CN115974841A - 一种取代的苯并氮卓氨基类化合物及其制备方法与应用 - Google Patents
一种取代的苯并氮卓氨基类化合物及其制备方法与应用 Download PDFInfo
- Publication number
- CN115974841A CN115974841A CN202310027470.6A CN202310027470A CN115974841A CN 115974841 A CN115974841 A CN 115974841A CN 202310027470 A CN202310027470 A CN 202310027470A CN 115974841 A CN115974841 A CN 115974841A
- Authority
- CN
- China
- Prior art keywords
- compound
- acid
- pharmaceutically acceptable
- cancer
- acceptable salt
- 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.)
- Pending
Links
- -1 benzoazepine amino compound Chemical class 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 claims abstract description 20
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000003112 inhibitor Substances 0.000 claims abstract description 14
- 239000002207 metabolite Substances 0.000 claims abstract description 11
- 229940002612 prodrug Drugs 0.000 claims abstract description 11
- 239000000651 prodrug Substances 0.000 claims abstract description 11
- 239000012453 solvate Substances 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 30
- 238000003786 synthesis reaction Methods 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 229910052805 deuterium Inorganic materials 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 2
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims 1
- 229940092714 benzenesulfonic acid Drugs 0.000 claims 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- 235000015165 citric acid Nutrition 0.000 claims 1
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 claims 1
- 229940114124 ferulic acid Drugs 0.000 claims 1
- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 claims 1
- 235000001785 ferulic acid Nutrition 0.000 claims 1
- 239000001530 fumaric acid Substances 0.000 claims 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 1
- 239000004310 lactic acid Substances 0.000 claims 1
- 235000014655 lactic acid Nutrition 0.000 claims 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims 1
- 239000011976 maleic acid Substances 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- 235000006408 oxalic acid Nutrition 0.000 claims 1
- 235000011007 phosphoric acid Nutrition 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 229940107700 pyruvic acid Drugs 0.000 claims 1
- 239000011975 tartaric acid Substances 0.000 claims 1
- 235000002906 tartaric acid Nutrition 0.000 claims 1
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 238000009510 drug design Methods 0.000 abstract description 2
- 150000004677 hydrates Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 239000000243 solution Substances 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 30
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 239000007788 liquid Substances 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- NUGMENVSVAURGO-UHFFFAOYSA-N 2-bromo-6-chlorobenzaldehyde Chemical compound ClC1=CC=CC(Br)=C1C=O NUGMENVSVAURGO-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- YGUFCDOEKKVKJK-UHFFFAOYSA-N 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine Chemical compound NC1(CCN(CC1)C1=CN=C(C(=N1)N)C1=C(C(=CC=C1)Cl)Cl)C YGUFCDOEKKVKJK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000003281 allosteric effect Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000009987 spinning Methods 0.000 description 3
- YDYNSAUGVGAOLO-UHFFFAOYSA-N 2,6-dibromobenzaldehyde Chemical compound BrC1=CC=CC(Br)=C1C=O YDYNSAUGVGAOLO-UHFFFAOYSA-N 0.000 description 2
- PKOHICLUFHSXDI-UHFFFAOYSA-N 3-chloro-4-(5-chloropyrazin-2-yl)sulfanylpyridin-2-amine Chemical compound ClC=1C(=NC=CC=1SC1=NC=C(N=C1)Cl)N PKOHICLUFHSXDI-UHFFFAOYSA-N 0.000 description 2
- 101800001401 Activation peptide Proteins 0.000 description 2
- 102400000069 Activation peptide Human genes 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- QDFKKJYEIFBEFC-UHFFFAOYSA-N 1-bromo-3-fluorobenzene Chemical compound FC1=CC=CC(Br)=C1 QDFKKJYEIFBEFC-UHFFFAOYSA-N 0.000 description 1
- DUPGMUNOAGCXRA-UHFFFAOYSA-N 2-bromo-4-chloro-6-methylbenzaldehyde Chemical compound Cc1cc(Cl)cc(Br)c1C=O DUPGMUNOAGCXRA-UHFFFAOYSA-N 0.000 description 1
- HQTWYBVWOIOMBX-UHFFFAOYSA-N 2-bromo-4-fluoro-6-methylbenzaldehyde Chemical compound CC1=CC(F)=CC(Br)=C1C=O HQTWYBVWOIOMBX-UHFFFAOYSA-N 0.000 description 1
- DMQSWMRWBJCGFH-UHFFFAOYSA-N 2-bromo-6-(trifluoromethoxy)benzaldehyde Chemical compound FC(F)(F)OC1=CC=CC(Br)=C1C=O DMQSWMRWBJCGFH-UHFFFAOYSA-N 0.000 description 1
- RQLOLSOZFHENIV-UHFFFAOYSA-N 2-bromo-6-methoxybenzaldehyde Chemical compound COC1=CC=CC(Br)=C1C=O RQLOLSOZFHENIV-UHFFFAOYSA-N 0.000 description 1
- WRIAMYXQKSDDRP-UHFFFAOYSA-N 2-bromo-6-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(Br)=C1C=O WRIAMYXQKSDDRP-UHFFFAOYSA-N 0.000 description 1
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 1
- JEZLXFDCFQIRRQ-UHFFFAOYSA-N 3-bromo-2-formylbenzonitrile Chemical compound Brc1cccc(C#N)c1C=O JEZLXFDCFQIRRQ-UHFFFAOYSA-N 0.000 description 1
- LBUNNMJLXWQQBY-UHFFFAOYSA-N 4-fluorophenylboronic acid Chemical compound OB(O)C1=CC=C(F)C=C1 LBUNNMJLXWQQBY-UHFFFAOYSA-N 0.000 description 1
- WLHCBQAPPJAULW-UHFFFAOYSA-N 4-methylbenzenethiol Chemical compound CC1=CC=C(S)C=C1 WLHCBQAPPJAULW-UHFFFAOYSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
- 102000008096 B7-H1 Antigen Human genes 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- 208000012239 Developmental disease Diseases 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 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 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
- 102000007607 Non-Receptor Type 11 Protein Tyrosine Phosphatase Human genes 0.000 description 1
- 108010032107 Non-Receptor Type 11 Protein Tyrosine Phosphatase Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 102100028516 Receptor-type tyrosine-protein phosphatase U Human genes 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 101710097943 Viral-enhancing factor Proteins 0.000 description 1
- UIRFWOOIGULZQN-UHFFFAOYSA-L [Ru](Cl)Cl.C1(=CC=CC=C1)C([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1 Chemical compound [Ru](Cl)Cl.C1(=CC=CC=C1)C([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1 UIRFWOOIGULZQN-UHFFFAOYSA-L 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229940125528 allosteric inhibitor Drugs 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 229940101006 anhydrous sodium sulfite Drugs 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- PAVZHTXVORCEHP-UHFFFAOYSA-N ethylboronic acid Chemical compound CCB(O)O PAVZHTXVORCEHP-UHFFFAOYSA-N 0.000 description 1
- 229960002089 ferrous chloride Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000006712 oncogenic signaling pathway Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920001843 polymethylhydrosiloxane Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- QIPHSSYCQCBJAX-UHFFFAOYSA-N propan-2-ylboronic acid Chemical compound CC(C)B(O)O QIPHSSYCQCBJAX-UHFFFAOYSA-N 0.000 description 1
- 230000021014 regulation of cell growth Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学技术领域,具体涉及一种苯并氮卓氨基类化合物及其制备方法与应用。含有通式I的化合物及其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物。本发明基于理性药物设计,制备出一类取代的苯并氮卓氨基类全新化合物,以提供结构多样、活性高的SHP2抑制剂。
Description
技术领域
本发明属于药物化学技术领域,具体涉及一种取代的苯并氮卓氨基类化合物及其制备方法与应用。
背景技术
含Src同源2结构域蛋白酪氨酸磷酸酶(Src homology-2-containing proteintyrosine phosphatase,SHP2)隶属于PTP蛋白家族,在人类体内广泛表达,参与调控细胞的生长、增殖、分化和凋亡等生命活动。在人体细胞中,SHP2作为连接多个致癌信号通路的重要枢纽,其突变和异常表达会引起各种各样的疾病,包括发育障碍、白血病和实体瘤等。一方面,SHP2作为RAS/RAF/ERK/MEK信号通路的上游核心调控因子,抑制SHP2能够阻断RAS/RAF/ERK/MEK信号通路的激活,从而抑制肿瘤细胞生长;另一方面,SHP2也是调节PD-1/PD-L1介导的肿瘤免疫的重要协同因子,抑制SHP2可以激活T细胞免疫功能,特异性地杀伤肿瘤细胞。因此,靶向SHP2被认为是一种有效的抗癌策略。
针对SHP2抑制剂的研究,人们初期主要致力于开发靶向SHP2催化域的抑制剂,但这类抑制剂普遍存在生物利用度低、选择性差等问题,难以成药。因此,研究人员开始把目光转向SHP2变构抑制剂的研发上。2016年,诺华公司开创性地报道了第一个SHP2变构抑制剂SHP099,极大地推动了SHP2抑制剂的研发进程。目前,虽有多个SHP2变构抑制剂进入临床试验阶段,但目前在国内外没有上市的产品,同时初步的临床数据显示安全性并不好。因此,研制具有良好抗肿瘤活性的新型SHP2小分子抑制剂具有重要意义。
发明内容
本发明需解决的技术问题之一是现有SHP2抑制剂结构骨架单一等问题。因此提供一类取代的苯并氮卓氨基类全新化合物,为后续抗癌药物开发提供可能
解决上述技术问题的方案如下:
一种如式I所示的苯并氮卓氨基类化合物,或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物,其结构如下:
其中:
R1为卤素、C1-C3烷基、甲氧基、三氟甲基、三氟甲氧基、硝基、氨基、氰基、环丙基、4-氟苯基;
R2为氢、氘、卤素;
R3为氢、氘、卤素。
优选地,所述的一种如式I所示的苯并氮卓氨基类化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物为以下任一化合物:
上述式I所示化合物的制备方法,所述化合物的合成路线如下:
其中,R1、R2和R3与所述式I中的定义一致,具体合成步骤如下:
(1)化合物II与III通过芳香环的亲核取代反应得到化合物IV;
(2)化合物IV进行脱保护反应得到化合物I。
其中,步骤(1)中的芳香环的亲核取代反应所采用的溶剂包括但不限于:乙醇、四氢呋喃、1,4-二氧六环、丙酮、N,N-二甲基甲酰胺、二甲亚砜、N-甲基吡咯烷酮或者用这些溶剂任选组成的混合溶剂,优选N-甲基吡咯烷酮;所采用的碱包括但不限于:N,N-二异丙基乙胺、三乙胺、碳酸钾、碳酸铯、磷酸钾、醋酸钾、醋酸钠,优选N,N-二异丙基乙胺;
步骤(2)中脱除保护基反应所采用的溶剂包括但不限于:苯、甲苯、乙醇、甲醇、1,4-二氧六环、四氢呋喃、丙酮、乙腈、乙酸乙酯、正己烷、二氯甲烷、氯仿、N,N-二甲基甲酰胺、二甲亚砜或者用这些溶剂任选组成的混合溶剂,优选乙酸乙酯;所采用的试剂包括但不限于:盐酸的乙酸乙酯溶液、二氧六环的乙酸乙酯溶液,优选盐酸的乙酸乙酯溶液。
本发明提供了一种苯并氮卓氨基类化合物的药物组合物,所述药物组合物为由所述苯并氮卓氨基类化合物或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物作为活性成分和药学上可接受的载体或辅料。化合物可以添加药学上可接受的载体制成常见的药用制剂,如片剂、胶囊、糖浆、悬浮剂、注射剂,可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明提供了一种如式I所示化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物、水合物或一种药物组合物在制备SHP2抑制剂中的用途。
本发明提供了一种如式I所示化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物、水合物或一种药物组合物在制备用于预防和/或治疗癌症的药物中的用途。
本发明所述的用途,其特征在于,所述的癌症为肺癌、食管鳞癌、结直肠癌、胰腺癌、乳腺癌、白血病、肝癌、胃癌。
有益效果:
与现有技术相比,本发明具有如下优点:本发明基于理性药物设计,制备出一类取代的苯并氮卓氨基类全新化合物,其结构新颖,且活性显著优于阳性药SHP099,为后续开发抗肿瘤药物提供支持。
具体实施方式
为了更好的理解本发明,通过以下实施例来进一步阐明本发明,但是本发明的内容不仅仅局限于以下实施例。
SHP2抑制剂(SHP099)购自上海源叶生物科技有限公司。
实施例1
合成路线:
化合物I-1a的合成
将2-氯-6-溴苯甲醛(1.00g,4.6mmol)、醋酸钯(15.3mg,0.09mmol,2mol%)、三苯基膦(36.7mg,0.14mmol,3mol%)、碳酸铯(3.00g,9.2mmol,2.0eq)溶于9.0mL的四氢呋喃和1.0mL的水混合溶液中,于70℃氮气保护的密封管中搅拌12小时。反应完全后抽滤,滤液用乙酸乙酯稀释,水洗后合并的有机相用无水硫酸钠干燥、过滤和浓缩,柱层析纯化得到无色液体I-1a(590.1mg,收率78%),ESI-MS(m/z):166.0[M+H]+。
化合物I-1b的合成
将I-1a(590.1mg,3.6mmol)、烯丙基胺盐酸盐(365.4mg,3.9mmol,1.1eq)、三乙胺(395.7mg,3.9mmol,1.1eq)、硫酸镁(854.6mg,7.1mmol,2.0eq)溶于10mL的二氯甲烷溶液中,于25℃下搅拌12小时。反应完全后抽滤,滤液旋干,加入硼氢化钠(147.9mg,3.9mmol,1.1eq)和10mL甲醇,于0℃下搅拌2小时。反应完全后加水淬灭,用乙酸乙酯萃取,合并有机相用无水硫酸钠干燥、过滤和浓缩,柱层析纯化得到无色液体I-1b(511.4mg,收率75%),ESI-MS(m/z):193.1[M+H]+。
化合物I-1c的合成
将I-1b(511.4mg,2.7mmol)、对硝基苯磺酰氯(587.3mg,2.7mmol,1.0eq)、三乙胺(267.7mg,2.7mmol,1.0eq)溶于5.0mL的二氯甲烷溶液中,于25℃下搅拌12小时。反应完全后用二氯甲烷萃取,合并有机相用无水硫酸钠干燥、过滤和浓缩,柱层析纯化得到黄色液体I-1c(588.1mg,收率59%),ESI-MS(m/z):378.0[M+H]+。
化合物I-1d的合成
将I-1c(588.1mg,1.6mmol)、苯基亚甲基双(三环己基磷)二氯化钌(131.8mg,0.16mmol,10mol%)、溶于5.0mL的二氯甲烷溶液中,于25℃下搅拌12小时。反应完全后浓缩、柱层析纯化得到无色液体I-1d(351.6mg,收率64%),ESI-MS(m/z):364.0[M+H]+。
化合物I-1e的合成
将I-1d(341.0mg,0.94mmol)、对甲基苯硫酚(233.5mg,1.9mmol,2.0eq)、碳酸钾(259.8mg,1.9mmol,2.0eq)溶于2.0mL的N,N-二甲基甲酰胺溶液中,于25℃下搅拌12小时。反应结束后抽滤浓缩,加入二碳酸二叔丁酯(204.9mg,0.94mmol,1.0eq)、三乙胺(94.9mg,0.94mmol,1.0eq)和3.0mL二氯甲烷,于25℃下搅拌1小时。反应完全后浓缩、柱层析纯化得到无色液体I-1e(214.8mg,收率82%),ESI-MS(m/z):279.1[M+H]+。
化合物I-1f的合成
将I-1e(214.8mg,0.77mmol)、氯化亚铁(10.1mg,0.08mmol,10mol%)、聚甲基氢硅氧烷(257.0mg,1.2mmol,1.5eq)溶于5.0mL的无水乙醇溶液中,于80℃敞口搅拌12小时。反应完全后浓缩、柱层析纯化得到无色液体I-1f(92.1mg,收率40%),ESI-MS(m/z):295.1[M+H]+。
化合物I-1g的合成
将I-1f(92.1mg,0.31mmol)、(R)-(+)-叔丁基亚磺酰胺(75.1mg,0.62mmol,2.0eq)、钛酸四乙酯(141.4mg,0.62mmol,2.0eq)溶于3.0mL的无水四氢呋喃溶液中,于70℃氮气保护下搅拌12小时。反应完全后转至0℃加0.2mL三仲丁基硼氢化锂四氢呋喃络合物(0.62mmol,2.0eq),于0℃下反应2小时。反应结束加水淬灭并抽滤,滤液萃取后浓缩、柱层析纯化得到无色液体I-1g(83.1mg,收率67%),ESI-MS(m/z):400.2[M+H]+。
化合物I-1h的合成
将三氟乙酸(119.7mg,1.1mmol,5.0eq)缓慢滴加入I-1g(83.1mg,0.21mmol)和1.0mL的二氯甲烷溶液中,于25℃下搅拌0.5小时。反应结束后旋干溶剂得无色液体I-1h(63.0mg,收率95%),ESI-MS(m/z):300.2[M+H]+。
化合物I-1i的合成
将I-1h(63.0mg,0.20mmol)、3-氯-4-((5-氯吡嗪-2-基)硫代)吡啶-2-胺(54.4mg,0.20mmol,1.0eq)溶于1.0mL的N,N-二异丙基乙胺和1.0mL的二甲基亚砜溶液中,于100℃氮气保护下搅拌2小时。反应结束后用乙酸乙酯萃取,合并有机相用无水硫酸钠干燥,过滤和浓缩、柱层析纯化得到灰色液体I-1i(34.1mg,收率32%),ESI-MS(m/z):536.9[M+H]+。
化合物I-1的合成
缓慢将0.2mL氯化氢乙酸乙酯溶液(0.30mmol,5.0eq)滴加入I-2i(34.1mg,0.06mmol)和1.0mL的乙酸乙酯溶液中,于25℃下搅拌12小时。反应结束后用乙酸乙酯萃取,合并有机相用无水硫酸钠干燥,过滤和浓缩得到白色固体I-1(20.5mg,收率74%):1H NMR(300MHz,CDCl3)δ8.36(d,J=1.4Hz,1H),8.25(d,J=1.4Hz,1H),7.68(d,J=5.5Hz,1H),7.35–7.28(m,2H),7.24–7.15(m,1H),6.00(d,J=5.4Hz,1H),5.34(d,J=15.9Hz,1H),4.98(d,J=15.9Hz,1H),4.88(s,2H),4.43(dd,J=7.6,2.4Hz,1H),4.25–4.06(m,2H),2.29–2.14(m,1H),1.97–1.84(m,1H).ESI-MS(m/z):432.1[M+H]+.
实施例2
参照化合物I-1的合成方法,将2-氯-6-溴苯甲醛替换为2-溴-6-甲氧基苯甲醛,可制得化合物I-2。1H NMR(300MHz,CDCl3)δ8.41(d,J=1.4Hz,1H),8.20(d,J=1.4Hz,1H),7.67(d,J=5.5Hz,1H),7.26–7.19(m,1H),7.06–6.97(m,1H),6.89–6.81(m,1H),5.98(d,J=5.5Hz,1H),5.20(d,J=15.8Hz,1H),4.96–4.73(m,3H),4.43(dd,J=7.6,2.0Hz,1H),4.39–4.07(m,2H),3.93(s,3H),2.17–2.05(m,1H),1.96–1.82(m,1H).
实施例3
参照化合物I-1的合成方法,将2-氯-6-溴苯甲醛替换为2-溴-6-(三氟甲基)苯甲醛,可制得化合物I-3。1H NMR(300MHz,CDCl3)δ8.32(d,J=1.4Hz,1H),8.21(d,J=1.4Hz,1H),7.79(d,J=7.5Hz,1H),7.70(d,J=5.5Hz,1H),7.66(dd,J=7.7,1.1Hz,1H),7.49(t,J=7.8Hz,1H),6.04(d,J=5.5Hz,1H),5.12(d,J=15.8Hz,1H),4.91(s,2H),4.79(d,J=15.8Hz,1H),4.35(dd,J=9.2,4.7Hz,1H),4.12–4.01(m,1H),3.58–3.44(m,1H),2.54–2.40(m,1H),1.78–1.64(m,1H).
实施例4
参照化合物I-1的合成方法,将2-氯-6-溴苯甲醛替换为2-溴-4-氟-6-甲基苯甲醛,可制得化合物I-4。1H NMR(300MHz,CDCl3)δ8.27(d,J=1.3Hz,1H),8.13(d,J=1.3Hz,1H),7.68(d,J=5.5Hz,1H),7.05(d,J=7.5Hz,1H),6.79(dd,J=9.2,2.6Hz,1H),6.01(d,J=5.5Hz,1H),5.08(d,J=15.1Hz,1H),4.91(s,2H),4.68(d,J=15.1Hz,1H),4.36(dd,J=8.5,3.2Hz,1H),4.04–3.85(m,2H),2.58(s,3H),2.30–2.19(m,1H),1.87–1.77(m,1H).
实施例5
参照化合物I-1的合成方法,将2-氯-6-溴苯甲醛替换为2-溴-4-氯-6-甲基苯甲醛,可制得化合物I-5。1H NMR(300MHz,CDCl3)δ8.26(d,J=1.2Hz,1H),8.13(d,J=1.2Hz,1H),7.68(d,J=5.5Hz,1H),7.28(s,1H),7.08(d,J=1.9Hz,1H),6.00(d,J=5.4Hz,1H),5.07(d,J=15.1Hz,1H),4.90(s,2H),4.74(d,J=15.1Hz,1H),4.35(dd,J=8.2,3.0Hz,1H),4.0–3.90(m,2H),2.57(s,3H),2.32–2.16(m,1H),1.90–1.76(m,1H).
实施例6
参照化合物I-1的合成方法,将2-氯-6-溴苯甲醛替换为2-硝基-6-溴苯甲醛,可制得化合物I-6。1H NMR(300MHz,CDCl3)δ8.14(d,J=1.4Hz,1H),8.09(d,J=1.4Hz,1H),7.67–7.56(m,3H),7.32(t,J=7.9Hz,1H),5.94(d,J=5.5Hz,1H),5.52(d,J=15.4Hz,1H),5.03-4.86(m,3H),4.65(d,J=7.5Hz,1H),4.37–4.23(m,1H),4.05–3.90(m,1H),2.15–2.03(m,1H),1.98–1.85(m,1H).
实施例7
参照化合物I-1的合成方法,将2-氯-6-溴苯甲醛替换为2-氰基-6-溴苯甲醛,可制得化合物I-7。1H NMR(300MHz,CDCl3)δ8.32(d,J=1.4Hz,1H),8.26(d,J=1.4Hz,1H),7.69–7.61(m,2H),7.55(dd,J=7.8,1.4Hz,1H),7.35(t,J=7.7Hz,1H),5.99(d,J=5.5Hz,1H),5.38(d,J=15.4Hz,1H),5.06(d,J=15.4Hz,1H),4.89(s,2H),4.48(dd,J=7.7,2.5Hz,1H),4.27–4.03(m,2H),2.24–2.12(m,1H),1.99–1.85(m,1H).
实施例8
参照化合物I-1的合成方法,将2-氯-6-溴苯甲醛替换为2,6-二溴苯甲醛,可制得化合物I-8。1H NMR(300MHz,CDCl3)δ8.36(d,J=1.4Hz,1H),8.26(d,J=1.4Hz,1H),7.67(d,J=5.4Hz,1H),7.49(dd,J=8.1,1.2Hz,1H),7.36(d,J=7.3Hz,1H),7.12(t,J=7.8Hz,1H),6.00(d,J=5.4Hz,1H),5.35(d,J=15.9Hz,1H),5.08–4.90(m,3H),4.49–4.38(m,1H),4.23–4.04(m,2H),2.31–2.07(m,1H),1.97–1.88(m,1H).
实施例9
参照化合物I-1的合成方法,将2-氯-6-溴苯甲醛替换为6-溴-3-氟-2-甲基苯甲醛,可制得化合物I-9。1H NMR(300MHz,CDCl3)δ8.26(d,J=1.2Hz,1H),8.13(d,J=1.2Hz,1H),7.68(d,J=5.5Hz,1H),7.23–7.16(m,1H),6.92(t,J=8.8Hz,1H),6.01(d,J=5.4Hz,1H),5.12(d,J=15.2Hz,1H),4.92(s,2H),4.85(d,J=15.2Hz,1H),4.39(d,J=5.0Hz,1H),4.07–3.98(m,2H),2.49(d,J=2.1Hz,3H),2.28–2.14(m,1H),1.93–1.79(m,1H).
实施例10
参照化合物I-1的合成方法,将2-氯-6-溴苯甲醛替换为2-溴-6-三氟甲氧基苯甲醛,可制得化合物I-10。1H NMR(300MHz,DMSO)δ8.33(s,1H),8.24(s,1H),7.62(d,J=5.3Hz,1H),7.50–7.37(m,2H),7.29(d,J=7.6Hz,1H),6.35(s,2H),5.75(d,J=5.3Hz,1H),5.24(d,J=15.7Hz,1H),4.87(d,J=15.7Hz,1H),4.58(d,J=7.5Hz,1H),4.21–4.08(m,1H),4.07–3.94(m,1H),2.23–2.07(m,1H),1.87–1.74(s,1H).
实施例11
参照化合物I-1的合成方法,将2-氯-6-溴苯甲醛替换为2-氟-6-溴苯,可制得化合物I-11。1H NMR(300MHz,CDCl3)δ8.30(d,J=1.4Hz,1H),8.23(d,J=1.4Hz,1H),7.68(d,J=5.5Hz,1H),7.25–7.15(m,2H),7.04–6.95(m,1H),6.00(d,J=5.4Hz,1H),5.17(d,J=15.8Hz,1H),4.94–4.75(m,3H),4.46(dd,J=7.6,2.4Hz,1H),4.33–4.15(m,2H),2.19–2.07(m,1H),1.96–1.83(m,1H).
实施例12
合成路线:
化合物I-12a的合成
将2,6-二溴苯甲醛(5.00g,19.0mmol)、烯丙基胺盐酸b盐(2.25g,22.9mmol,1.1eq)、三乙胺(2.32g,22.9mmol,1.1eq)、硫酸镁(4.56g,37.9mmol,2.0eq)溶于100mL的二氯甲烷溶液中,于25℃下搅拌12小时。反应完全后抽滤,滤液旋干,加入硼氢化钠(867.5mg,22.9mmol,1.1eq)和100mL甲醇,于0℃下搅拌2小时。反应完全后加水淬灭,用乙酸乙酯萃取,合并的有机相用无水硫酸钠干燥、过滤和浓缩。柱层析纯化得到无色液体I-12a(4.59g,收率80%),ESI-MS(m/z):302.9[M+H]+。
化合物I-12b的合成
将I-12a(4.59g,15.2mmol)、二碳酸二叔丁酯(3.31g,15.2mmol,1.0eq)、三乙胺(1.53g,15.2mmol,1.0eq)和50mL二氯甲烷,于25℃下搅拌1小时。反应完全后浓缩、柱层析纯化得到淡黄色液体I-12b(5.67g,收率93%),ESI-MS(m/z):402.9[M+H]+。
化合物I-12c的合成
将I-12b(5.67g,14.1mmol)、醋酸钯(46.8mg,0.28mmol,2mol%)、三苯基膦(110.2mg,0.42mmol,3mol%)、碳酸铯(9.18g,28.2mmol,2.0eq)溶于90mL的二氧六环和10mL的水混合溶液中,于70℃氮气保护中搅拌12小时。反应完全后抽滤,滤液用乙酸乙酯稀释,水洗后用无水硫酸钠干燥、过滤和浓缩,柱层析纯化得到白色固体I-12c(1.41g,收率31%),ESI-MS(m/z):323.1[M+H]+。
化合物I-12d的合成
在0℃下缓慢将6.5mL硼烷四氢呋喃络合物(13.1mmol,3.0eq)滴入I-12c(1.41g,4.4mmol)和50mL无水四氢呋喃溶液中,加毕转至25℃氮气保护中搅拌12小时,反应完全后在0℃下先后缓慢滴加26.2mL的10%氢氧化钠溶液、4.5mL的33%过氧化氢溶液,加毕转至25℃下搅拌1小时。反应完全后加入无水亚硫酸钠至淀粉碘化钾试纸不再变蓝,用乙酸乙酯萃取,有机相用无水硫酸钠干燥、过滤和浓缩,后加入戴斯-马丁氧化剂(2.04g,4.8mmol,1.1eq)和10mL二氯甲烷,于25℃下搅拌0.5小时。反应结束后加入碳酸氢钠溶液淬灭,抽滤和浓缩后、干燥,柱层析纯化得到黄色固体I-12d(1.07g,收率72%),ESI-MS(m/z):339.0[M+H]+。
化合物I-12e的合成
将I-12d(1.07g,3.2mmol)、甲基硼酸(226.8mg,3.8mmol,1.2eq)、醋酸钯(10.5mg,0.06mmol,2mol%)、三环己基膦(25.2mg,0.09mmol,3mol%)、磷酸钾(1.34g,6.3mmol,2.0eq)溶于9.0mL的甲苯和1.0mL的水混合溶液中,于100℃氮气保护中搅拌4小时。反应完全后抽滤,滤液用乙酸乙酯稀释,水洗后用无水硫酸钠干燥、过滤和浓缩,柱层析纯化得到白色固体I-12e(736.3mg,收率85%),ESI-MS(m/z):275.2[M+H]+。
化合物I-12f的合成
将I-12e(736.3mg,2.7mmol)、(R)-(+)-叔丁基亚磺酰胺(648.6mg,5.4mmol,2.0eq)、钛酸四乙酯(1.22g,5.4mmol,2.0eq)溶于5.0mL的无水四氢呋喃溶液中,于70℃氮气保护下搅拌12小时,反应完全后转至0℃加1.8mL三仲丁基硼氢化锂四氢呋喃络合物(5.4mmol,2.0eq),于0℃下反应2小时。反应结束后加水淬灭并抽滤,滤液萃取后浓缩、柱层析纯化得到无色液体I-12f(529.6mg,收率52%),ESI-MS(m/z):380.2[M+H]+。
化合物I-12g的合成
将三氟乙酸(794.4mg,7.0mmol,5.0eq)缓慢滴加入I-12e(529.6mg,1.4mmol)和3.0mL的二氯甲烷溶液中,于25℃下搅拌0.5小时。反应结束后旋干溶剂得到无色液体I-12g(369.9mg,收率95%),ESI-MS(m/z):280.1[M+H]+。
化合物I-12h的合成
将I-12g(369.9mg,1.3mmol)、3-氯-4-((5-氯吡嗪-2-基)硫代)吡啶-2-胺(359.3mg,1.3mmol,1.0eq)溶于2.0mL的N,N-二异丙基乙胺和2.0mL的二甲基亚砜溶液中,于100℃氮气保护下搅拌2小时。反应结束后用乙酸乙酯萃取,合并的有机相用无水硫酸钠干燥,过滤和浓缩、柱层析纯化得到白色固体I-12h(326.9mg,收率48%),ESI-MS(m/z):516.2[M+H]+。
化合物I-12的合成
缓慢将1.6mL氯化氢乙酸乙酯溶液(3.2mmol,5.0eq)滴加入I-12h(326.9mg,0.63mmol)和3.0mL的乙酸乙酯溶液中,于25℃下搅拌12小时。反应结束后用乙酸乙酯萃取,合并的有机相用无水硫酸钠干燥,过滤和浓缩后得到白色固体I-12(205.0mg,收率79%):1H NMR(300MHz,CDCl3)δ8.26(d,J=1.4Hz,1H),8.13(d,J=1.4Hz,1H),7.68(d,J=5.4Hz,1H),7.29–7.23(m,1H),7.18(t,J=7.5Hz,1H),7.12–7.07(m,1H),6.01(d,J=5.4Hz,1H),5.09(d,J=15.1Hz,1H),4.91–4.75(m,3H),4.38(dd,J=8.1,3.2Hz,1H),4.08–3.89(m,2H),2.59(s,3H),2.34–2.20(m,1H),1.91–1.78(m,1H).ESI-MS(m/z):412.1[M+H]+.
实施例13
参照化合物I-12的合成方法,将甲基硼酸替换为4-氟苯硼酸,可制得化合物I-13。1HNMR(300MHz,CDCl3)δ8.11(d,J=1.3Hz,1H),7.68-7.60(m,2H),7.45(d,J=7.6Hz,1H),7.36-7.282(m,3H),7.22-7.11(m,3H),5.90(d,J=5.4Hz,1H),5.03(d,J=15.4Hz,1H),4.88(s,2H),4.69(d,J=15.4Hz,1H),4.50(dd,J=8.0,3.0Hz,1H),4.18–3.96(m,2H),2.35-2.20(m,1H),1.94–1.85(m,1H).
实施例14
参照化合物I-12的合成方法,将甲基硼酸替换为乙基硼酸,可制得化合物I-14。1HNMR(300MHz,CDCl3)δ8.27(d,J=1.4Hz,1H),8.15(d,J=1.4Hz,1H),7.65(d,J=5.5Hz,1H),7.33–7.22(m,2H),7.14(dd,J=7.3,1.8Hz,1H),6.01(d,J=5.5Hz,1H),5.15-5.02(m,3H),4.77(d,J=15.2Hz,1H),4.37(dd,J=8.6,3.7Hz,1H),4.08–3.96(m,1H),3.87–3.70(m,1H),2.95(q,J=7.5Hz,2H),2.39–2.25(m,1H),1.83–1.70(td,J=9.0,4.3Hz,1H),1.23(t,J=7.5Hz,3H).
实施例15
参照化合物I-12的合成方法,将甲基硼酸替换为环丙基硼酸,可制得化合物I-15。1HNMR(300MHz,CDCl3)δ8.26(d,J=1.2Hz,1H),8.22(d,J=1.2Hz,1H),7.69(d,J=5.5Hz,1H),7.29(d,J=7.2Hz,1H),7.22(t,J=7.6Hz,1H),7.07(d,J=7.4Hz,1H),6.02(d,J=5.5Hz,1H),5.41(d,J=15.3Hz,1H),4.96(d,J=15.3Hz,1H),4.89(s,2H),4.37(dd,J=8.3,3.4Hz,1H),4.12-3.99(m,1H),3.94–3.79(m,1H),2.40–2.23(m,2H),1.88-1.74(m,1H),1.07–0.95(m,2H),0.76–0.62(m,2H).
实施例16
参照化合物I-12的合成方法,将甲基硼酸替换为氨基甲酸叔丁酯,可制得化合物I-16。1H NMR(300MHz,CDCl3)δ8.23(d,J=1.4Hz,1H),8.21(d,J=1.4Hz,1H),7.68(d,J=5.5Hz,1H),7.05(t,J=7.7Hz,1H),6.81(d,J=7.6Hz,1H),6.63(d,J=7.9Hz,1H),6.02(d,J=5.5Hz,1H),5.22(d,J=15.2Hz,1H),4.92(s,2H),4.68(d,J=15.2Hz,1H),4.46(d,J=7.6Hz,1H),4.36–4.23(m,2H),2.16–2.03(m,1H),2,01–1.87(m,1H).
实施例17
参照化合物I-12的合成方法,将甲基硼酸替换为异丙基硼酸,可制得化合物I-17。1HNMR(300MHz,CDCl3)δ8.23(d,J=1.1Hz,1H),8.21(d,J=1.1Hz,1H),7.66(d,J=5.5Hz,1H),7.31(d,J=7.8Hz,1H),7.20(d,J=1.7Hz,1H),7.14(d,J=8.1Hz,1H),5.99(d,J=5.5Hz,1H),5.05–4.93(m,3H),4.70(d,J=15.2Hz,1H),4.40(d,J=7.1Hz,1H),4.20–4.09(m,2H),2.90(p,J=6.9Hz,1H),2.22–2.09(m,1H),1.94–1.88(m,1H),1.24(d,J=6.9Hz,6H).
实施例18
体外SHP2酶水平活性测试
对上述实施例中化合物的SHP2酶水平活性进行测试,具体操作如下:
1化合物配制
化合物溶解在100%DMSO中,配制成30mM储存液,于-20度冰箱避光保存。
2SHP2反应过程
(1)配制1×ReactionBuffer。
(2)化合物浓度梯度的配制:受试化合物测试起始浓度为30μM,3倍稀释,10个浓度,单孔测试。在384孔板中稀释成100倍终浓度的100%DMSO溶液,用Precision 3倍稀释化合物,10个浓度。使用分液器Echo 550向目的板384板中转移250nL 100倍终浓度的化合物。正对照加入250nLDMSO,负对照加入250nL的1mM SHP099。
(3)用1×ReactionBuffer配制5倍终浓度的激活肽溶液,分别加入5μL到反应板中,1000rpm离心1分钟。
(4)用1×ReactionBuffer配制2.5倍终浓度的酶溶液,分别加入10μL到反应板中,1000rpm离心1分钟,室温孵育60分钟。
(5)用1×ReactionBuffer配制2.5倍终浓度的底物溶液,分别加入10μL到反应板中,1000rpm离心1分钟,孵育20分钟。
(6)用EnSight读取Ex355/Em460荧光数值。
3数据分析
计算公式
其中:RFU:样品的荧光值;Mean(NC):含10μM SHP099的对照孔荧光值均值;
Mean(PC):阳性对照孔荧光值均值。
拟合量效曲线以浓度的log值作为X轴,百分比抑制率为Y轴,采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线,从而得出各个化合物对酶活性的IC50值。
计算公式是Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
4实验结果
具体结果如表所示:
化合物编号 | <![CDATA[SHP2IC<sub>50</sub>(nM)]]> | 化合物编号 | <![CDATA[SHP2IC<sub>50</sub>(nM)]]> |
I-1 | 19 | I-10 | 638 |
I-2 | 8 | I-11 | 131 |
I-3 | 55 | I-12 | 7 |
1-4 | 14 | I-13 | 235 |
I-5 | 89 | I-14 | 26 |
I-6 | 174 | I-15 | 14 |
I-7 | 76 | I-16 | 281 |
I-8 | 18 | I-17 | 41 |
I-9 | 61 | SHP099 | 107 |
以上数据显示,本发明实施例对SHP2磷酸酶具有变构抑制作用,且多个实施例显著优于阳性对照SHP099。
实施例19
化合物体外抗增殖活性测试
1.实验步骤
(1)细胞铺板:取对数生长期的人非小细胞肺癌细胞NCI-H358、人食管鳞癌细胞KYSE520、人结直肠癌细胞SW620、人胰腺癌细胞MIA-PaCa-2配置成细胞悬液,按每孔1×103个/50μL的密度加入96孔细胞培养板中。
(2)药物处理:受试化合物测试起始浓度为90μM,3倍稀释,8个浓度,每个浓度设置3个复孔测试。在培养孔中加入50μL待测化合物继续培养72h。
(3)细胞培养72h后,取出培养板室温静置平衡10分钟,加入CellTiter-LumiTM溶液用微孔板震荡器2分钟,于室温放置10分钟后用酶标仪检测化学发光值。
2.数据处理
绘制曲线并计算药物对细胞的抑制率及IC50。
抑制率=[(Signal_sample-Signal_min)/(Signal_max-Signal_min]×100%拟合量效曲线:以浓度的log值作为X轴,百分比抑制率为Y轴,采用分析软件GraphPad Prism5的log(inhibitor)vs.response-Variable slope拟合量效曲线,从而得出化合物抑制细胞增殖的IC50值。Signal_sample:实验孔化学发光值(含细胞、培养基、CellTiter-Lumi溶液和药物溶液);Signal_max:对照孔化学发光值(含细胞、培养基、CellTiter-Lumi溶液,不含药物);Signal_min:空白孔化学发光值(含培养基、CellTiter-Lumi溶液,不含细胞、药物)。
3.实验结果
化合物对人非小细胞肺癌细胞NCI-H358、人食管鳞癌细胞KYSE520、人结直肠癌细胞SW620、人胰腺癌细胞MIA-PaCa-2的抑制
活性如下:
实验结论:以上数据显示,本发明实施例化合物对NCI-H358、KYSE520、SW620、MIA-PaCa-2细胞的增殖具有良好的抑制作用。相比较SHP099而言,本发明实施例具备新颖的结构和更优越的体外抗增殖活性。
Claims (8)
3.根据权利要求1~2中任一项的苯并氮卓氨基类化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物,其特征在于,所述药学上可接受的盐为权利要求1~2中任一项的化合物与下列酸形成的酸加成盐:氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、富马酸、对甲苯磺酸或阿魏酸。
5.含有权利要求1~2中任一项所述的苯并氮卓氨基类化合物的药物组合物,其特征在于:所述药物组合物为由所述苯并氮卓氨基类化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物作为活性成分和药学上可接受的载体或辅料。
6.一种如权利要求1~2所述的苯并氮卓氨基类化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物及权利要求5所述的药物组合物在制备SHP2抑制剂中的用途。
7.一种如权利要求1~2所述的苯并氮卓氨基类化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物及权利要求5所述的药物组合物在制备用于预防和/或治疗癌症的药物中的用途。
8.根据权利要求7所述的用途,其特征在于,所述的癌症为肺癌、食管鳞癌、结直肠癌、胰腺癌、乳腺癌、白血病、肝癌、胃癌。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310027470.6A CN115974841A (zh) | 2023-01-09 | 2023-01-09 | 一种取代的苯并氮卓氨基类化合物及其制备方法与应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310027470.6A CN115974841A (zh) | 2023-01-09 | 2023-01-09 | 一种取代的苯并氮卓氨基类化合物及其制备方法与应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115974841A true CN115974841A (zh) | 2023-04-18 |
Family
ID=85970051
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310027470.6A Pending CN115974841A (zh) | 2023-01-09 | 2023-01-09 | 一种取代的苯并氮卓氨基类化合物及其制备方法与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115974841A (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113248449A (zh) * | 2021-05-06 | 2021-08-13 | 中国药科大学 | 一种含甲脒的芳基螺环类化合物及其制备方法与应用 |
CN114478403A (zh) * | 2022-02-28 | 2022-05-13 | 中国药科大学 | 一种含芳香胍基类化合物及其制备方法与应用 |
CN114539223A (zh) * | 2022-03-01 | 2022-05-27 | 中国药科大学 | 一种含芳基并氮杂七元环类化合物及其制备方法与应用 |
-
2023
- 2023-01-09 CN CN202310027470.6A patent/CN115974841A/zh active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113248449A (zh) * | 2021-05-06 | 2021-08-13 | 中国药科大学 | 一种含甲脒的芳基螺环类化合物及其制备方法与应用 |
CN114478403A (zh) * | 2022-02-28 | 2022-05-13 | 中国药科大学 | 一种含芳香胍基类化合物及其制备方法与应用 |
CN114539223A (zh) * | 2022-03-01 | 2022-05-27 | 中国药科大学 | 一种含芳基并氮杂七元环类化合物及其制备方法与应用 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107382879B (zh) | 一种嘧啶类化合物、egfr抑制剂及其应用 | |
CN107840846B (zh) | 一种含嘧啶环的化合物、egfr抑制剂及其应用 | |
EP3590924B1 (en) | Novel isoindoline derivative, and pharmaceutical composition and application thereof | |
CA2736097C (en) | Carbazole compounds for inhibition of nf-kb activity | |
EP3283486B1 (en) | Maleate salts of a b-raf kinase inhibitor, crystalline forms, methods of preparation, and uses therefore | |
EP3287463A1 (en) | Condensed-ring pyrimidylamino derivative, preparation method therefor, and intermediate, pharmaceutical composition and applications thereof | |
CN116535401A (zh) | 新的parp1抑制剂及其应用 | |
WO2015120800A1 (zh) | 一类氮杂环化合物及其制备方法和用途 | |
CN114539223A (zh) | 一种含芳基并氮杂七元环类化合物及其制备方法与应用 | |
JP2019518776A (ja) | Egfr阻害剤としてのアニリンピリミジン化合物の結晶 | |
WO2023001229A1 (zh) | 嘧啶并环类衍生物及其制备方法和用途 | |
TW201904973A (zh) | 作為mek抑制劑的類香豆素環類化合物及其應用 | |
CN102134234A (zh) | 吲唑脲类化合物及其制法和药物用途 | |
JP7101781B2 (ja) | Akt阻害剤としての塩形態及びその結晶形態 | |
CN114848648B (zh) | C-6位芳基化去氮嘌呤衍生物在制备抗肿瘤药物中的应用 | |
CN115974841A (zh) | 一种取代的苯并氮卓氨基类化合物及其制备方法与应用 | |
CN117447449A (zh) | Parp1抑制剂及其应用 | |
EP4322947A1 (en) | Heteroaryl compounds as inhibitors of rip2 kinase, composition and application thereof | |
CN111606888B (zh) | 吡咯类衍生物及其制备方法与应用 | |
CN115433207A (zh) | 作为egfr抑制剂的大环杂环类化合物及其应用 | |
WO2022007841A1 (zh) | 一种egfr抑制剂、其制备方法和在药学上的应用 | |
CN110283174B (zh) | 一类PI3Kδ抑制剂及其用途 | |
CN111377934B (zh) | 一类杂环化合物,其制备及用途 | |
CN110650961A (zh) | Parp抑制剂、其药物组合物、制备方法和应用 | |
CN115232134B (zh) | 一种伐地那非类似物及其合成方法和应用 |
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 |