WO2019085895A1 - 一类氨基取代含氮稠环化合物及其制备方法和用途 - Google Patents
一类氨基取代含氮稠环化合物及其制备方法和用途 Download PDFInfo
- Publication number
- WO2019085895A1 WO2019085895A1 PCT/CN2018/112661 CN2018112661W WO2019085895A1 WO 2019085895 A1 WO2019085895 A1 WO 2019085895A1 CN 2018112661 W CN2018112661 W CN 2018112661W WO 2019085895 A1 WO2019085895 A1 WO 2019085895A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- compound
- formula
- membered
- cancer
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 134
- -1 amino-substituted nitrogen Chemical class 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
- 108091008794 FGF receptors Proteins 0.000 claims abstract description 24
- 201000010099 disease Diseases 0.000 claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- 238000011282 treatment Methods 0.000 claims abstract description 13
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 claims abstract description 7
- 230000014509 gene expression Effects 0.000 claims abstract description 5
- 229940043355 kinase inhibitor Drugs 0.000 claims abstract description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims abstract description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 48
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 29
- 125000001072 heteroaryl group Chemical group 0.000 claims description 27
- 239000000651 prodrug Substances 0.000 claims description 26
- 229940002612 prodrug Drugs 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 23
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 23
- 239000012453 solvate Substances 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 230000000694 effects Effects 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- 208000014018 liver neoplasm Diseases 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 201000007270 liver cancer Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 150000003462 sulfoxides Chemical class 0.000 claims description 4
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 3
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 201000009030 Carcinoma Diseases 0.000 claims description 3
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims description 3
- 208000005016 Intestinal Neoplasms Diseases 0.000 claims description 3
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims description 3
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 210000002919 epithelial cell Anatomy 0.000 claims description 3
- 239000012634 fragment Substances 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 3
- 201000002313 intestinal cancer Diseases 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 201000005249 lung adenocarcinoma Diseases 0.000 claims description 3
- 201000005243 lung squamous cell carcinoma Diseases 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 201000000849 skin cancer Diseases 0.000 claims description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
- 229910052723 transition metal Inorganic materials 0.000 claims description 3
- 150000003624 transition metals Chemical class 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 125000006618 5- to 10-membered aromatic heterocyclic group Chemical group 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 102000001253 Protein Kinase Human genes 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 201000010175 gallbladder cancer Diseases 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 108060006633 protein kinase Proteins 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims description 2
- 125000001174 sulfone group Chemical group 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- 125000003375 sulfoxide group Chemical group 0.000 claims description 2
- PFXVKGGZWQQTSE-UHFFFAOYSA-N sulfuryl dicyanide Chemical group N#CS(=O)(=O)C#N PFXVKGGZWQQTSE-UHFFFAOYSA-N 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 7
- 230000002401 inhibitory effect Effects 0.000 abstract description 21
- 230000004663 cell proliferation Effects 0.000 abstract description 9
- 210000004881 tumor cell Anatomy 0.000 abstract description 9
- 230000002159 abnormal effect Effects 0.000 abstract description 4
- 230000035772 mutation Effects 0.000 abstract description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 24
- 239000000543 intermediate Substances 0.000 description 23
- 239000000203 mixture Substances 0.000 description 20
- 125000004432 carbon atom Chemical group C* 0.000 description 19
- 238000012360 testing method Methods 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- 150000002460 imidazoles Chemical class 0.000 description 16
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 108091000080 Phosphotransferase Proteins 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 12
- 102000020233 phosphotransferase Human genes 0.000 description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 125000004122 cyclic group Chemical group 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000013642 negative control Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 239000001301 oxygen Chemical group 0.000 description 7
- 239000011593 sulfur Chemical group 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 230000035755 proliferation Effects 0.000 description 6
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 4
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 4
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 description 4
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 description 4
- 241000699660 Mus musculus Species 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- LLGRXDHFGMSZNB-UHFFFAOYSA-N methyl 5-chloro-4-oxopentanoate Chemical compound COC(=O)CCC(=O)CCl LLGRXDHFGMSZNB-UHFFFAOYSA-N 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 238000011580 nude mouse model Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- GXJWHTKHHNHFQH-UHFFFAOYSA-N 2-(2,6-dichloro-3,5-dimethoxyphenyl)-6-methylsulfanylpyridine Chemical compound ClC1=C(C(=C(C=C1OC)OC)Cl)C1=CC=CC(=N1)SC GXJWHTKHHNHFQH-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 2
- RIZBLVRXRWHLFA-UHFFFAOYSA-N 3,5-dimethoxytoluene Chemical compound COC1=CC(C)=CC(OC)=C1 RIZBLVRXRWHLFA-UHFFFAOYSA-N 0.000 description 2
- TVJPTOKPOUDFGK-UHFFFAOYSA-N 3-(bromomethyl)-2,4-dichloro-1,5-dimethoxybenzene Chemical compound COc1cc(OC)c(Cl)c(CBr)c1Cl TVJPTOKPOUDFGK-UHFFFAOYSA-N 0.000 description 2
- ISLLQWJXOVDCJW-UHFFFAOYSA-N 6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methylsulfanylpyrido[2,3-d]pyrimidin-7-amine Chemical compound COc1cc(OC)c(Cl)c(c1Cl)-c1cc2cnc(SC)nc2[nH]c1=N ISLLQWJXOVDCJW-UHFFFAOYSA-N 0.000 description 2
- VFMMPHCGEFXGIP-UHFFFAOYSA-N 7,8-Benzoflavone Chemical compound O1C2=C3C=CC=CC3=CC=C2C(=O)C=C1C1=CC=CC=C1 VFMMPHCGEFXGIP-UHFFFAOYSA-N 0.000 description 2
- QZUZLFNBDSFDJY-UHFFFAOYSA-N 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1,6-naphthyridin-2-amine Chemical compound ClC1=NC=C2C=C(C(=NC2=C1)N)C1=C(C(=CC(=C1Cl)OC)OC)Cl QZUZLFNBDSFDJY-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 238000011725 BALB/c mouse Methods 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical class CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 241000711955 Turkey rhinotracheitis virus Species 0.000 description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 210000001853 liver microsome Anatomy 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 2
- 229960003793 midazolam Drugs 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 2
- 125000005561 phenanthryl group Chemical group 0.000 description 2
- 150000004032 porphyrins Chemical class 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical class [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000000725 suspension Substances 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
- 238000010998 test method Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000012384 transportation and delivery Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- IGLYMJRIWWIQQE-QUOODJBBSA-N (1S,2R)-2-phenylcyclopropan-1-amine (1R,2S)-2-phenylcyclopropan-1-amine Chemical compound N[C@H]1C[C@@H]1C1=CC=CC=C1.N[C@@H]1C[C@H]1C1=CC=CC=C1 IGLYMJRIWWIQQE-QUOODJBBSA-N 0.000 description 1
- 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 1
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- LQQKDSXCDXHLLF-UHFFFAOYSA-N 1,3-dibromopropan-2-one Chemical compound BrCC(=O)CBr LQQKDSXCDXHLLF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical group CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- SHCFCJUJGBRSPO-UHFFFAOYSA-N 1-cyclohexylcyclohexan-1-amine Chemical compound C1CCCCC1C1(N)CCCCC1 SHCFCJUJGBRSPO-UHFFFAOYSA-N 0.000 description 1
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- 125000005938 2,3-dihydro-1H-isoindolyl group Chemical group 0.000 description 1
- GNZVDWNVKZQTAV-UHFFFAOYSA-N 2,4-dichloro-1,5-dimethoxy-3-methylbenzene Chemical compound COC1=CC(OC)=C(Cl)C(C)=C1Cl GNZVDWNVKZQTAV-UHFFFAOYSA-N 0.000 description 1
- 125000005983 2,5-diazabicyclo[2.2.1]heptan-2-yl group Chemical group 0.000 description 1
- AZUUAIVVBYHHDN-UHFFFAOYSA-N 2-(2,6-dichloro-3,5-dimethoxyphenyl)acetonitrile Chemical compound COC1=CC(OC)=C(Cl)C(CC#N)=C1Cl AZUUAIVVBYHHDN-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- MBUPVGIGAMCMBT-UHFFFAOYSA-N 2-bromo-1-(4-nitrophenyl)ethanone Chemical group [O-][N+](=O)C1=CC=C(C(=O)CBr)C=C1 MBUPVGIGAMCMBT-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- OQHQOOLVQDEIGL-UHFFFAOYSA-N 2-methyl-2,7-diazaspiro[4.4]nonane Chemical compound C1N(C)CCC11CNCC1 OQHQOOLVQDEIGL-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- VLYWUKFKWSOOOV-UHFFFAOYSA-N 2-phenylsulfanylguanidine Chemical compound C1(=CC=CC=C1)SNC(=N)N VLYWUKFKWSOOOV-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- CGMIFAMRODWNJB-UHFFFAOYSA-N 4-amino-6-chloropyridine-3-carbaldehyde Chemical compound NC1=CC(Cl)=NC=C1C=O CGMIFAMRODWNJB-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 230000035502 ADME Effects 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical group NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 0 C*1CC*(CNC)CC1 Chemical compound C*1CC*(CNC)CC1 0.000 description 1
- HDQIPSJMWYHVND-UHFFFAOYSA-N COCCNc1nc([n]2c(c(-c(c(Cl)c(cc3OC)OC)c3Cl)c3)nc(CCCN(CC4)CCN4C(C=C)=O)c2)c3cn1 Chemical compound COCCNc1nc([n]2c(c(-c(c(Cl)c(cc3OC)OC)c3Cl)c3)nc(CCCN(CC4)CCN4C(C=C)=O)c2)c3cn1 HDQIPSJMWYHVND-UHFFFAOYSA-N 0.000 description 1
- NLAHVGBBVGWKQA-UHFFFAOYSA-N COc(cc(c(F)c1-c(c2nc(CCC=O)c[n]22)cc(cn3)c2nc3SC)OC)c1F Chemical compound COc(cc(c(F)c1-c(c2nc(CCC=O)c[n]22)cc(cn3)c2nc3SC)OC)c1F NLAHVGBBVGWKQA-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- MMMJYAMQEDQEJC-UHFFFAOYSA-N ClC1=NC(=CC=C1)C1=C(C(=CC(=C1Cl)OC)OC)Cl Chemical compound ClC1=NC(=CC=C1)C1=C(C(=CC(=C1Cl)OC)OC)Cl MMMJYAMQEDQEJC-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241001125671 Eretmochelys imbricata Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 101150081124 FGFR gene 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
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- NVSPJDGXKBDYIZ-UHFFFAOYSA-N [1,2,4]triazolo[4,3-a]pyrazine Chemical compound C1=NC=CN2C=NN=C21 NVSPJDGXKBDYIZ-UHFFFAOYSA-N 0.000 description 1
- AYSYSOQSKKDJJY-UHFFFAOYSA-N [1,2,4]triazolo[4,3-a]pyridine Chemical compound C1=CC=CN2C=NN=C21 AYSYSOQSKKDJJY-UHFFFAOYSA-N 0.000 description 1
- YRACHDVMKITFAZ-UHFFFAOYSA-N [1,2,4]triazolo[4,3-b]pyridazine Chemical compound C1=CC=NN2C=NN=C21 YRACHDVMKITFAZ-UHFFFAOYSA-N 0.000 description 1
- XUFCBCHWTOAVAA-UHFFFAOYSA-N [1,2,4]triazolo[4,3-c]pyrimidine Chemical compound C1=CN=CN2C=NN=C21 XUFCBCHWTOAVAA-UHFFFAOYSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- 210000001099 axilla Anatomy 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 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
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 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
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 125000004652 decahydroisoquinolinyl group Chemical group C1(NCCC2CCCCC12)* 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 229960001985 dextromethorphan Drugs 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-M dichloroacetate Chemical compound [O-]C(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-M 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 239000012972 dimethylethanolamine Substances 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- MBVAHHOKMIRXLP-UHFFFAOYSA-N imidazo[1,2-a]pyrazine Chemical compound C1=CN=CC2=NC=CN21 MBVAHHOKMIRXLP-UHFFFAOYSA-N 0.000 description 1
- VTVRXITWWZGKHV-UHFFFAOYSA-N imidazo[1,2-b]pyridazine Chemical compound N1=CC=CC2=NC=CN21 VTVRXITWWZGKHV-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 159000000014 iron salts Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000002696 manganese Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N monoethyl amine Natural products CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 230000017066 negative regulation of growth Effects 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
- 150000002823 nitrates Chemical class 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 125000005474 octanoate group Chemical group 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- CQDAMYNQINDRQC-UHFFFAOYSA-N oxatriazole Chemical compound C1=NN=NO1 CQDAMYNQINDRQC-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 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
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229960003893 phenacetin Drugs 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000011574 phosphorus Chemical group 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- ZTRPYTHOEREHEN-UHFFFAOYSA-N piperazine pyridine Chemical compound N1CCNCC1.N1=CC=CC=C1.N1=CC=CC=C1 ZTRPYTHOEREHEN-UHFFFAOYSA-N 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000002952 polymeric resin Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 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
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- QWCJHSGMANYXCW-UHFFFAOYSA-N sulfaphenazole Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=NN1C1=CC=CC=C1 QWCJHSGMANYXCW-UHFFFAOYSA-N 0.000 description 1
- 229960004818 sulfaphenazole Drugs 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000012747 synergistic agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RIDCLKHITCZAPV-UHFFFAOYSA-N tert-butyl 2-[3-(2-bromoacetyl)phenyl]acetate Chemical compound BrCC(=O)C=1C=C(CC(=O)OC(C)(C)C)C=CC=1 RIDCLKHITCZAPV-UHFFFAOYSA-N 0.000 description 1
- OWYHAYAJHNQBGG-UHFFFAOYSA-N tert-butyl 3-oxospiro[2h-indene-1,4'-piperidine]-1'-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC11C2=CC=CC=C2C(=O)C1 OWYHAYAJHNQBGG-UHFFFAOYSA-N 0.000 description 1
- KOZONEASBDEEEY-UHFFFAOYSA-N tert-butyl 4-[3-(2-bromoacetyl)phenyl]piperazine-1-carboxylate Chemical group C(C)(C)(C)OC(=O)N1CCN(CC1)C1=CC(=CC=C1)C(CBr)=O KOZONEASBDEEEY-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229960005053 tinidazole Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960003741 tranylcypromine Drugs 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 229940075466 undecylenate Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
Definitions
- the invention belongs to the field of medicinal chemistry, and particularly relates to a class of amino-substituted nitrogen-containing fused ring compounds, a preparation method thereof and use thereof.
- FGFR fibroblast growth factor receptor
- the technical problem to be solved by the present invention is to provide a kind of amino-substituted nitrogen-containing fused ring compound, a preparation method and use thereof for developing more FGFR small molecule inhibitors, and the amino-substituted nitrogen-containing fused ring compound of the invention belongs to a novel type.
- the specific FGFR kinase inhibitor is excellent in FGFR-related tumor cell proliferation inhibitory activity and can be used for treating diseases such as tumors caused by abnormal FGFR kinase.
- the present invention solves the above technical problems by the following technical solutions.
- the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, or a plurality thereof Crystal form or prodrug,
- R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, cyano; preferably from hydrogen, halogen, methyl;
- R 2 is selected from hydrogen, C 1 -C 10 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl; preferably substituted from hydrogen, C 1 -C 6 or Unsubstituted alkyl group;
- R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, sulfone, sulfoxide, acyl, sulfonyl, nitro; each independently preferably selected from hydrogen, halogen, methyl ;
- M 1 is selected from CR 6 or N;
- R 6 is selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl;
- Ar is selected from a 5-6 membered aryl or heteroaryl group
- L is selected from a chemical bond, C 1 -C 10 alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, acyl, sulfonyl, 4-8 membered cycloalkyl or heterocycloalkyl, 5 a -10 membered aryl or heteroaryl; preferably from a C 1 -C 6 alkyl group;
- A is selected from a 4-8 membered cycloalkyl or heterocycloalkyl group, a 5-10 membered aryl group or a heteroaryl group; preferably a 5-6 membered heterocycloalkyl group, a 5-6 membered aryl group or a heteroaryl group;
- One or more hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of hydrazine, halogen, hydroxy, amino, cyano, sulfone or sulfoxide, C 1 -C 8 alkyl , C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 acyl Or a sulfonyl group, a 5-8 membered aryl or heteroaryl group, a 4-8 membered saturated cycloalkyl group or a heterocycloalkyl group; wherein said heteroaryl group comprises 1-3 heteroatoms selected from the group consisting of: N, O, P and S; the heterocycloalkyl group contains from 1 to 3 heteroatoms selected from the group consisting of N, O, P and S.
- Each of the ring systems described in the above definitions may each independently be a monocyclic ring, a fused ring, a bridged ring or a spiro ring; the heteroaryl group may be partially oxidized and/or reduced.
- the compound of the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer or solvate thereof, of the present invention polymorph or prodrug,
- M 1 is preferably selected from CH or N;
- R 1 is preferably selected from the group consisting of hydrogen, halogen (eg, fluorine), C 1 -C 3 alkyl (eg, methyl);
- R 3 , R 4 and R 5 are each independently preferably selected from hydrogen, halogen (e.g., fluorine) or N(R 9 )(R 10 )-(CH 2 )p- (wherein R 9 and R 10 are both C 1 - C 6 alkyl, p is selected from 0, 1 or 2; for example, N(R 9 )(R 10 )-(CH 2 )p- is dimethylaminomethylene); more preferably R 3 is selected from hydrogen or fluorine And R 4 and R 5 are selected from hydrogen;
- Ar is preferably selected from a 6-membered aryl group, that is, a phenyl group, and further preferably one or more (for example, one, two, three or four) hydrogen atoms on the phenyl group are selected from halogen, cyano, C 1 Substituted with a substituent of -C 8 alkyl, C 1 -C 8 alkoxy, amino, hydroxy, C 2 -C 6 acyl or sulfonyl (further preferably halogen or C 1 -C 8 alkoxy); further Preferably substituted by two halogens (for example fluorine or chlorine) and two C 1 -C 8 alkoxy groups (for example methoxy groups), for example
- halogens for example fluorine or chlorine
- C 1 -C 8 alkoxy groups for example methoxy groups
- A is preferably selected from a 5-6 membered heterocycloalkyl group (the 5-6 membered heterocycloalkyl group is further preferably piperazinyl, piperidinyl or tetrahydropyrrolyl), and 5-6 membered heteroaryl-NH- (The 5-6 membered heteroaryl group is further preferably pyridyl, oxazolyl or triazolyl), -Ph-(CH 2 ) o -NH- (where o is selected from 0 or 1), 5-6 a heteroaryl-(CH 2 ) m -5-6 membered heterocycloalkyl- (wherein the 5-6 membered heterocycloalkyl group is further preferably piperazinyl, piperidinyl or tetrahydropyrrolyl,
- the 5-6 membered heteroaryl group is further preferably a pyridyl group, an oxazolyl group or a triazozolyl group, and m is
- A is the following structural fragment:
- L is always attached to one end of an aryl group, a heteroaryl group or a non-fatty amine group in the A structure.
- the compound of the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer or solvate thereof, of the present invention a polymorph or a prodrug, wherein the compound represented by the formula (I) has the following structure:
- B ring is a 5-10 membered aromatic or aromatic heterocyclic ring; preferably a benzene ring, a pyridine ring, an oxazole ring or three Azole ring.
- the compound of the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer or solvate thereof, of the present invention a polymorph or a prodrug, wherein the compound represented by the formula (I) has the following structure:
- n is selected from 0, 1 or 2, and R 2 is as defined above.
- R 2 is as defined above.
- the present invention is a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, or a plurality thereof a crystal form or a prodrug, wherein the compound represented by the formula (I) is any one of the following compounds:
- the present invention provides a method for producing a compound represented by the formula (I), which comprises the steps of:
- a compound of the formula (B) is obtained by subjecting a compound of the formula (A) to an ⁇ -halocarbonyl compound or an equivalent thereof in the presence of an acid or a base to prepare a compound of the formula (B);
- LG represents a leaving group conventionally used in such reactions in the art, such as a halogen, a sulfone group, a sulfoxide group, a sulfonate group, and the other groups are as defined above.
- the steps a), b), c) are each carried out in a solvent, and the solvents are each independently selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, two Methyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dioxane
- the solvents are each independently selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, two Methyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide
- the transition metal catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), palladium acetate, chlorine Palladium, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, double One or more of (tri-o-phenylmethylphosphine)palladium dichloride, and 1,2-bis(diphenylphosphino)ethanepalladium dichloride;
- the catalyst ligand is selected from the group consisting of tri-tert-butyl One or more of a phosphine, a tri-tert-butylphosphin
- the condensation reagent is selected from one or more of DCC, DIC, CDI, EDCI, HOAt, HOBt, BOP, PyBOP, HATU, and TBTU;
- the base comprises an organic base and/or an inorganic base; wherein the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium t-butoxide, sodium t-butoxide, potassium fluoride One or more of cesium fluoride, potassium phosphate, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, and sodium hydrogencarbonate; the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropyl Ethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), hexamethyldisilazide, hexamethyldisilazide, and lutidine One or more of cesium fluoride, potassium phosphate, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, and sodium hydrogencarbonate; the organic base is selected from the group consisting of pyridine, triethylamine, N,
- the acid is selected from one or more of the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, and trifluoromethanesulfonic acid.
- the compound of the above formula (A) and the respective reagents involved in the above production method are commercially available or can be prepared by a person skilled in the art with reference to a synthesis method in the prior art.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, a diastereomer Isomer, tautomer, solvate, polymorph or prodrug, and at least one pharmaceutical excipient.
- the present invention provides a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereomer thereof, a tautomer thereof, The use of a solvate, polymorph or prodrug, or a pharmaceutical composition as described above for the preparation of a FGFR kinase inhibitor.
- the present invention provides a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereomer thereof, a tautomer thereof,
- a solvate, polymorph or prodrug, or a pharmaceutical composition as described above for the manufacture of a medicament for the prevention and/or treatment of a disease associated with the activity or expression of a protein kinase, in particular a FGFR kinase, in particular for the preparation of prophylaxis and/or Application in the treatment of anti-tumor drugs.
- the tumor includes, but is not limited to, one or more of the following: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, epithelial cell carcinoma. , gastrointestinal stromal tumors, intestinal cancer, cholangiocarcinoma, gallbladder cancer, colorectal cancer, brain cancer, leukemia, lymphoma, nasopharyngeal cancer, bladder cancer, pancreatic cancer, etc., especially liver cancer or cholangiocarcinoma.
- the present invention provides a method for preventing and/or treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable compound thereof a salt, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof.
- the compound represented by the formula (I) of the present invention can inhibit a variety of tumor cells, in particular, can efficiently kill hepatocellular cancer cells, and is a novel therapeutic mechanism for hepatocellular carcinoma.
- reaction can be carried out and purified using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention.
- the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification.
- group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
- substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
- substituent -CH2O- is equivalent to -OCH2-.
- C1-6 alkyl refers to an alkyl group as defined below having a total of from 1 to 6 carbon atoms.
- the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
- halogen means fluoro, chloro, bromo or iodo.
- Haldroxy means an -OH group.
- Hydroalkyl means an alkyl group as defined below which is substituted by a hydroxy group (-OH).
- Niro means -NO 2 .
- Amino means -NH 2 .
- Substituted amino means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkyl Amido, aralkylamino, heteroarylalkylamino.
- Carboxyl means -COOH.
- alkyl group means consisting only of carbon atoms and hydrogen atoms, and is not unsaturated.
- a bond a straight or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and attached to the remainder of the molecule by a single bond.
- alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, decyl and decyl.
- alkenyl as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) And more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group attached to the remainder of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, butyl- 1-Alkenyl, but-2-enyl, pent-1-enyl, pentane-1,4-dienyl and the like.
- alkynyl as a group or part of another group means consisting solely of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group bonded to the remainder of the molecule by a single bond, such as, but not limited to, an ethynyl group , prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl and the like.
- cycloalkyl as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include condensing a ring system, a bridged ring system or a spiro ring system having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be suitably employed
- the carbon atom is connected to the rest of the molecule by a single bond.
- a carbon atom in a cycloalkyl group may be optionally oxidized.
- cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene And cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , fluorenyl, bicyclo [2.2.1] heptyl, 7,7-dimethyl-bicyclo[2.2.1]hept
- heterocyclyl as a group or part of another group means consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
- a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system;
- the nitrogen, carbon or sulfur atom may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated.
- the heterocyclic group may be bonded to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond.
- one or more of the rings may be an aryl or heteroaryl group as defined hereinafter, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
- the heterocyclic group is preferably a stable 4 to 11 membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
- heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]fluorene.
- Alkan-7-yl 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutane, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazolinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indanyl, octahydroindenyl, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl , phthalimido and the like.
- aryl as a group or part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms.
- an aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond.
- aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazine-3(4H)-one-7-yl and the like.
- arylalkyl refers to an alkyl group as defined above substituted with an aryl group as defined above.
- heteroaryl as a group or part of another group means having from 1 to 15 carbon atoms (preferably having from 1 to 10 carbon atoms) and from 1 to 6 selected from nitrogen in the ring. a 5- to 16-membered conjugated ring system of a hetero atom of oxygen and sulfur. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that The aryl group is attached to the remainder of the molecule via a single bond through an atom on the aromatic ring.
- the nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized.
- the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably from 1 to 4 selected
- heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, fluorenyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, isodecyl, oxazolyl, isoxazolyl , mercapto, quinolyl, isoquinolyl, diazaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrin, phenanthryl, phenanthroline, acridine Base, phenazinyl,
- heteroarylalkyl refers to an alkyl group as defined above which is substituted by a heteroaryl group as defined above.
- optionally or “optionally” means that the subsequently described event or condition may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or condition.
- optionally substituted aryl means that the aryl group is substituted or unsubstituted, and the description includes both the substituted aryl group and the unsubstituted aryl group.
- a chemical moiety refers to a particular fragment or functional group in a molecule.
- a chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.
- Stepoisomer refers to a compound composed of the same atoms bonded by the same bond but having a different three-dimensional structure.
- the invention will cover various stereoisomers and mixtures thereof.
- the compounds of the present invention are intended to include E- and Z-geometric isomers unless otherwise stated.
- Tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be embraced within the scope of the invention.
- the compounds of the invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms.
- Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
- the invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof.
- the preparation of the compounds of the invention may employ racemates, diastereomers or enantiomers as starting materials or intermediates.
- Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by crystallization and chiral chromatography.
- pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
- “Pharmaceutically acceptable acid addition salt” means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without any other side effects.
- Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, hexane Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, me
- “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic or organic base which is capable of retaining the biological effectiveness of the free acid without other side effects.
- Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like.
- Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
- Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins.
- ammonia isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclo Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, hydrazine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, and the like.
- Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
- Polymorph refers to a different solid crystalline phase of certain compounds of the invention resulting from the presence of two or more different molecular arrangements in a solid state. Certain compounds of the invention may exist in more than one crystal form, and the invention is intended to include various crystal forms and mixtures thereof.
- solvate refers to an aggregate comprising one or more molecules of the compound of the invention and one or more solvent molecules.
- the solvent may be water, and the solvate in this case is a hydrate.
- the solvent may be an organic solvent.
- the compounds of the invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.
- the compounds of the invention may form true solvates, but in some cases, it is also possible to retain only a variable amount of water or a mixture of water and a portion of the indefinite solvent.
- the compound of the present invention can be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
- the invention also includes prodrugs of the above compounds.
- prodrug means a compound which can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis.
- prodrug refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention.
- Prodrugs may be inactive when administered to an individual in need thereof, but are converted in vivo to the active compound of the invention.
- Prodrugs are typically rapidly converted in vivo to produce the parent compound of the invention, for example by hydrolysis in blood.
- Prodrug compounds generally provide the advantage of solubility, tissue compatibility or sustained release in mammalian organisms.
- Prodrugs include known amino protecting groups and carboxy protecting groups.
- pharmaceutical composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human.
- the medium includes a pharmaceutically acceptable carrier.
- the purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the active ingredient and thereby exerting biological activity.
- pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.
- pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government authorities for acceptable use by humans or livestock. , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
- tumor include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
- preventing include the possibility of reducing the occurrence or progression of a disease or condition by a patient.
- treatment and other similar synonyms as used herein includes the following meanings:
- an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
- an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
- An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
- administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
- parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
- topical administration and rectal administration.
- the techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa.
- the compounds and compositions discussed herein are administered orally.
- pharmaceutical combination means a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, It includes both fixed and unfixed combinations of active ingredients.
- fixed combination refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
- unfixed combination refers to the simultaneous administration, combination or sequential administration of at least one of the compounds described herein and at least one synergistic formulation to the patient in the form of separate entities. These are also applied to cocktail therapy, for example the administration of three or more active ingredients.
- the intermediate compound functional groups may need to be protected by a suitable protecting group.
- suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like.
- Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like.
- Suitable mercapto protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
- Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
- Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T. W. and P. G. M. Wuts, Protective Groups in Organic Synthesis, (1999), 4th Ed., Wiley.
- the protecting group can also be a polymeric resin.
- the present inventors prepared a novel compound having the structure shown in Formula I, and found that it has a good FGFR kinase inhibitory activity, and the compound is at a very low concentration (as low as ⁇ At 1 nmol/L, it has a specific inhibitory effect on FGFR kinase and is excellent in FGFR-related tumor cell proliferation inhibitory activity, and thus can be used for treating diseases associated with abnormal FGFR kinase mutation or expression, such as tumors. Based on the above findings, the inventors completed the present invention.
- the second step 2,4-dichloro-1,5-dimethoxy-3-methylbenzene (31 g, 0.14 mol) was dissolved in carbon tetrachloride (600 mL) and placed in a dry round bottom flask ( In 1000 mL), azobisisobutyronitrile (3.0 g, 0.018 mol) and N-bromosuccinimide (27.6 g, 0.154 mol) were successively added at room temperature. The reaction was carried out at 80 °C for 3 h, and the reaction was quenched with aqueous sodium hydrogen carbonate, and then extracted with dichloromethane. The organic phase was dried, concentrated, and crystallized from methyl tert-butyl ether to give compound 3-bromomethyl-2,4-dichloro- 1,5-Dimethoxybenzene (30 g, white solid).
- Step 3 Add the compound 3-bromomethyl-2,4-dichloro-1,5-dimethoxybenzene (30 g, 0.1 mol) and acetonitrile (500 mL) to a dry 1000 mL round bottom flask at room temperature Trimethylsilyl cyanide (12 g, 0.34 mmol) and tetrabutylammonium fluoride (100 mL, 1 mol/L) were added. After stirring at room temperature for 1 h, TLC showed the reaction was completed. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjj Base)-acetonitrile (20 g, white solid).
- Step 4 In a dry 250 mL round bottom flask, add (2,6-dichloro-3,5-dimethoxy-phenyl)-acetonitrile (10.4 g, 0.028 mol) and N,N-dimethyl Base carboxamide (100 mL) was added 4-amino-2-methylthio-pyrimidine-5-carbaldehyde (5 g, 0.02 mol) and potassium carbonate (12.25 g, 0.06 mol), and then stirred overnight until the reaction was completed. The reaction mixture was extracted with EtOAc. EtOAc (EtOAc m.
- Step 2 3-[4-(2,6-Dichloro-3,5-dimethoxy-phenyl)-8-methylthio-3,7,9,9b-tetraaza-cyclo Methyl amyl [a]naphthalen-2-yl]-propanoate (2.4 g) was dissolved in anhydrous methanol (20 mL). The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and the solvent was evaporated.
- the third step 3-[4-(2,6-dichloro-3,5-dimethoxy-phenyl)-8-methylthio-3,7,9,9b-tetraaza-cyclo Amyl [a]naphthalen-2-yl]-propan-1-ol (1.8 g) was dissolved in ethyl acetate (20 mL), and then evaporated and evaporated. The reaction mixture was quenched by the addition of sodium thiosulfate solution, and the organic phase was separated. The organic phase was washed with saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, filtered, and evaporated.
- Step 1 Reductive amination of N-Boc diamine
- Step 2 Oxidation of methylthio groups to methylsulfonyl groups
- the methylsulfonate intermediate (1 eq.) and the starting amine (2 eq.) were dissolved in anhydrous N,N-dimethylformamide and heated to 100 ° C for 2 hours. After completion of the reaction, the mixture was extracted with methylene chloride. The organic phase was washed with saturated sodium hydrogen sulfate and water, dried over anhydrous sodium sulfate, filtered,
- the starting material (1 eq.) was dissolved in dichloromethane, and the mixture was stirred for 2 hr. After completion of the reaction, the mixture was concentrated under reduced pressure.
- Example 2 1-(4-(3-(4-(2,6-Difluoro-3,5-dimethoxyaniline)-8-(methylamine)imidazole [1,2-a][1 ,6]naphthyridin-2-yl)propyl)piperazin-1-yl)prop-2-en-1-one
- Example 4 1-(4-(3-(2-((cyclopropylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyaniline) imidazole [1' , 2':1,6]pyridine [2,3-d]pyrimidin-8-yl)propyl)piperazin-1-yl)prop-2-en-1-one
- Example 5 1-(4-(3-(4-(2,6-Dichloro-3,5-dimethoxyaniline)-8-(methylamine)imidazole [1,2-a][1 ,6]naphthyridin-2-yl)propyl)piperazin-1-yl)prop-2-en-1-one
- Example 6 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyaniline)-2-((2-methoxyethyl)amino)imidazole [ 1',2':1,6]pyridine [2,3-d]pyrimidin-8-yl)propyl)piperazin-1-yl)prop-2-en-1-one
- Example 7 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyaniline)-2-((2-(4-methylpiperazin-1-) Ethyl ethyl)amino)imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-8-yl)propyl)piperazin-1-yl)prop-2-ene 1-ketone
- Example 8 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyaniline)-2-(ethylamine)imidazole [1', 2': 1, 6]pyridine [2,3-d]pyrimidin-8-yl)propyl)piperazin-1-yl)prop-2-en-1-one
- Example 10 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyaniline)-2-((2,3-dihydroxypropyl)amino)imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-8-yl)propyl)piperazin-1-yl)prop-2-en-1-one
- Example 12 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyaniline)-2-((2-hydroxy-2-methylpropyl)amino) Imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-8-yl)propyl)piperazin-1-yl)prop-2-en-1-one
- Example 14 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyaniline)-2-(methylamine)imidazole [1', 2':1, 6]pyridine [2,3-d]pyrimidin-8-yl)propyl)-2,2-dimethylpiperazin-1-yl)prop-2-en-1-one
- Example 15 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyaniline)-2-(methylamine)imidazole [1', 2':1, 6]pyridine [2,3-d]pyrimidin-8-yl)-2,2-dimethylpropyl)piperazin-1-yl)prop-2-en-1-one
- Example 16 1-(4-((6-(2,6-Dichloro-3,5-phenyldimethoxyphenyl)-2-(methylamine)imidazole [1', 2': 1 ,6]pyridine [2,3-d]pyrimidin-8-yl)methyl)piperazin-1-yl)acrylamide
- the second step the above intermediate (500 mg) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and 1,3-dibromopropan-2-one (1.1 eq) was added at room temperature, heated at 80 degrees. The mixture was stirred until the reaction was completed. m ⁇
- the third step the above crude product was dissolved in anhydrous N,N-dimethylformamide (10 mL), and N-Boc-piperazine (1.1 eq) was added to the mixture, and the mixture was stirred at room temperature for 2 hours, and the reaction was completed. The organic layer was extracted with EtOAc (EtOAc)EtOAc. LC-MS: 602.1/604.1.
- Example 16 The compound of Example 16 was synthesized by the method described in General Method Three-General Method 5.
- the intermediate 8-(4-aminophenyl)-6-(2,6-dichloro-3) is then prepared by the second step of the methylthio group oxidation reaction and the third step of the methylamine substitution reaction.
- ,5-dimethoxyphenyl)-N-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-amine, LC-MS: ESI [M+H ]+ 496.1/498.1.
- the target compound N-(4-(6-(2,6-dichloro-3,5-phenyldimethoxyphenyl)-), was synthesized by the method of the fifth step of the acrylation reaction in the general method of the examples.
- Example 18 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamine)imidazole [1', 2':1 ,6]pyridine [2,3-d]pyrimidin-8-yl)phenyl)piperazin-1-yl)acrylamide
- Test Example 1 Determination of Inhibitory Activity of FGFR1 and FGFR4 Kinases by the Compounds of the Invention
- Examples 1 to 19 provided by the present invention have better inhibitory activities against FGFR1 and FGFR4, and most of the compounds of the examples have inhibitory activity IC 50 values of less than 10 nM, and some examples (such as the examples) The inhibitory activity of 3) even an IC 50 of less than 1 nM showed a strong inhibitory activity. As shown in Table 1.
- Test Example 2 Effect of the compound of the present invention on FGFR-mediated tumor cell proliferation ability
- Test method Hep3B cells (ATCC) in logarithmic growth phase were inoculated into 96-well culture plates at a suitable density, 100 ⁇ L per well, and cultured overnight, and different concentrations of compounds were added for 72 hr, and set. The solvent control group (negative control) was incubated at 37 degrees under 5% CO 2 . 10 mM compound stock solution was added to the cells.
- the effect of the compound on cell proliferation was determined by CellTiter- (Promega) assay, 30 ⁇ L of CTG reagent was added to each well, placed in a 37-degree incubator for 2-4 hours, and read with a full-wavelength microplate reader Envision at a wavelength of 450 nm.
- Examples 1 to 19 provided by the present invention have an IC 50 value of less than 500 nM for the proliferation inhibitory activity of Hep3B cells, and most of the compounds of the examples have an inhibitory activity IC 50 value of less than 50 nM.
- IC 50 ⁇ 20 nM is represented by "+++”
- 20 nM ⁇ IC 50 ⁇ 200 nM is represented by "++”
- IC 50 >200 nM is represented by "+”.
- Test Example 3 Test of Example Compounds Not Different in Kinase Inhibitory Activity
- the compounds of the invention also have inhibitory activities against different kinases such as EGFR, VEGFR, PDGFR, FGFR, RET, MET, Src, Lyn, Syk, MEK, CDK, RAF, ROS, etc., some of the compounds of the examples (eg
- Example 3 shows better kinase selectivity with a selectivity greater than 100 fold.
- Test Example 4 Proliferation inhibitory activity test of the compound of the example on different tumor cells
- tumor cells such as HuH-7, JHH-7, DMS114, SNU-16, KG1, UM-UC-14, HCT116, NCI-H716, MCF-7, Colo-205, were tested by SRB staining or CCK8 assay.
- Test Example 5 ADME-PK test of the compound of the example
- Metabolic stability test 150 ⁇ L of liver microsomes (final concentration 0.5 mg/mL) were used for metabolic stability incubation.
- the system contained NADPH (final concentration 1 mM), 1 ⁇ M test compound and positive control midazolam.
- the lenil or negative control atenolol was stopped at 0 min, 5 min, 10 min and 30 min with tinidazole-containing acetonitrile, vortexed for 10 min, centrifuged at 15000 rpm for 10 min, and 50 ⁇ L of supernatant was injected into a 96-well plate.
- the metabolic stability of the compound was calculated by measuring the relative reduction in the original drug.
- Direct inhibition test direct inhibition of incubation with 100 ⁇ L of human liver microsomes (final concentration 0.2 mg/mL) containing NADPH (final concentration 1 mM), 10 ⁇ M compound, positive inhibitor cocktail (ketoconazole 10 ⁇ M, quinidine 10 ⁇ M, sulfaphenazole 100 ⁇ M, ⁇ -naphthoflavone 10 ⁇ M, tranylcypromine 1000 ⁇ M), negative control (0.1% DMSO in BPS) and mixed probe substrate (midazolam) 10 ⁇ M, testosterone 100 ⁇ M, dextromethorphan 10 ⁇ M, diclofenac 20 ⁇ M, phenacetin 100 ⁇ M, mefenexine 100 ⁇ M), and the reaction was terminated after incubation for 20 min. The relative activity of the enzyme was calculated by measuring the relative amount of production of the metabolite.
- test animals were healthy adult male SD rats or BALB/c mice, provided by Shanghai Xipuerkekai Experimental Animal Co., Ltd.; administration mode and sample collection: respectively given to SD rats or BALB/c mice
- Example 3 and Example 17 showed better ADME properties, and good in vivo absorption and metabolism properties of rats and mice, and indicators such as AUC/Cmax showed excellent compounds.
- the medicinal properties were better ADME properties, and good in vivo absorption and metabolism properties of rats and mice, and indicators such as AUC/Cmax showed excellent compounds.
- the medicinal properties were better ADME properties, and good in vivo absorption and metabolism properties of rats and mice, and indicators such as AUC/Cmax showed excellent compounds. The medicinal properties.
- Test Example 6 Test of inhibition of growth inhibition of nude mice by the compound of the example
- the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of the nude mice under aseptic conditions.
- the nude mice were transplanted subcutaneously with a vernier caliper to measure the diameter of the transplanted tumor.
- the animals were randomly divided into tumors with an average volume of about 130 mm 3 .
- the compound of the example administered to the desired concentration with water for injection containing 1% Tween 80
- the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
- Example 3 and Example 17 showed better tumor inhibition in nude mice, and at lower doses (even below 20 mg/kg), greater than 80% inhibition was achieved. rate.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims (10)
- 一种如式(I)所示的化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,式中:R 1选自氢、卤素、C 1-C 3烷基、氰基;R 2选自氢、C 1-C 10烷基、3-8元环烷基或杂环烷基、5-8元芳基或杂芳基;R 3、R 4和R 5各自独立地选自氢、卤素、氰基、烷基、砜基、亚砜基、酰基、磺酰基、硝基;M 1选自CR 6或N;R 6选自氢、卤素、C 1-C 3烷基;Ar选自5-6元芳基或杂芳基;L选自化学键、C 1-C 10烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、酰基、磺酰基、4-8元环烷基或杂环烷基、5-10元芳基或杂芳基;A选自4-8元环烷基或杂环烷基、5-10元芳基或杂芳基;上述的任一基团上的一个或多个氢原子或被选自下组的取代基取代:氘、卤素、羟基、氨基、氰基、砜基或亚砜基、C 1-C 8烷基、C 3-C 8环烷基、C 1-C 8烷氧基、C 1-C 8烷基氨基、C 2-C 6烯基、C 2-C 6炔基、C 2-C 6酰基或磺酰基、5-8元芳基或杂芳基、4-8元饱和环烷基或杂环烷基;其中,所述的杂芳基包含1-3个选自下组的杂原子:N、O、P和S;所述的杂环烷基包含1-3个选自下组的杂原子:N、O、P和S。
- 如权利要求1所述的如式(I)所示的化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,其特征在于,式中,M 1选自CH或N;和/或,R 1选自氢、卤素、C 1-C 3烷基;和/或,R 2选自氢、C 1-C 6烷基、C 1-C 6氘代烷基、C 1-C 6卤代烷基、5-8元芳基或杂芳基、4-6元环烷基或杂环烷基-(CH 2)x-、O(R 6)-(CH 2)y-、N(R 7)(R 8)-(CH 2)z-、N(CH 3) 2C(=O)CH-、HOC(CH 3) 2CH-或CH(CH 2OH) 2-CH 2-;其中,所述的5-8元芳基或杂芳基优选为吡啶基、且优选进一步被一个6元杂环烷基取代;所述的4-6元的环烷基或杂环烷基优选为环丙基、四氢呋喃基、哌嗪基、哌啶基或四氢吡咯基,且优选进一步被C 1-C 6烷基或氨基取代;R 6、R 7和R 8各自独立地选自氢或C 1-C 6烷基;x、y和z各自独立地选自0、1、2、3或4;和/或,R 3、R 4和R 5各自独立地选自氢、卤素或N(R 9)(R 10)-(CH 2)p-;其中R 9和R 10均为C 1-C 6烷基,p选自0、1或2;更优选R 3选自氢或氟,且R 4和R 5选自氢;和/或,Ar选自苯基,且进一步优选所述苯基上的一个或多个氢原子被选自卤素、氰基、C 1-C 8烷基、C 1-C 8烷氧基、氨基、羟基、C 2-C 6酰基或磺酰基的取代基所取代;更进一步优选为被两个卤素和两个C 1-C 8烷氧基所取代;和/或,L选自化学键、-(CH 2) d-、-(CH 2) e-CH=CH-,或-O-(CH 2) n-;其中d为1、2或3,e为1或2,n为1、2、3或4;和/或,A选自5-6元杂环烷基、5-6元杂芳基-NH-、-Ph-(CH 2) o-NH-、5-6元杂芳基-(CH 2) m-5-6元杂环烷基-;其中,o选自0或1;所述5-6元杂环烷基进一步优选为哌嗪基、哌啶基或四氢吡咯基,所述的5-6元杂芳基进一步优选为吡啶基、噁唑基或三氮唑基,m选自0或1;且A优选其上两个取代基为间位或对位取代关系;其中,L总是与A结构中芳基、杂芳基或者非脂肪胺基的一端连接。
- 一种药物组合物,其包括治疗有效量的如权利要求1-6任一项所述的式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,以及至少一种药用辅料。
- 一种如权利要求1-6任一项所述的式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,或如权利要求8所述的药物组合物在制备FGFR激酶抑制剂中的应用。
- 一种如权利要求1-6任一项所述的式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,或如权利要求8所述的药物组合物在制备预防和/或治疗与蛋白激酶特别是FGFR激酶活性或表达量相关的疾病的药物中的应用,特别是制备预防和/或治疗抗肿瘤药物中的应用;其中,所述的肿瘤选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、肝癌、皮肤癌、胃癌、上皮细胞癌、胃肠道间质瘤、肠癌、胆管癌、胆囊癌、结直肠癌、脑癌、白血病、淋巴癌、鼻咽癌、膀胱癌、胰腺癌,特别是肝癌或胆管癌。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/760,005 US11267815B2 (en) | 2017-10-30 | 2018-10-30 | Class of amino-substituted nitrogen-containing fused ring compounds, preparation method therefor, and use thereof |
EP18874000.5A EP3705480B1 (en) | 2017-10-30 | 2018-10-30 | Class of amino-substituted nitrogen-containing fused ring compounds, preparation method therefor, and use thereof |
JP2020544089A JP7041821B2 (ja) | 2017-10-30 | 2018-10-30 | アミノ置換窒素含有縮合環化合物、その調製方法及び使用 |
KR1020207015596A KR102421137B1 (ko) | 2017-10-30 | 2018-10-30 | 아미노치환 질소함유 축합고리 화합물 및 그의 제조방법과 용도 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711039980.6 | 2017-10-30 | ||
CN201711039980 | 2017-10-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2019085895A1 true WO2019085895A1 (zh) | 2019-05-09 |
Family
ID=66295774
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2018/112661 WO2019085895A1 (zh) | 2017-10-30 | 2018-10-30 | 一类氨基取代含氮稠环化合物及其制备方法和用途 |
Country Status (6)
Country | Link |
---|---|
US (1) | US11267815B2 (zh) |
EP (1) | EP3705480B1 (zh) |
JP (1) | JP7041821B2 (zh) |
KR (1) | KR102421137B1 (zh) |
CN (1) | CN109721599B (zh) |
WO (1) | WO2019085895A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2022523448A (ja) * | 2019-03-08 | 2022-04-22 | ショウヤオ ホールディングス(ベイジン) カンパニー, リミテッド | Fgfr4キナーゼ阻害剤、その製造方法及び用途 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2021075483A (ja) * | 2019-11-08 | 2021-05-20 | 静岡県公立大学法人 | 化合物又はその塩 |
TW202321253A (zh) * | 2021-08-04 | 2023-06-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | 含氮雜環化合物、其製備方法及其在醫藥上的應用 |
CN115703724B (zh) * | 2021-08-09 | 2024-02-13 | 中国石油化工股份有限公司 | 一种磺酸化合物及一种速溶型耐温抗盐驱油用聚丙烯酰胺和其制法及应用 |
WO2024044713A1 (en) * | 2022-08-25 | 2024-02-29 | Enliven Inc. | Naphthyridine compounds for inhibition of raf kinases |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105481858A (zh) * | 2014-10-11 | 2016-04-13 | 上海医药集团股份有限公司 | 一种含氮稠杂环化合物、其制备方法、组合物及应用 |
US20160332971A1 (en) * | 2015-05-15 | 2016-11-17 | University Of Kentucky Research Foundation | Arylquinoline, arylquinolone and arylthioquinolone derivatives and use thereof to treat cancer |
CN106588920A (zh) * | 2016-12-27 | 2017-04-26 | 云南大学 | 1,3‑二氮杂环并[1,2‑a]喹啉类化合物及其制备方法和抗肿瘤应用 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MXPA04009585A (es) | 2002-04-03 | 2005-01-11 | Hoffmann La Roche | Compuestos imidazo fusionados. |
US9580423B2 (en) | 2015-02-20 | 2017-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
RU2745035C1 (ru) | 2017-02-27 | 2021-03-18 | Бетта Фармасьютикалз Ко., Лтд. | Ингибитор fgfr и его применение |
-
2018
- 2018-10-30 KR KR1020207015596A patent/KR102421137B1/ko active IP Right Grant
- 2018-10-30 EP EP18874000.5A patent/EP3705480B1/en active Active
- 2018-10-30 WO PCT/CN2018/112661 patent/WO2019085895A1/zh unknown
- 2018-10-30 CN CN201811276459.9A patent/CN109721599B/zh active Active
- 2018-10-30 JP JP2020544089A patent/JP7041821B2/ja active Active
- 2018-10-30 US US16/760,005 patent/US11267815B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105481858A (zh) * | 2014-10-11 | 2016-04-13 | 上海医药集团股份有限公司 | 一种含氮稠杂环化合物、其制备方法、组合物及应用 |
US20160332971A1 (en) * | 2015-05-15 | 2016-11-17 | University Of Kentucky Research Foundation | Arylquinoline, arylquinolone and arylthioquinolone derivatives and use thereof to treat cancer |
CN106588920A (zh) * | 2016-12-27 | 2017-04-26 | 云南大学 | 1,3‑二氮杂环并[1,2‑a]喹啉类化合物及其制备方法和抗肿瘤应用 |
Non-Patent Citations (9)
Title |
---|
"Methods in Molecular Biology", vol. 243, 2004, article "Chiral Separations, Methods and Protocols" |
"VOGEL'S TESTBOOK CYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY", 1991, LONGMAN SCIENTIFIC AND TECHNICAL LTD., pages: 809 - 816 |
A.M. STALCUP: "Chiral Separations", ANNU. REV. ANAL. CHEM., vol. 3, 2010, pages 341 - 63 |
CAREYSUNDBERG: "ADVANCED ORGANIC CHEMISTRY 4TH ED.", vol. B, 2001, PLENUM PRESS |
GREENE, T. W.P. G. M. WUTS: "The Pharmaceutical Basis of Therapeutics", 1999, MACK PUBLISHING CO. |
GREENWALD, R. B. ET AL., J. MED. CHEM., vol. 43, 2000, pages 475 |
HELLER,, ACC. CHEM. RES., vol. 23, 1990, pages 128 |
SAULNIER, M. G. ET AL., BIOORG. MED. CHEM. LETT., vol. 4, 1994, pages 1985 - 1990 |
See also references of EP3705480A4 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2022523448A (ja) * | 2019-03-08 | 2022-04-22 | ショウヤオ ホールディングス(ベイジン) カンパニー, リミテッド | Fgfr4キナーゼ阻害剤、その製造方法及び用途 |
JP7378488B2 (ja) | 2019-03-08 | 2023-11-13 | ショウヤオ ホールディングス(ベイジン) カンパニー, リミテッド | Fgfr4キナーゼ阻害剤、その製造方法及び用途 |
Also Published As
Publication number | Publication date |
---|---|
KR20200078610A (ko) | 2020-07-01 |
CN109721599A (zh) | 2019-05-07 |
KR102421137B1 (ko) | 2022-07-13 |
JP7041821B2 (ja) | 2022-03-25 |
US20200347061A1 (en) | 2020-11-05 |
EP3705480A1 (en) | 2020-09-09 |
EP3705480B1 (en) | 2024-02-28 |
CN109721599B (zh) | 2020-12-15 |
US11267815B2 (en) | 2022-03-08 |
JP2021501215A (ja) | 2021-01-14 |
EP3705480C0 (en) | 2024-02-28 |
EP3705480A4 (en) | 2021-07-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3269370B1 (en) | Novel condensed pyrimidine compound or salt thereof | |
KR102058366B1 (ko) | 축합 피리미딘 화합물 또는 그의 염 | |
WO2019085895A1 (zh) | 一类氨基取代含氮稠环化合物及其制备方法和用途 | |
JP6035423B2 (ja) | 新規な縮合ピリミジン化合物又はその塩 | |
WO2019085894A1 (zh) | 一类含氮稠环化合物及其制备方法和用途 | |
WO2017084640A1 (zh) | 一种含氮杂环化合物及其制备方法与在抑制激酶活性中的应用 | |
WO2013170770A1 (zh) | 具有抗肿瘤活性的乙炔衍生物 | |
WO2016173557A1 (zh) | 一类具有激酶抑制活性的化合物、制备方法和用途 | |
CN117730075A (zh) | 一种吡唑衍生物,其制备方法和在药学上的应用 | |
JP7273030B6 (ja) | シクロオレフィン置換複素芳香族化合物およびそれらの使用 | |
WO2020063976A1 (zh) | 一类稠杂环联芳基苄醇类化合物、制备方法和用途 | |
CN113527299B (zh) | 一类含氮稠环类化合物、制备方法和用途 | |
WO2022135590A1 (zh) | 一类嘧啶并杂环类化合物、制备方法和用途 | |
WO2020038458A1 (zh) | 一类稠环三氮唑类化合物、制备方法和用途 | |
WO2022105921A1 (zh) | 一类嘧啶并杂环类化合物、制备方法和用途 | |
WO2022095904A1 (zh) | 吡唑并哒嗪酮化合物、其药物组合物及其用途 | |
WO2020187123A1 (zh) | 一类吡咯酰胺并吡啶酮类化合物、制备方法和用途 | |
CN114907350B (zh) | 一类含氮稠环类化合物、制备方法和用途 | |
CN115611888A (zh) | 吡啶并嘧啶酮类衍生物及其制备方法和用途 | |
CN114380827A (zh) | Kras g12c抑制剂及其在医药上的应用 | |
WO2021209039A1 (zh) | 一种喹唑啉类化合物、制备方法及其应用 | |
TW202312995A (zh) | 氮雜芳基化合物、其製備方法及應用 | |
WO2023134374A1 (zh) | 一类嘧啶并杂环类化合物、制备方法和用途 | |
WO2019170063A1 (zh) | 吲嗪类化合物、其制备方法及用途 | |
WO2023116763A1 (zh) | 一种哒嗪类化合物、其药物组合物及应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18874000 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2020544089 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 20207015596 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2018874000 Country of ref document: EP Effective date: 20200602 |