WO2016091207A1 - 硝基咪唑类化合物及其制备方法和在制药中的用途 - Google Patents

硝基咪唑类化合物及其制备方法和在制药中的用途 Download PDF

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WO2016091207A1
WO2016091207A1 PCT/CN2015/097096 CN2015097096W WO2016091207A1 WO 2016091207 A1 WO2016091207 A1 WO 2016091207A1 CN 2015097096 W CN2015097096 W CN 2015097096W WO 2016091207 A1 WO2016091207 A1 WO 2016091207A1
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compound
formula
acid
solvent
mmol
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PCT/CN2015/097096
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English (en)
French (fr)
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赵传生
张冰宾
周同瑞
王天才
孙俊
樊后兴
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上海阳帆医药科技有限公司
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Priority to US15/534,886 priority Critical patent/US20170334927A1/en
Priority to JP2017531244A priority patent/JP2017537133A/ja
Priority to AU2015360133A priority patent/AU2015360133A1/en
Priority to CA2970388A priority patent/CA2970388A1/en
Publication of WO2016091207A1 publication Critical patent/WO2016091207A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the fields of pharmacy, medicinal chemistry and pharmacology, and more particularly to a novel class of nitroimidazole compounds, a preparation method thereof, and the use of the compounds for treating diseases associated with infection caused by Mycobacterium tuberculosis .
  • Tuberculosis is caused by infection with Mycobacterium tuberculosis and is one of the oldest diseases in humans. Today, tuberculosis still seriously jeopardizes human health. According to WHO statistics, about one-third of the world's people are infected with tuberculosis, and tuberculosis is the most infectious disease.
  • tuberculosis mainly uses several first-line drugs such as isoniazid, rifampicin, ethambutol and pyrazinamide.
  • This treatment has the following disadvantages: long treatment period, usually takes more than half a year; adverse reactions are more serious, such as rifampicin and isoniazid combination may lead to severe hepatotoxicity, ethambutol can cause optic nerve damage; Mycobacterium tuberculosis, especially multidrug-resistant tuberculosis (MDR-TB), is not effective or even effective.
  • MDR-TB multidrug-resistant tuberculosis
  • This new type of drug should have the following characteristics: It is effective against drug-resistant bacteria, especially multi-drug resistant bacteria; it can be used in combination with the first-line anti-tuberculosis drugs currently used; it has ideal metabolic properties and can be administered orally.
  • WO9701562 discloses a number of nitroimidazole compounds, representing the compound PA-824, which have a novel mechanism of action for the treatment of tuberculosis.
  • PA-824 has a low water solubility and low bioavailability, and it requires a complicated tablet formulation for oral administration and needs to further increase its anti-tuberculosis activity [Bioorg. Med. Chem. Lett, 2008, 18 (7), 2256-2262.].
  • OPC-67683 [J. Med. Chem., 2006, 49 (26), 7854-7860.] of Otsuka Pharmaceutical Co., Ltd., the mechanism of action is similar to that of PA-824, for treatment tuberculosis.
  • the compound was approved by the European Commission in May 2014 for the treatment of adult patients with multidrug-resistant tuberculosis (MDR-TB). Although the compound is more active, it has the same problems as PA-824, and the solubility of the compound in water is small, resulting in low oral bioavailability.
  • PA-824 and OPC-67683 have strong inhibitory activity on hERG potassium current, clinically produce side effects of prolonged QT-QTc interval, and there are serious cardiotoxic problems.
  • the object of the present invention is to provide a novel nitroimidazole antituberculous compound which has no hERG inhibitory activity, stronger antibacterial activity and improved water solubility, in order to overcome the serious defects currently prevalent in such compounds and to develop a new generation.
  • Candidate drugs which has no hERG inhibitory activity, stronger antibacterial activity and improved water solubility, in order to overcome the serious defects currently prevalent in such compounds and to develop a new generation.
  • the object of the present invention is to provide a novel antitubercular compound of the formula (I), or an optical isomer thereof, a pharmaceutically acceptable inorganic or organic salt thereof;
  • the above compound of the present invention or each of the optical isomers thereof, a pharmaceutically acceptable inorganic or organic salt, for use in the preparation of a disease caused by Mycobacterium tuberculosis infection, particularly multidrug-resistant tuberculosis Use in drugs for infectious diseases caused by bacilli.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and a compound of the formula (I) of the present invention, or each of the optical isomers thereof, pharmaceutically acceptable Inorganic or organic salts are used as active ingredients.
  • a novel class of nitroimidazoles which are compounds of the following formula (I) or optical isomers thereof, or pharmaceutically acceptable salts (inorganic or organic salts) ;
  • n represents an integer between 1 and 4;
  • L is O, S, NH or a chemical bond
  • X is C or N
  • R 1 is hydrogen or C 1-6 alkyl
  • R 2 and R 3 may be the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, C 1-4 alkyl, C 3-6 cycloalkyl or C 1-4 alkoxy. ;
  • R 4 is an aromatic ring or a heteroaryl ring containing at least one hetero atom selected from N, O or S, the aromatic ring or the aromatic heterocyclic ring being unsubstituted or optionally one to three independently selected from the group consisting of cyano, CF 3 , Substituted by a group of OCF 3 , halogen, methyl or methoxy;
  • A may be selected from saturated or unsaturated C 5-7 cycloalkyl, C 8-10 cycloalkyl, C 7-9 bridged cycloalkyl, C 7-11 spirocycloalkyl, in cycloalkyl At least one carbon atom is replaced by a nitrogen atom and is bonded through a nitrogen atom and a heteroaromatic ring (pyridine or pyrimidine) which may be one or more of fluorine, cyano, hydroxy, C 1-4 alkyl, C 1 -4 alkoxy group substitution.
  • pyridine or pyrimidine which may be one or more of fluorine, cyano, hydroxy, C 1-4 alkyl, C 1 -4 alkoxy group substitution.
  • the pharmaceutically acceptable salt comprises a salt of a compound represented by the formula (I) and an acid; wherein the acid comprises: an inorganic acid, an organic acid or an acidic amino acid; the inorganic acid comprises: hydrochloric acid, hydrobromic acid , hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid; the organic acid includes: formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, Tartaric acid, citric acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid or benzenesulfonic acid; the acidic amino acid comprises aspartic acid or glutamic acid.
  • the acidic amino acid comprises aspartic acid or glutamic acid.
  • Alkyl means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 6 carbon atoms. Preference is given to lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl.
  • Cycloalkyl refers to a 3 to 6 membered all carbon monocyclic aliphatic hydrocarbon group in which one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • Alkoxy refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are alkoxy groups having from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy And tert-butoxy.
  • alkoxy includes both unsubstituted and substituted alkoxy, especially alkoxy substituted by one or more halogens.
  • Preferred alkoxy groups are selected from the group consisting of OCH 3 , OCF 3 , CHF 2 O, CF 3 CH 2 O, iPrO, nPrO, iBuO, cPrO, nBuO or tBuO.
  • Aryl means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated ⁇ -electron system, including a carbocyclic aryl group, a heteroaryl group.
  • Halogen means fluoro, chloro, bromo or iodo.
  • “Chemical bond” is a collective term for a strong interaction force between two or more atoms (or ions) within a pure molecule or within a crystal.
  • C 8-10 cycloalkyl group means a cycloalkyl group in which two rings share two ring atoms.
  • C 7-9 bridged cycloalkyl group means a cycloalkyl group in which two rings share two or more ring atoms.
  • C 7-11 spirocycloalkyl group means a cycloalkyl group in which two rings share one ring atom.
  • the compounds of the invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers.
  • the asymmetric center that can exist depends on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention. The invention is meant to include all such isomeric forms of these compounds.
  • the "pharmaceutically acceptable salt” as used herein means that it is not particularly limited as long as it is a pharmaceutically acceptable salt, and includes inorganic salts and organic salts. Specifically, a salt formed by the compound of the present invention and an acid may be mentioned. Suitable acids for forming a salt include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and C.
  • Acid oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Acids and acidic amino acids such as aspartic acid and glutamic acid.
  • the inventors have extensively studied, synthesized and screened a large number of compounds, and found for the first time that the compound of the formula (I) has a strong inhibitory activity against Mycobacterium tuberculosis, and is particularly suitable for the preparation of a medicament for treating diseases associated with infection caused by Mycobacterium tuberculosis.
  • the inventors have completed the present invention on this basis.
  • the structural compound of the formula (I) of the present invention can be obtained by the following method, however, the conditions of the method, such as the reactant, the solvent, the base, the amount of the compound used, the reaction temperature, the time required for the reaction, and the like are not limited to the following explanations.
  • the compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.
  • the preparation method of the nitroimidazole antibacterial compound of the present invention may include the following steps:
  • the solvent may be selected from the group consisting of acetonitrile, acetone, dioxane, tetrahydrofuran, methanol, ethanol, isopropanol, dimethylformamide, dimethylacetamide, ethylene glycol dimethyl ether, and dimethyl
  • the solvent such as sulfoxide and water may be a single solvent or a mixed solvent.
  • the base may be selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate, barium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium t-butoxide, and tert-butyl.
  • the optimum reaction conditions are as follows: dimethylformamide (DMF) is the solvent, potassium carbonate is the base, and the raw materials I-1-1-I-1-2 and I-2-1-I-2-21 are reacted at 120 ° C. 2 to 12 hours.
  • the solvent may be selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, Dioxane, dimethylformamide, acetonitrile, ethylene glycol dimethyl ether, water, etc. may be a single solvent or a mixed solvent.
  • the base may be selected from an organic base such as pyridine, triethylamine or diisopropylethylamine.
  • the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • the optimum reaction conditions are: dichloromethane as solvent, triethylamine as base, intermediate I-3-1-I-3-35 and amine I-4 reacted at room temperature to form an imine and then triacetoxy. Reduction with sodium borohydride and further reaction at room temperature for 4 to 16 hours.
  • the starting materials II-1-1-II-1-8 and I-2-4 are subjected to a substitution reaction in a solvent at 20 ° C to 150 ° C or a solvent reflux temperature for 1 to 24 hours.
  • the intermediate II-2-1-II-2-8 was obtained.
  • the solvent may be selected from the group consisting of acetonitrile, acetone, dioxane, tetrahydrofuran, methanol, ethanol, isopropanol, dimethylformamide, dimethylacetamide, ethylene glycol dimethyl ether, and dimethyl
  • the solvent such as sulfoxide and water may be a single solvent or a mixed solvent.
  • the base may be selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate, barium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium t-butoxide, and tert-butyl.
  • the optimum reaction conditions are as follows: dimethylformamide is a solvent, potassium carbonate is a base, and raw materials II-1-1-II-1-8 and I-2-4 are reacted at 90 ° C for 2 to 12 hours.
  • the solvent may be selected from the group consisting of toluene, tetrahydrofuran, n-hexane, cyclohexane, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether and water, and may be a single solvent or a solvent. It is a mixed solvent.
  • the reducing agent may be selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, and red aluminum.
  • the optimum reaction conditions are as follows: anhydrous tetrahydrofuran is used as a solvent, and lithium tetrahydrogenate is used as a reducing agent, and is reacted at -30 to 20 ° C for 1 to 3 hours.
  • the intermediate II-3-1-II-3-8 is subjected to an oxidation reaction in a solvent at 20 ° C to 150 ° C or a reflux temperature of the solvent for 1 to 24 hours to obtain an intermediate II-4-1-II-4. -8.
  • the solvent may be selected from the group consisting of ethyl acetate, dichloromethane, dioxane, tetrahydrofuran, chloroform, cyclohexane, dimethylformamide, dimethylacetamide, ethylene glycol
  • the solvent such as ether or dimethyl sulfoxide may be a single solvent or a mixed solvent.
  • the oxidizing agent may be selected from the group consisting of active manganese dioxide, 2-iodobenzoic acid (IBX), Des Martin oxidizing agent (DMP), pyridinium chlorochromate (PCC), pyridinium dichromate ( PDC), pyridine trioxide or dimethyl sulfoxide And a mixed oxidizing agent such as swern oxidation.
  • the optimum reaction conditions are as follows: anhydrous ethyl acetate is used as a solvent, and IBX is an oxidizing agent, which is reacted at 60 ° C for 4 to 12 hours.
  • the solvent may be selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, dioxane, dimethylformamide, acetonitrile, ethylene glycol Methyl ether, water, etc. may be a single solvent or a mixed solvent.
  • the base may be selected from an organic base such as pyridine, triethylamine or diisopropylethylamine.
  • the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • the optimum reaction conditions are: dichloromethane as solvent, triethylamine as base, intermediate II-4-1-II-4-8 and amine I-4 reacted at room temperature to form an imine and then triacetoxy. Reduction with sodium borohydride and further reaction at room temperature for 4 to 16 hours.
  • the compound 18 is reacted in a solvent with a different aldehyde under acidic conditions to form an intermediate state of the imine, and then subjected to a reductive amination reaction in the presence of a reducing reagent for 1 to 24 hours to obtain a compound 44-compound 45.
  • the solvent may be selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, dioxane, dimethylformamide, acetonitrile, ethylene glycol dimethyl ether, and water. It may be a single solvent or a mixed solvent.
  • the acid may be an organic weak acid or a Lewis acid selected from the group consisting of acetic acid, zinc chloride, zinc bromide, boron trifluoride etherate and the like.
  • the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • the optimal reaction conditions are as follows: tetrahydrofuran is a solvent, acetic acid is an acid, and compound 18 and an aldehyde are reacted at room temperature to form an imine, which is then reduced by sodium triacetoxyborohydride, and further reacted at room temperature for 4 to 16 hours.
  • the solvent may be selected from the group consisting of acetonitrile, acetone, dioxane, tetrahydrofuran, methanol, ethanol, isopropanol, dimethylformamide, dimethylacetamide, ethylene glycol dimethyl ether, and dimethyl
  • the solvent such as sulfoxide and water may be a single solvent or a mixed solvent.
  • the base may be selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate, Barium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium t-butoxide, sodium t-butoxide, sodium hydride, potassium hydride, triethylamine, diisopropylethylamine and the like.
  • the optimum reaction conditions are as follows: dimethylformamide is a solvent, potassium carbonate is a base, and starting materials IV-1 and I-2-4 are reacted at 120 ° C for 2 to 12 hours.
  • the solvent may be selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, dioxane, dimethylformamide, acetonitrile, ethylene glycol Methyl ether, water, etc. may be a single solvent or a mixed solvent.
  • the base may be selected from an organic base such as pyridine, triethylamine or diisopropylethylamine.
  • the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • the optimum reaction conditions are: dichloromethane as solvent, triethylamine as base, intermediate IV-2 and amine I-4 reacted at room temperature to form an imine, and then reduced by sodium triacetoxyborohydride at room temperature. Re-react for 4 to 16 hours.
  • compound 4 and hydrochloric acid, compound 18 and phosphoric acid, compound 36 and methanesulfonic acid, compound 44 and fumaric acid are reacted at -20 ° C to 100 ° C for 1 to 48 hours, respectively, to directly precipitate solids or stand still. Recrystallization from solid or concentrated affords compound 47 - compound 50.
  • the molar ratio of compound 4 to hydrochloric acid, compound 18 and phosphoric acid, compound 36 and methanesulfonic acid, compound 44 and fumaric acid are preferably 1:1 to 1:10;
  • the solvent is selected from the group consisting of acetone, tetrahydrofuran, acetonitrile, ethanol, methanol, isopropanol, dichloromethane, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl Sulfoxide or water, etc., may be a single solvent or a mixed solvent;
  • the reaction is preferably carried out by reacting a mixed solution of dichloromethane and methanol in a volume ratio of 5:1 to 1:5 as a solvent at room temperature for 1 to 24 hours.
  • the use of the above novel nitroimidazole compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease associated with infection caused by Mycobacterium tuberculosis is provided.
  • the compound of the formula (I) of the present invention has a strong anti-tuberculosis effect, and particularly has an excellent effect on multidrug-resistant M. tuberculosis.
  • the compounds of the general formula (I) of the present invention have an increased water solubility, and the compounds of the present invention have excellent pharmacokinetic properties in animal drug metabolism studies. This compound enhances anti-tuberculous mycobacterial activity, improves drug efficacy, reduces side effects, and Provincial costs are important.
  • active ingredient means a compound represented by the formula (I), and a pharmaceutically acceptable inorganic or organic salt of the compound of the formula (I).
  • the compounds of the invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers.
  • the asymmetric center that can exist depends on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
  • the invention is meant to include all such isomeric forms of these compounds.
  • a compound of the present invention can be produced by reacting a polar protic solvent such as methanol, ethanol, isopropanol, and a pharmaceutically acceptable acid to form a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable inorganic or organic acid may be: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid.
  • maleic acid lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamic acid.
  • TB tuberculosis caused by TB
  • TB tuberculosis drug
  • drug-resistant Mycobacterium tuberculosis to a clinical drug
  • drug-resistant Mycobacterium tuberculosis and a drug-resistant tubercle bacillus.
  • infectious disease refers to tuberculosis, lymphatic tuberculosis, intestinal tuberculosis, bone tuberculosis, tuberculous pleurisy, and tuberculous meningitis. Wait.
  • the compound of the present invention Since the compound of the present invention has excellent activity against Mycobacterium tuberculosis, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient can be used for treatment and treatment Mycobacterium tuberculosis related diseases. According to the prior art, the compounds of the invention are useful in the treatment of tuberculosis and other infectious diseases.
  • the present invention also provides a pharmaceutical composition for treating a disease associated with infection caused by Mycobacterium tuberculosis, which comprises a therapeutically effective amount of the above nitroimidazole compound and a pharmaceutically acceptable excipient or carrier.
  • compositions of the present invention comprise a nitroimidazole compound of the invention in a safe and effective amount and a pharmaceutically acceptable excipient or carrier.
  • safe, effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 1000 mg of the compound of the invention per dose, preferably from 5 to 500 mg of the compound of the invention per agent, more preferably from 10 to 200 mg of the compound of the invention per agent.
  • the compounds of the present invention and pharmaceutically acceptable salts thereof can be formulated into various formulations comprising a safe or effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe, effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective amount of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity .
  • “compatibility” it is meant herein that the components of the composition are capable of intermixing with the compounds of the invention and with each other without significantly reducing the potency of the compound.
  • Examples of pharmaceutically acceptable excipients or carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as stearic acid, magnesium stearate
  • the compound of the present invention when administered, it can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously) or topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 1000 mg, preferably from 10 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the compound of the present invention has a specific effect on Mycobacterium tuberculosis.
  • the compound of the present invention has an excellent effect on multidrug resistant Mycobacterium tuberculosis.
  • the compounds of the present invention have increased water solubility, and the compounds of the present invention have excellent pharmacokinetic properties in animal drug metabolism studies. This has important significance for improving the activity of anti-tuberculous mycobacteria, improving drug efficacy, reducing side effects and saving costs.
  • the compounds of the invention are very safe for the cardiovascular system.
  • the melting point was measured by an X-4 melting point apparatus, the thermometer was not corrected; 1 H-NMR was recorded with a Varian Mercury 300 or 400 nuclear magnetic resonance apparatus, and the chemical shift was expressed by ⁇ (ppm); the MS was measured using Shimadzu LC- MS-2020 mass spectrometer.
  • the silica gel for separation is not described as 200-300 mesh, and the ratio of the eluents is a volume ratio.
  • Example 28 (6S)-2-Nitro-N-((6-(3-(4-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.1]octane -8-yl)pyrimidin-3-yl)methyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-amine (Compound 28)
  • the compound 48-50 of Table 1 can be prepared according to the method of Example 47, specifically using an acid, and the salt melting point and yield of the obtained compound are shown in Table 2.
  • Example Compound number acid Salt melting point (°C) Yield Example 48 48 hydrochloric acid 192-194 54.2%
  • Example 49 Methanesulfonic acid 175-177 70.2%
  • Example 50 50 Fumaric acid 143-145 80.7%
  • test strain H37Rv was transferred to a liquid medium, cultured at 37 ° C for 2 weeks, a little culture medium was aspirated, placed in 4 mL of liquid medium, and 10 to 20 pieces of sterile glass beads having a diameter of 2 to 3 mm were added, and the mixture was shaken for 20 to 30 seconds. , static precipitation for 10-20 min, the supernatant of the bacterial suspension was aspirated, and the turbidity was adjusted to 1 Meth's unit with liquid medium, which was equivalent to 1 ⁇ 10 7 CFU/mL. Each drug was dissolved in an appropriate amount of DMSO to 1 mg/mL, and filtered through a 0.22 ⁇ m filter. Dilute to the desired experimental concentration in liquid medium.
  • the final concentration of the test drug was set as follows: 0.001 ⁇ g/mL, 0.002 ⁇ g/mL, 0.0039 ⁇ g/mL, 0.0078 ⁇ g/mL, 0.0165 ⁇ g/mL, 0.03125 ⁇ g/mL, 0.0625 ⁇ g/mL, 0.125 ⁇ g/mL, 0.25 ⁇ g. /mL, 0.5 ⁇ g/mL, 1 ⁇ g/mL, a total of 11 concentration gradients. 100 ⁇ L of each of the above drug solutions was added to a 96-well microplate, and 100 ⁇ L of the bacterial solution at a concentration of 1 mg/mL was added to bring the drug concentration to the set final concentration, and cultured at 37 °C.
  • H37Rv As shown in Table 3, the in vitro screening of H37Rv showed that Compound 4, Compound 6, Compound 10, Compound 20 and Compound 44 were the most active, and its minimum inhibitory concentration (MIC) for H37Rv was 256 times that of ethambutol. It is 32 times the activity of PA-824 that is undergoing clinical research; Compound 5 and Compound 24 exhibit the same strong anti-tuberculosis activity, 128 times that of ethambutol and 16 times that of PA-824. Compound 1, Compound 14, Compound 18, Compound 19, Compound 31, Compound 36 and Compound 40 exhibited activities of equal strength, and their antitubercular activity was 64 times that of ethambutol and 8 times that of PA-824, respectively.
  • MIC minimum inhibitory concentration
  • Test strains (246: streptomycin resistance; 242: isoniazid resistance; 261: rifampicin resistance.
  • Clinical isolates of Mycobacterium tuberculosis clinically isolated from Shanghai Pulmonary Hospital, the steps are as follows: a Collecting sputum specimens from inpatients of tuberculosis in Shanghai Pulmonary Hospital, after alkali treatment, inoculation on modified Roche medium for 2 weeks; b.
  • Absolute concentration method for measuring drug sensitivity scraping fresh culture from the inclined surface of the medium The turbidity of the bacteria was adjusted to 1 Meth's unit (1 mg/mL) with physiological saline, diluted to 10-2 mg/mL, and 0.1 mL was inoculated on the susceptibility medium, and the results were observed after four weeks.
  • Tuberculosis Diagnostic Laboratory Test Procedures edited by the Basic Professional Committee of China National Defense Association, China Education and Culture Press, January 2006) transferred to liquid medium, cultured at 37 °C for 2 weeks, aspirate culture medium a little, placed in 4mL liquid
  • 10-20 pieces of sterile glass beads with a diameter of 2 to 3 mm were added, shaken for 20 to 30 seconds, and statically precipitated for 10 to 20 minutes.
  • the supernatant of the bacterial suspension was aspirated, and the turbidity was adjusted to 1 Meth's unit with a liquid medium. Equivalent to 1 ⁇ 10 7 CFU / mL spare.
  • each drug was dissolved in an appropriate amount of DMSO to 1 mg/mL, and filtered through a 0.22 ⁇ m filter. Dilute to the desired experimental concentration in liquid medium.
  • the final concentration of the test drug was set as follows: 0.0039 ⁇ g/mL, 0.0078 ⁇ g/mL, 0.0165 ⁇ g/mL, 0.03125 ⁇ g/mL, 0.0625 ⁇ g/mL, 0.125 ⁇ g/mL, 0.25 ⁇ g/mL, 0.5 ⁇ g/mL, 1 ⁇ g/ mL, 2 ⁇ g/mL, 4 ⁇ g/mL, a total of 11 concentration gradient detection, each take 100 ⁇ L of the above drug solution, added to a 96-well microplate, and then add 100 ⁇ L of 1mg / mL concentration of bacteria, so that the drug concentration reached the setting The final concentration was incubated at 37 °C.
  • the inoculation amount was set to 100%, 10%, and 1%, respectively.
  • the minimum inhibitory concentration (MIC) of each drug against Mycobacterium tuberculosis was observed and compared with the MIC results of PA-824. The results are shown in the table below.
  • test compounds have strong anti-drug resistant Mycobacterium tuberculosis activity, especially the MIC values of Compound 4, Compound 10, Compound 20 and Compound 44 against various drug-resistant Mycobacterium tuberculosis are 0.00195 ⁇ g.
  • the MIC value of compound 24 against various drug-resistant Mycobacterium tuberculosis was 0.0039 ⁇ g / mL, respectively, 128, 256 and 128 of the control drug PA-824
  • the MIC values of Compound 1, Compound 18, Compound 19, Compound 36 and Compound 40 for various drug-resistant Mycobacterium tuberculosis were 0.0078 ⁇ g/mL, which were 64, 128 and 64 times, respectively, of the control drug PA-824.
  • To the scale make a sample solution; accurately weigh 2.6mg of the sample into a 50mL volumetric flask, add methanol to dissolve. Add water to the mark and shake to obtain a control sample solution.
  • the sample solution and the control sample solution were each injected with 20 ⁇ L in a liquid phase test. Calculated as follows:
  • Solubility (mg/mL) C (pair) * 25 * A (sample) / A (pair)
  • sample liquid phase peak area of the sample solution
  • Good water solubility can improve the pharmacokinetic properties of the drug and facilitate the preparation of pharmaceutical preparations.
  • the dosage was 10 mg/kg and the administration volume was 10 mL/kg. Fasting for 12 hours before the test, free to drink water. Uniformly eaten 2 hours after administration.
  • 0.3 mL of blood was taken from the venous plexus of the mouse eyeball, placed in a heparinized test tube, centrifuged at 3000 rpm for 10 min, and the plasma was separated and frozen in a refrigerator at -20 °C.
  • the samples were treated according to the plasma sample processing method during the measurement, and the drug concentration in the plasma was determined by LC-MS/MS method, and the pharmacokinetic parameters were calculated.
  • the above compounds all have good pharmacokinetic properties, especially Compound 1, Compound 10, Compound 20 and Compound 31, which are excellent in pharmacokinetic properties.
  • HEK-293 cells stably expressing hERG were used to record hERG potassium channel currents at room temperature using whole-cell patch clamp technique.
  • a glass microelectrode with a tip resistance of about 1-4 M ⁇ is connected to an Axon 200A patch clamp amplifier.
  • Clamping voltage and data recording were controlled by clampex 9.2 software via Axon DigiData 1322A A/D converter, cell clamped at -80mV, induced hERG potassium current (I hERG ) step voltage from -80mV given a 2s depolarization The voltage is +20mV, and then repolarized to -40mV, and returns to -80mV after 4s. This voltage step was administered before and after administration to induce hERG potassium current.
  • the Fractional block represents the percentage inhibition of the hERG potassium current by the compound, and I and Io respectively indicate the magnitude of the hERG potassium current after dosing and before dosing.
  • the IC 50 of the compound was calculated using the following equation:
  • Io and I indicate the magnitude of hERG potassium current before and after dosing, respectively.
  • [C] is the concentration of the compound, n is Hill coefficient.
  • Table 7 shows the inhibition of hERG by some compounds:
  • Table 7 shows that the compounds of the present invention have a weak inhibition of hERG potassium current, suggesting that the compounds of the present invention are safe for the cardiovascular system and are safer than the control drug PA-824.
  • Preparation method the above active ingredient, lactose and starch are mixed, uniformly moistened with water, the wetted mixture is sieved and dried, sieved, magnesium stearate is added, and then the mixture is tableted, each tablet weighs 660 mg, active ingredient The content is 50 mg.
  • Preparation method the above active ingredient, starch and microcrystalline cellulose are mixed, sieved, uniformly mixed in a suitable container, and the obtained mixture is filled into hard gelatin capsules each weighing 650 mg and having an active ingredient content of 50 mg.

Abstract

通式(I)的硝基咪唑化合物或其光学异构体、或药学上可接受的盐以及其制备方法和其在制备治疗与结合杆菌引起的感染相关的疾病的药物中的应用。通式(I)的具体基团定义如说明书所示。 <img file="195370dest_path_image001.jpg" he="56.89" img-content="drawing" img-format="jpg" inline="yes" orientation="portrait" wi="98.43"/>

Description

硝基咪唑类化合物及其制备方法和在制药中的用途 技术领域
本发明属于药物学、药物化学和药理学领域，更具体而言，涉及一类新型硝基咪唑类化合物，及其制备方法，及将该类化合物用于治疗与结核杆菌引起的感染相关的疾病。
背景技术
结核病是由结核分枝杆菌(Mycobacterium tuberculosis)感染引起的，是人类最古老的疾病之一，时至今日，结核仍严重危害着人类的健康。根据WHO的统计，世界约有1/3的人感染过结核杆菌，结核是导致死亡人数最多的感染性疾病。
目前结核疾病的治疗主要采用几种一线药物如异烟肼、利福平、乙胺丁醇和吡嗪酰胺联合用药的方法。这种治疗方法存在以下缺点：治疗周期长，通常需要半年以上；不良反应较为严重，如利福平和异烟肼联合用药有可能导致严重的肝毒性，乙胺丁醇可导致视神经损害；对耐药性结核杆菌特别是多药耐药结核杆菌(MDR－TB)效果不好甚至无效。
鉴于以上情形，目前迫切需要开发出新型的抗结核药物。这种新型的药物应当具有以下特征：对耐药菌，特别是多药耐药菌有效；与目前使用的一线抗结核药物可以联合用药；具有理想的代谢性质，能够口服给药。
WO9701562公布了许多硝基咪唑类化合物，代表化合物PA-824，具有全新的作用机制，可用于治疗结核。然而，PA-824由于其水溶解性小,生物利用度低,口服给药时需要制成复杂的片剂配方，且需要进一步提高其抗结核活性[Bioorg.Med.Chem.Lett,2008,18(7),2256-2262.]。
日本大冢制药株式会社(Otsuka Pharmaceutical Co.,Ltd)的OPC-67683[J.Med.Chem.,2006,49(26),7854-7860.]，作用机制类似于PA-824，用于治疗结核。该化合物于2014年5月获得欧盟委员会的上市批准，用于成人耐多药肺结核病(MDR-TB)患者的治疗。虽然化合物活性较强，但具有和PA-824同样的问题，该化合物在水中溶解度很小，导致口服生物利用度很低。同时PA-824和OPC-67683对hERG钾电流抑制活性很强，临床产生QT-QTc间期延长的副作用，存在严重的心脏毒性问题。
为此,本发明的目的就是提供一种没有hERG抑制活性、抗菌活性更强、水溶性改善的新型硝基咪唑类抗结核化合物,以克服该类化合物目前普遍存在的严重缺陷，开发出新一代候选药物。
Figure PCTCN2015097096-appb-000001
发明内容
本发明的目的是提供一类结构通式如(I)所示的新型抗结核化合物，或其光学异构体、药学上可接受的无机或有机盐；
本发明的第二方面，提供了一种式(I)所示的化合物，或其各种光学异构体药学上可接受的无机或有机盐的制备方法。
本发明的第三方面，提供了本发明的上述化合物、或其各光学异构体、药学上可接受的无机或有机盐用于制备治疗结核杆菌感染引起的疾病、特别是多药耐药结核杆菌引起的感染性疾病的药物中的应用。
本发明的第四方面，提供了一种药物组合物，它含有药理上可接受的赋形剂或载体，以及本发明的式(I)化合物、或其各光学异构体、药学上可接受的无机或有机盐做为活性成分。
在本发明的第一方面，提供了一类新型硝基咪唑类化合物，其是下述通式(I)化合物或其光学异构体、或药学上可接受的盐类(无机或有机盐)；
Figure PCTCN2015097096-appb-000002
通式(I)中，n表示1～4之间的整数；
L为O，S,NH或化学键；
X为C或N；
R1为氢或C1-6烷基；
R2和R3可以相同也可以不相同，分别独立选自氢，卤素，氰基，三氟甲基，C1-4烷基，C3-6环烷基或C1-4烷氧基；
R4为芳环或至少含有一个选自N，O或S杂原子的杂芳环，所述芳环或芳杂环是未取代的或任意被一至三个独立选自氰基，CF3，OCF3，卤素，甲基或甲氧基的基团所取代；
A可以选自饱和的或不饱和的C5-7环烷基，C8-10并环烷基，C7-9桥环烷基，C7-11螺环烷基，其环烷基中至少有一个碳原子被氮原子取代且通过氮原子和杂芳环(吡啶或嘧啶)相连，上述环烷基可以被一个或多个氟，氰基，羟基，C1-4烷基，C1-4烷氧基基团取代。
所述药学上可接受的盐包括：通式(I)所示的化合物与酸形成的盐；其中，酸包括：无机酸、有机酸或酸性氨基酸；所述无机酸包括：盐酸、氢溴酸、氢氟酸、硫酸、硝酸或磷酸；所述有机酸包括：甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、对甲基苯磺酸、乙磺酸或苯磺酸；所述酸性氨基酸包括：天冬氨酸或谷氨酸。
除非有特别说明，下列用在说明书和权利要求书中的术语具有下述含义：
“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。
“环烷基”指3至6元全碳单环脂肪烃基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。例如，环丙基、环丁基、环戊基、环己烷、环己二烯等。更优选的是环丙基和环丁基。
“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-4个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH3，OCF3，CHF2O，CF3CH2O，iPrO，nPrO，iBuO，cPrO，nBuO或tBuO。
“芳基”指具有至少一个芳环结构的基团，即具有共轭的π电子系统的芳环，包括碳环芳基、杂芳基。
“卤素”指氟、氯、溴或碘。
“化学键”是指纯净物分子内或晶体内相邻两个或多个原子(或离子)间强烈的相互作用力的统称。
上述“C8-10并环烷基”是指两个环共用两个环原子的环烷基。例如：
Figure PCTCN2015097096-appb-000003
上述结构为更好理解“并环结构”的例证，但并非是对于“并环结构”的限制。
上述“C7-9桥环烷基”是指两个环共用二个或以上环原子的环烷基。例如，
Figure PCTCN2015097096-appb-000004
以上结构为更好理解“桥环烷基”的例证，但并非是对于“桥环烷基”的限制。
上述“C7-11螺环烷基”是指两个环共用一个环原子的环烷基。例如：
Figure PCTCN2015097096-appb-000005
上述结构为更好理解“螺环烷基”的例证，但并非是对于“螺环烷基”的限制。
本发明的化合物可以含有一个或多个不对称中心，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
本文所用“药学上可接受的盐”是指只要是药学上可以接受的盐就没有特别的限定，包括无机盐和有机盐。具体地可列举本发明化合物与酸形成的盐，适合成盐的酸包括(但不限于)盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。
本发明人经过广泛的研究，合成并筛选了大量的化合物，首次发现式(I)化合物对结核杆菌具有很强的抑制活性，特别适合用于制备治疗与结核杆菌引起的感染相关的疾病药物。本发明人在此基础上完成了本发明。
优选地，本发明如式(Ⅰ)结构所示化合物中，代表性的化合物名称及结构式见下表1。
Figure PCTCN2015097096-appb-000006
表1 本发明代表性化合物及其结构式
Figure PCTCN2015097096-appb-000007
Figure PCTCN2015097096-appb-000008
Figure PCTCN2015097096-appb-000009
Figure PCTCN2015097096-appb-000010
Figure PCTCN2015097096-appb-000011
Figure PCTCN2015097096-appb-000012
Figure PCTCN2015097096-appb-000013
在本发明的第二方面，提供了上述新型硝基咪唑类化合物或其药学上可接受的无机或有机盐的制备方法。
下面具体地描述本发明通式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。
本发明通式(I)结构化合物可通过如下的方法制得，然而该方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。
本发明的硝基咪唑类抗菌化合物的制备方法，其流程可包括：
流程1：
Figure PCTCN2015097096-appb-000014
(1)在20℃～150℃或溶剂回流温度下，原料I-1-1-I-1-2和I-2-1-I-2-21在溶剂中并在碱性条件下发生取代反应1～24小时得到中间体I-3-1-I-3-35。
步骤(1)中，溶剂可以选自乙腈、丙酮、二氧六环、四氢呋喃、甲醇、乙醇、异丙醇、二甲基甲酰胺、二甲基乙酰胺、乙二醇二甲醚、二甲亚砜和水等溶剂，可以是单一溶剂也可以是混合溶剂。
步骤(1)中，碱可以选自氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钡、碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、叔丁醇钾、叔丁醇钠、氢化钠、氢化钾、三乙胺、二异丙基乙胺等。最佳反应条件为：二甲基甲酰胺(DMF)为溶剂，碳酸钾为碱，原料I-1-1-I-1-2和I-2-1-I-2-21于120℃反应2～12小时。
(2)中间体I-3-1-I-3-35在溶剂中和胺I-4(参考文献J.Med.Chem.2009,52(5),1329-1344.)在碱性条件下反应形成亚胺中间态，再在还原试剂的存在下进行还原胺化反应1～24小时得到化合物1-化合物35。
步骤(2)中，溶剂可以选自甲醇、乙醇、异丙醇、四氢呋喃、二氯甲烷、1,2-二氯乙烷、 二氧六环、二甲基甲酰胺、乙腈、乙二醇二甲醚和水等，可以是单一溶剂也可以是混合溶剂。
步骤(2)中，碱可以选自吡啶，三乙胺，二异丙基乙基胺等有机碱。还原试剂选自硼氢化钠，硼氢化钾，氰基硼氢化钠，三乙酰氧基硼氢化钠等。最佳反应条件为：二氯甲烷为溶剂，三乙胺为碱，中间体I-3-1-I-3-35和胺I-4于室温反应先形成亚胺，再经三乙酰氧基硼氢化钠还原，于室温下再反应4～16小时。
流程2：
Figure PCTCN2015097096-appb-000015
(1)在20℃～150℃或溶剂回流温度下，原料II-1-1-II-1-8和I-2-4(参考文献WO2003/105853A1)在溶剂中发生取代反应1～24小时得到中间体II-2-1-II-2-8。
步骤(1)中，溶剂可以选自乙腈、丙酮、二氧六环、四氢呋喃、甲醇、乙醇、异丙醇、二甲基甲酰胺、二甲基乙酰胺、乙二醇二甲醚、二甲亚砜和水等溶剂，可以是单一溶剂也可以是混合溶剂。
步骤(1)中，碱可以选自氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钡、碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、叔丁醇钾、叔丁醇钠、氢化钠、氢化钾、三乙胺、二异丙基乙胺等。最佳反应条件为：二甲基甲酰胺为溶剂，碳酸钾为碱，原料II-1-1-II-1-8和I-2-4于90℃反应2～12小时。
(2)在-78℃～40℃下，中间体II-2-1-II-2-8在溶剂中发生还原反应0.5～24小时得到中间体II-3-1-II-3-8。
步骤(2)中，溶剂可以选自甲苯、四氢呋喃、正己烷、环己烷、甲基四氢呋喃、乙醚、甲基叔丁醚、乙二醇二甲醚和水等溶剂，可以是单一溶剂也可以是混合溶剂。
步骤(2)中，还原剂可以选自硼氢化钠、硼氢化钾、硼氢化锂、四氢铝锂、二异丁基氢化铝和红铝等。最佳反应条件为：无水四氢呋喃为溶剂，四氢铝锂为还原剂，在-30℃～20℃反应1～3小时。
(3)在20℃～150℃或溶剂回流温度下，中间体II-3-1-II-3-8在溶剂中发生氧化反应1～24小时得到中间体II-4-1-II-4-8。
步骤(3)中，溶剂可以选自乙酸乙酯、二氯甲烷、二氧六环、四氢呋喃、三氯甲烷、环己烷、二甲基甲酰胺、二甲基乙酰胺、乙二醇二甲醚、二甲亚砜等溶剂，可以是单一溶剂也可以是混合溶剂。
步骤(3)中，氧化剂可以选自活性二氧化锰、2-碘酰基苯甲酸(IBX)、戴斯马丁氧化剂(DMP)、氯铬酸吡啶鎓盐(PCC)、重铬酸吡啶鎓盐(PDC)、吡啶三氧化硫或二甲亚砜 和草酰氯(swern oxidation)的混合氧化剂等。最佳反应条件为：无水乙酸乙酯为溶剂，IBX为氧化剂，在60℃反应4～12小时。
(4)中间体II-4-1-II-4-8在溶剂中和胺I-4在碱性条件下反应形成亚胺中间态，再在还原试剂的存在下进行还原胺化反应1～24小时得到化合物36-化合物43。
步骤(4)中，溶剂可以选自甲醇、乙醇、异丙醇、四氢呋喃、二氯甲烷、1,2-二氯乙烷、二氧六环、二甲基甲酰胺、乙腈、乙二醇二甲醚和水等，可以是单一溶剂也可以是混合溶剂。
步骤(4)中，碱可以选自吡啶，三乙胺，二异丙基乙基胺等有机碱。还原试剂选自硼氢化钠，硼氢化钾，氰基硼氢化钠，三乙酰氧基硼氢化钠等。最佳反应条件为：二氯甲烷为溶剂，三乙胺为碱，中间体II-4-1-II-4-8和胺I-4于室温反应先形成亚胺，再经三乙酰氧基硼氢化钠还原，于室温下再反应4～16小时。
流程3：
Figure PCTCN2015097096-appb-000016
化合物18在溶剂中和不同的醛在酸性条件下反应形成亚胺中间态，再在还原试剂的存在下进行还原胺化反应1～24小时得到化合物44-化合物45。溶剂可以选自甲醇、乙醇、异丙醇、四氢呋喃、二氯甲烷、1,2-二氯乙烷、二氧六环、二甲基甲酰胺、乙腈、乙二醇二甲醚和水等，可以是单一溶剂也可以是混合溶剂。
酸可以是有机弱酸或路易斯酸，选自乙酸，氯化锌，溴化锌、三氟化硼乙醚等。还原剂选自硼氢化钠，硼氢化钾，氰基硼氢化钠，三乙酰氧基硼氢化钠等。最佳反应条件为：四氢呋喃为溶剂，乙酸为酸，化合物18和醛于室温反应先形成亚胺，再经三乙酰氧基硼氢化钠还原，于室温下再反应4～16小时。
流程4：
Figure PCTCN2015097096-appb-000017
(1)在20℃～150℃或溶剂回流温度下，原料IV-1(参考文献Journal of the American Chemical Society,2012,134(30)：12466-12469)和I-2-4在溶剂中并在碱性条件下发生取代反应1～24小时得到中间体IV-2。
步骤(1)中，溶剂可以选自乙腈、丙酮、二氧六环、四氢呋喃、甲醇、乙醇、异丙醇、二甲基甲酰胺、二甲基乙酰胺、乙二醇二甲醚、二甲亚砜和水等溶剂，可以是单一溶剂也可以是混合溶剂。
步骤(1)中，碱可以选自氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钡、碳酸钾、碳酸钠、 碳酸铯、碳酸氢钠、碳酸氢钾、叔丁醇钾、叔丁醇钠、氢化钠、氢化钾、三乙胺、二异丙基乙胺等。最佳反应条件为：二甲基甲酰胺为溶剂，碳酸钾为碱，原料IV-1和I-2-4于120℃反应2～12小时。
(2)中间体IV-2在溶剂中和胺I-4在碱性条件下反应形成亚胺中间态，再在还原试剂的存在下进行还原胺化反应1～24小时得到化合物46。
步骤(2)中，溶剂可以选自甲醇、乙醇、异丙醇、四氢呋喃、二氯甲烷、1,2-二氯乙烷、二氧六环、二甲基甲酰胺、乙腈、乙二醇二甲醚和水等，可以是单一溶剂也可以是混合溶剂。
步骤(2)中，碱可以选自吡啶，三乙胺，二异丙基乙基胺等有机碱。还原剂选自硼氢化钠，硼氢化钾，氰基硼氢化钠，三乙酰氧基硼氢化钠等。最佳反应条件为：二氯甲烷为溶剂，三乙胺为碱，中间体IV-2和胺I-4于室温反应先形成亚胺，再经三乙酰氧基硼氢化钠还原，于室温下再反应4～16小时。
流程5：
Figure PCTCN2015097096-appb-000018
在溶剂中，化合物4与盐酸、化合物18与磷酸、化合物36与甲磺酸、化合物44与富马酸分别在-20℃～100℃条件下反应1～48小时，直接析出固体或静置析出固体或浓缩重结晶，得到化合物47-化合物50。
其中，化合物4与盐酸、化合物18与磷酸、化合物36与甲磺酸、化合物44与富马酸的摩尔比均优选为1：1～1：10；
溶剂选自丙酮、四氢呋喃、乙腈、乙醇、甲醇、异丙醇、二氯甲烷、1,4-二氧六环、二甲基甲酰胺、二甲基乙酰胺、N-甲基吡咯烷酮、二甲亚砜或水等，可以是单一溶剂也可以混合溶剂；
反应的优选条件为：体积比为5:1～1:5的二氯甲烷与甲醇的混合液作为溶剂，在室温条件下反应1～24小时。
在本发明的第三方面，提供了上述新型硝基咪唑类化合物或其药学上可接受的盐在制备治疗与结核杆菌引起的感染相关的疾病的药物中的用途。
本发明通式(I)化合物有很强的抗结核分枝杆菌效果，特别是对多药耐药结核分枝杆菌具有优异的效果。
本发明通式(I)化合物具有增大的水溶性，在动物药物代谢研究中显示本发明化合物具有优良的药代动力学性质。这对本化合物提高抗结核分枝杆菌活性，提高药效，减少副作用，节 省成本都有重要的意义。
本发明中，“活性成分”指通式(I)所示化合物，以及通式(I)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
另外，根据需要，可以将本发明的化合物在极性质子性溶剂中，如甲醇、乙醇、异丙醇，和药学上可以接受的酸反应生成药学上可接受的盐制备得到。所述的药学上可接受的无机或有机酸可为：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸、甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、乙磺酸、对甲基苯磺酸、天冬氨酸或者谷氨酸等。
术语“结核杆菌引起”，如本文所用，指由对临床结核药物敏感结核杆菌、对临床某一药物耐药结核杆菌、对临床多种药物耐药结核杆菌和广泛耐药结核杆菌引起。
术语“由结核杆菌引起的感染的疾病”或“结核杆菌感染性疾病”可以互换使用，如本文所用，都是指肺结核、淋巴结核、肠结核、骨结核、结核性胸膜炎和结核性脑膜炎等。
由于本发明化合物具有优异的抗结核杆菌活性，因此本发明化合物及其各种晶型、药学上可接受的无机或有机盐，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗与结核杆菌相关的疾病。根据现有技术，本发明化合物可用于治疗结核病及其他感染疾病。
本发明还提供一种用于治疗与结核杆菌引起的感染相关的疾病的药物组合物，其中含有治疗有效量的上述硝基咪唑类化合物和药学上可接受的赋形剂或载体。
本发明的药物组合物包含安全、有效量范围内的本发明硝基咪唑类化合物及药学上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-1000mg本发明化合物/剂，较佳地5-500mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2015097096-appb-000019
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、娇味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～1000mg，优选10～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
1.本发明化合物对结核分枝杆菌具有特异性效果。本发明化合物对多药耐药结核分枝杆菌具有优异的效果。
2.本发明化合物具有增大的水溶性，在动物药物代谢研究中显示本发明化合物具有优良的药代动力学性质。这对本化合物提高抗结核分枝杆菌活性，提高药效，减少副作用，节省成本都有重要的意义。
3.本发明化合物对心血管系统具有很好的安全性。
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。
具体实施方式
在下述实施例中更具体地解释本发明。然而，应当理解，这些实施例是为了举例说明本发明，而并不是以任何方式限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比为重量份和重量百分比。
所有实施例中，熔点用X-4熔点仪测定，温度计未校正；1H-NMR用Varian Mercury 300或400核磁共振仪记录，化学位移以δ(ppm)表示；MS的测定用岛津LC-MS-2020质谱仪。分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。
实施例1(S)-2-硝基-N-((6-(4-(4-(三氟甲氧基)苯氧基)哌啶-1-基)吡啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物1)
Figure PCTCN2015097096-appb-000020
(1)将4-(4-(三氟甲氧基)苯氧基)哌啶I-2-1(200mg,0.77mmol)(参考文献：US3260723)和2-氯-5-醛基吡啶I-1-1(130mg,0.92mmol)溶于DMF(5mL)，滴加K2CO3(317mg,2.30mmol)，滴毕，120℃反应8小时。反应完全冷至室温，倒入冰水中，乙酸乙酯(20mL*2)萃取，无水硫酸钠干燥，过滤，旋干柱层析(石油醚：乙酸乙酯＝4:1)得黄色油状中间体I-3-1(260mg，收率93.2％)。
中间体I-3-1：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),8.57-8.53(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.18-7.12(m,2H),6.95-6.88(m,2H),6.70(d,J＝9.1Hz,1H),4.62-4.55(m,1H),4.02-3.92(m,2H),3.81-3.72(m,2H),2.08-1.98(m,2H),1.95-1.83(m,2H).
(2)将中间体I-3-1(260mg,0.71mmol)，三乙胺(93mg,0.92mmol)溶于二氯甲烷(10mL)中，然后加入原料I-4(131mg,0.71mmol)中，室温反应过夜，加入NaBH(OAc)3(602mg,2.84mmol)，继续室温反应过夜。加入碳酸氢钠溶液(10mL)，分层，水层用二氯甲烷(20mL*2)萃取，合并二氯甲烷层，饱和氯化钠溶液洗，无水硫酸钠干燥，旋干，残留物柱层析(二氯甲烷： 甲醇＝50:1)得到淡黄色粉末状化合物1(205mg,收率54.1％)。
化合物1：1H-NMR(400MHz,CDCl3)δ8.08(s,1H),7.45(dd,J＝8.7,2.4Hz,1H),7.37(s,1H),7.14(d,J＝8.6Hz,2H),6.94-6.87(m,2H),6.68(d,J＝8.7Hz,1H),4.73-4.50(m,1H),4.44-4.31(m,2H),4.15(dd,J＝12.4,4.5Hz,1H),3.90-3.79(m,3H),3.84-3.74(m,2H),3.42-3.37(m,3H),2.09-1.98(m,2H),1.88-1.80(m,2H).ESI-LR:535.18[M+1]+.
实施例2(6S)-2-硝基-N-((6-(3-(4-(三氟甲氧基)苯氧基)吡咯烷-1-基)吡啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物2)
Figure PCTCN2015097096-appb-000021
(1)将4-(4-(三氟甲氧基)苯氧基)吡咯烷I-2-2(190mg,0.77mmol)(参考文献：J.Med.Chem.2012,55(1),312-326)和2-氯-5-醛基吡啶I-1-1(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-2(189mg,收率69.7％)。
中间体I-3-2：1H-NMR(400MHz,CDCl3)δ9.75(s,1H),8.57-8.53(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.18-7.12(m,2H),6.95-6.88(m,2H),6.70(d,J＝9.1Hz,1H),4.64-4.57(m,1H),4.22-4.17(m,2H),3.57-3.50(m,2H),2.08-1.98(m,1H),1.95-1.90(m,1H).
(2)将中间体I-3-2(176mg,0.50mmol)和I-4(92mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物2(149mg,收率57.3％)。
化合物2：1H-NMR(400MHz,CDCl3)δ8.05(s,1H),7.43(dd,J＝8.7,2.4Hz,1H),7.38(s,1H),7.13(d,J＝8.6Hz,2H),6.93–6.88(m,2H),6.66(d,J＝8.7Hz,1H),4.50-4.42(m,1H),4.45-4.30(m,2H),4.14-4.08(m,1H),3.99-3.91(m,1H),3.76-3.56(m,3H),3.19(d,J＝0.4Hz,1H),2.47(s,1H),2.36-2.30(m,2H),2.24–2.07(m,2H).ESI-LR:521.46[M+1]+.
实施例3：(6S)-N-((6-(3-氟-4-(4-(三氟甲氧基)苯氧基)哌啶-1-基)吡啶-3-基)甲基)-2-硝基-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物3)
Figure PCTCN2015097096-appb-000022
(1)将3-氟-4-(4-(三氟甲氧基)苯氧基)哌啶I-2-3(214mg,0.77mmol))(参考文献：WO2008124323)和2-氯-5-醛基吡啶I-1-1(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-3(242mg,收率82.1％)。
中间体I-3-3：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),8.57-8.53(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.18-7.12(m,2H),6.95-6.88(m,2H),6.70(d,J＝9.1Hz,1H),4.82-4.75(m,1H),4.32-4.27(m,1H),4.18-4.01(m,1H),3.77-3.74(m,3H),2.91-2.86(m,1H),1.90-1.86(m,1H).
(2)将中间体I-3-3(230mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同 实施例1中(2)的方法，得淡黄色化合物3(180mg,收率54.4％)。
化合物3：1H NMR(400MHz,CDCl3)δ7.93(d,J＝2.3Hz,1H),7.40(dd,J＝8.7,2.4Hz,1H),7.35(s,1H),7.11(d,J＝8.6Hz,2H),6.90–6.85(m,2H),6.62(d,J＝8.7Hz,1H),4.89-4.65(m,1H),4.52-4.36(m,2H),4.35-4.26(m,1H),4.14-4.10(m,1H),3.93-3.87(m,1H),3.79-3.63(m,1H),3.48(dd,1H),3.40-3.23(m,2H),3.19-3.03(m,1H),2.25-2.13(m,2H),1.98-1.84(m,2H).ESI-LR:553.17[M+1]+.
实施例4：(S)-2-硝基-N-((6-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)吡啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物4)
Figure PCTCN2015097096-appb-000023
(1)将4-(4-(三氟甲氧基)苯基)哌嗪I-2-4(189mg,0.77mmol)(参考文献：WO2003105853)和2-氯-5-醛基吡啶I-1-1(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-4(242mg,收率89.5％)。
中间体I-3-4：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),8.57-8.53(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.18-7.12(m,2H),6.95-6.88(m,2H),6.70(d,J＝9.1Hz,1H),4.95-4.31(m,4H),3.37-3.32(m,4H).
(2)将中间体I-3-4(211mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物4(205mg,收率65.8％)。
化合物4：1H-NMR(400MHz,CDCl3)δ8.11(s,1H),7.48(dd,J＝8.6,2.4Hz,1H),7.36(s,1H),7.13(d,J＝8.7Hz,2H),6.94(t,J＝6.3Hz,2H),6.69(d,J＝8.7Hz,1H),4.41-4.35(m,2H),4.14(dd,J＝12.3,4.5Hz,1H),3.92(dd,J＝12.2,3.4Hz,1H),3.86-3.76(m,2H),3.79-3.70(m,4H),3.40(dd,J＝4.7,2.6Hz,1H),3.31-3.25(m,4H).ESI-LR:520.18[M+1]+.
实施例5：(3S)-N-((6-(3-甲基-4-(4-(三氟甲氧基)苯基)哌嗪-1-基)吡啶-3-基)甲基)-7-硝基-3,4-二氢-2H-咪唑并[2,1-b][1,3]噁嗪-3-胺(化合物5)
Figure PCTCN2015097096-appb-000024
(1)将2-甲基-1-(4-(三氟甲氧基)苯基)哌嗪I-2-5(200mg,0.77mmol)(参考文献：WO2006079653)和2-氯-5-醛基吡啶I-1-1(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-5(240mg,收率85.7％)。
中间体I-3-5：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),8.57-8.53(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.18-7.12(m,2H),6.95-6.88(m,2H),6.70(d,J＝9.1Hz,1H),4.75-4.13(m,4H),3.05-2.96(m,3H),1.03(d,J＝6.5Hz,3H).
(2)将中间体I-3-5(219mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物5(191mg,收率59.7％)。
化合物5：1H-NMR(400MHz,CDCl3)δ8.13(s,1H),7.52(dd,J＝8.6,2.4Hz,1H),7.38(s,1H),7.14(d,J＝8.7Hz,2H),6.97(t,J＝6.3Hz,2H),6.71(d,J＝8.7Hz,1H),4.44(s,1H),4.40(dd,J＝8.6,3.6Hz,2H),4.3-4.25(m,1H),4.18(dd,J＝12.4,4.5Hz,1H),3.99-3.92(m,1H),3.90-3.84(m,1H),3.75(s,2H),3.60(dd,J＝12.9,3.5Hz,1H),3.46(ddd,J＝13.0,6.6,3.5Hz,1H),3.40(dd,J＝4.4,2.6Hz,1H),3.28-3.21(m,1H),3.20-3.11(m,1H),1.01(d,J＝6.5Hz,3H).ESI-LR:534.20[M+1]+.
实施例6：(3S)-N-((6-(2-甲基-4-(4-(三氟甲氧基)苯基)哌嗪-1-基)吡啶-3-基)甲基)-7-硝基-3,4-二氢-2H-咪唑并[2,1-b][1,3]噁嗪-3-胺(化合物6)
Figure PCTCN2015097096-appb-000025
(1)将3-甲基-1-(4-(三氟甲氧基)苯基)哌嗪I-2-6(200mg,0.77mmol)(参考文献：WO2006079653)和2-氯-5-醛基吡啶I-1-1(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-6(191mg,收率67.9％)。
中间体I-3-6：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),8.57-8.53(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.18-7.12(m,2H),6.95-6.88(m,2H),6.70(d,J＝9.1Hz,1H),4.80-4.47(m,3H),3.25-3.10(m,4H),1.17(d,J＝6.5Hz,3H).
(2)将中间体I-3-6(183mg,0.50mmol)和I-4(92mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物6(169mg,收率63.4％)。
化合物6：1H-NMR(400MHz,CDCl3)δ8.13(s,1H),7.52(dd,J＝8.6,2.4Hz,1H),7.38(s,1H),7.14(d,J＝8.7Hz,2H),6.97(t,J＝6.3Hz,2H),6.71(d,J＝8.7Hz,1H),4.89-4.82(m,1H),4.40-4.30(m,1H),4.16(dd,J＝12.8,4.0Hz,1H),3.97(dd,J＝12.7,3.2Hz,1H),3.70(d,J＝11.9Hz,1H),3.61(d,J＝10.7Hz,3H),3.29-3.20(m,3H),2.94-2.90(m,1H),2.78-2.64(m,2H),1.20(d,J＝6.6Hz,3H).ESI-LR:534.20[M+1]+.
实施例7：(S)-7-硝基-N-((6-(4-(4-(三氟甲氧基)苯基)哌啶-1-基)吡啶-3-基)甲基)-3,4-二氢-2H-咪唑并[2,1-b][1,3]噁嗪-3-胺(化合物7)
Figure PCTCN2015097096-appb-000026
(1)将4-(4-(三氟甲氧基)苯基)哌啶I-2-7(188mg,0.77mmol)(参考文献：WO2010081904)和2-氯-5-醛基吡啶I-1-1(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-7(248mg,收率92.3％)。
中间体I-3-7：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),8.57-8.53(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.68-7.62(m,2H),6.97-6.90(m,2H),6.70(d,J＝9.1Hz,1H),4.00-3.90(m,2H),3.76-3.73(m,2H),3.68-3.57(m,1H),2.00-1.89(m,2H),1.82-1.78(m,2H).
(2)将中间体I-3-7(210mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物7(167mg,收率53.8％)。
化合物7：1H-NMR(400MHz,CDCl3)δ8.13(s,1H),7.53(dd,J＝8.6,2.4Hz,1H),7.39(s,1H),7.15(d,J＝8.7Hz,2H),6.97(t,J＝6.3Hz,2H),6.73(d,J＝8.7Hz,1H),4.79(d,J＝12.9Hz,2H),4.41-4.29(m,2H),4.13(dd,J＝12.7,4.0Hz,1H),3.98-3.91(m,1H),3.61(s,2H),2.97-2.81(m,4H),1.85-1.81(m,2H),1.52-1.45(m,2H).ESI-LR:519.19[M+1]+.
实施例8：(S)-1-(5-(((7-硝基-3,4-二氢-2H-咪唑并[2,1-b][1,3]噁嗪-3-基)氨基)甲基)吡啶-2-基)-4-(4-(三氟甲氧基)苯基)哌啶-4-醇(化合物8)
Figure PCTCN2015097096-appb-000027
(1)将4-(4-(三氟甲氧基)苯基)哌啶-4-醇I-2-8(200mg,0.77mmol)(参考文献：WO2005118587)和2-氯-5-醛基吡啶I-1-1(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-8(214mg,收率75.9％)。
中间体I-3-8：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),8.57-8.53(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.24-7.18(m,2H),6.96-6.89(m,2H),6.70(d,J＝9.1Hz,1H),4.00-3.90(m,2H),3.76-3.73(m,2H),2.14-2.03(m,2H),1.96-1.91(m,2H).
(2)将中间体I-3-8(183mg,0.50mmol)和I-4(92mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物8(89mg,收率33.6％)。
化合物8：1H-NMR(400MHz,CDCl3)δ8.15(s,1H),7.54(dd,J＝8.6,2.4Hz,1H),7.39(s,1H),7.16(d,J＝8.7Hz,2H),6.97(t,J＝6.3Hz,2H),6.73(d,J＝8.7Hz,1H),4.34(dt,J＝11.2,8.0Hz,2H),4.13-4.09(m,1H),3.98-3.79(m,3H),3.59(d,J＝11.6Hz,2H),3.38(s,1H),3.26(t,J＝12.6Hz,2H),2.23-2.19(m,2H),1.88-1.84(m,2H).ESI-LR:535.18[M+1]+.
实施例9：(S)-N-((6-(4-甲氧基-4-(4-(三氟甲氧基)苯基)哌啶-1-基)吡啶-3-基)甲基)-7-硝基-3,4-二氢-2H-咪唑并[2,1-b][1,3]噁嗪-3-胺(化合物9)
Figure PCTCN2015097096-appb-000028
(1)将4-甲氧基-4-(4-(三氟甲氧基)苯基)哌啶I-2-9(212mg,0.77mmol)(参考文献：WO2013096744)和2-氯-5-醛基吡啶I-1-1(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-9(228mg,收率77.9％)。
中间体I-3-9：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),8.57-8.53(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.24-7.18(m,2H),6.96-6.89(m,2H),6.70(d,J＝9.1Hz,1H),4.00-3.90(m,2H),3.76-3.73(m,2H),3.57(s,3H),2.12-2.01(m,2H),1.94-1.89(m,2H).
(2)将中间体I-3-9(190mg,0.50mmol)和I-4(92mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物9(133mg,收率47.6％)。
化合物9：1H-NMR(400MHz,CDCl3)δ8.14(s,1H),7.53(dd,J＝8.6,2.4Hz,1H),7.39(s,1H),7.14(d,J＝8.7Hz,2H),6.97(t,J＝6.3Hz,2H),6.73(d,J＝8.7Hz,1H),4.40(dt,J＝11.2,8.0Hz,2H),4.11-4.07(m,1H),4.00-3.81(m,6H),3.59(d,J＝11.6Hz,2H),3.38(s,1H),3.26-3.20(m,2H),2.23-2.19(m,2H),1.88-1.84(m,2H).ESI-LR:549.20[M+1]+.
实施例10：(S)-1-(5-(((7-硝基-3,4-二氢-2H-咪唑并[2,1-b][1,3]噁嗪-3-基)氨基)甲基)吡啶-2-基)-4-(4-(三氟甲氧基)苯基)哌啶-4-甲腈(化合物10)
Figure PCTCN2015097096-appb-000029
(1)将4-(4-(三氟甲氧基)苯基)哌啶-4-甲腈I-2-10(208mg,0.77mmol)(参考文献：J.Med.Chem.2011,54(13),4773-4780)和2-氯-5-醛基吡啶I-1-1(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-10(234mg,收率81.3％)。
中间体I-3-10：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),8.57-8.53(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.08-7.02(m,2H),6.94-6.87(m,2H),6.70(d,J＝9.1Hz,1H),4.03-3.91(m,2H),3.77-3.74(m,2H),2.32-2.23(m,2H),2.14-2.09(m,2H).
(2)将中间体I-3-10(225mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物10(158mg,收率48.6％)。
化合物10：1H-NMR(400MHz,CDCl3)δ8.14(s,1H),7.53(dd,J＝8.6,2.4Hz,1H),7.39(s,1H),7.14(d,J＝8.7Hz,2H),6.97(t,J＝6.3Hz,2H),6.73(d,J＝8.7Hz,1H),4.43(dt,J＝11.2,8.0Hz,2H),4.13-4.08(m,1H),4.03-3.92(m,3H),3.61(d,J＝11.6Hz,2H),3.42(s,1H),3.32-3.25(m,2H),2.94-2.87(m,2H),2.30-2.25(m,2H).ESI-LR:543.19[M+1]+.
实施例11：(6S)-2-硝基-N-((6-(5-(4-(三氟甲氧基)苯基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)吡啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物11)
Figure PCTCN2015097096-appb-000030
(1)将2-(4-(三氟甲氧基)苯基)八氢吡咯[3,4]吡咯I-2-11(209mg,0.77mmol)(参考文献：WO2013021054)和2-氯-5-醛基吡啶I-1-1(130mg,0.92mmol)作为原料，操作方法同实 施例1中(1)的方法，得中间体I-3-11(250mg,收率86.2％)。
中间体I-3-11：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),8.57-8.53(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.18-7.12(m,2H),6.95-6.88(m,2H),6.70(d,J＝9.1Hz,1H),3.83-3.71(m,4H),3.49-3.35(m,4H),3.18(s,2H)..
(2)将中间体I-3-11(226mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物11(177mg,收率54.1％)。
化合物11：1H-NMR(400MHz,CDCl3)δ8.04(d,J＝2.0Hz,1H),7.42(dd,J＝8.7,2.3Hz,1H),7.35(s,1H),7.08(d,J＝8.3Hz,2H),6.49(d,J＝9.1Hz,2H),6.35(d,J＝8.4Hz,1H),4.41-4.32(m,2H),4.12(dd,J＝12.3,4.5Hz,1H),3.90(dd,J＝12.4,3.4Hz,1H),3.83-3.71(m,4H),3.63-3.55(m,2H),3.49-3.35(m,4H),3.27(dd,J＝9.5,3.8Hz,2H),3.18(s,2H).ESI-LR:546.20[M+1]+.
实施例12：(6S)-2-硝基-N-((6-(5-(4-(三氟甲氧基)苯基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)吡啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物12)
Figure PCTCN2015097096-appb-000031
(1)将2-(4-(三氟甲氧基)苯基)-2,5-二氮杂二环[2.2.1]庚烷I-2-12(198mg,0.77mmol)(参考文献：WO2005117909)和2-氯-5-醛基吡啶I-1-1(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-12(210mg,收率75.3％)。
中间体I-3-12：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),8.57-8.54(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.18-7.11(m,2H),6.95-6.89(m,2H),6.70(d,J＝9.1Hz,1H),3.71-3.65(m,3H),3.31-3.25(m,3H),1.78-1.73(m,1H),1.53-1.47(m,1H).
(2)将中间体I-3-12(181mg,0.50mmol)和I-4(84mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物12(152mg,收率57.6％)。
化合物12：1H-NMR(400MHz,CDCl3)δ8.11(s,1H),7.48(dd,J＝8.6,2.4Hz,1H),7.36(s,1H),7.13(d,J＝8.7Hz,2H),6.94(t,J＝6.3Hz,2H),6.69(d,J＝8.7Hz,1H),4.40-4.38(m,1H),4.32(dd,J＝12.0,4.3Hz,1H),4.13(dd,J＝12.3,4.5Hz,1H),3.90(dd,J＝12.2,3.4Hz,1H),3.86-3.76(m,2H),3.70-3.63(m,3H),3.40(dd,J＝4.7,2.6Hz,1H),3.30-3.24(m,3H),1.77-1.72(m,1H),1.52-1.49(m,1H).ESI-LR:532.18[M+1]+.
实施例13：(S)-2-硝基-N-((6-(2-(4-(三氟甲氧基)苯基)-2,7-二氮杂螺[3.5]壬烷-7-基)吡啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物13)
Figure PCTCN2015097096-appb-000032
(1)将2-(4-(三氟甲氧基)苯基)-2,7-二氮杂螺[3.5]壬烷I-2-13(220mg,0.77mmol)(参考文献：WO2010108268)和2-氯-5-醛基吡啶I-1-1(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-13(231mg,收率76.8％)。
中间体I-3-13：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),8.57-8.53(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.18-7.12(m,2H),6.95-6.88(m,2H),6.70(d,J＝9.1Hz,1H),5.21-4.61(m,4H),3.57-3.50(m,4H),1.59-1.51(m,4H),.
(2)将中间体I-3-13(195mg,0.50mmol)和I-4(84mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物13(119mg,收率42.8％)。
化合物13：1H-NMR(400MHz,CDCl3)δ8.14(s,1H),7.53(dd,J＝8.6,2.4Hz,1H),7.39(s,1H),7.14(d,J＝8.7Hz,2H),6.97(t,J＝6.3Hz,2H),6.73(d,J＝8.7Hz,1H),4.40(dt,J＝11.2,8.0Hz,2H),4.11-4.07(m,1H),4.00-3.81(m,6H),3.59-3.50(m,6H),3.39(s,1H),3.28-3.21(m,2H),2.27-2.20(m,2H),1.95-1.89(m,2H).ESI-LR:560.22[M+1]+.
实施例14：(6S)-2-硝基-N-((6-(3-(4-(三氟甲氧基)苯氧基)-8-氮杂二环[3.2.1]辛烷-8-基)吡啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物14)
Figure PCTCN2015097096-appb-000033
(1)将2-(4-(三氟甲氧基)苯基)-8-氮杂二环[3.2.1]辛烷I-2-14(220mg,0.77mmol)(参考文献：WO2007079239)和2-氯-5-醛基吡啶I-1-1(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-14(219mg,收率72.8％)。
中间体I-3-14：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),8.57-8.53(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.18-7.12(m,2H),6.95-6.88(m,2H),6.70(d,J＝9.1Hz,1H),4.62-4.54(m,1H),3.57-3.51(m,2H),2.05-1.95(m,2H),1.87-1.83(m,2H),1.79-1.75(m,2H),1.47-1.50(m,2H).
(2)将中间体I-3-14(196mg,0.50mmol)和I-4(84mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物14(141mg,收率50.4％)。
化合物14：1H-NMR(400MHz,CDCl3)δ8.11(s,1H),7.45(dd,J＝8.7,2.4Hz,1H),7.36(s,1H),7.15(d,J＝8.6Hz,2H),6.94-6.89(m,2H),6.67(d,J＝8.7Hz,1H),4.73-4.50(m,1H),4.42-4.30(m,2H),4.13(dd,J＝12.4,4.5Hz,1H),3.87-3.79(m,3H),3.81-3.72(m,2H),3.42-3.37(m,1H),2.07-1.98(m,2H),1.88-1.80(m,2H),1.70-1.65(m,2H),1.45-1.48(m,2H).ESI-LR:561.20[M+1]+.
实施例15：(S)-2-硝基-N-((6-(4-(4-(三氟甲氧基)苯氧基)哌啶-1-基)嘧啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物15)
Figure PCTCN2015097096-appb-000034
(1)将4-(4-(三氟甲氧基)苯氧基)哌啶I-2-1(200mg,0.77mmol)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-15(230mg,收率81.7％)。
中间体I-3-15：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.62-4.54(m,1H),4.02-3.92(m,2H),3.57-3.51(m,2H),2.05-1.95(m,2H),1.87-1.83(m,2H).
(2)将中间体I-3-15(220mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物15(186mg,收率58.1％)。
化合物15：1H-NMR(400MHz,CDCl3)δ8.30(s,2H),8.03(s,1H),7.28(d,J＝8.7Hz,2H),7.09(d,J＝9.1Hz,2H),4.72-4.62(m,1H),4.45-4.33(m,2H),4.23-4.11(m,3H),4.00-3.92(m,1H),3.61(s,2H),3.54-3.44(m,2H),3.27-3.19(m,1H),2.01-1.92(m,2H),1.61-1.49(m,2H).ESI-LR:536.18[M+1]+.
实施例16：(6S)-2-硝基-N-((6-(3-(4-(三氟甲氧基)苯氧基)吡咯烷-1-基)嘧啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物16)
Figure PCTCN2015097096-appb-000035
(1)将4-(4-(三氟甲氧基)苯氧基)吡咯烷I-2-2(190mg,0.77mmol)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-16(183mg,收率67.3％)。
中间体I-3-16：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.64-4.57(m,1H),4.22-4.17(m,2H),3.57-3.50(m,2H),2.08-1.98(m,1H),1.95-1.90(m,1H).
(2)将中间体I-3-16(176mg,0.50mmol)和I-4(92mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物16(156mg,收率60.1％)。
化合物16：1H-NMR(400MHz,CDCl3)δ8.32(s,2H),8.03(s,1H),7.21(d,J＝8.7Hz,2H),7.05(d,J＝9.2Hz,2H),4.50-4.42(m,1H),4.45-4.30(m,2H),4.14-4.08(m,1H),3.99-3.91(m,1H),3.76-3.56(m,3H),3.19(d,J＝0.4Hz,1H),2.47(s,1H),2.36-2.30(m,2H),2.24–2.07(m,2H).ESI-LR:522.16[M+1]+.
实施例17：(6S)-N-((6-(3-氟-4-(4-(三氟甲氧基)苯氧基)哌啶-1-基)嘧啶-3-基)甲基)-2-硝基-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物17)
Figure PCTCN2015097096-appb-000036
(1)将3-氟-4-(4-(三氟甲氧基)苯氧基)哌啶I-2-3(214mg,0.77mmol)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-17(233mg,收率78.5％)。
中间体I-3-17：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.82-4.75(m,1H),4.32-4.27(m,1H),4.18-4.01(m,1H),3.77-3.74(m,3H),2.91-2.86(m,1H),1.90-1.86(m,1H).
(2)将中间体I-3-17(230mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物17(153mg,收率46.2％)。
化合物17：1H NMR(400MHz,CDCl3)δ8.34(s,2H),8.03(s,1H),7.21(d,J＝8.7Hz,2H),7.05(d,J＝9.2Hz,2H),4.89-4.65(m,1H),4.52-4.36(m,2H),4.35-4.26(m,1H),4.14-4.10(m,1H),3.93-3.87(m,1H),3.79-3.63(m,1H),3.48(dd,1H),3.40-3.23(m,2H),3.19-3.03(m,1H),2.25-2.13(m,2H),1.98-1.84(m,2H).ESI-LR:554.18[M+1]+.
实施例18：(S)-2-硝基-N-((6-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)嘧啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物18)
Figure PCTCN2015097096-appb-000037
(1)将4-(4-(三氟甲氧基)苯基)哌嗪I-2-4(189mg,0.77mmol)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-18(232mg,收率85.7％)。
中间体I-3-18：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.16-4.13(m,4H),3.27-3.24(m,4H).
(2)将中间体I-3-18(211mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物18(180mg,收率57.9％)。
化合物18：1H-NMR(400MHz,CDCl3)δ8.33(s,2H),8.03(s,1H),7.21(d,J＝8.7Hz,2H),7.05(d,J＝9.2Hz,2H),4.41-4.35(m,2H),4.14(dd,J＝12.3,4.5Hz,1H),3.92(dd,J＝12.2,3.4Hz,1H),3.82-3.70(m,4H),3.62(s,2H),3.31-3.21(m,5H).ESI-LR:521.18[M+1]+.
实施例19：(3S)-N-((6-(3-甲基-4-(4-(三氟甲氧基)苯基)哌嗪-1-基)嘧啶-3-基)甲基)-7-硝基-3,4-二氢-2H-咪唑并[2,1-b][1,3]噁嗪-3-胺(化合物19)
Figure PCTCN2015097096-appb-000038
(1)将2-甲基-1-(4-(三氟甲氧基)苯基)哌嗪I-2-5(200mg,0.77mmol)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-19(238mg,收率84.6％)。
中间体I-3-19：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.75-4.13(m,4H),3.05-2.96(m,3H),1.03(d,J＝6.5Hz,3H).
(2)将中间体I-3-19(219mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物19(162mg,收率50.8％)。
化合物19：1H-NMR(400MHz,CDCl3)δ8.33(s,2H),8.03(s,1H),7.21(d,J＝8.7Hz,2H),7.05(d,J＝9.2Hz,2H),4.48-4.40(m,3H),4.31-4.25(m,1H),4.18(dd,J＝12.4,4.5Hz,1H),3.99-3.92(m,1H),3.90-3.84(m,1H),3.75(s,2H),3.60(dd,J＝12.9,3.5Hz,1H),3.46(ddd,J＝13.0,6.6,3.5Hz,1H),3.40(dd,J＝4.4,2.6Hz,1H),3.28-3.21(m,1H),3.20-3.11(m,1H),1.01(d,J＝6.5Hz,3H).ESI-LR:535.20[M+1]+.
实施例20：(3S)-N-((6-(2-甲基-4-(4-(三氟甲氧基)苯基)哌嗪-1-基)嘧啶-3-基)甲基)-7-硝基-3,4-二氢-2H-咪唑并[2,1-b][1,3]噁嗪-3-胺(化合物20)
Figure PCTCN2015097096-appb-000039
(1)将3-甲基-1-(4-(三氟甲氧基)苯基)哌嗪I-2-6(200mg,0.77mmol)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-20(185mg,收率65.3％)。
中间体I-3-20：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.80-4.47(m,3H),3.25-3.10(m,4H),1.17(d,J＝6.5Hz,3H).
(2)将中间体I-3-20(183mg,0.50mmol)和I-4(92mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物20(131mg,收率49.2％)。
化合物20：1H-NMR(400MHz,CDCl3)δ8.33(s,2H),8.03(s,1H),7.20(d,J＝8.5Hz,2H),7.03(d,J＝9.3Hz,2H),4.89-4.82(m,1H),4.40-4.30(m,1H),4.16(dd,J＝12.8,4.0Hz,1H),3.97(dd,J＝12.7,3.2Hz,1H),3.70(d,J＝11.9Hz,1H),3.61(d,J＝10.7Hz,3H),3.29-3.20(m,3H),2.94-2.90(m,1H),2.78-2.64(m,2H),1.20(d,J＝6.6Hz,3H).ESI-LR:535.20[M+1]+.
实施例21：(S)-7-硝基-N-((6-(4-(4-(三氟甲氧基)苯基)哌啶-1-基)嘧啶-3-基)甲基)-3,4-二氢-2H-咪唑并[2,1-b][1,3]噁嗪-3-胺(化合物21)
Figure PCTCN2015097096-appb-000040
(1)将4-(4-(三氟甲氧基)苯基)哌啶I-2-7(188mg,0.77mmol)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-21(231mg,收率85.4％)。
中间体I-3-21：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.00-3.90(m,2H),3.76-3.73(m,2H),3.68-3.57(m,1H),2.00-1.89(m,2H),1.82-1.78(m,2H).
(2)将中间体I-3-21(210mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物21(149mg,收率48.7％)。
化合物21：1H-NMR(400MHz,CDCl3)δ8.30(s,2H),8.01(s,1H),7.36(d,J＝8.7Hz,2H),7.25(d,J＝9.2Hz,2H),4.79(d,J＝12.9Hz,2H),4.41-4.29(m,2H),4.13(dd,J＝12.7,4.0Hz,1H),3.98-3.91(m,1H),3.61(s,2H),2.97-2.81(m,4H),1.85-1.81(m,2H),1.52-1.45(m,2H).ESI-LR:520.18[M+1]+.
实施例22：(S)-1-(5-(((7-硝基-3,4-二氢-2H-咪唑并[2,1-b][1,3]噁嗪-3-基)氨基)甲基)嘧啶-2-基)-4-(4-(三氟甲氧基)苯基)哌啶-4-醇(化合物22)
Figure PCTCN2015097096-appb-000041
(1)将4-(4-(三氟甲氧基)苯基)哌啶-4-醇I-2-8(200mg,0.77mmol)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-22(191mg,收率67.8％)。
中间体I-3-22:1H-NMR(400MHz,CDCl3)δ9.78(s,1H),9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.00-3.90(m,2H),3.76-3.73(m,2H),2.14-2.03(m,2H),1.96-1.91(m,2H).
(2)将中间体I-3-22(183mg,0.50mmol)和I-4(92mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物22(103mg,收率38.5％)。
化合物22:1H-NMR(400MHz,CDCl3)δ8.31(s,2H),8.02(s,1H),7.37(d,J＝8.5Hz,2H),7.24(d,J＝9.3Hz,2H),4.34(dt,J＝11.2,8.0Hz,2H),4.13-4.09(m,1H),3.98-3.79(m,3H),3.59(d,J＝11.6Hz,2H),3.38(s,1H),3.26(t,J＝12.6Hz,2H),2.23-2.19(m,2H),1.88-1.84(m,2H).ESI-LR:536.18[M+1]+.
实施例23：(S)-N-((6-(4-甲氧基-4-(4-(三氟甲氧基)苯基)哌啶-1-基)嘧啶-3-基)甲基)-7-硝基-3,4-二氢-2H-咪唑并[2,1-b][1,3]噁嗪-3-胺(化合物23)
Figure PCTCN2015097096-appb-000042
(1)将4-甲氧基-4-(4-(三氟甲氧基)苯基)哌啶I-2-9(212mg,0.77mmol)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-23(208mg,收率70.9％)。
中间体I-3-23：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.00-3.90(m,2H),3.76-3.73(m,2H),3.57(s,3H),2.12-2.01(m,2H),1.94-1.89(m,2H).
(2)将中间体I-3-23(190mg,0.50mmol)和I-4(92mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物23(115mg,收率42.1％)。
化合物23：1H-NMR(400MHz,CDCl3)δ8.33(s,2H),8.03(s,1H),7.38(d,J＝8.5Hz,2H),7.27(d,J＝9.3Hz,2H),4.40(dt,J＝11.2,8.0Hz,2H),4.11-4.07(m,1H),4.00-3.81(m,6H),3.59(d,J＝11.6Hz,2H),3.38(s,1H),3.26-3.20(m,2H),2.23-2.19(m,2H),1.88-1.84(m,2H).ESI-LR:550.19[M+1]+.
实施例24：(S)-1-(5-(((7-硝基-3,4-二氢-2H-咪唑并[2,1-b][1,3]噁嗪-3-基)氨基)甲基)嘧啶-2-基)-4-(4-(三氟甲氧基)苯基)哌啶-4-甲腈(化合物24)
Figure PCTCN2015097096-appb-000043
(1)将4-(4-(三氟甲氧基)苯基)哌啶-4-甲腈I-2-10(208mg,0.77mmol)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-24(227mg,收率78.5％)。
中间体I-3-24：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.03-3.91(m,2H),3.77-3.74(m,2H),2.32-2.23(m,2H),2.14-2.09(m,2H).
(2)将中间体I-3-24(225mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物24(139mg,收率42.8％)。
化合物24：1H-NMR(400MHz,CDCl3)δ8.32(s,2H),8.00(s,1H),7.40(d,J＝8.5Hz,2H),7.31(d,J＝9.3Hz,2H),4.43(dt,J＝11.2,8.0Hz,2H),4.13-4.08(m,1H),4.03-3.92(m,3H),3.61(d,J＝11.6Hz,2H),3.42(s,1H),3.32-3.25(m,2H),2.94-2.87(m,2H),2.30-2.25(m,2H).ESI-LR:545.18[M+1]+.
实施例25：(6S)-2-硝基-N-((6-(5-(4-(三氟甲氧基)苯基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)嘧啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物25)
Figure PCTCN2015097096-appb-000044
(1)将2-(4-(三氟甲氧基)苯基)八氢吡咯[3,4]吡咯I-2-11(209mg,0.77mmol)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-25(241mg,收率82.7％)。
中间体I-3-25：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),3.83-3.71(m,4H),3.49-3.35(m,4H),3.18(s,2H)..
(2)将中间体I-3-25(226mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物25(166mg,收率50.7％)。
化合物25：1H-NMR(400MHz,CDCl3)δ8.33(s,2H),8.01(s,1H),7.38(d,J＝8.5Hz,2H),7.30(d,J＝9.3Hz,2H),4.41-4.32(m,2H),4.12(dd,J＝12.3,4.5Hz,1H),3.90(dd,J＝12.4,3.4Hz,1H),3.83-3.71(m,4H),3.63-3.55(m,2H),3.49-3.35(m,4H),3.27(dd,J＝9.5,3.8Hz,2H),3.18(s,2H).ESI-LR:547.20[M+1]+.
实施例26：(6S)-2-硝基-N-((6-(5-(4-(三氟甲氧基)苯基)-2,5-二氮杂二环[2.2.1]庚烷-2-基)嘧啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物26)
Figure PCTCN2015097096-appb-000045
(1)将2-(4-(三氟甲氧基)苯基)-2,5-二氮杂二环[2.2.1]庚烷I-2-12(198mg,0.77mmol)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-26(201mg,收率71.7％)。
中间体I-3-26：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),3.71-3.65(m,3H),3.31-3.25(m,3H),1.78-1.73(m,1H),1.53-1.47(m,1H).
(2)将中间体I-3-26(181mg,0.50mmol)和I-4(84mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物26(110mg,收率42.5％)。
化合物26：1H-NMR(400MHz,CDCl3)δ8.32(s,2H),8.01(s,1H),7.38(d,J＝8.5Hz,2H),7.27(d,J＝9.3Hz,2H),4.40-4.38(m,1H),4.32(dd,J＝12.0,4.3Hz,1H),4.13(dd,J＝12.3,4.5Hz,1H),3.90(dd,J＝12.2,3.4Hz,1H),3.86-3.76(m,2H),3.70-3.63(m,3H),3.40(dd,J＝4.7,2.6Hz,1H),3.30-3.24(m,3H),1.77-1.72(m,1H),1.52-1.49(m,1H).ESI-LR:533.18[M+1]+.
实施例27：(S)-2-硝基-N-((6-(2-(4-(三氟甲氧基)苯基)-2,7-二氮杂螺[3.5]壬烷-7-基)嘧啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物27)
Figure PCTCN2015097096-appb-000046
(1)将2-(4-(三氟甲氧基)苯基)-2,7-二氮杂螺[3.5]壬烷I-2-13(220mg,0.77mmol)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-27(220mg,收率73.1％)。
中间体I-3-27：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),5.21-4.61(m,4H),3.57-3.50(m,4H),1.59-1.51(m,4H),.
(2)将中间体I-3-27(195mg,0.50mmol)和I-4(84mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物27(110mg,收率39.6％)。
化合物27：1H-NMR(400MHz,CDCl3)δ8.32(s,2H),8.01(s,1H),7.38(d,J＝8.5Hz,2H),7.27(d,J＝9.3Hz,2H),4.40(dt,J＝11.2,8.0Hz,2H),4.11-4.07(m,1H),4.00-3.81(m,6H),3.59-3.50(m,6H),3.39(s,1H),3.28-3.21(m,2H),2.27-2.20(m,2H),1.95-1.89(m,2H).ESI-LR:561.21[M+1]+.
实施例28：(6S)-2-硝基-N-((6-(3-(4-(三氟甲氧基)苯氧基)-8-氮杂二环[3.2.1]辛烷-8-基)嘧啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物28)
Figure PCTCN2015097096-appb-000047
(1)将2-(4-(三氟甲氧基)苯基)-8-氮杂二环[3.2.1]辛烷I-2-14(220mg,0.77mmol)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-28(214mg,收率70.9％)。
中间体I-3-28：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.62-4.54(m,1H),3.57-3.51(m,2H),2.05-1.95(m,2H),1.87-1.83(m,2H),1.79-1.75(m,2H),1.47-1.50(m,2H).
(2)将中间体I-3-28(196mg,0.50mmol)和I-4(84mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物28(128mg,收率45.7％)。
化合物28：1H-NMR(400MHz,CDCl3)δ8.11(s,1H),7.45(dd,J＝8.7,2.4Hz,1H),7.36(s,1H),7.15(d,J＝8.6Hz,2H),6.94-6.89(m,2H),6.67(d,J＝8.7Hz,1H),4.73-4.50(m,1H),4.42-4.30(m,2H),4.13(dd,J＝12.4,4.5Hz,1H),3.87-3.79(m,3H),3.81-3.72(m,2H),3.42-3.37(m,1H),2.07-1.98(m,2H),1.88-1.80(m,2H),1.70-1.65(m,2H),1.45-1.48(m,2H).ESI-LR:562.19[M+1]+.
实施例29：(S)-2-硝基-N-((2-(4-(4-(三氟甲氧基)苯基)-1,4-重氮基庚环-1-基)嘧啶-5-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物29)
Figure PCTCN2015097096-appb-000048
(1)将1-(4-(三氟甲氧基)苯基)-1,4-二氮杂庚烷I-2-15(200mg,0.77mmol)(参考文献：WO 2005100365)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-29(137mg,收率68.7％)。
中间体I-3-29：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),9.79(s,1H),8.75(s,2H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.58-4.54(m,2H),4.18-4.14(m,4H),3.27-3.24(m,2H)，2.73-2.69(m,2H).
(2)将中间体I-3-29(130mg,0.50mmol)和I-4(84mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物29(134mg,收率50.5％)。
化合物29：1H-NMR(400MHz,CDCl3)δ8.33(s,2H),8.03(s,1H),7.21(d,J＝8.7Hz,2H),7.05(d,J＝9.2Hz,2H),4.58-4.54(m,2H),4.41-4.35(m,2H),4.14(dd,J＝12.3,4.5Hz,1H),3.92(dd,J＝12.2,3.4Hz,1H),3.82-3.70(m,4H),3.62(s,2H),3.31-3.21(m,3H),2.73-2.69(m,2H).,ESI-LR:535.20[M+1]+.
实施例30：(S)-2-硝基-N-((2-(4-((4-(三氟甲氧基)苯基)氨基)哌啶-1-基)嘧啶-5-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物30)
Figure PCTCN2015097096-appb-000049
(1)将N-(4-(三氟甲胺基)苯氧基)哌啶-4-胺I-2-16(200mg,0.77mmol)(参考文献：WO2011134296)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-30(189mg,收率67.3％)。
中间体I-3-30：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.75(s,2H),7.07-7.03(m,2H),6.84-6.81(m,2H),4.02-3.92(m,2H),3.57-3.51(m,3H),1.85-1.75(m,2H),1.78-1.74(m,2H).
(2)将中间体I-3-30(183mg,0.50mmol)和I-4(92mg,0.50mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物30(186mg,收率58.1％)。
化合物30：1H-NMR(400MHz,CDCl3)δ8.30(s,2H),8.03(s,1H),7.28(d,J＝8.7Hz,2H),7.09(d,J＝9.1Hz,2H),4.51-4.40(m,2H),4.37-4.34(m,2H),4.17-4.13(m,1H),3.98-3.95(m,1H),3.60(s,2H),3.26-3.22(m,2H),3.10-3.04(m,2H),1.95-1.91(m,2H),1.30-1.21(m,2H).ESI-LR:535.20[M+1]+.
实施例31：(S)-2-硝基-N-((2-(4-(4-(三氟甲基)苯基)哌嗪-1-基)嘧啶-5-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物31)
Figure PCTCN2015097096-appb-000050
(1)将4-(4-(三氟甲基)苯基)哌嗪I-2-17(177mg,0.77mmol)(参考文献：J.Med.Chem.2013,56(24),10158-10170)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-31(226mg,收率87.6％)。
中间体I-3-31：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.75(s,2H),7.81-7.77(m,2H),6.99-6.96(m,2H),4.18-4.15(m,4H),3.30-3.25(m,4H).
(2)将中间体I-3-31(201mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物31(168mg,收率55.8％)。
化合物31：1H-NMR(400MHz,CDCl3)δ8.33(s,2H),8.03(s,1H),7.84(d,J＝8.7Hz,2H),7.09(d,J＝9.2Hz,2H),4.41-4.35(m,2H),4.14(dd,J＝12.3,4.5Hz,1H),3.92(dd,J＝12.2,3.4Hz,1H),3.85-3.73(m,4H),3.62(s,2H),3.34-3.23(m,5H).ESI-LR:505.18[M+1]+.
实施例32：(S)-N-((2-(4-(4-氟-3-甲基苯基)哌嗪-1-基)嘧啶-5-基)甲基)-2-硝基-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物32)
Figure PCTCN2015097096-appb-000051
(1)将1-(4-氟-3-甲基苯基)哌嗪I-2-18(149mg,0.77mmol)(参考文献：Letters in organic chemistry,2011,8(9),628-630)和2-氯-5-醛基嘧啶I-1-2(130mg,0.92mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-32(185mg,收率80.4％)。
中间体I-3-32：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.75(s,2H),7.31-7.27(m,1H),6.97(s,1H),6.82(d,J＝8.8Hz,1H),4.18-4.15(m,4H),3.30-3.25(m,4H),2.37(s,3H).
(2)将中间体I-3-32(180mg,0.60mmol)和I-4(110mg,0.60mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物32(147mg,收率52.7％)。
化合物32：1H-NMR(400MHz,CDCl3)δ8.33(s,2H),8.03(s,1H),7.31-7.27(m,1H),6.97(s,1H),6.82(d,J＝8.8Hz,1H),4.41-4.35(m,2H),4.14(dd,J＝12.3,4.5Hz,1H),3.92(dd,J＝12.2,3.4Hz,1H),3.85-3.73(m,4H),3.62(s,2H),3.34-3.23(m,5H),2.37(s,3H).ESI-LR:469.20[M+1]+.
实施例33：(S)-N-((2-(4-(6-甲氧基吡啶-3-基)哌嗪-1-基)嘧啶-5-基)甲基)-2-硝基-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物33)
Figure PCTCN2015097096-appb-000052
(1)将1-(6-甲氧基吡啶-3-基)哌嗪I-2-19(194mg,1.0mmol)(参考文献：WO2010146083)和2-氯-5-醛基嘧啶I-1-2(171mg,1.2mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-33(265mg,收率88.5％)。
中间体I-3-33：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.75(s,2H),7.15(dd,J＝8.8Hz,2.0Hz,1H),6.97(s,1H),6.82(d,J＝8.8Hz,1H),4.18-4.15(m,4H),3.63(s,3H),3.30-3.25(m,4H).
(2)将中间体I-3-33(260mg,0.87mmol)和I-4(160mg,0.87mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物33(240mg,收率60.0％)。
化合物33：1H-NMR(400MHz,CDCl3)δ8.33(s,2H),8.03(s,1H),7.15(dd,J＝8.8Hz,2.0Hz,1H),6.97(s,1H),6.82(d,J＝8.8Hz,1H),4.41-4.35(m,2H),4.14(dd,J＝12.3,4.5Hz,1H),3.92(dd,J＝12.2,3.4Hz,1H),3.85-3.73(m,4H),3.65(s,3H),3.62(s,2H),3.34-3.23(m,5H).ESI-LR:468.20[M+1]+.
实施例34：(S)-2-硝基-N-((2-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)嘧啶-5-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物34)
Figure PCTCN2015097096-appb-000053
(1)将1-(4-氟-3-甲基苯基)哌嗪I-2-20(232mg,1.0mmol)(参考文献：J.Med.Chem.2010,53(12),4603-4614)和2-氯-5-醛基嘧啶I-1-2(171mg,1.2mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-34(230mg,收率68.0％)。
中间体I-3-34：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.95(s,2H),8.75(s,2H),4.18-4.15(m,4H),3.30-3.25(m,4H).
(2)将中间体I-3-34(220mg,0.65mmol)和I-4(120mg,0.65mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物34(160mg,收率48.6％)。
化合物34：1H-NMR(400MHz,CDCl3)δ8.53(s,2H),8.33(s,2H),8.03(s,1H),4.41-4.35(m,2H),4.14(dd,J＝12.3,4.5Hz,1H),3.92(dd,J＝12.2,3.4Hz,1H),3.85-3.73(m,4H),3.62(s,2H),3.34-3.23(m,5H).ESI-LR:507.18[M+1]+.
实施例35：(S)-2-(4-(5-(((2-硝基-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-基)氨基)甲基)嘧啶-2-基)哌嗪-1-基)噻唑-4-甲腈(化合物35)
Figure PCTCN2015097096-appb-000054
(1)将1-(4-氟-3-甲基苯基)哌嗪I-2-21(194mg,1.0mmol)(参考文献：WO2006072436)和2-氯-5-醛基嘧啶I-1-2(171mg,1.2mmol)作为原料，操作方法同实施例1中(1)的方法，得中间体I-3-35(249mg,收率83.0％)。
中间体I-3-35：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.75(s,2H),7.31(s,1H),4.18-4.15(m,4H),3.30-3.25(m,4H).
(2)将中间体I-3-35(240mg,0.80mmol)和I-4(147mg,0.80mmol)作为原料，操作方法同实施例1中(2)的方法，得淡黄色化合物35(208mg,收率55.6％)。
化合物35：1H-NMR(400MHz,CDCl3)δ8.33(s,2H),8.03(s,1H),7.31(s,1H),4.41-4.35(m,2H),4.14(dd,J＝12.3,4.5Hz,1H),3.92(dd,J＝12.2,3.4Hz,1H),3.85-3.73(m,4H),3.62(s,2H),3.34-3.23(m,5H).ESI-LR:469.14[M+1]+.
实施例36：(S)-N-((4-甲基-2-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)嘧啶-5-基)甲基)-2-硝基-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物36)
Figure PCTCN2015097096-appb-000055
(1)将4-(4-(三氟甲氧基)苯基)哌嗪I-2-4(492mg,2.00mmol)，2-氯-4-甲基嘧啶-5-甲酸乙酯II-1-1(440mg,2.20mmol)(参考文献：WO2012123467)溶于DMF(8mL)，滴加K2CO3(828mg,6.00mmol)，滴毕，90℃反应4小时。反应完全冷至室温，倒入冰水中，乙酸乙酯(20mL*2)萃取，无水硫酸钠干燥，过滤，旋干柱层析(石油醚：乙酸乙酯＝4:1)，得淡黄色固体中间体II-2-1(739mg，收率90.2％)。
中间体II-2-1：1H-NMR(400MHz,CDCl3)δ8.57(s,1H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.43(q,J＝7.1Hz,2H),4.10-4.07(m,4H),3.27-3.24(m,4H),2.32(s,3H),1.43(t,J＝7.1Hz,3H).
(2)将中间体II-2-1(697mg,1.70mmol)溶于无水四氢呋喃(10mL)中，冷至-30℃，加入四氢铝锂(65mg,1.70mmol)，在此温度下反应1.5小时，加入十水硫酸钠(200mg),并缓慢升值室温，搅拌半小时，过滤，固体用四氢呋喃洗涤，有机相用无水硫酸钠干燥，过滤，浓缩得 无色油状物中间体II-3-1(587mg,收率93.9％)，不经纯化，直接投入下步反应。ESI-LR:369.15[M+1]+.
(3)将中间体II-3-1(478mg,1.30mmol)溶于乙酸乙酯(10mL)中，加入IBX(2-碘酰基苯甲酸，546mg,1.95mmol)，升温至60℃反应8小时。反应结束后冷至室温，过滤除去不溶物，有机相直接旋干柱层析(石油醚：乙酸乙酯＝4:1)，得淡黄色油状物中间体II-4-1(349mg,收率73.5％)。
中间体II-4-1：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.59(s,1H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.16-4.13(m,4H),3.27-3.24(m,4H),2.32(s,3H).
(4)将中间体II-4-1(260mg,0.71mmol)，三乙胺(93mg,0.92mmol)溶于二氯甲烷(10mL)中，然后加入原料I-4(131mg,0.71mmol)中，室温反应过夜，加入NaBH(OAc)3(602mg,2.84mmol)，继续室温反应过夜。加入碳酸氢钠溶液(10mL)，分层，水层用二氯甲烷(20mL*2)萃取，合并二氯甲烷层，饱和氯化钠溶液洗，无水硫酸钠干燥，旋干，残留物柱层析(二氯甲烷：甲醇＝50:1)得到淡黄色粉末状化合物36(216mg,收率57.2％)。
化合物36：1H-NMR(400MHz,CDCl3)δ8.13(s,1H),7.74(s,1H),7.18-7.09(m,2H),7.05-6.94(m,2H),4.55-4.44(m,2H),4.26(dd,J＝12.7,4.1Hz,1H),4.07(dd,J＝12.8,4.0Hz,1H),3.97-3.88(m,4H),3.78-3.74(m,2H),3.43-3.40(m,1H),3.26-3.14(m,4H),2.38(s,3H).ESI-LR:535.20[M+1]+.
实施例37：(S)-N-((4-甲基-2-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)嘧啶-5-基)乙基)-2-硝基-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物37)
Figure PCTCN2015097096-appb-000056
(1)以4-(4-(三氟甲氧基)苯基)哌嗪I-2-4(492mg,2.00mmol)和2-氯-4-乙基嘧啶-5-甲酸乙酯II-1-2(470mg,2.20mmol)(参考文献：US5935966)为原料，操作方法同实施例36中(1)的方法，得中间体II-2-2(741mg，收率87.4％)。
中间体II-2-2：1H-NMR(400MHz,CDCl3)δ8.57(s,1H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.43(q,J＝7.1Hz,2H),4.09-4.04(m,4H),3.78(q,J＝7.2Hz,2H),3.27-3.24(m,4H),1.32-1.24(m,6H).
(2)以中间体II-2-2(720mg,1.70mmol)和四氢铝锂(65mg,1.70mmol)为原料，操作方法同实施例36中(2)的方法，得中间体II-3-2(534mg，收率82.3％)。中间体II-3-2：ESI-LR:383.16[M+1]+.
(3)以中间体II-3-2(496mg,1.30mmol)和IBX(546mg,1.95mmol)为原料，操作方法同实施例33中(3)的方法，得淡黄色油状物中间体II-4-2(324mg,收率65.7％)。
中间体II-4-2：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.59(s,1H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.16-4.13(m,4H),3.78(q,J＝7.2Hz,2H),3.27-3.24(m,4H),1.28(t,J＝7.2Hz,3H).
(4)以中间体II-4-2(260mg,0.71mmol)和I-4(131mg,0.71mmol)为原料，操作方法同实施例36中(4)的方法，得到淡黄色粉末状化合物37(169mg,收率43.5％)。
化合物37：1H-NMR(400MHz,CDCl3)δ8.09(s,1H),7.40(s,1H),7.13-7.06(m,2H),6.99-6.91(m,2H),4.47-4.38(m,2H),4.18(dd,J＝12.7,4.1Hz,1H),3.97-3.88(m,5H),3.78-3.74(m,2H),3.43-3.40(m,1H),3.26-3.18(m,4H),2.72-2.65(m,2H)1.28(t,J＝7.2Hz,3H).ESI-LR:549.21[M+1]+.
实施例38：(S)-N-((4-甲氧基-2-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)嘧啶-5-基)甲基)-2-硝基-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物38)
Figure PCTCN2015097096-appb-000057
(1)以4-(4-(三氟甲氧基)苯基)哌嗪I-2-4(492mg,2.00mmol)和2-氯-4-甲氧基嘧啶-5-甲酸乙酯II-1-3(475mg,2.20mmol)(参考文献：WO2004060308)为原料，操作方法同实施例36中(1)的方法，得中间体II-2-3(750mg，收率88.1％)。
中间体II-2-3：1H-NMR(400MHz,CDCl3)δ8.71(s,1H),7.15-7.11(m,2H),6.91-6.87(m,2H),4.33(q,J＝7.1Hz,2H),3.97(s,3H),3.78-3.72(m,4H),3.27-3.24(m,4H),1.43(t,J＝7.1Hz,3H).
(2)以中间体II-2-3(724mg,1.70mmol)和四氢铝锂(65mg,1.70mmol)为原料，操作方法同实施例36中(2)的方法，得中间体II-3-3(526mg，收率80.7％)。中间体II-3-3：ESI-LR:385.14[M+1]+.
(3)以中间体II-3-3(499mg,1.30mmol)和IBX(546mg,1.95mmol)为原料，操作方法同实施例36中(3)的方法，得淡黄色油状物中间体II-4-3(282mg,收率56.8％)。
中间体II-4-3：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.59(s,1H),7.18-7.14(m,2H),6.95-6.92(m,2H),3.97(s,3H),3.78-3.72(m,4H),3.27-3.24(m,4H).
(4)以中间体II-4-3(271mg,0.71mmol)和I-4(131mg,0.71mmol)为原料，操作方法同实施例36中(4)的方法，得到淡黄色粉末状化合物38(143mg,收率36.8％)。
化合物38：1H-NMR(400MHz,CDCl3)δ8.09(s,1H),7.40(s,1H),7.13-7.06(m,2H),6.99-6.91(m,2H),4.47-4.38(m,1H),4.15(dd,J＝12.3,4.4Hz,1H),3.97-3.88(m,8H),3.78-3.74(m,2H),3.38-3.34(m,1H),3.24-3.19(m,4H).ESI-LR:551.19[M+1]+.
实施例39：(S)-N-((4-氯-2-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)嘧啶-5-基)甲基)-2-硝基-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物39)
Figure PCTCN2015097096-appb-000058
(1)以4-(4-(三氟甲氧基)苯基)哌嗪I-2-4(984mg,4.00mmol)和2，4-二氯-嘧啶-5-甲酸乙酯II-1-4(972mg,4.40mmol)(参考文献：WO2009074749)为原料，操作方法同实施例36中(1)的方法，得中间体II-2-4(782mg，收率45.5％)。
中间体II-2-4：1H-NMR(400MHz,CDCl3)δ8.75(s,1H),7.15-7.11(m,2H),6.91-6.87(m,2H),4.33(q,J＝7.1Hz,2H),3.78-3.72(m,4H),3.27-3.24(m,4H),1.43(t,J＝7.1Hz,3H).
(2)以中间体II-2-4(731mg,1.70mmol)和四氢铝锂(65mg,1.70mmol)为原料，操作方法同实施例36中(2)的方法，得中间体II-3-4(449mg，收率68.1％)。中间体II-3-4：ESI-LR:389.09[M+1]+.
(3)以中间体II-3-4(426mg,1.10mmol)和IBX(462mg,1.65mmol)为原料，操作方法同实施例36中(3)的方法，得淡黄色油状物中间体II-4-4(257mg,收率60.7％)。
中间体II-4-4：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.61(s,1H),7.18-7.14(m,2H),6.95-6.92(m,2H),3.78-3.72(m,4H),3.27-3.24(m,4H).
(4)以中间体II-4-4(231mg,0.60mmol)和I-4(110mg,0.60mmol)为原料，操作方法同实施例36中(4)的方法，得到淡黄色粉末状化合物39(144mg,收率43.5％)。
化合物39：1H-NMR(400MHz,CDCl3)δ8.11(s,1H),7.43(s,1H),7.13-7.06(m,2H),6.99-6.91(m,2H),4.47-4.38(m,1H),4.15(dd,J＝12.3,4.4Hz,1H),3.97-3.88(m,5H),3.78-3.74(m,2H),3.38-3.34(m,1H),3.24-3.19(m,4H).ESI-LR:555.14[M+1]+.
实施例40：(S)-5-(((2-硝基-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-基)氨基)甲基)-2-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)嘧啶-4-甲腈(化合物40)
Figure PCTCN2015097096-appb-000059
(1)以4-(4-(三氟甲氧基)苯基)哌嗪I-2-4(492mg,2.00mmol)和2-氯-4-氰基嘧啶-5-甲酸 乙酯II-1-5(464mg,2.20mmol)(参考文献：WO2010036632)为原料，操作方法同实施例36中(1)的方法，得中间体II-2-5(726mg，收率86.3％)。
中间体II-2-5：1H-NMR(400MHz,CDCl3)δ8.99(s,1H),7.17-7.14(m,2H),6.95-6.92(m,2H),4.43(q,J＝7.1Hz,2H),4.12-4.09(m,4H),3.27-3.24(m,4H),1.43(t,J＝7.1Hz,3H).
(2)以中间体II-2-5(715mg,1.70mmol)和四氢铝锂(65mg,1.70mmol)为原料，操作方法同实施例36中(2)的方法，得中间体II-3-5(417mg，收率64.8％)。中间体II-3-5：ESI-LR:380.13[M+1]+.
(3)以中间体II-3-5(417mg,1.10mmol)和IBX(462mg,1.65mmol)为原料，操作方法同实施例36中(3)的方法，得淡黄色油状物中间体II-4-5(254mg,收率61.4％)。
中间体II-4-5：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),9.04(s,1H),7.20-7.15(m,2H),6.95-6.92(m,2H),4.12-4.09(m,4H),3.27-3.24(m,4H).
(4)以中间体II-4-5(226mg,0.60mmol)和I-5(110mg,0.60mmol)为原料，操作方法同实施例36中(4)的方法，得到淡黄色粉末状化合物40(126mg,收率38.7％)。
化合物40：1H-NMR(400MHz,CDCl3)δ8.46(s,1H),7.40(s,1H),7.15-7.12(m,2H),6.95-6.91(m,2H),4.46-4.44(m,1H),4.23(dd,J＝12.6,4.4Hz,1H),4.08(dd,J＝12.6,3.6Hz,1H),4.00-3.95(m,4H),3.93(s,2H),3.47-3.43(m,1H),3.24-3.19(m,4H).ESI-LR:546.17[M+1]+.
实施例41：(S)-2-硝基-N-((2-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)-4-(三氟甲基)嘧啶-5-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物41)
Figure PCTCN2015097096-appb-000060
(1)以4-(4-(三氟甲氧基)苯基)哌嗪I-2-4(492mg,2.00mmol)和2-氯-4-(三氟甲基)嘧啶-5-甲酸乙酯II-1-6(558mg,2.20mmol)(参考文献：WO2006048297)为原料，操作方法同实施例36中(1)的方法，得中间体II-2-6(790mg，收率85.1％)。
中间体II-2-6：1H-NMR(400MHz,CDCl3)δ8.42(s,1H),7.16-7.12(m,2H),6.94-6.91(m,2H),4.43(q,J＝7.1Hz,2H),4.01-3.96(m,4H),3.27-3.24(m,4H),1.43(t,J＝7.1Hz,3H).
(2)以中间体II-2-6(788mg,1.70mmol)和四氢铝锂(65mg,1.70mmol)为原料，操作方法同实施例36中(2)的方法，得中间体II-3-6(483mg，收率67.4％)。中间体II-3-6：ESI-LR:423.12[M+1]+.
(3)以中间体II-3-6(464mg,1.10mmol)和IBX(462mg,1.65mmol)为原料，操作方法同实施例36中(3)的方法，得淡黄色油状物中间体II-4-6(254mg,收率61.4％)。
中间体II-4-6：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.56(s,1H),7.19-7.15(m,2H), 6.95-6.92(m,2H),4.01-3.96(m,4H),3.27-3.24(m,4H).
(4)以中间体II-4-6(252mg,0.60mmol)和I-4(110mg,0.60mmol)为原料，操作方法同实施例36中(4)的方法，得到淡黄色粉末状化合物41(146mg,收率41.6％)。
化合物41：1H-NMR(400MHz,CDCl3)δ8.51(s,1H),7.38(s,1H),7.14-7.11(m,2H),6.93-6.90(m,2H),4.46-4.44(m,1H),4.36(dd,J＝12.6,4.4Hz,1H),4.18(dd,J＝12.5,4.5Hz,1H),4.02-3.98(m,4H),3.89(s,2H),3.47-3.43(m,1H),3.24-3.19(m,4H).ESI-LR:589.17[M+1]+.
实施例42：(S)-N-((4-环丙基-2-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)嘧啶-5-基)甲基)-2-硝基-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物42)
Figure PCTCN2015097096-appb-000061
(1)以4-(4-(三氟甲氧基)苯基)哌嗪I-2-4(492mg,2.00mmol)和2-氯-4-环丙基嘧啶-5-甲酸乙酯II-1-7(497mg,2.20mmol)(参考文献：WO2012129338)为原料，操作方法同实施例36中(1)的方法，得中间体II-2-7(751mg，收率86.2％)。
中间体II-2-7：1H-NMR(400MHz,CDCl3)δ8.57(s,1H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.43(q,J＝7.1Hz,2H),4.10-4.07(m,4H),3.27-3.24(m,4H),2.25-2.20(m,1H),1.43(t,J＝7.1Hz,3H),1.28-1.26(m,2H),1.10-1.04(m,2H).
(2)以中间体II-2-7(741mg,1.70mmol)和四氢铝锂(65mg,1.70mmol)为原料，操作方法同实施例36中(2)的方法，得中间体II-3-7(505mg，收率75.4％)。中间体II-3-7：ESI-LR:395.16[M+1]+.
(3)以中间体II-3-7(433mg,1.10mmol)和IBX(462mg,1.65mmol)为原料，操作方法同实施例36中(3)的方法，得淡黄色油状物中间体II-4-7(223mg,收率51.8％)。
中间体II-4-7：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),8.59(s,1H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.16-4.13(m,4H),3.27-3.24(m,4H),2.25-2.20(m,1H),1.28-1.26(m,2H),1.10-1.04(m,2H).
(4)以中间体II-4-7(196mg,0.50mmol)和I-4(92mg,0.50mmol)为原料，操作方法同实施例36中(4)的方法，得到淡黄色粉末状化合物42(107mg,收率38.4％)。
化合物42：1H-NMR(400MHz,CDCl3)δ8.13(s,1H),7.74(s,1H),7.18-7.09(m,2H),7.05-6.94(m,2H),4.55-4.44(m,2H),4.26(dd,J＝12.7,4.1Hz,1H),4.07(dd,J＝12.8,4.0Hz,1H),3.97-3.88(m,4H),3.78-3.74(m,2H),3.43-3.40(m,1H),3.26-3.14(m,4H),2.30-2.25(m,1H),1.34-1.29(m,2H),1.15-1.09(m,2H).ESI-LR:561.21[M+1]+.
实施例43：(S)-N-((4，6-二甲基-2-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)嘧啶-5-基)甲基)-2-硝基-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物43)
Figure PCTCN2015097096-appb-000062
(1)以4-(4-(三氟甲氧基)苯基)哌嗪I-2-4(492mg,2.00mmol)和2-氯-4,6-二甲基嘧啶-5-甲酸乙酯II-1-8(470mg,2.20mmol)(参考文献：WO2008157404)为原料，操作方法同实施例36中(1)的方法，得中间体II-2-8(832mg，收率89.3％)。
中间体II-2-8：1H-NMR(400MHz,CDCl3)δ7.18-7.14(m,2H),6.95-6.92(m,2H),4.43(q,J＝7.1Hz,2H),4.10-4.07(m,4H),3.27-3.24(m,4H),2.33(s,6H),1.43(t,J＝7.1Hz,3H).
(2)以中间体II-2-8(697mg,1.70mmol)和四氢铝锂(65mg,1.70mmol)为原料，操作方法同实施例36中(2)的方法，得中间体II-3-8(438mg，收率67.5％)。中间体II-3-8：ESI-LR:383.16[M+1]+.
(3)以中间体II-3-8(420mg,1.10mmol)和IBX(462mg,1.65mmol)为原料，操作方法同实施例36中(3)的方法，得淡黄色油状物中间体II-4-8(203mg,收率48.7％)。
中间体II-4-8：1H-NMR(400MHz,CDCl3)δ9.79(s,1H),7.18-7.14(m,2H),6.95-6.92(m,2H),4.16-4.13(m,4H),3.27-3.24(m,4H),2.38(s,6H).
(4)以中间体II-4-8(190mg,0.50mmol)和I-4(92mg,0.50mmol)为原料，操作方法同实施例36中(4)的方法，得到淡黄色粉末状化合物43(73mg,收率26.8％)。
化合物43：1H-NMR(400MHz,CDCl3)δ7.48(s,1H),7.18-7.09(m,2H),7.05-6.94(m,2H),4.50-4.43(m,2H),4.22(dd,J＝12.7,4.1Hz,1H),3.95-3.88(m,5H),3.86-3.75(m,2H),3.46(s,1H),3.22-3.18(m,4H),2.38(s,6H).ESI-LR:549.21[M+1]+.
实施例44：(S)-N-甲基-2-硝基-N-((2-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)嘧啶-5-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物44)
Figure PCTCN2015097096-appb-000063
将化合物18(104mg,0.20mmol)，溶于四氢呋喃(10mL)中，然后加入原料多聚甲醛(60mg)和催化量乙酸3滴，室温反应过夜，加入NaBH(OAc)3(168mg,0.8mmol)，继续室温反应过夜。加入碳酸氢钠溶液(10mL)，分层，水层用二氯甲烷(20mL*2)萃取，合并二氯甲烷层， 饱和氯化钠溶液洗，无水硫酸钠干燥，旋干，残留物柱层析(二氯甲烷：甲醇＝100:1)得到淡黄色粉末状化合物44(71mg,收率67.3％)。
化合物44：1H-NMR(400MHz,CDCl3)δ8.22(s,2H),7.41(s,1H),7.13(d,J＝8.5Hz,2H),6.93(d,J＝8.9Hz,2H),4.52-4.46(m,2H),4.16(dd,J＝12.3,4.5Hz,1H),3.99-3.94(m,4H),3.59-3.54(m,2H),3.33(s,1H),3.26-3.18(m,4H),2.32(s,3H).ESI-LR:535.20[M+1]+.
实施例45：(S)-N-乙基-2-硝基-N-((2-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)嘧啶-5-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物45)
Figure PCTCN2015097096-appb-000064
将化合物18(104mg,0.20mmol)，和乙醛(18mg)作为原料，操作方法同实施例44中的方法，得到淡黄色粉末状化合物45(79mg,收率72.3％)。
化合物45：1H-NMR(400MHz,CDCl3)δ8.22(s,2H),7.41(s,1H),7.13(d,J＝8.5Hz,2H),6.93(d,J＝8.9Hz,2H),4.52-4.46(m,2H),4.16(dd,J＝12.3,4.5Hz,1H),3.99-3.94(m,4H),3.59-3.54(m,2H),3.33(s,1H),3.26-3.18(m,4H),2.71(q,J＝7.1Hz,2H),1.09(t,J＝7.1Hz,3H).ESI-LR:549.21[M+1]+.
实施例46：(S)-2-硝基-N-(2-(6-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)吡啶-3-基)乙基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺(化合物46)
Figure PCTCN2015097096-appb-000065
(1)将4-(4-(三氟甲氧基)苯基)哌嗪I-2-4(492mg,2.00mmol)，2-(6-氯-吡啶-3-基)乙醛IV-1(341mg,2.20mmol)溶于DMF(8mL)，滴加K2CO3(828mg,6.00mmol)，滴毕，90℃反应6小时。反应完全冷至室温，倒入冰水中，乙酸乙酯(20mL*2)萃取，无水硫酸钠干燥，过滤，旋干柱层析(石油醚：乙酸乙酯＝4:1)，得淡黄色固体中间体IV-2(638mg，收率87.5％)。
中间体IV-2：1H-NMR(400MHz,CDCl3)δ9.78(s,1H),8.57-8.53(m,1H),7.93(dd,J＝9.1,2.3Hz,1H),7.18-7.12(m,2H),6.95-6.88(m,2H),6.70(d,J＝9.1Hz,1H),4.95-4.31(m,4H),3.66(d,J＝1.2,2H),3.37-3.32(m,4H).
(2)将中间体IV-2(259mg,0.71mmol)，三乙胺(93mg,0.92mmol)溶于二氯甲烷(10mL)中，然后加入原料I-4(131mg,0.71mmol)中，室温反应过夜，加入NaBH(OAc)3(602mg,2.84mmol)，继续室温反应过夜。加入碳酸氢钠溶液(10mL)，分层，水层用二氯甲烷(20mL*2)萃取，合并二氯甲烷层，饱和氯化钠溶液洗，无水硫酸钠干燥，旋干，残留物柱层析(二氯甲烷：甲醇＝50:1)得到淡黄色粉末状化合物46(265mg,收率70.2％)。
化合物46：1H-NMR(400MHz,CDCl3)δ8.11(s,1H),7.48(dd,J＝8.6,2.4Hz,1H),7.36(s,1H),7.13(d,J＝8.7Hz,2H),6.94(t,J＝6.3Hz,2H),6.69(d,J＝8.7Hz,1H),4.41-4.35(m,2H),4.14(dd,J＝12.3,4.5Hz,1H),3.92(dd,J＝12.2,3.4Hz,1H),3.79-3.70(m,4H),3.40(dd,J＝4.7,2.6Hz,1H),3.31-3.25(m,4H)2.91-3.86(m,2H),2.78-3.74(t,J＝7.3Hz,2H).ESI-LR:534.20[M+1]+.
实施例47：(S)-2-硝基-N-((6-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)吡啶-3-基)甲基)-6,7-二氢-5H-咪唑并[2,1-b][1,3]噁嗪-6-胺磷酸盐(化合物47)
Figure PCTCN2015097096-appb-000066
化合物4(1.04g,2.0mmol)溶于二氯甲烷(10mL)和甲醇(6mL)的混合溶剂中，全溶后，滴加磷酸(253mg,2.2mmol)，加热至回流。冷却，有固体析出，过滤，烘干，得到白色固体化合物47(839mg,69.8％)，熔点：181-183℃。
化合物47：元素分析：C23H27F3N7O8P，理论值C,44.74；H,4.41；N,15.88；实测值C,44.68；H,4.43；N,15.81。
实施例48-50：化合物48～化合物50的制备
类似于化合物47的合成，表1的化合物48-50可以按照实施例47的方法制备，具体采用的酸，所得化合物的盐熔点及收率见表2。
表2
实施例 化合物编号 酸 盐熔点(℃) 收率
实施例48 48 盐酸 192-194 54.2％
实施例49 49 甲磺酸 175-177 70.2％
实施例50 50 富马酸 143-145 80.7％
实施例51结核杆菌活性测试
将受试菌株H37Rv转入液体培养基，于37℃培养2周，吸取培养菌液少许，置于4mL液体培养基中，加入直径2～3mm无菌玻璃珠10～20粒，振荡20～30S，静止沉淀l0～20min，吸取菌悬液上清，用液体培养基调整比浊至1个麦氏单位，相当于1×107CFU/mL备用。每种药物用适量DMSO溶解至1mg/mL，0.22μm滤器过滤。再以液体培养基稀释至所需实验浓度。受试药物终浓度设置如下：0.001μg/mL、0.002μg/mL、0.0039μg/mL、0.0078μg/mL、0.0165μg/mL、0.03125μg/mL、0.0625μg/mL、0.125μg/mL、0.25μg/mL、0.5μg/mL、1μg/mL，共11个浓度梯度。各取上述药物溶液100μL，加到96孔微孔板中，再加入1mg/mL浓度的菌液100μL，使药物浓度达到设置的终浓度，37℃培养。同一药物稀释度设三组平行对照，对 照组不加药物，接菌量分别设置为100％、10％和1％。观察各药对结核分枝杆菌的最低抑菌浓度(MIC)，同时与一线抗结核药乙胺丁醇和处于临床研究阶段的PA-824的MIC结果进行比较。结果如下表3所示。
表3.部分化合物对结核杆菌H37Rv的MIC值
Figure PCTCN2015097096-appb-000067
如表3所示，体外对H37Rv的筛选结果表明,化合物4、化合物6、化合物10、化合物20和化合物44活性最强，它对H37Rv的最小抑制浓度(MIC)是乙胺丁醇的256倍，是正在进行临床研究的PA-824的活性的32倍；化合物5和化合物24表现出同样强的抗结核杆菌活性，分别为乙胺丁醇的128倍，PA-824的16倍。化合物1、化合物14、化合物18、化合物19、化合物31、化合物36和化合物40表现出同等强度的活性，它们的抗结核活性分别是乙胺丁醇的64倍，PA-824的8倍。
这些结果说明本发明化合物具有比一线抗结核药乙胺丁醇以及处于临床研究阶段的PA-824高得多的抗结核杆菌活性。
实施例52耐药结核试验
将受试菌株(246：链霉素耐药；242：异烟肼耐药；261：利福平耐药。结核分枝杆菌临床分离株，来自上海市肺科医院临床分离，步骤如下：a.采集上海市肺科医院结核科住院病人的痰标本，经碱处理后，接种到改良罗氏培养基上，培养2周；b.绝对浓度法测药敏：从培养基斜面上刮取新鲜培养物，用生理盐水磨菌比浊到1个麦氏单位(1mg/mL)，稀释到10-2mg/mL，取0.1mL接种于药敏培养基上，四周后观察结果。参考资料：《结核病诊断实验室检验规程》，中国防痨协会基础专业委员会编著，中国教育文化出版社，2006年1月)转入液体培养基，于37℃培养2周，吸取培养菌液少许，置于4mL液体培养基中，加入直径2～3mm无菌玻璃珠10～20粒，振荡20～30S，静止沉淀l0～20min，吸取菌悬液上清，用液体 培养基调整比浊至1个麦氏单位，相当于1×107CFU/mL备用。每种药物用适量DMSO溶解至1mg/mL，0.22μm滤器过滤。再以液体培养基稀释至所需实验浓度。受试药物终浓度设置如下：0.0039μg/mL、0.0078μg/mL、0.0165μg/mL、0.03125μg/mL、0.0625μg/mL、0.125μg/mL、0.25μg/mL、0.5μg/mL、1μg/mL、2μg/mL、4μg/mL，共11个浓度梯度检测时，各取上述药物溶液100μL，加到96孔微孔板中，再加入1mg/mL浓度的菌液100μL，使药物浓度达到设置的终浓度，37℃培养。同一药物稀释度设三组平行对照，对照组不加药物，接菌量分别设置为100％、10％和1％。观察各药对结核分枝杆菌的最低抑菌浓度(MIC)，同时与PA-824的MIC结果进行比较。结果如下表所示。
表4.部分化合物对耐药结核杆菌的MIC值
Figure PCTCN2015097096-appb-000068
S:链霉素，H:异烟肼，R:利福平。
由上述表4试验结果可知，受试化合物均具有很强的抗耐药结核杆菌活性，特别是化合物4、化合物10、化合物20和化合物44对各种耐药结核杆菌的MIC值均为0.00195μg/mL，分别为对照药物PA-824的256，512和256倍；化合物24对各种耐药结核杆菌的MIC值均为0.0039μg/mL，分别为对照药物PA-824的128，256和128倍；化合物1、化合物18、化合物19、化合物36和化合物40对各种耐药结核杆菌的MIC值均为0.0078μg/mL，分别为对照药物PA-824的64，128和64倍。
上述结果表明本发明化合物对各种耐药结核杆菌有很强活性,其活性远远优于阳性对照PA-824。
实施例53水中溶解度测试
3-5mg供试化合物加入0.5mL pH＝1.2HCl水溶液中，在摇床上摇三天，样品在离心机上以10000转/分离心五分钟，取上层清液2mL于50mL容量瓶中，加水定容到刻度，制成样品溶液；精密称量样品2.6mg于50mL容量瓶中，加甲醇适量溶解。加水定容到刻度，摇匀得对照样品溶液。将样品溶液和对照样品溶液，各进样20μL，液相测试。计算如下：
溶解度(mg/mL)＝C(对)*25*A(样)/A(对)
C(对)：对照样品浓度
A(样)：样品溶液液相峰面积
A(对)：对照样品溶液液相峰面积
表5.部分化合物的水溶性
供试化合物 溶解度
化合物1 0.7842mg/mL
化合物4 1.2572mg/mL
化合物10 0.5217mg/mL
化合物18 1.5321mg/mL
化合物19 1.3218mg/mL
化合物20 1.0238mg/mL
化合物24 0.7815mg/mL
化合物31 1.3548mg/mL
化合物36 1.1237mg/mL
PA-824 0.017mg/mL
由上述表5试验结果可知，本发明化合物均具有较好的水溶性，化合物4、化合物18、化合物19、化合物20、化合物31和化合物36的水溶性都大于1mg/mL，溶解性远远大于对照PA-824。
良好的水溶性可以提高药物的学代动力学性质，同时有利于药物制剂的制备。
实施例54药物代谢试验
健康ICR小鼠18只，雄性，体重18-22g。灌胃给予，给药剂量分别为10mg/kg，给药体积为10mL/kg。试验前禁食12h，自由饮水。给药后2h统一进食。按设定时间点经小鼠眼球后静脉丛取血0.3mL，置肝素化试管中，3000rpm离心10min，分离血浆，于–20℃冰箱中冷冻。测定时按血浆样品处理方法处理样品，用LC-MS/MS法测定血浆中的药物浓度，并计算其药代参数。
表6.部分化合物小鼠口服给药(10mg/kg)药代动力学参数
Figure PCTCN2015097096-appb-000069
由上述表6数据可以看出，上述化合物均具有的较好药代动力学性质，尤其是化合物1、化合物10、化合物20和化合物31，其药代动力学性质优异。
这些都表明本发明化合物有很好的成药性，很可能发展成为有效的结核治疗药物。
实施例55:化合物对hERG钾离子通道抑制作用试验
稳定表达hERG的HEK-293细胞(法国CreacellTM)，在室温下，用全细胞膜片钳技术记录hERG钾通道电流。尖端电阻为1-4MΩ左右的玻璃微电极连接至Axon 200A膜片钳放大器。钳制电压和数据记录由clampex 9.2软件经Axon DigiData 1322A A/D转换器通过电脑控制，细胞钳制在-80mV，诱发hERG钾电流(I hERG)的步阶电压从-80mV给予一个2s的去极化电压到+20mV，再复极化到-40mV，持续4s后回到-80mV。分别在给药前后给予此电压步阶诱发出hERG钾电流。
数据分析处理采用PatchMaster,GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度用以下公式计算：
Fractional block％＝[1–(I/Io)]×100％
其中，Fractional block代表化合物对hERG钾电流的抑制百分率，I和Io分别表示在加药后和加药前hERG钾电流的幅度。
化合物的IC50使用以下方程进行拟合计算得出：
I/Io＝1/{1+([C]/IC50)^n}
其中，Io和I分别表示加药前和加药后hERG钾电流的幅度。[C]为化合物的浓度，n为 Hill系数。
表7部分化合物对hERG的抑制：
化合物 IC50(μM)
化合物18 41.07
化合物19 38.28
化合物31 39.53
PA-824 5.8
表7表明，本发明化合物对hERG钾电流的抑制很弱，提示本发明化合物对心血管系统具有很好的安全性，其安全性优于对照药物PA-824。
实施例56:片剂
Figure PCTCN2015097096-appb-000070
制备方法：将上述活性成分、乳糖和淀粉混合，用水均匀湿润，把湿润后的混合物过筛并干燥，再过筛，加入硬脂酸镁，然后将混合物压片，每片重660mg，活性成分含量为50mg。
实施例57:胶囊剂
片剂：活性成分(化合物18)  50g
      淀粉                400g
      微晶纤维素          200g
制备方法：将上述活性成分、淀粉和微晶纤维素混合，过筛，在合适的容器中均匀混合，把得到的混合物装入硬明胶胶囊，每个胶囊重650mg，活性成分含量为50mg。
此处描述的实施例只用于说明(作为例证)，技术人员所做的各种修改或变更也应包括在专利申请的实质和范围内以及附加权利要求范畴之内。

Claims (10)

  1. 一类硝基咪唑类化合物，其是下述通式(I)化合物或其光学异构体、或药学上可接受的盐：
    Figure PCTCN2015097096-appb-100001
    通式(I)中，n表示1～4之间的整数；
    L为O，S,NH或化学键；
    X为C或N；
    R1为氢或C1-6烷基；
    R2和R3相同或不相同，分别独立选自氢，卤素，氰基，三氟甲基，C1-4烷基，C3-6环烷基或C1-4烷氧基；
    R4为芳环或至少含有一个选自N，O或S杂原子的杂芳环，所述芳环或芳杂环是未取代的或任意被一至三个独立选自氰基，CF3，OCF3，卤素，甲基或甲氧基的基团所取代；
    A选自饱和的或不饱和的C5-7环烷基，C8-10并环烷基，C7-9桥环烷基，C7-11螺环烷基，其环烷基中至少有一个碳原子被氮原子取代且通过氮原子和杂芳环相连，上述环烷基被一个或多个氟，氰基，羟基，C1-4烷基，C1-4烷氧基基团取代。
  2. 如权利要求1所述的硝基咪唑类化合物，其特征在于，所述药学上可接受的盐包括：通式(I)所示的化合物与酸形成的盐；其中，酸包括：无机酸、有机酸或酸性氨基酸；所述无机酸包括：盐酸、氢溴酸、氢氟酸、硫酸、硝酸或磷酸；所述有机酸包括：甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、对甲基苯磺酸、乙磺酸或苯磺酸；所述酸性氨基酸包括：天冬氨酸或谷氨酸。
  3. 如权利要求1所述的硝基咪唑类化合物，其特征在于，所述化合物为下述式1化合物，式2化合物，式3化合物，式4化合物，式5化合物，式6化合物，式7化合物，式8化合物，式9化合物，式10化合物，式11化合物，式12化合物，式13化合物，式14化合物，式15化合物，式16化合物，式17化合物，式18化合物，，式19化合物，式20化合物，式21化合物，式22化合物，式23化合物，式24化合物，式25化合物，式26化合物，式27化合物，式28化合物，式29化合物，式30化合物，式31化合物，式32化合物，式33化合物，式34化合物，式35化合物，式36化合物，式37化合物，式38化合物，式39化合物，式40化合物，式41化合物，式42化合物，式43化合物，式44化合物，式45化合物，式46化合物，式47化合物，式48化合物，式49化合物，式50化合物：
    Figure PCTCN2015097096-appb-100002
    Figure PCTCN2015097096-appb-100003
    Figure PCTCN2015097096-appb-100004
    Figure PCTCN2015097096-appb-100005
  4. 一种如权利要求1所述硝基咪唑类化合物的制备方法，其反应式如下：
    Figure PCTCN2015097096-appb-100006
    该方法包括如下步骤：
    (1)在20℃～150℃或溶剂回流温度下，原料I-1-1-I-1-2和I-2-1-I-2-21在溶剂中并在碱性条件下发生取代反应1～24小时得到中间体I-3-1-I-3-35；所述溶剂选自乙腈、丙酮、二氧六环、四氢呋喃、甲醇、乙醇、异丙醇、二甲基甲酰胺、二甲基乙酰胺、乙二醇二甲醚、二甲亚砜和水中的一种或多种；所述碱选自氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钡、碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、叔丁醇钾、叔丁醇钠、氢化钠、氢化钾、三乙胺、或二异丙基乙胺；
    (2)中间体I-3-1-I-3-35在溶剂中和胺I-4在碱性条件下反应形成亚胺中间态，再在还原试剂的存在下进行还原胺化反应1～24小时得到化合物1-化合物35；所述溶剂选自甲醇、乙醇、异丙醇、四氢呋喃、二氯甲烷、1,2-二氯乙烷、二氧六环、二甲基甲酰胺、乙腈、乙二醇二甲醚和水中的一种或多种；所述碱选自包括吡啶，三乙胺，二异丙基乙基胺的有机碱，所述还原试剂选自硼氢化钠，硼氢化钾，氰基硼氢化钠，或三乙酰氧基硼氢化钠。
  5. 一种如权利要求1所述硝基咪唑类化合物的制备方法，其反应式如下：
    Figure PCTCN2015097096-appb-100007
    该方法包括如下步骤：
    (1)在20℃～150℃或溶剂回流温度下，原料II-1-1-II-1-8和I-2-4在溶剂中发生取代反应1～24小时得到中间体II-2-1-II-2-8；所述溶剂选自乙腈、丙酮、二氧六环、四氢呋喃、甲醇、乙醇、异丙醇、二甲基甲酰胺、二甲基乙酰胺、乙二醇二甲醚、二甲亚砜和水中的一种或多种；所述碱选自氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钡、碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、叔丁醇钾、叔丁醇钠、氢化钠、氢化钾、三乙胺、或二异丙基乙胺；
    (2)在-78℃～40℃下，中间体II-2-1-II-2-8在溶剂中发生还原反应0.5～24小时得到中间体II-3-1-II-3-8；所述溶剂选自甲苯、四氢呋喃、正己烷、环己烷、甲基四氢呋喃、乙醚、甲基叔丁醚、乙二醇二甲醚和水中的一种或多种；所述还原剂选自硼氢化钠、硼氢化钾、硼氢化锂、四氢铝锂、二异丁基氢化铝或红铝；
    (3)在20℃～150℃或溶剂回流温度下，中间体II-3-1-II-3-8在溶剂中发生氧化反应1～24小时得到中间体II-4-1-II-4-8；所述溶剂选自乙酸乙酯、二氯甲烷、二氧六环、四氢呋喃、三氯甲烷、环己烷、二甲基甲酰胺、二甲基乙酰胺、乙二醇二甲醚、二甲亚砜中的一种或多种；所述氧化剂选自活性二氧化锰、2-碘酰基苯甲酸、戴斯马丁氧化剂、氯铬酸吡啶鎓盐、重铬酸吡啶鎓盐、吡啶三氧化硫或二甲亚砜和草酰氯；
    (4)中间体II-4-1-II-4-8在溶剂中和胺I-4在碱性条件下反应形成亚胺中间态，再在还原试剂的存在下进行还原胺化反应1～24小时得到化合物36-化合物43；所述溶剂选自甲醇、乙醇、异丙醇、四氢呋喃、二氯甲烷、1,2-二氯乙烷、二氧六环、二甲基甲酰胺、乙腈、乙二醇二甲醚和水中的一种或多种；所述碱选自包括吡啶，三乙胺，二异丙基乙基胺的有机碱；所述还原试剂选自硼氢化钠，硼氢化钾，氰基硼氢化钠，或三乙酰氧基硼氢化钠。
  6. 一种如权利要求1所述硝基咪唑类化合物的制备方法，其反应式如下：
    Figure PCTCN2015097096-appb-100008
    该方法包括如下步骤：化合物18在溶剂中和不同的醛在酸性条件下反应形成亚胺中间态，再在还原试剂的存在下进行还原胺化反应1～24小时得到化合物44-化合物45；所述溶剂选自 甲醇、乙醇、异丙醇、四氢呋喃、二氯甲烷、1,2-二氯乙烷、二氧六环、二甲基甲酰胺、乙腈、乙二醇二甲醚和水中的一种或多种；所述酸是有机弱酸或路易斯酸，选自乙酸，氯化锌，溴化锌、或三氟化硼乙醚；所述还原剂选自硼氢化钠，硼氢化钾，氰基硼氢化钠，或三乙酰氧基硼氢化钠。
  7. 一种如权利要求1所述硝基咪唑类化合物的制备方法，其反应式如下：
    Figure PCTCN2015097096-appb-100009
    该方法包括如下步骤：
    (1)在20℃～150℃或溶剂回流温度下，原料IV-1和I-2-4在溶剂中并在碱性条件下发生取代反应1～24小时得到中间体IV-2；所述溶剂选自乙腈、丙酮、二氧六环、四氢呋喃、甲醇、乙醇、异丙醇、二甲基甲酰胺、二甲基乙酰胺、乙二醇二甲醚、二甲亚砜和水中的一种或多种；所述碱选自氢氧化钠、氢氧化钾、氢氧化锂、氢氧化钡、碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、叔丁醇钾、叔丁醇钠、氢化钠、氢化钾、三乙胺、或二异丙基乙胺；
    (2)中间体IV-2在溶剂中和胺I-4在碱性条件下反应形成亚胺中间态，再在还原试剂的存在下进行还原胺化反应1～24小时得到化合物46；所述溶剂选自甲醇、乙醇、异丙醇、四氢呋喃、二氯甲烷、1,2-二氯乙烷、二氧六环、二甲基甲酰胺、乙腈、乙二醇二甲醚和水中的一种或多种；所述碱选自包括吡啶，三乙胺，二异丙基乙基胺的有机碱；所述还原剂选自硼氢化钠，硼氢化钾，氰基硼氢化钠，或三乙酰氧基硼氢化钠。
  8. 一种如权利要求1所述硝基咪唑类化合物的制备方法，其反应式如下：
    Figure PCTCN2015097096-appb-100010
    该方法包括如下步骤：在溶剂中，化合物4与盐酸、化合物18与磷酸、化合物36与甲磺酸、化合物44与富马酸分别在-20℃～100℃条件下反应1～48小时，直接析出固体或静置析出固体或浓缩重结晶，得到化合物47-化合物50；所述溶剂选自丙酮、四氢呋喃、乙腈、乙醇、甲醇、异丙醇、二氯甲烷、1,4-二氧六环、二甲基甲酰胺、二甲基乙酰胺、N-甲基吡咯烷酮、二甲亚砜或水中的一种或多种。
  9. 一种如权利要求1所述硝基咪唑类化合物在制备治疗与结核杆菌引起的感染相关的疾病的药物中的应用。
  10. 用于治疗与结核杆菌引起的感染相关的疾病的药物组合物，其中含有治疗有效量的权利要求1所述硝基咪唑类化合物和药学上可接受的赋形剂或载体。
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