TWI726968B - Egfr酪胺酸激酶之臨床重要突變體之選擇性抑制劑 - Google Patents
Egfr酪胺酸激酶之臨床重要突變體之選擇性抑制劑 Download PDFInfo
- Publication number
- TWI726968B TWI726968B TW106100545A TW106100545A TWI726968B TW I726968 B TWI726968 B TW I726968B TW 106100545 A TW106100545 A TW 106100545A TW 106100545 A TW106100545 A TW 106100545A TW I726968 B TWI726968 B TW I726968B
- Authority
- TW
- Taiwan
- Prior art keywords
- alkyl
- independently
- compound
- methyl
- formula
- Prior art date
Links
- 229940124639 Selective inhibitor Drugs 0.000 title description 3
- 108060006698 EGF receptor Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 386
- 150000003839 salts Chemical class 0.000 claims abstract description 82
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 59
- 201000011510 cancer Diseases 0.000 claims abstract description 19
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 548
- 125000000217 alkyl group Chemical group 0.000 claims description 516
- -1 cyclopropoxy, methoxy Chemical group 0.000 claims description 383
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 246
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 211
- 229910052739 hydrogen Inorganic materials 0.000 claims description 200
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 187
- 229910052760 oxygen Inorganic materials 0.000 claims description 186
- 125000003545 alkoxy group Chemical group 0.000 claims description 178
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 173
- 239000001257 hydrogen Substances 0.000 claims description 171
- 229910052717 sulfur Inorganic materials 0.000 claims description 161
- 125000005842 heteroatom Chemical group 0.000 claims description 159
- 125000005843 halogen group Chemical group 0.000 claims description 157
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 149
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 127
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 117
- 125000001424 substituent group Chemical group 0.000 claims description 106
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 103
- 239000000460 chlorine Substances 0.000 claims description 92
- 229910052801 chlorine Inorganic materials 0.000 claims description 91
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 79
- 229910052731 fluorine Inorganic materials 0.000 claims description 67
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 63
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 63
- 150000002431 hydrogen Chemical class 0.000 claims description 63
- 125000002950 monocyclic group Chemical group 0.000 claims description 62
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 59
- 125000000623 heterocyclic group Chemical group 0.000 claims description 47
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 45
- 229910052794 bromium Inorganic materials 0.000 claims description 44
- 239000011737 fluorine Substances 0.000 claims description 43
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 42
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 26
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 24
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 24
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 14
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 14
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 13
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 206010009944 Colon cancer Diseases 0.000 claims description 8
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000010536 head and neck cancer Diseases 0.000 claims description 4
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 206010046766 uterine cancer Diseases 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
- 229940002612 prodrug Drugs 0.000 abstract description 66
- 239000000651 prodrug Substances 0.000 abstract description 66
- 239000012453 solvate Substances 0.000 abstract description 59
- 150000002148 esters Chemical class 0.000 abstract description 58
- 238000000034 method Methods 0.000 abstract description 27
- 239000000203 mixture Substances 0.000 abstract description 6
- 230000002159 abnormal effect Effects 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 230000002062 proliferating effect Effects 0.000 abstract description 3
- 229920000728 polyester Polymers 0.000 description 136
- 125000003118 aryl group Chemical group 0.000 description 72
- 229910052799 carbon Inorganic materials 0.000 description 68
- 125000001072 heteroaryl group Chemical group 0.000 description 68
- 125000004432 carbon atom Chemical group C* 0.000 description 61
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 54
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 52
- 125000005113 hydroxyalkoxy group Chemical group 0.000 description 47
- AEOHOYJYFOWEHR-UHFFFAOYSA-N C(C=C)(=O)NC=1C(=CC(=C(C=1)NC1=NC=CC(=N1)C1=CNC2=C(C=CC=C12)C(=O)NC)OC)N(C)CCN(C)C Chemical compound C(C=C)(=O)NC=1C(=CC(=C(C=1)NC1=NC=CC(=N1)C1=CNC2=C(C=CC=C12)C(=O)NC)OC)N(C)CCN(C)C AEOHOYJYFOWEHR-UHFFFAOYSA-N 0.000 description 45
- 229910052757 nitrogen Inorganic materials 0.000 description 43
- 238000006467 substitution reaction Methods 0.000 description 42
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 40
- 239000003112 inhibitor Substances 0.000 description 40
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 39
- 108091000080 Phosphotransferase Proteins 0.000 description 36
- 125000003342 alkenyl group Chemical group 0.000 description 36
- 230000035772 mutation Effects 0.000 description 36
- 102000020233 phosphotransferase Human genes 0.000 description 36
- 125000002252 acyl group Chemical group 0.000 description 34
- 210000004027 cell Anatomy 0.000 description 31
- 125000000304 alkynyl group Chemical group 0.000 description 28
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 27
- 125000000392 cycloalkenyl group Chemical group 0.000 description 25
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 23
- 125000006413 ring segment Chemical group 0.000 description 22
- 150000001335 aliphatic alkanes Chemical class 0.000 description 21
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 19
- 230000000694 effects Effects 0.000 description 19
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 18
- 125000000753 cycloalkyl group Chemical group 0.000 description 18
- 229940121647 egfr inhibitor Drugs 0.000 description 18
- 108090000623 proteins and genes Proteins 0.000 description 18
- 238000003419 tautomerization reaction Methods 0.000 description 18
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 17
- 125000004429 atom Chemical group 0.000 description 17
- 125000002619 bicyclic group Chemical group 0.000 description 17
- 235000018102 proteins Nutrition 0.000 description 17
- 102000004169 proteins and genes Human genes 0.000 description 17
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 17
- 229920002554 vinyl polymer Polymers 0.000 description 17
- 229910052736 halogen Inorganic materials 0.000 description 16
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 16
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 15
- 125000002947 alkylene group Chemical group 0.000 description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 14
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 13
- 150000002367 halogens Chemical class 0.000 description 13
- 230000027455 binding Effects 0.000 description 12
- 229940043355 kinase inhibitor Drugs 0.000 description 12
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 12
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 11
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 102200048955 rs121434569 Human genes 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 10
- 125000003710 aryl alkyl group Chemical group 0.000 description 9
- 125000000262 haloalkenyl group Chemical group 0.000 description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 9
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 9
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 9
- 239000000758 substrate Substances 0.000 description 9
- 150000003536 tetrazoles Chemical class 0.000 description 9
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 8
- 229910014033 C-OH Inorganic materials 0.000 description 8
- 229910014570 C—OH Inorganic materials 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 8
- 125000002723 alicyclic group Chemical group 0.000 description 8
- 229940088598 enzyme Drugs 0.000 description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 7
- 102000001253 Protein Kinase Human genes 0.000 description 7
- 125000002915 carbonyl group Chemical class [*:2]C([*:1])=O 0.000 description 7
- 239000012039 electrophile Substances 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 125000005647 linker group Chemical group 0.000 description 7
- 125000004193 piperazinyl group Chemical group 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 108060006633 protein kinase Proteins 0.000 description 7
- 230000011664 signaling Effects 0.000 description 7
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 6
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 6
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000002393 azetidinyl group Chemical group 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 6
- 229960001433 erlotinib Drugs 0.000 description 6
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 6
- 229960002584 gefitinib Drugs 0.000 description 6
- 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 6
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 125000002757 morpholinyl group Chemical group 0.000 description 6
- 125000003551 oxepanyl group Chemical group 0.000 description 6
- 125000003566 oxetanyl group Chemical group 0.000 description 6
- 230000026731 phosphorylation Effects 0.000 description 6
- 238000006366 phosphorylation reaction Methods 0.000 description 6
- 230000019491 signal transduction Effects 0.000 description 6
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- 125000002837 carbocyclic group Chemical group 0.000 description 5
- 125000000532 dioxanyl group Chemical group 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 125000002009 alkene group Chemical group 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 4
- 125000000732 arylene group Chemical group 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 230000022131 cell cycle Effects 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 4
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 4
- 235000018417 cysteine Nutrition 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 4
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 4
- 230000002427 irreversible effect Effects 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 3
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 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
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 102000056372 ErbB-3 Receptor Human genes 0.000 description 3
- 101000972946 Homo sapiens Hepatocyte growth factor receptor Proteins 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 3
- RKAVZJOUGJKLJD-UHFFFAOYSA-N N1(CCCCCC1)OC1(OCCO1)NN1CCCCCC1 Chemical compound N1(CCCCCC1)OC1(OCCO1)NN1CCCCCC1 RKAVZJOUGJKLJD-UHFFFAOYSA-N 0.000 description 3
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 3
- 108091023040 Transcription factor Proteins 0.000 description 3
- 102000040945 Transcription factor Human genes 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 125000005347 halocycloalkyl group Chemical group 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 125000005961 oxazepanyl group Chemical group 0.000 description 3
- 125000005475 oxolanyl group Chemical group 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 2
- 125000004008 6 membered carbocyclic group Chemical group 0.000 description 2
- 125000003341 7 membered heterocyclic group Chemical group 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 230000004543 DNA replication Effects 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102100022623 Hepatocyte growth factor receptor Human genes 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 229960001686 afatinib Drugs 0.000 description 2
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 125000004450 alkenylene group Chemical group 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 150000001361 allenes Chemical class 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000004305 biphenyl Chemical group 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000004709 cell invasion Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 150000001925 cycloalkenes Chemical group 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 150000001944 cysteine derivatives Chemical class 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 125000004474 heteroalkylene group Chemical group 0.000 description 2
- 125000005549 heteroarylene group Chemical group 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 230000006951 hyperphosphorylation Effects 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229910052740 iodine Chemical group 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
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 235000018977 lysine Nutrition 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- PUOLRFAQKKYEDE-UHFFFAOYSA-N n,n-diphenylpyrimidin-2-amine Chemical group C1=CC=CC=C1N(C=1N=CC=CN=1)C1=CC=CC=C1 PUOLRFAQKKYEDE-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- AHLKSOXEVRYIRD-UHFFFAOYSA-N n-phenylquinazolin-2-amine Chemical compound N=1C=C2C=CC=CC2=NC=1NC1=CC=CC=C1 AHLKSOXEVRYIRD-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- AQNQGBUEVCAVML-UHFFFAOYSA-N oxazepane Chemical group C1CCNOCC1 AQNQGBUEVCAVML-UHFFFAOYSA-N 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000005561 phenanthryl group Chemical group 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 238000012877 positron emission topography Methods 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 102200048928 rs121434568 Human genes 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 231100000588 tumorigenic Toxicity 0.000 description 2
- 230000000381 tumorigenic effect Effects 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 description 1
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 description 1
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 1
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 description 1
- JVTAAEKCZFNVCJ-UWTATZPHSA-M (R)-lactate Chemical compound C[C@@H](O)C([O-])=O JVTAAEKCZFNVCJ-UWTATZPHSA-M 0.000 description 1
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 1
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 description 1
- 125000001989 1,3-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([H])C([*:2])=C1[H] 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical group C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- DJQYYYCQOZMCRC-UHFFFAOYSA-N 2-aminopropane-1,3-dithiol Chemical compound SCC(N)CS DJQYYYCQOZMCRC-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 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
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical class C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- KDOPAZIWBAHVJB-UHFFFAOYSA-N 5h-pyrrolo[3,2-d]pyrimidine Chemical compound C1=NC=C2NC=CC2=N1 KDOPAZIWBAHVJB-UHFFFAOYSA-N 0.000 description 1
- 125000006164 6-membered heteroaryl group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 description 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 1
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 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
- 208000035473 Communicable disease Diseases 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 1
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 101150020251 NR13 gene Proteins 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-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
- 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102000003425 Tyrosinase Human genes 0.000 description 1
- 108060008724 Tyrosinase Proteins 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000003926 acrylamides Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000002355 alkine group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 125000004419 alkynylene group Chemical group 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 125000000477 aza group Chemical group 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 125000003943 azolyl group Chemical group 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 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
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960005069 calcium Drugs 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
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 230000008859 change Effects 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
- 238000003776 cleavage reaction Methods 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- CHVJITGCYZJHLR-UHFFFAOYSA-N cyclohepta-1,3,5-triene Chemical compound C1C=CC=CC=C1 CHVJITGCYZJHLR-UHFFFAOYSA-N 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000002498 deadly effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000005034 decoration Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 125000005266 diarylamine group Chemical group 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- 229940125436 dual inhibitor Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 230000009088 enzymatic function Effects 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 231100000722 genetic damage Toxicity 0.000 description 1
- 230000009395 genetic defect Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000000232 haloalkynyl group Chemical group 0.000 description 1
- 238000005734 heterodimerization reaction Methods 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 125000006038 hexenyl group Chemical group 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
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 231100000171 higher toxicity Toxicity 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 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
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000010262 intracellular communication Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 108091005573 modified proteins Proteins 0.000 description 1
- 102000035118 modified proteins Human genes 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- WIDKTXGNSOORHA-CJHXQPGBSA-N n,n'-dibenzylethane-1,2-diamine;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;tetrahydrate Chemical compound O.O.O.O.C=1C=CC=CC=1CNCCNCC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 WIDKTXGNSOORHA-CJHXQPGBSA-N 0.000 description 1
- 125000004370 n-butenyl group Chemical group [H]\C([H])=C(/[H])C([H])([H])C([H])([H])* 0.000 description 1
- LZEBHQQBLHMJOG-UHFFFAOYSA-N n-methyl-2-(4-methylpiperazin-1-yl)ethanamine Chemical group CNCCN1CCN(C)CC1 LZEBHQQBLHMJOG-UHFFFAOYSA-N 0.000 description 1
- MTSNDBYBIZSILH-UHFFFAOYSA-N n-phenylquinazolin-4-amine Chemical compound N=1C=NC2=CC=CC=C2C=1NC1=CC=CC=C1 MTSNDBYBIZSILH-UHFFFAOYSA-N 0.000 description 1
- 125000005487 naphthalate group Chemical group 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000003544 oxime group Chemical group 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- QZZYYBQGTSGDPP-UHFFFAOYSA-N quinoline-3-carbonitrile Chemical compound C1=CC=CC2=CC(C#N)=CN=C21 QZZYYBQGTSGDPP-UHFFFAOYSA-N 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000009094 second-line therapy Methods 0.000 description 1
- 150000003335 secondary amines Chemical group 0.000 description 1
- 231100000046 skin rash Toxicity 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- FYGUBWKMMCWIKB-UHFFFAOYSA-N spiro[2.3]hexane Chemical compound C1CC11CCC1 FYGUBWKMMCWIKB-UHFFFAOYSA-N 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 229940086735 succinate Drugs 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
- 229960004793 sucrose Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000007984 tetrahydrofuranes Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F20/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
- C08F20/02—Monocarboxylic acids having less than ten carbon atoms, Derivatives thereof
- C08F20/52—Amides or imides
- C08F20/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F20/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
- C08F20/02—Monocarboxylic acids having less than ten carbon atoms, Derivatives thereof
- C08F20/52—Amides or imides
- C08F20/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
- C08F20/58—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing oxygen in addition to the carbonamido oxygen, e.g. N-methylolacrylamide, N-acryloylmorpholine
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F20/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
- C08F20/02—Monocarboxylic acids having less than ten carbon atoms, Derivatives thereof
- C08F20/52—Amides or imides
- C08F20/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
- C08F20/60—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing nitrogen in addition to the carbonamido nitrogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Polymers & Plastics (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662276221P | 2016-01-07 | 2016-01-07 | |
| US62/276,221 | 2016-01-07 | ||
| US201662399730P | 2016-09-26 | 2016-09-26 | |
| US62/399,730 | 2016-09-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201734013A TW201734013A (zh) | 2017-10-01 |
| TWI726968B true TWI726968B (zh) | 2021-05-11 |
Family
ID=59274526
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW106100545A TWI726968B (zh) | 2016-01-07 | 2017-01-06 | Egfr酪胺酸激酶之臨床重要突變體之選擇性抑制劑 |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US10435388B2 (OSRAM) |
| EP (1) | EP3399968B8 (OSRAM) |
| JP (2) | JP2019501222A (OSRAM) |
| KR (1) | KR20180105161A (OSRAM) |
| CN (1) | CN109328059B (OSRAM) |
| TW (1) | TWI726968B (OSRAM) |
| WO (1) | WO2017120429A1 (OSRAM) |
Families Citing this family (47)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117185B (zh) | 2015-08-31 | 2017-11-07 | 广州必贝特医药技术有限公司 | 2,4‑二含氮基团取代嘧啶类化合物及其制备方法和应用 |
| JP2019501222A (ja) | 2016-01-07 | 2019-01-17 | シーエス ファーマテック リミテッド | Ｅｇｆｒチロシンキナーゼの臨床的に重要な変異体の選択的阻害薬 |
| EP3464275B1 (en) | 2016-05-26 | 2024-05-08 | Recurium IP Holdings, LLC | Egfr inhibitor compounds |
| EP3492462B1 (en) * | 2016-07-26 | 2023-08-30 | Shenzhen TargetRx, Inc. | Amino pyrimidine compound for inhibiting protein tyrosine kinase activity |
| IL292977A (en) | 2016-09-09 | 2022-07-01 | Incyte Corp | Pyrazolopyridine derivatives as modulators of hpk1 and their use in cancer therapy |
| WO2018049214A1 (en) | 2016-09-09 | 2018-03-15 | Incyte Corporation | Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancer |
| KR102388312B1 (ko) * | 2017-06-13 | 2022-04-19 | 베이징 아다메이들 바이오테크놀로지 리미티드 라이어빌리티 컴퍼니 | 아미노피리미딘 화합물, 이의 제조방법 및 용도 |
| EP3648753A4 (en) * | 2017-07-05 | 2021-03-17 | CS Pharmatech Limited | SELECTIVE INHIBITORS OF CLINICALLY IMPORTANT MUTANTS OF EGFR TYROSINE KINASE |
| EP3659307A4 (en) * | 2017-07-28 | 2021-09-22 | Yale University | ANTI-CANCER PRODUCTS AND METHOD FOR MANUFACTURING AND USING THEREOF |
| PT3658547T (pt) * | 2017-07-28 | 2023-10-20 | Yuhan Corp | Processo de preparação de n -(5 -(4 -(4 -formil -3- fenil- 1h -pirazol- 1 -il)pirimidin -2- ilamino) -4 -metoxi 2- morfolinofenil) acrilamida |
| WO2019042187A1 (zh) * | 2017-08-30 | 2019-03-07 | 深圳市塔吉瑞生物医药有限公司 | 一种氨基嘧啶类化合物及包含该化合物的组合物及其用途 |
| CN109503573A (zh) * | 2017-09-14 | 2019-03-22 | 昆明圣加南生物科技有限公司 | 2-取代苯胺基嘧啶衍生物及其用途 |
| CN107827875B (zh) * | 2017-09-25 | 2021-07-09 | 文韬创新药物研究（北京）有限责任公司 | 一种苯并咪唑类衍生物作为周期蛋白依赖性激酶4/6抑制剂的应用 |
| US20210101881A1 (en) * | 2018-02-12 | 2021-04-08 | Ancureall Pharmaceutical (Shanghai) Co., Ltd. | Pyrimidine compound, preparation method thereof and medical use thereof |
| LT3755703T (lt) | 2018-02-20 | 2022-10-10 | Incyte Corporation | N-(fenil)-2-(fenil)pirimidin-4-karboksamido dariniai ir susiję junginiai, kaip hpk1 inhibitoriai, skirti vėžio gydymui |
| WO2019164949A1 (en) * | 2018-02-20 | 2019-08-29 | Dana-Farber Cancer Institute, Inc. | Pharmaceutical combinations of egfr inhibitors and methods of use thereof |
| EP3755338A4 (en) * | 2018-02-20 | 2021-11-03 | Dana-Farber Cancer Institute, Inc. | PHARMACEUTICAL COMBINATIONS OF EGFR INHIBITORS AND THEIR METHODS OF USE |
| US12448374B2 (en) | 2018-06-07 | 2025-10-21 | Disarm Therapeutics, Inc. | Inhibitors of SARM1 |
| CN112543757A (zh) | 2018-06-15 | 2021-03-23 | 卡迪拉保健有限公司 | 对结核菌具有抗菌活性的缩合氮杂杂芳基化合物 |
| CN110790749B (zh) * | 2018-08-03 | 2023-07-14 | 北京普祺医药科技股份有限公司 | 一种含氮杂环化合物、药物组合物以及其用途 |
| US10899755B2 (en) | 2018-08-08 | 2021-01-26 | Incyte Corporation | Benzothiazole compounds and uses thereof |
| CN110857292A (zh) * | 2018-08-22 | 2020-03-03 | 上海艾力斯医药科技有限公司 | 一种egfr激酶抑制剂及其制备方法和应用 |
| EP3897670A4 (en) | 2018-12-19 | 2022-09-07 | Disarm Therapeutics, Inc. | MRSA1 INHIBITORS IN COMBINATION WITH NEUROPROTECTIVE AGENTS |
| CN113227073B (zh) * | 2019-01-05 | 2022-09-16 | 山东轩竹医药科技有限公司 | Egfr酪氨酸激酶的选择性抑制剂的盐及其晶型 |
| CN111410651B (zh) * | 2019-01-05 | 2021-06-04 | 山东轩竹医药科技有限公司 | 酪氨酸激酶抑制剂的盐及其晶型 |
| US12157730B2 (en) | 2019-03-19 | 2024-12-03 | Voronoi Inc. | Heteroaryl derivative, method for producing same, and pharmaceutical composition comprising same as effective component |
| PL3943491T3 (pl) | 2019-03-19 | 2025-11-17 | Voronoi Inc. | Pochodna heteroarylowa, sposób jej wytwarzania i kompozycja farmaceutyczna zawierająca ją jako skuteczny składnik |
| CN111825658B (zh) * | 2019-04-18 | 2024-11-08 | 华东理工大学 | Egfr三突变抑制剂及其应用 |
| CN112174961A (zh) * | 2019-07-04 | 2021-01-05 | 微境生物医药科技(上海)有限公司 | 一类抑制egfr激酶的化合物及其制备方法和用途 |
| KR102470980B1 (ko) * | 2019-07-26 | 2022-11-25 | 차이나 리소시즈 파마수티컬 홀딩스 컴퍼니 리미티드 | Egfr 및 erbb2에 작용하는 피리미딘계 화합물 |
| EP4010338A1 (en) | 2019-08-06 | 2022-06-15 | Incyte Corporation | Solid forms of an hpk1 inhibitor |
| TW202128670A (zh) * | 2019-11-26 | 2021-08-01 | 大陸商上海翰森生物醫藥科技有限公司 | 含氮多環類衍生物抑制劑、其製備方法和應用 |
| CN113045475A (zh) * | 2019-12-27 | 2021-06-29 | 上海泓博智源医药股份有限公司 | 一种5-溴-7-甲基吲哚的制备方法 |
| CN113493419A (zh) * | 2020-03-18 | 2021-10-12 | 南京药石科技股份有限公司 | Egfr酪氨酸激酶抑制剂及其用途 |
| WO2021243596A1 (en) * | 2020-06-03 | 2021-12-09 | InventisBio Co., Ltd. | Aminopyrimidine compounds, preparation methods and uses thereof |
| TW202214600A (zh) * | 2020-09-24 | 2022-04-16 | 大陸商廣州費米子科技有限責任公司 | 嘧啶基衍生物、其製備方法及其用途 |
| WO2022081478A1 (en) * | 2020-10-12 | 2022-04-21 | Dana-Farber Cancer Institute, Inc. | Covalent egfr inhibitors and methods of use thereof |
| JP2023550591A (ja) * | 2020-11-02 | 2023-12-04 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ＥＧＦＲ阻害薬としての置換１Ｈ－ピラゾロ［４，３－ｃ］及び誘導体 |
| CN114539269B (zh) * | 2020-11-19 | 2023-04-28 | 上海医药工业研究院有限公司 | 一种含氮大环化合物、其制备方法及其应用 |
| WO2022115753A1 (en) * | 2020-11-30 | 2022-06-02 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Merged scaffold taf1 inhibitors |
| CA3196068A1 (en) * | 2020-12-02 | 2022-06-09 | Abbisko Therapeutics Co., Ltd | 2,3-dihydro-1h-pyrrolo[3,2-b]pyridine derivative, preparation method therefor, and application thereof |
| EP4359400B1 (en) * | 2021-06-23 | 2025-07-02 | Blueprint Medicines Corporation | Salt and crystal form of an azetidinyl substituted isoquinline acting as epidermal growth factor receptor inhibitor for the treatment of cancer |
| TW202317542A (zh) * | 2021-06-23 | 2023-05-01 | 美商纜圖藥品公司 | 製備egfr抑制劑的方法 |
| CN115701429B (zh) * | 2021-08-02 | 2024-03-12 | 上海和誉生物医药科技有限公司 | 4-(1h-吲哚-1-基)嘧啶-2-氨基衍生物及其制备方法和应用 |
| WO2023011505A1 (zh) * | 2021-08-06 | 2023-02-09 | 上海和誉生物医药科技有限公司 | 嘧啶或吡啶衍生物及其制备方法和在药学上的应用 |
| CN115703760B (zh) * | 2021-08-11 | 2024-05-31 | 山东大学 | 2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂及其制备方法和应用 |
| CN116283914A (zh) * | 2021-12-01 | 2023-06-23 | 上海艾力斯医药科技股份有限公司 | 一类嘧啶类化合物、其制备方法及应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015127872A1 (zh) * | 2014-02-25 | 2015-09-03 | 上海海雁医药科技有限公司 | 2,4-二取代苯-1,5-二胺衍生物及其应用以及由其制备的药物组合物和药用组合物 |
| CN105085489A (zh) * | 2014-11-05 | 2015-11-25 | 上海页岩科技有限公司 | 嘧啶或吡啶类化合物、其制备方法和医药用途 |
| WO2015195228A1 (en) * | 2014-06-19 | 2015-12-23 | Ariad Pharmaceuticals, Inc. | Heteroaryl compounds for kinase inhibition |
Family Cites Families (41)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5376645A (en) | 1990-01-23 | 1994-12-27 | University Of Kansas | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
| KR0166088B1 (ko) | 1990-01-23 | 1999-01-15 | . | 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도 |
| GB9518953D0 (en) | 1995-09-15 | 1995-11-15 | Pfizer Ltd | Pharmaceutical formulations |
| WO2000035298A1 (en) | 1996-11-27 | 2000-06-22 | Wm. Wrigley Jr. Company | Chewing gum containing medicament active agents |
| CA2280515A1 (en) | 1997-03-11 | 1998-09-17 | E.I. Du Pont De Nemours And Company | Heteroaryl azole herbicides |
| GB9711643D0 (en) | 1997-06-05 | 1997-07-30 | Janssen Pharmaceutica Nv | Glass thermoplastic systems |
| GB9905075D0 (en) | 1999-03-06 | 1999-04-28 | Zeneca Ltd | Chemical compounds |
| US6897208B2 (en) * | 2001-10-26 | 2005-05-24 | Aventis Pharmaceuticals Inc. | Benzimidazoles |
| US7582631B2 (en) * | 2004-01-14 | 2009-09-01 | Amgen Inc. | Substituted heterocyclic compounds and methods of use |
| ATE502920T1 (de) | 2007-12-14 | 2011-04-15 | Pulmagen Therapeutics Asthma Ltd | Indole und ihre therapeutische verwendung |
| TWI458721B (zh) | 2008-06-27 | 2014-11-01 | Celgene Avilomics Res Inc | 雜芳基化合物及其用途 |
| WO2010142934A1 (en) | 2009-06-12 | 2010-12-16 | Pulmagen Therapeutics (Asthma) Limited | Indole derivatives as ligands of crth2 receptors |
| ES2654177T3 (es) | 2011-07-27 | 2018-02-12 | Astrazeneca Ab | Derivados de 2-(2,4,5-anilino sustituido)pirimidina como moduladores de EGFR útiles para tratar el cáncer |
| EP2763976B1 (en) * | 2011-10-05 | 2016-05-18 | Merck Sharp & Dohme Corp. | 2-pyridyl carboxamide-containing spleen tyrosine kinase (syk) inhibitors |
| NZ703162A (en) | 2012-07-03 | 2017-05-26 | 3-V Biosciences Inc | Heterocyclic modulators of lipid synthesis |
| CN104513253A (zh) * | 2013-10-01 | 2015-04-15 | 南京波尔泰药业科技有限公司 | 用于治疗增殖性疾病的大环化合物 |
| CN104761544B (zh) | 2014-01-03 | 2019-03-15 | 北京轩义医药科技有限公司 | Egfr酪氨酸激酶的临床重要突变体的选择性抑制剂 |
| US20170166598A1 (en) | 2014-05-13 | 2017-06-15 | Ariad Pharmaceuticals, Inc. | Heteroaryl compounds for kinase inhibition |
| CN111892579B (zh) * | 2014-06-12 | 2023-07-25 | 上海艾力斯医药科技股份有限公司 | 一类激酶抑制剂 |
| CN105315259B (zh) | 2014-07-29 | 2018-03-09 | 上海艾力斯医药科技有限公司 | 吡啶胺基嘧啶衍生物、其制备方法及应用 |
| CN113121575A (zh) | 2014-08-25 | 2021-07-16 | 四川海思科制药有限公司 | 一种(取代的苯基)(取代的嘧啶)胺基衍生物及其制备方法和药物用途 |
| CN105461695B (zh) | 2014-09-29 | 2018-03-27 | 齐鲁制药有限公司 | 嘧啶或三嗪衍生物及其制备方法和用途 |
| SI3205650T1 (sl) * | 2014-10-11 | 2021-10-29 | Shanghai Hansoh Biomedical Co Ltd | Zaviralec EGFR-ja in priprava ter uporaba le-tega |
| HRP20250213T1 (hr) | 2014-10-13 | 2025-04-25 | Yuhan Corporation | Spojevi i pripravci za modulaciju aktivnosti egfr mutantne kinaze |
| KR102387699B1 (ko) | 2014-12-23 | 2022-04-18 | 미츠비시 하이텍 페이퍼 유럽 게엠베하 | 오프셋 인쇄용 감열 기록 재료 |
| WO2016105525A2 (en) | 2014-12-23 | 2016-06-30 | Dana-Farber Cancer Institute, Inc. | Novel pyrimidines as egfr inhibitors and methods of treating disorders |
| CN104788427B (zh) | 2015-02-05 | 2017-05-31 | 上海泓博智源医药股份有限公司 | 3‑(2‑嘧啶氨基)苯基丙烯酰胺类化合物及其应用 |
| CN104844580B (zh) | 2015-04-17 | 2017-10-20 | 中国药科大学 | 嘧啶类化合物、其制备方法及医药用途 |
| JP6457697B2 (ja) | 2015-04-29 | 2019-01-23 | カントン チョンション ファーマシューティカル カンパニー，リミティド | キナーゼ阻害剤としての縮合環式または三環式アリールピリミジン化合物 |
| WO2016183278A1 (en) | 2015-05-13 | 2016-11-17 | Ariad Pharmaceuticals, Inc. | Heteroaryl compounds for kinase inhibition |
| KR102666414B1 (ko) | 2015-07-16 | 2024-05-17 | 치아타이 티안큉 파마수티컬 그룹 주식회사 | 아닐린 피리미딘 유도체 및 그의 용도 |
| CN105001208A (zh) | 2015-08-06 | 2015-10-28 | 南京雷科星生物技术有限公司 | 一种表皮生长因子受体egfr抑制剂及其制备方法与用途 |
| CN106117185B (zh) | 2015-08-31 | 2017-11-07 | 广州必贝特医药技术有限公司 | 2,4‑二含氮基团取代嘧啶类化合物及其制备方法和应用 |
| CN106749193B (zh) * | 2015-11-23 | 2020-11-20 | 南京圣和药业股份有限公司 | 吲唑取代的表皮生长因子受体抑制剂及其应用 |
| CN106928150B (zh) | 2015-12-31 | 2020-07-31 | 恩瑞生物医药科技（上海）有限公司 | 丙烯酰胺苯胺衍生物及其药学上的应用 |
| JP2019501222A (ja) | 2016-01-07 | 2019-01-17 | シーエス ファーマテック リミテッド | Ｅｇｆｒチロシンキナーゼの臨床的に重要な変異体の選択的阻害薬 |
| CN106279160B (zh) | 2016-03-18 | 2017-09-26 | 海南越康生物医药有限公司 | N‑苯基‑2‑氨基嘧啶类化合物制备方法和用途 |
| WO2017190637A1 (zh) | 2016-05-06 | 2017-11-09 | 深圳市塔吉瑞生物医药有限公司 | 用于抑制蛋白酪氨酸激酶活性的稠合嘧啶类化合物 |
| KR20190006991A (ko) | 2016-05-11 | 2019-01-21 | 베타 파마, 인크. | 뇌암의 치료를 위한 치료제로서의 2-아닐리노피리미딘 유도체 |
| EP3492462B1 (en) | 2016-07-26 | 2023-08-30 | Shenzhen TargetRx, Inc. | Amino pyrimidine compound for inhibiting protein tyrosine kinase activity |
| EP3648753A4 (en) | 2017-07-05 | 2021-03-17 | CS Pharmatech Limited | SELECTIVE INHIBITORS OF CLINICALLY IMPORTANT MUTANTS OF EGFR TYROSINE KINASE |
-
2017
- 2017-01-06 JP JP2018554640A patent/JP2019501222A/ja not_active Withdrawn
- 2017-01-06 KR KR1020187022731A patent/KR20180105161A/ko not_active Withdrawn
- 2017-01-06 CN CN201780016875.2A patent/CN109328059B/zh active Active
- 2017-01-06 WO PCT/US2017/012466 patent/WO2017120429A1/en not_active Ceased
- 2017-01-06 EP EP17736401.5A patent/EP3399968B8/en not_active Not-in-force
- 2017-01-06 TW TW106100545A patent/TWI726968B/zh not_active IP Right Cessation
- 2017-01-06 US US16/068,559 patent/US10435388B2/en active Active
-
2021
- 2021-02-26 JP JP2021029700A patent/JP2021091703A/ja not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015127872A1 (zh) * | 2014-02-25 | 2015-09-03 | 上海海雁医药科技有限公司 | 2,4-二取代苯-1,5-二胺衍生物及其应用以及由其制备的药物组合物和药用组合物 |
| WO2015195228A1 (en) * | 2014-06-19 | 2015-12-23 | Ariad Pharmaceuticals, Inc. | Heteroaryl compounds for kinase inhibition |
| CN105085489A (zh) * | 2014-11-05 | 2015-11-25 | 上海页岩科技有限公司 | 嘧啶或吡啶类化合物、其制备方法和医药用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20180105161A (ko) | 2018-09-27 |
| WO2017120429A1 (en) | 2017-07-13 |
| TW201734013A (zh) | 2017-10-01 |
| EP3399968A4 (en) | 2019-07-24 |
| EP3399968A1 (en) | 2018-11-14 |
| CN109328059B (zh) | 2021-08-17 |
| US10435388B2 (en) | 2019-10-08 |
| JP2021091703A (ja) | 2021-06-17 |
| EP3399968B1 (en) | 2021-10-20 |
| US20190023689A1 (en) | 2019-01-24 |
| CN109328059A (zh) | 2019-02-12 |
| EP3399968B8 (en) | 2021-12-01 |
| JP2019501222A (ja) | 2019-01-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI726968B (zh) | Egfr酪胺酸激酶之臨床重要突變體之選擇性抑制劑 | |
| CN111093645A (zh) | Egfr酪氨酸激酶的临床上重要的突变体的选择性抑制剂 | |
| JP5832524B2 (ja) | ピリドン及びアザピリドン化合物、並びにそれらの使用方法 | |
| TWI304061B (en) | Nitrogen-containing aromatic ring derivatives | |
| CN115297861A (zh) | 化合物及其用途 | |
| US9957251B2 (en) | Heterocyclic compound | |
| CN108026105B (zh) | TGFβ受体拮抗剂 | |
| CN118286225A (zh) | 作为细胞周期蛋白依赖性激酶抑制剂的2-氨基-吡啶或2-氨基-嘧啶衍生物 | |
| CN107922431A (zh) | Hpk1抑制剂及其使用方法 | |
| CN114456176A (zh) | 作为tam抑制剂的吡咯并三嗪化合物 | |
| TW201838981A (zh) | 嘧啶基-吡啶氧基-萘基化合物以及治療ire1相關之疾病及病症的方法 | |
| US12152027B2 (en) | Heterocyclic compound | |
| TWI818424B (zh) | 含氮多環稠環類化合物，其藥物組合物、製備方法和用途 | |
| US9353107B2 (en) | 3-(pyrazolyl)-1H-pyrrolo[2,3-b]pyridine derivatives as kinase inhibitors | |
| CN115698004A (zh) | 作为hpk1抑制剂的氮杂内酰胺化合物 | |
| WO2020182188A1 (zh) | 取代的杂芳基化合物及其组合物和用途 | |
| CN104016979A (zh) | 取代的环化合物及其使用方法和用途 | |
| CN117177973A (zh) | 吡啶并[3,2-d]嘧啶化合物及其用于治疗增殖性疾病的用途 | |
| HK40004229A (en) | Selective inhibitors of clinically important mutants of the egfr tyrosine kinase | |
| HK40004229B (zh) | Egfr酪氨酸激酶的临床重要突变体的选择性抑制剂 | |
| HK40017966A (en) | Selective inhibitors of clinically important mutants of the egfr tyrosine kinase | |
| TW202005967A (zh) | Ｅｇｆｒ酪胺酸激酶之臨床上重要的突變體之選擇性抑制劑 | |
| CN103748095B (zh) | 二环杂芳族化合物 | |
| HK40084694A (en) | Azalactam compounds as hpk1 inhibitors | |
| HK40057478B (zh) | Hpk1抑制剂及其使用方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Annulment or lapse of patent due to non-payment of fees |