TW202308643A - 組合療法(二) - Google Patents
組合療法(二) Download PDFInfo
- Publication number
- TW202308643A TW202308643A TW111117441A TW111117441A TW202308643A TW 202308643 A TW202308643 A TW 202308643A TW 111117441 A TW111117441 A TW 111117441A TW 111117441 A TW111117441 A TW 111117441A TW 202308643 A TW202308643 A TW 202308643A
- Authority
- TW
- Taiwan
- Prior art keywords
- alkyl
- formula
- ethyl
- group
- dihydro
- Prior art date
Links
- 238000002648 combination therapy Methods 0.000 title description 262
- 150000001875 compounds Chemical class 0.000 claims abstract description 544
- 150000003839 salts Chemical class 0.000 claims abstract description 508
- 239000012453 solvate Substances 0.000 claims abstract description 474
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 341
- 229940034982 antineoplastic agent Drugs 0.000 claims abstract description 339
- SRQYLNYQAPCPIR-UHFFFAOYSA-N 4-[4-(5,5-dimethyl-4H-thiazol-2-yl)-1-piperazinyl]-6-propylthieno[2,3-d]pyrimidine Chemical compound N1=CN=C2SC(CCC)=CC2=C1N(CC1)CCN1C1=NCC(C)(C)S1 SRQYLNYQAPCPIR-UHFFFAOYSA-N 0.000 claims abstract description 122
- 229940119544 Menin-MLL inhibitor Drugs 0.000 claims abstract description 122
- 239000012664 BCL-2-inhibitor Substances 0.000 claims abstract description 66
- 229940123711 Bcl2 inhibitor Drugs 0.000 claims abstract description 65
- 238000000034 method Methods 0.000 claims abstract description 65
- 208000018706 hematopoietic system disease Diseases 0.000 claims abstract description 64
- 125000000217 alkyl group Chemical group 0.000 claims description 434
- 229910052739 hydrogen Inorganic materials 0.000 claims description 123
- 239000001257 hydrogen Substances 0.000 claims description 103
- 239000002904 solvent Substances 0.000 claims description 101
- 125000001424 substituent group Chemical group 0.000 claims description 88
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 78
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 52
- 208000032839 leukemia Diseases 0.000 claims description 48
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 46
- 239000003112 inhibitor Substances 0.000 claims description 45
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 229940126062 Compound A Drugs 0.000 claims description 33
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 33
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 32
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 32
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 claims description 30
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 30
- 125000002950 monocyclic group Chemical group 0.000 claims description 30
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical group O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims description 28
- 229960002756 azacitidine Drugs 0.000 claims description 28
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 229940075628 hypomethylating agent Drugs 0.000 claims description 17
- 229940043355 kinase inhibitor Drugs 0.000 claims description 13
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 13
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
- 239000012625 DNA intercalator Substances 0.000 claims description 11
- 102000012011 Isocitrate Dehydrogenase Human genes 0.000 claims description 11
- 108010075869 Isocitrate Dehydrogenase Proteins 0.000 claims description 11
- 101001109719 Homo sapiens Nucleophosmin Proteins 0.000 claims description 10
- 102100022678 Nucleophosmin Human genes 0.000 claims description 10
- 230000002519 immonomodulatory effect Effects 0.000 claims description 10
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 9
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 7
- 150000003230 pyrimidines Chemical class 0.000 claims description 6
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 claims description 4
- HPLNQCPCUACXLM-PGUFJCEWSA-N ABT-737 Chemical compound C([C@@H](CCN(C)C)NC=1C(=CC(=CC=1)S(=O)(=O)NC(=O)C=1C=CC(=CC=1)N1CCN(CC=2C(=CC=CC=2)C=2C=CC(Cl)=CC=2)CC1)[N+]([O-])=O)SC1=CC=CC=C1 HPLNQCPCUACXLM-PGUFJCEWSA-N 0.000 claims description 3
- PQAPVTKIEGUPRN-UHFFFAOYSA-N N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide Chemical compound CC(C)C1=CC=CC=C1CC1=CC(C(=O)NC=2C=CC(=CC=2)S(=O)(=O)C=2C(=CC=CC=2)C(C)(C)C)=C(O)C(O)=C1O PQAPVTKIEGUPRN-UHFFFAOYSA-N 0.000 claims description 3
- 101710200609 Nucleolin 1 Proteins 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 6
- GEZHEQNLKAOMCA-RRZNCOCZSA-N (-)-gambogic acid Chemical compound C([C@@H]1[C@]2([C@@](C3=O)(C\C=C(\C)C(O)=O)OC1(C)C)O1)[C@H]3C=C2C(=O)C2=C1C(CC=C(C)C)=C1O[C@@](CCC=C(C)C)(C)C=CC1=C2O GEZHEQNLKAOMCA-RRZNCOCZSA-N 0.000 claims 2
- 239000003363 dihydroorotate dehydrogenase inhibitor Substances 0.000 claims 2
- GEZHEQNLKAOMCA-UHFFFAOYSA-N epiisogambogic acid Natural products O1C2(C(C3=O)(CC=C(C)C(O)=O)OC4(C)C)C4CC3C=C2C(=O)C2=C1C(CC=C(C)C)=C1OC(CCC=C(C)C)(C)C=CC1=C2O GEZHEQNLKAOMCA-UHFFFAOYSA-N 0.000 claims 2
- GEZHEQNLKAOMCA-GXSDCXQCSA-N gambogic acid Natural products C([C@@H]1[C@]2([C@@](C3=O)(C\C=C(/C)C(O)=O)OC1(C)C)O1)[C@H]3C=C2C(=O)C2=C1C(CC=C(C)C)=C1O[C@@](CCC=C(C)C)(C)C=CC1=C2O GEZHEQNLKAOMCA-GXSDCXQCSA-N 0.000 claims 2
- QALPNMQDVCOSMJ-UHFFFAOYSA-N isogambogic acid Natural products CC(=CCc1c2OC(C)(CC=C(C)C)C=Cc2c(O)c3C(=O)C4=CC5CC6C(C)(C)OC(CC=C(C)/C(=O)O)(C5=O)C46Oc13)C QALPNMQDVCOSMJ-UHFFFAOYSA-N 0.000 claims 2
- 229940045793 B-cell lymphoma-2 inhibitor Drugs 0.000 claims 1
- JEVCWSUVFOYBFI-UHFFFAOYSA-N cyanyl Chemical compound N#[C] JEVCWSUVFOYBFI-UHFFFAOYSA-N 0.000 claims 1
- 229910052727 yttrium Inorganic materials 0.000 abstract description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 438
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
- 125000005843 halogen group Chemical group 0.000 description 79
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 73
- 239000000203 mixture Substances 0.000 description 69
- -1 besylate salt Chemical class 0.000 description 68
- 239000002585 base Substances 0.000 description 65
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 53
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- 229940083266 Dihydroorotate dehydrogenase inhibitor Drugs 0.000 description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 125000006239 protecting group Chemical group 0.000 description 35
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 29
- 238000011282 treatment Methods 0.000 description 29
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- 235000019439 ethyl acetate Nutrition 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 239000003054 catalyst Substances 0.000 description 23
- 229910001868 water Inorganic materials 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 20
- 239000003208 petroleum Substances 0.000 description 20
- 150000001204 N-oxides Chemical class 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 18
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 14
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 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 12
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 12
- 241001467552 Mycobacterium bovis BCG Species 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 229960000190 bacillus calmette–guérin vaccine Drugs 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 229910052763 palladium Inorganic materials 0.000 description 12
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 12
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 11
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 11
- 239000007832 Na2SO4 Substances 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 229940045799 anthracyclines and related substance Drugs 0.000 description 11
- GYQYAJJFPNQOOW-UHFFFAOYSA-N gilteritinib Chemical compound N1=C(NC2CCOCC2)C(CC)=NC(C(N)=O)=C1NC(C=C1OC)=CC=C1N(CC1)CCC1N1CCN(C)CC1 GYQYAJJFPNQOOW-UHFFFAOYSA-N 0.000 description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 11
- 229960001614 levamisole Drugs 0.000 description 11
- CVWXJKQAOSCOAB-UHFFFAOYSA-N quizartinib Chemical compound O1C(C(C)(C)C)=CC(NC(=O)NC=2C=CC(=CC=2)C=2N=C3N(C4=CC=C(OCCN5CCOCC5)C=C4S3)C=2)=N1 CVWXJKQAOSCOAB-UHFFFAOYSA-N 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- 229960003433 thalidomide Drugs 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- QGFYFOHMBDMGBZ-UHFFFAOYSA-N 5-[(7-chloroquinolin-4-yl)amino]-2-(diethylaminomethyl)phenol Chemical compound C1=C(O)C(CN(CC)CC)=CC=C1NC1=CC=NC2=CC(Cl)=CC=C12 QGFYFOHMBDMGBZ-UHFFFAOYSA-N 0.000 description 10
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 10
- 239000007983 Tris buffer Substances 0.000 description 10
- YYLKKYCXAOBSRM-JXMROGBWSA-N [4-[(e)-2-(1h-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone Chemical compound C=1C=C(\C=C\C=2C3=CC=CC=C3NN=2)C=CC=1C(=O)N1CCNCC1 YYLKKYCXAOBSRM-JXMROGBWSA-N 0.000 description 10
- 239000000010 aprotic solvent Substances 0.000 description 10
- 229960003852 atezolizumab Drugs 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 229960000684 cytarabine Drugs 0.000 description 10
- 229960003603 decitabine Drugs 0.000 description 10
- 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 10
- 238000010828 elution Methods 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 229960003301 nivolumab Drugs 0.000 description 10
- 229960002621 pembrolizumab Drugs 0.000 description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
- 229950001626 quizartinib Drugs 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 9
- 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 9
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 9
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 9
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 229960000390 fludarabine Drugs 0.000 description 9
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical group C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 9
- 125000000262 haloalkenyl group Chemical group 0.000 description 9
- 229960004942 lenalidomide Drugs 0.000 description 9
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 9
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 229960003787 sorafenib Drugs 0.000 description 9
- 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 9
- 229960001796 sunitinib Drugs 0.000 description 9
- 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 8
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 150000001412 amines Chemical group 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000000132 electrospray ionisation Methods 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 239000000377 silicon dioxide Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 7
- 108010052167 Dihydroorotate Dehydrogenase Proteins 0.000 description 7
- 102100032823 Dihydroorotate dehydrogenase (quinone), mitochondrial Human genes 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 125000001188 haloalkyl group Chemical group 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 229950010895 midostaurin Drugs 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 229910004298 SiO 2 Inorganic materials 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 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 6
- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 description 6
- 229960001183 venetoclax Drugs 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
- 206010000830 Acute leukaemia Diseases 0.000 description 5
- 229940124291 BTK inhibitor Drugs 0.000 description 5
- 238000007341 Heck reaction Methods 0.000 description 5
- 102100022103 Histone-lysine N-methyltransferase 2A Human genes 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 208000003747 lymphoid leukemia Diseases 0.000 description 5
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 5
- 235000011056 potassium acetate Nutrition 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 238000011894 semi-preparative HPLC Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 5
- 238000004808 supercritical fluid chromatography Methods 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 5
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 5
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 5
- 239000011995 wilkinson's catalyst Substances 0.000 description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 4
- FSPQCTGGIANIJZ-UHFFFAOYSA-N 2-[[(3,4-dimethoxyphenyl)-oxomethyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NC1=C(C(N)=O)C(CCCC2)=C2S1 FSPQCTGGIANIJZ-UHFFFAOYSA-N 0.000 description 4
- CEBKHWWANWSNTI-UHFFFAOYSA-N 2-methylbut-3-yn-2-ol Chemical compound CC(C)(O)C#C CEBKHWWANWSNTI-UHFFFAOYSA-N 0.000 description 4
- YGHRJJRRZDOVPD-UHFFFAOYSA-N 3-methylbutanal Chemical compound CC(C)CC=O YGHRJJRRZDOVPD-UHFFFAOYSA-N 0.000 description 4
- IWTBVKIGCDZRPL-UHFFFAOYSA-N 3-methylpentanol Chemical compound CCC(C)CCO IWTBVKIGCDZRPL-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 230000010558 Gene Alterations Effects 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- 208000006404 Large Granular Lymphocytic Leukemia Diseases 0.000 description 4
- 206010025323 Lymphomas Diseases 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 239000012270 PD-1 inhibitor Substances 0.000 description 4
- 239000012668 PD-1-inhibitor Substances 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 description 4
- 208000033759 Prolymphocytic T-Cell Leukemia Diseases 0.000 description 4
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 4
- 101710151245 Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 description 4
- 208000026651 T-cell prolymphocytic leukemia Diseases 0.000 description 4
- 230000004075 alteration Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000005808 aromatic amination reaction Methods 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
- YKYOUMDCQGMQQO-UHFFFAOYSA-L cadmium dichloride Chemical compound Cl[Cd]Cl YKYOUMDCQGMQQO-UHFFFAOYSA-L 0.000 description 4
- 208000024207 chronic leukemia Diseases 0.000 description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 201000009277 hairy cell leukemia Diseases 0.000 description 4
- IQZZFVDIZRWADY-UHFFFAOYSA-N isocumarine Natural products C1=CC=C2C(=O)OC=CC2=C1 IQZZFVDIZRWADY-UHFFFAOYSA-N 0.000 description 4
- 230000000155 isotopic effect Effects 0.000 description 4
- 208000025113 myeloid leukemia Diseases 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- 239000001301 oxygen Chemical group 0.000 description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 229940121655 pd-1 inhibitor Drugs 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 description 4
- 235000011009 potassium phosphates Nutrition 0.000 description 4
- 150000003212 purines Chemical class 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 230000008707 rearrangement Effects 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- VRQUZSIVUKYRLC-UHFFFAOYSA-N 3-methylbuta-1,2-dienyl acetate Chemical compound CC(=O)OC=C=C(C)C VRQUZSIVUKYRLC-UHFFFAOYSA-N 0.000 description 3
- QFXSWGXWZXSGLC-UHFFFAOYSA-N 3-methylpent-2-en-1-ol Chemical compound CCC(C)=CCO QFXSWGXWZXSGLC-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 3
- VDCNVTSJBHEPPC-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)C(F)(F)F)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)C(F)(F)F)C(C)C)CO VDCNVTSJBHEPPC-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- JIAAFQOLGVGLEY-UHFFFAOYSA-N ClC1=C(C(=CC=C1)F)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound ClC1=C(C(=CC=C1)F)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O JIAAFQOLGVGLEY-UHFFFAOYSA-N 0.000 description 3
- FZNQUWGYWWDEHO-UHFFFAOYSA-N ClC1=C(C(=CC=C1)F)N1C(C2=CC=C(C=C2C(=C1)C1(CC1)C)N1N=C(N(C1=O)CC)CO)=O Chemical compound ClC1=C(C(=CC=C1)F)N1C(C2=CC=C(C=C2C(=C1)C1(CC1)C)N1N=C(N(C1=O)CC)CO)=O FZNQUWGYWWDEHO-UHFFFAOYSA-N 0.000 description 3
- SQQWRGZCCQOGPU-UHFFFAOYSA-N ClC1=NC=CC(=C1N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O)C Chemical compound ClC1=NC=CC(=C1N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O)C SQQWRGZCCQOGPU-UHFFFAOYSA-N 0.000 description 3
- QOLSWSBEDJJWIF-UHFFFAOYSA-N FC(C1=C(C=CC=C1)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O)F Chemical compound FC(C1=C(C=CC=C1)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O)F QOLSWSBEDJJWIF-UHFFFAOYSA-N 0.000 description 3
- GBQUIPYCMXLLQT-UHFFFAOYSA-N FC1=CC(=C(C(=O)Cl)C=C1F)I Chemical compound FC1=CC(=C(C(=O)Cl)C=C1F)I GBQUIPYCMXLLQT-UHFFFAOYSA-N 0.000 description 3
- 206010064571 Gene mutation Diseases 0.000 description 3
- 229910003803 Gold(III) chloride Inorganic materials 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 3
- 101150029107 MEIS1 gene Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 description 3
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 3
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 3
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 3
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 3
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 3
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 201000008717 T-cell large granular lymphocyte leukemia Diseases 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 239000005441 aurora Substances 0.000 description 3
- 229940077388 benzenesulfonate Drugs 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- RJHLTVSLYWWTEF-UHFFFAOYSA-K gold trichloride Chemical compound Cl[Au](Cl)Cl RJHLTVSLYWWTEF-UHFFFAOYSA-K 0.000 description 3
- 201000005787 hematologic cancer Diseases 0.000 description 3
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229940124303 multikinase inhibitor Drugs 0.000 description 3
- 201000000050 myeloid neoplasm Diseases 0.000 description 3
- 239000012454 non-polar solvent Substances 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 3
- PENAXHPKEVTBLF-UHFFFAOYSA-L palladium(2+);prop-1-ene;dichloride Chemical compound [Pd+]Cl.[Pd+]Cl.[CH2-]C=C.[CH2-]C=C PENAXHPKEVTBLF-UHFFFAOYSA-L 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000011593 sulfur Chemical group 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- FFSJPOPLSWBGQY-UHFFFAOYSA-N triazol-4-one Chemical compound O=C1C=NN=N1 FFSJPOPLSWBGQY-UHFFFAOYSA-N 0.000 description 3
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 3
- 150000004917 tyrosine kinase inhibitor derivatives Chemical group 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- CGMWMYHEKGCISN-UHFFFAOYSA-N (2-chloro-6-fluorophenyl)hydrazine Chemical compound NNC1=C(F)C=CC=C1Cl CGMWMYHEKGCISN-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 2
- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 description 2
- GKECDORWWXXNRY-UHFFFAOYSA-N 2h-pyridin-3-one Chemical compound O=C1CN=CC=C1 GKECDORWWXXNRY-UHFFFAOYSA-N 0.000 description 2
- SEPQTYODOKLVSB-UHFFFAOYSA-N 3-methylbut-2-enal Chemical compound CC(C)=CC=O SEPQTYODOKLVSB-UHFFFAOYSA-N 0.000 description 2
- XGADWNHARGAKQG-UHFFFAOYSA-N 3-methylpent-2-enal Chemical compound CCC(C)=CC=O XGADWNHARGAKQG-UHFFFAOYSA-N 0.000 description 2
- BCKVHOUUJMYIAN-UHFFFAOYSA-N 5-bromo-2-benzofuran-1,3-dione Chemical compound BrC1=CC=C2C(=O)OC(=O)C2=C1 BCKVHOUUJMYIAN-UHFFFAOYSA-N 0.000 description 2
- MDUBYOAIVAPYDY-UHFFFAOYSA-N 6-[4-ethyl-3-(hydroxymethyl)-5-oxo-1,2,4-triazol-1-yl]-2-(3-fluorophenyl)-4-phenylisoquinolin-1-one Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1)=O)C1=CC(=CC=C1)F)C1=CC=CC=C1)CO MDUBYOAIVAPYDY-UHFFFAOYSA-N 0.000 description 2
- HROFXLZYQCLRIO-UHFFFAOYSA-N 6-[4-ethyl-3-(hydroxymethyl)-5-oxo-1,2,4-triazol-1-yl]-2-(3-fluorophenyl)-4-prop-1-en-2-ylisoquinolin-1-one Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1)=O)C1=CC(=CC=C1)F)C(=C)C)CO HROFXLZYQCLRIO-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 208000032568 B-cell prolymphocytic leukaemia Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- NPCPTNIDFPIDIF-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1)=O)C1=C(C=CC=C1)C(F)(F)F)C(=C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1)=O)C1=C(C=CC=C1)C(F)(F)F)C(=C)C)CO NPCPTNIDFPIDIF-UHFFFAOYSA-N 0.000 description 2
- YYMNDXDCONMGAF-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1)=O)C1=C(C=CC=C1)C)C(=C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1)=O)C1=C(C=CC=C1)C)C(=C)C)CO YYMNDXDCONMGAF-UHFFFAOYSA-N 0.000 description 2
- JOFQEOAJGGRLHG-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C(COC)CC)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C(COC)CC)C(C)C)CO JOFQEOAJGGRLHG-UHFFFAOYSA-N 0.000 description 2
- PLPNZXLHMZXAHI-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C(=CC=C1)F)C)C(=C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C(=CC=C1)F)C)C(=C)C)CO PLPNZXLHMZXAHI-UHFFFAOYSA-N 0.000 description 2
- MQRPFUOSVDGSKO-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C(=NC=C1)O)C)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C(=NC=C1)O)C)C(C)C)CO MQRPFUOSVDGSKO-UHFFFAOYSA-N 0.000 description 2
- JMAZGXWGXIUCLH-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C(=NC=C1)OC)C)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C(=NC=C1)OC)C)C(C)C)CO JMAZGXWGXIUCLH-UHFFFAOYSA-N 0.000 description 2
- LTGJFMOROVXZJT-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C(=NC=C1C)OC)C)C(=C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C(=NC=C1C)OC)C)C(=C)C)CO LTGJFMOROVXZJT-UHFFFAOYSA-N 0.000 description 2
- VJMYVGFKMLRAOY-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C(=NC=C1C)OC)C)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C(=NC=C1C)OC)C)C(C)C)CO VJMYVGFKMLRAOY-UHFFFAOYSA-N 0.000 description 2
- XYJWHXGXSDQQPV-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC(=C1)C)F)C(=C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC(=C1)C)F)C(=C)C)CO XYJWHXGXSDQQPV-UHFFFAOYSA-N 0.000 description 2
- DHRVBBHPLTWMHW-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC(=C1)C)F)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC(=C1)C)F)C(C)C)CO DHRVBBHPLTWMHW-UHFFFAOYSA-N 0.000 description 2
- VSVLPCNXMQPWSB-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC(=C1)F)C)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC(=C1)F)C)C(C)C)CO VSVLPCNXMQPWSB-UHFFFAOYSA-N 0.000 description 2
- XXYIOZTXXBYYSH-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC(=C1)OC)F)C(=C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC(=C1)OC)F)C(=C)C)CO XXYIOZTXXBYYSH-UHFFFAOYSA-N 0.000 description 2
- WVFXLHZIKFCUBJ-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC(=C1)OC)F)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC(=C1)OC)F)C(C)C)CO WVFXLHZIKFCUBJ-UHFFFAOYSA-N 0.000 description 2
- ZWYJXUREFIEHIL-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)C)C(=C)C(F)(F)F)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)C)C(=C)C(F)(F)F)CO ZWYJXUREFIEHIL-UHFFFAOYSA-N 0.000 description 2
- FWMYUWRDJQZRCZ-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)C)C(C(F)(F)F)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)C)C(C(F)(F)F)C)CO FWMYUWRDJQZRCZ-UHFFFAOYSA-N 0.000 description 2
- BZKHQYHQHLKJNX-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)C)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)C)C(C)C)CO BZKHQYHQHLKJNX-UHFFFAOYSA-N 0.000 description 2
- UQGHOMFQXYMGGJ-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)CC)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)CC)C(C)C)CO UQGHOMFQXYMGGJ-UHFFFAOYSA-N 0.000 description 2
- VCYLCWJHUGTABX-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)F)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)F)C(C)C)CO VCYLCWJHUGTABX-UHFFFAOYSA-N 0.000 description 2
- DOQNBOSSGXXSQA-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)OC)C(=C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)OC)C(=C)C)CO DOQNBOSSGXXSQA-UHFFFAOYSA-N 0.000 description 2
- WWAGZECENXJZTJ-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1C)F)C(=C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1C)F)C(=C)C)CO WWAGZECENXJZTJ-UHFFFAOYSA-N 0.000 description 2
- UIRGQWIQOZDXSJ-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=NC=C1)C)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=NC=C1)C)C(C)C)CO UIRGQWIQOZDXSJ-UHFFFAOYSA-N 0.000 description 2
- MUYKLWPIDIANPZ-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(N=CS1)C)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(N=CS1)C)C(C)C)CO MUYKLWPIDIANPZ-UHFFFAOYSA-N 0.000 description 2
- NPFACWBLORJYFU-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=CC(=NC=C1C)O)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=CC(=NC=C1C)O)C(C)C)CO NPFACWBLORJYFU-UHFFFAOYSA-N 0.000 description 2
- DEAZOLLYSJDSNX-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=CC(=NC=C1C)OC)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=CC(=NC=C1C)OC)C(C)C)CO DEAZOLLYSJDSNX-UHFFFAOYSA-N 0.000 description 2
- XQHXJBYDSYEJSC-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=CC(=NC=C1F)OC)C(=C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=CC(=NC=C1F)OC)C(=C)C)CO XQHXJBYDSYEJSC-UHFFFAOYSA-N 0.000 description 2
- ZRJWUYQUYDVVPJ-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=CC(=NC=C1F)OC)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=CC(=NC=C1F)OC)C(C)C)CO ZRJWUYQUYDVVPJ-UHFFFAOYSA-N 0.000 description 2
- YUFVRINVFZQHLU-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=NC(=CC=C1F)OC)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=NC(=CC=C1F)OC)C(C)C)CO YUFVRINVFZQHLU-UHFFFAOYSA-N 0.000 description 2
- LVJZKPBHUFNBBJ-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C=1C(=NC=CC=1)C)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C=1C(=NC=CC=1)C)C(C)C)CO LVJZKPBHUFNBBJ-UHFFFAOYSA-N 0.000 description 2
- RJTPESDOIQMENN-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C=1C(=NC=CC=1C)OC)C(=C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C=1C(=NC=CC=1C)OC)C(=C)C)CO RJTPESDOIQMENN-UHFFFAOYSA-N 0.000 description 2
- YJIDHSKAOKQZHC-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C=1C(=NC=NC=1)C)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C=1C(=NC=NC=1)C)C(C)C)CO YJIDHSKAOKQZHC-UHFFFAOYSA-N 0.000 description 2
- MAUAHGKDNZWUPU-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C=1C(=NSC=1)C)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C=1C(=NSC=1)C)C(C)C)CO MAUAHGKDNZWUPU-UHFFFAOYSA-N 0.000 description 2
- XNJBEIZSJASFAV-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C=1C=NC=CC=1C)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C=1C=NC=CC=1C)C(C)C)CO XNJBEIZSJASFAV-UHFFFAOYSA-N 0.000 description 2
- YWKWJCUXGHHYLG-JKSUJKDBSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)[C@@H]1C[C@@H](CCC1)OC)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)[C@@H]1C[C@@H](CCC1)OC)C(C)C)CO YWKWJCUXGHHYLG-JKSUJKDBSA-N 0.000 description 2
- IUEZCRGBKKGQJN-QRWLVFNGSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)[C@@H]1[C@@H](CCCC1)C)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)[C@@H]1[C@@H](CCCC1)C)C(C)C)CO IUEZCRGBKKGQJN-QRWLVFNGSA-N 0.000 description 2
- IUEZCRGBKKGQJN-MGPUTAFESA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)[C@H]1[C@H](CCCC1)C)C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)[C@H]1[C@H](CCCC1)C)C(C)C)CO IUEZCRGBKKGQJN-MGPUTAFESA-N 0.000 description 2
- VSKXRWHJWQCXML-UHFFFAOYSA-N C1(CC1)CN1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound C1(CC1)CN1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O VSKXRWHJWQCXML-UHFFFAOYSA-N 0.000 description 2
- MLIXMBDAQDLZTE-UHFFFAOYSA-N C1(CCCCC1)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound C1(CCCCC1)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O MLIXMBDAQDLZTE-UHFFFAOYSA-N 0.000 description 2
- RCHOAJCYOOMHTM-UHFFFAOYSA-N C12(CCC(CC1)C2)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound C12(CCC(CC1)C2)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O RCHOAJCYOOMHTM-UHFFFAOYSA-N 0.000 description 2
- SEMDGQPQAXHEIQ-UHFFFAOYSA-N CC=C=C(C)OC(C)=O Chemical compound CC=C=C(C)OC(C)=O SEMDGQPQAXHEIQ-UHFFFAOYSA-N 0.000 description 2
- ALTJBTYSZIRTFO-IFXJQAMLSA-N CCN1C(CO)=NN(C1=O)C1=C(F)C=C2C(=O)N(C=C(C(C)C)C2=C1)[C@@H]1CCC[C@@H]1C Chemical compound CCN1C(CO)=NN(C1=O)C1=C(F)C=C2C(=O)N(C=C(C(C)C)C2=C1)[C@@H]1CCC[C@@H]1C ALTJBTYSZIRTFO-IFXJQAMLSA-N 0.000 description 2
- ALTJBTYSZIRTFO-AUUYWEPGSA-N CCN1C(CO)=NN(C1=O)C1=C(F)C=C2C(=O)N(C=C(C(C)C)C2=C1)[C@@H]1CCC[C@H]1C Chemical compound CCN1C(CO)=NN(C1=O)C1=C(F)C=C2C(=O)N(C=C(C(C)C)C2=C1)[C@@H]1CCC[C@H]1C ALTJBTYSZIRTFO-AUUYWEPGSA-N 0.000 description 2
- IUEZCRGBKKGQJN-YWZLYKJASA-N CCN1C(CO)=NN(C1=O)C1=C(F)C=C2C(=O)N(C=C(C(C)C)C2=C1)[C@H]1CCCC[C@@H]1C Chemical compound CCN1C(CO)=NN(C1=O)C1=C(F)C=C2C(=O)N(C=C(C(C)C)C2=C1)[C@H]1CCCC[C@@H]1C IUEZCRGBKKGQJN-YWZLYKJASA-N 0.000 description 2
- ALTJBTYSZIRTFO-LIRRHRJNSA-N CCN1C(CO)=NN(C1=O)C1=C(F)C=C2C(=O)N(C=C(C(C)C)C2=C1)[C@H]1CCC[C@@H]1C Chemical compound CCN1C(CO)=NN(C1=O)C1=C(F)C=C2C(=O)N(C=C(C(C)C)C2=C1)[C@H]1CCC[C@@H]1C ALTJBTYSZIRTFO-LIRRHRJNSA-N 0.000 description 2
- HEBNUUKWUFTOGG-UHFFFAOYSA-N CN(C1=CN(C(C2=CC=C(C=C12)N1N=C(N(C1=O)CC)CO)=O)C1=C(C=CC=C1)C)C Chemical compound CN(C1=CN(C(C2=CC=C(C=C12)N1N=C(N(C1=O)CC)CO)=O)C1=C(C=CC=C1)C)C HEBNUUKWUFTOGG-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- SMANCDZCXIFAPB-UHFFFAOYSA-N ClC1=C(C(=CC=C1)Cl)N1C(C2=CC=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)=O Chemical compound ClC1=C(C(=CC=C1)Cl)N1C(C2=CC=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)=O SMANCDZCXIFAPB-UHFFFAOYSA-N 0.000 description 2
- CMSIJIMYODVIGA-UHFFFAOYSA-N ClC1=C(C(=CC=C1)Cl)N1C(C2=CC=C(C=C2C(=C1)C1(CC1)C)N1N=C(N(C1=O)CC)CO)=O Chemical compound ClC1=C(C(=CC=C1)Cl)N1C(C2=CC=C(C=C2C(=C1)C1(CC1)C)N1N=C(N(C1=O)CC)CO)=O CMSIJIMYODVIGA-UHFFFAOYSA-N 0.000 description 2
- VGYUVZDBJOPOOA-UHFFFAOYSA-N ClC1=C(C(=CC=C1)F)N1C(C2=CC=C(C=C2C(=C1)C(=C)C(F)(F)F)N1N=C(N(C1=O)CC)CO)=O Chemical compound ClC1=C(C(=CC=C1)F)N1C(C2=CC=C(C=C2C(=C1)C(=C)C(F)(F)F)N1N=C(N(C1=O)CC)CO)=O VGYUVZDBJOPOOA-UHFFFAOYSA-N 0.000 description 2
- BJTDLDPTJSRNTH-UHFFFAOYSA-N ClC1=C(C(=CC=C1OC)F)N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound ClC1=C(C(=CC=C1OC)F)N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O BJTDLDPTJSRNTH-UHFFFAOYSA-N 0.000 description 2
- NCKWOIGPCLBBOD-UHFFFAOYSA-N ClC1=C(C(=CC=C1OC)F)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound ClC1=C(C(=CC=C1OC)F)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O NCKWOIGPCLBBOD-UHFFFAOYSA-N 0.000 description 2
- HNJQBRIYSVUWBE-UHFFFAOYSA-N ClC1=C(C(=NN1)C)N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound ClC1=C(C(=NN1)C)N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O HNJQBRIYSVUWBE-UHFFFAOYSA-N 0.000 description 2
- ARIFMPDOUNGTJK-UHFFFAOYSA-N ClC1=C(C(=NN1)C)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound ClC1=C(C(=NN1)C)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O ARIFMPDOUNGTJK-UHFFFAOYSA-N 0.000 description 2
- XIYHEJBMRDRNNN-UHFFFAOYSA-N ClC1=C(C=C(C=C1)OC)N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound ClC1=C(C=C(C=C1)OC)N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O XIYHEJBMRDRNNN-UHFFFAOYSA-N 0.000 description 2
- IDPYJXJLLYLHKL-UHFFFAOYSA-N ClC1=C(C=CC=C1)N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound ClC1=C(C=CC=C1)N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O IDPYJXJLLYLHKL-UHFFFAOYSA-N 0.000 description 2
- VIDWAIHJHDDOAR-UHFFFAOYSA-N ClC1=C(C=CC=C1OC)N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound ClC1=C(C=CC=C1OC)N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O VIDWAIHJHDDOAR-UHFFFAOYSA-N 0.000 description 2
- YMIFGGFPLKFLQZ-UHFFFAOYSA-N ClC1=C(C=CC=C1OCCO)N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound ClC1=C(C=CC=C1OCCO)N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O YMIFGGFPLKFLQZ-UHFFFAOYSA-N 0.000 description 2
- AJAWOZTVDURYGN-UHFFFAOYSA-N ClC1=NC=C(C=C1N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O)C Chemical compound ClC1=NC=C(C=C1N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O)C AJAWOZTVDURYGN-UHFFFAOYSA-N 0.000 description 2
- MMNQBNCHTXTSFM-UHFFFAOYSA-N ClC1=NC=C(C=C1N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O)C Chemical compound ClC1=NC=C(C=C1N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O)C MMNQBNCHTXTSFM-UHFFFAOYSA-N 0.000 description 2
- VGRFQPKLLKGPGU-UHFFFAOYSA-N ClC=1C(=NC(=CC=1)C)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound ClC=1C(=NC(=CC=1)C)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O VGRFQPKLLKGPGU-UHFFFAOYSA-N 0.000 description 2
- AOXDUOMZWFKNJB-UHFFFAOYSA-N ClC=1C(=NC=C(C=1N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O)C)OC Chemical compound ClC=1C(=NC=C(C=1N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O)C)OC AOXDUOMZWFKNJB-UHFFFAOYSA-N 0.000 description 2
- JBVOWLVSEMJSHW-UHFFFAOYSA-N ClC=1C(=NC=C(C=1N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O)C)OC Chemical compound ClC=1C(=NC=C(C=1N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O)C)OC JBVOWLVSEMJSHW-UHFFFAOYSA-N 0.000 description 2
- WHTRGQNTONEUJG-UHFFFAOYSA-N ClC=1C(=NC=CC=1N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O)OC Chemical compound ClC=1C(=NC=CC=1N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O)OC WHTRGQNTONEUJG-UHFFFAOYSA-N 0.000 description 2
- OGDLHHMZIAAHQS-UHFFFAOYSA-N ClC=1C(=NC=CC=1OC)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound ClC=1C(=NC=CC=1OC)N1C(C2=CC(=C(C=C2C(=C1)C(C)C)N1N=C(N(C1=O)CC)CO)F)=O OGDLHHMZIAAHQS-UHFFFAOYSA-N 0.000 description 2
- 229910020366 ClO 4 Inorganic materials 0.000 description 2
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- PHNLBFNRVLZBKM-UHFFFAOYSA-N FC1=C(C=C(C=C1)F)N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O Chemical compound FC1=C(C=C(C=C1)F)N1C(C2=CC(=C(C=C2C(=C1)C(=C)C)N1N=C(N(C1=O)CC)CO)F)=O PHNLBFNRVLZBKM-UHFFFAOYSA-N 0.000 description 2
- 241000079420 Fluda Species 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
- 239000007818 Grignard reagent Substances 0.000 description 2
- 101150033506 HOX gene Proteins 0.000 description 2
- 206010066476 Haematological malignancy Diseases 0.000 description 2
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 101100237041 Homo sapiens MEIS1 gene Proteins 0.000 description 2
- 101001052849 Homo sapiens Tyrosine-protein kinase Fer Proteins 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- UIARLYUEJFELEN-LROUJFHJSA-N LSM-1231 Chemical compound C12=C3N4C5=CC=CC=C5C3=C3C(=O)NCC3=C2C2=CC=CC=C2N1[C@]1(C)[C@](CO)(O)C[C@H]4O1 UIARLYUEJFELEN-LROUJFHJSA-N 0.000 description 2
- 206010023791 Large granular lymphocytosis Diseases 0.000 description 2
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- 241000872931 Myoporum sandwicense Species 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 208000035416 Prolymphocytic B-Cell Leukemia Diseases 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 229910006124 SOCl2 Inorganic materials 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 238000006932 Simmons-Smith cyclopropanation reaction Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 102100024537 Tyrosine-protein kinase Fer Human genes 0.000 description 2
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 208000013593 acute megakaryoblastic leukemia Diseases 0.000 description 2
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 206010002449 angioimmunoblastic T-cell lymphoma Diseases 0.000 description 2
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 238000006254 arylation reaction Methods 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- GTXRYQGMNAPQDP-UHFFFAOYSA-N butyl-chloro-diphenylsilane Chemical group C=1C=CC=CC=1[Si](Cl)(CCCC)C1=CC=CC=C1 GTXRYQGMNAPQDP-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 2
- 229960003529 diazepam Drugs 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- DGODWNOPHMXOTR-UHFFFAOYSA-N dipotassium;dioxido(dioxo)osmium;dihydrate Chemical compound O.O.[K+].[K+].[O-][Os]([O-])(=O)=O DGODWNOPHMXOTR-UHFFFAOYSA-N 0.000 description 2
- DCSRPHQBFSYJNN-UHFFFAOYSA-L disodium 4-[(2-arsonophenyl)diazenyl]-3-hydroxynaphthalene-2,7-disulfonate Chemical compound [Na+].[Na+].Oc1c(N=Nc2ccccc2[As](O)(O)=O)c2ccc(cc2cc1S([O-])(=O)=O)S([O-])(=O)=O DCSRPHQBFSYJNN-UHFFFAOYSA-L 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- PHSWWKXTGAJPCQ-UHFFFAOYSA-N ethyl 2-phenylmethoxyacetate Chemical compound CCOC(=O)COCC1=CC=CC=C1 PHSWWKXTGAJPCQ-UHFFFAOYSA-N 0.000 description 2
- WDKJGPAUJRARSH-UHFFFAOYSA-N ethyl 3-methylpent-2-enoate Chemical compound CCOC(=O)C=C(C)CC WDKJGPAUJRARSH-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- IKGLACJFEHSFNN-UHFFFAOYSA-N hydron;triethylazanium;trifluoride Chemical compound F.F.F.CCN(CC)CC IKGLACJFEHSFNN-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- ODBLHEXUDAPZAU-UHFFFAOYSA-N isocitric acid Chemical compound OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 229910052750 molybdenum Inorganic materials 0.000 description 2
- 239000011733 molybdenum Substances 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000077 silane Inorganic materials 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- UXXQOJXBIDBUAC-UHFFFAOYSA-N tandutinib Chemical compound COC1=CC2=C(N3CCN(CC3)C(=O)NC=3C=CC(OC(C)C)=CC=3)N=CN=C2C=C1OCCCN1CCCCC1 UXXQOJXBIDBUAC-UHFFFAOYSA-N 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- SSJXIUAHEKJCMH-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-diamine Chemical compound N[C@@H]1CCCC[C@H]1N SSJXIUAHEKJCMH-PHDIDXHHSA-N 0.000 description 1
- IMIGJFNGDJQHMS-UHFFFAOYSA-N (2-chloro-6-fluorophenyl)hydrazine;hydrochloride Chemical compound Cl.NNC1=C(F)C=CC=C1Cl IMIGJFNGDJQHMS-UHFFFAOYSA-N 0.000 description 1
- SCZGZDLUGUYLRV-UHFFFAOYSA-N (2-methylphenyl)hydrazine Chemical compound CC1=CC=CC=C1NN SCZGZDLUGUYLRV-UHFFFAOYSA-N 0.000 description 1
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- CVCLJVVBHYOXDC-IAZSKANUSA-N (2z)-2-[(5z)-5-[(3,5-dimethyl-1h-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole Chemical group COC1=C\C(=C/2N=C3C=CC=CC3=C\2)N\C1=C/C=1NC(C)=CC=1C CVCLJVVBHYOXDC-IAZSKANUSA-N 0.000 description 1
- 239000001618 (3R)-3-methylpentan-1-ol Substances 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
- GRZHHTYDZVRPIC-UHFFFAOYSA-N (benzyloxy)acetic acid Chemical compound OC(=O)COCC1=CC=CC=C1 GRZHHTYDZVRPIC-UHFFFAOYSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- LZTSCEYDCZBRCJ-UHFFFAOYSA-N 1,2-dihydro-1,2,4-triazol-3-one Chemical class OC=1N=CNN=1 LZTSCEYDCZBRCJ-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- LOYZVRIHVZEDMW-UHFFFAOYSA-N 1-bromo-3-methylbut-2-ene Chemical compound CC(C)=CCBr LOYZVRIHVZEDMW-UHFFFAOYSA-N 0.000 description 1
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 1
- PAOHAQSLJSMLAT-UHFFFAOYSA-N 1-butylperoxybutane Chemical group CCCCOOCCCC PAOHAQSLJSMLAT-UHFFFAOYSA-N 0.000 description 1
- RAYNZUHYMMLQQA-ZEQRLZLVSA-N 2,3,5-trihydroxy-7-methyl-n-[(2r)-2-phenylpropyl]-6-[1,6,7-trihydroxy-3-methyl-5-[[(2r)-2-phenylpropyl]carbamoyl]naphthalen-2-yl]naphthalene-1-carboxamide Chemical compound C1([C@@H](C)CNC(=O)C=2C3=CC(C)=C(C(=C3C=C(O)C=2O)O)C=2C(O)=C3C=C(O)C(O)=C(C3=CC=2C)C(=O)NC[C@H](C)C=2C=CC=CC=2)=CC=CC=C1 RAYNZUHYMMLQQA-ZEQRLZLVSA-N 0.000 description 1
- OBHCCORLMBZISY-UHFFFAOYSA-N 2,3-dimethylbutane-2,3-diol;ethenylboronic acid Chemical class OB(O)C=C.CC(C)(O)C(C)(C)O OBHCCORLMBZISY-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- ZJLAWMDJTMMTQB-UHFFFAOYSA-N 2-chloro-6-fluoroaniline Chemical compound NC1=C(F)C=CC=C1Cl ZJLAWMDJTMMTQB-UHFFFAOYSA-N 0.000 description 1
- HBSFTVGBQDJTAW-UHFFFAOYSA-N 2-methylbut-3-yn-2-yl acetate Chemical compound CC(=O)OC(C)(C)C#C HBSFTVGBQDJTAW-UHFFFAOYSA-N 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-L 2-oxoglutarate(2-) Chemical compound [O-]C(=O)CCC(=O)C([O-])=O KPGXRSRHYNQIFN-UHFFFAOYSA-L 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- STCTWLFYHWUGLV-UHFFFAOYSA-N 3-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]-2-chloroaniline Chemical compound [Si](C1=CC=CC=C1)(C1=CC=CC=C1)(C(C)(C)C)OCCOC=1C(=C(N)C=CC=1)Cl STCTWLFYHWUGLV-UHFFFAOYSA-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
- XKJUKVTZSPIGSI-UHFFFAOYSA-N 3-methylbutanal Chemical compound CC(C)CC=O.CC(C)CC=O XKJUKVTZSPIGSI-UHFFFAOYSA-N 0.000 description 1
- KUYDBRALXUFAAD-UHFFFAOYSA-N 4-[4-ethyl-5-oxo-3-(phenylmethoxymethyl)-1,2,4-triazol-1-yl]-5-fluoro-2-iodobenzoyl chloride Chemical compound C(C1=CC=CC=C1)OCC1=NN(C(N1CC)=O)C1=CC(=C(C(=O)Cl)C=C1F)I KUYDBRALXUFAAD-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- MCJZTHXAZZCAEK-UHFFFAOYSA-N 4-bromo-2-iodo-3-methylbenzoic acid Chemical class CC1=C(Br)C=CC(C(O)=O)=C1I MCJZTHXAZZCAEK-UHFFFAOYSA-N 0.000 description 1
- DYQXIHALMKCBKY-UHFFFAOYSA-N 4-bromo-2-iodobenzoyl chloride Chemical compound BrC1=CC(=C(C(=O)Cl)C=C1)I DYQXIHALMKCBKY-UHFFFAOYSA-N 0.000 description 1
- OMAPJRUXTMJWMQ-UHFFFAOYSA-N 4-ethyl-3-(phenylmethoxymethyl)-1H-1,2,4-triazol-5-one Chemical compound C(C1=CC=CC=C1)OCC1=NNC(N1CC)=O OMAPJRUXTMJWMQ-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- UATBWQQFLABWKR-UHFFFAOYSA-N 5,6-difluoro-2-benzofuran-1,3-dione Chemical compound C1=C(F)C(F)=CC2=C1C(=O)OC2=O UATBWQQFLABWKR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 229910015844 BCl3 Inorganic materials 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- VOFIUEPQGNFBMN-UHFFFAOYSA-N BrC1=CC(=C(C(=O)OC)C=C1)C(C(C)C)=O Chemical compound BrC1=CC(=C(C(=O)OC)C=C1)C(C(C)C)=O VOFIUEPQGNFBMN-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- IOCWREHFKJSDRA-UHFFFAOYSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1)=O)C1=C(C=C(C=C1)[N+](=O)[O-])F)I)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1)=O)C1=C(C=C(C=C1)[N+](=O)[O-])F)I)CO IOCWREHFKJSDRA-UHFFFAOYSA-N 0.000 description 1
- BZKHQYHQHLKJNX-GKOSEXJESA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)C([2H])([2H])[2H])C(C)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)C([2H])([2H])[2H])C(C)C)CO BZKHQYHQHLKJNX-GKOSEXJESA-N 0.000 description 1
- FWMYUWRDJQZRCZ-CQSZACIVSA-N C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)C)[C@H](C(F)(F)F)C)CO Chemical compound C(C)N1C(=NN(C1=O)C=1C=C2C(=CN(C(C2=CC=1F)=O)C1=C(C=CC=C1)C)[C@H](C(F)(F)F)C)CO FWMYUWRDJQZRCZ-CQSZACIVSA-N 0.000 description 1
- OLRBAAGQGWUOGC-UHFFFAOYSA-N C(C1=CC=CC=C1)OCC=1N(C(N(N=1)C=1C=C2C(C(OC(C2=CC=1F)=O)O)C(C)C)=O)CC Chemical compound C(C1=CC=CC=C1)OCC=1N(C(N(N=1)C=1C=C2C(C(OC(C2=CC=1F)=O)O)C(C)C)=O)CC OLRBAAGQGWUOGC-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KGQMSDFMGICOJM-UHFFFAOYSA-N ClC1=C(C(=NN1C1OCCCC1)C)N Chemical compound ClC1=C(C(=NN1C1OCCCC1)C)N KGQMSDFMGICOJM-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 230000007067 DNA methylation Effects 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 206010061819 Disease recurrence Diseases 0.000 description 1
- 101000827763 Drosophila melanogaster Fibroblast growth factor receptor homolog 1 Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 229910003771 Gold(I) chloride Inorganic materials 0.000 description 1
- 229910003953 H3PO2 Inorganic materials 0.000 description 1
- 102000012258 Histone-lysine N-methyltransferase 2A Human genes 0.000 description 1
- 108050002855 Histone-lysine N-methyltransferase 2A Proteins 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229940127446 Isocitrate Dehydrogenase 2 Inhibitors Drugs 0.000 description 1
- 229940123392 Isocitrate dehydrogenase 1 inhibitor Drugs 0.000 description 1
- 229940124202 Isocitrate dehydrogenase 2 inhibitor Drugs 0.000 description 1
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 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
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 description 1
- 235000014647 Lens culinaris subsp culinaris Nutrition 0.000 description 1
- 244000043158 Lens esculenta Species 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- MPCRDALPQLDDFX-UHFFFAOYSA-L Magnesium perchlorate Chemical compound [Mg+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O MPCRDALPQLDDFX-UHFFFAOYSA-L 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 101710169972 Menin Proteins 0.000 description 1
- 102100030550 Menin Human genes 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 108700041619 Myeloid Ecotropic Viral Integration Site 1 Proteins 0.000 description 1
- 102000047831 Myeloid Ecotropic Viral Integration Site 1 Human genes 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- WEEAIULATZCDEJ-UHFFFAOYSA-N N-(2-chloro-6-fluorophenyl)-3-methylpent-2-en-1-imine Chemical compound ClC1=C(C(=CC=C1)F)N=CC=C(CC)C WEEAIULATZCDEJ-UHFFFAOYSA-N 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
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 238000012879 PET imaging Methods 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 229910019032 PtCl2 Inorganic materials 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 239000005463 Tandutinib Substances 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
- ACWQBUSCFPJUPN-UHFFFAOYSA-N Tiglaldehyde Natural products CC=C(C)C=O ACWQBUSCFPJUPN-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
- SLGBZMMZGDRARJ-UHFFFAOYSA-N Triphenylene Natural products C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C2=C1 SLGBZMMZGDRARJ-UHFFFAOYSA-N 0.000 description 1
- 208000016025 Waldenstroem macroglobulinemia Diseases 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 208000015230 aggressive NK-cell leukemia Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical compound Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 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
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- HGXJOXHYPGNVNK-UHFFFAOYSA-N butane;ethenoxyethane;tin Chemical compound CCCC[Sn](CCCC)(CCCC)C(=C)OCC HGXJOXHYPGNVNK-UHFFFAOYSA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 238000009096 combination chemotherapy Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- YMHQVDAATAEZLO-UHFFFAOYSA-N cyclohexane-1,1-diamine Chemical compound NC1(N)CCCCC1 YMHQVDAATAEZLO-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000021185 dessert Nutrition 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- NLHWCTNYFFIPJT-UHFFFAOYSA-N disodium bis(trimethylsilyl)azanide Chemical compound [Na+].[Na+].C[Si](C)(C)[N-][Si](C)(C)C.C[Si](C)(C)[N-][Si](C)(C)C NLHWCTNYFFIPJT-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- UZZWBUYVTBPQIV-UHFFFAOYSA-N dme dimethoxyethane Chemical compound COCCOC.COCCOC UZZWBUYVTBPQIV-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- LHWWETDBWVTKJO-UHFFFAOYSA-N et3n triethylamine Chemical compound CCN(CC)CC.CCN(CC)CC LHWWETDBWVTKJO-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 150000002222 fluorine compounds Chemical class 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- FDWREHZXQUYJFJ-UHFFFAOYSA-M gold monochloride Chemical compound [Cl-].[Au+] FDWREHZXQUYJFJ-UHFFFAOYSA-M 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 206010066957 hepatosplenic T-cell lymphoma Diseases 0.000 description 1
- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 150000002512 isocoumarins Chemical class 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- WIJZXSAJMHAVGX-DHLKQENFSA-N ivosidenib Chemical compound FC1=CN=CC(N([C@H](C(=O)NC2CC(F)(F)C2)C=2C(=CC=CC=2)Cl)C(=O)[C@H]2N(C(=O)CC2)C=2N=CC=C(C=2)C#N)=C1 WIJZXSAJMHAVGX-DHLKQENFSA-N 0.000 description 1
- 229950010738 ivosidenib Drugs 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000003738 lymphoid progenitor cell Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 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
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- ZCGAVEFBZYWYJW-UHFFFAOYSA-N methyl 2-bromo-4,5-difluorobenzoate Chemical compound COC(=O)C1=CC(F)=C(F)C=C1Br ZCGAVEFBZYWYJW-UHFFFAOYSA-N 0.000 description 1
- VAYKANWZAJRNOM-UHFFFAOYSA-N methyl 4-bromo-2-iodobenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1I VAYKANWZAJRNOM-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 206010028537 myelofibrosis Diseases 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
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- JLYAXFNOILIKPP-KXQOOQHDSA-N navitoclax Chemical compound C([C@@H](NC1=CC=C(C=C1S(=O)(=O)C(F)(F)F)S(=O)(=O)NC(=O)C1=CC=C(C=C1)N1CCN(CC1)CC1=C(CCC(C1)(C)C)C=1C=CC(Cl)=CC=1)CSC=1C=CC=CC=1)CN1CCOCC1 JLYAXFNOILIKPP-KXQOOQHDSA-N 0.000 description 1
- 229950004847 navitoclax Drugs 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 101150083701 npm1 gene Proteins 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 229950006584 obatoclax Drugs 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000005949 ozonolysis reaction Methods 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Chemical group 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229960000688 pomalidomide Drugs 0.000 description 1
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 208000003476 primary myelofibrosis Diseases 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 229940107700 pyruvic acid Drugs 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
- 229960001404 quinidine Drugs 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000009118 salvage therapy Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 description 1
- 235000021309 simple sugar Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 206010062113 splenic marginal zone lymphoma Diseases 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229950009893 tandutinib Drugs 0.000 description 1
- 238000011361 targeted radionuclide therapy Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 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 1
- 150000003510 tertiary aliphatic amines Chemical class 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- ISXOBTBCNRIIQO-UHFFFAOYSA-N tetrahydrothiophene 1-oxide Chemical compound O=S1CCCC1 ISXOBTBCNRIIQO-UHFFFAOYSA-N 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 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
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- NNLPAMPVXAPWKG-UHFFFAOYSA-N trimethyl(1-methylethoxy)silane Chemical compound CC(C)O[Si](C)(C)C NNLPAMPVXAPWKG-UHFFFAOYSA-N 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- MHNHYTDAOYJUEZ-UHFFFAOYSA-N triphenylphosphane Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 MHNHYTDAOYJUEZ-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-O triphenylphosphanium Chemical compound C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-O 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Images
Classifications
-
- 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
- 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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- 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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2021093036 | 2021-05-11 | ||
| WOPCT/CN2021/093036 | 2021-05-11 | ||
| CN2021100523 | 2021-06-17 | ||
| WOPCT/CN2021/100523 | 2021-06-17 | ||
| CN2022086004 | 2022-04-11 | ||
| WOPCT/CN2022/086004 | 2022-04-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW202308643A true TW202308643A (zh) | 2023-03-01 |
Family
ID=81753154
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW111117441A TW202308643A (zh) | 2021-05-11 | 2022-05-10 | 組合療法(二) |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP4337216A1 (https=) |
| JP (1) | JP2024518497A (https=) |
| KR (1) | KR20240006631A (https=) |
| CN (2) | CN117460513A (https=) |
| AU (1) | AU2022274071A1 (https=) |
| CA (1) | CA3215313A1 (https=) |
| CL (2) | CL2023003239A1 (https=) |
| CO (1) | CO2023014322A2 (https=) |
| DO (1) | DOP2023000246A (https=) |
| IL (1) | IL308335A (https=) |
| MX (1) | MX2023013410A (https=) |
| PE (1) | PE20240593A1 (https=) |
| PH (1) | PH12023552974A1 (https=) |
| TW (1) | TW202308643A (https=) |
| UY (1) | UY39761A (https=) |
| WO (1) | WO2022237720A1 (https=) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW202525813A (zh) | 2019-12-19 | 2025-07-01 | 比利時商健生藥品公司 | 經取代之直鏈螺環接衍生物 |
| EP4626426A1 (en) * | 2022-11-30 | 2025-10-08 | JANSSEN Pharmaceutica NV | Combinations comprising a menin-mll inhibitor and at least one other therapeutic agent |
| WO2024114666A1 (en) * | 2022-11-30 | 2024-06-06 | Janssen Pharmaceutica Nv | Combinations comprising a menin-mll inhibitor and a bcl-2 inhibitor |
| EP4698182A1 (en) * | 2023-04-17 | 2026-02-25 | Janssen Pharmaceutica NV | Combination of a menin-ll1 inhibitor, a dna intercalating agent and a pyrimidine analogue to treat a hematopoietic disorder |
| WO2025082444A2 (en) * | 2023-10-20 | 2025-04-24 | Janssen Pharmaceutica Nv | (r) -n-ethyl-5-fluoro-n-isopropyl-2- ( (5- (2- (6- ( (2-methoxyethyl) (methyl) amino) -2-methylhexan-3-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -1, 2, 4-triazin-6-yl) oxy) benzamide, formulations and dosage regimens thereof, for use in treating cancer |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TN2017000080A1 (en) | 2014-12-18 | 2018-07-04 | Takeda Pharmaceuticals Co | Solid state forms of fused heteroaromatic pyrrolidinones |
| AU2016378579A1 (en) * | 2015-12-22 | 2018-06-14 | Vitae Pharmaceuticals, Inc. | Inhibitors of the menin-MLL interaction |
| WO2017214367A1 (en) * | 2016-06-10 | 2017-12-14 | Vitae Pharmaceuticals, Inc. | Inhibitors of the menin-mll interaction |
| TW202104207A (zh) | 2019-04-17 | 2021-02-01 | 美商健生生物科技公司 | 二氫乳清酸脫氫酶抑制劑 |
| TW202525813A (zh) | 2019-12-19 | 2025-07-01 | 比利時商健生藥品公司 | 經取代之直鏈螺環接衍生物 |
-
2022
- 2022-05-09 MX MX2023013410A patent/MX2023013410A/es unknown
- 2022-05-09 KR KR1020237042402A patent/KR20240006631A/ko active Pending
- 2022-05-09 PH PH1/2023/552974A patent/PH12023552974A1/en unknown
- 2022-05-09 PE PE2023003030A patent/PE20240593A1/es unknown
- 2022-05-09 EP EP22725158.4A patent/EP4337216A1/en active Pending
- 2022-05-09 CA CA3215313A patent/CA3215313A1/en active Pending
- 2022-05-09 WO PCT/CN2022/091679 patent/WO2022237720A1/en not_active Ceased
- 2022-05-09 JP JP2023569789A patent/JP2024518497A/ja active Pending
- 2022-05-09 CN CN202280034525.XA patent/CN117460513A/zh active Pending
- 2022-05-09 CN CN202410897512.6A patent/CN118845787A/zh active Pending
- 2022-05-09 IL IL308335A patent/IL308335A/en unknown
- 2022-05-09 AU AU2022274071A patent/AU2022274071A1/en active Pending
- 2022-05-10 UY UY0001039761A patent/UY39761A/es unknown
- 2022-05-10 TW TW111117441A patent/TW202308643A/zh unknown
-
2023
- 2023-10-25 CO CONC2023/0014322A patent/CO2023014322A2/es unknown
- 2023-10-31 CL CL2023003239A patent/CL2023003239A1/es unknown
- 2023-11-08 DO DO2023000246A patent/DOP2023000246A/es unknown
-
2024
- 2024-09-23 CL CL2024002832A patent/CL2024002832A1/es unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU2022274071A1 (en) | 2024-01-04 |
| MX2023013410A (es) | 2023-12-06 |
| JP2024518497A (ja) | 2024-05-01 |
| CO2023014322A2 (es) | 2023-11-20 |
| DOP2023000246A (es) | 2024-04-30 |
| IL308335A (en) | 2024-01-01 |
| CL2024002832A1 (es) | 2025-02-14 |
| CA3215313A1 (en) | 2022-11-17 |
| PH12023552974A1 (en) | 2024-03-11 |
| CL2023003239A1 (es) | 2024-06-07 |
| PE20240593A1 (es) | 2024-03-21 |
| CN118845787A (zh) | 2024-10-29 |
| UY39761A (es) | 2022-11-30 |
| CN117460513A (zh) | 2024-01-26 |
| EP4337216A1 (en) | 2024-03-20 |
| WO2022237720A1 (en) | 2022-11-17 |
| KR20240006631A (ko) | 2024-01-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TW202308643A (zh) | 組合療法(二) | |
| TW202308642A (zh) | 組合療法(一) | |
| JP7554829B2 (ja) | 置換直鎖スピロ誘導体 | |
| AU2017338269B2 (en) | Novel monocyclic and bicyclic ring system substituted carbanucleoside analogues for use as PRMT5 inhibitors | |
| AU2015238298B2 (en) | Substituted 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrimidine derivatives and 2,3-dihydro-1H-imidazo[1,2-b]pyrazole derivatives as ROS1 inhibitors | |
| WO2019074809A1 (en) | INDAZOLYL-SPIRO [2.2] PENTANE-CARBONITRILE DERIVATIVES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF | |
| JP2025515285A (ja) | 大環状複素環及びその使用 | |
| WO2024114664A1 (en) | Combinations comprising a menin-mll inhibitor and at least one other therapeutic agent | |
| WO2024114666A1 (en) | Combinations comprising a menin-mll inhibitor and a bcl-2 inhibitor | |
| US20250302840A1 (en) | Combination therapies | |
| EA051809B1 (ru) | Комбинированные терапии | |
| EA051795B1 (ru) | Комбинированные терапии | |
| HK40117870A (zh) | 组合疗法 | |
| HK40100348A (zh) | 组合疗法 | |
| HK40118806A (zh) | 组合疗法 | |
| HK40098242A (zh) | 组合疗法 |