CN105085483B - Kinase inhibitor and its application - Google Patents
Kinase inhibitor and its application Download PDFInfo
- Publication number
- CN105085483B CN105085483B CN201510304709.5A CN201510304709A CN105085483B CN 105085483 B CN105085483 B CN 105085483B CN 201510304709 A CN201510304709 A CN 201510304709A CN 105085483 B CN105085483 B CN 105085483B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- compound represented
- reaction
- acid
- 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.)
- Expired - Fee Related
Links
- 229940043355 kinase inhibitor Drugs 0.000 title abstract description 7
- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 330
- 239000003814 drug Substances 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 229940122531 Anaplastic lymphoma kinase inhibitor Drugs 0.000 claims abstract description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 34
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 54
- 206010028980 Neoplasm Diseases 0.000 abstract description 41
- 201000011510 cancer Diseases 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 12
- 238000011282 treatment Methods 0.000 abstract description 11
- 239000000651 prodrug Substances 0.000 abstract description 9
- 229940002612 prodrug Drugs 0.000 abstract description 9
- 239000012453 solvate Substances 0.000 abstract description 7
- 239000002207 metabolite Substances 0.000 abstract description 4
- 230000035755 proliferation Effects 0.000 abstract description 3
- 230000001093 anti-cancer Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- 238000006243 chemical reaction Methods 0.000 description 88
- 230000002829 reductive effect Effects 0.000 description 47
- 238000003756 stirring Methods 0.000 description 40
- 239000000203 mixture Substances 0.000 description 39
- 239000000243 solution Substances 0.000 description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 27
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 27
- 208000020816 lung neoplasm Diseases 0.000 description 25
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 24
- 201000005202 lung cancer Diseases 0.000 description 24
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
- 238000004440 column chromatography Methods 0.000 description 21
- 238000004809 thin layer chromatography Methods 0.000 description 21
- 230000000694 effects Effects 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000001914 filtration Methods 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 230000005764 inhibitory process Effects 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 238000001035 drying Methods 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 239000012043 crude product Substances 0.000 description 15
- 238000001514 detection method Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 14
- 230000002401 inhibitory effect Effects 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 13
- 238000010791 quenching Methods 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- 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 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 9
- 238000011580 nude mouse model Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 108091000080 Phosphotransferase Proteins 0.000 description 8
- 230000012010 growth Effects 0.000 description 8
- 102000020233 phosphotransferase Human genes 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- KJRCEJOSASVSRA-UHFFFAOYSA-N propane-2-thiol Chemical compound CC(C)S KJRCEJOSASVSRA-UHFFFAOYSA-N 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- -1 C5-10Aryl Chemical group 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 5
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 229960005061 crizotinib Drugs 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical group O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 208000000649 small cell carcinoma Diseases 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- WZCQRUWWHSTZEM-UHFFFAOYSA-N 1,3-phenylenediamine Chemical compound NC1=CC=CC(N)=C1 WZCQRUWWHSTZEM-UHFFFAOYSA-N 0.000 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-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
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 101150023956 ALK gene Proteins 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 229940018564 m-phenylenediamine Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000012089 stop solution Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- CBCKQZAAMUWICA-UHFFFAOYSA-N 1,4-phenylenediamine Chemical compound NC1=CC=C(N)C=C1 CBCKQZAAMUWICA-UHFFFAOYSA-N 0.000 description 1
- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical compound ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 102100027100 Echinoderm microtubule-associated protein-like 4 Human genes 0.000 description 1
- 241000258955 Echinodermata Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001057929 Homo sapiens Echinoderm microtubule-associated protein-like 4 Proteins 0.000 description 1
- 101000801643 Homo sapiens Retinal-specific phospholipid-transporting ATPase ABCA4 Proteins 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
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000007727 Muscle Tissue Neoplasms Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102100033617 Retinal-specific phospholipid-transporting ATPase ABCA4 Human genes 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229940088623 biologically active substance Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000008711 chromosomal rearrangement Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011337 individualized treatment Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000024305 myofibroblastoma Diseases 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 102220197961 rs1057519784 Human genes 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides kinase inhibitor and its applications.The compound is officinal salt, hydrate, solvate, metabolite or the prodrug of compound shown in compound shown in Formulas I or Formulas I, wherein R1、R2It is defined as in the description.It can be used in ALK inhibitor, treatment or pre- anti-cancer using the compound and pharmaceutical composition and inhibit the preparation of the drug of the proliferation function of cancer cell.
Description
Technical Field
The invention belongs to the field of medicines, relates to novel compounds serving as kinase inhibitors, and particularly relates to compounds serving as ALK inhibitors and application of the compounds in preparation of medicines for treating and preventing cancers.
Background
Non-small cell lung cancer (Non-small-cell carcinoma, NSCLC) is synonymous with "Non-small cell carcinoma". Non-small cell lung cancers, including squamous cell carcinomas, adenocarcinomas, large cell carcinomas, have slower growth and division of cancer cells and relatively late metastatic spread as compared to small cell carcinomas. Non-small cell lung cancer accounts for approximately 80-85% of the total lung cancer. The data show that the lung cancer incidence rate in China is increased by 26.9% every year at present, and the number of lung cancer incidence in China is estimated to increase by 12 thousands of people from 2000 to 2005. Of these, men have increased from 26 to 33 million in 2000 to 2005, while women have increased from 12 to 17 million. In addition, lung cancer is the leading cause of "cancer of numerous" in many areas throughout the country. The incidence of lung cancer in Beijing city increases by 56% from 2001 to 2010. One fifth of the new cancer patients in Beijing is lung cancer patients in ten years; among the 2011 Zhejiang cancer "cancer spectra published by Zhejiang tumor hospitals, lung cancer is still the first ranked cancer; compared with the lung cancer in Guangzhou region before 30 years, the incidence rate of lung cancer is increased by 7 times.
With the progress of molecular medicine and the continuous emergence of targeted drugs, the treatment of advanced NSCLC has entered the age of individualized treatment. At present, the individual target therapy applied clinically mainly aims at the EGFR mutant type and ALK (anaplastic lymphoma kinase) fusion genotype lung cancer, and the two genetically modified lung cancers have definite molecular targets, target detection technologies and targeted drugs on the market, so the clinical curative effect is obviously improved. ALK variation in lung cancer is mainly caused by ALK gene rearrangement and fusion with other genes. Genetic abnormalities at the ALK gene site have been reported to be associated with a variety of cancers. Echinoderm tubulin-like 4(EML4) -ALK fusions due to chromosomal rearrangements have been reported in non-small cell lung cancer (NSCLC) patient populations.
Although a large number of compounds having inhibitory activity against protein kinases have been studied and some protein kinase inhibitors such as crizotinib and the like have been marketed for the treatment of NSCLC, they are resistant and have some drawbacks. Patients who are therapeutically effective, e.g., crizotinib, typically develop resistance after 6 months to 1 year of administration. Moreover, the most common adverse reactions observed in two clinical studies of crizotinib are visual disturbance, nausea, diarrhea, vomiting, edema and constipation, and the incidence rate of the adverse reactions is more than or equal to 25 percent. Therefore, the development of a novel ALK inhibitor drug for treating cancer with higher safety and efficiency has great social value and economic benefit, and is also a research hotspot of various large drug enterprises at present.
Thus, current ALK inhibitors remain to be improved.
Disclosure of Invention
The present invention aims to solve at least one of the above technical problems to at least some extent or to at least provide a useful commercial choice. To this end, it is an object of the present invention to propose a compound as kinase inhibitor which can be used for the preparation of a medicament for the treatment of cancer.
According to one aspect of the invention, a compound is provided. According to an embodiment of the invention, the compound is a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug of a compound of formula I,
wherein,
R1is halogen orIn some embodiments of the invention, R1Can be fluorine, chlorine or
R2Is a 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl, each of which is independently substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C, hydroxy, 5-6 membered heterocyclyl, 5-6 membered aryl, and 5-6 membered heteroaryl according to embodiments of the present invention1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C5-10Aryl, 5-10 membered heteroaryl, C1-6Alkoxy radical, C3-8Cycloalkoxy, -S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7or-C (O) NR7Wherein R is5、R6、R7Each independently is hydrogen or Cl-4Alkyl, p is 0, 1 or 2.
In some embodiments of the invention, R2Is one of the following:
according to an embodiment of the invention, R1Is fluorine or chlorine, and R2Is one of the following:
according to an embodiment of the invention, R1Is composed ofAnd R is2Is one of the following:
it will be understood by those skilled in the art that, according to the convention used in the art, in the structural formulae of the present application,for delineating chemical bonds, which are the points at which moieties or substituents are attached to a core structure or a backbone structure. In addition, in the structural formula of the present application,the positions of the substituents on the benzene ring are described as two positions adjacent to the chemical bond of the substituents in the structural formula, namely the positions marked by the circular rings in the chemical formulaMonosubstitution may occur.
Thus, throughout this specification, the skilled artisan will be able to work with compounds of formula IThe R is1～R4And substituents thereof are selected to provide stable compounds of formula I as described in the examples of the invention or pharmaceutically acceptable salts, hydrates, solvates, metabolites or prodrugs thereof.
According to an embodiment of the present invention, the compound of formula I according to the present invention may be at least one selected from the group consisting of:
as used herein, the term "pharmaceutically acceptable salts" refers to the conventional non-toxic salts formed by the reaction of a compound of formula I with an inorganic or organic acid. For example, the conventional non-toxic salts can be prepared by reacting a compound of formula I with an inorganic or organic acid. Wherein, the inorganic acid can be hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid and the like, and the organic acid can be citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid and the like. Or the "pharmaceutically acceptable salts" of the compounds of formula I may be prepared by esterifying a compound of formula I with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid and then reacting with an inorganic base to form a sodium, potassium, calcium, aluminum or ammonium salt. Or the compound shown in the general formula I and organic base form methylamine salt, ethylamine salt or ethanolamine salt. Or the compound shown in the general formula I forms ester with lysine, arginine and ornithine and then forms corresponding inorganic acid salt with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid and phosphoric acid or forms corresponding organic acid salt with formic acid, acetic acid, picric acid, methanesulfonic acid and ethanesulfonic acid.
As used herein, the term "prodrug" means that upon administration of the compound to a subject, the compound undergoes chemical transformation by metabolic or chemical processes to yield the compound of formula I and/or a salt and/or solvate thereof. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the present invention. For example, compounds containing a carboxyl group may form physiologically hydrolyzable esters that act as prodrugs by hydrolyzing in vivo to give the compounds of formula I themselves. The prodrugs are preferably administered orally, since hydrolysis in many cases takes place mainly under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.
It is also understood that hydrates, solvates (e.g., methanolate, ethanolate, DMSO) of the compounds of formula I of the present invention are also within the scope of the present invention. Methods of solvation are well known in the art.
According to a second aspect of the present invention, the present invention provides a method for preparing the compound shown in formula i. According to the embodiment of the invention, the method for preparing the compound shown in formula I comprises the following steps:
(1) contacting a compound represented by formula 1 with a compound represented by formula 2 to obtain a compound represented by formula 3;
(2) contacting a compound represented by formula 3 with a compound represented by formula 4 to obtain a compound represented by formula 5;
(3) contacting a compound of formula 5 with dioxane hydrochloride to obtain a compound of formula I,
according to the embodiment of the present invention, R in the compound represented by the formula 1, the compound represented by the formula 2, the compound represented by the formula 3, the compound represented by the formula 5, and the compound represented by the formula I1And R2As defined in the preceding description.
The inventor finds that the compound shown in the formula I can be quickly and effectively prepared by the method disclosed by the embodiment of the invention, the synthetic route is short, the environment is friendly, the yield and purity of a target product are higher, the raw materials are easy to obtain, the operation and the post-treatment are simple, and the method is suitable for industrial production.
In one embodiment of the present invention, the synthetic route for the compound of formula I is:
the following describes the general process for preparing compounds of formula I used in the examples of the present invention:
step (1): preparation of Compound (intermediate) represented by formula 3
According to a specific embodiment of the present invention, in step (1), the compound represented by formula 1 is contacted with the compound represented by formula 2 in the presence of NaH in a first organic solvent. According to a specific example of the present invention, the first organic solvent may be at least one selected from the group consisting of N-methylpyrrolidone, N-Dimethylformamide (DMF), dimethyl sulfoxide, dimethylacetamide, and N, N-dimethylacetamide. In one specific example of the present invention, the first organic solvent is DMF. Therefore, a good reaction environment can be provided for the compound shown in the formula 1 and the compound shown in the formula 2, and the yield of the compound shown in the formula 3 can be improved.
According to a specific example of the present invention, in step (1), the compound represented by formula 1 is contacted with the compound represented by formula 2 at 0 ℃. By selecting an appropriate reaction temperature, the yield of the compound represented by formula 3 can be further improved. According to another specific example of the present invention, in the step (1), the molar ratio of the compound represented by formula 1 to the compound represented by formula 2 may be (25 to 30): (15-30). According to a preferred embodiment of the present invention, the molar ratio of the compound represented by formula 1 to the compound represented by formula 2 may be (27 to 28): (20-26). Further, the yield of the compound represented by the formula 3 can be improved, and the raw material cost can be saved.
According to one embodiment of the present invention, the preparation of the compound (intermediate) represented by formula 3 may be specifically carried out according to the following steps: dissolving the compound shown in the formula 2 in DMF, adding NaH in batches at 0 ℃, continuously stirring the reaction solution for half an hour at 0 ℃ after the addition is finished, dripping 2,5, 6-trichloropyrimidine (the compound shown in the formula 1) into the reaction solution at 0 ℃, and naturally heating the mixture to room temperature after the dripping is finished and stirring the mixture overnight. After the reaction is finished, ice water is dripped to quench, the mixture is extracted by ethyl acetate, organic phases are combined, the mixture is washed by saturated salt for three times, dried and concentrated under reduced pressure, and the obtained crude product is subjected to column chromatography to obtain the compound shown in the formula 3.
Step (2): preparation of Compound (intermediate) represented by formula 5
According to the specific embodiment of the invention, in the step (2), the compound shown in the formula 3 is contacted with the compound shown in the formula 4 in isopropanol and in the presence of p-toluenesulfonic acid, and the temperature is raised to 60-80 ℃ for stirring reaction. Thus, a good reaction environment can be provided for the compound represented by formula 3 and the compound represented by formula 4, and the yield of the compound represented by formula 5 can be improved.
And (3): preparation of Compounds of formula I
According to the specific embodiment of the invention, in the step (3), the compound shown in the formula 5 is contacted with dioxane hydrochloride, and the reaction is carried out by contacting and stirring for 1.5-5 hours at 15-25 ℃. Thus, the yield of the compound of formula I can be increased.
According to a third aspect of the present invention, the present invention provides an intermediate, according to a specific embodiment of the present invention, the intermediate is a compound represented by formula 5, and the compound represented by formula 5 is an intermediate for preparing the compound represented by formula I of the present invention, and the compound represented by formula 5 can be used for preparing the compound represented by formula I of the present invention.
Wherein R is1Is halogen orAccording to a preferred embodiment of the invention, R1Is fluorine, chlorine or
R2Is one of the following:
according to an embodiment of the invention, R1Is fluorine or chlorine, and R2Is one of the following:
according to an embodiment of the invention, R1Is composed ofAnd R is2Is one of the following:
according to a fourth aspect of the invention, a pharmaceutical composition is proposed. According to a particular embodiment of the invention, the pharmaceutical composition comprises a compound as described above. According to a specific example of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
According to a particular embodiment of the invention, the pharmaceutical composition is in the form of a tablet, capsule, injection, powder, syrup, solution, suspension or aerosol. Thereby the applicability of the pharmaceutical composition can be remarkably improved. And the pharmaceutical compositions of the above embodiments of the invention may be presented in a suitable solid or liquid carrier or diluent and in a suitable sterile device for injection or instillation.
Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The compounds and pharmaceutical compositions of the present invention may be administered to mammals in clinical use, including humans and animals, by oral, nasal, dermal, pulmonary or gastrointestinal routes, among others. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment regimen. Usually starting with a small dose and gradually increasing the dose until the most suitable dose is found. The most preferred route of administration is oral.
According to a fifth aspect of the present invention, the present invention proposes the use of a compound as described above, a compound prepared by a method as described above, or a pharmaceutical composition as described above, for the manufacture of a medicament for use as an ALK inhibitor.
According to an embodiment of the present invention, the use of a compound of the present invention for the manufacture of a medicament for the treatment or prevention of a disease responsive to the inhibition of anaplastic lymphoma kinase, wherein the administration of an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, is useful for the treatment of a disease responsive to the inhibition of anaplastic lymphoma kinase, said disease responsive to the inhibition of anaplastic lymphoma kinase being at least one selected from the group consisting of anaplastic large cell lymphoma, non-hodgkin's lymphoma, inflammatory myofibroblastoma, neuroblastoma, and neoplastic disease.
According to a particular embodiment of the invention, the medicament is for at least one of: useful as kinase inhibitors, inhibiting ALK kinase activity, treating or preventing cancer, and inhibiting proliferation of cancer cells. According to the specific example of the invention, the in vitro ALK kinase inhibitory activity assay experiment results of the compound show that the compounds shown in the formula I have good ALK kinase inhibitory activity, and the compounds can be used as ALK inhibitors and used for preparing antitumor treatment medicines for diseases responding to the inhibition of anaplastic lymphoma kinase.
According to the specific example of the invention, the compound shown in the formula I has obvious curative effect on the inhibition of the growth of the transplanted tumor of a nude mouse of human lung cancer A549 cells, and the curative effect is superior to that of the existing ALK inhibitor drug crizotinib. The cancer which can be treated or prevented by the medicament is preferably lung cancer; preferably, the inhibition of the proliferation of cancer cells is the inhibition of lung cancer cells.
Therefore, the medicine of the invention can be effectively used as an ALK inhibitor and is used for treating one or more tumor diseases related to ALK activity, wherein the tumor diseases include but are not limited to lung cancer. The kinase inhibitor and the application thereof have good clinical application and medical application as an ALK inhibitor.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications.
In the specific examples described below, the compound structure was determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). Wherein the NMR shift (. delta.) is given in parts per million (ppm), NMR is measured using a Bruker AVANCE-400 nuclear magnetic spectrometer, and solvent is deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD3OD) with internal standard Tetramethylsilane (TMS); LC-MS was measured using an Agilent1200Infinity Series Mass spectrometer. HPLC was carried out using an Agilent1200 DAD high pressure liquid chromatograph (SunfireC 18150X 4.6mm column).
The progress of the reaction in the following examples was monitored by Thin Layer Chromatography (TLC) using a system of developing reagents: dichloromethane and methanol system, n-hexane/petroleum ether and ethyl acetate system, and the volume ratio of the solvent is adjusted according to the polarity of the compound. The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The eluent system for column chromatography and the developing agent system for thin layer chromatography used for purifying compounds in the following examples include: a: dichloromethane and methanol system, B: the volume ratio of the n-hexane/petroleum ether and ethyl acetate system is adjusted according to the different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.
The starting materials used in the examples below may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical technology (Accela ChemBio Inc), Darri Chemicals, and the like.
The embodiment of the invention provides a compound shown in formula I or a pharmaceutically acceptable salt, a hydrate, a solvate, a metabolite or a prodrug thereof, a method and an intermediate for preparing the compound shown in formula I or the pharmaceutically acceptable salt, the hydrate, the solvate or the prodrug thereof, a pharmaceutical composition, and application of the compound and the pharmaceutical composition in preparing medicines.
Example 1: preparation of the Compound represented by formula 2-a (intermediate)
Placing a compound shown as a formula a (15g,106.31mmol) and potassium carbonate (29.38g,212.61mmol) in a 500mL round-bottom bottle, adding 150 mL of DMF, adding isopropylmercaptan (a compound shown as a formula b) (8.5g,111.62mmol) under stirring, stirring and heating the mixture to 80 ℃, reacting for 5 hours, evaporating a reaction solvent under reduced pressure after the reaction is finished, washing the obtained crude product with water, extracting with ethyl acetate, drying, concentrating, and performing column chromatography to obtain a compound shown as a formula c (the yield is 19.5g, and the yield is 95%).
Placing a compound shown as a formula c (19.5g,98.86mmol) and m-chloroperoxybenzoic acid (mCPBA, a compound shown as a formula d) (60.2g, 348.84mmol) in a 1000mL round-bottomed bottle, adding 500mL of dichloromethane, stirring the mixture at room temperature overnight, quenching with saturated sodium sulfite aqueous solution, extracting with dichloromethane, washing with saturated potassium carbonate solution and saturated common salt solution, drying, spin-drying, and performing column chromatography to obtain a compound shown as a formula e (the yield is 20.4g and is 90 percent).
Putting the compound shown as the formula e (20.4g,88.98mmol) into a 500mL hydrogenation bottle, adding 250 mL of methanol, replacing with nitrogen, adding 1000mg of palladium-carbon (Pd content 5%) into the bottle, replacing with a hydrogen balloon, stirring overnight under the condition of hydrogen (1atm), monitoring the reaction, filtering the reaction solution, and performing reduced pressure spin-drying on the filtrate to obtain the compound shown as the formula 2-a (15.95 g, 90% yield).
Example 2: preparation of the Compound represented by formula 2-b (intermediate)
Placing a compound shown as a formula f (14.2g,0.1mol) and potassium carbonate (27.6g,0.2mol) in a 500mL round-bottom bottle, adding 150 mL of DMF, adding isopropylmercaptan (a compound shown as a formula b) (8.0g,0.105mol) under stirring, stirring and heating the mixture to 75 ℃, reacting for 6 hours, evaporating a reaction solvent under reduced pressure after the reaction is finished, washing the obtained crude product with water, extracting with ethyl acetate, drying, concentrating, and performing column chromatography to obtain the compound shown as the formula g (the yield is 17.9g, and the yield is 92.5%).
Placing a compound shown as a formula g (19.8g,0.1mol) and m-chloroperoxybenzoic acid (mCPBA, a compound shown as a formula d) (60.9g, 0.35mol) in a 1000mL round-bottomed bottle, adding 500mL of dichloromethane, stirring the mixture at room temperature overnight, quenching with a saturated sodium sulfite solution, extracting with dichloromethane, washing with a saturated potassium carbonate solution and a saturated common salt solution, drying, spin-drying, and performing column chromatography to obtain a compound shown as a formula h (the yield is 21.1g, and the yield is 92%).
Putting the compound (23.0g,0.1mol) shown in the formula h into a 500mL hydrogenation bottle, adding 250 mL of methanol, replacing with nitrogen, adding 1000mg of palladium-carbon (Pd content is 5%) into the bottle, replacing with a hydrogen balloon, stirring overnight under the condition of hydrogen (1atm), monitoring the reaction, filtering the reaction solution, and performing reduced pressure spin-drying on the filtrate to obtain the compound shown in the formula 2-b (the obtained amount is 18.6g, and the yield is 93.5%).
Example 3: preparation of the Compound represented by formula 2-b (intermediate)
Putting a compound shown as a formula j (15.9g,0.1mmol) and potassium carbonate (27.6g,0.2mmol) into a 500mL round-bottom bottle, adding 150 mL of DMF, adding isopropylmercaptan (a compound shown as a formula b) (8.0g,0.105mol) under stirring, stirring the mixture, heating to 80 ℃, reacting for 5 hours, evaporating a reaction solvent under reduced pressure after the reaction is finished, washing the obtained crude product with water, extracting with ethyl acetate, drying, concentrating, and performing column chromatography to obtain a compound shown as a formula g (the yield is 18.1g, and the yield is 93%).
Placing a compound shown as a formula g (19.8g,0.1mol) and m-chloroperoxybenzoic acid (mCPBA, a compound shown as a formula d) (48.7g, 0.28mol) in a 1000mL round-bottomed bottle, adding 500mL of dichloromethane, stirring the mixture at room temperature overnight, quenching with a saturated sodium sulfite solution, extracting with dichloromethane, washing with a saturated potassium carbonate solution and a saturated common salt solution, drying, spin-drying, and performing column chromatography to obtain a compound shown as a formula h (the yield is 21.5g, and the yield is 93.5%).
Putting a compound (23.0g,0.1mol) shown in the formula h into a 500mL hydrogenation bottle, adding 250 mL of methanol, replacing with nitrogen, adding 1000mg of palladium-carbon (Pd content is 5%) into the bottle, replacing with a hydrogen balloon, stirring overnight under the condition of hydrogen (1.5atm), monitoring the reaction, filtering the reaction solution, and performing reduced pressure spin-drying on the filtrate to obtain a compound shown in the formula 2-b (the yield is 18.4g, and the yield is 92%).
Example 4: preparation of the Compound of formula 2-c (intermediate)
Placing a compound shown as a formula k (16.4g,0.1mol) and potassium carbonate (27.6g,0.2mol) in a 500mL round-bottom bottle, adding 150 mL of DMF, adding isopropylmercaptan (a compound shown as a formula b) (8.0g,0.105mol) under stirring, stirring and heating the mixture to 75 ℃, reacting for 6 hours, evaporating a reaction solvent under reduced pressure after the reaction is finished, washing the obtained crude product with water, extracting with ethyl acetate, drying, concentrating, and performing column chromatography to obtain a compound shown as a formula m (the yield is 18.3g, and the yield is 92%).
Placing a compound shown as a formula m (20.3g,0.1mol) and m-chloroperoxybenzoic acid (mCPBA, a compound shown as a formula d) (60.9g, 0.35mol) in a 1000mL round-bottomed bottle, adding 500mL of dichloromethane, stirring the mixture at room temperature overnight, quenching with a saturated sodium sulfite solution, extracting with dichloromethane, washing with a saturated potassium carbonate solution and a saturated common salt solution, drying, spin-drying, and performing column chromatography to obtain a compound shown as a formula n (the yield is 21.7g and 92.5 percent).
Putting a compound (23.5g,0.1mol) shown as a formula n into a 500mL hydrogenation bottle, adding 250 mL of methanol, replacing with nitrogen, adding 1000mg of palladium-carbon (Pd content is 5%) into the bottle, replacing with a hydrogen balloon, stirring overnight under the condition of hydrogen (1atm), monitoring the reaction, filtering the reaction solution, and performing reduced pressure spin-drying on the filtrate to obtain a compound (18.9 g, 92% yield) shown as a formula 2-c.
Example 5: preparation of the Compound represented by formula 4-a (intermediate)
(tert-butoxycarbonyl) glycine (a compound represented by formula 6) (1g,5.7mmol) was dissolved in 15mL of dry DMF, N-Diisopropylethylamine (DIPEA) (2.21g,17mmol), HATU (chemical name 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate) (2.34g,6.15mmol) and m-phenylenediamine (a compound represented by formula 7) (616mg,5.7mmol) were sequentially added, the mixture was stirred at room temperature overnight, the reaction solution was poured into 50mL of water and extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated aqueous sodium carbonate solution, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, and analyzed by column chromatography (PE/EA ═ 2:1) to give a compound represented by formula 4-a (937mg, yield 62%).
Example 6: preparation of the Compound represented by formula 4-a (intermediate)
(tert-butoxycarbonyl) glycine (a compound represented by formula 6) (1g,5.7mmol) was dissolved in 15mL of dry DMF, N-Diisopropylethylamine (DIPEA) (2.21g,17mmol), HATU (chemical name 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate) (2.34g,6.15mmol) and m-phenylenediamine (a compound represented by formula 7) (627mg,5.8mmol) were sequentially added, the mixture was stirred at room temperature overnight, the reaction solution was poured into 50mL of water and extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated aqueous sodium carbonate solution, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, and analyzed by column chromatography (PE/EA ═ 6:1) to give a compound represented by formula 4-a (980mg, yield 64.85%).
Example 7: preparation of the Compound represented by formula 4-b (intermediate)
(tert-butoxycarbonyl) glycine (a compound represented by formula 6) (1g,5.7mmol) was dissolved in 15mL of dry DMF, N-Diisopropylethylamine (DIPEA) (2.21g,17mmol), HATU (chemical name 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate) (2.34g,6.15mmol) and p-phenylenediamine (a compound represented by formula 8) (648mg,6.0mmol) were sequentially added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into 50mL of water and extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated aqueous sodium carbonate solution, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, and analyzed by column chromatography (PE/EA ═ 4:1) to give a compound represented by formula 4-b (1013mg, yield 67%).
Example 8: preparation of the Compound represented by formula 3-a
The compound represented by the formula 2-a (5g,25.09mmol) was dissolved in DMF (100mL), NaH (0.66g,27.6mmol) was slowly added at 0 ℃ and after the addition, the reaction solution was stirred at 0 ℃ for half an hour, and then the compound represented by the formula 1-c (5.93g,27.6mmol) was added dropwise to the reaction solution at 0 ℃ and after the addition, the mixture was allowed to spontaneously warm to room temperature and stirred overnight. After the reaction was completed, 300mL of water was added to quench, and extraction was performed with ethyl acetate (200mL × 3), the organic phases were combined, washed three times with saturated brine, dried, and concentrated under reduced pressure, and the resulting crude product was subjected to column chromatography (PE/EA ═ 4:1) to give the compound represented by formula 3-a (yield 3.41g, yield 36%).
Example 9: preparation of the Compound represented by formula 3-b
The compound represented by the formula 2-b (5g,25.09mmol) was dissolved in DMF (100mL), NaH (0.66g,27.6mmol) was slowly added at 0 ℃ and after the addition, the reaction mixture was stirred at 0 ℃ for half an hour, and then the compound represented by the formula 1-c (5.93g,27.6mmol) was added dropwise to the reaction mixture at 0 ℃ and after the addition, the mixture was allowed to spontaneously warm to room temperature and stirred overnight. After the reaction was completed, 300mL of water was added to quench, and extraction was performed with ethyl acetate (200mL × 3), the organic phases were combined, washed three times with saturated brine, dried, and concentrated under reduced pressure, and the resulting crude product was subjected to column chromatography (PE/EA ═ 4:1) to give a compound represented by formula 3-b (yield 3.23g, yield 34%).
Example 10: preparation of the Compound of formula 3-c
Dissolving the compound represented by the formula 2-c (20.5g,0.1mol) in DMF (300mL), slowly adding NaH (2.64g,0.11mol) at 0 ℃, continuing to stir the reaction liquid at 0 ℃ for half an hour after the addition is finished, dripping the compound represented by the formula 1-c (23.65g,0.1mol) into the reaction liquid at 0 ℃, and naturally raising the temperature of the mixture to room temperature and stirring overnight after the dripping is finished. After the reaction, 600mL of water was added to quench, and extraction was performed with ethyl acetate (600mL × 3), the organic phases were combined, washed three times with saturated brine, dried, and concentrated under reduced pressure, and the resulting crude product was subjected to column chromatography (PE/EA ═ 4:1) to give a compound represented by formula 3-c (yield 11.52g, yield 30%).
Example 11: preparation of the Compound represented by formula 3-d
The compound represented by the formula 2-b (5g,25.09mmol) was dissolved in DMF (100mL), NaH (0.66g,27.6mmol) was slowly added at 0 ℃ and the reaction mixture was stirred at 0 ℃ for half an hour, then the compound represented by the formula 1-a (5.06g,27.6mmol) was added dropwise to the reaction mixture at 0 ℃ and after completion of the addition, the mixture was allowed to spontaneously warm to room temperature and stirred overnight. After the reaction, 300mL of water was added to quench, and extraction was performed with ethyl acetate (200mL × 3), the organic phases were combined, washed three times with saturated brine, dried, and concentrated under reduced pressure, and the resulting crude product was subjected to column chromatography (PE/EA ═ 4:1) to give a compound represented by formula 3-d (yield 2.70g, yield 31%).
Example 12: preparation of the Compound represented by formula 3-e
The compound represented by the formula 2-c (20.5g,0.1mol) was dissolved in DMF (300mL), NaH (2.64g,0.11mol) was slowly added at 0 ℃ and the reaction mixture was stirred at 0 ℃ for half an hour, then the compound represented by the formula 1-a (22.04g,0.12mol) was added dropwise to the reaction mixture at 0 ℃ and after the addition was completed, the mixture was allowed to spontaneously warm to room temperature and stirred overnight. After the reaction, 600mL of water was added to quench, and extraction was performed with ethyl acetate (600mL × 3), the organic phases were combined, washed three times with saturated brine, dried, and concentrated under reduced pressure, and the resulting crude product was subjected to column chromatography (PE/EA ═ 4:1) to give a compound represented by formula 3-e (yield 13.39g, yield 38%).
Example 13: preparation of a Compound of formula 3-f
Dissolving the compound represented by the formula 2-b (20g,0.1mol) in DMF (500mL), slowly adding NaH (2.64g,0.11mol) at 0 ℃, continuing to stir the reaction liquid at 0 ℃ for half an hour after the addition is finished, dripping the compound represented by the formula 1-b (18.4g,0.11mol) into the reaction liquid at 0 ℃, and naturally raising the temperature of the mixture to room temperature and stirring overnight after the dripping is finished. After the reaction, 500mL of water was added to quench, and extraction was performed with ethyl acetate (600mL × 3), the organic phases were combined, washed three times with saturated brine, dried, and concentrated under reduced pressure, and the resulting crude product was subjected to column chromatography (PE/EA ═ 4:1) to give a compound represented by formula 3-f (yield 14.6g, yield 44%).
Example 14: preparation of the Compound represented by formula 3-g
Dissolving the compound represented by the formula 2-c (20g,0.1mol) in DMF (500mL), slowly adding NaH (2.64g,0.11mol) at 0 ℃, continuing to stir the reaction solution at 0 ℃ for half an hour after the addition is finished, dripping the compound represented by the formula 1-b (18.4g,0.11mol) into the reaction solution at 0 ℃, and naturally raising the temperature of the mixture to room temperature and stirring overnight after the dripping is finished. After the reaction, 500mL of water was added to quench, and extraction was performed with ethyl acetate (600mL × 3), the organic phases were combined, washed three times with saturated brine, dried, and concentrated under reduced pressure, and the resulting crude product was subjected to column chromatography (PE/EA ═ 4:1) to obtain the compound represented by formula 3-g (yield 15.11g, yield 45%).
Example 15: preparation of the Compound represented by formula 5-a
The compound represented by the formula 3-a (1.98g,5.24mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-a (1.53g,5.76mmol) and p-toluenesulfonic acid (993mg,5.76mmol) were added thereto, and the mixture was stirred at a temperature of 70 ℃ for 8 hours. After completion of the TLC detection reaction, the solvent was evaporated under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound represented by the formula 5-a (1.27g, yield 40%).
Example 16: preparation of the Compound represented by formula 5-b
The compound represented by the formula 3-a (1.98g,5.24mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-b (1.53g,5.76mmol) and p-toluenesulfonic acid (993mg,5.76mmol) were added thereto, and the mixture was stirred at a temperature of 65 ℃ for reaction for 8 hours. After completion of the TLC detection reaction, the solvent was evaporated under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound represented by the formula 5-b (2.01g, yield 63%).
Example 17: preparation of the Compound of formula 5-c
The compound represented by the formula 3-b (2.2g,5.76mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-a (1.53g,5.76mmol) and p-toluenesulfonic acid (993mg,5.76mmol) were added thereto, and the mixture was stirred at a temperature of 80 ℃ for 6 hours. After completion of the TLC detection reaction, the solvent was evaporated under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, which was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound represented by the formula 5-c (1.92g, yield 55%).
Example 18: preparation of the Compound represented by formula 5-d
The compound represented by the formula 3-b (2.2g,5.76mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-b (1.53g,5.76mmol) and p-toluenesulfonic acid (993mg,5.76mmol) were added thereto, and the mixture was stirred at a temperature of 60 ℃ for 10 hours. After completion of the TLC detection reaction, the solvent was evaporated under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, which was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound represented by formula 5-d (2.45g, yield 70%).
Example 19: preparation of the Compound represented by formula 5-e
The compound represented by the formula 3-c (2g,5.45mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-a (1.53g,5.76mmol) and p-toluenesulfonic acid (993mg,5.76mmol) were added thereto, and the mixture was stirred at a temperature of 70 ℃ for 10 hours. After completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, which was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound represented by the formula 5-e (1869mg, yield 56%).
Example 20: preparation of the Compound of formula 5-f
The compound represented by the formula 3-c (2g,5.45mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-b (1.53g,5.76mmol) and p-toluenesulfonic acid (993mg,5.76mmol) were added thereto, and the mixture was stirred at a temperature of 80 ℃ for 6 hours. After completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, which was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound represented by the formula 5-f (2.504g, yield 75%).
Example 21: preparation of the Compound of formula 5-g
The compound represented by the formula 3-d (2g,5.76mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-a (1.53g,5.76mmol) and p-toluenesulfonic acid (993mg,5.76mmol) were added thereto, and the mixture was stirred at a temperature of 80 ℃ for 6 hours. After completion of the TLC detection reaction, the solvent was evaporated under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-g of the compound represented by the formula (2.12g, yield 64%).
Example 22: preparation of the Compound of formula 5-h
The compound represented by the formula 3-d (2g,5.76mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-b (1.53g,5.76mmol) and p-toluenesulfonic acid (993mg,5.76mmol) were added thereto, and the mixture was stirred at a temperature of 60 ℃ for 6.5 hours. After completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, which was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound represented by the formula 5-h (2058mg, yield 62%).
Example 23: preparation of the Compound of formula 5-i
The compound represented by the formula 3-e (2g,5.68mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-a (1.53g,5.76mmol) and p-toluenesulfonic acid (993mg,5.76mmol) were added thereto, and the mixture was stirred at a temperature of 80 ℃ for 6 hours. After completion of the TLC detection reaction, the solvent was evaporated under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a compound represented by formula 5-i (2376mg, yield 72%).
Example 24: preparation of the Compound of formula 5-j
The compound represented by the formula 3-e (2g,5.68mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-b (1.53g,5.76mmol) and p-toluenesulfonic acid (993mg,5.76mmol) were added thereto, and the mixture was stirred at a temperature of 80 ℃ for 6 hours. After completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, which was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound represented by the formula 5-j (2.310g, yield 70%).
Example 25: preparation of the Compound of formula 5-k
The compound represented by the formula 3-f (1.73g,5.24mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-a (1.53g,5.76mmol) and p-toluenesulfonic acid (993mg,5.76mmol) were added thereto, and the mixture was stirred at a temperature of 70 ℃ for 5 hours. After completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, which was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound represented by formula 5-k (1760mg, yield 60%).
Example 26: preparation of the Compound of formula 5-l
The compound represented by the formula 3-f (1.73g,5.24mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-b (1.53g,5.76mmol) and p-toluenesulfonic acid (993mg,5.76mmol) were added thereto, and the mixture was stirred at a temperature of 80 ℃ for 6 hours. After completion of the TLC detection reaction, the solvent was evaporated under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, which was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound represented by formula 5-l (2.58g, yield 88%).
Example 27: preparation of a Compound of formula 5-m
The compound represented by the formula 3-g (1.76g,5.24mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-a (1.53g,5.76mmol) and p-toluenesulfonic acid (993mg,5.76mmol) were added thereto, and the mixture was stirred at a temperature of 60 ℃ for 12 hours. After completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, which was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a compound represented by the formula 5-m (1479mg, yield 50%).
Example 28: preparation of a Compound of formula 5-n
The compound represented by the formula 3-g (1.76g,5.24mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-b (1.53g,5.76mmol) and p-toluenesulfonic acid (993mg,5.76mmol) were added thereto, and the mixture was stirred at a temperature of 80 ℃ for 5 hours. After completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, which was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound represented by the formula 5-n (1.625g, yield 55%).
Example 29: preparation of the Compound of formula I-1
The compound represented by the formula 5-g (400mg,0.694mmol) was placed in a 100mL reaction flask, 50mL of dioxane hydrochloride (2M) was added, stirring was conducted at 20 ℃ for 2 hours, completion of the reaction was monitored, filtration was conducted, and the filter cake was washed with ether to give the product of the compound represented by the formula I-1 (281mg, yield 85%).
MS m/z(ESI)：475.9(M+H+)
Example 30: preparation of the Compound of formula I-2
The compound represented by the formula 5-h (400mg,0.694mmol) was placed in a 100mL reaction flask, 50mL of dioxane hydrochloride (2M) was added, stirring was performed at 15 ℃ for 5 hours, completion of the reaction was monitored, filtration was performed, and the filter cake was washed with ether to give the product of the compound represented by the formula I-2 (231mg, yield 70%).
MS m/z(ESI)：475.9(M+H+)
Example 31: preparation of the Compound of formula I-3
The compound represented by the formula 5-I (400mg,0.688mmol) was placed in a 100mL reaction flask, 50mL of dioxane hydrochloride (2M) was added, stirring was performed at 20 ℃ for 2.5 hours, completion of the reaction was monitored, filtration was performed, and the filter cake was washed with ether to give the product of the compound represented by the formula I-3 (385mg, yield 92%).
MS m/z(ESI)：481.0(M+H+)
Example 32: preparation of the Compound of formula I-4
The compound represented by the formula 5-j (400mg,0.688mmol) was placed in a 100mL reaction flask, 50mL of dioxane hydrochloride (2M) was added, stirring was performed at 25 ℃ for 1.5 hours, completion of the reaction was monitored, filtration was performed, and the filter cake was washed with ether to give the product of the compound represented by the formula I-4 (352mg, yield 84%).
MS m/z(ESI)：480.9(M+H+)
Example 33: preparation of the Compound of formula I-5
The compound represented by the formula 5-k (400mg,0.715mmol) was placed in a 100mL reaction flask, 50mL of dioxane hydrochloride (2M) was added, stirring was performed at 20 ℃ for 3 hours, completion of the reaction was monitored, filtration was performed, and the filter cake was washed with ether to obtain the product of the compound represented by the formula I-5 (356mg, yield 85%).
MS m/z(ESI)：459.5(M+H+)
Example 34: preparation of the Compound of formula I-6
The compound represented by the formula 5-l (400mg,0.715mmol) was placed in a 100mL reaction flask, 50mL of dioxane hydrochloride (2M) was added, stirring was performed at 20 ℃ for 2 hours, completion of the reaction was monitored, filtration was performed, and the filter cake was washed with ether to obtain a product of the compound represented by the formula I-6 (335mg, yield 80%).
MS m/z(ESI)：459.5(M+H+)
Example 35: preparation of the Compound represented by the formula I-7
The compound represented by the formula 5-M (400mg,0.709mmol) was placed in a 100mL reaction flask, 50mL of dioxane hydrochloride (2M) was added, stirring was performed at 15 ℃ for 2.5 hours, completion of the reaction was monitored, filtration was performed, and the filter cake was washed with ether to give the product of the compound represented by the formula I-7 (293mg, yield 70%).
MS m/z(ESI)：464.6(M+H+)
Example 36: preparation of the Compound of formula I-8
The compound represented by the formula 5-n (400mg,0.709mmol) was placed in a 100mL reaction flask, 50mL of dioxane hydrochloride (2M) was added, stirring was performed at 18 ℃ for 4 hours, completion of the reaction was monitored, filtration was performed, and the filter cake was washed with ether to obtain the product of the compound represented by the formula I-8 (327mg, yield 78%).
MS m/z(ESI)：464.6(M+H+)
Example 37: preparation of the Compound of formula I-9
The compound represented by the formula 5-c (400mg,0.676mmol) was placed in a 100mL reaction flask, 50mL of dioxane hydrochloride (2M) was added, stirring was performed at 25 ℃ for 2 hours, completion of the reaction was monitored, and filtration was performed, and the filter cake was washed with ether to obtain the product of the compound represented by the formula I-9 (399mg, yield 93%).
MS m/z(ESI)：507.5(M+H+)
Example 38: preparation of the Compound of formula I-10
The compound represented by the formula 5-d (400mg,0.676mmol) was placed in a 100mL reaction flask, 50mL of dioxane hydrochloride (2M) was added, stirring was performed at 20 ℃ for 5 hours, completion of the reaction was monitored, and filtration was performed, and the filter cake was washed with ether to obtain the product of the compound represented by the formula I-10 (390mg, 91% yield).
MS m/z(ESI)：507.5(M+H+)
Example 39: preparation of the Compound of formula I-11
The compound represented by the formula 5-e (400mg,0.670mmol) was placed in a 100mL reaction flask, 50mL of dioxane hydrochloride (2M) was added, stirring was performed at 25 ℃ for 1.5 hours, completion of the reaction was monitored, filtration was performed, and the filter cake was washed with ether to give the product of the compound represented by the formula I-11 (343mg, yield 80%).
MS m/z(ESI)：512.6(M+H+)
Example 40: preparation of the Compound of formula I-12
The compound represented by the formula 5-f (400mg,0.670mmol) was placed in a 100mL reaction flask, 50mL of dioxane hydrochloride (2M) was added, stirring was performed at 25 ℃ for 2 hours, completion of the reaction was monitored, and filtration was performed, and the filter cake was washed with ether to obtain the product of the compound represented by the formula I-12 (360mg, yield 84%).
MS m/z(ESI)：512.6(M+H+)
Example 41: preparation of the Compound of formula I-13
The compound represented by the formula 5-a (400mg,0.677mmol) was placed in a 100mL reaction flask, 50mL of dioxane hydrochloride (2M) was added, stirring was performed at 15 ℃ for 3 hours, completion of the reaction was monitored, filtration was performed, and the filter cake was washed with ether to give the product of the compound represented by the formula I-13 (317mg, yield 74%).
MS m/z(ESI)：506.5(M+H+)
Example 42: preparation of the Compound of formula I-14
The compound represented by the formula 5-b (400mg,0.677mmol) was placed in a 100mL reaction flask, 50mL of dioxane hydrochloride (2M) was added, stirring was performed at 20 ℃ for 2 hours, after completion of the reaction was monitored, filtration was performed, and the filter cake was washed with ether to give the product of the compound represented by the formula I-14 (334mg, yield 78%).
MS m/z(ESI)：506.5(M+H+)
Example 43: measurement of ALK kinase inhibitory Activity
The inhibitory activity of the compound of the present invention on ALK kinase in vitro was measured by the following method, and the inhibitory activity was expressed by IC50, which is an index, i.e., the concentration of the compound at which the activity of ALK kinase was inhibited by 50%.
Shorthand and definition
mg of
mL of
Microgram of μ g
Microliter of
mM millimole
EDTA ethylene diamine tetraacetic acid
DMSO dimethyl sulfoxide
Standard deviation of SD
SOP Standard operating program
Experimental materials:
ALK(Carna,Cat.No 08-105,Lot.No.08CBS-0112)
ALK L1196M(Carna,Cat.No 08-529,Lot.No.11CBS-1134)
Peptide FAM-P22(GL Biochem,Cat.No.112393,Lot.No.P080401-XY112393)
ATP(Sigma,Cat.No.A7699-1G,CAS No.987-65-5)
DMSO(Sigma,Cat.No.D2650,Lot.No.474382)
EDTA(Sigma,Cat.No.E5134,CAS No.60-00-4)
96-well plate (Corning, Cat.No.3365, Lot.No.22008026)
384 well plates (Corning, Cat.No.3573, Lot.No.12608008)
Staurosporine(Sigma,Cat.No.S4400-1MG,Lot.No.046K4080)
The experimental method comprises the following steps:
1. preparing 1 time of kinase buffer solution and stop solution
1) 1-fold kinase buffer
50mM HEPES,pH 7.5
0.0015％Brij-35
10mM MgCl2
2mM DTT
2) Stopping liquid
100mM HEPES,pH 7.5
0.015％Brij-35
0.2％Coating Reagent#3
50mM EDTA
2. Compound preparation
1) Compounds were diluted 50-fold into 100% DMSO at the final desired maximum inhibitory concentration. Transfer 100 μ L of this compound dilution in 96-well plates. For example, if the highest inhibitor concentration of 1. mu.M is desired, a 50. mu.M DMSO solution is prepared at this step.
2) Compounds were diluted in 3-fold order to 10 concentrations.
3) 100 μ l of 100% DMSO was added to 2 empty identical 96-well plates without compound control and without enzyme control. The source plate is marked.
4) Preparation of intermediate plate
Transfer 10 μ L of compound from source plate to a new 96-well plate as an intermediate plate.
Add 90 μ L of 1 fold kinase buffer to the wells of each intermediate plate.
Mix the compound into the middle plate and shake for 10 minutes.
3. Preparing the test plate
Transfer 5 μ l from each well of the 96-well intermediate plate to 384-well plates as replicates. For example, a1 in a 96-well plate was transferred to a1 and a2 in a 384-well plate. A2 in 96-well plates was transferred to A3 and A4 in 384-well plates.
4. Kinase reaction
1) Preparing 2.5 times of enzyme solution
The kinase was added to 1 fold kinase buffer to form a 2.5 fold enzyme solution.
2) Preparing 2.5 times of substrate solution
FAM-labeled polypeptide and ATP were added to 1-fold kinase buffer to form a 2.5-fold substrate solution.
3) The assay plate already contains 5. mu.l of compound in 10% DMSO.
4) Transfer 2.5 times enzyme solution to assay plate.
5) Incubate at room temperature for 10 minutes
6) Transfer 2.5 fold peptide solution to assay plate.
7) Reaction and cessation of kinase
Incubate at 28 ℃ for 20 minutes. The reaction was stopped by adding 25. mu.l of stop solution.
Reading data by Caliper
Conversion data were read on the Caliper.
6. Fitting of curves
1) Conversion data was copied from the Caliper.
2) The conversion was converted to inhibition data. Wherein max refers to the conversion rate of a DMSO control, and min refers to the conversion rate of an enzyme-free control. Percent inhibition is (max-conversion)/(max-min) × 100.
3) Data were imported into MS Excel and curve fitted using XLFit Excel add-in version 4.3.1.
The formula used is:
the following table shows the activity of the compounds of formulae I-1 to I-14 of the present invention in an in vitro ALK kinase inhibition assay. The results show that the compounds shown in the formula I have good ALK kinase inhibitory activity, and the compounds can be used as ALK inhibitors, used for treating one or more tumor diseases related to ALK activity, and used for preparing anti-tumor treatment medicines for inhibiting anaplastic lymphoma kinase.
| Compound numbering | IC50(nM) |
| I-1 | <10 |
| I-2 | <10 |
| I-3 | <10 |
| I-4 | <100 |
| I-5 | <100 |
| I-6 | <100 |
| I-7 | <10 |
| I-8 | <10 |
| I-9 | <10 |
| I-10 | <100 |
| I-11 | <100 |
| I-12 | <10 |
| I-13 | <100 |
| I-14 | <10 |
According to the experimental results of ALK kinase inhibitory activity tests of the compounds, the compounds have high inhibitory activity on anaplastic lymphoma kinase. The IC50 of the compounds I-1, I-2, I-3, I-7, I-8, I-9, I-12 and I-14 is less than 10nM, the IC50 of the compounds I-4, I-5, I-6, I-10, I-11 and I-13 is less than 100nM, the IC50 is between 10nM and 100nM, and the IC50 values of all the compounds are less than 100 nM. These results indicate that the compounds of the present invention are excellent ALK inhibitors and are effective in treating tumor diseases associated with ALK activity.
Example 44: tablets for oral administration, formula shown in Table 2
Table 2: tablet formulations for oral administration
| Composition (I) | Bulk drug (gram) |
| Active ingredient | 25 |
| Lactose | 40 |
| Microcrystalline cellulose | 100 |
| Cross-linked polyvidone | 6 |
| Magnesium stearate | 1.5 |
| Is prepared into | 1000 tablets |
The preparation process comprises the following steps:
the active ingredients of the compound are pulverized by airflow, the pulverizing pressure is 0.3Mpa, D90 is 50 microns, the prescription amount is weighed, then the active ingredients and the microcrystalline cellulose with the prescription amount are uniformly mixed in a multi-item motion mixer, then the crospovidone, the lactose and the magnesium stearate are added and uniformly mixed, the mixture is pressed on a rotary tablet press by a direct tabletting process to form tablets, 1000 tablets are prepared, and the active ingredient (the compound of the invention) of each tablet is 25 mg.
Example 45: influence of the compound on the growth of the transplanted tumor of a nude mouse of human lung cancer A549 cell
(1) Preparation of human lung cancer nude mouse transplantation tumor model
SPF-grade BALB/c-nu mice 36, 6 weeks old, weigh l6g-18 g. Taking lung cancer cell strain A549 cells in logarithmic growth phase, and adjusting the concentration of the A549 cells to be 3 multiplied by 10 by sterile PBS7A549 cells (0.1 mL) were subcutaneously inoculated on the back of BALB/c-nu mice to a volume of 75mm for subcutaneous transplantation3About (about 10 days), the model was successfully made.
(2) Grouping and administration of drugs
Dividing the mice into 8 groups according to the principle of tumor volume and tumor-bearing mouse weight balance, wherein each group comprises 12 mice:
A. model control group: 1 time/day of equivalent physiological saline for intragastric administration for 30 days;
B. oxaliplatin group: injecting 10mg/kg oxaliplatin intraperitoneally, and administering for 1 time every other day, and 8 times in total;
C. crizotinib group: powder of crizotinib capsule (trade name: tecoraib, produced by the company pfeiri) was administered by gavage at a dose of 25mg/kg for 2 times per day for 8 times in total;
D. the group of compounds represented by formula I-1: gavage the tablet powder prepared according to example 44 at a dose of 10mg/kg 2 times per day for a total of 30 days;
the longest diameter (L) and the shortest diameter (w) of the graft were measured with a vernier caliper every 4 days during the administration period. Mice were sacrificed by dislocation 48 hours after the last administration, the transplanted tumors were excised, and the tumors were weighed. Tumor weight inhibition (%) IR ═ 1 (experimental group tumor weight mean/model control group tumor weight mean) × 100%. The effect of the medicament on the tumor growth inhibition of the nude mice of the human lung cancer A549 cells is reflected by the comparison of tumor weights. Data are expressed as means ± standard deviation (x ± s), and anova was performed using SPSS15.0 software.
(3) Results and analysis
The experimental results of the effect of the compound of formula I-1 on the growth of nude mouse transplanted tumor of human lung cancer A549 cell are shown in Table 4.
TABLE 4
| Group of | Tumor weight (mg) | Average tumor inhibition (%) |
| Model control group | 402.3±76.7 | / |
| Oxaliplatin group | 216.3±51.0* | 44.05 |
| Crizotinib group | 195.0±47.8* | 49.33 |
| Group of Compounds represented by formula I-1 | 177.6±45.0** | 53.20 |
Note: p < 0.05, P < 0.01 compared to model control.
The test results in table 4 show that: compared with a model control group, each treatment group has significant difference in the inhibition effect on the growth of a human lung cancer A549 cell nude mouse transplanted tumor, and particularly compared with the model control group, the compound shown in the formula I-1 has significant difference (P is less than 0.01) in the inhibition effect on the growth of the human lung cancer A549 cell nude mouse transplanted tumor, and compared with a chemotherapy oxaliplatin group and an ALK inhibitor crizotinib group, the average tumor inhibition rate is improved, which shows that the compound has significant curative effect on the treatment of non-small cell lung cancer, has the advantage of low toxic and side effects while obtaining significant drug effect, and obtains unexpected technical effect.
Similarly, the effect of the compound shown in the formula I-2 to the compound shown in the formula I-14 on the growth of the nude mouse transplanted tumor of the human lung cancer A549 cell is tested, and the result is shown in Table 5.
TABLE 5
| Group of | Tumor weight (mg) | Average tumor inhibition (%) |
| Model control group | 402.3±76.7 | / |
| Oxaliplatin group | 216.3±51.0* | 44.05 |
| Crizotinib group | 195.0±47.8* | 49.33 |
| Group of Compounds represented by formula I-2 | 172.7±43.5** | 53.20 |
| Group of compounds represented by the formula I-3 | 175.3±43.2** | 52.90 |
| Group of Compounds represented by formula I-4 | 179.9±44.6** | 54.22 |
| Group of Compounds represented by formula I-5 | 184.5±50.3** | 55.01 |
| Group of Compounds represented by formula I-6 | 182.8±49.6** | 53.72 |
| Group of compounds represented by the formula I-7 | 170.3±42.5** | 50.34 |
| Group of compounds of formula I-8 | 172.1±43.1** | 51.00 |
| Group of compounds of formula I-9 | 174.4±45.8** | 53.21 |
| Group of compounds represented by the formula I-10 | 175.6±46.9** | 54.30 |
| Group of compounds of formula I-11 | 173.9±50.2** | 52.69 |
| Group of compounds of formula I-12 | 176.8±51.9** | 53.70 |
| Group of compounds of formula I-13 | 185.0±42.1** | 56.12 |
| Group of compounds of formula I-14 | 183.2±43.7** | 55.80 |
Note: p < 0.05, P < 0.01 compared to model control.
The results in Table 5 show that the compounds of formula I, in particular the compounds of formula I-2 to I-14, have significant efficacy in inhibiting the growth of transplanted tumors of nude mice of human lung cancer A549 cells, have the advantages of significant efficacy and low toxic and side effects, and have all unexpected technical effects.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made in the above embodiments by those of ordinary skill in the art without departing from the principle and spirit of the present invention.
Claims (7)
1. A compound selected from one of the following or a pharmaceutically acceptable salt thereof:
2. a process for preparing a compound of claim 1, comprising:
(1) reacting the compound shown in the formula 1 with the compound shown in the formula 2 at 0 ℃ so as to obtain a compound shown in a formula 3;
(2) reacting the compound shown in the formula 3 with a compound shown in a formula 4-a or 4-b in isopropanol in the presence of p-toluenesulfonic acid at 60-80 ℃ to obtain a compound shown in a formula 5-c or 5-b;
(3) reacting the compound represented by the formula 5-c or 5-b with dioxane hydrochloride at 15-25 ℃ for 1.5-5 hours to obtain a compound represented by the formula I-9 or I-14,
wherein R is1Is composed ofAnd R is2Is one of the following:
3. the method according to claim 2, wherein in step (1), the compound represented by formula 1 is reacted with the compound represented by formula 2 in a first organic solvent in the presence of NaH.
4. The method according to claim 3, wherein the first organic solvent is at least one selected from the group consisting of N-methylpyrrolidone, N-dimethylformamide, dimethyl sulfoxide, and N, N-dimethylacetamide.
5. The method of claim 4, wherein the first organic solvent is N, N-dimethylformamide.
6. An intermediate, which is a compound represented by formula 5-c or 5-b,
7. use of a compound of claim 1 in the manufacture of a medicament for use as an ALK inhibitor.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510304709.5A CN105085483B (en) | 2015-06-04 | 2015-06-04 | Kinase inhibitor and its application |
| PCT/CN2015/081483 WO2016192131A1 (en) | 2015-06-04 | 2015-06-15 | Kinase inhibitor and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510304709.5A CN105085483B (en) | 2015-06-04 | 2015-06-04 | Kinase inhibitor and its application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105085483A CN105085483A (en) | 2015-11-25 |
| CN105085483B true CN105085483B (en) | 2019-01-01 |
Family
ID=54566899
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510304709.5A Expired - Fee Related CN105085483B (en) | 2015-06-04 | 2015-06-04 | Kinase inhibitor and its application |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN105085483B (en) |
| WO (1) | WO2016192131A1 (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104987324B (en) * | 2015-06-04 | 2018-05-04 | 湖北生物医药产业技术研究院有限公司 | Pyrimidine derivatives as ALK inhibitor |
| GB201514021D0 (en) | 2015-08-07 | 2015-09-23 | Arner Elias Set Jeno | Novel Pyridines and their use in the treatment of cancer |
| CN106883213B (en) * | 2015-12-15 | 2021-04-20 | 合肥中科普瑞昇生物医药科技有限公司 | Dual inhibitor of EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) |
| CN106083670A (en) * | 2016-06-08 | 2016-11-09 | 常州安迪沃克医药科技有限公司 | The synthetic method of cancer therapy drug Ceritinib intermediate 1 amino 2 (isopropyl sulphonyl) benzene |
| CN107586278B (en) * | 2016-07-08 | 2020-01-10 | 中国科学院上海药物研究所 | 2, 4-diamino pyrimidine compound, preparation method, pharmaceutical composition and application thereof |
| MA47450A (en) | 2017-02-07 | 2019-12-18 | Oblique Therapeutics Ab | SULFINYLPYRIDINES AND THEIR USE IN THE TREATMENT OF CANCER |
| JP7229176B2 (en) | 2017-02-07 | 2023-02-27 | オブリーク セラピューティクス アーベー | Hydrocarbylsulfonyl-substituted pyridines and their use in treating cancer |
| EP3580215A1 (en) | 2017-02-07 | 2019-12-18 | Oblique Therapeutics AB | Heteroarylsulfonyl-substituted pyridines and their use in the treatment of cancer |
| AU2018218521C1 (en) | 2017-02-07 | 2022-06-09 | Oblique Therapeutics Ab | Heterocyclylsulfonyl-substituted pyridines and their use in the treatment of cancer |
| CN109836415B (en) * | 2017-11-29 | 2020-11-06 | 北京博远精准医疗科技有限公司 | Urea compounds as ALK inhibitors |
| JP2022539208A (en) | 2019-07-03 | 2022-09-07 | スミトモ ファーマ オンコロジー， インコーポレイテッド | Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090306067A1 (en) * | 2006-04-10 | 2009-12-10 | Harald Engelhardt | 2, 4-diaminopyrimidide derivates and their use for the treatment of cancer |
| WO2013169401A1 (en) * | 2012-05-05 | 2013-11-14 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
| CN104230954A (en) * | 2013-06-08 | 2014-12-24 | 中国科学院上海药物研究所 | 2,4-diaminopyrimidine compounds and medical applications thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2099771A1 (en) * | 2006-12-19 | 2009-09-16 | Genentech, Inc. | Pyrimidine kinase inhibitors |
-
2015
- 2015-06-04 CN CN201510304709.5A patent/CN105085483B/en not_active Expired - Fee Related
- 2015-06-15 WO PCT/CN2015/081483 patent/WO2016192131A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090306067A1 (en) * | 2006-04-10 | 2009-12-10 | Harald Engelhardt | 2, 4-diaminopyrimidide derivates and their use for the treatment of cancer |
| WO2013169401A1 (en) * | 2012-05-05 | 2013-11-14 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
| CN104230954A (en) * | 2013-06-08 | 2014-12-24 | 中国科学院上海药物研究所 | 2,4-diaminopyrimidine compounds and medical applications thereof |
Non-Patent Citations (1)
| Title |
|---|
| Discovery of Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent Inhibitory Activities against Both Wild-type and Mutant ALK Kinases;Zilan Song，et al.，;《 J. Med. Chem.》;20140430;第58卷;第197-211页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2016192131A1 (en) | 2016-12-08 |
| CN105085483A (en) | 2015-11-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105085483B (en) | Kinase inhibitor and its application | |
| CN104987324B (en) | Pyrimidine derivatives as ALK inhibitor | |
| ES2558780T3 (en) | Imidazopyridazines as Akt kinase inhibitors | |
| TW200803863A (en) | Method for inhibiting protein kinases | |
| JP2016521721A (en) | Pyrazolopyridine derivatives for use in the treatment of bladder cancer | |
| CN110167941B (en) | Substituted fused heteroaryl compounds as kinase inhibitors and uses thereof | |
| CA2863673A1 (en) | 2-amino, 6-phenyl substituted pyrido [2,3-d] pyrimidine derivatives useful as raf kinase inhibitors | |
| AU2016312011A1 (en) | Process for preparing Parp inhibitor, crystalline forms, and uses thereof | |
| TW200811176A (en) | Dihydropyrazolopyrimidinone derivatives | |
| US20240360085A1 (en) | Glucose Uptake Inhibitors | |
| WO2012138809A1 (en) | Heterocyclic compounds as kinase inhibitors | |
| US20170296537A1 (en) | Azabicyclo derivatives, process for preparation therof and medical use thereof | |
| WO2015188681A1 (en) | Novel heterocyclic compound and preparation method therefor and use thereof as kinase inhibitor | |
| JPWO2020111087A1 (en) | Heterocyclic compound | |
| CN110312717B (en) | Substituted fused heteroaromatic tricyclic compounds as kinase inhibitors and uses thereof | |
| EP2900667B1 (en) | Means and method for treating solid tumours | |
| WO2019029629A1 (en) | Substituted pyrazolopyrimidines useful as kinases inhibitors | |
| US10308654B2 (en) | Preparation and use of kinase inhibitor | |
| WO2021249319A1 (en) | Tricyclic compound, pharmaceutical composition, and use thereof | |
| CN107793363B (en) | Substituted arylamino aromatic heterocyclic compound and application thereof as antitumor drug | |
| WO2023190748A1 (en) | Pharmaceutical composition for treating tumors | |
| CN108239075A (en) | Quinazoline compounds and preparation method thereof, purposes and pharmaceutical composition | |
| WO2015014283A1 (en) | Protein tyrosine kinase inhibitor and application thereof | |
| US9499552B2 (en) | Pyrazolo[1,5-A]pyrimidine derivative and use of anti-tumor thereof | |
| JP7110335B2 (en) | Pyridoquinazoline derivatives useful as protein kinase inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190101 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |