCN2018097386-appb-000162
利用通用制备流程二制备，化合物为紫红色固体，产率59％。
1H NMR(400MHz,CDCl 3):δ8.13(d,J＝9.4Hz,2H),6.86(dd,J＝9.2Hz,1.8Hz,2H),6.58(d,J＝1.8Hz,2H),3.55(q,J＝7.1Hz,8H),1.30(t,J＝7.1Hz,12H). 13C NMR(101MHz,CDCl 3):δ159.1,155.4,134.2,113.2,110.5,100.1,95.6,45.8,12.7.EI-HRMS(m/z):[M] +calcd.forC 22H 27N 2O 3,367.2022；found 367.2021。
实施例124：CXIIIz的制备
Figure PCTCN2018097386-appb-000163
利用通用制备流程二制备，化合物为紫红色固体，产率75％。
1H NMR(400MHz,CDCl 3):δ7.19(d,J＝8.6Hz,1H),7.01(d,J＝8.6Hz,1H),6.48-6.42(m,4H),6.33-6.31(m,1H),6.17-6.15(m,1H),3.57(dd,J＝8.9Hz,5.1Hz,1H),3.40-3.32(m,8H),3.28(s,1H),2.92(dd,J＝8.9Hz,3.7Hz,1H),2.61(s,1H),1.46(d,J＝8.0Hz,1H),1.25(d,J＝5.7Hz,1H),1.19(t,J＝7.0Hz,6H),1.16(t,J＝7.0Hz,6H)；13C NMR(101MHz,CDCl 3)δ178.4,153.1,151.8,148.8,148.4,136.0,134.9,127.4,123.3,117.9,110.8,107.4,106.3,99.4,98.8,81.6,58.2,53.1,48.5,46.0,45.5,44.6,44.6,12.7,12.7.ESI-HRMS(m/z):[M+H] +calcd.for C 29H 34N 2O 3,459.2648；found459.2646。
实施例125：CXIIIaa的制备
Figure PCTCN2018097386-appb-000164
利用通用制备流程二制备，化合物为紫红色固体，产率69％。
1H NMR(400MHz,CDCl 3):δ7.26(d,J＝8.6Hz,1H),7.07(d,J＝8.6Hz,1H), 6.50-6.40(m,4H),3.40-3.29(m,8H),3.25(t,J＝7.6Hz,1H),2.32-2.17(m,2H),1.54-1.42(m,2H),1.20(s,3H),1.17(t,J＝7.0Hz,12H),1.09-0.97(m,4H)； 13C NMR(101MHz,CDCl 3)δ178.9,153.0,152.8,148.4,148.4,126.3,124.1,113.4,110.2,106.9,106.7,106.6,99.4,98.8,81.3,77.4,77.0,76.7,48.0,47.3,44.5,44.4,39.1,38.0,35.1,32.4,31.4,31.3,30.3,29.2,26.9,22.9,22.6,22.2,12.6,12.5.ESI-HRMS(m/z):[M+H] +calcd.for C 29H 39N 2O 3,463.2961；found 463.2968。
生物实验
1、罗丹明系列化合物对耐甲氧西林金黄色葡萄球菌(ATCC43300)和鲍曼不动杆菌敏感株(ATCC19606)的最低抑菌浓度和抗菌增效活性。采用微量稀释法，参照CLSI M07-A9标准制备倍比稀释的抗菌药物，测定CXIIIo最低抑菌活性(MICs)。
采用生长方法制备相当于0.5麦氏单位的标准化接种物，再用MHB培养基按1：150稀释，得到用于实验的初始菌液，并在15min内接种，用于测定药物MIC实验。以不含药物的CAMHB接种管为阳性对照，不接种细菌的培养物作为阴性对照,使每管最终菌液浓度约为0.25-0.5×10 6CFU/ml。将培养物置于37℃，培养16h-20h后，观察细菌的生长情况，并判读药物单独的最低抑菌浓度(MICs)。化合物抗菌活性的评判标准：MIC＞64μg/ml，化合物无抗菌活性；16μg/ml＜MIC≤64μg/ml，化合物具有弱抗菌活性；MIC≤16μg/ml，化合物具有较强的抗菌活性。
对MIC＞32μg/ml的化合物，进一步与64μg/ml苯唑西林联合，筛选其对耐甲氧西林金黄色葡萄球菌(ATCC43300)的抗菌增效活性。采用微量稀释法,固定不同罗丹明染料化合物的终浓度，再按照M07-A9操作步骤依次将苯唑西林倍比稀释。以含单一苯唑西林或单一罗丹明染料化合物的培养液为阳性对照，不接种细菌的培养物为阴性对照,使培养液最终菌浓度约为0.25-0.5×10 6CFU/ml。将培养物置于37℃，培养16h-20h后，观察细菌的生长情况，判读各组合药物中苯唑西林的MICs。
FIC指数(FICI)＝A药联合时MIC/A药单测时MIC+B药联合时MIC/B药单测MIC，其中判断标准：FICI≤0.5，增效；0.5<FICI≤1，叠加，1.0<FICI≤2.0，无关；FICI>2.0，拮抗。
结果如下表1所示。结果证明，罗丹明染料是可以高效发现具有抑菌杀菌活性化合物的化学结构空间，同时也是可以高效发现具有抗菌增效活性化合物的化学结构空间。
表1
Figure PCTCN2018097386-appb-000165
Figure PCTCN2018097386-appb-000166
Figure PCTCN2018097386-appb-000167
Figure PCTCN2018097386-appb-000168
Figure PCTCN2018097386-appb-000169
2、化合物CXIIIo对不同细菌的最低抑菌浓度。
采用微量稀释法，参照CLSI M07-A9标准制备倍比稀释的抗菌药物，测定CXIIIo最低抑菌活性(MICs)。采用生长方法制备相当于0.5麦氏单位的标准化接种物，再用MHB培养基按1∶150稀释，得到用于实验的初始菌液，并在15min内接种，用于测定药物MIC实验。以不含药物的CAMHB接种管为阳性对照，不接种细菌的培养物作为阴性对照,使每管最终菌液浓度约为0.25-0.5×10 6CFU/ml。将培养物置于37℃，培养16h-20h后，观察细菌的生长情况，并判读药物单独的最低抑菌浓度(MICs)。
结果如下表2所示。结果证明化合物CXIIIo对多种革兰氏阳性菌和革兰氏阴性菌均有较好杀菌活性。
表2
Figure PCTCN2018097386-appb-000170
Figure PCTCN2018097386-appb-000171
3、化合物CXIIIo、万古霉素、利萘唑胺、替加环素对处于对数生长早期的耐甲氧西林金黄色葡萄球菌的杀菌曲线。
将过夜培养的ATCC43300(37℃，12h)1:10000接种于20ml MHB液体培养基中。将37℃、225rpm培养2h后的菌液作为初始菌液。向制备好的初始菌液中加入2.5倍，5倍，10倍MIC的CXIIIo化合物及10倍MIC的万古霉素，利奈唑胺，替加环素，同时以不加任何药物做空白对照组，分别于0h,2h,4h,8h,16h,24h定量取样。将取出的菌液依次10倍稀释,分别取适宜稀释倍数的稀释液100μl涂布于计数培养基平板上，且每个稀释倍数涂布2-3个平行板,在36℃±1℃恒温培养箱中倒置培养16～20h，进行菌落计数，以菌 落形成单位(CFU)表示。将各培养管菌落计数的对数与培养时间在直角坐标作图，得到时间-杀菌曲线，评价CXIIIo的杀菌效力。
结果如图1所示。图1显示，CXIIIo在同等浓度下或更低的浓度下对耐甲氧西林金黄色葡萄球菌的杀菌效果较临床药物万古霉素、利萘唑胺、替加环素等更好。
4、化合物CXIIIo、替加环素对处于对数生长早期的鲍氏不动杆菌的杀菌曲线。
将过夜培养(37℃,220rpm,16h)的ATCC19606(鲍曼不动杆菌)1:1000接种于LB液体培养基的菌液作为初始菌液。向制备好的初始菌液中加入2.5倍，5倍，10倍MIC的CXIIIo化合物及10倍MIC的替加环素，同时以不加任何药物的做空白对照组，分别于0h,1h,2h,4h,8h,24h定量取样。将取出的菌液依次10倍稀释,分别取适宜稀释倍数的稀释液100μl涂布于计数培养基平板上，且每个稀释倍数涂布2-3个平行板,在36℃±1℃恒温培养箱中倒置培养16～20h，进行菌落计数，以菌落形成单位(CFU)表示。将各培养管菌落计数的对数与培养时间在直角坐标作图，得到时间-杀菌曲线，评价CXIIIo的杀菌效力。
结果如图2所示。图2显示，CXIIIo在等倍数MIC浓度(10*MIC)下鲍氏不动杆菌的杀菌效果较替加环素效果更好。
5、化合物CXIIIo、万古霉素、利萘唑胺对处于对数生长早期的抗万古霉素粪肠球菌(ATCC51299)的杀菌曲线。
将过夜培养的ATCC51299(37℃，12h)1:10000接种于20mlBHI(4μg/ml万古霉素)液体培养基中，37℃，225rpm培养2h后的菌液作为初始菌液。向制备好的初始菌液中加入2.5倍，5倍，10倍MIC的CXIIIo化合物及10倍MIC的利奈唑胺，同时以等浓度(20μg/ml)的万古霉素做阴性对照组，分别于0h,2h,4h,8h,16h,24h定量取样。将取出的菌液依次10倍稀释,分别取适宜稀释倍数的稀释液100μl涂布于计数培养基平板上，且每个稀释倍数涂布2-3个平行板,在36℃±1℃恒温培养箱中倒置培养16～20h，进行菌落计数，以菌落形成单位(Colony-Forming Units，CFU)表示。将各培养管菌落计数的对数与培养时间在直角坐标作图，得到时间-杀菌曲线，评价CXIIIo的杀菌效力。
结果如图3所示。图3显示，CXIIIo在等倍数MIC浓度(10*MIC)或者更低倍数MIC浓度下(2.5MIC或5MIC)对抗万古霉素粪肠球菌的杀菌效果较万古霉素和利萘唑胺效果更好。
6、耐甲氧西林金黄色葡萄球菌(ATCC43300)对CXIIIo的诱导耐药实验。
对左氧氟沙星(Levofloxacin)、万古霉素(Vancomycin)、68#化合物的诱导浓度从0.25MIC开始诱导，第一天诱导浓度为0.25MIC 220rmp 37℃培养24h，第二天浓度梯度为0.25MIC，0.5MIC，1MIC，2MIC，4MIC。37℃培养24h培养以OD 600>1.8且cfu/ml>10 9的最高浓度为第三天浓度梯度的中间浓度进行诱导，接种量为1:100，重复25天。
结果如图4所示，耐甲氧西林金黄色葡萄球菌(ATCC43300)在25天内没有对CXIIIo产生耐药性。
7、甲氧西林敏感株金黄色葡萄球菌(ATCC25923)对CXIIIo的诱导耐药实验。
选用的抗生素有左氧氟沙星(Levofloxacin)、万古霉素(Vancomycin)、四环素(Tetracycline)、庆大霉素(Gentamycin)、红霉素(Erythromycin)等抗生素为对照。CXIIIo及对照抗生素的诱导浓度从0.25MIC开始诱导，第一天诱导浓度为0.25MIC，220rmp，37℃培养24h，第二天浓度梯度为0.25MIC，0.5MIC，1MIC，2MIC，4MIC。37℃培养24h培养以OD 600>1.8且cfu/ml>10 9的最高浓度为第三天浓度梯度的中间浓度进行诱导，接种量为1:100，重复25天。
结果如图5所示，甲氧西林敏感株金黄色葡萄球菌(ATCC25923)在25天内没有对CXIIIo产生耐药性。
8、不同罗丹明染料化合物的浓度与苯唑西林共同作用于甲氧西林金黄色葡萄球菌(ATCC43300)时的部分抑菌浓度。
进一步测定有较好增效活性的罗丹明染料化合物的浓度与增效活性间的关系。采用微量稀释法,固定不同罗丹明染料化合物的终浓度分别为4μg/ml,2μg/ml,1μg/ml,0.5μg/ml，再按照M07-A9操作步骤依次将组合药物中的待测抗生素倍比稀释.以含苯唑西林或单一罗丹明染料化合物的培养液为阳性对照，不接种细菌的培养物为阴性对照,使培养液最终菌浓度约为0.25-0.5×10 6CFU/ml。将培养物置于37℃，培养16h-20h后，观察细菌的生长情况，判读各组合药物中抗生素的MICs。FIC指数(FICI)＝A药联合时MIC/A药单测时MIC+B药联合时MIC/B药单测MIC，其中判断标准：FICI≤0.5，增效；0.5<FICI≤1，叠加，1.0<FICI≤2.0，无关；FICI>2.0，拮抗。
结果如下表3所示，罗丹明染料还是可以发现具有抗菌增效活性化合物的化学结构空间。
表3：浓度-增效活性依赖关系
Figure PCTCN2018097386-appb-000172
Figure PCTCN2018097386-appb-000173
注：
Figure PCTCN2018097386-appb-000174
由实验结果可知，增效活性和化合物浓度依赖关系良好。其中化合物CXIIIt增效活性最佳。
9、CXIIIt的广谱抗菌增效实验。
采用微量稀释法,固定CXIIIt的终浓度分别为4μg/ml,2μg/ml,1μg/ml,0.5μg/ml，再按照M07-A9操作步骤依次将组合药物中的待测抗生素倍比稀释。以含单一抗生素(包括β内酰胺类抗生素：头孢克洛、头孢吡肟、青霉素钠、氨苄西林舒巴坦苯唑西林；喹诺酮类：左氧氟沙星；氨基糖苷类：阿米卡星、庆大霉素；糖肽类：万古霉素等)或CXIIIt的培养液为阳性对照，不接种细菌的培养物为阴性对照,使培养液最终菌浓度约为0.25-0.5×10 6CFU/ml。将培养物置于37℃，培养16h-20h后，观察细菌的生长情况，判读各组合药物中抗生素的MICs。FIC指数(FICI)＝A药联合时MIC/A药单测时MIC+B药联合时MIC/B药单测MIC，其中判断标准：FICI≤0.5，增效；0.5<FICI≤1，叠加，1.0<FICI≤2.0，无关；FICI>2.0，拮抗。
结果如下表4所示，表明CXIIIt对各种β内酰胺类抗生素均有抗菌增效效果。
表4
Figure PCTCN2018097386-appb-000175
Figure PCTCN2018097386-appb-000176
研究发现，化合物CXIIIt的溶液中还含有下式化合物CXIIIt2：
Figure PCTCN2018097386-appb-000177
推测可能是化合物CXIIIt关环形成该化合物CXIIIt2。且溶液中两种化合物形成一个化学平衡，这个平衡受酸碱影响。酸性情况下，CXIIIt会多一些，碱性或中性条件下，CXIIIt2会多一些。

Claims (11)

  1. 通式A所示的化合物：
    Figure PCTCN2018097386-appb-100001
    式中，
    X －为可构成盐的阴离子，包括但不限于F -、Cl -、Br -、I -、OAc -、HSO 4 -、H 2PO 4 -、ClO 4 -、F 3CCOO -、CH 3SO 3 -、CF 3SO 3 -、BF 4 －、PF 6 －、柠檬酸根和NO 3 -；
    R 1、R 2、R 3、R 4各自独立选自H、卤素和C1-C6烷基；
    R 5、R 6、R 7、R 8各自独立选自H和C1-C6烷基；
    其中，R 5和R 7可与它们所连接的N形成任选取代的5或6元含氮杂环，和/或R 6和R 8可与它们所连接的N形成任选取代的5或6元含氮杂环；其中，所述5或6元含氮杂环任选地含有环氧原子；或R 3与R 7与它们各自所连接的原子一起形成6元含氮杂环，和/或R 4与R 8与它们各自所连接的原子一起形成6元含氮杂环；
    其中，R 1和R 5可与它们所连接的原子形成任选取代的6元含氮杂环，同时R 3和R 7可与它们所连接的原子形成任选取代的6元含氮杂环，和/或R 2和R 6可与它们所连接的原子形成任选取代的6元含氮杂环，同时R 4和R 8可与它们所连接的原子形成任选取代的6元含氮杂环；和
    R 9选自H，任选取代的C1-C6烷基，任选取代的芳基，任选取代的杂芳基，任选取代的杂环基，和任选取代的C2-C6烯基。
  2. 如权利要求1所述的化合物，其特征在于，
    R 1和R 2各自独立为H；和/或
    R 3和R 4各自独立为H或C1-C6烷基；和/或
    R 5、R 6、R 7、R 8各自独立选自H和C1-C6烷基；和/或
    R 5和R 7与它们所连接的N形成任选取代的5或6元含氮杂环，如吡咯烷基或哌啶基，和/或R 6和R 8可与它们所连接的N形成任选取代的5或6元含氮杂环，如吡咯烷基或哌啶基；其中，所述5或6元含氮杂环任选地含有环氧原子，如吗啉基。
  3. 如权利要求1所述的化合物，其特征在于，
    通式A中，R 1和R 2各自独立为H，R 5和R 6各自独立为H或C1-C6烷基；R 3与R 7 与它们各自所连接的原子一起形成6元含氮杂环且R 4与R 8与它们各自所连接的原子一起形成6元含氮杂环；或
    通式A中，R 9选自：C1-C6烷基，任选被金刚烷基或苯基取代，所述金刚烷基任选被1～3个选自羟基、C1-C6烷氧基和C1-C6烷基的取代基取代，所述苯基任选被1～3个选自羟基和C1-C6烷氧基的取代基取代；苯基，任选被1～3个选自硝基、卤素、C1-C6烷基、苯基重氮基或萘基重氮基的取代基取代，其中，所述苯基重氮基或萘基重氮基任选被1～3个选自卤素和NR aR b的取代基取代，R a和R b各自独立为H或C1-C6烷基；任选被硝基取代的1,3-苯并二氧戊环基；或
    通式A中，R 1和R 2各自独立为H或C1-C6烷基；R 3和R 4各自独立为H或C1-C6烷基；R 9选自：C1-C6烷基，任选被金刚烷基或苯基取代，所述金刚烷基任选被1～3个选自羟基、C1-C6烷氧基和C1-C6烷基的取代基取代，所述苯基任选被1～3个选自羟基和C1-C6烷氧基的取代基取代；苯基，任选被1～3个选自硝基、卤素、C1-C6烷基、苯基重氮基或萘基重氮基的取代基取代，其中，所述苯基重氮基或萘基重氮基任选被1～3个选自卤素和NR aR b的取代基取代，R a和R b各自独立为H或C1-C6烷基；任选被硝基取代的1,3-苯并二氧戊环基；或
    通式A中，R 1和R 2各自独立为H；R 3和R 4各自独立为H或C1-C6烷基；R 5、R 6、R 7、R 8各自独立选自H和C1-C6烷基，或R 5和R 7与它们所连接的N形成任选取代的5或6元含氮杂环(如吡咯烷基或哌啶基)，和/或R 6和R 8可与它们所连接的N形成任选取代的5或6元含氮杂环(如吡咯烷基或哌啶基)；其中，所述5或6元含氮杂环任选地含有环氧原子(如吗啉基)，或R 3与R 7与它们各自所连接的原子一起形成6元含氮杂环且R 4与R 8与它们各自所连接的原子一起形成6元含氮杂环；和R 9选自：C1-C6烷基，任选被金刚烷基或苯基取代，所述金刚烷基任选被1～3个选自羟基、C1-C6烷氧基和C1-C6烷基的取代基取代，所述苯基任选被1～3个选自羟基和C1-C6烷氧基的取代基取代；苯基，任选被1～3个选自硝基、卤素、C1-C6烷基、苯基重氮基或萘基重氮基的取代基取代，其中，所述苯基重氮基或萘基重氮基任选被1～3个选自卤素和NR aR b的取代基取代，R a和R b各自独立为H或C1-C6烷基；任选被硝基取代的1,3-苯并二氧戊环基。
  4. 如权利要求1所述的化合物，其特征在于，通式A化合物的结构如下式BI、BII、BIII、BIV、BV、BVI、BVII、BVIII或BIX所示：
    Figure PCTCN2018097386-appb-100002
    Figure PCTCN2018097386-appb-100003
    式BI中，R 9选自任选取代的C1-C6烷基，任选取代的芳基和任选取代的杂芳基；
    式BII中，R 9选自任选取代的C1-C6烷基，任选取代的芳基和任选取代的杂芳基；
    式BIII中，R 9选自任选取代的C1-C6烷基，任选取代的芳基和任选取代的杂芳基；
    式BIV中，R 9选自任选取代的芳基，任选取代的杂芳基，任选取代的杂环基，和任选取代的C2-C6烯基；
    式BV中，R 9选自任选取代的芳基和任选取代的C1-C6烷基；
    式BVI中，R 9选自任选取代的芳基和任选取代的C1-C6烷基；
    式BVII中，R 9选自任选取代的芳基和任选取代的C1-C6烷基；
    式BVIII中，R 5和R 6各自独立选自H和C1-C6烷基；R 9选自任选取代的芳基和任选取代的C1-C6烷基；
    式BIX中，R 9选自任选取代的芳基；和
    上述结构式中，X -选自F -、Cl -、Br -、I -、OAc -、HSO 4 -、H 2PO 4 -、ClO 4 -、F 3CCOO -、CH 3SO 3 -、CF 3SO 3 -、BF 4 －、PF 6 －、柠檬酸根和NO 3 -。
  5. 如权利要求1所述的化合物，其特征在于，所述化合物的结构如下式CI到CXIII中任一所示：
    Figure PCTCN2018097386-appb-100004
    Figure PCTCN2018097386-appb-100005
    式中，
    R 10、R 11、R 12、R 13和R 14各自独立选自H，硝基，任选取代的C1-C6烷基，C1-C6烷氧基，羧基，卤素，羟基，巯基，C1-C6烷巯基，NR aR b，任选取代的芳基，二苯磷基，和任选取代的芳基重氮基和C1-C6酰基，其中，R a和R b独立选自H、C1-C6烷基和C1-C6酰基；或者R 10、R 11、R 12、R 13和R 14中的两个或两个以上可与它们所连接的苯基一起形成任选取代的萘基、蒽基、喹啉基、二萘嵌苯基(苝基)、苯并咪唑基或1,3-苯并二氧戊环基；
    Y选自O、S、或NR 19；
    R 16、R 17、R 18、R 20、R 21、R 22、R 24和R 25各自独立选自H和C1-C6烷基；或者，Y与R 25及所述含Y的环一同形成任选取代的下式结构：
    Figure PCTCN2018097386-appb-100006
    R 19选自H和任选取代的C1-C6烷基，如苯基取代的C1-C6烷基，如三苯甲基或苄基；
    R 27、R 28各自独立选自H和C1-C6烷基；
    R 30、R 31、R 32和R 33各自独立选自H，卤素和C1-C6烷基；
    R 34、R 35、R 36和R 37各自独立选自H，卤素和C1-C6烷基；
    R 38、R 39和R 40各自独立选自H，卤素和C1-C6烷基；
    R 41、R 42和R 43各自独立选自H，卤素和C1-C6烷基；
    R 44、R 45和R 46各自独立选自H，卤素，羧基和C1-C6烷基；
    R 47、R 48和R 49各自独立选自H，卤素和C1-C6烷基；
    R 50、R 51和R 52各自独立选自H，羧基，任选取代的芳基，或任选取代的以下基团：
    Figure PCTCN2018097386-appb-100007
    或者，R 50、R 51和R 52与它们所连接的C原子一起形成任选取代的以下基团：
    Figure PCTCN2018097386-appb-100008
    其中，取代基选自C1-C6烷基、NR aR b、卤素、羟基、C1-C6烷氧基、和C1-C6烷基取代的哌嗪基；其中，R a和R b各自独立选自H和C1-C6烷基；
    R 53、R 54和R 55各自独立选自H，任选取代的C1-C6烷基，羧基；或者R 53、R 54和R 55中的任意两个与它们所连接的C一起形成任选取代的C3-C8环烷基或任选取代的以下基团：
    Figure PCTCN2018097386-appb-100009
    其中，所述取代基选自羟基，羧基，任选取代的C1-C6烷基，NR aR b，C1-C6烷氧基，C2-C6烯基，任选被羟基、C1-C6烷氧基或C1-C6烷基取代的金刚烷基，任选取代的芳烷基(如任选被羟基、C1-C6烷氧基、NR aR b、硝基或氰基取代的苯基-C1-C6烷基)；其中，R a和R b各自独立选自H和C1-C6烷基；
    X -选自F -、Cl -、Br -、I -、OAc -、HSO 4 -、H 2PO 4 -、ClO 4 -、F 3CCOO -、CH 3SO 3 -、CF 3SO 3 -、BF 4 －、PF 6 －、柠檬酸根或NO 3 -。
  6. 如权利要求1所述的化合物，其特征在于，所述化合物选自：
    Figure PCTCN2018097386-appb-100010
    Figure PCTCN2018097386-appb-100011
    Figure PCTCN2018097386-appb-100012
    Figure PCTCN2018097386-appb-100013
    Figure PCTCN2018097386-appb-100014
    Figure PCTCN2018097386-appb-100015
    Figure PCTCN2018097386-appb-100016
  7. 一种药物组合物，含有权利要求1～6中任一项所述的化合物和药学上可接受的载体，和任选的抗菌药。
  8. 权利要求1～6中任一项所述的化合物在制备抗菌药中的应用，或在制备增强抗菌药抗菌活性的药物中的应用。
  9. 如权利要求8所述的应用，其特征在于，
    所述抗菌药用于抑制或杀死选自以下的细菌：金黄色葡萄球菌，如甲氧西林耐药金黄色葡萄球菌；万古霉素耐药粪肠球菌；碳青霉烯耐药肺炎克雷伯菌；泛耐药鲍曼不动杆菌；多药耐药铜绿假单胞菌；多药耐药肠杆菌；抗万古霉素屎肠球菌；肺炎链球菌；甲氧西林敏感表皮葡萄球菌；化脓性链球菌；肺炎克雷伯菌(ESBL+)；肺炎克雷伯菌(ESBL-)；抗碳青霉烯肺炎克雷伯菌；大肠埃细菌(ESBL+)；大肠埃细菌(ESBL-)；和痢疾桿菌；或
    所述化合物用于增强β内酰胺类抗生素，如头孢克洛、头孢吡肟、青霉素钠、氨苄西林、舒巴坦和苯唑西林的抗菌活性。
  10. 一种抑菌或杀菌方法，所述方法包括给予需要的对象有效量的权利要求1～6中任一项所述的化合物或权利要求7所述的药物组合物；
    优选地，所述细菌选自：金黄色葡萄球菌，如甲氧西林耐药金黄色葡萄球菌；万古霉素耐药粪肠球菌；碳青霉烯耐药肺炎克雷伯菌；泛耐药鲍曼不动杆菌；多药耐药铜绿假单胞菌；多药耐药肠杆菌；抗万古霉素屎肠球菌；肺炎链球菌；甲氧西林敏感表皮葡萄球菌；化脓性链球菌；肺炎克雷伯菌(ESBL+)；肺炎克雷伯菌(ESBL-)；抗碳青霉烯肺炎克雷伯菌；大肠埃细菌(ESBL+)；大肠埃细菌(ESBL-)；和痢疾桿菌。
  11. 一种制备本文权利要求1－6中任一项所述的通式A化合物的方法，所述方法包括使下式所示的二溴苯甲醚和羰基化合物在有机溶剂和烷基锂试剂的存在下进行反应，从而制备得到式A化合物：
    Figure PCTCN2018097386-appb-100017
    式中，R 1-R 9如权利要求1－6中任一项所述；LG为离去基团，可选自卤素，氰基，C1-C6烷氧基和C1-C6烷基-COO-；
    优选地，所述有机溶剂是正己烷，或醚类溶剂，如四氢呋喃、乙醚、甲基叔丁基醚和1,4-二氧六环；
    优选地，所述烷基锂试剂为C1-C6烷基锂试剂，包括但不限于正丁基锂、叔丁基锂和仲丁基锂；
    优选地，反应在零下78℃到0℃之间进行；和
    所述二溴苯甲醚化合物与烷基锂试剂的摩尔比在1：2－3之间。
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WO2010033011A1 (en) * 2008-09-19 2010-03-25 Cancer Research Initiatives Foundation Rosamine derivatives as agents for the treatment of cancer
CN102307878A (zh) * 2008-12-10 2012-01-04 维斯塔实验室有限公司 3，6-二取代的呫吨鎓盐
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