CN106496222A - A kind of imidazo [1,2 a] pyridine compounds and its preparation method and application - Google Patents
A kind of imidazo [1,2 a] pyridine compounds and its preparation method and application Download PDFInfo
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- 0 CCCN(C)CC*c1cc2ncc(C(C3)C=CC(C(N)=O)=C3OCc3ccccc3)[n]2cc1 Chemical compound CCCN(C)CC*c1cc2ncc(C(C3)C=CC(C(N)=O)=C3OCc3ccccc3)[n]2cc1 0.000 description 5
- GDRDXANLQNZDOE-VAWYXSNFSA-N CC/C(/C1C=C[n]2c(I)cnc2C1)=C\N(CCN(C)C)N Chemical compound CC/C(/C1C=C[n]2c(I)cnc2C1)=C\N(CCN(C)C)N GDRDXANLQNZDOE-VAWYXSNFSA-N 0.000 description 1
- VUNKMRDZZOPJBJ-UHFFFAOYSA-N CN(CC1)CCN1c(cc[n]12)cc1ncc2I Chemical compound CN(CC1)CCN1c(cc[n]12)cc1ncc2I VUNKMRDZZOPJBJ-UHFFFAOYSA-N 0.000 description 1
- MAUSVBRBZGNJKM-JTQLQIEISA-N C[C@@H](COC(C=C)=C)c1ccccc1C(F)(F)F Chemical compound C[C@@H](COC(C=C)=C)c1ccccc1C(F)(F)F MAUSVBRBZGNJKM-JTQLQIEISA-N 0.000 description 1
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- 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
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Abstract
The invention discloses a kind of imidazo [1,2 a] pyridine compounds and its application, the imidazo [1,2 a] pyridine compounds are used as the novel NEK2 micromolecular inhibitors of a class formation, NEK2 kinase activities can be suppressed, simultaneously the invention also discloses the imidazo [1,2 a] pyridine compounds can stop suppressing the propagation of tumor cell with apoptosis by induced cell cycle and suppress the effect of growth of tumour cell in animal body.
Description
Technical field
The invention belongs to medicine synthesis chemical technology field, and in particular to a kind of imidazo [1,2-a] pyridine compounds and
Its synthetic method and application, imidazo [1,2-a] pyridine compounds, can be by inducing cell weeks used as NEK2 inhibitor
Phase stops suppressing the propagation of tumor cell with apoptosis, is respectively provided with good anti-tumor activity in vivo and in vitro.
Background technology
Agency for Research on Cancer (IARC) the Publishing Study report in 2012 of World Health Organization (WHO) and its subordinate claims, and the whole world is made an appointment
Disconnected 1400 million news increase cases of cancer.The half new cancer cases in the whole world occur in Asia, and wherein most occurs in China
[http://china.caixin.com/2014-02-08/100636253.html？Cx_from=news.baidu.com].
It was reported that estimating, after 20 years, the annual new cancer cases in the whole world will rise to 22,000,000.At the same time, Cancer death number
Annual about 13,000,000 people will be risen to from current annual about 8,200,000 people.NEKS (NIMA-related kinases) kinases is one
Kind of protein serine/threonine, NEKS families totally 11 kinds of protein kinases from NEK1 to NEK11, to cell mitogen and cell
Cycle regulating plays an important role, and relation between tumor is close.
Wherein in mammal, NEK2 (NIMA-related kinase 2) is most characteristic and representational
A member, the homology highest with NIMA are also presently considered to be most important, research most, most deep one.The main positions of NEK2
On centrosome, spindle is participated in by phosphorylation to substrate protein and is formed and is separated, so as to cell cycle regulation in
The separation of G2/M phase centrosomes.In human protein, NEK2 is contacted the most closely, as a kind of cell cycle with fungal kinase
Regulation and control kinases, its are expressed and are strictly controlled in a cell cycle with activity.Expression G1 is very low, and increases in S/G2
Plus.NEK2 increases in G2 phases activity, by phosphorylation β-catenin, ninein-like protein (Nlp), centrosome NEK2
Associated proteins (centrosomal NEK2asspciated protein 1, C-Nap1) and root fibroin (rootletin) are caused
Make chromosome separation.According to the different phase of cell division cycle, NEK2 can be distributed in nucleus and Cytoplasm and have
A lot of other functions related to cell cycle.Meanwhile, the activity of NEK2 also receives 1 (protein of protein phosphatase
Phosphatase 1, PP1) regulation, but it is interesting that PP1 is the crucial actuator of Akt again.NEK2 had both participated in centrosome
Separate and participate in chromatin condensation again, therefore can adjust indirectly centrosome or direct interference chromosome, so as to affect whole gene group
Stablize, cause induction, deterioration and the transfer of CIN and tumor.In sum, in normal cell, the overexpression of NEK2 can produce cause
, in the cancers such as breast carcinoma, pulmonary carcinoma, hepatocarcinoma, carcinoma of prostate, cervical cancer, cancer of pancreas, all there is NEK2 in the intracellular environment of tumor
High expression phenomenon.
NEK2 plays an important role to mitosiss regulation and control as a kind of cell protein cycle kinase, generation with tumor,
Development deteriorates and transfer is closely related.Tumor cell NEK2 overexpressions simultaneously can significantly increase the work of drug efflux proteins
Property, and then chemotherapeutics are pumped out cell, produce drug resistance.By suppressing the overexpression of NEK2 in tumor cell, can be effective
Suppress the regeneration of tumor cell, transfer while the generation of drug resistance can be suppressed, strengthen the sensitivity of Drug therapy, therefore
NEK2 is also used as the post operative diagnosis instrument for the treatment of of cancer, for assessing treatment of cancer effect and monitoring tumor patient to treatment
Reaction.
Generally speaking, at present it has been reported that NEK2 micromolecular inhibitors out are also fewer, there is not yet international monopoly, only
See NEK2 inhibitor [J.Med.Chem., the 2010,53,7682-7698 of three kinds of framing structures of document report；J.Med.Chem.,
2011,54,1626-1639；J.Med.Chem.,2012,55,3228-3241；J.Med.Chem.,2011,54,4133-
4146].These inhibitor cytoactives are very undesirable, there is no the report of the inhibitor with in-vivo tumour inhibition at present.
Therefore, NEK2 designs wide synthesizing new antitumor scope, kinase activity and selection as a kind of new type anticancer target
Property is good, while PK, PD data are preferable, toxic and side effects are little, can be used for preclinical exploitation NEK2 micromolecular inhibitors have huge
Big researching value and using value, the treatment for cancer provide effectively help, are that exploitation has China's independent intellectual property right
Cancer treatment drugs are taken a firm foundation.
Content of the invention
One of the object of the invention is to provide a kind of imidazo [1,2-a] pyridine compounds, shown in its structure such as formula (1),
Wherein, R1, R2, R3All it is hydrogen, or one of them when being hydrogen, another two functional group is nitro, cyano group, methyl, halogen
Deng, or two of which, when being hydrogen, another functional group is nitro, cyano group, methyl, halogen etc.；
R4For hydrogen or methyl；
R5For piperidine ring, alkoxyl or heterocycle such as pyrazole ring containing substituent group etc.；
Preferably, R1, R2, R3All it is hydrogen, or when wherein one or two are hydrogen, another Liang Huoyige functional groups is nitro, cyanogen
Base, methyl, fluorine or chlorine etc.；
R4For hydrogen or methyl；
R5For piperidine ring, alkoxyl or heterocycle such as pyrazole ring containing substituent group etc.；Such as
A kind of imidazo [1,2-a] pyridine compounds involved in the present invention, imidazo [1,2-a] pyridine compounds
During containing one or more chiral centres, corresponding corresponding isomer, non-corresponding isomers and raceme are all contained in this
Bright interior.
The present invention includes the various salt corresponding to involved imidazo [1,2-a] pyridine compounds.
A kind of imidazo [1,2-a] pyridine compounds, shown in its structure such as formula (I),
In formula (I), R6For hydrogen, methyl, or Boc (tertbutyloxycarbonyl)；R7For hydrogen or methyl；
A kind of imidazo [1,2-a] pyridine compounds, shown in its structure such as formula (II),
In formula (II), R8And R9For hydrogen or methyl；
A kind of imidazo [1,2-a] pyridine compounds, shown in its structure such as formula (III),
In formula (III), R10, R11, R12All it is hydrogen；Or one of them be hydrogen when, another two functional group be nitro, cyano group, first
Base, halogen etc.；Or two of which, when being hydrogen, another functional group is nitro, cyano group, methyl, halogen etc.；
R13For hydrogen or methyl；
Preferably, R10, R11, R12All it is hydrogen；Or one of them be hydrogen when, another two functional group be nitro, cyano group, methyl,
Fluorine or chlorine etc.；Or two of which, when being hydrogen, another functional group is nitro, cyano group, methyl, fluorine or chlorine etc.；
R13For hydrogen or methyl.
Present invention also offers a kind of by repeatedly with Mitsunobu reaction, Miyaura boration,
Suzuki cross-coupling, Buchwald-Hartwig cross-coupling and SN2 reactions carry out synthesis type (1) imidazoles
And the method for [1,2-a] pyridine compounds.
Mitsunobu reaction are related to solvent, temperature, response time, catalyst etc..This reaction solvent for use bag
DCM, THF etc. is included but is not limited to, used catalyst includes but is not limited to DIAD, DEAD and DBAD.
Miyaura boration are related to solvent, alkali, catalyst etc..This substrate used by reaction is included but is not limited to
Triflated compound and halides etc..Solvent includes but is not limited to Isosorbide-5-Nitrae-dioxane, DMF, DMSO, THF, toluene etc..
Used catalyst includes but is not limited to Pd2(dba)3,Pd(PPh3)4,Pd(dppf)Cl2·DCM,PdCl2(PPh3)4.Alkali bag used
Include but be not limited to Na2CO3,Ba(OH)2,K3PO4,Cs2CO3,K2CO3,TlOH,KF,CsF,Bu4F,NaOH,M+(-O-alkyl)
Deng.
SN2 reactions are related to solvent, alkali, substrate etc..So this substrate used by reaction includes but is not limited to halides, trifluoro
Methanesulfonates and mesylate compound, solvent include but is not limited to DMF, and DMSO, acetonitrile, alkali include but is not limited to Na2CO3,
Cs2CO3,K2CO3, TlOH, NaOH etc..
Present invention also offers imidazo [1,2-a] pyridine compounds shown in formula as above (1) are made in vitro
For the application in NEK2 inhibitor.
Present invention also offers prepared by imidazo [1,2-a] pyridine compounds shown in formula as above (1)
Application in NEK2 inhibitor.
Present invention also offers imidazo [1,2-a] pyridine compounds shown in formula as above (1) are pressed down in vitro
Application in activity of tumor cells processed.
Present invention also offers imidazo [1,2-a] pyridine compounds shown in formula as above (1) are lured in preparation
Lead tumour cell cycle stopping, inducing apoptosis of tumour cell and suppress the application in the medicine of tumor cell proliferation.
Wherein, the tumor cell is stomach cancer cell, colon cancer cell, B cell lymphoma cell, pancreatic cancer cell, breast
Adenocarcinoma cell or hepatoma carcinoma cell.
Imidazo [1,2-a] pyridine compounds shown in formula (1) as above of the invention are being moved as NEK2 inhibitor
There is in object obvious tumor inhibitory effect, and without obvious toxic and side effects.
Present invention also offers formula (1) imidazo [1,2-a] pyridine compounds, as NEK2 inhibitor, can pass through
Induced cell cycle stops suppressing the propagation of tumor cell with apoptosis, is respectively provided with good antitumor in vivo and in vitro and lives
Property.
Present invention also offers a kind of formula (1) imidazo [1,2-a] pyridine compounds are in modulate tumor cell growth
Application.In the present invention, formula (1) imidazo [1,2-a] pyridine compounds are NEK2 micromolecular inhibitors, can effectively suppress tumor
Cell propagation and tumour growth, can be used for the further exploitation of cancer therapy drug as lead compound.
In the present invention, tumor cell includes but is not limited to stomach cancer cell, colon cancer cell, B cell lymphoma cell, pancreas
Cancerous cell, breast cancer cell and hepatoma carcinoma cell.
Present invention research shows compound MBM-17 (IC50=3nM) and MBM-55 (IC50=1nM) with very efficient
NEK2 inhibitions, and selectivity is good.In addition, they can stop suppressing tumor cell with apoptosis by induced cell cycle
Propagation.What is more important, its corresponding succinate MBM-17S (49.5%TGI) and MBM-55S (36.0%TGI) have
There is obvious tumor inhibitory effect, and without obvious toxic and side effects.Generally speaking compound MBM-17 and MBM-55 are current
The best compound of known NEK2 inhibitory activity, at the same be also uniquely have internal antitumor activity compound, therefore they
There are good oncotherapy potentiality, the exploitation for subsequent candidate medicine to provide guidance and help.
The beneficial effects of the present invention is, formula (1) imidazo [1, the 2-a] pyridine compounds of the present invention have significant suppression
Tumor cell proliferation processed and the ability of tumour growth.
Description of the drawings
Fig. 1 blocked and makes for MBM-17 the and MBM-55 inducing cell G2/M phases>The cellular accumulation of 4N；(A) fluidic cell
MBM-17 is acted on the cell cycle distribution feelings after HCT-116 and MGC-803 cell 24h by instrument detection with concentration 0.25-1 μM
Condition, only show representational data；(B) each period proportional of cell in (A) figure is carried out quantitatively.Numerical value is with three groups of independences
Mean ± the SD of experiment is represented；(C) MBM-55 is acted on HCT-116 cells for 0.5 μM and 1 μM with concentration by Flow cytometry
Cell cycle distribution situation after 24h, representational data do not show；(D) each period proportional of cell in (C) figure is carried out
Quantitatively, numerical value is represented with the Mean ± SD of three groups of independent experiments.
Fig. 2 is MBM-17 and MBM-55 inducing cell apoptosis；(A) MBM-17 acts on HCT-116 with concentration 0.25-1 μM
With detection apoptosis situation after MGC-803 cell 24h；(B) MBM-55 respectively with concentration 0.5 μM and 1 μM act on HCT-116
Apoptosis situation is detected after cell 24h, apoptosis are carried out using flow cytometry using V/PI of Annexin colouring methods
Detection, apoptotic cell and quantitative data show that numerical value is with Mean ± SD tables of three groups of independent experiments in the picture
Show；* */###P ＜ 0.001, * */##P ＜ 0.01, */#P ＜ 0.05vs matched groups.
Anti-tumor in vivo activity of the Fig. 3 for MBM-17S and MBM-55S, HCT-116 xenograft tumor nude mice models, wherein
Solvent control group, MBM-17S groups, MBM-55S groups give medicine twice a day, and irinotecan group biweekly, is treated 21 days；
(A) the tumor volume record case after tumor inoculation, numerical value are represented with Mean ± SEM (n=5).(B) compared with body weight during initial therapy
Situation of change, * * P ＜ 0.01, * P ＜ 0.05vs-. solvent control groups.
Specific embodiment
In conjunction with specific examples below and accompanying drawing, the present invention is described in further detail, the protection content of the present invention
Including but not limited to following examples.Under the spirit and scope without departing substantially from inventive concept, those skilled in the art can think
To change and advantage be all included in the present invention, and with appending claims as protection domain.Implement the present invention
Process, condition, reagent, experimental technique etc., in addition to the following content for specially referring to, be the universal knowledege and public affairs of this area
Know that general knowledge, the present invention are not particularly limited content.
A kind of imidazo [1,2-a] pyridine compounds preparation method：
Scheme 1:
First, compound 2- amino-4-hydroxies pyridine 2 and 2-Chloro-1-ethanal cyclisation in high yield obtain compound 6, subsequently pass through
Mitsunobu reactions are reacted with N-Boc-4- hydroxy piperidines, then NIS iodination reactions, and TAF takes off Boc.4- bromo ortho-oxybenzoic acid compounds
11 under sulfuric acid catalysis and methanol under reflux conditions reaction overnight generate 12 methyl ester of compound, then pass through Mitsunobu anti-
Aryl ether 13 should be synthesized with SN2, subsequently pass through Miyaura boration synthesizing aryls borate 14.Last aryl boric acid
Ester 14 and iodide 10 are obtained compound 15, are just obtained target compound 16 in ammonolysis by Suzuki coupling reactions.
Scheme 2:
Or can also pass course two carry out synthesising target compound, after 12 ammonolysis first by Mitsunobu or SN2 anti-
Aryl ether 18 should be synthesized, then passes through Miyaura boration synthesizing aryls borate 19, then its with iodo thing 8
Reaction, just can be directly synthesized target molecule.Wherein, compound 20a can slough Boc protection groups under the conditions of TFA, be changed
Compound 21a.
A kind of imidazo [1,2-a] pyridine compounds preparation method:
Scheme 3:
Compound 2-Chloro-1-ethanal obtains compound 23 with -4 bromopyridine cyclization of 2- amino, then passes through with N methyl piperazine
Buchwald coupling obtain 24,24 and subsequently obtain iodo thing 25 with NIS reactions.Then iodo thing 25 and aryl-boric acid ester
14 by Suzuki coupling synthesis 26, and ammonolysis just can obtain target molecule 27；Or iodo thing 25 directly with contain acyl
The aryl-boric acid ester 19 of amido passes through Suzuki coupling one-step synthesis target molecules.
A kind of imidazo [1,2-a] pyridine compounds preparation method:
Scheme 4:
Compound 17 is combined to intermediate 35 by Miyaura boration first, logical with a series of bromo-derivatives after allowing
Cross SN2 reactions and generate aryl ether 36.4- bromines pyrazoles 37 generates 38 by SN2 reactions, then successively passes through Miyaura
Boration, Suzuki coupling and iodination reaction synthesis iodide 41, then again with the aryl-boric acid ester containing amide groups
19 pass through Suzuki coupling one-step synthesis target molecules.
Embodiment 1：The synthesis of imidazo [1,2-a] pyridine compounds 16
Synthetic route：
By 2- amino-4-hydroxy pyridines (4.4g, 40.0mmol), after being dissolved in 200mL EtOH, 2-Chloro-1-ethanal is added
(16.5mL, 100mmol), is stirred at reflux overnight.Concentration of reaction solution, column chromatography obtain white solid 6 imidazo [1,2-a] pyridine-
7- alcohol, yield 88%.1H NMR (400MHz, MeOD) δ 8.56 (d, J=8.2Hz, 1H), 7.93 (d, J=1.7Hz, 1H),
7.74 (d, J=1.9Hz, 1H), 7.05-7.01 (m, 2H).
By imidazo [1,2-a] pyridine -7- alcohol (218mg, 1.63mmol), N-Boc-4- hydroxy piperidines (654mg,
3.25mmol)and Ph3P (1.71g, 6.52mmol) is dissolved in THF (30mL), then will be dissolved in the DBAD of THF (10mL)
(748mg, 3.25mmol) is instilled in reactant liquor, after room temperature reaction is complete at 0 DEG C, adds water quenching to go out reaction, and vacuum is spin-dried for post layer
Analyse product 7 (250mg, 48%).1H NMR(400MHz,CDCl3) δ 7.96 (d, J=7.4Hz, 1H), 7.47 (d, J=
1.3Hz, 1H), 7.42 (s, 1H), 6.88 (d, J=2.3Hz, 1H), 6.50 (dd, J=7.4,2.4Hz, 1H), 4.57 4.45
(m, 1H), 3.71 (ddd, J=11.3,6.8,3.8Hz, 2H), 3.35 (ddd, J=13.4,7.9,3.8Hz, 2H), 2.04-
1.92(m,2H),1.83-1.72(m,2H),1.48(s,9H).
Compound 8 (6.12g, 13.81mmol), is dissolved in 130mL DCM, adds 15mL TFA that 4h is stirred at room temperature.0℃
Add the sodium hydrate aqueous solution of 100mL 2M that reaction is quenched, PH is now alkalescence, has white solid to generate, and sucking filtration obtains one
Divide product.Filter liquor is extracted with DCM, merges organic faciess, anhydrous sodium sulfate drying, and concentration there are compound as white solid 9 altogether
4.87 grams, it is directly used in next step reaction.Compound 9 (0.53g, 14.87mmol), is dissolved in 18mL DCM and 9mL ethanol,
The formalin (37%w/w in water, 0.7mL, 9.3mmol) of addition 37%, AcOH (0.125g, 1.85mmol,
1.2eq),NaBH(OAc)3(0.6 6g, 1.85mmol, 2.0eq), is stirred at room temperature 3h.Add saturation NaHCO3Solution is quenched instead
Should, after concentration removes organic faciess, DCM is extracted, and merges organic faciess, and anhydrous sodium sulfate drying, column chromatography obtain compound as white solid
10, two step yields 57%.1H NMR(400MHz,CDCl3) δ 7.93 (d, J=7.5Hz, 1H), 7.51 (s, 1H), 6.87 (d, J=
2.4Hz, 1H), 6.62 (dd, J=7.5,2.4Hz, 1H), 4.41-4.32 (m, 1H), 2.75-2.64 (m, 2H), 2.26 2.24
(m,5H),2.12–2.01(m,2H),1.90–1.81(m,2H).HRMS(ESI)m/z calcd for C13H17N3OI(M+H)+
358.0416,found358.0427.
2- hydroxyls -4- bromobenzoic acids (5.0g, 23.1mmol) is dissolved in 20mL absolute methanols, adds 1.7mL sulphuric acid.Instead
Liquid is answered to be stirred at reflux 24h.After adding frozen water, concentration to remove methanol reactant liquor, EA is extracted, and adds saturation NaHCO3Solution is washed
Organic faciess, anhydrous sodium sulfate drying, concentration there are 12 totally 5.31 grams of red brown solid 2- hydroxyl -4- methyl-bromobenzoates, directly
React for next step.
(S) -1- [2- (trifluoromethyl) phenyl] ethanol (1.25g, 6.58mmol), 2- hydroxyl -4- methyl-bromobenzoates
(1.97g,8.55mmol),
Ph3P (2.24g, 8.55mmol) is dissolved in 40mL DCM, in the DBAD that 0 DEG C of Deca is dissolved in 10mLDCM
(1.97g, 8.55mmol) solution, adds rear room temperature stir about 5h.Add 30mL H2O is quenched reaction, and DCM is extracted,
Merge organic faciess, anhydrous sodium sulfate drying, column chromatography obtain the common 2.89g of compound 13b.
Compound 13b (2.645g, 6.58mmol), connection boric acid pinacol ester (2.73g, 1.5eq), KOAc (1.4g,
2.0eq) 20mL is dissolved in
Dioxane, adds Pd (dppf) Cl2.DCM (0.29g, 0.05eq), argon is protected 90 DEG C and is stirred overnight.Kieselguhr
Sucking filtration, concentration, column chromatography obtain the common 2.74g of compound 14b.Yield 92.6%.
Compound 14b (1.23g, 3.44mmol), compound 10 (1.86g, 4.14mmol, 1.2eq), K2CO3(0.95g,
6.88mmol, 2.0eq) it is dissolved in 1,4-dioxane/H2O (4/1,17.6mL), adds Pd (PPh3)4(0.95g,
0.826mmol, 0.2eq), argon protects 90 DEG C of stirring 3h.Suction filtered through kieselguhr, concentration, column chromatography obtain faint yellow solid compound
15, yield 56%.1H NMR(400MHz,CDCl3)δ7.94-7.84(m,2H),7.69(s,1H),7.67(s,1H),7.56(t,
J=7.6Hz, 1H), 7.43 (s, 1H), 7.39 (t, J=7.6Hz, 1H), 7.05 (d, J=7.9Hz, 1H), 6.88 (s, 1H),
6.86 (d, J=1.8Hz, 1H), 6.39 (dd, J=7.5,2.1Hz, 1H), 5.81 (d, J=6.1Hz, 1H), 4.40-4.31 (m,
1H),3.96(s,3H),2.80-2.62(m,2H),2.30(s,3H),2.26-2.12(m,2H),2.11-2.01(m,2H),
1.94-1.79 (m, 2H), 1.73 (d, J=6.1Hz, 3H) .HRMS (ESI) m/z calcd for C30H30N3O4NaF3(M+Na)+
576.2086,found 576.2088.
Compound 15b (1.237g, 2.236mmol) is dissolved in 13mL 7M methanolic ammonia solutions in a tube sealing, and 90 DEG C are stirred
4d.It is spin-dried for column chromatography and obtains the common 0.955g of white solid 16b, yield 80%.1H NMR (400MHz, MeOD) δ 7.95 (d, J=
8.1Hz, 1H), 7.71 (m, 2H), 7.66 (d, J=7.6Hz, 1H), 7.56 (t, J=7.6Hz, 1H), 7.46 (t, J=7.6Hz,
1H), 7.32 (s, 1H), 7.06 (dd, J=8.1,1.5Hz, 1H), 6.97 (d, J=2.3Hz, 1H), 6.78 (d, J=1.1Hz,
1H), 6.62 (d, J=6.1Hz, 1H), 5.83 (q, J=6.0Hz, 1H), 4.88 (m, 1H), 3.53 (m, 2H), 3.41 (m, 2H),
2.96 (s, 3H), 2.32 (m, 2H), 2.15 (m, 2H), 1.73 (d, J=6.2Hz, 3H) .HRMS (ESI) m/z calcd for
C29H29N4O3Na F3(M+Na)+561.2089,found 561.2082.
Embodiment 2：The synthesis of imidazo [1,2-a] pyridine compounds 21
Bromo- for 4- 2 hydroxybenzoic acid methyl ester (4.6g) is dissolved in isopropanol (20mL), ammonia (40mL) is subsequently adding,
It is spin-dried for obtaining the bromo- 2-Hydroxylbenzamides of crude product 4- after 50 DEG C of reaction 5h and is directly used in next step reaction.
Bromo- for 4- 2-Hydroxylbenzamide (8.64g, 40.0mmol) is dissolved in DMF (80mL), 2- (three is subsequently adding
Methyl fluoride) benzyl bromine (11.5g, 1.2eq) and K2CO3(6.08g, 1.1eq), then 50 DEG C are reacted 6h.Question response adds EA completely afterwards
(500mL) dilute, wash with water (2 250mL), saturated common salt washes (150mL), Na2SO4After drying, concentration is spin-dried for, column chromatography EA:
PE=1:10 compound 18c (12.4g, 82.9%).1H NMR(400MHz,CDCl3) δ 8.09 (d, J=8.4Hz, 1H),
7.77 (d, J=7.8Hz, 1H), 7.62 (t, J=6.1Hz, 2H), 7.53 (dt, J=8.3,4.2Hz, 1H), 7.40 (s, 1H),
7.31 7.23 (m, 1H), 7.18 (d, J=1.2Hz, 1H), 5.97 (s, 1H), 5.37 (s, 2H).
Compound 18c (2.9g) be dissolved in 1,4-dioxane (30mL) add afterwards connection boric acid pinacol ester (2.95g,
1.5eq), Pd (dppf) Cl2 DCM (316.4mg, 5%) and KOAc (1.52g, 2.0eq). and then use nitrogen displacement gas, 90
DEG C reaction is overnight. be spin-dried for filtrate after suction filtered through kieselguhr, column chromatography (1-2%MeOH/DCM) purification obtain compound 19c (2.61g,
80.1%).1H NMR (400MHz, DMSO) δ 7.86 (d, J=7.7Hz, 1H), 7.82 (d, J=7.8Hz, 1H), 7.74 (t, J
=7.7Hz, 2H), 7.62 (d, J=7.6Hz, 1H), 7.54 (s, 1H), 7.51 (s, 1H), 7.37 (d, J=7.9Hz, 2H),
5.38(s,2H),1.30(s,12H).
Compound 8 (133.0mg, 0.30mmol) and 19c (127.2mg, 0.36mmol, 1.2eq) are dissolved in DMF/H2O(10/
1,3.3mL), in, K is added2CO3(82.9mg, 0.6mmol 2.0eq) and Pd (PPh3)4(34.7mg, 0.03mmol 0.10eq),
Then filtrate is spin-dried for after 80 DEG C of reaction 10h. suction filtered through kieselguhr, column chromatography (2-10%MeOH/DCM) obtains compound 20.1H
NMR(400MHz,CDCl3) δ 8.34 (d, J=8.1Hz, 1H), 8.03 (d, J=7.5Hz, 1H), 7.78 (d, J=7.8Hz,
1H), 7.71 7.60 (m, 3H), 7.58 (s, 1H), 7.52 (t, J=7.5Hz, 1H), 7.28 (dd, J=6.3,1.6Hz, 1H),
7.07 (s, 1H), 6.94 (d, J=1.9Hz, 1H), 6.58 6.48 (m, 1H), 6.52 (dd, J=7.5,2.3Hz, 1H), 6.15
(s,1H),5.48(s,2H),4.60–4.47(m,1H),3.85–3.66(m,2H),3.49–3.26(m,2H),2.17(s,1H),
2.08–1.93(m,2H),1.90–1.73(m,2H),1.48(s,9H).RMS(ESI)m/z calcd for C32H34N4O5F3(M
+H)+611.2481,found 611.2457.
Compound 20 (51.0mg, 0.084mmol) is dissolved in DCM (4mL) and adds TFA (0.5mL), is then stirred at room temperature anti-
Should excessively.Concentration be spin-dried for crude product DCM, PE and MeOH are beaten to obtain pale solid 21, yield 60%.1H NMR
(400MHz, MeOD) δ 8.58 (d, J=7.5Hz, 1H), 8.16 (d, J=7.9Hz, 1H), 8.04 (s, 1H), 7.86 7.79 (m,
2H), 7.72 (t, J=7.5Hz, 1H), 7.61 (t, J=7.8Hz, 1H), 7.57 7.38 (m, 3H), 7.18 (d, J=7.8Hz,
1H),5.56(s,2H),3.56–3.41(m,2H),3.33(s,2H),2.41–2.27(m,2H),2.24–2.09(m,2H)
.HRMS(ESI)m/z calcd for C27H26N4O3F3(M+H)+511.1957,found 511.1947.
Embodiment 3：The 20d synthesis of imidazo [1,2-a] pyridine compounds
Iodide 10 (71.4mg, 0.20mmol) and borate 19d (106mg, 0.30mmol, 1.5eq) are dissolved in
DMF/H2After in O (10/1,2.2mL), K is added2CO3(55.3mg, 0.40mmol 2.0eq) and Pd (PPh3)4(23.1mg,
0.02mmol 0.10eq), then filtrate, column chromatography (2-10%MeOH/DCM) is spin-dried for after 80 DEG C of reaction 12h. suction filtered through kieselguhr
Purification obtain compound 20d (75mg, 78%).1H NMR (400MHz, DMSO) δ 8.35 (s, 1H), 7.94 (d, J=7.6Hz,
1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.59 (s, 1H), 7.53 (d, J=6.5Hz, 2H), 7.48 7.32 (m, 4H),
7.31–7.19(m,2H),6.74(s,1H),5.40(s,2H),4.85(s,1H),3.28–3.06(m,4H),2.85(s,3H),
2.30–1.87(m,4H).HRMS(ESI)m/z calcd for C27H29N4O3(M+H)+457.2240,found 457.2222.
Embodiment 4：The synthesis of imidazo [1,2-a] pyridine compounds 16c
The synthesis of imidazo [1,2-a] pyridine compounds 16c same 21, (20%yield).1H NMR(400MHz,MeOD)δ
8.25 (t, J=10.0Hz, 1H), 8.10 (d, J=8.1Hz, 1H), 7.79 (t, J=7.6Hz, 1H), 7.68 (t, J=7.6Hz,
1H), 7.64 7.53 (m, 2H), 7.33 (dd, J=8.1,1.3Hz, 1H), 7.24 (d, J=1.0Hz, 1H), 6.99 (d, J=
1.8Hz, 1H), 6.69 (dd, J=7.6,2.1Hz, 1H), 5.56 (s, 2H), 4.67 4.53 (m, 1H), 3.22 3.07 (m,
1H),3.05–2.88(m,1H),2.67(s,3H),2.30–2.13(m,2H),2.09–1.93(m,1H).
Embodiment 5：The synthesis of imidazo [1,2-a] pyridine compounds 27b
Synthetic route：
Compound 2- amino -4- bromopyridines 22 (5.0g) and 2- 2-Chloro-1-ethanals (40percent wt aqueous
Solution, 12mL, 2.5eq) it is dissolved in dehydrated alcohol (50mL), add NaHCO3After (4.89g, 2.0eq), back flow reaction
6h.Suction filtered through kieselguhr, after vacuum is spin-dried for organic solvent, adds EA (60mL) dilutions, washing, saturated aqueous common salt water, Na2SO4Dry
After be spin-dried for column chromatography obtain brown solid 23 (4.38g, 78%).1H NMR(400MHz,CDCl3) δ 7.99 (d, J=7.1Hz, 1H),
7.81 (s, 1H), 7.59 (s, 1H), 7.56 (s, 1H), 6.88 (dd, J=7.2,1.6Hz, 1H).
By compound 7- bromine imidazo [1,2-a] pyridines 23 (487.9mg, 1.0eq), N methyl piperazine (0.83mL,
3.0eq),Pd2(dba)3(45.8mg, 2%), (6%) 86.8mg is dissolved in first with t-BuONa (0.36g, 1.5eq) to Xantphos
In benzene (3.5mL), 12h at 100 DEG C, is reacted.Suction filtered through kieselguhr, vacuum are spin-dried for column chromatography (1-10%MeOH/ after rear organic solvent
DCM) white solid 24 (476mg, 88.0%).1H NMR(400MHz,CDCl3) δ 7.88 (d, J=7.5Hz, 1H), 7.41
(d, J=0.8Hz, 1H), 7.31 (s, 1H), 6.77 (d, J=1.7Hz, 1H), 6.56 (dd, J=7.5,2.3Hz, 1H), 3.21
(t, J=4.8Hz, 4H), 2.54 (t, J=4.8Hz, 4H), 2.32 (s, 3H).
24 (476mg, 1.0eq) are dissolved in acetonitrile (7.0mL), add NIS (495.0mg, 1.0eq) to react half afterwards little
When.It is spin-dried for column chromatography (eluted with MeOH after solvent:DCM=1:100-1:5) yellow solid 25 (576mg, 75%)
.1H NMR(400MHz,CDCl3) δ 7.82 (d, J=7.4Hz, 1H), 7.40 (s, 1H), 6.66-6.69 (m, 2H), 3.20-3.23
(m,4H),2.50-2.51(m,4H),2.28(s,3H).
Compound 25 (430mg, 1.26mmol) and 19c (822mg, 1.88mmol, 1.5eq) are dissolved in Isosorbide-5-Nitrae-dioxane/
H2In O (4/1,4mL), Cs is added2CO3(821mg, 2.52mmol 2.0eq) and Pd (dppf) Cl2 DCM (34.7mg,
0.03mmol 0.10eq) 90 DEG C of reaction 10h. suction filtered through kieselguhr, vacuum is spin-dried for column chromatography (2-10%MeOH/ after rear organic solvent
DCM) white solid 26b (165mg, 25%). compound 26b (150mg) is dissolved in 7M methanolic ammonia solutions (15.0mL), envelope
In pipe, 90 DEG C are reacted six days. the product 27b of concentration of reaction solution column chromatography (1-10%MeOH/DCM) (43mg, 30%).1H NMR
(400MHz, MeOD) δ 8.12 (d, J=7.7Hz, 1H), 8.01 (d, J=8.0Hz, 1H), 7.71 (t, J=7.8Hz, 2H),
7.60 (t, J=7.5Hz, 1H), 7.54 7.44 (m, 2H), 7.24 (d, J=8.1Hz, 1H), 7.16 (s, 1H), 6.78 (d, J=
7.7Hz,1H),6.68(s,1H),5.46(s,2H),3.34–3.24(m,4H),2.62–2.51(m,4H),2.30(s,3H).
Embodiment 6：The synthesis of imidazo [1,2-a] pyridine compounds 29a
Compound 25 (102.6mg, 0.30mmol) and 19a (156.9mg, 0.36mmol) are dissolved in DMF/H2O(10/1,
3.3mL), K is subsequently adding2CO3(82.9mg, 0.6mmol) and Pd (PPh3)4(34.7mg, 0.03mmol), 90 DEG C of reaction 10h.
Suction filtered through kieselguhr, vacuum be spin-dried for after organic solvent column chromatography (2-10%MeOH/DCM) white solid 29a (119.3mg,
76%).1H NMR(400MHz,CDCl3) δ 8.29 (d, J=8.2Hz, 1H), 7.93 (d, J=2.7Hz, 1H), 7.79 (d, J=
7.7Hz, 1H), 7.72 (d, J=7.7Hz, 1H), 7.68 (d, J=7.8Hz, 1H), 7.57 (t, J=7.5Hz, 1H), 7.43 (t,
J=7.7Hz, 1H), 7.39 (s, 1H), 7.18 (dd, J=8.2,1.5Hz, 1H), 6.86 (d, J=1.4Hz, 1H), 6.79 (d, J
=2.3Hz, 1H), 6.51 (dd, J=7.7,2.5Hz, 1H), 5.97 (s, 1H, b), 5.94 (q, J=6.3Hz, 1H), 3.27 (t,
J=5.2Hz, 4H), 2.58 (t, J=5.2Hz, 4H), 2.36 (s, 3H), 1.81 (d, J=6.2Hz, 3H) .HRMS (ESI) m/z
calcd for C28H29N5O2F3(M+H)+524.2273,found 524.2289.
Embodiment 7：The synthesis of imidazo [1,2-a] pyridine compounds 29b
The same 29a of the synthesis of imidazo [1,2-a] pyridine compounds 29b.Yield, 70%.
1H NMR(400MHz,CDCl3) δ 8.33 (d, J=8.1Hz, 1H), 8.06 (d, J=7.7Hz, 1H), 7.77 (d, J
=7.8Hz, 1H), 7.69 7.48 (m, 5H), 7.31 7.23 (m, 2H), 7.08 (s, 1H), 6.84 (s, 1H), 6.62 (dd, J=
7.7,1.8Hz, 1H), 5.91 (s, 1H), 5.49 (s, 2H), 3.30 (t, J=4.8Hz, 4H), 2.59 (t, J=4.8Hz, 4H),
2.37(s,3H).
Embodiment 8：The synthesis of imidazo [1,2-a] pyridine compounds 42b
The synthesis of compound 36：4- bromine pyrazoles (22.0g) is dissolved in DMF (75mL), adds K2CO3(51.8g, 2.5eq) and
Dimethylamino chloroethene heptane hydrochloride, then room temperature reaction two days.EA (500mL) dilutions are added, then successively with water and saturated common salt
Washing, Na2SO4Drying be spin-dried for rear column chromatography (1-20%MeOH/DCM) 36 (21.85g, 66.5%).H NMR(400MHz,
CDCl3) δ 7.50 (s, 1H), 7.44 (s, 1H), 4.18 (t, J=6.5Hz, 2H), 2.71 (t, J=6.5Hz, 2H), 2.25 (s,
6H).
The synthesis of compound 37：Compound 36 (2.5g, 11.46mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (12.5mL),
Add connection boric acid pinacol ester (4.37g, 1.5eq), Pd (dppf) Cl2 DCM (468mg, 5%) and KOAc (2.81g,
2.5eq).100 DEG C of reactant liquor reaction 12h. suction filtered through kieselguhr, it is direct that vacuum is spin-dried for the 37 common 6.7g of crude product after rear organic solvent
React for next step.
Compound 37 (1.3eq) is dissolved in DMF (169.3mL), adds 7- bromine imidazo [1,2-a] pyridines (3.48g), 1N
Na2CO3Aqueous solution (26.64mL) and Pd (dppf) Cl2 DCM (0.05eq), then the reaction of 80 DEG C of reactant liquor is overnight. kieselguhr
Sucking filtration, vacuum be spin-dried for after organic solvent column chromatography (2-10%MeOH/DCM) white solid 31 (4.88g, 72%).1H NMR
(400MHz,CDCl3) δ 8.07 (d, J=7.0Hz, 1H), 7.81 (s, 1H), 7.80 (s, 1H), 7.66 (s, 1H), 7.59 (s,
1H), 7.52 (s, 1H), 6.92 (d, J=6.9Hz, 1H), 4.26 (t, J=6.5Hz, 2H), 2.80 (t, J=6.5Hz, 2H),
2.29(s,6H).
The same 29a of the synthesis of imidazo [1,2-a] pyridine compounds 42b, yield 67%.1H NMR(400MHz,MeOD)δ
8.55 (s, 1H), 8.02 7.95 (m, 2H), 7.79 (d, J=7.4Hz, 1H), 7.75 7.65 (m, 2H), 7.65 7.58 (m,
2H), 7.58 7.51 (m, 1H), 7.44 (s, 1H), 7.12 (dd, J=8.1,1.3Hz, 1H), 7.00 (dd, J=7.2,1.7Hz,
1H), 6.79 (d, J=1.1Hz, 1H), 5.84 (q, J=5.4Hz, 1H), 4.73 (t, J=5.6Hz, 2H), 3.88 (t, J=
5.6Hz, 2H), 3.08 (s, 6H), 1.76 (d, J=6.0Hz, 3H).13C NMR(101MHz,MeOD)δ169.27,157.00,
147.09,142.16,139.29(s),134.74,133.82,133.50,133.15,131.70,131.05,130.03,
(d, J=5.9Hz), 128.00,127.55 127.28 (d, J=5.3Hz), 126.02,125.36,124.54,123.49,
121.95,121.26,114.19,113.91,111.12,74.93,58.21,47.66,44.50,25.10.
Embodiment 9：The synthesis of imidazo [1,2-a] pyridine compounds MBM-17
The same 29a of the synthesis of imidazo [1,2-a] pyridine compounds MBM-17, yield 67%.1H NMR(400MHz,CDCl3)
δ 8.38 (d, J=8.1Hz, 1H), 8.16 (dd, J=7.2,0.8Hz, 1H), 7.85 (d, J=5.1Hz, 2H), 7.75 (s, 1H),
7.73 (s, 2H), 7.50 7.40 (m, 5H), 7.32 (dd, J=8.1,1.5Hz, 1H), 7.20 (d, J=1.4Hz, 1H), 6.95
(dd, J=7.2,1.8Hz, 1H), 5.77 (s, 1H), 5.30 (s, 2H), 4.28 (t, J=6.3Hz, 2H), 2.82 (t, J=
6.3Hz,2H),2.31(s,6H).13C NMR(101MHz,CDCl3)δ166.26,157.46,147.42,136.84,135.28,
134.32,134.00,133.76,129.93,129.16,128.86,127.74,127.12,124.50,123.44,120.71,
120.30,119.95,112.34,112.16,112.16,111.78,71.40,59.05,50.68,45.65.
Embodiment 10：The synthesis of imidazo [1,2-a] pyridine compounds 44
Compound 35 (425mg, 1.62mmol) and 3- bromine chlorides (331.9mg, 1.62mmol) are dissolved in acetone (8mL)
In, add K2CO3(425mg, 1.78mmol), is then refluxed for reacting two days.After question response is complete, suction filtered through kieselguhr is spin-dried for filtrate
Obtain 43 white solid 660mg of crude product and be directly used in next step reaction.
Iodide 41 (76.2mg, 0.20mmol) and crude product 43 (154.7mg, 0.40mmol 2.0eq) are dissolved in DMF/
H2After O (10/1,2.2mL), K is added2CO3(55.3mg, 0.40mmol 2.0eq) and Pd (PPh3)4(46.2mg,0.044mmol
0.20eq), after then 80 DEG C of reaction 12h. question responses are complete, suction filtered through kieselguhr is spin-dried for filtrate column chromatography (2-10%MeOH/DCM
White solid product 44 (62mg, 60.2%).1H NMR (400MHz, DMSO) δ 8.49 (s, 1H), 8.43 (d, J=7.1Hz,
1H), 8.23 (s, 1H), 7.93 (d, J=7.5Hz, 2H), 7.85 (s, 1H), 7.71 (s, 1H), 7.64 (s, 2H), 7.56 7.40
(m, 4H), 7.35 (d, J=7.9Hz, 1H), 7.21 (d, J=6.9Hz, 1H), 5.42 (s, 2H), 4.54 (t, J=5.8Hz,
2H),2.76(s,6H),2.50(s,2H).13C NMR(101MHz,DMSO)δ166.09,156.17,146.58,139.17,
137.49,133.81,133.29,132.42,131.65,130.58,129.30,128.83,128.04,127.41,126.20,
124.51,124.17,122.57,120.30,119.27,111.73,11.64,110.96,69.06,56.11,46.71,
43.13.HRMS(ESI)m/z calcd for C28H28N6O2Cl(M+H)+515.1962,found 515.1944.
Embodiment 11：The synthesis of imidazo [1,2-a] pyridine compounds MBM-55
The same 29a of the synthesis of imidazo [1,2-a] pyridine compounds MBM-55, yield 72%.1H NMR(400MHz,DMSO)
δ 9.60 (s, 1H), 8.52 (s, 1H), 8.48 (d, J=7.2Hz, 1H), 8.27 (s, 1H), 8.04 7.90 (m, 2H), 7.87 (s,
1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.58 7.47 (m, 1H), 7.44 7.32 (m, 3H), 7.23 (d, J=5.7Hz,
2H), 5.43 (s, 2H), 4.58 (t, J=6.1Hz, 2H), 3.61 (t, J=6.1Hz, 2H), 2.83 (s, 6H).19F NMR
(376MHz, DMSO) δ -112.71 (dd, J=15.6,9.2Hz).13C NMR(101MHz,DMSO)δ166.07,162.24(d,J
=243.9Hz), 156.18,146.41,139.52 (d, J=7.6Hz), 137.66,133.57,132.30,131.58,
130.70 (d, J=8.2Hz), 129.41,128.98,124.67,124.23,123.59 (d, J=2.4Hz), 122.68,
(120.33,119.27,114.89 d, J=20.9Hz), 114.33 (d, J=22.0Hz), 111.74,111.66,110.86,
69.13,55.77,46.35,42.87.HRMS(ESI)m/z calcd for C28H28N6O2F(M+H)+499.2258,found
499.2278.
Embodiment 12：The synthesis of imidazo [1,2-a] pyridine compounds 42f
The same 29a of the synthesis of imidazo [1,2-a] pyridine compounds 42f, yield 66%.1H NMR(400MHz,DMSO)δ
8.56 (d, J=7.2Hz, 1H), 8.43 (s, 1H), 8.13 (s, 1H), 7.97 (d, J=8.0Hz, 1H), 7.90 (s, 1H), 7.86
(s,1H),7.68–7.64(m,1H),7.61(s,1H),7.56(s,1H),7.52(s,1H),7.49–7.44(m,1H),7.41–
7.36 (m, 1H), 7.34 7.27 (m, 2H), 7.24 (dd, J=7.4,1.7Hz, 1H), 5.47 (s, 2H), 4.29 (t, J=
6.3Hz, 2H), 2.86 (t, J=6.1Hz, 2H), 2.30 (s, 6H).19F NMR(376MHz,DMSO)δ-117.84(s),-
118.35(s).HRMS(ESI)m/z calcd forC28H28N6O2F C28H28N6O2F(M+H)+499.2258,found
499.2252.
Embodiment 13：The synthesis of imidazo [1,2-a] pyridine compounds 42d
The same 29a of the synthesis of imidazo [1,2-a] pyridine compounds 42d, yield 55%.1H NMR(400MHz,MeOD)δ
8.36 (d, J=7.2Hz, 1H), 8.24 (s, 1H), 8.11 (d, J=8.0Hz, 1H), 8.00 (s, 1H), 7.89 (s, 1H), 7.83
(d, J=7.5Hz, 1H), 7.79 7.70 (m, 3H), 7.67 (d, J=7.6Hz, 1H), 7.41 (s, 1H), 7.37 (d, J=
8.0Hz, 1H), 7.19 (dd, J=7.2,1.5Hz, 1H), 5.49 (s, 2H), 4.35 (t, J=6.6Hz, 2H), 2.90 (t, J=
6.6Hz,2H),2.34(s,6H).19F NMR(376MHz,MeOD)δ-64.02(s).13C NMR(101MHz,DMSO)δ
(166.13,156.20,146.78,138.17,136.51,133.89,132.55,131.61 d, J=4.4Hz), 129.72,
(q, J=31.8Hz), 129.64,129.32 128.29,124.77 (q, J=3.8Hz), 124.36,124.21 (q, J=
3.9Hz), 124.14 (d, J=270.7Hz), 124.05,122.69,119.66,119.25,111.72,111.60,110.72,
69.16,58.31,49.53,44.96.HRMS(ESI)m/z calcd for C29H28N6O2F3(M+H)+549.2226,found
549.2215.
Embodiment 14：The synthesis of imidazo [1,2-a] pyridine compounds 42e
The same 29a of the synthesis of imidazo [1,2-a] pyridine compounds 42e, yield 50%.1H NMR(400MHz,CDCl3)δ
8.38 (d, J=8.1Hz, 1H), 8.05 (d, J=7.2Hz, 1H), 7.89 7.81 (m, 2H), 7.79 7.68 (m, 4H), 7.65
7.56 (m, 3H), 7.38 7.30 (m, 1H), 7.12 (s, 1H), 6.91 (dd, J=7.2,1.7Hz, 1H), 5.85 (s, 1H),
5.36 (d, J=9.1Hz, 2H), 4.29 (t, J=6.5Hz, 2H), 2.83 (t, J=6.5Hz, 2H), 2.32 (s, 6H).19F NMR
(376MHz,CDCl3)δ-62.58(s).HRMS(ESI)m/z calcd for C29H28N6O2F3(M+H)+549.2226,found
549.2249.
Embodiment 15：The synthesis of imidazo [1,2-a] pyridine compounds 45
The synthesis of imidazo [1,2-a] pyridine compounds 45 same 44, yield 19%.1H NMR(400MHz,DMSO)δ
8.80 8.67 (m, 2H), 8.38 (s, 1H), 8.31 8.23 (m, 1H), 8.06 (s, 1H), 7.96 (d, J=7.9Hz, 1H),
7.67 7.57 (m, 1H), 7.55 (d, J=6.7Hz, 1H), 7.50 (d, J=7.1Hz, 1H), 7.41 (d, J=8.4Hz, 1H),
7.33 7.23 (m, 2H), 5.38 (s, 2H), 4.64 (t, J=5.9Hz, 2H), 3.67 (t, J=6.0Hz, 2H), 2.87 (s,
6H),2.38(s,3H).13C NMR(101MHz,DMSO)δ165.95,156.50,138.29(s),136.66,134.17,
131.48,130.39,130.20,126.25(s),125.97,125.20(s),123.87(s),120.26(s),119.40
(s),113.82,112.95,68.96,55.52,46.33,42.76,18.56.HRMS(ESI)m/z calcd for
C29H31N6O2(M+H)+495.2508,found495.2507.
Embodiment 16：The synthesis of imidazo [1,2-a] pyridine compounds 46
The synthesis of imidazo [1,2-a] pyridine compounds 46 same 44, yield 19%.1H NMR(400MHz,MeOD)δ8.39
(d, J=6.8Hz, 1H), 8.29 (s, 1H), 8.12 (d, J=7.8Hz, 1H), 8.07 (s, 1H), 7.77 (s, 1H), 7.62 (d, J
=7.7Hz, 2H), 7.50 7.33 (m, 3H), 7.22 (d, J=7.0Hz, 1H), 5.52 (s, 2H), 4.53 (s, 2H), 3.27 (s,
2H),2.77(s,6H).13C NMR(101MHz,MeOD)δ169.44,158.28,148.32,138.72,137.58,134.87,
134.51,133.79,133.63,132.58,132.21,131.81,129.97,129.55,129.35,125.53,122.96,
122.23,121.29,113.56,113.26,111.92,69.88,58.98,49.71,44.77.HRMS(ESI)m/z calcd
for C28H27N6O2Cl2(M+H)+549.1573,found 549.1559.
Embodiment 17：The synthesis of imidazo [1,2-a] pyridine compounds 47
The synthesis of imidazo [1,2-a] pyridine compounds 47 same 44, yield 68%.1H NMR(400MHz,DMSO)δ8.48
(d, J=9.0Hz, 2H), 8.24 (s, 1H), 7.95 (s, 1H), 7.91 (d, J=8.0Hz, 1H), 7.86 (s, 2H), 7.74 (d, J
=8.2Hz, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.55 (dd, J=8.2,1.7Hz, 1H), 7.42 (s, 1H), 7.37 (d,
J=8.0Hz, 1H), 7.21 (dd, J=7.2,1.4Hz, 1H), 5.42 (s, 2H), 4.55 (t, J=6.1Hz, 2H), 3.53 (t, J
=6.1Hz, 2H), 2.78 (s, 6H).13C NMR(101MHz,DMSO)δ166.10,156.02,146.57,137.88,
137.51,133.86,132.37,131.57,131.25,130.85,130.60,129.67,129.25,128.84,127.91,
124.57,124.15,122.81,120.31,119.30,111.72,111.55,110.98,68.41,56.02,46.63,
43.06.HRMS(ESI)m/z calcd for C28H27N6O2Cl2(M+H)+549.1573,found 549.1555.
Embodiment 18：The synthesis of imidazo [1,2-a] pyridine compounds 48
The synthesis of imidazo [1,2-a] pyridine compounds 48 same 44, yield 74%1H NMR(400MHz,DMSO)δ8.71
(d, J=6.8Hz, 1H), 8.66 (s, 1H), 8.37 (s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 8.01 7.94 (m, 2H),
7.89–7.79(m,2H),7.71–7.57(m,3H),7.54(s,1H),7.51–7.42(m,2H),5.55(s,1H),4.62(t,
J=6.0Hz, 2H), 3.66 (t, J=6.0Hz, 2H), 2.94 2.81 (m, 6H).13C NMR(101MHz,DMSO)δ165.88,
156.09,139.40,138.12,133.69,133.42,131.70,129.85,129.63,129.40(s),125.85,
125.84,123.70,120.44,119.69,117.19,113.22,112.61,110.99,68.39,55.61,46.29,
42.81.HRMS(ESI)m/zcalcd for C29H28N7O2(M+H)+506.2304,found 506.2308.
Embodiment 19：The synthesis of imidazo [1,2-a] pyridine compounds 49
The synthesis of imidazo [1,2-a] pyridine compounds 49 same 44, yield 49%.1H NMR(400MHz,MeOD)δ
8.36 (dd, J=20.8,7.1Hz, 1H), 8.29 8.11 (m, 2H), 8.05 (d, J=8.0Hz, 1H), 7.98 (d, J=
4.2Hz, 1H), 7.87 (d, J=7.7Hz, 1H), 7.77 (t, J=7.2Hz, 1H), 7.72 7.59 (m, 2H), 7.54 (d, J=
18.9Hz, 1H), 7.41 7.27 (m, 1H), 7.16 (d, J=7.0Hz, 1H), 5.73 (s, 1H), 4.35 (t, J=6.3Hz,
2H), 2.93 (t, J=6.4Hz, 2H), 2.37 (d, J=1.5Hz, 6H)
Embodiment 20：The synthesis of imidazo [1,2-a] pyridine compounds MBM-17S
MBM-17 (664mg, 1.38mmol) is dissolved in DCM (40mL), the succinic acid being dissolved in 10ML acetone is added
(326mg, 2.76mmol) solution, is stirred overnight at room temperature, and has solid to separate out, the dried faint yellow solid MBM-17S of sucking filtration
(858mg, 87%).1H NMR(400MHz,CD3OD) δ 8.34 (d, J=7.2Hz, 1H), 8.30 (s, 1H), 8.18 (d, J=
8.1Hz,1H),8.09(s,1H),7.80–7.74(m,2H),7.59–7.52(m,2H),7.51–7.41(m,4H),7.40–
(7.34 m, 1H), 7.22 (dd, J=7.2,1.6Hz, 1H), 5.44 (s, 2H), 4.52 (t, J=6.2Hz, 2H), 3.30 (d, J=
6.3Hz,2H),2.66(s,6H),2.57(s,8H).13C NMR(100MHz,CD3OD)δ177.27,169.27,158.84,
148.27,138.76,137.61,134.85,133.71,132.21,130.02,129.59,128.90,126.34,125.62,
122.27,120.97,113.54,111.87,72.21,59.52–58.47,44.61,30.83.HRMS(ESI)m/z calcd
for C28H29N6(M+H)+481.2352,found 481.2364.
Embodiment 21：The synthesis of imidazo [1,2-a] pyridine compounds MBM-55S
MBM-55 (696mg, 1.40mmol) is dissolved in DCM (100mL), the succinic acid being dissolved in 10ML acetone is added
(329mg, 2.79mmol) solution, is stirred overnight at room temperature, and has solid to separate out, the dried faint yellow solid of sucking filtration (800mg,
78%).1H NMR(400MHz,CD3OD) δ 8.35 (d, J=7.1Hz, 1H), 8.30 (s, 1H), 8.14 (d, J=8.0Hz, 1H),
8.08(s,1H),7.81–7.73(m,2H),7.52–7.44(m,1H),7.42–7.35(m,3H),7.35–7.29(m,1H),
7.22 (d, J=6.9Hz, 1H), 7.18 7.11 (m, 1H), 5.43 (s, 2H), 4.56 (t, J=6.0Hz, 2H), 3.39 (t, J=
6.0Hz,2H),2.74(s,6H),2.56(s,8H).13C NMR(100MHz,CD3OD)δ177.28,169.38,164.51(d,
JC-F=243.6Hz), 158.1,148.18,140.46,138.89,134.76,133.61,132.20,131.88 (d, JC-F=
8.3Hz),130.12,126.30,125.60,124.55,122.71,122.32,121.06,116.23(d,JC-F=
21.2Hz),115.53(d,JC-F=22.3Hz), 113.54,111.85,71.29,58.43,44.33,30.78.HRMS (ESI)
m/z calcd for C28H28N6O2F(M+H)+499.2258,found 499.2271.
The selectivity of embodiment 22 formula (1) imidazo [1,2-a] pyridine compounds and anti tumor activity in vitro evaluation
Present invention research on a cellular level shows that formula (1) imidazo [1,2-a] pyridine compounds can be used as to AurA
Kinases has extraordinary selectivity, while there is good inhibiting effect to kinds of tumor cells.
Table 1, Nek2 inhibitor are to AurA kinases and the active anticancer in tumor cell
Table 2：A series of selectivitys of the MBM-55 in kinases
Table 2 shows that compound MBM-55 has good selectivity to multiple kinases.
Embodiment 23
Fig. 1 and 2 shows that compound MBM-17 and MBM-55 can stop suppressing swollen with apoptosis by induced cell cycle
The propagation of oncocyte.
PI dyeing combines the impact of flow cytometry compound on tumor cell period profile：
By MGC-803 the or HCT-116 cells kind in exponential phase in 6 orifice plates, respective concentration after 24h, is given
MBM-17 or MBM-55, after medicine effect 24h, receives cell, and 70% ethanol is fixed, flow cytomery cell week after PI dyeing
Phase distribution situation.
V/PI of Annexin dyeing carries out apoptosis detection with reference to flow cytometry：
By MGC-803 the or HCT-116 cells kind in exponential phase in 6 orifice plates, respective concentration after 24h, is given
MBM-17 or MBM-55, after medicine effect 24h, receives cell, and after V/PI of Annexin dyeing, directly the detection of flow cytometer art is thin
Born of the same parents' apoptosis situation.
Embodiment 24：Modulate tumor growth experiment in MBM-17S and MBM-55S bodies
The internal pharmacodynamic evaluation of MBM-17S and MBM-55S is carried out on HCT-116 xenograft tumor models.Experiment choosing
With the Female nude mice of 4～5 week old, in its left fore axillary fossa subcutaneous injection HCT-116 cell suspension.Treat that gross tumor volume reaches
100mm3It is grouped during left and right at random, is divided into 4 groups, respectively solvent control group, MBM-17S groups (20mg/kg), MBM-55S
Group (20mg/kg), irinotecan group (10mg/kg) 5 per group, after packet, the same day gives medicine.Wherein solvent control group, MBM-
17S groups and MBM-55S groups administration number of times are for twice a day, irinotecan group is for biweekly.Administration is after measuring three-times-weekly
The tumor volume of mouse and body weight, common Ureteral Calculus 21 days.
The succinate MBM-17S (49.5%TGI) and MBM-55S (36.0%TGI) of compound MBM-17 and MBM-55
There is obvious tumor inhibitory effect, and without obvious toxic and side effects.Generally speaking compound MBM-17 and MBM-55 are mesh
The best compound of front known NEK2 inhibitory activity, at the same be also uniquely have internal antitumor activity compound, therefore it
With good oncotherapy potentiality, the exploitation for subsequent candidate medicine provides guidance and help.
Claims (10)
1. a kind of imidazo [1,2-a] pyridine compounds, it is characterised in that shown in its structure such as formula (1),
Wherein：
R1, R2, R3All it is hydrogen；Or one of them be hydrogen when, another two functional group be nitro, cyano group, methyl, halogen；Or wherein two
Individual for hydrogen when, another functional group be nitro, cyano group, methyl, halogen；
R4For hydrogen or methyl；
R5For piperidine ring, alkoxyl or heterocycle containing substituent group.
2. imidazo [1,2-a] pyridine compounds as claimed in claim 1, it is characterised in that imidazo [1,2-a] pyrrole
When acridine compound contains one or more chiral centres, it is corresponding corresponding isomer, non-corresponding isomers and raceme.
3. imidazo [1,2-a] pyridine compounds as claimed in claim 1, it is characterised in that the present invention includes involved
A kind of various salt corresponding to imidazo [1,2-a] pyridine compounds.
4. imidazo [1,2-a] pyridine compounds as claimed in claim 1, it is characterised in that the R5It is selected from：
5. a kind of imidazo [1,2-a] pyridine compounds, it is characterised in that shown in its structure such as formula (I)～(III),
Wherein：
In formula (I), R6For hydrogen, methyl, or tertbutyloxycarbonyl；R7For hydrogen or methyl；
In formula (II), R8And R9For hydrogen or methyl；
In formula (III), R10, R11, R12All be hydrogen, or one of them be when being hydrogen, another two functional group be nitro, cyano group, methyl,
Halogen；R13For hydrogen or methyl.
6. by imidazo [1,2-a] pyridine compounds shown in the formula (1) as described in any one such as Claims 1 to 5 in vitro
As the application in NEK2 inhibitor.
7. prepared by imidazo [1,2-a] pyridine compounds shown in the formula (1) as described in any one such as Claims 1 to 5
Application in NEK2 inhibitor.
8. by imidazo [1,2-a] pyridine compounds shown in the formula (1) as described in any one such as Claims 1 to 5 in vitro
Suppress the application in activity of tumor cells.
9. prepared by imidazo [1,2-a] pyridine compounds shown in the formula (1) as described in any one such as Claims 1 to 5
In the medicine of the stopping of inducing tumor cell cycle, inducing apoptosis of tumour cell and suppression tumor cell proliferation and tumour growth
Application.
10. will apply as claimed in claim 8 or 9, it is characterised in that the tumor is gastric cancer, colon cancer, B cell lymph
Tumor, cancer of pancreas, breast carcinoma or hepatocarcinoma.
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| WO2019238424A1 (en) * | 2018-06-15 | 2019-12-19 | Galapagos Nv | Novel compounds and pharmaceutical compositions thereof for the treatment of diseases |
| CN114702501A (en) * | 2022-04-27 | 2022-07-05 | 中山大学 | Imidazole peptide deformylase inhibitor with anti-tumor effect |
| WO2023066204A1 (en) * | 2021-10-18 | 2023-04-27 | 上海美悦生物科技发展有限公司 | Sik inhibitor, composition thereof, preparation method therefor, and use thereof |
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Cited By (8)
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|---|---|---|---|---|
| WO2019238424A1 (en) * | 2018-06-15 | 2019-12-19 | Galapagos Nv | Novel compounds and pharmaceutical compositions thereof for the treatment of diseases |
| CN112292129A (en) * | 2018-06-15 | 2021-01-29 | 加拉帕戈斯股份有限公司 | Novel compounds and pharmaceutical compositions thereof for the treatment of diseases |
| JP7399116B2 (en) | 2018-06-15 | 2023-12-15 | ガラパゴス・ナムローゼ・フェンノートシャップ | Novel compounds and pharmaceutical compositions thereof for the treatment of diseases |
| CN112292129B (en) * | 2018-06-15 | 2024-04-19 | 加拉帕戈斯股份有限公司 | Novel compounds and pharmaceutical compositions thereof for the treatment of diseases |
| CN110003202A (en) * | 2019-03-25 | 2019-07-12 | 华东师范大学 | The preparation method and application of imidazo [1,2-a] pyridine derivatives |
| WO2023066204A1 (en) * | 2021-10-18 | 2023-04-27 | 上海美悦生物科技发展有限公司 | Sik inhibitor, composition thereof, preparation method therefor, and use thereof |
| CN114702501A (en) * | 2022-04-27 | 2022-07-05 | 中山大学 | Imidazole peptide deformylase inhibitor with anti-tumor effect |
| CN114702501B (en) * | 2022-04-27 | 2023-10-17 | 中山大学 | Imidazole peptide deformylase inhibitor with anti-tumor effect |
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