WO2018184561A1 - 取代咪唑盐类化合物、其制备方法、药用组合物及其应用 - Google Patents

取代咪唑盐类化合物、其制备方法、药用组合物及其应用 Download PDF

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WO2018184561A1
WO2018184561A1 PCT/CN2018/081898 CN2018081898W WO2018184561A1 WO 2018184561 A1 WO2018184561 A1 WO 2018184561A1 CN 2018081898 W CN2018081898 W CN 2018081898W WO 2018184561 A1 WO2018184561 A1 WO 2018184561A1
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alkyl
hydrogen
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pharmaceutically acceptable
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French (fr)
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邓贤明
林圣彩
张宸崧
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厦门华绰生物医药科技有限公司
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Priority to CN201880020591.5A priority Critical patent/CN110612288B/zh
Priority to AU2018249237A priority patent/AU2018249237B2/en
Priority to US16/500,774 priority patent/US11584722B2/en
Priority to EP18781729.1A priority patent/EP3608312B1/en
Priority to CA3058687A priority patent/CA3058687A1/en
Priority to JP2019543929A priority patent/JP2020515527A/ja
Publication of WO2018184561A1 publication Critical patent/WO2018184561A1/zh
Priority to US18/097,640 priority patent/US20230202986A1/en

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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
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    • C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a class of compounds having aldolase selective inhibitory activity, a process for the preparation thereof, a pharmaceutical composition comprising the same, and the preparation of these compounds for reducing fatty acid synthesis.
  • Drugs, drugs for inhibiting triglyceride and cholesterol synthesis, drugs for preventing and/or treating obesity and type II diabetes, drugs for preventing and/or treating tumors, drugs for preventing and/or treating Parkinson's disease, prevention and/or treatment A drug for Alzheimer's disease or a drug that prolongs the lifespan of a mammal.
  • AMPK 5'-adenosine monophosphate-activated protein kinase
  • AMPK is one of the most attractive drug targets for treating major diseases.
  • AMPK is one of the most attractive drug targets for treating major diseases.
  • a number of methods have been used in academia, many activators have been obtained with AMPK as a target and systematic studies have been carried out.
  • the results indicate that AMPK as a direct target for drugs has many drawbacks, such as insufficient efficacy or low specificity. Therefore, there is an urgent need to develop drugs with new mechanisms of action to achieve the purpose of activating AMPK and treating related diseases.
  • Fructose-1 (6-bisphosphate aldolase, abbreviated as FBP aldolase, also known as aldolase in the present invention, including aldolase A, aldolase B and aldolase C) - a novel regulator of AMPK It is an important metabolic enzyme in the process of sugar metabolism. In the glycolytic pathway, it catalyzes the formation of fructose 1,6-diphosphate (FBP) to produce glyceraldehyde-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP) (Eur. J. Biochem. 2000, 267, 1858–1868) .), the latter undergoes multiple enzymatic reactions to produce pyruvic acid.
  • FBP aldolase also known as aldolase in the present invention, including aldolase A, aldolase B and aldolase C
  • FBP aldolase also known as aldolase in the present invention, including aldolase A, aldolase
  • aldolase plays a role that cannot be replaced by other metabolic enzymes.
  • the understanding of the function of aldolase is only limited to the nature of its metabolic enzyme itself. It has been reported that some mutants of aldolase may be related to lactose intolerance, but the specific mechanism is still unclear. It is worth mentioning that in the tumor tissue, the expression level of aldolase is significantly increased, which is likely to increase the level of the Warburg effect and promote the development of tumor cells (J.Biol.Chem .2010, 285, 11983–11990, and Am. J. Physiol. Cell Physiol. 2011, 300, C1442–1455.). There is also evidence that knockdown of aldolase in tumor cells directly leads to the cessation of tumor cell growth (J. Biol. Chem. 2012, 287, 42554-42563.).
  • Aldolase can directly regulate the activation of AMPK, so it can be used as an important target for the regulation of AMPK.
  • Aldolase inhibitors can significantly activate AMPK by inhibiting the activity of intracellular aldolase, and can be used for the prevention and treatment of related diseases caused by low AMPK levels.
  • the inventors of the present invention have designed and synthesized a series of multi-substituted imidazole salt derivatives with novel structure, high safety and high activity, and studied this.
  • the inhibitory activity of a novel class of derivatives on aldolase and its effect on the AMPK signaling pathway is a novel class of derivatives on aldolase and its effect on the AMPK signaling pathway.
  • the present invention provides a compound of the formula:
  • Another object of the present invention is to provide a process for the preparation of the above compounds.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the above compound.
  • Another object of the present invention is to provide a use of the above compound and a pharmaceutical composition comprising the same for the preparation of a medicament for inhibiting aldolase activity.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the above compound and a pharmaceutical composition comprising the same for the preparation of a medicament for inhibiting cholesterol synthesis, a medicament for reducing fatty acid synthesis, a medicament for preventing and/or treating obesity, preventing and/or treating diabetes, and prevention And/or a drug for treating a tumor, a drug for preventing and/or treating Parkinson's disease, a drug for preventing and/or treating Alzheimer's disease, or a drug for prolonging the lifespan of a mammal.
  • Figure 1 illustrates that compounds are effective in inhibiting aldolase activity in mouse embryonic fibroblasts (MEFs).
  • the results in a), b) and c) show that the tested compounds can inhibit the aldolase activity in MEFs cells at different levels at 200 nM, thereby activating AMPK to different degrees and promoting AMPK phosphorylation (p-AMPK) and Phosphorylation (p-ACC) of its downstream substrate ACC1/ACC2.
  • Figure 2 illustrates the activation of AMPK by a protein via a protein AXIN-dependent signaling pathway.
  • AXIN knockout MEFs none of the tested compounds could effectively activate AMPK (compound concentration 200 nM).
  • Figure 3 illustrates the activation of AMPK by a compound via a protein LAMTOR1-dependent signaling pathway.
  • LAMTOR1 knockout MEFs none of the tested compounds could effectively activate AMPK (compound concentration 200 nM).
  • Figure 4 illustrates that the compound (IA-47) is capable of activating the activity of AMPK in the liver by inhibiting aldolase activity in mice.
  • oral administration (1 mg/kg, once/day) for two weeks effectively inhibited aldolase activity and activated AMPK activity in the liver of mice.
  • Figure 5 illustrates that the compound (IA-47) is capable of lowering the level of triglyceride by inhibiting aldolase activity in mice.
  • oral administration (1 mg/kg, once/day) for two weeks can effectively inhibit aldolase activity and reduce the level of triglyceride in the liver of mice.
  • Figure 6 illustrates that compound (IA-47) is effective in reducing body weight in high fat fed obese mice.
  • the drug is dissolved in drinking water (200 ⁇ g/ml), and the body weight can be reduced from 50 g or more to a normal level of about 30 g for about 30 days.
  • Figure 7 illustrates that compound (IA-47) is effective in the treatment of fatty liver in high fat fed obese mice.
  • the liver of the mice treated according to Figure 6 was taken and sectioned. The histological features of the liver were directly observed after HE staining. The lipid droplets in the sections were significantly reduced, indicating that the fatty liver was effectively relieved.
  • Figure 8 illustrates that compound (IA-47) is effective in reducing blood sugar in iv-GTT.
  • the fasting normal mice were intragastrically administered with 2 mg/kg of IA-47, and after 2 hours of absorption, glucose (1 g/kg) was intraperitoneally injected, and the blood glucose change was measured at the corresponding time point.
  • Figure 9 illustrates that the compound (IA-47) is capable of extending the lifespan of nematodes.
  • the present invention has been achieved by the following technical solutions.
  • the invention provides a compound of the formula:
  • R 1 is selected from the group consisting of C1-C24 alkyl, C1-C24 oxyalkyl, C1-C24 fluoroalkyl, C1-C24 fluorine-containing oxyalkyl;
  • R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;
  • R 3 is selected from:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from:
  • Z 2 and Z 3 may form an oxygen-containing substituted or unsubstituted five-membered or six-membered ring; the substituent may be selected from the same substituents as Z 1 ;
  • Z 4 and Z 5 may form a nitrogen-containing substituted or unsubstituted five-membered or six-membered ring; the substituent may be selected from the same substituents as Z 1 ;
  • Z 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl;
  • the A ring is a benzene ring which is not present or optionally substituted, and in the case where the benzene ring is substituted, the substituent is one or more substituents selected from the group consisting of halogen, nitro, cyano, C1-C3 alkane a C1-C3 alkoxy group, a C1-C3 oxyalkyl group, a C1-C3 fluoroalkyl group, a C1-C3 fluoroalkoxy group; preferably, the substituent is one or two substituents selected from the group consisting of a group: a halogen, a nitro group, a C1-C3 alkoxy group; more preferably, the substituent is one or two substituents selected from the group consisting of fluorine, chlorine, nitro, methoxy;
  • X - is an anion of a pharmaceutically acceptable inorganic or organic acid salt
  • R 1 is C 16 H 33 -, R 2 is CH 3 -, and R 3 is X - is Br - ;
  • R 1 is C 16 H 33 -, R 2 is CH 3 -, and R 3 is X - is Br - ;
  • R 1 is C 16 H 33 -, R 2 is CH 3 -, and R 3 is X - is Br - ;
  • R 1 is C 16 H 33 -, R 2 is CH 3 -, and R 3 is X - is Br - ;
  • R 1 is C 16 H 33 -, R 2 is CH 3 -, and R 3 is X - is Br - ;
  • R 1 is C 4 H 9 -, R 2 is CH 3 -, and R 3 is X - is I - ;
  • R 1 is C 8 H 17 -, R 2 is CH 3 -, and R 3 is X - is I - ;
  • R 1 is C 12 H 25 -, R 2 is CH 3 -, and R 3 is X - is I - ;
  • R 1 is C 14 H 29 -, R 2 is CH 3 -, and R 3 is X - is I - ;
  • R 1 is C 16 H 33 -, R 2 is CH 3 -, and R 3 is X - is I - ;
  • R 1 is C 18 H 37 -, R 2 is CH 3 -, and R 3 is X - is I - ;
  • R 1 is C 20 H 41 -, R 2 is CH 3 -, and R 3 is X - is I - ;
  • R 1 is C 22 H 45 -
  • R 2 is CH 3 -
  • R 3 is X - is I - .
  • R 1 is selected from C1-C24 alkyl.
  • R 1 is selected from C 1 -C 22 alkyl.
  • R 2 is selected from the group consisting of hydrogen, C1-C4 alkyl, C3 cycloalkyl.
  • R 2 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclopropyl.
  • R 3 is Wherein two of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are independently selected from the following, and the remainder are hydrogen:
  • Z 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl; preferably Z 6 is hydrogen or methyl.
  • R 3 is Wherein one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is independently selected from the group consisting of the following:
  • Z 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl; preferably Z 6 is hydrogen or methyl.
  • Ring A is a substituted phenyl ring having a substituent of 1 or 2 substituents selected from the group consisting of halogen, nitro, C1-C3 alkoxy; more preferably, the substituent is 1 Or two substituents selected from the group consisting of fluorine, chlorine, nitro, methoxy.
  • the mineral acid salt is a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a bicarbonate, and a carbonate, sulfate or phosphate
  • the organic acid salt being a Acid salts, acetates, propionates, benzoates, maleates, fumarates, succinates, tartrates, citrates, ascorbates, alpha-ketoglutarate, alpha- a glycerol phosphate, an alkyl sulfonate or an aryl sulfonate; preferably, the alkyl sulfonate is a methyl sulfonate or an ethyl sulfonate; the aryl sulfonate is benzene sulfonic acid Salt or p-toluenesulfonate.
  • the present invention provides a compound represented by the following formula I, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,
  • R 1 is selected from the group consisting of C1-C24 alkyl, C1-C24 oxyalkyl, C1-C24 fluoroalkyl, C1-C24 fluorine-containing oxyalkyl;
  • R 2 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl;
  • R 3 is selected from
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from:
  • Z 2 and Z 3 may form an oxygen-containing substituted or unsubstituted five-membered or six-membered ring; the substituent may be selected from the same substituents as Z 1 ;
  • Z 4 and Z 5 may form a nitrogen-containing substituted or unsubstituted five-membered or six-membered ring; the substituent may be selected from the same substituents as Z 1 ;
  • Z 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl;
  • X - is an anion of a pharmaceutically acceptable inorganic or organic acid salt.
  • R 1 is selected from C1-C24 alkyl.
  • R 1 is selected from C 1 -C 22 alkyl.
  • R 2 is selected from the group consisting of hydrogen, C1-C4 alkyl, C3 cycloalkyl.
  • R 2 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclopropyl.
  • R 3 is Wherein two of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the group consisting of hydrogen:
  • Z 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, and C3-C6 cycloalkyl.
  • R 3 is Wherein two of Z 1 , Z 2 , Z 4 , and Z 5 are each independently selected from the group consisting of the following: and the remaining Z 3 is hydrogen:
  • Z 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl; preferably Z 6 is hydrogen.
  • R 3 is Wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 1 , Z 5 , or Z 2 , Z 4 , or Z 1 , Z 4 are each independently selected from the following, and the rest are hydrogen:
  • Z 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl; preferably Z 6 is hydrogen or methyl.
  • R 3 is Wherein one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is independently selected from the group consisting of the following:
  • Z 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl; preferably Z 6 is hydrogen or methyl.
  • the mineral acid salt is a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a bicarbonate, and a carbonate, sulfate or phosphate
  • the organic acid salt being a Acid salts, acetates, propionates, benzoates, maleates, fumarates, succinates, tartrates, citrates, ascorbates, alpha-ketoglutarate, alpha- a glycerol phosphate, an alkyl sulfonate or an aryl sulfonate; preferably, the alkyl sulfonate is a methyl sulfonate or an ethyl sulfonate; the aryl sulfonate is benzene sulfonic acid Salt or p-toluenesulfonate.
  • the invention provides the following compounds:
  • R 1 , R 3 and X ⁇ are as defined above,
  • the present invention provides a compound of the following formula II, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:
  • R 1 is selected from the group consisting of C1-C24 alkyl, C1-C24 oxyalkyl, C1-C24 fluoroalkyl, C1-C24 fluorine-containing oxyalkyl
  • R 2 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl;
  • R 3 is selected from
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from:
  • Z 2 and Z 3 may form an oxygen-containing substituted or unsubstituted five-membered or six-membered ring; the substituent may be selected from the same substituents as Z 1 ;
  • Z 4 and Z 5 may form a nitrogen-containing substituted or unsubstituted five-membered or six-membered ring; the substituent may be selected from the same substituents as Z 1 ;
  • Z 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl;
  • n is selected from 0, 1, 2;
  • R 4 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxyformyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, Carbamate, N-methylformyl, N-ethylformyl, N-n-propylformyl, N-isopropylformyl, N-cyclopropylformyl, N-n-butylformyl, N- Isobutylformyl, N-tert-butylformyl, N-cyclobutylformyl, N-n-pentylcarbonyl, N-isopentylformyl, N-cyclopentylformyl, N-n-hexylformyl, N-isohexyl Carboxyyl, N-cyclohexylcarbonyl, N,N-dimethylformyl, N,N-
  • X - is an anion of a pharmaceutically acceptable inorganic or organic acid salt.
  • R 1 is selected from C1-C24 alkyl.
  • R 1 is selected from C 1 -C 16 alkyl.
  • R 1 is C16 alkyl.
  • R 2 is selected from the group consisting of hydrogen, C1-C4 alkyl, C3 cycloalkyl.
  • R 2 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclopropyl.
  • R 2 is methyl
  • R 3 is Wherein two of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the group consisting of hydrogen:
  • Z 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl; preferably Z 6 is hydrogen.
  • R 3 is Wherein 2 of Z 1 , Z 2 , Z 4 , Z 5 are independently selected from the following, and the rest and Z 3 are hydrogen:
  • Z 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl; preferably Z 6 is hydrogen.
  • R 3 is Wherein Z 1, Z 2, Z 3 , Z 4, Z 5 is Z 1, Z 5 are each independently selected from the rest is hydrogen:
  • Z 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, and C3-C6 cycloalkyl.
  • n is selected from the group consisting of 0, 1.
  • R 4 is independently selected from the group consisting of hydrogen, halogen, nitro, C1-C3 alkyl, C1-C3 alkoxy.
  • R 4 is independently selected from the group consisting of hydrogen, halogen, nitro, C1-C3 alkoxy.
  • R 4 is independently selected from the group consisting of hydrogen, fluorine, chlorine, nitro, methoxy.
  • the pharmaceutically acceptable mineral acid salt is a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a bicarbonate, and a carbonate, sulfate or phosphate
  • Pharmaceutically acceptable organic acid salts are formates, acetates, propionates, benzoates, maleates, fumarates, succinates, tartrates, citrates, ascorbates, Alpha-ketoglutarate, alpha-glycerophosphate, alkylsulfonate or arylsulfonate; preferably, the alkylsulfonate is a methanesulfonate or ethylsulfonate; The aryl sulfonate is a besylate or p-toluenesulfonate.
  • the invention provides the following compounds:
  • the pharmaceutically acceptable salt is a mineral acid salt or an organic acid salt
  • the inorganic acid salt is a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a hydrogencarbonate, and a carbonate, a sulfate or a phosphate
  • the organic acid salt being a formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, a citrate, an ascorbate, an alpha-ketoglutarate, an alpha-glycerophosphate, an alkylsulfonate or an arylsulfonate
  • the alkylsulfonate is a methylsulfonate or Ethyl sulfonate
  • the aryl sulfonate is a besylate or p-toluenesulfonate.
  • C 1 -C 24 alkyl refers to any straight or branched chain group containing from 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl and linear or branched lower alkyl: C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, C11 Alkyl, C12 alkyl, C13 alkyl, C14 alkyl, C15 alkyl, C16 alkyl, C17 alkyl, C18 alkyl, C19 alkyl, C20 alkyl, C21 alkyl, C22 alkyl, C23 alkyl , C24 alkyl and the like.
  • C 1 -C 24 alkyl group includes a straight-chain or branched-chain group having an interval in which any two integers between 1 and 24 are an endpoint.
  • C 1 -C 24 alkyl includes C 1 -C 22 alkyl, C 1 -C 16 alkyl, C 1 -C 4 alkyl, C 2 -C 24 alkyl, C 2 -C 16 alkane
  • C 1 -C 22 alkyl refers to any straight or branched chain group containing from 1 to 22 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl and linear or branched lower alkyl: C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, C11 Alkyl, C12 alkyl, C13 alkyl, C14 alkyl, C15 alkyl, C16 alkyl, C17 alkyl, C18 alkyl, C19 alkyl, C20 alkyl, C21 alkyl, C22 alkyl, and the like.
  • C 1 -C 6 alkyl refers to any straight or branched chain group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl and the like.
  • C 1 -C 4 alkyl refers to any straight or branched chain group containing from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, sec-butyl and the like.
  • oxyalkyl group means a group in which an alkyl skeleton is substituted by one or more alkoxy groups, for example, a methoxyethyl group, a methoxyethoxymethyl group, or the like. .
  • C1-C24 oxyalkyl refers to a group in which a C 1 -C 24 alkyl group is substituted by one or more alkoxy groups, such as methoxy C 1 -C 24 alkyl, methoxy. Ethyl ethoxy group C 1 -C 24 alkyl group and the like.
  • C1-C3 oxyalkyl group means a group in which a C 1 -C 3 alkyl group is substituted by one or more alkoxy groups, such as a methoxy C 1 -C 3 alkyl group, methoxy Ethylethoxy C 1 -C 3 alkyl group and the like.
  • fluorinated alkyl group means a group in which an alkyl skeleton is substituted by one or more fluorine groups, for example, a monofluoromethyl group, a difluoroethyl group, a trifluoromethyl group or the like.
  • C1-C24 fluorine-containing alkyl group means a group in which a C1-C24 alkyl skeleton is substituted by one or more fluorine groups.
  • a C1-C24 alkyl group substituted with 1-3 fluoro groups For example, a C1-C24 alkyl group substituted with 1-3 fluoro groups.
  • C 3 -C 6 cycloalkyl refers to a 3- to 6-membered all-carbon monocyclic ring which may contain zero, one or more double bonds, but does not have a fully conjugated ⁇ -electron system .
  • Examples of cycloalkyl groups are, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene.
  • cyano refers to the -CN residue.
  • nitro refers to a -NO 2 group.
  • alkoxy refers to any of the above alkyl groups (eg, C 1 -C 24 alkyl, C 1 -C 6 alkyl, etc.), cycloalkyl (eg, C). 3 -C 6 cycloalkyl), which is connected to the rest of the molecule through an oxygen atom (-O-).
  • a substituted oxyalkyl group is constructed wherein the alkyl group is as defined above.
  • oxygen-substituted or unsubstituted five- or six-membered ring or "nitrogen-substituted or unsubstituted five- or six-membered ring” means 5- or 6-membered saturated or partially unsaturated A carbocyclic ring in which one or more carbon atoms are replaced by oxygen or nitrogen.
  • Non-limiting examples are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, dihydrofuran, tetrahydrofuran, 1,3-dioxolan, piperidine, piperazine , morpholine, tetrahydropyrrolyl and the like.
  • Z 1 , Z 4 are each independently selected from the following, the remainder being hydrogen: (1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano; (2) C1-C3 alkyl, C1-C3 alkoxy, C1-C3 oxyalkyl, C1-C3 fluoroalkyl, C1-C3 fluoroalkoxy", which means: "Z 1 , Z 5 each Independently selected from the following "including Z 1 , Z 5 are independently listed as "(1) hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano; (2) C1-C3 alkyl, C1- "any combination of any of a group consisting of,” C3 alkoxy, C1-C3 alkyl group containing oxygen, C1-C3
  • the term “pre "Pharmaceutical” means a derivative which can be hydrolyzed, oxidized or otherwise subjected to biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs undergo this reaction to become active compounds only under biological conditions, or they are active in their unreacted form. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, ed., 5th Edition).
  • the term "pharmaceutically acceptable salt of a compound of formula (I)" is an organic acid addition salt formed from an organic acid forming a pharmaceutically acceptable anion, including but not limited to formate, Acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, ascorbate, alpha-ketoglutarate, alpha-glycerophosphate Or an alkyl sulfonate or an aryl sulfonate; preferably, the alkyl sulfonate is a methanesulfonate or ethyl sulfonate; the aryl sulfonate is a besylate or a Tosylate.
  • Suitable inorganic salts can also be formed including, but not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate and carbonate, sulfate or phosphate, and the like.
  • compositions can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.
  • treating generally refers to obtaining the desired pharmacological and/or physiological effects.
  • the effect may be prophylactic according to the prevention of the disease or its symptoms in whole or in part; and/or may be therapeutic according to the partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • treatment encompasses any treatment for a patient's condition, including: (a) prevention of a disease or condition in a patient who is susceptible to an infectious disease or condition but has not yet diagnosed the disease; (b) inhibition of the symptoms of the disease, That is, to prevent its development; or (c) to alleviate the symptoms of the disease, that is, to cause the disease or symptoms to degenerate.
  • the compound, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof wherein the compound is the following example One of the compounds described.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to any one of the above aspects, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvent And a pharmaceutically acceptable carrier, diluent or excipient.
  • a method of preparing the pharmaceutical composition comprises incorporating a suitable pharmaceutical excipient, carrier, diluent, and the like.
  • the pharmaceutical preparations of the invention are prepared in a known manner, including conventional methods of mixing, dissolving or lyophilizing.
  • the compounds of the present invention can be formulated into pharmaceutical compositions and administered to a patient in a variety of ways suitable for the chosen mode of administration, for example, orally or parenterally (by intravenous, intramuscular, topical or subcutaneous routes).
  • the compounds of the invention may be administered systemically, for example, orally, in association with a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules and can be compressed into tablets.
  • a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules and can be compressed into tablets.
  • the active compound may be combined with one or more excipients and in the form of swallowable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. use.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the ratio of such compositions and formulations may of course vary and may range from about 1% to about 99% by weight of a given unit dosage form.
  • the amount of active compound is such that an effective dosage level can be obtained.
  • Tablets, lozenges, pills, capsules and the like may also contain: a binder such as tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, Potato starch, alginic acid, etc.; a lubricant such as magnesium stearate; and a sweetener such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as mint, wintergreen or cherry.
  • a binder such as tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, Potato starch, alginic acid, etc.
  • a lubricant such as magnesium stearate
  • a sweetener such as sucrose, fructose, lactose or aspartame
  • a flavoring agent such as mint, wintergreen or cherry
  • any material used to prepare any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound can be incorporated into sustained release formulations and sustained release devices.
  • the active compound can also be administered intravenously or intraperitoneally by infusion or injection.
  • An aqueous solution of the active compound or a salt thereof can be prepared, optionally mixed with a non-toxic surfactant.
  • Dispersing agents in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof, and oils can also be prepared. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions of the active ingredient (optionally encapsulated in liposomes) containing the immediate formulation of a suitable injectable or injectable solution or dispersing agent. Or sterile powder. In all cases, the final dosage form must be sterile, liquid, and stable under the conditions of manufacture and storage.
  • the liquid carrier can be a solvent or liquid dispersion medium including, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glycerides, and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by liposome formation, by maintaining the desired particle size in the case of a dispersing agent, or by the use of a surfactant.
  • the action of preventing microorganisms can be produced by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents such as sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use of compositions that delay the absorbent (for example, aluminum monostearate and gelatin).
  • Sterile injectable solutions are prepared by combining the required active compound in a suitable solvent with the various other ingredients enumerated above, followed by filter sterilization.
  • the preferred preparation methods are vacuum drying and lyophilization techniques which result in a powder of the active ingredient plus any additional ingredients present in the previously sterile filtration solution. .
  • Useful solid carriers include comminuted solids (e.g., talc, clay, microcrystalline cellulose, silica, alumina, etc.).
  • Useful liquid carriers include water, ethanol or ethylene glycol or a water-ethanol/ethylene glycol mixture, and the compounds of the present invention may be dissolved or dispersed in an effective amount, optionally with the aid of a non-toxic surfactant.
  • Adjuvants such as fragrances
  • additional antimicrobial agents can be added to optimize the properties for a given use.
  • Thickeners can also be used with liquid carriers to form coatable pastes, gels, ointments , soap, etc., used directly on the user's skin.
  • the therapeutic requirements of a compound or an active salt or derivative thereof depend not only on the particular salt selected, but also on the mode of administration, the nature of the disease to be treated, and the age and condition of the patient, ultimately depending on the attending physician or clinician decision.
  • unit dosage form is a unit dispersion unit containing a unit dosage unit suitable for administration to humans and other mammalian bodies.
  • the unit dosage form can be a capsule or tablet, or a plurality of capsules or tablets.
  • the amount of unit dose of the active ingredient may vary or be adjusted between about 0.1 and about 1000 mg or more, depending on the particular treatment involved.
  • milk liposomes such as milk liposomes, microspheres and nanospheres
  • microparticle dispersion systems including polymeric micelles, nanoemulsions, submicroemuls Agents prepared from microcapsules, microspheres, liposomes, and niosomes (also known as nonionic surfactant vesicles).
  • the present invention provides a method for preparing the compound according to any one of the above technical solutions, comprising the steps of:
  • Reaction conditions (a) substitution reaction of brominated hydrocarbons; (b) substitution reaction of brominated hydrocarbons or
  • Reaction conditions (a) a brominated hydrocarbon substitution reaction under basic conditions (such as sodium hydride, sodium t-butylate, etc.); (b) a substitution reaction of a brominated hydrocarbon.
  • the present invention provides a compound according to any one of the above aspects, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, and a compound comprising the same
  • the compounds of the invention are synthesized using the methods described herein or other methods well known in the art.
  • Thin layer chromatography was carried out on a silica gel GF254 precoated plate (Qingdao Marine Chemical Plant). Column chromatography was carried out by silica gel (300-400 mesh, Yantai Zhihuang Silica Gel Development Reagent Factory) under medium pressure or by column chromatography using a pre-packed silica gel cartridge (ISCO or Welch) using an ISCO Combiflash Rf200 rapid purification system. The ingredients were developed by UV light ( ⁇ : 254 nm) and by iodine vapor.
  • the compounds were prepared by preparative HPLC on a Waters Symmetry C18 (19 x 50 mm, 5 ⁇ m) column or via a Waters X Terra RP 18 (30 x 150 mm, 5 ⁇ m) column using a Waters preparative HPLC 600 equipped with a 996 Waters PDA detector and Micromass mod.ZMD single quadrupole mass spectrometry (electrospray ionization, cationic mode).
  • Method 1 Phase A: 0.1% TFA / MeOH 95/5; Phase B: MeOH / H2O 95/5. Gradient: 10 to 90% B for 8 min, 90% B 2 min; flow rate 20 mL/min.
  • Method 2 Phase A: 0.05% NH4OH / MeOH 95/5; Phase B: MeOH / H2O 95/5. Gradient: 10 to 100% B for 8 min, maintaining 100% B 2 min. The flow rate was 20 mL/min.
  • Electrospray (ESI) mass spectra were obtained on a Finnigan LCQ ion trap.
  • HPLC-UV-MS analysis for evaluating compound purity was performed by combining an ion trap MS apparatus with an HPLC system SSP4000 (Thermo Separation Products) equipped with an autosampler LC Pal (CTC Analytics) and a UV6000LP diode array Detector (UV detection 215-400 nm). Device control, data acquisition and processing with Xcalibur 1.2 software (Finnigan). HPLC chromatography was carried out at room temperature and a flow rate of 1 mL/min using a Waters X Terra RP 18 column (4.6 x 50 mm; 3.5 [mu]m).
  • Mobile phase A was ammonium acetate 5 mM buffer (pH 5.5 with acetic acid): acetonitrile 90:10
  • mobile phase B ammonium acetate 5 mM buffer (pH 5.5 with acetic acid): acetonitrile 10:90; gradient 0 to 100% B Perform for 7 minutes and then maintain 100% B for 2 minutes before rebalancing.
  • the ⁇ -substituted benzylamine (10 mmol) was dissolved in 8 mL of methanol and 2 mL of water, stirred in an oil bath at 100 ° C, and 2-chloroethylamine hydrochloride (580 mg, 5 mmol) was dissolved in 8 mL of water. After the pH was adjusted to 7, the mixture was slowly added dropwise to the above solution, and stirred in an oil bath at 100 ° C for 3 hours to stop the reaction.
  • the reaction system was cooled to room temperature, and 20 mL of 2N aqueous sodium hydroxide solution and 50 mL of dichloromethane were added and separated, and the aqueous phase was extracted with dichloromethane (3 ⁇ 40 mL), and the organic phase was collected with saturated sodium chloride. The solution was washed, dried over anhydrous sodium sulfate and concentrated. The obtained product was subjected to silica gel column chromatography (dichloromethane/methanol) to afford compound 1'-a (1.99 mmol).
  • the obtained compound 1'-a was all dissolved in 12 mL of acetonitrile, and triethyl orthoacetate (388 ⁇ L, 2.12 mmol) and acetic acid (122 ⁇ L, 2.12 mmol) were added dropwise under reflux under nitrogen atmosphere for 3.5 hr.
  • the reaction system was cooled to room temperature, concentrated, diluted with 2N aqueous sodium sulfate (20 mL) and dichloromethane (2 ⁇ 40 mL), extracted and separated, and the organic phase was collected, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate After concentration, the compound 1'-b (1.94 mmol) was obtained.
  • the bromoalkane (0.75 mmol) and optionally potassium iodide (187 mg, 1.13 mmol) were dissolved in 2 mL of chloroform, sealed and placed in a 72 ° C oil bath for half an hour, then dissolved in compound 1 ' (0.43 mmol)
  • the above system was added to 1 mL of chloroform, and stirring was continued for 12 hours in an oil bath at 72 ° C to stop the reaction.
  • Compound IIB can also be synthesized using a similar method.
  • the 2-methylbenzimidazole (2.0 mmol, 264 mg) in the starting material B (Schedule 1) was dissolved in 5 mL of N,N-dimethylformamide, stirred at 0 ° C in an ice bath, and then added to the solution.
  • Sodium hydride (3.5 mmol, 140 mg) (CAS: 7646-69-7, Angie, Shanghai) was slowly added, and after stirring for 30 minutes in an ice bath, 1-bromohexadecane in the starting material A (Schedule 1) was added.
  • (2.1 mmol, 641 mg) was dissolved in 1 mL of N,N-dimethylformamide and slowly added dropwise to the above solution, then stirred at room temperature for 4 h.
  • the inhibition of the aldolase activity by the compound is evaluated by its inhibition of the rate of the fructose-1,6-biphosphate (FBP) substrate, which is catalytically decomposed by aldolase.
  • FBP fructose-1,6-biphosphate
  • the method of constructing the enzyme/3-phosphoglycerol dehydrogenase [Racker, E. (1952) J. Biol. Chem. 196, 347-351] performed a biochemical activity test (Table 3).
  • Enzyme activity buffer 50 mM TEA-HCl, pH 7.4, 10 mM EDTA
  • Aldolase activity inhibition rate% (V experimental group- V blank group )/V blank group *100%
  • the inhibitory effect of compounds on aldolase in mouse embryonic fibroblasts can be characterized by detecting the activation of AMPK in MEFs, specifically by Western blot.
  • the phosphorylation level of p-threonine (p-AMPK) and the phosphorylation level (p-ACC) of serine at position 79 of AMPK substrate ACC1/ACC2 were achieved (Fig. 1).
  • MEFs carrying a loxP insertion sequence or wild type were plated in a six-well plate and cultured in DMEM containing 10% serum. If a gene needs to be knocked out at this time, the adenovirus capable of expressing cre should be added to the culture well when the density of the corresponding MEFs with the loxP insertion sequence reaches about 30%, and cultured for more than 24 hours;
  • AMPK ⁇ subunit primary antibody (Cell Signaling Technology, #2532), AMPK 172th threonine phosphorylation primary antibody (Cell Signaling Technology, #2535), ACC primary antibody (Cell Signaling Technology, #3662), ACC 79th serine phosphorylation primary antibody (Cell Signaling Technology, #3661), LAMTOR1 primary antibody (Cell Signaling Technology, #8975), AXIN primary antibody (Cell Signaling Technology, #2074) or LKB1 primary antibody (Cell Signaling Technology, #3047) Dilute 1:1000 to the primary antibody dilution (attached), react with the PVDF membrane for 12 hours at room temperature, and rinse 3 times with TBST buffer;
  • the PVDF membrane was wiped dry, reacted in an ECL mixture (WesternBright ECL HRP substrate, Advansta) and exposed to a medical X-ray film, developed, finally rinsed, dried, and scanned to obtain data on AMPK activation.
  • ECL mixture CosmeticBright ECL HRP substrate, Advansta
  • Cell lysate 20 mM Tris-base, pH 7.5, 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 2.5 mM Sodium pyrophosphate, 1 mM ⁇ -glycerolphosphate, 1% Triton X-100 (v/v);
  • TBST buffer 4.84% Tris-base (m/v), 8% NaCl (m/v), 0.1% Tween-20 (v/v);
  • the compound activates the AMPK test in the liver of mice by inhibiting the activity of aldolase. It is administered by intragastric administration or dissolution of the drug in drinking water, and then the level of triglyceride (TAG) in the liver is detected.
  • TAG triglyceride
  • the method of (western blot) was carried out to detect the phosphorylation level of threonine at position 172 of AMPK and the phosphorylation level of serine at position 79 of the substrate ACC1/ACC2 of AMPK (Fig. 4 and Fig. 5).
  • the effect of the compound by AMPK was further explained by measuring the body weight of the mice after administration (Fig. 6), the morphology of the liver sections (Fig.
  • FIG. 7 shows that the compound (IA-47) activates AMPK activity in the liver by inhibiting aldolase activity in mice.
  • Figure 5 shows that the compound (IA-47) can inhibit aldolase activity in mice by inhibiting aldolase activity. The level of triglycerides.
  • Figure 6 illustrates that compound (IA-47) is effective in reducing body weight in high fat fed obese mice.
  • Figure 7 illustrates that compound (IA-47) is effective in the treatment of fatty liver in high fat fed obese mice.
  • Figure 8 illustrates that compound (IA-47) is effective in reducing blood sugar in iv-GTT.
  • mice The body weight of the mice was weighed at 5 pm every day, and the mice were intragastrically administered with IA-47 at a concentration of 1 mg/kg, and the vehicle was administered intragastrically in the same ratio.
  • mice were sacrificed by cervical dislocation, and the liver of the mice was quickly taken out and placed in a 1.5 mL tube and quenched with liquid nitrogen.
  • AMPK ⁇ subunit primary antibody (Cell Signaling Technology, #2532), AMPK 172th threonine phosphorylation primary antibody (Cell Signaling Technology, #2535), ACC primary antibody (Cell Signaling Technology, #3662), ACC 79th serine phosphorylation primary antibody (Cell Signaling Technology, #3661), LAMTOR1 primary antibody (Cell Signaling Technology, #8975), AXIN primary antibody (Cell Signaling Technology, #2074) or LKB1 primary antibody (Cell Signaling Technology, #3047) Dilute 1:1000 to the primary antibody dilution (attached to the formulation), react with the PVDF membrane for 12 hours at room temperature, and rinse 3 times with TBST buffer;
  • the PVDF membrane was dried, reacted in an ECL mixture (Western Bright ECL HRP substrate, Advansta) and exposed to a medical X-ray film, developed, finally rinsed, dried, and scanned to obtain data on AMPK activation.
  • ECL mixture Cosmetic Bright ECL HRP substrate, Advansta
  • liver lysate (attached), homogenized and crushed, and incubated in boiling water for 5 min.
  • 6-week wild-type C57BL/6J male rats began to withdraw the feed for fasting for four hours at 6:00, measured blood glucose (-120 min) and weighed the body, and administered IA-47 at a dose of 2 mg/kg.
  • the vehicle was administered intragastrically in the same proportion.
  • Cell lysate 20 mM Tris-base, pH 7.5, 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 2.5 mM Sodium pyrophosphate, 1 mM ⁇ -glycerolphosphate, 1% Triton X-100 (v/v);
  • TBST buffer 4.84% Tris-base (m/v), 8% NaCl (m/v), 0.1% Tween-20 (v/v);
  • Liver lysate PBS solution containing 5% Triton X-100 (v/v).
  • the compound activates AMPK in the liver of mice by inhibiting aldolase activity by dissolving the drug in nematode medium, observing the number of surviving nematodes per day, and counting the survival curve (Fig. 9).
  • Compounds by inhibiting aldolase Figure 9 illustrates that compound (IA-47) can extend the lifespan of nematodes.

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Abstract

本发明公开了一类具有醛缩酶选择性抑制活性的化合物，其制备方法、包含该化合物的药物组合物，以及这些化合物在制备用于抑制甘油三酯和胆固醇合成的药物、降低脂肪酸合成的药物、预防和/或治疗肥胖和II型糖尿病的药物、预防和/或治疗肿瘤的药物、预防和/或治疗帕金森症的药物、预防和/或治疗阿尔茨海默症的药物或者延长哺乳动物寿命的药物中的用途

Description

取代咪唑盐类化合物、其制备方法、药用组合物及其应用 技术领域
本发明涉及药物化学领域，具体地，涉及一类具有醛缩酶(aldolase)选择性抑制活性的化合物，其制备方法、包含该化合物的药物组合物，以及这些化合物在制备用于降低脂肪酸合成的药物、抑制甘油三酯和胆固醇合成的药物、预防和/或治疗肥胖以及II型糖尿病的药物、预防和/或治疗肿瘤的药物、预防和/或治疗帕金森症的药物、预防和/或治疗阿尔茨海默症的药物或者延长哺乳动物寿命的药物中的用途。
背景技术
5’-腺苷一磷酸活化的蛋白激酶(AMPK)是调节细胞和机体能量平衡的重要分子(Nat.Rev.Mol.Cell Biol.2012,13,251-262.)。由于AMPK对碳水化合物、脂肪和胆固醇代谢及生物合成具有多功能性的作用，而这些作用又与许多重大疾病，例如糖尿病(Nat.Rev.Endocrinol.2014,10,24-36.)、帕金森症和阿尔兹海默症(Nat.Rev.Mol.Cell Biol.2014,15,634-646.)、肿瘤(Nat.Cell Biol.2011,13,1016-1023.,and Annu Rev Genet.2009,43,67-93.)，以及延长有机体的寿命(Curr.Biol.2007,17,1646-1656,Cell Metab.2013,17,101-112,and Nat.Commun.2013,4,2192.)等密切相关，所以AMPK是治疗重大疾病最吸引人的药物靶标之一。尽管学术界已经运用了多种方法，以AMPK作为靶标得到了诸多激活剂并展开系统研究。然而结果表明，以AMPK作为药物的直接靶标有诸多的缺陷，例如药效不足或特异性较低。因此，亟需开发具有新的作用机制的药物来达到激活AMPK、治疗相关疾病的目的。
醛缩酶(fructose-1,6-bisphosphate aldolase，简称FBP aldolase，本发明中亦称为aldolase，包括醛缩酶A、醛缩酶B以及醛缩酶C)——一个新的AMPK的调节因子，是糖代谢过程中的重要代谢酶。在糖酵解途径中，它催化1,6-二磷酸果糖(FBP)生成3-磷酸甘油醛(G3P)和磷酸二羟丙酮(DHAP)(Eur.J.Biochem.2000,267,1858–1868.)，后者经过多次酶促反应生成丙酮酸。同时，在糖异生途径中，它能够催化这一反应的逆过程。在此过程中，醛缩酶所起的作用是不能被其它代谢酶替代的。在现阶段，对醛缩酶的功能的认识还仅仅局限在其代谢酶本身的性质上。目前已有相关报道表明醛缩酶的某些突变体可能与乳糖不耐受有关，但具体机制还不明确。值得一提的是，在肿瘤组织中，醛缩酶的表达水平明显升高，这很有可能提高了瓦伯格效应(Warburg effect)的水平和促进了肿瘤细胞的发展(J.Biol.Chem.2010,285,11983–11990,and Am.J.Physiol.Cell Physiol.2011,300,C1442–1455.)。亦有证据标明，在肿瘤细胞中敲低醛缩酶会直接引起肿瘤细胞生长的停止(J.Biol.Chem.2012,287,42554-42563.)。
早在1970年以前，研究人员就设计了众多不能被醛缩酶催化转化的1,6-二磷酸果糖类似物，通过与1,6-二磷酸果糖竞争性的结合醛缩酶来达到抑制效果。然而，这些抑制剂都不具有良好的细胞通透性，无法进入细胞内部发挥作用，导致其应用大为受限。目前唯一报道的在生理水平上有效地醛缩酶抑制剂是TDZD-8(Cancer Res.2016,76,4259-4269.)，但该抑制剂存在明确的非醛缩酶的靶标——激酶GSK3。
醛缩酶能够直接调节AMPK的激活，因此可作为一个调节AMPK的重要靶点。醛缩酶抑制剂通过抑制细胞内醛缩酶的活性，能够显著地激活AMPK，可用于预防和治疗低AMPK 水平引起的相关疾病。
发明内容
本发明发明人为了寻找新醛缩酶抑制剂，经过广泛深入的研究，设计、合成了一系列结构新颖、安全性高、具有较高的活性的多取代咪唑盐类衍生物，并且研究了这一类新型衍生物对醛缩酶的抑制活性以及对AMPK信号通路的影响。
本发明提供了以下通式的化合物：
Figure PCTCN2018081898-appb-000001
或上述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物。
更具体地说，本发明提供了以下通式(I、II)的化合物：
Figure PCTCN2018081898-appb-000002
其中取代基和符号的定义下面详细说明。
本发明的一个目的是提供一类具有抑制醛缩酶活性的化合物及其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物。
本发明的另一个目的是提供上述化合物的制备方法。
本发明的另一个目的是提供包含上述化合物的药物组合物。
本发明的另一个目的是提供上述化合物及包含所述化合物的药物组合物在制备抑制醛缩酶活性的药物中的用途。
本发明的另一个目的是提供上述化合物及包含所述化合物的药物组合物在制备抑制胆固醇合成的药物、降低脂肪酸合成的药物、预防和/或治疗肥胖、预防和/或治疗糖尿病的药物、预防和/或治疗肿瘤的药物、预防和/或治疗帕金森症的药物、预防和/或治疗阿尔茨海默症的药物或者延长哺乳动物寿命的药物中的用途。
附图说明
图1说明化合物在小鼠胚胎成纤维细胞(mouse embryonic fibroblasts,MEFs)中能有效抑制醛缩酶的活性。a),b)和c)中的结果显示，所测化合物在200nM时能通过不同程度抑制MEFs细胞中醛缩酶活性，从而不同程度的激活AMPK，促进AMPK的磷酸化(p-AMPK)和其下游底物ACC1/ACC2的磷酸化(p-ACC)。
图2说明化合物对AMPK的激活通过蛋白AXIN依赖的信号通路。在AXIN敲除的MEFs中，所测化合物均不能有效激活AMPK(化合物浓度为200nM)。
图3说明化合物对AMPK的激活通过蛋白LAMTOR1依赖的信号通路。在LAMTOR1 敲除的MEFs中，所测化合物均不能有效激活AMPK(化合物浓度为200nM)。
图4说明化合物(IA-47)在小鼠中能通过抑制醛缩酶活性激活肝脏中AMPK的活性。在高脂喂养的肥胖小鼠中，口服给药(1mg/kg，1次/天)两周能有效抑制醛缩酶活性，激活小鼠肝脏中AMPK的活性。
图5说明化合物(IA-47)在小鼠中能通过抑制醛缩酶活性降低甘油三酯的水平。在高脂喂养的肥胖小鼠中，口服给药(1mg/kg，1次/天)两周能有效抑制醛缩酶活性，降低小鼠肝脏中甘油三酯的水平。
图6说明化合物(IA-47)在高脂喂养的肥胖小鼠中能有效降低其体重。在高脂喂养的肥胖小鼠中，将药物溶于饮水中(200μg/ml)，饲养30天左右就可使其体重由50g以上降至30g左右的正常水平。
图7说明化合物(IA-47)在高脂喂养的肥胖小鼠中能有效治疗脂肪肝。取按照图6给药处理的小鼠肝脏，切片，HE染色之后直接观察肝脏的组织学特征，可见其切片中的脂滴含量明显降低，说明脂肪肝得到有效缓解。
图8说明化合物(IA-47)在iv-GTT中能有效降糖。给空腹的正常小鼠灌胃2mg/kg的IA-47，吸收2小时后再腹腔注射葡萄糖(1g/kg)，在相应的时间点测量其血糖变化。
图9说明化合物(IA-47)能够延长线虫的寿命。
发明详述
本文描述了各种具体实施方案、方式和实施例，包括为了理解所要求保护的本发明而采用的示例性实施方式和定义。尽管以下详细描述给出了具体的优选实施方案，但是本领域技术人员将理解，这些实施方式仅是示例性的，并且本发明可以以其他方式实践。为了确定侵权的目的，本发明的范围将涉及所附权利要求中的任何一个或多个，包括其等同物，以及等同于所述的那些的要素或限制。
本发明是通过下面技术方案实现的。
第一方面，本发明提供了以下通式的化合物：
Figure PCTCN2018081898-appb-000003
或上述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物，
其中，R 1选自C1-C24烷基，C1-C24含氧烷基，C1-C24含氟烷基，C1-C24含氟含氧烷基；
R 2选自氢，C1-C6烷基，C3-C6环烷基；
R 3选自：
1)
Figure PCTCN2018081898-appb-000004
其中Z 1，Z 2，Z 3，Z 4，Z 5各自独立地选自：
(1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基， 乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基，N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基，正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基；
(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
(3)Z 2与Z 3可以形成含氧的取代或未取代的五元环或六元环；取代基可以选自与Z 1相同的取代基；
(4)Z 4与Z 5可以形成含氮的取代或未取代的五元环或六元环；取代基可以选自与Z 1相同的取代基；
Z 6选自氢，C1-C3烷基，C3-C6环烷基；
2)
Figure PCTCN2018081898-appb-000005
其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
3)
Figure PCTCN2018081898-appb-000006
其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
4)
Figure PCTCN2018081898-appb-000007
其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
A环为不存在或任选被取代的苯环，在苯环为取代的情况下，其取代基为一个或多个选自以下的取代基：卤素，硝基，氰基，C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；优选，其取代基为1个或2个选自以下的取代基：卤素，硝基，C1-C3烷氧基；更优选，其取代基为1个或2个选自以下的取代基：氟，氯，硝基，甲氧基；
X -为药学上可以接受的无机酸盐或有机酸盐的阴离子；
但是，排除以下化合物：
Figure PCTCN2018081898-appb-000008
化合物a,b,c,d,e,f,g,h,i,j,k,l,m：
化合物a：R 1为C 16H 33-，R 2为CH 3-，R 3为
Figure PCTCN2018081898-appb-000009
X -为Br -；
化合物b：R 1为C 16H 33-，R 2为CH 3-，R 3为
Figure PCTCN2018081898-appb-000010
X -为Br -；
化合物c：R 1为C 16H 33-，R 2为CH 3-，R 3为
Figure PCTCN2018081898-appb-000011
X -为Br -；
化合物d：R 1为C 16H 33-，R 2为CH 3-，R 3为
Figure PCTCN2018081898-appb-000012
X -为Br -；
化合物e：R 1为C 16H 33-，R 2为CH 3-，R 3为
Figure PCTCN2018081898-appb-000013
X -为Br -；
化合物f：R 1为C 4H 9-，R 2为CH 3-，R 3为
Figure PCTCN2018081898-appb-000014
X -为I -；
化合物g：R 1为C 8H 17-，R 2为CH 3-，R 3为
Figure PCTCN2018081898-appb-000015
X -为I -；
化合物h：R 1为C 12H 25-，R 2为CH 3-，R 3为
Figure PCTCN2018081898-appb-000016
X -为I -；
化合物i：R 1为C 14H 29-，R 2为CH 3-，R 3为
Figure PCTCN2018081898-appb-000017
X -为I -；
化合物j：R 1为C 16H 33-，R 2为CH 3-，R 3为
Figure PCTCN2018081898-appb-000018
X -为I -；
化合物k：R 1为C 18H 37-，R 2为CH 3-，R 3为
Figure PCTCN2018081898-appb-000019
X -为I -；
化合物l：R 1为C 20H 41-，R 2为CH 3-，R 3为
Figure PCTCN2018081898-appb-000020
X -为I -；
化合物m：R 1为C 22H 45-，R 2为CH 3-，R 3为
Figure PCTCN2018081898-appb-000021
X -为I -。
在一些实施方案中，R 1选自C1-C24烷基。
在一些实施方案中，R 1选自C1-C22烷基。
在一些实施方案中，R 2选自氢，C1-C4烷基，C3环烷基。
在一些实施方案中，R 2选自氢，甲基，乙基，异丙基，叔丁基，环丙基。
在一些实施方案中，R 3为
Figure PCTCN2018081898-appb-000022
其中Z 1，Z 2，Z 3，Z 4，Z 5中的2个独立地选 自以下，其余为氢：
(1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基，乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基，N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基，正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基；
(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
Z 6选自氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢或甲基。
在一些实施方案中，R 3为
Figure PCTCN2018081898-appb-000023
其中Z 1，Z 2，Z 3，Z 4，Z 5中的1个独立地选自以下，其余为氢：
(1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基，乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基，N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁 胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基，正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基；
(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
Z 6选自氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢或甲基。
在一些实施方案中，A环为取代的苯环，其取代基为1个或2个选自以下的取代基：卤素，硝基，C1-C3烷氧基；更优选，其取代基为1个或2个选自以下的取代基：氟，氯，硝基，甲氧基。
在一些实施方案中，所述无机酸盐为盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸氢盐和碳酸盐、硫酸盐或磷酸盐，所述有机酸盐为甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、α-酮戊二酸盐、α-甘油磷酸盐、烷基磺酸盐或芳基磺酸盐；优选地，所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐；所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐。
第二方面，本发明提供了一种下面通式I表示的化合物、其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物，
Figure PCTCN2018081898-appb-000024
其中：
R 1选自C1-C24烷基，C1-C24含氧烷基，C1-C24含氟烷基，C1-C24含氟含氧烷基；
R 2选自C1-C6烷基，C3-C6环烷基；
R 3选自
1)
Figure PCTCN2018081898-appb-000025
其中Z 1，Z 2，Z 3，Z 4，Z 5各自独立地选自：
(1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基，乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基，N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰 基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基，正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基；
(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
(3)Z 2与Z 3可以形成含氧的取代或未取代的五元环或六元环；取代基可以选自与Z 1相同的取代基；
(4)Z 4与Z 5可以形成含氮的取代或未取代的五元环或六元环；取代基可以选自与Z 1相同的取代基；
Z 6选自氢，C1-C3烷基，C3-C6环烷基；
2)
Figure PCTCN2018081898-appb-000026
其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
3)
Figure PCTCN2018081898-appb-000027
其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
4)
Figure PCTCN2018081898-appb-000028
其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
X -为药学上可以接受的无机酸盐或有机酸盐的阴离子。
在一些实施方案中，R 1选自C1-C24烷基。
在一些实施方案中，R 1选自C1-C22烷基。
在一些实施方案中，R 2选自氢，C1-C4烷基，C3环烷基。
在一些实施方案中，R 2选自氢，甲基，乙基，异丙基，叔丁基，环丙基。
在一些实施方案中，R 3为
Figure PCTCN2018081898-appb-000029
其中Z 1，Z 2，Z 3，Z 4，Z 5中的2个各自独立地选自以下，其余为氢：
(1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基，乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌 嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基，N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基，正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基；
(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
Z 6选自氢，C1-C3烷基，C3-C6环烷基。
在一些实施方案中，R 3为
Figure PCTCN2018081898-appb-000030
其中Z 1，Z 2，Z 4，Z 5中的2个各自独立地选自以下，其余的以及Z 3为氢：
(1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基，乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基，N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基，正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基；
(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
Z 6选自氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢。
在一些实施方案中，R 3为
Figure PCTCN2018081898-appb-000031
其中Z 1，Z 2，Z 3，Z 4，Z 5中的Z 1，Z 5各自、或Z 2，Z 4各自、或Z 1，Z 4各自独立地选自以下，其余的为氢：
(1)氢，氟，氯，溴，碘，硝基，氰基；
(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
Z 6选自氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢或甲基。
在一些实施方案中，R 3为
Figure PCTCN2018081898-appb-000032
其中Z 1，Z 2，Z 3，Z 4，Z 5中的1个独立地选自以下，其余为氢：
(1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基，乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基，N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基，正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基；
(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
Z 6选自氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢或甲基。
在一些实施方案中，所述无机酸盐为盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸氢盐和碳酸盐、硫酸盐或磷酸盐，所述有机酸盐为甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、α-酮戊二酸盐、α-甘油磷酸盐、烷基磺酸盐或芳基磺酸盐；优选地，所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐；所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐。
第三方面，本发明提供了以下的化合物：
Figure PCTCN2018081898-appb-000033
其中，对于R 1、R 3以及X －的定义如上，
或上述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物。
第四方面，本发明提供了以下通式II结构的化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物：
Figure PCTCN2018081898-appb-000034
其中：
R 1选自C1-C24烷基，C1-C24含氧烷基，C1-C24含氟烷基，C1-C24含氟含氧烷基
R 2选自C1-C6烷基，C3-C6环烷基；
R 3选自
1)
Figure PCTCN2018081898-appb-000035
其中Z 1，Z 2，Z 3，Z 4，Z 5各自独立地选自：
(1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基，乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基，N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁 胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基，正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基；
(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
(3)Z 2与Z 3可以形成含氧的取代或未取代的五元环或六元环；取代基可以选自与Z 1相同的取代基；
(4)Z 4与Z 5可以形成含氮的取代或未取代的五元环或六元环；取代基可以选自与Z 1相同的取代基；
Z 6选自氢，C1-C3烷基，C3-C6环烷基；
2)
Figure PCTCN2018081898-appb-000036
其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
3)
Figure PCTCN2018081898-appb-000037
其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
4)
Figure PCTCN2018081898-appb-000038
其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
n选自0，1，2；
R 4独立地选自氢，卤素，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基，乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基，N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基， 正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基，C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
X -为药学上可以接受的无机酸盐或有机酸盐的阴离子。
在一些实施方案中，R 1选自C1-C24烷基。
在一些实施方案中，R 1选自C1-C16烷基。
在一些实施方案中，R 1为C16烷基。
在一些实施方案中，R 2选自氢，C1-C4烷基，C3环烷基。
在一些实施方案中，R 2选自氢，甲基，乙基，异丙基，叔丁基，环丙基。
在一些实施方案中，R 2为甲基。
在一些实施方案中，R 3为
Figure PCTCN2018081898-appb-000039
其中Z 1，Z 2，Z 3，Z 4，Z 5中的2个各自独立地选自以下，其余为氢：
(1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基，乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基，N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基，正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基；
(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
Z 6选自氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢。
在一些实施方案中，R 3为
Figure PCTCN2018081898-appb-000040
其中Z 1，Z 2，Z 4，Z 5中的2个独立地选自以下，其余以及Z 3为氢：
(1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基， 乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基，N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基，正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基；
(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
Z 6选自为氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢。
在一些实施方案中，R 3为
Figure PCTCN2018081898-appb-000041
其中Z 1，Z 2，Z 3，Z 4，Z 5中的Z 1，Z 5各自独立地选自以下，其余为氢：
(1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基，乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基，N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基 哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基，正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基；
(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
Z 6选自氢，C1-C3烷基，C3-C6环烷基。
在一些实施方案中，n选自0，1。
在一些实施方案中，R 4独立地选自氢，卤素，硝基，C1-C3烷基，C1-C3烷氧基。
在一些实施方案中，R 4独立地选自氢，卤素，硝基，C1-C3烷氧基。
在一些实施方案中，R 4独立地选自氢，氟，氯，硝基，甲氧基。
在一些实施方案中，所述药学上可接受的无机酸盐为盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸氢盐和碳酸盐、硫酸盐或磷酸盐，所述药学上可接受的有机酸盐为甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、α-酮戊二酸盐、α-甘油磷酸盐、烷基磺酸盐或芳基磺酸盐；优选地，所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐；所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐。
第五方面，本发明提供了以下的化合物：
Figure PCTCN2018081898-appb-000042
对于R 1、R 4、n以及X －的定义如上，
或上述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物。
本发明中，所述药学上可接受的盐为无机酸盐或有机酸盐，其中，所述无机酸盐为盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸氢盐和碳酸盐、硫酸盐或磷酸盐，所述有机酸盐为甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、α-酮戊二酸盐、α-甘油磷酸盐、烷基磺酸盐或芳基磺酸盐；优选地，所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐；所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐。
除非特殊说明，上述基团和取代基具有药物化学领域的普通含义。
术语“C 1-C 24烷基”指的是任意的含有1－24个碳原子的直链或支链基团，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、叔戊基、正己基以及直链或支链的以下烷基：C7烷基、C8烷基、C9烷基、C10烷基、C11烷基、C12烷基、C13烷基、C14烷基、C15烷基、C16烷基、C17烷基、C18烷基、C19烷基、C20烷基、C21烷基、C22烷基、C23烷基、C24烷基等。
而且，所述“C 1-C 24烷基”包括碳原子数为1－24之间的任意两个整数为端点的区间的直链或支链基团。例如，“C 1-C 24烷基”包括C 1-C 22烷基、C 1-C 16烷基、C 1-C 4烷基、C 2-C 24烷基、C 2-C 16烷基、C 6-C 24烷基、C 6-C 16烷基、等等，以上所列仅仅为举例而言，并不是对于所述区间的限定。
术语“C 1-C 22烷基”指的是任意的含有1－22个碳原子的直链或支链基团，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、叔戊基、 正己基以及直链或支链的以下烷基：C7烷基、C8烷基、C9烷基、C10烷基、C11烷基、C12烷基、C13烷基、C14烷基、C15烷基、C16烷基、C17烷基、C18烷基、C19烷基、C20烷基、C21烷基、C22烷基等。
术语“C 1-C 6烷基”指的是任意的含有1－6个碳原子的直链或支链基团，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、叔戊基、正己基等。
术语“C 1-C 4烷基”指的是任意的含有1－4个碳原子的直链或支链基团，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基等。
需要说明的是，“含氧烷基”是指是指烷基骨架被一个或多个烷氧基取代所成的基团，例如，甲氧基乙基，甲氧基乙氧基甲基等。
例如，“C1-C24含氧烷基”是指C 1-C 24烷基被一个或多个烷氧基取代所成的基团，诸如，甲氧基C 1-C 24烷基，甲氧基乙氧基C 1-C 24烷基等。
或者，“C1-C3含氧烷基”是指C 1-C 3烷基被一个或多个烷氧基取代所成的基团，诸如，甲氧基C 1-C 3烷基，甲氧基乙氧基C 1-C 3烷基等。
“含氟烷基”是指烷基骨架被一个或多个氟基取代所成的基团，例如，单氟甲基，二氟乙基，三氟甲基等。
“C1-C24含氟烷基”是指C1-C24烷基骨架被一个或多个氟基取代所成的基团。例如，被1-3个氟基取代的C1-C24烷基。
术语“C 3-C 6环烷基”指的是3-至6-元全-碳单环，其可以包含0个、一个或多个双键，但不具有完全共轭的π-电子系统。环烷基的实例是、但不限于环丙烷、环丁烷、环戊烷、环戊烯、环己烷、环己烯、环己二烯。
术语“氰基”指的是-CN残基。
术语“硝基”指的是-NO 2基团。
术语“烷氧基”、“环基氧基”及其衍生物指的是任意上述烷基(例如C 1-C 24烷基、C 1-C 6烷基等)、环烷基(例如C 3-C 6环烷基)，其通过氧原子(-O-)连接到分子的其余部分。
从所有上述描述中，对本领域技术人员显而易见的是，其名称是复合名称的任意基团，例如“含氟含氧烷基”，应该指的是常规地从其衍生的部分例如从被氟基取代的含氧烷基来构建，其中烷基如上文所定义。
术语“含氧的取代或未取代的五元环或六元环”或“含氮的取代或未取代的五元环或六元环”指的是5-或6-元饱和或部分不饱和碳环，其中一个或多个碳原子被氧或氮替代。非限制性实例是，例如吡喃、吡咯烷、吡咯啉、咪唑啉、咪唑烷、吡唑烷、吡唑啉、二氢呋喃、四氢呋喃、1,3-二氧戊环、哌啶、哌嗪、吗啉、四氢吡咯基等。
在上述对于R 3中的Z 1，Z 2，Z 3，Z 4，Z 5的定义中，对于“其中，Z 1，Z 2，Z 3，Z 4，Z 5中的Z 1，Z 5各自、或Z 2，Z 4各自、或Z 1，Z 4各自独立地选自以下，其余的为氢：(1)氢，氟，氯，溴，碘，硝基，氰基；(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基”，其意指：“Z 1，Z 5各自独立地选自以下”包括Z 1，Z 5独立地分别为所列举的“(1)氢，氟，氯，溴，碘，硝基，氰基；(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基”中的任一个基团所构成的任意组合，“Z 2，Z 4各自独立地选自以下”包括Z 2，Z 4独立地分别为所列举的“(1)氢，氟，氯，溴，碘，硝基，氰基；(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基”中的任一个基团所构成的任意组合，“Z 1，Z 4各自 独立地选自以下”包括Z 1，Z 4独立地分别为所列举的“(1)氢，氟，氯，溴，碘，硝基，氰基；(2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基”中的任一个基团所构成的任意组合.如本文所使用，除非另外说明，术语“前药”是指可以在生物学条件(体外或体内)下水解、氧化或进行其他反应以提供本发明的化合物的衍生物。前药仅在生物学条件下经过该反应成为活性化合物，或者它们在它们不反应的形式中具有活性。通常可以使用公知的方法制备前药，例如Burger's Medicinal Chemistry and Drug Discovery(1995)172-178,949-982(Manfred E.Wolff编,第5版)中描述的那些方法。
如本文所使用，术语“式(I)化合物的药学上可以接受的盐”的例子是由形成药学上可以接受的阴离子的有机酸形成的有机酸加合盐，包括但不限于甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、α-酮戊二酸盐、α-甘油磷酸盐、烷基磺酸盐或芳基磺酸盐；优选地，所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐；所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐。也可形成合适的无机盐，包括但不限于盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸氢盐和碳酸盐、硫酸盐或磷酸盐等。
药学上可以接受的盐可使用本领域熟知的标准程序获得，例如，通过将足量的碱性化合物和提供药学上可以接受的阴离子的合适的酸反应。
本文使用的术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据完全或部分地预防疾病或其症状，可以是预防性的；和/或根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)预防易感染疾病或症状但还没诊断出患病的患者所发生的疾病或症状；(b)抑制疾病的症状，即阻止其发展；或(c)缓解疾病的症状，即，导致疾病或症状退化。
按照本发明的一种具体技术方案，所述化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物，其中所述化合物为下面实施例中所述化合物之一。
另一方面，本发明提供了药物组合物，其包含上述任一技术方案所述的化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物，和药学上可接受的载体、稀释剂或赋形剂。
制备各种含有一定量的活性成分的药物组合物的方法是已知的，或根据本发明的公开内容对于本领域技术人员是显而易见的。如REMINGTON’S PHARMACEUTICAL SCIENCES,Martin,E.W.,ed.,Mack Publishing Company,19th ed.(1995)所述，制备所述药物组合物的方法包括掺入适当的药学赋形剂、载体、稀释剂等。
以已知的方法制造本发明的药物制剂，包括常规的混合、溶解或冻干方法。本发明的化合物可以制成药物组合物，并向患者以适于选定的施用方式的各种途径施用，例如，口服或肠胃外(通过静脉内、肌内、局部或皮下途径)。
因此，本发明的化合物结合药学上可以接受的载体(如惰性稀释剂或可同化的可食用的载体)可以全身施用，例如，口服。它们可以封闭在硬或软壳的明胶胶囊中，可以压为片剂。对于口服治疗施用，活性化合物可以结合一种或多种赋形剂，并以可吞咽的片剂、颊含片剂、含片、胶囊剂、酏剂、悬浮剂、糖浆、圆片等的形式使用。这种组合物和制剂应该包含至少0.1％的活性化合物。这种组合物和制剂的比例当然可以变化，可以占给定的单位剂型重量的大约1％至大约99％。在这种治疗有用的组合物中，活性化合物的量使得能够获得有效剂量水平。
片剂、含片、丸剂、胶囊剂等也可以包含：粘合剂，如黄蓍胶、阿拉伯胶、玉米淀粉或明胶；赋形剂，如磷酸氢二钙；崩解剂，如玉米淀粉、马铃薯淀粉、藻酸等；润滑剂， 如硬脂酸镁；和甜味剂，如蔗糖、果糖、乳糖或阿司帕坦；或调味剂，如薄荷、冬青油或樱桃香味。当单位剂型是胶囊时，除了上面类型的材料，它还可以包含液体载体，如植物油或聚乙二醇。各种其他材料可以存在，作为包衣，或以其他方式改变固体单位剂型的物理形式。例如，片剂、丸剂或胶囊剂可以用明胶、蜡、虫胶或糖等包衣。糖浆或酏剂可以包含活性化合物，蔗糖或果糖作为甜味剂，对羟苯甲酸甲酯或对羟苯甲酸丙酯作为防腐剂，染料和调味剂(如樱桃香料或桔子香料)。当然，用于制备任何单位剂型的任何材料应该是药学上可以接受的且以应用的量基本上无毒。此外，活性化合物可以掺入缓释制剂和缓释装置中。
活性化合物也可以通过输注或注射来静脉内或腹膜内施用。可以制备活性化合物或其盐的水溶液，任选地混和无毒的表面活性剂。也可以制备在甘油、液体聚乙二醇、甘油三乙酸酯及其混合物以及油中的分散剂。在普通的储存和使用条件下，这些制剂包含防腐剂以防止微生物生长。
适于注射或输注的药物剂型可以包括包含适于无菌的可注射或可输注的溶液或分散剂的即时制剂的活性成分(任选封装在脂质体中)的无菌水溶液或分散剂或无菌粉末。在所有情况下，最终的剂型在生产和储存条件下必须是无菌的、液体的和稳定的。液体载体可以是溶剂或液体分散介质，包括，例如水、乙醇、多元醇(例如，甘油、丙二醇、液体聚乙二醇等)、植物油、无毒的甘油酯及其合适的混合物。可以维持合适的流动性，例如，通过脂质体的形成，通过在分散剂的情况下维持所需的粒子大小，或通过表面活性剂的使用。可以通过各种抗细菌剂和抗真菌剂(如对羟苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)产生预防微生物的作用。在许多情况下，优选包括等渗剂，如糖、缓冲剂或氯化钠。通过使用延缓吸收剂的组合物(例如，单硬脂酸铝和明胶)可以产生可注射的组合物的延长吸收。
通过将合适的溶剂中的需要量的活性化合物与需要的上面列举的各种其他成分结合，然后进行过滤灭菌，制备无菌可注射溶液。在用于制备无菌注射溶液的无菌粉末的情况下，优选的制备方法是真空干燥和冷冻干燥技术，这会产生活性成分加上任何另外需要的以前无菌过滤溶液中存在的成分的粉末。
有用的固体载体包括粉碎的固体(如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等)。有用的液体载体包括水、乙醇或乙二醇或水-乙醇/乙二醇混合物，本发明的化合物可以任选在无毒的表面活性剂的帮助下以有效含量溶解或分散在其中。可以加入佐剂(如香味)和另外的抗微生物剂来优化对于给定用途的性质。
增稠剂(如合成的聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性无机材料)也可和液体载体用于形成可涂覆的糊剂、凝胶、软膏、肥皂等，直接用于使用者的皮肤上。
化合物或其活性盐或衍生物的治疗需要量，不仅取决于选择的特定的盐，而且取决于施药方式、待治疗的疾病的本质和患者的年龄和状态，最终取决于在场医师或临床医生的决定。
上述制剂可以以单位剂型存在，该单位剂型是含有单位剂量的物理分散单元，适于向人体和其它哺乳动物体给药。单位剂型可以是胶囊或片剂，或是很多胶囊或片剂。根据所涉及的具体治疗，活性成分的单位剂量的量可以在大约0.1到大约1000毫克或更多之间进行变化或调整。
此外，还包括各种药物新剂型如乳脂质体、微球和纳米球的应用，如使用微粒分散体系包括聚合物胶束(polymeric micelles)、纳米乳(nanoemulsion)、亚微乳(submicroemuls 微囊(microcapsule)、微球(microsphere)、脂质体(liposomes)和类脂囊泡(niosomes)(又称非离子表面活性剂囊泡)等制备的药剂。
另一方面，本发明还提供了上述任一技术方案所述化合物的制备方法，包括下面步骤：
Figure PCTCN2018081898-appb-000043
反应条件：(a)溴代烃类的取代反应；(b)溴代烃类的取代反应或
Figure PCTCN2018081898-appb-000044
反应条件：(a)碱性条件下(如氢化钠，叔丁基醇钠等)的溴代烃类取代反应；(b)溴代烃类的取代反应。
另一方面，本发明还提供了上述任一技术方案所述化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物及包含该化合物的药物组合物在制备用于抑制胆固醇合成的药物、降低脂肪酸合成的药物、预防和/或治疗糖尿病的药物、预防和/或治疗肿瘤的药物、预防和/或治疗帕金森症的药物、预防和/或治疗阿尔茨海默症的药物或者延长哺乳动物寿命的药物中的用途。
实验部分
就如下涉及的实施例而言，使用本文所述的方法或本领域众所周知的其他方法合成本发明的化合物。
通用纯化和分析方法
在硅胶GF254预涂覆板(青岛海洋化工厂)上进行薄层色谱。在中压下经硅胶(300-400目，烟台芝黄务硅胶开发试剂厂)进行柱色谱分离或通过使用ISCO Combiflash Rf200快速纯化系统用预装的硅胶筒(ISCO或Welch)进行柱色谱分离。成分通过UV光(λ:254nm)和通过碘蒸气显影。当必要时，将化合物通过制备型HPLC制备经Waters Symmetry C18(19x50mm,5μm)柱或经Waters X Terra RP 18(30x150mm,5μm)柱纯化，使用装配有996Waters PDA检测器的Waters制备型HPLC 600和Micromass mod.ZMD单四级质谱(电喷雾离子化，阳离子模式)。方法1：相A:0.1％TFA/MeOH 95/5；相B:MeOH/H2O 95/5。梯度：10至90％B进行8min，保持90％B 2min；流速20mL/min。方法2：相A:0.05％NH4OH/MeOH 95/5；相B:MeOH/H2O 95/5。梯度：10至100％B进行8min，保持100％B 2min。流速20mL/min。
将 1H-NMR谱在DMSO-d6或CDCl3中经在600MHz操作的Bruker Avance 600谱仪(对于1H而言)进行记录。将残留溶剂信号用作参比(δ＝2.50或7.27ppm)。化学位移(δ)以百万分率(ppm)进行报道且偶合常数(J)以Hz计。以下缩写用于峰裂分:s＝单；br.s.＝宽信号；d＝双；t＝三；m＝多重；dd＝双双。
电喷雾(ESI)质谱经Finnigan LCQ离子阱获得。
除非另外说明，所有最终化合物均是均质的(纯度不低于95％)，如高效液相色谱(HPLC)所确定。用于评价化合物纯度的HPLC-UV-MS分析通过组合离子阱MS设备与HPLC系统 SSP4000(Thermo Separation Products)来进行，所述HPLC系统装配有自动进样器LC Pal(CTC Analytics)和UV6000LP二极管阵列检测器(UV检测215-400nm)。用Xcalibur 1.2软件(Finnigan)进行设备控制、数据采集和处理。HPLC色谱法在室温和1mL/min流速下进行，其使用Waters X Terra RP 18柱(4.6x50mm；3.5μm)。流动相A是乙酸铵5mM缓冲液(采用乙酸得到pH 5.5):乙腈90:10，流动相B乙酸铵5mM缓冲液(采用乙酸得到pH 5.5):乙腈10:90；梯度为0至100％B进行7分钟，然后在再平衡前保持100％B达2分钟。
试剂纯化参考Purification of Laboratory Chemicals(Perrin,D.D.,Armarego,W.L.F.and Perrins Eds,D.R.；Pergamon Press:Oxford,1980)一书进行。石油醚是60-90℃馏分、乙酸乙酯、甲醇、二氯甲烷均为分析纯。
具体实施方式
下面通过具体实施例详细描述本发明的实施方式，但是无论如何它们不能解释为对本发明的限制。
Figure PCTCN2018081898-appb-000045
上述通式化合物分成两类合成制备。
化合物I的通式
Figure PCTCN2018081898-appb-000046
其中，
化合物IA的合成方法一通式
Figure PCTCN2018081898-appb-000047
化合物1的制备
Figure PCTCN2018081898-appb-000048
将化合物2-甲基咪唑(821mg,10mmol)溶于10mL乙醇中，向该溶液加入溴代烷烃(12mmol)后置于70℃油浴中搅拌，直至2-甲基咪唑反应完全(LC-MS跟踪)。停止反应，将体系浓缩，硅胶柱层析(二氯甲烷/甲醇)，得到化合物1-烷基-2-甲基咪唑(1)。
化合物IA的制备
Figure PCTCN2018081898-appb-000049
将多取代苄基溴(0.23mmol)和可任选存在或不存在的碘化钾(74.7mg,0.462mmol)先后溶于1.5mL氯仿中，在密闭条件下置于65℃油浴中搅拌20分钟，再向该体系中加入化合物1(0.154mmol)，在密闭条件下置于65℃油浴中继续搅拌直至反应完全(LC-MS跟踪)。停止反应，将体系过滤，滤液浓缩，硅胶柱层析(二氯甲烷/甲醇)，获得化合物IA。
下面描述化合物IA的合成方法一的具体实施。
1.化合物IA-1:
Figure PCTCN2018081898-appb-000050
将原料B(附表1)中的2-甲基咪唑(328.4mg,4mmol)溶于4mL乙醇中，向该溶液加入原料A(附表1)中的溴甲烷(455.7mg,4.8mmol)，体系置于70℃油浴中搅拌10h，将体系浓缩，硅胶柱层析(二氯甲烷/甲醇＝20/1)，得到化合物1,2-二甲基咪唑(150.8mg,39.2％)。
将原料C(附表1)中的3,5-二甲氧基溴苄(46.2mg,0.2mmol)和可任选存在或不存在的碘化钾(49.8mg,0.3mmol)(CAS:7681-11-0，安耐吉，上海)先后溶于1.5mL氯仿中，在密闭条件下置于65℃油浴中搅拌20分钟，再向该体系中加入1,2-二甲基咪唑(10mg,0.1mmol)，在密闭条件下置于65℃油浴中继续搅拌6h。停止反应，将体系过滤，滤液浓缩，硅胶柱层析(二氯甲烷/甲醇＝12/1)，获得化合物IA-1(29.5mg,90.2％)。
2.化合物IA-2～IA-98使用类似的方法合成，相应的原料见附表1。
3.化合物IB、IC、ID、IE、IF均可使用类似的方法合成，相应的原料见附表1。
化合物IA的合成方法二通式
Figure PCTCN2018081898-appb-000051
化合物1’-a的制备
Figure PCTCN2018081898-appb-000052
将α-取代苄胺(10mmol)溶于8mL甲醇和2mL水中，置于100℃油浴搅拌，将2- 氯乙胺盐酸盐(580mg，5mmol)溶于8mL水，用饱和碳酸钾溶液将其pH调至7后，缓慢滴加至上述溶液中，100℃油浴搅拌3h，停止反应。反应体系冷却至室温，在快速搅拌条件下加入20mL 2N的氢氧化钠水溶液和50mL二氯甲烷并分液，水相用二氯甲烷(3×40mL)萃取，收集有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥后浓缩。得到的产物经硅胶柱层析(二氯甲烷/甲醇)获得化合物1’-a(1.99mmol)。
化合物1’-b的制备
Figure PCTCN2018081898-appb-000053
将得到的化合物1’-a全部溶于12mL乙腈，滴加原乙酸三乙酯(388μL，2.12mmol)和醋酸(122μL，2.12mmol)在氮气保护条件下回流搅拌3.5h，停止反应。反应体系冷却至室温，浓缩，用2N氢氧化钠水溶液(20mL)和二氯甲烷(2×40mL)溶解、萃取并分液，收集有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥后浓缩，得到化合物1’-b(1.94mmol)。
化合物1’的制备
Figure PCTCN2018081898-appb-000054
将化合物1’-b(0.8mmol)溶于苯(3mL)，高锰酸钾(188mg，1.19mmol)溶于水(6mL)，两相混合，加入苄基三乙基溴化铵(10.9mg，0.04mmol)在室温下剧烈搅拌4h，停止反应。用二氯甲烷稀释反应体系，硅藻土过滤，用二氯甲烷(100mL)和水(100mL)冲洗，将滤液分液，收集有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥后浓缩，得到化合物1’(0.43mmol)。
化合物IA的制备
Figure PCTCN2018081898-appb-000055
将溴代烷烃(0.75mmol)和可任选存在或不存在的碘化钾(187mg，1.13mmol)溶于2mL氯仿，封口置于72℃油浴搅拌半小时，再将化合物1’(0.43mmol)溶于1mL氯仿加入以上体系，继续72℃油浴搅拌12h，停止反应。将体系过滤，浓缩，用硅胶柱层析(二氯甲烷/甲醇)，再经反相制备型HPLC纯化(以含0.35％三氟乙酸的水溶液和甲醇为流动相)，经真空浓缩得化合物I(0.086mmol)。
化合物IB、IC、ID、IE、IF均可使用类似的方法合成。
下面描述化合物IA的合成方法二的具体实施。
1.化合物IA-99:
Figure PCTCN2018081898-appb-000056
将R(+)-α-甲基苄胺(1211.8mg,10mmol)(CAS:3886-69-9，毕得，上海)溶于8mL甲醇和2mL水中，置于100℃油浴搅拌，将2-氯乙胺盐酸盐(580mg，5mmol)(CAS:870-24-6，毕得，上海)溶于8mL水，用饱和碳酸钾溶液将其pH调至7后，缓慢滴加至上述溶液中，100℃油浴搅拌3h，停止反应。反应体系冷却至室温，在快速搅拌条件下加入20mL 2N的氢氧化钠水溶液和50mL二氯甲烷并分液，水相用二氯甲烷(3×40mL)萃取，收集有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥后浓缩。得到的产物经硅胶柱层析(二氯甲烷/甲醇＝10/1)获得化合物
Figure PCTCN2018081898-appb-000057
(327mg,40％)。
将化合物
Figure PCTCN2018081898-appb-000058
(1.99mmol，327mg)溶于12mL乙腈，滴加原乙酸三乙酯(388μL，2.12mmol)(CAS:78-39-7，迈瑞尔，上海)和醋酸(122μL，2.12mmol)在氮气保护条件下回流搅拌3.5h，停止反应。反应体系冷却至室温，浓缩，用2N氢氧化钠水溶液(20mL)和二氯甲烷(2×40mL)溶解、萃取并分液，收集有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥后浓缩，得到化合物
Figure PCTCN2018081898-appb-000059
(365mg,97％)。
将化合物
Figure PCTCN2018081898-appb-000060
(0.8mmol,150mg)溶于苯(3mL)，高锰酸钾(1.19mmol,188mg)(CAS:7722-64-7，杭州萧山，浙江)溶于水(6mL)，两相混合，加入苄基三乙基溴化铵(0.04mmol,10.9mg)(CAS:5197-95-5,麦克林，上海)在室温下剧烈搅拌4h，停止反应。用二氯甲烷稀释反应体系，硅藻土过滤，用二氯甲烷(100mL)和水(100mL)冲洗，将滤液分液，收集有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥后浓缩，得到化合物
Figure PCTCN2018081898-appb-000061
(80mg,53.7％)。
将1-溴十六烷(0.75mmol，229.8mg)(CAS:112-82-3，麦克林，上海)和可任选存在或不存在的碘化钾(187mg，1.13mmol)(CAS:7681-11-0，安耐吉，上海)溶于2mL氯仿，封口置于72℃油浴搅拌半小时，再将化合物
Figure PCTCN2018081898-appb-000062
(0.37mmol，70mg)溶于1mL氯仿加入以上体系，继续72℃油浴搅拌12h，停止反应。将体系过滤，浓缩，用硅胶柱层 析(二氯甲烷/甲醇＝40/1)，再经反相制备型HPLC纯化(以含0.35％三氟乙酸的水溶液和甲醇为流动相)，经真空浓缩得化合物
Figure PCTCN2018081898-appb-000063
(42.4mg,22.9％)。
2.化合物IA-100:
Figure PCTCN2018081898-appb-000064
以化合物(S)-(-)-α-甲基苄胺(CAS:2627-86-3,毕得，上海)为起始原料，以类似IA-99的合成方法获得化合物IA-100。
3.化合物IA-101:
Figure PCTCN2018081898-appb-000065
以化合物(R)-1-(2,6-二氯苯基)乙胺盐酸盐(CAS:1131737-05-7,一飞，上海)为起始原料，以类似IA-99的合成方法获得化合物IA-101。
4.化合物IA-102:
Figure PCTCN2018081898-appb-000066
以化合物(S)-1-(2,6-二氯苯基)乙胺盐酸盐(CAS:121443-79-6,一飞，上海)为起始原料，以类似IA-99的合成方法获得化合物IA-102。
表1.化合物IA—IF结构及表征
Figure PCTCN2018081898-appb-000067
Figure PCTCN2018081898-appb-000068
Figure PCTCN2018081898-appb-000069
Figure PCTCN2018081898-appb-000070
Figure PCTCN2018081898-appb-000071
Figure PCTCN2018081898-appb-000072
Figure PCTCN2018081898-appb-000073
Figure PCTCN2018081898-appb-000074
Figure PCTCN2018081898-appb-000075
Figure PCTCN2018081898-appb-000076
Figure PCTCN2018081898-appb-000077
Figure PCTCN2018081898-appb-000078
Figure PCTCN2018081898-appb-000079
Figure PCTCN2018081898-appb-000080
Figure PCTCN2018081898-appb-000081
Figure PCTCN2018081898-appb-000082
Figure PCTCN2018081898-appb-000083
Figure PCTCN2018081898-appb-000084
Figure PCTCN2018081898-appb-000085
Figure PCTCN2018081898-appb-000086
化合物II的通式
Figure PCTCN2018081898-appb-000087
其中，
化合物IIA的合成通式
Figure PCTCN2018081898-appb-000088
化合物2的制备
Figure PCTCN2018081898-appb-000089
将化合物2(2.0mmol)溶于5mL N,N-二甲基甲酰胺中，置于0℃冰浴搅拌，然后向此溶液中缓慢加入氢化钠(140mg，3.5mmol)，继续冰浴搅拌30分钟后，将溴代烷烃(2.1mmol)溶于1mL N,N-二甲基甲酰胺，再缓慢滴加至以上溶液中，然后置于室温搅拌，至化合物2反应完全(LC-MS跟踪)。停止反应，向反应液中先后加入大量水和乙酸乙酯，萃取并分液，有机相用饱和氯化钠溶液洗涤两次，无水硫酸钠干燥，浓缩硅胶柱层析(二氯甲烷/甲醇)得化合物3。
化合物IIA的制备
Figure PCTCN2018081898-appb-000090
将2-氯-6-氟苄基溴(58mg,0.252mmol)和可任选存在或不存在的碘化钾(83.6mg,0.5mmol)先后溶于1.5mL氯仿中，在密闭条件下置于75℃油浴中搅拌20分钟，再向该体系中加入化合物3(0.168mmol)，在密闭条件下置于75℃油浴中继续搅拌直至反应完全(LC-MS跟踪)。停止反应，将体系过滤，滤液浓缩，硅胶柱层析(二氯甲烷/甲醇)，获得化合物IIA。
化合物IIB亦可使用类似的方法合成。
下面具体描述实施例化合物的合成。
1.化合物IIA-1
Figure PCTCN2018081898-appb-000091
将原料B(附表1)中的2-甲基苯并咪唑(2.0mmol,264mg)溶于5mL N,N-二甲基甲酰胺中，置于0℃冰浴搅拌，然后向此溶液中缓慢加入氢化钠(3.5mmol,140mg)(CAS:7646-69-7，安耐吉，上海)，继续冰浴搅拌30分钟后，将原料A(附表1)中的1-溴十六烷(2.1mmol，641mg)溶于1mL N,N-二甲基甲酰胺，再缓慢滴加至以上溶液中，然后置于室温搅拌4h。停止反应，向反应液中先后加入大量水和乙酸乙酯，萃取并分液，有机相用饱和氯化钠溶液洗涤两次，无水硫酸钠干燥，浓缩硅胶柱层析(二氯甲烷)得化合物
Figure PCTCN2018081898-appb-000092
(499mg，70％)。
将原料C(附表1)中的2-氯-6-氟苄基溴(0.252mmol，58mg)和可任选存在或不存在的碘化钾(0.5mmol，83.6mg)(CAS:7681-11-0，安耐吉，上海)先后溶于1.5mL氯仿中，在密闭条件下置于75℃油浴中搅拌20分钟，再向该体系中加入化合物
Figure PCTCN2018081898-appb-000093
(0.168mmol，60mg)，在密闭条件下置于75℃油浴中继续搅拌8h。停止反应，将体系过滤，滤液浓缩，硅胶柱层析(二氯甲烷/甲醇＝50/1)，获得化合物IIA-1。
2.化合物IIA-2～IIA-5以及IIB-1～IIB-4均可使用类似的方法合成，相应的原料见附表1。
表2.化合物IIA、IIB结构及表征
Figure PCTCN2018081898-appb-000094
Figure PCTCN2018081898-appb-000095
Figure PCTCN2018081898-appb-000096
试验例
生物活性测试：
1.蛋白水平活性测试
化合物对醛缩酶活性的抑制通过其对醛缩酶催化分解底物果糖1，6二磷酸(fructose-1,6-biphosphate,FBP)速度的抑制进行评价，我们具体采用偶联磷酸丙糖异构酶/3-磷酸甘油脱氢酶的方法[Racker,E.(1952)J.Biol.Chem.196,347–351]进行生物化学活性测试(表3)。
具体方法如下：
(1)将大约250ng醛缩酶A溶于30μL水中，加到石英底96孔板底部，并向醛缩酶A溶液中加入化合物(溶解于DMSO，含量不超过反应总体积的1％)，晃动混匀，室温孵育30分钟；
(2)加入70μL酶活反应体系(配方附后)，立即放入酶标仪(SpectraMax M5,Molecular Devices)中，37℃进行反应，同时每30s测量一次340nM的吸光值，每孔共测得61个吸光值，吸光值随时间线性变化，斜率即为该孔中醛缩酶的酶活力，具体数值由SoftMax Pro 5.4.1计算得出；
酶活反应体系:
a.酶活反应缓冲液(50mM TEA-HCl,pH 7.4,10mM EDTA)
b.FBP(500μM)
c.NADH(1mM)
d.磷酸丙糖异构酶(约20U)
e.3-磷酸甘油脱氢酶(约2U)
f.DTE(20mM)
(3)每组实验设置两个平行，以终浓度为1％DMSO为空白对照，化合物终浓度为100μM。醛缩酶活性的抑制率由以下公式计算：
醛缩酶活性抑制率％＝(V 实验组-V 空白组)/V 空白组*100％
表3.化合物抑制醛缩酶活性的结果
Figure PCTCN2018081898-appb-000097
*化合物测试浓度为100μM。
2.细胞水平活性测试
化合物在小鼠胚胎成纤维细胞(mouse embryonic fibroblasts,MEFs)中对醛缩酶抑制效果的可通过检测MEFs中的AMPK的激活进行表征，具体可以通过免疫印迹(western blot)的方法检测AMPK第172位苏氨酸的磷酸化水平(p-AMPK)以及AMPK的底物ACC1/ACC2第79位丝氨酸的磷酸化水平(p-ACC)实现(图1)。
进一步实验表明在蛋白AXIN(图2)和LAMTOR1(图3)敲除的MEFs中，化合物均不能有效激活AMPK，证明所测化合物对AMPK的激活是通过Aldolase-AXIN-LAMTOR1信号通路起作用的。
具体方法如下：
(1)将带有loxP插入序列的或者野生型的MEFs铺到六孔板中，培养在含有10％血清的DMEM中。若此时需要敲除某个基因，则应在相应的带有loxP插入序列的MEFs密度达到30％左右时向培养孔中加入能够表达cre的腺病毒，再培养24小时以上；
(2)当细胞密度接近90％时，给细胞换上新鲜的DMEM，同时向细胞中加入化合物(终浓度200μM)培养2小时，用等体积DMSO作为阴性对照，并用不含葡萄糖的DMEM培养基处理的细胞作为阳性对照；
(3)吸掉培养液，用200μL细胞裂解液(配方附后)裂解细胞，将细胞从培养皿中刮下，超声破碎，以20000g低温离心10分钟；
(4)将上清与等体积2*SDS溶液(配方附后)混合，跑浓度为8％的SDS-PAGE，之后将蛋白转至PVDF膜上，每张PVDF膜用25mL脱脂牛奶封闭1小时，再之后用TBST缓冲液(配方附后)漂洗3次，每次10分钟；
(5)将AMPKα亚基一抗(Cell Signaling Technology,#2532)、AMPK第172位苏氨酸磷酸化一抗(Cell Signaling Technology,#2535)、ACC一抗(Cell Signaling Technology,#3662)、ACC第79位丝氨酸磷酸化一抗(Cell Signaling Technology,#3661)、LAMTOR1一抗(Cell Signaling Technology,#8975)、AXIN一抗(Cell Signaling Technology,#2074)或LKB1一抗(Cell Signaling Technology,#3047)按1：1000稀释到一抗稀释液(配方附后) 中，与PVDF膜室温反应12小时，并用TBST缓冲液漂洗3次；
(6)加入1：1000稀释的HRP偶联的山羊抗兔的二抗(Jackson ImmunoResearch,111-035-003)，室温反应1小时，并用TBST缓冲液漂洗3次；
(7)将PVDF膜擦干，在ECL混合液(WesternBright ECL HRP substrate,Advansta)中反应并用医用X-射线胶片曝光、显色，最后冲洗、烘干，再扫描得到AMPK激活的相关数据。
所用试剂配方：
细胞裂解液：20mM Tris-base,pH 7.5，150mM NaCl,1mM EDTA,1mM EGTA,2.5mM Sodium pyrophosphate,1mM β-glycerolphosphate,1％Triton X-100(v/v)；
2*SDS溶液：20％Glycerol(v/v),4％SDS(m/v),10％β-mecaptoethanol(v/v),0.01％Bromophenol blue(m/v)；
TBST缓冲液：4.84％Tris-base(m/v),8％NaCl(m/v),0.1％Tween-20(v/v)；
一抗稀释液：含有5％BSA(v/v)的TBST缓冲液
3.小鼠生理活性测试
化合物通过抑制醛缩酶活力从而激活小鼠肝脏中AMPK的测试，是通过灌胃给药或把药溶解于饮水中喂饲小鼠，后检测肝脏中甘油三酯(TAG)的水平、免疫印迹(western blot)的方法检测AMPK第172位苏氨酸的磷酸化水平以及AMPK的底物ACC1/ACC2第79位丝氨酸的磷酸化水平实现的(图4和图5)。此外还通过检测给药后小鼠的体重(图6)、肝切片的形态(图7)和灌胃给药后对血糖水平的影响(图8)进一步说明化合物通过AMPK起到的效果。图4结果表明化合物(IA-47)在小鼠中能通过抑制醛缩酶活性激活肝脏中AMPK的活性，图5结果表明化合物(IA-47)在小鼠中能通过抑制醛缩酶活性降低甘油三酯的水平。图6说明化合物(IA-47)在高脂喂养的肥胖小鼠中能有效降低其体重。图7说明化合物(IA-47)在高脂喂养的肥胖小鼠中能有效治疗脂肪肝。图8说明化合物(IA-47)在iv-GTT中能有效降糖。
具体方法如下：
(1)6周的野生型C57BL/6J雄鼠进行60％脂肪的高脂喂养，10周后体重达到50g左右，开始进行给药处理，给药期间保持高脂饮食。
(2)每天下午5点称量小鼠体重，按1mg/kg的浓度给小鼠灌胃给药IA-47，并按相同比例灌胃给药vehicle。
(3)给药两周后，将小鼠断颈处死，迅速取出小鼠肝脏装入1.5mL管中放入液氮淬灭。
(4)切取50mg左右肝脏，并按照1mg/μL的比例加入细胞裂解液(配方附后)，匀浆并超声破碎，以20000g低温离心10分钟。
(5)将上清与等体积2*SDS溶液(配方附后)混合，跑浓度为8％的SDS-PAGE，之后将蛋白转至PVDF膜上，每张PVDF膜用25mL脱脂牛奶封闭1小时，再之后用TBST缓冲液(配方附后)漂洗3次，每次10分钟；
(6)将AMPKα亚基一抗(Cell Signaling Technology,#2532)、AMPK第172位苏氨酸磷酸化一抗(Cell Signaling Technology,#2535)、ACC一抗(Cell Signaling Technology,#3662)、ACC第79位丝氨酸磷酸化一抗(Cell Signaling Technology,#3661)、LAMTOR1 一抗(Cell Signaling Technology,#8975)、AXIN一抗(Cell Signaling Technology,#2074)或LKB1一抗(Cell Signaling Technology,#3047)按1：1000稀释到一抗稀释液(配方附后)中，与PVDF膜室温反应12小时，并用TBST缓冲液漂洗3次；
(7)加入1：1000稀释的HRP偶联的山羊抗兔的二抗(Jackson ImmunoResearch,111-035-003)，室温反应1小时，并用TBST缓冲液漂洗3次；
(8)将PVDF膜擦干，在ECL混合液(WesternBright ECL HRP substrate,Advansta)中反应并用医用X-射线胶片曝光、显色，最后冲洗、烘干，再扫描得到AMPK激活的相关数据。
(9)另取80mg肝脏，加入800μL肝脏裂解液(配方附后)，匀浆破碎，并在沸水中孵育5min。
(10)趁热离心，将上清转移到新管中。
(11)吸取2μL上清加到96孔板中，用标准溶液(Wako 290-63701)配置标准曲线加到96孔板中，每孔加入300μL显色液(Wako 290-63701)，37℃反应5分钟。
(12)用酶标仪(SpectraMax M5,Molecular Devices)读取样品600nm处吸光值，按照说明书计算甘油三酯水平。
(13)取高脂喂养至体重50g以上的肥胖小鼠，将药物溶于饮水中(200μg/ml)，连续喂饲70天，每天称取其重量并做记录，在第70天对小鼠进行安乐死，取肝脏，固定，切片，HE染色之后直接观察其组织学特征。
(14)6周的野生型C57BL/6J雄鼠早晨6：00开始撤掉饲料空腹四小时，测量血糖(-120min)并称量体重，按照2mg/kg的剂量灌胃给药IA-47并按相同比例灌胃给药vehicle。
(15)两小时后测量血糖(0min)，并按照1g/kg的浓度给小鼠腹腔注射20％(v/v)葡萄糖溶液，注射后的20、40、60、90min分别测量小鼠血糖。
所用试剂配方：
细胞裂解液：20mM Tris-base,pH 7.5，150mM NaCl,1mM EDTA,1mM EGTA,2.5mM Sodium pyrophosphate,1mM β-glycerolphosphate,1％Triton X-100(v/v)；
2*SDS溶液：20％Glycerol(v/v),4％SDS(m/v),10％β-mecaptoethanol(v/v),0.01％Bromophenol blue(m/v)；
TBST缓冲液：4.84％Tris-base(m/v),8％NaCl(m/v),0.1％Tween-20(v/v)；
一抗稀释液：含有5％BSA(v/v)的TBST缓冲液
肝脏裂解液：含有5％Triton X-100(v/v)的PBS溶液。
4.线虫寿命测试
化合物通过抑制醛缩酶活力从而激活小鼠肝脏中AMPK的测试，是通过把药物溶解于线虫培养基中，每天观察存活的线虫数目，并统计生存曲线(图9)。化合物通过抑制醛缩酶图9说明化合物(IA-47)能够延长线虫的寿命。
附表1.合成实例化合物用到的部分商用原料
原料A
溴甲烷，CAS:74-83-9，阿拉丁，上海
溴乙烷，CAS:74-96-4，麦克林，上海
1-溴丙烷，CAS:106-94-5，麦克林，上海
2-溴丙烷，CAS:75-26-3，麦克林，上海
正溴丁烷，CAS:109-65-9，麦克林，上海
溴代正戊烷，CAS:110-53-2，麦克林，上海
溴己烷，CAS:111-25-1，麦克林，上海
1-溴代庚烷，CAS:629-04-9，麦克林，上海
溴辛烷，CAS:111-83-1，麦克林，上海
1-溴壬烷，CAS:693-58-3，麦克林，上海
癸基溴，CAS:112-29-8，麦克林，上海
1-溴十一烷，CAS:693-67-4，麦克林，上海
1-溴十二烷，CAS:143-15-7，麦克林，上海
1-溴十三烷，CAS:765-09-3，麦克林，上海
1-溴十四烷，CAS:112-71-0，麦克林，上海
1-溴十五烷，CAS:629-72-1，麦克林，上海
1-溴十六烷，CAS:112-82-3，麦克林，上海
1-溴十七烷，CAS:3508-00-7，麦克林，上海
1-溴十八烷，CAS:112-89-0，麦克林，上海
1-溴二十烷，CAS:4276-49-7，麦克林，上海
1-溴二十二烷，CAS:6938-66-5，麦克林，上海
 
原料B
咪唑，CAS:288-32-4，麦克林，上海
2-甲基咪唑，CAS:693-98-1，Acros Organics，比利时
2-乙基咪唑，CAS:1072-62-4，麦克林，上海
2-异丙基咪唑，CAS:36947-68-9，毕得，上海
2-叔丁基咪唑，CAS:36947-69-0，韶远，上海
2-环丙基-1H-咪唑，CAS:89532-38-7，华威锐科，北京
2-甲基苯并咪唑，CAS:615-15-6,毕得，上海
2-甲基-5-氯苯并咪唑，CAS:2818-69-1，韶远，上海
2-甲基-5-硝基苯并咪唑，CAS:1792-40-1，毕得，上海
5-氟-2-甲基苯并咪唑，CAS:118469-15-1，毕得，上海
 
原料C
2-氯-6-氟苄基溴，CAS:68220-26-8，毕得，上海
2,6-二氯苄基溴，CAS:20443-98-5，安耐吉，上海
5-氟-2-甲氧基溴苄，CAS:20-3-560364，安耐吉，上海
3,5-二甲氧基溴苄，CAS:877-88-3，Adamas，上海
2-氟溴苄，CAS:446-48-0，安耐吉，上海
3-氟溴苄，CAS:456-41-7，安耐吉，上海
4-氟溴苄，CAS:459-46-1，安耐吉，上海
2-氯溴苄，CAS:611-17-6，安耐吉，上海
3-氯溴苄，CAS:766-80-3，安耐吉，上海
4-氯溴苄，CAS:622-95-7，安耐吉，上海
2-溴溴苄，CAS:3433-80-5，安耐吉，上海
3-溴溴苄，CAS:823-78-9，安耐吉，上海
4-溴溴苄，CAS:589-15-1，安耐吉，上海
2-甲基溴苄，CAS:9-92-9，安耐吉，上海
3-甲基溴苄，CAS:620-13-3，安耐吉，上海
4-甲基溴苄，CAS:104-81-4，安耐吉，上海
3-甲氧基溴苄，CAS:874-98-6，安耐吉，上海
4-甲氧基溴苄，CAS:2746-25-0，安耐吉，上海
2-(三氟甲基)苄溴，CAS:395-44-8，安耐吉，上海
3-(三氟甲基)苄溴，CAS:402-23-3，安耐吉，上海
1-溴-三氟对二甲苯，CAS:402-49-3，安耐吉，上海
2-(三氟甲氧基)苄基溴，CAS:198649-68-2，安耐吉，上海
3-三氟甲氧基溴苄，CAS:159689-88-0，安耐吉，上海
4-三氟甲氧基溴苄，CAS:50824-05-0，安耐吉，上海
2-氰基溴苄，CAS:22115-41-9，安耐吉，上海
3-氰基溴苄，CAS:28188-41-2，安耐吉，上海
对氰基溴化苄，CAS:17201-43-3，安耐吉，上海
2,6-二甲基溴苄，CAS:83902-02-7，安耐吉，上海
2,6-二氟溴苄，CAS:85118-00-9，安耐吉，上海

Claims (10)

  1. 以下通式的化合物：
    Figure PCTCN2018081898-appb-100001
    其中，R 1选自C1-C24烷基，C1-C24含氧烷基，C1-C24含氟烷基，C1-C24含氟含氧烷基；
    优选R 1选自C1-C24烷基；
    更优选R 1选自C1-C22烷基；
    R 2选自氢，C1-C6烷基，C3-C6环烷基；
    优选R 2选自氢，C1-C4烷基，C3环烷基；
    更优选R 2选自氢，甲基，乙基，异丙基，叔丁基，环丙基；
    R 3选自：
    1)
    Figure PCTCN2018081898-appb-100002
    其中Z 1，Z 2，Z 3，Z 4，Z 5各自独立地选自：
    (1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基，乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基，N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基，正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基；
    (2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟 烷氧基；
    (3)Z 2与Z 3可以形成含氧的取代或未取代的五元环或六元环；取代基可以选自与Z 1相同的取代基；
    (4)Z 4与Z 5可以形成含氮的取代或未取代的五元环或六元环；取代基可以选自与Z 1相同的取代基；
    Z 6选自氢，C1-C3烷基，C3-C6环烷基；
    2)
    Figure PCTCN2018081898-appb-100003
    其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
    3)
    Figure PCTCN2018081898-appb-100004
    其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
    4)
    Figure PCTCN2018081898-appb-100005
    其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
    优选，R 3为
    Figure PCTCN2018081898-appb-100006
    其中Z 1，Z 2，Z 3，Z 4，Z 5中的2个各自独立地选自以下，其余为氢：
    (1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，氨基甲酰基，甲磺酰基，羟基磺酰基，氨基磺酰基，甲酰胺基，甲磺酰胺基；
    (2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
    Z 6选自氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢或甲基；
    和/或，
    优选，R 3为
    Figure PCTCN2018081898-appb-100007
    其中Z 1，Z 2，Z 3，Z 4，Z 5中的1个独立地选自以下，其余为氢：
    (1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，氨基甲酰基，甲磺酰基，羟基磺酰基，氨基磺酰基，甲酰胺基，甲磺酰胺基；
    (2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
    Z 6选自氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢或甲基；
    A环为不存在或任选被取代的苯环，在苯环为取代的情况下，其取代基为一个或多个 选自以下的取代基：卤素，硝基，氰基，氨基，羟基，羟基甲酰基，氨基甲酰基，甲磺酰基，羟基磺酰基，氨基磺酰基，甲酰胺基，甲磺酰胺基，C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；优选，其取代基为1个或2个选自以下的取代基：卤素，硝基，氨基，羟基，羟基甲酰基，氨基甲酰基，甲磺酰基，羟基磺酰基，氨基磺酰基，甲酰胺基，甲磺酰胺基，C1-C3烷氧基；更优选，其取代基为1个或2个选自以下的取代基：氟，氯，硝基，甲氧基；
    X -为药学上可以接受的无机酸盐或有机酸盐的阴离子；
    优选，所述无机酸盐为盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸氢盐和碳酸盐、硫酸盐或磷酸盐，所述有机酸盐为甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、α-酮戊二酸盐、α-甘油磷酸盐、烷基磺酸盐或芳基磺酸盐；优选地，所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐；所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐；
    或上述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物，
    但是，排除以下化合物：
    Figure PCTCN2018081898-appb-100008
    化合物a,b,c,d,e,f,g,h,i,j,k,l,m：
    化合物a：R 1为C 16H 33-，R 2为CH 3-，R 3为
    Figure PCTCN2018081898-appb-100009
    X -为Br -；
    化合物b：R 1为C 16H 33-，R 2为CH 3-，R 3为
    Figure PCTCN2018081898-appb-100010
    X -为Br -；
    化合物c：R 1为C 16H 33-，R 2为CH 3-，R 3为
    Figure PCTCN2018081898-appb-100011
    X -为Br -；
    化合物d：R 1为C 16H 33-，R 2为CH 3-，R 3为
    Figure PCTCN2018081898-appb-100012
    X -为Br -；
    化合物e：R 1为C 16H 33-，R 2为CH 3-，R 3为
    Figure PCTCN2018081898-appb-100013
    X -为Br -；
    化合物f：R 1为C 4H 9-，R 2为CH 3-，R 3为
    Figure PCTCN2018081898-appb-100014
    X -为I -；
    化合物g：R 1为C 8H 17-，R 2为CH 3-，R 3为
    Figure PCTCN2018081898-appb-100015
    X -为I -；
    化合物h：R 1为C 12H 25-，R 2为CH 3-，R 3为
    Figure PCTCN2018081898-appb-100016
    X -为I -；
    化合物i：R 1为C 14H 29-，R 2为CH 3-，R 3为
    Figure PCTCN2018081898-appb-100017
    X -为I -；
    化合物j：R 1为C 16H 33-，R 2为CH 3-，R 3为
    Figure PCTCN2018081898-appb-100018
    X -为I -；
    化合物k：R 1为C 18H 37-，R 2为CH 3-，R 3为
    Figure PCTCN2018081898-appb-100019
    X -为I -；
    化合物l：R 1为C 20H 41-，R 2为CH 3-，R 3为
    Figure PCTCN2018081898-appb-100020
    X -为I -；
    化合物m：R 1为C 22H 45-，R 2为CH 3-，R 3为
    Figure PCTCN2018081898-appb-100021
    X -为I -。
  2. 根据权利要求1的化合物，其为以下：
    Figure PCTCN2018081898-appb-100022
    其中，
    R 1选自C1-C24烷基，C1-C24含氧烷基，C1-C24含氟烷基，C1-C24含氟含氧烷基；
    优选，R 1选自C1-C24烷基；
    更优选，R 1选自C1-C22烷基；
    R 2选自氢，C1-C6烷基，C3-C6环烷基；
    优选，R 2选自氢，C1-C4烷基，C3环烷基；
    更优选，R 2选自氢，甲基，乙基，异丙基，叔丁基，环丙基；
    R 3选自
    1)
    Figure PCTCN2018081898-appb-100023
    其中Z 1，Z 2，Z 3，Z 4，Z 5各自独立地选自：
    (1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基，乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基，N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰 基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基，正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基；
    (2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
    (3)Z 2与Z 3可以形成含氧的取代或未取代的五元环或六元环；取代基可以选自与Z 1相同的取代基；
    (4)Z 4与Z 5可以形成含氮的取代或未取代的五元环或六元环；取代基可以选自与Z 1相同的取代基；
    Z 6选自氢，C1-C3烷基，C3-C6环烷基；
    2)
    Figure PCTCN2018081898-appb-100024
    其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
    3)
    Figure PCTCN2018081898-appb-100025
    其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
    4)
    Figure PCTCN2018081898-appb-100026
    其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
    优选，R 3为
    Figure PCTCN2018081898-appb-100027
    其中Z 1，Z 2，Z 3，Z 4，Z 5中的2个各自独立地选自以下，其余为氢：
    (1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，氨基甲酰基，甲磺酰基，羟基磺酰基，氨基磺酰基，甲酰胺基，甲磺酰胺基；
    (2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
    Z 6选自氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢或甲基；
    更优选，R 3为
    Figure PCTCN2018081898-appb-100028
    其中Z 1，Z 2，Z 4，Z 5中的2个各自独立地选自以下，其余的以及Z 3为氢：
    (1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，氨基甲酰基，甲磺酰基，羟基磺酰基，氨基磺酰基，甲酰胺基，甲磺酰胺基；
    (2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
    Z 6选自氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢或甲基；
    进一步更优选，R 3为
    Figure PCTCN2018081898-appb-100029
    其中，Z 1，Z 2，Z 3，Z 4，Z 5中的Z 1，Z 5各自、或Z 2，Z 4各自、或Z 1，Z 4各自独立地选自以下，其余的为氢：
    (1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，氨基甲酰基，甲磺酰基，羟基磺酰基，氨基磺酰基，甲酰胺基，甲磺酰胺基；
    (2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
    Z 6选自氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢或甲基；
    和/或，
    优选，R 3为
    Figure PCTCN2018081898-appb-100030
    其中Z 1，Z 2，Z 3，Z 4，Z 5中的1个独立地选自以下，其余为氢：
    (1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，氨基甲酰基，甲磺酰基，羟基磺酰基，氨基磺酰基，甲酰胺基，甲磺酰胺基；
    (2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
    Z 6选自氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢或甲基；
    X -为药学上可以接受的无机酸盐或有机酸盐的阴离子；
    优选，所述无机酸盐为盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸氢盐和碳酸盐、硫酸盐或磷酸盐，所述有机酸盐为甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、α-酮戊二酸盐、α-甘油磷酸盐、烷基磺酸盐或芳基磺酸盐；优选地，所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐；所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐。
  3. 根据权利要求2的化合物，其为以下：
    Figure PCTCN2018081898-appb-100031
    Figure PCTCN2018081898-appb-100032
    其中，对于R 1、R 3以及X －的定义如权利要求2中所述，
    或上述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物。
  4. 根据权利要求1的化合物，其为以下：
    Figure PCTCN2018081898-appb-100033
    其中：
    R 1选自C1-C24烷基，C1-C24含氧烷基，C1-C24含氟烷基，C1-C24含氟含氧烷基；
    优选，R 1选自C1-C24烷基；
    更优选，R 1选自C1-C16烷基；
    进一步更优选，R 1为C16烷基；
    R 2选自氢，C1-C6烷基，C3-C6环烷基；
    优选，R 2选自氢，C1-C4烷基，C3环烷基；
    更优选，R 2选自氢，甲基，乙基，异丙基，叔丁基，环丙基；
    进一步更优选，R 2为甲基；
    R 3选自
    1)
    Figure PCTCN2018081898-appb-100034
    其中Z 1，Z 2，Z 3，Z 4，Z 5各自独立地选自：
    (1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，甲氧基甲酰基，乙氧基甲酰基，正丙氧基甲酰基，异丙氧基甲酰基，氨基甲酰基，N-甲基甲酰基，N-乙基甲酰基，N-正丙基甲酰基，N-异丙基甲酰基，N-环丙基甲酰基，N-正丁基甲酰基，N-异丁基甲酰基，N-叔丁基甲酰基，N-环丁基甲酰基，N-正戊基甲酰基，N-异戊基甲酰基，N-环戊基甲酰基，N-正己基甲酰基，N-异己基甲酰基，N-环己基甲酰基，N，N-二甲基甲酰基，N，N-二乙基甲酰基，N，N-二正丙基甲酰基，N，N-二异丙基甲酰基，环丙胺基甲酰基，环丁胺基甲酰基，环戊胺基甲酰基，环己胺基甲酰基，4-羟基哌啶基甲酰基，哌嗪基甲酰基，4-N-甲基哌嗪基甲酰基，4-N-乙基哌嗪基甲酰基，4-N-正丙基哌嗪基甲酰基，4-N-异丙基哌嗪基甲酰基，甲磺酰基，乙磺酰基，正丙基磺酰基，异丙基磺酰基，正丁基磺酰基，异丁基磺酰基，羟基磺酰基，氨基磺酰基，N-甲基磺酰基，N-乙基磺酰基，N-正丙基磺酰基，N-异丙基磺酰基，N-环丙基磺酰基，N-正丁基磺酰基，N-异丁基磺酰基， N-叔丁基磺酰基，N-环丁基磺酰基，N-正戊基磺酰基，N-异戊基磺酰基，N-环戊基磺酰基，N-正己基磺酰基，N-异己基磺酰基，N-环己基磺酰基，N，N-二甲基磺酰基，N，N-二乙基磺酰基，N，N-二正丙基磺酰基，N，N-二异丙基磺酰基，环丙胺基磺酰基，环丁胺基磺酰基，环戊胺基磺酰基，环己胺基磺酰基，4-羟基哌啶基磺酰基，哌嗪基磺酰基，4-N-甲基哌嗪基磺酰基，4-N-乙基哌嗪基磺酰基，4-N-正丙基哌嗪基磺酰基，4-N-异丙基哌嗪基磺酰基，甲酰胺基，乙酰胺基，丙酰胺基，正丁酰胺基，异丁酰胺基，环丙基甲酰胺基，环丁基甲酰胺基，环戊基甲酰胺基，环己基甲酰胺基，甲磺酰胺基，乙磺酰胺基，正丙磺酰胺基，异丙磺酰胺基，正丁磺酰胺基，异丁磺酰胺基；
    (2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
    (3)Z 2与Z 3可以形成含氧的取代或未取代的五元环或六元环；取代基可以选自与Z 1相同的取代基；
    (4)Z 4与Z 5可以形成含氮的取代或未取代的五元环或六元环；取代基可以选自与Z 1相同的取代基；
    Z 6选自氢，C1-C3烷基，C3-C6环烷基；
    2)
    Figure PCTCN2018081898-appb-100035
    其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
    3)
    Figure PCTCN2018081898-appb-100036
    其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
    4)
    Figure PCTCN2018081898-appb-100037
    其中Z 2，Z 3，Z 4，Z 5与上述1)中定义相同；
    优选，R 3为
    Figure PCTCN2018081898-appb-100038
    其中Z 1，Z 2，Z 3，Z 4，Z 5中的2个各自独立地选自以下，其余为氢：
    (1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，氨基甲酰基，甲磺酰基，羟基磺酰基，氨基磺酰基，甲酰胺基，甲磺酰胺基；
    (2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
    Z 6选自氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢；
    更优选，R 3为
    Figure PCTCN2018081898-appb-100039
    其中Z 1，Z 2，Z 4，Z 5中的2个独立地选自以下，其余以及Z 3为氢：
    (1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，氨基甲酰基，甲磺酰基，羟基磺酰基，氨基磺酰基，甲酰胺基，甲磺酰胺基；
    (2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
    Z 6选自为氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢；
    进一步更优选，R 3为
    Figure PCTCN2018081898-appb-100040
    其中Z 1，Z 2，Z 3，Z 4，Z 5中的Z 1，Z 5各自独立地选自以下，其余为氢：
    (1)氢，氟，氯，溴，碘，硝基，氰基，氨基，羟基，羟基甲酰基，氨基甲酰基，甲磺酰基，羟基磺酰基，氨基磺酰基，甲酰胺基，甲磺酰胺基；
    (2)C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
    Z 6选自氢，C1-C3烷基，C3-C6环烷基；优选Z 6为氢；
    n选自0，1，2；
    优选，n选自0，1；
    R 4独立地选自氢，卤素，硝基，氰基，氨基，羟基，羟基甲酰基，氨基甲酰基，甲磺酰基，羟基磺酰基，氨基磺酰基，甲酰胺基，甲磺酰胺基，C1-C3烷基，C1-C3烷氧基，C1-C3含氧烷基，C1-C3含氟烷基，C1-C3含氟烷氧基；
    优选，R 4独立地选自氢，卤素，硝基，C1-C3烷基，C1-C3烷氧基；
    更优选，R 4独立地选自氢，卤素，硝基，C1-C3烷氧基；
    进一步更优选，R 4独立地选自氢，氟，氯，硝基，甲氧基；
    X -为药学上可以接受的无机酸盐或有机酸盐的阴离子；
    优选，所述药学上可接受的无机酸盐为盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸氢盐和碳酸盐、硫酸盐或磷酸盐，所述药学上可接受的有机酸盐为甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、α-酮戊二酸盐、α-甘油磷酸盐、烷基磺酸盐或芳基磺酸盐；优选地，所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐；所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐；
    或上述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物。
  5. 根据权利要求4的化合物，其为以下：
    Figure PCTCN2018081898-appb-100041
    对于R 1、R 4、n以及X －的定义如权利要求4中所述，
    或上述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物。
  6. 根据权利要求1－5任一项所述的化合物，选自以下：
    Figure PCTCN2018081898-appb-100042
    Figure PCTCN2018081898-appb-100043
    Figure PCTCN2018081898-appb-100044
    Figure PCTCN2018081898-appb-100045
    Figure PCTCN2018081898-appb-100046
    Figure PCTCN2018081898-appb-100047
    Figure PCTCN2018081898-appb-100048
    或上述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物。
  7. 制备权利要求1－6任一项所述的化合物的方法，其中，制备化合物IA-1至IA-98以及IB、IC、ID、IE、IF的方法为：
    Figure PCTCN2018081898-appb-100049
    反应条件：(a)溴代烃类的取代反应；(b)溴代烃类的取代反应；
    优选为：
    Figure PCTCN2018081898-appb-100050
    或制备化合物IA-99至IA-102的方法为
    Figure PCTCN2018081898-appb-100051
    或制备化合物II的方法为：
    Figure PCTCN2018081898-appb-100052
    反应条件：(a)碱性条件下(如氢化钠，叔丁基醇钠等)的溴代烃类取代反应；(b)溴代烃类的取代反应；
    优选为：
    Figure PCTCN2018081898-appb-100053
  8. 药物组合物，其包含权利要求1-6中任一项的化合物或其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物以及任选的药学上可以接受的赋形剂。
  9. 权利要求1-6中任一项的化合物以及另外的以下具体化合物或其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物或者权利要求8所述的药物组合物在制备用于抑制醛缩酶活性的药物中的用途：
    Figure PCTCN2018081898-appb-100054
    Figure PCTCN2018081898-appb-100055
  10. 权利要求1-6中任一项的化合物以及另外的以下具体化合物或其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物或者权利要求8所述的药物组合物在制备用于降低脂肪酸合成的药物、抑制甘油三酯和胆固醇合成的药物、预防和/或治疗肥胖以及II型糖尿病的药物、预防和/或治疗肿瘤的药物、预防和/或治疗帕金森症的药物、预防和/或治疗阿尔茨海默症的药物或者延长哺乳动物寿命的药物中的用途：
    Figure PCTCN2018081898-appb-100056
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