CN110577524A - Kinase selective inhibitor - Google Patents
Kinase selective inhibitor Download PDFInfo
- Publication number
- CN110577524A CN110577524A CN201810580435.6A CN201810580435A CN110577524A CN 110577524 A CN110577524 A CN 110577524A CN 201810580435 A CN201810580435 A CN 201810580435A CN 110577524 A CN110577524 A CN 110577524A
- Authority
- CN
- China
- Prior art keywords
- compound
- salt
- stereoisomer
- room temperature
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108091000080 Phosphotransferase Proteins 0.000 title abstract description 9
- 102000020233 phosphotransferase Human genes 0.000 title abstract description 9
- 229940124639 Selective inhibitor Drugs 0.000 title abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims description 129
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 claims description 57
- 101710182387 Fibroblast growth factor receptor 4 Proteins 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 44
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 15
- 102100031734 Fibroblast growth factor 19 Human genes 0.000 claims description 14
- 101000846394 Homo sapiens Fibroblast growth factor 19 Proteins 0.000 claims description 14
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 10
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 10
- 230000002018 overexpression Effects 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 230000003321 amplification Effects 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 6
- 238000003199 nucleic acid amplification method Methods 0.000 claims description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 201000010997 liver sarcoma Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- 150000003852 triazoles Chemical class 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000002950 monocyclic group Chemical group 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 120
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 76
- -1 2-methyl-3-butyl Chemical group 0.000 description 59
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 57
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- 239000003153 chemical reaction reagent Substances 0.000 description 47
- 239000007787 solid Substances 0.000 description 45
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 235000019439 ethyl acetate Nutrition 0.000 description 41
- 229910001868 water Inorganic materials 0.000 description 41
- 238000005160 1H NMR spectroscopy Methods 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- 238000006243 chemical reaction Methods 0.000 description 36
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 33
- 238000004440 column chromatography Methods 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 31
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 29
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 28
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 27
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 27
- 239000000203 mixture Substances 0.000 description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 21
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 21
- 229910000027 potassium carbonate Inorganic materials 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- 108090000623 proteins and genes Proteins 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
- 239000003112 inhibitor Substances 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 14
- 238000004949 mass spectrometry Methods 0.000 description 14
- 229910052786 argon Inorganic materials 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 12
- QRXMUCSWCMTJGU-UHFFFAOYSA-N 5-bromo-4-chloro-3-indolyl phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP(O)(=O)O)=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-N 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 11
- 238000000605 extraction Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229910000024 caesium carbonate Inorganic materials 0.000 description 9
- 238000004896 high resolution mass spectrometry Methods 0.000 description 9
- 229940124597 therapeutic agent Drugs 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 7
- DPJCXCZTLWNFOH-UHFFFAOYSA-N 2-nitroaniline Chemical compound NC1=CC=CC=C1[N+]([O-])=O DPJCXCZTLWNFOH-UHFFFAOYSA-N 0.000 description 7
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 6
- 229940125408 FGFR4 inhibitor Drugs 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 230000000155 isotopic effect Effects 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000010452 phosphate Chemical group 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical group [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- VFZRZRDOXPRTSC-UHFFFAOYSA-N 3,5-Dimethoxybenzaldehyde Chemical compound COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 description 4
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 4
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical group [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 150000002148 esters Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 150000002894 organic compounds Chemical class 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 4
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 4
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 229940124530 sulfonamide Drugs 0.000 description 4
- 150000003456 sulfonamides Chemical group 0.000 description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- 229910052623 talc Inorganic materials 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
- 238000005406 washing Methods 0.000 description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 3
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-p-benzoquinone Substances ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 3
- FCMRHMPITHLLLA-UHFFFAOYSA-N 2-methyl-6-nitroaniline Chemical compound CC1=CC=CC([N+]([O-])=O)=C1N FCMRHMPITHLLLA-UHFFFAOYSA-N 0.000 description 3
- DSCOSIUAQUDGJM-UHFFFAOYSA-N 6-chloro-1h-pyrrolo[2,3-b]pyridine Chemical compound ClC1=CC=C2C=CNC2=N1 DSCOSIUAQUDGJM-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 108091008794 FGF receptors Proteins 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 241001465754 Metazoa Species 0.000 description 3
- DMLAKEGRRFGXOQ-UHFFFAOYSA-N N-(2-nitrophenyl)-1H-pyrrolo[2,3-b]pyridin-6-amine Chemical compound C1=CC=C(C(=C1)NC2=NC3=C(C=C2)C=CN3)[N+](=O)[O-] DMLAKEGRRFGXOQ-UHFFFAOYSA-N 0.000 description 3
- HNWOWYIKEKFVRM-UHFFFAOYSA-N N-[2-[[3-(3-methoxyphenyl)sulfinyl-1H-pyrrolo[2,3-b]pyridin-6-yl]amino]phenyl]prop-2-enamide Chemical compound C(C=C)(=O)NC1=C(C=CC=C1)NC1=CC=C2C(=N1)NC=C2S(=O)C2=CC(=CC=C2)OC HNWOWYIKEKFVRM-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 229920001615 Tragacanth Polymers 0.000 description 3
- 235000010419 agar Nutrition 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 235000012216 bentonite Nutrition 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125808 covalent inhibitor Drugs 0.000 description 3
- 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 3
- 235000019441 ethanol Nutrition 0.000 description 3
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 3
- 229940126864 fibroblast growth factor Drugs 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical group [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 3
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical group [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 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 3
- 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 3
- 239000005720 sucrose Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- VALNWXMPJVPVLQ-UHFFFAOYSA-N tert-butyl n-(4-bromo-2-nitrophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(Br)C=C1[N+]([O-])=O VALNWXMPJVPVLQ-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000036962 time dependent Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 230000005945 translocation Effects 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 2
- XUIURRYWQBBCCK-UHFFFAOYSA-N (3,5-dimethoxyphenyl)boronic acid Chemical compound COC1=CC(OC)=CC(B(O)O)=C1 XUIURRYWQBBCCK-UHFFFAOYSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- HUSBBWQIJMRKLI-UHFFFAOYSA-N 1-ethynyl-3,5-dimethoxybenzene Chemical compound COC1=CC(OC)=CC(C#C)=C1 HUSBBWQIJMRKLI-UHFFFAOYSA-N 0.000 description 2
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 2
- FILNSUBFOZCJFZ-UHFFFAOYSA-N 2-N-[3-(3,5-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]benzene-1,2-diamine Chemical compound COC=1C=C(C=C(C1)OC)C1=CNC2=NC(=CC=C21)NC=2C(=CC=CC2)N FILNSUBFOZCJFZ-UHFFFAOYSA-N 0.000 description 2
- NCKPPXBOMHQKKG-UHFFFAOYSA-N 2-N-[3-(3-methoxyphenyl)sulfanyl-1H-pyrrolo[2,3-b]pyridin-6-yl]benzene-1,2-diamine Chemical compound COC=1C=C(C=CC1)SC1=CNC2=NC(=CC=C21)NC=2C(=CC=CC2)N NCKPPXBOMHQKKG-UHFFFAOYSA-N 0.000 description 2
- MHWQTPVBAMTYNV-UHFFFAOYSA-N 2-N-[3-[2-(3,5-dimethoxyphenyl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]benzene-1,2-diamine Chemical compound COC=1C=C(C=C(C1)OC)C#CC1=CNC2=NC(=CC=C21)NC=2C(=CC=CC2)N MHWQTPVBAMTYNV-UHFFFAOYSA-N 0.000 description 2
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 description 2
- ZCWBZRBJSPWUPG-UHFFFAOYSA-N 4-bromo-2-nitroaniline Chemical compound NC1=CC=C(Br)C=C1[N+]([O-])=O ZCWBZRBJSPWUPG-UHFFFAOYSA-N 0.000 description 2
- FJJRFAKIWVHENG-UHFFFAOYSA-N 6-chloro-3-(3-methoxyphenyl)sulfanyl-1H-pyrrolo[2,3-b]pyridine Chemical compound ClC1=CC=C2C(=N1)NC=C2SC2=CC(=CC=C2)OC FJJRFAKIWVHENG-UHFFFAOYSA-N 0.000 description 2
- LSAVUATUXRJQDA-UHFFFAOYSA-N 6-chloro-3-[(3,5-dimethoxyphenyl)methyl]-1H-pyrrolo[2,3-b]pyridine Chemical compound ClC1=CC=C2C(=N1)NC=C2CC2=CC(=CC(=C2)OC)OC LSAVUATUXRJQDA-UHFFFAOYSA-N 0.000 description 2
- DVGWFLBIDZEUSM-UHFFFAOYSA-N 6-chloro-3-iodo-1h-pyrrolo[2,3-b]pyridine Chemical compound ClC1=CC=C2C(I)=CNC2=N1 DVGWFLBIDZEUSM-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- ZGAUDASCRAOGAE-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1C=C(C=2C1=NC(=CC2)Cl)I Chemical compound C(C)(C)(C)OC(=O)N1C=C(C=2C1=NC(=CC2)Cl)I ZGAUDASCRAOGAE-UHFFFAOYSA-N 0.000 description 2
- WZHCKRZRQNTVTB-UHFFFAOYSA-N COC=1C=C(C=C(C1)OC)C1=CNC2=NC(=CC=C21)NC2=C(C=CC=C2)[N+](=O)[O-] Chemical compound COC=1C=C(C=C(C1)OC)C1=CNC2=NC(=CC=C21)NC2=C(C=CC=C2)[N+](=O)[O-] WZHCKRZRQNTVTB-UHFFFAOYSA-N 0.000 description 2
- JGQPGADYIQMKGL-UHFFFAOYSA-N COC=1C=C(C=CC1)S(=O)(=O)C1=CNC2=NC(=CC=C21)NC2=C(C=CC=C2)[N+](=O)[O-] Chemical compound COC=1C=C(C=CC1)S(=O)(=O)C1=CNC2=NC(=CC=C21)NC2=C(C=CC=C2)[N+](=O)[O-] JGQPGADYIQMKGL-UHFFFAOYSA-N 0.000 description 2
- RERTXCITFGUUAY-UHFFFAOYSA-N COC=1C=C(C=CC1)SC1=CN(C2=NC(=CC=C21)NC2=C(C=CC=C2)[N+](=O)[O-])COCC[Si](C)(C)C Chemical compound COC=1C=C(C=CC1)SC1=CN(C2=NC(=CC=C21)NC2=C(C=CC=C2)[N+](=O)[O-])COCC[Si](C)(C)C RERTXCITFGUUAY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- AXHCJVVUQCFLEY-UHFFFAOYSA-N ClC1=CC=C2C(=N1)N(C=C2SC2=CC(=CC=C2)OC)COCC[Si](C)(C)C Chemical compound ClC1=CC=C2C(=N1)N(C=C2SC2=CC(=CC=C2)OC)COCC[Si](C)(C)C AXHCJVVUQCFLEY-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- UDJJMTFUGRGQTK-UHFFFAOYSA-N IC1=CNC2=NC(=CC=C21)NC2=C(C=CC=C2)[N+](=O)[O-] Chemical compound IC1=CNC2=NC(=CC=C21)NC2=C(C=CC=C2)[N+](=O)[O-] UDJJMTFUGRGQTK-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JNVPFHNIWKCZNF-UHFFFAOYSA-N N-[2-[[3-(2,6-dichloro-3,5-dimethoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]amino]-3-methyl-5-(4-methylpiperazin-1-yl)phenyl]prop-2-enamide Chemical compound C(C=C)(=O)NC1=C(C(=CC(=C1)N1CCN(CC1)C)C)NC1=CC=C2C(=N1)NC=C2C(C2=C(C(=CC(=C2Cl)OC)OC)Cl)=O JNVPFHNIWKCZNF-UHFFFAOYSA-N 0.000 description 2
- ZCKJJGOVVXNREC-UHFFFAOYSA-N N-[2-[[3-(2,6-dichloro-3,5-dimethoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]amino]-5-(4-methylpiperazin-1-yl)phenyl]prop-2-enamide Chemical compound C(C=C)(=O)NC1=C(C=CC(=C1)N1CCN(CC1)C)NC1=CC=C2C(=N1)NC=C2C(C2=C(C(=CC(=C2Cl)OC)OC)Cl)=O ZCKJJGOVVXNREC-UHFFFAOYSA-N 0.000 description 2
- PUAVPPLHNLIXNY-UHFFFAOYSA-N N-[2-[[3-(3-methoxyphenyl)sulfonyl-1H-pyrrolo[2,3-b]pyridin-6-yl]amino]phenyl]prop-2-enamide Chemical compound C(C=C)(=O)NC1=C(C=CC=C1)NC1=CC=C2C(=N1)NC=C2S(=O)(=O)C2=CC(=CC=C2)OC PUAVPPLHNLIXNY-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 150000001299 aldehydes Chemical group 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000002576 ketones Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 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
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 238000005956 quaternization reaction Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical group [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- CPZLISWOONYFLM-UHFFFAOYSA-N tert-butyl 3-[2-(3,5-dimethoxyphenyl)ethynyl]-6-(2-nitroanilino)pyrrolo[2,3-b]pyridine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C=C(C=2C1=NC(=CC2)NC2=C(C=CC=C2)[N+](=O)[O-])C#CC2=CC(=CC(=C2)OC)OC CPZLISWOONYFLM-UHFFFAOYSA-N 0.000 description 2
- VFHBBPPWUTVFGC-UHFFFAOYSA-N tert-butyl 6-chloro-3-(3,5-dimethoxybenzoyl)pyrrolo[2,3-b]pyridine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C=C(C=2C1=NC(=CC2)Cl)C(C2=CC(=CC(=C2)OC)OC)=O VFHBBPPWUTVFGC-UHFFFAOYSA-N 0.000 description 2
- ZUZSJWWQMIQZPD-UHFFFAOYSA-N tert-butyl 6-chloro-3-[2-(3,5-dimethoxyphenyl)ethynyl]pyrrolo[2,3-b]pyridine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C=C(C=2C1=NC(=CC2)Cl)C#CC2=CC(=CC(=C2)OC)OC ZUZSJWWQMIQZPD-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- XFQNWPYGEGCIMF-HCUGAJCMSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].[Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 XFQNWPYGEGCIMF-HCUGAJCMSA-N 0.000 description 1
- AUDBREYGQOXIFT-UHFFFAOYSA-N (3,5-dimethoxyphenyl)methanol Chemical compound COC1=CC(CO)=CC(OC)=C1 AUDBREYGQOXIFT-UHFFFAOYSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical group CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical class CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- HLXOVAMYQUFLPE-UHFFFAOYSA-N 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound CN1N=CC=C1B1OC(C)(C)C(C)(C)O1 HLXOVAMYQUFLPE-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-UHFFFAOYSA-N 0.000 description 1
- JNODDICFTDYODH-UHFFFAOYSA-N 2-hydroxytetrahydrofuran Chemical compound OC1CCCO1 JNODDICFTDYODH-UHFFFAOYSA-N 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- QMVAZEHZOPDGHA-UHFFFAOYSA-N 3-methoxybenzenethiol Chemical compound COC1=CC=CC(S)=C1 QMVAZEHZOPDGHA-UHFFFAOYSA-N 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- RTDAMORRDXWYPT-UHFFFAOYSA-N 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O.ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O RTDAMORRDXWYPT-UHFFFAOYSA-N 0.000 description 1
- DDFZWYHSIIRISP-UHFFFAOYSA-N 4-(1-methylpyrazol-3-yl)-2-nitroaniline Chemical compound CN1N=C(C=C1)C1=CC(=C(N)C=C1)[N+](=O)[O-] DDFZWYHSIIRISP-UHFFFAOYSA-N 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- TVQADXWCXYBBJL-UHFFFAOYSA-N 4-morpholin-4-yl-2-nitroaniline Chemical compound C1=C([N+]([O-])=O)C(N)=CC=C1N1CCOCC1 TVQADXWCXYBBJL-UHFFFAOYSA-N 0.000 description 1
- XFZZDIHCNHYESF-UHFFFAOYSA-N 7-amino-1-bromo-4-phenyl-5,7,8,9-tetrahydrobenzo[7]annulen-6-one Chemical compound C=12CC(=O)C(N)CCC2=C(Br)C=CC=1C1=CC=CC=C1 XFZZDIHCNHYESF-UHFFFAOYSA-N 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 244000239659 Eucalyptus pulverulenta Species 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 1
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 1
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 1
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 1
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 1
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 1
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 102000016844 Immunoglobulin-like domains Human genes 0.000 description 1
- 108050006430 Immunoglobulin-like domains Proteins 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 229910006024 SO2Cl2 Inorganic materials 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GNVMUORYQLCPJZ-UHFFFAOYSA-M Thiocarbamate Chemical compound NC([S-])=O GNVMUORYQLCPJZ-UHFFFAOYSA-M 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- QUCCIIVILWRYMD-UHFFFAOYSA-N [6-(2-amino-6-methylanilino)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3,5-dimethoxyphenyl)methanone Chemical compound NC1=C(C(=CC=C1)C)NC1=CC=C2C(=N1)NC=C2C(=O)C2=CC(=CC(=C2)OC)OC QUCCIIVILWRYMD-UHFFFAOYSA-N 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 1
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 125000005021 aminoalkenyl group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 125000005014 aminoalkynyl group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000000611 antibody drug conjugate Substances 0.000 description 1
- 229940049595 antibody-drug conjugate Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000005827 chlorofluoro hydrocarbons Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000000562 conjugate Substances 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 125000004980 cyclopropylene group Chemical group 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical group N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000019439 energy homeostasis Effects 0.000 description 1
- LHWWETDBWVTKJO-UHFFFAOYSA-N et3n triethylamine Chemical compound CCN(CC)CC.CCN(CC)CC LHWWETDBWVTKJO-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-M lactobionate Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-M 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000004322 lipid homeostasis Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940124606 potential therapeutic agent Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229940100996 sodium bisulfate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- CZQOQBBBHJYQGU-UHFFFAOYSA-N tert-butyl 6-(2-amino-4-morpholin-4-ylanilino)-3-(3,5-dimethoxybenzoyl)pyrrolo[2,3-b]pyridine-1-carboxylate Chemical compound NC1=C(C=CC(=C1)N1CCOCC1)NC1=CC=C2C(=N1)N(C=C2C(C2=CC(=CC(=C2)OC)OC)=O)C(=O)OC(C)(C)C CZQOQBBBHJYQGU-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a kinase selective inhibitor, a pharmaceutical composition containing the same and medical application thereof.
Description
Technical Field
The invention relates to a kinase selective inhibitor, a pharmaceutical composition containing the same and medical application thereof.
Background
Fibroblast growth factor receptor 4(FGFR-4) is a protein encoded by the FGFR-4 gene in humans. Such proteins are members of the fibroblast growth factor receptor family, in which the amino acid sequences between the members are highly conserved throughout evolution. FGFR family members 1-4 have different ligand affinities and tissue distributions from each other. A full-length representative protein consists of an extracellular region consisting of three immunoglobulin-like domains, a single hydrophobic transmembrane segment, and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, initiating a downstream signaling cascade that ultimately affects mitosis and differentiation. The genomic organization of the FGFR-4 gene comprises 18 exons. Although alternative splicing has been observed, there is no evidence that half of the IgIII domain at the C-terminus of this protein differs between the other three forms (designated FGFR 1-3).
Disclosure of Invention
inhibitors of FGFR-4 are described. The invention also describes pharmaceutical formulations comprising an FGFR-4 inhibitor.
Specifically, the invention provides the following technical scheme:
Technical scheme 1. A compound represented by the formula (I), a salt thereof or a stereoisomer thereof
G1And G2Independently of one another, identical or different, from the group consisting of H, C (O) and S (O)2;
L1And L2Independently of one another, identical or different, from the group optionally substituted by C1-3Alkyl substituted C2-3Alkenyl radical, C0-3alkyl-C2-3Alkenyl and C1-3alkyl-NHC (O) -C2-3An alkenyl group;
Provided that when G is1when it is H, L1is absent, and when G2When it is H, L2Is absent.
Wherein,
Ar is a 5-or 6-membered monocyclic aromatic ring,
For example: furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzene, pyridine, pyrazine, pyrimidine, pyridazine, triazole,
Preferably: benzene, pyridine;
R1
Selected from H, halogen (preferably-Cl), -OH, -C1-4Alkyl radical, -C1-4An alkyl-oxy group, a carboxyl group,
m is an integer of 0,1, 2,3, 4, 5;
W1is CH, CR1or N;
W2Is CH, CR1Or N;
W3Is CH, CR1Or N;
W4Is CH, CR1Or N;
W5is CH, CR1Or N;
W6Is CH, CR1Or N;
W7Is CH, CR1Or N;
l is selected from: a bond, -O-, -NH-, -S-, -CH2-,-CH=CH-,-CH≡CH-,-C(CH3)H-, -C(CH3)2-,-C(CH2-CH2)-,-CClH-,-CCl2-, -CO-, -SO-, and-SO2-;
n is an integer of 0,1, 2,3, 4, 5;
R2
selected from H, halogen (preferably-Cl), -OH, -C1-4Alkyl radical, -C1-4An alkyl-oxy group, a carboxyl group,
R3Selected from H, -C1-4An alkyl group.
Technical scheme 2. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof,
Wherein G is2Is H, L2Is absent.
Technical scheme 3. the compound of any one of the aforementioned technical schemes, a salt thereof or a stereoisomer thereof,
Wherein W1,W2,W3,W4,W5,W6,W7Are all CH.
technical scheme 4. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof,
Wherein R is3is H.
technical scheme 5. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof,
wherein-N (G)1L1)(G2L2) is-NH-CO-C2-3an alkenyl group.
Technical scheme 6. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof,
Wherein Ar is phenyl.
Technical scheme 7. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof,
Wherein L is
Technical scheme 8. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, Ar or Ar- (R)1)mIs that
Technical scheme 9. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, Ar or Ar- (R)1)mIs that
Scheme 10. the compound of any of the preceding schemes, salts or stereoisomers thereof, Ar or Ar- (R)1)mIs that
Scheme 11. the compound of any of the preceding schemes, salts or stereoisomers thereof, Ar or Ar- (R)1)mIs that
Technical scheme 12. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, R2Or (R)2)nIs H.
technical scheme 13. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, R2Or (R)2)nIs that
Technical scheme 14. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, R2Or (R)2)nIs that
Technical scheme 15. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, R2Or (R)2)nIs that
Technical scheme 16. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, R2Or (R)2)nIs that
Technical scheme 17. the compound of any of the preceding technical schemes, a salt thereof or a stereoisomer thereof, R2Or (R)2)nis that
Technical scheme 18. the compound of any one of the preceding technical schemes, a salt thereof or a stereoisomer thereof, R2Or (R)2)nIs that
Technical scheme 19. a compound, a salt thereof, or a stereoisomer thereof, wherein the compound is selected from the following compounds 1-23:
Technical solution 20. a pharmaceutical composition comprising a compound of any one of the preceding technical solutions, a salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
Technical scheme 21 use of a compound of any one of the preceding technical schemes, a salt thereof, or a stereoisomer thereof, or a pharmaceutical composition of any one of the preceding technical schemes, in the manufacture of a medicament for treating a condition mediated by FGFR-4, a condition characterized by overexpression of FGFR-4, a condition characterized by amplification of FGFR4, a condition mediated by FGF19, a condition characterized by amplified FGF19, or a condition characterized by overexpression of FGF 19.
Technical solution 22 the use of any one of the preceding technical solutions, wherein the condition is hepatocellular carcinoma, breast cancer, ovarian cancer, lung cancer, liver cancer, sarcoma, or hyperlipidemia.
drawings
FIG. 1 illustrates the results of a "time-dependent inhibition experiment".
Detailed Description
In one aspect, the present invention provides a compound of formula (I) as described above (including stable isotope substitutes thereof), salts thereof, or stereoisomers thereof, which is an FGFR-4 selective inhibitor.
In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I (including stable isotopic substitutes thereof), or a pharmaceutically acceptable salt thereof, or a compound of formula II (including stable isotopic substitutes thereof), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include inert solid fillers or excipients and sterile aqueous or organic solutions. The compound should be present in the pharmaceutical composition in an amount sufficient to provide the desired dosage of the agent. Techniques for formulating and administering the compounds disclosed herein are well known to those skilled in the art and may be found, for example, in Remington: the Science and Practice of Pharmacy, Remington's pharmaceutical Science and Practice, 19 th edition, Mack publishing company, Easton, Pa (1995).
The invention provides the use of a compound of formula I (including stable isotopic surrogates thereof), or a pharmaceutically acceptable salt thereof, a compound of formula II (including stable isotopic surrogates thereof), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the treatment of a condition mediated by FGFR-4, a condition characterized by FGFR-4 overexpression, a condition characterized by FGFR4 amplification, a condition mediated by FGF19, a condition characterized by amplified FGF19, or a condition characterized by FGF19 overexpression; in particular the condition is hepatocellular carcinoma, breast cancer, ovarian cancer, lung cancer, liver cancer, sarcoma or hyperlipidemia.
as used herein, "alkyl" refers to a monovalent group of a saturated straight or branched chain hydrocarbon, such as a straight or branched chain group of 1-6, 1-4, or 1-3 carbon atoms. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-methyl-1-pentyl, 2-dimethyl-1-pentyl, 3-dimethyl-1-butyl, and, 2-ethyl-1-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like. In this context, an alkyl group is understood as a C1-6 alkyl group, if the upper and/or lower limit of the number of carbon atoms of the alkyl group is not specified. In this context, for example C0-3c in alkyl0Alkyl means a bond.
"alkenyl" as used herein refers to an aliphatic group containing at least one double bond.
"alkynyl" as used herein refers to a straight or branched hydrocarbon chain containing 2 to 12 carbon atoms and characterized by having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of an alkynyl substituent.
"amplification" as used herein means the production of additional copies of a gene or chromosome fragment in a cancer cell that may confer a growth or survival advantage.
As used herein, "aryl" or synonymous terms (e.g., aromatic ring) refer to 5-, 6-, and 7-membered monocyclic aromatic groups that may include 0 to 4 heteroatoms, e.g., furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzene, pyridine, pyrazine, pyrimidine, pyridazine, triazole, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics". The aromatic ring may be substituted at one or more ring positions with a substituent such as described above (e.g., halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, polycyclyl, hydroxyl, alkoxy, amino, nitro, thiol, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like).
As used herein, "-C- (CH2-CH2) -" refers to cyclopropylene.
any substitutable ring atom may be substituted (e.g., with one or more substituents).
"covalent inhibitor" as used herein means an inhibitor that can form a covalent bond with a protein.
"FGFR-4" or "FGFR-4 protein" refers to any form of FGFR-4 protein, including wild-type and all variant forms (including without limitation mutant forms and splice variants). The FGFR-4 protein is the product of the FGFR-4 gene, and thus the FGFR-4 protein includes any protein encoded by any form of the FGFR-4 gene, including all aberrations, e.g., point mutations, insertions/deletions, translocation fusions, and focal amplifications.
As used herein, "inhibitor" refers to a compound that inhibits an enzyme such that a decrease in enzyme activity is observable, for example, in biochemical assays.
In certain embodiments, the inhibitor has an IC50 of less than about 1 μ Μ, less than about 500nM, less than about 250nM, less than about 100nM, less than about 50nM or less than about 10 nM.
FGFR-4 inhibitors refer to compounds that inhibit FGFR-4.
As used herein, "overexpression" means that the yield of gene product in a sample is significantly higher than that observed in a control sample population (e.g., normal tissue).
by "selective" is meant that a compound inhibits the activity of a target protein (e.g., FGFR-4) more effectively than it inhibits the activity of other proteins. In this case, the isoforms FGFR-1, FGFR-2, FGFR-3 and FGFR-4 are all considered to be different proteins.
In some embodiments, a compound can inhibit the activity of a target protein (e.g., FGFR-4) at least 1.5-fold, at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least 1000-fold or more than it inhibits the activity of a non-target protein.
Whether preceded by the term "optionally", "substituted" or not, refers herein to moieties in which a hydrogen on one or more carbons of the backbone is replaced by a substituent. It is understood that "substitution" or "substitution with … …" includes the implicit proviso that such substitution is according to the allowed valences of the substituted atom and substituent, and that the substitution results in a stable compound, e.g., that it does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For suitable organic compounds, the permissible substituents can be one or more and the same or different. For purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and/or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatom. Substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thiocarbamate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidino, imino, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be appreciated by those skilled in the art that the substituted moiety on the hydrocarbon chain may itself be optionally substituted. For example, substituents for substituted alkyl groups may include amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamide, sulfamoyl, and sulfonate), and silyl groups in both substituted and unsubstituted forms, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like. Exemplary substituted alkyl groups are described below. Cycloalkyl groups may be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, and the like. Alkenyl and alkynyl groups can be similarly substituted to yield, for example, aminoalkenyl, aminoalkynyl, amidoalkenyl, amidoalkynyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, carbonyl-substituted alkenyl or alkynyl groups. As used herein, the definition of each expression (e.g., alkyl, m, n, etc.) appearing more than once in any structure is intended to be independent of its definition elsewhere in the same structure.
"sulfonyl" as used herein refers to-SO 2-.
"sulfonamide" as used herein refers to-S (O) -N (R1) (R)2) or-N (R1) -S (O) -R2Wherein R1 and R2Each independently is H orAn alkyl group.
The compounds described herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be treated with a radioactive isotope (such as for example tritium(s) (iii))3H) Or carbon-14 (14C) Is radiolabeled. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention. For example, deuterated compounds or compounds containing13Compounds of C are intended to be encompassed within the scope of the present invention.
Certain compounds may exist in different tautomeric forms, and all possible tautomeric forms of the compounds described herein are intended to be encompassed within the scope of the invention. The "enantiomeric excess" or "percent enantiomeric excess" of a composition can be calculated using the formula shown below. In the examples shown below, the compositions contain 90% of one enantiomer (e.g., the S-enantiomer) and 10% of the other enantiomer (i.e., the R-enantiomer).
ee=(90-10)/100=80%。
Thus, a composition containing 90% of one enantiomer and 10% of the other is said to have an enantiomeric excess of 80%. Some of the compositions described herein contain a compound (S-enantiomer) with an enantiomeric excess of at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In other words, the composition contains an enantiomeric excess of the S-enantiomer compared to the R-enantiomer.
Unless otherwise indicated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations (for each asymmetric center), Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The compounds described herein may be used as the free base or as a salt. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate salts, and the like. (see, e.g., Berge et al (1977) "Pharmaceutical Salts", J.pharm. Sci.66: 1-19.)
Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms (including hydrated forms). In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
Certain compounds disclosed herein can exist in multiple crystalline or amorphous forms.
In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
Pharmaceutical composition
although the compounds disclosed herein can be administered alone, the compounds are preferably administered as a pharmaceutical formulation, wherein the compounds are combined with one or more pharmaceutically acceptable excipients or carriers.
The compounds disclosed herein may be formulated for administration in any convenient manner for use in human or veterinary medicine.
In certain embodiments, the compounds included in the pharmaceutical formulation may be active themselves, or may be prodrugs capable of being converted to active compounds, for example, in a physiological environment.
In certain embodiments, the compounds provided herein include hydrates thereof.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Examples of pharmaceutically acceptable salts of the compounds described herein include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecylsulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate, and undecanoate.
Salts derived from suitable bases include alkali metal (e.g., sodium) salts, alkaline earth metal (e.g., magnesium) salts, ammonium salts, and N-(alkyl group)4 +And (3) salt. The present invention also contemplates the quaternization of any basic nitrogen-containing group of the compounds described herein. Water-or oil-soluble or dispersible products can be obtained by such quaternization.
Examples of pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) a phosphate buffer solution; (21) cyclodextrins, and (22) other non-toxic compatible materials used in pharmaceutical formulations, such as polymer-based compositions.
Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules, etc.) can include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; (8) adsorbents such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) a colorant.
Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
In addition to the active ingredients, the liquid dosage forms may contain inert diluents commonly used in the art (such as, for example, water or other solvents), solubilizing agents and emulsifiers (such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
Sprays can additionally contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.
the formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration.
The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
Dosage forms of the compounds of the invention for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants which may be required.
When administered as a medicament to humans and animals, the compounds disclosed herein can be administered as such or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.
The formulation may be administered topically, orally, transdermally, rectally, vaginally, parenterally (parentally), intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcuticularly, or by inhalation.
Indications of
FGFR-4 regulates proliferation, survival and α -fetoprotein secretion during hepatocellular carcinoma (HCC) progression; FGFR-4 inhibitors are therefore promising potential therapeutic agents for this unmet medical need (Ho et al, Journal of Hepatology,2009,50: 118-27).
HCC afflicts more than 550,000 people worldwide each year and is one of the worst 1-year survival rates among any type of cancer. The involvement of FGF19 (a Fibroblast Growth Factor (FGF) family member, which is composed of hormones) in the regulation of blood glucose, blood lipid and energy homeostasis shows additional evidence of a link between FGFR-4 and HCC. Increased hepatocyte proliferation and liver tumor formation have been observed in FGF19 transgenic mice. FGF19 activates FGFR-4, its major receptor in the liver, and FGFR-4 activation is believed to be the mechanism by which FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation (Wu et al, J Biol Chem (2010)285(8): 5165-5170). FGF19 has also been identified by others as a driver in HCC (Sawey et al, Cancer Cell (2011) 19: 347-358). Accordingly, the compounds disclosed herein, which are potential and selective inhibitors of FGFR-4, are believed to be useful in the treatment of HCC and other liver cancers. Tumor genome screening has identified the activated fibroblast growth factor receptor 4(FGFR-4) Y367C mutation in the human breast cancer cell line MDA-MB-453. Thus, it has been shown that FGFR-4 may be the driver of tumor growth in breast cancer (Roidl et al, Oncogene (2010)29(10): 1543-1552). Accordingly, the compounds disclosed herein, which are potent and selective inhibitors of FGFR-4, are believed to be useful in the treatment of FGFR-4 modulated breast cancer. Molecular changes (e.g., translocations) of genes upstream of FGFR-4 result in FGFR-4 activation/overexpression. For example, PAX3-FKHR translocation/gene fusion results in FGFR-4 overexpression. Thus, mechanistically induced overexpression of FGFR-4 is associated with Rhabdomyosarcoma (RMS) (Cao et al, Cancer Res (2010)70(16): 6497-. Mutations in FGFR-4 itself (e.g., kinase domain mutations) can lead to protein overactivation; this mechanism has been associated with the RMS subfamily (Taylor et al, J Clin Invest (2009)119: 3395-. Accordingly, the compounds disclosed herein, which are potent and selective inhibitors of FGFR-4, are believed to be useful in the treatment of FGFR-4 modulated RMS and other sarcomas. Other diseases are associated with changes in genes upstream of FGFR-4 or with mutations in FGFR-4 itself. For example, mutations in the kinase domain of FGFR-4 lead to overactivation, which is associated with lung adenocarcinoma (Ding et al, Nature (2008)455(7216): 1069-. Amplification of FGFR-4 is associated with pathologies such as renal cell carcinoma (TCGA transient data). In addition, silencing FGFR4 and inhibiting ligand-receptor binding significantly slowed ovarian tumor growth, suggesting that inhibitors of FGFR4 may be useful in the treatment of ovarian cancer. (Zaid et al, Clin. cancer Res. (2013) 809). The pathogenic elevation of bile acid levels is associated with changes in FGF19 levels (Vergnes et al, Cell Metabolism (2013)17,916-28). Thus, a reduced level of FGF19 may have a benefit in promoting bile acid synthesis and thus in the treatment of hyperlipidemia.
Dosage levels the actual dosage level of the active ingredient in the pharmaceutical compositions of the invention may be varied to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response, composition and mode of administration for a particular patient, and which is non-toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound disclosed herein or an ester, salt or amide thereof employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of the treatment, other drugs, compounds and/or substances used in combination with the particular compound employed, the age, sex, body weight, condition, general health and prior medical history of the patient to be treated, and like factors well known in the medical arts. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can begin administration of a compound of the invention for use in a pharmaceutical composition at a level below that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, an appropriate daily dose of a compound of the invention will be that amount of the lowest dose of the compound which is effective to produce a therapeutic effect. Such effective dosages will generally depend on the factors described above. Typically, the dose of a compound of the invention for a patient will be from about 0.0001mg to about 100mg per kilogram of body weight per day. For example, the dose may be between 10mg and 2000mg per day. Alternatively, the dose may be between 100mg and 1000mg per day, or between 200mg and 600mg per day. If desired, an effective daily dose of the active compound may be administered in one, two, three, four or more separately administered sub-doses at appropriate intervals throughout the day, optionally in unit dosage forms.
Combinations and targeted therapies the FGFR-4 inhibitors disclosed herein can be administered in combination with other cancer treatments. For example, the inhibitor may be administered in combination with surgical therapy, radiation or other therapeutic agents (such as antibodies), other selective kinase inhibitors, or chemotherapeutic agents. The inhibitor may also be administered in combination with RNAi therapy or antisense therapy. The FGFR-4 inhibitors described herein can be combined with one, two, or more other therapeutic agents. In the examples outlined below, it will be understood that "second therapeutic agent" also includes more than one therapeutic agent other than an FGFR-4 inhibitor. For example, the compounds disclosed herein may be combined with agents such as sorafenib. The FGFR-4 inhibitors described herein can be administered with one, two, or more other therapeutic agents. The FGFR-4 inhibitor and the second therapeutic agent described herein need not be administered in the same pharmaceutical composition and can be administered by different routes due to different physical and chemical properties. For example, the FGFR-4 inhibitor can be administered orally, while the second therapeutic agent is administered intravenously. The mode of administration and the determination of the rationality of the administration (if possible, in the same pharmaceutical composition) are well within the knowledge of the skilled clinician. Initial administration can be carried out according to established protocols known in the art, and the skilled clinician can then vary the dosage, mode of administration, and time of administration based on the observed effect. The FGFR-4 inhibitor and the second therapeutic agent can be administered simultaneously (e.g., simultaneously, substantially simultaneously or within the same treatment regimen) or sequentially (i.e., one after the other, with any time interval in between), depending on the nature of the proliferative disease, the condition of the patient, and the actual second therapeutic agent selected to be administered.
Additionally, the FGFR-4 inhibitors disclosed herein can be administered as part of an antibody-drug conjugate, wherein the FGFR-4 inhibitor is the "payload" portion of the conjugate.
Synthesis compounds of the invention (including salts and N-oxides thereof) may be prepared using known organic synthesis techniques and may be synthesized according to any of a number of possible synthetic routes, such as those in the schemes below. The reaction for preparing the compounds of the present invention may be carried out in a suitable solvent, which can be easily selected by one skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive with the starting materials (reactants), intermediates, or products at the temperatures at which the reaction is carried out (e.g., temperatures in the range of solvent freezing temperatures to solvent boiling temperatures). A given reaction may be carried out in one solvent or a mixture of more than one solvent. The skilled person can select a solvent suitable for a particular reaction step depending on the particular reaction step. The preparation of the compounds of the invention may involve the protection and deprotection of different chemical groups. The skilled person can easily decide whether protection and deprotection is required and the choice of appropriate protecting groups. The chemical nature of the protecting Groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4 th edition, John Wiley&Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety. The reaction may be monitored by any suitable method known in the art. For example, it can be determined by spectroscopic means, such as Nuclear Magnetic Resonance (NMR) spectroscopy (e.g.1H or13C) infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible light), Mass Spectrometry (MS)), or by chromatographic methods such as High Performance Liquid Chromatography (HPLC) or Thin Layer Chromatography (TLC).
The following examples are intended to be illustrative, and are not intended to be limiting in any way. The following schemes are intended to provide general guidance in connection with the preparation of the compounds of the present invention. It will be appreciated by those skilled in the art that modifications or optimisation of the preparation shown in the schemes may be made using common general knowledge of organic chemistry to prepare the compounds of the invention.
Synthetic examples
All reagents used herein were commercially available and were not purified, unless otherwise specified. The solvent was re-evaporated before use. The reaction was monitored on a thin layer silica gel plate (TLC, GF254,60-F250,0.2mm, Tintario silica gel thin layer chromatography). The flash column chromatography is carried out by using chemical silica gel (ZCX-II, 200-300 meshes) of the department of spectrometry. NMR was measured using a Bruker Advance 400 (1H: 400 MHz; 13C: 100MHz) or Bruker Advance 500 (1H: 500 MHz; 13C: 125MHz) nuclear magnetic resonance apparatus with TMS as an internal standard. High Resolution Mass Spectrometry (HRMS) was performed using an ABI Q-star Elite high resolution mass spectrometer; detection of end product purity the wavelength was determined to be 254 nm using a High Performance Liquid Chromatography (HPLC) Agilent 1260 series chromatograph (Agilent PN959990-902Eclipse Plus C18 (250 mm. times.4.6 mm) column).
The abbreviations used in the following examples are explained by the conventional meanings in the field of organic synthesis, for example, the following abbreviations have the following meanings.
ArCHO | Aryl aldehydes (optionally substituted) |
Boc | tert-butoxycarbonyl group |
DCM | Methylene dichloride |
DDQ | 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone |
DIEA | N, N-diisopropylethylamine |
DMAP | 4-dimethylaminopyridine |
DMF | Dimethyl formamide |
DMSO | Dimethyl sulfoxide |
EA | Ethyl acetate |
Et3N | Triethylamine |
Et3SiH | Triethylsilane |
EtOAc | Ethyl acetate |
m-CPBA | Meta-chloroperoxybenzoic acid |
MeOH | Methanol |
NIS | N-iodosuccinimide |
Pd(dppf)Cl2 | [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride |
Ac | Acetyl group |
Ph | Phenyl radical |
Pd2(dba)3 | Tris (dibenzylideneacetone) dipalladium (0) |
SEM-Cl | 2- (trimethylsilyl) ethoxymethyl chloride |
TFA | Trifluoroacetic acid |
THF | tetrahydrofuran (THF) |
X-phos | 2-dicyclohexylphosphonium-2 ', 4 ', 6 ' -triisopropylbiphenyl |
Xant-phos | 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene |
Scheme I
Conditions and reagents:
(a) 2-nitroaniline, Pd2(dba)3,X-phos,K2CO31, 4-dioxane, 110 ℃, and standing overnight;
(b) NIS, DMF, room temperature;
(c) (3, 5-Dimethoxyphenyl) boronic acid, Pd (dppf) Cl2H2O-3: 1,100 ℃, microwave 1H,
(d)H2Pd/C, EtOAc, room temperature;
(e) Acryloyl chloride, DIEA, THF,0 deg.C, then room temperature
Conditions and reagents:
Pd2(dba)3,X-phos,K2CO31, 4-dioxane, 110 ℃ overnight
n- (2-Nitrophenyl) -1H-pyrrolo [2,3-b]pyridin-6-amine (I1): mixing 6-chloro-7-azaindole (0.50g, 3.3mmol), 2-nitroaniline (0.50g, 3.6mmol) and Pd2(dba)3(0.30g, 0.33mmol), X-Phos (0.31g, 0.66mmol), and potassium carbonate (0.91g, 6.6mmol) were dissolved in anhydrous 1, 4-dioxane (25mL) and deoxygenated by passing argon through. The reaction mixture was stirred at 110 ℃ overnight, cooled to room temperature, filtered, extracted with water and ethyl acetate (3X 60 mL), the organic phase was collected, washed with saturated brine (2X 30mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give a yellow solid 0.49gThe yield was 58%.1H NMR (400MHz, chloroform-d) δ 10.24(s,1H),9.03(s,1H),8.61(dd, J ═ 8.8,1.3Hz,1H), 8.25(dd, J ═ 8.5,1.7Hz,1H),7.91(d, J ═ 8.3Hz,1H),7.52(ddd, J ═ 8.7,7.0,1.6Hz,1H),7.11(dd, J ═ 3.6,2.4, 1H),6.91(ddd, J ═ 8.4, 7.0,1.3Hz,1H),6.85(d, J ═ 8.3Hz,1H),6.47(dd, J ═ 3.6,2.1, 1H).13C NMR(101MHz,CDCl3)δ148.33,146.67,140.00,135.76,131.27, 126.44,123.25,119.00,118.90,115.88,108.62,101.61.
Conditions and reagents: NIS, DMF, Room temperature
3-iodo-N- (2-nitrophenyl) -1H-pyrrolo [2,3-b]pyridin-6-amine (I2): compound I1 (0.39g, 1.6mmol) was dissolved in anhydrous DMF (4.0mL) and NIS (0.38g, 1.7mmol) was added with stirring at 0 ℃. After the reaction mixture was stirred at room temperature for 2 hours, it was diluted with water, extracted with ethyl acetate (3X 80mL), and the organic phase and the brine (2X 40mL) were collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.37g of a yellow solid with a yield of 61%.1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),9.81(s,1H),8.32(d,J= 8.4Hz,1H),8.07(dd,J=8.5,1.6Hz,1H),7.67-7.63(m,1H),7.59(d,J =8.4Hz,1H),7.42(d,J=2.5Hz,1H),7.06(t,J=7.5Hz,1H),6.91(d, J=8.4Hz,1H).13C NMR(101MHz,DMSO)δ150.34,146.22,137.82, 137.34,135.52,130.95,128.30,126.21,121.71,120.91,117.51,108.35, 55.14.
Conditions and reagents: pd (dppf) Cl2H2O ═ 3:1,100 ℃ in 1, 4-dioxane, microwave, 1H
3- (3, 5-Dimethoxyphenyl) -N- (2-nitrophenyl) -1H-pyrrolo [2,3-b]pyridin-6-amine (I3): compound I2(0.15g, 0.39mmol), 3, 5-dimethoxyphenylboronic acid (0.11g, 0.59mmol), Pd (dppf) Cl2(0.39g, 1.6mmol) and potassium carbonate (0.16g, 1.2mmol) were dissolved in a mixed solvent (4mL) of 1, 4-dioxane and water (3: 1), and argon gas was introduced to remove oxygen. The reaction solution was reacted in a microwave reactor at 100 ℃ for 1 hour, cooled to room temperature, filtered, and the filtrate was extracted with water and ethyl acetate (3 × 40mL), and the organic phase was collected, washed with saturated brine (2 × 20mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 61mg of a yellow solid with a yield of 40%.1H NMR(400MHz,DMSO-d6) δ11.67(s,1H),9.84(s,1H),8.40(d,J=8.6Hz,1H),8.19(d,J=8.5Hz, 1H),8.09(d,J=8.4Hz,1H),7.64(d,J=10.6Hz,2H),7.05(t,J=7.8 Hz,1H),6.94(d,J=8.4Hz,1H),6.89-6.64(m,2H),6.50-6.26(m, 1H),3.79(s,6H).13C NMR(101MHz,DMSO)δ161.34,149.29,147.33, 138.27,137.60,136.79,135.63,130.62,126.27,122.24,121.32,120.52,115.43,113.00,107.97,104.67,98.32,55.69.
Conditions and reagents: h2Pd/C, EtOAc, room temperature;
N1- (3- (3, 5-dimethoxyphenyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) benzene-1, 2-diamine (I4): compound I3(61mg, 0.16mmol) was dissolved in ethyl acetate, reduced with 10% Pd/C, hydrogen (1atm) and stirred at room temperature overnight, filtered, the filtrate collected and concentrated to give intermediate I4(36mg) as a white solid which was used in the next reaction without further purification.
conditions and reagents: DIEA, THF,0 deg.C, then room temperature
N- (2- ((3- (3, 5-dimethoxyphenyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (1): compound I4(36mg, 0.10mmol) was dissolved in tetrahydrofuran (2.0mL), DIEA (33. mu.L, 0.20mmol) and acryloyl chloride (9.7. mu.L, 0.12mmol) were added sequentially in an ice-water bath, and reacted at room temperature for 30 min. After concentration, water (10mL) and ethyl acetate (3X 10mL) were added for extraction, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 25mg of a white solid with a yield of 61%.1H NMR(400MHz,DMSO-d6)δ11.46(d,J=2.6Hz,1H),9.81(s,1H), 8.12(s,1H),8.06(d,J=8.6Hz,1H),7.88-7.77(m,1H),7.63-7.55(m,1H),7.50(d,J=2.5Hz,1H),7.15(td,J=7.7,1.6Hz,1H),7.02(td,J= 7.7,1.5Hz,1H),6.76(d,J=2.3Hz,2H),6.69(d,J=8.6Hz,1H),6.47 (dd,J=17.0,10.1Hz,1H),6.35(t,J=2.2Hz,1H),6.23(dd,J=17.0, 2.0Hz,1H),5.72(dd,J=10.1,2.0Hz,1H),3.78(s,6H).13C NMR(101 MHz,DMSO)δ164.14,161.30,152.47,147.99,137.98,135.08,132.51, 130.31,129.72,127.14,125.81,125.39,122.74,122.65,120.46,115.38, 110.92,105.41,104.55,98.08,55.66.HRMS(ESI)m/z C24H22N4O3 [M+H]+414.1692; found 415.1767.
Scheme II
Conditions and reagents:
(a) 3-methoxybenzaldehyde, NaOH, DMSO, air, 100 ℃;
(b) SEM-Cl, NaH, DMF,0 deg.C, then room temperature;
(c) 2-nitroaniline, Pd2(dba)3,X-phos,K2CO31, 4-dioxane, 110 ℃, and standing overnight;
(d)i)TFA/DCM,ii)K2CO3MeOH, room temperature;
(e) m-CPBA, DCM, room temperature;
(f)H2Pd/C, EtOAc, room temperature;
(g) acryloyl chloride, DIEA, THF,0 deg.C, then room temperature
Conditions and reagents: NaOH, DMSO, air, 100 deg.C
6-chloro-3- ((3-methoxyphenyl) thio) -1H-pyrrolo [2,3-b]Pyridine (I5): 6-chloro-7-azaindole (0.3g, 2.0mmol) was dissolved in DMSO (5.0mL), and sodium hydroxide (0.16g, 3.9mmol) and 3-methoxythiophenol (0.55g, 0.49mL, 3.9mmol) were added in that order. The reaction solution was heated to 100 ℃ and stirred under air atmosphere overnight, after the completion of TLC monitoring, water (50mL) was added for dilution, ethyl acetate (3X 50mL) was extracted, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 0.52 g of a white solid with a yield of 89%.1H NMR(400MHz,DMSO)δ12.51(s,1H),7.98(d,J= 2.5Hz,1H),7.82(d,J=8.2Hz,1H),7.22-7.16(m,1H),7.16-7.10(m, 1H),6.68(ddd,J=8.2,2.3,1.0Hz,1H),6.58(ddd,J=2.5,1.9,1.0Hz, 2H),3.64(s,3H).13C NMR(101MHz,DMSO)δ160.18,148.21,144.68, 140.11,134.40,130.53,130.47,120.53,118.37,117.07,111.84,111.24, 99.91,55.54.
Conditions and reagents: SEM-Cl, NaH, DMF,0 deg.C, then room temperature
6-chloro-3- ((3-methoxyphenyl) thio) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridine (I6): compound I5(0.10g, 0.35mmol) was dissolved in anhydrous DMF (2.0mL) and 60% sodium hydride (0.021g, 0.53mmol) was added with stirring at 0 ℃. The reaction solution is stirred for 30min at the temperature of 0 ℃,SEM-Cl (0.087g, 0.093 mL, 0.53mmol) was added and the mixture was warmed to room temperature and stirred for 2 h. The reaction was monitored by TLC for completion, diluted with water (10mL), extracted with ethyl acetate (3X 10mL), the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.14g of a colorless oily liquid in 95% yield.1H NMR (500MHz,CDCl3)δ7.79(d,J=8.2Hz,1H),7.61(s,1H),7.13(d,J= 8.2Hz,1H),7.10(dd,J=8.8,7.8Hz,1H),6.68-6.62(m,3H),5.67(s, 2H),3.70(s,3H),3.62-3.57(m,2H),0.97-0.91(m,2H),-0.05(s,9H).13C NMR(101MHz,CDCl3)δ160.06,147.64,146.11,139.44,134.03, 130.61,129.81,120.59,118.65,117.71,112.13,110.88,102.66,73.13, 66.85,55.24,17.82,-1.37.
Conditions and reagents: pd2(dba)3,X-phos,K2CO31, 4-dioxane, 110 ℃ overnight
3- ((3-methoxyphenyl) thio) -N- (2-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-6-amine (I7): mixing compound I6(0.14g, 0.33mmol), 2-methyl-6-nitroaniline (0.051g, 0.37mmol), Pd2(dba)3(0.030 g, 0.033mmol), X-Phos (0.032g, 0.067mmol), and potassium carbonate (0.0.093g, 0.67mmol) were dissolved in anhydrous 1, 4-dioxane (4.0mL), and argon was passed through to remove oxygen. The reaction mixture was stirred at 110 ℃ overnight, cooled to room temperature, filtered, and the filtrate was extracted with water (20mL) and ethyl acetate (3X 20mL), the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give a yellow solid (0.15g, 87% yield).
1H NMR(400MHz,CDCl3)δ10.39(s,1H),8.96(dd,J=8.7,1.1 Hz,1H),8.26(dd,J=8.6,1.6Hz,1H),7.83-7.77(m,1H),7.58(ddd,J =8.6,7.1,1.5Hz,1H),7.50(s,1H),7.13-7.07(m,1H),6.96(ddd,J= 8.4,7.1,1.3Hz,1H),6.81(d,J=8.4Hz,1H),6.72-6.69(m,1H),6.69- 6.67(m,1H),6.64(ddd,J=8.2,2.4,0.7Hz,1H),5.66(s,2H),3.70(s, 3H),3.65-3.60(m,2H),0.97-0.92(m,2H),-0.08(s,9H).13C NMR (101MHz,CDCl3)δ160.04,149.67,146.91,139.97,139.34,135.61, 134.56,132.15,130.51,129.75,126.44,119.53,119.42,118.55,117.05, 111.99,110.72,109.11,102.55,73.24,66.71,55.25,17.82,-1.38.
Conditions and reagents: i) TFA/DCM; ii) K2CO3MeOH, room temperature;
3- ((3-methoxyphenyl) thio) -N- (2-nitrophenyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-amine (I8): compound I7(0.63g, 1.20mmol) was dissolved in dichloromethane (3.0mL) and trifluoroacetic acid (3.0mL) was added. The reaction mixture was stirred at room temperature for 5 hours, and the solid obtained after concentration was dissolved in methanol (3.0mL), and potassium carbonate was added to adjust the pH to 12, followed by stirring at room temperature overnight. After the completion of the TLC monitoring reaction, concentration was carried out, water (20mL) and ethyl acetate (3X 20mL) were added for extraction, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 100mg of a yellow solid with a yield of 21%.1H NMR(400MHz,DMSO-d6) δ11.99(d,J=2.6Hz,1H),9.81(s,1H),8.38(dd,J=8.6,1.3Hz,1H), 8.08(dd,J=8.4,1.6Hz,1H),7.69(d,J=8.4Hz,1H),7.66-7.62(m, 2H),7.13(t,J=8.0Hz,1H),7.07(ddd,J=8.4,7.1,1.3Hz,1H),6.91(d, J=8.5Hz,1H),6.66(ddd,J=8.3,2.5,1.0Hz,1H),6.61-6.56(m,1H), 3.63(s,3H).13C NMR(101MHz,DMSO)δ160.16,150.27,147.21, 140.78,137.86,137.28,135.54,131.04,130.43,129.68,126.22,121.72,120.90,118.23,116.35,111.71,110.94,108.48,99.51,55.53.
conditions and reagents: h2Pd/C, EtOAc, room temperature
N1- (3- ((3-methoxyphenyl) thio) -1H-pyrrolo [2,3-b ] pyridin-6-yl) benzene-1, 2-diamine (I9): compound I8(100mg, 0.25mmol) was dissolved in ethyl acetate, reduced with 10% Pd/C, hydrogen (1atm) and stirred overnight at room temperature, filtered, the filtrate collected and concentrated to give intermediate I9(69mg) as a white solid which was used in the next reaction without further purification.
Conditions and reagents: DIEA, THF,0 deg.C, then room temperature
N- (2- ((3- ((3-methoxyphenyl) thio) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (2): compound I9(69mg, 0.19mmol) was dissolved in tetrahydrofuran (2.0mL), DIEA (63. mu.L, 0.38mmol) and acryloyl chloride (18. mu.L, 0.23mmol) were added sequentially in an ice-water bath, and reacted at room temperature for 30 min. After concentration, water (10mL) and ethyl acetate (3X 10mL) were added for extraction, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give a yellowish solid 23mg with a yield of 29%. 1H NMR (400MHz, DMSO-d6) δ 11.78(d, J ═ 2.6Hz,1H),9.74(s,1H), 8.16(s,1H),7.81(dd, J ═ 8.1,1.5Hz,1H),7.60(d, J ═ 7.9Hz,1H),7.55(d, J ═ 8.5Hz,1H),7.48(d, J ═ 2.4Hz,1H),7.19-7.07(m,2H),7.03(td, J ═ 7.6,1.5Hz,1H),6.69-6.61(m,2H),6.60-6.53(m,2H),6.47 (esi, J ═ 17.0,10.2Hz,1H),6.22 (ddl, 17.22, 17.19, 17.42 MHz), 19-6.52H, 19 (hrddh), 19H), 19 (19, 3.19H), 19H), 7.6.6.6.6.19 (esi, 1H), 1H, 18 (mr, 17.22, 17.3.3, 18H), 1.3.3.3.3, 18H), 3.3, 18H, 18H23H20N4O2S[M+H]+416.1307; found 417.1382.
Conditions and reagents: m-CPBA, DCM, RT
3- ((3-methoxyphenyl) sulfinyl) -N- (2-nitrophenyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-amine (I10): compound I8(0.29g, 0.73mmol) was dissolved in dichloromethane (5.0mL) and m-CPBA (0.13g, 0.73mmol) was added. The reaction was stirred at room temperature for 2 h. TLC to monitor the reaction completion, add saturated sodium thiosulfate solution (10mL) to quench the reaction, extract with dichloromethane (3X 30mL), collect the organic phaseWashed with saturated brine (2X 20mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 175mg of a yellow solid in 59% yield. MS (ESI) 409[ M + H]+.
Conditions and reagents: m-CPBA, DCM, RT
3- ((3-methoxyphenyl) sulfonyl) -N- (2-nitrophenyl) -1H-pyrrolo [2,3-b]Pyridin-6-amine (I11): compound I8(0.11g, 0.28mmol) was dissolved in dichloromethane (3.0mL) and m-CPBA (0.12g, 0.28mmol) was added. The reaction was stirred at room temperature for 2 h. After completion of the reaction was monitored by TLC, the reaction was quenched by addition of saturated sodium thiosulfate solution (10mL), extracted with dichloromethane (3X 30mL), and the organic phase was collected, washed with saturated brine (2X 20mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 67mg of a yellow solid in 57% yield.1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),8.18(dd,J=8.5,1.3Hz, 1H),8.09(d,J=8.6Hz,1H),8.07-8.01(m,2H),7.64(ddd,J=8.6,7.2, 1.6Hz,1H),7.55(dt,J=7.8,1.3Hz,1H),7.50(d,J=8.0Hz,1H),7.46 (dt,J=2.6,1.6Hz,1H),7.18(ddd,J=8.1,2.6,1.1Hz,1H),7.12(ddd,J =8.4,7.1,1.3Hz,1H),7.01(d,J=8.6Hz,1H),3.81(s,3H).13C NMR (101MHz,DMSO)δ160.06,151.34,146.73,145.01,138.54,136.81, 135.28,131.28,130.08,129.58,126.09,122.59,121.72,119.14,118.93, 114.82,111.78,110.70,109.62,56.19.
N- (2- ((3- ((3-methoxyphenyl) sulfinyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) amino) phenyl) acrylamide (3): the synthesis method is the same as that of the compound 2.
1H NMR(400MHz,DMSO-d6)δ12.03(d,J=2.9Hz,1H),9.68(s, 1H),8.19(s,1H),7.87(d,J=2.8Hz,1H),7.73(dd,J=8.3,1.5Hz,1H), 7.66-7.58(m,1H),7.45-7.37(m,2H),7.23(dd,J=2.6,1.5Hz,1H), 7.18-7.09(m,2H),7.09-6.99(m,2H),6.55(d,J=8.7Hz,1H),6.47 (dd,J=17.0,10.2Hz,1H),6.22(dd,J=17.0,2.0Hz,1H),5.71(dd,J=10.1,2.0Hz,1H),3.78(s,3H).13C NMR(101MHz,DMSO)δ164.17, 160.20,153.71,148.30,147.22,134.24,132.44,130.72,130.41,129.83, 127.43,127.20,125.72,125.21,123.68,123.32,116.94,116.61,116.21, 109.87,108.63,106.31,55.95.
N- (2- ((3- ((3-methoxyphenyl) sulfonyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) amino) phenyl) acrylamide (4): the synthesis method is the same as that of the compound 2. White solid 16mg, yield 42%.
1H NMR(400MHz,DMSO-d6)δ12.37(d,J=3.0Hz,1H),9.69(s, 1H),8.31(s,1H),7.97(d,J=8.6Hz,1H),7.92(d,J=3.0Hz,1H),7.75 (dd,J=8.1,1.5Hz,1H),7.64(d,J=8.0Hz,1H),7.56-7.46(m,2H), 7.44(dd,J=2.6,1.6Hz,1H),7.22-7.13(m,2H),7.07(td,J=7.6,1.6 Hz,1H),6.78(d,J=8.7Hz,1H),6.49(dd,J=17.0,10.2Hz,1H),6.24 (dd,J=17.0,2.0Hz,1H),5.72(dd,J=10.2,2.0Hz,1H),3.81(s,3H).13C NMR(101MHz,DMSO)δ164.17,160.01,154.10,147.54,145.21, 134.07,132.42,131.22,130.56,129.62,128.14,127.20,125.73,125.21, 123.81,123.51,118.99,118.85,114.64,111.70,108.91,107.50,56.18. HRMS(ESI)m/z C23H20N4O4S[M+H]+448.1205; found 449.1279.
Scheme III
conditions and reagents:
(a) NIS, DMF, room temperature, 1 h;
(b)Boc2O, DMAP, DCM, room temperature;
(c) 1-ethynyl-3, 5-dimethoxybenzene, CuI, Pd (PPh)3)2Cl2,Et3n, DCM at room temperature for 16 h;
(d) 2-nitroaniline, Pd (AcO)2,Xant-phos,Cs2CO31, 4-dioxane, 100 ℃, and staying overnight;
(e)SnCl2EtOAc, reflux;
(f) Acryloyl chloride, DIEA, THF,0 deg.C, then room temperature
Conditions and reagents: NIS, DMF, RT, 1h
6-chloro-3-iodo-1H-pyrrolo [2,3-b]Pyridine (I14): compound 7-azaindole (0.20g, 1.3mmol) was dissolved in anhydrous DMF (5.0mL) and NIS (0.32g, 1.4mmol) was added with stirring at 0 ℃. After the reaction mixture was stirred at room temperature for 1 hour, it was diluted with water, extracted with ethyl acetate (3X 80mL), and the organic phase was collected, washed with brine (2X 40mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.31g of a yellow solid with a yield of 85%.1H NMR(400MHz,DMSO)δ12.33(s,1H),7.97-7.52(m,2H),7.19(d, J=8.2Hz,1H).13C NMR(101MHz,DMSO)δ147.23,144.70,131.80, 131.76,121.64,116.80,55.24.
conditions and reagents: boc2O, DMAP, DCM, at room temperature
6-chloro-3-iodo-1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester (I15): compound I14(0.31g, 1.1mmol) was dissolved in DCM and Boc was added sequentially2O (0.36g, 0.38mL, 1.7mmol), DMAP (0.007g, 0.056mmol), stirring at room temperature for 2h, concentrating, extracting with water and ethyl acetate, collecting the organic phase, washing with brine (2 × 40mL), drying over anhydrous sodium sulfate, concentrating, and purifying by column chromatography to give a yellow solid 0.41g, 96% yield.1H NMR(400MHz,CDCl3)δ7.79(s,1H),7.65(d,J=8.2Hz,1H),7.29(d, J=8.2Hz,1H),1.67(s,9H).13C NMR(101MHz,CDCl3)δ147.95, 146.69,145.93,132.08,131.11,124.07,119.82,85.40,61.25,28.12.
Conditions and reagents: CuI, Pd (PPh)3)2Cl2,Et3N, DCM, RT, 16h
6-chloro-3- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester (I16): mixing compound I15(0.10g, 0.26mmol), 3, 5-dimethoxyphenylacetylene (0.047g, 0.29mmol), Pd (PPh)3)2Cl2(0.018g,0.026mmol)、CuI(0.010g,0.052mmol)、Et3N (0.031g, 43. mu.L, 0.32mmol) was dissolved in dry dichloromethane (3.0mL) and purged with argon to remove oxygen. The reaction mixture was stirred at room temperature for 16h, cooled to room temperature, filtered, and the filtrate was extracted with water (20mL) and dichloromethane (3 × 20mL), and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.074g of a yellow solid, with a yield of 69%.1H NMR (500MHz, chloroform-d) δ 8.00(d, J ═ 8.1Hz,1H),7.88(s,1H),7.31(d, J ═ 8.2Hz,1H),6.70(d, J ═ 2.3Hz,2H),6.49(t, J ═ 2.2Hz,1H),3.82(s,6H),1.69(s,8H) ms (esi):413[ M + H esi ]]+.
conditions and reagents: pd (AcO)2,Xant-phos,Cs2CO31, 4-dioxane, 100 ℃ overnight
3- ((3, 5-Dimethoxyphenyl) ethynyl) -6- ((2-nitrophenyl) amino) -1H-pyrrolo [2,3-b]pyridine-1-carboxylic acid tert-butyl ester (I17): mixing compound I16(0.074g, 0.18mmol), 2-nitroaniline (0.027g, 0.20mmol), Pd (OAc)2(0.004g, 0.018mmol), Xant-Phos (0.021g, 0.036mmol), and cesium carbonate (0.12g, 0.36mmol) were dissolved in anhydrous 1, 4-dioxane (4.0mL) and purged with argon to remove oxygen. The reaction mixture was stirred at 100 ℃ overnight, cooled to room temperature, filtered, and the filtrate was extracted with water (20mL) and ethyl acetate (3X 20mL), the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.045g of a yellow solid in 48% yield.1H NMR (400MHz, chloroform-d) δ 10.60(s,1H),9.32(dd, J ═ 8.8,1.3Hz,1H),8.26(dd, J ═ 8.6,1.6Hz,1H),7.99(d, J ═ 8.4Hz,1H),7.80(s, 1H), and the like),7.66(ddd,J= 8.7,7.1,1.7Hz,1H),7.00-6.97(m,1H),6.94(d,J=8.4Hz,1H),6.72 (d,J=2.3Hz,2H),6.49(t,J=2.3Hz,1H),3.82(s,6H),1.69(s,9H).13C NMR(101MHz,CDCl3)δ160.70,150.82,147.58,145.50,139.17, 136.33,134.49,130.76,127.94,126.33,124.40,119.82,119.64,117.84, 110.29,109.46,101.96,101.11,92.76,84.74,80.32,55.55,28.30.
Conditions and reagents: SnCl2EtOAc, reflux
N1- (3- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-6-yl) benzene-1, 2-diamine (I18): compound I17(0.045g, 0.087mmol) was dissolved in ethyl acetate and SnCl was added2(0.084g, 0.44mmol), refluxing and stirring for 2h, cooling to room temperature, adding saturated sodium bicarbonate to dissolve in the quenching reaction, filtering, adding ethyl acetate into the filtrate for extraction, collecting the organic phase, washing with water, washing with saturated saline, and concentrating to obtain intermediate I9(37mg), which can be used in the next reaction without purification. MS (ESI) 385M + H]+.
Conditions and reagents: DIEA, THF,0 deg.C, then room temperature
N- (2- ((3- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2, 3-b)]pyridin-6-yl) amino) phenyl) acrylamide (5): compound I18(37mg, 0.098mmol) was dissolved in tetrahydrofuran (2.0mL), and DIEA (33. mu.L, 0.20mmol) and acryloyl chloride (9.5. mu.L, 0.12mmol) were added in this order under an ice-water bath and reacted at room temperature for 30 min. After concentration, water (10mL) and ethyl acetate (3X 10mL) were added for extraction, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 10mg of a white solid with a yield of 23%.1H NMR(500MHz,DMSO-d6)δ11.68(d,J=2.7Hz,1H),9.76 (s,1H),8.19(s,1H),7.88(d,J=8.5Hz,1H),7.84(d,J=8.0Hz,1H),7.61(d,J=8.0Hz,1H),7.51(d,J=2.4Hz,1H),7.20-7.14(m,1H), 7.04(td,J=7.6,1.5Hz,1H),6.73(d,J=8.5Hz,1H),6.68(d,J=2.3Hz, 2H),6.54-6.44(m,2H),6.24(dd,J=17.1,1.9Hz,1H),5.73(dd,J= 10.2,2.0Hz,1H),3.77(s,6H).MS(ESI):439[M+H]+.
Scheme IV
Conditions and reagents:
(a)TFA,Et3SiH, CH3CN, room temperature, 2 h;
(b) NaH, SEM-Cl,0 ℃ and then room temperature;
(c) 2-nitroaniline, Pd2(dba)3,X-phos,K2CO31, 4-dioxane, 110 ℃, and standing overnight;
(d)SnCl2EtOAc, reflux;
(e) Acryloyl chloride, DIEA, THF,0 deg.C, then room temperature
Conditions and reagents: TFA, Et3SiH, CH3CN, room temperature, 2h
6-chloro-3- (3, 5-dimethoxybenzyl) -1H-pyrrolo [2,3-b]Pyridine (I19): compound I24b (0.50g, 1.5mmol) was dissolved in acetonitrile (20mL) and trifluoroacetic acid (0.67 mL, 9.0mmol) and Et were added3SiH (0.74mL, 6.0 mmol). After stirring at room temperature for 2 hours, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (50mL), extracted with ethyl acetate (3X 50mL), the organic phase was collected and washed with saturated brine (3X 30mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.11g of a white solid with a yield of 24%. MS (ESI) 303[ M + H]+.
The remaining synthesis steps b-d for compound 6 are analogous to compound 5.
Conditions and reagents: DIEA, THF,0 deg.C, then room temperature
N- (2- ((3- (3, 5-dimethoxybenzyl) -1H-pyrrolo [2, 3-b)]pyridin-6-yl) amino) phenyl) acrylamide (6): white solid 8mg, yield 19%.1H NMR(400MHz, DMSO-d6)δ10.95(d,J=2.3Hz,1H),9.81(s,1H),7.97(s,1H),7.77(d, J=8.0Hz,1H),7.62(d,J=8.4Hz,1H),7.55(d,J=7.9Hz,1H),7.16- 7.09(m,1H),6.99(td,J=7.6,1.5Hz,1H),6.91(d,J=2.3Hz,1H),6.54 (d,J=8.5Hz,1H),6.49-6.37(m,3H),6.28(t,J=2.3Hz,1H),6.22(dd, J=17.0,2.0Hz,1H),5.71(dd,J=10.1,2.0Hz,1H),3.86(s,2H),3.67 (s,6H).13C NMR(101MHz,DMSO)δ164.12,160.88,152.22,147.57, 144.52,135.37,132.49,129.55,127.13,125.82,125.38,122.48,122.42, 119.97,113.49,113.03,107.13,104.18,97.91,55.55,32.08.HRMS(ESI)m/z C25H24N4O3[M+H]+428.4920; found 429.1924.
Scheme V
for I24-I29 and the product, R1 is 3-methoxy, 3, 5-dioxy, or 2, 6-dichloro-3, 5-dioxy; r2H or CH3.
conditions and reagents:
(a) ArCHO, KOH, MeOH, overnight;
(b) DDQ, H2O/1, 4-dioxane, room temperature, 2H;
(c) NaH, SEM-Cl,0 ℃ and then room temperature;
(d) 2-nitroaniline or 2-methyl-6-nitroaniline, Pd2(dba)3,X-phos,K2CO31, 4-dioxane, 110 ℃, and standing overnight;
(e) i) TFA, DCM, room temperature; ii) K2CO3MeOH, room temperature;
(f)H2Pd/C, EtOAc, room temperature or SnCl2EA, reflux;
(g) Acryloyl chloride, DIEA, THF,0 degrees celsius, then room temperature.
Conditions and reagents: KOH, MeOH, room temperature
(6-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl) (3, 5-dimethoxyphenyl) methanol (I24 b): 6-chloro-7-azaindole (2.0g, 13mmol) was dissolved in methanol (65mL), and potassium hydroxide (2.9g, 52mmol) and 3, 5-dimethoxybenzaldehyde (2.4g, 14mmol) were added in that order. The reaction solution was stirred overnight at room temperature, after TLC monitoring of the reaction, 4N hydrochloric acid was added to adjust the pH to 7, after concentration, ethyl acetate (3X 200mL) and water were added for extraction, the organic phase was collected and washed with saturated brine (3X 80mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 3.7g of a white solid with 89% yield.1H NMR(500MHz,DMSO)δ11.66 (s,1H),7.89(d,J=8.2Hz,1H),7.30(d,J=2.3Hz,1H),7.04(d,J=8.2 Hz,1H),6.61(d,J=2.2Hz,2H),6.34(t,J=2.3Hz,1H),5.84(d,J= 4.5Hz,1H),5.75(d,J=4.5Hz,1H),3.69(s,6H).13C NMR(126MHz, DMSO)δ160.69,148.22,148.00,143.35,131.32,123.94,119.27,117.25, 115.17,104.81,98.84,69.11,55.54.
Conditions and reagents: DDQ,1, 4-dioxane/H2O, Room temperature, 2H
(6-chloro-1H-pyrrolo [2,3-b ]]Pyridin-3-yl) (3, 5-dimethoxyphenyl) methanone (I25 b): compound I24b (0.65g, 2.0mmol) was dissolved in 1, 4-dioxane (20mL) and DDQ (0.74g, 3.3mmol) and water (0.80mL) were added sequentially. After stirring at room temperature for 2 hours, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (50mL), extracted with ethyl acetate (3X 50mL), the organic phase was collected and washed with saturated brine (3X 30mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.51g of a white solid with a yield of 81%.1H NMR (400MHz,DMSO)δ12.82(s,1H),8.52(d,J=8.2Hz,1H),8.22(d,J= 2.9Hz,1H),7.37(d,J=8.2Hz,1H),6.91(d,J=2.3Hz,2H),6.74(t,J =2.3Hz,1H),3.81(s,6H).13C NMR(101MHz,DMSO)δ189.81, 160.89,148.52,145.24,141.84,136.83,133.35,118.68,118.15,114.25, 106.81,104.11,55.99.
conditions and reagents: NaH, SEM-Cl,0 deg.C, then room temperature
(6-chloro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b)]pyridin-3-yl) (3, 5-dimethoxyphenyl) methanone (I26 b): compound I25b (0.38g, 1.2mmol) was dissolved in anhydrous DMF (5.0mL) and 60% sodium hydride (0.073 g, 1.8mmol) was added with stirring at 0 ℃. After the reaction mixture was stirred at 0 ℃ for 30min, SEM-Cl (0.31g, 0.32mL, 1.8mmol) was added, and the mixture was warmed to room temperature and stirred for 2 h. After completion of the reaction was monitored by TLC, it was diluted with water (50mL), extracted with ethyl acetate (3X 50mL), and the organic phase was collected and washed with saturated brine (3X 20mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.35g of a colorless oily liquid in 78% yield.1H NMR(400MHz,CDCl3)δ8.65- 8.53(m,1H),7.87(s,1H),7.33-7.27(m,1H),6.94(d,J=2.3Hz,2H), 6.65(t,J=2.3Hz,1H),5.66(s,2H),3.83(s,6H),3.64-3.55(m,2H), 0.98-0.87(m,2H),-0.06(s,9H).13C NMR(101MHz,CDCl3)δ190.26, 160.88,147.71,146.80,141.39,135.92,133.67,119.42,118.13,115.34, 106.77,103.86,73.53,67.28,55.68,17.82,-1.41.
conditions and reagents: pd2(dba)3,X-phos,K2CO31, 4-dioxane, 110 ℃ overnight
(3, 5-Dimethoxyphenyl) (6- ((2-methyl-6-nitrophenyl) amino) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) methanone (I27 d): compound I26b (0.18g, 0.41mmol), 2-methyl-6-nitroaniline (0.069g, 0.45mmol), Pd2(dba)3(0.038g, 0.041mmol), X-Phos (0.039g, 0.082mmol), and potassium carbonate (0.11g, 0.82mmol) were dissolved in anhydrous 1, 4-dioxane (4.0mL) and purged with argon to remove oxygen. The reaction solution is stirred for 6h at 110 ℃, cooled to room temperature, filtered and filteredTo the filtrate were added water (20mL) and ethyl acetate (3X 20mL) for extraction, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.16g of a yellow solid in 69% yield.1H NMR(400MHz,CDCl3)δ8.46(dd,J=8.5,4.3Hz, 1H),8.03(s,1H),7.92(dd,J=8.3,1.1Hz,1H),7.65(s,1H),7.50(d,J= 7.0Hz,1H),7.22-7.16(m,1H),6.95(d,J=2.3Hz,2H),6.66-6.60(m, 2H),5.46(s,2H),3.84(s,6H),3.51-3.45(m,2H),2.26(s,3H),0.87- 0.81(m,2H),-0.07--0.11(m,9H).13C NMR(101MHz,CDCl3)δ 190.54,160.75,152.07,147.44,144.29,141.87,136.52,136.17,134.10, 133.96,133.24,123.87,123.40,115.71,113.41,107.30,106.72,103.67, 73.32,66.87,55.65,19.58,17.83,-1.42.
conditions and reagents: i) TFA, DCM, room temperature; ii) K2CO3MeOH, room temperature
(3, 5-Dimethoxyphenyl) (6- ((2-methyl-6-nitrophenyl) amino) -1H-pyrrolo [2, 3-b)]Pyridin-3-yl) methanone (I28 d): compound I27d (0.12g, 0.21mmol) was dissolved in dichloromethane (2.0mL) and trifluoroacetic acid (2.0mL) was added. The reaction mixture was stirred at room temperature for 5 hours, and the solid obtained after concentration was dissolved in methanol (2.0mL), and potassium carbonate was added to adjust the pH to 12, followed by stirring at room temperature overnight. After the completion of the reaction monitored by TLC, the reaction mixture was concentrated, extracted with water (20mL) and ethyl acetate (3X 20mL), and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 39mg of a yellow solid in 43% yield.1H NMR(400MHz,CDCl3)δ10.60(s,1H),8.54(d,J=8.5Hz,1H),8.24 (s,1H),7.82(dd,J=8.3,1.0Hz,1H),7.41(d,J=7.1Hz,1H),7.11(d,J =2.9Hz,1H),7.10-7.04(m,1H),6.91(d,J=2.3Hz,2H),6.71(d,J= 8.5Hz,1H),6.69-6.66(m,1H),3.86(s,6H),2.24(s,3H).13C NMR (101MHz,CDCl3)δ190.64,160.80,151.87,147.41,144.07,141.84, 136.72,136.48,133.92,133.81,131.68,124.14,123.61,115.81,113.47, 107.77,106.67,103.53,55.68,19.76.
Conditions and reagents: h2, Pd/C, EtOAc, room temperature
(6- ((2-amino-6-methylphenyl) amino) -1H-pyrrolo [2,3-b ] pyridin-3-yl) (3, 5-dimethoxyphenyl) methanone (I29 d): compound I28d (39mg, 0.090mmol) was dissolved in ethyl acetate, reduced with 10% Pd/C under hydrogen (1atm) and stirred at room temperature overnight, filtered, the filtrate collected, and concentrated to give intermediate I29d (29mg) as a white solid, which was used in the next reaction without further purification.
Conditions and reagents: DIEA, THF,0 deg.C, then room temperature
N- (2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]pyridin-6-yl) amino) -3-methylphenyl) acrylamide (10): compound I29d (29mg, 0.072mmol) was dissolved in tetrahydrofuran (2.0mL) and reacted in ice water bath with DIEA (7.0. mu.L, 0.087mmol) and acryloyl chloride (24. mu.L, 0.14mmol) added sequentially for 30min at room temperature. After concentration, water (10mL) and ethyl acetate (3X 10mL) were added for extraction, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give a white solid 16mg, yield 49%.1H NMR(400MHz,DMSO-d6)δ12.07(d,J=2.8Hz, 1H),9.45(s,1H),8.20(d,J=8.5Hz,1H),7.89(s,1H),7.77(d,J=8.0 Hz,1H),7.62(d,J=2.7Hz,1H),7.15(t,J=7.8Hz,1H),7.11-7.00(m, 1H),6.83(d,J=2.3Hz,2H),6.69(t,J=2.3Hz,1H),6.56-6.40(m, 2H),6.17(dd,J=17.0,2.0Hz,1H),5.65(dd,J=10.2,2.0Hz,1H),3.78 (s,6H),2.14(s,3H).13C NMR(101MHz,DMSO)δ189.71,163.92, 160.76,155.45,148.77,142.52,137.24,135.88,132.53,132.08,131.63, 127.24,127.08,126.20,121.20,114.83,110.98,106.69,105.73,103.59, 55.94,19.02.HRMS(ESI)m/z C26H24N4O4[M+H]+456.1798; found 457.1868.
The synthesis of compounds 7, 8, 9, 11, 21 and 23 was similar to compound 10.
n- (2- ((3- (3-methoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (7):1H NMR(400MHz,DMSO-d6)δ12.16(d,J=3.0Hz, 1H),9.74(s,1H),8.37-8.17(m,2H),7.82(d,J=8.1Hz,1H),7.68(d,J =3.0Hz,1H),7.61(d,J=7.9Hz,1H),7.47-7.39(m,1H),7.34(dt,J= 7.6,1.2Hz,1H),7.25(dd,J=2.7,1.5Hz,1H),7.15(ddd,J=8.2,2.7,1.1Hz,2H),7.05(td,J=7.7,1.5Hz,1H),6.79(d,J=8.6Hz,1H),6.48 (dd,J=17.0,10.2Hz,1H),6.23(dd,J=17.0,2.0Hz,1H),5.72(dd,J= 10.1,2.0Hz,1H),3.81(s,3H).13C NMR(101MHz,DMSO)δ189.93, 164.20,159.67,153.80,148.21,141.79,134.58,132.64,132.47,132.19, 130.08,127.19,125.81,125.37,123.18,123.09,121.27,117.68,114.98, 113.73,111.74,107.25,55.79.HRMS(ESI)m/z C24H20N4O3[M+H]+412.1535; found 413.1609.
n- (2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (8):1H NMR (400MHz, chloroform-d) δ 12.32(s,1H),8.51 (s,1H),8.40(d, J ═ 8.5Hz,1H),7.64(d, J ═ 8.1Hz,1H),7.45(s,1H), 7.13(d, J ═ 8.0Hz,1H),7.11-7.01(m,1H),6.89(d, J ═ 2.3Hz,2H), 6.84(td, J ═ 7.7,1.4Hz,1H),6.68(t, J ═ 2.3Hz,1H),6.63(d, J ═ 8.5Hz,1H),6.54(d, J ═ 2.7Hz,1H),6.36(dd, 17.0, J ═ 1.6, 1.5H), 6.7 (dd, 1H, 9.85H), 9.5H, 9, 9.5H, 1H),6.7 (dd, 1H), 6.7H, 1H, 6.6.7 (dd, 17, 17.0, 1H, 6.6.5H), 6.5H, 1H, 9, 1H, 6.85 (dd, 1H).13C NMR(101MHz,CDCl3)δ190.28,164.79,160.48,152.72,147.69, 142.11,134.91,133.72,132.70,130.38,129.58,128.65,127.15,124.78, 124.07,123.30,115.28,112.97,107.73,107.28,103.26,60.50,55.89,31.67,22.74,21.15,14.28,14.21.HRMS(ESI)m/z C25H22N4O4[M+H]+442.1641; measured in factValue 443.1717.
n- (2- ((3- (2, 6-dichloro-3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (9):1H NMR(400MHz,DMSO-d6)δ12.26 (s,1H),9.73(s,1H),8.27(s,1H),7.81(d,J=8.1Hz,1H),7.62(d,J= 8.0Hz,1H),7.48(s,1H),7.15(td,J=7.7,1.6Hz,1H),7.05(td,J=7.6, 1.5Hz,1H),6.99(s,1H),6.79(d,J=8.6Hz,1H),6.49(dd,J=17.0,10.2Hz,1H),6.24(dd,J=17.0,2.0Hz,1H),5.72(dd,J=10.1,2.0Hz, 1H),3.95(s,6H).13C NMR(101MHz,DMSO)δ185.46,164.20,155.03, 154.06,148.54,140.20,134.43,132.45,130.31,127.22,125.79,125.31, 123.45,123.28,115.42,110.49,110.15,107.51,99.02,57.34.HRMS (ESI)m/z C25H20Cl2N4O4[M+H]+510.0862; found 511.0934.
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -3-methylphenyl) acrylamide (11):1H NMR(400MHz,DMSO-d6) δ12.18(s,1H),9.43(s,1H),8.14(s,1H),7.93(s,1H),7.79(d,J=8.0 Hz,1H),7.38(s,1H),7.17(t,J=7.8Hz,1H),7.12-7.07(m,1H),6.98 (s,1H),6.62-6.36(m,2H),6.18(dd,J=17.0,2.0Hz,1H),5.66(dd,J= 10.2,2.0Hz,1H),3.95(s,6H),2.15(s,3H).13C NMR(101MHz,DMSO) δ185.37,163.94,155.65,155.00,149.08,140.25,137.36,135.98,132.51, 131.45,127.26,127.04,126.30,121.19,115.38,110.14,109.73,106.01, 98.97,57.32,18.98.
n- (2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -3-methylphenyl) propanamide (21): MS (ESI)):459[M+H]+.
N- (2- ((3- (3, 5-dimethoxybenzoyl) -1-methyl-1H-pyrrolo [2, 3-b)]pyridin-6-yl) amino) phenyl) acrylamide (23):1H NMR(400MHz,DMSO-d6)δ9.70(s, 1H),8.35(s,1H),8.28(d,J=8.5Hz,1H),7.91(d,J=11.6Hz,2H), 7.60(d,J=8.0Hz,1H),7.18(t,J=7.8Hz,1H),7.05(t,J=7.7Hz,1H), 6.87(s,2H),6.81(d,J=8.5Hz,1H),6.72(s,1H),6.49(dd,J=17.1,10.1Hz,1H),6.25(d,J=16.9Hz,1H),5.73(d,J=10.3Hz,1H),3.81(s, 6H),3.74(s,3H).
scheme VI
for I32, I34-I36, products 12-18, R ═ 4-methylpiperazine, 4-morpholine, 4-acetylpiperazine, 4- (1-methyl-1H-pyrazol-3-yl); for products 16-18, when R ═ 4-morpholine, Ar ═ 2-chloro-3, 5-dimethoxyphenyl or 2, 6-dichloro-3, 5-dimethoxyphenyl, when R ═ 4- (1-methyl-1H-pyrazol-3-yl), Ar ═ 2, 6-dichloro-3, 5-dimethoxyphenyl
Conditions and reagents:
(a)Boc2O, THF, reflux, overnight;
(b) Amine, Pd2(dba)3,Xant-Phos,Cs2CO31, 4-dioxane, 100 ℃, and staying overnight;
(c) TFA/DCM, room temperature;
(d)Pd(dppf)Cl2,K2CO31, 4-dioxane/H2O (v: v ═ 3:1),100 ℃ microwave, 2H;
(e)Boc2O, DMAP, DCM, room temperature;
(f)Pd(OAc)2,Xant-phos,Cs2CO31, 4-dioxane, 110 ℃, and standing overnight;
(g)H2Pd/C, EA, room temperature;
(h) Acryloyl chloride, DIEA, THF,0 ℃, then room temperature;
(i) TFA, DCM, room temperature;
(j)SO2Cl2DCM,0 ℃.
Conditions and reagents: boc2o, THF, refluxing, overnight
Tert-butyl (4-bromo-2-nitrophenyl) carbamate (I30): 4-bromo-2-nitroaniline (1.6 g, 3.8mmol), Boc2O (0.91g, 0.96mL, 4.2mmol) was dissolved in THF, stirred at reflux overnight, cooled to room temperature, concentrated, and purified by column chromatography to give 0.98g of a white solid in 81% yield.1H NMR(400MHz,CDCl3)δ9.57(s,1H),8.52-8.42(m, 1H),8.28(d,J=2.4Hz,1H),7.65(dd,J=9.2,2.4Hz,1H),1.52(s,9H).13C NMR(101MHz,CDCl3)δ151.95,138.54,136.17,135.17,128.27, 122.21,113.74,82.31,28.22.
Conditions and reagents: pd2(dba)3,Xant-Phos,Cs2CO31, 4-dioxane, 100 ℃ overnight
Tert-butyl (4-morpholino-2-nitrophenyl) carbamate (I31 b): compound I30 (0.50g, 1.6mmol), morpholine (0.21g, 0.21mL, 2.36mmol), Pd2(dba)3(0.15g, 0.16mmol), Xant-Phos (0.18g, 0.32mmol), cesium carbonate (1.0 g, 3.2mmol) were dissolved in anhydrous 1, 4-dioxane (16.0mL) and purged with argon to remove oxygen. The reaction mixture was stirred at 100 ℃ overnight, cooled to room temperature, filtered, and the filtrate was extracted with water (50mL) and ethyl acetate (3X 50mL), the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.44g of a yellow solid with 86% yield.1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),7.40(d,J=9.0 Hz,1H),7.36(d,J=2.9Hz,1H),7.28(dd,J=9.0,2.9Hz,1H),3.79- 3.66(m,4H),3.21-3.09(m,4H),1.41(s,9H).13C NMR(101MHz, DMSO)δ153.45,148.28,143.34,126.59,123.99,121.07,110.28,80.34, 66.38,48.58,28.49.
Conditions and reagents: TFA/DCM, room temperature
4-morpholino-2-nitroaniline (I32 b): compound I31b (0.44g) was dissolved in DCM (3mL), trifluoroacetic acid (3mL) was added, stirring was carried out at room temperature for 1h, concentration was carried out, a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added for extraction, the organic phase was collected, washed with water and saturated brine in this order, and 0.30g of a yellow solid obtained by concentration was used in the next reaction without purification.
Conditions and reagents: pd (dppf) Cl2,K2CO31, 4-dioxane/H2O (v: v ═ 3:1),100 ℃ microwave, 2H
4- (1-methyl-1H-pyrazol-3-yl) -2-nitroaniline (I32 d): 4-bromo-2-nitroaniline (0.30g, 1.4mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.43g, 2.1 mmol), Pd (dppf) Cl2(0.23g, 0.28mmol) and potassium carbonate (0.57g, 4.1mmol) were dissolved in a mixed solvent (12mL) of 1, 4-dioxane and water (3: 1), and argon gas was introduced to remove oxygen. The reaction solution was reacted in a microwave reactor at 100 ℃ for 2 hours, cooled to room temperature, filtered, and the filtrate was extracted with water and ethyl acetate (3 × 40mL), and the organic phase was collected, washed with saturated brine (2 × 20mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.24g of a yellow solid, with a yield of 79%.1H NMR(400MHz,DMSO-d6)δ8.09(d,J= 0.9Hz,1H),8.07(d,J=2.2Hz,1H),7.79(d,J=0.8Hz,1H),7.64(dd,J =8.8,2.2Hz,1H),7.41(s,2H),7.03(d,J=8.8Hz,1H),3.83(s,3H).13C NMR(101MHz,DMSO)δ145.19,136.07,134.08,130.81,127.82, 121.10,121.00,120.55,120.40,39.16.
Conditions and reagents: boc2O, DMAP, DCM, at room temperature
6-chloro-3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b]Pyridine-1-carboxylic acid tert-butyl ester (I33): compound I25b (5.0g, 16mmol) was dissolved in DCM (80mL) and Boc was added sequentially2O (5.2g, 5.5mL, 24mmol), DMAP (0.097g, 0.8mmol), stirring at room temperature for 2h, concentrating, extracting with water and ethyl acetate, collecting the organic phase, washing with brine (2 × 40mL), drying over anhydrous sodium sulfate, concentrating, and purifying by column chromatography to give a yellow solid 4.1g, 62% yield.1H NMR(400MHz,CDCl3)δ8.54(d,J=8.3Hz, 1H),8.16(s,1H),7.35(d,J=8.3Hz,1H),6.95(d,J=2.3Hz,2H),6.67 (t,J=2.3Hz,1H),3.84(s,6H),1.68(s,9H).13C NMR(101MHz, CDCl3)δ190.17,160.95,148.03,147.35,146.80,140.49,133.83,133.57, 120.80,119.98,116.72,106.75,104.64,86.29,55.70,28.05.
conditions and reagents: pd (OAc)2, Xant-phos, Cs2CO31, 4-dioxane, 100 ℃ overnight
3- (3, 5-Dimethoxybenzoyl) -6- ((4-morpholino-2-nitrophenyl) amino) -1H-pyrrolo [2, 3-b)]Pyridine-1-carboxylic acid tert-butyl ester (I34 b): mixing compound I33(0.17g, 0.41mmol), 32b (0.088g, 0.40mmol), Pd (OAc)2(0.009g, 0.040mmol), Xant-Phos (0.047g, 0.080mmol), and cesium carbonate (0.27g, 0.80mmol) were dissolved in anhydrous 1, 4-dioxane (4.0mL) and purged with argon to remove oxygen. The reaction mixture was stirred at 100 ℃ overnight, cooled to room temperature, filtered, and the filtrate was extracted with water (20mL) and ethyl acetate (3X 20mL), the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.15g of a yellow solid with 62% yield.1H NMR(400MHz,DMSO-d6) δ9.58(s,1H),8.32(d,J=8.6Hz,1H),8.13(d,J=9.2Hz,1H),7.90(s, 1H),7.48(d,J=2.9Hz,1H),7.39(dd,J=9.2,3.0Hz,1H),7.02(d,J= 8.7Hz,1H),6.95(d,J=2.3Hz,2H),6.79(t,J=2.3Hz,1H),3.82(s, 6H),3.79-3.73(m,4H),3.18-3.11(m,4H),1.49(s,9H).13C NMR (101MHz,DMSO)δ190.11,161.01,153.22,146.61,146.19,141.12, 140.40,128.41,125.24,123.30,116.81,113.82,110.49,110.15,106.93, 85.49,66.47,56.10,49.06,27.98.
Conditions and reagents: h2Pd/C, EA, room temperature
Tert-butyl 6- ((2-amino-4-morpholinophenyl) amino) -3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b ] pyridine-1-carboxylate (I35 b): compound I34b (0.15g, 0.25mmol) was dissolved in ethyl acetate (5mL), reduced with 10% Pd/C and hydrogen (1atm) and stirred at room temperature overnight, filtered, the filtrate collected and concentrated to give intermediate I35b (0.1g) as a white solid which was used in the next reaction without further purification.
Conditions and reagents: DIEA, THF,0 deg.C, then room temperature
6- ((2-acrylamido-4-morpholinophenyl) amino) -3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridine-1-carboxylic acid tert-butyl ester (I36 b): compound I35b (0.1g, 0.18mmol) was dissolved in tetrahydrofuran (2.0mL), and DIEA (60. mu.L, 0.36mmol) and acryloyl chloride (18. mu.L, 0.22mmol) were added sequentially under ice-water bath conditions and reacted at room temperature for 30 min. After concentration, water (10mL) and ethyl acetate (3X 10mL) were added for extraction, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 70mg of a white solid with a yield of 62%. MS (ESI) 628M + H]+.
Conditions and reagents: TFA/DCM, room temperature
N- (2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]pyridin-6-yl) amino) -5-morpholinophenyl) acrylamide (13): compound I36b (70mg, 0.11mmol) was dissolved in DCM (1.0mL), trifluoroacetic acid (1.0mL) was added, stirred at room temperature for 1h, concentrated, extracted with saturated aqueous sodium bicarbonate and ethyl acetate, the organic phase was collected, washed successively with water, saturated brine, the white solid obtained was concentrated (63mg), a portion of the product was purified by column chromatography for activity test, and the remainder was used in the next reaction without purification.1H NMR (400MHz, chloroform-d) δ 12.20(s,1H),8.50(s,1H),8.40(d, J ═ 8.5Hz,1H),7.55(d, J ═ 8.9Hz,1H),7.14(s,1H),6.94(d, J ═ 2.3Hz,2H), 6.77(s,1H),6.73-6.66(m,2H),6.56(d, J ═ 8.5Hz,1H), 6.50-6.43 (m,1H),6.41(d, J ═ 1.5Hz,1H),6.30(dd, J ═ 16.9,10.1Hz,1H), 5.76(dd, J ═ 10.0,1.5, 1H),3.88(s,6H),3.70 (t, 4.4H), 4.70 (t, 4H), 4.4H, 4H).13C NMR(101MHz,CDCl3)δ189.85,164.63,160.61, 153.72,148.92,147.67,142.21,133.72,132.10,131.56,130.60,128.91, 128.59,125.62,115.23,115.02,112.46,110.76,107.57,107.17,103.38,66.69,56.01,49.25.
The synthesis of compounds 12, 14, 15 and 20 was similar to compound 13.
n- (2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -5- (4-methylpiperazin-1-yl) phenyl) acrylamide (12): a white solid.1H NMR(400 MHz,DMSO-d6)δ12.08(s,1H),9.65(s,1H),8.21(d,J=8.6Hz,1H), 7.98(s,1H),7.68(d,J=2.4Hz,1H),7.44(d,J=8.8Hz,1H),7.38- 7.34(m,1H),6.86(d,J=2.3Hz,2H),6.81(dd,J=8.9,2.8Hz,1H), 6.71(t,J=2.3Hz,1H),6.63(d,J=8.6Hz,1H),6.47(dd,J=17.0,10.2 Hz,1H),6.22(dd,J=17.0,2.0Hz,1H),5.71(dd,J=10.1,2.0Hz,1H), 3.80(s,6H),3.18-3.07(m,4H),2.57(s,4H).13C NMR(101MHz, DMSO)δ189.74,164.00,160.79,155.02,148.54,147.98,142.54, 132.54,132.32,132.06,127.22,125.88,125.75,114.92,113.42,111.61, 111.15,106.69,106.27,103.58,55.95,54.92,48.84,45.87.MS(ESI): 541[M+H]+.
N- (5- (4-acetylpiperazin-1-yl) -2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) phenyl) acrylamide (14): a white solid.1H NMR (400MHz, chloroform-d) δ 12.11(s,1H),8.64(s,1H),8.40(d, J ═ 8.5Hz,1H), 7.52(d, J ═ 8.8Hz,1H),7.16(s,1H),6.96-6.87(m,3H),6.73-6.64(m, 2H),6.64-6.52(m,2H),6.41(dd, J ═ 16.9,1.5Hz,1H),6.29(dd, J ═ 16.9,10.1Hz,1H),5.74(dd, J ═ 9.9,1.5Hz,1H),3.87(s,6H),3.55(t, J ═ 5.2, 2H),3.40(t, J ═ 2.5, 1.5Hz,1H), 3.06 (t, J ═ 2H), 3.6H), 3.55(t, J ═ 5.2H, 2H, 3.06 (t, J ═ 2H), 2H, 3.6H).13C NMR(101MHz,CDCl3)δ189.84, 169.08,164.62,160.64,153.79,148.40,147.76,142.16,133.64,131.96, 131.76,130.72,128.49,126.62,125.52,115.61,115.29,112.46,111.84, 107.47,107.09,103.26,55.97,49.62,49.25,46.06,41.23,21.32,14.26.
N- (2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -5- (1-methyl-1H-pyrazol-3-yl) phenyl) acrylamide (15): a white solid. MS (ESI) 523[ M + H]+.
N- (2- ((3- (3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -5- (4-methylpiperazin-1-yl) phenyl) propionamide (20): a white solid. MS (ESI) 543 [ M + H]+.
conditions and reagents: SO (SO)2Cl2DCM,0 deg.C
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -5-Morpholinophenyl) acrylamide (17): compound 13(50mg, 0.095 mmol) was dissolved in anhydrous dichloromethane (2.0mL), sulfonyl chloride (32mg, 19. mu.L, 0.24mmol) was added dropwise at 0 deg.C, stirring was carried out at 0 deg.C for 0.5h, a saturated aqueous sodium bicarbonate solution (10mL) and dichloromethane (10mL) were added for extraction, the organic phase was collected, washed with water and saturated brine in this order, and separation and purification by concentrated column chromatography gave 11mg of a white solid with a yield of 19%. MS (ESI):596[ M + H]+.
The synthesis of compounds 16, 18, 22, 19 was similar to compound 17.
N- (2- ((3- (2-chloro-3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -5-morpholinophenyl) acrylamide (16): a white solid.1H NMR(400MHz, DMSO-d6)δ12.12(s,1H),9.61(s,1H),8.08(s,1H),7.98(s,1H),7.44 (d,J=8.9Hz,1H),7.36(d,J=3.1Hz,2H),6.85-6.77(m,3H),6.65- 6.57(m,2H),6.46(dd,J=16.9,10.2Hz,1H),6.21(dd,J=16.9,2.0Hz, 1H),5.70(d,J=11.1Hz,1H),3.88(s,3H),3.78(s,3H),3.74(t,J=4.8 Hz,4H),3.06(t,J=4.8Hz,4H).MS(ESI):562[M+H]+.
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridin-6-yl) amino) -5- (1-methyl-1H-pyrazol-3-yl) phenyl) acrylamide (18):1H NMR (400MHz,DMSO-d6)δ12.25(s,1H),9.75(s,1H),8.24(s,1H),8.07(s, 1H),7.79(d,J=3.3Hz,3H),7.48(s,1H),7.36(dd,J=8.4,2.1Hz,1H), 7.00(s,1H),6.79(d,J=8.6Hz,1H),6.51(dd,J=17.0,10.2Hz,1H),6.26(dd,J=17.0,2.0Hz,1H),5.75(dd,J=10.1,2.0Hz,1H),3.96(s, 6H),3.86(s,3H).
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) amino) -5- (4-methylpiperazin-1-yl) phenyl) acrylamide (22): MS (ESI) 609 [ M + H ] +.
N- (2- ((3- (2, 6-dichloro-3, 5-dimethoxybenzoyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) amino) -3-methyl-5- (4-methylpiperazin-1-yl) phenyl) acrylamide (19): MS (ESI) 623[ M + H ] +.
Biological activity assay
(I) kinase Activity detection assay
Experimental materials: PE Envision microplate reader; a 384 well whiteboard (OptiPlate TM-384); FGFR4 kinase (08-136, Carna), Cisbio HTRF kit (Cisbio Assays 62TK0PEB)
The experimental method comprises the following steps: according toKinEaseTMThe standard method of assay is performed. An enzymatic reaction step: a1: 1 mixture (4. mu.L) of a concentration gradient inhibitor (30. mu.M to 0.1nM, 12 concentration gradients diluted 3.3-fold in a concentration gradient of 4. mu.L), FGFR4 kinase (2 ng/well, 2. mu.L), a substrate (1. mu.M) and ATP (120. mu.M) diluted with a kinase buffer was sequentially added to a 384-well plate, and incubated at 25 ℃ for 45min after shaking and centrifugation. A detection step: adding 1:1 mixed Eu3+The reaction was stopped by chelating the antibody (5. mu.L) and streptavidin-XL665 (0.125. mu.M, 5. mu.L), and the plate was read on a PE Envision microplate reader after standing at room temperature for 1 h. The IC was calculated by fitting a curve to GraphPad Prism5.0 using the concentration as the abscissa and the signal value at 615nm/665nm as the ordinate50The value is obtained.
Note: "+" denotes IC50>1000nM, "+ + +" denotes IC50100-1000 nM, "+ + + + +" indicates IC5010-100 nM, "+ ++" denotes IC50<10nM, "ND" means IC has not been tested yet50The value is obtained.
(II) cell proliferation inhibition experiment
Experimental materials: HUH-7 cells (Mediterranean cell bank), MDA-MB-453 cells (Mediterranean cell bank), DMEM medium (11995065, Gibco), Leibovitz's L-15 medium (11415064, Gibco), and detection reagents (G7570, Promega).
The experimental method comprises the following steps: after trypsinization of adherent cells, treatment was stopped by addition of complete medium containing serum, cells were collected, centrifuged (1000 × rpm), cells were dispersed in suspension in fresh complete medium for cell counting, and cells were diluted to 5 × 104one/mL. In a 96-well blackboard, 100. mu.L of the above cell dilution suspension or cell-free medium was added to each well, and cultured overnight at 37 ℃. Various concentrations of inhibitor (50. mu.L) or DMSO (50. mu.L) diluted with the medium were added and incubated at 37 ℃ for 72 h. And (3) standing the 96-well plate for balancing at room temperature for 0.5h, adding a detection reagent (40 mu L), fully and uniformly mixing, standing for 1h, reading the plate on an enzyme-linked immunosorbent assay (ELISA) reader, and calculating the growth inhibition rate by taking the DMSO (dimethylsulfoxide) hole signal value as a positive control. Cellular EC were calculated by fitting a graph Pad Prism5.0 plot of inhibition versus logarithm of inhibitor concentration50The value is obtained.
The compounds 1-22 of the present invention have excellent cell proliferation inhibiting effect, and some of the compounds have the following results in cell lines HuH-7 and MDA-MB-453.
note: "+" denotes IC50>1000nM, "+ + +" denotes IC50100-1000 nM, "+ + + + +" indicates IC50<100nM。
(III) time-dependent inhibition experiment
Staurosporine (Staurosporine, non-covalent inhibitor, 250nM), compound 11 (40nM) and kinase buffer (positive control) were incubated with FGFR4 kinase for different times (0, 1min, 2min, 4min, 8min, 16min, 30min, 45min) before adding ATP (120 μ M) and substrate (1 μ M) 1:1 mix (4. mu.L) to start the enzymatic reaction. After shaking and centrifugation, incubation was carried out for 45min at 25 ℃. Adding 1:1 mixed Eu3+The reaction was stopped by chelating antibody (5. mu.L) and streptavidin-XL665 (0.125. mu.M, 5. mu.L). The ratio of each time point to the positive control signal was used to calculate the inhibition ((1-signal)sample/signalcontrol) X 100%) were fitted with GraphPad prism5.0 to plot inhibition versus time to obtain a time-dependent inhibition curve. The intensity of inhibitory activity of compound 11 on FGFR4 increased with increasing co-incubation time of compound 11 with FGFR4 kinase; but the inhibition intensity of the non-covalent inhibitor Staurosporine on FGFR4 did not change with co-incubation time.
Claims (10)
1. a compound represented by formula (I), a salt thereof or a stereoisomer thereof
G1And G2Independently of one another, identical or different, from the group consisting of H, C (O) and S (O)2;
L1And L2independently of one another, identical or different, from the group optionally substituted by C1-3alkyl substituted C2-3Alkenyl radical, C0-3alkyl-C2-3Alkenyl and C1-3alkyl-NHC (O) -C2-3An alkenyl group;
Provided that when G is1When it is H, L1Is absent, and when G2When it is H, L2Is absent.
Wherein,
Ar is a 5-or 6-membered monocyclic aromatic ring,
For example: furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzene, pyridine, pyrazine, pyrimidine, pyridazine, triazole,
Preferably: benzene, pyridine;
R1
selected from H, halogen (preferably-Cl), -OH, -C1-4Alkyl radical, -C1-4An alkyl-oxy group, a carboxyl group,
m is an integer of 0,1, 2,3, 4, 5;
W1Is CH, CR1Or N;
W2Is CH, CR1or N;
W3Is CH, CR1Or N;
W4Is CH, CR1Or N;
W5is CH, CR1Or N;
W6Is CH, CR1or N;
W7Is CH, CR1Or N;
L is selected from: a bond, -O-, -NH-, -S-, -CH2-,-CH=CH-,-CH≡CH-,-C(CH3)H-,-C(CH3)2-,-C(CH2-CH2)-,-CClH-,-CCl2-, -CO-, -SO-, and-SO2-;
n is an integer of 0,1, 2,3, 4, 5;
R2
Selected from H, halogen (preferably-Cl) -OH-C1-4alkyl-C1-4alkyl oxy radical
R3Selected from H, -C1-4An alkyl group.
2. A compound according to any one of the preceding claims, a salt thereof or a stereoisomer thereof,
Wherein G is2is H, L2Is absent.
3. A compound according to any one of the preceding claims, a salt thereof or a stereoisomer thereof,
wherein W1,W2,W3,W4,W5,W6,W7Are all CH.
4. A compound according to any one of the preceding claims, a salt thereof or a stereoisomer thereof,
Wherein R is3Is H.
5. A compound according to any one of the preceding claims, a salt thereof or a stereoisomer thereof,
wherein-N (G)1L1)(G2L2) is-NH-CO-C2-3An alkenyl group.
6. A compound according to any one of the preceding claims, a salt thereof or a stereoisomer thereof,
Wherein Ar is phenyl.
7. A compound, a salt thereof, or a stereoisomer thereof, wherein the compound is selected from the following compounds 1-23:
8. A pharmaceutical composition comprising a compound of any one of the preceding claims, a salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
9. Use of a compound, salt or stereoisomer thereof according to any of the preceding claims, or a pharmaceutical composition according to any of the preceding claims, in the manufacture of a medicament for treating a condition mediated by FGFR-4, a condition characterized by overexpression of FGFR-4, a condition characterized by amplification of FGFR4, a condition mediated by FGF19, a condition characterized by amplified FGF19, or a condition characterized by overexpression of FGF 19.
10. The use of any one of the preceding claims, wherein the condition is hepatocellular carcinoma, breast cancer, ovarian cancer, lung cancer, liver cancer, sarcoma, or hyperlipidemia.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810580435.6A CN110577524B (en) | 2018-06-07 | 2018-06-07 | Kinase selective inhibitor |
PCT/CN2019/090131 WO2019233438A1 (en) | 2018-06-07 | 2019-06-05 | Kinase selective inhibitor |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810580435.6A CN110577524B (en) | 2018-06-07 | 2018-06-07 | Kinase selective inhibitor |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110577524A true CN110577524A (en) | 2019-12-17 |
CN110577524B CN110577524B (en) | 2022-01-28 |
Family
ID=68769610
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810580435.6A Expired - Fee Related CN110577524B (en) | 2018-06-07 | 2018-06-07 | Kinase selective inhibitor |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN110577524B (en) |
WO (1) | WO2019233438A1 (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101594871A (en) * | 2006-05-26 | 2009-12-02 | 诺瓦提斯公司 | Pyrrolopyrimidine compounds and uses thereof |
CN104540809A (en) * | 2012-07-11 | 2015-04-22 | 蓝印药品公司 | Inhibitors of the fibroblast growth factor receptor |
WO2015108992A1 (en) * | 2014-01-15 | 2015-07-23 | Blueprint Medicines Corporation | Heterobicyclic compounds and their use as fgfr4 receptor inhibitors |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR112015022191A8 (en) * | 2013-03-15 | 2018-01-23 | Celgene Avilomics Res Inc | heteroaryl compounds and uses thereof |
CN111278823B (en) * | 2017-10-24 | 2023-01-24 | 上海新契博生物科技有限公司 | Heterocyclic compounds as fibroblast growth factor receptor inhibitors |
-
2018
- 2018-06-07 CN CN201810580435.6A patent/CN110577524B/en not_active Expired - Fee Related
-
2019
- 2019-06-05 WO PCT/CN2019/090131 patent/WO2019233438A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101594871A (en) * | 2006-05-26 | 2009-12-02 | 诺瓦提斯公司 | Pyrrolopyrimidine compounds and uses thereof |
CN104540809A (en) * | 2012-07-11 | 2015-04-22 | 蓝印药品公司 | Inhibitors of the fibroblast growth factor receptor |
WO2015108992A1 (en) * | 2014-01-15 | 2015-07-23 | Blueprint Medicines Corporation | Heterobicyclic compounds and their use as fgfr4 receptor inhibitors |
Non-Patent Citations (3)
Title |
---|
QIAOMEI JIN ET AL.: ""Pyrrolo[2,3-b]pyridine-3-one derivatives as novel fibroblast growth factor receptor 4 inhibitors for the treatment of hepatocellular carcinoma"", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
QIUMENG ZHANG ET AL.: ""Design, synthesis and anti-proliferative activities of 2,6-substituted thieno[3,2-d]pyrimidine derivatives containing electrophilic warheads"", 《MOLECULES》 * |
尤启冬: "《药物化学》", 31 January 2004 * |
Also Published As
Publication number | Publication date |
---|---|
CN110577524B (en) | 2022-01-28 |
WO2019233438A1 (en) | 2019-12-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10774070B2 (en) | 2-(pyridin-3-yl)-pyrimidine derivatives as RET inhibitors | |
US10875837B2 (en) | Inhibitors of the fibroblast growth factor receptor | |
US11040979B2 (en) | Substituted pyrrolo[1,2-b]pyridazines for treating disorders related to KIT and PDGFR | |
WO2015108992A1 (en) | Heterobicyclic compounds and their use as fgfr4 receptor inhibitors | |
WO2022017444A1 (en) | Shp2 inhibitor and composition and application thereof | |
JP2020524159A (en) | Azaaryl derivative having CSF-1R inhibitory activity, production method and application thereof | |
CN111961034A (en) | Compounds useful as RET kinase inhibitors and uses thereof | |
WO2020038460A1 (en) | Novel quinoline derivative inhibitor | |
CN107312009B (en) | Quinoline compound, preparation method, intermediate, pharmaceutical composition and application thereof | |
TW202007687A (en) | Further substituted triazolo quinoxaline derivatives | |
JP6585729B2 (en) | 2-Aminopyridine derivatives as adenosine A2B receptor antagonists and ligands of melatonin MT3 receptor | |
CN100398540C (en) | Aryl heterocyclic imidazole naphthaimide kind compound and its application | |
CN110577524B (en) | Kinase selective inhibitor | |
WO2020082921A1 (en) | Nitrogen heteroaryl amide derivative, preparation method therefor, and application thereof | |
WO2024114765A1 (en) | Benzopyrone compounds as well as preparation method therefor and use thereof | |
CN114502556B (en) | Biphenyl fluoro double bond derivative, preparation method thereof and application thereof in pharmacy | |
CN112119065B (en) | Benzodiazepine compound, preparation method and application thereof | |
CN108341816A (en) | A kind of selective depression kinases compound | |
WO2022165402A1 (en) | Inhibitors of protein kinase a | |
CN108341837A (en) | It is a kind of to inhibit kinases compound and its purposes medically | |
CN111377906B (en) | Substituted pyrazine compounds, their preparation and use | |
WO2023083373A1 (en) | Compound used as src inhibitor | |
CN113214247A (en) | Azaindole derivative marrow cell proliferation inhibitor, preparation method and application thereof in pharmacy | |
CN117143107A (en) | 1, 2-dihydropyridine derivative, preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20220128 |
|
CF01 | Termination of patent right due to non-payment of annual fee |