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WO2020135569A1 - 乙二胺类化合物及其用途 - Google Patents

乙二胺类化合物及其用途 Download PDF

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Publication number
WO2020135569A1
WO2020135569A1 PCT/CN2019/128639 CN2019128639W WO2020135569A1 WO 2020135569 A1 WO2020135569 A1 WO 2020135569A1 CN 2019128639 W CN2019128639 W CN 2019128639W WO 2020135569 A1 WO2020135569 A1 WO 2020135569A1
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Prior art keywords
substituted
hydrogen
alkyl
pharmaceutically acceptable
unsubstituted
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PCT/CN2019/128639
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English (en)
French (fr)
Inventor
钟武
李松
萧红街
周梦蝶
Original Assignee
中国人民解放军军事科学院军事医学研究院
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Application filed by 中国人民解放军军事科学院军事医学研究院 filed Critical 中国人民解放军军事科学院军事医学研究院
Priority to EP19903000.8A priority Critical patent/EP3904330A4/en
Priority to CN201980086109.2A priority patent/CN113227036B/zh
Priority to US17/418,693 priority patent/US20220089521A1/en
Priority to JP2021538052A priority patent/JP2022515869A/ja
Publication of WO2020135569A1 publication Critical patent/WO2020135569A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/09—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/36—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing at least two amino groups bound to the carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/05—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention belongs to the field of medicinal chemistry and relates to ethylenediamine compounds, pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or prodrugs thereof, And its use in the treatment of tuberculosis.
  • Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis. According to the World Health Organization (WHO), about 2 million people die from tuberculosis worldwide each year. Although existing anti-tuberculosis drugs have largely curbed the spread of tuberculosis, their treatment cycle is too long, and patient compliance is poor, and with the rise in the incidence of multi-drug tuberculosis and pan-drug tuberculosis, and HIV/AIDS The concurrent occurrence of TB caused the TB epidemic to rise again, making TB a major public health and social issue of global concern.
  • WHO World Health Organization
  • SQ109 is sensitive to drug-sensitive Mycobacterium tuberculosis, multi-drug resistant and pan-drug-resistant Mycobacterium tuberculosis, and was recognized by the FDA and the European Medicines Agency as a "rare” in 2007. Management with drugs” for the treatment of drug-resistant tuberculosis.
  • Mechanism research shows that SQ109 acts on the MmpL3 transmembrane protein of Mycobacterium tuberculosis, inhibiting the generation of TDM, making mycolic acid esters fail to link with the arabinogalactose on the cell wall, thereby inhibiting the synthesis of the tuberculosis cell wall.
  • the object of the present invention is to provide an ethylenediamine compound, a pharmaceutically acceptable salt thereof, and its application in the treatment of drug-resistant tubercle bacillus.
  • the first aspect of the present invention provides a compound represented by the general formula A, a pharmaceutically acceptable salt, a stereoisomer, a tautomer or a mixture of isomers, a hydrate thereof, a solvate thereof or a prodrug thereof ,
  • R a is hydrogen, C 1-6 alkyl, C 3-14 cycloalkyl, 6-14 membered aryl, 3-14 membered heterocyclyl,
  • R b is hydrogen, C 1-10 alkyl, C 3-14 cycloalkyl, C 2-12 alkenyl or polyalkenyl, C 2-12 alkenoyl or polyalkenoyl, C 2-10 alkanoyl, substituted Or unsubstituted 6-14 membered aryl group, substituted or unsubstituted 3-14 membered heterocyclic group, substituted or unsubstituted 7-12 membered bridged ring group, phenyl substituted C 1-6 alkyl or indole -3-(CH 2 ) n -C(O)-, where n is an integer between 0-4;
  • X is -CH 2 -, -CHR 2 -or -C(O)-, wherein R 2 is C 1-6 alkyl;
  • R d is hydrogen, C 1-10 alkyl, C 3-14 cycloalkyl, C 2-12 alkenyl or polyalkenyl, C 2-12 alkenoyl or polyalkenoyl, C 2-12 alkanoyl, substituted Or unsubstituted 6-14 membered aryl group, substituted or unsubstituted 3-14 membered heterocyclic group, substituted or unsubstituted 7-12 membered bridged ring group, phenyl substituted C 1-10 alkyl group, substituted or Unsubstituted sulfonyl, substituted or unsubstituted benzoyl, indole-3-(CH 2 ) n -C(O)-, where n is an integer between 0-4.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, which:
  • R a is hydrogen
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or a prodrug thereof, wherein: R a is hydrogen.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, which:
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, which:
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, which:
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R b is hydrogen, C 1-10 alkyl, C 3-14 cycloalkyl, C 2-12 alkenyl or polyalkenyl, C 2-12 alkenyl or polyalkenyl, C 2-12 alkanoyl, substituted or unsubstituted 6-14 membered aryl, substituted or unsubstituted 3-14 membered heterocyclic group, substituted or unsubstituted 7-12 membered bridged ring group.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R b is hydrogen, C 3-10 alkyl, C 4-12 dienyl, phenyl substituted C 1-4 alkyl or indole-3-(CH 2 ) n -C (O)-, where n is an integer between 0-4.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R b is hydrogen, C 6-10 alkyl, C 8-12 dienyl, phenyl substituted C 1-3 alkyl or indole-3-(CH 2 ) n -C (O)-, where n is an integer between 0-4.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R b is hydrogen, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, Benzyl, phenylethyl, phenyl-n-propyl, phenyl-n-butyl, indole-3-C(O)-, indole-3-CH 2 -C(O)-, indole-3- (CH 2 ) 2 -C(O)-, indole-3-(CH 2 ) 3 -C(O)- or indole-3-(CH 2 ) 4 -C(O)-.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R b is n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R b is
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R b is benzyl or phenylethyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R b is phenyl n-propyl or phenyl n-butyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R b is indole-3-C(O)-.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R b is indole-3-CH 2 -C(O)-, indole-3-(CH 2 ) 2 -C(O)-.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R b is indole-3-(CH 2 ) 3 -C(O)- or indole-3-(CH 2 ) 4 -C(O)-.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R b is hydrogen, -CH 2 (CH 2 ) 6 CH 3 , or
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: X is -CH 2 -or -C(O)-.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: X is -CH 2 -.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R c is hydrogen, C 4-12 dienyl, C 4-12 dienyl acyl, C 1-4 alkyl substituted sulfonyl, C 2-10 alkanoyl, C 3- 10 alkyl, C 3-6 cycloalkyl, C 1-4 alkyl-phenyl substituted sulfonyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R c is hydrogen, C 8-12 dienyl, C 8-12 dienyl acyl, C 1-3 alkyl substituted sulfonyl, C 1-2 alkyl-phenyl substituted Sulfonyl, C 6-10 alkyl, C 3-4 cycloalkyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R c is hydrogen, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, p-toluenesulfonyl, p-ethylbenzenesulfonyl, p-n-propylbenzenesulfonamide , N-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, cyclopropyl, cyclobutyl,
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R c is hydrogen.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R c is methylsulfonyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R c is ethylsulfonyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R c is propylsulfonyl or butylsulfonyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R c is p-toluenesulfonyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R c is p-ethylbenzenesulfonyl or p-n-propylbenzenesulfonamide.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R c is n-hexyl or n-octyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R c is n-heptyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R c is n-nonyl or n-decyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R c is cyclopropyl, cyclobutyl,
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R c is
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R c is
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R c is hydrogen, Cyclopropyl, -CH 2 (CH 2 ) 6 CH 3 or -CH 2 (CH 2 ) 4 CH 3 .
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R c is hydrogen, -CH 2 (CH 2 ) 6 CH 3 , or -CH 2 (CH 2 ) 4 CH 3 .
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R d is hydrogen, C 1-4 alkyl substituted sulfonyl, C 1-4 alkyl-phenyl substituted sulfonyl, C 4-12 dienyl acyl, one or more Methoxy substituted benzoyl, phenyl substituted C 1-4 alkyl, C 3-10 alkyl, C 2-12 alkanoyl, C 3-6 cycloalkyl, or indole-3-( CH 2 ) n -C(O)-, where n is an integer between 0-4.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: Rd is hydrogen, C 1-3 alkyl substituted sulfonyl, C 1-2 alkyl-phenyl substituted sulfonyl, C 8-12 dienyl acyl, one or more Methoxy substituted benzoyl, phenyl substituted C 1-3 alkyl, C 6-10 alkyl, C 6-12 alkanoyl, C 3-4 cycloalkyl, or indole-3-( CH 2 ) n -C(O)-, where n is an integer between 0-4.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R d is hydrogen, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, p-toluenesulfonyl, p-ethylbenzenesulfonyl, p-n-propylbenzenesulfonamide , P-methoxybenzoyl, 3,4-dimethoxybenzoyl, 3,4,5-trimethoxybenzoyl, undecanoyl, decanoyl, nonanoyl, octanoyl, heptanoyl, Hexanoyl, valeryl, butyryl, benzyl, phenylethyl, phenyl
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: Rd is hydrogen,
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: Rd is hydrogen, -CH 2 (CH 2 ) 6 CH 3 .
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: Rd is hydrogen.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R d is methylsulfonyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: Rd is ethylsulfonyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R d is propylsulfonyl or butylsulfonyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: Rd is p-toluenesulfonyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: Rd is p-ethylbenzenesulfonyl or p-n-propylbenzenesulfonamide.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: Rd is
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: Rd is p-methoxybenzoyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: Rd is 3,4-dimethoxybenzoyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: Rd is 3,4,5-trimethoxybenzoyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: Rd is undecanoyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R d is decanoyl, nonanoyl or octanoyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: Rd is heptanoyl, hexanoyl, valeryl or butyryl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: Rd is benzyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: Rd is phenylethyl or phenyl n-propyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: Rd is phenyl n-butyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: Rd is n-hexyl or n-heptyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: Rd is n-octyl or n-nonyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: Rd is n-decyl.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein the compound is represented by formula I,
  • R 1 is hydrogen, C 1-10 alkyl, C 3-14 cycloalkyl, C 2-12 alkenyl or polyalkenyl, C 2-12 alkenoyl or polyalkenoyl, C 2-10 alkanoyl, substituted Or unsubstituted 6-14 membered aryl group, substituted or unsubstituted 3-14 membered heterocyclic group, substituted or unsubstituted 7-12 membered bridged ring group, phenyl substituted C 1-6 alkyl or indole -3-(CH 2 ) n -C(O)-, where n is an integer between 0-4;
  • X is -CH 2 -, -CHR 2 -or -C(O)-, wherein R 2 is C 1-6 alkyl;
  • R 3 is hydrogen, C 1-10 alkyl, C 3-14 cycloalkyl, C 2-12 alkenyl or polyalkenyl, C 2-12 alkenoyl or polyalkenoyl, C 2-10 alkanoyl, substituted Or unsubstituted 6-14 membered aryl group, substituted or unsubstituted 3-14 membered heterocyclic group, substituted or unsubstituted 7-12 membered bridged ring group, phenyl substituted C 1-10 alkyl group, substituted or Unsubstituted sulfonyl, substituted or unsubstituted benzoyl, indole-3-(CH 2 ) n -C(O)-, where n is an integer between 0-4;
  • R 4 is hydrogen, C 1-10 alkyl, C 3-14 cycloalkyl, C 2-10 alkanoyl, C 2-12 alkenyl or polyalkenyl, C 2-12 alkanoyl or polyalkenoyl, substituted Or unsubstituted sulfonyl, substituted or unsubstituted 6-14 membered aryl group, substituted or unsubstituted 3-14 membered heterocyclic group, substituted or unsubstituted 7-12 membered bridge ring group.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, which:
  • R 1 is hydrogen, C 1-10 alkyl, C 3-14 cycloalkyl, C 2-12 alkenyl or polyalkenyl, C 2-12 alkenoyl or polyalkenoyl, C 2-12 alkanoyl, substituted Or an unsubstituted 6-14 membered aryl group, a substituted or unsubstituted 3-14 membered heterocyclic group, a substituted or unsubstituted 7-12 membered bridged ring group;
  • R 3 is hydrogen, C 1-10 alkyl, C 3-14 cycloalkyl, C 2-12 alkenyl or polyalkenyl, C 2-12 alkenoyl or polyalkenoyl, C 2-12 alkanoyl, substituted Or unsubstituted 6-14 membered aryl group, substituted or unsubstituted 3-14 membered heterocyclic group, substituted or unsubstituted 7-12 membered bridged ring group.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: X is -CH 2 -or -C(O)-.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 1 is hydrogen, C 3-10 alkyl, C 4-12 dienyl, phenyl substituted C 1-4 alkyl or indole-3-(CH 2 ) n -C (O)-, where n is an integer between 0-4; C 4- 12 dienyl.
  • R 1 is hydrogen, C 6-10 alkyl, C 8-12 dienyl, phenyl substituted C 1-3 alkyl, or indole-3-(CH 2 ) n -C(O)-, Where n is an integer between 0-4;
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where R 1 is hydrogen, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, Benzyl, phenylethyl, phenyl-n-propyl, phenyl-n-butyl, indole-3-C(O)-, indole-3-CH 2 -C(O)-, indole-3- (CH 2 ) 2 -C(O)-, indole-3-(CH 2 ) 3 -C(O)- or indole-3-(CH 2 ) 4 -C(O)-.
  • R 1 is hydrogen, n-hexyl, n-heptyl, n-octyl, n-non
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where R 1 is hydrogen, -CH 2 (CH 2 ) 6 CH 3 or
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where R 1 is hydrogen.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein R 1 is n-hexyl or n-heptyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where R 1 is n-octyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein R 1 is n-nonyl or n-decyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where R 1 is
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein R 1 is benzyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein R 1 is phenylethyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein R 1 is phenyl n-propyl or phenyl n-butyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein R 1 is indole-3-C(O)-.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein R 1 is indole-3-CH 2 -C(O)-.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein R 1 is indole-3-(CH 2 ) 2 -C(O)-.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein R 1 is indole-3-(CH 2 ) 3 -C(O)- or indole-3-(CH 2 ) 4 -C(O)-.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is hydrogen, C 1-4 alkyl substituted sulfonyl, C 1-4 alkyl-phenyl substituted sulfonyl, C 4-12 dienyl acyl, one or more Methoxy substituted benzoyl, phenyl substituted C 1-4 alkyl, C 3-10 alkyl, C 2-12 alkanoyl, C 3-6 cycloalkyl, or indole-3-( CH 2 ) n -C(O)-, where n is an integer between 0-4.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is hydrogen, C 1-3 alkyl substituted sulfonyl, C 1-2 alkyl-phenyl substituted sulfonyl, C 8-12 dienyl acyl, one or more Methoxy substituted benzoyl, phenyl substituted C 1-3 alkyl, C 6-10 alkyl, C 6-12 alkanoyl, C 3-4 cycloalkyl, or indole-3-( CH 2 ) n -C(O)-, where n is an integer between 0-4.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is hydrogen, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, p-toluenesulfonyl, p-ethylbenzenesulfonyl, p-n-propylbenzenesulfonamide , P-methoxybenzoyl, 3,4-dimethoxybenzoyl, 3,4,5-trimethoxybenzoyl, undecanoyl, decanoyl, nonanoyl, octanoyl, heptanoyl, Hexanoyl, valeryl, butyryl, benzyl, phenylethyl, phenyl n
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R 3 is hydrogen, Cyclopropyl, -CH 2 (CH 2 ) 6 CH 3 or -CH 2 (CH 2 ) 4 CH 3 .
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R 3 is hydrogen.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is methylsulfonyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is ethylsulfonyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is propylsulfonyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is butylsulfonyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is p-toluenesulfonyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is p-ethylbenzenesulfonyl or p-n-propylbenzenesulfonamide.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R 3 is
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is p-methoxybenzoyl or 3,4-dimethoxybenzoyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is 3,4,5-trimethoxybenzoyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is undecanoyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is decanoyl, nonanoyl or octanoyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is heptanoyl or hexanoyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 3 is valeryl or butyryl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R 3 is benzyl, phenylethyl, phenyl n-propyl, phenyl n-butyl, cyclopropyl, cyclobutyl, n-hexyl, n-heptyl, n-octyl, n Nonyl, n-decyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 4 is hydrogen, C 4-12 dienyl, C 4-12 dienyl acyl, C 1-4 alkyl substituted sulfonyl, C 2-10 alkanoyl, C 3- 10 alkyl, C 3-6 cycloalkyl, C 1-4 alkyl-phenyl substituted sulfonyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 4 is hydrogen, C 8-12 dienyl, C 8-12 dienyl acyl, C 1-3 alkyl substituted sulfonyl, C 1-2 alkyl-phenyl substituted Sulfonyl, C 6-10 alkyl, C 3-4 cycloalkyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 4 is hydrogen, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, p-toluenesulfonyl, p-ethylbenzenesulfonyl, p-n-propylbenzenesulfonamide , N-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, cyclopropyl, cyclobutyl,
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R 4 is hydrogen, Cyclopropyl, -CH 2 (CH 2 ) 6 CH 3 or -CH 2 (CH 2 ) 4 CH 3 .
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R 4 is hydrogen.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 4 is methylsulfonyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 4 is ethylsulfonyl or propylsulfonyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 4 is butylsulfonyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 4 is p-toluenesulfonyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 4 is p-ethylbenzenesulfonyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R 4 is p-n-propylbenzenesulfonamide.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 4 is n-hexyl or n-heptyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 4 is n-octyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 4 is n-nonyl or n-decyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 4 is cyclopropyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 4 is cyclobutyl.
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R 4 is
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R 4 is
  • the compound represented by general formula I described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, which:
  • R 1 is hydrogen, -CH 2 (CH 2 ) 6 CH 3 ,
  • X is -CH 2 -or -C(O)-;
  • R 4 is hydrogen, or
  • R 3 is hydrogen, -CH 2 (CH 2 ) 4 CH 3 , -CH 2 (CH 2 ) 6 CH 3 ,
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein the compound is represented by formula II,
  • R 5 is hydrogen, C 1-6 alkyl, C 3-14 cycloalkyl, 6-14 membered aryl, 3-14 membered heterocyclyl;
  • R 6 is hydrogen, C 1-6 alkyl, C 3-14 cycloalkyl, 6-14 membered aryl, 3-14 membered heterocyclyl,
  • R 7 is hydrogen or substituted or unsubstituted sulfonyl.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 5 is hydrogen or C 1-4 alkyl.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 6 is hydrogen, C 1-4 alkyl,
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 7 is hydrogen, C 1-4 alkyl-substituted sulfonyl or C 1-4 alkyl-phenyl-substituted sulfonyl.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, which:
  • R 5 is hydrogen or C 1-4 alkyl
  • R 6 is hydrogen, C 1-4 alkyl
  • R 7 is hydrogen, C 1-4 alkyl-substituted sulfonyl or C 1-4 alkyl-phenyl-substituted sulfonyl.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 5 is hydrogen, methyl, ethyl, n-propyl or isopropyl.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 5 is hydrogen.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 5 is methyl or ethyl.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 5 is n-propyl or isopropyl.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 6 is hydrogen, methyl, ethyl, n-propyl, isopropyl,
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R 6 is hydrogen.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 6 is methyl or ethyl.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R 6 is n-propyl or isopropyl.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R 6 is
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, where: R 6 is
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 7 is hydrogen, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, p-toluenesulfonyl, p-ethylbenzenesulfonyl or p-n-propylbenzenesulfonamide .
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 7 is hydrogen.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 7 is methylsulfonyl.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 7 is ethylsulfonyl or propylsulfonyl.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 7 is butylsulfonyl.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 7 is p-toluenesulfonyl.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein: R 7 is p-ethylbenzenesulfonyl or p-n-propylbenzenesulfonamide.
  • the compound represented by the general formula II described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, which:
  • R 5 is hydrogen
  • R 6 is hydrogen
  • R 7 is hydrogen
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein the compound is selected from:
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein the compound is represented by formula I',
  • R 1 is hydrogen, or C 1-10 alkyl, C 3-14 cycloalkyl, C 2-12 alkenyl or polyalkenyl, C 2-12 alkanoyl or polyalkenoyl, C 2-10 alkanoyl , Substituted or unsubstituted 6-14 membered aryl group, substituted or unsubstituted 3-14 membered heterocyclic group, substituted or unsubstituted 7-12 membered bridged ring group;
  • R 2 is hydrogen or oxygen, or C 1-6 alkyl
  • R 3 is hydrogen, or C 1-10 alkyl, C 3-14 cycloalkyl, C 2-12 alkenyl or polyalkenyl, C 2-12 alkenyl or polyalkenyl, C 2-10 alkanoyl , Substituted or unsubstituted 6-14 membered aryl group, substituted or unsubstituted 3-14 membered heterocyclic group, substituted or unsubstituted 7-12 membered bridged ring group;
  • R 4 is hydrogen, or C 1-10 alkyl, C 3-14 cycloalkyl, C 2-10 alkanoyl, C 2-12 alkenyl or polyalkenyl, C 2-12 alkanoyl or polyalkenoyl , Substituted or unsubstituted sulfonyl, substituted or unsubstituted 6-14 membered aryl group, substituted or unsubstituted 3-14 membered heterocyclic group, substituted or unsubstituted 7-12 membered bridge ring group.
  • the compound represented by the general formula A described herein its pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, solvates or Its prodrug, wherein the compound is represented by formula II',
  • R 5 is hydrogen, or C 1-6 alkyl, C 3-14 cycloalkyl, 6-14 membered aryl, 3-14 membered heterocyclyl;
  • R 6 is hydrogen, or C 1-6 alkyl, C 3-14 cycloalkyl, 6-14 membered aryl, 3-14 membered heterocyclyl,
  • R 7 is hydrogen, or substituted or unsubstituted sulfonyl.
  • R 1 is hydrogen, or -CH 2 (CH 2 ) 6 CH 3 ,
  • R 2 is hydrogen or oxygen
  • R 3 is hydrogen, or
  • R 4 is hydrogen, or -CH 2 (CH 2 ) 4 CH 3 , -CH 2 (CH 2 ) 6 CH 3 ,
  • R 5 is hydrogen
  • R 6 is hydrogen, or
  • R 7 is hydrogen, or
  • the present application also provides a pharmaceutically acceptable salt of the ethylenediamine compound represented by the above formula A, formula I, formula II, formula I'or formula II', the salt is preferably
  • the conventional inorganic acid salts of the ethylenediamine compounds such as hydrochloride, sulfate, phosphate and organic acid salts, such as methanesulfonate, trifluoromethanesulfonate, acetate, trifluoroacetic acid
  • One of the salt and the benzoate salt is preferably the hydrochloride salt.
  • the ethylenediamine compounds represented by Formula A, Formula I, Formula II, Formula I'or Formula II' described in the present application are pharmaceutically acceptable salts, stereoisomers, tautomers or isomers
  • the body mixture, its hydrates, its solvates or its prodrugs have potential inhibitory activity against drug-resistant tubercle bacillus, so that such compounds can be used as active ingredients for the treatment of drug-resistant tubercle bacillus.
  • ethylenediamine compounds represented by Formula A, Formula I, Formula II, Formula I'or Formula II' their pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, which
  • the use of hydrates, solvates or prodrugs thereof in the preparation of drugs for the treatment of drug-resistant Mycobacterium tuberculosis also falls within the scope of protection of this application.
  • the second aspect of the present application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by A, formula I, formula II, formula I'or formula II' described herein, pharmaceutically acceptable salts and stereoisomers thereof , Tautomers or isomer mixtures, hydrates, solvates or prodrugs thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.
  • the third aspect of the present application provides the compounds represented by Formula I and Formula II described herein, pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates thereof, and solvates thereof
  • the use of the substance or its prodrug to inhibit Mycobacterium tuberculosis eg drug-resistant Mycobacterium tuberculosis.
  • the fourth aspect of the present application provides the compounds of formula A, formula I, formula II, formula I'or formula II' described in the present application, which are pharmaceutically acceptable salts, stereoisomers, tautomers or isomeric Use of a structur mixture, its hydrate, its solvate, or its prodrug in the preparation of a medicament for inhibiting the growth or reproduction of Mycobacterium tuberculosis (eg, drug-resistant tuberculosis).
  • Mycobacterium tuberculosis eg, drug-resistant tuberculosis
  • a fifth aspect of the present application provides a compound represented by Formula A, Formula I, Formula II, Formula I'or Formula II' described herein, which is a pharmaceutically acceptable salt, stereoisomer, tautomer or isomeric Use of a structur mixture, its hydrate, its solvate or its prodrug in the preparation of a medicament for treating tuberculosis.
  • the sixth aspect of the present application provides the compounds of formula A, formula I, formula II, formula I'or formula II' described in the present application, which are pharmaceutically acceptable salts, stereoisomers, tautomers or isomeric
  • the structur mixture, its hydrate, its solvate or its prodrug, is used to inhibit the growth or reproduction of Mycobacterium tuberculosis (eg drug-resistant Mycobacterium tuberculosis) or to treat tuberculosis.
  • a seventh aspect of the present application provides a method of treating tuberculosis, comprising administering to a subject in need thereof a therapeutically effective amount of at least one of Formula A, Formula I, Formula II, Formula I'or Formula II' described herein Compounds, their pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, their hydrates, their solvates or their prodrugs.
  • An eighth aspect of the present application provides a method for inhibiting the growth or reproduction of Mycobacterium tuberculosis (such as drug-resistant Mycobacterium tuberculosis) in vivo or in vitro, which comprises combining the Mycobacterium tuberculosis (such as drug-resistant Mycobacterium tuberculosis) with A.
  • Mycobacterium tuberculosis such as drug-resistant Mycobacterium tuberculosis
  • A Compounds represented by Formula I, Formula II, Formula I'or Formula II', pharmaceutically acceptable salts, stereoisomers, tautomers or isomer mixtures, hydrates, and solvates thereof Or its prodrug contact.
  • the compounds described in this application can be prepared by general chemical synthesis methods.
  • R a when R b is hydrogen, X is -CH 2 -, and R d is hydrogen, the compound described in this application can be prepared by the following method,
  • N-adamantan-2-yl-ethane-1,2-diamine is reacted with a compound represented by formula i to obtain a compound represented by formula I-1, wherein Hal is halogen, such as Cl or Br, and the definition of R c As described in this application.
  • N-adamantan-2-yl-ethane-1,2-diamine is reacted with a compound represented by formula ii to obtain a compound represented by formula I-2, wherein Hal is halogen, such as Cl or Br, and the definition of R b As described in this application.
  • R a and R b are both hydrogen
  • X is -CH 2 -
  • R c is
  • Rd is a substituted or unsubstituted sulfonyl group
  • N-geranyl-ethane-1,2-diamine is reacted with a compound represented by formula iii to obtain a compound represented by formula II-1, wherein Hal is a halogen, such as Cl or Br.
  • R a when R a is R b is hydrogen, X is -CH 2 -, R c is When R d is hydrogen, the compound described in the application can be prepared by the following method,
  • N-geranyl-2-yl-ethane-1,2-diamine is reacted with dipyridone or 3-benzoylpyridine to obtain the target compound.
  • R a is X is -CH 2 -
  • R c is
  • R b is hydrogen, C 1-10 alkyl, phenyl substituted C 1-6 alkyl or indole-3-(CH 2 ) n -C( O)-, where n is an integer between 0-4;
  • Rd is C 1-10 alkyl, C 2-12 alkenyl or polyalkenyl, C 2-12 alkenoyl or polyalkenyl, C 2- 12 alkanoyl, phenyl substituted C 1-10 alkyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted benzoyl, indole-3-(CH 2 ) n -C(O)-, wherein n is an integer between 0-4; Y is halogen (such as Cl or Br) or hydroxyl; Z is defined the same as R b or Rd .
  • the compounds of Formula A, Formula I, Formula II, Formula I'or Formula II' described herein are as follows:
  • the “/” in the melting point column indicates that the compound is liquid at room temperature, or is obtained by solidification under refrigeration, and melting point data cannot be obtained.
  • C 1-10 alkyl refers to a linear or branched alkyl group having 1-10 carbon atoms, such as C 3-10 alkyl, C 6-10 alkyl, C 1-2 alkyl Group, C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl, C 10 alkyl base,.
  • Specific examples include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl , N-nonyl, n-decyl, etc.
  • C 3-14 cycloalkyl refers to a saturated cyclic hydrocarbon group having 3 to 14 carbon atoms and having a monocyclic ring or a bicyclic ring or multiple condensed rings, for example, having 3-4, 5-8 , 3-6 or 5-6 carbon atoms.
  • C 3-14 cycloalkyl include, but are not limited to, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl Group, 2-methylcyclopentyl, 2-methylcyclooctyl, etc.; bicyclic structures such as bicyclo[2.2.1]heptyl and the like.
  • 3-14 membered aryl refers to an unsaturated aromatic carbocyclic group of 6-14 carbon atoms having a single ring or two or more fused rings.
  • the aryl group has, for example, 5-8 or 5-6 carbon atoms.
  • Typical examples of "C 6-14 aryl” include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.
  • the term "3-14 membered heterocyclyl” refers to a saturated group containing at least one heteroatom (eg, containing 1, 2, 3, 4, or 5) and having 3-14 ring atoms Or a partially saturated and non-aromatic monocyclic or bicyclic or multiple fused ring cyclic group, the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom.
  • the "3-14 membered heterocyclic group” may be oxo or thio.
  • the "3-14 membered heterocyclic group” described in this application contains 1-2 heteroatoms, such as 1 nitrogen atom, oxygen atom or sulfur atom, or 1 nitrogen atom and 1 oxygen atom.
  • the “3-14 membered heterocyclic group” such as “4-10 membered heterocyclic group”, “4-8 membered heterocyclic group”, “4-6 membered heterocyclic group”, “4-7 membered heterocyclic group” ", "5-6 membered heterocyclic group”, “4-6 membered saturated heterocyclic group”, “5-6 membered saturated heterocyclic group”, “4-8 membered oxygen-containing heterocyclic group”, "4-6 Element oxygen-containing heterocyclic group", “5-6 member oxygen-containing heterocyclic group”, “4-6 member saturated oxygen-containing heterocyclic group”, “4-10 member nitrogen-containing heterocyclic group”, “4-7 member "Nitrogen-containing heterocyclic group”, “4-8 membered nitrogen-containing heterocyclic group”, "5-6 membered nitrogen-containing heterocyclic group”, “5-6 membered saturated nitrogen-containing heterocyclic group", etc.
  • 3-14 membered heterocyclic group include, but are not limited to: azetidine, 1,4-dioxanyl, 1,3-dioxanyl, 1, 3-dioxolyl, 1,4-dioxanyl, dihydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazole Alkyl, 4,5-dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, piperazinyl, thiazinyl, piperidinyl, morpholinyl, etc.
  • 7-12 membered bridged ring group refers to a ring system group having 7-12 ring atoms formed by two or more ring structures sharing two atoms that are not directly connected to each other.
  • C 2-12 alkanoyl refers to “alkyl-C(O)-” and the group has 2-12 carbon atoms.
  • alkenyl refers to branched and unbranched unsaturated hydrocarbon groups containing at least one double bond.
  • polyalkenyl refers to a branched and unbranched unsaturated hydrocarbon group containing at least two double bonds.
  • C 2-12 alkenyl refers to an alkenyl group having 2-12 carbon atoms, such as vinyl, 1-methyl-1-vinyl, 2,2-dimethyl-1- Vinyl, 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl Alkenyl, 3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl and the like.
  • C 2-12 polyalkenyl refers to a polyalkenyl group having 2 to 12 carbon atoms, for example
  • C 2-12 alkenoyl refers to "alkenyl-C(O)-", and the group has 2-12 carbon atoms.
  • C 2-12 polyenoyl refers to "polyalkenyl-C(O)-", and the group has 2-12 carbon atoms, for example
  • the pharmaceutical composition described herein can be administered in any of the following ways: oral, spray inhalation, rectal, nasal, buccal, vaginal, topical, parenteral, such as subcutaneous, intravenous , Intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or by means of an explant reservoir.
  • the compounds described herein can be made into any orally acceptable formulation, including but not limited to tablets, capsules, aqueous solutions, or aqueous suspensions.
  • the carriers generally used for tablets include lactose and corn starch, and lubricants such as magnesium stearate can also be added.
  • Diluents commonly used in capsule formulations include lactose and dried corn starch.
  • Aqueous suspension formulations are usually used by mixing the active ingredient with suitable emulsifiers and suspending agents. If necessary, some sweeteners, flavoring agents or coloring agents may be added to the above oral preparation forms.
  • the compounds described herein can generally be prepared in the form of suppositories, which are prepared by mixing the drug with a suitable non-irritating excipient.
  • the excipient assumes a solid state at room temperature, and melts at the rectal temperature to release the drug.
  • excipients include cocoa butter, beeswax and polyethylene glycol.
  • the compounds described in this application can be formulated as a micronized suspension or solution.
  • the carrier used is sterile isotonic saline with a certain pH and can be added with or without preservatives such as chlorine Benzyl alkoxide.
  • the compound can also be prepared in the form of an ointment such as vaseline ointment.
  • the compounds described herein can be formulated in the form of suitable ointments, lotions or creams, in which the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers that can be used here for ointments include but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include but are not limited to: Mineral oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenyl aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds described in the present application can be prepared as rectal suppository formulations or suitable enema formulations as described above, and topical transdermal patches can also be used.
  • the compounds described herein can also be administered in the form of sterile injectable preparations, including sterile injectable water or oil suspensions, or sterile injectable solutions.
  • usable carriers and solvents include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized non-volatile oils can also be used as solvents or suspending media, such as monoglycerides or diglycerides.
  • therapeutically effective amount refers to an amount that is sufficient to treat or prevent a patient's disease but is sufficiently low to avoid serious side effects (at a reasonable benefit/risk ratio) within a reasonable medical judgment.
  • the therapeutically effective amount of the compound will depend on the specific compound selected (e.g., considering the potency, effectiveness, and half-life of the compound), the route of administration selected, the disease being treated, the severity of the disease being treated, the patient's Factors such as age, size, weight and physical disease, medical history of the patient being treated, duration of treatment, nature of concurrent therapy, desired therapeutic effect, etc. change, but can still be routinely determined by those skilled in the art.
  • the specific dosage and method of use of the compound described in this application for different patients depends on many factors, including the patient's age, weight, gender, natural health status, nutritional status, active strength of the compound, time taken, metabolic rate , The severity of the illness and the subjective judgment of the treating physician.
  • a dose between 0.01 and 100 mg/kg body weight/day.
  • 3,7-Dimethyl-oct-2,6-dienyl acid chloride is obtained by acylation of 3,7-dimethyl-oct-2,6-dienoic acid with oxalyl chloride, 1.5 times the amount The oxalyl chloride is added dropwise to 3,7-dimethyl-oct-2,6-dienoic acid. After the reaction is complete, the reaction liquid is distilled off, and the resulting solid can be directly used in the next reaction.
  • Example 3 Using 1-bromohexane as the raw material instead of 1-bromooctane, the synthesis procedure of Example 3 was repeated. After separation and purification, the target product XHJ-5-5 was obtained by salt formation with hydrochloric acid ether, yield 18.0%, mp212-216°C.
  • Example 3 Using geranyl chloride as the raw material instead of 1-bromooctane, the synthesis steps of Example 3 were repeated, and the isolated product included the positive drug SQ109 and the target product XHJ-3-45, mp102-104°C.
  • 1 HNMR 400 MHz, CDCl 3 ), ⁇ : 5.30 to 5.34 (t, 1H), 5.04 to 5.07 (t, 1H), 3.48 to 3.50 (d, 2H), 3.11 (s, 4H), 3.00 (s, 1H ), 2.01 to 2.09 (m, 8H), 1.89 to 1.92 (t, 4H), 1.68 to 1.77 (m, 10H), 1.60 to 1.64 (m, 3H).
  • Example 7 Using p-toluenesulfonyl chloride as the raw material instead of ethylsulfonyl chloride, the synthesis procedure of Example 7 was repeated to isolate and purify N-geranyl-N-(2-aminoethyl)-p-toluenesulfonamide as a pale yellow oil.
  • the ether forms a salt to obtain the target product XHJ-2-45, the yield is 18.2%, mp134-137°C.
  • Example 11 Using p-toluenesulfonyl chloride as the raw material instead of ethylsulfonyl chloride, the synthesis steps of Example 11 were repeated, and the pale yellow oil was isolated and purified to form a salt with diethyl ether hydrochloride to obtain a white solid, namely the target compound XHJ-3-3, mp179-182°C 1 HNMR (400 MHz, CDCl 3 ), ⁇ : 7.706 to 7.727 (d, 2H), 7.266 to 7.297 (t, 2H), 5.003 to 5.010 (t, 2H), 3.843 to 3.860 (d, 2H), 3.189 to 3.222 (t, 2H), 2.734 ⁇ 2.767(t, 2H), 2.666(s, 1H), 2.417(s, 3H), 1.912 ⁇ 2.025(m, 6H), 1.762 ⁇ 1.841(m, 6H), 1.668 ⁇ 1.698 (d, 7H), 1.575-1.610
  • Example 11 Using 3,7-dimethyl-oct-2,6-dienyl chloride as the raw material instead of ethylsulfonyl chloride, the synthesis steps of Example 11 were repeated to isolate and purify a light yellow oil, namely the target compound XHJ-3-11 .
  • 1 HNMR 400 MHz, CDCl 3 ), ⁇ : 5.79 (s, 1H), 5.051 to 5.064 (t, 3H), 3.959 to 3.975 (d, 2H), 3.645 to 3.655 (t, 2H), 3.093 (s, 2H ), 1.899 to 2.146 (t, 19H), 1.572 to 1.745 (m, 21H), 1.202 to 1.226 (d, 1H).
  • Example 14 Using 3,4,5-trimethoxybenzoic acid as the raw material instead of 3-indolepropionic acid, the synthesis steps of Example 14 were repeated, and a light yellow oil was isolated and purified, and a light yellow solid was obtained by freeze solidification, namely the target compound XHJ-3 -29.
  • Example 14 Using undecanoic acid as the raw material instead of 3-indolepropionic acid, the synthesis procedure of Example 14 was repeated, and the light yellow oil was isolated and purified, namely the target compound XHJ-3-31.
  • 1 HNMR 400 MHz, CDCl 3 ), ⁇ : 5.06 to 5.10 (m, 2H), 4.02 to 4.03 (d, 1H), 4.92 to 4.94 (d, 1H), 3.44 to 3.47 (t, 1H), 3.34 to 3.37 (t, 1H), 3.72 to 3.77 (m, 3H), 2.36 to 2.40 (t, 1H), 2.27 to 2.31 (t, 1H), 1.59 to 2.08 (m, 30H), 1.25 to 1.29 (m, 16H) , 0.86 ⁇ 0.89 (t, 3H).
  • Example 17 Using benzyl bromide as the raw material instead of 3-indolecarboxyl chloride, the synthesis procedure of Example 17 was repeated, and a pale yellow oil was isolated and purified, and freeze-solidified to obtain the target compound XHJ-4-11.
  • Example 17 Using 1-bromooctane as the raw material instead of 3-indolecarboxyl chloride, the synthesis procedure of Example 17 was repeated, and a pale yellow oil was isolated and purified, namely the target compound XHJ-4-15.
  • 1 HNMR 400MHz, CDCl 3 ), ⁇ : 5.24 ⁇ 5.25(t, 1H), 5.09 ⁇ 5.10(t, 1H), 3.05 ⁇ 3.06(d, 2H), 2.63(s, 2H), 2.40 ⁇ 2.52(d , 2H), 1.95 to 2.06 (m, 8H), 1.60 to 1.80 (m, 16H), 1.27 to 1.40 (m, 25H), 0.86 to 0.90 (t, 6H).
  • the Microplate Alamar Blue Assay (MABA) method was used to determine the minimum inhibitory concentration (MIC) of the compound against the Mycobacterium tuberculosis standard strain H 37 Rv. for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrobial Agents Chemother, 1997, 1004-1009).
  • the test compounds are the compounds prepared in this application 1-20, as well as the positive control compounds rifampin (RFP) and isoniazid (isoniazid, INH).
  • mice Sterile 96-well plate (Falcon3072; Becton Dickinson, Lincoln Park, NJ), the test compound is dissolved in dimethyl sulfoxide to prepare an initial solution with a concentration of 5mg/ml, and the highest concentration well is added with 199 ⁇ l 7H9 liquid culture Base (Difco), 1 ⁇ l of the initial compound solution, mix evenly, and the concentration of the remaining wells is sequentially diluted 2 times, the volume of the test compound solution is 200 ⁇ l, the final concentration of the test compound in each well is: 25, 12.5, 6.25, 3.125, 1.56, 0.78, 0.39, 0.2, 0.1, 0.05, 0.025, 0.0125 ⁇ g/ml.
  • the culture of Mycobacterium tuberculosis H 37 Rv (strain preserved by Beijing Tuberculosis and Thoracic Tumor Research Institute) cultured for 2 to 3 weeks was prepared as a bacterial suspension and inoculated into 0.05% Tween 80 and 10% ADC (albumin-glucose) -Catalase, albumin-dextrose-catalase (ADC) in 7H9 liquid culture medium, static culture at 37°C for 1 to 2 weeks, when grown to a turbidity of McFarland 1 (equivalent to 10 7 CFU/ml), by volume After a 1:20 dilution, 100 ⁇ l was added to each well, and the final concentration of bacterial solution in each well was approximately 10 6 CFU/ml.
  • ADC albumin-glucose
  • ADC albumin-dextrose-catalase
  • MABA Microplate Alamar Blue Assay

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Abstract

本发明属于药物化学领域，涉及式A所示的乙二胺化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，及其用于治疗结核病的用途。（A）

Description

乙二胺类化合物及其用途
本申请是以CN申请号为201811599918.7，申请日为2018年12月26日的申请为基础，并主张其优先权，该CN申请的公开内容在此作为整体引入本申请中。
技术领域
本发明属于药物化学领域，涉及乙二胺类化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，及其用于治疗结核病的用途。
背景技术
结核病(tuberculosis,TB)是由结核杆菌引起的慢性传染病，根据世界卫生组织(WHO)估计全球每年约有200万人死于结核病。虽然现有抗结核药物在很大程度上遏制了结核病的蔓延，但是它们的治疗周期过长，患者依从性差，而且随着多耐药结核病和泛耐药结核病发病率的上升，以及HIV/AIDS并发TB而导致TB疫情再度上升，使得TB成为全球关注的重大公共卫生问题和社会问题。
前期的动物实验和临床研究均表明SQ109对药物敏感的结核杆菌，多药耐药和泛药耐药的结核杆菌均有很好的疗效，并在2007年被FDA和欧洲药品管理局作为“罕用药物”进行管理，用于耐药结核病的治疗。机制研究显示SQ109作用于结核分枝杆菌MmpL3跨膜蛋白，抑制了TDM的生成，使得霉菌酸酯与细胞壁上的阿拉伯半乳糖链接失败，从而抑制结核杆菌细胞壁的合成。
发明内容
本申请基于SQ109设计合成了一系列乙二胺类治疗结核病药物的化合物，并对其体外抗结核活性进行了评价，显示出较好的体外抑制活性。本发明的目的在于提供一种乙二胺类化合物，其药学上可接受的盐，及其在治疗耐药性结核杆菌中的应用。
本发明的第一方面提供通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，
Figure PCTCN2019128639-appb-000001
其中：R a为氢、C 1-6烷基、C 3-14环烷基、6-14元芳基、3-14元杂环基、
Figure PCTCN2019128639-appb-000002
Figure PCTCN2019128639-appb-000003
R b为氢、C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-10烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基、苯基取代的C 1-6烷基或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数；
X为-CH 2-、-CHR 2-或-C(O)-，其中R 2为C 1-6烷基；
R c为氢、C 1-10烷基、C 3-14环烷基、C 2-10烷酰基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、取代或未取代的磺酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基；
R d为氢、C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-12烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基、苯基取代的C 1-10烷基、取代或未取代的磺酰基、取代或未取代的苯甲酰基、吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：
R a为氢、
Figure PCTCN2019128639-appb-000004
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R a为氢。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：
R a为
Figure PCTCN2019128639-appb-000005
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：
R a为
Figure PCTCN2019128639-appb-000006
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互 变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：
R a为
Figure PCTCN2019128639-appb-000007
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R b为氢、C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-12烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R b为氢、C 3-10烷基、C 4-12二烯基、苯基取代的C 1-4烷基或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R b为氢、C 6-10烷基、C 8-12二烯基、苯基取代的C 1-3烷基或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R b为氢、正己基、正庚基、正辛基、正壬基、正癸基、
Figure PCTCN2019128639-appb-000008
苄基、苯基乙基、苯基正丙基、苯基正丁基、吲哚-3-C(O)-、吲哚-3-CH 2-C(O)-、吲哚-3-(CH 2) 2-C(O)-、吲哚-3-(CH 2) 3-C(O)-或吲哚-3-(CH 2) 4-C(O)-。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R b为正己基、正庚基、正辛基、正壬基或正癸基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R b为
Figure PCTCN2019128639-appb-000009
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R b为苄基或苯基乙基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R b为苯基正丙基或苯基正丁基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R b为吲哚-3-C(O)-。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R b为吲哚-3-CH 2-C(O)-、吲哚-3-(CH 2) 2-C(O)-。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R b为吲哚-3-(CH 2) 3-C(O)-或吲哚-3-(CH 2) 4-C(O)-。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R b为氢、
Figure PCTCN2019128639-appb-000010
-CH 2(CH 2) 6CH 3、或
Figure PCTCN2019128639-appb-000011
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：X为-CH 2-或-C(O)-。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：X为-CH 2-。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为氢、C 4-12二烯基、C 4-12二烯基酰基、C 1-4烷基取代的磺酰基、C 2-10烷酰基、C 3-10烷基、C 3-6环烷基、C 1-4烷基-苯基取代的磺酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为氢、C 8-12二烯基、C 8-12二烯基酰基、C 1-3烷基取代的磺酰基、C 1-2烷基-苯基取代的磺酰基、C 6-10烷基、C 3-4环烷基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为氢、甲基磺酰基、乙基磺酰基、丙基磺酰基、丁基磺酰基、对甲苯磺酰基、对乙苯磺酰基、对正丙基苯磺酰胺、正己基、正庚基、正辛基、正壬基、正癸基、环丙基、环丁基、
Figure PCTCN2019128639-appb-000012
Figure PCTCN2019128639-appb-000013
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为氢。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为甲基磺酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互 变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为乙基磺酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为丙基磺酰基或丁基磺酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为对甲苯磺酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为对乙苯磺酰基或对正丙基苯磺酰胺。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为正己基或正辛基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为正庚基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为正壬基或正癸基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为环丙基、环丁基、
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为
Figure PCTCN2019128639-appb-000014
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为
Figure PCTCN2019128639-appb-000015
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为氢、
Figure PCTCN2019128639-appb-000016
Figure PCTCN2019128639-appb-000017
环丙基、-CH 2(CH 2) 6CH 3或-CH 2(CH 2) 4CH 3。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R c为氢、
Figure PCTCN2019128639-appb-000018
-CH 2(CH 2) 6CH 3、或-CH 2(CH 2) 4CH 3。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为氢、C 1-4烷基取代的磺酰基、C 1-4烷基-苯基取代的磺酰基、C 4-12二烯基酰基、被一个或多个甲氧基取代的苯甲酰基、苯基取代的C 1-4烷基、C 3-10烷基、C 2-12烷酰基、C 3-6环烷基、或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为氢、C 1-3烷基取代的磺酰基、C 1-2烷基-苯基取代的磺酰基、C 8-12二烯基酰基、被一个或多个甲氧基取代的苯甲酰基、苯基取代的C 1-3烷基、C 6-10烷基、C 6-12烷酰基、C 3-4环烷基、或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为氢、甲基磺酰基、乙基磺酰基、丙基磺酰基、丁基磺酰基、对甲苯磺酰基、对乙苯磺酰基、对正丙基苯磺酰胺、
Figure PCTCN2019128639-appb-000019
对甲氧基苯甲酰基、3,4-二甲氧基苯甲酰基、3,4,5-三甲氧基苯甲酰基、十一烷酰基、癸酰基、壬酰基、辛酰基、庚酰基、己酰基、戊酰基、丁酰基、苄基、苯基乙基、苯基正丙基、苯基正丁基、环丙基、环丁基、正己基、正庚基、正辛基、正壬基、正癸基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为氢、
Figure PCTCN2019128639-appb-000020
Figure PCTCN2019128639-appb-000021
Figure PCTCN2019128639-appb-000022
环丙基、-CH 2(CH 2) 6CH 3或-CH 2(CH 2) 4CH 3。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互 变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为氢、
Figure PCTCN2019128639-appb-000023
Figure PCTCN2019128639-appb-000024
Figure PCTCN2019128639-appb-000025
-CH 2(CH 2) 6CH 3。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为氢。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为甲基磺酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为乙基磺酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为丙基磺酰基或丁基磺酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为对甲苯磺酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为对乙苯磺酰基或对正丙基苯磺酰胺。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为
Figure PCTCN2019128639-appb-000026
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为对甲氧基苯甲酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为3,4-二甲氧基苯甲酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为3,4,5-三甲氧 基苯甲酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为十一烷酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为癸酰基、壬酰基或辛酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为庚酰基、己酰基、戊酰基或丁酰基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为苄基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为苯基乙基或苯基正丙基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为苯基正丁基。
环丙基、环丁基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为正己基或正庚基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为正辛基或正壬基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R d为正癸基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中所述化合物如式I所示，
Figure PCTCN2019128639-appb-000027
其中：
R 1为氢、C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-10烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的 7-12元桥环基、苯基取代的C 1-6烷基或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数；
X为-CH 2-、-CHR 2-或-C(O)-，其中R 2为C 1-6烷基；
R 3为氢、C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-10烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基、苯基取代的C 1-10烷基、取代或未取代的磺酰基、取代或未取代的苯甲酰基、吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数；
R 4为氢、C 1-10烷基、C 3-14环烷基、C 2-10烷酰基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、取代或未取代的磺酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：
R 1为氢、C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-12烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基；
R 3为氢、C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-12烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：X为-CH 2-或-C(O)-。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 1为氢、C 3-10烷基、C 4-12二烯基、苯基取代的C 1-4烷基或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数；C 4- 12二烯基。
例如，R 1为氢、C 6-10烷基、C 8-12二烯基、苯基取代的C 1-3烷基或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数；
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中R 1为氢、正己基、正庚基、正辛基、正壬基、正癸基、
Figure PCTCN2019128639-appb-000028
苄基、苯基乙基、苯基正丙基、苯基正丁基、吲哚-3-C(O)-、吲哚-3-CH 2-C(O)-、吲哚-3-(CH 2) 2-C(O)-、吲哚-3-(CH 2) 3-C(O)-或吲哚-3-(CH 2) 4-C(O)-。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中R 1为氢、
Figure PCTCN2019128639-appb-000029
-CH 2(CH 2) 6CH 3或
Figure PCTCN2019128639-appb-000030
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中R 1为氢。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中R 1为正己基或正庚基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中R 1为正辛基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中R 1为正壬基或正癸基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中R 1为
Figure PCTCN2019128639-appb-000031
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中R 1为苄基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中R 1为苯基乙基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中R 1为苯基正丙基或苯基正丁基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中R 1为吲哚-3-C(O)-。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中R 1为吲哚-3-CH 2-C(O)-。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中R 1为吲哚-3-(CH 2) 2-C(O)-。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中R 1为吲哚-3-(CH 2) 3-C(O)-或吲哚-3-(CH 2) 4-C(O)-。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互 变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为氢、C 1-4烷基取代的磺酰基、C 1-4烷基-苯基取代的磺酰基、C 4-12二烯基酰基、被一个或多个甲氧基取代的苯甲酰基、苯基取代的C 1-4烷基、C 3-10烷基、C 2-12烷酰基、C 3-6环烷基、或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为氢、C 1-3烷基取代的磺酰基、C 1-2烷基-苯基取代的磺酰基、C 8-12二烯基酰基、被一个或多个甲氧基取代的苯甲酰基、苯基取代的C 1-3烷基、C 6-10烷基、C 6-12烷酰基、C 3-4环烷基、或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为氢、甲基磺酰基、乙基磺酰基、丙基磺酰基、丁基磺酰基、对甲苯磺酰基、对乙苯磺酰基、对正丙基苯磺酰胺、
Figure PCTCN2019128639-appb-000032
对甲氧基苯甲酰基、3,4-二甲氧基苯甲酰基、3,4,5-三甲氧基苯甲酰基、十一烷酰基、癸酰基、壬酰基、辛酰基、庚酰基、己酰基、戊酰基、丁酰基、苄基、苯基乙基、苯基正丙基、苯基正丁基、环丙基、环丁基、正己基、正庚基、正辛基、正壬基、正癸基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为氢、
Figure PCTCN2019128639-appb-000033
Figure PCTCN2019128639-appb-000034
Figure PCTCN2019128639-appb-000035
环丙基、-CH 2(CH 2) 6CH 3或-CH 2(CH 2) 4CH 3。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为氢。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为甲基磺酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为乙基磺酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为丙基磺酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为丁基磺酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为对甲苯磺酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为对乙苯磺酰基或对正丙基苯磺酰胺。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为
Figure PCTCN2019128639-appb-000036
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为对甲氧基苯甲酰基或3,4-二甲氧基苯甲酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为3,4,5-三甲氧基苯甲酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为十一烷酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为癸酰基、壬酰基或辛酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为庚酰基或己酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为戊酰基或丁酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 3为苄基、苯基乙基、苯基正丙基、苯基正丁基、环丙基、环丁基、正己基、正庚基、正辛基、正壬基、正癸基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为氢、C 4-12二烯基、C 4-12二烯基酰基、C 1-4烷基取代的磺酰基、C 2-10烷酰基、C 3-10烷基、C 3-6环烷基、C 1-4烷基-苯基取代的磺酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为氢、C 8-12二烯基、C 8-12二烯基酰基、C 1-3烷基取代的磺酰基、C 1-2烷基-苯基取代的磺酰基、C 6-10烷基、C 3-4环烷基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为氢、甲基磺酰基、乙基磺酰基、丙基磺酰基、丁基磺酰基、对甲苯磺酰基、对乙苯磺酰基、对正丙基苯磺酰胺、正己基、正庚基、正辛基、正壬基、正癸基、环丙基、环丁基、
Figure PCTCN2019128639-appb-000037
Figure PCTCN2019128639-appb-000038
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为氢、
Figure PCTCN2019128639-appb-000039
Figure PCTCN2019128639-appb-000040
环丙基、-CH 2(CH 2) 6CH 3或-CH 2(CH 2) 4CH 3。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为氢。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为甲基磺酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为乙基磺酰基或丙基磺酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为丁基磺酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为对甲苯磺酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为对乙苯磺酰基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为对正丙基苯磺 酰胺。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为正己基或正庚基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为正辛基、。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为正壬基或正癸基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为环丙基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为环丁基。
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为
Figure PCTCN2019128639-appb-000041
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 4为
Figure PCTCN2019128639-appb-000042
在某些实施方案中，本申请所述通式I所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：
R 1为氢、-CH 2(CH 2) 6CH 3、
Figure PCTCN2019128639-appb-000043
X为-CH 2-或-C(O)-；
R 4为氢，或者
Figure PCTCN2019128639-appb-000044
R 3为氢、-CH 2(CH 2) 4CH 3、-CH 2(CH 2) 6CH 3、
Figure PCTCN2019128639-appb-000045
Figure PCTCN2019128639-appb-000046
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中所述化合物如式II所示，
Figure PCTCN2019128639-appb-000047
其中：
R 5为氢、C 1-6烷基、C 3-14环烷基、6-14元芳基、3-14元杂环基；
R 6为氢、C 1-6烷基、C 3-14环烷基、6-14元芳基、3-14元杂环基、
Figure PCTCN2019128639-appb-000048
R 7为氢或者取代或未取代的磺酰基。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 5为氢或C 1-4烷基。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 6为氢、C 1-4烷基、
Figure PCTCN2019128639-appb-000049
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 7为氢、C 1-4烷基取代的磺酰基或C 1-4烷基-苯基取代的磺酰基。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：
R 5为氢或C 1-4烷基；
R 6为氢、C 1-4烷基、
Figure PCTCN2019128639-appb-000050
R 7为氢、C 1-4烷基取代的磺酰基或C 1-4烷基-苯基取代的磺酰基。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 5为氢、甲基、乙基、正丙基或异丙基。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 5为氢。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 5为甲基或乙基。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 5为正丙基或异丙基。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 6为氢、甲基、乙基、正丙基、异丙基、
Figure PCTCN2019128639-appb-000051
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 6为氢。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 6为甲基或乙基。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 6为正丙基或异丙基。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 6为
Figure PCTCN2019128639-appb-000052
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互 变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 6为
Figure PCTCN2019128639-appb-000053
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 7为氢、甲基磺酰基、乙基磺酰基、丙基磺酰基、丁基磺酰基、对甲苯磺酰基、对乙苯磺酰基或对正丙基苯磺酰胺。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 7为氢。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 7为甲基磺酰基。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 7为乙基磺酰基或丙基磺酰基。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 7为丁基磺酰基。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 7为对甲苯磺酰基。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：R 7为对乙苯磺酰基或对正丙基苯磺酰胺。
在某些实施方案中，本申请所述通式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：
R 5为氢；
R 6为氢、
Figure PCTCN2019128639-appb-000054
R 7为氢、
Figure PCTCN2019128639-appb-000055
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中所述化合物选自:
Figure PCTCN2019128639-appb-000056
Figure PCTCN2019128639-appb-000057
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中所述化合物如式I’所示，
Figure PCTCN2019128639-appb-000058
其中：
R 1为氢，或者为C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-10烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基；
R 2为氢或氧，或者为C 1-6烷基；
R 3为氢，或者为C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-10烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基；
R 4为氢，或者为C 1-10烷基、C 3-14环烷基、C 2-10烷酰基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、取代或未取代的磺酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基。
在某些实施方案中，本申请所述通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中所述化合物如式II’所示，
Figure PCTCN2019128639-appb-000059
其中：
R 5为氢，或者为C 1-6烷基、C 3-14环烷基、6-14元芳基、3-14元杂环基；
R 6为氢，或者为C 1-6烷基、C 3-14环烷基、6-14元芳基、3-14元杂环基、
Figure PCTCN2019128639-appb-000060
Figure PCTCN2019128639-appb-000061
R 7为氢，或者取代或未取代的磺酰基。
在某些实施方案中，本申请所述式I’中，
R 1为氢，或者-CH 2(CH 2) 6CH 3、
Figure PCTCN2019128639-appb-000062
R 2为氢或氧；
R 3为氢，或者
Figure PCTCN2019128639-appb-000063
R 4为氢，或者-CH 2(CH 2) 4CH 3、-CH 2(CH 2) 6CH 3、
Figure PCTCN2019128639-appb-000064
Figure PCTCN2019128639-appb-000065
在某些实施方案中，本申请所述式II’中，
R 5为氢；
R 6为氢，或者
Figure PCTCN2019128639-appb-000066
R 7为氢，或者
Figure PCTCN2019128639-appb-000067
在某些实施方案种，本申请还提供了具有上述式A、式I、式II、式I’或式II’所示的乙二胺类化合物的药学上可接受的盐，所述盐优选为所述乙二胺类化合物的常规无机酸盐，如盐酸盐、硫酸盐、磷酸盐及有机酸盐，如甲磺酸盐、三氟甲磺酸盐、醋酸盐、三氟乙酸盐、苯甲酸盐中的一种，优选盐酸盐。
本申请所述式A、式I、式II、式I’或式II’所示所示的乙二胺类化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，对耐药性结核杆菌具有潜在的抑制活性，使得该类化合物可作为治疗耐药性结核杆菌药物的活性成分。
所述式A、式I、式II、式I’或式II’所示的乙二胺类化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药在制备用于治疗耐药性结核杆菌药物中的应用也属于本申请的保护范围。
本申请的第二方面还提供一种药物组合物，其包含本申请所述A、式I、式II、式I’或式II’所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，以及任选的一种或多种药学上可接受的载体或赋形剂。
本申请的第三方面提供本申请所述式I和式II所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药用于抑制结核杆菌(例如耐药性结核杆菌)的用途。
本申请的第四方面提供本申请所述式A、式I、式II、式I’或式II’所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药在制备用于抑制结核杆菌(例如耐药性结核杆菌)生长或繁殖的药物中的用途。
本申请的第五方面提供本申请所述式A、式I、式II、式I’或式II’所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药在制备用于治疗结核病的药物中的用途。
本申请的第六方面提供本申请所述式A、式I、式II、式I’或式II’所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其用于抑制结核杆菌(例如耐药性结核杆菌)生长或繁殖或用于治疗结核病。
本申请的第七方面提供一种治疗结核病的方法，包括给予有需要的受试者治疗有效量的至少一种本申请所述式A、式I、式II、式I’或式II’所示化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药。
本申请的第八方面提供一种抑制结核杆菌(例如耐药性结核杆菌)在体内或体外生长或繁殖的方法，包括使所述结核杆菌(例如耐药性结核杆菌)与本申请所述式A、式I、式II、式I’或式II’所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药接触。
本申请所述的化合物可通过通用的化学合成方法制备得到。
在某些实施方案中，当R a为
Figure PCTCN2019128639-appb-000068
R b为氢，X为-CH 2-，并且R d为氢时，本申请所述化合物可以通过以下方法制备得到，
Figure PCTCN2019128639-appb-000069
使N-金刚烷-2-基-乙烷-1,2-二胺与式i所示化合物发生反应得到式I-1所示化合物，其中Hal为卤素，例如Cl或Br，R c的定义如本申请所述。
在某些实施方案中，当R a为
Figure PCTCN2019128639-appb-000070
X为-CH 2-，并且R c和R d均为氢时，本申请所述化合物可以通过以下方法制备得到，
Figure PCTCN2019128639-appb-000071
使N-金刚烷-2-基-乙烷-1,2-二胺与式ii所示化合物发生反应得到式I-2所示化合物，其中Hal为卤素，例如Cl或Br，R b的定义如本申请所述。
在某些实施方案中，当R a和R b均为氢，X为-CH 2-，R c为
Figure PCTCN2019128639-appb-000072
并且R d为取代或未取代的磺酰基时，申请所述化合物可以通过以下方法制备得到，
Figure PCTCN2019128639-appb-000073
使N-香叶基-乙烷-1,2-二胺与式iii所示化合物发生反应得到式II-1所示化合物，其中Hal为卤素，例如Cl或Br。
在某些实施方案中，当R a为
Figure PCTCN2019128639-appb-000074
R b为氢，X为-CH 2-，R c为
Figure PCTCN2019128639-appb-000075
并且R d为氢时，申请所述化合物可以通过以下方法制备得到，
Figure PCTCN2019128639-appb-000076
使N-香叶基-2-基-乙烷-1,2-二胺与二吡啶甲酮或3-苯甲酰基吡啶反应得到目标化合物。
在某些实施方案中，当R a为
Figure PCTCN2019128639-appb-000077
X为-CH 2-，R c为
Figure PCTCN2019128639-appb-000078
Figure PCTCN2019128639-appb-000079
使SQ109与式iv所示化合物反应得到目标化合物，其中R b为氢、C 1-10烷基、苯基取代的C 1-6烷基或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数；R d为C 1-10烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-12烷酰基、苯基取代的C 1-10烷基、取代或未取代的磺酰基、取代或未取代的苯甲酰基、吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数；Y为卤素(例如Cl或Br)或羟基；Z的定义与R b或R d相同。
本申请所述的化合物的具体合成示例参见本申请的实施例。
在某些实施方案中，本申请所述式A、式I、式II、式I’或式II’所示的化合物如下:
Figure PCTCN2019128639-appb-000080
Figure PCTCN2019128639-appb-000081
Figure PCTCN2019128639-appb-000082
Figure PCTCN2019128639-appb-000083
注：熔点栏中标注“/”表示该化合物常温为液态，或者为冷藏固化所得，无法获得熔点数据。
本申请所用术语“C 1-10烷基”是指具有1-10个碳原子的直链或支链烷基，例如C 3-10烷基、C 6-10烷基、C 1-2烷基、C 1烷基、C 2烷基、C 3烷基、C 4烷基、C 5烷基、C 6烷基、C 7烷基、C 8烷基、C 9烷基、C 10烷基、。具体的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基、正庚基、正辛基、正壬基、正癸基等。
本申请所用术语“C 3-14环烷基”是指具有3-14个碳原子并且具有单环或二环或多个稠 合环的饱和环状烃基，例如具有3-4，5-8，3-6或5-6个碳原子。“C 3-14环烷基”的典型实例包括但不限于单环结构，诸如环丙基，环丁基，环戊基，环己基、环庚基、环辛基，1-甲基环丙基，2-甲基环戊基，2-甲基环辛基等；二环结构，诸如二环[2.2.1]庚基等。
本申请所用术语“3-14元芳基”是指具有一个单环或两个或多个稠合环的6-14个碳原子的不饱和芳族碳环基。所述芳基例如具有5-8或5-6个碳原子。“C 6-14芳基”的典型实例包括但不限于苯基，萘基和蒽基等。
本申请所用术语“3-14元杂环基”是指至少含有一个杂原子(例如，含有1个、2个、3个、4个或5个)且环原子数为3-14个的饱和或部分饱和的且不具有芳香性的单环或二环或多个稠合环的环状基团，所述杂原子为氮原子、氧原子和/或硫原子。所述“3-14元杂环基”可以被氧代或硫代。例如，本申请所述的“3-14元杂环基”含有1-2个杂原子，例如含有1个氮原子、氧原子或硫原子，或含有1个氮原子和1个氧原子。所述“3-14元杂环基”例如“4-10元杂环基”、“4-8元杂环基”、“4-6元杂环基”、“4-7元杂环基”、“5-6元杂环基”、“4-6元饱和杂环基”、“5-6元饱和杂环基”、“4-8元含氧杂环基”、“4-6元含氧杂环基”、“5-6元含氧杂环基”、“4-6元饱和含氧杂环基”、“4-10元含氮杂环基”、“4-7元含氮杂环基”、“4-8元含氮杂环基”、“5-6元含氮杂环基”、“5-6元饱和含氮杂环基”等。“3-14元杂环基”的具体实例包括但不仅限于：氮杂环丁烷基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、二氢吡咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、哌嗪基、噻嗪基、哌啶基、吗啉基等。
本申请所用术语“7-12元桥环基”指具有7-12个环原子的由两个或两个以上环状结构彼此共用两个不直接相连的原子所形成的环系基团。
本申请所用术语“C 2-12烷酰基”是指“烷基-C(O)-”，并且该基团具有2-12个碳原子。
本申请所用术语“烯基”是指含有至少一个双键的带支链的和不带支链的不饱和烃基。
本申请所用术语“多烯基”是指含有至少两个双键的带支链的和不带支链的不饱和烃基。
本申请所用术语“C 2-12烯基”是指具有2-12个碳原子的烯基，例如为乙烯基、1-甲基-1-乙烯基、2，2-二甲基-1-乙烯基、1-丙烯基、2-丙烯基(烯丙基)、1-丁烯基、2-丁烯基、3-丁烯基、4-戊烯基、1-甲基-4-戊烯基、3-甲基-1-戊烯基、1-己烯基、2-己烯基等。
本申请所用术语“C 2-12多烯基”是指具有2-12个碳原子的多烯基，例如
Figure PCTCN2019128639-appb-000084
本申请所用术语“C 2-12烯酰基”是指“烯基-C(O)-”，并且该基团具有2-12个碳原子。
本申请所用术语“C 2-12多烯酰基”指“多烯基-C(O)-”，并且该基团具有2-12个碳原子，例如
Figure PCTCN2019128639-appb-000085
本申请中所述的化合物，若其化学名称与结构式不一致，以化合物结构式为准。
根据本申请，本本申请所述的药用组合物可以以下面的任意方式施用：口服、喷 雾吸入、直肠用药、鼻腔用药、颊部用药、阴道用药、局部用药、非肠道用药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内和颅内注射或输入、或借助一种外植储器用药。
当口服用药时，本申请所述化合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。其中，片剂一般使用的载体包括乳糖和玉米淀粉，另外也可加入润滑剂如硬质酸镁。胶囊制剂一般使用的稀释剂包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当直肠用药时，本申请所述化合物一般可制成栓剂的形式，其通过将药物与一种适宜的非刺激性赋形剂混合而制得。该赋形剂在室温下呈现固体状态，而在直肠温度下熔化释出药物。该类赋形剂包括可可脂、蜂蜡和聚乙二醇。
当局部用药时，特别是治疗局部外敷容易达到的患面或器官，如眼睛、皮肤或下肠道神经性疾病时，本申请所述化合物可根据不同的患面或器官制成不同的局部用药制剂形式，具体说明如下：
当眼部局部施用时，本申请所述化合物可配制成一种微粉化悬浮液或溶液的制剂形式，所使用载体为等渗的一定pH的无菌盐水，其中可加入也可不加防腐剂如氯化苄基烷醇盐。此外对于眼用，也可将化合物制成膏剂形式如凡士林膏。
当皮肤局部施用时，本申请所述化合物可制成适当的软膏、洗剂或霜剂制剂形式，其中活性成分悬浮或溶解于一种或多种载体中。这里软膏即可使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
当下肠道局部施用时，本申请所述化合物可制成如上所述的直肠栓剂制剂或适宜的灌肠制剂形式，另外也可使用局部透皮贴剂。
本申请所述化合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液，或无菌注射溶液。其中，可使用的载体和溶剂包括水，林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
如本文所述的，“治疗有效量”是指在合理的医学判断范围内，足以治疗或预防患者疾病但足够低地避免严重副作用(在合理的利益/风险比)的量。化合物的治疗有效量将根据所选择的具体化合物(例如考虑化合物的效力、有效性和半衰期)、所选择的给药途径、所治疗的疾病、所治疗的疾病的严重性、所治疗的患者的年龄、大小、体重和身体疾病、所治疗的患者的医疗史、治疗持续时间、并行疗法的性质、所需的治疗效果等因素发生变化，但仍可以由本领域技术人员常规确定。
另外需要指出，本申请所述化合物针对不同患者的特定使用剂量和使用方法决定于诸多因素，包括患者的年龄，体重，性别，自然健康状况，营养状况，化合物的活性强度，服用时间，代谢速率，病症的严重程度以及诊治医师的主观判断。这里优选 使用剂量介于0.01-100mg/kg体重/天。
具体实施方式
下面将结合实施例对本申请的实施方案进行详细描述，但是本领域技术人员会理解，下列实施例仅用于说明本申请，而不应视为限制本申请的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1
3,7-二甲基-辛-2,6-二烯酸[2-(金刚烷-2-基氨基)乙基]酰胺(XHJ-2-32)的制备
1)N-金刚烷-2-基-乙烷-1,2-二胺的合成
Figure PCTCN2019128639-appb-000086
22ml(0.32mol)乙二胺溶于30ml无水甲醇中，置于冰浴中搅拌溶解清澈，氮气保护下加入2.0g(0.013mol)2-金刚烷酮，得透明澄清溶液，搅拌反应2h，缓慢分批次加入0.75g(0.019mol)NaBH 4，投料毕，室温搅拌过夜。反应毕，加50ml 100ml H 2O于反应瓶中，二氯甲烷提取(100ml×2)，提取液用饱和食盐水(50ml×2)洗涤，无水Na 2SO 4干燥，减压蒸除溶剂得无色油状物2.4g，产率93％，静置，油状物固化，得白色固体。 1HNMR(400MHz，CDCl 3),δ:2.790～2.820(t，2H)、2.714(s，1H)、2.650～2.679(t，2H)、1.953～1.983(d，2H)、1.839～1.860(d，6H)、1.691～1.713(m，4H)、1.480～1.509(d，2H)、1.424(s，3H)。
2)3,7-二甲基-辛-2,6-二烯酸[2-(金刚烷-2-基氨基)乙基]酰胺(XHJ-2-32)的合成
Figure PCTCN2019128639-appb-000087
3,7-二甲基-辛-2,6-二烯基酰氯由3,7-二甲基-辛-2,6-二烯酸与草酰氯经酰化反应而得，将1.5倍量的草酰氯滴加到3,7-二甲基-辛-2,6-二烯酸中，待反应完全，蒸除反应液，所得固体即可直接用于下一步反应。
投0.35g N-金刚烷-2-基-乙烷-1,2-二胺于反应瓶中，加10ml干燥的THF溶解，加0.6g碳酸钾，冰浴下缓慢滴加0.3g 3,7-二甲基-辛-2,6-二烯基酰氯(溶于5ml干燥的THF)，滴加完毕，反应液由无色变成红棕色，搅拌反应至3,7-二甲基-辛-2,6-二烯基酰氯反应完全，加50ml H 2O于反应瓶中，二氯甲烷(100ml×2)提取，提取液用饱和食盐水(50ml×2)洗涤，无水Na 2SO 4干燥，减压浓缩后经硅胶柱(洗脱剂为二氯甲烷：甲醇：氨水(v/v/v)＝500:10:1)分离纯化得淡黄色油状物154mg，产率28％，油状物经盐酸乙醚成盐得 白色固体，mp150-164。 1HNMR(400MHz，CDCl3),δ:5.645(s，1H)、5.074(t，1H)、3.572～3.584(t，2H)、2.964～2.996(d，3H)、2.110～2.155(m，10H)、1.881(t，4H)、1.682～1.734(t，7H)、1.568～1.605(d，5H)。LC-MS，m/z(％):345.3(M +)
实施例2
N-(金刚烷-2-基)-N′-乙基磺酰基-乙烷-1,2-二胺(XHJ-3-46)的制备
Figure PCTCN2019128639-appb-000088
以乙基磺酰氯为原料代替3,7-二甲基-辛-2,6-二烯基酰氯，重复实施例1合成步骤，分离纯化得目标产物XHJ-3-46，产率：28％，Mp 172-174℃。 1HNMR(400MHz，CDCl 3),δ:3.17～3.19(t，2H)、3.04～3.10(m，2H)、2.82～2.85(t，2H)、2.72(s，1H)、1.80～1.93(m，8H)、1.68～1.72(d，2H)、1.51～1.54(d，2H)、1.36～1.40(t，3H).LC-MS，m/z(％):287.3(M +)
实施例3
N-(金刚烷-2-基)-N′-辛烷基-乙烷-1,2-二胺二盐酸盐(XHJ-5-3)的制备
以1-溴辛烷为原料代替3,7-二甲基-辛-2,6-二烯基酰氯，重复实施例1合成步骤，后处理提取时用石油醚代替二氯甲烷，分离纯化得无色油状物N-(金刚烷-2-基)-N′-辛烷基-乙烷-1,2-二胺，经盐酸乙醚成盐得目标产物XHJ-5-3，收率15.2％，mp224-226℃。 1HNMR(400MHz，CDCl 3),δ:3.44～3.48(m，5H)、3.06～3.10(t，2H)、2.24(s，2H)、2.10～2.13(d，2H)、2.00～2.03(d，2H)、1.83～1.93(m，6H)、1.72～1.78(m，4H)、1.32～1.41(m，10H)、0.88～0.92(t，3H).LC-MS，m/z(％):307.4(M +)
实施例4
N-(金刚烷-2-基)-N′-己烷基-1,2-二胺二盐酸盐(XHJ-5-5)的制备
以1-溴己烷为原料代替1-溴辛烷，重复实施例3合成步骤，分离纯化后，经盐酸乙醚成盐得目标产物XHJ-5-5，收率18.0％，mp212-216℃。 1HNMR(400MHz，CDCl 3),δ:3.43～3.48(m，5H)、3.05～3.09(t，2H)、2.22(s，2H)、2.08～2.11(d，2H)、1.99～2.02(d，2H)、1.93(s，2H)、1.83～1.87(m，4H)、1.71～1.77(m，4H)、1.33～1.43(m，6H)、0.90～0.94(t，3H).LC-MS，m/z(％):279.4(M +)
实施例5
N-(金刚烷-2-基)-N′-环丙基-乙烷-1,2-二胺(XHJ-5-18)的制备
以溴代环丙烷为原料代替1-溴辛烷，重复实施例3合成步骤，分离纯化得目标产物XHJ-5-18，收率37.4％，mp197-200℃。 1HNMR(400MHz，CDCl 3),δ:2.94～3.16(m，3H)、2.77～2.78(d，2H)、2.12～2.15(d，2H)、1.99(s，2H)、1.68～1.83(m，8H)、1.43～1.47(d，2H)、1.07～1.09(m，1H)、0.54～0.55(d，2H)、0.35～0.38(t，2H).LC-MS，m/z(％):234.2(M +)
实施例6
N,N-(金刚烷-2-基)-(3，7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺(XHJ-3-45)的制备
以香叶基氯为原料代替1-溴辛烷，重复实施例3合成步骤，分离出的产物中有阳性药SQ109和目标产物XHJ-3-45，mp102-104℃。 1HNMR(400MHz，CDCl 3),δ:5.30～5.34(t，1H)、5.04～5.07(t，1H)、3.48～3.50(d，2H)、3.11(s，4H)、3.00(s，1H)、2.01～2.09(m，8H)、1.89～1.92(t，4H)、1.68～1.77(m，10H)、1.60～1.64(m，3H).LC-MS，m/z(％):331.6(M +)
实施例7
N-香叶基-N-(2-氨基乙基)乙基磺酰胺盐酸盐(XHJ-2-39)的制备
Figure PCTCN2019128639-appb-000089
投1.06g N-香叶基-乙烷-1,2-二胺于反应瓶中，加20ml干燥的THF，0.8ml三乙胺，冰浴下滴加0.73g乙基磺酰氯(溶于10ml)，滴加完毕，室温下搅拌反应至反应完毕，加50ml H 2O于反应瓶中，乙酸乙酯(50ml×3)提取，提取液用饱和食盐水(50ml×2)洗涤，无水Na 2SO 4干燥过夜，抽滤，蒸除溶剂得黄色油状物1.5g，硅胶柱(洗脱剂为二氯甲烷：甲醇：氨水(v/v/v)＝500:10:1)分离纯化得淡黄色油状物420mg，产率26.9％，盐酸乙醚成盐得白色固体，mp103-106℃。 1HNMR(400MHz，CDCl 3),δ:5.189～5.223(t，1H)、5.067～5.098(t，1H)、3.217～3.234(d，2H)、3.166～3.193(t，2H)、3.031～3.087(m，2H)、2.789～2.817(t，2H)、2.062～2.098(m，2H)、2.012～2.032(t，2H)、1.605～1.682(t，9H)、1.357～1.394(t，5H)。LC-MS，m/z(％):289.3(M+).LC-MS，m/z(％):289.3(M +)
实施例8
N-香叶基-N-(2-氨基乙基)-对甲苯磺酰胺盐酸盐(XHJ-2-45)的制备
以对甲苯磺酰氯为原料代替乙基磺酰氯，重复实施例7合成步骤，分离纯化得淡黄色油状物N-香叶基-N-(2-氨基乙基)-对甲苯磺酰胺，经盐酸乙醚成盐得目标产物XHJ-2-45，产率18.2％，mp134-137℃。 1HNMR(400MHz，CDCl3),δ:7.661～7.682(d，2H)、7.380～7.399(d，2H)、5.058～5.072(t，2H)、5.067～5.098(m，1H)、2.983～3.000(d，2H)、2.749～2.782(t，2H)、2.461～2.477(t，2H)、2.380(s，3H)、1.996～2.031(m，2H)、1.906～1.943t，2H)、1.633(s，3H)、1.531～1.558(d，6H)。LC-MS，m/z(％):351.3(M +)
实施例9
N-(二吡啶-2-基-甲基)-N'-(3,7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺(XHJ-5-14)的制备
Figure PCTCN2019128639-appb-000090
投1.0g(5mmol)N-香叶基-乙烷-1,2-二胺于反应瓶中，加20ml无水甲醇溶解，加1.1g(5.9mmol)二吡啶甲酮，N 2保护下室温搅拌反应4h，分批缓慢加入0.3g(7.9mmol)NaBH 4，投料毕，室温搅拌过夜。反应毕，加100ml H 2O于反应瓶中，石油醚提取(100ml×3)，有机层用饱和食盐水(50ml×2)洗涤，无水Na 2SO 4干燥，减压蒸除溶剂的浅黄色油状物2.03g，经柱层析(CH 2Cl 2:CH 3OH:NH 3·H 2O(v/v/v)＝500:10:1)得淡黄色油状物0.36g，收率：19.7％。 1HNMR(400MHz，CDCl3),δ:8.56～8.57(d，2H)、7.60～7.62(t，2H)、7.37～7.39(d，2H)、7.13～7.16(m，2H)、5.28～5.29(t，1H)、5.06～5.08(t，2H)、3.24～3.28(t，2H)、2.81～2.84(m，4H)、1.99～2.07(m，4H)、1.59～1.72(m，9H)、1.633(s，3H)、1.531～1.558(d，6H).LC-MS，m/z(％):365.3(M +)
实施例10
N-(苯基-吡啶-3-基-甲基)-N'-(3,7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺(XHJ-5-8)的制备
以3-苯甲酰基吡啶为原料代替二吡啶甲酮，氰基硼氢化钠代替硼氢化钠，重复实施例9合成步骤，分离纯化得目标化合物XHJ-5-8。 1HNMR(400MHz，CDCl 3),δ:8.51(d，1H)、8.29～8.30(m，1H)、7.80～7.82(m，1H)、7.23～7.36(m，5H)、7.15～7.17(m，1H)、5.13～5.15(t，1H)、5.01～5.03(t，1H)、3.11～3.13(d，2H)、2.59～2.65(m，4H)、1.94～2.03(m，5H)、1.48～1.60(m，10H)、1.19～1.20(d，1H)、1.10～1.13(t，1H).LC-MS，m/z(％):364.2(M +)
实施例11
N-金刚烷-2基-N',N'-乙基磺酰基-(3,7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺(XHJ-3-1)的制备
Figure PCTCN2019128639-appb-000091
将0.9g(2.72mmol)SQ109(N-金刚烷-2-基-N'-(3,7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺)溶于15ml干燥的THF中，加0.6g碳酸钾，室温下滴加0.35g(2.7mmol)乙基磺酰氯(溶于5mlTHF)，滴加完毕，升温回流反应4h。反应毕，加50mlH 2O于反应瓶中，石油醚提取(100ml×2)，有机层用饱和食盐水(50ml×2)洗涤，无水Na 2SO 4干燥过夜，抽滤，蒸除溶剂得黄色液体1.0g。硅胶柱(洗脱剂为二氯甲烷：甲醇：氨水(v/v/v)＝1000:10:1)分 离纯化得淡黄色油状物240mg，产率30.5％，盐酸乙醚成盐得白色固体，mp103-106℃。 1HNMR(400MHz，CDCl 3),δ:5.202～5.235(t，1H)、5.042～5.059(t，1H)、3.907～3.925(d，2H)、3.302～3.334(t，2H)、3.011～3.067(m，2H)、2.760～2.791(t，2H)、2.705(t，1H)、2.045～2.106(m，4H)、1.930～1.961(d，2H)、1.833～1.851(t，6H)、1.603～1.706(m，10H)、1.472～1.502(d，2H)、1.336～1.373(t，3H).LC-MS，m/z(％):423.4(M +)
实施例12
N-金刚烷-2基-N',N'-对甲苯磺酰基-(3,7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺(XHJ-3-3)的制备
以对甲苯磺酰氯为原料代替乙基磺酰氯，重复实施例11合成步骤，分离纯化得淡黄色油状物经盐酸乙醚成盐得白色固体，即目标化合物XHJ-3-3，mp179-182℃。 1HNMR(400MHz，CDCl 3),δ:7.706～7.727(d，2H)、7.266～7.297(t，2H)、5.003～5.010(t，2H)、3.843～3.860(d，2H)、3.189～3.222(t，2H)、2.734～2.767(t，2H)、2.666(s，1H)、2.417(s，3H)、1.912～2.025(m，6H)、1.762～1.841(m，6H)、1.668～1.698(d，7H)、1.575～1.610(d，6H)、1.452～1.483(d，2H)。LC-MS，m/z(％):485.6(M +)
实施例13
N-金刚烷-2-基-N',N'-(3,7-二甲基-辛-2,6-二烯基)-(3,7-二甲基-辛-2,6-二烯酰基)-乙烷-1,2-二胺(XHJ-3-11)的制备
以3,7-二甲基-辛-2,6-二烯基酰氯为原料代替乙基磺酰氯，重复实施例11合成步骤，分离纯化得淡黄色油状物，即目标化合物XHJ-3-11。 1HNMR(400MHz，CDCl 3),δ:5.779(s，1H)、5.051～5.064(t，3H)、3.959～3.975(d，2H)、3.645～3.655(t，2H)、3.093(s，2H)、1.899～2.146(t，19H)、1.572～1.745(m，21H)、1.202～1.226(d，1H)。LC-MS，m/z(％):481.6(M+)。
实施例14
N-金刚烷-2基-N',N'-(3-吲哚丙酰基)-(3,7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺(XHJ-3-27)的制备
Figure PCTCN2019128639-appb-000092
将0.4g 3-吲哚丙酸，0.35g HOBT(1-羟基苯并三唑)，0.32g DMAP(二甲氨基吡啶)溶于15ml DMF中，加2ml三乙胺，投0.75g SQ109，投毕，升温至50℃，加0.57EDCI(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)，TLC检测至反应完全，反应毕，静置冷却，加100ml H 2O于反应瓶中，乙酸乙酯(100ml×2)提取，有机层用饱和食盐水(50ml×2)洗涤，无水Na 2SO 4干燥过夜，抽滤，蒸除溶剂得红褐色油状物0.82g， 硅胶柱(洗脱剂为二氯甲烷：甲醇：氨水(v/v/v)＝1000:10:1)分离纯化得淡黄色油状物110mg，冷冻固化，得白色固体，产率9.4％。 1HNMR(400MHz，DMSO-D6),δ:8.58(s，1H)、7.57～7.62(t，1H)、7.32～7.34(d，1H)、7.14～7.18(t，1H)、7.06～7.10(t，1H)、6.98(s，1H)、5.07～5.13(t，1H)、4.98～5.05(t，1H)、4.05～4.06(d，1H)、3.83～3.85(d，2H)、3.45～3.49(t，1H)、3.27～3.30(t，1H)、3.11～3.17(m，2H)、2.65～2.81(m，5H)、1.57～2.08(m，25H)、1.43～1.49(t，2H).LC-MS，m/z(％):502.6(M +)
实施例15
N-金刚烷-2基-N',N'-(3，4,5-三甲氧基苯甲酰基)-(3,7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺(XHJ-3-29)的制备
以3,4,5-三甲氧基苯甲酸为原料代替3-吲哚丙酸，重复实施例14合成步骤，分离纯化得淡黄色油状物，冷冻固化得淡黄色固体，即目标化合物XHJ-3-29。 1HNMR(400MHz，CDCl 3),δ:6.65(s，2H)、5.27～5.30(t，1H)、5.07(s，1H)、4.18(s，1H)、3.82～3.93(m，10H)、3.60(s，2H)、2.91(s，1H)、2.74～2.77(d，2H)、2.04～2.08(d，5H)、1.52～1.84(m，20H).LC-MS，m/z(％):525.1(M +)
实施例16
N-金刚烷-2基-N',N'-十一烷酰基-(3,7-二甲基-辛-2,6-二烯基)-乙烷-1,2-二胺(XHJ-3-31)的制备
以十一烷酸为原料代替3-吲哚丙酸，重复实施例14合成步骤，分离纯化得淡黄色油状物，即目标化合物XHJ-3-31。 1HNMR(400MHz，CDCl 3),δ:5.06～5.10(m，2H)、4.02～4.03(d，1H)、4.92～4.94(d，1H)、3.44～3.47(t，1H)、3.34～3.37(t，1H)、3.72～3.77(m，3H)、2.36～2.40(t，1H)、2.27～2.31(t，1H)、1.59～2.08(m，30H)、1.25～1.29(m，16H)、0.86～0.89(t，3H).LC-MS，m/z(％):513.8(M +)
实施例17
N,N-金刚烷-2-基-(3-吲哚甲酰基)-N',N'-(3,7-二甲基-辛-2,6-二烯基)-(3-吲哚甲酰基)-乙烷-1,2-二胺(XHJ-3-15)的制备
Figure PCTCN2019128639-appb-000093
将1.0g(3.0mmol)SQ109溶于20ml干燥的THF中，加0.7ml三乙胺，冰浴下滴加1.1g(6.1mmol)3-吲哚甲酰氯(溶于5mlTHF)，滴加完毕，升温回流反应2h。反应毕，加50mlH 2O于反应瓶中，二氯甲烷提取(100ml×2)，有机层用饱和食盐水(50ml×2)洗涤，无水Na 2SO 4干燥过夜，抽滤，蒸除溶剂得黄色固体，甲醇重结晶得白色固体1.12g，产率 59.9％。mp248-252℃。 1HNMR(400MHz，DMSO-D6),δ:11.61(s，1H)、11.48(s，1H)、7.73(s，1H)、7.40～7.62(m，5H)、7.03～7.16(m，4H)、4.96～4.99(t，1H)、4.85～4.88(t，1H)、3.73(s，4H)、1.54～1.92(m，21H)、1.16(s，3H).LC-MS，m/z(％):618.8(M +)
实施例18
N,N-金刚烷-2-基-苄基-N',N'-(3,7-二甲基-辛-2,6-二烯基)-苄基-乙烷-1,2-二胺(XHJ-4-11)的制备
以溴苄为原料代替3-吲哚甲酰氯，重复实施例17合成步骤，分离纯化得淡黄色油状物，冷冻固化得目标化合物XHJ-4-11。 1HNMR(400MHz，CDCl 3),δ:7.22～7.29(m，10H)、5.17～5.20(t，1H)、5.06～5.10(t，1H)、3.62(s，2H)、3.40(s，2H)、2.89～3.91(d，2H)、2.63～2.67(t，2H)、2.37～2.41(t，2H)、1.94～2.12(m，8H)、1.79～1.81(t，4H)、1.66～1.71(t，6H)、1.60～1.63(d，5H)、1.51～1.53(t，3H)、1.35～1.38(d，2H).LC-MS，m/z(％):511.8(M +)
实施例19
N,N-金刚烷-2-基-辛基-N',N'-(3,7-二甲基-辛-2,6-二烯基)-辛基-乙烷-1,2-二胺(XHJ-4-15)的制备
以1-溴辛烷为原料代替3-吲哚甲酰氯，重复实施例17合成步骤，分离纯化得淡黄色油状物，即目标化合物XHJ-4-15。 1HNMR(400MHz，CDCl 3),δ:5.24～5.25(t，1H)、5.09～5.10(t，1H)、3.05～3.06(d，2H)、2.63(s，2H)、2.40～2.52(d，2H)、1.95～2.06(m，8H)、1.60～1.80(m，16H)、1.27～1.40(m，25H)、0.86～0.90(t，6H).LC-MS，m/z(％):555.7(M +)
实施例20
N-金刚烷-2-基-2-(3,7-二甲基-辛-2,6-二烯基氨基)-乙酰胺盐酸盐(XHJ-2-37)的制备
Figure PCTCN2019128639-appb-000094
1)香叶基胺的合成
2.51g(16.2mmol)香叶醇，2.86g(19.4mmol)邻苯二甲酰亚胺，5.12g(19.5mmol)三苯基磷置于50ml干燥的THF中，冰浴下滴加3.35g(19.2mmol)DEAD(偶氮二甲酸二乙酯)，滴加完毕，室温搅拌反应至反应完全，蒸除溶剂，得白色固体，石油醚提取后经硅胶柱(洗脱剂为石油醚：乙酸乙酯(v/v)＝10:1)分离纯化得中间体2-(3,7,-二甲基-辛-2,6-二烯基)-异 吲哚-1,3-二酮3.0g，产率65.4％。 1HNMR(400MHz，CDCl 3),δ:7.817～7.848(m，2H)、7.699～7.713(m，2H)、5.249～5.282(t，1H)、5.024～5.058(t，1H)、4.272～4.289(d，2H)、1.990～2.075(m，4H)、1.830(s，3H)、1.631(s，3H)、1.566(s，3H).
将3.0g(10.6mmol)2-(3,7,-二甲基-辛-2,6-二烯基)-异吲哚-1,3-二酮溶于70ml无水乙醇中，投5ml(85mmol)水合肼，升温至70℃反应3h，反应毕，加70mlH 2O于反应瓶中，用浓盐酸调PH至2，80ml乙醚洗涤，水相用2M的氢氧化钠溶液调PH至12，无水乙醚(100×2)提取 [48]，提取液用饱和食盐水(50ml×2)洗涤，无水Na 2SO 4干燥过夜，抽滤，蒸除溶剂得黄色液体1.0g，产率61.7％。 1HNMR(400MHz，CDCl 3),δ:5.243～5.274(t，1H)、5.082～5.099(t，1H)、3.269～3.286(d，2H)、1.978～2.117(m，4H)、1.606～1.685(m，8H)、1.442(s，3H).
2)N-金刚烷-2-基-2-(3,7-二甲基-辛-2,6-二烯基氨基)-乙酰胺盐酸盐的合成
将0.11g(0.48mmol)N-金刚烷基-乙酰基氯溶于20ml干燥的THF中，加0.3g碳酸钾，投0.63g(4.11mmol)香叶基胺，升温回流反应4h，反应毕，加30ml H 2O于反应瓶中，二氯甲烷提取(50ml×2)，有机层用饱和食盐水(30ml×2)洗涤，无水Na 2SO 4干燥过夜，抽滤，蒸除溶剂得红棕色液体0.55g，硅胶柱(洗脱剂为二氯甲烷：甲醇：氨水(v/v/v)＝500:10:1)分离纯化得淡黄色油状物42mg，产率26.2％，经盐酸乙醚成盐得白色固体。 1HNMR(400MHz，DMSO-D6),δ:7.825～7.845(t，1H)、5.208～5.243(t，1H)、5.064～5.096(t，1H)、4.061～4.082(d，1H)、3.245～3.391(m，3H)、1.997～2.096(m，4H)、1.816～1.906(t，10H)、1.750(s，2H)、1.593～1.684(m，12H).LC-MS，m/z(％):345.3(M +)
实施例21本发明化合物体外抗结核活性实验
应用Microplate Alamar Blue Assay(MABA)法测定化合物对结核分枝杆菌标准株H 37Rv的最低抑菌浓度(MIC)(该方法可参见Collins L A,Franzblau S G.,Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium.Antimicrobial Agents Chemother,1997,1004-1009)。待测化合物为本申请制备1-20的化合物，以及阳性对照化合物利福平(rifampin，RFP)和异烟肼(isoniazid，INH)。
实验方法：无菌96孔板(Falcon3072；Becton Dickinson,Lincoln Park,N.J.)，待测化合物以二甲基亚砜溶解，制成浓度为5mg/ml的初溶液，最高浓度孔加入199μl 7H9液体培养基(Difco公司)，1μl化合物初溶液，混合均匀，其余各孔浓度依次2倍稀释，待测化合物溶液的体积分别为200μl，各孔中的实验化合物终浓度分别为：25、12.5、6.25、3.125、1.56、0.78、0.39、0.2、0.1、0.05、0.025、0.0125μg/ml。选取结核分枝杆菌H 37Rv(北京市结核病胸部肿瘤研究所保存菌株)培养2～3周的培养物制成菌悬液，接种到含0.05％吐温80、10％ADC(白蛋白-葡萄糖-过氧化氢酶，albumin-dextrose-catalase，ADC)的7H9液体培养基中，37℃静止培养1～2周，生长至浊度为McFarland 1(相当于10 7CFU/ml)时，按体积比1：20稀释后，取100μl加入各孔，各孔中菌液的终浓度约为10 6CFU/ml。每板 上均设2个不含抗菌药的生长对照孔，将96孔板置于37℃孵育。7天后向生长对照孔加入20μl 10×Alamar Blue(Setotec公司)和5％Tween80 50μl的混合液，37℃孵育24小时，如果颜色从蓝色变为粉色，则在各待测药物的孔内加入上述量的Alamar Blue和Tween80混合液，37℃孵育24小时记录各孔的颜色，并应用酶标仪测定530nm和590nm荧光值，计算MIC，结果见表1。MIC定义为阻止颜色变化(从蓝色变为粉红色)的最低药物浓度。
表1 Microplate Alamar Blue Assay(MABA)法测定的对结核分枝杆菌标准株H37Rv的最低抑菌浓度(MIC)结果
Sample No. MIC(μg/ml)
XHJ-2-37 <0.5
XHJ-2-32 7.754
XHJ-2-39 >32
XHJ-2-45 31.459
XHJ-3-1 6.961
XHJ-3-3 3.757
XHJ-3-11 >32
XHJ-3-15 >32
XHJ-3-27 1.963
XHJ-3-29 3.91
XHJ-3-31 2.844
XHJ-3-45 <0.5
XHJ-3-46 >32
XHJ-4-11 30.822
XHJ-4-15 >32
XHJ-5-3 0.986
XHJ-5-5 0.982
XHJ-5-8 16
XHJ-5-14 4
XHJ-5-18 >32
INH 0.05
RFP 0.048
从表1中的实验数据可以看出，本发明化合物具有较好的体外抗结核活性，在保留SQ109基本骨架的前提下，对其结构进行改造中，直链酰胺类表现出较好的活性，N位上的单取代酰胺和磺酰胺均表现出较好的活性，例如XHJ-2-37，XHJ-2-32，XHJ-3-1，XHJ-3-3，XHJ-3-27，XHJ-3-29，XHJ-3-31。异戊烯基替换衍生物中，将异戊烯基替换成直链烷烃时表现出比较好的活性，例如XHJ-5-3和XHJ-5-5。金刚烷基替换衍生物中，XHJ-5-8和XHJ-5-14表现出较好的活性，其骨架重排衍生物XHJ-3-45的活性较优。

Claims (18)

  1. 通式A所示的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，
    Figure PCTCN2019128639-appb-100001
    其中：R a为氢、C 1-6烷基、C 3-14环烷基、6-14元芳基、3-14元杂环基、
    Figure PCTCN2019128639-appb-100002
    Figure PCTCN2019128639-appb-100003
    R b为氢、C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-10烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基、苯基取代的C 1-6烷基或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数；
    X为-CH 2-、-CHR 2-或-C(O)-，其中R 2为C 1-6烷基；
    R c为氢、C 1-10烷基、C 3-14环烷基、C 2-10烷酰基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、取代或未取代的磺酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基；
    R d为氢、C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-12烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基、苯基取代的C 1-10烷基、取代或未取代的磺酰基、取代或未取代的苯甲酰基、吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数，
    例如，R a为氢、
    Figure PCTCN2019128639-appb-100004
    例如，R b为氢、
    Figure PCTCN2019128639-appb-100005
    -CH 2(CH 2) 6CH 3、或
    Figure PCTCN2019128639-appb-100006
    X为-CH 2-或-C(O)-；
    例如，R c为氢、
    Figure PCTCN2019128639-appb-100007
    -CH 2(CH 2) 6CH 3、-CH 2(CH 2) 4CH 3；
    例如，R d为氢、
    Figure PCTCN2019128639-appb-100008
    Figure PCTCN2019128639-appb-100009
    -CH 2(CH 2) 6CH 3。
  2. 权利要求1所述的化合物、其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中所述化合物如式I所示，
    Figure PCTCN2019128639-appb-100010
    其中：
    R 1为氢、C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-10烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基、苯基取代的C 1-6烷基或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数；
    X为-CH 2-、-CHR 2-或-C(O)-，其中R 2为C 1-6烷基；
    R 3为氢、C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-10烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基、苯基取代的C 1-10烷基、取代或未取代的磺酰基、取代或未取代的苯甲酰基、吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数；
    R 4为氢、C 1-10烷基、C 3-14环烷基、C 2-10烷酰基、C 2-12烯基或多烯基、C 2-12烯酰基或多 烯酰基、取代或未取代的磺酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基。
  3. 权利要求2所述的化合物、其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，
    其中：R 1为氢、C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-12烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基；
    R 3为氢、C 1-10烷基、C 3-14环烷基、C 2-12烯基或多烯基、C 2-12烯酰基或多烯酰基、C 2-12烷酰基、取代或未取代的6-14元芳基、取代或未取代的3-14元杂环基、取代或未取代的7-12元桥环基。
  4. 权利要求2或3所述的化合物、其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，
    其中：X为-CH 2-或-C(O)-。
  5. 权利要求3至5任一项所述的化合物、其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，
    其中：R 1为氢、C 3-10烷基、C 4-12二烯基、苯基取代的C 1-4烷基或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数；
    例如，R 1为氢、C 6-10烷基、C 8-12二烯基、苯基取代的C 1-3烷基或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数；
    例如，R 1为氢、正己基、正庚基、正辛基、正壬基、正癸基、
    Figure PCTCN2019128639-appb-100011
    苄基、苯基乙基、苯基正丙基、苯基正丁基、吲哚-3-C(O)-、吲哚-3-CH 2-C(O)-、吲哚-3-(CH 2) 2-C(O)-、吲哚-3-(CH 2) 3-C(O)-或吲哚-3-(CH 2) 4-C(O)-；
    例如，R 1为氢、
    Figure PCTCN2019128639-appb-100012
    -CH 2(CH 2) 6CH 3或
    Figure PCTCN2019128639-appb-100013
  6. 权利要求2至5任一项所述的化合物、其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：
    R 3为氢、C 1-4烷基取代的磺酰基、C 1-4烷基-苯基取代的磺酰基、C 4-12二烯基酰基、被一个或多个甲氧基取代的苯甲酰基、苯基取代的C 1-4烷基、C 3-10烷基、C 2-12烷酰基、C 3-6环烷基、或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数，
    例如，R 3为氢、C 1-3烷基取代的磺酰基、C 1-2烷基-苯基取代的磺酰基、C 8-12二烯基酰基、被一个或多个甲氧基取代的苯甲酰基、苯基取代的C 1-3烷基、C 6-10烷基、C 6-12烷酰基、C 3-4环烷基、或吲哚-3-(CH 2) n-C(O)-，其中n为0-4之间的整数，
    例如，R 3为氢、甲基磺酰基、乙基磺酰基、丙基磺酰基、丁基磺酰基、对甲苯磺酰基、对乙苯磺酰基、对正丙基苯磺酰胺、
    Figure PCTCN2019128639-appb-100014
    对甲氧基苯甲酰基、3,4-二甲氧基苯甲酰基、3,4,5-三甲氧基苯甲酰基、十一烷酰基、癸酰基、壬酰基、辛酰基、庚酰基、己酰基、戊酰基、丁酰基、苄基、苯基乙基、苯基正丙基、苯基正丁基、环丙基、环丁基、正己基、正庚基、正辛基、正壬基、正癸基，
    例如，R 3为氢、
    Figure PCTCN2019128639-appb-100015
    Figure PCTCN2019128639-appb-100016
    环丙基、-CH 2(CH 2) 6CH 3或-CH 2(CH 2) 4CH 3。
  7. 权利要求2至6任一项所述的化合物、其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：
    R 4为氢、C 4-12二烯基、C 4-12二烯基酰基、C 1-4烷基取代的磺酰基、C 2-10烷酰基、C 3-10烷基、C 3-6环烷基、C 1-4烷基-苯基取代的磺酰基，
    例如，R 4为氢、C 8-12二烯基、C 8-12二烯基酰基、C 1-3烷基取代的磺酰基、C 1-2烷基-苯基取代的磺酰基、C 6-10烷基、C 3-4环烷基，
    例如，R 4为氢、甲基磺酰基、乙基磺酰基、丙基磺酰基、丁基磺酰基、对甲苯磺酰基、对乙苯磺酰基、对正丙基苯磺酰胺、正己基、正庚基、正辛基、正壬基、正癸基、环丙基、环丁基、
    Figure PCTCN2019128639-appb-100017
    例如，R 4为氢、
    Figure PCTCN2019128639-appb-100018
    环丙基、-CH 2(CH 2) 6CH 3或-CH 2(CH 2) 4CH 3。
  8. 权利要求1所述的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中所述化合物如式II所示，
    Figure PCTCN2019128639-appb-100019
    其中：
    R 5为氢、C 1-6烷基、C 3-14环烷基、6-14元芳基、3-14元杂环基；
    R 6为氢、C 1-6烷基、C 3-14环烷基、6-14元芳基、3-14元杂环基、
    Figure PCTCN2019128639-appb-100020
    R 7为氢或者取代或未取代的磺酰基。
  9. 根据权利要求2至7任一项所述的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：
    R 1为氢，或者-CH 2(CH 2) 6CH 3、
    Figure PCTCN2019128639-appb-100021
    X为-CH 2-或-C(O)-；
    R 4为氢，或者
    Figure PCTCN2019128639-appb-100022
    R 3为氢、-CH 2(CH 2) 4CH 3、-CH 2(CH 2) 6CH 3、
    Figure PCTCN2019128639-appb-100023
    Figure PCTCN2019128639-appb-100024
  10. 根据权利要求8所述化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中：
    R 5为氢或C 1-4烷基；
    R 6为氢、C 1-4烷基、
    Figure PCTCN2019128639-appb-100025
    R 7为氢、C 1-4烷基取代的磺酰基或C 1-4烷基-苯基取代的磺酰基，
    例如，R 5为氢、甲基、乙基、正丙基或异丙基；
    例如，R 6为氢、甲基、乙基、正丙基、异丙基、
    Figure PCTCN2019128639-appb-100026
    例如，R 7为氢、甲基磺酰基、乙基磺酰基、丙基磺酰基、丁基磺酰基、对甲苯磺酰基、对乙苯磺酰基或对正丙基苯磺酰胺。
  11. 根据权利要求9所述化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中
    R 5为氢；
    R 6为氢、
    Figure PCTCN2019128639-appb-100027
    R 7为氢、
    Figure PCTCN2019128639-appb-100028
  12. 根据权利要求1所述的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中所述化合物选自:
    Figure PCTCN2019128639-appb-100029
    Figure PCTCN2019128639-appb-100030
  13. 根据权利要求1-12任意一项所述的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其中所述可药用盐为所述化合物的无机酸盐，如盐酸盐、硫酸盐、磷酸盐，或有机酸盐，如甲磺酸盐、三氟甲磺酸盐、醋 酸盐、三氟乙酸盐、苯甲酸盐。
  14. 药物组合物，其包含权利要求1-12任意一项所述的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，以及任选的一种或多种药学上可接受的载体或赋形剂。
  15. 权利要求1-12任意一项所述的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药，其用于抑制结核杆菌(例如耐药性结核杆菌)生长或繁殖或用于治疗结核病。
  16. 权利要求1-12任意一项所述的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药在制备用于抑制结核杆菌(例如耐药性结核杆菌)生长或繁殖的药物或用于治疗结核病的药物中的用途。
  17. 一种治疗结核病的方法，包括给予有需要的受试者治疗有效量的至少一种权利要求1-12任意一项所述的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药。
  18. 一种抑制结核杆菌(例如耐药性结核杆菌)在体内或体外生长或繁殖的方法，包括使所述结核杆菌(例如耐药性结核杆菌)与权利要求1-12任意一项所述的化合物，其可药用盐、立体异构体、互变异构体或异构体混合物、其水合物、其溶剂合物或其前体药接触。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023287695A1 (en) 2021-07-12 2023-01-19 The Chemours Company Fc, Llc Stabilized fluoroethylene compositions and methods for their storage and usage
EP4296674A1 (en) 2022-06-20 2023-12-27 Université Toulouse III - Paul Sabatier Innovative molecules decreasing virulence of mycobacterium for the treatment of tuberculosis

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1665801A (zh) * 2002-05-17 2005-09-07 卫生与公众服务部 抗结核药:组合物和方法
CN1962646A (zh) * 2006-11-21 2007-05-16 浙江大学 抗结核病药物吡嗪酰胺关键中间体2－氰基吡嗪的合成方法
CN101636376A (zh) * 2005-07-01 2010-01-27 赛奎拉公司 抗结核药：组合物和方法
CN102757385A (zh) * 2011-04-27 2012-10-31 沈阳药科大学 二芳基喹啉类似物的制备与用途
WO2015035234A2 (en) * 2013-09-06 2015-03-12 The Board Of Trustees Of The University Of Illinois Anti-microbial compounds and compositions

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1157143A (en) * 1966-06-21 1969-07-02 Du Pont Adamantane Derivatives
US5576355A (en) * 1993-06-04 1996-11-19 Mobil Oil Corp. Diamondoid derivatives for pharmaceutical use
AU6115300A (en) * 1999-07-19 2001-02-05 California Institute Of Technology Detection of biomolecules by sensitizer-linked substrates
US7884097B2 (en) * 2003-09-05 2011-02-08 Sequella, Inc. Methods and compositions comprising diamines as new anti-tubercular therapeutics
JP2008518903A (ja) * 2004-11-02 2008-06-05 ファイザー・インク 置換および非置換アダマンチルアミドの新規化合物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1665801A (zh) * 2002-05-17 2005-09-07 卫生与公众服务部 抗结核药:组合物和方法
CN101636376A (zh) * 2005-07-01 2010-01-27 赛奎拉公司 抗结核药：组合物和方法
CN1962646A (zh) * 2006-11-21 2007-05-16 浙江大学 抗结核病药物吡嗪酰胺关键中间体2－氰基吡嗪的合成方法
CN102757385A (zh) * 2011-04-27 2012-10-31 沈阳药科大学 二芳基喹啉类似物的制备与用途
WO2015035234A2 (en) * 2013-09-06 2015-03-12 The Board Of Trustees Of The University Of Illinois Anti-microbial compounds and compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
COLLINS LAFRANZBLAU S G.: "Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium", ANTIMICROBIAL AGENTS CHEMOTHER, 1997, pages 1004 - 1009, XP055403703

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023287695A1 (en) 2021-07-12 2023-01-19 The Chemours Company Fc, Llc Stabilized fluoroethylene compositions and methods for their storage and usage
EP4296674A1 (en) 2022-06-20 2023-12-27 Université Toulouse III - Paul Sabatier Innovative molecules decreasing virulence of mycobacterium for the treatment of tuberculosis

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