JP6877407B2 - Ntrk関連障害の治療に有用な化合物および組成物 - Google Patents
Ntrk関連障害の治療に有用な化合物および組成物 Download PDFInfo
- Publication number
- JP6877407B2 JP6877407B2 JP2018510406A JP2018510406A JP6877407B2 JP 6877407 B2 JP6877407 B2 JP 6877407B2 JP 2018510406 A JP2018510406 A JP 2018510406A JP 2018510406 A JP2018510406 A JP 2018510406A JP 6877407 B2 JP6877407 B2 JP 6877407B2
- Authority
- JP
- Japan
- Prior art keywords
- mmol
- mixture
- tert
- added
- etoac
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims description 191
- 238000011282 treatment Methods 0.000 title claims description 9
- 239000000203 mixture Substances 0.000 title description 254
- 150000003839 salts Chemical class 0.000 claims description 29
- 206010028980 Neoplasm Diseases 0.000 claims description 21
- 201000011510 cancer Diseases 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 108091000080 Phosphotransferase Proteins 0.000 claims description 11
- 102000020233 phosphotransferase Human genes 0.000 claims description 11
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 230000002159 abnormal effect Effects 0.000 claims description 4
- 230000001575 pathological effect Effects 0.000 claims description 4
- 108010002164 tyrosine receptor Proteins 0.000 claims description 4
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 108010025020 Nerve Growth Factor Proteins 0.000 claims description 3
- 102000007072 Nerve Growth Factors Human genes 0.000 claims description 3
- 206010033701 Papillary thyroid cancer Diseases 0.000 claims description 3
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 208000029824 high grade glioma Diseases 0.000 claims description 3
- 208000030173 low grade glioma Diseases 0.000 claims description 3
- 201000011614 malignant glioma Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 239000003900 neurotrophic factor Substances 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 claims description 3
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 208000009956 adenocarcinoma Diseases 0.000 claims description 2
- 208000035269 cancer or benign tumor Diseases 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims 1
- 201000008274 breast adenocarcinoma Diseases 0.000 claims 1
- 208000024063 childhood astrocytic tumor Diseases 0.000 claims 1
- 201000011628 juvenile astrocytoma Diseases 0.000 claims 1
- 208000025113 myeloid leukemia Diseases 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 353
- -1 C 1 -C 6 alkyl Chemical group 0.000 description 223
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 179
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 176
- 235000019439 ethyl acetate Nutrition 0.000 description 167
- 239000000243 solution Substances 0.000 description 134
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 118
- 238000006243 chemical reaction Methods 0.000 description 115
- 239000004698 Polyethylene Substances 0.000 description 98
- 238000004809 thin layer chromatography Methods 0.000 description 78
- 238000005160 1H NMR spectroscopy Methods 0.000 description 75
- 239000011734 sodium Substances 0.000 description 70
- 238000005481 NMR spectroscopy Methods 0.000 description 67
- 125000000753 cycloalkyl group Chemical group 0.000 description 67
- 239000007787 solid Substances 0.000 description 66
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 66
- 125000000623 heterocyclic group Chemical group 0.000 description 64
- 238000003786 synthesis reaction Methods 0.000 description 61
- 230000015572 biosynthetic process Effects 0.000 description 60
- 239000011541 reaction mixture Substances 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 125000003118 aryl group Chemical group 0.000 description 55
- 239000003921 oil Substances 0.000 description 52
- 235000019198 oils Nutrition 0.000 description 52
- 239000012043 crude product Substances 0.000 description 51
- 238000010898 silica gel chromatography Methods 0.000 description 51
- 239000012044 organic layer Substances 0.000 description 50
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 44
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 239000011259 mixed solution Substances 0.000 description 40
- 229920006395 saturated elastomer Polymers 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- 125000000217 alkyl group Chemical group 0.000 description 37
- 239000002904 solvent Substances 0.000 description 37
- 239000007858 starting material Substances 0.000 description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- 125000005843 halogen group Chemical group 0.000 description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 31
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 30
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- 125000001072 heteroaryl group Chemical group 0.000 description 27
- 238000000746 purification Methods 0.000 description 26
- 125000003545 alkoxy group Chemical group 0.000 description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 25
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 24
- 125000004093 cyano group Chemical group *C#N 0.000 description 24
- 229910052739 hydrogen Inorganic materials 0.000 description 23
- 239000001257 hydrogen Substances 0.000 description 23
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 21
- 0 CC(C1C(C)NC(C)C1C)*=C Chemical compound CC(C1C(C)NC(C)C1C)*=C 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- 239000000706 filtrate Substances 0.000 description 20
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 20
- 238000004949 mass spectrometry Methods 0.000 description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
- 125000004404 heteroalkyl group Chemical group 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- 125000004429 atom Chemical group 0.000 description 17
- 125000001188 haloalkyl group Chemical group 0.000 description 17
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 17
- 238000000034 method Methods 0.000 description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 13
- 125000003710 aryl alkyl group Chemical group 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- 125000005842 heteroatom Chemical group 0.000 description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 13
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000002953 preparative HPLC Methods 0.000 description 12
- 150000001721 carbon Chemical group 0.000 description 11
- 239000012141 concentrate Substances 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 11
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 10
- 125000002619 bicyclic group Chemical group 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- JCGDTBHMOCDGSY-LLUDDFSJSA-N (1r,2r,5r)-2-[[(1s)-1-phenylethyl]amino]-5-phenylmethoxycyclohexan-1-ol Chemical compound O([C@@H]1CC[C@H]([C@@H](C1)O)N[C@@H](C)C=1C=CC=CC=1)CC1=CC=CC=C1 JCGDTBHMOCDGSY-LLUDDFSJSA-N 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 125000004104 aryloxy group Chemical group 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 125000004438 haloalkoxy group Chemical group 0.000 description 9
- 150000002431 hydrogen Chemical class 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- CSOYDALHEQEMAK-UHFFFAOYSA-N 2h-pyrimidine-1-carboxylic acid Chemical compound OC(=O)N1CN=CC=C1 CSOYDALHEQEMAK-UHFFFAOYSA-N 0.000 description 8
- 230000002378 acidificating effect Effects 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 230000004927 fusion Effects 0.000 description 8
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 7
- NGOTYFZFWPHNSU-UHFFFAOYSA-N 1,3-dioxol-4-amine Chemical compound NC1=COCO1 NGOTYFZFWPHNSU-UHFFFAOYSA-N 0.000 description 7
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 7
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Substances CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 125000001153 fluoro group Chemical group F* 0.000 description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
- VNSQXWISTNFYFV-UHFFFAOYSA-N 1,3-dioxol-4-ol Chemical compound OC1=COCO1 VNSQXWISTNFYFV-UHFFFAOYSA-N 0.000 description 6
- LPCQBTAOTIZGAE-UHFFFAOYSA-N 2h-pyrimidine-1-carboxamide Chemical compound NC(=O)N1CN=CC=C1 LPCQBTAOTIZGAE-UHFFFAOYSA-N 0.000 description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 125000002947 alkylene group Chemical group 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 238000004296 chiral HPLC Methods 0.000 description 6
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 6
- 239000002798 polar solvent Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- QZQVDIVTVLELOB-HSUXUTPPSA-N (1R,3R,4R)-4-aminocyclohexane-1,3-diol Chemical compound N[C@@H]1CC[C@@H](O)C[C@H]1O QZQVDIVTVLELOB-HSUXUTPPSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 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 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- KAYCKDOHSXLUGH-HCCKASOXSA-N tert-butyl (2R)-2-(2-chloro-5-fluoropyridin-3-yl)-4-hydroxypyrrolidine-1-carboxylate Chemical compound ClC1=NC=C(C=C1[C@@H]1N(CC(C1)O)C(=O)OC(C)(C)C)F KAYCKDOHSXLUGH-HCCKASOXSA-N 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 230000000699 topical effect Effects 0.000 description 5
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- BFHDJRWZCINSEQ-HSUXUTPPSA-N (1R,2R,4R)-2-amino-4-methylsulfonylcyclopentan-1-ol Chemical compound N[C@H]1[C@@H](C[C@@H](C1)S(=O)(=O)C)O BFHDJRWZCINSEQ-HSUXUTPPSA-N 0.000 description 4
- ZKCGXZHSOARULJ-FRRDWIJNSA-N (1s,4r,6r)-4-phenylmethoxy-7-oxabicyclo[4.1.0]heptane Chemical compound O([C@H]1C[C@H]2O[C@H]2CC1)CC1=CC=CC=C1 ZKCGXZHSOARULJ-FRRDWIJNSA-N 0.000 description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 4
- 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 4
- BKRHQMHIXPQFQI-UHFFFAOYSA-N 4-oxo-1,2-dihydropyrazolo[3,4-d]pyrimidine-3-carboxylic acid Chemical compound C1=NC(=O)C2=C(C(=O)O)NNC2=N1 BKRHQMHIXPQFQI-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 4
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 description 4
- 101000596894 Homo sapiens High affinity nerve growth factor receptor Proteins 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 150000001414 amino alcohols Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 description 4
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 125000004001 thioalkyl group Chemical group 0.000 description 4
- 150000003573 thiols Chemical class 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- MWKJRFUZYIKLNI-BSQWINAVSA-N (1R,2R,3S,4R,5S)-4-aminobicyclo[3.1.0]hexane-2,3-diol Chemical compound N[C@H]1[C@@H]([C@@H]([C@@H]2C[C@H]12)O)O MWKJRFUZYIKLNI-BSQWINAVSA-N 0.000 description 3
- GJFYOSYIUWJBTD-DEVUXVJFSA-N (1S,2R,5R)-2-amino-5-fluorocyclopentan-1-ol hydrochloride Chemical compound Cl.N[C@@H]1CC[C@@H](F)[C@H]1O GJFYOSYIUWJBTD-DEVUXVJFSA-N 0.000 description 3
- ZYVIUFSUCZLDTO-DMDPSCGWSA-N (1S,2R,5S)-2-[[3-bromo-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]amino]-5-fluorocyclopentan-1-ol Chemical compound BrC1=NN(C2=NC=NC(=C21)N[C@H]1[C@@H]([C@H](CC1)F)O)COCC[Si](C)(C)C ZYVIUFSUCZLDTO-DMDPSCGWSA-N 0.000 description 3
- QRTAWJHVRQCBIP-VPENINKCSA-N (1S,2R,5S)-2-amino-5-fluorocyclopentan-1-ol Chemical compound N[C@H]1[C@@H]([C@H](CC1)F)O QRTAWJHVRQCBIP-VPENINKCSA-N 0.000 description 3
- SPCYQHNDDCJHTC-YUPRTTJUSA-N (1S,2S,4S)-2-amino-4-fluorocyclopentan-1-ol Chemical compound N[C@@H]1[C@H](C[C@H](C1)F)O SPCYQHNDDCJHTC-YUPRTTJUSA-N 0.000 description 3
- JCGDTBHMOCDGSY-FIRPJDEBSA-N (1s,2s,5s)-2-[[(1s)-1-phenylethyl]amino]-5-phenylmethoxycyclohexan-1-ol Chemical compound O([C@H]1CC[C@@H]([C@H](C1)O)N[C@@H](C)C=1C=CC=CC=1)CC1=CC=CC=C1 JCGDTBHMOCDGSY-FIRPJDEBSA-N 0.000 description 3
- IUSMVOVCNMKOSU-RDDDGLTNSA-N (3S,5R)-5-(2,5-difluorophenyl)pyrrolidine-3-carbonitrile Chemical compound FC1=C(C=C(C=C1)F)[C@H]1C[C@@H](CN1)C#N IUSMVOVCNMKOSU-RDDDGLTNSA-N 0.000 description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 3
- GZTMCZAOQTVOJK-UHFFFAOYSA-N 1,3-dioxolan-4-one Chemical compound O=C1COCO1 GZTMCZAOQTVOJK-UHFFFAOYSA-N 0.000 description 3
- ALWOGRCGRHKOFW-UHFFFAOYSA-N 2-[(3-bromo-4-chloropyrazolo[3,4-d]pyrimidin-1-yl)methoxy]ethyl-trimethylsilane Chemical compound N1=CN=C2N(COCC[Si](C)(C)C)N=C(Br)C2=C1Cl ALWOGRCGRHKOFW-UHFFFAOYSA-N 0.000 description 3
- UCBJPGXLZYKKNA-MRVPVSSYSA-N 3-[(2R)-4,4-difluoropyrrolidin-2-yl]-5-fluoropyridine Chemical compound FC1(C[C@@H](NC1)C=1C=NC=C(C=1)F)F UCBJPGXLZYKKNA-MRVPVSSYSA-N 0.000 description 3
- KCKAIFFKJSPMKW-DTWKUNHWSA-N 3-fluoro-5-[(2R,4S)-4-fluoropyrrolidin-2-yl]pyridine Chemical compound FC=1C=NC=C(C=1)[C@@H]1NC[C@H](C1)F KCKAIFFKJSPMKW-DTWKUNHWSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- 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 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 3
- PGTMGJIVVGWLCS-VXGBXAGGSA-N O[C@H]1[C@@H](CCC1)NC1=C2C(=NC=N1)N(N=C2C(=O)O)COCC[Si](C)(C)C Chemical compound O[C@H]1[C@@H](CCC1)NC1=C2C(=NC=N1)N(N=C2C(=O)O)COCC[Si](C)(C)C PGTMGJIVVGWLCS-VXGBXAGGSA-N 0.000 description 3
- JMRSNMXWYFUSHO-UTLUCORTSA-N [(1S,2S,4R)-4-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopentyl] acetate Chemical compound C(C)(=O)O[C@@H]1[C@H](C[C@H](C1)O)NC(=O)OC(C)(C)C JMRSNMXWYFUSHO-UTLUCORTSA-N 0.000 description 3
- DGLRTNGMJQIUPG-NJDAHSKKSA-N [(1r,2r,3r)-3-(dibenzylamino)-2-hydroxycyclopentyl] acetate Chemical compound O[C@H]1[C@H](OC(=O)C)CC[C@H]1N(CC=1C=CC=CC=1)CC1=CC=CC=C1 DGLRTNGMJQIUPG-NJDAHSKKSA-N 0.000 description 3
- UUXOKMQFVLIIAH-NSISKUIASA-N [Si](C1=CC=CC=C1)(C1=CC=CC=C1)(C(C)(C)C)O[C@H]1[C@@H](C[C@H](C1)C(F)F)N Chemical compound [Si](C1=CC=CC=C1)(C1=CC=CC=C1)(C(C)(C)C)O[C@H]1[C@@H](C[C@H](C1)C(F)F)N UUXOKMQFVLIIAH-NSISKUIASA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000004452 carbocyclyl group Chemical group 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229940099112 cornstarch Drugs 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- PSBABBDEUFNFKJ-UHFFFAOYSA-N cyclopent-2-en-1-ol Chemical compound OC1CCC=C1 PSBABBDEUFNFKJ-UHFFFAOYSA-N 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 229940043355 kinase inhibitor Drugs 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- VFNBELKXKOPBJT-HSUXUTPPSA-N methyl (1R,3R,4R)-3-amino-4-hydroxycyclopentane-1-carboxylate Chemical compound N[C@@H]1C[C@H](C[C@H]1O)C(=O)OC VFNBELKXKOPBJT-HSUXUTPPSA-N 0.000 description 3
- SSATZBUCOTXXGA-IWSPIJDZSA-N methyl (1r,3r,4r)-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopentane-1-carboxylate Chemical compound COC(=O)[C@H]1C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C1 SSATZBUCOTXXGA-IWSPIJDZSA-N 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 125000003566 oxetanyl group Chemical group 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- ULOOSVXEXPTHKY-QMTHXVAHSA-N tert-butyl (2R,4S)-4-cyano-2-(2,5-difluorophenyl)pyrrolidine-1-carboxylate Chemical compound C(#N)[C@H]1C[C@@H](N(C1)C(=O)OC(C)(C)C)C1=C(C=CC(=C1)F)F ULOOSVXEXPTHKY-QMTHXVAHSA-N 0.000 description 3
- RYYFJUHFGMNLBX-JHJMLUEUSA-N tert-butyl (4R)-2-(5-fluoropyridin-3-yl)-4-hydroxypyrrolidine-1-carboxylate Chemical compound FC=1C=C(C=NC=1)C1N(C[C@@H](C1)O)C(=O)OC(C)(C)C RYYFJUHFGMNLBX-JHJMLUEUSA-N 0.000 description 3
- BZVXSFDGVDJRIT-ZIAGYGMSSA-N tert-butyl n-[(1r,2r)-2-[tert-butyl(dimethyl)silyl]oxy-4-oxocyclohexyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCC(=O)C[C@H]1O[Si](C)(C)C(C)(C)C BZVXSFDGVDJRIT-ZIAGYGMSSA-N 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- IIRDPYYCADCHRS-HSUXUTPPSA-N (1R,3R,4R)-3-amino-4-hydroxycyclopentane-1-carbonitrile Chemical compound N[C@@H]1C[C@H](C[C@H]1O)C#N IIRDPYYCADCHRS-HSUXUTPPSA-N 0.000 description 2
- LUFYOKRQPSBJIS-BWZBUEFSSA-N (1R,3R,4R)-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopentane-1-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N[C@@H]1C[C@H](C[C@H]1O)C(=O)O LUFYOKRQPSBJIS-BWZBUEFSSA-N 0.000 description 2
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 2
- HNLHTEPZSOZJND-SDDRHHMPSA-N (1S,2S,5S)-2-phenylmethoxy-6-oxabicyclo[3.1.0]hexane Chemical compound C(C1=CC=CC=C1)O[C@@H]1[C@H]2O[C@H]2CC1 HNLHTEPZSOZJND-SDDRHHMPSA-N 0.000 description 2
- PWQPGBOOZSURRK-CEXWTWQISA-N (1r,2r,5s)-n,n-dibenzyl-6-oxabicyclo[3.1.0]hexan-2-amine Chemical compound C=1C=CC=CC=1CN([C@H]1[C@H]2O[C@H]2CC1)CC1=CC=CC=C1 PWQPGBOOZSURRK-CEXWTWQISA-N 0.000 description 2
- KGKOUXFBWHTEOL-ZDQHTEEMSA-N (1r,2s,3r)-3-aminocyclopentane-1,2-diol;hydrochloride Chemical compound Cl.N[C@@H]1CC[C@@H](O)[C@H]1O KGKOUXFBWHTEOL-ZDQHTEEMSA-N 0.000 description 2
- PWQPGBOOZSURRK-QRVBRYPASA-N (1s,2r,5r)-n,n-dibenzyl-6-oxabicyclo[3.1.0]hexan-2-amine Chemical compound C=1C=CC=CC=1CN([C@H]1[C@@H]2O[C@@H]2CC1)CC1=CC=CC=C1 PWQPGBOOZSURRK-QRVBRYPASA-N 0.000 description 2
- PHMHDDCJMBXLMD-IPMKNSEASA-N (1s,2r,5s)-2-(dibenzylamino)-5-fluorocyclopentan-1-ol Chemical compound O[C@@H]1[C@@H](F)CC[C@H]1N(CC=1C=CC=CC=1)CC1=CC=CC=C1 PHMHDDCJMBXLMD-IPMKNSEASA-N 0.000 description 2
- GDFBHCMFIUBEQT-UHFFFAOYSA-N (2,5-difluorophenyl)methanamine Chemical compound NCC1=CC(F)=CC=C1F GDFBHCMFIUBEQT-UHFFFAOYSA-N 0.000 description 2
- WIDBVWOWNWWRFT-JHEVNIALSA-N (3R,4S,5R)-5-[[(1R)-1-phenylethyl]amino]oxane-3,4-diol Chemical compound C[C@@H](N[C@@H]1COC[C@@H](O)[C@H]1O)C1=CC=CC=C1 WIDBVWOWNWWRFT-JHEVNIALSA-N 0.000 description 2
- RYDQWPYEVUWVAX-WDCZJNDASA-N (3R,4S,5R)-5-aminooxane-3,4-diol Chemical compound N[C@H]1[C@@H]([C@@H](COC1)O)O RYDQWPYEVUWVAX-WDCZJNDASA-N 0.000 description 2
- JHGLFGRVJLJVDT-UHFFFAOYSA-N 1-(2-bromo-5-chlorophenyl)-n-methylmethanamine Chemical compound CNCC1=CC(Cl)=CC=C1Br JHGLFGRVJLJVDT-UHFFFAOYSA-N 0.000 description 2
- UTKGZXVMMFBCJC-UHFFFAOYSA-N 1-bromo-2-(bromomethyl)-4-chlorobenzene Chemical compound ClC1=CC=C(Br)C(CBr)=C1 UTKGZXVMMFBCJC-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QRXVTUPWDPQZEG-UPJWGTAASA-N 2-[(3as,4r,6ar)-2,2-dimethyl-4,5,6,6a-tetrahydro-3ah-cyclopenta[d][1,3]dioxol-4-yl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1[C@@H]1CC[C@H]2OC(C)(C)O[C@H]21 QRXVTUPWDPQZEG-UPJWGTAASA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- HUUMLJGKNHUSRP-POYBYMJQSA-N 2-chloro-5-fluoro-3-[(2R,4S)-4-fluoropyrrolidin-2-yl]pyridine Chemical compound ClC1=NC=C(C=C1[C@@H]1NC[C@H](C1)F)F HUUMLJGKNHUSRP-POYBYMJQSA-N 0.000 description 2
- ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 2-octanone Chemical compound CCCCCCC(C)=O ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 0.000 description 2
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 2
- MDFHFCAMBZNSLV-UHFFFAOYSA-N 3-bromo-4-chloro-2h-pyrazolo[3,4-d]pyrimidine Chemical compound ClC1=NC=NC2=NNC(Br)=C12 MDFHFCAMBZNSLV-UHFFFAOYSA-N 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- CDVSPTPCZCIMOT-MISXGVKJSA-N 4-[[(1R,2S,3S)-3-fluoro-2-hydroxycyclopentyl]amino]-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-d]pyrimidine-3-carboxylic acid Chemical compound F[C@@H]1[C@H]([C@@H](CC1)NC1=C2C(=NC=N1)N(N=C2C(=O)O)COCC[Si](C)(C)C)O CDVSPTPCZCIMOT-MISXGVKJSA-N 0.000 description 2
- FFGVIYUANJAFJS-UHFFFAOYSA-N 4-phenylmethoxycyclohexan-1-one Chemical compound C1CC(=O)CCC1OCC1=CC=CC=C1 FFGVIYUANJAFJS-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
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-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
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 2
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 2
- CMPKYIOCUOXKJG-XUJVJEKNSA-N N-[(2,5-difluorophenyl)methyl]-4-[[(1S,2R,3R)-3-fluoro-2-hydroxycyclopentyl]amino]-2H-pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound FC1=C(CNC(=O)C2=NNC3=NC=NC(=C32)N[C@@H]2[C@H]([C@@H](CC2)F)O)C=C(C=C1)F CMPKYIOCUOXKJG-XUJVJEKNSA-N 0.000 description 2
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- MVHLSTIRVKLGMB-GUBZILKMSA-N [(1S,2S,4S)-4-fluoro-2-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopentyl] acetate Chemical compound CC(=O)O[C@H]1C[C@@H](F)C[C@@H]1NC(=O)OC(C)(C)C MVHLSTIRVKLGMB-GUBZILKMSA-N 0.000 description 2
- DRBWRJPFNOBNIO-KOLCDFICSA-N [(2r)-1-[(2r)-2-(pyridine-4-carbonylamino)propanoyl]pyrrolidin-2-yl]boronic acid Chemical compound N([C@H](C)C(=O)N1[C@@H](CCC1)B(O)O)C(=O)C1=CC=NC=C1 DRBWRJPFNOBNIO-KOLCDFICSA-N 0.000 description 2
- MNZADOWXRIEHNS-UHFFFAOYSA-M [Br-].FC1=CC=C(F)C([Mg+])=C1 Chemical compound [Br-].FC1=CC=C(F)C([Mg+])=C1 MNZADOWXRIEHNS-UHFFFAOYSA-M 0.000 description 2
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 2
- 230000001594 aberrant effect Effects 0.000 description 2
- 125000004450 alkenylene group Chemical group 0.000 description 2
- 125000004419 alkynylene group Chemical group 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 235000015115 caffè latte Nutrition 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 229960005061 crizotinib Drugs 0.000 description 2
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 2
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 2
- YFPCLQKFNXUAAK-UHFFFAOYSA-N cyclopentyl acetate Chemical compound CC(=O)OC1CCCC1 YFPCLQKFNXUAAK-UHFFFAOYSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000006713 insertion reaction Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- MHCFAGZWMAWTNR-UHFFFAOYSA-M lithium perchlorate Chemical compound [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 description 2
- 229910001486 lithium perchlorate Inorganic materials 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- XDQSHKMDEPFBPJ-UEHLDXLESA-N methyl (1R,3R,4R)-3-[[3-[(2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidine-1-carbonyl]-2H-pyrazolo[3,4-d]pyrimidin-4-yl]amino]-4-hydroxycyclopentane-1-carboxylate Chemical compound FC1=C(C=C(C=C1)F)[C@@H]1N(C[C@H](C1)F)C(=O)C1=NNC2=NC=NC(=C21)N[C@@H]1C[C@H](C[C@H]1O)C(=O)OC XDQSHKMDEPFBPJ-UEHLDXLESA-N 0.000 description 2
- UROCOLNPYOTSSX-YWPYICTPSA-N methyl 4-[[(1R,2S,3S)-3-fluoro-2-hydroxycyclopentyl]amino]-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-d]pyrimidine-3-carboxylate Chemical compound F[C@@H]1[C@H]([C@@H](CC1)NC1=C2C(=NC=N1)N(N=C2C(=O)OC)COCC[Si](C)(C)C)O UROCOLNPYOTSSX-YWPYICTPSA-N 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical compound OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 231100000344 non-irritating Toxicity 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002893 slag Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- AXBIXVFQBHBANX-ZWNOBZJWSA-N tert-butyl (2R,4R)-2-(2,5-difluorophenyl)-4-hydroxypyrrolidine-1-carboxylate Chemical compound FC1=C(C=C(C=C1)F)[C@@H]1N(C[C@@H](C1)O)C(=O)OC(C)(C)C AXBIXVFQBHBANX-ZWNOBZJWSA-N 0.000 description 2
- DOJZBQXJHVDEQF-NWDGAFQWSA-N tert-butyl (2R,4S)-4-fluoro-2-(5-fluoropyridin-3-yl)pyrrolidine-1-carboxylate Chemical compound F[C@H]1C[C@@H](N(C1)C(=O)OC(C)(C)C)C=1C=NC=C(C=1)F DOJZBQXJHVDEQF-NWDGAFQWSA-N 0.000 description 2
- ASPAKSDHNNXVIB-LLVKDONJSA-N tert-butyl (4r)-4-[tert-butyl(dimethyl)silyl]oxy-2-oxopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O ASPAKSDHNNXVIB-LLVKDONJSA-N 0.000 description 2
- QCIWZIYBBNEPKB-UHFFFAOYSA-N tert-butyl(dimethyl)silane Chemical compound C[SiH](C)C(C)(C)C QCIWZIYBBNEPKB-UHFFFAOYSA-N 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- LLDIFHPLOFXLEQ-JHJVBQTASA-N (1R,2R,4R)-2-[[3-bromo-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-d]pyrimidin-4-yl]amino]-4-methylsulfonylcyclopentan-1-ol Chemical compound BrC1=NN(C2=NC=NC(=C21)N[C@H]1[C@@H](C[C@@H](C1)S(=O)(=O)C)O)COCC[Si](C)(C)C LLDIFHPLOFXLEQ-JHJVBQTASA-N 0.000 description 1
- DGGCJLFUXOIOQH-WCMLQCRESA-N (1R,2R,4S,5R,6S)-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-amine Chemical compound CC1(O[C@H]2[C@@H](O1)[C@@H]([C@@H]1[C@H]2C1)N)C DGGCJLFUXOIOQH-WCMLQCRESA-N 0.000 description 1
- MAQPKLNGHGQJGE-YMVPXFTJSA-N (1R,2R,4S,5S,6S)-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-ol Chemical compound O[C@@H]1[C@@H]2OC(C)(C)O[C@@H]2[C@@H]2C[C@@H]21 MAQPKLNGHGQJGE-YMVPXFTJSA-N 0.000 description 1
- WRTDISXTWWFXTH-WOPDTQHZSA-N (1S,2R,5S)-2-azido-5-phenylmethoxycyclopentan-1-ol Chemical compound N(=[N+]=[N-])[C@H]1[C@@H]([C@H](CC1)OCC1=CC=CC=C1)O WRTDISXTWWFXTH-WOPDTQHZSA-N 0.000 description 1
- QWGIRDKDEKOYIB-MROZADKFSA-N (1S,5R,6R)-3,7-dioxabicyclo[4.1.0]heptan-5-ol Chemical compound O[C@@H]1COC[C@@H]2O[C@H]12 QWGIRDKDEKOYIB-MROZADKFSA-N 0.000 description 1
- OHUKQADMTXLANM-XJXBIZEQSA-N (1r,2r,4r)-2-[tert-butyl(dimethyl)silyl]oxy-n-[(1s)-1-phenylethyl]-4-phenylmethoxycyclohexan-1-amine Chemical compound O([C@@H]1CC[C@H]([C@@H](C1)O[Si](C)(C)C(C)(C)C)N[C@@H](C)C=1C=CC=CC=1)CC1=CC=CC=C1 OHUKQADMTXLANM-XJXBIZEQSA-N 0.000 description 1
- JBSOEJULKZXSPK-WDCZJNDASA-N (1r,2s,3r)-3-aminocyclopentane-1,2-diol Chemical compound N[C@@H]1CC[C@@H](O)[C@H]1O JBSOEJULKZXSPK-WDCZJNDASA-N 0.000 description 1
- KAZDROFVEVUJAW-WOPDTQHZSA-N (1s,2s,4r)-2-azido-4-phenylmethoxycyclopentan-1-ol Chemical compound C1[C@H](N=[N+]=[N-])[C@@H](O)C[C@@H]1OCC1=CC=CC=C1 KAZDROFVEVUJAW-WOPDTQHZSA-N 0.000 description 1
- VYXHVRARDIDEHS-QGTKBVGQSA-N (1z,5z)-cycloocta-1,5-diene Chemical compound C\1C\C=C/CC\C=C/1 VYXHVRARDIDEHS-QGTKBVGQSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- AYIYPHDKKVWZKI-LJTMIZJLSA-N (2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol;piperazine Chemical compound C1CNCCN1.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO AYIYPHDKKVWZKI-LJTMIZJLSA-N 0.000 description 1
- SMQYQMQTCFRHEJ-OIBJUYFYSA-N (2r,4s)-2-(2,5-difluorophenyl)-4-fluoropyrrolidine Chemical compound C1[C@H](F)CN[C@H]1C1=CC(F)=CC=C1F SMQYQMQTCFRHEJ-OIBJUYFYSA-N 0.000 description 1
- PSOOETMCZCWPBV-XVMARJQXSA-N (3as,4s,6ar)-2,2-dimethyl-4,5,6,6a-tetrahydro-3ah-cyclopenta[d][1,3]dioxol-4-ol Chemical compound C1C[C@H](O)[C@@H]2OC(C)(C)O[C@@H]21 PSOOETMCZCWPBV-XVMARJQXSA-N 0.000 description 1
- FXOFSGSXPYHEMV-XVMARJQXSA-N (3as,4s,6ar)-2,2-dimethyl-4,6a-dihydro-3ah-cyclopenta[d][1,3]dioxol-4-ol Chemical compound C1=C[C@H](O)[C@@H]2OC(C)(C)O[C@@H]21 FXOFSGSXPYHEMV-XVMARJQXSA-N 0.000 description 1
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
- IHVWAXHWELFEAT-YFKPBYRVSA-N (3s)-3,6-dihydro-2h-pyran-3-ol Chemical compound O[C@@H]1COCC=C1 IHVWAXHWELFEAT-YFKPBYRVSA-N 0.000 description 1
- BEVGOGJIDJYUNN-MRVPVSSYSA-N (4r)-4-[tert-butyl(dimethyl)silyl]oxypyrrolidin-2-one Chemical compound CC(C)(C)[Si](C)(C)O[C@H]1CNC(=O)C1 BEVGOGJIDJYUNN-MRVPVSSYSA-N 0.000 description 1
- IOGISYQVOGVIEU-GSVOUGTGSA-N (4r)-4-hydroxypyrrolidin-2-one Chemical compound O[C@H]1CNC(=O)C1 IOGISYQVOGVIEU-GSVOUGTGSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- LUCJQCWSQUBWDD-HQYNXSMWSA-N (NE,R)-N-[(2-chloro-5-fluoropyridin-3-yl)methylidene]-2-methylpropane-2-sulfinamide Chemical compound ClC1=NC=C(C=C1\C=N\[S@](=O)C(C)(C)C)F LUCJQCWSQUBWDD-HQYNXSMWSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- BWMWMQPHIZNHGS-UHFFFAOYSA-N 1,2-dibenzyl-6-oxabicyclo[3.1.0]hexan-2-amine Chemical compound C(C1=CC=CC=C1)C1(C2(OC2CC1)CC1=CC=CC=C1)N BWMWMQPHIZNHGS-UHFFFAOYSA-N 0.000 description 1
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- AMMPLVWPWSYRDR-UHFFFAOYSA-N 1-methylbicyclo[2.2.2]oct-2-ene-4-carboxylic acid Chemical compound C1CC2(C(O)=O)CCC1(C)C=C2 AMMPLVWPWSYRDR-UHFFFAOYSA-N 0.000 description 1
- OWLIGDFTDZELCX-UHFFFAOYSA-N 1h-pyrano[4,3-c]pyridine Chemical compound N1=CC=C2COC=CC2=C1 OWLIGDFTDZELCX-UHFFFAOYSA-N 0.000 description 1
- QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical class C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 description 1
- 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 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- GCERGIDMVJEZFD-KGYLQXTDSA-N 2-[(3aS,6R,6aS)-2,2-dimethyl-4-oxo-3a,5,6,6a-tetrahydrocyclopenta[d][1,3]dioxol-6-yl]isoindole-1,3-dione Chemical compound CC1(O[C@@H]2[C@H](O1)C(C[C@H]2N1C(C2=CC=CC=C2C1=O)=O)=O)C GCERGIDMVJEZFD-KGYLQXTDSA-N 0.000 description 1
- NNMWRODQSAEWHU-WOPDTQHZSA-N 2-[(3aS,6R,6aS)-4,4-difluoro-2,2-dimethyl-3a,5,6,6a-tetrahydrocyclopenta[d][1,3]dioxol-6-yl]isoindole-1,3-dione Chemical compound CC1(C)O[C@H]2[C@@H](CC(F)(F)[C@H]2O1)N1C(=O)C2=C(C=CC=C2)C1=O NNMWRODQSAEWHU-WOPDTQHZSA-N 0.000 description 1
- MMYNCMNYRYZUTA-MROQNXINSA-N 2-[(3ar,4s,6r,6as)-4-hydroxy-2,2-dimethyl-4,5,6,6a-tetrahydro-3ah-cyclopenta[d][1,3]dioxol-6-yl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1[C@@H]1C[C@H](O)[C@H]2OC(C)(C)O[C@H]21 MMYNCMNYRYZUTA-MROQNXINSA-N 0.000 description 1
- IMQFWCDQEAIYJV-UHFFFAOYSA-N 2-chloro-5-fluoropyridine-3-carbaldehyde Chemical compound FC1=CN=C(Cl)C(C=O)=C1 IMQFWCDQEAIYJV-UHFFFAOYSA-N 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- HYBUYRZXNAZTPJ-UHFFFAOYSA-N 2h-pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound N1=CN=CC2=C(C(=O)N)NN=C21 HYBUYRZXNAZTPJ-UHFFFAOYSA-N 0.000 description 1
- XLZYKTYMLBOINK-UHFFFAOYSA-N 3-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(=O)C=2C=CC(O)=CC=2)=C1 XLZYKTYMLBOINK-UHFFFAOYSA-N 0.000 description 1
- WBCGTNPTUCTJKT-LLVKDONJSA-N 3-[(2R)-1-tert-butyl-4,4-difluoropyrrolidin-2-yl]-5-fluoropyridine Chemical compound C(C)(C)(C)N1[C@H](CC(C1)(F)F)C=1C=NC=C(C=1)F WBCGTNPTUCTJKT-LLVKDONJSA-N 0.000 description 1
- XBMJROUFLCYNNB-GXSJLCMTSA-N 3-[(2R,4S)-1-tert-butyl-4-fluoropyrrolidin-2-yl]-2-chloro-5-fluoropyridine Chemical compound C(C)(C)(C)N1[C@H](C[C@@H](C1)F)C=1C(=NC=C(C=1)F)Cl XBMJROUFLCYNNB-GXSJLCMTSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- DTBKKESEAXYGMM-UHFFFAOYSA-N 3-bromo-2h-pyrazolo[4,3-d]pyrimidine Chemical compound N1=CN=C2C(Br)=NNC2=C1 DTBKKESEAXYGMM-UHFFFAOYSA-N 0.000 description 1
- HNNNBQRRIHKFLI-UHFFFAOYSA-N 3-bromo-5-fluoropyridine Chemical compound FC1=CN=CC(Br)=C1 HNNNBQRRIHKFLI-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- COKHMUBYEFXMPJ-WDEREUQCSA-N 3-fluoro-5-[(2r,4s)-4-fluoropyrrolidin-2-yl]benzonitrile Chemical compound C1[C@H](F)CN[C@H]1C1=CC(F)=CC(C#N)=C1 COKHMUBYEFXMPJ-WDEREUQCSA-N 0.000 description 1
- XWWQLKYMTLWXKN-UHFFFAOYSA-N 3-hydroxycyclopentane-1-carboxylic acid Chemical compound OC1CCC(C(O)=O)C1 XWWQLKYMTLWXKN-UHFFFAOYSA-N 0.000 description 1
- YZGYKWJZOBALKZ-UHFFFAOYSA-N 3-hydroxypyrrolidine-1-carboxylic acid Chemical compound OC1CCN(C(O)=O)C1 YZGYKWJZOBALKZ-UHFFFAOYSA-N 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- ROADCYAOHVSOLQ-UHFFFAOYSA-N 3-oxetanone Chemical compound O=C1COC1 ROADCYAOHVSOLQ-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- CSUABHOMDQBGFZ-RSJOWCBRSA-N 329910-40-9 Chemical compound O=C1N[C@H]2[C@@H]3O[C@@H]3[C@@H]1C2 CSUABHOMDQBGFZ-RSJOWCBRSA-N 0.000 description 1
- FYNLRTWMACAXIY-UHFFFAOYSA-N 3H-dioxol-3-amine Chemical compound NC1OOC=C1 FYNLRTWMACAXIY-UHFFFAOYSA-N 0.000 description 1
- ALDYAAJAAVXYAW-TZMCWYRMSA-N 4-[[(1R,2R)-2-hydroxycyclopentyl]amino]-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-d]pyrimidine-3-carbaldehyde Chemical compound O[C@H]1[C@@H](CCC1)NC1=C2C(=NC=N1)N(N=C2C=O)COCC[Si](C)(C)C ALDYAAJAAVXYAW-TZMCWYRMSA-N 0.000 description 1
- ZAQQFIAGFQYNEU-UHFFFAOYSA-N 4-[tert-butyl(dimethyl)silyl]oxy-2-oxopyrrolidine-1-carboxylic acid Chemical compound CC(C)(C)[Si](C)(C)OC1CN(C(O)=O)C(=O)C1 ZAQQFIAGFQYNEU-UHFFFAOYSA-N 0.000 description 1
- GVCLNACSYKYUHP-UHFFFAOYSA-N 4-amino-7-(2-hydroxyethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbothioamide Chemical compound C1=NC(N)=C2C(C(=S)N)=CN(COCCO)C2=N1 GVCLNACSYKYUHP-UHFFFAOYSA-N 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- 125000004606 5,6,7,8-tetrahydroisoquinolinyl group Chemical group C1(=NC=CC=2CCCCC12)* 0.000 description 1
- 125000004608 5,6,7,8-tetrahydroquinolinyl group Chemical group N1=C(C=CC=2CCCCC12)* 0.000 description 1
- YAGPZRLCMRMSFP-UHFFFAOYSA-N 5-fluoro-2-methoxypyridine-3-carbaldehyde Chemical group COC1=NC=C(F)C=C1C=O YAGPZRLCMRMSFP-UHFFFAOYSA-N 0.000 description 1
- MPPRFQSUSJLXAQ-IONNQARKSA-N 5-fluoro-3-[(2R,4S)-4-fluoropyrrolidin-2-yl]-2-methoxypyridine Chemical compound FC=1C=C(C(=NC=1)OC)[C@@H]1NC[C@H](C1)F MPPRFQSUSJLXAQ-IONNQARKSA-N 0.000 description 1
- NKUWEFYHYZHAAC-UHFFFAOYSA-N 6h-cyclopenta[d][1,3]dioxol-5-amine Chemical compound O1COC2=C1CC(N)=C2 NKUWEFYHYZHAAC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000937413 Axia Species 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- XNDGYZXHZKEAIF-UHFFFAOYSA-N BrC1=C(C=C(C=C1)Cl)C.BrC1=C(CBr)C=C(C=C1)Cl Chemical compound BrC1=C(C=C(C=C1)Cl)C.BrC1=C(CBr)C=C(C=C1)Cl XNDGYZXHZKEAIF-UHFFFAOYSA-N 0.000 description 1
- LIXLKDPJQBKEEG-VXGBXAGGSA-N BrC1=NN(C2=NC=NC(=C21)N[C@H]1[C@@H](CCC1)O)COCC[Si](C)(C)C Chemical compound BrC1=NN(C2=NC=NC(=C21)N[C@H]1[C@@H](CCC1)O)COCC[Si](C)(C)C LIXLKDPJQBKEEG-VXGBXAGGSA-N 0.000 description 1
- FVGIORVBCKEHKB-RNFRBKRXSA-N C(C)(C)(C)N1C[C@H]([C@@H](C1)O)N Chemical compound C(C)(C)(C)N1C[C@H]([C@@H](C1)O)N FVGIORVBCKEHKB-RNFRBKRXSA-N 0.000 description 1
- CSTWMNALAYBRGH-ZCFIWIBFSA-N C1C=C[C@@H](CO1)CC(=O)O Chemical compound C1C=C[C@@H](CO1)CC(=O)O CSTWMNALAYBRGH-ZCFIWIBFSA-N 0.000 description 1
- BRELOTJQRMOSQL-UHFFFAOYSA-N C1COC2CC2C1O Chemical compound C1COC2CC2C1O BRELOTJQRMOSQL-UHFFFAOYSA-N 0.000 description 1
- GXYICLWPTRILHV-IENPIDJESA-P C[C@H](NC(OC(C)(C)C)=O)[IH]C(CCO)[S@+](C)(O)=O Chemical compound C[C@H](NC(OC(C)(C)C)=O)[IH]C(CCO)[S@+](C)(O)=O GXYICLWPTRILHV-IENPIDJESA-P 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 description 1
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- QEOSRTPSNGYFLV-WMLDXEAASA-N FC1=C(C=C(C=C1)F)[C@@H]1N(C[C@H](C1)F)C(=O)C1=NN(C=2N=CNC(C=21)=O)COCC[Si](C)(C)C Chemical compound FC1=C(C=C(C=C1)F)[C@@H]1N(C[C@H](C1)F)C(=O)C1=NN(C=2N=CNC(C=21)=O)COCC[Si](C)(C)C QEOSRTPSNGYFLV-WMLDXEAASA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000034951 Genetic Translocation Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-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
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 1
- 239000002137 L01XE24 - Ponatinib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Natural products OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- CUQAVBKLXGWTNE-MISYRCLQSA-N N-[(2,5-difluorophenyl)methyl]-4-[[(1R,2R,4R)-2-hydroxy-4-methylsulfonylcyclopentyl]amino]-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound FC1=C(CNC(=O)C2=NN(C3=NC=NC(=C32)N[C@H]2[C@@H](C[C@@H](C2)S(=O)(=O)C)O)COCC[Si](C)(C)C)C=C(C=C1)F CUQAVBKLXGWTNE-MISYRCLQSA-N 0.000 description 1
- MOGDFRWOENIEPK-MRVWCRGKSA-N N-[(2,5-difluorophenyl)methyl]-4-[[(1R,2R,4R)-2-hydroxy-4-methylsulfonylcyclopentyl]amino]-2H-pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound FC1=C(CNC(=O)C2=NNC3=NC=NC(=C32)N[C@H]2[C@@H](C[C@@H](C2)S(=O)(=O)C)O)C=C(C=C1)F MOGDFRWOENIEPK-MRVWCRGKSA-N 0.000 description 1
- VTEGSIDIYBUPBF-WAOWUJCRSA-N N-[(2,5-difluorophenyl)methyl]-4-[[(1R,2S,3S)-3-fluoro-2-hydroxycyclopentyl]amino]-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound C[Si](C)(C)CCOCN1N=C(C(=O)NCC2=C(F)C=CC(F)=C2)C2=C1N=CN=C2N[C@@H]1CC[C@H](F)[C@H]1O VTEGSIDIYBUPBF-WAOWUJCRSA-N 0.000 description 1
- CMPKYIOCUOXKJG-YWPYICTPSA-N N-[(2,5-difluorophenyl)methyl]-4-[[(1R,2S,3S)-3-fluoro-2-hydroxycyclopentyl]amino]-2H-pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound FC1=C(CNC(=O)C2=NNC3=NC=NC(=C32)N[C@H]2[C@@H]([C@H](CC2)F)O)C=C(C=C1)F CMPKYIOCUOXKJG-YWPYICTPSA-N 0.000 description 1
- IKSGXZWOGVGLOD-CPUCHLNUSA-N N-[(5-chloro-2-cyanophenyl)methyl]-4-[[(1R,2S,3R)-2,3-dihydroxycyclopentyl]amino]-N-methyl-2H-pyrazolo[3,4-d]pyrimidine-3-carboxamide Chemical compound ClC=1C=CC(=C(CN(C(=O)C2=NNC3=NC=NC(=C32)N[C@H]2[C@@H]([C@@H](CC2)O)O)C)C=1)C#N IKSGXZWOGVGLOD-CPUCHLNUSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- KDQLGFZYYZEKJQ-UHFFFAOYSA-N O=C1C2=C(N=CN1)N(N=C2C(=O)O)COCC[Si](C)(C)C Chemical compound O=C1C2=C(N=CN1)N(N=C2C(=O)O)COCC[Si](C)(C)C KDQLGFZYYZEKJQ-UHFFFAOYSA-N 0.000 description 1
- PDBATZYSEGGECF-CHWSQXEVSA-N O[C@H]1[C@@H](CCC1)NC1=C2C(=NC=N1)N(N=C2C(=O)OC)COCC[Si](C)(C)C Chemical compound O[C@H]1[C@@H](CCC1)NC1=C2C(=NC=N1)N(N=C2C(=O)OC)COCC[Si](C)(C)C PDBATZYSEGGECF-CHWSQXEVSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 206010055006 Pancreatic sarcoma Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920001774 Perfluoroether Polymers 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- AAWZDTNXLSGCEK-ZHQZDSKASA-N Quinic acid Natural products O[C@H]1CC(O)(C(O)=O)C[C@H](O)C1O AAWZDTNXLSGCEK-ZHQZDSKASA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- KEKVVITZUCNVDF-GMTAPVOTSA-N [(1R,2R,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-hydroxycyclohexyl]carbamic acid Chemical compound CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](O)CC[C@H]1NC(O)=O KEKVVITZUCNVDF-GMTAPVOTSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- AYVGBNGTBQLJBG-UHFFFAOYSA-N [3-(hydroxymethyl)cyclopentyl]methanol Chemical compound OCC1CCC(CO)C1 AYVGBNGTBQLJBG-UHFFFAOYSA-N 0.000 description 1
- WRRBWAZRKBXRPO-XDDVRUDJSA-N [4-[[(1R,2R,4R)-4-(difluoromethyl)-2-hydroxycyclopentyl]amino]-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-[(2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl]methanone Chemical compound FC([C@H]1C[C@H]([C@@H](C1)NC1=C2C(=NC=N1)NN=C2C(=O)N1[C@H](C[C@@H](C1)F)C1=C(C=CC(=C1)F)F)O)F WRRBWAZRKBXRPO-XDDVRUDJSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical class [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ONIQOQHATWINJY-UHFFFAOYSA-N cabozantinib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 description 1
- 229960001292 cabozantinib Drugs 0.000 description 1
- HFCFMRYTXDINDK-WNQIDUERSA-N cabozantinib malate Chemical compound OC(=O)[C@@H](O)CC(O)=O.C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 HFCFMRYTXDINDK-WNQIDUERSA-N 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229940081733 cetearyl alcohol Drugs 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940034568 cometriq Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream 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
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- WEIMJSIRDZDHAH-UHFFFAOYSA-N cyclopent-3-en-1-ol Chemical compound OC1CC=CC1 WEIMJSIRDZDHAH-UHFFFAOYSA-N 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004428 fluoroalkoxy group Chemical group 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 239000010440 gypsum Substances 0.000 description 1
- 229910052602 gypsum Inorganic materials 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 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
- 125000004474 heteroalkylene group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- WGBBUURBHXLGFM-UHFFFAOYSA-N hexan-2-amine Chemical compound CCCCC(C)N WGBBUURBHXLGFM-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010348 incorporation Methods 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
- 239000004615 ingredient Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229940030980 inova Drugs 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000000752 ionisation method Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 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
- 230000000155 isotopic effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 238000004989 laser desorption mass spectroscopy Methods 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- MDEBHDWZTOGBQT-RKDXNWHRSA-N methyl (3r,4r)-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopentene-1-carboxylate Chemical compound COC(=O)C1=C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C1 MDEBHDWZTOGBQT-RKDXNWHRSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- KDDNIXNWBDKJCN-UHFFFAOYSA-N n,n-dibenzylcyclopent-2-en-1-amine Chemical compound C=1C=CC=CC=1CN(C1C=CCC1)CC1=CC=CC=C1 KDDNIXNWBDKJCN-UHFFFAOYSA-N 0.000 description 1
- WWECJGLXBSQKRF-UHFFFAOYSA-N n,n-dimethylformamide;methanol Chemical compound OC.CN(C)C=O WWECJGLXBSQKRF-UHFFFAOYSA-N 0.000 description 1
- SJYQYOVTHISIKX-UHFFFAOYSA-N n,n-dimethylformamide;n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CN(C)C=O.CCN(C(C)C)C(C)C SJYQYOVTHISIKX-UHFFFAOYSA-N 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000013642 negative control Substances 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
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 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
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 201000002526 pancreas sarcoma Diseases 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000005545 phthalimidyl group Chemical group 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- PHXJVRSECIGDHY-UHFFFAOYSA-N ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 description 1
- 229960001131 ponatinib Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 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
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004929 pyrrolidonyl group Chemical group N1(C(CCC1)=O)* 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229950009390 symclosene Drugs 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- IMBMHLRNVAIPRG-GFCCVEGCSA-N tert-butyl (2R)-2-(5-fluoropyridin-3-yl)-4-oxopyrrolidine-1-carboxylate Chemical compound FC=1C=C(C=NC=1)[C@@H]1N(CC(C1)=O)C(=O)OC(C)(C)C IMBMHLRNVAIPRG-GFCCVEGCSA-N 0.000 description 1
- RYYFJUHFGMNLBX-VXGBXAGGSA-N tert-butyl (2R,4R)-2-(5-fluoropyridin-3-yl)-4-hydroxypyrrolidine-1-carboxylate Chemical compound FC=1C=C(C=NC=1)[C@@H]1N(C[C@@H](C1)O)C(=O)OC(C)(C)C RYYFJUHFGMNLBX-VXGBXAGGSA-N 0.000 description 1
- NVDMQLHGSHTBDF-GXSJLCMTSA-N tert-butyl (2R,4S)-2-(2-chloro-5-fluoropyridin-3-yl)-4-fluoropyrrolidine-1-carboxylate Chemical compound ClC1=NC=C(C=C1[C@@H]1N(C[C@H](C1)F)C(=O)OC(C)(C)C)F NVDMQLHGSHTBDF-GXSJLCMTSA-N 0.000 description 1
- AHJZEZIYOBGVSK-JGVFFNPUSA-N tert-butyl (3s,4s)-3-(aminomethyl)-4-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](O)[C@@H](CN)C1 AHJZEZIYOBGVSK-JGVFFNPUSA-N 0.000 description 1
- CKSVPIZNXAIFIN-UHFFFAOYSA-N tert-butyl 7-oxo-3-oxa-6-azatricyclo[3.2.1.02,4]octane-6-carboxylate Chemical compound O=C1N(C(=O)OC(C)(C)C)C2C3OC3C1C2 CKSVPIZNXAIFIN-UHFFFAOYSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 229910052722 tritium Inorganic materials 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
- 230000004614 tumor growth Effects 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- DYWSVUBJGFTOQC-UHFFFAOYSA-N xi-2-Ethylheptanoic acid Chemical compound CCCCCC(CC)C(O)=O DYWSVUBJGFTOQC-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562210264P | 2015-08-26 | 2015-08-26 | |
| US62/210,264 | 2015-08-26 | ||
| PCT/US2016/048698 WO2017035354A1 (en) | 2015-08-26 | 2016-08-25 | Compounds and compositions useful for treating disorders related to ntrk |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2018528200A JP2018528200A (ja) | 2018-09-27 |
| JP2018528200A5 JP2018528200A5 (OSRAM) | 2019-09-12 |
| JP6877407B2 true JP6877407B2 (ja) | 2021-05-26 |
Family
ID=56896780
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2018510406A Expired - Fee Related JP6877407B2 (ja) | 2015-08-26 | 2016-08-25 | Ntrk関連障害の治療に有用な化合物および組成物 |
Country Status (17)
| Country | Link |
|---|---|
| US (2) | US10017512B2 (OSRAM) |
| EP (1) | EP3341374A1 (OSRAM) |
| JP (1) | JP6877407B2 (OSRAM) |
| KR (1) | KR20180043810A (OSRAM) |
| CN (1) | CN108137607B (OSRAM) |
| AR (1) | AR105836A1 (OSRAM) |
| AU (1) | AU2016311426B2 (OSRAM) |
| BR (1) | BR112018003588A2 (OSRAM) |
| CA (1) | CA2995997A1 (OSRAM) |
| HK (1) | HK1255330A1 (OSRAM) |
| IL (1) | IL257702A (OSRAM) |
| MX (1) | MX2018002407A (OSRAM) |
| PH (1) | PH12018500397A1 (OSRAM) |
| RU (1) | RU2744974C2 (OSRAM) |
| TW (1) | TW201713665A (OSRAM) |
| WO (1) | WO2017035354A1 (OSRAM) |
| ZA (1) | ZA201801881B (OSRAM) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SMT202100451T1 (it) | 2012-07-11 | 2021-09-14 | Blueprint Medicines Corp | Inibitori del recettore di crescita dei fibroblasti |
| US9499522B2 (en) | 2013-03-15 | 2016-11-22 | Blueprint Medicines Corporation | Compositions useful for treating disorders related to kit |
| BR112016008541B1 (pt) | 2013-10-17 | 2022-11-22 | Blueprint Medicines Corporation | Composto ou sal farmaceuticamente aceitável, uso do mesmo para tratar mastocistose, tumor do estroma gastrointestinal e leucemia, e composição farmacêutica |
| AU2014339972B9 (en) | 2013-10-25 | 2019-05-30 | Blueprint Medicines Corporation | Inhibitors of the fibroblast growth factor receptor |
| WO2015108992A1 (en) | 2014-01-15 | 2015-07-23 | Blueprint Medicines Corporation | Heterobicyclic compounds and their use as fgfr4 receptor inhibitors |
| WO2016127074A1 (en) | 2015-02-06 | 2016-08-11 | Blueprint Medicines Corporation | 2-(pyridin-3-yl)-pyrimidine derivatives as ret inhibitors |
| KR20180048635A (ko) | 2015-07-24 | 2018-05-10 | 블루프린트 메디신즈 코포레이션 | Kit 및 pdgfr에 관련된 장애를 치료하는데 유용한 조성물 |
| RU2744974C2 (ru) | 2015-08-26 | 2021-03-17 | Блюпринт Медсинс Корпорейшн | Соединения и композиции, применяемые для лечения расстройств, связанных с ntrk |
| IL302209B2 (en) | 2015-11-02 | 2024-06-01 | Blueprint Medicines Corp | Inhibitors of ret |
| CA3005741A1 (en) | 2015-11-19 | 2017-05-26 | Blueprint Medicines Corporation | Compounds and compositions useful for treating disorders related to ntrk |
| WO2017161269A1 (en) | 2016-03-17 | 2017-09-21 | Blueprint Medicines Corporation | Inhibitors of ret receptor tyrosine kinases |
| EP4285996A3 (en) | 2016-04-15 | 2024-01-10 | Blueprint Medicines Corporation | Inhibitors of activin receptor-like kinase |
| WO2018017983A1 (en) | 2016-07-22 | 2018-01-25 | Blueprint Medicines Corporation | Compounds useful for treating disorders related to ret |
| US10035789B2 (en) | 2016-07-27 | 2018-07-31 | Blueprint Medicines Corporation | Compounds useful for treating disorders related to RET |
| US11040979B2 (en) | 2017-03-31 | 2021-06-22 | Blueprint Medicines Corporation | Substituted pyrrolo[1,2-b]pyridazines for treating disorders related to KIT and PDGFR |
| CN113735881A (zh) | 2017-08-23 | 2021-12-03 | 正大天晴药业集团股份有限公司 | 含有氨基吡唑并嘧啶的大环化合物及其药物组合物和用途 |
| CN111566102B (zh) | 2017-10-18 | 2023-09-08 | 缆图药品公司 | 作为激活素受体样激酶抑制剂的取代的吡咯并吡啶 |
| CN111936138B (zh) * | 2018-02-05 | 2024-03-08 | 深圳市原力生命科学有限公司 | 作为ep4受体拮抗剂的杂二环化合物 |
| CN111971287B (zh) * | 2018-03-28 | 2023-06-02 | 重庆复尚源创医药技术有限公司 | 作为trk激酶抑制剂的大环化合物 |
| PT3773589T (pt) | 2018-04-03 | 2024-02-06 | Blueprint Medicines Corp | Inibidor de ret para utilização no tratamento de cancro com alteração de ret |
| KR20220012221A (ko) * | 2019-02-27 | 2022-02-03 | 페로 테라퓨틱스 인코포레이티드 | 페롭토시스 유도 활성을 갖는 화합물 및 이의 사용 방법 |
| EP3856341B1 (en) | 2019-04-12 | 2023-09-06 | Blueprint Medicines Corporation | Crystalline forms of (s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine and methods of making |
| JP7787812B2 (ja) * | 2019-11-25 | 2025-12-17 | アルカームス インコーポレーテッド | 置換大環状化合物および関連する治療方法 |
| CA3183728A1 (en) | 2020-05-29 | 2021-12-02 | Blueprint Medicines Corporation | Solid forms of pralsetinib |
| US11760747B2 (en) | 2020-12-21 | 2023-09-19 | Alkermes, Inc. | Substituted piperidino compounds and related methods of treatment |
| CN113408945B (zh) * | 2021-07-15 | 2023-03-24 | 广西中烟工业有限责任公司 | 一种烤烟纯度的检测方法、装置、电子设备及存储介质 |
Family Cites Families (42)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998014450A1 (en) * | 1996-10-02 | 1998-04-09 | Novartis Ag | Pyrimidine derivatives and processes for the preparation thereof |
| PL224879B1 (pl) | 2002-09-04 | 2017-02-28 | Pharmacopeia Drug Discovery Inc | Pirazolo [1,5-a] pirymidynowy związek, jego zastosowanie do wytwarzania leku oraz zawierająca go farmaceutyczna kompozycja |
| US7329662B2 (en) | 2003-10-03 | 2008-02-12 | Hoffmann-La Roche Inc. | Pyrazolo-pyridine |
| EP2168968B1 (en) * | 2004-04-02 | 2017-08-23 | OSI Pharmaceuticals, LLC | 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors |
| US8076338B2 (en) * | 2004-04-23 | 2011-12-13 | Exelixis, Inc. | Kinase modulators and methods of use |
| WO2009032703A1 (en) * | 2007-08-28 | 2009-03-12 | Irm Llc | 2- (het) arylamino-6-aminopyridine derivatives and fused forms thereof as anaplastic lymphoma kinase inhibitors |
| TR201807039T4 (tr) | 2008-10-22 | 2018-06-21 | Array Biopharma Inc | Trk kinaz inhibitörleri olarak sübstitüe edilmiş pirazolo[1,5-]pirimidin bileşikleri. |
| AR077468A1 (es) | 2009-07-09 | 2011-08-31 | Array Biopharma Inc | Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa |
| EP2566866A1 (en) * | 2010-05-05 | 2013-03-13 | Vertex Pharmaceuticals Incorporated | 4 substituted pyrazolopyrimidines useful as pkc-theta inhibitors |
| WO2012034095A1 (en) | 2010-09-09 | 2012-03-15 | Irm Llc | Compounds and compositions as trk inhibitors |
| UY33597A (es) | 2010-09-09 | 2012-04-30 | Irm Llc | Compuestos y composiciones como inhibidores de la trk |
| CN102241678B (zh) | 2011-04-26 | 2014-10-29 | 辽宁利锋科技开发有限公司 | 含有脂环结构化合物的抗肿瘤作用与应用 |
| SMT202100451T1 (it) | 2012-07-11 | 2021-09-14 | Blueprint Medicines Corp | Inibitori del recettore di crescita dei fibroblasti |
| US20150218652A1 (en) * | 2012-08-31 | 2015-08-06 | The Regents Of The Unversity Of Colorado, A Body Corporate | Methods for diagnosis and treatment of cancer |
| JP6457942B2 (ja) | 2012-10-05 | 2019-01-23 | ライジェル ファーマシューティカルズ, インコーポレイテッド | Gdf−8阻害剤 |
| HK1214830A1 (zh) | 2012-11-05 | 2016-08-05 | Foundation Medicine, Inc. | 新型ntrk1融合分子及其应用 |
| TWI629266B (zh) | 2012-12-28 | 2018-07-11 | 藍印藥品公司 | 纖維母細胞生長因子受體之抑制劑 |
| HK1222173A1 (zh) * | 2013-02-01 | 2017-06-23 | Bayer Pharma Aktiengesellschaft | 取代的吡唑并嘧啶基氨基-吲唑类 |
| CN103965199B (zh) | 2013-02-02 | 2017-07-07 | 广东东阳光药业有限公司 | 一种芳杂环化合物、包含它的药物组合物及其用途 |
| ES2674705T3 (es) | 2013-02-21 | 2018-07-03 | Calitor Sciences, Llc | Compuestos heteroaromáticos como moduladores de la quinasa PI3 |
| EP2970307B1 (en) | 2013-03-13 | 2020-03-11 | Genentech, Inc. | Pyrazolo compounds and uses thereof |
| US9499522B2 (en) | 2013-03-15 | 2016-11-22 | Blueprint Medicines Corporation | Compositions useful for treating disorders related to kit |
| GB2515785A (en) * | 2013-07-03 | 2015-01-07 | Redx Pharma Ltd | Compounds |
| US9334263B2 (en) | 2013-10-17 | 2016-05-10 | Blueprint Medicines Corporation | Compositions useful for treating disorders related to kit |
| BR112016008541B1 (pt) | 2013-10-17 | 2022-11-22 | Blueprint Medicines Corporation | Composto ou sal farmaceuticamente aceitável, uso do mesmo para tratar mastocistose, tumor do estroma gastrointestinal e leucemia, e composição farmacêutica |
| AU2014339972B9 (en) | 2013-10-25 | 2019-05-30 | Blueprint Medicines Corporation | Inhibitors of the fibroblast growth factor receptor |
| WO2015108992A1 (en) | 2014-01-15 | 2015-07-23 | Blueprint Medicines Corporation | Heterobicyclic compounds and their use as fgfr4 receptor inhibitors |
| WO2015157093A1 (en) | 2014-04-08 | 2015-10-15 | Rigel Pharmaceuticals, Inc. | 2,3-disubstituted pyridine compounds as tgf-beta inhibitors and methods of use |
| WO2016022569A1 (en) | 2014-08-04 | 2016-02-11 | Blueprint Medicines Corporation | Compositions useful for treating disorders related to kit |
| HRP20240937T1 (hr) | 2014-12-15 | 2024-10-25 | Cmg Pharmaceutical Co., Ltd. | Heteroaril spoj sa kondeziranim prstenom i njihova primjena kao trk inhibitora |
| WO2016127074A1 (en) | 2015-02-06 | 2016-08-11 | Blueprint Medicines Corporation | 2-(pyridin-3-yl)-pyrimidine derivatives as ret inhibitors |
| WO2016133838A1 (en) | 2015-02-20 | 2016-08-25 | Rigel Pharmaceuticals, Inc. | Gdf-8 inhibitors |
| KR20180048635A (ko) | 2015-07-24 | 2018-05-10 | 블루프린트 메디신즈 코포레이션 | Kit 및 pdgfr에 관련된 장애를 치료하는데 유용한 조성물 |
| RU2744974C2 (ru) | 2015-08-26 | 2021-03-17 | Блюпринт Медсинс Корпорейшн | Соединения и композиции, применяемые для лечения расстройств, связанных с ntrk |
| IL302209B2 (en) | 2015-11-02 | 2024-06-01 | Blueprint Medicines Corp | Inhibitors of ret |
| CA3005741A1 (en) | 2015-11-19 | 2017-05-26 | Blueprint Medicines Corporation | Compounds and compositions useful for treating disorders related to ntrk |
| WO2017161269A1 (en) | 2016-03-17 | 2017-09-21 | Blueprint Medicines Corporation | Inhibitors of ret receptor tyrosine kinases |
| EP4285996A3 (en) | 2016-04-15 | 2024-01-10 | Blueprint Medicines Corporation | Inhibitors of activin receptor-like kinase |
| WO2018017983A1 (en) | 2016-07-22 | 2018-01-25 | Blueprint Medicines Corporation | Compounds useful for treating disorders related to ret |
| US10035789B2 (en) | 2016-07-27 | 2018-07-31 | Blueprint Medicines Corporation | Compounds useful for treating disorders related to RET |
| US20190192522A1 (en) | 2016-09-08 | 2019-06-27 | Blueprint Medicines Corporation | Inhibitors of the fibroblast growth factor receptor 4 in combination with cyclin-dependent kinase inhibitors |
| CN107844168B (zh) | 2017-11-23 | 2020-12-01 | 英业达科技有限公司 | 主板组件及其卡扣装置 |
-
2016
- 2016-08-25 RU RU2018110379A patent/RU2744974C2/ru active
- 2016-08-25 EP EP16763630.7A patent/EP3341374A1/en not_active Withdrawn
- 2016-08-25 MX MX2018002407A patent/MX2018002407A/es unknown
- 2016-08-25 KR KR1020187008146A patent/KR20180043810A/ko not_active Withdrawn
- 2016-08-25 CA CA2995997A patent/CA2995997A1/en not_active Abandoned
- 2016-08-25 WO PCT/US2016/048698 patent/WO2017035354A1/en not_active Ceased
- 2016-08-25 BR BR112018003588A patent/BR112018003588A2/pt not_active IP Right Cessation
- 2016-08-25 AU AU2016311426A patent/AU2016311426B2/en not_active Expired - Fee Related
- 2016-08-25 HK HK18114466.6A patent/HK1255330A1/zh unknown
- 2016-08-25 JP JP2018510406A patent/JP6877407B2/ja not_active Expired - Fee Related
- 2016-08-25 CN CN201680060799.0A patent/CN108137607B/zh not_active Expired - Fee Related
- 2016-08-26 AR ARP160102616A patent/AR105836A1/es unknown
- 2016-08-26 TW TW105127561A patent/TW201713665A/zh unknown
- 2016-08-26 US US15/248,207 patent/US10017512B2/en active Active
-
2018
- 2018-02-22 PH PH12018500397A patent/PH12018500397A1/en unknown
- 2018-02-25 IL IL257702A patent/IL257702A/en unknown
- 2018-03-20 ZA ZA2018/01881A patent/ZA201801881B/en unknown
- 2018-07-03 US US16/027,166 patent/US11046697B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| MX2018002407A (es) | 2018-11-29 |
| IL257702A (en) | 2018-04-30 |
| AU2016311426A1 (en) | 2018-04-05 |
| ZA201801881B (en) | 2019-05-29 |
| HK1255330A1 (zh) | 2019-08-16 |
| BR112018003588A2 (pt) | 2018-09-25 |
| PH12018500397A1 (en) | 2018-08-29 |
| JP2018528200A (ja) | 2018-09-27 |
| CN108137607B (zh) | 2021-04-06 |
| CA2995997A1 (en) | 2017-03-02 |
| AU2016311426B2 (en) | 2021-05-20 |
| RU2744974C2 (ru) | 2021-03-17 |
| RU2018110379A3 (OSRAM) | 2019-12-26 |
| US20190169194A1 (en) | 2019-06-06 |
| CN108137607A (zh) | 2018-06-08 |
| KR20180043810A (ko) | 2018-04-30 |
| US11046697B2 (en) | 2021-06-29 |
| AR105836A1 (es) | 2017-11-15 |
| US10017512B2 (en) | 2018-07-10 |
| RU2018110379A (ru) | 2019-09-27 |
| WO2017035354A1 (en) | 2017-03-02 |
| TW201713665A (zh) | 2017-04-16 |
| US20170066773A1 (en) | 2017-03-09 |
| EP3341374A1 (en) | 2018-07-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6877407B2 (ja) | Ntrk関連障害の治療に有用な化合物および組成物 | |
| TWI871397B (zh) | Kras突變蛋白抑制劑 | |
| CN113121530B (zh) | 作为krasg12c突变蛋白抑制剂的吡啶酮并嘧啶类衍生物 | |
| JP6494624B2 (ja) | カゼインキナーゼ1d/e阻害剤としての置換された4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピラジン誘導体 | |
| TWI733713B (zh) | 用於治療神經促進性酪氨酸受體激酶相關之異常的化合物與組成物 | |
| TWI751163B (zh) | Fgfr4抑制劑、其製備方法和應用 | |
| JP2022525749A (ja) | Jakキナーゼ阻害剤及びその調製方法、並びにその医薬分野での使用 | |
| TW201620900A (zh) | 1,3-苯并二呃衍生物 | |
| JP7278273B2 (ja) | アクチビン受容体様キナーゼの阻害剤としての置換ピロロピリジン | |
| CN117800975A (zh) | 具有抗kras突变肿瘤活性的化合物 | |
| CN106687446A (zh) | 作为t790m/wt‑egfr的选择性和不可逆的激酶抑制剂的5‑氨基‑4‑氨甲酰基‑吡唑化合物及其用途 | |
| JP2023536603A (ja) | Fgfr阻害剤化合物及びその使用 | |
| JP2023522863A (ja) | Egfr阻害剤としての三環式化合物 | |
| EP3632903A1 (en) | Compound used as autophagy regulator, and preparation method therefor and uses thereof | |
| JP7041821B2 (ja) | 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 | |
| JP2023522725A (ja) | 3-アザビシクロアルキル誘導体およびこれを含む薬剤学的組成物 | |
| TW202525800A (zh) | Ras抑制劑 | |
| KR20250022815A (ko) | Hpk1 억제제 및 이의 의약품에서의 응용 | |
| CN116425770A (zh) | 作为Cdc7抑制剂的四并环类化合物 | |
| TW202216728A (zh) | 一種噻吩並嘧啶類化合物、包含其藥物組合物及其應用 | |
| HK40065459A (en) | Kras mutant protein inhibitors | |
| HK40052926B (en) | Kras mutant protein inhibitors | |
| HK40052926A (en) | Kras mutant protein inhibitors | |
| CN113286594A (zh) | 吡啶并嘧啶类化合物在制备治疗鼻咽癌药物中的应用 | |
| HK1237783B (zh) | 作为t790m/wt-egfr的选择性和不可逆的激酶抑制剂的5-氨基-4-氨甲酰基-吡唑化合物及其用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7423 Effective date: 20180830 |
|
| RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20180906 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20180830 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190801 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190801 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20200611 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200630 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20200914 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20201224 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20210406 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210427 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6877407 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE Ref document number: 6877407 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| LAPS | Cancellation because of no payment of annual fees |