CN116082337B - 炔基取代的杂环化合物,其制法与医药上的用途 - Google Patents
炔基取代的杂环化合物,其制法与医药上的用途 Download PDFInfo
- Publication number
- CN116082337B CN116082337B CN202310251465.3A CN202310251465A CN116082337B CN 116082337 B CN116082337 B CN 116082337B CN 202310251465 A CN202310251465 A CN 202310251465A CN 116082337 B CN116082337 B CN 116082337B
- Authority
- CN
- China
- Prior art keywords
- mmol
- compound
- solution
- cdk7
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 239000003814 drug Substances 0.000 title claims description 7
- 238000000034 method Methods 0.000 title description 17
- 230000008569 process Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 230000002062 proliferating effect Effects 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims description 18
- 208000027866 inflammatory disease Diseases 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 7
- 101100495324 Caenorhabditis elegans cdk-7 gene Proteins 0.000 claims description 6
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- 208000026278 immune system disease Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229940125888 CDK7 inhibitor Drugs 0.000 claims description 2
- OBJNFLYHUXWUPF-IZZDOVSWSA-N n-[3-[[5-chloro-4-(1h-indol-3-yl)pyrimidin-2-yl]amino]phenyl]-4-[[(e)-4-(dimethylamino)but-2-enoyl]amino]benzamide Chemical compound C1=CC(NC(=O)/C=C/CN(C)C)=CC=C1C(=O)NC1=CC=CC(NC=2N=C(C(Cl)=CN=2)C=2C3=CC=CC=C3NC=2)=C1 OBJNFLYHUXWUPF-IZZDOVSWSA-N 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 15
- 201000011510 cancer Diseases 0.000 abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- 239000000243 solution Substances 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- -1 alkynyl substituted heterocyclic compound Chemical class 0.000 description 32
- 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 description 31
- 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 description 31
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 125000000217 alkyl group Chemical group 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 108091000080 Phosphotransferase Proteins 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 102000020233 phosphotransferase Human genes 0.000 description 18
- 239000012043 crude product Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 238000001514 detection method Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 229910052736 halogen Inorganic materials 0.000 description 10
- 150000002367 halogens Chemical class 0.000 description 10
- 108010068237 Cyclin H Proteins 0.000 description 9
- 102100036883 Cyclin-H Human genes 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000000758 substrate Substances 0.000 description 9
- 230000035897 transcription Effects 0.000 description 9
- 238000013518 transcription Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 8
- 102100038111 Cyclin-dependent kinase 12 Human genes 0.000 description 8
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 8
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 description 8
- 101000884345 Homo sapiens Cyclin-dependent kinase 12 Proteins 0.000 description 8
- 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 229920001184 polypeptide Polymers 0.000 description 8
- 102000004196 processed proteins & peptides Human genes 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 7
- 239000007987 MES buffer Substances 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 6
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 239000012131 assay buffer Substances 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 108091023040 Transcription factor Proteins 0.000 description 5
- 102000040945 Transcription factor Human genes 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- WMKYKQWKLILFBM-UHFFFAOYSA-N 2h-pyridine-1-carboxylic acid Chemical compound OC(=O)N1CC=CC=C1 WMKYKQWKLILFBM-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 4
- 102000009572 RNA Polymerase II Human genes 0.000 description 4
- 108010009460 RNA Polymerase II Proteins 0.000 description 4
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 4
- 229920000136 polysorbate Polymers 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 108091007914 CDKs Proteins 0.000 description 3
- 102100040428 Chitobiosyldiphosphodolichol beta-mannosyltransferase Human genes 0.000 description 3
- 108010068106 Cyclin T Proteins 0.000 description 3
- 102100036876 Cyclin-K Human genes 0.000 description 3
- 102100024109 Cyclin-T1 Human genes 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102100037858 G1/S-specific cyclin-E1 Human genes 0.000 description 3
- 101000891557 Homo sapiens Chitobiosyldiphosphodolichol beta-mannosyltransferase Proteins 0.000 description 3
- 101000713127 Homo sapiens Cyclin-K Proteins 0.000 description 3
- 101000738568 Homo sapiens G1/S-specific cyclin-E1 Proteins 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 description 2
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 2
- QBDAFARLDLCWAT-UHFFFAOYSA-N 2,3-dihydropyran-6-one Chemical compound O=C1OCCC=C1 QBDAFARLDLCWAT-UHFFFAOYSA-N 0.000 description 2
- IDRUEHMBFUJKAK-UHFFFAOYSA-N 2,4-dichloro-5-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CN=C(Cl)N=C1Cl IDRUEHMBFUJKAK-UHFFFAOYSA-N 0.000 description 2
- ARGCQEVBJHPOGB-UHFFFAOYSA-N 2,5-dihydrofuran Chemical compound C1OCC=C1 ARGCQEVBJHPOGB-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 2
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 2
- IHXNIOYEXQWUNI-UHFFFAOYSA-N 4,5-dihydro-1h-pyrimidin-6-one Chemical compound O=C1CCN=CN1 IHXNIOYEXQWUNI-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 101100327354 Caenorhabditis elegans cdk-12 gene Proteins 0.000 description 2
- 108010077544 Chromatin Proteins 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 108700039887 Essential Genes Proteins 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 208000000474 Poliomyelitis Diseases 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 208000025747 Rheumatic disease Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 230000006369 cell cycle progression Effects 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 210000003483 chromatin Anatomy 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 150000003997 cyclic ketones Chemical class 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 108091008039 hormone receptors Proteins 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical compound OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 102000042567 non-coding RNA Human genes 0.000 description 2
- 108091027963 non-coding RNA Proteins 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 2
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- RHNFTJZIJSQCAZ-VIFPVBQESA-N tert-butyl N-[(3S)-6,6-dimethylpiperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(N[C@@H]1CNC(C)(C)CC1)=O RHNFTJZIJSQCAZ-VIFPVBQESA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- JQLQRTIYJFIXIE-UHFFFAOYSA-N 1,1-dioxo-1,4-thiazinan-3-one Chemical compound O=C1CS(=O)(=O)CCN1 JQLQRTIYJFIXIE-UHFFFAOYSA-N 0.000 description 1
- OQJVXNHMUWQQEW-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrazine Chemical compound C1CNC=CN1 OQJVXNHMUWQQEW-UHFFFAOYSA-N 0.000 description 1
- OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- NQPJDJVGBDHCAD-UHFFFAOYSA-N 1,3-diazinan-2-one Chemical compound OC1=NCCCN1 NQPJDJVGBDHCAD-UHFFFAOYSA-N 0.000 description 1
- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical compound C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 description 1
- AICIYIDUYNFPRY-UHFFFAOYSA-N 1,3-dihydro-2H-imidazol-2-one Chemical compound O=C1NC=CN1 AICIYIDUYNFPRY-UHFFFAOYSA-N 0.000 description 1
- VIESAWGOYVNHLV-UHFFFAOYSA-N 1,3-dihydropyrrol-2-one Chemical compound O=C1CC=CN1 VIESAWGOYVNHLV-UHFFFAOYSA-N 0.000 description 1
- VAYTZRYEBVHVLE-UHFFFAOYSA-N 1,3-dioxol-2-one Chemical compound O=C1OC=CO1 VAYTZRYEBVHVLE-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- ABADUMLIAZCWJD-UHFFFAOYSA-N 1,3-dioxole Chemical compound C1OC=CO1 ABADUMLIAZCWJD-UHFFFAOYSA-N 0.000 description 1
- LQPOOAJESJYDLS-UHFFFAOYSA-N 1,3-oxazinane Chemical compound C1CNCOC1 LQPOOAJESJYDLS-UHFFFAOYSA-N 0.000 description 1
- VPVXHAANQNHFSF-UHFFFAOYSA-N 1,4-dioxan-2-one Chemical compound O=C1COCCO1 VPVXHAANQNHFSF-UHFFFAOYSA-N 0.000 description 1
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 description 1
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 1
- ZABMHLDQFJHDSC-UHFFFAOYSA-N 2,3-dihydro-1,3-oxazole Chemical compound C1NC=CO1 ZABMHLDQFJHDSC-UHFFFAOYSA-N 0.000 description 1
- GCRNUVFNHLFBRI-UHFFFAOYSA-N 2,5-dihydro-1h-pyridin-6-one Chemical compound O=C1CC=CCN1 GCRNUVFNHLFBRI-UHFFFAOYSA-N 0.000 description 1
- WURYWHAKEJHAOV-UHFFFAOYSA-N 2,5-dihydrothiophene Chemical compound C1SCC=C1 WURYWHAKEJHAOV-UHFFFAOYSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 description 1
- ZPOODPZCZLCUAN-UHFFFAOYSA-N 3,4-dihydro-1h-pyridin-2-one Chemical compound O=C1CCC=CN1 ZPOODPZCZLCUAN-UHFFFAOYSA-N 0.000 description 1
- BRNCTEUUWQPNBJ-UHFFFAOYSA-N 3,4-dihydro-2H-1,4-thiazine 1,1-dioxide Chemical compound O=S1(=O)CCNC=C1 BRNCTEUUWQPNBJ-UHFFFAOYSA-N 0.000 description 1
- NLXFKDHULKLENC-UHFFFAOYSA-N 3,4-dihydro-2h-1,3-oxazine Chemical compound C1NCC=CO1 NLXFKDHULKLENC-UHFFFAOYSA-N 0.000 description 1
- YEEGQDGJIXWFIQ-UHFFFAOYSA-N 3,4-dihydro-2h-1,4-oxazine Chemical compound C1COC=CN1 YEEGQDGJIXWFIQ-UHFFFAOYSA-N 0.000 description 1
- RUPLWPYHVWSFEF-UHFFFAOYSA-N 3,6-dihydro-2h-1,3-oxazine Chemical compound C1NC=CCO1 RUPLWPYHVWSFEF-UHFFFAOYSA-N 0.000 description 1
- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- FTAHXMZRJCZXDL-UHFFFAOYSA-N 3-piperideine Chemical compound C1CC=CCN1 FTAHXMZRJCZXDL-UHFFFAOYSA-N 0.000 description 1
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 1
- MUGSKSNNEORSJG-UHFFFAOYSA-N 3174-74-1 Chemical compound C1CC=CCO1 MUGSKSNNEORSJG-UHFFFAOYSA-N 0.000 description 1
- XYVMOLOUBJBNBF-UHFFFAOYSA-N 3h-1,3-oxazol-2-one Chemical compound OC1=NC=CO1 XYVMOLOUBJBNBF-UHFFFAOYSA-N 0.000 description 1
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 1
- DVGWFLBIDZEUSM-UHFFFAOYSA-N 6-chloro-3-iodo-1h-pyrrolo[2,3-b]pyridine Chemical compound ClC1=CC=C2C(I)=CNC2=N1 DVGWFLBIDZEUSM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 102100028292 Aladin Human genes 0.000 description 1
- 101710065039 Aladin Proteins 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
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZGAUDASCRAOGAE-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1C=C(C=2C1=NC(=CC2)Cl)I Chemical compound C(C)(C)(C)OC(=O)N1C=C(C=2C1=NC(=CC2)Cl)I ZGAUDASCRAOGAE-UHFFFAOYSA-N 0.000 description 1
- 101150012716 CDK1 gene Proteins 0.000 description 1
- 101100439046 Caenorhabditis elegans cdk-2 gene Proteins 0.000 description 1
- 101100383153 Caenorhabditis elegans cdk-9 gene Proteins 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 1
- 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 208000001490 Dengue Diseases 0.000 description 1
- 206010012310 Dengue fever Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 206010014909 Enterovirus infection Diseases 0.000 description 1
- 206010061126 Escherichia infection Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 102100038595 Estrogen receptor Human genes 0.000 description 1
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000007212 Foot-and-Mouth Disease Diseases 0.000 description 1
- 241000710198 Foot-and-mouth disease virus Species 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Natural products OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 102100026115 S-adenosylmethionine synthase isoform type-1 Human genes 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- XYLXXNFYVQYJRZ-UHFFFAOYSA-M [Cl-].[Mg+]C.C1CCOC1 Chemical compound [Cl-].[Mg+]C.C1CCOC1 XYLXXNFYVQYJRZ-UHFFFAOYSA-M 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- HTJWUNNIRKDDIV-UHFFFAOYSA-N bis(1-adamantyl)-butylphosphane Chemical compound C1C(C2)CC(C3)CC2CC13P(CCCC)C1(C2)CC(C3)CC2CC3C1 HTJWUNNIRKDDIV-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 208000014581 breast ductal adenocarcinoma Diseases 0.000 description 1
- 201000010983 breast ductal carcinoma Diseases 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
- VIHAEDVKXSOUAT-UHFFFAOYSA-N but-2-en-4-olide Chemical compound O=C1OCC=C1 VIHAEDVKXSOUAT-UHFFFAOYSA-N 0.000 description 1
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 208000025729 dengue disease Diseases 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000000959 ear middle Anatomy 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 208000020612 escherichia coli infection Diseases 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- KZGWPHUWNWRTEP-UHFFFAOYSA-N ethynyl-tri(propan-2-yl)silane Chemical group CC(C)[Si](C#C)(C(C)C)C(C)C KZGWPHUWNWRTEP-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 206010073095 invasive ductal breast carcinoma Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000003674 kinase activity assay Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- ZQHJAAMMKABEBS-UHFFFAOYSA-N morpholin-2-one Chemical compound O=C1CNCCO1 ZQHJAAMMKABEBS-UHFFFAOYSA-N 0.000 description 1
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 description 1
- NLHLJOYRZUKQLH-UHFFFAOYSA-N morpholine;piperazin-2-one Chemical compound C1COCCN1.O=C1CNCCN1 NLHLJOYRZUKQLH-UHFFFAOYSA-N 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 108091008820 oncogenic transcription factors Proteins 0.000 description 1
- 238000012803 optimization experiment Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000003998 progesterone receptors Human genes 0.000 description 1
- 108090000468 progesterone receptors Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- VIXWGKYSYIBATJ-UHFFFAOYSA-N pyrrol-2-one Chemical compound O=C1C=CC=N1 VIXWGKYSYIBATJ-UHFFFAOYSA-N 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
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 102000037983 regulatory factors Human genes 0.000 description 1
- 108091008025 regulatory factors Proteins 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical compound O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- AKQXKEBCONUWCL-QMMMGPOBSA-N tert-butyl (3s)-3-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H](N)C1 AKQXKEBCONUWCL-QMMMGPOBSA-N 0.000 description 1
- KBNSUMIBERIFIT-ZETCQYMHSA-N tert-butyl n-[(3s)-6-oxopiperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCC(=O)NC1 KBNSUMIBERIFIT-ZETCQYMHSA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000005029 transcription elongation Effects 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/04—Drugs for disorders of the respiratory system for throat disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Virology (AREA)
- Pulmonology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- Otolaryngology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hematology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Obesity (AREA)
- Tropical Medicine & Parasitology (AREA)
- Biotechnology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- AIDS & HIV (AREA)
- Dermatology (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Neurology (AREA)
- Transplantation (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了炔基取代的杂环化合物,其制法与医药上的用途,具体地,本发明公开了结构如式I所示的炔基取代的杂环化合物,各基团定义如说明书中所定义;包含所述化合物的药物组合物以及所述化合物在治疗细胞增殖性疾病(例如癌症)等中的用途。
Description
技术领域
本发明属于医药领域,具体涉及炔基取代的杂环化合物,其制法与医药上的用途。
背景技术
细胞周期蛋白依赖性激酶(CDK)/周期蛋白复合物被鉴定为RNA聚合酶II转录机制的保守组分。目前存在20种哺乳动物CDK。在哺乳动物CDK中,CDK7具有坚实的激酶活性,且仅有CDK7具有调控细胞周期进程和转录的双重功能。在胞质溶胶中,CDK7作为异源三聚体复合物存在并且被认为起着CDK1/2/4/6激活激酶(CAK)的作用,由此CDK7对CDK1/2/4/6中的保守残基的磷酸化是完全催化性CDK活性和细胞周期进程所必需的。在细胞核中,CDK7形成RNA聚合酶II转录因子复合物的激酶核心,并且负责磷酸化RNA聚合酶II的C-末端结构域(CTD),这是基因转录起始的必要步骤。CDK7的两个功能(即CAK和CTD磷酸化)一起支持细胞增殖、细胞周期和转录的关键方面。
CDK7作为总体转录的调控因子,可作为治疗许多疾病和综合症的治疗性靶点。CDK7可在转录调控区中和多个转录因子、辅因子、染色质调控因子以及非编码RNA中的相互作用以调控转录。而这些转录因子、辅因子、染色质调控物或非编码RNA的突变可以导致癌症、自身免疫病、神经系统障碍、发育综合症、糖尿病、心血管疾病和肥胖症等疾病。其中一些转录因子可控制RNA聚合酶II介导的转录起始和延伸,并且当它们的表达或功能改变时,可以产生侵袭性肿瘤细胞(例如c-Myc引起的)或某些形式的自身免疫性(例如AIRE引起的)。因此,CDK7激酶可通过调控总体转录过程来促进与肿瘤相关的某些转录因子的异常表达,以及通过调控细胞周期关键激酶的磷酸化以促进肿瘤发展。更重要的是,与癌细胞中其他管家基因相比,CDK7更显著地调控致癌转录因子的表达。CDK7的抑制可以差异性影响某些癌基因和管家基因的转录,因此可以确保治疗窗口。通过调控CDK7介导的磷酸化修饰来进行转录调控和细胞周期调控,可用于治疗包括癌症在内的增殖异常疾病。作为转录的总体调控因子,CDK7也可作为治疗疾病如炎症、病毒复制例如HIV、EBV、癌症和心脏肥大的治疗靶点。
CDK家族成员激酶结构域的高度序列和结构相似性阻碍了CDK7选择性抑制剂的发现。因此,开发选择性CDK7抑制剂,对于临床应用有重要价值。
发明内容
在本发明的一方面,本发明公开了式I所示的化合物或其药学上可接受的盐;
其中,
R1为氢、卤素或C1-6烷基,所述C1-6烷基任选被1、2或3个卤素或C1-3烷基取代;
Cy1环为5至6元杂环基,所述5至6元杂环基任选被1或2个卤素或C1-3烷基取代;
X1为N。
在发明的一些方案中,上述式I所示的化合物为式II化合物;
其中,
R1为氢、卤素或C1-6烷基,所述C1-6烷基任选被1、2或3个卤素或C1-3烷基取代;
X1为N;
R3、R4分别独立地为氢、卤素或C1-6烷基,所述C1-6烷基任选被1、2或3个卤素或C1-3烷基取代;
R5分别独立地为氢、卤素或C1-6烷基,所述C1-6烷基任选被1、2或3个卤素或C1-3烷基取代。
在发明的一些方案中,上述R1、R3、R4分别为氢或C1-3烷基,所述C1-3烷基任选被3个F取代,其余变量如本发明所定义。
在发明的一些方案中,上述X1为N;
R1为CF3;
R3、R4分别为氢或甲基;
R5为氢。
在发明的一些方案中,上述化合物为
本发明第二方面提供了一种药物组合物,其包含前面所述的化合物或其药学上可接受的盐;以及,药学可接受的载体。
如本文所用,术语“药学可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者受试者无毒副作用的任何制剂或载体介质代表性的载体,包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。
在另一个方面,本发明提供了第一方面所述的化合物或其药学上可接受的盐在制备治疗和/或预防CDK7相关疾病的药物中的用途。
在另一个方面,本发明提供了第一方面所述的化合物或其药学上可接受的盐在制备治疗和/或预防癌症的药物中的用途。
在另一个方面,本发明提供了一种治疗癌症的方法,其包括向有此需要的受试者施用治疗有效量的第一方面所述的化合物或其药学上可接受的盐,或上述的任意组合,或施用第二方面所述的药物组合物的步骤。
在另一个方面,本发明提供了第一方面所述的化合物或其药学上可接受的盐在制备CDK7抑制剂中的用途。
在一些实施方案中,所述CDK7相关疾病为增殖性疾病(例如肿瘤或癌症)、传染性疾病、免疫疾病、自身免疫疾病或炎性疾病。
在一些实施方案中,所述肿瘤或癌症包括实体瘤、血液瘤。在一些实施方案中,所述肿瘤或癌症包括黑色素瘤、骨癌(例如骨肉瘤、尤文氏肉瘤)、乳腺癌(例如激素受体阳性(HR+)乳腺癌(例如雌激素受体阳性(ER+)或孕酮受体阳性(PR+)乳腺癌)、激素受体阴性乳腺癌、三阴性乳腺癌(TNBC;ER-/PR-/HER2-)、结直肠癌、脑癌、肺癌(例如小细胞肺癌、非小细胞肺癌)、胰腺癌、卵巢癌、子宫内膜癌、宫颈癌、食道癌、胃癌、胆管癌、前列腺癌、肝癌、肾细胞癌、慢性淋巴细胞白血病(CLL)、急性成淋巴细胞白血病(ALL)、T-细胞急性成淋巴细胞白血病(T-ALL)、慢性髓细胞白血病(CML)、急性骨髓性白血病(AML)、淋巴瘤、多发性骨髓瘤、胶质母细胞瘤、神经母细胞瘤。
在一些实施方案中,所述传染性疾病包括AIDS、霍乱、结膜炎、登革热、脑炎、肠病毒感染(例如,脊髓灰质炎、非脊髓灰质炎)、大肠杆菌感染、口蹄疫、肝炎、带状疱疹、流感、麻疹等。
在一些实施方案中,所述免疫疾病和/或自身免疫疾病包括哮喘、糖尿病、风湿性疾病、AIDS、移植器官和组织的排斥、鼻炎、慢性阻塞性肺病、骨质疏松症、溃疡性结肠炎、红斑狼疮、过敏症、类风湿性关节炎、重症肌无力、克罗恩病、银屑病等。
在一些实施方案中,所述炎性疾病选自中枢神经系统(CNS)的炎性疾病、炎性风湿性疾病、血管的炎性疾病、中耳的炎性疾病、炎性肠病、皮肤的炎性疾病、葡萄膜炎炎性疾病和咽喉的炎性疾病。
如本文所用,术语“药学上可接受的盐”是指在制药上可接受的并且具有母体化合物药理学活性的本发明化合物的盐。这类盐包括:与无机酸或与有机酸形成的酸加成的盐,所述的无机酸诸如硝酸,磷酸,碳酸等;所述的有机酸诸如丙酸,己酸,环戊丙酸,乙醇酸,丙酮酸,葡糖酸,硬脂酸,粘康酸等;或在母体化合物上存在的酸性质子被金属离子,例如碱金属离子或碱土金属离子取代时形成的盐;或与有机碱形成的配位化合物,所述的有机碱诸如乙醇胺,二乙醇胺,三乙醇胺,N-甲基葡糖胺等。本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地,优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。除了盐的形式,本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外,前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
如本文所用,术语“C1-6烷基”指具有1至6个碳原子的直链或支链烷基。优选是C1-4烷基,更优选是C1-3烷基。具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基,及其各种支链异构体等。
如本文所用,术语“卤素”指氟、氯、溴或碘。
如本文所用,术语“杂环基”指饱和或部分不饱和单环或多环的环状烃基,例如包括单环杂环基、螺杂环基、稠杂环基和桥杂环基。本发明中所述杂环基的环碳原子可任选地被1、2或3个氧代基取代形成环酮、环内酯或环内酰胺结构。
术语“5至6元杂环基”指具有5至6个环原子,其中1、2或3个环原子为选自氮、氧或S(=O)m’(其中m’是整数0至2)的杂原子的饱和或部分不饱和单环环状烃基。其中1或2个环原子为杂原子的5或6元单环杂环基。当杂原子为氮原子时,氮原子可以是被取代的或未取代的(即N或NR,R为氢或本文已经定义过的其他取代基)。当杂原子为硫原子时,硫原子可以为任选地被氧化(即S(=O)m’,m’是整数0至2)。所述单环杂环基的环碳原子可任选地被1、2或3个氧代基取代形成环酮、环内酯或环内酰胺结构。单环的杂环基的具体实例包括但不限于氮丙环、环氧乙烷、氮杂环丁烷、氮杂环丁烷-2-酮、噁唑烷、吡咯烷-2-酮、吡咯烷-2,5-二酮、1,3-二氧戊环、二氢呋喃-2(3H)-酮、二氢呋喃-2,5-二酮、哌啶-2-酮、哌啶-2,6-二酮、四氢-2H-吡喃-2-酮、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、1,3-二氧戊环-2-酮、噁唑烷-2-酮、咪唑烷-2-酮、哌啶、哌嗪、哌嗪-2-酮、吗啉、吗啉-3-酮、吗啉-2-酮、硫代吗啉-3-酮1,1-二氧化物、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶、1,3-噁嗪烷、六氢嘧啶、1,4-二噁烷、四氢嘧啶-2(1H)-酮、1,4-二噁烷-2-酮、5,6-二氢-2H-吡喃-2-酮、5,6-二氢嘧啶-4(3H)-酮、3,4-二氢吡啶-2(1H)-酮、5,6-二氢吡啶-2(1H)-酮、5,6-二氢嘧啶-4(1H)-酮、嘧啶-4(3H)-酮、嘧啶-4(1H)-酮、4,5-二氢-1H-咪唑、2,3-二氢-1H-咪唑、2,3-二氢噁唑、1,3-二氧杂环戊烯、2,3-二氢噻吩、2,5-二氢噻吩、3,4-二氢-2H-1,4-噁嗪、3,4-二氢-2H-1,4-噻嗪1,1-二氧化物、1,2,3,4-四氢吡嗪、1,3-二氢-2H-吡咯-2-酮、1,5-二氢-2H-吡咯-2-酮、1H-吡咯-2,5-二酮、呋喃-2(3H)-酮、呋喃-2(5H)-酮、1,3-二氧杂环戊烯-2-酮、噁唑-2(3H)-酮、1,3-二氢-2H-咪唑-2-酮、呋喃-2,5-二酮、3,6-二氢吡啶-2(1H)-酮、吡啶-2,6-(1H,3H)-二酮、5,6-二氢-2H-吡喃-2-酮、3,6-二氢-2H-吡喃-2-酮、3,4-二氢-2H-1,3-噁嗪、3,6-二氢-2H-1,3-噁嗪、1,2,3,4-四氢嘧啶等。
在本发明中,上述各类杂环基可以是任选取代的,当被取代时,取代基优选为一个或多个本申请中所记载的取代基团。
如本文所用,术语“取代”是指特定原子上的任意一个或多个氢原子被取代基取代,可以包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代基(即=O)时,意味着两个氢原子被取代。氧代基取代不会发生在芳香基上。术语“任选取代”或“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
本发明式I所示的化合物可使用本领域已知的合成方法或使用本领域已知的方法与本发明记载的方法组合制备得到。本发明给出的溶剂、温度和其它反应条件均为示例性的,可根据本领域熟知的方法而变化。本发明所记载的实施例化合物可根据其具体结构,使用适当的起始原料按照实施例中记载的方法合成,也可以使用与实施例中记载的类似方法合成得到。用于合成本发明实施例化合物的起始原料可通过已知合成方法或文献记载的类似方法制备得到或从商业来源获得。化合物可根据需要,进一步通过本领域熟知的方法,例如结晶、色谱法等拆分得到其立体异构体,其拆分条件是本领域技术人员通过常规手段或有限试验而容易获得的。作为进一步说明,本发明式(I)化合物可利用以下的方法合成,其中每个步骤中的溶剂、温度及其它反应条件可与下述实施例中记载的相同或类似,或使用本领域已知的反应条件。
具体实施方式
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式。优选的实施方式包括但不限于本发明的实施例。
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1 化合物Z1的合成
步骤一:室温下,2,4二氯-5-(三氟甲基)嘧啶(0.5 g,2.3 mmol)的二氯甲烷(5.0mL)溶液中加入无水氯化锌(0.37 g,2.7 mmol)和三乙胺(0.25 g,2.5 mmol)。混合物室温下搅拌反应60分钟。(S)-1-叔丁氧羰基-3-氨基哌啶(0.49 g,2.5 mmol)缓慢滴加到反应液中。反应混合物继续于室温下反应16小时。冷却并倒入冰水(100 mL)中,用乙酸乙酯(50mLX3)萃取。合并有机相,饱和食盐水洗,无水硫酸干燥,浓缩。粗品经硅胶柱纯化(乙酸乙酯/石油醚:5~15%)得到叔丁基(S)-3-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸酯(0.4 g,1.05 mmol,收率:45.58%),白色固体。
步骤二:室温氮气保护下,6-氯-1H-吡咯并[2,3-b]吡啶(3.0 g,19.66 mmol)的N,N-二甲基甲酰胺(40 mL)溶液中加入N-碘代丁二酰亚胺(5.31 g,23.59 mmol)。混合物继续搅拌反应18小时。反应完毕倒入冰水中,并用乙酸乙酯萃取(100 mLX3)。合并有机相,饱和食盐水洗(100 mL),无水硫酸钠干燥,浓缩。粗品用硅胶柱纯化(乙酸乙酯/石油醚:0~50%)得6-氯-3-碘-1H-吡咯并[2,3-b]吡啶(3.6 g,12.9 mmol,收率:66%)黄色固体。LCMS:MS m/z(ESI):[M+H]+=278.9。
步骤三:室温下,6-氯-3-碘-1H-吡咯并[2,3-b]吡啶(3.39 g,12.21 mmol)的N,N-二甲基甲酰胺(60 mL)溶液中加入三乙胺(3.39 mL,24.42 mmol)和二碳酸二叔丁酯(3.135mL,14.65 mmol)。混合物在室温下搅拌4小时,LCMS监测反应完全。反应液浓缩并加入乙酸乙酯和饱和碳酸氢钠溶液萃取(100 mLX3)。合并有机相,饱和食盐水洗(150 mL),无水硫酸钠干燥,浓缩。粗品用硅胶柱纯化(乙酸乙酯/石油醚:0~30%)得叔丁基 6-氯-3-碘-1H-吡咯并[2,3-b]吡啶-1-羧酸酯(3.0 g,7.8 mmol,收率:63.8%),黄色固体。LCMS:MS m/z(ESI):[M+H]+=378.9。
步骤四:室温氮气保护下,叔丁基 6-氯-3-碘-1H-吡咯并[2,3-b]吡啶-1-羧酸酯(1.0 g,2.64 mmol)和频那醇联硼酸酯(805 mg,3.17 mmol)的二氧六环(20 mL)溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(28.99 mg,0.04 mmol)和醋酸钾(0.39 g,3.96mmol)。混合物升温到100℃反应16小时。冷却并倒入冰水中,用乙酸乙酯萃取(50 mLX3)。合并有机相,饱和食盐水洗(100 mL),无水硫酸钠干燥,浓缩。粗品用硅胶柱纯化(乙酸乙酯/石油醚:0~30%)得叔丁基 6-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-吡咯并[2,3-b]吡啶-1-羧酸酯(600 mg,1.58 mmol,收率:60%),白色固体。LCMS:MS m/z(ESI):[M+H]+=379.0。
步骤五:室温氮气保护下,叔丁基 6-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-吡咯并[2,3-b]吡啶-1-羧酸酯(600 mg,1.58 mmol)和叔丁基(S)-3-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)哌啶-1-羧酸酯(603.37 mg,1.58 mmol)的二氧六环/水(10 ml/3ml)溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(129.40 mg,0.16 mmol)和碳酸钾(328.49 mg,2.38 mmol)。混合物升温到100℃反应12小时。冷却并倒入冰水中,用乙酸乙酯萃取(50 mLX3)。合并有机相,饱和食盐水洗(100 mL),无水硫酸钠干燥,浓缩。粗品用硅胶柱纯化(甲醇/二氯甲烷:0~5%)得叔丁基(S)-3-(2-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-6-氯-1H-吡咯[2,3-b]吡啶-1-羧酸酯(380 mg,0.63 mmol,收率:40%),黄色固体。LCMS:MS m/z(ESI):[M+H]+=597.0。
步骤六:室温氮气保护下,叔丁基(S)-3-(2-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-6-氯-1H-吡咯[2,3-b]吡啶-1-羧酸酯(100 mg,0.17 mmol)和三甲基硅乙炔(140 mg,1.43 mmol)的乙腈/甲酸(10 ml/2 ml)溶液中加入双三苯基磷二氯化钯(13.03 mg,0.02 mmol),2-双环己基膦-2',6'-二甲氧基联苯(13.96 mg,0.03mmol),碘化亚铜(5.46 mg,0.03 mmol)和三乙胺(29 mg,0.29 mmol)。混合物升温到75℃反应16小时。冷却并倒入冰水中,用乙酸乙酯萃取(50 mLX5)。合并有机相,饱和食盐水洗(100mL),无水硫酸钠干燥,浓缩。粗品用硅胶柱纯化(甲醇/二氯甲烷:0~5%)得叔丁基(S)-3-(2-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-6-((三甲基甲硅烷基)乙炔基)-1H-吡咯并[2,3-b]吡啶-1-羧酸酯(50 mg,0.076 mmol,收率:44%),黄色固体。LCMS:MS m/z(ESI):[M+H]+=659.10。
步骤七:室温下,叔丁基(S)-3-(2-((1-(叔丁氧基羰基)哌啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-6-((三甲基甲硅烷基)乙炔基)-1H-吡咯并[2,3-b]吡啶-1-羧酸酯(200 mg,0.304 mmol)的二氯甲烷(10 mL)溶液中,加入三氟乙酸(2.0 mL,27 mmol)。混合物在室温下搅拌0.5小时,LCMS监测反应完全。反应液浓缩得到粗品(S)-N-(哌啶-3-基)-5-(三氟甲基)-4-(6-((三甲基甲硅烷基)乙炔基)-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-2-胺(120 mg,0.261 mmol,收率:85%),黄色固体。LCMS:MS m/z(ESI):[M+H]+=459.60。
步骤八:室温氮气保护下,(S)-N-(哌啶-3-基)-5-(三氟甲基)-4-(6-((三甲基甲硅烷基)乙炔基)-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-2-胺(120 mg,0.262 mmol)的甲醇(8mL)溶液中加入碳酸钾(108 mg,0.786 mmol)。混合物升温到30℃反应1小时。冷却并浓缩。粗品用制备色谱柱纯化(色谱柱:Sunfire Prep C8 OBD 19*250mm 10um; 流动相:水-乙腈(0.1%三氟乙酸); 流速:20 mL/min; 检测波长:254nm/214nm; 柱温:室温)得到(S)-4-(6-乙炔基-1H-吡咯并[2,3-b]吡啶-3-基)-N-(哌啶-3-基)-5-(三氟甲基)嘧啶-2-胺(Z1,16mg,0.041 mmol,收率:15.8%),灰色固体。LCMS:MS m/z(ESI):[M+H]+=387.1。1H NMR(400MHz,CD3OD)δ 8.700-8.592(m,1H),8.525(s,1H),8.040(d,J = 9.6Hz,1H),7.366(s,1H),4.366(s,1H),3.325-3.2.18(m,2H),2.945(d,J =12.4Hz,1H),2.633-2.530(m,2H),2.189(s,1H),1.821-1.746(s,1H),1.671-1.513(s,2H)。
实施例2 化合物Z2的合成
步骤一:向干燥的三口瓶中加入四氯化锆(38.3 g,164 mmol),氮气保护下,除水20 分钟后,于-10℃加入无水四氢呋喃(400 mL),降温至-10℃,称取(S)-叔丁基(6-氧哌啶-3-基)氨基甲酸酯(7.00 g,32.9 mmol)溶于无水四氢呋喃(300 mL)中并缓慢滴加到反应瓶中。滴加时控制温度-10℃,加完后继续搅拌30分钟。然后在-10℃向反应液中缓慢滴加甲基氯化镁四氢呋喃溶液(143 mL,428 mmol,3.0 M)。该反应液继续搅拌并升至室温搅拌14小时。LCMS 检测反应完全后,反应液在0℃下用20%氢氧化钠溶液(200 mL)淬灭,然后用二氯甲烷(300 mL×3)萃取,合并的有机层,用饱和食盐水(200 mL×3)洗涤,无水硫酸钠干燥,过滤,浓缩至干得到的粗品(S)-叔丁基(6,6-二甲基哌啶-3-基)氨基甲酸酯(6.4 g,收率:85%),淡黄色油状物。LCMS:MS m/z(ESI):[M+H]+= 229.2,tR = 0.87 min。
步骤二:氮气保护下,于 20℃向(S)-叔丁基(6,6-二甲基哌啶-3-基)氨基甲酸酯(6.40 g,28.0 mmol)的四氢呋喃(100 mL)和水(50 mL)溶液中加入碳酸氢钠(9.00 g,107mmol),反应液在氮气保护下 25oC 搅拌反应1小时。再向反应液中加入氯甲酸苄酯(4.80g,28.0 mmol),氮气保护下 25oC 搅拌反应16小时。LCMS检测反应完全后,反应液用水(40mL)和乙酸乙酯(100 mL × 3)萃取,合并有机层,饱和食盐水(100 mL × 3)洗涤,无水硫酸钠干燥,过滤,浓缩,粗品用硅胶柱层析(石油醚/乙酸乙酯 = 10/1 到 5/1)纯化得到(S)-苄基5-((叔丁氧羰基)氨基)-2,2-二甲基哌啶-1-羧酸盐(3.50 g,收率:35%),黄色油状物。LCMS:MS m/z(ESI):[M+H-56]+= 307.2,tR = 1.73 min。
步骤三:氮气保护下,于20℃向(S)-苄基5-((叔丁氧羰基)氨基)-2,2-二甲基哌啶-1-羧酸盐(3.50 g,9.67 mmol)的甲醇(5 mL)溶液中加入4M的甲醇氯化氢溶液(10 mL),反应液在氮气保护下升温至 40℃ 搅拌反应2小时。LCMS检测反应完全后,向反应液中缓慢加入饱和的碳酸氢钠溶液(30 mL),用乙酸乙酯(50 mL × 3)萃取,合并的有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,得到的粗品用硅胶柱层析(二氯甲烷/甲醇 = 30/1到 15/1)纯化得到(S)-苄基5-氨基-2,2-二甲基哌啶-1-羧酸盐(2.3 g,收率:89%),无色油状物。LCMS:MS m/z(ESI):[M+H]+= 263.0,tR = 1.31 min。
步骤四:向(S)-苄基5-氨基-2,2-二甲基哌啶-1-羧酸盐(2.25 g,8.6 mmol)的四氢呋喃(50 mL)溶液中加入N,N-二异丙基乙胺(4.43 g,34.0 mmol)和2,4-二氯 -5-(三氟甲基)嘧啶(1.90 g,8.60 mmol),反应液在25℃搅拌反应14小时。LCMS 检测反应完全后,将反应液直接浓缩,得到的粗品用硅胶柱层析(石油醚/乙酸乙酯 = 30/1到15/1)纯化得到(S)-苄基5-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-2,2-二甲基哌啶-1-羧酸盐(2.30 g,收率:61%),白色固体物。LCMS:MS m/z(ESI):[M+H]+= 443.2,tR = 1.84 min。
步骤五:在室温条件下,向 6-氯-1H-吡咯并[2,3-b]吡啶(5.00 g,32.8 mmol)的N,N-二甲基甲酰胺溶液(30 mL)中加入N-碘代丁二酰亚胺(8.85 g,39.3 mmol),反应液在25℃ 下搅拌 1 小时。LCMS 检测反应完全后,反应液用乙酸乙酯(100 mL × 3)萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩。得到的粗品经硅胶柱层析(石油醚/乙酸乙酯 = 60/1)纯化得到6-氯-3-碘-1H-吡咯并[2,3-b]吡啶(8.25 g,收率:90%),黄色固体。LCMS:MS m/z(ESI):[M+H]+= 278.8,tR = 1.63 min。
步骤六:向 6-氯-3-碘-1H-吡咯并[2,3-b]吡啶(6.60 g,23.7 mmol)的二氯甲烷(30 mL)溶液中依次加入 4-二甲氨基吡啶(290 mg,2.37 mmol)、二碳酸二叔丁酯(6.21 g,28.4 mmol)。反应液在 25℃ 下搅拌1小时。LCMS 检测反应完全后,反应液用二氯甲烷(150mL×3)萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩。得到的粗品经硅胶柱层析(石油醚/乙酸乙酯 = 30/1)纯化得到6-氯-3-碘-1H-吡咯并[2,3-b]吡啶-1-羧酸叔丁酯(8.00 g,收率:89%),黄色固体。LCMS:MS m/z(ESI):[M+H-56]+= 323.0,tR = 1.86min。
步骤七:氮气氛围下,向耐压管中依次加入 6-氯-3-碘-1H-吡咯并[2,3-b]吡啶-1-羧酸叔丁酯(1.20 g,3.17 mmol)、三(二亚苄基丙酮)二钯(0.58 g,0.63 mmol)、2-双环己基膦-2',6'-二甲氧基联苯(0.15 g,0.32 mmol)、三乙胺(1.60 g,15.8 mmol)、频那醇硼烷(1.22 g,9.50 mmol)和四氢呋喃(20 mL)。反应液在 90℃ 下搅拌 16小时。LCMS 检测反应完全后,过滤除去反应液中固体残渣,随后过滤,浓缩。得到的粗品经硅胶柱层析(石油醚/乙酸乙酯 = 50/1)纯化得到叔丁基6-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-吡咯并[2,3-b]吡啶-1-羧酸盐(0.47 g,收率:39%),黄色固体。LCMS:MS m/z(ESI):[M+H-56]+= 323.2,tR = 1.98 min。
步骤八:氮气保护下,于 20℃ 向叔丁基6-氯-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼-2-基)-1H-吡咯[2,3-b ]吡啶-1-羧酸盐(843 mg,2.23 mmol)和(S)-苄基5-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-2,2-二甲基哌啶-1-羧酸盐(820 mg,1.85 mmol)的四氢呋喃(15 mL)溶液中加入氯[(正丁基二(1-金刚烷基)膦)-2-(2-氨基联苯)]钯(II)(124 mg,0.185 mmol),磷酸钾(1.18 g,5.56 mmol)与水(3 mL)的混合溶液,该反应液在氮气保护下于60℃搅拌反应14小时。LCMS 检测反应完全后,向反应液中加入水(15 mL)和乙酸乙酯(50mL)分液。水相再用乙酸乙酯(50 mL × 2)萃取,合并的有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩。得到的粗品经硅胶柱层析(石油醚/乙酸乙酯= 10:1到5:1)纯化得到(S)-叔丁基 3-(2-((1-((苄基氧基)羰基)-6,6-二甲基哌啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-6-氯-1H-吡咯[2,3-b]吡啶-1-羧酸盐(680 mg,收率:56%),白色固体。LCMS:MSm/z(ESI):[M+H]+= 659.2,tR = 2.17 min。
步骤九:氮气保护下,于 20℃ 向(S)-叔丁基 3-(2-((1-((苄基氧基)羰基)-6,6-二甲基哌啶-3-基)氨基)-5-(三氟甲基)嘧啶-4-基)-6-氯-1H-吡咯[2,3-b]吡啶-1-羧酸盐(100 mg,0.152 mmol)的 N,N-二甲基甲酰胺(2 mL)溶液中加入三(二亚苄基丙酮)二钯(13.9 mg,0.015 mmol)、2-二环己膦基-2'-(N,N-二甲胺)-联苯(5.98 mg,0.015 mmol)、三乙胺(0.106 mL,0.760 mmol)和三异丙基硅基乙炔(139 mg,0.760 mmol),反应液在氮气保护下在100℃下于微波反应器中反应 1 小时。LCMS检测反应完全后,将反应液倒入水(10mL)中,用乙酸乙酯(50 mL × 3)萃取,合并的有机层用饱和食盐水(20 mL × 3)洗涤,无水硫酸钠干燥,过滤,浓缩。得到的粗品经硅胶柱层析(石油醚/乙酸乙酯 = 10/1 到 5/1)纯化得到(S)-苄基 2,2-二甲基-5-((5-(三氟甲基)-4-(6-((三异丙基硅基)乙炔基)-1H-吡咯[2,3-b]吡啶-3-基)嘧啶-2-基)氨基)哌啶-1-羧酸盐(80 mg,收率:75%),黄色油状物。LCMS:MS m/z(ESI):[M+H]+= 704.8,tR = 2.67 min。
步骤十:向(S)-苄基 2,2-二甲基-5-((5-(三氟甲基)-4-(6-((三异丙基硅基)乙炔基)-1H-吡咯[2,3-b]吡啶-3-基)嘧啶-2-基)氨基)哌啶-1-羧酸盐(60.0 mg,0.085mmol)的 N,N-二甲基甲酰胺(4 mL)溶液中加入氟化铯(64.7 mg,0.426 mmol),该反应液在20℃ 搅拌反应 1.5 小时。LCMS 检测反应完全后,向反应液中加水(10 mL)中,用乙酸乙酯(20 mL × 3)萃取,合并的有机层用饱和食盐水(20 mL × 3)洗涤,无水硫酸钠干燥,过滤,浓缩得到粗品苄基(S)-5-((4-(6-乙炔基-1H-吡咯[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2,2-二甲基哌啶-1-羧酸酯(25 mg,收率:54%),黄色油状物。LCMS:MS m/z(ESI):[M+H]+= 549.2,tR = 2.57 min。
步骤十一:向苄基(S)-5-((4-(6-乙炔基-1H-吡咯[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-基)氨基)-2,2-二甲基哌啶-1-羧酸酯(50 mg,0.091 mmol)加入三氟乙酸(2mL),反应液在 65℃ 下搅拌反应 1.5 小时。LCMS 检测反应完全后,将反应液直接浓缩除去大部分的三氟乙酸,再加入乙酸乙酯(20 mL)和饱和的碳酸氢钠溶液(10 mL)分液,水相再用乙酸乙酯(20mL × 3)萃取,合并的有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩。得到的粗品经制备色谱柱纯化(色谱柱:Ultimate XB-C18,50*250 mm,10 um(PARP-04);流动相:乙腈-水(0.1% 碳酸氢铵);流速:70 mL/min;柱温:25oC)得到(S)-N-(6,6-二甲基哌啶-3-基)-4-(6-乙炔基-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)嘧啶-2-胺(Z2,5.1 mg,收率:12%),白色粉状物。LCMS:MS m/z(ESI):[M+H]+= 415.2,tR = 0.93 min。1H NMR(400 MHz,CD3OD):δ 8.96 – 8.58(m,1H),8.53(s,1H),8.03(s,1H),7.43(s,1H),4.20 – 3.95(m,1H),3.66(s,1H),3.14 – 3.07(m,1H),2.85 – 2.75(m,1H),2.05 – 1.95(m,1H),1.80 – 1.63(m,2H),1.59 – 1.50(m,1H),1.21(s,3H),1.18(s,3H)。
测试例1:CDK激酶活性的体外抑制实验
CDK2/Cyclin E1购自佰翱得;批号:20150228-BP469/477/691;CDK7/Cyclin H/MAT1购自佰翺得;批号:20190326-BP487/492/479;CDK9/Cyclin T1购自佰翺得;批号:20200727-BP488/792/691;CDK12/Cyclin K购自佰翺得;批号:20200526-BP1642/1648/691;MES购自BioRoYee(宝如亿);批号:67GR9637;BSA购自Aladdin;批号:H1601024;ATP购自VWR;批号:97061-226;EDTA 购自国药集团;批号:20200521;星胞菌素购自Selleckchem;批号:S1421。
本实验用于测定化合物对CDK2、CDK7、CDK9和CDK12激酶活性的抑制作用。本发明所进行的激酶反应在384孔板中进行测定,最终测定体积是16 µl,反应温度为27℃。激酶的浓度由优化实验决定。具体实验过程如下:
1)激酶溶液配置:
激酶溶液(CDK2/Cyclin E1):激酶稀释于测定缓冲液(20 mM MES pH 6.75,0.01%Tween 20,0.05 mg/mL BSA,2 mM MgCl2)中得到相应2.4×浓度的酶溶液。
激酶溶液(CDK7/Cyclin H/MAT1):激酶稀释于测定缓冲液(20 mM MES pH 6.75,0.01% Tween 20,0.05 mg/mL BSA,6 mM MgCl2)中得到相应2.4×浓度的酶溶液。
激酶溶液(CDK9/Cyclin T1):激酶稀释于测定缓冲液(20 mM MES pH 6.75,0.01%Tween 20,0.05 mg/mL BSA,10 mM MgCl2)中得到相应2.4×浓度的酶溶液。
激酶溶液(CDK12/Cyclin K):激酶稀释于测定缓冲液(80 mM MES pH 6.5,0.01%Tween 20,0.05 mg/mL BSA,10 mM MgCl2)中得到相应2.4×浓度的酶溶液。
2)化合物溶液配置:化合物以10 mM的浓度溶于二甲基亚砜(DMSO)中,使用时化合物用DMSO稀释至25 nM到500 µM 的10个浓度梯度,分别8.3倍稀释于超纯水中,得到6X浓度的化合物溶液。
3)多肽底物及ATP溶液配置:多肽底物及ATP稀释于测定缓冲液中,得到2.4×浓度的多肽底物及ATP混合溶液。
4)激酶反应过程:
将2 ul测试化合物溶液,5 ul多肽底物及ATP混合溶液与5 ul酶溶液混合27℃孵育(CDK2为60分钟,CDK7为70分钟,CDK9为70分钟,CDK12为280分钟),然后通过向每种样品中加入4 ul浓度为150 mM的EDTA来终止反应。以含有20 µM 星胞菌素的测定缓冲液代替化合物溶液作为100% 抑制,以DMSO代替化合物溶液作为0% 抑制。每个试验至少2个平行对照。
CDK2测定中试剂的最终浓度:ATP为100 µM;多肽底物(5-FAM-YSPTSPSYSPTSPSYSPT SPSKKKK)为2 µM;CDK2/Cyclin E1为0.5 nM;
CDK7测定中试剂的最终浓度:ATP为50 µM;多肽底物(5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK)为2 µM;CDK7/Cyclin H/MAT1为3 nM;
CDK9测定中试剂的最终浓度:ATP为50 µM;多肽底物(FITC-Ahx-GSRTPMY-NH2)为2µM;CDK9/Cyclin T1为8 nM;
CDK12测定中试剂的最终浓度:ATP为30 µM;多肽底物(FITC-Ahx-GSRTPMY-NH2)为2 µM;CDK12/Cyclin K为50 nM。
5)数据计算和分析:在Caliper EZ Reader II上通过荧光底物和磷酸化产物进行电泳分离来对反应混合物进行分析。数据使用GraphPad Prism version 9.0进行计算,IC50值通过使用剂量反应曲线的非线性回归模型调整得到。计算公式:Y=Bottom +(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。其中,X为剂量或浓度的log值(log of doseor concentration);Y为随着X的增加而增加的抑制率(%inhibition,increasing as xincreases);Top为最大响应;Bottom基线响应;HillSlope为曲线斜率。由于CDK7/CyclinH/MAT1 激酶活性实验的检测下限限制,本发明化合物对的CDK7激酶活性抑制已达实验检测下限,IC50不能准确反映化合物的激酶活性抑制能力,我们采用表面等离子体共振(SPR)方法来检测化合物的结合亲和力KD。化合物对CDK2,CDK9,CDK12激酶活性的抑制作用,以KmATP条件下检测拟合得到的IC50用于计算Ki(Cheng and Prusoff,Biochem. Pharmacol.,22(23)3099-3108,1973),换算公式如下:IC50 = Ki(1+[底物/Km])+ [酶/2]。本发明示例化合物的结果如表1所示。
表1
测试例2:CDK7/Cyclin H表面等离子体共振(SPR)测定方法
CDK7/Cyclin H购自佰翱得;批号:20200309-BP487/492;MES缓冲液购自BioRoYee;批号:67GR9637;CM5传感芯片购自Cytiva;批号:10305527;HEPES缓冲液购自Cytiva;批号:32349。
本实验采用Biacore S200表面等离子共振设备(GE Healthcare)测试了CDK7/Cyclin H二聚体和化合物的动力学和亲和力参数。
在pH 6.5的10 mM MES缓冲液条件下,浓度为50µg/mL的CDK7/Cyclin H二聚体在5µL/min流速下被氨基偶联至CM5传感芯片。在600秒内目的蛋白被固定到芯片通道上,一般情况下达到7000-10000响应值。在具有150 mM NaCl、0 .05%表面活性剂P20和2%DMSO的pH7.4的10 mM HEPES缓冲液中把化合物2倍梯度稀释5步达到0.6-10 nM浓度范围。每个化合物浓度循环都以100 µL/min,180秒接触时间和1800秒解离时间被运行。对于每个化合物,0 nM化合物对照和参比通道的结合都被扣减来移除背景信号和归一化数据。使用Biacore S200评价软件和动力学模型对化合物滴定整体拟合。最优化拟合数据,测定CDK7/Cyclin H结合速率和解离速率参数,用以下的等式来计算化合物亲和力参数KD。KD(M)= koff(s-1)/ Kon(M-1s-1);其中,Kon(ka)是结合速率;Koff(kd)是解离速率;s-1(每秒)和M-1s-1(每摩尔每秒)是koff和kon的单位。基于脱靶CDK的Ki值相对于CDK7的直接化合物结合KD(通过SPR测量)的比率,根据以下等式确定CDK7相对于CDK2、CDK9或CDK12的化合物选择性。选择性 =Ki,脱靶 / KD,CDK7。结果显示:相对于CDK2/CDK9/CDK12,本发明化合物对CDK7具有优异的选择性,本发明化合物对CDK7的特异性为对其它CDK的至少100倍或300倍;甚至可以是1000倍以上。部分示例化合物结果如表2所示。
表2
测试例3:HCC70肿瘤细胞增殖抑制活性实验
HCC70购自ATCC;货号:CRL-2315;RPMI1640购自Gibco;货号:11875-093;胰酶(含EDTA)购自Gibco;货号:25200-072;FBS购自Gibco;货号:10099-141C;CellTiter-Glo购自Promega;货号:G7573;DMSO购自VWR AMRESCO;货号:0231-500ML;Staurosporine购自Selleck;货号:S1421;细胞计数仪购自CHEMOMETEC;型号:NC-200;酶标仪购自PerkinElmer;型号:Envison。
HCC70为人乳腺导管癌细胞,培养于含10% FBS的 RPMI-1640培养基中。取对数生长期的细胞,用胰酶-EDTA消化、收集和计数细胞,并接种2000个HCC70细胞/孔于384孔细胞板中,置于5% CO2培养过夜。使用DMSO配制1000X的化合物3.16倍梯度浓度储液,使用培养基稀释100倍至10X化合物储液,于细胞接种后的第二天,向每个细胞培养孔中加入10X化合物储液,终浓度为1X,DMSO含量为0.1%。使用DMSO处理细胞组作为实验对照(control),5μMStaurosporine处理细胞组为空白对照(blank)。加入化合物后继续培养细胞3天后,向每孔加入25μl CellTiter-Glo工作液,混匀,室温孵育5分钟,读取luminescence化学发光值,计算细胞增殖抑制率 IR(%)=(RLU对照- RLU化合物)/(RLU对照- RLU空白)×100%,使用XLFit四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率,计算出IC50值。结果显示,本发明化合物对HCC70人乳腺导管癌细胞增殖具有很强的抑制作用。部分化合物IC50 低于1000nM或500nM;甚至低于100 nM 或50 nM。部分示例性化合物的结果如下表3所示。
表3
尽管本发明的具体实施方式已经得到详细的描述,根据已经公开的所有教导,本领域技术人员可以对本发明技术方案的细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (6)
2.一种药物组合物,所述药物组合物包含
权利要求1所述的化合物或其药学上可接受的盐;
以及,药学可接受的载体。
3.一种如权利要求1所述的化合物或其药学上可接受的盐或如权利要求2所述的药物组合物在制备预防和/或治疗CDK7相关疾病的药物中的用途。
4.如权利要求3所述的用途,其特征在于,所述CDK7相关疾病为增殖性疾病、传染性疾病、免疫疾病或炎性疾病。
5.如权利要求4所述的用途,其特征在于,所述免疫疾病为自身免疫疾病。
6.一种如权利要求1所述的化合物或其药学上可接受的盐或如权利要求2所述的药物组合物在制备CDK7抑制剂中的用途。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310251465.3A CN116082337B (zh) | 2023-03-16 | 2023-03-16 | 炔基取代的杂环化合物,其制法与医药上的用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310251465.3A CN116082337B (zh) | 2023-03-16 | 2023-03-16 | 炔基取代的杂环化合物,其制法与医药上的用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN116082337A CN116082337A (zh) | 2023-05-09 |
CN116082337B true CN116082337B (zh) | 2023-06-23 |
Family
ID=86210368
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310251465.3A Active CN116082337B (zh) | 2023-03-16 | 2023-03-16 | 炔基取代的杂环化合物,其制法与医药上的用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116082337B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116239541B (zh) * | 2023-05-11 | 2023-07-21 | 英矽智能科技(上海)有限公司 | N-苯基-2-氧代喹唑啉类化合物及其应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006050076A1 (en) * | 2004-10-29 | 2006-05-11 | Janssen Pharmaceutica, N.V. | Pyrimidinyl substituted fused-pyrrolyl compounds useful in treating kinase disorders |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014089280A1 (en) * | 2012-12-07 | 2014-06-12 | Calitor Sciences, Llc | Alkynyl compounds and methods of use |
SG11201900328WA (en) * | 2016-07-13 | 2019-02-27 | Jason Marineau | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
US11918592B2 (en) * | 2018-01-16 | 2024-03-05 | Syros Pharmaceuticals, Inc. | Inhibitors of cyclin dependent kinase 7 (CDK7) |
WO2019143719A1 (en) * | 2018-01-16 | 2019-07-25 | Syros Pharmaceuticals, Inc. | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
CA3113732C (en) * | 2018-09-21 | 2023-07-11 | Shanghai Ennovabio Pharmaceuticals Co., Ltd. | Aromatic heterocyclic compound with kinase inhibitory activity |
KR20210118812A (ko) * | 2018-11-01 | 2021-10-01 | 사이로스 파마수티컬스, 인크. | 시클린-의존성 키나제 7 (cdk7)의 억제제 |
TW202214634A (zh) * | 2020-06-09 | 2022-04-16 | 大陸商賽諾哈勃藥業(成都)有限公司 | 雜環化合物及其衍生物 |
CN112661745A (zh) * | 2020-07-24 | 2021-04-16 | 浙江同源康医药股份有限公司 | 用作cdk7激酶抑制剂的化合物及其应用 |
TW202214600A (zh) * | 2020-09-24 | 2022-04-16 | 大陸商廣州費米子科技有限責任公司 | 嘧啶基衍生物、其製備方法及其用途 |
CN116745277A (zh) * | 2020-12-24 | 2023-09-12 | 湃隆生物科技有限公司(香港) | 芳香杂环类化合物、药物组合物及其应用 |
WO2023029943A1 (zh) * | 2021-09-03 | 2023-03-09 | 星药科技(北京)有限公司 | 一种芳杂环化合物及其制备方法和用途 |
-
2023
- 2023-03-16 CN CN202310251465.3A patent/CN116082337B/zh active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006050076A1 (en) * | 2004-10-29 | 2006-05-11 | Janssen Pharmaceutica, N.V. | Pyrimidinyl substituted fused-pyrrolyl compounds useful in treating kinase disorders |
Non-Patent Citations (1)
Title |
---|
Discovery of the Novel 1H‑Pyrrolo[2,3‑b]pyridine Derivative as a Potent Type II CDK8 Inhibitor against Colorectal Cancer;Xing Xing Zhang et al.;《J. Med. Chem.》;第65卷;《J. Med. Chem.》 * |
Also Published As
Publication number | Publication date |
---|---|
CN116082337A (zh) | 2023-05-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109422755B (zh) | 一种含氮杂环化合物、制备方法、中间体、组合物和应用 | |
AU2008272830B2 (en) | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors | |
CA2880251C (en) | Novel heteroaryl and heterocycle compounds, composition and methods thereof | |
WO2022061251A1 (en) | Compounds and methods for kras modulation and indications therefor | |
WO2018206539A1 (en) | Heteroaryl compounds that inhibit g12c mutant ras proteins | |
WO2018022911A1 (en) | Macrocycle kinase inhibitors | |
CA2736281C (en) | Tri-substituted pyrimidine compounds and their use as pde10 inhibitors | |
AU2012310168B2 (en) | 6 - substituted 3 - (quinolin- 6 - ylthio) - [1,2,4] triazolo [4, 3 -a] pyradines as tyrosine kinase | |
EP3426244B1 (en) | 3-phosphoglycerate dehydrogenase inhibitors and uses thereof | |
WO2011149827A1 (en) | Compounds and methods | |
WO2014194245A2 (en) | Cdk8 inhibitors and uses thereof | |
JP2024506909A (ja) | Hpk1アンタゴニスト及びその使用 | |
CN116082337B (zh) | 炔基取代的杂环化合物,其制法与医药上的用途 | |
CA2864672A1 (en) | Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme | |
KR101745741B1 (ko) | 신규한 트리아졸로 피라진 유도체 및 그의 용도 | |
AU2020214258A1 (en) | AKT inhibitor | |
JP2014510122A (ja) | mTOR阻害剤としてのジヒドロピロロピリミジン誘導体 | |
CA2755061A1 (en) | Pyrimidine derivatives as mtor inhibitors | |
CN116023367A (zh) | 含四氢呋喃多环类衍生物、其药学上可接受的盐及其制备方法和应用 | |
KR20240124992A (ko) | 피리미딘 헤테로시클릭 화합물, 그의 제조 방법 및 의약에서의 그의 용도 | |
CN114591334B (zh) | 二氢吡唑并嘧啶酮衍生物 | |
AU2020380828A1 (en) | WDR5 inhibitors and modulators | |
JP2022538042A (ja) | Cdkキナーゼ阻害剤 | |
CN115703760A (zh) | 2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂及其制备方法和应用 | |
WO2024020419A1 (en) | Aza-quinazoline compounds and methods of use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |