WO2022089514A1 - 多环类生物调节剂、其制备方法和应用 - Google Patents
多环类生物调节剂、其制备方法和应用 Download PDFInfo
- Publication number
- WO2022089514A1 WO2022089514A1 PCT/CN2021/126948 CN2021126948W WO2022089514A1 WO 2022089514 A1 WO2022089514 A1 WO 2022089514A1 CN 2021126948 W CN2021126948 W CN 2021126948W WO 2022089514 A1 WO2022089514 A1 WO 2022089514A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- membered
- alkoxy
- haloalkyl
- hydroxyalkyl
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title abstract description 424
- 125000003367 polycyclic group Chemical group 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 120
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 201000011510 cancer Diseases 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 353
- -1 amino, hydroxyl Chemical group 0.000 claims description 329
- 125000000623 heterocyclic group Chemical group 0.000 claims description 212
- 125000003545 alkoxy group Chemical group 0.000 claims description 203
- 229910052736 halogen Inorganic materials 0.000 claims description 142
- 150000002367 halogens Chemical class 0.000 claims description 142
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 140
- 229910052805 deuterium Inorganic materials 0.000 claims description 140
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 136
- 125000003118 aryl group Chemical group 0.000 claims description 119
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 117
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 108
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 106
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 106
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 103
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 103
- 229910052739 hydrogen Inorganic materials 0.000 claims description 101
- 239000001257 hydrogen Substances 0.000 claims description 101
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 100
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 100
- 150000002431 hydrogen Chemical class 0.000 claims description 89
- 238000006243 chemical reaction Methods 0.000 claims description 76
- 125000001424 substituent group Chemical group 0.000 claims description 74
- 229910020008 S(O) Inorganic materials 0.000 claims description 72
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 65
- 125000003342 alkenyl group Chemical group 0.000 claims description 62
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 60
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 59
- 125000000304 alkynyl group Chemical group 0.000 claims description 56
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 54
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 52
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 50
- 125000004043 oxo group Chemical group O=* 0.000 claims description 46
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 44
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 44
- 125000001072 heteroaryl group Chemical group 0.000 claims description 43
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 39
- 229910052757 nitrogen Inorganic materials 0.000 claims description 38
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 32
- DYMRYCZRMAHYKE-UHFFFAOYSA-N n-diazonitramide Chemical compound [O-][N+](=O)N=[N+]=[N-] DYMRYCZRMAHYKE-UHFFFAOYSA-N 0.000 claims description 30
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 30
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 27
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 27
- 125000001188 haloalkyl group Chemical group 0.000 claims description 25
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 22
- 239000001301 oxygen Substances 0.000 claims description 22
- 125000004429 atom Chemical group 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 14
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- 102000005289 Eukaryotic Initiation Factor-4A Human genes 0.000 claims description 12
- 108010056472 Eukaryotic Initiation Factor-4A Proteins 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 11
- 239000000460 chlorine Chemical group 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 239000011737 fluorine Chemical group 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 10
- 125000002393 azetidinyl group Chemical group 0.000 claims description 8
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000004193 piperazinyl group Chemical group 0.000 claims description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 206010025323 Lymphomas Diseases 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical group [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 6
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 6
- MKCBRYIXFFGIKN-UHFFFAOYSA-N bicyclo[1.1.1]pentane Chemical compound C1C2CC1C2 MKCBRYIXFFGIKN-UHFFFAOYSA-N 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 125000003003 spiro group Chemical group 0.000 claims description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
- KWEDUNSJJZVRKR-UHFFFAOYSA-N carbononitridic azide Chemical compound [N-]=[N+]=NC#N KWEDUNSJJZVRKR-UHFFFAOYSA-N 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 206010003805 Autism Diseases 0.000 claims description 4
- 208000020706 Autistic disease Diseases 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 125000005646 oximino group Chemical group 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 150000001336 alkenes Chemical class 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 201000005787 hematologic cancer Diseases 0.000 claims description 2
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 206010044412 transitional cell carcinoma Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 208000001914 Fragile X syndrome Diseases 0.000 claims 1
- 101001037191 Homo sapiens Hyaluronan synthase 1 Proteins 0.000 claims 1
- 102100040203 Hyaluronan synthase 1 Human genes 0.000 claims 1
- 150000001924 cycloalkanes Chemical group 0.000 claims 1
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 231
- 239000000243 solution Substances 0.000 description 128
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 94
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 62
- 238000005481 NMR spectroscopy Methods 0.000 description 56
- 239000012074 organic phase Substances 0.000 description 54
- 210000004027 cell Anatomy 0.000 description 42
- 239000003960 organic solvent Substances 0.000 description 40
- 238000004440 column chromatography Methods 0.000 description 39
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- FHSQSWUQTMNJBI-UHFFFAOYSA-N furo[3,2-c]pyridine-7-carboxamide Chemical compound NC(=O)C1=CN=CC2=C1OC=C2 FHSQSWUQTMNJBI-UHFFFAOYSA-N 0.000 description 28
- 238000003756 stirring Methods 0.000 description 28
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 22
- 239000005457 ice water Substances 0.000 description 22
- 230000003647 oxidation Effects 0.000 description 21
- 238000007254 oxidation reaction Methods 0.000 description 21
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 20
- YOTZYFSGUCFUKA-UHFFFAOYSA-N dimethylphosphine Chemical compound CPC YOTZYFSGUCFUKA-UHFFFAOYSA-N 0.000 description 19
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 18
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 150000002009 diols Chemical class 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- ZQQFOHVNHOYXQN-UHFFFAOYSA-N 2,6-dichloro-4-phenylmethoxypyridine Chemical compound ClC1=NC(Cl)=CC(OCC=2C=CC=CC=2)=C1 ZQQFOHVNHOYXQN-UHFFFAOYSA-N 0.000 description 12
- FAMKHDDCRDEROA-UHFFFAOYSA-N 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxypyrano[3,2-c]pyridin-4-one Chemical compound BrC1=CC=C(C=C1)C1=C(C(C=2C(=NC(=CC=2O1)Cl)OC)=O)O FAMKHDDCRDEROA-UHFFFAOYSA-N 0.000 description 12
- ATPJSPSCURMIFV-UHFFFAOYSA-N 2-chloro-6-methoxy-4-phenylmethoxypyridine Chemical compound C(C1=CC=CC=C1)OC1=CC(=NC(=C1)OC)Cl ATPJSPSCURMIFV-UHFFFAOYSA-N 0.000 description 12
- KASNHLCKYKIKNL-QPJJXVBHSA-N 3-[(E)-3-(4-bromophenyl)prop-2-enoyl]-6-chloro-2-methoxy-1H-pyridin-4-one Chemical compound BrC1=CC=C(C=C1)/C=C/C(=O)C=1C(=NC(=CC=1O)Cl)OC KASNHLCKYKIKNL-QPJJXVBHSA-N 0.000 description 12
- HCGBEFSUBAVHKE-UHFFFAOYSA-N 3-acetyl-6-chloro-2-methoxy-1H-pyridin-4-one Chemical compound ClC1=CC(=C(C(=N1)OC)C(C)=O)O HCGBEFSUBAVHKE-UHFFFAOYSA-N 0.000 description 12
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 12
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 235000019270 ammonium chloride Nutrition 0.000 description 12
- SEMOUXYGJCRUIQ-UHFFFAOYSA-N furo[3,2-c]pyridine-3-carbonitrile Chemical compound C1=NC=C2C(C#N)=COC2=C1 SEMOUXYGJCRUIQ-UHFFFAOYSA-N 0.000 description 12
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 12
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 11
- 125000002619 bicyclic group Chemical group 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- 125000006413 ring segment Chemical group 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- 125000005366 cycloalkylthio group Chemical group 0.000 description 10
- WJDMEHCIRPKRRQ-UHFFFAOYSA-N furo[3,2-c]pyridine Chemical compound N1=CC=C2OC=CC2=C1 WJDMEHCIRPKRRQ-UHFFFAOYSA-N 0.000 description 10
- RFLADSHTGHDBMC-UHFFFAOYSA-N furo[3,2-c]pyridine-7-carboxylic acid Chemical compound OC(=O)C1=CN=CC2=C1OC=C2 RFLADSHTGHDBMC-UHFFFAOYSA-N 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 125000003282 alkyl amino group Chemical group 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 150000007942 carboxylates Chemical group 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 125000000000 cycloalkoxy group Chemical group 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 125000003566 oxetanyl group Chemical group 0.000 description 9
- 230000035755 proliferation Effects 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- FOOCVKSACMIAIA-UHFFFAOYSA-N 1-(6-chloro-2-methoxy-4-phenylmethoxypyridin-3-yl)ethanol Chemical compound C(C1=CC=CC=C1)OC1=C(C(=NC(=C1)Cl)OC)C(C)O FOOCVKSACMIAIA-UHFFFAOYSA-N 0.000 description 8
- BPRIJLCOSTXCHV-UHFFFAOYSA-N 1-(6-chloro-2-methoxy-4-phenylmethoxypyridin-3-yl)ethanone Chemical compound C(C1=CC=CC=C1)OC1=C(C(=NC(=C1)Cl)OC)C(C)=O BPRIJLCOSTXCHV-UHFFFAOYSA-N 0.000 description 8
- PCXZJJBZMLOKRM-UHFFFAOYSA-N 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxypyrano[3,2-c]pyridin-4-one Chemical compound BrC1=CC=C(C=C1)C1=C(C(C=2C(=NC(=CC=2O1)OC)OC)=O)O PCXZJJBZMLOKRM-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- CCRCUPLGCSFEDV-UHFFFAOYSA-N cinnamic acid methyl ester Natural products COC(=O)C=CC1=CC=CC=C1 CCRCUPLGCSFEDV-UHFFFAOYSA-N 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- CCRCUPLGCSFEDV-BQYQJAHWSA-N methyl trans-cinnamate Chemical compound COC(=O)\C=C\C1=CC=CC=C1 CCRCUPLGCSFEDV-BQYQJAHWSA-N 0.000 description 8
- 239000012046 mixed solvent Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000003831 tetrazolyl group Chemical group 0.000 description 8
- 238000013519 translation Methods 0.000 description 8
- 239000002609 medium Substances 0.000 description 7
- 108020004999 messenger RNA Proteins 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 7
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 125000005605 benzo group Chemical group 0.000 description 6
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 6
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 6
- 150000002825 nitriles Chemical class 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 6
- 235000019345 sodium thiosulphate Nutrition 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 235000011089 carbon dioxide Nutrition 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 238000012054 celltiter-glo Methods 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- FJNNGKMAGDPVIU-UHFFFAOYSA-N 2,4,6-trichloropyridine Chemical compound ClC1=CC(Cl)=NC(Cl)=C1 FJNNGKMAGDPVIU-UHFFFAOYSA-N 0.000 description 4
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 description 4
- JRVBMXSJFMJDJM-UHFFFAOYSA-N 2h-furo[3,2-c]pyridin-4-one Chemical compound O=C1N=CC=C2OCC=C12 JRVBMXSJFMJDJM-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 4
- 238000011729 BALB/c nude mouse Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 239000012980 RPMI-1640 medium Substances 0.000 description 4
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- PBIUUJCEMUAWJJ-UHFFFAOYSA-N azetidine-3-carbonitrile Chemical compound N#CC1CNC1 PBIUUJCEMUAWJJ-UHFFFAOYSA-N 0.000 description 4
- 235000019445 benzyl alcohol Nutrition 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 4
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- ZIPLUEXSCPLCEI-UHFFFAOYSA-N iminomethylideneazanide Chemical compound [NH-]C#N ZIPLUEXSCPLCEI-UHFFFAOYSA-N 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 4
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 125000003226 pyrazolyl group Chemical group 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 210000003705 ribosome Anatomy 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- 101001082110 Acanthamoeba polyphaga mimivirus Eukaryotic translation initiation factor 4E homolog Proteins 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 3
- 210000001766 X chromosome Anatomy 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000005090 alkenylcarbonyl group Chemical group 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 229910000085 borane Inorganic materials 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 229940125632 eukaryotic translation initiation factor 4A inhibitor Drugs 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 108010082117 matrigel Proteins 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- HQQVXVKQOPZRBJ-OLQVQODUSA-N (3as,6ar)-3,3a,4,5,6,6a-hexahydro-1h-furo[3,4-c]pyrrole Chemical compound C1OC[C@@H]2CNC[C@@H]21 HQQVXVKQOPZRBJ-OLQVQODUSA-N 0.000 description 2
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 description 2
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 2
- 125000005960 1,4-diazepanyl group Chemical group 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 description 2
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- HPJALMWOZYIZGE-UHFFFAOYSA-N 2-oxa-6-azaspiro[3.3]heptane Chemical compound C1NCC11COC1 HPJALMWOZYIZGE-UHFFFAOYSA-N 0.000 description 2
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 2
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000005917 3-methylpentyl group Chemical group 0.000 description 2
- 125000003341 7 membered heterocyclic group Chemical group 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 101001082109 Danio rerio Eukaryotic translation initiation factor 4E-1B Proteins 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 101710091919 Eukaryotic translation initiation factor 4G Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 108010019160 Pancreatin Proteins 0.000 description 2
- 102000005877 Peptide Initiation Factors Human genes 0.000 description 2
- 108010044843 Peptide Initiation Factors Proteins 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- XPRVSYXHPUYSGF-UHFFFAOYSA-N azetidin-3-one Chemical compound O=C1CNC1 XPRVSYXHPUYSGF-UHFFFAOYSA-N 0.000 description 2
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- HFWIMJHBCIGYFH-UHFFFAOYSA-N cyanoform Chemical compound N#CC(C#N)C#N HFWIMJHBCIGYFH-UHFFFAOYSA-N 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000004404 heteroalkyl group Chemical group 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 231100000590 oncogenic Toxicity 0.000 description 2
- 230000002246 oncogenic effect Effects 0.000 description 2
- 102000027450 oncoproteins Human genes 0.000 description 2
- 108091008819 oncoproteins Proteins 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000003672 processing method Methods 0.000 description 2
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- DAPAQENNNINUPW-IDAMAFBJSA-N rocaglamide Chemical compound C1=CC(OC)=CC=C1[C@]1([C@@H]([C@H]([C@H]2O)C(=O)N(C)C)C=3C=CC=CC=3)[C@]2(O)C2=C(OC)C=C(OC)C=C2O1 DAPAQENNNINUPW-IDAMAFBJSA-N 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 2
- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical group O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000002053 thietanyl group Chemical group 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000014621 translational initiation Effects 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 1
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 1
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 1
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 1
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004336 3,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 1
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
- SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000004337 3-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 108020003589 5' Untranslated Regions Proteins 0.000 description 1
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 1
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- 241000349731 Afzelia bipindensis Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 101000911956 Bos taurus Cyclin-dependent-like kinase 5 Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 101710167800 Capsid assembly scaffolding protein Proteins 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 1
- 208000031640 Chromosome Fragility Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 1
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 1
- 102100030708 GTPase KRas Human genes 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 101710130420 Probable capsid assembly scaffolding protein Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 102000004409 RNA Helicases Human genes 0.000 description 1
- 108090000944 RNA Helicases Proteins 0.000 description 1
- 230000004570 RNA-binding Effects 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 101710204410 Scaffold protein Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 108020004417 Untranslated RNA Proteins 0.000 description 1
- 102000039634 Untranslated RNA Human genes 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 150000001602 bicycloalkyls Chemical group 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 201000010897 colon adenocarcinoma Diseases 0.000 description 1
- LNDJVIYUJOJFSO-UHFFFAOYSA-N cyanoacetylene Chemical compound C#CC#N LNDJVIYUJOJFSO-UHFFFAOYSA-N 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000002074 deregulated effect Effects 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 description 1
- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 description 1
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- QLBHNVFOQLIYTH-UHFFFAOYSA-L dipotassium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [K+].[K+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O QLBHNVFOQLIYTH-UHFFFAOYSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 102000038934 eIF4A family Human genes 0.000 description 1
- 108091065251 eIF4A family Proteins 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- DAPAQENNNINUPW-UHFFFAOYSA-N endo rocaglamide Natural products C1=CC(OC)=CC=C1C1(C(C(C2O)C(=O)N(C)C)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 DAPAQENNNINUPW-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- UIUXUFNYAYAMOE-UHFFFAOYSA-N methylsilane Chemical compound [SiH3]C UIUXUFNYAYAMOE-UHFFFAOYSA-N 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000009712 regulation of translation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 102200006532 rs112445441 Human genes 0.000 description 1
- 102200006531 rs121913529 Human genes 0.000 description 1
- 102200006538 rs121913530 Human genes 0.000 description 1
- 102220014328 rs121913535 Human genes 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- GVKXFVCXBFGBCD-QKDMMWSPSA-N silvestrol Chemical compound CO[C@@H]1OC[C@H]([C@H](O)CO)O[C@H]1OC(C=C1OC)=CC2=C1[C@]1(O)[C@H](O)[C@H](C(=O)OC)[C@@H](C=3C=CC=CC=3)[C@]1(C=1C=CC(OC)=CC=1)O2 GVKXFVCXBFGBCD-QKDMMWSPSA-N 0.000 description 1
- GVKXFVCXBFGBCD-UHFFFAOYSA-N silvestrol Natural products COC1OCC(C(O)CO)OC1OC(C=C1OC)=CC2=C1C1(O)C(O)C(C(=O)OC)C(C=3C=CC=CC=3)C1(C=1C=CC(OC)=CC=1)O2 GVKXFVCXBFGBCD-UHFFFAOYSA-N 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004354 sulfur functional group Chemical group 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229940121641 zotatifin Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention belongs to the field of drug synthesis, in particular to a polycyclic biological regulator, a preparation method and application thereof.
- mRNA messenger RNA
- mRNA messenger RNA
- oncogenic drivers is under strict translational control and is regulated by the eukaryotic translation initiation factor 4F (eukaryotic translation initiation factor 4F) complex, which mediates the recruitment of ribosomes to mRNA and initiates the translation of mRNA to protein.
- the eIF4F complex consists of three subunits of the mRNA 5' cap-binding protein eIF4E, the scaffold protein eIF4G and the RNA helicase eIF4A.
- eIF4F recognizes the 5'-mRNA cap structure by eIF4E, eIF4A unravels the mRNA 5'-UTR secondary structure in an ATP-dependent manner, cyclizes mRNA by binding to polyA-binding protein, and recruits 40S subunit ribosomal scanning and Translation starts.
- the eIF4F subunit is frequently overexpressed in various malignancies, thus targeting components of the eIF4F complex to renormalize deregulated translation is an emerging strategy for anticancer drug discovery.
- eIF4A Excessive activation of eIF4A, eIF4E, and eIF4G is associated with poor prognosis in related diseases, including lymphoma, lung, colorectal, liver, breast, and ovarian cancer.
- eIF4A is divided into free type and complex type according to whether it is combined with ribosomes, and the activity of free type is 1/20 of that of complex type.
- the eIF4A inhibitor eFT226 disclosed in the eFFECTOR Therapeutics International Application WO 2017091585 has been shown in preclinical experiments to inhibit the proliferation of RTK solid tumors and lymphomas, the translation of oncogenic proteins (FGFR1/2, HER2, KRAS) and the resistance in preclinical models. It has good receptivity and has entered the first phase of clinical research. As an emerging strategy for anti-cancer drug discovery, the regulation of translation is intended to provide a novel anti-tumor drug that inhibits the activity of eIF4A to meet the huge tumor market demand.
- the object of the present invention is to provide a kind of compound shown in general formula (I), its stereoisomer or its pharmaceutically acceptable salt, and its structure is as follows:
- X is selected from O, S, S(O), S(O) 2 , C(O), NR or CRR';
- Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;
- R and R' are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl , alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;
- R 1 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cyclic Alkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkane radicals, heterocyclyl, aryl and heteroaryl, optionally further substituted;
- R2 and R2 ' are each independently selected from hydrogen , deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkene alkynyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;
- R3 and R3 ' are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 R a , -(CH 2 ) n1 NR a OR b , -(CH 2 ) n1 C(O )NR a R b , -(CH 2 ) n1 NR a C(O)R b , -(CH 2 ) n1 S(O) m1 R a , -(CH 2 ) n1 S(O) m1 NR a R b , -(CH 2 ) n1 NR a S(O) m1 R b ,
- R4 and R4 ' are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n3 R c , -(CH 2 ) n3 NR c OR d , -(CH 2 ) n3 C(O )NR c R d , -(CH 2 ) n3 NR c C(O)R d , -(CH 2 ) n3 S(O) m2 R c , -(CH 2 ) n3 S(O) m2 c R d , -(CH 2 ) n3 S(O) m2 c R d , -(CH
- R 5 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkane radicals, heterocyclyl, aryl and heteroaryl, optionally further substituted;
- Ra is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cyclic Alkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkane radicals, heterocyclyl, aryl and heteroaryl, optionally further substituted;
- R a and R 4 are linked with the carbon atom or heteroatom to which they are attached to form a cycloalkyl or heterocyclyl group, which may optionally be further substituted;
- R a , R b , R c and R d are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkane Oxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;
- x 0, 1, 2, 3, 4, or 5;
- n1 to n4 are 0, 1, 2, 3, 4 or 5;
- n1 and m2 are 0, 1 or 2.
- the ring A is selected from C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-14 aryl or 5-14-membered heteroaryl, the C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C6-14 membered aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amino, hydroxyl, cyano, C1-6alkane base, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1 One or more of -6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl substituted by a substituent;
- the ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl
- the ring A is selected from 5-6 membered nitrogen-containing heteroaryl groups
- the ring A is selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl or pyrazolyl.
- R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocycle base, C 6-14 aryl or 5-14-membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroary
- R 2 and R 2 ' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterium Alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkyl , 3-12-membered heterocyclic group, C 6-14 -membered aryl group or 5-14-membered heteroaryl group, said C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 Cycloalkyl, 3-12 membered
- R 3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocycle base, C 6-14 aryl, 5-14 membered heteroaryl, -(CH 2 ) n1 R a , -(CH 2 ) n1 NR a OR b , -(CH 2 ) n1 C(O)NR a R b , -(CH 2 ) n1 NR a C(O)R b , -(CH 2 ) n1 S(O) m1 R a , -(CH 2 ) n1 S(O
- R 4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocycle base, C 6-14 aryl, 5-14 membered heteroaryl, -(CH 2 ) n3 R c , -(CH 2 ) n3 NR c OR d , -(CH 2 ) n3 C(O)NR c R d , -(CH 2 ) n3 NR c C(O)R d , -(CH 2 ) n3 S(O) m2 R c , -(CH 2 ) n3 S(O
- R 6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocycle base, C 6-14 aryl or 5-14-membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered hetero
- R 6 and R 4 are linked to the carbon atoms to which they are attached to form C 5-14 cycloalkyl or 5-14 membered heterocyclyl, said C 5-14 cycloalkyl and 5-14 membered heterocyclyl , optionally further by deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkane substituted by one or more substituents in the group, 3-12-membered heterocyclic group, C 6-14 -membered aryl group and 5-14-membered heteroaryl group;
- R 7 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocycle base, C 6-14 aryl or 5-14-membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroary
- R 8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oximo, azido, mercapto, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C6-14 membered aryl, 5-14 membered heteroaryl, -C(O)R e or -P(O)R e R f , said Oximino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1 -6 alkoxy, C
- R a , R b , R c , R d , Re and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azide, mercapto, C 1-6 alkyl , C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- 6 -alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-14 -membered aryl or 5-14-membered heteroaryl base, the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkane base, C
- n1 to n4 are 0, 1, 2, 3, 4 or 5;
- n1 and m2 are 0, 1 or 2;
- R 1 and R 2 are phenyl, and R 8 is halogen, cyano or C 1-6 haloalkyl, R 4 is not hydroxyl, or R 2 ' is not hydrogen, or R 3 is not
- the R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 Cycloalkyl, 3-12-membered heterocyclyl, C 6-14 -membered aryl or 5-14-membered heteroaryl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered hetero
- R 8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, oximo, mercapto, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 membered aryl, 5-14 membered heteroaryl, -C(O)R e , -SR e , -OR e , -NR e R f , -C(O)NR e R f , -NR e C(O)R f , -OC(O)R e R f , -C(O)OR e , -S(O
- the R 8 is selected from deuterium, halogen, cyano, azido, oximo, nitro, amino, C 1-3 alkyl, C 2-3 alkenyl, C 2 -3 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 membered aryl and 5-10 membered heteroaryl, -C(O)R e , -SR e , -NR e R f , -C(O)NR e R f , -NR e C(O) R f or -P(O)R e R f , said amino, oximo, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 membered aryl and 5-10 membered heteroaryl, optionally further deuterium , cyano
- the R 8 is selected from cyano, azido, nitro, oximo, amino, mercapto, methyl, ethynyl, cyclopropyl, oxetanyl, nitrogen Hetetanyl, tetrazolyl, -SR e , -NR e R f , -C(O)NR e R f , -NR e C(O)R f or -P(O)R e R f , the methyl group, ethynyl group, cyclopropyl group, oxetanyl group, azetidinyl group and tetrazolyl group are optionally further cyano, hydroxyl, fluorine, chlorine, bromine, oxygen Substituted by one or more substituents of substituted, methyl and trifluoromethyl;
- the R 8 is selected from -CN, -P(O)(CH 3 ) 2 , -N 3 , -NO 2 , -SCF 3 , -SCN, -NCH 3 C(O )CH 3 , -C(O)N(CH 3 ) 2 , -N(CN) 2 , -CH(CN) 2 , -C(CN) 3 , -(C ⁇ C)CN,
- R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azide, mercapto, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio , C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12-membered heterocyclic group, C 6-14 aryl or 5-14-membered heteroaryl, the amino, C 1-6 alkane base, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1 -6 alkylthio, C 1-6 haloalkoxy,
- the R 1 is selected from a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the C 3 -8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 membered aryl and 5-10 membered heteroaryl, optionally further substituted with one or more R8 ;
- said R 1 is selected from phenyl or bicyclo[1.1.1]pentane, and said phenyl and bicyclo[1.1.1]pentane are optionally further separated by one or replaced by multiple R 8 ;
- R 8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated alkyl, C 1- 3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycle base, C 6-10 aryl, 5-10 membered heteroaryl or -P(O)R e R f ;
- cyano or -P(O)R e R f Preferably cyano or -P(O)R e R f ;
- R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkoxy;
- R 1 is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the C 3 -8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 membered aryl and 5-10 membered heteroaryl, optionally further substituted with one or more R8 ,
- phenyl said phenyl, optionally further substituted by one or more R 8 ;
- R 8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oximo, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated Alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 haloalkoxy, C 3-8 cycloalkyl, 3-8-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl,
- Cyclopropyl, nitro or oximino are preferred.
- the R 2 is selected from a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the C 3 -8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 membered aryl and 5-10 membered heteroaryl, optionally further optionally deuterium, halogen, amino, hydroxyl, cyano, C1 -3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy , one of C 1-3 alkylthio, C 1-3 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl or more substituents;
- the R 2 is selected from phenyl or bicyclo[1.1.1]pentane
- the R 2 is selected from phenyl
- R 2 ' is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated alkyl, C 1 -3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkoxy;
- the R 2 ' is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or propyl.
- the R 3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azide, mercapto, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1- 6 -halogenated alkoxy, C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-14 -membered aryl, 5-14-membered heteroaryl, -(CH 2 ) n1 R a , -(CH 2 ) n1 NR a OR b , -(CH 2 ) n1 C(O)NR a R b , -(CH 2 ) n1 OC(O)R a , -(CH 2 )
- R a and R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, azide, mercapto, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio , C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12-membered heterocyclic group, C 6-14 aryl or 5-14-membered heteroaryl, the amino, C 1-6 alkane base, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1 -6 alkylthio, C 1-6 haloalkoxy, C
- n1 and n2 are 0, 1, 2, 3, 4, or 5;
- n1 0, 1 or 2.
- the R 3 is selected from -(CH 2 ) n1 R a , -(CH 2 ) n1 NR a OR b , -(CH 2 ) n1 C(O)NR a R b , - (CH 2 ) n1 NR a C(O)R b , -(CH 2 ) n1 S(O) m1 R a , -(CH 2 ) n1 S(O) m1 NR a R b , -(CH 2 ) n1 NR a S(O) m1 R b , -(CH 2 ) n1 NR a R b or -(CH 2 ) n1 NR a (CH 2 ) n2 R b ;
- the R 3 is selected from -CH 2 R a , -C(O)NR a R b , -S(O) 2 R b , -CH 2 NR a Rb d , -CH 2 ) NR a CH 2 R b or -CH 2 NR a (CH 2 ) 2 R b ;
- R a and R b are each independently selected from hydrogen, halogen, hydroxy, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or 4-8 membered Nitrogen-containing heterocyclic group, the C 1-3 alkyl group, C 1-3 hydroxyalkyl group, C 1-3 haloalkyl group, C 1-3 alkoxy group and 4-8 membered nitrogen-containing heterocyclic group, any C optionally further substituted with hydrogen, deuterium, hydroxy, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogen, cyano, cyano Substituted by one or more substituents in 1-3 alkyl or C 1-3 alkoxy-C 1-3 alkylene;
- n1 and n2 are 0, 1, 2, 3, 4, or 5;
- n1 0, 1 or 2.
- the R 4 is selected from -OH, -(CH 2 ) n3 R c , -(CH 2 ) n3 NR c OR d , -(CH 2 ) n3 C(O)NR c R d , -(CH 2 ) n3 NR c C(O)R d , -(CH 2 ) n3 S(O) m2 R c , -(CH 2 ) n3 S(O) m2 NR c R d , -(CH 2 ) n3 NR c S(O) m2 R d , -(CH 2 ) n3 NR c R d or -(CH 2 ) n3 NR c (CH 2 ) n4 R d
- the R 4 is selected from -OH, -(CH 2 ) n3 NR c R d or -(CH 2 ) n3 NR c OR d ;
- R c and R d are each independently selected from hydrogen, halogen, hydroxy, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl or C 1-3 alkoxy, the C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl and C 1-3 alkoxy, optionally further hydrogen, deuterium, hydroxyl, C 1-3 alkyl, C 1- substituted by one or more substituents in 3 hydroxyalkyl, C 1-3 haloalkyl or C 1-3 alkoxy;
- n3 and n4 are 0, 1, 2, 3, 4, or 5;
- n2 0, 1 or 2.
- the R 3 and R 4 , and the carbon atoms where they are located are linked together to form a C 3-12 cycloalkyl group, a 3-12-membered heterocyclic group, a C 6-14 aryl group or a 5- 14-membered heteroaryl, said C 3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, C 6-14 -membered aryl and 5-14-membered heteroaryl, optionally, further substituted by deuterium, halogen, Amino, hydroxyl, cyano, nitro, azido, mercapto, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterium Alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalk
- R 3 and R 4 , and the carbon atoms where they are located are linked together to form a 3-12-membered heterocyclic group
- the 3-12-membered heterocyclic group optionally, is further deuterium, halogen , amino, hydroxyl, cyano, nitro, azide, mercapto, oxo, thio, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 Deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 haloalkoxy, C 3-8 cycloalkane substituted by one or more substituents in the group, 3-8-membered heterocyclic group, C 6-10 -membered aryl group and 5-10-membered heteroaryl group
- R 3 and R 4 , and the carbon atoms where they are located are linked together to form the following heterocyclic group
- Said heterocyclic group is optionally further substituted by one or more substituents in deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, oxo or cyclopropyl.
- the R 6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1 -3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkoxy;
- the R 6 is selected from methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
- the R 7 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1 -3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkoxy;
- the R 7 is selected from cyano, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
- the R 4 and R 6 are linked with the carbon atoms to which they are attached to form a C 5-14 cycloalkyl group or a 5-14 membered heterocyclic group, the C 5-14 cycloalkyl group and 5-14 membered heterocyclyl, optionally further deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkane substituted by one or more substituents in the group, 3-12-membered heterocyclic group, C 6-14 -membered aryl group and 5-14-membered heteroaryl group;
- the R 4 and R 6 together with the carbon atoms to which they are attached form a 5-12-membered heterocyclic group
- the 5-12-membered heterocyclic group is optionally further Deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered Substituted with one or more substituents in heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
- the R 4 and R 6 together with the carbon atoms to which they are attached form the following heterocyclic group: Said heterocyclic group is optionally further substituted by one or more substituents in deuterium, fluorine, chlorine, bromine, methyl, ethyl, oxo or cyclopropyl.
- R 3 , R 7 and R d are as defined above.
- the R 2 ' is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkoxy;
- the R 2 ' is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or propyl;
- the R 3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azide, mercapto, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1- 6 -halogenated alkoxy, C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-14 -membered aryl, 5-14-membered heteroaryl, -(CH 2 ) n1 R a , -(CH 2 ) n1 NR a OR b , -(CH 2 ) n1 C(O)NR a R b , -(CH 2 ) n1 OC(O)R a , -(CH 2 )
- R a and R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, azide, mercapto, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio , C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12-membered heterocyclic group, C 6-14 aryl or 5-14-membered heteroaryl, the amino, C 1-6 alkane base, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1 -6 alkylthio, C 1-6 haloalkoxy, C
- n1 and n2 are 0, 1, 2, 3, 4, or 5;
- n1 0, 1 or 2.
- the R 7 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1 -3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkoxy;
- the R 7 is selected from cyano, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
- the R 8 is selected from cyano, azide, nitro, C 3-6 cycloalkyl, 5-6 membered heteroaryl containing 2-4 nitrogen atoms, containing 4-6-membered heterocyclic group containing 1 nitrogen or oxygen atom, 7-8-membered spiro heterocyclic group containing 2-3 atoms selected from nitrogen or oxygen, 7-membered heterocyclic group containing 2-3 atoms selected from nitrogen or oxygen 8-membered fused heterocyclic group, optionally further deuterium, halogen, amino, hydroxyl, cyano, azido, nitro, mercapto, oxo, C 1-3 alkyl, C 1-3 alkoxy , C 1-3 haloalkyl or cyano substituted C 1-3 alkyl substituted by one or more substituents;
- the R 8 is selected from -CN, -P(O)(CH 3 ) 2 , -N 3 , -NO 2 , -SCF 3 , -SCN, -NCH 3 C(O )CH 3 , -C(O)N(CH 3 ) 2 , -N(CN) 2 , -CH(CN) 2 , -C(CN) 3 , -(C ⁇ C)CN,
- R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azide, mercapto, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio , C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12-membered heterocyclic group, C 6-14 aryl or 5-14-membered heteroaryl, the amino, C 1-6 alkane base, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1 -6 alkylthio, C 1-6 haloalkoxy,
- R 2 ' is selected from hydrogen
- R 3 is selected from -(CH 2 ) n1 NR a C(O)R b or -(CH 2 ) n1 NR a R b ;
- R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, mercapto, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1 -3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkoxy;
- R a and R b and adjacent nitrogen atoms form a 4-8 membered heterocyclic group containing 1-2 atoms selected from nitrogen or oxygen, optionally further substituted by halogen, C 1-3 alkyl, C 1 -3 alkoxy, C 1-3 haloalkyl or C 1-3 hydroxyalkyl substituted by one or more substituents;
- R 7 is selected from cyano or C 1-3 alkoxy
- R 8 is selected from cyano, azido, nitro, C 3-6 cycloalkyl, 5-6 membered heteroaryl containing 2-4 nitrogen atoms, 4-6 membered containing 1 nitrogen or oxygen atom Heterocyclyl, 7-8 membered spiroheterocyclyl containing 2-3 atoms selected from nitrogen or oxygen, 7-8 membered fused heterocyclyl containing 2-3 atoms selected from nitrogen or oxygen, optionally further Substituted with deuterium, halogen, amino, hydroxyl, cyano, azido, nitro, mercapto, oxo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl or cyano substituted with one or more substituents in the C 1-3 alkyl group.
- R 2 ' is selected from hydrogen
- R 3 is selected from -(CH 2 ) n1 NR a R b ;
- R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, mercapto, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1 -3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkoxy; preferably hydrogen, deuterium, C 1-3 alkyl, C 1-3 deuterated alkyl or C 1-3 haloalkyl; more preferably methyl;
- R 7 is selected from cyano or C 1-3 alkoxy; more preferably methoxy;
- R 8 is selected from cyano, azido, oximo, nitro, C 3-6 cycloalkyl; more preferably oximo, nitro or cyclopropyl;
- n1 1
- R 2 ' is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated alkyl, C 1 -3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkoxy,
- R 6 and R 7 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkoxy,
- R 8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, oximo, mercapto, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C6-14 aryl, 5-14 membered heteroaryl, -SR e , -OR e , -NR e R f , -C(O)NR e R f , -NR e C(O)R f , -OC(O)R e R f , -C(O)OR e , -S(O) 2 R e , -S(O)R
- R a and R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, azide, mercapto, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio , C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12-membered heterocyclic group, C 6-14 aryl or 5-14-membered heteroaryl, the amino, C 1-6 alkane base, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1 -6 alkylthio, C 1-6 haloalkoxy, C
- R a and R b and adjacent nitrogen atoms form a 4-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen or oxygen, optionally further deuterium, halogen, amino, hydroxyl, cyano, Nitro, azido, mercapto, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocycle substituted by one or more substituents in the base, C 6-14 aryl and 5-14-membered heteroaryl;
- R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azide, mercapto, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio , C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12-membered heterocyclic group, C 6-14 aryl or 5-14-membered heteroaryl, the amino, C 1-6 alkane base, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1 -6 alkylthio, C 1-6 haloalkoxy,
- n1 and n2 are 0, 1, 2, 3, 4, or 5;
- n1 0, 1 or 2.
- the R 6 and R 7 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-3 alkenyl, C 2- 3 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkoxy base;
- the R 6 and R 7 are selected from cyano, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;
- the R 8 is selected from cyano, azide, nitro, C 3-6 cycloalkyl, 5-6 membered heteroaryl containing 2-4 nitrogen atoms, containing 4-6-membered heterocyclic group containing 1 nitrogen or oxygen atom, 7-8-membered spiro heterocyclic group containing 2-3 atoms selected from nitrogen or oxygen, 7-membered heterocyclic group containing 2-3 atoms selected from nitrogen or oxygen 8-membered fused heterocyclic group, optionally further deuterium, halogen, amino, hydroxyl, cyano, azido, nitro, mercapto, oxo, C 1-3 alkyl, C 1-3 alkoxy , C 1-3 haloalkyl or cyano substituted C 1-3 alkyl substituted by one or more substituents;
- the R 8 is selected from -CN, -P(O)(CH 3 ) 2 , -N 3 , -NO 2 , -SCF 3 , -SCN, -NCH 3 C(O )CH 3 , -C(O)N(CH 3 ) 2 , -N(CN) 2 , -CH(CN) 2 , -C(CN) 3 , -(C ⁇ C)CN,
- R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azide, mercapto, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio , C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12-membered heterocyclic group, C 6-14 aryl or 5-14-membered heteroaryl, the amino, C 1-6 alkane base, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1 -6 alkylthio, C 1-6 haloalkoxy,
- R 2 ' is selected from hydrogen
- R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, mercapto, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1 -3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkoxy; preferably hydrogen, deuterium, C 1-3 alkyl, C 1-3 deuterated alkyl or C 1-3 haloalkyl; more preferably methyl;
- R 6 and R 7 are each independently selected from cyano or C 1-3 alkoxy; more preferably methoxy;
- R 8 is selected from cyano, azido, oximo, nitro, C 3-6 cycloalkyl; more preferably oximo, nitro or cyclopropyl.
- the present invention further provides a compound represented by the intermediate general formula (M), its stereoisomer or its pharmaceutically acceptable salt:
- R is selected from -C(O)R g ;
- R g is selected from hydroxyl, C 1-3 alkoxy or -NR a R b ;
- R 4 , R 6 , R 7 , R 8 , Ra or R b are as previously described.
- the present invention further provides a method for preparing a compound of general formula (VI) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:
- the general formula (M-2) is obtained by the reaction of the general formula (M-1)
- the general formula (M-3) is obtained by the reaction of the general formula (M-2)
- the general formula (VI) is obtained by the reduction of the general formula (M-3);
- Pg is selected from C 1-3 alkoxy
- R 4 , R 6 , R 7 , R 8 , Ra or R b are as previously described.
- R 4 is preferably a hydroxyl group.
- the present invention further relates to a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective dose of a compound of general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, dilutions agent or excipient.
- the object of the present invention is to provide a compound comprising the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment and/or prevention of ATP Use in medicaments for dependent RNA helicase-related diseases, in particular in medicaments for the treatment and/or prevention of eukaryotic initiation factor 4A (eIF4A) inhibitor-related diseases.
- eIF4A eukaryotic initiation factor 4A
- the object of the present invention is to provide a compound comprising the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment and/or prevention of cancer , Myelodysplastic Syndrome, Alzheimer's Disease, Parkinson's Disease, X-chromosome Fragility Syndrome, Autism and other related diseases.
- the present invention also relates to a method for treating and/or preventing related diseases such as cancer, myelodysplastic syndrome, Alzheimer's disease, Parkinson's disease, X-chromosome fragile disease and autism.
- related diseases such as cancer, myelodysplastic syndrome, Alzheimer's disease, Parkinson's disease, X-chromosome fragile disease and autism.
- the object of the present invention is to provide the compound of general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the treatment and/or prevention of cancer, bone marrow Use in related diseases such as dysplasia, Alzheimer's disease, Parkinson's disease, X-chromosome fragile disorder and autism.
- the cancer-related diseases are selected from or hematological tumors, preferably colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, glioma, glioblastoma, Hepatocellular carcinoma, lung cancer, melanoma, myeloma, pancreatic cancer, renal cell carcinoma, cervical cancer, urothelial cancer, prostate cancer, ovarian cancer, breast cancer, leukemia or lymphoma.
- hematological tumors preferably colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, glioma, glioblastoma, Hepatocellular carcinoma, lung cancer, melanoma, myeloma, pancreatic cancer, renal cell carcinoma, cervical cancer, urothelial cancer, prostate cancer, ovarian cancer, breast cancer, leukemia or lymphoma.
- alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms atomic alkyl group, further preferably an alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 4 -Heptyl, 1-propylbutyl, 2-methylhexyl
- lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, 4-heptyl, 1-propylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylbutyl pentyl, 3-methylpentyl, 4-methylpentyl, 2,3-
- Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group, the present invention is preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl , deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
- alkylene means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene” means -CH2- , “ethylene” means -( CH2 ) 2- , "propylene” Refers to -(CH 2 ) 3 -, “butylene” refers to -(CH 2 ) 4 - and the like.
- alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl, etc.
- Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
- cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms carbon atoms.
- Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
- Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
- spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated ⁇ electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
- spirocycloalkyl More preferably, it is 3-membered/6-membered, 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
- spirocycloalkyl include:
- spirocycloalkyl groups in which a monospirocycloalkyl group shares a spiro atom with a heterocycloalkyl group, non-limiting examples include:
- fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:
- bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings have complete Conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
- bridged cycloalkyl include:
- the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring linked to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
- Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
- heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, C(O) or a heteroatom of S(O) m (where m is an integer from 0 to 2), excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
- a membered heterocyclic group, optionally substituted with 1-2 oxygen atoms, sulfur atoms, oxo groups, includes a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing spiro heterocyclic group or a nitrogen-containing fused heterocyclic group.
- Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyran base, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azeptyl, 1,4-diazepanyl, pyranyl or tetrahydrothiopyran dioxide group, etc.; preferably oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydro Pyranyl, tetrahydrothienyl, tetrahydrothi
- Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected with other groups through a single bond, or through a ring Any two or more atoms above are further cyclo-linked to other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.
- spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl.
- Non-limiting examples of spiroheterocyclyl include:
- fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds, but none of the rings have a fully conjugated pi-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), the remaining rings Atom is carbon.
- it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- fused heterocyclyl groups include:
- bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a complete common A pi-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
- m is an integer from 0 to 2
- it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- bridged heterocyclyl groups include:
- heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
- Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
- the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
- aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 12 membered, such as benzene base and naphthyl. More preferred is phenyl.
- the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered Heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclic group contains 1-3 nitrogen atoms, oxygen atoms, A heterocyclic group of sulfur atom; or a three-membered nitrogen-containing fused ring containing a benzene ring.
- ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
- Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
- heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
- Heteroaryl is preferably 5 to 12-membered, more preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably pyridyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrimidinyl or thiazole group; more preferably tetrazolyl, pyridyl, oxadiazolyl,
- Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
- alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
- alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy
- alkoxy may be is optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkane Sulfur group, carboxy
- Haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
- Haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
- Hydroalkyl refers to an alkyl group substituted with hydroxy, wherein alkyl is as defined above.
- Alkenyl refers to an alkenyl group, also known as an alkenyl group, wherein the alkenyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkanethio group, carboxyl group or carboxylate group.
- Alkynyl refers to (CH ⁇ C-), wherein the alkynyl group may be further substituted with other related groups such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxyl or carboxylate.
- alkenylcarbonyl refers to -C(O)-(alkenyl), wherein alkenyl is as defined above.
- alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl.
- Alkenylcarbonyl can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
- Halogen refers to fluorine, chlorine, bromine or iodine.
- Amino refers to -NH2 .
- Cyano refers to -CN.
- Niro refers to -NO2 .
- Carbonyl or “oxo” refers to -C(O)-.
- Carboxyl refers to -C(O)OH.
- THF tetrahydrofuran
- Ethyl acetate refers to ethyl acetate.
- MeOH refers to methanol
- DMF N,N-dimethylformamide
- DIPEA diisopropylethylamine
- TFA trifluoroacetic acid
- TAA triethylamine
- MeCN means acetonitrile
- DMA refers to N,N-dimethylacetamide.
- Et2O refers to diethyl ether.
- DCM dichloromethane
- DMAP refers to 4-dimethylaminopyridine.
- DCC refers to dicyclohexylcarbodiimide.
- DCE 1,2 dichloroethane
- DIPEA N,N-diisopropylethylamine
- NBS N-bromosuccinimide
- NIS N-iodosuccinimide
- Cbz-Cl refers to benzyl chloroformate
- Pd2(dba )3 refers to tris(dibenzylideneacetone)dipalladium.
- Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
- HATU refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.
- KHMDS refers to potassium hexamethyldisilazide
- LiHMDS refers to lithium bistrimethylsilylamide.
- MeLi refers to methyl lithium
- n-BuLi refers to n-butyllithium
- NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
- amino acid residue refers to a natural amino acid residue or an unnatural amino acid residue.
- Natural amino acid refers to the 20 conventional amino acids, namely alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), phenylalanine (F) , Glycine (G), Histidine (H), Isoleucine (I), Lysine (K), Leucine (L), Methionine (M), Asparagine (N), Proline (P), Glutamine (Q), Arginine (R), Serine (S), Threonine (T), Valine (V), Tryptophan (W) and Tyrosine (Y).
- Unnatural amino acid refers to amino acids that are not naturally encoded or found in the genetic code of any organism, which may be, for example, pure synthetic compounds.
- X is selected from A, B, or C
- X is selected from A, B and C
- X is A, B or C
- X is A, B and C
- X is A, B and C
- the hydrogen atom in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by deuterium atom.
- Optional or “optionally” means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
- a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
- Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
- “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
- the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
- “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and possess the desired biological activity.
- the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
- DMSO-d 6 dimethyl sulfoxide
- CD 3 OD deuterated methanol
- CDCl 3 deuterated chloroform
- TMS Methylsilane
- the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are 0.15mm ⁇ 0.20mm, and the specifications used for TLC separation and purification products are 0.4mm ⁇ 0.5mm.
- Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
- the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.
- the first step the preparation of 4-(benzyloxy)-2,6-dichloropyridine
- the second step the preparation of 4-(benzyloxy)-2-chloro-6-methoxypyridine
- the third step preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol
- the fourth step the preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-one
- the fifth step the preparation of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl) ethane-1-one
- the seventh step preparation of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one
- the eighth step preparation of 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one
- Step 9 Racemic-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl- Preparation of 2,3,4,5-tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate
- Step 10 Racemic-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-benzene Preparation of base-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylate
- Step 11 Racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-(hydroxymethyl)-1,3-dimethoxy-6- Preparation of phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol
- the crude product of the previous step was rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-benzene yl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylate (250 mg, about 0.424 mmol) was dissolved in MeOH ( 8 mL), then NaBH4 (81 mg, 2.12 mmol) was added portionwise and stirred at room temperature for 75 minutes.
- Step 12 Racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene Preparation of base-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carbaldehyde
- Racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7 ,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carbaldehyde 58 mg, 0.114 mmol
- dimethylamine hydrochloride 9.2 mg, 0.228 mmol
- sodium borohydride acetate 48 mg, 0.228 mmol
- Step 15 Racemic-4-((5aR,6S,7S,8aR)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl
- Racemic-(5aR,6S,7S,8aR)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-6 -Phenyl-5a,6,7,8a-tetrahydro-8H-cyclopentadieno[4,5]furo[3,2-c]pyridin-8-one 33 mg, 0.061 mmol
- Zn ( CN) 2 (30mg, 0.26mmol)
- zinc powder (6mg, 0.083mmol) were mixed with DMF (1mL), water (0.1mL), nitrogen was deoxygenated for 5 minutes, then Pd 2 (dba) 3 (7.5mg, 0.0082 mmol) and dppf (9 mg, 0.017 mmol), heated and stirred at 120°C for 90 minutes under microwave conditions.
- reaction solution was cooled to room temperature, the insoluble matter was removed by diatomaceous earth filtration, the filtrate was concentrated under reduced pressure and purified by preparative thin layer to obtain the title compound racemic-4-((5aR,6S,7S,8aR)-7-((dimethyl Amino)methyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5 ]furo[3,2-c]pyridin-5a-yl)benzonitrile (20 mg, 68%).
- Example 1 4-((1S,2S,2aR,2a1S,9aR)-1-((dimethylamino)methyl)-2a1-hydroxy-5-methoxy-2-phenyl-1,2,2a1,9a-
- Example 1 for the preparation method of tetrahydro-2aH-3,7,9-trioxa-6-azabenzo[cd]cyclopentadieno[ij]azulene-2a-yl)benzonitrile.
- the first step the preparation of 4-(benzyloxy)-2,6-dichloropyridine
- the second step the preparation of 4-(benzyloxy)-2-chloro-6-methoxypyridine
- the third step preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol
- the fourth step the preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-one
- the fifth step the preparation of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl) ethane-1-one
- the seventh step preparation of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one
- the eighth step preparation of 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one
- Step 9 Racemic-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl- Preparation of 2,3,4,5-tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate
- Step 10 Racemic-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-benzene Preparation of base-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylate
- Step 11 Racemic-(5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl- Preparation of 5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylic acid
- reaction solution was adjusted to 6 with 1N HCl, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to obtain the title compound racemic-(5aR,7R,8R,8aS)-5a-(4- bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furan and [3,2-c]pyridine-7-carboxylic acid (206 mg, 81%).
- Step 12 Racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N - Preparation of dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide
- reaction solution was diluted with DCM, washed with saturated brine, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography to obtain the title compound racemic-(5aR,6S,7R,8R,8aS)-5a- (4-Bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H- Cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide (215 mg, 89%).
- racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N- Dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide (0.215 g , 387.10 ⁇ mol) was dissolved in THF (6 mL), borane (3.87 mmol, 1.9 mL, 2M THF solution) was slowly added, and the reaction solution was stirred under ice bath for 10 minutes and at room temperature for 12 hours.
- reaction was quenched by adding methanol solution and stirred at 60°C for 12 hours.
- the reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl )-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine- 8,8a-Diol (120 mg, 57%).
- reaction solution was cooled to room temperature, diluted with water, extracted with DCM, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, concentrated and separated by reverse-phase preparation, and then resolved on a chiral column to obtain the optically pure title compound (5aR, 6S, 7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7 ,8-Tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol (8 mg, 8.6%).
- the first step the preparation of 4-(benzyloxy)-2,6-dichloropyridine
- the second step the preparation of 4-(benzyloxy)-2-chloro-6-methoxypyridine
- the third step preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol
- the fourth step the preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-one
- the fifth step the preparation of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl) ethane-1-one
- the seventh step preparation of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one
- the eighth step preparation of 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one
- Step 9 Racemic-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl- Preparation of 2,3,4,5-tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate
- Step 10 Racemic-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-benzene Preparation of base-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylate
- Step 11 Racemic-(5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl- Preparation of 5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylic acid
- reaction solution was adjusted to 6 with 1N HCl, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to obtain the title compound racemic-(5aR,7R,8R,8aS)-5a-(4- bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furan and [3,2-c]pyridine-7-carboxylic acid (206 mg, 81%).
- Step 12 Racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N - Preparation of dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide
- reaction solution was diluted with DCM, washed with saturated brine, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography to obtain the title compound racemic-(5aR,6S,7R,8R,8aS)-5a- (4-Bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H- Cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide (215 mg, 89%).
- the thirteenth step Racemic-(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-5a-(4- Nitrophenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide preparation
- Step 14 (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-nitrophenyl)-6 - Preparation of phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol
- reaction was quenched by adding methanol solution and stirred at 60°C for 12 hours.
- the reaction solution was concentrated under reduced pressure, separated by reverse-phase preparation, and then resolved on a chiral column to obtain the optically pure title compound (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1, 3-Dimethoxy-5a-(4-nitrophenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3 ,2-c]pyridine-8,8a-diol (27 mg, 11.7%).
- N-cyano-N-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy -6-Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)cyanoamide Refer to Example 1 for the preparation method.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种多环类生物调节剂、其制备方法和应用。特别地,涉及通式(II)所示的化合物或其立体异构体、其制备方法及含有该化合物的药物组合物,及其在制备治疗癌症及其他相关疾病药物中的应用。
Description
本发明属于药物合成领域,具体涉及一种多环类生物调节剂、其制备方法和应用。
信使RNA(mRNA)翻译异常是恶性肿瘤的一个常见特征,表现为与增殖、存活和转移相关的癌蛋白、生长因子和信号转导蛋白的上调。致癌驱动因子的表达受到严格的翻译控制,并受真核细胞翻译起始因子eIF4F(eukaryotic translation initiation factor 4F)复合物调控,eIF4F介导核糖体募集到mRNA上,开始mRNA至蛋白的翻译过程。eIF4F复合物由mRNA 5'帽状结合蛋白eIF4E、支架蛋白eIF4G和RNA解旋酶eIF4A三个亚单位组成。eIF4F经有eIF4E辨识5'-mRNA帽状结构,eIF4A以ATP依赖的方式解开mRNA 5'-UTR二级结构,通过与多聚A结合蛋白结合环化mRNA,募集40S亚基核糖体扫描和翻译启动。eIF4F亚基经常在各种恶性肿瘤中过表达,因此,靶向eIF4F复合物的成分使失调翻译重新正规化是抗癌药物发现的一种新兴策略。
eIF4A、eIF4E和eIF4G过度激活与相关疾病预后不良有关,包括淋巴瘤、肺癌、大肠癌、肝癌、乳腺癌和卵巢癌。eIF4A根据是否与核糖体结合而分为游离型和复合型,游离型活性为复合型的1/20。eIF4A家族成员有3个:eIF4A1、eIF4A2和eIF4A3,均属于一个称为DEAD-box的解旋酶蛋白家族,其家族蛋白均具有9个保守基序,分别参与RNA结合或ATP水解。
已有报道称,有天然产物可抑制eIF4A介导的翻译,并在体内和体外表现出抗增殖和抗肿瘤的表型。以silvestrol和rocaglamide A为例,已被证明可以结合和稳定不翻译的RNA/eIF4A复合物。这些稳定的eIF4A·RocA复合物阻断了扫描核糖体,从而抑制了目标mRNA的翻译,通过对eIF4A介导的翻译抑制从而调控相关致癌因子表达。目前有很多研发eIF4A抑制剂用于开发抗肿瘤药物。目前该类药物主要的挑战在于:代谢不稳定、溶解性差,以及开发一种稳健的合成方法来生产所需的药物物质以支持临床发展。因此,开发一种理化性质得到改善,且具有良好logP和水溶性,以支持临床控制静脉给药的最佳治疗剂量的eIF4A抑制剂药物是目前亟待解决的问题。
目前,eFFECTOR Therapeutics国际申请WO 2017091585已公开的eIF4A抑制剂eFT226,eFT226临床前实验显示可抑制RTK实体瘤和淋巴瘤的增殖,致癌蛋白翻译(FGFR1/2,HER2,KRAS)以及临床前模型中耐受性良好,目前已进入临床一期研究。调控翻译作为抗癌药物发现的新兴策略,本申请诣在提供一种新型抑制eIF4A活性的抗肿瘤药物,以满足巨大的肿瘤市场需求。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐,其结构如下:
其中:
X选自O、S、S(O)、S(O)
2、C(O)、NR或CRR’;
环A选自环烷基、杂环基、芳基或杂芳基,所述的环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;
R和R’各自独立地选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基,所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;
R
1选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基,所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;
R
2和R
2’各自独立地选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基,所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;
R
3和R
3’各自独立地选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH
2)
n1R
a、-(CH
2)
n1NR
aOR
b、-(CH
2)
n1C(O)NR
aR
b、-(CH
2)
n1NR
aC(O)R
b、-(CH
2)
n1S(O)
m1R
a、-(CH
2)
n1S(O)
m1NR
aR
b、-(CH
2)
n1NR
aS(O)
m1R
b、-(CH
2)
n1NR
aR
b或-(CH
2)
n1NR
a(CH
2)
n2R
b,所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;
R
4和R
4’各自独立地选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂 环基、芳基、杂芳基、-(CH
2)
n3R
c、-(CH
2)
n3NR
cOR
d、-(CH
2)
n3C(O)NR
cR
d、-(CH
2)
n3NR
cC(O)R
d、-(CH
2)
n3S(O)
m2R
c、-(CH
2)
n3S(O)
m2NR
cR
d、-(CH
2)
n3NR
cS(O)
m2R
d、-(CH
2)
n3NR
cR
d或-(CH
2)
n3NR
c(CH
2)
n4R
d,所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;
R
5选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基,所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;
R
a选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基,所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;
或者,R
a和R
4与它们所连的碳原子或杂原子链接形成环烷基或杂环基,所述的环烷基和杂环基,任选地可以进一步被取代;
R
a、R
b、R
c和R
d各自独立的各自独立地选自氢、氘、卤素、氨基、硝基、羟基、氰基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基,所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;
x为0、1、2、3、4或5;
n1~n4为0、1、2、3、4或5;且
m1和m2为0、1或2。
本发明的优选实施方式中,所述环A选自C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
本发明的进一步优选实施方式中,所述环A选自C
6-10芳基或5-10元杂芳基;
本发明的进一步优选实施方式中,所述环A选自5-6元含氮杂芳基;
本发明的进一步优选实施方式中,所述环A选自吡啶基、吡嗪基、嘧啶基、哒嗪基、吡咯基、咪唑基或吡唑基。
在本发明进一步优选的实施方式中,所述的化合物、其立体异构体或其药学上可接受盐,进一步如通式(II)所示:
其中:
R
1选自氢、氘、卤素、氨基、羟基、氰基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地进一步被一个或多个R
8所取代;
R
2和R
2’各自独立地选自氢、氘、卤素、氨基、羟基、氰基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
R
3选自氢、氘、卤素、氨基、羟基、氰基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基、5-14元杂芳基、-(CH
2)
n1R
a、-(CH
2)
n1NR
aOR
b、-(CH
2)
n1C(O)NR
aR
b、-(CH
2)
n1NR
aC(O)R
b、-(CH
2)
n1S(O)
m1R
a、-(CH
2)
n1S(O)
m1NR
aR
b、-(CH
2)
n1NR
aS(O)
m1R
b、-(CH
2)
n1NR
aR
b或-(CH
2)
n1NR
a(CH
2)
n2R
b,所述的C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
R
4选自氢、氘、卤素、氨基、羟基、氰基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基、5-14元杂芳基、-(CH
2)
n3R
c、-(CH
2)
n3NR
cOR
d、-(CH
2)
n3C(O)NR
cR
d、-(CH
2)
n3NR
cC(O)R
d、-(CH
2)
n3S(O)
m2R
c、 -(CH
2)
n3S(O)
m2NR
cR
d、-(CH
2)
n3NR
cS(O)
m2R
d、-(CH
2)
n3NR
cR
d或-(CH
2)
n3NR
c(CH
2)
n4R
d,所述的C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地,进一步被氘、卤素、氨基、羟基、氰基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
R
6选自氢、氘、卤素、氨基、羟基、氰基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
或者,R
6和R
4与它们所连的碳原子链接形成C
5-14环烷基或5-14元杂环基,所述的C
5-14环烷基和5-14元杂环基,任选地进一步被氘、卤素、氨基、羟基、氰基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
R
7选自氢、氘、卤素、氨基、羟基、氰基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
R
8选自氢、氘、卤素、氨基、羟基、氰基、硝基、肟基、叠氮基、巯基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基、5-14元杂芳基、-C(O)R
e或-P(O)R
eR
f,所述的肟基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基和-C(O)-, 任选地进一步被氘、卤素、氨基、羟基、氰基、叠氮基、硝基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
R
a、R
b、R
c、R
d、R
e和R
f各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-6烷基、C
1-6羟烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的氨基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地,进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
n1~n4为0、1、2、3、4或5;且
m1和m2为0、1或2;
本发明的优选实施方式中,所述R
1选自氢、氘、卤素、氨基、羟基、氰基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地进一步被一个或多个R
8所取代;
R
8选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、肟基、巯基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基、5-14元杂芳基、-C(O)R
e、-SR
e、-OR
e、-NR
eR
f、-C(O)NR
eR
f、-NR
eC(O)R
f、-OC(O)R
eR
f、-C(O)OR
e、-S(O)
2R
e、-S(O)R
e、-S(O)
2NR
eR
f、-S(O)NR
eR
f、-NR
eS(O)
2R
f、-NR
eS(O)R
f、-P(O)R
eR
f,所述的氨基、肟基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、叠氮基、硝基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯 基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
本发明的进一步优选实施方式中,所述R
8选自氘、卤素、氰基、叠氮基、肟基、硝基、氨基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳基、-C(O)R
e、-SR
e、-NR
eR
f、-C(O)NR
eR
f、-NR
eC(O)R
f或-P(O)R
eR
f,所述的氨基、肟基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳基,任选地进一步被氘、氰基、羟基、卤素、氧代基、C
1-3烷基、C
1-3卤代烷基、C
1-3烷氧基、C
2-3烯基、C
2-3炔基、C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳基中的一个或多个取代基所取代;
本发明的进一步优选实施方式中,所述R
8选自氰基、叠氮基、硝基、肟基、氨基、巯基、甲基、乙炔基、环丙基、氧杂环丁烷基、氮杂环丁烷基、四氮唑基、-SR
e、-NR
eR
f、-C(O)NR
eR
f、-NR
eC(O)R
f或-P(O)R
eR
f,所述的甲基、乙炔基、环丙基、氧杂环丁烷基、氮杂环丁烷基和四氮唑基,任选地进一步被氰基、羟基、氟、氯、溴、氧代基、甲基和三氟甲基中的一个或多个取代基所取代;
本发明的进一步优选实施方式中,所述R
8选自-CN、-P(O)(CH
3)
2、-N
3、-NO
2、-SCF
3、-SCN、-NCH
3C(O)CH
3、-C(O)N(CH
3)
2、-N(CN)
2、-CH(CN)
2、-C(CN)
3、-(C≡C)CN、
R
e和R
f各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-6烷基、C
1-6羟烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的氨基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地,进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代。
本发明的优选实施方式中,所述R
1选自C
3-8环烷基、3-8元杂环基、C
6-10芳基或5-10元杂芳基,所述的C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳基,任选地进一步被被一个或多个R
8所取代;
本发明的进一步优选实施方式中,所述R
1选自苯基或双环[1.1.1]戊烷,所述的苯基和双环[1.1.1]戊烷,任选地进一步被被一个或多个R
8所取代;
R
8选自氢、氘、卤素、氨基、羟基、氰基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基、C
1-3卤代烷氧基、C
3-8环烷基、3-8元杂环基、C
6-10芳基、5-10元杂芳基或-P(O)R
eR
f;
优选氰基或-P(O)R
eR
f;
R
e和R
f各自独立地选自氢、氘、卤素、氨基、羟基、氰基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基或C
1-3卤代烷氧基;
优选氰基、三氟甲基、甲基、乙基或丙基。
在本发明进一步优选的实施方式中,R
1选自C
3-8环烷基、3-8元杂环基、C
6-10芳基或5-10元杂芳基,所述的C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳基,任选地进一步被被一个或多个R
8所取代,
优选苯基,所述的苯基,任选地进一步被一个或多个R
8所取代;
R
8选自氢、氘、卤素、氨基、羟基、氰基、硝基、肟基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基、C
1-3卤代烷氧基、C
3-8环烷基、3-8元杂环基、C
6-10芳基、5-10元杂芳基,
优选环丙基、硝基或肟基。
本发明的优选实施方式中,所述R
2选自C
3-8环烷基、3-8元杂环基、C
6-10芳基或5-10元杂芳基,所述的C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳基,任选地任选地进一步被氘、卤素、氨基、羟基、氰基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基、C
1-3卤代烷氧基、C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳 基中的一个或多个取代基所取代;
本发明的进一步优选实施方式中,所述R
2选自苯基或双环[1.1.1]戊烷;
本发明的进一步优选实施方式中,所述R
2选自苯基;
R
2’选自氢、氘、卤素、氨基、羟基、氰基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基或C
1-3卤代烷氧基;
本发明的进一步优选实施方式中,所述R
2’选自氢、氘、氟、氯、溴、甲基、乙基或丙基。
本发明的优选实施方式中,所述R
3选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基、5-14元杂芳基、-(CH
2)
n1R
a、-(CH
2)
n1NR
aOR
b、-(CH
2)
n1C(O)NR
aR
b、-(CH
2)
n1OC(O)R
a、-(CH
2)
n1NR
aC(O)R
b、-(CH
2)
n1S(O)
m1R
a、-(CH
2)
n1S(O)
m1NR
aR
b、-(CH
2)
n1NR
aS(O)
m1R
b、-(CH
2)
n1NR
aR
b或-(CH
2)
n1NR
a(CH
2)
n2R
b,所述的氨基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
R
a和R
b各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-6烷基、C
1-6羟烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的氨基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地,进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、氰基取代的C
1-6烷基、C
1-6烷氧基-C
1-6亚烷基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
n1和n2为0、1、2、3、4或5;且
m1为0、1或2。
本发明的优选实施方式中,所述R
3选自-(CH
2)
n1R
a、-(CH
2)
n1NR
aOR
b、-(CH
2)
n1C(O)NR
aR
b、-(CH
2)
n1NR
aC(O)R
b、-(CH
2)
n1S(O)
m1R
a、-(CH
2)
n1S(O)
m1NR
aR
b、 -(CH
2)
n1NR
aS(O)
m1R
b、-(CH
2)
n1NR
aR
b或-(CH
2)
n1NR
a(CH
2)
n2R
b;
本发明的进一步优选实施方式中,所述R
3选自-CH
2R
a、-C(O)NR
aR
b、-S(O)
2R
b、-CH
2NR
aRb
d、-CH
2)NR
aCH
2R
b或-CH
2NR
a(CH
2)
2R
b;
R
a和R
b各自独立地选自氢、卤素、羟基、C
1-3烷基、C
1-3羟烷基、C
1-3卤代烷基、C
1-3烷氧基或4-8元含氮杂环基,所述的C
1-3烷基、C
1-3羟烷基、C
1-3卤代烷基、C
1-3烷氧基和4-8元含氮杂环基,任选地进一步被氢、氘、羟基、C
1-3烷基、C
1-3羟烷基、C
1-3卤代烷基、C
1-3烷氧基、卤素、氰基、氰基取代的C
1-3烷基或C
1-3烷氧基-C
1-3亚烷基中的一个或多个取代基所取代;
优选氢、氟、氯、溴、甲基、乙基、甲氧基、2-羟基异丙基、哌啶基、哌嗪基、吗啉基、吡咯烷基、氮杂环丁烷基、2-氧杂-6-氮杂螺[3.3]庚烷基、(1R,5S)-8-氮杂双环[3.2.1]辛烷基、(1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷基,所述的甲基、乙基、甲氧基、2-羟基异丙基、哌啶基、哌嗪基、吗啉基、吡咯烷基、氮杂环丁烷基、2-氧杂-6-氮杂螺[3.3]庚烷基、(1R,5S)-8-氮杂双环[3.2.1]辛烷基、(1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷基,任选地进一步被氢、氘、羟基、甲基、乙基、甲氧基、二氟甲基、三氟甲基、氟、氯、溴、氰基、一氟甲基、氰基亚甲基、甲氧基亚甲基中的一个或多个取代基所取代;
n1和n2为为0、1、2、3、4或5;且
m1为0、1或2。
本发明的优选实施方式中,所述R
4选自-OH、-(CH
2)
n3R
c、-(CH
2)
n3NR
cOR
d、-(CH
2)
n3C(O)NR
cR
d、-(CH
2)
n3NR
cC(O)R
d、-(CH
2)
n3S(O)
m2R
c、-(CH
2)
n3S(O)
m2NR
cR
d、-(CH
2)
n3NR
cS(O)
m2R
d、-(CH
2)
n3NR
cR
d或-(CH
2)
n3NR
c(CH
2)
n4R
d
本发明的进一步优选实施方式中,所述R
4选自-OH、-(CH
2)
n3NR
cR
d或-(CH
2)
n3NR
cOR
d;
R
c和R
d各自独立地选自氢、卤素、羟基、C
1-3烷基、C
1-3羟烷基、C
1-3卤代烷基或C
1-3烷氧基,所述的C
1-3烷基、C
1-3羟烷基、C
1-3卤代烷基和C
1-3烷氧基,任选地进一步被氢、氘、羟基、C
1-3烷基、C
1-3羟烷基、C
1-3卤代烷基或C
1-3烷氧基中的一个或多个取代基所取代;
n3和n4为0、1、2、3、4或5;且
m2为0、1或2。
本发明的优选实施方式中,所述R
3与R
4、以及它们所在的碳原子一起链接形成C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地,进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代。
本发明的优选实施方式中,R
3与R
4、以及它们所在的碳原子一起链接形成3-12元杂环基,所述3-12元杂环基,任选地,进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基、C
1-3卤代烷氧基、C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳基中的一个或多个取代基所取代
本发明的优选实施方式中,R
3与R
4、以及它们所在的碳原子一起链接形成以下杂环基
本发明的优选实施方式中,所述R
6选自氢、氘、卤素、氨基、羟基、氰基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基或C
1-3卤代烷氧基;
本发明的进一步优选实施方式中,所述R
6选自甲氧基、乙氧基、一氟甲氧基、二氟甲氧基或三氟甲氧基。
本发明的优选实施方式中,所述R
7选自氢、氘、卤素、氨基、羟基、氰基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基或C
1-3卤代烷氧基;
本发明的进一步优选实施方式中,所述R
7选自氰基、甲氧基、乙氧基、一氟甲氧基、二氟甲氧基或三氟甲氧基。
本发明的优选实施方式中,所述R
4和R
6与它们所连的碳原子链接形成C
5-14环烷基或5-14元杂环基,所述的C
5-14环烷基和5-14元杂环基,任选地进一步被氘、卤素、氨基、羟基、氰基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
本发明的进一步优选实施方式中,所述R
4和R
6与它们所连的碳原子共同形成一个5-12元杂环基,所述的5-12元杂环基,任选地进一步被氘、卤素、氨基、羟基、氰基、氧代基、硫代基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基、C
1-3卤代烷氧基、C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳基中的一个或多个取代基所取代;
在本发明进一步优选的实施方式中,所述的化合物、其立体异构体或其药学上可接受盐,进一步如通式(III)所示:
所述R
3,R
7和R
d的定义如前所述。
在本发明进一步优选的实施方式中,所述的化合物、其立体异构体或其药学上可接受盐,进一步如通式(IV)所示:
本发明的优选实施方式中,所述R
2’选自氢、氘、卤素、氨基、羟基、氰基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基或C
1-3卤代烷氧基;
本发明的进一步优选实施方式中,所述R
2’选自氢、氘、氟、氯、溴、甲基、乙基或丙基;
本发明的优选实施方式中,所述R
3选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基、5-14元杂芳基、-(CH
2)
n1R
a、-(CH
2)
n1NR
aOR
b、-(CH
2)
n1C(O)NR
aR
b、-(CH
2)
n1OC(O)R
a、-(CH
2)
n1NR
aC(O)R
b、-(CH
2)
n1S(O)
m1R
a、-(CH
2)
n1S(O)
m1NR
aR
b、-(CH
2)
n1NR
aS(O)
m1R
b、-(CH
2)
n1NR
aR
b或 -(CH
2)
n1NR
a(CH
2)
n2R
b,所述的氨基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
R
a和R
b各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-6烷基、C
1-6羟烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的氨基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地,进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、氰基取代的C
1-6烷基、C
1-6烷氧基-C
1-6亚烷基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
n1和n2为0、1、2、3、4或5;且
m1为0、1或2。
本发明的优选实施方式中,所述R
7选自氢、氘、卤素、氨基、羟基、氰基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基或C
1-3卤代烷氧基;
本发明的进一步优选实施方式中,所述R
7选自氰基、甲氧基、乙氧基、一氟甲氧基、二氟甲氧基或三氟甲氧基;
本发明的优选实施方式中,所述R
8选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基、5-14元杂芳基、-SR
e、-OR
e、-NR
eR
f、-C(O)R
e、-C=NR
e、-C(O)NR
eR
f、-NR
eC(O)R
f、-OC(O)R
eR
f、-C(O)OR
e、-S(O)
2R
e、-S(O)R
e、-S(O)
2NR
eR
f、-S(O)NR
eR
f、-NR
eS(O)
2R
f、-NR
eS(O)R
f、-P(O)R
eR
f,所述的氨基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、叠氮基、硝基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷氧基烷基、氰基取代的C
1-6烷基、C
1-6烷硫基、 C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
本发明的进一步优选实施方式中,所述R
8选自氘、卤素、氰基、叠氮基、硝基、氨基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳基、-SR
e、-NR
eR
f、-C(O)R
e、-C=NR
e、-C(O)NR
eR
f、-NR
eC(O)R
f或-P(O)R
eR
f,所述的氨基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳基,任选地进一步被氘、氰基、羟基、氨基、卤素、氧代基、C
1-3烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷氧基烷基、氰基取代的C
1-3烷基、C
2-3烯基、C
2-3炔基、C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳基中的一个或多个取代基所取代;
本发明的进一步优选实施方式中,所述R
8选自氰基、叠氮基、硝基、氨基、巯基、甲基、乙炔基、环丙基、氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氮唑基、2-氧杂-6-氮杂螺[3.3]庚烷、(3aR,6aS)-六氢-1H-呋喃[3,4-c]吡咯、-SR
e、-NR
eR
f、-C(O)R
e、-C=NR
e、-C(O)NR
eR
f、-NR
eC(O)R
f或-P(O)R
eR
f,所述的甲基、乙炔基、环丙基、氧杂环丁烷基、氮杂环丁烷基和四氮唑基,任选地进一步被氰基、羟基、氨基、氟、氯、溴、氧代基、甲基、一氟甲基、二氟甲基、三氟甲基、甲氧基、甲氧基甲基、羟甲基、羟基异丙基和氰基甲基中的一个或多个取代基所取代;
本发明的进一步优选实施方式中,所述R
8选自氰基、叠氮基、硝基、C
3-6环烷基、含2-4个氮原子的5-6元杂芳基、含1个氮或氧原子的4-6元杂环基、含2-3个选自氮或氧原子的7-8元螺杂环基、含2-3个选自氮或氧原子的7-8元稠杂环基,任选地进一步被氘、卤素、氨基、羟基、氰基、叠氮基、硝基、巯基、氧代基、C
1-3烷基、C
1-3烷氧基、C
1-3卤代烷基或氰基取代的C
1-3烷基中的一个或多个取代基所取代;
本发明的进一步优选实施方式中,所述R
8选自-CN、-P(O)(CH
3)
2、-N
3、-NO
2、-SCF
3、-SCN、-NCH
3C(O)CH
3、-C(O)N(CH
3)
2、-N(CN)
2、-CH(CN)
2、-C(CN)
3、-(C≡C)CN、
R
e和R
f各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-6烷基、C
1-6羟烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的氨基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地,进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代。
在本发明进一步优选的实施方式中,通式(IV)所示化合物、其立体异构体或其药学上可接受盐,其中:
R
2’选自氢;
R
3选自-(CH
2)
n1NR
aC(O)R
b或-(CH
2)
n1NR
aR
b;
R
a或R
b各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-3烷基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基或C
1-3卤代烷氧基;
或者,R
a和R
b与相邻的氮原子形成含1-2个选自氮或氧原子的4-8元杂环基,任选地进一步被卤素、C
1-3烷基、C
1-3烷氧基、C
1-3卤代烷基或C
1-3羟烷基中的一个或多个取代基所取代;
R
7选自氰基或C
1-3烷氧基;
R
8选自氰基、叠氮基、硝基、C
3-6环烷基、含2-4个氮原子的5-6元杂芳基、含1个氮或氧原子的4-6元杂环基、含2-3个选自氮或氧原子的7-8元螺杂环基、含2-3个选自氮或氧原子的7-8元稠杂环基,任选地进一步被氘、卤素、氨基、羟基、氰基、叠氮基、硝基、巯基、氧代基、C
1-3烷基、C
1-3烷氧基、C
1-3卤代烷基或氰基取代的C
1-3烷基中的一个或多个取代基所取代。
在本发明进一步优选的实施方式中,通式(IV)所示化合物、其立体异构体 或其药学上可接受盐,其中:
R
2’选自氢;
R
3选自-(CH
2)
n1NR
aR
b;
R
a或R
b各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-3烷基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基或C
1-3卤代烷氧基;优选氢、氘、C
1-3烷基、C
1-3氘代烷基或C
1-3卤代烷基;更优选甲基;
R
7选自氰基或C
1-3烷氧基;更优选甲氧基;
R
8选自氰基、叠氮基、肟基、硝基、C
3-6环烷基;更优选肟基、硝基或环丙基;
n1为1。
在本发明进一步优选的实施方式中,所述的化合物、其立体异构体或其药学上可接受盐,进一步如通式(V)所示:
R
2’选自氢、氘、卤素、氨基、羟基、氰基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基或C
1-3卤代烷氧基,
优选氢、氘、氟、氯、溴、甲基、乙基或丙基;更优选氢;
R
6和R
7各自独立地选自氢、氘、卤素、氨基、羟基、氰基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基或C
1-3卤代烷氧基,
更优选氰基、甲氧基、乙氧基、一氟甲氧基、二氟甲氧基或三氟甲氧基;
R
8选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、肟基、巯基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基、5-14元杂芳基、-SR
e、-OR
e、-NR
eR
f、-C(O)NR
eR
f、-NR
eC(O)R
f、-OC(O)R
eR
f、-C(O)OR
e、-S(O)
2R
e、-S(O)R
e、-S(O)
2NR
eR
f、-S(O)NR
eR
f、-NR
eS(O)
2R
f、-NR
eS(O)R
f、-P(O)R
eR
f,所述的氨基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、 羟基、氰基、叠氮基、硝基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷氧基烷基、氰基取代的C
1-6烷基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代,
优选为氰基、叠氮基、肟基、硝基、C
3-6环烷基、含2-4个氮原子的5-6元杂芳基、含1个氮或氧原子的4-6元杂环基、含2-3个选自氮或氧原子的7-8元螺杂环基、含2-3个选自氮或氧原子的7-8元稠杂环基;任选地进一步被氘、卤素、氨基、羟基、氰基、叠氮基、硝基、巯基、氧代基、C
1-3烷基、C
1-3烷氧基、C
1-3卤代烷基或氰基取代的C
1-3烷基、中的一个或多个取代基所取代;
R
a和R
b各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-6烷基、C
1-6羟烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的氨基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地,进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
或者,R
a和R
b与相邻的氮原子形成含1-3个选自氮或氧原子的4-10元杂环基,任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
R
e和R
f各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-6烷基、C
1-6羟烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的氨基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地,进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
n1和n2为0、1、2、3、4或5;且
m1为0、1或2。
本发明的优选实施方式中,所述R
6和R
7各自独立地选自氢、氘、卤素、氨基、羟基、氰基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基或C
1-3卤代烷氧基;
本发明的进一步优选实施方式中,所述R
6和R
7选自氰基、甲氧基、乙氧基、一氟甲氧基、二氟甲氧基或三氟甲氧基;
本发明的优选实施方式中,所述R
8选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基、5-14元杂芳基、-SR
e、-OR
e、-NR
eR
f、-C(O)R
e、-C=NR
e、-C(O)NR
eR
f、-NR
eC(O)R
f、-OC(O)R
eR
f、-C(O)OR
e、-S(O)
2R
e、-S(O)R
e、-S(O)
2NR
eR
f、-S(O)NR
eR
f、-NR
eS(O)
2R
f、-NR
eS(O)R
f、-P(O)R
eR
f,所述的氨基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、叠氮基、硝基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷氧基烷基、氰基取代的C
1-6烷基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;
本发明的进一步优选实施方式中,所述R
8选自氘、卤素、氰基、叠氮基、硝基、氨基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳基、-SR
e、-NR
eR
f、-C(O)R
e、-C=NR
e、-C(O)NR
eR
f、-NR
eC(O)R
f或-P(O)R
eR
f,所述的氨基、C
1-3烷基、C
2-3烯基、C
2-3炔基、C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳基,任选地进一步被氘、氰基、羟基、氨基、卤素、氧代基、C
1-3烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷氧基烷基、氰基取代的C
1-3烷基、C
2-3烯基、C
2-3炔基、C
3-8环烷基、3-8元杂环基、C
6-10芳基和5-10元杂芳基中的一个或多个取代基所取代;
本发明的进一步优选实施方式中,所述R
8选自氰基、叠氮基、硝基、氨基、巯基、甲基、乙炔基、环丙基、氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氮唑基、2-氧杂-6-氮杂螺[3.3]庚烷、(3aR,6aS)-六氢-1H-呋喃[3,4-c]吡咯、-SR
e、-NR
eR
f、-C(O)R
e、-C=NR
e、-C(O)NR
eR
f、-NR
eC(O)R
f或-P(O)R
eR
f,所述的甲基、乙炔基、环丙基、氧杂环丁烷基、氮杂环丁烷基和四氮唑基,任选地进一步被氰基、羟基、氨基、氟、氯、溴、氧代基、甲基、一氟甲基、二氟甲基、三氟甲基、甲氧基、甲氧基甲基、羟甲基、羟基异丙基和氰基甲基中的一个或多个取代基所取代;
本发明的进一步优选实施方式中,所述R
8选自氰基、叠氮基、硝基、C
3-6环烷基、含2-4个氮原子的5-6元杂芳基、含1个氮或氧原子的4-6元杂环基、含2-3个选自氮或氧原子的7-8元螺杂环基、含2-3个选自氮或氧原子的7-8元 稠杂环基,任选地进一步被氘、卤素、氨基、羟基、氰基、叠氮基、硝基、巯基、氧代基、C
1-3烷基、C
1-3烷氧基、C
1-3卤代烷基或氰基取代的C
1-3烷基中的一个或多个取代基所取代;
本发明的进一步优选实施方式中,所述R
8选自-CN、-P(O)(CH
3)
2、-N
3、-NO
2、-SCF
3、-SCN、-NCH
3C(O)CH
3、-C(O)N(CH
3)
2、-N(CN)
2、-CH(CN)
2、-C(CN)
3、-(C≡C)CN、
R
e和R
f各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-6烷基、C
1-6羟烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基或5-14元杂芳基,所述的氨基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基,任选地,进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6氘代烷基、C
1-6卤代烷基、C
1-6羟烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6卤代烷氧基、C
3-12环烷基、3-12元杂环基、C
6-14芳基和5-14元杂芳基中的一个或多个取代基所取代。
在本发明进一步优选的实施方式中,通式(V)所示化合物、其立体异构体或其药学上可接受盐,其中:
R
2’选自氢;
R
a或R
b各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C
1-3烷基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3羟烷基、C
1-3烷氧基、C
1-3烷硫基或C
1-3卤代烷氧基;优选氢、氘、C
1-3烷基、C
1-3氘代烷基或C
1-3卤代烷基;更优选甲基;
R
6和R
7各自独立地选自氰基或C
1-3烷氧基;更优选甲氧基;
R
8选自氰基、叠氮基、肟基、硝基、C
3-6环烷基;更优选肟基、硝基或环丙基。
本发明进一步提供一种中间体通式(M)所示的化合物、其立体异构体或其药学上可接受盐:
R
3选自-C(O)R
g;
R
g选自羟基,C
1-3烷氧基或-NR
aR
b;
R
4,R
6,R
7,R
8,R
a或R
b如前所述。
本发明进一步提供一种制备通式(VI)化合物或其立体异构体及其药学上可接受盐的方法,其特征在于,包含以下步骤:
由通式(M-1)反应得到通式(M-2),通式(M-2)反应得到通式(M-3),通式(M-3)还原得到通式(VI);
Pg选自C
1-3烷氧基;
R
4,R
6,R
7,R
8,R
a或R
b如前所述。
在本发明的一个实施方式中,所述通式(M-1)、(M-2)和(M-3)中,R
4优选为羟基。
本发明进一步涉及一种药物组合物,其包括治疗有效剂量的通式(I)化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
另一方面,本发明的目的还在于提供一种包含通式(I)所述的化合物、其立 体异构体或其药学上可接受的盐、或其药物组合物在治疗和/或预防ATP依赖的RNA解旋酶相关疾病的药物中的用途,特别是在治疗和/或预防真核起始因子4A(eIF4A)抑制剂相关疾病的药物中的用途。
另一方面,本发明的目的还在于提供一种包含通式(I)所述的化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在治疗和/或预防癌症、骨髓化生不良症候群、阿兹海默症、帕金森氏症、X染色体脆折症和自闭症等相关疾病的药物中的用途。
本发明的还涉及一种治疗和/或预防癌症、骨髓化生不良症候群、阿兹海默症、帕金森氏症、X染色体脆折症和自闭症等相关疾病的方法。另一方面,本发明的目的还在于提供包含通式(I)所述的化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在治疗和/或预防癌症、骨髓化生不良症候群、阿兹海默症、帕金森氏症、X染色体脆折症和自闭症等相关疾病中的用途。
在以上技术方案中,所述的癌症相关疾病选自或血液肿瘤,优选大肠直肠癌、膀胱癌、胃癌、甲状腺癌、食道癌、头颈癌、脑癌、胶质瘤、胶质母细胞瘤、肝细胞癌、肺癌、黑色素瘤、骨髓瘤、胰脏癌、肾细胞癌、子宫颈癌、泌尿上皮癌、前列腺癌、卵巢癌、乳腺癌、白血病或淋巴瘤。
发明的详细说明
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至12个碳原子的烷基,更优选含有1至8个碳原子的烷基,进一步优选1至6个碳原子的烷基,最优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、4-庚基、1-丙基丁基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基,及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基,非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、 正己基、正庚基、4-庚基、1-丙基丁基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基,本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。
术语“亚烷基”是指烷基的一个氢原子进一步被取代,例如:“亚甲基”指-CH
2-、“亚乙基”指-(CH
2)
2-、“亚丙基”指-(CH
2)
3-、“亚丁基”指-(CH
2)
4-等。术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基,例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,优选包含3至12个碳原子,更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等;多环环烷基包括螺环、稠环和桥环的环烷基,优选环丙基、环丁基、环己基、环戊基和环庚基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基,优选为单螺环烷基和双螺环烷基。更优选为3元/6元、3元/5元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括:
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基,非限制性实例包括:
术语“稠环烷基”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括:
术语“桥环烷基”指5至20元,任意两个环共用两个不直接连接的碳原子的全碳多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,优选为双环、三环或四环,更有选为双环或三环。桥环烷基的非限制性实例包括:
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上,其中与母体结构连接在一起的环为环烷基,非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧、C(O)或S(O)
m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1~4个是杂原子;更优选包含3至8个环原子;最优选包含3至8个环原子;进一步优选包含1-3氮原子的3-8元杂环基,任选地,被1-2个氧原子、硫原子、氧代基取代,包括含氮单环杂环基、含氮螺杂环基或含氮稠杂环基。
单环杂环基的非限制性实例包括氧杂环丁基、氮杂环丁烷基、硫杂环丁基、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、 高哌嗪基、吖庚基、1,4-二氮杂环庚基、吡喃基或四氢噻喃二氧化物基等;优选氧杂环丁基、氮杂环丁烷基、硫杂环丁基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢噻喃基、四氢噻喃二氧化物基、吡咯烷基、吗啉基、哌啶基、哌嗪基、六氢吡嗪基、六氢嘧啶基、吖庚基、1,4-二氮杂环庚基和哌嗪基;更优选哌啶基、哌嗪基、吡咯烷基、吗啉基、氧杂环丁烷基或氮杂环丁烷基。多环杂环基包括螺环、稠环和桥环的杂环基;其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接,或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团,其中一个或多个环原子为选自氮、氧或S(O)
m(其中m是整数0至2)的杂原子,其余环原子为碳。其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单螺杂环基和双螺杂环基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括:
术语“稠杂环基”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子为选自氮、氧或S(O)
m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基,优选为双环或三环,更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括:
术语“桥杂环基”指5至14元,任意两个环共用两个不直接连接的原子的多环杂环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子为选自氮、氧或S(O)
m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基,优选为双环、三环或四环,更有选为双环或三环。桥杂环基的非限制性实例包括:
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基,其非限制性实例包括:
杂环基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至12元,例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,包括苯并5-10元杂芳基、苯并3-8元环烷基和苯并3-8元杂烷基,优选苯并5-6元杂芳基、苯并3-6 元环烷基和苯并3-6元杂烷基,其中杂环基为含1-3氮原子、氧原子、硫原子的杂环基;或者还包含含苯环的三元含氮稠环。
其中与母体结构连接在一起的环为芳基环,其非限制性实例包括:
芳基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。杂芳基优选为5至12元,更优选为5元或6元,例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等,优选吡啶基、噁二唑基、三唑基、噻吩基、咪唑基、吡唑基、噁唑基、噻唑基、嘧啶基或噻唑基;更优选四氮唑基、吡啶基、噁二唑基、吡唑基、吡咯基、噻唑基和噁唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,其非限制性实例包括:
杂芳基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基),其中烷基的定义如上所述。烷氧基的非限制性实例包括:甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环 丁氧基、环戊氧基、环己氧基,烷氧基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“卤代烷基”指被一个或多个卤素取代的烷基,其中烷基如上所定义。
“卤代烷氧基”指被一个或多个卤素取代的烷氧基,其中烷氧基如上所定义。
“羟烷基”指被羟基取代的烷基,其中烷基如上所定义。
“烯基”指链烯基,又称烯烃基,其中所述的烯基可以进一步被其他相关基团取代,例如:烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“炔基”指(CH≡C-),其中所述的炔基可以进一步被其他相关基团取代,例如:烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烯基羰基”指-C(O)-(烯基),其中烯基的定义如上所述。烯基羰基的非限制性实例包括:乙烯基羰基、丙烯基羰基、丁烯基羰基。烯基羰基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“羟基”指-OH基团。
“卤素”指氟、氯、溴或碘。
“氨基”指-NH
2。
“氰基”指-CN。
“硝基”指-NO
2。
“羰基”或“氧代基”指-C(O)-。
“羧基”指-C(O)OH。
“THF”指四氢呋喃。
“乙酸乙酯”指乙酸乙酯。
“MeOH”指甲醇。
“DMF”指N,N-二甲基甲酰胺。
“DIPEA”指二异丙基乙胺。
“TFA”指三氟乙酸。
“TEA”指三乙胺。
“MeCN”指乙晴。
“DMA”指N,N-二甲基乙酰胺。
“Et
2O”指乙醚。
“DCM”指二氯甲烷。
“DMAP”指4-二甲氨基吡啶。
“DCC”指二环己基碳二亚胺。
“DCE”指1,2二氯乙烷。
“DIPEA”指N,N-二异丙基乙胺。
“NBS”指N-溴代琥珀酰亚胺。
“NIS”指N-碘代丁二酰亚胺。
“Cbz-Cl”指氯甲酸苄酯。
“Pd
2(dba)
3”指三(二亚苄基丙酮)二钯。
“Dppf”指1,1’-双二苯基膦二茂铁。
“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。
“KHMDS”指六甲基二硅基胺基钾。
“LiHMDS”指双三甲基硅基胺基锂。
“MeLi”指甲基锂。
“n-BuLi”指正丁基锂。
“NaBH(OAc)
3”指三乙酰氧基硼氢化钠。
“氨基酸残基”指天然氨基酸残基或非天然氨基酸残基。
“天然的氨基酸”是指20种常规氨基酸,即丙氨酸(A),半胱氨酸(C),天冬氨酸(D),谷氨酸(E),苯丙氨酸(F),甘氨酸(G),组氨酸(H),异亮氨酸(I),赖氨酸(K),亮氨酸(L),甲硫氨酸(M),天冬酰胺(N),脯氨酸(P),谷氨酰胺(Q),精氨酸(R),丝氨酸(S),苏氨酸(T),缬氨酸(V),色氨酸(W)和酪氨酸(Y)。
“非天然氨基酸”是指不是天然编码的或在任何生物体的遗传密码中发现的氨基酸,它们可以是例如纯合成的化合物。
“硫代氨基酸”指氨基酸上的氧原子被硫原子取代后的氨基酸,该氧原子可以为羰基(C=O)或羟基(OH)中的氧原子。
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义,即表示X可以是A、B、C中的任意一种或几种。
本发明所述的氢原子均可被其同位素氘所取代,本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生的场合。例如,“任选被烷基取代的杂环基团” 意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐,这类盐用于哺乳动物体内时具有安全性和有效性,且具有应有的生物活性。
以下结合实施例进一步描述本发明,但这些实施例并非限制着本发明的范围。
实施例
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d
6),氘代甲醇(CD
3OD)和氘代氯仿(CDCl
3),内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 1200 Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C
18 150×4.6mm色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,TLC采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明实施例中的起始原料是已知的并且可以在市场上买到,或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下,本发明的所有反应均在连续的磁力搅拌下,在干燥氮气或氩气氛下进行,溶剂为干燥溶剂,反应温度单位为摄氏度。
实施例1
4-((5aS,6S,7S,8R,8aR)-7-((二甲氨基)甲基)-8-(羟氨基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
第一步:4-(苄氧基)-2,6-二氯吡啶的制备
冰水浴下,往2,4,6-三氯吡啶(30.0g,165mmol)的DMF溶液(300mL)里分批加入NaH(7.59g,60wt%,190mmol),加完后,继续在该温度下搅拌15分钟,然后逐滴加入苄醇(17.9mL,173mmol),加毕,再在冰水浴下搅拌1小时。将反应液倒入冰水中,用乙酸乙酯萃取三次,合并有机相,再用饱和食盐水洗涤多次,分离有机相并用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物4-(苄氧基)-2,6-二氯吡啶(30.4g,73%)。
1H NMR(400MHz,CDCl
3)δ5.11(s,2H),6.86(s,2H),7.37-7.42(m,5H);
MS m/z(ESI):254.0[M+H]
+.
第二步:4-(苄氧基)-2-氯-6-甲氧基吡啶的制备
往4-(苄氧基)-2,6-二氯吡啶(27.0g,106mmol)的甲苯溶液(400mL)里加入甲醇钠的甲醇溶液(30wt%,36.4g,202mmol),然后在60℃下搅拌5小时。反应冷却至室温,反应液倒入水中,用乙酸乙酯萃取三次,合并有机相,用饱和食盐水洗涤,分离有机相用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物4-(苄氧基)-2-氯-6-甲氧基吡啶(19.6g,74%)。
1H NMR(400MHz,DMSO-d
6)δ3.81(s,3H),5.20(s,2H),6.46(d,J=1.9Hz,1H),6.81(d,J=1.9Hz,1H),7.32-7.47(m,5H);
MS m/z(ESI):250.2[M+H]
+.
第三步:1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-醇的制备
在干冰-丙酮浴下,往4-(苄氧基)-2-氯-6-甲氧基吡啶(19.5g,78.1mmol)的THF溶液(200mL)里,滴加入n-BuLi的正己烷溶液(41.0mL,2.4M,97.6mmol), 在该温度下搅拌30分钟,然后向反应体系中滴加乙醛(6.88g,156mmol),滴加完毕,继续搅拌10分钟,加入饱和氯化铵水溶液淬灭反应,反应液用乙酸乙酯萃取多次,合并有机相,用饱和食盐水洗涤,分离有机相用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得标题化合物1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-醇(16g,70%)。
1H NMR(400MHz,DMSO-d
6)δ1.39(d,J=6.6Hz,3H),3.84(s,3H),4.60(d,J=6.6Hz,1H),5.09-5.14(m,1H),5.25(s,2H),6.93(s,1H),7.32-7.49(m,5H);
MS m/z(ESI):294.1[M+H]
+.
第四步:1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-酮的制备
往1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-醇(16.0g,54.6mmol)的二氯甲烷溶液(320mL)里分批加入DMP(30.1g,71.0mmol),加毕,继续在室温下搅拌2小时。然后依次加入饱和碳酸氢钠水溶液和硫代硫酸钠水溶液,再搅拌15分钟。分离有机相,水相再用二氯甲烷萃取二次。合并有机相后,用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-酮(8.10g,51%)。
1H NMR(400MHz,DMSO-d
6)δ2.37(s,3H),3.84(s,3H),4.60(d,J=6.1Hz,1H),5.28(s,2H),7.10(s,1H),7.32-7.47(m,5H);
MS m/z(ESI):292.2[M+H]
+.
第五步:1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)乙烷-1-酮的制备
往1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-酮(4.67g,16.0mmol)的乙酸乙酯溶液(120mL)里,加入Pd/C(140mg,10wt%),在氢气氛下,常温常压,搅拌3小时,用硅藻土滤除不溶物,滤液减压浓缩后柱层析分离得到标题化合物1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)乙烷-1-酮(2.30g,71%)。
1H NMR(400MHz,DMSO-d
6)δ2.50(s,3H),3.90(s,3H),6.70(s,1H),13.00(s,1H);
MS m/z(ESI):202.2[M+H]
+.
第六步:(E)-3-(4-溴苯基)-1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)丙-2-烯-1-酮的制备
往1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)乙烷-1-酮(2.00g,9.92mmol),4-溴苯甲醛(1.65g,8.93mmol)的DMF溶液(31mL)里加入MeONa的MeOH溶液(5.36g,30wt%,29.8mmol),在50℃下剧烈搅拌30分钟,冷却,然后在冰水浴下倒入稀盐酸(0.3M,200mL)中,过滤收集析出的固体并干燥,然后用EtOAc/正庚烷混合溶剂(混合溶剂比1:10)打浆纯化,得到标题化合物(E)-3-(4-溴苯基)-1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)丙-2-烯-1-酮(1.87g,57%)。
1H NMR(400MHz,DMSO-d
6)δ3.80(s,3H),6.60(s,1H),7.20(d,J=16.0Hz,1H),7.40(d,J=16.0Hz,1H),7.56-7.73(m,4H);
MS m/z(ESI):368.0[M+H]
+.
第七步:2-(4-溴苯基)-7-氯-3-羟基-5-甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮的制备
水浴下,往(E)-3-(4-溴苯基)-1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)丙-2-烯-1-酮(1.40g,3.80mmol)的EtOH(27mL)和DCM(6.8mL)的混合溶液里,依次滴加入NaOH水溶液(3.36g,10wt%,8.39mmol)和H
2O
2水溶液(3.03g,30wt%,26.7mmol),然后在水浴下搅拌1小时。加入饱和氯化铵水溶液,用DCM萃取三次,合并有机相,用无水硫酸钠干燥,过滤后减压浓缩有机溶剂得到粗品2-(4-溴苯基)-7-氯-3-羟基-5-甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(700mg),未作进一步纯化,直接用于下一步。
MS m/z(ESI):381.9[M+H]
+.
第八步:2-(4-溴苯基)-3-羟基-5,7-二甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮的制备
往2-(4-溴苯基)-7-氯-3-羟基-5-甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(上一步粗品,700mg)的DMF溶液(30mL)里,加入甲醇钠的甲醇溶液(15mL,30wt%),然后在80℃下搅拌1小时,冷却,反应液倒入冰水中,再用盐酸(6M)调节pH至弱酸性,过滤析出的固体,滤饼用水洗涤,收集固体化合物并干燥,柱层析分离纯化得到标题化合物2-(4-溴苯基)-3-羟基-5,7-二甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(180mg,两步收率:13%)。
1H NMR(400MHz,DMSO-d
6)δ3.95(s,3H),4.00(s,3H),6.60(s,1H),7.75(d,J=9.6Hz,2H),8.10(d,J=8.0Hz,2H),9.65(br s,1H);
MS m/z(ESI):378.0[M+H]
+.
第九步:外消旋-甲基(3S,4R,5R)-2-(4-溴苯基)-5-羟基-6,8-二甲氧基-10-羰基-3-苯基-2,3,4,5-四氢-2,5-亚甲基噁庚并[3,2-c]吡啶-4-羧酸酯的制备
将2-(4-溴苯基)-3-羟基-5,7-二甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(160mg,0.424mmol)和肉桂酸甲酯(686mg,4.24mmol)溶于氯仿(7mL)和三氟乙醇(5.6mL)中,0℃,在450W UV光照射下剧烈搅拌5小时。减压浓缩有机溶剂柱层析除去多余的肉桂酸甲酯,得到粗品外消旋-甲基(3S,4R,5R)-2-(4-溴苯基)-5-羟基-6,8-二甲氧基-10-羰基-3-苯基-2,3,4,5-四氢-2,5-亚甲基噁庚并[3,2-c]吡啶-4-羧酸酯(250mg),直接用于下一步反应。
MS m/z(ESI):540.1[M+H]
+.
第十步:外消旋-甲基(5aR,6S,7R,8aR)-5a-(4-溴苯基)-8a-羟基-1,3-二甲氧基-8-羰基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸酯的制备
往外消旋-甲基(3S,4R,5R)-2-(4-溴苯基)-5-羟基-6,8-二甲氧基-10-羰基-3-苯基-2,3,4,5-四氢-2,5-亚甲基噁庚并[3,2-c]吡啶-4-羧酸酯(250mg,粗品,约0.424mmol)的甲醇溶液(8mL)里滴加入甲醇钠的甲醇溶液(30wt%,252mg,1.40mmol),然后在60℃下搅拌45分钟,反应冷却至室温,减压浓缩有机溶剂,残余物用二氯甲烷和饱和氯化铵水溶液分层,分离有机相并用无水硫酸钠干燥,过滤后减压浓缩有机溶剂得到粗品外消旋-甲基(5aR,6S,7R,8aR)-5a-(4-溴苯基)-8a-羟基-1,3-二甲氧基-8-羰基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸酯(250mg),直接用于下一步反应。
MS m/z(ESI):540.1[M+H]
+.
第十一步:外消旋-(5aR,6S,7S,8R,8aS)-5a-(4-溴苯基)-7-(羟甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
将上一步粗品外消旋-甲基(5aR,6S,7R,8aR)-5a-(4-溴苯基)-8a-羟基-1,3-二甲氧基-8-羰基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸酯(250mg,约0.424mmol)溶于MeOH(8mL)中,然后分批加入NaBH
4(81mg,2.12mmol),室温下搅拌75分钟。然后减压浓缩MeOH,残余液用二氯甲烷和水分层,分离有机相,用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物外消旋-(5aR,6S,7S,8R,8aS)-5a-(4-溴苯基)-7-(羟甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇(70mg,三步收率:32%)。
MS m/z(ESI):514.1[M+H]
+.
第十二步:外消旋-(5aR,6S,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲醛的制备
冰水浴,往外消旋-(5aR,6S,7S,8R,8aS)-5a-(4-溴苯基)-7-(羟甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇(70mg,0.136mmol)的二氯甲烷溶液(10mL)里,加入DMP(60mg,0.143mmol),然后在该温度下搅拌2小时。加入硫代硫酸钠和碳酸氢钠的混合水溶液,搅拌10分钟,用二氯甲烷萃取两次,合并有机相,无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物外消旋-(5aR,6S,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲醛(58mg,83%)。
MS m/z(ESI):512.1[M+H]
+.
第十三步:外消旋-(5aR,6S,7S,8R,8aS)-5a-(4-溴苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
外消旋-(5aR,6S,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲醛(58mg,0.114mmol),盐酸二甲胺(9.2mg,0.228mmol)混合于DCE中,搅拌30分钟,然后加入醋酸硼氢化钠(48mg,0.228mmol),在室温下搅拌过夜。用二氯甲烷稀释,再依次用饱和碳酸氢钠水溶液和饱和食盐水洗涤,分离有机相用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物外消旋-(5aR,6S,7S,8R,8aS)-5a-(4-溴苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇(45mg,73%)。
MS m/z(ESI):541.1[M+H]
+.
第十四步:外消旋-(5aR,6S,7S,8aR)-5a-(4-溴苯基)-7-((二甲氨基)甲基)-8a-羟基-1,3-二甲氧基-6-苯基-5a,6,7,8a-四氢-8H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8-酮的制备
冰水浴下,往外消旋-(5aR,6S,7S,8R,8aS)-5a-(4-溴苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇(45mg,0.083mmol)的DCM溶液(2mL)里滴加入DMP(70mg,0.166mmol),然后在室温下搅拌过夜。加入硫代硫酸钠和碳酸氢钠的混合水溶液,搅拌10分钟,用二氯甲烷萃取两次,合并有机相,用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,制备薄层分离纯化得到标题化合物外消旋-(5aR,6S,7S,8aR)-5a-(4-溴苯基)-7-((二甲氨基)甲基)-8a-羟基-1,3-二甲氧基-6-苯基-5a,6,7,8a-四氢-8H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8-酮(33mg,74%)。
MS m/z(ESI):539.2[M+H]
+.
第十五步:外消旋-4-((5aR,6S,7S,8aR)-7-((二甲氨基)甲基)-8a-羟基-1,3-二甲氧基-8-羰基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
外消旋-(5aR,6S,7S,8aR)-5a-(4-溴苯基)-7-((二甲氨基)甲基)-8a-羟基-1,3-二甲氧基-6-苯基-5a,6,7,8a-四氢-8H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8-酮(33mg,0.061mmol)、Zn(CN)
2(30mg,0.26mmol)、锌粉(6mg,0.083mmol)与DMF(1mL)、水(0.1mL)混合,氮气除氧5分钟,然后依次加入Pd
2(dba)
3(7.5mg,0.0082mmol)和dppf(9mg,0.017mmol),在微波条件下,120℃加热搅拌90分钟。反应液冷却至室温,硅藻土滤除不溶物,滤液减压浓缩后用制备薄层纯化得到标题化合物外消旋-4-((5aR,6S,7S,8aR)-7-((二甲氨基)甲基)-8a-羟基-1,3-二甲氧基-8-羰基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈(20mg,68%)。
MS(ESI)m/z:486.2[M+H]
+.
第十六步:4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
室温下,外消旋-4-((5aR,6S,7S,8aR)-7-((二甲氨基)甲基)-8a-羟基-1,3-二甲氧基-8-羰基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈(20mg,0.041mmol),盐酸羟胺(8.6mg,0.123mmol)混合于DCE(2mL)中,加入一滴醋酸,搅拌30分钟,然后加入醋酸硼氢化钠(17mg,0.082mmol),再搅拌5小时。加入饱和碳酸氢钠水溶液和DCM,分离有机相并用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,用制备薄层分离得到外消旋-4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈(实施例1外消旋体),然后手性柱拆分,得到光学纯标题化合物4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二 烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈(3.3mg)。
MS(ESI)m/z:503.2[M+H]
+.
实施例2
(5aR,6S,7R,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备
(5aR,6S,7R,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备方法参照实施例1。
MS m/z(ESI):517.2[M+H]
+.
实施例3
(5aR,6S,7R,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-N-甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备
(5aR,6S,7R,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-N-甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备方法参照实施例1。
MS m/z(ESI):503.2[M+H]
+.
实施例4
4-((5aR,6S,7S,8R,8aS)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-7-((甲基氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-7-((甲基氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):489.2[M+H]
+.
实施例5
(5aR,6S,7S,8R,8aS)-5a-(4-氰基苯基)-7-((二甲氨基)甲基)-8a-羟基-8-(羟氨基)-1-甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备
(5aR,6S,7S,8R,8aS)-5a-(4-氰基苯基)-7-((二甲氨基)甲基)-8a-羟基-8-(羟氨基)-1-甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):498.2[M+H]
+.
实施例6
4-((5aR,6S,7S,8R,8aS)-7-((二乙胺基)甲基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-7-((二乙胺基)甲基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):531.2[M+H]
+.
实施例7
4-((5aR,6S,7S,8R,8aS)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-7-(哌啶-1-基甲基)-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-7-(哌啶-1-基甲基)-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):543.2[M+H]
+.
实施例8
4-((5aR,6S,7S,8R,8aS)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-7-(吗啉代甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-7-(吗啉代甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):545.2[M+H]
+.
实施例9
4-((5aR,6S,7S,8R,8aS)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-7-((4-甲基哌嗪-1-基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-7-((4-甲基哌嗪-1-基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):558.3[M+H]
+.
实施例10
4-((5aR,6S,7S,8R,8aS)-7-((3-(二氟甲基)吖丁啶-1-基)甲基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-7-((3-(二氟甲基)吖丁啶-1-基)甲基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):565.2[M+H]
+.
实施例11
(5aR,6S,7S,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-7-(((2-羟基-2-甲基丙基)(甲基)氨基)甲基)-8-(羟氨基)-1-甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备
(5aR,6S,7S,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-7-(((2-羟基-2-甲基丙基)(甲基)氨基)甲基)-8-(羟氨基)-1-甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):556.3[M+H]
+.
实施例12
(5aR,6S,7S,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-8-(羟氨基)-1-甲氧基-7-(((2-甲氧基乙基)(甲基)氨基)甲基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备
(5aR,6S,7S,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-8-(羟氨基)-1-甲氧基-7-(((2-甲氧基乙基)(甲基)氨基)甲基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):542.2[M+H]
+.
实施例13
(5aR,6S,7R,8S,8aS)-5a-(4-氰基苯基)-8a-羟基-8-(羟氨基)-1-甲氧基-6-苯基-7-(吡咯烷-1-基磺酰)-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备
(5aR,6S,7R,8S,8aS)-5a-(4-氰基苯基)-8a-羟基-8-(羟氨基)-1-甲氧基-6-苯基-7-(吡咯烷-1-基磺酰)-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):574.2[M+H]
+.
实施例14
4-((5aR,6S,7S,8R,8aS)-7-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-7-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):557.2[M+H]
+.
实施例15
4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):569.3[M+H]
+.
实施例16
4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-8a-羟基-8-(羟氨基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):571.3[M+H]
+.
实施例17
4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):517.2[M+H]
+.
实施例18
(5aR,6S,7R,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备
(5aR,6S,7R,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备方法参照实施例1。
MS m/z(ESI):531.2[M+H]
+.
实施例19
(5aR,6S,7R,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-N-甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备
(5aR,6S,7R,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-N-甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备方法参照实施例1。
MS m/z(ESI):517.2[M+H]
+.
实施例20
4-((5aR,6S,7S,8R,8aS)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-7-((甲基氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-7-((甲基氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):503.2[M+H]
+.
实施例21
(5aR,6S,7S,8R,8aS)-5a-(4-氰基苯基)-7-((二甲氨基)甲基)-8a-羟基-1-甲氧基-8-(甲氧基氨基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备
(5aR,6S,7S,8R,8aS)-5a-(4-氰基苯基)-7-((二甲氨基)甲基)-8a-羟基-1-甲氧基-8-(甲氧基氨基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):512.2[M+H]
+.
实施例22
4-((5aR,6S,7S,8R,8aS)-7-((二乙胺基)甲基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-7-((二乙胺基)甲基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):545.3[M+H]
+.
实施例23
4-((5aR,6S,7S,8R,8aS)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-6-苯基-7-(哌啶-1-基甲基)-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-6-苯基-7-(哌啶-1-基甲基)-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):557.3[M+H]
+.
实施例24
4-((5aR,6S,7S,8R,8aS)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-7-(吗啉代甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-7-(吗啉代甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):559.3[M+H]
+.
实施例25
4-((5aR,6S,7S,8R,8aS)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-7-((4-甲基哌嗪-1-基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-7-((4-甲基哌嗪-1-基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):572.3[M+H]
+.
实施例26
4-((5aR,6S,7S,8R,8aS)-7-((3-(二氟甲基)吖丁啶-1-基)甲基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-7-((3-(二氟甲基)吖丁啶-1-基)甲基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):579.2[M+H]
+.
实施例27
(5aR,6S,7S,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-7-(((2-羟基-2-甲基丙基)(甲基)氨基)甲基)-1-甲氧基-8-(甲氧基氨基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备
(5aR,6S,7S,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-7-(((2-羟基-2-甲基丙基)(甲基)氨基)甲基)-1-甲氧基-8-(甲氧基氨基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):570.3[M+H]
+.
实施例28
(5aR,6S,7S,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-1-甲氧基-8-(甲氧基氨基)-7-(((2-甲氧基乙基)(甲基)氨基)甲基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备
(5aR,6S,7S,8R,8aS)-5a-(4-氰基苯基)-8a-羟基-1-甲氧基-8-(甲氧基氨基)-7-(((2-甲氧基乙基)(甲基)氨基)甲基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):556.3[M+H]
+.
实施例29
(5aR,6S,7R,8S,8aS)-5a-(4-氰基苯基)-8a-羟基-1-甲氧基-8-(甲氧基氨基)-6-苯基-7-(吡咯烷-1-基磺酰)-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备
(5aR,6S,7R,8S,8aS)-5a-(4-氰基苯基)-8a-羟基-1-甲氧基-8-(甲氧基氨基)-6-苯基-7-(吡咯烷-1-基磺酰)-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):588.2[M+H]
+.
实施例30
4-((5aR,6S,7S,8R,8aS)-7-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-7-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):571.3[M+H]
+.
实施例31
4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):583.3[M+H]
+.
实施例32
4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-8a-羟基-1,3-二甲氧基-8-(甲氧基氨基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):585.3[M+H]
+.
实施例33
4-((8aR,9S,10S,11R,11aS)-9-((二甲氨基)甲基)-11a-羟基-3-甲氧基-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备
4-((8aR,9S,10S,11R,11aS)-9-((二甲氨基)甲基)-11a-羟基-3-甲氧基-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):500.2[M+H]
+.
实施例34
(8aR,9R,10S,11R,11aS)-11-(4-氰基苯基)-11a-羟基-3-甲氧基-N,N-二甲基-10-苯基-6,7,8a,10,11,11a-六氢-9H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-9-甲酰胺的制备
(8aR,9R,10S,11R,11aS)-11-(4-氰基苯基)-11a-羟基-3-甲氧基-N,N-二甲基-10-苯基-6,7,8a,10,11,11a-六氢-9H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-9-甲酰胺的制备方法参照实施例1。
MS m/z(ESI):514.2[M+H]
+.
实施例35
(8aR,9R,10S,11R,11aS)-11-(4-氰基苯基)-11a-羟基-3-甲氧基-N-甲基-10-苯基-6,7,8a,10,11,11a-六氢-9H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-9-甲酰胺的制备
(8aR,9R,10S,11R,11aS)-11-(4-氰基苯基)-11a-羟基-3-甲氧基-N-甲基-10-苯基-6,7,8a,10,11,11a-六氢-9H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-9-甲酰胺的制备方法参照实施例1。
MS m/z(ESI):500.2[M+H]
+.
实施例36
4-((8aR,9S,10S,11R,11aS)-11a-羟基-3-甲氧基-9-((甲基氨基)甲基)-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备
4-((8aR,9S,10S,11R,11aS)-11a-羟基-3-甲氧基-9-((甲基氨基)甲基)-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):486.2[M+H]
+.
实施例37
(8aR,9S,10S,11R,11aS)-11-(4-氰基苯基)-9-((二甲氨基)甲基)-11a-羟基-10-苯基-6,7,8a,10,11,11a-六氢-9H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-3-甲腈的制备
(8aR,9S,10S,11R,11aS)-11-(4-氰基苯基)-9-((二甲氨基)甲基)-11a-羟基-10-苯基-6,7,8a,10,11,11a-六氢-9H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):495.2[M+H]
+.
实施例38
4-((8aR,9S,10S,11R,11aS)-9-((二乙胺基)甲基)-11a-羟基-3-甲氧基-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备
4-((8aR,9S,10S,11R,11aS)-9-((二乙胺基)甲基)-11a-羟基-3-甲氧基-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):528.2[M+H]
+.
实施例39
4-((8aR,9S,10S,11R,11aS)-11a-羟基-3-甲氧基-10-苯基-9-(哌啶-1-基甲基)-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备
4-((8aR,9S,10S,11R,11aS)-11a-羟基-3-甲氧基-10-苯基-9-(哌啶-1-基甲基)-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):540.2[M+H]
+.
实施例40
4-((8aR,9S,10S,11R,11aS)-11a-羟基-3-甲氧基-9-(吗啉代甲基)-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备
4-((8aR,9S,10S,11R,11aS)-11a-羟基-3-甲氧基-9-(吗啉代甲基)-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):542.2[M+H]
+.
实施例41
4-((8aR,9S,10S,11R,11aS)-11a-羟基-3-甲氧基-9-((4-甲基哌嗪-1-基)甲基)-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备
4-((8aR,9S,10S,11R,11aS)-11a-羟基-3-甲氧基-9-((4-甲基哌嗪-1-基)甲基)-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):555.3[M+H]
+.
实施例42
4-((8aR,9S,10S,11R,11aS)-9-((3-(二氟甲基)吖丁啶-1-基)甲基)-11a-羟基-3-甲氧基-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备
4-((8aR,9S,10S,11R,11aS)-9-((3-(二氟甲基)吖丁啶-1-基)甲基)-11a-羟基-3-甲氧基-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):552.2[M+H]
+.
实施例43
(8aR,9S,10S,11R,11aS)-11-(4-氰基苯基)-11a-羟基-9-(((2-羟基-2-甲基丙基)(甲基)氨基)甲基)-10-苯基-6,7,8a,10,11,11a-六氢-9H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-3-甲腈的制备
(8aR,9S,10S,11R,11aS)-11-(4-氰基苯基)-11a-羟基-9-(((2-羟基-2-甲基丙基)(甲基)氨基)甲基)-10-苯基-6,7,8a,10,11,11a-六氢-9H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):553.2[M+H]
+.
实施例44
(8aR,9S,10S,11R,11aS)-11-(4-氰基苯基)-11a-羟基-9-(((2-甲氧基乙基)(甲基)氨基)甲基)-10-苯基-6,7,8a,10,11,11a-六氢-9H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-3-甲腈的制备
(8aR,9S,10S,11R,11aS)-11-(4-氰基苯基)-11a-羟基-9-(((2-甲氧基乙基)(甲基)氨基)甲基)-10-苯基-6,7,8a,10,11,11a-六氢-9H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):539.2[M+H]
+.
实施例45
(8aS,9R,10S,11R,11aS)-11-(4-氰基苯基)-11a-羟基-10-苯基-9-(吡咯烷-1-基磺酰)-6,7,8a,10,11,11a-六氢-9H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-3-甲腈的制备
(8aS,9R,10S,11R,11aS)-11-(4-氰基苯基)-11a-羟基-10-苯基-9-(吡咯烷-1-基磺酰)-6,7,8a,10,11,11a-六氢-9H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):571.2[M+H]
+.
实施例46
4-((8aR,9S,10S,11R,11aS)-9-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)-11a-羟基-3-甲氧基-10-苯基-6,7,8a,9,10,11a-六氢-11H-[1,11]环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备
4-((8aR,9S,10S,11R,11aS)-9-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)-11a-羟基-3-甲氧基-10-苯基-6,7,8a,9,10,11a-六氢-11H-[1,11]环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):554.2[M+H]
+.
实施例47
4-((8aR,9S,10S,11R,11aS)-9-(((1R,5S)-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-11a-羟基-3-甲氧基-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备
4-((8aR,9S,10S,11R,11aS)-9-(((1R,5S)-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-11a-羟基-3-甲氧基-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):566.3[M+H]
+.
实施例48
4-((8aR,9S,10S,11R,11aS)-9-(((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-11a-羟基-3-甲氧基-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备
4-((8aR,9S,10S,11R,11aS)-9-(((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-11a-羟基-3-甲氧基-10-苯基-6,7,8a,9,10,11a-六氢-11H-1,11-环氧环戊二烯并[7,8][1,4]二噁辛英并[5,6-b]吡啶-11-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):568.2[M+H]
+.
实施例49
4-((1S,2S,2aR,2a1S,9aR)-1-((二甲氨基)甲基)-2a1-羟基-5-甲氧基-2-苯基-1,2,2a1,9a-四氢-2aH-3,7,9-三氧杂-6-氮杂苯并[cd]环戊二烯并[ij]薁-2a-基)苯甲腈的制备
4-((1S,2S,2aR,2a1S,9aR)-1-((二甲氨基)甲基)-2a1-羟基-5-甲氧基-2-苯基-1,2,2a1,9a-四氢-2aH-3,7,9-三氧杂-6-氮杂苯并[cd]环戊二烯并[ij]薁-2a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):486.2[M+H]
+.
实施例50
4-((9aR,10S,11S,12R,12aS)-10-((二甲氨基)甲基)-12a-羟基-3-甲氧基-11-苯基-7,8,9a,10,11,12a-六氢-6H,12H-1,12-环氧环戊二烯并[8,9][1,5]二噁壬英并[6,7-b]吡啶-12-基)苯甲腈的制备
4-((9aR,10S,11S,12R,12aS)-10-((二甲氨基)甲基)-12a-羟基-3-甲氧基-11-苯基-7,8,9a,10,11,12a-六氢-6H,12H-1,12-环氧环戊二烯并[8,9][1,5]二噁壬英并[6,7-b]吡啶-12-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):514.2[M+H]
+.
实施例51
4-((1S,2S,2aR,2a1S,9aR)-1-((二甲氨基)甲基)-2a1-羟基-5-甲氧基-1'-甲基-2-苯基-1,2,2a1,9a-四氢-2aH-3,7,9-三氧杂-6-氮杂螺[苯并[cd]环戊二烯并[ij]薁-8,4'-哌啶]-3a,3a1(6a),5-三烯-2a-基)苯甲腈的制备
4-((1S,2S,2aR,2a1S,9aR)-1-((二甲氨基)甲基)-2a1-羟基-5-甲氧基-1'-甲基-2-苯基-1,2,2a1,9a-四氢-2aH-3,7,9-三氧杂-6-氮杂螺[苯并[cd]环戊二烯并[ij]薁-8,4'-哌啶]-3a,3a1(6a),5-三烯-2a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):569.3[M+H]
+.
实施例52
4-((1S,2S,2aR,2a1S,9aR)-1-((二甲氨基)甲基)-2a1-羟基-5-甲氧基-7-甲基-8-羰基-2-苯基-1,2,2a1,7,8,9a-六氢-2aH-3,9-二氧杂-6,7-二氮杂苯并[cd]环戊二烯并[ij]薁-2a-基)苯甲腈的制备
4-((1S,2S,2aR,2a1S,9aR)-1-((二甲氨基)甲基)-2a1-羟基-5-甲氧基-7-甲基-8-羰基-2-苯基-1,2,2a1,7,8,9a-六氢-2aH-3,9-二氧杂-6,7-二氮杂苯并[cd]环戊二烯并[ij]薁-2a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):513.2[M+H]
+.
实施例53
4-((1S,2S,2aR,2a1S,9aR)-1-((二甲氨基)甲基)-2a1-羟基-5-甲氧基-8-羰基-2-苯基-1,2,2a1,7,8,9a-六氢-2aH-3,9-二氧杂-6,7-二氮杂苯并[cd]环戊二烯并[ij]薁-2a-基)苯甲腈的制备
4-((1S,2S,2aR,2a1S,9aR)-1-((二甲氨基)甲基)-2a1-羟基-5-甲氧基-8-羰基-2-苯基-1,2,2a1,7,8,9a-六氢-2aH-3,9-二氧杂-6,7-二氮杂苯并[cd]环戊二烯并[ij]薁-2a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):499.2[M+H]
+.
实施例54
(5aR,6S,7R,8S,8aS)-5a-(4-氰基苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-磺酰氟化的制备
(5aR,6S,7R,8S,8aS)-5a-(4-氰基苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-磺酰氟化的制备方法参照实施例1。
MS m/z(ESI):513.1[M+H]
+.
实施例55
4-((5aR,6R,7S,8R,8aS)-7-((二甲氨基)甲基)-6-氟-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6R,7S,8R,8aS)-7-((二甲氨基)甲基)-6-氟-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):506.2[M+H]
+.
实施例56
4-((5aS,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-甲基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aS,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-甲基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ1.21(s,3H),1.87-1.98(m,1H),2.02-2.09(m,1H),2.24(s,6H),2.68-2.76(m,1H),3.78(s,3H),3.82(s,3H),,4.52-4.59(m,1H),4.88-4.96(m,1H),5.09(s,1H),6.04(s,1H),6.81-6.88(m,1H),6.91-7.02(m,4H),7.18-7.24(m,2H),7.30-7.36(m,2H);
MS m/z(ESI):502.2[M+H]
+.
实施例57
4-((5aR,6S,7S,8R,8aS)-6-(二环[1.1.1]戊烷-1-基)-8,8a-二羟基-1,3-二甲氧基-7-((甲氧基(甲基)氨基)甲基)-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-6-(二环[1.1.1]戊烷-1-基)-8,8a-二羟基-1,3-二甲氧基-7-((甲氧基(甲基)氨基)甲基)-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):494.2[M+H]
+.
实施例58
3-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-((甲氧基(甲基)氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)二环[1.1.1]戊烷-1-甲腈的制备
3-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-((甲氧基(甲基)氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)二环[1.1.1]戊烷-1-甲腈的制备方法参照实施例1。
MS m/z(ESI):494.2[M+H]
+.
实施例59
4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-((甲氧基(甲基)氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-((甲氧基(甲基)氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):504.2[M+H]
+.
实施例60
4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-((甲氧基氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-((甲氧基氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):490.2[M+H]
+.
实施例61
(5aR,6S,7R,8R,8aS)-5a-(4-氰基苯基)-8,8a-二羟基-N,1,3-三甲氧基-N-甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备
(5aR,6S,7R,8R,8aS)-5a-(4-氰基苯基)-8,8a-二羟基-N,1,3-三甲氧基-N-甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备方法参照实施例1。
MS m/z(ESI):518.2[M+H]
+.
实施例62
(4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-((甲氧基(甲基)氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备
(4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-((甲氧基(甲基)氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备方法参照实施例1。
MS m/z(ESI):555.2[M+H]
+.
实施例63
(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备
(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备方法参照实施例1。
MS m/z(ESI):539.2[M+H]
+.
实施例64
(5aR,6S,7R,8R,8aS)-5a-(4-(二甲基磷基)苯基)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备
(5aR,6S,7R,8R,8aS)-5a-(4-(二甲基磷基)苯基)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备方法参照实施例1。
MS m/z(ESI):553.2[M+H]
+.
实施例65
(5aR,6S,7R,8R,8aS)-5a-(4-(二甲基磷基)苯基)-8,8a-二羟基-1,3-二甲氧基-N-甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备
(5aR,6S,7R,8R,8aS)-5a-(4-(二甲基磷基)苯基)-8,8a-二羟基-1,3-二甲氧基-N-甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备方法参照实施例1。
MS m/z(ESI):539.2[M+H]
+.
实施例66
(4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-((甲基氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备
(4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-((甲基氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备方法参照实施例1。
MS m/z(ESI):525.2[M+H]
+.
实施例67
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(二甲基磷基)苯基)-8,8a-二羟基-1-甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(二甲基磷基)苯基)-8,8a-二羟基-1-甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):534.2[M+H]
+.
实施例68
(4-((5aR,6S,7S,8R,8aS)-7-((二乙胺基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备
(4-((5aR,6S,7S,8R,8aS)-7-((二乙胺基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备方法参照实施例1。
MS m/z(ESI):567.3[M+H]
+.
实施例69
(4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-6-苯基-7-(哌啶-1-基甲基)-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备
(4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-6-苯基-7-(哌啶-1-基甲基)-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备方法参照实施例1。
MS m/z(ESI):579.3[M+H]
+.
实施例70
(4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-(吗啉代甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备
(4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-(吗啉代甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备方法参照实施例1。
MS m/z(ESI):581.2[M+H]
+.
实施例71
(4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-((4-甲基哌嗪-1-基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备
(4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-((4-甲基哌嗪-1-基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备方法参照实施例1。
MS m/z(ESI):594.3[M+H]
+.
实施例72
(4-((5aR,6S,7S,8R,8aS)-7-((3-(二氟甲基)吖丁啶-1-基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备
(4-((5aR,6S,7S,8R,8aS)-7-((3-(二氟甲基)吖丁啶-1-基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备方法参照实施例1。
MS m/z(ESI):601.2[M+H]
+.
实施例73
(5aR,6S,7S,8R,8aS)-5a-(4-(二甲基磷基)苯基)-8,8a-二羟基-7-(((2-羟基-2-甲基丙基)(甲基)氨基)甲基)-1-甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备
(5aR,6S,7S,8R,8aS)-5a-(4-(二甲基磷基)苯基)-8,8a-二羟基-7-(((2-羟基-2-甲基丙基)(甲基)氨基)甲基)-1-甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):592.3[M+H]
+.
实施例74
(5aR,6S,7S,8R,8aS)-5a-(4-(二甲基磷基)苯基)-8,8a-二羟基-1-甲氧基-7-(((2-甲氧基乙基)(甲基)氨基)甲基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备
(5aR,6S,7S,8R,8aS)-5a-(4-(二甲基磷基)苯基)-8,8a-二羟基-1-甲氧基-7-(((2-甲氧基乙基)(甲基)氨基)甲基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):578.2[M+H]
+.
实施例75
(5aR,6S,7R,8S,8aS)-5a-(4-(二甲基磷基)苯基)-8,8a-二羟基-1-甲氧基-6-苯基-7-(吡咯烷-1-基磺酰)-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备
(5aR,6S,7R,8S,8aS)-5a-(4-(二甲基磷基)苯基)-8,8a-二羟基-1-甲氧基-6-苯基-7-(吡咯烷-1-基磺酰)-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):610.2[M+H]
+.
实施例76
(4-((5aR,6S,7S,8R,8aS)-7-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备
(4-((5aR,6S,7S,8R,8aS)-7-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备方法参照实施例1。
MS m/z(ESI):593.2[M+H]
+.
实施例77
(4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备
(4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备方法参照实施例1。
MS m/z(ESI):605.3[M+H]
+.
实施例78
(4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备
(4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)二甲基膦氧化的制备方法参照实施例1。
MS m/z(ESI):607.3[M+H]
+.
实施例79
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):504.2[M+H]
+.
实施例80
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a-(4-((三氟甲基)硫代)苯基)-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a-(4-((三氟甲基)硫代)苯基)-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):563.2[M+H]
+.
实施例81
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a-(4-氰硫基<硫代氰酸基>苯基)-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a-(4-氰硫基<硫代氰酸基>苯基)-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):520.2[M+H]
+.
实施例82
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-(噁丁环-3-基)苯基)-6-
苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-(噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):519.2[M+H]
+.
实施例83
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
第一步:4-(苄氧基)-2,6-二氯吡啶的制备
冰水浴下,往2,4,6-三氯吡啶(30.0g,165mmol)的DMF溶液(300mL)里分批加入NaH(7.59g,60wt%,190mmol),加完后,继续在该温度下搅拌15分钟,然后逐滴加入苄醇(17.9mL,173mmol),加毕,再在冰水浴下搅拌1小时。将反应液倒入冰水中,用乙酸乙酯萃取三次,合并有机相,再用饱和食盐水洗涤多次,分离有机相并用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物4-(苄氧基)-2,6-二氯吡啶(30.4g,73%)。
1H NMR(400MHz,CDCl
3)δ5.11(s,2H),6.86(s,2H),7.37-7.42(m,5H);
MS m/z(ESI):254.0[M+H]
+.
第二步:4-(苄氧基)-2-氯-6-甲氧基吡啶的制备
往4-(苄氧基)-2,6-二氯吡啶(27.0g,106mmol)的甲苯溶液(400mL)里加入甲醇钠的甲醇溶液(30wt%,36.4g,202mmol),然后在60℃下搅拌5小时。反应冷却至室温,反应液倒入水中,用乙酸乙酯萃取三次,合并有机相,用饱和食盐水洗涤,分离有机相用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物4-(苄氧基)-2-氯-6-甲氧基吡啶(19.6g,74%)。
1H NMR(400MHz,DMSO-d
6)δ3.81(s,3H),5.20(s,2H),6.46(d,J=1.9Hz,1H),6.81(d,J=1.9Hz,1H),7.32-7.47(m,5H);
MS m/z(ESI):250.2[M+H]
+.
第三步:1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-醇的制备
在干冰-丙酮浴下,往4-(苄氧基)-2-氯-6-甲氧基吡啶(19.5g,78.1mmol)的 THF溶液(200mL)里,滴加入n-BuLi的正己烷溶液(41.0mL,2.4M,97.6mmol),在该温度下搅拌30分钟,然后向反应体系中滴加乙醛(6.88g,156mmol),滴加完毕,继续搅拌10分钟,加入饱和氯化铵水溶液淬灭反应,反应液用乙酸乙酯萃取多次,合并有机相,用饱和食盐水洗涤,分离有机相用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得标题化合物1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-醇(16g,70%)。
1H NMR(400MHz,DMSO-d
6)δ1.39(d,J=6.6Hz,3H),3.84(s,3H),4.60(d,J=6.6Hz,1H),5.09-5.14(m,1H),5.25(s,2H),6.93(s,1H),7.32-7.49(m,5H);
MS m/z(ESI):294.1[M+H]
+.
第四步:1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-酮的制备
往1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-醇(16.0g,54.6mmol)的二氯甲烷溶液(320mL)里分批加入DMP(30.1g,71.0mmol),加毕,继续在室温下搅拌2小时。然后依次加入饱和碳酸氢钠水溶液和硫代硫酸钠水溶液,再搅拌15分钟。分离有机相,水相再用二氯甲烷萃取二次。合并有机相后,用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-酮(8.10g,51%)。
1H NMR(400MHz,DMSO-d
6)δ2.37(s,3H),3.84(s,3H),4.60(d,J=6.1Hz,1H),5.28(s,2H),7.10(s,1H),7.32-7.47(m,5H);
MS m/z(ESI):292.2[M+H]
+.
第五步:1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)乙烷-1-酮的制备
往1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-酮(4.67g,16.0mmol)的乙酸乙酯溶液(120mL)里,加入Pd/C(140mg,10wt%),在氢气氛下,常温常压,搅拌3小时,用硅藻土滤除不溶物,滤液减压浓缩后柱层析分离得到标题化合物1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)乙烷-1-酮(2.30g,71%)。
1H NMR(400MHz,DMSO-d
6)δ2.50(s,3H),3.90(s,3H),6.70(s,1H),13.00(s,1H);
MS m/z(ESI):202.2[M+H]
+.
第六步:(E)-3-(4-溴苯基)-1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)丙-2-烯-1-酮的制备
往1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)乙烷-1-酮(2.00g,9.92mmol),4-溴苯甲醛(1.65g,8.93mmol)的DMF溶液(31mL)里加入MeONa的MeOH溶液(5.36g,30wt%,29.8mmol),在50℃下剧烈搅拌30分钟,冷却,然后在冰水浴下倒入稀盐酸(0.3M,200mL)中,过滤收集析出的固体并干燥,然后用EtOAc/正庚烷混合溶剂(混合溶剂比1:10)打浆纯化,得到标题化合物(E)-3-(4-溴苯基)-1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)丙-2-烯-1-酮(1.87g,57%)。
1H NMR(400MHz,DMSO-d
6)δ3.80(s,3H),6.60(s,1H),7.20(d,J=16.0Hz,1H),7.40(d,J=16.0Hz,1H),7.56-7.73(m,4H);
MS m/z(ESI):368.0[M+H]
+.
第七步:2-(4-溴苯基)-7-氯-3-羟基-5-甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮的制备
水浴下,往(E)-3-(4-溴苯基)-1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)丙-2-烯-1-酮(1.40g,3.80mmol)的EtOH(27mL)和DCM(6.8mL)的混合溶液里,依次滴加入NaOH水溶液(3.36g,10wt%,8.39mmol)和H
2O
2水溶液(3.03g,30wt%,26.7mmol),然后在水浴下搅拌1小时。加入饱和氯化铵水溶液,用DCM萃取三次,合并有机相,用无水硫酸钠干燥,过滤后减压浓缩有机溶剂得到粗品2-(4-溴苯基)-7-氯-3-羟基-5-甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(700mg),未作进一步纯化,直接用于下一步。
MS m/z(ESI):381.9[M+H]
+.
第八步:2-(4-溴苯基)-3-羟基-5,7-二甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮的制备
往2-(4-溴苯基)-7-氯-3-羟基-5-甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(上一步粗品,700mg)的DMF溶液(30mL)里,加入甲醇钠的甲醇溶液(15mL,30wt%),然后在80℃下搅拌1小时,冷却,反应液倒入冰水中,再用盐酸(6M)调节pH至弱酸性,过滤析出的固体,滤饼用水洗涤,收集固体化合物并干燥,柱层析分离纯化得到标题化合物2-(4-溴苯基)-3-羟基-5,7-二甲氧基-4H-吡喃并[3,2-c] 吡啶-4-酮(180mg,两步收率:13%)。
1H NMR(400MHz,DMSO-d
6)δ3.95(s,3H),4.00(s,3H),6.60(s,1H),7.75(d,J=9.6Hz,2H),8.10(d,J=8.0Hz,2H),9.65(br s,1H);
MS m/z(ESI):378.0[M+H]
+.
第九步:外消旋-甲基(3S,4R,5R)-2-(4-溴苯基)-5-羟基-6,8-二甲氧基-10-羰基-3-苯基-2,3,4,5-四氢-2,5-亚甲基噁庚并[3,2-c]吡啶-4-羧酸酯的制备
将2-(4-溴苯基)-3-羟基-5,7-二甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(160mg,0.424mmol)和肉桂酸甲酯(686mg,4.24mmol)溶于氯仿(7mL)和三氟乙醇(5.6mL)中,0℃,在450W UV光照射下剧烈搅拌5小时。减压浓缩有机溶剂柱层析除去多余的肉桂酸甲酯,得到粗品外消旋-甲基(3S,4R,5R)-2-(4-溴苯基)-5-羟基-6,8-二甲氧基-10-羰基-3-苯基-2,3,4,5-四氢-2,5-亚甲基噁庚并[3,2-c]吡啶-4-羧酸酯(250mg),直接用于下一步反应。
MS m/z(ESI):540.1[M+H]
+.
第十步:外消旋-甲基(5aR,6S,7R,8aR)-5a-(4-溴苯基)-8a-羟基-1,3-二甲氧基-8-羰基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸酯的制备
往外消旋-甲基(3S,4R,5R)-2-(4-溴苯基)-5-羟基-6,8-二甲氧基-10-羰基-3-苯基-2,3,4,5-四氢-2,5-亚甲基噁庚并[3,2-c]吡啶-4-羧酸酯(250mg,粗品,约0.424mmol)的甲醇溶液(8mL)里滴加入甲醇钠的甲醇溶液(30wt%,252mg,1.40mmol),然后在60℃下搅拌45分钟,反应冷却至室温,减压浓缩有机溶剂,残余物用二氯甲烷和饱和氯化铵水溶液分层,分离有机相并用无水硫酸钠干燥,过滤后减压浓缩有机溶剂得到粗品外消旋-甲基(5aR,6S,7R,8aR)-5a-(4-溴苯基)-8a-羟基-1,3-二甲氧基-8-羰基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸酯(250mg),直接用于下一步反应。
MS m/z(ESI):540.1[M+H]
+.
第十一步:外消旋-(5aR,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸的制备
冰浴下,外消旋-(5aR,6S,7S,8R,8aS)-5a-(4-溴苯基)-7-(羟甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇(0.26g,479.37μmol)溶于MeOH(3mL),THF(1.5mL)和H
2O(1.5mL)中,加入lithium hydroxide hydrate(201.16mg,4.79mmol),反应液冰浴下搅拌10分钟,缓慢升至25℃搅拌3小时。1N HCl调反应液pH至6,EA萃取,有机相用无水硫酸钠干燥,过滤后减压浓缩有机溶剂得到标题化合物外消旋-(5aR,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸(206mg,81%)。.
MS m/z(ESI):528.1[M+H]
+.
第十二步:外消旋-(5aR,6S,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备
冰浴下,(5aR,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸(0.23g,435.32μmol)溶于DCM(1.51mL)中,加入DIPEA(365.70mg,2.83mmol),再分批加入HATU(246.35mg,652.98μmol),反应液冰浴下搅拌10分钟,加入二甲胺盐酸盐(177.7mg,2.18mmol),缓慢升至室温,再搅拌2小时。DCM稀释反应液,饱和食盐水洗涤,分离有机相并用无水硫酸钠干燥,过滤,浓缩后经柱层析分离得到标题化合物外消旋-(5aR,6S,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺(215mg,89%)。
MS m/z(ESI):555.1[M+H]
+.
第十三步:外消旋-(5aR,6S,7S,8R,8aS)-5a-(4-溴苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
冰浴下,外消旋-(5aR,6S,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺(0.215g,387.10μmol)溶于THF(6mL)中,缓慢加入硼烷(3.87mmol,1.9mL,2M THF溶液),反应液冰浴下搅拌10分钟,室温再搅拌12小时。加入甲醇溶液淬灭反应,60℃搅拌12小时。反应液减压浓缩后经柱层析分离得到标题化合物外消旋-(5aR,6S,7S,8R,8aS)-5a-(4-溴苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇(120mg,57%)。
MS m/z(ESI):541.1[M+H]
+.
第十四步:(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
室温下,(5aR,6S,7S,8R,8aS)-5a-(4-溴苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇(100mg,180.47μmol)溶于1'4-Dioxane(5mL)和H
2O(1mL)中,氮气鼓泡5分钟,加入Pd(PPh
3)
4(64mg,55.4μmol)和K
3PO
4(117.6mg,554.1μmol),反应加热至100℃反应12小时。反应液冷却至室温,加水稀释,用DCM萃取,分离有机相并用无水硫酸钠干燥,过滤,浓缩后经反相制备分离,然后手性柱拆分,得到 光学纯标题化合物(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇(8mg,8.6%)。
1H NMR(400MHz,DMSO-d
6)δ0.43-0.53(m,2H),0.78-0.87(m,2H),1.67-1.78(m,1H),1.85-1.91(m,1H),2.18(s,6H),2.54-2.61(m,1H),2.96-3.04(m,1H),3.57(d,J=14.0Hz,1H),3.81-3.84(m,6H),4.42(d,J=4.6Hz,1H),4.82(s,1H),5.14(s,1H),6.00(s,1H),6.71-6.74(m,2H),6.87-6.91(m,2H),6.97-7.07(m,5H);
MS m/z(ESI):503.3[M+H]
+.
实施例84
N-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)-N-甲基乙酰胺的制备
N-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)-N-甲基乙酰胺的制备方法参照实施例1。
MS m/z(ESI):534.3[M+H]
+.
实施例85
4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)-N,N-二甲基苯酰胺的制备
4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)-N,N-二甲基苯酰胺的制备方法参照实施例1。
MS m/z(ESI):534.3[M+H]
+.
实施例86
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-硝基苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
第一步:4-(苄氧基)-2,6-二氯吡啶的制备
冰水浴下,往2,4,6-三氯吡啶(30.0g,165mmol)的DMF溶液(300mL)里分批加入NaH(7.59g,60wt%,190mmol),加完后,继续在该温度下搅拌15分钟,然后逐滴加入苄醇(17.9mL,173mmol),加毕,再在冰水浴下搅拌1小时。将反应液倒入冰水中,用乙酸乙酯萃取三次,合并有机相,再用饱和食盐水洗涤多次,分离有机相并用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物4-(苄氧基)-2,6-二氯吡啶(30.4g,73%)。
1H NMR(400MHz,CDCl
3)δ5.11(s,2H),6.86(s,2H),7.37-7.42(m,5H);
MS m/z(ESI):254.0[M+H]
+.
第二步:4-(苄氧基)-2-氯-6-甲氧基吡啶的制备
往4-(苄氧基)-2,6-二氯吡啶(27.0g,106mmol)的甲苯溶液(400mL)里加入甲醇钠的甲醇溶液(30wt%,36.4g,202mmol),然后在60℃下搅拌5小时。反应冷却至室温,反应液倒入水中,用乙酸乙酯萃取三次,合并有机相,用饱和食盐水洗涤,分离有机相用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物4-(苄氧基)-2-氯-6-甲氧基吡啶(19.6g,74%)。
1H NMR(400MHz,DMSO-d
6)δ3.81(s,3H),5.20(s,2H),6.46(d,J=1.9Hz,1H),6.81(d,J=1.9Hz,1H),7.32-7.47(m,5H);
MS m/z(ESI):250.2[M+H]
+.
第三步:1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-醇的制备
在干冰-丙酮浴下,往4-(苄氧基)-2-氯-6-甲氧基吡啶(19.5g,78.1mmol)的THF溶液(200mL)里,滴加入n-BuLi的正己烷溶液(41.0mL,2.4M,97.6mmol),在该温度下搅拌30分钟,然后向反应体系中滴加乙醛(6.88g,156mmol),滴加完毕,继续搅拌10分钟,加入饱和氯化铵水溶液淬灭反应,反应液用乙酸乙酯萃取多次,合并有机相,用饱和食盐水洗涤,分离有机相用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得标题化合物1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-醇(16g,70%)。
1H NMR(400MHz,DMSO-d
6)δ1.39(d,J=6.6Hz,3H),3.84(s,3H),4.60(d,J=6.6Hz,1H),5.09-5.14(m,1H),5.25(s,2H),6.93(s,1H),7.32-7.49(m,5H);
MS m/z(ESI):294.1[M+H]
+.
第四步:1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-酮的制备
往1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-醇(16.0g,54.6mmol)的二氯甲烷溶液(320mL)里分批加入DMP(30.1g,71.0mmol),加毕,继续在室温下搅拌2小时。然后依次加入饱和碳酸氢钠水溶液和硫代硫酸钠水溶液,再搅拌15分钟。分离有机相,水相再用二氯甲烷萃取二次。合并有机相后,用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-酮(8.10g,51%)。
1H NMR(400MHz,DMSO-d
6)δ2.37(s,3H),3.84(s,3H),4.60(d,J=6.1Hz,1H),5.28(s,2H),7.10(s,1H),7.32-7.47(m,5H);
MS m/z(ESI):292.2[M+H]
+.
第五步:1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)乙烷-1-酮的制备
往1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-酮(4.67g,16.0mmol)的乙酸乙酯溶液(120mL)里,加入Pd/C(140mg,10wt%),在氢气氛下,常温常压,搅拌3小时,用硅藻土滤除不溶物,滤液减压浓缩后柱层析分离得到标题化合物1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)乙烷-1-酮(2.30g,71%)。
1H NMR(400MHz,DMSO-d
6)δ2.50(s,3H),3.90(s,3H),6.70(s,1H),13.00(s,1H);
MS m/z(ESI):202.2[M+H]
+.
第六步:(E)-3-(4-溴苯基)-1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)丙-2-烯-1-酮的制备
往1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)乙烷-1-酮(2.00g,9.92mmol),4-溴苯甲醛(1.65g,8.93mmol)的DMF溶液(31mL)里加入MeONa的MeOH溶液(5.36g,30wt%,29.8mmol),在50℃下剧烈搅拌30分钟,冷却,然后在冰水浴下倒入稀盐酸(0.3M,200mL)中,过滤收集析出的固体并干燥,然后用EtOAc/正庚烷混合溶剂(混合溶剂比1:10)打浆纯化,得到标题化合物(E)-3-(4-溴苯基)-1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)丙-2-烯-1-酮(1.87g,57%)。
1H NMR(400MHz,DMSO-d
6)δ3.80(s,3H),6.60(s,1H),7.20(d,J=16.0Hz,1H),7.40(d,J=16.0Hz,1H),7.56-7.73(m,4H);
MS m/z(ESI):368.0[M+H]
+.
第七步:2-(4-溴苯基)-7-氯-3-羟基-5-甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮的制备
水浴下,往(E)-3-(4-溴苯基)-1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)丙-2-烯-1-酮(1.40g,3.80mmol)的EtOH(27mL)和DCM(6.8mL)的混合溶液里,依次滴加入NaOH水溶液(3.36g,10wt%,8.39mmol)和H
2O
2水溶液(3.03g,30wt%,26.7mmol),然后在水浴下搅拌1小时。加入饱和氯化铵水溶液,用DCM萃取三次,合并有机相,用无水硫酸钠干燥,过滤后减压浓缩有机溶剂得到粗品2-(4-溴苯基)-7-氯-3-羟基-5-甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(700mg),未作进一步纯化,直接用于下一步。
MS m/z(ESI):381.9[M+H]
+.
第八步:2-(4-溴苯基)-3-羟基-5,7-二甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮的制备
往2-(4-溴苯基)-7-氯-3-羟基-5-甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(上一步粗品,700mg)的DMF溶液(30mL)里,加入甲醇钠的甲醇溶液(15mL,30wt%),然后在80℃下搅拌1小时,冷却,反应液倒入冰水中,再用盐酸(6M)调节 pH至弱酸性,过滤析出的固体,滤饼用水洗涤,收集固体化合物并干燥,柱层析分离纯化得到标题化合物2-(4-溴苯基)-3-羟基-5,7-二甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(180mg,两步收率:13%)。
1H NMR(400MHz,DMSO-d
6)δ3.95(s,3H),4.00(s,3H),6.60(s,1H),7.75(d,J=9.6Hz,2H),8.10(d,J=8.0Hz,2H),9.65(br s,1H);
MS m/z(ESI):378.0[M+H]
+.
第九步:外消旋-甲基(3S,4R,5R)-2-(4-溴苯基)-5-羟基-6,8-二甲氧基-10-羰基-3-苯基-2,3,4,5-四氢-2,5-亚甲基噁庚并[3,2-c]吡啶-4-羧酸酯的制备
将2-(4-溴苯基)-3-羟基-5,7-二甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(160mg,0.424mmol)和肉桂酸甲酯(686mg,4.24mmol)溶于氯仿(7mL)和三氟乙醇(5.6mL)中,0℃,在450W UV光照射下剧烈搅拌5小时。减压浓缩有机溶剂柱层析除去多余的肉桂酸甲酯,得到粗品外消旋-甲基(3S,4R,5R)-2-(4-溴苯基)-5-羟基-6,8-二甲氧基-10-羰基-3-苯基-2,3,4,5-四氢-2,5-亚甲基噁庚并[3,2-c]吡啶-4-羧酸酯(250mg),直接用于下一步反应。
MS m/z(ESI):540.1[M+H]
+.
第十步:外消旋-甲基(5aR,6S,7R,8aR)-5a-(4-溴苯基)-8a-羟基-1,3-二甲氧基-8-羰基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸酯的制备
往外消旋-甲基(3S,4R,5R)-2-(4-溴苯基)-5-羟基-6,8-二甲氧基-10-羰基-3-苯基-2,3,4,5-四氢-2,5-亚甲基噁庚并[3,2-c]吡啶-4-羧酸酯(250mg,粗品,约0.424mmol)的甲醇溶液(8mL)里滴加入甲醇钠的甲醇溶液(30wt%,252mg,1.40mmol),然后在60℃下搅拌45分钟,反应冷却至室温,减压浓缩有机溶剂,残余物用二氯甲烷和饱和氯化铵水溶液分层,分离有机相并用无水硫酸钠干燥,过滤后减压浓缩有机溶剂得到粗品外消旋-甲基(5aR,6S,7R,8aR)-5a-(4-溴苯基)-8a-羟基-1,3-二甲氧基-8-羰基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸酯(250mg),直接用于下一步反应。
MS m/z(ESI):540.1[M+H]
+.
第十一步:外消旋-(5aR,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸的制备
冰浴下,外消旋-(5aR,6S,7S,8R,8aS)-5a-(4-溴苯基)-7-(羟甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇(0.26g,479.37μmol)溶于MeOH(3mL),THF(1.5mL)和H
2O(1.5mL)中,加入lithium hydroxide hydrate(201.16mg,4.79mmol),反应液冰浴下搅拌10分钟,缓慢升至25℃搅拌3小时。1N HCl调反应液pH至6,EA萃取,有机相用无水硫酸钠干燥,过滤后减压浓缩有机溶剂得到标题化合物外消旋-(5aR,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸(206mg,81%)。.
MS m/z(ESI):528.1[M+H]
+.
第十二步:外消旋-(5aR,6S,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备
冰浴下,(5aR,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸(0.23g,435.32μmol)溶于DCM(1.51mL)中,加入DIPEA(365.70mg,2.83mmol),再分批加入HATU(246.35mg,652.98μmol),反应液冰浴下搅拌10分钟,加入二甲胺盐酸盐(177.7mg,2.18mmol),缓慢升至室温,再搅拌2小时。DCM稀释反应液,饱和食盐水洗涤,分离有机相并用无水硫酸钠干燥,过滤,浓缩后经柱层析分离得到标题化合物外消旋-(5aR,6S,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7- 甲酰胺(215mg,89%)。
MS m/z(ESI):555.1[M+H]
+.
第十三步:外消旋-(5aR,6S,7R,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-5a-(4-硝基苯基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备
室温下,(5aR,6S,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺(0.3g,540.14μmol)溶于t-BuOH(4.5mL)中,加入亚硝酸钠(74.54mg,1.08mmol),Pd
2(dba)
3(148.38mg,162.04μmol),
tBuBrettPhos(157.08mg,324.08μmol)和三(3,6-二氧杂庚基)胺(8.73mg,27.01μmol),反应液加热至130℃搅拌16小时。反应液冷却至室温,DCM稀释反应液,饱和食盐水洗涤,分离有机相并用无水硫酸钠干燥,过滤,浓缩后经柱层析分离得到标题化合物外消旋-(5aR,6S,7R,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-5a-(4-硝基苯基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺(237mg,84%)。
MS m/z(ESI):522.1[M+H]
+.
第十四步:(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-硝基苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
冰浴下,(5aR,6S,7R,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-5a-(4-硝基苯基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺(0.237g,454.44μmol)溶于THF(10mL)中,缓慢加入硼烷(7.27mmol,3.6 mL,2M THF溶液),反应液冰浴下搅10分钟,升至25℃,再搅拌12小时。加入甲醇溶液淬灭反应,60℃搅拌12小时。反应液减压浓缩后经反相制备分离,然后手性柱拆分,得到光学纯标题化合物(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-硝基苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇(27mg,11.7%)。
1H NMR(400MHz,DMSO--d
6)δ1.95-2.01(m,1H),2.22(s,6H),2.53-2.61(m,1H),3.11-3.21(m,1H),3.77(d,J=14.0Hz,1H),3.81-3.85(m,6H),4.11-4.45(m,1H),5.03(s,1H),5.45(s,1H),6.07(s,1H),6.96-7.11(m,5H),7.42-7.46(m,2H),7.88-7.93(m,2H);
MS m/z(ESI):508.3[M+H]
+.
实施例87
N-氰基-N-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)氰基酰胺的制备
N-氰基-N-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)氰基酰胺的制备方法参照实施例1。
MS m/z(ESI):528.2[M+H]
+.
实施例88
2-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)丙二腈的制备
2-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)丙二腈的制备方法参照实施例1。
MS m/z(ESI):527.2[M+H]
+.
实施例89
(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)甲三甲腈的制备
(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)甲三甲腈的制备方法参照实施例1。
MS m/z(ESI):552.2[M+H]
+.
实施例90
3-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)丙炔腈的制备
3-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)丙炔腈的制备方法参照实施例1。
MS m/z(ESI):512.2[M+H]
+.
实施例91
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-氟吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-氟吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):536.3[M+H]
+.
实施例92
1-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)吖丁啶-3-酮的制备
1-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)吖丁啶-3-酮的制备方法参照实施例1。
MS m/z(ESI):532.2[M+H]
+.
实施例93
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-羟基吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-羟基吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):534.3[M+H]
+.
实施例94
(5aR,6S,7S,8R,8aS)-5a-(4-(3,3-二氟吖丁啶-1-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-(3,3-二氟吖丁啶-1-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):554.2[M+H]
+.
实施例95
((5aR,6S,7S,8R,8aS)-5a-(4-氰基苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-基)甲基氨基甲酸酯的制备
((5aR,6S,7S,8R,8aS)-5a-(4-氰基苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-基)甲基氨基甲酸酯的制备方法参照实施例1。
MS m/z(ESI):504.2[M+H]
+.
实施例96
(5aR,6S,7S,8R,8aS)-5a-(4-(2H-四唑-5-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-(2H-四唑-5-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):531.2[M+H]
+.
实施例97
(5aR,6S,7R,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-5a-(4-硝基苯基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备
(5aR,6S,7R,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-5a-(4-硝基苯基)-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备方法参照实施例1。
MS m/z(ESI):522.2[M+H]
+.
实施例98
(5aR,6S,7S,8R,8aS)-5a-(4-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):560.3[M+H]
+.
实施例99
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a-(4-((3aR,6aS)-四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)苯基)-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a-(4-((3aR,6aS)-四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)苯基)-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):574.3[M+H]
+.
实施例100
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-(3-甲氧基吖丁啶-1-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-(3-甲氧基吖丁啶-1-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):548.3[M+H]
+.
实施例101
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-(3-(甲氧基甲基)吖丁啶-1-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-(3-(甲氧基甲基)吖丁啶-1-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):562.3[M+H]
+.
实施例102
1-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)吖丁啶-3-甲腈的制备
1-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)吖丁啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):543.3[M+H]
+.
实施例103
2-(1-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)吖丁啶-3-基)乙酰腈的制备
2-(1-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)吖丁啶-3-基)乙酰腈的制备方法参照实施例1。
MS m/z(ESI):557.3[M+H]
+.
实施例104
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-(氟甲基)-3-羟基吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-(氟甲基)-3-羟基吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):566.3[M+H]
+.
实施例105
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-氟-3-(羟甲基)吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-氟-3-(羟甲基)吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):566.3[M+H]
+.
实施例106
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-氟-3-(2-羟基丙烷-2-基)吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-氟-3-(2-羟基丙烷-2-基)吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):594.3[M+H]
+.
实施例107
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-羟基-3-甲基吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-羟基-3-甲基吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):548.3[M+H]
+.
实施例108
(5aR,6S,7S,8R,8aS)-5a-(4-((3S,4R)-3,4-二氟吡咯烷-1-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-((3S,4R)-3,4-二氟吡咯烷-1-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):568.3[M+H]
+.
实施例109
(5aR,6S,7S,8R,8aS)-5a-(4-((3R,4R)-3,4-二氟吡咯烷-1-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-((3R,4R)-3,4-二氟吡咯烷-1-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):568.3[M+H]
+.
实施例110
(5aR,6S,7S,8R,8aS)-5a-(4-((3S,4S)-3,4-二氟吡咯烷-1-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-((3S,4S)-3,4-二氟吡咯烷-1-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):568.3[M+H]
+.
实施例111
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(1-氟环丙基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(1-氟环丙基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):521.2[M+H]
+.
实施例112
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(1-羟基环丙基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(1-羟基环丙基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):519.2[M+H]
+.
实施例113
(5aR,6S,7S,8R,8aS)-5a-(4-(1-氨基环丙基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-(1-氨基环丙基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):518.3[M+H]
+.
实施例114
1-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)环丙烷-1-甲腈的制备
1-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)环丙烷-1-甲腈的制备方法参照实施例1。
MS m/z(ESI):528.2[M+H]
+.
实施例115
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-(3-甲基噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-(3-甲基噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):533.3[M+H]
+.
实施例116
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((乙基(甲基)氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((乙基(甲基)氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ0.85-0.93(m,3H),1.94-2.02(m,1H),2.14(s,3H),2.18-2.28(m,1H),2.34-2.40(m,1H),2.48-2.55(m,2H),3.97-3.05(m,1H),3.55-3.61(m,1H),3.76(s,3H),3.80(s,3H),4.32-4.37(m,1H),5.20(s,1H),5.96(s,1H),6.71-6.77(m,2H),6.85-6.89(m,2H),6.90-6.96(m,1H),6.97-7.04(m,2H),7.08-7.16(m,2H);
MS m/z(ESI):518.2[M+H]
+.
实施例117
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((二乙胺基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((二乙胺基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ0.82-0.88(m,6H),2.08-2.16(m,1H),2.31-2.39(m,2H),2.46-2.60(m,4H),2.96-3.04(m,1H),3.56-3.64(m,1H),3.76(s,3H),3.78(s,3H),4.33-4.38(m,1H),5.20(s,1H),5.96(s,1H),6.72-6.78(m,2H),6.86-6.89(m,2H),6.91-6.96(m,1H),6.97-7.03(m,2H),7.10-7.15(m,2H);
MS m/z(ESI):532.3[M+H]
+.
实施例118
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-1,3-二甲氧基-7-((甲基(2,2,2-三氟乙基)氨基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-1,3-二甲氧基-7-((甲基(2,2,2-三氟乙基)氨基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):572.2[M+H]
+.
实施例119
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-1,3-二甲氧基-7-(((甲氧基甲基)(甲基)氨基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-1,3-二甲氧基-7-(((甲氧基甲基)(甲基)氨基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):534.2[M+H]
+.
实施例120
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((3,3-二氟吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((3,3-二氟吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):552.2[M+H]
+.
实施例121
(5aR,6S,7S,8R,8aS)-7-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)-5a-(4-叠氮苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)-5a-(4-叠氮苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ2.15-2.21(m,1H),2.53-2.61(m,2H),2.79-2.88(m,2H),3.27(s,3H),3.59-3.65(m,1H),3.83(s,3H),3.85(s,3H),4.34-4.37(m,1H),4.55-4.61(m,4H),5.24(s,1H),6.01(s,1H),6.77-6.81(m,2H),6.88-6.93(m,2H),6.98-7.03(m,1H),7.05-7.11(m,2H),7.15-7.19(m,2H);
MS m/z(ESI):558.2[M+H]
+.
实施例122
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((4,4-二氟哌啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((4,4-二氟哌啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):580.2[M+H]
+.
实施例123
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-1,3-二甲氧基-7-(吗啉代甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-1,3-二甲氧基-7-(吗啉代甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ1.98-2.05(m,1H),2.6-2.35(m,2H),2.52-2.62(m,3H),3.09-3.18(m,1H),3.56-3.68(m,5H),3.84(s,3H),3.86(s,3H),4.40-4.45(m,1H),4.80-4.86(m,1H),5.27(s,1H),6.03(s,1H),6.76-6.82(m,2H),6.92-6.96(m,2H),6.98-7.02(m,1H),7.04-7.10(m,2H),7.16-7.24(m,2H);
MS m/z(ESI):546.2[M+H]
+.
实施例124
(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-5a-(4-叠氮苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-5a-(4-叠氮苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):570.3[M+H]
+.
实施例125
(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-5a-(4-叠氮苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-5a-(4-叠氮苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ0.84-0.89(m,1H),1.40-1.46(m,1H),1.59-1.69(m,4H),1.97-2.03(m,2H),2.13-2.20(m,2H),2.32-2.36(m,1H), 2.67-2.69(m,1H),2.92-2.98(m,1H),3.03-3.07(m,1H),3.66-3.71(m,1H),3.82(s,3H),3.86(s,3H),4.51-4.54(m,1H),5.25(s,1H),6.03(s,1H),6.76-6.80(m,2H),6.93-6.98(m,2H),6.98-7.03(m,1H),7.04-7.10(m,2H),7.18-7.22(m,2H);
MS m/z(ESI):572.2[M+H]
+.
实施例126
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((乙基(甲基)氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((乙基(甲基)氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ0.39-0.44(m,2H),0.75-0.79(m,2H),0.86-0.91(m,3H),1.62-1.69(m,1H),1.92-1.98(m,1H),2.12(s,3H),2.17-2.24(m,1H),2.34-2.41(m,1H),2.46-2.54(m,2H),2.94-3.03(m,1H),3.49-3.56(m,1H),3.76(s,3H),3.78(s,3H),4.33-4.38(m,1H),5.08(s,1H),5.94(s,1H),6.65-6.70(m,2H),6.81-6.85(m,2H),6.91-7.00(m,5H);
MS m/z(ESI):517.3[M+H]
+.
实施例127
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((二乙胺基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((二乙胺基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ0.39-0.45(m,2H),0.72-0.80(m,2H),0.82-0.89(m,6H),1.62-1.70(m,1H),2.06-2.13(m,1H),2.30-2.38(m,2H),2.46-2.57(m,4H),2.92-3.01(m,1H),3.51-3.58(m,1H),3.75(s,3H),3.78(s,3H),4.32-4.38(m,1H),5.08(s,1H),5.94(s,1H),6.65-6.70(m,2H),6.79-6.85(m,2H),6.91-7.01(m,5H);
MS m/z(ESI):531.3[M+H]
+.
实施例128
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-1,3-二甲氧基-7-((甲基(2,2,2-三氟乙基)氨基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-1,3-二甲氧基-7-((甲基(2,2,2-三氟乙基)氨基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):571.2[M+H]
+.
实施例129
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((4,4-二氟哌啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((4,4-二氟哌啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):579.3[M+H]
+.
实施例130
(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-5a-(4-环丙基苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-5a-(4-环丙基苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ0.44-0.51(m,2H),0.80-0.87(m,2H),1.58-1.74(m,5H),2.10-2.18(m,1H),2.39-2.44(m,1H),2.92-3.06(m,2H),3.18-3.22(m,1H),3.44-3.46(m,2H),3.52-3.58(m,2H),3.60-3.66(m,1H),3.77(s,3H),3.78(s,3H),4.50-4.54(m,1H),5.08-5.12(m,1H),5.13(s,1H),6.01(s,1H),6.70-6.76(m,2H),6.89-6.93(m,2H),6.96-7.00(m,1H),7.01-7.08(m,4H);
MS m/z(ESI):571.3[M+H]
+.
实施例131
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-1,3-二甲氧基-7-(吗啉代甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-1,3-二甲氧基-7-(吗啉代甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照
实施例1。
1H NMR(400MHz,DMSO-d
6)δ0.45-0.51(m,2H),0.81-0.85(m,2H), 1.68-1.75(m,1H),1.96-2.02(m,1H),2.26-2.34(m,2H),2.54-2.60(m,2H),3.08-3.15(m,1H),3.54-3.67(m,6H),3.84(s,3H),3.86(s,3H),4.40-4.45(m,1H),4.74-4.78(m,1H),5.15(s,1H),6.00(s,1H),6.71-6.76(m,2H),6.86-6.92(m,2H),6.97-7.06(m,5H);
MS m/z(ESI):545.3[M+H]
+.
实施例132
(5aR,6S,7S,8R,8aS)-7-((乙基(甲基)氨基)甲基)-1,3-二甲氧基-5a-(4-(噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((乙基(甲基)氨基)甲基)-1,3-二甲氧基-5a-(4-(噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ0.85-0.92(m,3H),1.30-1.35(m,1H),1.93-1.99(m,1H),2.13(s,3H),2.18-2.26(m,1H),2.33-2.40(m,1H),2.47-2.54(m,1H),2.95-3.05(m,1H),3.52-3.58(m,1H),3.76(s,3H),3.78(s,3H),3.96-4.06(m,1H),4.33-4.44(m,3H),4.73-4.79(m,2H),5.13(s,1H),5.95(s,1H),6.80-6.86(m,2H),6.88-6.93(m,1H),6.94-7.03(m,4H),7.06-7.12(m,2H);
MS m/z(ESI):533.3[M+H]
+.
实施例133
(5aR,6S,7S,8R,8aS)-7-((二乙胺基)甲基)-1,3-二甲氧基-5a-(4-(噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二乙胺基)甲基)-1,3-二甲氧基-5a-(4-(噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ0.81-0.90(m,6H),2.06-2.13(m,1H),2.30-2.37(m,2H),2.48-2.54(m,3H),2.95-3.02(m,1H),3.54-3.60(m,1H),3.76(s,3H),3.79(s,3H),3.97-4.05(m,1H),4.34-4.42(m,3H),4.73-4.80(m,2H),4.82-4.88(m,1H),5.12(s,1H),5.96(s,1H),6.82-6.86(m,2H),6.88-6.93(m,1H),6.94-7.02(m,4H),7.07-7.11(m,2H);
MS m/z(ESI):547.3[M+H]
+.
实施例134
(5aR,6S,7S,8R,8aS)-1,3-二甲氧基-7-((甲基(2,2,2-三氟乙基)氨基)甲基)-5a-(4-(噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-1,3-二甲氧基-7-((甲基(2,2,2-三氟乙基)氨基)甲基)-5a-(4-(噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):587.2[M+H]
+.
实施例135
(5aR,6S,7S,8R,8aS)-7-((4,4-二氟哌啶-1-基)甲基)-1,3-二甲氧基-5a-(4-(噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((4,4-二氟哌啶-1-基)甲基)-1,3-二甲氧基-5a-(4-(噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):595.3[M+H]
+.
实施例136
(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-1,3-二甲氧基-5a-(4-(噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)甲基)-1,3-二甲氧基-5a-(4-(噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):587.3[M+H]
+.
实施例137
(5aR,6S,7S,8R,8aS)-1,3-二甲氧基-7-(吗啉代甲基)-5a-(4-(噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-1,3-二甲氧基-7-(吗啉代甲基)-5a-(4-(噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):561.3[M+H]
+.
实施例138
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-氟-3-甲基吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-氟-3-甲基吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):550.3[M+H]
+.
实施例139
(5aR,6S,7S,8R,8aS)-5a-(4-(3,3-二氟环丁基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-(3,3-二氟环丁基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):553.3[M+H]
+.
实施例140
(5aR,6S,7S,8R,8aS)-5a-(4-(3-(二甲氨基)吖丁啶-1-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-(3-(二甲氨基)吖丁啶-1-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):561.3[M+H]
+.
实施例141
(5aR,6S,7R,8R,8aS)-5a-(4-(3-(二甲氨基)吖丁啶-1-基)苯基)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备
(5aR,6S,7R,8R,8aS)-5a-(4-(3-(二甲氨基)吖丁啶-1-基)苯基)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备方法参照实施例1。
MS m/z(ESI):575.3[M+H]
+.
实施例142
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-羟基-3-(三氟甲基)吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(3-羟基-3-(三氟甲基)吖丁啶-1-基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):602.2[M+H]
+.
实施例143
(5aR,6S,7S,8R,8aS)-5a-(4-(吖丁啶-1-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-(吖丁啶-1-基)苯基)-7-((二甲氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):518.3[M+H]
+.
实施例144
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-(3-硝基吖丁啶-1-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-(3-硝基吖丁啶-1-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):563.2[M+H]
+.
实施例145
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-(((2-羟基乙基)(甲基)氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-(((2-羟基乙基)(甲基)氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ1.98-2.05(m,1H),2.16-2.28(m,5H),2.47-2.58(m,3H),3.01-3.08(m,2H),3.54-3.59(m,1H),3.76(s,3H),3.80(s,3H),4.37-4.41(m,1H),4.43-4.48(m,1H),5.18(s,1H),5.96(s,1H),6.71-6.76(m,2H),6.85-6.90(m,2H),6.92-6.97(m,1H),6.98-7.04(m,2H),7.10-7.17(m,2H);
MS m/z(ESI):534.2[M+H]
+.
实施例146
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((3-氟吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((3-氟吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ2.19-2.27(m,1H),2.52-2.69(m,2H),2.77-2.88(m,1H),2.96-3.08(m,2H),3.46-3.60(m,3H),3.76(s,3H),3.80(s,3H),4.27-4.32(m,1H),4.93-5.02(m,1H),5.19(s,1H),5.95(s,1H),6.70-6.76(m,2H),6.83-6.88(m,2H),6.91-6.97(m,1H),6.99-7.04(m,2H),7.08-7.14(m,2H);
MS m/z(ESI):534.2[M+H]
+.
实施例147
2-(1-(((5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-基)甲基)吖丁啶-3-基)乙酰腈的制备
2-(1-(((5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-基)甲基)吖丁啶-3-基)乙酰腈的制备方法参照实施例1。
MS m/z(ESI):555.3[M+H]
+.
实施例148
1-(((5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-基)甲基)吖丁啶-3-甲腈的制备
1-(((5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-基)甲基)吖丁啶-3-甲腈的制备方法参照实施例1。
MS m/z(ESI):541.2[M+H]
+.
实施例149
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-(((2-氟乙基)(甲基)氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-(((2-氟乙基)(甲基)氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):536.2[M+H]
+.
实施例150
3-((((5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-基)甲基)(甲基)氨基)丙腈的制备
3-((((5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-基)甲基)(甲基)氨基)丙腈的制备方法参照实施例1。
MS m/z(ESI):543.2[M+H]
+.
实施例151
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-(((2-(二甲氨基)乙基)(甲基)氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-(((2-(二甲氨基)乙基)(甲基)氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):561.3[M+H]
+.
实施例152
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-1,3-二甲氧基-7-(((2-甲氧基乙基)(甲基)氨基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-1,3-二甲氧基-7-(((2-甲氧基乙基)(甲基)氨基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):547.3[M+H]
+.
实施例153
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-(((2-羟基乙基)(甲基)氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-(((2-羟基乙基)(甲基)氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):533.3[M+H]
+.
实施例154
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-1,3-二甲氧基-7-((3-甲氧基吖丁啶-1-基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-1,3-二甲氧基-7-((3-甲氧基吖丁啶-1-基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ0.38-0.47(m,2H),0.72-0.81(m,2H),1.60-1.70(m,1H),2.13-2.19(m,1H),2.54-2.61(m,1H),2.63-2.72(m,2H),2.74-2.82(m,1H),3.05(s,3H),3.44-3.56(m,3H),3.76(s,3H),3.78(s,3H),3.82-3.88(m,1H),4.27-4.33(m,1H),5.00-5.08(m,2H),5.93(s,1H),6.64-6.70(m,2H),6.78-6.84(m,2H),6.92-7.01(m,5H);
MS m/z(ESI):545.2[M+H]
+.
实施例155
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-1,3-二甲氧基-7-((3-(甲氧基甲基)吖丁啶-1-基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-1,3-二甲氧基-7-((3-(甲氧基甲基)吖丁啶-1-基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ0.37-0.44(m,2H),0.73-0.79(m,2H),1.60-1.68(m,1H),2.16-2.22(m,1H),2.47-2.58(m,2H),2.68-2.81(m,3H),3.09-3.16(m,5H),3.37-3.42(m,2H),3.49-3.56(m,1H),3.74(s,3H),3.76(s,3H),4.28-4.33(m,1H),5.04(s,1H),5.17-5.25(m,1H),5.92(s,1H),6.64-6.69(m,2H),6.78-6.83(m,2H),6.91-7.01(m,5H);
MS m/z(ESI):559.2[M+H]
+.
实施例156
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((3-羟基-3-甲基吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((3-羟基-3-甲基吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ0.37-0.48(m,2H),0.72-0.81(m,2H),1.24(s,3H),1.62-1.68(m,1H),2.26-2.31(m,1H),2.56-2.63(m,2H),2.72-2.82(m,2H),3.04-3.09(m,1H),3.14-3.22(m,2H),3.52-3.60(m,1H),3.75(s,3H),3.78(s,3H),4.29-4.34(m,1H),4.97-5.06(m,1H),5.24-5.32(m,1H),5.93(s,1H),6.63-6.70(m, 2H),6.79-6.85(m,2H),6.92-7.01(m,5H);
MS m/z(ESI):545.2[M+H]
+.
实施例157
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((3-羟基吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((3-羟基吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):531.3[M+H]
+.
实施例158
(4a'S,5'S,5a'R,10b'S,10c'R)-5a'-(4-环丙基苯基)-8',10'-二甲氧基-3'-甲基-5'-苯基-3',4',4a',5',5a',10c'-六氢-10b'H-螺[噁丁环-3,2'-吡啶并[3”,4”:4',5']呋喃并[3',2':3,4]环戊二烯并[1,2-e][1,3]噁嗪]-10b'-醇的制备
(4a'S,5'S,5a'R,10b'S,10c'R)-5a'-(4-环丙基苯基)-8',10'-二甲氧基-3'-甲基-5'-苯基-3',4',4a',5',5a',10c'-六氢-10b'H-螺[噁丁环-3,2'-吡啶并[3”,4”:4',5']呋喃并[3',2':3,4]环戊二烯并[1,2-e][1,3]噁嗪]-10b'-醇的制备方法参照实施例1。
MS m/z(ESI):543.3[M+H]
+.
实施例159
(4aS,5S,5aR,10bS,10cR)-5a-(4-环丙基苯基)-10b-羟基-8,10-二甲氧基-3-甲基-5-苯基-4,4a,5,5a,10b,10c-六氢吡啶并[3”,4”:4',5']呋喃并[3',2':3,4]环戊二烯并[1,2-e][1,3]噁嗪-2(3H)-酮的制备
(4aS,5S,5aR,10bS,10cR)-5a-(4-环丙基苯基)-10b-羟基-8,10-二甲氧基-3-甲基-5-苯基-4,4a,5,5a,10b,10c-六氢吡啶并[3”,4”:4',5']呋喃并[3',2':3,4]环戊二烯并[1,2-e][1,3]噁嗪-2(3H)-酮的制备方法参照实施例1。
MS m/z(ESI):515.2[M+H]
+.
实施例160
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-1,3-二甲氧基-7-((甲基(噁丁环-3-基甲基)氨基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-1,3-二甲氧基-7-((甲基(噁丁环-3-基甲基)氨基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):559.3[M+H]
+.
实施例161
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-1,3-二甲氧基-7-((甲基(噁丁环-3-基)氨基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-1,3-二甲氧基-7-((甲基(噁丁环-3-基)氨基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):545.3[M+H]
+.
实施例162
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((3-(氟甲基)-3-羟基吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-环丙基苯基)-7-((3-(氟甲基)-3-羟基吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):563.3[M+H]
+.
实施例163
(5aR,6S,7S,8R,8aS)-7-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)-5a-(4-环丙基苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)-5a-(4-环丙基苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇制备方法参照实施例1。
MS m/z(ESI):557.3[M+H]
+.
实施例164
N-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)氰基酰胺的制备
N-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)氰基酰胺的制备方法参照实施例1。
MS m/z(ESI):503.2[M+H]
+.
实施例165
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-吗啉代苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-吗啉代苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,CDCl
3)δ2.02-2.00(d,J=7.2Hz,2H),2.90-2.50(m,7H),3.08-3.05(m,4H),3.83-3.80(m,4H),3.93(s,3H),4.03(s,3H),5.10(s,1H),5.35(s,1H),6.02(s,1H),6.70(d,J=8.0Hz,2H),6.88-6.83(m,2H),7.15-7.10(m,5H);
MS m/z(ESI):548.3[M+H]
+.
实施例166
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-(4-甲基哌嗪-1-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-(4-甲基哌嗪-1-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):561.3[M+H]
+.
实施例167
(E)-4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯(甲)醛O-甲基肟的制备
(E)-4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯(甲)醛O-甲 基肟的制备方法参照实施例1。
MS m/z(ESI):520.3[M+H]
+.
实施例168
(E)-4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯(甲)醛肟的制备
第一步:4-(苄氧基)-2,6-二氯吡啶的制备
冰水浴下,往2,4,6-三氯吡啶(30.0g,165mmol)的DMF溶液(300mL)里分批加入NaH(7.59g,60wt%,190mmol),加完后,继续在该温度下搅拌15分钟,然后逐滴加入苄醇(17.9mL,173mmol),加毕,再在冰水浴下搅拌1小时。将反应液倒入冰水中,用乙酸乙酯萃取三次,合并有机相,再用饱和食盐水洗涤多次,分离有机相并用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物4-(苄氧基)-2,6-二氯吡啶(30.4g,73%)。
1H NMR(400MHz,CDCl
3)δ5.11(s,2H),6.86(s,2H),7.37-7.42(m,5H);
MS m/z(ESI):254.0[M+H]
+.
第二步:4-(苄氧基)-2-氯-6-甲氧基吡啶的制备
往4-(苄氧基)-2,6-二氯吡啶(27.0g,106mmol)的甲苯溶液(400mL)里加入甲醇钠的甲醇溶液(30wt%,36.4g,202mmol),然后在60℃下搅拌5小时。反应冷却至室温,反应液倒入水中,用乙酸乙酯萃取三次,合并有机相,用饱和食盐水洗涤,分离有机相用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物4-(苄氧基)-2-氯-6-甲氧基吡啶(19.6g,74%)。
1H NMR(400MHz,DMSO-d
6)δ3.81(s,3H),5.20(s,2H),6.46(d,J=1.9Hz,1H),6.81(d,J=1.9Hz,1H),7.32-7.47(m,5H);
MS m/z(ESI):250.2[M+H]
+.
第三步:1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-醇的制备
在干冰-丙酮浴下,往4-(苄氧基)-2-氯-6-甲氧基吡啶(19.5g,78.1mmol)的THF溶液(200mL)里,滴加入n-BuLi的正己烷溶液(41.0mL,2.4M,97.6mmol),在该温度下搅拌30分钟,然后向反应体系中滴加乙醛(6.88g,156mmol),滴加完毕,继续搅拌10分钟,加入饱和氯化铵水溶液淬灭反应,反应液用乙酸乙酯萃取多次,合并有机相,用饱和食盐水洗涤,分离有机相用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得标题化合物1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-醇(16g,70%)。
1H NMR(400MHz,DMSO-d
6)δ1.39(d,J=6.6Hz,3H),3.84(s,3H),4.60(d,J=6.6Hz,1H),5.09-5.14(m,1H),5.25(s,2H),6.93(s,1H),7.32-7.49(m,5H);
MS m/z(ESI):294.1[M+H]
+.
第四步:1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-酮的制备
往1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-醇(16.0g,54.6mmol)的二氯甲烷溶液(320mL)里分批加入DMP(30.1g,71.0mmol),加毕,继续在室温下搅拌2小时。然后依次加入饱和碳酸氢钠水溶液和硫代硫酸钠水溶液,再搅拌15分钟。分离有机相,水相再用二氯甲烷萃取二次。合并有机相后,用无水硫酸钠干燥,过滤后减压浓缩有机溶剂,柱层析分离得到标题化合物1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-酮(8.10g,51%)。
1H NMR(400MHz,DMSO-d
6)δ2.37(s,3H),3.84(s,3H),4.60(d,J=6.1Hz,1H),5.28(s,2H),7.10(s,1H),7.32-7.47(m,5H);
MS m/z(ESI):292.2[M+H]
+.
第五步:1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)乙烷-1-酮的制备
往1-(4-(苄氧基)-6-氯-2-甲氧基吡啶-3-基)乙烷-1-酮(4.67g,16.0mmol)的乙酸乙酯溶液(120mL)里,加入Pd/C(140mg,10wt%),在氢气氛下,常温常压,搅拌3小时,用硅藻土滤除不溶物,滤液减压浓缩后柱层析分离得到标题化合物1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)乙烷-1-酮(2.30g,71%)。
1H NMR(400MHz,DMSO-d
6)δ2.50(s,3H),3.90(s,3H),6.70(s,1H),13.00(s,1H);
MS m/z(ESI):202.2[M+H]
+.
第六步:(E)-3-(4-溴苯基)-1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)丙-2-烯-1-酮的制备
往1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)乙烷-1-酮(2.00g,9.92mmol),4-溴苯甲醛(1.65g,8.93mmol)的DMF溶液(31mL)里加入MeONa的MeOH溶液(5.36g,30wt%,29.8mmol),在50℃下剧烈搅拌30分钟,冷却,然后在冰水浴下倒入稀盐酸(0.3M,200mL)中,过滤收集析出的固体并干燥,然后用EtOAc/正庚烷混合溶剂(混合溶剂比1:10)打浆纯化,得到标题化合物(E)-3-(4-溴苯基)-1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)丙-2-烯-1-酮(1.87g,57%)。
1H NMR(400MHz,DMSO-d
6)δ3.80(s,3H),6.60(s,1H),7.20(d,J=16.0Hz,1H),7.40(d,J=16.0Hz,1H),7.56-7.73(m,4H);
MS m/z(ESI):368.0[M+H]
+.
第七步:2-(4-溴苯基)-7-氯-3-羟基-5-甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮的制备
水浴下,往(E)-3-(4-溴苯基)-1-(6-氯-4-羟基-2-甲氧基吡啶-3-基)丙-2-烯-1-酮(1.40g,3.80mmol)的EtOH(27mL)和DCM(6.8mL)的混合溶液里,依次滴加入NaOH水溶液(3.36g,10wt%,8.39mmol)和H
2O
2水溶液(3.03g,30wt%,26.7mmol),然后在水浴下搅拌1小时。加入饱和氯化铵水溶液,用DCM萃取三次,合并有机相,用无水硫酸钠干燥,过滤后减压浓缩有机溶剂得到粗品2-(4-溴苯基)-7-氯-3-羟基-5-甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(700mg),未作进一步纯化,直接用于下一步。
MS m/z(ESI):381.9[M+H]
+.
第八步:2-(4-溴苯基)-3-羟基-5,7-二甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮的制备
往2-(4-溴苯基)-7-氯-3-羟基-5-甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(上一步粗品,700mg)的DMF溶液(30mL)里,加入甲醇钠的甲醇溶液(15mL,30wt%), 然后在80℃下搅拌1小时,冷却,反应液倒入冰水中,再用盐酸(6M)调节pH至弱酸性,过滤析出的固体,滤饼用水洗涤,收集固体化合物并干燥,柱层析分离纯化得到标题化合物2-(4-溴苯基)-3-羟基-5,7-二甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(180mg,两步收率:13%)。
1H NMR(400MHz,DMSO-d
6)δ3.95(s,3H),4.00(s,3H),6.60(s,1H),7.75(d,J=9.6Hz,2H),8.10(d,J=8.0Hz,2H),9.65(br s,1H);
MS m/z(ESI):378.0[M+H]
+.
第九步:外消旋-甲基(3S,4R,5R)-2-(4-溴苯基)-5-羟基-6,8-二甲氧基-10-羰基-3-苯基-2,3,4,5-四氢-2,5-亚甲基噁庚并[3,2-c]吡啶-4-羧酸酯的制备
将2-(4-溴苯基)-3-羟基-5,7-二甲氧基-4H-吡喃并[3,2-c]吡啶-4-酮(160mg,0.424mmol)和肉桂酸甲酯(686mg,4.24mmol)溶于氯仿(7mL)和三氟乙醇(5.6mL)中,0℃,在450W UV光照射下剧烈搅拌5小时。减压浓缩有机溶剂柱层析除去多余的肉桂酸甲酯,得到粗品外消旋-甲基(3S,4R,5R)-2-(4-溴苯基)-5-羟基-6,8-二甲氧基-10-羰基-3-苯基-2,3,4,5-四氢-2,5-亚甲基噁庚并[3,2-c]吡啶-4-羧酸酯(250mg),直接用于下一步反应。
MS m/z(ESI):540.1[M+H]
+.
第十步:外消旋-甲基(5aR,6S,7R,8aR)-5a-(4-溴苯基)-8a-羟基-1,3-二甲氧基-8-羰基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸酯的制备
往外消旋-甲基(3S,4R,5R)-2-(4-溴苯基)-5-羟基-6,8-二甲氧基-10-羰基-3-苯基-2,3,4,5-四氢-2,5-亚甲基噁庚并[3,2-c]吡啶-4-羧酸酯(250mg,粗品,约0.424mmol)的甲醇溶液(8mL)里滴加入甲醇钠的甲醇溶液(30wt%,252mg,1.40mmol),然后在60℃下搅拌45分钟,反应冷却至室温,减压浓缩有机溶剂,残余物用二氯甲烷和饱和氯化铵水溶液分层,分离有机相并用无水硫酸钠干燥,过滤后减压浓缩有机溶剂得到粗品外消旋-甲基(5aR,6S,7R,8aR)-5a-(4-溴苯基)-8a-羟基-1,3-二甲氧基-8-羰基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并 [3,2-c]吡啶-7-羧酸酯(250mg),直接用于下一步反应。
MS m/z(ESI):540.1[M+H]
+.
第十一步:外消旋-(5aR,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸的制备
冰浴下,外消旋-(5aR,6S,7S,8R,8aS)-5a-(4-溴苯基)-7-(羟甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇(0.26g,479.37μmol)溶于MeOH(3mL),THF(1.5mL)和H
2O(1.5mL)中,加入lithium hydroxide hydrate(201.16mg,4.79mmol),反应液冰浴下搅拌10分钟,缓慢升至25℃搅拌3小时。1N HCl调反应液pH至6,EA萃取,有机相用无水硫酸钠干燥,过滤后减压浓缩有机溶剂得到标题化合物外消旋-(5aR,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸(206mg,81%)。.
MS m/z(ESI):528.1[M+H]
+.
第十二步:外消旋-(5aR,6S,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备
冰浴下,(5aR,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-羧酸(0.23g,435.32μmol)溶于DCM(1.51mL)中,加入DIPEA(365.70mg,2.83mmol),再分批加入HATU(246.35mg,652.98μmol),反应液冰浴下搅拌10分钟,加入二甲胺盐酸盐(177.7mg,2.18mmol),缓慢升至室温,再搅拌2小时。DCM稀释反应液,饱和食盐水洗涤,分离有机相并用无水硫酸钠干燥,过滤,浓缩后经柱层析分离得到标题化合物外消旋-(5aR,6S,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3- 二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺(215mg,89%)。
MS m/z(ESI):555.1[M+H]
+.
第十三步:外消旋-甲基4-((5aR,6S,7R,8R,8aS)-7-(二甲基氨基甲酰)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯酸酯的制备
室温下,外消旋-(5aR,6S,7R,8R,8aS)-5a-(4-溴苯基)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺(0.356g,640.96μmol)溶于MeOH(20mL)和MeCN(7mL)中,加入反式-二(mu-乙酸基)双[o-(二邻甲苯磷)苄基]二钯(180.30mg,192.29μmol)和Mo(CO)
6(507.64mg,1.92mmol),氮气鼓泡5分钟,加热至135℃微波反应2小时。减压浓缩反应液,残余物用二氯甲烷和水分液,分离有机相并用无水硫酸钠干燥,过滤,浓缩后经柱层析分离得到标题化合物外消旋-甲基4-((5aR,6S,7R,8R,8aS)-7-(二甲基氨基甲酰)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯酸酯(210mg,61%)。
MS m/z(ESI):535.2[M+H]
+.
第十四步:外消旋-(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(羟甲基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
室温下,外消旋-甲基4-((5aR,6S,7R,8R,8aS)-7-(二甲基氨基甲酰)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a- 基)苯酸酯(0.23g,430.3μmol)溶于THF(5mL)中,缓慢加入硼烷(7.27mmol,5.15mL,2M THF溶液),升温至66℃,搅拌12小时。加入甲醇溶液淬灭反应,60℃搅拌12小时。反应液减压浓缩后经柱层析分离得到标题化合物外消旋(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(羟甲基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇(110mg,51.9%)。
MS m/z(ESI):493.2[M+H]
+.
第十五步:外消旋-4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯(甲)醛的制备
冰浴下,外消旋-(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-5a-(4-(羟甲基)苯基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇(0.09g,182.72μmol)溶于DCM(6.6mL)中,加入DMP(116.25mg,274.08μmol),反应冰浴下搅拌0.5小时。反应液减压浓缩后经柱层析分离得到标题化合物外消旋-4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯(甲)醛(71mg,79%)。
MS m/z(ESI):491.2[M+H]
+.
第十六步:(E)-4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯(甲)醛肟的制备
室温下,外消旋-4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3- 二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯(甲)醛(0.071g,144.74μmol)溶于EtOH(2mL)和H
2O(2mL)中,加入盐酸羟胺(20.12mg,289.47μmol)和DIPEA(73.23mg,723.68μmol),氮气鼓泡5分钟,室温搅拌1小时。反应液减压浓缩后经反相制备分离,然后手性柱拆分,得到光学纯标题化合物(E)-4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯(甲)醛肟(26mg,36%)。
1H NMR(400MHz,DMSO-d
6)δ1.96-2.02(m,1H),2.13-2.28(m,6H),2.55-2.59(m,1H),3.11-3.16(m,1H),3.68(d,J=14.0Hz,1H),3.81-3.85(m,6H),4.43-4.48(m,1H),4.95(s,1H),5.29(s,1H),6.04(s,1H),6.93-7.01(m,2H),7.03-7.09(m,2H),7.17-7.21(m,2H),7.23-7.28(m,2H),7.35–7.43(m,1H),7.95(s,1H),11.09(s,1H);
MS m/z(ESI):506.3[M+H]
+.
实施例169
N-((E)-4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯亚甲基)氰基酰胺的制备
N-((E)-4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯亚甲基)氰基酰胺的制备方法参照实施例1。
MS m/z(ESI):515.2[M+H]
+.
实施例170
环丙基(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)甲酮的制备
环丙基(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)甲酮的制备方法参照实施例1。
MS m/z(ESI):531.2[M+H]
+.
实施例171
(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)(噁丁环-3-基)甲酮的制备
(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)(噁丁环-3-基)甲酮的制备方法参照实施例1。
MS m/z(ESI):547.2[M+H]
+.
实施例172
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-(3-甲基噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-1,3-二甲氧基-5a-(4-(3-甲基噁丁环-3-基)苯基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):533.3[M+H]
+.
实施例173
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((3-羟基吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((3-羟基吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ1.96-2.04(m,2H),2.30-2.35(m,2H),2.66-2.71(m,1H),2.89-3.01(m,2H),3.49-3.52(m,1H),3.65(d,J=14.2Hz,2H),3.82(s,3H),3.85(s,3H),4.35-4.42(m,2H),5.25-5.31(m,1H),6.03(s,1H),6.78-6.83(m,2H),6.89-6.95(m,2H),7.01-7.05(m,1H),7.06-7.11(m,2H),7.14-7.20(m,2H);
MS m/z(ESI):532.2[M+H]
+.
实施例174
4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-7-(羟甲基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7S,8R,8aS)-8,8a-二羟基-7-(羟甲基)-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):461.2[M+H]
+.
实施例175
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-1,3-二甲氧基-7-((甲基(2,2,2-三氟乙基)氨基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-1,3-二甲氧基-7-((甲基(2,2,2-三氟乙基)氨基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):572.2[M+H]
+.
实施例176
1-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)丙烷-1-酮的制备
1-(4-((5aR,6S,7S,8R,8aS)-7-((二甲氨基)甲基)-8,8a-二羟基-1,3-二甲氧基-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯基)丙烷-1-酮的制备方法参照实施例1。
MS m/z(ESI):519.2[M+H]
+.
实施例177
(5aR,6S,7R,8R,8aS)-5a-(4-(3-(二甲氨基)吖丁啶-1-基)苯基)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备
(5aR,6S,7R,8R,8aS)-5a-(4-(3-(二甲氨基)吖丁啶-1-基)苯基)-8,8a-二羟基-1,3-二甲氧基-N,N-二甲基-6-苯基-5a,7,8,8a-四氢-6H-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-7-甲酰胺的制备方法参照实施例1。
MS m/z(ESI):575.2[M+H]
+.
实施例178
(5aR,6S,7S,8R,8aS)-5a-(4-(3-氟吖丁啶-1-基)苯基)-7-((3-羟基吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-(3-氟吖丁啶-1-基)苯基)-7-((3-羟基吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1
MS m/z(ESI):564.2[M+H]
+.
实施例179
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-(((2-(二甲氨基)乙基)(甲基)氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-(((2-(二甲氨基)乙基)(甲基)氨基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):561.2[M+H]
+.
实施例180
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-1,3-二甲氧基-7-((3-(甲氧基甲基)吖丁啶-1-基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-1,3-二甲氧基-7-((3-(甲氧基甲基)吖丁啶-1-基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ2.27-2.33(m,1H),2.58-2.63(m,1H),2.77-2.88(m,4H),3.15-3.19(m,1H),3.20(s,3H),3.21-3.24(m,1H),3.37-3.39(m,2H),3.62-3.67(m,1H),3.82(s,3H),3.84(s,3H),4.35-4.39(m,1H),5.21-5.24(m,1H),5.31-5.36(m,1H),6.01(s,1H),6.77-6.81(m,2H),6.89-6.94(m,2H),6.98-7.03(m,1H),7.04-7.10(m,2H),7.15-7.20(m,2H).
MS m/z(ESI):560.2[M+H]
+.
实施例181
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-1,3-二甲氧基-7-((3-甲氧基吖丁啶-1-基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-1,3-二甲氧基-7-((3-甲氧基吖丁啶-1-基)甲基)-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):546.2[M+H]
+.
实施例182
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((3-羟基-3-甲基吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((3-羟基-3-甲基吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
MS m/z(ESI):546.2[M+H]
+.
实施例183
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((3-(羟甲基)-3-甲基吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备
(5aR,6S,7S,8R,8aS)-5a-(4-叠氮苯基)-7-((3-(羟甲基)-3-甲基吖丁啶-1-基)甲基)-1,3-二甲氧基-6-苯基-5a,6,7,8-四氢-8aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-8,8a-二醇的制备方法参照实施例1。
1H NMR(400MHz,DMSO-d
6)δ1.00(s,3H),1.89-1.95(m,1H),2.60-2.73(m,4H),2.77-2.86(m,2H),2.93-3.04(m,3H),3.61-3.65(m,1H),3.76(s,3H),3.78(s,3H),4.30-4.34(m,1H),4.58-4.67(m,1H),5.16-5.19(m,1H),5.95(s,1H),6.70-6.74(m,2H),6.84-6.88(m,2H),6.93-6.97(m,1H),6.99-7.03(m,2H),7.09-7.13(m,2H).
MS m/z(ESI):560.2[M+H]
+.
实施例184
4-((5aR,6S,7R,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-((甲氧基(甲基)氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备
4-((5aR,6S,7R,8R,8aS)-8,8a-二羟基-1,3-二甲氧基-7-((甲氧基(甲基)氨基)甲基)-6-苯基-6,7,8,8a-四氢-5aH-环戊二烯并[4,5]呋喃并[3,2-c]吡啶-5a-基)苯甲腈的制备方法参照实施例1。
MS m/z(ESI):504.2[M+H]
+.
生物学测试评价
以下结合测试例进一步描述解释本发明,但这些实施例并非意味着限制本发明的范围。
一、细胞功能实验
测试例1、本发明化合物对淋巴瘤细胞株TMD8和SU-DHL-2的增殖抑制活性作用
1.1.实验目的:
测定实施例化合物对淋巴瘤细胞株TMD8和SU-DHL-2的增殖抑制活性。2.实验仪器:
2.1仪器:
酶标仪(BioTek Synergy H1);
移液器(Eppendorf&Rainin)。
2.2试剂:
TMD8购自南京科佰生物科技有限公司;
SU-DHL-2细胞购自ATCC,货号为CRL-2956;
Cell Titer-Glo细胞购自Promega公司,货号为G7573;
RPMI 1640购自Gibco,货号为22400089;
DMEM购自Gibco,货号为11995065;
FBS购自Gibco,货号为10091148;
PBS购自Gibco,货号为10010023;
胰酶购自Gibco,货号为25200056;
细胞培养板购自Corning公司,货号为3610。
3.实验方法:
培养TMD8或SU-DHL-2细胞至合适的融合度时,收集TMD8或SU-DHL-2细胞,使用完全培养基将细胞调整为合适的细胞密度,将细胞悬液铺于96孔板,每孔90μL,放入37℃,5%CO
2培养箱过夜,使用DMSO以及培养基配制不同浓度的化合物溶液,设置溶媒对照,将化合物溶液加入到96孔板中,每孔10μL,放入37℃,5%CO
2培养箱中继续培养约72小时后,加入CellTiter-Glo溶液,振荡混合均匀,避光孵育10分钟,用BioTek Synergy H1酶标仪进行读数。
4.实验数据处理方法:
使用发光信号值计算抑制率,将浓度以及抑制率使用Graphpad Prism软件进行非线性回归曲线拟合,得到GI
50值。
5.实验结果:
本发明实施例化合物对TMD8和SU-DHL-2细胞增殖抑制的IC
50显示出约0.01nM至500nM的生物活性。
在一些实施方案中,本发明的化合物对TMD8和SU-DHL-2细胞增殖抑制的IC
50小于约100nM、优选化合物小于约50nM、进一步优选小于约10nM、更优选小于约5nM、本发明所列示的化合物中最优选小于1nM。
表1 化合物对细胞增殖抑制活性的IC
50值
“NA”代表未测试。
6.实验结论:
本发明实施例化合物对TMD8和SU-DHL-2细胞具有显著的增殖抑制作用。
测试例2、本发明化合物对肿瘤细胞株的增殖抑制活性测定
1.实验目的:
测定实施例化合物对8株瘤细胞株的增殖抑制活性,分别为1株人胰腺癌细胞(KRAS G12C突变细胞株Mia PaCa-2),1株人肺癌腺癌细胞(KRAS G13C突变细胞株NCI-H1792)、3株人乳腺癌细胞(KRAS G13D突变细胞株MDA-MB-231、BT474和MDA-MB-361),1株人B淋巴细胞瘤细胞SU-DHL-6,2株人结肠癌细胞(KRAS G12V突变细胞株SW620和NCI-H716)。
2.实验仪器:
2.1仪器:
酶标仪(BioTek Synergy H1);
移液器(Eppendorf&Rainin)。
2.2试剂:
MDA-MB-231、MDA-MB-361、SW620和BT474购自南京科佰生物科技有限公司;
Mia PaCa-2和SU-DHL-6购自ATCC;NCI-H1792和NCI-H716购自广州吉妮欧生物科技有限公司;
Cell Titer-Glo细胞购自Promega公司,货号为G7573;
RPMI 1640购自Gibco,货号为22400089;
DMEM购自Gibco,货号为11995065;
FBS购自Gibco,货号为10091148;PBS购自Gibco,货号为10010023;
胰酶购自Gibco,货号为25200056;
细胞培养板购自Corning公司,货号为3610。
3.实验方法:
贴壁细胞:培养MDA-MB-231、MDA-MB-361、Mia PaCa-2、SW620、NCI-H1792和BT474细胞至合适的融合度时,收集MDA-MB-231、MDA-MB-361、Mia PaCa-2、SW620、NCI-H1792和BT474细胞,使用完全培养基将细胞调整为合适的细胞密度,将细胞悬液铺于96孔板,每孔90μL,放入37℃,5%CO
2培养箱贴壁过夜,使用DMSO以及培养基配制不同浓度的化合物溶液,设置溶媒对照,将化合物溶液加入到96孔板中,每孔10μL,放入37℃,5%CO
2培养箱中继续培养约72小时后,加入每孔50μL CellTiter-Glo溶液,振荡混合均匀,避光孵育10分钟,用BioTek Synergy H1酶标仪进行读数。
悬浮细胞:培养SU-DHL-6和NCI-H716细胞至合适的融合度时,收集SU-DHL-6和NCI-H716细胞,使用完全培养基将细胞调整为合适的细胞密度,将细胞悬液铺于96孔板,每孔90μL。使用DMSO以及培养基配制不同浓度的化合物溶液,设置溶媒对照,将化合物溶液加入到96孔板中,每孔10μL,放入37℃,5%CO
2培养箱中继续培养约72小时后,加入每孔50μL CellTiter-Glo溶液,振荡混合均匀,避光孵育10分钟,用BioTek Synergy H1酶标仪进行读数。
4.实验数据处理方法:
使用发光信号值计算抑制率,将浓度以及抑制率使用Graphpad Prism软件进行非线性回归曲线拟合,得到IC
50值。
5.实验结果:
实验结果如表2所示,实施例化合物对MDA-MB-231、MDA-MB-361、Mia PaCa-2、SW620、NCI-H1792、BT474、SU-DHL-6和NCI-H716细胞增殖抑制活性的IC
50值显示出约0.1nM至500nM的生物活性。
在一些实施方案中,本发明的化合物对MDA-MB-231、MDA-MB-361、Mia PaCa-2、SW620、NCI-H1792、BT474、SU-DHL-6和NCI-H716细胞增殖抑制的IC
50小于约100nM、优选化合物小于约50nM、进一步优选小于约20nM、更优选小于约10nM、本发明所列示的化合物中最优选小于1nM。
表2 化合物对细胞增殖抑制活性的IC
50值
表3 化合物对细胞增殖抑制活性的IC
50值
“NA”代表未测试。
6.实验结论:
本发明实施例化合物对MDA-MB-231、MDA-MB-361、Mia PaCa-2、SW620、NCI-H1792、BT474、SU-DHL-6和NCI-H716细胞具有显著的增殖抑制作用。
测试例3、NCI-H716在BALB/c裸小鼠皮下异种移植瘤模型的体内药效学研究
1.实验目的:
评价受试化合物在人源结肠腺癌细胞株NCI-H716在BALB/c裸小鼠皮下异种移植瘤模型上的药效。
2.实验仪器与试剂:
2.1仪器:
超净工作台(BSC-1300II A2,上海博讯实业有限公司医疗设备厂)
CO
2培养箱(Thermo-311,Thermo)
离心机(Centrifuge 5720R,Eppendorf)
恒温水浴锅(HSW-12,上海一恒科学仪器有限公司)
电动移液助吸器(Easypet 3,Eppendorf)
全自动细胞计数仪(Countess II,Life Technologies)
电子天平(BSA2202S-CW,赛多利斯)
游标卡尺(CD-6”AX,日本三丰)
细胞培养瓶(T25/T75/T225,Corning)
2.2试剂:
RPMI-1640(22400-089,Gibco)
胎牛血清FBS(10099-141C,Gibco)
0.25%Trypsin-EDTA(25200-056,Gibco)
磷酸盐缓冲液PBS(10010-023,Gibco)
Matrigel Matrix基质胶(356234,Corning)
3.实验操作及数据处理:
3.1实验操作:
从细胞库中取出NCI-H716细胞,复苏后加入完全培养基中(RPMI1640+10%FBS+1%P/S)置于CO
2培养箱中培养(培养箱温度为37℃,CO
2浓度为5%),待细胞数量扩增到体内接种所需数量时,收集NCI-H716细胞。用全自动细胞计数仪计数,根据计数结果用PBS和基质胶混合液(1:1)重悬细胞,制成细胞悬液(密度5×10
7/mL),置于冰盒中待用。
使用6-8周龄雌性BALB/c nude小鼠(18-20g,上海市计划生育科学研究所实验动物经营部)。小鼠饲养于SPF级动物房中,单笼饲养,每笼5只小鼠。所有的笼子、垫料和水在使用前进行高温消毒,所有动物均可自由饮食、饮水。实验开始前用一次性大小鼠通用耳标标记裸鼠,接种前用75%医用酒精消毒接种部位皮肤,每只小鼠在右后背皮下接种0.1mL(含5*10
6个细胞)NCI-H716细胞。当肿瘤体积达到60-200mm
3时开始分组给药,每组5只。各受试化合物每周尾静脉给药2次,共5次(分别于D0,D4,D7,D11,D14)。每周2次测量肿瘤体积、称量小鼠体重,并计算肿瘤TGI(%),并计算肿瘤TGI(%)。
3.2数据处理:
肿瘤体积(mm
3),计算公式为:V=0.5*D*d*d,其中D和d分别是肿瘤的长径和短径。
TGI(%)的计算:
当肿瘤无消退时,TGI(%)=[(1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100%;
当肿瘤有消退时,TGI(%)=[1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/该处理组开始给药时平均瘤体积]×100%。
4.实验结果:
表4 药效参数
5实验结论:
以上数据显示,本发明实施例83化合物(1.5mpk,BIW,I.V.)在给药后18天,体现出较显著的肿瘤抑制。
测试例4、小鼠药代动力学评价试验
1.实验目的:
研究化合物单次尾静脉给药在小鼠体内(肿瘤)的PKPD行为。
2.实验方案
2.1试验动物:
种属:小鼠
品系:BALB/c裸鼠
周龄及体重:8-10周龄,体重17-20克
性别:雌性
供应商:上海西普尔-必凯实验动物有限公司
2.2药物配制:
称取1mg待测化合物,加入0.098mL DMA,充分溶解药物。从中取0.045ml再加入2.55mL溶媒,涡旋得到1.5mg/mL的药液。
2.3给药方案:
2.3.1.肿瘤接种后,待肿瘤体积为300-500mm
3时,开始进行PDPK实验。
2.3.2.荷瘤小鼠禁食不禁水过夜,给药后按时间点安乐死小时。
2.4样品采集:
2.4.1.小鼠安乐死后,心脏采血,将采集的血液加入含EDTA-2K的离心管中,手动颠倒数次后置于冰上静置,4℃、8000转/分,离心5分钟。离心后的血浆取100μL转移至新的标记好的离心管中,干冰速冻后置于-80℃冰箱保存,用于PK检测。
2.4.2.取血后剥取瘤组织,将剥下的瘤组织分为2份(~0.1g每份),放入 标记好的2mL离心管中,然后转入-80℃冰箱保存。一份用于PK检测(需称重);1份用于PD检测。
2.5液相分析
液相条件:Shimadzu LC-20AD泵
质谱条件:AB Sciex API 4000质谱仪
移动相:A液为0.1%甲酸水溶液,B液为甲醇
流速:1.0mL/min
洗脱时间:0-4.0分钟,洗脱液如下:
2.6试验结果与分析
药代动力学主要参数用WinNonlin 8.2计算得到。
表5 本发明化合物的小鼠尾静脉给药药代动力学参数
3.实验结论:
表中数据显示,在小鼠药代动力学评价实验中,本发明实施例化合物尾静脉给药后显示出较高的暴露量,且在肿瘤中的分布更有优势。
Claims (15)
- 一种通式(II)所示的化合物、其立体异构体或其药学上可接受盐:其中:R 1选自氢、氘、卤素、氨基、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地进一步被一个或多个R 8所取代;R 2和R 2’各自独立地选自氢、氘、卤素、氨基、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;R 3选自氢、氘、卤素、氨基、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R a、-(CH 2) n1NR aOR b、-(CH 2) n1C(O)NR aR b、-(CH 2) n1NR aC(O)R b、-(CH 2) n1S(O) m1R a、-(CH 2) n1S(O) m1NR aR b、-(CH 2) n1NR aS(O) m1R b、-(CH 2) n1NR aR b或-(CH 2) n1NR a(CH 2) n2R b,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;R 4选自氢、氘、卤素、氨基、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、 C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n3R c、-(CH 2) n3NR cOR d、-(CH 2) n3C(O)NR cR d、-(CH 2) n3NR cC(O)R d、-(CH 2) n3S(O) m2R c、-(CH 2) n3S(O) m2NR cR d、-(CH 2) n3NR cS(O) m2R d、-(CH 2) n3NR cR d或-(CH 2) n3NR c(CH 2) n4R d,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地,进一步被氘、卤素、氨基、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;R 6选自氢、氘、卤素、氨基、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;或者,R 6和R 4与它们所连的碳原子链接形成C 5-14环烷基或5-14元杂环基,所述的C 5-14环烷基和5-14元杂环基,任选地进一步被氘、卤素、氨基、羟基、氰基、氧代基、硫代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;R 7选自氢、氘、卤素、氨基、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;R 8选自氢、氘、卤素、氨基、羟基、氰基、硝基、肟基、叠氮基、巯基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、 5-14元杂芳基、-C(O)R e或-P(O)R eR f,所述的肟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基和-C(O)-,任选地进一步被氘、卤素、氨基、羟基、氰基、叠氮基、硝基、巯基、氧代基、硫代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;R a、R b、R c、R d、R e和R f各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C 1-6烷基、C 1-6羟烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基,所述氨基、的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地,进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;n1~n4为0、1、2、3、4或5;且m1和m2为0、1或2;
- 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐,其特征在于,R 1选自氢、氘、卤素、氨基、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地进一步被一个或多个R 8所取代;R 8选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、肟基、巯基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-C(O)R e、-SR e、-OR e、-NR eR f、-C(O)NR eR f、-NR eC(O)R f、-OC(O)R eR f、-C(O)OR e、-S(O) 2R e、-S(O)R e、-S(O) 2NR eR f、-S(O)NR eR f、-NR eS(O) 2R f、-NR eS(O)R f、 -P(O)R eR f,所述的氨基、肟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、叠氮基、硝基、巯基、氧代基、硫代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;R e和R f各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C 1-6烷基、C 1-6羟烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基,所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地,进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代。
- 根据权利要求2所述的化合物、其立体异构体或其药学上可接受盐,其特征在于,R 1选自C 3-8环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基,所述的C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-10元杂芳基,任选地进一步被被一个或多个R 8所取代,优选苯基,所述的苯基,任选地进一步被一个或多个R 8所取代;R 8选自氢、氘、卤素、氨基、羟基、氰基、硝基、肟基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3烷硫基、C 1-3卤代烷氧基、C 3-8环烷基、3-8元杂环基、C 6-10芳基、5-10元杂芳基,优选环丙基、硝基或肟基。
- 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐,其特征在于,R 2选自C 3-8环烷基、3-8元杂环基、C 6-10芳基或5-10元杂芳基,所述的C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-10元杂芳基,任选地任选地进一步被氘、卤素、氨基、羟基、氰基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3烷硫基、C 1-3卤代烷氧基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-10元杂芳基中的一个或多个取代基所取代,优选地,R 2选自苯基或双环[1.1.1]戊烷;更优选地,R 2选自苯基;R 2’选自氢、氘、卤素、氨基、羟基、氰基、C 1-3烷基、C 2-3烯基、C 2-3炔基、 C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3烷硫基或C 1-3卤代烷氧基,优选地,R 2’选自氢、氘、氟、氯、溴、甲基、乙基或丙基;和/或,R 3选自-(CH 2) n1R a、-(CH 2) n1NR aOR b、-(CH 2) n1C(O)NR aR b、-(CH 2) n1NR aC(O)R b、-(CH 2) n1S(O) m1R a、-(CH 2) n1S(O) m1NR aR b、-(CH 2) n1NR aS(O) m1R b、-(CH 2) n1NR aR b或-(CH 2) n1NR a(CH 2) n2R b,优选地,R 3选自-CH 2R a、-C(O)NR aR b、-S(O) 2R a、-CH 2NR aR b、-CH 2NR aCH 2R b或-CH 2NR a(CH 2) 2R b;R a和R b各自独立地选自氢、卤素、羟基、C 1-3烷基、C 1-3羟烷基、C 1-3卤代烷基、C 1-3烷氧基或4-8元含氮杂环基,所述的C 1-3烷基、C 1-3羟烷基、C 1-3卤代烷基、C 1-3烷氧基和4-8元含氮杂环基,任选地进一步被氢、氘、羟基、C 1-3烷基、C 1-3羟烷基、C 1-3卤代烷基或C 1-3烷氧基中的一个或多个取代基所取代,优选地,R a和R b各自独立地氢、氟、氯、溴、甲基、乙基、甲氧基、2-羟基异丙基、哌啶基、哌嗪基、吗啉基、吡咯烷基、氮杂环丁烷基、2-氧杂-6-氮杂螺[3.3]庚烷基、(1R,5S)-8-氮杂双环[3.2.1]辛烷基、(1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷基,所述的甲基、乙基、甲氧基、2-羟基异丙基、哌啶基、哌嗪基、吗啉基、吡咯烷基、氮杂环丁烷基、2-氧杂-6-氮杂螺[3.3]庚烷基、(1R,5S)-8-氮杂双环[3.2.1]辛烷基、(1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷基,任选地进一步被氢、氘、羟基、甲基、乙基、甲氧基、二氟甲基或三氟甲基中的一个或多个取代基所取代;和/或,R 4选自-OH、-(CH 2) n3R c、-(CH 2) n3NR cOR d、-(CH 2) n3C(O)NR cR d、-(CH 2) n3NR cC(O)R d、-(CH 2) n3S(O) m2R c、-(CH 2) n3S(O) m2NR cR d、-(CH 2) n3NR cS(O) m2R d、-(CH 2) n3NR cR d或-(CH 2) n3NR c(CH 2) n4R d,优选-OH、-(CH 2) n3NR cR d或-(CH 2) n3NR cOR d;R c和R d各自独立地选自氢、卤素、羟基、C 1-3烷基、C 1-3羟烷基、C 1-3卤代烷基或C 1-3烷氧基,所述的C 1-3烷基、C 1-3羟烷基、C 1-3卤代烷基和C 1-3烷氧基,任选地进一步被氢、氘、羟基、C 1-3烷基、C 1-3羟烷基、C 1-3卤代烷基或C 1-3烷氧基中的一个或多个取代基所取代;和/或,R 6选自氢、氘、卤素、氨基、羟基、氰基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3烷硫基或C 1-3卤代烷氧基,更优选地,R 6选自甲氧基、乙氧基、一氟甲氧基、二氟甲氧基或三氟甲氧基;更优选甲氧基;和/或,R 7选自氢、氘、卤素、氨基、羟基、氰基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3烷硫基或C 1-3卤代烷氧基,更优选地,R 7选自氰基、甲氧基、乙氧基、一氟甲氧基、二氟甲氧基或三氟甲氧基;更优选甲氧基;n3和n4为0、1、2、3、4或5;且m2为0、1或2。
- 根据权利要求5所述的化合物、其立体异构体或其药学上可接受盐,其特征在于,R 2’选自氢;R 3选自-(CH 2) n1NR aC(O)R b或-(CH 2) n1NR aR b;R a或R b各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3烷硫基或C 1-3卤代烷氧基;或者,R a和R b与相邻的氮原子形成含1-2个选自氮或氧原子的4-8元杂环基,任选地进一步被卤素、C 1-3烷基、C 1-3烷氧基、C 1-3卤代烷基或C 1-3羟烷基中的一个或多个取代基所取代;R 7选自氰基或C 1-3烷氧基;R 8选自氰基、叠氮基、肟基、硝基、C 3-6环烷基、含2-4个氮原子的5-6元杂芳基、含1个氮或氧原子的4-6元杂环基、含2-3个选自氮或氧原子的7-8元螺杂环基、含2-3个选自氮或氧原子的7-8元稠杂环基;任选地进一步被氘、卤素、氨基、羟基、氰基、叠氮基、硝基、巯基、氧代基、C 1-3烷基、C 1-3烷氧基、C 1-3卤代烷基或氰基取代的C 1-3烷基中的一个或多个取代基所取代。
- 根据权利要求6所述的化合物、其立体异构体或其药学上可接受盐,其特征在于,R 2’选自氢;R 3选自-(CH 2) n1NR aR b;R a或R b各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、 巯基、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3烷硫基或C 1-3卤代烷氧基;优选氢、氘、C 1-3烷基、C 1-3氘代烷基或C 1-3卤代烷基;更优选甲基;R 7选自氰基或C 1-3烷氧基;更优选甲氧基;R 8选自氰基、叠氮基、肟基、硝基、C 3-6环烷基;更优选肟基、硝基或环丙基;n1为1。
- 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐,其特征在于,通式(II)进一步如通式(V)或通式(VI)所示:R 2’选自氢、氘、卤素、氨基、羟基、氰基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3烷硫基或C 1-3卤代烷氧基,优选氢、氘、氟、氯、溴、甲基、乙基或丙基;更优选氢;R 6和R 7各自独立地选自氢、氘、卤素、氨基、羟基、氰基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3烷硫基或C 1-3卤代烷氧基,更优选氰基、甲氧基、乙氧基、一氟甲氧基、二氟甲氧基或三氟甲氧基;R 8选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、肟基、巯基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-SR e、-OR e、-NR eR f、-C(O)NR eR f、-NR eC(O)R f、-OC(O)R eR f、-C(O)OR e、-S(O) 2R e、-S(O)R e、-S(O) 2NR eR f、-S(O)NR eR f、-NR eS(O) 2R f、-NR eS(O)R f、-P(O)R eR f,所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地进一步被氘、卤素、氨基、羟基、氰基、叠氮基、硝基、巯基、氧代基、硫代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷氧基烷基、氰基取代的C 1-6烷基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环 基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代,优选为氰基、叠氮基、肟基、硝基、C 3-6环烷基、含2-4个氮原子的5-6元杂芳基、含1个氮或氧原子的4-6元杂环基、含2-3个选自氮或氧原子的7-8元螺杂环基、含2-3个选自氮或氧原子的7-8元稠杂环基;任选地进一步被氘、卤素、氨基、羟基、氰基、叠氮基、硝基、巯基、氧代基、C 1-3烷基、C 1-3烷氧基、C 1-3卤代烷基或氰基取代的C 1-3烷基、中的一个或多个取代基所取代;R a和R b各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C 1-6烷基、C 1-6羟烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基,所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地,进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;或者,R a和R b与相邻的氮原子形成含1-3个选自氮或氧原子的4-10元杂环基,任选地进一步被氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、氧代基、硫代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代;R 4、R e和R f如权利要求1所述。
- 根据权利要求8所述的化合物、其立体异构体或其药学上可接受盐,其特征在于,R 2’选自氢;R a或R b各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、叠氮基、巯基、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3烷硫基或C 1-3卤代烷氧基;优选氢、氘、C 1-3烷基、C 1-3氘代烷基或C 1-3卤代烷基;更优选甲基;R 6和R 7各自独立地选自氰基或C 1-3烷氧基;更优选甲氧基;R 8选自氰基、叠氮基、肟基、硝基、C 3-6环烷基;更优选肟基、硝基或环丙基。
- 一种药物组合物,其包括治疗有效剂量的权利要求1~10所述的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。
- 根据权利要求1~10所述的化合物、其立体异构体或其药学上可接受的盐、权利要求13所述的药物组合物在治疗和/或预防ATP依赖的RNA解旋酶相关疾病的药物中的用途,特别是在治疗和/或预防真核起始因子4A抑制剂相关疾病的药物中的用途。
- 根据权利要求1~10所述的化合物、其立体异构体或其药学上可接受的盐、权利要求13所述的药物组合物在治疗和/或预防癌症、骨髓化生不良症候群、阿兹海默症、帕金森氏症、X染色体脆折症和自闭症相关疾病的药物中的用途;优选地,所述癌症选自实体肿瘤或血液肿瘤,更优选大肠直肠癌、膀胱癌、胃癌、甲状腺癌、食道癌、头颈癌、脑癌、胶质瘤、胶质母细胞瘤、肝细胞癌、肺癌、黑色素瘤、骨髓瘤、胰脏癌、肾细胞癌、子宫颈癌、泌尿上皮癌、前列腺癌、卵巢癌、乳腺癌、白血病或淋巴瘤。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202180080990.2A CN116547289A (zh) | 2020-10-28 | 2021-10-28 | 多环类生物调节剂、其制备方法和应用 |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011175220.X | 2020-10-28 | ||
CN202011175220 | 2020-10-28 | ||
CN202011358159 | 2020-11-27 | ||
CN202011358159.2 | 2020-11-27 | ||
CN202110126321.6 | 2021-01-29 | ||
CN202110126321 | 2021-01-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022089514A1 true WO2022089514A1 (zh) | 2022-05-05 |
Family
ID=81381951
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2021/126948 WO2022089514A1 (zh) | 2020-10-28 | 2021-10-28 | 多环类生物调节剂、其制备方法和应用 |
Country Status (3)
Country | Link |
---|---|
CN (1) | CN116547289A (zh) |
TW (1) | TW202221003A (zh) |
WO (1) | WO2022089514A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023030687A1 (en) * | 2021-09-01 | 2023-03-09 | KHR Biotec GmbH | Cyclopenta[4,5]furo[3,2-c]pyridine derivatives as ras inhibitors for use in the treatment of hyperproliferative diseases or genetic disorders |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120238766A1 (en) * | 2006-05-22 | 2012-09-20 | Trustees Of Boston University | Asymmetric synthesis of rocaglamides via enantioselective photocycloaddition mediated by chiral bronsted acids |
CN108601788A (zh) * | 2015-11-25 | 2018-09-28 | 效应治疗股份有限公司 | Eif4a-抑制化合物及其相关方法 |
CN110891567A (zh) * | 2017-05-24 | 2020-03-17 | 效应治疗股份有限公司 | 用于改善的抗肿瘤免疫应答的组合物和方法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9073881B2 (en) * | 2011-09-23 | 2015-07-07 | Hoffmann-La Roche Inc. | Benzoic acid derivatives |
-
2021
- 2021-10-28 CN CN202180080990.2A patent/CN116547289A/zh active Pending
- 2021-10-28 WO PCT/CN2021/126948 patent/WO2022089514A1/zh active Application Filing
- 2021-10-28 TW TW110140091A patent/TW202221003A/zh unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120238766A1 (en) * | 2006-05-22 | 2012-09-20 | Trustees Of Boston University | Asymmetric synthesis of rocaglamides via enantioselective photocycloaddition mediated by chiral bronsted acids |
CN108601788A (zh) * | 2015-11-25 | 2018-09-28 | 效应治疗股份有限公司 | Eif4a-抑制化合物及其相关方法 |
CN110891567A (zh) * | 2017-05-24 | 2020-03-17 | 效应治疗股份有限公司 | 用于改善的抗肿瘤免疫应答的组合物和方法 |
Non-Patent Citations (2)
Title |
---|
ERNST, J. ET AL.: "Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase", JOURNAL OF MEDICINAL CHEMISTRY, vol. 63, 29 May 2020 (2020-05-29), pages 5879 - 5955, XP055890843, DOI: 10.1021/acs.jmedchem.0c00182 * |
LIU, T. ET AL.: "Synthetic Silvestrol Analogues as Potent and Selective Protein Synthesis Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, 1 October 2012 (2012-10-01), pages 8859 - 8878, XP055160304, DOI: 10.1021/jm3011542 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023030687A1 (en) * | 2021-09-01 | 2023-03-09 | KHR Biotec GmbH | Cyclopenta[4,5]furo[3,2-c]pyridine derivatives as ras inhibitors for use in the treatment of hyperproliferative diseases or genetic disorders |
Also Published As
Publication number | Publication date |
---|---|
CN116547289A (zh) | 2023-08-04 |
TW202221003A (zh) | 2022-06-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI751163B (zh) | Fgfr4抑制劑、其製備方法和應用 | |
TWI601728B (zh) | 吡咯并六員雜芳環類衍生物、其製備方法及其在醫藥上的應用 | |
JP2018519343A (ja) | プロテインキナーゼのモジュレーターとしてのキラルジアリール大環状分子 | |
WO2020211798A1 (zh) | 含二并环类衍生物抑制剂、其制备方法和应用 | |
CA3026226A1 (en) | Substituted pyridines as inhibitors of dnmt1 | |
WO2012019427A1 (zh) | 酞嗪酮类衍生物、其制备方法及其在医药上的应用 | |
KR20160101162A (ko) | 코르티스타틴 유사체 및 그의 합성 및 용도 | |
WO2023274383A1 (zh) | Kras g12d抑制剂及其应用 | |
WO2023001123A1 (zh) | 新型吡啶并嘧啶衍生物 | |
WO2018028664A1 (zh) | Fgfr4抑制剂及其制备方法和应用 | |
CN109745321B (zh) | 包含fgfr4抑制剂的药物组合物 | |
WO2022247816A1 (zh) | 含氮杂环类化合物、其制备方法及其在医药上的应用 | |
JP5816087B2 (ja) | Smoアンタゴニストとしての飽和二環式複素環誘導体 | |
US20240165243A1 (en) | Egfr degraders and methods of use | |
WO2023280136A1 (zh) | 氘甲基取代吡嗪并吡嗪并喹啉酮类衍生物、其制备方法及其在医药上的应用 | |
WO2022228543A1 (zh) | 桥环类化合物、其制备方法及其在医药上的应用 | |
CN115677688A (zh) | 1,5-萘啶酮类化合物 | |
JP2015520204A (ja) | タンキラーゼのピラノピリドン阻害剤 | |
WO2022089514A1 (zh) | 多环类生物调节剂、其制备方法和应用 | |
CN109761986B (zh) | 三并环类衍生物抑制剂、其制备方法和应用 | |
CN115677682B (zh) | 螺环类plk4抑制剂及其用途 | |
JP2021514999A (ja) | タンパク質アルギニンメチルトランスフェラーゼの阻害剤としてのエタンジアミン−複素環誘導体 | |
WO2023072297A1 (zh) | 含氮的四环化合物、其制备方法及其在医药上的应用 | |
JP2022554385A (ja) | Wdr5阻害剤及び調節剤 | |
CN112839931A (zh) | 1,2,3,4-四氢喹喔啉衍生物及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21885241 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 202180080990.2 Country of ref document: CN |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 21885241 Country of ref document: EP Kind code of ref document: A1 |