TWI841200B - Heterocyclic compounds, drug compositions and applications thereof - Google Patents
Heterocyclic compounds, drug compositions and applications thereof Download PDFInfo
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- TWI841200B TWI841200B TW112102054A TW112102054A TWI841200B TW I841200 B TWI841200 B TW I841200B TW 112102054 A TW112102054 A TW 112102054A TW 112102054 A TW112102054 A TW 112102054A TW I841200 B TWI841200 B TW I841200B
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- ring
- membered
- mmol
- substituted
- alkyl
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- 150000002391 heterocyclic compounds Chemical class 0.000 title claims abstract description 27
- 239000000203 mixture Substances 0.000 title abstract description 129
- 239000003814 drug Substances 0.000 title abstract description 8
- 229940079593 drug Drugs 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 203
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 125000001931 aliphatic group Chemical group 0.000 claims description 278
- 229910052736 halogen Inorganic materials 0.000 claims description 159
- 150000002367 halogens Chemical class 0.000 claims description 159
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 155
- 229910052799 carbon Inorganic materials 0.000 claims description 117
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 66
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 53
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 40
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 229910003827 NRaRb Inorganic materials 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 336
- 239000000243 solution Substances 0.000 description 314
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 311
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 271
- 239000012071 phase Substances 0.000 description 269
- -1 guanine nucleotide diphosphate Chemical class 0.000 description 230
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 209
- 238000006243 chemical reaction Methods 0.000 description 189
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 155
- 125000000623 heterocyclic group Chemical group 0.000 description 155
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 143
- 125000004429 atom Chemical group 0.000 description 137
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 134
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 120
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 119
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 112
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 111
- 235000019439 ethyl acetate Nutrition 0.000 description 105
- 239000000741 silica gel Substances 0.000 description 100
- 229910002027 silica gel Inorganic materials 0.000 description 100
- 238000006467 substitution reaction Methods 0.000 description 91
- 238000003818 flash chromatography Methods 0.000 description 90
- 239000007787 solid Substances 0.000 description 89
- 238000005481 NMR spectroscopy Methods 0.000 description 88
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 87
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 87
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 82
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 81
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 76
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 70
- 229910052757 nitrogen Inorganic materials 0.000 description 68
- 239000003208 petroleum Substances 0.000 description 67
- 238000003756 stirring Methods 0.000 description 67
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 67
- 239000012074 organic phase Substances 0.000 description 63
- 239000012043 crude product Substances 0.000 description 59
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 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
- 239000000706 filtrate Substances 0.000 description 57
- 230000014759 maintenance of location Effects 0.000 description 57
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 55
- 239000001569 carbon dioxide Substances 0.000 description 55
- 229910002092 carbon dioxide Inorganic materials 0.000 description 55
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 54
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 52
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 49
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 49
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 47
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 40
- 125000001072 heteroaryl group Chemical group 0.000 description 40
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 38
- 239000007788 liquid Substances 0.000 description 36
- 150000001336 alkenes Chemical group 0.000 description 30
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 description 29
- 125000004432 carbon atom Chemical group C* 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 125000005842 heteroatom Chemical group 0.000 description 26
- 239000000543 intermediate Substances 0.000 description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- 125000000217 alkyl group Chemical group 0.000 description 22
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 22
- 125000000392 cycloalkenyl group Chemical group 0.000 description 22
- 238000002953 preparative HPLC Methods 0.000 description 21
- 125000001424 substituent group Chemical group 0.000 description 21
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 20
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 19
- 229910052938 sodium sulfate Inorganic materials 0.000 description 19
- 235000011152 sodium sulphate Nutrition 0.000 description 19
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 17
- 101000652482 Homo sapiens TBC1 domain family member 8 Proteins 0.000 description 16
- 102100030302 TBC1 domain family member 8 Human genes 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000012141 concentrate Substances 0.000 description 15
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 15
- 239000012299 nitrogen atmosphere Substances 0.000 description 15
- 239000000725 suspension Substances 0.000 description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 13
- 150000001721 carbon Chemical group 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 125000004122 cyclic group Chemical group 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 12
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 12
- 239000012267 brine Substances 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 10
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 10
- 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 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 9
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 9
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 9
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 8
- 125000002950 monocyclic group Chemical group 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 7
- 102100030708 GTPase KRas Human genes 0.000 description 7
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 7
- WHQDPSGUFIHZTE-UHFFFAOYSA-N naphthalen-2-ol Chemical compound C1=CC=CC2=CC(O)=CC=C21.C1=CC=CC2=CC(O)=CC=C21 WHQDPSGUFIHZTE-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- BJAHHTUQMZCNPO-UHFFFAOYSA-N 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl]ethynyl-tri(propan-2-yl)silane Chemical compound B1(OC(C(O1)(C)C)(C)C)C2=CC(=CC3=C2C(=C(C=C3)F)C#C[Si](C(C)C)(C(C)C)C(C)C)OCOC BJAHHTUQMZCNPO-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 6
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 229910000160 potassium phosphate Inorganic materials 0.000 description 6
- 235000011009 potassium phosphates Nutrition 0.000 description 6
- PLZDHJUUEGCXJH-UHFFFAOYSA-N pyrido[4,3-d]pyrimidine Chemical compound C1=NC=C2C=NC=CC2=N1 PLZDHJUUEGCXJH-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 5
- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 5
- 125000005330 8 membered heterocyclic group Chemical group 0.000 description 5
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- 239000005909 Kieselgur Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 235000011056 potassium acetate Nutrition 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 102000016914 ras Proteins Human genes 0.000 description 5
- 102200006539 rs121913529 Human genes 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- HZPQHQKQIQDTTN-AOOOYVTPSA-N tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Chemical compound ClC=1N=C(C2=C(N=1)C(=C(N=C2)Cl)F)N1C[C@H]2CC[C@@H](C1)N2C(=O)OC(C)(C)C HZPQHQKQIQDTTN-AOOOYVTPSA-N 0.000 description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 4
- ILTXDPMYCUSDQV-UHFFFAOYSA-N 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine Chemical compound C1(=C(C2=C(C=N1)C(Cl)=NC(=N2)Cl)F)Cl ILTXDPMYCUSDQV-UHFFFAOYSA-N 0.000 description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
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- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- GLWHHMBAMGJDAE-UHFFFAOYSA-N tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC2CC21 GLWHHMBAMGJDAE-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical group 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 description 1
- XHVSCKNABCCCAC-UHFFFAOYSA-N trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate Chemical compound C[Si](C)(C)OC(=O)C(F)(F)S(F)(=O)=O XHVSCKNABCCCAC-UHFFFAOYSA-N 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 description 1
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Abstract
本發明提供了一種雜環類化合物、藥物組成物及其應用。並具體公開了如式I-0所示的雜環類化合物、其藥學上可接受的鹽、其立體異構物或它們的溶劑合物。本發明化合物結構新穎,活性和選擇性較好。The present invention provides a heterocyclic compound, a drug composition and its application. Specifically disclosed are a heterocyclic compound as shown in formula I-0, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvent thereof. The compound of the present invention has a novel structure and good activity and selectivity.
Description
本申請要求申請日為2022/1/21的中國專利申請2022100698643的優先權;申請日為2022/5/6的中國專利申請2022105001306的優先權;申請日為2022/7/28的中國專利申請202210900237X的優先權;申請日為2022/9/28的中國專利申請2022111939164的優先權;申請日為2023/1/4的中國專利申請2023100101425的優先權。本申請引用上述中國專利申請的全文。This application claims the priority of Chinese patent application No. 2022100698643 with a filing date of 2022/1/21; Chinese patent application No. 2022105001306 with a filing date of 2022/5/6; Chinese patent application No. 202210900237X with a filing date of 2022/7/28; Chinese patent application No. 2022111939164 with a filing date of 2022/9/28; and Chinese patent application No. 2023100101425 with a filing date of 2023/1/4. This application cites the full text of the above Chinese patent applications.
本發明涉及一種雜環類化合物、藥物組成物及其應用。The present invention relates to a heterocyclic compound, a drug composition and applications thereof.
RAS癌基因突變是人類癌症中最常見的活化突變,發生在30%的人類腫瘤中。RAS基因家族包括三個亞型(KRAS、HRAS和NRAS),其中85%的RAS驅動的癌症是由KRAS亞型突變引起的。KRAS突變常見於固態腫瘤中,如:肺腺癌、胰腺導管癌和結直腸癌等。在KRAS突變腫瘤中,80%的致癌突變發生在密碼子12上,最常見的突變包括:p.G12D (41%)、p.G12V (28%)和p.G12C(14%)。RAS oncogene mutations are the most common activating mutations in human cancer, occurring in 30% of human tumors. The RAS gene family includes three subtypes (KRAS, HRAS, and NRAS), of which 85% of RAS-driven cancers are caused by KRAS subtype mutations. KRAS mutations are common in solid tumors, such as lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal cancer. In KRAS mutant tumors, 80% of oncogenic mutations occur at codon 12, and the most common mutations include: p.G12D (41%), p.G12V (28%), and p.G12C (14%).
KRAS基因的全名是Kirsten rat sarcoma viraloncogene homolog(Kristen大鼠肉瘤病毒癌基因同源物)。KRAS在細胞生長的信號調控中起著一個樞紐的作用,上游的EGFR(ErbBl), HER2(ErbB2)、ErbB3和ErbB4等細胞表面受體,在接受了外界信號之後,會透過RAS蛋白,把信號傳遞到下游。KRAS蛋白沒有被活化的時候,與GDP (鳥嘌呤核苷酸二磷酸)緊密結合。在被SOSl等鳥嘌呤核苷酸交換因子活化後,與GTP (鳥嘌呤核苷酸三磷酸)結合,變成激酶活性的狀態。KRAS基因突變後,可以不依賴於上游生長因子受體信號,獨立向下游途徑傳輸生長和増殖的信號,造成不受控制的細胞生長和腫瘤進展,同時KRAS基因是否有突變,也是腫瘤預後的一個重要指標。統計結果顯示,在KRAS的亞型中,KRAS G12D也是一種常見的亞突變,其中結直腸癌占12%,胰腺癌占36%,非小細胞肺癌占4%,因此開發一種新型KRAS G12D抑制劑是非常有必要,它有很大的潛力可以成為腫瘤治療領域的新治療手段,因此需要開發更有效,更安全,藥代性質更好的KRAS G12D抑制劑以滿足臨床需求。The full name of the KRAS gene is Kirsten rat sarcoma viral oncogene homolog. KRAS plays a pivotal role in the signal regulation of cell growth. After receiving external signals, the upstream cell surface receptors such as EGFR (ErbBl), HER2 (ErbB2), ErbB3 and ErbB4 will transmit the signal to the downstream through the RAS protein. When the KRAS protein is not activated, it is tightly bound to GDP (guanine nucleotide diphosphate). After being activated by guanine nucleotide exchange factors such as SOSl, it binds to GTP (guanine nucleotide triphosphate) and becomes a kinase active state. After the KRAS gene mutates, it can transmit growth and proliferation signals to downstream pathways independently without relying on upstream growth factor receptor signals, causing uncontrolled cell growth and tumor progression. At the same time, whether the KRAS gene has mutations is also an important indicator of tumor prognosis. Statistics show that among the subtypes of KRAS, KRAS G12D is also a common submutation, with colorectal cancer accounting for 12%, pancreatic cancer accounting for 36%, and non-small cell lung cancer accounting for 4%. Therefore, it is very necessary to develop a new KRAS G12D inhibitor, which has great potential to become a new treatment method in the field of tumor treatment. Therefore, it is necessary to develop more effective, safer, and better pharmacokinetic KRAS G12D inhibitors to meet clinical needs.
本發明所要解決的技術問題是針對現有KRAS G12D抑制劑結構較為單一的缺陷,提供了一種雜環類化合物、藥物組成物及其應用,本發明化合物結構新穎,活性和選擇性較好。The technical problem to be solved by the present invention is to address the defect that the existing KRAS G12D inhibitor has a relatively single structure, and to provide a heterocyclic compound, a drug composition and its application. The compound of the present invention has a novel structure and good activity and selectivity.
本發明是透過下述技術方案來解決上述技術問題的。The present invention solves the above technical problems through the following technical solutions.
本發明提供了一種如式I-0所示的雜環類化合物、其藥學上可接受的鹽、其立體異構物或它們(指前述如式I-0所示的雜環類化合物、其藥學上可接受的鹽或其立體異構物)的溶劑合物: 其中,環K為芳環或雜芳環; X 1為N、NR X1’或CR X1;X 2為N或CR X2; R X1和R X2各自獨立地為H、CN、鹵素、C 1-C 6烷基、被一個或多個鹵素取代的C 1-C 6烷基、被一個或多個羥基取代C 1-C 6烷基、PO(C 1-C 6烷基) 2、C 3-C 6環烷基、C 3-C 6環烯基、C 2-C 6烯基、C 2-C 6炔基、3~6員雜環烷基、3~6員雜環烯基、6-14員芳基、5~14員雜芳基、被一個或多個X 1-1取代的3~6員雜環烷基、被一個或多個X 1-2取代的5~14員雜芳基、NO 2、被一個或多個X 1-3取代的3~6員雜環烯基、OR a、SF 5、C(=O) X 1-4、C(=O) OR a、-NR aC(O)R a、NX 1-5X 1-6或SO 2X 1-7; X 1-1和X 1-3各自獨立地為(C=O)-C 1-C 6烷基;X 1-2獨立地為C 1-C 6烷基;X 1-4獨立地為H、C 3-C 8環烷基、3~8員雜環烷基、C 1-C 6烷基、或被一個或多個鹵素取代的C 1-C 6烷基;X 1-5和X 1-6各自獨立地為H、C 1-C 6烷基、C 3-C 6環烷基、SO 2-C 1-C 6烷基或(C=O)-C 1-C 6烷基,或者X 1-5和X 1-6一起與與之相連的原子形成C 3-C 6脂碳環、C 3-C 6碳烯環、3~6員脂雜環或3~6員碳雜烯環;X 1-7為OR a或C 1-C 6烷基; X 3為N或CR X3,R X3為H、鹵素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、鹵代(C 1-C 6烷基)、OR a、羥基(C 1-C 6烷基)、氰基、硝基、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a、5-14員雜芳基、6-14員芳基; R a和R b各自獨立地表示氫、C 1-C 6烷基或C 3-C 6環烷基;或者R a、R b一起與與之相連的原子形成C 3-C 6脂碳環、C 3-C 6碳烯環、3~6員脂雜環或3~6員碳雜烯環; 或者R X1與R X3和其相連的原子共同形成C 5-C 8環烯酮結構; 或者R X1’與R X3和其相連的原子共同形成5~8員雜芳環或被一個或多個羥基取代的5~8員雜芳環; R 1為C 6~C 14的芳基、被一個或多個R 1-1取代的C 6~C 14的芳基、5~14員雜芳基或被一個或多個R 1-2取代的5~14員雜芳基; R 1-1和R 1-2各自獨立地為鹵素、OH、CN、NO 2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、被一個或多個鹵素取代的C 1-C 6烷基、被一個或多個羥基取代的C 1-C 6烷基、OR a、B(OH) 2、O(C=O)- C 1-C 10烷基、SO 3R a、NR aR b、COR a、CONR aR b、C(O)OR a、NR aCOR a; 或者,相鄰的兩個R 1-1與其相連的原子一起形成C 3-C 8脂碳環或被一個或多個R 1-3取代的C 3-C 8脂碳環,其餘R 1-1獨立地為鹵素、OH、CN、NO 2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、被一個或多個鹵素取代的C 1-C 6烷基、被一個或多個羥基取代的C 1-C 6烷基、OR a、B(OH) 2、O(C=O)- C 1-C 10烷基、SO 3R a、NR aR b、COR a、CONR aR b、C(O)OR a、NR aCOR a; 或者,相鄰的兩個R 1-2與其相連的原子一起形成C 3-C 8脂碳環或被一個或多個R 1-4取代的C 3-C 8脂碳環,其餘R 1-2獨立地為鹵素、OH、CN、NO 2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、被一個或多個鹵素取代的C 1-C 6烷基、被一個或多個羥基取代的C 1-C 6烷基、OR a、B(OH) 2、O(C=O)- C 1-C 10烷基、SO 3R a、NR aR b、COR a、CONR aR b、C(O)OR a、NR aCOR a; R 1-3和R 1-4獨立地為鹵素; 或者X 1為CR X1,其中,X 1中的C原子與R 1中的芳基或雜芳基中的C原子透過-O-(CH 2) n1- *、 *-NH-(CH 2) n2-、-C≡C-(CH 2) n3-C≡C- *或-(CH 2) n4-O-(CH 2) n5- *相連,其中,*端與X 1中的C原子相連; n1、n2、n3、n4和n5各自獨立地為1、2、3、4、5或6; R 2為H、鹵素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、鹵代(C 1-C 6烷基)、OR a、羥基(C 1-C 6烷基)、氰基、硝基、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a、5-14員雜芳基、6-14員芳基; L 2表示不存在、-O-(C 1-C 6伸烷基)或-NR a-(C 1-C 6伸烷基); R 3為 ; 其中,R 1'、R 2'、R 3'、R 4'、R 5'、R 6'、R 7'、R 8'、R 9'、R 10'、R 11'、R 12'各自獨立地表示氫、鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-SO 3R a、-NR aR b、-CO(C 1-C 6烷基)或-C(O)NR aR b; 或者R 1'與R 2'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 3'與R 4'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 5'與R 6'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 7'與R 8'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 9'與R 10'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 11'與R 12'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 2'、R 3'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 4'、R 5'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 8'、R 9'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 10'、R 11'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 3'與R 4'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代;且R 9'與R 10'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; R 4為L 1-R 5,L 1表示不存在、CR aR b或NR a; R 5為以下式(i)、式(ii)或式(iii)的中的任意一種環狀結構: 其中,W 1表示CR W1R W2或NR W1; 其中,R W1、R W2各自獨立地表示氫、鹵素、氰基、硝基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、NR aR b、C(O)R a、C(O)OR a、C(O)NR aR b、NR aC(O)R a或(C=O)-O-C 1-C 6伸烷基O-(C=O)-C 1-C 10烷基;或者R W1、R W2一起與與之相連的原子共同形成3~8員脂雜環; 其中,W 2表示CH或N; 其中,Y為伸甲基、伸乙基、C 3伸烷基、C 2-C 3伸烯基、或 ; R c和R d與與其相連的原子共同形成C 3-C 6脂碳環或被一個或多個鹵素取代的C 3-C 6脂碳環;或者R d和R d’和與之相連的原子一起形成C 3-C 6脂碳環或被一個或多個鹵素取代的C 3-C 6脂碳環; 其中,R 1’’、R 2’’、R 3’’、R 4’’、R 5’’、R 6’’、R 7’’、R 8’’各自獨立地表示氫、鹵素、氰基、硝基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a; 或者R 1’’與R 2’’一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基) 、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 3’’與R 4’’一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 5’’與R 6’’一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 7’’與R 8’’一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 2’’、R 3’’一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 4’’、R 5’’一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 6’’、R 7’’一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 3’’與R 4’’一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代;且R 5’’與R 6’’一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 其滿足下述至少一個條件: 條件1:R 3中,R 1'與R 2'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 3'與R 4'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 5'與R 6'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 7'與R 8'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 9'與R 10'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 11'與R 12'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 2'、R 3'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 4'、R 5'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 8'、R 9'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 10'、R 11'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 或者R 3'與R 4'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代;且R 9'與R 10'一起與與之相連的原子形成C 3-C 8脂碳環、C 3-C 8碳烯環、3-8員脂雜環、3-8員碳雜烯環、取代的C 3-C 8脂碳環、取代的C 3-C 8碳烯環、取代的3-8員脂雜環或取代的3-8員碳雜烯環;所述的取代是指任意地被1-2個選自鹵素、氰基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、鹵代(C 1-C 6烷基)、羥基(C 1-C 6烷基)、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、-OR a、-SO 3R a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-NR aC(O)R a的取代基所取代;或者所述環中任意的CH 2被C=O所取代; 條件2: R 5為以下式(i)、式(ii)或式(iii)的中的任意一種環狀結構: 其中,式(ii)中,W 2為N,W 1為NR W1時,R W1不為H; 式(iii)中,W 2為N,W 1為NR W1,R W1為H時,Y不為伸乙基; 條件3:X 1為CR X1,R X1為C 1-C 6烷基、被一個或多個鹵素取代的C 1-C 6烷基、PO(C 1-C 6烷基) 2、C 2-C 6烯基、C 2-C 6炔基、被一個或多個X 1-1取代的3~6員雜環烷基、6-14員芳基、5~14員雜芳基、被一個或多個X 1-2取代的5~14員雜芳基、NO 2、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、被一個或多個X 1-3取代的3~6員雜環烯基、SF 5、C(=O) X 1-4、C(=O) OR a、-NR aC(O)R a、NX 1-5X 1-6或SO 2X 1-7;或者,R X1與R X3和其相連的原子共同形成C 5-C 8環烯酮結構; 或者,X 1為NR X1’,R X1’與R X3和其相連的原子共同形成5~8員雜芳環或被一個或多個羥基取代的5~8員雜芳環; 或者,X 1為CR X1,其中,X 1中的C原子與R 1中的芳基或雜芳基中的C原子透過-O-(CH 2) n1- *、 *-NH-(CH 2) n2-、-C≡C-(CH 2) n3-C≡C- *或-(CH 2) n4-O-(CH 2) n5- *相連,其中,*端與X 1中的C原子相連; 條件4:R 1為被一個或多個R 1-1取代的C 6~C 14的芳基或被一個或多個R 1-2取代的5~14員雜芳基; 當R 1為被一個或多個R 1-1取代的C 6~C 14的芳基時,相鄰的兩個R 1-1與其相連的原子一起形成C 3-C 8脂碳環或被一個或多個R 1-3取代的C 3-C 8脂碳環,其餘R 1-1獨立地為鹵素、OH、CN、NO 2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、被一個或多個鹵素取代的C 1-C 6烷基、被一個或多個羥基取代的C 1-C 6烷基、OR a、B(OH) 2、O(C=O)- C 1-C 10烷基、SO 3R a、NR aR b、COR a、CONR aR b、C(O)OR a、NR aCOR a; 當R 1為被一個或多個R 1-2取代的5~14員雜芳基時,相鄰的兩個R 1-2與其相連的原子一起形成C 3-C 8碳環或被一個或多個R 1-4取代的C 3-C 8碳環,其餘R 1-2獨立地為鹵素、OH、CN、NO 2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6環烷基、C 3-C 6環烯基、3~6員雜環烷基、3~6員雜環烯基、被一個或多個鹵素取代的C 1-C 6烷基、被一個或多個羥基取代的C 1-C 6烷基、OR a、B(OH) 2、O(C=O)- C 1-C 10烷基、SO 3R a、NR aR b、COR a、CONR aR b、C(O)OR a、NR aCOR a; R 1-3和R 1-4獨立地為鹵素; 其中,所述的3~6員雜環烷基、3~6員雜環烯基、5~14員雜芳基、3~8員雜環烷基、3~6員脂雜環、3~6員碳雜烯環、5~8員雜芳環、3~8員脂雜環、3-8員碳雜烯環、3-8員脂雜環和3-8員碳雜烯環中的雜原子的種類各自獨立地選自N、O和S中的一種、兩種或三種;所述的3~6員雜環烷基、3~6員雜環烯基、3~8員雜環烷基、3~6員脂雜環、3~6員碳雜烯環、3~8員脂雜環、3-8員碳雜烯環、3-8員脂雜環和3-8員碳雜烯環中的雜原子的個數各自獨立地為1個、2個或3個;所述5~14員雜芳基和5~8員雜芳環中雜原子的個數各自獨立地為1個、2個、3個或4個。 The present invention provides a heterocyclic compound as shown in Formula I-0, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvent complex thereof (referring to the aforementioned heterocyclic compound as shown in Formula I-0, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof): wherein Ring K is an aromatic ring or a heteroaromatic ring; X1 is N, NRX1 ' or CRX1 ; X2 is N or CRX2 ; RX1 and RX2 are each independently H, CN, halogen, C1 - C6 alkyl, C1- C6 alkyl substituted by one or more halogens, C1 - C6 alkyl substituted by one or more hydroxyl groups, PO( C1 - C6 alkyl) 2 , C3 -C6 cycloalkyl , C3- C6 cycloalkenyl, C2- C6 alkenyl, C2 -C6 alkynyl , 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 6-14 membered aryl, 5-14 membered heteroaryl, substituted by one or more X X1-1 is a 3-6 membered heterocycloalkyl substituted by one or more X1-2 , a 5-14 membered heteroaryl substituted by one or more X1-2, NO2 , a 3-6 membered heterocycloalkenyl substituted by one or more X1-3 , ORa , SF5 , C(=O) X1-4 , C(=O) ORa , -NRaC (O) Ra , NX1-5X1-6 or SO2X1-7 ; X1-1 and X1-3 are each independently (C=O) -C1 - C6 alkyl; X1-2 is independently C1 - C6 alkyl; X1-4 is independently H, C3 - C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1 - C6 alkyl, or C1 - C6 alkyl substituted by one or more halogens; X X1-5 and X1-6 are each independently H, C1 - C6 alkyl, C3 - C6 cycloalkyl, SO2 - C1 - C6 alkyl or (C=O) -C1 - C6 alkyl, or X1-5 and X1-6 together with the atoms to which they are connected form a C3 - C6 aliphatic carbocyclic ring, a C3 - C6 carboolefin ring, a 3-6 membered aliphatic heterocyclic ring or a 3-6 membered carboolefin ring; X1-7 is ORa or C1 - C6 alkyl; X3 is N or CRX3 , RX3 is H, halogen, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl, C3- C6 R a and R b each independently represent hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; or R a and R b together with the atoms to which they are attached form a C 3 -C 6 aliphatic ring , a C 3 -C 6 carboolefin ring , a 3-6 membered aliphatic heterocyclic ring or a 3-6 membered carboolefin ring; or R a and R b together with the atoms to which they are attached form a C 3 -C 6 aliphatic ring, a C 3 -C 6 carboolefin ring, a 3-6 membered aliphatic heterocyclic ring or a 3-6 membered carboolefin ring ; or R X1 and RX3 and the atoms to which they are connected together form a C5 - C8 cycloenone structure; or RX1' and RX3 and the atoms to which they are connected together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted by one or more hydroxyl groups; R1 is a C6 - C14 aryl, a C6 - C14 aryl substituted by one or more R1-1 , a 5-14 membered heteroaryl, or a 5-14 membered heteroaryl substituted by one or more R1-2 ; R1-1 and R1-2 are each independently halogen, OH, CN, NO2 , C1 - C6 alkyl, C2- C6 alkenyl, C2 - C6 alkynyl, C3 -C6 cycloalkyl, C3 - C6 substituted by one or more halogens , C 1 -C 6 alkyl groups, C 2 -C 8 alkyl groups, or C 3 -C 8 aliphatic carbocyclic rings or C 3 -C 8 aliphatic carbocyclic rings substituted by one or more R 1-3 ; or, two adjacent R 1-1 groups together with the atoms to which they are attached form a C 3 -C 8 aliphatic carbocyclic ring or a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more R 1-3 , and the remaining R 1-1 groups are independently halogens , OH , CN, NO 2 , C 1 -C 6 alkyl groups , C 2 -C C 2 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C 1 -C 6 alkyl substituted by one or more halogens, C 1 -C 6 alkyl substituted by one or more hydroxyl groups, OR a , B(OH) 2 , O(C=O)- C 1 -C 10 alkyl, SO 3 R a , NR a R b , COR a , CONR a R b , C(O)OR a , NR a COR a ; or, two adjacent R 1-2 together with the atoms to which they are attached form a C 3 -C 8 aliphatic carbocyclic ring or a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more R 1-4 , and the remaining R R 1-2 are independently halogen, OH, CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl , 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C 1 -C 6 alkyl substituted with one or more halogens, C 1 -C 6 alkyl substituted with one or more hydroxyl groups, OR a , B(OH) 2 , O(C=O)- C 1 -C 10 alkyl, SO 3 R a , NR a R b , COR a , CONR a R b , C(O)OR a , NR a COR a ; R 1-3 and R 1-4 are independently halogen; or X 1 is CR X1 , wherein X The C atom in X1 is connected to the C atom in the aryl or heteroaryl group in R1 through -O-( CH2 ) n1- * , * -NH-( CH2 ) n2- , -C≡C-( CH2 ) n3 -C≡C- * , or -( CH2 ) n4 -O-( CH2 ) n5- * , wherein the * end is connected to the C atom in X1 ; n1, n2, n3, n4 and n5 are each independently 1, 2, 3, 4, 5 or 6; R2 is H, halogen, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3- C6 cycloalkyl, C3 - C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, halogenated ( C1 - C6 alkyl), OR a , hydroxy(C 1 -C 6 alkyl), cyano, nitro, -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a , 5-14 membered heteroaryl, 6-14 membered aryl; L 2 represents absence, -O-(C 1 -C 6 alkylene) or -NR a -(C 1 -C 6 alkylene); R 3 represents ; wherein R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 7' , R 8' , R 9' , R 10' , R 11' , and R 12' each independently represent hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -SO 3 R a , -NR a R b , -CO(C 1 -C 6 alkyl) or -C(O)NR a R b ; or R 1' and R 2' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a C 3 -C 8 carboolefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carboolefin ring, a substituted C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 carboolefin ring, a substituted 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered carboolefin ring; the substitution refers to arbitrarily substituted with 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3~6 membered heterocycloalkyl, 3~6 membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R 3' and R 4' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbocyclic ring, a C 3 -C 8 carboolefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carboolefin ring, a substituted C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 carboolefin ring, a substituted 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered carboolefin ring; the substitution refers to arbitrarily being substituted by 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R 5' and R 6' together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbocyclic ring, a C 3 -C 8 carboolefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carboolefin ring, a substituted C 3 -C 8- membered aliphatic carbon ring, substituted C 3 -C 8- membered carbon olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered carbon heteroolefin ring; the substitution refers to arbitrarily 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R 7' and R 8' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbocyclic ring, a C 3 -C 8 carbon olefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carbon heteroolefin ring, a substituted C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 carbon olefin ring, a substituted 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to being arbitrarily replaced by 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6 -membered heterocycloalkenyl, -ORa , -SO3Ra, -NRaRb, -C (O) Ra , -C(O) ORa , -C(O) NRaRb , -NRaC (O)Ra; or any CH2 in the ring is substituted by C=O; or R9 ' and R10 ' together with the atoms connected thereto form a C3 - C8 aliphatic carbocyclic ring, a C3- C8 carboolefin ring, a 3-8 -membered aliphatic heterocyclic ring , a 3-8-membered carboolefin ring, a substituted C3 -C8 aliphatic carbocyclic ring, a substituted C3 -C8 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R R 11' and R 12' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a C 3 -C 8 carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6 -membered heterocycloalkenyl, -ORa , -SO3Ra, -NRaRb, -C (O) Ra , -C(O) ORa , -C(O) NRaRb , -NRaC (O)Ra; or any CH2 in the ring is substituted by C=O; or R2' and R3 ' together with the atoms connected thereto form a C3 -C8 aliphatic carbocyclic ring, a C3- C8 carboolefin ring, a 3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted C3 -C8 aliphatic carbocyclic ring, a substituted C3 -C8 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R 4' , R 5' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbocyclic ring, a C 3 -C 8 carboolefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carboolefin ring, a substituted C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 carboolefin ring, a substituted 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered carboolefin ring; the substitution refers to arbitrarily replacing by 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6 -membered heterocycloalkenyl, -ORa , -SO3Ra, -NRaRb, -C (O) Ra , -C(O) ORa , -C(O) NRaRb , -NRaC (O)Ra; or any CH2 in the ring is substituted by C= O ; or R8' , R9 ' together with the atoms connected thereto form a C3 -C8 aliphatic carbocyclic ring, a C3- C8 carboolefin ring, a 3-8 - membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted C3 -C8 aliphatic carbocyclic ring, a substituted C3 -C8 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to being arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R R 10' and R 11' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a C 3 -C 8 carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing by 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6 -membered heterocycloalkenyl, -ORa , -SO3Ra, -NRaRb, -C (O) Ra , -C(O) ORa , -C(O) NRaRb , -NRaC (O)Ra; or any CH2 in the ring is substituted by C= O ; or R3 ' and R4 ' together with the atoms connected thereto form a C3 -C8 aliphatic carbocyclic ring, a C3- C8 carboolefin ring, a 3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted C3 -C8 aliphatic carbocyclic ring, a substituted C3 -C8 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; and R R 9' and R 10' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a C 3 -C 8 carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; R 4 is L 1 -R 5 , L 1 represents absence, CR a R b or NR a ; R 5 is any cyclic structure of the following formula (i), formula (ii) or formula (iii): wherein W1 represents CRW1RW2 or NRW1 ; wherein RW1 and RW2 each independently represent hydrogen, halogen, cyano, nitro, C1- C6 alkyl, C2 -C6 alkenyl , C2 - C6 alkynyl, halogenated ( C1 - C6 alkyl), hydroxyl ( C1 - C6 alkyl), C3 - C6 cycloalkyl, C3- C6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, -ORa, -SO3Ra, NRaRb , C ( O ) Ra , C(O) ORa , C(O) NRaRb , NRaC (O) Ra or (C=O) -OC1 - C6 alkyleneO-(C=O) -C1 - C10alkyl ; or RW1 , R W2 together with the atoms connected to it form a 3-8 membered aliphatic heterocyclic ring; wherein W2 represents CH or N; wherein Y is methyl, ethyl, C3 alkyl, C2 - C3 alkenyl, or ; R c and R d together with the atoms to which they are connected form a C 3 -C 6 aliphatic carbon ring or a C 3 -C 6 aliphatic carbon ring substituted by one or more halogens; or R d and R d' together with the atoms to which they are connected form a C 3 -C 6 aliphatic carbon ring or a C 3 -C 6 aliphatic carbon ring substituted by one or more halogens; wherein R 1'' , R 2'' , R 3'' , R 4'' , R 5'' , R 6'' , R 7'' , and R 8'' each independently represent hydrogen, halogen, cyano, nitro, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C or R 1'' and R 2'' together with the atoms to which they are attached form a C 3 -C 8 aliphatic carbocyclic ring, a C 3 -C 8 carboolefin ring , a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carboolefin ring , a substituted C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 carboolefin ring , a substituted C 3 -C 8 aliphatic heterocyclic ring, a substituted C 3 -C 8 carboolefin ring, a substituted C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 aliphatic heterocyclic ring, a substituted C 3 -C 8 aliphatic heterocyclic ring, a substituted C 3 -C 8 aliphatic heterocyclic ring, a substituted C 3 -C 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to being arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R R 3'' and R 4'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a C 3 -C 8 carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6 -membered heterocycloalkenyl, -ORa , -SO3Ra, -NRaRb, -C (O) Ra , -C(O) ORa , -C(O) NRaRb , -NRaC (O)Ra; or any CH2 in the ring is substituted by C= O ; or R5 '' and R6 '' together with the atoms connected thereto form a C3 - C8 aliphatic carbocyclic ring, a C3- C8 carboolefin ring, a 3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted C3 -C8 aliphatic carbocyclic ring, a substituted C3- C8 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to being arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R 7'' and R 8'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a C 3 -C 8 carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing by 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6 -membered heterocycloalkenyl, -ORa , -SO3Ra, -NRaRb, -C (O) Ra , -C(O) ORa , -C(O) NRaRb , -NRaC (O)Ra; or any CH2 in the ring is substituted by C= O ; or R2'' and R3 '' together with the atoms connected thereto form a C3 - C8 aliphatic carbocyclic ring, a C3-C8 carboolefin ring, a 3-8 - membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted C3 -C8 aliphatic carbocyclic ring, a substituted C3- C8 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to being arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R R4'' , R5 '' together with the atoms connected thereto form a C3 - C8 aliphatic carbon ring, a C3 - C8 carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C3 - C8 aliphatic carbon ring, a substituted C3 - C8 carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing by 1-2 groups selected from halogen, cyano, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, halogenated ( C1 - C6 alkyl), hydroxyl ( C1 - C6 alkyl), C3 - C6 cycloalkyl, C3 -C 6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6 -membered heterocycloalkenyl, -ORa , -SO3Ra, -NRaRb, -C (O) Ra , -C(O) ORa , -C(O) NRaRb , -NRaC (O)Ra; or any CH2 in the ring is substituted by C= O ; or R6 '' and R7 '' together with the atoms connected thereto form a C3 - C8 aliphatic carbocyclic ring, a C3- C8 carboolefin ring, a 3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted C3 -C8 aliphatic carbocyclic ring, a substituted C3- C8 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to being arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R R 3'' and R 4'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a C 3 -C 8 carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6 -membered heterocycloalkenyl, -ORa , -SO3Ra, -NRaRb, -C (O) Ra , -C(O) ORa , -C(O) NRaRb , -NRaC (O) Ra ; or any CH2 in the ring is replaced by C=O; and R5 '' and R6 '' together with the atoms connected thereto form a C3 - C8 aliphatic carbocyclic ring, a C3- C8 carboolefin ring, a 3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted C3 -C8 aliphatic carbocyclic ring, a substituted C3- C8 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; It satisfies at least one of the following conditions: Condition 1: In R 3 , R 1' and R 2' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbocyclic ring, a C 3 -C 8 carbon olefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carbon heteroolefin ring, a substituted C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 carbon olefin ring, a substituted 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered carbon heteroolefin ring. The substitution refers to arbitrarily replacing 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6 -membered heterocycloalkenyl, -ORa , -SO3Ra, -NRaRb, -C (O) Ra , -C(O) ORa , -C(O) NRaRb , -NRaC (O)Ra; or any CH2 in the ring is substituted by C= O ; or R3 ' and R4 ' together with the atoms connected thereto form a C3 -C8 aliphatic carbocyclic ring, a C3- C8 carboolefin ring, a 3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted C3 -C8 aliphatic carbocyclic ring, a substituted C3 -C8 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R 5' and R 6' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a C 3 -C 8 carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily substituted with 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6 -membered heterocycloalkenyl, -ORa , -SO3Ra, -NRaRb, -C (O) Ra , -C(O) ORa , -C(O) NRaRb , -NRaC (O)Ra; or any CH2 in the ring is substituted by C= O ; or R7 ' and R8 ' together with the atoms connected thereto form a C3 -C8 aliphatic carbocyclic ring, a C3- C8 carboolefin ring, a 3-8 - membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted C3 -C8 aliphatic carbocyclic ring, a substituted C3 -C8 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R R 9' and R 10' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a C 3 -C 8 carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily replacing 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6- membered cycloalkenyl, 3-6 - membered heterocycloalkyl, 3-6 -membered heterocycloalkenyl, -ORa , -SO3Ra, -NRaRb, -C (O) Ra , -C(O) ORa , -C(O) NRaRb , -NRaC (O) Ra ; or any CH2 in the ring is substituted by C=O; or R11 ' and R12 ' together with the atoms connected thereto form a C3 - C8 aliphatic carbocyclic ring, a C3- C8 carboolefin ring, a 3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted C3 -C8 aliphatic carbocyclic ring, a substituted C3 -C8 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R 2' , R 3' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbocyclic ring, a C 3 -C 8 carboolefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carboolefin ring, a substituted C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 carboolefin ring, a substituted 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered carboolefin ring; the substitution refers to arbitrarily replacing by 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6 -membered heterocycloalkenyl, -ORa , -SO3Ra, -NRaRb, -C (O) Ra , -C(O) ORa , -C(O) NRaRb , -NRaC (O)Ra; or any CH2 in the ring is substituted by C= O ; or R4 ' and R5 ' together with the atoms connected thereto form a C3 -C8 aliphatic carbocyclic ring, a C3- C8 carboolefin ring, a 3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted C3 -C8 aliphatic carbocyclic ring, a substituted C3 -C8 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R 8' , R 9' together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbocyclic ring, a C 3 -C 8 carboolefin ring, a 3-8 membered aliphatic heterocyclic ring, a 3-8 membered carboolefin ring, a substituted C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 carboolefin ring, a substituted 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered carboolefin ring; the substitution refers to arbitrarily replacing by 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6- membered cycloalkenyl, 3-6 - membered heterocycloalkyl, 3-6 -membered heterocycloalkenyl, -ORa , -SO3Ra, -NRaRb, -C (O) Ra , -C(O) ORa , -C(O) NRaRb , -NRaC (O) Ra ; or any CH2 in the ring is substituted by C=O; or R10 ' and R11 ' together with the atoms connected thereto form a C3 - C8 aliphatic carbocyclic ring, a C3- C8 carboolefin ring, a 3-8 -membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted C3 -C8 aliphatic carbocyclic ring, a substituted C3 -C8 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to being arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; or R R 3' and R 4' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a C 3 -C 8 carbon olefin ring, a 3-8 membered aliphatic heterocycle, a 3-8 membered carbon heteroolefin ring, a substituted C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 carbon olefin ring, a substituted 3-8 membered aliphatic heterocycle or a substituted 3-8 membered carbon heteroolefin ring; the substitution refers to arbitrarily substituted with 1-2 groups selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; and R 9' and R 10' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbocyclic ring, a C 3 -C 8 carboolefin ring, a 3-8-membered aliphatic heterocyclic ring, a 3-8-membered carboolefin ring, a substituted C 3 -C 8 aliphatic carbocyclic ring, a substituted C 3 -C 8 8- membered olefin ring, substituted 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered olefin ring; the substitution refers to being arbitrarily substituted by 1-2 substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogenated (C 1 -C 6 alkyl), hydroxyl (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, -OR a , -SO 3 R a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R a ; or any CH 2 in the ring is substituted by C=O; Condition 2: R 5 is any cyclic structure of the following formula (i), formula (ii) or formula (iii): wherein, in formula (ii), when W2 is N, W1 is NRW1 , RW1 is not H; in formula (iii), when W2 is N, W1 is NRW1 , RW1 is H, Y is not ethylidene; Condition 3: X1 is CRX1 , RX1 is C1 - C6 alkyl, C1 - C6 alkyl substituted by one or more halogens, PO( C1 - C6 alkyl) 2 , C2 - C6 alkenyl, C2 - C6 alkynyl, 3-6 membered heterocycloalkyl substituted by one or more X1-1 , 6-14 membered aryl, 5-14 membered heteroaryl, 5-14 membered heteroaryl substituted by one or more X1-2 , NO2 , C3 - C6 cycloalkyl, C3- C6 6- membered cycloalkenyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, 3-6-membered heterocycloalkenyl substituted by one or more X 1-3 , SF 5 , C(=O) X 1-4 , C(=O) OR a , -NR a C(O)R a , NX 1-5 X 1-6 or SO 2 X 1-7 ; or, RX1 and RX3 and the atoms to which they are connected together form a C 5 -C 8 cycloalkenone structure; or, X 1 is NR X1' , RX1' and RX3 and the atoms to which they are connected together form a 5-8-membered heteroaromatic ring or a 5-8-membered heteroaromatic ring substituted by one or more hydroxyl groups; or, X 1 is CR X1 , wherein the C atom in X 1 and R The C atom in the aryl or heteroaryl in X1 is connected through -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 -, -C≡C-(CH 2 ) n3 -C≡C- * , or -(CH 2 ) n4 -O-(CH 2 ) n5 - * , wherein the * end is connected to the C atom in X1 ; Condition 4: R1 is a C 6 ~C 14 aryl substituted by one or more R 1-1 or a 5-14 membered heteroaryl substituted by one or more R 1-2 ; When R1 is a C 6 ~C 14 aryl substituted by one or more R 1-1 , two adjacent R 1-1s together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbocyclic ring or a C 3 -C 14 substituted by one or more R 1-3 8 aliphatic carbocyclic rings, the remaining R 1-1 are independently halogen, OH, CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C 1 -C 6 alkyl substituted with one or more halogens, C 1 -C 6 alkyl substituted with one or more hydroxyl groups, OR a , B(OH) 2 , O(C=O)- C 1 -C 10 alkyl, SO 3 R a , NR a R b , COR a , CONR a R b , C(O)OR a , NR a COR a ; when R 1 is substituted with one or more R When the 5- to 14-membered heteroaryl is substituted with 1-2 substituted 5- to 14-membered heteroaryl, two adjacent R 1-2 together with the atoms to which they are connected form a C 3 -C 8 carbon ring or a C 3 -C 8 carbon ring substituted with one or more R 1-4 , and the remaining R 1-2 are independently halogen, OH, CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkenyl, C 1 -C 6 alkyl substituted with one or more halogens, C 1 -C 6 alkyl substituted with one or more hydroxyl groups, OR a , B(OH) 2 , O(C=O)- C 1 -C 10 -alkyl, SO 3 R a , NR a R b , COR a , CONR a R b , C(O)OR a , NR a COR a ; R 1-3 and R 1-4 are independently halogen; wherein the types of heteroatoms in the 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, 5-14-membered heteroaryl, 3-8-membered heterocycloalkyl, 3-6-membered aliphatic heterocycle, 3-6-membered carbon heteroalkene ring, 5-8-membered heteroaryl ring, 3-8-membered aliphatic heterocycle, 3-8-membered carbon heteroalkene ring, 3-8-membered aliphatic heterocycle and 3-8-membered carbon heteroalkene ring are independently selected from one, two or three of N, O and S; the 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkenyl, 5-14-membered heteroaryl, 3-8-membered heterocycloalkyl, 3-6-membered aliphatic heterocycle, 3-6-membered carbon heteroalkene ring, 5-8-membered heteroaryl ring, 3-8-membered aliphatic heterocycle, 3-8-membered carbon heteroalkene ring, 3-8-membered heterocyclic ring and 3-8-membered carbon heteroalkene ring are independently selected from one, two or three of N, O and S; The number of heteroatoms in the heterocycloalkyl, 3-6 membered heterocycloalkenyl, 3-8 membered heterocycloalkyl, 3-6 membered aliphatic heterocycle, 3-6 membered carbon heteroalkene ring, 3-8 membered aliphatic heterocycle, 3-8 membered carbon heteroalkene ring, 3-8 membered aliphatic heterocycle and 3-8 membered carbon heteroalkene ring is independently 1, 2 or 3; the number of heteroatoms in the 5-14 membered heteroaryl and 5-8 membered heteroaryl ring is independently 1, 2, 3 or 4.
某一實施方案中,X 1為N、NR X1’或CR X1。 In one embodiment, X1 is N, NR X1′ or CR X1 .
某一實施方案中,R X1為CN、鹵素、C 1-C 6烷基、被一個或多個鹵素取代的C 1-C 6烷基、PO(C 1-C 6烷基) 2、C 3-C 6環烷基、C 2-C 6烯基、C 2-C 6炔基、3~6員雜環烷基、被一個或多個X 1-1取代的3~6員雜環烷基、5~14員雜芳基、被一個或多個X 1-2取代的5~14員雜芳基、NO 2、3~6員雜環烯基、被一個或多個X 1-3取代的3~6員雜環烯基、SF 5、C(=O) X 1-4、NX 1-5X 1-6或SO 2X 1-7。 In one embodiment, RX1 is CN, halogen, C1 - C6 alkyl , C1- C6 alkyl substituted by one or more halogens, PO( C1 - C6 alkyl) 2 , C3 - C6 cycloalkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl substituted by one or more X1-1 , 5-14 membered heteroaryl, 5-14 membered heteroaryl substituted by one or more X1-2 , NO2 , 3-6 membered heterocycloalkenyl, 3-6 membered heterocycloalkenyl substituted by one or more X1-3 , SF5, C(=O) X1-4 , NX1-5X1-6 or SO2X1-7 .
某一實施方案中,X 1-1和X 1-3各自獨立地為(C=O)-C 1-C 6烷基。 In one embodiment, X 1-1 and X 1-3 are each independently (C=O)-C 1 -C 6 alkyl.
某一實施方案中,X 1-2獨立地為C 1-C 6烷基。 In one embodiment, X 1-2 are independently C 1 -C 6 alkyl.
某一實施方案中,X 1-4獨立地為H、C 3-C 8環烷基、3~8員雜環烷基、C 1-C 6烷基、或被一個或多個鹵素取代的C 1-C 6烷基;X 1-5和X 1-6各自獨立地為H、C 1-C 6烷基、SO 2-C 1-C 6烷基或(C=O)-C 1-C 6烷基。 In one embodiment, X1-4 are independently H, C3 - C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1- C6 alkyl, or C1-C6 alkyl substituted with one or more halogens; X1-5 and X1-6 are each independently H, C1-C6 alkyl , SO2 - C1 - C6 alkyl , or (C=O) -C1 - C6 alkyl.
某一實施方案中,X 1-5和X 1-6各自獨立地為H、C 1-C 6烷基、SO 2-C 1-C 6烷基或(C=O)-C 1-C 6烷基。 In one embodiment, X 1-5 and X 1-6 are each independently H, C 1 -C 6 alkyl, SO 2 -C 1 -C 6 alkyl or (C=O)-C 1 -C 6 alkyl.
某一實施方案中,X 1-7為OH或C 1-C 6烷基。 In one embodiment, X 1-7 is OH or C 1 -C 6 alkyl.
某一實施方案中,X 2為N或CR X2,R X2為CN。 In one embodiment, X2 is N or CR X2 , and RX2 is CN.
某一實施方案中,X 3為N或CR X3,R X3為H或C 1-C 6烷基。 In one embodiment, X3 is N or CR X3 , and RX3 is H or C 1 -C 6 alkyl.
某一實施方案中,R 1-1和R 1-2各自獨立地為鹵素、OH、NH 2、CN、C 1-C 6烷基、(C=O)C 1-C 6烷基、C 2-C 6炔基、被一個或多個鹵素取代的C 1-C 6烷基、B(OH) 2或O(C=O)- C 1-C 10烷基。 In one embodiment, R 1-1 and R 1-2 are each independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted with one or more halogens, B(OH) 2 or O(C=O)- C 1 -C 10 alkyl.
某一實施方案中,相鄰的兩個R 1-1與其相連的原子一起形成C 3-C 8脂碳環或被一個或多個R 1-3取代的C 3-C 8脂碳環,其餘R 1-1獨立地為鹵素、OH、NH 2、CN、C 1-C 6烷基、(C=O)-C 1-C 6烷基、C 2-C 6炔基、被一個或多個鹵素取代的C 1-C 6烷基、B(OH) 2或O(C=O)- C 1-C 10烷基。 In one embodiment, two adjacent R 1-1 together with the atoms to which they are attached form a C 3 -C 8 aliphatic carbocyclic ring or a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more R 1-3 , and the remaining R 1-1 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)- C 1 -C 10 alkyl.
某一實施方案中,相鄰的兩個R 1-2與其相連的原子一起形成C 3-C 8脂碳環或被一個或多個R 1-4取代的C 3-C 8脂碳環,其餘R 1-2獨立地為鹵素、OH、NH 2、CN、C 1-C 6烷基、(C=O)-C 1-C 6烷基、C 2-C 6炔基、被一個或多個鹵素取代的C 1-C 6烷基、B(OH) 2或O(C=O)- C 1-C 10烷基。 In one embodiment, two adjacent R 1-2 together with the atoms to which they are attached form a C 3 -C 8 aliphatic carbocyclic ring or a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more R 1-4 , and the remaining R 1-2 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)- C 1 -C 10 alkyl.
某一實施方案中,R 2為鹵素、C 1-C 6烷基或C 1-C 6烷氧基。 In one embodiment, R 2 is halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
某一實施方案中,L 2表示-O-(C 1-C 6伸烷基)。 In one embodiment, L2 represents -O-( C1 - C6 alkylene).
某一實施方案中,R 3為以下的環狀結構: 其中,R 1'、R 2'、R 3'、R 4'、R 5'、R 6'、R 7'、R 8'、R 9'、R 10'、R 11'、R 12'各自獨立地表示氫或鹵素; 或者R 3'與R 4'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者R 9'與R 10'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者R 3'與R 4'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代;且R 9'與R 10'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者,R 4'、R 5'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者,R 8'、R 9'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者,R 2'、R 3'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者R 10'、R 11'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代。 In one embodiment, R3 is the following cyclic structure: wherein R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 7' , R 8' , R 9' , R 10' , R 11' , and R 12' independently represent hydrogen or halogen; or R 3' and R 4' together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring, or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or R 9' and R 10' together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring, or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or R 3' and R R 4 ' and R 5' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; and R 9' and R 10' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or, R 4' and R 5' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or, R 8' and R 9' together with the atoms connected thereto form a C 3 -C or R 2' and R 3' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution with 1-2 halogens; or R 10' and R 11' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution with 1-2 halogens.
某一實施方案中,R 4為L 1-R 5,L 1表示不存在或NR a, R a表示氫或C 1-C 6烷基。 In one embodiment, R 4 is L 1 -R 5 , L 1 is absent or NR a , and R a is hydrogen or C 1 -C 6 alkyl.
某一實施方案中,R 5為以下式(i)、式(ii)或式(iii)的中的任意一種環狀結構: 其中,W 1表示CR W1R W2或NR W1; 其中,R W1、R W2各自獨立地表示氫、C 1-C 6烷基、3~6員雜環烷基、NR aR b、或(C=O)-O- C 1-C 6伸烷基O-(C=O)-C 1-C 10烷基;或者R W1、R W2一起與與之相連的原子共同形成3~8員脂雜環; R a和R b各自獨立地表示氫或C 1-C 6烷基; 其中,W 2表示CH或N; Y為伸甲基、伸乙基、C 3伸烷基、C 2-C 3伸烯基、或 ;R c和R d與與其相連的原子共同形成C 3-C 6脂碳環或被一個或多個鹵素取代的C 3-C 6脂碳環;或者R d和R d’和與之相連的原子一起形成C 3-C 6脂碳環或被一個或多個鹵素取代的C 3-C 6脂碳環; 其中,R 1’’、R 2’’、R 3’’、R 4’’、R 5’’、R 6’’、R 7’’、R 8’’各自獨立地表示氫或C 1-C 6烷基; 或者,R 2’’、R 3’’一起與與之相連的原子形成C 3-C 8脂碳環、3~8員脂雜環或取代的3-8員脂雜環,所述的取代是指任意地被C 1-C 6烷基取代;或者環中任意的CH 2被C=O所取代; 或者,R 3’’與R 4’’一起與與之相連的原子形成C 3-C 8脂碳環、3~8員脂雜環或取代的3-8員脂雜環,所述的取代是指任意地被C 1-C 6烷基取代;或者環中任意的CH 2被C=O所取代; 或者,R 4’’、R 5’’一起與與之相連的原子形成C 3-C 8脂碳環、3~8員脂雜環或取代的3-8員脂雜環,所述的取代是指任意地被C 1-C 6烷基取代;或者環中任意的CH 2被C=O所取代; 或者,R 5’’與R 6’’一起與與之相連的原子形成C 3-C 8脂碳環、3~8員脂雜環或取代的3-8員脂雜環,所述的取代是指任意地被C 1-C 6烷基取代;或者環中任意的CH 2被C=O所取代; 或者,R 6’’、R 7’’一起與與之相連的原子形成C 3-C 8脂碳環、3~8員脂雜環或取代的3-8員脂雜環,所述的取代是指任意地被C 1-C 6烷基取代;或者環中任意的CH 2被C=O所取代; 或者R 3’’與R 4’’一起與與之相連的原子形成C 3-C 8脂碳環、3~8員脂雜環或取代的3-8員脂雜環,所述的取代是指任意地被C 1-C 6烷基取代;或者環中任意的CH 2被C=O所取代;且R 5’’與R 6’’一起與與之相連的原子形成C 3-C 8脂碳環、3~8員脂雜環或取代的3-8員脂雜環,所述的取代是指任意地被C 1-C 6烷基取代;或者環中任意的CH 2被C=O所取代。 In one embodiment, R 5 is a cyclic structure of any of the following formulas (i), (ii) or (iii): wherein W1 represents CRW1RW2 or NRW1 ; wherein RW1 and RW2 each independently represent hydrogen, C1 - C6 alkyl, 3-6 membered heterocycloalkyl, NRaRb , or (C=O)-O - C1 -C6 alkyleneO- (C=O) -C1 - C10 alkyl; or RW1 and RW2 together with the atoms to which they are connected form a 3-8 membered aliphatic heterocyclic ring; Ra and Rb each independently represent hydrogen or C1-C6 alkyl ; wherein W2 represents CH or N; Y is methylene, ethylene, C3 alkylene, C2 - C3 alkenyl, or ; R c and R d together with the atoms to which they are connected form a C 3 -C 6 aliphatic carbon ring or a C 3 -C 6 aliphatic carbon ring substituted by one or more halogens; or R d and R d' together with the atoms to which they are connected form a C 3 -C 6 aliphatic carbon ring or a C 3 -C 6 aliphatic carbon ring substituted by one or more halogens; wherein R 1'' , R 2'' , R 3'' , R 4'' , R 5'' , R 6'' , R 7'' , R 8'' each independently represents hydrogen or C 1 -C 6 alkyl; or R 2'' , R 3'' together with the atoms to which they are connected form a C 3 -C 8 -membered aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O; or, R 3'' and R 4'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O; or, R 4'' and R 5'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O. 2 is replaced by C=O; or, R 5'' and R 6'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O; or, R 6'' and R 7'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O; or R 3'' and R 4'' together with the atoms connected thereto form a C 3 -C 8 -membered aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrary substitution by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O; and R 5'' and R 6'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrary substitution by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O.
某一實施方案中,環K為芳環或雜芳環; X 1為N、NR X1’或CR X1, R X1為CN、鹵素、C 1-C 6烷基、被一個或多個鹵素取代的C 1-C 6烷基、PO(C 1-C 6烷基) 2、C 3-C 6環烷基、C 2-C 6烯基、C 2-C 6炔基、3~6員雜環烷基、被一個或多個X 1-1取代的3~6員雜環烷基、5~14員雜芳基、被一個或多個X 1-2取代的5~14員雜芳基、NO 2、3~6員雜環烯基、被一個或多個X 1-3取代的3~6員雜環烯基、SF 5、C(=O) X 1-4、NX 1-5X 1-6或SO 2X 1-7; X 1-1和X 1-3各自獨立地為(C=O)-C 1-C 6烷基;X 1-2獨立地為C 1-C 6烷基;X 1-4獨立地為H、C 3-C 8環烷基、3~8員雜環烷基、C 1-C 6烷基、或被一個或多個鹵素取代的C 1-C 6烷基;X 1-5和X 1-6各自獨立地為H、C 1-C 6烷基、SO 2-C 1-C 6烷基或(C=O)-C 1-C 6烷基;X 1-7為OH或C 1-C 6烷基; X 2為N或CR X2,R X2為CN; X 3為N或CR X3,R X3為H或C 1-C 6烷基; 或者R X1與R X3和其相連的原子共同形成C 5-C 8環烯酮結構; 或者R X1’與R X3和其相連的原子共同形成5~8員雜芳環或被一個或多個羥基取代的5~8員雜芳環; R 1為C 6~C 14的芳基、被一個或多個R 1-1取代的C 6~C 14的芳基、5~14員雜芳基或被一個或多個R 1-2取代的5~14員雜芳基; R 1-1和R 1-2各自獨立地為鹵素、OH、NH 2、CN、C 1-C 6烷基、(C=O)C 1-C 6烷基、C 2-C 6炔基、被一個或多個鹵素取代的C 1-C 6烷基、B(OH) 2或O(C=O)- C 1-C 10烷基, 或者,相鄰的兩個R 1-1與其相連的原子一起形成C 3-C 8脂碳環或被一個或多個R 1-3取代的C 3-C 8脂碳環,其餘R 1-1獨立地為鹵素、OH、NH 2、CN、C 1-C 6烷基、(C=O)-C 1-C 6烷基、C 2-C 6炔基、被一個或多個鹵素取代的C 1-C 6烷基、B(OH) 2或O(C=O)- C 1-C 10烷基; 或者,相鄰的兩個R 1-2與其相連的原子一起形成C 3-C 8脂碳環或被一個或多個R 1-4取代的C 3-C 8脂碳環,其餘R 1-2獨立地為鹵素、OH、NH 2、CN、C 1-C 6烷基、(C=O)-C 1-C 6烷基、C 2-C 6炔基、被一個或多個鹵素取代的C 1-C 6烷基、B(OH) 2或O(C=O)- C 1-C 10烷基; R 1-3和R 1-4獨立地為鹵素; 或者X 1為CR X1,其中,X 1中的C原子與R 1中的芳基或雜芳基中的C原子透過-O-(CH 2) n1- *、 *-NH-(CH 2) n2-、-C≡C-(CH 2) n3-C≡C- *或-(CH 2) n4-O-(CH 2) n5- *相連,其中,*端與X 1中的C原子相連; n1、n2、n3、n4和n5各自獨立地為1、2、3、4、5或6; R 2為鹵素、C 1-C 6烷基或C 1-C 6烷氧基; L 2表示-O-(C 1-C 6伸烷基); R 3為以下的環狀結構: 其中,R 1'、R 2'、R 3'、R 4'、R 5'、R 6'、R 7'、R 8'、R 9'、R 10'、R 11'、R 12'各自獨立地表示氫或鹵素; 或者R 3'與R 4'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者R 9'與R 10'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者R 3'與R 4'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代;且R 9'與R 10'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者,R 4'、R 5'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者,R 8'、R 9'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者,R 2'、R 3'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者R 10'、R 11'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; R 4為L 1-R 5,L 1表示不存在或NR a, R 5為以下式(i)、式(ii)或式(iii)的中的任意一種環狀結構: 其中,W 1表示CR W1R W2或NR W1; 其中,R W1、R W2各自獨立地表示氫、C 1-C 6烷基、3~6員雜環烷基、NR aR b、或(C=O)-O- C 1-C 6伸烷基O-(C=O)-C 1-C 10烷基;或者R W1、R W2一起與與之相連的原子共同形成3~8員脂雜環; R a和R b各自獨立地表示氫或C 1-C 6烷基; 其中,W 2表示CH或N; Y為伸甲基、伸乙基、C 3伸烷基、C 2-C 3伸烯基、或 ;R c和R d與與其相連的原子共同形成C 3-C 6脂碳環或被一個或多個鹵素取代的C 3-C 6脂碳環;或者R d和R d’和與之相連的原子一起形成C 3-C 6脂碳環或被一個或多個鹵素取代的C 3-C 6脂碳環; 其中,R 1’’、R 2’’、R 3’’、R 4’’、R 5’’、R 6’’、R 7’’、R 8’’各自獨立地表示氫或C 1-C 6烷基; 或者,R 2’’、R 3’’一起與與之相連的原子形成C 3-C 8脂碳環、3~8員脂雜環或取代的3-8員脂雜環,所述的取代是指任意地被C 1-C 6烷基取代;或者環中任意的CH 2被C=O所取代; 或者,R 3’’與R 4’’一起與與之相連的原子形成C 3-C 8脂碳環、3~8員脂雜環或取代的3-8員脂雜環,所述的取代是指任意地被C 1-C 6烷基取代;或者環中任意的CH 2被C=O所取代; 或者,R 4’’、R 5’’一起與與之相連的原子形成C 3-C 8脂碳環、3~8員脂雜環或取代的3-8員脂雜環,所述的取代是指任意地被C 1-C 6烷基取代;或者環中任意的CH 2被C=O所取代; 或者,R 5’’與R 6’’一起與與之相連的原子形成C 3-C 8脂碳環、3~8員脂雜環或取代的3-8員脂雜環,所述的取代是指任意地被C 1-C 6烷基取代;或者環中任意的CH 2被C=O所取代; 或者,R 6’’、R 7’’一起與與之相連的原子形成C 3-C 8脂碳環、3~8員脂雜環或取代的3-8員脂雜環,所述的取代是指任意地被C 1-C 6烷基取代;或者環中任意的CH 2被C=O所取代; 或者R 3’’與R 4’’一起與與之相連的原子形成C 3-C 8脂碳環、3~8員脂雜環或取代的3-8員脂雜環,所述的取代是指任意地被C 1-C 6烷基取代;或者環中任意的CH 2被C=O所取代;且R 5’’與R 6’’一起與與之相連的原子形成C 3-C 8脂碳環、3~8員脂雜環或取代的3-8員脂雜環,所述的取代是指任意地被C 1-C 6烷基取代;或者環中任意的CH 2被C=O所取代; 其滿足下述至少一個條件: 條件1:R 3中,R 3'與R 4'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者R 9'與R 10'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者R 3'與R 4'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代;且R 9'與R 10'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者,R 4'、R 5'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者,R 2'、R 3'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 或者R 10'、R 11'一起與與之相連的原子形成C 3-C 8脂碳環、取代的C 3-C 8脂碳環或3-8員脂雜環,所述的取代是指任意地被1-2個鹵素取代; 條件2:R 5為以下式(i)、式(ii)或式(iii)的中的任意一種環狀結構: 其中,式(ii)中,W 2為N,W 1為NR W1時,R W1不為H; 式(iii)中,W 2為N,W 1為NR W1,R W1為H時,Y不為伸乙基; 條件3:X 1為CR X1,R X1為被一個或多個鹵素取代的C 1-C 6烷基、PO(C 1-C 6烷基) 2、C 2-C 6烯基、C 2-C 6炔基、NO 2、C 3-C 6環烷基、3~6員雜環烷基、3~6員雜環烯基、被一個或多個X 1-1取代的3~6員雜環烷基、被一個或多個X 1-2取代的5~14員雜芳基、被一個或多個X 1-3取代的3~6員雜環烯基、SF 5、C(=O) X 1-4、NX 1-5X 1-6或SO 2X 1-7;或者,R X1與R X3和其相連的原子共同形成C 5-C 8環烯酮結構; 或者,X 1為NR X1’,R X1’與R X3和其相連的原子共同形成5~8員雜芳環或被一個或多個羥基取代的5~8員雜芳環; 或者,X 1為CR X1,其中,X 1中的C原子與R 1中的芳基或雜芳基中的C原子透過-O-(CH 2) n1- *、 *-NH-(CH 2) n2-、-C≡C-(CH 2) n3-C≡C- *或-(CH 2) n4-O-(CH 2) n5- *相連,其中,*端與X 1中的C原子相連; 條件4:R 1為被一個或多個R 1-1取代的C 6~C 14的芳基或被一個或多個R 1-2取代的5~14員雜芳基; 當R 1為被一個或多個R 1-1取代的C 6~C 14的芳基時,相鄰的兩個R 1-1與其相連的原子一起形成C 3-C 8脂碳環或被一個或多個R 1-3取代的C 3-C 8脂碳環,其餘R 1-1獨立地為鹵素、OH、NH 2、CN、C 1-C 6烷基、(C=O)-C 1-C 6烷基、C 2-C 6炔基、被一個或多個鹵素取代的C 1-C 6烷基、B(OH) 2或O(C=O)- C 1-C 10烷基; 當R 1為被一個或多個R 1-2取代的5~14員雜芳基時,相鄰的兩個R 1-2與其相連的原子一起形成C 3-C 8脂碳環或被一個或多個R 1-4取代的C 3-C 8脂碳環,其餘R 1-2獨立地為鹵素、OH、NH 2、CN、C 1-C 6烷基、(C=O)-C 1-C 6烷基、C 2-C 6炔基、被一個或多個鹵素取代的C 1-C 6烷基、B(OH) 2或O(C=O)- C 1-C 10烷基; R 1-3和R 1-4獨立地為鹵素。 In one embodiment, ring K is an aromatic ring or a heteroaromatic ring; X1 is N, NRX1 ' or CRX1 , RX1 is CN, halogen , C1 - C6 alkyl, C1- C6 alkyl substituted by one or more halogens, PO( C1 - C6 alkyl) 2 , C3 - C6 cycloalkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl substituted by one or more X1-1 , 5-14 membered heteroaryl, 5-14 membered heteroaryl substituted by one or more X1-2 , NO2 , 3-6 membered heterocycloalkenyl, 3-6 membered heterocycloalkenyl substituted by one or more X1-3 , SF5 , C (=O) X1-4 , NX1-5X1-6 or SO2X1-7 ; X1-1 and X1-3 are each independently (C=O) -C1 - C6 alkyl; X1-2 is independently C1 - C6 alkyl; X1-4 is independently H, C3 - C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1- C6 alkyl, or C1 - C6 alkyl substituted with one or more halogens; X1-5 and X1-6 are each independently H, C1 - C6 alkyl, SO2 - C1 - C6 alkyl or (C=O) -C1 - C6 alkyl; X1-7 is OH or C1 - C6 alkyl; X2 is N or CR X2 , RX2 is CN; X3 is N or CR X3 , R X3 is H or C 1 -C 6 alkyl; or RX1 , RX3 and the atoms to which they are connected together form a C 5 -C 8 cycloenone structure; or RX1' , RX3 and the atoms to which they are connected together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted with one or more hydroxyl groups; R 1 is a C 6 -C 14 aryl, a C 6 -C 14 aryl substituted with one or more R 1-1 , a 5-14 membered heteroaryl or a 5-14 membered heteroaryl substituted with one or more R 1-2 ; R 1-1 and R 1-2 are each independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 6 -C 14 substituted with one or more halogens; or, two adjacent R 1-1s together with the atoms to which they are attached form a C 3 -C 8 aliphatic carbocyclic ring or a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more R 1-3 , and the remaining R 1-1s are independently halogen , OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)- C 1 -C 10 alkyl; or, two adjacent R 1-2s together with the atoms to which they are attached form a C 3 -C 8 aliphatic carbocyclic ring or a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more R 1-4 ; -C 8 aliphatic carbocyclic ring, the remaining R 1-2 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted with one or more halogens, B(OH) 2 or O(C=O)- C 1 -C 10 alkyl; R 1-3 and R 1-4 are independently halogen; or X 1 is CR X1 , wherein the C atom in X 1 and the C atom in the aryl or heteroaryl group in R 1 are bonded via -O-(CH 2 ) n1 - * , * -NH-(CH 2 ) n2 -, -C≡C-(CH 2 ) n3 -C≡C- * or -(CH 2 ) n4 -O-(CH 2 ) n5 - * , wherein the * end is connected to the C atom in X1 ; n1, n2, n3, n4 and n5 are each independently 1, 2, 3, 4, 5 or 6; R2 is a halogen, a C1 - C6 alkyl or a C1 - C6 alkoxy; L2 represents -O-( C1 - C6 alkylene); R3 is the following cyclic structure: wherein R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 7' , R 8' , R 9' , R 10' , R 11' , and R 12' each independently represent hydrogen or a halogen; or R 3' and R 4' together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring, or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or R 9' and R 10' together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring, or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or R 3' and R R 4 ' and R 5' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; and R 9' and R 10' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or, R 4' and R 5' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution with 1-2 halogens; or, R 8' and R 9' together with the atoms connected thereto form a C 3 -C R 4 is L 1 -R 5 , L 1 is absent or NR a , R 5 is absent or NR a , R 6 is absent or NR a , R 7 is absent or NR a , R 8 is absent or NR a , R 9 is absent or NR b , R 10 is absent or NR b , R 11 is absent or NR a , R 12 is absent or NR b , R 13 is absent or NR b 5 is any one of the following cyclic structures of formula (i), formula (ii) or formula (iii): wherein W1 represents CRW1RW2 or NRW1 ; wherein RW1 and RW2 each independently represent hydrogen, C1 - C6 alkyl, 3-6 membered heterocycloalkyl, NRaRb , or (C=O)-O - C1 -C6 alkyleneO- (C=O) -C1 - C10 alkyl; or RW1 and RW2 together with the atoms to which they are connected form a 3-8 membered aliphatic heterocyclic ring; Ra and Rb each independently represent hydrogen or C1-C6 alkyl ; wherein W2 represents CH or N; Y is methylene, ethylene, C3 alkylene, C2 - C3 alkenyl, or ; R c and R d together with the atoms to which they are connected form a C 3 -C 6 aliphatic carbon ring or a C 3 -C 6 aliphatic carbon ring substituted by one or more halogens; or R d and R d' together with the atoms to which they are connected form a C 3 -C 6 aliphatic carbon ring or a C 3 -C 6 aliphatic carbon ring substituted by one or more halogens; wherein R 1'' , R 2'' , R 3'' , R 4'' , R 5'' , R 6'' , R 7'' , R 8'' each independently represents hydrogen or C 1 -C 6 alkyl; or R 2'' , R 3'' together with the atoms to which they are connected form a C 3 -C 8 -membered aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O; or, R 3'' and R 4'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O; or, R 4'' and R 5'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O. 2 is replaced by C=O; or, R 5'' and R 6'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O; or, R 6'' and R 7'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a substituted 3-8 membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O; or R 3'' and R 4'' together with the atoms connected thereto form a C 3 -C 8 -membered aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O; and R 5'' and R 6'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or substituted 3-8-membered aliphatic heterocyclic ring, the substitution means arbitrarily substituted by C 1 -C 6 alkyl; or any CH 2 in the ring is replaced by C=O; it satisfies at least one of the following conditions: Condition 1: in R 3 , R 3' and R 4' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, substituted C 3 -C or R 9' and R 10' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution by 1-2 halogens; or R 3' and R 4' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution by 1-2 halogens; and R 9' and R 10' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution by 1-2 halogens; or R 4' and R 5' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution by 1-2 halogens; or, R 2' and R 3' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution by 1-2 halogens; or, R 10' and R 11 ' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a substituted C 3 -C 8 aliphatic carbon ring or a 3-8 membered aliphatic heterocyclic ring, and the substitution refers to arbitrary substitution by 1-2 halogens; 8- membered aliphatic carbon ring or 3-8-membered aliphatic heterocyclic ring, wherein the substitution refers to arbitrary substitution by 1-2 halogens; Condition 2: R 5 is any one of the following cyclic structures of formula (i), formula (ii) or formula (iii): wherein, in formula (ii), when W2 is N, W1 is NRW1 , RW1 is not H; wherein in formula (iii), when W2 is N, W1 is NRW1 , RW1 is H, Y is not ethylidene; Condition 3: X1 is CRX1 , RX1 is C1 - C6 alkyl substituted by one or more halogens, PO( C1 - C6 alkyl) 2 , C2 - C6 alkenyl, C2 - C6 alkynyl, NO2 , C3 - C6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 3-6 membered heterocycloalkyl substituted by one or more X1-1 , 5-14 membered heteroaryl substituted by one or more X1-2 , 1-3 substituted 3-6 membered heterocycloalkenyl, SF5 , C(=O) X1-4 , NX1-5X1-6 or SO2X1-7 ; or, RX1 and RX3 and the atoms to which they are connected together form a C5 - C8 cycloalkenone structure; or, X1 is NRX1 ' , RX1' and RX3 and the atoms to which they are connected together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted with one or more hydroxyl groups; or, X1 is CRX1 , wherein the C atom in X1 and the C atom in the aryl or heteroaryl in R1 are bonded to each other through -O-( CH2 ) n1- * , * -NH-( CH2 ) n2- , -C≡C-( CH2 ) n3 -C≡C- * or -( CH2 ) n4 -O-(CH 2 ) n5 - * are connected, wherein the * end is connected to the C atom in X 1 ; Condition 4: R 1 is a C 6 ~C 14 aryl substituted by one or more R 1-1 or a 5-14 membered heteroaryl substituted by one or more R 1-2 ; When R 1 is a C 6 ~C 14 aryl substituted by one or more R 1-1 , two adjacent R 1-1s and the atoms to which they are connected together form a C 3 -C 8 aliphatic carbocyclic ring or a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more R 1-3 , and the remaining R 1-1s are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C when R 1 is a 5-14 membered heteroaryl substituted by one or more R 1-2 , two adjacent R 1-2 together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbocyclic ring or a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more R 1-4 , and the remaining R 1-2 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogen , B (OH) 2 or O(C=O)- C 1 -C 10 alkyl ; R R 1-3 and R 1-4 are independently halogen.
某一實施方案中,R X1為CN、鹵素、被一個或多個鹵素取代的C 1-C 6烷基、PO(C 1-C 6烷基) 2、C 3-C 6環烷基、C 2-C 6烯基、C 2-C 6炔基、3~6員雜環烷基、被一個或多個X 1-1取代的3~6員雜環烷基、被一個或多個X 1-2取代的5~14員雜芳基、NO 2、3~6員雜環烯基、被一個或多個X 1-3取代的3~6員雜環烯基、C(=O) X 1-4、NX 1-5X 1-6或SO 2X 1-7。 In one embodiment, RX1 is CN, halogen, C1 - C6 alkyl substituted by one or more halogens, PO( C1 - C6 alkyl) 2 , C3- C6 cycloalkyl, C2 - C6 alkenyl, C2 - C6 alkynyl , 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl substituted by one or more X1-1 , 5-14 membered heteroaryl substituted by one or more X1-2 , NO2 , 3-6 membered heterocycloalkenyl, 3-6 membered heterocycloalkenyl substituted by one or more X1-3 , C( = O) X1-4 , NX1-5X1-6 or SO2X1-7 .
某一實施方案中,X 1-4獨立地為C 1-C 6烷基。 In one embodiment, X 1-4 are independently C 1 -C 6 alkyl.
某一實施方案中,X 1-7為C 1-C 6烷基。 In one embodiment, X 1-7 is C 1 -C 6 alkyl.
某一實施方案中,X 3為CR X3,R X3為H。 In one embodiment, X3 is CR X3 and RX3 is H.
某一實施方案中,R X1’與R X3和其相連的原子共同形成5~8員雜芳環。 In one embodiment, RX1 ' and RX3 and the atoms to which they are connected together form a 5-8 membered heteroaryl ring.
某一實施方案中,R 1為被一個或多個R 1-1取代的C 6~C 14的芳基或被一個或多個R 1-2取代的5~14員雜芳基; R 1-1和R 1-2各自獨立地為鹵素、OH、NH 2、C 1-C 6烷基、(C=O)-C 1-C 6烷基、C 2-C 6炔基、被一個或多個鹵素取代的C 1-C 6烷基或B(OH) 2; 或者,相鄰的兩個R 1-1與其相連的原子一起形成C 3-C 8脂碳環,其餘R 1-1獨立地為鹵素、OH、NH 2、C 1-C 6烷基、(C=O)-C 1-C 6烷基、C 2-C 6炔基、被一個或多個鹵素取代的C 1-C 6烷基或B(OH) 2。 In one embodiment, R 1 is a C 6 -C 14 aryl substituted by one or more R 1-1 or a 5-14 membered heteroaryl substituted by one or more R 1-2 ; R 1-1 and R 1-2 are each independently a halogen, OH, NH 2 , C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, a C 1 -C 6 alkyl substituted by one or more halogens, or B(OH) 2 ; or, two adjacent R 1-1s together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbocyclic ring, and the remaining R 1-1s are independently a halogen, OH, NH 2 , C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, or B(OH) 2 .
某一實施方案中,X 1中的C原子與R 1中的芳基或雜芳基中的C原子透過-O-(CH 2) n1- *或-(CH 2) n4-O-(CH 2) n5- *相連,其中,*端與X 1中的C原子相連;n1、n4和n5各自獨立地為1、2、3、4、5或6。 In one embodiment, the C atom in X1 is connected to the C atom in the aryl or heteroaryl group in R1 through -O-( CH2 ) n1- * or -( CH2 ) n4 -O-( CH2 ) n5- * , wherein the * end is connected to the C atom in X1 ; n1, n4 and n5 are each independently 1, 2, 3, 4, 5 or 6.
某一實施方案中,R 2為鹵素。 In one embodiment, R2 is halogen.
某一實施方案中,R 3為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 時, 其中X為鹵素,環A、環B和環C與母體結構共用一個碳原子,環D和環E與母體結構共用兩個原子和一根鍵;環A、環B和環C與母體結構共用一個碳原子,環D和環E與母體結構共用兩個原子和一根鍵;環A、環B、環C、環D和環E各自獨立地為3~8員脂雜環、C 3-C 8脂碳環或被一個或多個鹵素取代的C 3-C 8脂碳環; 較佳地,環A為3~8員脂雜環、C 3-C 8脂碳環或被1個或2個鹵素取代的C 3-C 8脂碳環;環B和環C各自獨立地為3~8員脂雜環;環D為3~8員脂雜環或C 3-C 8脂碳環;環E為C 3-C 8脂碳環。 In one embodiment, R3 is , , , , , , , , , , , , , , , , , , , , , , When X is a halogen, Ring A, Ring B and Ring C share one carbon atom with the parent structure, and Ring D and Ring E share two atoms and one bond with the parent structure; Ring A, Ring B and Ring C share one carbon atom with the parent structure, and Ring D and Ring E share two atoms and one bond with the parent structure; Ring A, Ring B, Ring C, Ring D and Ring E are each independently a 3-8 membered aliphatic heterocyclic ring, a C 3 -C 8 aliphatic carbon ring, or a C 3 -C 8 aliphatic carbon ring substituted with one or more halogens; Preferably, Ring A is a 3-8 membered aliphatic heterocyclic ring, a C 3 -C 8 aliphatic carbon ring, or a C 3 -C 8 aliphatic carbon ring substituted with 1 or 2 halogens. 8-membered aliphatic carbon ring; Ring B and Ring C are each independently a 3-8-membered aliphatic heterocyclic ring; Ring D is a 3-8-membered aliphatic heterocyclic ring or a C 3 -C 8 aliphatic carbon ring; Ring E is a C 3 -C 8 aliphatic carbon ring.
某一實施方案中,R 4為式(i)、式(ii)或式(iii): 其中,式(i)中,R 1’’、R 2’’、R 7’’和R 8’’各自獨立地為氫; R 3’’與R 4’’一起與與之相連的原子形成C 3-C 8脂碳環、3-8員脂雜環或被一個或多個R a取代的3~8員脂雜環;或者所述環中任意的CH 2被C=O所取代; 或者,R 5’’與R 6’’一起與與之相連的原子形成C 3-C 8脂碳環、3-8員脂雜環或被一個或多個R a取代的3~8員脂雜環;或者所述環中任意的CH 2被C=O所取代; 或者,R 3’’與R 4’’一起與與之相連的原子形成C 3-C 8脂碳環、3-8員脂雜環或被一個或多個R a取代的3~8員脂雜環;或者所述環中任意的CH 2被C=O所取代;且R 5’’與R 6’’一起與與之相連的原子形成C 3-C 8脂碳環、3-8員脂雜環或被一個或多個R a取代的3~8員脂雜環;或者所述環中任意的CH 2被C=O所取代;R a獨立地表示氫或C 1-C 6烷基; 其中,式(ii)中,W 1表示CR W1R W2或NR W1;W 2表示N; 當W 1為CR W1R W2時,R W1、R W2各自獨立地表示H、3~8員雜環烷基或者R W1、R W2一起與與之相連的原子共同形成3~8員脂雜環; 當W 1為NR W1時,R W1為H,R 1’’、R 2’’、R 3’’、R 4’’、R 7’’和R 8’’各自獨立地為氫或C 1-C 6烷基; 或者,R 2’’、R 3’’一起與與之相連的原子形成C 3-C 8脂碳環、3-8員脂雜環或被一個或多個R a取代的3~8員脂雜環;或者所述環中任意的CH 2被C=O所取代; 或者R 6’’、R 7’’一起與與之相連的原子形成C 3-C 8脂碳環、3-8員脂雜環或被一個或多個R a取代的3~8員脂雜環;或者所述環中任意的CH 2被C=O所取代; 或者R 5’’與R 6’’一起與與之相連的原子形成C 3-C 8脂碳環、3-8員脂雜環或被一個或多個R a取代的3~8員脂雜環;或者所述環中任意的CH 2被C=O所取代; 或者R 3’’與R 4’’一起與與之相連的原子形成C 3-C 8脂碳環、3-8員脂雜環或被一個或多個R a取代的3~8員脂雜環;或者所述環中任意的CH 2被C=O所取代; R a獨立地表示氫或C 1-C 6烷基; 其中,式(iii)中,W 1表示CR W1R W2或NR W1,R W1、R W2各自獨立地表示氫、NR aR b、C 1-C 6烷基或(C=O)-O-CH 2-O-(C=O)-C 1-C 10烷基,R a和R b各自獨立地表示氫或C 1-C 6烷基;W 2表示CH或N;R 1’’、R 2’’、R 3’’和R 4’’為氫;Y為伸甲基、伸乙基、C 3伸烷基、C 2-C 3伸烯基、或 ;R c和R d與與其相連的原子共同形成C 3-C 6脂碳環或被一個或多個鹵素取代的C 3-C 6脂碳環;或者R d和R d’和與之相連的原子一起形成C 3-C 6脂碳環或被一個或多個鹵素取代的C 3-C 6脂碳環。 In one embodiment, R4 is formula (i), formula (ii) or formula (iii): wherein in formula (i), R 1'' , R 2'' , R 7'' and R 8'' are each independently hydrogen; R 3'' and R 4'' together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted with one or more Ras ; or any CH 2 in the ring is replaced by C=O; or, R 5'' and R 6'' together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted with one or more Ras ; or any CH 2 in the ring is replaced by C=O; or, R 3'' and R 4'' together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted with one or more Ras; or any CH 2 in the ring is replaced by C=O; 8-membered aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or 3-8-membered aliphatic heterocyclic ring substituted by one or more Ra ; or any CH2 in the ring is replaced by C=O; and R5 '' and R6 '' together with the atoms connected thereto form a C3 - C8 aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring or 3-8-membered aliphatic heterocyclic ring substituted by one or more Ra ; or any CH2 in the ring is replaced by C=O; Ra independently represents hydrogen or C1 - C6 alkyl; wherein, in formula (ii), W1 represents CRW1RW2 or NRW1 ; W2 represents N; when W1 is CRW1RW2 , RW1 and RW2 each independently represent H, 3-8 - membered heterocycloalkyl or RW1 , R W2 together with the atoms connected to it form a 3-8 membered aliphatic heterocyclic ring; when W1 is NR W1 , R W1 is H, R 1'' , R 2'' , R 3'' , R 4'' , R 7'' and R 8'' are each independently hydrogen or C 1 -C 6 alkyl; or, R 2'' , R 3'' together with the atoms connected to it form a C 3 -C 8 aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more Ra ; or any CH 2 in the ring is replaced by C=O; or R 6'' , R 7'' together with the atoms connected to it form a C 3 -C 8 aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more R or any CH 2 in the ring is substituted by C=O; or R 5'' and R 6'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a 3-8 membered aliphatic heterocycle or a 3-8 membered aliphatic heterocycle substituted by one or more Ra ; or any CH 2 in the ring is substituted by C=O; or R 3'' and R 4'' together with the atoms connected thereto form a C 3 -C 8 aliphatic carbon ring, a 3-8 membered aliphatic heterocycle or a 3-8 membered aliphatic heterocycle substituted by one or more Ra ; or any CH 2 in the ring is substituted by C=O; Ra independently represents hydrogen or C 1 -C 6 alkyl; wherein, in formula (iii), W 1 represents CR W1 R W2 or NR W1 , R W1 , R and W2 each independently represent hydrogen, NR a R b , C 1 -C 6 alkyl or (C=O)-O-CH 2 -O-(C=O)-C 1 -C 10 alkyl, Ra and R b each independently represent hydrogen or C 1 -C 6 alkyl; W 2 represents CH or N; R 1'' , R 2'' , R 3'' and R 4'' are hydrogen; Y is methyl, ethyl, C 3 alkyl, C 2 -C 3 alkenyl, or ; R c and R d together with the atoms to which they are attached form a C 3 -C 6 aliphatic carbon ring or a C 3 -C 6 aliphatic carbon ring substituted by one or more halogens; or R d and R d' together with the atoms to which they are attached form a C 3 -C 6 aliphatic carbon ring or a C 3 -C 6 aliphatic carbon ring substituted by one or more halogens.
某一實施方案中,R 4為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 ;其中,R 4-1為H、C 1-C 6烷基或(C=O)-O-CH 2-O-(C=O)-C 1-C 10烷基;R 4-2為C 1-C 6烷基,R 4-2的個數為一個或多個;R 4-3和R 4-4各自獨立地為H或3~8員雜環烷基,或者R 4-3和R 4-4與其相連的碳原子共同形成3~8員脂雜環;環G、環I和環J與母體結構共用一個碳原子,環F和環H與母體結構共用兩個原子和一根鍵,環F、環G、環H、環I和環J各自獨立地為C 3-C 8脂碳環、3~8員脂雜環、5~8員內醯胺環或被一個或多個R e取代的3~8員脂雜環;R e為C 1-C 6烷基; 較佳地,R 4-1為H或C 1-C 6烷基;R 4-2為C 1-C 6烷基,R 4-2的個數為一個或多個;R 4-3和R 4-4各自獨立地為H或3~6員雜環烷基,或者R 4-3和R 4-4與其相連的碳原子共同形成3~6員脂雜環;環G、環I和環J與母體結構共用一個碳原子,環F和環H與母體結構共用兩個原子和一根鍵,環F和環G各自獨立地為C 3-C 8脂碳環;環H為3~8員脂雜環或被一個或多個R e取代的3~8員脂雜環;環I和環J各自獨立地為3~8員脂雜環和5~8員內醯胺環;R e為C 1-C 6烷基。 In one embodiment, R4 is , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , , , , , , , , , or , , , , , , , wherein R 4-1 is H, C 1 -C 6 alkyl or (C=O)-O-CH 2 -O-(C=O)-C 1 -C 10 alkyl; R 4-2 is C 1 -C 6 alkyl, and the number of R 4-2 is one or more; R 4-3 and R 4-4 are each independently H or a 3-8 membered heterocyclic alkyl, or R 4-3 and R 4-4 and the carbon atoms to which they are connected together form a 3-8 membered aliphatic heterocyclic ring; Ring G, Ring I and Ring J share one carbon atom with the parent structure, Ring F and Ring H share two atoms and one bond with the parent structure, Ring F, Ring G, Ring H, Ring I and Ring J are each independently C 3 -C 8- membered aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring, 5-8-membered lactamic amide ring or 3-8-membered aliphatic heterocyclic ring substituted by one or more Re ; Re is C 1 -C 6 alkyl; preferably, R 4-1 is H or C 1 -C 6 alkyl; R 4-2 is C 1 -C 6 alkyl, and the number of R 4-2 is one or more; R 4-3 and R 4-4 are each independently H or 3-6-membered heterocyclic alkyl, or R 4-3 and R 4-4 and the carbon atom to which they are connected together form a 3-6-membered aliphatic heterocyclic ring; Ring G, Ring I and Ring J share one carbon atom with the parent structure, Ring F and Ring H share two atoms and one bond with the parent structure, Ring F and Ring G are each independently C 3 -C 8 aliphatic carbocyclic ring; Ring H is a 3-8 membered aliphatic heterocyclic ring or a 3-8 membered aliphatic heterocyclic ring substituted by one or more Re ; Ring I and Ring J are each independently a 3-8 membered aliphatic heterocyclic ring and a 5-8 membered lactam ring; Re is a C 1 -C 6 alkyl group.
某一實施方案中,R X1中,所述的鹵素可獨立地為F、Cl、Br或I,例如Cl。 In one embodiment, in RX1 , the halogen can independently be F, Cl, Br or I, such as Cl.
某一實施方案中,R X1中,所述的C 1-C 6烷基可獨立地為甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基,優選為甲基。 In one embodiment, in RX1 , the C1 - C6 alkyl group can independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.
某一實施方案中,R X1中,所述的C 3-C 6環烷基可為環丙基、環丁基、環戊基或環己基,優選為環丙基。 In one embodiment, in RX1 , the C 3 -C 6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.
某一實施方案中,R X1中,所述的C 2-C 6烯基可為C 2-C 4烯基,例如乙烯基。 In one embodiment, in RX1 , the C2 - C6 alkenyl group may be a C2 - C4 alkenyl group, such as a vinyl group.
某一實施方案中,R X1中,所述的C 2-C 6炔基可為C 2-C 4炔基,例如乙炔基。 In one embodiment, in RX1 , the C2 - C6 alkynyl group may be a C2 - C4 alkynyl group, such as ethynyl.
某一實施方案中,R X1中,所述的3~6員雜環烷基中,雜原子的種類可獨立地選自N和O,雜原子的個數可獨立地為1個; 某一實施方案中,R X1中,所述的3~6雜環烷基可獨立地為四氫吡咯基、氧雜環丁烷基、四氫吡喃基或呱啶基,更例如 、 、 或 。 In one embodiment, in RX1 , the type of heteroatoms in the 3-6 membered heterocycloalkyl group can be independently selected from N and O, and the number of heteroatoms can be independently 1; In one embodiment, in RX1 , the 3-6 membered heterocycloalkyl group can be independently tetrahydropyrrolyl, oxacyclobutane, tetrahydropyranyl or piperidinyl. For example , , or .
某一實施方案中,R X1中,所述的5~14員雜芳基中,雜原子的種類可為N,雜原子的個數可為2個。 In one embodiment, in RX1 , in the 5-14 membered heteroaryl group, the type of heteroatom may be N, and the number of heteroatom may be 2.
某一實施方案中,R X1中,所述的5~14員雜芳基可為5~6員雜芳基,例如吡唑基或咪唑基,更例如 或 。 In one embodiment, in R X1 , the 5-14 membered heteroaryl group may be a 5-6 membered heteroaryl group, such as pyrazolyl or imidazolyl, and more preferably or .
某一實施方案中,R X1中,所述的3~6員雜環烯基中,雜原子的種類可各自獨立地選自N和O,雜原子的個數可各自獨立地為1個。 In one embodiment, in RX1 , in the 3-6 membered heterocycloalkenyl group, the type of the heteroatom can be independently selected from N and O, and the number of the heteroatom can be independently 1.
某一實施方案中,R X1中,所述的3~6員雜環烯基可獨立地為6員雜環烯基,例如含1個O原子的6員雜環烯基或含1個N原子的6員雜環烯基,更例如 或 。 In one embodiment, in R X1 , the 3-6 membered heterocycloalkenyl group may be independently a 6 membered heterocycloalkenyl group, such as a 6 membered heterocycloalkenyl group containing 1 O atom or a 6 membered heterocycloalkenyl group containing 1 N atom, and more preferably or .
某一實施方案中,X 1-1、X 1-2、X 1-3、X 1-4、X 1-5、X 1-6和X 1-7中,所述的C 1-C 6烷基可獨立地為C 1-C 4烷基,例如甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基,優選為甲基或乙基。 In one embodiment, in X1-1 , X1-2 , X1-3 , X1-4 , X1-5 , X1-6 and X1-7 , the C1 - C6 alkyl group may independently be a C1 - C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.
某一實施方案中,X 1-4中,所述的C 3-C 8環烷基可為C 3-C 6環烷基,例如環丙基、環丁基、環戊基或環己基,優選為環丙基、環戊基或環己基。 In one embodiment, in X 1-4 , the C 3 -C 8 cycloalkyl group may be a C 3 -C 6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl, cyclopentyl or cyclohexyl.
某一實施方案中,X 1-4中,所述的3~8員雜環烷基可為3~6員雜環烷基,例如呱啶基、嗎啉基或呱嗪基。 In one embodiment, in X1-4 , the 3- to 8-membered heterocycloalkyl group may be a 3- to 6-membered heterocycloalkyl group, such as a piperidinyl group, a morpholinyl group or a piperazinyl group.
某一實施方案中,當R X1與R X3和其相連的原子共同形成C 5-C 8環烯酮結構時,所述的C 5-C 8環烯酮可為C 5-C 6環烯酮,例如環戊烯酮,此時, 可為 。 In one embodiment, when RX1 and RX3 and the atoms to which they are connected together form a C5 - C8 cycloenone structure, the C5 - C8 cycloenone may be a C5 - C6 cycloenone, such as cyclopentenone. In this case, Can .
某一實施方案中,當R X1’與R X3和其相連的原子共同形成5~8員雜芳環時或被一個或多個羥基取代的5~8員雜芳環,所述的5~8員雜芳環中雜原子的種類可獨立地為N,所述雜原子的個數可獨立地為2個、3個或4個。 In one embodiment, when RX1' and RX3 and the atoms to which they are connected together form a 5- to 8-membered heteroaryl ring or a 5- to 8-membered heteroaryl ring substituted with one or more hydroxyl groups, the type of heteroatom in the 5- to 8-membered heteroaryl ring may independently be N, and the number of the heteroatom may independently be 2, 3 or 4.
某一實施方案中,當R X1’與R X3和其相連的原子共同形成5~8員雜芳環時或被一個或多個羥基取代的5~8員雜芳環,所述的5~8員雜芳環可獨立地為5員雜芳環,例如吡唑環、三氮唑環、四氮唑環或噁二唑環,此時, 可為 、 、 、 、 或 。 In one embodiment, when RX1' and RX3 and the atoms to which they are connected together form a 5- to 8-membered heteroaryl ring or a 5- to 8-membered heteroaryl ring substituted with one or more hydroxyl groups, the 5- to 8-membered heteroaryl ring may independently be a 5-membered heteroaryl ring, such as a pyrazole ring, a triazole ring, a tetrazole ring or an oxadiazole ring, in this case, Can , , , , or .
某一實施方案中,R X1為CN、Cl、CF 3、NH 2、N(CH 3) 2、NO 2、NHSO 2CH 3、NHCOCH 3、PO(CH 3) 2、SF 5、C(=O)H、C(=O)CH 3、C(=O)CF 3、C(=O)CH 2CH 3、SO 2CH 3、SO 3H、環丙基、乙烯基、乙炔基、四氫吡咯基、氧雜環丁烷基、四氫吡喃基、乙醯基取代的呱啶基、甲基取代的咪唑基、甲基取代的吡唑基、含1個O原子的6員雜環烯基、乙醯基取代的含1個N原子的6員雜環烯基、環丙基取代的羰基、環戊基取代的羰基或環己基取代的羰基,例如CN、Cl、CF 3、NH 2、N(CH 3) 2、NO 2、NHSO 2CH 3、NHCOCH 3、PO(CH 3) 2、SF 5、C(=O)H、C(=O)CH 3、C(=O)CF 3、C(=O)CH 2CH 3、SO 2CH 3、SO 3H、環丙基、乙烯基、乙炔基、 、 、 、 、 、 、 、 、 、 或 。 In one embodiment, RX1 is CN, Cl, CF3 , NH2 , N( CH3 ) 2 , NO2 , NHSO2CH3 , NHCOCH3 , PO( CH3 ) 2 , SF5 , C(=O)H, C(=O) CH3 , C(=O ) CF3 , C(=O )CH2CH3 , SO2CH3 , SO3 H, cyclopropyl, vinyl, ethynyl, tetrahydropyrrolyl, oxacyclobutane, tetrahydropyranyl, acetyl-substituted piperidinyl, methyl-substituted imidazolyl, methyl-substituted pyrazolyl, 6-membered heterocycloalkenyl containing 1 O atom, 6-membered heterocycloalkenyl containing 1 N atom substituted by acetyl, cyclopropyl-substituted carbonyl, cyclopentyl-substituted carbonyl or cyclohexyl-substituted carbonyl, for example, CN, Cl, CF 3 , NH 2 , N(CH 3 ) 2 , NO 2 , NHSO 2 CH 3 , NHCOCH 3 , PO(CH 3 ) 2 , SF 5 , C(═O)H, C(═O)CH 3 , C(═O)CF 3 , C(═O)CH 2 CH 3 , SO 2 CH 3 , SO 3 H, cyclopropyl, vinyl, ethynyl, , , , , , , , , , or .
某一實施方案中,R 1中,所述的C 6~C 14的芳基可獨立地為苯基或萘基,例如 、 、 或 。 In one embodiment, in R1 , the C6 - C14 aryl group can be independently phenyl or naphthyl, for example , , or .
某一實施方案中,R 1中,所述的5~14員雜芳基中,雜原子的種類可獨立地為N,雜原子的個數可獨立地為1個。 In one embodiment, in R1 , in the 5- to 14-membered heteroaryl group, the type of heteroatom can be independently N, and the number of heteroatom can be independently 1.
某一實施方案中,R 1中,所述的5~14員雜芳基可獨立地為5~12員雜芳基,例如吡啶基、喹啉基或異喹啉基,更例如 、 或 。 In one embodiment, in R1 , the 5- to 14-membered heteroaryl group may independently be a 5- to 12-membered heteroaryl group, such as a pyridyl group, a quinolyl group or an isoquinolyl group, and more preferably , or .
某一實施方案中,R 1-1、R 1-2、R 1-3和R 1-4中,所述的鹵素可獨立地為F、Cl、Br或I,例如F或Cl。 In one embodiment, in R 1-1 , R 1-2 , R 1-3 and R 1-4 , the halogen can independently be F, Cl, Br or I, such as F or Cl.
某一實施方案中,R 1-1和R 1-2中,所述的C 1-C 6烷基可獨立地為C 1-C 4烷基,例如甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基,優選為甲基或乙基。 In one embodiment, in R 1-1 and R 1-2 , the C 1 -C 6 alkyl group may independently be a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.
某一實施方案中,R 1-1和R 1-2中,所述的C 1-C 10烷基可獨立地為C 1-C 9烷基,例如正壬基。 In one embodiment, in R 1-1 and R 1-2 , the C 1 -C 10 alkyl group may independently be a C 1 -C 9 alkyl group, such as n-nonyl.
某一實施方案中,n1為2。In one embodiment, n1 is 2.
某一實施方案中,n2為6。In one embodiment, n2 is 6.
某一實施方案中,n3為4。In one embodiment, n3 is 4.
某一實施方案中,n4為1。In one embodiment, n4 is 1.
某一實施方案中,n5為1。In one embodiment, n5 is 1.
某一實施方案中,R 1為一個或多個R 1-1取代的萘基、一個或多個R 1-1取代的苯基、被一個或多個R 1-2取代的吡啶基、被一個或多個R 1-2取代的喹啉基或被一個或多個R 1-2取代的異喹啉基,例如 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 ; 某一實施方案中,R 2中,所述的鹵素可為F、Cl、Br或I,例如F。 In one embodiment, R 1 is naphthyl substituted by one or more R 1-1 , phenyl substituted by one or more R 1-1 , pyridyl substituted by one or more R 1-2 , quinolyl substituted by one or more R 1-2 , or isoquinolyl substituted by one or more R 1-2 , for example , , , , , , , , , , , , , , , , , , , , , , , or In one embodiment, in R 2 , the halogen may be F, Cl, Br or I, for example, F.
某一實施方案中,R 2中,所述的C 1-C 6烷基可為C 1-C 4烷基,例如甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基。 In one embodiment, in R 2 , the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
某一實施方案中,R 2中,所述的C 1-C 6烷氧基可為C 1-C 4烷氧基,例如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基或叔丁氧基。 In one embodiment, in R 2 , the C 1 -C 6 alkoxy group may be a C 1 -C 4 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group or a tert-butoxy group.
某一實施方案中,R 2為F。 In one embodiment, R2 is F.
某一實施方案中,L 2中,所述的C 1-C 6伸烷基可為C 1-C 3伸烷基,例如伸甲基、伸乙基或伸丙基,優選為伸甲基。 In one embodiment, in L 2 , the C 1 -C 6 alkylene group may be a C 1 -C 3 alkylene group, such as a methylene group, an ethylene group or a propylene group, preferably a methylene group.
某一實施方案中,R 3定義中,所述的3~8員脂雜環中,雜原子的種類可獨立地為O,雜原子的數目可獨立地為1個。 In one embodiment, in the definition of R 3 , in the 3-8 membered aliphatic heterocyclic ring, the type of heteroatom can be independently O, and the number of heteroatom can be independently 1.
本文中,“R 3定義中,所述的3~8員脂雜環”指上述R 3定義範圍內所述的所有的3~8員脂雜環,例如環A、環B、環C、環D和環E中的3~8員脂雜環。 Herein, "the 3- to 8-membered aliphatic heterocyclic ring in the definition of R 3 " refers to all 3- to 8-membered aliphatic heterocyclic rings described within the above definition of R 3 , such as the 3- to 8-membered aliphatic heterocyclic rings in Ring A, Ring B, Ring C, Ring D and Ring E.
某一實施方案中,R 3定義中,所述的3~8員脂雜環可獨立地為4~5員脂雜環,例如氧雜環丁烷或四氫呋喃環。 In one embodiment, in the definition of R 3 , the 3-8 membered aliphatic heterocyclic ring can independently be a 4-5 membered aliphatic heterocyclic ring, such as cyclohexane or tetrahydrofuran ring.
某一實施方案中,R 3定義中,所述的3~ 8員脂雜環可獨立地為 ,例如環A 、環B和環C中所述的3~ 8員脂雜環可獨立地為 。 In one embodiment, in the definition of R3 , the 3- to 8-membered heterocyclic ring can be independently For example, the 3- to 8-membered heterocyclic rings in Ring A, Ring B and Ring C may be independently .
某一實施方案中,R 3定義中,所述的3~8員脂雜環可獨立地為 ,例如環D和環E中,所述的3~8員脂雜環可獨立地為 。 In one embodiment, in the definition of R3 , the 3-8 membered heterocyclic ring can be independently For example, in ring D and ring E, the 3- to 8-membered heterocyclic ring may be independently .
某一實施方案中,R 3定義中,所述的C 3-C 8脂碳環可獨立地為C 3-C 6脂碳環,例如環丙烷、環丁烷、環戊烷或環己烷,優選為環丙烷。 In one embodiment, in the definition of R 3 , the C 3 -C 8 aliphatic ring can independently be a C 3 -C 6 aliphatic ring, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane.
本文中,“R 3定義中,所述的C 3-C 8脂碳環”指上述R 3定義範圍內所述的所有的C 3-C 8脂碳環,例如。 Herein, "the C 3 -C 8 aliphatic carbon ring in the definition of R 3 " refers to all C 3 -C 8 aliphatic carbon rings described within the above definition of R 3 , for example.
某一實施方案中,R 3定義中,所述的C 3-C 8脂碳環可獨立地為 或 ,例如環A、環B和環C中,所述的C 3-C 8脂碳環可獨立地為 或 。 In one embodiment, in the definition of R 3 , the C 3 -C 8 aliphatic carbon ring can be independently or For example, in Ring A, Ring B and Ring C, the C 3 -C 8 aliphatic carbon ring may be independently or .
某一實施方案中,R 3定義中,所述的C 3-C 8脂碳環可獨立地為 、 或 ,例如環D和環E中,所述的C 3-C 8脂碳環可獨立地為 、 或 。 In one embodiment, in the definition of R 3 , the C 3 -C 8 aliphatic carbon ring can be independently , or For example, in ring D and ring E, the C 3 -C 8 aliphatic carbon ring may be independently , or .
某一實施方案中,R 3定義中,所述的鹵素可為F、Cl、Br或I,例如F。 In one embodiment, in the definition of R 3 , the halogen may be F, Cl, Br or I, such as F.
本文中,“R 3定義中,所述的鹵素”指上述R 3定義範圍內所述的所有的鹵素,例如環A、環B、環C、環D和環E中的鹵素。 Herein, "the halogen in the definition of R 3 " refers to all the halogens within the definition of R 3 , such as the halogens in Ring A, Ring B, Ring C, Ring D and Ring E.
某一實施方案中,R 4-1和R 4-2中,所述的C 1-C 6烷基可各自獨立地為C 1-C 4烷基,例如甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基,優選為甲基。 In one embodiment, in R 4-1 and R 4-2 , the C 1 -C 6 alkyl group may be independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably a methyl group.
某一實施方案中,R 4-1中,所述的C 1-C 10烷基可為C 1-C 9烷基,例如正壬基或異丙基。 In one embodiment, in R 4-1 , the C 1 -C 10 alkyl group may be a C 1 -C 9 alkyl group, such as n-nonyl or isopropyl.
某一實施方案中,R W1、R W2、R 4-3和R 4-4中,所述的3~8員雜環烷基中,雜原子的種類可獨立地選自N和O,雜原子的個數可獨立地為1個或2個。 In one embodiment, in R W1 , R W2 , R 4-3 and R 4-4 , the type of heteroatom in the 3- to 8-membered heterocycloalkyl group can be independently selected from N and O, and the number of heteroatom can be independently 1 or 2.
某一實施方案中,R W1、R W2、R 4-3和R 4-4中,所述的3~8員雜環烷基可獨立地為4~6員雜環烷基,例如四氫吡咯基、嗎啉基或呱啶基,更例如 、 或 。 In one embodiment, in R W1 , R W2 , R 4-3 and R 4-4 , the 3- to 8-membered heterocycloalkyl group may be independently a 4- to 6-membered heterocycloalkyl group, such as tetrahydropyrrolyl, morpholinyl or piperidinyl. , or .
某一實施方案中,當R W1和R W2與其相連的原子共同形成3~8員脂雜環或當R 4-3和R 4-4與其相連的碳原子共同形成3~8員脂雜環時,所述的3~8員脂雜環可為4~5員脂雜環,例如N雜環丁烷,更例如 。 In one embodiment, when R W1 and R W2 and the atoms to which they are connected together form a 3-8 membered aliphatic heterocyclic ring or when R 4-3 and R 4-4 and the carbon atoms to which they are connected together form a 3-8 membered aliphatic heterocyclic ring, the 3-8 membered aliphatic heterocyclic ring may be a 4-5 membered aliphatic heterocyclic ring, such as N-heterocyclobutane, and more preferably .
某一實施方案中,R 4定義中,所述的C 3-C 8脂碳環可獨立地為C 3-C 6脂碳環,例如環丙烷、環丁烷、環戊烷或環己烷,優選為環丙烷、環丁烷或環己烷。 In one embodiment, in the definition of R 4 , the C 3 -C 8 aliphatic ring may independently be a C 3 -C 6 aliphatic ring, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane, cyclobutane or cyclohexane.
本文中,“R 4定義中,所述的C 3-C 8脂碳環”是指上述R 4定義範圍內所有的C 3-C 8脂碳環,例如環F、環G、環H、環I和環J中的C 3-C 8脂碳環。 Herein, "the C 3 -C 8 aliphatic carbon ring in the definition of R 4 " refers to all C 3 -C 8 aliphatic carbon rings within the above definition of R 4 , such as the C 3 -C 8 aliphatic carbon rings in ring F, ring G, ring H, ring I and ring J.
某一實施方案中,R 4定義中,所述的C 3-C 8脂碳環可獨立地為 或 ,例如環F和環H中,所述的C 3-C 8脂碳環可獨立地為 或 。 In one embodiment, in the definition of R 4 , the C 3 -C 8 aliphatic carbon ring can be independently or For example, in ring F and ring H, the C 3 -C 8 aliphatic carbon ring may be independently or .
某一實施方案中,R 4定義中,所述的C 3-C 8脂碳環可獨立地為 ,例如環G、環I和環J中,所述的C 3-C 8脂碳環可獨立地為 。 In one embodiment, in the definition of R 4 , the C 3 -C 8 aliphatic carbon ring can be independently For example, in Ring G, Ring I and Ring J, the C 3 -C 8 aliphatic carbon ring may be independently .
某一實施方案中,R 4定義中,所述的3~8員脂雜環可獨立地為4~5員脂雜環,例如四氫吡咯環或N雜環丁烷。 In one embodiment, in the definition of R 4 , the 3-8 membered aliphatic heterocyclic ring can independently be a 4-5 membered aliphatic heterocyclic ring, such as a tetrahydropyrrole ring or N-heterocyclobutane.
本文中,“R 4定義中,所述的3~8員脂雜環”是指上述R 4定義範圍內所有的3~8員脂雜環,例如環F、環G、環H、環I和環J中的3~8員脂雜環。 Herein, "the 3- to 8-membered aliphatic heterocyclic ring in the definition of R 4 " refers to all 3- to 8-membered aliphatic heterocyclic rings within the above definition of R 4 , such as the 3- to 8-membered aliphatic heterocyclic rings in ring F, ring G, ring H, ring I and ring J.
某一實施方案中,R 4定義中,所述的3~8員脂雜環可獨立地為 ,例如環F和環H中,所述的3~8員脂雜環可獨立地為 。 In one embodiment, in the definition of R4 , the 3-8 membered heterocyclic ring can be independently For example, in ring F and ring H, the 3- to 8-membered heterocyclic ring may be independently .
某一實施方案中,R 4定義中,所述的3~8員脂雜環可獨立地為 ,例如環G、環I和環J中,所述的3~8員脂雜環可獨立地為 。 In one embodiment, in the definition of R 4 , the 3-8 membered heterocyclic ring can be independently For example, in ring G, ring I and ring J, the 3- to 8-membered heterocyclic ring may be independently .
某一實施方案中,環F、環G、環H、環I和環J中,所述的5~8員內醯胺環可獨立地為5員內醯胺環。In one embodiment, in ring F, ring G, ring H, ring I and ring J, the 5- to 8-membered lactam rings may independently be 5-membered lactam rings.
某一實施方案中,環G、環I和環J中,所述的5~8員內醯胺環可獨立地為 。 In one embodiment, in ring G, ring I and ring J, the 5- to 8-membered lactam rings may be independently .
某一實施方案中,R e中,所述的C 1-C 6烷基可為C 1-C 4烷基,例如甲基、乙基、正丙基、異丙基、正丁基、異丁基或叔丁基,優選為甲基。 In one embodiment, in R e , the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably a methyl group.
某一實施方案中,X可為F、Cl、Br或I,例如F或Br。In one embodiment, X may be F, Cl, Br or I, such as F or Br.
某一實施方案中,R 3為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 時, 某一實施方案中,R 4為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 。 In one embodiment, R3 is , , , , , , , , , , , , , , , , , , , , , , When, in one embodiment, R 4 is , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , , , , , , , , , or , , , , , , , .
某一實施方案中,當R 3為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 時; R 4為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 。 In one embodiment, when R3 is , , , , , , , , , , , , , , , , , , , , , , When R 4 is , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , , , , , , , , , or , , , , , , , .
某一實施方案中,當R 3為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 時, R 4為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 。 In one embodiment, when R3 is , , , , , , , , , , , , , , , , , , , , , , When R4 is , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , , , , , , , , , or , , , , , , , .
某一實施方案中, R 4為 、 或 ; R 4-3和R 4-4各自獨立地為H或3~8員雜環烷基,所述的3~8員雜環烷基較佳地為四氫吡咯基或呱啶基,例如 或 ; 環H為3~8員脂雜環或被一個或多個R e取代的3~8員脂雜環,較佳地為3~8員脂雜環,例如四氫吡咯環,更例如 。 In one embodiment, R4 is , or R 4-3 and R 4-4 are each independently H or a 3- to 8-membered heterocycloalkyl group, wherein the 3- to 8-membered heterocycloalkyl group is preferably a tetrahydropyrrolyl group or a piperidinyl group, for example or Ring H is a 3- to 8-membered aliphatic heterocyclic ring or a 3- to 8-membered aliphatic heterocyclic ring substituted by one or more Re , preferably a 3- to 8-membered aliphatic heterocyclic ring, such as a tetrahydropyrrole ring, more preferably .
某一實施方案中,X 1為N; R 3為 、 、 、 或 ; 環A為3~8員脂雜環、C 3-C 8脂碳環或一個或多個鹵素取代的C 3-C 8脂碳環,例如氧雜環丁烷、環丙烷、或F取代的環丙烷,更例如 、 、 或 ;環D和環E各自獨立地為為C 3-C 8脂碳環,例如環丙烷,更例如 、 或 。 In one embodiment, X1 is N; R3 is , , , or Ring A is a 3-8 membered aliphatic ring, a C 3 -C 8 aliphatic carbon ring, or a C 3 -C 8 aliphatic carbon ring substituted with one or more halogens, such as cyclohexane, cyclopropane, or F-substituted cyclopropane, and more preferably , , or Ring D and Ring E are each independently a C 3 -C 8 aliphatic carbon ring, such as cyclopropane, more such as , or .
某一實施方案中,X 1為CR X1; R X1為CN、NO 2、鹵素、被一個或多個鹵素取代的C 1-C 6烷基、C 3-C 6環烷基、3~6員雜環烷基、3~6員雜環烯基、C 2-C 6烯基、C 2-C 6炔基、PO(C 1-C 6烷基) 2、被一個或多個X 1-1取代的3~6員雜環烷基、被一個或多個X 1-2取代的5~14員雜芳基、被一個或多個X 1-3取代的3~6員雜環烯基、C(=O) X 1-4、NX 1-5X 1-6或SO 2X 1-7; 所述的3~6員雜環烷基較佳地為氧雜環丁烷基或四氫吡咯基,例如 或 ; 所述的5~14員雜芳基較佳地為吡唑基,例如 ; R 3為 或 ; 環A較佳地為被一個或多個鹵素取代的C 3-C 8脂碳環,例如被F取代的環丙烷,更例如 。 In one embodiment, X1 is CRX1 ; RX1 is CN, NO2 , halogen, C1 - C6 alkyl substituted by one or more halogens, C3 - C6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C2 - C6 alkenyl, C2 - C6 alkynyl, PO( C1 - C6 alkyl) 2 , 3-6 membered heterocycloalkyl substituted by one or more X1-1 , 5-14 membered heteroaryl substituted by one or more X1-2 , 3-6 membered heterocycloalkenyl substituted by one or more X1-3 , C(=O) X1-4 , NX1-5X1-6 or SO2X1-7 ; The 3-6 membered heterocycloalkyl group is preferably an oxacyclobutane group or a tetrahydropyrrolyl group, for example or The 5- to 14-membered heteroaryl group is preferably pyrazolyl, for example ; R 3 is or Ring A is preferably a C 3 -C 8 aliphatic carbon ring substituted with one or more halogens, such as a cyclopropane substituted with F, more preferably .
某一實施方案中,R 1為被一個或多個R 1-1取代的C 6~C 14的芳基或被一個或多個R 1-2取代的5~14員雜芳基; 當R 1為被一個或多個R 1-1取代的C 6~C 14的芳基時,相鄰的兩個R 1-1與其相連的原子一起形成C 3-C 8脂碳環或被一個或多個R 1-3取代的C 3-C 8脂碳環,其餘R 1-1獨立地為鹵素、OH、NH 2、CN、C 1-C 6烷基、(C=O)-C 1-C 6烷基、C 2-C 6炔基、被一個或多個鹵素取代的C 1-C 6烷基、B(OH) 2或O(C=O)- C 1-C 10烷基; 當R 1為被一個或多個R 1-2取代的5~14員雜芳基時,相鄰的兩個R 1-2與其相連的原子一起形成C 3-C 8脂碳環或被一個或多個R 1-4取代的C 3-C 8脂碳環,其餘R 1-2獨立地為鹵素、OH、NH 2、CN、C 1-C 6烷基、(C=O)-C 1-C 6烷基、C 2-C 6炔基、被一個或多個鹵素取代的C 1-C 6烷基、B(OH) 2或O(C=O)- C 1-C 10烷基; R 1-3和R 1-4獨立地為鹵素。 In one embodiment, R 1 is a C 6 -C 14 aryl substituted by one or more R 1-1 or a 5-14 membered heteroaryl substituted by one or more R 1-2 ; when R 1 is a C 6 -C 14 aryl substituted by one or more R 1-1 , two adjacent R 1-1s together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbocyclic ring or a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more R 1-3 , and the remaining R 1-1s are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)-C 1 -C 10 alkyl; when R 1 is a 5-14 membered heteroaryl substituted by one or more R 1-2 , two adjacent R 1-2 together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbocyclic ring or a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more R 1-4 , and the remaining R 1-2 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogens, B(OH) 2 or O(C=O)- C 1 -C 10 alkyl; R 1-3 and R 1-4 are independently halogen.
某一實施方案中,所述如式I-0所示的雜環類化合物為如式I所示的雜環類化合物: 其中, X 1為N或CR X1,R X1為CN、鹵素、CF 3、SO 2Me、POMe 2或NH 2; X 2為N或CR X2,R X2為CN; R 1為 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 或 ; R 2為鹵素; R 3和R 4的定義選自以下任一方案: 方案一: R 3為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 時, R 4為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 ; 方案二: R 3為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 時, R 4為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 。 In one embodiment, the heterocyclic compound as shown in formula I-0 is a heterocyclic compound as shown in formula I: wherein X1 is N or CR X1 , RX1 is CN, halogen, CF 3 , SO 2 Me, POMe 2 or NH 2 ; X2 is N or CR X2 , RX2 is CN; R1 is , , , , , , , , , , , , or , , , , , , or ; R 2 is a halogen; R 3 and R 4 are defined in any of the following schemes: Scheme 1: R 3 is , , , , , , , , , , , , , , , , , , , , , , When R4 is , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , , , , , , , , , or , , , , , , , ; Option 2: R 3 is , , , , , , , , , , , , , , , , , , , , , , When R4 is , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , , , , , , , , , or , , , , , , , .
在本發明某些優選實施方案中,所述的如式I所示的雜環類化合物、其藥學上可接受的鹽、其立體異構物或它們的溶劑合物中的某些基團如下定義,未提及的基團同本申請任一方案所述(簡稱“在本發明某一方案中”),X 1為N、C-CN、C-Cl、C-CF 3、C-SO 2Me、C-POMe 2或C-NH 2。 In certain preferred embodiments of the present invention, certain groups in the heterocyclic compound of formula I, its pharmaceutically acceptable salt, its stereoisomer or its solvate are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present application (referred to as "in a certain embodiment of the present invention" for short), X1 is N, C-CN, C-Cl, C- CF3 , C- SO2Me , C- POMe2 or C- NH2 .
在本發明某一方案中,X 2為N或C-CN。 In one embodiment of the present invention, X2 is N or C-CN.
在本發明某一方案中,R 2為F。 In one embodiment of the present invention, R2 is F.
某一實施方案中,所述如式I-0所示的化合物為如式I-1所示的化合物: ; 其中,R 4為 或 ;J為H或鹵素; 其為以下情況中的任一種: 1)X 1為CR X1,R X1為被一個或多個鹵素取代的C 1-C 6烷基、PO(C 1-C 6烷基) 2、C 3-C 6環烷基、C 2-C 6烯基、C 2-C 6炔基、3~6員雜環烷基、被一個或多個X 1-1取代的3~6員雜環烷基、被一個或多個X 1-2取代的5~8員雜芳基、NO 2、3~6員雜環烯基、被一個或多個X 1-3取代的3~6員雜環烯基、SF 5、C(=O) X 1-4、NX 1-5X 1-6或SO 2X 1-7;或者R X1與R X3和其相連的原子共同形成C 5-C 8環烯酮結構;其他取代基的定義均如本文任一方案所述; 2)X 1為NR X1’,R X1’與R X3和其相連的原子共同形成5~8員雜芳環或被一個或多個羥基取代的5~8員雜芳環;其他取代基的定義均如本文任一方案所述; 3)X 1為CR X1,其中,X 1中的C原子與R 1中的芳基或雜芳基中的C原子透過-O-(CH 2) n1- *、 *-NH-(CH 2) n2-、-C≡C-(CH 2) n3-C≡C- *或-(CH 2) n4-O-(CH 2) n5- *相連,其中,*端與X 1中的C原子相連;其他取代基的定義以及n1、n2、n3、n4和n5的定義均如本文任一方案所述; 4)R 1為被一個或多個R 1-1取代的C 6~C 14的芳基或被一個或多個R 1-2取代的5~14員雜芳基; 當R 1為被一個或多個R 1-1取代的C 6~C 14的芳基時,相鄰的兩個R 1-1與其相連的原子一起形成C 3-C 8脂碳環或被一個或多個R 1-3取代的C 3-C 8脂碳環,其餘R 1-1獨立地為鹵素、OH、NH 2、CN、C 1-C 6烷基、(C=O)-C 1-C 6烷基、C 2-C 6炔基、被一個或多個鹵素取代的C 1-C 6烷基、B(OH) 2或O(C=O)- C 1-C 10烷基; 當R 1為被一個或多個R 1-2取代的5~14員雜芳基時,相鄰的兩個R 1-2與其相連的原子一起形成C 3-C 8脂碳環或被一個或多個R 1-4取代的C 3-C 8脂碳環,其餘R 1-2獨立地為鹵素、OH、NH 2、CN、C 1-C 6烷基、(C=O)-C 1-C 6烷基、C 2-C 6炔基、被一個或多個鹵素取代的C 1-C 6烷基、B(OH) 2或O(C=O)- C 1-C 10烷基; R 1-3和R 1-4獨立地為鹵素; 其餘各取代基的定義均如本文任一方案所述。 In one embodiment, the compound shown in formula I-0 is a compound shown in formula I-1: ; Among them, R 4 is or ; J is H or a halogen; it is any one of the following: 1) X 1 is CR X 1 , RX 1 is C 1 -C 6 alkyl substituted by one or more halogens, PO(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl substituted by one or more X 1-1 , 5-8 membered heteroaryl substituted by one or more X 1-2 , NO 2 , 3-6 membered heterocycloalkenyl, 3-6 membered heterocycloalkenyl substituted by one or more X 1-3 , SF 5 , C(=O) X 1-4 , NX 1-5 X 1-6 or SO 2 X 1-7 ; or R X1 , RX3 and the atoms connected thereto together form a C5 - C8 cycloenone structure; the definitions of other substituents are as described in any scheme herein; 2) X1 is NRX1 ' , RX1' , RX3 and the atoms connected thereto together form a 5-8 membered heteroaryl ring or a 5-8 membered heteroaryl ring substituted with one or more hydroxyl groups; the definitions of other substituents are as described in any scheme herein; 3) X1 is CRX1 , wherein the C atom in X1 and the C atom in the aryl or heteroaryl group in R1 are connected through -O-( CH2 ) n1- * , * -NH-( CH2 ) n2- , -C≡C-( CH2 ) n3 -C≡C- * or -( CH2 ) n4 -O-( CH2 ) n5- * , wherein the * end is connected to X 1 is connected to the C atom in 1 ; the definitions of other substituents and n1, n2, n3, n4 and n5 are as described in any scheme herein; 4) R 1 is a C 6 ~ C 14 aryl substituted by one or more R 1-1 or a 5-14 membered heteroaryl substituted by one or more R 1-2 ; when R 1 is a C 6 ~ C 14 aryl substituted by one or more R 1-1 , two adjacent R 1-1s together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbocyclic ring or a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more R 1-3 , and the remaining R 1-1s are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C when R 1 is a 5-14 membered heteroaryl substituted by one or more R 1-2 , two adjacent R 1-2 together with the atoms to which they are connected form a C 3 -C 8 aliphatic carbocyclic ring or a C 3 -C 8 aliphatic carbocyclic ring substituted by one or more R 1-4 , and the remaining R 1-2 are independently halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, (C=O)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl substituted by one or more halogen , B (OH) 2 or O(C=O)- C 1 -C 10 alkyl ; R R 1-3 and R 1-4 are independently halogen; the definitions of the remaining substituents are as described in any scheme herein.
某一實施方案中,所述如式I-0所示的化合物為如式I-2所示的化合物: ; 其為以下情況中的任一種: 1)R 3為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 時,其中,環A、環B和環C與母體結構共用一個碳原子,環D和環E與母體結構共用兩個原子和一根鍵;環A、環B、環C、環D和環E各自獨立地為3~8員脂雜環、C 3-C 8脂碳環或被一個或多個鹵素取代的C 3-C 8脂碳環; R 4為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 ;其中,R 4-1為H、C 1-C 6烷基或(C=O)-O-CH 2-O-(C=O)-C 1-C 10烷基;R 4-2為C 1-C 6烷基,R 4-2的個數為一個或多個;R 4-3和R 4-4各自獨立地為H或3~8員雜環烷基,或者R 4-3和R 4-4與其相連的碳原子共同形成3~8員脂雜環;環G、環I和環J與母體結構共用一個碳原子,環F和環H與母體結構共用兩個原子和一根鍵,環F、環G、環H、環I和環J各自獨立地為C 3-C 8脂碳環、3~8員脂雜環、5~8員內醯胺環或被一個或多個R e取代的3~8員脂雜環;R e為C 1-C 6烷基; 其餘各取代基的定義均如本文任一方案所述; 2)R 3為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 時,其中X為鹵素;環A、環B和環C與母體結構共用一個碳原子,環D和環E與母體結構共用兩個原子和一根鍵;環A、環B、環C、環D和環E各自獨立地為3~8員脂雜環、C 3-C 8脂碳環或被一個或多個鹵素取代的C 3-C 8脂碳環; R 4為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 、 、 、 、 、 、 、 ;其中,X為鹵素;R 4-1為C 1-C 6烷基或(C=O)-O-CH 2-O-(C=O)- C 1-C 10烷基;R 4-3和R 4-4各自獨立地為H或3~8員雜環烷基,或者R 4-3和R 4-4與其相連的碳原子共同形成3~8員脂雜環;環G、環I和環J與母體結構共用一個碳原子,環F和環H與母體結構共用兩個原子和一根鍵,環F、環G、環H、環I和環J各自獨立地為C 3-C 8脂碳環、3~8員脂雜環、5~8員內醯胺環或被一個或多個R e取代的3~8員脂雜環;R e為C 1-C 6烷基; 其餘各取代基的定義均如本文任一方案所述。 In one embodiment, the compound shown in formula I-0 is a compound shown in formula I-2: ; It is any of the following: 1) R 3 is , , , , , , , , , , , , , , , , , , , , , , wherein Ring A, Ring B and Ring C share one carbon atom with the parent structure, and Ring D and Ring E share two atoms and one bond with the parent structure; Ring A, Ring B, Ring C, Ring D and Ring E are each independently a 3-8 membered aliphatic heterocyclic ring, a C 3 -C 8 aliphatic carbon ring, or a C 3 -C 8 aliphatic carbon ring substituted with one or more halogens; R 4 is , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , , , , , , , , , or , , , , , , , wherein R 4-1 is H, C 1 -C 6 alkyl or (C=O)-O-CH 2 -O-(C=O)-C 1 -C 10 alkyl; R 4-2 is C 1 -C 6 alkyl, and the number of R 4-2 is one or more; R 4-3 and R 4-4 are each independently H or a 3-8 membered heterocyclic alkyl, or R 4-3 and R 4-4 and the carbon atoms to which they are connected together form a 3-8 membered aliphatic heterocyclic ring; Ring G, Ring I and Ring J share one carbon atom with the parent structure, Ring F and Ring H share two atoms and one bond with the parent structure, Ring F, Ring G, Ring H, Ring I and Ring J are each independently C 3 -C 8 -membered aliphatic carbon ring, 3-8-membered aliphatic heterocyclic ring, 5-8-membered lactamic amide ring or 3-8-membered aliphatic heterocyclic ring substituted by one or more Re ; Re is C 1 -C 6 alkyl; the definitions of the remaining substituents are as described in any of the schemes herein; 2) R 3 is , , , , , , , , , , , , , , , , , , , , , , wherein X is a halogen; Ring A, Ring B and Ring C share one carbon atom with the parent structure, and Ring D and Ring E share two atoms and one bond with the parent structure; Ring A, Ring B, Ring C, Ring D and Ring E are each independently a 3-8 membered aliphatic heterocyclic ring, a C 3 -C 8 aliphatic carbon ring or a C 3 -C 8 aliphatic carbon ring substituted with one or more halogens; R 4 is , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , , , , , , , wherein X is a halogen; R 4-1 is a C 1 -C 6 alkyl group or a (C=O)-O-CH 2 -O-(C=O)- C 1 -C 10 alkyl group; R 4-3 and R 4-4 are each independently H or a 3-8 membered heterocyclic alkyl group, or R 4-3 and R 4-4 together with the carbon atom to which they are connected form a 3-8 membered aliphatic heterocyclic ring; Ring G, Ring I and Ring J share one carbon atom with the parent structure, Ring F and Ring H share two atoms and one bond with the parent structure, Ring F, Ring G, Ring H, Ring I and Ring J are each independently a C 3 -C 8 aliphatic carbon ring, a 3-8 membered aliphatic heterocyclic ring, a 5-8 membered lactamic ring or a ring substituted by one or more R e -substituted 3- to 8-membered aliphatic heterocyclic ring; Re is a C 1 -C 6 alkyl group; and the definitions of the remaining substituents are as described in any of the schemes herein.
本發明還提供了一種如下所示的雜環類化合物、其藥學上可接受的鹽、其立體異構物、或它們(指前述如下所示的雜環類化合物、其藥學上可接受的鹽或其立體異構物)的溶劑合物: 。 。 The present invention also provides a heterocyclic compound as shown below, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvent combination thereof (referring to the aforementioned heterocyclic compound as shown below, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof): . .
在某一優選方案中,所述雜環類化合物的藥學上可接受的鹽如下所示: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In a preferred embodiment, the pharmaceutically acceptable salt of the heterocyclic compound is as follows: , , , , , , , , , , , , , , , , , , , , , , or .
本發明還提供了一種如下所示的雜環類化合物、其藥學上可接受的鹽、其立體異構物或它們(指前述如下所示的雜環類化合物、其藥學上可接受的鹽或其立體異構物)的溶劑合物: 在下述條件下保留時間為0.660 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相5分鐘,流速:4毫升/分鐘; 在下述條件下保留時間為2.147 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相5分鐘,流速:4毫升/分鐘; 在下述條件下保留時間為2.311 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak IG-3 100*4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在4分鐘內從5%到40%,保持40%的B相2.5分鐘,保持5%的B相1.5分鐘,流速:2.8毫升/分鐘; 在下述條件下保留時間為3.397 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak IG-3 100*4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在4分鐘內從5%到40%,保持40%的B相2.5分鐘,保持5%的B相1.5分鐘,流速:2.8毫升/分鐘; 在下述條件下保留時間為4.236 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak IE 100*4.6mm 3um;流動相:A相為0.1%二乙胺/正庚烷,B相為異丙醇;梯度:A/B = 60/40,流速:1毫升/分鐘; 在下述條件下保留時間為1.942 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak IG-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在2分鐘內從5%到40%,保持40%的B相1.2分鐘,保持5%的B相0.8分鐘,流速:4毫升/分鐘; 在下述條件下保留時間為2.343 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak IG-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在2分鐘內從5%到40%,保持40%的B相1.2分鐘,保持5%的B相0.8分鐘,流速:4毫升/分鐘; 在下述條件下保留時間為3.004 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak IG-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在2分鐘內從5%到40%,保持40%的B相1.2分鐘,保持5%的B相0.8分鐘,流速:4毫升/分鐘; 在下述條件下保留時間為2.414 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak IC-3,100mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:40%的B相,流速:2.8毫升/分鐘; 在下述條件下保留時間為3.344 min的化合物,其為 中的一個立體異構物:層析管柱:Chiralpak IC-3,100mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:40%的B相,流速:2.8毫升/分鐘; 在下述條件下保留時間為1.150 min的化合物,其為 中的一個立體異構物:層析管柱:Chiralpak IG-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相,流速:4毫升/分鐘; 在下述條件下保留時間為2.203 min的化合物,其為 中的一個立體異構物:層析管柱:Chiralpak IG-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相,流速:4毫升/分鐘; 在下述條件下保留時間為1.696 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在2分鐘內從5%到40%,保持40%的B相1.2分鐘,保持5%的B相0.8分鐘;流速:4毫升/分鐘; 在下述條件下保留時間為2.137 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在2分鐘內從5%到40%,保持40%的B相1.2分鐘,保持5%的B相0.8分鐘;流速:4毫升/分鐘。 The present invention also provides a heterocyclic compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvent complex thereof (referring to the aforementioned heterocyclic compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof) as shown below: A compound having a retention time of 0.660 min under the following conditions, which is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Keep 50% of Phase B for 5 minutes, flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 2.147 min is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Keep 50% of Phase B for 5 minutes, flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 2.311 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 4 minutes, keep 40% Phase B for 2.5 minutes, keep 5% Phase B for 1.5 minutes, flow rate: 2.8 ml/min; The compound with a retention time of 3.397 min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IG-3 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 4 minutes, keep 40% Phase B for 2.5 minutes, keep 5% Phase B for 1.5 minutes, flow rate: 2.8 ml/min; The compound with a retention time of 4.236 min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IE 100*4.6mm 3um; Mobile phase: Phase A is 0.1% diethylamine/n-heptane, Phase B is isopropanol; Gradient: A/B = 60/40, Flow rate: 1 ml/min; Under the following conditions, the compound with a retention time of 1.942 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, keep 40% Phase B for 1.2 minutes, keep 5% Phase B for 0.8 minutes, flow rate: 4 ml/min; The compound with a retention time of 2.343 min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, keep 40% Phase B for 1.2 minutes, keep 5% Phase B for 0.8 minutes, flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 3.004 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, keep 40% Phase B for 1.2 minutes, keep 5% Phase B for 0.8 minutes, flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 2.414 min is A stereoisomer in: Chromatographic column: Chiralpak IC-3, 100mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: 40% Phase B, Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 3.344 min is A stereoisomer in: Chromatographic column: Chiralpak IC-3, 100mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: 40% Phase B, Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 1.150 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B, Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 2.203 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B, Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 1.696 min is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, keep 40% Phase B for 1.2 minutes, keep 5% Phase B for 0.8 minutes; Flow rate: 4 ml/min; The compound with a retention time of 2.137 min under the following conditions is A stereoisomer in: Chromatography column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, keep 40% phase B for 1.2 minutes, keep 5% phase B for 0.8 minutes; Flow rate: 4 ml/min.
在下述條件下保留時間為1.787 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在2分鐘內從5%到40%,保持40%的B相1.2分鐘,保持5%的B相0.8分鐘;流速:4毫升/分鐘; 在下述條件下保留時間為2.089 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在2分鐘內從5%到40%,保持40%的B相1.2分鐘,保持5%的B相0.8分鐘;流速:4毫升/分鐘; 在下述條件下保留時間為0.797 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak IG-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相;流速:4毫升/分鐘; 在下述條件下保留時間為2.514 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak IG-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相;流速:4毫升/分鐘; 在下述條件下保留時間為1.943 min的化合物,其為 中的一個立體異構物:層析管柱: ChiralPak AD-3,150 * 4.6 mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持40%的B相;流速:2.5毫升/分鐘; 在下述條件下保留時間為3.400 min的化合物,其為 中的一個立體異構物:層析管柱: ChiralPak AD-3,150 * 4.6 mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持40%的B相;流速:2.5毫升/分鐘; 在下述條件下保留時間為1.729 min和1.951 min的化合物,其為 中的兩個立體異構物混合物:層析管柱: Chiralpak IG-3,100 * 4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相,流速:2.8毫升/分鐘; 在下述條件下保留時間為6.088 min的化合物,其為 中的一個立體異構物混合物:層析管柱: Chiralpak IG-3 100 * 4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相,流速:2.8毫升/分鐘; 在下述條件下保留時間為8.998 min的化合物,其為 中的一個立體異構物混合物:層析管柱: Chiralpak IG-3 100 * 4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相,流速:2.8毫升/分鐘; 在下述條件下保留時間為1.374 min的化合物,其為 中的兩個立體異構物混合物:層析管柱: Chiralpak IG-3,100 * 4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持40%的B相,流速:2.8毫升/分鐘; 在下述條件下保留時間為2.812 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak IG-3,100 * 4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持40%的B相,流速:2.8毫升/分鐘; 在下述條件下保留時間為6.215 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak IG-3,100 * 4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持40%的B相,流速:2.8毫升/分鐘; 在下述條件下保留時間為0.438 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak AD-3, 50 *4.6mm, 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相;流速:4毫升/分鐘; 在下述條件下保留時間為1.251 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak AD-3, 50 *4.6mm, 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相;流速:4毫升/分鐘; 在下述條件下保留時間為0.369 min的化合物,其為 中的兩個立體異構物混合物:層析管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持B相在40%;流速:4毫升/分鐘; 在下述條件下保留時間為0.752 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持B相在40%;流速:4毫升/分鐘; 在下述條件下保留時間為1.937 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持B相在40%;流速:4毫升/分鐘; 在下述條件下保留時間為3.692 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak AD-3,150mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相保持在40%;流速:2.5毫升/分鐘。 The compound with a retention time of 1.787 min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, keep 40% Phase B for 1.2 minutes, keep 5% Phase B for 0.8 minutes; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 2.089 min is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 2 minutes, keep 40% Phase B for 1.2 minutes, keep 5% Phase B for 0.8 minutes; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 0.797 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 2.514 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 1.943 min is A stereoisomer in: Chromatographic column: ChiralPak AD-3, 150 * 4.6 mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 40% of Phase B; Flow rate: 2.5 ml/min; Under the following conditions, the compound with a retention time of 3.400 min is A stereoisomer in: Chromatographic column: ChiralPak AD-3, 150 * 4.6 mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 40% of Phase B; Flow rate: 2.5 ml/min; Under the following conditions, the retention time of the compound is 1.729 min and 1.951 min, which is The mixture of two stereoisomers in: Chromatographic column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B, Flow rate: 2.8 ml/min; The compound with a retention time of 6.088 min under the following conditions is A stereoisomer mixture in: Chromatographic column: Chiralpak IG-3 100 * 4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B, Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 8.998 min is A stereoisomer mixture in: Chromatographic column: Chiralpak IG-3 100 * 4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B, Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 1.374 min is The mixture of two stereoisomers in: Chromatographic column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 40% of Phase B, Flow rate: 2.8 ml/min; The compound with a retention time of 2.812 min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 40% of Phase B, Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 6.215 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 40% of Phase B, Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 0.438 min is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50 *4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 1.251 min is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50 *4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Maintain 40% of Phase B; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 0.369 min is The mixture of two stereoisomers in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Keep Phase B at 40%; Flow rate: 4 ml/min; The compound with a retention time of 0.752 min under the following conditions is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Keep Phase B at 40%; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 1.937 min is A stereoisomer in: Chromatographic column: Chiralpak AD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Gradient: Keep Phase B at 40%; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 3.692 min is One of the stereoisomers in the mixture: Chromatography column: Chiralpak AD-3, 150mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B is maintained at 40%; Flow rate: 2.5 ml/min.
在下述條件下保留時間為3.586 min的化合物,其為 中的一個立體異構物:層析管柱: Ultimate XB-C18, 3um, 3.0*50mm;流動相:A相為三氟乙酸/水 (1.5 mL/4 L),B相為三氟乙酸/乙腈 (0.75 mL/4 L);梯度:B相在1分鐘內從1%到5%,在5分鐘內從5%到100%,保持100%的B相2分鐘,保持1%的B相2分鐘;流速:1.2毫升/分鐘): 在下述條件下保留時間為為3.607 min的化合物,其為 中的一個立體異構物:層析管柱: Ultimate XB-C18, 3um, 3.0*50mm;流動相:A相為三氟乙酸/水 (1.5 mL/4 L),B相為三氟乙酸/乙腈 (0.75 mL/4 L);梯度:B相在1分鐘內從1%到5%,在5分鐘內從5%到100%,保持100%的B相2分鐘,保持1%的B相2分鐘;流速:1.2毫升/分鐘): 在下述條件下保留時間為為3.539 min的化合物,其為 中的一個立體異構物:層析管柱:Ultimate XB-C18, 3um, 3.0*50mm;流動相:A相為三氟乙酸/水 (1.5 mL/4 L),B相為三氟乙酸/乙腈 (0.75 mL/4 L);梯度:B相在1分鐘內從1%到5%,在5分鐘內從5%到100%,保持100%的B相2分鐘,保持1%的B相2分鐘;流速:1.2毫升/分鐘): 在下述條件下保留時間為為3.539 min的化合物,其為 中的一個立體異構物:層析管柱: Ultimate XB-C18, 3um, 3.0*50mm;流動相:A相為三氟乙酸/水 (1.5 mL/4 L),B相為三氟乙酸/乙腈 (0.75 mL/4 L);梯度:B相在1分鐘內從1%到5%,在5分鐘內從5%到100%,保持100%的B相2分鐘,保持1%的B相2分鐘;流速:1.2毫升/分鐘):出峰位置為3.565 min; 在下述條件下保留時間為3.754 min的化合物,其為 中的一個立體異構物:層析管柱: ChiralCel OD-3,150mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;保持40%的B相;流速:2.5毫升/分鐘; 在下述條件下保留時間為3.131 min的化合物,其為 中的一個立體異構物:層析管柱: ChiralCel OD-3,150mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;保持40%的B相;流速:2.5毫升/分鐘; 在下述條件下保留時間為1.653 min的化合物,其為 中的一個立體異構物:層析管柱: ChiralCel OD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;2 min從5%的B相升至40%的B相,保持40%的B相1.2 min,然後保持5%的B相0.8 min;流速:4毫升/分鐘; 在下述條件下保留時間為1.763 min的化合物,其為 中的一個立體異構物:層析管柱: ChiralCel OD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;2 min從5%的B相升至40%的B相,保持40%的B相1.2 min,然後保持5%的B相0.8 min;流速:4毫升/分鐘; 在下述條件下保留時間為1.343 min的化合物,其為 中的一個立體異構物:層析管柱: Cellulose-2 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相;流速:2.8毫升/分鐘; 在下述條件下保留時間為1.527 min的化合物,其為 中的一個立體異構物:層析管柱: Cellulose-2 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相;流速:2.8毫升/分鐘; 在下述條件下保留時間為1.739 min的化合物,其為 中的一個立體異構物:層析管柱: Cellulose-2 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相;流速:2.8毫升/分鐘; 在下述條件下保留時間為2.203 min的化合物,其為 中的一個立體異構物:層析管柱: Cellulose-2 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相;流速:2.8毫升/分鐘; 在下述條件下保留時間為3.304 min的化合物,其為 中的一個立體異構物:層析管柱: Cellulose 2 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/甲醇;梯度:保持50%的B相;流速:2.8毫升/分鐘; 在下述條件下保留時間為4.369 min的化合物,其為 中的一個立體異構物:層析管柱: Cellulose 2 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/甲醇;梯度:保持50%的B相;流速:2.8毫升/分鐘; 在下述條件下保留時間為4.500 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak IC-3 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相;流速:2.8毫升/分鐘; 在下述條件下保留時間為5.555 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak IC-3 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相;流速:2.8毫升/分鐘; 在下述條件下保留時間為2.676 min的化合物,其為 中的一個立體異構物:層析管柱: (S,S)Whelk-01 100×4.6mm I.D., 5.0um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:B相保持60%;流速:2.5毫升/分鐘; 在下述條件下保留時間為3.176 min的化合物,其為 中的一個立體異構物:層析管柱: (S,S)Whelk-01 100×4.6mm I.D., 5.0um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:B相保持60%;流速:2.5毫升/分鐘; 在下述條件下保留時間為0.634 min的化合物,其為 中的一個立體異構物:層析管柱: Chiralpak IG-3 50*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相保持40%;流速:4毫升/分鐘; 在下述條件下保留時間為1.129 min的化合物,其為 中的一個立體異構物:層析管柱: : Chiralpak IG-3 50*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相保持40%;流速:4毫升/分鐘; 以上保留時間的測試條件並非對化合物的限定,只要採用上述測試條件進行測定,得到的保留時間與上述記載的相同或在誤差範圍內,且該化合物為上述用保留時間限定的化合物中的一個立體異構物,則落入本發明的保護範圍內。 The compound with a retention time of 3.586 min under the following conditions is A stereoisomer in: Chromatography column: Ultimate XB-C18, 3um, 3.0*50mm; Mobile phase: A phase is trifluoroacetic acid/water (1.5 mL/4 L), B phase is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); Gradient: B phase from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% B phase for 2 minutes, keep 1% B phase for 2 minutes; Flow rate: 1.2 mL/min): The compound with a retention time of 3.607 min under the following conditions is A stereoisomer in: Chromatography column: Ultimate XB-C18, 3um, 3.0*50mm; Mobile phase: A phase is trifluoroacetic acid/water (1.5 mL/4 L), B phase is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); Gradient: B phase from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% B phase for 2 minutes, keep 1% B phase for 2 minutes; Flow rate: 1.2 mL/min): The compound with a retention time of 3.539 min under the following conditions is A stereoisomer in: Chromatography column: Ultimate XB-C18, 3um, 3.0*50mm; Mobile phase: A phase is trifluoroacetic acid/water (1.5 mL/4 L), B phase is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); Gradient: B phase from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% B phase for 2 minutes, keep 1% B phase for 2 minutes; Flow rate: 1.2 mL/min): The compound with a retention time of 3.539 min under the following conditions is A stereoisomer in: Chromatography column: Ultimate XB-C18, 3um, 3.0*50mm; Mobile phase: A phase is trifluoroacetic acid/water (1.5 mL/4 L), B phase is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); Gradient: B phase from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% B phase for 2 minutes, keep 1% B phase for 2 minutes; Flow rate: 1.2 mL/min): The peak position is 3.565 min; The compound with a retention time of 3.754 min under the following conditions is A stereoisomer in: Chromatographic column: ChiralCel OD-3, 150mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Maintain 40% of Phase B; Flow rate: 2.5 ml/min; Under the following conditions, the compound with a retention time of 3.131 min is A stereoisomer in: Chromatographic column: ChiralCel OD-3, 150mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/isopropanol; Maintain 40% of Phase B; Flow rate: 2.5 ml/min; Under the following conditions, the compound with a retention time of 1.653 min is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; 2 min from 5% phase B to 40% phase B, keep 40% phase B for 1.2 min, and then keep 5% phase B for 0.8 min; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 1.763 min is One stereoisomer in: Chromatographic column: ChiralCel OD-3, 50mm * 4.6mm, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; 2 min from 5% phase B to 40% phase B, keep 40% phase B for 1.2 min, and then keep 5% phase B for 0.8 min; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 1.343 min is A stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 1.527 min is A stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 1.739 min is A stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 2.203 min is A stereoisomer in: Chromatographic column: Cellulose-2 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 3.304 min is A stereoisomer in: Chromatographic column: Cellulose 2 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/methanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 4.369 min is A stereoisomer in: Chromatographic column: Cellulose 2 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/methanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 4.500 min is A stereoisomer in: Chromatographic column: Chiralpak IC-3 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 5.555 min is A stereoisomer in: Chromatographic column: Chiralpak IC-3 100*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Maintain 50% of Phase B; Flow rate: 2.8 ml/min; Under the following conditions, the compound with a retention time of 2.676 min is A stereoisomer in: chromatography column: (S,S)Whelk-01 100×4.6mm ID, 5.0um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: phase B is maintained at 60%; flow rate: 2.5 ml/min; Under the following conditions, the compound with a retention time of 3.176 min is A stereoisomer in: chromatography column: (S,S)Whelk-01 100×4.6mm ID, 5.0um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: phase B is maintained at 60%; flow rate: 2.5 ml/min; Under the following conditions, the compound with a retention time of 0.634 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3 50*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B is maintained at 40%; Flow rate: 4 ml/min; Under the following conditions, the compound with a retention time of 1.129 min is A stereoisomer in: Chromatographic column: Chiralpak IG-3 50*4.6mm ID, 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B is maintained at 40%; Flow rate: 4 ml/min; The above retention time test conditions are not limitations on the compounds. As long as the above test conditions are used for measurement, the retention time obtained is the same as the above record or within the error range, and the compound is a stereoisomer in the compounds defined by the retention time above, it falls within the protection scope of the present invention.
本發明還提供了一種藥物組成物,其包括: (1) 如前任一項所述的雜環類化合物、其藥學上可接受的鹽、其立體異構物或它們的溶劑合物,和 (2) 藥用佐劑。 The present invention also provides a pharmaceutical composition comprising: (1) a heterocyclic compound as described in any of the preceding items, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof, and (2) a pharmaceutical adjuvant.
本發明還提供了一種物質A或所述藥物組成物在製備KRAS G12D抑制劑的應用,所述的物質A為如前任一項所述的雜環類化合物、其藥學上可接受的鹽、其立體異構物或它們的溶劑合物。The present invention also provides a use of a substance A or the drug composition in the preparation of a KRAS G12D inhibitor, wherein the substance A is a heterocyclic compound as described in any of the preceding items, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof.
在所述的應用中,所述的KRAS G12D抑制劑可用於哺乳動物生物體內;也可用於生物體外,主要作為實驗用途,例如:作為標準樣品或對照樣品提供比對,或按照本領域常規方法製成套組,為KRAS G12D抑制效果提供快速檢測。In the application, the KRAS G12D inhibitor can be used in mammals; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in this field to provide rapid detection of KRAS G12D inhibitory effects.
本發明還提供了一種物質A或所述藥物組成物在製備藥物的應用,所述的物質A為如前任一項所述的雜環類化合物、其藥學上可接受的鹽、其立體異構物或它們的溶劑合物,所述藥物用於治療癌症,例如結直腸癌,胃癌,胰腺癌,非小細胞肺癌,前列腺癌,乳腺癌等。The present invention also provides a use of a substance A or the drug composition in the preparation of a drug, wherein the substance A is a heterocyclic compound as described in any of the preceding items, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof, and the drug is used to treat cancer, such as colorectal cancer, gastric cancer, pancreatic cancer, non-small cell lung cancer, prostate cancer, breast cancer, etc.
如無特別說明,本發明所用術語具有如下含義: 本領域技術人員可以理解,根據本領域中使用的慣例,本發明描述基團的結構式中所使用的“ ”是指,相應的基團透過該位點與化合物中的其它片段、基團進行連接。 Unless otherwise specified, the terms used in the present invention have the following meanings: Technical personnel in the field can understand that, according to the conventions used in the field, the " " used in the structural formula of the group described in the present invention means that the corresponding group is connected to other fragments and groups in the compound through this site.
術語“藥學上可接受的”是指鹽、溶劑、佐劑等一般無毒、安全,並且適合於患者使用。所述的“患者”優選哺乳動物,更優選為人類。The term "pharmaceutically acceptable" means that salts, solvents, adjuvants, etc. are generally non-toxic, safe, and suitable for use by patients. The "patient" is preferably a mammal, more preferably a human.
術語“藥學上可接受的鹽”是指本發明化合物與相對無毒的、藥學上可接受的酸或鹼製備得到的鹽。當本發明的化合物中含有相對酸性的官能基時,可以透過在純的溶液或合適的惰性溶劑中用足夠量的藥學上可接受的鹼與這類化合物的中性形式接觸的方式獲得鹼加成鹽。藥學上可接受的鹼加成鹽包括但不限於:鋰鹽、鈉鹽、鉀鹽、鈣鹽、鋁鹽、鎂鹽、鋅鹽、鉍鹽、銨鹽、二乙醇胺鹽。當本發明的化合物中含有相對鹼性的官能基時,可以透過在純的溶液或合適的惰性溶劑中用足夠量的藥學上可接受的酸與這類化合物的中性形式接觸的方式獲得酸加成鹽。所述的藥學上可接受的酸包括無機酸,所述無機酸包括但不限於:鹽酸、氫溴酸、氫碘酸、硝酸、碳酸、磷酸、亞磷酸、硫酸等。所述的藥學上可接受的酸包括有機酸,所述有機酸包括但不限於:乙酸、丙酸、草酸、異丁酸、馬來酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、鄰苯二甲酸、苯磺酸、對甲苯磺酸、檸檬酸、水楊酸、酒石酸、甲磺酸、異煙酸、酸式檸檬酸、油酸、單寧酸、泛酸、酒石酸氫、抗壞血酸、龍膽酸、富馬酸、葡糖酸、糖酸、甲酸、乙磺酸、雙羥萘酸(即4, 4’-伸甲基-雙(3-羥基-2-萘甲酸))、胺基酸(例如麩胺酸、精胺酸)等。當本發明的化合物中含有相對酸性和相對鹼性的官能基時,可以被轉換成鹼加成鹽或酸加成鹽。具體可參見Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)、或、Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002)。The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively non-toxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compounds of the present invention contain relatively alkaline functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, etc. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentianic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, bis(hydroxynaphthoic acid)), amino acids (e.g., glutamine, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).
術語“溶劑合物”是指本發明化合物與化學計量或非化學計量的溶劑結合形成的物質。溶劑合物中的溶劑分子可以有序或非有序排列的形式存在。所述的溶劑包括但不限於:水、甲醇、乙醇等。The term "solvent" refers to a substance formed by combining the compound of the present invention with a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvent may exist in an ordered or unordered arrangement. The solvent includes but is not limited to: water, methanol, ethanol, etc.
術語“化合物”、“藥學上可接受的鹽”、“溶劑合物”和“藥學上可接受的鹽的溶劑合物”如存在立體異構物,則可以以單一的立體異構物或它們的混合物(例如外消旋體)的形式存在。術語“立體異構物”是指順反異構物或旋光異構物。這些立體異構物可以透過不對稱合成方法或掌性分離法(包括但不限於薄層層析、旋轉層析、管柱層析、氣相層析、高壓液相層析等)分離、純化及富集,還可以透過與其它掌性化合物成鍵(化學結合等)或成鹽(物理結合等)等方式進行掌性拆分獲得。術語“單一的立體異構物”是指本發明化合物的一種立體異構物相對於該化合物的所有立體異構物的品質含量不低於95%。The terms "compound", "pharmaceutically acceptable salt", "solvent complex" and "pharmaceutically acceptable salt solvent complex" may exist as a single stereoisomer or a mixture thereof (e.g., a racemate) if stereoisomers exist. The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotational chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral separation by bonding (chemical bonding, etc.) or salification (physical bonding, etc.) with other chiral compounds. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention is not less than 95% relative to all stereoisomers of the compound.
術語“化合物”、“藥學上可接受的鹽”、“溶劑合物”和“藥學上可接受的鹽的溶劑合物”如存在互變異構物,則可以以單一的互變異構物或它們的混合物的形式存在,較佳地以較穩定的互變異構物為主的形式存在。The terms "compound", "pharmaceutically acceptable salt", "solvent complex" and "pharmaceutically acceptable salt solvent complex" may exist in the form of a single tautomer or a mixture thereof if tautomers exist, preferably in the form of a more stable tautomer as the main component.
術語“鹵素”是指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
術語“烷基”是指具有指定碳原子數(例如,C 1~C 6)的、直鏈或支鏈的、飽和的一價烴基。烷基包括但不限於:甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基、叔丁基、正戊基、正己基等。 The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 1 to C 6 ). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
術語“環烷基”是指具有指定碳原子數(例如,C 3~C 6)的、環狀的、飽和的一價烴基。環烷基包括但不限於: 、 、 、 等。 The term "cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 3 to C 6) . Cycloalkyl groups include, but are not limited to: , , , wait.
術語“環烯基”是指具有指定碳原子數(例如,C 3~C 6)的、環狀的、不飽和的一價烴基,其具有一個或多個(例如,1個、2個或3個)碳-碳sp 2雙鍵,其為單環,不具有芳香性。(單環)環烯基包括但不限於: 、 等。 The term "cycloalkenyl" refers to a cyclic, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 3 to C 6 ), which has one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 double bonds, is monocyclic, and is not aromatic. (Monocyclic) cycloalkenyl groups include, but are not limited to: , wait.
術語“碳烯環”的滿足下述任一條件,其餘定義同術語“環烯基”:1、透過兩個以上的單鍵與分子其餘部分相連;2、與分子其餘部分共用兩個原子和一根鍵。The term "carbene ring" has the same definition as the term "cycloalkenyl" if any of the following conditions are met: 1. It is attached to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
術語“烯基”是指具有指定碳原子數(例如,C 2-C 6)的、直鏈或支鏈的、不飽和的一價烴基,其具有一個或多個(例如,1個、2個或3個)碳-碳sp 2雙鍵。烯基包括但不限於:乙烯基、 、 等。 The term "alkenyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C2 - C6 ) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp2 double bonds. Alkenyl groups include, but are not limited to, vinyl, , wait.
術語“炔基”是指具有指定碳原子數(例如,C 2~C 6)的、直鏈或支鏈的、不飽和的一價烴基,其具有一個或多個(例如,1個、2個或3個)碳-碳sp 3三鍵。炔基包括但不限於:乙炔基等。 The term "alkynyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C 2 to C 6 ) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp 3 triple bonds. Alkynyl groups include, but are not limited to, ethynyl and the like.
術語“雜環烷基”是指具有指定環原子數(例如,3~8員)的、指定雜原子數(例如,1個、2個或3個)的、指定雜原子種類(N、O和S中的一種或多種)的、環狀的、飽和的一價基團,優選為單環。雜環烷基透過碳原子或雜原子與分子其餘部分相連。雜環烷基包括但不限於: 、 、 或 等。 The term "heterocycloalkyl" refers to a cyclic, saturated, monovalent group with a specified number of ring atoms (e.g., 3 to 8 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), preferably a monocyclic ring. The heterocycloalkyl is attached to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkyl includes, but is not limited to: , , or wait.
術語“雜芳基”是指具有指定環原子數(例如,5~10員)的、指定雜原子數(例如,1個、2個或3個)的、指定雜原子種類(N、O和S中的一種或多種)的、環狀的、不飽和的一價基團,其為單環或多環,單環之間共用兩個原子和一根鍵,且每個環均具有芳香性。雜芳基透過碳原子或雜原子與分子其餘部分相連。雜芳基包括但不限於: 、 、 、 或 等。 The term "heteroaryl" refers to a cyclic, unsaturated, monovalent group with a specified number of ring atoms (e.g., 5 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic, with two atoms and one bond shared between the monocyclic rings, and each ring is aromatic. Heteroaryl is connected to the rest of the molecule through a carbon atom or a heteroatom. Heteroaryl includes, but is not limited to: , , , or wait.
術語“雜環烯基”是指具有指定環原子數(例如,5~10員)的、指定雜原子數(例如,1個、2個或3個)的、指定雜原子種類(N、O和S中的一種或多種)的、環狀的、不飽和的一價烴基,其具有一個或多個(例如,1個、2個或3個)碳-碳sp 2雙鍵,其為單環,不具有芳香性。雜環烯基透過碳原子或雜原子與分子其餘部分相連。雜環烯基包括但不限於: 或 等。 The term "heterocycloalkenyl" refers to a cyclic, unsaturated, monovalent hydrocarbon radical with a specified number of ring atoms (e.g., 5 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S), which has one or more (e.g., 1, 2, or 3) carbon-carbon sp2 double bonds, is monocyclic, and is not aromatic. Heterocycloalkenyl is linked to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkenyls include, but are not limited to: or wait.
術語“碳雜烯環” 滿足下述任一條件,其餘定義同術語“雜環烯基”:1、透過兩個以上的單鍵與分子其餘部分相連;2、與分子其餘部分共用兩個原子和一根鍵。The term "carboheteroalkene" satisfies any of the following conditions, and the rest of the definition is the same as the term "heterocycloalkenyl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
術語“環烯酮”的例子包括但不限於 。 Examples of the term "cycloketones" include, but are not limited to .
術語“雜芳環”滿足下述任一條件,其餘定義同術語“雜芳基”:1、透過兩個以上的單鍵與分子其餘部分相連;2、與分子其餘部分共用兩個原子和一根鍵。The term "heteroaryl" satisfies any of the following conditions, and the rest of the definition is the same as the term "heteroaryl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
術語“芳基”是指具有指定碳原子數(例如,C 6~C 14)的、環狀的、不飽和的一價烴基,其為單環或多環(例如,2個或3個),為多環時,單環之間共用兩個原子和一根鍵,且(至少一個環/每個環均)具有芳香性。芳基透過芳香性環中的碳原子與分子其餘部分相連。芳基包括但不限於:苯基或萘基等。 The term "aryl" refers to a cyclic, unsaturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C 6 ~C 14 ), which is monocyclic or polycyclic (e.g., 2 or 3). In the case of polycyclic, the monocyclic rings share two atoms and one bond, and (at least one ring/each ring) is aromatic. The aryl group is connected to the rest of the molecule through the carbon atoms in the aromatic ring. Aryl groups include, but are not limited to, phenyl or naphthyl.
術語“芳環”滿足下述任一條件,其餘定義同術語“芳基”:1、透過兩個以上的單鍵與分子其餘部分相連;2、與分子其餘部分共用兩個原子和一根鍵。The term "aromatic ring" meets any of the following conditions, and the rest of the definition is the same as the term "aryl group": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
術語“脂雜環”滿足下述任一條件,其餘定義同術語“雜環烷基”:1、透過兩個以上的單鍵與分子其餘部分相連;2、與分子其餘部分共用兩個原子和一根鍵。The term "aliphatic heterocyclic" satisfies any of the following conditions, and the rest of the definition is the same as the term "heterocycloalkyl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
術語“脂碳環”滿足下述任一條件,其餘定義同術語“環烷基”:1、透過兩個以上的單鍵與分子其餘部分相連;2、與分子其餘部分共用兩個原子和一根鍵。The term "aliphatic ring" satisfies any of the following conditions, and the rest of the definition is the same as the term "cycloalkyl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.
術語“烷氧基”是指基團R X-O-,R X的定義同術語“烷基”。烷氧基包括但不限於:甲氧基、乙氧基、正丙氧基、異丙氧基等。 The term "alkoxy" refers to the group R X -O-, where R X is defined the same as the term "alkyl". Alkoxy includes but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
在不違背本領域常識的基礎上,上述各優選條件,可任意組合,即得本發明各較佳實例。Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.
本發明所用試劑和原料均市售可得。The reagents and raw materials used in the present invention are commercially available.
本發明的積極進步效果在於:本發明化合物對KRAS G12D突變的胃癌AGS細胞系、轉移胰腺腺癌AsPC-1細胞具有良好的細胞増殖抑制活性。有良好的肝微粒體、肝細胞、血漿、全血穩定性,有良好的PK性質,並且有顯著的抑瘤作用。The positive and progressive effects of the present invention are: the compound of the present invention has good cell proliferation inhibition activity on KRAS G12D mutated gastric cancer AGS cell line and metastatic pancreatic adenocarcinoma AsPC-1 cells. It has good stability in liver microsomes, liver cells, plasma and whole blood, good PK properties, and significant tumor inhibition effect.
具體實施方式Specific implementation methods
下面透過實施例的方式進一步說明本發明,但並不因此將本發明限制在所述的實施例範圍之中。下列實施例中未註明具體條件的實驗方法,按照常規方法和條件,或按照商品說明書選擇。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods without specific conditions in the following examples are carried out according to conventional methods and conditions, or selected according to the product instructions.
NMR的測定是用Bruker AVANCE-400核磁儀。測定溶劑在譜圖解析中註明。NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used for the measurements are indicated in the spectral analysis.
MS的測定用Agilent 1200-G1956A/1200-6110A/1200-6140A/1260-6125B/ Prime-6125B/1260-6120液質聯用儀,SHIMADZU 20A-2010/20A-2020液質聯用儀,Waters ACQ-QDA液質聯用儀。MS was determined using Agilent 1200-G1956A/1200-6110A/1200-6140A/1260-6125B/ Prime-6125B/1260-6120 LC/MS, SHIMADZU 20A-2010/20A-2020 LC/MS, and Waters ACQ-QDA LC/MS.
HPLC分析使用SHIMADZU 20A 高效液相層析儀。HPLC analysis was performed using a SHIMADZU 20A high performance liquid chromatograph.
SFC分析測定使用Waters UPCC with PDA Detector and QDa Detector超高效合相層析儀,Waters UPC2 with PDA detector超高效合相層析儀,Agilent 1260 with DAD detector高效液相層析儀,Shimadzu LC-20AB with PDA detector高效液相層析儀,Shimadzu LC-20AD with PDA detector高效液相層析儀。SFC analysis was performed using Waters UPCC with PDA Detector and QDa Detector, Waters UPC2 with PDA detector, Agilent 1260 with DAD detector, Shimadzu LC-20AB with PDA detector, and Shimadzu LC-20AD with PDA detector.
製備型HPLC分離使用Shimadzu LC-20AP pump, Shimadzu LH-40 Liquid Handler, Shimadzu SPD-20A Detector,Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV Detector製備型層析儀。Preparative HPLC separation was performed using Shimadzu LC-20AP pump, Shimadzu LH-40 Liquid Handler, Shimadzu SPD-20A Detector, Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV Detector.
SFC分離使用The Berger MG II、MG III,Sepiatec's Prep SFC 100 system,Waters Prep 80Q SFC SYSTEM、Prep 150 AP SFC SYSTEM、Prep 200 SFC SYSTEM、Prep 350 SFC SYSTEM。SFC separation was performed using The Berger MG II, MG III, Sepiatec's Prep SFC 100 system, Waters Prep 80Q SFC SYSTEM, Prep 150 AP SFC SYSTEM, Prep 200 SFC SYSTEM, and Prep 350 SFC SYSTEM.
快速管柱層析分離使用Biotage IsoleraOne快速製備層析儀。Rapid column separation was performed using the Biotage IsoleraOne rapid preparative chromatogram.
薄層層析矽膠板使用安徽良臣矽源材料有限公司的GF254丙烯酸粘合劑矽膠板,薄層層析法(TLC)使用的矽膠板採用的規格是0.25mm,薄層層析分離純化產品採用的規格是0.5mm。The thin layer chromatography silica plate uses the GF254 acrylic adhesive silica plate of Anhui Liangchen Silicon Source Material Co., Ltd. The specification of the silica plate used in thin layer chromatography (TLC) is 0.25mm, and the specification of the thin layer chromatography separation and purification product is 0.5mm.
加壓氫化反應氫化瓶和氫氣鋼瓶。Pressurized hydrogenation reaction hydrogenation bottles and hydrogen cylinders.
微波反應使用Biotage Initiator+ 微波合成儀。Microwave reactions were performed using a Biotage Initiator+ microwave synthesizer.
手套箱使用德力斯DELLIX 定制手套箱。 中間體 A1 :2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷 The glove box used was a DELLIX custom glove box. Intermediate A1 : 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane
第一步:向乙炔基三異丙基矽烷(135 g,742 mmol)的丙酮(2000 mL)溶液中慢慢加入N-溴代丁二醯亞胺(145 g,815 mmol)和硝酸銀(12.6 g,74.2 mmol),然後反應液在25 oC攪拌16小時。反應液濃縮,殘餘物和石油醚(1500 mL)攪拌0.5小時,過濾,濾液旋轉乾燥得到粗產物化合物 (溴乙炔基)三異丙基矽烷(171 g),為黃色油狀液體。 1H NMR (400 MHz, CDCl 3) δ ppm 1.13-0.84 (m, 21H). Step 1: Slowly add N-bromosuccinimide (145 g, 815 mmol) and silver nitrate (12.6 g, 74.2 mmol) to a solution of ethynyltriisopropylsilane (135 g, 742 mmol) in acetone (2000 mL), and then stir the reaction solution at 25 ° C for 16 hours. The reaction solution is concentrated, the residue is stirred with petroleum ether (1500 mL) for 0.5 hours, filtered, and the filtrate is rotary dried to obtain the crude product compound (bromoethynyl)triisopropylsilane (171 g), which is a yellow oily liquid. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 1.13-0.84 (m, 21H).
第二步:將2-(4-氟苯基)乙酸(200 g,1.30 mol),2,2-二甲基-1,3-二噁烷-4,6-二酮(205 g,1.42 mol)和4-二甲胺基吡啶(14 g,114 mmol)溶於乙腈(600 mL),降溫到0 oC緩慢滴加二異丙基乙胺(485 mL),並在0 oC下攪拌15分鐘。控制反應溫度低於30 oC下,特戊醯氯(175 mL)緩慢滴加到反應液中,室溫攪拌30分鐘,然後升到50 oC攪拌16小時。反應降到0 oC,緩慢加入到稀鹽酸(1 M,2000 mL)中,然後0 oC下反應攪拌2小時,有大量黃色固體產生,過濾,濾餅用乙腈和水的混合液(體積比為1/4,6000 mL)洗滌,真空乾燥,得到粗產物化合物5-(2-(4-氟苯基)乙醯基)-2,2-二甲基-1,3-二噁烷-4,6-二酮(364 g),為白色固體。LCMS (ESI): [M-H] -= 278.9; 1H NMR (400 MHz, DMSO- d 6) δ ppm 7.36 (dd, J= 5.6, 8.5 Hz, 2H), 7.16 (t, J= 8.9 Hz, 2H), 4.36 (s, 2H), 3.75 (s, 1H)1.69 (s, 6H) Step 2: Dissolve 2-(4-fluorophenyl)acetic acid (200 g, 1.30 mol), 2,2-dimethyl-1,3-dioxane-4,6-dione (205 g, 1.42 mol) and 4-dimethylaminopyridine (14 g, 114 mmol) in acetonitrile (600 mL), cool to 0 o C, slowly add diisopropylethylamine (485 mL), and stir at 0 o C for 15 minutes. Control the reaction temperature below 30 o C, slowly add trivaleryl chloride (175 mL) to the reaction solution, stir at room temperature for 30 minutes, and then raise to 50 o C and stir for 16 hours. The reaction temperature was lowered to 0 ° C, and dilute hydrochloric acid (1 M, 2000 mL) was slowly added, and then the reaction was stirred at 0 ° C for 2 hours. A large amount of yellow solid was generated. Filtered, the filter cake was washed with a mixture of acetonitrile and water (volume ratio of 1/4, 6000 mL), and vacuum dried to obtain the crude product compound 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (364 g) as a white solid. LCMS (ESI): [MH] - = 278.9; 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.36 (dd, J = 5.6, 8.5 Hz, 2H), 7.16 (t, J = 8.9 Hz, 2H), 4.36 (s, 2H), 3.75 (s, 1H)1.69 (s, 6H)
第三步:將5-(2-(4-氟苯基)乙醯基)-2,2-二甲基-1,3-二噁烷-4,6-二酮(362 g,1.29 mol)溶於叔丁醇(930 mL)中,加熱到90 oC攪拌2小時。反應液旋轉乾燥得到粗產物化合物4-(4-氟苯基)-3-氧代丁酸叔丁酯(280 g),為黃色固體。LCMS (ESI): [M-H] -= 250.9; 1H NMR (400 MHz, DMSO- d 6) δ ppm 7.23-7.19 (m, 2H), 7.17-7.11 (m, 2H), 3.86 (s, 2H), 3.54 (s, 2H), 1.40 (s, 9H). Step 3: Dissolve 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (362 g, 1.29 mol) in tert-butyl alcohol (930 mL), heat to 90 ° C and stir for 2 hours. The reaction solution was rotary dried to obtain the crude product compound tert-butyl 4-(4-fluorophenyl)-3-oxobutanoate (280 g) as a yellow solid. LCMS (ESI): [MH] - = 250.9; 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.23-7.19 (m, 2H), 7.17-7.11 (m, 2H), 3.86 (s, 2H), 3.54 (s, 2H), 1.40 (s, 9H).
第四步:4-(4-氟苯基)-3-氧代丁酸叔丁酯(278 g,1.10 mol)溶於二氯甲烷(2480 mL)中,在0 oC下加入三氟乙酸(575 mL, 7.50 mol),反應在25 oC攪拌16小時。反應結束後真空濃縮得到粗產物化合物4-(4-氟苯基)-3-氧代丁酸(231 g),為白色固體。LCMS (ESI): [M-H] -= 194.8; 1H NMR (400 MHz, CDCl 3) δ ppm 7.26-7.15 (m, 2H), 7.11-7.01 (m, 2H), 3.85 (s, 2H), 3.56 (s, 2H) Step 4: tert-Butyl 4-(4-fluorophenyl)-3-oxobutanoate (278 g, 1.10 mol) was dissolved in dichloromethane (2480 mL), trifluoroacetic acid (575 mL, 7.50 mol) was added at 0 ° C, and the reaction was stirred at 25 ° C for 16 hours. After the reaction was completed, the crude product compound 4-(4-fluorophenyl)-3-oxobutanoic acid (231 g) was obtained as a white solid by vacuum concentration. LCMS (ESI): [MH] - = 194.8; 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.26-7.15 (m, 2H), 7.11-7.01 (m, 2H), 3.85 (s, 2H), 3.56 (s, 2H)
第五步:將4-(4-氟苯基)-3-氧代丁酸(231 g,1.18 mol)溶於三氟甲磺酸(1230 mL,13.9 mol),反應在25 oC攪拌24小時。慢慢加入0 oC的冰水中(10 L),反應液用乙酸乙酯(5 L * 3)萃取。合併的有機相用水(2 L)和飽和食鹽水洗(2 L)洗滌,用硫酸鈉乾燥,過濾,濾液減壓旋轉乾燥,殘留物用快速管柱層析純化(矽膠,0-20%梯度的乙酸乙酯/石油醚)得到化合物7-氟萘-1,3-二醇(89 g,0.5 mol,4步產率: 38%),為紅色油狀液體。LCMS (ESI): [M+H] += 179.1; 1H NMR (400 MHz, DMSO- d 6) δ ppm 10.26 (s, 1H), 9.55 (s, 1H), 7.67-7.51 (m, 2H), 7.27-7.17 (m, 1H), 6.64 (d, J= 2.0 Hz, 1H), 6.55 (d, J= 1.8 Hz, 1H). Step 5: Dissolve 4-(4-fluorophenyl)-3-oxobutanoic acid (231 g, 1.18 mol) in trifluoromethanesulfonic acid (1230 mL, 13.9 mol) and stir at 25 ° C for 24 hours. Slowly add 0 ° C ice water (10 L), and extract the reaction solution with ethyl acetate (5 L * 3). Wash the combined organic phase with water (2 L) and saturated salt water (2 L), dry with sodium sulfate, filter, and rotate the filtrate under reduced pressure to dry. The residue is purified by flash column chromatography (silica gel, 0-20% gradient ethyl acetate/petroleum ether) to obtain compound 7-fluoronaphthalene-1,3-diol (89 g, 0.5 mol, 4-step yield: 38%), which is a red oily liquid. LCMS (ESI): [M+H] + = 179.1; 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 10.26 (s, 1H), 9.55 (s, 1H), 7.67-7.51 (m, 2H), 7.27-7.17 (m, 1H), 6.64 (d, J = 2.0 Hz, 1H), 6.55 (d, J = 1.8 Hz, 1H).
第六步:將7-氟萘-1,3-二醇(88g,494mmol),(溴乙炔基)三異丙基矽烷(155g,592 mmol)和乙酸鉀(98g,1.0 mol)混合於二氧六環(640 mL)中,氮氣下加入二氯(對甲基異丙基苯基)釕(II)二聚體(30.2g,49.6 mmol),反應液110 oC攪拌2小時。過濾,濾液旋轉乾燥,殘留物用快速管柱層析純化(矽膠,0-20%梯度的乙酸乙酯/石油醚)得到7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1,3-二醇(123 g,343 mmol,產率:69%)。LCMS (ESI): [M-H] -= 357.0; 1H NMR (400 MHz, CDCl 3) δ ppm 10.06 (s, 1H), 9.18 (s, 1H), 7.60 (dd, J= 5.6, 9.2 Hz, 1H), 7.22-7.13 (m, 1H), 6.76 (d, J= 2.3 Hz, 1H), 6.68 (d, J= 2.0 Hz, 1H), 1.23-1.16 (m, 21H). Step 6: 7-fluoronaphthalene-1,3-diol (88 g, 494 mmol), (bromoethynyl)triisopropylsilane (155 g, 592 mmol) and potassium acetate (98 g, 1.0 mol) were mixed in dioxane (640 mL), and dichloro(p-methylisopropylphenyl)ruthenium(II) dimer (30.2 g, 49.6 mmol) was added under nitrogen. The reaction solution was stirred at 110 ° C for 2 hours. Filter, the filtrate was rotary dried, and the residue was purified by flash column chromatography (silica gel, 0-20% gradient ethyl acetate/petroleum ether) to obtain 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (123 g, 343 mmol, yield: 69%). LCMS (ESI): [MH] - = 357.0; 1 H NMR (400 MHz, CDCl 3 ) δ ppm 10.06 (s, 1H), 9.18 (s, 1H), 7.60 (dd, J = 5.6, 9.2 Hz, 1H), 7.22-7.13 (m, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 1.23-1.16 (m, 21H).
第七步:將7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1,3-二醇(123 g,343 mmol)溶於二氯甲烷(1230 mL)中,降到0 oC,慢慢往反應液中加入二異丙基乙胺(180 mL,1030 mmol)和氯甲基甲醚(36.5 g,454 mmol),反應在20 oC攪拌16小時。反應完後用水(1000 mL)淬滅,然後用二氯甲烷(500 mL *2)萃取,合併有機相,旋轉乾燥,殘留物用快速管柱層析純化(矽膠,0-5%梯度的乙酸乙酯/石油醚)得到7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-醇(48 g,119 mmol,產率:35%)。LCMS (ESI): [M-H] -= 401.1; 1H NMR (400 MHz, CDCl 3) δ ppm 9.19-9.08 (m, 1H), 7.71-7.63 (m, 1H), 7.24-7.16 (m, 1H), 6.98 (d, J= 2.5 Hz, 1H), 6.82 (d, J= 2.0 Hz, 1H), 5.27 (s, 2H), 3.52 (s, 3H), 1.22-1.19 (m, 21H). Step 7: Dissolve 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (123 g, 343 mmol) in dichloromethane (1230 mL), cool to 0 ° C, slowly add diisopropylethylamine (180 mL, 1030 mmol) and chloromethyl methyl ether (36.5 g, 454 mmol) to the reaction solution, and stir the reaction at 20 ° C for 16 hours. After the reaction, the mixture was quenched with water (1000 mL), and then extracted with dichloromethane (500 mL *2). The organic phases were combined and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to obtain 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (48 g, 119 mmol, yield: 35%). LCMS (ESI): [MH] - = 401.1; 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.19-9.08 (m, 1H), 7.71-7.63 (m, 1H), 7.24-7.16 (m, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 5.27 (s, 2H), 3.52 (s, 3H), 1.22-1.19 (m, 21H).
第八步:將7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-醇(48.0 g,119 mmol),二異丙基乙胺(62 mL,357 mmol),4-二甲胺基吡啶(3.00 g,24.5 mmol)溶於二氯甲烷(480 mL),0 oC下慢慢加入特戊醯氯(29 mL,238 mmol),反應液在20 oC下攪拌2小時。向反應液中加入二氯甲烷(360 mL)和水(360 mL),分液,水相用二氯甲烷(200 mL * 2)萃取,合併有機相,用硫酸鈉乾燥,過濾,濾液旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-5%梯度的乙酸乙酯/石油醚)得到化合物7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基特戊酸酯(50 g,102 mmol,產率86%),為黃色油狀液體。 1HNMR (400 MHz, CDCl 3) δ ppm 7.60 (dd, J= 5.5, 9.1 Hz, 1H), 7.22-7.20 (m, 1H), 7.19-7.13 (m, 1H), 6.76 (d, J= 2.3 Hz, 1H), 5.18 (s, 2H), 3.45 (s, 3H), 1.39 (s, 9H), 1.11-1.05 (m, 21H). Step 8: Dissolve 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (48.0 g, 119 mmol), diisopropylethylamine (62 mL, 357 mmol), and 4-dimethylaminopyridine (3.00 g, 24.5 mmol) in dichloromethane (480 mL), slowly add trivaleryl chloride (29 mL, 238 mmol) at 0 o C, and stir the reaction solution at 20 o C for 2 hours. Add dichloromethane (360 mL) and water (360 mL) to the reaction solution, separate the liquids, extract the aqueous phase with dichloromethane (200 mL * 2), combine the organic phases, dry with sodium sulfate, filter, and spin dry the filtrate. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to give compound 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl pivalate (50 g, 102 mmol, yield 86%) as a yellow oily liquid. 1 HNMR (400 MHz, CDCl 3 ) δ ppm 7.60 (dd, J = 5.5, 9.1 Hz, 1H), 7.22-7.20 (m, 1H), 7.19-7.13 (m, 1H), 6.76 (d, J = 2.3 Hz, 1H), 5.18 (s, 2H), 3.45 (s, 3H), 1.39 (s, 9H), 1.11-1.05 (m, 21H).
第九步:將7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基特戊酸酯(50 g,102 mmol)溶於N,N-二甲基甲醯胺(916 mL),加入氟化銫(167 g,1099 mmol),反應在20 oC攪拌3小時。反應完後,減壓濃縮除去溶劑。將粗產物溶於乙酸乙酯(1000 mL)和水(2000 mL)中,分離出有機相,水相用乙酸乙酯(1000 mL * 2)萃取。合併有機相並用飽和食鹽水(1000 mL)洗滌,有機相用硫酸鈉乾燥,過濾,濾液旋轉乾燥,殘留物用快速管柱層析純化(矽膠,0-5%梯度的乙酸乙酯/石油醚)得到化合物8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基特戊酸酯(19 g,57.5 mmol,產率56%),為黃色油狀液體。LCMS (ESI): [M+H] += 331.1; 1HNMR (400 MHz, CDCl 3) δ ppm 7.66 (dd, J= 5.6, 9.1 Hz, 1H), 7.24 (d, J= 2.4 Hz, 1H), 7.20-7.16 (m, 1H), 6.79 (d, J= 2.1 Hz, 1H), 5.19 (s, 2H), 3.50 (s, 1H), 3.43 (s, 3H), 0.99 (s, 9H). Step 9 : Dissolve 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl pivalate (50 g, 102 mmol) in N,N-dimethylformamide (916 mL), add cesium fluoride (167 g, 1099 mmol), and stir at 20 ° C for 3 hours. After the reaction, reduce the pressure and concentrate to remove the solvent. Dissolve the crude product in ethyl acetate (1000 mL) and water (2000 mL), separate the organic phase, and extract the aqueous phase with ethyl acetate (1000 mL * 2). The organic phases were combined and washed with saturated brine (1000 mL), dried over sodium sulfate, filtered, and the filtrate was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to obtain compound 8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl pivalate (19 g, 57.5 mmol, yield 56%) as a yellow oily liquid. LCMS (ESI): [M+H] + = 331.1; 1 HNMR (400 MHz, CDCl 3 ) δ ppm 7.66 (dd, J = 5.6, 9.1 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.20-7.16 (m, 1H), 6.79 (d, J = 2.1 Hz, 1H), 5.19 (s, 2H), 3.50 (s, 1H), 3.43 (s, 3H), 0.99 (s, 9H).
第十步:將8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基特戊酸酯(19 g,57.5 mmol)溶於甲醇(200 mL)中,在氮氣下加入鈀碳(含量10%,2.00 g),反應液用氫氣置換3次。反應液在20 oC下用氫氣球氫化2小時。反應完後過濾,濾液旋轉乾燥得到粗產物化合物8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基特戊酸酯(16 g)。LCMS (ESI): [M+H] +=335.1; 1H NMR (400 MHz, CDCl 3) δ ppm 7.51 (dd, J= 5.6, 9.0 Hz, 1H), 7.23 (d, J= 2.5 Hz, 1H), 7.16-7.09 (m, 1H), 6.70 (d, J= 2.4 Hz, 1H), 5.18 (s, 2H), 3.43 (s, 3H), 3.04 (q, J= 7.5 Hz, 2H), 1.38 (s, 9H), 1.18-1.12 (m, 3H). Step 10: Dissolve 8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl pivalate (19 g, 57.5 mmol) in methanol (200 mL), add palladium carbon (content 10%, 2.00 g) under nitrogen, and replace the reaction solution with hydrogen three times. The reaction solution is hydrogenated with a hydrogen balloon at 20 o C for 2 hours. After the reaction is completed, filter and the filtrate is rotary dried to obtain the crude product compound 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl pivalate (16 g). LCMS (ESI): [M+H] + =335.1; 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.51 (dd, J = 5.6, 9.0 Hz, 1H), 7.23 (d, J = 2.5 Hz, 1H), 7.16-7.09 (m, 1H), 6.70 (d, J = 2.4 Hz, 1H), 5.18 (s, 2H), 3.43 (s, 3H), 3.04 (q, J = 7.5 Hz, 2H), 1.38 (s, 9H), 1.18-1.12 (m, 3H).
第十一步:將8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基特戊酸酯(16 g,47.8 mmol)溶於甲醇(250 mL),加入氫氧化鉀(8.50 g, 151 mmol),反應在20 oC攪拌2小時。反應完成後將反應液用稀鹽酸(1 M)在0 oC下調到pH為6,用乙酸乙酯(200 mL*3)萃取,合併有機相,用飽和食鹽水(100 ml)洗滌,硫酸鈉乾燥,過濾,濾液旋轉乾燥,殘留物用快速管柱層析純化(矽膠,0-5%梯度的乙酸乙酯/石油醚)得到化合物8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-醇(11 g,43.9 mmol,產率92%),為黃色固體。LCMS (ESI): [M+H] += 251.1; 1H NMR (400 MHz, CDCl 3) δ ppm 7.50 (dd, J= 5.6, 8.9 Hz, 1H), 7.19 (t, J= 9.2 Hz, 1H), 7.00 (d, J= 2.3 Hz, 1H), 6.59 (d, J= 2.0 Hz, 1H), 5.55-5.45 (m, 1H), 5.30-5.24 (m, 2H), 3.58-3.48 (m, 3H), 3.35 (dd, J= 3.0, 7.3 Hz, 2H), 1.35-1.26 (m, 3H). Step 11: Dissolve 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl pivalate (16 g, 47.8 mmol) in methanol (250 mL), add potassium hydroxide (8.50 g, 151 mmol), and stir the reaction at 20 ° C for 2 hours. After the reaction is completed, the reaction solution is adjusted to pH 6 with dilute hydrochloric acid (1 M) at 0 ° C, extracted with ethyl acetate (200 mL*3), the organic phases are combined, washed with saturated brine (100 ml), dried over sodium sulfate, filtered, the filtrate is rotary dried, and the residue is purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to obtain compound 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-ol (11 g, 43.9 mmol, yield 92%) as a yellow solid. LCMS (ESI): [M+H] + = 251.1; 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.50 (dd, J = 5.6, 8.9 Hz, 1H), 7.19 (t, J = 9.2 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 5.55-5.45 (m, 1H), 5.30-5.24 (m, 2H), 3.58-3.48 (m, 3H), 3.35 (dd, J = 3.0, 7.3 Hz, 2H), 1.35-1.26 (m, 3H).
第十二步:將8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-醇(11 g,43.9mmol),二異丙基乙胺(23 mL, 132 mmol)溶於二氯甲烷(220 mL),-40 oC慢慢滴加三氟甲磺酸酐(11 mL,67.1 mmol),反應在-40 oC攪拌2小時。反應結束後用冰水(200 mL)淬滅反應,用二氯甲烷(200 mL * 2)萃取。合併有機相,用飽和食鹽水(100 mL)洗滌,硫酸鈉乾燥,過濾,濾液旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-5%梯度的乙酸乙酯/石油醚)得到化合物8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基三氟甲磺酸酯(15 g,39.2 mmol,產率89%),為黃色油狀液體。LCMS (ESI): [M+H] += 382.9; 1H NMR (400 MHz, CDCl 3) δ ppm 7.64 (dd, J= 5.6, 8.9 Hz, 1H), 7.45 (d, J= 2.5 Hz, 1H), 7.39 (d, J= 2.3 Hz, 1H), 7.34-7.27 (m, 1H), 5.30 (s, 2H), 3.59-3.47 (m, 3H), 3.27 (dq, J= 2.8, 7.4 Hz, 2H), 1.26 (t, J= 7.4 Hz, 3H). Step 12: Dissolve 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-ol (11 g, 43.9 mmol) and diisopropylethylamine (23 mL, 132 mmol) in dichloromethane (220 mL), slowly add trifluoromethanesulfonic anhydride (11 mL, 67.1 mmol) at -40 ° C, and stir at -40 ° C for 2 hours. After the reaction is completed, quench the reaction with ice water (200 mL) and extract with dichloromethane (200 mL * 2). Combine the organic phases, wash with saturated brine (100 mL), dry with sodium sulfate, filter, and spin dry the filtrate. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to give compound 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (15 g, 39.2 mmol, yield 89%) as a yellow oily liquid. LCMS (ESI): [M+H] + = 382.9; 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.64 (dd, J = 5.6, 8.9 Hz, 1H), 7.45 (d, J = 2.5 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.34-7.27 (m, 1H), 5.30 (s, 2H), 3.59-3.47 (m, 3H), 3.27 (dq, J = 2.8, 7.4 Hz, 2H), 1.26 (t, J = 7.4 Hz, 3H).
第十三步:將8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基三氟甲磺酸酯(15 g,39.2 mmol),雙聯嚬哪醇硼酸酯(20 g,78.7 mmol),乙酸鉀(12 g,122 mmol)混合於甲苯(380 mL)中,氮氣下加入[1,1-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷(3.20 g,3.92 mmol),反應升到130 oC攪拌16小時。反應液過濾,濾液旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-5%梯度的乙酸乙酯/石油醚)得到黃色油狀粗產物,粗產物用快速管柱層析純化(C18,0-100%梯度的乙腈/純水)得到化合物2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(2.20 g,6.11 mmol,產率:16%),為黃色固體。LCMS (ESI): [M+H] += 361.0; 1HNMR (400 MHz, CDCl 3) δ ppm 7.49 (dd, J= 5.9, 8.9 Hz, 1H), 7.38-7.27 (m, 2H), 7.12 (t, J= 9.3 Hz, 1H), 5.24-5.16 (m, 2H), 3.49-3.38 (m, 3H), 3.11-2.97 (m, 2H), 1.42-1.33 (m, 12H), 1.19 (t, J= 7.5 Hz, 3H). 中間體 A2 :((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)萘-1-基)乙炔基)三異丙基矽 Step 13: 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (15 g, 39.2 mmol), bis(xanaphthene) boronate (20 g, 78.7 mmol), potassium acetate (12 g, 122 mmol) were mixed in toluene (380 mL), and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane (3.20 g, 3.92 mmol) was added under nitrogen. The reaction temperature was raised to 130 ° C and stirred for 16 hours. The reaction solution was filtered and the filtrate was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to give a yellow oily crude product. The crude product was purified by flash column chromatography (C18, 0-100% gradient of acetonitrile/pure water) to give compound 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.20 g, 6.11 mmol, yield: 16%) as a yellow solid. LCMS (ESI): [M+H] + = 361.0; 1 HNMR (400 MHz, CDCl 3 ) δ ppm 7.49 (dd, J = 5.9, 8.9 Hz, 1H), 7.38-7.27 (m, 2H), 7.12 (t, J = 9.3 Hz, 1H), 5.24-5.16 (m, 2H), 3.49-3.38 (m, 3H), 3.11-2.97 (m, 2H), 1.42-1.33 (m, 12H), 1.19 (t, J = 7.5 Hz, 3H). Intermediate A2 : ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane
第一步:在-40 oC下,向7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-醇(4.93 g,12.2 mmol)和二異丙基乙胺(7 mL,40.0 mmol)的二氯甲烷(75 mL)溶液中加入三氟甲磺酸酐(5.19 g,18.4 mmol)。溶液在-40 oC攪拌1小時,濃縮溶液。殘餘物透過快速管柱層析(矽膠,0-5%梯度乙酸乙酯/石油醚)純化,得到黃色油狀化合物7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基三氟甲磺酸酯(純度90%,6 g,10.1 mmol,產率82%)。 1H NMR (400 MHz, DMSO- d 6) δ = 8.10 (dd, J= 5.7, 9.2 Hz, 1H), 7.76 (d, J= 2.4 Hz, 1H), 7.63 (t, J= 9.0 Hz, 1H), 7.49 (d, J= 2.2 Hz, 1H), 5.36 (s, 2H), 3.43-3.41 (m, 3H), 1.15-1.04 (m, 21H). Step 1: Add trifluoromethanesulfonic anhydride (5.19 g, 18.4 mmol) to a solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (4.93 g, 12.2 mmol) and diisopropylethylamine (7 mL, 40.0 mmol) in dichloromethane (75 mL) at -40 ° C. Stir the solution at -40 ° C for 1 hour and concentrate the solution. The residue was purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to give a yellow oily compound 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (purity 90%, 6 g, 10.1 mmol, yield 82%). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.10 (dd, J = 5.7, 9.2 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.63 (t, J = 9.0 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 5.36 (s, 2H), 3.43-3.41 (m, 3H), 1.15-1.04 (m, 21H).
第二步:在25 oC的氮氣氛圍下向7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基三氟甲磺酸酯)純度90%,6 g,10.1 mmol)和雙聯頻哪醇硼酸酯(5.70 g,22.4 mmol)的甲苯(60 mL)溶液中加入醋酸鉀(3.31 g,33.7 mmol)和1,1-雙(二苯基磷)二茂鐵氯化鈀(0.92 g,1.13 mmol)。將懸浮液在130 oC下攪拌3小時。過濾懸浮液並濃縮,得到黑色粗產物。粗產物透過快速管柱層析(矽膠,0-10%梯度乙酸乙酯/石油醚)純化得到白色固體化合物 ((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(2.10 g,4.10 mmol,產率41%)。LCMS (ESI): [M+H] += 513.0. 中間體 A3 :((2-氟-8-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)萘-1-基)乙炔基)三異丙基矽烷 Step 2: Potassium acetate (3.31 g, 33.7 mmol ) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (0.92 g, 1.13 mmol) were added to a toluene (60 mL) solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate) (purity 90%, 6 g, 10.1 mmol) and bispinacol borate (5.70 g, 22.4 mmol) at 25 °C under nitrogen atmosphere. The suspension was stirred at 130 ° C for 3 hours. The suspension was filtered and concentrated to obtain a black crude product. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to give a white solid compound ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.10 g, 4.10 mmol, yield 41%). LCMS (ESI): [M+H] + = 513.0. Intermediate A3 : ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane
第一步:將化合物7-氟-1-四氫萘酮(18.0 g,109 mmol)溶於乙酸(300 mL)和氫溴酸(33% 的乙酸溶液,2.5 mL),0 oC下加入液態溴(19.2 g,120 mmol)溶於乙酸(20 mL)。反應在25 oC下攪拌3小時。反應液用二氯甲烷(300 mL)稀釋,用水洗滌(70 mL*3),硫酸鈉乾燥,過濾,濾液減壓濃縮。粗產物溶於二甲基甲醯胺(200 mL),加入溴化鋰(16.2 g,186 mmol)和碳酸鋰(13.7 g,186 mmol),反應在160 oC下攪拌3.5小時。反應液用乙酸乙酯(500 mL)稀釋,用工業鹽水(500 mL*2),硫酸鈉乾燥,過濾,濾液減壓濃縮。殘留物用快速管柱層析純化(矽膠,0-3%梯度的乙酸乙酯/石油醚)得到黃色固體7-氟萘-1-醇(14.3 g,88 mmol,產率80%)。LCMS (ESI): [M+H] +=163.1. 1H NMR (400MHz, CDCl 3) δ ppm 7.89-7.76 (m, 2H), 7.46 (d, J= 8.3 Hz, 1H), 7.34-7.24 (m, 2H), 6.86 (d, J= 7.5 Hz, 1H), 5.41-5.30 (m, 1H). Step 1: Dissolve the compound 7-fluoro-1-tetralone (18.0 g, 109 mmol) in acetic acid (300 mL) and hydrobromic acid (33% acetic acid solution, 2.5 mL), add liquid bromine (19.2 g, 120 mmol) dissolved in acetic acid (20 mL) at 0 o C. Stir the reaction at 25 o C for 3 hours. Dilute the reaction solution with dichloromethane (300 mL), wash with water (70 mL*3), dry with sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is dissolved in dimethylformamide (200 mL), lithium bromide (16.2 g, 186 mmol) and lithium carbonate (13.7 g, 186 mmol) are added, and the reaction is stirred at 160 o C for 3.5 hours. The reaction solution was diluted with ethyl acetate (500 mL), dried with industrial brine (500 mL*2), sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-3% gradient of ethyl acetate/petroleum ether) to obtain yellow solid 7-fluoronaphthalene-1-ol (14.3 g, 88 mmol, yield 80%). LCMS (ESI): [M+H] + =163.1. 1H NMR (400MHz, CDCl 3 ) δ ppm 7.89-7.76 (m, 2H), 7.46 (d, J = 8.3 Hz, 1H), 7.34-7.24 (m, 2H), 6.86 (d, J = 7.5 Hz, 1H), 5.41-5.30 (m, 1H).
第二步:將7-氟萘-1-醇(14.3 g,88.2 mmol),(溴乙炔基)三異丙基矽烷(27.6 g,105 mmol),乙酸鈉(1.45 g,17.6 mmol)和碳酸鉀(12.2 g,88.2 mmol)溶於二氯乙烷(192 mL),氮氣下加入二氯(對甲基異丙基苯基)釕(II)二聚體(8.10 g,13.2 mmol),反應液在50 oC攪拌16小時。反應完後過濾,濾液旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0~2%梯度的乙酸乙酯/石油醚)得到7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-醇(28.5 g,83.2 mmol,產率94%)。LCMS (ESI): [M+H] +=343.3. 1H NMR (400MHz, CDCl 3) δ ppm 9.11 (s, 1H), 7.80 (dd, J= 5.8, 9.3 Hz, 1H), 7.42-7.35 (m, 2H), 7.24 (t, J= 8.8 Hz, 1H), 7.08-7.01 (m, 1H), 1.24-1.18 (m, 21H). Step 2 : Dissolve 7-fluoronaphthalene-1-ol (14.3 g, 88.2 mmol), (bromoethynyl)triisopropylsilane (27.6 g, 105 mmol), sodium acetate (1.45 g, 17.6 mmol) and potassium carbonate (12.2 g, 88.2 mmol) in dichloroethane (192 mL), add dichloro(p-methylisopropylphenyl)ruthenium (II) dimer (8.10 g, 13.2 mmol) under nitrogen, and stir the reaction solution at 50 ° C for 16 hours. After the reaction, filter and spin dry the filtrate. The residue was purified by flash column chromatography (silica gel, 0-2% gradient of ethyl acetate/petroleum ether) to give 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (28.5 g, 83.2 mmol, 94% yield). LCMS (ESI): [M+H] + =343.3. 1H NMR (400MHz, CDCl 3 ) δ ppm 9.11 (s, 1H), 7.80 (dd, J = 5.8, 9.3 Hz, 1H), 7.42-7.35 (m, 2H), 7.24 (t, J = 8.8 Hz, 1H), 7.08-7.01 (m, 1H), 1.24-1.18 (m, 21H).
第三步:將7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-醇(28.5 g,83.2 mmol),二異丙基乙胺(59.0 mL,338 mmol)溶於二氯甲烷(500 mL),-40 oC慢慢滴加三氟甲磺酸酐(35.8 g,127 mmol),反應在-40 oC攪拌2小時。反應完後用冰水(500 mL)淬滅,用DCM(200 mL*2)萃取。合併有機相用飽和食鹽水(100 mL)洗,硫酸鈉乾燥,過濾,濾液減壓濃縮。殘留物用快速管柱層析純化(矽膠,0-5%梯度的乙酸乙酯/石油醚)得到黃色油狀7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基三氟甲磺酸酯(33 g,69.6 mmol,產率84%)。1H NMR (400MHz, CDCl 3) δ ppm 7.92-7.77 (m, 2H), 7.60-7.55 (m, 1H), 7.51-7.45 (m, 1H), 7.39 (t, J=8.8 Hz, 1H), 1.28-1.16 (m, 21H). Step 3: Dissolve 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (28.5 g, 83.2 mmol) and diisopropylethylamine (59.0 mL, 338 mmol) in dichloromethane (500 mL), slowly add trifluoromethanesulfonic anhydride (35.8 g, 127 mmol) at -40 o C, and stir for 2 hours at -40 o C. After the reaction, quench with ice water (500 mL) and extract with DCM (200 mL*2). The combined organic phases are washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to give 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (33 g, 69.6 mmol, 84% yield) as a yellow oil. 1H NMR (400MHz, CDCl 3 ) δ ppm 7.92-7.77 (m, 2H), 7.60-7.55 (m, 1H), 7.51-7.45 (m, 1H), 7.39 (t, J=8.8 Hz, 1H), 1.28-1.16 (m, 21H).
第四步:將7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基三氟甲磺酸酯(5.20 g,10.9 mmol),雙聯嚬哪醇硼酸酯(4.17 g,16.4 mmol),乙酸鉀(6.18 g,21.9 mmol)溶於甲苯(100 mL),氮氣下加入[1,1-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷(0.89 g,1.10 mmol),反應升到130 oC攪拌3小時。反應完過濾,濾液旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-5%梯度的四氫呋喃/石油醚)得到黃色固體((2-氟-8-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(1.77 g,3.91 mmol,產率35%)。LCMS (ESI): [M+H] +=453.3. 1H NMR (400MHz, CDCl 3) δ ppm 7.89-7.74 (m, 3H), 7.44 (dd, J= 7.0, 8.1 Hz, 1H), 7.28-7.25 (m, 1H), 1.46 (s, 12H), 1.25-1.12 (m, 21H). 中間體 A4 :(1R,5S)-叔丁基3-(7-氯-8-氟-2-(((2R,7aS)-2-氟六氫-1H-吡咯嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯 Step 4 : Dissolve 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (5.20 g, 10.9 mmol), bis(triisopropylsilyl)ethynyl)naphthalen-1-yl borate (4.17 g, 16.4 mmol), and potassium acetate (6.18 g, 21.9 mmol) in toluene (100 mL). Add [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium in dichloromethane (0.89 g, 1.10 mmol) under nitrogen, and stir at 130 ° C for 3 hours. After the reaction, filter and spin dry the filtrate. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of tetrahydrofuran/petroleum ether) to give yellow solid ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.77 g, 3.91 mmol, 35% yield). LCMS (ESI): [M+H] + =453.3. 1H NMR (400MHz, CDCl 3 ) δ ppm 7.89-7.74 (m, 3H), 7.44 (dd, J = 7.0, 8.1 Hz, 1H), 7.28-7.25 (m, 1H), 1.46 (s, 12H), 1.25-1.12 (m, 21H). Intermediate A4 : (1R,5S)-tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
第一步:在-40 oC下向化合物2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(4.00 g, 15.84 mmol)加入二異丙基乙胺(4 mL,23.77 mmol),二氯甲烷溶液(140 mL)和化合物(1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(3.87 g, 18.22 mmol)溶液並在-40 oC攪拌1小時。將混合物用水(20 mL) 稀釋並用乙酸乙酯(20 mL*3)萃取,有機相減壓濃縮得到黃色色固體(1R,5S)-3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(純度80%,8 g,14.94 mmol,產率94%)。LCMS (ESI): [M+H] += 428.1。 1H NMR (400 MHz, CDCl 3- d4) δ = 8.78 (s, 1H), 4.52-4.27 (m, 4H), 3.60 (dt, J = 6.6, 13.3 Hz, 2H), 1.98-1.82 (m, 4H), 1.47-1.43 (m, 9H) Step 1 : Add diisopropylethylamine (4 mL, 23.77 mmol), dichloromethane solution (140 mL) and ( 1R ,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.87 g, 18.22 mmol) solution to 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (4.00 g, 15.84 mmol) at -40 °C and stir at -40 ° C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3). The organic phase was concentrated under reduced pressure to give yellow solid (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (purity 80%, 8 g, 14.94 mmol, yield 94%). LCMS (ESI): [M+H] + = 428.1. 1 H NMR (400 MHz, CDCl 3 - d 4) δ = 8.78 (s, 1H), 4.52-4.27 (m, 4H), 3.60 (dt, J = 6.6, 13.3 Hz, 2H), 1.98-1.82 (m, 4H), 1.47-1.43 (m, 9H)
第二步:向化合物(1R,5S)-3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(純度80%,1.50 g,2.80 mmol)加入((2R,7aS)-2-氟六氫-1H-吡咯嗪-7a-基)甲醇(0.56 g, 3.50 mmol),在25 oC下加入二異丙基乙胺(2 mL, 10.51 mmol)和二氧六環(15 mL)。溶液在80 oC攪拌16小時。反應液用水(5 mL)稀釋並用乙酸乙酯(5 mL*3) 萃取,有機相減壓濃縮,殘餘物透過快速管柱層析純化(矽膠,0-10%二氯甲烷/甲醇)得到黃色固體化合物(1R,5S)-叔丁基3-(7-氯-8-氟-2-(((2R,7aS)-2-氟六氫-1H-吡咯嗪-7a-基)甲氧基)吡啶并[4,3- d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(純度60%,620 mg,0.68 mmol,產率19%)。LCMS (ESI): [M+H] += 551.2. 1H NMR (400 MHz, CDCl 3- d4) δ = 8.65 (s, 1H), 4.25-4.20 (m, 1H), 3.96 (d, J = 13.0 Hz, 1H), 3.69-3.65 (m, 1H), 3.55-3.48 (m, 2H), 3.45-3.35 (m, 1H), 3.19-3.09 (m, 2H), 2.99-2.91 (m, 1H), 2.66-2.49 (m, 1H), 2.31-2.19 (m, 3H), 1.93-1.84 (m, 4H), 1.78 (td, J = 3.2, 6.7 Hz, 2H), 1.62 (br d, J = 7.8 Hz, 3H), 1.49-1.47 (m, 1H), 1.45 (s, 9H) 中間體 A5 :叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯 Step 2 : Add ((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methanol (0.56 g, 3.50 mmol) to the compound (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (purity 80%, 1.50 g, 2.80 mmol), and add diisopropylethylamine (2 mL, 10.51 mmol) and dioxane (15 mL) at 25 ° C. The solution was stirred at 80 ° C for 16 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3). The organic phase was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 0-10% dichloromethane/methanol) to obtain a yellow solid compound (1R,5S)-tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 60%, 620 mg, 0.68 mmol, yield 19%). LCMS (ESI): [M+H] + = 551.2. 1 H NMR (400 MHz, CDCl 3 - d 4) δ = 8.65 (s, 1H), 4.25-4.20 (m, 1H), 3.96 (d, J = 13.0 Hz, 1H), 3.69-3.65 (m, 1H), 3.55-3.48 (m, 2H), 3.45-3.35 (m, 1H), 3.19-3.09 (m, 2H), 2.99-2.91 (m, 1H), 2.66-2.49 (m, 1H), 2.31-2.19 (m, 3H), 1.93-1.84 (m, 4H), 1.78 (td, J = 3.2, 6.7 Hz, 2H), 1.62 (br d, J = 7.8 Hz, 3H), 1.49-1.47 (m, 1H), 1.45 (s, 9H) Intermediate A5 : tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
第一步:在-40 oC下,向化合物2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(5.00 g,19.8 mmol)和二異丙基乙胺(4.2 mL,23.7 mmol)的二氯甲烷溶液(140 mL)中加入化合物 (1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(4.20 g,19.8 mmol)溶液在-40 oC攪拌1小時。將混合物用水(20 mL)稀釋並用乙酸乙酯(20 mL * 3)萃取,有機相減壓濃縮得到粗產物化合物 (1R,5S)-3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(4.50 g),為黃色固體。LCMS (ESI): [M+H] += 428.1. 1H NMR (400 MHz, CDCl 3) δ ppm 8.87 (s, 1H), 4.67-4.30 (m, 4H), 3.93-3.59 (m, 2H), 2.08-1.94 (m, 2H), 1.69 (m, 2H), 1.54 (s, 9H). Step 1 : To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (5.00 g, 19.8 mmol) and diisopropylethylamine (4.2 mL, 23.7 mmol) in dichloromethane (140 mL) was added a solution of ( 1R ,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4.20 g, 19.8 mmol) at -40 °C and stirred at -40 ° C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL * 3). The organic phase was concentrated under reduced pressure to give a crude product, compound (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4.50 g), as a yellow solid. LCMS (ESI): [M+H] + = 428.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.87 (s, 1H), 4.67-4.30 (m, 4H), 3.93-3.59 (m, 2H), 2.08-1.94 (m, 2H), 1.69 (m, 2H), 1.54 (s, 9H).
第二步:向化合物 (1R,5S)-3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(8.00 g,18.6 mmol)和2,2,2-三氟乙醇(18.6 g,186.7 mmol)的混合物中加入二異丙基乙胺(5 mL,28.0 mmol)。溶液在80 oC攪拌16小時。反應液用水(5 mL)稀釋並用乙酸乙酯(5 mL * 3)萃取,有機相減壓濃縮,殘餘物透過快速管柱層析純化(矽膠,0-10%甲醇/二氯甲烷)得到黃色固體化合物叔丁基(1R,5S)-3-(7-氯-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(9.00 g,18.3 mmol,產率98%)。LCMS (ESI): [M+H] += 492.0. Step 2 : Add diisopropylethylamine (5 mL, 28.0 mmol) to a mixture of (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (8.00 g, 18.6 mmol) and 2,2,2-trifluoroethanol (18.6 g, 186.7 mmol). The solution was stirred at 80 ° C for 16 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL * 3). The organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% methanol/dichloromethane) to obtain a yellow solid compound tert-butyl (1R, 5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.00 g, 18.3 mmol, yield 98%). LCMS (ESI): [M+H] + = 492.0.
第三步:在氮氣保護下,向化合物叔丁基(1R,5S)-3-(7-氯-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(9.00 g,18.3 mmol)和 ((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(10.7 g,20.9 mmol)的二氧六環(200 mL)溶液中加入碳酸銫溶液(1.5 M的水溶液,43 mL)和氯[(正丁基二(1-金剛烷基)膦)-2-(2-胺基聯苯)]鈀(II)(1.40 g,2.09 mmol)。將混合物在80 oC下攪拌3小時。反應液用水(200 mL)稀釋並用乙酸乙酯(200 mL*3)萃取,有機相用無水硫酸鎂乾燥,過濾,濾液減壓濃縮得到粗產物化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(19.2 g),為棕色固體。LCMS (ESI): [M+H] += 842.5. 中間體 A6 :叔丁基(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯 Step 3 : Under nitrogen protection, caesium carbonate solution (1.5 M aqueous solution, 43% HCl) was added to a solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.00 g, 18.3 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (10.7 g, 20.9 mmol) in dioxane (200 mL). mL) and chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (1.40 g, 2.09 mmol). The mixture was stirred at 80 ° C for 3 hours. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (200 mL*3). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (19.2 g) as a brown solid. LCMS (ESI): [M+H] + = 842.5. Intermediate A6 : tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
第一步:化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(19.2 g,22.9 mmol)的二甲基甲醯胺(250 mL)溶液中加入氟化銫(21.6 g,142.5 mmol)。混合物在25 oC下攪拌2小時。過濾反應液,收集濾液,用二甲基甲醯胺(3 mL *50)洗滌濾餅,濾液真空濃縮。殘餘物透過快速管柱層析純化(矽膠,0-10%乙酸乙酯/石油醚)得到棕色油狀化合物叔丁基(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(純度95%,8.50 g,11.7 mmol,產率51%)。LCMS (ESI): [M+H] += 686.3. Step 1 : Add cesium fluoride (21.6 g, 142.5 mmol) to a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (19.2 g, 22.9 mmol) in dimethylformamide (250 mL). Stir the mixture at 25 ° C for 2 hours. Filter the reaction solution, collect the filtrate, wash the filter cake with dimethylformamide (3 mL *50), and concentrate the filtrate in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% ethyl acetate/petroleum ether) to give a brown oily compound tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 95%, 8.50 g, 11.7 mmol, yield 51%). LCMS (ESI): [M+H] + = 686.3.
第二步:氮氣保護下,向叔丁基(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基) 吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(8.00 g, 11.6 mmol)的乙酸乙酯(200 mL)溶液中加入鈀碳(5%,4.00 g),反應系統用氫氣置換。將混合物在25 oC下攪拌16小時。過濾反應液並濃縮濾液,得到黃色油狀粗產物。粗產物透過快速管柱層析純化(矽膠,0-10%的甲醇/二氯甲烷)得到棕色固體化合物叔丁基(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(純度95%,4.20 g,5.79 mmol,產率50%)。LCMS (ESI): [M+H] += 689.9. 中間體 A7 :叔丁基(1R,5S)-3-(7-溴-6-碘-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯 Step 2 : Under nitrogen protection, palladium carbon (5%, 4.00 g) was added to a solution of tert-butyl (1R, 5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy) pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.00 g, 11.6 mmol) in ethyl acetate (200 mL), and the reaction system was replaced with hydrogen. The mixture was stirred at 25 ° C for 16 hours. The reaction solution was filtered and the filtrate was concentrated to obtain a yellow oily crude product. The crude product was purified by flash column chromatography (silica gel, 0-10% methanol/dichloromethane) to give a brown solid compound tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 95%, 4.20 g, 5.79 mmol, yield 50%). LCMS (ESI): [M+H] + = 689.9. Intermediate A7 : tert-butyl (1R,5S)-3-(7-bromo-6-iodo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
第一步:化合物2-胺基-4-溴-3-氟苯甲酸(25.0 g,107 mmol)溶於N,N-二甲基甲醯胺(100 mL),加入N-碘代丁二醯亞胺(36.0 g,160 mmol),混合物80 oC攪拌2小時。反應液冷卻至室溫後加入到水(3 L)中,室溫製漿1小時,過濾並用水(300 mL * 3)洗滌濾餅,濾餅真空乾燥得化合物2-胺基-4-溴-3-氟-5-碘苯甲酸(34.0 g,94 mmol,產率88%)。LCMS (ESI): [M+H] += 361.9. Step 1 : Compound 2-amino-4-bromo-3-fluorobenzoic acid (25.0 g, 107 mmol) was dissolved in N,N-dimethylformamide (100 mL), N-iodosuccinimide (36.0 g, 160 mmol) was added, and the mixture was stirred at 80 ° C for 2 hours. The reaction solution was cooled to room temperature and added to water (3 L), slurried at room temperature for 1 hour, filtered and washed with water (300 mL * 3), and the filter cake was vacuum dried to obtain compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (34.0 g, 94 mmol, yield 88%). LCMS (ESI): [M+H] + = 361.9.
第二步:化合物2-胺基-4-溴-3-氟-5-碘苯甲酸(30.0 g,83.3 mmol)和尿素(50.0 g,833 mmol)加入到反應瓶。反應系統升溫到200 oC反應4小時。冷卻到室溫,加入水(300 mL)升溫至80 oC製漿攪拌半小時,趁熱過濾,濾餅重複製漿過濾操作兩次,真空乾燥濾餅得7-溴-8-氟-6-碘喹唑啉-2,4-二羥基(26.7 g,69.3 mmol,產率83%)。LCMS (ESI): [M+H] += 387.0. Step 2 : Compound 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (30.0 g, 83.3 mmol) and urea (50.0 g, 833 mmol) were added to the reaction bottle. The reaction system was heated to 200 o C for 4 hours. After cooling to room temperature, water (300 mL) was added and the temperature was raised to 80 o C for slurrying and stirring for half an hour. The mixture was filtered while hot, and the filter cake was slurried and filtered twice. The filter cake was vacuum dried to obtain 7-bromo-8-fluoro-6-iodoquinazoline-2,4-dihydroxy (26.7 g, 69.3 mmol, yield 83%). LCMS (ESI): [M+H] + = 387.0.
第三步:將化合物7-溴-8-氟-6-碘喹唑啉-2,4-二醇(24.7 g,64.1 mmol)加入到氧氯化磷(300 mL)中,0 oC下加入二異丙基乙胺(40 mL,224 mmol),130 oC攪拌4小時。反應液減壓濃縮,殘留物加入到冰水(500 mL)中,二氯甲烷(500 mL * 3)萃取,有機相用無水硫酸鎂乾燥,過濾,濾液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-4%梯度的甲醇/二氯甲烷)得化合物7-溴-2,4-二氯-8-氟-6-碘喹唑啉(26.7 g,62 mmol,產率98%)。LCMS (ESI): [M+H] += 420.8. Step 3 : Add compound 7-bromo-8-fluoro-6-iodoquinazoline-2,4-diol (24.7 g, 64.1 mmol) to phosphorus oxychloride (300 mL), add diisopropylethylamine (40 mL, 224 mmol) at 0 ° C, and stir at 130 ° C for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was added to ice water (500 mL), extracted with dichloromethane (500 mL * 3), the organic phase was dried with anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-4% gradient methanol/dichloromethane) to obtain compound 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (26.7 g, 62 mmol, yield 98%). LCMS (ESI): [M+H] + = 420.8.
第四步:向化合物7-溴-2,4-二氯-8-氟-6-碘喹唑啉(10.0 g,23.7 mmol)的二氯甲烷(100 mL)溶液中,加入 (1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(5.54 g,26.1 mmol)和三乙胺(10 mL,71 mmol),反應液在20 oC攪拌2小時。反應液減壓濃縮,殘餘用快速管柱層析純化(矽膠,0-36%梯度的乙酸乙酯/石油醚)得化合物叔丁基(1R,5S)-3-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(3.60 g,5.93 mmol,產率25%)。LCMS (ESI): [M+H] += 599.0. Step 4 : To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (10.0 g, 23.7 mmol) in dichloromethane (100 mL) were added tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.54 g, 26.1 mmol) and triethylamine (10 mL, 71 mmol). The reaction solution was stirred at 20 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-36% gradient of ethyl acetate/petroleum ether) to obtain the compound tert-butyl (1R, 5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.60 g, 5.93 mmol, yield 25%). LCMS (ESI): [M+H] + = 599.0.
第五步:將化合物叔丁基(1R,5S)-3-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(3.00 g,5.00 mmol)加入到三氟乙醇(15 mL),加入二異丙基乙胺(1560 uL,8.94 mmol),反應液在50 oC攪拌3小時。反應液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-2%梯度的甲醇/二氯甲烷)得化合物叔丁基(1R,5S)-3-(7-溴-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(1.69 g,2.55 mmol,產率51%)。LCMS (ESI): [M+H] += 662.2. 中間體 A8 :叔丁基(1R,5S)-3-(7-溴-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯 Step 5 : Add the compound tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.00 g, 5.00 mmol) to trifluoroethanol (15 mL), add diisopropylethylamine (1560 uL, 8.94 mmol), and stir the reaction solution at 50 o C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-2% gradient of methanol/dichloromethane) to obtain the compound tert-butyl (1R, 5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.69 g, 2.55 mmol, yield 51%). LCMS (ESI): [M+H] + = 662.2. Intermediate A8 : tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
第一步:向化合物叔丁基 (1R,5S)-3-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(3.00 g,5.02 mmol)的N,N-二甲基乙醯胺(30 mL)溶液中,氮氣氛圍下加入氰化亞銅(4.50 g,50.2 mmol)和鋅粉(0.72 g,11.0 mmol),反應液在100 oC攪拌16小時。反應液減壓濃縮,殘餘用快速管柱層析純化(矽膠,0-15%梯度的乙酸乙酯/石油醚)得化合物 (1R,5S)-3-(7-溴-2-氯-6-氰基-8-氟喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(1.70 g,3.41 mmol,產率68%)。LCMS (ESI): [M+H] += 498.2. Step 1 : To a solution of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.00 g, 5.02 mmol) in N,N-dimethylacetamide (30 mL) were added cuprous cyanide (4.50 g, 50.2 mmol) and zinc powder (0.72 g, 11.0 mmol) under nitrogen atmosphere, and the reaction solution was stirred at 100 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-15% gradient of ethyl acetate/petroleum ether) to obtain the compound (1R,5S)-3-(7-bromo-2-chloro-6-cyano-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.70 g, 3.41 mmol, yield 68%). LCMS (ESI): [M+H] + = 498.2.
第二步:將化合物 (1R,5S)-3-(7-溴-2-氯-6-氰基-8-氟喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(1.48 g,2.98 mmol)加入到三氟乙醇(15 mL),加入二異丙基乙胺(1560 uL,8.94 mmol),反應液在50 oC攪拌3小時。反應液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-2%梯度的甲醇/二氯甲烷)得化合物叔丁基(1R,5S)-3-(7-溴-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(80% 純度,0.90 g,1.28 mmol,產率43%)。LCMS (ESI): [M+H] += 562.0. 中間體 A9 :叔丁基(1R,5S)-3-(7-溴-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯 Step 2 : Add the compound (1R,5S)-3-(7-bromo-2-chloro-6-cyano-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.48 g, 2.98 mmol) to trifluoroethanol (15 mL), add diisopropylethylamine (1560 uL, 8.94 mmol), and stir the reaction solution at 50 o C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-2% gradient of methanol/dichloromethane) to obtain the compound tert-butyl (1R, 5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80% purity, 0.90 g, 1.28 mmol, yield 43%). LCMS (ESI): [M+H] + = 562.0. Intermediate A9 : tert-butyl (1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
第一步:化合物7-溴-2,4,6-三氯-8-氟喹唑啉(0.50 g,1.51 mmol)溶於二氯甲烷(10 mL),加入 (1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(0.32 g,1.51 mmol)和三乙胺(630 uL,4.54 mmol),20 oC攪拌16小時。反應液加入到飽和食鹽水(10 mL)中,用二氯甲烷(10 mL)萃取,有機相減壓濃縮得化合物 (1R,5S)-3-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(90% 純度,0.83 g,1.48 mmol,產率98%)。LCMS (ESI): [M+H] += 507.2. Step 1 : Dissolve 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (0.50 g, 1.51 mmol) in dichloromethane (10 mL), add (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.32 g, 1.51 mmol) and triethylamine (630 uL, 4.54 mmol), and stir at 20 ° C for 16 hours. The reaction solution was added to saturated brine (10 mL), extracted with dichloromethane (10 mL), and the organic phase was concentrated under reduced pressure to obtain the compound (1R,5S)-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (90% purity, 0.83 g, 1.48 mmol, yield 98%). LCMS (ESI): [M+H] + = 507.2.
第二步:化合物 (1R,5S)-3-(7-溴-2,6-二氯-8-氟喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(90% 純度,550 mg,0.98 mmol)和 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(173 mg,1.09 mmol)加入到N,N-二甲基甲醯胺(5 mL)和四氫呋喃(5 mL)中,加入碳酸銫(1.06 g,3.26 mmol)和三乙烯二胺(24 mg,0.22 mmol)。反應系統在20 oC攪拌16小時。加入水(5 mL),用乙酸乙酯(5 mL * 3)萃取,有機相減壓濃縮得化合物叔丁基(1R,5S)-3-(7-溴-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(80% 純度,490 mg,0.62 mmol,產率63%)。LCMS (ESI): [M+H] += 629.9. 中間體 A10: 8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶 Step 2 : Compound (1R,5S)-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (90% purity, 550 mg, 0.98 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (173 mg, 1.09 mmol) were added to N,N-dimethylformamide (5 mL) and tetrahydrofuran (5 mL), and cesium carbonate (1.06 g, 3.26 mmol) and triethylenediamine (24 mg, 0.22 mmol) were added. The reaction system was stirred at 20 ° C for 16 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL * 3). The organic phase was concentrated under reduced pressure to obtain the compound tert-butyl (1R, 5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80% purity, 490 mg, 0.62 mmol, yield 63%). LCMS (ESI): [M+H] + = 629.9. Intermediate A10 : 8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine
第一步:將化合物2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(3.00 g,11.88 mmol)和三氟乙醇(1.43 g,14.2 mmol)溶於甲苯(60 mL),0 oC下加入叔丁醇鈉(1.14 g,11.8 mmol),混合物在0 oC攪拌2小時。反應液透過矽藻土過濾,濾餅用乙酸乙酯洗滌(30 mL * 3),濾液用飽和食鹽水洗滌(50 mL * 2),硫酸鈉乾燥,過濾,減壓濃縮得到粗產物化合物2,7-二氯-8-氟-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(3.76 g)。LCMS (ESI): [M+H] += 315.8. Step 1 : Dissolve the compound 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.00 g, 11.88 mmol) and trifluoroethanol (1.43 g, 14.2 mmol) in toluene (60 mL), add sodium tert-butoxide (1.14 g, 11.8 mmol) at 0 o C, and stir the mixture at 0 o C for 2 hours. The reaction solution is filtered through diatomaceous earth, the filter cake is washed with ethyl acetate (30 mL * 3), the filtrate is washed with saturated salt water (50 mL * 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product compound 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (3.76 g). LCMS (ESI): [M+H] + = 315.8.
第二步:向化合物 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(0.71 g,4.43 mmol),二異丙基乙胺(0.79 mL,4.43 mmol)和4A分子篩(1 g)的2-甲基四氫呋喃(10 mL)懸濁液中,0 oC下加入2,7-二氯-8-氟-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(70%純度,1.00 g,2.21 mmol)。反應系統升溫到25 oC反應1小時。將3個相同量的批次合併,反應液過濾,濾液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷)得黃色油狀7-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(純度75%,3.00 g,5.10 mmol,產率77%)。LCMS (ESI): [M+H] += 439.0. Step 2 : Add 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (70% purity, 1.00 g, 2.21 mmol) to a suspension of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.71 g, 4.43 mmol), diisopropylethylamine (0.79 mL, 4.43 mmol) and 4A molecular sieve (1 g) in 2-methyltetrahydrofuran (10 mL) at 0 ° C. The reaction system was heated to 25 ° C for 1 hour. Three batches of equal volume were combined, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain yellow oily 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 75%, 3.00 g, 5.10 mmol, yield 77%). LCMS (ESI): [M+H] + = 439.0.
第三步:化合物7-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(純度75%,2.75 g,4.69 mmol)加入到二氧六環(60 mL)中,加入 ((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(3.21 g,6.27 mmol)和碳酸銫(1.5 M的水溶液,12.5 mL,18.80 mmol),氮氣氛圍下加入氯[(正丁基二(1-金剛烷基)膦)-2-(2-胺基聯苯)]鈀(II)(419 mg,0.63 mmol),反應液在80 oC攪拌3小時。反應液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷),得到的粗產物再用製備型HPLC純化得到黃色固體化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(1.50 g,1.90 mmol,產率40%)。LCMS (ESI): [M+H] += 789.3. 1H NMR (400 MHz, CDCl 3) δ ppm 9.27 (d, J= 2.3 Hz, 1H), 7.82 (dd, J= 5.6, 8.9 Hz, 1H), 7.55 (d, J= 2.5 Hz, 1H), 7.38-7.29 (m, 2H), 5.57-5.38 (m, 1H), 5.36-5.29 (m, 2H), 5.27-5.17 (m, 1H), 5.11-4.92 (m, 1H), 4.87-4.51 (m, 2H), 3.85 (br s, 2H), 3.54 (s, 3H), 3.49-3.33 (m, 1H), 3.18 (br s, 1H), 2.66-2.10 (m, 6H), 0.91-0.82 (m, 18H), 0.54 (dtd, J= 3.8, 7.4, 14.8 Hz, 3H). 中間體 A11 :(二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)-甲醇 Step 3 : Compound 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 75%, 2.75 g, 4.69 mmol) was added to dioxane (60 mL), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.21 g, 6.27 mmol) and cesium carbonate (1.5 M aqueous solution, 12.5 mL, 18.80 mmol), chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (419 mg, 0.63 mmol) was added under nitrogen atmosphere, and the reaction solution was stirred at 80 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane). The crude product was purified by preparative HPLC to give a yellow solid compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.50 g, 1.90 mmol, yield 40%). LCMS (ESI): [M+H] + = 789.3. 1H NMR (400 MHz, CDCl 3 ) δ ppm 9.27 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 5.6, 8.9 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.38-7.29 (m, 2H), 5.57-5.38 (m, 1H), 5.36-5.29 (m, 2H), 5.27-5.17 (m, 1H), 5.11-4.92 (m, 1H), 4.87-4.51 (m, 2H), 3.85 (br s, 2H), 3.54 (s, 3H), 3.49-3.33 (m, 1H), 3.18 (br s, 1H), 2.66-2.10 (m, 6H), 0.91-0.82 (m, 18H), 0.54 (dtd, J = 3.8, 7.4, 14.8 Hz, 3H). Intermediate A11 : (Dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)-methanol
第一步:向L-脯胺酸甲酯鹽酸鹽(7.00 g,42.2 mmol)和 (3-(溴甲基)氧雜環丁烷-3-基)甲醇(10 g,55.2 mmol)的N,N-二甲基乙醯胺(80 mL)溶液中加入二異丙基乙基胺(21 mL,126 mmol),在氮氣保護下,將混合物加熱至50 oC攪拌12小時。反應混合物旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-70%梯度的四氫呋喃/石油醚)得到粗產物化合物 ((3-(羥甲基)氧雜環丁烷-3-基)甲基)-L-脯胺酸甲酯(3 g),為棕色油狀液體。LCMS (ESI): [M+H] += 230.2; Step 1: Add diisopropylethylamine (21 mL, 126 mmol) to a solution of L-proline methyl ester hydrochloride (7.00 g, 42.2 mmol) and (3-(bromomethyl)cyclohexyl-3-yl)methanol (10 g, 55.2 mmol) in N,N-dimethylacetamide (80 mL). Heat the mixture to 50 ° C and stir for 12 hours under nitrogen. Rotate the reaction mixture to dryness. The residue is purified by flash column chromatography (silica gel, 0-70% gradient of tetrahydrofuran/petroleum ether) to obtain the crude product compound ((3-(hydroxymethyl)cyclohexyl-3-yl)methyl)-L-proline methyl ester (3 g) as a brown oily liquid. LCMS (ESI): [M+H] + = 230.2;
第二步:在0 oC下向 ((3-(羥甲基)氧雜環丁烷-3-基)甲基)-L-脯胺酸甲酯(1.00 g,4.36 mmol)和四溴化碳(1.88 g,5.67 mmol)的二氯甲烷(25 mL)溶液中,分3批加入三苯基膦(1831 mg,6.98 mmol),然後將混合物氮氣保護下在25 oC下攪拌3小時。反應混合物旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-20%梯度的四氫呋喃/石油醚)得到無色液體化合物 ((3-(溴甲基)氧雜環丁烷-3-基)甲基)-L-脯胺酸甲酯(400 mg,1.37 mmol,產率31%)。LCMS (ESI): [M+H] +=294.0. Step 2 : To a solution of ((3-(hydroxymethyl)oxacyclobutane-3-yl)methyl)-L-proline methyl ester (1.00 g, 4.36 mmol) and carbon tetrabromide (1.88 g, 5.67 mmol) in dichloromethane (25 mL) at 0 ° C, triphenylphosphine (1831 mg, 6.98 mmol) was added in three batches, and then the mixture was stirred at 25 ° C for 3 hours under nitrogen protection. The reaction mixture was rotated to dryness. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran/petroleum ether) to obtain a colorless liquid compound ((3-(bromomethyl)oxacyclobutane-3-yl)methyl)-L-proline methyl ester (400 mg, 1.37 mmol, yield 31%). LCMS (ESI): [M+H] + =294.0.
第三步:氮氣保護下,將 ((3-(溴甲基)氧雜環丁烷-3-基)甲基)-L-脯胺酸甲酯(200 mg, 0.68 mmol)的N,N-二甲基甲醯胺(5 mL)和四氫呋喃(1 mL)溶液冷卻至-70 oC,在-60 oC至-70 oC下加入六甲基二矽基胺基鉀(1 M的四氫呋喃溶液,958 uL,0.96 mmol),然後將混合物在-60 oC至-70 oC下攪拌30分鐘。反應混合物加入水(10 mL),使用乙酸乙酯(10 mL * 3)萃取,合併有機相,用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-60%梯度的四氫呋喃/石油醚)得到無色液體化合物二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-羧酸甲酯(20 mg,0.09 mmol,產率14%)。LCMS (ESI): [M+H] += 212.1. 1H NMR (400 MHz, CDCl 3) δ ppm 4.69-4.52 (m, 4H), 3.69 (s, 3H), 3.60 (d, J= 9.9 Hz, 1H), 3.10 (td, J= 6.5, 10.8 Hz, 1H), 2.86-2.75 (m, 2H), 2.73-2.63 (m, 1H), 2.22 (td, J= 7.2, 12.7 Hz, 1H), 1.88-1.78 (m, 3H), 1.77-1.67 (m, 1H). Step 3 : Under nitrogen protection, a solution of ((3-(bromomethyl)oxacyclobutane-3-yl)methyl)-L-proline methyl ester (200 mg, 0.68 mmol) in N,N-dimethylformamide (5 mL) and tetrahydrofuran (1 mL) was cooled to -70 ° C, and potassium hexamethyldisilazide (1 M tetrahydrofuran solution, 958 uL, 0.96 mmol) was added at -60 ° C to -70 ° C, and then the mixture was stirred at -60 ° C to -70 ° C for 30 minutes. Water (10 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (10 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-60% gradient of tetrahydrofuran/petroleum ether) to give dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (20 mg, 0.09 mmol, yield 14%) as a colorless liquid compound. LCMS (ESI): [M+H] + = 212.1. 1H NMR (400 MHz, CDCl 3 ) δ ppm 4.69-4.52 (m, 4H), 3.69 (s, 3H), 3.60 (d, J = 9.9 Hz, 1H), 3.10 (td, J = 6.5, 10.8 Hz, 1H), 2.86-2.75 (m, 2H), 2.73-2.63 (m, 1H), 2.22 (td, J = 7.2, 12.7 Hz, 1H), 1.88-1.78 (m, 3H), 1.77-1.67 (m, 1H).
第四步:在氮氣保護,-10 oC下,向二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-羧酸甲酯(150 mg, 0.71 mmol)的四氫呋喃(3 mL)溶液中加入四氫鋁鋰(81 mg,2.13 mmol),然後將混合物在-10 oC下攪拌30分鐘。向反應混合物中加入水(81 uL),氫氧化鈉(15%的水溶液,81 uL),然後加入水(243 uL),混合物過濾,固體用四氫呋喃洗滌,濾液旋轉乾燥,得到無色液體化合物 (二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)-甲醇(120 mg,0.66 mmol,產率92%)。LCMS (ESI): [M+H] += 184.1. 中間體 A12 : ( 二氫 -1'H,3'H- 螺 [ 環丙烷 -1,2'- 吡咯嗪 ]-7a'(5'H)- 基 ) 甲醇 Step 4 : Under nitrogen protection, to a solution of dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (150 mg, 0.71 mmol) in tetrahydrofuran (3 mL) was added lithium tetrahydroaluminum (81 mg, 2.13 mmol) at -10 °C, and the mixture was stirred at -10 ° C for 30 minutes. Water (81 uL), sodium hydroxide (15% aqueous solution, 81 uL), and then water (243 uL) were added to the reaction mixture. The mixture was filtered, the solid was washed with tetrahydrofuran, and the filtrate was rotary dried to obtain a colorless liquid compound (dihydro-1'H, 3'H-spiro[cyclohexane-3,2'-pyrrolizine]-7a'(5'H)-yl)-methanol (120 mg, 0.66 mmol, yield 92%). LCMS (ESI): [M+H] + = 184.1. Intermediate A12 : ( dihydro -1'H, 3'H- spiro [ cyclopropane -1,2'- pyrrolizine ]-7a'(5'H) -yl ) methanol
第一步:在0 oC下向(S)-5-(叔丁氧基羰基)-5-氮雜螺[2.4]庚烷-6-羧酸(8.00 g,33.16 mmol)和碳酸鉀(9.16 g,66.3 mmol)的二甲基甲醯胺(80 mL)溶液中緩慢加入碘甲烷(11.7 g,82.8 mmol)。將溶液在0 oC攪拌1小時,然後將溶液在25 oC下攪拌12小時。反應用亞硫酸鈉溶液淬滅後濃縮,粗產物透過快速管柱層析(矽膠,0-25%梯度的四氫呋喃/石油醚)純化,得到無色油狀化合物5-(叔丁基)6-甲基(S)-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯(8.10 g,30.1 mmol,產率91%)。LCMS (ESI): [M+Na] += 278.1. Step 1 : To a solution of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (8.00 g, 33.16 mmol) and potassium carbonate (9.16 g, 66.3 mmol) in dimethylformamide (80 mL ) was slowly added iodomethane (11.7 g, 82.8 mmol) at 0 ° C. The solution was stirred at 0 ° C for 1 hour, and then the solution was stirred at 25 ° C for 12 hours. The reaction mixture was quenched with sodium sulfite solution and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-25% gradient of tetrahydrofuran/petroleum ether) to obtain a colorless oily compound 5-(tert-butyl) 6-methyl (S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (8.10 g, 30.1 mmol, yield 91%). LCMS (ESI): [M+Na] + = 278.1.
第二步:在-78 oC和氮氣保護下,向二異丙基胺基鋰(2 M的四氫呋喃正庚烷混合溶液,16 mL,32 mmol)的四氫呋喃(80 mL)溶液中加入5-(叔丁基)6-甲基(S)-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯(8.00 g,29.8 mmol)並攪拌1小時,然後在-78 oC下加入1-溴-3-氯丙烷(3 mL,31.3 mmol)並攪拌2小時,然後在25 oC下攪拌12小時。溶液用飽和氯化銨(20 mL)淬滅並用乙酸乙酯(10 mL*3)萃取。合併的有機層用無水硫酸鈉乾燥並濃縮,得到粗產物透過快速管柱層析(矽膠,0-20%梯度的四氫呋喃/石油醚)純化,得到無色油狀化合物5-(叔丁基)6-甲基6-(3-氯丙基)-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯(5.80 g,17.4 mmol,產率58%)。LCMS (ESI): [M+Na] += 354.0. Step 2 : At -78 o C and nitrogen protection, add 5-(tert-butyl) 6-methyl (S)-5-azaspiro [2.4] heptane-5,6-dicarboxylate (8.00 g, 29.8 mmol) to a solution of lithium diisopropylamide (2 M tetrahydrofuran n-heptane mixed solution, 16 mL, 32 mmol) in tetrahydrofuran (80 mL) and stir for 1 hour, then add 1-bromo-3-chloropropane (3 mL, 31.3 mmol) at -78 o C and stir for 2 hours, then stir at 25 o C for 12 hours. The solution was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a crude product which was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran/petroleum ether) to give a colorless oily compound 5-(tert-butyl)-6-methyl-6-(3-chloropropyl)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (5.80 g, 17.4 mmol, yield 58%). LCMS (ESI): [M+Na] + = 354.0.
第三步:在25 oC下,向5-(叔丁基)6-甲基(S)-6-(3-氯丙基)-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯(5.80 g,17.4 mmol)的二氯甲烷溶液(12 mL)中加入氯化氫(4 M的二氧六環溶液,3 mL,12 mmol)。溶液在25 oC攪拌16小時。將溶液減壓濃縮,得到黃色油狀化合物6-(3-氯丙基)-5-氮雜螺[2.4]庚烷-6-羧酸甲酯(純度85%,4.67 g,17.1 mmol,產率98%)。LCMS (ESI): [M+H] += 232.1. Step 3 : At 25 ° C, hydrogen chloride (4 M in dioxane, 3 mL, 12 mmol) was added to a solution of 5-(tert-butyl)-6-methyl (S)-6-(3-chloropropyl)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (5.80 g, 17.4 mmol) in dichloromethane (12 mL). The solution was stirred at 25 ° C for 16 hours. The solution was concentrated under reduced pressure to obtain a yellow oily compound 6-(3-chloropropyl)-5-azaspiro[2.4]heptane-6-carboxylic acid methyl ester (purity 85%, 4.67 g, 17.1 mmol, yield 98%). LCMS (ESI): [M+H] + = 232.1.
第四步:在25 oC下,向6-(3-氯丙基)-5-氮雜螺[2.4]庚烷-6-羧酸甲酯(純度85%,4.67 g,17.1 mmol)的甲醇(100 mL)溶液中加入碘化鉀(340 mg,2.06 mmol)和碳酸鉀(8.53 g,61.7 mmol)。溶液在25 oC攪拌16小時。將溶液過濾並濃縮,得到棕色油狀化合物二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-羧酸甲酯(純度85%,3.90 g,17.0 mmol,產率99%)。LCMS (ESI): [M+H] += 196.1. Step 4 : Potassium iodide (340 mg, 2.06 mmol) and potassium carbonate (8.53 g, 61.7 mmol) were added to a solution of methyl 6-(3-chloropropyl)-5-azaspiro[2.4]heptane-6-carboxylate (purity 85%, 4.67 g, 17.1 mmol) in methanol (100 mL) at 25 ° C. The solution was stirred at 25 ° C for 16 hours. The solution was filtered and concentrated to obtain a brown oily compound, dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylate (purity 85%, 3.90 g, 17.0 mmol, yield 99%). LCMS (ESI): [M+H] + = 196.1.
第五步:在0 oC的氮氣氛圍下,向氫化鋁鋰(0.58 g,15.3 mmol)的四氫呋喃(10 mL)溶液中加入二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-羧酸甲酯(純度85%,2.00 g,8.72 mmol)的四氫呋喃(0.50 mL)溶液,將混合物在60 oC攪拌4小時。冷至室溫後,混合物依次用水(600 uL),15%氫氧化鈉(600 uL)和水(1800 uL)淬滅。將懸浮液過濾並濃縮,得到棕色油狀化合物 (二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇(1.20 g,7.19 mmol,產率82%)。LCMS (ESI): [M+H] += 168.1. 中間體 A13-1 和 A13-2 :順式-六氫環丙[a]吡咯嗪-6a(4H)-基)甲醇A 13-1和反式-六氫環丙[a]吡咯嗪-6a(4H)-基)甲醇A 13-2 Step 5 : Under nitrogen atmosphere at 0 ° C, a solution of lithium aluminum hydroxide (0.58 g, 15.3 mmol) in tetrahydrofuran (10 mL) was added with a solution of dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (purity 85%, 2.00 g, 8.72 mmol) in tetrahydrofuran (0.50 mL), and the mixture was stirred at 60 ° C for 4 hours. After cooling to room temperature, the mixture was quenched with water (600 uL), 15% sodium hydroxide (600 uL) and water (1800 uL) in sequence. The suspension was filtered and concentrated to give a brown oily compound (dihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-yl)methanol (1.20 g, 7.19 mmol, yield 82%). LCMS (ESI): [M+H] + = 168.1. Intermediates A13-1 and A13-2 : cis-hexahydrocyclopropane[a]pyrrolazine-6a(4H)-yl)methanol A 13-1 and trans-hexahydrocyclopropane[a]pyrrolazine-6a(4H)-yl)methanol A 13-2
第一步:向化合物3-氮雜雙環[3.1.0]己烷鹽酸鹽(15 g,125 mmol)和三乙胺(35 mL,250 mmol)的二氯甲烷(150 mL)溶液中,20 oC下加入二碳酸二叔丁酯(31.7 mL,137 mmol)。反應在20 oC下攪拌16小時。反應液加入飽和氯化銨溶液(200 mL),然後用二氯甲烷(300 mL * 2)萃取,有機層用無水硫酸鎂乾燥,過濾,濾液減壓濃縮得到白色油狀化合物3-氮雜雙環[3.1.0]己烷-3-羧酸叔丁酯(20 g,109 mmol,產率78%)。LCMS (ESI): [M-56+H] += 128.1. Step 1 : Add di-tert-butyl dicarbonate (31.7 mL, 137 mmol) to a solution of 3-azabicyclo[3.1.0]hexane hydrochloride (15 g, 125 mmol) and triethylamine (35 mL, 250 mmol) in dichloromethane (150 mL) at 20 ° C. The reaction was stirred at 20 ° C for 16 hours. Saturated ammonium chloride solution (200 mL) was added to the reaction solution, and then extracted with dichloromethane (300 mL * 2). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a white oily compound 3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (20 g, 109 mmol, yield 78%). LCMS (ESI): [M-56+H] + = 128.1.
第二步:將化合物3-氮雜雙環[3.1.0]己烷-3-羧酸叔丁酯(20 g,108 mmol)和四甲基乙二胺(9150 uL,61.3 mmol)溶於四氫呋喃(150 mL),-65 oC和氮氣保護下加入仲丁基鋰(1.3 M的正己烷溶液,63 mL,81.9 mmol)。反應在-65 oC下攪拌3小時。用二氧化碳置換氮氣並將反應液在-65 oC和二氧化碳氣球下攪拌1小時。反應液中加入20%硫酸氫鉀溶液(300 mL)(pH=7)和水(200 mL)。將反應溶液升至室溫,減壓濃縮除去THF。殘餘物用乙酸乙酯(300 mL * 3)萃取,有機層用無水硫酸鎂乾燥,過濾,有機層減壓濃縮得到棕色油狀化合物3-(叔丁氧基羰基)-3-氮雜雙環[3.1.0]己烷-2-羧酸(純度80%,12 g,42.2 mmol,產率43%)。LCMS (ESI): [M-56+H] += 172.1. Step 2 : Dissolve the compound tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (20 g, 108 mmol) and tetramethylethylenediamine (9150 uL, 61.3 mmol) in tetrahydrofuran (150 mL), add sec-butyl lithium (1.3 M in n-hexane, 63 mL, 81.9 mmol) at -65 o C under nitrogen protection. Stir the reaction at -65 o C for 3 hours. Replace the nitrogen with carbon dioxide and stir the reaction solution at -65 o C under a carbon dioxide balloon for 1 hour. Add 20% potassium bisulfate solution (300 mL) (pH = 7) and water (200 mL) to the reaction solution. Warm the reaction solution to room temperature and remove THF by decompression and concentration. The residue was extracted with ethyl acetate (300 mL * 3), the organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic layer was concentrated under reduced pressure to obtain a brown oily compound 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (purity 80%, 12 g, 42.2 mmol, yield 43%). LCMS (ESI): [M-56+H] + = 172.1.
第三步:20 oC下,向化合物3-(叔丁氧基羰基)-3-氮雜雙環[3.1.0]己烷-2-羧酸(純度80%,12 g,42.2 mmol)和碳酸鉀(17.6 g,126 mmol)的丙酮(150 mL)懸濁液中,加入碘甲烷(5.2 mL,84.4 mmol)。反應在20 oC下攪拌16小時。反應液減壓濃縮。殘留物用快速管柱層析純化(矽膠,0-10%梯度的乙酸乙酯/石油醚)得到黃色油狀化合物3-(叔丁基)2-甲基3-氮雜雙環[3.1.0]己烷-2,3-二羧酸酯(5 g,20.7 mmol,產率36%)。LCMS (ESI): [M+Na] += 264.1. Step 3 : Add iodomethane (5.2 mL , 84.4 mmol) to a suspension of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (purity 80%, 12 g, 42.2 mmol) and potassium carbonate (17.6 g, 126 mmol) in acetone (150 mL) at 20 ° C. The reaction was stirred at 20 ° C for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate/petroleum ether) to give a yellow oily compound 3-(tert-butyl) 2-methyl 3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (5 g, 20.7 mmol, yield 36%). LCMS (ESI): [M+Na] + = 264.1.
第四步:將化合物3-(叔丁基)2-甲基3-氮雜雙環[3.1.0]己烷-2,3-二羧酸酯(5 g,20.7 mmol)和1-溴-3-氯丙烷(1.2 mL,12.4 mmol)溶於四氫呋喃(100 mL),-65 oC和氮氣氛圍下加入雙(三甲基矽基)胺基鋰(1.0 M的四氫呋喃溶液,41.4 mL,41.4 mmol)。反應在-65 oC下攪拌2小時然後升溫至0 oC,加入飽和氯化銨溶液(200 mL),然後用乙酸乙酯(100 mL * 2)萃取,有機層用無水硫酸鎂乾燥,過濾,有機層減壓濃縮。殘餘物透過快速管柱層析(矽膠,0-10%梯度的乙酸乙酯/石油醚)得到黃色油狀化合物3-(叔丁基)2-甲基2-(3-氯丙基)-3-氮雜雙環[3.1.0]己烷-2,3-二羧酸酯(純度80%,2.70 g,6.81 mmol,產率33%)。LCMS (ESI): [M+Na] += 340.1. Step 4 : Dissolve the compound 3-(tert-butyl) 2-methyl 3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (5 g, 20.7 mmol) and 1-bromo-3-chloropropane (1.2 mL, 12.4 mmol) in tetrahydrofuran (100 mL), add bis(trimethylsilyl)amide lithium (1.0 M tetrahydrofuran solution, 41.4 mL, 41.4 mmol) at -65 o C under nitrogen atmosphere. Stir the reaction at -65 o C for 2 hours and then raise the temperature to 0 o C, add saturated ammonium chloride solution (200 mL), and then extract with ethyl acetate (100 mL * 2), dry the organic layer with anhydrous magnesium sulfate, filter, and concentrate the organic layer under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to give a yellow oily compound 3-(tert-butyl) 2-methyl 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (purity 80%, 2.70 g, 6.81 mmol, yield 33%). LCMS (ESI): [M+Na] + = 340.1.
第五步:化合物3-(叔丁基)2-甲基2-(3-氯丙基)-3-氮雜雙環[3.1.0]己烷-2,3-二羧酸酯(純度80%,2.70 g,6.81 mmol)溶於二氯甲烷(60 mL),20 oC下加入氯化氫(4 M的二氧六環溶液,15 mL,60 mmol)。反應在25 oC下攪拌16小時。減壓濃縮,得到黃色油狀的粗產物化合物2-(3-氯丙基)-3-氮雜雙環[3.1.0]己烷-2-羧酸甲酯(1.72g)。LCMS (ESI): [M+H] += 218.1. Step 5 : Compound 3-(tert-butyl) 2-methyl 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (purity 80%, 2.70 g, 6.81 mmol) was dissolved in dichloromethane (60 mL), and hydrogen chloride (4 M dioxane solution, 15 mL, 60 mmol) was added at 20 ° C. The reaction was stirred at 25 ° C for 16 hours. The mixture was concentrated under reduced pressure to obtain a crude product compound 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (1.72 g) as a yellow oil. LCMS (ESI): [M+H] + = 218.1.
第六步:化合物2-(3-氯丙基)-3-氮雜雙環[3.1.0]己烷-2-羧酸甲酯(1.72g,6.81 mmol)溶於甲醇(50 mL),20 oC下加入碳酸鉀(8.57 g,62.0 mmol)和碘化鉀(0.34 g,2.07 mmol)。反應在20 oC下攪拌16小時。反應液過濾,減壓濃縮。殘餘物透過快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化得到兩個中間體。極性較小黃色油狀液體假定為反式-六氫環丙[a]吡咯嗪-6a(4H)-羧酸甲酯(110 mg,0.61 mmol,產率8.9%)。LCMS (ESI): [M+H] += 182.1;極性較大的黃色油狀液體假定為順式-六氫環丙[a]吡咯嗪-6a(4H)-羧酸甲酯(250 mg,1.38 mmol,產率20%)。LCMS (ESI): [M+H] += 182.1. Step 6 : Compound 2-(3-chloropropyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (1.72 g, 6.81 mmol) was dissolved in methanol (50 mL), and potassium carbonate (8.57 g, 62.0 mmol) and potassium iodide (0.34 g, 2.07 mmol) were added at 20 ° C. The reaction was stirred at 20 ° C for 16 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain two intermediates. The slightly polar yellow oily liquid was assumed to be trans-hexahydrocyclopropane[a]pyrrolizine-6a(4H)-carboxylic acid methyl ester (110 mg, 0.61 mmol, 8.9% yield). LCMS (ESI): [M+H] + = 182.1; The more polar yellow oily liquid was assumed to be cis-hexahydrocyclopropane[a]pyrrolizine-6a(4H)-carboxylic acid methyl ester (250 mg, 1.38 mmol, 20% yield). LCMS (ESI): [M+H] + = 182.1.
第七步:將四氫鋁鋰(35 mg,0.91 mmol)溶於四氫呋喃(6 mL),-40 oC的氮氣氛圍下加入 反式-六氫環丙[a]吡咯嗪-6a(4H)-羧酸甲酯(110 mg,0.61 mmol)的四氫呋喃(0.5 mL)溶液。反應在-10 oC下攪拌1小時。0 oC下反應液中加入水(110 uL)和15%氫氧化鈉水溶液(110 uL),然後加入水(330 uL)。加入無水硫酸鈉攪拌,過濾並減壓濃縮濾液以得到黃色油狀化合物 反式-(六氫環丙[a]吡咯嗪-6a(4H)-基)甲醇( 中間體 A13-1 ,90 mg,0.59 mmol,產率96%)。LCMS (ESI): [M+H] += 154.1. Step 7 : Dissolve lithium aluminum tetrahydrate (35 mg, 0.91 mmol) in tetrahydrofuran (6 mL), add a solution of trans-hexahydrocyclopropyl[a]pyrrolizine-6a(4H)-carboxylic acid methyl ester (110 mg, 0.61 mmol) in tetrahydrofuran (0.5 mL) under a nitrogen atmosphere at -40 ° C. Stir the reaction at -10 ° C for 1 hour. Add water (110 uL) and 15% sodium hydroxide aqueous solution (110 uL) to the reaction solution at 0 ° C, and then add water (330 uL). Anhydrous sodium sulfate was added and stirred, and the filtrate was filtered and concentrated under reduced pressure to obtain a yellow oily compound trans-(hexahydrocyclopropane[a]pyrrolizine-6a(4H)-yl)methanol ( intermediate A13-1 , 90 mg, 0.59 mmol, yield 96%). LCMS (ESI): [M+H] + = 154.1.
順式-(六氫環丙[a]吡咯嗪-6a(4H)-基)甲醇 中間體 A13-2在第七步以順式-六氫環丙[a]吡咯嗪-6a(4H)-羧酸甲酯為原料參照類似反應條件製備得到。LCMS (ESI): [M+H] += 154.2. 中間體 A14 :(六氫-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-基)甲醇 cis-(hexahydrocyclopropane[a]pyrrolazine-6a(4H)-yl)methanol intermediate A13-2 was prepared in the seventh step using cis-hexahydrocyclopropane[a]pyrrolazine-6a(4H)-carboxylic acid methyl ester as a raw material under similar reaction conditions. LCMS (ESI): [M+H] + = 154.2. Intermediate A14 : (hexahydro-2H-furan[2,3-b]pyrrolazine-7a(5H)-yl)methanol
第一步:0 oC下向乙醇鈉(44.2 g,650 mmol)的乙醇(1000 mL)溶液中加入呋喃-2-甲醛(50 g,520 mmol)和疊氮乙酸乙酯(80.6 g,624 mmol)。將該反應混合物在25 oC下攪拌16小時。混合物用飽和氯化銨(1 L)稀釋並用乙酸乙酯(1 L * 3)萃取。真空濃縮有機相,殘餘物透過快速管柱層析(矽膠,0-30%的二氯甲烷/石油醚)純化以得到黃色油狀化合物2-疊氮基-3-(呋喃-2-基)丙烯酸乙酯(25 g,120 mmol,產率23%)。 1H NMR (400MHz, CDCl 3) δ ppm 7.51 (d, J= 1.5 Hz, 1H), 7.12 (d, J= 3.5 Hz, 1H), 6.89 (s, 1H), 6.55 (dd, J= 1.8, 3.5 Hz, 1H), 4.37 (q, J= 7.0 Hz, 2H), 1.40 (t, J= 7.2 Hz, 3H). Step 1 : To a solution of sodium ethoxide (44.2 g, 650 mmol) in ethanol (1000 mL) were added furan-2-carboxaldehyde (50 g, 520 mmol) and ethyl azidoacetate (80.6 g, 624 mmol) at 0 ° C. The reaction mixture was stirred at 25 ° C for 16 hours. The mixture was diluted with saturated ammonium chloride (1 L) and extracted with ethyl acetate (1 L * 3). The organic phase was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-30% dichloromethane/petroleum ether) to obtain a yellow oily compound ethyl 2-azido-3-(furan-2-yl)acrylate (25 g, 120 mmol, yield 23%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.51 (d, J = 1.5 Hz, 1H), 7.12 (d, J = 3.5 Hz, 1H), 6.89 (s, 1H), 6.55 (dd, J = 1.8, 3.5 Hz, 1H), 4.37 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H).
第二步:將2-疊氮基-3-(呋喃-2-基)丙烯酸乙酯(24 g,115 mmol)的甲苯溶液在115 oC下攪拌3小時,反應有大量氣體放出。反應完成後,真空濃縮,得到呈棕色固體化合物的4H-呋喃[3,2-b]吡咯-5-羧酸乙酯(16 g,89.3 mmol,產率77%)。LCMS (ESI): [M+H] += 180.1. Step 2 : Stir the toluene solution of ethyl 2-azido-3-(furan-2-yl)acrylate (24 g, 115 mmol) at 115 ° C for 3 hours. A large amount of gas is released during the reaction. After the reaction is completed, vacuum concentrate to obtain ethyl 4H-furan[3,2-b]pyrrole-5-carboxylate (16 g, 89.3 mmol, yield 77%) as a brown solid compound. LCMS (ESI): [M+H] + = 180.1.
第三步:在0 oC下,向4H-呋喃[3,2-b]吡咯-5-羧酸乙酯(16.5 g,92.1 mmol)的乙腈(160 mL)溶液加入4-二甲胺基吡啶(1.07 g,8.75 mmol)和二碳酸二叔丁酯(27.7 g,127 mmol)。反應在25 oC下攪拌16小時。混合物真空濃縮,殘餘物透過快速管柱層析(矽膠,0-10%梯度的乙酸乙酯/石油醚)純化得到棕色油狀化合物4-(叔丁基)5-乙基4H-呋喃[3,2-b]吡咯-4,5-二羧酸酯(24 g,85.9 mmol,產率93%)。LCMS (ESI): [M-56+H] += 224.1. Step 3 : At 0 ° C, 4-dimethylaminopyridine (1.07 g, 8.75 mmol) and di-tert-butyl dicarbonate (27.7 g, 127 mmol) were added to a solution of ethyl 4H-furano[3,2-b]pyrrole-5-carboxylate (16.5 g, 92.1 mmol) in acetonitrile (160 mL). The reaction was stirred at 25 ° C for 16 hours. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate/petroleum ether) to obtain a brown oily compound 4-(tert-butyl) 5-ethyl 4H-furano[3,2-b]pyrrole-4,5-dicarboxylate (24 g, 85.9 mmol, yield 93%). LCMS (ESI): [M-56+H] + = 224.1.
第四步:向4-(叔丁基)5-乙基4H-呋喃[3,2-b]吡咯-4,5-二羧酸酯(8 g,28.6 mmol)的乙醇(200 mL)溶液中加入鈀碳(10%純度,6.10 g,5.73 mmol)。反應在60 oC及50 psi氫氣氣氛下攪拌16小時。過濾混合物,真空濃縮濾液,得到黃色油狀化合物4-(叔丁基)5-乙基六氫-4H-呋喃[3,2-b]吡咯-4,5-二羧酸酯(7.86 g,27.5 mmol,產率96%)。LCMS (ESI): [M+Na] += 308.1. Step 4 : Palladium on carbon (10% purity, 6.10 g, 5.73 mmol) was added to a solution of 4-(tert-butyl)5-ethyl 4H-furan[3,2-b]pyrrole-4,5-dicarboxylate (8 g, 28.6 mmol) in ethanol (200 mL). The reaction was stirred at 60 ° C and 50 psi hydrogen atmosphere for 16 hours. The mixture was filtered and the filtrate was concentrated under vacuum to obtain a yellow oily compound 4-(tert-butyl)5-ethyl hexahydro-4H-furan[3,2-b]pyrrole-4,5-dicarboxylate (7.86 g, 27.5 mmol, yield 96%). LCMS (ESI): [M+Na] + = 308.1.
第五步:在-65 oC和氮氣氣氛下,向4-(叔丁基)5-乙基六氫-4H-呋喃[3,2-b]吡咯-4,5-二羧酸酯(2 g,7.01 mmol)和1-溴-3-氯丙烷(3.31g,21.0mmol)的四氫呋喃(20 mL)溶液中加入雙(三甲矽基)胺基鋰(1M的四氫呋喃溶液,14.0 mL,14.0 mmol)。反應在25 oC下攪拌16小時。將混合物加入飽和氯化銨水溶液(15 mL)中。然後用乙酸乙酯(15 mL * 3)萃取。有機相用無水硫酸鎂乾燥並過濾。濾液真空濃縮。殘餘物透過快速管柱層析(矽膠,0-10%梯度的四氫呋喃/石油醚)純化得到無色油狀化合物4-(叔丁基)5-乙基5-(3-氯丙基)六氫-4H-呋喃[3,2-b]吡咯-4,5-二羧酸酯(1.62 g,4.48 mmol,產率64%)。LCMS (ESI): [M-Na] += 384.2. Step 5 : To a solution of 4-(tert-butyl) 5-ethylhexahydro-4H-furan[3,2-b]pyrrole-4,5-dicarboxylate (2 g, 7.01 mmol) and 1-bromo-3-chloropropane (3.31 g, 21.0 mmol) in tetrahydrofuran (20 mL) was added bis(trimethylsilyl)amide lithium (1M tetrahydrofuran solution, 14.0 mL, 14.0 mmol) at -65 °C under nitrogen atmosphere. The reaction was stirred at 25 ° C for 16 hours. The mixture was added to a saturated aqueous ammonium chloride solution (15 mL). It was then extracted with ethyl acetate (15 mL * 3). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran/petroleum ether) to give a colorless oily compound 4-(tert-butyl) 5-ethyl 5-(3-chloropropyl) hexahydro-4H-furano[3,2-b]pyrrole-4,5-dicarboxylate (1.62 g, 4.48 mmol, yield 64%). LCMS (ESI): [M-Na] + = 384.2.
第六步:在0 oC下,向4-(叔丁基)5-乙基5-(3-氯丙基)六氫-4H-呋喃[3,2-b]吡咯-4,5-二羧酸酯(1.62 g,4.48 mmol)的二氯甲烷(16 mL)溶液中加入三氟乙酸(4 mL)。反應在20 oC下攪拌2小時。真空濃縮混合物,得到粗產物化合物5-(3-氯丙基)六氫-2H-呋喃[3,2-b]吡咯-5-羧酸乙酯(1.10 g),為黃色油狀液體。LCMS (ESI): [M+H] += 262.1. Step 6 : Add trifluoroacetic acid (4 mL) to a solution of 4-(tert-butyl)-5-ethyl-5-(3-chloropropyl)hexahydro-4H-furan[3,2-b]pyrrole-4,5-dicarboxylate (1.62 g, 4.48 mmol) in dichloromethane (16 mL) at 0 °C. Stir the reaction at 20 ° C for 2 hours. Concentrate the mixture in vacuo to obtain the crude product compound 5-(3-chloropropyl)hexahydro-2H-furan[3,2-b]pyrrole-5-carboxylic acid ethyl ester (1.10 g) as a yellow oily liquid. LCMS (ESI): [M+H] + = 262.1.
第七步:向5-(3-氯丙基)六氫-2H-呋喃[3,2-b]吡咯-5-羧酸乙酯(1.10 g,4.21 mmol)的乙醇(50 mL)溶液中加入碳酸鉀(1.74 g,12.6 mmol)和碘化鉀(0.07 g,0.42 mmol)。將混合物在25 oC攪拌16小時。過濾混合物並真空濃縮濾液,殘餘物透過快速管柱層析(矽膠,0-10%梯度的乙醇/二氯甲烷)純化得到黃色油狀化合物六氫-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-羧酸乙酯(0.86 g,3.82 mmol,產率91%)。LCMS (ESI): [M+H] += 226.1. Step 7 : Potassium carbonate (1.74 g, 12.6 mmol) and potassium iodide (0.07 g, 0.42 mmol) were added to a solution of 5-(3-chloropropyl)hexahydro-2H-furano[3,2-b]pyrrole-5-carboxylic acid ethyl ester (1.10 g, 4.21 mmol) in ethanol (50 mL). The mixture was stirred at 25 ° C for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethanol/dichloromethane) to obtain a yellow oily compound hexahydro-2H-furano[2,3-b]pyrrolazine-7a(5H)-carboxylic acid ethyl ester (0.86 g, 3.82 mmol, yield 91%). LCMS (ESI): [M+H] + = 226.1.
第八步:在-40 oC下,向六氫-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-羧酸乙酯(0.86 g,3.82 mmol)的四氫呋喃(9.00 mL)溶液中加入四氫鋰鋁(156 mg,4.12 mmol)。將混合物在-10 oC攪拌1小時。向混合物中緩慢加入水(160 uL),然後加入 15%氫氧化鈉溶液(160 uL)以及水(480 uL),加入無水硫酸鈉攪拌,過濾並用四氫呋喃洗滌濾餅。真空濃縮濾液,得到棕色油狀化合物 (六氫-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-基)甲醇(510 mg,2.78 mmol,產率72%)。LCMS (ESI): [M+H] += 184.2. 1H NMR (400 MHz, CD 3OD) δ ppm 4.52-4.48 (m, 1H), 3.98 (q, J= 8.1 Hz, 1H), 3.82 (dt, J= 4.6, 7.6 Hz, 1H), 3.56-3.48 (m, 1H), 3.33 (td, J= 1.4, 3.1 Hz, 2H), 3.00-2.91 (m, 1H), 2.87-2.77 (m, 1H), 2.19 (d, J= 14.3 Hz, 1H), 2.00-1.94 (m, 2H), 1.91-1.82 (m, 3H), 1.81-1.70 (m, 1H), 1.67-1.55 (m, 1H). 中間體 A15 :(六氫環丙[b]吡咯嗪-5a(3H)-基)甲醇 Step 8 : Add tetrahydrolithium aluminum (156 mg, 4.12 mmol) to a solution of ethyl hexahydro-2H-furano[2,3-b]pyrrolizine-7a(5H)-carboxylate (0.86 g, 3.82 mmol) in tetrahydrofuran (9.00 mL) at -40 °C. Stir the mixture at -10 ° C for 1 hour. Slowly add water (160 uL) to the mixture, then add 15% sodium hydroxide solution (160 uL) and water (480 uL), add anhydrous sodium sulfate, stir, filter and wash the filter cake with tetrahydrofuran. The filtrate was concentrated in vacuo to obtain a brown oily compound (hexahydro-2H-furano[2,3-b]pyrrolizin-7a(5H)-yl)methanol (510 mg, 2.78 mmol, yield 72%). LCMS (ESI): [M+H] + = 184.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 4.52-4.48 (m, 1H), 3.98 (q, J = 8.1 Hz, 1H), 3.82 (dt, J = 4.6, 7.6 Hz, 1H), 3.56-3.48 (m, 1H), 3.33 (td, J = 1.4, 3.1 Hz, 2H), 3.00-2.91 (m, 1H), 2.87-2.77 (m, 1H), 2.19 (d, J = 14.3 Hz, 1H), 2.00-1.94 (m, 2H), 1.91-1.82 (m, 3H), 1.81-1.70 (m, 1H), 1.67-1.55 (m, 1H). Intermediate A15 : (hexahydrocyclopropyl[b]pyrrolizine-5a(3H)-yl)methanol
第一步:在-65 oC的氮氣環境下,向 (3R)-2-叔丁基-3-乙基-2-氮雜雙環[3.1.0]己烷-2,3-二羧酸酯(950 mg,3.72 mmol)和1-溴-3-氯丙烷(1.76 g,11.1 mmol)的四氫呋喃(10 mL)溶液中加入雙三甲基矽基胺基鋰(1 M的四氫呋喃溶液,7.44 mL,7.44 mmol)。反應在25 oC下攪拌16小時。混合物中加入飽和氯化銨溶液(10 mL),然後用乙酸乙酯(10 mL * 3)萃取,有機層用無水硫酸鎂乾燥,過濾,濾液真空濃縮。殘餘物透過快速管柱層析(矽膠,0-10%梯度的四氫呋喃/二氯甲烷)純化以得到無色油狀化合物2-叔丁基-3-乙基-3-(3-氯丙基)-2-氮雜雙環[3.1.0]己烷-2,3-二羧酸酯(630 mg,1.90 mmol,產率51%)。LCMS (ESI): [M+Na] += 354.3. Step 1 : Under nitrogen atmosphere at -65 ° C, add lithium bis(trimethylsilyl)amide (1 M tetrahydrofuran solution, 7.44 mL, 7.44 mmol) to a solution of (3R)-2-tert-butyl-3-ethyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (950 mg, 3.72 mmol) and 1-bromo-3-chloropropane (1.76 g, 11.1 mmol) in tetrahydrofuran (10 mL). The reaction was stirred at 25 ° C for 16 hours. Saturated ammonium chloride solution (10 mL) was added to the mixture, and then extracted with ethyl acetate (10 mL * 3). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran/dichloromethane) to give 2-tert-butyl-3-ethyl-3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (630 mg, 1.90 mmol, 51% yield) as a colorless oil. LCMS (ESI): [M+Na] + = 354.3.
第二步:向2-叔丁基-3-乙基-3-(3-氯丙基)-2-氮雜雙環[3.1.0]己烷-2,3-二羧酸酯(610 mg,1.84 mmol)的二氯甲烷(6 mL)溶液中加入氯化氫(4 M的二氧六環溶液,1.38 mL,5.51 mmol)。反應在25 oC下攪拌16小時。真空濃縮混合物,得到無色油狀的粗產物化合物3-(3-氯丙基)-2-氮雜雙環[3.1.0]己烷-3-羧酸乙酯(60%純度,690 mg)。LCMS (ESI): [M+H] += 232.2. Step 2 : To a solution of 2-tert-butyl-3-ethyl-3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (610 mg, 1.84 mmol) in dichloromethane (6 mL) was added hydrogen chloride (4 M in dioxane, 1.38 mL, 5.51 mmol). The reaction was stirred at 25 ° C for 16 hours. The mixture was concentrated in vacuo to give the crude product compound 3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester (60% purity, 690 mg) as a colorless oil. LCMS (ESI): [M+H] + = 232.2.
第三步:向3-(3-氯丙基)-2-氮雜雙環[3.1.0]己烷-3-羧酸乙酯(60%純度,670 mg,1.73 mmol)的乙醇(26 mL)溶液中加入碘化鉀(29 mg,0.17 mmol)和碳酸鉀(719 mg,5.20 mmol)。反應在25 oC下攪拌16小時。將混合物過濾並濃縮。殘餘物透過快速管柱層析(矽膠,0-10%梯度的乙醇/二氯甲烷)純化得到黃色油狀化合物六氫環丙[b]吡咯嗪-5a(3H)-羧酸乙酯(95%純度,320 mg,1.56 mmol,產率90%)。LCMS (ESI): [M+H] += 196.1. Step 3 : Potassium iodide (29 mg, 0.17 mmol) and potassium carbonate (719 mg, 5.20 mmol) were added to a solution of 3-(3-chloropropyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester (60% purity, 670 mg, 1.73 mmol) in ethanol (26 mL). The reaction was stirred at 25 ° C for 16 hours. The mixture was filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethanol/dichloromethane) to obtain a yellow oily compound hexahydrocyclopropyl[b]pyrrolazine-5a(3H)-carboxylic acid ethyl ester (95% purity, 320 mg, 1.56 mmol, 90% yield). LCMS (ESI): [M+H] + = 196.1.
第四步:在-40 oC下,向六氫環丙[b]吡咯嗪-5a(3H)-羧酸乙酯(95%純度,310 mg,1.50 mmol)的四氫呋喃(3 mL)溶液中加入四氫鋁鋰(72 mg,1.91 mmol)。將混合物在-10 oC下攪拌1小時。反應加入水(72 uL)和15%氫氧化鈉水溶液(72 uL),然後加入水(216 uL)。加入無水硫酸鈉乾燥。過濾並用四氫呋喃(30 mL)洗滌濾餅,濾液真空濃縮以得到粗產物化合物 (六氫環丙[b]吡咯嗪-5a(3H)-基)甲醇(230 mg),為黃色油狀液體。LCMS (ESI): [M+H] += 154.1. 中間體 A16-1 和 A16-2 :順式-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇 A16-1和 反式-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇 A16-2 Step 4 : Add lithium aluminum tetrahydrate (72 mg, 1.91 mmol) to a solution of ethyl hexahydrocyclopropyl[b]pyrrolizine-5a(3H)-carboxylate (95% purity, 310 mg, 1.50 mmol) in tetrahydrofuran (3 mL) at -40 o C. Stir the mixture at -10 o C for 1 hour. Add water (72 uL) and 15% aqueous sodium hydroxide solution (72 uL) to the reaction, then add water (216 uL). Add anhydrous sodium sulfate to dry. The filter cake was filtered and washed with tetrahydrofuran (30 mL), and the filtrate was concentrated in vacuo to give a crude product compound (hexahydrocyclopropane [b] pyrrolizine-5a (3H) -yl) methanol (230 mg) as a yellow oily liquid. LCMS (ESI): [M + H] + = 154.1. Intermediates A16-1 and A16-2 : cis-2,2-difluorodihydro-1'H, 3'H-spiro [cyclopropane-1,2'-pyrrolizine] -7a'(5'H) -yl) methanol A16-1 and trans-2,2-difluorodihydro-1'H, 3'H-spiro [cyclopropane-1,2'-pyrrolizine] -7a'(5'H) -yl) methanol A16-2
第一步:將化合物1-(叔丁基)2-甲基(S)-4-伸甲基吡咯烷-1,2-二羧酸酯(2.80 g,11.6 mmol))和三甲基(三氟甲基)矽烷(4.12 g,29.0 mmol)溶於四氫呋喃(100 mL),氮氣下加入碘化鈉(0.87 g,5.81 mmol)。反應在60 oC下攪拌16小時。冷卻到室溫,加入飽和氯化銨(50 mL)淬滅,反應液用乙酸乙酯(100 mL*2)萃取,合併有機相,依次用用飽和的亞硫酸鈉(50 mL)和飽和食鹽水(50 mL)洗滌,硫酸鈉乾燥,過濾,濾液減壓濃縮得到黃色油狀化合物5-(叔丁基)6-甲基(6S)-1,1-二氟-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯(純度80%,4.00 g,11.0 mmol,產率95%)。LCMS (ESI): [M+Na] += 313.9. 1H NMR (400 MHz, CDCl 3) δ ppm 4.58-4.35 (m, 1H), 3.77 (m, 3H), 3.75-3.65 (m, 1H), 3.59-3.44 (m, 1H), 2.57 (m, 1H), 2.13-1.93 (m, 1H), 1.50-1.43 (m, 9H), 1.41-1.30 (m, 2H). Step 1 : Dissolve 1-(tert-butyl) 2-methyl (S)-4-methylpyrrolidine-1,2-dicarboxylate (2.80 g, 11.6 mmol) and trimethyl(trifluoromethyl)silane (4.12 g, 29.0 mmol) in tetrahydrofuran (100 mL), and add sodium iodide (0.87 g, 5.81 mmol) under nitrogen. The reaction was stirred at 60 ° C for 16 hours. Cool to room temperature, add saturated ammonium chloride (50 mL) to quench, extract the reaction solution with ethyl acetate (100 mL*2), combine the organic phases, wash with saturated sodium sulfite (50 mL) and saturated brine (50 mL) in sequence, dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a yellow oily compound 5-(tert-butyl) 6-methyl (6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (purity 80%, 4.00 g, 11.0 mmol, yield 95%). LCMS (ESI): [M+Na] + = 313.9. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 4.58-4.35 (m, 1H), 3.77 (m, 3H), 3.75-3.65 (m, 1H), 3.59-3.44 (m, 1H), 2.57 (m, 1H), 2.13-1.93 (m, 1H), 1.50-1.43 (m, 9H), 1.41-1.30 (m, 2H).
第二步:將化合物5-(叔丁基)6-甲基(6S)-1,1-二氟-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯(純度80%,4.00 g,11.0 mmol)溶於四氫呋喃(65 mL)降到-70 oC,氮氣下加入二異丙基胺基鋰(2 M的四氫呋喃正庚烷混合溶液,10.3 mL,20.6 mmol),反應在-70 oC攪拌1小時。加入1-溴-3-氯丙烷(4.32 g, 27.4 mmol),反應在-70 oC攪拌2小時,然後升到25 oC反應16小時。反應液用飽和氯化銨(30 mL)淬滅,用乙酸乙酯(50 mL * 2)萃取,合併有機相,用飽和食鹽水(50 mL)洗滌,硫酸鈉乾燥,過濾,濾液減壓濃縮。殘留物用快速管柱層析純化(矽膠,0-20%梯度的四氫呋喃/石油醚),得到兩個立體異構物。分離得到極性較小的無色油狀液體異構物,經二維核磁譜確認為順式構型:順式-5-(叔丁基)6-甲基-6-(3-氯丙基)-1,1-二氟-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯(1.20 g,3.26 mmol,產率30%)。LCMS (ESI): [M+Na] += 390.3. 1H NMR (400 MHz, CDCl 3) δ ppm 3.91 (m, 1H), 3.80-3.71 (m, 3H), 3.65-3.44 (m, 3H), 2.48-2.00 (m, 4H), 1.94-1.74 (m, 2H), 1.50-1.42 (m, 9H), 1.41-1.29 (m, 2H);分離得到極性較大的異構物,經二維核磁譜確認為反式構型:反式-5-(叔丁基)6-甲基-6-(3-氯丙基)-1,1-二氟-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯(純度80%,0.70 g,1.52 mmol,產率14%)。LCMS (ESI): [M-100+H] += 268.2. 1H NMR (400 MHz, CDCl 3) δ ppm 3.80-3.73 (m, 3H), 3.71 (m, 1H), 3.67-3.42 (m, 3H), 2.46-2.17 (m, 3H), 2.16-1.73 (m, 3H), 1.50-1.42 (m, 9H), 1.39-1.23 (m, 2H). Step 2 : Dissolve the compound 5-(tert-butyl)6-methyl (6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (purity 80%, 4.00 g, 11.0 mmol) in tetrahydrofuran (65 mL) and cool to -70 o C. Add lithium diisopropylamide (2 M tetrahydrofuran n-heptane mixed solution, 10.3 mL, 20.6 mmol) under nitrogen and stir at -70 o C for 1 hour. Add 1-bromo-3-chloropropane (4.32 g, 27.4 mmol) and stir at -70 o C for 2 hours, then raise to 25 o C and react for 16 hours. The reaction solution was quenched with saturated ammonium chloride (30 mL), extracted with ethyl acetate (50 mL * 2), the organic phases were combined, washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran/petroleum ether) to obtain two stereoisomers. The less polar colorless oily liquid isomer was separated and confirmed to be of cis configuration by 2D-NMR: cis-5-(tert-butyl)6-methyl-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (1.20 g, 3.26 mmol, yield 30%). LCMS (ESI): [M+Na] + = 390.3. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 3.91 (m, 1H), 3.80-3.71 (m, 3H), 3.65-3.44 (m, 3H), 2.48-2.00 (m, 4H), 1.94-1.74 (m, 2H), 1.50-1.42 (m, 9H), 1.41-1.29 (m, 2H); the more polar isomer was separated and confirmed to be in trans configuration by 2D-NMR: trans-5-(tert-butyl)6-methyl-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (purity 80%, 0.70 g, 1.52 mmol, yield 14%). LCMS (ESI): [M-100+H] + = 268.2. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 3.80-3.73 (m, 3H), 3.71 (m, 1H), 3.67-3.42 (m, 3H), 2.46-2.17 (m, 3H), 2.16-1.73 (m, 3H), 1.50-1.42 (m, 9H), 1.39-1.23 (m, 2H).
第三步:化合物順式5-(叔丁基)6-甲基-6-(3-氯丙基)-1,1-二氟-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯(1.20 g,3.26 mmol)溶於二氯甲烷(4 mL),20 oC下加入氯化氫(4 M的二氧六環溶液,2 mL,9.78 mmol),反應液在20 oC下攪拌2小時。反應液減壓濃縮得到粗產物化合物順式-6-(3-氯丙基)-1,1-二氟-5-氮雜螺[2.4]庚烷-6-羧酸甲酯(0.83 g),為白色固體。LCMS (ESI): [M+H] += 268.1 Step 3 : Compound cis-5-(tert-butyl)6-methyl-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (1.20 g, 3.26 mmol) was dissolved in dichloromethane (4 mL), and hydrogen chloride (4 M dioxane solution, 2 mL, 9.78 mmol) was added at 20 ° C. The reaction solution was stirred at 20 ° C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product compound cis-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid methyl ester (0.83 g) as a white solid. LCMS (ESI): [M+H] + = 268.1
第四步:將化合物順式-6-(3-氯丙基)-1,1-二氟-5-氮雜螺[2.4]庚烷-6-羧酸甲酯(0.83 g,3.11 mmol)溶於甲醇(2 mL),25 oC下加入碘化鉀(62 mg, 0.37 mmol)和碳酸鉀(1.55 g, 11.21 mmol)。反應在25 oC下攪拌16小時。反應液過濾,濾液減壓濃縮,殘留物用快速管柱層析純化(矽膠,0-20%梯度的四氫呋喃/石油醚)得到無色油狀化合物 順式-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-羧酸甲酯(0.25 g,1.08 mmol,兩步產率:33%)。LCMS (ESI): [M+H] += 232.1。 1H NMR (400 MHz, CDCl 3) δ ppm 3.68 (s, 3H), 3.31 (d, J= 10.9 Hz, 1H), 3.19-3.10 (m, 1H), 2.75-2.64 (m, 2H), 2.43 (d, J= 13.4 Hz, 1H), 2.37-2.30 (m, 1H), 1.91-1.74 (m, 4H), 1.30-1.22 (m, 2H) Step 4 : Dissolve the compound cis-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid methyl ester (0.83 g, 3.11 mmol) in methanol (2 mL), add potassium iodide (62 mg, 0.37 mmol) and potassium carbonate (1.55 g, 11.21 mmol) at 25 ° C. The reaction was stirred at 25 ° C for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran/petroleum ether) to obtain a colorless oily compound cis-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (0.25 g, 1.08 mmol, two-step yield: 33%). LCMS (ESI): [M+H] + = 232.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 3.68 (s, 3H), 3.31 (d, J = 10.9 Hz, 1H), 3.19-3.10 (m, 1H), 2.75-2.64 (m, 2H), 2.43 (d, J = 13.4 Hz, 1H), 2.37-2.30 (m, 1H), 1.91-1.74 (m, 4H), 1.30-1.22 (m, 2H)
第五步:將化合物順式-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-羧酸甲酯(0.25 g,1.08 mmol)溶於四氫呋喃(4 mL),0 oC下加入四氫鋁鋰(61 mg,1.62 mmol)。反應在60 oC下攪拌2小時。向反應液中加入水(61 uL),氫氧化鈉(15%水溶液,61 uL),水(183 uL),無水硫酸鎂(1 g),攪拌30分鐘,反應液過濾,濾液減壓濃縮得到無色油狀順式-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇 A16-1(0.20 g,0.96 mmol,產率89%)。LCMS (ESI): [M+H] += 204.1. 1H NMR (400 MHz, CDCl 3) δ ppm 3.35-3.28 (m, 2H), 3.23 (d, J= 11.0 Hz, 1H), 3.06 (td, J= 6.2, 10.7 Hz, 1H), 2.82-2.73 (m, 2H), 2.04 (d, J= 13.1 Hz, 1H), 1.98-1.69 (m, 5H), 1.36-1.27 (m, 2H). Step 5 : Dissolve the compound cis-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid methyl ester (0.25 g, 1.08 mmol) in tetrahydrofuran (4 mL), and add lithium aluminum tetrahydrogen (61 mg, 1.62 mmol) at 0 o C. The reaction was stirred at 60 o C for 2 hours. Water (61 uL), sodium hydroxide (15% aqueous solution, 61 uL), water (183 uL), anhydrous magnesium sulfate (1 g) were added to the reaction solution and stirred for 30 minutes. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain colorless oily cis-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-1 ( 0.20 g, 0.96 mmol, yield 89%). LCMS (ESI): [M+H] + = 204.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 3.35-3.28 (m, 2H), 3.23 (d, J = 11.0 Hz, 1H), 3.06 (td, J = 6.2, 10.7 Hz, 1H), 2.82-2.73 (m, 2H), 2.04 (d, J = 13.1 Hz, 1H), 1.98-1.69 (m, 5H), 1.36-1.27 (m, 2H).
反式-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇 A16-2參考中間體 A16-1的合成方法,將反式5-(叔丁基)6-甲基-6-(3-氯丙基)-1,1-二氟-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯按類似反應條件製備得到。LCMS (ESI): [M+H] += 204.1. 1H NMR (400 MHz, CDCl 3) δ ppm 3.43-3.28 (m, 2H), 3.16-3.04 (m, 2H), 2.81 (d, J= 12.3 Hz, 1H), 2.70-2.60 (m, 1H), 2.02-1.94 (m, 1H), 1.92-1.64 (m, 5H), 1.38-1.18 (m, 2H). 中間體 A16-1A , A16-1B , A16-2A, 和 A16-2B : (1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇 A16-1A ;(1S,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇 A16-1B ;(1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇 A16-2A和 (1R,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇 A16-2B Trans -2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-2 was prepared by referring to the synthesis method of intermediate A16-1 , and trans-5-(tert-butyl)6-methyl-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate was prepared under similar reaction conditions. LCMS (ESI): [M+H] + = 204.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 3.43-3.28 (m, 2H), 3.16-3.04 (m, 2H), 2.81 (d, J = 12.3 Hz, 1H), 2.70-2.60 (m, 1H), 2.02-1.94 (m, 1H), 1.92-1.64 (m, 5H), 1.38-1.18 (m, 2H). Intermediates A16-1A , A16-1B , A16-2A, and A16-2B : ( (1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-1A ; (1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-1B ; (1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-2A and (1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-2B
第一步:在0 oC下向 (S)-1-(叔丁氧基羰基)-4-伸甲基吡咯烷-2-羧酸(90 g,396 mmol)的二甲基甲醯胺(1.8 L)溶液中加入碳酸銫(168 g,514 mmol)和苄溴(88 g,514 mmol)。懸濁液在25 oC攪拌16小時。反應液用水(1.8 L)稀釋,乙酸乙酯(1 L * 3)萃取,有機層用無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物透過快速管柱層析(矽膠,0-25%梯度的四氫呋喃/石油醚)純化,得到無色油狀化合物2-苄基1-(叔丁基)(S)-4-伸甲基吡咯烷-1,2-二羧酸酯(120 g,378 mmol,產率95%)。LCMS (ESI): [M-100+H] += 218.1. 1H NMR (400 MHz, CDCl 3) δ ppm 7.35 (m, 5H), 5.29-5.06 (m, 2H), 5.04-4.93 (m, 2H), 4.62-4.41 (m, 1H), 4.16-4.02 (m, 2H), 3.07-2.88 (m, 1H), 2.69-2.56 (m, 1H), 1.55-1.29 (m, 9H). Step 1 : To a solution of (S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (90 g, 396 mmol) in dimethylformamide (1.8 L) was added cesium carbonate (168 g, 514 mmol) and benzyl bromide (88 g, 514 mmol) at 0 ° C. The suspension was stirred at 25 ° C for 16 hours. The reaction solution was diluted with water (1.8 L), extracted with ethyl acetate (1 L * 3), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-25% gradient of tetrahydrofuran/petroleum ether) to obtain a colorless oily compound 2-benzyl 1-(tert-butyl) (S)-4-methylpyrrolidine-1,2-dicarboxylate (120 g, 378 mmol, yield 95%). LCMS (ESI): [M-100+H] + = 218.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.35 (m, 5H), 5.29-5.06 (m, 2H), 5.04-4.93 (m, 2H), 4.62-4.41 (m, 1H), 4.16-4.02 (m, 2H), 3.07-2.88 (m, 1H), 2.69-2.56 (m, 1H), 1.55-1.29 (m, 9H).
第二步:在氮氣下向2-苄基1-(叔丁基)(S)-4-伸甲基吡咯烷-1,2-二羧酸酯(8.00 g,25.2 mmol)和三甲基(三氟甲基)矽烷(8.96 g,63.0 mmol)的四氫呋喃(300 mL)溶液中加入碘化鈉(1.89 g,12.6 mmol),並將混合物在60 oC下攪拌16小時。混合物用飽和氯化銨(50 mL)淬滅,並用水(100 mL)稀釋,乙酸乙酯(50 mL * 3)萃取。合併的有機層依次用飽和亞硫酸鈉(50 mL)和鹽水(50 mL)洗滌,經無水硫酸鈉乾燥,過濾並濃縮。粗產物透過快速管柱層析(矽膠,0-25%梯度的四氫呋喃/石油醚)純化,得到兩個異構物。極性較小的黃色油狀液體產物,由二維核磁譜確認為6-苄基5-(叔丁基)(3S,6S)-1,1-二氟-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯(5.70 g,13.2 mmol,產率48%)。LCMS (ESI): [M+Na] += 390.1. 1H NMR (400 MHz, CDCl 3) δ ppm 7.36 (m, 5H), 5.33-5.05 (m, 2H), 4.62-4.39 (m, 1H), 3.80-3.64 (m, 1H), 3.55-3.37 (m, 1H), 2.65-2.49 (m, 1H), 2.01-1.81 (m, 1H), 1.51-1.23 (m, 10H), 1.23-1.08 (m, 1H). 極性較大的黃色油狀液體產物,由二維核磁譜確認為6-苄基5-(叔丁基)(3R,6S)-1,1-二氟-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯(2.70 g,7.35 mmol,產率27%)。LCMS (ESI): [M+Na] += 390.1. 1H NMR (400 MHz, CDCl 3) δ ppm 7.41-7.28 (m, 5H), 5.35-5.01 (m, 2H), 4.61-4.34 (m, 1H), 3.79-3.60 (m, 1H), 3.53-3.38 (m, 1H), 2.50-2.32 (m, 1H), 2.17-2.03 (m, 1H), 1.51-1.28 (m, 11H). Step 2 : Sodium iodide (1.89 g, 12.6 mmol) was added to a solution of 2-benzyl 1-(tert-butyl)(S)-4-methylpyrrolidine-1,2-dicarboxylate (8.00 g, 25.2 mmol) and trimethyl(trifluoromethyl)silane (8.96 g, 63.0 mmol) in tetrahydrofuran (300 mL) under nitrogen, and the mixture was stirred at 60 ° C for 16 hours. The mixture was quenched with saturated ammonium chloride (50 mL), diluted with water (100 mL), and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with saturated sodium sulfite (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-25% gradient of tetrahydrofuran/petroleum ether) to obtain two isomers. The less polar yellow oily liquid product was confirmed by 2D-NMR to be 6-benzyl 5-(tert-butyl) (3S,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (5.70 g, 13.2 mmol, yield 48%). LCMS (ESI): [M+Na] + = 390.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.36 (m, 5H), 5.33-5.05 (m, 2H), 4.62-4.39 (m, 1H), 3.80-3.64 (m, 1H), 3.55-3.37 (m, 1H), 2.65-2.49 (m, 1H), 2.01-1.81 (m, 1H), 1.51-1.23 (m, 10H), 1.23-1.08 (m, 1H). The highly polar yellow oily liquid product was confirmed by 2D-NMR to be 6-benzyl 5-(tert-butyl)(3R,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (2.70 g, 7.35 mmol, yield 27%). LCMS (ESI): [M+Na] + = 390.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.41-7.28 (m, 5H), 5.35-5.01 (m, 2H), 4.61-4.34 (m, 1H), 3.79-3.60 (m, 1H), 3.53-3.38 (m, 1H), 2.50-2.32 (m, 1H), 2.17-2.03 (m, 1H), 1.51-1.28 (m, 11H).
第三步:在-78 oC氮氣氛圍下向6-苄基5-(叔丁基)(3R,6S)-1,1-二氟-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯(15 g,40.8 mmol)的四氫呋喃(150 mL)溶液中加入二(三甲基矽)胺基鉀(2M的四氫呋喃溶液,41 mL,82 mmol)。反應液在-78 oC攪拌1小時。向溶液中加入1-溴-3-氯丙烷(13 g,81.6 mmol)並將溶液在-78 oC下攪拌1小時。然後在25 oC攪拌14小時。溶液用水(150 mL)淬滅,乙酸乙酯(150 mL * 3)萃取並濃縮,得到粗產物化合物6-苄基5-(叔丁基)(3R,6S)-6-(3-氯丙基)-1,1-二氟-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯(20 g,含有少量6-苄基5-(叔丁基)(3R,6R)-6-(3-氯丙基)-1,1-二氟-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯),其為棕色油狀液體。LCMS (ESI): [M-56+H] += 388.1。 Step 3 : To a solution of 6-benzyl 5-(tert-butyl)(3R,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (15 g, 40.8 mmol) in tetrahydrofuran (150 mL ) was added potassium bis(trimethylsilyl)amide (2M in tetrahydrofuran, 41 mL, 82 mmol) at -78 °C under nitrogen atmosphere. The reaction solution was stirred at -78 ° C for 1 hour. 1-Bromo-3-chloropropane (13 g, 81.6 mmol) was added to the solution and the solution was stirred at -78 ° C for 1 hour. Then stirred at 25 ° C for 14 hours. The solution was quenched with water (150 mL), extracted with ethyl acetate (150 mL * 3) and concentrated to give a crude product compound 6-benzyl 5-(tert-butyl) (3R, 6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (20 g, containing a small amount of 6-benzyl 5-(tert-butyl) (3R, 6R)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate) as a brown oily liquid. LCMS (ESI): [M-56+H] + = 388.1.
第四步:在25 oC下向化合物6-苄基5-(叔丁基)(3R,6S)-6-(3-氯丙基)-1,1-二氟-5-氮雜螺[2.4]庚烷-5,6-二羧酸酯(6 g,18.1 mmol)的二氯甲烷(200 mL)溶液中加入氯化氫(4M的二氧六環溶液,100 mL,400 mmol)。將反應液在25 oC攪拌16小時。將溶液濃縮,得到粗產物化合物 (3R,6S)-6-(3-氯丙基)-1,1-二氟-5-氮雜螺[2.4]庚烷-6-羧酸苄酯(17 g),其為棕色油狀液體。LCMS (ESI): [M+H] += 344.1。 Step 4 : Add hydrogen chloride (4M in dioxane, 100 mL , 400 mmol) to a solution of 6-benzyl 5-(tert-butyl)(3R,6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (6 g, 18.1 mmol) in dichloromethane (200 mL) at 25 °C. Stir the reaction mixture at 25 ° C for 16 hours. Concentrate the solution to obtain the crude product (3R,6S)-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate (17 g) as a brown oily liquid. LCMS (ESI): [M+H] + = 344.1.
第五步:在25 oC下向化合物 (3R,6S)-6-(3-氯丙基)-1,1-二氟-5-氮雜螺[2.4]庚烷-6-羧酸苄酯(16 g,46.5 mmol)的甲醇(500 mL)溶液中加入碘化鉀(0.77 g,4.65 mmol)和碳酸鉀(19.3 g,139 mmol)。溶液在25 oC攪拌16小時。將溶液濃縮並透過製備型HPLC純化,得到棕色油狀化合物苄基(1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-羧酸酯(350 mg,1.14 mmol,產率2%),其構型由二維核磁譜確認。LCMS (ESI): [M+H] += 308.1. 1H NMR (400 MHz, CDCl 3) δ ppm 7.43-7.29 (m, 5H), 5.31-5.09 (m, 2H), 3.41 (d, J= 10.9 Hz, 1H), 3.32-3.19 (m, 1H), 2.89-2.71 (m, 2H), 2.59 (d, J= 13.4 Hz, 1H), 2.46-2.31 (m, 1H), 1.97-1.81 (m, 4H), 1.39-1.27 (m, 2H). Step 5 : Potassium iodide (0.77 g, 4.65 mmol) and potassium carbonate (19.3 g, 139 mmol) were added to a solution of (3R, 6S )-6-(3-chloropropyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid benzyl ester (16 g, 46.5 mmol) in methanol (500 mL) at 25 ° C. The solution was stirred at 25 ° C for 16 hours. The solution was concentrated and purified by preparative HPLC to obtain a brown oily compound benzyl (1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylate (350 mg, 1.14 mmol, yield 2%), and its configuration was confirmed by 2D-NMR. LCMS (ESI): [M+H] + = 308.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.43-7.29 (m, 5H), 5.31-5.09 (m, 2H), 3.41 (d, J = 10.9 Hz, 1H), 3.32-3.19 (m, 1H), 2.89-2.71 (m, 2H), 2.59 (d, J = 13.4 Hz, 1H), 2.46-2.31 (m, 1H), 1.97-1.81 (m, 4H), 1.39-1.27 (m, 2H).
第六步:在0 oC下向苄基(1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-羧酸酯(350 mg,1.14 mmol)的四氫呋喃(4 mL)溶液中加入四氫鋁鋰(259 mg,6.83 mmol)。懸浮液在60 oC下攪拌2小時。懸浮液依次用水(260 uL)、15%氫氧化鈉(260 uL)溶液和水(780 uL)淬滅。然後將無水硫酸鈉加入懸浮液中,攪拌後過濾並濃縮濾液得到黃色油狀化合物((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇 A16-1A(純度60%,300 mg,0.89 mmol,產率78%)。LCMS (ESI): [M+H] += 204.1。 Step 6 : Add lithium aluminum tetrahydrate (259 mg, 6.83 mmol) to a solution of benzyl (1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylate (350 mg, 1.14 mmol) in tetrahydrofuran (4 mL) at 0 o C. Stir the suspension at 60 o C for 2 hours. Quench the suspension with water (260 uL), 15% sodium hydroxide solution (260 uL) and water (780 uL) in sequence. Then, anhydrous sodium sulfate was added to the suspension, stirred, filtered, and the filtrate was concentrated to obtain a yellow oily compound ((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-1A ( purity 60%, 300 mg, 0.89 mmol, yield 78%). LCMS (ESI): [M+H] + = 204.1.
中間體 A16-1B, A16-2A, A16-2B參考中間體 A16-1A的合成途徑,將中間分離得到的異構物按類似條件製備得到。 中間體 A17:4,7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶 Intermediate A16-1B, A16-2A, A16-2B were prepared by referring to the synthetic route of intermediate A16-1A . Intermediate A17: 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine
第一步:向4-((叔丁氧基羰基)胺基)-6-氯-5-氟煙酸(10.0 g, 34.40 mmol)的二氯甲烷(50 mL)溶液中,在0 oC下加入氯化氫(4 M的二氧六環溶液,172 mL,688 mmol),在20 oC下攪拌16小時。混合物旋轉乾燥,得到粗產物化合物4-胺基-6-氯-5-氟煙酸(9.00 g),為白色固體。LCMS (ESI): [M+H] += 191.0. Step 1: To a solution of 4-((tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid (10.0 g, 34.40 mmol) in dichloromethane (50 mL) at 0 ° C, add hydrogen chloride (4 M in dioxane, 172 mL, 688 mmol) and stir at 20 ° C for 16 hours. The mixture was rotary dried to give the crude product compound 4-amino-6-chloro-5-fluoronicotinic acid (9.00 g) as a white solid. LCMS (ESI): [M+H] + = 191.0.
第二步:將4-胺基-6-氯-5-氟煙酸(9.00 g,34.40 mmol)溶於三氯氧磷(50 mL),將混合物氮氣保護下在90 oC下攪拌2小時。旋轉乾燥。得到粗產物化合物4-胺基-6-氯-5-氟煙醯氯(10.0 g),其為棕色固體。檢測時用甲醇淬滅得甲酯的LCMS (ESI): [M+H] += 205.1. Step 2: Dissolve 4-amino-6-chloro-5-fluoronicotinic acid (9.00 g, 34.40 mmol) in phosphorus oxychloride (50 mL) and stir the mixture at 90 ° C for 2 hours under nitrogen. Rotate to dry. The crude product compound 4-amino-6-chloro-5-fluoronicotinic acid chloride (10.0 g) is obtained as a brown solid. The methyl ester is quenched with methanol for detection. LCMS (ESI): [M+H] + = 205.1.
第三步:向4-胺基-6-氯-5-氟煙醯氯(10.0 g,34.40 mmol)的四氫呋喃(100 mL)溶液中,加入硫氰酸銨(11.8 g,155.02 mmol),然後將混合物氮氣保護下在20 oC下攪拌12小時。加入水(100 mL),使用乙酸乙酯(100 mL * 3)萃取,有機相用飽和食鹽水(100 mL)洗滌,無水硫酸鈉乾燥,過濾,旋轉乾燥。殘留物用石油醚/乙酸乙酯(體積比為1/3,20 mL)製漿,得到白色固體化合物7-氯-8-氟-2-硫代-2,3-二氫吡啶并[4,3-d]嘧啶-4(1H)-酮(5.60 g,24.18 mmol,產率70%)。LCMS (ESI): [M+H] += 232.0. Step 3: Add ammonium thiocyanate (11.8 g, 155.02 mmol) to a solution of 4-amino-6-chloro-5-fluoronicotinoyl chloride (10.0 g, 34.40 mmol) in tetrahydrofuran (100 mL), and then stir the mixture at 20 ° C for 12 hours under nitrogen protection. Add water (100 mL), extract with ethyl acetate (100 mL * 3), wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and spin dry. The residue was slurried with petroleum ether/ethyl acetate (volume ratio of 1/3, 20 mL) to obtain a white solid compound 7-chloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (5.60 g, 24.18 mmol, yield 70%). LCMS (ESI): [M+H] + = 232.0.
第四步:向7-氯-8-氟-2-硫代-2,3-二氫吡啶并[4,3-d]嘧啶-4(1H)-酮(5.60 g,24.18 mmol)的N,N-二甲基甲醯胺(56 mL)溶液中,加入甲醇鈉(1.44 g,26.59 mmol)和碘甲烷(3.26 g,22.97 mmol)。將混合物氮氣保護下在20 oC下攪拌2小時。反應液倒入水(180 mL)中,過濾出固體,真空乾燥,得到白色固體化合物7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4(3H)-酮(5.10 g,20.76 mmol,產率86%)。LCMS (ESI): [M+H] += 246.0. Step 4: To a solution of 7-chloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (5.60 g, 24.18 mmol) in N,N-dimethylformamide (56 mL), sodium methanolate (1.44 g, 26.59 mmol) and iodomethane (3.26 g, 22.97 mmol) were added. The mixture was stirred at 20 ° C for 2 hours under nitrogen protection. The reaction solution was poured into water (180 mL), the solid was filtered out, and vacuum dried to obtain a white solid compound 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (5.10 g, 20.76 mmol, yield 86%). LCMS (ESI): [M+H] + = 246.0.
第五步:將7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4(3H)-酮(1.10 g, 4.48 mmol)溶於三氯氧磷(10.0 mL),加入二異丙基乙胺(2.23 mL,13.43 mmol)。將混合物氮氣保護下在95 oC下攪拌16小時。混合物旋轉乾燥,加入乙酸乙酯(30 mL)然後加入冰水(30 mL)並分液,水相用乙酸乙酯(30 mL * 3)萃取,合併所有有機相,用無水硫酸鈉乾燥,過濾,旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-10%梯度的乙酸乙酯/石油醚),得到白色固體化合物4,7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶(1.10 g,4.17 mmol,產率93%)。LCMS (ESI): [M+H] += 264.0. 實施例 1 : 4-(4-((1R,5S,8S)-8- 胺基 -3- 氮雜雙環 [3.2.1] 辛 -3- 基 )-8- 氟 -2-(( 四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 ) 吡啶并 [4,3-d] 嘧啶 -7- 基 )-5- 乙基 -6- 氟萘 -2- 醇甲酸鹽 Step 5: Dissolve 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1.10 g, 4.48 mmol) in phosphorus oxychloride (10.0 mL) and add diisopropylethylamine (2.23 mL, 13.43 mmol). Stir the mixture at 95 ° C for 16 hours under nitrogen protection. Rotate the mixture to dryness, add ethyl acetate (30 mL) and then ice water (30 mL) and separate the layers. Extract the aqueous phase with ethyl acetate (30 mL * 3). Combine all organic phases, dry over anhydrous sodium sulfate, filter, and rotate to dryness. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate/petroleum ether) to obtain a white solid compound 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (1.10 g, 4.17 mmol, yield 93%). LCMS (ESI): [M+H] + = 264.0. Example 1 : 4-(4-((1R,5S,8S)-8- amino -3- azabicyclo [3.2.1] octan -3- yl )-8- fluoro -2-(( tetrahydro -1H- pyrrolizin -7a(5H) -yl ) methoxy ) pyrido [4,3-d] pyrimidin -7- yl )-5- ethyl -6- fluoronaphthalen -2- ol carboxylate
第一步:在-40 oC下向2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(500 mg,1.68 mmol)和二異丙基乙胺(350 uL,2.02 mmol)的二氯甲烷(5 mL)溶液中加入((1R,5S,8S)-3-氮雜雙環[3.2.1]辛基-8-基)胺基甲酸叔丁酯(381 mg,1.68 mmol)。將溶液在-40 oC下攪拌1小時。加入水(8 mL)並用乙酸乙酯(5 mL * 2)萃取,有機相合併,用硫酸鎂乾燥,過濾,濾液減壓濃縮得到黃色固體化合物叔丁基((1R,5S,8S)-3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-氮雜雙環[3.2.1]辛-8-基)胺基甲酸酯(800 mg,2.30 mmol,產率86%)。LCMS (ESI): [M+H] += 442.1 Step 1 : To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (500 mg, 1.68 mmol) and diisopropylethylamine (350 uL, 2.02 mmol) in dichloromethane (5 mL) was added tert-butyl (( 1R ,5S,8S)-3-azabicyclo[3.2.1]octyl-8-yl)carbamate (381 mg, 1.68 mmol) at -40 o C. The solution was stirred at -40 o C for 1 hour. Add water (8 mL) and extract with ethyl acetate (5 mL * 2), combine the organic phases, dry with magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a yellow solid compound tert-butyl ((1R, 5S, 8S)-3-(2,7-dichloro-8-fluoropyrido [4,3-d] pyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl) carbamate (800 mg, 2.30 mmol, yield 86%). LCMS (ESI): [M+H] + = 442.1
第二步:在25 oC下向叔丁基((1R,5S,8S)-3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-氮雜雙環[3.2.1]辛-8-基)胺基甲酸酯(800 mg,2.30 mmol)的二氧六環(9 mL)溶液中加入 (四氫-1H-吡咯嗪-7a(5H)-基)甲醇(459 mg,3.26 mmol)和二異丙基乙胺(850 mL,4.88 mmol)。將溶液在80 oC攪拌16小時。反應液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷),得到黃色固體化合物叔丁基((1R,5S,8S)-3-(7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-氮雜雙環[3.2.1]辛基-8-基)胺基甲酸酯(440 mg,0.80 mmol,產率35%)。LCMS (ESI): [M+H] += 547.3. Step 2: To a solution of tert-butyl ((1R,5S,8S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate (800 mg, 2.30 mmol) in dioxane (9 mL) was added (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (459 mg, 3.26 mmol) and diisopropylethylamine (850 mL, 4.88 mmol) at 25 ° C. The solution was stirred at 80 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow solid compound tert-butyl ((1R,5S,8S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-yl)carbamate (440 mg, 0.80 mmol, yield 35%). LCMS (ESI): [M+H] + = 547.3.
第三步:在氮氣氛圍中,向叔丁基((1R,5S,8S)-3-(7-氯-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-氮雜雙環[3.2.1]辛基-8-基)胺基甲酸酯(304 mg,0.56 mmol),2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(200 mg, 0.56 mmol),磷酸鉀(1.5 M的水溶液,1120 uL,1.68 mmol)的二氧六環(4 mL)溶液中加入甲磺酸[正丁基二(1-金剛烷基)膦](2-胺基-1,1-聯苯-2-基)鈀(II) (41 mg, 60 umol),並將混合物在100 oC下攪拌3小時。將懸浮液濃縮並透過快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷)得到棕色固體化合物叔丁基((1R,5S,8S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-氮雜雙環[3.2.1]辛-8-基)胺基甲酸叔丁酯(85%純度,120 mg,0.14 mmol,產率25%)。LCMS (ESI): [M+H] += 745.6. 第四步:將叔丁基((1R,5S,8S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-氮雜雙環[3.2.1]辛-8-基)胺基甲酸叔丁酯(110 mg,0.15 mmol)的二氯甲烷/三氟乙酸 (v/v= 4/1,1000 uL)溶液在25 oC下攪拌1小時。反應液用飽和碳酸氫鈉溶液調節pH至7。混合物真空濃縮,殘留物透過製備型HPLC透過含有甲酸系統的流動相純化得到白色固體化合物4-(4-((1R,5S,8S)-8-胺基-3-氮雜雙環[3.2.1]辛-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇(甲酸鹽,2.06 mg,3.4 umol,產率2%)。LCMS (ESI): [M+H] += 601.0; 1H NMR (400 MHz, CD 3OD) δ ppm 9.08 (s, 1H), 8.55 (br s, 1H), 7.68 (dd, J= 5.8, 9.1 Hz, 1H), 7.34-7.21 (m, 2H), 7.06 (d, J= 2.5 Hz, 1H), 4.78 (m, J= 10.6 Hz, 2H), 4.48 (s, 2H), 3.69 (br dd, J= 7.3, 12.6 Hz, 2H), 3.41 (s, 3H), 3.08-2.96 (m, 2H), 2.48 (br dd, J= 7.3, 13.1 Hz, 1H), 2.34 (br s, 2H), 2.28-1.89 (m, 11H), 1.60 (br d, J= 9.0 Hz, 2H), 0.80 (t, J= 7.4 Hz, 3H) Step 3 : In a nitrogen atmosphere, tert-butyl ((1R,5S,8S)-3-(7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-yl)carbamate (304 mg, 0.56 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (200 mg, 0.56 mmol), potassium phosphate (1.5 M aqueous solution, 1120 uL, 1.68 mmol) in dioxane (4 To the 2% 4-nitropropene (2-amino-1,1-biphenyl-2-yl)palladium methanesulfonate (41 mg, 60 umol) solution was added [n-butyldi(1-adamantyl)phosphine](2-amino-1,1-biphenyl-2-yl)palladium(II) methanesulfonate (41 mg, 60 umol), and the mixture was stirred at 100 ° C for 3 hours. The suspension was concentrated and purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give a brown solid compound tert-butyl ((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate (85% purity, 120 mg, 0.14 mmol, 25% yield). LCMS (ESI): [M+H] + = 745.6. Step 4: A solution of tert-butyl ((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)carbamate (110 mg, 0.15 mmol) in dichloromethane/trifluoroacetic acid (v/v= 4/1, 1000 uL) was stirred at 25 o C for 1 hour. The reaction solution was adjusted to pH 7 with saturated sodium bicarbonate solution. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC using a mobile phase containing a formic acid system to give a white solid compound 4-(4-((1R,5S,8S)-8-amino-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (formate salt, 2.06 mg, 3.4 umol, yield 2%). LCMS (ESI): [M+H] + = 601.0; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.08 (s, 1H), 8.55 (br s, 1H), 7.68 (dd, J = 5.8, 9.1 Hz, 1H), 7.34-7.21 (m, 2H), 7.06 (d, J = 2.5 Hz, 1H), 4.78 (m, J = 10.6 Hz, 2H), 4.48 (s, 2H), 3.69 (br dd, J = 7.3, 12.6 Hz, 2H), 3.41 (s, 3H), 3.08-2.96 (m, 2H), 2.84 (br dd, J = 7.3, 13.1 Hz, 1H), 2.34 (br s, 2H), 2.28-1.89 (m, 11H), 1.60 (br d, J = 9.0 Hz, 2H), 0.80 (t, J = 7.4 Hz, 3H)
以下實施例透過實施例 1 的合成途徑方法進行製備: 實施例 2 :4-(4-((8-氮雜雙環[3.2.1]辛-3-基)胺基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇 The following examples were prepared by the synthetic route of Example 1 : Example 2 : 4-(4-((8-azabicyclo[3.2.1]oct-3-yl)amino)-8-fluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
LCMS (ESI): [M+H] += 601.5; 1H NMR (400 MHz, CD 3OD) δ ppm 9.28 (s, 1H), 7.69 (dd, J= 5.9, 9.2 Hz, 1H), 7.36-7.21 (m, 2H), 7.05 (d, J= 2.5 Hz, 1H), 4.53 (br s, 1H), 4.05 (br s, 2H), 3.51 (br s, 2H), 3.20-3.08 (m, 2H), 2.56-1.92 (m, 20H), 0.79 (t, J= 7.3 Hz, 3H)。 實施例 3 :4-(4-(2,5-二氮雜雙環[4.1.0]庚-2-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇 LCMS (ESI): [M+H] + = 601.5; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.28 (s, 1H), 7.69 (dd, J = 5.9, 9.2 Hz, 1H), 7.36-7.21 (m, 2H), 7.05 (d, J = 2.5 Hz, 1H), 4.53 (br s, 1H), 4.05 (br s, 2H), 3.51 (br s, 2H), 3.20-3.08 (m, 2H), 2.56-1.92 (m, 20H), 0.79 (t, J = 7.3 Hz, 3H). Example 3 : 4-(4-(2,5-diazabicyclo[4.1.0]hept-2-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
LCMS (ESI): [M+H] += 573.3. 1H NMR (400 MHz, CD 3OD) δ ppm 9.78-9.71 (m, 1H), 7.63-7.55 (m, 1H), 7.22 (br d, J= 2.5 Hz, 1H), 7.19-7.18 (m, 1H), 6.97 (br s, 1H), 4.41 (br s, 2H), 3.31 (m, 1H), 3.13-2.96 (m, 5H), 2.42-2.34 (m, 1H), 2.25-1.91 (m, 12H), 1.53-1.47 (m, 1H), 0.97-0.88 (m, 1H), 0.80 (br t, J= 6.8 Hz, 1H), 0.74-0.67 (m, 3H). 實施例 4 :5-乙基-6-氟-4-(8-氟-4-(八氫喹喔啉-1(2H)-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)萘-2-醇 甲酸鹽 LCMS (ESI): [M+H] + = 573.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.78-9.71 (m, 1H), 7.63-7.55 (m, 1H), 7.22 (br d, J = 2.5 Hz, 1H), 7.19-7.18 (m, 1H), 6.97 (br s, 1H), 4.41 (br s, 2H), 3.31 (m, 1H), 3.13-2.96 (m, 5H), 2.42-2.34 (m, 1H), 2.25-1.91 (m, 12H), 1.53-1.47 (m, 1H), 0.97-0.88 (m, 1H), 0.80 (br t, J = 6.8 Hz, 1H), 0.74-0.67 (m, 3H). Example 4 : 5-ethyl-6-fluoro-4-(8-fluoro-4-(octahydroquinoxaline-1(2H)-yl)-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)naphthalen-2-ol carboxylate
LCMS (ESI): [M+H] += 615.3 1H NMR (400 MHz, CD 3OD) δ ppm 9.16-8.98 (m, 1H), 8.53-8.36 (m, 2H), 7.76-7.18 (m, 2H), 7.10-7.00 (m, 1H), 4.72-4.42 (m, 5H), 4.23-4.06 (m, 1H), 3.97-3.61 (m, 2H), 3.28-3.22 (m, 2H), 2.59-1.99 (m, 13H), 1.86 (br s, 3H), 1.51 (br s, 4H), 0.87-0.66 (m, 3H). 實施例 5 :5-乙基-6-氟-4-(8-氟-4-(5,8-二氮雜螺[3.5]壬-8-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇 LCMS (ESI): [M+H] + = 615.3 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.16-8.98 (m, 1H), 8.53-8.36 (m, 2H), 7.76-7.18 (m, 2H), 7.10-7.00 (m, 1H), 4.72-4.42 (m, 5H), 4.23-4.06 (m, 1H), 3.97-3.61 (m, 2H), 3.28-3.22 (m, 2H), 2.59-1.99 (m, 13H), 1.86 (br s, 3H), 1.51 (br s, 4H), 0.87-0.66 (m, 3H). Example 5 : 5-Ethyl-6-fluoro-4-(8-fluoro-4-(5,8-diazaspiro[3.5]nonan-8-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
LCMS (ESI): [M+H] += 601.3; 1H NMR (400 MHz, CD 3OD) δ ppm 9.19 (s, 1H), 7.73-7.66 (m, 1H), 7.36-7.21 (m, 2H), 7.09 (s, 1H), 4.69-4.68 (m, 2H), 4.28-4.04 (m, 4H), 3.76-3.65 (m, 3H), 3.10-3.04 (m, 2H), 2.52-2.44 (m, 1H), 2.37-2.29 (m, 2H), 2.26-2.05 (m, 12H), 1.97-1.86 (m, 2H), 0.84-0.74 (m, 3H) 實施例 6 :4-(4-(3,9-二氮雜雙環[3.3.1]壬烷-3-基)-8-氟-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇 甲酸鹽 LCMS (ESI): [M+H] + = 601.3; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.19 (s, 1H), 7.73-7.66 (m, 1H), 7.36-7.21 (m, 2H), 7.09 (s, 1H), 4.69-4.68 (m, 2H), 4.28-4.04 (m, 4H), 3.76-3.65 (m, 3H), 3.10-3.04 (m, 2H), 2.52-2.44 (m, 1H), 2.37-2.29 (m, 2H), 2.26-2.05 (m, 12H), 1.97-1.86 (m, 2H), 0.84-0.74 (m, 3H) Example 6 : 4-(4-(3,9-diazabicyclo[3.3.1]nonane-3-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol carboxylate
LCMS (ESI): [M+H] += 601.3; 1H NMR (400 MHz, CD 3OD) δ ppm 9.25-9.19 (m, 1H), 8.58-8.46 (m, 1H), 7.75-7.68 (m, 1H), 7.36-7.33 (m, 1H), 7.29 (t, J= 9.4 Hz, 1H), 7.10-7.06 (m, 1H), 4.99 (br s, 2H), 4.72-4.70 (m, 2H), 4.10-3.92 (m, 3H), 3.78-3.66 (m, 3H), 3.61 (br s, 2H), 2.54-2.45 (m, 1H), 2.40-2.32 (m, 2H), 2.29-2.04 (m, 11H), 2.00-1.92 (m, 1H), 1.71-1.61 (m, 1H), 0.81 (t, J= 7.4 Hz, 3H) 實施例 7 :(S)-5-乙基-6-氟-4-(8-氟-4-(2-甲基呱嗪-1-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇 二甲酸鹽 LCMS (ESI): [M+H] + = 601.3; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.25-9.19 (m, 1H), 8.58-8.46 (m, 1H), 7.75-7.68 (m, 1H), 7.36-7.33 (m, 1H), 7.29 (t, J = 9.4 Hz, 1H), 7.10-7.06 (m, 1H), 4.99 (br s, 2H), 4.72-4.70 (m, 2H), 4.10-3.92 (m, 3H), 3.78-3.66 (m, 3H), 3.61 (br s, 2H), 2.54-2.46 (m, 1H), 2.40-2.32 (m, 2H), 2.29-2.04 (m, 11H), 2.00-1.92 (m, 1H), 1.71-1.61 (m, 1H), 0.81 (t, J = 7.4 Hz, 3H) Example 7 : (S)-5-Ethyl-6-fluoro-4-(8-fluoro-4-(2-methylpiperazin-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol dicarboxylate
LCMS (ESI): [M+H] += 575.3; 1H NMR (400 MHz, CD 3OD) δ ppm 9.12 (s, 1H), 8.46 (br s, 2H), 7.71 (dd, J= 5.9, 9.0 Hz, 1H), 7.34 (d, J= 2.4 Hz, 1H), 7.28 (t, J= 9.4 Hz, 1H), 7.12-7.01 (m, 1H), 5.13 (br s, 1H), 4.69 (s, 2H), 4.67-4.58 (m, 2H), 3.90 (br s, 1H), 3.80-3.64 (m, 2H), 3.38 (br s, 2H), 3.31-3.21 (m, 3H), 2.49 (br d, J= 6.5 Hz, 1H), 2.42-2.31 (m, 2H), 2.28-2.09 (m, 7H), 1.67 (d, J= 7.0 Hz, 3H), 0.90-0.75 (m, 3H). 實施例 8 :5-乙基-6-氟-4-(8-氟-4-((1R,5S)-8-甲基-3,8-二氮雜雙環[3.2.1]基-3-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇 甲酸鹽 LCMS (ESI): [M+H] + = 575.3; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.12 (s, 1H), 8.46 (br s, 2H), 7.71 (dd, J = 5.9, 9.0 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.28 (t, J = 9.4 Hz, 1H), 7.12-7.01 (m, 1H), 5.13 (br s, 1H), 4.69 (s, 2H), 4.67-4.71 (m, 2H), 3.90 (br s, 1H), 3.80-3.74 (m, 2H), 3.38 (br s, 2H), 3.31-3.21 (m, 3H), 2.49 (br d, J = 6.5 Hz, 1H), 2.42-2.31 (m, 2H), 2.28-2.09 (m, 7H), 1.67 (d, J = 7.0 Hz, 3H), 0.90-0.75 (m, 3H). Example 8 : 5-Ethyl-6-fluoro-4-(8-fluoro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]yl-3-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol carboxylate
LCMS (ESI): [M+H] += 601.3; 1H NMR (400 MHz, CD 3OD) δ = 9.14 (s, 1H), 8.44 (br s, 1H), 7.69 (dd, J= 6.0, 9.0 Hz, 1H), 7.35-7.21 (m, 2H), 7.05 (d, J= 2.5 Hz, 1H), 4.68-4.64 (m, 4H), 3.85 (br t, J= 14.3 Hz, 2H), 3.70 (br d, J= 7.5 Hz, 2H), 3.54 (br s, 2H), 3.29-3.24 (m, 1H), 3.29-3.24 (m, 1H), 2.54-2.42 (m, 4H), 2.34 (br dd, J= 6.8, 10.8 Hz, 2H), 2.26-2.08 (m, 9H), 1.77 (br d, J= 8.0 Hz, 2H), 0.79 (t, J= 7.4 Hz, 3H). 實施例 9 :5-乙基-6-氟-4-(8-氟-4-(2,7-二氮雜螺[3.5]壬-7-基)-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇 LCMS (ESI): [M+H] + = 601.3; 1 H NMR (400 MHz, CD 3 OD) δ = 9.14 (s, 1H), 8.44 (br s, 1H), 7.69 (dd, J = 6.0, 9.0 Hz, 1H), 7.35-7.21 (m, 2H), 7.05 (d, J = 2.5 Hz, 1H), 4.68-4.64 (m, 4H), 3.85 (br t, J = 14.3 Hz, 2H), 3.70 (br d, J = 7.5 Hz, 2H), 3.54 (br s, 2H), 3.29-3.24 (m, 1H), 3.29-3.24 (m, 1H), 3H), 2.54-2.42 (m, 4H), 2.34 (br dd, J = 6.8, 10.8 Hz, 2H), 2.26-2.08 (m, 9H), 1.77 (br d, J = 8.0 Hz, 2H), 0.79 (t, J = 7.4 Hz, 3H). Example 9 : 5-Ethyl-6-fluoro-4-(8-fluoro-4-(2,7-diazaspiro[3.5]nonan-7-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
LCMS (ESI): [M+H] += 601.4. 1H NMR (400 MHz, CD 3OD) δ ppm 9.10 (s, 1H), 7.69 (dd, J= 9.17, 5.75 Hz, 1H), 7.39-7.18 (m, 2H), 7.05 (d, J= 2.45 Hz, 1H), 4.68 (s, 2H), 4.09-4.02 (m, 6H), 3.70 (br d, J= 3.79 Hz, 2H), 3.48 (br s, 2H), 2.57-2.28 (m, 4H), 2.26-2.07 (m, 12H), 1.33-1.23 (m, 3H). 實施例 10:5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(4-(吡咯烷)-1-基)呱啶-1-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇 甲酸鹽 LCMS (ESI): [M+H] + = 601.4. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.10 (s, 1H), 7.69 (dd, J = 9.17, 5.75 Hz, 1H), 7.39-7.18 (m, 2H), 7.05 (d, J = 2.45 Hz, 1H), 4.68 (s, 2H), 4.09-4.02 (m, 6H), 3.70 (br d, J = 3.79 Hz, 2H), 3.48 (br s, 2H), 2.57-2.28 (m, 4H), 2.26-2.07 (m, 12H), 1.33-1.23 (m, 3H). Example 10: 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin)-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol carboxylate
第一步: 化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(150 mg,0.19 mmol)和二異丙基乙胺(113 uL,0.65 mmol)加入到二甲基亞碸(1.2 mL)中,加入4-(吡咯烷-1-基)呱啶(30 mg,0.19 mmol),90 oC攪拌3小時。反應液加入水(3 mL),用乙酸乙酯(3 mL * 3)萃取,有機相減壓濃縮得粗產物8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(4-(吡咯烷-1-基)呱啶-1-基)吡啶并[4,3-d]嘧啶(130 mg)。LCMS (ESI): [M+H] += 843.5. Step 1 : Compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (150 mg, 0.19 mmol) and diisopropylethylamine (113 uL, 0.65 mmol) were added to dimethyl sulfoxide (1.2 mL), and 4-(pyrrolidin-1-yl)piperidine (30 mg, 0.19 mmol) was added, and stirred at 90 o C for 3 hours. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL * 3). The organic phase was concentrated under reduced pressure to obtain the crude product 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (130 mg). LCMS (ESI): [M+H] + = 843.5.
第二步:化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(4-(吡咯烷-1-基)呱啶-1-基)吡啶并[4,3-d]嘧啶(130 mg,0.15 mmol)加入到N,N-二甲基甲醯胺(2 mL)中,加入氟化銫(234 mg,1.54 mmol),20 oC攪拌1小時。反應液加入水(1500 uL)稀釋,用乙酸乙酯(3 mL * 3)萃取,有機相減壓濃縮得粗產物化合物7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(4-(吡咯烷-1-基)呱啶-1-基)吡啶并[4,3-d]嘧啶(100 mg)。LCMS (ESI): [M+H] += 687.4. Step 2 : Compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (130 mg, 0.15 mmol) was added to N,N-dimethylformamide (2 mL), and cesium fluoride (234 mg, 1.54 mmol) was added and stirred at 20 ° C for 1 hour. The reaction mixture was diluted with water (1500 uL) and extracted with ethyl acetate (3 mL * 3). The organic phase was concentrated under reduced pressure to obtain the crude product compound 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (100 mg). LCMS (ESI): [M+H] + = 687.4.
第三步:化合物7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(4-(吡咯烷-1-基)呱啶-1-基)吡啶并[4,3-d]嘧啶(100 mg,0.13 mmol)加入到三氟乙酸/二氯甲烷(體積比為4:1,2.5 mL)中,20 oC攪拌2小時。反應液減壓濃縮,殘留物加入乙腈(500 uL),加入三乙胺調節pH到8,殘留物用製備型HPLC純化,得到黃色固體化合物5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(4-(吡咯烷)-1-基)呱啶-1-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇(甲酸鹽,21.1 mg,32 umol,產率25%)。LCMS (ESI): [M+H] += 643.0; 1H NMR (400 MHz, CD 3OD) δ ppm 9.04 (s, 1H), 8.54 (br s, 1H), 7.89 (dd, J= 5.6, 9.2 Hz, 1H), 7.44-7.31 (m, 2H), 7.25 (s, 1H), 5.50-5.30 (m, 1H), 4.78 (br d, J= 13.1 Hz, 2H), 4.48-4.34 (m, 2H), 3.55-3.37 (m, 6H), 3.26-3.11 (m, 6H), 2.49-2.20 (m, 5H), 2.14-1.87 (m, 9H). Step 3 : Compound 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidine (100 mg, 0.13 mmol) was added to trifluoroacetic acid/dichloromethane (volume ratio 4:1, 2.5 mL) and stirred at 20 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, acetonitrile (500 uL) was added to the residue, and triethylamine was added to adjust the pH to 8. The residue was purified by preparative HPLC to obtain a yellow solid compound 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (formate, 21.1 mg, 32 umol, yield 25%). LCMS (ESI): [M+H] + = 643.0; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.04 (s, 1H), 8.54 (br s, 1H), 7.89 (dd, J = 5.6, 9.2 Hz, 1H), 7.44-7.31 (m, 2H), 7.25 (s, 1H), 5.50-5.30 (m, 1H), 4.78 (br d, J = 13.1 Hz, 2H), 4.48-4.34 (m, 2H), 3.55-3.37 (m, 6H), 3.26-3.11 (m, 6H), 2.49-2.20 (m, 5H), 2.14-1.87 (m, 9H).
以下實施例透過實施例 10 的合成途徑方法進行製備: 實施例 11:5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(4-嗎啉呱啶-1-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇 甲酸鹽 The following examples were prepared by the synthetic route of Example 10 : Example 11: 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4-piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol carboxylate
LCMS (ESI): [M+H] += 659.3; 1H NMR (400 MHz, CD 3OD) δ ppm 9.06 (s, 1H), 8.45 (br s, 1H), 7.89 (dd, J=5.7, 9.1 Hz, 1H), 7.45-7.31 (m, 2H), 7.26 (s, 1H), 5.65-5.41 (m, 1H), 4.78 (br d, J=13.0 Hz, 2H), 4.63 (br s, 2H), 3.96-3.71 (m, 7H), 3.55-3.35 (m, 4H), 2.90-2.68 (m, 5H), 2.66-2.10 (m, 8H), 1.80 (br s, 2H). 實施例 12:4-(4-([1,4'-雙呱啶]-1'-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)- 基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇 LCMS (ESI): [M+H] + = 659.3; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.06 (s, 1H), 8.45 (br s, 1H), 7.89 (dd, J =5.7, 9.1 Hz, 1H), 7.45-7.31 (m, 2H), 7.26 (s, 1H), 5.65-5.41 (m, 1H), 4.78 (br d, J =13.0 Hz, 2H), 4.63 (br s, 2H), 3.96-3.71 (m, 7H), 3.55-3.35 (m, 4H), 2.90-2.71 (m, 5H), 2.66-2.10 (m, 8H), 1.80 (br s, 2H). Example 12 : 4-(4-([1,4'-piperidinyl]-1'-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS (ESI): [M+H] += 657.3; 1H NMR (400 MHz, CD 3OD) δ ppm 9.00 (s, 1H), 7.88 (dd, J=5.8, 9.1 Hz, 1H), 7.40-7.28 (m, 2H), 7.27-7.18 (m, 1H), 5.41-5.22 (m, 1H), 4.77 (br d, J=13.3 Hz, 2H), 4.35-4.22 (m, 2H), 3.47-3.38 (m, 3H), 3.29-3.18 (m, 3H), 3.06-2.97 (m, 1H), 2.80-2.73 (m, 1H), 2.67 (br s, 4H), 2.28-2.21 (m, 1H), 2.14 (br d, J=10.6 Hz, 3H), 2.05-1.89 (m, 3H), 1.84-1.74 (m, 2H), 1.67 (br d, J=4.5 Hz, 5H), 1.53 (br d, J=3.9 Hz, 2H). 實施例 13:5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(六氫吡咯并[3,4-c]吡咯-2(1H)-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇甲酸鹽 LCMS (ESI): [M+H] + = 657.3; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.00 (s, 1H), 7.88 (dd, J =5.8, 9.1 Hz, 1H), 7.40-7.28 (m, 2H), 7.27-7.18 (m, 1H), 5.41-5.22 (m, 1H), 4.77 (br d, J =13.3 Hz, 2H), 4.35-4.22 (m, 2H), 3.47-3.38 (m, 3H), 3.29-3.18 (m, 3H), 3.06-2.97 (m, 1H), 2.80-2.73 (m, 1H), 2.67 (br s, 4H), 2.28-2.21 (m, 1H), 2.14 (br d, J =10.6 Hz, 3H), 2.05-1.89 (m, 3H), 1.84-1.74 (m, 2H), 1.67 (br d, J =4.5 Hz, 5H), 1.53 (br d, J =3.9 Hz, 2H). Example 13 : 5-Ethynyl-6-fluoro-4-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-olcarboxylate
LCMS (ESI): [M+H] += 601.3; 1H NMR (400 MHz, CD 3OD) δ ppm 9.25 (s, 1H), 8.49 (br s, 1H), 7.89 (dd, J=5.8, 9.0 Hz, 1H), 7.41-7.29 (m, 2H), 7.24 (d, J=2.0 Hz, 1H), 5.59-5.37 (m, 1H), 4.61-4.50 (m, 2H), 4.38 (br s, 2H), 4.25-4.10 (m, 2H), 3.85-3.57 (m, 5H), 3.47-3.36 (m, 5H), 3.28 (br s, 1H), 2.66-2.41 (m, 2H), 2.37-2.29 (m, 1H), 2.28-2.17 (m, 2H), 2.15-2.05 (m, 1H). 實施例 14:5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-((3aR,6aS))-5-甲基六氫吡咯并[3,4-c]吡咯-2(1H)-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇甲酸鹽 LCMS (ESI): [M+H] + = 601.3; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.25 (s, 1H), 8.49 (br s, 1H), 7.89 (dd, J =5.8, 9.0 Hz, 1H), 7.41-7.29 (m, 2H), 7.24 (d, J =2.0 Hz, 1H), 5.59-5.37 (m, 1H), 4.61-4.50 (m, 2H), 4.38 (br s, 2H), 4.25-4.10 (m, 2H), 3.85-3.57 (m, 5H), 3.47-3.36 (m, 5H), 3.28 (br s, 1H), 2.66-2.41 (m, 2H), 2.37-2.29 (m, 1H), 2.28-2.17 (m, 2H), 2.15-2.05 (m, 1H). Example 14 : 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((3aR,6aS))-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol carboxylate
LCMS (ESI): [M+H] += 615.2; 1H NMR (400 MHz, CD 3OD) δ ppm 9.25 (s, 1H), 8.58-8.26 (m, 1H), 7.99-7.78 (m, 1H), 7.42-7.30 (m, 2H), 7.26-7.15 (m, 1H), 5.66-5.35 (m, 1H), 4.66-4.54 (m, 2H), 4.44-4.33 (m, 2H), 4.26-4.14 (m, 2H), 3.91-3.67 (m, 3H), 3.44-3.41 (m, 1H), 3.41-3.34 (m, 3H), 3.18 (br s, 4H), 2.73-2.65 (m, 3H), 2.64-2.47 (m, 2H), 2.41-2.33 (m, 1H), 2.32-2.22 (m, 2H), 2.18-2.02 (m, 1H). 實施例 15:11-(7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-2,7,11-三氮雜二螺 [3.0.4 5.3 4]十二烷-6-一 甲酸鹽 LCMS (ESI): [M+H] + = 615.2; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.25 (s, 1H), 8.58-8.26 (m, 1H), 7.99-7.78 (m, 1H), 7.42-7.30 (m, 2H), 7.26-7.15 (m, 1H), 5.66-5.35 (m, 1H), 4.66-4.54 (m, 2H), 4.44-4.33 (m, 2H), 4.26-4.14 (m, 2H), 3.91-3.67 (m, 3H), 3.44-3.41 (m, 1H), 3.41-3.34 (m, 3H), 3.18 (br s, 4H), 2.73-2.65 (m, 3H), 2.64-2.47 (m, 2H), 2.41-2.33 (m, 1H), 2.32-2.22 (m, 2H), 2.18-2.02 (m, 1H). Example 15 : 11-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,7,11-triazabispiro[3.0.4 5 .3 4 ]dodecane-6-monocarboxylate
LCMS (ESI): [M+H] += 669.9; 1H NMR (400 MHz, CD 3OD) δ ppm 9.24 (br s, 1H), 8.47 (br s, 1H), 7.87 (dd, J= 9.07, 5.82Hz, 1H), 7.38-7.34 (m, 2H), 7.21 (d, J= 2.13Hz, 1H), 5.60-5.32 (m, 1H), 4.67-4.44 (m, 5H), 4.29-4.09 (m, 4H), 3.79 (br d, J= 13.13Hz, 1H), 3.70-3.62 (m, 2H), 3.55-3.48 (m, 2H), 3.40-3.35 (m, 1H), 2.70-1.93 (m, 10H). 實施例 16:4-(4-((1R,2R,4S,5S)-3,3-二氟-7,9-二氮雜三環[3.3.1.0 2,4]壬-7-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇 LCMS (ESI): [M+H] + = 669.9; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.24 (br s, 1H), 8.47 (br s, 1H), 7.87 (dd, J = 9.07, 5.82Hz, 1H), 7.38-7.34 (m, 2H), 7.21 (d, J = 2.13Hz, 1H), 5.60-5.32 (m, 1H), 4.67-4.44 (m, 5H), 4.29-4.09 (m, 4H), 3.79 (br d, J = 13.13Hz, 1H), 3.72-3.81 (m, 2H), 3.80-3.91 (m, 2H), 3.40-3.35 (m, 1H), 2.70-1.93 (m, 10H). Example 16 : 4-(4-((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
第一步:向化合物 (1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮雜雙環[3.2.1]辛-6-烯-3-羧酸叔丁酯(2.00 g,6.08 mmol)的二氯甲烷(32 mL)溶液中加入三氟乙酸(8 mL),反應在50 oC攪拌16小時。反應液減壓濃縮,殘餘物溶於水中(32 mL),乙酸乙酯洗滌(32 mL*2),水相凍乾得到粗產物化合物 (1R,5S)-3,8-二氮雜雙環[3.2.1]辛-6-烯(3.7 g),其為黃色油狀液體。LCMS (ESI): [M+H] += 111.2; Step 1 : Add trifluoroacetic acid (8 mL) to a solution of (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylic acid tert-butyl ester (2.00 g, 6.08 mmol) in dichloromethane (32 mL), and stir at 50 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (32 mL), washed with ethyl acetate (32 mL*2), and the aqueous phase was freeze-dried to obtain a crude product compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (3.7 g), which was a yellow oily liquid. LCMS (ESI): [M+H] + = 111.2;
第二步:向化合物 (1R,5S)-3,8-二氮雜雙環[3.2.1]辛-6-烯(1.20 g,3.55 mmol)和二異丙基乙胺(5.8 mL,35.5 mmol)的二氯甲烷(12 mL)溶液中加入苯甲醯氯(1.65 mL,14.2 mmol),反應在25 oC攪拌16小時。反應液在0 oC下用水(40 mL)淬滅,二氯甲烷(20 mL * 3)萃取,合併的有機相用飽和食鹽水(10 mL)洗滌,硫酸鈉乾燥,過濾,減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-50%梯度的四氫呋喃/石油醚)得到白色固體化合物 ((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-6-烯-3,8-二基)雙(苯基甲酮)(0.60 g,1.18 mmol,產率53%)。LCMS (ESI): [M+H] += 319.0; Step 2: Add benzoyl chloride (1.65 mL, 14.2 mmol) to a solution of (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (1.20 g, 3.55 mmol) and diisopropylethylamine (5.8 mL, 35.5 mmol) in dichloromethane (12 mL) and stir the reaction at 25 ° C for 16 hours. The reaction solution was quenched with water (40 mL) at 0 o C, extracted with dichloromethane (20 mL * 3), the combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-50% gradient of tetrahydrofuran/petroleum ether) to obtain a white solid compound ((1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-diyl)bis(phenyl ketone) (0.60 g, 1.18 mmol, yield 53%). LCMS (ESI): [M+H] + = 319.0;
第三步:將化合物 ((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-6-烯-3,8-二基)雙(苯基甲酮)(400 mg,1.25 mmol),四丁基溴化銨(40 mg,0.13 mmol)溶於甲苯(5 mL),氮氣保護下加入 (溴二氟甲基)三甲基矽烷(5.10 g,25.1 mmol),反應在110 oC攪拌16小時。反應液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,50%梯度的四氫呋喃/石油醚)得到黃色油狀化合物 ((1R,2R,4S,5S)-3,3-二氟-7,9-二氮雜三環[3.3.1.0 2,4]壬烷-7,9-二基)雙(苯基甲酮)(200 mg,0.54 mmol,產率43%)。LCMS (ESI): [M+H] += 369.3; Step 3: Dissolve the compound ((1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-diyl)bis(phenyl ketone) (400 mg, 1.25 mmol) and tetrabutylammonium bromide (40 mg, 0.13 mmol) in toluene (5 mL). Add (bromodifluoromethyl)trimethylsilane (5.10 g, 25.1 mmol) under nitrogen protection and stir the reaction at 110 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 50% gradient of tetrahydrofuran/petroleum ether) to obtain a yellow oily compound ((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane-7,9-diyl)bis(phenyl ketone) (200 mg, 0.54 mmol, yield 43%). LCMS (ESI): [M+H] + = 369.3;
第四步:將化合物 ((1R,2R,4S,5S)-3,3-二氟-7,9-二氮雜三環[3.3.1.0 2,4]壬烷-7,9-二基)雙(苯基甲酮)(200 mg,0.25 mmol)溶於6M的鹽酸(2 mL)中,反應在100 oC攪拌16小時。反應液用EtOAc(2 mL * 3)洗滌,水相凍乾得到粗產物化合物 (1R,2R,4S,5S)-3,3-二氟-7,9-二氮雜三環[3.3.1.0 2,4]壬烷(二鹽酸鹽,120 mg),其為白色固體。 1H NMR (400MHz, D 2O) δ ppm 4.53 (d, J= 2.0 Hz, 2H), 3.66-3.47 (m, 4H), 2.71 (dd, J= 0.9, 11.9 Hz, 2H). Step 4: Dissolve the compound ((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane-7,9-diyl)bis(phenyl ketone) (200 mg, 0.25 mmol) in 6M hydrochloric acid (2 mL) and stir at 100 ° C for 16 hours. The reaction solution was washed with EtOAc (2 mL * 3) and the aqueous phase was freeze-dried to obtain the crude product compound (1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (dihydrochloride, 120 mg) as a white solid. 1 H NMR (400 MHz, D 2 O) δ ppm 4.53 (d, J = 2.0 Hz, 2H), 3.66-3.47 (m, 4H), 2.71 (dd, J = 0.9, 11.9 Hz, 2H).
第五步:將化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇(200 mg,0.66 mmol),(1R,2R,4S,5S)-3,3-二氟-7,9-二氮雜三環[3.3.1.0 2,4]壬烷(二鹽酸鹽,0.43 mmol)和二異丙基乙胺(748 uL,4.29 mmol)溶於二甲基乙醯胺(1.0 mL),0 oC下加入苯并三唑-1-氧代-三(二甲胺基磷)六氟磷鹽(280 mg,0.63 mmol),反應在50 oC攪拌2小時。降至在0 oC後,反應用飽和碳酸氫鈉(10 mL)淬滅,乙酸乙酯(10 mL * 3)萃取,合併的有機相用飽和食鹽水(10 mL)洗滌,硫酸鈉乾燥,過濾,減壓濃縮得到粗產物化合物 (1R,2R,4S,5S)-3,3-二氟-7-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-7,9-二氮雜三環[3.3.1.0 2,4]壬烷(200 mg),其為黃色油狀液體。LCMS (ESI): [M/2+H] += 425.0; Step 5: Compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (200 mg, 0.66 mmol), (1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (dihydrochloride, 0.43 mmol) and diisopropylethylamine (748 uL, 4.29 mmol) were dissolved in dimethylacetamide (1.0 mL), 0. Benzotriazole-1-oxo-tris(dimethylaminophosphine)hexafluorophosphonium salt (280 mg, 0.63 mmol) was added at 50°C and the reaction was stirred at 50 ° C for 2 hours. After cooling to 0 o C, the reaction mixture was quenched with saturated sodium bicarbonate (10 mL), extracted with ethyl acetate (10 mL * 3), and the combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product compound (1R, 2R, 4S, 5S)-3,3-difluoro-7-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (200 mg), which is a yellow oily liquid. LCMS (ESI): [M/2+H] + = 425.0;
第六步:化合物(1R,2R,4S,5S)-3,3-二氟-7-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-7,9-二氮雜三環[3.3.1.0 2,4]壬烷(200 mg,0.22 mmol)加入到N,N-二甲基甲醯胺(2 mL)中,加入氟化銫(343 mg,2.20 mmol),20 oC攪拌1小時。反應液加入水(2 mL)稀釋,用乙酸乙酯(3 mL * 3)萃取,有機相減壓濃縮得到粗產物化合物 (1R,2R,4S,5S)-7-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,3-二氟-7,9-二氮雜三環[3.3.1.0 2,4]壬烷(250 mg)。LCMS (ESI): [M+H] += 693.2. Step 6: Compound (1R,2R,4S,5S)-3,3-difluoro-7-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (200 mg, 0.22 mmol) was added to N,N-dimethylformamide (2 mL), and cesium fluoride (343 mg, 2.20 mmol) was added, and stirred at 20 ° C for 1 hour. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 mL * 3). The organic phase was concentrated under reduced pressure to obtain a crude product compound (1R,2R,4S,5S)-7-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (250 mg). LCMS (ESI): [M+H] + = 693.2.
第七步:向化合物 (1R,2R,4S,5S)-7-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,3-二氟-7,9-二氮雜三環[3.3.1.0 2,4]壬烷(250 mg,0.36 mmol)的乙腈(0.5 mL)溶液中加入氯化氫(4 M 的二氧六環溶液,340 uL),反應在20 oC攪拌1小時。反應液減壓濃縮,殘留物加入乙腈(500 uL),加入三乙胺調節pH到8,殘留物用製備型HPLC純化,得到黃色固體化合物4-(4-((1R,2R,4S,5S)-3,3-二氟-7,9-二氮雜三環[3.3.1.0 2,4]壬-7-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(4.71 mg,18 umol,產率5%)。LCMS (ESI): [M+H] += 648.8。 1H NMR (400MHz, CD 3OD) δ ppm 9.07 (s, 1H), 7.88 (dd, J= 5.8, 9.3 Hz, 1H), 7.42-7.30 (m, 2H), 7.21 (d, J= 2.5 Hz, 1H), 5.45-5.26 (m, 1H), 4.85-4.68 (m, 4H), 4.41-4.28 (m, 2H), 3.92-3.77 (m, 4H), 3.44 (m, 2H), 3.15-3.04 (m, 1H), 2.45-2.16 (m, 5H), 2.10-1.92 (m, 3H). 實施例 17:5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-((1R,2R,4S,5S)-3-(三甲基矽基)-7,9-二氮雜三環[3.3.1.0 2,4]壬-7-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇 Step 7: To a solution of (1R,2R,4S,5S)-7-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (250 mg, 0.36 mmol) in acetonitrile (0.5 mL) was added hydrogen chloride (4 M in dioxane, 340 uL) and the reaction was stirred at 20 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, acetonitrile (500 uL) was added to the residue, and triethylamine was added to adjust the pH to 8. The residue was purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,2R,4S,5S)-3,3-difluoro-7,9-diazatricyclo[3.3.1.0 2,4 ]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (4.71 mg, 18 umol, yield 5%). LCMS (ESI): [M+H] + = 648.8. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.07 (s, 1H), 7.88 (dd, J = 5.8, 9.3 Hz, 1H), 7.42-7.30 (m, 2H), 7.21 (d, J = 2.5 Hz, 1H), 5.45-5.26 (m, 1H), 4.85-4.68 (m, 4H), 4.41-4.28 (m, 2H), 3.92-3.77 (m, 4H), 3.44 (m, 2H), 3.15-3.04 (m, 1H), 2.45-2.16 (m, 5H), 2.10-1.92 (m, 3H). Example 17 :5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]non-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
第一步:向化合物 (1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮雜雙環[3.2.1]辛-6-烯-3-羧酸叔丁酯(1.00 g,3.04 mmol)的二氯甲烷(16 mL)溶液中加入三氟乙酸(4 mL),反應在50 oC攪拌16小時。反應液減壓濃縮,殘餘物溶於水(16 mL)中,用乙酸乙酯(16 mL*2)洗滌,水相凍乾得到粗產物化合物(1R,5S)-3,8-二氮雜雙環[3.2.1]辛-6-烯(2.80 g),其為黃色油狀。LCMS (ESI): [M+H] += 111.2。 1H NMR (500MHz, D 2O) δ ppm 6.37 (s, 2H), 3.48 (dd, J= 1.5, 14.3 Hz, 2H), 3.38-3.29 (m, 2H). Step 1: Add trifluoroacetic acid (4 mL) to a solution of (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylic acid tert-butyl ester (1.00 g, 3.04 mmol) in dichloromethane (16 mL), and stir at 50 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (16 mL), washed with ethyl acetate (16 mL*2), and the aqueous phase was freeze-dried to obtain a crude product compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (2.80 g) as a yellow oil. LCMS (ESI): [M+H] + = 111.2. 1 H NMR (500 MHz, D 2 O) δ ppm 6.37 (s, 2H), 3.48 (dd, J = 1.5, 14.3 Hz, 2H), 3.38-3.29 (m, 2H).
第二步:向化合物 (1R,5S)-3,8-二氮雜雙環[3.2.1]辛-6-烯(1.20 g,1.31 mmol)和二異丙基乙胺(5.36 mL,38.4 mmol)的二氯甲烷(12 mL)溶液中加入二碳酸二叔丁酯(5.00 mL,23.1 mmol),反應在25 oC攪拌16小時。反應液在0 oC下用水(40 mL)淬滅,二氯甲烷(20 mL * 3)萃取,合併的有機相用飽和食鹽水(10 mL)洗滌,硫酸鈉乾燥,過濾,減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-20%梯度的四氫呋喃/石油醚)得到白色固體化合物 (1R,5S)-3,8-二氮雜雙環[3.2.1]辛-6-烯-3,8-二羧酸二叔丁酯(0.35 g,1.12 mmol,產率86%)。LCMS (ESI): [M+Na] += 333.1。 1H NMR (400 MHz, CDCl 3) δ ppm 6.18 (br s, 2H), 4.56 (br s, 2H), 3.78 (br d, J= 12.8 Hz, 1H), 3.64 (br d, J= 12.8 Hz, 1H), 3.26-3.02 (m, 2H), 1.50-1.44 (m, 18H). Step 2: Add di-tert-butyl dicarbonate (5.00 mL, 23.1 mmol) to a solution of (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene (1.20 g, 1.31 mmol) and diisopropylethylamine (5.36 mL, 38.4 mmol) in dichloromethane (12 mL) and stir the mixture at 25 ° C for 16 hours. The reaction solution was quenched with water (40 mL) at 0 o C, extracted with dichloromethane (20 mL * 3), the combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran/petroleum ether) to obtain a white solid compound (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-dicarboxylic acid di-tert-butyl ester (0.35 g, 1.12 mmol, yield 86%). LCMS (ESI): [M+Na] + = 333.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 6.18 (br s, 2H), 4.56 (br s, 2H), 3.78 (br d, J = 12.8 Hz, 1H), 3.64 (br d, J = 12.8 Hz, 1H), 3.26-3.02 (m, 2H), 1.50-1.44 (m, 18H).
第三步:將化合物 (1R,5S)-3,8-二氮雜雙環[3.2.1]辛-6-烯-3,8-二羧酸二叔丁酯(200 mg,0.61 mmol)和 (三甲基矽基)重氮甲烷(2M 的正己烷溶液,3.00 mL,6.10 mmol)溶於二氯甲烷(4 mL),氮氣保護下加入醋酸鈀(27.0 mg,0.12 mmol),反應在20 oC攪拌16小時。反應液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,10%梯度的甲醇/二氯甲烷)得到黃色油狀化合物 (1R,2R,4S,5S)-3-(三甲基矽基)-7,9-二氮雜三環[3.3.1.0 2,4]壬烷-7,9-二羧酸二叔丁酯(130 mg,0.32 mmol,產率53%)。LCMS (ESI): [M+Na] += 419.0。 1H NMR (400MHz, CDCl 3) δ ppm 4.10 (br d, J= 19.0 Hz, 1H), 4.01-3.90 (m, 2H), 3.82 (br d, J= 12.6 Hz, 1H), 3.20-2.95 (m, 2H), 1.50 (m, 18H), 1.18 (br t, J= 5.4 Hz, 1H), 1.11-1.05 (m, 1H), 0.04 -0.05 (m, 9H), -0.50 (t, J= 4.8 Hz, 1H). Step 3: Dissolve (1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-ene-3,8-dicarboxylic acid di-tert-butyl ester (200 mg, 0.61 mmol) and (trimethylsilyl)diazomethane (2M in n-hexane, 3.00 mL, 6.10 mmol) in dichloromethane (4 mL). Add sodium acetate (27.0 mg, 0.12 mmol) under nitrogen protection and stir the reaction at 20 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 10% gradient methanol/dichloromethane) to obtain a yellow oily compound (1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane-7,9-dicarboxylic acid di-tert-butyl ester (130 mg, 0.32 mmol, yield 53%). LCMS (ESI): [M+Na] + = 419.0. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 4.10 (br d, J = 19.0 Hz, 1H), 4.01-3.90 (m, 2H), 3.82 (br d, J = 12.6 Hz, 1H), 3.20-2.95 (m, 2H), 1.50 (m, 18H), 1.18 (br t, J = 5.4 Hz, 1H), 1.11-1.05 (m, 1H), 0.04 -0.05 (m, 9H), -0.50 (t, J = 4.8 Hz, 1H).
第四步:將化合物 (1R,2R,4S,5S)-3-(三甲基矽基)-7,9-二氮雜三環[3.3.1.0 2,4]壬烷-7,9-二羧酸二叔丁酯(100 mg,0.25 mmol)溶於二氯甲烷(1 mL),0 oC下加入氯化氫(4 M 的二氧六環溶液,630 uL),反應在20 oC攪拌1小時。反應液減壓濃縮得到粗產物化合物 (1R,2R,4S,5S)-3-(三甲基矽基)-7,9-二氮雜三環[3.3.1.0 2,4]壬烷(二鹽酸鹽,65 mg),其為黃色油狀液體。LCMS (ESI): [M+H] += 197.1。 Step 4: Dissolve the compound (1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane-7,9-dicarboxylic acid di-tert-butyl ester (100 mg, 0.25 mmol) in dichloromethane (1 mL), add hydrogen chloride (4 M dioxane solution, 630 uL) at 0 o C, and stir the reaction at 20 o C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product compound (1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (dihydrochloride, 65 mg), which is a yellow oily liquid. LCMS (ESI): [M+H] + = 197.1.
第五步:將化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇(170 mg,0.24 mmol),(1R,2R,4S,5S)-3-(三甲基矽基)-7,9-二氮雜三環[3.3.1.0 2,4]壬烷(二鹽酸鹽,65 mg,0.24 mmol)和二異丙基乙胺(420 uL,2.41 mmol)溶於二甲基乙醯胺(1.7 mL),0 oC下加入苯并三唑-1-氧代-三(二甲胺基磷)六氟磷鹽(160 mg,0.36 mmol),反應在50 oC攪拌2小時。在0 oC下用飽和碳酸氫鈉(10 mL)淬滅,乙酸乙酯(10 mL * 3)萃取,合併的有機相用飽和食鹽水(10 mL)洗滌,硫酸鈉乾燥,過濾,減壓濃縮得到粗產物化合物 (1R,2R,4S,5S)-7-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-(三甲基矽基)-7,9-二氮雜三環[3.3.1.0 2,4]壬烷(200 mg),其為黃色油狀液體。LCMS (ESI): [M+H] += 885.6; Step 5: Compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (170 mg, 0.24 mmol), (1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazotricyclo[3.3.1.0 2,4 ]nonane (dihydrochloride, 65 mg, 0.24 mmol) and diisopropylethylamine (420 uL, 2.41 mmol) were dissolved in dimethylacetamide (1.7 mL), 0. Benzotriazole-1-oxo-tris(dimethylaminophosphine)hexafluorophosphonium salt (160 mg, 0.36 mmol) was added at 50 °C and the reaction was stirred at 50 ° C for 2 hours. The mixture was quenched with saturated sodium bicarbonate (10 mL) at 0 ° C, extracted with ethyl acetate (10 mL * 3), and the combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product compound (1R, 2R, 4S, 5S)-7-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (200 mg), which is a yellow oily liquid. LCMS (ESI): [M+H] + = 885.6;
第六步:化合物 (1R,2R,4S,5S)-7-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-(三甲基矽基)-7,9-二氮雜三環[3.3.1.0 2,4]壬烷(200 mg,0.22 mmol)加入到N,N-二甲基甲醯胺(2 mL)中,加入氟化銫(343 mg,2.20 mmol),20 oC攪拌1小時。反應液加入水(2 mL)稀釋,用乙酸乙酯(3 mL * 3)萃取,有機相減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷)得到 (1R,2R,4S,5S)-7-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-(三甲基矽基)-7,9-二氮雜三環[3.3.1.0 2,4]壬烷(100 mg,0.22 mmol,產率60%)。LCMS (ESI): [M+H] += 728.8. Step 6: Compound (1R,2R,4S,5S)-7-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (200 mg, 0.22 mmol) was added to N,N-dimethylformamide (2 mL), and cesium fluoride (343 mg, 2.20 mmol) was added, and stirred at 20 ° C for 1 hour. The reaction solution was diluted with water (2 mL), extracted with ethyl acetate (3 mL * 3), the organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain (1R,2R,4S,5S)-7-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (100 mg, 0.22 mmol, yield 60%). LCMS (ESI): [M+H] + = 728.8.
第七步:向化合物 (1R,2R,4S,5S)-7-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-(三甲基矽基)-7,9-二氮雜三環[3.3.1.0 2,4]壬烷(100 mg,0.14 mmol)的乙腈溶液中加入氯化氫(4 M 的二氧六環溶液,630 uL),反應在20 oC攪拌1小時。反應液減壓濃縮,殘留物溶於乙腈(500 uL),加入三乙胺調節pH到8,殘留物用製備型HPLC純化,得到黃色固體化合物5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-((1R,2R,4S,5S)-3-(三甲基矽基)-7,9-二氮雜三環[3.3.1.0 2,4]壬-7-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇(4.30 mg,6 umol,產率4%)。LCMS (ESI): [M+H] += 685.1。 1H NMR (400MHz, DMSO- d 6) δ ppm 10.19 (br s, 1H), 9.14 (s, 1H), 7.98 (dd, J= 6.0, 8.9 Hz, 1H), 7.47 (br t, J= 9.1 Hz, 1H), 7.40 (d, J= 2.2 Hz, 1H), 7.17 (s, 1H), 5.40-5.20 (m, 1H), 4.42 (br s, 2H), 4.20-4.11 (m, 1H), 4.03 (br d, J= 10.5 Hz, 1H), 3.94 (br s, 1H), 3.67 (br s, 2H), 3.24 (br d, J= 9.9 Hz, 2H), 3.18-3.08 (m, 2H), 3.03 (br s, 1H), 2.85 (br d, J= 5.7 Hz, 1H), 2.14-1.76 (m, 6H), 1.32-1.09 (m, 2H), -0.06 (s, 9H), -0.20 (m, 1H). 實施例 18:4-(4-((1R, 5S)-8-氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇 甲酸鹽 Step 7: To a solution of (1R,2R,4S,5S)-7-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]nonane (100 mg, 0.14 mmol) in acetonitrile was added hydrogen chloride (4 M in dioxane, 630 uL) and the reaction was stirred at 20 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (500 uL). Triethylamine was added to adjust the pH to 8. The residue was purified by preparative HPLC to obtain a yellow solid compound 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,2R,4S,5S)-3-(trimethylsilyl)-7,9-diazatricyclo[3.3.1.0 2,4 ]non-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (4.30 mg, 6 umol, yield 4%). LCMS (ESI): [M+H] + = 685.1. 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 10.19 (br s, 1H), 9.14 (s, 1H), 7.98 (dd, J = 6.0, 8.9 Hz, 1H), 7.47 (br t, J = 9.1 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.17 (s, 1H), 5.40-5.20 (m, 1H), 4.42 (br s, 2H), 4.20-4.11 (m, 1H), 4.03 (br d, J = 10.5 Hz, 1H), 3.94 (br s, 1H), 3.67 (br s, 2H), 3.24 (br d, J = 9.9 Hz, 2H), 3.18-3.08 (m, 2H), 3.03 (br s, 1H), 2.85 (br d, J = 5.7 Hz, 1H), 2.14-1.76 (m, 6H), 1.32-1.09 (m, 2H), -0.06 (s, 9H), -0.20 (m, 1H). Example 18 : 4-(4-((1R, 5S)-8-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol carboxylate
第一步:在手套箱中,向4,7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶(500 mg,1.89 mmol),叔丁基3-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)-8-氮雜雙環[3.2.1]辛-2-烯-8-羧酸酯(825 mg,2.46 mmol)的1,4-二氧六環(15 mL)溶液中,加入磷酸鉀(1.5 M的水溶液,3.16 mL,4.73 mmol)和甲磺酸[正丁基二(1-金剛烷基)膦](2-胺基-1,1-聯苯-2-基)鈀(II)(69 mg,0.09 mmol)。將混合物氮氣保護下在50 oC下攪拌16小時。反應液過濾,濾液加入水(2 mL)稀釋,使用乙酸乙酯(10 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-10%梯度的乙酸乙酯/石油醚),得到黃色固體化合物叔丁基(1S,5R)-3-(7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-8-氮雜雙環[3.2.1]辛-2-烯-8-羧酸酯(530 mg,1.21 mmol,產率64%)。LCMS (ESI): [M+H] += 437.1. Step 1: In a glove box, potassium phosphate (1.5 M in water, 3.16 mL, 4.73 mmol) and [n-butyldi(1-adamantyl)phosphine](2-amino-1,1-biphenyl-2-yl)palladium(II) methanesulfonate (69 mg, 0.09 mmol) were added to a solution of 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (500 mg, 1.89 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentane-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (825 mg, 2.46 mmol) in 1,4-dioxane (15 mL). The mixture was stirred at 50 ° C for 16 hours under nitrogen protection. The reaction solution was filtered, the filtrate was diluted with water (2 mL), extracted with ethyl acetate (10 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to obtain a yellow solid compound tert-butyl (1S, 5R)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (530 mg, 1.21 mmol, yield 64%). LCMS (ESI): [M+H] + = 437.1.
第二步:在-15 oC度下,向叔丁基(1S,5R)-3-(7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-8-氮雜雙環[3.2.1]辛-2-烯-8-羧酸酯(2.00 g,4.58 mmol)的二氯甲烷(120 mL)溶液中,加入三乙基矽烷(4.40 mL,27.46 mmol)和三氟乙酸(6.80 mL,91.55 mmol)。混合物在氮氣保護下在25 oC攪拌16小時。反應液旋轉乾燥,得到粗產物化合物4-((1R,3s,5S)-8-氮雜雙環[3.2.1]辛-3-基)-7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶(2.00 g),其為棕色油狀液體。LCMS (ESI): [M+H] += 339.0. Step 2: To a solution of tert-butyl (1S,5R)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct- 2 -ene-8-carboxylate (2.00 g, 4.58 mmol) in dichloromethane (120 mL) was added triethylsilane (4.40 mL, 27.46 mmol) and trifluoroacetic acid (6.80 mL, 91.55 mmol) at -15 ° C. The mixture was stirred at 25 ° C for 16 hours under nitrogen protection. The reaction mixture was rotary dried to give the crude product 4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (2.00 g) as a brown oily liquid. LCMS (ESI): [M+H] + = 339.0.
第三步:向4-((1R,3s,5S)-8-氮雜雙環[3.2.1]辛-3-基)-7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶(2.00 g,4.58 mmol)的二氯甲烷(20 mL)溶液中,加入三乙胺(1.97 mL,14.17 mmol)和二碳酸二叔丁酯(2.03 mL,8.85 mmol)。混合物在氮氣保護下20 oC攪拌16小時,然後旋轉乾燥。加入水(5 mL),使用乙酸乙酯(10 mL * 3)萃取,有機相用無水硫酸鎂乾燥,過濾,旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-15%梯度的四氫呋喃/石油醚),得到白色固體化合物叔丁基(1R,3s,5S)-3-(7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸酯(1.01 g,2.30 mmol,產率50%)。LCMS (ESI): [M+H] += 439.2. 1H NMR (400 MHz, CDCl 3) δ ppm 9.04 (s, 1H), 4.60-4.23 (m, 2H), 4.15-3.90 (m, 1H), 2.67 (s, 3H), 2.40-2.25 (m, 2H), 2.22-2.10 (m, 2H), 1.95-1.83 (m, 2H), 1.74 (br dd, J= 1.7, 13.8 Hz, 2H), 1.51 (s, 9H). Step 3: Add triethylamine (1.97 mL, 14.17 mmol) and di-tert-butyl dicarbonate (2.03 mL, 8.85 mmol) to a solution of 4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (2.00 g, 4.58 mmol) in dichloromethane (20 mL). Stir the mixture at 20 ° C for 16 hours under nitrogen protection and then spin dry. Add water (5 mL) and extract with ethyl acetate (10 mL * 3). Dry the organic phase with anhydrous magnesium sulfate, filter, and spin dry. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran/petroleum ether) to give a white solid compound tert-butyl (1R, 3s, 5S)-3-(7-chloro-8-fluoro-2-(methylthio) pyrido [4, 3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octane-8-carboxylate (1.01 g, 2.30 mmol, yield 50%). LCMS (ESI): [M+H] + = 439.2. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.04 (s, 1H), 4.60-4.23 (m, 2H), 4.15-3.90 (m, 1H), 2.67 (s, 3H), 2.40-2.25 (m, 2H), 2.22-2.10 (m, 2H), 1.95-1.83 (m, 2H), 1.74 (br dd, J = 1.7, 13.8 Hz, 2H), 1.51 (s, 9H).
第四步:在手套箱中,向叔丁基(1R,3s,5S)-3-(7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸酯(500 mg,1.14 mmol),((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(701 mg,1.37 mmol)和碳酸銫(1113 mg,3.42 mmol)的二氧六環(10 mL)和水(2 mL)溶液中,加入氯[(正丁基二(1-金剛烷基)膦)-2-(2-胺基聯苯)]鈀(II)(14.7 mg,0.02 mmol)。將混合物氮氣保護下在100 oC下攪拌3小時。反應液過濾,濾液加入水(4 mL)稀釋,使用乙酸乙酯(10 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-30%梯度的四氫呋喃/石油醚),得到黃色固體化合物叔丁基(1R,3s,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(甲硫基))吡啶并[4,3-d]嘧啶-4-基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸酯(750 mg,0.95 mmol,產率83%)。LCMS (ESI): [M+H] += 789.4. Step 4: In a glove box, tert-butyl (1R, 3s, 5S)-3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 1.14 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (701 mg, 1.37 mmol) and cesium carbonate (1113 mg, 3.42 mmol) in dioxane (10 mL) and water (2 mL) solution, add chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (14.7 mg, 0.02 mmol). The mixture was stirred at 100 ° C for 3 hours under nitrogen protection. The reaction solution was filtered, diluted with water (4 mL), extracted with ethyl acetate (10 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran/petroleum ether) to obtain a yellow solid compound tert-butyl (1R, 3s, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio))pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (750 mg, 0.95 mmol, yield 83%). LCMS (ESI): [M+H] + = 789.4.
第五步:向叔丁基(1R,3s,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(甲硫基))吡啶并[4,3-d]嘧啶-4-基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸酯(400 mg,0.51 mmol)的二氯甲烷(10 mL)溶液中,加入間氯過氧化苯甲酸(85%含量,257 mg,1.27 mmol)。混合物在氮氣保護下25 oC攪拌2小時。加入水(3 mL),使用二氯甲烷(5 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,旋轉乾燥,得到粗產物化合物叔丁基(1R,3s,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(甲磺醯基))吡啶并[4,3-d]嘧啶-4-基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸酯(600 mg),其為黃色固體。LCMS (ESI): [M-56+H] += 765.1. Step 5: To a solution of tert-butyl (1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio))pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.51 mmol) in dichloromethane (10 mL) was added m-chloroperoxybenzoic acid (85% content, 257 mg, 1.27 mmol). The mixture was stirred at 25 ° C for 2 hours under nitrogen protection. Water (3 mL) was added, and the mixture was extracted with dichloromethane (5 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried to obtain the crude product compound tert-butyl (1R, 3s, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl))pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (600 mg) as a yellow solid. LCMS (ESI): [M-56+H] + = 765.1.
第六步:在25 oC下,向叔丁基(1R,3s,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(甲磺醯基))吡啶并[4,3-d]嘧啶-4-基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸酯(600 mg,0.73 mmol)和二異丙基乙胺(510 uL,3.65 mmol)的二氧六環(6.00 mL)溶液中加入 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(357 mg,2.24mmol),混合物在80 oC下攪拌4小時。將溶液濃縮並透過快速管柱層析(矽膠,0-10%梯度甲醇/二氯甲烷)純化得到棕色油狀化合物叔丁基(1R,3s,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸酯(430 mg,0.38 mmol,產率52%)。LCMS (ESI): [M+H] += 900.3。 Step 6: To a solution of tert-butyl (1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl))pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (600 mg, 0.73 mmol) and diisopropylethylamine (510 uL, 3.65 mmol) in dioxane (6.00 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (357 mg, 2.24 mmol) at 25 °C and the mixture was stirred at 80 ° C for 4 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give brown oily compound tert-butyl (1R, 3s, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (430 mg, 0.38 mmol, 52% yield). LCMS (ESI): [M+H] + = 900.3.
第七步:在25 oC下,向叔丁基(1R,3s,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸酯(430 mg,0.48 mmol)的二甲基甲醯胺(5.00 mL)溶液中加入氟化銫(726 mg,4.78 mmol)。溶液在25 oC攪拌16小時。將溶液濃縮,殘餘物透過快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化得到棕色油狀化合物叔丁基(1R,3s,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸酯(360 mg,0.39mmol,產率81%)。LCMS (ESI): [M+H] += 744.2. Step 7: CsF (726 mg, 4.78 mmol ) was added to a solution of tert-butyl (1R,3s,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (430 mg, 0.48 mmol) in dimethylformamide (5.00 mL) at 25 ° C. The solution was stirred at 25 ° C for 16 hours. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a brown oily compound tert-butyl (1R, 3s, 5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (360 mg, 0.39 mmol, yield 81%). LCMS (ESI): [M+H] + = 744.2.
第八步:在25 oC下,將叔丁基(1R,3s,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-8-氮雜雙環[3.2.1]辛烷-8-羧酸酯(360 mg,0.48 mmol)溶於三氟乙酸/二氯甲烷(體積比為1/4,4.00 mL),攪拌2小時。溶液用三乙胺(1 mL)中和並用水(5 mL)稀釋,用二氯甲烷(5 mL * 3)萃取。乾燥有機層並濃縮,得到的粗產物透過製備型HPLC純化得到黃色固體化合物4-(4-((1R,3s,5S)-8-氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(甲酸鹽,5.58 mg,9.68 umol,產率2%)。LCMS (ESI): [M+H] += 600.2; 1H NMR (400 MHz, CD 3OD) δ = 9.47 (s, 1H), 8.47 (s, 1H), 7.89 (dd, J= 5.7, 9.1 Hz, 1H), 7.43-7.30 (m, 2H), 7.23 (d, J= 2.3 Hz, 1H), 5.48-5.26 (m, 1H), 4.51-4.44 (m, 1H), 4.24 (br s, 2H), 3.37 (br s, 5H), 3.22-3.17 (m, 1H), 3.15-3.08 (m, 1H), 2.61-1.93 (m, 14H). 實施例 19 :(異丁醯氧基)甲基(1R,5S)-3-(2-((2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯 Step 8: Dissolve tert-butyl (1R,3s,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (360 mg, 0.48 mmol) in trifluoroacetic acid/dichloromethane (1/4 by volume, 4.00 mL) at 25 °C and stir for 2 hours. The solution was neutralized with triethylamine (1 mL) and diluted with water (5 mL), and extracted with dichloromethane (5 mL * 3). The organic layer was dried and concentrated, and the crude product was purified by preparative HPLC to give a yellow solid compound 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (formate salt, 5.58 mg, 9.68 umol, yield 2%). LCMS (ESI): [M+H] + = 600.2; 1 H NMR (400 MHz, CD 3 OD) δ = 9.47 (s, 1H), 8.47 (s, 1H), 7.89 (dd, J = 5.7, 9.1 Hz, 1H), 7.43-7.30 (m, 2H), 7.23 (d, J = 2.3 Hz, 1H), 5.48-5.26 (m, 1H), 4.51-4.44 (m, 1H), 4.24 (br s, 2H), 3.37 (br s, 5H), 3.22-3.17 (m, 1H), 3.15-3.08 (m, 1H), 2.61-1.93 (m, 14H). Example 19 : (Isobutyryloxy)methyl (1R,5S)-3-(2-((2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
第一步:在20 oC下,將化合物4-硝基苯酚(5.00 g,35.94 mmol)加入到四氫呋喃(65.0 mL)中,加入氯甲酸氯甲酯(5.10 g,39.54 mmol),然後緩慢滴加N,N-二異丙基乙胺(6.91 mL,39.54 mmol),反應在20 oC攪拌2小時。將混合物溶於乙酸乙酯(50.0 mL)並用飽和碳酸氫鈉溶液(50.0 mL*2)和鹽水(50.0 mL*2)洗滌,用無水硫酸鎂乾燥,過濾並濃縮,得到黃色固體化合物(4-硝基苯基)碳酸氯甲酯(8.10 g,34.98 mmol,產率97%)。 1H NMR (400 MHz, CDCl 3) δ ppm 8.39-8.32 (m, 2H), 7.48-7.43 (m, 2H), 5.87 (s, 2H). Step 1 : At 20 o C, add compound 4-nitrophenol (5.00 g, 35.94 mmol) to tetrahydrofuran (65.0 mL), add chloromethyl chloroformate (5.10 g, 39.54 mmol), then slowly add N,N-diisopropylethylamine (6.91 mL, 39.54 mmol), and stir the reaction at 20 o C for 2 hours. Dissolve the mixture in ethyl acetate (50.0 mL) and wash with saturated sodium bicarbonate solution (50.0 mL*2) and brine (50.0 mL*2), dry with anhydrous magnesium sulfate, filter and concentrate to obtain a yellow solid compound (4-nitrophenyl) chloromethyl carbonate (8.10 g, 34.98 mmol, yield 97%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.39-8.32 (m, 2H), 7.48-7.43 (m, 2H), 5.87 (s, 2H).
第二步:將化合物(4-硝基苯基)碳酸氯甲酯(5.00 g,21.59 mmol)加入到丙酮(100 mL)中,在20 oC下加入碘化鈉(9.71 g,64.77 mmol)和4A分子篩(5.00 g),反應在40 oC攪拌16小時。將反應液冷卻至室溫,並透過矽藻土過濾。濾液減壓除去揮發物並將殘餘物溶解在二氯甲烷(100 mL)中,分別用飽和碳酸氫鈉溶液(100 mL)、水(100 mL)和鹽水(100 mL)洗滌,有機相用無水硫酸鎂乾燥,過濾並濃縮得到黃色油狀化合物碘甲基(4-硝基苯基)碳酸酯(6.76 g,20.94 mmol,產率97%)。 1H NMR (400 MHz, CDCl 3) δ ppm 8.36-8.30 (m, 2H), 7.49-7.42 (m, 2H), 6.09 (s, 2H). Step 2 : Add the compound (4-nitrophenyl) chloromethyl carbonate (5.00 g, 21.59 mmol) to acetone (100 mL), add sodium iodide (9.71 g, 64.77 mmol) and 4A molecular sieve (5.00 g) at 20 ° C, and stir the reaction at 40 ° C for 16 hours. Cool the reaction solution to room temperature and filter through diatomaceous earth. The filtrate was depressurized to remove volatiles and the residue was dissolved in dichloromethane (100 mL), washed with saturated sodium bicarbonate solution (100 mL), water (100 mL) and brine (100 mL), respectively. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a yellow oily compound iodomethyl (4-nitrophenyl) carbonate (6.76 g, 20.94 mmol, yield 97%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.36-8.30 (m, 2H), 7.49-7.42 (m, 2H), 6.09 (s, 2H).
第三步:把異丁酸(5.00 g,56.75 mmol)加入到乙腈(200 mL)中,在20 oC下加入氧化銀(4.76 g,34.05 mmol),在70 oC避光攪拌6小時。將混合物冷卻至環境溫度並透過矽藻土過濾。濾液透過真空除去揮發物,得到棕褐色固體化合物異丁酸銀(1.00 g,5.12 mmol,產率9%)。 Step 3 : Add isobutyric acid (5.00 g, 56.75 mmol) to acetonitrile (200 mL), add silver oxide (4.76 g, 34.05 mmol) at 20 ° C, and stir at 70 ° C for 6 hours in the dark. The mixture was cooled to ambient temperature and filtered through diatomaceous earth. The filtrate was vacuum-filtered to remove volatiles to obtain a brown solid compound, silver isobutyrate (1.00 g, 5.12 mmol, 9% yield).
第四步:將化合物碘甲基(4-硝基苯基)碳酸酯(414 mg,1.28 mmol)加入到甲苯中(7.00 mL)中,加入異丁酸銀(500 mg,2.56 mmol),在55 oC攪拌16小時。將反應液冷卻至室溫,並透過矽藻土過濾,濾液分別用10%碳酸鉀溶液(3 mL*2)和鹽水(3 mL*2)洗滌,有機相用無水硫酸鎂乾燥,濾液濃縮,殘餘物透過快速管柱層析(矽膠,0-30%梯度的乙酸乙酯/石油醚)純化得到黃色油狀化合物(((4-硝基苯氧基)羰基)氧基)異丁酸甲酯(220 mg,0.78 mmol,產率61%)。 1H NMR (400 MHz, CDCl 3) δ ppm 8.36-8.30 (m, 2H), 7.48-7.41 (m, 2H), 5.91 (s, 2H), 2.69 (m, 1H), 1.29-1.22 (m, 6H). Step 4 : Add iodomethyl (4-nitrophenyl) carbonate (414 mg, 1.28 mmol) to toluene (7.00 mL), add silver isobutyrate (500 mg, 2.56 mmol), and stir at 55 ° C for 16 hours. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filtrate was washed with 10% potassium carbonate solution (3 mL*2) and brine (3 mL*2), respectively. The organic phase was dried over anhydrous magnesium sulfate. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a yellow oily compound (((4-nitrophenoxy)carbonyl)oxy)isobutyric acid methyl ester (220 mg, 0.78 mmol, yield 61%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.36-8.30 (m, 2H), 7.48-7.41 (m, 2H), 5.91 (s, 2H), 2.69 (m, 1H), 1.29-1.22 (m, 6H).
第五步:在25 oC下,向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(500 mg,0.59 mmol)的四氫呋喃(5.00 mL)溶液中加入 ((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇(121 mg,0.59 mmol)和叔丁醇鈉(115 mg,0.89 mmol),將該溶液在25 oC攪拌2小時。將反應液濃縮,殘餘物透過快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化得到黃色固體化合物叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(350 mg,0.37 mmol,產率62%)。LCMS (ESI): [M+Na] += 967.4。 Step 5 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.59 mmol) in tetrahydrofuran (5.00 mL) at 25 °C was added ((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (121 mg, 0.59 mmol) and sodium tert-butoxide (115 mg, 0.89 mmol), and the solution was stirred at 25 ° C. for 2 hours. The reaction solution was concentrated and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a yellow solid compound tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.37 mmol, yield 62%). LCMS (ESI): [M+Na] + = 967.4.
第六步:在25 oC下,向叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(350 mg,0.37 mmol)的二甲基甲醯胺(3.50 mL)溶液中加入氟化銫(562 mg,3.70 mmol),將該溶液在25 oC攪拌2小時。將反應液濃縮,殘餘物透過快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化得到棕色油狀化合物叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(290 mg,0.37 umol,產率99%)。LCMS (ESI): [M+H] += 788.8。 Step 6 : To a solution of tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.37 mmol) in dimethylformamide (3.50 mL) was added cesium fluoride (562 mg, 3.70 mmol) at 25°C and the solution was stirred at 25 ° C for 2 hours. The reaction solution was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a brown oily compound tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (290 mg, 0.37 umol, yield 99%). LCMS (ESI): [M+H] + = 788.8.
第七步:在25 oC下,向叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(50.0 mg,0.06 mmol)的乙腈(1.00 mL)溶液中加入氯化氫(4 M的二氧六環溶液,317 uL,1.27 mmol),將該溶液在20 oC攪拌2小時。反應液用三乙胺調節pH至7,減壓濃縮除去溶劑得到粗產物化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(純度50%,80.0 mg),其為棕色固體。LCMS (ESI): [M+H] += 644.9。 Step 7 : To a solution of tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 0.06 mmol) in acetonitrile (1.00 mL) at 25 °C was added hydrogen chloride (4 M in dioxane, 317 uL, 1.27 mmol) and the solution was stirred at 20 ° C for 2 hours. The reaction solution was adjusted to pH 7 with triethylamine, and the solvent was removed by concentration under reduced pressure to obtain a crude product, compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (purity 50%, 80.0 mg), which was a brown solid. LCMS (ESI): [M+H] + = 644.9.
第八步:在20 oC下,向4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(純度50%,50.0 mg,0.04 mmol)的二甲基甲醯胺(1.00 mL)溶液中加入 (((4-硝基苯氧基)羰基)氧基)異丁酸甲酯(19.8 mg,0.07 mmol),將該溶液在20 oC攪拌2小時。混合物透過製備型HPLC純化,得到白色固體化合物 (異丁醯氧基)甲基(1R,5S)-3-(2-((2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(15.26 mg,0.02 mmol,產率50%)。LCMS (ESI): [M+H] += 789.4。 1H NMR (400 MHz, CD 3OD) δ ppm 9.12-9.00 (m, 1H), 7.88 (dd, J= 5.6, 9.1 Hz, 1H), 7.44-7.29 (m, 2H), 7.23 (d, J= 2.3 Hz, 1H), 5.97-5.77 (m, 2H), 4.73 (br s, 2H), 4.58-4.46 (m, 2H), 4.36-4.20 (m, 2H), 3.92-3.69 (m, 2H), 3.40-3.37 (m, 1H), 3.29-3.23 (m, 1H), 3.20-3.09 (m, 1H), 2.96-2.80 (m, 2H), 2.73-2.59 (m, 1H), 2.40-2.28 (m, 1H), 2.17-1.84 (m, 9H), 1.56-1.42 (m, 2H), 1.32-1.15 (m, 6H). 實施例 20 :4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)喹啉-2-醇 Step 8 : To a solution of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (50% purity, 50.0 mg, 0.04 mmol) in dimethylformamide (1.00 mL) was added methyl (((4-nitrophenoxy)carbonyl)oxy)isobutyrate (19.8 mg, 0.07 mmol) at 20°C and the solution was stirred at 20 ° C for 2 hours. The mixture was purified by preparative HPLC to give a white solid compound (isobutyryloxy)methyl (1R,5S)-3-(2-((2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15.26 mg, 0.02 mmol, yield 50%). LCMS (ESI): [M+H] + = 789.4. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.12-9.00 (m, 1H), 7.88 (dd, J = 5.6, 9.1 Hz, 1H), 7.44-7.29 (m, 2H), 7.23 (d, J = 2.3 Hz, 1H), 5.97-5.77 (m, 2H), 4.73 (br s, 2H), 4.58-4.46 (m, 2H), 4.36-4.20 (m, 2H), 3.92-3.69 (m, 2H), 3.40-3.37 (m, 1H), 3.29-3.23 (m, 1H), 3.20-3.09 (m, 1H), 2.96-2.80 (m, 3H), 2.73-2.59 (m, 1H), 2.40-2.28 (m, 1H), 2.17-1.84 (m, 9H), 1.56-1.42 (m, 2H), 1.32-1.15 (m, 6H). Example 20 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)quinolin-2-ol
第一步:在氮氣下向4-溴喹啉-2-醇(500 mg,2.23 mmol)的二噁烷(25 mL)溶液中加入雙聯頻哪醇硼酸酯(681 g,2.68 mmol)和(1,1-雙(二苯基膦)二茂鐵)二氯化鈀二氯甲烷(273 mg,0.37 mmol),2-乙基己酸鉀(610 mg,3.35 mmol)。並將所得混合物在80 oC下攪拌1.5小時。將懸浮液過濾並濃縮,得到粗產物,將其透過快速管柱層析(矽膠,0-10%梯度二氯甲烷/甲醇)純化,得到棕色固體化合物4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)喹啉-2-醇(220 mg,0.56 mmol,產率25%)。LCMS (ESI): [M+H] += 272.1。 Step 1 : Under nitrogen, add bis-pinacol borate (681 g, 2.68 mmol), (1,1-bis(diphenylphosphino)ferrocene)palladium dichloride in dichloromethane (273 mg, 0.37 mmol), potassium 2-ethylhexanoate (610 mg, 3.35 mmol) to a solution of 4-bromoquinolin-2-ol (500 mg, 2.23 mmol) in dioxane (25 mL). Stir the resulting mixture at 80 ° C for 1.5 hours. The suspension was filtered and concentrated to give a crude product, which was purified by flash column chromatography (silica gel, 0-10% gradient dichloromethane/methanol) to give a brown solid compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-ol (220 mg, 0.56 mmol, yield 25%). LCMS (ESI): [M+H] + = 272.1.
第二步:在氮氣下向(1R,5S)-叔丁基3-(7-氯-8-氟-2-(((2R,7aS)-2-氟六氫-1H-吡咯嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(150 mg,0.27 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)喹啉-2-醇(74 mg,0.27 mmol)的二噁烷(2000 uL)溶液中加入磷酸鉀溶液(549 uL,0.82 mmol)和甲磺醯氧基(二金剛烷基-正丁基膦基)-2-胺基-1,1-聯苯-2-基)鈀(II)(20 mg,0.03 mmol)。將該懸浮液在100 oC攪拌2小時。將混合物濃縮並用快速管柱層析(矽膠,0-10%梯度二氯甲烷/甲醇)純化,得到棕色固體化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(2-羥基喹啉-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(130 mg,0.16 mmol,產率58%)。LCMS (ESI): [M+H] += 660.3。 Step 2: To a solution of (1R,5S)-tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.27 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-ol (74 mg, 0.27 mmol) in dioxane (2000 uL) was added potassium phosphate solution (549 uL, 0.82 mmol) and methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (20 mg, 0.03 mmol). The suspension was stirred at 100 ° C for 2 hours. The mixture was concentrated and purified by flash column chromatography (silica gel, 0-10% gradient dichloromethane/methanol) to give tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(2-hydroxyquinolin-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.16 mmol, 58% yield) as a brown solid compound. LCMS (ESI): [M+H] + = 660.3.
第三步:將叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(2-羥基喹啉-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(110 mg,0.17 mmol)的三氟乙酸/二氯甲烷(2200 uL)溶液在25 oC下攪拌2小時。該溶液用三乙胺(450 uL)鹼化並用二氯甲烷(2 mL*3)萃取。乾燥並濃縮合併的有機層。透過製備型HPLC純化得到白色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)喹啉-2-醇(12.9 mg,22 umol,產率14%)。LCMS (ESI): [M+H] += 560.3。 1H NMR (400 MHz, CD 3OD- d 4) δ = 9.20 (s, 1H), 7.69-7.57 (m, 1H), 7.52-7.39 (m, 2H), 7.27-7.19 (m, 1H), 6.77 (s, 1H), 5.60-5.40 (m, 1H), 4.81 (br s, 2H), 4.64-4.53 (m, 2H), 4.08 (br s, 2H), 3.91 (br d, J= 11.0 Hz, 2H), 3.84-3.61 (m, 3H), 3.39-3.33 (m, 1H), 2.69-1.91 (m, 10H) 實施例 21 : 7a'-(((4-((1R,5S)-3,8- 二氮雜雙環 [3.2.1] 辛烷 -3- 基 )-7-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟吡啶并 [4,3-d] 嘧啶 -2- 基 ) 氧基 ) 甲基 ) 四氫 -1'H,3'H- 螺 [ 氧雜環丁烷 -3,2'- 吡咯嗪 ] Step 3: A solution of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(2-hydroxyquinolin-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.17 mmol) in trifluoroacetic acid/dichloromethane (2200 uL) was stirred at 25 o C for 2 hours. The solution was alkalized with triethylamine (450 uL) and extracted with dichloromethane (2 mL*3). The combined organic layers were dried and concentrated. Purification by preparative HPLC gave a white solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)quinolin-2-ol (12.9 mg, 22 umol, yield 14%). LCMS (ESI): [M+H] + = 560.3. 1 H NMR (400 MHz, CD 3 OD- d 4 ) δ = 9.20 (s, 1H), 7.69-7.57 (m, 1H), 7.52-7.39 (m, 2H), 7.27-7.19 (m, 1H), 6.77 (s, 1H), 5.60-5.40 (m, 1H), 4.81 (br s, 2H), 4.64-4.53 (m, 2H), 4.08 (br s, 2H), 3.91 (br d, J = 11.0 Hz, 2H), 3.84-3.61 (m, 3H), 3.39-3.33 (m, 1H), 2.69-1.91 (m, 10H) Example 21 : 7a'-(((4-((1R,5S)-3,8- diazabicyclo [3.2.1] octan -3 -yl ) -7- (8- ethynyl- 7- fluoronaphthalen -1 -yl )-8 -fluoropyrido [4,3-d] pyrimidin -2- yl ) oxy ) methyl ) tetrahydro -1'H,3'H- spiro [ oxacyclobutane -3,2'- pyrrolizine ]
第一步:將叔丁基(1R,5S)-3-(7-氯-2-((二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯烷]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(200 mg, 0.35 mmol)和((2-氟-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(189 mg,0.42 mmol)的二氧六環(4 mL)溶液,在手套箱中加入1.5M磷酸鉀溶液(696 uL,1.04 mmol)和甲磺醯氧基(二金剛烷基-正丁基膦基)-2-胺基-1,1-聯苯-2-基)鈀(II)(23 mg,0.03 mmol),然後將混合物氮氣保護下在100度下攪拌3小時。反應混合物旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-7%梯度的甲醇/二氯甲烷)得到白色固體化合物叔丁基(1R,5S)-3-(2-((二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1 ]辛烷-8-羧酸酯(230 mg,0.27 mmol,產率76%)。LCMS (ESI): [M+H] +=865.6. Step 1 : Add 1.5 M potassium phosphate solution (696 μL, 1.04 μL) to a solution of tert-butyl (1R,5S)-3-(7-chloro-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.35 mmol) and ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (189 mg, 0.42 mmol) in dioxane (4 mL) in a glove box. mmol) and methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (23 mg, 0.03 mmol) were added, and the mixture was stirred at 100 degrees for 3 hours under nitrogen protection. The reaction mixture was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-7% gradient of methanol/dichloromethane) to give a white solid compound tert-butyl (1R,5S)-3-(2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.27 mmol, yield 76%). LCMS (ESI): [M+H] + =865.6.
第二步:將叔丁基(1R,5S)-3-(2-((二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1 ]辛烷-8-羧酸酯(220 mg, 0.25 mmol),加入三氟乙酸/二氯甲烷=1:4(4.4 mL)。混合物在氮氣保護下25度攪拌1小時。然後用氮氣快速吹乾,再油泵旋轉乾燥。得到棕色油狀化合物7a'-(((4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基))萘-1-基)吡啶并[4,3-d]嘧啶-2-基)氧基)甲基)四氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪](200 mg, 0.25 mmol,粗產物)。LCMS (ESI): [M+H] +=765.4. Step 2 : Add trifluoroacetic acid/dichloromethane = 1:4 (4.4 mL) to tert-butyl (1R,5S)-3-(2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 0.25 mmol). The mixture was stirred at 25 degrees for 1 hour under nitrogen protection. Then it was quickly blown dry with nitrogen and then dried by oil pump rotation. The brown oily compound 7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl))naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine] (200 mg, 0.25 mmol, crude product) was obtained. LCMS (ESI): [M+H] + =765.4.
第三步:將7a'-(((4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基))萘-1-基)吡啶并[4,3-d]嘧啶-2-基)氧基)甲基)四氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪](200 mg, 0.25 mmol)的N,N二甲基甲醯胺(2 mL)溶液,加入氟化銫(4468 mg, 26.1 mmol)。混合物在氮氣保護下25度攪拌2小時。然後過濾。殘留物用製備型HPLC純化,得到黃色固體化合物7a'-(((4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-2-基)氧基)甲基)四氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪](55 mg,0.09 mmol,產率35%)。LCMS (ESI): [M+H] +=609.3. 1H NMR (400MHz, CD 3OD) δ ppm 9.04 (s, 1H), 8.23 - 8.05 (m, 2H), 7.77 - 7.58 (m, 2H), 7.46 (t, J= 9.0 Hz, 1H), 4.73 (br d, J= 6.1 Hz, 2H), 4.68 - 4.60 (m, 4H), 4.28 - 4.08 (m, 2H), 3.81 - 3.62 (m, 4H), 3.53 (d, J= 10.4 Hz, 1H), 3.45 (d, J= 9.0 Hz, 1H), 3.11 - 3.01 (m, 1H), 2.97 (br d, J= 10.3 Hz, 1H), 2.78 (td, J= 5.2, 10.6 Hz, 1H), 2.56 (dd, J= 1.8, 13.3 Hz, 1H), 2.07 - 1.93 (m, 3H), 1.93 - 1.76 (m, 6H). 實施例 22:7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-甲腈 Step 3 : Add cesium fluoride (4468 mg, 26.1 mmol) to a solution of 7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl))naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine] (200 mg, 0.25 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred at 25 degrees for 2 hours under nitrogen protection. Then filtered. The residue was purified by preparative HPLC to give yellow solid compound 7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)tetrahydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine] (55 mg, 0.09 mmol, yield 35%). LCMS (ESI): [M+H] + = 609.3. 1 H NMR (400MHz, CD 3 OD) δ ppm 9.04 (s, 1H), 8.23 - 8.05 (m, 2H), 7.77 - 7.58 (m, 2H), 7.46 (t, J = 9.0 Hz, 1H), 4.73 (br d, J = 6.1 Hz, 2H), 4.68 - 4.60 (m, 4H), 4.28 - 4.08 (m, 2H), 3.81 - 3.62 (m, 4H), 3.53 (d, J = 10.4 Hz, 1H), 3.45 (d, J = 9.0 Hz, 1H), 3.11 - 3.01 (m, 1H), 2.97 (br d, J = 10.3 Hz, 1H), 2.78 (td, J = 5.2, 10.6 Hz, 1H), 2.56 (dd, J = 1.8, 13.3 Hz, 1H), 2.07 - 1.93 (m, 3H), 1.93 - 1.76 (m, 6H). Example 22 : 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile
第一步:向6-溴-4-甲基吡啶-2-胺(1.00 g,5.35 mmol)的N,N-二甲基甲醯胺(17 mL)溶液中,在0 oC下加入60%鈉氫(1.10 g,27.5 mmol),在25 oC下攪拌1小時,然後在0 oC下加入1-(氯甲基)-4-甲氧基苯(1.90 g,12.1 mmol),將混合物氮氣保護下在25 oC下攪拌2小時。在0 oC加入飽和氯化銨溶液(17 mL)淬滅,使用乙酸乙酯(25 mL)萃取5次,合併有機相,食鹽水(50 mL)洗滌,無水硫酸鈉乾燥,過濾旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-15%梯度的乙酸乙酯/石油醚)得到黃色固體化合物6-溴-N,N-雙(4-甲氧基苄基)-4-甲基吡啶-2-胺(2.00 g,4.68 mmol,產率79%)。LCMS (ESI): [M+H] += 427.1. Step 1 : To a solution of 6-bromo-4-methylpyridin-2-amine (1.00 g, 5.35 mmol) in N,N-dimethylformamide (17 mL) at 0 o C, add 60% sodium hydrogen (1.10 g, 27.5 mmol), stir at 25 o C for 1 hour, then add 1-(chloromethyl)-4-methoxybenzene (1.90 g, 12.1 mmol) at 0 o C, and stir the mixture at 25 o C for 2 hours under nitrogen protection. Quench with saturated ammonium chloride solution (17 mL) at 0 o C, extract five times with ethyl acetate (25 mL), combine the organic phases, wash with brine (50 mL), dry over anhydrous sodium sulfate, filter and spin dry. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of ethyl acetate/petroleum ether) to obtain a yellow solid compound 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (2.00 g, 4.68 mmol, yield 79%). LCMS (ESI): [M+H] + = 427.1.
第二步:向6-溴-N,N-雙(4-甲氧基苄基)-4-甲基吡啶-2-胺(2.00 g, 4.68 mmol),三環己基膦(0.26 g,0.94 mmol)和氯化鋰(0.99 g,23.4 mmol)的1,4-二氧六環(13 mL)溶液中,加入六丁基二錫(8.14 g,14.04 mmol)和三(二伸苄基丙酮)二鈀(0)(0.43 g,9.47 mmol)。將混合物氮氣保護下在110 oC下攪拌5小時,旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-10%梯度的乙酸乙酯/石油醚)3次,得到無色油狀化合物N,N-雙(4-甲氧基苄基)-4-甲基-6-(三丁基錫烷基)吡啶-2-胺(1.80 g,2.82 mmol,產率60%)。LCMS (ESI): [M+H] += 639.2. 1H NMR (400 MHz, CDCl 3) δ ppm 7.24-7.15 (m, 4H), 6.92-6.81 (m, 4H), 6.65-6.43 (m, 1H), 6.17 (s, 1H), 4.71 (s, 4H), 3.81 (s, 6H), 2.24-2.13 (m, 3H), 1.73-1.46 (m, 6H), 1.43-1.24 (m, 6H), 1.20-0.95 (m, 6H), 0.89-0.85 (m, 9H). Step 2 : To a solution of 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (2.00 g, 4.68 mmol), tricyclohexylphosphine (0.26 g, 0.94 mmol) and lithium chloride (0.99 g, 23.4 mmol) in 1,4-dioxane (13 mL), hexabutyl ditin (8.14 g, 14.04 mmol) and tris(dibenzylacetone) dipalladium (0) (0.43 g, 9.47 mmol) were added. The mixture was stirred at 110 ° C for 5 hours under nitrogen protection and then rotary dried. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) three times to obtain a colorless oily compound N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributylstannyl)pyridin-2-amine (1.80 g, 2.82 mmol, yield 60%). LCMS (ESI): [M+H] + = 639.2. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.24-7.15 (m, 4H), 6.92-6.81 (m, 4H), 6.65-6.43 (m, 1H), 6.17 (s, 1H), 4.71 (s, 4H), 3.81 (s, 6H), 2.24-2.13 (m, 3H), 1.73-1.46 (m, 6H), 1.43-1.24 (m, 6H), 1.20-0.95 (m, 6H), 0.89-0.85 (m, 9H).
第三步:在手套箱中,向叔丁基(1R,5S)-3-(7-溴-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(615 mg,1.10 mmol),N,N-雙(4-甲氧基苄基)-4-甲基-6-(三丁基甲錫烷基)吡啶-2-胺(1.40 g,2.2 mmol),碘化亞銅(63 mg,0.33 mmol)和氯化鋰(116 mg,2.75 mmol)的1,4-二氧六環(18 mL)溶液中,加入四(三苯基磷)鈀(254 mg,0.22 mmol)。將混合物氮氣保護下在120 oC下攪拌16小時。過濾,加入水(10 mL),使用乙酸乙酯(20 mL)萃取3次,合併的有機相用無水硫酸鈉乾燥,過濾旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-20%梯度的四氫呋喃/石油醚)。得到粗產物化合物叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基吡啶-2-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(800 mg),為黃色固體。LCMS (ESI): [M+H] += 828.3. Step 3 : In a glove box, to a solution of tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (615 mg, 1.10 mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributylmethanyl)pyridin-2-amine (1.40 g, 2.2 mmol), cuprous iodide (63 mg, 0.33 mmol) and lithium chloride (116 mg, 2.75 mmol) in 1,4-dioxane (18 mL) was added tetrakis(triphenylphosphine)palladium (254 mg, 0.22 mmol). The mixture was stirred at 120 ° C for 16 hours under nitrogen protection. Filtered, water (10 mL) was added, and extracted with ethyl acetate (20 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran/petroleum ether). The crude product compound tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg) was obtained as a yellow solid. LCMS (ESI): [M+H] + = 828.3.
第四步:向叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基吡啶-2-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(780 mg,0.94 mmol)的乙腈(16 mL)溶液中,加入N-碘琥珀醯亞胺(1060 mg,4.71 mmol)和對甲苯磺酸(6 mg,0.04 mmol)。將混合物氮氣保護下在25 oC下攪拌5小時。混合物旋轉乾燥,加入食鹽水(10 mL),使用乙酸乙酯(20 mL)萃取3次,合併的有機相用無水硫酸鈉乾燥,過濾旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-20%梯度的四氫呋喃/石油醚)。得到黃色固體化合物叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-3-碘-4-甲基吡啶-2-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(710 mg,0.74 mmol,產率79%)。LCMS (ESI): [M+H] += 954.4. Step 4 : To a solution of tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (780 mg, 0.94 mmol) in acetonitrile (16 mL) was added N-iodosuccinimide (1060 mg, 4.71 mmol) and p-toluenesulfonic acid (6 mg, 0.04 mmol). The mixture was stirred at 25 ° C for 5 hours under nitrogen protection. The mixture was rotary dried, brine (10 mL) was added, and ethyl acetate (20 mL) was used for extraction three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-20% gradient tetrahydrofuran/petroleum ether). The yellow solid compound tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (710 mg, 0.74 mmol, yield 79%) was obtained. LCMS (ESI): [M+H] + = 954.4.
第五步:向叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-3-碘-4-甲基吡啶-2-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(700 mg,0.73 mmol)的N,N-二甲基乙醯胺(17.5 mL)溶液中,加入2,2-二氟-2-(氟磺醯基)乙酸甲酯(3525 mg,18.3 mmol)和碘化亞銅(1677 mg,8.81 mmol)。將混合物氮氣保護下在90 oC下攪拌12小時。混合物過濾,濾液旋轉乾燥,加入食鹽水(10 mL),使用乙酸乙酯(10 mL)萃取3次,合併的有機相用無水硫酸鈉乾燥,過濾旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-20%梯度的四氫呋喃/石油醚)。得到黃色固體化合物叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(280 mg,0.31 mmol,產率43%)。LCMS (ESI): [M+H] += 897.3. Step 5 : To a solution of tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 0.73 mmol) in N,N-dimethylacetamide (17.5 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3525 mg, 18.3 mmol) and cuprous iodide (1677 mg, 8.81 mmol). The mixture was stirred at 90 ° C for 12 hours under nitrogen protection. The mixture was filtered, the filtrate was rotary dried, brine (10 mL) was added, and ethyl acetate (10 mL) was used for extraction three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-20% gradient tetrahydrofuran/petroleum ether). The yellow solid compound tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280 mg, 0.31 mmol, yield 43%) was obtained. LCMS (ESI): [M+H] + = 897.3.
第六步:向叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(150 mg,0.17 mmol)和 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(70 mg,0.44 mmol)的四氫呋喃(3 mL)溶液中,加入叔丁醇鈉(24 mg,0.25 mmol)。混合物在氮氣保護下25 oC攪拌2小時。加入水(3 mL),使用乙酸乙酯(3 mL)萃取3次,合併的有機相用無水硫酸鈉乾燥,過濾旋轉乾燥。得到粗產物化合物叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氰基-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(230 mg),其為黃色油狀液體。LCMS (ESI): [M+H] += 955.7. Step 6 : To a solution of tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.17 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (70 mg, 0.44 mmol) in tetrahydrofuran (3 mL) was added sodium tert-butoxide (24 mg, 0.25 mmol). The mixture was stirred at 25 ° C for 2 hours under nitrogen. Water (3 mL) was added, and the mixture was extracted three times with ethyl acetate (3 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and rotary dried. The crude product compound tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg) was obtained as a yellow oily liquid. LCMS (ESI): [M+H] + = 955.7.
第七步:將叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氰基-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(220 mg,0.16 mmol)溶於三氟乙酸(3 mL),混合物在氮氣保護下50 oC攪拌2小時。然後旋轉乾燥。加入二氯甲烷(2 mL),使用三乙胺調節pH = 7,旋轉乾燥。殘留物用製備型HPLC純化,得到白色固體化合物7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-甲腈(28.5 mg,0.05 mmol,產率20%)。LCMS (ESI): [M+H] += 615.2. 1H NMR (400 MHz, CD 3OD) δ ppm 8.25 (s, 1H), 6.64 (s, 1H), 5.43-5.21 (m, 1H), 4.53 (q, J= 10.4 Hz, 2H), 4.33-4.18 (m, 2H), 3.77-3.60 (m, 4H), 3.31-3.13 (m, 3H), 3.02 (dt, J= 5.6, 9.3 Hz, 1H), 2.48 (d, J= 1.3 Hz, 3H), 2.40-2.09 (m, 3H), 2.05-1.95 (m, 2H), 1.94-1.70 (m, 5H). 實施例 23:(4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛)-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-基)硼酸 Step 7 : Dissolve tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 0.16 mmol) in trifluoroacetic acid (3 mL), and stir the mixture at 50 ° C for 2 hours under nitrogen. Then rotate to dryness. Add dichloromethane (2 mL), adjust pH to 7 with triethylamine, and rotate to dryness. The residue was purified by preparative HPLC to give a white solid compound 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile (28.5 mg, 0.05 mmol, yield 20%). LCMS (ESI): [M+H] + = 615.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.25 (s, 1H), 6.64 (s, 1H), 5.43-5.21 (m, 1H), 4.53 (q, J = 10.4 Hz, 2H), 4.33-4.18 (m, 2H), 3.77-3.60 (m, 4H), 3.31-3.13 (m, 3H), 3.02 (dt, J = 5.6, 9.3 Hz, 1H), 2.48 (d, J = 1.3 Hz, 3H), 2.40-2.09 (m, 3H), 2.05-1.95 (m, 2H), 1.94-1.70 (m, 5H). Example 23 : (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane)-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid
第一步:在氮氣保護下,向化合物叔丁基(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(300 mg,0.54 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)萘-2-醇(176 mg,0.65 mmol)的二氧六環(5.00 mL)溶液中,加入磷酸鉀(1.5 M的水溶液,1.09 mL,1.63 mmol),甲磺酸[正丁基二(1-金剛烷基)膦](2-胺基-1,1'-聯苯-2-基)鈀(II),(36.4 mg,0.05 mmol),將混合物在80 oC下攪拌2小時。反應液用水(2 mL)稀釋並用二氯甲烷(2 mL * 3)萃取,用無水硫酸鎂乾燥有機相,過濾,濾液減壓濃縮,殘餘物透過快速管柱層析純化(矽膠,0-50%石油醚/四氫呋喃,然後0-10%二氯甲烷/甲醇)得到棕色油狀化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羥基萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(350 mg,0.53 mmol,產率98%)。LCMS (ESI): [M+H] += 659.3. Step 1 : Under nitrogen protection, potassium phosphate (1.5 M aqueous solution, 1.09 mL, 1.63 mmol) was added to a solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.54 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentane-2-yl)naphthalen-2-ol (176 mg, 0.65 mmol) in dioxane (5.00 mL). mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, (36.4 mg, 0.05 mmol), and the mixture was stirred at 80 ° C for 2 hours. The reaction solution was diluted with water (2 mL) and extracted with dichloromethane (2 mL * 3). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-50% petroleum ether/tetrahydrofuran, then 0-10% dichloromethane/methanol) to obtain a brown oily compound tert-butyl (1R, 5S)-3-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.53 mmol, yield 98%). LCMS (ESI): [M+H] + = 659.3.
第二步:將化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羥基萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(300 mg,0.46 mmol)緩慢加入吡啶(3 mL)中,在0 oC下加入三氟甲磺酸酐(82.0 uL,0.50 mmol),混合物在0 oC攪拌1小時。反應液用水(1 mL)稀釋並用甲苯(1 mL * 2)萃取,用無水硫酸鈉乾燥有機相,過濾,濾液減壓濃縮,殘餘物透過快速管柱層析純化(矽膠,0-10%的二氯甲烷/甲醇)得到棕色固體化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(((三氟甲基)磺醯基)氧基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(280 mg,0.35 mmol,產率78%)。LCMS (ESI): [M+H] += 791.4. Step 2 : The compound tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.46 mmol) was slowly added to pyridine (3 mL), trifluoromethanesulfonic anhydride (82.0 uL, 0.50 mmol) was added at 0 o C, and the mixture was stirred at 0 o C for 1 hour. The reaction solution was diluted with water (1 mL) and extracted with toluene (1 mL * 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% dichloromethane/methanol) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280 mg, 0.35 mmol, yield 78%). LCMS (ESI): [M+H] + = 791.4.
第三步:在25 oC和氮氣保護下向叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(((三氟甲基)磺醯基)氧基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(100 mg,0.13 mmol),次硼酸(17.0 mg,0.19 mmol),三苯基膦(2 mg,7.6 umol)和二異丙基乙胺(67.0 uL,0.38 mmol)的異丙醇(1000 uL)溶液中加入[1,3-二(二苯基磷)丙烷]氯化鎳(3.00 mg,3.8 umol),混合物在80 oC攪拌16小時。將反應液過濾並濃縮,得到粗產物化合物(4-(4-((1R,5S)-8-(叔丁氧羰基)-3,8-二氮雜雙環[3.2.1]辛)-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-基)硼酸(110 mg),其為棕色固體。LCMS (ESI): [M+H] += 687.4 Step 3 : Tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin- 7a (5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.13 mmol), boronic acid (17.0 mg, 0.19 mmol), triphenylphosphine (2 mg, 7.6 umol) and diisopropylethylamine (67.0 uL, 0.38 mmol) in isopropanol (1000 μL, 4% d-butyl)-1-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.13 mmol), boronic acid (17.0 mg, 0.19 mmol), triphenylphosphine (2 mg, 7.6 umol) and diisopropylethylamine (67.0 μL, 0.38 mmol) were added to the mixture at 25 °C under nitrogen. uL) solution was added with [1,3-bis(diphenylphosphino)propane]nickel chloride (3.00 mg, 3.8 umol), and the mixture was stirred at 80 ° C for 16 hours. The reaction solution was filtered and concentrated to obtain a crude product compound (4-(4-((1R,5S)-8-(tert-butyloxycarbonyl)-3,8-diazabicyclo[3.2.1]octane)-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid (110 mg) as a brown solid. LCMS (ESI): [M+H] + = 687.4
第四步:在25 oC下,向 (4-(4-((1R,5S)-8-(叔丁氧羰基)-3,8-二氮雜雙環[3.2.1]辛)-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-基)硼酸(76.0 mg,0.11 mmol)的乙腈(1600 uL)溶液中,加入氯化氫(4 M的二氧六環溶液,277 uL,1.11 mmol)。將該溶液在25 oC攪拌1小時。將溶液用三乙胺(155 uL,1.11 mmol)淬滅,然後濃縮並透過製備型HPLC純化,得到白色固體化合物 (4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛)-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-基)硼酸(甲酸鹽,11.19 mg,18.7 umol,產率17%)。LCMS (ESI): [M+H] += 587.2 1H NMR (400 MHz, CD 3OD) δ ppm 9.16 (s, 1H), 8.46 (br s, 1H), 8.42 (br s, 1H), 8.02 (d, J= 8.1 Hz, 1H), 7.94 (s, 1H), 7.67 (br d, J= 8.3 Hz, 1H), 7.59-7.43 (m, 2H), 5.57-5.35 (m, 1H), 4.78 (br s, 2H), 4.60-4.47 (m, 2H), 4.02 (br s, 2H), 3.88 (br dd, J= 5.6, 13.0 Hz, 2H), 3.77-3.51 (m, 3H), 3.29-3.24 (m, 1H), 2.62-2.36 (m, 2H), 2.36-2.13 (m, 3H), 2.12-1.91 (m, 5H). 實施例 24 :7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)- 8-氟-喹唑啉-6-甲腈 Step 4 : To a solution of (4-(4-((1R,5S)-8-(tert-butyloxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid (76.0 mg, 0.11 mmol) in acetonitrile (1600 uL) at 25 °C was added hydrogen chloride (4 M in dioxane, 277 uL, 1.11 mmol). The solution was stirred at 25 ° C for 1 hour. The solution was quenched with triethylamine (155 uL, 1.11 mmol), then concentrated and purified by preparative HPLC to give a white solid compound (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane)-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl)boronic acid (formate, 11.19 mg, 18.7 umol, yield 17%). LCMS (ESI): [M+H] + = 587.2 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.16 (s, 1H), 8.46 (br s, 1H), 8.42 (br s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H), 7.67 (br d, J = 8.3 Hz, 1H), 7.59-7.43 (m, 2H), 5.57-5.35 (m, 1H), 4.78 (br s, 2H), 4.60-4.47 (m, 2H), 4.02 (br s, 2H), 3.88 (br dd, J = 5.6, 13.0 Hz, 2H), 3.77-3.51 (m, 3H), 3.29-3.24 (m, 1H), 2.62-2.36 (m, 2H), 2.36-2.13 (m, 3H), 2.12-1.91 (m, 5H). Example 24 : 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-quinazoline-6-carbonitrile
實施例 24 透過實施例 22 的合成途徑方法進行製備 ,用中間體向叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯和中間體(1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇 A16-2A Example 24 was prepared by the synthetic route of Example 22 , using the intermediate to tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate and the intermediate (1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-2A
LCMS (ESI): [M+H] +=659.2; 1H NMR (400 MHz, CD 3OD) δ ppm 8.26 (s, 1H), 6.65 (s, 1H), 4.62-4.47 (m, 2H), 4.43-4.29 (m, 2H), 3.79-3.56 (m, 4H), 3.32-3.25 (m, 1H), 3.22-3.10 (m, 1H), 2.85 (d, J= 12.2 Hz, 1H), 2.78-2.64 (m, 1H), 2.48 (br d, J= 0.9 Hz, 3H), 2.28 (br dd, J= 6.1, 13.4 Hz, 1H), 2.20-2.10 (m, 1H), 2.03 (br d, J= 13.6 Hz, 1H), 1.98-1.71 (m, 7H), 1.55-1.36 (m, 2H). 19F NMR (400 MHz, CD 3OD) δ ppm -55.85 (s, 3F), -127.71 (br s, 1F), -135.41 (d, J= 151.1 Hz, 1F), -138.12 (d, J= 151.1 Hz, 1F). 實施例 25 :4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-1-氟萘-2-醇 LCMS (ESI): [M+H] + =659.2; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.26 (s, 1H), 6.65 (s, 1H), 4.62-4.47 (m, 2H), 4.43-4.29 (m, 2H), 3.79-3.56 (m, 4H), 3.32-3.25 (m, 1H), 3.22-3.10 (m, 1H), 2.85 (d, J = 12.2 Hz, 1H), 2.78-2.64 (m, 1H), 2.48 (br d, J = 0.9 Hz, 3H), 2.28 (br dd, J = 6.1, 13.4 Hz, 1H), 1H), 2.20-2.10 (m, 1H), 2.03 (br d, J = 13.6 Hz, 1H), 1.98-1.71 (m, 7H), 1.55-1.36 (m, 2H). 19 F NMR (400 MHz, CD 3 OD) δ ppm -55.85 (s, 3F), -127.71 (br s, 1F), -135.41 (d, J = 151.1 Hz, 1F), -138.12 (d, J = 151.1 Hz, 1F). Example 25 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-fluoronaphthalen-2-ol
第一步:在0 oC下向4-溴萘-2-醇(2.00 g,8.96 mmol)的二氯甲烷(30 mL)溶液中加入雙(苯磺醯基)氟胺(9.33 g,29.59 mmol)和四氯化鋯(0.10 g,0.45 mmol)。將該溶液在25 oC攪拌16小時。將溶液濃縮並透過快速管柱層析(矽膠,0-20%梯度的石油醚/乙酸乙酯)純化,得到棕色固體化合物4-溴-1-氟萘-2-醇(0.94 g,3.50 mmol,產率39%)。LCMS (ESI): [M-H] += 240.8. Step 1 : Add bis(phenylsulfonyl)fluoroamine (9.33 g, 29.59 mmol) and zirconium tetrachloride (0.10 g, 0.45 mmol) to a solution of 4-bromonaphthalene-2-ol (2.00 g, 8.96 mmol) in dichloromethane (30 mL) at 0 ° C. Stir the solution at 25 ° C for 16 hours. Concentrate the solution and purify it by flash column chromatography (silica gel, 0-20% gradient of petroleum ether/ethyl acetate) to obtain a brown solid compound 4-bromo-1-fluoronaphthalene-2-ol (0.94 g, 3.50 mmol, 39% yield). LCMS (ESI): [MH] + = 240.8.
第二步:在25 oC和氮氣保護下,向4-溴-1-氟萘-2-醇(300 mg,1.24 mmol),雙聯頻哪醇硼酸酯(475 mg,1.87 mmol)和醋酸鉀(367 mg,3.73 mmol)的二氧六環(6000 uL)溶液中加入雙(三苯基膦)氯化鈀(II)(44.0 mg,0.06 mmol)。將該溶液在110 oC攪拌3小時。將溶液濃縮並透過快速管柱層析(矽膠,0-25%梯度石油醚/乙酸乙酯)純化,得到黃色固體化合物1-氟-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)萘-2-醇(324 mg,1.13 mmol,產率90%)。LCMS (ESI): [M-H] += 287.0. Step 2 : At 25 ° C and under nitrogen protection, add bis(triphenylphosphine)palladium(II) chloride (44.0 mg, 0.06 mmol) to a solution of 4-bromo-1-fluoronaphthalen-2-ol (300 mg, 1.24 mmol), bis(pinacol borate) (475 mg, 1.87 mmol) and potassium acetate (367 mg, 3.73 mmol) in dioxane (6000 uL). Stir the solution at 110 ° C for 3 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-25% gradient petroleum ether/ethyl acetate) to give a yellow solid compound 1-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (324 mg, 1.13 mmol, yield 90%). LCMS (ESI): [MH] + = 287.0.
第三步:在25 oC和氮氣保護下,向1-氟-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)萘-2-醇(157 mg,0.54 mmol)和叔丁基(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(150 mg,0.27 mmol)的二氧六環(3.00 mL)溶液中,加入碳酸鉀(2.0 M的水溶液,409 uL,0.82 mmol)和四(三苯基膦)鈀(32.0 mg,0.03 mmol)。將該溶液在85 oC攪拌16小時。濃縮溶液並將粗產物透過快速管柱層析(矽膠,0-10%梯度二氯甲烷/甲醇)純化得到棕色固體化合物叔丁基(1R,5S)-3-(8-氟-7-(4-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(210 mg,0.26 mmol,產率97%)。LCMS (ESI): [M+H] += 677.2. Step 3 : Potassium carbonate (2.0 M aqueous solution, 409 uL, 0.82 mmol) and tetrakis(triphenylphosphine)palladium (32.0 mL) were added to a solution of 1-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (157 mg, 0.54 mmol) and tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.27 mmol) in dioxane (3.00 mL) at 25 °C under nitrogen protection. The solution was stirred at 85 ° C for 16 hours. The solution was concentrated and the crude product was purified by flash column chromatography (silica gel, 0-10% gradient dichloromethane/methanol) to give a brown solid compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(4-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (210 mg, 0.26 mmol, yield 97%). LCMS (ESI): [M+H] + = 677.2.
第四步:在25 oC下,向叔丁基(1R,5S)-3-(8-氟-7-(4-氟-3-羥基萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(200 mg,0.30 mmol)的乙腈(4000 uL)溶液中加入氯化氫(4 M的二氧六環溶液,739 uL,2.96 mmol)。將該溶液在25 oC攪拌1小時。加入三乙胺(206 uL,1.48 mmol)將pH值調節至8。然後將溶液濃縮並透過製備型HPLC純化得到白色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-1-氟萘-2-醇(甲酸鹽,77.19 mg,0.13 mmol,產率45%)。LCMS (ESI): [M+H] += 577.0. 1H NMR (400 MHz, CD 3OD) δ ppm 9.15 (s, 1H), 8.48 (s, 1H), 8.05 (d, J= 8.5 Hz, 1H), 7.65-7.51 (m, 2H), 7.42-7.30 (m, 2H), 5.55-5.33 (m, 1H), 4.77 (br d, J= 8.5 Hz, 2H), 4.48 (q, J= 11.3 Hz, 2H), 3.95 (br s, 2H), 3.89-3.78 (m, 2H), 3.70-3.49 (m, 3H), 3.23 (dt, J= 6.0, 9.8 Hz, 1H), 2.58-2.23 (m, 3H), 2.21-2.11 (m, 2H), 2.09-1.86 (m, 5H). 實施例 26:7-(3-胺基-7,8-二氟異喹啉-1-基)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-甲腈 Step 4 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(4-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.30 mmol) in acetonitrile (4000 uL) was added hydrogen chloride (4 M in dioxane, 739 uL, 2.96 mmol) at 25 o C. The solution was stirred at 25 o C for 1 hour. The pH was adjusted to 8 by adding triethylamine (206 uL, 1.48 mmol). The solution was then concentrated and purified by preparative HPLC to give a white solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-fluoronaphthalen-2-ol (formate salt, 77.19 mg, 0.13 mmol, yield 45%). LCMS (ESI): [M+H] + = 577.0. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.15 (s, 1H), 8.48 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.65-7.51 (m, 2H), 7.42-7.30 (m, 2H), 5.55-5.33 (m, 1H), 4.77 (br d, J = 8.5 Hz, 2H), 4.48 (q, J = 11.3 Hz, 2H), 3.95 (br s, 2H), 3.89-3.78 (m, 2H), 3.70-3.49 (m, 3H), 3.23 (dt, J = 6.0, 9.8 Hz, 1H), 2.58-2.23 (m, 3H), 2.21-2.11 (m, 2H), 2.09-1.86 (m, 5H). Example 26 : 7-(3-amino-7,8-difluoroisoquinolin-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile
第一步:在0 oC下,向2-溴-3,4-二氟苯甲酸(25.0 g,105.49 mmol)的四氫呋喃(100 mL)溶液中滴加硼烷的四氫呋喃溶液(422 mL,422 mmol)。升溫至室溫並攪拌16小時。溶液用冰浴冷卻,然後緩慢加入10%碳酸鈉水溶液(180 mL)。將懸浮液真空濃縮,得到白色固體。用3摩爾/升鹽酸水溶液(600 mL)酸化,用二氯甲烷(300 mL)稀釋,混合物透過矽藻土過濾。將濾液分液,有機層用無水硫酸鈉乾燥,然後過濾。將所得濾液真空濃縮,得到 (2-溴-3,4-二氟苯基)甲醇(22.0 g,98.65 mmol,產率94%),為灰白色固體。 1H NMR (400MHz, DMSO- d 6) δ ppm 7.57-7.45 (m, 1H), 7.43-7.31 (m, 1H), 5.58 (t, J= 5.6 Hz, 1H), 4.50 (br d, J= 5.4 Hz, 2H). Step 1: At 0 ° C, add a solution of 2-bromo-3,4-difluorobenzoic acid (25.0 g, 105.49 mmol) in tetrahydrofuran (100 mL) dropwise with a solution of borane in tetrahydrofuran (422 mL, 422 mmol). Warm to room temperature and stir for 16 hours. Cool the solution with an ice bath, then slowly add a 10% aqueous sodium carbonate solution (180 mL). Concentrate the suspension in vacuo to obtain a white solid. Acidify with 3 mol/L aqueous hydrochloric acid solution (600 mL), dilute with dichloromethane (300 mL), and filter the mixture through diatomaceous earth. Separate the filtrate, dry the organic layer with anhydrous sodium sulfate, and then filter. The filtrate was concentrated in vacuo to give (2-bromo-3,4-difluorophenyl)methanol (22.0 g, 98.65 mmol, 94% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.57-7.45 (m, 1H), 7.43-7.31 (m, 1H), 5.58 (t, J = 5.6 Hz, 1H), 4.50 (br d, J = 5.4 Hz, 2H).
第二步:在0 oC下,向 (2-溴-3,4-二氟苯基)甲醇(22.0 g,98.65 mmol)和三乙胺的二氯甲烷(220 mL)溶液中加入甲基磺酸酐(25.78 g,148 mmol)。將反應在0 oC攪拌1小時。向混合物中加入水(200 mL)並用二氯甲烷(100 mL * 3)萃取,有機相用鹽水(200 mL * 1)洗滌。有機層用無水硫酸鎂乾燥並過濾。將濾液真空濃縮得到棕色油狀化合物2-溴-3,4-二氟苄基甲磺酸酯(29.0 g,96.31 mmol,產率97%)。 1H NMR (400MHz, DMSO- d 6) δ ppm 7.64-7.51 (m, 2H), 5.40-5.32 (m, 2H), 3.32-3.25 (m, 3H). Step 2: At 0 o C, add methanesulfonic anhydride (25.78 g, 148 mmol) to a solution of (2-bromo-3,4-difluorophenyl)methanol (22.0 g, 98.65 mmol) and triethylamine in dichloromethane (220 mL). Stir the reaction at 0 o C for 1 hour. Add water (200 mL) to the mixture and extract with dichloromethane (100 mL * 3), and wash the organic phase with brine (200 mL * 1). The organic layer is dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated in vacuo to obtain a brown oily compound 2-bromo-3,4-difluorobenzyl methanesulfonate (29.0 g, 96.31 mmol, yield 97%). 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.64-7.51 (m, 2H), 5.40-5.32 (m, 2H), 3.32-3.25 (m, 3H).
第三步:在0 oC下,向2-溴-3,4-二氟苄基甲磺酸酯(29.0 g,96.31 mmol)的乙腈(300 mL)溶液中加入碳酸鉀(26.0 g,192 mmol)和三甲基氰矽烷(19.0 g,192 mmol)。將反應在80 oC攪拌16小時。將混合物用水(200 mL)稀釋並用乙酸乙酯(200 mL)萃取,有機相用鹽水(200 mL)洗滌,無水硫酸鎂乾燥並過濾。濾液旋轉乾燥,得到的殘餘物透過快速管柱層析(矽膠,0-15%梯度四氫呋喃/石油醚)純化得到黃色固體化合物2-(2-溴-3,4-二氟苯基)乙腈(9.80 g,42 mmol,產率44%)。 1H NMR (400MHz, DMSO- d 6) δ ppm 7.64-7.52 (m, 1H), 7.50-7.42 (m, 1H), 4.14 (s, 2H). Step 3: To a solution of 2-bromo-3,4-difluorobenzyl methanesulfonate (29.0 g, 96.31 mmol) in acetonitrile (300 mL) was added potassium carbonate (26.0 g, 192 mmol) and trimethylsilyl cyanide (19.0 g, 192 mmol) at 0 ° C. The reaction was stirred at 80 ° C for 16 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL), and the organic phase was washed with brine (200 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was rotary dried, and the residue was purified by flash column chromatography (silica gel, 0-15% gradient tetrahydrofuran/petroleum ether) to obtain a yellow solid compound 2-(2-bromo-3,4-difluorophenyl)acetonitrile (9.80 g, 42 mmol, yield 44%). 1 H NMR (400MHz, DMSO- d 6 ) δ ppm 7.64-7.52 (m, 1H), 7.50-7.42 (m, 1H), 4.14 (s, 2H).
第四步:向2-(2-溴-3,4-二氟苯基)乙腈(9.50 g,40.94 mmol)的二甲基乙醯胺(100 mL)溶液中加入四(三苯基膦)鈀(4.73 g,4.09 mmol)和氰化鋅(5.77 g,49.13 mmol)。混合物在120 oC和氮氣保護下加熱5小時。反應液旋轉乾燥,殘餘物透過快速管柱層析(矽膠,0-25%梯度四氫呋喃/石油醚)純化得到黃色固體化合物6-(氰基甲基)-2,3-二氟苯甲腈(4.50 g,25.26 mmol,產率62%)。 1H NMR (400MHz, DMSO- d 6) δ ppm 8.00-7.84 (m, 1H), 7.52 (br dd, J=4.1, 8.4 Hz, 1H), 4.33 (s, 2H). Step 4: Add tetrakis(triphenylphosphine)palladium (4.73 g, 4.09 mmol) and zinc cyanide (5.77 g, 49.13 mmol) to a solution of 2-(2-bromo-3,4-difluorophenyl)acetonitrile (9.50 g, 40.94 mmol) in dimethylacetamide (100 mL). The mixture was heated at 120 ° C for 5 hours under nitrogen protection. The reaction solution was rotary dried, and the residue was purified by flash column chromatography (silica gel, 0-25% gradient tetrahydrofuran/petroleum ether) to obtain a yellow solid compound 6-(cyanomethyl)-2,3-difluorobenzonitrile (4.50 g, 25.26 mmol, yield 62%). 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.00-7.84 (m, 1H), 7.52 (br dd, J =4.1, 8.4 Hz, 1H), 4.33 (s, 2H).
第五步:在0 oC下,將化合物6-(氰基甲基)-2,3-二氟苯甲腈(4.50 g,25.26 mmol)緩慢溶於33%的氫溴酸/醋酸溶液(45.00 mL),混合物在0 oC攪拌0.2小時,然後在20 oC攪拌1.5小時。將混合物用水(150 mL)稀釋並透過飽和碳酸鈉溶液鹼化。用乙酸乙酯(150 mL*3)萃取,有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥,殘餘物透過快速管柱層析(矽膠,0-25%梯度四氫呋喃/石油醚)純化得到黃色固體化合物1-溴-7,8-二氟異喹啉-3-胺(0.76 g,2.90 mmol,產率12%)。LCMS (ESI): [M+H] += 260.8。 1H NMR (400MHz, DMSO- d 6) δ ppm 7.63 (dt, J= 7.4, 9.8 Hz, 1H), 7.49 (ddd, J= 1.6, 5.0, 9.3 Hz, 1H), 6.69 (d, J= 2.4 Hz, 1H), 6.49 (s, 2H). Step 5: At 0 o C, the compound 6-(cyanomethyl)-2,3-difluorobenzonitrile (4.50 g, 25.26 mmol) was slowly dissolved in 33% hydrobromic acid/acetic acid solution (45.00 mL), and the mixture was stirred at 0 o C for 0.2 hours and then at 20 o C for 1.5 hours. The mixture was diluted with water (150 mL) and alkalized by saturated sodium carbonate solution. Extract with ethyl acetate (150 mL*3), dry the organic phase with anhydrous sodium sulfate, filter, and spin dry the filtrate. The residue is purified by flash column chromatography (silica gel, 0-25% gradient tetrahydrofuran/petroleum ether) to obtain a yellow solid compound 1-bromo-7,8-difluoroisoquinolin-3-amine (0.76 g, 2.90 mmol, yield 12%). LCMS (ESI): [M+H] + = 260.8. 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.63 (dt, J = 7.4, 9.8 Hz, 1H), 7.49 (ddd, J = 1.6, 5.0, 9.3 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.49 (s, 2H).
第六步:在氮氣氣氛下,向1-溴-7,8-二氟異喹啉-3-胺(150 mg,0.58 mmol)的二氧六環(1.5 mL)溶液中加入六丁基二錫(1.00 g,1.74 mmol),三環己基膦(32.5 mg,0.12 mmol),氯化鋰(123 mg,2.9 mmol)和三(二伸苄基丙酮)二鈀(53 mg,0.06 mmol)。反應液在120 oC攪拌16小時。混合物減壓旋轉乾燥,殘餘物透過快速管柱層析(中性氧化鋁,0-5%梯度乙酸乙酯/石油醚)純化得到黃色油狀化合物7,8-二氟-1-(三丁基甲錫烷基)異喹啉-3-胺(260 mg,0.55 mmol,產率95%)。LCMS (ESI): [M+H] += 471.0. Step 6: Under nitrogen atmosphere, hexabutyl ditin (1.00 g, 1.74 mmol), tricyclohexylphosphine (32.5 mg, 0.12 mmol), lithium chloride (123 mg, 2.9 mmol) and tris(dibenzylacetone) dipalladium (53 mg, 0.06 mmol) were added to a solution of 1-bromo-7,8-difluoroisoquinolin-3-amine (150 mg, 0.58 mmol) in dioxane (1.5 mL). The reaction solution was stirred at 120 ° C for 16 hours. The mixture was dried under reduced pressure and rotary vortexed. The residue was purified by flash column chromatography (neutral alumina, 0-5% gradient ethyl acetate/petroleum ether) to give a yellow oily compound 7,8-difluoro-1-(tributylmethylstannyl)isoquinolin-3-amine (260 mg, 0.55 mmol, yield 95%). LCMS (ESI): [M+H] + = 471.0.
第七步:在氮氣氣氛下,向叔丁基(1R,5S)-3-(7-溴-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(250 mg,0.45 mmol)的二氧六環(5 mL)溶液中加入7,8-二氟-1-(三丁基甲錫烷基)異喹啉-3-胺(251 mg,0.54 mmol),碘化亞銅(25.5 mg,0.13 mmol),氯化鋰(47 mg,1.11 mmol)和四(三苯基膦)鈀(103 mg,0.09 mmol)。反應在氮氣氣氛和120 oC下攪拌16小時。混合物旋轉乾燥,得到的粗產物透過快速管柱層析(矽膠,0-50%梯度乙酸乙酯/石油醚)純化得到黃色固體化合物叔丁基(1R,5S)-3-(7-(3-胺基-7,8-二氟異喹啉-1-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(120 mg,0.18 mmol,產率40%)。LCMS (ESI): [M+H] += 660.1. Step 7: Under nitrogen atmosphere, 7,8-difluoro-1-(tributylmethylstannyl)isoquinolin-3-amine (251 mg, 0.54 mmol), cuprous iodide (25.5 mg, 0.13 mmol), lithium chloride (47 mg, 1.11 mmol) and tetrakis(triphenylphosphine)palladium (103 mg, 0.09 mmol) were added to a solution of tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.45 mmol) in dioxane (5 mL). The reaction was stirred under nitrogen atmosphere at 120 ° C for 16 hours. The mixture was rotary dried and the crude product was purified by flash column chromatography (silica gel, 0-50% gradient ethyl acetate/petroleum ether) to give a yellow solid compound tert-butyl (1R,5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.18 mmol, yield 40%). LCMS (ESI): [M+H] + = 660.1.
第八步:向叔丁基(1R,5S)-3-(7-(3-胺基-7,8-二氟異喹啉-1-基)-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(60 mg,91 umol)的四氫呋喃(1 mL)溶液中加入4A分子篩(60 mg),叔丁醇鈉(11 mg,0.11 mmol)和 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(17 mg,0.11 mmol)。將反應在20 oC攪拌2小時。混合物用水(2 mL)稀釋並用乙酸乙酯(2 mL*3)萃取,合併的有機相用飽和食鹽水(2 mL)洗滌,無水硫酸鎂乾燥,過濾,濾液濃縮,殘餘物透過快速管柱層析(矽膠,0-10%梯度甲醇/二氯甲烷)純化得到棕色固體化合物叔丁基(1R,5S)-3-(7-(3-胺基-7,8-二氟異喹啉-1-基)-6-氰基-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(47.3 mg,66 umol,產率72%)。LCMS (ESI): [M+H] += 719.2. Step 8: To a solution of tert-butyl (1R,5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 91 umol) in tetrahydrofuran (1 mL) was added 4A molecular sieve (60 mg), sodium tert-butoxide (11 mg, 0.11 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (17 mg, 0.11 mmol). The reaction was stirred at 20 ° C for 2 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL*3). The combined organic phases were washed with saturated brine (2 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (47.3 mg, 66 umol, yield 72%). LCMS (ESI): [M+H] + = 719.2.
第九步:向叔丁基(1R,5S)-3-(7-(3-胺基-7,8-二氟異喹啉-1-基)-6-氰基-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(47.3 mg,66 umol)的乙腈(1 mL)溶液中加入氯化氫(4 M的二氧六環溶液,330 uL,1.3 mmol)。將反應在20 oC攪拌1小時。溶液濃縮後溶於乙腈(1 mL),用三乙胺中和並濃縮。混合物透過製備型HPLC純化,得到黃色固體化合物7-(3-胺基-7,8-二氟異喹啉-1-基)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-甲腈(9.45 mg,15.3 umol,產率23%)。LCMS (ESI): [M+H] += 619.1。 1H NMR (400MHz, CD 3OD) δ ppm 8.35 (s, 1H), 7.55 (br d, J= 5.0 Hz, 2H), 7.01 (br s, 1H), 5.48 (br s, 1H), 4.64 (br d, J= 10.5 Hz, 2H), 4.49-4.38 (m, 2H), 3.91-3.79 (m, 4H), 3.48 (br d, J= 10.5 Hz, 3H), 3.20 (br s, 1H), 2.46-2.24 (m, 3H), 1.96 (br s, 7H). 實施例 27:6-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-4-甲基-5-(三氟甲基)吡啶-2-胺 實施例 29:6-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-4-甲基-5-(全氟乙基)吡啶-2-胺 Step 9: To a solution of tert-butyl (1R,5S)-3-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (47.3 mg, 66 umol) in acetonitrile (1 mL) was added hydrogen chloride (4 M in dioxane, 330 uL, 1.3 mmol). The reaction was stirred at 20 ° C for 1 hour. The solution was concentrated and dissolved in acetonitrile (1 mL), neutralized with triethylamine and concentrated. The mixture was purified by preparative HPLC to give a yellow solid compound 7-(3-amino-7,8-difluoroisoquinolin-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile (9.45 mg, 15.3 umol, yield 23%). LCMS (ESI): [M+H] + = 619.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.35 (s, 1H), 7.55 (br d, J = 5.0 Hz, 2H), 7.01 (br s, 1H), 5.48 (br s, 1H), 4.64 (br d, J = 10.5 Hz, 2H), 4.49-4.38 (m, 2H), 3.91-3.79 (m, 4H), 3.48 (br d, J = 10.5 Hz, 3H), 3.20 (br s, 1H), 2.46-2.24 (m, 3H), 1.96 (br s, 7H). Example 27 : 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine Example 29 :6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(perfluoroethyl)pyridin-2-amine
第一步:在手套箱中,向叔丁基(1R,5S)-3-(7-氯-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(1.40 g,2.85 mmol),N,N-雙(4-甲氧基苄基)-4-甲基-6-(三丁基甲錫烷基)吡啶-2-胺(3.27 g,5.12 mmol),碘化亞銅(163 mg,0.85 mmol)和氯化鋰(302 mg,7.12 mmol)的二氧六環(28 mL)溶液中,加入四(三苯基磷)鈀(657 mg,0.57 mmol)。將混合物氮氣保護下在120 oC下攪拌16小時。過濾,旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-30%梯度的乙酸乙酯/石油醚),得到黃色固體化合物叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基))吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(1.80 g,2.24 mmol,產率79%)。LCMS (ESI): [M+H] += 804.6. Step 1 : In a glove box, to a solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.40 g, 2.85 mmol), N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributylmethanyl)pyridin-2-amine (3.27 g, 5.12 mmol), cuprous iodide (163 mg, 0.85 mmol) and lithium chloride (302 mg, 7.12 mmol) in dioxane (28 mL) was added tetrakis(triphenylphosphine)palladium (657 mg, 0.57 mmol). The mixture was stirred at 120 ° C for 16 hours under nitrogen. Filtered and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a yellow solid compound tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy))pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.80 g, 2.24 mmol, yield 79%). LCMS (ESI): [M+H] + = 804.6.
第二步:向叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基))吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(500 mg,0.62 mmol)的乙腈(10 mL)溶液中,加入N-碘琥珀醯亞胺(700 mg,3.11 mmol)和對甲苯磺酸(4.30 mg,0.02 mmol)。將混合物在氮氣保護和25 oC下攪拌12小時。混合物旋轉乾燥,加入食鹽水(10 mL),使用乙酸乙酯(20 mL * 3)萃取,有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-30%梯度的乙酸乙酯/石油醚)得到粗產物。該粗產物加入水(20 mL)中,室溫攪拌1小時,過濾,並用石油醚(10 mL)洗滌,濾餅真空乾燥得到粗產物化合物叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-3-碘-4-甲基吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(660 mg),其為黃色固體。LCMS (ESI): [M+H] += 930.3. 1HNMR (400 MHz, CDCl 3) δ ppm 9.11 (s, 1H), 7.19 (d, J= 8.6 Hz, 4H), 6.87 (d, J= 8.6 Hz, 4H), 6.52 (s, 1H), 4.92 (q, J= 8.3 Hz, 2H), 4.69 (s, 4H), 4.63-4.38 (m, 4H), 3.81 (s, 6H), 3.76 (br dd, J= 4.9, 12.4 Hz, 2H), 2.39 (s, 3H), 2.05-1.96 (m, 2H), 1.76 (br d, J= 7.7 Hz, 2H), 1.55 (s, 9H). Step 2 : To a solution of tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy))pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.62 mmol) in acetonitrile (10 mL) was added N-iodosuccinimide (700 mg, 3.11 mmol) and p-toluenesulfonic acid (4.30 mg, 0.02 mmol). The mixture was stirred at 25 ° C for 12 hours under nitrogen protection. The mixture was rotary dried, brine (10 mL) was added, and ethyl acetate (20 mL * 3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain a crude product. The crude product was added to water (20 mL), stirred at room temperature for 1 hour, filtered, and washed with petroleum ether (10 mL). The filter cake was dried in vacuo to give a crude product compound tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (660 mg) as a yellow solid. LCMS (ESI): [M+H] + = 930.3. 1 HNMR (400 MHz, CDCl 3 ) δ ppm 9.11 (s, 1H), 7.19 (d, J = 8.6 Hz, 4H), 6.87 (d, J = 8.6 Hz, 4H), 6.52 (s, 1H), 4.92 (q, J = 8.3 Hz, 2H), 4.69 (s, 4H), 4.63-4.38 (m, 4H), 3.81 (s, 6H), 3.76 (br dd, J = 4.9, 12.4 Hz, 2H), 2.39 (s, 3H), 2.05-1.96 (m, 2H), 1.76 (br d, J = 7.7 Hz, 2H), 1.55 (s, 9H).
第三步:將叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-3-碘-4-甲基吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(290 mg, 0.31 mmol)和碘化亞銅(178 mg, 0.94 mmol)的N,N-二甲基乙醯胺(7.2 mL)溶液,在0 oC下加入2,2-二氟-2-(氟磺醯基)乙酸三甲基甲矽烷酯(468 mg,1.87 mmol)。將混合物氮氣保護下在20 oC下攪拌1小時。加入水(30 mL),使用乙酸乙酯(30 mL)萃取3次,無水硫酸鈉乾燥,過濾旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-30%梯度的四氫呋喃/石油醚)。得到化合物叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯和叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基-3-(全氟乙基)吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯的混合物(150 mg),其為黃色固體。LCMS (ESI): [M+H] += 872.5; 922.7. Step 3 : tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (290 mg, 0.31 mmol) and cuprous iodide (178 mg, 0.94 mmol) in N,N-dimethylacetamide (7.2 mL) were added with trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (468 mg, 1.87 mmol) at 0 ° C. The mixture was stirred at 20 ° C for 1 hour under nitrogen protection. Water (30 mL) was added, and the mixture was extracted three times with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, filtered and spin-dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran/petroleum ether). A mixture of the compounds tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(perfluoroethyl)pyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mL) was obtained. mg) as a yellow solid. LCMS (ESI): [M+H] + = 872.5; 922.7.
第四步:向化合物叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯和叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基-3-(全氟乙基)吡啶-2-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯的混合物(140 mg,0.16 mmol)及 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(51.0 mg,0.32 mmol)的四氫呋喃(2.8 mL)溶液中,加入叔丁醇鈉(23.0 mg,0.24 mmol)。混合物在氮氣保護下20 oC攪拌2小時。加入水(5 mL),使用乙酸乙酯(10 mL * 3)萃取3,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥,得到粗產物化合物叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯和叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基-3-(全氟乙基)吡啶-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯的混合物(230 mg),其為黃色油狀液體。LCMS (ESI): [M+Na] += 953.7; [M+H] += 982.5. Step 4 : To a mixture of tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(perfluoroethyl)pyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (51.0 mg, 0.32 mmol) in tetrahydrofuran (2.8 mL) was added sodium tert-butoxide (23.0 mg, 0.24 mmol). The mixture was stirred at 20 ° C for 2 hours under nitrogen protection. Water (5 mL) was added and ethyl acetate (10 mL * 3) Extraction 3, the combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary dried to obtain a crude product compound tert-butyl (1R, 5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclic A mixture of [3.2.1]octane-8-carboxylate and tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(perfluoroethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg) was obtained as a yellow oily liquid. LCMS (ESI): [M+Na] + = 953.7; [M+H] + = 982.5.
第五步:將叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基-3-(三氟甲基)吡啶-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯和叔丁基(1R,5S)-3-(7-(6-(雙(4-甲氧基苄基)胺基)-4-甲基-3-(全氟乙基)吡啶-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯的混合物(230 mg,0.16 mmol)溶於三氟乙酸(2.3 mL),在氮氣保護下50 oC攪拌2小時,然後旋轉乾燥。加入二氯甲烷(0.5 mL),使用三乙胺調節至pH=7,旋轉乾燥。殘留物用製備型HPLC純化,得到兩個化合物。保留時間較短的化合物為 實施例 27(6-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-4-甲基-5-(三氟甲基)吡啶-2-胺)(43.98 mg,0.07 mmol,產率30%),其為白色固體。LCMS (ESI): [M+H] += 591.2. 1H NMR (400 MHz, CD 3OD) δ ppm 9.03 (s, 1H), 6.63 (s, 1H), 5.48-5.16 (m, 1H), 4.70-4.54 (m, 2H), 4.38-4.18 (m, 2H), 3.75-3.59 (m, 4H), 3.31-3.18 (m, 3H), 3.02 (dt, J= 5.7, 9.4 Hz, 1H), 2.47 (br d, J= 1.2 Hz, 3H), 2.40-2.20 (m, 2H), 2.19-2.11 (m, 1H), 2.07-1.96 (m, 2H), 1.94-1.73 (m, 5H). Step 5 : tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate A mixture of butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(perfluoroethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.16 mmol) was dissolved in trifluoroacetic acid (2.3 mL), stirred at 50 ° C for 2 hours under nitrogen, and then rotated to dryness. Dichloromethane (0.5 mL) was added, and the pH was adjusted to 7 with triethylamine and rotated to dryness. The residue was purified by preparative HPLC to give two compounds. The compound with a shorter retention time was Example 27 (6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine) (43.98 mg, 0.07 mmol, 30% yield), which was a white solid. LCMS (ESI): [M+H] + = 591.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.03 (s, 1H), 6.63 (s, 1H), 5.48-5.16 (m, 1H), 4.70-4.54 (m, 2H), 4.38-4.18 (m, 2H), 3.75-3.59 (m, 4H), 3.31-3.18 (m, 3H), 3.02 (dt, J = 5.7, 9.4 Hz, 1H), 2.47 (br d, J = 1.2 Hz, 3H), 2.40-2.20 (m, 2H), 2.19-2.11 (m, 1H), 2.08-1.91 (m, 2H), 1.94-1.73 (m, 5H).
保留時間較長的化合物為 實施例 29(6-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-4-甲基-5-(全氟乙基)吡啶-2-胺)(5.26 mg,8.2 umol,產率3%),其為白色固體。LCMS (ESI): [M+H] += 641.2. 1H NMR (400 MHz, CD 3OD) δ ppm 8.99 (s, 1H), 6.64 (s, 1H), 5.44-5.21 (m, 1H), 4.60 (br s, 2H), 4.37-4.18 (m, 2H), 3.67 (br s, 4H), 3.30-3.14 (m, 3H), 3.03 (dt, J= 5.7, 9.3 Hz, 1H), 2.47 (br s, 3H), 2.41-2.21 (m, 2H), 2.20-2.11 (m, 1H), 2.07-1.96 (m, 2H), 1.96-1.71 (m, 5H). 實施例 28:N-(6-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-4-甲基-5-(三氟甲基)吡啶-2-基)乙醯胺 The compound with a longer retention time was Example 29 (6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(perfluoroethyl)pyridin-2-amine) (5.26 mg, 8.2 umol, yield 3%), which was a white solid. LCMS (ESI): [M+H] + = 641.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.99 (s, 1H), 6.64 (s, 1H), 5.44-5.21 (m, 1H), 4.60 (br s, 2H), 4.37-4.18 (m, 2H), 3.67 (br s, 4H), 3.30-3.14 (m, 3H), 3.03 (dt, J = 5.7, 9.3 Hz, 1H), 2.47 (br s, 3H), 2.41-2.21 (m, 2H), 2.20-2.11 (m, 1H), 2.07-1.96 (m, 2H), 1.96-1.71 (m, 5H). Example 28 : N-(6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-yl)acetamide
第一步:在25 oC下,將化合物6-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-(三氟甲基)吡啶-2-胺(35.0 mg,0.06 mmol)加入到二氯甲烷(500 uL)中,加入三乙胺(89 uL,0.59 mmol)和二碳酸二叔丁酯(15 uL, 0.07 mmol),混合液在25 oC攪拌16小時。減壓濃縮反應液得到粗產物化合物叔丁基(1R,5S)-3-(7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(40 mg,0.06 mmol,產率98%)。LCMS (ESI): [M+H] += 691.2。 Step 1 : At 25 ° C, compound 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrol-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-(trifluoromethyl)pyridin-2-amine (35.0 mg, 0.06 mmol) was added to dichloromethane (500 uL), triethylamine (89 uL, 0.59 mmol) and di-tert-butyl dicarbonate (15 uL, 0.07 mmol), and the mixture was stirred at 25 ° C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product compound tert-butyl (1R, 5S)-3-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.06 mmol, yield 98%). LCMS (ESI): [M+H] + = 691.2.
第二步:在25 oC下,將化合物叔丁基(1R,5S)-3-(7-(6-胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(35.0 mg,0.05 mmol)溶於二甲基甲醯胺(400 uL),冷卻至0 oC,加入吡啶(50 uL),然後緩慢加入乙醯氯(7 uL,0.10 mmol),混合液升溫至25 oC攪拌1小時。反應液用乙酸乙酯(1 mL)和水(1 mL)分液,水層用乙酸乙酯(1 mL*2)萃取。合併的有機層用無水硫酸鎂乾燥,過濾並濃縮濾液得到棕色油狀化合物叔丁基(1R,5S)-3-(7-(6-乙醯胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(37 mg,0.05 mmol,產率99%)。LCMS (ESI): [M+H] += 733.2。 Step 2 : At 25 ° C, dissolve the compound tert-butyl (1R,5S)-3-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35.0 mg, 0.05 mmol) in dimethylformamide (400 uL), cool to 0 ° C, add pyridine (50 uL), and then slowly add acetyl chloride (7 uL, 0.10 mmol), and the mixture is heated to 25 ° C and stirred for 1 hour. The reaction solution was separated by ethyl acetate (1 mL) and water (1 mL), and the aqueous layer was extracted with ethyl acetate (1 mL*2). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated to obtain a brown oily compound tert-butyl (1R, 5S)-3-(7-(6-acetamido-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37 mg, 0.05 mmol, yield 99%). LCMS (ESI): [M+H] + = 733.2.
第三步:在0 oC下,將化合物叔丁基(1R,5S)-3-(7-(6-乙醯胺基-4-甲基-3-(三氟甲基)吡啶-2-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯啉-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(35.0 mg,0.05 mmol)溶於乙睛(1 mL),加入氯化氫(4 M的二氧六環溶液,239 uL,0.96 mmol),反應在20 oC下攪拌2小時。真空濃縮反應液,殘餘物溶於乙睛(500 uL)並用三乙胺中和至pH>7,減壓濃縮除去溶劑,殘留物用製備型HPLC純化,得到白色固體N-(6-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛基-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-4-甲基-5-(三氟甲基)吡啶-2-基)乙醯胺(15.0 mg,0.02 mmol,產率50%)。LCMS (ESI): [M+H] += 633.2。 1H NMR (400 MHz, CD 3OD) δ ppm 9.05 (s, 1H), 8.33 (s, 1H), 5.44-5.19 (m, 1H), 4.60 (br d, J= 19.3 Hz, 3H), 4.37-4.21 (m, 2H), 3.77-3.57 (m, 4H), 3.27-3.19 (m, 2H), 3.09-2.97 (m, 1H), 2.71-2.57 (m, 3H), 2.42-2.10 (m, 6H), 2.06-1.97 (m, 2H), 1.95-1.72 (m, 5H). 實施例 30 :4-(4-(-3,8-二氮雜雙環[3.2.1]辛-3-基-2-((二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇 Step 3 : At 0 ° C, the compound tert-butyl (1R,5S)-3-(7-(6-acetamido-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35.0 mg, 0.05 mmol) was dissolved in acetonitrile (1 mL), and hydrogen chloride (4 M in dioxane, 239 uL, 0.96 mmol) was added, and the reaction was stirred at 20 ° C for 2 hours. The reaction solution was concentrated in vacuo, the residue was dissolved in acetonitrile (500 uL) and neutralized with triethylamine to pH>7, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative HPLC to obtain white solid N-(6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-yl)acetamide (15.0 mg, 0.02 mmol, yield 50%). LCMS (ESI): [M+H] + = 633.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.05 (s, 1H), 8.33 (s, 1H), 5.44-5.19 (m, 1H), 4.60 (br d, J = 19.3 Hz, 3H), 4.37-4.21 (m, 2H), 3.77-3.57 (m, 4H), 3.27-3.19 (m, 2H), 3.09-2.97 (m, 1H), 2.71-2.57 (m, 3H), 2.42-2.10 (m, 6H), 2.06-1.97 (m, 2H), 1.95-1.72 (m, 5H). Example 30 : 4-(4-(-3,8-diazabicyclo[3.2.1]octan-3-yl-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
第一步:向叔丁基(1R,5S)-3–(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(269 mg, 0.63 mmol)和 (二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)-甲醇(115 mg,0.63 mmol)的二氧六環(2.5 mL)溶液中加入二異丙基乙胺(334 uL,1.88 mmol),然後將混合物氮氣保護下在80 oC下攪拌16小時。反應混合物旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-5%梯度的甲醇/二氯甲烷)得到黃色固體化合物叔丁基-3-(7-氯-2-((二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(83 mg,0.14 mmol,產率23%)。LCMS (ESI): [M+H] += 575.4. Step 1 : To a solution of tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (269 mg, 0.63 mmol) and (dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)-methanol (115 mg, 0.63 mmol) in dioxane (2.5 mL) was added diisopropylethylamine (334 uL, 1.88 mmol), and the mixture was stirred at 80 o C under nitrogen for 16 hours. The reaction mixture was spun dry. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of methanol/dichloromethane) to give a yellow solid compound tert-butyl-3-(7-chloro-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (83 mg, 0.14 mmol, yield 23%). LCMS (ESI): [M+H] + = 575.4.
第二步:在手套箱中,向叔丁基-3-(7-氯-2-((二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(110 mg, 0.19 mmol)和2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(83 mg,0.23 mmol)的二氧六環(2.2 mL)溶液中,加入磷酸鉀(1.5 M的水溶液,386 uL,0.58 mmol)和甲磺酸[正丁基二(1-金剛烷基)膦](2-胺基-1,1-聯苯-2-基)鈀(II)(14 mg,0.02 mmol),然後將混合物氮氣保護下在100 oC下攪拌3小時。反應混合物旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-5%梯度的甲醇/二氯甲烷)得到黃色油狀化合物叔丁基-3-(2-((二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(129 mg,0.17 mmol,產率87%)。LCMS (ESI): [M+H] += 773.5. Step 2 : In a glove box, potassium phosphate (1.5 M in water, 386 μL, 0.58 μL) was added to a solution of tert-butyl-3-(7-chloro-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.19 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (83 mg, 0.23 mmol) in dioxane (2.2 mL). mmol) and [n-butyldi(1-adamantyl)phosphine](2-amino-1,1-biphenyl-2-yl)palladium(II) methanesulfonate (14 mg, 0.02 mmol), and the mixture was stirred at 100 ° C for 3 hours under nitrogen. The reaction mixture was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of methanol/dichloromethane) to give yellow oily compound tert-butyl-3-(2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (129 mg, 0.17 mmol, yield 87%). LCMS (ESI): [M+H] + = 773.5.
第三步:向叔丁基-3-(2-((二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(110 mg,0.14 mmol)的二氯甲烷(1760 uL)溶液中,加入三氟乙酸(440 uL)。混合物在25 oC攪拌1小時。用氮氣流除去大部分溶劑,再用油泵旋轉乾燥。然後加入三乙胺(0.5 mL)和四氫呋喃(0.5 mL),旋轉乾燥。殘留物用製備型HPLC純化,得到白色固體化合物4-(4-(3,8-二氮雜雙環[3.2.1]辛-3-基-2-((二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇(30.6 mg,0.05 mmol,產率34%)。LCMS (ESI): [M+H] += 629.3. 1H NMR (400 MHz, CD 3OD) δ ppm 9.07 (s, 1H), 7.69 (dd, J= 5.8, 9.1 Hz, 1H), 7.32 (d, J= 2.5 Hz, 1H), 7.26 (t, J= 9.4 Hz, 1H), 7.07 (d, J= 2.4 Hz, 1H), 4.73 (br d, J= 6.1 Hz, 2H), 4.67-4.58 (m, 4H), 4.28-4.10 (m, 2H), 3.81-3.60 (m, 4H), 3.53 (d, J= 10.4 Hz, 1H), 3.04 (br dd, J= 6.8, 10.6 Hz, 1H), 2.97 (d, J= 10.5 Hz, 1H), 2.78 (td, J= 5.2, 10.8 Hz, 1H), 2.62-2.42 (m, 2H), 2.28-2.12 (m, 1H), 2.05-1.93 (m, 3H), 1.91-1.76 (m, 6H), 0.81 (dt, J= 2.4, 7.3 Hz, 3H). 實施例 31A和 實施例 31B :4-(4 -((1R,5S)-(3,8-二氮雜雙環[3.2.1]辛-3-基-2-((二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇,和 4-(4- ((1R,5S )-(3,8-二氮雜雙環[3.2.1]辛-3-基-2-((二氫-1’H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇 Step 3 : To a solution of tert-butyl-3-(2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.14 mmol) in dichloromethane (1760 uL) was added trifluoroacetic acid (440 uL). The mixture was stirred at 25 o C for 1 hour. Most of the solvent was removed with a stream of nitrogen and then the mixture was rotated to dryness using an oil pump. Then triethylamine (0.5 mL) and tetrahydrofuran (0.5 mL) were added and the mixture was rotated to dryness. The residue was purified by preparative HPLC to give a white solid compound 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (30.6 mg, 0.05 mmol, yield 34%). LCMS (ESI): [M+H] + = 629.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.07 (s, 1H), 7.69 (dd, J = 5.8, 9.1 Hz, 1H), 7.32 (d, J = 5.7, 9.2 Hz, 1H), 7.70 (d, J = 5.9, 10.8 Hz, 1H). 3.71 (m, 2H), 3.59 (d, J = 10.5 Hz, 1H), 3.55 (t, J = 9.4 Hz, 1H), 3.24 (d, J = 2.5 Hz, 1H), 3.75 (t, J = 10.8 Hz, 1H), 3.54 (t, J = 3.1, 10.6 Hz, 1H), 3.85 (m, 2H), 3.24 (d, J = 10.5 Hz, 1H), 3.55 (t, J = 10.8 Hz, 1H), 3.54 (t, J = 2.5, 10.6 Hz, 1H), 3.85 (t, J = 3.1, 10.8 Hz, 1H), 3.94 (t, J = 3.2, 10.8 Hz, 1H), 2.28-2.12 (m, 1H), 2.05-1.93 (m, 3H), 1.91-1.76 (m, 6H), 0.81 (dt, J = 2.4, 7.3 Hz, 3H). Example 31A and Example 31B : 4-(4 -((1R,5S)- (3,8-diazabicyclo[3.2.1]octan-3-yl-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, and 4-(4 -(( 1R,5S )- (3,8-diazabicyclo[3.2.1]octan-3-yl-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
實施例 30經SFC分離(管柱:DAICEL CHIRALPAK AD (250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/乙醇;B相保持50%;流速:80毫升/分鐘),得到目標化合物。 Example 30 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 50%; flow rate: 80 ml/min) to obtain the target compound.
異構物 1, 實施例 31A:LCMS (ESI): [M+H] += 629.3; SFC分析(管柱:Chiralpak AD-3(50mm * 4.6mm),3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相5分鐘,流速:4毫升/分鐘):掌性管柱出峰位置為0.660 min; 1H NMR (400 MHz, MeOD) δ ppm 9.07 (s, 1H), 7.69 (dd, J= 5.9, 9.0 Hz, 1H), 7.32 (d, J= 2.6 Hz, 1H), 7.27 (t, J= 9.4 Hz, 1H), 7.07 (d, J= 2.6 Hz, 1H), 4.73 (dd, J= 1.5, 6.1 Hz, 2H), 4.68-4.56 (m, 4H), 4.27-4.12 (m, 2H), 3.81-3.63 (m, 4H), 3.54 (d, J= 10.4 Hz, 1H), 3.11-3.01 (m, 1H), 2.97 (d, J= 10.4 Hz, 1H), 2.78 (td, J= 5.3, 10.8 Hz, 1H), 2.62-2.42 (m, 2H), 2.24-2.14 (m, 1H), 2.07-1.93 (m, 3H), 1.93-1.75 (m, 6H), 0.81 (dt, J= 2.8, 7.4 Hz, 3H). Isomer 1, Example 31A : LCMS (ESI): [M+H] + = 629.3; SFC analysis (column: Chiralpak AD-3 (50 mm * 4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B for 5 minutes, flow rate: 4 ml/min): the elution position of the palmar column is 0.660 min; 1 H NMR (400 MHz, MeOD) δ ppm 9.07 (s, 1H), 7.69 (dd, J = 5.9, 9.0 Hz, 1H), 7.32 (d, J = 2.6 Hz, 1H), 7.27 (t, J = 9.4 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 4.73 3H), 4.68-4.56 (m, 4H), 4.27-4.12 (m, 2H), 3.81-3.63 (m, 4H), 3.54 (d, J = 10.4 Hz, 1H), 3.11-3.01 (m, 1H), 2.97 (d, J = 10.4 Hz, 1H), 2.78 (td, J = 5.3, 10.8 Hz, 1H), 2.62-2.42 (m, 2H) , 2.24-2.14 (m, 1H), 2.07-1.93 (m, 3H), 1.93-1.75 (m, 6H), 0.81 (dt, J = 2.8, 7.4 Hz, 3H).
異構物 2 , 實施例 31B :LCMS (ESI): [M+H] += 629.3; SFC分析(管柱:Chiralpak AD-3(50mm * 4.6mm),3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相5分鐘,流速:4毫升/分鐘):掌性管柱出峰位置為 2.147 min; 1H NMR (400 MHz, CD 3OD) δ ppm 9.07 (s, 1H), 7.69 (dd, J= 5.8, 9.1 Hz, 1H), 7.32 (d, J= 2.7 Hz, 1H), 7.27 (t, J= 9.4 Hz, 1H), 7.07 (d, J= 2.6 Hz, 1H), 4.73 (dd, J= 1.3, 6.1 Hz, 2H), 4.68-4.56 (m, 4H), 4.30-4.10 (m, 2H), 3.81-3.63 (m, 4H), 3.55 (d, J= 10.5 Hz, 1H), 3.13-2.94 (m, 2H), 2.87-2.74 (m, 1H), 2.63-2.43 (m, 2H), 2.25-2.15 (m, 1H), 2.07-1.94 (m, 3H), 1.93-1.77 (m, 6H), 0.82 (dt, J= 2.7, 7.4 Hz, 3H). 實施例 32 :4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-((六氫-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇 二甲酸鹽 Isomer 2 , Example 31B : LCMS (ESI): [M+H] + = 629.3; SFC analysis (column: Chiralpak AD-3 (50mm * 4.6mm), 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B for 5 minutes, flow rate: 4 ml/min): the elution position of the palmar column is 2.147 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.07 (s, 1H), 7.69 (dd, J = 5.8, 9.1 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 7.27 (t, J = 9.4 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 3H), 4.73 (dd, J = 1.3, 6.1 Hz, 2H), 4.68-4.56 (m, 4H), 4.30-4.10 (m, 2H), 3.81-3.63 (m, 4H), 3.55 (d, J = 10.5 Hz, 1H), 3.13-2.94 (m, 2H), 2.87-2.74 (m, 1H), 2.63-2.43 (m, 2H), 2.25-2.15 (m, 1H), 2.07-1.94 (m, 3H), 1.93-1.77 (m, 6H), 0.82 (dt, J = 2.7, 7.4 Hz, 3H). Example 32 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol dicarboxylate
第一步:向叔丁基(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(800 mg,1.16 mmol)和 (六氫-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-基)甲醇(106 mg,0.58 mmol)的四氫呋喃(5 mL)溶液中加入叔丁醇鈉(375 mg,2.90 mmol)。反應在25 oC攪拌16小時。過濾混合物並真空濃縮濾液。殘餘物透過快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化得到棕色固體化合物叔丁基(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((六氫-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(70%純度,430 mg,0.39 mmol,產率67%)。LCMS (ESI): [M+H] += 773.4. Step 1 : To a solution of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.16 mmol) and (hexahydro-2H-furo[2,3-b]pyrrolizin-7a(5H)-yl)methanol (106 mg, 0.58 mmol) in tetrahydrofuran (5 mL) was added sodium tert-butoxide (375 mg, 2.90 mmol). The reaction was stirred at 25 ° C for 16 hours. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give brown solid compound tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 430 mg, 0.39 mmol, 67% yield). LCMS (ESI): [M+H] + = 773.4.
第二步:在0 oC下,向含有叔丁基(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((六氫-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(70%純度,410 mg,0.37 mmol)的反應瓶中加入三氟乙酸/二氯甲烷混合溶液(體積比為1/4,5 mL)。反應在25 oC下攪拌1小時。將該混合物用氮氣流在室溫下吹乾,用二氯甲烷(1 mL)稀釋並加入三乙胺調節pH至7-8。將混合物真空濃縮,殘餘物用製備型HPLC純化得到黃色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-((六氫-2H-呋喃[2,3-b]吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇(二甲酸鹽,17.6 mg,27 umol,產率7%)。LCMS (ESI): [M+H] += 629.3. 1H NMR (400 MHz, CD 3OD) δ ppm 9.14 (s, 1H), 8.49 (s, 2H), 7.70 (dd, J= 6.0, 9.0 Hz, 1H), 7.34 (d, J= 2.8 Hz, 1H), 7.28 (t, J= 9.3 Hz, 1H), 7.07 (d, J= 2.5 Hz, 1H), 4.86-4.75 (m, 2H), 4.65-4.58 (m, 2H), 4.55 (t, J= 4.3 Hz, 1H), 4.19-4.06 (m, 3H), 4.03-3.90 (m, 3H), 3.90-3.81 (m, 1H), 3.50-3.40 (m, 1H), 3.27 (br dd, J= 5.4, 10.2 Hz, 1H), 2.57-2.51 (m, 1H), 2.51-2.43 (m, 1H), 2.33-2.02 (m, 12H), 0.84-0.77 (m, 3H) Step 2 : To a reaction bottle containing tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 410 mg, 0.37 mmol) was added a trifluoroacetic acid/dichloromethane mixed solution (1/4 by volume, 5 mL) at 0 °C. The reaction was stirred at 25 ° C for 1 hour. The mixture was blown dry at room temperature with a stream of nitrogen, diluted with dichloromethane (1 mL) and triethylamine was added to adjust the pH to 7-8. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC to give a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((hexahydro-2H-furo[2,3-b]pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (dicarboxylate, 17.6 mg, 27 umol, 7% yield). LCMS (ESI): [M+H] + = 629.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.14 (s, 1H), 8.49 (s, 2H), 7.70 (dd, J = 6.0, 9.0 Hz, 1H), 7.34 (d, J = 2.8 Hz, 1H), 7.28 (t, J = 9.3 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 4.86-4.75 (m, 2H), 4.65-4.71 (m, 2H), 4.54 (t, J = 4.3 Hz, 1H), 4.19-4.08 (m, 3H), 4.23-4.84 (m, 3H), 3.90-3.81 (m, 1H), 3.50-3.40 (m, 1H), 3.27 (br dd, J = 5.4, 10.2 Hz, 1H), 2.57-2.51 (m, 1H), 2.51-2.43 (m, 1H), 2.33-2.02 (m, 12H), 0.84-0.77 (m, 3H)
以下實施例透過實施例 32 的合成途徑方法進行製備: 實施例 33A :反式-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((1aR,6aS,6bS)-六氫環丙[a]吡咯嗪-6a(4H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇 甲酸鹽 The following examples were prepared by the synthetic route of Example 32 : Example 33A : trans-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((1aR,6aS,6bS)-hexahydrocyclopropane[a]pyrrolazin-6a(4H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol carboxylate
LCMS (ESI): [M+H] += 599.3. 1H NMR (400 MHz, CD 3OD) δ ppm 9.12 (s, 1H), 8.64-8.37 (m, 2H), 7.68 (dd, J= 9.1, 5.8 Hz, 1H), 7.41-7.20 (m, 2H), 7.05 (d, J= 2.6 Hz, 1H), 4.78-4.64 (m, 4H), 3.96-3.75 (m, 4H), 3.66 (br d, J= 11.4 Hz, 2H), 3.38 (br dd, J= 11.7, 4.3 Hz, 2H), 2.55-2.15 (m, 6H), 2.03-1.87 (m, 6H), 0.92-0.70 (m, 5H). 實施例 33B :順式-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-((六氫環丙[a]吡咯嗪-6a(4H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇 LCMS (ESI): [M+H] + = 599.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.12 (s, 1H), 8.64-8.37 (m, 2H), 7.68 (dd, J = 9.1, 5.8 Hz, 1H), 7.41-7.20 (m, 2H), 7.05 (d, J = 2.6 Hz, 1H), 4.78-4.64 (m, 4H), 3.96-3.75 (m, 4H), 3.66 (br d, J = 11.4 Hz, 2H), 3.38 (br dd, J = 11.7, 4.3 Hz, 2H), 2.55-2.15 (m, 6H), 2.03-1.87 (m, 6H), 0.92-0.70 (m, 5H). Example 33B : cis-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((hexahydrocyclopropane[a]pyrrolizine-6a(4H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
LCMS (ESI): [M+H] += 599.3. 1H NMR (400 MHz, CD 3OD) δ ppm 9.06 (s, 1H), 7.68 (dd, J= 9.1, 5.9 Hz, 1H), 7.38-7.18 (m, 2H), 7.06 (d, J= 2.6 Hz, 1H), 4.73-4.57 (m, 2H), 4.49-4.24 (m, 2H), 3.80-3.63 (m, 4H), 3.44 (br dd, J= 11.6, 4.10 Hz, 1H), 3.07 (br d, J= 5.5 Hz, 1H), 2.90 (d, J= 11.6 Hz, 1H), 2.73-2.60 (m, 1H), 2.57-2.42 (m, 1H), 2.25-2.13 (m, 1H), 2.08 (br d, J= 3.2 Hz, 1H), 2.02-1.93 (m, 3H), 1.92-1.76 (m, 5H), 1.70 (br d, J= 7.6 Hz, 1H), 0.88-0.67 (m, 4H), 0.36-0.25 (m, 1H). 實施例 34 :4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-((二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇 甲酸鹽 LCMS (ESI): [M+H] + = 599.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.06 (s, 1H), 7.68 (dd, J = 9.1, 5.9 Hz, 1H), 7.38-7.18 (m, 2H), 7.06 (d, J = 2.6 Hz, 1H), 4.73-4.57 (m, 2H), 4.49-4.24 (m, 2H), 3.80-3.63 (m, 4H), 3.44 (br dd, J = 11.6, 4.10 Hz, 1H), 3.07 (br d, J = 5.5 Hz, 1H), 2.91 (d, J = 11.6 Hz, 1H), d, J = 3.2 Hz, 1H), 2.08 (br d, J = 3.2 Hz, 1H), 2.02-1.93 (m, 3H), 1.92-1.76 (m, 5H), 1.70 (br d, J = 7.6 Hz, 1H), 0.88-0.67 (m, 4H), 0.36-0.25 (m, 1H). Example 34 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol carboxylate
LCMS (ESI): [M+H] += 613.3. 1H NMR (400 MHz, CD 3OD) δ ppm 9.12 (s, 1H), 8.54 (br s, 1H), 7.69 (dd, J= 6.0, 9.0 Hz, 1H), 7.34-7.21 (m, 2H), 7.06 (d, J= 2.3 Hz, 1H), 4.67-4.56 (m, 4H), 3.83-3.67 (m, 7H), 3.16 (m, 1H), 2.56-2.05 (m, 8H), 1.88 (br s, 2H), 1.79 (br d, J= 8.8 Hz, 2H), 0.87-0.67 (m, 7H). 實施例 35 :反式-4-(4-((1S,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇 LCMS (ESI): [M+H] + = 613.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.12 (s, 1H), 8.54 (br s, 1H), 7.69 (dd, J = 6.0, 9.0 Hz, 1H), 7.34-7.21 (m, 2H), 7.06 (d, J = 2.3 Hz, 1H), 4.67-4.56 (m, 4H), 3.83-3.67 (m, 7H), 3.16 (m, 1H), 2.56-2.05 (m, 8H), 1.88 (br s, 2H), 1.79 (br d, J = 8.8 Hz, 2H), 0.87-0.67 (m, 7H). Example 35 : trans-4-(4-((1S,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
LCMS (ESI): [M+H] += 649.3. 1H NMR (400 MHz, CDCl 3) δ ppm 9.08 (s, 1H), 7.69 (dd, J= 6.0, 9.0 Hz, 1H), 7.35-7.24 (m, 2H), 7.07 (d, J= 2.5 Hz, 1H), 4.70-4.59 (m, 2H), 4.42-4.35 (m, 2H), 3.78-3.65 (m, 4H), 3.32-3.27 (m, 1H), 3.20-3.14 (m, 1H), 2.86 (d, J= 12.3 Hz, 1H), 2.75-2.68 (m, 1H), 2.51 (br dd, J= 7.0, 15.1 Hz, 1H), 2.33-2.12 (m, 3H), 2.04 (d, J= 13.6 Hz, 1H), 1.95-1.77 (m, 7H), 1.52-1.35 (m, 2H), 0.88-0.75 (m, 3H). 實施例 35A和 實施例 35B :4-(4-((1S,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇,和 4-(4-((1S,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇 LCMS (ESI): [M+H] + = 649.3. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.08 (s, 1H), 7.69 (dd, J = 6.0, 9.0 Hz, 1H), 7.35-7.24 (m, 2H), 7.07 (d, J = 2.5 Hz, 1H), 4.70-4.59 (m, 2H), 4.42-4.35 (m, 2H), 3.78-3.65 (m, 4H), 3.32-3.27 (m, 1H), 3.20-3.14 (m, 1H), 2.86 (d, J = 12.3 Hz, 1H), 2.75-2.68 (m, 1H), 2.51 (br dd, J = 7.0, 15.1 Hz, 1H), 2.33-2.12 (m, 3H), 2.04 (d, J = 13.6 Hz, 1H), 1.95-1.77 (m, 7H), 1.52-1.35 (m, 2H), 0.88-0.75 (m, 3H). Example 35A and Example 35B : 4-(4-((1S,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol, and 4-(4-((1S,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
實施例 35經SFC分離(管柱:DAICEL CHIRALPAK IG (250mm*30mm,10um);流動相:A相為二氧化碳,B相為乙醇;B相保持45%;流速:80毫升/分鐘)得到出峰時間較短的掌性單體 35A及出峰時間較長的掌性單體 35B。 Example 35 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is ethanol; phase B is maintained at 45%; flow rate: 80 ml/min) to obtain chiral monomer 35A with a shorter elution time and chiral monomer 35B with a longer elution time.
實施例 35A :異構物 1 ,白色固體,LCMS (ESI): [M+H] += 649.3; SFC分析(管柱:Chiralpak IG-3 100*4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在4分鐘內從5%到40%,保持40%的B相2.5分鐘,保持5%的B相1.5分鐘,流速:2.8毫升/分鐘):RT = 2.311 min, ee = 98.68%; 1H NMR (400 MHz, CD 3OD) δ ppm 8.96 (s, 1H), 7.57 (dd, J= 5.9, 8.9 Hz, 1H), 7.20 (d, J= 2.4 Hz, 1H), 7.14 (t, J= 9.4 Hz, 1H), 6.95 (d, J= 2.3 Hz, 1H), 4.56-4.48 (m, 2H), 4.31-4.20 (m, 2H), 3.66-3.51 (m, 4H), 3.19-3.16 (m, 1H), 3.09-3.01 (m, 1H), 2.74 (br d, J= 12.3 Hz, 1H), 2.63-2.55 (m, 1H), 2.38 (br dd, J= 7.1, 13.9 Hz, 1H), 2.21-2.01 (m, 3H), 1.96-1.91 (m, 1H), 1.82-1.64 (m, 7H), 1.37-1.28 (m, 2H), 0.69 (br t, J= 7.3 Hz, 3H)。 Example 35A : Isomer 1 , white solid, LCMS (ESI): [M+H] + = 649.3; SFC analysis (column: Chiralpak IG-3 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B from 5% to 40% in 4 minutes, keep 40% phase B for 2.5 minutes, keep 5% phase B for 1.5 minutes, flow rate: 2.8 ml/min): RT = 2.311 min, ee = 98.68%; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.96 (s, 1H), 7.57 (dd, J = 5.9, 8.9 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), rms, 5H), 7.14 (t, J = 9.4 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 4.56-4.48 (m, 2H), 4.31-4.20 (m, 2H), 3.66-3.51 (m, 4H), 3.19-3.16 (m, 1H), 3.09-3.01 (m, 1H), 2.74 (br d, J = 12.3 Hz, 1H), 2.63-2.55 (m, 1H), 2.38 (br dd, J = 7.1, 13.9 Hz, 1H), 2.21-2.01 (m, 3H), 1.96-1.91 (m, 1H), 1.82-1.64 (m, 7H), 1.37-1.28 (m, 2H), 0.69 (br t, J = 7.3 Hz, 3H).
實施例 35B :異構物 2 ,白色固體,LCMS (ESI): [M+H] += 649.3; SFC分析(管柱:Chiralpak IG-3 100*4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在4分鐘內從5%到40%,保持40%的B相2.5分鐘,保持5%的B相1.5分鐘,流速:2.8毫升/分鐘):RT = 3.397 min, ee = 96.08%; 1H NMR (400 MHz, CD 3OD) δ ppm 9.00-8.92 (m, 1H), 7.61-7.53 (m, 1H), 7.24-7.10 (m, 2H), 7.00-6.93 (m, 1H), 4.48-4.42 (m, 2H), 4.32-4.23 (m, 2H), 3.66-3.53 (m, 4H), 3.17 (br s, 1H), 3.08-3.03 (m, 1H), 2.78-2.69 (m, 1H), 2.64-2.55 (m, 1H), 2.44-2.33 (m, 1H), 2.23-2.13 (m, 1H), 2.12-2.01 (m, 2H), 1.97-1.92 (m, 1H), 1.83-1.63 (m, 7H), 1.39-1.29 (m, 2H), 0.73-0.65 (m, 3H). 實施例 36 :順式-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇 Example 35B : Isomer 2 , white solid, LCMS (ESI): [M+H] + = 649.3; SFC analysis (column: Chiralpak IG-3 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B from 5% to 40% in 4 minutes, keep 40% phase B for 2.5 minutes, keep 5% phase B for 1.5 minutes, flow rate: 2.8 ml/min): RT = 3.397 min, ee = 96.08%; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.00-8.92 (m, 1H), 7.61-7.53 (m, 1H), 7.24-7.10 (m, 2H), 7.00-6.93 3H), 1.77-1.64 (m, 4H), 1.22-1.83 (m, 7H), 1.40-1.62 (m, 5H ), 0.71-0.71 (m, 3H ). : cis-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol
LCMS (ESI): [M+H] += 649.3. 1H NMR (400 MHz, CDCl 3) δ ppm 9.01-8.95 (m, 1H), 7.55 (dd, J= 5.8, 8.8 Hz, 1H), 7.23-7.17 (m, 2H), 7.04 (br s, 1H), 4.68-4.47 (m, 2H), 4.24-4.16 (m, 2H), 3.73-3.57 (m, 4H), 3.28 (d, J= 10.5 Hz, 1H), 3.17 (td, J= 5.2, 10.2 Hz, 1H), 2.86-2.72 (m, 2H), 2.50 (br d, J= 6.5 Hz, 1H), 2.41-2.33 (m, 1H), 2.27-2.08 (m, 3H), 2.05-1.83 (m, 7H), 1.39-1.31 (m, 2H), 0.88-0.81 (m, 3H). 實施例 37 : 4-(4-((1R,5S)-3,8- 二氮雜雙環 [3.2.1] 辛 -3- 基 )-8- 氟 -2-(( 六氫環丙 [b] 吡咯嗪 -5a(3H)- 基 ) 甲氧基 ) 吡啶并 [4,3-d] 嘧啶 -7- 基 )-5- 乙炔基 -6- 氟萘 -2- 醇 LCMS (ESI): [M+H] + = 649.3. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.01-8.95 (m, 1H), 7.55 (dd, J = 5.8, 8.8 Hz, 1H), 7.23-7.17 (m, 2H), 7.04 (br s, 1H), 4.68-4.47 (m, 2H), 4.24-4.16 (m, 2H), 3.73-3.57 (m, 4H), 3.28 (d , J = 10.5 Hz, 1H), 3.17 (td, J = 5.2, 10.2 Hz, 1H), 2.86-2.72 (m, 2H), 2.5 Hz, 1H), 2.41-2.33 (m, 1H), 2.27-2.08 (m, 3H), 2.05-1.83 (m, 7H), 1.39-1.31 (m, 2H), 0.88-0.81 (m, 3H). Example 37 : 4-(4-((1R,5S)-3,8 -diazabicyclo [3.2.1] oct -3- yl )-8- fluoro -2-(( hexahydrocyclopropane [b] pyrrolazin -5a(3H)-yl ) methoxy ) pyrido [ 4,3-d] pyrimidin -7- yl )-5- ethynyl -6- fluoronaphthalen -2- ol
第一步:向 (1R,5S)-叔丁基3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(200 mg,0.47 mmol)的二氧六環(5 mL)溶液中加入 (六氫環丙[b]吡咯嗪-5a(3H)-基)甲醇(85%純度,257 mg,1.40 mmol),二異丙基乙胺(0.39 mL,2.33 mmol)。反應在80 oC下攪拌16小時。真空濃縮混合物。殘餘物透過快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化得到黃色固體化合物叔丁基(1R,5S)-3-(7-氯-8-氟-2-((六氫環丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(130 mg,0.24 mmol,產率51%)。LCMS (ESI): [M+H] += 545.3. Step 1 : To a solution of (1R,5S)-tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.47 mmol) in dioxane (5 mL) was added (hexahydrocyclopropane[b]pyrrolizine-5a(3H)-yl)methanol (85% purity, 257 mg, 1.40 mmol), diisopropylethylamine (0.39 mL, 2.33 mmol). The reaction was stirred at 80 ° C for 16 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a yellow solid compound tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((hexahydrocyclopropane[b]pyrrolizin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.24 mmol, yield 51%). LCMS (ESI): [M+H] + = 545.3.
第二步:在氮氣環境下中,向叔丁基(1R,5S)-3-(7-氯-8-氟-2-((六氫環丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(120 mg,0.22 mmol)的二氧六環(2 mL)和水(0.40 mL)溶液中加入((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(135 mg,0.26 mmol),碳酸銫(215 mg,0.66 mmol)和 [(二(1-金剛烷基)-N-丁基膦)-2-(2-胺基聯苯)氯化鈀(II)(14.72 mg,0.02 mmol),並將混合物在100 oC下攪拌3小時。將混合物真空濃縮。殘餘物透過快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化,得到黃色固體化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-((六氫環丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(44 mg,0.05 mmol,產率22%)。LCMS (ESI): [M+H] += 896.5. Step 2 : To a solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((hexahydrocycloprop[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.22 mmol) in dioxane (2 mL) and water (0.40 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (135 mg, 0.26 mmol), cesium carbonate (215 mg, 0.66 mmol) and [(bis(1-adamantyl)-N-butylphosphino)-2-(2-aminobiphenyl)palladium(II) chloride (14.72 mg, 0.02 mmol) were added and the mixture was stirred at 100 ° C for 3 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a yellow solid compound tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((hexahydrocycloprop[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (44 mg, 0.05 mmol, yield 22%). LCMS (ESI): [M+H] + = 896.5.
第三步:向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-((六氫環丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(40 mg,0.04 mmol)的二氯甲烷(400 uL)溶液中,在0 oC下加入三氟乙酸(80 uL)。反應在25 oC下攪拌2小時。將混合物真空濃縮,得到粗產物化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-((六氫環丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三異丙基甲矽烷基)乙炔基)萘-2-醇(30 mg),為棕色固體。LCMS (ESI): [M+H] += 751.4. Step 3 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((hexahydrocycloprop[b]pyrrolazin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.04 mmol) in dichloromethane (400 uL) was added trifluoroacetic acid (80 uL) at 0 ° C. The reaction was stirred at 25 ° C for 2 hours. The mixture was concentrated in vacuo to give the crude product compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((hexahydrocycloprop[b]pyrrolizin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (30 mg) as a brown solid. LCMS (ESI): [M+H] + = 751.4.
第四步:向4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-((六氫環丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三異丙基甲矽烷基)乙炔基)萘-2-醇(40 mg,0.05 mmol)的二甲基甲醯胺(400 uL)溶液中加入氟化銫(162 mg,1.07 mmol)。反應在20 oC下攪拌2小時。反應液真空濃縮,殘餘物經過製備型HPLC純化,得到黃色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-((六氫環丙[b]吡咯嗪-5a(3H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(3.06 mg,4.5 umol,產率9%)。LCMS (ESI): [M+H] += 595.3. 1HNMR (400 MHz, CD 3OD) δ ppm 9.02 (s, 1H), 7.88 (dd, J= 5.8, 9.0 Hz, 1H), 7.41-7.30 (m, 2H), 7.23 (d, J= 2.3 Hz, 1H), 4.28-4.15 (m, 2H), 3.78-3.65 (m, 4H), 3.38 (d, J= 3.8 Hz, 1H), 3.28-3.21 (m, 1H), 3.03-2.95 (m, 1H), 2.79-2.71 (m, 1H), 2.23-2.13 (m, 2H), 2.08 (br dd, J= 6.1, 13.4 Hz, 1H), 2.01-1.77 (m, 8H), 1.65 (br dd, J= 5.0, 9.0 Hz, 1H), 1.33 (br d, J= 18.3 Hz, 1H), 0.69 (q, J= 7.7 Hz, 1H), 0.50 (br s, 1H). Step 4 : To a solution of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((hexahydrocyclopropyl[b]pyrrolizin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (40 mg, 0.05 mmol) in dimethylformamide (400 uL) was added cesium fluoride (162 mg, 1.07 mmol). The reaction was stirred at 20 ° C for 2 hours. The reaction solution was concentrated in vacuo, and the residue was purified by preparative HPLC to give a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((hexahydrocycloprop[b]pyrrolizin-5a(3H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (3.06 mg, 4.5 umol, yield 9%). LCMS (ESI): [M+H] + = 595.3. 1 HNMR (400 MHz, CD 3 OD) δ ppm 9.02 (s, 1H), 7.88 (dd, J = 5.8, 9.0 Hz, 1H), 7.41-7.30 (m, 2H) , 7.23 (d, J = 2.3 Hz, 1H), 4.28-4.15 (m, 2H), 3.78-3.65 (m, 4H), 3.28-3.21 (m, 1H), 3.03-2.95 (m, 1H), 2.79-2.71 (m, 1H), 2.23-2.13 (m, 2H), 2.08 (br dd, J = 6.1, 13.4 Hz, 1H), 2.01-1.77 (m, 8H), 1.65 (br dd, J = 5.0, 9.0 Hz, 1H), 1.33 (br d, J = 18.3 Hz, 1H), 0.69 (q, J = 7.7 Hz, 1H), 0.50 (br s, 1H).
以下實施例透過實施例 37 的合成途徑方法進行製備: 實施例 38 :4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-2-((二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇 The following examples were prepared by the synthetic route of Example 37 : Example 38 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS (ESI): [M+H] += 609.3. 1H NMR (400 MHz, CD 3OD) δ ppm 9.02 (s, 1H), 7.86 (dd, J= 5.7, 9.1 Hz, 1H), 7.38-7.28 (m, 2H), 7.21 (d, J= 2.2 Hz, 1H), 4.52-4.32 (m, 2H), 3.79-3.61 (m, 5H), 3.36 (br d, J= 4.5 Hz, 2H), 3.23-3.16 (m, 1H), 3.03-2.80 (m, 3H), 2.17-1.78 (m, 10H), 0.70-0.54 (m, 4H). 實施例 39 :4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-2-((二氫-1'H,3'H-螺[氧雜環丁烷-3,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇 LCMS (ESI): [M+H] + = 609.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.02 (s, 1H), 7.86 (dd, J = 5.7, 9.1 Hz, 1H), 7.38-7.28 (m, 2H), 7.21 (d, J = 2.2 Hz, 1H), 4.52-4.32 (m, 2H), 3.79-3.61 (m, 5H), 3.36 (br d, J = 4.5 Hz, 2H), 3.23-3.16 (m, 1H), 3.03-2.80 (m, 3H), 2.17-1.78 (m, 10H), 0.70-0.54 (m, 4H). Example 39 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((dihydro-1'H,3'H-spiro[oxacyclobutane-3,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS (ESI): [M+H] += 625.5. 1H NMR (400MHz, CD 3OD) δ ppm 9.02 (s, 1H), 7.87 (dd, J= 5.6, 9.2 Hz, 1H), 7.39-7.30 (m, 2H), 7.22 (d, J= 2.0 Hz, 1H), 4.73 (br d, J= 6.0 Hz, 2H), 4.70-4.52 (m, 4H), 4.26-4.10 (m, 2H), 3.79-3.60 (m, 4H), 3.53 (d, J= 10.3 Hz, 1H), 3.37 (d, J= 9.0 Hz, 1H), 3.09-3.00 (m, 1H), 2.97 (br d, J= 10.5 Hz, 1H), 2.83-2.70 (m, 1H), 2.55 (dd, J= 2.3, 13.3 Hz, 1H), 2.04 (s, 3H), 1.92-1.76 (m, 6H). 實施例 40A :4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇 LCMS (ESI): [M+H] + = 625.5. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.02 (s, 1H), 7.87 (dd, J = 5.6, 9.2 Hz, 1H), 7.39-7.30 (m, 2H), 7.22 (d, J = 2.0 Hz, 1H), 4.73 (br d, J = 6.0 Hz, 2H), 4.70-4.52 (m, 4H), 4.26-4.10 (m, 2H), 3.79-3.60 (m, 4H), 3.53 (d, J = 10.3 Hz, 1H), 3.37 (d, J = 9.0 Hz, 1H), 3.09-3.01 (m, 1H), 2.97 (br d, J = 10.5 Hz, 1H), 2.83-2.70 (m, 1H), 2.55 (dd, J = 2.3, 13.3 Hz, 1H), 2.04 (s, 3H), 1.92-1.76 (m, 6H). Example 40A : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
第一步:在25 oC下向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(547 mg,0.65 mmol)和 ((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇 A16-1A(120 mg,0.59 mmol)的四氫呋喃(5 mL)溶液中加入叔丁醇鈉(85 mg,0.89 mmol)。將溶液在25 oC攪拌2小時。將溶液濃縮並透過快速管柱層析(矽膠,0-10%梯度甲醇/二氯甲烷)純化得到棕色油狀化合物叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(純度50%,470 mg,0.25 mmol,產率42%)。LCMS (ESI): [M+H] += 944.9. Step 1 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (547 mg, 0.65 mmol) and ((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol A16-1A ( 120 mg, 0.59 mmol) in tetrahydrofuran (5 mL) was added sodium tert-butoxide (85 The solution was stirred at 25 ° C for 2 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a brown oily compound tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 50%, 470 mg, 0.25 mmol, yield 42%). LCMS (ESI): [M+H] + = 944.9.
第二步:在25 oC下向叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(純度50%,470 mg,0.25 mmol)在二甲基甲醯胺(5 mL)中的溶液中加入氟化銫(604 mg,3.98 mmol)。懸浮液在25 oC下攪拌2小時。將溶液濃縮並透過快速管柱層析(矽膠,0-10%梯度二氯甲烷/甲醇)純化,得到棕色油狀化合物叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基))萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(純度79%,370 mg,0.37 mmol,產率93%)。LCMS (ESI): [M+H] += 789.4。 Step 2 : To a solution of tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50% purity, 470 mg, 0.25 mmol) in dimethylformamide (5 mL) was added cesium fluoride (604 mg, 3.98 mmol) at 25 °C. The suspension was stirred at 25 ° C for 2 hours. The solution was concentrated and purified by flash column chromatography (silica gel, 0-10% gradient dichloromethane/methanol) to give a brown oily compound tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy))naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 79%, 370 mg, 0.37 mmol, yield 93%). LCMS (ESI): [M+H] + = 789.4.
第三步:在25 oC下將叔丁基(1R,5S)-3-(2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基))萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(純度79%,370 mg,0.37 mmol)溶於三氟乙酸/二氯甲烷(體積比為1/4,4 mL)並攪拌2小時。溶液用三乙胺(1.5 mL)調節至中性並用水(8 mL)稀釋,乙酸乙酯(4 mL * 3)萃取。乾燥合併的有機層並濃縮,得到的粗產物透過製備型HPLC純化,得到黃色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(27.3 mg,39.8 umol,產率11%)。LCMS (ESI): [M+H] += 645.3。 1H NMR (400 MHz, CD 3OD) δ ppm 9.01 (s, 1H), 7.85 (dd, J= 5.7, 9.2 Hz, 1H), 7.39-7.28 (m, 2H), 7.24-7.19 (m, 1H), 4.69-4.43 (m, 2H), 4.35-4.17 (m, 2H), 3.79-3.62 (m, 4H), 3.36-3.33 (m, 1H), 3.26-3.21 (m, 1H), 3.14-3.07 (m, 1H), 2.92-2.79 (m, 2H), 2.32 (dd, J= 5.1, 13.4 Hz, 1H), 2.15-1.76 (m, 9H), 1.52-1.39 (m, 2H). Step 3 : Dissolve tert-butyl (1R,5S)-3-(2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane - 1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy))naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 79%, 370 mg, 0.37 mmol) in trifluoroacetic acid/dichloromethane (1/4 by volume, 4 mL) and stir at 25 °C for 2 hours. The solution was adjusted to neutrality with triethylamine (1.5 mL) and diluted with water (8 mL), and extracted with ethyl acetate (4 mL * 3). The combined organic layers were dried and concentrated, and the crude product was purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (27.3 mg, 39.8 umol, yield 11%). LCMS (ESI): [M+H] + = 645.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.01 (s, 1H), 7.85 (dd, J = 5.7, 9.2 Hz, 1H), 7.39-7.28 (m, 2H), 7.24-7.19 (m, 1H), 4.69-4.43 (m, 2H), 4.35-4.17 (m, 2H), 3.79-3.62 (m, 4H), 3.36-3.33 (m, 1H), 3.26-3.21 (m, 1H), 3.14-3.07 (m, 1H), 2.92-2.79 (m, 2H), 2.32 (dd, J = 5.1, 13.4 Hz, 1H), 2.15-1.76 (m, 9H), 1.52-1.39 (m, 2H).
以下實施例透過實施例 40A 的合成途徑方法進行製備: 實施例 40B :4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-2-((((1S,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇 The following examples were prepared by the synthetic route of Example 40A : Example 40B : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS (ESI): [M+H] += 645.3。 1H NMR (400 MHz, CD 3OD) δ ppm 9.01 (s, 1H), 7.86 (br dd, J= 5.8, 8.8 Hz, 1H), 7.39-7.29 (m, 2H), 7.21 (s, 1H), 4.68-4.57 (m, 2H), 4.31-4.19 (m, 2H), 3.81-3.61 (m, 4H), 3.36 (br d, J= 7.3 Hz, 1H), 3.24 (br d, J=10.8 Hz, 1H), 3.10 (br d, J= 5.3 Hz, 1H), 2.95-2.77 (m, 2H), 2.31 (br dd, J= 4.8, 13.3 Hz, 1H), 2.13-1.79 (m, 9H), 1.52-1.41 (m, 2H). 實施例 40C : 4-(4-((1R,5S)-3,8- 二氮雜雙環 [3.2.1] 辛 -3- 基 )-2-((((1S,7a'S)-2,2- 二氟二氫 -1'H,3'H- 螺 [ 環丙烷 -1,2'- 吡咯嗪 ]-7a'(5'H)- 基 ) 甲氧基 )-8- 氟吡啶并 [4,3-d] 嘧啶 -7- 基 )-5- 乙炔基 -6- 氟萘 -2- 醇 甲酸鹽 LCMS (ESI): [M+H] + = 645.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.01 (s, 1H), 7.86 (br dd, J = 5.8, 8.8 Hz, 1H), 7.39-7.29 (m, 2H), 7.21 (s, 1H), 4.68-4.57 (m, 2H), 4.31-4.19 (m, 2H), 3.81-3.61 (m, 4H), 3.36 (br d, J = 7.3 Hz, 1H), 3.24 (br d, J=10.8 Hz, 1H), 3.10 (br d, J = 5.3 Hz, 1H), 2.95-2.77 (m, 2H), 2.31 (br dd, J = 4.8, 13.3 Hz, 1H), 2.13-1.79 (m, 9H), 1.52-1.41 (m, 2H). Example 40C : 4-(4-((1R,5S)-3,8- diazabicyclo [3.2.1] oct - 3- yl )-2-((((1S,7a'S)-2,2 -difluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2'- pyrrolizine ]-7a'(5'H)-yl) methoxy ) -8 - fluoropyrido [4,3-d] pyrimidin -7- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol carboxylate
LCMS (ESI): [M+H] += 645.3 1H NMR (400 MHz, CD 3OD) δ ppm 9.08 (s, 1H), 8.49 (br s, 1H), 7.89 (dd, J=5.7, 9.0 Hz, 1H), 7.42-7.29 (m, 2H), 7.23 (d, J=2.2 Hz, 1H), 4.79 (br s, 2H), 4.58-4.49 (m, 2H), 4.05 (br s, 2H), 3.89 (br s, 2H), 3.60 (br dd, J=6.5, 12.3 Hz, 1H), 3.50-3.42 (m, 1H), 3.38 (s, 1H), 3.11 (br d, J=12.2 Hz, 1H), 3.00-2.87 (m, 1H), 2.43 (br dd, J=6.1, 13.6 Hz, 1H), 2.27 (br dd, J=5.8, 11.7 Hz, 1H), 2.19-1.89 (m, 8H), 1.68-1.52 (m, 2H). 實施例 40D : 4-(4-((1R,5S)-3,8- 二氮雜雙環 [3.2.1] 辛 -3- 基 )-2-((((1R,7a'R)-2,2- 二氟二氫 -1'H),3'H- 螺 [ 環丙烷 -1,2'- 吡咯嗪 ]-7a'(5'H)- 基 ) 甲氧基 )-8- 氟吡啶并 [4,3-d] 嘧啶 -7- 基 )-5- 乙炔基 -6- 氟萘 -2- 醇 二甲酸鹽 LCMS (ESI): [M+H] + = 645.3 1H NMR (400 MHz, CD 3 OD) δ ppm 9.08 (s, 1H), 8.49 (br s, 1H), 7.89 (dd, J =5.7, 9.0 Hz, 1H), 7.42-7.29 (m, 2H), 7.23 (d, J =2.2 Hz, 1H), 4.79 (br s, 2H), 4.58-4.49 (m, 2H), 4.05 (br s, 2H), 3.89 (br s, 2H), 3.60 (br dd, J =6.5, 12.3 Hz, 1H), 3.50-3.42 (m, 1H), 3.38 (s, 1H), 3.11 (br d, J =12.2 Hz, 1H), 3.00-2.87 (m, 1H), 2.43 (br dd, J =6.1, 13.6 Hz, 1H), 2.27 (br dd, J =5.8, 11.7 Hz, 1H), 2.19-1.89 (m, 8H), 1.68-1.52 (m, 2H). Example 40D : 4-(4-((1R,5S)-3,8- diazabicyclo [3.2.1] octan - 3- yl )-2-((((1R,7a'R)-2,2 -difluorodihydro -1'H),3'H- spiro [ cyclopropane -1,2'- pyrrolizine ]-7a'(5'H)-yl ) methoxy ) -8- fluoropyrido [4,3-d] pyrimidin -7- yl )-5- ethynyl -6- fluoronaphthalen -2- ol dicarboxylate
LCMS (ESI): [M+H] += 645.4. 1H NMR (400 MHz, CD 3OD) δ ppm 9.07 (s, 1H), 8.44 (br s, 2H), 7.88 (dd, J= 5.8, 9.0 Hz, 1H), 7.39-7.29 (m, 2H), 7.21 (d, J= 2.5 Hz, 1H), 4.83-4.73 (m, 2H), 4.62-4.52 (m, 2H), 4.10 (br s, 2H), 3.90 (br t, J= 11.4 Hz, 2H), 3.72-3.61 (m, 1H), 3.51 (td, J= 5.6, 11.2 Hz, 1H), 3.37 (s, 1H), 3.15 (d, J= 12.3 Hz, 1H), 3.02-2.91 (m, 1H), 2.45 (dd, J= 6.0, 13.6 Hz, 1H), 2.28 (br dd, J= 6.3, 11.3 Hz, 1H), 2.19-1.92 (m, 8H), 1.68-1.55 (m, 2H). 實施例 41: 4-(2-((1'H,3'H,5'H-二硫雜環[氧雜環丁烷-3,2'-吡咯烷-6',3'-氧雜環丁烷-7a'(7'H)-基甲氧基]-4-((1R,5S)-3,8-二氮雜環[3.2.1]辛烷-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇 LCMS (ESI): [M+H] + = 645.4. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.07 (s, 1H), 8.44 (br s, 2H), 7.88 (dd, J = 5.8, 9.0 Hz, 1H), 7.39-7.29 (m, 2H), 7.21 (d, J = 2.5 Hz, 1H), 4.83-4.73 (m, 2H), 4.62-4.72 (m, 2H), 4.10 (br s, 2H), 3.90 (br t, J = 11.4 Hz, 2H), 3.72-3.61 (m, 1H), 3.51 (td, J = 5.6, 11.2 Hz, 1H), 3.37 (s, 1H), 3.15 (d, J = 12.3 Hz, 1H), 3.02-2.91 (m, 1H), 2.45 (dd, J = 6.0, 13.6 Hz, 1H), 2.28 (br dd, J = 6.3, 11.3 Hz, 1H), 2.19-1.92 (m, 8H), 1.68-1.55 (m, 2H). Example 41 : 4-(2-((1'H, 3'H, 5'H-dithiocyclo[oxacyclobutane-3,2'-pyrrolidine-6', 3'-oxacyclobutane-7a'(7'H)-ylmethoxy]-4-((1R, 5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
第一步:N2氛圍下,在0℃將(叔丁氧羰基)甘胺酸乙酯(10 g,49.20 mmol) 和3,3-雙(溴甲基)氧代烷(14.4 g, 59.04 mmol)溶於DMA(100 mL)後緩慢滴加到含有NaH(7.9 g, 196.81 mmol)和DMA(50 mL)的反應液中,滴加完成後,反應液在20℃下攪拌2小時,反應液用NH4Cl水溶液淬滅(100 mL)然後用EtOAc(100 mL x 3)萃取,有機相用無水Na 2SO 4乾燥,過濾並濃縮後經管柱層析純化(矽膠,0-30%梯度的乙酸乙酯/石油醚)得到化合物6-(叔丁基)7-乙基2-氧代-6-氮雜螺環[3.4]辛烷-6,7-二甲酸酯(11.2 g),為無色油狀液體。TLC (hexanes:EtOAc =2:1) 確認了產物。 Step 1: Under N2 atmosphere, ethyl (tert-butyloxycarbonyl)glycine (10 g, 49.20 mmol) and 3,3-bis(bromomethyl)oxoalkane (14.4 g, 59.04 mmol) were dissolved in DMA (100 mL) at 0°C and slowly added dropwise to the reaction solution containing NaH (7.9 g, 196.81 mmol) and DMA (50 mL). After the addition was completed, the reaction solution was stirred at 20°C for 2 hours. The reaction solution was quenched with NH4Cl aqueous solution (100 mL) and then extracted with EtOAc (100 mL x 3). The organic phase was washed with anhydrous Na2SO 4 was dried, filtered and concentrated, and then purified by column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain compound 6-(tert-butyl)7-ethyl 2-oxo-6-azaspiro[3.4]octane-6,7-dicarboxylate (11.2 g) as a colorless oily liquid. TLC (hexanes:EtOAc =2:1) confirmed the product.
第二步:含有7-[(叔丁基)氧羰基]-2-氧-7-氮雜螺環[3.4]辛烷-6-羧酸乙酯(5 g,17.52 mmol)、TFA(10 mL)和DCM(50 mL)的反應液在20℃下攪拌4小時,向反應液中加入三乙胺(4 mL)後經濃縮得到化合物2-氧-6-氮雜螺環[3.4]辛烷-7-羧酸乙酯(6.9 g),為黃色油狀液體。TLC(DCM:MeOH=10:1)確認了產物。Step 2: The reaction solution containing 7-[(tert-butyl)oxycarbonyl]-2-oxo-7-azaspiro[3.4]octane-6-carboxylic acid ethyl ester (5 g, 17.52 mmol), TFA (10 mL) and DCM (50 mL) was stirred at 20°C for 4 hours. Triethylamine (4 mL) was added to the reaction solution and concentrated to obtain the compound 2-oxo-6-azaspiro[3.4]octane-7-carboxylic acid ethyl ester (6.9 g) as a yellow oily liquid. TLC (DCM:MeOH=10:1) confirmed the product.
第三步:含有2-氧-6-氮雜螺環[3.4]辛烷-7-羧酸乙酯(6.9 g,37.25 mmol)、3-(溴甲基)氧代烷-3-碳醛(8 g,44.70 mmol)、三乙胺(11.5 g,111.76 mmol)、和甲醇(50 mL)的反應液在20℃下攪拌1 h,將反應液倒入水中(100 mL)並用EtOAc(100 mL x 3)萃取,有機相用無水Na 2SO 4乾燥,過濾並濃縮後經管柱層析純化(矽膠,0-30%梯度的乙酸乙酯/石油醚)得到化合物6-((3-(溴甲基)氧代烷-3-基)甲基)-2-氧代-6-氮雜螺環[3.4]辛烷-7-羧酸乙酯(2.9 g),為無色油狀液體。LCMS (ESI): [M+H] += 348.1。 Step 3: A reaction solution containing ethyl 2-oxo-6-azaspiro[3.4]octane-7-carboxylate (6.9 g, 37.25 mmol), 3-(bromomethyl)oxoalkane-3-carbaldehyde (8 g, 44.70 mmol), triethylamine (11.5 g, 111.76 mmol), and methanol (50 mL) was stirred at 20 °C for 1 h. The reaction solution was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The organic phase was washed with anhydrous Na 2 SO 4 was dried, filtered and concentrated, and purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to give compound 6-((3-(bromomethyl)oxoalkane-3-yl)methyl)-2-oxo-6-azaspiro[3.4]octane-7-carboxylic acid ethyl ester (2.9 g) as a colorless oily liquid. LCMS (ESI): [M+H] + = 348.1.
第四步:-78℃,N2氛圍下,將KHMDS(11 mL, 111.26 mmol)滴加到含有6-((3-(溴甲基)氧代烷-3-基)甲基)-2-氧代-6-氮雜螺環[3.4]辛烷-7-羧酸乙酯(2.8 g, 8.04 mmol),THF (18 mL)和DMF(90 mL)的溶液中,反應液在-78℃下攪拌30分鐘,向反應液中加入三乙胺(20 mL)後倒入水中(100 mL),然後經EA(100 mL x 3)萃取,有機相用無水Na 2SO 4乾燥,過濾並濃縮後經管柱層析純化(矽膠,0-100%梯度的乙酸乙酯/石油醚)得到化合物1'H,3'H,5'H-二硫氰酸乙酯[氧雜環丁烷-3,2'-吡咯利嗪-6',3'-氧雜環丁烷]-7a'(7'H)-羧酸乙酯(640 mg),為黃色油狀產物。LCMS (ESI): [M+H] += 268.1。 Step 4: KHMDS (11 mL, 111.26 mmol) was added dropwise to a solution containing ethyl 6-((3-(bromomethyl)oxoalkane-3-yl)methyl)-2-oxo-6-azaspiro[3.4]octane-7-carboxylate (2.8 g, 8.04 mmol), THF (18 mL) and DMF (90 mL) at -78°C under N2 atmosphere. The reaction solution was stirred at -78°C for 30 minutes. Triethylamine (20 mL) was added to the reaction solution and then poured into water (100 mL). The mixture was then extracted with EA (100 mL x 3). The organic phase was washed with anhydrous Na2SO4 . 4 , dried, filtered and concentrated, and purified by column chromatography (silica gel, 0-100% gradient of ethyl acetate/petroleum ether) to give compound 1'H,3'H,5'H-dithiocyanatoethyl[cyclohexane-3,2'-pyrrolizine-6',3'-cyclohexane]-7a'(7'H)-carboxylic acid ethyl ester (640 mg) as a yellow oily product. LCMS (ESI): [M+H] + = 268.1.
第五步:0℃下,將LiAlH4(80 mg,2.24 mmol)加入到含有1'H,3'H,5'H-二硫氰酸乙酯[氧雜環丁烷-3,2'-吡咯利嗪-6',3'-氧雜環丁烷]-7a'(7'H)-羧酸乙酯(600 mg, 2.24 mmol)和THF(6 mL)的溶液中,反應液在室溫下攪拌1小時,向反應液中加入過量的水水硫酸鈉,攪拌30 分鐘後過濾,濾液經濃縮後得到化合物(1'H,3'H,5'H-二吡咯[氧雜環丁烷-3,2'-吡咯烷-6',3'-氧雜環丁烷]-7a'(7'H)-基)甲醇(210 mg),為黃色油狀產物。LCMS (ESI): [M+H]+ = 226.2。Step 5: At 0°C, LiAlH4 (80 mg, 2.24 mmol) was added to a solution containing 1'H, 3'H, 5'H-dithiocyanatoethyl [cyclohexane-3,2'-pyrrolidine-6', 3'-cyclohexane]-7a'(7'H)-carboxylic acid ethyl ester (600 mg, 2.24 mmol) and THF (6 mL). The reaction solution was stirred at room temperature for 1 hour. An excess of aqueous sodium sulfate was added to the reaction solution. After stirring for 30 minutes, the solution was filtered. The filtrate was concentrated to obtain the compound (1'H, 3'H, 5'H-dipyrrole [cyclohexane-3,2'-pyrrolidine-6', 3'-cyclohexane]-7a'(7'H)-yl)methanol (210 mg), as a yellow oily product. LCMS (ESI): [M+H]+ = 226.2.
第六步:含有叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基矽基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮雜二環[3.2.1]辛烷-8-羧酸鹽(200 mg,0.24 mmol), (1'H,3'H,5'H-二吡咯[氧雜環丁烷-3,2'-吡咯烷-6',3'-氧雜環丁烷]-7a'(7'H)-基)甲醇(54 mg, 0.24 mmol), 叔丁醇鈉(70 mg, 0.71 mmol)和THF(2 mL)的反應液在60℃下攪拌3小時,將反應液倒入水中(20 mL)並用EA(20 mL x 3)萃取,有機相用無水Na2SO4乾燥,過濾並濃縮後經管柱層析純化(矽膠,0-30%梯度的甲醇/二氯甲烷)得到化合物叔丁基(1R,5S)-3-(2-((1'H,3'H,5'H-二螺環[氧雜環丁烷-3,2'-吡咯利嗪-6',3'-氧雜環丁烷]-7a'(7'H)-基甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基矽基)乙炔基)萘-1-基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮雜環[3.2.1]辛烷-8-羧酸鹽(50 mg),為黃色油狀液體。LCMS (ESI): [M/2+H]+ = 484.5。Step 6: A mixture containing tert-butyl (1R, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.24 mmol), (1'H, 3'H, 5'H-dipyrrolo[oxacyclobutane-3,2'-pyrrolidine-6', 3'-oxacyclobutane]-7a'(7'H)-yl)methanol (54 mg, 0.24 mmol), sodium tert-butoxide (70 mg, 0.71 mmol) and THF (2 The reaction solution (20 mL) was stirred at 60 °C for 3 h, poured into water (20 mL) and washed with EA (20 mL x 3) extraction, the organic phase was dried over anhydrous Na2SO4, filtered and concentrated, and then purified by column chromatography (silica gel, 0-30% gradient methanol/dichloromethane) to obtain the compound tert-butyl (1R, 5S)-3-(2-((1'H, 3'H, 5'H-dispiro[oxacyclobutane-3,2'-pyrrolizine-6', 3'-oxacyclobutane]-7a'(7'H)-ylmethoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (50 mg), as a yellow oily liquid. LCMS (ESI): [M/2+H]+ = 484.5.
第七步:在0℃下,將三氟乙酸(0.5 mL)加入到含有叔丁基(1R,5S)-3-(2-((1'H,3'H,5'H-二螺環[氧雜環丁烷-3,2'-吡咯利嗪-6',3'-氧雜環丁烷]-7a'(7'H)-基甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基矽基)乙炔基)萘-1-基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮雜環[3.2.1]辛烷-8-羧酸鹽(50 mg,0.052 mmol)和二氯甲烷(3 mL)的反應液中,反應液在0℃下攪拌30分鐘,三乙胺(1 mL)加入到反應液中,反應液倒入水中(20 mL),EA萃取(20 mL*3),有機相經無水硫酸鈉乾燥後濃縮得到化合物4-(2-((1'H,3'H,5'H-二硫雜環[氧雜環丁烷-3,2'-吡咯烷-6',3'-氧雜環丁烷-7a'(7'H)-基]甲氧基)-4-((1R,5S)-3,8-二氮雜環[3.2.1]辛烷-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-6-氟-5-((三異丙基矽基)乙炔基)萘-2-醇(30 mg),為黃色油狀產物。LCMS (ESI): [M/2+H]+ = 412.2。Step 7: At 0°C, trifluoroacetic acid (0.5 mL) was added to a reaction solution containing tert-butyl (1R, 5S)-3-(2-((1'H, 3'H, 5'H-dispiro[cyclohexane-3,2'-pyrrolizine-6', 3'-cyclohexane]-7a'(7'H)-ylmethoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (50 mg, 0.052 mmol) and dichloromethane (3 mL). The reaction solution was stirred at 0°C for 30 minutes. Triethylamine (1 The reaction solution was poured into water (20 mL), extracted with EA (20 mL*3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 4-(2-((1'H, 3'H, 5'H-dithiocyclo[oxacyclobutane-3,2'-pyrrolidine-6', 3'-oxacyclobutane-7a'(7'H)-yl]methoxy)-4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (30 mg) as a yellow oily product. LCMS (ESI): [M/2+H]+ = 412.2.
第八步:含有4-(2-((1'H,3'H,5'H-二硫雜環[氧雜環丁烷-3,2'-吡咯烷-6',3'-氧雜環丁烷-7a'(7'H)-基]甲氧基)-4-((1R,5S)-3,8-二氮雜環[3.2.1]辛烷-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-6-氟-5-((三異丙基矽基)乙炔基)萘-2-醇(30 mg,0.036 mmol),氟化銫(28 mg, 0.18 mmol)和DMF(1mL)的反應液在50℃下攪拌2小時,將反應液倒入水中(20 mL)並用EA(20 mL x 3)萃取,有機相用無水Na2SO4乾燥,過濾並濃縮後經管柱層析純化(C18,0-50%梯度的水/乙腈)得到化合物4-(2-((1'H,3'H,5'H-二硫雜環[氧雜環丁烷-3,2'-吡咯烷-6',3'-氧雜環丁烷-7a'(7'H)-基甲氧基]-4-((1R,5S)-3,8-二氮雜環[3.2.1]辛烷-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇(0.85 mg),為白色固體產物。LCMS (ESI): [M/2+H]+ = 667.4。 實施例 42:4-(2-((1'氫,3'氫,5'氫-二螺[環丙烷-1,2'-吡咯里嗪-6',1''-環丙烷基]-7a'(7'氫)-基)甲氧基)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇 Step 8: A reaction solution containing 4-(2-((1'H, 3'H, 5'H-dithiocyclo[oxacyclobutane-3,2'-pyrrolidin-6', 3'-oxacyclobutane-7a'(7'H)-yl]methoxy)-4-((1R, 5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (30 mg, 0.036 mmol), cesium fluoride (28 mg, 0.18 mmol) and DMF (1 mL) was stirred at 50°C for 2 hours. The reaction solution was poured into water (20 mL) and washed with EA (20 mL x 10% ethyl acetate). 3) extraction, the organic phase was dried over anhydrous Na2SO4, filtered and concentrated, and then purified by column chromatography (C18, 0-50% gradient of water/acetonitrile) to obtain compound 4-(2-((1'H, 3'H, 5'H-dithiocyclo[oxacyclobutane-3,2'-pyrrolidine-6', 3'-oxacyclobutane-7a'(7'H)-ylmethoxy]-4-((1R, 5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (0.85 mg) as a white solid product. LCMS (ESI): [M/2+H]+ = 667.4. Example 42 :4-(2-((1'hydrogen, 3'hydrogen, 5'hydrogen-dispiro[cyclopropane-1,2'-pyrrolizine-6', 1''-cyclopropane]-7a'(7'hydrogen)-yl)methoxy)-4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
第一步:在20℃下,將碘甲烷(6.60 g, 45.59 mmol)加到6-[(叔丁基)氧羰基]-6-氮雜螺環[2.4]庚烷-5-甲酸(10.00 g, 41.44 mmol)、碳酸鉀(11.70 g, 82.89 mmol)的N,N-二甲基甲醯胺(100 mL)溶液中,反應液在20℃下攪拌12小時。將反應液倒入水(300 mL)中,用乙酸乙酯(50 mL x 3)萃取,將有機相用無水硫酸鈉乾燥、過濾、濃縮得到淡黃色油狀液體6-[(叔丁基)氧羰基]-6-氮雜螺環[2.4]庚烷-5-甲酸甲酯 (7.2 g,產率68.1%)。LCMS (ESI): [M+H] +=156.1. Step 1 : At 20°C, add iodomethane (6.60 g, 45.59 mmol) to a solution of 6-[(tert-butyl)oxycarbonyl]-6-azaspiro[2.4]heptane-5-carboxylic acid (10.00 g, 41.44 mmol) and potassium carbonate (11.70 g, 82.89 mmol) in N,N-dimethylformamide (100 mL). Stir the reaction solution at 20°C for 12 hours. The reaction solution was poured into water (300 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a light yellow oily liquid 6-[(tert-butyl)oxycarbonyl]-6-azaspiro[2.4]heptane-5-carboxylic acid methyl ester (7.2 g, yield 68.1%). LCMS (ESI): [M+H] + =156.1.
第二步:在20℃下,將三氟乙酸(15.0 mL, 195.84 mmol)加到6-[(叔丁基)氧羰基]-6-氮雜螺環[2.4]庚烷-5-甲酸甲酯 (5.00 g, 19.58 mmol)的二氯甲烷(20 mL)溶液中。反應液在20℃下攪拌2小時。將反應液濃縮乾得粘稠狀黃色液體6-氮雜螺環[2.4]庚烷-5-甲酸甲酯 (3.0 g, 產率99%)。LCMS (ESI): [M+H] +=156.2. Step 2 : Add trifluoroacetic acid (15.0 mL, 195.84 mmol) to a solution of methyl 6-[(tert-butyl)oxycarbonyl]-6-azaspiro[2.4]heptane-5-carboxylate (5.00 g, 19.58 mmol) in dichloromethane (20 mL) at 20°C. Stir the reaction mixture at 20°C for 2 hours. Concentrate the reaction mixture to obtain viscous yellow liquid methyl 6-azaspiro[2.4]heptane-5-carboxylate (3.0 g, yield 99%). LCMS (ESI): [M+H] + =156.2.
第三步:在20℃下,將碳酸鉀(3.40 g,24.16 mmol)加到6-氮雜螺環[2.4]庚烷-5-甲酸甲酯 (1.50 g, 9.66 mmol)、((1-(溴甲基)環丙基)甲氧基)(叔丁基)二苯基矽烷 (3.90 g, 9.66 mmol)的乙腈(20 mL)溶液中。將反應在60℃下攪拌16小時。將反應液過濾,加入矽膠10g,濃縮後經管柱層析(矽膠,0-10%的梯度乙酸乙酯/石油醚)得無色油狀液體5-((1-(((叔丁基二苯基矽基)氧基)甲基)環丙基)甲基)-5-氮雜螺環[2.4]庚烷-6-甲酸甲酯(3.8 g,產率82.5%)。LCMS (ESI): [M+H]+ =478.4. Step 3 : Potassium carbonate (3.40 g, 24.16 mmol) was added to a solution of methyl 6-azaspiro[2.4]heptane-5-carboxylate (1.50 g, 9.66 mmol), ((1-(bromomethyl)cyclopropyl)methoxy)(tert-butyl)diphenylsilane (3.90 g, 9.66 mmol) in acetonitrile (20 mL) at 20 °C. The reaction was stirred at 60 °C for 16 hours. The reaction solution was filtered, 10 g of silica gel was added, and the mixture was concentrated and chromatographed on a column (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to obtain 5-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)-5-azaspiro[2.4]heptane-6-carboxylic acid methyl ester (3.8 g, yield 82.5%) as a colorless oily liquid. LCMS (ESI): [M+H]+ =478.4.
第四步:在20℃下,將5-((1-(((叔丁基二苯基矽基)氧基)甲基)環丙基)甲基)-5-氮雜螺環[2.4]庚烷-6-甲酸甲酯(1.5 g, 3.14 mmol)和鹽酸二氧六環 (15.0 mL, 60.01 mmol)的混合溶液攪拌1小時。將反應液濃縮乾得殘餘物,殘餘物經管柱層析純化(矽膠,0-50%梯度的乙酸乙酯/石油醚, 0-10%梯度的甲醇/二氯甲烷)得1 g 粗產物。該粗產物再次經管柱層析純化(矽膠,0-3%梯度的甲醇/二氯甲烷) 得白色粘稠狀固體6-{[(羥甲基)環丙基]甲基}-6-氮雜螺環[2.4]庚烷-5-甲酸甲酯(480 mg,產率63.9%)。LCMS (ESI): [M+H]+ =240.2. Step 4 : Stir a mixed solution of methyl 5-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)-5-azaspiro[2.4]heptane-6-carboxylate (1.5 g, 3.14 mmol) and dioxane hydrochloride (15.0 mL, 60.01 mmol) for 1 hour at 20°C. Concentrate the reaction solution to obtain a residue, which is purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate/petroleum ether, 0-10% gradient of methanol/dichloromethane) to obtain 1 g of crude product. The crude product was purified again by column chromatography (silica gel, 0-3% gradient of methanol/dichloromethane) to obtain methyl 6-{[(hydroxymethyl)cyclopropyl]methyl}-6-azaspiro[2.4]heptane-5-carboxylate (480 mg, yield 63.9%) as a white viscous solid. LCMS (ESI): [M+H]+ =240.2.
第五步:在20℃氮氣保護下,將三苯基膦(385 mg,1.47 mmol)、四溴化碳(491 mg,1.47 mmol)加到6-{[(羥甲基)環丙基]甲基}-6-氮雜螺環[2.4]庚烷-5-甲酸甲酯(270 mg, 1.13 mmol)的二氯甲烷(5 ml)溶液中,反應液在20℃下攪拌2小時。將反應液濃縮得殘餘物,殘餘物經管柱層析 (矽膠, 0-20%的乙酸乙酯/石油醚, 0-5%梯度的甲醇/二氯甲烷) 得到無色液體6-{[(溴甲基)環丙基]甲基}-6-氮雜螺環[2.4]庚烷-5-甲酸甲酯(140 mg,產率41.2%)。LCMS (ESI): [M+H]+ =302.2. Step 5 : Under nitrogen protection at 20°C, triphenylphosphine (385 mg, 1.47 mmol) and carbon tetrabromide (491 mg, 1.47 mmol) were added to a solution of methyl 6-{[(hydroxymethyl)cyclopropyl]methyl}-6-azaspiro[2.4]heptane-5-carboxylate (270 mg, 1.13 mmol) in dichloromethane (5 ml). The reaction solution was stirred at 20°C for 2 hours. The reaction solution was concentrated to obtain a residue, which was purified by column chromatography (silica gel, 0-20% ethyl acetate/petroleum ether, 0-5% gradient methanol/dichloromethane) to obtain colorless liquid 6-{[(bromomethyl)cyclopropyl]methyl}-6-azaspiro[2.4]heptane-5-carboxylic acid methyl ester (140 mg, yield 41.2%). LCMS (ESI): [M+H]+ =302.2.
第六步:在20℃下,將6-{[(溴甲基)環丙基]甲基}-6-氮雜螺環[2.4]庚烷-5-甲酸甲酯(300 mg,0.99 mmol)溶於N,N-二甲基甲醯胺(15 mL)和四氫呋喃(5 mL)中,用氮氣置換3次,並冷卻至-70℃,向反應液中滴加雙(三甲基矽烷基)胺基鉀 (1.4 mL, 1.39 mmol,1M),反應液在該溫度下攪拌50分鐘。向反應液中加入飽和氯化銨溶液(10 mL)中 用乙酸乙酯(20 mL x 3)萃取,有機相經無水硫酸鈉乾燥,水相用二氯甲烷/甲醇(20 mL x 3,20:1)萃取,有機相經無水硫酸鈉乾燥,有機相經過合併、過濾、濃縮得殘餘物。殘餘物經管柱層析(矽膠, 0-10%梯度的甲醇/二氯甲烷)得灰色油狀物1'氫,3'氫,5'氫-二螺[環丙烷-1,2'-吡咯里嗪-6',1''-環丙烷基]-7a'(7'氫)-甲酸甲酯 (30 mg,產率13.7%)。LCMS (ESI): [M+H]+ =194.2. Step 6 : At 20°C, methyl 6-{[(bromomethyl)cyclopropyl]methyl}-6-azaspiro[2.4]heptane-5-carboxylate (300 mg, 0.99 mmol) was dissolved in N,N-dimethylformamide (15 mL) and tetrahydrofuran (5 mL), replaced with nitrogen three times, and cooled to -70°C. Potassium bis(trimethylsilyl)amide (1.4 mL, 1.39 mmol, 1 M) was added dropwise to the reaction solution, and the reaction solution was stirred at this temperature for 50 minutes. Saturated ammonium chloride solution (10 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, and the aqueous phase was extracted with dichloromethane/methanol (20 mL x 3, 20:1). The organic phase was dried over anhydrous sodium sulfate, and the organic phase was combined, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a gray oily substance 1'H, 3'H, 5'H-dispiro[cyclopropane-1,2'-pyrrolizine-6',1''-cyclopropane]-7a'(7'H)-carboxylic acid methyl ester (30 mg, yield 13.7%). LCMS (ESI): [M+H]+ =194.2.
第七步:在0℃下,將氫化鋁鋰(15 mg,0.39 mmol)加到1'氫,3'氫,5'氫-二螺[環丙烷-1,2'-吡咯里嗪-6',1''-環丙烷基]-7a'(7'氫)-甲酸甲酯(30 mg,0.15 mmol)的四氫呋喃(2 mL)溶液中,反應液在0℃下攪拌1小時。在1 小時。向反應液中補加氫化鋁鋰 (15 mg,3 eq),在20℃攪拌1 小時。向反應液中加入水(30 ul)、15%的氫氧化鈉溶液(90 uL),在20℃下攪拌10分鐘。將反應混合物過濾、濃縮乾得白色固體 (1'氫,3'氫,5'氫-二螺[環丙烷-1,2'-吡咯里嗪-6',1''-環丙烷基]-7a'(7'氫)-基)甲醇(25 mg,產率99%)。LCMS (ESI): [M+H]+ =. Step 7 : At 0°C, lithium aluminum hydroxide (15 mg, 0.39 mmol) was added to a solution of 1'hydro, 3'hydro, 5'hydro-dispiro[cyclopropane-1,2'-pyrrolizine-6', 1''-cyclopropane]-7a'(7'hydro)-carboxylic acid methyl ester (30 mg, 0.15 mmol) in tetrahydrofuran (2 mL), and the reaction solution was stirred at 0°C for 1 hour. At 1 hour. Lithium aluminum hydroxide (15 mg, 3 eq) was added to the reaction solution and stirred at 20°C for 1 hour. Water (30 ul) and 15% sodium hydroxide solution (90 uL) were added to the reaction solution and stirred at 20°C for 10 minutes. The reaction mixture was filtered and concentrated to obtain a white solid (1'H, 3'H, 5'H-dispiro[cyclopropane-1,2'-pyrrolizine-6', 1''-cyclopropane]-7a'(7'H)-yl)methanol (25 mg, yield 99%). LCMS (ESI): [M+H]+ =.
第八步:在0℃下,將叔丁醇鈉(17 mg, 0.18 mmol)加到(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基矽基)乙炔基)萘-1-基-2-(2,2,2-三氟乙基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸叔丁酯(78 mg,0.093 mmol)和(1'氫,3'氫,5'氫-二螺[環丙烷-1,2'-吡咯里嗪-6',1''-環丙烷基]-7a'(7'氫)-基)甲醇(24.00 mg, 0.12 mmol)的四氫呋喃(3 mL)的溶液中。反應液在20℃下攪拌4小時。向反應液中補加3次叔丁醇鈉(2 mg x 3),在60℃下攪拌2小時。向反應液中加入水(2 mL)、 用乙酸乙酯(2 mL X 3)萃取。有機相經過無水硫酸鈉乾燥、過濾和濃縮得殘餘物,殘餘物經管柱層析純化(矽膠,0-50%梯度的乙酸乙酯/石油醚,0-5%梯度的甲醇/二氯甲烷)的無色油狀物(1R,5S)-3-(2-((1'氫,3'氫,5'氫-二螺[環丙烷-1,2'-吡咯里嗪-6',1''-環丙烷基]-7a'(7'氫)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧甲氧基)-8-((三異丙基矽基)乙炔基)萘-1-基)吡啶基[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸叔丁酯(37 mg,產率33%)。LCMS (ESI): [M+H]+ =468.5. Step 8: Sodium tert-butoxide (17 mg, 0.18 mmol) was added to tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl-2-(2,2,2-trifluoroethyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (78 mg, 0.093 mmol) and (1'hydro,3'hydro,5'hydro-dispiro[cyclopropane-1,2'-pyrrolizine-6',1''-cyclopropaneyl]-7a'(7'hydro)-yl)methanol (24.00 mg, 0.12 mmol) in tetrahydrofuran (3 mL). The reaction solution was stirred at 20°C for 4 hours. Sodium tert-butoxide (2 mg x 3) was added three times to the reaction solution and stirred at 60°C for 2 hours. Water (2 mL) was added to the reaction solution and extracted with ethyl acetate (2 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate/petroleum ether, 0-5% gradient of methanol/dichloromethane) to obtain a colorless oily substance (1R,5S)-3-(2-((1'hydro,3'hydro,5'hydro-dispiro[cyclopropane-1,2'-pyrrole) tert-Butyl pyridazine-6',1''-cyclopropane-7a'(7'-hydrogen)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyridinyl[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37 mg, yield 33%). LCMS (ESI): [M+H]+ =468.5.
第九步:在20℃下,將氟化銫(61 mg, 0.40 mmol)加到(1R,5S)-3-(2-((1'氫,3'氫,5'氫-二螺[環丙烷-1,2'-吡咯里嗪-6',1''-環丙烷基]-7a'(7'氫)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧甲氧基)-8-((三異丙基矽基)乙炔基)萘-1-基)吡啶基[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸叔丁酯(37 mg,0.039 mmol)的N,N-二甲基甲醯胺(3 mL)中。反應液在20℃下攪拌1.5小時。反應液用乙酸乙酯(2 mL)稀釋,用水(1 mL x 2)洗。有機相經過無水硫酸鈉乾燥、過濾和濃縮得殘餘物,殘餘物經管柱層析純化(矽膠,0-50%梯度的乙酸乙酯/石油醚,0-5%梯度的甲醇/二氯甲烷)得無色粘稠狀液體(1R,5S)-3-(2-((1'氫,3'氫,5'氫-二螺[環丙烷-1,2'-吡咯里嗪-6',1''-環丙烷基]-7a'(7'氫)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧甲氧基)萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸叔丁酯(29 mg,產率62.7%,2批次合併)。LCMS (ESI): [M+H]+ =390.4. Step 9 : CsF (61 mg, 0.40 mmol) was added to tert-butyl (1R,5S)-3-(2-((1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrrolizine-6',1''-cyclopropaneyl]-7a'(7'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyridinyl[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37 mg, 0.039 mmol) in N,N-dimethylformamide (3 mL) at 20°C. The reaction solution was stirred at 20°C for 1.5 hours. The reaction solution was diluted with ethyl acetate (2 mL) and washed with water (1 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was purified by column chromatography (silica gel, 0-50% gradient of ethyl acetate/petroleum ether, 0-5% gradient of methanol/dichloromethane) to obtain a colorless viscous liquid (1R,5S)-3-(2-((1'H,3'H,5'H-dispiro[cyclopropane-1,2 '-Pyrrolizine-6',1''-cyclopropane]-7a'(7'-hydrogen)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (29 mg, yield 62.7%, 2 batches combined). LCMS (ESI): [M+H]+ =390.4.
第十步:20℃下,向(1R,5S)-3-(2-((1'氫,3'氫,5'氫-二螺[環丙烷-1,2'-吡咯里嗪-6',1''-環丙烷基]-7a'(7'氫)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧甲氧基)萘-1-基)-8-氟吡啶[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸叔丁酯(7 mg, 0.009 mmol)的乙腈(1 mL)中加入三氟乙酸(480 ul, 6.29 mmol),反應液在 20℃的氮氣下攪拌4小時。將反應液濃縮,用乙腈(1 mL)稀釋,用三乙胺將pH調至7,經反相管柱層析純化(C18,5-95%乙腈/水的梯度)得4-(2-((1'氫,3'氫,5'氫-二螺[環丙烷-1,2'-吡咯里嗪-6',1''-環丙烷基]-7a'(7'氫)-基)甲氧基)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇 (1.80 mg, 產率32%)。LCMS(ESI):[M+H]+=635.4. 實施例 43 :4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-3-甲腈 Step 10 : To a solution of tert-butyl (1R,5S)-3-(2-((1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrrolizine-6',1''-cyclopropaneyl]-7a'(7'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7 mg, 0.009 mmol) in acetonitrile (1 mL) was added trifluoroacetic acid (480 ul, 6.29 mmol) at 20°C, and the reaction mixture was stirred under nitrogen at 20°C for 4 hours. The reaction solution was concentrated and diluted with acetonitrile (1 mL), the pH was adjusted to 7 with triethylamine, and purified by reverse phase column chromatography (C18, 5-95% acetonitrile/water gradient) to give 4-(2-((1'H,3'H,5'H-dispiro[cyclopropane-1,2'-pyrrolizine-6',1''-cyclopropaneyl]-7a'(7'H)-yl)methoxy)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (1.80 mg, yield 32%). LCMS (ESI): [M+H]+=635.4. Example 43 : 4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridine-3-carbonitrile
第一步:在氮氣環境下,向2-氯-3-氟異煙酸(100 g,569 mmol)和三乙胺(158 mL,1133 mmol)的甲苯(500 mL)和叔丁醇(500 mL)溶液中加入二碳酸二叔丁酯(13 mL,56.5 mmol)和疊氮磷酸二苯酯(147 mL,682 mmol),將溶液在80 oC下攪拌16小時。混合物濃縮並加入500 mL飽和食鹽水,並用500 mL乙酸乙酯萃取。真空濃縮有機層,得到的殘餘物透過快速管柱層析(矽膠,0-5%梯度的乙酸乙酯/石油醚)純化得到淡黃色油狀化合物 (2-氯-3-氟吡啶-4-基)胺基甲酸叔丁酯(112 g,454 mmol,產率80%)。LCMS (ESI): [M+H] += 247.1. Step 1 : Under nitrogen, add di-tert-butyl dicarbonate (13 mL, 56.5 mmol) and diphenyl phosphate azide (147 mL, 682 mmol) to a solution of 2-chloro-3-fluoroisonicotinic acid (100 g, 569 mmol) and triethylamine (158 mL, 1133 mmol) in toluene (500 mL) and tert-butyl alcohol (500 mL), and stir the solution at 80 ° C for 16 hours. The mixture is concentrated and 500 mL of saturated brine is added, and extracted with 500 mL of ethyl acetate. The organic layer was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to obtain a light yellow oily compound (2-chloro-3-fluoropyridin-4-yl)carbamic acid tert-butyl ester (112 g, 454 mmol, yield 80%). LCMS (ESI): [M+H] + = 247.1.
第二步:將 (2-氯-3-氟吡啶-4-基)胺基甲酸叔丁酯(50 g,202 mmol)和四甲基乙二胺(70.6 g,608 mmol)的無水甲基叔丁基醚(500 mL)溶液冷卻至-70 oC。並將正丁基鋰(2.5 M的正己烷溶液,203 mL,506 mmol)緩慢加入到混合物中。在-70 oC的氮氣環境下攪拌1小時,然後將混合物升溫至-30 oC,氮氣環境下攪拌1小時,然後將混合物冷卻至-70 oC,將含有乾燥的二氧化碳的氣袋連接到攪拌的溶液中,半小時過後將混合物緩慢升溫至20 oC並攪拌10小時。向混合物中加入水(500 mL)淬滅並靜置分液,棄去有機相,將水相冷卻至0 oC,用稀鹽酸(4 M)調節pH = 6-7,有白色固體析出,過濾,收集濾餅並真空乾燥,得到白色固體化合物4-((叔丁氧基羰基胺基)-6-氯-5-氟煙酸(39.8 g,136 mmol,產率68%)。LCMS (ESI): [M+H] += 291.0. Step 2 : A solution of tert-butyl (2-chloro-3-fluoropyridin-4-yl)carbamate (50 g, 202 mmol) and tetramethylethylenediamine (70.6 g, 608 mmol) in anhydrous methyl tert-butyl ether (500 mL) was cooled to -70 ° C. And n-butyl lithium (2.5 M in n-hexane, 203 mL, 506 mmol) was slowly added to the mixture. Stirred under nitrogen at -70 ° C for 1 hour, then the mixture was warmed to -30 ° C, stirred under nitrogen for 1 hour, then cooled to -70 ° C, and a bag containing dry carbon dioxide was connected to the stirred solution. After half an hour, the mixture was slowly warmed to 20 ° C and stirred for 10 hours. Water (500 mL) was added to the mixture to quench the mixture and the mixture was allowed to stand for separation. The organic phase was discarded and the aqueous phase was cooled to 0 ° C. The pH was adjusted to 6-7 with dilute hydrochloric acid (4 M). A white solid was precipitated. The mixture was filtered, the filter cake was collected and vacuum dried to obtain a white solid compound 4-((tert-butoxycarbonylamino)-6-chloro-5-fluoronicotinic acid (39.8 g, 136 mmol, yield 68%). LCMS (ESI): [M+H] + = 291.0.
第三步:向4-((叔丁氧基羰基)胺基)-6-氯-5-氟煙酸(10 g,34.4 mmol)的二氧六環(100 mL)溶液中加入三光氣(7.45 g,25.1 mmol),混合物在100 oC下攪拌4個小時。反應液真空濃縮,殘餘物用石油醚製漿得到7-氯-8-氟-2H-吡啶并[4,3-d][1,3]噁嗪-2,4(1H)-二酮(7.40 g,34.4 mmol,產率99%),為白色固體。 1H NMR (400 MHz, DMSO- d 6) δ ppm 12.84 (br s, 1H), 8.73 (s, 1H). Step 3 : Triphosgene (7.45 g, 25.1 mmol) was added to a solution of 4-((tert-butoxycarbonyl)amino)-6-chloro-5-fluoronicotinic acid (10 g, 34.4 mmol) in dioxane (100 mL), and the mixture was stirred at 100 ° C for 4 hours. The reaction solution was concentrated in vacuo, and the residue was slurried with petroleum ether to obtain 7-chloro-8-fluoro-2H-pyrido[4,3-d][1,3]oxazine-2,4(1H)-dione (7.40 g, 34.4 mmol, yield 99%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 12.84 (br s, 1H), 8.73 (s, 1H).
第四步:向7-氯-8-氟-2H-吡啶并[4,3-d][1,3]噁嗪-2,4(1H)-二酮(5.40 g,24.9 mmol)的二甲苯(54 mL)溶液中加入2-氰基乙酸乙酯(4.23 g,37.4 mmol)和三乙胺(6.91 mL,49.8 mmol)。反應在145 oC下攪拌5小時。真空濃縮混合物,將殘餘物用石油醚/乙酸乙酯(體積比為1:1)製漿,得到棕色固體化合物7-氯-8-氟-2,4-二氧代-1,2,3,4-四氫-1,6-萘啶-3-甲腈(4.30 g,17.95 mmol,產率72%)。LCMS (ESI): [M+H] += 239.9. Step 4 : Ethyl 2-cyanoacetate (4.23 g, 37.4 mmol) and triethylamine (6.91 mL, 49.8 mmol) were added to a solution of 7-chloro-8-fluoro-2H-pyrido[4,3-d][1,3]oxazine-2,4(1H)-dione (5.40 g, 24.9 mmol) in xylene (54 mL). The reaction was stirred at 145 ° C for 5 hours. The mixture was concentrated in vacuo and the residue was slurried with petroleum ether/ethyl acetate (1:1 by volume) to give a brown solid compound 7-chloro-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbonitrile (4.30 g, 17.95 mmol, 72% yield). LCMS (ESI): [M+H] + = 239.9.
第五步:小心地將7-氯-8-氟-2,4-二氧代-1,2,3,4-四氫-1,6-萘啶-3-甲腈(5.80 g,24.2 mmol)加入到三氯氧磷(50 mL,536 mmol)中。反應物在90 oC下攪拌16小時。混合物真空濃縮,殘留物溶於乙酸乙酯(100 ml),用飽和碳酸氫鈉(100 ml)洗滌,水相用乙酸乙酯(50 ml * 3)萃取。合併的有機層用無水硫酸鎂乾燥並過濾。濾液真空濃縮,得到的殘餘物透過快速管柱層析(矽膠,0-15%梯度的乙酸乙酯/石油醚)純化得到黃色固體化合物2,4,7-三氯-8-氟-1,6-萘啶-3-甲腈(3.10 g,11.2 mmol,產率46%)。LCMS (ESI): [M+H] +=275.9, 277.9. Step 5 : Carefully add 7-chloro-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbonitrile (5.80 g, 24.2 mmol) to phosphorus oxychloride (50 mL, 536 mmol). The reactants were stirred at 90 ° C for 16 hours. The mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate (100 ml), washed with saturated sodium bicarbonate (100 ml), and the aqueous phase was extracted with ethyl acetate (50 ml * 3). The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-15% gradient ethyl acetate/petroleum ether) to obtain a yellow solid compound 2,4,7-trichloro-8-fluoro-1,6-naphthyridine-3-carbonitrile (3.10 g, 11.2 mmol, yield 46%). LCMS (ESI): [M+H] + =275.9, 277.9.
第六步:在-70 oC下向2,4,7-三氯-8-氟-1,6-萘啶-3-甲腈(2.00 g,7.23 mmol)的二氯甲烷(30 mL)溶液中加入 (1R,5S)-叔丁基3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(1.38 g,6.51 mmol)的二氯甲烷(10 mL)溶液。然後緩慢加入三乙胺(2.52 mL,18.1 mmol)的二氯甲烷(10 mL)溶液。反應在-70 oC下攪拌0.5小時。混合物加入水(20 ml),然後用二氯甲烷(20 mL*3)萃取,合併的有機相用鹽水(20 mL)洗滌。有機層用無水硫酸鎂乾燥並過濾。濾液真空濃縮。殘餘物透過快速管柱層析(矽膠,0-12%梯度的四氫呋喃/二氯甲烷)純化得到黃色固體化合物叔丁基(1R,5S)-3-(2,7-二氯-3-氰基-8-氟-1,6-萘啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(2.20 g,4.86 mmol,產率67%)。LCMS (ESI): [M+H] += 452.1. Step 6 : Add a solution of (1R,5S)-tert-butyl 3,8-diazobicyclo[3.2.1]octane - 8-carboxylate (1.38 g, 6.51 mmol) in dichloromethane (10 mL) to a solution of 2,4,7-trichloro-8-fluoro-1,6-naphthyridine-3-carbonitrile (2.00 g, 7.23 mmol) in dichloromethane (30 mL) at -70 ° C. Then slowly add a solution of triethylamine (2.52 mL, 18.1 mmol) in dichloromethane (10 mL). The reaction was stirred at -70 ° C for 0.5 hours. Water (20 ml) was added to the mixture, and then extracted with dichloromethane (20 mL*3), and the combined organic phases were washed with brine (20 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-12% gradient tetrahydrofuran/dichloromethane) to give a yellow solid compound tert-butyl (1R,5S)-3-(2,7-dichloro-3-cyano-8-fluoro-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.20 g, 4.86 mmol, yield 67%). LCMS (ESI): [M+H] + = 452.1.
第七步:向叔丁基(1R,5S)-3-(2,7-二氯-3-氰基-8-氟-1,6-萘啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(1.00 g,2.21 mmol)的四氫呋喃(20 mL)溶液中加入4A分子篩(1.00 g),((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(0.35 g,2.21 mmol)和叔丁醇鈉(0.32 g,3.32 mmol)。反應在20 oC下攪拌2小時。混合物加入水(30 mL),然後用乙酸乙酯(30 mL*2)和二氯甲烷(30 mL * 2)萃取。合併的有機層用無水硫酸鎂乾燥並過濾。真空濃縮濾液,殘餘物透過快速管柱層析(矽膠,0-8%梯度的甲醇/二氯甲烷)純化得到黃色固體化合物叔丁基(1R,5S)-3-(7-氯-3-氰基-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(1.10 g,1.91 mmol,產率86 %)。LCMS (ESI): [M+H] += 575.3. Step 7 : To a solution of tert-butyl (1R,5S)-3-(2,7-dichloro-3-cyano-8-fluoro-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 2.21 mmol) in tetrahydrofuran (20 mL) was added 4A molecular sieve (1.00 g), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (0.35 g, 2.21 mmol) and sodium tert-butoxide (0.32 g, 3.32 mmol). The reaction was stirred at 20 o C for 2 hours. Water (30 mL) was added to the mixture, and then extracted with ethyl acetate (30 mL*2) and dichloromethane (30 mL * 2). The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 0-8% gradient methanol/dichloromethane) to give a yellow solid compound tert-butyl (1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.10 g, 1.91 mmol, yield 86 %). LCMS (ESI): [M+H] + = 575.3.
第八步:在氮氣環境中,向叔丁基(1R,5S)-3-(7-氯-3-氰基-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(500 mg,0.87 mmol),((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(535 mg,1.04 mmol)和碳酸銫(850 mg,2.61 mmol)的二氧六環(5 mL)和水(1 mL)溶液中加入氯[(正丁基二(1-金剛烷基)膦)-2-(2-胺基聯苯)]鈀(II)(58 mg,0.09 mmol),並將混合物在100 oC下攪拌3小時。混合物加入水(5 mL),然後用乙酸乙酯(5 mL * 2)萃取,合併的有機相用鹽水(6 mL * 1)洗滌,無水硫酸鎂乾燥並過濾。濾液真空濃縮。殘餘物透過快速管柱層析(矽膠,0-7%梯度的甲醇/二氯甲烷)純化得到棕色固體化合物叔丁基(1R,5S)-3-(3-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(800 mg,0.86 mmol,產率99%)。LCMS (ESI): [M+H] += 925.5 Step 8 : In a nitrogen atmosphere, tert-butyl (1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.87 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (535 mg, 1.04 mmol) and cesium carbonate (850 mg, 2.61 mmol) in dioxane (5 mL) and water (1 mL) were added. To the 1% 4-nitropropene (2-nitropropene) solution was added chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (58 mg, 0.09 mmol), and the mixture was stirred at 100 ° C for 3 hours. Water (5 mL) was added to the mixture, and then extracted with ethyl acetate (5 mL * 2), and the combined organic phases were washed with brine (6 mL * 1), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-7% gradient methanol/dichloromethane) to give a brown solid compound tert-butyl (1R, 5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 0.86 mmol, yield 99%). LCMS (ESI): [M+H] + = 925.5
第九步:向叔丁基(1R,5S)-3-(3-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(750 mg,0.81 mmol)的二甲基甲醯胺(7.5 mL)溶液中加入氟化銫(2.40 g,15.8 mmol)。反應在20 oC下攪拌2小時。將混合物真空濃縮。殘餘物透過快速管柱層析法(矽膠,0-3%梯度的甲醇/二氯甲烷)純化得到叔丁基(1R,5S)-3-(3-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(450 mg,0.59 mmol,產率73%),為棕色固體。LCMS (ESI): [M+H] += 768.9. Step 9 : To a solution of tert-butyl (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (750 mg, 0.81 mmol) in dimethylformamide (7.5 mL) was added cesium fluoride (2.40 g, 15.8 mmol). The reaction was stirred at 20 ° C for 2 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-3% gradient of methanol/dichloromethane) to give tert-butyl (1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.59 mmol, 73% yield) as a brown solid. LCMS (ESI): [M+H] + = 768.9.
第十步:向溶有三氟乙酸(1.80 mL)的二氯甲烷(7.20 mL)中添加叔丁基(1R,5S)-3-(3-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(450 mg,0.59 mmol)。反應在20 oC下攪拌2小時。將混合物真空濃縮得到殘餘物。將殘餘物用二氯甲烷(3 mL)稀釋並加入三乙胺以將pH值調節至7-8。然後真空濃縮,殘餘物透過製備型HPLC純化得到黃色固體化合物4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-1,6-萘啶-3-甲腈(13.5 mg,21 umol,產率3.5%)。LCMS (ESI): [M+H] += 625.2. 1H NMR (400 MHz, CD 3OD) δ ppm 9.23 (s, 1H), 7.88 (dd, J= 5.8, 9.0Hz, 1H), 7.39-7.32 (m, 2H), 7.24 (s, 1H), 5.47-5.26 (m, 1H), 4.47-4.32 (m, 2H), 4.05-3.92 (m, 2H), 3.90-3.78 (m, 2H), 3.70 (br s, 2H), 3.51-3.35 (m, 2H), 3.30-3.14 (m, 2H), 3.12-3.01 (m, 1H), 2.45-1.98 (m, 10H). 實施例 44 :2-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-3-氟苯酚 Step 10 : To trifluoroacetic acid (1.80 mL) in dichloromethane (7.20 mL) was added tert-butyl (1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.59 mmol). The reaction was stirred at 20 ° C for 2 hours. The mixture was concentrated in vacuo to a residue. The residue was diluted with dichloromethane (3 mL) and triethylamine was added to adjust the pH to 7-8. The mixture was then concentrated in vacuo, and the residue was purified by preparative HPLC to give a yellow solid compound 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridine-3-carbonitrile (13.5 mg, 21 umol, yield 3.5%). LCMS (ESI): [M+H] + = 625.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.23 (s, 1H), 7.88 (dd, J = 5.8, 9.0 Hz, 1H), 7.39-7.32 (m, 2H), 7.24 (s, 1H), 5.47-5.26 (m, 1H), 4.47-4.32 (m, 2H), 4.05-3.92 (m, 2H), 3.90-3.78 (m, 2H), 3.70 (br s, 2H), 3.51-3.36 (m, 2H), 3.23-3.14 (m, 2H), 3.19-3.28 (m, 1H), 2.45-1.98 (m, 10H). Example 44 : 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-fluorophenol
第一步:向化合物叔丁基(1R,5S)-3-(7-溴-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(150 mg,0.19 mmol)和 (2-氟-6-羥基苯基)硼酸(59 mg,0.38 mmol)的二氧六環(3 mL)和水(600 uL)溶液中加入碳酸鈉(76 mg,0.72 mmol),氮氣氛圍下加入(2-二環己基膦基-2,6-二異丙氧基-1,1-聯苯基)[2-(2-胺基-1,1-聯苯基)]鈀(II)(17 mg,0.02 mmol)和 (2-二環己基膦-2,4,6-三異丙基-1,1-聯苯)[2-(2-胺基-1,1-聯苯]甲磺酸鈀(20 mg,0.02 mmol),60 oC攪拌2小時。反應液減壓濃縮,殘留物用快速管柱層析純化(矽膠,0-80%梯度的四氫呋喃/石油醚)得化合物叔丁基(1R,5S)-3-(6-氯-8-氟-7-(2-氟-6-羥基苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯烷-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(67% 純度,40 mg,0.04 mmol,產率21%)。LCMS (ESI): [M+H] += 660.0. Step 1 : To a solution of tert-butyl (1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.19 mmol) and (2-fluoro-6-hydroxyphenyl)boronic acid (59 mg, 0.38 mmol) in dioxane (3 mL) and water (600 uL) was added sodium carbonate (76 mg, 0.72 mmol), and (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (17 mg, 0.02 mmol) and (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl]methanesulfonate (20 mg, 0.02 mmol), 60 ° C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-80% gradient of tetrahydrofuran/petroleum ether) to obtain the compound tert-butyl (1R, 5S)-3-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (67% purity, 40 mg, 0.04 mmol, yield 21%). LCMS (ESI): [M+H] + = 660.0.
第二步:化合物叔丁基(1R,5S)-3-(6-氯-8-氟-7-(2-氟-6-羥基苯基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯烷-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(30.0 mg,0.03 mmol)溶於二氯甲烷/三氟乙酸(體積比為4:1,600 uL)中,反應液在20 oC攪拌2小時。反應液減壓濃縮,加入乙腈(0.5 mL),然後用三乙胺調節pH到8,濃縮後的殘留物用製備型HPLC純化,得到白色固體化合物2-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-3-氟苯酚(12.0 mg,21.5 umol,產率71%)。LCMS (ESI): [M+H] += 560.1; 1H NMR (400 MHz, DMSO- d 6) δ ppm 10.49-9.92 (m, 1H), 8.10-7.70 (m, 1H), 7.52-7.23 (m, 1H), 6.99-6.62 (m, 2H), 5.46-5.03 (m, 1H), 4.27 (br t, J= 9.2 Hz, 2H), 4.15-3.93 (m, 2H), 3.51 (br s, 3H), 3.48 (br d, J= 4.8 Hz, 1H), 3.08 (br d, J= 5.8 Hz, 2H), 3.01 (s, 1H), 2.88-2.75 (m, 1H), 2.16-2.10 (m, 1H), 2.06-1.93 (m, 2H), 1.91-1.71 (m, 3H), 1.62 (br s, 4H). 實施例 45 :4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇 和 實施例 46 :1-(8-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-2-氟-6-羥基萘-1-基)乙-1-酮 Step 2 : Compound tert-butyl (1R,5S)-3-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30.0 mg, 0.03 mmol) was dissolved in dichloromethane/trifluoroacetic acid (volume ratio of 4:1, 600 uL), and the reaction solution was stirred at 20 o C for 2 hours. The reaction solution was concentrated under reduced pressure, acetonitrile (0.5 mL) was added, and then the pH was adjusted to 8 with triethylamine. The concentrated residue was purified by preparative HPLC to obtain a white solid compound 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-fluorophenol (12.0 mg, 21.5 umol, yield 71%). LCMS (ESI): [M+H] + = 560.1; 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 10.49-9.92 (m, 1H), 8.10-7.70 (m, 1H), 7.52-7.23 (m, 1H), 6.99-6.62 (m, 2H), 5.46-5.03 (m, 1H), 4.27 (br t, J = 9.2 Hz, 2H), 4.15-3.93 (m, 2H), 3.51 (br s, 3H), 3.48 (br d, J = 4.8 Hz, 1H), 3.08 (br d, J = 5.8 Hz, 2H), 3.01 (s, 1H), 2.88-2.75 (m, 1H), 2.16-2.10 (m, 1H), 2.06-1.93 (m, 2H), 1.91-1.71 (m, 3H), 1.62 (br s, 4H). Example 45 : 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and Example 46 : 1-(8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)ethan-1-one
實施例 45 和實施例 46 透過實施例 44 的合成途徑方法進行製備 ,用中間體((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)三異丙基矽烷和中間體叔丁基(1R,5S)-3-(7-溴-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯 A9反應,第三步和第四步合併成一步,用TFA/DCM脫保護,得到主產物 4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇 。LCMS (ESI): [M+H] += 634.4; 1H NMR (400 MHz, CD 3OD) δ ppm 7.89-7.79 (m, 2H), 7.37-7.27 (m, 2H), 7.05 (d, J= 2.1 Hz, 1H), 5.45-5.24 (m, 1H), 4.58-4.41 (m, 2H), 4.35-4.20 (m, 2H), 3.68 (br s, 3H), 3.61 (br dd, J= 6.2, 12.6 Hz, 1H), 3.27 (m, 4H), 3.10-2.99 (m, 1H), 2.44-2.23 (m, 2H), 2.16 (m, 1H), 2.07-1.96 (m, 2H), 1.90 (br s, 5H). Examples 45 and 46 were prepared by the synthetic route of Example 44 , using an intermediate ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane and an intermediate tert-butyl (1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-4 The third step and the fourth step were combined into one step, and the reaction mixture was deprotected with TFA/DCM to obtain the main product 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. LCMS (ESI): [M+H] + = 634.4; 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.89-7.79 (m, 2H), 7.37-7.27 (m, 2H), 7.05 (d, J = 2.1 Hz, 1H), 5.45-5.24 (m, 1H), 4.58-4.41 (m, 2H), 4.35-4.20 (m, 2H), 3.68 (br s, 3H), 3.61 (br dd, J = 6.2, 12.6 Hz, 1H), 3.27 (m, 4H), 3.10-2.99 (m, 1H), 2.44-2.23 (m, 2H), 2.16 (m, 1H), 2.07-1.96 (m, 2H), 1.90 (br s, 5H).
同時得到次產物1-(8-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-2-氟-6-羥基萘-1-基)乙-1-酮。LCMS (ESI): [M+H] += 652.3; 1HNMR (400 MHz, MeOD- d 4 ) δ ppm 7.98-7.85 (m, 2H), 7.39-7.29 (m, 2H), 7.08 (d, J= 2.4 Hz, 1H), 5.44-5.23 (m, 1H), 4.57-4.45 (m, 2H), 4.38-4.19 (m, 2H), 3.79-3.62 (m, 4H), 3.50-3.37 (m, 1H), 3.31-3.21 (m, 2H), 3.14-2.99 (m, 1H), 2.46-2.31 (m, 1H), 2.30-2.16 (m, 2H), 2.13 (s, 3H), 2.08-1.98 (m, 2H), 1.96-1.77 (m, 5H). 實施例 47 :4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-甲腈 At the same time, the secondary product 1-(8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)ethan-1-one was obtained. LCMS (ESI): [M+H] + = 652.3; 1 HNMR (400 MHz, MeOD- d 4 ) δ ppm 7.98-7.85 (m, 2H), 7.39-7.29 (m, 2H), 7.08 (d, J = 2.4 Hz, 1H), 5.44-5.23 (m, 1H), 4.57-4.45 (m, 2H), 4.38-4.19 (m, 2H), 3.79-3.62 (m, 4H), 3.50-3.37 (m, 1H), 3.31-3.21 (m, 2H), 3.14-2.99 (m, 1H), 2.46-2.31 (m, 1H), 2.30-2.16 (m, dH), 2.13 (s, 3H), 2.08-1.98 (m, 2H), 1.96-1.77 (m, 5H). Example 47 : 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile
第一步:化合物叔丁基(1R,5S)-3-(7-溴-6-氰基-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(80% 純度,292 mg,0.57 mmol)加入到二氧六環(5 mL)和水(1 mL)中,加入((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(200 mg,0.29 mmol)和磷酸鉀(182 mg,0.86 mmol),氮氣氛圍下加入甲磺醯氧基(二金剛烷基-正丁基膦基)-2-胺基-1,1-聯苯-2-基)鈀(II)(41 mg,0.06 mmol),反應液在100 oC攪拌2小時。反應液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-2%梯度的甲醇/二氯甲烷)得化合物叔丁基(1R,5S)-3-(6-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(70% 純度,187 mg,0.14 mmol,產率53%)。LCMS (ESI): [M+H] += 866.5. Step 1: Compound tert-butyl (1R,5S)-3-(7-bromo-6-cyano-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80% purity, 292 mg, 0.57 mmol) was added to dioxane (5 mL) and water (1 mL), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (200 mg, 0.29 mmol) and potassium phosphate (182 mg, 0.86 mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (41 mg, 0.06 mmol) was added under nitrogen atmosphere, and the reaction solution was stirred at 100 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-2% gradient methanol/dichloromethane) to obtain the compound tert-butyl (1R, 5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 187 mg, 0.14 mmol, yield 53%). LCMS (ESI): [M+H] + = 866.5.
第二步:化合物叔丁基(1R,5S)-3-(6-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(70% 純度,147 mg,0.12 mmol)加入到四氫呋喃(2 mL)中,加入 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(57 mg,0.36 mmol)和叔丁醇鈉(17 mg,0.18 mmol),50 oC攪拌2小時。反應液加入水(3 mL),用乙酸乙酯(3 mL * 3)萃取,有機相減壓濃縮得化合物叔丁基(1R,5S)-3-(6-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(66% 純度,156 mg,0.11 mmol,產率93%)。LCMS (ESI): [M+H] += 924.9. Step 2: Compound tert-butyl (1R,5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 147 mg, 0.12 mmol) was added to tetrahydrofuran (2 mL), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (57 mg, 0.36 mmol) and sodium tert-butoxide (17 mg, 0.18 mmol) were added, and stirred at 50 ° C for 2 hours. Water (3 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL * 3). The organic phase was concentrated by reduced pressure to obtain the compound tert-butyl (1R, 5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (66% purity, 156 mg, 0.11 mmol, yield 93%). LCMS (ESI): [M+H] + = 924.9.
第三步:化合物叔丁基(1R,5S)-3-(6-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(66% 純度,156 mg,0.11 mmol)加入到N,N-二甲基甲醯胺(2 mL)中,加入氟化銫(169 mg,1.11 mmol),20 oC攪拌1小時。反應液加入水(500 uL)稀釋,用乙酸乙酯(1 mL * 3)萃取,有機相減壓濃縮得化合物叔丁基(1R,5S)-3-(6-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(60% 純度,135 mg,0.10 mmol,產率94%)。LCMS (ESI): [M+H] += 769.3. Step 3: Compound tert-butyl (1R,5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (66% purity, 156 mg, 0.11 mmol) was added to N,N-dimethylformamide (2 mL), and cesium fluoride (169 mg, 1.11 mmol) was added, and stirred at 20 ° C for 1 hour. The reaction solution was diluted with water (500 uL), extracted with ethyl acetate (1 mL * 3), and the organic phase was concentrated under reduced pressure to obtain the compound tert-butyl (1R, 5S)-3-(6-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60% purity, 135 mg, 0.10 mmol, yield 94%). LCMS (ESI): [M+H] + = 769.3.
第四步:化合物叔丁基(1R,5S)-3-(6-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(60% 純度,135 mg,0.10 mmol)加入到三氟乙酸/二氯甲烷(體積比為4:1,2.5 mL)中,20 oC攪拌2小時。反應液減壓濃縮,殘留物加入乙腈(500 uL),加入三乙胺調節pH到8,殘留物用製備型HPLC純化,得到黃色固體化合物4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-甲腈(9.11 mg,15 umol,產率14%)。LCMS (ESI): [M+H] += 624.9; 1H NMR (400 MHz, DMSO- d 6) δ ppm 10.40-10.21 (m, 1H), 8.29 (s, 1H), 8.02 (dd, J= 5.9, 9.2 Hz, 1H), 7.56-7.40 (m, 2H), 7.17 (s, 1H), 5.41-5.14 (m, 1H), 4.44-4.23 (m, 2H), 4.10 (dd, J= 6.5, 10.3 Hz, 1H), 4.05-3.95 (m, 2H), 3.65 (br d, J= 12.3 Hz, 1H), 3.56 (br d, J= 10.3 Hz, 3H), 3.16-3.04 (m, 2H), 3.01 (s, 1H), 2.89-2.77 (m, 1H), 2.12 (br s, 1H), 2.07-1.94 (m, 2H), 1.90-1.72 (m, 3H), 1.70-1.54 (m, 4H). Step 4: Compound tert-butyl (1R,5S)-3-(6-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60% purity, 135 mg, 0.10 mmol) was added to trifluoroacetic acid/dichloromethane (volume ratio of 4:1, 2.5 mL) and stirred at 20 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, acetonitrile (500 uL) was added to the residue, and triethylamine was added to adjust the pH to 8. The residue was purified by preparative HPLC to obtain a yellow solid compound 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazoline-6-carbonitrile (9.11 mg, 15 umol, yield 14%). LCMS (ESI): [M+H] + = 624.9; 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 10.40-10.21 (m, 1H), 8.29 (s, 1H), 8.02 (dd, J = 5.9, 9.2 Hz, 1H), 7.56-7.40 (m, 2H), 7.17 (s, 1H), 5.41-5.14 (m, 1H), 4.44-4.23 (m, 2H), 4.10 (dd, J = 6.5, 10.3 Hz, 1H), 4.05-3.95 (m, 2H), 3.65 (br d, J = 12.3 Hz, 1H), 3.5 10.3 Hz, 3H), 3.16-3.04 (m, 2H), 3.01 (s, 1H), 2.89-2.77 (m, 1H), 2.12 (br s, 1H), 2.07-1.94 (m, 2H), 1.90-1.72 (m, 3H), 1.70-1.54 (m, 4H).
以下實施例透過實施例 47 的合成途徑方法進行製備:第二步中間體化合物叔丁基(1R,5S)-3-(6-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯與中間體 A16-2反應,參照類似反應條件製備得到反式產物。 經SFC分離(管柱:DAICEL CHIRALPAK IG (250mm*30mm, 10um);流動相:A相為二氧化碳,B相為0.1%氨水/乙醇;B相保持45%;流速:80毫升/分鐘),得到目標化合物 實施例 48A~ 實施例 48D。 實施例 48A~48D:4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(R)-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟喹唑啉-6-腈,4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(S)-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟喹唑啉-6-腈,4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-((R)-8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟喹唑啉-6-腈,4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-((S)-8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟喹唑啉-6-腈 , , , The following examples were prepared by the synthetic route of Example 47 : In the second step, the intermediate compound tert-butyl (1R, 5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was reacted with the intermediate A16-2 to obtain the trans product under similar reaction conditions. After SFC separation (column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 45%; flow rate: 80 ml/min), the target compounds Example 48A to Example 48D were obtained. Example 48A to Example 48D :4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(R)-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6- Nitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(S)-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6- Nitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-((R)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6- Nitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-((S)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile , , ,
實施例 48A :異構物1, SFC分析(管柱: Chiralpak IE 100*4.6mm 3um;流動相:A相為0.1%二乙胺/正庚烷,B相為異丙醇;梯度:A/B = 60/40,流速:1毫升/分鐘):RT = 4.236 min, 掌性純度:100%; 1H NMR (400 MHz, CD 3OD) δ ppm 8.11 (s, 1H), 7.78 (br dd, J= 5.8, 9.0 Hz, 1H), 7.32-7.17 (m, 2H), 7.05 (d, J= 2.1 Hz, 1H), 4.50 (br d, J= 11.8 Hz, 1H), 4.39 (br d, J= 12.4 Hz, 1H), 4.31-4.17 (m, 2H), 3.69-3.49 (m, 4H), 3.26 (s, 1H), 3.17 (br s, 1H), 3.10-3.00 (m, 1H), 2.74 (br d, J= 12.3 Hz, 1H), 2.65-2.53 (m, 1H), 2.18 (br dd, J= 6.0, 13.4 Hz, 1H), 2.03 (br dd, J= 6.6, 11.9 Hz, 1H), 1.92 (br d, J= 13.5 Hz, 1H), 1.83-1.61 (m, 7H), 1.41-1.28 (m, 2H). Example 48A : Isomer 1, SFC analysis (column: Chiralpak IE 100*4.6mm 3um; mobile phase: phase A is 0.1% diethylamine/n-heptane, phase B is isopropanol; gradient: A/B = 60/40, flow rate: 1 ml/min): RT = 4.236 min, chiral purity: 100%; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.11 (s, 1H), 7.78 (br dd, J = 5.8, 9.0 Hz, 1H), 7.32-7.17 (m, 2H), 7.05 (d, J = 2.1 Hz, 1H), 4.50 (br d, J = 11.8 Hz, 1H), 4.39 (br d, J = = 12.4 Hz, 1H), 4.31-4.17 (m, 2H), 3.69-3.49 (m, 4H), 3.26 (s, 1H), 3.17 (br s, 1H), 3.10-3.00 (m, 1H), 2.74 (br d, J = 12.3 Hz, 1H), 2.65-2.53 (m, 1H), 2.18 (br dd, J = 6.0, 13.4 Hz, 1H), 2.03 (br dd, J = 6.6, 11.9 Hz, 1H), 1.92 (br d, J = 13.5 Hz, 1H), 1.83-1.61 (m, 7H), 1.41-1.28 (m, 2H).
實施例 48B :異構物2, SFC分析(管柱:Chiralpak IG-3(50mm * 4.6mm),3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在2分鐘內從5%到40%,保持40%的B相1.2分鐘,保持5%的B相0.8分鐘,流速:4毫升/分鐘):RT = 1.942 min, 掌性純度:100%; LCMS (ESI): [M+H] += 669.2; 1H NMR (400 MHz, CD 3OD) δ ppm 8.23 (s, 1H), 7.90 (dd, J= 5.8, 9.0 Hz, 1H), 7.44-7.30 (m, 2H), 7.17 (d, J= 2.5 Hz, 1H), 4.66-4.48 (m, 2H), 4.40-4.31 (m, 2H), 3.79-3.61 (m, 4H), 3.40-3.36 (m, 1H), 3.30 (d, J= 6.8 Hz, 1H), 3.20-3.13 (m, 1H), 2.86 (d, J= 12.0 Hz, 1H), 2.76-2.67 (m, 1H), 2.33-2.25 (m, 1H), 2.20-2.11 (m, 1H), 2.04 (br d, J= 13.6 Hz, 1H), 1.97-1.75 (m, 7H), 1.52-1.37 (m, 2H). Example 48B : Isomer 2, SFC analysis (column: Chiralpak IG-3 (50 mm * 4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B from 5% to 40% in 2 minutes, keep 40% phase B for 1.2 minutes, keep 5% phase B for 0.8 minutes, flow rate: 4 ml/min): RT = 1.942 min, chiral purity: 100%; LCMS (ESI): [M+H] + = 669.2; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.23 (s, 1H), 7.90 (dd, J = 5.8, 9.0 Hz, 1H), 7.44-7.30 (m, 2H), 7.17 (d, J = d, J = 12.0 Hz, 1H), 2.76-2.67 (m, 1H), 2.33-2.25 (m, 1H) , 2.20-2.11 (m, 1H), 2.04 (br d, J = 13.6 Hz, 1H), 1.97-1.75 (m, 7H), 1.52-1.37 (m, 2H).
實施例 48C :異構物3, SFC分析(管柱:Chiralpak IG-3(50mm * 4.6mm),3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在2分鐘內從5%到40%,保持40%的B相1.2分鐘,保持5%的B相0.8分鐘,流速:4毫升/分鐘):RT = 2.343 min, 掌性純度 = 97.12%; 1H NMR (400 MHz, CD 3OD) δ ppm 8.23 (s, 1H), 7.89 (dd, J= 5.8, 9.1 Hz, 1H), 7.42-7.32 (m, 2H), 7.17 (d, J= 2.3 Hz, 1H), 4.62-4.48 (m, 2H), 4.36 (s, 2H), 3.80-3.61 (m, 4H), 3.37 (s, 1H), 3.31-3.26 (m, 1H), 3.20-3.12 (m, 1H), 2.85 (d, J= 12.2 Hz, 1H), 2.76-2.65 (m, 1H), 2.28 (dd, J= 6.2, 13.6 Hz, 1H), 2.19-2.12 (m, 1H), 2.03 (d, J= 13.6 Hz, 1H), 1.96-1.74 (m, 7H), 1.50-1.37 (m, 2H). Example 48C : Isomer 3, SFC analysis (column: Chiralpak IG-3 (50 mm * 4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B from 5% to 40% in 2 minutes, keep 40% phase B for 1.2 minutes, keep 5% phase B for 0.8 minutes, flow rate: 4 ml/min): RT = 2.343 min, chiral purity = 97.12%; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.23 (s, 1H), 7.89 (dd, J = 5.8, 9.1 Hz, 1H), 7.42-7.32 (m, 2H), 7.17 (d, J = 2.3 Hz, 1H), 4.62-4.48 (m, 2H), 4.36 (s, 2H), 3.80-3.61 (m, 4H), 3.37 (s, 1H), 3.31-3.26 (m, 1H), 3.20-3.12 (m, 1H), 2.85 (d, J = 12.2 Hz, 1H), 2.76-2.65 (m, 1H), 2.28 (dd, J = 6.2, 13.6 Hz, 1H), 2.19-2.12 (m, 1H), 2.03 (d, J = 13.6 Hz, 1H), 1.96-1.74 (m, 7H), 1.50-1.37 (m, 2H).
實施例 48D :異構物4, SFC分析(管柱:Chiralpak IG-3(50mm * 4.6mm),3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在2分鐘內從5%到40%,保持40%的B相1.2分鐘,保持5%的B相0.8分鐘,流速:4毫升/分鐘):RT = 3.004 min, 掌性純度:98.43%; 1H NMR (400 MHz, CD 3OD) δ ppm 8.11 (s, 1H), 7.77 (br dd, J= 5.9, 8.9 Hz, 1H), 7.32-7.18 (m, 2H), 7.05 (s, 1H), 4.48 (br d, J= 12.8 Hz, 1H), 4.38 (br d, J= 12.4 Hz, 1H), 4.23 (q, J= 10.5 Hz, 2H), 3.67-3.49 (m, 4H), 3.26 (s, 1H), 3.17 (br d, J= 7.0 Hz, 1H), 3.09-3.00 (m, 1H), 2.73 (br d, J= 12.3 Hz, 1H), 2.59 (br d, J= 6.4 Hz, 1H), 2.17 (br dd, J= 6.0, 13.5 Hz, 1H), 2.02 (br dd, J= 5.8, 10.5 Hz, 1H), 1.91 (br d, J= 13.5 Hz, 1H), 1.84-1.62 (m, 7H), 1.40-1.25 (m, 2H). Example 48D : Isomer 4, SFC analysis (column: Chiralpak IG-3 (50 mm * 4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B from 5% to 40% in 2 minutes, keep 40% phase B for 1.2 minutes, keep 5% phase B for 0.8 minutes, flow rate: 4 ml/min): RT = 3.004 min, chiral purity: 98.43%; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.11 (s, 1H), 7.77 (br dd, J = 5.9, 8.9 Hz, 1H), 7.32-7.18 (m, 2H), 7.05 (s, 1H), 4.48 (br d, J = 12.8 Hz, 1H), 4.38 (br d, J = 12.4 Hz, 1H), 4.23 (q, J = 10.5 Hz, 2H), 3.67-3.49 (m, 4H), 3.26 (s, 1H), 3.17 (br d, J = 7.0 Hz, 1H), 3.09-3.01 (m, 1H), 2.73 (br d, J = 12.3 Hz, 1H), 2.59 (br d, J = 6.4 Hz, 1H), 2.17 (br dd, J = 6.0, 13.5 Hz, 1H), 2.03 (br dd, J = 5.8, 10.5 Hz, 1H), 1.91 (br d, J = 13.5 Hz, 1H), 1.84-1.62 (m, 7H), 1.40-1.25 (m, 2H).
以下實施例透過實施例 47 的合成途徑方法進行製備:第二步中間體化合物叔丁基(1R,5S)-3-(6-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯與中間體 A16-1反應,參照類似反應條件製備得到順式產物。經SFC分離(管柱:DAICEL CHIRALPAK IG (250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/異丙醇;B相保持50%;流速:80毫升/分鐘),得到目標化合物 實施例 49A~ 實施例 49D。 實施例 49A~49D: 4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-((R)-8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟喹唑啉-6-腈,4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-((S)-8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟喹唑啉-6-腈, 4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-((R)-8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟喹唑啉-6-腈,4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-((S)-8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟喹唑啉-6-腈 , , , The following examples were prepared by the synthetic route of Example 47 : In the second step, the intermediate compound tert-butyl (1R, 5S)-3-(6-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was reacted with the intermediate A16-1 to obtain the cis product under similar reaction conditions. After SFC separation (column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 50%; flow rate: 80 ml/min), the target compounds Example 49A to Example 49D were obtained. Example 49A to Example 49D: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-((R)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-((S)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile, 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-((R)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile , 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-((S)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazoline-6-carbonitrile , , ,
實施例 49A :異構物1, SFC分析(管柱:Chiralpak IC-3(100mm * 4.6mm),3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:40%的B相,流速:2.8毫升/分鐘):RT = 2.414 min, 掌性純度:100%; 1H NMR (400 MHz, CD 3OD) δ ppm 8.10 (s, 1H), 7.76 (dd, J= 5.7, 9.2 Hz, 1H), 7.27-7.16 (m, 2H), 7.05 (d, J= 2.5 Hz, 1H), 4.52 (br d, J= 11.6 Hz, 1H), 4.37 (br d, J= 12.5 Hz, 1H), 4.17-4.07 (m, 2H), 3.65 (br d, J= 12.1 Hz, 1H), 3.58-3.43 (m, 3H), 3.26 (s, 1H), 3.11 (d, J= 10.8 Hz, 1H), 3.01-2.93 (m, 1H), 2.79-2.64 (m, 2H), 2.19 (d, J= 13.3 Hz, 1H), 2.05-1.62 (m, 9H), 1.37-1.30 (m, 2H). Example 49A : Isomer 1, SFC analysis (column: Chiralpak IC-3 (100 mm * 4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: 40% phase B, flow rate: 2.8 ml/min): RT = 2.414 min, chiral purity: 100%; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.10 (s, 1H), 7.76 (dd, J = 5.7, 9.2 Hz, 1H), 7.27-7.16 (m, 2H), 7.05 (d, J = 2.5 Hz, 1H), 4.52 (br d, J = 11.6 Hz, 1H), 4.37 (br d, J = 12.5 Hz, 1H), 4.17-4.07 (m, 2H), 3.65 (br d, J = 12.1 Hz, 1H), 3.58-3.43 (m, 3H), 3.26 (s, 1H), 3.11 (d, J = 10.8 Hz, 1H), 3.01-2.93 (m, 1H), 2.79-2.64 (m, 2H), 2.19 (d, J = 13.3 Hz, 1H), 2.05-1.62 (m, 9H), 1.37-1.30 (m, 2H).
實施例 49B :異構物2, SFC分析(管柱:Chiralpak IC-3(100mm * 4.6mm),3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:40%的B相,流速:2.8毫升/分鐘):RT = 3.344 min, 掌性純度:92.10%; 1H NMR (400 MHz, CD 3OD) δ ppm 8.22 (s, 1H), 7.93-7.85 (m, 1H), 7.40-7.30 (m, 2H), 7.17 (d, J= 2.2 Hz, 1H), 4.56 (br d, J= 12.3 Hz, 2H), 4.31-4.18 (m, 2H), 3.78-3.62 (m, 4H), 3.41-3.37 (m, 1H), 3.24 (d, J= 10.8 Hz, 1H), 3.16-3.04 (m, 1H), 2.94-2.78 (m, 2H), 2.37-2.27 (m, 1H), 2.09 (ddd, J= 5.9, 11.2, 14.5 Hz, 2H), 2.01-1.91 (m, 3H), 1.87-1.77 (m, 4H), 1.49-1.44 (m, 2H). Example 49B : Isomer 2, SFC analysis (column: Chiralpak IC-3 (100mm * 4.6mm), 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: 40% phase B, flow rate: 2.8 ml/min): RT = 3.344 min, chiral purity: 92.10%; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.22 (s, 1H), 7.93-7.85 (m, 1H), 7.40-7.30 (m, 2H), 7.17 (d, J = 2.2 Hz, 1H), 4.56 (br d, J = 12.3 Hz, 2H), 4.31-4.18 (m, 2H), 3.78-3.62 (m, 4H), 3.41-3.37 (m, 1H), 3.24 (d, J = 10.8 Hz, 1H), 3.16-3.04 (m, 1H), 2.94-2.78 (m, 2H), 2.37-2.27 (m, 1H), 2.09 (ddd, J = 5.9, 11.2, 14.5 Hz, 2H), 2.01-1.91 (m, 3H), 1.87-1.77 (m, 4H), 1.49-1.44 (m, 2H).
實施例 49C :異構物3, SFC分析(管柱:Chiralpak IG-3(50mm * 4.6mm),3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相,流速:4毫升/分鐘):RT = 1.150 min, 掌性純度:91.48%; 1H NMR (400 MHz, CD 3OD) δ ppm 8.28-8.18 (m, 1H), 7.94-7.80 (m, 1H), 7.42-7.28 (m, 2H), 7.22-7.15 (m, 1H), 4.64 (br d, J= 12.5 Hz, 1H), 4.49 (br d, J= 12.3 Hz, 1H), 4.27-4.19 (m, 2H), 3.81-3.62 (m, 4H), 3.38 (s, 1H), 3.23 (d, J= 10.8 Hz, 1H), 3.14-3.05 (m, 1H), 2.93-2.76 (m, 2H), 2.31 (br d, J= 13.3 Hz, 1H), 2.18-2.04 (m, 2H), 2.01-1.90 (m, 3H), 1.88-1.73 (m, 4H), 1.49-1.41 (m, 2H). Example 49C : Isomer 3, SFC analysis (column: Chiralpak IG-3 (50 mm * 4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 4 ml/min): RT = 1.150 min, chiral purity: 91.48%; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.28-8.18 (m, 1H), 7.94-7.80 (m, 1H), 7.42-7.28 (m, 2H), 7.22-7.15 (m, 1H), 4.64 (br d, J = 12.5 Hz, 1H), 4.49 (br d, J = 12.3 Hz, 1H), 4.27-4.19 (m, 2H), 3.81-3.62 (m, 4H), 3.38 (s, 1H), 3.23 (d, J = 10.8 Hz, 1H), 3.14-3.05 (m, 1H), 2.93-2.76 (m, 2H), 2.31 (br d, J = 13.3 Hz, 1H), 2.18-2.04 (m, 2H), 2.01-1.90 (m, 3H), 1.88-1.73 (m, 4H), 1.49-1.41 (m, 2H).
實施例 49D :異構物4, SFC分析(管柱:Chiralpak IG-3(50mm * 4.6mm),3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相,流速:4毫升/分鐘):RT = 2.203 min, 掌性純度:98.67%; 1H NMR (400 MHz, CD 3OD) δ ppm 8.10 (s, 1H), 7.76 (dd, J= 5.8, 9.1 Hz, 1H), 7.28-7.18 (m, 2H), 7.05 (d, J= 2.4 Hz, 1H), 4.44 (br d, J= 12.4 Hz, 2H), 4.20-4.04 (m, 2H), 3.65-3.44 (m, 4H), 3.31-3.23 (m, 1H), 3.12 (d, J= 10.8 Hz, 1H), 2.98 (td, J= 5.6, 10.8 Hz, 1H), 2.80-2.64 (m, 2H), 2.21 (d, J= 13.4 Hz, 1H), 1.99-1.61 (m, 9H), 1.41-1.26 (m, 2H). 實施例 50:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-7-基)萘-2-醇 Example 49D : Isomer 4, SFC analysis (column: Chiralpak IG-3 (50 mm * 4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 4 ml/min): RT = 2.203 min, chiral purity: 98.67%; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.10 (s, 1H), 7.76 (dd, J = 5.8, 9.1 Hz, 1H), 7.28-7.18 (m, 2H), 7.05 (d, J = 2.4 Hz, 1H), 4.44 (br d, J = 12.4 Hz, 2H), 4.20-4.04 3.65-3.44 (m, 4H), 3.31-3.23 (m, 1H), 3.12 (d, J = 10.8 Hz, 1H), 2.98 (td, J = 5.6, 10.8 Hz, 1H), 2.80-2.64 (m, 2H), 2.21 (d, J = 13.4 Hz, 1H), 1.99-1.61 (m, 9H), 1.41-1.26 (m, 2H). Example 50 :4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)naphthalen-2-ol
第一步:化合物叔丁基(1R,5S)-3-(7-溴-8-氟-6-碘-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(1.00 g,1.51 mmol)溶於N,N-二甲基甲醯胺(15 mL),氮氣氛圍中,20 oC下加入2,2-二氟-2-(氟磺醯基)乙酸甲酯(2.03 g,10.5 mmol)和碘化亞銅(2.02 g,10.5 mmol)。反應在60 oC下攪拌16小時。反應液過濾,減壓濃縮。殘留物用快速管柱層析純化(矽膠,0-20%梯度的乙酸乙酯/石油醚)得到白色固體化合物叔丁基(1R,5S)-3-(7-溴-8-氟-2-(2,2,2-三氟乙氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(0.80 g,1.32 mmol,產率88%)。LCMS (ESI): [M+H] += 605.0. Step 1 : Compound tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 1.51 mmol) was dissolved in N,N-dimethylformamide (15 mL). Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.03 g, 10.5 mmol) and cuprous iodide (2.02 g, 10.5 mmol) were added at 20 ° C in a nitrogen atmosphere. The reaction was stirred at 60 ° C for 16 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate/petroleum ether) to obtain a white solid compound tert-butyl (1R, 5S)-3-(7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.80 g, 1.32 mmol, yield 88%). LCMS (ESI): [M+H] + = 605.0.
第二步:在氮氣環境下中,向叔丁基(1R,5S)-3-(7-溴-8-氟-2-(2,2,2-三氟乙氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(200 mg,0.33 mmol)的四氫呋喃(3 mL)溶液中加入4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)萘-2-醇(107 mg,0.40 mmol),磷酸鉀(1.5 M的水溶液,663 uL,0.99 mmol),(2-二環己基膦-2,4,6-三異丙基-1,1-聯苯)[2-(2-胺基-1,1-聯苯]甲磺酸鈀(28 mg,0.03 mmol)。並將混合物在60 oC下攪拌2小時。將混合物真空濃縮。殘餘物透過快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化得到淡黃色固體化合物叔丁基(1R,5S)-3-(8-氟-7-(3-羥基萘-1-基)-2-(2,2,2-三氟乙氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(190 mg,0.29 mmol,產率86%)。LCMS (ESI): [M+H] += 667.2. Step 2 : Under nitrogen atmosphere, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)naphthalen-2-ol (107 mg, 0.40 mmol), potassium phosphate (1.5 M aqueous solution, 663 uL, 0.99 mmol), (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl]methanesulfonate palladium (28 mg, 0.03 mmol). The mixture was stirred at 60 ° C for 2 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a light yellow solid compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (190 mg, 0.29 mmol, yield 86%). LCMS (ESI): [M+H] + = 667.2.
第三步:將叔丁基(1R,5S)-3-(8-氟-7-(3-羥基萘-1-基)-2-(2,2,2-三氟乙氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(170 mg,0.26 mmol)溶於二氯甲烷(3 mL)降到0 oC,慢慢往反應液中加入二異丙基乙胺(133 uL,0.77 mmol)和溴甲基甲醚(27 uL,0.33 mmol),反應在25 oC攪拌16小時。反應完用水(5 mL)淬滅,然後用二氯甲烷(3 mL * 2)萃取,合併有機相減壓濃縮。殘留物用快速管柱層析純化(矽膠,0-20%梯度的乙酸乙酯/石油醚)得到白色固體化合物叔丁基(1R,5S)-3-(8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(170 mg,0.24 mmol,產率94%)。LCMS (ESI): [M+H] += 710.8. Step 3 : Dissolve tert-butyl (1R, 5S)-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 0.26 mmol) in dichloromethane (3 mL) and cool to 0 o C. Slowly add diisopropylethylamine (133 uL, 0.77 mmol) and bromomethyl methyl ether (27 uL, 0.33 mmol) to the reaction solution and stir at 25 o C for 16 hours. After the reaction, quench with water (5 mL), then extract with dichloromethane (3 mL * 2), and combine the organic phases and concentrate under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate/petroleum ether) to obtain a white solid compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 0.24 mmol, yield 94%). LCMS (ESI): [M+H] + = 710.8.
第四步:將((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(40 mg,0.25 mmol)溶於四氫呋喃(1 mL)降到0 oC,慢慢往反應液中加入氫化鈉 (60%含量,13 mg,0.32 mmol),反應在20 oC攪拌1小時。然後向反應液中加入叔丁基(1R,5S)-3-(8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(150 mg,0.21 mmol)的四氫呋喃(1 mL)溶液。反應在20 oC下攪拌16小時。反應液中加入乙酸(500 uL)調節pH為5-6,反應液減壓濃縮。殘留物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷)得到黃色油狀化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)萘-1-基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(130 mg,0.16 mmol,產率80%)。LCMS (ESI): [M+H] += 770.2. Step 4 : Dissolve ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (40 mg, 0.25 mmol) in tetrahydrofuran (1 mL) and cool to 0 o C. Slowly add sodium hydride (60% content, 13 mg, 0.32 mmol) to the reaction solution and stir at 20 o C for 1 hour. Then add tert-butyl (1R,5S)-3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.21 mmol) in tetrahydrofuran (1 mL). The reaction was stirred at 20 ° C for 16 hours. Acetic acid (500 uL) was added to the reaction solution to adjust the pH to 5-6, and the reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow oily compound tert-butyl (1R, 5S)-3-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.16 mmol, yield 80%). LCMS (ESI): [M+H] + = 770.2.
第五步:化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)萘-1-基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(160 mg,0.21 mmol)溶於二氯甲烷(2 mL),20 oC下加入三氟乙酸(0.5 mL)。反應在20 oC下攪拌2小時。氮氣下濃縮。殘留物溶於四氫呋喃(2 mL),向溶液中加入三乙胺(400 uL)調節pH為7-8,混合物減壓濃縮。殘留物用製備型HPLC純化,得到白色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪 -7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-7-基)萘-2-醇(1.03 mg,1.64 umol,產率0.77%)。LCMS (ESI): [M+H] +=626.1. 1H NMR (400 MHz, CH 3OD) δ ppm 8.24 (s, 1H), 7.76 (d, J= 7.7 Hz, 1H), 7.53-7.37 (m, 1H), 7.27 (s, 1H), 7.19 (br d, J= 3.6 Hz, 2H), 7.05 (s, 1H), 5.43-5.29 (m, 1H), 4.58 (m, 2H), 4.41-4.30 (m, 2H), 3.77 (m, 4H), 3.22-3.00 (m, 4H), 2.40-2.17 (m, 3H), 2.06 (m, 2H), 1.91 (m, 5H). 實施例 51:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(甲基磺醯基)喹唑啉-7-基)萘-2-醇 Step 5 : Compound tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was added at 20 ° C. The reaction was stirred at 20 ° C for 2 hours. Concentrated under nitrogen. The residue was dissolved in tetrahydrofuran (2 mL), triethylamine (400 uL) was added to the solution to adjust the pH to 7-8, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give a white solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)naphthalen-2-ol (1.03 mg, 1.64 umol, yield 0.77%). LCMS (ESI): [M+H] + = 626.1. 1 H NMR (400 MHz, CH 3 OD) δ ppm 8.24 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.53-7.37 (m, 1H), 7.27 (s, 1H), 7.19 (br d, J = 3.6 Hz, 2H), 7.05 (s, 1H), 5.43-5.29 (m, 1H), 4.58 (m, 2H), 4.41-4.30 (m, 2H), 3.77 (m, 4H), 3.22-3.00 (m, 4H), 2.40-2.17 (m, 3H), 2.06 (m, 2H), 1.91 (m, 5H). Example 51 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-(methylsulfonyl)quinazolin-7-yl)naphthalen-2-ol
實施例 51的製備參考 實施例 50的合成途徑,第一步向叔丁基(1R,5S)-3-(8-氟-6-碘-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯和碘化亞銅和甲基亞磺酸鈉反應得到相應的中間體,然後經過類似反應,製備得到4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(甲基磺醯基)喹唑啉-7-基)萘-2-醇。LCMS (ESI): [M+H] += 636.1; 1H NMR (400 MHz, CD 3OD) δ ppm 8.70-8.62 (m, 1H), 8.36-7.73 (m, 1H), 7.45-7.33 (m, 1H), 7.30-6.91 (m, 4H), 5.40-5.19 (m, 1H), 4.64-4.56 (m, 2H), 4.35-4.20 (m, 2H), 3.74-3.62 (m, 4H), 3.27-3.16 (m, 3H), 3.06-2.96 (m, 1H), 2.68-2.39 (m, 3H), 2.38-1.78 (m, 10H). 實施例 52:(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羥基萘-1-基)喹唑啉-6-基)二甲基氧化膦 Preparation of Example 51 Referring to the synthetic route of Example 50 , the first step is to tert-butyl (1R, 5S)-3-(8-fluoro-6-iodo-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, cuprous iodide and sodium methanesulfinate. The corresponding intermediate is obtained by reaction, and then 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(methylsulfonyl)quinazolin-7-yl)naphthalen-2-ol is prepared through similar reaction. LCMS (ESI): [M+H] + = 636.1; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.70-8.62 (m, 1H), 8.36-7.73 (m, 1H), 7.45-7.33 (m, 1H), 7.30-6.91 (m, 4H), 5.40-5.19 (m, 1H), 4.64-4.56 (m, 2H), 4.35-4.20 (m, 2H), 3.74-3.62 (m, 4H), 3.27-3.16 (m, 3H), 3.06-2.96 (m, 1H), 2.68-2.39 (m, 3H), 2.38-1.78 (m, 10H). Example 52 : (4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)dimethylphosphine oxide
實施例 52的製備參考 實施例 50的合成途徑,第一步向叔丁基(1R,5S)-3-(8-氟-6-碘-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯 與二甲基氧化膦,二異丙基乙胺,三(二伸苄基丙酮)二鈀,4,5-雙二苯基膦-9,9-二甲基氧雜蒽反應得到相應的中間體,然後經過類似反應,製備得到(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羥基萘-1-基)喹唑啉-6-基)二甲基氧化膦。LCMS (ESI): [M+H] += 634.2; 1H NMR (400MHz, CD 3OD) δ ppm 8.62 (d, J= 14.1 Hz, 1H), 7.79 (d, J= 8.3 Hz, 1H), 7.49-7.42 (m, 1H), 7.34 (d, J= 2.3 Hz, 1H), 7.28-7.21 (m, 2H), 7.15 (d, J= 2.5 Hz, 1H), 5.42-5.22 (m, 1H), 4.65-4.58 (m, 2H), 4.38-4.19 (m, 2H), 3.77-3.65 (m, 4H), 3.31-3.13 (m, 3H), 3.08-2.98 (m, 1H), 2.41-2.11 (m, 3H), 2.08-1.96 (m, 2H), 1.94-1.79 (m, 5H), 1.50 (d, J= 13.6 Hz, 3H), 0.95 (d, J= 13.6 Hz, 3H). 實施例 53:1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羥基萘-1-基)喹唑啉-6-基)乙-1-酮 Preparation of Example 52 Referring to the synthetic route of Example 50 , the first step is to react tert-butyl (1R, 5S)-3-(8-fluoro-6-iodo-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate with dimethylphosphine oxide, diisopropylethylamine, tri(dibenzylacetone)dipalladium, 4,5- Bis(diphenylphosphino)-9,9-dimethyloxanthracene was reacted to obtain the corresponding intermediate, and then (4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)dimethylphosphine oxide was prepared through a similar reaction. LCMS (ESI): [M+H] + = 634.2; 1 H NMR (400MHz, CD 3 OD) δ ppm 8.62 (d, J = 14.1 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.49-7.42 (m, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.28-7.21 (m, 2H), 7.15 (d, J = 2.5 Hz, 1H), 5.42-5.22 (m, 1H), 4.65-4.58 (m, 2H), 4.38-4.19 (m, 2H), 3.77-3.65 (m, 4H), 3.21-3.13 (m, 3H), 3.08-2.98 (m, 1H), 2.41-2.11 (m, 3H), 2.08-1.96 (m, 2H), 1.94-1.79 (m, 5H), 1.50 (d, J = 13.6 Hz, 3H), 0.95 (d, J = 13.6 Hz, 3H). Example 53 : 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)ethan-1-one
第一步:將化合物叔丁基(1R,5S)-3-(8-氟-6-碘-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(150 mg,200 umol)和三丁基(1-乙氧基乙烯基)錫烷(280 mg,775 umol)溶於二氧六環(2.00 mL),氮氣下加入四(三苯基膦)鈀(22.0 mg,20 umol),反應在100 oC攪拌16小時。反應液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-30%梯度的乙酸乙酯/石油醚)得化合物叔丁基(1R,5S)-3-(6-(1-乙氧基乙烯基)-8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(75.0 mg,112 umol,產率56%)。LCMS (ESI): [M+H] += 713.3. Step 1: Dissolve the compound tert-butyl (1R,5S)-3-(8-fluoro-6-iodo-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 200 umol) and tributyl(1-ethoxyvinyl)tinane (280 mg, 775 umol) in dioxane (2.00 mL), add tetrakis(triphenylphosphine)palladium (22.0 mg, 20 umol) under nitrogen, and stir the reaction at 100 o C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain the compound tert-butyl (1R, 5S)-3-(6-(1-ethoxyvinyl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75.0 mg, 112 umol, yield 56%). LCMS (ESI): [M+H] + = 713.3.
第二步:將化合物叔丁基(1R,5S)-3-(6-(1-乙氧基乙烯基)-8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(65.0 mg,91 umol)加入到四氫呋喃(0.60 mL)中,加入 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(21.0 mg,136 umol)和叔丁醇鈉(26.0 mg,274 umol),20 oC攪拌16小時。反應液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷)得叔丁基(1R,5S)-3-(6-(1-乙氧基乙烯基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)萘-1-基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(75.0 mg,90 umol,產率99%)。LCMS (ESI): [M+H] += 772.3. Step 2: Add the compound tert-butyl (1R,5S)-3-(6-(1-ethoxyvinyl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (65.0 mg, 91 umol) to tetrahydrofuran (0.60 mL), add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (21.0 mg, 136 umol) and sodium tert-butoxide (26.0 mg, 274 umol), and stir at 20 o C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain tert-butyl (1R,5S)-3-(6-(1-ethoxyvinyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75.0 mg, 90 umol, yield 99%). LCMS (ESI): [M+H] + = 772.3.
第三步:化合物叔丁基(1R,5S)-3-(6-(1-乙氧基乙烯基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)萘-1-基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(65.0 mg,84 umol)加入到三氟乙酸/二氯甲烷(體積比為4:1,1.20 mL)中,20 oC攪拌2小時。反應液減壓濃縮,殘留物加入乙腈(500 uL),加入三乙胺調節pH到8,混合物用製備型HPLC純化,得到白色固體化合物1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羥基萘-1-基)喹唑啉-6-基)乙-1-酮(8.14 mg,15 umol,產率14%)。LCMS (ESI): [M+H] += 600.6. 1H NMR (400 MHz, CD 3OD) δ ppm 8.24 (s, 1H), 7.77 (br d, J= 8.3 Hz, 1H), 7.43 (br t, J= 7.4 Hz, 1H), 7.35 (br d, J= 8.4 Hz, 1H), 7.30-7.19 (m, 2H), 7.02 (d, J= 2.0 Hz, 1H), 5.46-5.23 (m, 1H), 4.67-4.58 (m, 2H), 4.39-4.23 (m, 2H), 3.71 (br s, 4H), 3.43-3.35 (m, 1H), 3.31-3.22 (m, 2H), 3.12-3.00 (m, 1H), 2.46-2.13 (m, 3H), 2.08-1.80 (m, 10H). Step 3: Compound tert-butyl (1R,5S)-3-(6-(1-ethoxyvinyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (65.0 mg, 84 umol) was added to trifluoroacetic acid/dichloromethane (volume ratio of 4:1, 1.20 mL) and stirred at 20 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, acetonitrile (500 uL) was added to the residue, triethylamine was added to adjust the pH to 8, and the mixture was purified by preparative HPLC to obtain a white solid compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)ethan-1-one (8.14 mg, 15 umol, yield 14%). LCMS (ESI): [M+H] + = 600.6. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.24 (s, 1H), 7.77 (br d, J = 8.3 Hz, 1H), 7.43 (br t, J = 7.4 Hz, 1H), 7.35 (br d, J = 8.4 Hz, 1H), 7.30-7.19 (m, 2H), 7.02 (d, J = 2.0 Hz, 1H), 5.46-5.23 (m, 1H), 4.67-4.58 (m, 2H), 4.39-4.23 (m, 2H), 3.71 (br s, 4H), 3.43-3.35 (m, 1H), 3.31-3.22 (m, 2H), 3.12-3.00 (m, 1H), 2.46-2.13 (m, 3H), 2.08-1.80 (m, 10H).
以下實施例 54~ 實施例 65 透過實施例 53 的合成途徑方法進行製備: 實施例 54:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-6-環丙基-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)萘-2-醇 The following Examples 54 to 65 were prepared by the synthetic route of Example 53: Example 54 : 4- (4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol
LCMS (ESI): [M+H] += 598.5. 1H NMR (400 MHz, CD 3OD) δ ppm 7.72 (br d, J= 8.0 Hz, 1H), 7.43-7.30 (m, 2H), 7.27-7.11 (m, 3H), 7.04 (br d, J= 2.3 Hz, 1H), 5.41-5.19 (m, 1H), 4.71-4.38 (m, 3H), 4.31-4.16 (m, 2H), 3.61 (br s, 3H), 3.20 (br d, J= 15.6 Hz, 3H), 3.00 (br d, J= 4.8 Hz, 1H), 2.48-1.80 (m, 10H), 1.58-1.46 (m, 1H), 0.79-0.51 (m, 4H). 實施例 55:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-乙烯基喹唑啉-7-基)萘-2-醇 LCMS (ESI): [M+H] + = 598.5. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.72 (br d, J = 8.0 Hz, 1H), 7.43-7.30 (m, 2H), 7.27-7.11 (m, 3H), 7.04 (br d, J = 2.3 Hz, 1H), 5.41-5.19 (m, 1H), 4.71-4.38 (m, 3H), 4.31-4.16 (m, 2H), 3.61 (br s, 3H), 3.20 (br d, J = 15.6 Hz, 3H), 3.00 (br d, J = 4.8 Hz, 1H), 2.48-1.80 (m, 10H), 1.58-1.46 (m, 1H), 0.79-0.51 (m, 4H). Example 55 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)naphthalen-2-ol
LCMS (ESI): [M+H] +=583.9. 1H NMR (400 MHz, CD 3OD) δ ppm 8.05 (s, 1H), 7.74 (d, J= 8.3 Hz, 1H), 7.40 (ddd, J= 8.2, 6.2, 1.8 Hz, 1H), 7.28-7.14 (m, 3H), 7.00-6.93 (m, 1H), 6.23 (dd, J= 17.6, 11.0 Hz, 1H), 5.69 (d, J= 17.6 Hz, 1H), 5.42-5.21 (m, 1H), 5.07 (d, J= 11.3 Hz, 1H), 4.61-4.46 (m, 2H), 4.34-4.16 (m, 2H), 3.71-3.59 (m, 4H), 3.27-3.17 (m, 3H), 3.06-2.97 (m, 1H), 2.39-2.11 (m, 3H), 2.04-1.94 (m, 2H), 1.86 (m, 5H). 實施例 56:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-6-乙炔基-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)萘-2-醇 LCMS (ESI): [M+H] + =583.9. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.05 (s, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.40 (ddd, J = 8.2, 6.2, 1.8 Hz, 1H), 7.28-7.14 (m, 3H), 7.00-6.93 (m, 1H), 6.23 (dd, J = 17.6, 11.0 Hz, 1H), 5.69 (d, J = 17.6 Hz, 1H), 5.42-5.21 (m, 1H), 5.07 (d, J = 11.3 Hz, 1H), 4.61-4.46 (m, 2H), 4.34-4.16 (m, 2H), 3.71-3.59 (m, 4H), 3.27-3.17 (m, 3H), 3.06-2.97 (m, 1H), 2.39-2.11 (m, 3H), 2.04-1.94 (m, 2H), 1.86 (m, 5H). Example 56 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol
LCMS (ESI): [M+H] += 582.2; 1H NMR (400 MHz, CD 3OD) δ ppm 8.04 (s, 1H), 7.74 (br d, J= 8.0 Hz, 1H), 7.40 (br t, J= 7.3 Hz, 1H), 7.30-7.15 (m, 3H), 7.07 (br s, 1H), 5.43-5.20 (m, 1H), 4.55 (br s, 2H), 4.32-4.19 (m, 2H), 3.63 (br s, 4H), 3.27-3.15 (m, 4H), 3.02 (br d, J= 5.0 Hz, 1H), 2.41-2.09 (m, 4H), 2.00 (br s, 2H), 1.84 (br s, 4H). 實施例 57:4-(6-胺基-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)萘-2-醇 LCMS (ESI): [M+H] + = 582.2; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.04 (s, 1H), 7.74 (br d, J = 8.0 Hz, 1H), 7.40 (br t, J = 7.3 Hz, 1H), 7.30-7.15 (m, 3H), 7.07 (br s, 1H), 5.43-5.20 (m, 1H), 4.55 (br s, 2H), 4.32-4.19 (m, 2H), 3.63 (br s, 4H), 3.27-3.15 (m, 4H), 3.02 (br d, J = 5.0 Hz, 1H), 2.41-2.09 (m, 4H), 2.00 (br s, 2H), 1.84 (br s, 4H). Example 57 : 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol
實施例 57的製備參考 實施例 50的合成途徑,第一步向叔丁基(1R,5S)-3-(8-氟-6-碘-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯 與二苯甲酮亞胺,碳酸銫,三(二伸苄基丙酮)二鈀,(±)-2,2-雙(二苯膦基)-1,1-聯萘反應得到相應的中間體,然後經過類似反應,製備得到4-(6-胺基-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)萘-2-醇。LCMS (ESI): [M+H] += 573.6; 1H NMR (400 MHz, DMSO- d 6) δ ppm 8.56 (br s, 1H), 7.78 (d, J= 8.5 Hz, 1H), 7.45 (t, J= 7.7 Hz, 1H), 7.38-7.28 (m, 2H), 7.26-7.13 (m, 2H), 7.10 (s, 1H), 5.56-5.30 (m, 1H), 4.60-4.36 (m, 4H), 3.99 (br s, 2H), 3.74-3.50 (m, 5H), 3.24 (br s, 1H), 2.60-2.37 (m, 2H), 2.28 (br d, J= 8.3 Hz, 1H), 2.23-2.11 (m, 4H), 2.06 (br d, J= 8.5 Hz, 3H). 實施例 58 :4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-6-(二甲胺基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)萘-2-醇 Preparation of Example 57 Referring to the synthetic route of Example 50 , the first step is to react tert-butyl (1R, 5S)-3-(8-fluoro-6-iodo-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate with benzophenone imine, cesium carbonate, tris(dibenzylacetone)dipalladium, (±) -2,2-bis(diphenylphosphino)-1,1-binaphthyl to obtain the corresponding intermediate, and then a similar reaction was performed to prepare 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol. LCMS (ESI): [M+H] + = 573.6; 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.56 (br s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.38-7.28 (m, 2H), 7.26-7.13 (m, 2H), 7.10 (s, 1H), 5.56-5.30 (m, 1H), 4.60-4.36 (m, 4H), 3.99 (br s, 2H), 3.74-3.71 (m, 5H), 3.24 (br s, 1H), 2.60-2.37 (m, 2H), 2.28 (br d, J = 8.3 Hz, 1H), 2.23-2.11 (m, 4H), 2.06 (br d, J = 8.5 Hz, 3H). Example 58 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol
第一步:化合物叔丁基(1R,5S)-3-(6-胺基-8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(100 mg,0.15 mmol)溶於乙酸(5 mL),20 oC下向反應液加入多聚甲醛(45.0 mg,1.52 mmol)和氰基硼氫化鈉(29.0 mg,0.46 mmol)。反應在20 oC下攪拌16小時。在0 oC下將反應混合物倒入0.1 M的氫氧化鈉溶液(20 mL)中,用二氯甲烷(10 mL * 2)萃取。將合併的有機相用無水硫酸鈉乾燥,過濾,減壓濃縮。殘留物用快速管柱層析純化(矽膠,0-20%梯度的乙酸乙酯/石油醚)得到得到黃色固體化合物叔丁基(1R,5S)-3-(6-(二甲基胺基)-8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(80.0 mg,0.12 mmol,產率77%)。LCMS (ESI): [M+H] += 686.2. Step 1: Compound tert-butyl (1R, 5S)-3-(6-amino-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.15 mmol) was dissolved in acetic acid (5 mL), and paraformaldehyde (45.0 mg, 1.52 mmol) and sodium cyanoborohydride (29.0 mg, 0.46 mmol) were added to the reaction solution at 20 o C. The reaction was stirred at 20 o C for 16 hours. The reaction mixture was poured into 0.1 M sodium hydroxide solution (20 mL) at 0 o C and extracted with dichloromethane (10 mL * 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate/petroleum ether) to obtain a yellow solid compound tert-butyl (1R, 5S)-3-(6-(dimethylamino)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80.0 mg, 0.12 mmol, yield 77%). LCMS (ESI): [M+H] + = 686.2.
第二步:將化合物叔丁基(1R,5S)-3-(6-(二甲基胺基)-8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(80.0 mg,0.12 mmol)和 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(40 mg,0.25 mmol)溶於四氫呋喃(1.00 mL),在0 oC下,慢慢往反應液中加入叔丁醇鈉(27.9 mg,0.29 mmol),反應在20 oC攪拌16小時。反應液減壓濃縮,殘留物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷)得到黃色油狀化合物叔丁基(1R,5S)-3-(6-(二甲基胺基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)萘-1-基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(純度80%,75.0 mg,0.08 mmol,產率69%)。LCMS (ESI): [M+H] += 745.3. Step 2: Dissolve the compound tert-butyl (1R,5S)-3-(6-(dimethylamino)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80.0 mg, 0.12 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (40 mg, 0.25 mmol) in tetrahydrofuran (1.00 mL). At 0 o C, sodium tert-butoxide (27.9 mg, 0.29 mmol) was slowly added to the reaction solution. The reaction was stirred at 20 o C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow oily compound tert-butyl (1R, 5S)-3-(6-(dimethylamino)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 80%, 75.0 mg, 0.08 mmol, yield 69%). LCMS (ESI): [M+H] + = 745.3.
第三步:將化合物叔丁基(1R,5S)-3-(6-(二甲基胺基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)萘-1-基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(純度80%,70.0 mg,0.07 mmol)溶於乙腈(1.00 mL),20 oC下加入氯化氫(4 M的二氧六環溶液,376 uL,1.50 mmol)。反應在20 oC下攪拌2小時。反應液減壓濃縮。殘留物溶於三乙胺(400 uL)的二甲亞碸溶液(2 mL),用製備型HPLC純化,得到黃色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-6-(二甲胺基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)萘-2-醇(9.19 mg,0.01 mmol,產率17%)。LCMS (ESI): [M+H] += 601.5. 1H NMR (400 MHz, CD 3OD) δ ppm 7.74 (d, J= 8.1 Hz, 1H), 7.44-7.37 (m, 2H), 7.29-7.17 (m, 3H), 7.12 (d, J= 1.5 Hz, 1H), 5.51-5.28 (m, 1H), 4.54 (br s, 2H), 4.47-4.32 (m, 2H), 3.98-3.64 (m, 4H), 3.53-3.37 (m, 3H), 3.20-3.11 (m, 1H), 2.51 (s, 6H), 2.42-1.95 (m, 10 H). 實施例 59:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(吡咯烷-1-基)喹唑啉-7-基)萘-2-醇 Step 3: Dissolve the compound tert-butyl (1R,5S)-3-(6-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 80%, 70.0 mg, 0.07 mmol) in acetonitrile (1.00 mL), and add hydrogen chloride (4 M dioxane solution, 376 uL, 1.50 mmol) at 20 o C. The reaction was stirred at 20 o C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in a dimethyl sulfoxide solution (2 mL) of triethylamine (400 uL) and purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol (9.19 mg, 0.01 mmol, yield 17%). LCMS (ESI): [M+H] + = 601.5. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.74 (d, J = 8.1 Hz, 1H), 7.44-7.37 (m, 2H), 7.29-7.17 (m, 3H), 7.12 (d, J = 1.5 Hz, 1H), 5.51-5.28 (m, 1H), 4.54 (br s, 2H), 4.47-4.32 (m, 2H), 3.98-3.64 (m, 4H), 3.53-3.37 (m, 3H), 3.20-3.11 (m, 1H), 2.51 (s, 6H), 2.42-1.91 (m, 10 H). Example 59 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-(pyrrolidin-1-yl)quinazolin-7-yl)naphthalen-2-ol
實施例 59參考 實施例 58的合成途徑, 按照類似方法合成製備得到; LCMS (ESI): [M+H] += 627.3; 1H NMR (400 MHz, CD 3OD) δ ppm 7.74 (br d, J= 8.0 Hz, 1H), 7.45-7.36 (m, 2H), 7.28-7.16 (m, 2H), 7.08 (s, 1H), 6.96 (s, 1H), 5.48-5.23 (m, 1H), 4.51 (br t, J= 11.3 Hz, 2H), 4.41-4.25 (m, 2H), 3.83 (br s, 2H), 3.67-3.57 (m, 2H), 3.41 (br d, J= 5.0 Hz, 3H), 3.17-3.05 (m, 1H), 2.87 (br d, J= 6.5 Hz, 2H), 2.73 (br d, J= 5.8 Hz, 2H), 2.45-2.21 (m, 3H), 2.10-1.94 (m, 7H), 1.66 (br s, 4H). 實施例 60:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(1-甲基-1H-吡唑-4-基)喹唑啉-7-基)萘-2-醇 Example 59 was prepared by a similar method with reference to the synthetic route of Example 58 ; LCMS (ESI): [M+H] + = 627.3; 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.74 (br d, J = 8.0 Hz, 1H), 7.45-7.36 (m, 2H), 7.28-7.16 (m, 2H), 7.08 (s, 1H), 6.96 (s, 1H), 5.48-5.23 (m, 1H), 4.51 (br t, J = 11.3 Hz, 2H), 4.41-4.25 (m, 2H), 3.83 (br s, 2H), 3.67-3.57 (m, 2H), 3.41 (br d, J = 5.0 Hz, 3H), 3.17-3.05 (m, 1H), 2.87 (br d, J = 6.5 Hz, 2H), 2.73 (br d, J = 5.8 Hz, 2H), 2.45-2.21 (m, 3H), 2.10-1.94 (m, 7H), 1.66 (br s, 4H). Example 60 :4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(1-methyl-1H-pyrazol-4-yl)quinazolin-7-yl)naphthalen-2-ol
LCMS (ESI): [M+H] += 638.3; 1H NMR (400 MHz, CD 3OD) δ ppm 7.80 (s, 1H), 7.62 (d, J= 8.3 Hz, 1H), 7.27 (t, J= 7.5 Hz, 1H), 7.18-7.09 (m, 2H), 7.08-6.97 (m, 2H), 6.87 (d, J= 2.3 Hz, 1H), 6.79 (s, 1H), 5.36-5.09 (m, 1H), 4.65-4.41 (m, 2H), 4.23-4.07 (m, 2H), 3.73-3.44 (m, 7H), 3.19-3.03 (m, 3H), 3.00-2.85 (m, 1H), 2.44-2.12 (m, 2H), 2.04 (br d, J= 8.3 Hz, 1H), 1.94-1.70 (m, 7H). 實施例 61:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(1-甲基-1H-咪唑-2-基)喹唑啉-7-基)萘-2-醇 LCMS (ESI): [M+H] + = 638.3; 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.80 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.18-7.09 (m, 2H), 7.08-6.97 (m, 2H), 6.87 (d, J = 2.3 Hz, 1H), 6.79 (s, 1H), 5.36-5.09 (m, 1H), 4.65-4.41 (m, 2H), 4.23-4.07 (m, 2H), 3.73-3.44 (m, 7H), 3.19-3.03 (m, 3H), 3.00-2.85 (m, 1H), 2.44-2.12 (m, 2H), 2.04 (br d, J = 8.3 Hz, 1H), 1.94-1.70 (m, 7H). Example 61 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(1-methyl-1H-imidazol-2-yl)quinazolin-7-yl)naphthalen-2-ol
LCMS (ESI): [M+H] += 638.2。 1H NMR (400 MHz, CD 3OD) δ ppm 7.94 (s, 1H), 7.67 (d, J= 8.2 Hz, 1H), 7.58-7.49 (m, 1H), 7.37 (t, J= 7.4 Hz, 1H), 7.25-7.17 (m, 1H), 7.13 (d, J= 2.1 Hz, 1H), 6.87 (s, 2H), 6.78 (s, 1H), 5.42-5.22 (m, 1H), 4.66-4.54 (m, 2H), 4.35-4.22 (m, 2H), 3.69-3.56 (m, 4H), 3.27-3.14 (m, 3H), 3.08-2.98 (m, 1H), 2.94 (s, 3H), 2.42-2.10 (m, 3H), 2.06-1.74 (m, 7H). 實施例 62:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(氧雜環丁烷-3-基)喹唑啉-7-基)萘-2-醇 LCMS (ESI): [M+H] + = 638.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.94 (s, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.58-7.49 (m, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.25-7.17 (m, 1H), 7.13 (d, J = 2.1 Hz, 1H), 6.87 (s, 2H), 6.78 (s, 1H), 5.42-5.22 (m, 1H), 4.66-4.54 (m, 2H), 4.35-4.22 (m, 2H), 3.69-3.56 (m, 4H), 3.27-3.14 (m, 3H), 3.08-2.98 (m, 1H), 2.94 (s, 3H), 2.42-2.10 (m, 3H), 2.06-1.74 (m, 7H). Example 62 : 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(oxacyclobutane-3-yl)quinazolin-7-yl)naphthalen-2-ol
LCMS (ESI): [M+H] += 614.1. 1H NMR (400 MHz, CD 3OD) δ ppm 8.55 (br s, 1H), 7.84-7.78 (m, 1H), 7.76-7.71 (m, 1H), 7.41 (br t, J=7.5 Hz, 1H), 7.34 (br d, J=8.5 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 7.21-7.16 (m, 1H), 7.01 (d, J=2.1 Hz, 1H), 5.49-5.34 (m, 1H), 5.25-5.04 (m, 2H), 4.65 (br d, J=11.9 Hz, 2H), 4.43 (br dd, J=4.3, 15.5 Hz, 2H), 4.01-3.85 (m, 2H), 3.78-3.70 (m, 4H), 3.47 (br d, J=17.9 Hz, 4H), 3.23-3.12 (m, 1H), 2.54-2.24 (m, 3H), 2.19-2.09 (m, 3H), 1.99 (br s, 4H). 實施例 63:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-6-(3,6-二氫-2H-吡喃-4-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)萘-2-醇 LCMS (ESI): [M+H] + = 614.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.55 (br s, 1H), 7.84-7.78 (m, 1H), 7.76-7.71 (m, 1H), 7.41 (br t, J =7.5 Hz, 1H), 7.34 (br d, J =8.5 Hz, 1H), 7.22 (d, J =2.4 Hz, 1H), 7.21-7.16 (m, 1H), 7.01 (d, J =2.1 Hz, 1H), 5.49-5.34 (m, 1H), 5.25-5.04 (m, 2H), 4.65 (br d, J =11.9 Hz, 2H), 4.43 (br dd, J =4.3, 15.5 Hz, 2H), 4.01-3.85 (m, 2H), 3.78-3.70 (m, 4H), 3.47 (br d, J =17.9 Hz, 4H), 3.23-3.12 (m, 1H), 2.54-2.24 (m, 3H), 2.19-2.09 (m, 3H), 1.99 (br s, 4H). Example 63 :4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol
LCMS (ESI): [M+H] += 640.2. 1H NMR (400 MHz, CD 3OD) δ ppm 7.77-7.66 (m, 2H), 7.45-7.31 (m, 2H), 7.26-7.15 (m, 2H), 7.02 (d, J= 2.4 Hz, 1H), 5.71 (br s, 1H), 5.45-5.23 (m, 1H), 4.63-4.51 (m, 2H), 4.35-4.20 (m, 2H), 4.08-3.94 (m, 2H), 3.71-3.60 (m, 4H), 3.43-3.34 (m, 2H), 3.29-3.15 (m, 3H), 3.03 (td, J= 9.4, 5.8 Hz, 1H), 2.42-2.13 (m, 3H), 2.08-1.80 (m, 8H), 1.66 (br d, J= 17.1 Hz, 1H). 實施例 64 :4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(四氫-2H-吡喃-4-基)喹唑啉-7-基)萘-2-醇 LCMS (ESI): [M+H] + = 640.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.77-7.66 (m, 2H), 7.45-7.31 (m, 2H), 7.26-7.15 (m, 2H), 7.02 (d, J = 2.4 Hz, 1H), 5.71 (br s, 1H), 5.45-5.23 (m, 1H), 4.63-4.51 (m, 2H), 4.35-4.20 (m, 2H), 4.08-3.94 (m, 2H), 3.71-3.60 (m, 4H), 3.43-3.34 (m, 2H), 3.29-3.15 (m, 3H), 3.03 (td, J = 9.4, 5.8 Hz, 1H), 2.42-2.13 (m, 3H), 2.08-1.80 (m, 8H), 1.66 (br d, J = 17.1 Hz, 1H). Example 64 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(tetrahydro-2H-pyran-4-yl)quinazolin-7-yl)naphthalen-2-ol
第一步:在20 oC下,向叔丁基(1R,5S)-3-(6-(3,6-二氫-2H-吡喃-4-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羥基萘-1-基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(100 mg,0.14 mmol)的乙酸乙酯(2.00 mL)中加入濕鈀碳(10%含量,7.19 mg,0.01 mmol)。將該溶液在15psi的氫氣氛圍下20 oC攪拌16小時。反應液過濾,濾液減壓濃縮得到黃色油狀化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羥基萘-1-基)-6-(四氫-2H-吡喃-4-基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(100 mg,0.13 mmol,產率99%)。LCMS (ESI): [M+H] += 742.3. Step 1: To a solution of tert-butyl (1R,5S)-3-(6-(3,6-dihydro-2H-pyran-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.14 mmol) in ethyl acetate (2.00 mL) was added wet palladium on carbon (10% content, 7.19 mg, 0.01 mmol) at 20°C. The solution was stirred at 20 ° C for 16 hours under 15 psi of hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily compound tert-butyl (1R, 5S)-3-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-(tetrahydro-2H-pyran-4-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.13 mmol, yield 99%). LCMS (ESI): [M+H] + = 742.3.
第二步:在20 oC下,向叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羥基萘-1-基)-6-(四氫-2H-吡喃-4-基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(100 mg,0.13 mmol)的乙腈(1.50 mL)溶液中加入氯化氫(4 M的二氧六環溶液,673 uL,2.69 mmol)。將該溶液在20 oC攪拌1小時。溶液用三乙胺(200 uL)淬滅並濃縮。殘餘物透過製備型HPLC純化,得到白色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(四氫-2H-吡喃-4-基)喹唑啉-7-基)萘-2-醇(二甲酸鹽,9.84 mg,15.2 umol,產率11%)。LCMS (ESI): [M+H] += 642.3。 1H NMR (400 MHz, CD 3OD) δ ppm 8.48 (br s, 2H), 7.84-7.70 (m, 2H), 7.43 (ddd, J= 8.2, 5.1, 2.9 Hz, 1H), 7.28 (d, J= 2.4 Hz, 1H), 7.22-7.12 (m, 2H), 7.07-6.95 (m, 1H), 5.59-5.36 (m, 1H), 4.66 (br d, J= 12.9 Hz, 2H), 4.59-4.49 (m, 2H), 4.08 (br s, 2H), 3.87 (br d, J= 9.9 Hz, 3H), 3.84-3.75 (m, 2H), 3.71-3.63 (m, 2H), 3.20-3.09 (m, 1H), 2.99 (br t, J= 10.9 Hz, 1H), 2.64-1.98 (m, 12H), 1.86-1.69 (m, 3H), 1.48 (br d, J= 12.3 Hz, 1H). 實施例 65:1-(4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羥基萘-1-基)喹唑啉-6-基)-3,6-二氫吡啶-1(2H)-基)乙-1-酮 Step 2: To a solution of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-(tetrahydro-2H-pyran-4-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.13 mmol) in acetonitrile (1.50 mL) was added hydrogen chloride (4 M in dioxane, 673 uL, 2.69 mmol) at 20 °C. The solution was stirred at 20 ° C for 1 hour. The solution was quenched with triethylamine (200 uL) and concentrated. The residue was purified by preparative HPLC to give a white solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(tetrahydro-2H-pyran-4-yl)quinazolin-7-yl)naphthalen-2-ol (dicarboxylate, 9.84 mg, 15.2 umol, yield 11%). LCMS (ESI): [M+H] + = 642.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.48 (br s, 2H), 7.84-7.70 (m, 2H), 7.43 (ddd, J = 8.2, 5.1, 2.9 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.22-7.12 (m, 2H), 7.07-6.95 (m, 1H), 5.59-5.36 (m, 1H), 4.66 (br d, J = 12.9 Hz, 2H), 4.59-4.49 (m, 2H), 4.08 (br s, 2H), 3.87 (br d, J = 9.9 Hz, 3H), 3.84-3.75 (m, 3H), 3.71-3.63 (m, 2H), 3.20-3.09 (m, 1H), 2.99 (br t, J = 10.9 Hz, 1H), 2.64-1.98 (m, 12H), 1.86-1.69 (m, 3H), 1.48 (br d, J = 12.3 Hz, 1H). Example 65 :1-(4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one
LCMS (ESI): [M+H] += 681.3. 1H NMR (400 MHz, CD 3OD) δ ppm 8.53 (br s, 1H), 7.79-7.71 (m, 2H), 7.42 (t, J= 7.5 Hz, 1H), 7.35 (br t, J= 8.6 Hz, 1H), 7.28-7.19 (m, 2H), 7.06-7.02 (m, 1H), 5.78-5.67 (br s, 1H), 5.58-5.37 (m, 1H), 4.76-4.65 (m, 2H), 4.59-4.46 (m, 2H), 4.01 (br s, 2H), 3.98-3.79 (m, 4H), 3.77-3.52 (m, 3H), 3.32-3.00 (m, 3H), 2.62-2.38 (m, 2H), 2.31 (m, 1H), 2.26-2.16 (m, 2H), 2.04 (m, 5H), 1.98-1.89 (m, 4H), 1.85-1.68 (m, 1H). LCMS (ESI): [M+H] + = 681.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.53 (br s, 1H), 7.79-7.71 (m, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.35 (br t, J = 8.6 Hz, 1H), 7.28-7.19 (m, 2H), 7.06-7.02 (m, 1H), 5.78-5.67 (br s, 1H), 5.58-5.37 (m, 1H), 4.76-4.65 (m, 2H), 4.59-4.46 (m, 2H), 4.01 (br s, 2H), 3.98-3.79 (m, 4H), 3.77-3.52 (m, 3H), 3.32-3.00 (m, 3H), 2.62-2.38 (m, 2H), 2.31 (m, 1H), 2.26-2.16 (m, 2H), 2.04 (m, 5H), 1.98-1.89 (m, 4H), 1.85-1.68 (m, 1H).
以下實施例 66 透過實施例 64 的合成途徑方法進行製備: 實施例 66:1-(4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羥基萘-1-基)喹唑啉-6-基)呱啶-1-基)乙-1-酮 The following Example 66 was prepared by the synthetic route method of Example 64 : Example 66 : 1-(4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)piperidin-1-yl)ethan-1-one
LCMS (ESI): [M+H] += 683.4. 1H NMR (400 MHz, CD 3OD) δ ppm 7.78 (d, J= 8.3 Hz, 1H), 7.69 (s, 1H), 7.49-7.35 (m, 1H), 7.28 (d, J= 2.2 Hz, 1H), 7.21 (s, 2H), 7.05 (s, 1H), 5.43-5.24 (m, 1H), 4.66-4.43 (m, 4H), 4.35-4.19 (m, 2H), 3.90-3.80 (m, 1H), 3.75-3.62 (m, 4H), 3.30-3.16 (m, 3H), 3.04 (dt, J= 5.6, 9.3 Hz, 1H), 2.84-2.48 (m, 2H), 2.43-2.11 (m, 4H), 2.06 (d, J= 8.9 Hz, 3H), 2.04-1.97 (m, 2H), 1.96-1.82 (m, 6H), 1.68-1.61 (m, 2H). 實施例 67:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)萘-2-醇 LCMS (ESI): [M+H] + = 683.4. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.78 (d, J = 8.3 Hz, 1H), 7.69 (s, 1H), 7.49-7.35 (m, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.21 (s, 2H), 7.05 (s, 1H), 5.43-5.24 (m, 1H), 4.66-4.43 (m, 4H), 4.35-4.19 (m, 2H), 3.90-3.80 (m, 1H), 3.75-3.62 (m, 4H), 3.24-3.16 (m, 3H), 3.03 (dt, J = 11.1 Hz, 7.83 5.6, 9.3 Hz, 1H), 2.84-2.48 (m, 2H), 2.43-2.11 (m, 4H), 2.06 (d, J = 8.9 Hz, 3H), 2.04-1.97 (m, 2H), 1.96-1.82 (m, 6H), 1.68-1.61 (m, 2H). Example 67 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)naphthalen-2-ol
第一步:將2-胺基-4-溴-3-氟苯甲酸(3.50 g,14.96 mmol)和尿素(8.98 g,149.56 mmol)的混合物在200 oC下攪拌2小時。冷卻到100 oC,加入水(30 mL),攪拌1小時,過濾,固體產物再加入水(25 mL),在50 oC下攪拌1小時,過濾,固體產物再加入水(25 mL),在25 oC下攪拌12小時,過濾,固體真空乾燥,得到粗產物化合物7-溴-8-氟喹唑啉-2,4(1H,3H)-二酮(4.40 g),其為灰色固體。LCMS (ESI): [M+H] += 258.8. Step 1 : Stir a mixture of 2-amino-4-bromo-3-fluorobenzoic acid (3.50 g, 14.96 mmol) and urea (8.98 g, 149.56 mmol) at 200 ° C for 2 hours. Cool to 100 ° C, add water (30 mL), stir for 1 hour, filter, add water (25 mL) to the solid product, stir at 50 ° C for 1 hour, filter, add water (25 mL) to the solid product, stir at 25 ° C for 12 hours, filter, and vacuum dry the solid to obtain the crude product compound 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (4.40 g) as a gray solid. LCMS (ESI): [M+H] + = 258.8.
第二步:在0 oC下,向7-溴-8-氟喹唑啉-2,4(1H,3H)-二酮(4.40 g,14.96 mmol)的濃硫酸溶液(35 mL)中加入硝酸鉀(3.43 g,33.97 mmol)。將該溶液在0 oC攪拌1小時。混合物倒入水(35 mL)中,過濾出固體,真空乾燥,得到灰色固體化合物7-溴-8-氟-6-硝基喹唑啉-2,4(1H,3H)-二酮(3.50 g,11.51 mol,產率77%)。LCMS (ESI): [M+H] += 303.9. 1H NMR (400 MHz, DMSO- d 6) δ ppm 11.98 (br s, 1H), 11.85 (s, 1H), 8.34 (s, 1H). Step 2 : Potassium nitrate (3.43 g, 33.97 mmol) was added to a concentrated sulfuric acid solution (35 mL) of 7-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (4.40 g, 14.96 mmol) at 0 ° C. The solution was stirred at 0 ° C for 1 hour. The mixture was poured into water (35 mL), the solid was filtered out, and vacuum dried to obtain a gray solid compound 7-bromo-8-fluoro-6-nitroquinazoline-2,4(1H,3H)-dione (3.50 g, 11.51 mol, yield 77%). LCMS (ESI): [M+H] + = 303.9. 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 11.98 (br s, 1H), 11.85 (s, 1H), 8.34 (s, 1H).
第三步:在0 oC下,向7-溴-8-氟-6-硝基喹唑啉-2,4(1H,3H)-二酮(1.50 g,4.93 mmol)和氧氯化磷(3.67 mL,39.47 mmol)的甲苯(22 mL)溶液中,加入二異丙基乙胺(2.45 mL,14.80 mmol)。將混合物在氮氣保護下100 oC下攪拌3小時。混合物旋轉乾燥,加入乙酸乙酯(30 mL),然後加入冰和冰水(30 mL),使用乙酸乙酯(20 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥,得到粗產物化合物7-溴-2,4-二氯-8-氟-6-硝基喹唑啉(1.55 g),其為灰色固體。LCMS (ESI): [M+H] += 341.8. Step 3 : At 0 ° C, diisopropylethylamine (2.45 mL, 14.80 mmol) was added to a toluene (22 mL) solution of 7-bromo-8-fluoro-6-nitroquinazoline-2,4 (1H, 3H)-dione (1.50 g, 4.93 mmol) and phosphorus oxychloride (3.67 mL, 39.47 mmol). The mixture was stirred at 100 ° C for 3 hours under nitrogen protection. The mixture was rotated to dryness, ethyl acetate (30 mL) was added, and then ice and ice water (30 mL) were added, and ethyl acetate (20 mL * 3) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotated to dryness to obtain the crude product compound 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (1.55 g) as a gray solid. LCMS (ESI): [M+H] + = 341.8.
第四步:向7-溴-2,4-二氯-8-氟-6-硝基喹唑啉(1.55 g,4.55 mmol)和3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(965 mg,4.55 mmol)的二氯甲烷(15 mL)溶液中,加入三乙胺(1.84 mL,13.20 mmol)。將混合物在25 oC下攪拌2小時。加入水(10 mL),使用二氯甲烷(15 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。殘留物用快速管柱層析(矽膠,0-30%梯度的乙酸乙酯/石油醚)純化,得到灰色固體化合物 (1R,5S)-3-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(590 mg,1.14 mmol,產率25%)。LCMS (ESI): [M+H] += 517.7. Step 4 : Add triethylamine (1.84 mL, 13.20 mmol) to a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (1.55 g, 4.55 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (965 mg, 4.55 mmol) in dichloromethane (15 mL). Stir the mixture at 25 ° C for 2 hours. Add water (10 mL), extract with dichloromethane (15 mL * 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and spin dry the filtrate. The residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain a gray solid compound (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (590 mg, 1.14 mmol, yield 25%). LCMS (ESI): [M+H] + = 517.7.
第五步:向 (1R,5S)-3-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(590 mg,1.14 mmol)的三氟乙醇(4.4 mL)溶液中,加入二異丙基乙胺(944 uL,5.71 mmol)。將混合物在70 oC下攪拌12小時,然後旋轉乾燥。殘留物用快速管柱層析(矽膠,0-30%梯度的乙酸乙酯/石油醚)純化,得到黃色固體化合物叔丁基(1R,5S)-3-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(500 mg,0.86 mmol,產率75%)。LCMS (ESI): [M+H] += 581.7. Step 5 : To a solution of (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (590 mg, 1.14 mmol) in trifluoroethanol (4.4 mL) was added diisopropylethylamine (944 uL, 5.71 mmol). The mixture was stirred at 70 ° C for 12 hours and then rotary dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether) to obtain a yellow solid compound tert-butyl (1R, 5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.86 mmol, yield 75%). LCMS (ESI): [M+H] + = 581.7.
第六步:手套箱中,向叔丁基(1R,5S)-3-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(150 mg,0.26 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)萘-2-醇(90.8 mg,0.34 mmol)的二氧六環(3 mL)溶液中,加入磷酸鉀(1.5 M的水溶液,517 uL,0.78 mmol)和甲磺酸[正丁基二(1-金剛烷基)膦](2-胺基-1,1'-聯苯-2-基)鈀(II)(18.8 mg,0.03 mmol)。將混合物在氮氣保護下100 oC攪拌12小時。過濾,濾液用水(3 mL)稀釋,使用乙酸乙酯(5 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。殘留物用快速管柱層析(矽膠,0-30%梯度的乙酸乙酯/石油))純化,得到棕色固體化合物叔丁基(1R,5S)-3-(8-氟-7-(3-羥基萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(110 mg,1.21 mmol,產率66%)。LCMS (ESI): [M+H] += 644.1. Step 6 : In a glove box, potassium phosphate (1.5 M aqueous solution, 517 uL, 0.78 mmol) and [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonate (18.8 mg, 0.03 mmol) were added to a solution of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.26 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (90.8 mg, 0.34 mmol) in dioxane (3 mL). mmol). The mixture was stirred at 100 ° C for 12 hours under nitrogen protection. Filtered, the filtrate was diluted with water (3 mL), extracted with ethyl acetate (5 mL * 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 1.21 mmol, yield 66%). LCMS (ESI): [M+H] + = 644.1.
第七步:向叔丁基(1R,5S)-3-(8-氟-7-(3-羥基萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(100 mg,0.16 mmol)和 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(49.5 mg,0.31 mmol)的四氫呋喃(2 mL)溶液中,加入叔丁醇鈉(22.4 mg,0.23 mmol)。將混合物在氮氣保護下20 oC攪拌4小時。加入水(5 mL)稀釋,使用乙酸乙酯(10 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥,得到粗產物化合物叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羥基萘-1-基)-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(150 mg),其為棕色油狀液體。LCMS (ESI): [M+H] += 703.4. Step 7 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.16 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (49.5 mg, 0.31 mmol) in tetrahydrofuran (2 mL) was added sodium tert-butoxide (22.4 mg, 0.23 mmol). The mixture was stirred at 20 ° C for 4 hours under nitrogen protection. Add water (5 mL) to dilute, extract with ethyl acetate (10 mL * 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and spin dry the filtrate to obtain the crude product compound tert-butyl (1R, 5S)-3-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg) as a brown oily liquid. LCMS (ESI): [M+H] + = 703.4.
第八步:在20 oC下,向叔丁基(1R,5S)-3-(8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羥基萘-1-基)-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(145 mg,0.14 mmol)rongye的乙腈(2 mL)溶液中加入氯化氫(4 M的二氧六環溶液,722 uL,2.89 mmol)。將該溶液在20 oC攪拌1小時。溶液用氮氣吹乾。殘餘物透過製備型HPLC純化,得到黃色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)萘-2-醇(甲酸鹽,5.95 mg,0.98 umol,產率7%)。LCMS (ESI): [M+H] += 603.1. 1H NMR (400 MHz, CD 3OD) δ ppm 8.66 (s, 1H), 8.53 (br s, 1H), 7.77 (d, J= 8.3 Hz, 1H), 7.44 (t, J= 7.5 Hz, 1H), 7.36-7.25 (m, 2H), 7.25-7.16 (m, 1H), 7.02 (d, J= 2.3 Hz, 1H), 5.55-5.32 (m, 1H), 4.72 (br d, J= 12.0 Hz, 2H), 4.53-4.38 (m, 2H), 4.01-3.79 (m, 4H), 3.50 (br d, J= 12.5 Hz, 3H), 3.26-3.16 (m, 1H), 2.58-2.21 (m, 3H), 2.20-2.09 (m, 2H), 2.08-1.90 (m, 5H). 實施例 68:4-(6-胺基-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇 Step 8 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3 - hydroxynaphthalen-1-yl)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (145 mg, 0.14 mmol) in acetonitrile (2 mL) was added hydrogen chloride (4 M in dioxane, 722 uL, 2.89 mmol) at 20 °C. The solution was stirred at 20 ° C for 1 hour. The solution was blown dry with nitrogen. The residue was purified by preparative HPLC to give a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)naphthalen-2-ol (formate salt, 5.95 mg, 0.98 umol, 7% yield). LCMS (ESI): [M+H] + = 603.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.66 (s, 1H), 8.53 (br s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.36-7.25 (m, 2H), 7.25-7.16 (m, 1H), 7.02 (d, J = 2.3 Hz, 1H), 5.55-5.32 (m, 1H), 4.72 (br d, J = 12.0 Hz, 2H), 4.53-4.38 (m, 2H), 4.01-3.79 (m, 4H), 3.54 (br d, J = 12.0 Hz, 1H). J = 12.5 Hz, 3H), 3.26-3.16 (m, 1H), 2.58-2.21 (m, 3H), 2.20-2.09 (m, 2H), 2.08-1.90 (m, 5H). Example 68 : 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
第一步:在手套箱中,向叔丁基(1R,5S)-3-(7-溴-6-((二苯基伸甲基)胺基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(500 mg,0.70 mmol)和 ((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(466 mg,0.91 mmol)的1,4-二氧六環(10.0 mL)溶液中加入磷酸鉀(1.5 M的水溶液,1.40 mL,2.10 mmol)和甲磺酸[正丁基二(1-金剛烷基)膦](2-胺基-1,1'-聯苯-2-基)鈀(II)(51 mg,0.07 mmol)。將混合物氮氣保護下在100 oC下攪拌2小時。加入水(10 mL),使用二氯甲烷(10 mL)萃取3次,無水硫酸鈉乾燥,過濾旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-30%梯度的乙酸乙酯/石油醚)。得到黃色固體化合物叔丁基(1R,5S)-3-(6-((二苯基伸甲基)胺基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(650 mg,1.21 mmol,產率91%)。LCMS (ESI): [M+H] += 1020.7. Step 1 : In a glove box, potassium phosphate (1.5 M in water, 1.40 mL, 2.10 mL) was added to a solution of tert-butyl (1R,5S)-3-(7-bromo-6-((diphenylmethyl)amino)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.70 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (466 mg, 0.91 mmol) in 1,4-dioxane (10.0 mL). mmol) and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl)palladium (II) (51 mg, 0.07 mmol). The mixture was stirred at 100 ° C for 2 hours under nitrogen protection. Water (10 mL) was added, extracted with dichloromethane (10 mL) three times, dried over anhydrous sodium sulfate, filtered and rotated to dryness. The residue was purified by flash column chromatography (silica gel, 0-30% gradient ethyl acetate/petroleum ether). The yellow solid compound tert-butyl (1R, 5S)-3-(6-((diphenylmethyl)amino)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (650 mg, 1.21 mmol, yield 91%) was obtained. LCMS (ESI): [M+H] + = 1020.7.
第二步:向叔丁基(1R,5S)-3-(6-((二苯基伸甲基)胺基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(150 mg, 0.15 mmol)和 ((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲醇(60 mg, 0.29 mmol)的四氫呋喃(3.00 mL)溶液中,加入叔丁醇鈉(42.0 mg,0.44 mmol)。將混合物氮氣保護下在60 oC下攪拌12小時。反應液用水(3 mL)稀釋,用乙酸乙酯(10 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,旋轉乾燥。得到粗產物化合物叔丁基(1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-6-((二苯基伸甲基)胺基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(250 mg),其為黃色油狀化合物。LCMS (ESI): [M+2H] 2+/2 = 562.7. Step 2 : To a solution of tert-butyl (1R,5S)-3-(6-((diphenylmethyl)amino)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.15 mmol) and ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methanol (60 mg, 0.29 mmol) in tetrahydrofuran (3.00 mL) was added sodium tert-butoxide (42.0 The mixture was stirred at 60 ° C for 12 hours under nitrogen protection. The reaction solution was diluted with water (3 mL), extracted with ethyl acetate (10 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried. The crude product compound tert-butyl (1R, 5S)-3-(2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethyl)amino)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg) was obtained as a yellow oily compound. LCMS (ESI): [M+2H] 2+ /2 = 562.7.
第三步:向叔丁基(1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-6-((二苯基伸甲基)胺基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(230 mg,0.20 mmol)的N,N-二甲基甲醯胺(4.6 mL)溶液中加入氟化銫(249 mg,1.64 mmol)。將混合物氮氣保護下在20 oC下攪拌1小時。加入水(10 mL),使用乙酸乙酯(15 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-7%梯度的甲醇/二氯甲烷),得到棕色固體化合物叔丁基(1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-6-((二苯基伸甲基)胺基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(170 mg,0.17 mmol,產率86%)。LCMS (ESI): [M+H] += 967.5. Step 3 : To a solution of tert-butyl (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethyl)amino)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.20 mmol) in N,N-dimethylformamide (4.6 mL) was added cesium fluoride (249 mg, 1.64 mmol). The mixture was stirred at 20 ° C for 1 hour under nitrogen protection. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-7% gradient of methanol/dichloromethane) to give brown solid compound tert-butyl (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethyl)amino)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 0.17 mmol, yield 86%). LCMS (ESI): [M+H] + = 967.5.
第四步:在0 oC下,向叔丁基(1R,5S)-3-(2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-6-((二苯基伸甲基)胺基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(45.0 mg,0.05 mmol)的乙腈(540 uL)溶液中,加入氯化氫(4 M的二氧六環溶液,270 uL,1.08 mmol)。將混合物氮氣保護下在25 oC下攪拌1小時。混合物用氮氣吹乾,加入乙腈(0.50 mL)攪拌,混合物用離心機離心,分離掉液體,固體用製備型HPLC純化,得到黃色固體化合物4-(6-胺基-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇(4.99 mg,0.75 umol,產率16%)。LCMS (ESI): [M+H] += 659.2. 1H NMR (400 MHz, CD 3OD) δ ppm 7.85 (dd, J= 5.8, 9.0 Hz, 1H), 7.40-7.24 (m, 2H), 7.11 (d, J= 2.3 Hz, 1H), 7.04 (s, 1H), 4.66 (br s, 1H), 4.47-4.35 (m, 2H), 4.34-4.25 (m, 2H), 3.67 (br s, 2H), 3.51 (br t, J= 13.9 Hz, 2H), 3.20 (br d, J= 3.0 Hz, 2H), 2.87 (br d, J= 12.0 Hz, 1H), 2.79-2.62 (m, 1H), 2.31 (br dd, J= 5.4, 13.0 Hz, 1H), 2.17 (br dd, J= 5.5, 11.1 Hz, 1H), 2.09-1.75 (m, 8H), 1.57-1.36 (m, 2H). 實施例 69: 4-(6-胺基-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5,6-二氟萘-2-醇 Step 4 : To a solution of tert-butyl (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethyl)amino)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45.0 mg, 0.05 mmol) in acetonitrile (540 uL) at 0 °C was added hydrogen chloride (4 M in dioxane, 270 uL, 1.08 mmol). The mixture was stirred at 25 ° C for 1 hour under nitrogen protection. The mixture was dried with nitrogen, acetonitrile (0.50 mL) was added and stirred, the mixture was centrifuged, the liquid was separated, and the solid was purified by preparative HPLC to obtain a yellow solid compound 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (4.99 mg, 0.75 umol, yield 16%). LCMS (ESI): [M+H] + = 659.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.85 (dd, J = 5.8, 9.0 Hz, 1H), 7.40-7.24 (m, 2H), 7.11 (d, J = 2.3 Hz, 1H), 7.04 (s, 1H), 4.66 (br s, 1H), 4.47-4.35 (m, 2H), 4.34-4.25 (m, 2H), 3.67 (br s, 2H), 3.51 (br t, J = 13.9 Hz, 2H), 3.20 (br d, J = 3.0 Hz, 2H), 2.87 (br d, J = 12.0 Hz, 1H), 2.79-2.62 (m, 1H), 2.31 (br dd, J = 5.4, 13.0 Hz, 1H), 2.17 (br dd, J = 5.5, 11.1 Hz, 1H), 2.09-1.75 (m, 8H), 1.57-1.36 (m, 2H). Example 69 : 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
第一步:在手套箱中,向叔丁基(1R,5S)-3-(7-溴-6-((二苯基伸甲基)胺基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(112 mg,0.16 mmol)和2-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(50.0 mg,0.14 mmol)的二氧六環(2.10 mL)溶液中,加入磷酸鉀(1.5 M的水溶液,286 uL,0.43 mmol)和甲磺酸[正丁基二(1-金剛烷基)膦](2-胺基-1,1'-聯苯-2-基)鈀(II)(10.0 mg,0.014 mmol)。將混合物氮氣保護下在100 oC下攪拌2小時。冷卻至室溫後加入水(2.00 mL)稀釋,用乙酸乙酯(10 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-30%梯度的四氫呋喃/石油醚)。得到黃色固體化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-6-((二苯基伸甲基)胺基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(105 mg,1.21 mmol,產率86%)。LCMS (ESI): [M+H] += 858.4. Step 1 : In a glove box, potassium phosphate (1.5 M in water, 286 μL, 0.43 μL) was added to a solution of tert-butyl (1R,5S)-3-(7-bromo-6-((diphenylmethyl)amino)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (112 mg, 0.16 mmol) and 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (50.0 mg, 0.14 mmol) in dioxane (2.10 mL). mmol) and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (10.0 mg, 0.014 mmol). The mixture was stirred at 100 ° C for 2 hours under nitrogen protection. After cooling to room temperature, water (2.00 mL) was added for dilution, and it was extracted with ethyl acetate (10 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotated to dryness. The residue was purified by flash column chromatography (silica gel, 0-30% gradient tetrahydrofuran/petroleum ether). The yellow solid compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-((diphenylmethyl)amino)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, 1.21 mmol, yield 86%) was obtained. LCMS (ESI): [M+H] + = 858.4.
第二步:將叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-6-((二苯基伸甲基)胺基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(100 mg, 0.12 mmol)和 ((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲醇(36.0 mg, 0.17 mmol)溶於四氫呋喃(1 mL),加入叔丁醇鈉(34.0 mg,0.35 mmol)。將混合物氮氣保護下在60 oC下攪拌5小時。加入水(3 mL),使用乙酸乙酯(10 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥,得到粗產物化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-6-((二苯基伸甲基)胺基)-8-氟喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(170 mg),其為棕色油狀液體。LCMS (ESI): [M+H] += 961.5. Step 2 : Dissolve tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-((diphenylmethyl)amino)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.12 mmol) and ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methanol (36.0 mg, 0.17 mmol) in tetrahydrofuran (1 mL) and add sodium tert-butoxide (34.0 mg, 0.35 mmol). The mixture was stirred at 60 ° C for 5 hours under nitrogen. Water (3 mL) was added, and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried to give a crude product compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethyl)amino)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg) as a brown oily liquid. LCMS (ESI): [M+H] + = 961.5.
第三步:在0 oC下,向叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-6-((二苯基伸甲基)胺基)-8-氟喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(45.0 mg,0.05 mmol)的乙腈(200 uL)溶液中,加入氯化氫(4 M的二氧六環溶液,234 uL,0.94 mmol)。將混合物氮氣保護下在25 oC下攪拌1小時。混合物用氮氣吹乾,加入乙腈(0.5 mL)攪拌,混合物用離心機離心,分離掉液體,固體用製備型HPLC純化,得到黃色固體化合物4-(6-胺基-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-7-基)-5,6-二氟萘-2-醇(6.13 mg,0.94 umol,產率20%)。LCMS (ESI): [M+H] += 653.2. 1H NMR (400 MHz, CD 3OD) δ ppm 7.61 (br dd, J= 4.5, 8.8 Hz, 1H), 7.46-7.34 (m, 1H), 7.31 (s, 1H), 7.12 (br s, 2H), 4.44 (br d, J= 12.3 Hz, 2H), 4.39-4.27 (m, 2H), 3.74 (br s, 2H), 3.54 (br d, J= 12.0 Hz, 2H), 3.40-3.35 (m, 1H), 3.23 (br d, J= 5.3 Hz, 1H), 2.90 (br d, J= 12.3 Hz, 1H), 2.83-2.66 (m, 1H), 2.33 (br dd, J= 6.0, 13.4 Hz, 1H), 2.24-2.13 (m, 1H), 2.10-1.79 (m, 8H), 1.57-1.35 (m, 2H). 實施例 70:N-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-6-基)甲磺醯胺 Step 3 : To a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-6-((diphenylmethylamino)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45.0 mg, 0.05 mmol) in acetonitrile (200 uL) at 0 o C was added hydrogen chloride (4 M in dioxane, 234 uL, 0.94 mmol). The mixture was stirred at 25 o C for 1 hour under nitrogen protection. The mixture was dried with nitrogen, acetonitrile (0.5 mL) was added and stirred, the mixture was centrifuged, the liquid was separated, and the solid was purified by preparative HPLC to obtain a yellow solid compound 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (6.13 mg, 0.94 umol, yield 20%). LCMS (ESI): [M+H] + = 653.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.61 (br dd, J = 4.5, 8.8 Hz, 1H), 7.46-7.34 (m, 1H), 7.31 (s, 1H), 7.12 (br s, 2H), 4.44 (br d, J = 12.3 Hz, 2H), 4.39-4.27 (m, 2H), 3.74 (br s, 2H), 3.54 (br d, J = 12.0 Hz, 2H), 3.40-3.35 (m, 1H), 3.23 (br d, J = 5.3 Hz, 1H), 2.96 (br d, J = 12.3 Hz, 1H), 2.83-2.66 (m, 1H), 2.33 (br dd, J = 6.0, 13.4 Hz, 1H), 2.24-2.13 (m, 1H), 2.10-1.79 (m, 8H), 1.57-1.35 (m, 2H). Example 70 :N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-6-yl)methanesulfonamide
第一步:向叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-6-((二苯基伸甲基)胺基)-8-氟喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(90.0 mg,0.09 mmol)和乙酸鈉(76.8 mg,0.94 mmol)的甲醇(1.44 mL)和四氫呋喃(0.45 mL)溶液中,加入鹽酸羥胺(42.3 mg,0.61 mmol)。將混合物氮氣保護下在20 oC下攪拌16小時。加水(5 mL)稀釋,使用二氯甲烷(10 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾旋轉乾燥,得到粗產物化合物叔丁基(1R,5S)-3-(6-胺基-7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(90.0 mg),其為棕色油狀液體。LCMS (ESI): [M+H] += 797.5. Step 1 : To a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-6-((diphenylmethylamino)-8-fluoroquinazolin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (90.0 mg, 0.09 mmol) and sodium acetate (76.8 mg, 0.94 mmol) in methanol (1.44 mL) and tetrahydrofuran (0.45 mL) was added hydroxylamine hydrochloride (42.3 mg, 0.61 mmol). The mixture was stirred at 20 ° C for 16 hours under nitrogen protection. Water (5 mL) was added for dilution, and dichloromethane (10 mL * 3) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered and rotary dried to obtain the crude product compound tert-butyl (1R, 5S)-3-(6-amino-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg) as a brown oily liquid. LCMS (ESI): [M+H] + = 797.5.
第二步:向叔丁基(1R,5S)-3-(6-胺基-7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(40.0 mg,0.05 mmol)和三乙胺(112 uL,0.80 mmol)的二氯甲烷(1.6 mL)溶液中,在0 oC下加入甲磺酸酐(35.0 mg,0.20 mmol)。將混合物氮氣保護下在20 oC下攪拌1小時。旋轉乾燥,加入氨氣(7M的甲醇溶液,2.00 mL,14.0 mmol),將混合物在25 oC下攪拌4小時,旋轉乾燥。得到粗產物化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-(甲磺醯基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(44.0 mg),其為棕色固體。LCMS (ESI): [M+2H] 2+/2 = 874.8. Step 2 : To a solution of tert-butyl (1R,5S)-3-(6-amino-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40.0 mg, 0.05 mmol) and triethylamine (112 uL, 0.80 mmol) in dichloromethane (1.6 mL) was added methanesulfonic anhydride (35.0 mg, 0.20 mmol) at 0 ° C. The mixture was stirred at 20 ° C for 1 hour under nitrogen protection. The mixture was dried by rotary evaporation, and ammonia (7M in methanol, 2.00 mL, 14.0 mmol) was added, and the mixture was stirred at 25 ° C for 4 hours and dried by rotary evaporation. The crude product compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-(methylsulfonyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (44.0 mg) was obtained as a brown solid. LCMS (ESI): [M+2H] 2+ /2 = 874.8.
第三步:向叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-(甲磺醯基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(40.0 mg,0.05 mmol)的乙腈(800 uL)溶液中,在0 oC下加入氯化氫(4 M的二氧六環溶液,229 uL,0.91 mmol)。將混合物在20 oC下攪拌1小時。混合物用氮氣吹乾。殘留物用製備型HPLC純化,得到黃色固體化合物N-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-6-基)甲磺醯胺(4.30 mg,0.58 umol,產率13%)。LCMS (ESI): [M+H] += 731.2. 1H NMR (400 MHz, CD 3OD) δ ppm 7.96 (d, J= 1.3 Hz, 1H), 7.60 (br dd, J= 4.1, 8.5 Hz, 1H), 7.45-7.34 (m, 1H), 7.31 (s, 1H), 7.11 (d, J= 2.1 Hz, 1H), 4.58-4.42 (m, 2H), 4.40-4.28 (m, 2H), 3.69 (br s, 2H), 3.59 (br dd, J= 12.8, 18.1 Hz, 2H), 3.34 (br s, 1H), 3.22-3.09 (m, 1H), 2.85 (d, J= 12.1 Hz, 1H), 2.79-2.64 (m, 4H), 2.30 (br dd, J= 5.6, 12.8 Hz, 1H), 2.16 (br dd, J= 5.3, 10.9 Hz, 1H), 2.05-1.77 (m, 8H), 1.54-1.35 (m, 2H). Step 3 : To a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-(methylsulfonyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40.0 mg, 0.05 mmol) in acetonitrile (800 uL) was added hydrogen chloride (4 M in dioxane, 229 uL, 0.91 mmol) at 0 ° C. The mixture was stirred at 20 ° C for 1 hour. The mixture was blown dry with nitrogen. The residue was purified by preparative HPLC to give a yellow solid compound N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-6-yl)methanesulfonamide (4.30 mg, 0.58 umol, yield 13%). LCMS (ESI): [M+H] + = 731.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.96 (d, J = 1.3 Hz, 1H), 7.60 (br dd, J = 4.1, 8.5 Hz, 1H), 7.45-7.34 (m, 1H), 7.31 (s, 1H), 7.11 (d, J = 2.1 Hz, 1H), 4.58-4.42 (m, 2H), 4.40-4.28 (m, 2H), 3.69 (br s, 2H), 3.59 (br dd, J = 12.8, 18.1 Hz, 2H), 3.34 (br s, 1H), 3.22-3.09 (m, 1H), 2.85 (d, J = 12.1 Hz, 1H), 2.79-2.64 (m, 4H), 2.30 (br dd, J = 5.6, 12.8 Hz, 1H), 2.16 (br dd, J = 5.3, 10.9 Hz, 1H), 2.05-1.77 (m, 8H), 1.54-1.35 (m, 2H).
實施例 71~ 實施例 73 參考 實施例 70 的合成途徑按照類似反應條件製備得到。 實施例 71:N-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟喹唑啉-6-基)甲磺醯胺 Examples 71 to 73 were prepared by referring to the synthetic route of Example 70 under similar reaction conditions. Example 71 : N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-6-yl)methanesulfonamide
LCMS (ESI): [M+H] += 737.2. 1H NMR (400MHz, MeOD) δ ppm 7.96 (s, 1H), 7.87 (dd, J= 5.8, 9.2 Hz, 1H), 7.40-7.26 (m, 2H), 7.12 (d, J= 2.5 Hz, 1H), 4.63 (br s, 1H), 4.51-4.42 (m, 2H), 4.39-4.28 (m, 2H), 3.70 (br s, 2H), 3.63-3.51 (m, 2H), 3.35-3.33 (m, 1H), 3.23-3.12 (m, 1H), 2.85 (br d, J= 12.0 Hz, 1H), 2.80 (s, 3H), 2.76-2.64 (m, 1H), 2.38-2.23 (m, 1H), 2.21-2.11 (m, 1H), 2.06-1.76 (m, 8H), 1.52-1.38 (m, 2H). 實施例 72: N-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟喹唑啉-6-基)乙醯胺 LCMS (ESI): [M+H] + = 737.2. 1 H NMR (400 MHz, MeOD) δ ppm 7.96 (s, 1H), 7.87 (dd, J = 5.8, 9.2 Hz, 1H), 7.40-7.26 (m, 2H), 7.12 (d, J = 2.5 Hz, 1H), 4.63 (br s, 1H), 4.51-4.42 (m, 2H), 4.39-4.28 (m, 2H), 3.70 (br s, 2H), 3.63-3.51 (m, 2H), 3.35-3.33 (m, 1H), 3.23-3.12 (m, 1H), 2.85 (br d, J = 12.0 Hz, 1H), 2.80 (s, 3H), 2.76-2.64 (m, 1H), 2.38-2.23 (m, 1H), 2.21-2.11 (m, 1H), 2.06-1.76 (m, 8H), 1.52-1.38 (m, 2H). Example 72 : N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoroquinazolin-6-yl)acetamide
LCMS (ESI): [M+H] += 695.4. 1H NMR (400 MHz, CD 3OD) δ ppm 8.50 (s, 1H), 8.27 (s, 1H), 7.63 (br dd, J= 4.4, 8.7 Hz, 1H), 7.47-7.37 (m, 1H), 7.34 (s, 1H), 7.07 (d, J= 1.7 Hz, 1H), 4.70 (br d, J= 12.7 Hz, 1H), 4.65-4.52 (m, 3H), 4.13 (br s, 2H), 3.93-3.73 (m, 2H), 3.68 (br dd, J= 6.2, 12.2 Hz, 1H), 3.52 (br dd, J= 5.7, 11.1 Hz, 1H), 3.17 (br d, J= 12.2 Hz, 1H), 2.98 (br d, J= 8.8 Hz, 1H), 2.48 (br dd, J= 5.0, 13.9 Hz, 1H), 2.37-2.25 (m, 1H), 2.24-2.09 (m, 6H), 2.08-1.94 (m, 2H), 1.90 (s, 3H), 1.69-1.54 (m, 2H). 實施例 73:N-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟喹唑啉-6-基)乙醯胺 LCMS (ESI): [M+H] + = 695.4. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.50 (s, 1H), 8.27 (s, 1H), 7.63 (br dd, J = 4.4, 8.7 Hz, 1H), 7.47-7.37 (m, 1H), 7.34 (s, 1H), 7.07 (d, J = 1.7 Hz, 1H), 4.70 (br d, J = 12.7 Hz, 1H), 4.65-4.72 (m, 3H), 4.13 (br s, 2H), 3.93-3.73 (m, 2H), 3.68 (br dd, J = 6.2, 12.2 Hz, 1H), 3.52 (br dd, J = 5.7, 11.1 Hz, 1H), 3.17 (br d, J = 12.2 Hz, 1H), 2.98 (br d, J = 8.8 Hz, 1H), 2.48 (br dd, J = 5.0, 13.9 Hz, 1H), 2.37-2.25 (m, 1H), 2.24-2.09 (m, 6H), 2.08-1.94 (m, 2H), 1.90 (s, 3H), 1.69-1.54 (m, 2H). Example 73 :N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-6-yl)acetamide
LCMS (ESI): [M+H] += 701.3. 1H NMR (400 MHz, CD 3OD) δ ppm 8.48 (s, 1H), 8.37 (s, 1H), 7.88 (dd, J= 5.7, 9.1 Hz, 1H), 7.42-7.26 (m, 2H), 7.06 (d, J= 2.4 Hz, 1H), 4.67-4.59 (m, 2H), 4.57-4.45 (m, 3H), 4.05 (br s, 2H), 3.79-3.59 (m, 2H), 3.59-3.51 (m, 1H), 3.40 (br dd, J= 5.5, 10.3 Hz, 1H), 3.08 (br d, J= 12.4 Hz, 1H), 2.97-2.83 (m, 1H), 2.47-2.34 (m, 1H), 2.29-2.17 (m, 2H), 2.16-1.99 (m, 6H), 1.92 (s, 4H), 1.64-1.46 (m, 2H). 實施例 74:1-(7-(3-胺基-7,8-二氟異喹啉-1-基)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮 LCMS (ESI): [M+H] + = 701.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.48 (s, 1H), 8.37 (s, 1H), 7.88 (dd, J = 5.7, 9.1 Hz, 1H), 7.42-7.26 (m, 2H), 7.06 (d, J = 2.4 Hz, 1H), 4.67-4.59 (m, 2H), 4.57-4.45 (m, 3H), 4.05 (br s, 2H), 3.79-3.71 (m, 2H), 3.59-3.51 (m, 1H), 3.40 (br dd, J = 5.5, 10.3 Hz, 1H), 3.08 (br d, J = 12.4 Hz, 1H), 2.97-2.83 (m, 1H), 2.47-2.34 (m, 1H), 2.29-2.17 (m, 2H), 2.16-1.99 (m, 6H), 1.92 (s, 4H), 1.64-1.46 (m, 2H). Example 74 : 1-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one
第一步:在氮氣氣氛下,向叔丁基(1R,5S)-3-(6-乙醯-7-溴-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(250 mg,0.43 mmol)的二氧六環(5 mL)溶液中加入7,8-二氟-1-(三丁基甲錫烷基)異喹啉-3-胺(244 mg,0.52 mmol),碘化亞銅(25 mg,0.13 mmol),氯化鋰(46 mg,1.08 mmol)和四(三苯基膦)鈀(100 mg,0.09 mmol)。反應液在氮氣氣氛和120 oC下攪拌16小時。混合物旋轉乾燥,得到的粗產物透過快速管柱層析(矽膠,0-50%梯度乙酸乙酯/石油醚)純化得到黃色固體化合物叔丁基(1R,5S)-3-(6-乙醯基-7-(3-胺基-7,8-二氟異喹啉-1-基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(130 mg,0.2 mmol,產率46%)。LCMS (ESI): [M+H] += 677.1. Step 1 : To a solution of tert-butyl (1R,5S)-3-(6-acetyl-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.43 mmol) in dioxane (5 mL) was added 7,8-difluoro-1-(tributylmethylstannyl)isoquinolin-3-amine (244 mg, 0.52 mmol), cuprous iodide (25 mg, 0.13 mmol), lithium chloride (46 mg, 1.08 mmol) and tetrakis(triphenylphosphine)palladium (100 mg, 0.09 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 120 ° C for 16 hours under nitrogen atmosphere. The mixture was rotary dried and the crude product was purified by flash column chromatography (silica gel, 0-50% gradient ethyl acetate/petroleum ether) to give a yellow solid compound tert-butyl (1R,5S)-3-(6-acetyl-7-(3-amino-7,8-difluoroisoquinolin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.2 mmol, yield 46%). LCMS (ESI): [M+H] + = 677.1.
第二步:向叔丁基(1R,5S)-3-(6-乙醯基-7-(3-胺基-7,8-二氟異喹啉-1-基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(80 mg,0.12 mmol)的四氫呋喃(800 uL)溶液中加入4A分子篩(80 mg),叔丁醇鈉(17 mg,0.18 mmol)和 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(28 mg,0.18 mmol)。將反應在20 oC攪拌2小時。混合物用水(2 mL)稀釋並用乙酸乙酯(2 mL*3)萃取,合併的有機相用飽和食鹽水(2 mL)洗滌,無水硫酸鎂乾燥,過濾,濾液濃縮,殘餘物透過快速管柱層析(矽膠,0-10%梯度甲醇/二氯甲烷)純化得到棕色固體化合物叔丁基(1R,5S)-3-(6-乙醯基-7-(3-胺基-7,8-二氟異喹啉-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(24.50 mg,33 umol,產率28%)。LCMS (ESI): [M+H] += 736.1. Step 2 : To a solution of tert-butyl (1R,5S)-3-(6-acetyl-7-(3-amino-7,8-difluoroisoquinolin-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 0.12 mmol) in tetrahydrofuran (800 uL) was added 4A molecular sieves (80 mg), sodium tert-butoxide (17 mg, 0.18 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (28 mg, 0.18 mmol). The reaction was stirred at 20 ° C for 2 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL*3). The combined organic phases were washed with saturated brine (2 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(6-acetyl-7-(3-amino-7,8-difluoroisoquinolin-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (24.50 mg, 33 umol, yield 28%). LCMS (ESI): [M+H] + = 736.1.
第三步:向叔丁基(1R,5S)-3-(6-乙醯基-7-(3-胺基-7,8-二氟異喹啉-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(24.50 mg,33 umol)的乙腈(500 uL)溶液中加入氯化氫(4M的二氧六環溶液,166 uL,0.67 mmol)。將反應在20 oC攪拌1小時。溶液濃縮後溶於乙腈(1 mL),用三乙胺淬滅中和至pH=7並濃縮。殘餘物透過製備型HPLC純化,得到黃色固體化合物1-(7-(3-胺基-7,8-二氟異喹啉-1-基)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮(甲酸鹽,13.08 mg,20.6 umol,產率62%)。LCMS (ESI): [M+H] += 636.3。 1H NMR (400MHz, CD 3OD) δ ppm 8.53 (br s, 1H), 8.44 (s, 1H), 7.53-7.44 (m, 2H), 6.90 (d, J= 2.3 Hz, 1H), 5.56-5.41 (m, 1H), 4.80-4.72 (m, 2H), 4.59-4.50 (m, 2H), 4.07 (br s, 2H), 3.93 (dt, J= 5.5, 14.1 Hz, 2H), 3.77-3.57 (m, 3H), 3.32-3.26 (m, 1H), 2.63-2.33 (m, 6H), 2.25-2.03 (m, 7H). 實施例 75:1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮 Step 3 : To a solution of tert-butyl (1R,5S)-3-(6-acetyl-7-(3-amino-7,8-difluoroisoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (24.50 mg, 33 umol) in acetonitrile (500 uL) was added hydrogen chloride (4M in dioxane, 166 uL, 0.67 mmol). The reaction was stirred at 20 ° C for 1 hour. The solution was concentrated and dissolved in acetonitrile (1 mL), quenched with triethylamine to pH = 7 and concentrated. The residue was purified by preparative HPLC to give a yellow solid compound 1-(7-(3-amino-7,8-difluoroisoquinolin-1-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one (formate salt, 13.08 mg, 20.6 umol, yield 62%). LCMS (ESI): [M+H] + = 636.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.53 (br s, 1H), 8.44 (s, 1H), 7.53-7.44 (m, 2H), 6.90 (d, J = 2.3 Hz, 1H), 5.56-5.41 (m, 1H), 4.80-4.72 (m, 2H), 4.59-4.50 (m, 2H), 4.07 (br s, 2H), 3.93 (dt, J = 5.5, 14.1 Hz, 2H), 3.77-3.57 (m, 3H), 3.32-3.26 (m, 1H), 2.63-2.33 (m, 6H), 2.25-2.03 (m, 7H). Example 75 :1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one
第一步:在25 oC下,化合物叔丁基(1S,5R)-3-[7-溴-8-氟-6-碘-2-(2,2,2-三氟乙氧基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(1.00 g,1.51 mmol)溶於二氧六環(20.0 mL),加入三丁基(1-乙氧基乙烯基)錫烷(510 mg,1.41 mmol),氮氣氛圍下加入四(三苯基膦)鈀(170 mg,0.15 mmol),100 oC攪拌16小時。反應液冷卻至室溫,減壓濃縮,殘留物用快速管柱層析純化(矽膠,0-30%梯度的乙酸乙酯/石油醚)得白色固體化合物叔丁基(1R,5S)-3-(7-溴-6-(1-乙氧基乙烯基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(680 mg,1.12 mmol,產率74%)。LCMS (ESI): [M+H] += 605.0. Step 1 : At 25 ° C, the compound tert-butyl (1S, 5R)-3-[7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 1.51 mmol) was dissolved in dioxane (20.0 mL), tributyl (1-ethoxyvinyl) tin ane (510 mg, 1.41 mmol) was added, and tetrakis(triphenylphosphine)palladium (170 mg, 0.15 mmol) was added under nitrogen atmosphere, and stirred at 100 ° C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a white solid compound tert-butyl (1R, 5S)-3-(7-bromo-6-(1-ethoxyvinyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (680 mg, 1.12 mmol, yield 74%). LCMS (ESI): [M+H] + = 605.0.
第二步:在25 oC下,將化合物叔丁基(1R,5S)-3-(7-溴-6-(1-乙氧基乙烯基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(400 mg,0.66 mmol)和鹽酸(2 M的水溶液,1.65 mL,3.30 mmol)加入到四氫呋喃(8.00 mL)中,反應系統20 oC反應2小時。加入飽和碳酸氫鈉調節pH到7,用乙酸乙酯(4 mL*3)萃取。有機相減壓濃縮,殘留物用快速管柱層析純化(矽膠,0-15%梯度的乙酸乙酯/石油醚)得白色固體化合物叔丁基(1R,5S)-3-(6-乙醯基-7-溴-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(220 mg,0.38 mmol,產率58%)。LCMS (ESI): [M+H] += 579.2. Step 2 : At 25 ° C, add the compound tert-butyl (1R, 5S)-3-(7-bromo-6-(1-ethoxyvinyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.66 mmol) and hydrochloric acid (2 M aqueous solution, 1.65 mL, 3.30 mmol) to tetrahydrofuran (8.00 mL), and react at 20 ° C for 2 hours. Add saturated sodium bicarbonate to adjust the pH to 7, and extract with ethyl acetate (4 mL*3). The organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-15% gradient of ethyl acetate/petroleum ether) to obtain a white solid compound tert-butyl (1R, 5S)-3-(6-acetyl-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 0.38 mmol, yield 58%). LCMS (ESI): [M+H] + = 579.2.
第三步:在25 oC下,叔丁基(1R,5S)-3-(6-乙醯基-7-溴-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(90.0 mg,0.16 mmol),2-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(81.9 mg,0.23 mmol)和碳酸鈉(49.6 mg,0.47 mmol)加入到二氧六環(1.80 mL)和水(360 uL)中,氮氣氛圍下加入四(三苯基膦)鈀(10.2 mg,0.02 mmol),反應系統80 oC反應2小時。冷卻至室溫,減壓濃縮,殘留物用快速管柱層析純化(矽膠,0-30%梯度的乙酸乙酯/石油醚)得黃色固體化合物叔丁基(1R,5S)-3-(6-乙醯基-7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(60% 純度,140 mg,0.12 mmol,產率75%)。LCMS (ESI): [M+H] += 721.4. Step 3 : At 25 ° C, tert-butyl (1R,5S)-3-(6-acetyl-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg, 0.16 mmol), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (81.9 mg, 0.23 mmol) and sodium carbonate (49.6 mg, 0.47 mmol) were added to dioxane (1.80 mL) and water (360 uL). Tetrakis(triphenylphosphine)palladium (10.2 mg, 0.02 mmol) was added under nitrogen atmosphere. The reaction system was heated to 80 °C . C for 2 hours. Cool to room temperature, concentrate under reduced pressure, and purify the residue by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a yellow solid compound tert-butyl (1R, 5S)-3-(6-acetyl-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60% purity, 140 mg, 0.12 mmol, yield 75%). LCMS (ESI): [M+H] + = 721.4.
第四步:在25 oC下,叔丁基(1R,5S)-3-(6-乙醯基-7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(60% 純度,83.0 mg,0.07 mmol)加入到四氫呋喃(200 uL)中,加入 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(12.1 mg,0.08 mmol)和叔丁醇鈉(20.0 mg,0.21 mmol),反應系統20 oC反應2小時。加入水(1 mL),乙酸乙酯(1 mL * 3)萃取,有機相減壓濃縮得粗產物化合物叔丁基(1R,5S)-3-(6-乙醯基-7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(50% 純度,100 mg),其為黃色油狀液體。LCMS (ESI): [M+H] += 780.4. Step 4 : At 25 ° C, tert-butyl (1R, 5S)-3-(6-acetyl-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60% purity, 83.0 mg, 0.07 mmol) was added to tetrahydrofuran (200 uL), ((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (12.1 mg, 0.08 mmol) and sodium tert-butoxide (20.0 mg, 0.21 mmol) were added, and the reaction system was reacted at 20 ° C for 2 hours. Water (1 mL) was added, and the mixture was extracted with ethyl acetate (1 mL * 3). The organic phase was concentrated under reduced pressure to obtain the crude product compound tert-butyl (1R, 5S)-3-(6-acetyl-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50% purity, 100 mg), which was a yellow oily liquid. LCMS (ESI): [M+H] + = 780.4.
第五步:在25 oC下,將叔丁基(1R,5S)-3-(6-乙醯基-7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(50% 純度,90.0 mg,0.06 mmol)加入到乙腈(1.00 mL)中,加入鹽酸(4 M的二氧六環溶液,216 uL,0.86 mmol),反應系統20 oC反應2小時。減壓濃縮,殘留物溶於乙腈(1 mL)並用三乙胺調節pH到7-8。混合物透過製備型HPLC純化,得到白色固體化合物1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮(甲酸鹽,4.03 mg,6.35 umol,產率11%)。LCMS (ESI): [M+H] += 635.9。 1H NMR (400 MHz, CD 3OD) δ ppm 8.54 (br s, 1H), 8.32 (s, 1H), 7.61 (br dd, J= 4.4, 8.4 Hz, 1H), 7.44-7.32 (m, 1H), 7.28 (br s, 1H), 6.93 (s, 1H), 5.55-5.30 (m, 1H), 4.76-4.62 (m, 2H), 4.48 (q, J= 11.5 Hz, 2H), 4.07-3.77 (m, 4H), 3.61-3.37 (m, 3H), 3.27-3.19 (m, 1H), 2.55-2.26 (m, 6H), 2.18 (br d, J= 6.1 Hz, 2H), 2.02 (m, 5H). 實施例 75A 和實施例 75B :1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-((S)-7,8-二氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮和 1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-((R)-7,8-二氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮 Step 5 : At 25 ° C, tert-butyl (1R, 5S)-3-(6-acetyl-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50% purity, 90.0 mg, 0.06 mmol) was added to acetonitrile (1.00 mL), and hydrochloric acid (4 M dioxane solution, 216 uL, 0.86 mmol) was added, and the reaction system was reacted at 20 ° C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (1 mL) and the pH was adjusted to 7-8 with triethylamine. The mixture was purified by preparative HPLC to give a white solid compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one (formate salt, 4.03 mg, 6.35 umol, yield 11%). LCMS (ESI): [M+H] + = 635.9. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.54 (br s, 1H), 8.32 (s, 1H), 7.61 (br dd, J = 4.4, 8.4 Hz, 1H), 7.44-7.32 (m, 1H), 7.28 (br s, 1H), 6.93 (s, 1H), 5.55-5.30 (m, 1H), 4.76-4.62 (m, 2H), 4.48 (q, J = 11.5 Hz, 2H), 4.07-3.77 (m, 4H), 3.61-3.37 (m, 3H), 3.27-3.19 (m, 1H), 2.55-2.26 (m, 6H), 2.18 (br d, J = 6.1 Hz, 2H), 2.02 (m, 5H). Example 75A and Example 75B : 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-((S)-7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one and 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((R)-7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one
實施例 75經SFC分離(管柱:DAICEL CHIRALPAK AD(250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/乙醇;梯度:B相保持40%;流速:80毫升/分鐘)得到目標產物。 Example 75 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia/ethanol; gradient: phase B was maintained at 40%; flow rate: 80 ml/min) to obtain the target product.
異構物 1, 實施例 75A:LCMS (ESI): [M+H] += 636.4; SFC分析(層析管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;B相在2分鐘內從5%到40%,保持40%的B相1.2分鐘,保持5%的B相0.8分鐘;流速:4毫升/分鐘):掌性管柱出峰位置為 1.787 min; 1H NMR (400 MHz, MeOD) δ ppm 8.33 (s, 1H), 7.60 (br dd, J= 4.2, 8.3 Hz, 1H), 7.41-7.34 (m, 1H), 7.30-7.26 (m, 1H), 6.92 (d, J= 1.7 Hz, 1H), 5.47-5.24 (m, 1H), 4.57 (br d, J= 6.0 Hz, 2H), 4.40-4.29 (m, 2H), 3.83-3.59 (m, 4H), 3.45-3.35 (m, 3H), 3.10 (br d, J= 5.0 Hz, 1H), 2.43-2.13 (m, 6H), 2.06 (br dd, J= 6.8, 10.9 Hz, 2H), 1.98-1.85 (m, 5H). Isomer 1, Example 75A : LCMS (ESI): [M+H] + = 636.4; SFC analysis (chromatographic column: Chiralpak AD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; phase B is increased from 5% to 40% in 2 minutes, 40% phase B is maintained for 1.2 minutes, and 5% phase B is maintained for 0.8 minutes; flow rate: 4 ml/min): the palmar column peak position is 1.787 min; 1 H NMR (400 MHz, MeOD) δ ppm 8.33 (s, 1H), 7.60 (br dd, J = 4.2, 8.3 Hz, 1H), 7.41-7.34 (m, 1H), 7.30-7.26 (m, 1H), 6.92 (d, J = 1.7 Hz, 1H), 5.47-5.24 (m, 1H), 4.57 (br d, J = 6.0 Hz, 2H), 4.40-4.29 (m, 2H), 3.83-3.59 (m, 4H), 3.45-3.35 (m, 3H), 3.10 (br d, J = 5.0 Hz, 1H), 2.43-2.13 (m, 6H), 2.06 (br dd, J = 6.8, 10.9 Hz, 2H), 1.98-1.85 (m, 5H).
異構物 2 , 實施例 75B :LCMS (ESI): [M+H] += 636.1; SFC分析(層析管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;B相在2分鐘內從5%到40%,保持40%的B相1.2分鐘,保持5%的B相0.8分鐘;流速:4毫升/分鐘):掌性管柱出峰位置為 2.089 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.39-8.25 (m, 1H), 7.61 (br dd, J= 4.5, 9.4 Hz, 1H), 7.45-7.34 (m, 1H), 7.28 (s, 1H), 6.93 (s, 1H), 5.50-5.26 (m, 1H), 4.56 (s, 2H), 4.45-4.30 (m, 2H), 3.86-3.60 (m, 4H), 3.55-3.40 (m, 3H), 3.20-3.08 (m, 1H), 2.53-2.17 (m, 6H), 2.15-2.06 (m, 2H), 1.94 (br s, 5H). 實施例 76:1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮 Isomer 2 , Example 75B : LCMS (ESI): [M+H] + = 636.1; SFC analysis (chromatographic column: Chiralpak AD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; phase B is increased from 5% to 40% in 2 minutes, 40% phase B is maintained for 1.2 minutes, and 5% phase B is maintained for 0.8 minutes; flow rate: 4 ml/min): the elution position of the palmar column is 2.089 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.39-8.25 (m, 1H), 7.61 (br dd, J = 4.5, 9.4 Hz, 1H), 7.45-7.34 (m, 1H), 7.28 (s, 7H), 5.76-5.11 (m, 1H), 4.54 (s, 2H), 4.70-4.83 (m, 2H), 3.54-3.30 (m, 3H), 3.20-3.08 (m, 1H), 2.53-2.17 (m, 6H), 2.15-2.06 (m, 2H), 1.94 (br s, 5H ) . :1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one
第一步:在25 oC下,化合物叔丁基(1R,5S)-3-(6-乙醯基-7-溴-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(100 mg,0.17 mmol)溶於二氧六環(2.00 mL)和水(400 uL),加入 ((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(115 mg,0.23 mmol)和磷酸鉀(110 mg,0.52 mmol),氮氣氛圍下加入甲磺酸[正丁基二(1-金剛烷基)膦](2-胺基-1,1'-聯苯-2-基)鈀(II)(12.6 mg,0.02 mmol),100 oC攪拌2小時。反應液冷卻至室溫,減壓濃縮,殘留物用快速管柱層析純化(矽膠,0-30%梯度的四氫呋喃/石油醚)得黃色油狀化合物叔丁基(1R,5S)-3-(6-乙醯基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(90.0 mg,0.10 mmol,產率59%)。LCMS (ESI): [M+H] += 883.5. Step 1 : At 25 ° C, compound tert-butyl (1R,5S)-3-(6-acetyl-7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.17 mmol) was dissolved in dioxane (2.00 mL) and water (400 uL), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (115 mg, 0.23 mmol) and potassium phosphate (110 mg, 0.52 mmol), and under nitrogen atmosphere, [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (12.6 mg, 0.02 mmol) was added, and the mixture was stirred at 100 ° C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran/petroleum ether) to obtain a yellow oily compound tert-butyl (1R, 5S)-3-(6-acetyl-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg, 0.10 mmol, yield 59%). LCMS (ESI): [M+H] + = 883.5.
第二步:在25 oC下,叔丁基(1R,5S)-3-(6-乙醯基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(90.0 mg,0.10 mmol)加入到四氫呋喃(1.80 mL)中,加入 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(17.9 mg,0.11 mmol)和叔丁醇鈉(29.4 mg,0.31 mmol),反應系統20 oC反應2小時。加入水(1 mL)稀釋,用乙酸乙酯(1 mL * 3)萃取,有機相減壓濃縮得粗產物化合物叔丁基(1R,5S)-3-(6-乙醯基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-((((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(90.0 mg),其為黃色油狀液體。LCMS (ESI): [M+H] += 942.5. Step 2 : At 25 ° C, tert-butyl (1R,5S)-3-(6-acetyl-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg, 0.10 mmol) was added to tetrahydrofuran (1.80 mL), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (17.9 mg, 0.11 mmol) and sodium tert-butoxide (29.4 mg, 0.31 mmol) were added, and the reaction system was reacted at 20 ° C for 2 hours. Water (1 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (1 mL * 3). The organic phase was concentrated under reduced pressure to obtain a crude product compound, tert-butyl (1R, 5S)-3-(6-acetyl-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg), which was a yellow oily liquid. LCMS (ESI): [M+H] + = 942.5.
第三步:在25 oC下,叔丁基(1R,5S)-3-(6-乙醯基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-((((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(85.0 mg,0.09 mmol)加入到二甲基甲醯胺(1.80 mL)中,加入氟化銫(41.1 mg,0.27 mmol),反應系統20 oC反應1小時。加入水(5 mL),乙酸乙酯(5 mL*3)萃取,有機相減壓濃縮得粗產物化合物叔丁基(1R,5S)-3-(6-乙醯基-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(50% 純度,100 mg),其為黃色固體。LCMS (ESI): [M+H] += 786.5. Step 3 : At 25 ° C, tert-butyl (1R, 5S)-3-(6-acetyl-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (85.0 mg, 0.09 mmol) was added to dimethylformamide (1.80 mL), and cesium fluoride (41.1 mg, 0.27 mmol) was added. The reaction system was reacted at 20 ° C for 1 hour. Water (5 mL) and ethyl acetate (5 mL*3) extraction, the organic phase was concentrated under reduced pressure to obtain the crude product compound tert-butyl (1R, 5S)-3-(6-acetyl-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50% purity, 100 mg), which is a yellow solid. LCMS (ESI): [M+H] + = 786.5.
第四步:在25 oC下,叔丁基(1R,5S)-3-(6-乙醯基-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(50% 純度,95 mg,0.06 mmol)加入到乙腈(2.00 mL)中,加入氯化氫(4 M的二氧六環溶液,393 uL,1.57 mmol),反應系統20 oC反應2小時。減壓濃縮,殘留物溶於乙腈(1 mL)並用三乙胺調節pH到7-8。混合物透過製備型HPLC純化,得到白色固體化合物1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮(甲酸鹽,3.65 mg,5.68 umol,產率9%)。LCMS (ESI): [M+H] += 642.5. 1H NMR (400 MHz, CD 3OD) δ ppm 8.54 (br s, 1H), 8.25 (s, 1H), 7.87 (br dd, J= 6.0, 8.9 Hz, 1H), 7.50-7.22 (m, 2H), 7.00-6.92 (m, 1H), 5.53-5.29 (m, 1H), 4.72-4.60 (m, 2H), 4.49-4.34 (m, 2H), 3.86 (br s, 3H), 3.73 (br dd, J= 7.0, 12.6 Hz, 1H), 3.60-3.39 (m, 4H), 3.18 (br s, 1H), 2.52-2.40 (m, 1H), 2.36 (br d, J= 8.9 Hz, 1H), 2.25 (br s, 1H), 2.20 (s, 3H), 2.17-2.09 (m, 2H), 1.98 (br s, 5H). 實施例 76A 和實施例 76B1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-((S)-8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮,和 1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-((R)-8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮 Step 4 : At 25 ° C, tert-butyl (1R,5S)-3-(6-acetyl-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50% purity, 95 mg, 0.06 mmol) was added to acetonitrile (2.00 mL), and hydrogen chloride (4 M in dioxane, 393 uL, 1.57 mmol) was added, and the reaction system was reacted at 20 ° C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (1 mL) and the pH was adjusted to 7-8 with triethylamine. The mixture was purified by preparative HPLC to obtain a white solid compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one (formate salt, 3.65 mg, 5.68 umol, yield 9%). LCMS (ESI): [M+H] + = 642.5. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.54 (br s, 1H), 8.25 (s, 1H), 7.87 (br dd, J = 6.0, 8.9 Hz, 1H), 7.50-7.22 (m, 2H), 7.00-6.92 (m, 1H), 5.53-5.29 (m, 1H), 4.72-4.60 (m, 2H), 4.49-4.34 (m, 2H), 3.86 (br s, 3H), 3.73 (br dd, J = 7.0, 12.6 Hz, 1H), 3.60-3.39 (m, 4H), 3.18 (br s, 1H), 2.52-2.40 (m, 1H), 2.36 (br d, J = 8.9 Hz, 1H), 2.25 (br s, 1H), 2.20 (s, 3H), 2.17-2.09 (m, 2H), 1.98 (br s, 5H). Example 76A and Example 76B 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((S)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one, and 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((R)-8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one
實施例 76經SFC分離(管柱:DAICEL CHIRALPAK AD (250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/乙醇;B相保持35%;流速:120毫升/分鐘),得到目標化合物。 Example 76 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 35%; flow rate: 120 ml/min) to obtain the target compound.
異構物 1 , 實施例 76A:LCMS (ESI): [M+H] += 642.3; SFC分析(管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在2分鐘內從5%到40%,保持40%的B相1.2分鐘,保持5%的B相0.8分鐘;流速:4毫升/分鐘):掌性管柱出峰位置為 1.696 min; 1H NMR (400 MHz, MeOD) δ ppm 8.26 (s, 1H), 7.89 (dd, J= 5.9, 9.2 Hz, 1H), 7.38-7.31 (m, 2H), 6.95 (d, J= 2.3 Hz, 1H), 5.61-5.43 (m, 1H), 4.83 (br d, J= 13.8 Hz, 1H), 4.71 (br d, J= 14.1 Hz, 1H), 4.68-4.55 (m, 2H), 4.21-4.12 (m, 2H), 4.01 (br d, J= 13.6 Hz, 1H), 3.94-3.68 (m, 4H), 3.41-3.35 (m, 2H), 2.69-2.47 (m, 2H), 2.41-2.34 (m, 1H), 2.34-2.23 (m, 2H), 2.20 (s, 3H), 2.15-1.99 (m, 5H). Isomer 1 , Example 76A : LCMS (ESI): [M+H] + = 642.3; SFC analysis (column: Chiralpak AD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B from 5% to 40% in 2 minutes, keep 40% phase B for 1.2 minutes, keep 5% phase B for 0.8 minutes; flow rate: 4 ml/min): palmaris column elution position is 1.696 min; 1 H NMR (400 MHz, MeOD) δ ppm 8.26 (s, 1H), 7.89 (dd, J = 5.9, 9.2 Hz, 1H), 7.38-7.31 (m, 2H), 6.95 (d, J = 2.3 Hz, 1H), 5.61-5.43 (m, 1H), 4.83 (br d, J = 13.8 Hz, 1H), 4.71 (br d, J = 14.1 Hz, 1H), 4.68-4.55 (m, 2H), 4.21-4.12 (m, 2H), 4.01 (br d, J = 13.6 Hz, 1H), 3.94-3.68 (m, 4H), 3.41-3.35 (m, 2H), 2.69-2.47 (m, 2H), 2.41-2.34 (m, 1H), 2.34-2.23 (m, 2H), 2.20 (s, 3H), 2.15-1.99 (m, 5H).
異構物 2 , 實施例 76B :LCMS (ESI): [M+H] += 642.4; SFC分析(管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相在2分鐘內從5%到40%,保持40%的B相1.2分鐘,保持5%的B相0.8分鐘;流速:4毫升/分鐘):掌性管柱出峰位置為 2.137 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.25 (s, 1H), 7.85 (dd, J= 5.8, 9.0 Hz, 1H), 7.34-7.30 (m, 2H), 6.95 (d, J= 2.3 Hz, 1H), 5.40-5.22 (m, 1H), 4.67-4.49 (m, 2H), 4.31-4.21 (m, 2H), 3.79-3.62 (m, 4H), 3.33 (br s, 1H), 3.31-3.16 (m, 3H), 3.02 (dt, J= 5.9, 9.3 Hz, 1H), 2.39-2.11 (m, 6H), 2.06-1.79 (m, 7H). 實施例 77:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-乙烯基喹唑啉-7-基)-5,6-二氟萘-2-醇 Isomer 2 , Example 76B : LCMS (ESI): [M+H] + = 642.4; SFC analysis (column: Chiralpak AD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B from 5% to 40% in 2 minutes, keep 40% phase B for 1.2 minutes, keep 5% phase B for 0.8 minutes; flow rate: 4 ml/min): palmaris column elution position is 2.137 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.25 (s, 1H), 7.85 (dd, J = 5.8, 9.0 Hz, 1H), 7.34-7.30 (m, 2H), 6.95 (d, J = 2.3 Hz, 3H), 3.02 (dt, J = 5.9, 9.3 Hz, 1H) , 2.39-2.11 (m, 6H), 2.06-1.79 (m, 7H). Example 77 :4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-vinylquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
第一步:將化合物叔丁基(1R,5S)-3-(7-溴-8-氟-6-碘-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(1.00 g,1.51 mmol)溶於四氫呋喃(10 mL)中,20 oC下加入三氟(乙烯基)硼酸鉀(220 mg,1.66 mmol)和碳酸鈉(1 M的水溶液,4.54 mL,4.54 mmol)。氮氣氛圍下,向反應液中加入[1,1-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷(120 mg,0.15 mmol)。反應在60 oC下攪拌5小時。反應液減壓濃縮,殘留物用快速管柱層析純化(矽膠,0-30%梯度的乙酸乙酯/石油醚)得到淡黃色固體化合物叔丁基(1R,5S)-3-(7-溴-8-氟-2-(2,2,2-三氟乙氧基)-6-乙烯基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(純度85%,500 mg,0.75 mmol,產率50%)。LCMS (ESI): [M+H] += 561.0. Step 1 : Dissolve the compound tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 1.51 mmol) in tetrahydrofuran (10 mL), add potassium trifluoro(vinyl)borate (220 mg, 1.66 mmol) and sodium carbonate (1 M aqueous solution, 4.54 mL, 4.54 mmol) at 20 ° C. Under a nitrogen atmosphere, add [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane (120 mg, 0.15 mmol) to the reaction solution. Stir the reaction at 60 ° C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a light yellow solid compound tert-butyl (1R, 5S)-3-(7-bromo-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (purity 85%, 500 mg, 0.75 mmol, yield 50%). LCMS (ESI): [M+H] + = 561.0.
第二步:在氮氣環境下,向叔丁基(1R,5S)-3-(7-溴-8-氟-2-(2,2,2-三氟乙氧基)-6-乙烯基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(純度85%,352 mg,0.53 mmol)的四氫呋喃(5 mL)溶液中加入2-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷(200 mg,0.57 mmol),磷酸鉀溶液(1.5 M,856 uL,1.71 mmol),[1,1-雙(二叔丁基膦)二茂鐵]二氯化鈀(II)(37.0 mg,0.06 mmol)。並將混合物在20 oC下攪拌16小時。加入水(5 mL),乙酸乙酯萃取(5 mL * 2)萃取,有機相用無水硫酸鎂乾燥,過濾,濾液減壓濃縮。殘餘物透過快速矽膠層析法(矽膠,0-65%梯度的乙酸乙酯/石油醚)純化得到淡黃色固體化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)-6-乙烯基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(230 mg,0.32 mmol,產率57%)。LCMS (ESI): [M+H] += 704.8. Step 2 : Under nitrogen atmosphere, 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane cyclopentane (200 mg, 0.57 mmol), potassium phosphate solution (1.5 M, 856 uL, 1.71 mmol), [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (37.0 mg, 0.06 mmol). The mixture was stirred at 20 ° C for 16 hours. Water (5 mL) was added, and ethyl acetate (5 mL * 2) was extracted. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica gel, 0-65% gradient ethyl acetate/petroleum ether) to give a pale yellow solid compound tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.32 mmol, yield 57%). LCMS (ESI): [M+H] + = 704.8.
第三步:將化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(2,2,2-三氟乙氧基)-6-乙烯基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(220 mg,0.31 mmol)和 ((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯啉]-7a'(5'H)-基)甲醇(95.0 mg,0.47 mmol)溶於四氫呋喃(3 mL),在0 oC下,慢慢往反應液中加入叔丁醇鈉(90.0 mg,0.94 mmol),反應在60 oC攪拌5小時。反應液減壓濃縮,殘留物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷)得到黃色固體化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-乙烯基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(250 mg,0.30 mmol,產率99%)。LCMS (ESI): [M+H] += 808.2. Step 3 : Dissolve tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 0.31 mmol) and ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrroline]-7a'(5'H)-yl)methanol (95.0 mg, 0.47 mmol) in tetrahydrofuran (3 mL). Slowly add sodium tert-butoxide (90.0 mg, 0.94 mmol) to the reaction mixture at 0 ° C. The reaction mixture is stirred at 60 °C for 2 h. C and stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow solid compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S, 7a'S)-2,2-difluorodihydro-1'H, 3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.30 mmol, yield 99%). LCMS (ESI): [M+H] + = 808.2.
第四步:將化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-乙烯基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(240 mg,0.30 mmol)溶於乙腈(3 mL),0 oC下加入氯化氫(4 M的二氧六環溶液,1.49 mL,5.96 mmol)。反應在20 oC下攪拌2小時。反應液減壓濃縮。殘留物溶於三乙胺(400 uL)的二甲亞碸(2 mL)溶液,反應液減壓濃縮。殘留物用製備型HPLC純化,得到白色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-乙烯基喹唑啉-7-基)-5,6-二氟萘-2-醇(20.87 mg,0.02 mmol,產率10%)。LCMS (ESI): [M+H] += 664.2. 1H NMR (400 MHz, CD 3OD) δ ppm 7.99 (s, 1H), 7.59 (br dd, J= 8.5, 4.2 Hz, 1H), 7.42-7.33 (m, 1H), 7.29 (s, 1H), 6.98 (d, J= 2.0 Hz, 1H), 6.32 (dd, J= 17.4, 11.0 Hz, 1H), 5.69 (d, J= 17.4 Hz, 1H), 5.13 (d, J= 11.1 Hz, 1H), 4.64-4.50 (m, 2H), 4.40-4.32 (m, 2H), 3.77-3.64 (m, 4H), 3.40-3.34 (m, 1H), 3.24-3.16 (m, 1H), 2.87 (br d, J= 12.1 Hz, 1H), 2.78-2.68 (m, 1H), 2.31 (br dd, J= 13.5, 4.2 Hz, 1H), 2.23-2.12 (m, 1H), 2.04 (br d, J= 13.4 Hz, 1H), 1.96-1.86 (m, 6H), 1.81 (br dd, J= 11.9, 7.4 Hz, 1H), 1.53-1.37 (m, 2H). 實施例 78:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-乙烯基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇 Step 4 : Dissolve the compound tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.30 mmol) in acetonitrile (3 mL), and add hydrogen chloride (4 M in dioxane, 1.49 mL, 5.96 mmol) at 0 ° C. The reaction was stirred at 20 ° C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in a solution of triethylamine (400 uL) and dimethyl sulfoxide (2 mL), and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain a white solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-vinylquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (20.87 mg, 0.02 mmol, yield 10%). LCMS (ESI): [M+H] + = 664.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.99 (s, 1H), 7.59 (br dd, J = 8.5, 4.2 Hz, 1H), 7.42-7.33 (m, 1H), 7.29 (s, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.32 (dd, J = 17.4, 11.0 Hz, 1H), 5.69 (d, J = 17.4 Hz, 1H), 5.13 (d, J = 11.1 Hz, 1H), 4.64-4.50 (m, 2H), 4.40-4.32 (m, 2H), 3.77-3.64 3.40-3.34 (m, 1H), 3.24-3.16 (m, 1H), 2.87 (br d, J = 12.1 Hz, 1H), 2.78-2.68 (m, 1H), 2.31 (br dd, J = 13.5, 4.2 Hz, 1H), 2.23-2.12 (m, 1H), 2.04 (br d, J = 13.4 Hz, 1H), 1.96-1.86 (m, 6H), 1.81 (br dd, J = 11.9, 7.4 Hz, 1H), 1.53-1.37 (m, 2H). Example 78 :4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
實施例 78的製備參考 實施例 76,採用類似的合成途徑合成得到。LCMS (ESI): [M+H] += 626.7. 1H NMR (400 MHz, MeOD- d 4) δ ppm 7.92 (s, 1H), 7.85 (dd, J= 5.9, 9.1 Hz, 1H), 7.36-7.27 (m, 2H), 7.00 (d, J= 2.5 Hz, 1H), 6.32-6.22 (m, 1H), 5.66 (d, J= 17.4 Hz, 1H), 5.45-5.25 (m, 1H), 5.15-5.07 (m, 1H), 4.62-4.46 (m, 2H), 4.36-4.19 (m, 2H), 3.76-3.60 (m, 4H), 3.41-3.34 (m, 1H), 3.29-3.15 (m, 3H), 3.10-3.00 (m, 1H), 2.45-2.15 (m, 3H), 2.07-1.86 (m, 7H). 實施例 79:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-6-乙炔基-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-5,6-二氟萘-2-醇 The preparation of Example 78 refers to Example 76 and is synthesized using a similar synthetic route. LCMS (ESI): [M+H] + = 626.7. 1 H NMR (400 MHz, MeOD- d 4 ) δ ppm 7.92 (s, 1H), 7.85 (dd, J = 5.9, 9.1 Hz, 1H), 7.36-7.27 (m, 2H), 7.00 (d, J = 2.5 Hz, 1H), 6.32-6.22 (m, 1H), 5.66 (d, J = 17.4 Hz, 1H), 5.45-5.25 (m, 1H), 5.15-5.07 (m, 1H), 4.62-4.46 (m, 2H), 4.36-4.19 (m, 2H), 3.76-3.60 (m, 4H), 3.41-3.34 (m, 1H), 3.29-3.15 (m, 3H), 3.10-3.00 (m, 1H), 2.45-2.15 (m, 3H), 2.07-1.86 (m, 7H). Example 79 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-ethynyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
實施例 79的製備參考 實施例 75,採用類似的合成途徑合成得到LCMS (ESI): [M+H] +=618.7. 1H NMR (400 MHz, CD 3OD- d 4) δ ppm 7.98 (s, 1H), 7.57 (dd, J= 9.0, 4.0 Hz, 1H), 7.41-7.31 (m, 1H), 7.26 (s, 1H), 7.07 (d, J= 2.3 Hz, 1H), 5.41-5.21 (m, 1H), 4.53 (br t, J= 17.8 Hz, 2H), 4.34-4.26 (m, 1H), 4.26-4.19 (m, 1 H), 3.73-3.59 (m, 4H), 3.30-3.15 (m, 4H), 3.08-2.98 (m, 1H), 2.41-1.79 (m, 10H). 實施例 80:1-(8-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-6-烯-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-2-氟-6-羥基萘-1-基)乙-1-酮 Example 79 was prepared by referring to Example 75 , and a similar synthetic route was used to obtain LCMS (ESI): [M+H] + = 618.7. 1 H NMR (400 MHz, CD 3 OD- d 4 ) δ ppm 7.98 (s, 1H), 7.57 (dd, J = 9.0, 4.0 Hz, 1H), 7.41-7.31 (m, 1H), 7.26 (s, 1H), 7.07 (d, J = 2.3 Hz, 1H), 5.41-5.21 (m, 1H), 4.53 (br t, J = 17.8 Hz, 2H), 4.34-4.26 (m, 1H), 4.26-4.19 (m, 1H), 3.73-3.59 (m, 4H), 3.30-3.15 (m, 4H), 3.08-2.98 (m, 1H), 2.41-1.79 (m, 10H). Example 80 : 1-(8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-en-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)ethan-1-one
第一步:化合物2,5-二氫-1H-吡咯-1-羧酸叔丁酯(145 g,856 mmol)溶於丙酮(580 mL)和水(145 mL)中,0 oC和氮氣保護下加入二水合鋨酸鉀(320 mg,0.87 mmol)和N-甲基嗎啡啉氧化物(151 g,1294 mmol),反應在20 oC攪拌16小時。反應液在0 oC下用飽和的硫代硫酸鈉(2500 mL)淬滅,1 M鹽調節pH為5,乙酸乙酯(2 L * 3)萃取,合併有機相,用飽和碳酸氫鈉(1 L)和飽和食鹽水(1 L)洗滌,硫酸鈉乾燥,過濾,減壓濃縮得到黃色油狀化合物3,4-二羥基吡咯烷-1-羧酸叔丁酯(120 g,590 mmol,產率69%)。 1H NMR (400 MHz, CDCl 3) δ ppm 4.24 (m, 2H), 3.58 (m 2H), 3.35 (m, 2H), 1.47 (s, 9H). Step 1: Dissolve tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (145 g, 856 mmol) in acetone (580 mL) and water (145 mL). Add potassium diatomite dihydrate (320 mg, 0.87 mmol) and N-methylmorpholine oxide (151 g, 1294 mmol) at 0 ° C under nitrogen protection, and stir the reaction at 20 ° C for 16 hours. The reaction solution was quenched with saturated sodium thiosulfate (2500 mL) at 0 o C, the pH was adjusted to 5 with 1 M salt, extracted with ethyl acetate (2 L * 3), the organic phases were combined, washed with saturated sodium bicarbonate (1 L) and saturated brine (1 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oily compound tert-butyl 3,4-dihydroxypyrrolidine-1-carboxylate (120 g, 590 mmol, yield 69%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 4.24 (m, 2H), 3.58 (m 2H), 3.35 (m, 2H), 1.47 (s, 9H).
第二步:化合物3,4-二羥基吡咯烷-1-羧酸叔丁酯(115 g,565 mmol)溶於四氫呋喃(575 mL)和水(230 mL)中,0 oC下加入高碘酸鈉(157 g,735 mmol),反應在20 oC攪拌16小時。反應液在0 oC下用亞硫酸鈉(125 g)的水(1 L)溶液淬滅,乙酸乙酯(2 L * 3)萃取,合併有機相,用飽和碳酸氫鈉(1 L)和飽和食鹽水(1 L)洗滌,硫酸鈉乾燥,過濾,減壓濃縮得到雙(2-氧代乙基)胺基甲酸叔丁酯(108 g,537 umol,產率95%)。 1H NMR (400 MHz, CDCl 3) δ ppm 9.59 (s, 1H), 9.58 (s, 1H), 4.11 (s, 2H), 3.90 (s, 2H), 1.38 (s, 9H). Step 2: Compound 3,4-dihydroxypyrrolidine-1-carboxylic acid tert-butyl ester (115 g, 565 mmol) was dissolved in tetrahydrofuran (575 mL) and water (230 mL), sodium periodate (157 g, 735 mmol) was added at 0 o C, and the reaction was stirred at 20 o C for 16 hours. The reaction solution was quenched with a solution of sodium sulfite (125 g) in water (1 L) at 0 o C, extracted with ethyl acetate (2 L * 3), and the organic phases were combined, washed with saturated sodium bicarbonate (1 L) and saturated brine (1 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl bis(2-oxoethyl)carbamate (108 g, 537 umol, yield 95%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.59 (s, 1H), 9.58 (s, 1H), 4.11 (s, 2H), 3.90 (s, 2H), 1.38 (s, 9H).
第三步:-70 oC下,向乙烯基溴化鎂(1 M的四氫呋喃溶液,1250 mL,1250 mmol)中加入化合物雙(2-氧代乙基)胺基甲酸叔丁酯(50.0 g,248 mmol)的四氫呋喃(108 mL)溶液,反應在20 oC攪拌16小時。將2個批次的該反應合併,在0 oC下用飽和氯化銨(1500 mL)淬滅,乙酸乙酯(2 L * 3)萃取,合併有機相,用飽和碳酸氫鈉(1 L)和飽和食鹽水(1 L)洗滌,硫酸鈉乾燥,過濾,減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-30%梯度的乙酸乙酯/石油醚)得到黃色油狀雙(2-羥基丁-3-烯-1-基)胺基甲酸叔丁酯(32.0 g,124 mmol,產率25%)。 1H NMR (400 MHz, CDCl 3) δ ppm 5.87-5.66 (m, 2H), 5.37-5.19 (m, 2H), 5.10 (m, 2H), 4.52-4.09 (m, 2H), 3.83-2.77 (m, 4H), 1.43-1.36 (m, 9H). Step 3: Add a solution of tert-butyl bis(2-oxoethyl)carbamate (50.0 g, 248 mmol) in tetrahydrofuran (108 mL) to vinyl magnesium bromide (1 M tetrahydrofuran solution, 1250 mL, 1250 mmol) at -70 ° C and stir the reaction at 20 ° C for 16 hours. The two batches of the reaction were combined, quenched with saturated ammonium chloride (1500 mL) at 0 ° C, extracted with ethyl acetate (2 L * 3), and the organic phases were combined, washed with saturated sodium bicarbonate (1 L) and saturated brine (1 L), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to give tert-butyl bis(2-hydroxybut-3-en-1-yl)carbamate (32.0 g, 124 mmol, yield 25%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 5.87-5.66 (m, 2H), 5.37-5.19 (m, 2H), 5.10 (m, 2H), 4.52-4.09 (m, 2H), 3.83-2.77 (m, 4H), 1.43-1.36 (m, 9H).
第四步:將化合物雙(2-羥基丁-3-烯-1-基)胺基甲酸叔丁酯(31.0 g,120 mmol)溶於二氯甲烷(320 mL),0 oC下加入三氯乙腈(52.1 g,361 mmol)和1.8-二氮雜二環[5.4.0]十一烷-7-烯(9.00 mL,60.2 mmol),反應在0 oC攪拌1小時。反應液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,6%梯度的乙酸乙酯/石油醚)得到黃色油狀化合物 ((叔丁氧基羰基)氮雜二基)雙(丁-3-烯-1,2-二基)雙(2,2,2-三氯乙醯亞胺酯)(44.0 g,80.6 mmol,產率67%)。 1H NMR (400 MHz, CDCl 3) δ ppm 8.30 (s, 2H), 5.84-5.69 (m, 2H), 5.64-5.50 (m, 2H), 5.42-5.28 (m, 2H), 5.26-5.14 (m, 2H), 3.80-3.69 (m, 1H), 3.65-3.50 (m, 2H), 3.43-3.31 (m, 1H), 1.42-1.39 (m, 9H). Step 4: Dissolve tert-butyl bis(2-hydroxybut-3-en-1-yl)carbamate (31.0 g, 120 mmol) in dichloromethane (320 mL), add trichloroacetonitrile (52.1 g, 361 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (9.00 mL, 60.2 mmol) at 0 ° C, and stir the reaction at 0 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 6% gradient ethyl acetate/petroleum ether) to obtain a yellow oily compound ((tert-butoxycarbonyl)azinediyl)bis(but-3-ene-1,2-diyl)bis(2,2,2-trichloroacetimidate) (44.0 g, 80.6 mmol, yield 67%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.30 (s, 2H), 5.84-5.69 (m, 2H), 5.64-5.50 (m, 2H), 5.42-5.28 (m, 2H), 5.26-5.14 (m, 2H), 3.80-3.69 (m, 1H), 3.65-3.50 (m, 2H), 3.43-3.31 (m, 1H), 1.42-1.39 (m, 9H).
第五步:將化合物2-苯基丙-2-胺(13.1 g,96.7 mmol)溶於二氯乙烷(100 mL),0 oC和氮氣保護下加入1,5-環辛二烯氯化銥二聚體(2.71 g,4.03 mmol)和((叔丁氧基羰基)氮雜二基)雙(丁-3-烯-1,2-二基)雙(2,2,2-三氯乙醯亞胺酯)(44 g,80.6 mmol)的二氯乙烷(350 mL)溶液,反應在0 oC攪拌2小時,然後升溫到20 oC攪拌16小時。反應液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-3%梯度的乙酸乙酯/石油醚)得到黃色油狀化合物 (3S,5R)-4-(2-苯基丙-2-基)-3,5-二乙烯基呱嗪-1-羧酸叔丁酯(22.0 g,61.7 mmol,產率77%)。 1H NMR (400 MHz, CDCl 3) δ ppm 7.56 (dd, J= 1.0, 8.3 Hz, 2H), 7.32 (t, J= 7.6 Hz, 2H), 7.26-7.16 (m, 1H), 6.05-5.92 (m, 2H), 5.18-5.06 (m, 2H), 5.01 (d, J= 10.4 Hz, 2H), 3.64-3.48 (m, 4H), 3.35 (br t, J= 13.8 Hz, 2H), 1.49-1.45 (m, 15H). Step 5: Dissolve the compound 2-phenylpropan-2-amine (13.1 g, 96.7 mmol) in dichloroethane (100 mL ) . Add 1,5-cyclooctadiene iridium chloride dimer (2.71 g, 4.03 mmol) and ((tert-butoxycarbonyl)azinediyl)bis(but-3-ene-1,2-diyl)bis(2,2,2-trichloroacetamide) (44 g, 80.6 mmol) in dichloroethane (350 mL) at 0 ° C under nitrogen protection. Stir the reaction at 0 ° C for 2 hours, then heat to 20 ° C and stir for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-3% gradient of ethyl acetate/petroleum ether) to obtain a yellow oily compound (3S,5R)-4-(2-phenylpropan-2-yl)-3,5-divinylpiperazine-1-carboxylic acid tert-butyl ester (22.0 g, 61.7 mmol, yield 77%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.56 (dd, J = 1.0, 8.3 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.26-7.16 (m, 1H), 6.05-5.92 (m, 2H), 5.18-5.06 (m, 2H), 5.01 (d, J = 10.4 Hz, 2H), 3.64-3.48 (m, 4H), 3.35 (br t, J = 13.8 Hz, 2H), 1.49-1.45 (m, 15H).
第六步:將化合物(3S,5R)-4-(2-苯基丙-2-基)-3,5-二乙烯基呱嗪-1-羧酸叔丁酯(22.0 g,61.7 mmol)溶於甲苯(510 mL),氮氣下加入(1,3-雙(2,4,6-三甲基苯基)-2-咪唑伸烷基)二氯(苯基伸甲基)(三環己基膦)釕(2.62 g,3.09 mmol),反應在120 oC攪拌16小時。反應液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-4%梯度的乙酸乙酯/石油醚)得到白色固體化合物 (1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮雜雙環[3.2.1]辛-6-烯-3-羧酸叔丁酯(12.0 g,36.4 mmol,產率59%)。LCMS (ESI): [M+H] += 329.1; 1H NMR (400 MHz, CDCl 3) δ ppm 7.51 (br d, J= 7.9 Hz, 2H), 7.29-7.21 (m, 2H), 7.15 (br d, J= 7.4 Hz, 1H), 5.96-5.83 (m, 2H), 3.62-3.49 (m, 2H), 3.48-3.36 (m, 2H), 3.02 (ddd, J= 2.4, 11.6, 17.9 Hz, 2H), 1.34 (s, 9H), 1.18 (d, J= 6.1 Hz, 6H). Step 6: Dissolve the compound (3S,5R)-4-(2-phenylpropan-2-yl)-3,5-divinylpiperazine-1-carboxylic acid tert-butyl ester (22.0 g, 61.7 mmol) in toluene (510 mL), add (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidene)dichloro(phenylisothiazolide)(tricyclohexylphosphine)ruthenium (2.62 g, 3.09 mmol) under nitrogen, and stir the reaction at 120 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-4% gradient of ethyl acetate/petroleum ether) to obtain a white solid compound (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylic acid tert-butyl ester (12.0 g, 36.4 mmol, yield 59%). LCMS (ESI): [M+H] + = 329.1; 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.51 (br d, J = 7.9 Hz, 2H), 7.29-7.21 (m, 2H), 7.15 (br d, J = 7.4 Hz, 1H), 5.96-5.83 (m, 2H), 3.62-3.49 (m, 2H), 3.48-3.36 (m, 2H), 3.02 (ddd, J = 2.4, 11.6, 17.9 Hz, 2H), 1.34 (s, 9H), 1.18 (d, J = 6.1 Hz, 6H).
第七步:將化合物 (1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮雜雙環[3.2.1]辛-6-烯-3-羧酸叔丁酯(600 mg,1.83 mmol)和2,6-二甲基吡啶(590 mg,5.48 mmol)溶於二氯甲烷(10 mL),0 oC下加入三甲矽基三氟甲磺酸酯(810 mg,3.65 mmol),反應在0 oC攪拌1小時。在0 oC下用飽和碳酸氫鈉溶液(10 mL)淬滅,混合物用乙酸乙酯(10 mL * 3)萃取,合併的有機相用飽和食鹽水(10 mL)洗滌,硫酸鈉乾燥,過濾,減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷)得到黃色油狀化合物 (1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮雜雙環[3.2.1]辛-6-烯(560 mg,1.72 mmol,產率94 %)。LCMS (ESI): [M+H] += 229.1; 1H NMR (400 MHz, CDCl 3) δ ppm 7.59-7.50 (m, 2H), 7.35 (t, J= 7.6 Hz, 2H), 7.29-7.22 (m, 1H), 6.16 (s, 2H), 3.68 (s, 2H), 3.14 (dd, J= 2.0, 11.9 Hz, 2H), 2.81 (dd, J= 1.7, 11.9 Hz, 2H), 1.26 (s, 6H). Step 7: Dissolve the compound (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene-3-carboxylic acid tert-butyl ester (600 mg, 1.83 mmol) and 2,6-lutidine (590 mg, 5.48 mmol) in dichloromethane (10 mL), add trimethylsilyl trifluoromethanesulfonate (810 mg, 3.65 mmol) at 0 ° C, and stir the reaction at 0 ° C for 1 hour. The mixture was quenched with saturated sodium bicarbonate solution (10 mL) at 0 ° C, and extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain a yellow oily compound (1R, 5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene (560 mg, 1.72 mmol, yield 94%). LCMS (ESI): [M+H] + = 229.1; 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.59-7.50 (m, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.29-7.22 (m, 1H), 6.16 (s, 2H), 3.68 (s, 2H), 3.14 (dd, J = 2.0, 11.9 Hz, 2H), 2.81 (dd, J = 1.7, 11.9 Hz, 2H), 1.26 (s, 6H).
第八步:將化合物2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(3.00 g,11.88 mmol)和三氟乙醇(1.43 g,14.26 mmol)溶於甲苯(60 mL),0 oC加入叔丁醇鈉(1.14 g,11.88 mmol),混合物0 oC攪拌2小時。反應液透過矽藻土過濾,濾餅用乙酸乙酯(30 mL * 3)洗滌,濾液用飽和食鹽水(50 mL * 2)洗滌,硫酸鈉乾燥,過濾,減壓濃縮得到2,7-二氯-8-氟-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(純度70%,3.76 g,8.31 mmol,產率70%)。LCMS (ESI): [M+H] += 315.8. Step 8: Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.00 g, 11.88 mmol) and trifluoroethanol (1.43 g, 14.26 mmol) in toluene (60 mL), add sodium tert-butoxide (1.14 g, 11.88 mmol) at 0 ° C, and stir the mixture at 0 ° C for 2 hours. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (30 mL * 3), the filtrate was washed with saturated brine (50 mL * 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 70%, 3.76 g, 8.31 mmol, yield 70%). LCMS (ESI): [M+H] + = 315.8.
第九步:將化合物 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(0.710 g,4.43 mmol),二異丙基乙胺(0.790 mL,4.43 mmol)和4A分子篩(1 g)混合於甲基四氫呋喃(10 mL)中,0 oC加入2,7-二氯-8-氟-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(純度70%,1.00 g,2.21 mmol)。反應系統升溫到25 oC反應1小時。將3個批次的反應混合,過濾,濾液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷)得黃色油狀化合物7-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2,2,2-三氟乙氧基)吡啶并[4 ,3-d]嘧啶(純度75%,3.00 g,5.10 mmol,產率77%)。LCMS (ESI): [M+H] += 439.0. Step 9: Compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (0.710 g, 4.43 mmol), diisopropylethylamine (0.790 mL, 4.43 mmol) and 4A molecular sieve (1 g) were mixed in methyltetrahydrofuran (10 mL), and 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 70%, 1.00 g, 2.21 mmol) was added at 0 ° C. The reaction system was heated to 25 ° C for 1 hour. The three batches of reactions were mixed, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow oily compound 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (purity 75%, 3.00 g, 5.10 mmol, yield 77%). LCMS (ESI): [M+H] + = 439.0.
第十步:向化合物7-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2,2,2-三氟乙氧基)吡啶并[4 ,3-d]嘧啶(75%純度,2.75 g,4.69 mmol)的二氧六環(60 mL)溶液中,加入 ((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(3.21 g,6.27 mmol)和碳酸銫(1.5 M的水溶液,12.5 mL,18.80 mmol),氮氣氛圍下加入氯[(正丁基二(1-金剛烷基)膦)-2-(2-胺基聯苯)]鈀(II)(419 mg,0.63 mmol),反應液在80 oC攪拌3小時。反應液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷),得到的粗產物用快速管柱層析純化(C18,0-60%梯度的乙腈/水(含1%甲酸))得黃色固體化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(1.50 g,1.90 mmol,產率40%)。LCMS (ESI): [M+H] += 789.3. 1H NMR (400 MHz, CDCl 3) δ ppm 9.27 (d, J= 2.3 Hz, 1H), 7.82 (dd, J= 5.6, 8.9 Hz, 1H), 7.55 (d, J= 2.5 Hz, 1H), 7.38-7.29 (m, 2H), 5.57-5.38 (m, 1H), 5.36-5.29 (m, 2H), 5.27-5.17 (m, 1H), 5.11-4.92 (m, 1H), 4.87-4.51 (m, 2H), 3.85 (br s, 2H), 3.54 (s, 3H), 3.49-3.33 (m, 1H), 3.18 (br s, 1H), 2.66-2.10 (m, 6H), 0.91-0.82 (m, 18H), 0.54 (m, 3H). Step 10: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (75% purity, 2.75 g, 4.69 mmol) in dioxane (60 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.21 g, 6.27 mmol) and cesium carbonate (1.5 M aqueous solution, 12.5 mL, 18.80 mmol), chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (419 mg, 0.63 mmol) was added under nitrogen atmosphere, and the reaction solution was stirred at 80 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane). The crude product was purified by flash column chromatography (C18, 0-60% gradient of acetonitrile/water (containing 1% formic acid)) to give a yellow solid compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.50 g, 1.90 mmol, yield 40%). LCMS (ESI): [M+H] + = 789.3. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.27 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 5.6, 8.9 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.38-7.29 (m, 2H), 5.57-5.38 (m, 1H), 5.36-5.29 (m, 2H), 5.27-5.17 (m, 1H), 5.11-4.92 (m, 1H), 4.87-4.51 (m, 2H), 3.85 (br s, 2H), 3.54 (s, 3H), 3.49-3.33 (m, 1H), 3.18 (br s, 1H), 2.66-2.10 (m, 6H), 0.91-0.82 (m, 18H), 0.54 (m, 3H).
第十一步:化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶(250 mg,0.32 mmol)溶於四氫呋喃(2.50 mL)中,加入氫氧化鈉(44.0 mg,1.09 mmol)的水(2.50 mL)溶液,反應液在25 oC攪拌16小時。向反應液加入乙酸(60 uL),二氯甲烷(5 mL * 3)萃取,有機相用飽和食鹽水(5 mL)洗滌,硫酸鈉乾燥,減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷)得黃色固體化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇(224 mg,0.21 mmol,產率67%)。LCMS (ESI): [M+H] += 707.2. Step 11: Compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (250 mg, 0.32 mmol) was dissolved in tetrahydrofuran (2.50 mL), and a solution of sodium hydroxide (44.0 mg, 1.09 mmol) in water (2.50 mL) was added. The reaction solution was stirred at 25 ° C for 16 hours. Acetic acid (60 uL) was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL * 3). The organic phase was washed with saturated brine (5 mL), dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to obtain a yellow solid compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (224 mg, 0.21 mmol, yield 67%). LCMS (ESI): [M+H] + = 707.2.
第十二步:將化合物8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-醇(230 mg,0.33 mmol),(1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮雜雙環[3.2.1]辛-6-烯(223 mg,0.98 mmol)和二異丙基乙胺(566 uL,3.25 mmol)溶於二甲基乙醯胺(2.3 mL),0 oC下加入苯并三唑-1-氧代-三(二甲胺基磷)六氟磷鹽(287 mg,0.65 mmol),反應在50 oC攪拌2小時。在0 oC下用飽和碳酸氫鈉(10 mL)淬滅,混合物用乙酸乙酯(10 mL * 3)萃取,合併的有機相用飽和食鹽水(10 mL)洗滌,硫酸鈉乾燥,過濾,減壓濃縮得到粗產物化合物8-氟-7-(7-氟-3-((甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-((1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮雜雙環[3.2.1]辛-6-烯-3-基)吡啶并[4,3-d]嘧啶(300 mg),其為黃色油狀液體。LCMS (ESI): [M+H] += 916.9; Step 12: Compound 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (230 mg, 0.33 mmol), (1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-ene (223 mg, 0.98 mmol) and diisopropylethylamine (566 uL, 3.25 mmol) were dissolved in dimethylacetamide (2.3 mL), 0. Benzotriazole-1-oxo-tris(dimethylaminophosphine)hexafluorophosphonium salt (287 mg, 0.65 mmol) was added at 50 °C and the reaction was stirred at 50 ° C for 2 hours. The mixture was quenched with saturated sodium bicarbonate (10 mL) at 0 ° C, extracted with ethyl acetate (10 mL * 3), and the combined organic phases were washed with saturated brine (10 mL * 3). The mixture was washed with 4% paraformaldehyde (2% ethyl acetate) and 0.1% paraformaldehyde (2% paraformaldehyde). The mixture was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, compound 8-fluoro-7-(7-fluoro-3-((methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-en-3-yl)pyrido[4,3-d]pyrimidine (300 mg), which was a yellow oily liquid. LCMS (ESI): [M+H] + = 916.9;
第十三步:化合物8-氟-7-(7-氟-3-((甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-((1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮雜雙環[3.2.1]辛-6-烯-3-基)吡啶并[4,3-d]嘧啶(300 mg,0.33 mmol)加入到N,N-二甲基甲醯胺(2 mL)中,加入氟化銫(500 mg,3.27 mmol),20 oC攪拌1小時。反應液加入水(1500 uL)稀釋,用乙酸乙酯(3 mL * 3)萃取,有機相減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷)得到7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-((1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮雜雙環[3.2.1]辛-6-烯-3-基)吡啶并[4,3-d]嘧啶(240 mg,0.32 mmol,產率96%)。LCMS (ESI): [M+H] += 760.9. Step 13: Compound 8-fluoro-7-(7-fluoro-3-((methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-en-3-yl)pyrido[4,3-d]pyrimidine (300 mg, 0.33 mmol) was added to N,N-dimethylformamide (2 mL), and cesium fluoride (500 mg, 3.27 mmol) was added, and stirred at 20 ° C for 1 hour. The reaction solution was diluted with water (1500 uL) and ethyl acetate (3 mL * 3) extraction, the organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-en-3-yl)pyrido[4,3-d]pyrimidine (240 mg, 0.32 mmol, yield 96%). LCMS (ESI): [M+H] + = 760.9.
第十四步:化合物7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-((1R,5S)-8-(2-苯基丙-2-基)-3,8-二氮雜雙環[3.2.1]辛-6-烯-3-基)吡啶并[4,3-d]嘧啶(190 mg,0.25 mmol)加入到三氟乙酸(1.9 mL)中,50 oC攪拌1小時。反應液減壓濃縮,殘留物加入乙腈(500 uL),加入三乙胺調節pH到8,溶液用製備型HPLC純化,得到紅色固體化合物1-(8-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-6-烯-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-2-氟-6-羥基萘-1-基)乙-1-酮(二甲酸鹽,16.06 mg,23 umol,產率9%)。LCMS (ESI): [M+H] += 617.2; 1H NMR (400 MHz, CD 3OD) δ ppm 9.09 (s, 1H), 8.46 (br s, 2H), 8.00-7.91 (m, 1H), 7.40-7.33 (m, 2H), 7.30 (s, 1H), 6.35 (s, 2H), 5.63-5.46 (m, 1H), 4.76-4.65 (m, 2H), 4.65-4.55 (m, 2H), 4.36 (br s, 2H), 4.05-3.92 (m, 2H), 3.88-3.68 (m, 3H), 3.40 (br dd, J= 4.5, 10.0 Hz, 1H), 2.72-2.48 (m, 2H), 2.43-2.14 (m, 7H). 實施例 81: 9-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基))-8-氟-2-(((2R,7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲基)吡啶并[4,3-d]嘧啶-7-基)-2,3-二氫-1H-環戊[a]萘-7-醇 Step 14: Compound 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,5S)-8-(2-phenylpropan-2-yl)-3,8-diazabicyclo[3.2.1]oct-6-en-3-yl)pyrido[4,3-d]pyrimidine (190 mg, 0.25 mmol) was added to trifluoroacetic acid (1.9 mL) and stirred at 50 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, acetonitrile (500 uL) was added to the residue, triethylamine was added to adjust the pH to 8, and the solution was purified by preparative HPLC to obtain a red solid compound 1-(8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-6-en-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6-hydroxynaphthalen-1-yl)ethan-1-one (dicarboxylate, 16.06 mg, 23 umol, yield 9%). LCMS (ESI): [M+H] + = 617.2; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.09 (s, 1H), 8.46 (br s, 2H), 8.00-7.91 (m, 1H), 7.40-7.33 (m, 2H), 7.30 (s, 1H), 6.35 (s, 2H), 5.63-5.46 (m, 1H), 4.76-4.65 (m, 2H), 4.65-4.55 (m, 2H), 4.36 (br s, 2H), 4.05-3.92 (m, 2H), 3.88-3.68 (m, 3H), 3.40 (br dd, J = 4.5, 10.0 Hz, 1H), 2.72-2.48 (m, 2H), 2.43-2.14 (m, 7H). Example 81 : 9-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl))-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl)pyrido[4,3-d]pyrimidin-7-yl)-2,3-dihydro-1H-cyclopenta[a]naphthalen-7-ol
第一步: 向4-氟-5-溴-1-茚酮(10.00 g, 43.22 mmol)的三氟乙酸(10 mL)溶液中加入三乙基矽烷(50.77 g, 432.22 mmol),反應液加熱至80℃攪拌16小時。反應液冷卻至室溫後,用飽和碳酸氫鈉水溶液將pH調至7,乙酸乙酯(100 mL X 3)萃取。合併有機相,無水硫酸鈉乾燥,濃縮得殘餘物。殘餘物快速管柱層析(矽膠,0-4%梯度的乙酸乙酯/石油醚)得5-溴-4-氟-2,3-二氫-1H-茚化合物無色油狀液體(8.00 g, 86%); 1H NMR (400 MHz, CD 3Cl) δ ppm 7.29 (t, J= 8.0 Hz, 1H), 6.87 (d, J= 8.0 Hz, 1H), 2.99-2.88 (m, 4H), 2.16-2.09 (m, 2H). Step 1: Add triethylsilane (50.77 g, 432.22 mmol) to a solution of 4-fluoro-5-bromo-1-indanone (10.00 g, 43.22 mmol) in trifluoroacetic acid (10 mL), heat the reaction solution to 80°C and stir for 16 hours. After the reaction solution is cooled to room temperature, the pH is adjusted to 7 with a saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (100 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-4% gradient of ethyl acetate/petroleum ether) to obtain 5-bromo-4-fluoro-2,3-dihydro-1H-indene as a colorless oily liquid (8.00 g, 86%); 1 H NMR (400 MHz, CD 3 Cl) δ ppm 7.29 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 2.99-2.88 (m, 4H), 2.16-2.09 (m, 2H).
第二步: 氮氣保護下,5-溴-4-氟-2,3-二氫-1H-茚(8.00 g, 37.20 mmol),呋喃(12.79 g, 186.00 mmol)加到甲苯(50 mL)中。反應液冷卻至零下30℃。正丁基鋰(1.6 M, 25.57mL)緩慢滴加至反應液。滴加完後,反應液升溫至25℃攪拌18小時。反應液加入水(50 mL), 乙酸乙酯(50 mL x 3)萃取,合併有機相,無水硫酸鈉乾燥,濃縮得殘餘物。殘餘物快速管柱層析(矽膠,0-9%梯度的乙酸乙酯/石油醚)得2,3,6,9-四氫-1H-6,9-環氧環戊并[a]萘化合物棕紅色固體(5.30g, 77%)。Step 2: Under nitrogen protection, 5-bromo-4-fluoro-2,3-dihydro-1H-indene (8.00 g, 37.20 mmol) and furan (12.79 g, 186.00 mmol) were added to toluene (50 mL). The reaction solution was cooled to -30°C. n-Butyl lithium (1.6 M, 25.57 mL) was slowly added dropwise to the reaction solution. After the addition, the reaction solution was heated to 25°C and stirred for 18 hours. Water (50 mL) and ethyl acetate (50 mL x 3) were added to the reaction solution for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the residue. The residue was purified by flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) to obtain 2,3,6,9-tetrahydro-1H-6,9-epoxycyclopenta[a]naphthalene as a brown-red solid (5.30 g, 77%).
第三步: 向2,3,6,9-四氫-1H-6,9-環氧環戊并[a]萘(5.30 g, 28.77 mmol)的乙醇(20 mL)溶液中加入濃鹽酸(10 mL, 12 M)。反應液加熱至85℃攪拌2小時。反應液冷卻至室溫後,用氫氧化鈉固體緩慢將pH調至6,乙酸乙酯(50 mLx3)萃取,合併有機相,濃縮得殘餘物。殘餘物快速管柱層析(矽膠,0-9%梯度的乙酸乙酯/石油醚)得2,3-二氫-1H-環戊二[a]萘-9-醇化合物棕色固體(2.70 g, 51%)。Step 3: Add concentrated hydrochloric acid (10 mL, 12 M) to a solution of 2,3,6,9-tetrahydro-1H-6,9-epoxycyclopenta[a]naphthalene (5.30 g, 28.77 mmol) in ethanol (20 mL). Heat the reaction mixture to 85°C and stir for 2 hours. After the reaction mixture is cooled to room temperature, the pH is slowly adjusted to 6 with solid sodium hydroxide, extracted with ethyl acetate (50 mLx3), the organic phases are combined, and the residue is concentrated. The residue is subjected to rapid column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) to obtain 2,3-dihydro-1H-cyclopenta[a]naphthalene-9-ol as a brown solid (2.70 g, 51%).
第四步: 向2,3-二氫-1H-環戊二[a]萘-9-醇(3.30g, 17.91mmol)的二氯甲烷(20 mL)溶液中加入N,N-二異丙基乙胺(5.90 g, 44.78 mmol), 反應液冷卻至0℃。溴(甲氧基)甲烷(5.59 g, 44.78 mmol)緩慢加至反應液,加完後,反應液0℃繼續攪拌1小時。反應液倒入水(50 mL),乙酸乙酯(50 mL x 3)萃取,合併有機相,無水硫酸鈉乾燥,濃縮得殘餘物。殘餘物快速管柱層析(矽膠,0-5%梯度的乙酸乙酯/石油醚)得9-(甲氧基甲氧基)-2,3-二氫-1H-環戊[a]萘化合物白色固體(2.70 g, 17.91 mmol)。Step 4: Add N,N-diisopropylethylamine (5.90 g, 44.78 mmol) to a solution of 2,3-dihydro-1H-cyclopentadi[a]naphthalene-9-ol (3.30 g, 17.91 mmol) in dichloromethane (20 mL), and cool the reaction solution to 0°C. Slowly add bromo(methoxy)methane (5.59 g, 44.78 mmol) to the reaction solution, and after the addition, continue stirring the reaction solution at 0°C for 1 hour. Pour the reaction solution into water (50 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of ethyl acetate/petroleum ether) to obtain 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene as a white solid (2.70 g, 17.91 mmol).
第五步: 氮氣保護下,9-(甲氧基甲氧基)-2,3-二氫-1H-環戊[a]萘(2.70 g, 11.83 mmol), 甲氧基(環辛二烯)合銥二聚體(380 mg, 0.591 mmol), 頻哪醇硼烷(3.09 g, 23.65 mmol), 4,4'-二叔丁基-2,2'-二吡啶(393 mg, 1.42 mmol)加到正己烷(6 mL)中,加熱至85℃反應16小時。反應冷卻至室溫後,倒入水(50 mL),乙酸乙酯(50 mL x 3)萃取,合併有機相,濃縮得殘留物。殘餘物快速管柱層析(矽膠,0-9%梯度的乙酸乙酯/石油醚)得2-(9-(甲氧基甲氧基)-2,3-二氫-1H-環戊[a]萘-7-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷化合物棕色固體(1.80 g, 43%)。Step 5: Under nitrogen protection, 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene (2.70 g, 11.83 mmol), methoxy(cyclooctadiene) iridium dimer (380 mg, 0.591 mmol), pinacol borane (3.09 g, 23.65 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (393 mg, 1.42 mmol) were added to n-hexane (6 mL), heated to 85°C and reacted for 16 hours. After the reaction was cooled to room temperature, it was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined and concentrated to obtain the residue. The residue was purified by flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) to obtain 2-(9-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalen-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a brown solid (1.80 g, 43%).
第六步: 向2-(9-(甲氧基甲氧基)-2,3-二氫-1H-環戊[a]萘-7-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(1.80 g, 5.08 mmol)的四氫呋喃(5 mL)溶液中加入乙酸(3.05 g, 50.81 mmol), 雙氧水(925 mg,50.81 mmol, 30%)。反應液25℃攪拌2小時。反應液倒入水(30 mL),用氫氧化鈉固體將pH調至6,乙酸乙酯(30 mL x 3)萃取,合併有機相,無水硫酸鈉乾燥,濃縮得粗產物9-(甲氧基甲氧基)-2,3-二氫-1H-環戊二[a]萘-7-醇化合物棕色固體(1.20 g, 97%)。LCMS (ESI): [M+H] += 245.1 Step 6: To a solution of 2-(9-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalen-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (1.80 g, 5.08 mmol) in tetrahydrofuran (5 mL) was added acetic acid (3.05 g, 50.81 mmol) and hydrogen peroxide (925 mg, 50.81 mmol, 30%). The reaction mixture was stirred at 25°C for 2 hours. The reaction solution was poured into water (30 mL), and the pH was adjusted to 6 with solid sodium hydroxide. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalen-7-ol as a brown solid (1.20 g, 97%). LCMS (ESI): [M+H] + = 245.1
第七步: 向9-(甲氧基甲氧基)-2,3-二氫-1H-環戊二[a]萘-7-醇(1.20 g, 4.91 mmol)的二氯甲烷(20 mL)溶液中加入N,N-二異丙基乙胺(1.94 g, 14.74 mmol)。反應液冷卻至-40℃,乙醯氯(433 mg, 5.40 mmol)緩慢滴加到反應液,滴加完後,反應液零下40℃繼續攪拌30分鐘。反應液倒入水(30 mL),乙酸乙酯(30 mL x 3)萃取,有機相合併,無水硫酸鈉乾燥,濃縮得殘餘物。殘餘物快速管柱層析(矽膠,0-9%梯度的乙酸乙酯/石油醚)得9-(甲氧基甲氧基)-2,3-二氫-1H-環戊二[a]萘-7-乙酸酯化合物白色固體(1.30 g, 92%)。LCMS (ESI): [M+H] += 287.1 Step 7: Add N,N-diisopropylethylamine (1.94 g, 14.74 mmol) to a solution of 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-7-ol (1.20 g, 4.91 mmol) in dichloromethane (20 mL). The reaction solution was cooled to -40°C, and acetyl chloride (433 mg, 5.40 mmol) was slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred at -40°C for 30 minutes. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-9% gradient ethyl acetate/petroleum ether) to obtain 9-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-7-acetate as a white solid (1.30 g, 92%). LCMS (ESI): [M+H] + = 287.1
第八步: 9-(甲氧基甲氧基)-2,3-二氫-1H-環戊二[a]萘-7-乙酸酯(1.39 g, 4.85 mmol)加到二氯甲烷(5 mL)中,反應液冷卻至-65℃。鹽酸乙酸乙酯溶液(4 M, 20 mL)緩慢滴加至反應液,滴加完後,-65℃繼續攪拌30分鐘,然後緩慢升溫至0℃,繼續攪拌30分鐘。反應液直接濃縮得9-羥基-2,3-二氫-1H-環戊[a]萘-7-乙酸酯化合物棕色固體(1.15 g, 97%)。LCMS (ESI): [M+H] += 243.1 Step 8: 9-(Methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalene-7-acetate (1.39 g, 4.85 mmol) was added to dichloromethane (5 mL), and the reaction solution was cooled to -65°C. Ethyl acetate hydrochloride solution (4 M, 20 mL) was slowly added dropwise to the reaction solution. After the addition was complete, the mixture was stirred at -65°C for 30 minutes, then slowly heated to 0°C and stirred for 30 minutes. The reaction solution was directly concentrated to obtain 9-hydroxy-2,3-dihydro-1H-cyclopenta[a]naphthalene-7-acetate as a brown solid (1.15 g, 97%). LCMS (ESI): [M+H] + = 243.1
第九步: 9-羥基-2,3-二氫-1H-環戊[a]萘-7-乙酸酯(1.15 g, 4.75 mmol)加到二氯甲烷(10 mL)中,反應液冷卻至-65℃。N,N-二異丙基乙胺(1.88 g, 14.24 mmol)緩慢加到反應液,反應液-65℃攪拌15分鐘。三氟甲磺酸酐(1.60 g, 5.70 mmol)緩慢滴加至反應液,反應液-65℃攪拌30分鐘。反應液倒入水(30 mL),乙酸乙酯(30 mL x 3)萃取,合併有機相,無水硫酸鈉乾燥,濃縮得殘留物。殘餘物殘餘物快速管柱層析(矽膠,0-9%梯度的乙酸乙酯/石油醚)得9-((((三氟甲基)磺醯基)氧基)-2,3-二氫-1H-環戊二[a]萘-7-乙酸酯化合物白色固體(1.05 g, 59%)。Step 9: 9-Hydroxy-2,3-dihydro-1H-cyclopenta[a]naphthalene-7-acetate (1.15 g, 4.75 mmol) was added to dichloromethane (10 mL), and the reaction solution was cooled to -65°C. N,N-Diisopropylethylamine (1.88 g, 14.24 mmol) was slowly added to the reaction solution, and the reaction solution was stirred at -65°C for 15 minutes. Trifluoromethanesulfonic anhydride (1.60 g, 5.70 mmol) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at -65°C for 30 minutes. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) to give 9-((((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-7-acetate as a white solid (1.05 g, 59%).
第十步: 9-((((三氟甲基)磺醯基)氧基)-2,3-二氫-1H-環戊二[a]萘-7-乙酸酯(1.05 g, 2.81 mmol)加到四氫呋喃(10 mL),水(3 mL)溶液中,反應液冷卻至0℃。氫氧化鋰(0.10 g, 4.21 mmol)加到反應液,反應液0℃繼續攪拌30分鐘。反應液用乙酸調pH至6,乙酸乙酯(20 mL x 3)萃取,有機相飽和氯化鈉水溶液(30 mL x 3)洗,合併有機相,無水硫酸鈉乾燥,濃縮得粗產物7-羥基-2,3-二氫-1H-環戊二[a]萘-9-基三氟甲磺酸酯化合物白色固體(0.90 g, 96%)。LCMS (ESI): [M+H] += 333.1 Step 10: 9-((((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalene-7-acetate (1.05 g, 2.81 mmol) was added to a solution of tetrahydrofuran (10 mL) and water (3 mL), and the reaction solution was cooled to 0°C. Lithium hydroxide (0.10 g, 4.21 mmol) was added to the reaction solution, and the reaction solution was stirred at 0°C for 30 minutes. The reaction solution was adjusted to pH 6 with acetic acid, extracted with ethyl acetate (20 mL x 3), and the organic phase was saturated with aqueous sodium chloride solution (30 mL x 4). 3) Wash, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product 7-hydroxy-2,3-dihydro-1H-cyclopentadi[a]naphthalen-9-yl trifluoromethanesulfonate as a white solid (0.90 g, 96%). LCMS (ESI): [M+H] + = 333.1
第十一步: 7-羥基-2,3-二氫-1H-環戊二[a]萘-9-基三氟甲磺酸酯(900 mg, 2.71 mmol)加到二氯甲烷(5 mL),反應液冷卻至0℃。N,N-二異丙基乙胺(1.07 g, 8.12 mmol)緩慢加至反應液。反應液0℃繼續攪拌5分鐘。溴(甲氧基)甲烷(508 mg, 4.06 mmol)緩慢加至反應液,反應液0℃攪拌1小時。水(30 mL)倒入反應液,乙酸乙酯(30 mL x 3)萃取,合併有機相,無水硫酸鈉乾燥,濃縮得殘餘物。殘餘物快速管柱層析(矽膠,0-9%梯度的乙酸乙酯/石油醚)得7-(甲氧基甲氧基)-2,3-二氫-1H-環戊[a]萘-9-基三氟甲磺酸酯化合物(750 mg, 74%)。Step 11: 7-Hydroxy-2,3-dihydro-1H-cyclopentadi[a]naphthalen-9-yl trifluoromethanesulfonate (900 mg, 2.71 mmol) was added to dichloromethane (5 mL), and the reaction solution was cooled to 0°C. N,N-Diisopropylethylamine (1.07 g, 8.12 mmol) was slowly added to the reaction solution. The reaction solution was stirred at 0°C for 5 minutes. Bromo(methoxy)methane (508 mg, 4.06 mmol) was slowly added to the reaction solution, and the reaction solution was stirred at 0°C for 1 hour. Water (30 mL) was poured into the reaction solution, and ethyl acetate (30 mL x 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by flash column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) to give 7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalen-9-yl trifluoromethanesulfonate (750 mg, 74%).
第十二步: 氮氣保護下,7-(甲氧基甲氧基)-2,3-二氫-1H-環戊[a]萘-9-基三氟甲磺酸酯(750 mg,1.99 mmol),聯硼酸頻哪醇酯(1.01 g, 3.98 mmol),[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀(151 mg, 0.20 mmol),乙酸鉀(395 mg, 3.98 mmol)加到N,N-二甲基甲醯胺(3 mL)中,反應液加熱至100℃攪拌4小時。反應液冷卻至室溫後抽濾,濾液倒入水(30 mL)中,乙酸乙酯(30 mL)萃取,飽和氯化鈉水溶液(30 mL x 3)洗,合併有機相,無水硫酸鈉乾燥,濃縮得殘餘物。殘餘物快速管柱層析(矽膠,0-9%梯度的乙酸乙酯/石油醚)得2-(7-(甲氧基甲氧基)-2,3-二氫-1H-環戊二[a]萘-9-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷化合物白色固體(600 mg, 85%)。Step 12: Under nitrogen protection, 7-(methoxymethoxy)-2,3-dihydro-1H-cyclopenta[a]naphthalen-9-yl trifluoromethanesulfonate (750 mg, 1.99 mmol), pinacol diboron (1.01 g, 3.98 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (151 mg, 0.20 mmol), and potassium acetate (395 mg, 3.98 mmol) were added to N,N-dimethylformamide (3 mL), and the reaction solution was heated to 100°C and stirred for 4 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was poured into water (30 mL), extracted with ethyl acetate (30 mL), washed with saturated sodium chloride aqueous solution (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was subjected to rapid column chromatography (silica gel, 0-9% gradient of ethyl acetate/petroleum ether) to obtain 2-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalen-9-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane as a white solid (600 mg, 85%).
第十三步 :氮氣保護下,2-(7-(甲氧基甲氧基)-2,3-二氫-1H-環戊二[a]萘-9-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(128 mg, 0.36 mmol),叔丁基 (1R,5S)-3-(7-氯-8-氟-2-((((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(200 mg, 0.36 mmol),甲磺酸[正丁基二(1-金剛烷基)膦](2-胺基-1,1'-聯苯-2-基)鈀(II)(26 mg, 0.04 mmol),磷酸鉀(157 mg, 0.72 mmol)加到1,4-二氧六環(2 mL)中,反應液加熱到95℃攪拌18小時。反應液冷卻至室溫後,反應液抽濾,濾液製備薄層層析(二氯甲烷/甲醇=12/1)純化得(1R,5S)-3- (8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(7-(甲氧基甲氧基)-2,3-二氫-1H-環戊二[a]萘-9-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷- 8-羧酸酯化合物白色固體(180 mg, 66%)。LCMS (ESI): [M+H] += 743.3 Step 13 : Under nitrogen protection, 2-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalen-9-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (128 mg, 0.36 mmol), tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-((((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.36 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (26 mg, 0.04 mmol), potassium phosphate (157 mg, 0.72 mmol) were added to 1,4-dioxane (2 mL), and the reaction solution was heated to 95°C and stirred for 18 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered, and the filtrate was purified by preparative thin layer chromatography (dichloromethane/methanol = 12/1) to obtain (1R,5S)-3- (8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalen-9-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate compound as white solid (180 mg, 66%). LCMS (ESI): [M+H] + = 743.3
第十四步 :(1R,5S)-3- (8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(7-(甲氧基甲氧基)-2,3-二氫-1H-環戊二[a]萘-9-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷- 8-羧酸酯(180 mg, 0.24 mmol)加到鹽酸乙酸乙酯(4 M, 4 mL),反應液0℃下攪拌1小時。反應液濃縮得殘餘物。殘餘物快速管柱層析(C18, 5-35%乙腈/水,0.5% HCl)得9-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基))-8-氟-2-(((2R,7aR)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲基)吡啶并[4,3-d]嘧啶-7-基)-2,3-二氫-1H-環戊[a]萘-7-醇鹽酸鹽化合物淡黃色固體(49 mg, 34%)。LCMS (ESI): [M+H] += 599.3; 1H NMR (400 MHz, DMSO) δ ppm 11.61-11.50 (m, 1H), 10.15-10.00 (m, 1H), 9.8 (s, 1H), 9.25(s, 1H), 7.65-7.55(m, 1H), 7.40-7.25(m, 2H), 7.10-7.00(m, 1H), 5.60-5.50(m, 1H), 4.79-4.65(m, 5H), 4.23-4.15(m, 3H), 4.00-3.75(m, 4H), 3.30-3.25(m, 1H), 2.90-2.75(m, 2H), 2.68-2.63(m, 1H), 2.50-2.41(m, 2H), 2.25-1.75(m, 11H). 實施例 82: 4-(10-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-6-氟-8-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-5-基)-5-乙炔基-6-氟萘-2-醇 Step 14 : (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(7-(methoxymethoxy)-2,3-dihydro-1H-cyclopentadi[a]naphthalen-9-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (180 mg, 0.24 mmol) was added to ethyl acetate hydrochloride (4 M, 4 mL), and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated to obtain a residue. The residue was purified by flash column chromatography (C18, 5-35% acetonitrile/water, 0.5% HCl) to give 9-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl))-8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl)pyrido[4,3-d]pyrimidin-7-yl)-2,3-dihydro-1H-cyclopenta[a]naphthalen-7-ol hydrochloride as a light yellow solid (49 mg, 34%). LCMS (ESI): [M+H] + = 599.3; 1 H NMR (400 MHz, DMSO) δ ppm 11.61-11.50 (m, 1H), 10.15-10.00 (m, 1H), 9.8 (s, 1H), 9.25(s, 1H), 7.65-7.55(m, 1H), 7.40-7.25(m, 2H), 7.10-7.00(m, 1H), 5.60-5.50(m, 1H), 4.79-4.65(m, 5H), 4.23-4.15(m, 3H), 4.00-3.75(m, 4H), 3.30-3.25(m, 1H), 2.90-2.75(m, 2H), 2.68-2.63 (m, 1H), 2.50-2.41 (m, 2H), 2.25-1.75 (m, 11H). Example 82 : 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)tetrazo[1',5':1,2]pyrido[4,3-d]pyrimidin-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
第一步:向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(1.00 g,1.19 mmol)的二氯甲烷(3.00 mL)溶液中加入間氯過氧苯甲酸(85%純度,844 mg,4.16 mmol),將混合物在20 oC攪拌16小時。將溶液濃縮,殘餘物溶於乙酸乙酯(5 mL),用飽和碳酸鉀溶液(5 mL * 3)洗滌,濃縮有機相,殘餘物用快速管柱層析(矽膠,0-71%梯度的乙酸乙酯/石油醚)純化,得到黃色固體化合物4-((1R,5S)-8-(叔丁氧基羰基)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶6-氧化物(420 mg,0.49 mmol,產率41%)。LCMS (ESI): [M+H] += 858.3. Step 1: To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 1.19 mmol) in dichloromethane (3.00 mL) was added m-chloroperbenzoic acid (85% purity, 844 mg, 4.16 mmol) and the mixture was stirred at 20 ° C for 16 hours. The solution was concentrated, the residue was dissolved in ethyl acetate (5 mL), washed with saturated potassium carbonate solution (5 mL * 3), the organic phase was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-71% gradient of ethyl acetate/petroleum ether) to obtain a yellow solid compound 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine 6-oxide (420 mg, 0.49 mmol, yield 41%). LCMS (ESI): [M+H] + = 858.3.
第二步:將化合物4-((1R,5S)-8-(叔丁氧基羰基)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)吡啶并[4,3-d]嘧啶6-氧化物(200 mg,0.23 mmol),疊氮磷酸二苯酯(1.92 g,6.99 mmol)和吡啶(225 uL,2.80 mmol)的混合物在110 oC攪拌16小時。混合物用快速管柱層析(矽膠,0-50%梯度的乙酸乙酯/石油醚)純化,得到黃色油狀化合物叔丁基(1R,5S)-3-(6-氟-5-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-8-(2,2,2-三氟乙氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-10-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(70%純度,200 mg,0.23 mmol,產率68%)。LCMS (ESI): [M+H] += 883.3. Step 2: A mixture of compound 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine 6-oxide (200 mg, 0.23 mmol), diphenyl phosphate azide (1.92 g, 6.99 mmol) and pyridine (225 uL, 2.80 mmol) was stirred at 110 ° C for 16 hours. The mixture was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate/petroleum ether) to give yellow oily compound tert-butyl (1R,5S)-3-(6-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-(2,2,2-trifluoroethoxy)tetraazolo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 200 mg, 0.23 mmol, 68% yield). LCMS (ESI): [M+H] + = 883.3.
第三步:向化合物叔丁基(1R,5S)-3-(6-氟-5-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-8-(2,2,2-三氟乙氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-10-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(70%純度,180 mg,0.14 mmol)和 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(64.9 mg,0.41 mmol)的四氫呋喃(3.60 mL)溶液中加入叔丁醇鈉(60.0 mg,0.61 mmol)。混合物在20 oC下攪拌16小時。加入水(4 mL)稀釋,用乙酸乙酯(4 mL * 3)萃取,濃縮有機相得到粗產物化合物叔丁基(1R,5S)-3-(6-氟-5-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-8-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-10-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(125 mg),其為黃色固體。LCMS (ESI): [M+H] += 942.4. Step 3: To a solution of compound tert-butyl (1R,5S)-3-(6-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-(2,2,2-trifluoroethoxy)tetraazolo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70% purity, 180 mg, 0.14 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (64.9 mg, 0.41 mmol) in tetrahydrofuran (3.60 mL) was added sodium tert-butoxide (60.0 mg, 0.61 mmol). The mixture was stirred at 20 ° C for 16 hours. Water (4 mL) was added for dilution, and the mixture was extracted with ethyl acetate (4 mL * 3). The organic phase was concentrated to obtain the crude product compound tert-butyl (1R, 5S)-3-(6-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)tetrazo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (125 mg) as a yellow solid. LCMS (ESI): [M+H] + = 942.4.
第四步:向化合物叔丁基(1R,5S)-3-(6-氟-5-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-8-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-10-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(125 mg,0.13 mmol)的二甲基甲醯胺(2.00 mL)溶液中加入氟化銫(202 mg,1.33 mmol),反應液在20 oC下攪拌1小時,然後用水(3 mL)稀釋,用乙酸乙酯(4 mL * 3)萃取。濃縮有機相,殘餘物用快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化,得到粗產物化合物叔丁基(1R,5S)-3-(5-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-6-氟-8-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-10-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(50.0 mg),其為黃色固體。LCMS (ESI): [M+H] += 786.5. Step 4: CsF (202 mg, 1.33 mmol) was added to a solution of tert-butyl (1R,5S)-3-(6-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)tetrazo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (125 mg, 0.13 mmol) in dimethylformamide (2.00 mL). The reaction mixture was stirred at 20 ° C for 1 hour, then diluted with water (3 mL) and washed with ethyl acetate (4 mL). * 3). The organic phase was concentrated and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give the crude compound tert-butyl (1R,5S)-3-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)tetrazo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg) as a yellow solid. LCMS (ESI): [M+H] + = 786.5.
第五步:向化合物叔丁基(1R,5S)-3-(5-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-6-氟-8-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-10-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(45.0 mg,0.03 mmol)的乙腈(900 uL)溶液中加入氯化氫(4 M的二氧六環溶液,143 uL,0.57 mmol),將溶液在20 oC下攪拌1.5 小時,濃縮,殘餘物溶於乙腈(2 mL)並加入三乙胺將pH調節至8,溶液用製備型HPLC純化,得到化合物4-(10-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-6-氟-8-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)四唑并[1',5':1,2]吡啶并[4,3-d]嘧啶-5-基)-5-乙炔基-6-氟萘-2-醇(2.10 mg,3.27 umol,產率11%)。LCMS (ESI): [M+H] += 642.4. 1H NMR (400 MHz, CD 3OD) δ ppm 7.98 (dd, J= 5.6, 9.2 Hz, 1H), 7.55-7.50 (m, 2H), 7.41 (t, J= 8.9 Hz, 1H), 5.42 (br d, J= 4.0 Hz, 1H), 4.69-4.53 (m, 2H), 4.44-4.27 (m, 3H), 3.82 (br dd, J= 1.6, 13.7 Hz, 2H), 3.69 (br dd, J= 5.6, 13.2 Hz, 1H), 3.57 (br dd, J= 3.3, 13.8 Hz, 1H), 3.30-3.20 (m, 3H), 3.10-3.03 (m, 1H), 2.42-2.14 (m, 5H), 2.08-1.88 (m, 5H). 實施例 83 :(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羥基萘-1-基)喹唑啉-6-基)(環丙基)甲酮 甲酸鹽 Step 5: To a solution of tert-butyl (1R,5S)-3-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)tetrazo[1',5':1,2]pyrido[4,3-d]pyrimidin-10-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45.0 mg, 0.03 mmol) in acetonitrile (900 uL) was added hydrogen chloride (4 M in dioxane, 143 uL, 0.57 mmol). The solution was stirred at 20 o C for 1.5 hours, concentrated, and the residue was dissolved in acetonitrile (2 mL) and triethylamine was added to adjust the pH to 8. The solution was purified by preparative HPLC to obtain compound 4-(10-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)tetrazo[1',5':1,2]pyrido[4,3-d]pyrimidin-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (2.10 mg, 3.27 umol, yield 11%). LCMS (ESI): [M+H] + = 642.4. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.98 (dd, J = 5.6, 9.2 Hz, 1H), 7.55-7.50 (m, 2H), 7.41 (t, J = 8.9 Hz, 1H), 5.42 (br d, J = 4.0 Hz, 1H), 4.69-4.53 (m, 2H), 4.44-4.27 (m, 3H), 3.82 (br dd, J = 1.6, 13.7 Hz, 2H), 3.69 (br dd, J = 5.6, 13.2 Hz, 1H), 3.57 (br dd, J = 3.3, 13.8 Hz, 1H), 3.30-3.20 (m, 3H), 3.10-3.03 (m, 1H), 2.42-2.14 (m, 5H), 2.08-1.88 (m, 5H). Example 83 : (4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-6-yl)(cyclopropyl)methanone formate
實施例 83透過實 施例 53的合成途徑方法進行製備:LCMS (ESI): [M+H] += 626.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.53 (br s, 1H), 8.11 (s, 1H), 7.78 (d, J= 8.1 Hz, 1H), 7.50-7.38 (m, 2H), 7.31-7.19 (m, 2H), 7.07 (d, J= 2.4 Hz, 1H), 5.51-5.36 (m, 1H), 4.70-4.40 (m, 4H), 3.95-3.86 (m, 2H), 3.83-3.75 (m, 2H), 3.56-3.48 (m, 3H), 3.24-3.18 (m, 1H), 2.56-2.36 (m, 2H), 2.32-2.24 (m, 1H), 2.21-2.11 (m, 2H), 2.05-1.96 (m, 5H), 1.75-1.66 (m, 1H), 0.98-0.87 (m, 1H), 0.79-0.70 (m, 1H), 0.64-0.55 (m, 1H), 0.42-0.39 (m, 1H). 實施例 84:(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯啉-7a(5H)-基)甲氧基)喹唑啉-6-基)(環己基)甲酮 Example 83 was prepared by the synthetic route method of Example 53 : LCMS (ESI): [M+H] + = 626.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.53 (br s, 1H), 8.11 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.50-7.38 (m, 2H), 7.31-7.19 (m, 2H), 7.07 (d, J = 2.4 Hz, 1H), 5.51-5.36 (m, 1H), 4.70-4.40 (m, 4H), 3.95-3.86 (m, 2H), 3.83-3.75 (m, 2H), 3.56-3.48 (m, 3H), 3.24-3.18 (m, 1H), 2.56-2.36 (m, 2H), 2.32-2.24 (m, 1H), 2.21-2.11 (m, 2H), 2.05-1.96 (m, 5H), 1.75-1.66 (m, 1H), 0.98-0.87 (m, 1H), 0.79-0.70 (m, 1H), 0.64-0.55 (m, 1H), 0.42-0.39 (m, 1H). Example 84 :(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-6-yl)(cyclohexyl)methanone
第一步:在-78 oC下,向1.3M異丙基氯化鎂氯化鋰溶液(232 uL, 0.30 mmol)的四氫呋喃(300 uL)溶液中加入氰化亞銅(13.5 mg,0.15 mmol)的四氫呋喃(300 uL)溶液,溶液在-78 oC下攪拌30分鐘,然後在-78 oC下加入叔丁基(1R,5S)-3-(7-溴-8-氟-6-碘-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(100.0 mg,0.15 mmol)的四氫呋喃(300 uL)溶液,撤除冷浴,攪拌30分鐘,然後加入四氫呋喃(300 uL),攪拌40分鐘,然後加入環己烷甲醯氯(26.6 mg,0.18 mmol)的四氫呋喃溶液(300 uL),攪拌15分鐘。反應液倒入飽和氯化銨溶液(10 mL),使用乙酸乙酯(10 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-10%梯度的乙酸乙酯/石油醚),得到無色液體化合物叔丁基(1R,5S)-3-(7-溴-6-(環己烷羰基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(34.0 mg,0.05 mmol,產率34%)。LCMS (ESI): [M+H] += 647.2. Step 1 : At -78 o C, add a solution of cuprous cyanide (13.5 mg, 0.15 mmol) in tetrahydrofuran (300 uL) to a solution of 1.3M isopropylmagnesium chloride and lithium chloride (232 uL, 0.30 mmol) in tetrahydrofuran (300 uL). The solution was stirred at -78 o C for 30 minutes. Then, tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-iodo-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100.0 mg, 0.15 mmol) in tetrahydrofuran (300 uL) was added at -78 o C. uL) solution, remove the cooling bath, stir for 30 minutes, then add tetrahydrofuran (300 uL), stir for 40 minutes, then add cyclohexane methyl chloride (26.6 mg, 0.18 mmol) tetrahydrofuran solution (300 uL), stir for 15 minutes. The reaction solution was poured into saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotated to dryness. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate/petroleum ether) to obtain a colorless liquid compound tert-butyl (1R,5S)-3-(7-bromo-6-(cyclohexanecarbonyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (34.0 mg, 0.05 mmol, yield 34%). LCMS (ESI): [M+H] + = 647.2.
第二步:在手套箱中,向叔丁基(1R,5S)-3-(7-溴-6-(環己烷羰基)-8-氟-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(100.0 mg,0.15 mmol)和((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(103.2 mg, 0.20 mmol)的1,4-二氧六環(2 mL)溶液中,加入1.5M 磷酸鉀水溶液(309 uL, 0.46 mmol)和甲磺酸[正丁基二(1-金剛烷基)膦](2-胺基-1,1'-聯苯-2-基)鈀(II)(11.3 mg,0.02 mmol)。將混合物在氮氣保護下100 oC下攪拌2小時。加入水(3 mL),使用乙酸乙酯(5 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-30%梯度的乙酸乙酯/石油醚),得到棕色固體化合物叔丁基(1R,5S)-3-(6-(環己烷羰基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(100.0 mg,0.04 mmol,純度40%,產率28%)。LCMS (ESI): [M+H] += 951.6. Step 2 : In a glove box, 1.5 M potassium phosphate aqueous solution (309 uL, 0.46 mmol) was added to a solution of tert-butyl (1R,5S)-3-(7-bromo-6-(cyclohexanecarbonyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100.0 mg, 0.15 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (103.2 mg, 0.20 mmol) in 1,4-dioxane (2 mL). mmol) and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (11.3 mg, 0.02 mmol). The mixture was stirred at 100 ° C for 2 hours under nitrogen. Water (3 mL) was added, and ethyl acetate (5 mL * 3) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(6-(cyclohexanecarbonyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100.0 mg, 0.04 mmol, purity 40%, yield 28%). LCMS (ESI): [M+H] + = 951.6.
第三步:向叔丁基(1R,5S)-3-(6-(環己烷羰基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(100 mg, 0.10 mmol)和 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(33.5 mg, 0.21 mmol)的四氫呋喃(2 mL)溶液中,加入叔丁醇鈉(15.2 mg,0.16 mmol)。將混合物氮氣保護下在50 oC攪拌3小時。加入水(5 mL),使用乙酸乙酯(10 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。得到粗產物化合物叔丁基(1R,5S)-3-(6-(環己烷羰基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(125 mg),其為棕色油狀液體。LCMS (ESI): [M+2H] 2+/2=506.0. Step 3 : To a solution of tert-butyl (1R,5S)-3-(6-(cyclohexanecarbonyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.10 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (33.5 mg, 0.21 mmol) in tetrahydrofuran (2 mL) was added sodium tert-butoxide (15.2 mg, 0.16 mmol). The mixture was stirred at 50 ° C for 3 hours under nitrogen. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The crude product compound tert-butyl (1R, 5S)-3-(6-(cyclohexanecarbonyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (125 mg) was obtained as a brown oily liquid. LCMS (ESI): [M+2H] 2+ /2=506.0.
第四步:向叔丁基(1R,5S)-3-(6-(環己烷羰基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(120 mg, 0.12 mmol)的N,N二甲基甲醯胺(2.4 mL)溶液中,加入氟化銫(180.4 mg,1.19 mmol)。將混合物在25 oC下攪拌1小時。加入水(7 mL)稀釋,使用乙酸乙酯(10 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷),得到棕色油狀化合物叔丁基(1R,5S)-3-(6-(環己烷羰基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(42 mg,0.05 mmol,產率41%)。LCMS (ESI): [M+H] += 854.5. Step 4 : To a solution of tert-butyl (1R,5S)-3-(6-(cyclohexanecarbonyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.12 mmol) in N,N-dimethylformamide (2.4 mL) was added cesium fluoride (180.4 mg, 1.19 mmol). The mixture was stirred at 25 ° C for 1 hour. Add water (7 mL) to dilute, extract with ethyl acetate (10 mL * 3), dry the combined organic phases over anhydrous sodium sulfate, filter, and spin dry the filtrate. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give brown oily compound tert-butyl (1R,5S)-3-(6-(cyclohexanecarbonyl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (42 mg, 0.05 mmol, yield 41%). LCMS (ESI): [M+H] + = 854.5.
第五步:在20 oC下,向叔丁叔丁基(1R,5S)-3-(6-(環己烷羰基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(42 mg,0.05 mmol)的乙腈(840 uL)溶液中加入氯化氫(4 M的二氧六環溶液,246 uL,0.98 mmol)。將該溶液在20 oC攪拌1小時。溶液用氮氣吹除HCl氣並濃縮。混合物透過製備型HPLC純化,得到白色固體化合物 (4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯啉-7a(5H)-基)甲氧基)喹唑啉-6-基)(環己基)甲酮(7.88 mg,0.01 mmol,產率23%)。LCMS (ESI): [M+H] += 710.2。 1H NMR (400 MHz, CD 3OD) δ ppm 7.99 (s, 1H), 7.89 (dd, J= 5.8, 9.0 Hz, 1H), 7.37 (t, J= 8.9 Hz, 1H), 7.33 (d, J= 2.3 Hz, 1H), 6.91 (d, J= 2.3 Hz, 1H), 5.43 - 5.28 (m, 1H), 4.69 - 4.49 (m, 3H), 4.40 - 4.26 (m, 2H), 3.77 - 3.63 (m, 4H), 3.36 (br d, J= 5.3 Hz, 2H), 3.13 - 3.06 (m, 1H), 2.62 - 2.53 (m, 1H), 2.47 - 2.26 (m, 2H), 2.25 - 1.98 (m, 4H), 1.92 (br s, 4H), 1.72 - 1.59 (m, 2H), 1.49 (br s, 2H), 1.28 - 0.99 (m, 5H), 0.95 - 0.86 (m, 1H), 0.58 (br d, J= 13.3 Hz, 1H). 實施例 85:1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮肟 Step 5 : To a solution of tert-butyl (1R,5S)-3-(6-(cyclohexanecarbonyl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (42 mg, 0.05 mmol) in acetonitrile (840 uL) was added hydrogen chloride (4 M in dioxane, 246 uL, 0.98 mmol) at 20 °C. The solution was stirred at 20 ° C for 1 hour. The solution was purged with nitrogen to remove HCl gas and concentrated. The mixture was purified by preparative HPLC to give a white solid compound (4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-6-yl)(cyclohexyl)methanone (7.88 mg, 0.01 mmol, yield 23%). LCMS (ESI): [M+H] + = 710.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.99 (s, 1H), 7.89 (dd, J = 5.8, 9.0 Hz, 1H), 7.37 (t, J = 8.9 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 5.43 - 5.28 (m, 1H), 4.69 - 4.49 (m, 3H), 4.40 - 4.26 (m, 2H), 3.77 - 3.63 (m, 4H), 3.36 (br d, J = 5.3 Hz, 2H), 3.13 - 3.06 (m, 1H), 2.62 - 2.53 (m, 1H), 2.47 - 2.26 (m, 2H), 2.25 - 1.98 (m, 4H), 1.92 (br s, 4H), 1.72 - 1.59 (m, 2H), 1.49 (br s, 2H), 1.28 - 0.99 (m, 5H), 0.95 - 0.86 (m, 1H), 0.58 (br d, J = 13.3 Hz, 1H). Example 85 :1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one oxime
第一步:在25 oC下,將化合物1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮(20.0 mg,0.03 mmol),碳酸鈉(6.67 mg,0.06 mmol)和鹽酸羥胺(21.8 mg,0.31 mmol)溶於乙醇(200 uL),20 oC攪拌2小時。反應液減壓濃縮,殘留物用製備型HPLC純化,得到黃色固體化合物1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙-1-酮肟(0.85 mg,1.3 umol,產率1%)。LCMS (ESI): [M+H] += 651.2。 1H NMR (400 MHz, CD 3OD) δ ppm 7.75-7.48 (m, 2H), 7.48-7.27 (m, 2H), 7.02-6.88 (m, 1H), 5.62-5.38 (m, 1H), 4.71-4.68 (m, 2H), 4.03 (br s, 2H), 3.84-3.60 (m, 7H), 3.05 (s, 1H), 2.62-2.48 (m, 2H), 2.29 (s, 3H), 2.08-1.99 (m, 5H), 1.59 (s, 3H). 實施例 86:1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙烷-1-酮O-甲基肟 Step 1 : At 25 ° C, compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one (20.0 mg, 0.03 mmol), sodium carbonate (6.67 mg, 0.06 mmol) and hydroxylamine hydrochloride (21.8 mg, 0.31 mmol) were dissolved in ethanol (200 uL) and stirred at 20 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain a yellow solid compound 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one oxime (0.85 mg, 1.3 umol, yield 1%). LCMS (ESI): [M+H] + = 651.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.75-7.48 (m, 2H), 7.48-7.27 (m, 2H), 7.02-6.88 (m, 1H), 5.62-5.38 (m, 1H), 4.71-4.68 (m, 2H), 4.03 (br s, 2H), 3.84-3.60 (m, 7H), 3.05 (s, 1H), 2.62-2.48 (m, 2H), 2.29 (s, 3H), 2.08-1.99 (m, 5H), 1.59 (s, 3H). Example 86 :1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one O-methyl oxime
實施例 86使用與 實施例 85相同的操作方法,合成該化合物。1-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(7,8-二氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-6-基)乙烷-1-酮O-甲基肟(1.43 mg,白色固體)。LCMS (ESI): [M+H] += 665.3。 1H NMR (400 MHz, CD 3OD) δ ppm 7.83 (s, 1H), 7.67-7.54 (m, 1H), 7.49-7.21 (m, 2H), 6.97 (d, J= 2.1 Hz, 1H), 5.47-5.25 (m, 1H), 4.71-4.62 (m, 2H), 4.45-4.28 (m, 2H), 3.86-3.61 (m, 7H), 3.53-3.35 (m, 3H), 3.12 (br d, J= 6.0 Hz, 1H), 2.45-2.17 (m, 3H), 2.14-2.03 (m, 2H), 1.94 (br s, 5H), 1.64 (s, 3H). 實施例 87:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)萘-2-醇 Example 86 The compound was synthesized using the same operation method as Example 85. 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-6-yl)ethan-1-one O-methyloxime (1.43 mg, white solid). LCMS (ESI): [M+H] + = 665.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.83 (s, 1H), 7.67-7.54 (m, 1H), 7.49-7.21 (m, 2H), 6.97 (d, J = 2.1 Hz, 1H), 5.47-5.25 (m, 1H), 4.71-4.62 (m, 2H), 4.45-4.28 (m, 2H), 3.86-3.61 (m, 7H), 3.53-3.35 (m, 3H), 3.12 (br d, J = 6.0 Hz, 1H), 2.45-2.17 (m, 3H), 2.14-2.03 (m, 2H), 1.94 (br s, 5H), 1.64 (s, 3H). Example 87 : 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)naphthalen-2-ol
第一步:在25 oC下,向叔丁基(1R,5S)-3-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(1.60 g,2.76 mmol)和2-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(1.35 g,3.86 mmol)的二氧六環(32 mL)溶液中,加入碳酸鈉(1.3 M的水溶液,6.36 mL,0.78 mmol),氮氣氛圍下加入四(三苯基膦)鈀(18.8 mg,0.03 mmol)。反應系統在氮氣氛圍下100 oC攪拌16小時。冷卻至室溫,減壓濃縮,殘留物用快速管柱層析(矽膠,5-12%梯度的四氫呋喃/石油醚)純化,得到淺黃色固體化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(1.40 g,1.93 mmol,產率70%)。 1H NMR (400 MHz, CDCl 3) δ ppm 8.63 (s, 1H), 7.62-7.58 (m, 1H), 7.51 (s, 1H), 7.36-7.34 (m, 1H), 7.10 (d, J= 2.0 Hz, 1H), 5.33-5.28 (m, 2H), 4.92-4.88 (m, 2H), 4.60-4.52 (m, 2H), 4.47-4.44 (m, 2H), 3.79-3.72 (m, 2H), 3.54 (s, 3H), 2.05-2.01 (m, 2H), 1.84-1.80 (m, 2H), 1.55 (s, 9H). Step 1 : To a solution of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.60 g, 2.76 mmol) and 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.35 g, 3.86 mmol) in dioxane (32 mL) was added sodium carbonate (1.3 M in water, 6.36 mL, 0.78 mmol) at 25 °C. Under nitrogen atmosphere, palladium tetrakis(triphenylphosphine) (18.8 mg, 0.03 mmol) was added. The reaction system was stirred at 100 ° C for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 5-12% gradient tetrahydrofuran/petroleum ether) to obtain a light yellow solid compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.40 g, 1.93 mmol, yield 70%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.63 (s, 1H), 7.62-7.58 (m, 1H), 7.51 (s, 1H), 7.36-7.34 (m, 1H), 7.10 (d, J = 2.0 Hz, 1H), 5.33-5.28 (m, 2H), 4.92-4.88 (m, 2H), 4.60-4.52 (m, 2H), 4.47-4.44 (m, 2H), 3.79-3.72 (m, 2H), 3.54 (s, 3H), 2.05-2.01 (m, 2H), 1.84-1.80 (m, 2H), 1.55 (s, 9H).
第二步:在25 oC下,向叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(700 mg,0.97 mmol)和 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(176 mg,1.10 mmol)的四氫呋喃(14 mL)溶液中,加入叔丁醇鈉(279 mg,2.90 mmol)。反應系統25 oC攪拌2小時。加入水(50 mL)稀釋,使用乙酸乙酯(20 mL * 3)萃取,合併的有機相用飽和食鹽水(10 mL)洗滌,無水硫酸鈉乾燥,過濾,濾液旋轉乾燥,殘留物用快速管柱層析(矽膠,1-5%梯度的甲醇/二氯甲烷)純化。產品再用製備型HPLC純化得到淺黃色固體化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a-基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(300 mg,383 umol,產率39%)。 1H NMR (400 MHz, CDCl 3) δ ppm 8.62 (s, 1H), 7.60-7.57 (m, 1H), 7.50 (s, 1H), 7.38-7.31 (m, 1H), 7.11 (s, 1H), 5.56-5.42 (m, 1H), 5.33-5.28 (m, 2H), 4.77 (t, J= 7.8 Hz, 1H), 4.77-4.54 (m, 5H), 3.82-3.71 (m, 2H), 3.65-3.55 (m, 2H), 3.54 (m, 4H), 3.27-3.24 (m, 1H), 2.56-2.44 (m, 3H), 2.26-2.25 (m, 3H), 2.22-2.02 (m, 2H), 1.80-1.74 (m, 2H), 1.55 (s, 9H). Step 2 : Sodium tert-butoxide (279 mg, 2.90 mmol ) was added to a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 0.97 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (176 mg, 1.10 mmol) in tetrahydrofuran (14 mL) at 25 ° C. The reaction system was stirred at 25 ° C for 2 hours. Add water (50 mL) to dilute, extract with ethyl acetate (20 mL * 3), wash the combined organic phase with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, spin dry the filtrate, and purify the residue by flash column chromatography (silica gel, 1-5% gradient methanol/dichloromethane). The product was purified by preparative HPLC to obtain a light yellow solid compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 383 umol, yield 39%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.62 (s, 1H), 7.60-7.57 (m, 1H), 7.50 (s, 1H), 7.38-7.31 (m, 1H), 7.11 (s, 1H), 5.56-5.42 (m, 1H), 5.33-5.28 (m, 2H), 4.77 (t, J = 7.8 Hz, 1H), 4.77-4.54 (m, 5H), 3.82-3.71 (m, 2H), 3.65-3.55 (m, 2H), 3.54 (m, 4H), 3.27-3.24 (m, 1H), 2.56-2.46 (m, 3H), 2.26-2.25 (m, 3H), 2.22-2.02 (m, 2H), 1.80-1.74 (m, 2H), 1.55 (s, 9H).
第三步:在20 oC下,向叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a-基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(200 mg,0.26 mmol)的乙腈(2 mL)溶液中加入氯化氫(4 M的二氧六環溶液,958 uL,3.83 mmol)。將該溶液在20 oC攪拌2小時。溶液減壓濃縮,溶於乙腈(3 mL),加入三乙胺調節pH至7-8,減壓濃縮,殘留物用製備型HPLC純化,得到黃色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛基-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯啉-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇(51 mg,79.9 umol,產率31%)。LCMS (ESI): [M+H] += 639.2 實施例 87A和 實施例 87B :(S)-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇,和 (R)- 4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇 Step 3 : To a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.26 mmol) in acetonitrile (2 mL) was added hydrogen chloride (4 M in dioxane, 958 uL, 3.83 mmol) at 20 ° C. The solution was stirred at 20 ° C for 2 hours. The solution was concentrated under reduced pressure, dissolved in acetonitrile (3 mL), triethylamine was added to adjust the pH to 7-8, the solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (51 mg, 79.9 umol, yield 31%). LCMS (ESI): [M+H] + = 639.2 Example 87A and Example 87B : (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and (R)- 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
實施例 87經SFC分離(管柱:DAICEL CHIRALPAK IG (250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/異丙醇;B相保持60%;流速:80毫升/分鐘),得到目標化合物。 Example 87 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 60%; flow rate: 80 ml/min) to obtain the target compound.
異構物 1, 實施例 87A:LCMS (ESI): [M+H] += 639.1; SFC分析(層析管柱: Chiralpak IG-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相;流速:4毫升/分鐘):掌性管柱出峰位置為 0.829 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.71 (s, 1H), 7.63 (dd, J= 4.3, 8.8 Hz, 1H), 7.48-7.34 (m, 1H), 7.31 (s, 1H), 7.01 (d, J= 2.0 Hz, 1H), 5.53-5.30 (m, 1H), 4.78 (br d, J= 13.6 Hz, 1H), 4.69 (br d, J= 12.3 Hz, 1H), 4.56-4.43 (m, 2H), 4.11-3.84 (m, 4H), 3.60 (s, 1H), 3.58 (d, J= 3.5 Hz, 1H), 3.56 (s, 1H), 3.27-3.18 (m, 1H), 2.46-1.95 (m, 10H). Isomer 1, Example 87A : LCMS (ESI): [M+H] + = 639.1; SFC analysis (chromatographic column: Chiralpak IG-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B; flow rate: 4 ml/min): the elution position of the palmar column is 0.829 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.71 (s, 1H), 7.63 (dd, J = 4.3, 8.8 Hz, 1H), 7.48-7.34 (m, 1H), 7.31 (s, 1H), 7.01 (d, J = 2.0 Hz, 1H), 5.53-5.30 (m, 1H), 4.78 (br d, J = 13.6 Hz, 1H), 4.69 (br d, J = 12.3 Hz, 1H), 4.56-4.43 (m, 2H), 4.11-3.84 (m, 4H), 3.60 (s, 1H), 3.58 (d, J = 3.5 Hz, 1H), 3.56 (s, 1H), 3.27-3.18 (m, 1H), 2.46-1.95 (m, 10H).
異構物 2 , 實施例 87B :LCMS (ESI): [M+H] += 639.1; SFC分析(層析管柱: Chiralpak IG-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相;流速:4毫升/分鐘):掌性管柱出峰位置為 2.576 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.70 (s, 1H), 7.61 (dd, J= 3.6, 9.2 Hz, 1H), 7.46-7.32 (m, 1H), 7.33-7.21 (m, 1H), 7.00 (d, J= 2.3 Hz, 1H), 5.41-5.17 (m, 1H), 4.69-4.49 (m, 2H), 4.35-4.20 (m, 2H), 3.84-3.63 (m, 4H), 3.30-3.14 (m, 3H), 3.02 (dt, J= 5.8, 9.3 Hz, 1H), 2.30-1.75 (m, 10H). 實施例 88:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇 Isomer 2 , Example 87B : LCMS (ESI): [M+H] + = 639.1; SFC analysis (chromatographic column: Chiralpak IG-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B; flow rate: 4 ml/min): the elution position of the palmar column is 2.576 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.70 (s, 1H), 7.61 (dd, J = 3.6, 9.2 Hz, 1H), 7.46-7.32 (m, 1H), 7.33-7.21 (m, 1H), 7.00 (d, J = 2.3 Hz, 1H), 5.41-5.17 (m, 1H), 4.69-4.49 (m, 2H), 4.35-4.20 (m, 2H), 3.84-3.63 (m, 4H), 3.30-3.14 (m, 3H), 3.02 (dt, J = 5.8, 9.3 Hz, 1H), 2.30-1.75 (m, 10H). Example 88 :4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
第一步:在氮氣環境下,向叔丁基(1R,5S)-3-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(3.10 g,5.34 mmol)和 (((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(3.56 g,6.94 mmol)的甲苯(124 mL)和水(31 mL)的混合溶液中,加入碳酸銫(5.22 g,16.03 mmol),甲磺醯氧基(二金剛烷基-正丁基膦基)-2-胺基-1,1-聯苯-2-基)鈀(II)(0.78 g,1.07 mmol)。將混合物在100 oC攪拌16小時。將殘餘物加水(150 mL)稀釋並用乙酸乙酯(150 mL * 3)萃取,合併的有機相用飽和食鹽水(150 mL)洗滌,無水硫酸鎂乾燥並過濾,濾液真空濃縮。殘餘物透過快速管柱層析(矽膠,0-10%梯度四氫呋喃/石油醚)純化得到棕色固體化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(3.27 g,3.69 mmol,產率69%)。LCMS (ESI): [M+H] += 886.1. Step 1 : To a mixed solution of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.10 g, 5.34 mmol) and (((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.56 g, 6.94 mmol) in toluene (124 mL) and water (31 mL) under nitrogen atmosphere, cesium carbonate (5.22 g, 16.03 mmol) was added. mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (0.78 g, 1.07 mmol). The mixture was stirred at 100 o C for 16 hours. The residue was diluted with water (150 mL) and extracted with ethyl acetate (150 mL * 3), the combined organic phases were washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient tetrahydrofuran/petroleum ether) to give a brown solid compound tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.27 g, 3.69 mmol, yield 69%). LCMS (ESI): [M+H] + = 886.1.
第二步:向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(500 mg,0.56 mmol)的四氫呋喃(10 mL)溶液中加入4A分子篩(500 mg),叔丁醇鈉(108 mg,1.12 mmol)和 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(180 mg,1.12 mmol)。將反應在20 oC攪拌2小時。混合物用水(10 mL)稀釋並用乙酸乙酯(10 mL*3)萃取,並用飽和食鹽水(20 mL)洗滌,無水硫酸鎂乾燥。濾液濃縮,殘餘物透過快速管柱層析(矽膠,0-7%梯度甲醇/二氯甲烷)純化得到棕色固體化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(460 mg,0.49 mmol,產率87%)。LCMS (ESI): [M+H] += 945.6. Step 2 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.56 mmol) in tetrahydrofuran (10 mL) was added 4A molecular sieve (500 mg), sodium tert-butoxide (108 mg, 1.12 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (180 mg, 1.12 mmol). The reaction was stirred at 20 ° C for 2 hours. The mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL*3), washed with saturated brine (20 mL), and dried over anhydrous magnesium sulfate. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 0-7% gradient methanol/dichloromethane) to give a brown solid compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (460 mg, 0.49 mmol, yield 87%). LCMS (ESI): [M+H] + = 945.6.
第三步:向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(440 mg,0.47 mmol)的二甲基甲醯胺(5 mL)溶液中加入氟化銫(566 mg,3.7 mmol)。將反應在20 oC攪拌2小時。混合物用水(15 mL)稀釋並用乙酸乙酯(10 mL*3)萃取,合併的有機相用飽和食鹽水(20 mL)洗滌,無水硫酸鎂乾燥,過濾,濾液濃縮,殘餘物透過快速管柱層析(矽膠,0-7%梯度甲醇/二氯甲烷)純化得到棕色固體化合物叔丁基(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(330 mg,0.42 mmol,產率89%)。LCMS (ESI): [M+H] += 789.2. Step 3 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (440 mg, 0.47 mmol) in dimethylformamide (5 mL) was added cesium fluoride (566 mg, 3.7 mmol). The reaction was stirred at 20 ° C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-7% gradient methanol/dichloromethane) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (330 mg, 0.42 mmol, yield 89%). LCMS (ESI): [M+H] + = 789.2.
第四步:向叔丁基(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(330 mg,0.42 mmol)的乙腈(6.5 mL)溶液中加入氯化氫(4 M的二氧六環溶液,2 mL,8 mmol)。將反應在20 oC攪拌1小時。真空旋轉乾燥後溶於乙腈(5 mL)並用三乙胺中和,然後減壓濃縮。殘餘物透過製備型HPLC純化,得到黃色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇(118 mg,0.18 mmol,產率43%)。LCMS (ESI): [M+H] += 645.1. 實施例 88A和 實施例 88B :(S)- 4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇,和 (R)- 4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇 Step 4 : To a solution of tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (330 mg, 0.42 mmol) in acetonitrile (6.5 mL) was added hydrogen chloride (4 M in dioxane, 2 mL, 8 mmol). The reaction was stirred at 20 ° C for 1 hour. After vacuum rotary drying, it was dissolved in acetonitrile (5 mL) and neutralized with triethylamine, then concentrated under reduced pressure. The residue was purified by preparative HPLC to give a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (118 mg, 0.18 mmol, yield 43%). LCMS (ESI): [M+H] + = 645.1. Example 88A and Example 88B : (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, and (R)- 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
實施例 88經SFC分離(管柱:DAICEL CHIRALPAK AD(250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/乙醇;B相保持50%;流速:80毫升/分鐘),得到目標化合物。 Example 88 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 50%; flow rate: 80 ml/min) to obtain the target compound.
異構物 1, 實施例 88A:LCMS (ESI): [M+H] += 645.2; SFC分析(管柱: ChiralPak AD-3,150 * 4.6 mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持40%的B相;流速:2.5毫升/分鐘;):掌性管柱出峰位置為 1.865 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.69-8.65 (m, 1H), 7.86 (dd, J= 5.6, 9.2 Hz, 1H), 7.35-7.29 (m, 2H), 7.00 (d, J= 2.3 Hz, 1H), 5.40-5.24 (m, 1H), 4.67 (br d, J= 12.5 Hz, 1H), 4.52 (br d, J= 12.5 Hz, 1H), 4.36-4.21 (m, 2H), 3.82 (br d, J= 12.0 Hz, 1H), 3.72-3.62 (m, 3H), 3.36 (s, 1H), 3.32-3.19 (m, 3H), 3.04 (dt, J= 5.6, 9.5 Hz, 1H), 2.40-2.12 (m, 3H), 2.05-1.79 (m, 7H). Isomer 1, Example 88A : LCMS (ESI): [M+H] + = 645.2; SFC analysis (column: ChiralPak AD-3, 150 * 4.6 mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 40% phase B; flow rate: 2.5 ml/min;): the elution position of the palmar column is 1.865 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.69-8.65 (m, 1H), 7.86 (dd, J = 5.6, 9.2 Hz, 1H), 7.35-7.29 (m, 2H), 7.00 (d, J = 2.3 Hz, 1H), 5.40-5.24 (m, 1H), 4.67 (br d, J = 12.5 Hz, 1H), 4.52 (br d, J = 12.5 Hz, 1H), 4.36-4.21 (m, 2H), 3.82 (br d, J = 12.0 Hz, 1H), 3.72-3.62 (m, 3H), 3.36 (s, 1H), 3.32-3.19 (m, 3H), 3.04 (dt, J = 5.6, 9.5 Hz, 1H), 2.40-2.12 (m, 3H), 2.05-1.79 (m, 7H).
異構物 2, 實施例 88B:LCMS (ESI): [M+H] += 645.1; SFC分析(管柱: ChiralPak AD-3,150 * 4.6 mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持40%的B相;流速:2.5毫升/分鐘;):掌性管柱出峰位置為 3.293 min; 1H NMR (400 MHz, CD 3OD) δppm 8.68-8.65 (m, 1H), 7.86 (dd, J= 5.8, 9.3 Hz, 1H), 7.35-7.30 (m, 2H), 7.00 (d, J= 2.5 Hz, 1H), 5.40-5.24 (m, 1H), 4.66 (br d, J= 12.3 Hz, 1H), 4.54 (br d, J= 12.3 Hz, 1H), 4.29 (q, J= 10.5 Hz, 2H), 3.80 (br d, J= 12.0 Hz, 1H), 3.71-3.65 (m, 3H), 3.38-3.36 (m, 1H), 3.32-3.19 (m, 3H), 3.04 (dt, J= 5.8, 9.5 Hz, 1H), 2.40-2.14 (m, 3H), 2.04-1.80 (m, 7H). 實施例 89:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇 Isomer 2, Example 88B : LCMS (ESI): [M+H] + = 645.1; SFC analysis (column: ChiralPak AD-3, 150 * 4.6 mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 40% phase B; flow rate: 2.5 ml/min;): the palmar column peak position is 3.293 min; 1 H NMR (400 MHz, CD 3 OD) δppm 8.68-8.65 (m, 1H), 7.86 (dd, J = 5.8, 9.3 Hz, 1H), 7.35-7.30 (m, 2H), 7.00 (d, J = 2.5 Hz, 1H), 5.40-5.24 (m, 1H), 4.66 (br d, J = 12.3 Hz, 1H), 4.54 (br d, J = 12.3 Hz, 1H), 4.29 (q, J = 10.5 Hz, 2H), 3.80 (br d, J = 12.0 Hz, 1H), 3.71-3.65 (m, 3H), 3.38-3.36 (m, 1H), 3.32-3.19 (m, 3H), 3.04 (dt, J = 5.8, 9.5 Hz, 1H), 2.40-2.14 (m, 3H), 2.04-1.80 (m, 7H). Example 89 :4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
實施例 89採用與 實施例 87相同的方法,合成了該化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇(甲酸鹽,220 mg,黃色固體)。LCMS (ESI): [M+H] += 683.1。 1H-NMR (400 MHz, CD 3OD) δ ppm 8.71 (s, 1H), 8.46 (s, 1H), 7.63 (dd, J= 4.0, 9.0 Hz, 1H), 7.45-7.38 (m, 1H), 7.31 (s, 1H), 7.01 (d, J = 2.1 Hz, 1H), 4.78-4.69 (m, 2H), 4.59-4.51 (m, 2H), 4.07 (br s, 2H), 4.00-3.83 (m, 2H), 3.61 (br dd, J= 6.3, 12.1 Hz, 1H), 3.51-3.42 (m, 1H), 3.13 (br d, J= 12.4 Hz, 1H), 3.00-2.88 (m, 1H), 2.44 (br dd, J= 4.1, 13.6 Hz, 1H), 2.27 (br dd, J= 5.9, 11.7 Hz, 1H), 2.19-1.90 (m, 8H), 1.67-1.53 (m, 2H). 實施例 89AB和 實施例 89C和 實施例 89D :(S)-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇,和 (S)-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇,和 (R)-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇,和 (R)-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇 Example 89 The compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2' - pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (formate salt, 220 mg, yellow solid) was synthesized by the same method as Example 87. LCMS (ESI): [M+H] + = 683.1. 1 H-NMR (400 MHz, CD 3 OD) δ ppm 8.71 (s, 1H), 8.46 (s, 1H), 7.63 (dd, J = 4.0, 9.0 Hz, 1H), 7.45-7.38 (m, 1H), 7.31 (s, 1H), 7.01 (d, J = 2.1 Hz, 1H), 4.78-4.69 (m, 2H), 4.59-4.51 (m, 2H), 4.07 (br s, 2H), 4.00-3.83 (m, 2H), 3.61 (br dd, J = 6.3, 12.1 Hz, 1H), 3.51-3.42 (m, 1H), 3.13 (br d, J = 12.4 Hz, 1H), 3.00-2.88 (m, 1H), 2.44 (br dd, J = 4.1, 13.6 Hz, 1H), 2.27 (br dd, J = 5.9, 11.7 Hz, 1H), 2.19-1.90 (m, 8H), 1.67-1.53 (m, 2H). Example 89AB , Example 89C and Example 89D : (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and (R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol , and (R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
實施例 89經SFC分離(管柱:DAICEL CHIRALPAK IG (250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/異丙醇;B相保持55%;流速:80毫升/分鐘),得到目標化合物。 Example 89 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 55%; flow rate: 80 ml/min) to obtain the target compound.
異構物 1&2 混合物, 實施例 89AB :LCMS (ESI): [M+H] += 683.1; SFC分析(管柱:Chiralpak AD-3 150 * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持40%的B相,流速:2.5毫升/分鐘):掌性管柱出峰位置為 1.771 min和2.830 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.69 (s, 1H), 7.60 (dd, J= 3.7, 9.2 Hz, 1H), 7.38 (q, J= 9.1 Hz, 1H), 7.27 (s, 1H), 6.99 (d, J= 2.1 Hz, 1H), 4.64 (br d, J= 14.0 Hz, 1H), 4.55 (br d, J= 12.3 Hz, 1H), 4.40-4.32 (m, 2H), 3.80-3.62 (m, 4H), 3.30-3.24 (m, 1H), 3.17-3.12 (m, 1H), 2.83 (d, J= 12.3 Hz, 1H), 2.73-2.65 (m, 1H), 2.27 (br dd, J= 5.3, 13.4 Hz, 1H), 2.13 (br dd, J= 5.4, 10.4 Hz, 1H), 2.02 (d, J= 13.4 Hz, 1H), 1.96-1.75 (m, 7H), 1.50-1.35 (m, 2H). Isomer 1 & 2 mixture, Example 89AB : LCMS (ESI): [M+H] + = 683.1; SFC analysis (column: Chiralpak AD-3 150 * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 40% phase B, flow rate: 2.5 ml/min): palmitic column peak positions are 1.771 min and 2.830 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.69 (s, 1H), 7.60 (dd, J = 3.7, 9.2 Hz, 1H), 7.38 (q, J = 9.1 Hz, 1H), 7.27 (s, 1H), 6.99 (d, J = 2.1 Hz, 1H), 3.86 (m, 4H), 3.24-3.32 (m, 1H), 3.19 (d, J = 12.3 Hz, 1H), 3.73-3.76 (m, 1H), 3.25 (br dd, J = 5.3, 13.4 Hz, 1H), 3.14 (br dd, J = 5.8, 10.5 Hz, 1H), 3.55 (d, J = 12.3 Hz, 1H), 3.24 (m, 4H), 3.16 (m, 1H) , 3.54 (d, J = 12.3 Hz, 1H), 3.25 (m, 1H), 3.30 (m, 1H), 3.19 (m, 1H), 3. 7H), 1.50-1.35 (m, 2H).
異構物 3 , 實施例 89C :LCMS (ESI): [M+H] += 683.1; SFC分析(管柱:Chiralpak IG-3,100 * 4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相,流速:2.8毫升/分鐘):掌性管柱出峰位置為 6.175 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.69 (s, 1H), 7.60 (dd, J= 3.7, 9.3 Hz, 1H), 7.45-7.31 (m, 1H), 7.27 (s, 1H), 6.99 (d, J= 2.1 Hz, 1H), 4.66-4.55 (m, 2H), 4.40-4.31 (m, 2H), 3.81-3.61 (m, 4H), 3.27 (br d, J= 6.9 Hz, 1H), 3.18-3.12 (m, 1H), 2.83 (d, J= 12.1 Hz, 1H), 2.75-2.64 (m, 1H), 2.32-2.09 (m, 2H), 2.02 (br d, J= 13.5 Hz, 1H), 1.96-1.72 (m, 7H), 1.49-1.36 (m, 2H). Isomer 3 , Example 89C : LCMS (ESI): [M+H] + = 683.1; SFC analysis (column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min): the palmar column peak position is 6.175 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.69 (s, 1H), 7.60 (dd, J = 3.7, 9.3 Hz, 1H), 7.45-7.31 (m, 1H), 7.27 (s, 1H), 6.99 (d, J = 2.1 Hz, 1H), 4.66-4.55 (m, 2H), 4.40-4.31 (m, 2H), 3.81-3.61 (m, 4H), 3.27 (br d, J = 6.9 Hz, 1H), 3.18-3.12 (m, 1H), 2.83 (d, J = 12.1 Hz, 1H), 2.75-2.64 (m, 1H), 2.32-2.09 (m, 2H), 2.02 (br d, J = 13.5 Hz, 1H), 1.96-1.72 (m, 7H), 1.49-1.36 (m, 2H).
異構物 4 ,實施例 89D :LCMS (ESI): [M+H] += 683.1; SFC分析(管柱:Chiralpak IG-3,100 * 4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相,流速:2.8毫升/分鐘):掌性管柱出峰位置為 9.134 min; 1H NMR (400 MHz, CD3OD) δ ppm 8.69 (s, 1H), 7.60 (d, J= 9.0 Hz, 1H), 7.38 (q, J= 8.9 Hz, 1H), 7.28 (s, 1H), 6.99 (d, J= 2.1 Hz, 1H), 4.67 (br d, J= 11.6 Hz, 1H), 4.57 (br d, J= 12.3 Hz, 1H), 4.43-4.33 (m, 2H), 3.85-3.67 (m, 4H), 3.38-3.32 (m, 1H), 3.23-3.15 (m, 1H), 2.87 (d, J= 12.1 Hz, 1H), 2.79-2.66 (m, 1H), 2.29 (dd, J= 6.2, 13.7 Hz, 1H), 2.22-2.09 (m, 1H), 2.03 (br d, J= 13.5 Hz, 1H), 1.98-1.75 (m, 7H), 1.52-1.36 (m, 2H). 實施例 90:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇 Isomer 4 , Example 89D : LCMS (ESI): [M+H] + = 683.1; SFC analysis (column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min): the elution position of the palmar column is 9.134 min; 1 H NMR (400 MHz, CD3OD) δ ppm 8.69 (s, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.38 (q, J = 8.9 Hz, 1H), 7.28 (s, 1H), 6.99 (d, J = 2.1 Hz, 1H), 4.67 (br d, J = 11.6 Hz, 1H), 4.57 (br d, J = 12.3 Hz, 1H), 4.43-4.33 (m, 2H), 3.85-3.67 (m, 4H), 3.38-3.32 (m, 1H), 3.23-3.15 (m, 1H), 2.87 (d, J = 12.1 Hz, 1H), 2.79-2.66 (m, 1H), 2.29 (dd, J = 6.2, 13.7 Hz, 1H), 2.22-2.09 (m, 1H), 2.03 (br d, J = 13.5 Hz, 1H), 1.98-1.75 (m, 7H), 1.52-1.36 (m, 2H). Example 90 :4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
實施例 90採用與 實施例 88相同的方法,合成了該化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇(甲酸鹽,328 mg,黃色固體0.47 mmol)。LCMS (ESI): [M+H] += 689.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.67 (s, 1H), 8.47 (s, 1H), 7.88 (dd, J = 5.8, 9.1 Hz, 1H), 7.38-7.29 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 4.77-4.64 (m, 2H), 4.59-4.49 (m, 2H), 4.07 (br s, 2H), 3.97 (br d, J = 13.3 Hz, 1H), 3.88-3.78 (m, 1H), 3.65-3.54 (m, 1H), 3.50-3.40 (m, 1H), 3.39-3.35 (m, 1H), 3.11 (d, J = 12.3 Hz, 1H), 2.97-2.88 (m, 1H), 2.49-2.36 (m, 1H), 2.32-2.20 (m, 1H), 2.18-1.89 (m, 8H), 1.66-1.52 (m, 2H). 實施例 90A和 實施例 90B和 實施例 90C :(S)-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇,和 (S)-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇,和 (R)-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇,和 (R)-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇 Example 90 The compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2' - pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (formate salt, 328 mg, yellow solid 0.47 mmol) was synthesized by the same method as Example 88. LCMS (ESI): [M+H] + = 689.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.67 (s, 1H), 8.47 (s, 1H), 7.88 (dd, J = 5.8, 9.1 Hz, 1H), 7.38-7.29 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 4.77-4.64 (m, 2H), 4.59-4.49 (m, 2H), 4.07 (br s, 2H), 3.97 (br d, J = 13.3 Hz, 1H), 3.88-3.78 (m, 1H), 3.65-3.54 (m, 1H), 3.50-3.40 (m, 1H), 3.39-3.35 (m, 1H), 3.11 (d, J = 12.3 Hz, 1H), 2.97-2.88 (m, 1H), 2.49-2.36 (m, 1H), 2.32-2.20 (m, 1H), 2.18-1.89 (m, 8H), 1.66-1.52 (m, 2H). Example 90A , Example 90B and Example 90C : (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, and (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, and (R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol , and (R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
實施例 90經SFC分離(管柱:DAICEL CHIRALPAK IG (250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/乙醇;B相保持55%;流速:80毫升/分鐘),得到目標化合物。 Example 90 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 55%; flow rate: 80 ml/min) to obtain the target compound.
異構物 1&2 混合物, 實施例 90A :LCMS (ESI): [M+H] += 689.2; SFC分析(管柱:Chiralpak IG-3,100 * 4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持40%的B相,流速:2.8毫升/分鐘):掌性管柱出峰位置為 1.381 min和1.413 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.66 (s, 1H), 7.85 (dd, J= 5.8, 9.1 Hz, 1H), 7.35-7.25 (m, 2H), 6.98 (d, J= 2.3 Hz, 1H), 4.65 (br d, J= 12.9 Hz, 1H), 4.51 (br d, J= 12.4 Hz, 1H), 4.39-4.30 (m, 2H), 3.79 (br d, J= 12.4 Hz, 1H), 3.67 (br s, 3H), 3.36-3.33 (m, 1H), 3.29-3.24 (m, 1H), 3.20-3.09 (m, 1H), 2.83 (d, J= 12.3 Hz, 1H), 2.74-2.64 (m, 1H), 2.26 (td, J= 5.2, 13.4 Hz, 1H), 2.18-2.09 (m, 1H), 2.01 (br d, J= 13.6 Hz, 1H), 1.94-1.75 (m, 7H), 1.49-1.35 (m, 2H). Isomer 1 & 2 mixture, Example 90A : LCMS (ESI): [M+H] + = 689.2; SFC analysis (column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min): palmitic column peak positions are 1.381 min and 1.413 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.66 (s, 1H), 7.85 (dd, J = 5.8, 9.1 Hz, 1H), 7.35-7.25 (m, 2H), 6.98 (d, J = 2.3 Hz, 1H), 4.65 (br d, J = 12.9 Hz, 1H), 4.51 (br d, J = 12.4 Hz, 1H), 4.39-4.30 (m, 2H), 3.79 (br d, J = 12.4 Hz, 1H), 3.67 (br s, 3H), 3.36-3.33 (m, 1H), 3.29-3.24 (m, 1H), 3.20-3.09 (m, 1H), 2.83 (d, J = 12.3 Hz, 1H), 2.74-2.64 (m, 1H), 2.26 (td, J = 5.6, 13.4 Hz, 1H), 2.18-2.09 (m, 1H), 2.18 (br d, J = 13.6 Hz, 1H), 1.94-1.75 (m, 7H), 1.49-1.35 (m, 2H).
異構物 3 , 實施例 90B :LCMS (ESI): [M+H] += 689.2; SFC分析(管柱:Chiralpak IG-3,100 * 4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持40%的B相,流速:2.8毫升/分鐘):掌性管柱出峰位置為 2.974 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.66 (s, 1H), 7.85 (dd, J = 5.8, 9.1 Hz, 1H), 7.37-7.27 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 4.64 (br d, J = 11.5 Hz, 1H), 4.52 (br d, J = 12.6 Hz, 1H), 4.35 (s, 2H), 3.79 (br d, J = 12.0 Hz, 1H), 3.71-3.63 (m, 3H), 3.36-3.34 (m, 1H), 3.30-3.24 (m, 1H), 3.18-3.11 (m, 1H), 2.83 (d, J = 12.1 Hz, 1H), 2.74-2.65 (m, 1H), 2.30-2.10 (m, 2H), 2.01 (br d, J = 13.5 Hz, 1H), 1.96-1.75 (m, 7H), 1.50-1.35 (m, 2H). Isomer 3 , Example 90B : LCMS (ESI): [M+H] + = 689.2; SFC analysis (column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min): the palmar column peak position is 2.974 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.66 (s, 1H), 7.85 (dd, J = 5.8, 9.1 Hz, 1H), 7.37-7.27 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 4.64 (br d, J = 11.5 Hz, 1H), 4.52 (br d, J = 12.6 Hz, 1H), 4.35 (s, 2H), 3.79 (br d, J = 12.0 Hz, 1H), 3.71-3.63 (m, 3H), 3.36-3.34 (m, 1H), 3.30-3.24 (m, 1H), 3.18-3.11 (m, 1H), 2.83 (d, J = 12.1 Hz, 1H), 2.74-2.65 (m, 1H), 2.30-2.10 (m, 2H), 2.01 (br d, J = 13.5 Hz, 1H), 1.96-1.75 (m, 7H), 1.50-1.35 (m, 2H).
異構物 4 , 實施例 90C :LCMS (ESI): [M+H] += 689.2; SFC分析(管柱:Chiralpak IG-3,100 * 4.6mm I.D.,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持40%的B相,流速:2.8毫升/分鐘):掌性管柱出峰位置為 6.670 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.66 (s, 1H), 7.85 (dd, J = 5.9, 9.1 Hz, 1H), 7.35-7.27 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 4.65 (br d, J = 12.0 Hz, 1H), 4.51 (br d, J = 12.3 Hz, 1H), 4.40-4.29 (m, 2H), 3.79 (br d, J = 12.4 Hz, 1H), 3.71-3.61 (m, 3H), 3.34 (s, 1H), 3.27 (d, J = 6.8 Hz, 1H), 3.18-3.11 (m, 1H), 2.83 (d, J = 12.1 Hz, 1H), 2.74-2.65 (m, 1H), 2.27 (dd, J = 6.3, 13.4 Hz, 1H), 2.21-2.08 (m, 1H), 2.02 (br d, J = 13.4 Hz, 1H), 1.96-1.74 (m, 7H), 1.50-1.35 (m, 2H). 實施例 91:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇 Isomer 4 , Example 90C : LCMS (ESI): [M+H] + = 689.2; SFC analysis (column: Chiralpak IG-3, 100 * 4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 40% phase B, flow rate: 2.8 ml/min): the palmar column peak position is 6.670 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.66 (s, 1H), 7.85 (dd, J = 5.9, 9.1 Hz, 1H), 7.35-7.27 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 4.65 (br d, J = 12.0 Hz, 1H), 3.54 (m, 2H), 3.76 (m, 3H), 3.23 (d, J = 6.8 Hz, 1H), 3.12 (m, 1H), 3.54 (d, J = 12.1 Hz, 1H), 3.74 (m, 2H), 3.85 (m, 3H), 3.24 (d, J = 12.2 Hz, 1H), 3.19 (m, 1H), 3.85 (m, 1H), 3.23 (d, J = 12.1 Hz, 1H), 3.28 (m, 1H), 3.82 (m, 1H), 3.60 (m, 3H), 3.89 (m, 1H), 3.91 (m, 1H), 3.80 (m, 1H), (m, 7H), 1.50-1.35 (m, 2H). Example 91 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
實施例 91使用與 實施例 87相同的方法,合成了目標化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1R,7a'S)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇。LCMS (ESI): [M+H] += 683.1。 1H NMR (400MHz, DMSO- d6) δ ppm 10.32 (br s, 1H), 8.64 (s, 1H), 7.74 (dd, J= 4.6, 8.9 Hz, 1H), 7.61-7.53 (m, 1H), 7.35 (s, 1H), 7.07 (s, 1H), 4.51-4.33 (m, 2H), 4.10-3.96 (m, 2H), 3.75-3.49 (m, 4H), 3.03 (d, J= 10.3 Hz, 1H), 2.99-2.93 (m, 1H), 2.77 (br dd, J= 5.9, 10.4 Hz, 1H), 2.67 (td, J= 6.5, 9.6 Hz, 2H), 2.13-2.08 (m, 1H), 1.99-1.72 (m, 5H), 1.68-1.58 (m, 4H), 1.57-1.49 (m, 2H). 實施例 92:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇 Example 91 The target compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'S)-2,2-difluorodihydro-1'H,3'H - spiro[cyclopropane- 1,2' -pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol was synthesized using the same method as Example 87. LCMS (ESI): [M+H] + = 683.1. 1 H NMR (400 MHz, DMSO- d 6) δ ppm 10.32 (br s, 1H), 8.64 (s, 1H), 7.74 (dd, J = 4.6, 8.9 Hz, 1H), 7.61-7.53 (m, 1H), 7.35 (s, 1H), 7.07 (s, 1H), 4.51-4.33 (m, 2H), 4.10-3.96 (m, 2H), 3.75-3.49 (m, 4H), 3.03 (d, J = 10.3 Hz, 1H), 2.99-2.93 (m, 1H), 2.77 (br dd, J = 5.9, 10.4 Hz, 1H), 2.67 (td, J = 6.5, 9.6 Hz, 2H), 2.13-2.08 (m, 1H), 1.99-1.72 (m, 5H), 1.68-1.58 (m, 4H), 1.57-1.49 (m, 2H). Example 92 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
實施例 92採用與 實施例 88相同的方法,合成了該化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((1S,7a'R)-2,2-二氟二氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇(52.95 mg,黃色固體)。LCMS (ESI): [M+H] += 689.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.67 (s, 1H), 8.47 (br s, 1H), 7.88 (dd, J = 5.7, 9.3 Hz, 1H), 7.38-7.30 (m, 2H), 7.01 (d, J = 2.3 Hz, 1H), 4.77-4.64 (m, 2H), 4.52-4.43 (m, 2H), 4.10-3.92 (m, 3H), 3.85 (br dd, J = 6.5, 13.6 Hz, 1H), 3.58-3.46 (m, 1H), 3.43-3.35 (m, 2H), 3.23-3.07 (m, 2H), 2.45 (br d, J = 13.4 Hz, 1H), 2.26-2.14 (m, 3H), 2.13-1.95 (m, 6H), 1.64-1.56 (m, 2H). 實施例 93:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2,8-雙((1-(嗎啉代甲基)環丙基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇 實施例 94:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇 Example 92 The compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2' - pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (52.95 mg, yellow solid) was synthesized by the same method as Example 88. LCMS (ESI): [M+H] + = 689.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.67 (s, 1H), 8.47 (br s, 1H), 7.88 (dd, J = 5.7, 9.3 Hz, 1H), 7.38-7.30 (m, 2H), 7.01 (d, J = 2.3 Hz, 1H), 4.77-4.64 (m, 2H), 4.52-4.43 (m, 2H), 4.10-3.92 (m, 3H), 3.85 (br dd, J = 6.5, 13.6 Hz, 1H), 3.58-3.46 (m, 1H), 3.43-3.35 (m, 2H), 3.23-3.07 (m, 2H), 2.45 (br d, J = 13.4 Hz, 1H), 2.26-2.14 (m, 3H), 2.13-1.95 (m, 6H), 1.64-1.56 (m, 2H). Example 93 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2,8-bis((1-(oxolinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol Example 94 :4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(oxo-1-methyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
第一步:在0 oC下,向化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(200 mg,0.28 mmol)和 (1-(嗎啉甲基)環丙基)甲醇(236 mg,1.38 mmol)的四氫呋喃(3 mL)溶液中慢慢加入叔丁醇鈉(106 mg,1.11 mmol),反應在25 oC攪拌2小時。反應液加入水(4 mL)稀釋,乙酸乙酯(3 mL * 2)萃取,有機相用無水硫酸鎂乾燥,過濾,減壓濃縮。殘餘物透過快速矽膠層析法(矽膠,0-30%梯度的四氫呋喃/石油醚)純化得到黃色油狀化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(75% purity,210.0 mg,0.17 mmol,產率62%)LCMS (ESI): [M+2H] 2+/2 = 398.0和化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2,8-雙((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(90.0 mg,0.09 mmol,產率35%)。LCMS (ESI): [M+2H] 2+/2 = 473.6. Step 1 : At 0 ° C, sodium tert-butoxide (106 mg, 1.11 mmol) was slowly added to a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.28 mmol) and (1-(morpholinomethyl)cyclopropyl)methanol (236 mg, 1.38 mmol) in tetrahydrofuran (3 mL) at 0 ° C. The reaction was stirred at 25 ° C for 2 hours. The reaction solution was diluted with water (4 mL), extracted with ethyl acetate (3 mL * 2), and the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica gel, 0-30% gradient tetrahydrofuran/petroleum ether) to give a yellow oily compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75% purity, 210.0 mg, 0.17 mmol, yield 62%). LCMS (ESI): [M+2H] 2+ /2 = 398.0 and compound tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,8-bis((1-(phenolinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg, 0.09 mmol, yield 35%). LCMS (ESI): [M+2H] 2+ /2 = 473.6.
第二步:在25 oC下,向叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(200 mg,0.19 mmol)的乙腈(2 mL)溶液中加入氯化氫(4 M的二氧六環溶液,943 uL,3.77 mmol)。將該溶液在20 oC攪拌1小時。溶液用三乙胺(100 uL)淬滅並濃縮。混合物透過製備型HPLC純化,得到黃色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇 實施例 94(甲酸鹽,17.10 mg,26.0 umol,產率14%)。LCMS (ESI): [M+H] += 650.9。 1H NMR (400 MHz, CD 3OD) δ ppm 8.67 (s, 1H), 8.43 (br s, 1H), 7.61 (dd, J= 9.4, 4.0Hz, 1H), 7.45-7.35 (m, 1H), 7.29 (s, 1H), 6.99 (d, J= 1.9Hz, 1H), 4.80-4.56 (m, 2H), 4.49-4.41 (m, 2H), 4.11 (br s, 2H), 3.96-3.83 (m, 2H), 3.68 (br t, J= 4.2Hz, 4H), 2.67-2.54 (m, 6H), 2.08 (br s, 4H), 0.75 (s, 2H), 0.56 (s, 2H). Step 2 : To a solution of tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.19 mmol) in acetonitrile (2 mL) was added hydrogen chloride (4 M in dioxane, 943 uL, 3.77 mmol) at 25 °C. The solution was stirred at 20 ° C for 1 hour. The solution was quenched with triethylamine (100 uL) and concentrated. The mixture was purified by preparative HPLC to give a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol Example 94 (formate salt, 17.10 mg, 26.0 umol, yield 14%). LCMS (ESI): [M+H] + = 650.9. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.67 (s, 1H), 8.43 (br s, 1H), 7.61 (dd, J = 9.4, 4.0Hz, 1H), 7.45-7.35 (m, 1H), 7.29 (s, 1H), 6.99 (d, J = 1.9Hz, 1H), 4.80-4.56 (m, 2H), 4.49-4.41 (m, 2H), 4.11 (br s, 2H), 3.96-3.83 (m, 2H), 3.68 (br t, J = 4.2Hz, 4H), 2.67-2.54 (m, 6H), 2.08 (br s, 4H), 0.75 (s, 2H), 0.56 (s, 2H).
以化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2,8-雙((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯為原料,採用相同的方法,得到化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2,8-雙((1-(嗎啉代甲基)環丙基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇 實施例 93(二甲酸鹽,27.57 mg,34.0 umol,產率36%)。LCMS (ESI): [M+H] += 801.9。 1H NMR (400 MHz, CD 3OD) δ ppm 8.68 (s, 1H), 8.44 (br s, 2H), 7.65 (br dd, J= 8.4, 4.4Hz, 1H), 7.51-7.35 (m, 1H), 7.28 (s, 1H), 6.95 (d, J= 2.1Hz, 1H), 4.77-4.44 (m, 6H), 4.30 (d, J= 10.9Hz, 1H), 4.14-3.77 (m, 9H), 3.69 (br t, J= 4.4Hz, 4H), 3.53 (br d, J= 12.8Hz, 2H), 3.10 (br d, J= 9.5Hz, 1H), 2.83 (br d, J= 12.8Hz, 1H), 2.66-2.47 (m, 5H), 2.29 (br d, J= 12.6Hz, 1H), 2.15-1.82 (m, 4H), 0.82-0.66 (m, 2H), 0.64-0.43 (m, 4H), 0.31--0.24 (m, 2H). 實施例 94A和 實施例 94B :(S)-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇,和 (R)-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇 Using the compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,8-bis((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a raw material, the same method was used to obtain the compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2,8-bis((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol Example 93 (dicarboxylate, 27.57 mg, 34.0 umol, yield 36%). LCMS (ESI): [M+H] + = 801.9. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.68 (s, 1H), 8.44 (br s, 2H), 7.65 (br dd, J = 8.4, 4.4Hz, 1H), 7.51-7.35 (m, 1H), 7.28 (s, 1H), 6.95 (d, J = 2.1Hz, 1H), 4.77-4.44 (m, 6H), 4.30 (d, J = 10.9Hz, 1H), 4.14-3.77 (m, 9H), 3.69 (br t, J = 4.4Hz, 4H), 3.53 (br d, J = 12.8Hz, 2H), 3.10 (br d, J = 9.5Hz, 1H), 2.83 (br d, J = 12.8 Hz, 1H), 2.66-2.47 (m, 5H), 2.29 (br d, J = 12.6 Hz, 1H), 2.15-1.82 (m, 4H), 0.82-0.66 (m, 2H), 0.64-0.43 (m, 4H), 0.31-0.24 (m, 2H). Example 94A and Example 94B : (S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(oxolinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and (R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(oxolinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
實施例 94經SFC分離(管柱:DAICEL CHIRALPAK AD (250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/異丙醇;B相保持50%;流速:80毫升/分鐘),得到目標化合物。 Example 94 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 50%; flow rate: 80 ml/min) to obtain the target compound.
異構物 1, 實施例 94A:LCMS (ESI): [M+H] += 651.3; SFC分析(管柱: Chiralpak AD-3, 50 *4.6mm, 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相;流速:4毫升/分鐘):掌性管柱出峰位置為 0.435 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.69 (d, J= 1.25Hz, 1H), 7.60 (dd, J= 9.16, 2.4 Hz, 1H), 7.38 (q, J= 8.9 Hz, 1H), 7.27 (s, 1H), 6.99 (d, J= 2.5 Hz, 1H), 4.74-4.51 (m, 4H), 4.46-4.38 (m, 2H), 3.77 (br d, J= 12.8 Hz, 1H), 3.70 (br d, J= 10.5 Hz, 3H), 3.63 (t, J= 4.5 Hz, 4H), 2.56-2.44 (m, 4H), 1.93-1.78 (m, 4H), 0.74-0.67 (m, 2H), 0.53-0.46 (m, 2H). Isomer 1, Example 94A : LCMS (ESI): [M+H] + = 651.3; SFC analysis (column: Chiralpak AD-3, 50 *4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B; flow rate: 4 ml/min): the elution position of the palmar column is 0.435 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.69 (d, J = 1.25 Hz, 1H), 7.60 (dd, J = 9.16, 2.4 Hz, 1H), 7.38 (q, J = 8.9 Hz, 1H), 7.27 (s, 1H), 6.99 (d, J = 2.5 Hz, 1H), 4.74-4.51 (m, 4H), 4.46-4.38 (m, 2H), 3.77 (br d, J = 12.8 Hz, 1H), 3.70 (br d, J = 10.5 Hz, 3H), 3.63 (t, J = 4.5 Hz, 4H), 2.56-2.44 (m, 4H), 1.93-1.78 (m, 4H), 0.74-0.67 (m, 2H), 0.53-0.46 (m, 2H).
異構物 2 , 實施例 94B :LCMS (ESI): [M+H] += 651.3; SFC分析(管柱: Chiralpak AD-3, 50 *4.6mm, 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持40%的B相;流速:4毫升/分鐘):掌性管柱出峰位置為 1.264 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.69 (d, J= 1.3 Hz, 1H), 7.61 (d, J= 9.3 Hz, 1H), 7.39 (q, J= 9.0 Hz, 1H), 7.28 (s, 1H), 7.00 (d, J= 2.3 Hz, 1H), 4.77-4.53 (m, 4H), 4.49-4.38 (m, 2H), 3.87-3.70 (m, 4H), 3.64 (t, J= 4.6 Hz, 4H), 2.61-2.47 (m, 4H), 2.01-1.83 (m, 4H), 0.77-0.67 (m, 2H), 0.55-0.47 (m, 2H). 實施例 95:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇 Isomer 2 , Example 94B : LCMS (ESI): [M+H] + = 651.3; SFC analysis (column: Chiralpak AD-3, 50 *4.6mm, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: maintain 40% phase B; flow rate: 4 ml/min): the elution position of the palmar column is 1.264 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.69 (d, J = 1.3 Hz, 1H), 7.61 (d, J = 9.3 Hz, 1H), 7.39 (q, J = 9.0 Hz, 1H), 7.28 (s, 1H), 7.00 (d, J = 2.3 Hz, 1H), 4.77-4.53 (m, 4H), 4.49-4.38 (m, 2H), 3.87-3.70 (m, 4H), 3.64 (t, J = 4.6 Hz, 4H), 2.61-2.47 (m, 4H), 2.01-1.83 (m, 4H), 0.77-0.67 (m, 2H), 0.55-0.47 (m, 2H). Example 95 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(oxo- linomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
實施例 95採用與 實施例 88相同的方法,合成了化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇(甲酸鹽,9 mg,黃色固體)。LCMS (ESI): [M+H] += 657.3。 1H NMR (400 MHz, CD 3OD) δ ppm 8.65 (s, 1H), 8.41 (br s, 1H), 7.88 (dd, J= 5.8, 9.1 Hz, 1H), 7.41-7.26 (m, 2H), 7.00 (d, J= 2.4 Hz, 1H), 4.77 (br d, J= 13.9 Hz, 1H), 4.69 (br d, J= 13.5 Hz, 1H), 4.52-4.40 (m, 2H), 4.21 (br s, 2H), 4.00 (br d, J= 13.5 Hz, 1H), 3.89 (br d, J= 13.4 Hz, 1H), 3.75 (br t, J= 4.4 Hz, 4H), 3.39 (s, 1H), 2.87-2.67 (m, 6H), 2.21-2.01 (m, 4H), 0.86-0.77 (m, 2H), 0.69-0.58 (m, 2H). 實施例 96:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-((3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇 Example 95 The same method as Example 88 was used to synthesize the compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(oxo-methyl)cyclopropyl)methoxy)-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (formate salt, 9 mg, yellow solid). LCMS (ESI): [M+H] + = 657.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.65 (s, 1H), 8.41 (br s, 1H), 7.88 (dd, J = 5.8, 9.1 Hz, 1H), 7.41-7.26 (m, 2H), 7.00 (d, J = 2.4 Hz, 1H), 4.77 (br d, J = 13.9 Hz, 1H), 4.69 (br d, J = 13.5 Hz, 1H), 4.52-4.40 (m, 2H), 4.21 (br s, 2H), 4.00 (br d, J = 13.5 Hz, 1H), 3.89 (br d, J = 13.4 Hz, 1H), 3.75 (br t, J = 4.4 Hz, 4H), 3.39 (s, 1H), 2.87-2.67 (m, 6H), 2.21-2.01 (m, 4H), 0.86-0.77 (m, 2H), 0.69-0.58 (m, 2H). Example 96 : 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
第一步:在25 °C和氮氣保護下向2-伸甲基-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯(15.0 g,71.69 mmol)的二氧六環溶液(240 mL)中分批加入鋅粉(23.44 g,358.45 mmol),隨後緩慢滴加三氯乙醯氯(65.18 g,358.45 mmol)。滴加完畢將反應液在25 °C下攪拌4個小時。將反應液透過矽藻土進行過濾並用乙酸乙酯(100 mL * 3)進行沖洗。濾液再用飽和碳酸氫鈉溶液(300 mL * 2)進行洗滌,用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥,得到粗產物化合物2,2-二氯-3,5'-二氧代二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-甲酸乙酯(22.0 g),其為棕色油狀液體。LCMS (ESI): [M+H] += 320.2 Step 1 : Zinc powder (23.44 g, 358.45 mmol) was added in batches to a dioxane solution (240 mL) of 2-methyl-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid ethyl ester (15.0 g, 71.69 mmol) at 25 °C under nitrogen protection, followed by slow dropwise addition of trichloroacetyl chloride (65.18 g, 358.45 mmol). After the addition, the reaction solution was stirred at 25 °C for 4 hours. The reaction solution was filtered through diatomaceous earth and rinsed with ethyl acetate (100 mL * 3). The filtrate was then washed with a saturated sodium bicarbonate solution (300 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried to obtain a crude product compound 2,2-dichloro-3,5'-dioxodhidro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester (22.0 g), which was a brown oily liquid. LCMS (ESI): [M+H] + = 320.2
第二步:在25 °C和氮氣保護下,向2,2-二氯-3,5'-二氧代二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-甲酸乙酯(22.0 g,68.71 mmol)的乙酸(220 mL)溶液中分批加入鋅粉(23.44 g,358.46 mmol)。然後將反應液在50 oC攪拌16小時。將反應液用乙酸乙酯(500 mL)稀釋後過濾,濾液用飽和碳酸氫鈉溶液(500 mL * 2)洗滌,用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥得到粗產物。將所得粗產物用快速管柱層析(矽膠,0-30%梯度的乙酸乙酯/石油醚)純化,得到黃色油狀產品3,5'-二氧代二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-甲酸乙酯(4.50 g,17.91 mmol,產率26%)。LCMS (ESI): [M+H] += 252. 2 Step 2 : Zinc powder (23.44 g, 358.46 mmol) was added in batches to a solution of 2,2-dichloro-3,5'-dioxodhidro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester (22.0 g, 68.71 mmol) in acetic acid (220 mL) at 25 °C under nitrogen protection. The reaction solution was then stirred at 50 ° C for 16 hours. The reaction solution was diluted with ethyl acetate (500 mL) and filtered. The filtrate was washed with saturated sodium bicarbonate solution (500 mL * 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was rotary dried to obtain a crude product. The crude product was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a yellow oily product, 3,5'-dioxodhidro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester (4.50 g, 17.91 mmol, yield 26%). LCMS (ESI): [M+H] + = 252.2
第三步:在-70 °C和氮氣保護下,向3,5'-二氧代二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-甲酸乙酯(3.30 g,13.13 mmol)的二氯甲烷(33 mL)溶液中緩慢加入二乙胺基三氟化硫(4.20 g,26.26 mmol)。然後將反應液自然升至20 oC並在20 oC和氮氣保護下攪拌16小時。將反應液用飽和碳酸氫鈉溶液(30 mL * 2)洗滌,用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥得到粗產物。將所得粗產物用快速管柱層析(矽膠,0-30%梯度的乙酸乙酯/石油醚)純化,得到黃色油狀化合物3,3-二氟-5'-氧代二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-甲酸乙酯(1.20 g,4.39 mmol,產率33%)。LCMS (ESI): [M+H] += 274.1。 1H NMR (400 MHz, CDCl 3) δ ppm 4.27-4.19 (m, 2H), 3.87-3.80 (m, 1H), 3.36-3.24 (m, 1H), 2.83-2.72 (m, 1H), 2.71-2.62 (m, 2H), 2.61-2.51 (m, 4H), 2.42 (ddd, J= 1.3, 9.2, 16.6 Hz, 1H), 2.13-2.02 (m, 1H), 1.98-1.91 (m, 1H), 1.30 (t, J= 7.2 Hz, 3H). Step 3 : Slowly add diethylaminosulfur trifluoride (4.20 g, 26.26 mmol) to a solution of 3,5'-dioxodhidro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester (3.30 g, 13.13 mmol) in dichloromethane (33 mL) at -70 °C under nitrogen protection. Then the reaction solution was naturally raised to 20 ° C and stirred at 20 ° C under nitrogen protection for 16 hours. The reaction solution was washed with saturated sodium bicarbonate solution (30 mL * 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was rotary dried to obtain a crude product. The crude product was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a yellow oily compound 3,3-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester (1.20 g, 4.39 mmol, yield 33%). LCMS (ESI): [M+H] + = 274.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 4.27-4.19 (m, 2H), 3.87-3.80 (m, 1H), 3.36-3.24 (m, 1H), 2.83-2.72 (m, 1H), 2.71-2.62 (m, 2H), 2.61-2.51 (m, 4H), 2.42 (ddd, J = 1.3, 9.2, 16.6 Hz, 1H), 2.13-2.02 (m, 1H), 1.98-1.91 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H).
第四步:將化合物3,3-二氟-5'-氧代二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-甲酸乙酯(400 mg,1.46 mmol)溶於四氫呋喃(4 mL),0 oC下加入四氫鋁鋰(333 mg,8.78 mmol)。反應在60 oC下攪拌2小時。冷卻後小心向反應液中加入水(333 uL),氫氧化鈉(15%水溶液,333 uL),水(666 uL),無水硫酸鎂(1 g),攪拌30分鐘,反應液過濾,濾液減壓濃縮得到無色油狀粗產物化合物 (3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇(0.39 g)。LCMS (ESI): [M+H] += 218.1 Step 4 : Dissolve the compound 3,3-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester (400 mg, 1.46 mmol) in tetrahydrofuran (4 mL), and add lithium aluminum tetrahydrogen (333 mg, 8.78 mmol) at 0 o C. The reaction was stirred at 60 o C for 2 hours. After cooling, water (333 uL), sodium hydroxide (15% aqueous solution, 333 uL), water (666 uL), anhydrous magnesium sulfate (1 g) were carefully added to the reaction solution, and stirred for 30 minutes. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless oily crude product compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (0.39 g). LCMS (ESI): [M+H] + = 218.1
第五步:將化合物 (3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇(390 mg,1.79 mmol)和二異丙基乙胺(1.5 mL,8.98 mmol)溶於二氯甲烷(4 mL)中,0 oC下加入苯甲醯氯(420 uL,3.59 mmol),反應液在25 oC攪拌16小時。反應液用水(15 mL)稀釋,二氯甲烷萃取(5 mL * 3),有機相用飽和食鹽水洗滌(5 mL),硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物用快速管柱層析純化(矽膠,0-30%梯度的四氫呋喃/石油醚)得黃色油狀化合物 (3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)苯甲酸甲酯(360 mg,1.11 mmol,產率62%)。LCMS (ESI): [M+H] += 322.1。 1H NMR (400MHz, CDCl 3) δ ppm 8.16-7.97 (m, 2H), 7.68-7.32 (m, 3H), 4.42-4.21 (m, 2H), 3.59 (d, J= 10.5 Hz, 1H), 3.35 (td, J= 6.7, 11.2 Hz, 1H), 2.95-2.75 (m, 3H), 2.72-2.57 (m, 3H), 2.31 (d, J= 13.6 Hz, 1H), 2.16-2.06 (m, 1H), 2.05-1.94 (m, 3H), 1.90-1.77 (m, 1H). Step 5 : Dissolve the compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (390 mg, 1.79 mmol) and diisopropylethylamine (1.5 mL, 8.98 mmol) in dichloromethane (4 mL), add benzoyl chloride (420 uL, 3.59 mmol) at 0 o C, and stir the reaction solution at 25 o C for 16 hours. The reaction solution was diluted with water (15 mL), extracted with dichloromethane (5 mL * 3), the organic phase was washed with saturated brine (5 mL), dried over sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran/petroleum ether) to obtain a yellow oily compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)benzoic acid methyl ester (360 mg, 1.11 mmol, yield 62%). LCMS (ESI): [M+H] + = 322.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.16-7.97 (m, 2H), 7.68-7.32 (m, 3H), 4.42-4.21 (m, 2H), 3.59 (d, J = 10.5 Hz, 1H), 3.35 (td, J = 6.7, 11.2 Hz, 1H), 2.95-2.75 (m, 3H), 2.72-2.57 (m, 3H), 2.31 (d, J = 13.6 Hz, 1H), 2.16-2.06 (m, 1H), 2.05-1.94 (m, 3H), 1.90-1.77 (m, 1H).
第六步:化合物 (3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)苯甲酸甲酯(250 mg,0.78 mmol)溶於四氫呋喃(3 mL)中,加入氫氧化鈉(93 mg,2.33 mmol)的水(3 mL)溶液,反應液在25 oC攪拌16小時。反應液用乙酸乙酯萃取(5 mL * 3),有機相用飽和食鹽水洗滌(5 mL),硫酸鈉乾燥,過濾,濾液減壓濃縮得黃色油狀化合物 (3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇(106 mg,0.48 mmol,產率62%)。LCMS (ESI): [M+H] += 218.0。 1H NMR (400MHz, CDCl 3) δ ppm 3.36-3.22 (m, 2H), 3.18 (br d, J= 10.0 Hz, 1H), 2.97 (br s, 1H), 2.80 (br d, J= 10.0 Hz, 2H), 2.67-2.51 (m, 4H), 2.13 (br d, J= 13.3 Hz, 1H), 1.98-1.73 (m, 4H), 1.71-1.61 (m, 1H). Step 6 : Compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)benzoic acid methyl ester (250 mg, 0.78 mmol) was dissolved in tetrahydrofuran (3 mL), and a solution of sodium hydroxide (93 mg, 2.33 mmol) in water (3 mL) was added. The reaction solution was stirred at 25 ° C for 16 hours. The reaction solution was extracted with ethyl acetate (5 mL * 3), the organic phase was washed with saturated brine (5 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily compound (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (106 mg, 0.48 mmol, yield 62%). LCMS (ESI): [M+H] + = 218.0. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 3.36-3.22 (m, 2H), 3.18 (br d, J = 10.0 Hz, 1H), 2.97 (br s, 1H), 2.80 (br d, J = 10.0 Hz, 2H), 2.67-2.51 (m, 4H), 2.13 (br d, J = 13.3 Hz, 1H), 1.98-1.73 (m, 4H), 1.71-1.61 (m, 1H).
第七步:將化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(100 mg,138 umol)溶於四氫呋喃(2 mL)中,加入 (3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇(60 mg,276 umol)和叔丁醇鈉(26 mg,276 umol),20 oC攪拌2小時。反應液減壓濃縮得到粗產物化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-((3,3-二氟二氫-1'H,3'H)-螺[環丁烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(120 mg)。LCMS (ESI): [M+H] += 841.2。 Step 7 : Dissolve the compound tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 138 umol) in tetrahydrofuran (2 mL), add (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (60 mg, 276 umol) and sodium tert-butoxide (26 mg, 276 umol), and stir at 20 o C for 2 hours. The reaction solution was concentrated under reduced pressure to give a crude product compound tert-butyl (1R, 5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((3,3-difluorodihydro-1'H, 3'H)-spiro[cyclobutane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg). LCMS (ESI): [M+H] + = 841.2.
第八步:將化合物叔丁基(1R,5S)-3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-((3,3-二氟二氫-1'H,3'H)-螺[環丁烷-1,2'-吡咯啉]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(120 mg,142 umol)溶於乙腈(0.2 mL),加入氯化氫(4M的二氧六環,0.6 mL,2.37 mmol),20 oC攪拌2小時。反應液減壓濃縮,殘留物溶於乙腈(500 uL),加入三乙胺調節pH到8,混合物用製備型HPLC純化,得到黃色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-((3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇(25 mg,36 umol,產率15%)。LCMS (ESI): [M+H] += 697.1。 1H NMR (400MHz, CD 3OD) δ ppm 8.71 (s, 1H), 7.61 (br d, J= 9.2 Hz, 1H), 7.39 (q, J= 8.7 Hz, 1H), 7.29 (s, 1H), 7.01 (d, J= 2.2 Hz, 1H), 4.68-4.49 (m, 2H), 4.33-4.19 (m, 2H), 3.82-3.64 (m, 4H), 3.25 (d, J= 10.5 Hz, 1H), 3.16-3.05 (m, 1H), 2.92-2.80 (m, 2H), 2.76-2.56 (m, 4H), 2.38 (d, J= 13.3 Hz, 1H), 2.09-1.78 (m, 9H). 實施例 96B和 實施例 96C :4-((S)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((R)-3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇,和 4-((S)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((S)-3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇,和 4-((R)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((R)-3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇,和 4-((R)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((S)-3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5,6-二氟萘-2-醇 Step 8: Dissolve the compound tert-butyl (1R,5S)-3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((3,3-difluorodihydro-1'H,3'H)-spiro[cyclobutane-1,2'-pyrroline]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 142 umol) in acetonitrile (0.2 mL), add hydrogen chloride (4M in dioxane, 0.6 mL, 2.37 mmol), and stir at 20 o C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (500 uL). Triethylamine was added to adjust the pH to 8, and the mixture was purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (25 mg, 36 umol, yield 15%). LCMS (ESI): [M+H] + = 697.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.71 (s, 1H), 7.61 (br d, J = 9.2 Hz, 1H), 7.39 (q, J = 8.7 Hz, 1H), 7.29 (s, 1H), 7.01 (d, J = 2.2 Hz, 1H), 4.68-4.49 (m, 2H), 4.33-4.19 (m, 2H), 3.82-3.64 (m, 4H), 3.25 (d, J = 10.5 Hz, 1H), 3.16-3.05 (m, 1H), 2.92-2.80 (m, 2H), 2.76-2.56 (m, 4H), 2.38 (d, J = 13.3 Hz, 1H), 2.09-1.78 (m, 9H). Example 96B and Example 96C : 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol, and 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol , and 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5,6-difluoronaphthalen-2-ol
實施例 96經SFC分離(管柱:DAICEL CHIRALPAK AD (250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/異丙醇;B相保持55%;流速:80毫升/分鐘),得到目標化合物。 Example 96 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 55%; flow rate: 80 ml/min) to obtain the target compound.
異構物 1&2 混合物 , 實施例 96A:LCMS (ESI): [M+H] += 697.1; SFC分析(層析管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持B相在40%;流速:4毫升/分鐘):掌性管柱出峰位置為 0.370 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.58 (s, 1H), 7.52-7.45 (m, 1H), 7.27 (q, J= 8.8 Hz, 1H), 7.17 (s, 1H), 6.91-6.86 (m, 1H), 4.55-4.50 (m, 1H), 4.47-4.39 (m, 1H), 4.24-4.05 (m, 2H), 3.69-3.51 (m, 4H), 3.16-3.08 (m, 1H), 3.03-2.92 (m, 1H), 2.81-2.68 (m, 2H), 2.64-2.44 (m, 4H), 2.25 (br d, J= 13.4 Hz, 1H), 1.95-1.83 (m, 3H), 1.82-1.64 (m, 6H). Mixture of isomers 1 & 2 , Example 96A : LCMS (ESI): [M+H] + = 697.1; SFC analysis (chromatographic column: Chiralpak AD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: keep phase B at 40%; flow rate: 4 ml/min): the elution position of the palmar column is 0.370 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.58 (s, 1H), 7.52-7.45 (m, 1H), 7.27 (q, J = 8.8 Hz, 1H), 7.17 (s, 1H), 6.91-6.86 (m, 1H), 4.55-4.50 (m, 1H), 4.47-4.39 (m, 1H), 4.24-4.05 (m, 2H), 3.69-3.51 (m, 4H), 3.16-3.08 (m, 1H), 3.03-2.92 (m, 1H), 2.81-2.68 (m, 2H), 2.64-2.44 (m, 4H), 2.25 (br d, J = 13.4 Hz, 1H), 1.95-1.83 (m, 3H), 1.82-1.64 (m, 6H).
異構物 3, 實施例 96B:LCMS (ESI): [M+H] += 697.1; SFC分析(層析管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持B相在40%;流速:4毫升/分鐘):掌性管柱出峰位置為 0.739 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.68 (s, 1H), 7.59 (br d, J= 9.0 Hz, 1H), 7.37 (q, J= 8.9 Hz, 1H), 7.27 (br s, 1H), 6.99 (s, 1H), 4.63 (br d, J= 12.1 Hz, 1H), 4.54 (br d, J= 12.3 Hz, 1H), 4.33-4.18 (m, 2H), 3.82-3.62 (m, 4H), 3.25-3.18 (m, 1H), 3.12-3.03 (m, 1H), 2.86 (br d, J= 10.0 Hz, 2H), 2.74-2.55 (m, 4H), 2.35 (br d, J= 13.1 Hz, 1H), 2.05-1.95 (m, 3H), 1.90-1.73 (m, 6H). Isomer 3, Example 96B : LCMS (ESI): [M+H] + = 697.1; SFC analysis (chromatographic column: Chiralpak AD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: keep phase B at 40%; flow rate: 4 ml/min): the elution position of the palmar column is 0.739 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.68 (s, 1H), 7.59 (br d, J = 9.0 Hz, 1H), 7.37 (q, J = 8.9 Hz, 1H), 7.27 (br s, 1H), 6.99 (s, 1H), 4.63 (br d, J = 12.1 Hz, 1H), 4.54 (br d, J = 12.3 Hz, 1H), 4.33-4.18 (m, 2H), 3.82-3.62 (m, 4H), 3.25-3.18 (m, 1H), 3.12-3.03 (m, 1H), 2.86 (br d, J = 10.0 Hz, 2H), 2.74-2.55 (m, 4H), 2.35 (br d, J = 13.1 Hz, 1H), 2.05-1.95 (m, 3H), 1.90-1.73 (m, 6H).
異構物 4, 實施例 96C:LCMS (ESI): [M+H] += 697.1; SFC分析(層析管柱: Chiralpak AD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:保持B相在40%;流速:4毫升/分鐘):掌性管柱出峰位置為 1.893 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.69 (s, 1H), 7.59 (dd, J= 4.1, 9.1 Hz, 1H), 7.41-7.34 (m, 1H), 7.27 (s, 1H), 6.99 (d, J= 2.1 Hz, 1H), 4.58 (br d, J= 12.0 Hz, 2H), 4.31-4.17 (m, 2H), 3.79-3.60 (m, 4H), 3.24-3.17 (m, 1H), 3.10-3.01 (m, 1H), 2.87-2.76 (m, 2H), 2.75-2.55 (m, 4H), 2.39-2.29 (m, 1H), 2.06-1.96 (m, 3H), 1.90-1.74 (m, 6H). 實施例 97:4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-((3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇 Isomer 4, Example 96C : LCMS (ESI): [M+H] + = 697.1; SFC analysis (chromatographic column: Chiralpak AD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: keep phase B at 40%; flow rate: 4 ml/min): the elution position of the palmar column is 1.893 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.69 (s, 1H), 7.59 (dd, J = 4.1, 9.1 Hz, 1H), 7.41-7.34 (m, 1H), 7.27 (s, 1H), 6.99 (d, J = 2.1 Hz, 1H), 4.58 (br d, J = 12.0 Hz, 2H), 4.31-4.17 (m, 2H), 3.79-3.60 (m, 4H), 3.24-3.17 (m, 1H), 3.10-3.01 (m, 1H), 2.87-2.76 (m, 2H), 2.75-2.55 (m, 4H), 2.39-2.29 (m, 1H), 2.06-1.96 (m, 3H), 1.90-1.74 (m, 6H). Example 97 :4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
第一步:將化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(180 mg,203 umol)溶於四氫呋喃(2 mL)中,加入 (3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲醇(88 mg,406 umol)和叔丁醇鈉(39 mg,406 umol),20 oC攪拌2小時。反應液用矽藻土過濾,濾液減壓濃縮得到粗產物化合物叔丁基(1R,5S)-3-(2-((3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(240 mg)。LCMS (ESI): [M+H] += 1003.3. Step 1 : Dissolve the compound tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (180 mg, 203 umol) in tetrahydrofuran (2 mL), add (3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol (88 mg, 406 umol) and sodium tert-butoxide (39 mg, 406 umol), and stir at 20 o C for 2 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product compound tert-butyl (1R, 5S)-3-(2-((3,3-difluorodihydro-1'H, 3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg). LCMS (ESI): [M+H] + = 1003.3.
第二步:將化合物叔丁基(1R,5S)-3-(2-((3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(240 mg,0.24 mmol)和氟化銫(364 mg,2.4 mmol)的二甲基甲醯胺(2 mL)溶液在25 oC下攪拌2小時。反應液用水(5 mL)稀釋,乙酸乙酯(5 mL * 3)萃取,合併有機相,減壓濃縮得到粗產物化合物叔丁基(1R,5S)-3-(2-((3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(200 mg)。LCMS (ESI): [M+H] += 847.2. Step 2 : A solution of tert-butyl (1R,5S)-3-(2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.24 mmol) and cesium fluoride (364 mg, 2.4 mmol) in dimethylformamide (2 mL) was stirred at 25 ° C for 2 hours. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL * 3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product compound tert-butyl (1R, 5S)-3-(2-((3,3-difluorodihydro-1'H, 3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg). LCMS (ESI): [M+H] + = 847.2.
第三步:將化合物叔丁基(1R,5S)-3-(2-((3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(200 mg,237 umol)溶於乙腈(0.2 mL),加入氯化氫(4M的二氧六環溶液,0.6 mL,2.37 mmol),20 oC攪拌2小時。反應液減壓濃縮,殘留物溶於乙腈(500 uL),加入三乙胺調節pH到8,混合物用製備型HPLC純化,得到黃色固體化合物4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-((3,3-二氟二氫-1'H,3'H-螺[環丁烷-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇(25 mg,36 umol,產率15%)。LCMS (ESI): [M+H] += 703.3. 1H NMR (400MHz, CD 3OD) δ ppm 8.67 (s, 1H), 7.86 (dd, J= 5.9, 9.1 Hz, 1H), 7.37-7.26 (m, 2H), 7.00 (s, 1H), 4.69-4.49 (m, 2H), 4.32-4.17 (m, 2H), 3.86-3.75 (m, 1H), 3.67 (br s, 3H), 3.36 (d, J= 6.0 Hz, 1H), 3.21 (d, J= 10.4 Hz, 1H), 3.11-3.01 (m, 1H), 2.89-2.77 (m, 2H), 2.74-2.55 (m, 4H), 2.36 (br d, J= 14.1 Hz, 1H), 2.09-1.80 (m, 9H). 實施例 97B和 實施例 97C :4-((S)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((R)-3,3-二氟二氫-1'H,3'H-螺[環丁烷)-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇,或 4-((S)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((S)-3,3-二氟二氫-1'H,3'H-螺[環丁烷)-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇,或 4-((R)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((R)-3,3-二氟二氫-1'H,3'H-螺[環丁烷)-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇,或 4-((R)-4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-2-(((S)-3,3-二氟二氫-1'H,3'H-螺[環丁烷)-1,2'-吡咯嗪]-7a'(5'H)-基)甲氧基)-8-氟-6-硝基喹唑啉-7-基)-5-乙炔基-6-氟萘-2-醇 Step 3 : Dissolve the compound tert-butyl (1R,5S)-3-(2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 237 umol) in acetonitrile (0.2 mL), add hydrogen chloride (4M solution in dioxane, 0.6 mL, 2.37 mmol), and stir at 20 o C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (500 uL). Triethylamine was added to adjust the pH to 8, and the mixture was purified by preparative HPLC to obtain a yellow solid compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (25 mg, 36 umol, yield 15%). LCMS (ESI): [M+H] + = 703.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.67 (s, 1H), 7.86 (dd, J = 5.9, 9.1 Hz, 1H), 7.37-7.26 (m, 2H), 7.00 (s, 1H), 4.69-4.49 (m, 2H), 4.32-4.17 (m, 2H), 3.86-3.75 (m, 1H), 3.67 (br s, 3H), 3.36 (d, J = 6.0 Hz, 1H), 3.21 (d, J = 10.4 Hz, 1H), 3.11-3.01 (m, 1H), 2.89-2.77 (m, 2H), 2.74-2.55 (m, 4H), 2.36 (br d, J = 14.1 Hz, 1H), 2.09-1.80 (m, 9H). Example 97B and Example 97C : 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane)-1,2'-pyrrolazine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, or 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane)-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, or 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((R)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane)-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol , or 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-3,3-difluorodihydro-1'H,3'H-spiro[cyclobutane)-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoro-6-nitroquinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
實施例 97經SFC分離(管柱:DAICEL CHIRALPAK AD (250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/乙醇;B相保持50%;流速:80毫升/分鐘),得到目標化合物。 Example 97 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 50%; flow rate: 80 ml/min) to obtain the target compound.
異構物 4, 實施例 97C:LCMS (ESI): [M+H] += 703.1; SFC分析(層析管柱: Chiralpak AD-3,150mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相保持在40%;流速:2.5毫升/分鐘):掌性管柱出峰位置為 4.050 min; 1H NMR (400MHz, CD 3OD) δ ppm 8.67 (d, J=1.1 Hz, 1H), 7.86 (dd, J=5.8, 9.1 Hz, 1H), 7.39-7.28 (m, 2H), 7.00 (d, J=2.3 Hz, 1H), 4.66-4.50 (m, 2H), 4.29-4.16 (m, 2H), 3.84-3.75 (m, 1H), 3.71-3.61 (m, 3H), 3.37 (s, 1H), 3.21 (br d, J=10.1 Hz, 1H), 3.11-3.00 (m, 1H), 2.88-2.79 (m, 2H), 2.75-2.56 (m, 4H), 2.35 (d, J=13.2 Hz, 1H), 2.04-1.79 (m, 9H). 實施例 98 : 4-(4-((1R,5S)-3,8- 二氮雜雙環 [3.2.1] 辛 -3- 基 )-2-(( 二氫 -1'H,3'H- 螺 [ 氧雜環丁烷 -3,2'- 吡咯嗪 ]-7a'(5'H)- 基 ) 甲氧基 )-8- 氟 -6- 硝基喹唑啉 -7- 基 )-5- 乙炔基 -6- 氟萘 -2- 醇 Isomer 4, Example 97C : LCMS (ESI): [M+H] + = 703.1; SFC analysis (chromatographic column: Chiralpak AD-3, 150 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is maintained at 40%; flow rate: 2.5 ml/min): the elution position of the palmar column is 4.050 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.67 (d, J =1.1 Hz, 1H), 7.86 (dd, J =5.8, 9.1 Hz, 1H), 7.39-7.28 (m, 2H), 7.00 (d, J =2.3 Hz, 1H), 4.66-4.50 (m, 2H), 4.29-4.16 (m, 2H), 3.84-3.75 (m, 1H), 3.71-3.61 (m, 3H), 3.37 (s, 1H), 3.21 (br d, J =10.1 Hz, 1H), 3.11-3.00 (m, 1H), 2.88-2.79 (m, 2H), 2.75-2.56 (m, 4H), 2.35 (d, J =13.2 Hz, 1H), 2.04-1.79 (m, 9H). Example 98 : 4-(4-((1R,5S)-3,8- diazabicyclo [3.2.1] octan - 3- yl )-2-(( dihydro -1'H,3'H- spiro [ oxacyclobutane -3,2'- pyrrolizine ]-7a'(5'H) -yl ) methoxy )-8- fluoro -6- nitroquinazolin -7- yl )-5- ethynyl- 6- fluoronaphthalen -2 - ol
實施例 98參照 實施例 97類似合成途徑製備得到的: LCMS (ESI): [M+H] += 669.2; 1H NMR (400 MHz, CD 3OD) δ ppm 8.67 (s, 1H), 7.87 (dd, J =5.6, 9.2 Hz, 1H), 7.36 -7.30 (m, 2H), 7.00 (s, 1H), 4.73 (br d, J =6.3 Hz, 2H), 4.64 (br d, J =6.3 Hz, 2H), 4.56 -4.48 (m, 1H), 4.23 -4.12 (m, 2H), 3.80 (br d, J =13.3 Hz, 1H), 3.68 (br s, 3H), 3.54 (br d, J =10.3 Hz, 1H), 3.38 -3.36 (m, 1H), 3.08 -3.01 (m, 1H), 2.97 (d, J =10.3 Hz, 1H), 2.78 (td, J =5.1, 10.8 Hz, 1H), 2.56 (d, J =13.3 Hz, 1H), 2.11 -1.91 (m, 4H), 1.91 -1.77 (m, 6H). 實施例 99:4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉 Example 98 was prepared by a similar synthetic route to Example 97 : LCMS (ESI): [M+H] + = 669.2; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.67 (s, 1H), 7.87 (dd, J = 5.6, 9.2 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.00 (s, 1H), 4.73 (br d, J = 6.3 Hz, 2H), 4.64 (br d, J = 6.3 Hz, 2H), 4.56 - 4.48 (m, 1H), 4.23 - 4.12 (m, 2H), 3.80 (br d, J = 13.3 Hz, 1H), 3.68 (br s, 3H), 3.54 (br d, J = 10.3 Hz, 1H), 3.38 - 3.36 (m, 1H), 3.08 - 3.01 (m, 1H), 2.97 (d, J = 10.3 Hz, 1H), 2.78 (td, J = 5.1, 10.8 Hz, 1H), 2.56 (d, J = 13.3 Hz, 1H), 2.11 - 1.91 (m, 4H), 1.91 - 1.77 (m, 6H). Example 99 :4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazoline
第一步:在氮氣環境下,將叔丁基(1R,5S)-3-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(800 mg,1.38 mmol)和 (((2-氟-8-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(810 mg,1.79 mmol)加入到甲苯(32 mL)和水(8 mL)的混合溶液中,然後加入碳酸銫(1.35 g,4.14 mmol),甲磺醯氧基(二金剛烷基-正丁基膦基)-2-胺基-1,1-聯苯-2-基)鈀(II)(200 mg,0.28 mmol)。將混合物在100 oC攪拌16小時。將殘餘物用水(60 mL)稀釋並用乙酸乙酯(30 mL * 3)萃取,合併的有機相用鹽水(60 mL)洗滌,無水硫酸鎂乾燥並過濾,濾液真空濃縮。殘餘物透過快速管柱層析(矽膠,0-10%梯度四氫呋喃/石油醚)純化得到棕色固體化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(950 mg,1.15 mmol,產率83%)。LCMS (ESI): [M+H] += 826.3. Step 1 : Under nitrogen atmosphere, tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.38 mmol) and (((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (810 mg, 1.79 mmol) were added to a mixed solution of toluene (32 mL) and water (8 mL), and then cesium carbonate (1.35 g, 4.14 mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (200 mg, 0.28 mmol). The mixture was stirred at 100 ° C for 16 hours. The residue was diluted with water (60 mL) and extracted with ethyl acetate (30 mL * 3), the combined organic phases were washed with brine (60 mL), dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-10% gradient tetrahydrofuran/petroleum ether) to give a brown solid compound tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (950 mg, 1.15 mmol, yield 83%). LCMS (ESI): [M+H] + = 826.3.
第二步:向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(400 mg,0.48 mmol)的四氫呋喃(8 mL)溶液中加入4A分子篩(400 mg),叔丁醇鈉(93 mg,0.97 mmol)和 (四氫-1H-吡咯嗪-7a(5H)-基)甲醇(137 mg,0.97 mmol)。將反應在20 oC攪拌2小時。混合物用水(15 mL)稀釋並用乙酸乙酯(15 mL*3)萃取,合併的有機相用飽和食鹽水(20 mL)洗滌,無水硫酸鎂乾燥,過濾,濾液濃縮,殘餘物透過快速管柱層析(矽膠,0-6%梯度甲醇/二氯甲烷)純化得到棕色固體化合物叔丁基(1R,5S)-3-(8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-((四氫-1H-吡咯啉-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(270 mg,0.31 mmol,產率65%)。LCMS (ESI): [M+H] += 867.2. Step 2 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.48 mmol) in tetrahydrofuran (8 mL) was added 4A molecular sieve (400 mg), sodium tert-butoxide (93 mg, 0.97 mmol) and (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (137 mg, 0.97 mmol). The reaction was stirred at 20 ° C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL*3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-6% gradient methanol/dichloromethane) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (270 mg, 0.31 mmol, yield 65%). LCMS (ESI): [M+H] + = 867.2.
第三步:向叔丁基(1R,5S)-3-(8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-((四氫-1H-吡咯啉-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(260 mg,0.3 mmol)的二甲基甲醯胺(3 mL)溶液中加入氟化銫(364 mg,2.4 mmol)。將反應在20 oC攪拌2小時。混合物用水(15 mL)稀釋並用乙酸乙酯(15 mL*2)萃取,合併的有機相用飽和食鹽水(20 mL)洗滌,無水硫酸鎂乾燥,過濾,濾液濃縮,殘餘物透過快速管柱層析(矽膠,0-7%梯度甲醇/二氯甲烷)純化得到棕色固體化合物叔丁基(1R,5S)-3-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(160 mg,0.23 mmol,產率77%)。LCMS (ESI): [M+H] += 711.3. Step 3 : To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (260 mg, 0.3 mmol) in dimethylformamide (3 mL) was added cesium fluoride (364 mg, 2.4 mmol). The reaction was stirred at 20 ° C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL*2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-7% gradient methanol/dichloromethane) to obtain a brown solid compound tert-butyl (1R, 5S)-3-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.23 mmol, yield 77%). LCMS (ESI): [M+H] + = 711.3.
第四步:向叔丁基(1R,5S)-3-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-羧酸酯(155 mg,0.22 mmol)的乙腈(3 mL)溶液中加入氯化氫(4 M的二氧六環溶液,1 mL,4 mmol)。將反應在20 oC攪拌1小時。真空旋轉乾燥後溶於乙腈(2 mL),用三乙胺中和並濃縮。殘餘物透過製備型HPLC純化,得到黃色固體化合物4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉(60 mg,0.1 mmol,產率45%)。LCMS (ESI): [M+H] += 611.1. 1H-NMR (400 MHz, CD 3OD) δ ppm 8.70 (d, J= 1.3 Hz, 1H), 8.17-8.04 (m, 2H), 7.60 (t, J= 7.8 Hz, 1H), 7.49-7.37 (m, 2H), 4.68 (br d, J= 11.3 Hz, 1H), 4.54 (br d, J= 12.0 Hz, 1H), 4.36-4.27 (m, 2H), 3.82 (br d, J= 11.5 Hz, 1H), 3.72-3.63 (m, 3H), 3.45 (s, 1H), 3.21-3.09 (m, 2H), 2.85-2.71 (m, 2H), 2.11 (td, J= 6.3, 12.4 Hz, 2H), 2.02-1.75 (m, 10H). Step 4 : To a solution of tert-butyl (1R,5S)-3-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (155 mg, 0.22 mmol) in acetonitrile (3 mL) was added hydrogen chloride (4 M in dioxane, 1 mL, 4 mmol). The reaction was stirred at 20 ° C for 1 hour. After vacuum rotary drying, it was dissolved in acetonitrile (2 mL), neutralized with triethylamine and concentrated. The residue was purified by preparative HPLC to give a yellow solid compound 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazoline (60 mg, 0.1 mmol, yield 45%). LCMS (ESI): [M+H] + = 611.1. 1 H-NMR (400 MHz, CD 3 OD) δ ppm 8.70 (d, J = 1.3 Hz, 1H), 8.17-8.04 (m, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.49-7.37 (m, 2H), 4.68 (br d, J = 11.3 Hz, 1H), 4.54 (br d, J = 12.0 Hz, 1H), 4.36-4.27 (m, 2H), 3.82 (br d, J = 11.5 Hz, 1H), 3.72-3.63 (m, 3H), 3.45 (s, 1H), 3.21-3.09 (m, d, J = 6.3, 12.4 Hz, 2H), 2.02-1.75 (m, 10H).
實施例 100 ,實施例 101 參照實施例 99 的合成途徑 , 第二步與不同的醇反應製備得到: 實施例 100 :4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉 Example 100 and Example 101 are prepared by the same synthetic route as Example 99 , and reacting with different alcohols in the second step to obtain: Example 100 : 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-nitroquinazoline
LCMS (ESI): [M+H] += 629.3。 1H NMR (400MHz, CD 3OD) δ ppm 8.69 (d, J= 1.3 Hz, 1H), 8.15-8.05 (m, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.49-7.38 (m, 2H), 5.39-5.23 (m, 1H), 4.70-4.64 (m, 1H), 4.57-4.49 (m, 1H), 4.34-4.20 (m, 2H), 3.81 (br dd, J= 5.2, 12.5 Hz, 1H), 3.72-3.62 (m, 3H), 3.43 (d, J= 5.4 Hz, 1H), 3.30-3.17 (m, 3H), 3.02 (dt, J= 5.4, 9.4 Hz, 1H), 2.41-2.12 (m, 3H), 2.04-1.78 (m, 7H). 實施例 101 :反式-7a'-(((4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-2-基)氧基)甲基)-2,2-二氟四氫-1'H,3'H-螺[環丙烷-1,2'-吡咯嗪] LCMS (ESI): [M+H] + = 629.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.69 (d, J = 1.3 Hz, 1H), 8.15-8.05 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.49-7.38 (m, 2H), 5.39-5.23 (m, 1H), 4.70-4.64 (m, 1H), 4.57-4.49 (m, 1H), 4.34-4.20 (m, 2H), 3.81 (br dd, J = 5.2, 12.5 Hz, 1H), 3.72-3.62 (m, 3H), 3.46 (d, J = 5.4 Hz, 1H), 3.23-3.17 (m, 3H), 3.02 (dt, J = 5.4, 9.4 Hz, 1H), 2.41-2.12 (m, 3H), 2.04-1.78 (m, 7H). Example 101 : trans-7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]
LCMS (ESI): [M+H] += 673.2。 1H NMR (400 MHz, CD 3OD) δ ppm 8.71-8.68 (m, 1H), 8.14-8.06 (m, 2H), 7.60 (t, J= 7.6 Hz, 1H), 7.48-7.39 (m, 2H), 4.67 (br d, J= 13.1 Hz, 1H), 4.53 (br d, J= 12.8 Hz, 1H), 4.41-4.32 (m, 2H), 3.81 (br d, J= 12.5 Hz, 1H), 3.69 (br s, 3H), 3.44 (d, J= 2.1 Hz, 1H), 3.32-3.26 (m, 1H), 3.20-3.13 (m, 1H), 2.85 (d, J= 12.2 Hz, 1H), 2.75-2.67 (m, 1H), 2.28 (ddd, J= 3.4, 6.1, 13.5 Hz, 1H), 2.19-2.11 (m, 1H), 2.03 (br d, J= 13.3 Hz, 1H), 1.95-1.77 (m, 7H), 1.52-1.37 (m, 2H) 實施例 101A:(1S,7a'S)-7a'-((((S)-4-((1R,5S)-3,8-二氮雜二環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘基-1-基)-8-氟-6-硝基喹唑啉-2-基)氧)甲基)-2,2-二氟四氫-1'H,3'H-螺旋[環丙烷-1,2'-吡咯嗪]、 實施例 101B :(1R,7a'R)-7a'-((((R)-4-((1R,5S)-3,8-二氮雜二環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘基-1-基)-8-氟-6-硝基喹唑啉-2-基)氧)甲基)-2,2-二氟四氫-1'H,3'H-螺旋[環丙烷-1,2'-吡咯嗪]、 實施例 101C:(1R,7a'R)-7a'-((((S)-4-((1R,5S)-3,8-二氮雜二環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘基-1-基)-8-氟-6-硝基喹唑啉-2-基)氧)甲基)-2,2-二氟四氫-1'H,3'H-螺旋[環丙烷-1,2'-吡咯嗪]和 實施例 101D:(1S,7a'S)-7a'-((((R)-4-((1R,5S)-3,8-二氮雜二環[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘基-1-基)-8-氟-6-硝基喹唑啉-2-基)氧)甲基)-2,2-二氟四氫-1'H,3'H-螺旋[環丙烷-1,2'-吡咯嗪] LCMS (ESI): [M+H] + = 673.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.71-8.68 (m, 1H), 8.14-8.06 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.48-7.39 (m, 2H), 4.67 (br d, J = 13.1 Hz, 1H), 4.53 (br d, J = 12.8 Hz, 1H), 4.41-4.32 (m, 2H), 3.81 (br d, J = 12.5 Hz, 1H), 3.69 (br s, 3H), 3.44 (d, J = 2.1 Hz, 1H), 3.32-3.26 (m, 1H), 3.20-3.13 (m, d, J = 13.3 Hz, 1H ) , 1.95-1.77 (m, 7H), 1.52-1.37 (m, 2H) Example 101A: (1S,7a'S)-7a'-((((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine], Example 101B : (1R,7a'R)-7a'-((((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine], Example 101C: (1R,7a'R)-7a'-((((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine] and Example 101D: (1S,7a'S)-7a'-((((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoronaphthyl-1-yl)-8-fluoro-6-nitroquinazolin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]
實施例 101經SFC分離(管柱:DAICEL CHIRALPAK IC(250mm*30mm,10um));流動相:A相為二氧化碳,B相為0.1%氨水/異丙醇;B相保持60%;流速:80毫升/分鐘),得到 異構物 1 和異構物 2 的混合物、異構物 3 和異構物 4 的混合物。 Example 101 was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um)); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 60%; flow rate: 80 ml/min) to obtain a mixture of isomers 1 and 2 , and a mixture of isomers 3 and 4 .
異構物 1 和異構物 2 的混合物經SFC分離(管柱:REGIS(S,S)WHELK-O1(250mm*25mm,10um));流動相:A相為二氧化碳,B相為0.1%氨水/異丙醇;B相保持60%;流速:80毫升/分鐘),得到光學純的 實施例 101A 和實施例 101B 。 The mixture of isomers 1 and 2 was separated by SFC (column: REGIS (S, S) WHELK-O1 (250 mm*25 mm, 10 um)); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 60%; flow rate: 80 ml/min) to obtain optically pure Example 101A and Example 101B .
異構物 3 和異構物 4 的混合物經SFC分離(管柱:DAICEL CHIRALPAK IG (250mm*30mm,10um));流動相:A相為二氧化碳,B相為0.1%氨水/乙醇;B相保持50%;流速:80毫升/分鐘),得到光學純的 實施例 101C 和 實施例 101D 。 The mixture of isomers 3 and 4 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um)); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 50%; flow rate: 80 ml/min) to obtain optically pure Example 101C and Example 101D .
實施例 101A:LCMS (ESI): [M+H] += 673.4; SFC分析(管柱: (S,S)Whelk-01 100×4.6mm I.D., 5.0um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:B相保持60%;流速:2.5毫升/分鐘):掌性管柱出峰位置為 2.676 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.69 (d, J= 1.4 Hz, 1H), 8.17-8.03 (m, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.50-7.37 (m, 2H), 4.68 (br d, J= 11.6 Hz, 1H), 4.53 (br d, J= 12.5 Hz, 1H), 4.42-4.30 (m, 2H), 3.82 (br d, J= 12.3 Hz, 1H), 3.73-3.61 (m, 3H), 3.52-3.36 (m, 1H), 3.31-3.27 (m, 1H), 3.16 (ddd, J= 3.9, 5.8, 9.9 Hz, 1H), 2.84 (d, J= 12.1 Hz, 1H), 2.76-2.65 (m, 1H), 2.29 (dd, J= 6.3, 13.5 Hz, 1H), 2.19-2.10 (m, 1H), 2.03 (d, J= 13.5 Hz, 1H), 1.98-1.75 (m, 7H), 1.52-1.37 (m, 2H). Example 101A : LCMS (ESI): [M+H] + = 673.4; SFC analysis (column: (S,S)Whelk-01 100×4.6mm ID, 5.0um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: phase B is maintained at 60%; flow rate: 2.5 ml/min): the elution position of the palmar column is 2.676 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.69 (d, J = 1.4 Hz, 1H), 8.17-8.03 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.50-7.37 (m, 2H), 4.68 (br d, J = 11.6 Hz, 1H), 3.71 (m, 3H), 3.59 (d, J = 12.5 Hz, 1H), 3.55 (m, 2H), 3.25 (m, 3H), 3.30 (m, 1H), 3.54 (d, J = 12.5 Hz, 1H), 3.72 (m, 3H), 3.53 (br d, J = 12.5 Hz, 1H), 4.53 (br d, J = 12.5 Hz, 1H), 4.42-4.30 (m, 2H), 3.82 (br d, J = 12.3 Hz, 1H), 3.73-3.61 (m, 3H), 3.52-3.36 (m, 1H), 3.31-3.27 (m, 1H), 3.16 (ddd, J = 3.9, 5.8, 9.9 Hz, 1H), 2.84 (d, J = 12.1 Hz, 1H), 2.76-2.65 (m, 1H), 2.29 (dd, J = 6.3, 13.5 Hz, 1H), 1H), 1.98-1.75 (m, 7H), 1.52-1.37 (m, 2H).
實施例 101B:LCMS (ESI): [M+H] += 673.6; SFC分析(管柱: (S,S)Whelk-01 100×4.6mm I.D., 5.0um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;梯度:B相保持60%;流速:2.5毫升/分鐘):掌性管柱出峰位置為 3.176 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.57 (s, 1H), 8.04-7.93 (m, 2H), 7.48 (t, J= 7.6 Hz, 1H), 7.37-7.26 (m, 2H), 4.55 (br d, J= 11.8 Hz, 1H), 4.42 (br d, J= 12.3 Hz, 1H), 4.24 (s, 2H), 3.69 (br d, J= 12.4 Hz, 1H), 3.56 (br d, J= 10.9 Hz, 3H), 3.33 (s, 1H), 3.19-3.15 (m, 1H), 3.08-3.01 (m, 1H), 2.72 (d, J= 12.1 Hz, 1H), 2.63-2.54 (m, 1H), 2.16 (dd, J= 6.2, 13.4 Hz, 1H), 2.07-2.00 (m, 1H), 1.94-1.88 (m, 1H), 1.84-1.65 (m, 7H), 1.38-1.25 (m, 2H). Example 101B : LCMS (ESI): [M+H] + = 673.6; SFC analysis (column: (S,S)Whelk-01 100×4.6mm ID, 5.0um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; gradient: phase B is maintained at 60%; flow rate: 2.5 ml/min): the elution position of the palmar column is 3.176 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.57 (s, 1H), 8.04-7.93 (m, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.37-7.26 (m, 2H), 4.55 (br d, J = 11.8 Hz, 1H), 4.42 (br d, J = 13.8 Hz, 1H), 4.80 (br d, J = 20.1 Hz, 1H), 4.69 (br d, J = 31.7 Hz, 1H), 4.80 (br d, J = 23.9 Hz, 1H), 4.64 ( br = 12.3 Hz, 1H), 4.24 (s, 2H), 3.69 (br d, J = 12.4 Hz, 1H), 3.56 (br d, J = 10.9 Hz, 3H), 3.33 (s, 1H), 3.19-3.15 (m, 1H), 3.08-3.01 (m, 1H), 2.72 (d, J = 12.1 Hz, 1H), 2.63-2.54 (m, 1H), 2.16 (dd, J = 6.2, 13.4 Hz, 1H), 2.07-2.01 (m, 1H), 1.94-1.88 (m, 1H), 1.84-1.65 (m, 7H), 1.38-1.25 (m, 2H).
實施例 101C:LCMS (ESI): [M+H] += 673.4; SFC分析(管柱: Chiralpak IG-3 50*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相保持40%;流速:4毫升/分鐘):掌性管柱出峰位置為 0.634 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.69 (d, J= 1.4 Hz, 1H), 8.16-8.03 (m, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.48-7.37 (m, 2H), 4.67 (br d, J= 11.9 Hz, 1H), 4.54 (br d, J= 12.3 Hz, 1H), 4.37 (s, 2H), 3.81 (br d, J= 11.3 Hz, 1H), 3.68 (br d, J= 10.8 Hz, 3H), 3.44 (s, 1H), 3.28 (br d, J= 7.0 Hz, 1H), 3.20-3.13 (m, 1H), 2.85 (d, J= 12.4 Hz, 1H), 2.76-2.65 (m, 1H), 2.28 (dd, J= 6.2, 13.6 Hz, 1H), 2.19-2.11 (m, 1H), 2.03 (d, J= 13.5 Hz, 1H), 1.97-1.77 (m, 7H), 1.51-1.37 (m, 2H). Example 101C : LCMS (ESI): [M+H] + = 673.4; SFC analysis (column: Chiralpak IG-3 50*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is maintained at 40%; flow rate: 4 ml/min): the elution position of the palmar column is 0.634 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.69 (d, J = 1.4 Hz, 1H), 8.16-8.03 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.48-7.37 (m, 2H), 4.67 (br d, J = 11.9 Hz, 1H), 4.54 (br d, J = d, J = 12.3 Hz, 1H), 4.37 (s, 2H), 3.81 (br d, J = 11.3 Hz, 1H), 3.68 (br d, J = 10.8 Hz, 3H), 3.44 (s, 1H), 3.28 (br d, J = 7.0 Hz, 1H), 3.20-3.13 (m, 1H), 2.85 (d, J = 12.4 Hz, 1H), 2.76-2.65 (m, 1H), 2.28 (dd, J = 6.2, 13.6 Hz, 1H), 2.19-2.11 (m, 1H), 2.03 (d, J = 13.5 Hz, 1H), 1.97-1.81 (m, 7H), 1.51-1.37 (m, 2H).
實施例 101D:LCMS (ESI): [M+H] += 673.4; SFC分析(管柱: Chiralpak IG-3 50*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:B相保持40%;流速:4毫升/分鐘):掌性管柱出峰位置為 1.129 min; 1H NMR (400 MHz, CD 3OD) δ ppm 8.57 (s, 1H), 8.03-7.92 (m, 2H), 7.48 (t, J= 7.7 Hz, 1H), 7.36-7.27 (m, 2H), 4.56 (br d, J= 11.4 Hz, 1H), 4.41 (br d, J= 12.6 Hz, 1H), 4.30-4.17 (m, 2H), 3.69 (br d, J= 12.6 Hz, 1H), 3.60-3.51 (m, 3H), 3.31 (s, 1H), 3.19-3.14 (m, 1H), 3.08-3.01 (m, 1H), 2.73 (d, J= 12.1 Hz, 1H), 2.64-2.54 (m, 1H), 2.16 (dd, J= 6.3, 13.5 Hz, 1H), 2.07-1.98 (m, 1H), 1.91 (d, J= 13.5 Hz, 1H), 1.85-1.64 (m, 7H), 1.38-1.26 (m, 2H). 實施例 102 : 4-(4-(1R,5S)-3,8- 二氮雜二環 [3.2.1] 辛 -3- 基 )-8- 氟 -2-( 四氫 -2H- 吡喃 -4- 基 ) 氧 ) 吡啶 [4,3-d] 嘧啶 -7- 基 )-5- 乙炔基 -6- 氟萘 -2- 醇 Example 101D : LCMS (ESI): [M+H] + = 673.4; SFC analysis (column: Chiralpak IG-3 50*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: phase B is maintained at 40%; flow rate: 4 ml/min): the elution position of the palmar column is 1.129 min; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.57 (s, 1H), 8.03-7.92 (m, 2H), 7.48 (t, J = 7.7 Hz, 1H), 7.36-7.27 (m, 2H), 4.56 (br d, J = 11.4 Hz, 1H), 4.41 (br d, J = 12.6 Hz, 1H), 4.30-4.17 (m, 2H), 3.69 (br d, J = 12.6 Hz, 1H), 3.60-3.51 (m, 3H), 3.31 (s, 1H), 3.19-3.14 (m, 1H), 3.08-3.01 (m, 1H), 2.73 (d, J = 12.1 Hz, 1H), 2.64-2.54 (m, 1H), 2.16 (dd, J = 6.3, 13.5 Hz, 1H), 2.07-1.98 (m, 1H), 1.91 (d, J = 13.5 Hz, 1H), 1.85-1.64 (m, 7H), 1.38-1.26 (m, 2H). Example 102 : 4-(4-(1R,5S)-3,8 -diazabicyclo [3.2.1] oct -3- yl )-8- fluoro -2-( tetrahydro -2H- pyran -4- yl ) oxy ) pyridin [4,3-d] pyrimidin -7- yl )-5- ethynyl- 6- fluoronaphthalen -2 - ol
LCMS (ESI): [M+H] += 544.1。 1H NMR (400 MHz, CD 3OD) δ = 9.02 (br s, 1H), 8.53 (br s, 1H), 7.86 (dd, J= 5.7, 8.9 Hz, 1H), 7.43-7.26 (m, 2H), 7.21 (s, 1H), 5.45-5.34 (m, 1H), 4.75-4.61 (m, 2H), 4.09-3.93 (m, 4H), 3.85 (br d, J= 8.9 Hz, 2H), 3.65 (br t, J= 8.8 Hz, 2H), 3.38 (s, 1H), 2.14 (br d, J= 10.6 Hz, 2H), 2.08-1.91 (m, 4H), 1.85 (br dd, J= 3.4, 8.6 Hz, 2H). 實施例 103 : 1-(((4-((1R,5S)-3,8- 二氮雜雙環 [3.2.1] 辛 -3- 基 )-7-(8- 乙炔基 -7- 氟 -3- 羥基萘 -1- 基 )-8- 氟吡啶 [4,3-d] 嘧啶 -2- 基 ) 氧基 ) 甲基 ) 環丙烷 -1- 甲腈 LCMS (ESI): [M+H] + = 544.1. 1 H NMR (400 MHz, CD 3 OD) δ = 9.02 (br s, 1H), 8.53 (br s, 1H), 7.86 (dd, J = 5.7, 8.9 Hz, 1H), 7.43-7.26 (m, 2H), 7.21 (s, 1H), 5.45-5.34 (m, 1H), 4.75-4.61 (m, 2H), 4.09-3.93 (m, 4H), 3.85 (br d, J = 8.9 Hz, 2H), 3.65 (br t, J = 8.8 Hz, 2H), 3.38 (s, 1H), 2.14 (br d, J = 10.6 Hz, 2H), 2.08-1.91 (m, 4H), 1.85 (br dd, J = 3.4, 8.6 Hz, 2H). Example 103 : 1-(((4-((1R,5S)-3,8- diazabicyclo [3.2.1] oct -3- yl )-7-(8- ethynyl -7 - fluoro -3- hydroxynaphthalen -1- yl )-8- fluoropyridin [4,3-d] pyrimidin -2- yl ) oxy ) methyl ) cyclopropane -1- carbonitrile
LCMS (ESI): [M+H] += 539.5。 1H NMR (400 MHz, CD 3OD) δ ppm 9.06 (s, 1H), 8.52 (s, 1H), 7.89 (dd, J= 5.7, 9.2 Hz, 1H), 7.39-7.31 (m, 2H), 7.23 (d, J= 2.5 Hz, 1H), 4.78-4.69 (m, 2H), 4.57-4.52 (m, 2H), 3.96 (br s, 2H), 3.84 (br d, J= 13.0 Hz, 2H), 3.41-3.37 (m, 1H), 2.05-1.96 (m, 4H), 1.45-1.38 (m, 2H), 1.33-1.28 (m, 2H). 實施例 104 : 4-(4-(1R,5S)-3,8- 二氮雜二環 [3.2.1] 辛 -3- 基 )-8- 氟 -2-(2,2,2- 三氟乙氧基 ) 吡啶 [4,3-d] 嘧啶 -7- 基 )-5- 乙炔基 -6- 氟萘 -2- 醇 LCMS (ESI): [M+H] + = 539.5. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.06 (s, 1H), 8.52 (s, 1H), 7.89 (dd, J = 5.7, 9.2 Hz, 1H), 7.39-7.31 (m, 2H), 7.23 (d, J = 2.5 Hz, 1H), 4.78-4.69 (m, 2H), 4.57-4.52 (m, 2H), 3.96 (br s, 2H), 3.84 (br d, J = 13.0 Hz, 2H), 3.41-3.37 (m, 1H), 2.05-1.96 (m, 4H), 1.45-1.38 (m, 2H), 1.33-1.28 (m, 2H). Example 104 : 4-(4-(1R,5S)-3,8 -diazabicyclo [3.2.1] oct -3- yl )-8- fluoro -2-(2,2,2 -trifluoroethoxy ) pyridin [4,3-d] pyrimidin -7- yl )-5- ethynyl -6- fluoronaphthalen -2- ol
LCMS (ESI): [M+H] += 542.0。 1H NMR (400 MHz, CH 3OD) δ ppm 9.07 (s, 1H), 7.87 (dd, J= 9.05, 5.8 Hz, 1H), 7.39-7.27 (m, 2 H), 7.22 (d, J= 2.6 Hz, 1H), 5.01 (q, J= 8.9 Hz, 2H), 4.71-4.57 (m, 2 H), 3.83-3.65 (m, 4H), 3.38 (s, 1H), 1.96-1.75 (m, 4H). 實施例 105 : 4-(4-(1R,5S)-3,8- 二氮雜二環 [3.2.1] 辛 -3- 基 )-8- 氟 -2-( 四氫 -2H- 吡喃 -4- 基 ) 甲氧基 ) 吡啶 [4,3-d] 嘧啶 -7- 基 )-5- 乙炔基 -6- 氟萘 -2- 醇 LCMS (ESI): [M+H] + = 542.0. 1 H NMR (400 MHz, CH 3 OD) δ ppm 9.07 (s, 1H), 7.87 (dd, J = 9.05, 5.8 Hz, 1H), 7.39-7.27 (m, 2 H), 7.22 (d, J = 2.6 Hz, 1H), 5.01 (q, J = 8.9 Hz, 2H), 4.71-4.57 (m, 2 H), 3.83-3.65 (m, 4H), 3.38 (s, 1H), 1.96-1.75 (m, 4H). Example 105 : 4-(4-(1R,5S)-3,8- diazabicyclo [3.2.1] octan -3- yl )-8- fluoro -2-( tetrahydro -2H- pyran -4- yl ) methoxy ) pyridin [4,3-d] pyrimidin -7- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol
LCMS (ESI): [M+H] += 558.1。 1H NMR (400 MHz, CH 3OD) δ ppm 9.01 (s, 1H), 7.86 (dd, J= 9.0, 5.8 Hz, 1H), 7.41-7.27 (m, 2H), 7.21 (d, J= 2.1 Hz, 1H), 4.75-4.59 (m, 2H), 4.34 (br d, J= 5.4 Hz, 2H), 3.99 (br dd, J= 10.8, 3.7 Hz, 2H), 3.93-3.71 (m, 4H), 3.47 (br t, J= 11.2 Hz, 2H), 3.38 (s, 1H), 2.23-2.05 (m, 1H), 2.02-1.84 (m, 4H), 1.79 (br d, J= 12.5 Hz, 2H), 1.55-1.40 (m, 2H). 實施例 106 : 4-(2-((2- 氧雜二環 [2.2.2] 辛 -4- 基 ) 甲氧基 )-4-((1R,5S)-3,8- 二氮雜二環 [3.2.1] 辛 -3- 基 )-8- 氟吡啶 [4,3-d] 嘧啶 -7- 基 )-5- 乙炔基 -6- 氟萘 -2- 醇 LCMS (ESI): [M+H] + = 558.1. 1 H NMR (400 MHz, CH 3 OD) δ ppm 9.01 (s, 1H), 7.86 (dd, J = 9.0, 5.8 Hz, 1H), 7.41-7.27 (m, 2H), 7.21 (d, J = 2.1 Hz, 1H), 4.75-4.59 (m, 2H), 4.34 (br d, J = 5.4 Hz, 2H), 3.99 (br dd, J = 10.8, 3.7 Hz, 2H), 3.93-3.71 (m, 4H), 3.47 (br t, J = 11.2 Hz, 2H), 3.38 (s, 1H), 2.23-2.05 (m, 1H), 2.03-1.84 (m, 4H), 1.79 (br d, J = 12.5 Hz, 2H), 1.55-1.40 (m, 2H). Example 106 : 4-(2-((2- oxabicyclo [2.2.2] oct -4- yl ) methoxy )-4-((1R,5S)-3,8 -diazabicyclo [3.2.1] oct -3- yl )-8- fluoropyrido [4,3-d] pyrimidin -7- yl )-5- ethynyl- 6- fluoronaphthalen -2 - ol
LCMS (ESI): [M+H] += 584.3。 1H NMR (400 MHz, CD 3OD) δ ppm 9.02 (s, 1H), 7.91-7.84 (m, 1H), 7.37 (d, J= 2.4 Hz, 2H), 7.24-7.21 (m, 1H), 4.66-4.58 (m, 2H), 4.18 (d, J = 3.7 Hz, 2H), 3.90 (s, 2H), 3.83-3.80 (m, 1H), 3.75 (br s, 4H), 3.36-3.35 (m, 1H), 2.11-2.04 (m, 2H), 1.95-1.90 (m, 2H), 1.88-1.81 (m, 4H), 1.77-1.69 (m, 4H). 實施例 107:4-(2-((2-氧雜二環[2.1.1]己-1-基)甲氧基)-4-((1R,5S)-3,8-二氮雜二環[3.2.1]辛-3-基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇 LCMS (ESI): [M+H] + = 584.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.02 (s, 1H), 7.91-7.84 (m, 1H), 7.37 (d, J = 2.4 Hz, 2H), 7.24-7.21 (m, 1H), 4.66-4.58 (m, 2H), 4.18 (d, J = 3.7 Hz, 2H), 3.90 (s, 2H), 3.83-3.80 (m, 1H), 3.75 (br s, 4H), 3.36-3.35 (m, 1H), 2.11-2.04 (m, 2H), 1.95-1.90 (m, 2H), 1.88-1.81 (m, 4H), 1.77-1.69 (m, 4H). Example 107 : 4-(2-((2-oxabicyclo[2.1.1]hex-1-yl)methoxy)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS (ESI): [M+H] += 556.1。 1H NMR (400 MHz, CD 3OD) δ ppm 9.04 (s, 1H), 7.88 (dd, J= 5.7, 9.0 Hz, 1H), 7.40-7.31 (m, 2H), 7.23 (d, J= 2.2 Hz, 1H), 4.74 (br d, J= 3.1 Hz, 2H), 4.72-4.62 (m, 2H), 3.93 (br s, 2H), 3.88-3.77 (m, 4H), 3.38 (s, 1H), 3.00 (br s, 1H), 2.06-1.91 (m, 6H), 1.59 (br d, J= 4.8 Hz, 2H). 實施例 108 : 4-(((4-((1R,5S)-3,8- 二氮雜二環 [3.2.1] 辛 -3- 基 )-7-(8- 乙炔基 -7- 氟 -3- 羥基萘 -1- 基 )-8- 氟吡啶 [4,3-d] 嘧啶 -2- 基 ) 氧基 ) 甲基 ) 四氫 -2H- 吡喃 -4- 腈 LCMS (ESI): [M+H] + = 556.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.04 (s, 1H), 7.88 (dd, J = 5.7, 9.0 Hz, 1H), 7.40-7.31 (m, 2H), 7.23 (d, J = 2.2 Hz, 1H), 4.74 (br d, J = 3.1 Hz, 2H), 4.72-4.62 (m, 2H), 3.93 (br s, 2H), 3.88-3.77 (m, 4H), 3.38 (s, 1H), 3.00 (br s, 1H), 2.06-1.91 (m, 6H), 1.59 (br d, J = 4.8 Hz, 2H). Example 108 : 4-(((4-((1R,5S)-3,8- diazabicyclo [3.2.1] octan -3- yl ) -7- (8- ethynyl- 7- fluoro -3- hydroxynaphthalen -1- yl )-8 -fluoropyridin [4,3-d] pyrimidin -2- yl ) oxy ) methyl ) tetrahydro -2H- pyran -4- carbonitrile
LCMS (ESI): [M+H] += 583.5。 1H NMR (400 MHz, CD 3OD) δ ppm 9.06 (s, 1H), 7.92-7.84 (m, 1H), 7.34 (s, 2H), 7.25-7.21 (m, 1H), 4.60 (s, 4H), 3.98 (br d, J= 1.8 Hz, 2H), 3.79-3.67 (m, 6H), 3.35-3.35 (m, 1H), 2.13-2.04 (m, 2H), 1.86 (br d, J= 15.6 Hz, 6H). 實施例 109 : 4-(4-((1R,5S)-3,8- 二氮雜雙環 [3.2.1] 辛 -3- 基 )-8- 氟 -2-((4-( 三氟甲基 ) 四氫 -2H- 吡喃 -4- 基 ) 甲氧基 ) 吡啶并 [4,3-d] 嘧啶 -7- 基 )-5- 乙炔基 -6- 氟萘 -2- 醇 LCMS (ESI): [M+H] + = 583.5. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.06 (s, 1H), 7.92-7.84 (m, 1H), 7.34 (s, 2H), 7.25-7.21 (m, 1H), 4.60 (s, 4H), 3.98 (br d, J = 1.8 Hz, 2H), 3.79-3.67 (m, 6H), 3.35-3.35 (m, 1H), 2.13-2.04 (m, 2H), 1.86 (br d, J = 15.6 Hz, 6H). Example 109 : 4-(4-((1R,5S)-3,8 -diazabicyclo [3.2.1] octan -3 -yl )-8- fluoro -2-((4-( trifluoromethyl ) tetrahydro -2H- pyran -4- yl ) methoxy ) pyrido [4,3-d] pyrimidin -7- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol
LCMS (ESI): [M+H] += 626.2。 1H NMR (400 MHz, CD 3OD) δ ppm 9.05 (s, 1H), 7.88 (dd, J= 5.8, 9.1 Hz, 1H), 7.40-7.29 (m, 2H), 7.24 (d, J= 2.5 Hz, 1H), 4.86 (br d, J= 3.3 Hz, 2H), 4.71-4.60 (m, 2H), 3.90 (br d, J= 12.0 Hz, 2H), 3.81-3.67 (m, 6H), 3.42-3.36 (m, 1H), 2.04-1.81 (m, 8H). 實施例 110 : 4-(4-((1R,5S)-3,8- 二氮雜二環 [3.2.1] 辛 -3- 基 )-8- 氟 -2-( 反式 -3- 羥基環丁基 ) 甲氧基 ) 吡啶 [4,3-d] 嘧啶 -7- 基 )-5- 乙炔基 -6- 氟萘 -2- 醇 LCMS (ESI): [M+H] + = 626.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.05 (s, 1H), 7.88 (dd, J = 5.8, 9.1 Hz, 1H), 7.40-7.29 (m, 2H), 7.24 (d, J = 2.5 Hz, 1H), 4.86 (br d, J = 3.3 Hz, 2H), 4.71-4.60 (m, 2H), 3.90 (br d, J = 12.0 Hz, 2H), 3.81-3.67 (m, 6H), 3.42-3.36 (m, 1H), 2.04-1.81 (m, 8H). Example 110 : 4-(4-((1R,5S)-3,8 -diazabicyclo [3.2.1] octan -3- yl )-8 - fluoro -2-( trans -3- hydroxycyclobutyl ) methoxy ) pyridin [4,3-d] pyrimidin -7- yl )-5- ethynyl - 6- fluoronaphthalen -2- ol
LCMS (ESI): [M+H] += 544.1。 1H NMR (400 MHz, CD 3OD) δ ppm 9.02 (s, 1H), 7.87 (dd, J= 5.7, 9.2 Hz, 1H), 7.38-7.31 (m, 2H), 7.23 (d, J= 2.2 Hz, 1H), 4.69-4.59 (m, 2H), 4.49 (s, 2H), 4.48-4.39 (m, 1H), 3.72 (br d, J= 10.6 Hz, 4H), 3.37-3.36 (m, 1H), 2.78-2.67 (m, 1H), 2.30 (br d, J= 4.2 Hz, 2H), 2.17 (br s, 2H), 1.87 (br d, J= 17.2 Hz, 4H). 實施例 111 : 4-(2-((3- 氧雜雙環 [3.1.0] 己 -6- 基 ) 甲氧基 )-4-((1R,5S)-3,8- 二氮雜雙環 [3.2.1] 辛 -3- 基 )-8- 氟吡啶 [4,3-d] 嘧啶 -7- 基 )-5- 乙炔基 -6- 氟萘 -2- 醇 LCMS (ESI): [M+H] + = 544.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.02 (s, 1H), 7.87 (dd, J = 5.7, 9.2 Hz, 1H), 7.38-7.31 (m, 2H), 7.23 (d, J = 2.2 Hz, 1H), 4.69-4.59 (m, 2H), 4.49 (s, 2H), 4.48-4.39 (m, 1H), 3.72 (br d, J = 10.6 Hz, 4H), 3.37-3.36 (m, 1H), 2.78-2.67 (m, 1H), 2.30 (br d, J = 4.2 Hz, 2H), 2.17 (br s, 2H), 1.87 (br d, J = 17.2 Hz, 4H). Example 111 : 4-(2-((3- oxabicyclo [3.1.0] hex -6- yl ) methoxy )-4-((1R,5S)-3,8 -diazabicyclo [3.2.1] oct -3- yl )-8- fluoropyrido [4,3-d] pyrimidin -7- yl )-5- ethynyl- 6 -fluoronaphthalen -2 - ol
LCMS (ESI): [M+H] += 556.3。 1H NMR (400 MHz, CD 3OD) δ ppm 9.02 (s, 1H), 7.88 (dd, J= 5.8, 9.1 Hz, 1H), 7.40-7.29 (m, 2H), 7.23 (d, J= 2.4 Hz, 1H), 4.72-4.59 (m, 3H), 4.40 (d, J= 7.4 Hz, 1H), 4.07-4.00 (m, 1H), 3.97-3.86 (m, 2H), 3.84-3.69 (m, 5H), 3.43-3.37 (m, 1H), 1.99-1.76 (m, 6H), 1.55-1.26 (m, 1H). 實施例 112 : 4-(4-((1R,5S)-3,8- 二氮雜二環 [3.2.1] 辛 -3- 基 )-8- 氟 -2-( 順式 -3- 羥基環丁基 ) 甲氧基 ) 吡啶 [4,3-d] 嘧啶 -7- 基 )-5- 乙炔基 -6- 氟萘 -2- 醇 LCMS (ESI): [M+H] + = 556.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.02 (s, 1H), 7.88 (dd, J = 5.8, 9.1 Hz, 1H), 7.40-7.29 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 4.72-4.59 (m, 3H), 4.40 (d, J = 7.4 Hz, 1H), 4.07-4.00 (m, 1H), 3.97-3.86 (m, 2H), 3.84-3.69 (m, 5H), 3.43-3.37 (m, 1H), 1.99-1.76 (m, 6H), 1.55-1.26 (m, 1H). Example 112 : 4-(4-((1R,5S)-3,8 -diazabicyclo [3.2.1] octan -3- yl )-8 - fluoro -2-( cis -3- hydroxycyclobutyl ) methoxy ) pyridin [4,3-d] pyrimidin -7- yl )-5- ethynyl - 6- fluoronaphthalen -2- ol
LCMS (ESI): [M+H] += 544.1。 1H NMR (400 MHz, CD 3OD) δ ppm 9.02 (s, 1H), 7.88 (dd, J= 5.8, 9.1 Hz, 1H), 7.39-7.29 (m, 2H), 7.23 (d, J= 2.4 Hz, 1H), 4.70-4.59 (m, 2H), 4.49-4.41 (m, 2H), 4.15 (quin, J= 7.4 Hz, 1H), 3.84-3.68 (m, 4H), 3.39-3.35 (m, 1H), 2.53-2.42 (m, 2H), 2.37-2.24 (m, 1H), 1.98-1.78 (m, 6H). 實施例 113:4-(4-(1R,5S)-3,8-二氮雜雙環[3.2.1]辛-3-基)-8-氟-2-(1-氮雜雙環[2.2.2]辛-4-基甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇 LCMS (ESI): [M+H] + = 544.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.02 (s, 1H), 7.88 (dd, J = 5.8, 9.1 Hz, 1H), 7.39-7.29 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 4.70-4.59 (m, 2H), 4.49-4.41 (m, 2H), 4.15 (quin, J = 7.4 Hz, 1H), 3.84-3.68 (m, 4H), 3.39-3.35 (m, 1H), 2.53-2.42 (m, 2H), 2.37-2.24 (m, 1H), 1.98-1.78 (m, 6H). Example 113 :4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(1-azabicyclo[2.2.2]oct-4-ylmethoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
LCMS (ESI): [M+H] += 583.5. 實施例 114 : 4- ( 2- ( 雙環 [2.2.2] 辛 -1- 基甲氧基 ) -4- (( 1R,5S ) -3,8- 二氮雜雙環 [3.2.1] 辛 -3- 基 ) -8- 氟吡啶并 [4,3-d] 嘧啶 -7- 基 ) -5- 乙炔基 -6- 氟萘 -2- 醇 LCMS (ESI): [M+H] + = 583.5. Example 114 : 4- ( 2- ( bicyclo [2.2.2] octan -1 -ylmethoxy ) -4 -(( 1R,5S ) -3,8 -diazabicyclo [3.2.1] octan -3- yl ) -8 - fluoropyrido [4,3-d] pyrimidin -7- yl ) -5- ethynyl- 6- fluoronaphthalen -2 -ol
LCMS (ESI): [M+H] += 582.5. 實施例 115 : 4-(4-(1R,5S)-3,8- 二氮雜雙環 [3.2.1] 辛 -3- 基 )-8- 氟 -2-((4- 甲氧基雙環 [2.2.2] 辛 -1- 基 ) 甲氧基 ) 吡啶 [4,3-d] 嘧啶 -7- 基 )-5- 乙炔基 -6- 氟萘 -2- 醇 LCMS (ESI): [M+H] + = 582.5. Example 115 : 4-(4-(1R,5S)-3,8 -diazabicyclo [3.2.1] oct -3- yl )-8- fluoro -2-((4- methoxybicyclo [2.2.2] oct -1 -yl ) methoxy ) pyridin [4,3-d] pyrimidin -7- yl )-5- ethynyl- 6- fluoronaphthalen -2- ol
LCMS (ESI): [M+H] += 612.6。 1H NMR (400 MHz, CD 3OD) δ ppm 9.01 (s, 1H), 7.88 (dd, J= 5.7, 9.2 Hz, 1H), 7.40-7.29 (m, 2H), 7.22 (d, J= 2.5 Hz, 1H), 4.67-4.55 (m, 2H), 4.16-4.09 (m, 2H), 3.77-3.66 (m, 4H), 3.40-3.36 (m, 1H), 3.21 (s, 3H), 1.92-1.79 (m, 4H), 1.78-1.70 (m, 12H). 實施例 116 : 1-(7-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基 -2-(( 四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 ) 喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 LCMS (ESI): [M+H] + = 612.6. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.01 (s, 1H), 7.88 (dd, J = 5.7, 9.2 Hz, 1H), 7.40-7.29 (m, 2H), 7.22 (d, J = 2.5 Hz, 1H), 4.67-4.55 (m, 2H), 4.16-4.09 (m, 2H), 3.77-3.66 (m, 4H), 3.40-3.36 (m, 1H), 3.21 (s, 3H), 1.92-1.79 (m, 4H), 1.78-1.70 (m, 12H). Example 116 : 1-(7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -6- nitro -2-(( tetrahydro -1H- pyrrolizin -7a(5H) -yl ) methoxy ) quinazolin -4- yl )-3- methylpiperidin -3- ol
第一步:在氮氣環境下,將1-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(550 mg,1.14 mmol)和 (((2-氟-8-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(670 mg,1.48 mmol)加入到甲苯(20 mL)和水(5 mL)的混合溶液中,然後加入碳酸銫(1.1 g,3.4 mmol),甲磺醯氧基(二金剛烷基-正丁基膦基)-2-胺基-1,1-聯苯-2-基)鈀(II)(166 mg,0.23 mmol)。將混合物在100 oC攪拌16小時。將反應液加水(60 mL)稀釋並用乙酸乙酯(30 mL * 3)萃取,合併的有機相用鹽水(60 mL)洗滌,無水硫酸鎂乾燥並過濾,濾液真空濃縮。殘餘物透過快速管柱層析(矽膠,0-15%梯度四氫呋喃/石油醚)純化得到棕色固體化合物1-(8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(565 mg,0.78 mmol,產率68%)。LCMS (ESI): [M+H] += 729.3. Step 1 : Under nitrogen atmosphere, 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (550 mg, 1.14 mmol) and (((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-cyclopentane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (670 mg, 1.48 mmol) were added to a mixed solution of toluene (20 mL) and water (5 mL), followed by cesium carbonate (1.1 g, 3.4 mmol), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (166 mg, 0.23 mmol). The mixture was stirred at 100 ° C for 16 hours. The reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-15% gradient tetrahydrofuran/petroleum ether) to obtain a brown solid compound 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (565 mg, 0.78 mmol, yield 68%). LCMS (ESI): [M+H] + = 729.3.
第二步:向1-(8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(400 mg,0.55 mmol)的四氫呋喃(8 mL)溶液中加入4A分子篩(400 mg),叔丁醇鈉(105 mg,1.1 mmol)和 (四氫-1H-吡咯嗪-7a(5H)-基)甲醇(155 mg,1.1 mmol)。將反應在20 oC攪拌2小時。混合物用水(15 mL)稀釋並用乙酸乙酯(15 mL*3)萃取,合併的有機相用飽和食鹽水(20 mL)洗滌,無水硫酸鎂乾燥並過濾,濾液減壓濃縮,殘餘物透過快速管柱層析(矽膠,0-10%梯度甲醇/二氯甲烷)純化得到棕色固體化合物1-(8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(254 mg,0.33 mmol,產率60%)。LCMS (ESI): [M+H] += 770.2. Step 2 : To a solution of 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (400 mg, 0.55 mmol) in tetrahydrofuran (8 mL) was added 4A molecular sieve (400 mg), sodium tert-butoxide (105 mg, 1.1 mmol) and (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (155 mg, 1.1 mmol). The reaction was stirred at 20 ° C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL*3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a brown solid compound 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (254 mg, 0.33 mmol, yield 60%). LCMS (ESI): [M+H] + = 770.2.
第三步:向1-(8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(244 mg,0.32 mmol)的二甲基甲醯胺(3 mL)溶液中加入氟化銫(385 mg,2.53 mmol)。將反應在20 oC攪拌2小時。混合物用水(15 mL)稀釋並用乙酸乙酯(15 mL*2)萃取,合併的有機相用飽和食鹽水(20 mL)洗滌,無水硫酸鎂乾燥並過濾,濾液濃縮,殘餘物透過快速管柱層析(矽膠,0-10%梯度甲醇/二氯甲烷)純化得到棕色固體化合物1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(140 mg,0.23 mmol,產率72%)。LCMS (ESI): [M+H] += 614.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.88 (s, 1H), 8.15-8.06 (m, 2H), 7.61 (t, J= 7.7 Hz, 1H), 7.48-7.40 (m, 2H), 4.56 (br d, J= 13.6 Hz, 1H), 4.39-4.23 (m, 3H), 3.70-3.51 (m, 2H), 3.45-3.39 (m, 1H), 3.27-3.17 (m, 2H), 2.90-2.79 (m, 2H), 2.20-2.09 (m, 2H), 2.06-1.76 (m, 10H), 1.30 (s, 3H). 實施例 116A:(R)-1-((R)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇 實施例 116B:(R)-1-((S)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇, Step 3 : To a solution of 1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (244 mg, 0.32 mmol) in dimethylformamide (3 mL) was added cesium fluoride (385 mg, 2.53 mmol). The reaction was stirred at 20 ° C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL*2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a brown solid compound 1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (140 mg, 0.23 mmol, yield 72%). LCMS (ESI): [M+H] + = 614.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.88 (s, 1H), 8.15-8.06 (m, 2H), 7.61 (t, J = 7.7 Hz, 1H), 7.48-7.40 (m, 2H), 4.56 (br d, J = 13.6 Hz, 1H), 4.39-4.23 (m, 3H), 3.70-3.51 (m, 2H), 3.45-3.39 (m, 1H), 3.27-3.17 (m, 2H), 2.90-2.79 (m, 2H), 2.20-2.09 (m, 2H), 2.06-1.76 (m, 10H), 1.30 (s, 3H). Example 116A: (R)-1-((R)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol Example 116B: (R)-1-((S)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol,
實施例 116經SFC分離(管柱:DAICEL CHIRALCEL OD (250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/異丙醇;B相保持40%;流速:110毫升/分鐘),得到目標化合物。 Example 116 was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/isopropanol; phase B is maintained at 40%; flow rate: 110 ml/min) to obtain the target compound.
實施例 116A :SFC分析(層析管柱: ChiralCel OD-3,150mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;保持40%的B相;流速:2.5毫升/分鐘):掌性管柱出峰位置為 3.754 min; LCMS (ESI): [M+H] += 614.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.80 (d, J= 1.1 Hz, 1H), 8.08-7.87 (m, 2H), 7.49 (t, J= 7.7 Hz, 1H), 7.40-7.27 (m, 2H), 4.53-4.39 (m, 3H), 4.21 (br d, J= 13.5 Hz, 1H), 3.51-3.42 (m, 2H), 3.41-3.34 (m, 2H), 3.33-3.24 (m, 1H), 3.03-2.94 (m, 2H), 2.19-2.06 (m, 3H), 2.05-1.84 (m, 6H), 1.79-1.65 (m, 3H), 1.19 (s, 3H). Example 116A : SFC analysis (chromatographic column: ChiralCel OD-3, 150 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; phase B is maintained at 40%; flow rate: 2.5 ml/min): the elution position of the palmicular column is 3.754 min; LCMS (ESI): [M+H] + = 614.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.80 (d, J = 1.1 Hz, 1H), 8.08-7.87 (m, 2H), 7.49 (t, J = 7.7 Hz, 1H), 7.40-7.27 (m, 2H), 4.53-4.39 (m, 3H), 4.21 (br d, J = 13.5 Hz, 1H), 3.51-3.42 (m, 2H), 3.41-3.34 (m, 2H), 3.33-3.24 (m, 1H), 3.03-2.94 (m, 2H), 2.19-2.06 (m, 3H), 2.05-1.84 (m, 6H), 1.79-1.65 (m, 3H), 1.19 (s, 3H).
實施例 116B: SFC分析(層析管柱: ChiralCel OD-3,150mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/異丙醇;保持40%的B相;流速:2.5毫升/分鐘):掌性管柱出峰位置為 3.131 min; LCMS (ESI): [M+H] += 614.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.84 (s, 1H), 8.10-7.91 (m, 2H), 7.50 (t, J= 7.7 Hz, 1H), 7.40-7.24 (m, 2H), 4.61-4.46 (m, 3H), 4.21 (br d, J= 13.4 Hz, 1H), 3.65-3.51 (m, 3H), 3.39-3.26 (m, 2H), 3.20-3.13 (m, 2H), 2.28-2.18 (m, 2H), 2.15-1.95 (m, 7H), 1.83-1.66 (m, 3H), 1.22 (s, 3H). 實施例 117 : 1-(7-(8- 乙基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基 -2-(( 四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 ) 喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Example 116B : SFC analysis (chromatographic column: ChiralCel OD-3, 150 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/isopropanol; phase B is maintained at 40%; flow rate: 2.5 ml/min): the elution position of the palmar column is 3.131 min; LCMS (ESI): [M+H] + = 614.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.84 (s, 1H), 8.10-7.91 (m, 2H), 7.50 (t, J = 7.7 Hz, 1H), 7.40-7.24 (m, 2H), 4.61-4.46 (m, 3H), 4.21 (br d, J = 13.4 Hz, 1H), 3.65-3.51 (m, 3H), 3.39-3.26 (m, 2H), 3.20-3.13 (m, 2H), 2.28-2.18 (m, 2H), 2.15-1.95 (m, 7H), 1.83-1.66 (m, 3H), 1.22 (s, 3H). Example 117 : 1-(7-(8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -6- nitro -2-(( tetrahydro -1H- pyrrolizine -7a(5H)-yl ) methoxy ) quinazolin - 4- yl )-3- methylpiperidin -3- ol
第一步:向1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(20 mg,0.032 mmol)的四氫呋喃(400 uL)溶液中加入2-硝基苯磺醯肼(70.8 mg,0.32 mmol)和三乙胺(45.4 uL,0.32 mmol)。將反應在20 oC攪拌16小時。混合物用水(2 mL)稀釋並用乙酸乙酯(2 mL*2)萃取,合併的有機相用飽和食鹽水(2 mL)洗滌,無水硫酸鎂乾燥,過濾,濾液濃縮,殘餘物透過製備型HPLC純化得到黃色固體化合物1-(7-(8-乙基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(7.00 mg,11.3 umol,35%)。LCMS (ESI): [M+H] += 618.1。 1H NMR (400 MHz, CD 3OD) δ ppm 9.10-8.84 (m, 1H), 8.07-7.88 (m, 2H), 7.54-7.36 (m, 2H), 7.23 (br s, 1H), 4.53 (br s, 1H), 4.45-4.20 (m, 3H), 3.83-3.54 (m, 1H), 3.48 (br s, 1H), 3.18 (br s, 1H), 3.00-2.61 (m, 3H), 2.48 (br s, 1H), 2.30-1.68 (m, 13H), 1.33 (br d, J= 15.2 Hz, 3H), 0.88 (br s, 3H). Step 1 : To a solution of 1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (20 mg, 0.032 mmol) in tetrahydrofuran (400 uL) was added 2-nitrobenzenesulfonylhydrazine (70.8 mg, 0.32 mmol) and triethylamine (45.4 uL, 0.32 mmol). The reaction was stirred at 20 ° C for 16 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL*2). The combined organic phases were washed with saturated brine (2 mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC to give a yellow solid compound 1-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (7.00 mg, 11.3 umol, 35%). LCMS (ESI): [M+H] + = 618.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.10-8.84 (m, 1H), 8.07-7.88 (m, 2H), 7.54-7.36 (m, 2H), 7.23 (br s, 1H), 4.53 (br s, 1H), 4.45-4.20 (m, 3H), 3.83-3.54 (m, 1H), 3.48 (br s, 1H), 3.18 (br s, 1H), 3.00-2.61 (m, 3H), 2.48 (br s, 1H), 2.30-1.68 (m, 13H), 1.33 (br d, J = 15.2 Hz, 3H), 0.88 (br s, 3H).
實施例 118 和實施例 119 ,以及實施例 127 至實施例 131 參照實施例 116 的合成途徑 , 第二步與不同的醇反應製備得到的: 實施例 118 : 1-(7-(8- 乙炔基 -7- 氟萘基 -1- 基 )-8- 氟 -2-(((2R,7aS)-2- 氟四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Examples 118 and 119 , as well as Examples 127 to 131 , refer to the synthetic route of Example 116 , and react with different alcohols in the second step to prepare: Example 118 : 1-(7-(8- ethynyl -7- fluoronaphthyl -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolizine -7a(5H)-yl ) methoxy ) -6 -nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
LCMS (ESI): [M+H] += 632.2。 1H NMR (400 MHz, CD 3OD) δ ppm 8.87 (br s, 1H), 8.17-8.01 (m, 2H), 7.59 (t, J= 7.7 Hz, 1H), 7.47-7.37 (m, 2H), 5.45-5.23 (m, 1H), 4.82-4.68 (m, 1H), 4.66-4.15 (m, 6H), 3.68-3.45 (m, 1H), 3.50-3.37 (m, 2H), 3.16-3.03 (m, 1H), 2.47-2.13 (m, 4H), 2.11-2.00 (m, 2H), 1.99-1.72 (m, 4H), 1.30 (d, J= 7.6 Hz, 3H). 實施例 119 : 1-(2-(( 反式 -2,2- 二氟二氫 -1'H,3'H- 螺 [ 環丙烷 -1,2'- 吡咯嗪 ]-7a'(5'H)- 基 ) 甲氧基 )-7-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 LCMS (ESI): [M+H] + = 632.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.87 (br s, 1H), 8.17-8.01 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.47-7.37 (m, 2H), 5.45-5.23 (m, 1H), 4.82-4.68 (m, 1H), 4.66-4.15 (m, 6H), 3.68-3.45 (m, 1H), 3.50-3.37 (m, 2H), 3.16-3.03 (m, 1H), 2.47-2.13 (m, 4H), 2.11-2.00 (m, 2H), 1.99-1.72 (m, 4H), 1.30 (d, J = 7.6 Hz, 3H). Example 119 : 1-(2-(( trans -2,2- difluorodihydro -1'H,3'H- spiro [ cyclopropane -1,2'- pyrrolizine ]-7a'(5'H) -yl ) methoxy )-7-(8- ethynyl -7 - fluoronaphthalen -1- yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
LCMS (ESI): [M+H] += 676.2; 1H NMR (400 MHz, CD 3OD) δ ppm 8.87 (s, 1H), 8.14-8.05 (m, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.48-7.39 (m, 2H), 4.54 (br d, J= 12.8 Hz, 1H), 4.42-4.34 (m, 2H), 4.28 (br d, J= 13.2 Hz, 1H), 3.64-3.53 (m, 2H), 3.41 (br t, J= 11.0 Hz, 1H), 3.32-3.26 (m, 1H), 3.20-3.12 (m, 1H), 2.85 (d, J= 12.1 Hz, 1H), 2.75-2.66 (m, 1H), 2.31-2.12 (m, 3H), 2.04 (br d, J= 13.9 Hz, 1H), 1.95-1.74 (m, 6H), 1.52-1.36 (m, 2H), 1.30 (s, 3H). 實施例 120 : (3R)-1-(7-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -2-((2- 伸甲基四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 LCMS (ESI): [M+H] + = 676.2; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.87 (s, 1H), 8.14-8.05 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.48-7.39 (m, 2H), 4.54 (br d, J = 12.8 Hz, 1H), 4.42-4.34 (m, 2H), 4.28 (br d, J = 13.2 Hz, 1H), 3.64-3.53 (m, 2H), 3.41 (br t, J = 11.0 Hz, 1H), 3.32-3.26 (m, 1H), 3.20-3.16 (m, 1H), d, J = 12.1 Hz, 1H), 2.75-2.66 (m, 1H), 2.31-2.12 (m, 3H), 2.04 (br d, J = 13.9 Hz, 1H), 1.95-1.74 (m, 6H), 1.52-1.36 (m, 2H), 1.30 (s, 3H). Example 120 : (3R)-1-(7-(8- ethynyl-7-fluoronaphthalen- 1 - yl ) -8- fluoro -2-((2 -methyltetrahydro -1H- pyrrolizin -7a(5H)-yl ) methoxy ) -6 -nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
LCMS (ESI): [M+H] += 626.1; 1H NMR (400 MHz, CD 3OD) δ ppm 8.87 (br d, J= 3.4 Hz, 1H), 8.14-8.03 (m, 2H), 7.59 (t, J= 7.6 Hz, 1H), 7.48-7.38 (m, 2H), 5.06 (br s, 2H), 4.58-4.18 (m, 4H), 3.89 (br d, J= 13.7 Hz, 1H), 3.66-3.35 (m, 4H), 2.85 (br d, J= 13.3 Hz, 2H), 2.56 (br d, J= 16.0 Hz, 1H), 2.26-1.69 (m, 9H), 1.29 (d, J= 7.6 Hz, 3H). 實施例 120A : (R)-1-((R)-7-(8- 乙基 -7- 氟萘 -1- 基 )-8- 氟 -2-((S)-2- 伸甲基四氫 -1H- 吡咯 -7a(5H)- 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇, 實施例 120B: (R)-1-((S)-7-(8- 乙基 -7- 氟萘 -1- 基 )-8- 氟 -2-((S)-2- 伸甲基四氫 -1H- 吡咯 -7a(5H)- 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 , 實施例 120C: (R)-1-((R)-7-(8- 乙基 -7- 氟萘 -1- 基 )-8- 氟 -2-((R)-2- 伸甲基四氫 -1H - 吡咯 -7a(5H)- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇和 實施例 120D: (R)-1-((S)-7-(8- 乙基 -7- 氟萘 -1- 基 )-8- 氟 -2-((R)-2- 甲基四氫 -1H- 吡咯 -7a(5H)- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 LCMS (ESI): [M+H] + = 626.1; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.87 (br d, J = 3.4 Hz, 1H), 8.14-8.03 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.48-7.38 (m, 2H), 5.06 (br s, 2H), 4.58-4.18 (m, 4H), 3.89 (br d, J = 13.7 Hz, 1H), 3.66-3.35 (m, 4H), 2.85 (br d, J = 13.3 Hz, 2H), 2.56 (br d, J = 16.0 Hz, 1H), 2.26-1.69 (m, 9H), 1.29 (d, J = 7.6 Hz, 3H). Example 120A : (R)-1-((R)-7-(8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-((S)-2- methyltetrahydro -1H- pyrrole -7a(5H) -methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol, Example 120B: (R)-1-((S)-7-(8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-((S)-2- methyltetrahydro - 1H- pyrrole -7a(5H) -methoxy )-6- nitroquinazolin -4- yl )-3 -methylpiperidin -3- ol , Example 120C: (R)-1-((R)-7-(8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-((R)-2- methyltetrahydro -1H- pyrrol -7a(5H)-yl ) methoxy ) -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol and Example 120D: (R)-1-((S)-7-(8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-((R)-2- methyltetrahydro -1H- pyrrol -7a(5H)-yl ) methoxy ) -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
實施例 120 :經SFC分離(管柱:Phenomenex-Cellulose-2 (250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/乙醇;B相保持45%;流速:80毫升/分鐘),得到目標化合物。 Example 120 : The target compound was obtained by SFC separation (column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 45%; flow rate: 80 ml/min).
實施例 120A:LCMS (ESI): [M+H] += 626.1; SFC分析(管柱: Cellulose-2 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相;流速:2.8毫升/分鐘):掌性管柱出峰位置為 1.343 min; 1H NMR (400 MHz, CD 3OD) δ = 8.87 (s, 1H), 8.15-8.01 (m, 2H), 7.58 (t, J= 7.7 Hz, 1H), 7.50-7.36 (m, 2H), 5.03 (br s, 2H), 4.55-4.16 (m, 4H), 3.83 (br d, J= 14.2 Hz, 1H), 3.69-3.56 (m, 1H), 3.47-3.37 (m, 2H), 3.27-3.18 (m, 1H), 2.87-2.72 (m, 2H), 2.52 (br d, J= 15.3 Hz, 1H), 2.28-2.12 (m, 2H), 2.09-1.71 (m, 7H), 1.30 (s, 3H). Example 120A : LCMS (ESI): [M+H] + = 626.1; SFC analysis (column: Cellulose-2 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the palmar column peak position is 1.343 min; 1 H NMR (400 MHz, CD 3 OD) δ = 8.87 (s, 1H), 8.15-8.01 (m, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.50-7.36 (m, 2H), 5.03 (br s, 2H), 4.55-4.16 (m, 4H), 3.83 (br d, J = 14.2 Hz, 1H), 3.69-3.56 (m, 1H), 3.47-3.37 (m, 2H), 3.27-3.18 (m, 1H), 2.87-2.72 (m, 2H), 2.52 (br d, J = 15.3 Hz, 1H), 2.28-2.12 (m, 2H), 2.09-1.71 (m, 7H), 1.30 (s, 3H).
實施例 120B:LCMS (ESI): [M+H] += 626.1; SFC分析(管柱: Cellulose-2 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相;流速:2.8毫升/分鐘):掌性管柱出峰位置為 1.527 min; 1H NMR (400 MHz, CD 3OD) δ = 8.89 (s, 1H), 8.15-8.04 (m, 2H), 7.59 (t, J= 7.7 Hz, 1H), 7.48-7.37 (m, 2H), 5.22-5.11 (m, 2H), 4.58-4.44 (m, 3H), 4.27 (br d, J= 13.5 Hz, 1H), 4.10 (br d, J= 13.8 Hz, 1H), 3.73-3.59 (m, 2H), 3.57-3.44 (m, 2H), 3.09-2.91 (m, 2H), 2.72-2.60 (m, 1H), 2.36-1.74 (m, 9H), 1.35-1.25 (m, 3H). Example 120B : LCMS (ESI): [M+H] + = 626.1; SFC analysis (column: Cellulose-2 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the palmar column peak position is 1.527 min; 1 H NMR (400 MHz, CD 3 OD) δ = 8.89 (s, 1H), 8.15-8.04 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.48-7.37 (m, 2H), 5.22-5.11 (m, 2H), 4.58-4.44 (m, 3H), 4.27 (br d, J = 13.5 Hz, 1H), 4.10 (br d, J = 13.8 Hz, 1H), 3.73-3.59 (m, 2H), 3.57-3.44 (m, 2H), 3.09-2.91 (m, 2H), 2.72-2.60 (m, 1H), 2.36-1.74 (m, 9H), 1.35-1.25 (m, 3H).
實施例 120C:LCMS (ESI): [M+H] += 626.1; SFC分析(管柱: Cellulose-2 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相;流速:2.8毫升/分鐘):掌性管柱出峰位置為 1.739 min; 1H NMR (400 MHz, CD 3OD) δ = 8.87 (s, 1H), 8.14-8.01 (m, 2H), 7.59 (t, J= 7.7 Hz, 1H), 7.48-7.37 (m, 2H), 5.06 (br s, 2H), 4.55 (br d, J= 14.3 Hz, 1H), 4.45-4.24 (m, 3H), 3.89 (br d, J= 14.1 Hz, 1H), 3.63-3.34 (m, 4H), 2.86 (br d, J= 15.1 Hz, 2H), 2.56 (br d, J= 15.9 Hz, 1H), 2.29-1.72 (m, 9H), 1.29 (s, 3H). Example 120C : LCMS (ESI): [M+H] + = 626.1; SFC analysis (column: Cellulose-2 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the palmar column peak position is 1.739 min; 1 H NMR (400 MHz, CD 3 OD) δ = 8.87 (s, 1H), 8.14-8.01 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.48-7.37 (m, 2H), 5.06 (br s, 2H), 4.55 (br d, J = 14.3 Hz, 1H), 4.45-4.24 (m, 3H), 3.89 (br d, J = 14.1 Hz, 1H), 3.63-3.34 (m, 4H), 2.86 (br d, J = 15.1 Hz, 2H), 2.56 (br d, J = 15.9 Hz, 1H), 2.29-1.72 (m, 9H), 1.29 (s, 3H).
實施例 120D:LCMS (ESI): [M+H] += 626.2; SFC分析(管柱: Cellulose-2 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相;流速:2.8毫升/分鐘):掌性管柱出峰位置為 2.203 min; 1H NMR (400 MHz, CD 3OD) δ = 8.87 (s, 1H), 8.15-8.00 (m, 2H), 7.59 (t, J= 7.7 Hz, 1H), 7.48-7.35 (m, 2H), 5.05 (br s, 2H), 4.54 (br d, J= 13.2 Hz, 1H), 4.45-4.23 (m, 3H), 3.94-3.83 (m, 1H), 3.63-3.36 (m, 4H), 3.16-3.12 (m, 1H), 2.91-2.78 (m, 2H), 2.55 (br d, J= 15.8 Hz, 1H), 2.29-2.12 (m, 2H), 2.12-1.71 (m, 6H), 1.29 (s, 3H). 實施例 121 : (3R)-1-(7-(8- 乙炔基 -7- 氟萘基 -1- 基 )-8- 氟 -2-(-2-( 氟伸甲基 ) 四氫 -1H- 吡咯啉 -7a(5H)- 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 實施例 122 : (3R)-1-(2-(2-( 二氟伸甲基 ) 四氫 -1H- 吡咯 -7a(5H)- 甲氧基 )-7-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Example 120D : LCMS (ESI): [M+H] + = 626.2; SFC analysis (column: Cellulose-2 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the palmar column peak position is 2.203 min; 1 H NMR (400 MHz, CD 3 OD) δ = 8.87 (s, 1H), 8.15-8.00 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.48-7.35 (m, 2H), 5.05 (br s, 2H), 4.54 (br d, J = 13.2 Hz, 1H), 4.45-4.23 (m, 3H), 3.94-3.83 (m, 1H), 3.63-3.36 (m, 4H), 3.16-3.12 (m, 1H), 2.91-2.78 (m, 2H), 2.55 (br d, J = 15.8 Hz, 1H), 2.29-2.12 (m, 2H), 2.12-1.71 (m, 6H), 1.29 (s, 3H). Example 121 : (3R)-1-(7-(8- ethynyl- 7- fluoronaphthyl -1 - yl )-8- fluoro -2-(-2-( fluoromethyl ) tetrahydro -1H- pyrroline -7a(5H) -methoxy )-6- nitroquinazolin- 4- yl )-3 -methylpiperidin -3- ol Example 122 : (3R)-1-(2-(2-( difluoromethyl ) tetrahydro -1H - pyrrol -7a(5H) -methoxy )-7-(8- ethynyl- 7- fluoronaphthyl -1- yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
第一步:在-50 oC下,向叔丁醇鉀(0.95 g,8.52 mmol)的N,N-二甲基甲醯胺(11 mL)溶液中,加入2,5-二氧四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯(1.0 g,4.73 mmol)和2-(二氟甲基磺醯)吡啶(0.82 g,4.26 mmol)的N,N-二甲基甲醯胺(5 mL)溶液。將混合物氮氣保護下緩慢升溫至25 oC,並在25 oC下攪拌0.5小時。在冰浴下,加入飽和氯化銨溶液(5 mL)和2M鹽酸(9mL),加入水(30 mL),使用乙酸乙酯(30 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-50%梯度的四氫呋喃/石油醚),得到黃色油狀化合物2-(二氟伸甲基)-5-氧四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯(250 mg,1.02 mmol,產率22%)。LCMS (ESI): [M+H] += 246.0。 1H NMR (400 MHz, CDCl 3) δ ppm 4.36 (br d, J= 14.7 Hz, 1H), 4.23 (q, J= 7.1 Hz, 2H), 3.75 (br d, J= 14.7 Hz, 1H), 3.13 (td, J= 1.3, 15.4 Hz, 1H), 2.90-2.73 (m, 1H), 2.63 (ddd, J= 2.0, 9.2, 13.2 Hz, 1H), 2.55-2.34 (m, 2H), 2.15 (td, J= 10.1, 13.2 Hz, 1H), 1.29 (t, J= 7.2 Hz, 3H). Step 1 : To a solution of potassium tert-butoxide (0.95 g, 8.52 mmol) in N,N-dimethylformamide (11 mL) at -50 ° C, add a solution of ethyl 2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (1.0 g, 4.73 mmol) and 2-(difluoromethylsulfonyl)pyridine (0.82 g, 4.26 mmol) in N,N-dimethylformamide (5 mL). The mixture was slowly heated to 25 ° C under nitrogen protection and stirred at 25 ° C for 0.5 hours. Under ice bath, add saturated ammonium chloride solution (5 mL) and 2M hydrochloric acid (9 mL), add water (30 mL), extract with ethyl acetate (30 mL * 3), dry the combined organic phase with anhydrous sodium sulfate, filter, and spin dry the filtrate. The residue is purified by flash column chromatography (silica gel, 0-50% gradient of tetrahydrofuran/petroleum ether) to obtain a yellow oily compound 2-(difluoromethyl)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid ethyl ester (250 mg, 1.02 mmol, yield 22%). LCMS (ESI): [M+H] + = 246.0. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 4.36 (br d, J = 14.7 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.75 (br d, J = 14.7 Hz, 1H), 3.13 (td, J = 1.3, 15.4 Hz, 1H), 2.90-2.73 (m, 1H), 2.63 (ddd, J = 2.0, 9.2, 13.2 Hz, 1H), 2.55-2.34 (m, 2H), 2.15 (td, J = 10.1, 13.2 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H).
第二步:在0 oC下,向四氫鋁鋰(15.5 mg,0.41 mmol)的四氫呋喃(1 mL)溶液中加入2-(二氟伸甲基)-5-氧四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯(100.0 mg,0.41 mmol)的四氫呋喃(1 mL)溶液。將混合物在65 oC下攪拌5小時,再加入四氫鋁鋰(7.7 mg,0.20 mmol),在65 oC下攪拌3小時。冷卻到0 oC,加入水(23 uL),15%氫氧化鈉(23 uL),水(69 uL)。用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。得到黃色油狀化合物 (2-(二氟伸甲基)四氫-1H-吡咯啉-7a(5H)-基)甲醇和 (2-(氟伸甲基)四氫-1H-吡咯啉-7a(5H)-基)甲醇的粗產物混合物(74.0 mg)。LCMS (ESI): [M+H] += 190.1 和 172.1. Step 2 : At 0 o C, add 2-(difluoromethyl)-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid ethyl ester (100.0 mg, 0.41 mmol) in tetrahydrofuran (1 mL) to a solution of lithium aluminum tetrahydrate (15.5 mg, 0.41 mmol) in tetrahydrofuran (1 mL). Stir the mixture at 65 o C for 5 hours, add lithium aluminum tetrahydrate (7.7 mg, 0.20 mmol), and stir at 65 o C for 3 hours. Cool to 0 o C, add water (23 uL), 15% sodium hydroxide (23 uL), and water (69 uL). Dry with anhydrous sodium sulfate, filter, and spin dry the filtrate. A crude product mixture of (2-(difluoromethyl)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol and (2-(fluoromethyl)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (74.0 mg) was obtained as a yellow oily compound. LCMS (ESI): [M+H] + = 190.1 and 172.1.
第三步:向 (3R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(229.7 mg,0.40 mmol)以及 (2-(二氟伸甲基)四氫-1H-吡咯啉-7a(5H)-基)甲醇和(2-(氟伸甲基)四氫-1H-吡咯啉-7a(5H)-基)甲醇混合物(69.0 mg, 0.36 mmol)的四氫呋喃(2.3 mL)溶液中,加入叔丁醇鈉(70.1 mg,0.73 mmol)。將混合物氮氣保護下在25 oC下攪拌3小時。在0 oC下加入水(6 mL)稀釋,使用乙酸乙酯(10 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。殘餘物透過製備型HPLC純化兩次,得到兩個化合物: 實施例 121 (3R)-1-(7-(8- 乙炔基 -7- 氟萘基 -1- 基 )-8- 氟 -2-(-2-( 氟伸甲基 ) 四氫 -1H- 吡咯啉 -7a(5H)- 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 (23.97 mg,0.04 mmol,產率10%,黃色固體)。LCMS (ESI): [M+H] += 644.3。 1H NMR (400 MHz, CD 3OD) δ ppm 8.90 (br s, 1H), 8.18-8.00 (m, 2H), 7.61 (t, J= 7.7 Hz, 1H), 7.51-7.36 (m, 2H), 6.97-6.58 (m, 1H), 4.60-4.39 (m, 3H), 4.35-4.22 (m, 1H), 4.13-3.92 (m, 1H), 3.75-3.44 (m, 3H), 3.43-3.35 (m, 2H), 3.01-2.79 (m, 2H), 2.77-2.52 (m, 1H), 2.32-2.16 (m, 2H), 2.14-1.93 (m, 3H), 1.93-1.73 (m, 3H), 1.31 (d, J= 7.8 Hz, 3H). Step 3 : To a solution of (3R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (229.7 mg, 0.40 mmol) and a mixture of (2-(difluoromethyl)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol and (2-(fluoromethyl)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (69.0 mg, 0.36 mmol) in tetrahydrofuran (2.3 mL) was added sodium tert-butoxide (70.1 mg, 0.73 mmol). The mixture was stirred at 25 ° C for 3 hours under nitrogen protection. Water (6 mL) was added for dilution at 0 ° C, and ethyl acetate (10 mL * 3) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The residue was purified twice by preparative HPLC to obtain two compounds: Example 121 (3R)-1-(7-(8- ethynyl- 7- fluoronaphthyl -1- yl )-8- fluoro -2-(-2-( fluoromethyl ) tetrahydro -1H- pyrroline -7a(5H) -methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol ( 23.97 mg, 0.04 mmol, yield 10%, yellow solid). LCMS (ESI): [M+H] + = 644.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.90 (br s, 1H), 8.18-8.00 (m, 2H), 7.61 (t, J = 7.7 Hz, 1H), 7.51-7.36 (m, 2H), 6.97-6.58 (m, 1H), 4.60-4.39 (m, 3H), 4.35-4.22 (m, 1H), 4.13-3.92 (m, 1H), 3.75-3.44 (m, 3H), 3.43-3.35 (m, 2H), 3.01-2.79 (m, 2H), 2.77-2.52 (m, 1H), 2.32-2.16 (m, 2H), 2.14-1.93 (m, 3H), 1.93-1.73 (m, 3H), 1.31 (d, J = 7.8 Hz, 3H).
實施例 122 (3R)-1-(2-(2-( 二氟伸甲基 ) 四氫 -1H- 吡咯 -7a(5H)- 甲氧基 )-7-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 (13.75 mg,0.02 mmol,產率6%,黃色固體)。LCMS (ESI): [M+H] += 662.3。 1H NMR (400 MHz, CD 3OD) δ ppm 8.88 (d, J= 7.3 Hz, 1H), 8.24-7.99 (m, 2H), 7.60 (t, J= 7.6 Hz, 1H), 7.51-7.31 (m, 2H), 4.59-4.45 (m, 1H), 4.44-4.35 (m, 1H), 4.35-4.18 (m, 2H), 3.83 (br d, J= 13.8 Hz, 1H), 3.70-3.39 (m, 4H), 3.23-3.13 (m, 1H), 2.89-2.68 (m, 2H), 2.54 (br d, J= 15.8 Hz, 1H), 2.30-2.09 (m, 2H), 2.08-1.72 (m, 6H), 1.31 (d, J= 8.0 Hz, 3H). 實施例 123 : (3R)-1-(2-((2- 伸環丙基四氫 -1H- 吡咯嗪 -7a(5H) 基 ) 甲氧基 )-7-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Example 122 (3R)-1-(2-(2-( difluoromethyl ) tetrahydro -1H- pyrrole -7a(5H) -methoxy )-7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8 - fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol ( 13.75 mg, 0.02 mmol, yield 6%, yellow solid). LCMS (ESI): [M+H] + = 662.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.88 (d, J = 7.3 Hz, 1H), 8.24-7.99 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.51-7.31 (m, 2H), 4.59-4.45 (m, 1H), 4.44-4.35 (m, 1H), 4.35-4.18 (m, 2H), 3.83 (br d, J = 13.8 Hz, 1H), 3.70-3.39 (m, 4H), 3.23-3.13 (m, 1H), 2.89-2.70 (m, 2H), 2.88 (d, J = 7.3 Hz, 1H), 2.54 (br d, J = 15.8 Hz, 1H), 2.30-2.09 (m, 2H), 2.08-1.72 (m, 6H), 1.31 (d, J = 8.0 Hz, 3H). Example 123 : (3R)-1-(2-((2- cyclopropanetetrahydro -1H- pyrrolizine -7a(5H) yl ) methoxy )-7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
第一步:在25 oC和氮氣保護下,向環丙基三苯基溴化鏻(3.63 g,9.47 mmol)的四氫呋喃溶液(15 mL)中分批加入鈉氫(60%含量,378.73 mg,9.47 mmol)。將反應液在25 oC下攪拌2個小時後,向反應液中依次緩慢加入2,5-二氧代四氫-1H-吡咯嗪-7a(5H)-甲酸乙酯(1.00 g,4.73 mmol)和三(3,6-二氧雜庚基)胺(153.13 mg,473.45 umol)。將反應液在25 °C下攪拌10分鐘後升溫至62 oC,並在62 oC攪拌18小時。將反應混合物緩慢加入到飽和氯化銨(20 mL)中進行淬滅,然後用乙酸乙酯(10 mL * 3)萃取。合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。粗產物用快速管柱層析(矽膠,0-30%梯度的乙酸乙酯/石油醚)純化,得到黃色油狀化合物2-伸環丙基-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯(0.10 g,425.03 umol,產率8%)。 1H NMR (400 MHz, CDCl 3) δ ppm 4.43-4.31 (m, 1H), 4.25-4.15 (m, 2H), 3.85-3.75 (m, 1H), 3.23-3.13 (m, 1H), 2.85-2.75 (m, 1H), 2.68-2.59 (m, 1H), 2.56-2.42 (m, 2H), 2.23-2.08 (m, 1H), 1.30-1.21 (m, 3H), 1.15-1.03 (m, 4H). Step 1 : At 25 ° C and nitrogen protection, sodium hydroxide (60% content, 378.73 mg, 9.47 mmol) was added in batches to a tetrahydrofuran solution (15 mL) of cyclopropyltriphenylphosphonium bromide (3.63 g, 9.47 mmol). After the reaction solution was stirred at 25 ° C for 2 hours, 2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (1.00 g, 4.73 mmol) and tri(3,6-dioxoheptyl)amine (153.13 mg, 473.45 umol) were slowly added to the reaction solution in sequence. After stirring the reaction solution at 25 ° C for 10 minutes, the temperature was raised to 62 ° C and stirred at 62 ° C for 18 hours. The reaction mixture was slowly added to saturated ammonium chloride (20 mL) for quenching, and then extracted with ethyl acetate (10 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The crude product was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a yellow oily compound 2-cyclopropyl-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid ethyl ester (0.10 g, 425.03 umol, yield 8%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 4.43-4.31 (m, 1H), 4.25-4.15 (m, 2H), 3.85-3.75 (m, 1H), 3.23-3.13 (m, 1H), 2.85-2.75 (m, 1H), 2.68-2.59 (m, 1H), 2.56-2.42 (m, 2H), 2.23-2.08 (m, 1H), 1.30-1.21 (m, 3H), 1.15-1.03 (m, 4H).
第二步:在0 oC的氮氣氛圍下,將四氫鋁鋰(83.9 mg,2.21 mmol)加入2-伸環丙基-5-氧代四氫-1H-吡咯嗪-7a(5H)-羧酸乙酯(130 mg,0.55 mmol)的四氫呋喃(5 mL)溶液中。混合物在65 oC下攪拌2小時。溶液冷卻至室溫後依次用水(84 uL)、15%氫氧化鈉溶液(84 uL)、水(252 uL)淬滅。懸浮液用無水硫酸鈉乾燥,在25 oC攪拌0.5小時,然後過濾,濾液濃縮得到黃色油狀化合物 (2-伸環丙基四氫-1H-吡咯嗪-7a(5H)-基)甲醇(95.0 mg,0.530 mmol,產率96%)。LCMS (ESI): [M+H] += 180.1 Step 2 : Under nitrogen atmosphere at 0 ° C, lithium aluminum tetrahydride (83.9 mg, 2.21 mmol) was added to a solution of 2-cyclopropyl-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid ethyl ester (130 mg, 0.55 mmol) in tetrahydrofuran (5 mL). The mixture was stirred at 65 ° C for 2 hours. After the solution was cooled to room temperature, it was quenched with water (84 uL), 15% sodium hydroxide solution (84 uL), and water (252 uL) in sequence. The suspension was dried over anhydrous sodium sulfate, stirred at 25 ° C for 0.5 hours, and then filtered. The filtrate was concentrated to obtain a yellow oily compound (2-cyclopropanetetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (95.0 mg, 0.530 mmol, yield 96%). LCMS (ESI): [M+H] + = 180.1
第三步:在25 ℃下,向 (3R)-1-(8-氟-7-(7-氟-8-((三異丙基矽基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(200 mg,0.27 mmol)的四氫呋喃(2 mL)溶液中加入叔丁醇鈉(52.7 mg,0.55 mmol)和 (2-伸環丙基四氫-1H-吡咯嗪-7a(5H)-基)甲醇(9.18 mg,0.05 mmol)。溶液在25 ℃攪拌2小時。混合物用水(5 mL)稀釋並用乙酸乙酯(5 mL * 3)萃取,合併的有機相乾燥,過濾,濾液旋轉乾燥。得到的粗產物用快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化,得到棕色固體化合物 (3R)-1-(2-(2-伸環丙基四氫-1H-吡咯嗪-7a(5H)-甲氧基)-8-氟-7-(7-氟-8-((三異丙基矽基)乙炔基)萘-1-基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(200 mg,0.248 mmol,產率90%)。LCMS (ESI): [M+H] += 808.3. Step 3 : To a solution of (3R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (200 mg, 0.27 mmol) in tetrahydrofuran (2 mL) at 25 °C, sodium tert-butoxide (52.7 mg, 0.55 mmol) and (2-cyclopropenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (9.18 mg, 0.05 mmol) were added. The solution was stirred at 25 °C for 2 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL * 3), and the combined organic phases were dried, filtered, and the filtrate was rotary dried. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a brown solid compound (3R)-1-(2-(2-cyclopropyltetrahydro-1H-pyrrolizine-7a(5H)-methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (200 mg, 0.248 mmol, yield 90%). LCMS (ESI): [M+H] + = 808.3.
第四步:在25 ℃下,向氟化銫(141 mg,0.93 mmol)的二甲基甲醯胺(2 mL)溶液中加入 (3R)-1-(2-(2-伸環丙基四氫-1H-吡咯嗪-7a(5H)-甲氧基)-8-氟-7-(7-氟-8-((三異丙基矽基)乙炔基)萘-1-基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(150 mg,0.19 mmol)。溶液在25 ℃攪拌2小時。混合物用水(5 mL)稀釋,用乙酸乙酯(5 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,濾液旋轉乾燥。粗產物經快速管柱層析(矽膠,0-10%梯度的甲醇/ 二氯甲烷)後,用製備型HPLC純化得到黃色固體化合物 (3R)-1-(2-((2-伸環丙基四氫-1H-吡咯嗪-7a(5H)基)甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(14.14 mg,21.7 umol,產率12%)。LCMS (ESI): [M+H] += 652.4。 1H NMR (400 MHz, CD 3OD) δ ppm 8.89 (br s, 1H), 8.15-8.04 (m, 2H), 7.59 (t, J= 7.7 Hz, 1H), 7.47-7.38 (m, 2H), 4.60-4.44 (m, 3H), 4.33-4.21 (m, 1H), 4.09 (br d, J= 13.9 Hz, 1H), 3.73-3.54 (m, 2H), 3.52 (s, 2H), 2.98 (br d, J= 12.8 Hz, 2H), 2.76-2.65 (m, 1H), 2.32-1.72 (m, 9H), 1.30 (d, J= 6.8 Hz, 3H), 1.21-1.04 (m, 4H). 實施例 124 : (3R)-1-(2-((2,6- 二伸甲基四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 )-7-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Step 4 : (3R)-1-(2-(2-cyclopropyltetrahydro-1H-pyrrolizine-7a(5H)-methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (150 mg, 0.19 mmol) was added to a solution of cesium fluoride (141 mg, 0.93 mmol) in dimethylformamide (2 mL) at 25 °C. The solution was stirred at 25 °C for 2 hours. The mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) and preparative HPLC to give a yellow solid compound (3R)-1-(2-((2-cyclopropanetetrahydro-1H-pyrrolizine-7a(5H)yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (14.14 mg, 21.7 umol, yield 12%). LCMS (ESI): [M+H] + = 652.4. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.89 (br s, 1H), 8.15-8.04 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.47-7.38 (m, 2H), 4.60-4.44 (m, 3H), 4.33-4.21 (m, 1H), 4.09 (br d, J = 13.9 Hz, 1H), 3.73-3.54 (m, 2H), 3.52 (s, 2H), 2.98 (br d, J = 12.8 Hz, 2H), 2.76-2.65 (m, 1H), 2.32-1.72 (m, 9H), 1.30 (d, J = 6.8 Hz, 3H), 1.21-1.04 (m, 4H). Example 124 : (3R)-1-(2-((2,6- dimethyltetrahydro -1H- pyrrolizine -7a(5H) -yl ) methoxy )-7-(8- ethynyl-7- fluoronaphthalen - 1 - yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
第一步:將溴化甲基三苯基磷(20. g,56.0 mmol)溶於四氫呋喃(75 mL)中,溫度降到0 oC,氮氣保護下加入叔丁醇鉀(1M的四氫呋喃溶液,66.0 mL,66.0 mmol),0 oC攪拌0.5小時。將1-叔丁基2-甲基4-氧代吡咯烷-1,2-二甲酸酯(11.3 g,46.4 mmol)的四氫呋喃(150 mL)溶液加入反應液中,反應液20 oC攪拌16小時。反應液加入飽和氯化銨(100 mL)淬滅,乙酸乙酯(100 mL * 3)萃取,合併有機相,用飽和食鹽水(100 mL)洗滌,硫酸鈉乾燥,過濾,減壓濃縮,殘餘物透過快速管柱層析(矽膠,0-10%梯度乙酸乙酯/石油醚)純化得到無色油狀化合物1-叔丁基2-甲基4-伸甲基吡咯烷-1,2-二甲酸酯(5.80 g,24.0 mmol,產率50%)。LCMS (ESI): [M+H-56] += 186.1。 1H NMR (400MHz, CDCl 3) δ ppm 5.02-4.87 (m, 2H), 4.49-4.27 (m, 1H), 4.00 (br d, J= 15.0 Hz, 2H), 3.71-3.61 (m, 3H), 2.97-2.82 (m, 1H), 2.62-2.50 (m, 1H), 1.43-1.32 (m, 9H). Step 1 : Dissolve methyltriphenylphosphine bromide (20. g, 56.0 mmol) in tetrahydrofuran (75 mL), cool to 0 o C, add potassium tert-butoxide (1M tetrahydrofuran solution, 66.0 mL, 66.0 mmol) under nitrogen protection, and stir at 0 o C for 0.5 hours. Add a solution of 1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (11.3 g, 46.4 mmol) in tetrahydrofuran (150 mL) to the reaction solution, and stir the reaction solution at 20 o C for 16 hours. The reaction mixture was quenched by adding saturated ammonium chloride (100 mL), extracted with ethyl acetate (100 mL * 3), the organic phases were combined, washed with saturated brine (100 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to obtain a colorless oily compound 1-tert-butyl 2-methyl 4-methylpyrrolidine-1,2-dicarboxylate (5.80 g, 24.0 mmol, yield 50%). LCMS (ESI): [M+H-56] + = 186.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 5.02-4.87 (m, 2H), 4.49-4.27 (m, 1H), 4.00 (br d, J = 15.0 Hz, 2H), 3.71-3.61 (m, 3H), 2.97-2.82 (m, 1H), 2.62-2.50 (m, 1H), 1.43-1.32 (m, 9H).
第二步:化合物1-叔丁基2-甲基4-伸甲基吡咯烷-1,2-二甲酸酯(5.80 g,24.0 mmol)溶於四氫呋喃(75 mL)中,溫度降到-78 oC,氮氣下加入二(三甲基矽)胺基鋰(1M的四氫呋喃溶液,48.0 mL,48.0 mmol),-78 oC攪拌1小時。3-氯-2-(氯甲基)丙-1-烯(7.51 g,60.1 mmol)加入反應液中,反應液20 oC攪拌16小時。反應液加入水(100 mL)淬滅,乙酸乙酯(100 mL * 3)萃取,合併有機相,用飽和食鹽水(100 mL)洗滌,硫酸鈉乾燥,過濾,減壓濃縮,殘餘物透過快速管柱層析(矽膠,0-20%梯度乙酸乙酯/石油醚)純化得到無色油狀化合物1-叔丁基2-甲基2-[2-(氯甲基)丙-2-烯-1-基]-4-伸甲基吡咯烷-1,2-二甲酸酯(6.20 g,20.6 mmol,產率78%)。LCMS (ESI): [M-56+H] += 274.1. Step 2 : Dissolve the compound 1-tert-butyl 2-methyl 4-methylpyrrolidine-1,2-dicarboxylate (5.80 g, 24.0 mmol) in tetrahydrofuran (75 mL), cool to -78 ° C, add lithium bis(trimethylsilyl)amide (1M tetrahydrofuran solution, 48.0 mL, 48.0 mmol) under nitrogen, and stir at -78 ° C for 1 hour. Add 3-chloro-2-(chloromethyl)prop-1-ene (7.51 g, 60.1 mmol) to the reaction solution, and stir the reaction solution at 20 ° C for 16 hours. The reaction mixture was quenched by adding water (100 mL), extracted with ethyl acetate (100 mL * 3), the organic phases were combined, washed with saturated brine (100 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-20% gradient ethyl acetate/petroleum ether) to obtain a colorless oily compound 1-tert-butyl 2-methyl 2-[2-(chloromethyl)prop-2-en-1-yl]-4-methylpyrrolidine-1,2-dicarboxylate (6.20 g, 20.6 mmol, yield 78%). LCMS (ESI): [M-56+H] + = 274.1.
第三步:化合物1-叔丁基2-甲基2-[2-(氯甲基)丙-2-烯-1-基]-4-伸甲基吡咯烷-1,2-二甲酸酯(6.20 g,20.6 mmol)溶於二氯甲烷(68 mL),加入三氟乙酸(23 mL,309 mmol),反應在20 oC攪拌16小時。反應液減壓濃縮,二氯甲烷(100 mL)稀釋,加入三乙胺調到鹼性,減壓濃縮,殘餘物透過快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化,得到黃色油狀化合物2,6-二伸甲基四氫-1H-吡咯嗪-7a(5H)-羧酸甲酯(3.50 g,17.9 mmol,產率87%)。LCMS (ESI): [M+H] += 194.1。 1H NMR (400MHz, CDCl 3) δ ppm 4.98-4.88 (m, 4H), 3.83 (br d, J= 15.0 Hz, 2H), 3.70-3.67 (m, 3H), 3.23 (br dd, J= 1.8, 15.0 Hz, 2H), 2.95 (dd, J= 1.1, 16.6 Hz, 2H), 2.54 (dd, J= 1.8, 16.6 Hz, 2H). Step 3 : Dissolve the compound 1-tert-butyl 2-methyl 2-[2-(chloromethyl)prop-2-en-1-yl]-4-methylpyrrolidine-1,2-dicarboxylate (6.20 g, 20.6 mmol) in dichloromethane (68 mL), add trifluoroacetic acid (23 mL, 309 mmol), and stir the reaction at 20 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane (100 mL), and triethylamine was added to make it alkaline. The solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow oily compound 2,6-dimethyltetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid methyl ester (3.50 g, 17.9 mmol, yield 87%). LCMS (ESI): [M+H] + = 194.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 4.98-4.88 (m, 4H), 3.83 (br d, J = 15.0 Hz, 2H), 3.70-3.67 (m, 3H), 3.23 (br dd, J = 1.8, 15.0 Hz, 2H), 2.95 (dd, J = 1.1, 16.6 Hz, 2H), 2.54 (dd, J = 1.8, 16.6 Hz, 2H).
第四步:將四氫鋁鋰(147 mg,3.88 mmol)溶於四氫呋喃(4 mL),0 oC下加入2,6-二伸甲基四氫-1H-吡咯嗪-7a(5H)-羧酸甲酯(500 mg,2.58 mmol),反應液在20 oC攪拌2小時。向反應液加入水(147 uL),氫氧化鈉(15%的水溶液,147 uL),水(147 uL*3)淬滅,混合物過濾,濾液減壓濃縮得到 (2,6-二伸甲基四氫-1H-吡咯嗪-7a(5H)-基)甲醇(250 mg,1.50 mmol,產率58%)。LCMS (ESI): [M+H] += 166.1。 1H NMR (400MHz, CDCl 3) δ ppm 4.92-4.80 (m, 4H), 3.59 (dd, J= 0.8, 15.1 Hz, 2H), 3.24-3.13 (m, 4H), 2.50-2.41 (m, 2H), 2.38-2.29 (m, 2H). Step 4 : Dissolve lithium aluminum tetrahydride (147 mg, 3.88 mmol) in tetrahydrofuran (4 mL), add 2,6-dimethyltetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid methyl ester (500 mg, 2.58 mmol) at 0 o C, and stir the reaction solution at 20 o C for 2 hours. Add water (147 uL), sodium hydroxide (15% aqueous solution, 147 uL), and water (147 uL*3) to the reaction solution for quenching, filter the mixture, and concentrate the filtrate under reduced pressure to obtain (2,6-dimethyltetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (250 mg, 1.50 mmol, yield 58%). LCMS (ESI): [M+H] + = 166.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 4.92-4.80 (m, 4H), 3.59 (dd, J = 0.8, 15.1 Hz, 2H), 3.24-3.13 (m, 4H), 2.50-2.41 (m, 2H), 2.38-2.29 (m, 2H).
第五步:將化合物(3R)-1-(8-氟-7-(7-氟-8-((三異丙基矽基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(100 mg,0.14 mmol)和 (2,6-二伸甲基四氫-1H-吡咯嗪-7a(5H)-基)甲醇(45 mg,0.27 mmol)溶於四氫呋喃(2 mL)中,加入叔丁醇鈉(40 mg,0.41 mmol),20 oC攪拌16小時。反應液透過矽藻土過濾,濾液減壓濃縮得粗產物化合物 (3R)-1-(2-((2,6-二伸甲基四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(100 mg)。LCMS (ESI): [M+H] += 794.3. Step 5 : Compound (3R)-1-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (100 mg, 0.14 mmol) and (2,6-dimethyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (45 mg, 0.27 mmol) were dissolved in tetrahydrofuran (2 mL), sodium tert-butoxide (40 mg, 0.41 mmol) was added, and the mixture was stirred at 20 ° C for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product compound (3R)-1-(2-((2,6-dimethyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (100 mg). LCMS (ESI): [M+H] + = 794.3.
第六步:化合物 (3R)-1-(2-((2,6-二伸甲基四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(100 mg,0.12 mmol)加入到N,N-二甲基甲醯胺(2.0 mL)中,加入氟化銫(352 mg,2.32 mmol),20 oC攪拌1小時。反應液透過矽藻土過濾,濾液減壓濃縮,殘留物用製備型HPLC純化得到 (3R)-1-(2-((2,6-二伸甲基四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(8.10 mg,12 umol,產率10%)。LCMS (ESI): [M+H] += 638.5; 1H NMR (400MHz, CD 3OD) δ ppm 8.78 (d, J= 1.3 Hz, 1H), 8.06-7.93 (m, 2H), 7.51 (t, J= 7.7 Hz, 1H), 7.39-7.28 (m, 2H), 4.97 (br d, J= 6.5 Hz, 4H), 4.44 (br d, J= 13.1 Hz, 1H), 4.37-4.27 (m, 2H), 4.19 (br d, J= 13.4 Hz, 1H), 3.77 (br d, J= 14.9 Hz, 2H), 3.54-3.43 (m, 2H), 3.39-3.28 (m, 3H), 2.81-2.70 (m, 2H), 2.54 (br d, J= 16.5 Hz, 2H), 2.17-2.02 (m, 1H), 1.81-1.62 (m, 3H), 1.21 (s, 3H). 實施例 125 : (3R)-1-(-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -(2-(((1aR,6aR)-4- 伸甲基六氫環丙烷并 [b] 吡咯嗪 -5a(3H)- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Step 6 : Compound (3R)-1-(2-((2,6-dimethyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (100 mg, 0.12 mmol) was added to N,N-dimethylformamide (2.0 mL), and cesium fluoride (352 mg, 2.32 mmol) was added, and the mixture was stirred at 20 ° C for 1 hour. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give (3R)-1-(2-((2,6-dimethyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (8.10 mg, 12 umol, yield 10%). LCMS (ESI): [M+H] + = 638.5; 1 H NMR (400MHz, CD 3 OD) δ ppm 8.78 (d, J = 1.3 Hz, 1H), 8.06-7.93 (m, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.39-7.28 (m, 2H), 4.97 (br d, J = 6.5 Hz, 4H), 4.44 (br d, J = 13.1 Hz, 1H), 4.37-4.27 (m, 2H), 4.19 (br d, J = 13.4 Hz, 1H), 3.77 (br d, J = 14.9 Hz, 2H), 3.53-3.43 (m, 2H), 3.39-3.28 (m, 3H), 2.81-2.70 (m, 2H), 2.54 (br d, J = 1 6.5 Hz, 2H), 2.17-2.02 (m, 1H), 1.81-1.62 (m, 3H), 1.21 (s, 3H). Example 125 : (3R)-1-(-(8- ethynyl- 7- fluoronaphthalen- 1- yl )-8 - fluoro- (2-(((1aR,6aR)-4- methylhexahydrocyclopropane [b] pyrrolizine -5a(3H) -yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
第一步:氮氣保護下,將化合物2-叔丁基3-乙基(1R,3R,5R)-2-氮雜雙環[3.1.0]己烷-2,3-二羧酸酯(1.50 g,5.87 mmol)的四氫呋喃(30 mL)溶液降到-78 oC,加入二(三甲基矽)胺基鋰91M的四氫呋喃,10.0 mL,10.0 mmol),-78 oC攪拌1小時。3-氯-2-(氯甲基)丙-1-烯(1.84 g,14.7 mmol)加入反應液中,反應液20 oC攪拌16小時。反應液加入水(100 mL)淬滅,乙酸乙酯(50 mL * 3)萃取,合併的有機相用飽和食鹽水(100 mL)洗滌,硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物透過快速管柱層析(矽膠,0-10%梯度乙酸乙酯/石油醚)純化,得到無色油狀化合物2-叔丁基3-乙基(1R,3R,5R)-3-(2-(氯甲基)烯丙基)2-氮雜雙環[3.1.0]己烷-2,3-二羧酸酯(1.20 g,3.48 mmol,產率59%)。LCMS (ESI): [M-56+H] += 288.0。 1H NMR (400 MHz, CDCl 3) δ ppm 5.36-5.27 (m, 1H), 5.09-5.03 (m, 1H), 4.20-4.09 (m, 1H), 4.07-3.95 (m, 3H), 3.32-3.05 (m, 2H), 2.59-2.34 (m, 2H), 2.12-2.03 (m, 1H), 1.40-1.35 (m, 9H), 1.26-1.18 (m, 3H), 0.97 (dq, J=2.6, 5.3 Hz, 1H), 0.83-0.60 (m, 2H). Step 1 : Under nitrogen protection, cool the tetrahydrofuran (30 mL) solution of the compound 2-tert-butyl 3-ethyl (1R, 3R, 5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.50 g, 5.87 mmol) to -78 o C, add 91M lithium bis(trimethylsilyl)amide in tetrahydrofuran (10.0 mL, 10.0 mmol), and stir at -78 o C for 1 hour. Add 3-chloro-2-(chloromethyl)prop-1-ene (1.84 g, 14.7 mmol) to the reaction solution, and stir the reaction solution at 20 o C for 16 hours. The reaction solution was quenched by adding water (100 mL), extracted with ethyl acetate (50 mL * 3), and the combined organic phases were washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10% gradient ethyl acetate/petroleum ether) to obtain a colorless oily compound 2-tert-butyl 3-ethyl (1R, 3R, 5R)-3-(2-(chloromethyl)allyl) 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.20 g, 3.48 mmol, yield 59%). LCMS (ESI): [M-56+H] + = 288.0. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 5.36-5.27 (m, 1H), 5.09-5.03 (m, 1H), 4.20-4.09 (m, 1H), 4.07-3.95 (m, 3H), 3.32-3.05 (m, 2H), 2.59-2.34 (m, 2H), 2.12-2.03 (m, 1H), 1.40-1.35 (m, 9H), 1.26-1.18 (m, 3H), 0.97 (dq, J =2.6, 5.3 Hz, 1H), 0.83-0.60 (m, 2H).
第二步:將化合物2-叔丁基3-乙基(1R,3R,5R)-3-(2-(氯甲基)烯丙基)2-氮雜雙環[3.1.0]己烷-2,3-二羧酸酯(1.20 g,3.48 mmol)溶於二氯甲烷(17 mL),加入三氟乙酸(4 mL,52 mmol),反應在20 oC攪拌16小時。反應液減壓濃縮,加入二氯甲烷(50 mL)稀釋,加入三乙胺調到pH > 7,再次減壓濃縮,得到粗產物化合物 (1R,5R)-3-(2-(氯甲基)烯丙基]-2-氮雜二環[3.1.0]己烷-3-羧酸乙酯(1.20 g),其為黃色油狀液體。LCMS (ESI): [M+H] += 244.1. Step 2 : Dissolve 2-tert-butyl 3-ethyl (1R,3R,5R)-3-(2-(chloromethyl)allyl) 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.20 g, 3.48 mmol) in dichloromethane (17 mL), add trifluoroacetic acid (4 mL, 52 mmol), and stir the reaction at 20 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, and then diluted with dichloromethane (50 mL). The pH was adjusted to > 7 by adding triethylamine, and the solution was concentrated under reduced pressure again to obtain the crude product compound (1R,5R)-3-(2-(chloromethyl)allyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester (1.20 g) as a yellow oily liquid. LCMS (ESI): [M+H] + = 244.1.
第三步:將化合物 (1R,5R)-3-(2-(氯甲基)烯丙基]-2-氮雜二環[3.1.0]己烷-3-羧酸乙酯(1.20 g,4.92 mmol)溶於乙醇(12 mL),25 oC下加入碘化鉀(81.0 mg,0.49 mmol)和碳酸鉀(2.00 g,14.7 mmol)。反應在25 oC下攪拌16小時。反應液過濾,濾液減壓濃縮,殘留物用快速管柱層析純化(矽膠,0-10%梯度的甲醇/二氯甲烷)得到黃色油狀化合物 (1aR,6aR)-4-伸甲基六氫環丙烷并[b]吡咯嗪-5a(3H)-羧酸乙酯(0.60 g,兩步產率:80%)。LCMS (ESI): [M+H] += 208.2。 1H NMR (400 MHz, CDCl 3) δ ppm 4.89-4.77 (m, 2H), 4.22-4.07 (m, 2H), 3.96 (br d, J= 4.3 Hz, 1H), 3.27 (dd, J= 1.9, 14.3 Hz, 1H), 2.73 (br dd, J= 1.6, 15.9 Hz, 1H), 2.64 (ddd, J= 2.8, 5.2, 7.5 Hz, 1H), 2.59-2.47 (m, 2H), 1.81 (dd, J= 4.6, 13.1 Hz, 1H), 1.46-1.36 (m, 1H), 1.20 (t, J= 7.1 Hz, 3H), 0.50-0.42 (m, 1H), 0.20 (ddd, J= 2.9, 4.0, 6.9 Hz, 1H). Step 3 : Dissolve the compound (1R,5R)-3-(2-(chloromethyl)allyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester (1.20 g, 4.92 mmol) in ethanol (12 mL), add potassium iodide (81.0 mg, 0.49 mmol) and potassium carbonate (2.00 g, 14.7 mmol) at 25 ° C . C for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow oily compound (1aR, 6aR)-4-methylhexahydrocyclopropane [b] pyrrolizine-5a (3H) -carboxylic acid ethyl ester (0.60 g, two-step yield: 80%). LCMS (ESI): [M + H] + = 208.2. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 4.89-4.77 (m, 2H), 4.22-4.07 (m, 2H), 3.96 (br d, J = 4.3 Hz, 1H), 3.27 (dd, J = δ 5.1 (m, 2H), 1.81 (dd, J = 4.6, 13.1 Hz, 1H), 1.46-1.36 (m, 1H) , 1.20 (t, J = 7.1 Hz, 3H), 0.50-0.42 (m, 1H), 0.20 (ddd , J = 2.9, 4.0, 6.9 Hz, 1H).
第四步:將四氫鋁鋰(220 mg,5.79 mmol)溶於四氫呋喃(6 mL),0 oC下加入 (1aR,6aR)-4-伸甲基六氫環丙烷并[b]吡咯嗪-5a(3H)-羧酸乙酯(600 mg,2.89 mmol),反應液在20 oC攪拌2小時。向反應液加入水(220 uL),氫氧化鈉(15%的水溶液,220 uL),水(220 uL*3)淬滅,過濾,濾液減壓濃縮得到粗產物化合物 ((1aR,6aR)-4-伸甲基六氫環丙烷并[b]吡咯嗪-5a(3H)-基)甲醇(300 mg,1.81 mmol,產率62%)。LCMS (ESI): [M+H] += 166.2. Step 4 : Dissolve lithium aluminum tetrahydride (220 mg, 5.79 mmol) in tetrahydrofuran (6 mL), add (1aR,6aR)-4-methylhexahydrocyclopropane[b]pyrrolizine- 5a (3H)-carboxylic acid ethyl ester (600 mg, 2.89 mmol) at 0 ° C, and stir the reaction solution at 20 ° C for 2 hours. Water (220 uL), sodium hydroxide (15% aqueous solution, 220 uL), and water (220 uL*3) were added to the reaction solution for quenching, and the filtrate was filtered and concentrated under reduced pressure to obtain the crude product compound ((1aR, 6aR)-4-methylhexahydrocyclopropane [b] pyrrolizine-5a (3H) -yl) methanol (300 mg, 1.81 mmol, yield 62%). LCMS (ESI): [M+H] + = 166.2.
第五步:向化合物 (3R)-1-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(100 mg,0.17 mmol)和((1aR,6aR)-4-伸甲基六氫環丙烷并[b]吡咯嗪-5a(3H)-基)甲醇(60 mg,0.36 mmol)的四氫呋喃(2 mL)溶液中,加入叔丁醇鈉(60 mg,0.62 mmol),20 oC攪拌16小時。反應液透過矽藻土過濾,濾液減壓濃縮,殘留物用製備型HPLC純化得到化合物 (3R)-1-(-(8-乙炔基-7-氟萘-1-基)-8-氟-(2-(((1aR,6aR)-4-伸甲基六氫環丙烷并[b]吡咯嗪-5a(3H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(8.66 mg,13 umol,產率7%)。LCMS (ESI): [M+H] += 638.5; 1H NMR (400 MHz, CD 3OD) δ ppm 8.74 (d, J=1.4 Hz, 1H), 8.05-7.92 (m, 2H), 7.49 (t, J=7.7 Hz, 1H), 7.37-7.28 (m, 2H), 4.87 (br s, 2H), 4.41 (br d, J=13.1 Hz, 1H), 4.18-4.05 (m, 3H), 3.71 (br d, J=14.4 Hz, 1H), 3.54-3.43 (m, 3H), 3.34-3.25 (m, 1H), 2.71-2.65 (m, 1H), 2.59 (dt, J=2.7, 6.5 Hz, 1H), 2.52 (br d, J=15.4 Hz, 1H), 2.14-2.06 (m, 2H), 1.99-1.90 (m, 2H), 1.70 (br dd, J=3.7, 13.9 Hz, 2H), 1.60-1.54 (m, 1H), 1.18 (s, 3H), 0.71-0.63 (m, 1H), 0.45-0.37 (m, 1H). 實施例 126 : (3R)-1-(2-(( 二氫 -1'H,3'H- 螺 [ 環丙烷 -1,2'- 吡咯嗪 ]-7a'(5'H)- 基 ) 甲氧基 )-7-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Step 5 : To a solution of compound (3R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (100 mg, 0.17 mmol) and ((1aR,6aR)-4-methylhexahydropropano[b]pyrrolizin-5a(3H)-yl)methanol (60 mg, 0.36 mmol) in tetrahydrofuran (2 mL) was added sodium tert-butoxide (60 mg, 0.62 mmol) and stirred at 20 ° C for 16 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give compound (3R)-1-(-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-(2-(((1aR,6aR)-4-methylhexahydrocyclopropane[b]pyrrolizine-5a(3H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (8.66 mg, 13 umol, yield 7%). LCMS (ESI): [M+H] + = 638.5; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.74 (d, J =1.4 Hz, 1H), 8.05-7.92 (m, 2H), 7.49 (t, J =7.7 Hz, 1H), 7.37-7.28 (m, 2H), 4.87 (br s, 2H), 4.41 (br d, J =13.1 Hz, 1H), 4.18-4.05 (m, 3H), 3.71 (br d, J =14.4 Hz, 1H), 3.54-3.43 (m, 3H), 3.34-3.25 (m, 1H), 2.71-2.65 (m, 1H), 2.59 (dt, J =2.7, 6.5 Hz, 1H), 2.52 (br d, J =15.4 Hz, 1H), 2.14-2.06 (m, 2H), 1.98-1.91 (m, 2H), 1.70 (br dd, J =3.7, 13.9 Hz, 2H), 1.60-1.54 (m, 1H), 1.18 (s, 3H), 0.71-0.63 (m, 1H), 0.45-0.37 (m, 1H). Example 126 : (3R)-1-(2-(( dihydro -1'H,3'H- spiro [ cyclopropane -1,2'- pyrrolizine ]-7a'(5'H) -yl ) methoxy )-7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
LCMS (ESI): [M+H] += 640.2; 1H NMR (400 MHz, CD 3OD) δ ppm 8.89 (s, 1H), 8.14-8.05 (m, 2H), 7.59 (t, J= 7.7 Hz, 1H), 7.49-7.38 (m, 2H), 4.58-4.46 (m, 3H), 4.35-4.22 (m, 1H), 3.71-3.45 (m, 2H), 3.44-3.34 (m, 2H), 3.23 (br s, 1H), 3.10 (br s, 1H), 3.00 (br d, J= 6.2 Hz, 1H), 2.31-1.72 (m, 10H), 1.35-1.25 (m, 3H), 0.78-0.69 (m, 2H), 0.68-0.55 (m, 2H). 實施例 126A : (R)-1-((R)-2-(((S)- 二氫 -1'H,3'H- 螺 [ 環丙烷 -1,2'- 吡咯啉 ]-7a'(5'H)- 基 ) 甲氧基 )-7-(8 - 乙炔基 -7- 氟萘 -1- 基 ) -8- 氟 -6- 硝基喹唑啉 -4- 基 ) -3- 甲基呱啶 -3- 醇 實施例 126B: (R)-1-((S)-2-(((S)- 二氫 -1'H,3'H- 螺 [ 環丙烷 -1,2'- 吡咯啉 ]-7a'(5'H)- 基 ) 甲氧基 )-7-(8 - 乙炔基 -7- 氟萘 -1- 基 ) -8- 氟 -6- 硝基喹唑啉 -4- 基 ) -3- 甲基呱啶 -3- 醇 實施例 126C: (R)-1-((R)-2-(((R)- 二氫 -1'H,3'H- 螺 [ 環丙烷 -1,2'- 吡咯啉 ]-7a'(5'H)- 基 ) 甲氧基 )-7-(8 - 乙炔基 -7- 氟萘 -1- 基 ) -8- 氟 -6- 硝基喹唑啉 -4- 基 ) -3- 甲基呱啶 -3- 醇 實施例 126D: (R)-1-((S)-2-(((R)- 二氫 -1'H,3'H- 螺 [ 環丙烷 -1,2'- 吡咯啉 ]-7a'(5'H)- 基 ) 甲氧基 )-7-(8 - 乙炔基 -7- 氟萘 -1- 基 ) -8- 氟 -6- 硝基喹唑啉 -4- 基 ) -3- 甲基呱啶 -3- 醇 LCMS (ESI): [M+H] + = 640.2; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.89 (s, 1H), 8.14-8.05 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.49-7.38 (m, 2H), 4.58-4.46 (m, 3H), 4.35-4.22 (m, 1H), 3.71-3.45 (m, 2H), 3.44-3.34 (m, 2H), 3.23 (br s, 1H), 3.10 (br s, 1H), 3.00 (br d, J = 6.2 Hz, 1H), 2.31-1.72 (m, 10H), 1.35-1.25 (m, 3H), 0.78-0.69 (m, 2H), 0.68-0.55 (m, 2H). Example 126A : (R)-1-((R)-2-(((S) -dihydro -1'H,3'H- spiro [ cyclopropane -1,2'- pyrroline ]-7a'(5'H)-yl ) methoxy ) -7-(8- ethynyl- 7 - fluoronaphthalen -1- yl ) -8 - fluoro -6- nitroquinazolin -4- yl ) -3- methylpiperidin -3- ol Example 126B: (R)-1-((S)-2-(((S) -dihydro -1'H,3'H- spiro [ cyclopropane -1,2'- pyrroline ]-7a'(5'H)-yl ) methoxy ) -7-(8 -ethynyl -7- fluoronaphthalen -1- yl ) -8 - fluoro -6- nitroquinazolin -4- yl ) -3 -methylpiperidin -3- ol Example 126C: (R)-1-((R)-2-(((R) -dihydro -1'H,3'H- spiro [ cyclopropane -1,2'- pyrroline ]-7a'(5'H) -yl ) methoxy )-7-(8- ethynyl -7 - fluoronaphthalen -1- yl ) -8 - fluoro -6- nitroquinazolin -4- yl ) -3- methylpiperidin -3- ol Example 126D: (R)-1-((S)-2-(((R) -dihydro -1'H,3'H- spiro [ cyclopropane -1,2'- pyrroline ]-7a'(5'H) -yl ) methoxy )-7-(8- ethynyl - 7 - fluoronaphthalen - 1- yl ) -8- fluoro -6- nitroquinazolin -4- yl ) -3- methylpiperidin -3- ol
實施例 126經過SFC分離(管柱:DAICEL CHIRALPAK IC(250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/乙醇;B相保持60%;流速:80毫升/分鐘),得到異構物1和異構物2的混合物、光學純的異構物3以及光學純的異構物4三個組分。異構物1和異構物2的混合物經過SFC分離(管柱:Phenomenex-Cellulose-2 (250mm*30mm,10um);流動相:A相為二氧化碳,B相為0.1%氨水/甲醇;B相保持50%;流速:80毫升/分鐘),得到光學純的 實 施例 126A 實以及光學純的 實施例 126B。 Example 126 was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia/ethanol; phase B is maintained at 60%; flow rate: 80 ml/min) to obtain three components: a mixture of isomers 1 and 2, optically pure isomers 3, and optically pure isomers 4. The mixture of isomers 1 and 2 was separated by SFC (column: Phenomenex-Cellulose-2 (250mm*30mm, 10um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water/methanol; phase B is maintained at 50%; flow rate: 80 ml/min) to obtain optically pure Example 126A and optically pure Example 126B .
實施例 126A:LCMS (ESI): [M+H] += 640.1; SFC分析(管柱: Cellulose 2 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/甲醇;梯度:保持50%的B相;流速:2.8毫升/分鐘):掌性管柱出峰位置為 3.304 min; 1H NMR (400 MHz, CD 3OD) δ = 8.89 (d, J= 1.4 Hz, 1H), 8.15-8.02 (m, 2H), 7.59 (t, J= 7.7 Hz, 1H), 7.50-7.35 (m, 2H), 4.62-4.48 (m, 3H), 4.27 (br d, J= 13.1 Hz, 1H), 3.69-3.60 (m, 1H), 3.52-3.33 (m, 4H), 3.15 (br d, J= 11.9 Hz, 1H), 3.05 (br d, J= 10.6 Hz, 1H), 2.34-1.98 (m, 7H), 1.93-1.72 (m, 3H), 1.37-1.24 (m, 3H), 0.82-0.59 (m, 4H). Example 126A : LCMS (ESI): [M+H] + = 640.1; SFC analysis (column: Cellulose 2 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/methanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the palmar column peak position is 3.304 min; 1 H NMR (400 MHz, CD 3 OD) δ = 8.89 (d, J = 1.4 Hz, 1H), 8.15-8.02 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.50-7.35 (m, 2H), 4.62-4.48 (m, 3H), 4.27 (br d, J = 13.1 Hz, 3.69-3.60 (m, 1H), 3.52-3.33 (m, 4H), 3.15 (br d, J = 11.9 Hz, 1H), 3.05 (br d, J = 10.6 Hz, 1H), 2.34-1.98 (m, 7H), 1.93-1.72 (m, 3H), 1.37-1.24 (m, 3H), 0.82-0.59 (m, 4H).
實施例 126B:LCMS (ESI): [M+H] += 640.1; SFC分析(管柱: Cellulose 2 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/甲醇;梯度:保持50%的B相;流速:2.8毫升/分鐘):掌性管柱出峰位置為 4.369 min; 1H NMR (400 MHz, CD 3OD) δ = 8.89 (s, 1H), 8.14-8.00 (m, 2H), 7.59 (t, J= 7.6 Hz, 1H), 7.49-7.35 (m, 2H), 4.64-4.50 (m, 3H), 4.26 (br d, J= 13.0 Hz, 1H), 3.64 (d, J= 13.4 Hz, 1H), 3.51-3.36 (m, 4H), 3.13-3.01 (m, 2H), 2.33-1.74 (m, 10H), 1.36-1.21 (m, 3H), 0.81-0.57 (m, 4H). Example 126B : LCMS (ESI): [M+H] + = 640.1; SFC analysis (column: Cellulose 2 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/methanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the elution position of the palmar column is 4.369 min; 1 H NMR (400 MHz, CD 3 OD) δ = 8.89 (s, 1H), 8.14-8.00 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.49-7.35 (m, 2H), 4.64-4.50 (m, 3H), 4.26 (br d, J = 13.0 Hz, 1H), 3.64 (d, J = 13.4 Hz, 1H), 3.51-3.36 (m, 4H), 3.13-3.01 (m, 2H), 2.33-1.74 (m, 10H), 1.36-1.21 (m, 3H), 0.81-0.57 (m, 4H).
實施例 126C:LCMS (ESI): [M+H] += 640.2; SFC分析(管柱: Chiralpak IC-3 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相;流速:2.8毫升/分鐘):掌性管柱出峰位置為 4.500 min; 1H NMR (400 MHz, CD 3OD) δ = 8.88 (s, 1H), 8.15-8.03 (m, 2H), 7.59 (t, J= 7.6 Hz, 1H), 7.48-7.36 (m, 2H), 4.64-4.45 (m, 3H), 4.30 (br d, J= 13.4 Hz, 1H), 3.64-3.51 (m, 2H), 3.46-3.33 (m, 2H), 3.15 (br d, J= 9.1 Hz, 1H), 3.09-2.92 (m, 2H), 2.30-1.74 (m, 10H), 1.29 (s, 3H), 0.77-0.54 (m, 4H). Example 126C : LCMS (ESI): [M+H] + = 640.2; SFC analysis (column: Chiralpak IC-3 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the elution position of the palmar column is 4.500 min; 1 H NMR (400 MHz, CD 3 OD) δ = 8.88 (s, 1H), 8.15-8.03 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.48-7.36 (m, 2H), 4.64-4.45 (m, 3H), 4.30 (br d, J = 13.4 Hz, 1H), 3.64-3.51 (m, 2H), 3.46-3.33 (m, 2H), 3.15 (br d, J = 9.1 Hz, 1H), 3.09-2.92 (m, 2H), 2.30-1.74 (m, 10H), 1.29 (s, 3H), 0.77-0.54 (m, 4H).
實施例 126D:LCMS (ESI): [M+H] += 640.2; SFC分析(管柱: Chiralpak IC-3 100*4.6mm I.D., 3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;梯度:保持50%的B相;流速:2.8毫升/分鐘):掌性管柱出峰位置為 5.555 min; 1H NMR (400 MHz, CD 3OD) δ = 8.87 (s, 1H), 8.15-7.99 (m, 2H), 7.59 (t, J= 7.6 Hz, 1H), 7.48-7.37 (m, 2H), 4.59-4.43 (m, 3H), 4.30 (br d, J= 13.2 Hz, 1H), 3.65-3.52 (m, 2H), 3.39 (br t, J= 13.3 Hz, 2H), 3.15 (br d, J= 10.9 Hz, 1H), 3.08-2.88 (m, 2H), 2.28-1.72 (m, 10H), 1.40 (s, 3H), 0.75-0.56 (m, 4H). 實施例 127A :(R)-1-(7-((S)- 8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -2-((1-( 嗎啉甲基 ) 環丙基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇的兩個立體異構物 實施例 127B :(R)-1-(7-((R)- 8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -2-((1-( 嗎啉甲基 ) 環丙基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Example 126D : LCMS (ESI): [M+H] + = 640.2; SFC analysis (column: Chiralpak IC-3 100*4.6mm ID, 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; gradient: maintain 50% phase B; flow rate: 2.8 ml/min): the palmar column peak position is 5.555 min; 1 H NMR (400 MHz, CD 3 OD) δ = 8.87 (s, 1H), 8.15-7.99 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.48-7.37 (m, 2H), 4.59-4.43 (m, 3H), 4.30 (br d, J = 13.2 Hz, 1H), 3.65-3.52 (m, 2H), 3.39 (br t, J = 13.3 Hz, 2H), 3.15 (br d, J = 10.9 Hz, 1H), 3.08-2.88 (m, 2H), 2.28-1.72 (m, 10H), 1.40 (s, 3H), 0.75-0.56 (m, 4H). Example 127A : Two stereoisomers of (R)-1-(7-((S) -8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-((1-( fluoroquinolinemethyl ) cyclopropyl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 127B : (R)-1-(7-((R)- 8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-((1-( fluoroquinolinemethyl ) cyclopropyl ) methoxy )-6 -nitroquinazolin -4- yl )-3- methylpiperidin -3 - ol
實施例 127A(16.56 mg,黃色固體),HPLC分析(管柱: Ultimate XB-C18, 3um, 3.0*50mm;流動相:A相為三氟乙酸/水 (1.5 mL/4 L),B相為三氟乙酸/乙腈 (0.75 mL/4 L);梯度:B相在1分鐘內從1%到5%,在5分鐘內從5%到100%,保持100%的B相2分鐘,保持1%的B相2分鐘;流速:1.2毫升/分鐘):出峰位置為3.586 min;LCMS (ESI): [M+H] += 644.3; 1H NMR (400 MHz, CD 3OD) δ ppm 8.89 (d, J= 1.2 Hz, 1H), 8.14-8.06 (m, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.49-7.39 (m, 2H), 4.49-4.41 (m, 3H), 4.20 (br d, J= 13.2 Hz, 1H), 3.68-3.61 (m, 5H), 3.52-3.40 (m, 2H), 2.55-2.47 (m, 4H), 2.44 (d, J= 2.8 Hz, 2H), 2.27-2.18 (m, 1H), 1.88 (br s, 1H), 1.85-1.78 (m, 2H), 1.32 (s, 3H), 0.75-0.68 (m, 2H), 0.53-0.46 (m, 2H). Example 127A (16.56 mg, yellow solid), HPLC analysis (column: Ultimate XB-C18, 3um, 3.0*50mm; mobile phase: phase A is trifluoroacetic acid/water (1.5 mL/4 L), phase B is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); gradient: phase B from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% phase B for 2 minutes, keep 1% phase B for 2 minutes; flow rate: 1.2 ml/min): peak position is 3.586 min; LCMS (ESI): [M+H] + = 644.3; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.89 (d, J = 1.2 Hz, 1H), 8.14-8.06 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.49-7.39 (m, 2H), 4.49-4.41 (m, 3H), 4.20 (br d, J = 13.2 Hz, 1H), 3.68-3.61 (m, 5H), 3.52-3.40 (m, 2H), 2.55-2.47 (m, 4H), 2.44 (d, J = 2.8 Hz, 2H), 2.27-2.18 (m, 1H), 1.88 (br s, 1H), 1.85-1.78 (m, 2H), 1.32 (s, 3H), 0.75-0.68 (m, 2H), 0.53-0.46 (m, 2H).
實施例 127B(20.17 mg,黃色固體),HPLC分析(管柱: Ultimate XB-C18, 3um, 3.0*50mm;流動相:A相為三氟乙酸/水 (1.5 mL/4 L),B相為三氟乙酸/乙腈 (0.75 mL/4 L);梯度:B相在1分鐘內從1%到5%,在5分鐘內從5%到100%,保持100%的B相2分鐘,保持1%的B相2分鐘;流速:1.2毫升/分鐘):出峰位置為3.607 min;LCMS (ESI): [M+H] += 644.2; 1H NMR (400 MHz, CD 3OD) δ ppm 8.86 (d, J= 1.2 Hz, 1H), 8.14-8.05 (m, 2H), 7.60 (t, J= 7.6 Hz, 1H), 7.48-7.40 (m, 2H), 4.54-4.40 (m, 3H), 4.25 (br d, J= 13.4 Hz, 1H), 3.66 (t, J= 4.5 Hz, 4H), 3.61 (d, J= 13.4 Hz, 1H), 3.55 (s, 1H), 3.42 (br t, J= 10.9 Hz, 1H), 2.60-2.47 (m, 4H), 2.46-2.41 (m, 2H), 2.30-2.16 (m, 1H), 1.90-1.75 (m, 3H), 1.30 (s, 3H), 0.76-0.69 (m, 2H), 0.54-0.48 (m, 2H). 實施例 128 : (3R)-1-(7-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -2-((1-((4- 甲基呱嗪 -1- 基 ) 甲基 ) 環丙基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Example 127B (20.17 mg, yellow solid), HPLC analysis (column: Ultimate XB-C18, 3um, 3.0*50mm; mobile phase: phase A is trifluoroacetic acid/water (1.5 mL/4 L), phase B is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); gradient: phase B from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% phase B for 2 minutes, keep 1% phase B for 2 minutes; flow rate: 1.2 ml/min): peak position is 3.607 min; LCMS (ESI): [M+H] + = 644.2; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.86 (d, J = 1.2 Hz, 1H), 8.14-8.05 (m, 2H), 7.60 3H), 3.54-3.81 (m, 2H) , 3.70-3.77 (m, 3H), 1.89-1.91 (m, 4H) , 1.30-1.53 (m, 3H) , 3.57-3.58 (m, 2H), 3.54-3.53 ( m, 3H), 3.70-3.71 (m, 2H), 3.57-3.58 (m, 3H), 3.57-3.58 (m, 2H), 3.57-3.58 (m, 3H), 3.57-3.58 (m, 2H), 0.54-0.48 (m, 2H). Example 128 : (3R)-1-(7-(8- ethynyl- 7 - fluoronaphthalen -1- yl )-8- fluoro -2-((1-((4- methylpiperazine -1- yl ) methyl ) cyclopropyl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
LCMS (ESI): [M+H] += 657.3。 1H NMR (400 MHz, CD 3OD) δ ppm 8.88 (d, J= 9.9 Hz, 1H), 8.19-8.02 (m, 2H), 7.61 (t, J= 7.6 Hz, 1H), 7.50-7.34 (m, 2H), 4.76-4.20 (m, 5H), 3.72-3.34 (m, 4H), 2.78 (br s, 6H), 2.53 (br t, J= 6.1 Hz, 2H), 2.48 (br d, J= 2.4 Hz, 3H), 2.22 (br d, J= 10.8 Hz, 1H), 1.92-1.70 (m, 3H), 1.32 (d, J= 8.1 Hz, 3H), 0.75 (s, 2H), 0.53 (s, 2H). 實施例 129 : (3R)-1-(7-(8- 乙炔基 -7- 氟萘基 -1- 基 )-8- 氟 -6- 硝基 -2-(((S)-1-(2,2,2- 三氟乙基 ) 吡咯烷 -2- 基 ) 甲氧基 ) 喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 LCMS (ESI): [M+H] + = 657.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.88 (d, J = 9.9 Hz, 1H), 8.19-8.02 (m, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.50-7.34 (m, 2H), 4.76-4.20 (m, 5H), 3.72-3.34 (m, 4H), 2.78 (br s, 6H), 2.53 (br t, J = 6.1 Hz, 2H), 2.48 (br d, J = 2.4 Hz, 3H), 2.22 (br d, J = 10.8 Hz, 1H), 1.92-1.70 (m, 3H), 1.32 (d, J = 8.1 Hz, 3H), 0.75 (s, 2H), 0.53 (s, 2H). Example 129 : (3R)-1-(7-(8- ethynyl- 7- fluoronaphthyl- 1- yl )-8- fluoro -6- nitro -2-(((S)-1-(2,2,2- trifluoroethyl ) pyrrolidin -2- yl ) methoxy ) quinazolin -4- yl )-3- methylpiperidin -3- ol
LCMS (ESI): [M+H] += 656.2; 1H NMR (400 MHz, CD 3OD) δ ppm 8.89 (d, J= 1.4 Hz, 1H), 8.16-8.04 (m, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.51-7.37 (m, 2H), 4.57-4.44 (m, 2H), 4.33-4.19 (m, 2H), 3.78-3.59 (m, 2H), 3.51-3.39 (m, 2H), 3.31-3.13 (m, 3H), 2.63-2.56 (m, 1H), 2.29-2.17 (m, 1H), 2.13-1.98 (m, 1H), 1.93-1.74 (m, 6H), 1.32 (s, 3H). 實施例 130 : (3R)-1-(7-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -2-(((S)-1- 甲基吡咯烷 -2- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 LCMS (ESI): [M+H] + = 656.2; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.89 (d, J = 1.4 Hz, 1H), 8.16-8.04 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.51-7.37 (m, 2H), 4.57-4.44 (m, 2H), 4.33-4.19 (m, 2H), 3.78-3.59 (m, 2H), 3.51-3.39 (m, 2H), 3.31-3.13 (m, 3H), 2.63-2.56 (m, 1H), 2.29-2.17 (m, 1H), 2.13-1.98 (m, 1H), 1.93-1.74 (m, 6H), 1.32 (s, 3H). Example 130 : (3R)-1-(7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(((S)-1 -methylpyrrolidin -2 - yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
LCMS (ESI): [M+H] += 588.3。 1H NMR (400 MHz, CD 3OD) δ ppm 8.92-8.85 (m, 1H), 8.15-8.01 (m, 2H), 7.60 (t, J= 7.6 Hz, 1H), 7.50-7.39 (m, 2H), 4.68-4.48 (m, 3H), 4.35-4.23 (m, 1H), 3.67-3.37 (m, 3H), 3.30-3.21 (m, 1H), 2.80-2.64 (m, 4H), 2.29-2.14 (m, 2H), 2.02-1.75 (m, 6H), 1.36-1.26 (m, 3H). 實施例 131A :(R)-1-(7-((S)- 8- 乙炔基 -7- 氟萘基 -1- 基 )-8- 氟 -2-((3-( 嗎啉代甲基 ) 氧雜環丁烷 -3- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 實施例 131B :(R)-1-(7-((S)- 8- 乙炔基 -7- 氟萘基 -1- 基 )-8- 氟 -2-((3-( 嗎啉代甲基 ) 氧雜環丁烷 -3- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 LCMS (ESI): [M+H] + = 588.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.92-8.85 (m, 1H), 8.15-8.01 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.50-7.39 (m, 2H), 4.68-4.48 (m, 3H), 4.35-4.23 (m, 1H), 3.67-3.37 (m, 3H), 3.30-3.21 (m, 1H), 2.80-2.64 (m, 4H), 2.29-2.14 (m, 2H), 2.02-1.75 (m, 6H), 1.36-1.26 (m, 3H). Example 131A : (R)-1-(7-((S) -8 -ethynyl- 7 -fluoronaphthyl- 1 -yl )-8 - fluoro -2-((3-( oxolinomethyl ) oxacyclobutan -3- yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 131B : (R)-1-(7-((S) -8- ethynyl- 7 -fluoronaphthyl- 1- yl )-8- fluoro -2-((3-( oxolinomethyl ) oxacyclobutan -3- yl ) methoxy )-6 -nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
實施例 131A(7.62 mg,黃色固體),HPLC分析(管柱: Ultimate XB-C18, 3um, 3.0*50mm;流動相:A相為三氟乙酸/水 (1.5 mL/4 L),B相為三氟乙酸/乙腈 (0.75 mL/4 L);梯度:B相在1分鐘內從1%到5%,在5分鐘內從5%到100%,保持100%的B相2分鐘,保持1%的B相2分鐘;流速:1.2毫升/分鐘):出峰位置為3.539 min;LCMS (ESI): [M+H] += 660.2; 1H NMR (400 MHz, CD 3OD) δ ppm 8.91 (d, J= 1.3 Hz, 1H), 8.11 (dt, J= 6.6, 9.7 Hz, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.51-7.37 (m, 2H), 4.86-4.82 (m, 1H), 4.82-4.77 (m, 1H), 4.64 (dd, J= 4.2, 6.2 Hz, 2H), 4.60-4.56 (m, 2H), 4.51 (br d, J= 13.4 Hz, 1H), 4.24 (br d, J= 13.4 Hz, 1H), 3.70-3.57 (m, 5H), 3.54-3.41 (m, 2H), 2.85 (s, 2H), 2.51-2.34 (m, 4H), 2.31-2.17 (m, 1H), 1.95-1.76 (m, 3H), 1.33 (s, 3H). Example 131A (7.62 mg, yellow solid), HPLC analysis (column: Ultimate XB-C18, 3um, 3.0*50mm; mobile phase: phase A is trifluoroacetic acid/water (1.5 mL/4 L), phase B is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); gradient: phase B from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% phase B for 2 minutes, keep 1% phase B for 2 minutes; flow rate: 1.2 ml/min): peak position is 3.539 min; LCMS (ESI): [M+H] + = 660.2; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.91 (d, J = 1.3 Hz, 1H), 8.11 (dt, J = 6.6, 9.7 Hz, 7.7 Hz, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.51-7.37 (m, 2H), 4.86-4.82 (m, 1H), 4.82-4.77 (m, 1H), 4.64 (dd, J = 4.2, 6.2 Hz, 2H), 4.60-4.56 (m, 2H), 4.51 (br d, J = 13.4 Hz, 1H), 4.24 (br d, J = 13.4 Hz, 1H), 3.70-3.57 (m, 5H), 3.54-3.41 (m, 2H), 2.85 (s, 2H), 2.51-2.34 (m, 4H), 2.31-2.17 (m, 1H), 1.95-1.76 (m, 3H), 1.33 (s, 3H).
實施例 131B(7.91 mg,黃色固體),HPLC分析(管柱: Ultimate XB-C18, 3um, 3.0*50mm;流動相:A相為三氟乙酸/水 (1.5 mL/4 L),B相為三氟乙酸/乙腈 (0.75 mL/4 L);梯度:B相在1分鐘內從1%到5%,在5分鐘內從5%到100%,保持100%的B相2分鐘,保持1%的B相2分鐘;流速:1.2毫升/分鐘):出峰位置為3.565 min;LCMS (ESI): [M+H] += 660.3; 1H NMR (400 MHz, CD 3OD) δ ppm 8.88 (d, J= 1.3 Hz, 1H), 8.19-7.99 (m, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.49-7.36 (m, 2H), 4.82 (s, 1H), 4.66-4.54 (m, 5H), 4.28 (br d, J= 13.4 Hz, 1H), 3.67-3.59 (m, 5H), 3.56 (s, 1H), 3.42 (br t, J= 11.0 Hz, 1H), 2.84 (s, 2H), 2.50-2.32 (m, 4H), 2.30-2.16 (m, 1H), 1.95-1.68 (m, 3H), 1.37-1.22 (m, 3H). 實施例 132A: (R)-1-(2-((1-((4,4- 二氟呱啶 -1- 基 ) 甲基 ) 環丙基 ) 甲氧基 )-7-((S)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 和實施例 132B: (R)-1-(2-((1-((4,4- 二氟呱啶 -1- 基 ) 甲基 ) 環丙基 ) 甲氧基 )-7-((R)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Example 131B (7.91 mg, yellow solid), HPLC analysis (column: Ultimate XB-C18, 3um, 3.0*50mm; mobile phase: phase A is trifluoroacetic acid/water (1.5 mL/4 L), phase B is trifluoroacetic acid/acetonitrile (0.75 mL/4 L); gradient: phase B from 1% to 5% in 1 minute, from 5% to 100% in 5 minutes, keep 100% phase B for 2 minutes, keep 1% phase B for 2 minutes; flow rate: 1.2 ml/min): peak position is 3.565 min; LCMS (ESI): [M+H] + = 660.3; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.88 (d, J = 1.3 Hz, 1H), 8.19-7.99 (m, 2H), 7.60 (t, 7.7 Hz, 1H), 7.49-7.36 (m, 2H), 4.82 (s, 1H), 4.66-4.54 (m, 5H), 4.28 (br d, J = 13.4 Hz, 1H), 3.67-3.59 (m, 5H), 3.56 (s, 1H), 3.42 (br t, J = 11.0 Hz, 1H), 2.84 (s, 2H), 2.50-2.32 (m, 4H), 2.30-2.16 (m, 1H), 1.95-1.68 (m, 3H), 1.37-1.22 (m, 3H). Example 132A: (R)-1-(2-((1-((4,4 -difluoropiperidin -1 -yl ) methyl ) cyclopropyl ) methoxy )-7-((S)-8- ethynyl- 7 -fluoronaphthalen -1- yl )-8 - fluoro -6 -nitroquinazolin -4- yl )-3- methylpiperidin -3- ol and Example 132B: (R)-1-(2-((1-((4,4 -difluoropiperidin -1 -yl ) methyl ) cyclopropyl ) methoxy )-7-((R)-8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
實施例 132A: LCMS (ESI): [M+H] += 678.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.94-8.83 (m, 1H), 8.17-8.05 (m, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.50-7.36 (m, 2H), 4.54-4.15 (m, 4H), 3.63 (d, J= 13.4 Hz, 1H), 3.51-3.39 (m, 2H), 2.96-2.58 (m, 6H), 2.22 (d, J= 13.6 Hz, 1H), 2.05 (dt, J= 6.2, 13.2 Hz, 4H), 1.93-1.64 (m, 3H), 1.32 (s, 3H), 0.83-0.73 (m, 2H), 0.58 (s, 2H). Example 132A : LCMS (ESI): [M+H] + = 678.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.94-8.83 (m, 1H), 8.17-8.05 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.50-7.36 (m, 2H), 4.54-4.15 (m, 4H), 3.63 (d, J = 13.4 Hz, 1H), 3.51-3.39 (m, 2H), 2.96-2.58 (m, 6H), 2.22 (d, J = 13.6 Hz, 1H), 2.05 (dt, J = 6.2, 13.2 Hz, 4H), 1.93-1.64 (m, 3H), 1.32 (s, 3H), 0.83-0.73 (m, 2H), 0.58 (s, 2H).
實施例 132B: SFC分析(層析管柱: ChiralCel OD-3,50mm * 4.6mm,3um;流動相:A相為二氧化碳,B相為0.05%二乙胺/乙醇;2 min從5%的B相升至40%的B相,保持40%的B相1.2 min,然後保持5%的B相0.8 min;流速:4毫升/分鐘):掌性管柱出峰位置為 1.763 min。LCMS (ESI): [M+H] += 678.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.85 (s, 1H), 8.15-8.06 (m, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.50-7.41 (m, 2H), 4.53-4.22 (m, 4H), 3.64-3.52 (m, 2H), 3.44-3.37 (m, 1H), 2.76-2.48 (m, 6H), 2.23 (d, J= 13.0 Hz, 1H), 2.04-1.93 (m, 4H), 1.90-1.74 (m, 3H), 1.34-1.27 (m, 3H), 0.75 (s, 2H), 0.57-0.49 (m, 2H). 實施例 133 : (3R)-1-(7-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基 -2-((1-( 呱啶 -1- 基 ) 甲基 ) 環丙基 ) 甲氧基 ) 喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇甲酸鹽 Example 132B : SFC analysis (chromatographic column: ChiralCel OD-3, 50 mm * 4.6 mm, 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/ethanol; 2 min from 5% phase B to 40% phase B, keep 40% phase B for 1.2 min, and then keep 5% phase B for 0.8 min; flow rate: 4 ml/min): the peak position of the palmar column is 1.763 min. LCMS (ESI): [M+H] + = 678.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.85 (s, 1H), 8.15-8.06 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.50-7.41 (m, 2H), 4.53-4.22 (m, 4H), 3.64-3.52 (m, 2H), 3.44-3.37 (m, 1H), 2.76-2.48 (m, 6H), 2.23 (d, J = 13.0 Hz, 1H), 2.04-1.93 (m, 4H), 1.90-1.74 (m, 3H), 1.34-1.27 (m, 3H), 0.75 (s, 2H), 0.57-0.49 (m, 2H). Example 133 : (3R)-1-(7-(8- ethynyl- 7 -fluoronaphthalen -1- yl )-8- fluoro -6- nitro -2-((1-( piperidin -1- yl ) methyl ) cyclopropyl ) methoxy ) quinazolin -4- yl )-3 -methylpiperidin -3- ol carboxylate
LCMS (ESI): [M+H] += 642.2。 1H NMR (400 MHz, CD 3OD) δ ppm 8.93-8.85 (m, 1H), 8.56 (s, 1H), 8.18-8.07 (m, 2H), 7.62 (t, J= 7.6 Hz, 1H), 7.50-7.41 (m, 2H), 4.60-4.46 (m, 3H), 4.43-4.22 (m, 2H), 3.65-3.52 (m, 2H), 3.45-3.36 (m, 2H), 3.21-2.83 (m, 4H), 1.97-1.72 (m, 8H), 1.62 (br s, 2H), 1.33-1.29 (m, 3H), 0.91 (br s, 2H), 0.82-0.71 (m, 2H). 實施例 134 : (3R)-1-(2-((1-( 二甲胺基 ) 甲基 ) 環丙基 ) 甲氧基 )-7-(8- 乙基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 LCMS (ESI): [M+H] + = 642.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.93-8.85 (m, 1H), 8.56 (s, 1H), 8.18-8.07 (m, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.50-7.41 (m, 2H), 4.60-4.46 (m, 3H), 4.43-4.22 (m, 2H), 3.65-3.52 (m, 2H), 3.45-3.36 (m, 2H), 3.21-2.83 (m, 4H), 1.97-1.72 (m, 8H), 1.62 (br s, 2H), 1.33-1.29 (m, 3H), 0.91 (br s, 2H), 0.82-0.71 (m, 2H). Example 134 : (3R)-1-(2-((1-( dimethylamino ) methyl ) cyclopropyl ) methoxy )-7-(8- ethyl -7- fluoronaphthalen -1- yl )-8 - fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
LCMS (ESI): [M+H] += 602.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.93-8.87 (m, 1H), 8.15-8.07 (m, 2H), 7.61 (t, J= 7.8 Hz, 1H), 7.49-7.40 (m, 2H), 4.57-4.37 (m, 3H), 4.32-4.20 (m, 1H), 3.67-3.58 (m, 1H), 3.50-3.37 (m, 2H), 2.72 (br s, 2H), 2.51 (br s, 6H), 2.22 (br d, J= 7.3 Hz, 1H), 1.92-1.77 (m, 3H), 1.34-1.29 (m, 3H), 0.82 (s, 2H), 0.64 (br s, 2H). 實施例 135 : 1-(7-(8- 乙炔基 -7- 氟 -3- 羥基萘 -1- 基 )-8- 氟 -2-((1-( 嗎啉甲基 ) 環丙基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 LCMS (ESI): [M+H] + = 602.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.93-8.87 (m, 1H), 8.15-8.07 (m, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.49-7.40 (m, 2H), 4.57-4.37 (m, 3H), 4.32-4.20 (m, 1H), 3.67-3.58 (m, 1H), 3.50-3.37 (m, 2H), 2.72 (br s, 2H), 2.51 (br s, 6H), 2.22 (br d, J = 7.3 Hz, 1H), 1.92-1.77 (m, 3H), 1.34-1.29 (m, 3H), 0.82 (s, 2H), 0.64 (br s, 2H). Example 135 : 1-(7-(8- ethynyl - 7- fluoro -3- hydroxynaphthalen -1- yl )-8- fluoro -2-((1-( oxo-1-ylmethyl ) cyclopropyl ) methoxy )-6 -nitroquinazolin -4- yl )-3 -methylpiperidin -3- ol
第一步:在25 oC下,向1-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(1.40 g,3.34 mmol)的三氟乙醇(15 mL)溶液中加入二異丙基乙胺(2.33 mL,13.35 mmol)。將溶液在70 oC攪拌3小時。將溶液濃縮並透過快速管柱層析(矽膠,0-30%梯度的乙酸乙酯/石油醚)純化得到棕色油狀化合物1-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(1.29 g,2.67 mmol,產率80%)。LCMS (ESI): [M+H] += 485.1. Step 1 : Add diisopropylethylamine (2.33 mL, 13.35 mmol) to a solution of 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (1.40 g, 3.34 mmol) in trifluoroethanol (15 mL) at 25 °C. Stir the solution at 70 ° C for 3 hours. Concentrate the solution and purify it by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a brown oily compound 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (1.29 g, 2.67 mmol, 80% yield). LCMS (ESI): [M+H] + = 485.1.
第二步:在25 oC和氮氣氛圍下,向1-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(0.50 g,1.03 mmol)和 (((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(0.80 g,1.55 mmol)的甲苯(20 mL)和水(5 mL)溶液中加入碳酸銫(1.01 g,3.10 mmol)和甲磺酸(二金剛烷基-正丁基膦基)-2'-胺基-1,1'-聯苯-2-基)鈀(II)二氯甲烷(0.15 g,0.21 mmol)。將該溶液在100 oC攪拌16小時。將溶液濃縮,殘餘物透過快速管柱層析(矽膠, 0-30%梯度的四氫呋喃/石油醚)純化得到棕色固體化合物1-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(0.58 g,0.62 mmol,產率60%)。LCMS (ESI): [M+H] += 789.1. Step 2 : To a solution of 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.50 g, 1.03 mmol) and (((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (0.80 g, 1.55 mmol) in toluene (20 mL) and water (5 mL) at 25 °C under nitrogen atmosphere was added cesium carbonate (1.01 g, 3.10 mmol) and (diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate in dichloromethane (0.15 g, 4% ethanol). g, 0.21 mmol). The solution was stirred at 100 ° C for 16 hours. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 0-30% gradient of tetrahydrofuran/petroleum ether) to obtain a brown solid compound 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (0.58 g, 0.62 mmol, yield 60%). LCMS (ESI): [M+H] + = 789.1.
第三步:在25 oC下,向1-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(500 mg,0.63 mmol)和 (1-(嗎啉甲基)環丙基)甲醇(217 mg,1.27 mmol)的四氫呋喃(5 mL)溶液中加入叔丁醇鈉(122 mg,1.27 mmol)。將該溶液在25 oC攪拌2小時。溶液用水(10 mL)稀釋並用乙酸乙酯(10 mL * 3)萃取。然後將有機層乾燥並濃縮,粗產物透過快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化,得到棕色油狀化合物1-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(540 mg,0.50 mmol,產率88%)。LCMS (ESI): [M+H] += 860.4. Step 3 : To a solution of 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (500 mg, 0.63 mmol) and (1-(morpholinomethyl)cyclopropyl)methanol (217 mg, 1.27 mmol) in tetrahydrofuran (5 mL) was added sodium tert-butoxide (122 mg, 1.27 mmol) at 25 ° C. The solution was stirred at 25 ° C for 2 hours. The solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL * 3). The organic layer was then dried and concentrated, and the crude product was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a brown oily compound 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(fluoromethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (540 mg, 0.50 mmol, yield 88%). LCMS (ESI): [M+H] + = 860.4.
第四步:在25 oC下,向1-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(500 mg,0.58 mmol)的二甲基甲醯胺(5 mL)溶液中添加氟化銫(883 mg,5.81 mmol)。將該溶液在25 oC攪拌2小時。溶液用水(10 mL)稀釋並乙酸乙酯(10 mL * 3)萃取。將合併的有機相乾燥並濃縮。粗產物透過快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化,得到黃色固體化合物1-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(280 mg,0.34mmol,產率58%)。LCMS (ESI): [M+H] += 704.2. Step 4 : To a solution of 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (500 mg, 0.58 mmol) in dimethylformamide (5 mL) at 25 °C was added cesium fluoride (883 mg, 5.81 mmol). The solution was stirred at 25 ° C for 2 hours. The solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic phases were dried and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a yellow solid compound 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(oxolinylmethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (280 mg, 0.34 mmol, yield 58%). LCMS (ESI): [M+H] + = 704.2.
第五步:在25 oC下,向1-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(20 mg,28.4 umol)的乙腈(200 uL)溶液中加入氯化氫(4M的二氧六環溶液,71 uL,0.28 mmol)。將該溶液在25 oC攪拌1小時。將溶液濃縮,殘餘物分散到乙腈(1 mL)中,加入三乙胺將其pH值調節至8。將溶液濃縮並透過製備型HPLC純化得到黃色固體化合物1-(7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(6.63 mg,9.9 umol,產率35%)。[M+H] += 660.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.84 (d, J= 10.3 Hz, 1H), 7.84 (dd, J= 5.8, 8.9 Hz, 1H), 7.36-7.25 (m, 2H), 7.00 (dd, J= 2.4, 10.6 Hz, 1H), 4.51-4.37 (m, 3H), 4.20 (br dd, J= 13.5, 19.9 Hz, 1H), 3.68-3.56 (m, 5H), 3.51-3.34 (m, 2H), 2.62-2.37 (m, 6H), 2.28-2.14 (m, 1H), 1.92-1.72 (m, 3H), 1.29 (d, J= 8.1 Hz, 3H), 0.75-0.67 (m, 2H), 0.53-0.44 (m, 2H). 實施例 136 : 1-(7-(8- 乙基 -7- 氟 -3- 羥基萘 -1- 基 )-8- 氟 -2-((1-( 嗎啉甲基 ) 環丙基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Step 5 : To a solution of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (20 mg, 28.4 umol) in acetonitrile (200 uL) was added hydrogen chloride (4M in dioxane, 71 uL, 0.28 mmol) at 25 o C. The solution was stirred at 25 o C for 1 hour. The solution was concentrated and the residue was dispersed in acetonitrile (1 mL). The pH was adjusted to 8 by adding triethylamine. The solution was concentrated and purified by preparative HPLC to give a yellow solid compound 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(oxo-methyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (6.63 mg, 9.9 umol, yield 35%). [M+H] + = 660.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.84 (d, J = 10.3 Hz, 1H), 7.84 (dd, J = 5.8, 8.9 Hz, 1H), 7.36-7.25 (m, 2H), 7.00 (dd, J = 2.4, 10.6 Hz, 1H), 4.51-4.37 (m, 3H), 4.20 (br dd, J = 13.5, 19.9 Hz, 1H), 3.68-3.56 (m, 5H), 3.51-3.34 (m, 2H), 2.62-2.37 (m, 6H), 2.28-2.14 (m, 1H), 1.92-1.72 (m, 3H), 1.29 (d, J = 8.1 Hz, 3H), 0.75-0.67 (m, 2H), 0.53-0.44 (m, 2H). Example 136 : 1-(7-(8- ethyl -7- fluoro -3- hydroxynaphthalen -1- yl )-8 - fluoro -2-((1-( fluoroquinolinemethyl ) cyclopropyl ) methoxy )-6 -nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
第一步:在25 oC和氮氣氛圍下,向1-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(30 mg,0.04 mmol)的四氫呋喃(100 uL)溶液中加入2-硝基苯磺醯肼(47 mg,0.21 mmol)和三乙胺(30 uL,0.21 mmol)。將該溶液在25 oC攪拌16小時。溶液加水(500 uL)稀釋並用乙酸乙酯(500 uL * 3)萃取,有機相乾燥,過濾,濾液旋轉乾燥得到棕色固體化合物1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(30 mg,38.1 umol,產率89%)。LCMS (ESI): [M+H] += 708.4. Step 1 : To a solution of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (30 mg, 0.04 mmol) in tetrahydrofuran (100 uL) at 25 °C under nitrogen atmosphere, 2-nitrobenzenesulfonylhydrazine (47 mg, 0.21 mmol) and triethylamine (30 uL, 0.21 mmol) were added. The solution was stirred at 25 ° C for 16 hours. The solution was diluted with water (500 uL) and extracted with ethyl acetate (500 uL * 3). The organic phase was dried, filtered, and the filtrate was rotary dried to obtain a brown solid compound 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(oxo-methyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (30 mg, 38.1 umol, yield 89%). LCMS (ESI): [M+H] + = 708.4.
第二步:在25 oC下,向1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(30 mg,0.04 mmol)的乙腈(300 uL)溶液中加入氯化氫(4 M的二氧六環溶液,106 uL,0.42 mmol)。將溶液在25 oC攪拌1小時。濃縮溶液,然後用二氯甲烷(1 mL)稀釋並加入三乙胺將其pH值調節至8。濃縮溶液並透過製備型HPLC純化得到黃色固體化合物1-(7-(8-乙基-7-氟-3-羥基萘-1-基)-8-氟-2-((1-(嗎啉甲基)環丙基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(4.95 mg,7.1 umol,產率17%)。LCMS (ESI): [M+H] += 664.2。 1H NMR (400 MHz, CD 3OD) δ ppm 8.93 (d, J= 16.8 Hz, 1H), 7.67 (dd, J= 5.9, 9.0 Hz, 1H), 7.30-7.21 (m, 2H), 6.85-6.78 (m, 1H), 4.50-4.40 (m, 3H), 4.28-4.16 (m, 1H), 3.66 (br t, J= 4.5 Hz, 4H), 3.63-3.53 (m, 1H), 3.51-3.40 (m, 1H), 2.60 (br s, 5H), 2.52 (br s, 2H), 2.40 (br s, 1H), 2.19 (br d, J= 8.4 Hz, 1H), 1.92-1.75 (m, 3H), 1.32 (d, J= 15.9 Hz, 3H), 0.83 (q, J= 7.4 Hz, 3H), 0.73 (s, 2H), 0.53 (s, 2H). Step 2 : To a solution of 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(phenolinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (30 mg, 0.04 mmol) in acetonitrile (300 uL) at 25 °C was added hydrogen chloride (4 M in dioxane, 106 uL, 0.42 mmol). The solution was stirred at 25 ° C for 1 hour. The solution was concentrated and then diluted with dichloromethane (1 mL) and its pH was adjusted to 8 by the addition of triethylamine. The solution was concentrated and purified by preparative HPLC to give a yellow solid compound 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(fluoroquinolinemethyl)cyclopropyl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (4.95 mg, 7.1 umol, yield 17%). LCMS (ESI): [M+H] + = 664.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.93 (d, J = 16.8 Hz, 1H), 7.67 (dd, J = 5.9, 9.0 Hz, 1H), 7.30-7.21 (m, 2H), 6.85-6.78 (m, 1H), 4.50-4.40 (m, 3H), 4.28-4.16 (m, 1H), 3.66 (br t, J = 4.5 Hz, 4H), 3.63-3.53 (m, 1H), 3.51-3.40 (m, 1H), 2.60 (br s, 5H), 2.52 (br s, 2H), 2.40 (br s, 1H), 2.19 (br d, J = 8.4 Hz, 1H), 1.92-1.75 (m, 3H), 1.32 (d, J = 15.9 Hz, 3H), 0.83 (q, J = 7.4 Hz, 3H), 0.73 (s, 2H), 0.53 (s, 2H).
乙炔基)三異丙基矽烷(425 mg,0.83 mmol)的甲苯(12 mL)和水(3 mL)溶液中加入甲磺酸(二金剛烷基-正丁基膦基)-2'-胺基-1,1'-聯苯-2-基)鈀(II)二氯甲烷(81 mg,0.11 mmol)和碳酸銫(541 mg,1.66 mmol)。將該溶液在100 oC攪拌16小時。將反應液旋轉乾燥並透過快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化得到粗產物化合物1-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(290 mg),其為棕色固體。[M+H] += 848.4 To a solution of (diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonate (81 mg, 0.11 mmol) and cesium carbonate (541 mg, 1.66 mmol) was added (425 mg, 0.83 mmol) in toluene (12 mL) and water (3 mL). The solution was stirred at 100 ° C for 16 hours. The reaction solution was spin dried and purified by flash column chromatography (silica gel, 0-10% gradient of methanol/dichloromethane) to give the crude product compound 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (290 mg) as a brown solid. [M+H] + = 848.4
第六步:在25 oC下,向1-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(430 mg,0.51 mmol)的二甲基甲醯胺(4300 uL)溶液中加入氟化銫(771 mg,5.07 mmol)。將溶液在25 oC攪拌2小時。反應液加水(8 mL)稀釋,用乙酸乙酯(4 mL * 3)萃取。合併的有機層用鹽水(8 mL)洗滌並用無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物透過快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化,得到棕色固體化合物1-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(300 mg,0.36 mmol,產率72%)。[M+H] += 692.3 Step 6 : At 25 ° C, add cesium fluoride (771 mg, 5.07 mmol) to a solution of 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (430 mg, 0.51 mmol) in dimethylformamide (4300 uL). Stir the solution at 25 ° C for 2 hours. The reaction solution was diluted with water (8 mL) and extracted with ethyl acetate (4 mL * 3). The combined organic layers were washed with brine (8 mL) and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to give a brown solid compound 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (300 mg, 0.36 mmol, yield 72%). [M+H] + = 692.3
第七步:在25 oC下,向1-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(30 mg,43.37 umol)的乙腈(300 uL)溶液中加入氯化氫(4M的二氧六環溶液,109 uL,0.436 mmol)並攪拌2小時。將溶液旋轉乾燥並加入二氯甲烷(1 mL)稀釋,用三乙胺調節pH至8。粗產物經製備型HPLC純化得到黃色固體化合物1-(7-(8-乙炔基-7-氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(甲酸鹽,5.66 mg,8.57 umol,產率20%)。[M+H] += 648.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.89 (s, 1H), 8.51 (s, 1H), 7.87 (dd, J= 6.2, 9.0 Hz, 1H), 7.38-7.29 (m, 2H), 7.02 (dd, J= 2.3, 8.9 Hz, 1H), 5.54-5.33 (m, 1H), 4.84-4.75 (m, 1H), 4.56-4.44 (m, 2H), 4.29 (br dd, J= 13.3, 19.7 Hz, 1H), 3.70-3.40 (m, 6H), 3.23 (br s, 1H), 2.57-1.74 (m, 10H), 1.32 (d, J= 7.0 Hz, 3H). 實施例 137 : 1-(7-(8- 乙炔基 -7- 氟 -3- 羥基萘 -1- 基 )-8- 氟 -2-(((2R,7aS)-2- 氟四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Step 7 : To a solution of 1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (30 mg, 43.37 umol) in acetonitrile (300 uL) was added hydrogen chloride (4M in dioxane, 109 uL, 0.436 mmol) at 25 °C and stirred for 2 hours. The solution was spun dry and diluted with dichloromethane (1 mL) and the pH was adjusted to 8 with triethylamine. The crude product was purified by preparative HPLC to give a yellow solid compound 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (formate salt, 5.66 mg, 8.57 umol, yield 20%). [M+H] + = 648.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.89 (s, 1H), 8.51 (s, 1H), 7.87 (dd, J = 6.2, 9.0 Hz, 1H), 7.38-7.29 (m, 2H), 7.02 (dd, J = 2.3, 8.9 Hz, 1H), 5.54-5.33 (m, 1H), 4.84-4.75 (m, 1H), 4.56-4.44 (m, 2H), 4.29 (br dd, J = 13.3, 19.7 Hz, 1H), 3.70-3.40 (m, 6H), 3.23 (br s, 1H), 2.57-1.74 (m, 10H), 1.32 (d, J = 7.0 Hz, 3H). Example 137 : 1-(7-(8- ethynyl- 7 - fluoro - 3- hydroxynaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolizine -7a(5H)-yl ) methoxy ) -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
第一步:在0 oC下,向7-溴-8-氟-1,3-二氫喹唑啉-2,4-二酮(18.00 g,69.49 mmol)的硫酸(150 mL)溶液中分批加入硝酸鉀(14.05 g,138.98 mmol),將混合物在0 oC攪拌1小時,小心倒入冰水(400 mL)中,過濾,濾餅用水(100 mL * 3)洗滌並真空乾燥得到棕色固體化合物7-溴-8-氟-6-硝基-1,3-二氫喹唑啉-2,4-二酮(21.50 g,63.64 mmol,產率92%)。LCMS (ESI): [M+H] += 303.8 Step 1 : At 0 o C, potassium nitrate (14.05 g, 138.98 mmol) was added in batches to a solution of 7-bromo-8-fluoro-1,3-dihydroquinazoline-2,4-dione (18.00 g, 69.49 mmol) in sulfuric acid (150 mL). The mixture was stirred at 0 o C for 1 hour, carefully poured into ice water (400 mL), filtered, and the filter cake was washed with water (100 mL * 3) and vacuum dried to obtain a brown solid compound 7-bromo-8-fluoro-6-nitro-1,3-dihydroquinazoline-2,4-dione (21.50 g, 63.64 mmol, yield 92%). LCMS (ESI): [M+H] + = 303.8
第二步:在0 oC下,向7-溴-8-氟-6-硝基-1,3-二氫喹唑啉-2,4-二酮(2.00 g,6.58 mmol)和三氯氧磷(4.89 mL,52.63 mmol)的甲苯(30 mL)溶液中加入二異丙基乙胺(3.45 mL,19.74mmol)。將該溶液在110 oC攪拌0.33小時,點板顯示反應結束。溶液用乙酸乙酯(15 mL)稀釋,然後加入冰(30 g)。混合物用乙酸乙酯(30 mL * 2)萃取。將合併的有機層用無水硫酸鈉乾燥,過濾並真空濃縮,得到棕色固體化合物7-溴-2,4-二氯-8-氟-6-硝基喹唑啉(2.00 g,5.28 mmol,產率80%)。 1H NMR (400 MHz, DMSO- d 6) δ ppm 8.56 (d, J= 2.0 Hz, 1H) Step 2 : At 0 ° C, diisopropylethylamine (3.45 mL, 19.74 mmol) was added to a toluene (30 mL) solution of 7-bromo-8-fluoro-6-nitro-1,3-dihydroquinazoline-2,4-dione (2.00 g, 6.58 mmol) and phosphorus oxychloride (4.89 mL, 52.63 mmol). The solution was stirred at 110 ° C for 0.33 hours, and the plate showed that the reaction was complete. The solution was diluted with ethyl acetate (15 mL), and then ice (30 g) was added. The mixture was extracted with ethyl acetate (30 mL * 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid compound 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (2.00 g, 5.28 mmol, yield 80%). 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.56 (d, J = 2.0 Hz, 1H)
第三步:在-40 oC下,向7-溴-2,4-二氯-8-氟-6-硝基喹唑啉(2.00 g,5.87 mmol)和3-甲基呱啶-3-醇(0.89 g,5.87 mmol)的二氯甲烷(20 mL)溶液中加入二異丙基乙胺(2.30 mL,12.91 mmol)。將混合物在-40 oC攪拌1小時。向混合物中加入水(20 ml),用二氯甲烷(20 mL * 3)萃取。合併的有機層用無水硫酸鈉乾燥,過濾並減壓濃縮,得到棕色固體化合物1-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(2.28g,4.52mmol,產率77%)。LCMS (ESI): [M+H] += 420.9 Step 3 : Add diisopropylethylamine (2.30 mL , 12.91 mmol) to a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (2.00 g, 5.87 mmol) and 3-methylpiperidin-3-ol (0.89 g, 5.87 mmol) in dichloromethane (20 mL) at -40 ° C. Stir the mixture at -40 ° C for 1 hour. Add water (20 ml) to the mixture and extract with dichloromethane (20 mL * 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid compound 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (2.28 g, 4.52 mmol, yield 77%). LCMS (ESI): [M+H] + = 420.9
第四步:在25 oC下,向1-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(750 mg,1.49 mmol)和碳酸銫(971 mg,2.98 mmol)的二氧六環(8 mL)懸濁液中,加入 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(237 mg,1.49 mmol)。將溶液在100 oC氮氣氛圍下在攪拌16小時,減壓濃縮,殘餘物透過快速管柱層析(矽膠,0-10%梯度的甲醇/二氯甲烷)純化,得到黃色固體化合物1-(7-溴-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(490 mg,0.90 mmol,產率61%)。LCMS (ESI): [M+H] += 544.1 Step 4 : To a suspension of 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (750 mg, 1.49 mmol) and cesium carbonate (971 mg, 2.98 mmol) in dioxane (8 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (237 mg, 1.49 mmol) at 25 °C. The solution was stirred at 100 ° C under nitrogen atmosphere for 16 hours, concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10% gradient methanol/dichloromethane) to obtain a yellow solid compound 1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (490 mg, 0.90 mmol, yield 61%). LCMS (ESI): [M+H] + = 544.1
第五步:在25 oC氮氣氛圍下,向1-(7-溴-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(300 mg,0.55 mmol)和 (((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)萘-1-基) 實施例 138:1-(7-(8-乙基-7-氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇 Step 5 : At 25 ° C under nitrogen atmosphere, 1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (300 mg, 0.55 mmol) and (((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)naphthalen-1-yl) Example 138 were added to the mixture. :1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol
第一步:在-40 oC下向7-溴-2,4-二氯-8-氟-6-硝基喹唑啉(2.00 g,5.87 mmol)和3-甲基呱啶-3-醇(0.89 g,5.87 mmol)的二氯甲烷(20 mL)溶液中加入二異丙基乙胺(2.30 mL,12.91 mmol)。將混合物在-40 oC攪拌1小時。向混合物中加入水(20 ml),用二氯甲烷(20 mL * 3)萃取。合併的有機層用無水硫酸鈉乾燥,過濾並減壓濃縮,得到粗產物化合物1-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(2.28g),其為棕色固體。LCMS (ESI): [M+H] += 420.9 Step 1 : Add diisopropylethylamine (2.30 mL, 12.91 mmol ) to a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (2.00 g, 5.87 mmol) and 3-methylpiperidin-3-ol (0.89 g, 5.87 mmol) in dichloromethane (20 mL) at -40 ° C. Stir the mixture at -40 ° C for 1 hour. Add water (20 ml) to the mixture and extract with dichloromethane (20 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product compound 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazoline-4-yl)-3-methylpiperidin-3-ol (2.28 g) as a brown solid. LCMS (ESI): [M+H] + = 420.9
第二步:在25 oC下向1-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(2.00 g,4.77 mmol)的三氟乙醇(20 mL)溶液中加入二異丙基乙胺(3.33 mL,19.06 mmol)。將溶液在70 oC攪拌3小時。將溶液旋轉乾燥並透過快速管柱層析(矽膠,石油醚/乙酸乙酯=0-40%)純化得到黃色固體化合物1-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(1.82g,3.77mmol,產率79%)。LCMS (ESI): [M+H] += 483.1 Step 2 : Add diisopropylethylamine (3.33 mL, 19.06 mmol ) to a solution of 1-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (2.00 g, 4.77 mmol) in trifluoroethanol (20 mL) at 25 °C. Stir the solution at 70 ° C for 3 hours. Rotate the solution to dryness and purify by flash column chromatography (silica gel, petroleum ether/ethyl acetate = 0-40%) to obtain a yellow solid compound 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (1.82 g, 3.77 mmol, yield 79%). LCMS (ESI): [M+H] + = 483.1
第三步:在25 oC氮氣氛圍下向1-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(1.80 g,3.32 mmol)和1-乙基-2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基(1,3,2-二氧硼雜環戊烷-2-基))的甲苯(400 uL)和水(100 uL)溶液中加入甲磺酸(二金剛烷基-正丁基膦基)-2'-胺基-1,1'-聯苯-2-基)鈀(II)二氯甲烷(0.48 g,0.66 mmol)和碳酸銫(3.24 g,9.96 mmol)。將該溶液在100 oC攪拌16小時。將反應液旋轉乾燥並透過快速管柱層析(矽膠,石油醚/四氫呋喃=0-30%)純化得到棕色固體化合物1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(1.10g,1.58mmol,產率48%)。LCMS (ESI): [M+H] += 637.3 Step 3 : To a solution of 1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (1.80 g, 3.32 mmol) and 1-ethyl-2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl(1,3,2-dioxaborol-2-yl)) in toluene (400 uL) and water (100 uL) at 25 °C under nitrogen atmosphere, (diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate dichloromethane (0.48 g, 0.66 mmol) and cesium carbonate (3.24 g, 9.96 mmol) were added. The solution was stirred at 100 ° C for 16 hours. The reaction solution was rotary dried and purified by flash column chromatography (silica gel, petroleum ether/tetrahydrofuran = 0-30%) to obtain a brown solid compound 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (1.10 g, 1.58 mmol, yield 48%). LCMS (ESI): [M+H] + = 637.3
第四步:在25 oC下向1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(500 mg,0.79 mmol)和 ((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲醇(125 mg,0.79 mmol)的四氫呋喃(5 mL)溶液中加入叔丁醇鈉。將混合物在25 oC下攪拌16小時。將混合物旋轉乾燥並透過快速管柱層析純化得到棕黃色固體化合物1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(350 mg,0.50mmol,產率64%)。LCMS (ESI): [M+H] += 696.3 Step 4 : To a solution of 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (500 mg, 0.79 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (125 mg, 0.79 mmol) in tetrahydrofuran (5 mL) was added sodium tert-butoxide at 25° C. The mixture was stirred at 25 ° C for 16 hours. The mixture was rotary dried and purified by flash column chromatography to give a brown solid compound 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (350 mg, 0.50 mmol, yield 64%). LCMS (ESI): [M+H] + = 696.3
第五步:在25 oC下,向1-(7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(350 mg,0.50 mmol)的乙腈(4 mL)溶液中加入氯化氫(4M的二氧六環溶液,1.26 mL, 5.03 mmol)並攪拌4小時。將溶液旋轉乾燥並加入二氯甲烷(4 mL)稀釋,用三乙胺調節pH值至8。粗產物經製備型HPLC純化得到白色固體化合物1-(7-(8-乙基-7-氟-3-羥基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-硝基喹唑啉-4-基)-3-甲基呱啶-3-醇(150 mg,0.23mmol,產率46%)。LCMS (ESI): [M+H] += 652.3。 1H NMR (400 MHz, CD 3OD) δ ppm 9.00-8.91 (m, 1H), 8.52 (s, 1H), 7.68 (dd, J= 5.8, 9.1 Hz, 1H), 7.31-7.22 (m, 2H), 6.81 (dd, J= 2.6, 5.0 Hz, 1H), 5.44 (br s, 1H), 4.53-4.21 (m, 4H), 3.67-3.48 (m, 2H), 3.42 (br s, 3H), 3.14 (br s, 1H), 2.71-1.83 (m, 12H), 1.30 (s, 3H), 0.87-0.80 (m, 3H). 實施例 139 : 1-(7-(8- 乙炔基 -7- 氟 -3- 羥基萘基 )-8- 氟 -6- 硝基 -2-(2,2,2- 三氟乙氧基 ) 喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Step 5 : To a solution of 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (350 mg, 0.50 mmol) in acetonitrile (4 mL) was added hydrogen chloride (4M in dioxane, 1.26 mL, 5.03 mmol) at 25 °C and stirred for 4 hours. The solution was spun dry and diluted with dichloromethane (4 mL) and the pH was adjusted to 8 with triethylamine. The crude product was purified by preparative HPLC to give a white solid compound 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-nitroquinazolin-4-yl)-3-methylpiperidin-3-ol (150 mg, 0.23 mmol, yield 46%). LCMS (ESI): [M+H] + = 652.3. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.00-8.91 (m, 1H), 8.52 (s, 1H), 7.68 (dd, J = 5.8, 9.1 Hz, 1H), 7.31-7.22 (m, 2H), 6.81 (dd, J = 2.6, 5.0 Hz, 1H), 5.44 (br s, 1H), 4.53-4.21 (m, 4H), 3.67-3.48 (m, 2H), 3.42 (br s, 3H), 3.14 (br s, 1H), 2.71-1.83 (m, 12H), 1.30 (s, 3H), 0.87-0.80 (m, 3H). Example 139 : 1-(7-(8- ethynyl- 7- fluoro -3- hydroxynaphthyl )-8- fluoro -6- nitro -2-(2,2,2 -trifluoroethoxy ) quinazolin -4- yl )-3- methylpiperidin -3- ol
LCMS (ESI): [M+H] += 589.5。 1H NMR (400 MHz, CD 3OD) δ ppm 8.90 (dd, J= 1.4, 14.1 Hz, 1H), 7.87 (dd, J= 5.8, 9.1 Hz, 1H), 7.36-7.29 (m, 2H), 7.03 (dd, J= 2.4, 9.9 Hz, 1H), 5.06-4.97 (m, 2H), 4.63-4.51 (m, 1H), 4.30 (br dd, J= 13.4, 18.9 Hz, 1H), 3.68-3.58 (m, 1H), 3.51-3.36 (m, 2H), 2.24 (br d, J= 14.0 Hz, 1H), 1.93-1.74 (m, 3H), 1.32 (d, J= 8.6 Hz, 3H). 實施例 140A : (R)-1-(7-(S)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -2-(4- 甲基四氫 -2H- 吡喃 -4- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 實施例 140B : (R)-1-(7-(R)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -2-(4- 甲基四氫 -2H- 吡喃 -4- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 LCMS (ESI): [M+H] + = 589.5. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.90 (dd, J = 1.4, 14.1 Hz, 1H), 7.87 (dd, J = 5.8, 9.1 Hz, 1H), 7.36-7.29 (m, 2H), 7.03 (dd, J = 2.4, 9.9 Hz, 1H), 5.06-4.97 (m, 2H), 4.63-4.51 (m, 1H), 4.30 (br dd, J = 13.4, 18.9 Hz, 1H), 3.68-3.58 (m, 1H), 3.51-3.36 (m, 2H), 2.24 (br d, J = 14.0 Hz, 1H), 1.93-1.74 (m, 3H), 1.32 (d, J = 8.6 Hz, 3H). Example 140A : (R)-1-(7-(S)-8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(4- methyltetrahydro -2H- pyran -4- yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 140B : (R)-1-(7-(R)-8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(4- methyltetrahydro -2H- pyran -4- yl ) methoxy )-6- nitroquinazolin - 4- yl )-3- methylpiperidin -3- ol
實施例 140A: LCMS (ESI): [M+H] += 603.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.89 (s, 1H), 8.23-8.02 (m, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.54-7.30 (m, 2H), 4.47 (br d, J= 13.2 Hz, 1H), 4.40-4.15 (m, 3H), 3.85-3.58 (m, 5H), 3.54-3.41 (m, 2H), 2.31-2.16 (m, 1H), 1.94-1.68 (m, 5H), 1.48 (br d, J= 13.9 Hz, 2H), 1.32 (s, 3H), 1.21 (s, 3H). Example 140A : LCMS (ESI): [M+H] + = 603.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.89 (s, 1H), 8.23-8.02 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.54-7.30 (m, 2H), 4.47 (br d, J = 13.2 Hz, 1H), 4.40-4.15 (m, 3H), 3.85-3.58 (m, 5H), 3.54-3.41 (m, 2H), 2.31-2.16 (m, 1H), 1.94-1.68 (m, 5H), 1.48 (br d, J = 13.9 Hz, 2H), 1.32 (s, 3H), 1.21 (s, 3H).
實施例 140B: LCMS (ESI): [M+H] += 603.0。 1H NMR (400 MHz, CD 3OD) δ ppm 8.86 (s, 1H), 8.20-7.96 (m, 2H), 7.59 (t, J= 7.6 Hz, 1H), 7.48-7.37 (m, 2H), 4.51 (br d, J= 13.6 Hz, 1H), 4.34-4.21 (m, 3H), 3.83-3.65 (m, 4H), 3.63-3.53 (m, 2H), 3.45-3.35 (m, 1H), 2.30-2.16 (m, 1H), 1.91-1.71 (m, 5H), 1.47 (br d, J= 13.9 Hz, 2H), 1.30 (s, 3H), 1.21 (s, 3H). 實施例 141A : (R)-1-(7-(S)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -2-(4- 羥甲基 ) 雙環 [2.2.2] 辛烷 -1- 基 ) 氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 實施例 142B : (R)-1-(7-(R)-8- 乙基 -7- 氟萘 -1- 基 )-8- 氟 -2-(4-( 羥甲基 ) 雙環 [2.2.2] 辛烷 -1- 基 ) 氧基 -6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Example 140B : LCMS (ESI): [M+H] + = 603.0. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.86 (s, 1H), 8.20-7.96 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.48-7.37 (m, 2H), 4.51 (br d, J = 13.6 Hz, 1H), 4.34-4.21 (m, 3H), 3.83-3.65 (m, 4H), 3.63-3.53 (m, 2H), 3.45-3.35 (m, 1H), 2.30-2.16 (m, 1H), 1.91-1.71 (m, 5H), 1.47 (br d, J = 13.9 Hz, 2H), 1.30 (s, 3H), 1.21 (s, 3H). Example 141A : (R)-1-(7-(S)-8- ethynyl- 7 -fluoronaphthalen -1- yl )-8- fluoro -2-(4- hydroxymethyl ) bicyclo [2.2.2] octan -1- yl ) oxy )-6 -nitroquinazolin -4- yl )-3 -methylpiperidin -3- ol Example 142B : (R)-1-(7-(R)-8- ethyl -7- fluoronaphthalen -1- yl )-8- fluoro -2-(4-( hydroxymethyl ) bicyclo [2.2.2] octan -1- yl ) oxy -6 -nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
實施例 141A :LCMS (ESI): [M+H] += 629.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.88 (s, 1H), 8.22-8.00 (m, 2H), 7.60 (t, J= 7.6 Hz, 1H), 7.49-7.31 (m, 2H), 4.45 (br d, J= 13.0 Hz, 1H), 4.24-4.05 (m, 3H), 3.63 (d, J= 13.2 Hz, 1H), 3.52-3.39 (m, 2H), 2.29-2.14 (m, 1H), 1.92-1.63 (m, 15H), 1.39-1.23 (m, 3H). Example 141A : LCMS (ESI): [M+H] + = 629.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.88 (s, 1H), 8.22-8.00 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.49-7.31 (m, 2H), 4.45 (br d, J = 13.0 Hz, 1H), 4.24-4.05 (m, 3H), 3.63 (d, J = 13.2 Hz, 1H), 3.52-3.39 (m, 2H), 2.29-2.14 (m, 1H), 1.92-1.63 (m, 15H), 1.39-1.23 (m, 3H).
實施例 142B :LCMS (ESI): [M+H] += 629.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.84 (d, J= 0.9 Hz, 1H), 8.16-7.99 (m, 2H), 7.59 (t, J= 7.7 Hz, 1H), 7.52-7.33 (m, 2H), 4.48 (br d, J= 13.2 Hz, 1H), 4.23 (br d, J= 13.4 Hz, 1H), 4.18-4.05 (m, 2H), 3.64-3.50 (m, 2H), 3.43-3.34 (m, 1H), 2.30-2.15 (m, 1H), 1.91-1.63 (m, 15H), 1.36-1.24 (m, 3H). 實施例 143A : (R)-1-(2-( 雙環 [1.1.1] 戊烷 -1- 基甲氧基 )-7-((S)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 實施例 143B : (R)-1-(2-( 雙環 [1.1.1] 戊烷 -1- 基甲氧基 )-7-((R)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Example 142B : LCMS (ESI): [M+H] + = 629.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.84 (d, J = 0.9 Hz, 1H), 8.16-7.99 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.52-7.33 (m, 2H), 4.48 (br d, J = 13.2 Hz, 1H), 4.23 (br d, J = 13.4 Hz, 1H), 4.18-4.05 (m, 2H), 3.64-3.50 (m, 2H), 3.43-3.34 (m, 1H), 2.30-2.15 (m, 1H), 1.91-1.63 (m, 15H), 1.36-1.24 (m, 3H). Example 143A : (R)-1-(2-( Bicyclo [1.1.1] pentan -1 -ylmethoxy )-7-((S)-8- ethynyl- 7- fluoronaphthalen -1- yl )-8 - fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 143B : (R)-1-(2-( Bicyclo [1.1.1] pentan -1 -ylmethoxy )-7-((R)-8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
實施例 143A: LCMS (ESI): [M+H] += 571.1。 1H NMR (400 MHz, CD 3OD) δ ppm 9.02-8.83 (m, 1H), 8.18-8.02 (m, 2H), 7.67-7.53 (m, 1H), 7.52-7.29 (m, 2H), 4.56-4.14 (m, 4H), 3.75-3.38 (m, 3H), 2.58-2.48 (m, 1H), 2.30-2.16 (m, 1H), 1.88 (s, 7H), 1.85-1.76 (m, 2H), 1.36-1.25 (m, 3H). Example 143A : LCMS (ESI): [M+H] + = 571.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.02-8.83 (m, 1H), 8.18-8.02 (m, 2H), 7.67-7.53 (m, 1H), 7.52-7.29 (m, 2H), 4.56-4.14 (m, 4H), 3.75-3.38 (m, 3H), 2.58-2.48 (m, 1H), 2.30-2.16 (m, 1H), 1.88 (s, 7H), 1.85-1.76 (m, 2H), 1.36-1.25 (m, 3H).
實施例 143B: LCMS (ESI): [M+H] += 571.1。 1H NMR (400 MHz, CD 3OD) δ ppm 9.02-8.81 (m, 1H), 8.24-7.99 (m, 2H), 7.66-7.52 (m, 1H), 7.48-7.30 (m, 2H), 4.58-4.14 (m, 4H), 3.66-3.36 (m, 3H), 2.57-2.50 (m, 1H), 2.27-2.13 (m, 1H), 1.87 (s, 7H), 1.83-1.73 (m, 2H), 1.28 (s, 3H). 實施例 144A : 4-(((7-((S)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -4-((R)-3- 羥基 -3- 甲基呱啶 -1- 基 )-6- 硝基喹唑啉 -2- 基 ) 氧基 ) 甲基 ) 四氫 -2H- 吡喃 -4- 氰 實施例 144B : 4-(((7-((R)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -4-((R)-3- 羥基 -3- 甲基呱啶 -1- 基 )-6- 硝基喹唑啉 -2- 基 ) 氧基 ) 甲基 ) 四氫 -2H- 吡喃 -4- 氰 Example 143B : LCMS (ESI): [M+H] + = 571.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.02-8.81 (m, 1H), 8.24-7.99 (m, 2H), 7.66-7.52 (m, 1H), 7.48-7.30 (m, 2H), 4.58-4.14 (m, 4H), 3.66-3.36 (m, 3H), 2.57-2.50 (m, 1H), 2.27-2.13 (m, 1H), 1.87 (s, 7H), 1.83-1.73 (m, 2H), 1.28 (s, 3H). Example 144A : 4-(((7-((S)-8- ethynyl- 7 -fluoronaphthalen -1- yl )-8 - fluoro -4-((R)-3 - hydroxy -3- methylpiperidin -1- yl )-6- nitroquinazolin -2- yl ) oxy ) methyl ) tetrahydro -2H- pyran -4- cyanoacetate Example 144B : 4-(((7-((R)-8- ethynyl- 7 -fluoronaphthalen -1- yl )-8 - fluoro -4-((R)-3- hydroxy -3- methylpiperidin -1- yl )-6- nitroquinazolin -2- yl ) oxy ) methyl ) tetrahydro -2H- pyran -4- cyanoacetate
實施例 144A: LCMS (ESI): [M+H] += 614.1。 1H NMR (400 MHz, CD 3OD) δ ppm 9.06-8.75 (m, 1H), 8.22-7.98 (m, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.51-7.25 (m, 2H), 4.68-4.50 (m, 3H), 4.25 (br d, J= 13.2 Hz, 1H), 4.09-3.96 (m, 2H), 3.81-3.58 (m, 3H), 3.54-3.39 (m, 2H), 2.31-1.75 (m, 8H), 1.32 (s, 3H). Example 144A : LCMS (ESI): [M+H] + = 614.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.06-8.75 (m, 1H), 8.22-7.98 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.51-7.25 (m, 2H), 4.68-4.50 (m, 3H), 4.25 (br d, J = 13.2 Hz, 1H), 4.09-3.96 (m, 2H), 3.81-3.58 (m, 3H), 3.54-3.39 (m, 2H), 2.31-1.75 (m, 8H), 1.32 (s, 3H).
實施例 144B:LCMS (ESI): [M+H] += 614.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.88 (d, J= 1.1 Hz, 1H), 8.17-7.99 (m, 2H), 7.64-7.55 (m, 1H), 7.48-7.32 (m, 2H), 4.64-4.49 (m, 3H), 4.34-4.20 (m, 1H), 4.08-3.95 (m, 2H), 3.79-3.66 (m, 2H), 3.63-3.51 (m, 2H), 3.46-3.37 (m, 1H), 2.33-1.71 (m, 8H), 1.36-1.23 (m, 3H). 實施例 145A : (R)-1-(7-(S)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -2-(3- 甲基氧雜環丁烷 -3- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 實施例 145B : (R)-1-(7-(R)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -2-(3- 甲基氧雜環丁烷 -3- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Example 144B : LCMS (ESI): [M+H] + = 614.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.88 (d, J = 1.1 Hz, 1H), 8.17-7.99 (m, 2H), 7.64-7.55 (m, 1H), 7.48-7.32 (m, 2H), 4.64-4.49 (m, 3H), 4.34-4.20 (m, 1H), 4.08-3.95 (m, 2H), 3.79-3.66 (m, 2H), 3.63-3.51 (m, 2H), 3.46-3.37 (m, 1H), 2.33-1.71 (m, 8H), 1.36-1.23 (m, 3H). Example 145A : (R)-1-(7-(S)-8- ethynyl- 7 -fluoronaphthalen -1- yl )-8- fluoro -2-(3- methyloxacyclobutane -3- yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 145B : (R)-1-(7-(R)-8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -2-(3- methyloxacyclobutane -3- yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3 - ol
實施例 145A: LCMS (ESI): [M+H] += 575.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.90 (d, J= 1.1 Hz, 1H), 8.14-8.06 (m, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.48-7.40 (m, 2H), 4.70 (dd, J= 3.1, 5.9 Hz, 2H), 4.65-4.50 (m, 3H), 4.47 (d, J= 5.9 Hz, 2H), 4.24 (br d, J= 13.2 Hz, 1H), 3.64 (d, J= 13.2 Hz, 1H), 3.51-3.41 (m, 2H), 2.29-2.16 (m, 1H), 1.94-1.77 (m, 3H), 1.47 (s, 3H), 1.32 (s, 3H). Example 145A : LCMS (ESI): [M+H] + = 575.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.90 (d, J = 1.1 Hz, 1H), 8.14-8.06 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.48-7.40 (m, 2H), 4.70 (dd, J = 3.1, 5.9 Hz, 2H), 4.65-4.50 (m, 3H), 4.47 (d, J = 5.9 Hz, 2H), 4.24 (br d, J = 13.2 Hz, 1H), 3.64 (d, J = 13.2 Hz, 1H), 3.51-3.41 (m, 2H), 2.29-2.16 (m, 1H), 1.94-1.77 (m, 3H), 1.47 (s, 3H), 1.32 (s, 3H).
實施例 145B: LCMS (ESI): [M+H] += 575.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.87 (s, 1H), 8.25-7.98 (m, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.50-7.39 (m, 2H), 4.69 (d, J= 5.9 Hz, 2H), 4.59 (s, 2H), 4.53 (br d, J= 13.0 Hz, 1H), 4.46 (d, J= 5.9 Hz, 2H), 4.27 (br d, J= 13.4 Hz, 1H), 3.65-3.52 (m, 2H), 3.44-3.36 (m, 1H), 2.30-2.16 (m, 1H), 1.93-1.74 (m, 3H), 1.47 (s, 3H), 1.30 (s, 3H). 實施例 146A : (R)-1-(2-(4,4- 二氟環己基 ) 氧基 )-7-((S)-8- 乙炔基 -7- 氟萘基 -1- 基 )-8- 氟 -6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 實施例 146B : (R)-1-(2-(4,4- 二氟環己基 ) 氧基 )-7-((R)-8- 乙炔基 -7- 氟萘基 -1- 基 )-8- 氟 -6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Example 145B : LCMS (ESI): [M+H] + = 575.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.87 (s, 1H), 8.25-7.98 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.50-7.39 (m, 2H), 4.69 (d, J = 5.9 Hz, 2H), 4.59 (s, 2H), 4.53 (br d, J = 13.0 Hz, 1H), 4.46 (d, J = 5.9 Hz, 2H), 4.27 (br d, J = 13.4 Hz, 1H), 3.65-3.52 (m, 2H), 3.44-3.36 (m, 1H), 2.30-2.16 (m, 1H), 1.93-1.74 (m, 3H), 1.47 (s, 3H), 1.30 (s, 3H). Example 146A : (R)-1-(2-(4,4 -difluorocyclohexyl ) oxy )-7-((S)-8- ethynyl- 7 -fluoronaphthyl -1- yl )-8- fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 146B : (R)-1-(2-(4,4 -difluorocyclohexyl ) oxy )-7-((R)-8- ethynyl- 7- fluoronaphthyl -1- yl )-8 - fluoro -6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol
實施例 146A: LCMS (ESI): [M+H] += 609.1。 1H NMR (400 MHz, CD 3OD) δ ppm 9.05-8.76 (m, 1H), 8.21-7.98 (m, 2H), 7.68-7.53 (m, 1H), 7.49-7.35 (m, 2H), 5.47-5.29 (m, 1H), 4.56-4.43 (m, 1H), 4.31-4.15 (m, 1H), 3.69-3.59 (m, 1H), 3.52-3.39 (m, 2H), 2.32-1.75 (m, 12H), 1.31 (s, 3H). Example 146A : LCMS (ESI): [M+H] + = 609.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.05-8.76 (m, 1H), 8.21-7.98 (m, 2H), 7.68-7.53 (m, 1H), 7.49-7.35 (m, 2H), 5.47-5.29 (m, 1H), 4.56-4.43 (m, 1H), 4.31-4.15 (m, 1H), 3.69-3.59 (m, 1H), 3.52-3.39 (m, 2H), 2.32-1.75 (m, 12H), 1.31 (s, 3H).
實施例 146B: LCMS (ESI): [M+H] += 609.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.92-8.79 (m, 1H), 8.17-8.04 (m, 2H), 7.65-7.53 (m, 1H), 7.49-7.39 (m, 2H), 5.42-5.31 (m, 1H), 4.58-4.44 (m, 1H), 4.26 (br d, J= 13.2 Hz, 1H), 3.64-3.56 (m, 2H), 3.44-3.35 (m, 1H), 2.30-1.93 (m, 9H), 1.91-1.72 (m, 3H), 1.29 (s, 3H). 實施例 147A : (R)-1-(7-(S)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -2-(3- 氟氧雜環丁烷 -3- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 實施例 147B : (R)-1-(7-(R)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -2-(3- 氟氧雜環丁烷 -3- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Example 146B : LCMS (ESI): [M+H] + = 609.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.92-8.79 (m, 1H), 8.17-8.04 (m, 2H), 7.65-7.53 (m, 1H), 7.49-7.39 (m, 2H), 5.42-5.31 (m, 1H), 4.58-4.44 (m, 1H), 4.26 (br d, J = 13.2 Hz, 1H), 3.64-3.56 (m, 2H), 3.44-3.35 (m, 1H), 2.30-1.93 (m, 9H), 1.91-1.72 (m, 3H), 1.29 (s, 3H). Example 147A : (R)-1-(7-(S)-8- ethynyl- 7 -fluoronaphthalen -1- yl )-8- fluoro -2-(3 -fluorooxocyclobutane -3 - yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 147B : (R)-1-(7-(R)-8- ethynyl- 7 -fluoronaphthalen -1 -yl )-8- fluoro - 2-(3 -fluorooxocyclobutane -3- yl ) methoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3 - ol
實施例 147A: LCMS (ESI): [M+H] += 579.0。 1H NMR (400 MHz, CD 3OD) δ ppm 8.98-8.75 (m, 1H), 8.26-7.95 (m, 2H), 7.67-7.54 (m, 1H), 7.52-7.35 (m, 2H), 4.89-4.76 (m, 6H), 4.58-4.46 (m, 1H), 4.31-4.22 (m, 1H), 3.69-3.57 (m, 1H), 3.51-3.39 (m, 2H), 2.37-2.11 (m, 1H), 2.00-1.69 (m, 3H), 1.41-1.22 (m, 3H). Example 147A : LCMS (ESI): [M+H] + = 579.0. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.98-8.75 (m, 1H), 8.26-7.95 (m, 2H), 7.67-7.54 (m, 1H), 7.52-7.35 (m, 2H), 4.89-4.76 (m, 6H), 4.58-4.46 (m, 1H), 4.31-4.22 (m, 1H), 3.69-3.57 (m, 1H), 3.51-3.39 (m, 2H), 2.37-2.11 (m, 1H), 2.00-1.69 (m, 3H), 1.41-1.22 (m, 3H).
實施例 147B: LCMS (ESI): [M+H] += 579.0。 1H NMR (400 MHz, CD 3OD) δ ppm 8.93-8.84 (m, 1H), 8.18-8.01 (m, 2H), 7.65-7.53 (m, 1H), 7.50-7.36 (m, 2H), 4.90-4.74 (m, 6H), 4.61-4.51 (m, 1H), 4.36-4.22 (m, 1H), 3.66-3.51 (m, 2H), 3.44-3.35 (m, 1H), 2.29-2.11 (m, 1H), 1.93-1.70 (m, 3H), 1.34-1.23 (m, 3H). 實施例 148A : (R)-1-(7-(S)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -2-(2- 甲氧基 -2- 甲基丙氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 實施例 148B : (R)-1-(7-(R)-8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -2-(2- 甲氧基 -2- 甲基丙氧基 )-6- 硝基喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Example 147B : LCMS (ESI): [M+H] + = 579.0. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.93-8.84 (m, 1H), 8.18-8.01 (m, 2H), 7.65-7.53 (m, 1H), 7.50-7.36 (m, 2H), 4.90-4.74 (m, 6H), 4.61-4.51 (m, 1H), 4.36-4.22 (m, 1H), 3.66-3.51 (m, 2H), 3.44-3.35 (m, 1H), 2.29-2.11 (m, 1H), 1.93-1.70 (m, 3H), 1.34-1.23 (m, 3H). Example 148A : (R)-1-(7-(S)-8- ethynyl- 7- fluoronaphthalen -1 -yl )-8- fluoro -2-(2- methoxy -2- methylpropoxy )-6- nitroquinazolin -4- yl )-3- methylpiperidin -3- ol Example 148B : (R)-1-(7-(R)-8- ethynyl- 7 -fluoronaphthalen -1 -yl )-8- fluoro -2-(2- methoxy -2- methylpropoxy )-6 -nitroquinazolin -4- yl )-3 -methylpiperidin -3- ol
實施例 148A: LCMS (ESI): [M+H] += 577.0。 1H NMR (400 MHz, CD 3OD) δ ppm 9.08-8.80 (m, 1H), 8.33-7.95 (m, 2H), 7.72-7.58 (m, 1H), 7.53-7.36 (m, 2H), 4.54-4.33 (m, 3H), 4.22 (br d, J= 13.4 Hz, 1H), 3.64 (d, J= 13.2 Hz, 1H), 3.52-3.41 (m, 2H), 3.34-3.32 (m, 3H), 2.36-2.12 (m, 1H), 1.99-1.69 (m, 3H), 1.47-1.21 (m, 9H). Example 148A : LCMS (ESI): [M+H] + = 577.0. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.08-8.80 (m, 1H), 8.33-7.95 (m, 2H), 7.72-7.58 (m, 1H), 7.53-7.36 (m, 2H), 4.54-4.33 (m, 3H), 4.22 (br d, J = 13.4 Hz, 1H), 3.64 (d, J = 13.2 Hz, 1H), 3.52-3.41 (m, 2H), 3.34-3.32 (m, 3H), 2.36-2.12 (m, 1H), 1.99-1.69 (m, 3H), 1.47-1.21 (m, 9H).
實施例 148B: LCMS (ESI): [M+H] += 577.1。 1H NMR (400 MHz, CD 3OD) δ ppm 8.86 (d, J= 1.3 Hz, 1H), 8.17-7.97 (m, 2H), 7.63-7.36 (m, 3H), 4.56-4.15 (m, 4H), 3.65-3.50 (m, 2H), 3.44-3.35 (m, 1H), 3.31 (s, 3H), 2.37-2.10 (m, 1H), 1.91-1.69 (m, 3H), 1.42-1.16 (m, 9H). Example 148B : LCMS (ESI): [M+H] + = 577.1. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.86 (d, J = 1.3 Hz, 1H), 8.17-7.97 (m, 2H), 7.63-7.36 (m, 3H), 4.56-4.15 (m, 4H), 3.65-3.50 (m, 2H), 3.44-3.35 (m, 1H), 3.31 (s, 3H), 2.37-2.10 (m, 1H), 1.91-1.69 (m, 3H), 1.42-1.16 (m, 9H).
實施例 149 , 實施例 152和 實施例 153參照 實施例 137的合成途徑 製備得到的: 實施例 149 : 4-(7-(8- 乙炔基 -7- 氟 -3- 羥基萘 -1- 基 )-8- 氟 -2-(((2R,7aS)-2- 氟四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-6- 甲基 -1,4- 氧氮雜環庚烷 -6- 醇 Example 149 , Example 152 and Example 153 were prepared by referring to the synthetic route of Example 137 : Example 149 : 4-(7-(8- ethynyl -7- fluoro -3- hydroxynaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolizine -7a(5H) -yl ) methoxy )-6- nitroquinazolin -4- yl )-6- methyl -1,4- oxazolidinone -6- ol
LCMS (ESI): [M+H] += 664.5; 1H NMR (400 MHz, CD 3OD) δ ppm 9.27-9.17 (m, 1H), 7.75 (dd, J= 5.8, 9.1 Hz, 1H), 7.25-7.15 (m, 2H), 6.90 (d, J= 2.3 Hz, 1H), 5.31-5.09 (m, 1H), 4.46-4.35 (m, 2H), 4.26-4.08 (m, 3H), 3.99-3.72 (m, 3H), 3.66-3.55 (m, 2H), 3.35-3.23 (m, 1H), 3.20-3.06 (m, 3H), 2.92 (dt, J= 5.7, 9.4 Hz, 1H), 2.30-1.99 (m, 3H), 1.95-1.75 (m, 3H), 1.22 (s, 3H). 實施例 150 : 4-(7-(8- 乙基 -7- 氟 -3- 羥基萘 -1- 基 )-8- 氟 -2-(((2R,7aS)-2- 氟四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-6- 甲基 -1,4- 氧氮雜環庚烷 -6- 醇 實施例 151 : 4-(8- 氟 -7-(7- 氟 -3- 羥基 -8- 乙烯基萘 -1- 基 )-2-(((2R,7aS)- 2- 氟四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-6- 甲基 -1,4- 氧氮雜環庚烷 -6- 醇 LCMS (ESI): [M+H] + = 664.5; 1H NMR (400 MHz, CD 3 OD) δ ppm 9.27-9.17 (m, 1H), 7.75 (dd, J = 5.8, 9.1 Hz, 1H), 7.25-7.15 (m, 2H), 6.90 (d, J = 2.3 Hz, 1H), 5.31-5.09 (m, 1H), 4.46-4.35 (m, 2H), 4.26-4.08 (m, 3H), 3.99-3.72 (m, 3H), 3.66-3.55 (m, 2H), 3.35-3.23 (m, 1H), 3.20-3.09 (m, 3H), 2.92 (dt, J = 5.7, 9.4 Hz, 1H), 2.30-1.99 (m, 3H), 1.95-1.75 (m, 3H), 1.22 (s, 3H). Example 150 : 4-(7-(8- ethyl -7- fluoro -3 - hydroxynaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H - pyrrolizin -7a(5H)-yl ) methoxy ) -6- nitroquinazolin -4- yl )-6- methyl -1,4- oxazolidinone -6- ol Example 151 : 4-(8- fluoro -7-(7- fluoro -3- hydroxy -8- vinylnaphthalen -1- yl )-2-(((2R,7aS)- 2- Fluorotetrahydro -1H- pyrrolizin -7a(5H)-yl ) methoxy ) -6- nitroquinazolin -4- yl )-6- methyl -1,4- oxazolocycloheptan - 6- ol
實施例 150 和實施例 151參照 實施例 136的合成途徑製備得到的: Embodiment 150 and embodiment 151 are prepared by referring to the synthetic route of embodiment 136 :
實施例 150 : 4-(7-(8- 乙基 -7- 氟 -3- 羥基萘 -1- 基 )-8- 氟 -2-(((2R,7aS)-2- 氟四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-6- 甲基 -1,4- 氧氮雜環庚烷 -6- 醇(5.43 mg,7 umol,產率5%)為黃色固體,LCMS (ESI): [M+H] += 668.5; 1H NMR (400 MHz, CD 3OD) δ ppm 9.54-9.36 (m, 1H), 7.69 (dd, J= 5.9, 9.0 Hz, 1H), 7.32-7.21 (m, 2H), 6.87-6.79 (m, 1H), 5.41-5.21 (m, 1H), 4.58-4.47 (m, 2H), 4.38-4.17 (m, 3H), 4.09-3.82 (m, 3H), 3.72 (s, 2H), 3.28-3.16 (m, 2H), 3.08-2.99 (m, 1H), 2.72-2.57 (m, 1H), 2.45-2.31 (m, 2H), 2.31-2.08 (m, 3H), 2.05-1.86 (m, 3H), 1.37-1.30 (m, 3H), 0.89-0.77 (m, 3H). Example 150 : 4-(7-(8- ethyl -7- fluoro -3- hydroxynaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolizin -7a(5H) -yl ) methoxy )-6- nitroquinazolin -4- yl )-6 - methyl -1,4- oxazinecycloheptan- 6- ol (5.43 mg, 7 umol, yield 5%) was obtained as a yellow solid. LCMS (ESI): [M+H] + = 668.5; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.54-9.36 (m, 1H), 7.69 (dd, J = 5.9, 9.0 Hz, 1H), 7.32-7.21 (m, 2H), 6.87-6.79 (m, 1H), 5.41-5.21 (m, 1H), 4.58-4.47 (m, 2H), 4.38-4.17 (m, 3H), 4.09-3.82 (m, 3H), 3.72 (s, 2H), 3.28-3.16 (m, 2H), 3.08-2.99 (m, 1H), 2.72-2.57 (m, 1H), 2.45-2.31 (m, 2H), 2.31-2.08 (m, 3H), 2.05-1.86 (m, 3H), 1.37-1.30 (m, 3H), 0.89-0.77 (m, 3H).
實施例 151 : 4-(8- 氟 -7-(7- 氟 -3- 羥基 -8- 乙烯基萘 -1- 基 )-2-(((2R,7aS)- 2- 氟四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-6- 甲基 -1,4- 氧氮雜環庚烷 -6- 醇(2.29 mg,3 umol,產率2%)為黃色固體,LCMS (ESI): [M+H] += 666.5; 1H NMR (400 MHz, CD 3OD) δ ppm 9.43-9.11 (m, 1H), 7.82-7.59 (m, 1H), 7.25-7.10 (m, 2H), 6.90-6.76 (m, 1H), 6.10-5.89 (m, 1H), 5.41-4.86 (m, 3H), 4.41 (br dd, J= 4.9, 14.5 Hz, 2H), 4.28-4.05 (m, 3H), 3.97-3.69 (m, 3H), 3.60 (s, 2H), 3.19-3.02 (m, 3H), 2.98-2.85 (m, 1H), 2.29-1.99 (m, 3H), 1.94-1.73 (m, 3H), 1.25-1.17 (m, 3H). 實施例 152 6-(7-(8- 乙炔基 -7- 氟 -3- 羥基萘 -1- 基 )-8- 氟 -2-(((2R,7aS)-2- 氟四氫 -1H- 吡咯嗪 -7a(5H))- 基 ) 甲氧基 )-6- 硝基喹唑啉 -4- 基 )-6- 氮雜螺 [3.5] 壬 -2- 醇 Example 151 : 4-(8- fluoro -7-(7- fluoro -3- hydroxy -8- vinylnaphthalen -1- yl )-2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolizin -7a(5H) -yl ) methoxy )-6- nitroquinazolin -4- yl )-6 - methyl -1,4- oxazinecycloheptan -6- ol (2.29 mg, 3 umol, yield 2%) was obtained as a yellow solid. LCMS (ESI): [M+H] + = 666.5; 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.43-9.11 (m, 1H), 7.82-7.59 (m, 1H), 7.25-7.10 (m, 2H), 6.90-6.76 (m, 1H), 6.10-5.89 (m, 1H), 5.41-4.86 (m, 3H), 4.41 (br dd, J = 4.9, 14.5 Hz, 2H), 4.28-4.05 (m, 3H), 3.97-3.69 (m, 3H), 3.60 (s, 2H), 3.19-3.02 (m, 3H), 2.98-2.85 (m, 1H), 2.29-1.99 (m, 3H), 1.94-1.73 (m, 3H), 1.25-1.17 (m, 3H). Example 152 6-(7-(8- ethynyl- 7- fluoro -3- hydroxynaphthalen -1- yl )-8- fluoro -2-(((2R,7aS)-2- fluorotetrahydro -1H- pyrrolizin -7a(5H))- yl ) methoxy )-6- nitroquinazolin -4- yl )-6- azaspiro [3.5] nonan -2- ol
LCMS (ESI): [M+H] += 674.3; 1H NMR (400 MHz, CD 3OD) δ ppm 8.67 (s, 1H), 7.87 (br dd, J= 5.8, 8.9 Hz, 1H), 7.37-7.18 (m, 2H), 7.01 (s, 1H), 5.42-5.22 (m, 1H), 4.66-4.58 (m, 1H), 4.41-4.25 (m, 3H), 4.07-3.86 (m, 4H), 3.37 (br d, J= 3.9 Hz, 1H), 3.26 (br s, 1H), 3.24-3.18 (m, 1H), 3.04 (br s, 1H), 2.44-2.35 (m, 2H), 2.31-2.11 (m, 3H), 2.08-1.94 (m, 3H), 1.92-1.72 (m, 6H). 實施例 153 : 3- 氯 -5-(7-(8- 乙炔基 -7- 氟 -3- 羥基萘 -1- 基 )-8- 氟 -6- 硝基 2-(( 四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 )- 喹唑啉 -4- 基 )-N,N- 二甲基 -5,6,7,8- 四氫 -4H- 吡唑并 [1,5-a][1,4] 二氮雜環庚烷 -2- 甲醯胺 LCMS (ESI): [M+H] + = 674.3; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.67 (s, 1H), 7.87 (br dd, J = 5.8, 8.9 Hz, 1H), 7.37-7.18 (m, 2H), 7.01 (s, 1H), 5.42-5.22 (m, 1H), 4.66-4.58 (m, 1H), 4.41-4.25 (m, 3H), 4.07-3.86 (m, 4H), 3.37 (br d, J = 3.9 Hz, 1H), 3.26 (br s, 1H), 3.24-3.18 (m, 1H), 3.04 (br s, 1H), 2.44-2.35 (m, 2H), 2.31-2.11 (m, 3H), 2.08-1.94 (m, 3H), 1.92-1.72 (m, 6H). Example 153 : 3- Chloro -5-(7-(8- ethynyl- 7- fluoro -3- hydroxynaphthalen -1- yl )-8- fluoro -6- nitro- 2-(( tetrahydro -1H- pyrrolizine -7a(5H)-yl ) methoxy ) -quinazolin - 4- yl )-N,N -dimethyl -5,6,7,8- tetrahydro -4H- pyrazolo [1,5-a][1,4] diazocycloheptane -2- carboxamide
LCMS (ESI): [M+H] += 757.3; 1H NMR (400 MHz, CD 3OD) δ ppm 8.65 (s, 1H), 7.87 (dd, J= 5.8, 9.1 Hz, 1H), 7.36-7.26 (m, 2H), 7.00 (d, J= 2.4 Hz, 1H), 5.19 (s, 2H), 4.52-4.48 (m, 2H), 4.44-4.32 (m, 4H), 3.42 (s, 1H), 3.30-3.22 (m, 2H), 3.14 (d, J= 14.0 Hz, 6H), 2.91-2.82 (m, 2H), 2.54 (br d, J= 4.4 Hz, 2H), 2.17-2.08 (m, 2H), 1.98 (qt, J= 6.6, 13.6 Hz, 4H), 1.89-1.79 (m, 2H). 實施例 154 : 4-(7-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基 -2-(( 四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 ) 喹唑啉 -4- 基 )-1,4- 氧氮雜環庚烷 LCMS (ESI): [M+H] + = 757.3; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.65 (s, 1H), 7.87 (dd, J = 5.8, 9.1 Hz, 1H), 7.36-7.26 (m, 2H), 7.00 (d, J = 2.4 Hz, 1H), 5.19 (s, 2H), 4.52-4.48 (m, 2H), 4.44-4.32 (m, 4H), 3.42 (s, 1H), 3.26-3.26 (m, 2H), 3.14 (d, J = 14.0 Hz, 6H), 2.91-2.82 (m, 2H), 2.54 (br d, J = 4.4 Hz, 2H), 2.17-2.08 (m, 2H), 1.98 (qt, J = 6.6, 13.6 Hz, 4H), 1.89-1.79 (m, 2H). Example 154 : 4-(7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -6- nitro -2-(( tetrahydro -1H- pyrrolizine -7a(5H) -yl ) methoxy ) quinazolin -4- yl )-1,4- oxazolidine cycloheptane
第一步:在-40 oC下,向7-溴-2,4-二氯-8-氟-6-硝基喹唑啉(500 mg,1.47 mmol)和1,4-氧氮雜環庚烷鹽酸鹽(141.3 mg,1.03 mmol)的二氯甲烷(10 mL)溶液中,加入二異丙基乙基胺(1.5 mL,8.43 mmol)。將混合物在-40 oC和氮氣保護下攪拌1小時。加入水(20 mL),使用二氯甲烷(20 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-25%梯度的乙酸乙酯/石油醚),得到黃色固體化合物4-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-1,4-氧氮雜環庚烷(330 mg,0.81 mmol,產率55%)。LCMS (ESI): [M+H] += 407.1. Step 1 : Add diisopropylethylamine (1.5 mL, 8.43 mmol ) to a solution of 7-bromo-2,4-dichloro-8-fluoro-6-nitroquinazoline (500 mg, 1.47 mmol) and 1,4-oxazolidinone hydrochloride (141.3 mg, 1.03 mmol) in dichloromethane (10 mL) at -40 o C. Stir the mixture at -40 o C for 1 hour under nitrogen protection. Add water (20 mL), extract with dichloromethane (20 mL * 3), and dry the combined organic phases with anhydrous sodium sulfate, filter, and spin dry. The residue was purified by flash column chromatography (silica gel, 0-25% gradient of ethyl acetate/petroleum ether) to obtain a yellow solid compound 4-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-1,4-oxazolidinone (330 mg, 0.81 mmol, yield 55%). LCMS (ESI): [M+H] + = 407.1.
第二步:向4-(7-溴-2-氯-8-氟-6-硝基喹唑啉-4-基)-1,4-氧氮雜環庚烷(330 mg,0.81 mmol)的三氟乙醇(3.3 mL)溶液中,加入二異丙基乙基胺(568 uL,3.25 mmol)。將混合物在70 oC和氮氣保護下攪拌3小時,旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-30%梯度的乙酸乙酯/石油醚),得到黃色固體化合物4-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-1,4-氧氮雜環庚烷(340 mg,0.73 mmol,產率89%)。LCMS (ESI): [M+H] += 468.9. Step 2 : Add diisopropylethylamine (568 uL, 3.25 mmol) to a solution of 4-(7-bromo-2-chloro-8-fluoro-6-nitroquinazolin-4-yl)-1,4-oxazacycloheptane (330 mg, 0.81 mmol) in trifluoroethanol (3.3 mL). Stir the mixture at 70 ° C for 3 hours under nitrogen protection and rotate to dryness. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate/petroleum ether) to obtain a yellow solid compound 4-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-1,4-oxazacycloheptane (340 mg, 0.73 mmol, yield 89%). LCMS (ESI): [M+H] + = 468.9.
第三步:在手套箱中,向4-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-1,4-氧氮雜環庚烷(120 mg,0.26 mmol)和 ((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)萘-1-基)乙炔基)三異丙基矽烷(151 mg,0.33 mmol)的甲苯(4.8 mL)和水(1.2 mL)溶液中,加入碳酸銫(250 mg,0.77 mmol)和甲磺酸[正丁基二(1-金剛烷基)膦](2-胺基-1,1'-聯苯-2-基)鈀(II)(37.3 mg,0.05 mmol)。將混合物在100 oC和氮氣保護下攪拌16小時。加入水(5 mL)稀釋,使用乙酸乙酯(10 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,旋轉乾燥。殘留物用快速管柱層析純化(矽膠,0-15%梯度的四氫呋喃/石油醚),得到棕色固體化合物4-(8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-1,4-氧氮雜環庚烷(150 mg,0.21 mmol,產率82%)。LCMS (ESI): [M+H] += 715.3. Step 3 : In a glove box, cesium carbonate (250 mg, 0.77 mmol) and [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (37.3 mL) were added to a solution of 4-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-1,4-oxazinecycloheptane (120 mg, 0.26 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (151 mg, 0.33 mmol) in toluene (4.8 mL) and water (1.2 mL). The mixture was stirred at 100 ° C under nitrogen for 16 hours. Water (5 mL) was added for dilution, and ethyl acetate (10 mL * 3) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of tetrahydrofuran/petroleum ether) to obtain a brown solid compound 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-1,4-oxazacycloheptane (150 mg, 0.21 mmol, yield 82%). LCMS (ESI): [M+H] + = 715.3.
第四步:向4-(8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-1,4-氧氮雜環庚烷(140 mg,0.20 mmol)和 (四氫-1H-吡咯嗪-7a(5H)-基)甲醇(55.0 mg,0.39 mmol)的四氫呋喃(2.8 mL)溶液中,加入叔丁醇鈉(37.6 mg,0.39 mmol)。將混合物在25 oC和氮氣保護下攪拌6小時。反應液冷卻至0 oC後加入水(3 mL)稀釋,使用乙酸乙酯(3 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,旋轉乾燥,得到粗產物化合物4-(8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-1,4-氧氮雜環庚烷(240 mg),其為棕色油狀液體。LCMS (ESI): [M+H] += 756.4. Step 4 : To a solution of 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-1,4-oxazolidine cycloheptane (140 mg, 0.20 mmol) and (tetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (55.0 mg, 0.39 mmol) in tetrahydrofuran (2.8 mL) was added sodium tert-butoxide (37.6 mg, 0.39 mmol). The mixture was stirred at 25 ° C under nitrogen for 6 hours. The reaction mixture was cooled to 0 ° C and diluted with water (3 mL). The mixture was extracted with ethyl acetate (3 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried to obtain the crude product 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazolidine cycloheptane (240 mg) as a brown oily liquid. LCMS (ESI): [M+H] + = 756.4.
第五步:向4-(8-氟-7-(7-氟-8-((三異丙基甲矽烷基)乙炔基)萘-1-基)-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-1,4-氧氮雜環庚烷(230.0 mg,0.20 mmol)的二甲基甲醯胺(4.6 mL)溶液中加入氟化銫(192 mg,3.04 mmol)。將該溶液在25 oC攪拌1小時。加入水(15 mL),使用乙酸乙酯(15 mL * 3)萃取,合併的有機相用無水硫酸鈉乾燥,過濾,旋轉乾燥。殘餘物透過製備型HPLC純化,得到黃色固體化合物4-(7-(8-乙炔基-7-氟萘-1-基)-8-氟-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-1,4-氧氮雜環庚烷(55.0 mg,0.09 mmol,產率30%)。LCMS (ESI): [M+H] += 600.2。 1H NMR (400 MHz, DMSO- d 6) δ ppm 8.74 (s, 1H), 8.24 (dd, J= 6.2, 9.2 Hz, 1H), 8.17 (d, J= 7.3 Hz, 1H), 7.70-7.56 (m, 2H), 7.50 (d, J= 6.8 Hz, 1H), 4.24-4.15 (m, 3H), 4.14-4.09 (m, 2H), 4.07 (s, 2H), 3.97 (br t, J= 4.6 Hz, 2H), 3.86-3.72 (m, 2H), 2.98-2.90 (m, 2H), 2.60-2.53 (m, 2H), 2.14 (br d, J= 4.0 Hz, 2H), 1.95-1.85 (m, 2H), 1.85-1.69 (m, 4H), 1.58 (td, J= 7.4, 12.0 Hz, 2H). 實施例 155 : 5-(7-(8- 乙炔基 -7- 氟萘 -1- 基 )-8- 氟 -6- 硝基 -2-(( 四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 ) 喹唑啉 -4- 基 )-N,N- 二甲基 -5,6,7,8- 四氫 -4H- 吡唑并 [1,5-a][1,4] 二氮雜環庚烷 -2- 甲醯胺 Step 5 : To a solution of 4-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazinecycloheptane (230.0 mg, 0.20 mmol) in dimethylformamide (4.6 mL) was added cesium fluoride (192 mg, 3.04 mmol). The solution was stirred at 25 ° C for 1 hour. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary dried. The residue was purified by preparative HPLC to give a yellow solid compound 4-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazolidine cycloheptane (55.0 mg, 0.09 mmol, yield 30%). LCMS (ESI): [M+H] + = 600.2. 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.74 (s, 1H), 8.24 (dd, J = 6.2, 9.2 Hz, 1H), 8.17 (d, J = 7.3 Hz, 1H), 7.70-7.56 (m, 2H), 7.50 (d, J = 6.8 Hz, 1H), 4.24-4.15 (m, 3H), 4.14-4.09 (m, 2H), 4.07 (s, 2H), 3.97 (br t, J = 4.6 Hz, 2H), 3.86-3.72 (m, 2H), 2.98-2.90 (m, 2H), 2.60-2.53 (m, 2H), 2.14 (br d, J = 4.0 Hz, 2H), 1.95-1.85 (m, 2H), 1.85-1.69 (m, 4H), 1.58 (td, J = 7.4, 12.0 Hz, 2H). Example 155 : 5-(7-(8- ethynyl- 7- fluoronaphthalen -1- yl )-8- fluoro -6- nitro -2-(( tetrahydro -1H- pyrrolizine -7a(5H)-yl ) methoxy ) quinazolin - 4- yl )-N,N -dimethyl -5,6,7,8- tetrahydro -4H- pyrazolo [1,5-a][1,4] diazocycloheptane -2- carboxamide
實施例 155參照的合成途徑製備得到的:LCMS (ESI): [M+H] += 707.5; 1H NMR (400 MHz, CD 3OD) δ ppm 8.80 (s, 1H), 8.16-8.01 (m, 2H), 7.59 (t, J= 7.7 Hz, 1H), 7.47-7.37 (m, 2H), 6.88 (s, 1H), 5.32-5.16 (m, 2H), 4.60 (br d, J= 4.4 Hz, 2H), 4.48-4.33 (m, 2H), 4.32-4.24 (m, 2H), 3.48 (s, 1H), 3.35 (s, 3H), 3.15-3.07 (m, 5H), 2.80-2.68 (m, 2H), 2.45 (br d, J= 5.1 Hz, 2H), 2.10-2.02 (m, 2H), 1.98-1.85 (m, 4H), 1.81-1.71 (m, 2H). 實施例 156 : (3R)-1-(7-(7,8- 二氟萘 -1- 基 )-8- 氟 -6- 硝基 -2-(( 四氫 -1H- 吡咯嗪 -7a(5H)- 基 ) 甲氧基 ) 喹唑啉 -4- 基 )-3- 甲基呱啶 -3- 醇 Example 155 prepared by the synthetic route: LCMS (ESI): [M+H] + = 707.5; 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.80 (s, 1H), 8.16-8.01 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.47-7.37 (m, 2H), 6.88 (s, 1H), 5.32-5.16 (m, 2H), 4.60 (br d, J = 4.4 Hz, 2H), 4.48-4.33 (m, 2H), 4.32-4.24 (m, 2H), 3.48 (s, 1H), 3.35 (s, 3H), 3.15-3.07 (m, 5H), 2.80-2.68 (m, 2H), 2.45 (br d, J = 5.1 Hz, 2H), 2.10-2.02 (m, 2H), 1.98-1.85 (m, 4H), 1.81-1.71 (m, 2H). Example 156 : (3R)-1-(7-(7,8 -difluoronaphthalen -1- yl )-8- fluoro -6- nitro -2-(( tetrahydro -1H- pyrrolizin -7a(5H) -yl ) methoxy ) quinazolin -4- yl )-3- methylpiperidin -3- ol
第一步:把1-溴-2,3,4-三氟苯(10.0 g,47.40 mmol)和呋喃(20.4 mL,284.39 mmol)加入到甲苯(130 mL)中,冷卻至-15 oC,氮氣保護下,緩慢滴加正丁基鋰(2 M, 28.4 mL,56.8 mmol),將混合物在-15 oC攪拌30分鐘,然後升溫至25 oC並攪拌16小時。將反應混合物用水(100 mL)淬滅並過濾。濾液用乙酸乙酯(50 mL*3)萃取。合併的有機層用無水硫酸鈉乾燥,過濾並減壓濃縮。殘餘物透過快速管柱層析(C18,0-65%梯度水/乙腈)純化得到棕色油狀化合物5,6-二氟-1,4-二氫-1,4-環氧萘(2.00 g,11.10 mmol,產率23%)。 1H NMR (400 MHz, CDCl 3) δ ppm 7.12-7.03 (m, 2H), 6.98-6.90 (m, 1H), 6.84-6.73 (m, 1H), 5.99 (s, 1H), 5.73 (s, 1H). Step 1 : Add 1-bromo-2,3,4-trifluorobenzene (10.0 g, 47.40 mmol) and furan (20.4 mL, 284.39 mmol) to toluene (130 mL), cool to -15 ° C, slowly add n-butyl lithium (2 M, 28.4 mL, 56.8 mmol) under nitrogen protection, stir the mixture at -15 ° C for 30 minutes, then heat to 25 ° C and stir for 16 hours. Quench the reaction mixture with water (100 mL) and filter. Extract the filtrate with ethyl acetate (50 mL*3). Dry the combined organic layers with anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue was purified by flash column chromatography (C18, 0-65% gradient water/acetonitrile) to obtain a brown oily compound 5,6-difluoro-1,4-dihydro-1,4-epoxynaphthalene (2.00 g, 11.10 mmol, yield 23%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.12-7.03 (m, 2H), 6.98-6.90 (m, 1H), 6.84-6.73 (m, 1H), 5.99 (s, 1H), 5.73 (s, 1H).
第二步:向5,6-二氟-1,4-二氫-1,4-環氧萘(1.80 g,9.99 mmol)的乙醇(10.8 mL)溶液中緩慢加入濃鹽酸(10.2 mL,122 mmol),將混合物在80 oC攪拌16小時。真空去除溶劑,在殘渣中加入飽和碳酸氫鈉(直到pH > 7),加入乙酸乙酯(5 mL*3)進行萃取,合併的有機層用無水硫酸鎂乾燥,過濾並減壓濃縮得到黑色固體化合物7,8-二氟萘-1-醇(1.70 g,9.39 mmol,產率94%)。 1H NMR (400 MHz, CDCl 3) δ ppm 7.64-7.56 (m, 1H), 7.42-7.35 (m, 2H), 7.02 (br d, J= 6.2 Hz, 1H), 6.76-6.54 (m, 1H) Step 2 : Slowly add concentrated hydrochloric acid (10.2 mL, 122 mmol) to a solution of 5,6-difluoro-1,4-dihydro-1,4-epoxynaphthalene (1.80 g, 9.99 mmol) in ethanol (10.8 mL), and stir the mixture at 80 ° C for 16 hours. Remove the solvent in vacuo, add saturated sodium bicarbonate to the residue (until pH > 7), add ethyl acetate (5 mL*3) for extraction, and dry the combined organic layers with anhydrous magnesium sulfate, filter and concentrate under reduced pressure to obtain a black solid compound 7,8-difluoronaphthalene-1-ol (1.70 g, 9.39 mmol, yield 94%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.64-7.56 (m, 1H), 7.42-7.35 (m, 2H), 7.02 (br d, J = 6.2 Hz, 1H), 6.76-6.54 (m, 1H)
第三步:將7,8-二氟萘-1-醇(500 mg,2.78 mmol)和二異丙基乙胺(1.38 mL,8.33 mmol)加入到二氯甲烷(5 mL)中,然後在-40 oC,緩慢滴加三氟甲磺酸酐(0.70 mL,4.16 mmol),將混合物在-40 oC攪拌30分鐘。真空去除溶劑,殘餘物透過快速管柱層析(矽膠,0-5%梯度乙酸乙酯/石油醚)純化得到黃色油狀化合物7,8-二氟萘-1-基三氟甲磺酸酯(610 mg,1.95 mmol,產率70%)。LCMS (ESI): [M+H] += 313.0. Step 3 : 7,8-difluoronaphthalene-1-ol (500 mg, 2.78 mmol) and diisopropylethylamine (1.38 mL, 8.33 mmol) were added to dichloromethane (5 mL), and then trifluoromethanesulfonic anhydride (0.70 mL, 4.16 mmol) was slowly added dropwise at -40 ° C. The mixture was stirred at -40 ° C for 30 minutes. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to obtain a yellow oily compound 7,8-difluoronaphthalene-1-yl trifluoromethanesulfonate (610 mg, 1.95 mmol, yield 70%). LCMS (ESI): [M+H] + = 313.0.
第四步:氮氣保護下,將7,8-二氟萘-1-基三氟甲磺酸酯(500 mg,1.60 mmol),雙聯嚬哪醇硼酸酯(813 mg,3.20 mmol)和醋酸鉀(658 mg,8.01 mmol)加入到N,N-二甲基甲醯胺(5 mL)中,然後加入[1,1-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷(117 mg,0.16 mmol),將混合物在80 oC攪拌16小時。反應液冷卻至室溫,減壓濃縮並透過快速管柱層析(矽膠,0-5%梯度乙酸乙酯/石油醚)純化得到白色固體化合物2-(7,8-二氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(400 mg,1.38 mmol,產率86%)。LCMS (ESI): [M+H] += 291.1。 1H NMR (400 MHz, CDCl 3) δ ppm 7.87 (d, J= 7.9 Hz, 1H), 7.74 (d, J= 6.8 Hz, 1H), 7.61 (ddd, J= 1.6, 4.8, 9.0 Hz, 1H), 7.49 (dd, J= 6.9, 8.2 Hz, 1H), 7.40 - 7.30 (m, 1H), 1.47 (s, 12H). Step 4 : Under nitrogen protection, 7,8-difluoronaphthalen-1-yl trifluoromethanesulfonate (500 mg, 1.60 mmol), bis(xanthocyanol) borate (813 mg, 3.20 mmol) and potassium acetate (658 mg, 8.01 mmol) were added to N,N-dimethylformamide (5 mL), and then [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium (117 mg, 0.16 mmol) was added, and the mixture was stirred at 80 ° C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure and purified by flash column chromatography (silica gel, 0-5% gradient ethyl acetate/petroleum ether) to obtain a white solid compound 2-(7,8-difluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (400 mg, 1.38 mmol, yield 86%). LCMS (ESI): [M+H] + = 291.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.87 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.61 (ddd, J = 1.6, 4.8, 9.0 Hz, 1H), 7.49 (dd, J = 6.9, 8.2 Hz, 1H), 7.40 - 7.30 (m, 1H), 1.47 (s, 12H).
第五步:將2-(7,8-二氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(135 mg,0.46 mmol)和 (R)-1-(7-溴-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(150 mg,0.31 mmol)加入到二氧六環(3 mL)中,在氮氣保護下加入1.3M的碳酸鈉水溶液(0.72 mL,0.92 mmol)和四(三苯基膦)鈀(35.9 mg,0.03 mmol),將混合物在100 oC攪拌16小時。反應液冷卻至室溫,減壓濃縮並透過快速管柱層析(矽膠,0-30%梯度四氫呋喃/石油醚)純化得到棕色固體化合物 (3R)-1-(7-(7,8-二氟萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(150 mg,0.26 mmol,產率85%)。LCMS (ESI): [M+H] += 567.1. Step 5 : 2-(7,8-Difluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (135 mg, 0.46 mmol) and (R)-1-(7-bromo-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (150 mg, 0.31 mmol) were added to dioxane (3 mL). Under nitrogen protection, 1.3 M aqueous sodium carbonate solution (0.72 mL, 0.92 mmol) and tetrakis(triphenylphosphine)palladium (35.9 mg, 0.03 mmol) were added. The mixture was stirred at 100 ° C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure and purified by flash column chromatography (silica gel, 0-30% gradient tetrahydrofuran/petroleum ether) to obtain a brown solid compound (3R)-1-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (150 mg, 0.26 mmol, yield 85%). LCMS (ESI): [M+H] + = 567.1.
第六步:把 (3R)-1-(7-(7,8-二氟萘-1-基)-8-氟-6-硝基-2-(2,2,2-三氟乙氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(140 mg,0.25 mmol)和 (四氫-1H-吡咯啉-7a(5H)-基)甲醇(69.8 mg,0.49 mmol)加入到四氫呋喃(2.80 mL)溶液中,然後加入叔丁醇鈉(47.5 mg,0.49 mmol),在25 oC攪拌6小時。反應液加入水(1 mL),用乙酸乙酯(1 mL * 3)萃取,有機相用無水硫酸鎂乾燥,過濾並減壓濃縮,粗產物用製備型HPLC純化,得到黃色固體純化化合物 (3R)-1-(7-(7,8-二氟萘-1-基)-8-氟-6-硝基-2-((四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-甲基呱啶-3-醇(甲酸鹽,21.3 mg,0.25 mmol,產率14%)。LCMS (ESI): [M+H] += 608.2。 1H NMR (400 MHz, CD 3OD) δ ppm 9.05-8.92 (m, 1H), 8.56 (s, 1H), 8.09 (br d, J= 8.4 Hz, 1H), 7.94-7.85 (m, 1H), 7.67-7.59 (m, 1H), 7.59-7.49 (m, 1H), 7.46-7.40 (m, 1H), 4.59-4.49 (m, 3H), 4.30 (br dd, J= 5.4, 13.3 Hz, 1H), 3.63 (dd, J= 13.4, 16.3 Hz, 1H), 3.51-3.40 (m, 3H), 3.14-3.02 (m, 2H), 2.24 (br dd, J= 6.5, 12.2 Hz, 3H), 2.15-2.04 (m, 4H), 2.03-1.95 (m, 2H), 1.93-1.77 (m, 3H), 1.33 (d, J= 8.6 Hz, 3H). 效果實施例 1 : AlphaLISA 化合物篩選實驗 Step 6 : Add (3R)-1-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (140 mg, 0.25 mmol) and (tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (69.8 mg, 0.49 mmol) to a tetrahydrofuran (2.80 mL) solution, then add sodium tert-butoxide (47.5 mg, 0.49 mmol) and stir at 25 ° C for 6 hours. Water (1 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (1 mL * 3). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain a yellow solid purified compound (3R)-1-(7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-6-nitro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (formate, 21.3 mg, 0.25 mmol, yield 14%). LCMS (ESI): [M+H] + = 608.2. 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.05-8.92 (m, 1H), 8.56 (s, 1H), 8.09 (br d, J = 8.4 Hz, 1H), 7.94-7.85 (m, 1H), 7.67-7.59 (m, 1H), 7.59-7.49 (m, 1H), 7.46-7.40 (m, 1H), 4.59-4.49 (m, 3H), 4.30 (br dd, J = 5.4, 13.3 Hz, 1H), 3.63 (dd, J = 13.4, 16.3 Hz, 1H), 3.51-3.40 (m, 3H), 3.14-3.02 (m, 2H), 2.24 (br dd, J = 6.5, 12.2 Hz, 3H), 2.15-2.04 (m, 4H), 2.03-1.95 (m, 2H), 1.93-1.77 (m, 3H), 1.33 (d, J = 8.6 Hz, 3H). Example 1 : AlphaLISA compound screening experiment
實驗方法:Experimental methods:
1. 配製實驗緩衝液(assay buffer): 緩衝液1的成分及終濃度: 25 mM HEPES pH7.5, 10 mM MgCl2, 0.01% Triton X-100 緩衝液2的成分及終濃度:25 mM HEPES pH7.5, 10 mM MgCl2, 0.01% Triton X-100, 1 mM DTT 1. Prepare the assay buffer: Ingredients and final concentration of buffer 1: 25 mM HEPES pH7.5, 10 mM MgCl2, 0.01% Triton X-100 Ingredients and final concentration of buffer 2: 25 mM HEPES pH7.5, 10 mM MgCl2, 0.01% Triton X-100, 1 mM DTT
2. 實驗設計及化合物準備: 1> 用ECHO555自動化打板儀器準備化合物,測試濃度:化合物最高檢測濃度為10 uM或1 uM,3倍稀釋,10個濃度,每個濃度2個重複,0.5% DMSO。 2> 高訊號對照組(High control):30個重複,0.5% DMSO,有KRAS 蛋白參與反應,作為0%抑制 3> 低訊號對照組(Low control):30個重複,0.5% DMSO,無KRAS 蛋白參與反應,作為100%抑制 2. Experimental design and compound preparation: 1> Prepare compounds using ECHO555 automated plate reader, test concentration: the highest concentration of the compound is 10 uM or 1 uM, 3-fold dilution, 10 concentrations, 2 replicates for each concentration, 0.5% DMSO. 2> High signal control group (High control): 30 replicates, 0.5% DMSO, KRAS protein participates in the reaction, as 0% inhibition 3> Low signal control group (Low control): 30 replicates, 0.5% DMSO, no KRAS protein participates in the reaction, as 100% inhibition
3. 實驗步驟:3. Experimental steps:
a. KRAS-GDP 蛋白實驗步驟1> 向測試板高訊號對照組及化合物測試孔每孔加5 μl用緩衝液1配好的KRAS溶液;向低訊號對照組每孔加5 μl緩衝液1,KRAS 反應終濃度為(最初用40 nM,優化後用5 nM)5 nM,室溫培育1 h。 2> 向測試板每孔加5 μl用緩衝液2配好的SOS1和GTP混合溶液,反應終濃度分別為(最初用250 nM 和625 μM)50 nM和125 μM,室溫培育1 h。 3> 向測試板每孔加5 μl用緩衝液2配好的cRAF和AlphaLISA Nickel Acceptor beads混合溶液,反應終濃度分別為50 nM和20 μg/ml,室溫培育1 h。 4> 向測試板每孔加5 μl用緩衝液2配好的AlphaScreen GSH Donor beads溶液,反應終濃度為20 μg/ml,室溫培育1 h。 5> 用EnVision酵素標示讀取儀讀取測試板訊號值,激發光波長680 nm,發射光波長615 nm。 a. KRAS-GDP protein experimental steps 1> Add 5 μl of KRAS solution prepared with buffer 1 to each well of the high signal control group and compound test wells of the test plate; add 5 μl of buffer 1 to each well of the low signal control group. The final concentration of KRAS reaction is (40 nM initially, 5 nM after optimization) 5 nM, and incubate at room temperature for 1 hour. 2> Add 5 μl of SOS1 and GTP mixed solution prepared with buffer 2 to each well of the test plate. The final concentrations of the reaction are (250 nM and 625 μM initially) 50 nM and 125 μM, respectively, and incubate at room temperature for 1 hour. 3> Add 5 μl of cRAF and AlphaLISA Nickel Acceptor beads mixed solution prepared in buffer 2 to each well of the test plate, the final reaction concentration is 50 nM and 20 μg/ml, respectively, and incubate at room temperature for 1 hour. 4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared in buffer 2 to each well of the test plate, the final reaction concentration is 20 μg/ml, and incubate at room temperature for 1 hour. 5> Read the signal value of the test plate using the EnVision enzyme label reader, the excitation wavelength is 680 nm, and the emission wavelength is 615 nm.
b. KRAS-GTP 蛋白實驗步驟1> 將配好的蛋白溶液與SOS1-GTP混合溶液(濃度與GDP蛋白一致)按體積1:1混合後,室溫預培育1 h。 2> 向測試板高訊號對照組及化合物測試孔每孔加10 μl步驟1混合溶液;向低訊號對照組每孔加5 μl緩衝液1與5 μl SOS1和GTP混合溶液,室溫培育1 h。 3> 向測試板每孔加5 μl用緩衝液2配好的cRAF和AlphaLISA Nickel Acceptor beads混合溶液,反應終濃度分別為50 nM和20 μg/ml,室溫培育1 h。 4> 向測試板每孔加5 μl用緩衝液2配好的AlphaScreen GSH Donor beads溶液,反應終濃度為20 μg/ml,室溫培育1 h。 5> 用EnVision酵素標示讀取儀讀取測試板訊號值,激發光波長680 nm,發射光波長615 nm。 b. KRAS-GTP protein experimental steps 1> Mix the prepared protein solution with the SOS1-GTP mixed solution (the concentration is the same as that of GDP protein) at a volume ratio of 1:1, and pre-incubate at room temperature for 1 hour. 2> Add 10 μl of the mixed solution in step 1 to each well of the high signal control group and compound test wells of the test plate; add 5 μl of buffer 1 and 5 μl of the mixed solution of SOS1 and GTP to each well of the low signal control group, and incubate at room temperature for 1 hour. 3> Add 5 μl of the mixed solution of cRAF and AlphaLISA Nickel Acceptor beads prepared in buffer 2 to each well of the test plate, and the final reaction concentrations are 50 nM and 20 μg/ml, respectively, and incubate at room temperature for 1 hour. 4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared with buffer 2 to each well of the test plate. The final concentration of the reaction is 20 μg/ml. Incubate at room temperature for 1 hour. 5> Read the signal value of the test plate using the EnVision enzyme label reader. The excitation wavelength is 680 nm and the emission wavelength is 615 nm.
c. KRAS-GCP 蛋白實驗步驟1> 向測試板高訊號對照組及化合物測試孔每孔加5 μl用緩衝液1配好的KRAS溶液;向低訊號對照組每孔加5 μl緩衝液1,KRAS 反應終濃度為5 nM,室溫培育1 h。 2> 向測試板每孔加5 μl緩衝液2,室溫培育1 h。 3> 向測試板每孔加5 μl用緩衝液2配好的cRAF和AlphaLISA Nickel Acceptor beads混合溶液,反應終濃度分別為50 nM和20 μg/ml,室溫培育1 h。 4> 向測試板每孔加5 μl用緩衝液2配好的AlphaScreen GSH Donor beads溶液,反應終濃度為20 μg/ml,室溫培育1 h。 5> 用EnVision酵素標示讀取儀讀取測試板訊號值,激發光波長680 nm,發射光波長615 nm。 c. KRAS-GCP protein experimental steps 1> Add 5 μl of KRAS solution prepared in buffer 1 to each well of the high signal control group and compound test wells of the test plate; add 5 μl of buffer 1 to each well of the low signal control group, the final concentration of KRAS reaction is 5 nM, and incubate at room temperature for 1 hour. 2> Add 5 μl of buffer 2 to each well of the test plate, and incubate at room temperature for 1 hour. 3> Add 5 μl of cRAF and AlphaLISA Nickel Acceptor beads mixed solution prepared in buffer 2 to each well of the test plate, the final concentration of the reaction is 50 nM and 20 μg/ml, respectively, and incubate at room temperature for 1 hour. 4> Add 5 μl of AlphaScreen GSH Donor beads solution prepared with buffer 2 to each well of the test plate. The final reaction concentration is 20 μg/ml. Incubate at room temperature for 1 hour. 5> Read the signal value of the test plate using the EnVision enzyme label reader. The excitation wavelength is 680 nm and the emission wavelength is 615 nm.
4. 實驗資料分析:
1> 根據原始資料分別計算出高訊號對照和低訊號對照的平均值High control average和Low control average。
2> 計算化合物樣品孔(Sample signal)的抑制率,計算公式如下:
(High control average-Sample signal/High control average-Low control average)*100%
3> 利用Graphpad Prism軟體中四參數擬合模式(log(inhibitor) vs. response -- Variable slope (four parameters))對化合物及其不同濃度下對實驗訊號的抑制率做濃度回應曲線擬合,計算化合物的IC50值。
實驗材料:
實驗結果:本發明化合物對KRAS G12D的GDP,GTP,GCP蛋白的抑制效果見表1。
表1
AGS_ERK蛋白磷酸化檢測AGS_ERK protein phosphorylation detection
第一天:將AGS細胞接種於384孔細胞培養盤中,於37℃,5%二氧化碳細胞培養箱中過夜培養。Day 1: AGS cells were seeded into 384-well cell culture plates and cultured overnight in a 37°C, 5% CO2 cell culture incubator.
第二天:用Echo550將化合物加入板中,繼續在37℃,5%二氧化碳細胞培養箱中培養3小時。最後細胞培養盤經過多聚甲醛固定、甲醇滲透、封閉液封閉後,加入一抗混合液(rabbit anti pERK, mouse anti GAPDH),於4℃培育過夜。The next day: Add the compound to the plate using Echo550 and continue to culture at 37°C in a 5% carbon dioxide cell culture incubator for 3 hours. Finally, the cell culture plate was fixed with paraformaldehyde, permeabilized with methanol, and sealed with sealing solution, and then the primary antibody mixture (rabbit anti pERK, mouse anti GAPDH) was added and incubated at 4°C overnight.
第三天:棄掉一抗,加入二抗混合液(goat anti rabbit 800CW , goat anti mouse 680RD),於室溫避光培育。最後用PBST清洗3次後,將細胞培養盤倒扣離心1分鐘。用Odyssey CLx讀取螢光訊號值。Day 3: Discard the primary antibody and add the secondary antibody mixture (goat anti rabbit 800CW, goat anti mouse 680RD) and incubate at room temperature in the dark. Finally, wash with PBST three times and centrifuge the cell culture plate upside down for 1 minute. Read the fluorescence signal value with Odyssey CLx.
根據以下公式計算ERK磷酸化: 相對表達量:(化合物的螢光訊號比值 – 陽性對照平均值)/ (陰性對照平均值 - 陽性對照平均值) 陰性對照: DMSO 陽性對照: 10 μM Reference ERK phosphorylation was calculated according to the following formula: Relative expression: (fluorescence signal ratio of compound – average value of positive control)/ (average value of negative control – average value of positive control) Negative control: DMSO Positive control: 10 μM Reference
XLFit 5.0按參數公式擬合計算IC50值: Y = Bottom + ( Top – Bottom ) / ( 1 + 10 ^ ( ( Log IC50 – X ) × HillSlope ) ) X: 化合物濃度log值 Y : 複孔間p-ERK相對表達量的平均值 XLFit 5.0 calculates the IC50 value according to the parameter formula: Y = Bottom + ( Top – Bottom ) / ( 1 + 10 ^ ( ( Log IC50 – X ) × HillSlope ) ) X: log value of compound concentration Y: average relative expression of p-ERK between duplicate wells
本發明化合物對AGS 和AsPC-1細胞的pERK的抑制效果見表2。
表2
AGSAGS 、, AsPC-1AsPC-1 細胞的Cellular 3D3D 增殖實驗Proliferation experiment
利用納升移液系統(LABCYTE,P-0200)將稀釋好的待測化合物加入384孔低吸附細胞培養盤中,舖入細胞後,將培養盤放置於37℃,5%CO 2恆溫培養箱。化合物與細胞共培育5天後,加入CellTiter-Glo® 3D試劑,用Envision多功能酵素標示讀取儀讀取發光值( 光訊號和系統中ATP量成正比,而ATP的含量直接特徵鑑定系統中的活細胞數)。最後使用XLFIT軟體用非線性擬合公式得到化合物的IC50(半數抑制濃度)。 The diluted test compound was added to a 384-well low-adhesion cell culture plate using a nanoliter pipetting system (LABCYTE, P-0200). After the cells were placed, the culture plate was placed in a 37°C, 5% CO 2 constant temperature incubator. After the compound and cells were co-cultured for 5 days, CellTiter-Glo® 3D reagent was added and the luminescence value was read using an Envision multifunctional enzyme labeled reader (the light signal is proportional to the amount of ATP in the system, and the ATP content directly characterizes the number of live cells in the identification system). Finally, the IC50 (half-maximal inhibitory concentration) of the compound was obtained using the nonlinear fitting formula using the XLFIT software.
Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)× HillSlope)) X : 化合物濃度log值 Y : 抑制率(%) 抑制率(%)=100× (陰性對照平均值-化合物讀值)/ (陰性對照平均值-陽性對照平均值) 陰性對照: DMSO 陽性對照: Medium only Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)× HillSlope)) X: log value of compound concentration Y: inhibition rate (%) Inhibition rate (%)=100× (negative control average value-compound reading)/ (negative control average value-positive control average value) Negative control: DMSO Positive control: Medium only
本發明化合物對AGS 和AsPC-1細胞的3D增殖抑制效果見表3。
表3
實驗結論:本發明化合物比已知化合物具有更優活性。 實驗例 4. CD-I 小鼠口服及靜脈注射受試化合物的藥代動力學研究 Experimental conclusion: The compounds of the present invention have better activity than known compounds. Experimental Example 4. Pharmacokinetic study of the test compounds in CD-I mice after oral administration and intravenous injection
實驗目的:測試CD-I小鼠口服及靜脈注射化合物的體內藥代動力學 Objective: To test the pharmacokinetics of the compound in CD-I mice after oral and intravenous administration
實驗步驟:受試化合物與5% DMSO/40% PEG400/55% Water水溶液混合,渦旋並超音波,製備得到0.6 mg/mL澄清溶液(靜脈)或3 mg/mL澄清溶液(口服),微孔濾膜過濾後備用。選取6至8周齡的雄性CD小鼠,靜脈注射給予候選化合物溶液,劑量約為3mg/kg。口服給予候選化合物溶液,劑量約為60 mg/kg和100mpk。收集一定時間的全血,製備得到血漿,以LC-MSMS方法分析藥物濃度,並用WinNonlin (Phoenix
TM, version 8.3)軟體計算藥代參數。
表 5 :靜脈(IV) PK數據
實驗結論:本發明化合物具有良好的口服生物利用度。 Experimental conclusion: The compound of the present invention has good oral bioavailability.
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US20190144444A1 (en) * | 2017-11-15 | 2019-05-16 | Mirati Therapeutics, Inc. | Kras g12c inhibitors |
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WO2023138583A1 (en) | 2023-07-27 |
TW202330536A (en) | 2023-08-01 |
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