CN115698011B - Pb2抑制剂及其制备方法和用途 - Google Patents
Pb2抑制剂及其制备方法和用途 Download PDFInfo
- Publication number
- CN115698011B CN115698011B CN202180041967.2A CN202180041967A CN115698011B CN 115698011 B CN115698011 B CN 115698011B CN 202180041967 A CN202180041967 A CN 202180041967A CN 115698011 B CN115698011 B CN 115698011B
- Authority
- CN
- China
- Prior art keywords
- mmol
- pyrrolo
- compound
- amino
- triazin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 101710102873 Polymerase basic protein 2 Proteins 0.000 title claims abstract description 8
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- 238000002360 preparation method Methods 0.000 title description 36
- 150000001875 compounds Chemical class 0.000 claims abstract description 268
- 150000003839 salts Chemical class 0.000 claims abstract description 62
- 239000003814 drug Substances 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 71
- 241000712461 unidentified influenza virus Species 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000009385 viral infection Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000013078 crystal Substances 0.000 abstract description 59
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 abstract description 57
- 239000012453 solvate Substances 0.000 abstract description 55
- 239000002207 metabolite Substances 0.000 abstract description 50
- 239000000651 prodrug Substances 0.000 abstract description 49
- 229940002612 prodrug Drugs 0.000 abstract description 49
- 229940079593 drug Drugs 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 410
- 238000006243 chemical reaction Methods 0.000 description 260
- -1 nitroxides Chemical class 0.000 description 251
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 232
- 125000000217 alkyl group Chemical group 0.000 description 213
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 194
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 188
- 229910001868 water Inorganic materials 0.000 description 168
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 161
- NSSSSLKQIAIXNW-UHFFFAOYSA-N ethyl bicyclo[2.2.2]octane-3-carboxylate Chemical compound C1CC2C(C(=O)OCC)CC1CC2 NSSSSLKQIAIXNW-UHFFFAOYSA-N 0.000 description 158
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 150
- PNKGHXVHKCJNBW-UHFFFAOYSA-N bicyclo[2.2.2]octane-3-carboxylic acid Chemical compound C1CC2C(C(=O)O)CC1CC2 PNKGHXVHKCJNBW-UHFFFAOYSA-N 0.000 description 116
- 239000000243 solution Substances 0.000 description 112
- 238000004440 column chromatography Methods 0.000 description 103
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 92
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 88
- 239000003208 petroleum Substances 0.000 description 88
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 87
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 85
- 239000012074 organic phase Substances 0.000 description 85
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 83
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 69
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 64
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 63
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
- 150000002367 halogens Chemical class 0.000 description 62
- 125000003545 alkoxy group Chemical group 0.000 description 59
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 58
- 239000012071 phase Substances 0.000 description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
- 238000005481 NMR spectroscopy Methods 0.000 description 55
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
- 239000004698 Polyethylene Substances 0.000 description 50
- 229910052757 nitrogen Inorganic materials 0.000 description 50
- 229910052736 halogen Inorganic materials 0.000 description 49
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 48
- 239000000460 chlorine Substances 0.000 description 48
- 239000000706 filtrate Substances 0.000 description 46
- 229910000027 potassium carbonate Inorganic materials 0.000 description 46
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 46
- 229910052805 deuterium Inorganic materials 0.000 description 45
- 125000001072 heteroaryl group Chemical group 0.000 description 44
- 239000007787 solid Substances 0.000 description 44
- 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 40
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 40
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 40
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 229910052799 carbon Inorganic materials 0.000 description 33
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 33
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 31
- 239000011541 reaction mixture Substances 0.000 description 29
- 238000010898 silica gel chromatography Methods 0.000 description 27
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 26
- 238000006467 substitution reaction Methods 0.000 description 25
- 229910052717 sulfur Inorganic materials 0.000 description 23
- 125000004432 carbon atom Chemical group C* 0.000 description 22
- 238000001816 cooling Methods 0.000 description 21
- 125000005843 halogen group Chemical group 0.000 description 21
- 239000007791 liquid phase Substances 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- 238000001914 filtration Methods 0.000 description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 238000010828 elution Methods 0.000 description 18
- 239000011259 mixed solution Substances 0.000 description 18
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 18
- 238000000746 purification Methods 0.000 description 18
- 239000012153 distilled water Substances 0.000 description 17
- 230000014759 maintenance of location Effects 0.000 description 17
- 238000002953 preparative HPLC Methods 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 17
- 239000012046 mixed solvent Substances 0.000 description 16
- 238000005406 washing Methods 0.000 description 16
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 15
- 241000700605 Viruses Species 0.000 description 15
- 125000000623 heterocyclic group Chemical group 0.000 description 15
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 description 15
- 229910052760 oxygen Inorganic materials 0.000 description 15
- 125000003118 aryl group Chemical group 0.000 description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 14
- 238000001035 drying Methods 0.000 description 14
- 238000000605 extraction Methods 0.000 description 14
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 14
- 230000008878 coupling Effects 0.000 description 13
- 238000010168 coupling process Methods 0.000 description 13
- 238000005859 coupling reaction Methods 0.000 description 13
- 125000005842 heteroatom Chemical group 0.000 description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- 206010022000 influenza Diseases 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 229910052731 fluorine Inorganic materials 0.000 description 12
- 239000005457 ice water Substances 0.000 description 12
- 238000000926 separation method Methods 0.000 description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 11
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 125000003367 polycyclic group Chemical group 0.000 description 10
- 101100446506 Mus musculus Fgf3 gene Proteins 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 9
- 125000002619 bicyclic group Chemical group 0.000 description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 9
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- 239000012488 sample solution Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 239000003643 water by type Substances 0.000 description 9
- 241000394635 Acetomicrobium mobile Species 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- CFRFVTFZTABHIF-UANYXRBSSA-N ethyl (2S,3S)-3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride Chemical compound Cl.CCOC(=O)[C@@H]1[C@@H](N)C2CCC1CC2 CFRFVTFZTABHIF-UANYXRBSSA-N 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 7
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 125000000304 alkynyl group Chemical group 0.000 description 7
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 7
- 239000008367 deionised water Substances 0.000 description 7
- 229910021641 deionized water Inorganic materials 0.000 description 7
- 150000001975 deuterium Chemical group 0.000 description 7
- 150000002430 hydrocarbons Chemical group 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 238000004949 mass spectrometry Methods 0.000 description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 7
- GUMNWRMUBOJYLH-UHFFFAOYSA-N pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid Chemical compound C1=NC=NN2C(C(=O)O)=CC=C21 GUMNWRMUBOJYLH-UHFFFAOYSA-N 0.000 description 7
- 230000002441 reversible effect Effects 0.000 description 7
- CZVQOXGVEXSLQH-UHFFFAOYSA-N 1H-imidazo[5,1-f][1,2,4]triazine-2,4-dione Chemical compound O=c1[nH]n2cncc2c(=O)[nH]1 CZVQOXGVEXSLQH-UHFFFAOYSA-N 0.000 description 6
- YSEQNZOXHCKLOG-UHFFFAOYSA-N 2-methyl-octanoic acid Chemical compound CCCCCCC(C)C(O)=O YSEQNZOXHCKLOG-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 6
- 101000767160 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Intracellular protein transport protein USO1 Proteins 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 6
- SBRUFQZCYBJGNX-UHFFFAOYSA-N ethyl 2-propylheptanoate Chemical compound CCCCCC(CCC)C(=O)OCC SBRUFQZCYBJGNX-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 6
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 5
- DHRYCPPLDCKSDJ-UHFFFAOYSA-N 2,4-dichloro-7-nitropyrrolo[2,1-f][1,2,4]triazine Chemical compound [O-][N+](C1=CC=C(C(Cl)=N2)N1N=C2Cl)=O DHRYCPPLDCKSDJ-UHFFFAOYSA-N 0.000 description 5
- HVOGNDAZVKZHOB-UHFFFAOYSA-N 2,4-dichloroimidazo[5,1-f][1,2,4]triazine Chemical compound N1=C(Cl)N=C(Cl)C2=CN=CN21 HVOGNDAZVKZHOB-UHFFFAOYSA-N 0.000 description 5
- BPZJNMLBWODZEC-UHFFFAOYSA-N 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde Chemical compound N1=C(Cl)N=C(Cl)C2=CC=C(C=O)N21 BPZJNMLBWODZEC-UHFFFAOYSA-N 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 5
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 5
- 229960003971 influenza vaccine Drugs 0.000 description 5
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 125000003003 spiro group Chemical group 0.000 description 5
- ILRVFARRVJLQAK-IJGQKCBJSA-N (1R,6S,7S,8S)-8-[[2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]tricyclo[4.2.2.02,5]decane-7-carboxylic acid Chemical compound OC([C@@H]([C@@H]1C(CC2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=CNC2=NC=C3F)=NN2C1=CC=C2)=O ILRVFARRVJLQAK-IJGQKCBJSA-N 0.000 description 4
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 4
- JZYQIWPTSKBPFL-VVUBSENTSA-N (2S,3S)-3-[[2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[2,1-f][1,2,4]triazin-4-yl]amino]bicyclo[2.2.2]octane-2-carboxylic acid Chemical compound OC([C@@H](C1CCC2CC1)[C@H]2NC1=NC(C(C2=C3)=CNC2=NC=C3F)=NN2C1=NC=C2)=O JZYQIWPTSKBPFL-VVUBSENTSA-N 0.000 description 4
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 4
- DWRQHPCGXPPRBO-UHFFFAOYSA-N 2,4-dichloro-7-(difluoromethyl)pyrrolo[2,1-f][1,2,4]triazine Chemical compound FC(C1=CC=C(C(Cl)=N2)N1N=C2Cl)F DWRQHPCGXPPRBO-UHFFFAOYSA-N 0.000 description 4
- LHASZEBEQGPCFM-CJFMBICVSA-N 2-amino-4-[(1r)-1-[[(6r)-6-[(5-chloro-2-methoxyphenyl)methyl]-7-oxo-3-(phenoxyamino)-5,6-dihydro-2h-1,4-diazepine-1-carbonyl]amino]propyl]benzoic acid Chemical compound C([C@@H]1CNC(CN(C1=O)C(=O)N[C@H](CC)C=1C=C(N)C(C(O)=O)=CC=1)=NOC=1C=CC=CC=1)C1=CC(Cl)=CC=C1OC LHASZEBEQGPCFM-CJFMBICVSA-N 0.000 description 4
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- FCBOUJYKAGWYQM-DEOSSOPVSA-N 6-[[(2s)-1-hydroxy-3-phenylpropan-2-yl]amino]-n-(2-phenoxyethyl)-2-(3,4,5-trimethoxyphenyl)pyridine-3-carboxamide Chemical compound COC1=C(OC)C(OC)=CC(C=2C(=CC=C(N[C@H](CO)CC=3C=CC=CC=3)N=2)C(=O)NCCOC=2C=CC=CC=2)=C1 FCBOUJYKAGWYQM-DEOSSOPVSA-N 0.000 description 4
- BAWWEBPYOBYGPY-UHFFFAOYSA-N 7-bromo-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine Chemical compound N1=C(Cl)N=C(Cl)C2=CC=C(Br)N21 BAWWEBPYOBYGPY-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 229940126639 Compound 33 Drugs 0.000 description 4
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 4
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 4
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 4
- 108091034135 Vault RNA Proteins 0.000 description 4
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 4
- 125000004450 alkenylene group Chemical group 0.000 description 4
- 125000004419 alkynylene group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229910052789 astatine Inorganic materials 0.000 description 4
- 229940125797 compound 12 Drugs 0.000 description 4
- 229940126543 compound 14 Drugs 0.000 description 4
- 229940125758 compound 15 Drugs 0.000 description 4
- 229940126208 compound 22 Drugs 0.000 description 4
- 229940125801 compound 7f Drugs 0.000 description 4
- HRJHQOXWONBAJC-UHFFFAOYSA-N ethyl 2-methyloctanoate Chemical compound CCCCCCC(C)C(=O)OCC HRJHQOXWONBAJC-UHFFFAOYSA-N 0.000 description 4
- LERIOFHGELUHFG-UHFFFAOYSA-N ethyl 3-aminoimidazole-4-carboxylate Chemical compound CCOC(=O)C1=CN=CN1N LERIOFHGELUHFG-UHFFFAOYSA-N 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- GQJCAQADCPTHKN-UHFFFAOYSA-N methyl 2,2-difluoro-2-fluorosulfonylacetate Chemical compound COC(=O)C(F)(F)S(F)(=O)=O GQJCAQADCPTHKN-UHFFFAOYSA-N 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
- 238000007347 radical substitution reaction Methods 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 4
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 3
- UEGBESVAORMZLH-ARSQAMJASA-N (1R,6S,7S,8S)-8-[[2-(5-fluoro-2H-pyrazolo[3,4-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]tricyclo[4.2.2.02,5]decane-7-carboxylic acid Chemical compound COCC1=CC=C2N1N=C(C(C1=C3)=NNC1=NC=C3F)N=C2N[C@@H]([C@H]1C(CC2)C2[C@@H]2CC1)[C@H]2C(O)=O UEGBESVAORMZLH-ARSQAMJASA-N 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- WDHDGWKLEOJKBA-UHFFFAOYSA-N (2-chloro-4-phenoxypyrrolo[2,1-f][1,2,4]triazin-6-yl)methanol Chemical compound OCC(C=C1C(OC2=CC=CC=C2)=N2)=CN1N=C2Cl WDHDGWKLEOJKBA-UHFFFAOYSA-N 0.000 description 3
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 3
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 3
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 3
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 3
- OQCZUWSXPMWUJM-UHFFFAOYSA-N 1h-imidazo[2,1-f][1,2,4]triazine-2,4-dione Chemical compound O=C1NC(=O)NN2C=CN=C21 OQCZUWSXPMWUJM-UHFFFAOYSA-N 0.000 description 3
- WLHRHHIDKGSWKY-UHFFFAOYSA-N 2,4,5-trichloropyrrolo[2,1-f][1,2,4]triazine Chemical compound N1=C(Cl)N=C(Cl)C2=C(Cl)C=CN21 WLHRHHIDKGSWKY-UHFFFAOYSA-N 0.000 description 3
- FAXRNTWTNVMMKI-UHFFFAOYSA-N 2,4-dichloro-6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine Chemical compound CN1N=CC(C(C=C2C(Cl)=N3)=CN2N=C3Cl)=C1 FAXRNTWTNVMMKI-UHFFFAOYSA-N 0.000 description 3
- JJZFAZQVYQBMES-UHFFFAOYSA-N 2,4-dichloroimidazo[2,1-f][1,2,4]triazine Chemical compound N1=C(Cl)N=C(Cl)C2=NC=CN21 JJZFAZQVYQBMES-UHFFFAOYSA-N 0.000 description 3
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- IOOWNWLVCOUUEX-WPRPVWTQSA-N 2-[(3r,6s)-2-hydroxy-3-[(2-thiophen-2-ylacetyl)amino]oxaborinan-6-yl]acetic acid Chemical compound OB1O[C@H](CC(O)=O)CC[C@@H]1NC(=O)CC1=CC=CS1 IOOWNWLVCOUUEX-WPRPVWTQSA-N 0.000 description 3
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 3
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 3
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 3
- DFMOUHQCOYRRJX-UHFFFAOYSA-N 2-chloro-6-(difluoromethyl)-4-phenoxypyrrolo[2,1-f][1,2,4]triazine Chemical compound FC(C(C=C1C(OC2=CC=CC=C2)=N2)=CN1N=C2Cl)F DFMOUHQCOYRRJX-UHFFFAOYSA-N 0.000 description 3
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 3
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 3
- CKBGAZOHOBTHIQ-UHFFFAOYSA-N 5-chloro-1h-pyrrolo[2,1-f][1,2,4]triazine-2,4-dione Chemical compound N1C(=O)NC(=O)C2=C(Cl)C=CN21 CKBGAZOHOBTHIQ-UHFFFAOYSA-N 0.000 description 3
- ZWHJLEXFSZFNCB-UHFFFAOYSA-N 5-fluoro-3-iodo-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridine Chemical compound Cc1ccc(cc1)S(=O)(=O)n1cc(I)c2cc(F)cnc12 ZWHJLEXFSZFNCB-UHFFFAOYSA-N 0.000 description 3
- SKGPKXOWCGPCBE-UHFFFAOYSA-N 5-fluoro-3-iodo-1h-pyrrolo[2,3-b]pyridine Chemical compound FC1=CN=C2NC=C(I)C2=C1 SKGPKXOWCGPCBE-UHFFFAOYSA-N 0.000 description 3
- VGRTVXQJOLFRIS-UHFFFAOYSA-N 6-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,1-f][1,2,4]triazine-2,4-dione Chemical compound CN1N=CC(C(C=C2C(N3)=O)=CN2NC3=O)=C1 VGRTVXQJOLFRIS-UHFFFAOYSA-N 0.000 description 3
- NETCQPWEMRFZLK-UHFFFAOYSA-N 6-bromo-1h-pyrrolo[2,1-f][1,2,4]triazine-2,4-dione Chemical compound N1C(=O)NC(=O)C=2N1C=C(Br)C=2 NETCQPWEMRFZLK-UHFFFAOYSA-N 0.000 description 3
- NRVGOQKEQWXMOO-UHFFFAOYSA-N 6-bromo-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine Chemical compound BrC=1C=C2C(=NC(=NN2C=1)Cl)Cl NRVGOQKEQWXMOO-UHFFFAOYSA-N 0.000 description 3
- TYYCNSUODPEVQP-UHFFFAOYSA-N 8-[(4-fluorophenyl)sulfonylamino]-4-(3-pyridin-3-ylpropyl)octanoic acid Chemical compound C=1C=CN=CC=1CCCC(CCC(=O)O)CCCCNS(=O)(=O)C1=CC=C(F)C=C1 TYYCNSUODPEVQP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- CCYYKQSUFHCVBH-UHFFFAOYSA-N BrC=1C=C(N(C=1)NC(=O)OC)C(=O)OC Chemical compound BrC=1C=C(N(C=1)NC(=O)OC)C(=O)OC CCYYKQSUFHCVBH-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 229940126657 Compound 17 Drugs 0.000 description 3
- 229940127007 Compound 39 Drugs 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 101710154606 Hemagglutinin Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 3
- 108010006232 Neuraminidase Proteins 0.000 description 3
- 102000005348 Neuraminidase Human genes 0.000 description 3
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 3
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 101710176177 Protein A56 Proteins 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 3
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 230000001028 anti-proliverative effect Effects 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940126142 compound 16 Drugs 0.000 description 3
- 229940125810 compound 20 Drugs 0.000 description 3
- 229940126086 compound 21 Drugs 0.000 description 3
- 229940125833 compound 23 Drugs 0.000 description 3
- 229940125961 compound 24 Drugs 0.000 description 3
- 229940125846 compound 25 Drugs 0.000 description 3
- 229940125851 compound 27 Drugs 0.000 description 3
- 229940127204 compound 29 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940125877 compound 31 Drugs 0.000 description 3
- 229940125878 compound 36 Drugs 0.000 description 3
- 229940125807 compound 37 Drugs 0.000 description 3
- 229940127573 compound 38 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- NITLQFRQRWXROL-UHFFFAOYSA-N diethyl 1-aminopyrrole-2,4-dicarboxylate Chemical compound CCOC(=O)C=1C=C(C(=O)OCC)N(N)C=1 NITLQFRQRWXROL-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- BQQUTNXEAIWAKN-HXFLIBJXSA-N ethyl (1R,2S,3S,4R)-3-amino-6,6-difluorobicyclo[2.2.2]octane-2-carboxylate Chemical compound CCOC([C@@H]([C@@H](CC[C@@H]1C2)C2(F)F)[C@H]1N)=O BQQUTNXEAIWAKN-HXFLIBJXSA-N 0.000 description 3
- WBODOVAXHFEBRJ-WCVJEAGWSA-N ethyl (1R,2S,3S,4R)-6,6-difluoro-3-(phenylmethoxycarbonylamino)bicyclo[2.2.2]octane-2-carboxylate Chemical compound CCOC([C@@H]([C@@H](CC[C@@H]1C2)C2(F)F)[C@H]1NC(OCC1=CC=CC=C1)=O)=O WBODOVAXHFEBRJ-WCVJEAGWSA-N 0.000 description 3
- ZZPRGIVNIHMGIE-GVRKNTCVSA-N ethyl (1R,2S,3S,4R)-6-hydroxy-3-(phenylmethoxycarbonylamino)bicyclo[2.2.2]octane-2-carboxylate Chemical compound CCOC([C@@H]([C@@H](CC[C@@H]1C2)C2O)[C@H]1NC(OCC1=CC=CC=C1)=O)=O ZZPRGIVNIHMGIE-GVRKNTCVSA-N 0.000 description 3
- DWLPNZXXPOYXPN-IHQRNOLKSA-N ethyl (1R,6S,7S,8S)-8-[(2-chloro-7-formylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]tricyclo[4.2.2.02,5]decane-7-carboxylate Chemical compound CCOC([C@@H]([C@@H]1C(CC2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2C=O)=O DWLPNZXXPOYXPN-IHQRNOLKSA-N 0.000 description 3
- NXNZQUIWWLRLJV-LXAHODSZSA-N ethyl (1R,6S,7S,8S)-8-[[2-(5-fluoro-2H-pyrazolo[3,4-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]tricyclo[4.2.2.02,5]decane-7-carboxylate Chemical compound CCOC([C@@H]([C@@H]1C(CC2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NNC2=NC=C3F)=NN2C1=CC=C2COC)=O NXNZQUIWWLRLJV-LXAHODSZSA-N 0.000 description 3
- GGNTZWWLPVMTOU-ARSQAMJASA-N ethyl (1R,6S,7S,8S)-8-[[2-(5-fluoro-2H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]tricyclo[4.2.2.02,5]decane-7-carboxylate Chemical compound CCOC([C@@H]([C@@H]1C(CC2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NNC2=NC=C3F)=NN2C1=CC=C2)=O GGNTZWWLPVMTOU-ARSQAMJASA-N 0.000 description 3
- JNSGQDMYKXYYJW-IHQRNOLKSA-N ethyl (1R,6S,7S,8S)-8-[[2-chloro-7-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]tricyclo[4.2.2.02,5]decane-7-carboxylate Chemical compound CCOC([C@@H]([C@@H]1C(CC2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2CO)=O JNSGQDMYKXYYJW-IHQRNOLKSA-N 0.000 description 3
- ANJRQUKLRDRXND-YTLKXPSESA-N ethyl (1R,6S,7S,8S)-8-[[2-chloro-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]tricyclo[4.2.2.02,5]decane-7-carboxylate Chemical compound CCOC([C@@H]([C@@H]1C(CC2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2COC)=O ANJRQUKLRDRXND-YTLKXPSESA-N 0.000 description 3
- BPRAPKLHYYUNDC-BFFWMKGCSA-N ethyl (1R,6S,7S,8S)-8-aminotricyclo[4.2.2.02,5]decane-7-carboxylate Chemical compound CCOC([C@@H]([C@@H]1C(CC2)C2[C@H]2CC1)[C@H]2N)=O BPRAPKLHYYUNDC-BFFWMKGCSA-N 0.000 description 3
- LVQMAKUVPGKVAQ-HFCHRNICSA-N ethyl (2S,3S)-3-[(2-chloroimidazo[5,1-f][1,2,4]triazin-4-yl)amino]bicyclo[2.2.2]octane-2-carboxylate Chemical compound CCOC([C@@H](C1CCC2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CN=C2)=O LVQMAKUVPGKVAQ-HFCHRNICSA-N 0.000 description 3
- RHCKXIZYYOSXDX-UHFFFAOYSA-N ethyl 1-[bis(methoxycarbonyl)amino]imidazole-2-carboxylate Chemical compound CCOC(C1=NC=CN1N(C(OC)=O)C(OC)=O)=O RHCKXIZYYOSXDX-UHFFFAOYSA-N 0.000 description 3
- FFWLZPRKLVFVNV-UHFFFAOYSA-N ethyl 1-amino-3-chloropyrrole-2-carboxylate Chemical compound CCOC(=O)C1=C(Cl)C=CN1N FFWLZPRKLVFVNV-UHFFFAOYSA-N 0.000 description 3
- VUEWVPSSFIXDKG-UHFFFAOYSA-N ethyl 1-aminoimidazole-2-carboxylate Chemical compound CCOC(=O)C1=NC=CN1N VUEWVPSSFIXDKG-UHFFFAOYSA-N 0.000 description 3
- HPKDURIJRBYACA-UHFFFAOYSA-N ethyl 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine-6-carboxylate Chemical compound ClC1=NC(Cl)=NN2C=C(C(=O)OCC)C=C21 HPKDURIJRBYACA-UHFFFAOYSA-N 0.000 description 3
- UTHMZUJFJAVCDT-UHFFFAOYSA-N ethyl 2-chloro-4-phenoxypyrrolo[2,1-f][1,2,4]triazine-6-carboxylate Chemical compound ClC1=NN2C(C(=N1)OC1=CC=CC=C1)=CC(=C2)C(=O)OCC UTHMZUJFJAVCDT-UHFFFAOYSA-N 0.000 description 3
- WMPHKNOHMBYAAX-UHFFFAOYSA-N ethyl 3-[bis(methoxycarbonyl)amino]imidazole-4-carboxylate Chemical compound CCOC(C1=CN=CN1N(C(OC)=O)C(OC)=O)=O WMPHKNOHMBYAAX-UHFFFAOYSA-N 0.000 description 3
- FHRZZERGIPPZFC-UHFFFAOYSA-N ethyl 3-chloro-1-(methoxycarbonylamino)pyrrole-2-carboxylate Chemical compound CCOC(C(N(C=C1)NC(OC)=O)=C1Cl)=O FHRZZERGIPPZFC-UHFFFAOYSA-N 0.000 description 3
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
- 125000001475 halogen functional group Chemical group 0.000 description 3
- 239000000185 hemagglutinin Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- XPIIWQZHXIKVMR-UHFFFAOYSA-N methyl 1-(methoxycarbonylamino)-4-(1-methylpyrazol-4-yl)pyrrole-2-carboxylate Chemical compound CN1N=CC(C(C=C2C(OC)=O)=CN2NC(OC)=O)=C1 XPIIWQZHXIKVMR-UHFFFAOYSA-N 0.000 description 3
- YXQMYSVAFKVIND-UHFFFAOYSA-N methyl 1-amino-4-(1-methylpyrazol-4-yl)pyrrole-2-carboxylate Chemical compound CN1N=CC(C(C=C2C(OC)=O)=CN2N)=C1 YXQMYSVAFKVIND-UHFFFAOYSA-N 0.000 description 3
- ACXDDRPCBGQPBV-UHFFFAOYSA-N methyl 1-amino-4-bromopyrrole-2-carboxylate Chemical compound COC(=O)C1=CC(Br)=CN1N ACXDDRPCBGQPBV-UHFFFAOYSA-N 0.000 description 3
- TUSUKUVWCJVHSR-UHFFFAOYSA-N methyl 4-(1-methylpyrazol-4-yl)-1H-pyrrole-2-carboxylate Chemical compound CN1N=CC(C2=CNC(C(OC)=O)=C2)=C1 TUSUKUVWCJVHSR-UHFFFAOYSA-N 0.000 description 3
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 3
- IHUQJPKASFTOBM-UHFFFAOYSA-N n-(2,4-dinitrophenyl)hydroxylamine Chemical compound ONC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O IHUQJPKASFTOBM-UHFFFAOYSA-N 0.000 description 3
- 125000006574 non-aromatic ring group Chemical group 0.000 description 3
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 3
- DVSNHEFWGMUAPK-WGJNUXFISA-N (1R,2S,3S,4R)-6,6-difluoro-3-[[2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]bicyclo[2.2.2]octane-2-carboxylic acid Chemical compound OC([C@@H]([C@@H](CC[C@@H]1C2)C2(F)F)[C@H]1NC1=NC(C(C2=C3)=CNC2=NC=C3F)=NN2C1=CC=C2)=O DVSNHEFWGMUAPK-WGJNUXFISA-N 0.000 description 2
- RYTHZATZHVPILC-VBZZLHDLSA-N (1R,6S,7S,8S)-8-[[2-(5-fluoro-2H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]tricyclo[4.2.2.02,5]decane-7-carboxylic acid Chemical compound OC([C@@H]([C@@H]1C(CC2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NNC2=NC=C3F)=NN2C1=CC=C2)=O RYTHZATZHVPILC-VBZZLHDLSA-N 0.000 description 2
- UPNZHPDDLUSWPC-WOCNJWPNSA-N (1S,6R,7S,8S)-8-ethoxycarbonyltricyclo[4.2.2.02,5]deca-3,9-diene-7-carboxylic acid Chemical compound CCOC([C@@H]([C@H]1C=C[C@@H]2C3C=CC13)[C@H]2C(O)=O)=O UPNZHPDDLUSWPC-WOCNJWPNSA-N 0.000 description 2
- DAAXYQZSKBPJOX-FQEVSTJZSA-N (2S)-2-amino-3-[4-[5-[3-(4-hydroxyphenyl)-4-methoxyphenyl]-1,2,4-oxadiazol-3-yl]phenyl]propanoic acid Chemical compound COC1=C(C=C(C=C1)C2=NC(=NO2)C3=CC=C(C=C3)C[C@@H](C(=O)O)N)C4=CC=C(C=C4)O DAAXYQZSKBPJOX-FQEVSTJZSA-N 0.000 description 2
- PCHSDJRKGJKOAG-ZDUSSCGKSA-N (2S)-N-[(2,4-dichlorophenyl)methyl]-5-oxo-1-thiophen-2-ylpyrrolidine-2-carboxamide Chemical compound Clc1ccc(CNC(=O)[C@@H]2CCC(=O)N2c2cccs2)c(Cl)c1 PCHSDJRKGJKOAG-ZDUSSCGKSA-N 0.000 description 2
- UDWONNYJIGZGEB-VOGSPBGVSA-N (2S,3S)-3-[[2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[5,1-f][1,2,4]triazin-4-yl]amino]bicyclo[2.2.2]octane-2-carboxylic acid Chemical compound OC([C@@H](C1CCC2CC1)[C@H]2NC1=NC(C(C2=C3)=CNC2=NC=C3F)=NN2C1=CN=C2)=O UDWONNYJIGZGEB-VOGSPBGVSA-N 0.000 description 2
- SLTBMTIRYMGWLX-XMMPIXPASA-N (2r)-2-[(4-chloroanilino)carbamoylamino]-3-(1h-indol-3-yl)-n-(2-phenylethyl)propanamide Chemical compound C1=CC(Cl)=CC=C1NNC(=O)N[C@@H](C(=O)NCCC=1C=CC=CC=1)CC1=CNC2=CC=CC=C12 SLTBMTIRYMGWLX-XMMPIXPASA-N 0.000 description 2
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 2
- AEVBPXDFDKBGLT-YOUFYPILSA-N (2s,3s,4r,5r)-n-[2-[4-(diethoxyphosphorylmethyl)anilino]-2-oxoethyl]-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolane-2-carboxamide Chemical compound C1=CC(CP(=O)(OCC)OCC)=CC=C1NC(=O)CNC(=O)[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 AEVBPXDFDKBGLT-YOUFYPILSA-N 0.000 description 2
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 2
- ZXGVFUKWWWNTTQ-VSGBNLITSA-N (3r,5r)-7-[4-[[3-(2-amino-2-oxoethyl)phenyl]sulfamoyl]-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)CCN1C(C(C)C)=C(S(=O)(=O)NC=2C=C(CC(N)=O)C=CC=2)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 ZXGVFUKWWWNTTQ-VSGBNLITSA-N 0.000 description 2
- FOLCUFKJHSQMEL-BIXPGCQOSA-N (4-butylcyclohexyl) N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CCCCC1CCC(CC1)OC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@@H]2CCNC2=O)C=O FOLCUFKJHSQMEL-BIXPGCQOSA-N 0.000 description 2
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 2
- JHLIGYPHPBLDDL-UHFFFAOYSA-N (5-pyridin-3-ylthiophen-2-yl)methanamine Chemical compound S1C(CN)=CC=C1C1=CC=CN=C1 JHLIGYPHPBLDDL-UHFFFAOYSA-N 0.000 description 2
- RXNPEQZHMGFNAY-GEALJGNFSA-N (5R)-4-[(1S,6R)-5-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one Chemical compound C[C@@H]1CC(=O)NC2=C1C(=NC=N2)N3CCN([C@H]4[C@@H]3C4)C(=O)[C@H](CNC(C)C)C5=CC=C(C=C5)Cl RXNPEQZHMGFNAY-GEALJGNFSA-N 0.000 description 2
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 2
- UXKLQDCALAWFIU-VKNDCNMPSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-tetradecoxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCCCC)C1=CC=CC=C1 UXKLQDCALAWFIU-VKNDCNMPSA-N 0.000 description 2
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 description 2
- 125000006591 (C2-C6) alkynylene group Chemical group 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 2
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 2
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 2
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 2
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 2
- YCGQPIRMLGEWMW-UHFFFAOYSA-N 1-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]-3-[4-[(dimethylamino)methyl]-2,6-di(propan-2-yl)phenyl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN(C)C)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 YCGQPIRMLGEWMW-UHFFFAOYSA-N 0.000 description 2
- MXPCZHSTOIKVST-UHFFFAOYSA-N 1-[3-amino-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-[3-(2-hydroxyethoxy)phenyl]-2-oxo-1,8-naphthyridin-3-yl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=CC(N)=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OCCO)=C1 MXPCZHSTOIKVST-UHFFFAOYSA-N 0.000 description 2
- SZCBDIVMCGFVPW-UHFFFAOYSA-N 1-[4-(aminomethyl)-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 SZCBDIVMCGFVPW-UHFFFAOYSA-N 0.000 description 2
- OXTVBHDILDPYAS-UHFFFAOYSA-N 1-[4-(aminomethyl)-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-[3-(3-hydroxypropoxy)phenyl]-2-oxo-1,8-naphthyridin-3-yl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OCCCO)=C1 OXTVBHDILDPYAS-UHFFFAOYSA-N 0.000 description 2
- JENUMEXEVAAAJX-SNVBAGLBSA-N 2-(3,5-dimethyl-1,2,4-triazol-1-yl)-1-[(2r)-2-methyl-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]ethanone Chemical compound C([C@H]1C)N(C2=C(N=C(S2)C(F)(F)F)C=2C=NC(=NC=2)C(F)(F)F)CCN1C(=O)CN1N=C(C)N=C1C JENUMEXEVAAAJX-SNVBAGLBSA-N 0.000 description 2
- AXHVEQQLKVIZLO-UHFFFAOYSA-N 2-[4-[2-[5-(2,2-dimethylbutyl)-1h-imidazol-2-yl]ethyl]phenyl]benzoic acid Chemical compound CCC(C)(C)CC1=CNC(CCC=2C=CC(=CC=2)C=2C(=CC=CC=2)C(O)=O)=N1 AXHVEQQLKVIZLO-UHFFFAOYSA-N 0.000 description 2
- WGABOZPQOOZAOI-UHFFFAOYSA-N 2-[4-[[(3,5-dimethoxy-4-methylbenzoyl)-(3-phenylpropyl)amino]methyl]phenyl]acetic acid Chemical compound COC1=C(C)C(OC)=CC(C(=O)N(CCCC=2C=CC=CC=2)CC=2C=CC(CC(O)=O)=CC=2)=C1 WGABOZPQOOZAOI-UHFFFAOYSA-N 0.000 description 2
- KWSIQJUNYMMCTB-UHFFFAOYSA-N 2-[[4-[carboxymethyl-(4-methoxyphenyl)sulfonylamino]naphthalen-1-yl]-(4-methoxyphenyl)sulfonylamino]acetic acid Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(CC(O)=O)C(C1=CC=CC=C11)=CC=C1N(CC(O)=O)S(=O)(=O)C1=CC=C(OC)C=C1 KWSIQJUNYMMCTB-UHFFFAOYSA-N 0.000 description 2
- QLVGHFBUSGYCCG-UHFFFAOYSA-N 2-amino-n-(1-cyano-2-phenylethyl)acetamide Chemical compound NCC(=O)NC(C#N)CC1=CC=CC=C1 QLVGHFBUSGYCCG-UHFFFAOYSA-N 0.000 description 2
- SDPOKXRORMSMIG-UHFFFAOYSA-N 2-chloro-4-phenoxypyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde Chemical compound O=CC(C=C1C(OC2=CC=CC=C2)=N2)=CN1N=C2Cl SDPOKXRORMSMIG-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- HNFMVVHMKGFCMB-UHFFFAOYSA-N 3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine Chemical compound NC1=NC=CC=C1C1=NC2=CC=C(C=3C=CC=CC=3)N=C2N1C1=CC=C(C2(N)CCC2)C=C1 HNFMVVHMKGFCMB-UHFFFAOYSA-N 0.000 description 2
- UNSHMXUHOHBLIQ-UHFFFAOYSA-N 3-[4-chloro-3-(2-methylphenoxy)naphthalen-1-yl]-6-(trifluoromethyl)-1H-pyrimidine-2,4-dione Chemical compound ClC1=C(C=C(C2=CC=CC=C12)N1C(NC(=CC1=O)C(F)(F)F)=O)OC1=C(C=CC=C1)C UNSHMXUHOHBLIQ-UHFFFAOYSA-N 0.000 description 2
- BCNLLDVODACBHT-INIZCTEOSA-N 3-[[(cyanoamino)-[(2s)-2-methyl-4-(5-methyl-7h-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl]methylidene]amino]-n-(2-hydroxyethyl)benzamide Chemical compound C([C@@H]1C)N(C=2C=3C(C)=CNC=3N=CN=2)CCN1\C(=N\C#N)NC1=CC=CC(C(=O)NCCO)=C1 BCNLLDVODACBHT-INIZCTEOSA-N 0.000 description 2
- XAAFAPOSALSONG-UHFFFAOYSA-N 3-bromo-5-fluoro-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=C(F)C=C2C(Br)=C1 XAAFAPOSALSONG-UHFFFAOYSA-N 0.000 description 2
- UREJONRZBSEKIC-UHFFFAOYSA-N 3-bromo-5-fluoro-1-tritylpyrazolo[3,4-b]pyridine Chemical compound N1=C(Br)C2=CC(F)=CN=C2N1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UREJONRZBSEKIC-UHFFFAOYSA-N 0.000 description 2
- QKRFTNZERDLUQL-UHFFFAOYSA-N 3-bromo-5-fluoro-2h-pyrazolo[3,4-b]pyridine Chemical compound FC1=CN=C2NN=C(Br)C2=C1 QKRFTNZERDLUQL-UHFFFAOYSA-N 0.000 description 2
- MWDVCHRYCKXEBY-LBPRGKRZSA-N 3-chloro-n-[2-oxo-2-[[(1s)-1-phenylethyl]amino]ethyl]benzamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(=O)CNC(=O)C1=CC=CC(Cl)=C1 MWDVCHRYCKXEBY-LBPRGKRZSA-N 0.000 description 2
- NVVPMZUGELHVMH-UHFFFAOYSA-N 3-ethyl-4-[4-[4-(1-methylpyrazol-4-yl)imidazol-1-yl]-3-propan-2-ylpyrazolo[3,4-b]pyridin-1-yl]benzamide Chemical compound CCC1=CC(C(N)=O)=CC=C1N1C2=NC=CC(N3C=C(N=C3)C3=CN(C)N=C3)=C2C(C(C)C)=N1 NVVPMZUGELHVMH-UHFFFAOYSA-N 0.000 description 2
- MVXAKOGJWVQPKC-UHFFFAOYSA-N 5-(3-ethynyl-5-fluorophenyl)-2-pyridin-2-yl-4,6,7,8-tetrahydro-[1,3]oxazolo[4,5-c]azepine Chemical compound FC1=CC(C#C)=CC(N2CC=3N=C(OC=3CCC2)C=2N=CC=CC=2)=C1 MVXAKOGJWVQPKC-UHFFFAOYSA-N 0.000 description 2
- NBTQILYOTKPKRZ-UHFFFAOYSA-N 5-fluoro-1-(4-methylphenyl)sulfonyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=C(F)C=C2C(B2OC(C)(C)C(C)(C)O2)=C1 NBTQILYOTKPKRZ-UHFFFAOYSA-N 0.000 description 2
- PCGDTHBAHOVVRW-UHFFFAOYSA-N 5-fluoro-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=C(F)C=C2C=C1 PCGDTHBAHOVVRW-UHFFFAOYSA-N 0.000 description 2
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 2
- UFONWAPOQPJJLL-UHFFFAOYSA-N 5-fluoro-2h-pyrazolo[3,4-b]pyridin-3-amine Chemical compound C1=C(F)C=C2C(N)=NNC2=N1 UFONWAPOQPJJLL-UHFFFAOYSA-N 0.000 description 2
- UGPRKYAMNVLJEL-UHFFFAOYSA-N 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tritylpyrazolo[3,4-b]pyridine Chemical compound O1C(C)(C)C(C)(C)OB1C1=NN(C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C2=NC=C(F)C=C12 UGPRKYAMNVLJEL-UHFFFAOYSA-N 0.000 description 2
- RRELDGDKULRRDM-UHFFFAOYSA-N 6-[2-chloro-4-nitro-5-(oxan-4-yloxy)anilino]-3,4-dihydro-1H-quinolin-2-one Chemical compound [O-][N+](=O)c1cc(Cl)c(Nc2ccc3NC(=O)CCc3c2)cc1OC1CCOCC1 RRELDGDKULRRDM-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- LDIOUQIXNSSOGU-UHFFFAOYSA-N 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5h-cyclopenta[d]pyrazolo[1,5-a]pyrimidine Chemical compound CC1=NN2C(NC(CC)CC)=C3CCCC3=NC2=C1C1=CC=C(OC)C=C1Cl LDIOUQIXNSSOGU-UHFFFAOYSA-N 0.000 description 2
- MITGKKFYIJJQGL-UHFFFAOYSA-N 9-(4-chlorobenzoyl)-6-methylsulfonyl-2,3-dihydro-1H-carbazol-4-one Chemical compound ClC1=CC=C(C(=O)N2C3=CC=C(C=C3C=3C(CCCC2=3)=O)S(=O)(=O)C)C=C1 MITGKKFYIJJQGL-UHFFFAOYSA-N 0.000 description 2
- LPWKFUVWWQYLOD-UHFFFAOYSA-N 9-(dimethylamino)-3-(4-methylphenyl)pyrido[2,3]thieno[2,4-d]pyrimidin-4-one Chemical compound C1=2C(N(C)C)=CN=CC=2SC(C2=O)=C1N=CN2C1=CC=C(C)C=C1 LPWKFUVWWQYLOD-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- VWVKUNOPTJGDOB-BDHVOXNPSA-N Anhydrous tofogliflozin Chemical compound C1=CC(CC)=CC=C1CC1=CC=C(CO[C@@]23[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C2=C1 VWVKUNOPTJGDOB-BDHVOXNPSA-N 0.000 description 2
- QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 2
- WERBQDABMTUBPP-UBDQQSCGSA-N CCOC([C@@H]([C@@H](CC[C@@H]1C2)C2=C=O)[C@H]1NC(OCC1=CC=CC=C1)=O)=O Chemical compound CCOC([C@@H]([C@@H](CC[C@@H]1C2)C2=C=O)[C@H]1NC(OCC1=CC=CC=C1)=O)=O WERBQDABMTUBPP-UBDQQSCGSA-N 0.000 description 2
- GOQHNCVTROCABZ-DDEALCKXSA-N CNC(C1=CC=C2N1N=C(C(C1=C3)=CNC1=NC=C3F)N=C2N[C@@H]([C@H]1C(C2)C2[C@@H]2CC1)[C@H]2C(O)=O)=O Chemical compound CNC(C1=CC=C2N1N=C(C(C1=C3)=CNC1=NC=C3F)N=C2N[C@@H]([C@H]1C(C2)C2[C@@H]2CC1)[C@H]2C(O)=O)=O GOQHNCVTROCABZ-DDEALCKXSA-N 0.000 description 2
- KKWCMLPBEKZALZ-VFESSSEDSA-N COCC1=CC=C2N1N=C(C(C1=C3)=CNC1=NC=C3F)N=C2N[C@@H]([C@H]1C(C2)C2[C@@H]2CC1)[C@H]2C(O)=O Chemical compound COCC1=CC=C2N1N=C(C(C1=C3)=CNC1=NC=C3F)N=C2N[C@@H]([C@H]1C(C2)C2[C@@H]2CC1)[C@H]2C(O)=O KKWCMLPBEKZALZ-VFESSSEDSA-N 0.000 description 2
- DWYILSVYNNHOAT-SATMMKAJSA-N COCC1=CC=C2N1N=C(C(C1=C3)=NNC1=NC=C3F)N=C2N[C@@H]([C@H]1C(C2)C2[C@@H]2CC1)[C@H]2C(O)=O Chemical compound COCC1=CC=C2N1N=C(C(C1=C3)=NNC1=NC=C3F)N=C2N[C@@H]([C@H]1C(C2)C2[C@@H]2CC1)[C@H]2C(O)=O DWYILSVYNNHOAT-SATMMKAJSA-N 0.000 description 2
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 2
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 2
- 229940126650 Compound 3f Drugs 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- QUXLMUDEKJGUCD-GPISYNIWSA-N OC([C@@H]([C@@H](CC[C@H]12)CC1(F)F)[C@H]2NC1=NC(C(C2=C3)=CNC2=NC=C3F)=NN2C1=CC=C2)=O Chemical compound OC([C@@H]([C@@H](CC[C@H]12)CC1(F)F)[C@H]2NC1=NC(C(C2=C3)=CNC2=NC=C3F)=NN2C1=CC=C2)=O QUXLMUDEKJGUCD-GPISYNIWSA-N 0.000 description 2
- QAGCADSQNIZWDE-FOYDCFKMSA-N OC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=CNC2=NC=C3F)=NN2C1=CC=C2C(F)(F)F)=O Chemical compound OC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=CNC2=NC=C3F)=NN2C1=CC=C2C(F)(F)F)=O QAGCADSQNIZWDE-FOYDCFKMSA-N 0.000 description 2
- MRVHOLURQCDDBK-GHGQPCMUSA-N OC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NNC2=NC=C3F)=NN2C1=CC=C2C(F)(F)F)=O Chemical compound OC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NNC2=NC=C3F)=NN2C1=CC=C2C(F)(F)F)=O MRVHOLURQCDDBK-GHGQPCMUSA-N 0.000 description 2
- GCKKQRFREZDWEG-HGPNWVHJSA-N OC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NNC2=NC=C3F)=NN2C1=CC=C2C1CC1)=O Chemical compound OC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NNC2=NC=C3F)=NN2C1=CC=C2C1CC1)=O GCKKQRFREZDWEG-HGPNWVHJSA-N 0.000 description 2
- ZGGHCGHBFBRYTN-IJGQKCBJSA-N OC([C@@H]([C@@H]1C(CC2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C=C23)=CNC2=CN=C3F)=NN2C1=CC=C2)=O Chemical compound OC([C@@H]([C@@H]1C(CC2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C=C23)=CNC2=CN=C3F)=NN2C1=CC=C2)=O ZGGHCGHBFBRYTN-IJGQKCBJSA-N 0.000 description 2
- 101710093543 Probable non-specific lipid-transfer protein Proteins 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 2
- 229940124393 anti-influenza virus drug Drugs 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- DIKBFYAXUHHXCS-UHFFFAOYSA-N bromoform Chemical compound BrC(Br)Br DIKBFYAXUHHXCS-UHFFFAOYSA-N 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 229940126212 compound 17a Drugs 0.000 description 2
- 229940125796 compound 3d Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000012258 culturing Methods 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
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 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
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000000120 cytopathologic effect Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- VXYKBJRRCIUIBE-UOIJDSNFSA-N ethyl (2S,3S)-3-[[2-[5-fluoro-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridin-3-yl]imidazo[2,1-f][1,2,4]triazin-4-yl]amino]bicyclo[2.2.2]octane-2-carboxylate Chemical compound CCOC([C@@H](C1CCC2CC1)[C@H]2NC1=NC(C(C2=CC(F)=CN=C22)=CN2S(C2=CC=C(C)C=C2)(=O)=O)=NN2C1=NC=C2)=O VXYKBJRRCIUIBE-UOIJDSNFSA-N 0.000 description 2
- JMMIBDLYWDKNDC-QFJJDKIVSA-N ethyl (2S,3S)-3-[[2-[5-fluoro-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridin-3-yl]imidazo[5,1-f][1,2,4]triazin-4-yl]amino]bicyclo[2.2.2]octane-2-carboxylate Chemical compound CCOC([C@@H](C1CCC2CC1)[C@H]2NC1=NC(C(C2=CC(F)=CN=C22)=CN2S(C2=CC=C(C)C=C2)(=O)=O)=NN2C1=CN=C2)=O JMMIBDLYWDKNDC-QFJJDKIVSA-N 0.000 description 2
- ZQFMUFONNBAZAY-UHFFFAOYSA-N ethyl 1,2,4-triazine-6-carboxylate Chemical compound CCOC(=O)C1=CN=CN=N1 ZQFMUFONNBAZAY-UHFFFAOYSA-N 0.000 description 2
- NANCCNXMWJXHFM-UHFFFAOYSA-N ethyl 2-propyloctanoate Chemical compound CCCCCCC(CCC)C(=O)OCC NANCCNXMWJXHFM-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 230000005496 eutectics Effects 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000004973 liquid crystal related substance Substances 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- MUJNAWXXOJRNGK-UHFFFAOYSA-N n-[3-(6-methyl-1,2,3,4-tetrahydrocarbazol-9-yl)propyl]cyclohexanamine Chemical compound C1=2CCCCC=2C2=CC(C)=CC=C2N1CCCNC1CCCCC1 MUJNAWXXOJRNGK-UHFFFAOYSA-N 0.000 description 2
- RCSBCWXPGSPJNF-UHFFFAOYSA-N n-[4-[5-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl]butyl]-4-(1,8-naphthyridin-2-yl)butanamide Chemical compound C1=C(Cl)C(OC(F)(F)F)=CC=C1C(O1)=NN=C1CCCCNC(=O)CCCC1=CC=C(C=CC=N2)C2=N1 RCSBCWXPGSPJNF-UHFFFAOYSA-N 0.000 description 2
- NJKRDPIHNOWVJI-UHFFFAOYSA-N n-diphenylphosphorylhydroxylamine Chemical compound C=1C=CC=CC=1P(=O)(NO)C1=CC=CC=C1 NJKRDPIHNOWVJI-UHFFFAOYSA-N 0.000 description 2
- HBEDNENASUYMPO-LJQANCHMSA-N n-hydroxy-4-[[(2r)-3-oxo-2-(thiophen-2-ylmethyl)-2,4-dihydroquinoxalin-1-yl]methyl]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1CN1C2=CC=CC=C2NC(=O)[C@H]1CC1=CC=CS1 HBEDNENASUYMPO-LJQANCHMSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- ASOADIZOVZTJSR-UHFFFAOYSA-N opicapone Chemical compound CC1=C(Cl)C(C)=[N+]([O-])C(Cl)=C1C1=NOC(C=2C=C(C(O)=C(O)C=2)[N+]([O-])=O)=N1 ASOADIZOVZTJSR-UHFFFAOYSA-N 0.000 description 2
- PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000003566 oxetanyl group Chemical group 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N phthalic anhydride Chemical compound C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 230000001932 seasonal effect Effects 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 2
- 229960002218 sodium chlorite Drugs 0.000 description 2
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- JYRWUSXRTGACLY-UHFFFAOYSA-N tert-butyl 4-[[3-(4-methylsulfonylphenyl)-[1,2]oxazolo[4,5-d]pyrimidin-7-yl]oxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=NC=NC2=C1ON=C2C1=CC=C(S(C)(=O)=O)C=C1 JYRWUSXRTGACLY-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- JRHPOFJADXHYBR-HTQZYQBOSA-N (1r,2r)-1-n,2-n-dimethylcyclohexane-1,2-diamine Chemical compound CN[C@@H]1CCCC[C@H]1NC JRHPOFJADXHYBR-HTQZYQBOSA-N 0.000 description 1
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- LAJAFFLJAJMYLK-CVOKMOJFSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[[(7s)-4-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5h-benzo[7]annulen-3-yl]amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound N1([C@H]2CCC3=CC=C(C(=C3CC2)OC)NC=2N=C(C(=CN=2)Cl)N[C@H]2[C@H]([C@@]3([H])C[C@@]2(C=C3)[H])C(N)=O)CCOCC1 LAJAFFLJAJMYLK-CVOKMOJFSA-N 0.000 description 1
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- TWYYFYNJOJGNFP-CUXYNZQBSA-N (2s,4r,5s,6s)-2-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-2-carbamoyl-4-[[(e,4s,6s)-4,6-dimethyloct-2-enoyl]oxymethyl]-5-hydroxy-1,3-dioxane-4,5,6-tricarboxylic acid Chemical compound O1[C@H](C(O)=O)[C@](C(O)=O)(O)[C@](COC(=O)/C=C/[C@@H](C)C[C@@H](C)CC)(C(O)=O)O[C@]1(C(N)=O)CCC(=C)[C@@H](OC(C)=O)[C@H](C)CC1=CC=CC=C1 TWYYFYNJOJGNFP-CUXYNZQBSA-N 0.000 description 1
- LENAVORGWBTPJR-UHFFFAOYSA-N (5-pyridin-3-ylfuran-2-yl)methanamine Chemical compound O1C(CN)=CC=C1C1=CC=CN=C1 LENAVORGWBTPJR-UHFFFAOYSA-N 0.000 description 1
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 1
- SQHSJJGGWYIFCD-UHFFFAOYSA-N (e)-1-diazonio-1-dimethoxyphosphorylprop-1-en-2-olate Chemical compound COP(=O)(OC)C(\[N+]#N)=C(\C)[O-] SQHSJJGGWYIFCD-UHFFFAOYSA-N 0.000 description 1
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 1
- IGERFAHWSHDDHX-UHFFFAOYSA-N 1,3-dioxanyl Chemical group [CH]1OCCCO1 IGERFAHWSHDDHX-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- ILWJAOPQHOZXAN-UHFFFAOYSA-N 1,3-dithianyl Chemical group [CH]1SCCCS1 ILWJAOPQHOZXAN-UHFFFAOYSA-N 0.000 description 1
- YRTFLDFDKPFNCJ-UHFFFAOYSA-N 1-[4-amino-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-2-oxo-4-[3-(3-pyrrolidin-1-ylpropoxy)phenyl]-1,8-naphthyridin-3-yl]urea;dihydrochloride Chemical compound Cl.Cl.CC(C)C=1C=C(N)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C(C=1)=CC=CC=1OCCCN1CCCC1 YRTFLDFDKPFNCJ-UHFFFAOYSA-N 0.000 description 1
- ZFNNBIMQDHBELV-UHFFFAOYSA-N 1-[4-amino-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-[3-(3-cyclohexylpropoxy)phenyl]-2-oxo-1,8-naphthyridin-3-yl]urea;dihydrochloride Chemical compound Cl.Cl.CC(C)C=1C=C(N)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C(C=1)=CC=CC=1OCCCC1CCCCC1 ZFNNBIMQDHBELV-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000006025 1-methyl-1-butenyl group Chemical group 0.000 description 1
- 125000006044 1-methyl-1-pentenyl group Chemical group 0.000 description 1
- UCNGGGYMLHAMJG-UHFFFAOYSA-N 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound C1=NN(C)C=C1B1OC(C)(C)C(C)(C)O1 UCNGGGYMLHAMJG-UHFFFAOYSA-N 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BSZGZNRUUJXKKQ-UHFFFAOYSA-N 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine Chemical compound N1=C(Cl)N=C(Cl)C2=CC=CN21 BSZGZNRUUJXKKQ-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000006045 2-methyl-1-pentenyl group Chemical group 0.000 description 1
- 125000006031 2-methyl-3-butenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- YCYMCMYLORLIJX-UHFFFAOYSA-N 2-propyloctanoic acid Chemical compound CCCCCCC(C(O)=O)CCC YCYMCMYLORLIJX-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([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
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- DGKRLDCSKQHWRK-UHFFFAOYSA-N 3a,4,4a,6a,7,7a-hexahydro-4,7-ethenocyclobuta[f][2]benzofuran-1,3-dione Chemical compound C1=CC2C3C(=O)OC(=O)C3C1C1C=CC12 DGKRLDCSKQHWRK-UHFFFAOYSA-N 0.000 description 1
- DPGSPRJLAZGUBQ-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane Substances CC1(C)OB(C=C)OC1(C)C DPGSPRJLAZGUBQ-UHFFFAOYSA-N 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- JYSLFQTWNRYWJT-UHFFFAOYSA-N 8-(3,5-dichlorophenyl)sulfanyl-9-[3-(propan-2-ylamino)propyl]purin-6-amine Chemical compound N=1C2=C(N)N=CN=C2N(CCCNC(C)C)C=1SC1=CC(Cl)=CC(Cl)=C1 JYSLFQTWNRYWJT-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical compound C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 1
- GNVUICFALJJTLK-UHFFFAOYSA-N CCCCCCC(C)C(OCC)=O.Cl Chemical compound CCCCCCC(C)C(OCC)=O.Cl GNVUICFALJJTLK-UHFFFAOYSA-N 0.000 description 1
- WTNQOPQGPMRRHA-VGWMRTNUSA-N CCOC([C@@H]([C@@H](CC[C@H]12)CC1(F)F)[C@H]2NC(OCC1=CC=CC=C1)=O)=O Chemical compound CCOC([C@@H]([C@@H](CC[C@H]12)CC1(F)F)[C@H]2NC(OCC1=CC=CC=C1)=O)=O WTNQOPQGPMRRHA-VGWMRTNUSA-N 0.000 description 1
- XOAYDFJTSBGIBR-UKJIMTQDSA-N CCOC([C@@H]([C@@H](CC[C@H]12)CC1(F)F)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2)=O Chemical compound CCOC([C@@H]([C@@H](CC[C@H]12)CC1(F)F)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2)=O XOAYDFJTSBGIBR-UKJIMTQDSA-N 0.000 description 1
- LXTBHTGWGCLVFM-PJJMEMEKSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NN(C(C4=CC=CC=C4)(C4=CC=CC=C4)C4=CC=CC=C4)C2=NC=C3F)=NN2C1=CC=C2C(F)(F)F)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NN(C(C4=CC=CC=C4)(C4=CC=CC=C4)C4=CC=CC=C4)C2=NC=C3F)=NN2C1=CC=C2C(F)(F)F)=O LXTBHTGWGCLVFM-PJJMEMEKSA-N 0.000 description 1
- DLNJXOSCNGBYLA-IJZMFDALSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NN(C(C4=CC=CC=C4)(C4=CC=CC=C4)C4=CC=CC=C4)C2=NC=C3F)=NN2C1=CC=C2C1CC1)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NN(C(C4=CC=CC=C4)(C4=CC=CC=C4)C4=CC=CC=C4)C2=NC=C3F)=NN2C1=CC=C2C1CC1)=O DLNJXOSCNGBYLA-IJZMFDALSA-N 0.000 description 1
- DXZPUMLFJOQINF-ACPLZFKQSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NNC2=NC=C3F)=NN2C1=CC=C2C(F)(F)F)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NNC2=NC=C3F)=NN2C1=CC=C2C(F)(F)F)=O DXZPUMLFJOQINF-ACPLZFKQSA-N 0.000 description 1
- HABRPQMDQHZKRN-VQZPWVRUSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NNC2=NC=C3F)=NN2C1=CC=C2C1CC1)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NNC2=NC=C3F)=NN2C1=CC=C2C1CC1)=O HABRPQMDQHZKRN-VQZPWVRUSA-N 0.000 description 1
- JYABKWALMZOQBI-LVMSAAHCSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=CC(F)=CN=C22)=CN2S(C2=CC=C(C)C=C2)(=O)=O)=NN2C1=CC=C2C(F)(F)F)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=CC(F)=CN=C22)=CN2S(C2=CC=C(C)C=C2)(=O)=O)=NN2C1=CC=C2C(F)(F)F)=O JYABKWALMZOQBI-LVMSAAHCSA-N 0.000 description 1
- MHUKABYQDACWAC-DXODNDRQSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=CC(F)=CN=C22)=CN2S(C2=CC=C(C)C=C2)(=O)=O)=NN2C1=CC=C2C(NC)=O)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=CC(F)=CN=C22)=CN2S(C2=CC=C(C)C=C2)(=O)=O)=NN2C1=CC=C2C(NC)=O)=O MHUKABYQDACWAC-DXODNDRQSA-N 0.000 description 1
- UFLCTGZQFRQAHO-DDEQCPQSSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=CC(F)=CN=C22)=CN2S(C2=CC=C(C)C=C2)(=O)=O)=NN2C1=CC=C2COC)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=CC(F)=CN=C22)=CN2S(C2=CC=C(C)C=C2)(=O)=O)=NN2C1=CC=C2COC)=O UFLCTGZQFRQAHO-DDEQCPQSSA-N 0.000 description 1
- BPUNHACWZTXDOU-OFRGVZQOSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C(Br)=CC=C12)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C(Br)=CC=C12)=O BPUNHACWZTXDOU-OFRGVZQOSA-N 0.000 description 1
- IOTIPTGKEFZPEV-OFRGVZQOSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C(I)=CC=C12)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C(I)=CC=C12)=O IOTIPTGKEFZPEV-OFRGVZQOSA-N 0.000 description 1
- VBJMLMKTBRWZDT-ZMTBKHNVSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2)=O VBJMLMKTBRWZDT-ZMTBKHNVSA-N 0.000 description 1
- SAZHJMQUJUIUKF-OFRGVZQOSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2C(F)(F)F)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2C(F)(F)F)=O SAZHJMQUJUIUKF-OFRGVZQOSA-N 0.000 description 1
- WNMDJOYTBNIQDK-SCXSBGKZSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2C(NC)=O)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2C(NC)=O)=O WNMDJOYTBNIQDK-SCXSBGKZSA-N 0.000 description 1
- DTIUBNOXLVEJOC-OFRGVZQOSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2C(O)=O)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2C(O)=O)=O DTIUBNOXLVEJOC-OFRGVZQOSA-N 0.000 description 1
- XGQDGJVNXJCHPE-IKUJZSLQSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2C1CC1)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2C1CC1)=O XGQDGJVNXJCHPE-IKUJZSLQSA-N 0.000 description 1
- CMPBUWUGSSFVLC-IKJGNNCDSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2C=O)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2C=O)=O CMPBUWUGSSFVLC-IKJGNNCDSA-N 0.000 description 1
- MPJHPRWRRGCQHO-IKJGNNCDSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2CO)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2CO)=O MPJHPRWRRGCQHO-IKJGNNCDSA-N 0.000 description 1
- KSBUDMQLKNOCRE-ITGRAJHYSA-N CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2COC)=O Chemical compound CCOC([C@@H]([C@@H]1C(C2)C2[C@H]2CC1)[C@H]2NC1=NC(Cl)=NN2C1=CC=C2COC)=O KSBUDMQLKNOCRE-ITGRAJHYSA-N 0.000 description 1
- WTNQOPQGPMRRHA-LVQVYYBASA-N CCOC([C@@H]([C@H](CC[C@@H]12)CC1(F)F)[C@@H]2NC(OCC1=CC=CC=C1)=O)=O Chemical compound CCOC([C@@H]([C@H](CC[C@@H]12)CC1(F)F)[C@@H]2NC(OCC1=CC=CC=C1)=O)=O WTNQOPQGPMRRHA-LVQVYYBASA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 241000712431 Influenza A virus Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- LAHGJLYRKUBZOP-UHFFFAOYSA-N N-diphenylphosphanylhydroxylamine Chemical compound C1(=CC=CC=C1)P(C1=CC=CC=C1)NO LAHGJLYRKUBZOP-UHFFFAOYSA-N 0.000 description 1
- ANOFLIFCBIKVDD-UHFFFAOYSA-N N1C(Cl)=NC=C2N=CC=C21 Chemical compound N1C(Cl)=NC=C2N=CC=C21 ANOFLIFCBIKVDD-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- NPUXORBZRBIOMQ-RUZDIDTESA-N [(2R)-1-[[4-[[3-(benzenesulfonylmethyl)-5-methylphenoxy]methyl]phenyl]methyl]-2-pyrrolidinyl]methanol Chemical compound C=1C(OCC=2C=CC(CN3[C@H](CCC3)CO)=CC=2)=CC(C)=CC=1CS(=O)(=O)C1=CC=CC=C1 NPUXORBZRBIOMQ-RUZDIDTESA-N 0.000 description 1
- KDUIUFJBNGTBMD-DLMDZQPMSA-N [8]annulene Chemical compound C/1=C/C=C\C=C/C=C\1 KDUIUFJBNGTBMD-DLMDZQPMSA-N 0.000 description 1
- AQMHNCQZLQUNJI-UHFFFAOYSA-N [CH2]CCCCCC Chemical compound [CH2]CCCCCC AQMHNCQZLQUNJI-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- XEFCWBLINXJUIV-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.CC(O)=O.IC1=CC=CC=C1 XEFCWBLINXJUIV-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000005257 alkyl acyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000005334 azaindolyl group Chemical class N1N=C(C2=CC=CC=C12)* 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 229950005228 bromoform Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000004452 carbocyclyl group Chemical group 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001352 cyclobutyloxy group Chemical group C1(CCC1)O* 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005050 dihydrooxazolyl group Chemical group O1C(NC=C1)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- SGDINNZGYDHHKM-UHFFFAOYSA-N dilithium;trimethylsilylazanide Chemical compound [Li+].[Li+].C[Si](C)(C)[NH-].C[Si](C)(C)[NH-] SGDINNZGYDHHKM-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- MCYYJHPHBOPLMH-UHFFFAOYSA-L disodium;dioxido-oxo-sulfanylidene-$l^{6}-sulfane;hydrate Chemical compound O.[Na+].[Na+].[O-]S([O-])(=O)=S MCYYJHPHBOPLMH-UHFFFAOYSA-L 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- 125000003438 dodecyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HHRKFGMMAHZWIM-UHFFFAOYSA-N ethenoxyboronic acid Chemical compound OB(O)OC=C HHRKFGMMAHZWIM-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- NCZDTJIENYNSOZ-LURQLKTLSA-N ethyl (1R,2S,3S,4R)-3-amino-5,5-difluorobicyclo[2.2.2]octane-2-carboxylate Chemical compound CCOC([C@@H]([C@H](CC[C@@H]12)CC1(F)F)[C@@H]2N)=O NCZDTJIENYNSOZ-LURQLKTLSA-N 0.000 description 1
- LMYBIMNKLDVCKI-VLODPIEWSA-N ethyl (1R,2S,3S,4R)-6,6-difluoro-3-[[2-[5-fluoro-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]bicyclo[2.2.2]octane-2-carboxylate Chemical compound CCOC([C@@H]([C@@H](CC[C@@H]1C2)C2(F)F)[C@H]1NC1=NC(C(C2=CC(F)=CN=C22)=CN2S(C2=CC=C(C)C=C2)(=O)=O)=NN2C1=CC=C2)=O LMYBIMNKLDVCKI-VLODPIEWSA-N 0.000 description 1
- ICBXMIVPCUTYAY-OHFALNGGSA-N ethyl (1R,2S,3S,4R)-6-oxo-3-(phenylmethoxycarbonylamino)bicyclo[2.2.2]octane-2-carboxylate Chemical compound CCOC([C@@H]([C@@H](CC[C@@H]1C2)C2=O)[C@H]1NC(OCC1=CC=CC=C1)=O)=O ICBXMIVPCUTYAY-OHFALNGGSA-N 0.000 description 1
- SOVPWWGXASPXKT-QFYCONQBSA-N ethyl (1R,6S,7S,8S)-8-(phenylmethoxycarbonylamino)tricyclo[4.2.2.02,5]deca-3,9-diene-7-carboxylate Chemical compound CCOC([C@@H]([C@H]1C=C[C@@H]2C3C=CC13)[C@H]2NC(OCC1=CC=CC=C1)=O)=O SOVPWWGXASPXKT-QFYCONQBSA-N 0.000 description 1
- YPPBJXZEPCTGEV-MQZMIVJESA-N ethyl (1R,6S,7S,8S)-8-[[2-(5-fluoro-1-tritylpyrazolo[3,4-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]tricyclo[4.2.2.02,5]decane-7-carboxylate Chemical compound CCOC([C@@H]([C@@H]1C(CC2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NN(C(C4=CC=CC=C4)(C4=CC=CC=C4)C4=CC=CC=C4)C2=NC=C3F)=NN2C1=CC=C2COC)=O YPPBJXZEPCTGEV-MQZMIVJESA-N 0.000 description 1
- HZBMTIMOUXWTIH-WBIDAKPYSA-N ethyl (1R,6S,7S,8S)-8-[[2-(5-fluoro-1-tritylpyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]tricyclo[4.2.2.02,5]decane-7-carboxylate Chemical compound CCOC([C@@H]([C@@H]1C(CC2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=C3)=NN(C(C4=CC=CC=C4)(C4=CC=CC=C4)C4=CC=CC=C4)C2=NC=C3F)=NN2C1=CC=C2)=O HZBMTIMOUXWTIH-WBIDAKPYSA-N 0.000 description 1
- QFDTXRWZTISJJH-SBBYPDFYSA-N ethyl (1R,6S,7S,8S)-8-[[2-[5-fluoro-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]tricyclo[4.2.2.02,5]decane-7-carboxylate Chemical compound CCOC([C@@H]([C@@H]1C(CC2)C2[C@H]2CC1)[C@H]2NC1=NC(C(C2=CC(F)=CN=C22)=CN2S(C2=CC=C(C)C=C2)(=O)=O)=NN2C1=CC=C2)=O QFDTXRWZTISJJH-SBBYPDFYSA-N 0.000 description 1
- BPOVDPINWJDISS-YXYVBFQVSA-N ethyl (1S,2S,3R,4S)-5,5-difluoro-3-[[2-[5-fluoro-1-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]bicyclo[2.2.2]octane-2-carboxylate Chemical compound CCOC([C@@H]([C@@H](CC[C@H]12)CC1(F)F)[C@H]2NC1=NC(C(C2=CC(F)=CN=C22)=CN2S(C2=CC=C(C)C=C2)(=O)=O)=NN2C1=CC=C2)=O BPOVDPINWJDISS-YXYVBFQVSA-N 0.000 description 1
- XCJSYVVMWQFKQE-FSDCSDTHSA-N ethyl (1S,2S,3S,4S)-5-oxo-3-(phenylmethoxycarbonylamino)bicyclo[2.2.2]octane-2-carboxylate Chemical compound CCOC([C@@H]([C@@H](CC[C@H]12)CC1=O)[C@H]2NC(OCC1=CC=CC=C1)=O)=O XCJSYVVMWQFKQE-FSDCSDTHSA-N 0.000 description 1
- FVZLROZSNIVORF-QQFIATSDSA-N ethyl (2S,3S)-3-[(2-chloroimidazo[2,1-f][1,2,4]triazin-4-yl)amino]bicyclo[2.2.2]octane-2-carboxylate Chemical compound CCOC([C@@H](C1CCC2CC1)[C@H]2NC1=NC(Cl)=NN2C1=NC=C2)=O FVZLROZSNIVORF-QQFIATSDSA-N 0.000 description 1
- QEAUPUSWGDMTQU-OQSWDALSSA-N ethyl (2S,3S)-3-[(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]bicyclo[2.2.2]octane-2-carboxylate Chemical compound CCOC(=O)[C@@H]1[C@H](C2CCC1CC2)NC3=NC(=NN4C3=CC=C4)Cl QEAUPUSWGDMTQU-OQSWDALSSA-N 0.000 description 1
- BDHDGKDBPAJZEG-UHFFFAOYSA-N ethyl 2,4-dioxo-1h-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate Chemical compound N1C(=O)NC(=O)C=2N1C=C(C(=O)OCC)C=2 BDHDGKDBPAJZEG-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- OCVXZQOKBHXGRU-UHFFFAOYSA-N iodine(1+) Chemical compound [I+] OCVXZQOKBHXGRU-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- LVBWRNKEBGYENR-UHFFFAOYSA-N n-cyclopropyl-4-[8-(oxan-4-ylmethylamino)-6-[(1,1,1-trifluoro-2-methylpropan-2-yl)amino]imidazo[1,2-b]pyridazin-3-yl]benzamide Chemical compound C12=NC=C(C=3C=CC(=CC=3)C(=O)NC3CC3)N2N=C(NC(C)(C)C(F)(F)F)C=C1NCC1CCOCC1 LVBWRNKEBGYENR-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 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 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- QYZLKGVUSQXAMU-UHFFFAOYSA-N penta-1,4-diene Chemical compound C=CCC=C QYZLKGVUSQXAMU-UHFFFAOYSA-N 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- NESLWCLHZZISNB-UHFFFAOYSA-M sodium phenolate Chemical compound [Na+].[O-]C1=CC=CC=C1 NESLWCLHZZISNB-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000005496 tempering Methods 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 239000003981 vehicle 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
- 238000010792 warming Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Abstract
本发明公开一种式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,或含它们的药物组合物,及其作为PB2抑制剂在制备治疗相关疾病的药物中的用途,式(I)中各基团如说明书之定义。Cy1‑L1‑Cy2‑L2‑Cy3(I)。
Description
技术领域
本发明属于药物领域,尤其涉及一种桥环化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,及其在制备治疗相关疾病的药物中的用途。
背景技术
流行性感冒(简称流感)是流感病毒引起的急性呼吸道感染,也是一种传染性强、传播速度快的疾病。一般秋冬季节是其高发期,所引起的并发症和死亡现象非常严重。根据WHO的报告,流感病毒每年会造成三到五百万例感染,以及65万例死亡。根据流感病毒基因特性和核蛋白抗原的不同,将流感病毒分为甲,乙,丙三型。其中甲型流感是这三种类型中对人类毒力最强的病毒,可造成严重的疾病和爆发性的流行。同时甲型流感病毒也最容易发生变异,根据其表面抗原血凝素和神经氨酸酶的不同分为不同的亚型,其中血凝素共有H1到H17这17种亚型,而神经氨酸酶有N1到N10这10中不同的类型,这两种进行搭配可形成甲型流感的不同亚型。
预防和控制流感的主要措施是接种流感疫苗。可以减少接种者感染流感的机会或者减轻流感症状。但是,季节性流感疫苗仍具有其自身局限性。首先,流感疫苗对健康成年人具有较好的保护作用,而对老年人的效果较差。其次,季节性流感疫苗必须每年更新,以应对预测将在新流感季流行的病毒种类。然而,由于新的病毒种类的出现导致其防护作用并不一定能达到预期。
另外,这些流感疫苗的功效可变。由于病毒的高突变率,特定流感疫苗通常赋予不超过几年的保护。由于病毒随时间快速变化,并且不同菌株成为优势,配制一年的疫苗可能在下一年无效。
同样,由于缺乏RNA校正读码酶,流感vRNA的依赖于RNA依赖的RNA聚合酶大约每1万个核苷酸(这是流感vRNA的近似长度)产生一个核苷酸插入错误。因此,几乎每种新制流感病毒均为突变-抗原漂移。如果不止一个病毒系感染了单个细胞,则基因组分离为8个单独的vRNA片段使vRNA混合或重配。所产生的病毒遗传学上的快速变化产生抗原抗原转变并且使病毒感染新宿主物种并迅速克服保性免疫。
抗病毒药物也可用于治疗流感,现有抗流感病毒药物的作用靶点主要针对病毒包膜的血凝素受体、神经氨酸酶和基质蛋白。随着已有的抗流感病毒药物的大量使用,对这些药物具有抗药性的病毒株所占的比例越来越大,而选择性作用于流感病毒RNA聚合酶的药物则不易产生抗药性,对人体无严重的毒副反应。流感病毒RNA聚合酶在流感病毒生命周期中发挥着重要的作用,近年来已经成为备受关注的抗流感病毒的新靶点。
因此,仍需要治疗流感感染的流感病毒RNA聚合酶碱性蛋白2抑制剂(PB2抑制剂)的药物,例如治疗窗扩大和/或对病毒滴度的敏感性降低的药物。
发明内容
本发明的目的是提供一种结构新颖的氮杂吲哚衍生物,作为一种流感病毒RNA聚合酶碱性蛋白2抑制剂,具有药效好、生物利用度高、副作用小的优点。
本发明涉及一种式(I)所示的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,
Cy1——L1——Cy2—L2——Cy3 (I)
Cy1选自或者/>进一步,Cy1选自/> 进一步,Cy1选自/>进一步,Cy1选自/>
Y1选自-CH-或者-N-;
n选自1、2或3,进一步,n选自1;
R1、R2各自独立选自F、Cl、Br、NH2、C1-6烷基或者C3-6单环环烷基,所述的R1、R2任选进一步被1-5个选自卤素、OH或者氘的基团取代,进一步,R1、R2各自独立选自F;
Cy2选自键、C3-12碳环或者3-12元杂环,所述的Cy2任选进一步被1-5个选自RA的基团取代;
RA各自独立选自卤素、C1-6烷基、C2-6烯基、C2-6炔基、5-12元杂芳基、苯基、-NRBC(O)C1-6烷基、-C(O)NRBC1-6烷基、-C(O)C1-6烷基、CN、=O、C1-6烷氧基C(O)-、-COOH、OH、-NRBRC、氘、-SH、-S(C1-6烷基)、-S(O)2(C1-6烷基)或者C3-6单环环烷基,所述的RA任选进一步被1-5个选自卤素、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、-Si(C1-6烷基)3、OH、5-6元杂芳基、C3-6单环环烷基、-S(C1-6烷基)或者氘的基团取代;
Cy3选自所述的Cy3任选被1-5个选自Rcy3的基团取代;进一步,Cy3选自/>所述的Cy3任选被1-3个选自Rcy3的基团取代;进一步,Cy3选自所述的Cy3任选被1-3个选自Rcy3的基团取代,且此时t选自1、2或3,每个Y2各自独立选自-CH2-、-NH-、O、S,Y2中每个H原子可以独立地被Rcy3的基团取代;进一步,Cy3选自/>所述的Cy3任选被1-3个选自Rcy3的基团取代;
t选自0、1、2、3或4,进一步,t选自0、1、2、3,进一步,t选自0、1、2,进一步,t选自0、1,进一步,t选自0;
每个Y2各自独立选自-CH2-、-N-、-NH-、O、S、S(O)、S(O)2,Y2中每个H原子可以独立地被Rcy3的基团取代;进一步,每个Y2各自独立选自-CH-、-CH2-、-NH-、O、S,Y2中每个H原子可以独立地被Rcy3的基团取代;进一步,每个Y2各自独立选自-CH-、-CH2-、-NH-、O,Y2中每个H原子可以独立地被Rcy3的基团取代;进一步,每个Y2各自独立选自-CH-、-CH2-,Y2中每个H原子可以独立地被Rcy3的基团取代;
每个Rcy3各自独立地选自F、Cl、Br、OH、CN、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟基C1-6烷基;进一步,每个Rcy3各自独立地选自F、Cl、OH、CN、C1-2烷基、C1-2烷氧基、卤代C1-2烷基、羟基C1-2烷基;进一步,每个Rcy3各自独立地选自F、Cl、OH、C1-2烷基、卤代C1-2烷基;进一步,每个Rcy3各自独立地选自F、Cl、OH;
R3各自独立选自H、C1-6烷基;进一步,R3各自独立选自H、C1-2烷基;进一步,R3各自独立选自H;
L1选自键、C2-6亚炔基、C2-6亚烯基或者-C(O)-;进一步,L1选自键、C2-4亚炔基、C2-4亚烯基或者-C(O)-;进一步,L1选自键;进一步,L1选自C2-4亚炔基、C2-4亚烯基;进一步,L1选自-C(O)-;
L2选自键、-NRB-或者-C(O)NRB-;进一步,L2选自键、-NH-、-NCH3-或者-C(O)NH-;进一步,L2选自-NH-、-NCH3-或者-C(O)NH-;进一步,L2选自-NH-、-NCH3-;进一步,L2选自-NH-;以及
其中RB、RC各自独立选自H、氘、C1-6烷基、卤代C1-6烷基、-OC(O)CH3或者氘代C1-6烷基。
作为本发明第一技术方案,涉及一种式(I)所示的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,
Cy1——L1—Cy2—L2——Cy3 (I)
Cy1选自或者/>
Y1选自-CH-或者-N-;
n选自1、2或3;
R1、R2各自独立选自F、Cl、Br、NH2、C1-6烷基或者C3-6单环环烷基,所述的R1、R2任选进一步被1-5个选自卤素、OH或者氘的基团取代;
Cy2选自键、C3-12碳环或者3-12元杂环,所述的Cy2任选进一步被1-5个选自RA的基团取代;
RA各自独立选自卤素、C1-6烷基、C2-6烯基、C2-6炔基、5-12元杂芳基、苯基、-NRBC(O)C1-6烷基、-C(O)NRBC1-6烷基、-C(O)C1-6烷基、CN、=O、C1-6烷氧基C(O)-、-COOH、OH、-NRBRC、氘、-SH、-S(C1-6烷基)、-S(O)2(C1-6烷基)或者C3-6单环环烷基,所述的RA任选进一步被1-5个选自卤素、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、-Si(C1-6烷基)3、OH、5-6元杂芳基、C3-6单环环烷基、-S(C1-6烷基)或者氘的基团取代;
Cy3选自所述的Cy3任选被1-5个选自Rcy3的基团取代;
t选自0、1、2、3或4;
每个Y2各自独立选自-CH2-、-N-、-NH-、O、S、S(O)、S(O)2,Y2中每个H原子可以独立地被Rcy3的基团取代;
每个Rcy3各自独立地选自F、Cl、Br、OH、CN、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟基C1-6烷基;
R3各自独立选自H、C1-6烷基;
L1选自键、C2-6亚炔基、C2-6亚烯基或者-C(O)-;
L2选自键、-NRB-或者-C(O)NRB-;
其中RB、RC各自独立选自H、氘、C1-6烷基、-OC(O)CH3、卤代C1-6烷基或者氘代C1-6烷基。
作为本发明的第二技术方案,第一技术方案中所述的式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,具有式(II)、(III)、(IV)、(V)的结构:
Cy1——Cy2a——NH—Cy3 (II)
Cy1——Cy2b—Cy3 (III)
Cy1—L1a——Cy2c——L2a—Cy3 (IV)
Cy1—L1b——L2b——Cy3 (V)
其中,
Cy1选自或者/>
Cy3选自或者/>所述的Cy3任选被1-5个选自Rcy3的基团取代;
每个Y2各自独立选自-CH2-、-N-、-NH-、O、S、S(O)、S(O)2,Y2中每个H原子可以独立地被Rcy3的基团取代;
t选自1、2、3或4;
每个Rcy3各自独立地选自F、Cl、Br、OH、CN、C1-4烷基、C1-4烷氧基、卤代C1-4烷基或者羟基C1-4烷基;
Cy2a选自如下基团,*代表Cy2a与NH的偶联位点:
(a)、
(b)、
(c)、
(d)、
(e)、5元杂芳基、5元不饱和单环杂环烷基、6元饱和单环杂环烷基;
(f)、6元不饱和单环杂环烷基;
(g)、
(h)、
其中Cy2a中(a)-(f)的基团任选进一步被1-5个选自RA的基团取代,Cy2a中(g)的基团被1个选自RD的基团取代;
当Cy1选自时,Cy2a中(h)的基团被1-3个选自RE的基团取代;或
当Cy1选自Cy2a为(h)时,Cy3被1-5个选自Rcy3的基团取代;或
当Cy1选自Cy2a为(h)时,Cy3选自/>t=2、3或4;
当Cy1选自时,Cy2a中(h)的基团任选进一步被1-3个选自RA的基团取代;
每个A环各自独立选自4-6元单环环烷基、4-6元单环杂环烷基、5-6元杂芳基或者苯基;
每个C环各自独立选自5元单环环烷基、5元单环杂环烷基或者5元杂芳基;
每个E环各自独立选自6元单环环烷基、6元单环杂环烷基、6元杂芳基或者苯基;
每个X11、X12、X13各自独立选自-CH-、-CRA-、-CH2-、-CHRA-、-C(RA)2-、-N-、-NH-、-NRA-、O、S、S(O)或S(O)2,每个X14、X15各自独立选自-C-、-CH-、-CRA-或-N-,且B环为饱和环、部分不饱和环或者杂芳基环;
每个X21、X22、X23、X24各自独立选自-CH-、-CRA-、-CH2-、-CHRA-、-C(RA)2-、-N-、-NH-、-NRA-、O、S、S(O)或S(O)2,每个X25、X26各自独立选自-C-、-CH-、-CRA-或者-N-,且D环为饱和环、部分不饱和环、苯环或者杂芳基环,条件是,D并C环不形成取代或未取代的
每个X31、X32、X33、X34各自独立选自-CH-、-CRA-、-CH2-、-CHRA-、-C(RA)2-、-N-、-NH-、-NRA-、O、S、S(O)或S(O)2,每个X35、X36各自独立选自-C-、-CH-、-CRA-或者-N-,且F环为饱和环、部分不饱和环、苯环或者杂芳环,条件是,F并E环不形成取代或未取代的
每个RA各自独立选自卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、5-12元杂芳基、苯基、-NRBC(O)C1-6烷基、-C(O)NRBC1-6烷基、-C(O)C1-6烷基、CN、=O、C1-6烷氧基C(O)-、-COOH、OH、-NRBRC、氘、-SH、-S(C1-6烷基)、-S(O)2(C1-6烷基)、C3-6单环环烷基,所述的RA任选进一步被1-5个选自卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-Si(C1-6烷基)3、OH、5-6元杂芳基、C3-6单环环烷基、-S(C1-6烷基)、氘的基团取代;
每个RD选自C1-6烷基、5-6元杂芳基、苯基,所述的杂芳基、苯基被1-2个选自-Si(C1-6烷基)3的基团取代;
每个RE选自羟基C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、C2-6烯基、C2-6炔基、5-12元杂芳基、苯基、-NRBC(O)C1-6烷基、-C(O)NRBC1-6烷基、-C(O)C1-6烷基、=O、C1-6烷氧基C(O)-、-COOH、OH、-NRBRC、氘、-SH、-S(C1-6烷基)、-S(O)2(C1-6烷基)、C3-6单环环烷基、C3-6单环杂环环烷基的基团取代,所述的RE任选进一步被1-5个选自卤素、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、-Si(C1-6烷基)3、OH、5-6元杂芳基、C3-6单环环烷基、-S(C1-6烷基)、氘的基团取代;
Cy2b选自其中*代表Cy2b与的偶联位点,所述的Cy2b任选被1-5个选自RA的基团取代;
Cy2c选自C3-12碳环、5-12元杂环,所述的Cy2c任选进一步被1-5个选自RA的基团取代;
L1a选自键、C2-4亚炔基、C2-4亚烯基或-C(O)-;L2a选自-NRB-、-*C(O)NRB-,其中*表示L2a与Cy2c偶联位点,条件是当L1a选自键时,L2a选自-*C(O)NRB-;
L1b选自C2-4亚炔基或C2-4亚烯基,L2b选自-NRB-或-*C(O)NRB-,其中*表示L2b与L1b偶联位点;
其中每个RB、RC各自独立选自H、氘、C1-6烷基、-OC(O)CH3、卤代C1-6烷基、氘代C1-6烷基;
条件是Cy2a不选自取代或未取代的及取代或未取代的/>
本发明的第三技术方案,涉及式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy1选自或者
Cy1选自或者
Cy1选自
其他基团定义与第一或第二技术方案一致。
本发明第四技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy3选自所述的Cy3任选被1-3个选自Rcy3的基团取代;或者
Cy3选自所述的Cy3任选被1-3个选自Rcy3的基团取代,t选自1、2或3,每个Y2各自独立选自-CH2-、-NH-、O、S,Y2中每个H原子可以独立地被Rcy3的基团取代;或者
Cy3选自所述的Cy3任选被1-3个选自Rcy3的基团取代;
其他基团定义与第一至第三任一技术方案一致。
本发明第五技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy3选自
其他基团定义与第一至第三任一技术方案一致。
本发明第六技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
每个Rcy3各自独立地选自F、Cl、CN;
其他基团定义与第一至第五任一技术方案一致。
本发明第七技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy3选自所述的Cy3任选被1-3个选自Rcy3的基团取代;
Cy1选自
其他基团定义与第一至第六任一技术方案一致。
本发明第八技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy2a选自
所述的Cy2a任选被1-3个选自RA的基团取代;或者
Cy2a选自被1个选自甲基、5元杂芳基的基团取代,所述的5元杂芳基被1个三甲基硅烷基取代;或者
Cy1选自Cy2a选自/>Cy2a被1个选自羟基C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、C2-6烯基、C2-6炔基、5-6元杂芳基、-NRBC(O)C1-6烷基、-C(O)NRBC1-6烷基、-C(O)C1-6烷基、C1-6烷氧基C(O)-、-COOH、OH、-NRBRC、氘、C3-6单环环烷基、C3-6单环杂环环烷基的基团取代,所述的杂芳基任选进一步被1-3个选自卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-Si(C1-3烷基)3、OH、5-6元杂芳基、C3-6单环环烷基、-S(C1-6烷基)、氘的基团取代;或者
Cy1选自Cy2a选自/>Cy2a任选被1-2个选自羟基C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、C2-6烯基、C2-6炔基、5-6元杂芳基、-NRBC(O)C1-6烷基、-C(O)NRBC1-6烷基、-C(O)C1-6烷基、C1-6烷氧基C(O)-、-COOH、OH、-NRBRC、氘、C3-6单环环烷基、C3-6单环杂环环烷基的基团取代,所述的杂芳基任选进一步被1-3个选自卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-Si(C1-3烷基)3、OH、5-6元杂芳基、C3-6单环环烷基、-S(C1-6烷基)、氘的基团取代;
其他基团定义与第一至第七任一技术方案一致
本发明第九技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy2a选自
所述的Cy2a任选被1-3个选自RA的基团取代;
其他基团定义与上述任一技术方案一致。
本发明第十技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy2a选自被1个选自甲基、5元杂芳基的基团取代,所述的5元杂芳基被1个三甲基硅烷基取代;
其他基团定义与上述任一技术方案一致。
本发明第十一技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy1选自Cy2a选自/>Cy2a被1个选自羟基C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、C2-6烯基、C2-6炔基、5-6元杂芳基、-NRBC(O)C1-6烷基、-C(O)NRBC1-6烷基、-C(O)C1-6烷基、C1-6烷氧基C(O)-、-COOH、OH、-NRBRC、氘、C3-6单环环烷基、C3-6单环杂环环烷基的基团取代,所述的杂芳基任选进一步被1-3个选自卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-Si(C1-3烷基)3、OH、5-6元杂芳基、C3-6单环环烷基、-S(C1-6烷基)、氘的基团取代;
其他基团定义与上述任一技术方案一致。
本发明第十二技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy1选自Cy2a选自/>Cy2a任选被1-2个选自羟基C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、C2-6烯基、C2-6炔基、5-6元杂芳基、-NRBC(O)C1-6烷基、-C(O)NRBC1-6烷基、-C(O)C1-6烷基、C1-6烷氧基C(O)-、-COOH、OH、-NRBRC、氘、C3-6单环环烷基、C3-6单环杂环环烷基的基团取代,所述的杂芳基任选进一步被1-3个选自卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-Si(C1-3烷基)3、OH、5-6元杂芳基、C3-6单环环烷基、-S(C1-6烷基)、氘的基团取代;
其他基团定义与上述任一技术方案一致。
9、本发明第十三技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy1选自
Cy2a选自五元环并五元环、五元环并六元环、六元环并五元环、六元环并六元环,所述的Cy2任选进一步被1-5个选自RA的基团取代;或者
Cy2a选自五元杂芳基并六元杂芳基、六元杂芳基并六元杂芳基、五元杂芳基并五元杂芳基、六元杂芳基并五元杂芳基,所述的Cy2任选进一步被1-3个选自卤素、羟基C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、C2-6烯基、C2-6炔基、5-6元杂芳基、-NRBC(O)C1-6烷基、-C(O)NRBC1-6烷基、-C(O)C1-6烷基、C1-6烷氧基C(O)-、-COOH、OH、-NRBRC、氘、C3-6单环环烷基、C3-6单环杂环环烷基的基团取代,所述的杂芳基任选进一步被1-3个选自卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-Si(C1-3烷基)3、OH、5-6元杂芳基、C3-6单环环烷基、-S(C1-6烷基)、氘的基团取代;或者
Cy2a选自五元杂芳基并六元杂芳基、六元杂芳基并六元杂芳基、五元杂芳基并五元杂芳基、六元杂芳基并五元杂芳基,所述的Cy2任选进一步被1-3个选自卤素、-NRBRC、的基团取代;或者
Cy2a选自
/>所述的Cy2任选进一步被1-3个选自卤素、-NRBRC的基团取代;或者
Cy2a选自
本发明第十四技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy1选自
Cy2a选自五元环并五元环、五元环并六元环、六元环并五元环、六元环并六元环,所述的Cy2任选进一步被1-5个选自RA的基团取代;
其他基团定义与前文任一技术方案一致。
本发明第十五技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy1选自
Cy2a选自五元杂芳基并六元杂芳基、六元杂芳基并六元杂芳基、五元杂芳基并五元杂芳基、六元杂芳基并五元杂芳基,所述的Cy2任选进一步被1-3个选自卤素、羟基C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、C2-6烯基、C2-6炔基、5-6元杂芳基、-NRBC(O)C1-6烷基、-C(O)NRBC1-6烷基、-C(O)C1-6烷基、C1-6烷氧基C(O)-、-COOH、OH、-NRBRC、氘、C3-6单环环烷基、C3-6单环杂环环烷基的基团取代,所述的杂芳基任选进一步被1-3个选自卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、-Si(C1-3烷基)3、OH、5-6元杂芳基、C3-6单环环烷基、-S(C1-6烷基)、氘的基团取代;
其他基团定义与前文任一技术方案一致。
本发明第十六技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy1选自
Cy2a选自五元杂芳基并六元杂芳基、六元杂芳基并六元杂芳基、五元杂芳基并五元杂芳基、六元杂芳基并五元杂芳基,所述的Cy2任选进一步被1-3个选自卤素、-NRBRC、的基团取代;
其他基团定义与前文任一技术方案一致。
本发明第十七技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy1选自
Cy2a选自
所述的Cy2任选进一步被1-3个选自卤素、-NRBRC、的基团取代;
其他基团定义与前文任一技术方案一致。
本发明第十八技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy1选自
Cy2a选自
其他基团定义与前文任一技术方案一致。
本发明第十九技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy1选自
Cy2a选自
其他基团定义与前文任一技术方案一致。11、本发明第二十技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy1选自
Cy2a选自
其他基团定义与前文任一技术方案一致。
本发明第二十一技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy2b选自其中*代表Cy2b与的偶联位点;
其他基团定义与前文任一技术方案一致。
本发明第二十二技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy2c选自5元杂芳基、6元杂芳基或者C3-6环烷基,所述的Cy2c任选进一步被1-5个选自RA的基团取代;或者
Cy2c选自所述的Cy2c任选被1-3个选自RA的基团取代;或者/>
Cy2c选自
其他基团定义与前文任一技术方案一致。
本发明第二十三技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy2c选自5元杂芳基、6元杂芳基或者C3-6环烷基,所述的Cy2c任选进一步被1-5个选自RA的基团取代;
其他基团定义与前文任一技术方案一致。
本发明第二十四技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy2c选自所述的Cy2c任选被1-3个选自RA的基团取代;
其他基团定义与前文任一技术方案一致。
本发明第二十五技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
Cy2c选自
其他基团定义与前文任一技术方案一致。
本发明第二十六技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
RA各自独立选自卤素、C1-4烷基、5-6元杂芳基、苯基、-NRBC(O)C1-4烷基、-C(O)NRBC1-4烷基、-C(O)C1-4烷基、CN、=O、-C(O)C1-4烷氧基、C2-6烯基、C2-6炔基、-COOH、OH、-NRBRC、氘、-SH、-S(C1-4烷基)、-S(O)2(C1-4烷基)、C3-6单环环烷基,所述的RA任选进一步被1-3个选自卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、C1-6烷基氨基、-Si(C1-4烷基)3、OH、5-6元杂芳基、C3-6单环环烷基、-S(C1-4烷基)、氘的基团取代;或者
RA各自独立选自卤素、C1-4烷基、5-6元杂芳基、苯基、-NRBC(O)C1-4烷基、-C(O)NRBC1-4烷基、-C(O)C1-4烷基、CN、=O、氨基,所述的RA任选进一步被1-3个选自卤素、C1-2烷基、-Si(C1-2烷基)3的基团取代;
其他基团定义与前文任一技术方案一致。
本发明第二十七技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
RA各自独立选自卤素、C1-4烷基、5-6元杂芳基、苯基、-NRBC(O)C1-4烷基、-C(O)NRBC1-4烷基、-C(O)C1-4烷基、CN、=O、氨基,所述的RA任选进一步被1-3个选自卤素、C1-2烷基、-Si(C1-2烷基)3的基团取代;
其他基团定义与前文任一技术方案一致。
本发明第二十八技术方案,式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中
RB、RC各自独立选自H、氘、-OC(O)CH3或C1-3烷基。
本文前述所述的技术方案中的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy1选自
本文前述所述的技术方案中的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy1选自
本文前述所述的技术方案中的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy1选自
本文前述所述的技术方案中的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy3选自所述的Cy3任选被1-3个选自Rcy3的基团取代。
本文前述所述的技术方案中的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy3选自 所述的Cy3任选被1-3个选自Rcy3的基团取代。
本文前述所述的技术方案中的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy3选自所述的Cy3任选被1-3个选自Rcy3的基团取代,t选自1、2或3,每个Y2各自独立选自-CH2-、-NH-、O、S,Y2中每个H原子可以独立地被Rcy3的基团取代。
本文前述所述的技术方案中的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy3选自所述的Cy3任选被1-3个选自Rcy3的基团取代。
本文前述所述的技术方案中的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy2选自C8-12碳环或者8-12元杂环,所述的Cy2任选进一步被1-3个选自RA的基团取代;进一步,Cy2选自C8-10碳环或者8-10元杂环,所述的Cy2任选进一步被1-2个选自RA的基团取代;进一步,Cy2选自任选进一步被1-5个选自RA的基团取代;进一步,Cy2选自/>任选进一步被1-5个选自RA的基团取代,条件是,D并C环不形成取代或未取代的/>进一步,Cy2选自/>任选进一步被1-5个选自RA的基团取代,条件是,F并E环不形成取代或未取代的/>进一步,Cy2选自任选进一步被1-5个选自RA的基团取代;进一步,Cy2选自5元杂芳基、5元不饱和单环杂环烷基、6元饱和单环杂环烷基,任选进一步被1-5个选自RA的基团取代;进一步,Cy2选自6元不饱和单环杂环烷基,任选进一步被1-5个选自RA的基团取代,条件是不选自/>及/>进一步,Cy2选自/>被1个选自RD的基团取代;进一步,Cy2选自被1-3个选自RE的基团取代;其中,以上*表示*代表与L2的偶联位点。
本文前述所述的式(II)化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy2a选自*代表Cy2a与NH的偶联位点,Cy2a任选进一步被1-3个选自RA的基团取代;
本文前述所述的式(II)化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy2a选自*代表Cy2a与NH的偶联位点,Cy2a任选进一步被1-3个选自RA的基团取代,每个X21、X22、X23、X24各自独立选自-CH-、-CRA-、-CH2-、-CHRA-、-C(RA)2-、-N-、-NH-、-NRA-、O、S、S(O)或S(O)2,每个X25、X26各自独立选自-C-、-CH-、-CRA-或者-N-,且D环为饱和环、部分不饱和环、苯环或者杂芳基环,条件是,D并C环不形成取代或未取代的/> 进一步,Cy2a选自
本文前述所述的式(II)化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy2a选自*代表Cy2a与NH的偶联位点,Cy2a任选进一步被1-3个选自RA的基团取代,每个X31、X32、X33、X34各自独立选自-CH-、-CRA-、-CH2-、-CHRA-、-C(RA)2-、-N-、-NH-、-NRA-、O、S、S(O)或S(O)2,每个X35、X36各自独立选自-C-、-CH-、-CRA-或者-N-,且F环为饱和环、部分不饱和环、苯环或者杂芳环,条件是,F并E环不形成取代或未取代的/>
本文前述所述的式(II)化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy2a选自 *代表Cy2a与NH的偶联位点,Cy2a任选进一步被1-3个选自RA的基团取代。
本文前述所述的式(II)化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy2a选自5元杂芳基、5元不饱和单环杂环烷基、6元饱和单环杂环烷基,Cy2a任选进一步被1-3个选自RA的基团取代。
本文前述所述的式(II)化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy2a选自6元不饱和单环杂环烷基,Cy2a任选进一步被1-3个选自RA的基团取代,条件是Cy2a不选自取代或未取代的及取代或未取代的/>
本文前述所述的式(II)化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy2a选自*代表Cy2a与NH的偶联位点,条件是,
当Cy1选自时,Cy2a被1-3个选自RE的基团取代;或
当Cy1选自Cy2a为(h)时,Cy3被1-5个选自Rcy3的基团取代;或
当Cy1选自Cy2a为(h)时,Cy3选自/>t=2、3或4;或
当Cy1选自时,Cy2a任选进一步被1-3个选自RA的基团取代。
本文前述所述的式(II)化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中Cy2a选自*代表Cy2a与NH的偶联位点,Cy2a任选进一步被1-3个选自RA的基团取代。
本文前述所述的式(II)化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中每个RA各自独立选自卤素、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、5-10元杂芳基、苯基、-NRBC(O)C1-4烷基、-C(O)NRBC1-4烷基、-C(O)C1-4烷基、CN、=O、-C(O)C1-4烷氧基、-COOH、OH、-NRBRC、氘、-SH、-S(C1-4烷基)、-S(O)2(C1-4烷基)、C3-6单环环烷基的基团取代,所述的RA任选进一步被1-3个选自卤素、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、卤代C1-3烷氧基、-Si(C1-3烷基)3、OH、5-6元杂芳基、C3-6单环环烷基、-S(C1-3烷基)、氘的基团取代;进一步,RA各自独立选自卤素、C1-2烷基、5-10元杂芳基、-NRBC(O)C1-4烷基、-NRBC(O)C1-4烷基、CN、苯基,所述的RA任选进一步被1-2个选自卤素、C1-2烷基、C1-2烷氧基、C2-4烯基、C2-4炔基、C3-6单环环烷基、OH、=O、-C(O)C1-2烷基、C1-3烷氧基;
每个RB、RC各自独立选自H、氘、C1-2烷基、卤代C1-2烷基、氘代C1-2烷基;进一步,RB、RC各自独立选自H、氘、C1-2烷基;进一步,RB、RC各自独立选自H、氘。
本文前述所述的式(II)化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中每个RE选自羟基C1-4烷基、卤代C1-4烷基、C1-4烷氧基、C1-4烷氧基-C1-4烷基、C2-4烯基、C2-4炔基、5-6元杂芳基、苯基、-NRBC(O)C1-4烷基、-C(O)NRBC1-4烷基、-C(O)C1-4烷基、=O、-C(O)C1-4烷氧基、-COOH、OH、-NRBRC、氘、-SH、-S(C1-4烷基)、-S(O)2(C1-4烷基)、C3-6单环环烷基、C3-6单环杂环环烷基的基团取代,所述的RE任选进一步被1-3个选自卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、C1-6烷基氨基、卤代C1-4烷氧基、-Si(C1-4烷基)3、OH、5-6元杂芳基、C3-6单环环烷基、-S(C1-4烷基)、氘的基团取代;进一步,RE选自羟基C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基-C1-4烷基、5-6元杂芳基、-NRBC(O)C1-4烷基、-C(O)NRBC1-4烷基、-C(O)C1-4烷基、-C(O)C1-4烷氧基,所述的RE任选进一步被1-3个选自卤素、C1-2烷基。
本发明所述的式(I)的化合物,其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中所述化合物选自以下结构之一:
/>
/>
/>
作为本发明的又一技术方案,本发明提供了一种药物组合物,其含有前述任意一项技术方案所述的化合物,其立体异构体、药学上可接受的盐、溶剂化物、共晶或氘代物,以及药学上可接受的载体和/或赋形剂。
作为本发明的再一技术方案,本发明提供了任意一项技术方案所述的化合物,其立体异构体、药学上可接受的盐、溶剂化物、共晶或氘代物,或者前述组合物在制备治疗PB2介导的疾病的药物中的应用。所述PB2介导的疾病为肿瘤或自身免疫疾病。
合成路线
专利文献WO2010148197A1中介绍了一类PB2抑制剂的制备方法,本领域技术人员可以结合该文献以及已知的有机合成技术制备本发明的化合物,其起始原料为市售化学品和(或)化学文献中所述的化合物。
合成方法一:
通式I-A与I-B化合物在适当的催化剂、碱与溶剂的条件下经过偶连反应得到通式(II)化合物,其中U、L代表相同或不同的离去基团,比如卤素,其中Cy1为
术语
在本发明未特殊说明的情况下,本发明的术语具有以下含义:
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(氘,又称为重氢)、氚(T,又称为超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
Cx-y基团的表达是指包含x至y个碳原子的基团,比如“C1-6烷基”指包含1-6个碳原子的烷基。
“卤素”是指氟(F)、氯(Cl)、溴(Br)、碘(I)或者它们的同位素。
“卤代”或“卤素取代”是指氢原子被一个及以上选自F、Cl、Br、I或者它们的同位素取代,卤素取代基的数量的上限等于被取代基团可被取代的氢数之和,在未作特殊限定下,卤素取代基数量为1至该上限之间的任意整数,优选1-5个卤素取代、1-3卤素取代、1-2个卤素取代、1个卤素取代;当卤素取代基数量大于1时,可以是相同或不同的卤素进行取代。
“卤代C1-6烷基”是指包含1-6个碳原子的烷基中的一个或多个氢被一个或多个卤素原子(如氟、氯、溴、碘)替代的烷基,卤素取代基的数量的上限等于烷基中可被取代的氢数之和,在未作特殊限定下,卤素取代基数量为1至该上限之间的任意整数,优选1-5个卤素取代、1-3卤素取代、1-2个卤素取代或1个卤素取代;当卤素取代基数量大于1时,可以是相同或不同的卤素进行取代;包括但不限于-CF3、-CH2Cl、-CH2CF3、-CCl2、CF3等。
“氘”是指氢(H)的同位素氘。
“氘代”或“氘代物”是指烷基、环烷基、亚烷基、芳基、杂芳基、巯基、杂环烷基、烯基、炔基等基团上的氢原子被至少一个氘原子取代的情形,氘代的数量上限等于被取代基团可被取代的氢数之和,在未作特殊限定下,氘代数量为1至该上限之间的任意整数,优选1-20个氘原子取代、1-10个氘原子取代、1-6个氘原子取代、1-3个氘原子取代、1-2个氘原子取代或1个氘原子取代。
“烷基”是指直链或支链的饱和脂肪烃基,无特殊说明时,为1至20个碳原子的烷基,优选为1至8个碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基,进一步优选1-2个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基等;所述的烷基可以进一步被任意取代基取代。
“烯基”是指包含至少一个碳碳双键(C=C)的直链烃基或支链烃基的烃基,无特殊说明时,主链包含2至18个(如2至8个,进一步如2至6个,再进一步如2至4个)碳原子,包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等;所述的烯基可以任选进一步被任意基团取代。
“炔基”是指含有至少一个碳碳三键(C≡C)直链烃基、支链烃基的烃基,主链包括2至18个(如2至8个,进一步如2至6个,再进一步如2至4个)碳原子。包括但不限于,乙炔基、1-丙炔基、2-丙炔基、丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、4-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基和4-癸炔基等;所述的炔基可以任选进一步被任意取代基取代。
“烷氧基”或“烷基氧基”是指-O-烷基,未特殊限定时,为-O-C1-8烷基,优选为-O-C1-6烷基,更优选为-O-C1-4烷基,进一步优选为-O-C1-2烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基等;所述的烷氧基可以任选进一步被任意取代基取代。
“卤代烷氧基”是指-O-卤代烷基,未特殊限定时,为-O-卤代C1-8烷基,优选为-O-卤代C1-6烷基,更优选为-O-卤代C1-4烷基,进一步优选为-O-卤代C1-2烷基;卤素取代基的数量的上限等于被取代基团可被取代的氢数之和,在未作特殊限定下,卤素取代基数量为1至该上限之间的任意整数,优选1-5个卤素取代、1-3卤素取代、1-2个卤素取代、1个卤素取代;当卤素取代基数量大于1时,可以是相同或不同的卤素进行取代;非限制性实施例包括一氟甲氧基、二氟甲氧基、三氟甲氧基、二氟乙基氧基等。
“C1-6烷基酰基”是指C1-6烷基-C(O)-。非限制性实施例包括甲酰基、乙酰基、丙酰基。
“C1-6烷基磺酰基”是指C1-6烷基-S(O)2-。非限制性实施例包括甲磺酰基、乙磺酰基、丙磺酰基。
“碳环”或“碳环基”是指取代或未取代的饱和、部分不饱和或完全不饱和的非芳香性的或芳香性的烃环,无特殊说明时,指包含有3-15个碳原子的烃环(C3-15碳环,进一步如C3-10碳环,再进一步如C3-8碳环,再进一步如C3-6碳环),可以包含任何稳定的3-、4-、5-、6-、7-或8-元单环或二环或7-、8-、9-、10-、11-、12-、13-、14-或15元二环或多环烃环,二环或三环包含螺环、桥环、并环;其定义包含环烷基、芳基;非限制性实施例包括环丙基、环丁基、环丁烯基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环庚烯基、金刚烷基、环辛基、环辛烯基、环辛二烯基、苯基、萘基、茚满基、蒽基、 所述的碳环可以任选进一步被任意基团取代。
“杂环”或“杂环基”是指取含至少一个杂原子的取代或未取代的饱和、部分不饱和或完全不饱和的非芳香的或芳香性的环,所述的杂原子选自N、P、O、S、Si及其各自的氧化态,无特殊说明时,指包含有3-15个环原子的环(3-15元杂环,进一步如3-10元杂环,再进一步如3-8元杂环),可以包含任何稳定的3-、4-、5-、6-、7-或8-元单环或二环或7-、8-、9-、10-、11-、12-、13-、14-或15元二环或多环,二环或三环包含螺环、桥环、并环;杂环为二环或多环时,至少其中的一个环中包含至少一个杂原子,可以是含杂原子的环与不含杂原子的环形成的二环或多环;当杂环与其他基团连接时,可以是杂原子或碳原子处作为连接点;其包括杂环烷基、杂芳基;非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、二氢噁唑基、四氢噁唑基、四氢噻唑基、四氢吡喃基、呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、吡啶基、嘧啶基、吡喃基、哒嗪基、吡嗪基、吲哚基、喹啉基、异喹啉基、嘌呤基、苯并呋喃基、苯并噻吩基、苯并吡咯基、苯并吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基、 ;所述的杂环可以任选进一步被任意基团取代。
“环烷基”是指取代或未取代的、饱和、部分不饱和或者完全不饱和的非芳香性环的烃环,可以是单环、双环或多环,双环或多环可以是并环、螺环或桥环,无特殊说明时,通常有3至20个碳原子;当为单环环烷基时,优选3-15个碳原子,优选3-10个碳原子,再优选3-8个碳原子,更优选有3-6个碳原子,进一步优选有3-4个碳原子;当为双环或多环环烷基时,优选4-12个碳原子,优选4-11个碳原子,再优选5-11个碳原子,更优选有6-11个碳原子,进一步优选有6-10个碳原子;非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、丁烯基、环戊烯基、环己烯基、 等。
“杂环烷基”是指取代或未取代的、包含至少一个杂原子的饱和、部分不饱和或者完全不饱和的非芳香性环的环,无特殊说明时,杂环烷基为3至20元环,当为单环杂环烷基时,优选3至15元,优选3-10元,再优选3-8元,进一步优选3-6元;当为双环或多环环杂环烷基时,优选4-12元,优选4-11元,再优选5-11元,更优选有6-11元,进一步优选有6-10元;杂环烷基可以是单环、双环或多环,双环或多环可以是桥环、并环和螺环,其中的杂原子选自N、S、O、P、Si杂原子及其氧化态;杂环烷基为双环或多环时,至少其中的一个环中包含至少一个杂原子,可以是含杂原子的环与不含杂原子的环形成的二环或多环;当与其他基团连接时,可以是杂原子或碳原子处作为连接点;非限制性实施例包括氮杂环丁基、吗啉基、哌嗪基、哌啶基、四氢吡喃基、氧杂环丁基、吡喃基、氮杂环戊烯基、氮杂环己烯基、氧杂环戊烯基、氧杂环己烯基等。
“芳基”是指取代的或未取代的5至15元具有芳香性的碳环,包括单环芳香基和稠环芳香基。优选5至10元芳香环,进一步优选5至8元芳香环;芳基环可以稠合于非芳基的环(比如杂芳基、杂环烷基或环烷基环)上,其中芳基环为连接位点,非限制性实施例包含苯基、萘基、蒽基、菲基、
所述的芳基可以任选进一步被任意取代基所取代。
“杂芳环”或“杂芳基”是指取代或未取代的、包含至少一个选自N、S、O、P、Si杂原子及其氧化态的杂原子或基团的、具有芳香性的环,可以是单环、双环或多环,可以是桥环、并环、螺环;当为双环或多环时,可以是杂芳基与非杂芳基环比如环烷基、杂环烷基、芳基稠和,也可以是杂芳基与杂芳基的稠和,其中杂芳基环为连接位点;非限制性实施例包括呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吲哚基、嘌呤基、 等;所述的杂芳基可以任选进一步被任意取代基所取代。
“羧基”是指-C(=O)-OH。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”表示一种或多种本文所述化合物或其立体异构体、溶剂化物、药学上可接受的盐、共晶、氘代物,与其他组成成分的混合物,其中其他组分包含生理学/药学上可接受的载体和/赋形剂。
“载体”指的是:不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性,并能改变药物进入人体的方式和在体内的分布、控制药物的释放速度并将药物输送到靶向器官的体系,非限制性的实例包括微囊与微球、纳米粒、脂质体等。
“赋形剂”指的是:其本身并非治疗剂,用作稀释剂、辅料、粘合剂和/或媒介物,用于添加至药物组合物中以改善其处置或储存性质或允许或促进化合物或药物组合物形成用于给药的单位剂型。如本领域技术人员所已知的,药用赋形剂可提供各种功能且可描述为润湿剂、缓冲剂、助悬剂、润滑剂、乳化剂、崩解剂、吸收剂、防腐剂、表面活性剂、着色剂、矫味剂及甜味剂。药用赋形剂的实例包括但不限于:(1)糖,例如乳糖、葡萄糖及蔗糖;(2)淀粉,例如玉米淀粉及马铃薯淀粉;(3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素、乙酸纤维素、羟丙基甲基纤维素、羟丙基纤维素、微晶纤维素及交联羧甲基纤维素(例如交联羧甲基纤维素钠);(4)黄蓍胶粉;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,例如可可脂及栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨醇、甘露醇及聚乙二醇;(12)酯,例如油酸乙酯及月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁及氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格溶液(Ringer’s solution);(19)乙醇;(20)pH缓冲溶液;(21)聚酯、聚碳酸酯和/或聚酐;及(22)其他用于药物制剂中的无毒相容物质。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“溶剂化物”指本发明化合物或其盐与分子间非共价力结合的化学计量或非化学计量的溶剂形成的物质。当溶剂为水时,则为水合物。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。
具体实施方式
以下将通过实施例对本发明的内容进行详细描述。实施例中未注明具体条件的,按照常规条件的实验方法进行。所举实施例是为了更好地对本发明的内容进行说明,但并不能理解为本发明的内容仅限于所举实例。本领域常规技术人员根据上述发明内容对实施方案进行非本质的改进和调整,仍属于本发明的保护范围。
无特殊说明,原料购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、南京药石、药明康德和百灵威科技等公司。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm;
柱层析一股使用烟台黄海硅胶200-300目硅胶为载体。
THF:四氢呋喃
NBS:N-溴代丁二酰亚胺
DCM:二氯甲烷
Pd(dppf)Cl2:[1,1′-双(二苯基膦基)二茂铁]二氯化钯
TFA:三氟乙酸
DIPEA:N,N-二异丙基乙胺
PE:石油醚
EA:乙酸乙酯
DMF:N,N二甲基甲酰胺
DIBAL-H:二异丁基氢化铝
DAST:二乙胺基三氟化硫
NMP:N-甲基吡咯烷酮
HATU:2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯
X-phos:2-二环己基磷-2,4,6-三异丙基联苯
DCE:1,2二氯乙烷
NIS:N-碘代丁二酰亚胺
DPPA:叠氮磷酸二苯酯
DIEA:N,N-二异丙基乙胺
中间体1:5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧代硼戊烷-2-基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(中间体int-1)
5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine
第一步:5-氟-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(int-1b)
5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine
氮气保护下化合物int-1a(5.0g,36.7mmol)溶于THF(50ml)中,降温至0~5℃,缓慢加入氢化钠(1.76g,44.0mmol),加完0℃下搅拌30min,对甲苯磺酰氯(7.3g,38.5mmol)溶于THF(10ml)中,控温0~10℃缓慢滴加到反应液中,加完自然回温反应15小时。反应完毕缓慢加入冰水(100ml)中淬灭反应,乙酸乙酯(100ml*2)萃取,饱和食盐水洗,无水硫酸钠干燥,过滤浓缩,乙酸乙酯/石油醚(1/6,v/v)重结晶得化合物int-1b(8.5g,80%)。
LC-MS(ESI):m/z=290.1[M+H]+.
第二步:3-溴-5-氟-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(int-1c)
3-bromo-5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine
化合物int-1b(8.5g,29.4mmol)溶于二氯甲烷(85ml)中,分批次加入NBS(10.5g,58.8mmol),加完室温反应18小时,加入硫代硫酸钠水溶液淬灭反应,DCM(100ml*2)萃取两次,合并有机层,水洗,盐水洗,干燥浓缩过硅胶柱纯化(PE/EA=10/1-5/1,v/v)得化合物int-1c(6.5g,60%)。
LC-MS(ESI):m/z=369.1[M+H]+.
第三步:5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧代硼戊烷-2-基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(中间体int-1)
5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine
氮气保护下,化合物int-1c(6.5g,17.6mmol)溶于二氧六环(65ml)中,依次加入乙酸钾(5.17g,52.8mmol),联硼酸频那醇酯(6.7g,26.4mmol),Pd(dppf)Cl2(1.2g,1.7mmol)加完升温至100℃反应16小时,反应完毕过滤,滤液浓缩加水150ml,乙酸乙酯(100ml*2)萃取两次,合并有机层,水洗,盐水洗,干燥浓缩用二氯甲烷/石油醚(0/1-3/1,v/v)过柱纯化得中间体int-1(1.5g,20%)。
LC-MS(ESI):m/z=417.2[M+H]+.
1H NMR(400MHz,CDCl3)δ8.26-8.25(m,1H),8.17(s,1H),8.16(d,2H),7.88-7.86(m,1H),7.27(d,2H),2.37(s,3H),1.35(s,12H).
中间体2:5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环-2-基)-1-三苯甲基-1H-吡唑并[3,4-b]吡啶(Int-2)
5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine
第一步:5-氟-1H-吡唑并[3,4-b]吡啶-3-胺(Int-2-b)
5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine
室温下,将化合物Int-2-a(45g,0.29mol)加入正丁醇(300mL)和水合肼(200mL)的混合溶液中,100℃反应5小时后,将反应液浓缩至剩余约一半体积,过滤,所得固体用异丙醇(200mL)淋洗,固体干燥,得化合物Int-2-b(40g,收率为91%)。
LC-MS(ESI):m/z=153.1[M+H]+.
第二步:3-溴-5-氟-1H-吡唑并[3,4-b]吡啶(Int-2-c)
3-bromo-5-fluoro-1H-pyrazolo[3,4-b]pyridine
室温下,将化合物Int-2-b(40g,0.26mol)加入至三溴甲烷(250mL)中,于室温将亚硝酸叔丁酯(54g,0.52mol)滴加至其中,然后升温至60℃反应2小时,再升温至90℃反应2小时,得到的反应液倒入冰水(1L)中,二氯甲烷(500mL×1)萃取,有机相浓缩干,得到的固体用PE/EA=3/1(v/v,200mL)打浆,过滤,得化合物Int-2-c(38g,收率为65%)。
LC-MS(ESI):m/z=215.0[M+H]+.
第三步:3-溴-5-氟-1-三苯甲基-1H-吡唑并[3,4-b]吡啶(Int-2-d)
3-bromo-5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridine
室温下,将化合物Int-2-c(15g,69.7mmol)加入DMF(100mL)中,冷却至0℃,加入碳酸钾(24g,174mmol),搅拌反应20分钟,将三苯基氯甲烷(25g,89.7mmol)加至其中,自然回至室温反应16小时,将反应液倒入(500mL)水中,用EA(300mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA,50/1~10/1,v/v)得化合物Int-2-d(10g,产率31%)。
第四步:5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环-2-基)-1-三甲苯基-1H-吡唑并[3,4-b]吡啶(Int-2)
5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine
室温下,将化合物Int-2-d(1g,2.2mmol)加入乙二醇二甲醚(10mL)中,依次加入联硼酸频那醇酯(1.1g,4.4mmol)、乙酸钾(0.65g,6.6mmol)、Pd(dppf)Cl2(150mg,0.2mmol)。氮气置换并保护,微波95℃反应1小时,将反应液倒入(40mL)水中,用乙酸乙酯(40mL×1)萃取,有机相浓缩干,得粗品化合物Int-2(1.2g,),直接用于下一步。
实施例1(1R,2S,3S,4R)-3-((E)-3-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)丙烯酰氨基)双环[2.2.2]辛烷-2-羧酸(化合物1)
(1R,2S,3S,4R)-3-((E)-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acrylamido)bicyclo[22.2]octane-2-carboxylic acid(化合物1)
第一步:(E)-3-(5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)丙烯酸叔丁酯(1c)
tert-butyl(E)-3-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acrylate(1c)
向化合物1a(2.0g,5.43mmol)的乙腈(20ml)溶液中加入化合物1b(1.04g,8.1mmol),三乙胺(1.64g,16.3mmol)和醋酸钯(0.12g,0.54mmol),将混合物在85℃下搅拌16小时。反应完成后,将混合物用蒸馏水(30mL)稀释,并用乙酸乙酯(50mL*3)萃取。用蒸馏水和饱和盐水洗涤有机相,用无水硫酸钠干燥,浓缩。通过硅胶柱分离纯化(PE/EA=10/1-5/1,v/v)得到标题化合物1c,呈棕色固体(1.3g,57%)。
LC-MS(ESI):m/z=417.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.45(t,J=2.8Hz,1H),8.44(s,1H),8.00(s,1H),7.98(s,1H),7.70(d,J=16.0Hz,1H),7.45(s,1H),7.43(s,1H),6.60(d,J=16.0Hz,1H),2.35(s,3H),1.45(s,9H).
第二步:(E)-3-(5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)丙烯酸(1d)
(E)-3-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acrylic acid(1d)
向化合物1c(0.5g,1.20mmol)的二氯甲烷(10mL)溶液中加入TFA(4ml),将混合物在室温下反应16小时。反应完成后,将反应液用二氯甲烷(20mL)稀释。用蒸馏水和饱和盐水洗涤有机相,用无水硫酸钠干燥,浓缩,得到标题化合物1d,呈淡黄色固体(340mg,79%)。
LC-MS(ESI):m/z=361.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),8.59(s,1H),8.44(s,1H),8.42(t,J=2.8Hz,1H),8.01(s,1H),7.99(s,1H),7.74(d,J=16.4Hz,1H),7.45(s,1H),7.43(s,1H),6.63(d,J=16.4Hz,1H),2.35(s,3H).
第三步:(1R,2S,3S,4R)-3-((E)-3-(5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)丙烯酰氨基)双环[2.2.2]辛烷-2-羧酸乙酯(1f)
ethyl(1R,2S,3S,4R)-3-((E)-3-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acrylamido)bicyclo[2.2.2]octane-2-carboxylate(1f)
向化合物1d(0.35g,0.94mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入1e(0.26g,1.13mmol)、2-(7-氮杂苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(0.43g,1.13mmol)和N,N-二异丙基乙胺(0.36g,2.82mmol),将混合物在室温下反应4小时。反应完成后,将混合物用蒸馏水(30mL)稀释,并用二氯甲烷(20mL*3)萃取。用蒸馏水和饱和盐水洗涤有机相,用无水硫酸钠干燥,浓缩。得到标题化合物1f,呈淡黄色固体(450mg,89%)。
LC-MS(ESI):m/z=540.2[M-H]+
1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.43(s,1H),8.23(d,J=9.2Hz,1H),8.01~7.96(m,3H),7.51(d,J=16.0Hz,1H),7.45(s,1H),7.43(s,1H),6.78(d,J=16.0Hz,1H),4.27(t,J=6.4Hz,1H),4.17-4.00(m,2H),2.89(s,1H),1.98(s,1H),2.35(s,3H),1.67~1.37(m,9H),1.20-1.58(m,3H).
第四步:(1R,2S,3S,4R)-3-((E)-3-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)丙烯酰氨基)双环[2.2.2]辛烷-2-羧酸(化合物1)
(1R,2S,3S,4R)-3-((E)-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acrylamido)bicyclo[22.2]octane-2-carboxylic acid(化合物1)
将化合物1f(0.2g,0.37mmol)溶于四氢呋喃(6mL)/甲醇(2ml)和蒸馏水(2ml)中,再加入一水合氢氧化锂(0.12g,2.96mmol);然后,在50℃下反应5小时。反应完成后,加1N盐酸调pH=3,减压除去溶剂。通过柱层析(PE/EA=10/1-1/2,v/v)得到白色固体目标化合物1(78mg,59%)。
LC-MS(ESI):m/z=358.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.31(s,1H),8.11(d,J=10.0Hz,1H),7.98(s,1H),7.83(d,J=7.2Hz,1H),7.51(d,J=16.0Hz,1H),6.63(d,J=16.0Hz,1H),4.25(s 1H),2.30(s,1H),1.93(s,1H),1.71~1.23(m,9H).
实施例2(1R,2S,3S,4R)-3-(3-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)丙炔酰氨基)双环[2.2.2]辛烷-2-羧酸(化合物2)
(1R,2S,3S,4R)-3-(3-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)propiolamido)bicyclo[2.22]octane-2-carboxylic acid
第一步:5-氟-3-碘-1H-吡咯并[2,3-b]吡啶(2b)
5-fluoro-3-iodo-1H-pyrrolo[2,3-b]pyridine(2b)
将化合物2a(0.2g,1.47mmol)溶于甲醇(10ml)和蒸馏水(0.5ml)中,加入氢氧化钠(0.06g,1.47mmol),碘化钾(0.24g,1.47mmol)和碘单质(0.37g,1.47mmol);然后,在室温下反应2小时。反应完成后,将混合物用蒸馏水(30mL)稀释,并用乙酸乙酯(30mL*3)萃取。用蒸馏水和饱和盐水洗涤有机相,用无水硫酸钠干燥,浓缩。通过硅胶柱分离(PE/EA=10/1-5/1,v/v)纯化得到标题化合物2b,呈棕色固体(0.35g,90%)。
LC-MS(ESI):m/z=263.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.24(s,1H),7.81(s,1H),7.55(dd,J=9.0,2.6Hz,1H).
第二步:5-氟-3-碘-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(2c)
5-fluoro-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine(2c)
将化合物2b(0.2g,0.76mmol)溶于N-甲基吡咯烷酮(10mL)中,加入叔丁醇钠(0.87g,0.91mmol)和4-甲苯磺酰氯(0.17g,0.91mmol);然后,在室温下反应2小时。反应完成后,将混合物用蒸馏水(30mL)稀释,并用乙酸乙酯(30mL*3)萃取。用蒸馏水和饱和盐水洗涤有机相,用无水硫酸钠干燥,浓缩。通过硅胶柱分离纯化(PE/EA=10/1-5/1,v/v)得到标题化合物2c,呈淡棕色固体(0.3g,95%)。
LC-MS(ESI):m/z=417.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.24(s,1H),8.00(d,J=8.4Hz,2H),7.74(dd,J=8.5,2.6Hz,1H),7.43(d,J=8.2Hz,2H),2.35(s,3H).
第三步:3-(5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)丙炔酸甲酯(2e)
methyl 3-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propiolate(2e)
向化合物2c(1.0g,2.4mmol)的乙腈(10ml)溶液中加入化合物2d(0.60g,7.2mmol),三乙胺(0.73g,7.2mmol),碘化亚铜(0.046g,0.24mmol)和四(三苯基膦)钯(0.139g,0.12mmol),将混合物在80℃下搅拌16小时。反应完成后,将混合物用蒸馏水(30mL)稀释,并用乙酸乙酯(30mL*3)萃取。用蒸馏水和饱和盐水洗涤有机相,用无水硫酸钠干燥,浓缩。通过硅胶柱分离纯化(PE/EA=10/1-1/2,v/v)得到标题化合物2e(0.08g,9%)。
LC-MS(ESI):m/z=373.1[M+H]+
第四步:3-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)丙炔酸(2f)
3-(5-fluoro-1H-pyrrolo[2,3-b]pyfidin-3-yl)propiolic acid(2f)
将化合物2e(0.08g,0.22mmol)溶于四氢呋喃(6mL)/甲醇(2ml)和蒸馏水(2ml)中,再加入一水合氢氧化锂(0.07g,1.72mmol);然后,在50℃下反应5小时。反应完成后,加水20mL,加1N盐酸调pH=3,再加DCM(20mL*3)萃取,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到类白色固体2f(0.04g,89%)。
LC-MS(ESI):m/z=205.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.68(s,1H),8.36(s,1H),8.28(s,1H),7.89(dd,J1=2.4Hz,J2=8.8Hz,1H).
第五步:(1R,2S,3S,4R)-3-(3-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)丙炔酰氨基)双环[2.2.2]辛烷-2-羧酸乙酯(2h)
ethyl(1R,2S,3S,4R)-3-(3-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)propiolamido)bicyclo[2.2.2]octane-2-carboxylate(2h)
向化合物2f(40mg,0.20mmol)的N,N-二甲基甲酰胺(6mL)溶液中加入2g(55mg,0.24mmol)、2-(7-氮杂苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(91mg,0.24mmol)和N,N-二异丙基乙胺(77mg,0.6mmol),将混合物在在室温下反应4小时。反应完成后,将混合物用蒸馏水(30mL)稀释,并用二氯甲烷(20mL*3)萃取。用蒸馏水和饱和盐水洗涤有机相,用无水硫酸钠干燥,浓缩。得到标题化合物2h(0.03g,40%)。
LC-MS(ESI):m/z=384.2[M+H]+
第六步:(1R,2S,3S,4R)-3-(3-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)丙炔酰氨基)双环[2.2.2]辛烷-2-羧酸(化合物2)
(1R,2S,3S,4R)-3-(3-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)propiolamido)bicyclo[2.2.2]octane-2-carboxylic acid(化合物2)
将化合物2h(0.03g,0.08mmol)溶于四氢呋喃(4mL)/甲醇(1ml)和蒸馏水(1ml)中,再加入一水合氢氧化锂(0.01g,0.24mmol);然后,在50℃下反应5小时。反应完成后,加1N盐酸调pH=3,旋干。通过柱层析(PE/EA=10/1-1/2,v/v)分离得到白色固体目标化合物2(7mg,65%)。
LC-MS(ESI):m/z=356.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.56(d,J=7.2Hz,1H),8.34(t,J=2.4Hz,1H),8.13(s,1H),7.98(dd,J1=2.4Hz,J2=8.8Hz,1H),4.24(t,J=6.4Hz,1H),4.24(t,J=6.0Hz,1H),1.93(s,1H),1.67-1.36(m,9H).
实施例3
(2S,3S)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)咪唑并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物3)
(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:1-氨基-1H-咪唑-2-羧酸乙酯(3b)
ethyl 1-amino-1H-imidazole-2-carboxylate
氮气保护下,化合物3a(5.0g,35.7mmol)溶于四氢呋喃(100ml)中,冰浴降温至0~5℃,分批次加入钠氢(1.7g,42.8mmol,60%含量),加完控温0~5℃搅拌30分钟,再加入2,4-二硝基苯基羟胺(10.6g,53.6mmol),加完升温至室温搅拌15小时。反应完毕将反应液缓慢倾倒入200ml冰水中,乙酸乙酯(150ml*4)萃取,合并乙酸乙酯相,饱和食盐水洗,无水硫酸钠干燥,过滤,滤液减压浓缩后残留物用柱层析分离纯化(石油醚:乙酸乙酯(v/v)=10∶1~1∶1)得到化合物3b(3.6g,65%)。
LC-MS(ESI):m/z=156.1[M+H]+.
第二步:1-(二(甲氧羰基)氨基)-1H-咪唑-2-羧酸乙酯(3c)
ethyl 1-(bis(methoxycarbonyl)amino)-1H-imidazole-2-carboxylate
化合物3b(3.6g,23.2mmol)溶于四氢呋喃(100ml)和水(20ml)的混合溶剂中,加入碳酸钠(12.2g,116.0mmol),控温0~5℃滴加氯甲酸甲酯(8.7g,92.8mmol),加完自然回温反应3小时,反应完毕过滤,滤液用乙酸乙酯(100ml*2)萃取,合并乙酸乙酯相,饱和食盐水洗,无水硫酸钠干燥,过滤,滤液减压浓缩后残留物用柱层析分离纯化(石油醚:乙酸乙酯(v/v)=10∶1~5∶1)得到化合物3c(4.2g,67%)。
LC-MS(ESI):m/z=272.1[M+H]+.
第三步:咪唑并[2,1-f][1,2,4]三嗪-2,4(1H,3H)-二酮(3d)
imidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione
在120ml封管中加入化合物3c(4.2g,15.5mmol),异丙醇(20ml),氨水(60ml,28%~30%),密封后升温至110℃反应15小时,反应完毕冷却至室温后减压浓缩,浓缩残留物用乙醚与甲醇10∶1(20ml,v/v)混合体系打浆,过滤,滤饼用乙醚(5ml)淋洗,滤饼干燥后得化合物3d(1.2g,51%)。
LC-MS(ESI):m/z=151.1[M-H]-.
第四步:2,4-二氯咪唑并[2,1-f][1,2,4]三嗪(3e)
2,4-dichloroimidazo[2,1-f][1,2,4]triazine
在48ml封管中加入化合物3d(1.2g,7.9mmol),三乙胺盐酸盐(543.5mg,3.9mmol),三氯氧磷(30ml),加完密封后升温至110℃反应23h,反应完毕,冷却至室温后减压浓缩,残留物用柱层析分离纯化(二氯甲烷∶甲醇(v/v)=1∶0~20∶1)得到化合物3e(720mg,48%)。
第五步:(2S,3S)-3-((2-二氯咪唑并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(3f)
Ethyl-(2S,3S)-3-((2-chloroimidazo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
化合物3e(720mg,3.8mmol)溶于异丙醇(15ml)中,加入DIPEA(1.5g,11.4mmol),乙基-(2S,3S)-3-氨基二环[2.2.2]辛烷-2-甲酸基酯盐酸(977.0mg,4.1mmol)加完升温至70℃反应6小时,反应完毕直接减压浓缩,残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物3f(870mg,66%)。
LC-MS(ESI):m/z=350.1[M+H]+.
第六步:(2S,3S)-3-((2-(5-氟-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)咪唑并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(3g)
Ethyl-(2S,3S)-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
化合物3f(450.0mg,1.3mmol)溶于1,4-二氧六环(5ml)和水(1ml)的混合溶剂中,加入中间体1(650mg,1.5mmol),碳酸钾(538mg,3.9mmol),Pd(dppf)Cl2(95mg,0.13mmol),加完用微波反应器120℃反应1小时,反应完毕,过滤,滤液浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~5∶1)得到化合物3g(110mg,14%)。
LC-MS(ESI):m/z=604.2[M+H]+.
第七步:(2S,3S)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)咪唑并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物3)
(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
化合物3g(110mg,0.18mmol)溶于甲醇(5ml)中,加入氢氧化锂(70.5mg,1.7mmol溶于2ml水),加完升温至60℃反应5小时,反应完毕用1N盐酸调PH=5~6后用二氯甲烷(50ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶1)得到化合物3(24.0mg,32%)。
LC-MS(ESI):m/z=422.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.31(s,2H),8.73(d,1H),8.52-8.48(m,1H),8.32-8.30(m,1H),8.23(d,1H),8.10(s,1H),7.58(s,1H),4.85-4.81(m,1H),3.03(d,1H),2.02(s,2H),1.81-1.39(m,8H).
实施例4:(1R,2S,3S,4R)-3-((7-乙酰氨基-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基]吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物4)
(1R,2S,3S,4R)-3-((7-acetamido-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid
第一步:(1R,2S,3S,4R)-3-(((7-乙酰氨基-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(4a)
Ethyl(1R,2S,3S,4R)-3-((7-acetamido-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将18c(300mg,0.63mmol)溶于二氧六环(20mL)中,加入乙酰胺(186mg,3.15mmol),磷酸钾(400mg,1.89mmol),碘化亚铜(24mg,0.13mmol)和反-(1R,2R)-N,N′-二甲基1,2-环己烷二胺(18mg,0.13mmol),氮气保护,110℃反应4小时,浓缩后用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=1∶5~1∶2)得到标题化合物(4a),粗品,淡黄色液体(130mg,产率50%)。
LCMS m/z=406.16[M+1]
第二步:(1R,2S,3S,4R)-3-((7-乙酰氨基-2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基]吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(4b)
ethyl(1R,2S,3S,4R)-3-((7-acetamido-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将(4a)(100mg,0.25mmol)溶于二氧六环中(10mL),加入5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(156mg,0.38mmol),碳酸钾(104mg,0.75mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯化钯(50mg,0.07mmol),再加入水(1mL),氮气保护,微波120℃反应1小时,浓缩后用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=1∶5~1∶2)得到标题化合物(4b),黄色固体(60mg,产率36%)。
LCMS m/z=660.23[M+1]
第三步:(1R,2S,3S,4R)-3-((7-乙酰氨基-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基]吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物4)
(1R,2S,3S,4R)-3-((7-acetamido-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid
将(4b)(60mg,0.09mmol)溶于甲醇中(10mL),加入水(5mL),氢氧化锂(22mg,0.9mmol),60℃反应2小时,用1N盐酸调节ph=5~6,加入水(20mL),用二氯甲烷萃取(50mL×3),合并有机相,有机相用饱和氯化钠水溶液洗涤(50mL),无水硫酸钠干燥,浓缩得到的粗品化合物用液相制备柱分离提纯(液相制备条件:C18反相制备柱,流动相为含0.1%三氟乙酸的去离子水(A),乙腈(B),梯度洗脱,B含量=5%~50%,洗脱时间15min,流速12mL/min,柱温:30℃);得到标题化合物(化合物4)(10mg,21%,保留时间约为6min)。
1H NMR(400MHz,DMSO-d6)δ12.18(d,2H),9.97(s,1H),8.65-8.60(m,1H),8.29-8.24(m,2H),7.84(d,1H),6.93(d,1H),6.64(d,1H),4.83-4.76(m,1H),2.76(d,1H),2.21(s,3H),2.05-2.02(m,2H),1.79-1.46(m,8H).
MS M/Z(ESI):m/z=478.19(M+1)
实施例5:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-6-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物5)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:(1R,2S,3S,4R)-3-(((2-氯-6-碘吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(5a)
Ethyl ethyl(1R,2S,3S,4R)-3-((2-chloro-6-iodopyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将7f(300mg,0.7mmol)溶于二氧六环(20mL)中,加入碘化钠(300mg,0.7mmol),碘化亚铜(50mg,0.27mmol),(1R,2R)-N1,N2-二甲基环己烷-1,2-二胺(50mg,0.35mmol),氮气保护,100℃反应4小时,浓缩后用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=0.1∶1~0.3∶1),得到标题化合物(5a),黄色固体(260mg,产率70%)
LCMS m/z=475.03[M+1]
第二步:(1R,2S,3S,4R)-3-(((2-氯-6-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]-2-辛烷羧酸乙酯(5b)
ethyl(1R,2S,3S,4R)-3-((2-chloro-6-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将5a(260mg,0.55mmol)溶于DMF(20mL)中,加入碘化亚铜(314mg,1.65mmol),2,2-二氟-2-(氟磺酰基)乙酸甲酯(1056mg,5.5mmol),氮气保护,110℃反应4小时,加入水(30mL),用乙酸乙酯萃取(30mL×3),水洗(30mL×3),无水硫酸钠干燥,用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=0.1∶1~0.3∶1),得到标题化合物(5b),淡黄色固体(180mg,产率78.5%)。
LCMS m/z=417.12[M+1]
第三步:
(1R,2S,3S,4R)-3-((2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基)-6-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(5c)
ethyl(1R,2S,3S,4R)-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将5b(180mg,0.43mmol)溶于二氧六环中(10mL),加入5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(268mg,0.65mmol),碳酸钾(178mg,1.29mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯化钯(50mg,0.07mmol),再加入水(1mL),氮气保护,微波120℃反应1小时,浓缩后用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=1∶5~1∶2)得到标题化合物(5c),黄色固体(80mg,产率27%)。
LCMS m/z=671.02[M+1]
第四步:
(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-6-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物5)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
将5c(80mg,0.12mmol)溶于甲醇中(10mL),加入水(5mL),氢氧化锂(29mg,1.2mmol),60℃反应2小时,用1N盐酸调节ph=5~6,加入水(20mL),用二氯甲烷萃取(50mL×3),合并有机相,有机相用饱和氯化钠水溶液洗涤(50mL),无水硫酸钠干燥,浓缩得到的粗品化合物用液相制备柱分离提纯(液相制备条件:C18反相制备柱,流动相为含0.1%三氟乙酸的去离子水(A),乙腈(B),梯度洗脱,B含量=5%~50%,洗脱时间15min,流速12mL/min,柱温:30℃);得到标题化合物(化合物5)(30mg,51%,保留时间约为6.5min)。
1H NMR(400MHz,DMSO-d6)δ12.28(d,2H),8.54-8.50(m,1H),8.30(d,1H),8.26(s,1H),8.23(d,1H),8.18(d,1H),7.35(s,1H),4.82-4.78(m,1H),2.72(d,1H),2.05-2.02(m,2H),1.82-1.42(m,8H).
MS M/Z(ESI):m/z=489.16(M+1)
实施例6:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物6)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:4-(1-甲基-1H-吡唑-4-基)-1H-吡咯-2-羧酸甲酯(6b)
methyl 4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-2-carboxylate
室温下,将化合物6a(3g,14.7mmol)加入二氧六环(60mL)和水(6mL)的混合溶液中,依次加入1-甲基-1H-吡唑-4-硼酸频哪醇酯(4.3g,20.6mmol)、醋酸钾(4.3g,44.1mmol)、Pd(dppf)Cl2(150mg,0.2mmol)。氮气置换并保护,100℃反应4小时,将反应液倒入200mL水中,用乙酸乙酯(200mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA,5/1~1/1,v/v),得化合物6b(2g,产率65%)。
LC-MS(ESI):m/z=206.1[M+H]+.
第二步:1-氨基-4-(1-甲基-1H-吡唑-4-基)-1H-吡咯-2-羧酸甲酯(6c)
methyl 1-amino-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-2-carboxylate
室温下,将化合物6b(1.7g,8.3mmol)加入至DMF(250mL)中,氮气保护,冷却至0℃,将氢化钠(0.4g,10.0mmol)于0-5℃分批加入其中,自然升温反应1小时,将二苯基磷酰羟胺(2.4g,10.0mmol)加入其中,室温反应1小时,将反应液倒入冰水(1L)中,乙酸乙酯(300mL×1)萃取,有机相浓缩干,得化合物6c(1.5g,产率82%)。
LC-MS(ESI):m/z=221.1[M+H]+.
第三步:1-((甲氧羰基)氨基)-4-(1-甲基-1H-吡唑-4-基)-1H-吡咯-2-羧酸甲酯(6d)
Methyl-1-((methoxycarbonyl)amino)-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-2-carboxylate
室温下,将化合物6c(1.5g,6.8mmol)加入DCM(30mL)中,冷却至0℃,氮气保护,加入吡啶(0.65g,8.2mmol),将氯甲酸甲酯(0.77g,8.2mmol)于0-2℃滴加至其中,自然升温至室温反应1小时,将反应液倒入(100mL)水中,用DCM(50mL×1)萃取,有机相浓缩干,得化合物6d(1.7g,产率90%)。
LC-MS(ESI):m/z=279.1[M+H]+.
第四步:6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-2,4(1H,3H)-二酮(6e)
6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione
室温下,将化合物6d(1g,3.6mmol)加入二氧六环(10mL)和氨水(50mL)的混合溶液中,封管加热至120℃反应5小时,反应液冷却至室温,将反应液浓缩干,用异丙醇(50mL)打浆,过滤,固体干燥,得化合物6e(0.5g,产率61%)。
LC-MS(ESI):m/z=232.1[M+H]+.
第五步:2,4-二氯-6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪(6f)
2,4-dichloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine
室温下,将化合物6e(0.5g,2.2mmol)加入甲苯(20mL)中,依次加入三氯氧磷(0.8g,5.5mmol),DIPEA(0.8g,6.6mmol),130℃反应5小时,将反应液冷却至室温,倒入50mL冰水中,用乙酸乙酯(30mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA,10/1~5/1,v/v),得化合物6f(100mg,产率17%)。
LC-MS(ESI):m/z=269.1[M+H]+.
第六步:(1R,2S,3S,4R)-3-((2-氯-6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(6g)
(1R,2S,3S,4R)-ethyl-3-((2-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物6f(0.1g,0.37mmol)加入异丙醇(10mL)中,依次加入(1R,2S,3S,4R)-3-氨基双环[2.2.2]辛烷-2-羧酸乙酯盐酸盐(0.1g,0.44mmol)、DIPEA(0.1g,0.81mmol)。90℃反应2小时,将反应液浓缩干,倒入50mL水中,用乙酸乙酯(50mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA,10/1~2/1,v/v),得化合物6g(80mg,产率51%)。
LC-MS(ESI):m/z=429.2[M+H]+.
第七步:((1R,2S,3S,4R)-3-((2-(5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(6h)
(1R,2S,3S,4R)-ethyl-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物6g(80mg,0.19mmol)加入二氧六环(10mL)和水(1mL)的混合溶液中,依次加入5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环-2-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(93mg,0.22mmol)、碳酸钾(26mg,0.38mmol)、Pd(dppf)Cl2(20mg,0.027mmol)。微波120℃反应1小时,将反应液倒入30mL水中,用乙酸乙酯(30mL×1)萃取,有机相浓缩干,制备板纯化(PE/EA,3/1,v/v),得化合物6h(20mg,产率15%)。
第八步:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物6)(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
室温下,向化合物6h(20mg,0.03mmol)中依次加入THF(2mL)、水(1mL),氢氧化钠(23mg,0.6mmol)。室温反应18小时,将反应液用6N盐酸调节pH至5-6,反应液浓缩干,制备板分离纯化(DCM/MeOH,10/1,v/v),得到化合物6(4mg,产率27%)
LC-MS(ESI):m/z=501.2[M+H]+.
1H NMR(400MHz,CD3OD)δ8.61-8.56(m,1H),8.28(s,1H),8.18-8.17(m,1H),7.84-7.82(m,2H),7.73(s,1H),7.10(s,1H),4.90-4.89(m,1H),3.93(s,3H),2.79-2.78(m,1H),2.13-2.08(m,2H),1.98-1.86(m,3H),1.76-1.68(m,3H),1.59-1.56(m,2H).
实施例7:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-6-乙烯基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物7)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:1-氨基-4-溴-1H-吡咯-2-羧酸甲酯(7b)
methyl 1-amino-4-bromo-1H-pyrrole-2-carboxylate
室温下,将化合物6a(12.0g,58.8mmol)加入至DMF(300mL)中,氮气保护,冷却至0℃,将氢化钠(2.8g,70.6mmol)于0-5℃分批加入其中,自然升温反应1小时,将二苯基磷酰羟胺(15.2g,64.7mmol)加入其中,室温反应1小时,将反应液倒入冰水(1.5L)中,乙酸乙酯(500mL×1)萃取,有机相浓缩干,得化合物7b(12g,产率94%)。。
LC-MS(ESI):m/z=220.1[M+H]+.
第二步:4-溴-1-((甲氧羰基)氨基)-1H-吡咯-2-羧酸甲酯(7c)
methyl 4-bromo-1-((methoxycarbonyl)amino)-1H-pyrrole-2-carboxylate
室温下,将化合物7b(12.0g,55.0mmol)加入DCM(120mL)中,冷却至0℃,氮气保护,加入吡啶(8.7g,110.1mmol),将氯甲酸甲酯(6.2g,66.0mmol)于0-2℃滴加至其中,自然回至室温反应1小时,将反应液倒入(150mL)水中,用DCM(80mL×1)萃取,有机相浓缩干,得化合物7c(12g,产率79%)。
LC-MS(ESI):m/z=278.1[M+H]+.
第三步:6-溴吡咯并[2,1-f][1,2,4]三嗪-2,4(1H,3H)-二酮(7d)
6-bromopyrrolo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione
室温下,将化合物7c(12g,43.3mmol)加入二氧六环(25mL)和氨水(75mL)的混合溶液中,封管加热至120℃反应5小时,反应液冷却至室温,将反应液浓缩干,用异丙醇(50mL)打浆,过滤,固体干燥,得化合物7d(8g,产率80%)。
LC-MS(ES):m/z=231.1[M+H]+.
第四步:6-溴-2,4-二氯吡咯并[2,1-f][1,2,4]三嗪(7e)
6-bromo-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine
室温下,将化合物7d(7.0g,30.4mmol)加入三氯氧磷(70mL)中、加入三乙胺盐酸盐(12.5g,91.2mmol),100℃反应16小时,将反应液冷却至室温,浓缩除去三氯氧磷,浓缩液倒入(200mL)冰水中,用乙酸乙酯(200mL×1)萃取,有机相浓缩干,得化合物7e(5g,产率62%)。
第五步:(1R,2S,3S,4R)-3-((6-溴-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(7f)(1R,2S,3S,4R)-ethyl-3-((6-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物7e(1.0g,3.7mmol)加入异丙醇(20mL)中,依次加入(1R,2S,3S,4R)-3-氨基双环[2.2.2]辛烷-2-羧酸乙酯盐酸盐(1.0g,4.4mmol)、DIPEA(1.0g,8.1mmol)。90℃反应2小时,将反应液浓缩干,倒入(50mL)水中,用乙酸乙酯(50mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA,10/1~2/1,v/v),得化合物7f(1g,产率63%)。
LC-MS(ESI):m/z=428.1[M+H]+.
第六步:(1R,2S,3S,4R)-3-((2-氯-6-乙烯基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(7g)
(1R,2S,3S,4R)-ethyl-3-((2-chloro-6-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物7f(1g,2.3mmol)加入二氧六环(20mL)和水(2mL)的混合溶液中,依次加入乙烯基硼酸频哪醇酯(0.4g,2.5mmol)、碳酸钾(0.8g,5.8mmol)、Pd(dppf)Cl2(150mg,0.2mmol)。氮气置换并保护,100℃反应16小时,将反应液倒入(40mL)水中,用乙酸乙酯(40mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA,5/1~1/1,v/v),得化合物7g(0.3g,产率35%)。
LC-MS(ESI):m/z=375.1[M+H]+.
第七步:(1R,2S,3S,4R)-3-((2-(5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)-6-乙烯基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(7h)
(1R,2S,3S,4R)-ethyl-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物7g(300mg,0.8mmol)加入二氧六环(5mL)和水(0.5mL)的混合溶液中,依次加入5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环-2-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(400mg,0.96mmol)、碳酸钾(220mg,1.6mmol)、Pd(dppf)Cl2(30mg,0.04mmol)。微波120℃反应1小时,将反应液倒入(30mL)水中,用乙酸乙酯(30mL×1)萃取,有机相浓缩干,柱层析纯化((PE/EA,10/1~2/1,v/v),得化合物7h(200mg,产率40%)。
第八步:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-6-乙烯基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸((化合物7)(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
室温下,向化合物7h(50mg,0.08mmol)中依次加入THF(2mL)、水(1mL),氢氧化钠(63mg,0.16mmol)。室温反应18小时,将反应液用6N盐酸调节pH至5-6,反应液浓缩干,制备板分离纯化(DCM/MeOH,10/1,v/v),得到化合物7(20mg,产率56%)
LC-MS(ESI):m/z=447.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.52-8.49(s,1H),8.29-8.28(m,1H),8.18-8.17(m,1H),7.92-7.70(m,1H),7.83-7.82(m,1H),7.10-7.09(m,1H),6.76-6.69(m,1H),5.64-5.59(m,1H),5.16-5.13(m,1H),4.81-4.77(m,1H),2.77-2.73(m,1H),2.03(m,2H),1.81-1.74(m,3H),1.62-1.58(m,3H),1.49-1.42(m,2H).
实施例8:(1R,2S,3S,4R)-3-((6-环丙基-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物8)
(1R,2S,3S,4R)-3-((6-cyclopropyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:(1R,2S,3S,4R)-3-((2-氯-6-环丙基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(8b)
(1R,2S,3S,4R)-ethyl-3-((2-chloro-6-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物7f(1g,2.3mmol)加入DMF(50mL)和水(5mL)的混合溶液中,依次加入环丙基基硼酸(0.5g,5.9mmol)、碳酸钾(1g,6.9mmol)、Pd(dppf)Cl2(150mg,0.2mmol)。氮气置换并保护,100℃反应16小时,将反应液倒入(200mL)水中,用乙酸乙酯(200mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA,5/1~1/1,v/v),得化合物8b(0.2g,产率22%)。
LC-MS(ESI):m/z=389.2[M+H]+.
第二步:(1R,2S,3S,4R)-3-((6-环丙基-2-(5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(8c)
(1R,2S,3S,4R)-ethyl-3-((6-cyclopropyl-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物8b(200mg,0.5mmol)加入二氧六环(5mL)和水(0.5mL)的混合溶液中,依次加入5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环-2-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(400mg,0.96mmol)、碳酸钾(220mg,1.6mmol)、Pd(dppf)Cl2(30mg,0.04mmol)。微波120℃反应1小时,将反应液倒入(50mL)水中,用乙酸乙酯(50mL×1)萃取,有机相浓缩干,柱层析纯化((PE/EA,10/1~2/1,v/v),得化合物8c(30mg,产率10%)。
第八步:(1R,2S,3S,4R)-3-((6-环丙基-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物8)
(1R,2S,3S,4R)-3-((6-cyclopropyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
室温下,向化合物8c(30mg,0.05mmol)中依次加入THF(2mL)、水(1mL),氢氧化钠(56mg,1.5mmol)。室温反应18小时,将反应液用6N盐酸调节pH至5-6,反应液浓缩后用EA(20mL×1)萃取,有机相浓缩干,制备板分离纯化(DCM/MeOH,10/1,v/v),得到化合物8(10mg,产率43%)
LC-MS(ESI):m/z=461.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),8.51-8.48(m,1H),8.27(m,1H),8.15-8.14(m,1H),7.73-7.71(m,1H),7.54-7.53(m,1H),6.09-6.08(m,1H),4.79-4.75(m,1H),2.75-2.73(m,1H),2.01-2.00(m,2H),1.92-1.88(m,1H),1.80-1.73(m,3H),1.61-1.57(m,3H),1.49-1.43(m,2H),0.95-0.90(m,2H),0.62-0.58(m,2H).
实施例9:((1R,2S,3S,4R)-3-((6-(二氟甲基)-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物9)
(1R,2S,3S,4R)-3-((6-(difluoromethyl)-2-(5-fluoro-lH-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:1-氨基-1H-吡咯-2,4-二甲酸二乙酯(9b)
diethyl 1-amino-1H-pyrrole-2,4-dicarboxylate
室温下,将化合物9a(10g,47.4mmol)加入THF中,氮气保护下,0℃分批加入钠氢(1.4g,56.8mmol),加完后,自然升温反应1小时,将2,4-二硝基苯基羟胺(10.4g,52.1mmol)加入其中,室温反应1小时,将反应液倒入水(500mL)中,EA(300mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA=10/1-5/1,v/v),得化合物9b(8g,产率75%)。
LC-MS(ESI):m/z=227.1[M+H]+.
第二步:2,4-二氧基-1,2,3,4-四氢吡咯并[2,1-f][1,2,4]三嗪-6-羧酸乙酯(9c)
ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylate
室温下,将尿素(21.2g,354.4mmol)加热至180℃融化,将化合物9b(8g,35.4mmol)加入至其中,保温反应4小时。冷却至100℃,加入乙醇(100mL)回流反应,过滤,滤液浓缩干,得化合物9c(8g)粗品,直接投下一步。
LC-MS(ESI):m/z=224.1[M+H]+.
第三步:2,4-二氯吡咯并[2,1-f][1,2,4]三嗪-6-羧酸乙酯(9d)
ethyl 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine-6-carboxylate
室温下,将化合物9c(8g)粗品,三乙胺盐酸盐(14.8g,107.5mmol)加入至三氯氧磷(100mL)中,100℃反应16小时,浓缩除去大多数三氯氧磷,浓缩液倒入冰水(100mL)中,EA(100mL×1)萃取,有机相浓缩干,得化合物9d(2g,产率22%)。
第四步:2-氯-4-苯氧基吡咯并[2,1-f][1,2,4]三嗪-6-羧酸乙酯(9e)
ethyl 2-chloro-4-phenoxypyrrolo[2,1-f][1,2,4]triazine-6-carboxylate
室温下,将9d(2g,7.7mmol)加入THF中,加入苯酚钠(1.3g,10.8mmol),室温反应2小时,将反应液倒入(150mL)水中,EA(50mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA=10/1-5/1,v/v)得化合物9e(1.5g,产率61%)。
LC-MS(ESI):m/z=318.1[M+H]+.
第五步:(2-氯-4-苯氧基吡咯并[2,1-f][1,2,4]三嗪-6-基)甲醇(9f)
(2-chloro-4-phenoxypyrrolo[2,1-f][1,2,4]triazin-6-yl)methanol
室温下,将化合物9e(1.5g,4.7mmol)加入DCM(50mL)中,0℃加入DIBAL-H(16mL,23.6mmol),自然升至室温反应2小时,将反应液倒入(100mL)水中,加入DCM(100mL),过滤,滤液浓缩干,得化合物9f(800mg,产率61%)。
LC-MS(ESI):m/z=276.1[M+H]+.
第六步:2-氯-4-苯氧基吡咯并[2,1-f][1,2,4]三嗪-6-甲醛(9g)
2-chloro-4-phenoxypyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde
室温下,将化合物9f(0.3g,1.1mmol),二氧化锰(0.95g,11.0mmol)加入二氯甲烷(10mL)中,室温反应16小时。将反应液过滤,滤液浓缩干,柱层析纯化(PE/EA=20/1-5/1,v/v),得化合物9g(200mg,产率67%)。
LC-MS(ESI):m/z=274.1[M+H]+.
第七步:2-氯-6-(二氟甲基)-4-苯氧基吡咯并[2,1-f][1,2,4]三嗪(9h)
2-chloro-6-(difluoromethyl)-4-phenoxypyrrolo[2,1-f][1,2,4]triazine
室温下,将化合物9g(0.2g,0.73mmol),DAST(0.6g,3.6mmol)依次加入100ml DCM中,反应16小时。将反应液倒入水(50mL)中,DCM(50mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA=20/1-5/1,v/v),得化合物9h(150mg,,产率70%)。
LC-MS(ESI):m/z=296.1[M+H]+
第八步:(1R,2S,3S,4R)-3-((2-氯-6-(二氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(9i)
(1R,2S,3S,4R)-ethyl3-((2-chloro-6-(difluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物9h(0.15g,0.51mmol),(1R,2S,3S,4R)-3-氨基双环[2.2.2]辛烷-2-羧酸乙酯盐酸盐(0.18g,0.77mmol)、DIPEA(0.16g,1.3mmol)依次加入NMP(5mL)中。120℃反应2小时。将反应液倒入(50mL)水中,EA(50mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA=10/1-2/1,v/v),化合物9i(100mg,产率49%)。
LC-MS(ESI):m/z=399.1[M+H]+
第九步:(1R,2S,3S,4R)-3-((6-(二氟甲基)-2-(5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(9j)
(1R,2S,3S,4R)-ethyl-3-((6-(difluoromethyl)-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物9i(100mg,0.25mmol)加入二氧六环(5mL)和水(0.5mL)的混合溶液中,依次加入5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环-2-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(160mg,0.38mmol)、碳酸钾(87mg,0.63mmol)、Pd(dppf)Cl2(18mg,0.025mmol),氮气置换并保护,微波加热至120℃反应1小时,将反应液浓缩干,柱层析纯化(PE/EA=10/1-1/1,v/v),得将化合物9j(40mg,产率25%)。
第十步:(1R,2S,3S,4R)-3-((6-(二氟甲基)-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物9)
(1R,2S,3S,4R)-3-((6-(difluoromethyl)-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
室温下,向化合物9j(30mg,0.046mmol)中依次加入乙醇(1mL)、水(2mL),氢氧化钠(37mg,0.92mmol)。室温反应18小时,将反应液用6N盐酸调节pH至5-6,反应液浓缩干,制备板分离纯化(DCM/MeOH,10/1,v/v),得到化合物9(9mg,产率41%)
LC-MS(ESI):m/z=470.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.53-8.50(m,1H),8.30-8.29(m,1H),8.22-8.21(m,1H),8.22-8.10(m,1H),7.98-7.96(m,1H),7.28-7.00(m,2H),4.82-4.79(m,1H),,2.76-2.74(m,1H),2.03-2.01(m,2H),1.81-1.71(m,3H),1.64-1.56(m,3H),1.50-1.40(m,2H).
实施例10:(1R,2S,3S,4R)-3-((6-乙炔基-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物10)
(1R,2S,3S,4R)-3-((6-ethynyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid
第一步:(1R,2S,3S,4R)-3-((2-氯-6-(羟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(10a)
(1R,2S,3S,4R)-ethyl3-((2-chloro-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物9f(0.5g,1.8mmol),(1R,2S,3S,4R)-3-氨基双环[2.2.2]辛烷-2-羧酸乙酯盐酸盐(0.5g,2.2mmol)、DIPEA(0.6g,4.6mmol)依次加入NMP(10mL)中。120℃反应2小时。将反应液倒入(50mL)水中,EA(50mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA=10/1-1/1,v/v),得化合物10a(500mg,产率73%)。
LC-MS(ESI):m/z=379.2[M+H]+
第二步:(1R,2S,3S,4R)-3-((2-(5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)-6-(羟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(10b)
(1R,2S,3S,4R)-ethyl-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物10a(500mg,1.3mmol)加入二氧六环(10mL)和水(1mL)的混合溶液中,依次加入5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环-2-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(800mg,2.0mmol)、碳酸钾(550mg,4.0mmol)、Pd(dppf)Cl2(100mg,0.13mmol),氮气置换并保护,微波加热至120℃反应1小时。将反应液浓缩干,柱层析纯化(PE/EA=10/1-1/1,v/v),得化合物10b(300mg,产率36%)。
第三步:(1R,2S,3S,4R)-3-((2-(5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)-6-甲酰基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(10c)
(1R,2S,3S,4R)-ethyl-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-formylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物10b(0.3g,0.47mmol),二氧化锰(0.4g,4.7mmol)加入二氯甲烷(10mL)中,室温反应16小时。将反应液过滤,滤液浓缩干,柱层析纯化(PE/EA=10/1-1/1,v/v),得化合物10c(200mg,产率67%)。
第四步:(1R,2S,3S,4R)-3-((6-乙炔基-2-(5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(10d)
(1R,2S,3S,4R)-ethyl-3-((6-ethynyl-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,l-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物10c(0.2g,0.32mmol)加入甲醇(3mL)和四氢呋喃(1mL)中,室温下加入碳酸钾(0.18g,1.3mmol),(1-重氮基-2-氧代丙基)膦酸二甲酯(0.12g,0.64mmol),反应16小时。将反应液倒入(50mL)水中,EA(50mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA=10/1-1/1,v/v),得化合物10d(60mg,产率30%)。
第五步:(1R,2S,3S,4R)-3-((6-乙炔基-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物10)
(1R,2S,3S,4R)-3-((6-ethynyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid
室温下,向化合物10d(60mg,0.1mmol)中依次加入乙醇(1mL)、水(2mL),氢氧化钠(77mg,2mmol)。室温反应18小时,将反应液用6N盐酸调节pH至5-6,反应液浓缩干,柱层析分离纯化(PE/EA=10/1-1/2,v/v),得到化合物10(20mg,产率46%)
LC-MS(ESI):m/z=445.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.32(s,1H),12.24(s,1H),8.51-8.48(m,1H),8.29-8.28(m,1H),8.20-8.19(m,1H),7.98-7.97(m,1H),7.94-7.93(m,1H),7.13-7.12(m,1H),4.81-4.77(m,1H),4.03(s,1H),2.74-2.72(m,1H),2.03-2.01(m,2H),1.80-1.74(m,3H),1.62-1.58(m,3H),1.46-1.42(m,2H).
实施例11:(1R,2S,3S,4R)-3-((7-(二氟甲基)-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基]吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物11)(1R,2S,3S,4R)-3-((7-(difluoromethyl)-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid
第一步:2,4-二氯吡咯并[2,1-f][1,2,4]三嗪-7-甲醛(11b)
2,4-dichloropyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde
将DMF(19.3g,0.265mol)加入三口瓶(250ml),N2置换,降温至0℃,滴入三氯氧磷(81.4g,0.53mol),0℃搅拌15min,加入(11a)(10g,0.053mol),升温至95℃反应5h。降至室温,缓慢将反应液倒入水(500ml)中,用乙酸乙酯萃取(200ml*3),合并有机相,有机相用碳酸氢钠水溶液洗涤,再用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩,残留物用硅胶柱色谱分离提纯(石油醚∶二氯甲烷(v/v)=1∶0~1∶3),得到化合物(11b)(7g,产率61%)。
第二步:2,4-二氯-7-(二氟甲基)吡咯并[2,1-f][1,2,4]三嗪(11c)
2,4-dichloro-7-(difluoromethyl)pyrrolo[2,1-f][1,2,4]triazine
将(11b)(1g,4.6mmol)加入DCM(15ml),0℃下滴入二乙胺基三氟化硫(3.7g,23mmol),室温反应2h。将反应液滴入冰水(30ml)中,用DCM萃取(15ml*2),合并有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到(11c)(1.16g)
第三步:(1R,2S,3S,4R)-3-(((2-氯-7-(二氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(11d)
(1R,2S,3S,4R)-ethyl3-((2-chloro-7-(difluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将(11c)(340mg,1.43mmol)和(1R,2S,3S,4R)-3-氨基双环[2.2.2]辛烷-2-羧酸乙酯(350mg,1.5mmol)加入DCM(10mL),加入DIPEA(53mg,4.3mmol),室温反应1h。加入水(20mL),用DCM萃取(15ml*2),合并有机相,用盐酸水溶液(1mol/L)洗涤,再用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩得到粗品化合物(11d)(560mg)。
LC-MS(ESI):m/z=399.1[M+H]+.
第四步:(1R,2S,3S,4R)-3-((7-(二氟甲基)-2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(11e)(1R,2S,3S,4R)-ethyl3-((7-(difluoromethyl)-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将(11d)(560mg,1.4mmol)、中间体1(700mg,1.68mmol)、Pd(dppf)Cl2(114mg,0.14mmol)和碳酸钾(400mg,2.8mmol)加入二氧六环(10mL)中,再加入水(0.5ml).N2置换后升温至120℃微波反应1h。降至室温,过滤,滤液减压浓缩后硅胶柱色谱分离提纯(石油醚:乙酸乙酯(v/v)=10∶1~1∶4),得到化合物(11e)(370mg,产率40%)。
LC-MS(ESI):m/z=653.2[M+H]+.
第五步:(1R,2S,3S,4R)-3-((7-(二氟甲基)-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基]吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物11)(1R,2S,3S,4R)-3-((7-(difluoromethyl)-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid室温下,将(11e)(170mg,0.26mmol)和LiOH.H2O(110mg,2.6mmol)加入THF(3ml)中,再加入乙醇(3ml)和水(1ml),升温至60℃反应2h。降至室温,用稀盐酸调至pH=5-6,EA萃取(15ml*3),合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到的粗产物经制备HPLC分离提纯得到化合物11(5mg 4%)。制备HPLC分离方法:1.仪器:waters 2767制备液相;色谱柱:SunFire@Prep C18(19mm×250mm)2.样品用DMF溶解,用0.45μm滤头过滤,制成样品液。3制备色谱条件:a流动相A,B组成:流动相A:乙腈;流动相B:水(含0.1%TFA)b.梯度洗脱,流动相A含量从5%-50%c.流量12mL/min。d洗脱时间20min。
化合物11保留时间:14.2min;
1H NMR(400MHz,DMSO-d6)δ12.26(m,2H),8.49-8.46(m,1H),8.32-8.29(m,1H),8.24(d,1H),8.13(d,1H),7.59(t,1H),7.05(d,1H),6.90(d,1H),4.80(t,1H),2.76(d,1H),2.03(s,2H),1.85-1.70(m,3H),1.66-1.52(m,3H),1.49-1.40(m,2H).
LC-MS(ESI):m/z=471.2[M+H]+.
实施例12:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-乙烯基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物12)(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:(1R,2S,3S,4R)-3-((2-氯-7-甲酰基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(12a)
(1R,2S,3S,4R)-ethyl3-((2-chloro-7-formylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将(11b)(500mg,2.32mmol)和(1R,2S,3S,4R)-3-氨基双环[2.2.2]辛烷-2-羧酸乙酯盐酸盐(568mg,2.43mmol)加入DCM(10mL)中,加入DIPEA(895mg,6.95mmol),室温反应1h。加入水(20mL),用DCM萃取(15ml*2),合并有机相,用盐酸水溶液(1mol/L)洗涤,再用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩后硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶9),得到化合物(12a)(700mg,产率80%)。
LC-MS(ESI):m/z=377.1[M+H]+.
第二步:(1R,2S,3S,4R)-3-(((2-氯-7-乙烯基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(12b)
(1R,2S,3S,4R)-ethyl3-((2-chloro-7-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将甲基三苯基溴化磷(2g,5.59mmol)加入THF(10ml)中,0℃下滴入叔丁醇钾的四氢呋喃溶液(1mol/L,5.6ml),0℃下反应30min,再加入(12a)(700mg,1.86mmol),升温至室温反应1h。加入氯化铵水溶液,用EA萃取(30ml*3),合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩,残留物用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶9),得到化合物(12b)(500mg,产率76%)。
LC-MS(ESI):m/z=375.2[M+H]+.
第三步:(1R,2S,3S,4R)-3-((2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基)-7-乙烯基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(12c)
(1R,2S,3S,4R)-ethyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将(12b)(500mg,1.34mmol)、中间体1(667mg,1.6mmol)、Pd(dppf)Cl2(114mg,0.14mmol)和碳酸钾(370mg,2.68mmol)加入二氧六环(10mL),再加入水(0.5ml).N2置换后升温至110℃微波反应1h。降至室温,过滤,滤液减压浓缩后硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶4),得到化合物(12c)(240mg,产率29%)。
第四步:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-乙烯基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物12)(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
室温下,将(12c)(240mg,0.38mmol)和LiOH H2O(160mg,3.8mmol)加入THF(3ml)中,再加入乙醇(3ml)和水(1ml),升温至60℃反应2h。降至室温,用稀盐酸调至pH=5-6,EA萃取(15ml*3),合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到的粗产物经制备HPLC分离提纯得到化合物12(40mg 24%)。制备HPLC分离方法:1.仪器:waters 2767制备液相;色谱柱:SunFire@Prep C18(19mm×250mm)2.样品用DMF溶解,用0.45μm滤头过滤,制成样品液。3.制备色谱条件:a.流动相A,B组成:流动相A:乙腈;流动相B:水(含0.1%TFA)b.梯度洗脱,流动相A含量从5%-50%c.流量12mL/min。d洗脱时间20min。
化合物12保留时间:14.5min;
1H NMR(400MHz,DMSO-d6)δ12.23(d,2H),8.46(dd,1H),8.30-8.29(m,1H),8.24(d,1H),7.89(d,1H),7.26(dd,1H),7.02(d,1H),6.89(d,1H),5.97(dd,1H),5.36(dd,1H),4.81(t,1H),2.77(d,1H),2.03(s,2H),1.82-1.74(m,3H),1.64-1.55(m,3H),1.49-1.42(m,2H).
LC-MS(ESI):m/z=447.2[M+H]+.
实施例13:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-((甲氨基)甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物13)(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-((methylamino)methyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:(1R,2S,3S,4R)-3-(((2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基)-7-甲酰基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(13a)
(1R,2S,3S,4R)-ethyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-formylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将(12a)(600mg,1.6mmol)、中间体1(730mg,1.76mmol)、Pd(dppf)Cl2(260mg,0.32mmol)和碳酸钾(442mg,3.2mmol)加入二氧六环(10mL),再加入水(0.5ml).N2置换后升温至100℃微波反应1h。降至室温,过滤,滤液减压浓缩后硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶4),得到化合物(13a)(600mg,产率60%)。
第二步:(1R,2S,3S,4R)-3-(((2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基)-7-((甲基氨基)甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(13b)
(1R,2S,3S,4R)-ethyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-((methylamino)methyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将(13a)(300mg,0.476mmol)、甲胺(甲醇溶液)(0.2ml)和乙酸(0.1ml)加入甲醇(5ml)中,室温反应1h.再加入硼氢化钠(54mg,1.543mmol),室温反应2h。加入水(15ml),用乙酸乙酯萃取(15ml*3),饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物(13b)(330mg)。
LC-MS(ESI):m/z=646.3[M+H]+.
第三步:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-((甲氨基)甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物13)(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-((methylamino)methyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
室温下,将(13b)(330mg,0.51mmol)和LiOH·H2O(214mg,5.1mmol)加入THF(3ml)中,再加入乙醇(3ml)和水(2ml),升温至60℃反应2h。降至室温,用稀盐酸调至pH=6-7.直接将反应液减压浓缩后得到的粗产物经制备HPLC分离提纯得到化合物13(25mg,11%),。制备HPLC分离方法:1仪器:waters 2767制备液相;色谱柱:SunFire@Prep C18(19mm×250mm)2.样品用DMF溶解,用0.45μm滤头过滤,制成样品液。3.制备色谱条件:a.流动相A,B组成:流动相A:乙腈;流动相B:水(含0.1%乙酸铵)b.梯度洗脱,流动相A含量从5%-50%c.流量12mL/min。d洗脱时间20min。
化合物13保留时间:12.2min;
1H NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.45(dd,1H),8.28(d,1H),8.20(s,1H),7.82-7.80(m,1H),6.94(d,1H),6.52(d,1H),4.78(t,1H),4.06(s,2H),3.33(s,2H),2.75(d,1H),2.36(s,3H),2.02(s,2H),1.86-1.70(m,3H),1.64-1.56(m,3H),1.44-1.41(m,2H)
LC-MS(ESI):m/z=464.2[M+H]+.
实施例14:(1R,2S,3S,4R)-3-((7-环丙基-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物14)(1R,2S,3S,4R)-3-((7-cyclopropyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:7-溴-2,4-二氯吡咯并[2,1-f][1,2,4]三嗪(14b)
7-bromo-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine
将(14a)(1g,5.32mmol)加入乙腈(15ml)中,0℃下将N-溴代丁二酰亚胺(1.04g,2.85mmol)溶于乙腈(5ml)滴入反应体系中,室温反应16h。直接将反应液减压浓缩后硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶9),得到化合物(14b)(1.2g,产率84%)。
第二步:(1R,2S,3S,4R)-3-((7-溴-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(14c)
(1R,2S,3S,4R)-ethyl3-((7-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将(14b)(1.2g,4.49mmol)和(1R,2S,3S,4R)-3-氨基双环[2.2.2]辛烷-2-羧酸乙酯盐酸盐(1.05g,4.49mmol)加入DCM(10mL),加入DIPEA(1.74g,13.47mmol),室温反应1h。加入水(20mL),用DCM萃取(15ml*2),合并有机相,用盐酸水溶液(1mol/L)洗涤,再用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩后硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶9),得到化合物(14c)(1.8g,产率94%)。
LC-MS(ESI):m/z=427.1[M+H]+,429.1[M+H]+.
第三步:(1R,2S,3S,4R)-3-(((2-氯-7-环丙基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(14d)
(1R,2S,3S,4R)-ethyl3-((2-chloro-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将(14c)(500mg,1.17mmol)、环丙基硼酸(252mg,2.93mmol)、Pd(dppf)Cl2(190mg,0.23mmol)和碳酸钾(485mg,3.5mmol)加入二氧六环(10mL),再加入水(0.5ml).N2置换后升温至100℃微波反应1h。降至室温,过滤,滤液减压浓缩后硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶5),得到化合物(14d)(340mg,产率75%)。
LC-MS(ESI):m/z=389.2[M+H]+.
第四步:(1R,2S,3S,4R)-3-((7-环丙基-2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(14e)
(1R,2S,3S,4R)-ethyl3-((7-cyclopropyl-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将(14d)(300mg,0.77mmol)、中间体1(354mg,0.85mmol)、Pd(dppf)Cl2(122mg,0.15mmol)和K3PO4·7H2O(760mg,2.3mmol)加入二氧六环(10mL),再加入水(0.5ml).N2置换后升温至100℃微波反应1h。降至室温,过滤,滤液减压浓缩后硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶5),得到化合物(1R,2S,3S,4R)-3-((7-环丙基-2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(14e)(350mg,产率71%)。
第五步:1R,2S,3S,4R)-3-((7-环丙基-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物14)(1R,2S,3S,4R)-3-((7-cyclopropyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
室温下,将(14e)(350mg,0.545mmol)和LiOH H2O(230mg,5.5mmol)加入THF(5ml)中,再加入乙醇(5ml)和水(2ml),升温至60℃反应2h。降至室温,用稀盐酸调至pH=6-7.直接将反应液减压浓缩后得到的粗产物经制备HPLC分离提纯得到化合物14(110mg,44%),。制备HPLC分离方法:1.仪器:waters 2767制备液相;色谱柱:SunFire@Prep C18(19mm×250mm)2.样品用DMF溶解,用0.45μm滤头过滤,制成样品液。3.制备色谱条件:a.流动相A,B组成:流动相A:乙腈;流动相B:水(含0.1%TFA)b.梯度洗脱,流动相A含量从5%-50%c.流量12mL/min。d洗脱时间20min。
化合物14保留时间:14.5min;
1H NMR(400MHz,DMSO-d6)δ12.18(s,2H),8.52(dd,1H),8.29(d,1H),8.19(d,1H),7.78(d,1H),6.91(d,1H),6.24(d,1H),4.78(t,1H),2.77(d,1H),2.43-2.37(m,1H),2.02(s,2H),1.81-1.71(m,3H),1.67-1.51(m,3H),1.48-1.38(m,2H),1.10-1.03(m,2H),0.83-0.79(m,2H).
LC-MS(ESI):m/z=461.2[M+H]+.
实施例15:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-(甲基氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物15)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(methylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:2-氯-4-(((((1R,2S,3S,4R)-3-(乙氧基羰基)双环[2.2.2]辛烷-2-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-羧酸(15a)
2-chloro-4-(((1R,2S,3S,4R)-3-(ethoxycarbonyl)bicyclo[2.2.2]octan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid
将(12a)(900mg,2.39mmol)和2-甲基丁-2-烯(838mg,12mmol)溶于THF(10ml),再将亚氯酸钠(860mg,9.56mmol)和二水合磷酸二氢钠(1.5g,9.56mmol)溶于水(2ml)后滴入反应体系,室温反应1h。加入氯化铵水溶液,用EA萃取(20ml*3),合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩得到粗品化合物(15a)(1g)。
LC-MS(ESI):m/z=392.1[M+H]+.
第二步:(1R,2S,3S,4R)-3-(((2-氯-7-(甲基氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(15b)
(1R,2S,3S,4R)-ethyl3-((2-chloro-7-(methylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,向(15a)(500mg,1.276mmol)中依次加入盐酸甲胺(258mg,3.83mmol),DCM(10mL),HATU(970mg,2.55mmol),N,N-二异丙基乙胺(823mg,6.38mmol)。室温搅拌2小时,加水稀释,DCM萃取,有机相用饱和食盐水(20mL)洗,无水硫酸钠干燥,减压浓缩后得到的粗产物经硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶4),得到(15b)(400mg,产率77%)。
LC-MS(ESI):m/z=406.2[M+H]+.
第三步:(1R,2S,3S,4R)-3-(((2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基]-7-(甲基氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(15c)
(1R,2S,3S,4R)-ethyl3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(methylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将(15b)(400mg,0.99mmol)、中间体1(453mg,1.1mmol)、Pd(dppf)Cl2(163mg,0.2mmol)和碳酸钾(414mg,3mmol)加入二氧六环(10mL),再加入水(0.5ml).N2置换后升温至100℃微波反应1h。降至室温,过滤,滤液减压浓缩后硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶4),得到化合物(15c)(300mg,产率46%)。
第四步:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-(甲基氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物15)(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(methylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
室温下,将(15c)(300mg,0.46mmol)和LiOH·H2O(193mg,4.6mmol)加入THF(5ml)中,再加入乙醇(5ml)和水(2ml),升温至60℃反应2h。降至室温,用稀盐酸调至pH=6-7.直接将反应液减压浓缩后得到的粗产物经制备HPLC分离提纯得到化合物15(40mg,18%),。制备HPLC分离方法:1.仪器:waters 2767制备液相;色谱柱:SunFire@Prep C18(19mm×250mm)2.样品用DMF溶解,用0.45μm滤头过滤,制成样品液。3.制备色谱条件:a.流动相A,B组成:流动相A:乙腈;流动相B:水(含0.1%TFA)b.梯度洗脱,流动相A含量从5%-50%c.流量12mL/min。d洗脱时间20min。
化合物15保留时间:14.2min;
1H NMR(400MHz,DMSO-d6)δ12.39(d,2H),8.94(q,1H),8.45(m,2H),8.32(m,1H),8.25(d,1H),7.15(d,1H),7.09(d,1H),4.89(t,1H),3.01(d,3H),2.83(d,1H),2.06(s,2H),1.89-1.72(m,3H),1.70-1.54(m,3H),1.52-1.44(m,2H).
LC-MS(ESI):m/z=478.2[M+H]+.
实施例16:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-5-乙烯基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物16)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:1-氨基-3-氯-1H-吡咯-2-羧酸乙酯(16b)
ethyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate
氮气保护下,化合物16a(5.0g,28.8mmol)溶于四氢呋喃(100ml)中,冰浴降温至0~5℃,分批次加入钠氢(1.4g,34.5mmol,60%含量),加完控温0~5℃搅拌30分钟,再加入2,4-二硝基苯基羟胺(8.6g,43.2mmol),加完升温至室温搅拌15小时。反应完毕将反应液缓慢倾倒入冰水(150ml)中,乙酸乙酯(150ml*4)萃取,合并乙酸乙酯相,饱和食盐水洗,无水硫酸钠干燥,过滤,滤液减压浓缩后残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~2∶1)得到化合物16b(4.1g,75%)。
LC-MS(ESI):m/z=189.1[M+H]+.
第二步:3-氯-1-((甲氧羰基)氨基)-1H-吡咯-2-羧酸乙酯(16c)
ethyl 3-chloro-1-((methoxycarbonyl)amino)-1H-pyrrole-2-carboxylate
化合物16b(4.1g,21.7mmol)溶于二氯甲烷(100ml)中,加入吡啶(2.5g,32.5mmol),控温0~5℃滴加氯甲酸甲酯(2.2g,23.9mmol),加完自然回温反应3小时,反应完毕加入冰水(100ml),分液,水相用二氯甲烷(100ml*2)萃取两次,合并有机相,饱和食盐水洗,无水硫酸钠干燥,过滤,滤液减压浓缩后残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~2∶1)得到化合物16c(3.5g,65%)。
LC-MS(ESI):m/z=247.1[M+H]+.
第三步:5-氯吡咯并[2,1-f][1,2,4]三嗪-2,4(1H,3H)-二酮(16d)
5-chloropyrrolo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione
在120ml封管中加入化合物16c(3.5g,14.2mmol),异丙醇(20ml),氨水(60ml,28%~30%),密封后升温至110℃反应15小时,反应完毕冷却至室温后减压浓缩,浓缩残留物用乙醚与甲醇10∶1(20ml,v/v)混合体系打浆,过滤,滤饼用乙醚(10ml)淋洗,滤饼干燥后得化合物16d(1.5g,57%)。
LC-MS(ESI):m/z=184.1[M-H]-.
第四步:2,4,5-三氯吡咯并[2,1-f][1,2,4]三嗪(16e)
2,4,5-trichloropyrrolo[2,1-f][1,2,4]triazine
在48ml封管中加入化合物16d(1.5g,8.1mmol),DIPEA(2.1g,16.2mmol),三氯氧磷(10ml),甲苯(20ml)加完密封后升温至110℃反应23h,反应完毕,冷却至室温后减压浓缩,残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~5∶1)得到化合物16e(810mg,45%)。
第五步:(1R,2S,3S,4R)-3-((2,5-二氯吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(16f)
ethyl(1R,2S,3S,4R)-3-((2,5-dichloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyc[2.2.2]octane-2-carboxylate
化合物16e(810mg,3.6mmol)溶于异丙醇(15ml)中,加入DIPEA(0.9g,7.2mmol),乙基-(2S,3S)-3-氨基二环[2.2.2]辛烷-2-甲酸基酯盐酸(950.0mg,4.0mmol),加完升温至60℃反应6小时,反应完毕直接减压浓缩,残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物16f(1.05g,80%)。
LC-MS(ESI):m/z=383.1[M+H]+.
第六步:(1R,2S,3S,4R)-3-((5-氯-2-(5-氟-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(16g)
ethyl(1R,2S,3S,4R)-3-((5-chloro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
化合物16f(800.0mg,2.1mmol)溶于1,4-二氧六环(15ml)和水(1ml)的混合溶剂中,加入中间体1(1050.0mg,2.5mmol),碳酸钾(870.0mg,6.3mmol),Pd(dppf)Cl2(146.0mg,0.2mmol),加完用微波反应器120℃反应2小时,反应完毕,过滤,滤液浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~5∶1)得到化合物16g(880mg,67%)。
LC-MS(ESI):m/z=636.1[M+H]+.
第七步:(1R,2S,3S,4R)-3-((2-(5-氟-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)-5-乙烯基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(16i)
Ethyl(1R,2S,3S,4R)-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
化合物16g(350.0mg,0.56mmol)溶于1,4-二氧六环(10ml)和水(1ml)的混合溶剂中,加入乙烯基硼酸频哪醇酯(172.5mg,1.12mmol),X-phos(95.5mg,0.2mmol),醋酸钯(22.5mg,0.1mmol),碳酸钾(232.0mg,1.7mmol),加完后氮气置换3次,加热到100℃反应15小时,反应完毕,过滤,滤液浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~5∶1)得到化合物16i(180mg,50%)。
LC-MS(ESI):m/z=629.2[M+H]+
第八步:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-5-乙烯基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物16)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
化合物16i(180mg,0.28mmol)溶于甲醇(2ml)中,加入氢氧化锂(117mg,2.8mmol溶于0.5ml水),加完升温至60℃反应5小时,反应完毕用1N盐酸调pH=5~6后用二氯甲烷(50ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶1)得到化合物16(76.0mg,60%)。
LC-MS(ESI):m/z=447.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.15(s,2H),8.50(d,1H),8.26(s,1H),8.25-8.24(m,1H),8.18(d,1H),7.69(d,1H),7.27-7.20(m,1H),6.85(d,1H),6.61(d,1H),5.65(d,1H),5.28(d,1H),4.83-4.83(m,1H),2.90(d,1H),2.02(s,1H),1.78-1.46(m,8H).
实施例17:(1R,2S,3S,4R)-3-((5-环丙基-2-(5-氟-1H-]吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物17)
(1R,2S,3S,4R)-3-((5-cyclopropyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:(1R,2S,3S,4R)-3-((5-环丙基-2-(5-氟-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(17a)
ethyl(1R,2S,3S,4R)-3-((5-cyclopropyl-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
化合物16g(300.0mg,0.47mmol)溶于1,4-二氧六环(10ml)和水(1ml)的混合溶剂中,加入环丙基硼酸(81.5mg,0.94mmol),X-phos(95.5mg,0.2mmol),醋酸钯(22.5mg,0.1mmol),碳酸钾(195.0mg,1.4mmol),加完后氮气置换3次,加热到100℃反应15小时,反应完毕,过滤,滤液浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~5∶1)得到化合物17a(130mg,43%)。
LC-MS(ESI):m/z=643.2[M+H]+.
第二步:(1R,2S,3S,4R)-3-((5-环丙基-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物17)
(1R,2S,3S,4R)-3-((5-cyclopropyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
化合物17a(130mg,0.20mmol)溶于甲醇(5ml)中,加入氢氧化锂(84.0mg,2.0mmol溶于0.5ml水),加完升温至60℃反应5小时,反应完毕用1N盐酸调pH=5~6后用二氯甲烷(50ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶1)得到化合物17(38.0mg,41%)。
LC-MS(ESI):m/z=461.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.15(s,2H),8.50(d,1H),8.26(s,1H),8.25-8.24(m,1H),8.18(d,1H),7.69(d,1H),7.27-7.20(m,1H),6.85(d,1H),6.61(d,1H),5.65(d,1H),5.28(d,1H),4.83-4.83(m,1H),2.90(d,1H),2.02(s,1H),1.78-1.46(m,8H).
实施例18:(1R,2S,3S,4R)-3-((2-(5-氟-1H-[吡咯并[2,3-b]吡啶-3-基)-7-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物18)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:(2S,3S)-3-((2-氯吡咯并嘧啶[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(18b)
ethyl(2S,3S)-3-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
化合物18a(1.0g,5.4mmol)溶于异丙醇(10ml)中,加入DIPEA(2.1g,16.2mmol)加入乙基(2S,3S)-3-氨基二环[2.2.2]辛烷-2-甲酸基酯盐酸(1.38g,5.9mmol),升温至60℃反应3小时,反应完毕直接浓缩,浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~5∶1)得到化合物18b(1.6g,85%)。
LC-MS(ESI):m/z=349.2[M+H]+.
第二步:(1R,2S,3S,4R)-3-((2-氯-7-碘吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(18c)
ethyl(1R,2S,3S,4R)-3-((2-chloro-7-iodopyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
(1R,2S,3S,4R)-3-((2-氯-5-碘吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(18d)
ethyl(1R,2S,3S,4R)-3-((2-chloro-5-iodopyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
氮气保护下,化合物18b(1.6g,4.6mmol)溶于DCE(20ml)中,降温至0℃,分批次加入NIS(1.14g,5.1mmol),加完自然回温反应3小时,反应完毕加入水(20ml),二氯甲烷(50ml*2)萃取,合并有机相,饱和食盐水(20ml)洗,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶1)得到化合物18c(620mg,28%),化合物18d(1.25g,59%)。
化合物18c:LC-MS(ESI):m/z=475.1[M+H]+.
化合物18c:1H NMR(400MHz,CDCl3)δ6.81(s,1H),6.70(s,1H),5.47(s,1H),4.68(s,1H),4.24-4.17(m,2H),2.45(s,1H),2.05-2.04(m,1H),1.96-1.95(m,1H),1.83-1.58(m,7H),1.48-1.43(m,1H),1.27-1.24(m,3H).
化合物18d:LC-MS(ESI):m/z=475.1[M+H]+.
化合物18d:1H NMR(400MHz,CDCl3)δ7.42(d,1H),7.04(s,1H),6.70(d,1H),4.67-4.65(m,1H),4.26-4.21(m,2H),2.47-2.45(m,1H),2.04-2.01(m,1H),1.96-1.94(m,1H),1.85-1.62(m,7H),1.48-1.43(m,1H),1.30-1.26(m,3H).
第三步:(1R,2S,3S,4R)-3-((2-氯-7-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(18e)
ethyl(1R,2S,3S,4R)-3-((2-chloro-7-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
氮气保护下,化合物18c(620mg,1.3mmol)溶于DMF(10ml)中,加入碘化亚铜(380mg,2.0mmol),氟磺酰基二氟乙酸甲酯(1.25g,6.5mmol)加完升温至100℃反应5小时,反应完毕过滤,滤液加入水(30ml),乙酸乙酯(100ml*2)萃取,合并有机相,饱和食盐水(20ml)洗,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物18e(420mg,77%)。
LC-MS(ESI):m/z=417.2[M+H]+.
第四步:(1R,2S,3S,4R)-3-((2-(5-氟-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)-7-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(18f)
ethyl(1R,2S,3S,4R)-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
氮气保护下,化合物18e(420mg,1.0mmol)溶于1,4-二氧六环和水的混合溶剂(10ml/0.5ml,v/v)中,再依次加入碳酸钾(414mg,3.0mmol),Pd(dppf)Cl2(73mg,0.1mmol),中间体1(625.0mg,1.5mmol),加完120℃微波反应1小时。反应完毕后直接浓缩,浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物18f(180mg,29%)。
第五步:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物18)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
化合物18f(180mg,0.27mmol)溶于甲醇(5ml)中,加入氢氧化锂(113.0mg,2.7mmol溶于0.5ml水),加完升温至60℃反应5小时,反应完毕用1N盐酸调pH=5~6后用二氯甲烷(50ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶1)得到化合物18(53.0mg,40%)。
LC-MS(ESI):m/z=489.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.32(d,2H),8.41-8.36(m,1H),8.35(d,1H),8.32-8.31(m,1H),8.24(d,1H),7.45(d,1H),7.10(d,1H),4.81-4.78(m,1H),2.79(d,1H),2.02(s,2H),1.82-1.42(m,8H).
实施例19:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物19)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:(1R,2S,3S,4R)-3-((2-氯-5-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(19a)
ethyl(1R,2S,3S,4R)-3-((2-chloro-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
氮气保护下,化合物18d(530mg,1.11mmol)溶于DMF(10ml)中,加入碘化亚铜(315mg,1.65mmol),氟磺酰基二氟乙酸甲酯(1.05g,5.55mmol),加完升温至100℃反应5小时,反应完毕过滤,滤液加入水(30ml),乙酸乙酯(100ml*2)萃取,合并有机相,饱和食盐水(20ml)洗,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物19a(380mg,82%)。
LC-MS(ESI):m/z=417.2[M+H]+.
第二步:(1R,2S,3S,4R)-3-((2-(5-氟-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(19b)
ethyl(1R,2S,3S,4R)-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
氮气保护下,化合物19a(380mg,0.91mmol)溶于1,4-二氧六环和水的混合溶剂(10ml/0.5ml,v/v)中,再依次加入碳酸钾(377mg,2.73mmol),Pd(dppf)Cl2(73mg,0.1mmol),中间体int-1(570.0mg,1.37mmol),加完120℃微波反应1小时。反应完毕后直接浓缩,浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物19b(160mg,26%)。
第三步:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-5-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物19)
化合物19b(160mg,0.24mmol)溶于甲醇(5ml)中,加入氢氧化锂(101.0mg,2.4mmol溶于0.5ml水),加完升温至60℃反应5小时,反应完毕用1N盐酸调pH=5~6后用二氯甲烷(50ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶1)得到化合物19(45.0mg,38%)。
LC-MS(ESI):m/z=489.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.37(d,2H),8.53-8.50(m,1H),8.33-8.31(m,2H),7.98(d,1H),7.09(d,1H),6.10-6.08(m,1H),4.81(s,1H),2.48(d,1H),1.99(s,2H),1.68-1.46(m,8H).
实施例20:(1R,5S,6S,7S)-7-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-(甲氧甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸(化合物20)
(1R,5S,6S,7S)-7-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylic acid
第一步:(1R,5S,6S,7S)-7-((2-氯-7-醛基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(20a)
ethyl(1R,5S,6S,7S)-7-((2-chloro-7-formylpyrrolo[2,1-f][1,2,4]triazin-4-yl)
amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
化合物11b(1.0g,4.6mmol)溶于异丙醇(10ml)中,加入DIPEA(1.78g,13.8mmol),加入(1R,5S,6S,7S)-7-氨基三环[3.2.2.02,4]壬烷-6-羧酸乙酯(1.14g,4.6mmol),升温至60℃反应3小时,反应完毕直接浓缩,浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物20a(1.3g,71%)。
LC-MS(ESI):m/z=389.2[M+H]+.
第二步:(1R,5S,6S,7S)-7-((2-氯-7-(羟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(20b)
ethyl(1R,5S,6S,7S)-7-((2-chloro-7-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
化合物20a(1.3g,3.3mmol)溶于甲醇(10ml)中,降温至0℃加入硼氢化钠(166mg,4.0mmol),加完回温反应30分钟,反应完毕后加入水(20ml),用二氯甲烷(100ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,减压浓缩得化合物20b(1.1g,84%)。
LC-MS(ESI):m/z=391.2[M+H]+.
第三步:(1R,5S,6S,7S)-7-((2-氯-7-(甲氧甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(20c)
ethyl(1R,5S,6S,7S)-7-((2-chloro-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
化合物20b(1.1g,2.8mmol)溶于甲醇(10ml)和三氟乙酸(2ml)中,室温下缓慢滴加三甲硅基充氮甲烷(14ml,28mmol,2.0mol/L正己烷溶液),滴加完后继续反应30分钟,反应完毕后将反应液加入到饱和碳酸氢钠溶液(50ml)中,用乙酸乙酯(100ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物20c(850mg,75%)。
LC-MS(ESI):m/z=405.2[M+H]+.
第四步:(1R,5S,6S,7S)-7-((2-(5-氟-1-对甲苯磺酰基1H-吡咯并[2,3-b]吡啶-3-基)-7-(甲氧甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(20d)
ethyl(1R,5S,6S,7S)-7-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
氮气保护下,化合物20c(125mg,0.31mmol)溶于1,4-二氧六环和水的混合溶剂(10ml/0.5ml,v/v)中,再依次加入碳酸钾(128mg,0.92mmol),Pd(dppf)Cl2(36mg,0.05mmol),中间体1(119.0mg,0.47mmol),加完120℃微波反应1小时。反应完毕后直接浓缩,浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物20d(120mg,59%)。
第五步:(1R,5S,6S,7S)-7-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-(甲氧甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸(化合物20)
(1R,5S,6S,7S)-7-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylic acid
化合物20d(120mg,0.18mmol)溶于甲醇(5ml)中,加入氢氧化锂(75.0mg,1.8mmol溶于2ml水),加完升温至60℃反应5小时,反应完毕用1N盐酸调pH=5~6后用二氯甲烷(50ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶1)得到化合物20(50.0mg,58%)。
LC-MS(ESI):m/z=477.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.17(d,2H),8.51-8.48(m,1H),8.31-8.30(m,1H),8.23(d,1H),7.70(d,1H),7.01(d,1H),6.64(d,1H),4.79(s,2H),4.44(s,1H),3.35(s,3H),2.65-2.64(m,2H),2.38(s,1H),1.72-1.56(m,4H),1.07-1.03(m,2H),0.87-0.84(m,1H),0.40-0.34(m,1H).
实施例21:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡唑[3,4-b]吡啶-3-基)-7-(甲氧甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物21)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:(1R,2S,3S,4R)-3-((2-(5-氟-1-三苯甲基-1H-吡唑[3,4-b]吡啶-3-基)-7-(甲氧甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(21a)
ethyl(1R,2S,3S,4R)-3-((2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
氮气保护下,化合物28b(200mg,0.51mmol)溶于1,4-二氧六环和水的混合溶剂(5ml/0.2ml,v/v)中,再依次加入碳酸钾(207mg,1.5mmol),Pd(dppf)Cl2(36mg,0.05mmol),int-2(505.0mg,1.0mmol),加完120℃微波反应1小时。反应完毕后直接浓缩,浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物21a(120mg,31%)。
第二步:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡唑[3,4-b]吡啶-3-基)-7-(甲氧甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(21b)
ethyl(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
化合物21a(120mg,0.16mmol)溶于二氯甲烷(5ml)中,加入三氟乙酸(1ml),三乙基硅烷(370.0mg,3.2mmol),加完室温反应5小时,反应完毕后将反应液加入到饱和碳酸氢钠溶液(10ml)中,用二氯甲烷(50ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶2)得到化合物21b(27mg,34%)。
LC-MS(ESI):m/z=494.2[M+H]+.
第三步:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡唑[3,4-b]吡啶-3-基)-7-(甲氧甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物21)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
化合物21b(27mg,0.054mmol)溶于甲醇(2ml)中,加入氢氧化锂(23.0mg,0.54mmol溶于0.5ml水),加完升温至60℃反应5小时,反应完毕用1N盐酸调pH=5~6后用二氯甲烷(50ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶5)得到化合物21(12.0mg,48%)。
LC-MS(ESI):m/z=466.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ14.09(s,1H),12.38(s,1H),8.64(s,1H),8.56(d,1H),8.09(d,1H),7.04(d,1H),6.71(d,1H),4.92(s,1H),4.78(s,2H),3.33(s,3H),2.81(d,1H),2.05(d,2H),1.78-1.42(m,8H).
实施例22:(1S,2S,3R,4S)-5,5-二氟-3-((2-(5-F氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物22)
(1S,2S,3R,4S)-5,5-difluoro-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:(1R,2S,3S,4R)-3-(((苄氧基)羰基)氨基)-6-羟基二环[2.2.2]辛烷-2-羧酸乙酯(22b)
ethyl(1R,2S,3S,4R)-3-(((benzyloxy)carbonyl)amino)-6-hydroxybicyclo[2.2.2]octane-2-carboxylate
(1R,2S,3S,4R)-3-(((苄氧基)羰基)氨基)-5-羟基二环[2.2.2]辛烷-2-羧酸乙酯(22c)ethyl(1S,2S,3S,4S)-3-(((benzyloxy)carbonyl)amino)-5-hydroxybicyclo[2.2.2]octane-2-carboxylate
氮气保护下,化合物22a(2.0g,6.1mmol)溶于四氢呋喃(20ml)中,降温至0℃,缓慢滴加硼烷四氢呋喃溶液(7.3ml,7.3mmol,1.0mol/L溶液),加完自然回温反应2小时,反应完毕降温至0℃,将氢氧化钠(306mg,7.3mmol,5ml水)溶液滴加入反应瓶中,再次滴加双氧水(1.38g,12.2mmol,30%水溶液),加完自然回温反应5小时,反应完毕加入硫代硫酸钠水溶液(10ml)淬灭反应后,乙酸乙酯(100ml*2)萃取两次,合并有机相,饱和食盐水洗,无水硫酸钠干燥,过滤,滤液浓缩得化合物22b和化合物22c的混合物(2.0g,94%),直接用于下一步反应。
LC-MS(ESI):m/z=348.2[M+H]+.
第二步:(1R,2S,3S,4R)-3-(((苄氧基)羰基)氨基)-6-羰基二环[2.2.2]辛烷-2-羧酸乙酯(22d)
ethyl(1R,2S,3S,4R)-3-(((benzyloxy)carbonyl)amino)-6-oxobicyclo[2.2.2]octane-2-carboxylate
(1R,2S,3S,4R)-3-(((苄氧基)羰基)氨基)-5-羰基二环[2.2.2]辛烷-2-羧酸乙酯(22e)
ethyl(1S,2S,3S,4S)-3-(((benzyloxy)carbonyl)amino)-5-oxobicyclo[2.2.2]octane-2-carboxylate
氮气保护下,化合物22b和化合物22c的混合物(2.0g,5.7mmol)溶于二氯甲烷(20ml)中,控温0℃分批次加入戴斯-马丁氧化剂(3.6g,8.5mmol),加完自然回温反应5小时,反应完毕加入硫代硫酸钠水溶液(10ml)淬灭反应后,乙酸乙酯(100ml*2)萃取两次,合并有机相,饱和食盐水洗,无水硫酸钠干燥,过滤,滤液减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶1)得到化合物22d和化合物22e混合物(1.60g,80%),直接用于下一步反应。
LC-MS(ESI):m/z=346.2[M+H]+.
第三步:(1R,2S,3S,4R)-3-(((苄氧基)羰基)氨基)-6,6-二氟二环[2.2.2]辛烷-2-羧酸乙酯(22f)
ethyl(1R,2S,3S,4R)-3-(((benzyloxy)carbonyl)amino)-6,6-difluorobicyclo[2.2.2]octane-2-carboxylate
(1R,2S,3S,4R)-3-(((苄氧基)羰基)氨基)-5,5-二氟二环[2.2.2]辛烷-2-羧酸乙酯(22g)
ethyl(1S,2S,3R,4S)-3-(((benzyloxy)carbonyl)amino)-5,5-difluorobicyclo[2.2.2]octane-2-carboxylate
氮气保护下,化合物22d和化合物22e混合物(1.6g,4.65mmol)溶于二氯甲烷(16ml)中,降温至0~5℃滴加DAST(3.75g,23.23mmol)加完升温至40℃反应8小时,反应完毕将反应液缓慢倾倒入饱和碳酸氢钠溶液(100ml)中,淬灭完毕得到的反应液用二氯甲烷(100ml*2)萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,滤液减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶1)得到化合物22f和化合物22g混合物(1.3g,76%),直接用于下一步反应。
LC-MS(ESI):m/z=368.2[M+H]+.
第四步:(1R,2S,3S,4R)-3-氨基-6,6-二氟二环[2.2.2]辛烷-2-羧酸乙酯(22h)
ethyl(1R,2S,3S,4R)-3-amino-6,6-difluorobicyclo[2.2.2]octane-2-carboxylate
(1R,2S,3S,4R)-3-氨基-5,5-二氟二环[2.2.2]辛烷-2-羧酸乙酯(22i)
ethyl(1S,2S,3R,4S)-3-amino-5,5-difluorobicyclo[2.2.2]octane-2-carboxylate
氮气保护下,化合物22f和化合物22g混合物(1.3g,3.54mmol)溶于乙腈(15ml)中,降温至0℃滴加碘代三甲硅烷(1.06g,5.31mmol),加完自然回温反应,TLC监控反应完毕后滴加三乙胺(1.07g,10.62mmol),加完将反应液缓慢倾倒入冰水中,二氯甲烷(100ml*2)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液浓缩得化合物22h和化合物22i混合物(720mg,87%),产物未纯化直接下一步。
LC-MS(ESI):m/z=234.2[M+H]+.
第五步:(1S,2S,3R,4S)-3-((2-二氯吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)-5,5-二氟二环[2.2.2]辛烷-2-羧酸乙酯(22j)
ethyl(1S,2S,3R,4S)-3-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-5,5-difluorobicyclo[2.2.2]octane-2-carboxylate
(1S,2S,3R,4S)-3-((2-二氯吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)-6,6-二氟二环[2.2.2]辛烷-2-羧酸乙酯(22k)
ethyl(1S,2S,3R,4S)-3-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-6,6-difluorobicyclo[2.2.2]octane-2-carboxylate
化合物22h和化合物22i混合物(720.0mg,3.10mmol),化合物18a(553.0mg,2.95mmol)溶于异丙醇(10ml)中,加入DIPEA(1.20g,9.3mmol),加完升温至60℃反应,反应完毕后直接浓缩掉溶剂,残留物制备纯化得化合物22.j和化合物22k,制备HPLC分离方法:1.仪器:waters 2767制备液相;色谱柱:SunFire@Prep C18(19mm×250mm)2.样品用DMF溶解,用0.45μm滤头过滤,制成样品液。3.制备色谱条件:a.流动相A,B组成:流动相A:乙腈;流动相B:水(含0.1%TFA)b.梯度洗脱,流动相A含量从5%-50%c.流量12mL/min。d洗脱时间20min。化合物22j(140mg,12%),保留时间:11.3min;化合物22k(330mg,28%),保留时间:13.3min,具体构型未确定。
化合物22j:LC-MS(ESI):m/z=385.1[M+H]+.
化合物22j:1H NMR(400MHz,CDCl3)δ7.52(s,1H),6.62-6.61(m,1H),6.56(s,1H),4.95-4.90(m,1H),4.27-4.18(m,2H),2.52-1.87(m,10H),1.28-1.24(m,3H).
化合物22k:LC-MS(ESI):m/z=385.1[M+H]+.
化合物22k:1H NMR(400MHz,CDCl3)δ7.53(s,1H),6.63(s,1H),5.41(s,1H),4.76(s,1H),4.27-4.21(m,2H),2.79(d,1H),2.54-2.52(m,1H),2.40-2.38(m,1H),2.22-1.95(m,2H),1.81-1.59(m,4H),1.29-1.24(m,4H).
第六步:(1S,2S,3R,4S)-5,5-二氟-3-((2-(5-氟o-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(22m)
ethyl(1S,2S,3R,4S)-5,5-difluoro-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
氮气保护下,化合物22j(140mg,0.36mmol)溶于1,4-二氧六环和水的混合溶剂(6ml/0.2ml,v/v)中,再依次加入碳酸钾(150mg,1.08mmol),Pd(dppf)Cl2(37mg,0.05mmol),中间体1(225.0mg,0.54mmol),加完120℃微波反应1小时。反应完毕后直接浓缩,浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物22m(120mg,53%)。
第七步:(1S,2S,3R,4S)-5,5-二氟-3-((2-(5-F氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物22)
(1S,2S,3R,4S)-5,5-difluoro-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
化合物22m(120mg,0.19mmol)溶于甲醇(3ml)中,加入氢氧化锂(80.0mg,1.9mmol溶于0.5ml水),加完升温至60℃反应5小时,反应完毕用1N盐酸调pH=5~6后用二氯甲烷(50ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶2)得到化合物22(65.0mg,74%)。
LC-MS(ESI):m/z=457.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.21(d,2H),8.50(dd,1H),8.30-8.29(m,1H),8.20(d,1H),7.82(d,1H),7.73-7.72(m,1H),6.95(dd,1H),6.61-6.60(m,1H),4.92-4.86(m,1H),2.98(d,1H),2.63(s,1H),2.42(s,1H),2.30-2.07(m,2H),1.91-1.76(m,2H),1.57-1.53(m,2H).
实施例23:(1S,2S,3R,4S)-6,6二氟-3-((2-(5-F氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物23)
(1R,2S,3S,4R)-6,6-difluoro-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:(1S,2S,3R,4S)-6,6-二氟-3-((2-(5-氟o-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸乙酯(23a)
ethyl(1R,2S,3S,4R)-6,6-difluoro-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
氮气保护下,化合物22k(330mg,0.86mmol)溶于1,4-二氧六环和水的混合溶剂(10ml/0.5ml,v/v)中,再依次加入碳酸钾(356mg,2.58mmol),Pd(dppf)Cl2(73mg,0.1mmol),中间体1(538.0mg,1.29mmol),加完120℃微波反应1小时。反应完毕后直接浓缩,浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物23a(380mg,69%)。
第二步:(1S,2S,3R,4S)-6,6二氟-3-((2-(5-F氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)二环[2.2.2]辛烷-2-羧酸(化合物23)
(1R,2S,3S,4R)-6,6-difluoro-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
化合物23a(380mg,0.69mmol)溶于甲醇(5ml)中,加入氢氧化锂(290.0mg,6.9mmol溶于1ml水),加完升温至60℃反应5小时,反应完毕用1N盐酸调pH=5~6后用二氯甲烷(50ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶2)得到化合物23(150.0mg,47%)。
LC-MS(ESI):m/z=457.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.80(s,1H),12.20(d,1H),8.50(dd,1H),8.30-8.29(m,1H),8.21(d,1H),8.01(d,1H),7.73-7.72(m,1H),6.97(dd,1H),6.62-6.60(m,1H),4.74-4.72(m,1H),3.05(d,1H),2.46-2.25(m,3H),2.07-1.54(m,5H).
实施例24:(1R,6S,7S,8S)-8-((2-(5-氟-1H-吡咯并[3,4-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸(化合物24)
(1R,6S,7S,8S)-8-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylic acid
/>
第一步:(1R,6S,7S,8S)-8-((2-(5-氟-1-三苯甲基-1H-吡唑[3,4-b]三嗪-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸乙酯(24a)
ethyl(1R,6S,7S,8S)-8-((2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylate
氮气保护下,化合物26f(200mg,0.53mmol)溶于1,4-二氧六环和水的混合溶剂(5ml/0.2ml,v/v)中,再依次加入碳酸钾(220mg,1.6mmol),Pd(dppf)Cl2(36mg,0.05mmol),int-2(505.0mg,1.0mmol),加完120℃微波反应1小时。反应完毕后直接浓缩,浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物24a(140mg,37%)。
第二步:(1R,6S,7S,8S)-8-((2-(5-氟-1H-吡唑[3,4-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸乙酯(24b)
ethyl(1R,6S,7S,8S)-8-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylate
化合物24a(140mg,0.19mmol)溶于二氯甲烷(5ml)中,加入三氟乙酸(1ml),三乙基硅烷(440.0mg,3.2mmol),加完室温反应5小时,反应完毕后将反应液加入到饱和碳酸氢钠溶液(10ml)中,用二氯甲烷(50ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶2)得到化合物24b(24mg,26%)。
LC-MS(ESI):m/z=476.2[M+H]+.
第三步:(1R,6S,7S,8S)-8-((2-(5-氟-1H-吡咯并[3,4-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸(化合物24)
(1R,6S,7S,8S)-8-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylic acid
化合物24b(24mg,0.05mmol)溶于甲醇(2ml)中,加入氢氧化锂(21.0mg,0.5mmol溶于0.5ml水),加完升温至60℃反应5小时,反应完毕用1N盐酸调pH=5~6后用二氯甲烷(50ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶5)得到化合物24(12.0mg,53%)。
LC-MS(ESI):m/z=448.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ14.09(s,1H),12.38(s,1H),8.64(s,1H),8.53(d,1H),8.14(d,1H),7.76(s,1H),7.06(d,1H),6.69(d,1H),4.76(s,1H),4.07(s,2H),2.94-2.93(m,1H),2.72-2.69(m,1H),2.45-2.43(m,1H),2.19-1.71(m,8H).
实施例25(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-6-(乙酰氨基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物25)
(1R,2S,3S,4R)-3-((6-acetamido-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid
第一步:(1R,2S,3S,4R)-3-(((2-氯-6-(乙酰氨基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(25a)
Ethyl-(1R,2S,3S,4R)-3-((6-acetamido-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将化合物7f(300mg,0.7mmol)、乙酰胺(62mg,1.05mmol)、CuI(13mg,0.07mmol)、K3PO4(300mg,1.4mmol)、N,N′-二甲基-1,2-乙二胺(6.2mg,0.07mmol)混合溶于5mL 1,4-二氧六环中,微波加热至120℃,反应2小时。
LC-MS监测原料反应完全后,反应液浓缩,柱层析分离(PE∶EA=2∶1,v/v)得到160mg棕色固体化合物25a,收率56%。
LC-MS(ESI):m/z=373.1[M+H]+
第二步:(1R,2S,3S,4R)-3-((6-6-乙酰氨基-2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基]吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(25b)
ethyl(1R,2S,3S,4R)-3-((6-acetamido-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将25a(230mg,0.55mmol)、Pd(dppf)Cl2(34mg,0.046mmol),碳酸钾(127mg,0.92mmol)混合溶于5mL1,4-二氧六环、0.1mL水中,微波加热至120℃,反应1小时.LC-MS监测原料反应完全后,浓缩反应液,柱层析分离(PE∶EA=2∶1,v/v)得到220mg棕色固体化合物25b,收率:72.5%。
LC-MS(ESI):m/z=660.2[M+H]+
第三步:
(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-6-(乙酰氨基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物25)
(1R,2S,3S,4R)-3-((6-acetamido-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid
将25b(220mg,0.33mmol)溶于10mL甲醇中,加入氢氧化锂(79mg,3.3mmol)水溶液,加热至60℃,反应6小时。LC-MS监测反应完全后,加入2N盐酸水溶液调pH至6,浓缩反应液,pre-HPLC制备分离(液相制备条件:C18反相制备柱,流动相为含0.1%三氟乙酸的去离子水(A),乙腈(B),梯度洗脱,B含量=5%~50%,洗脱时间15min,流速12mL/min,柱温:30℃),得到90mg黄色固体化合物25,保留时间6.5min,收率:55%。
LC-MS(ESI):m/z=478.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),10.15(s,1H),8.52-8.49(m,1H),8.28-8.26(m,1H),8.16-8.15(d,1H),7.88-7.86(d,1H),7.79(d,1H),7.02(d,1H),4.80-4.77(m,1H),2.81-2.79(d,1H),2.06(s,2H),2.02(s,2H),1.82-1.42(m,8H).
实施例26(1R,6S,7S,8S)-8-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸(化合物26)
(1R,6S,7S,8S)-8-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylic acid
第一步:3a,4,4a,6a,7,7a-六氢-4,7-乙炔环丁[f]异苯并呋喃-1,3-二酮(26-B)
3a,4,4a,6a,7,7a-hexahydro-4,7-ethenocyclobuta[f]isobenzofuran-1,3-dione
将马来酸酐(16.95g,172.83mmol)溶于250mL氯苯中,冰浴下加入环辛-1,3,5,7-四烯(18g,172.83mmol),升温至120摄氏度,反应过夜。浓缩反应液至干,有黄色固体析出,加入50mL甲醇打浆1小时,抽滤,滤饼用少量甲醇洗,滤饼烘干,得到22g白色固体化合物26b,收率:63%。
LC-MS(ESI):m/z=203.1[M+H]+
第二步:(1S,6R,7S,8S)-8-(乙氧羰基)三环[4.2.2.02,5]deca-3,9-二烯-7-羧酸(26c)
(1S,6R,7S,8S)-8-(ethoxycarbonyl)tricyclo[4.2.2.02.5]deca-3,9-diene-7-carboxylic acid
将26b(10g,49.45)溶于500mL甲苯中,加入奎宁(17.65g,54.40mmol),-20℃下加入无水乙醇(17mL),该温度下反应过夜。原料反应完全后,加入6N盐酸水溶液8mL,搅拌半小时,分液,有机相用无水硫酸钠干燥半小时,干燥后的有机相-20℃下滴加叔戊醇钾(1.7M,58mL),保持该温度继续搅拌半小时,加入2mL乙酸,再加入80mL 2N盐酸水溶液搅拌15分钟,萃取分液。有机相用饱和食盐水洗一次,干燥有机相,浓缩至干,柱层析(PE∶EA=5∶1,v/v)得到6.9g无色油状物化合物26c,收率:56%。
LC-MS(ESI):m/z=249.1[M+H]+
第三步:(1R,6S,7S,8S)-8-((((苄氧基)羰基)氨基)三环[4.2.2.02,5]deca-3,9-diene-7-羧酸乙酯(26d)
Ethyl-(1R,6S,7S,8S)-8-(((benzyloxy)carbonyl)amino)tricyclo[4.2.2.02,5]deca-3,9-diene-7-carboxylate
将26c(0.55g,2.22mmol)、三乙胺(0.62mL,0.45mmol)溶于10ml甲苯中,搅拌下加入DPPA(0.73g,2.66mmol),升温至96℃反应1小时,在加入苯甲醇(0.23ml,2.22mmol),继续96℃下反应5小时。原料反应完全后,分别加入25mlEA、10ml饱和碳酸氢钠水溶液,萃取分离有机相,有机相干燥浓缩过柱(PE∶EA=10∶1,v/v),得到无色油状物645mg化合物26d,收率:82%。
LC-MS(ESI):m/z=354.2[M+H]+
第四步:(1R,6S,7S,8S)-8-氨基三环[4.2.2.02,5]癸烷-7-羧酸乙酯(26e)
ethyl(1R,6S,7S,8S)-8-aminotricyclo[4.2.2.02,5]decane-7-carboxylate
将26d(0.644g,1.82mmol)溶于50mL甲醇中,加入120mg 10%钯碳,氢气置换2次,氢气条件下室温反应2小时。原料反应完全后,抽滤去除钯碳,甲醇洗一次滤饼,母液浓缩至干,得到无色油状物405mg,即化合物26e,收率:99%。
LC-MS(ESI):m/z=224.2[M+H]+
第五步:(1R,6S,7S,8S)-8-((2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸乙酯(26f)
Ethyl-(1R,6S,7S,8S)-8-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylate
将26e(0.34g,1.79mmol)、DIEA(0.59mL,3.58mmol)混合溶于20mL异丙醇中,升温至60℃,搅拌2小时。浓缩反应液,柱层析分离(PE∶EA=4∶1,v/v)得到无色油状物(26f)316mg,收率47%。
LC-MS(ESI):m/z=375.2[M+H]+
第六步:(1R,6S,7S,8S)-8-((2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸乙酯(26g)
Ethyl-(1R,6S,7S,8S)-8-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylate
将26f(0.1g,0.27mmol)、5-氟-1-(4-甲基苯磺酰基)-3-(四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡咯并[2,3-b]吡啶(0.13g,0.32mmol)、碳酸钾(75mg,0.54mmol)、Pd(dppf)Cl2(20mg,0.027)混合溶于3mL1,4-二氧六环和0.2mL水中,N2置换,微波加热至120℃反应1小时。浓缩反应液,柱层析分离(PE∶EA=3∶1,v/v)得到白色固体(26g)114mg,收率67%。
LC-MS(ESI):m/z=629.2[M+H]+
第七步:(1R,6S,7S,8S)-8-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸(化合物26)
(1R,6S,7S,8S)-8-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylic acid
将26g(114mg,0.18mmol)溶于10mL甲醇中,加入氢氧化锂(86mg,3.6mmol)水溶液,加热至60℃,反应5小时。LC-MS监测反应完全后,加入2N盐酸水溶液调pH至6,浓缩反应液,pre-HPLC制备分离(液相制备条件:C18反相制备柱,流动相为含0.1%三氟乙酸的去离子水(A),乙腈(B),梯度洗脱,B含量=5%~50%,洗脱时间15min,流速12mL/min,柱温:30℃)。得到72mg黄色固体化合物26,保留时间:7.5min,收率:89%。
LC-MS(ESI):m/z=447.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.50-8.47(m,1H),8.28-8.27(m,1H),8.15-8.14(d,1H),7.92-7.90(d,1H),7.67(d,1H),6.96(d,1H),6.60-6.58(m,1H),4.67-4.63(m,1H),2.90-2.87(d,1H),2.73(s,1H),2.45-2.40(m,1H),2.22-2.08(m,4H),2.03-2.00(m,3H),1.89-1.63(m,4H).
实施例27:(2S,3S)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基]咪唑[5,1-f][1,2,4]三嗪-4-(基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物27)
(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[5,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:1-氨基-1H-咪唑-5-羧酸乙酯(27b)
ethyl 1-amino-1H-imidazole-5-carboxylate
将27a(1.4g,10mmol)溶于N,N-二甲基甲酰胺(50mL)中,氮气保护,在-10℃的条件下加入双三甲基硅基胺基锂(2.5M,4mL),30min后加入二苯基膦酰羟胺(2.35g,10mmol),自然升温到室温反应4小时,减压浓缩后用二氯甲烷洗涤(100mL×3),洗涤液浓缩后用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=0.1∶1~0.3∶1),得到标题化合物(27b),黄色固体(600mg,产率38%)
LCMS m/z=156.07[M+1]
第二步:1-(双(甲氧基羰基)氨基)-1H-咪唑-5-羧酸乙酯(27c)
ethyl 1-(bis(methoxycarbonyl)amino)-1H-imidazole-5-carboxylate
将27b(600mg,3.87mmol)溶于DMF(20mL)中,加氯甲酸甲酯(1.1g,11.61mmol),吡啶(930mg,11.61mmol),氮气保护,室温下反应1小时,加入水(30mL),用二氯甲烷萃取(30mL×3),稀盐酸洗涤(1N,30mL×1),无水硫酸钠干燥,用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=0.1∶1~0.5∶1),得到标题化合物27c,淡黄色固体(500mg,产率48%)。
LC-MS m/z=272.08[M+1]
第三步:咪唑并[5,1-f][1,2,4]三嗪-2,4(1H,3H)-二酮(27d)
imidazo[5,1-f][1,2,4]triazine-2,4(1H,3H)-dione
将27c(500mg,1.85mmol)置于封管中(100mL),加入异丙醇(10mL),再加入氨水(10mL),110℃反应12小时,浓缩后得到标题化合物(27d),黄色固体(300mg,产率100%)。
LC-MS m/z=153.03[M+1]
第四步:2,4-二氯咪唑并[5,1-f][1,2,4]三嗪(27e)
2,4-dichloroimidazo[5,1-f][1,2,4]triazine
将咪唑并[5,1-f][1,2,4]三嗪-2,4(1H,3H)-二酮(27d)(300mg,1.85mmol)置于封管中(100mL),加入三氯氧磷(20mL),三乙胺盐酸盐(754mg,5.55mmol),110℃反应12小时,浓缩后用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=0.1∶1~0.5∶1)得到标题化合物2,4-二氯咪唑并[5,1-f][1,2,4]三嗪(27e),黄色固体(150mg,产率43%)。
LCMS m/z=189.01[M+1]
第五步:(2S,3S)-3-((2-氯咪唑并[5,1-f][1,2,4]三嗪-4基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(27f)
ethyl(2S,3S)-3-((2-chloroimidazo[5,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将27e(150mg,0.79mmol)溶于异丙醇中(10mL),加入(2S,3S)-3-氨基双环[2.2.2]辛烷-2-羧酸乙酯盐酸盐(233mg,1.0mmol),N,N-二异丙基乙胺(516mg,4.0mmol),60℃反应1小时,浓缩后用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=0.1∶1~0.3∶1)得到标题化合物27f,黄色固体(100mg,产率36%)。
LC-MS m/z=350.13[M+1]
第六步:(2S,3S)-3-((2-(5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)咪唑[5,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(27g)
ethyl(2S,3S)-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[5,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将27f(80mg,0.43mmol)溶于二氧六环中(10mL),加入5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(247mg,0.60mmol),碳酸钾(166mg,1.2mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯化钯(50mg,0.07mmol),再加入水(1mL),氮气保护,微波120℃反应1小时,浓缩后用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=1∶5~1∶1)得到标题化合物27g,黄色固体(80mg,产率46%)。
LC-MS m/z=604.21[M+1]
第七步:(2S,3S)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基]咪唑[5,1-f][1,2,4]三嗪-4-(基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物27)
(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[5,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
将27g(80mg,0.13mmol)溶于甲醇中(10mL),加入水(5mL),氢氧化锂(29mg,1.2mmol),60℃反应2小时,用1N盐酸调节pH=5~6,加入水(20mL),用二氯甲烷萃取(50mL×3),合并有机相,有机相用饱和氯化钠水溶液洗涤(50mL),无水硫酸钠干燥,浓缩得到的粗品化合物用液相制备柱分离提纯(液相制备条件:C18反相制备柱,流动相为含0.1%三氟乙酸的去离子水(A),乙腈(B),梯度洗脱,B含量=5%~50%,洗脱时间15min,流速12mL/min,柱温:30℃);得到标题化合物(化合物27)(19mg,32%,保留时间约为6.3min)。
1H NMR(400MHz,DMSO-d6)δ12.35(d,2H),8.54-8.44(m,3H),8.27(d,2H),7.83(s,1H),4.94-4.66(m,1H),2.72(d,1H),2.05-2.02(m,2H),1.80-1.46(m,8H).
MS M/Z(ESI):m/z=422.17(M+1)
实施例28(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物28)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:(1R,2S,3S,4R)-3-((2-氯-7-(羟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(28a)
ethyl-(1R,2S,3S,4R)-3-((2-chloro-7-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
化合物12a(700mg,1.86mmol)溶于甲醇(7mL)中,加入硼氢化钠(70mg,1.86mmol),室温反应30分钟。加水和乙酸乙酯萃取,乙酸乙酯相减压浓缩至干,残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~2∶1)得到化合物28a(400mg,56.9%)。
LC-MS(ESI):m/z=379.2[M+H]+.
1H NMR(400MHz,CDCl3)δ6.55(s,2H),5.58(s,1H),4.90(s,2H),4.67(s,1H),4.24-4.19(m,2H),2.83(s,1H),2.45-2.43(m,1H),2.04-2.03(m,1H),1.96-1.95(m,1H),1.84-1.80(m,1H),1.73-1.58(m,6H),1.48-1.42(m,1H),1.28-1.25(t,3H).
第二步:(1R,2S,3S,4R)-3-((2-氯-7-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(28b)
ethyl-(1R,2S,3S,4R)-3-((2-chloro-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
化合物28a(120mg,0.32mmol)溶于二氯甲烷(5mL)和甲醇(5mL)的混合溶剂中,加入2mol/L三甲基硅基重氮甲烷的正己烷溶液(1.3mL,3.2mmol),室温反应4小时,间隔2小时反复补加2mol/L三甲基硅基重氮甲烷的正己烷溶液(1.3mL*3,3.2mmol),室温搅拌过夜。加入二氯甲烷和水萃取,二氯甲烷相减压浓缩,残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物28b(48mg,38.7%)。
LC-MS(ESI):m/z=393.2[M+H]+.
1H NMR(400MHz,CDCl3)δ6.62(m,2H),5.51(s,1H),4.74(s,2H),4.67(s,1H),4.24-4.19(m,2H),3.41(s,3H),2.43-2.42(m,1H),2.03-2.02(m,1H),1.95-1.94(m,1H),1.84-1.81(m,1H),1.75-1.56(m,6H),1.47-1.42(m,1H),1.28-1.24(t,3H).
第三步:(1R,2S,3S,4R)-3-((2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基)-7-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(28c)
ethyl-(1R,2S,3S,4R)-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将化合物28b(48mg,0.122mmol)溶于1,4-二氧六环(2mL)和水(0.2mL)的混合溶剂中,加入中间体2(77mg,0.183mmol),碳酸钾(36mg,0.244mmol),Pd(dppf)Cl2(22mg,0.025mmol),氮气保护下,用微波反应器120℃反应1小时,加入乙酸乙酯和水萃取,乙酸乙酯相减压浓缩,残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~2∶1)得到化合物28c(70mg,88.6%)。
LC-MS(ESI):m/z=647.2[M-H]+.
第四步:(1R,2S,3S,4R)-3-((7-乙炔基-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物28)
(1R,2S,3S,4R)-3-((7-ethynyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid
化合物28c(70mg,0.108mmol)溶于甲醇(5mL)和水(1mL)中,加入氢氧化锂(91mg,2.16mmol),加完升温至60℃反应2小时,反应完毕用1N盐酸调pH=5~6后用乙酸乙酯(50mL*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶1)得到化合物28(25mg,50%)。
LC-MS(ESI):m/z=465.2[M+H]+.
1H NMR(400MHz,CDCl3,small MeOD)δ8.68-8.66(d,1H),8.36(s,1H),8.13(s,1H),6.66-6.63(d,2H),4.90(s,2H),4.76(s,1H),3.52(s,3H),2.59(s,1H),2.13(s,1H),1.99(s,1H),1.84-1.73(m,7H),1.53-1.48(m,1H).
实施例29:(1R,2S,3S,4R)-3-((7-乙炔基-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物29)
(1R,2S,3S,4R)-3-((7-ethynyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid
第一步:(1R,2S,3S,4R)-3-((2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基)-7-甲酰基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(29a)
ethyl-(1R,2S,3S,4R)-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-formylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
化合物12a(500mg,1.33mmol)溶于1,4-二氧六环(5mL)和水(0.5mL)的混合溶剂中,加入中间体2(830mg,1.99mmol),碳酸钾(367mg,2.66mmol),Pd(dppf)Cl2(217mg,0.26mmol),氮气保护下,用微波反应器120℃反应1小时,加入乙酸乙酯和水萃取,乙酸乙酯相减压浓缩,残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物29a(600mg,71.7%)。
LC-MS(ESI):m/z=631.2[M+H]+.
第三步:(1R,2S,3S,4R)-3-((7-乙炔基-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(29b)
ethyl-(1R,2S,3S,4R)-3-((7-ethynyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将化合物29a(300mg,0.476mmol)加入到甲醇(3mL)和四氢呋喃(3mL)中,再加入碳酸钾(132mg,0.952mmol),降温至0℃,滴加(1-重氮-2-氧丙基)膦酸二甲酯(138mg,0.714mmol),滴毕,移至室温搅拌过夜,加入乙酸乙酯和水萃取,乙酸乙酯相减压浓缩,残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~2∶1)得到化合物29b(60mg,26.7%)。
LC-MS(ESI):m/z=473.2[M-H]+.
第四步:(1R,2S,3S,4R)-3-((7-乙炔基-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物29)
(1R,2S,3S,4R)-3-((7-ethynyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylicacid
化合物29b(60mg,0.127mmol)溶于甲醇(5mL)和水(1mL)中,加入氢氧化锂(106mg,2.54mmol),加完升温至60℃反应2小时,反应完毕用1N盐酸调pH=5~6后用乙酸乙酯(50mL*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶1)得到化合物29(20mg,35.7%)。
LC-MS(ESI):m/z=445.2[M+H]+.
1H NMR(400MHz,CDCl3,small MeOD)δ8.73(d,1H),8.32(s,1H),8.14(s,1H),6.86-6.84(d,1H),6.60-6.58(d,1H),4.73-4.71(m,1H),3.75(s,1H),2.59-2.57(m,1H),2.12-2.11(m,1H),1.90-1.82(m,4H),1.76-1.70(m,4H),1.52-1.51(m,1H).
实施例30:(1R,5S,6S,7S)-7-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸(化合物30)
(1R,5S,6S,7S)-7-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylic acid
第一步:(1R,5S,6S,7S)-7-(((2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(30b)
ethyl(1R,5S,6S,7S)-7-((2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
将(30a)(800mg,3.26mmol)溶于异丙醇(30mL),加入2,4-二氯吡咯并[2,1-f][1,2,4]三嗪(610mg,3.26mmol),N,N-二异丙基乙胺(1.2g,9.78mmol),60℃反应2小时,减压浓缩后用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=0.1∶1~0.4∶1),得到标题化合物(30b),黄色固体(1.0g,产率85%)
LCMS m/z=361.14[M+1]
第二步:(1R,5S,6S,7S)-7-(((2-氯-7-碘吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[32.2.02,4]壬烷-6-羧酸乙酯(30c)
ethyl(1R,5S,6S,7S)-7-((2-chloro-7-iodopyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
将30b(1.0g,2.7mmol)溶于DCE(50mL)中,冰浴下加入N-碘代丁二酰亚胺(608mg,2.7mmol),自然升温到室温下反应2小时,用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=0.1∶1~0.4∶1),得到标题化合物(30c),淡黄色固体(500mg,产率38%)。
LCMS m/z=487.03[M+1]
第三步:
(1R,5S,6S,7S)-7-(((2-氯-7-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(30d)
ethyl(1R,5S,6S,7S)-7-((2-chloro-7-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
将30c(500mg,1.03mmol)溶于DMF(40mL)中,加入碘化亚铜(391mg,2.06mmol),2,2-二氟-2-(氟磺酰基)乙酸甲酯(1056mg,5.5mmol),氮气保护,110℃反应4小时,加入水(30mL),用乙酸乙酯萃取(30mL×3),水洗(30mL×3),无水硫酸钠干燥,用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=0.1∶1~0.4∶1),得到标题化合物(30d),淡黄色固体(320mg,产率72%)。
LCMS m/z=429.12[M+1]
第四步:
(1R,5S,6S,7S)-7-((2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基)-7-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(30e)
ethyl(1R,5S,6S,7S)-7-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
将30d(120mg,0.28mmol)溶于二氧六环中(10mL),加入5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(165mg,0.4mmol),碳酸钾(116mg,0.84mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯化钯(50mg,0.07mmol),再加入水(1mL),氮气保护,微波120℃反应1小时,浓缩后用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=1∶5~1∶1)得到标题化合物30e,黄色固体(90mg,产率47%)。
LCMS m/z=683.20[M+1]
第七步:
(1R,5S,6S,7S)-7-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸(化合物30)
(1R,5S,6S,7S)-7-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylic acid
将(30e)(90mg,0.13mmol)溶于甲醇中(10mL),加入水(5mL),氢氧化锂(29mg,1.2mmol),60℃反应2小时,用1N盐酸调节pH=5~6,加入水(20mL),用二氯甲烷萃取(50mL×3),合并有机相,有机相用饱和氯化钠水溶液洗涤(50mL),无水硫酸钠干燥,浓缩得到的粗品化合物用液相制备柱分离提纯(液相制备条件:C18反相制备柱,流动相为含0.1%三氟乙酸的去离子水(A),乙腈(B),梯度洗脱,B含量=5%~50%,洗脱时间15min,流速12mL/min,柱温:30℃);得到标题化合物(化合物30)(10mg,15%,保留时间约为6.5min)。
1H NMR(400MHz,DMSO-d6)δ12.28(d,2H),8.38(d,2.9Hz,1H),8.31(d,1H),8.27(d,1H),8.15(d,1H),7.16(d,1H),7.09(d,1H),4.45-4.39(m,1H),2.64-2.59(m,2H),2.39-2.31(m,1H),1.76-1.65(m,2H),1.62-1.48(m,2H),1.13-1.02(m,1H),0.97-0.84(m,2H),0.44-0.33(m,1H).
MS M/Z(ESI):m/z=501.16(M+1)
实施例31(1R,5S,6S,7S)-7-((2-(5-氟-1H-吡唑并[3,4-b]吡啶-3-基)-7-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸(化合物31)
(1R,5S,6S,7S)-7-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylic acid
第一步:(1R,5S,6S,7S)-7-((2-(5-氟-1-三苯甲基-1H-吡唑并[3,4-b]吡啶-3-基)-7-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(31a)
ethyl(1R,5S,6S,7S)-7-((2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
将30d(200mg,0.47mmol)溶于二氧六环中(10mL),加入5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-三苯甲基-1H-吡唑并[3,4-b]吡啶(中间体int-2)(712mg,1.4mmol),碳酸钾(194mg,1.41mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯化钯(50mg,0.07mmol),再加入水(1mL),氮气保护,微波120℃反应1小时,浓缩后用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=1∶5~1∶1)得到标题化合物(31a),黄色固体(110mg,产率30%)。
LCMS m/z=772.29[M+1]
第二步:(1R,5S,6S,7S)-7-((2-(5-氟-1H-]吡唑并[3,4-b]吡啶-3-基)-7-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(31b)
ethyl(1R,5S,6S,7S)-7-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
将31a(110mg,0.14mmol)溶于二氯甲烷(20mL)中,加入三氟乙酸(1mL),三乙基硅烷(0.5mL),室温下反应1小时,加入水(30mL),用二氯甲烷萃取(30mL×3),无水硫酸钠干燥,用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=0.1∶1~1∶1),得到标题化合物(31b),淡黄色固体(50mg,产率67%)。
LCMS m/z=530.18[M+1]
第三步:
(1R,5S,6S,7S)-7-((2-(5-氟-1H-吡唑并[3,4-b]吡啶-3-基)-7-(三氟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸(化合物31)
(1R,5S,6S,7S)-7-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylic acid
将31b(50mg,0.10mmol)溶于甲醇中(10mL),加入水(5mL),氢氧化锂(29mg,1.2mmol),60℃反应2小时,用1N盐酸调节pH=5~6,加入水(20mL),用二氯甲烷萃取(50mL×3),合并有机相,有机相用饱和氯化钠水溶液洗涤(50mL),无水硫酸钠干燥,浓缩得到的粗品化合物用液相制备柱分离提纯(液相制备条件:C18反相制备柱,流动相为含0.1%三氟乙酸的去离子水(A),乙腈(B),梯度洗脱,B含量=5%~50%,洗脱时间15min,流速12mL/min,柱温:30℃);得到标题化合物(化合物31),(20mg,39%,保留时间约为6.0min)
1H NMR(400MHz,DMSO-d6)δ13.92(d,2H),8.65(s,1H),8.43(d,1H),8.20(s,1H),7.33-6.94(m,2H),4.89-4.51(m,1H),2.80-2.58(m,2H),2.48-2.43(m,1H),1.71-1.62(m,2H),1.54-1.41(m,1H),1.27-1.22(m,1H),1.11-0.95(m,2H),0.86-0.70(m,1H),0.39-0.19(m,1H).
MS M/Z(ESI):m/z=502.15(M+1)
实施例32:(1R,5S,6S,7S)-7-((2-(5-氟-1H-吡唑[3,4-b]吡啶-3-基)-7-(甲氧甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸(化合物32)
(1R,5S,6S,7S)-7-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylic acid
第一步:乙基(1R,5S,6S,7S)-7-((2-(5-氟-1-三苯甲基-1H-吡唑[3,4-b]吡啶-3-基)-7-甲氧甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧(32a)
Ethyl(1R,5S,6S,7S)-7-((2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-
(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
氮气保护下,化合物20c(1.0g,247mmol)溶于1,4-二氧六环和水的混合溶剂(15ml/0.3ml,v/v)中,再依次加入碳酸钾(1.0g,7.42mmol),Pd(dppf)Cl2(146mg,0.2mmol),中间体2(2.5g,4.94mmol),加完120℃微波反应1小时。反应完毕后直接浓缩,浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~3∶1)得到化合物32a(1.1g,61%)。
第二步:(1R,5S,6S,7S)-7-((2-(5-氟-1H-吡唑[3,4-b]吡啶-3-基)-7-(甲氧甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(32b)
ethyl(1R,5S,6S,7S)-7-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-
(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
化合物32a(1.1g,1.5mmol)溶于二氯甲烷(15ml)中,加入三氟乙酸(1ml),三乙基硅烷(1.7g,15.0mmol),加完室温反应5小时,反应完毕后将反应液加入到饱和碳酸氢钠溶液(50ml)中,用二氯甲烷(100ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶2)得到化合物32b(310.0mg,41%)。
LC-MS(ESI):m/z=506.2[M+H]+.
第三步:(1R,5S,6S,7S)-7-((2-(5-氟-1H-吡唑[3,4-b]吡啶-3-基)-7-(甲氧甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸(化合物32)
(1R,5S,6S,7S)-7-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylic acid
化合物32b(310.0mg,0.61mmol)溶于甲醇(5ml)中,加入氢氧化锂(256.0mg,6.1mmol溶于1ml水),加完升温至60℃反应5小时,反应完毕用1N盐酸调pH=5~6后用二氯甲烷(50ml*2)萃取两次,合并有机层,无水硫酸钠干燥,过滤,减压浓缩残留物用柱层析分离纯化(石油醚∶乙酸乙酯(v/v)=10∶1~1∶5)得到化合物32(220.0mg,75%)。
LC-MS(ESI):m/z=478.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ14.12(s,1H),12.52(s,1H),8.65(s,1H),8.53(dd,1H),7.43(d,1H),7.06(d,1H),6.73(d,1H),4.79(s,2H),4.61(s,1H),3.34(s,3H),2.85-2.76(m,2H),2.49-2.47(m,1H),1.68-1.53(m,4H),1.14-1.03(m,2H),0.82-0.80(m,1H),0.35-0.30(m,1H).
实施例33:(1R,2S,3S,4R)-3-((7-(二甲基氨基)-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物33)
(1R,2S,3S,4R)-3-((7-(dimethylamino)-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:2,4-二氯-7-硝基吡咯并[2,1-f][1,2,4]三嗪(33b)
2,4-dichloro-7-nitropyrrolo[2,1-f][1,2,4]triazine
将HNO3(3.35g,53mmol)滴入乙酸酐(5ml)中,得到的混合液在0℃将其滴入2,4-二氯吡咯并[2,1-f][1,2,4]三嗪(33a)(2g,10.64mmol)的乙酸酐(30ml)溶液中,缓慢升至室温反应1h。得到的反应液倒入水(150ml)中,过滤。固体用水洗涤,干燥,得到粗品化合物2,4-二氯-7-硝基吡咯并[2,1-f][1,2,4]三嗪(33b)(2g)。
第二步:(1R,2S,3S,4R)-3-(((2-氯-7-硝基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(33c)
(1R,2S,3S,4R)-ethyl3-((2-chloro-7-nitropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将33b(2g,8.56mmol)和(1R,2S,3S,4R)-3-氨基双环[2.2.2]辛烷-2-羧酸乙酯盐酸盐(1.995g,8.56mmol)加入DCM(20mL)中,加入DIPEA(3.3g,25.68mmol),室温反应1h。加入水(50mL),用DCM萃取(30ml*2),合并有机相,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩后用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶8)得到(33c)(1.9g)。
LC-MS(ESI):m/z=394.1[M+H]+.
第三步:(1R,2S,3S,4R)-3-((7-氨基-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(33d)
(1R,2S,3S,4R)-ethyl3-((7-amino-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将33c(1.2g,3mmol)和乙酸(1.8g,30mmol)加入甲醇(15ml)中,再分批加入锌粉(1.95g,30mmol),室温反应1h,过滤,滤液浓缩得到粗品化合物(1R,2S,3S,4R)-3-((7-氨基-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(33d)(1.2g)。
LC-MS(ESI):m/z=364.2[M+H]+.
第四步:(1R,2S,3S,4R)-3-(((2-氯-7-(二甲基氨基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2--羧酸乙酯(33e)
(1R,2S,3S,4R)-ethyl3-((2-chloro-7-(dimethylamino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将33d(500mg,1.38mmol)、碳酸钾(571mg,4.14mmol)和碘甲烷(583mg,4.14mmol)加入DMF(5ml)中,室温反应2h。加入水(50ml),乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶4),得到化合物(33e)(360mg,67%)
LC-MS(ESI):m/z=392.2[M+H]+.
第五步:(1R,2S,3S,4R)-3-((7-(二甲基氨基)-2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基]吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(33f)
ethyl(1R,2S,3S,4R)-3-((7-(dimethylamino)-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将33e(360mg,0.92mmol)、中间体1(500mg,1.2mmol)、Pd(dppf)Cl2(150mg,0.18mmol)和碳酸钾(380mg,2.76mmol)加入二氧六环(8mL)中,再加入水(0.5ml).N2置换后升温至110℃微波反应1h。降至室温,过滤,滤液减压浓缩后硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶4),得到化合物(33f)(400mg,产率60.6%)。
LC-MS(ESI):m/z=646.2[M+H]+.
第六步:(1R,2S,3S,4R)-3-((7-(二甲基氨基)-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物33)
(1R,2S,3S,4R)-3-((7-(dimethylamino)-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
室温下,将33f(330mg,0.51mmol)和LiOH H2O(210mg,5.1mmol)加入THF(5ml)中,再加入乙醇(5ml)和水(2ml),升温至60℃反应2h。降至室温,用稀盐酸调至pH=5-6,EA萃取(15ml*3),合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到的粗产物经制备HPLC分离提纯得到化合物33(200mg 75.8%)。制备HPLC分离方法:1.仪器:waters 2767制备液相;色谱柱:SunFire@Prep C18(19mm×250mm)2.样品用DMF溶解,用0.45μm滤头过滤,制成样品液。3.制备色谱条件:a.流动相A,B组成:流动相A:乙腈;流动相B:水(含0.1%TFA)b.梯度洗脱,流动相A含量从5%-50%c.流量12mL/min。d洗脱时间20min。
化合物33保留时间:14.1min;
1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),12.18(d,1H),8.48(dd,1H),8.28(dd,1H),8.19(d,1H),7.58-7.53(t,2H),6.58(d,1H),4.72-4.68(m,1H),2.70(s,6H),2.49(m,1H),1.98(s,2H),1.78-1.50(m,7H),1.48-1.45(m,1H).
LC-MS(ESI):m/z=464.2[M+H]+.
实施例34:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-甲氧基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物34)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methoxypyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:(1R,2S,3S,4R)-3-((7-乙酰氧基-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(34b)ethyl(1R,2S,3S,4R)-3-((7-acetoxy-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将34a(同化合物18b)(3.56g,10.2mmol)和碘苯二乙酸(3.9g,12.3mmol)加入乙酸(30ml),室温反应2h,再加入醋酸钯(456mg,2mmol),N2置换后室温反应过夜。向反应体系中加入水(150ml),EA萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶6)得到(34b)(1.2g,29%)。
LC-MS(ESI):m/z=407.1[M+H]+.
第二步:(1R,2S,3S,4R)-3-(((2-氯-7-羟基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(34c)ethyl(1R,2S,3S,4R)-3-((2-chloro-7-hydroxypyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将34b(1.2g,3mmol),乙酸钠(2.4g,30mmol)和水(10ml)加入乙醇(15ml)中,外温85℃反应1h。反应液降至室温,将反应液减压浓缩掉部分乙醇,加水(20ml),用EA萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到化合物(34c)(1.05g,96%)。
LC-MS(ESI):m/z=365.1[M+H]+.
第三步:(1R,2S,3S,4R)-3-(((2-氯-7-甲氧基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(34d)
ethyl(1R,2S,3S,4R)-3-((2-chloro-7-methoxypyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将34c(500mg,1.37mmol)加入甲醇(10ml),再滴入三甲基硅烷化重氮甲烷(7mmol),室温反应2h。直接将反应液减压浓缩后用硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶6)得到(34d)(400mg,77%)。
LC-MS(ESI):m/z=379.2[M+H]+.
第四步:(1R,2S,3S,4R)-3-((2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基)-7-甲氧基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(34e)
ethyl(1R,2S,3S,4R)-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methoxypyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
将34d(300mg,0.79mmol)、中间体1(400mg,0.95mmol)、Pd(dppf)Cl2(129mg,0.16mmol)和碳酸钾(327mg,2.37mmol)加入二氧六环(8mL)中,再加入水(0.5ml)。N2置换后升温至110℃微波反应1h。降至室温,过滤,滤液减压浓缩后硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶4),得到化合物(34e)(400mg,80%)。
LC-MS(ESI):m/z=633.2[M+H]+.
第五步:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-甲氧基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物34)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-methoxypyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
室温下,将34e(400mg,0.63mmol)和LiOH·H2O(265mg,6.3mmol)加入THF(5ml)中,再加入乙醇(5ml)和水(2ml),升温至60℃反应2h。降至室温,用稀盐酸调至pH=5-6,EA萃取(15ml*3),合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到的粗产物经制备HPLC分离提纯得到化合物34(100mg 35%)。制备HPLC分离方法:1.仪器:waters 2767制备液相;色谱柱:SunFire@Prep C18(19mm×250mm)2.样品用DMF溶解,用0.45μm滤头过滤,制成样品液。3.制备色谱条件:a.流动相A,B组成:流动相A:乙腈;流动相B:水(含0.1%TFA)b.梯度洗脱,流动相A含量从5%-50%c.流量12mL/min。d洗脱时间20min。
化合物34保留时间:14.3min;
1H NMR(400MHz,DMSO-d6)δ12.17(m,2H),8.48(dd,1H),8.27(dd,1H),8.17(d,1H),7.54(d,1H),6.39(d,1H),6.35(d,1H),4.72(t,1H),3.90(s,3H),2.62(d,1H),1.98(s,2H),1.73-1.68(m,3H),1.64-1.58(m,3H),1.52-1.38(m,2H).
LC-MS(ESI):m/z=450.2[M+H]+.
实施例35:(1R,5S,6S,7S)-7-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-(甲基氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸(化合物35)
(1R,5S,6S,7S)-7-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(methylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylic acid
第一步:(1R,5S,6S,7S)-7-(((2-氯-7-甲酰基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(35b)
ethyl(1R,5S,6S,7S)-7-((2-chloro-7-formylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
将2,4-二氯吡咯并[2,1-f][1,2,4]三嗪-7-甲醛(1.06g,4.9mmol)35a(同化合物11b)和DIPEA(1.6g,12.2mmol)加入异丙醇中,升温至外温60℃,再加入(1R,5S,6S,7S)-7-氨基三环[3.2.2.02,4]壬烷-6-羧酸乙酯盐酸盐(1g,4.08mmol),60℃反应1h。降至室温,直接将反应液减压浓缩后硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=0∶1~1∶8),得到化合物(35b)(1.3g,82%)。
LC-MS(ESI):m/z=389.1[M+H]+.
第二步:2-氯-4-((((1S,5R,6S,7S)-7-(乙氧羰基)三环[3.2.2.02,4]壬基-6-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-羧酸(35c)
2-chloro-4-(((1S,5R,6S,7S)-7-(ethoxycarbonyl)tricyclo[3.2.2.02,4]nonan-6-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid
将35b(1.3g,3.35mmol)和2-甲基丁-2-烯(1.17g,16.7mmol)溶于THF(15ml)中,再将亚氯酸钠(1.2g,13.4mmol)和二水合磷酸二氢钠(2.09g,13.4mmol)溶于水(4ml)后滴入反应体系,室温反应1h。加入氯化铵水溶液,用EA萃取(20ml*3),合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩得后硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶3)得到化合物(35c)(1g,74%)。
LC-MS(ESI):m/z=405.1[M+H]+.
第三步:(1R,5S,6S,7S)-7-(((2-氯-7-(甲基氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(35d)
ethyl(1R,5S,6S,7S)-7-((2-chloro-7-(methylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
将35c(350mg,0.87mmol)、盐酸甲胺(175mg,2.6mmol)、HATU(660mg,1.73mmol)、DIPEA(671mg,5.2mmol)依次加入DCM(10ml)中,室温反应2h。加入水(20ml),用DCM萃取,有机相用稀盐酸调至pH=6,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物(1R,5S,6S,7S)-7-(((2-氯-7-(甲基氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(35d)(400mg)。
LC-MS(ESI):m/z=418.2[M+H]+.
第四步:(1R,5S,6S,7S)-7-((2-(5-氟-1-甲苯基-1H-吡咯并[2,3-b]吡啶-3-基)-7-(甲基氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(35e)
ethyl(1R,5S,6S,7S)-7-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(methylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
将35d(400mg,0.96mmol)、中间体1(520mg,1.25mmol)、Pd(dppf)Cl2(156mg,0.19mmol)和碳酸钾(397mg,2.88mmol)加入二氧六环(8mL)中,再加入水(0.5ml).N2置换后升温至110℃微波反应1h。降至室温,过滤,滤液减压浓缩后硅胶柱色谱分离提纯(石油醚∶乙酸乙酯(v/v)=10∶1~1∶4),得到化合物(35e)(500mg,77%)。
第五步:((1R,5S,6S,7S)-7-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-7-(甲基氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸(化合物35)
(1R,5S,6S,7S)-7-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-7-(methylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylic acid
室温下,将35e(500mg,0.74mmol)和LiOH·H2O(310mg,7.4mmol)加入THF(5ml)中,再加入乙醇(5ml)和水(2ml),升温至60℃反应2h。降至室温,用稀盐酸调至pH=5-6,EA萃取(15ml*3),合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后得到的粗产物经制备HPLC分离提纯得到化合物35(100mg 28%)。制备HPLC分离方法:1.仪器:waters 2767制备液相;色谱柱:SunFire@Prep C18(19mm×250mm)2.样品用DMF溶解,用0.45μm滤头过滤,制成样品液。3.制备色谱条件:a.流动相A,B组成:流动相A:乙腈;流动相B:水(含0.1%TFA)b.梯度洗脱,流动相A含量从5%-50%c.流量12mL/min。d洗脱时间20min。
化合物35保留时间:14.2min;
1H NMR(400MHz,DMSO-d6)δ12.38(m,2H),8.91(t,1H),8.44(d,1H),8.40(dd,1H),8.33(m,1H),7.97(d,1H),7.14(q,2H),4.54(t,1H),3.01(d,3H),2.75(m,1H),2.70(m,1H),2.43(m,1H),1.83-1.66(m,2H),1.60-1.54(m,2H),1.09-1.01(m,2H),0.90-0.81(m,1H),0.37(q,1H).
LC-MS(ESI):m/z=490.2[M+H]+.
实施例36:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物36)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:(1R,2S,3S,4R)-3-((2-氯-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(36a)
(1R,2S,3S,4R)-ethyl-3-((2-chloro-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物10a(0.3g,0.79mmol),加入甲醇(5mL)中,加入三甲基硅基重氮甲烷(40ml,0.04mol),滴加三氟乙酸(11.8mL,158mmol),反应2小时。将反应液倒入(100mL)水中,EA(50mL×1)萃取,有机相用碳酸氢钠水溶液洗一次,有机相浓缩干,柱层析纯化(PE/EA=10/1-1/1,v/v),得化合物36a(150mg,产率48%)。
LC-MS(ESI):m/z=393.1[M+H]+
第二步:(1R,2S,3S,4R)-3-((2-(5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-基)-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(36b)
(1R,2S,3S,4R)-ethyl-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物36a(150mg,0.38mmol)加入二氧六环(10mL)和水(1mL)的混合溶液中,依次加入5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环-2-基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(240mg,0.57mmol)、碳酸钾(160mg,1.14mmol)、Pd(dppf)Cl2(28mg,0.038mmol),氮气置换并保护,微波加热至120℃反应1小时。将反应液浓缩干,柱层析纯化(PE/EA=10/1-1/1,v/v),得化合物36b(60mg,产率24%)。
第三步:(1R,2S,3S,4R)-3-((2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物36)
(1R,2S,3S,4R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
室温下,向化合物36b(60mg,0.093mmol)中依次加入乙醇(1mL)、水(2mL),氢氧化钠(74mg,1.86mmol)。室温反应18小时,将反应液用6N盐酸调节pH至5-6,乙酸乙酯(30mL×1)萃取,有机相浓缩干,制备板分离纯化(DCM/MeOH=10/1,v/v),得到化合物36(20mg,产率46%)
LC-MS(ESI):m/z=465.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.18(s,1H),8.52-8.49(m,1H),8.28-8.27(m,1H),8.18-8.17(m,1H),7.87-7.85(m,1H),7.66-7.65(m,1H),6.97-6.96(m,1H),4.81-4.78(m,1H),4.46(s,2H),3.29(s,3H),2.76-2.75(m,1H),2.03-1.99(m,2H),1.81-1.73(m,3H),1.62-1.57(m,3H),1.49-1.40(m,2H).
实施例37:(1R,2S,3S,4R)-3-((7-环丙基-2-(5-氟-1H-吡唑并[3,4-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物37)
(1R,2S,3S,4R)-3-((7-cyclopropyl-2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
第一步:(1R,2S,3S,4R)-3-((7-溴-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(37b)
(1R,2S,3S,4R)-ethyl-3-((7-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物37a(0.5g,1.9mmol)加入DCM(20mL)中,依次加入(1R,2S,3S,4R)-3-氨基双环[2.2.2]辛烷-2-羧酸乙酯盐酸盐(0.6g,2.4mmol)、DIPEA(0.5g,3.8mmol)。室温反应2小时,将反应液倒入(50mL)水中,用DCM(50mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA,20/1~10/1,v/v),得化合物37b(300mg,产率37%)。
LC-MS(ESI):m/z=427.1[M+H]+.
第二步:(1R,2S,3S,4R)-3-((2-氯-7-环丙基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(37c)
(1R,2S,3S,4R)-ethyl-3-((2-chloro-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物37b(300mg,0.7mmol)加入二氧六环(5mL)和水(0.5mL)的混合溶液中,依次加入环丙基硼酸(120mg,1.4mmol)、碳酸钾(240mg,1.7mmol)、Pd(dppf)Cl2(30mg,0.04mmol)。微波120℃反应1小时,将反应液倒入(30mL)水中,用乙酸乙酯(30mL×1)萃取,有机相浓缩干,柱层析纯化((PE/EA,20/1~10/1,v/v),得化合物37c(200mg,产率72%)
LC-MS(ESI):m/z=389.1[M+H]+.
第三步:(1R,2S,3S,4R)-3-((7-环丙基-2-(5-氟-1-三苯甲基-1H-吡唑并[3,4-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(37d)
(1R,2S,3S,4R)-ethyl-3-((7-cyclopropyl-2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物37c(200mg,0.5mmol)加入二氧六环(5mL)和水(0.5mL)的混合溶液中,依次加入中间体Int-2(515mg,1.0mmol)、碳酸钾(170mg,1.2mmol)、Pd(dppf)Cl2(30mg,0.04mmol)。微波120℃反应1小时,将反应液倒入(30mL)水中,用乙酸乙酯(30mL×1)萃取,有机相浓缩干,柱层析纯化((PE/EA,20/1~10/1,v/v),得化合物37d(30mg,产率8%)
第四步:(1R,2S,3S,4R)-3-((7-环丙基-2-(5-氟-1H-吡唑并[3,4-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸乙酯(37e)
(1R,2S,3S,4R)-ethyl-3-((7-cyclopropyl-2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate
室温下,将化合物37d(30mg,0.04mmol)加入DCM(10mL)中,依次加入三氟乙酸(90mg,0.8mmol)、三乙基硅烷(93mg,0.8mmol)。室温反应5小时,将反应液倒入(50mL)水中,用DCM(50mL×1)萃取,有机相浓缩干,制备板纯化(PE/EA,1/1,v/v),得化合物37e(10mg,产率50%)。
LC-MS(ESI):m/z=490.2[M+H]+.
第五步:(1R,2S,3S,4R)-3-((7-环丙基-2-(5-氟-1H-吡唑并[3,4-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)双环[2.2.2]辛烷-2-羧酸(化合物37)
(1R,2S,3S,4R)-3-((7-cyclopropyl-2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid
室温下,向化合物37e(10mg,0.02mmol)中依次加入乙醇(1mL)、水(2mL)、氢氧化钠(16mg,0.4mmol)。室温反应18小时,将反应液用6N盐酸调节pH至5-6,乙酸乙酯(30mL×1)萃取,有机相浓缩干,制备板分离纯化(DCM/MeOH=10/1,v/v),得到化合物37(2.5mg,产率25%)
LC-MS(ESI):m/z=462.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.64-8.63(m,1H),8.58-8.55(m,1H),7.96-7.94(m,1H),6.96-6.95(m,1H),6.32-6.31(m,1H),4.91-4.88(m,1H),2.84-2.82(m,1H),2.42-2.39(m,1H),2.05-2.03(m,2H),1.78-1.74(m,3H),1.61-1.41(m,5H),1.08-1.04(m,2H),0.80-0.77(m,2H).
实施例38:(1R,5S,6S,7S)-7-((7-环丙基-2-(5-氟-1H-吡唑[3,4-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸(化合物38)
(1R,5S,6S,7S)-7-((7-cyclopropyl-2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylic acid
第一步:(1R,5S,6S,7S)-7-((7-溴-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(38a)
(1R,5S,6S,7S)-ethyl-7-((7-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
室温下,将化合物37a(1.5g,5.7mmol)加入DCM(30mL)中,依次加入(1R,5S,6S,7S)-7-氨基三环[3.2.2.02,4]壬烷-6-羧酸乙酯盐酸盐(1.7g,6.8mmol)、DIPEA(1.5g,11.4mmol)。室温反应2小时,将反应液倒入(50mL)水中,用DCM(50mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA,20/1~10/1,v/v),得化合物38a(800mg,产率31%)。
LC-MS(ESI):m/z=438.1[M+H]+.
第二步:(1R,5S,6S,7S)-7-((2-氯-7-环丙基吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(38b)
(1R,5S,6S,7S)-ethyl-7-((2-chloro-7-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
室温下,将化合物38a(800mg,1.8mmol)加入二氧六环(10mL)和水(1mL)的混合溶液中,依次加入环丙基硼酸(310mg,3.6mmol)、碳酸钾(620mg,4.5mmol)、Pd(dppf)Cl2(140mg,0.2mmol)。微波120℃反应1小时,将反应液倒入(50mL)水中,用乙酸乙酯(5mL×1)萃取,有机相浓缩干,柱层析纯化((PE/EA,20/1~10/1,v/v),得化合物38b(600mg,产率83%)
LC-MS(ESI):m/z=401.1[M+H]+.
第三步:((1R,5S,6S,7S)-7-((7-环丙基-2-(5-氟-1-三苯甲基-1H-吡唑[3,4-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(38c)
(1R,5S,6S,7S)-ethyl-7-((7-cyclopropyl-2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
室温下,将化合物38b(600mg,1.5mmol)加入二氧六环(10mL)和水(1mL)的混合溶液中,依次加入中间体Int-2(1.5g,3.0mmol)、碳酸钾(510mg,3.8mmol)、Pd(dppf)Cl2(140mg,0.2mmol)。微波120℃反应1小时,将反应液倒入(50mL)水中,用乙酸乙酯(50mL×1)萃取,有机相浓缩干,柱层析纯化((PE/EA,20/1~10/1,v/v),得粗品化合物38c(700mg)
第四步:(1R,5S,6S,7S)-7-((7-环丙基-2-(5-氟-1H-吡唑[3,4-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸乙酯(38d)
(1R,5S,6S,7S)-ethyl-7-((7-cyclopropyl-2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylate
室温下,将粗品化合物38c(700mg,0.9mmol)加入DCM(30mL)中,依次加入三氟乙酸(2g,18mmol)、三乙基硅烷(2.1mg,18mmol)。室温反应5小时,将反应液倒入(50mL)水中,用DCM(50mL×1)萃取,有机相浓缩干,制备板纯化(PE/EA,20/1~3/1,v/v),得化合物38d(120mg)。
LC-MS(ESI):m/z=502.2[M+H]+.
第五步:((1R,5S,6S,7S)-7-((7-环丙基-2-(5-氟-1H-吡唑[3,4-b]吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[3.2.2.02,4]壬烷-6-羧酸(化合物38)
(1R,5S,6S,7S)-7-((7-cyclopropyl-2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[3.2.2.02,4]nonane-6-carboxylic acid
室温下,向化合物38d(120mg,0.24mmol)中依次加入乙醇(3mL)、水(6mL)、氢氧化钠(190mg,4.8mmol)。室温反应5小时,将反应液用6N盐酸调节pH至5-6,析出固体,过滤,固体用水(50mL)淋洗,干燥,得到化合物38(70mg,产率62%)
LC-MS(ESI):m/z=474.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.64-8.63(m,1H),8.55-8.53(m,1H),7.63-7.62(m,1H),6.98-6.97(m,1H),6.28-6.27(m,1H),4.62-4.59(m,1H),2.83-2.75(m,2H),2.46-2.39(m,2H),1.71-1.54(m,4H),1.09-1.04(m,4H),0.79-0.73(m,3H),0.33-0.27(m,1H).
实施例39:(1R,6S,7S,8S)-8-((2-(5-氟-1H-吡唑[3,4-b]吡啶-3-基)-7-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸(化合物39)
(1R,6S,7S,8S)-8-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylic acid
/>
第一步:(1R,6S,7S,8S)-8-((2-氯-7-甲酰吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸乙酯(39b)
(1R,6S,7S,8S)-ethyl-8-((2-chloro-7-formylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylate
室温下,将化合物39a(同化合物11b)(3g,13.9mmol)、DIPEA(4.5g,35mmol)加入DCM(30mL)和异丙醇(60mL)的混合溶液中,60℃反应10分钟,将(1R,6S,7S,8S)-8-氨基三环[4.2.2.02,5]癸-7-羧酸乙酯(2.5g,11.2mmol)加入反应液中,保温反应50分钟,将反应液浓缩干,加入水(50mL),用EA(50mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA,20/1~10/1,v/v),得化合物39b(3g,产率53%)。
LC-MS(ESI):m/z=403.2[M+H]+.
第二步:(1R,6S,7S,8S)-8-((2-氯-7-(羟甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸乙酯(39c)
(1R,6S,7S,8S)-ethyl-8-((2-chloro-7-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylate
室温下,将化合物39b(3g,7.5mmol)加入甲醇(50mL)中、加入硼氢化钠(340mg,9.0mmol)。室温反应1小时,将反应液倒入(100mL)水中,用EA(50mL×1)萃取,有机相浓缩干,得化合物39c(2.8g,产率93%)。
LC-MS(ESI):m/z=405.2[M+H]+.
第三步:(1R,6S,7S,8S)-8-((2-氯-7-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸乙酯(39d)
(1R,6S,7S,8S)-ethyl-8-((2-chloro-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylate
室温下,将化合物39c(2.8g,6.9mmol)加入甲醇(20mL)中,加入(三甲基硅基重氮甲烷(50mL,100mmol),加毕,将三氟乙酸(11.4g,100mmol)滴加至反应液中,室温反应2小时,将反应液倒入(100mL)水中,用EA(100mL×1)萃取,有机相浓缩干,柱层析纯化(PE/EA,10/1~5/1,v/v),得化合物39d(1.2g,产率41%)。
LC-MS(ESI):m/z=419.2[M+H]+.
第四步:(1R,6S,7S,8S)-8-((2-(5-氟-1-三苯甲基-1H-吡唑[3,4-b]吡啶-3-基)-7-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸乙酯(39e)
(1R,6S,7S,8S)-ethyl-8-((2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylate
室温下,将化合物39d(1.2g,2.86mmol)加入二氧六环(15mL)和水(1.5mL)的混合溶液中,依次加入中间体Int-2(2.9g,5.7mmol)、碳酸钾(1g,7.2mmol)、Pd(dppf)Cl2(210mg,0.29mmol)。微波120℃反应1小时,将反应液浓缩干,直接柱层析纯化((PE/EA,10/1~5/1,v/v),得粗品化合物39e(400mg)
第五步:(1R,6S,7S,8S)-8-((2-(5-氟-1H-吡唑[3,4-b]吡啶-3-基)-7-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸乙酯(39f)
(1R,6S,7S,8S)-ethyl-8-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylate
室温下,将粗品化合物39e(400mg,0.53mmol)加入DCM(20mL)中,依次加入三氟乙酸(1.2g,10.6mmol)、三乙基硅烷(1.2g,10.6mmol)。室温反应16小时,将反应液浓缩干,柱层析纯化(PE/EA,10/1~1/1,v/v),得化合物39f(100mg,产率36%)。
LC-MS(ESI):m/z=520.2[M+H]+.
第六步:1R,6S,7S,8S)-8-((2-(5-氟-1H-吡唑[3,4-b]吡啶-3-基)-7-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)三环[4.2.2.02,5]癸烷-7-羧酸(化合物39)
(1R,6S,7S,8S)-8-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)-7-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)tricyclo[4.2.2.02,5]decane-7-carboxylic acid
室温下,向化合物39f(100mg,0.19mmol)中依次加入乙醇(2mL)、水(4mL)、氢氧化钠(150mg,3.8mmol)。室温反应16小时,向反应液中加入水(10mL),用6N盐酸调节pH至5-6,析出固体,过滤,固体用水(5mL)淋洗,干燥,得到化合物39(30mg,产率31.5%)
LC-MS(ESI):m/z=492.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.65-8.64(m,1H),8.52-8.50(m,1H),8.13-812(m,1H),7.05-7.04(m,1H),6.74-6.73(m,1H),4.78(s,2H),3.33(s,3H),2.96-2.94(m,1H),2.69-2.41(m,2H),2.21-1.98(m,10H),1.85-1.71(m,2H).
生物测试
试验方法:应用细胞病变(CPE)法测试本发明化合物对流感病毒的抗病毒活性,同时测定MDCK细胞毒性。化合物将测试8个浓度,双复孔。使用CCK-8试剂检测细胞活力。MDCK细胞以一定密度接种于微孔板内,于37℃、5%CO2培养过夜。第二天加入化合物和病毒。设置细胞(无化合物处理或病毒感染)和病毒感染(细胞感染病毒,无化合物处理)对照。细胞培养液中DMSO终浓度为0.5%。细胞于37℃、5%CO2培养5天至病毒对照孔细胞病变率达80-95%。使用CCK-8试剂检测细胞活力,原始数据用于化合物抗病毒活性计算。应用GraphPadPrism软件分析化合物剂量反应曲线并计算EC50值。
测试结果:本发明化合物对IFV A/PR/8/34病毒显示了抗增值活性。实施例化合物对IFV A/PR/8/34病毒的IC50值在0.01-3nM范围内。其中,部分实施例的测试结果如表1所示:
表1本发明化合物对于IFV A/PR/8/34病毒抗增殖活性结果
实施例 | EC50(IFV A/PR/8/34)nM |
8 | 0.8 |
18 | 0.3 |
20 | 0.3 |
30 | 0.37 |
31 | 0.08 |
32 | 0.24 |
38 | 0.09 |
结论:本发明化合物对于IFV A/PR/8/34病毒显示了较高的抗增殖活性。
Claims (4)
1.化合物,其互变异构体、或其药学上可接受的盐,其中所述化合物选自以下结构:。
2.一种药物组合物,其特征在于,含有权利要求1所述的化合物,其互变异构体、或其药学上可接受的盐,以及药学上可接受的载体和/或赋形剂。
3.权利要求1所述的化合物,其互变异构体、或其药学上可接受的盐,或者权利要求2所述的组合物,在制备治疗PB2介导的疾病的药物中的应用。
4.根据权利要求3所述的应用,其特征在于,所述PB2介导的疾病为流感病毒感染。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311238123.4A CN117362318A (zh) | 2020-07-10 | 2021-07-09 | Pb2抑制剂及其制备方法和用途 |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2020106580379 | 2020-07-10 | ||
CN202010658037 | 2020-07-10 | ||
CN2020111218392 | 2020-10-20 | ||
CN202011121839 | 2020-10-20 | ||
PCT/CN2021/105622 WO2022007966A1 (zh) | 2020-07-10 | 2021-07-09 | Pb2抑制剂及其制备方法和用途 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311238123.4A Division CN117362318A (zh) | 2020-07-10 | 2021-07-09 | Pb2抑制剂及其制备方法和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115698011A CN115698011A (zh) | 2023-02-03 |
CN115698011B true CN115698011B (zh) | 2023-10-20 |
Family
ID=79552271
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202180041967.2A Active CN115698011B (zh) | 2020-07-10 | 2021-07-09 | Pb2抑制剂及其制备方法和用途 |
CN202311238123.4A Pending CN117362318A (zh) | 2020-07-10 | 2021-07-09 | Pb2抑制剂及其制备方法和用途 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311238123.4A Pending CN117362318A (zh) | 2020-07-10 | 2021-07-09 | Pb2抑制剂及其制备方法和用途 |
Country Status (5)
Country | Link |
---|---|
US (1) | US20230265107A1 (zh) |
EP (1) | EP4180434A1 (zh) |
CN (2) | CN115698011B (zh) |
TW (1) | TW202202500A (zh) |
WO (1) | WO2022007966A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023196975A1 (en) * | 2022-04-08 | 2023-10-12 | Shy Therapeutics, Llc | Compounds that interact with ras superfamily proteins for treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106854205A (zh) * | 2015-12-09 | 2017-06-16 | 广东东阳光药业有限公司 | 流感病毒复制抑制剂及其使用方法和用途 |
WO2017133664A1 (en) * | 2016-02-05 | 2017-08-10 | Savira Pharmaceuticals Gmbh | Bicyclic pyridine and pyrimidine derivatives and their use in the treatment, amelioration or prevention of influenza |
CN108727369A (zh) * | 2017-04-25 | 2018-11-02 | 广东东阳光药业有限公司 | 流感病毒复制抑制剂及其用途 |
CN109641868A (zh) * | 2016-08-30 | 2019-04-16 | 广东东阳光药业有限公司 | 流感病毒复制抑制剂及其使用方法和用途 |
CN110637022A (zh) * | 2017-04-24 | 2019-12-31 | 共晶制药公司 | 可作为流感病毒复制抑制剂的吡咯并嘧啶衍生物 |
WO2020125673A1 (zh) * | 2018-12-19 | 2020-06-25 | 南京药石科技股份有限公司 | 流感病毒复制抑制剂及其中间体和用途 |
CN111518094A (zh) * | 2019-02-01 | 2020-08-11 | 四川大学华西医院 | 一种抗流感小分子化合物及其制备方法和用途 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PE20120508A1 (es) | 2009-06-17 | 2012-05-09 | Vertex Pharma | Inhibidores de la replicacion de los virus de la gripe |
WO2017133667A1 (en) * | 2016-02-05 | 2017-08-10 | Savira Pharmaceuticals Gmbh | Pyrimidine and pyridine derivatives and use in treatment, amelioration or prevention of influenza thereof |
WO2018033082A1 (en) * | 2016-08-16 | 2018-02-22 | Sunshine Lake Pharma Co., Ltd. | Inhibitors of influenza virus replication, application methods and uses thereof |
-
2021
- 2021-07-09 TW TW110125399A patent/TW202202500A/zh unknown
- 2021-07-09 CN CN202180041967.2A patent/CN115698011B/zh active Active
- 2021-07-09 EP EP21838608.4A patent/EP4180434A1/en active Pending
- 2021-07-09 WO PCT/CN2021/105622 patent/WO2022007966A1/zh unknown
- 2021-07-09 CN CN202311238123.4A patent/CN117362318A/zh active Pending
- 2021-07-09 US US18/015,309 patent/US20230265107A1/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106854205A (zh) * | 2015-12-09 | 2017-06-16 | 广东东阳光药业有限公司 | 流感病毒复制抑制剂及其使用方法和用途 |
WO2017133664A1 (en) * | 2016-02-05 | 2017-08-10 | Savira Pharmaceuticals Gmbh | Bicyclic pyridine and pyrimidine derivatives and their use in the treatment, amelioration or prevention of influenza |
CN109641868A (zh) * | 2016-08-30 | 2019-04-16 | 广东东阳光药业有限公司 | 流感病毒复制抑制剂及其使用方法和用途 |
CN110637022A (zh) * | 2017-04-24 | 2019-12-31 | 共晶制药公司 | 可作为流感病毒复制抑制剂的吡咯并嘧啶衍生物 |
CN108727369A (zh) * | 2017-04-25 | 2018-11-02 | 广东东阳光药业有限公司 | 流感病毒复制抑制剂及其用途 |
WO2020125673A1 (zh) * | 2018-12-19 | 2020-06-25 | 南京药石科技股份有限公司 | 流感病毒复制抑制剂及其中间体和用途 |
CN111518094A (zh) * | 2019-02-01 | 2020-08-11 | 四川大学华西医院 | 一种抗流感小分子化合物及其制备方法和用途 |
Also Published As
Publication number | Publication date |
---|---|
WO2022007966A1 (zh) | 2022-01-13 |
EP4180434A1 (en) | 2023-05-17 |
CN115698011A (zh) | 2023-02-03 |
US20230265107A1 (en) | 2023-08-24 |
CN117362318A (zh) | 2024-01-09 |
TW202202500A (zh) | 2022-01-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6489338B2 (en) | Imidazopyridine and imidazopyrimidine antiviral agents | |
JP5674483B2 (ja) | 新規なhsp90阻害性カルバゾール誘導体、同誘導体を含む組成物およびその使用 | |
CA2481482C (en) | Tropane derivatives as ccr5 modulators | |
AU2018314980B2 (en) | Diarylthiohydantoin compound as androgen receptor antagonist | |
BR112015020350B1 (pt) | Derivados de 6-(5-hidróxi-1h-pirazol-1-il)nicotinamida, sua composição farmacêutica e seus usos | |
AU2001272906A1 (en) | Imidazopyridine and imidazopyrimidine antiviral agents | |
AU2014209853A1 (en) | Quinoxalinones and dihydroquinoxalinones as respiratory syncytial virus antiviral agents | |
AU2020385527B2 (en) | Compound used as EGFR kinase inhibitor and use thereof | |
CN115698011B (zh) | Pb2抑制剂及其制备方法和用途 | |
CN112805287B (zh) | 含有呋喃并[3,4-b]吡咯的BTK抑制剂 | |
CN116217566A (zh) | 一种抗凋亡蛋白bcl-2抑制剂、药物组合物及其应用 | |
CN116199685A (zh) | Her2降解剂及其用途 | |
RU2804108C9 (ru) | Соединение диарилтиогидантоина в качестве антагониста андрогенового рецептора | |
RU2804108C1 (ru) | Соединение диарилтиогидантоина в качестве антагониста андрогенового рецептора | |
WO2023113023A1 (ja) | H-pgdsを阻害するアザインドール誘導体 | |
TW202330519A (zh) | 作為tam抑制劑的吡唑并吡啶化合物 | |
CN116354932A (zh) | 嘧啶衍生物及其制备方法和用途 | |
JP2023551272A (ja) | ジアシルグリセロールキナーゼ阻害剤としての複素環化合物及びその用途 | |
CN117088884A (zh) | 作为gabaa受体调节剂的咪唑并哒嗪衍生物、药物组合物和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
TR01 | Transfer of patent right |
Effective date of registration: 20231219 Address after: 856099 Xingfu Jiayuan Economic Development Zone, Gyerba, Nedong District, Shannan City, Tibet Autonomous Region Patentee after: Tibet Haisike Pharmaceutical Co.,Ltd. Address before: 611130 No.136 Baili Road, Chengdu cross strait science and Technology Industrial Development Park, Wenjiang District, Chengdu City, Sichuan Province Patentee before: SICHUAN HAISCO PHARMACEUTICAL Co.,Ltd. |
|
TR01 | Transfer of patent right |