CN116239594B - 6- (imidazo [1,2-a ] pyridin-6-yl) quinazoline derivatives and uses thereof - Google Patents
6- (imidazo [1,2-a ] pyridin-6-yl) quinazoline derivatives and uses thereof Download PDFInfo
- Publication number
- CN116239594B CN116239594B CN202310199761.3A CN202310199761A CN116239594B CN 116239594 B CN116239594 B CN 116239594B CN 202310199761 A CN202310199761 A CN 202310199761A CN 116239594 B CN116239594 B CN 116239594B
- Authority
- CN
- China
- Prior art keywords
- quinazolin
- amine
- imidazo
- pyridin
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 6- (imidazo [1,2-a ] pyridin-6-yl) quinazoline derivatives Chemical class 0.000 title claims description 142
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000004547 quinazolin-6-yl group Chemical group N1=CN=CC2=CC(=CC=C12)* 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 2
- VWOXYENNPRDCGO-UHFFFAOYSA-N methyl imidazo[1,2-a]pyridine-2-carboxylate Chemical compound C1=CC=CC2=NC(C(=O)OC)=CN21 VWOXYENNPRDCGO-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 24
- 238000000034 method Methods 0.000 abstract description 19
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 11
- 206010028980 Neoplasm Diseases 0.000 abstract description 9
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- 208000002154 non-small cell lung carcinoma Diseases 0.000 abstract description 6
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 abstract description 6
- 230000006907 apoptotic process Effects 0.000 abstract description 4
- 201000011510 cancer Diseases 0.000 abstract description 4
- 210000004881 tumor cell Anatomy 0.000 abstract description 4
- 206010006187 Breast cancer Diseases 0.000 abstract description 3
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 3
- 150000003246 quinazolines Chemical class 0.000 abstract description 3
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 abstract description 2
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 abstract description 2
- 208000036566 Erythroleukaemia Diseases 0.000 abstract description 2
- 206010029260 Neuroblastoma Diseases 0.000 abstract description 2
- 208000021841 acute erythroid leukemia Diseases 0.000 abstract description 2
- 230000004614 tumor growth Effects 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 97
- 239000007787 solid Substances 0.000 description 55
- BDAIUOPDSRAOKI-UHFFFAOYSA-N 4-chloro-6-iodoquinazoline Chemical compound C1=C(I)C=C2C(Cl)=NC=NC2=C1 BDAIUOPDSRAOKI-UHFFFAOYSA-N 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- 238000002844 melting Methods 0.000 description 23
- 230000008018 melting Effects 0.000 description 23
- 239000011734 sodium Substances 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 102000038030 PI3Ks Human genes 0.000 description 12
- 108091007960 PI3Ks Proteins 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 108091005625 BRD4 Proteins 0.000 description 7
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- YUEFBUYEPRXDBB-UHFFFAOYSA-N 6-iodoquinazolin-4-amine Chemical class C1=C(I)C=C2C(N)=NC=NC2=C1 YUEFBUYEPRXDBB-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 230000001028 anti-proliverative effect Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 102000020233 phosphotransferase Human genes 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000011161 development Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- WQLJLPDGSLZYEP-UHFFFAOYSA-M imidazo[1,2-a]pyridine-2-carboxylate Chemical compound C1=CC=CC2=NC(C(=O)[O-])=CN21 WQLJLPDGSLZYEP-UHFFFAOYSA-M 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- AYJDUJFYKLQVMB-UHFFFAOYSA-N C1(C=CC=C1)[Fe]C1C=CC=C1.C1(=CC=CC=C1)PC1=CC=CC=C1 Chemical compound C1(C=CC=C1)[Fe]C1C=CC=C1.C1(=CC=CC=C1)PC1=CC=CC=C1 AYJDUJFYKLQVMB-UHFFFAOYSA-N 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BJHWZAMXHDRJAG-UHFFFAOYSA-N FC=1C=C(C=CC=1)NC1=NC=NC2=CC=C(C=C12)I Chemical compound FC=1C=C(C=CC=1)NC1=NC=NC2=CC=C(C=C12)I BJHWZAMXHDRJAG-UHFFFAOYSA-N 0.000 description 2
- 108010040476 FITC-annexin A5 Proteins 0.000 description 2
- 230000004668 G2/M phase Effects 0.000 description 2
- 239000012828 PI3K inhibitor Substances 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- 108091008611 Protein Kinase B Proteins 0.000 description 2
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 150000005232 imidazopyridines Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- MQONVZMIFQQQHA-UHFFFAOYSA-N methyl 3-bromo-2-oxopropanoate Chemical compound COC(=O)C(=O)CBr MQONVZMIFQQQHA-UHFFFAOYSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- NPJBPJIQMCHZLJ-UHFFFAOYSA-N (6-aminopyridin-3-yl)boronic acid Chemical class NC1=CC=C(B(O)O)C=N1 NPJBPJIQMCHZLJ-UHFFFAOYSA-N 0.000 description 1
- ZNEHIDGAPGVZSA-UHFFFAOYSA-N 1,2-difluoro-3-methylbenzene Chemical compound CC1=CC=CC(F)=C1F ZNEHIDGAPGVZSA-UHFFFAOYSA-N 0.000 description 1
- LMWWLNKVUIHGBR-UHFFFAOYSA-N 1-ethyl-2-fluorobenzene Chemical compound CCC1=CC=CC=C1F LMWWLNKVUIHGBR-UHFFFAOYSA-N 0.000 description 1
- BTQZKHUEUDPRST-UHFFFAOYSA-N 1-fluoro-3-methylbenzene Chemical compound CC1=CC=CC(F)=C1 BTQZKHUEUDPRST-UHFFFAOYSA-N 0.000 description 1
- WRWPPGUCZBJXKX-UHFFFAOYSA-N 1-fluoro-4-methylbenzene Chemical compound CC1=CC=C(F)C=C1 WRWPPGUCZBJXKX-UHFFFAOYSA-N 0.000 description 1
- NRGGMCIBEHEAIL-UHFFFAOYSA-N 2-ethylpyridine Chemical compound CCC1=CC=CC=N1 NRGGMCIBEHEAIL-UHFFFAOYSA-N 0.000 description 1
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- ZCUJYXPAKHMBAZ-UHFFFAOYSA-N 2-phenyl-1h-imidazole Chemical compound C1=CNC(C=2C=CC=CC=2)=N1 ZCUJYXPAKHMBAZ-UHFFFAOYSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- CAARDVKATXZGKP-UHFFFAOYSA-N 4-ethyloxane Chemical compound CCC1CCOCC1 CAARDVKATXZGKP-UHFFFAOYSA-N 0.000 description 1
- XKVUYEYANWFIJX-UHFFFAOYSA-N 5-methyl-1h-pyrazole Chemical compound CC1=CC=NN1 XKVUYEYANWFIJX-UHFFFAOYSA-N 0.000 description 1
- PUGXMZKDRVGIHC-UHFFFAOYSA-N 6-iodo-1h-quinazolin-4-one Chemical compound N1C=NC(=O)C2=CC(I)=CC=C21 PUGXMZKDRVGIHC-UHFFFAOYSA-N 0.000 description 1
- 108090000672 Annexin A5 Proteins 0.000 description 1
- 102000001805 Bromodomains Human genes 0.000 description 1
- 108050009021 Bromodomains Proteins 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 230000037059 G2/M phase arrest Effects 0.000 description 1
- 102000001267 GSK3 Human genes 0.000 description 1
- 108060006662 GSK3 Proteins 0.000 description 1
- 101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 description 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- 229940124607 PI3Kα inhibitor Drugs 0.000 description 1
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 1
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 102100038332 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Human genes 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 108091005646 acetylated proteins Proteins 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- VQFAIAKCILWQPZ-UHFFFAOYSA-N bromoacetone Chemical class CC(=O)CBr VQFAIAKCILWQPZ-UHFFFAOYSA-N 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- FOTXAJDDGPYIFU-UHFFFAOYSA-N ethylcyclopropane Chemical compound CCC1CC1 FOTXAJDDGPYIFU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 210000004024 hepatic stellate cell Anatomy 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- VNXBKJFUJUWOCW-UHFFFAOYSA-N methylcyclopropane Chemical compound CC1CC1 VNXBKJFUJUWOCW-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- NFVJNJQRWPQVOA-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-2-[3-(4-ethyl-5-ethylsulfanyl-1,2,4-triazol-3-yl)piperidin-1-yl]acetamide Chemical compound CCN1C(SCC)=NN=C1C1CN(CC(=O)NC=2C(=CC=C(C=2)C(F)(F)F)Cl)CCC1 NFVJNJQRWPQVOA-UHFFFAOYSA-N 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical class CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000009452 underexpressoin Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a structural general formula (I) 6- (imidazo [1, 2-a)]Pyridin-6-yl) quinazolines wherein R 1 、R 2 、R 3 Pharmaceutical compositions, methods of making, and methods of using the compounds defined below as active ingredients. The invention provides an antitumor compound which has the activity of inhibiting human non-small cell lung cancer, human erythroleukemia, human neuroblastoma and human breast cancer, and can inhibit the growth of tumor cells, block the cycle and induce the apoptosis of cancer cells.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a 6- (imidazo [1,2-a ] pyridine-6-yl) quinazoline derivative, a preparation method and application of the 6- (imidazo [1,2-a ] pyridine-6-yl) quinazoline derivative in preparation of antitumor drugs.
Background
Phosphatidylinositol 3-kinase (PI 3K) is a lipid kinase that plays a key regulatory role in a variety of physiological processes such as cell growth, proliferation, survival and metabolism. PI3 ks are generally classified into three classes (class I, class II and class III). Pi3kα belongs to class I and mainly comprises one regulatory subunit (p 85) and one catalytic subunit (p 110). Mutation of PIK3CA, the coding gene for pi3kα, is one of the most common mutations in tumors, leading to under-expression or disappearance of PTEN and excessive activation of PI3K downstream signaling pathways. Inhibitors against PI3 ks have attracted considerable attention due to the key role of PI3K signaling in tumorigenesis, development and drug resistance. Currently, tens of subtype selective and pan PI3K inhibitors are in different stages of clinical research for the treatment of human malignancies. However, since the expression of pi3kα, pi3kβ, pi3kδ and pi3kγ in normal tissues and immune cells is ubiquitous, there remains a need to develop selective PI3K inhibitors to reduce toxicity. BRD4 is an important member of the nuclear transcription factor family of bromodomain proteins, and BRD4 participates in cell cycle regulation by binding to acetylated proteins, regulates DNA replication, gene transcription, plays an important role in differentiation and development, and is closely related to the occurrence of many tumors. Given its important role in tumors, BRD4 makes it one of the targets for cancer treatment. Single-target inhibitors are often associated with resistance, low drug screening efficiency and poor prognosis, and many neoplastic diseases are incurable with a single target. However, drugs that interfere with dual targets simultaneously can act on multiple pathological links and pathogenesis of the same disease, producing synergistic effects, and can improve clinical efficacy. Therefore, the development of the targeting drugs has become a new research hotspot of anti-tumor drugs.
The quinazoline compounds are nitrogen-containing heterocyclic compounds with good biological activity, and have various pharmacological and biological activities, such as anti-inflammatory, antibacterial, anti-tuberculosis, anti-diabetes, anti-HIV and anti-cancer effects. Of the quinazoline compounds, 4-arylamine quinazoline exhibits excellent activity in the anticancer field. The imidazopyridine compounds are very important nitrogen-containing condensed heterocyclic compounds, and many imidazopyridine compounds have antibacterial, antiviral, antimicrobial, antitumor and other activities, so that the imidazopyridine has attracted wide attention due to the effect of effectively inhibiting the growth of cancer cells. At present, no related research and report on the synthesis of 6- (imidazo [1,2-a ] pyridin-6-yl) quinazoline derivatives and related antitumor application thereof exist.
Disclosure of Invention
The invention aims to provide a 6- (imidazo [1,2-a ] pyridine-6-yl) quinazoline derivative and application of the derivative in anti-tumor effect.
In order to achieve the above purpose, the invention adopts the following technical scheme: 6- (imidazo [1,2-a ] pyridin-6-yl) quinazoline compounds of general formula (I)
Wherein R is 1 Selected from H, methyl or ethyl;
R 2 selected from ethylcyclopropane, 2-ethylpyridine, 1-ethyl-2-fluorobenzene, 1-fluoro-3-methylbenzene, 1, 2-difluoro-3-methylbenzene, 3-methyl-1H-pyrazole, 4-ethyltetrahydro-2H-pyran, p-xylene or toluene;
R 3 selected from ethyl acetate, methyl acetate, toluene, 1-fluoro-4-methylbenzene or methylcyclopropane.
Further, the compounds include analogs, pharmaceutically acceptable salts, stereoisomers, and/or solvates.
Further, the compound is selected from the following:
(A1) 6- (4- ((cyclopropylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester
(A2) 6- (4- ((pyridin-2-ylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester
(A3) 6- (4- ((2-Fluorobenzyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester
(A4) 6- (4- ((3-fluorophenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester
(A5) 6- (4- ((2, 3-difluorophenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester
(A6) 6- (4- (Ethyl (phenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester
(A7) 6- (4- ((pyridin-2-ylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid methyl ester
(A8) 6- (4- ((2-Fluorobenzyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid methyl ester
(A9) 6- (4- ((3-fluorophenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid methyl ester
(A10) Methyl 6- (4- (methyl (p-toluene) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate (A11) methyl 6- (4- ((cyclopropylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate (A12) N- (2-fluorobenzyl) -6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine
(A13) N- (2-fluorobenzyl) -6- (2- (4-fluorophenyl) imidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine
(A14) N- (2, 3-difluorophenyl) -6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine
(A15) N- (2, 3-difluorophenyl) -6- (2- (4-fluorophenyl) imidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine
(A16) N- (cyclopropylmethyl) -6- (2- (4-fluorophenyl) imidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine
(A17) 6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) -N- (1H-pyrazol-3-yl) quinazolin-4-amine
(A18) 6- (2-Cyclopropylimidazo [1,2-a ] pyridin-6-yl) -N- (cyclopropylmethyl) quinazolin-4-amine (A19) 6- (2-Cyclopropylimidazo [1,2-a ] pyridin-6-yl) -N-ethyl-N-phenylquinazolin-4-amine
(A20) N-ethyl-N-phenyl-6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine
(A21) 6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) -N- (pyridin-2-ylmethyl) quinazolin-4-amine
(A22) 6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) -N- ((tetrahydropyran-4-yl) methyl) quinazolin-4-amine
(A23) N- (cyclopropylmethyl) -6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine.
A method for synthesizing the end products A1-A11 in the general formula (I) comprises the following steps:
(1) Preparation of 4-chloro-6-iodoquinazoline intermediate: preparing a 4-chloro-6-iodoquinazoline intermediate by chlorating raw materials of iodoquinazoline-4 (3H) -ketone, N-diisopropylethylamine and phosphorus oxychloride under the condition that a solvent is anhydrous toluene;
(2) Preparation of differently substituted 6-iodoquinazolin-4-amine intermediates: preparing intermediates of different substituted 6-iodoquinazolin-4-amine by taking 4-chloro-6-iodoquinazolin and different primary amine or secondary amine as raw materials and isopropanol as a solvent;
(3) Takes 6-iodoquinazolin-4-amine, 2-aminopyridine-5-boric acid, pinacol ester and potassium carbonate which are substituted differently as raw materials, V (1, 4-Dioxahexacyclic ring) :V (H2O) =4:1 as solvent, 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride as catalyst to prepare differently substituted 6- (6-aminopyridin-3-yl) quinazolin-4-amine intermediates;
(4) Preparing end products A1-A11 by adding absolute ethyl alcohol into differently substituted 6- (6-aminopyridin-3-yl) quinazoline-4-amine intermediates, methyl bromopyruvate/ethyl bromopyruvate and sodium bicarbonate;
a method for synthesizing the end product A12-A23 in the general formula (I) comprises the following steps:
(1) Preparation of 4-chloro-6-iodoquinazoline intermediate: preparing a 4-chloro-6-iodoquinazoline intermediate by chlorating raw materials of iodoquinazoline-4 (3H) -ketone, N-diisopropylethylamine and phosphorus oxychloride under the condition that a solvent is anhydrous toluene;
(2) Preparation of differently substituted 6-iodoquinazolin-4-amine intermediates: preparing intermediates of different substituted 6-iodoquinazolin-4-amine by taking 4-chloro-6-iodoquinazolin and different primary amine or secondary amine as raw materials and isopropanol as a solvent;
(3) Different substituted 2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) imidazo [1,2-a ] pyridine intermediates were prepared from different substituted bromoacetones, 2-aminopyridine-5-boronic acid, pinacol esters, and sodium bicarbonate in anhydrous ethanol.
(4) 2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) imidazo [1,2-a ] with different substitutions]Pyridine, different substituted 6-iodoquinazolin-4-amine and potassium carbonate are used as raw materials, V (1, 4-Dioxahexacyclic ring) :V (H2O) =4:1 as solvent, 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride as catalyst to prepare the final product a23-a34;
the beneficial technical effects of the invention are as follows: the invention provides an antitumor compound which has the activity of inhibiting human non-small cell lung cancer, human erythroleukemia, human neuroblastoma and human breast cancer, and can inhibit the growth of tumor cells, block the cycle and induce the apoptosis of cancer cells.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions of the prior art, the drawings which are used in the description of the embodiments or the prior art will be briefly described, it being obvious that the drawings in the description below are only some embodiments of the invention, and that other drawings can be obtained according to these drawings without inventive faculty for a person skilled in the art.
FIG. 1 is a graph showing the effect of compound A22 of the present invention on PI3K signaling pathway in HCC827 (human non-small cell lung cancer cell);
FIG. 2 is a graph showing the G2/M results of the compound A22 of the present invention for inducing HCC827 cells;
fig. 3 is the induction of apoptosis of HCC827 cells by compound a22 of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The synthesis of ethyl 6- (4- ((cyclopropylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate (compound No. A1) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
A mixture of 6-iodoquinazolin-4 (3H) -one (2.45 g,9 mmol), N-diisopropylethylamine (2.33 g,18 mmol), phosphorus oxychloride (2.76 g,18 mmol) and anhydrous toluene (50 mL) was weighed and reacted under argon at 80℃for 4 hours. After completion of the reaction monitored by TLC, the reaction mixture was cooled and the solvent was removed under reduced pressure. The mixture was extracted 2-3 times with ethyl acetate and saturated sodium bicarbonate solution. Organic compoundAnhydrous Na for phase 2 SO 4 Drying, filtering, vacuum spin drying, and separating and purifying [ V ] by chromatography column chromatography (Ethyl acetate) ：V (Petroleum ether) ＝100：1]A white solid was obtained, 2.29g, yield 58.6%.
(2) N- (cyclopropylmethyl) -6-iodoquinazolin-4-amine
A mixture of 4-chloro-6-iodoquinazoline (0.58 g,2 mmol) and cyclopropylmethylamine (0.17 g,2.4 mmol) was added to isopropanol (10 ml) and refluxed at 60℃for 2 hours under argon. After the reaction was completed, the solvent of the reaction mixture was removed under reduced pressure, and ethyl acetate and saturated Na were used 2 CO 3 The solution is extracted for 2 to 3 times. Anhydrous Na for organic phase 2 SO 4 The mixture was dried over, filtered and spun-dried in vacuo to give N- (cyclopropylmethyl) -6-iodoquinazolin-4-amine as an off-white solid (0.593 g, 1.284 mmol) in 91.2% yield.
(3) Preparation of 6- (6-aminopyridin-3-yl) -N- (cyclopropylmethyl) quinazolin-4-amine
N- (cyclopropylmethyl) -6-iodoquinazolin-4-amine (0.5 g,1.5 mmol), 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (0.34 g,1.5 mmol) and K 2 CO 3 (0.64 g,4.6 mmol) to 15ml of 1, 4-dioxane/water [ V (1, 4-Dioxahexacyclic ring) ：V (Water) ＝4:1]In the process, the mixture is heated to 100 ℃ under the protection of argon, and then Pd (dppf) Cl is added 2 . The mixture was stirred under these conditions for a further 4-6 hours. After the reaction is completed, the 1, 4-dioxane and water are removed under reduced pressure, and the [ V ] is separated and purified by chromatography column chromatography (dichloromethane) ：V (methanol) ＝33：1]6- (6-Aminopyridin-3-yl) -N- (4-methoxybenzyl) quinazolin-4-amine was obtained as a white solid (0.315 g,1.08 mmol) in 72.1% yield.
(4) Preparation procedure of ethyl 6- (4- ((cyclopropylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate
6- (6-Aminopyridin-3-yl) -N- (4-methoxybenzyl) quinazolin-4-amine (0.17 g,0.58 mmol), ethyl bromopyruvate (0.34 g,1.75 mmol) and NaHCO 3 (0.15 g,1.75 mmol) was added to EtOH (5 ml) and the mixture was heated to 80℃and condensed under argon reflux for 4 hours. ReactionAfter completion, the solvent was removed under reduced pressure, and [ V ] was purified by column chromatography (dichloromethane) ：V (methanol) ＝50：1]Obtaining 6- (4- ((4-methoxybenzyl) amino) quinazolin-6-yl) imidazo [1,2-a]Pyridine-2-carboxylic acid ethyl ester as white solid (0.112 g,0.289 mmol) yield 49.8%, melting point 128.5-130.8 ℃, HRMS (ESI): [ M+H ]] + 388.1760；[M+Na] + 410.1580。
Example 2
The synthesis of ethyl 6- (4- ((pyridin-2-ylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate (compound No. A2) comprises the following steps:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of 6-iodo-N- (pyridin-2-ylmethyl) quinazolin-4-amine
As in step (2) of example 1, a pale yellow solid was obtained in 92.1% yield.
(3) Preparation of 6- (6-aminopyridin-3-yl) -N- (pyridin-2-ylmethyl) quinazolin-4-amine
As in step (3) of example 1, yellow solid, 70.6% yield.
(4) Preparation of ethyl 6- (4- ((pyridin-2-ylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate
As in example 1, step (4) was a yellow solid in 57.3% yield, melting point 129.6-131.5℃HRMS (ESI): [ M+H ]] + 425.1712；[M+Na] + 447.1532。
Example 3
The synthesis of ethyl 6- (4- ((2-fluorobenzyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate (compound number A3) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N- (2-fluorobenzyl) -6-iodoquinazolin-4-amine
As in step (2) of example 1, an off-white solid was obtained in 61.9% yield.
(3) Preparation of 6- (6-aminopyridin-3-yl) -N- (2-fluorobenzyl) quinazolin-4-amine
As in step (3) of example 1, an off-white solid, 86.3% yield.
(4) Preparation of ethyl 6- (4- ((2-fluorobenzyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate
As in step (4) of example 1, the product was an off-white solid in 59.2% yield, melting point 142.3-144.6℃and HRMS (ESI): [ M+H ]] + 442.1664；[M+Na] + 464.1486。
Example 4
The synthesis of ethyl 6- (4- ((3-fluorophenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate (compound No. A4) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N- (3-fluorophenyl) -6-iodoquinazolin-4-amine
As in step (2) of example 1, light yellow solid was obtained in 85.3% yield.
(3) Preparation of 6- (6-aminopyridin-3-yl) -N- (3-fluorophenyl) quinazolin-4-amine
As in step (3) of example 1, light yellow solid, 77.6% yield.
(4) Preparation of ethyl 6- (4- ((3-fluorophenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate
As in example 1, step (4) was a yellow solid in 46.7% yield, melting point 148.3-150.1 ℃, HRMS (ESI): [ M+Na ]] + 450.1328。
Example 5
The synthesis of ethyl 6- (4- ((2, 3-difluorophenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate (compound No. A5) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N- (2, 3-difluorophenyl) -6-iodoquinazolin-4-amine
As in step (2) of example 1, an off-white solid was obtained in 93.6% yield.
(3) Preparation of 6- (6-aminopyridin-3-yl) -N- (2, 3-difluorophenyl) quinazolin-4-amine
As in step (3) of example 1, a white solid, 88.7% yield.
(4) Preparation of ethyl 6- (4- ((2, 3-difluorophenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate
As in step (4) of example 1, the product was a white solid with a yield of 55.3%, a melting point of 131.2-133.6℃and an HRMS (ESI): [ M+H ]] + found 446.1411；[M+Na] + 468.1231。
Example 6
The synthesis of ethyl 6- (4- (ethyl (phenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate (compound No. A6) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N-ethyl-6-iodo-N-phenylquinazolin-4-amine
As in step (2) of example 1, a pale yellow solid was obtained in 95.7% yield.
(3) Preparation of 6- (6-aminopyridin-3-yl) -N-ethyl-N-phenylquinazolin-4-amine
As in step (3) of example 1, a yellow solid was obtained in 75.7% yield.
(4) Preparation of ethyl 6- (4- (ethyl (phenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate
As in example 1, step (4), was a pink floccule, yield 63.1%, melting point 176.7-177.8deg.C, HRMS (ESI): [ M+H ]] + found 438.1916；[M+Na] + 460.1735。
Example 7
The synthesis of methyl 6- (4- ((pyridin-2-ylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate (compound No. A7) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of 6-iodo-N- (pyridin-2-ylmethyl) quinazolin-4-amine
As in step (2) of example 1, a pale yellow solid was obtained in 92.1% yield.
(3) Preparation of 6- (6-aminopyridin-3-yl) -N- (pyridin-2-ylmethyl) quinazolin-4-amine
As in step (3) of example 1, yellow solid, 70.6% yield.
(4) Preparation of methyl 6- (4- ((pyridin-2-ylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate
6- (6-Aminopyridin-3-yl) -N- (pyridin-2-ylmethyl) quinazolin-4-amine (0.18 g,0.55 mmol), methyl bromopyruvate (0.298 g,1.6 mmol) and NaHCO were weighed out 3 (0.138 g,1.6 mmol) was added to EtOH (5 ml) and the mixture was heated to 80℃and condensed under argon reflux for 4 hours. After the completion of the reaction, the solvent was removed under reduced pressure, and [ V ] was purified by column chromatography (dichloromethane) ：V (methanol) ＝50：1]Obtaining 6- (4- ((pyridin-2-ylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a]Pyridine-2-carboxylic acid methyl ester as yellow solid (0.1215 g, 0.292 mmol), yield 53.8%, melting point 143.7-145.6deg.C, HRMS (ESI): [ M+H ]] + 411.1556；[M+Na] + 433.1372。
Example 8
The synthesis of methyl 6- (4- ((2-fluorobenzyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate (compound number A8) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N- (2-fluorobenzyl) -6-iodoquinazolin-4-amine
As in step (2) of example 1, an off-white solid was obtained in 61.9% yield.
(3) Preparation of 6- (6-aminopyridin-3-yl) -N- (2-fluorobenzyl) quinazolin-4-amine
As in step (3) of example 1, an off-white solid, 86.3% yield.
(4) Preparation of methyl 6- (4- ((2-fluorobenzyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate
As in example 7, step (4) was an off-white solid, 52.1% yield, melting point 174.0-176.2 ℃, HRMS (ESI): [ M+H ]] + 428.1509；[M+Na] + 450.1330。
Example 9
The synthesis of methyl 6- (4- ((3-fluorophenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate (compound No. A9) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N- (3-fluorophenyl) -6-iodoquinazolin-4-amine
As in step (2) of example 1, light yellow solid was obtained in 85.3% yield.
(3) Preparation of 6- (6-aminopyridin-3-yl) -N- (3-fluorophenyl) quinazolin-4-amine
As in step (3) of example 1, light yellow solid, 77.6% yield.
(4) Preparation of methyl 6- (4- ((3-fluorophenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate
As in example 7, step (4) was an off-white solid, 52.1% yield, melting point 174.0-176.2 ℃, HRMS (ESI): [ M+H ]] + 414.1347；[M+Na] + 436.1172。
Example 10
The synthesis of methyl 6- (4- (methyl (p-toluene) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate (compound No. a 10) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of 6-iodo-N-methyl-N- (p-tolyl) quinazolin-4-amine
As in step (2) of example 1, a pale yellow solid was obtained in 94.0% yield.
(3) Preparation of 6- (6-aminopyridin-3-yl) -N-methyl-N- (p-tolyl) quinazolin-4-amine
As in step (3) of example 1, a pale yellow solid was obtained in 79.8% yield.
(4) Preparation of methyl 6- (4- (methyl (p-toluene) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate
As in example 7, step (4), 39.5% yield of pink floc, melting point 172.8-174.3 ℃, HRMS (ESI): M+H] + 424.1757；[M+Na] + 446.1580。
Example 11
The synthesis of methyl 6- (4- ((cyclopropylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate (compound No. a 11) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N- (cyclopropylmethyl) -6-iodoquinazolin-4-amine
As in example 1, step (2) was an off-white solid in 91.2% yield.
(3) Preparation of 6- (6-aminopyridin-3-yl) -N- (cyclopropylmethyl) quinazolin-4-amine
As in example 1, step (3) was an off-white solid in 71.2% yield.
(4) Preparation of methyl 6- (4- ((cyclopropylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylate
As in example 7, step (4), was an orange floc, yield 30.1%, melting point 164.6-166.9 ℃, HRMS (ESI): [ M+H ]] + 374.1612；[M+Na] + 396.1431。
Example 12
The synthesis of N- (2-fluorobenzyl) -6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine (compound No. a 12) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N- (2-fluorobenzyl) -6-iodoquinazolin-4-amine
As in step (2) of example 1, an off-white solid was obtained in 61.9% yield.
(3) Preparation of 2-phenyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) imidazo [1,2-a ] pyridine
Weighing 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (1.2 g,5.4 mmol), 2-bromo-1-acetophenone (1.3 g,6.5 mmol) and NaHCO 3 (1.4 g,16 mmol) was added to absolute ethanol (10 ml) and the mixture was heated to 80℃and condensed under argon reflux for 4 hours. After the reaction was completed, the solvent was removed under reduced pressure, and ethyl acetate and saturated Na were used 2 CO 3 The mixture was extracted 2-3 times with the solution. Organic compoundAnhydrous Na for phase 2 SO 4 Drying, filtering and spin-drying under vacuum to obtain 2-phenyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) imidazole [1,2-a ]]Pyridine was a pale yellow oily substance in 86.8% yield.
(4) Preparation of N- (2-fluorobenzyl) -6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine
N- (2-Fluorobenzyl) -6-iodoquinazolin-4-amine (0.19 g,0.5 mmol) was weighed out, 2-phenyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) imidazole [1,2-a ]]Pyridine (0.16 g,0.5 mmol) and K 2 CO 3 (0.21 g,1.5 mmol) was added to 10ml 1, 4-dioxane/water [ V (1, 4-Dioxahexacyclic ring) ：V (Water) ＝4:1]In the process, the mixture is heated to 100 ℃ under the protection of argon, pd (dppf) Cl is added 2 . The mixture was continued to react for 4-5 hours. After the reaction is completed, the solvent is removed under reduced pressure, and the [ V ] is separated and purified by chromatography column chromatography (dichloromethane) ：V (methanol) ＝80：1]To obtain N- (2-fluorobenzyl) -6- (2-phenylimidazole [1, 2-a)]Pyridin-6-yl) quinazolin-4-amine as pink floc in 67.3% yield, melting point 130.8-132.2 ℃, HRMS (ESI): [ M+H ]] + 446.1768。
Example 13
The synthesis of N- (2-fluorobenzyl) -6- (2- (4-fluorophenyl) imidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine (compound No. a 13) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N- (2-fluorobenzyl) -6-iodoquinazolin-4-amine
As in step (2) of example 1, an off-white solid was obtained in 61.9% yield.
(3) Preparation of 2- (4-fluorophenyl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) imidazo [1,2-a ] pyridine
As in example 12, step (3), yellow solid was obtained in 81.5% yield.
(4) Preparation of N- (2-fluorobenzyl) -6- (2- (4-fluorophenyl) imidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine
Step (4) of the method as in example 12, a pink floccule, yield70.7% and melting point 133.7-135.6deg.C, HRMS (ESI): [ M+H ]] + 464.1677。
Example 14
The synthesis of N- (2, 3-difluorophenyl) -6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine (compound No. a 14) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N- (2, 3-difluorophenyl) -6-iodoquinazolin-4-amine
Step (2) as in example 1 was an off-white solid in 93.6% yield.
(3) Preparation procedure of 2-phenyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) imidazo [1,2-a ] pyridine
As in example 12, in the step (3), a pale yellow oily substance was obtained in 86.8% yield.
(4) Preparation of N- (2, 3-difluorophenyl) -6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine
As in example 12, step (4), in the form of pink floccule, yield 73.2%, melting point 142.0-144.3 ℃, HRMS (ESI): [ M+H ]] + 450.1520；[M+Na] + 472.1337。
Example 15
The synthesis of N- (2, 3-difluorophenyl) -6- (2- (4-fluorophenyl) imidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine (compound number a 15) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N- (2, 3-difluorophenyl) -6-iodoquinazolin-4-amine
Step (2) as in example 1 was an off-white solid in 93.6% yield.
(3) Preparation of 2- (4-fluorophenyl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) imidazo [1,2-a ] pyridine
As in example 12, step (3), yellow solid was obtained in 81.5% yield.
(4) Preparation of N- (2, 3-difluorophenyl) -6- (2- (4-fluorophenyl) imidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine
As in example 12, step (4), in the form of pink floc, yield 72.5%, melting point 136.1-138.2 ℃, HRMS (ESI): [ M+H ]] + 468.1426；[M+Na] + 490.1239。
Example 16
The synthesis of N- (cyclopropylmethyl) -6- (2- (4-fluorophenyl) imidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine (compound No. a 16) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N- (cyclopropylmethyl) -6-iodoquinazolin-4-amine
As in example 1, step (2) was an off-white solid in 91.2% yield.
(3) Preparation of 2- (4-fluorophenyl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) imidazo [1,2-a ] pyridine
As in example 12, step (3), yellow solid was obtained in 81.5% yield.
(4) Preparation of N- (cyclopropylmethyl) -6- (2- (4-fluorophenyl) imidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine
As in example 12, step (4), was a pink floccule, yield 56.1%, melting point 227.5-229.7 ℃, HRMS (ESI): [ M+H ]] + 410.1773。
Example 17
The synthesis of 6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) -N- (1H-pyrazol-3-yl) quinazolin-4-amine (compound No. a 17) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of 6-iodo-N- (1H-pyrazol-3-yl) quinazolin-4-amine
Step (2) as in example 1 was a white solid in 91.5% yield.
(3) Preparation procedure of 2-phenyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) imidazo [1,2-a ] pyridine
As in example 12, in the step (3), a pale yellow oily substance was obtained in 86.8% yield.
(4) Preparation of 6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) -N- (1H-pyrazol-3-yl) quinazolin-4-amine
As in example 12, step (4), as a pink solid, yield 54.6%, melting point 289.1-290.1 ℃, HRMS (ESI): [ M+H ]] + 404.1613；[M+Na] + 426.1426。
Example 18
The synthesis of 6- (2-cyclopropylimidazo [1,2-a ] pyridin-6-yl) -N- (cyclopropylmethyl) quinazolin-4-amine (compound No. a 18) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N- (cyclopropylmethyl) -6-iodoquinazolin-4-amine
As in example 1, step (2) was an off-white solid in 91.2% yield.
(3) Preparation procedure of 2-cyclopropyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) imidazo [1,2-a ] pyridine
As in example 12, step (3) was a yellow solid in 81.5% yield.
(4) Preparation of 6- (2-cyclopropylimidazo [1,2-a ] pyridin-6-yl) -N- (cyclopropylmethyl) quinazolin-4-amine
As in example 12, step (4) was a yellow solid in 60.6% yield, melting point 118.6-120.5℃HRMS (ESI): [ M+H ]] + 356.1863；[M+Na] + 378.1682。
Example 19
The synthesis of 6- (2-cyclopropylimidazo [1,2-a ] pyridin-6-yl) -N-ethyl-N-phenylquinazolin-4-amine (compound No. a 19) comprises the steps of:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N-ethyl-6-iodo-N-phenylquinazolin-4-amine
As in step (2) of example 1, a pale yellow solid was obtained in 95.7% yield.
(3) Preparation procedure of 2-cyclopropyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) imidazo [1,2-a ] pyridine
As in example 12, step (3) was a yellow solid in 81.5% yield.
(4) Preparation of 6- (2-cyclopropylimidazo [1,2-a ] pyridin-6-yl) -N-ethyl-N-phenylquinazolin-4-amine
As in example 12, step (4) was a yellow solid in 58.3% yield, melting point 166.8-168.7 ℃, HRMS (ESI): M+H] + 406.2019；[M+Na] + 428.1840。
Example 20
The synthesis of N-ethyl-N-phenyl-6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine (compound No. a 20) comprises the following steps:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N-ethyl-6-iodo-N-phenylquinazolin-4-amine
As in step (2) of example 1, a pale yellow solid was obtained in 95.7% yield.
(3) Preparation procedure of 2-phenyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) imidazo [1,2-a ] pyridine
As in example 12, in the step (3), a pale yellow oily substance was obtained in 86.8% yield.
(4) Preparation of N-ethyl-N-phenyl-6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine
As in example 12, step (4) was a pink solid in 67.4% yield, melting point 203.0-205.1℃HRMS (ESI): [ M+H ]] + 442.2021。
Example 21
The synthesis of 6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) -N- (pyridin-2-ylmethyl) quinazolin-4-amine (compound No. a 21) comprises the following steps:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of 6-iodo-N- (pyridin-2-ylmethyl) quinazolin-4-amine
As in step (2) of example 1, a pale yellow solid was obtained in 92.1% yield.
(3) Preparation procedure of 2-phenyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) imidazo [1,2-a ] pyridine
As in example 12, in the step (3), a pale yellow oily substance was obtained in 86.8% yield.
(4) Preparation of 6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) -N- (pyridin-2-ylmethyl) quinazolin-4-amine
As in example 12, step (4) was performed as a pink solid in 70.2% yield, melting point 141.9-143.3℃HRMS (ESI): [ M+H ]] + 429.1817。
Example 22
The synthesis of 6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) -N- ((tetrahydropyran-4-yl) methyl) quinazolin-4-amine (compound No. a 22) comprises the following steps:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of 6-iodo-N- ((tetrahydropyran-4-yl) methyl) quinazolin-4-amine
Step (2) as in example 1 was a white solid in 90.1% yield.
(3) Preparation procedure of 2-phenyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) imidazo [1,2-a ] pyridine
As in example 12, in the step (3), a pale yellow oily substance was obtained in 86.8% yield.
(4) Preparation of 6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) -N- ((tetrahydropyran-4-yl) methyl) quinazolin-4-amine
As in example 12, step (4), as a pink solid, yield 69.8%, melting point 127.0-129.3 ℃, HRMS (ESI): [ M+H ]] + 436.2126。
Example 23
The synthesis of N- (cyclopropylmethyl) -6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine (compound No. a 23) comprises the following steps:
(1) Preparation of 4-chloro-6-iodoquinazoline
Step (1) as in example 1.
(2) Preparation of N- (cyclopropylmethyl) -6-iodoquinazolin-4-amine
As in example 1, step (2) was an off-white solid in 91.2% yield.
(3) Preparation procedure of 2-phenyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) imidazo [1,2-a ] pyridine
As in example 12, in the step (3), a pale yellow oily substance was obtained in 86.8% yield.
(4) Preparation of N- (cyclopropylmethyl) -6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine
As in example 12, step (4) was performed as a white solid in 41.6% yield, melting point 137.1-139.0 ℃, HRMS (ESI): [ M+H ]] + 392.1870。
Table 1 shows the target compounds obtained in the above examples A1 to A23 1 H NMR data
/>
/>
Table 2 shows the target compounds obtained in the above examples A1 to A23 13 C NMR data
/>
/>
Biological experiments
1. Detection of tumor proliferation inhibitory Activity of inventive Compounds Using MTT method
The method comprises the following steps: in vitro culture of HCC827 (human non-small cell lung cancer cell), A549 (human non-small cell lung cancer cell), SH-SY5Y (human nerve)Blastoma cells), HEL (human erythrocytes and leucocytes leukemia cells), MCF-7 (human breast cancer cells) and LX2 (human hepatic stellate cells), cells were isolated at 37℃with 5% CO 2 Culturing in incubator under the condition until logarithmic phase. The cells are inoculated in 96-well plates with the inoculation density of 3000-5000 cells per well and 100 mu L per well, then the cells are continuously cultured in a cell culture box for 24 hours, 100 mu L of medicine-containing culture medium is respectively added into each well, 3 compound wells are arranged at each concentration, and blank control wells are arranged at the same time. After further incubation for 72h, 20. Mu.L of 5 mg.mL was added -1 After continuous culture for 4 hours under the same conditions, the culture solution is discarded, 150 mu L of DMSO is added to each well to dissolve formazan, the plate shaker is vibrated for 10min, and the OD value at the wavelength of 490nm is measured in an enzyme-labeling instrument. Cell viability% = (OD Average value of samples /OD Average value of control ) X 100%. Inhibition% = 100-cell viability%. The results are shown in Table 3.
Table 3 shows the antiproliferative activity of the compounds of examples A1-A23 described above on tumor cells
Analysis according to the test results in table 3: (1) When esters are synthesized, the antiproliferative activity of methyl esters is generally higher than ethyl esters; (e.g., A9 and A4, A7 and A2, etc.); (2) When esters are synthesized and R2 is a benzene ring, the introduction of an electron withdrawing group (e.g., F) on the benzene ring helps to increase the antiproliferative activity of the compounds. (3) The antiproliferative activity is best when synthesizing amines, wherein the R3 substituent is benzene. And introducing electron withdrawing group F into benzene ring can reduce antiproliferative activity of the compound; (4) The synthesized amine compounds have better antiproliferative activity than ester compounds. Of these, representative compounds A1, A22 and A23 have strong antitumor effect, and they have IC against HCC827 50 The values were 78nM, 87nM and 39nM, respectively. The active compounds have good safety and are suitable for human liverIC of astrocytes 50 The value is significantly greater than the IC of the gene against tumor cells 50 Values.
2. Preferably, the activity of the active compound A22 on PI3K alpha kinase is detected.
To evaluate the in vitro kinase inhibitory activity of a22 on pi3kα, the kinase activity of pi3kα was tested using the ADP-GloTM Max assay, HS-173, a known pi3kα inhibitor as a positive control. As shown in Table 3, A22 significantly inhibited the kinase activity of PI3K alpha with an IC50 value of 1.94nM. This suggests that compound 13K may act as a potential inhibitor of PI3kα.
Table 4 shows the inhibitory activity (IC 50 nM) of the preferred active compounds A11, A22 and A23 against PI3K alpha kinase.
3. Preferably the influence of active compound A22 on the PI3K signaling pathway in HCC827 (human non-small cell lung cancer cell)
Abnormal expression of the PI3K signaling pathway is closely related to the process of tumorigenesis. Since 13K significantly inhibited PI3kα activity, we performed analysis by Westernblot in order to further verify whether 13K could modulate downstream targets by inhibiting PI3K/AKT pathways. As shown in fig. 1, the phosphorylation level of PI3K was significantly reduced in a dose-dependent manner after a22 treatment. The phosphorylation levels of the downstream proteins AKT, mTOR and GSK3 beta are correspondingly reduced. These results confirm the inhibitory effect of the compounds on PI3K pathway expression. In addition, BRD4 is a transcriptional regulator, playing a key role in the development of cancer and gene expression. Therefore, we also discuss the influence of the compounds on BRD4, and as shown in figure 1, A22 is found to obviously reduce the protein level of BRD4 and a downstream target point c-Myc thereof, which indicates that A22 inhibits the BRD4 to exert anti-tumor activity.
4. Preferably, active compound a22 induces G2/M phase retardation of HCC827 cells.
HCC827 cells were seeded in six well plates, treated with specific concentrations of compound a22 for 48 hours, collected and washed with PBS buffer, fixed overnight with pre-chilled 70% ethanol at-20 ℃, the supernatant discarded, washed with PBS buffer, stained with a mixture of Propidium Iodide (PI) and RNase, incubated at room temperature in the dark for 30 minutes, and then detected with a flow cytometer. The results show, as shown in figure 2, that cells had a significant G2/M phase arrest after 48 hours of compound treatment compared to the control group, with increasing concentrations, the percentage of cells in the G2/M phase gradually increasing from 20.84% -52.21%.
5. Preferably, active compound a22 induces apoptosis of HCC827 cells
Apoptosis was detected by flow cytometry after staining with annexin v-FITC and Propidium Iodide (PI). HCC827 cells were seeded in 6-well plates overnight and treated with compound a22 at a specific concentration for 48 hours. Cells were collected, incubated with 5. Mu.L of annexin V-FITC and 5. Mu.L of LPI for 15-20 minutes in the dark, and then analyzed by flow cytometry. The results show a dose-dependent increase in the number of early and late apoptotic cells induced by the compounds from 1.73% -37.61%, as shown in figure 3.
Finally, what should be said is: the above embodiments are only for illustrating the technical aspects of the present invention, and although the present invention has been described in detail with reference to the above embodiments, it should be understood by those skilled in the art that: modifications and equivalents may be made thereto without departing from the spirit and scope of the invention, which is intended to be encompassed by the claims.
Claims (3)
- A 6- (imidazo [1,2-a ] pyridin-6-yl) quinazoline compound, characterized in that said compound is selected from the group consisting of:(A1) 6- (4- ((cyclopropylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester(A2) 6- (4- ((pyridin-2-ylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester(A3) 6- (4- ((2-Fluorobenzyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester(A4) 6- (4- ((3-fluorophenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester(A5) 6- (4- ((2, 3-difluorophenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester(A6) 6- (4- (Ethyl (phenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester(A7) 6- (4- ((pyridin-2-ylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid methyl ester(A8) 6- (4- ((2-Fluorobenzyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid methyl ester(A9) 6- (4- ((3-fluorophenyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid methyl ester(A10) 6- (4- (methyl (p-toluene) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid methyl ester(A11) 6- (4- ((cyclopropylmethyl) amino) quinazolin-6-yl) imidazo [1,2-a ] pyridine-2-carboxylic acid methyl ester(A12) N- (2-fluorobenzyl) -6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine(A13) N- (2-fluorobenzyl) -6- (2- (4-fluorophenyl) imidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine(A14) N- (2, 3-difluorophenyl) -6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine(A15) N- (2, 3-difluorophenyl) -6- (2- (4-fluorophenyl) imidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine(A16) N- (cyclopropylmethyl) -6- (2- (4-fluorophenyl) imidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine(A17) 6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) -N- (1H-pyrazol-3-yl) quinazolin-4-amine(A18) 6- (2-Cyclopropylimidazo [1,2-a ] pyridin-6-yl) -N- (cyclopropylmethyl) quinazolin-4-amine(A19) 6- (2-Cyclopropylimidazo [1,2-a ] pyridin-6-yl) -N-ethyl-N-phenylquinazolin-4-amine(A20) N-ethyl-N-phenyl-6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine(A21) 6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) -N- (pyridin-2-ylmethyl) quinazolin-4-amine(A22) 6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) -N- ((tetrahydropyran-4-yl) methyl) quinazolin-4-amine(A23) N- (cyclopropylmethyl) -6- (2-phenylimidazo [1,2-a ] pyridin-6-yl) quinazolin-4-amine.
- 2. The compound of claim 1, wherein the compound comprises a pharmaceutically acceptable salt.
- 3. Use of a 6- (imidazo [1,2-a ] pyridin-6-yl) quinazoline compound according to any one of claims 1-2 for the manufacture of an anti-tumour medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310199761.3A CN116239594B (en) | 2023-03-05 | 2023-03-05 | 6- (imidazo [1,2-a ] pyridin-6-yl) quinazoline derivatives and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310199761.3A CN116239594B (en) | 2023-03-05 | 2023-03-05 | 6- (imidazo [1,2-a ] pyridin-6-yl) quinazoline derivatives and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116239594A CN116239594A (en) | 2023-06-09 |
| CN116239594B true CN116239594B (en) | 2023-09-22 |
Family
ID=86634760
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310199761.3A Active CN116239594B (en) | 2023-03-05 | 2023-03-05 | 6- (imidazo [1,2-a ] pyridin-6-yl) quinazoline derivatives and uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116239594B (en) |
Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008012326A1 (en) * | 2006-07-28 | 2008-01-31 | Novartis Ag | 2,4-substituted quinazolines as lipid kinase inhibitors |
| WO2008144463A1 (en) * | 2007-05-18 | 2008-11-27 | Smithkline Beecham Corporation | Quinoline derivatives as pi3 kinase inhibitors |
| WO2010059788A1 (en) * | 2008-11-20 | 2010-05-27 | Genentech, Inc. | Pyrazolopyridine pi3k inhibitor compounds and methods of use |
| CN103570709A (en) * | 2012-07-19 | 2014-02-12 | 中国科学院上海药物研究所 | Pyrazolopyridine compounds, preparation method, uses and drug composition thereof |
| CN105237484A (en) * | 2015-09-28 | 2016-01-13 | 西安交通大学 | 6-aryl substituted quinoline compounds and applications thereof |
| CN106432202A (en) * | 2016-09-22 | 2017-02-22 | 郑州大学第附属医院 | Quinazoline derivative and application thereof |
| CN108727342A (en) * | 2017-04-21 | 2018-11-02 | 沈阳药科大学 | 4- virtue ammonia -6- (3- sulfoamidos pyridine)-quinazoline derivative and its preparation method and application |
| CN109988165A (en) * | 2018-12-24 | 2019-07-09 | 华东师范大学 | As PI3K/mTOR kinase modulator heteroaromatic compounds and its preparation method and application |
| CN110655505A (en) * | 2019-10-23 | 2020-01-07 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) quinazolin-4 (3H) -ones |
| CN111892581A (en) * | 2020-08-03 | 2020-11-06 | 中国药科大学 | Quinazoline derivative with anti-tumor activity and synthesis method and application thereof |
| CN113501819A (en) * | 2021-07-09 | 2021-10-15 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Pyridoimidazole-substituted quinazolinone derivative and synthesis method and application thereof |
| CN114292259A (en) * | 2021-11-30 | 2022-04-08 | 西安交通大学 | 4-amino acid side chain substituted quinazoline derivative and application thereof |
| CN114315826A (en) * | 2021-11-30 | 2022-04-12 | 西安交通大学 | Pyridopyrimidine compound and application thereof |
-
2023
- 2023-03-05 CN CN202310199761.3A patent/CN116239594B/en active Active
Patent Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008012326A1 (en) * | 2006-07-28 | 2008-01-31 | Novartis Ag | 2,4-substituted quinazolines as lipid kinase inhibitors |
| WO2008144463A1 (en) * | 2007-05-18 | 2008-11-27 | Smithkline Beecham Corporation | Quinoline derivatives as pi3 kinase inhibitors |
| WO2010059788A1 (en) * | 2008-11-20 | 2010-05-27 | Genentech, Inc. | Pyrazolopyridine pi3k inhibitor compounds and methods of use |
| CN103570709A (en) * | 2012-07-19 | 2014-02-12 | 中国科学院上海药物研究所 | Pyrazolopyridine compounds, preparation method, uses and drug composition thereof |
| CN105237484A (en) * | 2015-09-28 | 2016-01-13 | 西安交通大学 | 6-aryl substituted quinoline compounds and applications thereof |
| CN106432202A (en) * | 2016-09-22 | 2017-02-22 | 郑州大学第附属医院 | Quinazoline derivative and application thereof |
| CN108727342A (en) * | 2017-04-21 | 2018-11-02 | 沈阳药科大学 | 4- virtue ammonia -6- (3- sulfoamidos pyridine)-quinazoline derivative and its preparation method and application |
| CN109988165A (en) * | 2018-12-24 | 2019-07-09 | 华东师范大学 | As PI3K/mTOR kinase modulator heteroaromatic compounds and its preparation method and application |
| CN110655505A (en) * | 2019-10-23 | 2020-01-07 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) quinazolin-4 (3H) -ones |
| CN111892581A (en) * | 2020-08-03 | 2020-11-06 | 中国药科大学 | Quinazoline derivative with anti-tumor activity and synthesis method and application thereof |
| CN113501819A (en) * | 2021-07-09 | 2021-10-15 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Pyridoimidazole-substituted quinazolinone derivative and synthesis method and application thereof |
| CN114292259A (en) * | 2021-11-30 | 2022-04-08 | 西安交通大学 | 4-amino acid side chain substituted quinazoline derivative and application thereof |
| CN114315826A (en) * | 2021-11-30 | 2022-04-12 | 西安交通大学 | Pyridopyrimidine compound and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116239594A (en) | 2023-06-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5926727B2 (en) | Substituted imidazo [1,2-b] pyridazine | |
| CN104066723B (en) | 1-(aryl methyl)-5,6,7,8-tetrahydro quinazoline-2,4-diketone and related compound and application thereof | |
| CN103588792B (en) | Pyridopyrimidine or pyrimido-pyrimidine compounds, its preparation method, medical composition and its use | |
| CN104169283A (en) | Fused tetra or penta-cyclic pyridophthalazinones as PARP inhibitors | |
| CN110167941B (en) | Substituted fused heteroaryl compounds as kinase inhibitors and uses thereof | |
| CN111712491B (en) | Tetrahydroisoquinoline compounds, preparation method thereof, pharmaceutical composition containing compounds and application of compounds | |
| JP5820080B2 (en) | Tricyclic PI3K and / or mTOR inhibitors | |
| CN102224152A (en) | Pyrazolopyridine pi3k inhibitor compounds and methods of use | |
| CA2692922A1 (en) | Azaindole-indole coupled derivatives, preparation methods and uses thereof | |
| JP2018135268A (en) | Novel heteroaryl amino-3-pyrazole derivative and pharmacologically acceptable salt thereof | |
| CN116323562A (en) | Compounds with kinase inhibitory activity | |
| EP3284746B1 (en) | Preparation and use of kinase inhibitor | |
| WO2018022868A1 (en) | Pi 4-kinase inhibitor as a therapeutic for viral hepatitis, cancer, malaria. autoimmune disorders and inflammation, and a radiosensitizer and immunosuppressant | |
| CN112479974B (en) | Preparation and application of 3-carbonyl-2, 3' -bisindole nitrogen oxide derivative | |
| CN116239594B (en) | 6- (imidazo [1,2-a ] pyridin-6-yl) quinazoline derivatives and uses thereof | |
| CN116332944A (en) | Tri-ring ubiquitin-specific protease 1 inhibitors and uses thereof | |
| Yong et al. | Synthesis of Isoxazole moiety containing thieno [2, 3-d] pyrimidine Derivatives and preliminarily in vitro anticancer activity (Part II) | |
| CN115433207A (en) | Macrocyclic heterocyclic compound as EGFR inhibitor and application thereof | |
| CN110590778B (en) | 3, 10 di-p-methoxyphenyl 6, 12 diaza tetracubane compound, synthetic method and pharmaceutical composition | |
| CN104804016B (en) | Four and ring class anaplastic lymphoma kinase inhibitor | |
| CN111247143B (en) | Pyridoquinazoline derivatives useful as inhibitors of protein kinases | |
| CN109438279B (en) | Small molecule compound for overcoming EGFR drug-resistant mutation and preparation method and application thereof | |
| CN110903289A (en) | Purine-aminomethyl-pyridone derivative, preparation method and application thereof | |
| CN103596953A (en) | Pyridonaphthyridine PI3K/mTOR dual inhibitors and preparation and use thereof | |
| CN112300235B (en) | Benzimidazole derivative BI321 and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |