CN107709320A - 一种吡啶并氮杂环化合物及其制备方法和用途 - Google Patents
一种吡啶并氮杂环化合物及其制备方法和用途 Download PDFInfo
- Publication number
- CN107709320A CN107709320A CN201680031083.8A CN201680031083A CN107709320A CN 107709320 A CN107709320 A CN 107709320A CN 201680031083 A CN201680031083 A CN 201680031083A CN 107709320 A CN107709320 A CN 107709320A
- Authority
- CN
- China
- Prior art keywords
- compound
- alkyl
- substituted
- unsubstituted
- hydrogen
- 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
- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 215
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 51
- 239000003814 drug Substances 0.000 claims abstract description 21
- 108091000080 Phosphotransferase Proteins 0.000 claims abstract description 19
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 19
- 102000020233 phosphotransferase Human genes 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000012453 solvate Substances 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 239000003112 inhibitor Substances 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 158
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 78
- 238000006243 chemical reaction Methods 0.000 claims description 73
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 62
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 52
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 50
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 43
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 32
- -1 compounds compound Chemical class 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 31
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- MRQFCJJRLCSCFG-UHFFFAOYSA-N dimethylazanium;formate Chemical compound C[NH2+]C.[O-]C=O MRQFCJJRLCSCFG-UHFFFAOYSA-N 0.000 claims description 28
- 239000003153 chemical reaction reagent Substances 0.000 claims description 27
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 25
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 25
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 25
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 24
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 22
- 239000002585 base Substances 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 235000019441 ethanol Nutrition 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 12
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 12
- 150000007529 inorganic bases Chemical class 0.000 claims description 12
- 150000007530 organic bases Chemical class 0.000 claims description 12
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000012312 sodium hydride Substances 0.000 claims description 12
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 12
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 12
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical group CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 201000005202 lung cancer Diseases 0.000 claims description 9
- 208000020816 lung neoplasm Diseases 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 8
- 125000003368 amide group Chemical class 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 239000012320 chlorinating reagent Substances 0.000 claims description 8
- 238000005660 chlorination reaction Methods 0.000 claims description 8
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 8
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 230000004663 cell proliferation Effects 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 6
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 5
- 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 claims 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- XZPOBRKGGPAVOS-UHFFFAOYSA-K aluminum;ethanethiol;trichloride Chemical compound [Al+3].[Cl-].[Cl-].[Cl-].CCS XZPOBRKGGPAVOS-UHFFFAOYSA-K 0.000 claims description 4
- BXILREUWHCQFES-UHFFFAOYSA-K aluminum;trichloride;hydrochloride Chemical compound [Al+3].Cl.[Cl-].[Cl-].[Cl-] BXILREUWHCQFES-UHFFFAOYSA-K 0.000 claims description 4
- 230000033115 angiogenesis Effects 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 4
- 229940125773 compound 10 Drugs 0.000 claims description 4
- 229940125758 compound 15 Drugs 0.000 claims description 4
- 229940125810 compound 20 Drugs 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 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 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 4
- 150000003053 piperidines Chemical class 0.000 claims description 4
- 125000005936 piperidyl group Chemical group 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- 238000012546 transfer Methods 0.000 claims description 4
- 239000011701 zinc Substances 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 101100381481 Caenorhabditis elegans baz-2 gene Proteins 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 206010027476 Metastases Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 claims description 3
- 108060006706 SRC Proteins 0.000 claims description 3
- 102000001332 SRC Human genes 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 claims description 3
- 230000002159 abnormal effect Effects 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 230000029052 metamorphosis Effects 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 230000004614 tumor growth Effects 0.000 claims 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 claims 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 claims 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 claims description 2
- 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 claims 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 claims description 2
- BTDUOYHOTYFZIC-UHFFFAOYSA-N 6-dibutylphosphanylhex-2-enenitrile Chemical compound C(#N)C=CCCCP(CCCC)CCCC BTDUOYHOTYFZIC-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 229940126657 Compound 17 Drugs 0.000 claims description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 2
- 108091008794 FGF receptors Proteins 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims description 2
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 claims description 2
- 101150028321 Lck gene Proteins 0.000 claims description 2
- 101100268648 Mus musculus Abl1 gene Proteins 0.000 claims 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 claims description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 2
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 2
- 108010089836 Proto-Oncogene Proteins c-met Proteins 0.000 claims description 2
- 102000008022 Proto-Oncogene Proteins c-met Human genes 0.000 claims description 2
- 229910006124 SOCl2 Inorganic materials 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- HIVLDXAAFGCOFU-UHFFFAOYSA-N ammonium hydrosulfide Chemical compound [NH4+].[SH-] HIVLDXAAFGCOFU-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 208000009060 clear cell adenocarcinoma Diseases 0.000 claims description 2
- 229940125797 compound 12 Drugs 0.000 claims description 2
- 229940126543 compound 14 Drugs 0.000 claims description 2
- 229940126142 compound 16 Drugs 0.000 claims description 2
- 229940126086 compound 21 Drugs 0.000 claims description 2
- 229940126208 compound 22 Drugs 0.000 claims description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-O dimethylaminium Chemical compound C[NH2+]C ROSDSFDQCJNGOL-UHFFFAOYSA-O 0.000 claims description 2
- VDQVEACBQKUUSU-UHFFFAOYSA-M disodium;sulfanide Chemical compound [Na+].[Na+].[SH-] VDQVEACBQKUUSU-UHFFFAOYSA-M 0.000 claims description 2
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- JBQYATWDVHIOAR-UHFFFAOYSA-N tellanylidenegermanium Chemical group [Te]=[Ge] JBQYATWDVHIOAR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 210000001685 thyroid gland Anatomy 0.000 claims description 2
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 claims 2
- WGVWLKXZBUVUAM-UHFFFAOYSA-N Pentanochlor Chemical compound CCCC(C)C(=O)NC1=CC=C(C)C(Cl)=C1 WGVWLKXZBUVUAM-UHFFFAOYSA-N 0.000 claims 2
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 claims 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 102000001253 Protein Kinase Human genes 0.000 abstract description 7
- 108060006633 protein kinase Proteins 0.000 abstract description 7
- 230000014509 gene expression Effects 0.000 abstract description 3
- 210000004881 tumor cell Anatomy 0.000 abstract description 2
- 230000002018 overexpression Effects 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 114
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 95
- 230000015572 biosynthetic process Effects 0.000 description 92
- 238000003786 synthesis reaction Methods 0.000 description 92
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 72
- 238000005406 washing Methods 0.000 description 61
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 58
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 44
- 239000000243 solution Substances 0.000 description 36
- 239000007832 Na2SO4 Substances 0.000 description 28
- 235000002639 sodium chloride Nutrition 0.000 description 28
- 229910052938 sodium sulfate Inorganic materials 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000007787 solid Substances 0.000 description 25
- 239000011780 sodium chloride Substances 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- BHHMPZQRVWVAAR-UHFFFAOYSA-N 7-bromo-8-methylpyrido[2,3-b]pyrazine Chemical compound C1=CN=C2C(C)=C(Br)C=NC2=N1 BHHMPZQRVWVAAR-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 238000000605 extraction Methods 0.000 description 13
- 239000002994 raw material Substances 0.000 description 13
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000011580 nude mouse model Methods 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 238000007920 subcutaneous administration Methods 0.000 description 8
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000002054 transplantation Methods 0.000 description 7
- 238000010792 warming Methods 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 6
- DQAZPZIYEOGZAF-UHFFFAOYSA-N 4-ethyl-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound C1CN(CC)CCN1C(=O)NC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 DQAZPZIYEOGZAF-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 239000004202 carbamide Substances 0.000 description 6
- 235000013877 carbamide Nutrition 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 229940043355 kinase inhibitor Drugs 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 5
- 210000003462 vein Anatomy 0.000 description 5
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 4
- XLEYXHRMSUPJST-UHFFFAOYSA-N 3-fluoro-4-phenylmethoxyaniline Chemical compound FC1=CC(N)=CC=C1OCC1=CC=CC=C1 XLEYXHRMSUPJST-UHFFFAOYSA-N 0.000 description 4
- SFWWGMKXCYLZEG-UHFFFAOYSA-N 3-methylmorpholine Chemical compound CC1COCCN1 SFWWGMKXCYLZEG-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 238000001994 activation Methods 0.000 description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 4
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 4
- FEHLGOYZDFFMND-UHFFFAOYSA-N cyclopropane-1,1-dicarboxamide Chemical class NC(=O)C1(C(N)=O)CC1 FEHLGOYZDFFMND-UHFFFAOYSA-N 0.000 description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
- 230000009036 growth inhibition Effects 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 4
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 4
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 3
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 3
- FICAQKBMCKEFDI-UHFFFAOYSA-N 3,5-dimethyl-1,2-oxazole Chemical compound CC=1C=C(C)ON=1 FICAQKBMCKEFDI-UHFFFAOYSA-N 0.000 description 3
- MPMKMQHJHDHPBE-RUZDIDTESA-N 4-[[(2r)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid Chemical compound O=C([C@@]1(N(CC1)C(=O)C=1C2=CC=CC=C2SC=1)C)N(CCCC(O)=O)CC1=CC=CC(Cl)=C1 MPMKMQHJHDHPBE-RUZDIDTESA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229940121647 egfr inhibitor Drugs 0.000 description 3
- 229960004979 fampridine Drugs 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 206010020718 hyperplasia Diseases 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 229960003742 phenol Drugs 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 2
- FDZXRKYONGCKLC-UHFFFAOYSA-N 1,4-dihydropyridine-2,3-dione Chemical compound O=C1CC=CNC1=O FDZXRKYONGCKLC-UHFFFAOYSA-N 0.000 description 2
- WPJGHIVGAOVUAT-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-oxopyridine-3-carboxylic acid Chemical compound O=C1C(C(=O)O)=CC=CN1C1=CC=C(F)C=C1 WPJGHIVGAOVUAT-UHFFFAOYSA-N 0.000 description 2
- PFMAFXYUHZDKPY-UHFFFAOYSA-N 1-[(4-fluorophenyl)carbamoyl]cyclopropane-1-carboxylic acid Chemical compound C=1C=C(F)C=CC=1NC(=O)C1(C(=O)O)CC1 PFMAFXYUHZDKPY-UHFFFAOYSA-N 0.000 description 2
- ZELAUPRECLNAEE-UHFFFAOYSA-N 1-ethoxy-4-methylpiperazine Chemical compound CCON1CCN(C)CC1 ZELAUPRECLNAEE-UHFFFAOYSA-N 0.000 description 2
- IZYOHLOUZVEIOS-UHFFFAOYSA-N 1-methoxycarbonylcyclopropane-1-carboxylic acid Chemical compound COC(=O)C1(C(O)=O)CC1 IZYOHLOUZVEIOS-UHFFFAOYSA-N 0.000 description 2
- KKFDCBRMNNSAAW-UHFFFAOYSA-N 2-(morpholin-4-yl)ethanol Chemical compound OCCN1CCOCC1 KKFDCBRMNNSAAW-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- OJZYVZNGKDTSFP-UHFFFAOYSA-N 2-morpholin-2-ylethanol Chemical compound OCCC1CNCCO1 OJZYVZNGKDTSFP-UHFFFAOYSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- UIKUBYKUYUSRSM-UHFFFAOYSA-N 3-morpholinopropylamine Chemical compound NCCCN1CCOCC1 UIKUBYKUYUSRSM-UHFFFAOYSA-N 0.000 description 2
- JGOTXCGNCXEAAY-UHFFFAOYSA-N 4,7-dichloro-1,6-naphthyridine Chemical class C1=CC(Cl)=C2C=NC(Cl)=CC2=N1 JGOTXCGNCXEAAY-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 2
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 2
- 101150105382 MET gene Proteins 0.000 description 2
- 229940125895 MET kinase inhibitor Drugs 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- HFCFMRYTXDINDK-WNQIDUERSA-N cabozantinib malate Chemical compound OC(=O)[C@@H](O)CC(O)=O.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 HFCFMRYTXDINDK-WNQIDUERSA-N 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 229940127271 compound 49 Drugs 0.000 description 2
- 229940125900 compound 59 Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000012362 glacial acetic acid Substances 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
- 230000036541 health Effects 0.000 description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 2
- BYWNRDHMVLYAPC-UHFFFAOYSA-N n-(3-fluorophenyl)hydroxylamine Chemical compound ONC1=CC=CC(F)=C1 BYWNRDHMVLYAPC-UHFFFAOYSA-N 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000011535 reaction buffer Substances 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- SRKGZXIJDGWVAI-GVAVTCRGSA-M (e,3r)-7-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)C1=NC(C(C)(C)C)=CC(C=2C=CC(F)=CC=2)=C1\C=C\C(O)C[C@@H](O)CC([O-])=O SRKGZXIJDGWVAI-GVAVTCRGSA-M 0.000 description 1
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- MHSLDASSAFCCDO-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyrazol-3-yl)-3-(4-pyridin-4-yloxyphenyl)urea Chemical compound CN1N=C(C(C)(C)C)C=C1NC(=O)NC(C=C1)=CC=C1OC1=CC=NC=C1 MHSLDASSAFCCDO-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 1
- WSNAQLAHCVPEGN-UHFFFAOYSA-N 1-ethoxy-2h-pyridine Chemical compound CCON1CC=CC=C1 WSNAQLAHCVPEGN-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- YAXQOLYGKLGQKA-UHFFFAOYSA-N 1-morpholin-4-ylpropan-2-ol Chemical compound CC(O)CN1CCOCC1 YAXQOLYGKLGQKA-UHFFFAOYSA-N 0.000 description 1
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 1
- IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- GNTGEMWEXKBWBX-UHFFFAOYSA-N 2-bromopyridin-4-amine Chemical compound NC1=CC=NC(Br)=C1 GNTGEMWEXKBWBX-UHFFFAOYSA-N 0.000 description 1
- ZKYKRMVSSXLKSB-UHFFFAOYSA-N 2-chloro-1,6-naphthyridine Chemical class C1=NC=CC2=NC(Cl)=CC=C21 ZKYKRMVSSXLKSB-UHFFFAOYSA-N 0.000 description 1
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 1
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 1
- KOSZHDVTNURERE-UHFFFAOYSA-N 2-fluoro-3-methoxyaniline Chemical compound COC1=CC=CC(N)=C1F KOSZHDVTNURERE-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- AXNUZKSSQHTNPZ-UHFFFAOYSA-N 3,4-difluoroaniline Chemical compound NC1=CC=C(F)C(F)=C1 AXNUZKSSQHTNPZ-UHFFFAOYSA-N 0.000 description 1
- PWRBCZZQRRPXAB-UHFFFAOYSA-N 3-chloropyridine Chemical compound ClC1=CC=CN=C1 PWRBCZZQRRPXAB-UHFFFAOYSA-N 0.000 description 1
- ZSGXAJPKAMPOIZ-UHFFFAOYSA-N 3-dimethylphosphanylprop-2-enenitrile Chemical compound CP(C)C=CC#N ZSGXAJPKAMPOIZ-UHFFFAOYSA-N 0.000 description 1
- VZKSLWJLGAGPIU-UHFFFAOYSA-N 3-morpholin-4-ylpropan-1-ol Chemical compound OCCCN1CCOCC1 VZKSLWJLGAGPIU-UHFFFAOYSA-N 0.000 description 1
- BPYHGTCRXDWOIQ-UHFFFAOYSA-N 3-nitropyridin-2-amine Chemical compound NC1=NC=CC=C1[N+]([O-])=O BPYHGTCRXDWOIQ-UHFFFAOYSA-N 0.000 description 1
- LUWACRUAJXZANC-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C([N+]([O-])=O)C=C1 LUWACRUAJXZANC-UHFFFAOYSA-N 0.000 description 1
- BLBDTBCGPHPIJK-UHFFFAOYSA-N 4-Amino-2-chloropyridine Chemical compound NC1=CC=NC(Cl)=C1 BLBDTBCGPHPIJK-UHFFFAOYSA-N 0.000 description 1
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 1
- MXJQJURZHQZLNN-UHFFFAOYSA-N 4-amino-2-fluorophenol Chemical compound NC1=CC=C(O)C(F)=C1 MXJQJURZHQZLNN-UHFFFAOYSA-N 0.000 description 1
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 1
- GVWBJJLCTWNTRU-UHFFFAOYSA-N 4-benzylmorpholine Chemical compound C=1C=CC=CC=1CN1CCOCC1 GVWBJJLCTWNTRU-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- YYBXNWIRMJXEQJ-UHFFFAOYSA-N 4-piperidin-4-ylmorpholine Chemical compound C1CNCCC1N1CCOCC1 YYBXNWIRMJXEQJ-UHFFFAOYSA-N 0.000 description 1
- HNRPBMNTCYRAJD-UHFFFAOYSA-N 5,7-dichloro-1,6-naphthyridine Chemical class C1=CC=C2C(Cl)=NC(Cl)=CC2=N1 HNRPBMNTCYRAJD-UHFFFAOYSA-N 0.000 description 1
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 1
- XASOHFCUIQARJT-UHFFFAOYSA-N 8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C(N1C(=O)C2=C(OC)C=C(C=3N4C(=NC=3)C=C(C=C4)OCCN3CCOCC3)C=C2CC1)C(F)(F)F XASOHFCUIQARJT-UHFFFAOYSA-N 0.000 description 1
- YEEZFQPVKLCKML-UHFFFAOYSA-N C(C)(C)C1(CC=CC=C1)N1CCCCC1 Chemical class C(C)(C)C1(CC=CC=C1)N1CCCCC1 YEEZFQPVKLCKML-UHFFFAOYSA-N 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 1
- AIZIUVBLRHTDSF-UHFFFAOYSA-N COC=C1COC(OC1)(C)C Chemical compound COC=C1COC(OC1)(C)C AIZIUVBLRHTDSF-UHFFFAOYSA-N 0.000 description 1
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- IVDFJHOHABJVEH-UHFFFAOYSA-N HOCMe2CMe2OH Natural products CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 1
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 description 1
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910020700 Na3VO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 229940126179 compound 72 Drugs 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 1
- FDKLLWKMYAMLIF-UHFFFAOYSA-N cyclopropane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CC1 FDKLLWKMYAMLIF-UHFFFAOYSA-N 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000005034 decoration Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 229940127263 dual kinase inhibitor Drugs 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229940089468 hydroxyethylpiperazine ethane sulfonic acid Drugs 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000001967 indiganyl group Chemical group [H][In]([H])[*] 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000003041 laboratory chemical Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid group Chemical group C(CC(=O)O)(=O)O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 description 1
- REPVNSJSTLRQEQ-UHFFFAOYSA-N n,n-dimethylacetamide;n,n-dimethylformamide Chemical compound CN(C)C=O.CN(C)C(C)=O REPVNSJSTLRQEQ-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- RGQCAJMEHUBUKW-UHFFFAOYSA-N n-fluoro-n-methylaniline Chemical compound CN(F)C1=CC=CC=C1 RGQCAJMEHUBUKW-UHFFFAOYSA-N 0.000 description 1
- MGNPLIACIXIYJE-UHFFFAOYSA-N n-fluoroaniline Chemical compound FNC1=CC=CC=C1 MGNPLIACIXIYJE-UHFFFAOYSA-N 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- RXCVUXLCNLVYIA-UHFFFAOYSA-N orthocarbonic acid Chemical compound OC(O)(O)O RXCVUXLCNLVYIA-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 1
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical compound NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 229940043267 rhodamine b Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了一种如下通式I所示的吡啶并氮杂环化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其制备方法以及包含所述化合物的组合物,以及作为多靶点蛋白激酶抑制剂在制备用于治疗肿瘤疾病等与蛋白激酶特别是c‐Met有关的疾病的药物中的用途。通式I表示的化合物对c‐Met激酶高表达的肿瘤细胞有高效的抑制活性,能够有效的靶向c‐Met介导的信号通路,能够用于与c‐Met激酶过度表达引起的肿瘤等相关疾病的治疗。
Description
本发明涉及药物化学领域,具体涉及一种吡啶并氮杂环化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其制备方法以及包含所述化合物的组合物。本发明还涉及所述化合物、其异构体及药学上可接受的盐及药物组合物作为多靶点蛋白激酶抑制剂在制备用于治疗肿瘤疾病等与蛋白激酶特别是c-Met有关的疾病的药物中的用途。
世界卫生组织(WHO)在《全球癌症报告2014》称,2012年全球癌症患者为1400万人,预计到2025年递增至1900万人,到2035年将达到2400万人。2012年,中国新增307万癌症患者并造成约220万人死亡,分别占全球总量的21.9%和26.8%。在中国,每五个死亡者中就有一个死于癌症。癌症成为仅次于心血管疾病的第二大杀手,严重威胁着人类的健康。近年随着人们对肿瘤生物学的深入研究,受体酪氨酸激酶由于在肿瘤发生、发展、耐药中发挥重要的作用,已成为一种抗肿瘤药物研发的靶点。
c-Met是受体酪氨酸激酶家族的重要成员,在绝大部分的癌及部分肉瘤中具有高表达且和预后差紧密相关,如肺癌、乳腺癌、结肠癌、前列腺癌、胰癌、胃癌、肝癌、卵巢癌、肾癌、神经胶质瘤、黑色素瘤等。c-Met通过与其配体HGF/SF相互作用或者通过其他途径激活胞内段的酪氨酸激酶,诱导细胞增殖、侵袭、迁移,抑制细胞凋亡,促进血管生成,在肿瘤的发生发展过程中发挥重要的作用。不同于其他激酶,c-Met作为肿瘤信号网络通路中的关键节点,可以与细胞表面其他肿瘤相关分子相互作用,从而交联激活放大肿瘤相关效应,极大地促进了肿瘤的发生、发展和转移。研究表明,Met基因扩增与20%的表皮生长因子抑制剂(EGFR-TKIs)获得性耐药密切相关;Met抑制剂与EGFR抑制剂的联合用药能够延缓EGFR-TKIs获得性耐药的产生,延长其临床使用寿命。因此,靶向c-Met/HGF通路成为引人注目的肿瘤治疗新策略,基于c-Met信号通路的化学阻断特别是小分子c-Met激酶抑制剂的抗癌药物研究成为目前癌症治疗领域的研究热点。到目前为止,已有17个小分子c-Met抑制剂进入或正在进行临床试验,其中PF-2341066(Crizotinib)作为高度选择性的ALK/c-Met双重激酶抑制剂,于2011年被美国FDA批准用于ALK融合基因阳性的非小细胞肺癌的治疗;XL184/BMS907351作为Met、VEGFR-2和RET等多重激酶抑制剂,于2012年底获准用于甲状腺髓样癌的治疗。虽然激酶抑制剂在临床上表现出优良的靶向治疗效果,但肿瘤耐药性变异的发生大大降低了这类药物长期治疗的有效
性。化学结构的相似也使得激酶抑制剂的交叉耐药性问题日益严重。另一方面,虽然没有直接证据证明特异性激酶抑制剂优于多重激酶抑制剂,但激酶的选择性与脱靶效应密切相关。因此,新结构新机制先导化合物的发现是目前靶向c-Met激酶的抗肿瘤药物研发的重点方向。
发明内容
为了解决上述技术问题,本发明的一个目的是提供一种吡啶并氮杂环化合物、其异构体、药学上可接受的盐或药学上可接受的溶剂合物,以及包含该化合物的药物组合物。
本发明另一方面的目的是提供上述化合物的制备方法。
本发明又一方面的目的是提供上述化合物在制备用于抑制酪氨酸激酶c-Met活性的药物中的应用,在制备用于预防或治疗与生物体内的肝细胞生长因子及其受体(c-Met)相关的细胞异常增殖、形态变化以及运动功能亢进相关的疾病以及与血管新生或癌转移相关的疾病的药物中的应用,尤其是用于制备预防或治疗肿瘤生长与转移的药物中的应用。
为了实现上述发明目的,本发明采用如下的技术方案:
本发明一方面提供一种吡啶并氮杂环化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其具有如下通式I所示的结构:
其中,
表示单键或双键;
R1和R2各自独立地选自氢和卤素;优选地,R1和R2各自独立地选自氢、F、Cl和Br;更优选地,R1选自氢、Cl和Br;R2选自氢、F和Cl;进一步优选地,R1为氢、Cl或Br;R2为氢或F;
X不存在(为直键),或者X和Y各自独立地为选自C、N、O和S;优选地,X不存在,或者X和Y各自独立地选自C、N和O;
n为0、1、2或3;优选地,n为0、1或2;m为0或1;
R3不存在或者为氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基羰基、或者取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元杂芳环基团,其中,所述取代基可以为1或2个并各自独立地为选自卤素、-CN、-CF3、-NO2、羟基、C1-C6烷基、C1-C6烷基取代的胺基、C1-C6烷氧基、苄基、卤素取代的C1-C6烷氧基、C1-C6烷基磺酰基和未取代的或C1-C6烷基取代的含有1-2个选自N和O中的杂原子的五元或六元饱和或不饱和杂环基或杂芳环基;更优选地,R3不存在或者为氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基羰基、或者取代或未取代的含有1-2个选自N和O中的杂原子的五元或六元杂芳环基团,其中,所述取代基可以为1或2个并各自独立地选自卤素、-CN、苄基、C1-C6烷基、C1-C6烷基取代的胺基、C1-C6烷基磺酰基和未取代的或C1-C6烷基取代的含有1-2个选自N和O中的杂原子的五元或六元饱和或不饱和杂环基团;进一步优选地,R3不存在或者为氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基羰基、或者取代或未取代的含有1-2个选自N和O中的杂原子的五元或六元杂芳环基团,其中,所述取代基可以为1或2个并各自独立地选自卤素、苄基、C1-C4烷基、C1-C4烷基取代的胺基、C1-C4烷基磺酰基和未取代的或C1-C6烷基取代的含有1-2个选自N和O中的杂原子的五元或六元饱和或不饱和杂环基团;最优选地,R3不存在或者为C1-C3的烷基、取代或未取代的吡啶基、取代或未取代的吗啉基、取代或未取代的吗啉基羰基、代或未取代的哌啶基、取代或未取代的咪唑基、取代或未取代的哌嗪基、取代或未取代的恶唑基、取代或未取代的异恶唑基、取代或未取代的嘧啶基、取代或未取代的噻唑基、取代或未取代的异噻唑基、
取代或未取代的苯基、或者取代或未取代的吡唑基,其中,所述取代基可以为1或2个并各自独立地选自F、Cl、Br、-NO2、C1-C3烷基、苄基、C1-C3烷基磺酰基、C1-C3烷基取代的胺基、未取代的或C1-C6烷基取代的哌啶基和吗啉基;
R6不存在或者选自氢和C1-C6的烷基;优选不存在或者选自氢和C1-C4的烷基;更优选不存在或者选自氢和C1-C2的烷基;最优选不存在或者为氢或甲基;
R7不存在或者选自氢和C1-C6的烷基;优选不存在或者为氢、甲基、乙基或丙基;最优选不存在或者为甲基;
Z为氨基、苯基乙酰胺基或以下任一结构:
在上述通式II、III、IV、V中,R4选自氢、C1-C6烷基和C5-C10芳基或者杂芳基;优选地,R4选自氢和C1-C6烷基;更优选地,R4选自氢和C1-C3烷基;最优选地,R4为氢或甲基;R5和R5’各自独立地选自氢、卤素和C1-C6烷氧基;优选地,R5和R5’各自独立地选自氢、F、Cl、Br和C1-C4烷氧基;更优选地,R5和R5’各自独立地选自氢、F和C1-C2烷氧基;
最优选地,Z为氨基、苯基乙酰胺基或以下任一结构:
环B为含有1或2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团或者杂芳香基团;优选地,环B为含有1或2个选自N或O中的杂原子的五元或六元饱和或不饱和杂环基团或者杂芳香基团;更优选地,环B为含有1或2个N原子的五元或六元饱和或不饱和杂环基团或者杂芳香基团;最优选地,环B与吡啶或者连同X形成具有如下简式之一所示的结构:
其中,卤素包括F、Cl、Br、I;
最优选地,所述化合物选自下述化合物中的一种化合物:
本发明另一方面提供一种上述通式I所示吡啶并氮杂环化合物、其异构体、其药学上可接受的盐或其药学上可接受的溶剂合物的制备方法,该方法如以下反应方案之一所示:
反应方案一:
其中,R8为R9为Y、R2、R3、R7、Z、m和n的定义与上述通式I中的定义相同;
(1)化合物5由化合物4经氯代反应得到,氯代试剂为氯化亚砜(SOCl2)/N,N-二甲基甲酸铵(DMF)、三氯氧磷(POCl3)/DMF或POCl3/N,N-二异丙基乙胺(DIEA)/乙腈(MeCN)等,优选为POCl3/DMF。
(2)化合物6由化合物5去保护得到。去保护试剂为:三溴化硼(BBr3)/二氯甲烷(DCM)、40%溴化氢(HBr)水溶液、吡啶盐酸盐、盐酸或硫酸、盐酸-氯化铝、氯化铝-乙硫醇、三甲基氯硅烷(TMSCl)/碘化钠(NaI)、三氟甲磺酸。优选为三氟甲磺酸。(3)化合物6经Mitsunobu反应生成化合物7,所选试剂为偶氮二甲酸二乙酯(DEAD)/三苯基膦(PPh3)、N′,N′-四异丙基偶氮二羧酰胺(TIPA)-三丁膦TBP、1,1′-(偶氮二羧酸)二哌啶(ADDP)-TBP、四甲基偶氮二甲酸铵(TMAD)-TBP、4,7-二甲基-3,4,5,6,7,8-六氢-1,2,4,7-四氮杂辛因-3,8-二酮(DHTD)-TBP、氰基亚甲基三正丁基膦(CMBP)或氰基亚甲基三甲基膦(CMMP)。优选为DEAD/PPh3。
(4)化合物7经亲核取代反应生成化合物8,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、三乙胺(TEA)、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾。
(5)化合物8经脱溴得到化合物9,优选反应条件为:钯碳Pd/C-甲酸铵、Pd/C-乙酰胺,Pd/C-氢气;优选为Pd/C-甲酸铵。
反应方案二:
其中,R8为R9为Y、R2、R3、R7、Z、m和n的定义与上述通式I中的定义相同;
(1)化合物5脱溴得到化合物10,优选反应条件为:Pd/C-甲酸铵、Pd/C-乙酰胺,Pd/C-氢气;优选为Pd/C-甲酸铵。
(2)化合物11由化合物10去保护得到。去保护试剂为:BBr3/DCM、40%HBr水溶液、吡啶盐酸盐、盐酸或硫酸、盐酸-氯化铝、氯化铝-乙硫醇、TMSCl/NaI、三氟甲磺酸。优选为三氟甲磺酸。
(3)化合物11经Mitsunobu反应生成化合物12,所选试剂为DEAD/PPh3、TIPA-TBP、ADDP-TBP、TMAD-TBP、DHTD-TBP、CMBP或CMMP。优选为DEAD/PPh3。
(4)化合物12经亲核取代反应生成化合物9,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾。
反应方案三:
其中,R10为R9为X、Y、R2、R3、R6、R7、Z、m和n的定义分别与权利要求1-5相同;X’为Cl或者Br;
(1)化合物14经脱氯得到化合物15,反应试剂为锌(Zn)/醋酸(MeCOOH);
(2)化合物16经氯代反应得到化合物17,氯代试剂为SOCl2/DMF、POCl3/DMF、POCl3/DIEA/MeCN等,优选为POCl3/DIEA/MeCN;
(3)化合物17经亲核取代反应生成化合物18,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;
反应方案四:
其中,R10为R9为X、Y、R2、R3、R6、R7、Z、m和n的定义分别与权利要求1-5相同;X’为Cl或者Br;
(1)化合物15经氯代反应得到化合物15I,氯代试剂为SOCl2/DMF、POCl3/DMF、POCl3/DIEA/MeCN等,优选为POCl3/DIEA/MeCN;
(2)化合物15I经亲核取代反应生成化合物15II,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;
(3)化合物15II经Suzuki偶联反应生成化合物18,所用的碱为醋酸钾、磷酸钾或碳酸钾;所用溶剂为二甲基亚砜,DMF,二氧六环或者甲苯,加入适量的水;所用的催化剂为四三苯基膦钯,1,1′-双二苯基膦二茂铁二氯化钯PdCl2(dppf);
反应方案五:
其中,R10为R9为X、Y、R2、R3、R6、R7、Z、m和n的定义分别与权利要求1-5相同;
(1)取代反应生成化合物19,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;
(2)化合物19经还原得到化合物20,所用的还原试剂为氯化镍(NiCl2)/硼氢化钠(NaBH4)、Zn/AcOH、Pd/C-H2、Fe/氯化氢(HCl)、硫化钠(Na2S)/乙醇(EtOH)、硫氢化铵(NH4HS)、氢化铝锂(LiAlH4);优选为NiCl2/NaBH4、Pd/C-H2;
(3)化合物20经环合得到化合物21及22,环合条件为醛基乙酸乙酯,溶剂为各种常规溶剂,例如甲醇(MeOH)、EtOH、乙腈(MeCN)、二氧六环等;
(4)氯代反应,其氯代试剂为SOCl2/DMF、POCl3/DMF、POCl3/DIEA/MeCN等,优选为POCl3/DIEA/MeCN;
(5)亲核取代反应,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾。
本发明另一方面还提供一种包含治疗有效量的选自一种或多种通式I所示化合物、其异构体、药学上可接受的盐或药学上可接受的溶剂合物的组合物。
本发明另一方面还提供通式I所示化合物、其异构体、药学上可接受的盐、药学上可接受的溶剂合物及其组合物在制备作为多靶点蛋白激酶抑制剂的药物中的应用,在制备用
于抑制酪氨酸激酶c-Met活性的药物中的应用,在制备用于预防或治疗与生物体内的肝细胞生长因子受体(c-Met)相关的细胞异常增殖、形态变化以及运动功能亢进相关的疾病以及与血管新生或肿瘤转移相关的疾病的药物中的应用,尤其是在制备预防或治疗肿瘤生长与转移的药物中的应用。
所述激酶包括c-Met、Flt-1、PDGFR-α、PDGFR-β、RET、c-Src、EPH-A2、FGFR、Abl、Lck、KDR、IGF-1α和ALK。
所述药物用于治疗和/或预防与蛋白激酶特别是c-Met有关的疾病,如肿瘤。
在本发明中,所述肿瘤为肺癌、甲状腺髓样瘤、恶性胶质瘤、胃癌、肾细胞癌、乳腺癌、卵巢癌、前列腺癌或结直肠癌。
本发明有如下有益效果:
通过对c-Met激酶活性筛选,发明人发现:上述通式I表示的化合物在10nM下对c-Met激酶有高效的抑制活性;在100nM下对c-Met激酶高表达的肿瘤细胞有高效的抑制活性。代表性化合物7S表现出良好的药代性质:生物利用度F=51.8%,平均滞留时间MRT=2.6h,半衰期t1/2=1.66h,药时面积AUC=16652h*ng/ml。而且,该小分子抑制剂动物体内疗效良好:每天口服给药一次,100mg/kg组连续给药21天,对人肺癌EBC-1裸小鼠皮下移植瘤相对肿瘤增殖率T/C为9.5%,肿瘤体积增长抑制率GI为96.5%,瘤重抑制率为86.9%,有效剂量内安全无毒。因此,通式I表示的化合物能够有效的靶向c-Met介导的信号通路,能够用于与c-Met激酶过度表达引起的肿瘤等相关疾病的治疗。制剂学上允许的含有通式I表示的化合物的药物组合物同样能起到有效的靶向c-Met介导的信号通路,能够用于与c-Met激酶过度表达引起的肿瘤等相关疾病的治疗。
图1显示了化合物7S对人肺癌EBC-1裸小鼠移植瘤的实验治疗作用。
实施例:
下面结合实施例对本发明作进一步描述,但不限制本发明的保护范围。
化合物的1H-NMR光谱数据测量使用Varian Mercury-300MHz或Varian Mercury-400MHz核磁共振,质谱EI-MS用Finnigan MAT 95质谱仪,ESI-MS使用Finnigan LCQ Deca质谱仪测定。快速柱层析在硅胶H(10-40μM)上进行。试剂纯化参照Purification of laboratory Chemicals;D.D.Perrin;W.L.F.Armarego and D.R.Perrin Eds.,
Pergamon Press:Oxiford,1980。
如未作特别说明,本发明所采用的试剂和方法等为本领域熟知的试剂和方法。
实施例1片段II系列的合成
本片段合成参考WO 2011/137342 A1
1-(甲氧基羰基)环丙烷单羧酸(23)
将环丙烷二羧酸二甲酯(10.12g,63.99mmol)溶解在100mL(1∶1V∶V)CH3OH/H2O中,室温下搅拌,称取(2.68g,63.99mmol)氢氧化锂溶于20ml H2O中,室温下分三次慢慢加入上述溶液中,加完后继续搅拌反应1h,反应完成后用稀盐酸调节pH值到3,DCM萃取,无水硫酸钠干燥,不经纯化继续下一步反应。
1-((4-氟苯基)氨基甲酰)环丙烷单羧酸(25)
将(9.21g,63.99mmol)化合物23、(12.15ml,127.98mmol)对氟苯胺溶于150ml DCM中,室温下加入(12.97g,95.98mmol)HOBt(羟基苯并三唑)、(14.90g,95.98mmol)1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC),室温搅拌,TLC跟踪反应,反应完成后蒸去大部分的DCM,加入EA萃取,饱和NaHCO3洗,pH=3的水洗,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到化合物24粗品。将得到的粗品直接溶于100mL(1∶1V∶V)MeOH/H2O中,室温下搅拌,后加入(3.06g,127.98mmol)氢氧化锂,加完后继续搅拌反应1h,TLC跟踪反应,反应完成后用稀盐酸调节pH值到3,即析出大量固体,过滤,干燥得灰白色固体10.56g,两步产率74.1%。1H NMR(CDCl3,300MHz):δ7.57-7.53(m,2H),7.05-7.00(m,2H),1.46-1.43(m,2H),1.40-1.37(m,2H)。
N-(3-氟-4-羟基苯基)-N-(4-氟苯基)环丙烷-1,1-二酰胺(26)
将(2.00g,8.97mmol)化合物25、(1.14g,8.97mmol)4-氨基-2-氟苯酚溶于10ml DCM中,室温下加入(1.21g,13.46mmol)HOBt,(1.77g,13.46mmol)EDC,室温搅拌,TLC跟踪反应,反应完成后蒸去大部分的DCM,加入EA萃取,饱和NaHCO3洗,pH=3的水
洗,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到粗品,甲醇结晶得黄褐色固体63%。1H NMR(DMSO,400MHz):δ10.51(s,1H),10.32(s,1H),10.00(s,1H),7.77(d,J=12.9Hz,1H),7.66-7.61(m,2H),7.41(d,J=8.7Hz,1H),7.30(t,J=8.8Hz,1H),7.15(d,J=9.0Hz,2H),1.61(m,2H),1.44(m,2H).
N-(3-氟-4-羟基苯基)-N-(4-氟苯基)-N-甲基环丙烷-1,1-二酰胺(27)
化合物27的制备同化合物26,初始原料为对氟-N-甲基苯胺;1H NMR(DMSO,300MHz):δ9.56(s,1H),9.42(s,1H),7.35-7.23(m,2H),7.19-7.03(m,2H),6.97-6.87(m,1H),6.85-6.75(m,1H),3.22(s,3H),1.38-1.10(m,4H).
N-(3,4-二氟苯基)-N-(3-氟-4-羟基苯基)环丙烷-1,1-二酰胺(28)
化合物28的制备同化合物26,初始原料为3,4-二氟苯胺;1H NMR(CDCl3,300MHz):δ10.64(s,1H),7.72-7.58(m,1H),7.13-7.00(m,2H),6.83(t,J=8.5Hz,1H),6.52-6.34(m,2H),1.97(m,2H).
N-(4-氟-3-甲氧基)-N-(3-氟-4-羟基苯基)环丙烷-1,1-二酰胺(29)
化合物29的制备同化合物26,初始原料为4-氟-3-甲氧基苯胺;1H NMR(DMSO,400MHz):δ10.08(s,1H),9.87(s,1H),9.62(s,1H),7.57-7.48(m,2H),7.21-7.11(m,3H),6.87(t,J=9.2Hz,1H),3.80(s,3H),1.50-1.37(m,4H)
N-(4-氟苯基)-N-(4-羟基苯基)环丙烷-1,1-二酰胺(31)
将(0.50g,2.24mmol)化合物25加入圆底烧瓶中,加入2ml SOCl2,80℃反应2h,后浓缩得化合物30粗品,将浓缩物用5ml DCM稀释;称取(366mg,3.36mmol)对羟基苯胺溶入30ml DCM中,加入(386mg,3.36mmol)DIEA,冰浴下将化合物30慢慢滴加到反应液中,滴加完毕后移至室温继续搅拌反应1h,反应完成后加入EA萃取,饱和NaHCO3洗,pH=3的水洗,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到粗品,柱层析得土黄色固体化合物31,两步产率63%。1H NMR(DMSO,300MHz):δ10.18(s,1H),9.74(s,1H),9.25(s,1H),7.63(dd,J=8.1,5.2Hz,2H),7.36(d,J=8.2Hz,2H),7.15(t,J=8.4Hz,2H),6.70(d,J=7.9Hz,2H),1.47-1.41(m,2H),1.14-1.06(m,2H).
N-(4-氨基苯基)-N-(4-羟基苯基)环丙烷-1,1-二酰胺(32)
化合物32的制备同化合物31,初始原料为对1,4-苯二胺,两步产率56%。1H NMR(DMSO,300MHz):δ10.25(s,1H),9.57(s,1H),7.68-7.60(m,2H),7.30-7.10(m,4H),6.51(d,J=8.6Hz,2H),4.96(s,2H),1.53-1.37(m,4H).
实施例2片段III的合成
1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酸(34)
将(300mg,1.95mmol)2-氧代-2H-吡喃-3-甲酸甲酯、(0.19ml,1.96mmol)对氟苯胺溶于5ml DMF中,室温下搅拌反应6h后,后向反应液中加入(0.49g,2.54mmol)EDC、(60mg,0.49mmol)DMAP(二甲基氨基吡啶),室温下搅拌反应过夜,反应完成后,加入EA萃取,饱和NaHCO3洗,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到粗品。将得到的粗品直接溶于20mL 2N的NaOH的THF/H2O(1∶1V∶V)中,65℃搅拌反应2h,反应完成后用稀盐酸调节pH值到1,即析出大量固体,过滤,干燥得土黄色固体化合物34。1H NMR
(DMSO,300MHz):δ8.47(dd,J=7.1,2.2Hz,1H),8.19(dd,J=6.6,2.2Hz,1H),7.59-7.63(m,2H),7.39-7.44(m,2H),6.78(dd,J=6.6,7.1Hz,1H).
N-(3-氟-4-羟基苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-碳酰胺(36)
将(0.52g,2.24mmol)化合物34加入圆底烧瓶中,加入2ml SOCl2,80℃反应2h,后浓缩得化合物35,将浓缩物用5ml DCM稀释;称取(427mg,3.36mmol)对羟基-3氟-苯胺溶入30ml DCM中,加入(386mg,3.36mmol)DIEA,冰浴下将化合物35慢慢滴加到反应液中,滴加完毕后移至室温继续搅拌反应1h,反应完成后加入EA萃取,饱和NaHCO3洗,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到粗品,柱层析得土黄色固体化合物36,两步产率52%。1H NMR(DMSO,300MHz):δ11.79(s,1H),9.72(s,1H),8.55(d,J=7.2Hz,1H),8.11(dd,J=13.6,6.3Hz,1H),7.74(d,J=13.5Hz,1H),7.59(dt,J=13.0,6.5Hz,2H),7.41(dd,J=16.3,7.6Hz,2H),7.20-7.09(m,1H),6.92(t,J=9.2Hz,1H),6.72(dd,J=14.6,7.3Hz,1H).
实施例3片段IV的合成
4-(苄氧基)-3-氟苯胺(37)
将对羟基-3-氟苯胺(1.0g,7.87mmol)溶解在10mL无水DMF中,冷却到0℃,加入(0.88g,7.87mmol)叔丁醇钾,搅拌10min后,加入(1.35g,7.87mmol)苄溴,TLC跟踪,反应完成后加入EA萃取,饱和NaHCO3洗,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到化合物37粗品,柱层析得无色液体,产率52%。1H NMR(CDCl3,300MHz):δ7.41-7.28(m,5H),6.91(dd,1H),6.46(dd,1H),6.32(m,1H),4.97(s,2H),4.98(s,2H).
1-(4-(苄基氧基)-3-氟苯基)-N-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-碳酰胺(41)
化合物41的合成同36,初始原料为4-(苄氧基)-3-氟苯胺(37)。1H NMR(DMSO,300MHz):δ11.93(s,1H),8.56(dd,J=7.2,1.9Hz,1H),8.10(dd,J=6.6,1.9Hz,1H),7.79-7.70(m,2H),7.65-7.37(m,7H),7.37-7.27(m,1H),7.20(t,J=8.8Hz,2H),6.70(t,J=7.0
Hz,1H),5.30(s,2H).
1-(3-氟-4-羟基苯基)-N-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-碳酰胺(42)
将上述(432mg,1mmol)化合物41溶入3ml三氟乙酸中,后滴入100μl三氟甲磺酸,搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用2N的NaOH调节pH=6,EA萃取,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到化合物42粗品,柱层析得淡黄色固体,产率87%。1H NMR(DMSO,300MHz):δ11.96(s,1H),10.40(s,1H),8.55(dd,J=7.3,2.1Hz,1H),8.08(dd,J=6.6,2.1Hz,1H),7.73(dd,J=8.9,5.0Hz,2H),7.47(dd,J=11.8,2.3Hz,1H),7.26-7.03(m,4H),6.69(t,J=6.9Hz,1H).
实施例4 片段V的合成
本片段合成参考J Med Chem,2008,51,5330-5341
3-氧代-4-苯丁酸乙酯(44)
称取(2g,13.9mmol)丙二酸环(亚)异丙酯溶于40ml二氯甲烷中,加入(1.65g,20.9mmol)吡啶,冷却到0℃,后慢慢滴加(2.14g,13.9mmol)苯乙酰氯,0℃下继续搅拌反应3h,完成后加入100mlDCM冲稀,加入50ml 1N的HCl,搅拌,分离有机相,无水Na2SO4干燥,浓缩得到粗品。将粗品直接加入50ml EtOH中,回流过夜,浓缩后柱层析得浅黄色油状物,两步反应产率44%。1H NMR(CDCl3,300MHz):δ7.42-7.14(m,5H),4.15(q,J=7.1Hz,2H),3.81(s,2H),3.43(s,2H),1.24(t,J=7.2Hz,3H).
4-(二甲氨基)-2-((二甲氨基)亚甲基)-3-氧代-4-苯丁酸乙酯(45)
将上述液体加入DMF-DMA中,110℃下搅拌反应3h,反应完成后浓缩,加入EA搅拌得白色固体,产率81%。1H NMR(DMSO,300MHz):δ7.37-7.14(m,5H),7.06(s,1H),7.04(s,1H),4.07-3.87(m,2H),2.92(s,6H),2.65(s,6H),1.13(t,J=7.1Hz,3H).
4-氧代-5-苯基-1,4-二氢吡啶-3-甲酸乙酯(46)
将上述固体溶于EtOH中,加入3eq的NH4Cl,回流2h,后冷却到室温,过滤干燥得淡黄色固体,产率76%。1H NMR(DMSO,300MHz):δ8.22(s,1H),7.86(s,1H),7.64-7.56(m,2H),7.47-7.25(m,3H),4.21(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H).
4-氧代-5-苯基-1,4-二氢吡啶-3-甲酸(47)
将上述固体溶于乙醇中,加入2N的NaOH,70℃搅拌反应2h,完成后冷却,加入1.5N的HCl,得固体,过滤干燥,产率90%。1H NMR(DMSO,300MHz):δ13.21(s,1H),8.62(s,1H),8.25(s,1H),7.75-7.62(m,2H),7.53-7.36(m,3H).
5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸(48)
化合物48的合成同47,初始原料为对氟苯乙酰氯。1H NMR(DMSO,300MHz):δ13.21(s,1H),8.63(s,1H),8.27(s,1H),7.73(dd,J=8.7,5.7Hz,2H),7.29(t,J=8.9Hz,2H).
实施例5 N-(4-((7-氯-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(1S)的合成
5-(甲氧基亚甲基)-2,2-二甲基-1,3-二氧六环-4,6-二酮(49)
将10g米氏酸加入40ml原碳酸三甲酯中,100℃搅拌反应3h,反应完成后冷却,加入石油醚超声得大量沉淀,过滤,PE冲洗得产物,无需纯化直接用于下一步。
5,7-二氯-1,6-萘啶-4(1H)-酮(51)
将1g,6.13mmol的2,6-二氯-4-氨基吡啶溶于异丙醇中,后加入2eq化合物49,后升
温至110℃搅拌反应1h后析出大量固体,继续搅拌反应2h,后冷却到室温,用异丙醇洗,乙醚洗得产物,产率96%;
将上述得到的化合物悬浮于二苯醚中10ml/g,升温至220℃搅拌反应1h后析出大量固体,冷却到室温,加入大量PE洗涤,过滤得产物,产率94%。1H NMR(300MHz,DMSO)δ12.11(s,1H),7.93(dd,J=7.7,5.5Hz,1H),7.48(s,1H),6.17(d,J=7.5Hz,1H).
7-氯-1,6-萘啶-4(1H)-酮(52)
锌的处理:称取一定量的锌粉加入稀盐酸,加入稀盐酸的量为使锌粉缓慢冒出气泡,室温下搅拌30min,以除去锌表面的氧化层,后将水倒掉,再用水洗两次,丙酮洗两次,乙醚洗两次,减压抽干备用。
将1eq的化合物51溶于干燥的MeOH溶液中,后加入4eq的锌粉,室温下搅拌加入10eq的醋酸,后迅速升温至70℃,TLC跟踪,反应完成后过滤,浓缩后加入水超声的固体,过滤,1∶1的EtOH/Et2O洗涤得目标化合物,产率74%;1H NMR(300MHz,DMSO)δ8.99(s,1H),8.00(d,J=7.6Hz,1H),7.49(s,1H),6.17(d,J=7.6Hz,1H).
4,7-二氯-1,6-萘啶(53)
将(340mg,1.89mmol)的化合物52溶于1,2-二氯乙烷中,加入(653μl,3.95mmol)DIEA,搅拌下滴入(345μl,3.78mmol)三氯氧磷,70℃搅拌反应30min,冷却到室温,后倒入冰水中,用2N的NaOH调节pH到8,EA萃取,饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率94%;1H NMR(300MHz,DMSO)δ9.47(d,J=0.6Hz,1H),9.10(d,J=4.7Hz,1H),8.18(s,1H),7.94(d,J=4.8Hz,1H).
N-(4-((7-氯-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(1S)
将(0.2g,1mmol)的化合物53溶于无水DMF中,加入1.1eq的酚,后加入1.1eq叔丁醇钾,用N2置换三次,110℃搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率76%;1H NMR(300MHz,DMSO)δ10.77(s,1H),9.92(s,1H),9.57(d,J=0.7Hz,1H),8.95(d,J=5.3Hz,1H),8.23-8.04(m,2H),7.62(dd,J=9.2,5.1Hz,2H),7.51(dd,J=11.2,2.6Hz,1H),7.36-7.13(m,3H),6.82(d,J=5.3Hz,1H),1.68-1.52(m,4H).
实施例6 N-(4-((7-二甲氨基-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(2S)的合成
7-(二甲氨基)-1,6-萘啶-4(1H)-酮(54)
将1eq的化合物52溶于干燥的DMF溶液中,后加入2eq的叔丁醇钾(t-BuOK),升温至110℃搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物;1H NMR(400MHz,DMSO)δ11.28(s,1H),8.80(s,1H),7.70(dd,J=7.5,5.8Hz,1H),6.22(s,1H),5.82(d,J=7.6Hz,1H),3.08(s,6H).
4-氯-1,6-萘啶-7-二甲胺(55)
将1eq的化合物54溶于1,2-二氯乙烷溶液中,后加入3eq的DIEA,2eq的三氯氧磷,升温至70℃搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物;1H NMR(300MHz,CDCl3)δ9.23(s,1H),8.63(d,J=4.7Hz,1H),7.07(d,J=4.7Hz,1H),6.80(s,1H),3.20(d,J=0.9Hz,6H).
N-(4-((7-二甲氨基-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(2S)
将(0.2g,0.97mmol)的化合物55溶于无水DMF中,加入1.1eq的酚,后加入1.1eq叔丁醇钾,用N2置换三次,110℃搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率81%。1H NMR(300MHz,CDCl3)δ7.74-7.61(m,1H),7.43-7.29(m,2H),7.14-7.05(m,1H),7.05-6.95(m,1H),6.95-6.82(m,2H),6.72-6.64(m,1H),6.63-6.53(m,1H),6.38(d,J=2.4Hz,1H),6.20(d,J=2.3Hz,1H),3.25(s,6H),1.49(m,4H);EI MS m/z 503[M]+.
实施例7 N-(4-((7-甲氧基-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(3S)的合成
3-溴-2-甲氧基-4-氨基吡啶(56)
将(5g,40.3mmol)的2-甲氧基-4-氨基吡啶溶于MeCN中,0℃下分批加入(7.18g,40.3mmol)的NBS,后慢慢回到室温搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,保险粉洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率77%。1H NMR(300MHz,CDCl3)δ7.57(d,1H),6.36(d,1H),6.20(s,2H),3.7(s,3H).
7-甲氧基-1,6-萘啶-4(1H)-酮(59)
将1eq的3-溴-2-甲氧基-4-氨基吡啶溶于异丙醇中,后加入2eq化合物49,后升温至110℃搅拌反应1h后析出大量固体,2h后冷却到室温,用异丙醇洗,乙醚洗得产物化合物57,产率92%;
将上述得到的化合物悬浮于二苯醚中10ml/g,升温至220℃搅拌反应1h后析出大量固体,冷却到室温,加入大量石油醚洗涤,过滤得产物化合物58,产率96%。
将上述固体溶于甲醇中,加入2eq的甲酸铵,后加入10%重量的10%Pd/C,60℃下搅拌反应,TLC跟踪,反应完成后,冷却过滤,滤液浓缩,后用EA萃取,饱和和NaCl洗涤,无水Na2SO4干燥,减压浓缩得化合物59。1H NMR(400MHz,DMSO)δ8.89(s,1H),8.46(s,1H),7.87(d,J=7.6Hz,1H),6.75(s,1H),5.97(d,J=7.6Hz,1H),3.91(s,3H).
4-氯-7-甲氧基-1,6-萘啶(60)
将(332mg,1.89mmol)的化合物59溶于20ml乙腈中,加入(653μl,3.95mmol)DIEA,搅拌下滴入(345μl,3.78mmol)三氯氧磷,70℃搅拌反应30min,冷却到室温,后倒入冰水中,用2N的NaOH调节pH到8,EA萃取,饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率92%;1H NMR(300MHz,CD3OD)δ9.33(s,1H),8.85(d,J=4.8Hz,1H),7.55(d,J=4.8Hz,1H),7.23(s,1H),
4.10(s,3H).
N-(4-((7-甲氧基-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(3S)
合成路线同2S,初始原料为化合物60。1H NMR(DMSO,300MHz):δ10.43(s,1H),10.02(s,1H),9.48(s,1H),8.79(d,J=5.2Hz,1H),7.94(d,J=13.3Hz,1H),7.66(dd,J=9.2,5.1Hz,2H),7.58-7.46(m,2H),7.26(s,1H),7.17(t,J=8.9Hz,2H),6.49(d,J=5.1Hz,1H),4.04(s,3H),1.55-1.36(m,4H).
实施例8 4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯胺(4S)的合成
8-溴-4-氯-7-甲氧基-1,6-萘啶(61)
将(482mg,1.89mmol)的化合物58溶于10ml DMF中,搅拌下滴入(345μl,3.78mmol)三氯氧磷,室温搅拌反应30min,TLC跟踪,反应完成后倒入冰水中,用2N的NaOH调节pH到8,EA萃取,饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率83%;1H NMR(300MHz,CDCl3)δ9.25(s,1H),8.94(d,J=4.7Hz,1H),7.39(d,J=4.7Hz,1H),4.18(s,3H).
8-溴-4-氯-7-羟基-1,6-萘啶(62)
取3ml三氟甲磺酸于圆底烧瓶中,冰浴下分批加入(516mg,1.89mmol)的化合物61,搅拌溶解后移入180℃油浴搅拌反应10min,TLC跟踪,反应完成后冷却到室温,加入少量EA冲稀,加入大量的DCM,静置得到大量固体,过滤。滤饼用MeCN溶解,用2N的NaOH调节pH到8,得到大量黄色固体。过滤,滤饼干燥后快速柱得目标化合物,黄色固体,产率84%;1H NMR(300MHz,DMSO)δ8.86(s,1H),8.55(d,J=4.6Hz,1H),7.00
(d,J=4.8Hz,1H).
7-(4-吗啡啉乙氧基)-8-溴-4-氯-1,6-萘啶(63)
将(1.5g,5.79mmol)的化合物62溶于40ml THF中,搅拌下加入(1.14g,8.69mmol)4-羟乙基吗啉,(1.58g,8.69mmol)无水硫酸镁,室温搅拌10min,后加入(2.28g,8.69mmol)三苯基膦,慢慢滴加(1.7ml,8.69mmol)DEAD,室温搅拌6h,TLC跟踪,反应完成后EA萃取,饱和NaHCO3洗涤两次取有机相,有机相用pH等于3的稀HCl洗涤两次,取无机相,用2N的NaOH调节pH等于8,EA萃取,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率73%;1H NMR(300MHz,CDCl3)δ9.23(s,1H),8.95(d,J=4.7Hz,1H),7.62(d,J=4.6Hz,1H),4.72(t,J=5.7Hz,2H),3.77-3.62(m,4H),2.89(t,J=5.8Hz,2H),2.70-2.56(m,4H).
4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯胺(4S)
合成路线同2S,初始原料为63和对羟基-3-氟苯胺。1H NMR(DMSO,300MHz):δ9.40(s,1H),8.87(d,J=5.3Hz,1H),7.15(t,J=9.0Hz,1H),6.63-6.53(m,2H),6.50(d,J=8.6Hz,1H),5.58(s,2H),4.67(t,J=5.7Hz,2H),3.63-3.52(m,4H),2.89-2.75(m,2H),2.63-2.53(m,4H).
实施例9 2-氟-N1-(7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)苯基-1,4-二胺(5S)的合成
将(0.93g,2mmol)的化合物4S溶于40ml甲醇中,加入(0.18g,4mmol)的甲酸铵,后加入20mg的10%Pd/C,60℃下反应30min,TLC跟踪,反应完成后,冷却过滤,滤液浓缩,后用EA萃取,饱和和NaCl洗涤,无水Na2SO4干燥,减压浓缩柱层析得产物。1H NMR(400MHz,DMSO)δ11.15(s,1H),9.38(s,1H),8.84(d,J=5.1Hz,1H),7.83(d,J=12.3Hz,1H),7.38-7.30(m,1H),7.29-7.17(m,1H),6.44(d,J=5.3Hz,1H),4.74(t,J=5.7Hz,2H),3.74(d,J=5.2Hz,4H),2.91(t,J=9.8Hz,2H),2.76-2.62(m,4H)。
实施例10 N-(4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(6S)的合成
合成路线同2S,初始原料为化合物63和化合物26。1H NMR(DMSO,300MHz):δ10.43(s,1H),10.02(s,1H),9.45(s,1H),8.77(d,J=5.4Hz,1H),7.93(d,J=13.0Hz,1H),7.68-7.59(m,2H),7.57-7.47(m,2H),7.22(s,1H),7.18-7.12(m,1H),6.47(d,J=5.1Hz,1H),4.49(t,J=5.8Hz,2H),2.75(t,J=5.4Hz,2H),2.57-2.51(m,4H),2.41-2.26(m,4H),2.15(s,3H),1.55-1.43(m,4H).
实施例11 N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(7S)的合成
合成路线同5S,初始原料为6S。1H NMR(DMSO,300MHz):δ10.43(s,1H),10.01(s,1H),9.45(s,1H),8.78(d,J=5.2Hz,1H),7.93(d,J=13.9Hz,1H),7.65(dd,J=8.7,5.1Hz,2H),7.60-7.45(m,2H),7.24(s,1H),7.17(t,J=8.8Hz,2H),6.48(d,J=5.2Hz,1H),4.52(t,J=5.6Hz,2H),3.65-3.53(m,4H),2.77(t,J=5.6Hz,2H),2.56-2.50(m,4H),1.54-1.40(m,4H).
实施例12 N-(3-氟-4-((7-(2-吗啡啉丙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(8S)的合成
4-氯-7-羟基-1,6-萘啶(64)
取3ml三氟甲磺酸于圆底烧瓶中,冰浴下分批加入(367mg,1.89mmol)的60,搅拌溶解后移入150℃油浴搅拌反应2h,TLC跟踪,反应完成后冷却到室温,后倒入冰中,用2N的NaOH调节pH到8,EA多次萃取,浓缩。快速柱得目标化合物,黄色固体,由于化合物不稳定,产率不稳定,产率41%;1H NMR(300MHz,DMSO)δ11.57(s,1H),9.16(s,1H),8.83(d,J=4.7Hz,1H),7.52(d,J=4.7Hz,1H),7.01(s,1H).
4-(3-((4-氯-1,6-萘啶-7-烷基)氧基)丙基)吗啉(65)
合成路线同化合物63,初始原料为N-(3-羟丙基)吗啉。1H NMR(CDCl3,300MHz):δ9.31(s,1H),8.80(d,J=4.7Hz,1H),7.32(d,J=4.6Hz,1H),7.25(s,1H),4.45(t,J=6.3Hz,2H),3.73-3.65(m,4H),2.60-2.53(m,2H),2.52-2.43(m,4H),2.05(t,J=7.0Hz,2H).
N-(3-氟-4-((7-(2-吗啡啉丙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(8S)
合成路线同化合物2S,初始原料为化合物65和化合物26。1H NMR(DMSO,300MHz):δ10.43(s,1H),10.01(s,1H),9.45(s,1H),8.77(d,J=5.2Hz,1H),7.94(d,J=12.3Hz,1H),7.73-7.61(m,2H),7.60-7.44(m,2H),7.27-7.11(m,3H),6.48(d,J=5.1Hz,1H),4.43(t,J=6.3Hz,2H),3.72-3.54(m,4H),2.49-2.21(m,5H),2.04-1.90(m,2H),1.55-1.36(m,4H).
实施例13 N-(3-氟-4-((7-((1-甲基哌啶-4-烷基)甲氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(9S)的合成
4-氯-7-((1-甲基哌啶-4-烷基)甲氧基)-1,6-萘啶(66)
化合物66的合成同化合物63,初始原料为4-哌啶甲醇,产率63%。1H NMR(300MHz,CDCl3)δ9.27(s,1H),8.77(d,J=4.7Hz,1H),7.28(d,J=4.7Hz,1H),7.20(s,1H),4.21(d,J=6.2Hz,2H),2.87(d,J=11.4Hz,2H),2.33-2.21(s,3H),1.95-1.82(m,4H),1.54-1.34(m,2H),1.33-1.16(m,1H).
N-(3-氟-4-((7-((1-甲基哌啶-4-烷基)甲氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(9S)
合成路线同化合物2S,初始原料为化合物66和化合物26。1H NMR(DMSO,300MHz):
δ10.48(s,1H),10.05(s,1H),9.46(s,1H),8.78(d,J=5.3Hz,1H),7.95(d,J=13.1Hz,1H),7.72-7.61(m,2H),7.61-7.43(m,2H),7.25(s,1H),7.16(t,J=7.9Hz,2H),6.49(d,J=5.2Hz,1H),4.32(d,J=6.1Hz,2H),3.01-2.79(m,2H),2.69(s,3H),2.19-1.87(m,3H),1.77-1.57(m,2H),1.56-1.32(m,4H).
实施例14 N-(4-((8-溴-7-(2-(4-甲基哌嗪-1-烷基)乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3--氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(10S)的合成
8-溴-4-氯-7-(2-(4-甲基哌嗪-1-烷基)乙氧基)-1,6-萘啶(67)
合成路线同63,初始原料为化合物62和1-(2-羟乙基)-4-甲基哌嗪。1H NMR(CDCl3,300MHz):δ9.20(s,1H),8.92(d,J=4.7Hz,1H),7.37(d,J=4.7Hz,1H),4.69(t,J=5.9Hz,2H),2.89(t,J=5.9Hz,2H),2.79-2.61(m,4H),2.54-2.34(m,4H),2.26(s,3H).
N-(4-((8-溴-7-(2-(4-甲基哌嗪-1-烷基)乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3--氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(10S)
合成路线同化合物2S,初始原料为化合物67和化合物26。1H NMR(DMSO,300MHz):δ10.47(s,1H),10.02(s,1H),9.43(s,1H),8.89(d,J=5.3Hz,1H),7.95(d,J=12.4Hz,1H),7.77-7.44(m,3H),7.17(t,J=8.2Hz,2H),6.62(d,J=5.4Hz,1H),4.66(t,J=5.1Hz,2H),3.41-3.24(m,4H),2.85(t,J=5.4Hz,2H),2.78-2.57(m,4H),2.39(s,3H),1.56-1.32(m,4H).
实施例15 N-(3-氟-4-((7-(2-(4-甲基哌嗪-1-烷基)乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(11S)的合成
合成路线同化合物5S,初始原料为化合物10S。1H NMR(DMSO,300MHz):δ10.43(s,1H),10.02(s,1H),9.45(s,1H),8.77(d,J=5.4Hz,1H),7.93(d,J=13.0Hz,1H),7.68-7.59(m,2H),7.57-7.47(m,2H),7.22(s,1H),7.18-7.12(m,1H),6.47(d,J=5.1Hz,1H),
4.49(t,J=5.8Hz,2H),2.75(t,J=5.4Hz,2H),2.57-2.51(m,4H),2.41-2.26(m,4H),2.15(s,3H),1.55-1.43(m,4H).
实施例16 N-(4-氟苯基)-N-(4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)环丙基-1,1-二酰胺(12S)的合成
4-(2-((4-氯-1,6-萘啶-7-烷基)氧基)乙基)吗啉(68)
合成路线同化合物63,初始原料为化合物64和4-羟乙基吗啉。1H NMR(DMSO,300MHz):δ9.27(s,1H),8.77(d,J=4.7Hz,1H),7.29(d,J=4.7Hz,1H),7.24(s,1H),4.54(t,J=5.8Hz,2H),3.72-3.66(m,4H),2.83(t,J=5.8Hz,2H),2.61-2.53(m,4H).
N-(4-氟苯基)-N-(4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)环丙基-1,1-二酰胺(12S)
合成路线同化合物2S,初始原料为化合物68和化合物31。1H NMR(DMSO,300MHz):δ10.24(s,1H),10.06(s,1H),9.42(s,1H),8.75(d,J=5.2Hz,1H),7.80(d,J=9.1Hz,2H),7.71-7.57(m,2H),7.31(d,J=9.0Hz,2H),7.23-7.10(m,3H),6.43(d,J=5.2Hz,1H),4.52(t,J=7.2Hz,2H),3.58(d,J=4.9Hz,4H),2.77(t,J=7.1Hz,2H),2.52(m,4H),1.63-1.38(m,2H).
实施例17 N-(4-氟苯基)-N-(4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氨基)苯基)环丙基-1,1-二酰胺(13S)的合成
将1eq的化合物68溶于干燥的DMF溶液中,后加入1.2eq的68,升温至130℃搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物;产率72%。1H NMR(DMSO,300MHz):δ10.16(s,1H),10.07(s,1H),9.47(s,1H),8.42(s,1H),7.84-7.59(m,5H),7.33(d,J=8.6Hz,2H),7.17(t,J=8.8Hz,2H),6.98(s,1H),6.61(d,J=5.6Hz,1H),4.47(t,J=
5.9Hz,2H),3.66-3.55(m,4H),2.76(t,J=5.7Hz,2H),2.51-2.48(m,4H),1.55-1.39(m,4H).
实施例18 N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)-N-甲基环丙基-1,1-二酰胺(14S)的合成
合成路线同化合物2S,初始原料为化合物68和化合物27。1H NMR(DMSO,300MHz):δ10.00(s,1H),9.45(s,1H),8.79(d,J=5.0Hz,1H),7.60-7.39(m,3H),7.37-7.27(m,2H),7.24(s,1H),7.21-7.05(m,2H),6.46(d,J=5.1Hz,1H),4.52(t,J=6.3Hz,2H),3.66-3.51(m,4H),3.25(s,3H),2.77(t,J=6.0Hz,2H),2.56-2.49(m,4H),1.51-1.38(m,2H),1.30-1.20(m,2H).
实施例22 N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-碳酰胺(15S)的合成
合成路线同化合物2S,初始原料为化合物68和化合物36。1H NMR(DMSO,300MHz):δ12.18(s,1H),9.52(s,1H),8.83(d,J=5.3Hz,1H),8.61(d,J=7.2Hz,1H),8.22-8.06(m,2H),7.71-7.47(m,4H),7.53-7.23(m,3H),6.76(t,J=7.5Hz,1H),6.61(d,J=5.1Hz,1H),4.90-4.75(m,2H),4.02-3.76(m,4H),3.69-3.60(m,2H),2.53-2.43(m,4H).
实施例23 1-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-碳酰胺(16S)的合成
合成路线同化合物2S,初始原料为化合物68和化合物42。1H NMR(DMSO,300MHz):δ11.65(s,1H),9.46(s,1H),8.74(s,2H),7.74-7.60(m,3H),7.56-7.40(m,2H),7.38-7.30(m,1H),7.28(s,1H),7.02(t,J=8.7Hz,2H),6.65(t,J=7.1Hz,1H),6.48(d,J=5.3Hz,1H),4.58(t,J=5.3Hz,2H),3.82-3.66(m,4H),2.88(t,J=5.6Hz,2H),2.71-2.54(m,4H).
实施例24 1-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-2-氧代-1,2-二氢吡啶-3-甲酸甲酯(17S)的合成
1-(3-氟-4-羟基苯基)-2-氧代-1,2-二氢吡啶-3-甲酸甲酯(69)的合成
将(400mg,1.13mmol)25溶液3ml的TFA中,加入3%的三氟甲磺酸,室温搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物。1H NMR(DMSO,300MHz):δ10.31(s,1H),8.11(d,J=7.1Hz,1H),7.93(d,J=4.6Hz,1H),7.34(d,J=11.5Hz,1H),7.05(s,2H),6.39(t,J=6.3Hz,1H),3.76(s,3H).
1-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-2-氧代-1,2-二氢吡啶-3-甲酸甲酯(17S)的合成
合成路线同化合物2S,初始原料为化合物68和化合物69。1H NMR(CDCl3,300MHz):δ9.45(s,1H),8.72(d,J=5.2Hz,1H),8.27(d,J=4.9Hz,1H),7.61(d,J=4.7Hz,2H),7.49-7.37(m,2H),7.29(d,J=9.2Hz,1H),6.47-6.32(m,2H),4.57(t,J=5.8Hz,2H),3.91(s,3H),3.79-3.65(m,4H),2.88(t,J=5.7Hz,2H),2.71-2.56(m,4H).
实施例25 N-(4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3--氟苯基)-2-苯乙酰胺(18S)的合成
将(100mg,0.22mmol)4S溶于10ml THF中,加入3eq的DIEA,冷却到0℃。将1.5eq苯乙酰氯慢慢加入,继续保持温度搅拌反应1h。反应完全后,加入EA冲稀,用
饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物。产率86%。1H NMR(CDCl3,300MHz):δ10.58(s,1H),9.43(s,1H),8.87(d,J=5.3Hz,1H),7.92(d,J=13.3Hz,1H),7.64-7.20(m,6H),6.64(d,J=5.2Hz,1H),4.67(t,J=5.7Hz,2H),3.70(s,2H),3.63-3.49(m,4H),2.82(t,J=6.0Hz,2H),2.60-2.50(m,4H).
实施例26 N-(4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-4-氧代-5-苯基-1,4-二氢吡啶-3-碳酰胺(19S)的合成
将(100mg,0.22mmol)化合物4S、(71mg,0.33mmol)化合物47溶于10ml DCM中,室温下加入(130mg,0.66mmol)HOBt、(89mg,0.66mmol)EDC,室温搅拌,TLC跟踪反应,反应完成后蒸去大部分的DCM,加入EA萃取,饱和NaHCO3洗,pH=3的水洗,饱和盐水洗涤,加无水Na2SO4干燥,浓缩得到粗品,柱层析得目标化合物。产率63%。1H NMR(DMSO,300MHz):δ13.60(s,1H),9.44(s,1H),8.89(s,1H),8.65(s,1H),8.26-8.04(m,2H),7.74-7.63(m,2H),7.63-7.30(m,5H),6.69(d,J=5.4Hz,1H),4.68(t,J=5.7Hz,2H),3.64-3.53(m,4H),2.81(t,J=5.8Hz,2H),2.60-2.52(m,4H).
实施例27 N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-4-氧代-5-苯基-1,4-二氢吡啶-3-碳酰胺(20S)的合成
合成路线同化合物5S,初始原料为化合物19S。1H NMR(DMSO,300MHz):δ13.31(s,1H),9.47(s,1H),8.78(d,J=5.2Hz,1H),8.65(s,1H),8.17-8.04(m,2H),7.67(d,J=6.8Hz,2H),7.61-7.53(m,2H),7.50-7.32(m,4H),7.25(s,1H),6.56(d,J=5.2Hz,1H),4.54(t,J=5.7Hz,2H),3.65-3.54(m,4H),2.81(t,J=6.8Hz,2H),2.58-2.52(m,4H).
实施例28 N-(4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-碳酰胺(21S)的合成
合成路线同化合物19S,初始原料为化合物4S和化合物48。1H NMR(DMSO,300MHz):δ13.39(s,1H),9.44(s,1H),8.89(d,J=5.3Hz,1H),8.65(s,1H),8.18-8.03(m,2H),7.81-7.65(m,2H),7.55(s,2H),7.34-7.20(m,2H),6.68(d,J=4.3Hz,1H),4.68(t,J=5.6Hz,2H),3.61-3.54(m,4H),2.81(t,J=5.7Hz,2H),2.61-2.53(m,4H).
实施例29 N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-碳酰胺(22S)的合成
合成路线同化合物5S,初始原料为化合物21S。1H NMR(DMSO,300MHz):δ13.26(s,1H),9.46(s,1H),8.78(d,J=5.3Hz,1H),8.64(s,1H),8.16-8.07(m,2H),7.76-7.67(m,3H),7.55-7.48(m,2H),7.30-7.24(m,3H),6.55(d,J=5.4Hz,1H),4.54(t,J=5.6Hz,2H),3.63-3.57(m,4H),2.82(t,J=7.3Hz,2H),2.61-2.52(m,4H).
实施例30 N-(3,4-二氟苯基)-N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)环丙基-1,1-二酰胺(23S)的合成
N-(4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(3,4-二氟苯基)环丙基-1,1-二酰胺(70)
合成路线同化合物2S,初始原料为化合物63和化合物28。1H NMR(DMSO,300MHz):δ10.40(s,1H),10.21(s,1H),9.43(s,1H),8.89(d,J=5.4Hz,1H),7.94(d,J=13.6Hz,1H),7.89-7.75(m,1H),7.64-7.48(m,2H),7.46-7.32(m,2H),6.62(d,J=5.3Hz,1H),
4.68(t,J=5.7Hz,2H),3.67-3.52(m,4H),2.83(t,J=6.0Hz,2H),2.68-2.54(m,4H),1.57-1.41(m,4H).
N-(3,4-二氟苯基)-N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)环丙基-1,1-二酰胺(23S)
合成路线同化合物5S,初始原料为化合物70。1H NMR(CD3OD,300MHz):δ9.48(d,J=0.6Hz,1H),8.71(d,J=5.4Hz,1H),7.86(d,J=12.7Hz,1H),7.71(dd,J=11.7,6.3Hz,1H),7.46-7.36(m,2H),7.28-7.15(m,3H),6.52(d,J=5.4Hz,1H),4.70-4.64(m,2H),3.80-3.71(m,4H),3.08-3.01(m,2H),2.85-2.75(m,4H),1.64(m,4H).
实施例31 N-(4-氟-3-甲氧基)-N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)环丙基-1,1-二酰胺(24S)的合成
N-(4-((8-溴-7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(3-甲氧基-4-氟苯基)环丙基-1,1-二酰胺(71)
合成路线同化合物2S,初始原料为化合物63和化合物29。1H NMR(DMSO,300MHz):δ10.40(s,1H),10.00(s,1H),9.43(s,1H),8.88(d,J=7.4Hz,1H),7.94(d,J=12.9Hz,1H),7.64-7.50(m,3H),7.25-7.14(m,2H),6.60(d,J=8.2Hz,1H),4.66(t,J=6.1Hz,2H),3.81(s,3H),3.64-3.55(m,4H),2.80(t,J=8.4Hz,2H),2.65-2.55(m,4H),1.54-1.44(m,4H).
N-(4-氟-3-甲氧基)-N-(3-氟-4-((7-(2-吗啡啉乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)环丙基-1,1-二酰胺(24S)
合成路线同化合物5S,初始原料为化合物71。1H NMR(DMSO,300MHz):δ9.97(s,1H),9.44(s,1H),9.32(s,1H),8.68(d,J=5.1Hz,1H),8.30(s,1H),7.80(t,J=12.8Hz,1H),7.45-7.29(m,2H),7.23-7.19(m,1H),7.06-6.83(m,2H),6.32(t,J=4.9Hz,1H),4.56(t,J=5.7Hz,2H),3.89(s,3H),3.79-3.69(m,4H),2.88(t,J=5.8Hz,2H),2.68-2.57(m,4H),1.83-1.75(m,2H),1.68-1.57(m,2H).
实施例32 N-(3-氟-4-((7-(2-(吡啶-4-烷基)乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(25S)的合成
8-溴-4-氯-7-(2-(吡啶-4-烷基)乙氧基)-1,6-二氮杂萘(72)
合成路线同化合物63,初始原料为化合物62和1-(2-羟乙基)吡啶。1H NMR(CDCl3,300MHz):δ9.21(s,1H),8.94(d,J=4.7Hz,1H),8.52(d,J=5.9Hz,2H),7.40(d,J=4.7Hz,1H),7.30(d,J=5.9Hz,2H),4.77(t,J=6.5Hz,2H),3.18(t,J=6.5Hz,2H).
N-(4-((8-溴-7-(2-(吡啶-4-烷基)乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(73)
合成路线同化合物2S,初始原料为化合物72和化合物26。1H NMR(DMSO,300MHz):δ10.44(s,1H),10.01(s,1H),9.44(s,1H),8.89(d,J=5.3Hz,1H),8.51(d,J=7.6Hz,2H),7.94(d,J=13.9Hz,1H),7.69-7.62(m,2H),7.58-7.48(m,2H),7.49-7.37(m,2H),7.17(t,J=8.9Hz,2H),6.62(d,J=6.2Hz,1H),4.80(t,J=7.2Hz,2H),3.16(t,J=7.2Hz,2H),1.54-1.43(m,4H).
N-(3-氟-4-((7-(2-(吡啶-4-烷基)乙氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(25S)
合成路线同化合物5S,初始原料为化合物73。1H NMR(CDCl3,300MHz):δ10.19(s,1H),9.44(s,1H),8.68(d,J=5.2Hz,1H),8.52(d,J=6.0Hz,2H),8.10(s,1H),7.78(dd,J=12.1,2.3Hz,1H),7.48-7.38(m,2H),7.29-7.25(m,3H),7.21(m,2H),7.10-6.99(m,2H),6.33(d,J=5.4Hz,1H),4.67(t,J=6.7Hz,2H),3.17(t,J=6.6Hz,2H),1.86-1.76(m,2H),1.61-1.57(m,2H).
实施例33 N-(3-氟-4-((7-((1-吗啡啉丙基-2-烷基)氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(26S)的合成
4-(2-((8-溴-4-氯-1,6-二氮杂萘-7-烷基)氧代)丙基)吗啡啉(74)
合成路线同化合物63,初始原料为化合物62和N-(2-羟丙基)吗啉。1H NMR(CDCl3,300MHz):δ9.21(s,1H),8.93(d,J=4.7Hz,1H),7.38(d,J=4.7Hz,1H),5.68-5.57(m,1H),3.57(t,J=4.6Hz,4H),2.65-2.50(m,4H),1.81-1.66(m,2H),1.43(d,J=6.2Hz,3H).
N-(4-((8-溴-7-((1-吗啉丙基-2-烷基)氧基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(75)
合成路线同化合物2S,初始原料为化合物74和化合物26。1H NMR(CDCl3,300MHz):δ110.20(s,1H),9.35(s,1H),8.81(d,J=5.3Hz,1H),8.00(s,1H),7.78(d,J=12.4Hz,1H),7.48-7.38(m,2H),7.28-7.25(m),7.06(t,J=8.6Hz,2H),6.40(d,J=5.4Hz,1H),5.72-5.59(m,1H),3.60(t,J=4.4Hz,4H),2.63-2.53(m,4H),1.86-1.78(m,2H),1.63-1.58(m,4H),1.45(d,J=6.3Hz,3H).
N-(3-氟-4-((7-((1-吗啡啉丙基-2-烷基)氧基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(26S)
合成路线同化合物5S,初始原料为化合物75。1H NMR(DMSO,300MHz):δ10.43(s,1H),10.01(s,1H),9.44(s,1H),8.75(d,J=5.2Hz,1H),7.93(dd,J=13.1,2.3Hz,1H),7.64(dd,J=9.1,5.0Hz,2H),7.59-7.45(m,2H),7.22-7.10(m,3H),6.46(d,J=5.2Hz,1H),5.58-5.46(m,1H),3.55-3.48(m,4H),2.78-2.56(m,2H),2.50-2.43(m,4H),1.52-1.44(m,4H),1.34(d,J=6.2Hz,3H).
实施例34 N-(3-氟-4-((7-吗啡啉-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(27S)的合成
7-吗啡啉-1,6-二氮杂萘-4(1H)-酮(76)
将(340mg,1.89mmol)的化合物52溶于吗啡啉中,190℃下反应1h,TLC跟踪,反应完成后冷却到室温,加入乙醚沉淀,过滤,乙醚洗得粗品。1H NMR(DMSO,400MHz):δ8.83(s,1H),7.74(d,J=7.6Hz,1H),6.45(s,1H),5.87(d,J=7.6Hz,1H),3.75-3.65(m,4H),3.54-3.45(m,4H).
N-(3-氟-4-((7-吗啡啉-1,6-二氮杂萘-4-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(27S)
合成路线同化合物2S,初始原料为化合物76。1H NMR(DMSO,400MHz):δ10.54(s,1H),10.02(s,1H),9.55(s,1H),8.84(d,J=6.0Hz,1H),7.99(d,J=12.8Hz,1H),7.72-7.62(m,2H),7.62-7.51(m,2H),7.17(t,J=8.5Hz,2H),7.03(s,1H),6.63(d,J=7.1Hz,1H),3.84-3.76(m,4H),3.75-3.69(m,4H),1.57-1.43(m,4H).
实施例35 N-(3-氟-4-((7-(4-吗啡啉哌啶-1-基)-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(28S)的合成
合成路线同化合物27S,初始原料为4-(4-哌啶基)吗啉。1H NMR(CDCl3,300MHz):δ10.05(s,1H),9.39(s,1H),8.55(d,J=5.3Hz,1H),8.15(s,1H),7.75(d,J=12.5Hz,1H),7.43(dd,J=9.3,4.4Hz,2H),7.23-7.16(m,1H),7.05(t,J=8.8Hz,2H),6.96(s,1H),6.17(d,J=4.7Hz,1H),4.50(d,J=12.3Hz,2H),3.84-3.63(m,4H),3.04-2.85(m,2H),2.67-2.54(m,4H),2.52-2.41(m,1H),2.04-1.92(m,2H),1.87-1.75(m,2H),1.69-1.54(m,4H).
实施例36(S)-N-(3-氟-4-((7-(2-(3-甲基吗啡啉)乙氧基)-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(29S)的合成
合成路线同化合物26S,初始原料为化合物62和(S)-2-(3-甲基吗啉)乙醇。1H NMR(CDCl3,300MHz):δ10.17(s,1H),9.45(s,1H),8.68(d,J=5.2Hz,1H),8.10(s,1H),7.77(d,J=12.3Hz,1H),7.43(dd,J=9.0,4.8Hz,2H),7.30-7.22(m,3H),7.05(t,J=8.6Hz,2H),6.32(d,J=4.9Hz,1H),4.53(t,J=6.0Hz,2H),3.80(d,J=11.5Hz,1H),3.72-3.60(m,2H),
3.31-3.15(m,2H),2.95-2.74(m,2H),2.65-2.51(m,2H),1.85-1.77(m,2H),1.63-1.56(m,2H),1.04(d,J=6.3Hz,3H).
实施例37(R)-N-(3-氟-4-((7-(2-(3-甲基吗啡啉)乙氧基)-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(30S)的合成
合成路线同化合物26S,初始原料为化合物62和(R)-2-(3-甲基吗啉)乙醇。1H NMR(CDCl3,300MHz):δ10.19(s,1H),9.45(s,1H),8.68(d,J=5.2Hz,1H),8.13(s,1H),7.77(d,J=12.5Hz,1H),7.55-7.35(m,2H),7.27-7.19(m,2H),7.05(t,J=8.6Hz,2H),6.33(d,J=5.2Hz,1H),4.55(t,J=4.5Hz,2H),3.86-3.74(m,1H),3.75-3.60(m,2H),3.37-3.14(m,2H),3.01-2.76(m,2H),2.70-2.51(m,2H),1.87-1.74(m,2H),1.68-1.53(m,2H),1.05(d,J=6.1Hz,3H).
实施例38 N-(4-((7-(2-(1H-咪唑-1-基)乙氧基)-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(31S)的合成
合成路线同化合物26S,初始原料为化合物62和2-(1H-咪唑-1-烷基)乙醇。1H NMR(CDCl3,300MHz):δ10.40(s,1H),9.41(s,1H),8.68(d,J=5.3Hz,1H),8.55(s,1H),7.78(d,J=12.1Hz,1H),7.65(s,1H),7.43(dd,J=9.0,4.7Hz,2H),7.33-7.26(m,1H),7.24-7.15
(m,2H),7.11-6.97(m,4H),6.34(d,J=5.2Hz,1H),4.72(t,J=5.3Hz,2H),4.41(t,J=5.2Hz,2H),1.86-1.75(m,2H),1.67-1.55(m,2H).
实施例39 N-(4-((7-(4-苄基哌嗪基-1-基)-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(32S)的合成
合成路线同化合物27S,初始原料为4-苄基吗啉。1H NMR(CDCl3,300MHz):δ10.03(s,1H),9.39(s,1H),8.55(d,J=5.3Hz,1H),8.18(s,1H),7.74(d,J=12.1Hz,1H),7.49-7.39(m,2H),7.39-7.26(m,5H),7.23-7.15(m,1H),7.05(t,J=8.5Hz,2H),6.92(s,1H),6.18(d,J=5.1Hz,1H),3.74-3.63(m,4H),3.57(s,2H),2.69-2.54(m,4H),1.84-1.75(m,2H),1.61-1.54(m,2H).
实施例40 N-(3-氟-4-((3-氧代-3,4-二氢吡啶酮[2,3-b]二氮杂苯-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(33S)的合成
N-(3-氟-4-((2-氧代-1,2-二氢吡啶酮[2,3-b]二氮杂苯-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(34S)的合成
N-(4-((2-氨基-3-硝基吡啶-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(88)
将(1g,5.8mmol)的2-氨基-3-硝基-4-氯吡啶溶于无水DMF中,加入1.1eq的26,后加入1.1eq叔丁醇钾,用N2置换三次,80℃搅拌反应1h,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,81%。1H NMR(300MHz,DMSO)δ10.64(s,1H),9.94(s,1H),8.05(d,J=5.7Hz,1H),7.97(t,J=8.6Hz,1H),7.62(dd,J=9.0,5.0Hz,2H),7.32(d,J=11.2Hz,1H),7.25(s,2H),7.18(t,J=8.9Hz,2H),7.06(d,J=8.4Hz,1H),6.06(d,J=5.6Hz,1H),1.58(t,J=10.6Hz,4H).
N-(4-((2,3-二氨基吡啶-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(89)
将1eq的化合物88溶于20ml THF/MeOH(V∶V=1∶1)溶液中,后加入4eq的NiCl2·6H2O,0℃下搅拌下分批加入2eq的NaBH4,继续搅拌反应10min,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物。1H NMR(300MHz,CD3OD)δ8.02(d,J=5.7Hz,1H),7.87(dd,J=13.2,2.3Hz,1H),7.68-7.58(m,2H),7.48(d,J=9.0Hz,1H),7.36(t,J=9.0Hz,1H),7.24(s,1H),7.20-7.07(m,2H),5.97(d,J=5.7Hz,1H),1.52-1.40(m,4H).
N-(3-氟-4-((3-氧代-3,4-二氢吡啶酮[2,3-b]二氮杂苯-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(33S)的合成
N-(3-氟-4-((2-氧代-1,2-二氢吡啶酮[2,3-b]二氮杂苯-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(34S)的合成
将(100mg,0.23mmol)化合物89溶于乙醇中,60℃搅拌下,加入2eq的醛基乙酸乙酯的甲苯溶液,继续搅拌反应3h,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物。产率:
33S:31%,34S:48%。33S:1H NMR(DMSO,300MHz):δ12.96(s,1H),10.40(s,1H),10.01(s,1H),8.37(d,J=5.7Hz,1H),8.20(s,1H),7.91(d,J=13.3Hz,1H),7.65(dd,J=9.1,5.1Hz,2H),7.51(d,J=8.0Hz,1H),7.39(t,J=9.0Hz,1H),7.16(t,J=8.9Hz,2H),6.56(d,J=5.6Hz,1H),1.58-1.36(m,4H).34S:1H NMR(DMSO,300MHz):δ12.67(s,1H),10.41(s,1H),10.00(s,1H),8.43(s,1H),8.35(d,J=5.4Hz,1H),7.89(d,J=13.7Hz,1H),7.64(dd,J=8.7,5.0Hz,2H),7.50(d,J=9.2Hz,1H),7.40(t,J=8.9Hz,1H),7.16(t,J=8.9Hz,2H),6.81(d,J=5.5Hz,1H),1.49-1.44(m,4H).
实施例41 N-(4-((7-((1-乙基-3-氟哌啶-4-基)氨基)-1,6-萘啶-4-基)氧基)-3-氟苯基)-2-(4-氟苯基)-3-氧-2,3-二氢哒嗪-4-碳酰胺(35S)的合成
合成路线同27S,初始原料为N-乙基-4-氨基-3-氟哌啶。1H NMR(DMSO,300MHz):δ9.06(d,J=15.0Hz,1H),8.93(s,1H),8.82(d,J=12.5Hz,1H),8.59(d,J=12.3Hz,1H),7.55(dd,J=16.0,3.0Hz,1H),7.50-7.41(m,2H),7.41-7.31(m,2H),7.25(d,J=14.8Hz,1H),7.16(s,1H),7.12(dd,J=14.9,3.0Hz,1H),6.83(dd,J=14.9,10.0Hz,1H),5.23-4.91(m,1H),4.06-3.80(m,1H),3.23-2.98(m,1H),2.83-2.69(m,1H),2.57-2.28(m,4H),2.19-2.02(m,1H),1.86-1.68(m,1H),1.09(t,J=12.6Hz,3H).
实施例42 N-(3-氟-4-((7-(2-吗啡啉-2-乙酰氧基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(36S)的合成
合成路线同化合物26S,初始原料为化合物62和2-羟基-1-吗啡啉乙酰胺。1H NMR(CDCl3,300MHz):δ10.07(s,1H),9.37(s,1H),8.72(s,1H),8.65(d,J=5.3Hz,1H),7.62(d,J=12.0Hz,1H),7.50-7.41(m,2H),7.31(s,1H),7.21-7.14(m,1H),7.13-7.07(m,1H),7.07-7.00(m,2H),6.24(d,J=5.9Hz,1H),5.18(s,2H),3.79-3.68(m,4H),3.68-3.56(m,4H),1.80-1.72(m,2H),1.62-1.57(m,2H).
实施例43 N-(3-氟-4-((7-(2-(3-氧代吗啡啉)乙氧基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(37S)的合成
合成路线同化合物26S,初始原料为化合物62和2-羟基乙基-2-吗啡啉酮。1H NMR(CDCl3,300MHz):δ10.23(s,1H),9.43(s,1H),8.68(d,J=5.3Hz,1H),8.26(s,1H),7.78(d,J=12.0Hz,1H),7.43(dd,J=8.9,4.7Hz,2H),7.29(d,J=8.8Hz,1H),7.24-7.17(m,2H),7.05(t,J=8.5Hz,2H),6.34(d,J=5.2Hz,1H),4.63(t,J=4.9Hz,2H),4.17(s,2H),3.93-3.81(m,4H),3.67-3.55(m,2H),1.86-1.75(m,2H),1.65-1.54(m,2H).
实施例44 N-(3-氟-4-((7-(1-甲基-1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(38S)的合成
将(50mg,0.10mmol)化合物1S溶于的二氧六环水中(v∶v=3∶2)中,后加入2eq的磷酸钾,2eq的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑,N2保护下130℃下搅拌反应3h,TLC跟踪,反应完成后加入EA冲稀,用饱和的NH4Cl溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率81%。1H NMR(CDCl3,300MHz):δ10.20(s,1H),9.70(s,1H),8.73(d,J=5.4Hz,1H),8.23(s,1H),8.06(d,J=8.3Hz,2H),7.96(s,1H),7.78(d,J=12.0Hz,1H),7.50-7.35(m,2H),7.30-7.26(m,1H),7.04(t,J=8.6Hz,2H),6.46(d,J=5.3Hz,1H),3.98(s,3H),1.84-1.78(m,2H),1.63-1.57(m,2H).
实施例45 N-(4-((7-(1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(39S)的合成
合成路线同化合物38S,初始原料为化合物1S和1-叔丁氧基甲酰-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑。1H NMR(CDCl3,300MHz):δ9.61(s,1H),8.64(d,J=5.3Hz,1H),8.14(s,1H),7.93(s,1H),7.69(d,J=12.0Hz,1H),7.41-7.31(m,2H),7.31-7.20(m,2H),7.20-7.06(m,1H),6.91(t,J=8.5Hz,2H),6.46(d,J=5.3Hz,1H),1.69-1.49(m,4H).
实施例46 N-(3-氟-4-((7-(1-(甲磺酰基)-1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(40S)的合成
将化合物39S溶于四氢呋喃中,室温搅拌下加入2eq的DIEA,后慢慢滴加1.1eq的甲基磺酰氯,继续室温下搅拌反应30min,TLC跟踪,反应完成后加入EA冲稀,用饱和的Na2CO3溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率68%。1H NMR(CDCl3,300MHz):δ10.25(s,1H),9.77(s,1H),8.93-8.86(m,1H),8.80(d,J=6.0Hz,1H),8.69(s,1H),8.43(s,1H),8.07(s,1H),7.99(s,1H),7.80(d,J=11.7Hz,1H),7.45-7.41(m,2H),7.32-7.28(m,1H),7.09-7.00(m,2H),6.55(d,J=5.5Hz,1H),3.41(s,3H),1.85-1.80(m,2H),1.59-1.57(m,2H).
实施例47 N-(3-氟-4-((7-(1-(异丙基)-1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(41S)的合成
合成路线同化合物38S,初始原料为化合物1S和1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑。1H NMR(CDCl3,300MHz):δ10.22(s,1H),9.75(d,J=0.8Hz,1H),8.78(d,J=5.3Hz,1H),8.18(s,2H),8.13(s,1H),8.02(d,J=0.8Hz,1H),7.83(dd,J=12.1,2.2Hz,1H),7.50-7.43(m,2H),7.33-7.31(m,1H),7.30-7.29(m,1H),7.14-7.05(m,2H),6.50(dd,J=5.3,1.2Hz,1H),4.61(dt,J=13.4,6.7Hz,1H),1.85(dd,J=7.9,4.8Hz,2H),1.65-1.60(m,8H).
实施例48 N-(3-氟-4-((7-(1-(哌啶-4烷基)-1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(42S)的合成
化合物96的合成同化合物38S,初始原料为化合物1S和4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯。1H NMR(CDCl3,300MHz):δ10.21(s,1H),9.70(s,1H),8.74(d,J=5.3Hz,1H),8.27-8.07(m,3H),7.97(s,1H),7.79(d,J=12.0Hz,1H),7.43(dd,J=9.0,4.8Hz,2H),7.35-7.26(m,2H),7.05(t,J=8.5Hz,1H),6.46(d,J=5.2Hz,1H),4.46-4.18(m,3H),3.03-2.82(m,2H),2.30-2.12(m,2H),2.07-1.89(m,2H),1.88-1.76(m,2H),1.66-1.55(m,2H),1.47(s,9H).
将化合物96溶于DCM中,加入5%的TFA,室温下搅拌反应30min,TLC跟踪反应,反应完成后浓缩,柱层析得产物42S。1H NMR(DMSO,300MHz):δ9.72(s,1H),8.82(d,J=5.5Hz,1H),8.45(s,1H),8.25(s,1H),8.08(s,1H),7.88(d,J=12.5Hz,1H),7.56(dd,J=9.1,4.8Hz,2H),7.51-7.35(m,2H),7.07(t,J=8.8Hz,2H),6.69(d,J=5.4Hz,1H),4.73-4.60(m,1H),3.68-3.50(m,2H),3.27-3.18(m,2H),2.48-2.22(m,4H),1.69-1.54(m,4H).
实施例48 N-(3-氟-4-((7-(1-(1-异丙基哌啶-4烷基)-1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(43S)的合成
将化合物42S溶于乙腈中,室温搅拌下加入2eq的碳酸铯,后滴加2eq的2-碘代丙烷,升温至85℃下搅拌反应,TLC跟踪,反应完成后加入EA冲稀,用饱和的Na2CO3溶液洗涤,饱和NaCl洗涤,无水Na2SO4干燥,减压浓缩,柱层析得目标化合物,产率
67%。1H NMR(CD3OD,300MHz):δ9.64(s,1H),8.64(d,J=5.4Hz,1H),8.44(s,1H),8.23(s,1H),8.04(s,1H),7.44-7.36(m,2H),7.18(t,J=8.7Hz,2H),7.03-6.96(m,1H),6.89-6.81(m,2H),6.25(d,J=5.2Hz,1H),5.29-5.19(m,1H),4.73-4.59(m,1H),3.67-3.56(m,4H),2.46-2.41(m,4H),1.49(m,2H),1.42-1.39(m,8H).
实施例49 N-(4-((7-(3,5-二甲基异恶唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(45S)的合成
7-溴-4-氯-1,6-二氮杂萘(97)
化合物97的合成同53,起始原料为2,6-二溴-4-氨基吡啶。1H NMR(300MHz,CDCl3)δ9.40(s,1H),8.93(d,J=4.7Hz,1H),8.16(s,1H),7.57(d,J=4.7Hz,1H).
4-(4-氯-1,6-二氮杂萘-7-烷基)-3,5-二甲基异恶唑(98)
化合物97的合成同38S,起始原料为3,5-二甲基异恶唑-4-硼酸频哪醇酯,反应温度为50℃。1H NMR(400MHz,DMSO)δ9.68(s,1H),9.09(d,J=4.8Hz,1H),8.11(s,1H),7.92(d,J=4.7Hz,1H),2.67(s,3H),2.47(s,3H).
N-(4-((7-(3,5-二甲基异恶唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(45S)
化合物45S的合成同1S,起始原料为98和26。1H NMR(300MHz,CDCl3)δ10.28(s,1H),9.83(s,1H),8.81(d,J=5.3Hz,1H),7.99(s,1H),7.88(s,1H),7.81(d,J=12.4Hz,1H),7.53-7.37(m,2H),7.28(m,2H),7.06(t,J=8.6Hz,2H),6.56(d,J=5.2Hz,1H),2.67(s,3H),2.52(s,3H),1.83(m,2H),1.60(m,2H).
实施例50 N-(3-氟-4-((7-(吡啶-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(46S)的合成
化合物46S的合成同化合物38S,初始原料为化合物1S和4-吡啶硼酸频哪醇酯。1H NMR(400MHz,DMSO):δ10.39(s,1H),9.92(s,1H),8.89(d,J=5.3Hz,1H),8.82(s,2H),8.44(s,1H),8.14(d,J=4.5Hz,2H),7.86(dd,J=12.1,2.2Hz,1H),7.54-7.43(m,2H),7.39-7.30(m,2H),7.17-7.04(m,2H),6.65(d,J=5.2Hz,1H),1.93-1.87(m,2H),1.70-1.60(m,2H).
实施例51 N-(3-氟-4-((7-(嘧啶-5-烷基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(47S)的合成
化合物47S的合成同化合物38S,初始原料为化合物1S和嘧啶-5-硼酸嚬哪醇酯。1H NMR(400MHz,DMSO):δ10.46(s,1H),10.03(s,1H),9.88(s,1H),9.67(s,2H),9.32(s,1H),8.97(d,J=5.3Hz,1H),8.75(s,1H),7.96(d,J=13.5Hz,1H),7.65(dd,J=9.1,5.1Hz,2H),7.61-7.51(m,2H),7.17(t,J=8.9Hz,2H),6.79(d,J=5.4Hz,1H),1.53-1.44(m,4H).
实施例52 N-(3-氟-4-((7-(4-硝基苯基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(48S)的合成
化合物48S的合成同化合物38S,初始原料为化合物1S和4-硝基苯硼酸频哪醇酯。1H NMR(400MHz,DMSO):δ10.47(s,1H),10.03(s,1H),9.88(s,1H),8.97(d,J=5.3Hz,1H),8.69(s,1H),8.62(s,1H),8.60(s,1H),8.41(s,1H),8.39(s,1H),7.97(d,J=12.7Hz,1H),
7.65(dd,J=9.1,5.1Hz,2H),7.59-7.54(m,2H),7.17(t,J=8.9Hz,2H),6.79(d,J=4.8Hz,1H),1.53-1.44(m,4H).
实施例52 N-(3-氟-4-((7-(3,4-二氟苯基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(49S)的合成
化合物49S的合成同化合物38S,初始原料为化合物1S和3,4-二氟苯硼酸频哪醇酯。1H NMR(400MHz,DMSO):δ10.46(s,1H),10.03(s,1H),9.81(s,1H),8.93(d,J=6.4Hz,1H),8.58(s,1H),8.44-8.34(m,1H),8.23(s,1H),7.96(d,J=13.4Hz,1H),7.73-7.60(m,5H),7.60-7.48(m,3H),7.17(t,J=8.7Hz,2H),6.74(d,J=6.9Hz,1H),1.55-1.41(m,4H).
实施例53 N-(3-氟-4-((7-(4-吗啡啉苯基)-1,6-二氮杂萘-4-烷基)氧基)-苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(50S)的合成
化合物50S的合成同化合物38S,初始原料为化合物1S和4-吗啡啉苯硼酸频哪醇酯。1H NMR(400MHz,DMSO):δ10.45(s,1H),10.03(s,1H),9.74(s,1H),8.86(d,J=5.0Hz,1H),8.31(s,1H),8.20(d,J=8.5Hz,2H),7.95(d,J=12.9Hz,1H),7.65(dd,J=9.0,5.0Hz,2H),7.58-7.50(m,2H),7.16(t,J=8.9Hz,2H),7.10(d,J=8.5Hz,2H),6.64(d,J=4.7Hz,1H),3.86-3.72(m,4H),3.31-3.19(m,4H),1.54-1.42(m,4H).
实施例54 N-(4-((7-(异恶唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(51S)的合成
N-(4-((7-溴-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(99)
化合物99的合成同1S,所需原料为4-氯-7-溴-1,6-二氮杂萘。1H NMR(CDCl3,300MHz):δ10.32(s,1H),9.56(s,1H),8.81(d,J=5.2Hz,1H),8.14(s,1H),8.01(s,1H),7.82(d,J=11.6Hz,1H),7.54-7.39(m,2H),7.35-7.27(m,1H),7.07(t,J=8.4Hz,2H),6.58(d,J=5.1Hz,1H),1.91-1.79(m,2H),1.35-1.17(m,2H).
N-(4-((7-(异恶唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(51S)
化合物51S的合成同化合物38S,初始原料为化合物99和4-异恶唑硼酸频哪醇酯。1H NMR(DMSO,300MHz):δ10.43(s,1H),9.99(s,1H),9.74(s,2H),9.42(s,1H),8.89(d,J=5.3Hz,1H),8.40(s,1H),7.93(d,J=12.1Hz,1H),7.65-7.59(m,2H),7.58-7.49(m,2H),7.14(t,J=8.9Hz,2H),6.69(d,J=5.4Hz,1H),1.50-1.41(m,4H).
实施例55 N-(4-((7-(异噻唑-3-烷基)-1,6-二氮杂萘-4-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(52S)的合成
化合物52S的合成同化合物38S,初始原料为化合物99和3-异噻唑硼酸频哪醇酯。1H NMR(DMSO,300MHz):δ10.46(s,1H),10.03(s,1H),9.77(s,1H),8.95(d,J=5.3Hz,1H),8.72(d,J=1.7Hz,1H),8.66(s,1H),8.32(d,J=1.7Hz,1H),7.96(d,J=13.7Hz,1H),
7.66-7.62(m,2H),7.58-7.52(m,2H),7.17(t,J=8.9Hz,2H),6.77(d,J=5.0Hz,1H),1.48(d,J=3.9Hz,4H).
实施例56 N-(3-氟-4-((7-(1-甲基-1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-烷基)氧基)苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺(53S)的合成
化合物53S的合成同45S,所需原料为4-氯-7-溴-1,6-二氮杂萘。1H NMR(300MHz,CDCl3)δ9.64(s,1H),9.10(d,J=15.0Hz,1H),8.38(d,J=21.8Hz,1H),8.30(s,1H),8.22(s,1H),7.96(d,J=3.1Hz,1H),7.77(d,J=3.1Hz,1H),7.61-7.57(m,1H),7.58-7.55(m,1H),7.56-7.52(m,1H),7.45-7.36(m,2H),7.25(d,J=15.0Hz,1H),7.15(dd,J=15.0,3.0Hz,1H),6.86(dd,J=15.0,10.1Hz,1H),5.95(d,J=21.8Hz,1H),3.94(s,3H).
实施57 N-(3-氟-4-((7-(1-甲基-1氢-吡唑-4-烷基)-1,6-二氮杂萘-4-基)氧基)苯基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-碳酰胺(54S)的合成
化合物53S的合成同45S,所需原料为4-氯-7-溴-1,6-二氮杂萘。1H NMR(300MHz,CDCl3)δ9.64(s,1H),9.49(s,1H),9.10(d,J=15.0Hz,1H),8.30(s,1H),7.96(d,J=3.1Hz,1H),7.93(s,1H),7.71(d,J=2.9Hz,1H),7.58(dd,J=16.0,3.0Hz,1H),7.32-7.24(m,3H),7.23(s,2H),7.15(dd,J=15.0,3.0Hz,1H),6.86(dd,J=15.0,10.1Hz,1H),3.94(s,3H).
实施例58 N-(4-((3-氯吡啶[2,3-b]吡嗪-8-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(55S)的合成
将200mg的33S溶于乙腈中,加入2eq的DIEA,室温下滴入三氯氧磷0.5ml,搅拌反应,TLC跟踪,反应完成后用乙酸乙酯萃取,依次用碳酸氢钠,饱和食盐水洗,无水硫酸钠干燥,浓缩上柱最终得到产物55S,产率80%。1H NMR(400MHz,DMSO):δ10.43(s,1H),10.01(s,1H),9.14(s,1H),8.96(d,J=5.1Hz,1H),7.93(d,J=13.0Hz,1H),7.64(dd,J=8.8,5.1Hz,2H),7.54(d,J=9.1Hz,1H),7.45(t,J=8.9Hz,1H),7.16(t,J=8.9Hz,2H),7.03(d,J=5.2Hz,1H),1.58-1.40(m,4H);
实施59 N-(4-((2-氯吡啶[2,3-b]吡嗪-8-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(56S)的合成
反应操作同55S,原料为34S,产率83%。1H NMR(400MHz,DMSO):δ10.44(s,1H),10.01(s,1H),9.24(s,1H),8.96(d,J=5.3Hz,1H),7.94(dd,J=13.3,2.2Hz,1H),7.64(dd,J=9.1,5.1Hz,2H),7.54(d,J=8.9Hz,1H),7.46(t,J=8.9Hz,1H),7.16(t,J=8.9Hz,2H),7.03(d,J=5.2Hz,1H),1.51-1.45(m,4H);
实施60 N-(4-((3-吗啡啉基吡啶[2,3-b]吡嗪-8-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(57S)的合成
室温下将20mg的55S溶于四氢呋喃中,加入吗啉0.5mL,室温下搅拌反应,TLC跟踪,反应完成后,乙酸乙酯萃取,碳酸氢钠,饱和食盐水洗,无水硫酸钠干燥,浓缩过柱得目标化合物。微黄色固体产物,产率68%。1H NMR(400MHz,DMSO):δ10.38(s,1H),10.01(s,1H),8.86(s,1H),8.60(d,J=5.4Hz,1H),7.88(d,J=13.1Hz,1H),7.64(dd,J=9.0,
5.0Hz,2H),7.49(d,J=10.2Hz,1H),7.37(t,J=9.0Hz,1H),7.16(t,J=8.9Hz,2H),6.55(d,J=5.4Hz,1H),3.84(d,J=4.5Hz,4H),3.77(d,J=4.6Hz,4H),1.47(m,J=3.4Hz,4H);
实施61 N-(4-((2-吗啡啉基吡啶[2,3-b]吡嗪-8-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(58S)的合成
反应操作同57S,原料为56S,产率74%。1H NMR(400MHz,DMSO):δ10.34(s,1H),10.02(s,1H),9.00(s,1H),8.51(d,J=5.1Hz,1H),7.86(dd,J=13.3,2.2Hz,1H),7.64(dd,J=9.1,5.0Hz,2H),7.46(d,J=8.7Hz,1H),7.32(t,J=9.0Hz,1H),7.22-7.11(m,2H),6.86(d,J=5.1Hz,1H),3.8-3.63(m,8H),1.52-1.42(m,4H);
实施62 N-(3-氟-4-((3-(4-甲基哌嗪-1-烷基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(59S)的合成
反应操作同57S,原料为55S及N-甲基哌嗪,产率44%。1H NMR(400MHz,DMSO):δ10.39(s,1H),10.02(s,1H),8.87(s,1H),8.58(d,J=5.3Hz,1H),7.89(d,J=14.8Hz,1H),7.73-7.57(m,2H),7.49(d,J=10.1Hz,1H),7.36(t,J=9.0Hz,1H),7.16(t,J=8.8Hz,2H),6.53(d,J=5.3Hz,1H),3.90-3.83(m,4H),2.50-2.43(m,4H),2.26(s,3H),1.51-1.44(m,4H);
实施63 N-(3-氟-4-((3-(2-吗啡啉乙氧基基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(60S)的合成
室温下将4eq的2-吗啉乙醇加入到四氢呋喃溶液,后加入1.5二氢的叔丁醇钾,搅拌反应10min后,加入1eq的55S,继续搅拌反应,TLC跟踪,反应完成后,EA萃取,饱和碳酸氢钠洗,饱和食盐水洗,无水硫酸钠干燥,柱层析得产物。微黄色固体,产率62%。1H NMR(400MHz,DMSO):δ10.41(s,1H),10.01(s,1H),8.76(d,J=5.5Hz,1H),8.71(s,1H),7.91(d,J=11.9Hz,1H),7.64(dd,J=8.8,5.0Hz,2H),7.51(d,J=8.6Hz,1H),7.42(t,J=9.0Hz,1H),7.16(t,J=9.0Hz,2H),6.79(d,J=5.2Hz,1H),4.63(t,J=5.6Hz,2H),3.68-3.49(m,4H),2.81(t,J=7.3Hz,2H),2.56-2.51(m,4H),1.56-1.39(m,4H);
实施64 N-(3-氟-4-((3-(3-吗啡啉丙氧基基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(61S)的合成
反应操作同57S,原料为55S及3-吗啉丙醇,产率42%。1H NMR(DMSO,400MHz):δ10.42(s,1H),10.02(s,1H),8.75(d,J=5.4Hz,1H),7.93(d,J=13.4Hz,1H),7.69-7.61(m,2H),7.54(d,J=8.9Hz,1H),7.45(t,J=8.9Hz,1H),7.16(t,J=8.9Hz,2H),6.77(d,J=5.3Hz,1H),4.58(t,J=6.4Hz,2H),3.66-3.57(m,4H),2.70-2.53(m,4H),2.49-2.42(m,2H),2.11-1.97(m,2H),1.54-1.41(m,4H).
实施65 N-(3-氟-4-((3-((3-吗啡啉丙基)氨基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(62S)的合成
将20mg的55S和N-(3-氨丙基)吗啉100μL溶于四氢呋喃溶液,油浴60℃下搅拌反应,TLC跟踪,反应完成后,EA萃取,饱和碳酸氢钠洗,饱和食盐水洗,无水硫酸钠干燥,柱层析得产物。白色固体,产率62%。1H NMR(400MHz,DMSO):δ10.37(s,1H),10.01(s,1H),8.50(d,J=5.4Hz,1H),8.33(s,1H),8.11(t,J=6.2Hz,1H),7.88(d,J=13.1Hz,1H),7.64(dd,J=9.0,5.0Hz,2H),7.48(d,J=8.8Hz,1H),7.35(t,J=9.0Hz,1H),7.16(t,J=8.9Hz,2H),6.46(d,J=5.2Hz,1H),3.68-3.54(m,4H),3.47-3.42(m,2H),2.44-2.30(m,6H),1.84-1.72(m,2H),1.52-1.39(m,4H);
实施66 N-(3-氟-4-((2-((3-吗啡啉丙基)氨基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(63S)的合成
反应操作同62S,原料为56S及N-(3-氨丙基)吗啉,产率66%。1H NMR(DMSO,400MHz):δ10.34(s,1H),10.01(s,1H),8.46(s,1H),8.40(d,J=5.3Hz,1H),7.98(t,J=5.5Hz,1H),7.86(d,J=13.8Hz,1H),7.68-7.58(m,2H),7.44(d,J=8.1Hz,1H),7.28(t,J=9.1Hz,1H),7.16(t,J=8.9Hz,2H),6.81(d,J=5.0Hz,1H),3.55-3.47(m,6H),2.44-2.25(m,6H),1.76-1.63(m,2H),1.54-1.42(m,4H);
实施67 N-(4-((2-哌嗪基吡啶[2,3-b]吡嗪-8-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(64S)的合成
反应操作同62S,原料为56S及哌嗪,产率45%。1H NMR(400MHz,CDCl3):δ8.61(s,1H),8.57(d,J=5.6Hz,1H),7.75(d,J=12.3Hz,1H),7.49-7.43(m,2H),7.27-7.21(m,2H),7.05-7.00(m,2H),6.46(d,J=3.4Hz,2H),3.95-3.89(m,4H),3.11-2.95(m,4H),1.71-1.62(m,4H);
实施68 N-(4-((2-哌嗪基吡啶[2,3-b]吡嗪-8-烷基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(65S)的合成
反应操作同62S,原料为56S及哌嗪,产率48%。1H NMR(400MHz,DMSO):δ10.33(s,1H),10.01(s,1H),8.97(s,1H),8.48(d,J=5.1Hz,1H),7.85(d,J=13.2Hz,1H),7.64(dd,J=9.1,5.1Hz,2H),7.45(d,J=8.5Hz,1H),7.30(t,J=9.1Hz,1H),7.15(t,J=8.9Hz,2H),6.85(d,J=5.1Hz,1H),3.73-3.63(m,4H),2.86-2.77(m,4H),1.50-1.44(m,4H);
实施69 N-(3-氟-4-((2-(2-(4-甲基哌嗪-1-烷基)乙氧基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(66S)的合成
反应操作同57S,原料为56S及1-羟乙基-4-甲基哌嗪,产率63%。1H NMR(400MHz,DMSO):δ10.73(s,1H),10.35(s,1H),9.15(s,1H),9.06(d,J=5.2Hz,1H),8.23(d,J=12.9Hz,1H),8.03-7.92(m,2H),7.87-7.79(m,1H),7.69(t,J=9.0Hz,1H),7.49(t,J=8.7Hz,2H),7.33(d,J=5.2Hz,1H),4.84(t,J=5.4Hz,2H),3.67(s,4H),3.05(t,J=5.7Hz,2H),2.90-2.76(m,7H),1.90-1.72(m,4H).
实施70 N-(3-氟-4-((2-(2-吗啡啉乙氧基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(67S)的合成
反应操作同57S,原料为56S及2-吗啉乙醇,产率68%。1H NMR(400MHz,DMSO):δ10.40(s,1H),10.02(s,1H),8.84(s,1H),8.75(d,J=5.0Hz,1H),7.91(d,J=12.6Hz,1H),7.73-7.60(m,2H),7.50(d,J=9.5Hz,1H),7.37(t,J=9.8Hz,1H),7.17(t,J=9.5Hz,2H),7.01(d,J=4.3Hz,1H),4.64-4.46(m,2H),3.68-3.46(m,4H),2.84-2.66(m,2H),2.60-2.33
(m,4H),1.60-1.41(m,4H);
实施71 N-(3-氟-4-((2-(3-吗啡啉丙氧基)吡啶[2,3-b]吡嗪-8-烷基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二酰胺(68S)的合成
反应操作同57S,原料为56S及3-吗啉丙醇,产率64%。1H NMR(400MHz,DMSO):δ10.40(s,1H),10.02(s,1H),8.81(s,1H),8.76-8.64(m,1H),7.91(d,J=13.0Hz,1H),7.72-7.56(m,2H),7.51(d,J=8.7Hz,1H),7.39(t,J=9.1Hz,1H),7.17(t,J=7.6Hz,2H),6.97(d,J=4.7Hz,1H),4.48(t,J=7.1Hz,2H),3.64-3.46(m,4H),2.50-2.26(m,6H),1.98(t,J=9.1Hz,2H),1.59-1.40(m,4H).
实验实施例
实验实施例1:吡啶并氮杂环化合物对c-Met激酶的抑制作用
受体酪氨酸激酶c-Met分子水平酶活抑制初步评价实验
1、试验方法
将酶反应底物Poly(Glu,Tyr)4∶1用无钾离子的PBS(10mM磷酸钠缓冲液,150mM NaCl,pH7.2-7.4)稀释成20μg/ml,125μL/孔包被酶标板,置37℃反应12-16小时。弃去孔中液体后洗板,用200μL/孔的T-PBS(含0.1%Tween-20的PBS)洗板三次,每次5分钟。于37℃烘箱中干燥酶标板1-2小时。
每孔加入用反应缓冲液(50mM 4-羟乙基哌嗪乙磺酸(HEPES)pH 7.4,50mM MgCl2,0.5mM MnCl2,0.2mM Na3VO4,1mM二硫苏糖醇(DTT))稀释的三磷酸腺苷(ATP)溶液50μL,终浓度5μM。化合物用二甲基亚砜(DMSO)稀释成合适的浓度,1μL/孔或者或含相应浓度的DMSO(阴性对照孔),再加入用49μL反应缓冲液稀释的c-Met激酶域重组蛋白启动反应,每次实验需设无ATP对照孔两孔。置37℃摇床(100rpm)反应1小时。T-PBS洗板三次。加入一抗PY99稀释液100μL/孔,37℃摇床反应0.5小时。T-PBS洗板三次。加入二抗辣根过氧化物酶标记羊抗鼠的IgG稀释液100μL/孔,37℃摇床反应0.5小时。T-PBS洗板三次。加入2mg/ml的邻苯二胺(OPD)显色液100μL/孔(用含有0.03%H2O2的0.1M柠檬酸-柠檬酸钠缓冲液(pH=5.4)稀释),25℃避光反应1-10分钟。(OPD溶解时需用超声,显色液需现配现用)。加入2M H2SO4 50μL/孔中止反应,用可调
波长式微孔板酶标仪SPECTRA MAX 190读数,波长为490nm。
样品的抑制率通过下列公式求得:
将上述筛选得到的具有有效抑制c-Met激酶活性的化合物(化合物在10-5M对受体酪氨酸激酶c-Met的抑制率>50%)配成梯度浓度,进行IC50评价。用四参数法计算各化合物分子水平抑制蛋白酪氨酸激酶的IC50值,按照其浓度范围将所得结果分类列入下表1中:
表1 本发明的化合物对c-Met激酶的抑制活性及其对c-Met介导的EBC-1细胞增殖的抑制活性
a被测化合物抑制c-Met激酶活性。A:1nM<IC50<10nM;B:10nM<IC50<100nM;C:100nM<IC50<1μM;D:1μM<IC50<10μM;ND:未测试。
结果:研究发现多个本发明化合物对c-Met激酶有不同程度的抑制活性,部分化合物在10nM浓度下对c-Met激酶具有非常强的抑制作用,其半抑制浓度为1nM<IC50<10nM。提示本发明的化合物具有高效作用于c-Met激酶,是结构新颖的c-Met激酶抑制剂。
实验实施例2:本发明化合物对c-Met介导的细胞株增殖能力的影响
化合物对非小细胞癌细胞EBC-1细胞(MET基因扩增导致Met持续活化细胞株,为Met依赖性肿瘤细胞株)的生长抑制检测采用磺酰罗单明B(sulforhodamine B,SRB)染色法。接种一定数量处于对数生长期的EBC-1细胞于96孔培养板中,每孔90μL,培养过夜后分别加入10μL不同浓度的化合物或者溶剂对照,每个浓度3复孔。化合物作用72小时后,作用结束后,贴壁细胞去培养液,加入10%(w/v)三氯乙酸(100μL/孔)于4℃固定1hr,随后用蒸馏水冲洗五次,待在室温下干燥后,每孔加入SRB溶液(4mg/mL,溶于1%冰乙酸)100μL,室温下孵育染色15min后,用1%冰乙酸冲洗五次洗去未结合的SRB,室温下干燥后,每孔加入10mM Tris溶液100μL,VERSMax酶标仪测定515nm波长下的光密度(OD值)。按以下列公式计算化合物对肿瘤细胞生长的抑制率:抑制率(%)=(OD对照孔-OD给药孔)/OD对照孔×100%。实验重复两次。IC50数据根据初筛设置浓度的测试结果推算出范围。
结果:本发明的多个化合物对c-Met激酶高表达的EBC-1细胞增殖有明显的抑制作
用,表明该化合物能够抑制由c-Met活化介导的细胞增殖活性。具体数据见上表1,表中ND表示未进行相关测试,无相关数据。
实验实施例3:化合物7S对多个蛋白激酶的抑制作用
实验方法同实验实施例1,实验结果如表2所示。
表2.化合物7S对酪氨酸激酶活性的抑制率(%)
由上表可以看出,本发明的化合物7S表现出对c-Met、Flt-1、PDGFR-α、PDGFR-β、RET、c-Src、EPH-A2等多种激酶的抑制活性,是一个新结构的多重激酶抑制剂。
实验实施例4:化合物7S和8S对大鼠药代药动学试验
1.给药方案
SD大鼠14只,雄性,体重200-220g,随机分成4组,每组4/3只,分别灌胃和静脉给予7S和8S,化合物溶于5%的DMSO的生理盐水中,加入5%的tween-80(吐温80)助溶,最终样品浓度为1mg/ml。具体安排见下表3:
表3 化合物7S和8S大鼠药代药动学试验给药方案
试验前禁食12h,自由饮水。给药后2h统一进食。
2.采血时间点及样品处理:
灌胃给药:给药后0.25、0.5、1.0、2.0、3.0、4.0、6.0、8.0和24h;
静脉给药:给药后5min、0.25、0.5、1.0、2.0、4.0、6.0、8.0和24h;
在以上设定时间点经大鼠眼球后静脉丛取静脉血0.3ml,置肝素化试管中,11000rpm离心5min,分离血浆,于-20℃冰箱中冷冻。
3.样品测试和数据分析
采用LC/MS/MS法测定大鼠血浆中化合物的浓度。
采用Phoenix 1.3软件(美国Pharsight公司)的非房室模型计算给药后的药代动力学参数。
达峰浓度Cmax和达峰时间Tmax为实测值;
药时曲线下面积AUC0-t值:采用梯形法计算;AUC0-∞=AUC0-t+Ct/ke,Ct为最后一个可测得时间点的血药浓度,ke为消除速率常数;
消除半衰期t1/2=0.693/ke;
平均滞留时间MRT=AUMC/AUC。
清除率CL=D/AUC0-∞;
稳态分布容积Vss=CL×MRT
绝对生物利用度F=(AUC灌胃×D静脉)/(AUC静脉×D灌胃)×100%
实验数据详见表4和表5。
表4、大鼠静脉注射5mg/kg化合物7S和8S的药动学参数
表5、大鼠灌胃10mg/kg化合物7S和8S的药动学参数
结果显示,化合物7S表现出良好的药代性质:生物利用度F=51.8%,平均滞留时间MRT=2.6h,半衰期t1/2=1.66h,药时面积AUC=16652h*ng/ml。
实验实施例5:化合物7S对人肺癌EBC-1裸小鼠皮下移植瘤的生长抑制作用
实验方法
EBC-1细胞按5×106/只分别皮下接种于裸小鼠右侧腋窝,形成移植瘤后再在裸小鼠体内传三代后使用。取生长旺盛期的肿瘤组织,无菌条件下剪切成1.5mm3左右,接种于裸小鼠右侧腋窝皮下。用游标卡尺测定移植瘤直径,裸小鼠皮下移植瘤用游标卡尺测量移植瘤直径,待肿瘤平均体积生长至120-130mm3左右将动物随机分组。7S,100mg/kg和10mg/kg组,每天口服给药一次,连续给药21天(qd/21,po)。阳性对照药物PF2341066 50mg/kg,每天口服给药一次,连续给药21天。溶剂对照给等量溶剂。整个实验过程中,每周2次测量移植瘤直径,同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为:TV=1/2×a×b2,其中a、b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume,RTV),计算公式为:RTV=Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为1)相对肿瘤增殖率T/C(%),计算公式如下:T/C(%)=(TRTV/CRTV)×100%,TRTV:治疗组RTV;CRTV:阴性对照组RTV;2)肿瘤体积增长抑制率GI%,计算公式如下:GI%=[1-(TVt-TV0)/(CVt-CV0)]×100%,TVt为治疗组每次测量的瘤体积;TV0为治疗组分笼给药时所得瘤体积;CVt为对照组每次测量的瘤体积;CV0为对照组分笼给药时所得瘤体积;3)瘤重抑制率,计算公式如下:瘤重抑制率%=(Wc-WT)/Wc×100%,Wc:对照组瘤重,WT:治疗组瘤重。
实验结果:如图1和表6所示,化合物7S 100mg/kg组,每天口服给药一次,连续给药21天,对人肺癌EBC-1裸小鼠皮下移植瘤的生长有极其显著的抑制作用,在第21天所得T/C百分数为9.58%。化合物7S 10mg/kg组,每天口服给药一次,连续给药21天,对人肺癌EBC-1裸小鼠皮下移植瘤的生长有一定的抑制作用,在第21天所得T/C百分数为46.24%。阳性对照药物PF2341066 50mg/kg组,每天口服给药一次,连续给药21天,对EBC-1裸小鼠皮下移植瘤有极其显著的抑制作用,第21天所有小鼠肿瘤均完全消退,所得T/C百分数为0.00%。给药期间各给药组小鼠状态均良好,无小鼠死亡。
表6. 7S对人肺癌EBC-1裸小鼠皮下移植瘤的实验治疗作用
*p<0.001,“()”内为肿瘤消退小鼠数
Claims (9)
- 一种具有如下通式I所示的结构的吡啶并氮杂环化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其中,表示单键或双键;R1和R2各自独立地选自氢和卤素;X不存在,或者X和Y各自独立地为选自C、N、O和S;n为0、1、2或3;m为0或1;R3不存在或者为氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基羰基、或者取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元杂芳环基团,其中,所述取代基可以为1或2个并各自独立地为选自卤素、-CN、-CF3、-NO2、羟基、C1-C6烷基、C1-C6烷基取代的胺基、C1-C6烷氧基、苄基、卤素取代的C1-C6烷氧基、C1-C6烷基磺酰基和未取代的或C1-C6烷基取代的含有1-2个选自N和O中的杂原子的五元或六元饱和或不饱和杂环基或杂芳环基;R6不存在或者选自氢和C1-C6的烷基;R7不存在或者选自氢和C1-C6的烷基;Z为氨基、苯基乙酰胺基或以下任一结构:在上述通式II、III、IV、V中,R4选自氢、C1-C6烷基和C5-C10芳基或者杂芳基;R5和R5′各自独立地选自氢、卤素和C1-C6烷氧基;环B为含有1或2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团或者杂芳香基团。
- 根据权利要求1所述的化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其中,R1和R2各自独立地选自氢、F、Cl和Br;X不存在,或者X和Y各自独立地选自C、N和O;n为0、1或2;m为0或1;R3不存在或者为氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基羰基、或者取代或未取代的含有1-2个选自N和O中的杂原子的五元或六元杂芳环基团,其中,所述取代基可以为1或2个并各自独立地选自卤素、-CN、苄基、-NO2、C1-C6烷基、C1-C6烷基取代的胺基、C1-C6烷基磺酰基和未取代的或C1-C6烷基取代的含有1-2个选自N和O中的杂原子的五元或六元饱和或不饱和杂环基团;R6不存在或者选自氢和C1-C4的烷基;R7不存在或者选自氢、甲基、乙基和丙基;R4选自氢和C1-C6烷基;R5和R5′各自独立地选自氢、F、Cl、Br和C1-C4烷氧基;环B为含有1或2个选自N或O中的杂原子的五元或六元饱和或不饱和杂环基团或者杂芳香基团。
- 根据权利要求1或2所述的化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其中,R1选自氢、Cl和Br;R2选自氢、F和Cl;X不存在,或者X和Y各自独立地选自C、N和O;n为0、1或2;m为0或1;R3不存在或者为氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C10芳基、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基团、取代或未取代的含有1-2个选自N、O、S中的杂原子的五元或六元饱和或不饱和杂环基羰基、或者取代或未取代的含有1-2个选自N和O中的杂原子的五元或六元杂芳环基团,其中,所述取代基可以为1或2个并各自独立地选自卤素、-NO2、苄基、C1-C4烷基、C1-C4烷基取代的胺基、C1-C4烷基磺酰基和未取代的或C1-C6烷基取代的含有1-2个选自N和O中的杂原子的五元或六元饱和或不饱和杂环基团;R6不存在或者选自氢和C1-C2的烷基;R7不存在或者为甲基;R4选自氢和C1-C3烷基;优选地,R4为氢或甲基;R5和R5′各自独立地选自氢、F和C1-C2烷氧基;;环B为含有1或2个N原子的五元或六元饱和或不饱和杂环基团或者杂芳香基团。
- 根据权利要求1-3所述的化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其中,R1为氢、Cl或Br;R2为氢或F;X不存在,或者X和Y各自独立地选自C、N和O;n为0、1或2;m为0或1;R3不存在或者为C1-C3的烷基、取代或未取代的吡啶基、取代或未取代的吗啉基、取代或未取代的吗啉基羰基、取代或未取代的哌啶基、取代或未取代的咪唑基、取代或未取代的哌嗪基、取代或未取代的恶唑基、取代或未取代的异恶唑基、取代或未取代的嘧啶基、取代或未取代的噻唑基、取代或未取代的异噻唑基、取代或未取代的苯基、或者取代或未取代的吡唑基,其中,所述取代基可以为1或2个并各自独立地选自F、Cl、Br、-NO2、苄基、C1-C3烷基、C1-C3烷基取代的胺基、C1-C3烷基磺酰基、未取代的或 C1-C6烷基取代的哌啶基和吗啉基;R6不存在或者为氢或甲基;R7不存在或者为甲基;Z为氨基、苯基乙酰胺基或以下任一结构:环B与吡啶或者连同X形成具有如下简式之一所示的结构:
- 根据权利要求1-4中任一项所述的化合物、其异构体及药学上可接受的盐或药学上可接受的溶剂合物,其中,所述化合物选自下述化合物中的一种化合物:
- 根据权利要求1-5任一项所述的化合物、其异构体、其药学上可接受的盐或其药学上可接受的溶剂合物的制备方法,该方法如以下反应方案之一所示:反应方案一:其中,R8为R9为Y、R2、R3、R7、Z、m和n的定义与权利要求1-5中相同;(1)化合物5由化合物4经氯代反应得到,氯代试剂为氯化亚砜(SOCl2)/N,N-二甲基甲酸铵(DMF)、三氯氧磷(POCl3)/DMF或POCl3/N,N-二异丙基乙胺(DIEA)/乙腈(MeCN)等,优选为POCl3/DMF;(2)化合物6由化合物5去保护得到,去保护试剂为:三溴化硼(BBr3)/二氯甲烷(DCM)、40%溴化氢(HBr)水溶液、吡啶盐酸盐、盐酸或硫酸、盐酸-氯化铝、氯化铝-乙硫醇、三甲基氯硅烷(TMSCl)/碘化钠(NaI)、三氟甲磺酸,优选为三氟甲磺酸;(3)化合物6经Mitsunobu反应生成化合物7,所选试剂为偶氮二甲酸二乙酯(DEAD)/三苯基膦(PPh3)、N′,N′-四异丙基偶氮二羧酰胺(TIPA)-三丁膦TBP、1,1′-(偶氮二羧酸)二哌啶(ADDP)-TBP、四甲基偶氮二甲酸铵(TMAD)-TBP、4,7-二甲基-3,4,5,6,7,8-六氢-1,2,4,7-四氮杂辛因-3,8-二酮(DHTD)-TBP、氰基亚甲基三正丁基膦(CMBP)或氰基亚甲 基三甲基膦(CMMP),优选为DEAD/PPh3;(4)化合物7经亲核取代反应生成化合物8,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、三乙胺(TEA)、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;(5)化合物8经脱溴得到化合物9,优选反应条件为:钯碳(Pd/C)-甲酸铵、Pd/C-乙酰胺,Pd/C-氢气;优选为Pd/C-甲酸铵;反应方案二:其中,R8为R9为Y、R2、R3、R7、Z、m和n的定义分别与权利要求1-5相同;(1)化合物5脱溴得到化合物10,优选反应条件为:Pd/C-甲酸铵、Pd/C-乙酰胺,Pd/C-氢气;优选为Pd/C-甲酸铵;(2)化合物11由化合物10去保护得到;去保护试剂为:BBr3/DCM、40%HBr水溶液、吡啶盐酸盐、盐酸或硫酸、盐酸-氯化铝、氯化铝-乙硫醇、TMSCl/NaI、三氟甲磺酸,优选为三氟甲磺酸;(3)化合物11经Mitsunobu反应生成化合物12,所选试剂为DEAD/PPh3、TIPA-TBP、ADDP-TBP、TMAD-TBP、DHTD-TBP、CMBP或CMMP;优选为DEAD/PPh3;(4)化合物12经亲核取代反应生成化合物9,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;反应方案三:其中,R10为R9为X、Y、R2、R3、R6、R7、Z、m和n的定义分别与权利要求1-5相同;X’为Cl或者Br;(1)化合物14经脱氯得到化合物15,反应试剂为锌(Zn)/醋酸(MeCOOH);(2)化合物16经氯代反应得到化合物17,氯代试剂为SOCl2/DMF、POCl3/DMF、POCl3/DIEA/MeCN等,优选为POCl3/DIEA/MeCN;(3)化合物17经亲核取代反应生成化合物18,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;反应方案四:其中,R10为R9为X、Y、R2、R3、R6、R7、Z、m和n的定义分别与权利要求1-5相同;X’为Cl或者Br;(1)化合物15经氯代反应得到化合物15I,氯代试剂为SOCl2/DMF、POCl3/DMF、 POCl3/DIEA/MeCN等,优选为POCl3/DIEA/MeCN;(2)化合物15I经亲核取代反应生成化合物15II,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;(3)化合物15II经Suzuki偶联反应生成化合物18,所用的碱为醋酸钾、磷酸钾或碳酸钾;所用溶剂为二甲基亚砜,DMF,二氧六环或者甲苯,加入适量的水;所用的催化剂为四三苯基膦钯,1,1′-双二苯基膦二茂铁二氯化钯PdCl2(dppf);反应方案五:其中,R10为R9为X、Y、R2、R3、R6、R7、Z、m和n的定义分别与权利要求1-5相同;(1)取代反应生成化合物19,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾;(2)化合物19经还原得到化合物20,所用的还原试剂为氯化镍(NiCl2)/硼氢化钠(NaBH4)、Zn/AcOH、Pd/C-H2、Fe/氯化氢(HCl)、硫化钠(Na2S)/乙醇(EtOH)、硫氢化铵(NH4HS)、氢化铝锂(LiAlH4);优选为NiCl2/NaBH4、Pd/C-H2;(3)化合物20经环合得到化合物21及22,环合条件为醛基乙酸乙酯,溶剂为各种常规溶剂,例如甲醇(MeOH)、EtOH、乙腈(MeCN)、二氧六环等;(4)氯代反应,其氯代试剂为SOCl2/DMF、POCl3/DMF、POCl3/DIEA/MeCN等, 优选为POCl3/DIEA/MeCN;(5)亲核取代反应,所选试剂为常用的有机碱或无机碱,例如无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾、氢化钠、甲醇钠、乙醇钠;优选为无水碳酸钾、碳酸铯、TEA、DIEA、叔丁醇钾。
- 包含治疗有效量的选自权利要求1-5中任一项所述化合物中的一种或多种化合物、其异构体、药学上可接受的盐或药学上可接受的溶剂合物的组合物。
- 权利要求1-5中任一项所述化合物、其异构体、药学上可接受的盐、药学上可接受的溶剂合物及其权利要求7所述组合物在制备作为多靶点蛋白激酶抑制剂的药物中的应用;在制备用于抑制酪氨酸激酶c-Met活性的药物中的应用;在制备用于预防或治疗与生物体内的肝细胞生长因子受体(c-Met)相关的细胞异常增殖、形态变化以及运动功能亢进相关的疾病以及与血管新生或肿瘤转移相关的疾病的药物中的应用;在制备预防或治疗肿瘤生长与转移的药物中的应用;其中,所述激酶包括c-Met、Flt-1、PDGFR-α、PDGFR-β、RET、c-Src、EPH-A2、FGFR、Abl、Lck、KDR、IGF-1α和ALK。
- 根据权利要求8所述的应用,其中,所述肿瘤为肺癌、甲状腺髓样瘤、恶性胶质瘤、胃癌、肾细胞癌、乳腺癌、卵巢癌、前列腺癌或结直肠癌。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2015102645852 | 2015-05-21 | ||
CN201510264585.2A CN106279147A (zh) | 2015-05-21 | 2015-05-21 | 一种吡啶并氮杂环化合物及其制备方法和用途 |
PCT/CN2016/083011 WO2016184434A1 (zh) | 2015-05-21 | 2016-05-23 | 一种吡啶并氮杂环化合物及其制备方法和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107709320A true CN107709320A (zh) | 2018-02-16 |
CN107709320B CN107709320B (zh) | 2020-11-06 |
Family
ID=57319481
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510264585.2A Pending CN106279147A (zh) | 2015-05-21 | 2015-05-21 | 一种吡啶并氮杂环化合物及其制备方法和用途 |
CN201680031083.8A Active CN107709320B (zh) | 2015-05-21 | 2016-05-23 | 一种吡啶并氮杂环化合物及其制备方法和用途 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510264585.2A Pending CN106279147A (zh) | 2015-05-21 | 2015-05-21 | 一种吡啶并氮杂环化合物及其制备方法和用途 |
Country Status (5)
Country | Link |
---|---|
US (1) | US10710996B2 (zh) |
EP (1) | EP3299369B1 (zh) |
JP (1) | JP6621486B2 (zh) |
CN (2) | CN106279147A (zh) |
WO (1) | WO2016184434A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112239469A (zh) * | 2020-10-20 | 2021-01-19 | 苏州大学 | 靶向蛋白降解c-Met降解剂及其制备方法与应用 |
CN113563293A (zh) * | 2021-08-24 | 2021-10-29 | 苏州大学 | 基于n-氧化物的前药复合物及其制备方法和应用 |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108503650B (zh) * | 2017-02-27 | 2021-02-12 | 北京赛特明强医药科技有限公司 | 二噁烷并喹唑啉类化合物或其药用盐或其水合物及其作为酪氨酸激酶抑制剂的应用 |
US11261184B2 (en) | 2017-10-02 | 2022-03-01 | Boehringer Ingelheim International Gmbh | [1,6]naphthyridine compounds and derivatives as CDK8/CDK19 inhibitors |
CN111615514B (zh) | 2018-01-18 | 2022-10-11 | 奥瑞生物药品公司 | 作为ret激酶抑制剂的取代的吡唑并[4,3-c]吡啶化合物 |
WO2019143977A1 (en) | 2018-01-18 | 2019-07-25 | Array Biopharma Inc. | Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors |
CR20200358A (es) | 2018-01-26 | 2021-02-22 | Exelixis Inc | Compuestos para el tratamiento de trastornos dependientes de cinasas |
PE20210044A1 (es) * | 2018-01-26 | 2021-01-08 | Exelixis Inc | Compuestos para el tratamiento de trastornos dependientes de cinasas |
WO2019148043A1 (en) * | 2018-01-26 | 2019-08-01 | Exelixis, Inc. | Compounds for the treatment of kinase-dependent disorders |
CN109438279B (zh) * | 2018-11-22 | 2021-08-31 | 四川大学 | 一种克服egfr耐药突变的小分子化合物及其制备方法和用途 |
CN109846840B (zh) * | 2018-12-18 | 2021-08-10 | 江西润泽药业有限公司 | 一种血管内皮生长因子抑制剂的固体剂型及其制备方法 |
CN109758422B (zh) * | 2018-12-18 | 2021-07-06 | 江西润泽药业有限公司 | 一种小分子蛋白激酶抑制剂注射液及其制备方法 |
CN109651294B (zh) * | 2018-12-18 | 2021-07-06 | 江西润泽药业有限公司 | 一种1,4-二胺萘衍生物及其制备方法和应用 |
CN109549931B (zh) * | 2018-12-18 | 2021-09-24 | 江西润泽药业有限公司 | 一种抗肿瘤药物的冻干粉剂及其制备方法 |
AR119069A1 (es) * | 2019-06-04 | 2021-11-24 | Exelixis Inc | Compuestos para el tratamiento de trastornos dependientes de quinasas |
EP4005637A4 (en) * | 2019-07-29 | 2023-07-19 | Takeda Pharmaceutical Company Limited | HETEROCYCLIC COMPOUND |
CN112625026B (zh) * | 2019-09-24 | 2022-09-09 | 药捷安康(南京)科技股份有限公司 | Tam家族激酶抑制剂的喹啉衍生物 |
CN110981865B (zh) * | 2019-12-03 | 2021-01-12 | 佳木斯大学 | 一种用于治疗脑胶质瘤的药物及其制备方法 |
WO2021156787A1 (en) | 2020-02-04 | 2021-08-12 | Janssen Biotech, Inc. | Heterocyclic compounds as dihydroorotate dehydrogenase inhibitors |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005030140A2 (en) * | 2003-09-26 | 2005-04-07 | Exelixis, Inc. | C-met modulators and methods of use |
WO2008048375A1 (en) * | 2006-05-19 | 2008-04-24 | Bayer Healthcare Ag | Pyridonecarboxamide derivatives useful in treating hyper-proliferative and angiogenesis disorders |
CN101248059A (zh) * | 2005-04-27 | 2008-08-20 | 安姆根有限公司 | 作为蛋白激酶抑制剂的取代的酰胺衍生物 |
WO2008124083A2 (en) * | 2007-04-05 | 2008-10-16 | Amgen Inc. | Aurora kinase modulators and method of use |
CN101437820A (zh) * | 2006-03-07 | 2009-05-20 | 阿雷生物药品公司 | 杂二环吡唑化合物和使用方法 |
CN101945869A (zh) * | 2007-12-19 | 2011-01-12 | 癌症研究技术有限公司 | 吡啶并[2,3-b]吡嗪-8-取代化合物及其用途 |
CN102827186A (zh) * | 2011-06-16 | 2012-12-19 | 中国科学院上海药物研究所 | 一类吡啶并五元杂环衍生物及其制备方法和用途 |
CN104507930A (zh) * | 2012-06-29 | 2015-04-08 | 贝达药业股份有限公司 | 作为c-Met酪氨酸激酶抑制剂的新型稠合吡啶衍生物 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1993130B (zh) * | 2004-06-28 | 2010-06-23 | 布里斯托尔-迈尔斯斯奎布公司 | 用于制备稠合杂环激酶抑制剂的方法和中间体 |
JP2008537748A (ja) | 2005-04-06 | 2008-09-25 | エクセリクシス、インコーポレイテッド | c−Metモジュレーター及び使用方法 |
JP5449540B2 (ja) * | 2009-06-05 | 2014-03-19 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 新規化合物 |
JP5718332B2 (ja) * | 2009-08-06 | 2015-05-13 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | 新規な二環式尿素化合物 |
EP2423208A1 (en) * | 2010-08-28 | 2012-02-29 | Lead Discovery Center GmbH | Pharmaceutically active compounds as Axl inhibitors |
TWI520962B (zh) * | 2012-06-29 | 2016-02-11 | As the c-Met tyrosine kinase inhibitors novel fused pyridine derivatives | |
CN102942530A (zh) | 2012-11-26 | 2013-02-27 | 吴春勇 | 一种新型抗肿瘤化合物及其药物组合物 |
CN104402880A (zh) * | 2014-11-02 | 2015-03-11 | 湖南华腾制药有限公司 | 一种咪唑并吡啶衍生物的制备方法 |
-
2015
- 2015-05-21 CN CN201510264585.2A patent/CN106279147A/zh active Pending
-
2016
- 2016-05-23 WO PCT/CN2016/083011 patent/WO2016184434A1/zh active Application Filing
- 2016-05-23 US US15/575,903 patent/US10710996B2/en active Active
- 2016-05-23 EP EP16795921.2A patent/EP3299369B1/en active Active
- 2016-05-23 CN CN201680031083.8A patent/CN107709320B/zh active Active
- 2016-05-23 JP JP2017560796A patent/JP6621486B2/ja not_active Expired - Fee Related
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005030140A2 (en) * | 2003-09-26 | 2005-04-07 | Exelixis, Inc. | C-met modulators and methods of use |
CN101248059A (zh) * | 2005-04-27 | 2008-08-20 | 安姆根有限公司 | 作为蛋白激酶抑制剂的取代的酰胺衍生物 |
CN101437820A (zh) * | 2006-03-07 | 2009-05-20 | 阿雷生物药品公司 | 杂二环吡唑化合物和使用方法 |
WO2008048375A1 (en) * | 2006-05-19 | 2008-04-24 | Bayer Healthcare Ag | Pyridonecarboxamide derivatives useful in treating hyper-proliferative and angiogenesis disorders |
WO2008124083A2 (en) * | 2007-04-05 | 2008-10-16 | Amgen Inc. | Aurora kinase modulators and method of use |
CN101945869A (zh) * | 2007-12-19 | 2011-01-12 | 癌症研究技术有限公司 | 吡啶并[2,3-b]吡嗪-8-取代化合物及其用途 |
CN102827186A (zh) * | 2011-06-16 | 2012-12-19 | 中国科学院上海药物研究所 | 一类吡啶并五元杂环衍生物及其制备方法和用途 |
CN104507930A (zh) * | 2012-06-29 | 2015-04-08 | 贝达药业股份有限公司 | 作为c-Met酪氨酸激酶抑制剂的新型稠合吡啶衍生物 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112239469A (zh) * | 2020-10-20 | 2021-01-19 | 苏州大学 | 靶向蛋白降解c-Met降解剂及其制备方法与应用 |
CN113563293A (zh) * | 2021-08-24 | 2021-10-29 | 苏州大学 | 基于n-氧化物的前药复合物及其制备方法和应用 |
CN113563293B (zh) * | 2021-08-24 | 2022-12-30 | 苏州大学 | 基于n-氧化物的前药复合物及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
US20180244667A1 (en) | 2018-08-30 |
JP6621486B2 (ja) | 2019-12-18 |
WO2016184434A1 (zh) | 2016-11-24 |
CN106279147A (zh) | 2017-01-04 |
CN107709320B (zh) | 2020-11-06 |
EP3299369B1 (en) | 2020-11-11 |
EP3299369A4 (en) | 2018-05-02 |
JP2018520109A (ja) | 2018-07-26 |
EP3299369A1 (en) | 2018-03-28 |
US10710996B2 (en) | 2020-07-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107709320A (zh) | 一种吡啶并氮杂环化合物及其制备方法和用途 | |
EP3237385B1 (en) | Mutant idh1 inhibitors useful for treating cancer | |
Smaill et al. | Tyrosine kinase inhibitors. 18. 6-Substituted 4-anilinoquinazolines and 4-anilinopyrido [3, 4-d] pyrimidines as soluble, irreversible inhibitors of the epidermal growth factor receptor | |
Tsou et al. | 6-Substituted-4-(3-bromophenylamino) quinazolines as putative irreversible inhibitors of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases with enhanced antitumor activity | |
CA3115830C (en) | Compounds for inhibition of .alpha.4.beta.7 integrin | |
EP3475276B1 (en) | Thiazole derivatives useful as mutant idh1 inhibitors for treating cancer | |
WO2017101803A1 (zh) | 一种新型egfr和alk激酶的双重抑制剂 | |
KR101716068B1 (ko) | 신규한 퀴놀린 유도체 및 이의 적용 | |
CN104341425B (zh) | 氘代乙炔衍生物、其药物组合物及应用 | |
NZ525324A (en) | Nitrogenous aromatic ring compounds | |
JP6692354B2 (ja) | 1,4−ジ置換イミダゾール誘導体 | |
CN108779096A (zh) | 一类氟取代的环丙胺类化合物及其制备方法、药物组合物和用途 | |
CN104302292A (zh) | 表现出抗癌和抗增殖活性的吡啶酮酰胺以及类似物 | |
US10689361B2 (en) | Quinoline derivative and use thereof | |
CN103130792A (zh) | 一种2-氨基噻唑类化合物 | |
TW202200575A (zh) | 一種免疫抑制劑、其製備方法和應用 | |
Ding et al. | Discovery of novel pyridine-dimethyl-phenyl-DAPY hybrids by molecular fusing of methyl-pyrimidine-DAPYs and difluoro-pyridinyl-DAPYs: improving the druggability toward high inhibitory activity, solubility, safety, and PK | |
CN106117182B (zh) | 喹唑啉-n-苯乙基四氢异喹啉类化合物及其制备方法和应用 | |
AU2020324561A1 (en) | Quinoline derivatives as protein kinase inhibitors | |
CN106966986B (zh) | N-苄基硝基杂环烯酮缩胺类衍生物及合成方法和抗肿瘤应用 | |
WO2019154133A1 (zh) | 二噁烷并喹啉类化合物及其制备方法与应用 | |
CN109384788A (zh) | 嘌呤系列衍生物及其制备方法和用途 | |
CN106946896A (zh) | 呋喃并[2,3‑d]嘧啶‑4‑胺衍生物 | |
JP2019520359A (ja) | ビアリール尿素誘導体またはそれらの塩、およびそれらの調製方法および使用 | |
CN102827160B (zh) | PI3K或PI3K/m-TOR通路抑制剂及其在药学中的用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |