CN111349093B - 5,6-双环化合物作为wnt信号通路抑制剂及其医学应用 - Google Patents
5,6-双环化合物作为wnt信号通路抑制剂及其医学应用 Download PDFInfo
- Publication number
- CN111349093B CN111349093B CN201811573629.XA CN201811573629A CN111349093B CN 111349093 B CN111349093 B CN 111349093B CN 201811573629 A CN201811573629 A CN 201811573629A CN 111349093 B CN111349093 B CN 111349093B
- Authority
- CN
- China
- Prior art keywords
- methylpyridin
- compound
- pyridine
- carboxamide
- benzyl
- 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
- 230000019491 signal transduction Effects 0.000 title claims abstract description 12
- 239000003112 inhibitor Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 7
- 210000001519 tissue Anatomy 0.000 claims abstract description 7
- 208000020084 Bone disease Diseases 0.000 claims abstract description 6
- 208000015100 cartilage disease Diseases 0.000 claims abstract description 6
- 206010016654 Fibrosis Diseases 0.000 claims abstract description 5
- 230000004761 fibrosis Effects 0.000 claims abstract description 5
- 208000033787 Rare developmental defect during embryogenesis Diseases 0.000 claims abstract description 4
- 208000022734 developmental defect during embryogenesis Diseases 0.000 claims abstract description 4
- 208000035853 malformation syndrome Diseases 0.000 claims abstract description 4
- -1 5-methoxypyrazolo [1,5-a ] pyridin-2-yl Chemical group 0.000 claims description 40
- 108050003627 Wnt Proteins 0.000 claims description 35
- 102000013814 Wnt Human genes 0.000 claims description 34
- 238000004519 manufacturing process Methods 0.000 claims description 25
- 150000003254 radicals Chemical class 0.000 claims description 23
- 230000004156 Wnt signaling pathway Effects 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- JPEMJQVVPKFLSW-UHFFFAOYSA-N N-(6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-[4-(2-methylpyridin-4-yl)phenyl]acetamide Chemical compound CC1=NC=CC(=C1)C2=CC=C(C=C2)CC(=O)NC3=NN4C=C(C=CC4=N3)OC JPEMJQVVPKFLSW-UHFFFAOYSA-N 0.000 claims description 5
- FQWRFXOHHGXVFE-UHFFFAOYSA-N N-(6-methoxyimidazo[1,2-a]pyridin-2-yl)-2-[3-methyl-4-(2-methylpyridin-4-yl)phenyl]acetamide Chemical compound CC1=C(C=CC(=C1)CC(=O)NC2=CN3C=C(C=CC3=N2)OC)C4=CC(=NC=C4)C FQWRFXOHHGXVFE-UHFFFAOYSA-N 0.000 claims description 5
- IUEKQTQIJQZONH-UHFFFAOYSA-N N-(6-methoxyimidazo[1,2-a]pyridin-2-yl)-2-[4-(2-methylpyridin-4-yl)phenyl]acetamide Chemical compound CC1=NC=CC(=C1)C2=CC=C(C=C2)CC(=O)NC3=CN4C=C(C=CC4=N3)OC IUEKQTQIJQZONH-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 229940124597 therapeutic agent Drugs 0.000 claims description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 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 claims description 4
- 208000001132 Osteoporosis Diseases 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 4
- OWLPBYZOWVAOSX-UHFFFAOYSA-N 4-methoxy-N-[[3-methyl-4-(2-methylpyridin-4-yl)phenyl]methyl]pyrazolo[1,5-a]pyridine-2-carboxamide Chemical compound CC1=C(C=CC(=C1)CNC(=O)C2=NN3C=CC=C(C3=C2)OC)C4=CC(=NC=C4)C OWLPBYZOWVAOSX-UHFFFAOYSA-N 0.000 claims description 3
- HLMROZSTZQZBLY-UHFFFAOYSA-N 4-methoxy-N-[[4-(2-methylpyridin-4-yl)phenyl]methyl]pyrazolo[1,5-a]pyridine-2-carboxamide Chemical compound CC1=NC=CC(=C1)C2=CC=C(C=C2)CNC(=O)C3=NN4C=CC=C(C4=C3)OC HLMROZSTZQZBLY-UHFFFAOYSA-N 0.000 claims description 3
- YZNZRSAMGBJITH-UHFFFAOYSA-N 5-methoxy-N-[[3-methyl-4-(2-methylpyridin-4-yl)phenyl]methyl]pyrazolo[1,5-a]pyridine-2-carboxamide Chemical compound CC1=C(C=CC(=C1)CNC(=O)C2=NN3C=CC(=CC3=C2)OC)C4=CC(=NC=C4)C YZNZRSAMGBJITH-UHFFFAOYSA-N 0.000 claims description 3
- NBWICIWDFMPEAG-UHFFFAOYSA-N 5-methoxy-N-[[4-(2-methylpyridin-4-yl)phenyl]methyl]pyrazolo[1,5-a]pyridine-2-carboxamide Chemical compound CC1=NC=CC(=C1)C2=CC=C(C=C2)CNC(=O)C3=NN4C=CC(=CC4=C3)OC NBWICIWDFMPEAG-UHFFFAOYSA-N 0.000 claims description 3
- SFZVGTMODHISRQ-UHFFFAOYSA-N 6-acetyl-N-[[3-methyl-4-(2-methylpyridin-4-yl)phenyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide Chemical compound CC1=C(C=CC(=C1)CNC(=O)C2=CN3C=C(C=CC3=N2)C(=O)C)C4=CC(=NC=C4)C SFZVGTMODHISRQ-UHFFFAOYSA-N 0.000 claims description 3
- QMVUNRIRHMWNHB-UHFFFAOYSA-N 6-acetyl-N-[[4-(2-methylpyridin-4-yl)phenyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide Chemical compound CC1=NC=CC(=C1)C2=CC=C(C=C2)CNC(=O)C3=CN4C=C(C=CC4=N3)C(=O)C QMVUNRIRHMWNHB-UHFFFAOYSA-N 0.000 claims description 3
- CZSRQYSMFZASSA-UHFFFAOYSA-N 6-cyano-N-[[3-methyl-4-(2-methylpyridin-4-yl)phenyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide Chemical compound CC1=C(C=CC(=C1)CNC(=O)C2=CN3C=C(C=CC3=N2)C#N)C4=CC(=NC=C4)C CZSRQYSMFZASSA-UHFFFAOYSA-N 0.000 claims description 3
- DTZBFBKQRYKKLS-UHFFFAOYSA-N 6-cyano-N-[[4-(2-methylpyridin-4-yl)phenyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide Chemical compound CC1=NC=CC(=C1)C2=CC=C(C=C2)CNC(=O)C3=CN4C=C(C=CC4=N3)C#N DTZBFBKQRYKKLS-UHFFFAOYSA-N 0.000 claims description 3
- CPTXISBHVQHTBO-UHFFFAOYSA-N 6-methoxy-N-[[3-methyl-4-(2-methylpyridin-4-yl)phenyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide Chemical compound CC1=C(C=CC(=C1)CNC(=O)C2=NN3C=C(C=CC3=N2)OC)C4=CC(=NC=C4)C CPTXISBHVQHTBO-UHFFFAOYSA-N 0.000 claims description 3
- KVBHRBCWDZOWGF-UHFFFAOYSA-N 6-methoxy-N-[[3-methyl-4-(2-methylpyridin-4-yl)phenyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide Chemical compound CC1=C(C=CC(=C1)CNC(=O)C2=CN3C=C(C=CC3=N2)OC)C4=CC(=NC=C4)C KVBHRBCWDZOWGF-UHFFFAOYSA-N 0.000 claims description 3
- HTHDYVCSVVVOJW-UHFFFAOYSA-N 6-methoxy-N-[[4-(2-methylpyridin-4-yl)phenyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide Chemical compound CC1=NC=CC(=C1)C2=CC=C(C=C2)CNC(=O)C3=NN4C=C(C=CC4=N3)OC HTHDYVCSVVVOJW-UHFFFAOYSA-N 0.000 claims description 3
- ZQPQAYCACSCCSZ-UHFFFAOYSA-N 6-methoxy-N-[[4-(2-methylpyridin-4-yl)phenyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide Chemical compound CC1=NC=CC(=C1)C2=CC=C(C=C2)CNC(=O)C3=CN4C=C(C=CC4=N3)OC ZQPQAYCACSCCSZ-UHFFFAOYSA-N 0.000 claims description 3
- CPCPNRULOXZMSS-UHFFFAOYSA-N 7-acetyl-N-[[4-(2-methylpyridin-4-yl)phenyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide Chemical compound CC1=NC=CC(=C1)C2=CC=C(C=C2)CNC(=O)C3=CN4C=CC(=CC4=N3)C(=O)C CPCPNRULOXZMSS-UHFFFAOYSA-N 0.000 claims description 3
- OHTXIDFXSQCXDU-UHFFFAOYSA-N 7-cyano-N-[[3-methyl-4-(2-methylpyridin-4-yl)phenyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide Chemical compound CC1=C(C=CC(=C1)CNC(=O)C2=CN3C=CC(=CC3=N2)C#N)C4=CC(=NC=C4)C OHTXIDFXSQCXDU-UHFFFAOYSA-N 0.000 claims description 3
- IMSQFBIUDVGHFG-UHFFFAOYSA-N 7-cyano-N-[[4-(2-methylpyridin-4-yl)phenyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide Chemical compound CC1=NC=CC(=C1)C2=CC=C(C=C2)CNC(=O)C3=CN4C=CC(=CC4=N3)C#N IMSQFBIUDVGHFG-UHFFFAOYSA-N 0.000 claims description 3
- IYSBXDDVLPKYPJ-UHFFFAOYSA-N 7-methoxy-N-[[3-methyl-4-(2-methylpyridin-4-yl)phenyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide Chemical compound CC1=C(C=CC(=C1)CNC(=O)C2=NN3C=CC(=CC3=N2)OC)C4=CC(=NC=C4)C IYSBXDDVLPKYPJ-UHFFFAOYSA-N 0.000 claims description 3
- AAVKIRLFHLCADZ-UHFFFAOYSA-N 7-methoxy-N-[[3-methyl-4-(2-methylpyridin-4-yl)phenyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide Chemical compound CC1=C(C=CC(=C1)CNC(=O)C2=CN3C=CC(=CC3=N2)OC)C4=CC(=NC=C4)C AAVKIRLFHLCADZ-UHFFFAOYSA-N 0.000 claims description 3
- ICAGKIKJXKZJKM-UHFFFAOYSA-N 7-methoxy-N-[[4-(2-methylpyridin-4-yl)phenyl]methyl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide Chemical compound CC1=NC=CC(=C1)C2=CC=C(C=C2)CNC(=O)C3=NN4C=CC(=CC4=N3)OC ICAGKIKJXKZJKM-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- ROWFWINTSCVEKB-UHFFFAOYSA-N CC1=C(C=CC(=C1)CNC(=O)C2=CN3C=CC(=CC3=N2)C(=O)C)C4=CC(=NC=C4)C Chemical compound CC1=C(C=CC(=C1)CNC(=O)C2=CN3C=CC(=CC3=N2)C(=O)C)C4=CC(=NC=C4)C ROWFWINTSCVEKB-UHFFFAOYSA-N 0.000 claims description 3
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 3
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 3
- DLTMJFBSUZLVKQ-UHFFFAOYSA-N N-(6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-[3-methyl-4-(2-methylpyridin-4-yl)phenyl]acetamide Chemical compound CC1=C(C=CC(=C1)CC(=O)NC2=NN3C=C(C=CC3=N2)OC)C4=CC(=NC=C4)C DLTMJFBSUZLVKQ-UHFFFAOYSA-N 0.000 claims description 3
- WQCJACNYMDXXPI-UHFFFAOYSA-N N-(7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-[3-methyl-4-(2-methylpyridin-4-yl)phenyl]acetamide Chemical compound CC1=C(C=CC(=C1)CC(=O)NC2=NN3C=CC(=CC3=N2)OC)C4=CC(=NC=C4)C WQCJACNYMDXXPI-UHFFFAOYSA-N 0.000 claims description 3
- SLVPCFAQAUZELP-UHFFFAOYSA-N N-(7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-[4-(2-methylpyridin-4-yl)phenyl]acetamide Chemical compound CC1=NC=CC(=C1)C2=CC=C(C=C2)CC(=O)NC3=NN4C=CC(=CC4=N3)OC SLVPCFAQAUZELP-UHFFFAOYSA-N 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 229960002087 pertuzumab Drugs 0.000 claims description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 3
- 229960003787 sorafenib Drugs 0.000 claims description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 claims description 2
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 claims description 2
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 claims description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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-VTZDEGQISA-N 0.000 claims 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 claims description 2
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 2
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 2
- 206010014733 Endometrial cancer Diseases 0.000 claims description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 206010019668 Hepatic fibrosis Diseases 0.000 claims description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 2
- 108010000817 Leuprolide Proteins 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 208000000172 Medulloblastoma Diseases 0.000 claims description 2
- 206010027406 Mesothelioma Diseases 0.000 claims description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 201000009859 Osteochondrosis Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 229930012538 Paclitaxel Natural products 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)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]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 201000000582 Retinoblastoma Diseases 0.000 claims description 2
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 2
- 208000034254 Squamous cell carcinoma of the cervix uteri Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000008383 Wilms tumor Diseases 0.000 claims description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 2
- 229960000397 bevacizumab Drugs 0.000 claims description 2
- 229960000997 bicalutamide Drugs 0.000 claims description 2
- 229960004117 capecitabine Drugs 0.000 claims description 2
- 229960004562 carboplatin Drugs 0.000 claims description 2
- 208000002458 carcinoid tumor Diseases 0.000 claims description 2
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 2
- 201000006612 cervical squamous cell carcinoma Diseases 0.000 claims description 2
- 229960005395 cetuximab Drugs 0.000 claims description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 2
- 229960004316 cisplatin Drugs 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 229960004397 cyclophosphamide Drugs 0.000 claims description 2
- 229960000684 cytarabine Drugs 0.000 claims 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 claims description 2
- 229960000975 daunorubicin Drugs 0.000 claims description 2
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 2
- 229960003668 docetaxel Drugs 0.000 claims description 2
- 229960004679 doxorubicin Drugs 0.000 claims description 2
- 229960004671 enzalutamide Drugs 0.000 claims description 2
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 claims description 2
- 229960001904 epirubicin Drugs 0.000 claims description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 2
- 229960001433 erlotinib Drugs 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 229960000255 exemestane Drugs 0.000 claims description 2
- 229960002949 fluorouracil Drugs 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 230000002496 gastric effect Effects 0.000 claims description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 2
- 229960002584 gefitinib Drugs 0.000 claims description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 2
- 229960005277 gemcitabine Drugs 0.000 claims description 2
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 2
- 208000006359 hepatoblastoma Diseases 0.000 claims description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 2
- 229960002411 imatinib Drugs 0.000 claims description 2
- 229960005386 ipilimumab Drugs 0.000 claims description 2
- 229960004768 irinotecan Drugs 0.000 claims description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 2
- 229960004891 lapatinib Drugs 0.000 claims description 2
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims description 2
- 229960003881 letrozole Drugs 0.000 claims description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 claims description 2
- 229960004338 leuprorelin Drugs 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims description 2
- 229960004961 mechlorethamine Drugs 0.000 claims description 2
- 229960004616 medroxyprogesterone Drugs 0.000 claims description 2
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 claims description 2
- 229960001786 megestrol Drugs 0.000 claims description 2
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 229960001428 mercaptopurine Drugs 0.000 claims description 2
- 229960000485 methotrexate Drugs 0.000 claims description 2
- 206010028537 myelofibrosis Diseases 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 2
- 229960001756 oxaliplatin Drugs 0.000 claims description 2
- 229960001592 paclitaxel Drugs 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 229960001972 panitumumab Drugs 0.000 claims description 2
- 229960002621 pembrolizumab Drugs 0.000 claims description 2
- 229960005079 pemetrexed Drugs 0.000 claims description 2
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 claims description 2
- 229960001221 pirarubicin Drugs 0.000 claims description 2
- 229960004432 raltitrexed Drugs 0.000 claims description 2
- 229960002633 ramucirumab Drugs 0.000 claims description 2
- 201000002793 renal fibrosis Diseases 0.000 claims description 2
- 229960004641 rituximab Drugs 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 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 claims description 2
- 229960001796 sunitinib Drugs 0.000 claims description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 2
- 229960001712 testosterone propionate Drugs 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 229960000303 topotecan Drugs 0.000 claims description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 2
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 claims description 2
- 229960005026 toremifene Drugs 0.000 claims description 2
- 229960000575 trastuzumab Drugs 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 229960004528 vincristine Drugs 0.000 claims description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 2
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 claims description 2
- 229960004355 vindesine Drugs 0.000 claims description 2
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 claims description 2
- 229960002066 vinorelbine Drugs 0.000 claims description 2
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 claims 1
- 208000014018 liver neoplasm Diseases 0.000 claims 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 claims 1
- 229960002073 sertraline Drugs 0.000 claims 1
- 239000012453 solvate Substances 0.000 abstract description 13
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 description 72
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 55
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 35
- 210000004027 cell Anatomy 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 26
- 150000003462 sulfoxides Chemical class 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 230000037361 pathway Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 229910052805 deuterium Inorganic materials 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 241000208140 Acer Species 0.000 description 6
- 108060000903 Beta-catenin Proteins 0.000 description 6
- 102000015735 Beta-catenin Human genes 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 229910052727 yttrium Inorganic materials 0.000 description 6
- MGIXALWFXBQXRE-UHFFFAOYSA-N 7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine Chemical compound C1=C(OC)C=CN2N=C(N)N=C21 MGIXALWFXBQXRE-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- UCPQVNYTDUMFJH-UHFFFAOYSA-N 2-[4-(2-methylpyridin-4-yl)phenyl]acetic acid Chemical compound C1=NC(C)=CC(C=2C=CC(CC(O)=O)=CC=2)=C1 UCPQVNYTDUMFJH-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [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
- 238000012054 celltiter-glo Methods 0.000 description 4
- 238000006243 chemical reaction Methods 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
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 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 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
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 3
- QPHBCOSULYSASF-UHFFFAOYSA-N 4-methoxypyridin-2-amine Chemical compound COC1=CC=NC(N)=C1 QPHBCOSULYSASF-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241001481760 Erethizon dorsatum Species 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 108060001084 Luciferase Proteins 0.000 description 3
- 239000005089 Luciferase Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910003204 NH2 Inorganic materials 0.000 description 3
- 108700008625 Reporter Genes Proteins 0.000 description 3
- 229920002472 Starch Chemical class 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- RRPKGUUYTHFUPN-UHFFFAOYSA-N n-hydroxy-2,4,6-trimethylbenzenesulfonamide Chemical compound CC1=CC(C)=C(S(=O)(=O)NO)C(C)=C1 RRPKGUUYTHFUPN-UHFFFAOYSA-N 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 230000026792 palmitoylation Effects 0.000 description 3
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000008107 starch Chemical class 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- 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 2
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- CXMISGPOTMRORO-UHFFFAOYSA-N 5-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid Chemical compound FC(F)(F)C1=CC=CC2=NC(C(=O)O)=CN21 CXMISGPOTMRORO-UHFFFAOYSA-N 0.000 description 2
- CVFNVXPJVITGNO-UHFFFAOYSA-N 6-cyanoimidazo[1,2-a]pyridine-2-carboxylic acid Chemical compound C1=C(C#N)C=CC2=NC(C(=O)O)=CN21 CVFNVXPJVITGNO-UHFFFAOYSA-N 0.000 description 2
- BLGYAIWJMVWVDS-UHFFFAOYSA-N 6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine Chemical compound C1=C(OC)C=CC2=NC(N)=NN21 BLGYAIWJMVWVDS-UHFFFAOYSA-N 0.000 description 2
- VFFWSISDEZUDIA-UHFFFAOYSA-N 6-methoxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid Chemical compound COC1=CN2C(=NC(=N2)C(=O)O)C=C1 VFFWSISDEZUDIA-UHFFFAOYSA-N 0.000 description 2
- WRUWSPQXXPEDPZ-UHFFFAOYSA-N 6-methoxyimidazo[1,2-a]pyridin-2-amine Chemical compound COc1ccc2nc(N)cn2c1 WRUWSPQXXPEDPZ-UHFFFAOYSA-N 0.000 description 2
- IZMWSZOKMOYZDD-UHFFFAOYSA-N 6-methoxyimidazo[1,2-a]pyridine-2-carboxylic acid Chemical compound C1=C(OC)C=CC2=NC(C(O)=O)=CN21 IZMWSZOKMOYZDD-UHFFFAOYSA-N 0.000 description 2
- RXUNFAGGSOSJIF-UHFFFAOYSA-N 6-methoxypyrazolo[1,5-a]pyridine-2-carboxylic acid Chemical compound COc1ccc2cc(nn2c1)C(O)=O RXUNFAGGSOSJIF-UHFFFAOYSA-N 0.000 description 2
- VQNWFPGJYOHAGY-UHFFFAOYSA-N 7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylic acid Chemical compound C1=CC=C(C(F)(F)F)N2N=C(C(=O)O)C=C21 VQNWFPGJYOHAGY-UHFFFAOYSA-N 0.000 description 2
- NDUXOTHIAALPPU-UHFFFAOYSA-N 7-cyanoimidazo[1,2-a]pyridine-2-carboxylic acid Chemical compound C1=CC(C#N)=CC2=NC(C(=O)O)=CN21 NDUXOTHIAALPPU-UHFFFAOYSA-N 0.000 description 2
- UFLYUHVOHHGIFC-UHFFFAOYSA-N 7-methoxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid Chemical compound COC1=CC2=NC(=NN2C=C1)C(=O)O UFLYUHVOHHGIFC-UHFFFAOYSA-N 0.000 description 2
- BEVGTHQRAJRKRA-UHFFFAOYSA-N 7-methoxyimidazo[1,2-a]pyridin-2-amine Chemical compound COc1ccn2cc(N)nc2c1 BEVGTHQRAJRKRA-UHFFFAOYSA-N 0.000 description 2
- MGQAEKZHTQUATF-UHFFFAOYSA-N 7-methoxyimidazo[1,2-a]pyridine-2-carboxylic acid Chemical compound C1=C(OC)C=CN2C=C(C(O)=O)N=C21 MGQAEKZHTQUATF-UHFFFAOYSA-N 0.000 description 2
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 2
- BXFZUXJUHFJSCP-UHFFFAOYSA-N CC(=O)c1ccn2cc(nc2c1)C(O)=O Chemical compound CC(=O)c1ccn2cc(nc2c1)C(O)=O BXFZUXJUHFJSCP-UHFFFAOYSA-N 0.000 description 2
- SQSAGFBVRMMQFE-UHFFFAOYSA-N CC1=C(C=CC(=C1)NC)C2=CC(=NC=C2)C Chemical compound CC1=C(C=CC(=C1)NC)C2=CC(=NC=C2)C SQSAGFBVRMMQFE-UHFFFAOYSA-N 0.000 description 2
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 229940127399 DNA Polymerase Inhibitors Drugs 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 102000005698 Frizzled receptors Human genes 0.000 description 2
- 108010045438 Frizzled receptors Proteins 0.000 description 2
- 108091007911 GSKs Proteins 0.000 description 2
- 102000004103 Glycogen Synthase Kinases Human genes 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- HIHLXMAJXGCGAT-UHFFFAOYSA-N N-methyl-4-(2-methylpyridin-4-yl)aniline Chemical compound C1=CC(NC)=CC=C1C1=CC=NC(C)=C1 HIHLXMAJXGCGAT-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- 230000006819 RNA synthesis Effects 0.000 description 2
- 229940127395 Ribonucleotide Reductase Inhibitors Drugs 0.000 description 2
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940127538 Vascular Endothelial Growth Factor Receptor Inhibitors Drugs 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000003501 co-culture Methods 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940125851 compound 27 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 229940125878 compound 36 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000003166 dihydrofolate reductase inhibitor Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 2
- QBWLOOQDUOJHCG-UHFFFAOYSA-N ethyl 2-[4-(2-methylpyridin-4-yl)phenyl]acetate Chemical compound C1=CC(CC(=O)OCC)=CC=C1C1=CC=NC(C)=C1 QBWLOOQDUOJHCG-UHFFFAOYSA-N 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 239000003744 tubulin modulator Substances 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 210000001215 vagina Anatomy 0.000 description 2
- OZNURVDNAKVKGM-UHFFFAOYSA-N 1-(2-aminopyridin-4-yl)ethanone Chemical compound CC(=O)C1=CC=NC(N)=C1 OZNURVDNAKVKGM-UHFFFAOYSA-N 0.000 description 1
- GSVACXVMHAHOBH-UHFFFAOYSA-N 2-[3-methyl-4-(2-methylpyridin-4-yl)phenyl]acetic acid Chemical compound CC1=C(C=CC(=C1)CC(=O)O)C2=CC(=NC=C2)C GSVACXVMHAHOBH-UHFFFAOYSA-N 0.000 description 1
- MBTULFIFECUURA-UHFFFAOYSA-N 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound C1=NC(C)=CC(B2OC(C)(C)C(C)(C)O2)=C1 MBTULFIFECUURA-UHFFFAOYSA-N 0.000 description 1
- KTOXSFXMKFCJGE-UHFFFAOYSA-N 4-bromo-n,3-dimethylaniline Chemical compound CNC1=CC=C(Br)C(C)=C1 KTOXSFXMKFCJGE-UHFFFAOYSA-N 0.000 description 1
- AYVPVDWQZAAZCM-UHFFFAOYSA-N 4-bromo-n-methylaniline Chemical compound CNC1=CC=C(Br)C=C1 AYVPVDWQZAAZCM-UHFFFAOYSA-N 0.000 description 1
- XQABVLBGNWBWIV-UHFFFAOYSA-N 4-methoxypyridine Chemical compound COC1=CC=NC=C1 XQABVLBGNWBWIV-UHFFFAOYSA-N 0.000 description 1
- ZGSNZVRXASCXRP-UHFFFAOYSA-N 5-methoxy-1h-pyrazole Chemical compound COC=1C=CNN=1 ZGSNZVRXASCXRP-UHFFFAOYSA-N 0.000 description 1
- UENQQGFNTBPBJC-UHFFFAOYSA-N 5-methoxypyrazolo[1,5-a]pyridin-2-amine Chemical compound COC1=CC2=CC(=NN2C=C1)N UENQQGFNTBPBJC-UHFFFAOYSA-N 0.000 description 1
- 108700001666 APC Genes Proteins 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000051172 Axin Human genes 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 101710167800 Capsid assembly scaffolding protein Proteins 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000017944 Dishevelled Human genes 0.000 description 1
- 108050007016 Dishevelled Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 1
- 102100038104 Glycogen synthase kinase-3 beta Human genes 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 101001043594 Homo sapiens Low-density lipoprotein receptor-related protein 5 Proteins 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 102100021926 Low-density lipoprotein receptor-related protein 5 Human genes 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 102100025036 Norrin Human genes 0.000 description 1
- 101710085992 Norrin Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 101710130420 Probable capsid assembly scaffolding protein Proteins 0.000 description 1
- 108700005075 Regulator Genes Proteins 0.000 description 1
- 101710204410 Scaffold protein Proteins 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 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
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102000014420 Transcription factor TCF/LEF Human genes 0.000 description 1
- 108050003468 Transcription factor TCF/LEF Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229960003982 apatinib Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000001913 cellulose Chemical class 0.000 description 1
- 229920002678 cellulose Chemical class 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- STRNXFOUBFLVIN-UHFFFAOYSA-N diethyl but-2-ynedioate Chemical compound CCOC(=O)C#CC(=O)OCC STRNXFOUBFLVIN-UHFFFAOYSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- ZFDCWHPNBWPPHG-UHFFFAOYSA-N ethyl 2-(4-bromophenyl)acetate Chemical compound CCOC(=O)CC1=CC=C(Br)C=C1 ZFDCWHPNBWPPHG-UHFFFAOYSA-N 0.000 description 1
- OWZFULPEVHKEKS-UHFFFAOYSA-N ethyl 2-chloro-2-oxoacetate Chemical compound CCOC(=O)C(Cl)=O OWZFULPEVHKEKS-UHFFFAOYSA-N 0.000 description 1
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000010441 gene drive Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- WPEWQEMJFLWMLV-UHFFFAOYSA-N n-[4-(1-cyanocyclopentyl)phenyl]-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide Chemical compound C=1C=CN=C(NCC=2C=CN=CC=2)C=1C(=O)NC(C=C1)=CC=C1C1(C#N)CCCC1 WPEWQEMJFLWMLV-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
Abstract
本发明提供一种5,6‑双环结构的化合物，或药学上可接受的盐,溶剂化物,或立体异构体。本发明的5,6‑双环结构化合物具有WNT信号通路的抑制活性，可以用于WNT信号通路相关疾病的治疗。相关疾病包括但不限于：肿瘤、畸形综合症、骨或软骨疾病、糖尿病或其并发症、组织纤维化等。
Description
技术领域
本发明属于医药技术领域，涉及一种具有WNT信号通路抑制活性的5,6-双环化合物及其应用。
背景技术
WNT信号通路在胚胎发生和成体的稳态调节中都起着重要作用。Wnt基因家族负责编码一大类与Int1/Wnt1原癌基因及无翅果蝇(Wg，对应果蝇Wnt1)相关的分泌型WNT配体(Cadigen and Nusse.,(1997)Genes&Development 11：3286-3305)。多种Wnt-激发的通路协同调节关键的发育过程，以及成人组织的稳态及修复过程，不同疾病中均存在Wnt通路调节失调，例如癌症、畸形综合症、骨质疏松症、糖尿病视网膜病变以及肺纤维化(MacDonaldet al(2009)Dev.Cell 17：9-26；Williams and Insogna(2009)J.Bone Miner.Res.24：171-178；Polaskis(2007)Curr.Opin.Genet.Dev.17：45-51；Chen et al.,(2009)Am.J.Pathol.175：2676-2685)。WNT配体决定了WNT信号通路的活性。WNT蛋白合成的第一步是在内质网(ER)完成翻译，接着由ER固有的酶Porcupine(PORCN，一种膜结合的O-酰基转移酶(MBOAT))介导翻译后酰化(棕榈酰化)(Proffitt and Virshup.,(2012)J ofBiol.Chem.287：34167-34178)，WNT蛋白在1或2个高度保守位点上存在棕榈酰化(Zhai etal.,(2004)J.Biol.Chem.279：33220-33227；Takada et al.,(2006)Dev Cell 11：791-801)。WNT蛋白转运、分泌以及蛋白活性与WNT蛋白翻译后酰化紧密相关，而PORCN对于Wnt的翻译后酰化具有高选择性及精密调节作用(Proffitt and Virshup.,(2012)J ofBiol.Chem.287：34167-34178)，这一修饰过程是WNT蛋白分泌以及连接载体蛋白WLS所必须。除此之外，棕榈酰化对于WNT蛋白与细胞表面的Frizzled受体间的相互作用至关重要(Coombs et al.,(2010)J.Cell Sci 123：3357-3367；Herr and Basler(2012)Dev.Biol.361：392-402；Janda et al.,(2012)Dev.Biol.361：392-402)。
典型的WNT通路由WNT配体与细胞表面Frizzled受体结合而活化(Bhanot et al.,(1996)Nature 382：225-230)，继而激活胞浆蛋白Dishevelled(Boutros,et al.,(1999)Mech.Dev.83：27-37)以及LRP5/6的磷酸化，导致β-catenin在细胞核内的聚集并与TCF/LCF家族转录因子相互作用，促进特定基因的转录过程(Uthoff et al.,(2001)Mol.Carcinog.,31：56-62)。WNT通路非活化状态下，游离的胞浆β-catenin进入支架蛋白Axin、结肠腺瘤样息肉蛋白APC以及糖原合成激酶(GSK)-3β组成的复杂体系中。Axin、APC以及β-catenin被GSK-3β接连磷酸化，最终导致β-catenin进入泛素化途径，并被蛋白酶体降解(Uthoff et al.,(2001)Mol.Carcinog.,31：56-62；Matsuzawa et al.,(2001)Mol.Cell,7：915-926)。
众所周知，WNT信号通路对于多种类型的细胞的存活起到有利作用(Orford etal.,(1999)J.Cell Bio,146：855-868；Satoh et.al.,(2000)Nat.Genet,24：245-250；Ioannidis et al.,(2001)Nat.Immunol,2：691-697)。WNT通路活性的改变与肿瘤的发生发展紧密相关。例如，经典WNT通路高活性会导致细胞生长异常(Reya and Clevers,(2005)Nature 434：843-850)。另外，90％的结直肠癌有APC基因(其是WNT/β-catenin信号通路抑制剂)的缺失(Kinzler and Vogelstein,(1996)Cell 87：159-170)。再比如，WNT信号通路的活性异常与多种人体肿瘤相关，同时伴随C-Myc过度表达(Polakis et al.,(2000)GenesDev,14：1837-1851；Bienz et al.,(2000)Cell：311-320)。C-Myc现已证实为结直肠癌β-caternin/TCF通路中的一个翻译靶点(He et al.,(1998)Science,281：1509-1512；de LaCoste et al.,(1998)Proc Natl Acad Sci USA,95：8847-8851；Miller et al.,(1999)Oncogene,18：7860-7872；Uoi et al.,(2002)J.Cell Biol,157：429-440)。除此之外，WNT蛋白表达增强以及细胞外WNT蛋白功能抑制剂的缺失，可能会导致WNT依赖的肿瘤产生(Polaskis(2007)Curr.Opin.Genet.Dev.17：45-51)。近期研究发现，WNT信号通路在肿瘤干细胞中发挥作用(Takahashi-Yanaga and Kahn,(2010)Clin.Cancer Res16：3153-62)，并与干细胞自我更新相关(Kretzachmar and Clevers,(2017)Dev.Biol.428：273-282；Prieur et al.,(2017)Clin.Cancer Res.23：5267-5280)。
应用基因或化学方法，阻断多种肿瘤中的WNT信号通路，能够使异常的细胞生长停滞(Herbst and Kolligs,(2007)Methods Mol.Biol 361：63-91)。此外，抑制此信号通路可能直接影响支持肿瘤细胞生长和转移的细胞，其中肿瘤转移被认为是肿瘤细胞对传统化疗药耐药的重要因素。异常的WNT信号通路还与多种紊乱相关，包括但不限于骨和软骨疾病，例如骨质疏松症、骨关节炎、肥胖相关的II型糖尿病等(Hoeppner,(2009)ExpertOpin.Ther.Targets 13：485-96；Ouchi et al.,(2010)Science 329：454-457；Blom etal.,(2010)Curr.Drug Targets 11：620-629)。因此，调节WNT信号通路的物质或方法，具有潜在的治疗、预防以及改善WNT通路相关疾病的疗效。
发明内容
本发明提供一种结构式I的化合物，或其药学上可接受的盐，溶剂化物，或立体异构体
其中：B为-CONH-，或-NHCO-，
R1，R2分别代表H，D，F，Cl，Br，C1-C3烷基，C1-C3烷氧基，C1-C3亚烷基羟基，或者R1和R2连接形成一个包含0-1个杂原子的取代的或未取代3-6元饱和环，其中所述杂原子选自O，S或N之一；
R3，R4，R’3，R’4可在所在环的任意取代位置，其中R3，R4，R’3，R’4独立代表H，D，F，Cl，Br，I，NH2，NO2，CN，C1-C6烷基，取代的C1-C6烷基，取代或非取代的C3-C7环烷基，OR5，COR5，CONR5R6，NR5R6，NR5COR6，NR5CONHR6，NHSO2R5，SO2NHR5，SO2(C1-C6烷基)，取代或非取代的C3-C7杂环烷基，所述C3-C7杂环烷基为含O，S，N的杂环烷基，以C原子与环相连接；
R5，R6可独立代表H，D，C1-C6烷基，C2-C4亚烷基羟基，C3-C6环烷基或C3-C6杂环烷基，氨基C1-C6烷基，或取代氨基C1-C6烷基，或R5和R6与所连接的基团可连接形成包含1-2个杂原子的取代或未取代的3-6元饱和环，其中，所述杂原子进一步选自O，S或N原子；
上述“取代的”表示所述基团进一步被F，Cl，Br，C1-C6烷基，C1-C6烷氧基或C1-C6亚烷基羟基所取代；
X，Y，Z，X1，Y1，Z1可独立代表C，N；
A选自下列结构式代表的芳基或杂芳基，
其中R3，R4在所连接环的任意可取代位置，R3，R4的定义和上述相同；
R7可选自H，F，Cl，Br，I，C1-C6烷基。
进一步，本发明保护一种结构式I的化合物，其中，B为-CONH-结构，X为C，Y为N，Z为C，即为式Ia结构化合物
或，本发明保护一种式I结构化合物，其中B为-CONH-结构，X为N，Y为N，Z为C，即为式Ib结构化合物：
或，本发明保护一种式I结构化合物，其中B为-CONH-结构，X为C，Y为C，Z为N，即为式Ic结构化合物：
其中，所述R1，R2分别代表H，D，F，Cl，Br，C1-C3烷基，C1-C3烷氧基，C1-C3亚烷基羟基；
R3，R4，R’3，R’4可在所在环的任意取代位置，其中R3，R4，R’3，R’4独立代表H，D，F，Cl，Br，I，NH2，NO2，CN，C1-C6烷基，取代的C1-C6烷基，取代或非取代的C3-C7环烷基，OR5，COR5，CONR5R6，NR5R6，NR5COR6，NR5CONHR6，NHSO2R5，SO2NHR5，SO2(C1-C6烷基)，取代或非取代的C3-C7杂环烷基，所述C3-C7杂环烷基为含O，S，N的杂环烷基，以C原子与环相连接；
R5，R6可独立代表H，D，C1-C6烷基，C2-C4亚烷基羟基，C3-C6环烷基或C3-C6杂环烷基，氨基C1-C6烷基，或取代氨基C1-C6烷基，或R5和R6与所连接的基团可连接形成包含1-2个杂原子的取代或未取代的3-6元饱和环，其中，所述杂原子进一步选自O，S或N原子；
所述“取代的”表示所述基团进一步被F，Cl，Br，C1-C6烷基，C1-C6烷氧基或C1-C6亚烷基羟基所取代；
A选自下列结构式代表的芳基或杂芳基,
其中R3，R4在所连接环的任意可取代位置，R3，R4的定义和上述相同；
R7可选自H，F，Cl，Br，I，C1-C6烷基。
进一步，本发明保护一种结构式I的化合物，其中，B为-NHCO-结构，X为C，Y为N，Z为C，即为式IIa结构化合物
或，B为-NHCO-结构，X为N，Y为N，Z为C，即为式IIb结构化合物
或，B为-NHCO-结构，X为C，Y为C，Z为N，即为式IIc结构化合物
其中，所述R1，R2分别代表H，D，F，Cl，Br，C1-C3烷基，C1-C3烷氧基，C1-C3亚烷基羟基；
R3，R4，R’3，R’4可在所在环的任意取代位置，其中R3，R4，R’3，R’4独立代表H，D，F，Cl，Br，I，NH2，NO2，CN，C1-C6烷基，取代的C1-C6烷基，取代或非取代的C3-C7环烷基，OR5，COR5，CONR5R6，NR5R6，NR5COR6，NR5CONHR6，NHSO2R5，SO2NHR5，SO2(C1-C6烷基)，取代或非取代的C3-C7杂环烷基，所述C3-C7杂环烷基为含O，S，N的杂环烷基，以C原子与环相连接；
R5，R6可独立代表H，D，C1-C6烷基，C2-C4亚烷基羟基，C3-C6环烷基或C3-C6杂环烷基，氨基C1-C6烷基，或取代氨基C1-C6烷基，或R5和R6与所连接的基团可连接形成包含1-2个杂原子的取代或未取代的3-6元饱和环，其中，所述杂原子进一步选自O，S或N原子；
所述“取代的”表示所述基团进一步被F，Cl，Br，C1-C6烷基，C1-C6烷氧基或C1-C6亚烷基羟基所取代；
A选自下列结构式代表的芳基或杂芳基,
其中R3，R4在所连接环的任意可取代位置，R3，R4的定义和上述相同；
R7可选自H，F，Cl，Br，I，C1-C6烷基。
进一步，本发明保护如下式I具体化合物，该具体化合物选自：
上述所述化合物中B为-CONH-结构，或，
上述所述化合物中B为-NHCO-结构。
优选保护如下具体化合物：
N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)乙酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-7-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)乙酰胺、
2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)乙酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)乙酰胺、
N-(4-(2-甲基吡啶-4-基)苯基甲基)-7-乙酰基-咪唑[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-5-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-5-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-(三氟甲基)吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-4-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-4-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-5-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酰胺，或
N-(4-(2-甲基吡啶-4-基)苯甲基)-5-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酰胺。
进一步，保护上述通式I化合物或具体化合物，其中原子相应的同位素是2H，3H，11C，13C，14C，15N，17O，18O，35S，18F和36Cl的同位素化合物。
本发明进一步保护式I化合物的制备方法，其包括：有机酸化合物及其衍生物与有机胺化合物反应得到式I结构的酰胺化合物，所述有机酸化合物及其衍生物选自下式化合物：
所述有机胺化合物选自下式化合物：
其中M选自-OH，卤素，C1-C6烷氧基，C3-C7环烷氧基，金属离子或类似结构基团，取代基团X，Y，Z，X1，Y1，Z1，R1，R2，R3，R4，R’3，R’4，R5，R6，R7，A定义参照上述定义。
本发明的式I化合物或其药学上可接受的盐，溶剂化物，或立体异构体具有WNT信号通路的抑制活性，可以用于WNT信号通路相关疾病的治疗。
本发明提供式I化合物或其药学上可接受的盐，溶剂化物，或立体异构体在制备治疗WNT信号通路相关疾病的药物中的用途。
所述WNT信号通路相关疾病包括但不限于：肿瘤、畸形综合症、骨或软骨疾病、糖尿病或其并发症、组织纤维化等。
所述骨或软骨疾病包括但不限于：骨质疏松症、骨关节炎、骨软骨病。
所述糖尿病或其并发症包括但不限于：II型糖尿病、糖尿病性视网膜病变、糖尿病性肾病、糖尿病性脑血管病。
所述肿瘤包括但不限于：实体瘤或非实体瘤。所述实体瘤包括但不限限于：结肠直肠癌、结肠癌、胃癌、食道癌、骨肉瘤、乳腺癌、宫颈鳞状细胞癌、子宫内膜癌、间皮瘤、胰腺癌、膀胱癌、前列腺癌、肺癌、肝细胞癌、髓母细胞瘤、肝母细胞瘤、胃肠类癌、卵巢癌、黑色素瘤、头颈部鳞状细胞癌、甲状腺癌、肾母细胞瘤、视网膜母细胞瘤、胶质瘤。所述非实体瘤包括但不限于：白血病，例如慢性粒细胞性白血病；淋巴瘤。
组织纤维化可发生于多种器官，主要病理改变为器官组织内纤维结缔组织增多，实质细胞减少，持续进展可致器官结构破坏和功能减退。其包括但不限于：肺纤维化、肝纤维化、肾纤维化、骨髓纤维化等。
本发明提供一种药物组合物，其特征在于包括式I化合物或其药学上可接受的盐，溶剂化物，或立体异构体。
所述药物组合物可以用于治疗WNT信号通路相关疾病。所述WNT信号通路相关疾病的定义如前文所述。
所述药物组合物进一步含有药学上可接受的载体。
所述药学上可接受的载体是制药领域中常用或已知的各种辅料，包括但不限于：稀释剂、粘合剂、抗氧化剂、pH调节剂、防腐剂、润滑剂、崩解剂等。
所述稀释剂例如：乳糖、淀粉、纤维素衍生物、无机钙盐、山梨醇等。所述粘合剂例如：淀粉、明胶、羧甲基纤维素钠、聚乙烯吡咯烷酮等。所述抗氧化剂例如：维生素E、亚硫酸氢钠、亚硫酸钠、丁羟基茴香醚等。所述pH调节剂例如：盐酸、氢氧化钠、柠檬酸、酒石酸、Tris、乙酸、磷酸二氢钠、磷酸氢二钠等。所述防腐剂例如：对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、间甲酚、苯扎氯铵等。所述润滑剂例如：硬脂酸镁、微粉硅胶、滑石粉等。所述崩解剂例如：淀粉、甲基纤维素、黄原胶、交联羧甲基纤维素钠等。
所述药物组合物中含有式I化合物或其药学上可接受的盐，溶剂化物，或立体异构体的量为0.1-1000mg，优选1-500mg，更优选为5-100mg。
所述药物组合物中式I化合物或其药学上可接受的盐，溶剂化物，或立体异构体占药物组合物的质量百分比为10％-90％，优选为20％-80％，更优选为30％-70％。
所述药物组合物的剂型可以是口服剂的形式，例如片剂、胶囊、丸剂、粉剂、颗粒剂、悬浮剂、糖浆剂等；也可以是注射给药的剂型，例如注射液、粉针剂等，通过静脉内、腹膜内、皮下或肌肉内的途径注射给药。所有使用的剂型形式都是药学领域普通技术人员所熟知的。
所述药物组合物的施用途径包括但不限于：口服的；含服的；舌下的；透皮的；经黏膜的；鼻内的；眼用的；肺的；直肠的；阴道的；肠胃外的，例如，通过注射，包括皮下的、真皮内的、肌内的、静脉内的、动脉内的、心内的、鞘内的、脊柱内的、囊内的、囊下的、眼眶内的、腹膜内的、气管内的、表皮下的、关节内的、蛛网膜下的和胸骨内的；通过植入储库或储液器。
式I化合物或其药学上可接受的盐，溶剂化物，或立体异构体的施用剂量将取决于接受者的年龄、健康和体重，联用药物的种类，治疗频率，给药途径等。药物可以单一日剂量施用，每天给药一次、每两天给药一次、每三天给药一次、每四天给药一次，或者总日剂量以每天两次、三次或四次的分开剂量施用。剂量可以施用一次或多次，施药时间可以单日至几个月或更长时间。式I化合物或其药学上可接受的盐，溶剂化物，或立体异构体的用药量为0.01-1000mg/kg/天，优选为0.1-100mg/kg/天，例如为0.5mg/kg/天，1mg/kg/天、2mg/kg/天、5mg/kg/天等等。
所述药物组合物可以和其他的治疗WNT信号通路相关疾病的药物或治疗手段联合应用。
所述药物组合物可以进一步含有第二种治疗剂，所述第二种治疗剂是其他的治疗WNT信号通路相关疾病的药物。
本发明提供一种治疗WNT信号通路相关疾病的方法，其特征在于，对有需要的患者施用治疗有效量的式I化合物或其药学上可接受的盐，溶剂化物，或立体异构体。
所述式I化合物或其药学上可接受的盐，溶剂化物，或立体异构体的施用途径包括但不限于：口服的；含服的；舌下的；透皮的；经黏膜的；鼻内的；眼用的；肺的；直肠的；阴道的；肠胃外的，例如，通过注射，包括皮下的、真皮内的、肌内的、静脉内的、动脉内的、心内的、鞘内的、脊柱内的、囊内的、囊下的、眼眶内的、腹膜内的、气管内的、表皮下的、关节内的、蛛网膜下的和胸骨内的；通过植入储库或储液器。
式I化合物或其药学上可接受的盐，溶剂化物，或立体异构体的施用剂量将取决于接受者的年龄、健康和体重，联用药物的种类，治疗频率，给药途径等。药物可以单一日剂量施用，每天给药一次、每两天给药一次、每三天给药一次、每四天给药一次，或者总日剂量以每天两次、三次或四次的分开剂量施用。剂量可以施用一次或多次，施药时间可以单日至几个月或更长时间。式I化合物或其药学上可接受的盐，溶剂化物，或立体异构体的用药量为0.01-1000mg/kg/天，优选为0.1-100mg/kg/天，例如为0.5mg/kg/天，1mg/kg/天、2mg/kg/天、5mg/kg/天等等。
所述方法进一步包括，对有需要的患者给予其他的治疗WNT信号通路相关疾病的药物，或者联合使用其他的治疗手段。
其他的治疗WNT信号通路相关疾病的药物包括但不限于：破坏DNA结构和功能的药物、核苷酸合成酶抑制剂、DNA多聚酶抑制剂、二氢叶酸还原酶抑制剂、核苷酸还原酶抑制剂、抑制RNA合成的药物，拓扑异构酶抑制剂、微管蛋白抑制剂、影响激素平衡的药物、酪氨酸激酶抑制剂、表皮生长因子受体抑制剂、血管内皮生长因子受体抑制剂、免疫调节剂等。
所述破坏DNA结构和功能的药物包括但不限于：氮芥、环磷酰胺、顺铂、卡铂、奥沙利铂。
所述核苷酸合成酶抑制剂包括但不限于：5-氟尿嘧啶、卡培他滨、雷替曲塞、6-巯嘌呤。
所述DNA多聚酶抑制剂包括但不限于：阿糖胞苷、吉西他滨。
所述二氢叶酸还原酶抑制剂包括但不限于：氨甲喋呤、培美曲塞。
所述核苷酸还原酶抑制剂包括但不限于：羟基脲。
所述抑制RNA合成的药物包括但不限于：阿霉素、柔红霉素、表柔比星、吡柔比星。
所述拓扑异构酶抑制剂包括但不限于：羟喜树碱、伊立替康、拓扑替康。
所述微管蛋白抑制剂包括但不限于：长春新碱、长春地辛、长春瑞滨、紫杉醇、多西紫杉醇。
所述影响激素平衡的药物包括但不限于：托瑞米芬、依西美坦、来曲唑、比卡鲁胺、恩杂鲁胺、甲羟孕酮、甲地孕酮、丙酸睾丸酮、戈舍瑞林、亮丙瑞林。
所述酪氨酸激酶抑制剂包括但不限于：伊马替尼、吉非替尼、埃罗替尼、索拉菲尼、舒尼替尼、拉帕替尼、阿帕替尼。
所述表皮生长因子受体抑制剂包括但不限于：曲妥珠单抗、帕尼单抗、西妥昔单抗、帕妥珠单抗。
所述血管内皮生长因子受体抑制剂包括但不限于：贝伐单抗、雷莫芦单抗。
所述免疫调节剂包括但不限于：利妥昔单抗、派姆单抗、伊匹单抗。
所述其他治疗手段包括但不限于：放疗、手术切除。
具体实施方式
实施例中使用的化学试剂均为市售化合物，其中
DMF：N,N-二甲基甲酰胺；
HATU：N,N,N',N'-四甲基-O-(7-氮杂苯并三唑-1-基)脲六氟磷酸盐，英文名O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
DIEA：N,N-二异丙基乙胺；
TFAA：三氟乙酸酐
DCM：二氯甲烷
THF：四氢呋喃
Pyridine：吡啶
Pd(PPh3)4：四(三苯基膦)钯
Et：乙基，Ac：乙酰基；如EtOAc为乙酸乙酯或醋酸乙酯，ETOH为乙醇。
中间体合成实施例
2-(4-(2-甲基吡啶-4-基)苯基)乙酸乙酯(I-1)的制备
室温下，2-(4-溴苯基)乙酸乙酯(0.50克,2.06毫摩尔)溶解在20毫升无水THF，然后加入2-甲基-4-(4,4,5,5-甲基1,3,2-二杂氧戊硼烷-2基)吡啶
(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine)(0.45克，2.06毫摩尔)，Pd(PPh3)4(0.58克，0.1毫摩尔)和碳酸铯(1.34克，4.0毫摩尔)。反应混合物通氮气5分钟，然后在75℃搅拌过夜。反应冷却后，用饱和NaHCO3稀释并用EtOAc(3×100毫升)提取。有机层用盐水洗涤，Na2SO4干燥，过滤，并减压下浓缩。硅胶色谱纯化提供0.4克(76％)的I-1。
2-(4-(2-甲基吡啶-4-基)苯基)乙酸(I-2)的制备
室温下，10mL LiOH(0.19克，7.92毫摩尔)水溶液加到20毫升I-1(0.40克，1.57毫摩尔)的THF溶液中。反应混合物搅拌过夜，浓缩。残留物用1N盐酸中和到pH值6，EtOAc(3×100毫升)提取。有机层用盐水洗涤，Na2SO4干燥，过滤，并减压浓缩。硅胶色谱纯化提供0.2克(56％)的I-2。ESIMS发现：m/z 228.0(M+1)。
2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酸(I-3)的制备.
I-3的合成和I-2的合成方法一致。ESIMS发现：m/z 242.4(M+1)。
7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-胺(I-4)的制备
4-甲氧基吡啶-2-胺用O-乙基三异硫氰酸酯处理，得到的中间体用氨水处理得到7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-胺(I-4)，ESIMS发现：m/z 165.3(M+1)。
6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-胺(I-5)的制备
I-5的合成参考了I-4的合成。ESIMS发现：m/z 165.4(M+1)
5-甲氧基吡唑并[1,5-a]吡啶-2-胺(I-6)的制备.
在0℃下，3mL二氯甲烷中，依次加入2,4,6-三甲基苯磺酰羟胺和2-(4-甲氧基吡啶-2-)乙腈，搅拌一小时。除掉溶剂，并加入了10ml的甲醇。在0℃下加入碳酸钾，搅拌1小时，去除溶剂后，用清水清洗残渣，提取到乙酸乙酯中，干燥浓缩。硅胶色谱纯化得到I-6。1H核磁共振(亚砜,400兆赫)：7.98(d,1H,J＝3hz),7.18(d,1H,J＝5hz),6.82(d,1H,J＝5Hz),5.56(s,1H),5.03(s,2H),3.74(s,3H)
7-甲氧基咪唑并[1,2-a]吡啶-2-胺(I-7)的制备
在15mL吡啶中，依次加入1g 2-氨基-4-甲氧基吡啶和1.7g对甲苯磺酰氯，加热到50℃14小时。冷却后，加入30mL水，过滤得到的固体干燥后溶解在DMF中，依次加入0.5g碘乙酰胺和0.4g DIEA，室温搅拌过夜。硅胶柱纯化得到中间体E溶解在20mL二氯甲烷中，加入1mL三氟乙酸酐，回流14小时，冷却后硅胶柱纯化后得中间体F。碱性条件下水解得到中间体I-7。ESIMS发现：m/z 164.4(M+1)。
6-甲氧基咪唑并[1,2-a]吡啶-2-胺(I-8)的制备
I-8的合成和I-7类似。ESIMS：m/z 164.4(M+1)。1H NMR(DMSO,400MHz)：8.04(d,1H,J＝3Hz),7.07(d,1H,J＝5Hz),6.94(s,1H),6.76(d,1H,J＝5Hz),4.90(bs,2H),3.73(s,3H).
实施例1：N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物1)的制备
在0℃下2-(4-(2-甲基吡啶-4-基)苯基)乙酸(I-2)(0.04克,0.18毫摩尔)溶解在2mL无水DMF。然后依次加入7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2胺(I-4)(0.035克，0.21毫摩尔)，HATU(0.074克，0.19毫摩尔)和DIEA(0.068克，0.53毫摩尔)。混合物室温搅拌1小时。用饱和NaHCO3稀释，并提取到EtOAc。有机层用盐水洗两次，Na2SO4干燥，过滤，减压浓缩。硅胶色谱纯化得到12毫克(18％)的化合物1。ESIMS发现：m/z 374.3(M+1)。1H核磁共振(亚砜,400兆赫)：δ10.95(s,1H),8.64(d,1H,J＝5Hz),8.50(d,1H,J＝5Hz),7.77(d,2H,j＝5Hz),7.64(s,1H),7.55(d,1H,j＝5hz),7.47(d,2H,j＝5hz),7.07(d,1H,J＝3hz),6.75(d,1H,J＝5Hz),3.89(s,3H),3.83(s,2H),2.55(s,3H)
实施例2：N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物2)的制备
在0℃下2-(3-甲基,4-(2-甲基吡啶-4基)苯基)乙酸(I-3)(0.06克，0.25毫摩尔)溶解在2mL无水DMF。然后依次加入7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2胺(I-4)(0.049克，0.30毫摩尔)，HATU(0.104克，0.27毫摩尔)和DIEA(0.097克，0.75毫摩尔)。混合物室温搅拌1小时。用饱和NaHCO3稀释，并提取到EtOAc。有机层用盐水洗两次,Na2SO4干燥，过滤，减压浓缩。硅胶色谱纯化得到18毫克(19％)化合物2。ESIMS发现：m/z 388.2(M+1)。1H核磁共振(亚砜,400兆赫)：δ10.93(s,1H),8.64(d,1H,J＝5Hz),8.57(d,1H,J＝3Hz),7.45(s,1H),7.38(s,1H),7.30(m,3H),7.07(d,1H,J＝3hz),6.75(d,1H,J＝5hz),3.89(s,3H),3.78(s,2H),2.58(s,3H),2.33(s,3H)。
实施例3：N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物3)的制备
化合物3的制备同化合物1。ESIMS发现：m/z 373.3(M+1)。
实施例4：N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物4)的制备
化合物4的制备同化合物1。ESIMS发现：m/z 374.0(M+1)。
实施例5：N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物5)的制备
化合物5的制备同化合物1。ESIMS发现：m/z 388.5(M+1).1H NMR(二甲亚枫,400MHz)：δ10.92(s,1H),8.61(s,1H),8.49(d,1H,J＝3Hz),7.60(d,1H,J＝5Hz),7.40(d,1H,J＝5Hz),7.26(m,3H),7.19(d,2H,J＝5Hz),3.85(s,3H),3.79(s,2H),2.52(s,3H),2.25(s,3H)。
实施例6：N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物6)的制备
化合物6的制备同化合物1。ESIMS发现：m/z 387.3(M+1).1H NMR(二甲亚枫,400MHz)：δ10.92(s,1H),8.47(d,1H,J＝3Hz),8.20(s,1H),7.49(d,1H,J＝5Hz),7.16–7.49(m,5H),7.01(d,1H,J＝3Hz),6.76(s,1H),3.81(s,3H),3.71(s,2H),2.51(s,3H),2.25(s,3H)。
实施例7：N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物7)的制备
化合物7的制备同化合物1。ESIMS发现：m/z 387.3(M+1).1H NMR(二甲亚枫,400MHz)：δ10.87(s,1H),8.48(s,1H),8.27(d,1H,J＝3Hz),8.00(s,1H),7.25–7.35(m,3H),7.18(d,2H,J＝5Hz),6.98(d,1H,J＝5Hz),3.76(s,3H),3.70(s,2H),2.52(s,3H),2.25(s,3H)。
实施例8：N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物8)的制备
化合物8的制备同化合物1。ESIMS发现：m/z 373.0(M+1).1H NMR(二甲亚枫,400MHz)：δ10.91(s,1H),8.48(s,1H),8.27(S,1H),8.01(s,1H),7.73(d,2H,J＝5Hz),7.32–7.56(m,4H),6.97(d,1H,J＝7.5Hz),3.76(s,5H),2.52(s,3H)。
实施例9：N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物9)的制备
化合物9的制备同化合物1。ESIMS发现：m/z 373.1(M+1).1H NMR(二甲亚枫,400MHz)：δ10.92(s,1H),8.49(d,1H,J＝3Hz),8.38(d,1H,J＝5Hz),7.75(d,2H,J＝5Hz),7.60(s,1H),7.52(d,1H,J＝3Hz),7.40(d,1H,J＝5Hz),7.12(d,1H,J＝3Hz),6.63(d,1H,J＝5Hz),6.48(s,2H),4.25(s,2H),3.91(s,3H),2.52(s,3H)。
实施例10：N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物10)的制备
化合物10的制备同化合物1。ESIMS发现：m/z 387.4(M+1).1H NMR(二甲亚枫,400MHz)：δ10.92(s,1H),8.47(d,1H,J＝3Hz),8.38(d,1H,J＝5Hz),7.13–7.24(m,5H),6.63(d,1H,J＝5Hz),6.48(s,2H),4.19(s,2H),3.91(s,3H),2.52(s,3H),2.24(s,3H)。
中间体化合物制备
(4-(2-甲基吡啶-4-基)苯基)甲胺(I-9)的制备
室温下(4-溴苯基)甲胺(0.74克,4.0毫摩尔)溶解在40毫升无水THF中。依次加入2-甲基-4-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶(0.90克，4.0毫摩尔)，Pd(PPh3)4(0.95克，1.0毫摩尔)和碳酸铯(2.68克，8.0毫摩尔)。反应混合物氮气下脱氧5分钟，氮气保护下加热到75℃搅拌过夜。反应冷却后，饱和NaHCO3稀释并提取成到EtOAc(3×100毫升)。有机层用盐水洗涤,Na2SO4干燥，过滤，减压浓缩。硅胶色谱纯化得到0.4克(49％)的I-9。ESIMS发现：m/z 199.2(M+1)。
(3-甲基-4-(2-甲基吡啶-4-基)苯基)甲胺(I-10)的制备
室温下(4-溴-3-甲基苯基)甲胺(1.00克，5.0毫摩尔)溶解在无水THF中，依次加入2-甲基-4-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶(1.10克，5.0毫摩尔)，Pd(PPh3)4(1.16克,1.0毫摩尔)和碳酸铯(3.26克,10.0毫摩尔)。反应混合物氮气下脱氧5分钟，氮气保护下加热到75℃搅拌过夜。反应冷却后，饱和NaHCO3稀释并提取成到EtOAc(3×100毫升)。有机层用盐水洗涤，Na2SO4干燥，过滤，减压浓缩。硅胶色谱纯化得到0.45克(42％)的I-10。ESIMS发现：m/z 213.0(M+1)。
7-乙酰基咪唑并[1,2-a]吡啶-2-羧酸(I-11)的制备
4-乙酰基-2-氨基吡啶(1.2克，9.0毫摩尔)溶解在无水四氢呋喃(60毫升)中，慢慢滴加3-溴-2-氧代丙酸乙酯(2.5克，13.0毫摩尔)。产生的悬浊液回流加热6小时，冷却到室温，过滤干燥得到粗产物。酯(0.5克，2.0毫摩尔)溶解在THF(10毫升)。然后滴加氢氧化锂(0.5g，22.0毫摩尔)水溶液(10毫升)。室温搅拌过夜，浓缩。残渣酸化至pH 5。固体过滤收集，然后干燥，得到I-11。1H核磁共振(亚砜,400兆赫)：8.60(d,1H,J＝5Hz),8.46(s,1H),8.30(s,1H),7.36(d,1H,J＝3Hz),2.65(s,3H)。
7-甲氧基咪唑并[1,2-a]吡啶-2-羧酸(I-12)的制备
I-12的制备同I-11。ESIMS发现：m/z 193.2(M+1)。
7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-羧酸(I-13)的制备
冷却2,4,6-三甲基苯磺酰羟胺(0.87g，4mmol)的二氯甲烷溶液到0℃。然后分批慢慢加入4-甲氧基吡啶-2-胺(0.5g，4mmol)。1小时后，用乙醚稀释悬浮液，过滤收集，用乙醚清洗干燥。然后将0.5g的白色固体与2-氯-2-氧乙酸乙酯混合在吡啶中，在100℃加热18h。冷却后加入饱和碳酸钾(sat.)溶液，搅拌2小时。过滤收集固体，然后用水清洗干燥，得到产品0.3g。然后碱性条件下水解，得到中间体I-13。ESIMS发现：m/z 194.1(M+1)。6-甲氧基咪唑并[1,2-a]吡啶-2-羧酸(I-14)的制备
I-14的制备同I-11。ESIMS发现：m/z 193.2(M+1).。
6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-羧酸(I-15)的制备
I-15的制备同I-13。ESIMS发现：m/z 194.1(M+1)。
6-氰基咪唑并[1,2-a]吡啶-2-羧酸(I-16)的制备
I-16的制备同I-11。ESIMS发现：m/z 188.2(M+1)。
7-氰基咪唑并[1,2-a]吡啶-2-羧酸(I-17)的制备
I-17的制备同I-11。ESIMS发现：m/z 188.2(M+1)。
实施例11：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物11)的制备
由I-10与上式化合物反应制备得到化合物11，其制备方法操作步骤类似化合物1的制备方法。ESIMS发现：m/z 387.0(M+1).1H核磁共振(亚砜,400兆赫)：8.74(s,1H),8.47(m,2H),8.20(s,1H),7.16-7.28(m,4H),6.86(d,1H,J＝3hz),6.70(d,1H J＝5hz),4.48(d,2H,J＝3Hz),3.86(s,3H),2.52(s,3H),2.23(s,3H)。
实施例12：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺(化合物12)的制备
化合物12的制备同化合物1。ESIMS发现：m/z 388.2(M+1).1H核磁共振(亚砜,400兆赫)：9.26(t,1H,J＝3hz),8.83(d,1H,J＝5hz),8.47(s,1H),7.15-7.29(m,5H),6.97(d,1H,J＝5hz),4.49(d,2H,J＝5hz),3.93(s,3H),2.52(s,3H),2.24(s,3H)。
实施例13：N-(4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺(化合物13)的制备
化合物13的制备同化合物1。ESIMS找到：m/z 373.4(M+1).1H核磁共振(亚砜,400兆赫)：9.31(t,1H,J＝3hz),8.83(d,1H,J＝3hz),8.48(s,1H),7.75(d,2H,J＝5Hz),7.58(s,1H),7.47(m,3H),7.22(s,1H),6.97(d,1H,J＝5Hz),4.54(d,2H,J＝3hz),3.94(s,3H),2.53(s,3H)。
实施例14：N-(4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物14)的制备
化合物14的制备同化合物1。ESIMS发现：m/z 373.2(M+1).1H核磁共振(亚砜,400兆赫)：8.92(t,1H,J＝3Hz),8.47(d,1H,J＝5Hz),8.28(d,2H J＝5hz),7.73(d,2H,J＝5hz),7.47(m,4H),7.13(d,1H,J＝3hz),4.51(d,2H,J＝3hz),3.81(s,3H),2.52(s,3H)。
实施例15：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物15)的制备
化合物15的制备同化合物1。ESIMS找到：m/z 387.2(M+1).1H核磁共振(CDCl3,400兆赫)：8.51(d,1H,J＝3Hz),8.13(s,1H),7.65(d,1H J＝5Hz),7.64(s,1H),7.42(d,1H,J＝5hz),7.28(d,1H,J＝3hz),7.15(d,1H,J＝5hz),7.03(m,3H),4.66(d,2H,J＝5Hz),3.84(s,3H),2.60(s,3H),2.25(s,3H)。
实施例16：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺(化合物16)的制备
化合物16的制备同化合物1。ESIMS找到：m/z 388.4(M+1).1H核磁共振(亚砜,400兆赫)：9.29(t,1H,J＝3Hz),8.72(d,1H,J＝3hz),8.47(d,1H,J＝3hz),7.82(d,2H,J＝5hz),7.54(d,1H,J＝5Hz),7.20(m,4H),4.50(d,2H,J＝3Hz),3.90(s,3H),2.51(s,3H),2.24(s,3H)。
实施例17：N-(4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺(化合物17)的制备
化合物17的制备同化合物1。ESIMS发现：m/z 374.3(M+1).1H核磁共振(亚砜,400兆赫)：9.34(t,1H,J＝3 Hz),8.72(d,1H,J＝3 hz),8.48(d,1H,J＝3 hz),7.82(d,2H,J＝5hz),7.75(d,2H,J＝5 Hz),7.48(m,4H),4.54(d,2H,J＝5 Hz),3.90(s,3H),2.52(s,3H)。
实施例18：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物18)的制备
化合物18的制备同化合物1。ESIMS找到：m/z 399.2(M+1).1H核磁共振(CDCl3,400兆赫)：8.85(s,1H),8.51(d,1H,J＝5 Hz),8.29(s,1H),7.79(d,1H,J＝5 Hz),7.74(s,1H),7.57(d,1H,J＝5 hz),7.30(d,1H,J＝3 hz),7.16(d,1H,J＝5 hz),7.03(m,2H),4.68(d,2H,J＝5 Hz),2.65(s,3H),2.61(s,3H),2.26(s,3H)。
实施例19：N-(4-(2-甲基吡啶-4-基)苯甲基)-6-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物19)的制备
化合物19的制备同化合物1。ESIMS找到：m/z 384.4(M+1).1H核磁共振(CDCl3,400兆赫)：8.87(s,1H),8.53(d,1H,J＝3 Hz),8.30(s,1H),7.79(d,1H,J＝5 Hz),7.40-7.62(m,5H),7.35(s,1H),7.29(d,1H,J＝3 hz),4.73(d,2H,J＝3 hz),2.65(s,3H),2.62(s,3H)。
实施例20：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物20)的制备
化合物20的制备同化合物1。ESIMS找到：m/z 382.3(M+1).1H核磁共振(CDCl3,400兆赫)：8.64(s,1H),8.52(d,1H,J＝3Hz),8.28(s,1H),7.68(s,1H),7.64(d,1H,J＝5hz),7.35(d,1H,J＝5hz),7.29(m,1H),7.17(d,1H J＝5Hz),7.10(s,1H),7.04(d,1H,J＝5hz),4.68(d,2H,J＝5Hz),2.61(s,3H),2.26(s,3H)。
实施例21：N-(4-(2-甲基吡啶-4-基)苯甲基)-6-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物21)的制备
化合物21的制备同化合物1。ESIMS发现：m/z 368.1(M+1).1H核磁共振(亚砜,400兆赫)：9.39(s,1H),9.18(t,1H,J＝5Hz),8.45(m,2H),7.75(m,3H),7.61(d,1H,J＝5Hz),7.56(s,1H),7.45(d,2H,J＝5hz),4.53(d,2H,J＝5hz),3.17(s,3H)。
2-(4-(2-甲基吡啶)-3-甲基吡啶)-乙酸(I-18)的制备.
I-18的合成和I-2的合成方法一致。ESIMS发现：m/z 243.2(M+1)。
实施例22：2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)乙酰胺(化合物22)的制备
化合物22的制备同化合物1。ESIMS发现：m/z 389.0(M+1).
实施例23：N-(4-(2-甲基吡啶-4-基)苯甲基)-7-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物23)的制备
化合物23的制备同化合物1。ESIMS找到：m/z 368.2(M+1).1H核磁共振(亚砜,400兆赫)：9.22(t,1H,J＝3Hz),8.75(d,1H,J＝5Hz),8.59(s,1H),8.49(d,1H,J＝3Hz),8.41(s,1H),7.73(d,2H,J＝5Hz),7.57(s,1H),7.46(m,2H),7.30(d,1H,J＝3Hz),4.53(d,2H,J＝5hz),3.17(d,3H,J＝3hz)。
实施例24 2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)乙酰胺(化合物24)的制备
化合物24的制备同化合物1。ESIMS找到：m/z 389.4(M+1)。
实施例25：2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)乙酰胺(化合物25)的制备
化合物25的制备同化合物1。ESIMS找到：m/z 388.3(M+1).1H核磁共振(亚砜,400兆赫)：8.52(d,1H,J＝5Hz),8.33(m,2H),8.58(s,1H),7.51(s,1H),7.45(s,1H),7.12(d,1H,J＝3hz),6.59(d,1H,J＝5hz),6.38(bs,2H),4.22(s,2H),3.86(s,3H),2.52(s,3H)。
实施例26：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物26)的制备
化合物26的制备同化合物1。ESIMS找到：m/z 382.3(M+1).1H核磁共振(CDCl3,400兆赫)：8.65(d,1H,J＝5Hz),8.31(s,1H),8.27(d,1H,J＝3Hz),7.98(s,1H),7.77(s,1H),7.29(m,3H),7.18(d,1H J＝5Hz),7.01(d,1H,J＝5hz),4.70(d,2H,J＝3Hz),2.72(s,3H),2.26(s,3H)。
实施例27：2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)乙酰胺(化合物27)的制备
化合物27的制备同化合物1。ESIMS找到：m/z 388.0(M+1).1H核磁共振(CDCl3,400兆赫)：11.01(s,1H),8.60(m,1H),8.25(s,1H),7.70(s,1H),7.62(d,1H,J＝3Hz),7.33(m,3H),7.07(d,1H,J＝5Hz),3.90(s,3H),3.80(s,2H),2.64(s,3H),2.36(s,3H)。
实施例28：N-(4-(2-甲基吡啶-4-基)苯基甲基)-7-乙酰基-咪唑[1,2-a]吡啶-2-甲酰胺(化合物28)的制备
化合物28的制备同化合物1。ESIMS找到：m/z 388.0(M+1).1H核磁共振(亚砜,400兆赫)：9.09(t,1H,J＝3Hz),8.65(d,1H,J＝5Hz),8.56(s,1H),8.50(d,1H,J＝3Hz),8.27(s,1H),7.76(d,2H,J＝5Hz),7.62(s,1H),7.53(d,1H,J＝3Hz),7.48(d,1H,J＝5hz),7.40(d,1H,J＝5hz),4.55(d,2H,J＝5hz),2.67(s,3H),2.54(s,3H)。
实施例29：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物29)的制备
化合物29的制备同化合物1。ESIMS找到：m/z 398.0(M+1).1H核磁共振(亚砜,400兆赫)：9.03(t,1H,J＝3Hz),8.65(d,1H,J＝5Hz),8.56(s,1H),8.52(d,1H,J＝3Hz),8.27(s,1H),7.40(d,1H,J＝5Hz),7.31(m,4H),4.51(d,2H,J＝5Hz),2.67(s,3H),2.55(s,3H),2.25(s,3H)。
5-甲氧基吡唑[1,5-a]吡啶-2-甲酸(I-19)的制备
在3mL二氯甲烷中加入4-甲氧基吡啶(0.51克，5mmol)，在0℃下加入2,4,6-三甲基苯磺酰羟胺(1g，5mmol)。搅拌1小时。去除溶剂，并添加5ml DMSO。将反应液冷却至0℃后慢慢加入K2CO3。然后滴加丁炔二酸二乙酯(0.66g，5mmol)。由此产生的红色悬浮物在通入空气的情况下强烈搅拌3个小时。用冰水稀释，提取到乙酸乙酯中。有机相用盐水清洗，干燥，浓缩得到粗产品。然后加入5mL硫酸/水(1:1)加热到80℃ 3小时。用冰水冷却后，30％的NaOH中和后，用1N HCl酸化至pH 2～3。过滤和干燥得到固体酯。酯在LiOH中水解，得到中间体I-19。ESIMS发现：m/z 193.2(M+1)。
6-甲氧基吡唑并[1,5-a]吡啶-2-羧酸(I-20)的制备
I-20的合成和I-19的合成方法一致。ESIMS发现：m/z 193.2(M+1)。
7-(三氟甲基)吡唑并[1,5-a]吡啶-2-羧酸(I-21)的制备
I-21的合成和I-19的合成方法一致。ESIMS发现：m/z 231.2(M+1)。
5-(三氟甲基)咪唑并[1,2-a]吡啶-2-羧酸(I-22)的制备
I-22的合成和I-16的合成方法一致。ESIMS发现：m/z 231.2(M+1)。
实施例30：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-5-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺(化合物30)的制备
化合物30的制备同化合物1。ESIMS找到：m/z 387.0(M+1)。1H核磁共振(亚砜,400兆赫)：8.93(t,1H,J＝3hz),8.52(d,1H,J＝5hz),8.47(d,1H,J＝3hz),7.11-7 28(m,6H),6.80(s,1H),6.72(dd,1H,J＝5hz),4.47(d,2H,J＝5hz),3.85(s,3H),2.67(s,3H),2.52(s,3H),2.23(s,3H)。
实施例31：N-(4-(2-甲基吡啶-4-基)苯甲基)-5-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺(化合物31)的制备
化合物31的制备同化合物1。ESIMS发现：m/z 373.0(M+1)。1H核磁共振(亚砜,400兆赫)：8.97(t,1H,J＝3Hz),8.52(d,1H,J＝5hz),8.47(d,1H,J＝5hz),7.74(d,2H,J＝5hz),7.48(m,4H),7.11(d,1H,J＝3Hz),6.80(s,1H),6.70(d,1H,J＝5Hz),4.52(d,2H,J＝3Hz),3.85(s,3H),2.52(s,3H)。
实施例32：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-(三氟甲基)吡唑并[1,5-a]吡啶-2-甲酰胺(化合物32)的制备
化合物32的制备同化合物1。ESIMS发现：m/z 425.4(M+1)。1H核磁共振(CDCl3,400兆赫)：8.62(d,1H,J＝5hz),7.83(d,1H,J＝8Hz),7.69(m,2H),7.37(m,2H),7.28(m,3H),4.74(d,2H,J＝5Hz),2.96(s,3H),2.35(s,3H)。
实施例33：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-4-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺(化合物33)的制备
化合物33的制备同化合物1。ESIMS发现：m/z 387.0(M+1)。1H核磁共振(亚砜,400兆赫)：9.02(t,1H,J＝3Hz),8.47(d,1H,J＝5hz),8.31(d,1H,J＝5Hz),7.22(m,4H),6.98(m,3H),6.71(d,1H,J＝5hz),4.48(d,2H,J＝3Hz),3.97(s,3H),2.52(s,3H),2.23(s,3H)。
实施例34：N-(4-(2-甲基吡啶-4-基)苯甲基)-4-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺(化合物34)的制备
化合物34的制备同化合物1。ESIMS发现：m/z 372.7(M+1)。1H核磁共振(亚砜,400兆赫)：9.06(t,1H,J＝3Hz),8.47(d,1H,J＝5hz),8.31(d,1H,J＝5Hz),7.74(d,2H,J＝5Hz),7.56(s,1H),7.46(m,3H),6.98(m,2H),6.72(d,1H,J＝3Hz),4.52(d,2H,J＝3Hz),3.97(s,3H),2.52(s,3H)。
实施例35：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-5-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酰胺(化合物35)的制备
化合物35的制备同化合物1。ESIMS发现：m/z 425.0(M+1)。1H核磁共振(亚砜,400兆赫)：9.16(t,1H,J＝3Hz),8.46(d,1H,J＝5hz),8.31(d,1H,J＝5hz),7.99(d,1H,J＝7hz),7.69(d,1H,J＝5Hz),7.54(m,1H),7.22(m,5H),4.52(d,2H,J＝3Hz),2.52(s,3H),2.23(s,3H)。
实施例36：N-(4-(2-甲基吡啶-4-基)苯甲基)-5-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酰胺(化合物36)的制备
化合物36的制备同化合物1。ESIMS发现：m/z 411.1(M+1)。1H核磁共振(亚砜,400兆赫)：9.21(t,1H,J＝3Hz),8.47(d,1H,J＝5Hz),8.31(s,1H),8.00(d,1H,J＝75hz),7.74(d,2H,J＝5hz),7.69(d,1H,J＝5hz),7.54(m,5H),4.55(d,2H,J＝3Hz),2.52(s,3H)。
生物学活性试验
WNT通路活性研究
为证实本发明化合物对WNT通路活性是否有抑制作用，选择荧光素酶报告基因系统完成检测。以下实验采用L-Wnt3a细胞和HEK293/STF细胞共培养，其中L-Wnt3a细胞是WNT蛋白生成细胞，HEK293/STF细胞为WNT蛋白响应细胞。
经典的WNT信号通路需要β-catenin入核，进而与转录因子TCF/LEF结合形成复合物，共同起始下游调控基因的转录。HEK293/STF细胞株携带SuperTopflash(STF)报告基因(在报告基因中7个LEF/TCF串联DNA结合位点驱动萤火虫荧光素酶表达)，能够在Wnt/Norrin信号诱导下表达荧光素酶，因此可以通过检测荧光素酶表达水平方便地检测Wnt/Norrin-β-catenin信号通路的活化程度。
材料和方法：
依据用户手册，人胚胎肾脏293细胞(HEK293)(美国培养收集,ATCC,Mansassas,VA)，共转染STF-reporter 5-8xTCF/Lef-luc plus pcDNA3.1-Neo(Invitrogen,Carlsbad,CA)以及FuGENE6(Roche Diagnostics,Indianapolis,IL)。HEK293/STF细胞系于加有10％FBS(Hyclone)、50unit/ml青霉素、50ug/ml链霉素(Invitrogen,Carlsbad,CA)的Dulbecco’s modified Eagle’s完全培养基(DMEM)(Gibco/Invitrogen,Carlsbad,CA)中，在37摄氏度，5％CO2下，经G418筛选，获得稳定细胞系。为验证WNT信号通路的作用，HEK293/STF稳定细胞系与L-Wnt3a细胞(
CRL-2647TM)以1：1比例混合，在37摄氏度，5％CO2条件下，于96孔板中共培养(20K+20K)过夜。化合物用DMEM培养基稀释成不同浓度，与新鲜培养基一同以100ul/孔更换培养过夜的培养基，细胞在化合物处理下培养24小时。按50ul/孔从细胞培养板中取出培养基，加入50ul/孔的Bright-Glo试剂(Bright-Glo荧光素酶检测试剂盒，Promega，Madison，WI)，混匀60秒并常温避光孵育10分钟。在Envision上读板，剂量反应的IC50值由GraphPad Prism 6软件计算获得。
测试化合物以及它们的IC50值。
| 化合物 | IC50(nM) |
| 6 | 56.02 |
| 7 | 1.45 |
| 8 | 10.78 |
| 15 | 39.79 |
| 18 | 16.21 |
| 27 | 25.53 |
根据所示结果，共培养L-Wnt3a细胞诱导的STF报告基因活性会被化合物所抑制，这一现象不出现在单独培养的HEK293/STF细胞中，提示所述化合物具有抑制WNT信号通路的活性，且抑制作用发生在L-Wnt3a和受体作用的上游。
抑制作用与细胞死亡无关：
为证实STF报告分子的抑制作用并非源于细胞死亡，化合物使用CellTiter-Glo(CTG)(Promega,Madison,WI)进行测试。CTG实验采用HEK293/STF细胞与L-Wnt 3a细胞共培养，培养方法如上所述。实验中，直接加入50ul/孔CTG试剂，混匀60秒并常温避光孵育10分钟。用Envision读板。STSP(星形孢菌素，staurosporine)作为本实验参照化合物使用。实验使用Evision读板系统监测，重复样本的值用均数±标准误表示。剂量反应的IC50值由GraphPad Prism 6计算获得。结果显示，化合物浓度在10-11～10-6mol/L逐渐上升过程中，STSP处理的细胞存活率由100％逐渐降至80％，而测试的本发明化合物处理的细胞存活率能够保持在100％～120％之间，说明测试的本发明化合物对WNT信号通路的抑制作用与细胞死亡无关。
Claims (12)
1.一种结构式I的化合物，或药学上可接受的盐，
式Ia结构化合物
式Ib结构化合物：
式Ic结构化合物：
式IIa结构化合物
式IIb结构化合物
或，式IIc结构化合物
其中，R1，R2分别代表H，F，Cl，Br，C1-C3烷基，C1-C3烷氧基，C1-C3亚烷基羟基；R3，R4，R’3，R’4可在所在环的任意取代位置，其中R3，R4，R’3，R’4独立代表H，F，Cl，Br，I，CN，C1-C6烷基，取代的C1-C6烷基，OR5，COR5；
R5代表H，C1-C6烷基，C2-C4亚烷基羟基；
所述“取代的”表示所述基团进一步被F所取代；
X1为C，Y1为C或N，Z1为C；
A选自下列结构式代表的芳基或杂芳基，
其中R3，R4在所连接环的任意可取代位置，R3，R4的定义和上述相同。
2.如权利要求1所述化合物，或药学上可接受的盐，其中，
R1，R2分别代表H；
R3，R4可在所在环的任意取代位置，独立代表H，F，C1-C6烷基，OR5，COR5；
R’3，R’4可在所在环的任意取代位置，独立代表H，C1-C6烷基；
R5代表H，C1-C6烷基；
X1为C，Y1为N，Z1为C。
3.如权利要求1或2所述化合物，或药学上可接受的盐，其中，选自式Ia结构化合物
式Ic结构化合物：
式IIa结构化合物
或，式IIc结构化合物
A为
4.如权利要求1或2所述化合物，或药学上可接受的盐，所述化合物选自：
5.如权利要求1或2所述化合物，或药学上可接受的盐，所述化合物选自：
N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)乙酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-7-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)乙酰胺、
2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)乙酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)乙酰胺、
N-(4-(2-甲基吡啶-4-基)苯基甲基)-7-乙酰基-咪唑[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-5-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-5-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-(三氟甲基)吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-4-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-4-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-5-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酰胺，或
N-(4-(2-甲基吡啶-4-基)苯甲基)-5-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酰胺。
6.权利要求1-5任一项所述的式I化合物或其药学上可接受的盐在制备治疗WNT信号通路相关疾病的药物中的用途。
7.如权利要求6所述的用途，其特征在于，所述WNT信号通路相关疾病选自肿瘤、畸形综合症、骨或软骨疾病、糖尿病或其并发症、组织纤维化。
8.如权利要求7所述的用途，其特征在于，所述骨或软骨疾病选自：骨质疏松症、骨关节炎、骨软骨病；所述糖尿病或其并发症选自：II型糖尿病、糖尿病性视网膜病变、糖尿病性肾病、糖尿病性脑血管病；所述肿瘤选自：结肠直肠癌、结肠癌、胃癌、食道癌、骨肉瘤、乳腺癌、宫颈鳞状细胞癌、子宫内膜癌、间皮瘤、胰腺癌、膀胱癌、前列腺癌、肺癌、肝细胞癌、髓母细胞瘤、肝母细胞瘤、胃肠类癌、卵巢癌、黑色素瘤、头颈部鳞状细胞癌、甲状腺癌、肾母细胞瘤、视网膜母细胞瘤、胶质瘤，白血病；所述组织纤维化选自：肺纤维化、肝纤维化、肾纤维化、骨髓纤维化。
9.一种药物组合物，其包含权利要求1-5任一项所述的式I化合物或其药学上可接受的盐。
10.如权利要求9所述的药物组合物，其特征在于，所述药物组合物进一步含有药学上可接受的载体。
11.如权利要求9或10所述的药物组合物，其特征在于，进一步含有第二种治疗剂，所述第二种治疗剂是其他的治疗WNT信号通路相关疾病的药物。
12.如权利要求11所述的药物组合物，其特征在于，所述第二种治疗剂选自氮芥、环磷酰胺、顺铂、卡铂、奥沙利铂、5-氟尿嘧啶、卡培他滨、雷替曲塞、6-巯嘌呤、阿糖胞苷、吉西他滨、氨甲喋呤、培美曲塞、羟基脲、阿霉素、柔红霉素、表柔比星、吡柔比星、羟喜树碱、伊立替康、拓扑替康、长春新碱、长春地辛、长春瑞滨、紫杉醇、多西紫杉醇、托瑞米芬、依西美坦、来曲唑、比卡鲁胺、恩杂鲁胺、甲羟孕酮、甲地孕酮、丙酸睾丸酮、戈舍瑞林、亮丙瑞林、伊马替尼、吉非替尼、埃罗替尼、索拉菲尼、舒尼替尼、拉帕替尼、阿帕替尼、曲妥珠单抗、帕尼单抗、西妥昔单抗、帕妥珠单抗、贝伐单抗、雷莫芦单抗、利妥昔单抗、派姆单抗、伊匹单抗。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811573629.XA CN111349093B (zh) | 2018-12-21 | 2018-12-21 | 5,6-双环化合物作为wnt信号通路抑制剂及其医学应用 |
| PCT/CN2019/127056 WO2020125759A1 (zh) | 2018-12-21 | 2019-12-20 | 作为wnt信号通路抑制剂的化合物及其医学应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811573629.XA CN111349093B (zh) | 2018-12-21 | 2018-12-21 | 5,6-双环化合物作为wnt信号通路抑制剂及其医学应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111349093A CN111349093A (zh) | 2020-06-30 |
| CN111349093B true CN111349093B (zh) | 2021-07-02 |
Family
ID=71195161
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811573629.XA Active CN111349093B (zh) | 2018-12-21 | 2018-12-21 | 5,6-双环化合物作为wnt信号通路抑制剂及其医学应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111349093B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW202321244A (zh) * | 2021-07-26 | 2023-06-01 | 大陸商杭州阿諾生物醫藥科技有限公司 | 一種Ｗｎｔ通路抑制劑化合物 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012084971A1 (fr) * | 2010-12-20 | 2012-06-28 | Centre National De La Recherche Scientifique (Cnrs) | Derives d'indoles en tant qu'agents contre des bacteries a gram negatif et positif |
| CN102731379A (zh) * | 2009-03-02 | 2012-10-17 | Irm责任有限公司 | 用作wnt信号调节剂的n-(杂)芳基、2-(杂)芳基取代的乙酰胺类 |
| CN106795157A (zh) * | 2014-10-08 | 2017-05-31 | 莱德克斯制药公共有限公司 | 作为Wnt信号传送途径的抑制剂的N‑吡啶基乙酰胺衍生物 |
-
2018
- 2018-12-21 CN CN201811573629.XA patent/CN111349093B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731379A (zh) * | 2009-03-02 | 2012-10-17 | Irm责任有限公司 | 用作wnt信号调节剂的n-(杂)芳基、2-(杂)芳基取代的乙酰胺类 |
| WO2012084971A1 (fr) * | 2010-12-20 | 2012-06-28 | Centre National De La Recherche Scientifique (Cnrs) | Derives d'indoles en tant qu'agents contre des bacteries a gram negatif et positif |
| CN106795157A (zh) * | 2014-10-08 | 2017-05-31 | 莱德克斯制药公共有限公司 | 作为Wnt信号传送途径的抑制剂的N‑吡啶基乙酰胺衍生物 |
Non-Patent Citations (2)
| Title |
|---|
| "2-Aminobenzimidazole conjugates of NSAIDS: novel compounds with immunomodulatory, anti-inflammatory and antioxidant actions";Yogita Bansal et al.;《Med Chem Res》;20151231;第24卷;第1170-1179页 * |
| "STN检索报告1";来源于Aurora Fine Chemicals等公开的产品目录;《数据库Registry（在线）》;20160504;CAS号1903658-8等 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111349093A (zh) | 2020-06-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109311871B (zh) | 作为bcl-2抑制剂的n-(苯基磺酰基)苯甲酰胺及相关化合物 | |
| CA2828478C (en) | Serine/threonine kinase inhibitors | |
| CN106922146B (zh) | 用于治疗由布鲁顿酪氨酸激酶(btk)介导的疾病的吡唑甲酰胺化合物 | |
| US20070049603A1 (en) | Raf inhibitor compounds and methods of use thereof | |
| CA3046339A1 (en) | Amino-triazolopyridine compounds and their use in treating cancer | |
| AU2016272057B2 (en) | Use of pteridinone derivative serving as EGFR inhibitor | |
| CN110698481A (zh) | 杂芳基吡啶酮和氮杂-吡啶酮酰胺化合物 | |
| WO2020125759A1 (zh) | 作为wnt信号通路抑制剂的化合物及其医学应用 | |
| CN112585119A (zh) | 经取代的吲哚及其使用方法 | |
| EP2057168A2 (en) | Raf inhibitor compounds and methods of use thereof | |
| CN107531683B (zh) | Usp7抑制剂化合物及使用方法 | |
| AU2020342189A1 (en) | 3, 5-disubstituted pyrazole compounds as kinase inhibitors and uses thereof | |
| JP2022532195A (ja) | ユビキチン特異的プロテアーゼ阻害剤及びその製造方法と応用 | |
| CN112707905A (zh) | 一种三并杂环化合物及其制备方法和用途 | |
| CN111349093B (zh) | 5,6-双环化合物作为wnt信号通路抑制剂及其医学应用 | |
| CN112300173B (zh) | 一类含氮多环类化合物、制备方法和用途 | |
| CN112601734A (zh) | 肟基萘醌类化合物及其制备方法和用途 | |
| CN111620874B (zh) | 取代5,6-双杂环氨基化合物作为wnt信号通路抑制剂及其治疗应用 | |
| JP2020514260A (ja) | がんの治療における使用のためのオキサゾール誘導体 | |
| CN114026097A (zh) | 取代的吡唑并喹唑啉酮化合物及其应用 | |
| JP2023168298A (ja) | 化合物及びその使用 | |
| WO2009151599A1 (en) | Substituted pyrroles 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 | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20231222 Address after: 266000 13th floor, block a, building 1, Huizhi Park, Zhongke Qingdao R & D City, No. 378 Hedong Road, high tech Zone, Qingdao, Shandong Patentee after: Hanyuan Pharmaceutical Co.,Ltd. Address before: Room 101, 18-1 Hong Kong Road, Weihai Economic and Technological Development Zone, Shandong Province, 264200 Patentee before: Huihan Medical Technology Co.,Ltd. |
|
| TR01 | Transfer of patent right |