CN114573553A - Heteroaromatic ring derivative and preparation method and application thereof - Google Patents
Heteroaromatic ring derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN114573553A CN114573553A CN202210099079.2A CN202210099079A CN114573553A CN 114573553 A CN114573553 A CN 114573553A CN 202210099079 A CN202210099079 A CN 202210099079A CN 114573553 A CN114573553 A CN 114573553A
- Authority
- CN
- China
- Prior art keywords
- group
- reaction
- alkyl
- added
- compound
- 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.)
- Granted
Links
- 125000001072 heteroaryl group Chemical group 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 239000003937 drug carrier Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000002947 alkylene group Chemical group 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
- 229910003827 NRaRb Inorganic materials 0.000 claims description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- 229940043355 kinase inhibitor Drugs 0.000 claims description 6
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 4
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 abstract description 11
- 108091000080 Phosphotransferase Proteins 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 10
- 102000020233 phosphotransferase Human genes 0.000 abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- 238000006243 chemical reaction Methods 0.000 description 159
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 120
- 239000000243 solution Substances 0.000 description 95
- 206010028980 Neoplasm Diseases 0.000 description 66
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 57
- 239000012074 organic phase Substances 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 41
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 41
- 238000003756 stirring Methods 0.000 description 41
- 230000002829 reductive effect Effects 0.000 description 40
- 239000007787 solid Substances 0.000 description 38
- 238000004440 column chromatography Methods 0.000 description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 26
- 238000001308 synthesis method Methods 0.000 description 25
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 23
- 102100037236 Tyrosine-protein kinase receptor UFO Human genes 0.000 description 23
- 238000000605 extraction Methods 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- 230000002441 reversible effect Effects 0.000 description 19
- 241000699670 Mus sp. Species 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 238000005406 washing Methods 0.000 description 16
- 238000000034 method Methods 0.000 description 15
- 239000013641 positive control Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- 239000007821 HATU Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- 210000004881 tumor cell Anatomy 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 238000005191 phase separation Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 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 9
- 210000004027 cell Anatomy 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- -1 2-pentyl Chemical group 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 8
- 230000004614 tumor growth Effects 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- 230000012010 growth Effects 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 7
- 230000002194 synthesizing effect Effects 0.000 description 7
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 229940126208 compound 22 Drugs 0.000 description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000010189 synthetic method Methods 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- WLAVZAAODLTUSW-UHFFFAOYSA-N 1-n'-[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]-1-n-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=O)C4(CC4)C(=O)NC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 WLAVZAAODLTUSW-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 239000000872 buffer Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 229950010611 sitravatinib Drugs 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 238000013508 migration Methods 0.000 description 3
- 230000002018 overexpression Effects 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000003827 upregulation Effects 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- JJUTYYVZDKDLBC-UHFFFAOYSA-N 7-bromo-4-chloroquinoline Chemical compound BrC1=CC=C2C(Cl)=CC=NC2=C1 JJUTYYVZDKDLBC-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- 238000011729 BALB/c nude mouse Methods 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 2
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 239000003080 antimitotic agent Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 description 2
- 229960001292 cabozantinib Drugs 0.000 description 2
- ONIQOQHATWINJY-UHFFFAOYSA-N cabozantinib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229940044683 chemotherapy drug Drugs 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000001447 compensatory effect Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 230000007705 epithelial mesenchymal transition Effects 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- ORPHLVJBJOCHBR-UHFFFAOYSA-N 403-19-0 Chemical compound OC1=CC=C([N+]([O-])=O)C=C1F ORPHLVJBJOCHBR-UHFFFAOYSA-N 0.000 description 1
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 1
- VLZJBXYXSWZAJQ-UHFFFAOYSA-N 7-bromo-4-chloroquinazoline Chemical compound BrC1=CC=C2C(Cl)=NC=NC2=C1 VLZJBXYXSWZAJQ-UHFFFAOYSA-N 0.000 description 1
- 229940123877 Aurora kinase inhibitor Drugs 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 235000008317 Condalia obovata Nutrition 0.000 description 1
- 244000147935 Condalia obovata Species 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 101150022345 GAS6 gene Proteins 0.000 description 1
- 102100031487 Growth arrest-specific protein 6 Human genes 0.000 description 1
- 101000606129 Homo sapiens Tyrosine-protein kinase receptor TYRO3 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000016979 Other receptors Human genes 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 102100039127 Tyrosine-protein kinase receptor TYRO3 Human genes 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000003719 aurora kinase inhibitor Substances 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- ZTYYDUBWJTUMHW-UHFFFAOYSA-N furo[3,2-b]furan Chemical compound O1C=CC2=C1C=CO2 ZTYYDUBWJTUMHW-UHFFFAOYSA-N 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 108010004351 growth arrest-specific protein 6 Proteins 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- CVGDUJKDLGUWEI-UHFFFAOYSA-N n-[(6-bromopyridin-3-yl)methyl]-2-methoxyethanamine Chemical compound COCCNCC1=CC=C(Br)N=C1 CVGDUJKDLGUWEI-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- MHOZZUICEDXVGD-UHFFFAOYSA-N pyrrolo[2,3-d]imidazole Chemical compound C1=NC2=CC=NC2=N1 MHOZZUICEDXVGD-UHFFFAOYSA-N 0.000 description 1
- RQGPLDBZHMVWCH-UHFFFAOYSA-N pyrrolo[3,2-b]pyrrole Chemical compound C1=NC2=CC=NC2=C1 RQGPLDBZHMVWCH-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
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000007755 survival signaling Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- ONCNIMLKGZSAJT-UHFFFAOYSA-N thieno[3,2-b]furan Chemical compound S1C=CC2=C1C=CO2 ONCNIMLKGZSAJT-UHFFFAOYSA-N 0.000 description 1
- VJYJJHQEVLEOFL-UHFFFAOYSA-N thieno[3,2-b]thiophene Chemical compound S1C=CC2=C1C=CS2 VJYJJHQEVLEOFL-UHFFFAOYSA-N 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Images
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a heteroaromatic ring derivative with a structure shown as a formula (I), or a salt thereof, or a pharmaceutically acceptable carrier thereof. The heteroaromatic ring compound has c-Met-Axl double-effect kinase inhibition activity and can exert a better anti-tumor effect.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a heteroaromatic ring derivative and a preparation method and application thereof.
Background
Cancer is one of the diseases that present in the world seriously jeopardize human health and life. With the continuous and intensive research on tumor molecular biology, intracellular signal transduction, cell cycle regulation, apoptosis induction, angiogenesis, interaction between extracellular matrix and cells, and the like of malignant tumors are gradually elucidated. Among them, Receptor Tyrosine Kinases (RTKs) are closely related to the development and progression of tumors. Its effects include activating downstream signal transduction molecules, promoting cell proliferation, migration, survival, etc. Thus, RTKs have become interesting molecular therapeutic targets for antitumor therapy.
c-Met is a type of disulfide-linked heterodimeric receptor tyrosine kinase that is expressed in both normal and malignant cells of the human body. Mutations in the c-M et receptor tyrosine kinase have been found in both hereditary and secondary kidney cancers, liver cancers and a variety of other tumors. The c-Met-HGF/SF signaling pathway plays an important physiological role in embryonic development and tissue regeneration. In normal cells, the c-Met-HGF/SF signaling pathway is tightly regulated; in tumor cells, dysregulation occurs. A great deal of research shows that c-M et in tumor tissues can perform functional interaction with various signal molecules, which becomes an important reason for tumor canceration and generation of treatment resistance.
AXL is a member of the TAM (TYRO3, AXL, MER) Receptor Tyrosine Kinase (RTK) family. This kinase family was originally identified as transforming genes expressed in cells from patients with chronic myeloid leukemia or chronic myeloproliferative diseases. Activation of AXL is performed by its cognate protein ligand binding of growth arrest-specific protein 6(Gas6), by homodimerization of its extracellular domain or crosstalk via Interleukin (IL) -15 receptor or HER 2. AXL signaling stimulates cellular responses, including activation of the PI3K-Akt, extracellular signal-regulated kinase (ERK), and P38 mitogen-activated protein kinase cascade, the NF- κ beta pathway, and Signal Transducer and Activator of Transcription (STAT) signaling. Human biological consequences of AXL signaling include invasion, migration, survival signaling, angiogenesis, resistance to chemotherapy and targeted drugs, cellular transformation and proliferation. In addition, AXL overexpression is one of the important causes of drug resistance of patients to tumor chemotherapeutic drugs or targeted drugs.
Due to the high degree of amino acid sequence similarity (40%) between c-Met and AXL in the kinase domain, many compounds, including the drugs already on the market, are dual inhibitors of AXL and c-Met. In the course of cancer treatment, tumor metastasis and drug resistance are two major difficulties affecting the efficacy of anticancer drugs, and are also the main causes of high cancer mortality. The upregulation of AXL expression is closely associated with the pathological mechanism of tumor metastasis. Many studies have shown that inhibition of AXL kinase activity can effectively block the growth, migration and invasion of tumor cells. Therefore, it is possible to use AXL kinase inhibitors in patients with early stage cancer, especially those susceptible to cancer cell metastasis, to maximize the therapeutic effect of AXL kinase inhibitors. The mechanism by which resistance is conferred upon treatment of patients with receptor tyrosine kinase inhibitors is generally secondary mutations of the targeted kinase or compensatory upregulation of other receptor tyrosine kinases. Overexpression of AXL kinase is thought to be a major cause of drug resistance due to compensatory upregulation. The synergistic effect of a targeted drug in combination with an AXL kinase inhibitor results when it becomes resistant and has been demonstrated at the cellular level and in multiple tumor models in animals. In addition, tumor cells can also develop resistance through epithelial-mesenchymal transition mechanisms. In this process, overexpression of AXL kinase confers resistance to traditional chemotherapeutic drugs, such as antimitotic drugs, on tumor cells by epithelial-mesenchymal transition. Therefore, the combination of antimitotic drugs such as docetaxel or Aurora kinase inhibitor and AXL inhibitor can obviously enhance the effect of inhibiting tumor growth and can ensure that drug-resistant tumor cells regain sensitivity to drugs. Advanced cancer patients usually need second-line or even third-line medication to reduce the resistance to the first-line antitumor drug, in this case, the AXL inhibitor can be used in combination with the first-line drug to reduce the resistance of the patients, thereby achieving the effect of inhibiting the cancer progression. In recent years, AXL kinase has attracted extensive attention from drug developers as a novel cancer therapeutic target, and AXL kinase small molecule inhibitors have become a research hotspot.
Therefore, it is necessary to develop an antitumor drug having an effect on both targets of c-Met kinase and AXL kinase.
Disclosure of Invention
Based on the fact, the invention provides the heteroaromatic ring derivative which has c-Met-Axl double-effect kinase inhibition activity and can exert a good anti-tumor effect.
In a first aspect of the present invention, there is provided a heteroaromatic derivative having a structure represented by formula (I), or a salt thereof, or a pharmaceutically acceptable carrier thereof:
R1selected from: h or halogen; n is selected from: 0.1, 2,3 or 4;
W1、W2each independently selected from: CH or N;
ring A is selected from: pyridyl, phenyl or pyrazolyl;
R2each independently selected from: H. -L-NRaRbOR-L-ORaL is selected from: a single bond, a,
Or C1 to C5 alkylene;
Ra、Rbeach independently selected from: h or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted by 1 or 2 substituents selected from S1; substituents of group S1 are selected from: C1-C5 alkoxy and-S (O)2C1-C5 alkyl;
or Ra、RbTogether with the nitrogen atom to which they are attached form a 4-to 10-membered heterocycloalkyl group;
g is selected from: a 5-15 membered heteroaromatic ring, a 4-10 membered heterocycloalkyl group or a C3-C6 cycloalkyl group; wherein the 5-15 membered heteroaromatic ring, 4-10 membered heterocycloalkyl or C3-C6 cycloalkyl is unsubstituted or substituted with 1, 2,3, 4, 5 substituents selected from S2; substituents of group S2 are selected from: halogen, C1-C5 alkyl, C3-C5 cycloalkyl, C1-C5 alkoxy, oxo, halogen substituted or unsubstituted C6-C10 aromatic ring, and C1-C3 alkyl substituted or unsubstitutedSubstituted 5-to 10-membered heterocycloalkyl, hydroxy-substituted or unsubstituted 5-to 10-membered heterocycloalkyl, and-C (═ O) -NH-Rc；RcSelected from halogen substituted or unsubstituted C6-C10 aromatic rings;
and formula (I) satisfies the following conditions:
when in use
Is composed of
When W is1Is not CH.
In one embodiment, L is selected from: a single bond or a C1-C2 alkylene group.
In one embodiment, R2is-L-NRaRbL is selected from: a single bond or a C1-C2 alkylene group; raIs H, RbSelected from: C1-C4 alkyl, wherein the C1-C3 alkyl is unsubstituted or substituted with a substituent optionally selected from the group S1; substituents of group S1 are selected from: C1-C2 alkoxy and-S (O)2C1-C2 alkyl.
In one embodiment, R2is-L-NRaRbL is selected from: a single bond or a C1-C2 alkylene group; ra、RbThe nitrogen atoms connected with the heterocyclic ring form a 4-10-membered heterocyclic alkyl group together, and the heterocyclic alkyl group has a structure shown in the following general formula (I-1):
wherein, X1、X2Each independently selected from: CRdRe、O、NRdS or S (O)2Wherein R isd、ReSelected from H, C1-C6 alkyl or C3-C6 cycloalkyl.
In one embodiment, R2is-L-ORaL is selected from: a single bond or C1-C2 alkylene, RaIs H.
In one of the embodiments, the first and second electrodes are,
selected from the group consisting of:
in one embodiment, G is selected from any of the following structures:
in one embodiment, the heteroaromatic ring derivative is any one of the following compounds:
in the second aspect of the invention, the application of the heteroaromatic ring derivative, or the salt thereof, or the pharmaceutically acceptable carrier thereof in the preparation of the c-Met-Axl dual-purpose kinase inhibitor is provided.
In the third aspect of the invention, the application of the heteroaromatic ring derivative, or the salt thereof, or the pharmaceutically acceptable carrier thereof in preparing an antitumor drug is provided.
The heteroaromatic ring derivative shows excellent c-Met-Axl double-effect kinase inhibition activity in-vitro activity screening and animal models by carrying out specific substituent modification on the heteroaromatic ring, and can exert better anti-tumor effect.
Drawings
FIG. 1 is a graph showing the growth of tumor volumes in mice of the compound group, the solvent control group and the positive control group (Sitravatinib) in test example 2;
FIG. 2 is a graph showing the growth of tumor volumes of mice in the compound group, solvent control group and positive control group (Sitravatinib) in test example 2;
FIG. 3 shows the growth of tumor volume changes in mice of the compound group, solvent control group and positive control group (XL-092) in test example 3;
FIG. 4 shows the body weight of mice in the compound group, solvent control group and positive control group (XL-092) in test example 3 as a function of the treatment time.
Detailed Description
The heteroaromatic ring derivatives of the present invention, and the preparation method and application thereof will be described in further detail with reference to the following specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
In the present invention, "first aspect", "second aspect", "third aspect", "fourth aspect" and the like are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or quantity, nor as implying an importance or quantity indicating the technical feature indicated. Also, "first," "second," "third," "fourth," etc. are used for non-exhaustive enumeration of description purposes only and should not be construed as a closed limitation to the number.
In the present invention, the technical features described in the open type include a closed technical solution composed of the listed features, and also include an open technical solution including the listed features.
In the present invention, the numerical intervals are regarded as continuous, and include the minimum and maximum values of the range and each value between the minimum and maximum values, unless otherwise specified. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range-describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein.
The percentage contents referred to in the present invention mean, unless otherwise specified, mass percentages for solid-liquid mixing and solid-solid phase mixing, and volume percentages for liquid-liquid phase mixing.
The percentage concentrations referred to in the present invention refer to the final concentrations unless otherwise specified. The final concentration refers to the ratio of the additive component in the system to which the component is added.
The temperature parameter in the present invention is not particularly limited, and may be a constant temperature treatment or a treatment within a certain temperature range. The constant temperature process allows the temperature to fluctuate within the accuracy of the instrument control.
The term "alkyl" refers to a saturated hydrocarbon containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. Phrases containing such terms, such as "C1-C6 alkyl" refer to alkyl groups containing 1-6 carbon atoms, which at each occurrence, may be independently C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl. Suitable examples include, but are not limited to: methyl (Me, -CH)3) Ethyl (Et-CH)2CH3) 1-propyl (n-Pr, n-propyl, -CH)2CH2CH3) 2-propyl (i-Pr, i-propyl, -CH (CH)3)2) 1-butyl (n-Bu, n-butyl, -CH)2CH2CH2CH3) 2-methyl-1-propyl (i-Bu, i-butyl, -CH)2CH(CH3)2) 2-butyl (s-Bu, s-butyl, -CH (CH)3)CH2CH3) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH)3)3) 1-pentyl (n-pentyl, -CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) 1-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3。
"alkoxy" refers to a group having an-O-alkyl group, i.e., an alkyl group as defined above attached to the parent structure via an oxygen atom. Phrases comprising this term, such as "C1-C5 alkyl" refer to alkyl moieties containing 1 to 5 carbon atoms which, at each occurrence, may be independently C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy. Suitable examples include, but are not limited to: methoxy (-O-CH)3or-OMe), ethoxy (-O-CH)2CH3or-OEt) and tert-butoxy (-O-C (CH)3)3or-OtBu).
"heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring may be optionally substituted. In certain embodiments, heterocycloalkyl contains one or more carbonyl or thiocarbonyl groups, such as groups containing oxo and thioxo. "4-10 membered heterocycloalkyl" refers to a monocyclic cyclic hydrocarbon group having 4 to 10 ring atoms, wherein 1, 2, or 3 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. At each occurrence, independently of each other, may be 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 8-membered heterocycloalkyl, 9-membered heterocycloalkyl, 10-membered heterocycloalkyl.
"heteroaryl ring" means that on the basis of an aryl group at least one carbon atom is replaced by a non-carbon atom which may be a N atom, an O atom, an S atom, etc. For example, "5-to 15-membered heteroaryl" refers to a heteroaryl group comprising 5-to 15 ring atoms, which at each occurrence, independently of each other, can be a 5-membered heteroaryl, a 6-membered heteroaryl, a 7-membered heteroaryl, an 8-membered heteroaryl, a 9-membered heteroaryl, a 10-membered heteroaryl, an 11-membered heteroaryl, a 12-membered heteroaryl, a 13-membered heteroaryl, a 14-membered heteroaryl, or a 15-membered heteroaryl. Suitable examples include, but are not limited to: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazole, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, quinoline, isoquinoline, phthalazine, quinoxaline, phenanthridine, primadine, quinazoline, and quinazolinone.
"oxo" means "═ O".
"halogen" means F, Cl, Br or I.
"Single bond" means that the groups at both ends are directly connected by a single bond.
In the present invention, "normal temperature" and "room temperature" mean a temperature range of about 20 ℃ to 30 ℃.
The invention provides a heteroaromatic ring derivative with a structure shown as a formula (I), or a salt thereof, or a pharmaceutically acceptable carrier thereof:
R1selected from: h or halogen; n is selected from: 0.1, 2,3 or 4;
W1、W2each independently selected from: CH or N;
ring A is selected from: pyridyl, phenyl or pyrazolyl;
R2each independently selected from: H. -L-NRaRbOR-L-ORaL is selected from: a single bond, a,
Or C1 to C5 alkylene;
Ra、Rbeach independently selected from: h or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted by 1 or 2 substituents selected from S1; substituents of group S1 are selected from: C1-C5 alkoxy and-S (O)2C1-C5 alkyl;
or Ra、RbTogether with the nitrogen atom to which they are attached form a 4-to 10-membered heterocycloalkyl group;
g is selected from: a 5-15 membered heteroaromatic ring, a 4-10 membered heterocycloalkyl group or a C3-C6 cycloalkyl group; wherein the 5-15 membered heteroaromatic ring, 4-10 membered heterocycloalkyl or C3-C6 cycloalkyl is unsubstituted or substituted with 1, 2,3, 4, 5 substituents selected from S2; substituents of group S2 are selected from: halogen, C1-C5 alkyl, C3-C5 cycloalkyl, C1-C5 alkoxy, oxo, halogen substituted or unsubstituted C6-C10 aromatic ring, C1-C3 alkyl substituted or unsubstituted 5-to 10-membered heterocycloalkyl, hydroxy substituted or unsubstituted 5-to 10-membered heterocycloalkyl, and-C (═ O) -NH-Rc；RcSelected from halogen substituted or unsubstituted C6-C10 aromatic rings;
and formula (I) satisfies the following conditions:
when in use
Is composed of
When W is1Is not CH.
Understandably, substituents on each ring (e.g. R)1、R2) May be substituted at any position on the ring, and the hydrogen at the substituted position is replaced with a corresponding substituent.
In one particular example of this, the first and second,
is different from
In one particular example of this, the first and second,
selected from the group consisting of:
in one specific example, L is selected from: a single bond or a C1-C2 alkylene group.
In one specific example, R2is-L-ORaL is selected from: a single bond or a C1-C2 alkylene group. Further, L is ethylene. Further, RaIs H.
In one specific example, R2is-L-NRaRbL is selected from: a single bond or a C1-C2 alkylene group; raIs H, RbSelected from: C1-C4 alkyl, wherein the C1-C3 alkyl is unsubstituted or substituted with a substituent optionally selected from the group S1; substituents of group S1 are selected from: C1-C2 alkoxy and-S (O)2C1-C2 alkyl. Further, L is methylene.
In one specific example, R2is-L-NRaRbL is selected from: a single bond or a C1-C2 alkylene group, further, L is methylene; ra、RbTogether with the nitrogen atom to which they are attached form a 4-to 10-membered heterocycloalkyl ringHas a structure represented by the following general formula (I-1):
wherein, X1、X2Each independently selected from: CRdRe、O、NRdS or S (O)2Wherein R isd、ReIs H, C1-C6 alkyl or C3-C6 cycloalkyl. Further, X1、X2Each independently selected from: CH (CH)2O, NH or S.
In one specific example, X1、X2Selected from any one of the following groups:
X1is CH2And X2Is O;
X1is O, and X2Is CH2(ii) a And
X1is CH2And X2Is CH2。
In one specific example, G is selected from any of the following structures:
in a specific example, the heteroaromatic ring derivative is any one of the following compounds:
the invention also provides application of the heteroaromatic ring derivative, or a salt or a pharmaceutically acceptable carrier thereof in preparation of a c-Met-Axl dual-effect kinase inhibitor.
The invention also provides application of the heteroaromatic ring derivative, or salt thereof, or pharmaceutically acceptable carrier thereof in preparing antitumor drugs. Specifically, the tumor is at least one of gastric cancer, liver cancer, renal cancer, lung cancer, esophageal cancer, breast cancer, leukemia, prostate cancer, colorectal cancer, bone cancer, colorectal cancer, melanoma, lymphoma, leukemia, brain tumor, ovarian cancer, pancreatic cancer or skin cancer.
Specific examples are as follows.
The synthetic routes of examples 1, 6-7 and 10-17 are shown in the following technical route I:
technical scheme one
The synthesis method of the compound 1 comprises the following steps:
7-bromo-4-chloroquinoline (9.68g,40mmol,1.00eq),1,1' -bisdiphenylphosphinoferrocene palladium dichloride (2.92g,4mmol,0.1eq), potassium acetate (11.76g,120mmol,3.00eq) pinacol diboron (12.14g,48mmol,1.2eq) were added to the reaction flask at ambient temperature, dissolved in suspension with anhydrous 1, 4 dioxane (100mL), purged with nitrogen 3 times, transferred to a 70 ℃ oil bath and stirred for 6 hours. The reaction solution was cooled to 20 ℃, slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, stirred with silica gel, and purified by column chromatography to give 13.0g of a white solid.
LCMS(ESI):m/z 291[M+H]+。
The synthesis method of the compound 2 comprises the following steps:
6-bromo-N- (2-methoxyethyl) -3-pyridinemethylamine (1.50g,6.12mmol,1.0eq.), Boc-anhydride (1.60g,7.34mmol,1.2eq.) were added to a reaction flask at ambient temperature, suspended in anhydrous THF (15mL), purged with nitrogen 3 times, and stirred at ambient temperature for 1.5 hours. After the reaction was terminated, THF was removed by concentration under reduced pressure, the oil was dissolved with EA, the organic phase was washed with a saturated ammonium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 ℃ to obtain 1.90g of a yellow liquid.
LCMS(ESI):m/z:347[M]+。
The synthesis method of the compound 3 comprises the following steps:
compound 1(5.0g,17.3mmol,1.00eq),1,1' -bis-diphenylphosphino ferrocene palladium dichloride (1.26g,1.7mmol,0.1eq), potassium carbonate (7.2g,52mmol,3.0eq), compound 2(4.22g,17.3mmol,1.00eq) were added to a reaction flask at normal temperature, dissolved in suspension with 1, 4-dioxane (150mL) and water (50mL), nitrogen was exchanged 3 times, and the mixture was transferred to a 90 ℃ oil bath and stirred for 6.5 hours. The reaction solution is cooled to 20 ℃, slowly poured into a saturated ammonium chloride solution, added with ethyl acetate for extraction for 3 times, the organic phase is washed by saturated saline solution, dried by anhydrous sodium sulfate, decompressed and concentrated, added with silica gel for sample mixing, and purified by column chromatography to obtain 2.84g of near-white solid.
LCMS(ESI):m/z 428[M+H]+。
The synthesis method of the compound 4 comprises the following steps:
compound 3(2.0g,4.7mmol,1.00eq), p-aminophenol (0.563g,5.1mmol,1.1eq), potassium tert-butoxide (0.57g,5.1mmol,1.1eq), was added to the reaction flask at room temperature, dissolved in DMSO (20mL) to form a suspension, purged with nitrogen 3 times, transferred to a 100 ℃ oil bath and stirred for 3 hours. The reaction solution was cooled to 20 ℃, slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, stirred with silica gel, and purified by column chromatography to give 2.05g of a light brown solid.
LCMS(ESI):m/z 501[M+H]+。
Method for synthesizing compound 12:
compound 4(205mg,0.41mmol,1.00eq) was added to a reaction flask at room temperature, dissolved in DMF (2mL), HATU (171mg,0.45mmol,1.10eq) and DIEA (158mg,1.23mmol,3.0eq) were added to the reaction, and after stirring for 0.5 h, carboxylic acid 1(100mg,0.45mmol,1.10eq) was added to the reaction and stirring was continued for 4 h. After the reaction is stopped, the reaction solution is slowly poured into a saturated ammonium chloride solution, ethyl acetate is added for extraction for 3 times, a saturated saline solution is used for washing an organic phase, anhydrous sodium sulfate is dried, the organic phase is concentrated under reduced pressure at 40 ℃, silica gel is added for sample mixing, and column chromatography purification is carried out to obtain 200mg of off-white solid.
LCMS(ESI):m/z 707[M+H]+。
Example 1 synthesis method:
compound 12(200mg,0.28mmol,1.00eq) was charged into a reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution of hydrogen chloride (0.45mL,0.90mmol) was added dropwise to the reaction, followed by stirring at room temperature for 5 hours. After the reaction is stopped, the reaction mixture is heated,
slowly dropwise adding saturated sodium bicarbonate solution into the reaction solution, adding ethyl acetate for extraction for 3 times, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography reverse phase separation to obtain 97mg of white solid.
LCMS(ESI):m/z 607[M+H]+。
1H NMR(500MHz,DMSO-d6)δ10.19(s,1H),10.04(s,1H),8.73(d,J＝5.2Hz,1H),8.69(s,2H),8.41(s,2H),8.17(d,J＝8.1Hz,1H),7.91(d,J＝8.2Hz,1H),7.78(d,J＝8.5Hz,2H),7.64(dd,J＝8.7,5.0Hz,2H),7.28(d,J＝8.5Hz,2H),7.15(t,J＝8.7Hz,2H),6.61(d,J＝5.2Hz,1H),3.82(s,2H),3.43(t,J＝5.7Hz,2H),3.26(s,3H),2.70(t,J＝5.7Hz,2H),1.49(s,4H).
The synthesis method of the compound 13 comprises the following steps:
compound 4(205mg,0.41mmol,1.00eq) was added to a reaction flask at room temperature, dissolved in DMF (2mL), HATU (171mg,0.45mmol,1.10eq) and DIEA (158mg,1.23mmol,3.0eq) were added to the reaction, and after stirring for 0.5 h, carboxylic acid 2(104mg,0.45mmol,1.10eq) was added to the reaction and stirring was continued for 4 h. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, ethyl acetate was added for extraction 3 times, the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, and then stirred with silica gel and purified by column chromatography to obtain 222mg of an off-white solid.
LCMS(ESI):m/z 716[M+H]+。
Example 6 synthesis method:
compound 13(222mg,0.31mmol,1.00eq) was charged into a reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution of hydrogen chloride (0.45mL,0.90mmol) was added dropwise to the reaction, followed by stirring at room temperature for 6 hours. After the reaction is stopped, slowly dropwise adding a saturated sodium bicarbonate solution into the reaction solution, adding ethyl acetate for extraction for 3 times, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography reverse phase separation to obtain 23mg of a white solid.
LCMS(ESI):m/z 616[M+H]+。
1H NMR(500MHz,DMSO)δ13.18(s,1H),8.74(d,J＝5.1Hz,1H),8.70(s,2H),8.63(s,1H),8.42(s,2H),8.23(s,1H),8.19(d,J＝8.1Hz,1H),8.08(s,1H),7.92(dd,J＝8.1,1.6Hz,1H),7.87(d,J＝8.8Hz,2H),7.72(dd,J＝8.5,5.8Hz,2H),7.31(d,J＝8.8Hz,2H),7.26(t,J＝8.9Hz,2H),6.67(d,J＝5.1Hz,1H),3.86(s,4H),3.45(t,J＝5.6Hz,3H),2.73(t,J＝5.6Hz,2H),1.23(s,1H).
Method for synthesizing compound 14:
compound 4(205mg,0.41mmol,1.00eq) was added to a reaction flask at ambient temperature, dissolved in DMF (2mL), HATU (171mg,0.45mmol,1.10eq) and DIEA (158mg,1.23mmol,3.0eq) were added to the reaction, and after stirring for 0.5 h, carboxylic acid 3(131.6mg,0.45mmol,1.10eq) was added to the reaction and stirring was continued for 4 h. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, ethyl acetate was added for extraction 3 times, the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, and then stirred with silica gel and purified by column chromatography to obtain 220mg of an off-white solid.
LCMS(ESI):m/z 776[M+H]+。
Example 7 synthesis method:
compound 14(220mg,0.30mmol,1.00eq) was added to the reaction flask at ambient temperature, dissolved in 2mL of methanol, a solution of hydrogen chloride in dioxane (0.45mL,0.90mmol) was added dropwise to the reaction, and stirring was continued at ambient temperature for 6 hours. After the reaction is stopped, slowly dropwise adding a saturated sodium bicarbonate solution into the reaction solution, adding ethyl acetate for extraction for 3 times, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography reverse phase separation to obtain 25mg of a white solid.
LCMS(ESI):m/z 676[M+H]+。
1H NMR(500MHz,DMSO-d6)δ10.94(s,1H),8.74(d,J＝5.1Hz,1H),8.72–8.69(m,2H),8.67(s,1H),8.40(s,2H),8.19(d,J＝8.2Hz,1H),7.93(dd,J＝8.2,2.2Hz,1H),7.83(d,J＝8.8Hz,2H),7.44(dd,J＝8.8,5.2Hz,2H),7.39–7.29(m,4H),6.66(d,J＝5.2Hz,1H),4.78(p,J＝6.8Hz,1H),3.88(s,2H),3.45(t,J＝5.6Hz,3H),3.27(s,3H),2.76(t,J＝5.6Hz,2H),1.43(d,J＝6.8Hz,6H).
The synthesis method of the compound 15 comprises the following steps:
compound 4(205mg,0.41mmol,1.00eq) was added to a reaction flask at ambient temperature, dissolved in DMF (2mL), HATU (171mg,0.45mmol,1.10eq) and DIEA (158mg,1.23mmol,3.0eq) were added to the reaction, and after stirring for 0.5 h, carboxylic acid 4(152.3mg,0.45mmol,1.10eq) was added to the reaction and stirring was continued for 4 h. After the reaction is stopped, the reaction solution is slowly poured into a saturated ammonium chloride solution, ethyl acetate is added for extraction for 3 times, a saturated saline solution is used for washing an organic phase, anhydrous sodium sulfate is dried, the organic phase is concentrated under reduced pressure at 40 ℃, silica gel is added for sample mixing, and column chromatography purification is carried out to obtain 160mg of off-white solid.
LCMS(ESI):m/z 760[M+H]+。
Example 10 synthesis method:
compound 15(160mg,0.21mmol,1.00eq) was added to a reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution of hydrogen chloride (0.45mL,0.90mmol) was added dropwise to the reaction, followed by stirring at room temperature for 4 hours. After the reaction is stopped, slowly dropwise adding a saturated sodium bicarbonate solution into the reaction solution, adding ethyl acetate for extraction for 3 times, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography reverse phase separation to obtain 36mg of a white solid.
LCMS(ESI):m/z 660[M+H]+。
1H NMR(500MHz,DMSO-d6)δ10.40(s,1H),8.85(d,J＝2.1Hz,1H),8.75–8.71(m,2H),8.43(s,2H),8.28(d,J＝8.2Hz,1H),8.13(dd,J＝8.2,2.3Hz,1H),7.89–7.78(m,3H),7.50–7.43(m,2H),7.37(t,J＝8.8Hz,2H),7.32–7.25(m,2H),6.66(d,J＝5.2Hz,1H),6.51(d,J＝7.9Hz,1H),4.26(q,J＝7.0Hz,2H),4.16(s,2H),3.62(t,J＝5.3Hz,2H),3.30(s,3H),3.02(d,J＝7.3Hz,2H),1.31(t,J＝7.0Hz,3H),1.23(s,1H),1.20(t,J＝7.3Hz,1H).
The synthesis method of the compound 16 comprises the following steps:
compound 4(205mg,0.41mmol,1.00eq) was added to a reaction flask at ambient temperature, dissolved in DMF (2mL), HATU (171mg,0.45mmol,1.10eq) and DIEA (158mg,1.23mmol,3.0eq) were added to the reaction, and after stirring for 0.5 h, carboxylic acid 5(111.4mg,0.45mmol,1.10eq) was added to the reaction and stirring was continued for 4 h. After the reaction is stopped, the reaction solution is slowly poured into a saturated ammonium chloride solution, ethyl acetate is added for extraction for 3 times, a saturated saline solution is used for washing an organic phase, anhydrous sodium sulfate is dried, reduced pressure concentration is carried out at 40 ℃, silica gel is added for stirring a sample, and column chromatography purification is carried out to obtain 180mg of off-white solid.
LCMS(ESI):m/z 730[M+H]+。
Example 11 synthesis method:
compound 16(180mg,0.247mmol) was charged into a reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution of hydrogen chloride (0.45mL,0.90mmol) was added dropwise to the reaction, followed by stirring at room temperature for 3 hours. After the reaction is stopped, slowly dropwise adding a saturated sodium bicarbonate solution into the reaction solution, adding ethyl acetate for extraction for 3 times, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography reverse phase separation to obtain 130mg of a white solid.
LCMS(ESI):m/z 630[M+H]+。
1H NMR(500MHz,DMSO)δ11.96(s,1H),8.73(d,J＝5.1Hz,1H),8.70(d,J＝4.4Hz,2H),8.50(d,J＝7.5Hz,1H),8.40(s,2H),8.32(d,J＝7.5Hz,1H),8.23(s,1H),8.18(d,J＝8.1Hz,1H),7.92(dd,J＝8.1,1.7Hz,1H),7.85(d,J＝8.9Hz,2H),7.50(dd,J＝8.9,5.0Hz,2H),7.47–7.38(m,3H),7.30(d,J＝8.9Hz,2H),6.70(d,J＝7.7Hz,1H),6.65(d,J＝5.1Hz,1H),3.85(s,3H),3.45(t,J＝5.6Hz,2H),2.73(t,J＝5.6Hz,2H),2.08(s,3H).
The synthesis method of the compound 17 comprises the following steps:
compound 4(270mg,0.54mmol,1.0eq) was added to the reaction flask at ambient temperature, dissolved in DMF (2mL), HATU (308mg,0.81mmol,1.5eq) and DIEA (209mg,1.62mmol,3.0eq) were added to the reaction, and after stirring for 0.5 h carboxylic acid 6(150mg,0.65mmol,1.2eq) was added to the reaction and stirring continued for 16 h. After the reaction is stopped, the reaction solution is slowly poured into a saturated ammonium chloride solution, ethyl acetate is added for extraction for 3 times, a saturated saline solution is used for washing an organic phase, anhydrous sodium sulfate is dried, the organic phase is concentrated under reduced pressure at 40 ℃, silica gel is added for sample mixing, and column chromatography purification is carried out to obtain 200mg of off-white solid.
LCMS(ESI):m/z 737[M+Na]+。
Example 12 synthesis method:
compound 17(200mg,0.28mmol) was charged into a reaction flask at ordinary temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45mL,0.90mmol) of hydrogen chloride was added dropwise to the reaction, followed by continuous stirring at ordinary temperature for 6 hours. After the reaction is stopped, slowly dropwise adding a saturated sodium bicarbonate solution into the reaction solution, adding ethyl acetate for extraction for 3 times, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography reverse phase separation to obtain 57mg of white solid.
LCMS(ESI):m/z 615[M+H]+。
1H NMR(500MHz,DMSO)δ10.85(s,1H),8.73(d,J＝5.1Hz,1H),8.69(d,J＝2.4Hz,2H),8.41(s,2H),8.17(d,J＝8.1Hz,1H),7.90(dd,J＝8.1,2.3Hz,1H),7.78–7.73(m,2H),7.60(t,J＝7.7Hz,2H),7.52(t,J＝7.4Hz,1H),7.44(d,J＝7.7Hz,2H),7.32–7.26(m,2H),6.64(d,J＝5.1Hz,1H),3.82(s,2H),3.43(t,J＝5.6Hz,2H),3.36(s,3H),3.26(s,3H),2.71(d,J＝10.4Hz,5H),1.23(s,1H).
Method for synthesizing compound 18:
compound 4(80mg,0.16mmol,1.0eq) was added to a reaction flask at room temperature, dissolved in DMF (2mL), HATU (91mg,0.24mmol,1.5eq) and DIEA (62mg,0.48mmol,3.0eq) were added to the reaction, and after stirring for 0.5 h, carboxylic acid 7(34mg,0.18mmol,1.1eq) was added to the reaction and stirring was continued for 6 h. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, ethyl acetate was added to extract 3 times, the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, and then mixed with silica gel and purified by column chromatography to obtain 80mg of a yellow solid.
LCMS(ESI):m/z 673[M+H]+。
Example 13 synthesis method:
compound 18(80mg,0.12mmol) was charged into a reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution of hydrogen chloride (0.45mL,0.90mmol) was added dropwise to the reaction, followed by stirring at room temperature for 16 hours. After the reaction is stopped, slowly dropwise adding a saturated sodium bicarbonate solution into the reaction solution, adding ethyl acetate for extraction for 3 times, washing an organic phase with saturated saline water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing Flash column chromatography reverse phase separation to obtain 57mg of white solid.
LCMS(ESI):m/z 615[M+H]+。
1H NMR(500MHz,DMSO)δ11.96(s,1H),8.73(d,J＝5.1Hz,1H),8.70(d,J＝4.4Hz,2H),8.50(d,J＝7.5Hz,1H),8.40(s,2H),8.32(d,J＝7.5Hz,1H),8.23(s,1H),8.18(d,J＝8.1Hz,1H),7.92(dd,J＝8.1,1.7Hz,1H),7.85(d,J＝8.9Hz,2H),7.50(dd,J＝8.9,5.0Hz,2H),7.47–7.38(m,3H),7.30(d,J＝8.9Hz,2H),6.70(d,J＝7.7Hz,1H),6.65(d,J＝5.1Hz,1H),3.85(s,3H),3.45(t,J＝5.6Hz,2H),2.73(t,J＝5.6Hz,2H),2.08(s,3H).
Method for synthesizing compound 19:
compound 4(120mg,0.24mmol,1.0eq) was added to a reaction flask at room temperature, dissolved in DMF (2mL), HATU (137mg,0.36mmol,1.5eq) and DIEA (93mg,0.72mmol,3.0eq) were added to the reaction, and after stirring for 0.5 h, carboxylic acid 8(104mg,0.29mmol,1.2eq) was added to the reaction and stirring was continued for 16 h. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, ethyl acetate was added to extract 3 times, the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, and then mixed with silica gel and purified by column chromatography to obtain 90mg of a yellow solid.
LCMS(ESI):m/z 843[M+H]+。
Example 14 synthesis method:
compound 19(90mg,0.11mmol) was charged into a reaction flask at ordinary temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45mL,0.90mmol) of hydrogen chloride was added dropwise to the reaction, followed by stirring at ordinary temperature for 16 hours. After the reaction is stopped, slowly dropwise adding a saturated sodium bicarbonate solution into the reaction solution, adding ethyl acetate for extraction for 3 times, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing Flash column chromatography reverse phase separation to obtain 99mg of yellow solid.
LCMS(ESI):m/z 743[M+H]+。
1H NMR(500MHz,DMSO)δ12.64(s,1H),9.80–9.72(m,2H),9.14(s,1H),9.09(d,J＝6.5Hz,1H),8.99(s,1H),8.94(s,1H),8.74–8.67(m,2H),8.33(s,2H),7.98(d,J＝9.0Hz,2H),7.88(d,J＝12.8Hz,1H),7.49(d,J＝9.0Hz,2H),7.07(d,J＝6.4Hz,1H),4.87(dt,J＝7.3,3.6Hz,1H),4.32(t,J＝5.7Hz,3H),3.70(t,J＝5.3Hz,3H),3.31(s,2H),3.16(dt,J＝11.4,5.8Hz,5H),2.98–2.86(m,2H),2.19–2.12(m,1H),2.07(ddd,J＝13.3,8.8,4.6Hz,1H),1.89(dd,J＝10.0,5.6Hz,1H),1.84(d,J＝11.6Hz,1H),1.62(h,J＝6.7,5.4Hz,1H),1.49(dd,J＝14.0,7.9Hz,1H),1.43(d,J＝6.7Hz,3H),1.22(d,J＝2.4Hz,1H).
The synthesis method of the compound 20 comprises the following steps:
compound 4(70mg,0.14mmol,1.0eq) was added to a reaction flask at room temperature, dissolved in DMF (2mL), HATU (80mg,0.21mmol,1.5eq) and DIEA (54mg,0.42mmol,3.0eq) were added to the reaction, and after stirring for 0.5 h, carboxylic acid 9(55mg,0.15mmol,1.1eq) was added to the reaction and stirring was continued for 16 h. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, ethyl acetate was added to extract 3 times, the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, and then mixed with silica gel and purified by column chromatography to obtain 97mg of a yellow solid.
LCMS(ESI):m/z 842[M+H]+。
Example 15 synthesis method:
compound 20(97mg,0.11mmol) was charged into a reaction flask at ordinary temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45mL,0.90mmol) of hydrogen chloride was added dropwise to the reaction, followed by stirring at ordinary temperature for 16 hours. After the reaction is stopped, slowly dropwise adding a saturated sodium bicarbonate solution into the reaction solution, adding ethyl acetate for extraction for 3 times, washing an organic phase with saturated saline water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing Flash column chromatography reverse phase separation to obtain 80mg of light yellow solid.
LCMS(ESI):m/z 742[M+H]+。
1H NMR(500MHz,CDCl3)δ12.50(s,1H),8.88(s,1H),8.71(s,1H),8.58(d,J＝36.4Hz,2H),8.45(d,J＝8.8Hz,1H),8.23(s,1H),8.03(m,3H),7.83(d,J＝8.7Hz,2H),7.41(s,1H),7.17(s,2H),6.59(s,1H),4.27(m,1H),4.15(dd,J＝9.1,0.7Hz,2H),3.88(m,1H),3.72(s,3H),3.45(t,J＝5.6Hz,2H),3.35(t,J＝ 4.5Hz,4H),2.73(t,J＝5.6Hz,2H),2.69(s,4H),2.52(q,J ＝7.0Hz,2H),1.36(m,2H),1.21(m,2H),1.15(t,J＝ 7.0 Hz,3H).
The synthesis method of the compound 21 comprises the following steps:
compound 4(100mg,0.20mmol,1.0eq) was added to a reaction flask at ambient temperature, dissolved in DMF (2mL), HATU (114mg,0.30mmol,1.5eq) and DIEA (77mg,0.60mmol,3.0eq) were added to the reaction, and after stirring for 0.5 h, carboxylic acid 10(87mg,0.24mmol,1.2eq) was added to the reaction and stirring continued for 16 h. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, ethyl acetate was added to extract 3 times, the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, and then mixed with silica gel and purified by column chromatography to obtain 100mg of a yellow solid.
LCMS(ESI):m/z 844[M+H]+。
Example 16 synthesis method:
compound 21(100mg,0.12mmol) was charged into a reaction flask at ordinary temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45mL,0.90mmol) of hydrogen chloride was added dropwise to the reaction, followed by continuous stirring at ordinary temperature for 3.5 hours. After the reaction is stopped, slowly dropwise adding a saturated sodium bicarbonate solution into the reaction solution, adding ethyl acetate for extraction for 3 times, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography reverse phase separation to obtain 89mg of off-white solid.
LCMS(ESI):m/z 744[M+H]+。
1H NMR(500MHz,DMSO)δ12.51(s,1H),8.93(s,1H),8.74(d,J＝5.1Hz,1H),8.69(s,2H),8.41(s,2H),8.17(d,J＝8.1Hz,1H),7.90(t,J＝9.0Hz,3H),7.60(d,J＝12.5Hz,1H),7.34(d,J＝8.5Hz,2H),6.67(d,J＝5.1Hz,1H),4.91(d,J＝7.0Hz,1H),4.56(d,J＝11.1Hz,1H),4.38(dd,J＝11.7,2.5Hz,1H),3.81(s,1H),3.43(t,J＝5.7Hz,2H),3.29–3.25(m,8H),2.69(t,J＝5.7Hz,2H),2.45(d,J＝5.1Hz,4H),2.23(s,3H),1.46(d,J＝6.8Hz,3H),1.23(s,1H).
Method for synthesizing compound 22:
compound 4(100mg,0.20mmol,1.0eq) was added to a reaction flask at room temperature, dissolved in DMF (2mL), HATU (114mg,0.30mmol,1.5eq) and DIEA (77mg,0.60mmol,3.0eq) were added to the reaction, and after stirring for 0.5 h, carboxylic acid 11(87mg,0.24mmol,1.2eq) was added to the reaction and stirring was continued for 2 h. After the reaction is stopped, the reaction solution is slowly poured into a saturated ammonium chloride solution, ethyl acetate is added for extraction for 3 times, a saturated saline solution is used for washing an organic phase, anhydrous sodium sulfate is dried, reduced pressure concentration is carried out at 40 ℃, silica gel is added for stirring a sample, and column chromatography purification is carried out to obtain 25mg of yellow solid.
LCMS(ESI):m/z 818[M]+。
Example 17 synthesis method:
compound 22(25mg,0.03mmol) was charged into a reaction flask at ordinary temperature, dissolved in 2mL of methanol, and a dioxane solution (0.45mL,0.90mmol) of hydrogen chloride was added dropwise to the reaction, followed by continuous stirring at ordinary temperature for 3.5 hours. After the reaction is stopped, slowly dropwise adding a saturated sodium bicarbonate solution into the reaction solution, adding ethyl acetate for extraction for 3 times, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography reverse phase separation to obtain 17mg of a white solid.
LCMS(ESI):m/z 718[M]+。
1H NMR(500MHz,DMSO)δ12.19(s,1H),8.75(d,J＝3.6Hz,3H),8.71(s,1H),8.42(s,2H),8.30(d,J＝9.1Hz,1H),8.23(d,J＝8.2Hz,1H),7.98(dd,J＝8.2,2.3Hz,1H),7.90(d,J＝9.0Hz,2H),7.82(dd,J＝8.8,4.8Hz,2H),7.57(t,J＝8.7Hz,2H),7.35(d,J＝8.8Hz,2H),7.30(d,J＝6.1Hz,1H),6.68(d,J＝5.1Hz,1H),3.97(s,2H),3.50(t,J＝5.5Hz,2H),3.28(s,3H),2.85(t,J＝5.5Hz,2H),1.23(s,1H).
The synthetic routes for examples 2 and 8 are shown in scheme two below:
technical scheme two
The synthesis method of the compound 5 comprises the following steps:
compound 3(400mg,0.94mmol,1.00eq), 2-fluoro-p-nitrophenol (162mg,1.03mmol,1.1eq) were added to a reaction flask at room temperature, dissolved in 5mL of chlorobenzene, exchanged with nitrogen 3 times, and transferred to a 150 ℃ oil bath and stirred for 4 hours. After the reaction was terminated, the reaction mixture was cooled to room temperature, slowly poured into water, extracted with ethyl acetate 3 times, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, stirred with silica gel, and purified by column chromatography to give 410mg of a light brown solid.
LCMS(ESI):m/z 549[M+H]+。
The synthesis method of the compound 6 comprises the following steps:
compound 5(410mg,0.74mmol,1.00eq) was charged into a reaction flask at room temperature, dissolved in methanol (5mL), Pd/C (40mg, 10%) was added to the reaction, nitrogen was exchanged 3 times, hydrogen was replaced, and the reaction was stirred at room temperature for 4 hours. After the reaction is stopped, the palladium-carbon is filtered, the filtrate is decompressed and concentrated at 40 ℃, silica gel is added for mixing samples, and column chromatography purification is carried out to obtain 360mg of off-white solid.
LCMS(ESI):m/z 519[M+H]+
Method for synthesizing compound 22:
compound 6(180mg,0.35mmol,1.00eq) was added to a reaction flask at room temperature, dissolved in DMF (2mL), HATU (145mg,0.38mmol,1.10eq), DIEA (135mg,1.05mmol,3.0eq) were added to the reaction, and after stirring for 0.5 h, carboxylic acid 1(84mg,0.38mmol,1.10eq) was added to the reaction and stirring was continued for 4 h. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, ethyl acetate was added to extract 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, and then stirred with silica gel, and purified by column chromatography to obtain 230mg of an off-white solid.
LCMS(ESI):m/z 724[M+H]+。
Example 2 synthesis method:
compound 22(220mg,0.32mmol,1.00eq) was added to a reaction flask at room temperature, dissolved in 2mL of methanol, and a dioxane solution of hydrogen chloride (0.45mL,0.90mmol,2mol/L) was added dropwise to the reaction, followed by stirring at room temperature for 2.5 hours. After the reaction was stopped, a saturated sodium bicarbonate solution was slowly dropped into the reaction solution, ethyl acetate was added to extract 3 times, the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, and purified by reverse phase column chromatography to obtain 50mg of a white solid.
LCMS(ESI):m/z 624[M+H]+。
1H NMR(500MHz,DMSO)δ10.39(s,1H),9.99(s,1H),8.74(d,J＝5.1Hz,1H),8.70(d,J＝5.5Hz,2H),8.44(s,2H),8.18(d,J＝8.1Hz,1H),7.92(t,J＝9.1Hz,2H),7.65(dd,J＝8.0,5.2Hz,2H),7.54(d,J＝8.9Hz,1H),7.47(t,J＝8.9Hz,1H),7.15(t,J＝8.5Hz,2H),6.62(d,J＝5.1Hz,1H),3.82(s,2H),3.43(t,J＝5.4Hz,2H),2.69(t,J＝5.5Hz,2H),1.49(s,4H),1.23(s,2H).
Method for synthesizing compound 22:
compound 6(180mg,0.35mmol,1.00eq) was added to a reaction flask at ambient temperature, dissolved in DMF (2mL), HATU (145mg,0.38mmol,1.10eq), DIEA (135mg,1.05mmol,3.0eq) were added to the reaction, and after stirring for 0.5 h, carboxylic acid 2(111.6mg,0.38mmol,1.10eq) was added to the reaction and stirring continued for 8 h. After the reaction was stopped, the reaction solution was slowly poured into a saturated ammonium chloride solution, ethyl acetate was added to extract 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, stirred with silica gel, and purified by column chromatography to obtain 210mg of an off-white solid.
LCMS(ESI):m/z 793[M+H]+。
Example 8 synthesis method:
compound 22(210mg,0.26mmol) was charged into a reaction flask at ordinary temperature, dissolved in 2mL of methanol, and a dioxane solution of hydrogen chloride (0.45mL,0.90mmol,2mol/L) was added dropwise to the reaction, followed by stirring at ordinary temperature for 2.5 hours. After the reaction was stopped, a saturated sodium bicarbonate solution was slowly dropped into the reaction solution, ethyl acetate was added to extract 3 times, the organic phase was washed with a saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, and purified by reverse phase column chromatography to obtain 25mg of a white solid.
LCMS(ESI):m/z 693[M+H]+。
1H NMR(500MHz,DMSO)δ11.05(s,1H),8.78–8.66(m,4H),8.43(s,2H),8.19(d,J＝8.2Hz,1H),8.04(dd,J＝12.8,2.5Hz,1H),7.93(d,J＝8.1Hz,1H),7.59–7.53(m,1H),7.49(t,J＝8.9Hz,1H),7.44(dd,J＝8.7,5.1Hz,2H),7.36(t,J＝8.6Hz,2H),6.66(d,J＝5.1Hz,1H),4.78(h,J＝6.7Hz,1H),3.86(s,2H),3.45(t,J＝5.6Hz,2H),3.26(s,3H),2.73(t,J＝5.7Hz,2H),1.43(d,J＝6.7Hz,6H).
The synthetic route of the embodiment 3-5 is shown as the following technical route III:
technical route three
The synthesis of compound 7 refers to the method in patent CN 109761899 a.
Synthesis of compound 8:
7-bromo-4-chloroquinoline (968mg,4.00mmol,1.00eq), compound 7(1.38g,4.40mmol,1.10eq), potassium tert-butoxide (1.34g,12.04mmol,3.00eq) were added to a reaction flask at room temperature, 10mL of DMSO was added and dissolved, nitrogen was exchanged 3 times, and the mixture was transferred to a 100 ℃ oil bath and stirred for 6 hours. After the reaction was stopped, the reaction solution was cooled to room temperature, slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, and subjected to column chromatography to obtain 1.30g of a white solid.
LCMS(ESI):m/z 520/522[M+H]+。
Method for synthesis of compound 9:
compound 8(700mg,1.34mmol,1.00eq),1,1' -bis-diphenylphosphino ferrocene palladium dichloride (98mg,0.13mmol,0.10eq), potassium acetate (394mg,4.02mmol,3.00eq), pinacol diboron (406mg,1.61mmol,1.2eq) was added to a reaction flask at ambient temperature, dissolved by adding 10mL of 1, 4 dioxane, replaced with nitrogen gas 3 times, and transferred to a 90 ℃ oil bath pan and stirred for 6 hours. After the reaction was stopped, the reaction solution was cooled to 20 ℃, slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, and subjected to column chromatography to obtain 530mg of an off-white solid.
LCMS(ESI):m/z 568[M+H]+。
Synthetic method of example 3:
compound 9(500mg,0.88mmol,1.00eq),1,1' -bis-diphenylphosphino ferrocene dichloropalladium (64mg,0.09mmol,0.10eq), potassium carbonate (364mg,2.64mmol,3.0eq), L1(225mg,0.88mmol,1.00eq) were added to a reaction flask at room temperature, 1, 4-dioxane 15mL and water 5mL were added to dissolve into a suspension, nitrogen gas was exchanged for 3 times, and the mixture was transferred to a 90 ℃ oil bath and stirred for 6.5 hours. After the reaction was stopped, the reaction mixture was cooled to 20 ℃, poured slowly into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, and subjected to column chromatography to give 126mg of a white solid.
LCMS(ESI):m/z 618[M+H]+。
1H NMR(500MHz,DMSO)δ10.19(s,1H),10.04(s,1H),8.73(d,J＝5.1Hz,1H),8.71–8.66(m,2H),8.41(s,2H),8.19(d,J＝8.1Hz,1H),7.88(dd,J＝8.1,2.0Hz,1H),7.78(d,J＝8.9Hz,2H),7.64(dd,J＝9.0,5.1Hz,2H),7.28(d,J＝8.9Hz,2H),7.15(t,J＝8.9Hz,2H),6.61(d,J＝5.1Hz,1H),3.60(dd,J＝9.3,4.7Hz,6H),2.42(s,4H),1.49(s,4H),1.23(s,2H).
Synthetic method of example 4:
compound 9(500mg,0.88mmol,1.00eq),1,1' -bis-diphenylphosphino ferrocene palladium dichloride (64mg,0.09mmol,0.10eq), potassium carbonate (364mg,2.64mmol,3.0eq), L2(258mg,0.88mmol,1.00eq) were added to a reaction flask at room temperature, 1, 4-dioxane 15mL and water 5mL were added to dissolve into a suspension, nitrogen was exchanged for 3 times, and the mixture was transferred to a 90 ℃ oil bath and stirred for 6.5 hours. After the reaction was stopped, the reaction mixture was cooled to 20 ℃ and slowly poured into a saturated ammonium chloride solution, ethyl acetate was added to extract the mixture for 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃ and subjected to reverse phase column chromatography to obtain 85mg of a white solid.
LCMS(ESI):m/z 654[M+H]+。
1H NMR(500MHz,DMSO)δ10.19(s,1H),10.04(s,1H),8.72(dd,J＝10.9,7.1Hz,3H),8.41(s,2H),8.21(d,J＝8.1Hz,1H),7.95–7.90(m,1H),7.79(d,J＝8.5Hz,2H),7.65(dd,J＝8.8,5.1Hz,2H),7.28(d,J＝8.5Hz,2H),7.15(t,J＝8.7Hz,2H),6.61(d,J＝5.1Hz,1H),3.87(s,2H),3.33(s,2H),3.05(s,3H),3.00(t,J＝6.8Hz,2H),1.49(s,4H).
Synthetic method of example 5:
compound 9(500mg,0.88mmol,1.00eq),1,1' -bis-diphenylphosphino ferrocene palladium dichloride (64mg,0.09mmol,0.10eq), potassium carbonate (364mg,2.64mmol,3.0eq), L3(215mg,0.88mmol,1.00eq) were added to a reaction flask at room temperature, 1, 4-dioxane 15mL and water 5mL were added to dissolve into a suspension, nitrogen was exchanged for 3 times, and the mixture was transferred to a 90 ℃ oil bath and stirred for 6.5 hours. After the reaction was stopped, the reaction mixture was cooled to 20 ℃ and slowly poured into a saturated ammonium chloride solution, ethyl acetate was added to extract the mixture for 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃ and subjected to reverse phase column chromatography to obtain 282mg of a white solid.
LCMS(ESI):m/z 605[M+H]+。
1H NMR(500MHz,DMSO)δ10.19(s,1H),10.04(s,1H),8.71(d,J＝5.1Hz,1H),8.37(d,J＝8.6Hz,1H),8.27(d,J＝1.8Hz,1H),7.99(dd,J＝8.7,1.9Hz,1H),7.83(d,J＝8.2Hz,2H),7.80–7.75(m,2H),7.67–7.61(m,2H),7.50(d,J＝7.9Hz,2H),7.30–7.23(m,2H),7.15(t,J＝8.9Hz,2H),6.59(d,J＝5.1Hz,1H),3.81(s,2H),3.44(t,J＝5.7Hz,2H),3.26(s,3H),2.70(t,J＝5.7Hz,2H),1.49(s,4H).
The synthetic routes of examples 9 and 18-19 are shown in the following technical route IV:
technical route four
Method for synthesis of compound 10:
7-bromo-4-chloro-quinazoline (300mg,1.23mmol,1.00eq), compound 7(387mg,1.23mmol,1.00eq), t-BuOK (276mg,2.46mmol,2.00eq) were added to the reaction flask at room temperature, dissolved in 3mL of DMSO, purged with nitrogen 3 times, transferred to an 80 ℃ oil bath and stirred for 3.5 hours. After the reaction was stopped, the reaction solution was cooled to 20 ℃, slowly poured into a saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 40 ℃ to obtain 270mg of a brown oily crude product, which was used directly in the next step.
Method for synthesis of compound 11:
compound 10(270mg, crude), B2(Pin)2(138mg,533umol), potassium acetate (152mg,1.55mmol), Pd (dppf) Cl2·CH2Cl2(42mg) was added to a reaction flask at normal temperature, 2mL of dioxane was added and dissolved, nitrogen was exchanged 3 times, and the mixture was transferred to an oil bath at 80 ℃ and stirred for 3.5 hours. After the reaction was stopped, the reaction mixture was cooled to 20 ℃ and slowly poured into a saturated ammonium chloride solution, extracted with ethyl acetate 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃, and purified by reverse phase column chromatography to obtain 100mg of a yellow oily substance.
LCMS(ESI):m/z 569[M+H]+。
Synthetic method of example 9:
compound 11(100mg,176mmol,1.0eq), L4(51.0mg,208umol,1.2eq), potassium carbonate (73.0mg,529umol,3.0eq), Pd (dppf) Cl2(13.0mg,17.7umol,0.1eq) was added to a reaction flask at room temperature, 1.5mL of dioxane and 0.5mL of water were added and dissolved, nitrogen was exchanged for 3 times, and the mixture was transferred to a 90 ℃ oil bath and stirred for 3.5 hours. After the reaction was stopped, the reaction mixture was cooled to 20 ℃ and slowly poured into a saturated ammonium chloride solution, ethyl acetate was added to extract the mixture for 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃ and subjected to reverse phase column chromatography to obtain 27mg of a white solid.
LCMS(ESI):m/z 607[M+H]+。
1H NMR(500MHz,DMSO)δ10.15(s,1H),10.06(s,1H),8.76–8.69(m,2H),8.64(d,J＝1.7Hz,1H),8.53(dd,J＝8.6,1.8Hz,1H),8.46(d,J＝8.7Hz,1H),8.23(d,J＝8.1Hz,1H),7.93(dd,J＝8.2,2.3Hz,1H),7.73(d,J＝8.7Hz,2H),7.65(dd,J＝8.9,5.1Hz,2H),7.31(d,J＝8.8Hz,2H),7.15(t,J＝8.9Hz,2H),3.83(s,2H),3.43(t,J＝5.7Hz,2H),3.25(s,3H),2.69(t,J＝5.7Hz,2H),1.49(s,4H).
Synthetic method for example 18:
compound 11(100mg,0.176mmol,1.0eq), L6(33.0mg,0.208mmol,1.2eq), potassium carbonate (73.0mg,0.529mmol,3.0eq), Pd (dppf) Cl2(13.0mg, 17.7. mu. mol,0.1eq) was added to a reaction flask at room temperature, 1.5mL of 1, 4-dioxane and 0.5mL of water were added and dissolved, nitrogen was exchanged 3 times, and the mixture was stirred in an oil bath at 90 ℃ for 3.5 hours. After the reaction is stopped, the reaction solution is cooled to 20 ℃, slowly poured into saturated ammonium chloride solution, added with ethyl acetate for extraction for 3 times, the organic phase is washed by saturated saline solution, dried by anhydrous sodium sulfate, decompressed and concentrated at 40 ℃,the reverse phase column chromatography gave 24mg of a white solid.
LCMS(ESI):m/z 520[M+H]+。
1H NMR(500MHz,DMSO-d6)δ10.11(d,J＝44.4Hz,2H),8.80(d,J＝4.0Hz,1H),8.76(s,1H),8.66(d,J＝1.7Hz,1H),8.54(dd,J＝8.7,1.7Hz,1H),8.48(d,J＝8.6Hz,1H),8.28(d,J＝7.9Hz,1H),8.00(td,J＝7.7,1.8Hz,1H),7.77–7.70(m,2H),7.68–7.61(m,2H),7.50(ddd,J＝7.6,4.7,1.0Hz,1H),7.35–7.28(m,2H),7.18–7.11(m,2H),1.49(s,4H).
Synthetic method for example 19:
compound 10(200mg,0.384mmol,1eq), L5(138mg,0.533mmol), cesium carbonate (375mg,1.15mmol,2.99eq), XPhos-Pd-G3(32mg,0.038mmol,0.10eq) were added to a reaction flask at room temperature, dissolved in 4mL dioxane was added, nitrogen was exchanged 3 times, and the mixture was transferred to a 100 ℃ oil bath and stirred for 3.5 hours. After the reaction was stopped, the reaction solution was cooled to 20 ℃ and slowly poured into a saturated ammonium chloride solution, extracted with ethyl acetate 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 ℃ and purified by reverse phase column chromatography to obtain 28mg of a white powder.
LCMS(ESI):m/z 553[M+H]+。
1H NMR(500MHz,DMSO-d6)δ10.14(s,1H),10.06(s,1H),8.66(s,1H),8.49(s,1H),8.32(d,J＝8.6Hz,1H),8.21–8.14(m,2H),8.03(dd,J＝8.6,1.8Hz,1H),7.75–7.68(m,2H),7.68–7.60(m,2H),7.32–7.25(m,2H),7.18–7.11(m,2H),4.95(t,J＝5.4Hz,1H),4.21(t,J＝5.6Hz,2H),3.81(q,J＝5.4Hz,2H),1.49(s,4H).
Test example 1: inhibition of enzymatic Activity of the kinases AXL and C-MET (IC) by Compounds of the invention50) Evaluation experiment of
In the experiment, a Mobility shift assay method is used, compounds are screened on AXL and C-MET kinase, the initial concentration is 10000nM, the concentration is diluted by 3 times, the concentrations are 10, and compound hole detection is carried out.
Reagents and consumables (table 1):
TABLE 1
The instrument comprises:
a centrifuge (manufacturer: Eppendorf, model 5430);
enzyme-labeling instrument (manufacturer: Perkin Elmer, model: Caliper EZ Reader II);
echo 550 (manufacturer: Labcyte, model: Echo 550);
microplate reader (manufacturer: Perkin Elmer, model: Envision).
The experimental steps are as follows:
1) a1 XKinase buffer was prepared.
2) Preparation of compound concentration gradient: the test concentration of the tested compound is 10000nM, 3 times dilution, 10 concentrations, and multiple-hole detection; 100% DMSO solution diluted to 100-fold final concentration in 384source plates, 3-fold compound dilution, 10 concentrations. 250nL of 100-fold final concentration of compound was transferred to a 384-well plate of interest using a dispenser Echo 550.
3) A2.5 fold final concentration of Kinase solution was prepared using a 1 XKinase buffer.
4) Add 10. mu.L of 2.5 fold final concentration kinase solution to the compound well and positive control well, respectively; mu.L of 1 XKinase buffer was added to the negative control wells.
5) Centrifuge at 1000rpm for 30 seconds, shake the plate and incubate at room temperature for 10 minutes.
6) A mixture of ATP and Kinase substrate at 5/3 fold final concentration was made up using 1 XKinase buffer.
7) The reaction was initiated by adding 15. mu.L of a mixed solution of ATP and substrate at 5/3-fold final concentration.
8) The 384 well plates were centrifuged at 1000rpm for 30 seconds, shaken and mixed and incubated at room temperature for the appropriate time.
9) Add 30. mu.L of termination detection solution to stop the kinase reaction, centrifuge at 1000rpm for 30 seconds, shake and mix.
10) The conversion was read using a Caliper EZ Reader.
11) The dose-effect curves were fitted with the analytical software GraphPad Prism 5 log (inhibitor) vs. response-Variable slope to give IC50 values for each compound for enzyme activity. Cabozantinib (Cabozantinib) was used as a positive control.
The inhibitory activity of the compounds of the invention on the kinases AXL and C-MET is shown in Table 2 below.
TABLE 2
Test example 2: drug effect test of compound of the invention on mouse ectopic inoculation of human gastric cancer cell line A549
Selecting 50 female Balb/c nude mice with the age of 6-8 weeks, and inoculating a human lung cancer cell line A549 tumor cell strain 5 x 10 to the subcutaneous ectopic position626 days after the inoculation of the tumor cells, the tumor grows to 60mm3～250mm3At that time, 12 mice were randomly selected and administered to test samples by gavage.
Mice were divided into a negative solvent control group, a compound of the invention group (example 1 compound, 20mg/kg) and a positive control Sitravatinib group (20mg/kg, purchased from Shanghai blue Wood chemical Co., Ltd.), each group containing 4 mice. All dosage groups adopt equal-volume unequal-concentration oral administration with single intragastric administration per day, and the administration volume is 10 mL/kg. The negative solvent control group was administered the same volume of blank vehicle (DMSO: Solutol: water 1: 2: 7) once a day for 15 consecutive days.
After the start of the administration, the body weight and tumor size of the mice were measured twice a week. Tumor size calculation formula:
tumor volume (mm)3) 0.5 × (tumor major diameter × tumor minor diameter)2)。
The antitumor efficacy was evaluated based on the growth curve of the tumor under treatment (i.e., tumor volume per measurement versus its number of days of treatment) and relative tumor volume. Wherein the relative tumor inhibition ratio (TGI) is calculated according to the following formula:
relative tumor inhibition TGI (%): TGI% (1-T/C) × 100%.
T/C% is the relative tumor proliferation rate, i.e., the percentage value of the relative tumor volume or tumor weight of the treated and control groups at a certain time point. T and C are the Relative Tumor Volume (RTV) or Tumor Weight (TW) at a particular time point in the treated and control groups, respectively. The calculation formula is as follows: T/C%RTV/CRTV×100％(TRTV: treatment group mean RTV; cRTV: vehicle control mean RTV; RTV-V0, V0 is the tumor volume of the animal at the time of grouping and Vt is the tumor volume of the animal after treatment). Or T/C% ═ TTW/CTW × 100% (TTW: average tumor weight at the end of the test in the treatment group and CTW: average tumor weight at the end of the test in the vehicle control group).
FIG. 1 shows the growth changes in tumor volume in mice of compound, solvent control, and positive control groups. As shown in the figure, the compound can effectively inhibit the growth of tumor cells in a model mouse, and the relative tumor inhibition rate (TGI) is 107.58% by volume and is higher than 106.82% of positive control Sitravatinib.
Figure 2 shows the body weight of mice in the compound, solvent control and positive control groups as a function of time of treatment. As shown in the figure, the body weight of the tumor-bearing mice has no obvious change in the experimental process, and the compound provided by the invention has good safety and tolerance.
Table 3 shows the absolute mass (mg) of the tumors in each group of animals at the end of the test. As shown in the table, the compound can effectively inhibit the growth of tumor cells in a model mouse, wherein the growth is 68.34% by tumor weight and is higher than 57.37% of positive control Sitravatinib.
TABLE 3
Test example 3: drug effect test of the compound on mouse ectopic inoculation human gastric cancer cell line MKN45
Selecting 50 female Balb/c nude mice with the age of 6-8 weeks, inoculating a human lung cancer cell line MKN45 tumor cell line 5 x 10 in an ectopic manner under the skin69 days after inoculating the tumor cells, the tumor grows to 90mm3～300mm3At that time, 12 mice were randomly selected and administered to test samples by gavage.
Mice were divided into a negative solvent control group, a compound of the invention group (example 1 compound, 20mg/kg) and a positive control group XL092 (20mg/kg, compound 8 in CN 111757735A), with 4 mice per group. All dose groups adopt equal-volume unequal-concentration oral administration and single-time intragastric administration every day, and the administration volume is 10 mL/kg. The negative solvent control group was administered the same volume of blank vehicle (DMSO: Solutol: water 1: 2: 7) once a day at a dosing frequency for 11 consecutive days.
After the start of the administration, the body weight and tumor size of the mice were measured twice a week. Tumor size calculation formula:
tumor volume (mm)3) 0.5 × (tumor major diameter × tumor minor diameter)2)。
The antitumor efficacy was evaluated based on the growth curve of the tumor under treatment (i.e., tumor volume per measurement versus its number of days of treatment) and relative tumor volume. Wherein the relative tumor inhibition (TGI) is calculated according to the following formula:
relative tumor inhibition ratio TGI (%): TGI% (1-T/C) × 100%.
T/C% is the relative tumor proliferation rate, i.e., the percentage value of the relative tumor volume or tumor weight of the treated and control groups at a certain time point. T and C are the Relative Tumor Volume (RTV) or Tumor Weight (TW) at a particular time point in the treated and control groups, respectively. The calculation formula is as follows: T/C%RTV/CRTV×100％(TRTV: treatment group mean RTV; cRTV: vehicle control mean RTV; RTV-V0, V0 is the tumor volume of the animal at the time of the grouping, and Vt is the tumor volume of the animal after treatment). Or T/C% ═ TTW/CTW × 100% (TTW: average tumor weight at the end of the test in the treatment group and CTW: average tumor weight at the end of the test in the vehicle control group).
FIG. 3 shows the growth changes in tumor volume in mice of compound, solvent control, and positive control groups. As shown in the figure, the compound can effectively inhibit the growth of tumor cells in a model mouse, and the relative tumor inhibition rate (TGI) is 108.91% by volume and is higher than 105.21% of XL 092.
Figure 4 shows the body weight of mice in the compound, solvent control and positive control groups as a function of time of treatment. As shown in the figure, the body weight of tumor-bearing mice does not change obviously in the experimental process, and the compound provided by the invention has good safety and tolerance.
Table 4 shows the absolute mass (mg) of the tumors in each group of animals at the end of the test. As shown in the table, the compound can effectively inhibit the growth of tumor cells in a model mouse, wherein the growth is 87.93% in terms of tumor weight and is higher than 75.41% of positive control XL 092.
TABLE 4
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, so as to understand the technical solutions of the present invention specifically and in detail, but not to be understood as the limitation of the protection scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. It should be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the appended claims. Therefore, the protection scope of the patent of the invention is subject to the content of the appended claims, and the description can be used for explaining the content of the claims.
Claims (10)
1. A heteroaromatic ring derivative with a structure shown as a formula (I), or a salt thereof, or a pharmaceutically acceptable carrier thereof:
R1selected from: h or halogen; n is selected from: 0.1, 2,3 or 4;
W1、W2each independently selected from: CH or N;
ring A is selected from: pyridyl, phenyl or pyrazolyl;
R2each independently selected from: H. -L-NRaRbOR-L-ORaL is selected from: a single bond, a,
Or C1 to C5 alkylene;
Ra、Rbeach independently selected from: h or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted by 1 or 2 substituents selected from S1; substituents of group S1 are selected from: C1-C5 alkoxy and-S (O)2C1-C5 alkyl;
or Ra、RbTogether with the nitrogen atom to which they are attached form a 4-to 10-membered heterocycloalkyl group;
g is selected from: 5-15 membered heteroAn aromatic ring, a 4-to 10-membered heterocycloalkyl group or a C3-to C6 cycloalkyl group; wherein the 5-15 membered heteroaromatic ring, 4-10 membered heterocycloalkyl or C3-C6 cycloalkyl is unsubstituted or substituted with 1, 2,3, 4, 5 substituents selected from S2; substituents of group S2 are selected from: halogen, C1-C5 alkyl, C3-C5 cycloalkyl, C1-C5 alkoxy, oxo, halogen substituted or unsubstituted C6-C10 aromatic ring, C1-C3 alkyl substituted or unsubstituted 5-to 10-membered heterocycloalkyl, hydroxy substituted or unsubstituted 5-to 10-membered heterocycloalkyl, and-C (═ O) -NH-Rc；RcSelected from halogen substituted or unsubstituted C6-C10 aromatic rings;
and formula (I) satisfies the following conditions:
when the temperature is higher than the set temperature
Is composed of
When W is1Is not CH.
2. The heteroaromatic ring derivative according to claim 1, wherein L is selected from the group consisting of: a single bond or a C1-C2 alkylene group.
3. The heteroaromatic ring derivative according to claim 1, wherein R is R2is-L-NRaRbL is selected from: a single bond or a C1-C2 alkylene group; r isaIs H, RbSelected from: C1-C4 alkyl, wherein the C1-C3 alkyl is unsubstituted or substituted with a substituent optionally selected from the group S1; substituents of group S1 are selected from: C1-C2 alkoxy and-S (O)2C1-C2 alkyl.
4. The heteroaromatic ring derivative according to claim 1, wherein R is R or a salt thereof, or a pharmaceutically acceptable carrier thereof2is-L-NRaRbL is selected from: a single bond or a C1-C2 alkylene group; r isa、RbThe nitrogen atoms connected with the heterocyclic ring form a 4-10-membered heterocyclic alkyl group together, and the heterocyclic alkyl group has a structure shown in the following general formula (I-1):
wherein, X1、X2Each independently selected from: CRdRe、O、NRdS or S (O)2Wherein R isd、ReSelected from H, C1-C6 alkyl or C3-C6 cycloalkyl.
5. The heteroaromatic ring derivative according to claim 1, wherein R is R or a salt thereof, or a pharmaceutically acceptable carrier thereof2is-L-ORaL is selected from: a single bond or C1-C2 alkylene, RaIs H.
6. The heteroaromatic derivative according to any one of claims 1 to 5, wherein the heteroaromatic derivative is a salt thereof or a pharmaceutically acceptable carrier thereof,
selected from the group consisting of:
7. the heteroaromatic ring derivative according to any one of claims 1 to 5, wherein G is selected from the group consisting of the following structures:
8. the heteroaromatic derivative according to claim 1, wherein the heteroaromatic derivative is any one of the following compounds:
9. the use of the heteroaromatic ring derivative of any one of claims 1 to 8, or a salt thereof, or a pharmaceutically acceptable carrier thereof in the preparation of a c-Met-Axl dual-purpose kinase inhibitor.
10. Use of the heteroaromatic ring derivative according to any one of claims 1 to 8, or a salt thereof, or a pharmaceutically acceptable carrier thereof in preparation of an antitumor drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210099079.2A CN114573553B (en) | 2022-01-27 | 2022-01-27 | Heteroaromatic ring derivative and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210099079.2A CN114573553B (en) | 2022-01-27 | 2022-01-27 | Heteroaromatic ring derivative and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114573553A true CN114573553A (en) | 2022-06-03 |
| CN114573553B CN114573553B (en) | 2023-11-10 |
Family
ID=81771267
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210099079.2A Active CN114573553B (en) | 2022-01-27 | 2022-01-27 | Heteroaromatic ring derivative and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114573553B (en) |
Citations (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102212062A (en) * | 2010-04-02 | 2011-10-12 | 东莞市长安东阳光新药研发有限公司 | Derivative of amino ester, salt thereof and using method |
| CN102245595A (en) * | 2008-10-14 | 2011-11-16 | 株式会社新药 | Heterocyclic compound as protein kinase inhibitor |
| CN102675282A (en) * | 2011-03-15 | 2012-09-19 | 广东东阳光药业有限公司 | Substitutive quinoline compound and application method and uses thereof |
| CN103420986A (en) * | 2012-05-18 | 2013-12-04 | 广东东阳光药业有限公司 | Compound replacing quinoidines as well as using method and application of compound |
| CN107286140A (en) * | 2016-04-12 | 2017-10-24 | 上海医药工业研究院 | Substituted aromatic amines base heteroaromatic class compound and its application as antineoplastic |
| CN108358839A (en) * | 2018-03-13 | 2018-08-03 | 广州六顺生物科技有限公司 | A kind of tyrosine kinase inhibitor and its application |
| CN109776432A (en) * | 2019-03-21 | 2019-05-21 | 广州六顺生物科技股份有限公司 | A kind of preparation method and application of multiple target point kinase inhibitor, pharmaceutical composition and multiple target point kinase inhibitor |
| CN110218205A (en) * | 2019-07-05 | 2019-09-10 | 辽宁大学 | Pyridine structure contained 2,4- diarylamino pyridine derivatives and its application |
| CN111153860A (en) * | 2019-12-30 | 2020-05-15 | 广州六顺生物科技股份有限公司 | Crystal form of quinazoline compound and preparation method thereof |
| CN111303121A (en) * | 2020-04-20 | 2020-06-19 | 辽宁大学 | 4-phenoxypyridine compound containing quinoxalinone and application thereof |
| CN111372925A (en) * | 2017-11-24 | 2020-07-03 | 南京明德新药研发有限公司 | Uracil compounds as c-MET/AXL inhibitors |
| WO2020200160A1 (en) * | 2019-04-03 | 2020-10-08 | 北京国鸿生物医药科技有限公司 | Quinolyl-containing compound and pharmaceutical composition, and use thereof |
| CN111757735A (en) * | 2018-01-26 | 2020-10-09 | 埃克塞里艾克西斯公司 | Compounds for the treatment of kinase-dependent disorders |
| WO2020247418A1 (en) * | 2019-06-04 | 2020-12-10 | Exelixis, Inc. | Compounds for the treatment of kinase-dependent disorders |
| CN112457295A (en) * | 2019-09-06 | 2021-03-09 | 中国科学院上海药物研究所 | Compound with Axl and c-Met kinase inhibitory activity and preparation and application thereof |
| CN112876457A (en) * | 2021-02-03 | 2021-06-01 | 辽宁大学 | Novel 4-phenoxypyridine derivative and application thereof |
| CN113880845A (en) * | 2021-10-13 | 2022-01-04 | 广州六顺生物科技股份有限公司 | Pyrrolotriazine derivatives, and preparation method and application thereof |
-
2022
- 2022-01-27 CN CN202210099079.2A patent/CN114573553B/en active Active
Patent Citations (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102245595A (en) * | 2008-10-14 | 2011-11-16 | 株式会社新药 | Heterocyclic compound as protein kinase inhibitor |
| CN102212062A (en) * | 2010-04-02 | 2011-10-12 | 东莞市长安东阳光新药研发有限公司 | Derivative of amino ester, salt thereof and using method |
| CN102675282A (en) * | 2011-03-15 | 2012-09-19 | 广东东阳光药业有限公司 | Substitutive quinoline compound and application method and uses thereof |
| CN103420986A (en) * | 2012-05-18 | 2013-12-04 | 广东东阳光药业有限公司 | Compound replacing quinoidines as well as using method and application of compound |
| CN107286140A (en) * | 2016-04-12 | 2017-10-24 | 上海医药工业研究院 | Substituted aromatic amines base heteroaromatic class compound and its application as antineoplastic |
| CN111372925A (en) * | 2017-11-24 | 2020-07-03 | 南京明德新药研发有限公司 | Uracil compounds as c-MET/AXL inhibitors |
| CN111757735A (en) * | 2018-01-26 | 2020-10-09 | 埃克塞里艾克西斯公司 | Compounds for the treatment of kinase-dependent disorders |
| CN108358839A (en) * | 2018-03-13 | 2018-08-03 | 广州六顺生物科技有限公司 | A kind of tyrosine kinase inhibitor and its application |
| CN109776432A (en) * | 2019-03-21 | 2019-05-21 | 广州六顺生物科技股份有限公司 | A kind of preparation method and application of multiple target point kinase inhibitor, pharmaceutical composition and multiple target point kinase inhibitor |
| WO2020200160A1 (en) * | 2019-04-03 | 2020-10-08 | 北京国鸿生物医药科技有限公司 | Quinolyl-containing compound and pharmaceutical composition, and use thereof |
| WO2020247418A1 (en) * | 2019-06-04 | 2020-12-10 | Exelixis, Inc. | Compounds for the treatment of kinase-dependent disorders |
| CN110218205A (en) * | 2019-07-05 | 2019-09-10 | 辽宁大学 | Pyridine structure contained 2,4- diarylamino pyridine derivatives and its application |
| CN112457295A (en) * | 2019-09-06 | 2021-03-09 | 中国科学院上海药物研究所 | Compound with Axl and c-Met kinase inhibitory activity and preparation and application thereof |
| CN111153860A (en) * | 2019-12-30 | 2020-05-15 | 广州六顺生物科技股份有限公司 | Crystal form of quinazoline compound and preparation method thereof |
| CN111303121A (en) * | 2020-04-20 | 2020-06-19 | 辽宁大学 | 4-phenoxypyridine compound containing quinoxalinone and application thereof |
| CN112876457A (en) * | 2021-02-03 | 2021-06-01 | 辽宁大学 | Novel 4-phenoxypyridine derivative and application thereof |
| CN113880845A (en) * | 2021-10-13 | 2022-01-04 | 广州六顺生物科技股份有限公司 | Pyrrolotriazine derivatives, and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| STN: "《STN》" * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114573553B (en) | 2023-11-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6047184B2 (en) | Triazines, pyrimidines, and pyridine analogs, and their use as therapeutics and diagnostic probes | |
| JP6401773B2 (en) | BET bromodomain inhibitor and therapeutic method using the same | |
| TWI662026B (en) | Pyridinone derivatives, preparation process and pharmaceutical use thereof | |
| CN102712656B (en) | As 2,7-thieno-[3, the 2-D] pyrimidine compounds replaced of kinases inhibitor | |
| CN110627796B (en) | Nitrogenous heterocyclic derivative and application thereof in medicine | |
| CN110573500B (en) | N- (nitrogen heterocyclic aryl) lactam-1-formamide derivative and preparation method and application thereof | |
| CN105503827B (en) | EGFR inhibitor and its preparation method and application | |
| WO2008028141A2 (en) | Raf inhibitor compounds and methods of use thereof | |
| JP2016501251A (en) | Novel bicyclic phenyl-pyridine / pyrazine for the treatment of cancer | |
| EP3845527A1 (en) | Multi-substituted pyridone derivatives and medical use thereof | |
| CN104557871A (en) | Arylmorpholine compounds with spiro substituents as well as preparation method and use thereof | |
| CN104557913B (en) | Pyridopyrimidine compounds as well as preparation method and application thereof | |
| WO2022105921A1 (en) | Pyrimido-heterocyclic compound, preparation method therefor, and use thereof | |
| WO2020221209A1 (en) | Cd73 inhibitor, preparation method therefor and application thereof | |
| CN114716440B (en) | Pyrrolotriazine derivatives, and preparation method and application thereof | |
| CN114605391B (en) | Quinoxaline derivative, preparation method and application thereof | |
| CN114573553B (en) | Heteroaromatic ring derivative and preparation method and application thereof | |
| CN105541792B (en) | Polycyclic class PI3K inhibitor | |
| CN114394965A (en) | Triazolopyridine compound and preparation method and application thereof | |
| CN103906751A (en) | [1,3]dioxolo[4,5-g]quinoline-6(5h)thione and [1,3]dioxolo[4,5-g][1,2,4]triazolo[1,5-a]quinoline derivatives as inhibitors of the late sv40 factor (lsf) for use in treating cancer | |
| CN113880833A (en) | Biphenyl polycyclic derivative inhibitor, preparation method and application thereof | |
| CN113880814A (en) | Pyrimidinamine compound and application thereof | |
| CN111072640A (en) | Quinazoline derivative and preparation method and application thereof | |
| CN103467481B (en) | Dihydropyridine compounds, a combination thereof thing, preparation method and purposes | |
| WO2022161447A1 (en) | Dicarboxamide compound, preparation method therefor, and pharmaceutical use 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 | ||
| CB02 | Change of applicant information |
Address after: 510700 Floor 9, building B2, No. 11, Kaiyuan Avenue, Science City, high tech Industrial Development Zone, Huangpu District, Guangzhou City, Guangdong Province Applicant after: GUANGZHOU LIUSHUN BIOLOGICAL SCIENCE & TECHNOLOGY CO.,LTD. Applicant after: BEIKE HUAXIA BIOMEDICAL TECHNOLOGY Co.,Ltd. Address before: 510700 Floor 9, building B2, No. 11, Kaiyuan Avenue, Science City, high tech Industrial Development Zone, Huangpu District, Guangzhou City, Guangdong Province Applicant before: GUANGZHOU LIUSHUN BIOTECHNOLOGY Co.,Ltd. Applicant before: BEIKE HUAXIA BIOMEDICAL TECHNOLOGY Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |