CN108822103A - A kind of imidazo [4,5-b] pyridine compounds and its preparation method and application - Google Patents

A kind of imidazo [4,5-b] pyridine compounds and its preparation method and application Download PDF

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CN108822103A
CN108822103A CN201810849412.0A CN201810849412A CN108822103A CN 108822103 A CN108822103 A CN 108822103A CN 201810849412 A CN201810849412 A CN 201810849412A CN 108822103 A CN108822103 A CN 108822103A
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刘凤娟
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention discloses a kind of imidazo [4,5-b] pyridine compounds and its preparation method and application.Simultaneously [4,5-b] pyridine compounds can effectively inhibit the growth of knurl to novel imidazole provided by the invention, and can increase the weight of lung cancer in mice to improve its immunity.On the other hand, the preparation method of novel imidazole of the present invention simultaneously [4,5-b] pyridine compounds is simple to operation, can be effectively reduced to be produced into and original realize industrialized production.

Description

A kind of imidazo [4,5-b] pyridine compounds and its preparation method and application
Technical field
Field of the present invention belongs to drug field, and in particular to a kind of imidazo [4,5-b] pyridine compounds and its preparation side Method and application.
Background technique
With the pollution of environment, the disease incidence of lung cancer becomes one of highest malignant tumour of disease incidence at present, and it is dead Rate is also higher, becomes one of the most important malignant disease for threatening human life and health, and its disease incidence and the death rate also occupy In the umber one.Currently, the method for the treatment of lung cancer has radiotherapy and chemotherapy etc..Radiotherapy is best to Small Cell Lung Cancer curative effect, squamous cell carcinoma Take second place, gland cancer is worst.Radiotherapy in lung cancer irradiation field should include the mediastinum area of primary tumor, lymphatic metastasis, while also be aided with drug Treatment.
And chemotherapy is the primary treatments of lung cancer, 90% or more lung cancer needs to receive chemotherapeutic treatment.In consideration of it, this hair It is bright to provide novel imidazo [4,5-b] pyridine compounds of one kind to prevent and treat lung cancer.
Summary of the invention
For problems in the prior art, it is an object of that present invention to provide a kind of imidazo [4,5-b] pyridine chemical combination Object and its preparation method and application.
To achieve the goals above, the invention adopts the following technical scheme：
A kind of imidazo [4,5-b] pyridine compounds, structure are shown in formula I：
, Formulas I；
Wherein, A O, S or NH；
R is alkyl, the-(CH of C1-C62)nO(CH2)mCH3, benzyl or replace benzyl；Integer of the n between 1-4, m 0-4 Between integer；
Ar be phenyl, substituted phenyl,、、Or。
In above-mentioned imidazo [4,5-b] pyridine compounds, the A is O or NH as a preferred implementation manner,.
In above-mentioned imidazo [4,5-b] pyridine compounds, the R is-(CH as a preferred implementation manner,2)nO (CH2)mCH3Or the benzyl replaced；Integer of the n between 1-4, integer of the m between 0-4.
In above-mentioned imidazo [4,5-b] pyridine compounds, the A is O or NH as a preferred implementation manner,；Institute Stating R is-(CH2)nO(CH2)mCH3Or the benzyl replaced；Integer of the n between 1-4, integer of the m between 1-4.
In above-mentioned imidazo [4,5-b] pyridine compounds, the compound is as follows as a preferred implementation manner,：
A second object of the present invention is to provide a kind of preparation methods of imidazo [4,5-b] pyridine compounds, including such as Lower step：
, Formula II；
Wherein, A O, S or NH；
R is alkyl, the-(CH of C1-C62)nO(CH2)mCH3Or benzyl；Integer of the n between 1-4, integer of the m between 0-4；
Ar be phenyl, substituted phenyl,、、Or。
In the above preparation method, the synthetic method of compound 2 is such as in the Formula II as a preferred implementation manner, Under：
Take bromo- 3H- imidazoles [4,5-b] pyridine of 5-（As shown in Formula II compound 1）, R-Br and solvent be uniformly mixed, in 0-25 DEG C Lower addition alkaline matter then heats at 25-60 DEG C and stirs 2-6 hours, obtains reaction solution；
R is alkyl, the-(CH of C1-C62)nO(CH2)mCH3Or benzyl；Integer of the n between 1-4, integer of the m between 0-4；
Saturated sodium-chloride water solution, methylene chloride or ethyl acetate extraction, mistake after organic phase concentration are added into the reaction solution Column purification collects refined solution and is evaporated under reduced pressure to obtain compound 2 in the Formula II.
In the above preparation method, as a preferred implementation manner, in the Formula II compound 2 synthesis condition In, the dosage relation of compound 1 and the solvent is 0.1-0.5mol/L in the Formula II（Such as 0.2mol/L, 0.3mol/L,0.4mol/L）.
In the above preparation method, as a preferred implementation manner, in the Formula II compound 2 synthesis condition In, the mole of the R-Br is 1-2 times of 1 mole of compound in the Formula II（Such as 1.1 times, 1.2 times, 1.3 times, 1.5 Again, 1.7 times, 1.9 times）.
In the above preparation method, as a preferred implementation manner, in the Formula II compound 2 synthesis condition In, the mole of the alkaline matter is 1.1-2 times of 1 mole of compound in the Formula II（Such as 1.2 times, 1.3 times, 1.5 Again, 1.7 times, 1.9 times）；Preferably, the alkaline matter is selected from sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, three second Amine, pyridine, diisopropyl ethyl amine, DMAP（N, N- dimethylamino naphthyridine）One of or it is a variety of.
In the above preparation method, as a preferred implementation manner, in the Formula II compound 2 synthesis condition In, the solvent is one of dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, dioxane, chloroform or a variety of.
In the above preparation method, the synthetic method of compound 3 is such as in the Formula II as a preferred implementation manner, Under：
The Formula II compound 2, Ar-AH, catalyst, alkaline matter and solvent are uniformly mixed, under argon gas or condition of nitrogen gas It is stirred 6-12 hours at 60-120 DEG C, obtains reaction solution；
Wherein, A O, S or NH；
Ar be phenyl, substituted phenyl,、、Or；
Saturated sodium-chloride water solution, methylene chloride or ethyl acetate extraction, mistake after organic phase concentration are added into the reaction solution Column purification collects refined solution and is evaporated under reduced pressure to obtain compound 3 in the Formula II.
In the above preparation method, as a preferred implementation manner, in the Formula II compound 3 synthesis condition In, the dosage relation of compound 2 and the solvent is 0.1-0.5mol/L in the Formula II（Such as 0.2mol/L, 0.3mol/L,0.4mol/L）.
In the above preparation method, as a preferred implementation manner, in the Formula II compound 3 synthesis condition In, the mole of the Ar-AH is 1-2 times of 2 mole of compound in the Formula II（Such as 1.1 times, 1.2 times, 1.3 times, 1.5 times, 1.7 times, 1.9 times）.
In the above preparation method, as a preferred implementation manner, in the Formula II compound 3 synthesis condition In, the mole of the catalyst is 0.01-0.05 times of 2 mole of compound in the Formula II（Such as 0.02 times, 0.03 Again, 0.04 times）；Preferably, the catalyst be selected from tetrakis triphenylphosphine palladium, three (double BENZYLIDENE ACETONEs) two palladiums, [1,1'- is bis- (diphenylphosphino) ferrocene] palladium chloride, any one in bi triphenyl phosphorus palladium chloride.
In the above preparation method, as a preferred implementation manner, in the Formula II compound 3 synthesis condition In, the mole of the alkaline matter is 1.1-2 times of 2 mole of compound in the Formula II（Such as 1.2 times, 1.3 times, 1.5 Again, 1.7 times, 1.9 times）；Preferably, the alkaline matter is selected from sodium tert-butoxide, potassium tert-butoxide, tert-butyl alcohol lithium, sodium hydroxide, hydrogen One of potassium oxide, lithium hydroxide, triethylamine, pyridine, diisopropyl ethyl amine are a variety of.
In the above preparation method, as a preferred implementation manner, in the Formula II compound 3 synthesis condition In, the solvent be one of dimethyl sulfoxide, dimethylformamide, dimethyl acetamide, tetrahydrofuran, dioxane or It is a variety of.
Third object of the present invention is to provide a kind of imidazo [4,5-b] pyridine compounds in preparation for preventing and controlling Treat the application in the drug of lung cancer.
Compared with prior art, the present invention has the following technical effect that：
Simultaneously [4,5-b] pyridine compounds can effectively inhibit the growth of knurl to novel imidazole provided by the invention, and can increase Add the weight of lung cancer in mice to improve its immunity.On the other hand, the system of novel imidazole of the present invention simultaneously [4,5-b] pyridine compounds Preparation Method is simple to operation, can be effectively reduced and be produced into original realization industrialized production.
Specific embodiment
Below by specific embodiment, the present invention is described in detail, but these exemplary embodiments are not intended to Any type of any restriction is constituted to real protection scope of the invention.
Various drugs used in the following embodiment, reagent are commercial product, and the instrument not marked especially is conventional instrument Device.
Embodiment 1
N- (4- fluorophenyl) -3- (propoxy methyl) -3H- imidazoles [4,5-b] pyridine The preparation method of base -5- amine：
（1）5- bromo- 3- (propoxy methyl) -3H- imidazoles [4,5-b] pyridine synthetic method：Take bromo- 3H- imidazoles [4,5-b] pyrrole of 5- Pyridine（10mmol）,CH3CH2CH2OCH2-Br（12mmol）, it is added in 20mL DMF, NaH is added at 0 DEG C after mixing （15mmol）, then heat at 60 DEG C and stir 4 hours, obtain reaction solution；Saturated sodium chloride water is added into the reaction solution Solution, methylene chloride extraction, cross column purification after organic phase concentration, collect refined solution and are evaporated under reduced pressure to obtain the bromo- 3- (third of 2.29g 5- Oxygroup methyl) -3H- imidazoles [4,5-b] pyridine, yield 85%.
5- bromo- 3- (propoxy methyl) -3H- imidazoles [4,5-b] pyridine hydrogen spectrum is as follows：1H NMR (400 MHz, DMSO-d6) δ (ppm)= 0.90 (t, 3H), 1.35-1.50 (m, 2H), 3.37 (t, 2H), 5.81 (s, 2H), 7.52 (d, 1H), 7.83 (s, 1H), 8.35 (d, 1H)。
（2）By 5- bromo- 3- (propoxy methyl) -3H- imidazoles [4,5-b] pyridine（2mmol）, 4- fluoroaniline（1.5mmol）, Tetrakis triphenylphosphine palladium（0.05mmol）, tert-butyl alcohol lithium（1.5mmol）It is uniformly mixed with 4mL dimethylformamide, in nitrogen item It is stirred 12 hours at 120 DEG C under part, obtains reaction solution；Saturated sodium-chloride water solution, dichloromethane are added into the reaction solution Alkane extraction crosses column purification after organic phase concentration, collects refined solution and is evaporated under reduced pressure to obtain 450mg N- (4- fluorophenyl) -3- (third oxygen Ylmethyl) -3H- imidazoles [4,5-b] pyridyl group -5- amine, yield 75%.
N- (4- fluorophenyl) -3- (propoxy methyl) -3H- imidazoles [4,5-b] pyridyl group -5- amine hydrogen spectrum is as follows：1H NMR (400 MHz, DMSO-d6) δ (ppm)= 0.90 (t, 3H), 1.35-1.50 (m, 2H), 3.37 (t, 2H), 4.02 (s, 1H), 5.81 (s, 2H), 6.70 (d, 1H), 7.31 (dd, 2H), 7.41 (dd, 2H),7.83 (s, 1H), 7.87 (d, 1H)。
Embodiment 2
3- (propoxy methyl)-N- (pyrimidine -5- base) -3H- imidazoles [4,5-b] pyridine -5- The preparation method of amine is as follows：
By 5- bromo- 3- (propoxy methyl) -3H- imidazoles [4,5-b] pyridine（2mmol）, 5- aminopyridine（1.2mmol）, double three Phenyl phosphorus palladium chloride（0.02mmol）, sodium tert-butoxide（1.5mmol）It is uniformly mixed with 4mL dimethylformamide, in nitrogen item It is stirred 10 hours at 120 DEG C under part, obtains reaction solution；Saturated sodium-chloride water solution, dichloromethane are added into the reaction solution Alkane extraction crosses column purification after organic phase concentration, collect refined solution be evaporated under reduced pressure to obtain 443mg 3- (propoxy methyl)-N- it is (phonetic Pyridine -5- base) -3H- imidazoles [4,5-b] pyridin-5-amine, yield 78%.
The hydrogen spectrum of 3- (propoxy methyl)-N- (pyrimidine -5- base) -3H- imidazoles [4,5-b] pyridin-5-amine is as follows：1H NMR (400 MHz, DMSO-d6) δ (ppm)= 0.90 (t, 3H), 1.35-1.50 (m, 2H), 3.37 (t, 2H), 4.02 (s, 1H), 5.81 (s, 2H), 6.70 (d, 1H), 7.83 (s, 1H), 7.87 (d, 1H), 8.50 (s, 2H), 8.90 (s, 1H)。
Embodiment 3
3- (4- luorobenzyl)-N- (pyridin-3-yl) -3H- imidazoles [4,5-b] pyridine - The preparation method of 5- amine is as follows：
（1）The synthetic method of the bromo- 3- of 5- (4- luorobenzyl) -3H- imidazoles [4,5-b] pyridine：Take bromo- 3H- imidazoles [4,5-b] pyrrole of 5- Pyridine（10mmol）, 4- fluoro benzyl bromide（11mmol）, it is added in 20mL DMF, NaH is added at 0 DEG C after mixing （15mmol）, then heat at 40 DEG C and stir 4 hours, obtain reaction solution；Saturated sodium chloride water is added into the reaction solution Solution, methylene chloride extraction, cross column purification after organic phase concentration, collect refined solution and are evaporated under reduced pressure to obtain the bromo- 3- (4- of 2.76g 5- Luorobenzyl) -3H- imidazoles [4,5-b] pyridine, yield 91%.
（2）By the bromo- 3- of 5- (4- luorobenzyl) -3H- imidazoles [4,5-b] pyridine（2mmol）, 3- aminopyridine（1.5mmol）, [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride（0.03mmol）, potassium tert-butoxide（1.5mmol）With 4mL dimethyl methyl Amide is uniformly mixed, and is stirred 12 hours at 120 DEG C under a nitrogen atmosphere, is obtained reaction solution；It is added into the reaction solution full It is extracted with sodium-chloride water solution, methylene chloride, crosses column purification after organic phase concentration, collected refined solution and be evaporated under reduced pressure to obtain 504mg 3- (4- luorobenzyl)-N- (pyridin-3-yl) -3H- imidazoles [4,5-b] pyridin-5-amine, yield 79%.
The hydrogen spectrum of 3- (4- luorobenzyl)-N- (pyridin-3-yl) -3H- imidazoles [4,5-b] pyridin-5-amine is as follows：1H NMR (400 MHz, DMSO-d6) δ (ppm)= 4.03 (s, 1H), 5.46 (s, 2H), 6.70 (d, 1H), 7.12 (dd, 2H), 7.21 (dd, 2H), 7.33-7.36 (m, 1H), 7.50 (d, 1H), 7.87 (d, 1H), 7.96 (s, 1H), 8.04 (s, 1H), 8.09 (d, 1H)。
Embodiment 4
3- (4- luorobenzyl)-N- (3- fluorophenyl) -3H- imidazoles [4,5-b] pyridine - The preparation method of 5- amine is as follows：
By the bromo- 3- of 5- (4- luorobenzyl) -3H- imidazoles [4,5-b] pyridine（2mmol）, 3- fluoroaniline（1.2mmol）, [1,1'- is bis- (diphenylphosphino) ferrocene] palladium chloride（0.04mmol）, potassium tert-butoxide（1.5mmol）It is mixed with 4mL dimethylformamide Uniformly, it is stirred 12 hours at 120 DEG C under a nitrogen atmosphere, obtains reaction solution；Saturated sodium-chloride is added into the reaction solution Aqueous solution, methylene chloride extraction, cross column purification after organic phase concentration, collect refined solution and are evaporated under reduced pressure to obtain 518mg 3- (4- fluorine Benzyl)-N- (3- fluorophenyl) -3H- imidazoles [4,5-b] pyridin-5-amine, yield 77%.
The hydrogen spectrum of 3- (4- luorobenzyl)-N- (3- fluorophenyl) -3H- imidazoles [4,5-b] pyridin-5-amine is as follows：1H NMR (400 MHz, DMSO-d6) δ (ppm)= 4.03 (s, 1H), 5.46 (s, 2H), 6.61 (d, 1H), 6.70 (d, 1H), 7.17-7.19 (m, 1H), 7.40 (d, 1H), 7.76 (s, 1H), 7.87 (d, 1H), 7.96 (s, 1H)。
Embodiment 5
3- (3- luorobenzyl) -5- (3- fluorophenoxy) -3H- imidazoles [4,5-b] pyridine Preparation method it is as follows：
（1）The synthetic method of the bromo- 3- of 5- (3- luorobenzyl) -3H- imidazoles [4,5-b] pyridine：Take bromo- 3H- imidazoles [4,5-b] pyrrole of 5- Pyridine（10mmol）, 3- fluoro benzyl bromide（11mmol）, it is added in 20mL DMF, NaH is added at 0 DEG C after mixing （15mmol）, then heat at 40 DEG C and stir 4 hours, obtain reaction solution；Saturated sodium chloride water is added into the reaction solution Solution, methylene chloride extraction, cross column purification after organic phase concentration, collect refined solution and are evaporated under reduced pressure to obtain the bromo- 3- (3- of 2.81g 5- Luorobenzyl) -3H- imidazoles [4,5-b] pyridine, yield 92%.
（2）By the bromo- 3- of 5- (3- luorobenzyl) -3H- imidazoles [4,5-b] pyridine（2mmol）, 3- fluorophenol（2mmol）, three (double BENZYLIDENE ACETONEs) two palladiums（0.05mmol）, lithium hydroxide（2mmol）It is uniformly mixed with 4mL dimethyl sulfoxide, in nitrogen item It is stirred 12 hours at 100 DEG C under part, obtains reaction solution；Saturated sodium-chloride water solution, dichloromethane are added into the reaction solution Alkane extraction crosses column purification after organic phase concentration, collects refined solution and is evaporated under reduced pressure to obtain 458mg 3- (3- luorobenzyl) -5- (3- fluorine Phenoxy group) -3H- imidazoles [4,5-b] pyridine, yield 68%.
The hydrogen spectrum of 3- (3- luorobenzyl) -5- (3- fluorophenoxy) -3H- imidazoles [4,5-b] pyridine is as follows：1H NMR (400 MHz, DMSO-d6) δ (ppm)= 5.47 (s, 2H), 6.53 (d, 1H), 6.77 (d, 1H), 6.90 (d, 1H), 7.01 (d, 1H), 7.03-7.05 (m, 1H), 7.46 (d, 1H), 7.60 (d, 1H), 7.96 (s, 1H), 8.18 (m, 1H)。
Embodiment 6
2- ((3- (3- luorobenzyl) -3H- imidazoles [4,5-b] pyridine -5- base) oxygen Base) quinoline preparation method it is as follows：
By the bromo- 3- of 5- (3- luorobenzyl) -3H- imidazoles [4,5-b] pyridine（2mmol）, 2- oxyquinoline（2mmol）, three (double benzal Benzylacetone) two palladiums（0.05mmol）, lithium hydroxide（2mmol）With 4mL dimethyl sulfoxide be uniformly mixed, under a nitrogen atmosphere in It is stirred 12 hours at 100 DEG C, obtains reaction solution；Saturated sodium-chloride water solution, methylene chloride extraction are added into the reaction solution, Cross column purification after organic phase concentration, collect refined solution be evaporated under reduced pressure to obtain 481mg 2- ((3- (3- luorobenzyl) -3H- imidazoles [4, 5-b] pyridine -5- base) oxygroup) quinoline, yield 65%.
The hydrogen spectrum of 2- ((3- (3- luorobenzyl) -3H- imidazoles [4,5-b] pyridine -5- base) oxygroup) quinoline is as follows：1H NMR (400 MHz, DMSO-d6) δ (ppm)= 5.45 (s, 2H), 6.54 (d, 1H), 6.75 (d, 1H), 6.77 (d, 1H), 7.01 (d, 1H), 7.03-7.05 (m, 1H), 7.30-7.32 (m, 1H), 7.48-7.50 (m, 1H), 7.75-7.76 (m, 1H), 7.84 (d, 1H), 7.96 (s, 1H), 8.02 (d, 1H), 8.18 (d, 1H), 8.33 (d, 1H)。
Test example：
Weight 16-20g mouse 80 is taken, half male and half female selects 10 at random and is only used as the 1st group（Normal group）, remaining 70 percutaneous Lower Injection of Lewis Lung Carcinoma Cells suspension carries out modeling, is then randomly divided into 5 groups, every group 10；2nd group is model group；3-8 Group is administration group.Start to be administered within the 6th day after mouse modeling, normal group and model group give physiological saline, fill by each 10ml/kg Stomach is given once daily twice；3-8 group gives the embodiment 1-6 compound of preparation respectively, gives 10mg/kg every time, is given once daily Twice.Change in the 11st day observation mouse weight, specific data are referring to table 1；The dead mouse in 2-8 group each component other places 5 is taken out The knurl of mouse and weighing are put to death, calculates the inhibition rate of tumor growth of each group mouse, specific data are referring to table 2.
The changes of weight of 11st day each group mouse after table 1 is administered
Mouse tumor weight and knurl growth inhibition ratio situation after table 2 is administered
Group Tumor weight (g) Inhibiting rate (%)
2nd group 3.28±0.53 /
3rd group 1.28±0.45 60.9%
4th group 1.19±0.52 63.7%
5th group 1.08±0.42 67.1%
6th group 1.10±0.39 66.5%
7th group 1.32±0.46 59.8%
8th group 1.36±0.41 58.5%
By Tables 1 and 2 it is found that the compound of the present invention can effectively increase the weight of lung cancer in mice, to improve its immunity；Separately On the one hand, the growth of knurl also can effectively be inhibited.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit protection model of the invention It encloses.In addition, it should also be understood that, after reading the technical contents of the present invention, those skilled in the art can make the present invention each Kind change, modification and/or variation, all these equivalent forms equally fall within guarantor defined by the appended claims of the present invention Within the scope of shield.

Claims (10)

1. a kind of imidazo [4,5-b] pyridine compounds, which is characterized in that the structure of the compound is shown in formula I：
, Formulas I；
Wherein, A O, S or NH；
R is alkyl, the-(CH of C1-C62)nO(CH2)mCH3, benzyl or replace benzyl；Integer of the n between 1-4, m 0-4 Between integer；
Ar be phenyl, substituted phenyl,、、Or。
2. imidazo [4,5-b] pyridine compounds according to claim 1, which is characterized in that the A is O or NH.
3. imidazo [4,5-b] pyridine compounds according to claim 1, which is characterized in that the R is-(CH2)nO (CH2)mCH3Or the benzyl replaced；Integer of the n between 1-4, integer of the m between 0-4.
4. imidazo [4,5-b] pyridine compounds according to claim 1, which is characterized in that the A is O or NH；It is described R is-(CH2)nO(CH2)mCH3Or the benzyl replaced；Integer of the n between 1-4, integer of the m between 1-4.
5. imidazo [4,5-b] pyridine compounds according to claim 1-4, which is characterized in that the chemical combination Object is as follows：
、、、、Or。
The preparation method of imidazo described in claim 1-5 6. [4,5-b] pyridine compounds, which is characterized in that including walking as follows Suddenly：
, Formula II；
Wherein, A O, S or NH；
R is alkyl, the-(CH of C1-C62)nO(CH2)mCH3Or benzyl；Integer of the n between 1-4, integer of the m between 0-4；
Ar be phenyl, substituted phenyl,、、Or。
7. preparation method according to claim 6, which is characterized in that the synthetic method of compound 2 is as follows in the Formula II：
It takes bromo- 3H- imidazoles [4, the 5-b] pyridine of 5-, R-Br and solvent to be uniformly mixed, alkaline matter is added at 0-25 DEG C, then It is warming up at 25-60 DEG C and stirs 2-6 hours, obtain reaction solution；
R is alkyl, the-(CH of C1-C62)nO(CH2)mCH3Or benzyl；Integer of the n between 1-4, integer of the m between 0-4；
Saturated sodium-chloride water solution, methylene chloride or ethyl acetate extraction, mistake after organic phase concentration are added into the reaction solution Column purification collects refined solution and is evaporated under reduced pressure to obtain compound 2 in the Formula II；
Preferably, the dosage relation of compound 1 and the solvent is 0.1-0.5mol/L in the Formula II；
Preferably, the mole of the R-Br is 1-2 times of 1 mole of compound in the Formula II；
Preferably, the mole of the alkaline matter is 1.1-2 times of 1 mole of compound in the Formula II；It is highly preferred that institute State alkaline matter be selected from sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, pyridine, diisopropyl ethyl amine, One of DMAP or a variety of；
Preferably, the solvent be one of dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, dioxane, chloroform or It is a variety of.
8. preparation method according to claim 6 or 7, which is characterized in that the synthetic method of compound 3 is such as in the Formula II Under：
The Formula II compound 2, Ar-AH, catalyst, alkaline matter and solvent are uniformly mixed, under argon gas or condition of nitrogen gas It is stirred 6-12 hours at 60-120 DEG C, obtains reaction solution；
Wherein, A O, S or NH；
Ar be phenyl, substituted phenyl,、、Or；
Saturated sodium-chloride water solution, methylene chloride or ethyl acetate extraction, mistake after organic phase concentration are added into the reaction solution Column purification collects refined solution and is evaporated under reduced pressure to obtain compound 3 in the Formula II.
9. preparation method according to claim 7, which is characterized in that in the Formula II in the synthesis condition of compound 3, The dosage relation of compound 2 and the solvent is 0.1-0.5mol/L in the Formula II；
Preferably, the mole of the Ar-AH is 1-2 times of 2 mole of compound in the Formula II；
Preferably, the mole of the catalyst is 0.01-0.05 times of 2 mole of compound in the Formula II；It is highly preferred that The catalyst is selected from tetrakis triphenylphosphine palladium, three (double BENZYLIDENE ACETONEs) two palladiums, [bis- (diphenylphosphino) ferrocene of 1,1'-] Any one in palladium chloride, bi triphenyl phosphorus palladium chloride；
Preferably, the mole of the alkaline matter is 1.1-2 times of 2 mole of compound in the Formula II；It is highly preferred that institute It states alkaline matter and is selected from sodium tert-butoxide, potassium tert-butoxide, tert-butyl alcohol lithium, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, pyrrole One of pyridine, diisopropyl ethyl amine are a variety of；
Preferably, the solvent is dimethyl sulfoxide, in dimethylformamide, dimethyl acetamide, tetrahydrofuran, dioxane It is one or more.
10. any one of the claim 1-5 imidazo [4,5-b] pyridine compounds are in preparation for preventing and treating lung cancer Application in drug.
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Application publication date: 20181116