TW202136271A - 呋喃并吲唑衍生物 - Google Patents
呋喃并吲唑衍生物 Download PDFInfo
- Publication number
- TW202136271A TW202136271A TW109144136A TW109144136A TW202136271A TW 202136271 A TW202136271 A TW 202136271A TW 109144136 A TW109144136 A TW 109144136A TW 109144136 A TW109144136 A TW 109144136A TW 202136271 A TW202136271 A TW 202136271A
- Authority
- TW
- Taiwan
- Prior art keywords
- methyl
- furo
- indazole
- dihydro
- carboxamide
- Prior art date
Links
- LHTSYIHIIZNLCQ-UHFFFAOYSA-N 1h-furo[2,3-g]indazole Chemical class O1C=CC2=C1C=CC1=C2NN=C1 LHTSYIHIIZNLCQ-UHFFFAOYSA-N 0.000 title abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 427
- 238000000034 method Methods 0.000 claims abstract description 167
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 354
- -1 C 1 -C 3 alkoxy Chemical group 0.000 claims description 337
- 239000000203 mixture Substances 0.000 claims description 184
- 150000003839 salts Chemical class 0.000 claims description 153
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 101
- 239000012453 solvate Substances 0.000 claims description 101
- 150000004677 hydrates Chemical class 0.000 claims description 96
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 95
- 229910052739 hydrogen Inorganic materials 0.000 claims description 91
- 239000001257 hydrogen Substances 0.000 claims description 91
- 150000001204 N-oxides Chemical class 0.000 claims description 86
- 125000001072 heteroaryl group Chemical group 0.000 claims description 86
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 78
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 60
- 229910052805 deuterium Inorganic materials 0.000 claims description 57
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 56
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 53
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 52
- 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 claims description 44
- 150000002148 esters Chemical class 0.000 claims description 39
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 32
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 31
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- 239000000460 chlorine Substances 0.000 claims description 26
- 150000001412 amines Chemical class 0.000 claims description 25
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
- 125000005842 heteroatom Chemical group 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 14
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 4
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 4
- 125000003003 spiro group Chemical group 0.000 claims description 4
- 150000003857 carboxamides Chemical class 0.000 claims description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 2
- ZWZKHJQCLZIUIT-UHFFFAOYSA-N 1h-indazole-7-carboxamide Chemical compound NC(=O)C1=CC=CC2=C1NN=C2 ZWZKHJQCLZIUIT-UHFFFAOYSA-N 0.000 claims 184
- WRSXUNSJGJUKHE-UHFFFAOYSA-N indazole Chemical compound C1=CC=C[C]2C=NN=C21 WRSXUNSJGJUKHE-UHFFFAOYSA-N 0.000 claims 42
- 150000002431 hydrogen Chemical class 0.000 claims 18
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims 18
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 3
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims 3
- VCNAJMCPTTWKOL-UHFFFAOYSA-N NC(C1=CC(C2=NN(CC3=NC=CC=C3)C=C2CC2)=C2O1)=O Chemical compound NC(C1=CC(C2=NN(CC3=NC=CC=C3)C=C2CC2)=C2O1)=O VCNAJMCPTTWKOL-UHFFFAOYSA-N 0.000 claims 2
- 241000009298 Trigla lyra Species 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- SXXUSAQZRJMFBK-HNNXBMFYSA-N 2-(cyclopropylmethyl)-8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound C1(CC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 SXXUSAQZRJMFBK-HNNXBMFYSA-N 0.000 claims 1
- MCEPGYGBZPFBMS-KRWDZBQOSA-N 2-[(1-ethylpiperidin-4-yl)methyl]-N-[[(2S)-oxolan-2-yl]methyl]-8-(trifluoromethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound C(C)N1CCC(CC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C(F)(F)F)C(=O)NC[C@H]1OCCC1 MCEPGYGBZPFBMS-KRWDZBQOSA-N 0.000 claims 1
- CJWJVNSYJZEAGR-IBGZPJMESA-N 2-[(2,6-dimethylpyridin-4-yl)methyl]-8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=NC(=CC(=C1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1)C CJWJVNSYJZEAGR-IBGZPJMESA-N 0.000 claims 1
- WYTSJIFMOIBFTC-INIZCTEOSA-N 2-[(3-chloro-5-ethoxypyridin-2-yl)methyl]-8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound ClC=1C(=NC=C(C=1)OCC)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 WYTSJIFMOIBFTC-INIZCTEOSA-N 0.000 claims 1
- YSBBFMBUBYHAGK-HNNXBMFYSA-N 2-[(3-chloro-5-fluoropyridin-2-yl)methyl]-8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound ClC=1C(=NC=C(C=1)F)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 YSBBFMBUBYHAGK-HNNXBMFYSA-N 0.000 claims 1
- KTQFMZUPDZIXSW-HNNXBMFYSA-N 2-[(3-chloropyridin-2-yl)methyl]-8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound ClC=1C(=NC=CC=1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 KTQFMZUPDZIXSW-HNNXBMFYSA-N 0.000 claims 1
- JQUGXSHYHUARNP-AWEZNQCLSA-N 2-[(3-fluorooxetan-3-yl)methyl]-8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound FC1(COC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 JQUGXSHYHUARNP-AWEZNQCLSA-N 0.000 claims 1
- VMHQCEOKVCGTRB-IBGZPJMESA-N 2-[(6-ethylpyridin-3-yl)methyl]-8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound C(C)C1=CC=C(C=N1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 VMHQCEOKVCGTRB-IBGZPJMESA-N 0.000 claims 1
- KKXFTMGCZSJSDI-INIZCTEOSA-N 2-[(6-methylpyridin-3-yl)methyl]-N-[[(2S)-oxolan-2-yl]methyl]-8-(trifluoromethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=CC=C(C=N1)CN1N=C2C3=C(CCC2=C1)OC(=C3C(F)(F)F)C(=O)NC[C@H]1OCCC1 KKXFTMGCZSJSDI-INIZCTEOSA-N 0.000 claims 1
- WVGCABADKDXJMC-HOTGVXAUSA-N 2-[[(2S)-1,4-dioxan-2-yl]methyl]-8-methyl-N-[[(2S)-oxolan-2-yl]methyl]spiro[5H-furo[2,3-g]indazole-4,1'-cyclopropane]-7-carboxamide Chemical compound O1[C@H](COCC1)CN1N=C2C3=C(CC4(C2=C1)CC4)OC(=C3C)C(=O)NC[C@H]1OCCC1 WVGCABADKDXJMC-HOTGVXAUSA-N 0.000 claims 1
- GGNZSOCEWIGQFA-KRWDZBQOSA-N 2-[[1-(2-methoxyacetyl)piperidin-4-yl]methyl]-N-[[(2S)-oxolan-2-yl]methyl]-8-(trifluoromethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound COCC(=O)N1CCC(CC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C(F)(F)F)C(=O)NC[C@H]1OCCC1 GGNZSOCEWIGQFA-KRWDZBQOSA-N 0.000 claims 1
- GZBBXERJZQVWEV-UHFFFAOYSA-N 8-cyclopropyl-N-(1,3-oxazol-2-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound C1(CC1)C1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NCC=1OC=CN=1 GZBBXERJZQVWEV-UHFFFAOYSA-N 0.000 claims 1
- MLGKLFRWALSIOH-SFHVURJKSA-N 8-cyclopropyl-N-[[(2S)-oxolan-2-yl]methyl]-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound C1(CC1)C1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NC[C@H]1OCCC1 MLGKLFRWALSIOH-SFHVURJKSA-N 0.000 claims 1
- BWUKOVBTVFFFMI-AWEZNQCLSA-N 8-methyl-2-(1,3-oxazol-2-ylmethyl)-N-[[(2S)-oxolan-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC=1OC=CN=1)C(=O)NC[C@H]1OCCC1 BWUKOVBTVFFFMI-AWEZNQCLSA-N 0.000 claims 1
- FCXOTBCJOQSMIR-HNNXBMFYSA-N 8-methyl-2-(oxetan-3-ylmethyl)-N-[[(2S)-oxolan-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1COC1)C(=O)NC[C@H]1OCCC1 FCXOTBCJOQSMIR-HNNXBMFYSA-N 0.000 claims 1
- DPAKSUHFZBGZJU-UHFFFAOYSA-N 8-methyl-2-(pyridin-2-ylmethyl)-N-(1H-1,2,4-triazol-5-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC2=C1C3=NN(C=C3CC2)CC4=CC=CC=N4)C(=O)NCC5=NC=NN5 DPAKSUHFZBGZJU-UHFFFAOYSA-N 0.000 claims 1
- XOIDMMGUVKWWOP-KRWDZBQOSA-N 8-methyl-2-[(3-methylpyridin-2-yl)methyl]-N-[[(2S)-oxolan-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1C)C(=O)NC[C@H]1OCCC1 XOIDMMGUVKWWOP-KRWDZBQOSA-N 0.000 claims 1
- XEOZJCHDFHTAFZ-UHFFFAOYSA-N 8-methyl-2-[(6-methylpyridin-2-yl)methyl]-N-(2-pyrrolidin-1-ylethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC(=CC=C1)C)C(=O)NCCN1CCCC1 XEOZJCHDFHTAFZ-UHFFFAOYSA-N 0.000 claims 1
- GIMWAJYLZQGRGL-IRXDYDNUSA-N 8-methyl-2-[[(2S)-4-methylmorpholin-2-yl]methyl]-N-[[(2S)-oxolan-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@@H]1CN(CCO1)C)C(=O)NC[C@H]1OCCC1 GIMWAJYLZQGRGL-IRXDYDNUSA-N 0.000 claims 1
- DLTSIZAZVZAIRB-GJZGRUSLSA-N 8-methyl-2-[[(2S)-oxetan-2-yl]methyl]-N-[[(2S)-oxolan-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@H]1OCC1)C(=O)NC[C@H]1OCCC1 DLTSIZAZVZAIRB-GJZGRUSLSA-N 0.000 claims 1
- QJWSWBRVNQLOIT-HOTGVXAUSA-N 8-methyl-N,2-bis[[(2S)-oxolan-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@H]1OCCC1)C(=O)NC[C@H]1OCCC1 QJWSWBRVNQLOIT-HOTGVXAUSA-N 0.000 claims 1
- XYTAKRQZEYYZPI-UHFFFAOYSA-N 8-methyl-N-(1,2,4-oxadiazol-3-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NCC1=NOC=N1 XYTAKRQZEYYZPI-UHFFFAOYSA-N 0.000 claims 1
- MRSCAYWVQGIFSS-UHFFFAOYSA-N 8-methyl-N-(1,2-oxazol-3-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NCC1=NOC=C1 MRSCAYWVQGIFSS-UHFFFAOYSA-N 0.000 claims 1
- UFTQAUHUOJNSFU-UHFFFAOYSA-N 8-methyl-N-(1,2-oxazol-4-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NCC=1C=NOC=1 UFTQAUHUOJNSFU-UHFFFAOYSA-N 0.000 claims 1
- AIVBRSWEEMHJMJ-UHFFFAOYSA-N 8-methyl-N-(1,3-oxazol-2-ylmethyl)-2-(pyridin-2-ylmethyl)spiro[5H-furo[2,3-g]indazole-4,1'-cyclopropane]-7-carboxamide Chemical compound CC1=C(OC=2CC3(C4=CN(N=C4C=21)CC1=NC=CC=C1)CC3)C(=O)NCC=1OC=CN=1 AIVBRSWEEMHJMJ-UHFFFAOYSA-N 0.000 claims 1
- PPDSPRDBHXTACW-UHFFFAOYSA-N 8-methyl-N-(oxetan-3-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NCC1COC1 PPDSPRDBHXTACW-UHFFFAOYSA-N 0.000 claims 1
- AOIJRISPMYMNDG-UHFFFAOYSA-N 8-methyl-N-[(4-methyl-1,2-oxazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NCC1=NOC=C1C AOIJRISPMYMNDG-UHFFFAOYSA-N 0.000 claims 1
- RSXOWAYYQDPOIE-UHFFFAOYSA-N 8-methyl-N-[(5-methyl-1,2-oxazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NCC1=NOC(=C1)C RSXOWAYYQDPOIE-UHFFFAOYSA-N 0.000 claims 1
- NASFEEMGLOBQLN-UHFFFAOYSA-N 8-methyl-N-[(5-propan-2-yl-1,2-oxazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound C(C)(C)C1=CC(=NO1)CNC(=O)C1=C(C2=C(CCC3=CN(N=C23)CC2=NC=CC=C2)O1)C NASFEEMGLOBQLN-UHFFFAOYSA-N 0.000 claims 1
- FIJIBWIYQPEYTD-KRWDZBQOSA-N 8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-2-(pyridin-3-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC=1C=NC=CC=1)C(=O)NC[C@H]1OCCC1 FIJIBWIYQPEYTD-KRWDZBQOSA-N 0.000 claims 1
- YQQYGXMVXZJFDG-KRWDZBQOSA-N 8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-2-(pyridin-4-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=CC=NC=C1)C(=O)NC[C@H]1OCCC1 YQQYGXMVXZJFDG-KRWDZBQOSA-N 0.000 claims 1
- ZRLWABBNHRMYIY-HNNXBMFYSA-N 8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-2-(pyrimidin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=N1)C(=O)NC[C@H]1OCCC1 ZRLWABBNHRMYIY-HNNXBMFYSA-N 0.000 claims 1
- NGWLWWQGRYNVAE-INIZCTEOSA-N 8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-2-(pyrimidin-5-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC=1C=NC=NC=1)C(=O)NC[C@H]1OCCC1 NGWLWWQGRYNVAE-INIZCTEOSA-N 0.000 claims 1
- QJWSWBRVNQLOIT-JKSUJKDBSA-N 8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-2-[[(2R)-oxolan-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@@H]1OCCC1)C(=O)NC[C@H]1OCCC1 QJWSWBRVNQLOIT-JKSUJKDBSA-N 0.000 claims 1
- JHACMQNCNDEOHE-ZBFHGGJFSA-N 8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-2-[[(3R)-oxolan-3-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@@H]1COCC1)C(=O)NC[C@H]1OCCC1 JHACMQNCNDEOHE-ZBFHGGJFSA-N 0.000 claims 1
- RQJLBNXIMKVFRG-KRWDZBQOSA-N 8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-2-[[5-(trifluoromethyl)pyridin-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=C(C=C1)C(F)(F)F)C(=O)NC[C@H]1OCCC1 RQJLBNXIMKVFRG-KRWDZBQOSA-N 0.000 claims 1
- NKIJGADOABDWQM-INIZCTEOSA-N 8-methyl-N-[[(2S)-oxolan-2-yl]methyl]-2-[[6-(trifluoromethyl)pyridin-2-yl]methyl]-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC(=CC=C1)C(F)(F)F)C(=O)NC[C@H]1OCCC1 NKIJGADOABDWQM-INIZCTEOSA-N 0.000 claims 1
- ORVCSSOGEGBCLY-UHFFFAOYSA-N 8-methyl-N-pyridin-3-yl-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=C(OC2=C1C3=NN(C=C3CC2)CC4=CC=CC=N4)C(=O)NC5=CN=CC=C5 ORVCSSOGEGBCLY-UHFFFAOYSA-N 0.000 claims 1
- KJQSJVAWTGBIQU-SFHVURJKSA-N C(#N)C=1C=CC(=NC=1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 Chemical compound C(#N)C=1C=CC(=NC=1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 KJQSJVAWTGBIQU-SFHVURJKSA-N 0.000 claims 1
- WHSXFMLLCNGJSK-INIZCTEOSA-N C(C)(=O)N1CC(C1)(F)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 Chemical compound C(C)(=O)N1CC(C1)(F)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 WHSXFMLLCNGJSK-INIZCTEOSA-N 0.000 claims 1
- RDQCYTFJNGVCEG-KRWDZBQOSA-N C(C)(=O)N1CC(C1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 Chemical compound C(C)(=O)N1CC(C1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 RDQCYTFJNGVCEG-KRWDZBQOSA-N 0.000 claims 1
- YOQMMNQDFXJRJC-PBHICJAKSA-N C(C)(=O)N1CCC(CC1)CN1N=C2C3=C(C[C@H](C2=C1)C)OC(=C3C(F)(F)F)C(=O)NC[C@H]1OCCC1 Chemical compound C(C)(=O)N1CCC(CC1)CN1N=C2C3=C(C[C@H](C2=C1)C)OC(=C3C(F)(F)F)C(=O)NC[C@H]1OCCC1 YOQMMNQDFXJRJC-PBHICJAKSA-N 0.000 claims 1
- DEOXPAKRKTVYCG-UHFFFAOYSA-N C1(CC1)C1=CC(=NO1)CNC(=O)C1=C(C2=C(CCC3=CN(N=C23)CC2=NC(=CC=C2)C)O1)C Chemical compound C1(CC1)C1=CC(=NO1)CNC(=O)C1=C(C2=C(CCC3=CN(N=C23)CC2=NC(=CC=C2)C)O1)C DEOXPAKRKTVYCG-UHFFFAOYSA-N 0.000 claims 1
- XBDSDPYGYSKJCC-KRWDZBQOSA-N CC1(C2=CN(N=C2C2=C(C1)OC(=C2C)C(=O)NC[C@H]1OCCC1)CC1=NC=CC=C1)C Chemical compound CC1(C2=CN(N=C2C2=C(C1)OC(=C2C)C(=O)NC[C@H]1OCCC1)CC1=NC=CC=C1)C XBDSDPYGYSKJCC-KRWDZBQOSA-N 0.000 claims 1
- STDSQPBAWDYEEI-UHFFFAOYSA-N CC1=C(OC=2CC3(C4=CN(N=C4C=21)CC1=NC=CC=C1)CC3)C(=O)NCC1=NN(C=C1)C Chemical compound CC1=C(OC=2CC3(C4=CN(N=C4C=21)CC1=NC=CC=C1)CC3)C(=O)NCC1=NN(C=C1)C STDSQPBAWDYEEI-UHFFFAOYSA-N 0.000 claims 1
- NMVMCDXFDDQPNQ-TULHMLFLSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)C([2H])([2H])C1=CC=CC=C1)C(=O)NC[C@H]1OCCC1 Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C([2H])([2H])C1=CC=CC=C1)C(=O)NC[C@H]1OCCC1 NMVMCDXFDDQPNQ-TULHMLFLSA-N 0.000 claims 1
- HVBYOAWYMYSETA-GOSISDBHSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC(=CC=C1)C)C(=O)NC[C@@H]1OCCC1 Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC(=CC=C1)C)C(=O)NC[C@@H]1OCCC1 HVBYOAWYMYSETA-GOSISDBHSA-N 0.000 claims 1
- HVBYOAWYMYSETA-SFHVURJKSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC(=CC=C1)C)C(=O)NC[C@H]1OCCC1 Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC(=CC=C1)C)C(=O)NC[C@H]1OCCC1 HVBYOAWYMYSETA-SFHVURJKSA-N 0.000 claims 1
- WTLVBDOBNQYCAX-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NCC1=CC=C(C=C1)C Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NCC1=CC=C(C=C1)C WTLVBDOBNQYCAX-UHFFFAOYSA-N 0.000 claims 1
- XUZZCCIOCDWBMM-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NCC1=NOC(=C1)C(F)(F)F Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NCC1=NOC(=C1)C(F)(F)F XUZZCCIOCDWBMM-UHFFFAOYSA-N 0.000 claims 1
- UVYRBTNDTAPHQZ-QGZVFWFLSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NC[C@@H]1OCCC1 Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NC[C@@H]1OCCC1 UVYRBTNDTAPHQZ-QGZVFWFLSA-N 0.000 claims 1
- QYWFCRVCCPCLAQ-SFHVURJKSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NC[C@H]1CN(CCO1)C Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NC[C@H]1CN(CCO1)C QYWFCRVCCPCLAQ-SFHVURJKSA-N 0.000 claims 1
- YPGHHEUAXXQWEX-INIZCTEOSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NC[C@H]1OC(CC1)=O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NC[C@H]1OC(CC1)=O YPGHHEUAXXQWEX-INIZCTEOSA-N 0.000 claims 1
- UVYRBTNDTAPHQZ-KRWDZBQOSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NC[C@H]1OCCC1 Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)NC[C@H]1OCCC1 UVYRBTNDTAPHQZ-KRWDZBQOSA-N 0.000 claims 1
- FBNZSSBEDDNBSS-INIZCTEOSA-N CC1=CC=C(C=N1)CN1N=C2C3=C(CC4(C2=C1)CC4)OC(=C3C(F)(F)F)C(=O)NC[C@H]1OCCC1 Chemical compound CC1=CC=C(C=N1)CN1N=C2C3=C(CC4(C2=C1)CC4)OC(=C3C(F)(F)F)C(=O)NC[C@H]1OCCC1 FBNZSSBEDDNBSS-INIZCTEOSA-N 0.000 claims 1
- OOKNEPOJESXDBP-INIZCTEOSA-N CC=1C=CC(=NC=1)CN1N=C2C3=C(CC4(C2=C1)CC4)OC(=C3C(F)(F)F)C(=O)NC[C@H]1OCCC1 Chemical compound CC=1C=CC(=NC=1)CN1N=C2C3=C(CC4(C2=C1)CC4)OC(=C3C(F)(F)F)C(=O)NC[C@H]1OCCC1 OOKNEPOJESXDBP-INIZCTEOSA-N 0.000 claims 1
- KDFLVADPNOJIDR-INIZCTEOSA-N CN1CCC(CC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C(F)(F)F)C(=O)NC[C@H]1OCCC1 Chemical compound CN1CCC(CC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C(F)(F)F)C(=O)NC[C@H]1OCCC1 KDFLVADPNOJIDR-INIZCTEOSA-N 0.000 claims 1
- LFGZATNSLCHZEZ-UHFFFAOYSA-N CN1N=C(C=C1)CNC(=O)C1=C(C2=C(CC3(C4=CN(N=C24)CC2=NC=CC=C2)CCC3)O1)C(F)(F)F Chemical compound CN1N=C(C=C1)CNC(=O)C1=C(C2=C(CC3(C4=CN(N=C24)CC2=NC=CC=C2)CCC3)O1)C(F)(F)F LFGZATNSLCHZEZ-UHFFFAOYSA-N 0.000 claims 1
- VPQLSWWZYYMHEP-HNNXBMFYSA-N FC1(CN(C1)S(=O)(=O)C)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 Chemical compound FC1(CN(C1)S(=O)(=O)C)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 VPQLSWWZYYMHEP-HNNXBMFYSA-N 0.000 claims 1
- VKKKYXHUGRNZHW-HZPDHXFCSA-N N,2-bis[[(2R)-1,4-dioxan-2-yl]methyl]-8-methyl-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound O1[C@@H](COCC1)CNC(=O)C1=C(C2=C(CCC3=CN(N=C23)C[C@H]2OCCOC2)O1)C VKKKYXHUGRNZHW-HZPDHXFCSA-N 0.000 claims 1
- RLNXUUYGQPIVEQ-UHFFFAOYSA-N N-(2-hydroxy-2-methylpropyl)-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound OC(CNC(=O)C1=C(C2=C(CCC3=CN(N=C23)CC2=NC=CC=C2)O1)C)(C)C RLNXUUYGQPIVEQ-UHFFFAOYSA-N 0.000 claims 1
- OPUVASRNJWNGFN-UHFFFAOYSA-N N-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound CC1=NOC(=C1CNC(=O)C1=C(C2=C(CCC3=CN(N=C23)CC2=NC=CC=C2)O1)C)C OPUVASRNJWNGFN-UHFFFAOYSA-N 0.000 claims 1
- IBCLALINQUKDQS-UHFFFAOYSA-N N-[(3-fluorooxetan-3-yl)methyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound FC1(COC1)CNC(=O)C1=C(C2=C(CCC3=CN(N=C23)CC2=NC=CC=C2)O1)C IBCLALINQUKDQS-UHFFFAOYSA-N 0.000 claims 1
- SNPVJWXDVNXBNO-UHFFFAOYSA-N N-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound C1(CC1)C1=CC(=NO1)CNC(=O)C1=C(C2=C(CCC3=CN(N=C23)CC2=NC=CC=C2)O1)C SNPVJWXDVNXBNO-UHFFFAOYSA-N 0.000 claims 1
- BBPXWPRRFVATHN-QGZVFWFLSA-N N-[[(2R)-1,4-dioxan-2-yl]methyl]-2-[(5-methylpyridin-2-yl)methyl]-8-(trifluoromethyl)spiro[5H-furo[2,3-g]indazole-4,1'-cyclobutane]-7-carboxamide Chemical compound O1[C@@H](COCC1)CNC(=O)C1=C(C2=C(CC3(C4=CN(N=C24)CC2=NC=C(C=C2)C)CCC3)O1)C(F)(F)F BBPXWPRRFVATHN-QGZVFWFLSA-N 0.000 claims 1
- OJZXTRBHRNKXSI-UHFFFAOYSA-N N-[[5-(3-methoxyphenyl)-1,2-oxazol-3-yl]methyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide Chemical compound COC=1C=C(C=CC=1)C1=CC(=NO1)CNC(=O)C1=C(C2=C(CCC3=CN(N=C23)CC2=NC=CC=C2)O1)C OJZXTRBHRNKXSI-UHFFFAOYSA-N 0.000 claims 1
- CLSIVSJJWYFMQM-INIZCTEOSA-N N1=C(C=CC=C1)CN1N=C2C3=C(CC4(C2=C1)CCC4)OC(=C3C(F)(F)F)C(=O)NC[C@H]1OCCC1 Chemical compound N1=C(C=CC=C1)CN1N=C2C3=C(CC4(C2=C1)CCC4)OC(=C3C(F)(F)F)C(=O)NC[C@H]1OCCC1 CLSIVSJJWYFMQM-INIZCTEOSA-N 0.000 claims 1
- LJRGEHVEWSJQSY-HNNXBMFYSA-N N1CC(C1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 Chemical compound N1CC(C1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 LJRGEHVEWSJQSY-HNNXBMFYSA-N 0.000 claims 1
- VXWASMFLSVTQTO-ZDUSSCGKSA-N NCCN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 Chemical compound NCCN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)NC[C@H]1OCCC1 VXWASMFLSVTQTO-ZDUSSCGKSA-N 0.000 claims 1
- OPXHGQHUIDLJSW-HNNXBMFYSA-N O1[C@@H](CCC1)CNC(=O)C1=C(C2=C(CC3(C4=CN(N=C24)CC2=NC=CC=C2)CC3)O1)C(F)(F)F Chemical compound O1[C@@H](CCC1)CNC(=O)C1=C(C2=C(CC3(C4=CN(N=C24)CC2=NC=CC=C2)CC3)O1)C(F)(F)F OPXHGQHUIDLJSW-HNNXBMFYSA-N 0.000 claims 1
- KMDJGAYHSCOZLS-KGLIPLIRSA-N O1[C@@H](COCC1)CNC(=O)C1=C(C2=C(CC3(C4=CN(N=C24)C[C@@H]2OCCOC2)CC3)O1)C(F)(F)F Chemical compound O1[C@@H](COCC1)CNC(=O)C1=C(C2=C(CC3(C4=CN(N=C24)C[C@@H]2OCCOC2)CC3)O1)C(F)(F)F KMDJGAYHSCOZLS-KGLIPLIRSA-N 0.000 claims 1
- DCFUIFSJOBDHGV-QGZVFWFLSA-N O1[C@@H](COCC1)CNC(=O)C1=C(C2=C(CCC3=CN(N=C23)CC2=NC=CC=C2)O1)C Chemical compound O1[C@@H](COCC1)CNC(=O)C1=C(C2=C(CCC3=CN(N=C23)CC2=NC=CC=C2)O1)C DCFUIFSJOBDHGV-QGZVFWFLSA-N 0.000 claims 1
- NLHVFALCHLAAQY-FUHWJXTLSA-N O1[C@@H](COCC1)CNC(=O)C1=C(C2=C(C[C@@H](C3=CN(N=C23)CC2CCN(CC2)C(=O)C2(CC2)C)C)O1)C(F)(F)F Chemical compound O1[C@@H](COCC1)CNC(=O)C1=C(C2=C(C[C@@H](C3=CN(N=C23)CC2CCN(CC2)C(=O)C2(CC2)C)C)O1)C(F)(F)F NLHVFALCHLAAQY-FUHWJXTLSA-N 0.000 claims 1
- CJKDEFBQZRIVPB-ZDUSSCGKSA-N O1[C@H](COCC1)CN1N=C2C3=C(CC4(C2=C1)CCC4)OC(=C3C(F)(F)F)C(=O)NCC=1OC=CN=1 Chemical compound O1[C@H](COCC1)CN1N=C2C3=C(CC4(C2=C1)CCC4)OC(=C3C(F)(F)F)C(=O)NCC=1OC=CN=1 CJKDEFBQZRIVPB-ZDUSSCGKSA-N 0.000 claims 1
- JRFSRUQTLSPMHH-SNPRPXQTSA-N O1[C@H](COCC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C(F)(F)F)C(=O)NC[C@H]1O[C@@H](CC1)C Chemical compound O1[C@H](COCC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C(F)(F)F)C(=O)NC[C@H]1O[C@@H](CC1)C JRFSRUQTLSPMHH-SNPRPXQTSA-N 0.000 claims 1
- JRFSRUQTLSPMHH-QEJZJMRPSA-N O1[C@H](COCC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C(F)(F)F)C(=O)NC[C@H]1O[C@H](CC1)C Chemical compound O1[C@H](COCC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C(F)(F)F)C(=O)NC[C@H]1O[C@H](CC1)C JRFSRUQTLSPMHH-QEJZJMRPSA-N 0.000 claims 1
- TUCDMQSMPPUOFB-STQMWFEESA-N O1[C@H](COCC1)CN1N=C2C3=C(C[C@@H](C2=C1)C)OC(=C3C(F)(F)F)C(=O)NCC1=NC=CC=N1 Chemical compound O1[C@H](COCC1)CN1N=C2C3=C(C[C@@H](C2=C1)C)OC(=C3C(F)(F)F)C(=O)NCC1=NC=CC=N1 TUCDMQSMPPUOFB-STQMWFEESA-N 0.000 claims 1
- FEGAIZKERGMPQV-JSGCOSHPSA-N O1[C@H](COCC1)CN1N=C2C3=C(C[C@@H](C2=C1)C)OC(=C3C(F)(F)F)C(=O)NCC1=NN(C=C1)C Chemical compound O1[C@H](COCC1)CN1N=C2C3=C(C[C@@H](C2=C1)C)OC(=C3C(F)(F)F)C(=O)NCC1=NN(C=C1)C FEGAIZKERGMPQV-JSGCOSHPSA-N 0.000 claims 1
- SGSZJENAPPIZIU-AAEUAGOBSA-N O1[C@H](COCC1)CN1N=C2C3=C(C[C@@H](C2=C1)C)OC(=C3C(F)(F)F)C(=O)NCC=1N=COC=1 Chemical compound O1[C@H](COCC1)CN1N=C2C3=C(C[C@@H](C2=C1)C)OC(=C3C(F)(F)F)C(=O)NCC=1N=COC=1 SGSZJENAPPIZIU-AAEUAGOBSA-N 0.000 claims 1
- FJKJWODQSWGAKR-RYUDHWBXSA-N O1[C@H](COCC1)CN1N=C2C3=C(C[C@@H](C2=C1)C)OC(=C3C(F)(F)F)C(=O)NCC=1OC=CN=1 Chemical compound O1[C@H](COCC1)CN1N=C2C3=C(C[C@@H](C2=C1)C)OC(=C3C(F)(F)F)C(=O)NCC=1OC=CN=1 FJKJWODQSWGAKR-RYUDHWBXSA-N 0.000 claims 1
- QAUOBCYBEDYLHG-OFQRWUPVSA-N O1[C@H](COCC1)CN1N=C2C3=C(C[C@H](C2=C1)C(F)(F)F)OC(=C3C)C(=O)NC[C@H]1OCCC1 Chemical compound O1[C@H](COCC1)CN1N=C2C3=C(C[C@H](C2=C1)C(F)(F)F)OC(=C3C)C(=O)NC[C@H]1OCCC1 QAUOBCYBEDYLHG-OFQRWUPVSA-N 0.000 claims 1
- KVVMXWRFYAGASO-UHFFFAOYSA-N azetidine-1-carboxylic acid Chemical compound OC(=O)N1CCC1 KVVMXWRFYAGASO-UHFFFAOYSA-N 0.000 claims 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims 1
- 230000002757 inflammatory effect Effects 0.000 abstract description 39
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 34
- 230000002503 metabolic effect Effects 0.000 abstract description 31
- 201000010065 polycystic ovary syndrome Diseases 0.000 abstract description 26
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 25
- 230000001476 alcoholic effect Effects 0.000 abstract description 23
- 208000035475 disorder Diseases 0.000 abstract description 22
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 abstract description 14
- 208000019693 Lung disease Diseases 0.000 abstract description 14
- 208000017701 Endocrine disease Diseases 0.000 abstract description 13
- 201000009273 Endometriosis Diseases 0.000 abstract description 13
- 206010065390 Inflammatory pain Diseases 0.000 abstract description 13
- 206010022489 Insulin Resistance Diseases 0.000 abstract description 13
- 208000001145 Metabolic Syndrome Diseases 0.000 abstract description 13
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 abstract description 13
- 208000006673 asthma Diseases 0.000 abstract description 13
- 208000010706 fatty liver disease Diseases 0.000 abstract description 13
- 208000036971 interstitial lung disease 2 Diseases 0.000 abstract description 13
- 208000017169 kidney disease Diseases 0.000 abstract description 13
- 208000019423 liver disease Diseases 0.000 abstract description 13
- 201000006417 multiple sclerosis Diseases 0.000 abstract description 13
- 231100000331 toxic Toxicity 0.000 abstract description 13
- 230000002588 toxic effect Effects 0.000 abstract description 13
- 206010002556 Ankylosing Spondylitis Diseases 0.000 abstract description 12
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 12
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 abstract description 12
- 201000004681 Psoriasis Diseases 0.000 abstract description 12
- 201000010099 disease Diseases 0.000 abstract description 12
- 208000030533 eye disease Diseases 0.000 abstract description 12
- 208000004296 neuralgia Diseases 0.000 abstract description 12
- 208000021722 neuropathic pain Diseases 0.000 abstract description 12
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 12
- 201000000596 systemic lupus erythematosus Diseases 0.000 abstract description 12
- 201000001263 Psoriatic Arthritis Diseases 0.000 abstract description 11
- 208000036824 Psoriatic arthropathy Diseases 0.000 abstract description 11
- 201000004982 autoimmune uveitis Diseases 0.000 abstract description 11
- 230000002981 neuropathic effect Effects 0.000 abstract description 11
- 238000011282 treatment Methods 0.000 abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 10
- 241001465754 Metazoa Species 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 2
- 208000027866 inflammatory disease Diseases 0.000 abstract 1
- 238000011321 prophylaxis Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 235
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 151
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 136
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 117
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 105
- 235000019439 ethyl acetate Nutrition 0.000 description 103
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 83
- 238000005481 NMR spectroscopy Methods 0.000 description 76
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 71
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 70
- 239000000543 intermediate Chemical class 0.000 description 66
- 239000011541 reaction mixture Substances 0.000 description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- VLSDXINSOMDCBK-BQYQJAHWSA-N (E)-1,1'-azobis(N,N-dimethylformamide) Chemical compound CN(C)C(=O)\N=N\C(=O)N(C)C VLSDXINSOMDCBK-BQYQJAHWSA-N 0.000 description 57
- 230000002829 reductive effect Effects 0.000 description 55
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 49
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 46
- 239000000243 solution Substances 0.000 description 45
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- 238000004440 column chromatography Methods 0.000 description 41
- 229910004298 SiO 2 Inorganic materials 0.000 description 40
- 239000012074 organic phase Substances 0.000 description 38
- 239000012267 brine Substances 0.000 description 34
- 239000011734 sodium Substances 0.000 description 34
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
- 239000008346 aqueous phase Substances 0.000 description 32
- LJDCFYUTVHVXDW-UHFFFAOYSA-N ethyl 8-methyl-4,5-dihydro-1h-furo[2,3-g]indazole-7-carboxylate Chemical compound C1=2C(C)=C(C(=O)OCC)OC=2CCC2=C1NN=C2 LJDCFYUTVHVXDW-UHFFFAOYSA-N 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- 239000012071 phase Substances 0.000 description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 27
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 27
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 27
- 239000002904 solvent Chemical class 0.000 description 27
- 102100033864 G-protein coupled receptor 84 Human genes 0.000 description 25
- 101001069589 Homo sapiens G-protein coupled receptor 84 Proteins 0.000 description 25
- 238000000746 purification Methods 0.000 description 25
- 239000007864 aqueous solution Substances 0.000 description 24
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- 239000002253 acid Substances 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- AZOFSDWPAJNIAZ-UHFFFAOYSA-N ethyl 1h-indazole-7-carboxylate Chemical compound CCOC(=O)C1=CC=CC2=C1NN=C2 AZOFSDWPAJNIAZ-UHFFFAOYSA-N 0.000 description 21
- 238000001914 filtration Methods 0.000 description 21
- 239000003480 eluent Substances 0.000 description 19
- 239000002244 precipitate Substances 0.000 description 19
- 239000007858 starting material Substances 0.000 description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
- 150000001721 carbon Chemical group 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 238000002953 preparative HPLC Methods 0.000 description 16
- 238000009835 boiling Methods 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 150000001408 amides Chemical class 0.000 description 14
- 230000000875 corresponding effect Effects 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 230000004968 inflammatory condition Effects 0.000 description 12
- 230000020477 pH reduction Effects 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 230000000155 isotopic effect Effects 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000005557 antagonist Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 238000010790 dilution Methods 0.000 description 9
- 239000012895 dilution Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 8
- 241000237858 Gastropoda Species 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 229910002091 carbon monoxide Inorganic materials 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- 239000002207 metabolite Substances 0.000 description 8
- 125000006413 ring segment Chemical group 0.000 description 8
- FNYGDNZHTDQNBY-UHFFFAOYSA-N BrC1=NNC2=C3C(=CC=C12)OC=C3 Chemical compound BrC1=NNC2=C3C(=CC=C12)OC=C3 FNYGDNZHTDQNBY-UHFFFAOYSA-N 0.000 description 7
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 7
- 125000001309 chloro group Chemical group Cl* 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- WGSMVIHKBMAWRN-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1-benzofuran Chemical compound C1C=CC=C2OCCC21 WGSMVIHKBMAWRN-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 6
- SICFZQWKKLKXFW-UHFFFAOYSA-N CC1=COC2=CC=C3C=NNC3=C21 Chemical compound CC1=COC2=CC=C3C=NNC3=C21 SICFZQWKKLKXFW-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000007821 HATU Substances 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 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
- 238000005859 coupling reaction Methods 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- 235000021588 free fatty acids Nutrition 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
- LIAWOTKNAVAKCX-UHFFFAOYSA-N hydrazine;dihydrochloride Chemical compound Cl.Cl.NN LIAWOTKNAVAKCX-UHFFFAOYSA-N 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- HXRAMSFGUAOAJR-UHFFFAOYSA-N n,n,n',n'-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine Chemical compound CN(C)C(N(C)C)OC(C)(C)C HXRAMSFGUAOAJR-UHFFFAOYSA-N 0.000 description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 208000031295 Animal disease Diseases 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 238000010640 amide synthesis reaction Methods 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000012039 electrophile Substances 0.000 description 5
- 238000000132 electrospray ionisation Methods 0.000 description 5
- 150000002081 enamines Chemical class 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 239000002798 polar solvent Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 5
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 4
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000005810 carbonylation reaction Methods 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 229960002442 glucosamine Drugs 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 238000013537 high throughput screening Methods 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 3
- OFPWMRMIFDHXFE-UHFFFAOYSA-N 2-(bromomethyl)pyridine Chemical compound BrCC1=CC=CC=N1 OFPWMRMIFDHXFE-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 3
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 206010036049 Polycystic ovaries Diseases 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 210000001789 adipocyte Anatomy 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 230000006315 carbonylation Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 150000002240 furans Chemical class 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 150000002429 hydrazines Chemical class 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 210000004969 inflammatory cell Anatomy 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000007937 lozenge Substances 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 229910052750 molybdenum Inorganic materials 0.000 description 3
- 239000011733 molybdenum Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 description 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- VLSDXINSOMDCBK-UHFFFAOYSA-N 1,1'-azobis(N,N-dimethylformamide) Chemical compound CN(C)C(=O)N=NC(=O)N(C)C VLSDXINSOMDCBK-UHFFFAOYSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- FGRBYDKOBBBPOI-UHFFFAOYSA-N 10,10-dioxo-2-[4-(N-phenylanilino)phenyl]thioxanthen-9-one Chemical compound O=C1c2ccccc2S(=O)(=O)c2ccc(cc12)-c1ccc(cc1)N(c1ccccc1)c1ccccc1 FGRBYDKOBBBPOI-UHFFFAOYSA-N 0.000 description 2
- KJJPLEZQSCZCKE-UHFFFAOYSA-N 2-aminopropane-1,3-diol Chemical compound OCC(N)CO KJJPLEZQSCZCKE-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- KTXGNVBBIBXEDR-UHFFFAOYSA-N 4,5-dihydro-1h-furo[2,3-g]indazole Chemical compound C1=2NN=CC=2CCC2=C1C=CO2 KTXGNVBBIBXEDR-UHFFFAOYSA-N 0.000 description 2
- DXWQOYPYNPSVRL-UHFFFAOYSA-N 6,7-dihydro-5h-1-benzofuran-4-one Chemical compound O=C1CCCC2=C1C=CO2 DXWQOYPYNPSVRL-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- MGZFRIHKBCSXQI-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1(COC1)C)C(=O)OCC Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1(COC1)C)C(=O)OCC MGZFRIHKBCSXQI-UHFFFAOYSA-N 0.000 description 2
- LLJNPKSPENAIMQ-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC(=CC=C1)C(F)(F)F)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC(=CC=C1)C(F)(F)F)C(=O)O LLJNPKSPENAIMQ-UHFFFAOYSA-N 0.000 description 2
- DSPCLCSFJDDRNC-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=C(C=C1)C(F)(F)F)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=C(C=C1)C(F)(F)F)C(=O)O DSPCLCSFJDDRNC-UHFFFAOYSA-N 0.000 description 2
- RANZZVSAYJLWBT-SNVBAGLBSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@@H]1COCC1)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@@H]1COCC1)C(=O)O RANZZVSAYJLWBT-SNVBAGLBSA-N 0.000 description 2
- FMNMMGJCACFIPV-GFCCVEGCSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@@H]1OCC1)C(=O)OCC Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@@H]1OCC1)C(=O)OCC FMNMMGJCACFIPV-GFCCVEGCSA-N 0.000 description 2
- FHKZKSZITIYZPG-LLVKDONJSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@@H]1OCCC1)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@@H]1OCCC1)C(=O)O FHKZKSZITIYZPG-LLVKDONJSA-N 0.000 description 2
- RANZZVSAYJLWBT-JTQLQIEISA-N CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@H]1COCC1)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@H]1COCC1)C(=O)O RANZZVSAYJLWBT-JTQLQIEISA-N 0.000 description 2
- FMNMMGJCACFIPV-LBPRGKRZSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@H]1OCC1)C(=O)OCC Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@H]1OCC1)C(=O)OCC FMNMMGJCACFIPV-LBPRGKRZSA-N 0.000 description 2
- FHKZKSZITIYZPG-NSHDSACASA-N CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@H]1OCCC1)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@H]1OCCC1)C(=O)O FHKZKSZITIYZPG-NSHDSACASA-N 0.000 description 2
- ZTFYFOFGZDGSTE-UHFFFAOYSA-N CC1=C(OC=2CCC=3C=NNC=3C=21)C(=O)OC Chemical compound CC1=C(OC=2CCC=3C=NNC=3C=21)C(=O)OC ZTFYFOFGZDGSTE-UHFFFAOYSA-N 0.000 description 2
- PTBIEQQKJIQTTI-UHFFFAOYSA-N CC1=NC(=CC(=C1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)OCC)C Chemical compound CC1=NC(=CC(=C1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)OCC)C PTBIEQQKJIQTTI-UHFFFAOYSA-N 0.000 description 2
- OTKPMRRXSBKOOY-UHFFFAOYSA-N CC1=NC(=CC=C1CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)OCC)C Chemical compound CC1=NC(=CC=C1CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)OCC)C OTKPMRRXSBKOOY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 101710082751 Carboxypeptidase S1 homolog A Proteins 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 229920003134 Eudragit® polymer Polymers 0.000 description 2
- LOHPUXGMATWXSM-UHFFFAOYSA-N FC(C1=C(OC=2CCC=3C=NNC=3C=21)C(=O)OCC)(F)F Chemical compound FC(C1=C(OC=2CCC=3C=NNC=3C=21)C(=O)OCC)(F)F LOHPUXGMATWXSM-UHFFFAOYSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 238000006751 Mitsunobu reaction Methods 0.000 description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 2
- VGTADGNSGCICTA-ZCFIWIBFSA-N [(2r)-4-methylmorpholin-2-yl]methanol Chemical compound CN1CCO[C@@H](CO)C1 VGTADGNSGCICTA-ZCFIWIBFSA-N 0.000 description 2
- BSYVTEYKTMYBMK-RXMQYKEDSA-N [(2r)-oxolan-2-yl]methanol Chemical compound OC[C@H]1CCCO1 BSYVTEYKTMYBMK-RXMQYKEDSA-N 0.000 description 2
- VGTADGNSGCICTA-LURJTMIESA-N [(2s)-4-methylmorpholin-2-yl]methanol Chemical compound CN1CCO[C@H](CO)C1 VGTADGNSGCICTA-LURJTMIESA-N 0.000 description 2
- BSYVTEYKTMYBMK-YFKPBYRVSA-N [(2s)-oxolan-2-yl]methanol Chemical compound OC[C@@H]1CCCO1 BSYVTEYKTMYBMK-YFKPBYRVSA-N 0.000 description 2
- PCPUMGYALMOCHF-RXMQYKEDSA-N [(3r)-oxolan-3-yl]methanol Chemical compound OC[C@H]1CCOC1 PCPUMGYALMOCHF-RXMQYKEDSA-N 0.000 description 2
- PCPUMGYALMOCHF-YFKPBYRVSA-N [(3s)-oxolan-3-yl]methanol Chemical compound OC[C@@H]1CCOC1 PCPUMGYALMOCHF-YFKPBYRVSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000036755 cellular response Effects 0.000 description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000004431 deuterium atom Chemical group 0.000 description 2
- BADXJIPKFRBFOT-UHFFFAOYSA-N dimedone Chemical compound CC1(C)CC(=O)CC(=O)C1 BADXJIPKFRBFOT-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 150000002085 enols Chemical class 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 238000006170 formylation reaction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000000643 heteroaryl-fused-heterocycloalkyl group Chemical group 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 150000002576 ketones Chemical group 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 2
- KOCJDLLQHDXXAI-UHFFFAOYSA-N methyl 2-chloro-3-cyclopropyl-3-oxopropanoate Chemical compound COC(=O)C(Cl)C(=O)C1CC1 KOCJDLLQHDXXAI-UHFFFAOYSA-N 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical group 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 229920000193 polymethacrylate Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 2
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical compound OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 description 2
- PTMBWNZJOQBTBK-UHFFFAOYSA-N pyridin-4-ylmethanol Chemical compound OCC1=CC=NC=C1 PTMBWNZJOQBTBK-UHFFFAOYSA-N 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- HXRDRJKAEYHOBB-UHFFFAOYSA-N tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(CO)C1 HXRDRJKAEYHOBB-UHFFFAOYSA-N 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229960004418 trolamine Drugs 0.000 description 2
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- AGGDOLFSEUKNKM-UHFFFAOYSA-N (2,6-dimethylpyridin-3-yl)methanol Chemical compound CC1=CC=C(CO)C(C)=N1 AGGDOLFSEUKNKM-UHFFFAOYSA-N 0.000 description 1
- DLDGHMPQNVTNRC-UHFFFAOYSA-N (2,6-dimethylpyridin-4-yl)methanol Chemical compound CC1=CC(CO)=CC(C)=N1 DLDGHMPQNVTNRC-UHFFFAOYSA-N 0.000 description 1
- PRMLMDSFLIHHSO-UHFFFAOYSA-N (2-methylpyridin-3-yl)methanol Chemical compound CC1=NC=CC=C1CO PRMLMDSFLIHHSO-UHFFFAOYSA-N 0.000 description 1
- WCHFSXVRRCEWJL-UHFFFAOYSA-N (2-methylpyridin-4-yl)methanol Chemical compound CC1=CC(CO)=CC=N1 WCHFSXVRRCEWJL-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- DNISEZBAYYIQFB-PHDIDXHHSA-N (2r,3r)-2,3-diacetyloxybutanedioic acid Chemical compound CC(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(C)=O DNISEZBAYYIQFB-PHDIDXHHSA-N 0.000 description 1
- FWIVDMJALNEADT-SFTDATJTSA-N (2s)-n-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-[[(1s)-2,2,2-trifluoro-1-[4-(4-methylsulfonylphenyl)phenyl]ethyl]amino]pentanamide Chemical compound C1=CC([C@H](N[C@@H](CC(C)(F)C)C(=O)NC2(CC2)C#N)C(F)(F)F)=CC=C1C1=CC=C(S(C)(=O)=O)C=C1 FWIVDMJALNEADT-SFTDATJTSA-N 0.000 description 1
- KWMLJOLKUYYJFJ-GASJEMHNSA-N (2xi)-D-gluco-heptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C(O)=O KWMLJOLKUYYJFJ-GASJEMHNSA-N 0.000 description 1
- NLQMSBJFLQPLIJ-UHFFFAOYSA-N (3-methyloxetan-3-yl)methanol Chemical compound OCC1(C)COC1 NLQMSBJFLQPLIJ-UHFFFAOYSA-N 0.000 description 1
- JLEPZAUPTZFVIM-RHIZIOMBSA-N (3s,5s,9r,10s,13r,17r)-3-hydroxy-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-1,2,3,4,5,6,9,11,12,15,16,17-dodecahydrocyclopenta[a]phenanthrene-14-carbaldehyde Chemical compound C1[C@@H](O)CC[C@]2(C)[C@@H](CC[C@@]3([C@@H]([C@H](C)CCCC(C)C)CCC33C=O)C)C3=CC[C@H]21 JLEPZAUPTZFVIM-RHIZIOMBSA-N 0.000 description 1
- HYOBIUULDPLKIE-UHFFFAOYSA-N (5-methylpyridin-2-yl)methanol Chemical compound CC1=CC=C(CO)N=C1 HYOBIUULDPLKIE-UHFFFAOYSA-N 0.000 description 1
- DJCJOWDAAZEMCI-UHFFFAOYSA-N (6-methylpyridin-3-yl)methanol Chemical compound CC1=CC=C(CO)C=N1 DJCJOWDAAZEMCI-UHFFFAOYSA-N 0.000 description 1
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- AUYBSFAHQLKXSW-UHFFFAOYSA-N 1,2-dichloroethane;3-(ethyliminomethylideneamino)-n,n-dimethylpropan-1-amine;hydrochloride Chemical compound Cl.ClCCCl.CCN=C=NCCCN(C)C AUYBSFAHQLKXSW-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 1
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 description 1
- IPJNYEICOKRKJM-UHFFFAOYSA-N 2-(bromomethyl)-3-chloro-5-fluoropyridine Chemical compound Fc1cnc(CBr)c(Cl)c1 IPJNYEICOKRKJM-UHFFFAOYSA-N 0.000 description 1
- UMXIAVUQROUXKO-UHFFFAOYSA-N 2-(bromomethyl)-5-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=C(CBr)N=C1 UMXIAVUQROUXKO-UHFFFAOYSA-N 0.000 description 1
- WJFDCFHWFHCLIW-UHFFFAOYSA-N 2-(bromomethyl)-6-methylpyridine Chemical compound CC1=CC=CC(CBr)=N1 WJFDCFHWFHCLIW-UHFFFAOYSA-N 0.000 description 1
- DCKALIKGFDMDHB-UHFFFAOYSA-N 2-(chloromethyl)-3-methylpyridine;hydrochloride Chemical compound Cl.CC1=CC=CN=C1CCl DCKALIKGFDMDHB-UHFFFAOYSA-N 0.000 description 1
- IZCYKFUHFBLPJN-UHFFFAOYSA-N 2-(chloromethyl)-6-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=CC(CCl)=N1 IZCYKFUHFBLPJN-UHFFFAOYSA-N 0.000 description 1
- MSFVEEFXECBJPG-UHFFFAOYSA-N 2-(chloromethyl)pyrimidine Chemical compound ClCC1=NC=CC=N1 MSFVEEFXECBJPG-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- HKORFDDYEBYGAO-UHFFFAOYSA-N 2-[(4-hydroxyphenyl)methyl]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CC1=CC=C(O)C=C1 HKORFDDYEBYGAO-UHFFFAOYSA-N 0.000 description 1
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 1
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- UZVHBTHTYIWMGO-UHFFFAOYSA-N 3,6,6-trimethyl-5,7-dihydro-1-benzofuran-4-one Chemical compound C1C(C)(C)CC(=O)C2=C1OC=C2C UZVHBTHTYIWMGO-UHFFFAOYSA-N 0.000 description 1
- NJZVKJVPHVROMS-UHFFFAOYSA-N 3-(bromomethyl)-3-fluorooxetane Chemical compound BrCC1(F)COC1 NJZVKJVPHVROMS-UHFFFAOYSA-N 0.000 description 1
- LIPUPFCIDWQWAP-UHFFFAOYSA-N 3-(chloromethyl)oxetane Chemical compound ClCC1COC1 LIPUPFCIDWQWAP-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- KQIGMPWTAHJUMN-UHFFFAOYSA-N 3-aminopropane-1,2-diol Chemical compound NCC(O)CO KQIGMPWTAHJUMN-UHFFFAOYSA-N 0.000 description 1
- MNOCTFZHUCINGC-UHFFFAOYSA-N 3-chloro-2-(chloromethyl)pyridine Chemical compound ClCC1=NC=CC=C1Cl MNOCTFZHUCINGC-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- RAAHQGNJLIZEBA-UHFFFAOYSA-N 3-methyl-2,3,3a,4-tetrahydro-1-benzofuran Chemical compound CC1COC=2C1CC=CC=2 RAAHQGNJLIZEBA-UHFFFAOYSA-N 0.000 description 1
- MVQVNTPHUGQQHK-UHFFFAOYSA-N 3-pyridinemethanol Chemical compound OCC1=CC=CN=C1 MVQVNTPHUGQQHK-UHFFFAOYSA-N 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- WIFPJDJJFUSIFP-UHFFFAOYSA-N 4-aminobutane-1,2,3-triol Chemical compound NCC(O)C(O)CO WIFPJDJJFUSIFP-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 102100022089 Acyl-[acyl-carrier-protein] hydrolase Human genes 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- RDOMULXNRZNQBL-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CC(C1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)OCC Chemical compound C(C)(C)(C)OC(=O)N1CC(C1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)OCC RDOMULXNRZNQBL-UHFFFAOYSA-N 0.000 description 1
- SANPOKADZHTDGS-UHFFFAOYSA-N C1(CC1)C1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)O Chemical compound C1(CC1)C1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)O SANPOKADZHTDGS-UHFFFAOYSA-N 0.000 description 1
- VCVSISWGKFCSTB-UHFFFAOYSA-N C1(CC1)C1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)OC Chemical compound C1(CC1)C1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)OC VCVSISWGKFCSTB-UHFFFAOYSA-N 0.000 description 1
- WASTUFIQANNDHV-UHFFFAOYSA-N C1(CC1)C1=C(OC=2CCC=3C=NNC=3C=21)C(=O)OC Chemical compound C1(CC1)C1=C(OC=2CCC=3C=NNC=3C=21)C(=O)OC WASTUFIQANNDHV-UHFFFAOYSA-N 0.000 description 1
- UZYLBGHCWJABLW-UHFFFAOYSA-N C1(CC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)O Chemical compound C1(CC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)O UZYLBGHCWJABLW-UHFFFAOYSA-N 0.000 description 1
- DGTIGNYDIVRQFO-UHFFFAOYSA-N C1(CC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)OCC Chemical compound C1(CC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)OCC DGTIGNYDIVRQFO-UHFFFAOYSA-N 0.000 description 1
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 1
- GGKADEGZHIMFAP-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1(COC1)C)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1(COC1)C)C(=O)O GGKADEGZHIMFAP-UHFFFAOYSA-N 0.000 description 1
- GNNBEERCOYRSQW-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=CC(=NC=C1)C)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=CC(=NC=C1)C)C(=O)O GNNBEERCOYRSQW-UHFFFAOYSA-N 0.000 description 1
- RKXRTUGKUCOSGS-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=CC=NC=C1)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=CC=NC=C1)C(=O)O RKXRTUGKUCOSGS-UHFFFAOYSA-N 0.000 description 1
- JXDMNTDRBSTGDG-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=CC=NC=C1)C(=O)OCC Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=CC=NC=C1)C(=O)OCC JXDMNTDRBSTGDG-UHFFFAOYSA-N 0.000 description 1
- IAJFWIUYIZWFSU-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC(=CC=C1)C)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC(=CC=C1)C)C(=O)O IAJFWIUYIZWFSU-UHFFFAOYSA-N 0.000 description 1
- DCLYWSLRWTWCDK-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC(=CC=C1)C)C(=O)OC Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC(=CC=C1)C)C(=O)OC DCLYWSLRWTWCDK-UHFFFAOYSA-N 0.000 description 1
- QNAIFHKTNIDEEX-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=C(C=C1)C)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=C(C=C1)C)C(=O)O QNAIFHKTNIDEEX-UHFFFAOYSA-N 0.000 description 1
- JMVROYLGBYOSCU-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)O JMVROYLGBYOSCU-UHFFFAOYSA-N 0.000 description 1
- VQLMTTHETOMNMI-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)OCC Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1)C(=O)OCC VQLMTTHETOMNMI-UHFFFAOYSA-N 0.000 description 1
- WCJPIODWJFQBJZ-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1C)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1C)C(=O)O WCJPIODWJFQBJZ-UHFFFAOYSA-N 0.000 description 1
- IYSNEJLUFKCPSJ-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1C)C(=O)OCC Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=C1C)C(=O)OCC IYSNEJLUFKCPSJ-UHFFFAOYSA-N 0.000 description 1
- NSZXSAFZHKISKZ-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=N1)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=N1)C(=O)O NSZXSAFZHKISKZ-UHFFFAOYSA-N 0.000 description 1
- MTNHRVKFPZNMLT-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=N1)C(=O)OCC Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1=NC=CC=N1)C(=O)OCC MTNHRVKFPZNMLT-UHFFFAOYSA-N 0.000 description 1
- MFKJWUADNTWLCK-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1COC1)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1COC1)C(=O)O MFKJWUADNTWLCK-UHFFFAOYSA-N 0.000 description 1
- SQQMSZJJATXUBO-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC1COC1)C(=O)OCC Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC1COC1)C(=O)OCC SQQMSZJJATXUBO-UHFFFAOYSA-N 0.000 description 1
- ACTZHKYITBDTFE-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC=1C(=NC=CC=1)C)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC=1C(=NC=CC=1)C)C(=O)O ACTZHKYITBDTFE-UHFFFAOYSA-N 0.000 description 1
- FHRKCJXAELEHOZ-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC=1C=NC(=CC=1)C)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC=1C=NC(=CC=1)C)C(=O)O FHRKCJXAELEHOZ-UHFFFAOYSA-N 0.000 description 1
- SLOMWJGBPCQXSF-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC=1C=NC=CC=1)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC=1C=NC=CC=1)C(=O)O SLOMWJGBPCQXSF-UHFFFAOYSA-N 0.000 description 1
- ZIDQUFSCBALBLL-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC=1C=NC=CC=1)C(=O)OCC Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC=1C=NC=CC=1)C(=O)OCC ZIDQUFSCBALBLL-UHFFFAOYSA-N 0.000 description 1
- RYZXMWVMSBKICX-UHFFFAOYSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)CC=1C=NC=NC=1)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)CC=1C=NC=NC=1)C(=O)O RYZXMWVMSBKICX-UHFFFAOYSA-N 0.000 description 1
- OUGYYYGJXDFHDV-AWEZNQCLSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@@H]1CN(CCO1)C)C(=O)OCC Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@@H]1CN(CCO1)C)C(=O)OCC OUGYYYGJXDFHDV-AWEZNQCLSA-N 0.000 description 1
- NKEUDXWTMNILDH-SNVBAGLBSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@@H]1OCC1)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@@H]1OCC1)C(=O)O NKEUDXWTMNILDH-SNVBAGLBSA-N 0.000 description 1
- OUGYYYGJXDFHDV-CQSZACIVSA-N CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@H]1CN(CCO1)C)C(=O)OCC Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@H]1CN(CCO1)C)C(=O)OCC OUGYYYGJXDFHDV-CQSZACIVSA-N 0.000 description 1
- NKEUDXWTMNILDH-JTQLQIEISA-N CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@H]1OCC1)C(=O)O Chemical compound CC1=C(OC=2CCC3=CN(N=C3C=21)C[C@H]1OCC1)C(=O)O NKEUDXWTMNILDH-JTQLQIEISA-N 0.000 description 1
- CXZAMZFUESCICT-UHFFFAOYSA-N CC1=NC(=CC(=C1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)O)C Chemical compound CC1=NC(=CC(=C1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)O)C CXZAMZFUESCICT-UHFFFAOYSA-N 0.000 description 1
- KFEUBRWGLBEVNP-UHFFFAOYSA-N CC1=NC(=CC=C1CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)O)C Chemical compound CC1=NC(=CC=C1CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)O)C KFEUBRWGLBEVNP-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- HFVCQSSEDXQLSG-UHFFFAOYSA-N ClC(C(=O)O)C(=O)C1CC1 Chemical compound ClC(C(=O)O)C(=O)C1CC1 HFVCQSSEDXQLSG-UHFFFAOYSA-N 0.000 description 1
- MRTOFVRIAIQDLM-UHFFFAOYSA-N ClC=1C(=NC=C(C=1)F)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)OCC Chemical compound ClC=1C(=NC=C(C=1)F)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)OCC MRTOFVRIAIQDLM-UHFFFAOYSA-N 0.000 description 1
- IPJSCUFLMSEQMC-UHFFFAOYSA-N ClC=1C(=NC=C(C=1)OCC)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)O Chemical compound ClC=1C(=NC=C(C=1)OCC)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)O IPJSCUFLMSEQMC-UHFFFAOYSA-N 0.000 description 1
- QRPXFAUHNKPZAB-UHFFFAOYSA-N ClC=1C(=NC=CC=1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)O Chemical compound ClC=1C(=NC=CC=1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)O QRPXFAUHNKPZAB-UHFFFAOYSA-N 0.000 description 1
- SVSQOGBIZAIIGA-UHFFFAOYSA-N ClC=1C(=NC=CC=1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)OCC Chemical compound ClC=1C(=NC=CC=1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)OCC SVSQOGBIZAIIGA-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- GEUHDGBIDYWBHA-UHFFFAOYSA-N FC1(COC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)O Chemical compound FC1(COC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)O GEUHDGBIDYWBHA-UHFFFAOYSA-N 0.000 description 1
- BKAOJOOKHJEOPC-UHFFFAOYSA-N FC1(COC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)OCC Chemical compound FC1(COC1)CN1N=C2C3=C(CCC2=C1)OC(=C3C)C(=O)OCC BKAOJOOKHJEOPC-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 102100033049 G-protein coupled receptor 42 Human genes 0.000 description 1
- 101710107771 G-protein coupled receptor 84 Proteins 0.000 description 1
- 101150000419 GPC gene Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 101000824278 Homo sapiens Acyl-[acyl-carrier-protein] hydrolase Proteins 0.000 description 1
- 101000871098 Homo sapiens G-protein coupled receptor 42 Proteins 0.000 description 1
- 101000735429 Homo sapiens Terminal nucleotidyltransferase 4B Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- YZBOVSFWWNVKRJ-UHFFFAOYSA-N Monobutylphthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(O)=O YZBOVSFWWNVKRJ-UHFFFAOYSA-N 0.000 description 1
- 235000021360 Myristic acid Nutrition 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 1
- PUYHLIFIQCPTAJ-UHFFFAOYSA-N N1=C(C=CC=C1)CN1N=C2C3=C(CCC2=C1)OC(=C3)C=O Chemical compound N1=C(C=CC=C1)CN1N=C2C3=C(CCC2=C1)OC(=C3)C=O PUYHLIFIQCPTAJ-UHFFFAOYSA-N 0.000 description 1
- RBJRJGXBKLRINK-UHFFFAOYSA-N N1=C(C=CC=C1)CN1N=C2C3=C(CCC2=C1)OC(=C3C(F)(F)F)C(=O)O Chemical compound N1=C(C=CC=C1)CN1N=C2C3=C(CCC2=C1)OC(=C3C(F)(F)F)C(=O)O RBJRJGXBKLRINK-UHFFFAOYSA-N 0.000 description 1
- SWILPFGZTFTGRE-UHFFFAOYSA-N N1=C(C=CC=C1)CN1N=C2C3=C(CCC2=C1)OC=C3 Chemical compound N1=C(C=CC=C1)CN1N=C2C3=C(CCC2=C1)OC=C3 SWILPFGZTFTGRE-UHFFFAOYSA-N 0.000 description 1
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010061876 Obstruction Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 108091034057 RNA (poly(A)) Proteins 0.000 description 1
- 101710197776 Serine hydroxymethyltransferase 2 Proteins 0.000 description 1
- 102100034606 Serine hydroxymethyltransferase, mitochondrial Human genes 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 102100034938 Terminal nucleotidyltransferase 4B Human genes 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- PQZJTHGEFIQMCO-SCSAIBSYSA-N [(2R)-oxetan-2-yl]methanol Chemical compound OC[C@H]1CCO1 PQZJTHGEFIQMCO-SCSAIBSYSA-N 0.000 description 1
- CMEPUAROFJSGJN-YFKPBYRVSA-N [(2s)-1,4-dioxan-2-yl]methanol Chemical compound OC[C@H]1COCCO1 CMEPUAROFJSGJN-YFKPBYRVSA-N 0.000 description 1
- PQZJTHGEFIQMCO-BYPYZUCNSA-N [(2s)-oxetan-2-yl]methanol Chemical compound OC[C@@H]1CCO1 PQZJTHGEFIQMCO-BYPYZUCNSA-N 0.000 description 1
- QBCRLDPMQHPGIM-QGZVFWFLSA-N [2-fluoro-4-[2-(4-methoxyphenyl)ethynyl]phenyl]-[(3r)-3-hydroxypiperidin-1-yl]methanone Chemical compound C1=CC(OC)=CC=C1C#CC(C=C1F)=CC=C1C(=O)N1C[C@H](O)CCC1 QBCRLDPMQHPGIM-QGZVFWFLSA-N 0.000 description 1
- 238000010958 [3+2] cycloaddition reaction Methods 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 229960000250 adipic acid Drugs 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 229940059913 ammonium carbonate Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- XOZUGNYVDXMRKW-AATRIKPKSA-N azodicarbonamide Chemical compound NC(=O)\N=N\C(N)=O XOZUGNYVDXMRKW-AATRIKPKSA-N 0.000 description 1
- 235000019399 azodicarbonamide Nutrition 0.000 description 1
- 125000003943 azolyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960001716 benzalkonium Drugs 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- CYDRXTMLKJDRQH-UHFFFAOYSA-N benzododecinium Chemical compound CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 CYDRXTMLKJDRQH-UHFFFAOYSA-N 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- YOUGRGFIHBUKRS-UHFFFAOYSA-N benzyl(trimethyl)azanium Chemical compound C[N+](C)(C)CC1=CC=CC=C1 YOUGRGFIHBUKRS-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 229960002152 chlorhexidine acetate Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 210000003690 classically activated macrophage Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960003624 creatine Drugs 0.000 description 1
- 239000006046 creatine Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- GUDMZGLFZNLYEY-UHFFFAOYSA-N cyclopropylmethanol Chemical compound OCC1CC1 GUDMZGLFZNLYEY-UHFFFAOYSA-N 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- YVWUNJVPOCYLIM-UHFFFAOYSA-N ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate Chemical compound CCOC(=O)C(Cl)C(=O)C(F)(F)F YVWUNJVPOCYLIM-UHFFFAOYSA-N 0.000 description 1
- OCJKUQIPRNZDTK-UHFFFAOYSA-N ethyl 4,4,4-trifluoro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)C(F)(F)F OCJKUQIPRNZDTK-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000000105 evaporative light scattering detection Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 229940116364 hard fat Drugs 0.000 description 1
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 102000052494 human GPR84 Human genes 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000008311 hydrophilic ointment Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000001023 inorganic pigment Substances 0.000 description 1
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 238000001465 metallisation Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GEWJEKADAXWFPY-UHFFFAOYSA-N methyl 1h-indazole-7-carboxylate Chemical compound COC(=O)C1=CC=CC2=C1NN=C2 GEWJEKADAXWFPY-UHFFFAOYSA-N 0.000 description 1
- RIJWDPRXCXJDPK-UHFFFAOYSA-N methyl 3-cyclopropyl-3-oxopropanoate Chemical compound COC(=O)CC(=O)C1CC1 RIJWDPRXCXJDPK-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- IZXGZAJMDLJLMF-UHFFFAOYSA-N methylaminomethanol Chemical compound CNCO IZXGZAJMDLJLMF-UHFFFAOYSA-N 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000002025 microglial effect Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 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 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229950009755 odanacatib Drugs 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 229920003175 pectinic acid Polymers 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000011941 photocatalyst Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- TYRDEZUMAVRTEO-UHFFFAOYSA-N pyrimidin-5-ylmethanol Chemical compound OCC1=CN=CN=C1 TYRDEZUMAVRTEO-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- LMUMMJCCZMWLEN-UHFFFAOYSA-N spiro[3.3]heptyl Chemical group [CH]1CCC11CCC1 LMUMMJCCZMWLEN-UHFFFAOYSA-N 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 159000000008 strontium salts Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- FWMUJAIKEJWSSY-UHFFFAOYSA-N sulfur dichloride Chemical compound ClSCl FWMUJAIKEJWSSY-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 1
- 108010017101 telaprevir Proteins 0.000 description 1
- 229960002935 telaprevir Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000001166 thiolanyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- QCRXMFTZTSTGJM-UHFFFAOYSA-N triacetyl 2-hydroxypropane-1,2,3-tricarboxylate Chemical compound CC(=O)OC(=O)CC(O)(C(=O)OC(C)=O)CC(=O)OC(C)=O QCRXMFTZTSTGJM-UHFFFAOYSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 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
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Emergency Medicine (AREA)
- Dermatology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本發明涵蓋通式(I)之呋喃并吲唑化合物:
其中R1
、R2
、R3
、R4
、R5
、R6
、R7a
及R7b
如本文所定義;製備該等化合物之方法;適用於製備該等化合物之中間物化合物;包含該等化合物之醫藥組合物;及該等化合物用於製造醫藥組合物的用途,該等醫藥組合物用於治療或預防人類及動物的疾病,特定言之,自體免疫疾病,諸如多發性硬化症、牛皮癬、牛皮癬性關節炎、類風濕性關節炎、僵直性脊椎炎、全身性紅斑狼瘡、原發及繼發自體免疫葡萄膜炎、發炎病症(如子宮內膜異位、發炎眼病、發炎腎病、發炎肝病(如非酒精性、酒精性及毒性脂肪肝疾病))、肺病(如哮喘、特發性肺纖維化、慢性阻塞性肺病),以及代謝及代謝內分泌病症(如代謝症候群、抗胰島素症、I型及II型糖尿病),以及多囊性卵巢症候群(polycystic ovary syndrome;PCOS)病症、神經病變性及發炎性疼痛病症。
Description
本發明涵蓋如本文所述及所定義的通式(I)之呋喃并吲唑化合物;製備該等化合物之方法;適用於製備該等化合物的中間物化合物;包含該等化合物的醫藥組合物;以及該等化合物用於製造醫藥組合物的用途,該等醫藥組合物用於治療或預防疾病,特定言之,自體免疫疾病,諸如多發性硬化症、牛皮癬、牛皮癬性關節炎、類風濕性關節炎、僵直性脊椎炎、全身性紅斑狼瘡、原發及繼發自體免疫葡萄膜炎、發炎病症(如子宮內膜異位、發炎眼病、發炎腎病、發炎肝病(如非酒精性、酒精性及毒性脂肪肝疾病))、肺病(如哮喘、特發性肺纖維化、慢性阻塞性肺病)、以及代謝及代謝內分泌病症(如代謝症候群、抗胰島素症、I型及II型糖尿病),以及多囊性卵巢症候群(PCOS)病症、神經病變性及發炎性疼痛病症。
本發明涵蓋通式(I)之呋喃并吲唑化合物,其為G蛋白偶聯受體84 (亦稱為GPR84)之拮抗劑。GPR84與人類疾病的相關性在若干公開案已有描述及研究。
中長鏈游離脂肪酸(MCFFA)係尾部有6至12個碳之脂肪酸且可以活化GPR84 (Wang J等人, J. Biol. Chem. 2006年11月10日, 281(45): 34457-64)。動物代謝的FA存在兩種來源:外源性來源的(膳食) FA與內源性合成的FA。後者的生物合成由FASN催化。MCFFA刺激纖維母細胞釋放IL6 (Smith及Tasi, Nat. Prod. Rep. 2007年10月, 24(5): 1041-72)且肉豆蔻酸使人類冠狀動脈平滑肌(HCASM)及內皮(HCEC)細胞中的IL6及IL8含量增加(Soto-Vaca A.等人, J. Agric. Food Chem. 2013年10月23日, 61(42): 10074-9)。
GPR84屬於游離脂肪酸(FFA)受體群組(Wang J.等人, J. Biol. Chem. 2006年11月10日, 281(45): 34457-64)。FFA受體群組由4種GPCR (FFA1-FFA2)以及新成員GPR42及GPR84組成。FFA受體涉及諸如代謝及免疫功能受體之生物過程(Wang J.等人, J. Biol. Chem. 2006年11月10日, 281(45): 34457-64)。
與具有較寬表現譜式之所有其他FFA受體相比,已描述GPR84主要在多種白血球群體及脂肪細胞中表現(Wang J.等人, J. Biol. Chem. 2006年11月10日, 281(45): 34457-64;Lattin J.E.等人, Immunome Res. 2008年4月29日, 4: 5;Nagasaki H.等人, FEBS Lett. 2012年2月17日, 586(4): 368-72)。
GPR84的活化促進全面的纖維化及發炎細胞反應,此體現為增強的巨噬細胞及嗜中性球遷移、被促進的促炎性M1巨噬細胞極化及反應以及關鍵發炎細胞介素(諸如IL1β及TNFα)分泌(Gagnon L.等人, Am. J. Pathol. 2018年5月, 188(5): 1132-1148;Muredda L.等人, Arch. Physiol. Biochem. 2018年5月, 124(2): 97-108;Huang Q.等人, Dev. Comp. Immunol. 2014, 45(2): 252-258)。基於GPR84涉及纖維化及發炎細胞反應,已表明若干疾病與GPR84相關。
作為微神經膠質細胞相關蛋白的GPR84表現於神經發炎病狀中且被描述為用於治療多發性硬化症(Bouchard C.等人, Glia 2007年6月, 55(8): 790-800)及子宮內膜異位相關疼痛及發炎疼痛(Sacher F.等人, 2018, 2018年SRI會議摘要)的潛在目標。另外,在若干臨床前模型中抑制GPR84活性及/或剔除其基因亦有效地治療神經病變性疼痛(Roman等人, 2010, 歐洲神經科學第7屆論壇(7th Forum of European Neuroscience, FENS))。
GPR84與發炎腎病的相關性已在實驗中展示,該等實驗使用Gpr84基因剔除小鼠,或在腎臟纖維化模型及發炎肝病(如非酒精性、酒精性及毒性脂肪肝疾病)模型中使用GPR84拮抗劑(Puengel等人, 2018, 2018年歐洲肝臟研究協會國際肝臟會議(International Liver Congress (ILC) of the European Association for the Study of the Liver (EASL));Thibodeau J.F.等人, 2018, 美國腎病學學會第51屆年度會議及展覽會(51st Annual Meeting and Exposition of the American Society of Nephrology (ASN)): Kidney Week 2018)。
如先前針對巨噬細胞及單核球所述,脂肪組織的發炎變化使脂肪細胞中的GPR84表現增強且對GPR84的調節調控脂肪細胞免疫反應能力(Muredda等人, Archives of Physiology and Biochemistry 2017年8月, 124(2): 1-12),表明GPR84與代謝及代謝內分泌病症(如代謝症候群、抗胰島素症、I型及II型糖尿病,以及多囊性卵巢症候群(PCOS))相關(根據脂肪組織發炎的標準化)。
調控與肺病(如哮喘、特發性肺纖維化及慢性阻塞性肺病)相關之GPR84引起的嗜中性球活性及一般發炎亦有描述(Nguyen等人, 2018; 美國心臟協會年度會議科學對話(Annual Congress Scientific Sessions of the American Heart Association)(AHA 2018);Saniere L.等人, 2019; 2019年美國胸科學會國際會議(International Conference of the American Thoracic Society (ATS))。
有幾種化合物已知為GPR84拮抗劑,例如專利申請案WO2013092791及WO2014095798揭示二氫嘧啶并異喹啉酮具有GPR84拮抗劑活性。此類化合物用於若干治療應用,包括發炎病狀。
專利申請案WO2015197550及WO2016169911揭示相關的二氫吡啶并異喹啉酮為GPR84拮抗劑。
專利申請案WO2018161831揭示二苯并輪烯(dibenzoannulen)磷酸氫鹽為GPR84拮抗劑。
專利申請案WO2009023773揭示藉由高通量篩選方法鑑別出半乳糖激酶抑制劑。鑑別出的匹配結果中有兩種呋喃并吲唑化合物。
專利申請案US20090163545揭示藉由基於細胞的表型高通量篩選方法鑑別出用於改變真核生物體壽命的化合物。鑑別出的匹配結果中有兩種呋喃并吲唑化合物。
專利申請案US6245796B1、WO2001083487及WO2011071136揭示芳族三環吡咯或吡唑衍生物為5-HT2c配位體。
專利申請案WO2016085990揭示藉由高通量篩選方法鑑別出抑制絲胺酸羥甲基轉移酶2活性的化合物。鑑別出的匹配結果中有九種呋喃并吲唑化合物。
專利申請案WO2019084271揭示藉由高通量篩選方法鑑別出抑制含有非典型聚(A) RNA聚合酶相關域之蛋白質5 (PAPD5)、來源於不同化合物類別的化合物。鑑別出的匹配結果中有八種呋喃并吲唑化合物。
然而,目前先進技術未描述如本文所述及所定義之本發明之通式(I)之呋喃并吲唑化合物。
現已發現本發明之化合物具有驚人且有利的特性,且此構成本發明之基礎。
特定言之,已驚人地發現本發明化合物為人類GPR84之有效拮抗劑且可用於治療或預防疾病,特定言之,自體免疫疾病,諸如多發性硬化症、牛皮癬、牛皮癬性關節炎、類風濕性關節炎、僵直性脊椎炎、全身性紅斑狼瘡、原發及繼發自體免疫葡萄膜炎;發炎病症,如子宮內膜異位、發炎眼病、發炎腎病;發炎肝病,如非酒精性、酒精性及毒性脂肪肝疾病;肺病,如哮喘、特發性肺纖維化、慢性阻塞性肺病以及代謝及代謝內分泌病症,如代謝症候群、抗胰島素症、I型及II型糖尿病,及多囊性卵巢症候群(PCOS)病症、神經病變性及發炎性疼痛病症。
根據第一態樣,本發明涵蓋通式(I)化合物:
其中:
R1
表示氫、C1
-C4
烷基或C1
-C4
鹵烷基;
R2
表示氫、C1
-C4
烷基或C1
-C4
鹵烷基;或
R1
及R2
與其所連接之碳原子一起形成3員至6員環烷基或雜環烷基環;
R3
表示C3
-C6
環烷基、3員至6員雜環烷基、與苯基或雜芳基稠合的雜環烷基,或雜芳基,其中該等基團彼此獨立地視情況經R8
取代一或多次,或
R3
表示苯基,其彼此獨立地視情況經R8
取代一或多次,且另外,R7a
及R7b
表示氘;
R4
表示氫、C1
-C4
烷基、C1
-C4
鹵烷基或C3
-C6
環烷基;
R5
、R6
彼此獨立地表示氫、C1
-C4
烷基、C2
-C4
羥基烷基、(C1
-C4
烷氧基)-(C2
-C4
烷基)-、C3
-C6
環烷基、C1
-C4
鹵烷基、C3
-C6
鹵環烷基、3員至6員雜環烷基、雜螺環烷基、苯基、雜芳基、與苯基或雜芳基稠合的雜環烷基、3員至6員雜環烷基-(C1
-C3
烷基)-、雜螺環烷基-(C1
-C3
烷基)-、(與苯基或雜芳基稠合的雜環烷基)-(C1
-C3
烷基)-、苯基-(C1
-C3
烷基)-或雜芳基-(C1
-C3
烷基)-,其中該3員至6員雜環烷基、雜螺環烷基、與苯基或雜芳基稠合的雜環烷基、苯基或雜芳基彼此獨立地視情況經R9
取代一或多次,或
R5
及R6
連同其所連接之氮原子一起形成3員至6員含氮雜環,該含氮雜環視情況含有一個選自O、NH及S之額外雜原子或含雜原子基團,且可彼此獨立地視情況經R9
取代一或多次;
R7a
表示氫、氘或C1
-C4
烷基;
R7b
表示氫、氘或C1
-C4
烷基;
R8
表示鹵素、氰基、C1
-C4
烷基、C1
-C4
鹵烷基、C1
-C3
烷氧基、C1
-C3
鹵烷氧基、C3
-C6
環烷基、C3
-C6
環烷基-(C1
-C3
烷基)-、R13
-(C=O)-、R10
-O-(C=O)-、R11
-NH-(C=O)-,或R12
-(SO2
)-;
R9
表示鹵素、氰基、C1
-C4
烷基、C1
-C4
鹵烷基、H2
N-C1
-C4
烷基、C1
-C3
烷氧基、C1
-C3
鹵烷氧基、C3
-C6
環烷基、R10
-O-(C=O)-、側氧基、5員至6員雜環烷基-、5員至6員雜環烷基-(C1
-C3
烷基)-、苯基或雜芳基,其中該苯基或雜芳基彼此獨立地視情況經鹵素、C1
-C4
烷基、C1
-C4
鹵烷基、C1
-C3
烷氧基或C1
-C3
鹵烷氧基取代一或多次;
R10
表示氫、C1
-C4
烷基,或苯基-CH2
-;
R11
表示氫、C1
-C4
烷基,或5員至6員雜環烷基-(C1
-C3
烷基)-;
R12
表示C1
-C4
烷基或苯基;
R13
表示C1
-C4
烷基、C1
-C4
鹵烷基、(C1
-C4
烷氧基)-(C1
-C4
烷基)-、C1
-C4
烷基-(C=O)-、C3
-C6
環烷基或苯基,其中該C3
-C6
環烷基視情況經C1
-C4
烷基或羥基取代且該苯基彼此獨立地視情況經鹵素、C1
-C4
烷基、C1
-C4
鹵烷基、C1
-C3
烷氧基或C1
-C3
鹵烷氧基取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
定義
術語「經取代」意謂指定原子或基團上之一或多個氫原子經選自指定基團之選項置換,其限制條件為不超過指定原子在現有情形下之正常價。容許取代基及/或變數之組合。
術語「視情況經取代」意謂取代基之數目可等於零或異於零。除非另外指示,否則視情況經取代之基團可經視情況存在之許多取代基取代,只要任何可利用之碳或氮原子上的氫原子被非氫取代基置換可以容納該等取代基。通常,視情況存在之取代基當存在時之數目可以是1、2、3、4或5,特定而言,1、2或3。
如本文所用,術語「一或多個」,例如在本發明之通式(I)化合物之取代基定義中,意謂1、2、3、4或5個,特定言之,1、2、3或4個,更特定言之,1、2或3個,甚至更特定言之,1或2個。
如本文所用,側氧基取代基表示經由雙鍵結合至碳原子之氧原子。
若複合取代基由超過一個部分組成(例如(C1
-C4
烷氧基)-(C1
-C4
烷基)-),則指定部分之位置有可能位於該複合取代基之任何適合位置,亦即,C1
-C4
烷氧基部分可以連接至該(C1
-C4
烷氧基)-(C1
-C4
烷基)-基團之C1
-C4
烷基部分之任何碳原子。此類複合取代基之開頭或末尾處之連字符指示該複合取代基與分子之其餘部分之連接點。若包含碳原子及視情況存在之一或多個雜原子(諸如氮、氧或硫原子)之環例如經取代基取代,則該取代基有可能在該環之任何適合位置處鍵結,其鍵結至適合碳原子及/或適合雜原子。
術語「包含(comprising)」當用於說明書中時包括「由……組成(consisting of)」。
若任一項在本文內以「如本文所提及」提及,則意謂其可在本文中之任何位置提及。
如本文中提及之術語具有以下含義:
術語「鹵素原子」意謂氟、氯、溴或碘原子,特定言之,氟、氯或溴原子。
術語「C1
-C4
烷基」意謂具有1、2、3或4個碳原子的直鏈或分支鏈飽和單價烴基,例如甲基、乙基、丙基、異丙基、丁基、第二丁基、異丁基、第三丁基。特定言之,該基團具有1、2或3個碳原子(「C1
-C3
烷基」),例如甲基、乙基、丙基或異丙基;更特定言之,具有1或2個碳原子(「C1
-C2
烷基」),例如甲基或乙基。
術語「C2
-C4
羥基烷基」意謂直鏈或分支鏈飽和單價烴基,其中術語「C2
-C4
烷基」如上文所定義,且其中一個氫原子經羥基置換,例如1-羥基乙基、2-羥基乙基、3-羥基丙基、2-羥基丙基、1-羥基丙基、1-羥基丙-2-基、2-羥基丙-2-基、3-羥基-2-甲基-丙基、2-羥基-2-甲基-丙基、1-羥基-2-甲基-丙基。
術語「C1
-C4
鹵烷基」意謂直鏈或分支鏈飽和單價烴基,其中術語「C1
-C4
烷基」如上文所定義,且其中一或多個氫原子經鹵素原子相同或不同地置換。特定言之,該鹵素原子為氟原子。該C1
-C4
鹵烷基為例如氟甲基、二氟甲基、三氟甲基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、五氟乙基、3,3,3-三氟丙基或1,3-二氟丙-2-基。
術語「C1
-C4
烷氧基」意謂式(C1
-C4
烷基)-O-之直鏈或分支鏈飽和單價基團,其中術語「C1
-C4
烷基」如上文所定義,例如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第二丁氧基、異丁氧基或第三丁氧基。
術語「C1
-C4
鹵烷氧基」意謂如上文所定義之直鏈或分支鏈飽和單價C1
-C4
烷氧基,其中一或多個氫原子經鹵素原子相同或不同地置換。特定言之,該鹵素原子為氟原子。該C1
-C4
鹵烷氧基為例如氟甲氧基、二氟甲氧基、三氟甲氧基、2,2,2-三氟乙氧基或五氟乙氧基。
術語「C3
-C6
環烷基」意謂含有3、4、5或6個碳原子之飽和單價單環烴環(「C3
-C6
環烷基」)。該C3
-C6
環烷基為例如環丙基、環丁基、環戊基或環己基。
術語「C3
-C6
鹵環烷基」意謂飽和單價單環烴環,其中術語「C3
-C6
鹵環烷基」如上文所定義,且其中一或多個氫原子經鹵素原子相同或不同地置換。特定言之,該鹵素原子為氟原子。
術語「4員至6員雜環烷基」意謂總共具有4、5或6個環原子之單環飽和雜環,其含有一或兩個來自N、O及S系列之相同或不同的環雜原子,該雜環烷基可經由碳原子或(若存在)氮原子中之任一者連接至分子之其餘部分。
該雜環烷基可為(不限於)例如4員環,諸如氮雜環丁基、氧雜環丁基或硫雜環丁基;或5員環,諸如四氫呋喃基、1,3-二氧雜環戊基、硫雜環戊基、吡咯啶基、咪唑啶基、吡唑啶基、1,1-二氧離子基硫雜環戊基、1,2-㗁唑啶基、1,3-㗁唑啶基或1,3-噻唑啶基;或例如6員環,諸如四氫哌喃基、四氫硫哌喃基、哌啶基、嗎啉基、二噻烷基、硫嗎啉基、哌𠯤基、1,3-二㗁烷基、1,4-二㗁烷基或1,2-氧氮雜環己基。
特定言之,「4員至6員雜環烷基」意謂如上文所定義之4員至6員雜環烷基,其含有一個環氮或氧原子及視情況存在之另一個選自N、O、S系列的環雜原子。更特定言之,「5員或6員雜環烷基」意謂總共具有5或6個環原子的單環飽和雜環,其含有一個環氮或氧原子及視情況存在之另一個選自N、O系列的環雜原子。
術語「與苯基或雜芳基稠合的雜環烷基」意謂總共具有8、9或10個環原子的雙環雜環,其中兩個環共享兩個相鄰環原子,且其中「雜環烷基」部分含有一個或兩個選自N、O及/或S系列的相同或不同環雜原子,且術語「雜芳基」意謂具有5或6個環原子的單環芳族環(「5員至6員雜芳基」基團),其含有至少一個環雜原子及視情況存在的一個、兩個或三個選自N、O及/或S系列之其他環雜原子;該稠合的雜環烷基可經由碳原子或(若存在)氮原子中之任一者連接至分子之其餘部分。
術語「雜螺環烷基」意謂總共有6、7、8、9、10或11個環原子之雙環飽和雜環,其中兩個環共享一個共同環碳原子,該「雜螺環烷基」含有一或兩個選自N、O、S系列之相同或不同環雜原子;該雜螺環烷基可以經由除螺接碳原子之外之任一碳原子或(若存在)氮原子連接至分子之其餘部分。
該雜螺環烷基為例如氮雜螺[2.3]己基、氮雜螺[3.3]庚基、氧氮雜螺[3.3]庚基、硫氮雜螺[3.3]庚基、氧雜螺[3.3]庚基、氧氮雜螺[5.3]壬基、氧氮雜螺[4.3]辛基、氮雜螺[4,5]癸基、氧氮雜螺[5.5]十一烷基、二氮雜螺[3.3]庚基、硫氮雜螺[3.3]庚基、硫氮雜螺[4.3]辛基、氮雜螺[5.5]十一烷基,或其他同系物骨架之一,諸如螺[3.4]-、螺[4.4]-、螺[2.4]-、螺[2.5]-、螺[2.6]-、螺[3.5]-、螺[3.6]-、螺[4.5]-及螺[4.6]-。
術語「雜芳基」意謂具有5、6、8、9或10個環原子(特定言之,5、6、9或10個環原子)之單價、單環、雙環或三環芳族環(「5員至10員雜芳基」),其含有至少一個環雜原子及視情況存在之一個、兩個或三個選自N、O及/或S系列之其他環雜原子,且其經由環碳原子或視情況經由環氮原子(若價數允許)鍵結。
該雜芳基可為5員雜芳基,諸如噻吩基、呋喃基、吡咯基、㗁唑基、噻唑基、咪唑基、吡唑基、異㗁唑基、異噻唑基、㗁二唑基、三唑基、噻二唑基或四唑基;或6員雜芳基,諸如吡啶基、嗒𠯤基、嘧啶基、吡𠯤基或三𠯤基;或三環雜芳基,諸如咔唑基、吖啶基或啡𠯤基;或9員雜芳基,諸如苯并呋喃基、苯并噻吩基、苯并㗁唑基、苯并異㗁唑基、苯并咪唑基、苯并噻唑基、苯并三唑基、吲唑基、吲哚基、異吲哚基、吲哚𠯤基或嘌呤基;或10員雜芳基,諸如喹啉基、喹唑啉基、異喹啉基、㖕啉基、呔𠯤基、喹喏啉基或喋啶基。
一般而言,且除非另外提及,否則雜芳基包括其所有可能的異構體形式,例如就連至分子之其餘部分之連接點而言的互變異構體及位置異構體。因此,在一些說明性的非限制實例中,術語吡啶基包括吡啶-2-基、吡啶-3-基及吡啶-4-基;或術語噻吩基包括噻吩-2-基及噻吩-3-基。
特定言之,雜芳基為吡啶基。
如本發明文本中所用,例如在「C1
-C6
烷基」、「C1
-C6
鹵烷基」、「C1
-C6
羥烷基」、「C1
-C6
烷氧基」或「C1
-C6
鹵烷氧基」定義之上下文中所用,術語「C1
-C6
」意謂具有1至6有限數目個碳原子(亦即1、2、3、4、5或6個碳原子)之烷基。
另外,如本文所用,如本發明文本中所用,例如在「C3
-C8
環烷基」定義之上下文中所用,術語「C3
-C8
」意謂具有3至8有限數目個碳原子(亦即3、4、5、6、7或8個碳原子)的環烷基。
當給定值範圍時,該範圍涵蓋該範圍內之各值及子範圍。
舉例而言:
「C1
-C6
」涵蓋C1
、C2
、C3
、C4
、C5
、C6
、C1
-C6
、C1
-C5
、C1
-C4
、C1
-C3
、C1
-C2
、C2
-C6
、C2
-C5
、C2
-C4
、C2
-C3
、C3
-C6
、C3
-C5
、C3
-C4
、C4
-C6
、C4
-C5
及C5
-C6
;
「C2
-C6
」涵蓋C2
、C3
、C4
、C5
、C6
、C2
-C6
、C2
-C5
、C2
-C4
、C2
-C3
、C3
-C6
、C3
-C5
、C3
-C4
、C4
-C6
、C4
-C5
及C5
-C6
;
「C3
-C10
」涵蓋C3
、C4
、C5
、C6
、C7
、C8
、C9
、C10
、C3
-C10
、C3
-C9
、C3
-C8
、C3
-C7
、C3
-C6
、C3
-C5
、C3
-C4
、C4
-C10
、C4
-C9
、C4
-C8
、C4
-C7
、C4
-C6
、C4
-C5
、C5
-C10
、C5
-C9
、C5
-C8
、C5
-C7
、C5
-C6
、C6
-C10
、C6
-C9
、C6
-C8
、C6
-C7
、C7
-C10
、C7
-C9
、C7
-C8
、C8
-C10
、C8
-C9
及C9
-C10
;
「C3
-C8
」涵蓋C3
、C4
、C5
、C6
、C7
、C8
、C3
-C8
、C3
-C7
、C3
-C6
、C3
-C5
、C3
-C4
、C4
-C8
、C4
-C7
、C4
-C6
、C4
-C5
、C5
-C8
、C5
-C7
、C5
-C6
、C6
-C8
、C6
-C7
及C7
-C8
;
「C3
-C6
」涵蓋C3
、C4
、C5
、C6
、C3
-C6
、C3
-C5
、C3
-C4
、C4
-C6
、C4
-C5
及C5
-C6
;
「C4
-C8
」涵蓋C4
、C5
、C6
、C7
、C8
、C4
-C8
、C4
-C7
、C4
-C6
、C4
-C5
、C5
-C8
、C5
-C7
、C5
-C6
、C6
-C8
、C6
-C7
及C7
-C8
;
「C4
-C7
」涵蓋C4
、C5
、C6
、C7
、C4
-C7
、C4
-C6
、C4
-C5
、C5
-C7
、C5
-C6
及C6
-C7
;
「C4
-C6
」涵蓋C4
、C5
、C6
、C4
-C6
、C4
-C5
及C5
-C6
;
「C5
-C10
」涵蓋C5
、C6
、C7
、C8
、C9
、C10
、C5
-C10
、C5
-C9
、C5
-C8
、C5
-C7
、C5
-C6
、C6
-C10
、C6
-C9
、C6
-C8
、C6
-C7
、C7
-C10
、C7
-C9
、C7
-C8
、C8
-C10
、C8
-C9
及C9
-C10
;
「C6
-C10
」涵蓋C6
、C7
、C8
、C9
、C10
、C6
-C10
、C6
-C9
、C6
-C8
、C6
-C7
、C7
-C10
、C7
-C9
、C7
-C8
、C8
-C10
、C8
-C9
及C9
-C10
。
如本文所用,術語「離去基」意謂在化學反應中被置換的原子或原子基團,其與鍵結電子形成穩定物種。特定言之,此離去基選自包含以下之群:鹵離子,特定言之,氟離子、氯離子、溴離子或碘離子;(甲基磺醯基)氧基、[(三氟甲基)磺醯基]氧基、[(九氟丁基)磺醯基]氧基、(苯基磺醯基)氧基、[(4-甲基苯基)磺醯基]氧基、[(4-溴苯基)磺醯基]氧基、[(4-硝基苯基)磺醯基]氧基、[(2-硝苯)磺醯基]氧基、[(4-異丙基苯基)磺醯基]氧基、[(2,4,6-三異丙基苯基)磺醯基]氧基、[(2,4,6-三甲基苯基)磺醯基]氧基、[(4-第三丁基苯基)磺醯基]氧基及[(4-甲氧基苯基)磺醯基]氧基。
通式(I)化合物可以同位素變體形式存在。因此,本發明包括通式(I)化合物之一或多種同位素變體,特定言之,通式(I)之含氘化合物。
術語化合物或試劑之「同位素變體」定義為展現構成此類化合物之一或多種同位素之非天然比例的化合物。
術語「通式(I)化合物之同位素變體」定義為展現構成此類化合物之一或多種同位素之非天然比例的通式(I)化合物。
表述「非天然比例」意謂此類同位素之高於其天然豐度的比例。適用於本文中之同位素之天然豐度描述於「Isotopic Compositions of the Elements 1997」, Pure Appl. Chem., 70(1), 217-235, 1998中。
此類同位素之實例包括氫、碳、氮、氧、磷、硫、氟、氯、溴及碘之穩定的放射性同位素,分別諸如2
H (氘)、3
H (氚)、11
C、13
C、14
C、15
N、17
O、18
O、32
P、33
P、33
S、34
S、35
S、36
S、18
F、36
Cl、82
Br、123
I、124
I、125
I、129
I及131
I。
關於本文中所指定病症之治療及/或預防,通式(I)化合物之同位素變體較佳含有氘(「通式(I)之含氘化合物」)。其中併入一或多個放射性同位素(諸如3
H或14
C)的通式(I)化合物之同位素變體適用於例如藥物及/或受質組織分佈研究中。此等同位素就其容易併入及可偵測性而言尤其較佳。可以將諸如18
F或11
C之正電子發射同位素併入通式(I)化合物中。通式(I)化合物之此等同位素變體適用於活體內成像應用。含氘及含13
C之通式(I)化合物可以在臨床前或臨床研究之背景下用於質譜分析中。
通式(I)化合物之同位素變體通常可以藉由熟習此項技術者已知之方法製備,諸如本文流程及/或實例中所述之方法,藉由用試劑之同位素變體、較佳含氘試劑取代該試劑。視所要氘化位點而定,在一些情況下,來自D2
O之氘可直接併入化合物中或併入適用於合成此類化合物之試劑中。氘氣亦為適用於將氘併入分子中之試劑。烯鍵及炔鍵之催化氘化為併入氘之快速途徑。金屬催化劑(亦即Pd、Pt及Rh)在氘氣存在下可用於含官能基之烴中的氘與氫直接交換。多種氘化試劑及合成結構單元可購自各公司,諸如C/D/N Isotopes, Quebec, Canada;Cambridge Isotope Laboratories Inc., Andover, MA, USA;及CombiPhos Catalysts, Inc., Princeton, NJ, USA。
術語「通式(I)之含氘化合物」定義為其中一或多個氫原子經一或多個氘原子置換且其中通式(I)之化合物之各氘化位置之氘的豐度高於氘之天然豐度(其為約0.015%)的通式(I)化合物。特定言之,在通式(I)之含氘化合物中,通式(I)化合物之各氘化位置的氘豐度比該(等)位置高10%、20%、30%、40%、50%、60%、70%或80%,較佳高90%、95%、96%或97%,甚至更佳高98%或99%。應瞭解,各氘化位置處之氘豐度獨立於其他氘化位置處之氘豐度。
將一或多個氘原子選擇性併入通式(I)化合物中可以改變分子之物理化學特性(諸如酸性[C. L. Perrin等人, J. Am. Chem. Soc., 2007, 129, 4490]、鹼性[C. L. Perrin等人, J. Am. Chem. Soc., 2005, 127, 9641]、親脂性[B. Testa等人, Int. J. Pharm., 1984, 19(3), 271])及/或代謝概況,且可引起親本化合物與代謝物之比率或所形成代謝物之量變化。此類變化可以產生某些治療優勢且因此在一些情況下可為較佳的。減小之代謝及代謝轉換速率(其中代謝物比率改變)已有報導(A. E. Mutlib等人, Toxicol. Appl. Pharmacol., 2000, 169, 102)。暴露於親本藥物及代謝物之此等變化就通式(I)之含氘化合物之藥效學、耐受性及功效而言可以具有重要結果。在一些情況下,氘取代減少或消除非所要或毒性代謝物之形成且增強所要代謝物之形成(例如Nevirapine: A. M. Sharma等人, Chem. Res. Toxicol., 2013, 26, 410;Efavirenz: A. E. Mutlib等人, Toxicol. Appl. Pharmacol., 2000, 169, 102)。在其他情況下,氘化之主要作用為降低全身清除速率。從而延長化合物之生物半衰期。潛在臨床益處包括能夠經由降低峰值含量及增加谷值含量來維持類似的全身暴露。視特定化合物之藥物動力學/藥效學關係而定,此舉可減少副作用及增強功效。ML-337 (C. J. Wenthur等人, J. Med. Chem., 2013, 56, 5208)及奧當卡替(Odanacatib) (K. Kassahun等人, WO2012/112363)為此氘效應之實例。還已報導其他情況,其中代謝速率降低引起藥物暴露增加而全身性清除速率不變(例如羅非昔布(Rofecoxib):F. Schneider等人, Arzneim. Forsch./Drug. Res., 2006, 56, 295;特拉匹韋(Telaprevir):F. Maltais等人, J. Med. Chem., 2009, 52, 7993)。展示此作用之氘化藥物可以降低劑量需求(例如達成所要作用之給藥次數降低或劑量降低)及/或可產生較低之代謝物負荷。
通式(I)化合物可具有多個潛在的代謝攻擊位點。為了最佳化針對物理化學特性及代謝概況的上述作用,可以選擇具有一或多個氘-氫交換之某種模式的通式(I)之含氘化合物。特定言之,通式(I)之含氘化合物之氘原子連接至碳原子且/或位於通式(I)化合物之作為代謝酶(諸如細胞色素P450
)之攻擊位點的彼等位置。
在詞語化合物、鹽、多晶型物、水合物、溶劑合物及其類似物於本文中使用複數形式的情況下,其亦意指單一化合物、鹽、多晶型物、異構體、水合物、溶劑合物或其類似物。
「穩定化合物」或「穩定結構」意謂化合物足夠穩固以經受住自反應混合物分離至適用純度且調配為有效治療劑。
視所需不同取代基之位置及性質而定,本發明化合物視情況含有一或多個不對稱中心。一或多個不對稱碳原子有可能以(R)或(S)組態存在,此可在單一不對稱中心的情況下產生外消旋混合物且在多個不對稱中心的情況下產生非對映異構體混合物。在某些情況下,由於圍繞所指定鍵(與所指定化合物之兩個經取代芳族環鄰接的中心鍵)的旋轉受到限制,因此亦可能存在不對稱性。
較佳化合物為產生更需要之生物活性的彼等化合物。本發明化合物之經分離的純或部分純化異構體及立體異構體或外消旋或非對映異構體混合物亦包括在本發明之範疇內。此類物質之純化及分離可藉由此項技術中已知之標準技術實現。
較佳異構體為產生更需要之生物活性的彼等物。本發明化合物之此等經分離之純或部分純化異構體或外消旋混合物亦包括在本發明範疇內。此類物質之純化及分離可藉由此項技術中已知之標準技術實現。
光學異構體可藉由根據習知方法解析外消旋混合物來獲得,例如藉由使用光學活性酸或鹼形成非對映異構體鹽,或形成共價非對映異構體來獲得。適當酸之實例為酒石酸、二乙醯基酒石酸、二甲苯醯基酒石酸及樟腦磺酸。非對映異構體之混合物可藉由此項技術中已知之方法(例如藉由層析或分步結晶)基於其物理及/或化學差異分離成其個別非對映異構體。接著自經分離之非對映異構體鹽釋放光活性鹼或酸。分離光學異構體之不同方法包括聯合或不聯合習知衍生法使用對掌性層析(例如使用對掌相的HPLC管柱),其經最佳選擇以使對映異構體之分離最大化。使用對掌相之適合HPLC管柱可市購,諸如Daicel製造之管柱,例如Chiracel OD及Chiracel OJ,例如許多其他管柱,其均可以常規方式選擇。使用或不使用衍生法的酶分離亦為適用的。本發明之光學活性化合物同樣可藉由對掌性合成、利用光學活性起始物質來獲得。
為了將不同類型的異構體彼此區分開來,參考IUPAC規則第E章(Pure Appl Chem 45, 11-30, 1976)。
本發明包括本發明化合物之所有可能立體異構體,其呈單一立體異構體形式或呈該等立體異構體(例如(R)-異構體或(S)-異構體)之任何比率之任何混合物形式。本發明化合物之單一立體異構體(例如單一對映異構體或單一非對映異構體)的分離例如藉由任何適合的現有技術方法(諸如層析法,尤其對掌性層析法)達成。
另外,本發明的化合物可以互變異構體形式存在。舉例而言,含有吲唑部分的本發明任何化合物可以1H互變異構體或2H互變異構體形式存在,或甚至以任何量之兩種互變異構體的混合物存在,亦即:
1H互變異構體 | 2H互變異構體 |
本發明包括本發明化合物的所有可能互變異構體,其呈單一互變異構體形式或該等互變異構體之任何比率的任何混合物形式。
此外,本發明化合物可以N-氧化物形式存在,其定義為本發明化合物中之至少一個氮經氧化。本發明包括所有此類可能的N-氧化物。
本發明亦涵蓋本發明化合物之有用形式,諸如代謝物、水合物、溶劑合物、前藥、鹽(尤其醫藥學上可接受之鹽)及/或共沈澱物。
本發明化合物可以水合物或溶劑合物形式存在,其中本發明化合物含有極性溶劑(特定言之,例如水、甲醇或乙醇)作為化合物晶格的結構元素。極性溶劑(特定言之,水)之量可以化學計量或非化學計量比率存在。在化學計量溶劑合物(例如水合物)的情況下,半溶劑合物、單溶劑合物、倍半溶劑合物、二溶劑合物、三溶劑合物、四溶劑合物、五溶劑合物或水合物等分別係可能的。本發明包括所有此類水合物或溶劑合物。
此外,本發明化合物可以游離形式(例如游離鹼或游離酸形式)或兩性離子形式存在,或以鹽形式存在。該鹽可為製藥學中常用或用於例如分離或純化本發明化合物之任何鹽(有機或無機加成鹽),特定言之,醫藥學上可接受之任何有機或無機加成鹽。
術語「醫藥學上可接受之鹽」係指本發明化合物之無機或有機酸加成鹽。舉例而言,參見S. M. Berge,等人「Pharmaceutical Salts,」J. Pharm. Sci. 1977, 66, 1-19。
本發明化合物之醫藥學上可接受之適合鹽可為例如在例如鏈或環中具有氮原子之本發明化合物之酸加成鹽,其具有足夠鹼性,諸如與無機酸(諸如鹽酸、氫溴酸、氫碘酸、硫酸、胺磺酸、二硫酸、磷酸或硝酸)或與有機酸(諸如甲酸、乙酸、乙醯乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水楊酸、2-(4-羥基苯甲醯基)-苯甲酸、樟腦酸、肉桂酸、環戊烷丙酸、二葡萄糖酸、3-羥基-2-萘甲酸、菸鹼酸、雙羥萘酸、果膠酯酸、3-苯基丙酸、特戊酸、2-羥基乙烷磺酸、伊康酸、三氟甲烷磺酸、十二烷基硫酸、乙烷磺酸、苯磺酸、對甲苯磺酸、甲烷磺酸、2-萘磺酸、萘二磺酸、樟腦磺酸、檸檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、丁二酸、蘋果酸、己二酸、海藻酸、順丁烯二酸、反丁烯二酸、D-葡萄糖酸、杏仁酸、抗壞血酸、葡糖庚酸、甘油磷酸、天冬胺酸、磺基水楊酸或硫氰酸)之酸加成鹽。
此外,具有足夠酸性之本發明化合物的另一種醫藥學上可接受之適合鹽為鹼金屬鹽,例如鈉或鉀鹽;鹼土金屬鹽,例如鈣、鎂或鍶鹽;或鋁或鋅鹽;或衍生自氨或具有1至20個碳原子的一級、二級或三級有機胺之銨鹽,諸如乙胺、二乙胺、三乙胺、乙基二異丙胺、單乙醇胺、二乙醇胺、三乙醇胺、二環己胺、二甲胺基乙醇、二乙胺基乙醇、參(羥甲基)胺基甲烷、普魯卡因(procaine)、二苯甲基胺、N
-甲基嗎啉、精胺酸、離胺酸、1,2-乙二胺、N
-甲基哌啶、N
-甲基-還原葡糖胺、N,N
-二甲基-還原葡糖胺、N
-乙基-還原葡糖胺、1,6-己二胺、葡糖胺、肌胺酸、絲胺醇、2-胺基-1,3-丙二醇、3-胺基-1,2-丙二醇、4-胺基-1,2,3-丁三醇;或與具有1至20個碳原子的四級銨離子之鹽,諸如四甲銨、四乙銨、四(正丙基)銨、四(正丁基)銨、N
-苯甲基-N,N,N
-三甲銨、膽鹼或苯甲烴銨。
熟習此項技術者應進一步瞭解,可經由多種已知方法中之任一者使化合物與適當無機酸或有機酸反應來製備所主張化合物之酸加成鹽。或者,本發明之酸性化合物的鹼金屬鹽及鹼土金屬鹽係藉由使本發明化合物與適當鹼經由多種已知方法反應而製備。
本發明包括本發明化合物之所有可能鹽,其呈單一鹽形式或該等鹽之任何比率的任何混合物形式。
在本文中,尤其在實驗章節中,就本發明之中間物及實例的合成而言,當提及化合物為與對應鹼或酸形成之鹽形式時,如藉由各別製備及/或純化方法獲得之該鹽形式的確切化學計量組成在大多數情況下為未知的。
除非另外說明,否則關於鹽之化學名稱或結構式之後綴,諸如「鹽酸鹽」、「三氟乙酸鹽」、「鈉鹽」或「x HCl」、「x CF3
COOH」、「x Na+
」意謂鹽形式,該鹽形式之化學計量未指明。
此類似地適用於如下情況:合成中間物或實例化合物或其鹽已藉由所述製備及/或純化方法、以(若定義)化學計量組成未知的溶劑合物(諸如水合物)形式獲得。
此外,本發明包括本發明化合物之所有可能結晶形式或多晶型物,其為單一多晶型物或超過一種多晶型物之任何比率的混合物形式。
此外,本發明亦包括本發明化合物之前藥。術語「前藥」在此表示自身可以具有生物活性或無活性,但其在體內滯留時間期間轉化(例如以代謝或水解方式)為本發明化合物的化合物。
根據第一態樣之第二實施例,本發明涵蓋上述通式(I)化合物,其中:
R1
表示氫、C1
-C4
烷基或C1
-C4
鹵烷基;
R2
表示氫、C1
-C4
烷基或C1
-C4
鹵烷基;或
R1
及R2
與其所連接之碳原子一起形成3員至6員環烷基或雜環烷基環;
R3
表示C3
-C6
環烷基、3員至6員雜環烷基、與苯基或雜芳基稠合的雜環烷基,或雜芳基,其中該等基團彼此獨立地視情況經R8
取代一或多次,或
R3
表示苯基,其彼此獨立地視情況經R8
取代一或多次,且另外,R7a
及R7b
表示氘;
R4
表示氫、C1
-C4
烷基、C1
-C4
鹵烷基或C3
-C6
環烷基;
R5
、R6
彼此獨立地表示氫、C1
-C4
烷基、C2
-C4
羥基烷基、(C1
-C4
烷氧基)-(C2
-C4
烷基)-、C3
-C6
環烷基、C1
-C4
鹵烷基、C3
-C6
鹵環烷基、3員至6員雜環烷基、苯基、雜芳基、與苯基或雜芳基稠合的雜環烷基、3員至6員雜環烷基-(C1
-C3
烷基)-、(與苯基或雜芳基稠合的雜環烷基)-(C1
-C3
烷基)-、苯基-(C1
-C3
烷基)-或雜芳基-(C1
-C3
烷基)-,其中該3員至6員雜環烷基、苯基或雜芳基彼此獨立地視情況經R9
取代一或多次,或
R5
及R6
連同其所連接之氮原子一起形成3員至6員含氮雜環,該含氮雜環視情況含有一個選自O、NH及S之額外雜原子或含雜原子基團,且可彼此獨立地視情況經R9
取代一或多次;
R7a
表示氫、氘或C1
-C4
烷基;
R7b
表示氫、氘或C1
-C4
烷基;
R8
表示鹵素、氰基、C1
-C4
烷基、C1
-C4
鹵烷基、C1
-C3
烷氧基、C1
-C3
鹵烷氧基、C3
-C6
環烷基、C1
-C4
烷基-(C=O)-、R10
-O-(C=O)-、R11
-NH-(C=O)-,或R12
-(SO2
)-;
R9
表示鹵素、氰基、C1
-C4
烷基、C1
-C4
鹵烷基、H2
N-C1
-C4
烷基、C1
-C3
烷氧基、C1
-C3
鹵烷氧基、C3
-C6
環烷基、R10
-O-(C=O)-、側氧基、5員至6員雜環烷基-、5員至6員雜環烷基-(C1
-C3
烷基)-、苯基或雜芳基,其中該苯基或雜芳基彼此獨立地視情況經鹵素、C1
-C4
烷基、C1
-C4
鹵烷基、C1
-C3
烷氧基或C1
-C3
鹵烷氧基取代一或多次;
R10
表示氫、C1
-C4
烷基,或苯基-CH2
-;
R11
表示氫、C1
-C4
烷基,或5員至6員雜環烷基-(C1
-C3
烷基)-;
R12
表示C1
-C4
烷基或苯基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
根據第一態樣之第三實施例,本發明涵蓋上述通式(I)化合物,其中:
R1
表示氫、C1
-C4
烷基或C1
-C4
鹵烷基;
R2
表示氫或C1
-C4
烷基;或
R1
及R2
與其所連接之碳原子一起形成3員至4員環烷基或雜環烷基環;
R3
表示C3
-C6
環烷基、4員至6員雜環烷基、與雜芳基稠合的雜環烷基,或雜芳基,其中該等基團彼此獨立地視情況經R8
取代一或多次,或
R3
表示苯基,其彼此獨立地視情況經R8
取代一或多次,且另外,R7a
及R7b
表示氘;
R4
表示氫、C1
-C4
烷基、C1
-C4
鹵烷基或C3
-C6
環烷基;
R5
, R6
彼此獨立地表示氫、C2
-C4
羥基烷基、(C1
-C4
烷氧基)-(C2
-C4
烷基)-、3員至6員雜環烷基、雜螺環烷基、苯基、雜芳基、4員至6員雜環烷基-(C1
-C3
烷基)-、雜螺環烷基-(C1
-C3
烷基)-、(與雜芳基稠合的雜環烷基)-(C1
-C3
烷基)-,或雜芳基-(C1
-C3
烷基)-,其中該3員至6員雜環烷基、苯基或雜芳基彼此獨立地視情況經R9
取代一或多次,或
R5
及R6
與其所連接之氮原子一起形成5員含氮雜環,其視情況可經R9
取代一次;
R7a
表示氫、氘或甲基;
R7b
表示氫、氘或甲基;
R8
表示鹵素、氰基、C1
-C4
烷基、C1
-C4
鹵烷基、C1
-C3
烷氧基、C3
-C6
環烷基、C3
-C6
環烷基-(C1
-C3
烷基)-、R13
-(C=O)-、R10
-O-(C=O)-、R11
-NH-(C=O)-,或R12
-(SO2
)-;
R9
表示鹵素、氰基、C1
-C4
烷基、C1
-C4
鹵烷基、H2
N-C1
-C4
烷基、C3
-C6
環烷基、R10
-O-(C=O)-、側氧基、6員雜環烷基-(C1
-C3
烷基)-、苯基或雜芳基,其中該苯基或雜芳基彼此獨立地視情況經鹵素、C1
-C4
鹵烷基或C1
-C3
烷氧基取代一或多次;
R10
表示氫、C1
-C4
烷基,或苯基-CH2
-;
R11
表示5員至6員雜環烷基-(C1
-C3
烷基)-;
R12
表示C1
-C4
烷基;
R13
表示C1
-C4
烷基、(C1
-C4
烷氧基)-(C1
-C4
烷基)-、C1
-C4
烷基-(C=O)-、C3
-C6
環烷基或苯基,其中該C3
-C6
環烷基視情況經甲基或羥基取代;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
根據第一態樣之第四實施例,本發明涵蓋上述通式(I)化合物,其中:
R1
表示氫、甲基或三氟甲基;
R2
表示氫或甲基;或
R1
及R2
與其所連接之碳原子一起形成3員至4員環烷基環;
R3
表示環丙基、4員至6員雜環烷基、2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基,或雜芳基,其中該等基團彼此獨立地視情況經R8
取代一或多次,或
R3
表示苯基,其彼此獨立地視情況經R8
取代一或多次,且另外,R7a
及R7b
表示氘;
R4
表示氫、甲基、C1
鹵烷基或環丙基;
R5
表示氫;
R6
表示甲氧基-乙基、5員雜芳基、4員至6員雜環烷基-(C1
-C2
烷基)-、雜螺環烷基-甲基、2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基,或5員至6員雜芳基-(C1
-C2
烷基)-,其中該4員至6員雜環烷基或雜芳基彼此獨立地視情況經R9
取代一或多次;
R7a
表示氫、氘或甲基;
R7b
表示氫、氘或甲基;
R8
表示氟、氯、C1
-C2
烷基、三氟甲基、C1
-C3
烷氧基、環丙基、環丙基甲基、R13
-(C=O)-、R10
-O-(C=O)-、R11
-NH-(C=O)-,或R12
-(SO2
)-;
R9
表示氟、氯、C1
-C3
烷基、三氟甲基、環丙基或側氧基;
R10
表示C1
-C4
烷基,或苯基-CH2
-;
R11
表示5員至6員雜環烷基-甲基;
R12
表示甲基;
R13
表示甲基、甲氧基甲基、乙基-(C=O)-、環丙基或苯基,其中該環丙基視情況經甲基或羥基取代;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
根據第一態樣之第五實施例,本發明涵蓋上述通式(I)化合物,其中:
R1
表示氫或甲基;
R2
表示氫或甲基;或
R1
及R2
與其所連接之碳原子一起形成3員至4員環烷基環;
R3
表示環丙基、2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基、氧雜環丁-3-基、氧雜環戊-3-基、氧雜環戊-2-基、3-甲基氧雜環丁-3-基、3-氟氧雜環丁-3-基、吡啶-4-基、吡啶-3-基、吡啶-2-基、㗁烷-4-基、1,4-二㗁烷-2-基、6-甲基吡啶-3-基、5-甲基吡啶-2-基、3-甲基吡啶-2-基、2-甲基吡啶-4-基、6-甲基吡啶-2-基、3-氯吡啶-2-基、6-乙基吡啶-3-基、1-乙醯基哌啶-4-基、3-氯-5-乙氧基吡啶-2-基、1-苯甲醯基哌啶-4-基,或選自以下之基團: ,或
R3
表示苯基,且另外,R7a
及R7b
表示氘;
R4
表示甲基、二氟甲基、三氟甲基或環丙基;
R5
表示氫;
R6
表示(氧雜環戊-2-基)甲基、(1,3-㗁唑-4-基)甲基、(1,2-㗁唑-3-基)甲基、(4-甲基氧雜環戊-2-基)甲基、(嘧啶-2-基)甲基、(吡𠯤-2-基)甲基、(5-甲基氧雜環戊-2-基)甲基、(5-甲基氧雜環戊-2-基)甲基、(1,4-二㗁烷-2-基)甲基、(4-甲基苯基)甲基、(5-甲基嘧啶-2-基)甲基、(5-甲基吡𠯤-2-基)甲基、(5-氯吡𠯤-2-基)甲基、(5-環丙基-吡𠯤-2-基)甲基、2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基、1,3-㗁唑-2-基甲基、1,3-噻唑-2-基甲基、(1-甲基-1H-吡唑-3-基)甲基、(1-甲基-1H-咪唑-4-基)甲基、(5-異丙基-1,2-㗁唑-3-基)甲基、(5-環丙基-1,2-㗁唑-3-基)甲基、(5,5-二甲基四氫呋喃-2-基)甲基、(4,4-二氟四氫呋喃-2-基)甲基、(6,6-二甲基-1,4-二㗁烷-2-基)甲基、5-氧雜螺[2.4]庚-6-基甲基,或2,6-二氧雜螺[3.4]辛-7-基甲基;
R7a
表示氫;
R7b
表示氫;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
本發明之第一態樣的其他實施例:
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R1
表示氫、C1
-C4
烷基或C1
-C4
鹵烷基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R1
表示氫、甲基或三氟甲基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R1
表示氫或C1
-C4
烷基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R1
表示氫或C1
-C3
烷基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R1
表示氫或甲基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R2
表示氫、C1
-C4
烷基或C1
-C4
鹵烷基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R2
表示氫或C1
-C4
烷基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R2
表示氫或C1
-C3
烷基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R2
表示氫或甲基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R1
及R2
與其所連接之碳原子一起形成3員至6員環烷基或雜環烷基環;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R1
及R2
與其所連接之碳原子一起形成3員至6員環烷基環;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R1
及R2
與其所連接之碳原子一起形成3員至5員環烷基環;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R1
及R2
與其所連接之碳原子一起形成3員至4員環烷基環;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R3
表示C3
-C6
環烷基、3員至6員雜環烷基、與苯基或雜芳基稠合的雜環烷基,或雜芳基,其中該等基團彼此獨立地視情況經R8
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R3
表示C3
-C6
環烷基、4員至6員雜環烷基、與苯基或雜芳基稠合的雜環烷基,或5員至6員雜芳基,其中該等基團彼此獨立地視情況經R8
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R3
表示C3
-C6
環烷基、4員至6員雜環烷基、與雜芳基稠合的雜環烷基,或5員至6員雜芳基,其中該等基團彼此獨立地視情況經R8
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R3
表示環丙基、4員至6員雜環烷基、2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基,或5員至6員雜芳基,其中該等基團彼此獨立地視情況經R8
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R3
表示C3
-C6
環烷基、4員至6員雜環烷基、與雜芳基稠合的雜環烷基,或雜芳基,其中該等基團彼此獨立地視情況經R8
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R3
表示環丙基、4員至6員雜環烷基、2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基,或雜芳基,其中該等基團彼此獨立地視情況經R8
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R3
表示環丙基、2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基、氧雜環丁-3-基、氧雜環戊-3-基、氧雜環戊-2-基、3-甲基氧雜環丁-3-基、3-氟氧雜環丁-3-基、吡啶-4-基、吡啶-3-基、吡啶-2-基、㗁烷-4-基、1,4-二㗁烷-2-基、6-甲基吡啶-3-基、5-甲基吡啶-2-基、3-甲基吡啶-2-基、2-甲基吡啶-4-基、6-甲基吡啶-2-基、3-氯吡啶-2-基、6-乙基吡啶-3-基、1-乙醯基哌啶-4-基、3-氯-5-乙氧基吡啶-2-基、1-苯甲醯基哌啶-4-基,或選自以下之基團: ;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R3
表示苯基,其彼此獨立地視情況經R8
取代一或多次,且另外,R7a
及R7b
表示氘;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R3
表示苯基,其彼此獨立地視情況經R8
取代一次或兩次,且另外,R7a
及R7b
表示氘;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R3
表示苯基,且另外,R7a
及R7b
表示氘;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R4
表示氫、C1
-C4
烷基、C1
-C4
鹵烷基或C3
-C6
環烷基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R4
表示氫、C1
-C3
烷基、C1
-C3
鹵烷基或C3
-C6
環烷基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R4
表示氫、C1
-C3
烷基、C1
-C3
鹵烷基或C3
-C5
環烷基
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R4
表示氫、甲基、C1
鹵烷基或環丙基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R4
表示氫、甲基、三氟甲基或環丙基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R5
, R6
彼此獨立地表示氫、C1
-C4
烷基、C2
-C4
羥基烷基、(C1
-C4
烷氧基)-(C2
-C4
烷基)-、C3
-C6
環烷基、C1
-C4
鹵烷基、C3
-C6
鹵環烷基、3員至6員雜環烷基、雜螺環烷基、苯基、雜芳基、與苯基或雜芳基稠合的雜環烷基、3員至6員雜環烷基-(C1
-C3
烷基)-、雜螺環烷基-(C1
-C3
烷基)-、(與苯基或雜芳基稠合的雜環烷基)-(C1
-C3
烷基)-、苯基-(C1
-C3
烷基)-或雜芳基-(C1
-C3
烷基)-,其中該3員至6員雜環烷基、雜螺環烷基、與苯基或雜芳基稠合的雜環烷基、苯基或雜芳基彼此獨立地視情況經R9
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R5
、R6
彼此獨立地表示氫、C2
-C4
羥基烷基、(C1
-C4
烷氧基)-(C2
-C4
烷基)-、3員至6員雜環烷基、雜螺環烷基、苯基、雜芳基、4員至6員雜環烷基-(C1
-C3
烷基)-、雜螺環烷基-(C1
-C3
烷基)-、(與雜芳基稠合的雜環烷基)-(C1
-C3
烷基)-,或雜芳基-(C1
-C3
烷基)-,其中該3員至6員雜環烷基、苯基或雜芳基彼此獨立地視情況經R9
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R5
、R6
彼此獨立地表示氫、C1
-C4
烷基、C2
-C4
羥基烷基、(C1
-C4
烷氧基)-(C2
-C4
烷基)-、C3
-C6
環烷基、C1
-C4
鹵烷基、C3
-C6
鹵環烷基、3員至6員雜環烷基、苯基、雜芳基、與苯基或雜芳基稠合的雜環烷基、3員至6員雜環烷基-(C1
-C3
烷基)-、(與苯基或雜芳基稠合的雜環烷基)-(C1
-C3
烷基)-、苯基-(C1
-C3
烷基)-或雜芳基-(C1
-C3
烷基)-,其中該3員至6員雜環烷基、苯基或雜芳基彼此獨立地視情況經R9
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R5
及R6
連同其所連接之氮原子一起形成3員至6員含氮雜環,該含氮雜環視情況含有一個選自O、NH及S之額外雜原子或含雜原子基團,且可彼此獨立地視情況經R9
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R5
及R6
連同其所連接之氮原子一起形成5員至6員含氮雜環,該含氮雜環視情況含有一個選自O、NH及S之額外雜原子或含雜原子基團,且可彼此獨立地視情況經R9
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R5
及R6
與其所連接之氮原子一起形成5員至6員含氮雜環,該含氮雜環彼此獨立地可視情況經R9
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R5
及R6
與其所連接之氮原子一起形成經胺基甲基取代的5員含氮雜環;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R5
表示氫;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R6
表示甲氧基-乙基、5員雜芳基、4員至5員雜環烷基-(C1
-C2
烷基)-、雜螺環烷基-甲基、2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基,或5員至6員雜芳基-(C1
-C2
烷基)-,其中該4員至5員雜環烷基或雜芳基彼此獨立地視情況經R9
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R6
表示(氧雜環戊-2-基)甲基、(1,3-㗁唑-4-基)甲基、(1,2-㗁唑-3-基)甲基、(4-甲基氧雜環戊-2-基)甲基、(嘧啶-2-基)甲基、(吡𠯤-2-基)甲基、(5-甲基氧雜環戊-2-基)甲基、(5-甲基氧雜環戊-2-基)甲基、(1,4-二㗁烷-2-基)甲基、(4-甲基苯基)甲基、(5-甲基嘧啶-2-基)甲基、(5-甲基吡𠯤-2-基)甲基、(5-氯吡𠯤-2-基)甲基、(5-環丙基-吡𠯤-2-基)甲基、2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基、1,3-㗁唑-2-基甲基、1,3-噻唑-2-基甲基、(1-甲基-1H-吡唑-3-基)甲基、(1-甲基-1H-咪唑-4-基)甲基、(5-異丙基-1,2-㗁唑-3-基)甲基、(5-環丙基-1,2-㗁唑-3-基)甲基、(5,5-二甲基四氫呋喃-2-基)甲基、(4,4-二氟四氫呋喃-2-基)甲基、(6,6-二甲基-1,4-二㗁烷-2-基)甲基、5-氧雜螺[2.4]庚-6-基甲基,或2,6-二氧雜螺[3.4]辛-7-基甲基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R6
表示C1
-C4
烷基、C2
-C4
羥基烷基、(C1
-C4
烷氧基)-(C2
-C4
烷基)-、C3
-C6
環烷基、C1
-C4
鹵烷基、C3
-C6
鹵環烷基、3員至6員雜環烷基、苯基、雜芳基、與苯基或雜芳基稠合的雜環烷基、3員至6員雜環烷基-(C1
-C3
烷基)-、(與苯基或雜芳基稠合的雜環烷基)-(C1
-C3
烷基)-、苯基-(C1
-C3
烷基)-或雜芳基-(C1
-C3
烷基)-,其中該3員至6員雜環烷基、苯基或雜芳基彼此獨立地視情況經R9
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R6
表示C1
-C3
烷基、C2
-C4
羥基烷基、(C1
-C3
烷氧基)-(C2
-C4
烷基)-、C3
-C5
環烷基、C1
-C3
鹵烷基、4員至6員雜環烷基、苯基、5員至6員雜芳基、與雜芳基稠合的雜環烷基、4員至6員雜環烷基-(C1
-C3
烷基)-、(與雜芳基稠合的雜環烷基)-(C1
-C3
烷基)-、苯基-(C1
-C3
烷基)-或5員至6員雜芳基-(C1
-C3
烷基)-,其中該4員至6員雜環烷基、苯基或雜芳基彼此獨立地視情況經R9
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R6
表示C2
-C4
羥基烷基、甲氧基-(C2
-C4
烷基)-、苯基、5員至6員雜芳基、4員至6員雜環烷基-(C1
-C2
烷基)-、(2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基)-甲基、苯基-(C1
-C2
烷基)-或5員至6員雜芳基-甲基,其中該4員至6員雜環烷基、苯基或雜芳基彼此獨立地視情況經R9
取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R7a
表示氫、氘或C1
-C4
烷基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R7b
表示氫、氘或C1
-C4
烷基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R7a
表示氫、氘或甲基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R7b
表示氫、氘或甲基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R7a
表示氫或氘;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R7b
表示氫或氘;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R7a
表示氫;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R7b
表示氫;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R8
表示鹵素、氰基、C1
-C4
烷基、C1
-C4
鹵烷基、C1
-C3
烷氧基、C1
-C3
鹵烷氧基、C3
-C6
環烷基、C3
-C6
環烷基-(C1
-C3
烷基)-、R13
-(C=O)-、R10
-O-(C=O)-、R11
-NH-(C=O)-,或R12
-(SO2
)-;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R8
表示鹵素、氰基、C1
-C4
烷基、C1
-C4
鹵烷基、C1
-C3
烷氧基、C3
-C6
環烷基、C3
-C6
環烷基-(C1
-C3
烷基)-、R13
-(C=O)-、R10
-O-(C=O)-、R11
-NH-(C=O)-,或R12
-(SO2
)-;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R8
表示氟、氯、C1
-C2
烷基、三氟甲基、C1
-C3
烷氧基、環丙基、環丙基甲基、R13
-(C=O)-、R10
-O-(C=O)-、R11
-NH-(C=O)-,或R12
-(SO2
)-;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R8
表示鹵素、氰基、C1
-C4
烷基、C1
-C4
鹵烷基、C1
-C3
烷氧基、C1
-C3
鹵烷氧基、C3
-C6
環烷基、C1
-C4
烷基-(C=O)-、R10
-O-(C=O)-、R11
-NH-(C=O)-,或R12
-(SO2
)-;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R8
表示鹵素、C1
-C3
烷基、C1
-C3
鹵烷基、C1
-C3
烷氧基、C3
-C6
環烷基、C1
-C3
烷基-(C=O)-、R10
-O-(C=O)-、R11
-NH-(C=O)-,或R12
-(SO2
)-;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R8
表示氟、氯、甲基、三氟甲基、乙氧基、環丙基、甲基-(C=O)-、R10
-O-(C=O)-、R11
-NH-(C=O)-或R12
-(SO2
)-;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R9
表示鹵素、氰基、C1
-C4
烷基、C1
-C4
鹵烷基、H2
N-C1
-C4
烷基、C1
-C3
烷氧基、C1
-C3
鹵烷氧基、C3
-C6
環烷基、R10
-O-(C=O)-、側氧基、5員至6員雜環烷基-、5員至6員雜環烷基-(C1
-C3
烷基)-、苯基或雜芳基,其中該苯基或雜芳基彼此獨立地視情況經鹵素、C1
-C4
烷基、C1
-C4
鹵烷基、C1
-C3
烷氧基或C1
-C3
鹵烷氧基取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R9
表示鹵素、氰基、C1
-C4
烷基、C1
-C4
鹵烷基、H2
N-C1
-C4
烷基、C3
-C6
環烷基、R10
-O-(C=O)-、側氧基、6員雜環烷基-(C1
-C3
烷基)-、苯基或雜芳基,其中該苯基或雜芳基彼此獨立地視情況經鹵素、C1
-C4
鹵烷基或C1
-C3
烷氧基取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R9
表示鹵素、氰基、C1
-C3
烷基、C1
-C3
鹵烷基、H2
N-C1
-C3
烷基、C1
-C3
烷氧基、C3
-C6
環烷基、R10
-O-(C=O)-、側氧基、5員至6員雜環烷基-、5員至6員雜環烷基-(C1
-C2
烷基)-、苯基,或5員至6員雜芳基,其中該苯基或雜芳基彼此獨立地視情況經鹵素、C1
-C3
烷基、C1
-C3
鹵烷基或C1
-C3
烷氧基取代一或多次
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R9
表示氟、氰基、C1
-C3
烷基、三氟甲基、胺基甲基、乙氧基、環丙基、R10
-O-(C=O)-、側氧基、6員雜環烷基-甲基、苯基,或5員至6員雜芳基,其中該苯基或雜芳基視情況經氯、三氟甲基或甲氧基取代;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R9
表示氟、氯、C1
-C3
烷基、三氟甲基、環丙基或側氧基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R10
表示氫、C1
-C4
烷基,或苯基-CH2
-;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R10
表示C1
-C4
烷基,或苯基-CH2
-;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R11
表示氫、C1
-C4
烷基,或5員至6員雜環烷基-(C1
-C3
烷基)-;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R11
表示C1
-C4
烷基,或5員至6員雜環烷基-(C1
-C3
烷基)-;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R11
表示C1
-C3
烷基,或5員至6員雜環烷基-(C1
-C2
烷基)-
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R11
表示C1
-C3
烷基,或5員至6員雜環烷基-甲基
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R11
表示5員至6員雜環烷基-(C1
-C3
烷基)-;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R11
表示5員至6員雜環烷基-甲基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R11
表示四氫呋喃-2-基-甲基,或1,4-二㗁烷-2-基-甲基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R12
表示C1
-C4
烷基或苯基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R12
表示C1
-C3
烷基或苯基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R12
表示C1
-C4
烷基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R12
表示甲基;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R13
表示C1
-C4
烷基、C1
-C4
鹵烷基、(C1
-C4
烷氧基)-(C1
-C4
烷基)-、C1
-C4
烷基-(C=O)-、C3
-C6
環烷基或苯基,其中該C3
-C6
環烷基視情況經C1
-C4
烷基或羥基取代且該苯基彼此獨立地視情況經鹵素、C1
-C4
烷基、C1
-C4
鹵烷基、C1
-C3
烷氧基或C1
-C3
鹵烷氧基取代一或多次;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R13
表示C1
-C4
烷基、(C1
-C4
烷氧基)-(C1
-C4
烷基)-、C1
-C4
烷基-(C=O)-、C3
-C6
環烷基或苯基,其中該C3
-C6
環烷基視情況經甲基或羥基取代;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一實施例中,本發明涵蓋上述式(I)化合物,其中:
R13
表示甲基、甲氧基甲基、乙基-(C=O)-、環丙基或苯基,其中該環丙基視情況經甲基或羥基取代;
及其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,及該等化合物混合物。
在第一態樣之另一特定實施例中,本發明涵蓋標題「本發明第一態樣之其他實施例」下之兩個或更多個上述實施例之組合。
本發明涵蓋上述通式(I)化合物在本發明之任何實施例或態樣內的任何子組合。
本發明涵蓋通式(II)之中間物化合物在本發明之任何實施例或態樣內的任何子組合。
本發明涵蓋本文在下述實例章節中所揭示的通式(I)化合物。
本發明之通式(I)化合物可以根據以下流程1、2、3及4製備。下文所述之流程及程序說明本發明之通式(I)化合物之合成途徑且不希望具有限制性。熟習此項技術者清楚,可以多種方式修改如流程1、2、3及4中所例示之轉化次序。因此,此等流程中所例示之轉化次序不希望具有限制性。另外,可在所例示之轉化之前及/或之後達成取代基R1
、R2
、R3
、R4
、R5
、R6
、R7a
或R7b
中之任一者之相互轉化。此等修改可為諸如保護基引入、保護基裂解、官能基還原或氧化、鹵化、金屬化、取代或熟習此項技術者已知之其他反應。此等轉化包括引入官能基的轉化,從而允許取代基進一步相互轉化。適當保護基及其引入及裂解為熟習此項技術者所熟知。特定實例描述於後續段落中。
用於製備通式(I)化合物及相應中間物的途徑描述於流程1、2、3及4中。
流程1 流程 1 :
用於製備通式(I)化合物的途徑,其中X為離去基,R為甲基、乙基或第三丁基且R1
、R2
、R3
、R4
、R5
、R6
、R7a
及R7b
具有如針對上述通式(I)所給定的含義。
通式(3)之四氫苯并呋喃可經由(1)與(2)之醇醛縮合、隨後根據Stetter等人(Chem. Ber. 1960, 93, 603-607)所述的程序進行分子內環化而獲得,如流程1中所描繪。化合物(1)及(2)可市購或可根據獲自公共領域、如熟習此項技術者可理解之程序來製備。根據所涉及中心之反應性,可以獲得(3)之區位異構體[亦即,在與(2)之酮部分發生分子內縮合之前,使(2)之離去基被(1)之酸性亞甲基單元親核取代的情況下]。
一般而言,可使式(1)之1,3-二酮與通式(2)之α-羰基酯在質子溶劑(諸如甲醇、乙醇或水或其混合物,較佳為併入酯(2)中之醇與水之混合物)中、在無機鹼(如氫氧化鈉或氫氧化鉀,較佳為氫氧化鉀)存在下、在0℃與溶劑(混合物)沸點之間(較佳為室溫與50℃之間)的溫度下反應。反應時間在15小時與數天之間變化。通常需要藉由在0℃與溶劑(混合物)沸點之間的溫度(較佳在室溫下)下用酸(諸如pH 1-4的鹽酸水溶液)處理1-6小時而使初始形成的環化產物異構化,以產生通式(3)之四氫苯并呋喃。
或者,可以使(1)與(2)在非質子性溶劑(如二氯甲烷、二氯乙烷或四氫呋喃,較佳為二氯甲烷或二氯乙烷)中、在有機鹼(如三乙胺)存在下、在室溫與溶劑沸點之間的溫度(較佳為在40-60℃ (壓力管))下反應12-72小時,隨後在0℃與溶劑(混合物)沸點之間的溫度下、較佳在室溫下用酸(諸如pH 1-4的鹽酸水溶液)處理3-24小時。
或者,可以使(1)與(2)在室溫與120℃之間的溫度(較佳為80-120℃)下、在無其他添加劑的情況下反應12-20小時。
通式(4a)之烯胺可以由通式(3)之四氫苯并呋喃如下合成:在室溫與溶劑沸點之間的溫度(較佳在100-110℃)下,在非質子性溶劑(如苯、甲苯或二㗁烷,較佳為甲苯)中,在親電子劑(如1-第三丁氧基-N,N,N',N'
-四甲基甲二胺(布雷德奈克試劑(Bredereck's reagent))或1,1-二甲氧基-N,N-
二甲基甲胺,較佳為1-第三丁氧基-N,N,N',N'
-四甲基甲二胺)存在下發生α-甲基化歷時15小時或長達數天。
或者,可以如下將通式(3)之四氫苯并呋喃轉化成通式(4b)之α-羥基亞甲基酮:在0℃與溶劑(混合物)沸點之間(較佳在室溫與50℃之間)的溫度下,在溶劑(諸如甲醇、乙醇、甲苯或四氫呋喃或其混合物)中,在鹼(諸如甲醇鈉、乙醇鈉、第三丁醇鉀或氫化鈉)存在下,用甲酸衍生物(諸如羧酸乙酯或羧酸甲酯)進行甲醯化1-18小時。
通式(5)之呋喃并吲唑可以通式(4a)之烯胺或通式(4b)之α-羥基亞甲基酮為起始物如下獲得:使(4a)或(4b)與肼或肼衍生物(諸如水合肼或肼鹽,較佳為水合肼或肼二鹽酸鹽)在極性質子溶劑(如乙醇或水或其混合物,較佳為乙醇/水混合物)中、在室溫與溶劑(混合物)沸點之間的溫度(較佳在70-80℃)下反應4-18小時。
通式(8)之2位經取代之呋喃并吲唑酯可以由通式(5)之呋喃并吲唑如下合成:在室溫與溶劑沸點之間的溫度下,較佳在室溫下,在非質子性溶劑(諸如四氫呋喃或甲苯,較佳為甲苯)中,在活化試劑(諸如偶氮二羧酸二異丙酯(DIAD)或N,N,N'
,N'
-四甲基偶氮二羧醯胺(TMAD)及第三膦(諸如三苯膦或三-正丁基膦),較佳為TMAD與三-正丁基膦之組合)存在下,與通式(6)之醇發生光延反應(Mitsunobu reaction)歷時12-48小時。或者,通式(8)之2位經取代之呋喃并吲唑可以由通式(5)之呋喃并吲唑與通式(7)之親電子劑(諸如烷基鹵化物或甲苯磺酸烷酯或甲磺酸烷酯,較佳為烷基溴化物)在室溫與溶劑沸點之間的溫度下,較佳在60-75℃下,在極性非質子性溶劑(諸如乙腈或乙酸乙酯,較佳為乙腈)中,在無機鹼(諸如碳酸鉀)存在下或在有機鹼(諸如三乙胺或N,N-
二異丙基乙胺)(較佳為碳酸鉀)存在下反應而合成。將催化劑(如4-二甲胺基吡啶(DMAP))添加至混合物中可為有益的。一般而言,視所涉及之中心的反應性而定,亦可在某些情況下獲得(8)之1位經取代的區位異構體。
通式(9)之羧酸可以由式(8)之羧酸酯如下獲得:在0℃與溶劑(混合物)沸點之間的溫度下,典型地在70℃下,在適合溶劑(諸如甲醇、乙醇、四氫呋喃、水或其混合物,較佳為併入酯(8)中之醇、THF與水之混合物)中,與無機鹼(諸如氫氧化鋰、氫氧化鉀或氫氧化鈉,較佳為氫氧化鋰)發生皂化4-48小時。
通式(I)之呋喃并吲唑可以由通式(9)之適合官能化羧酸與適當胺HN(R5
)(R6
) (III)反應而合成。然而,就醯胺形成而言,可以應用熟習此項技術者已知的所有肽化學方法。可使通式(9)之酸與適當胺在非質子性極性溶劑(諸如DMF、乙腈或N
-甲基吡咯啶-2-酮)中、經由活化的酸衍生物反應,該活化的酸衍生物可例如用羥基苯并三唑與碳化二亞胺(諸如二異丙基碳化二亞胺)獲得,或另外用預先形成的試劑獲得,諸如六氟磷酸O-(7-氮雜苯并三唑-1-基)-1,1,3,3-四甲基(參見例如Chem. Comm. 1994
, 201-203),或另外用活化劑獲得,諸如二環己基碳二亞胺/N,N-
二甲胺基吡啶或N-
乙基-N',N'
-二甲基胺基丙基碳二亞胺/N,N-
二甲基胺基吡啶。可能需要添加適合鹼,諸如N
-甲基嗎啉、三乙胺或DIPEA。在某些情況下,可以在與適當胺反應之前,分離出活化的酸衍生物。醯胺形成亦可經由酸鹵化物(其可由羧酸與例如乙二醯氯、亞硫醯氯或硫醯氯反應而形成)、混合酸酐(其可由羧酸與例如氯羧酸異丁酯反應而形成)、咪唑化物(其可由羧酸與例如羰基二咪唑反應而形成)或疊氮化物(其可由羧酸與例如二苯基磷醯基疊氮化物反應而形成)完成。
用於製備通式(3)之四氫苯并呋喃中間物的替代途徑描繪於流程2中。通式(1)之1,3-二酮可以藉由如Synthesis 2011, 16, 2549-2552或Synlett 2009, 18, 2943-2944中所述的重氮轉移而轉化為通式(11)之重氮二羰基化合物。
通式(13)之雙環呋喃酯可根據Lee等人(Eur. J. Org. Chem. 2014, 3430-3442)所述的程序、以由通式(11)之重氮二羰基化合物與通式(12)之末端炔烴在金屬催化劑(諸如Ru(PPh3
)3
Cl2
)存在下、經由[3+2]環加成來合成。
通式(14)之鹵代呋喃可以由通式(13)之呋喃藉由熟習此項技術者已知的任何芳族鹵化反應獲得。舉例而言,可以使式(13)化合物與鹵素親電子劑(諸如N
-溴丁二醯亞胺(NBS)或N
-碘丁二醯亞胺(NIS),較佳為NBS)、在極性溶劑(諸如吡啶或N,N
-二甲基羧醯胺,較佳為吡啶)中、在0℃與溶劑沸點之間的溫度下(較佳在室溫下)反應。反應時間在2小時與數天之間變化。
通式(3)之四氫苯并呋喃中間物又可以由通式(14)之鹵代呋喃藉由鈴木反應或自由基過程(如應用光催化劑的光誘導反應)獲得。
用於製備通式(Ia)之8-甲基-呋喃并吲唑的替代途徑描繪於流程3中。通式(16)之3-甲基-四氫苯并呋喃可以由通式(1)之1,3-二羰基化物藉由兩步程序合成,該兩步程序包括(1)之烯醇化物與丙二烯硫鎓鹽(15)[由炔丙基溴化物與甲硫醚反應而原位製備]的反應及隨後根據Kanematsu等人(J. Org. Chem. 1993, 58, 3960-3968及Heterocycles 1990, 31, 6, 1003-1006)所述的程序進行酸催化之異構化而產生(16)。
通式(17)之溴化呋喃可以由通式(16)之呋喃藉由熟習此項技術者已知的任何芳族溴化反應獲得。舉例而言,可以使式(16)化合物與溴親電子劑(諸如N
-溴丁二醯亞胺(NBS))、在極性溶劑(諸如吡啶或N,N
-二甲基羧醯胺,較佳為吡啶)中、在0℃與溶劑沸點之間的溫度下(較佳在室溫下)反應。反應時間在2小時與數天之間變化。
通式(18a)之烯胺及通式(18b)之α-羥基亞甲基酮可以通式(17)化合物為起始物、根據流程1中針對(4a)及(4b)所述的程序合成。
通式(19)之8-甲基-呋喃并吲唑可以由(18a)或(18b)藉由與肼衍生物反應、如流程1中針對(5)之合成所述獲得。
通式(20)之2位經取代之呋喃并吲唑可以如流程1中自(5)合成(8)所述、由通式(19)化合物及醇(6)或親電子劑(7)合成。
通式(21)之羧酸可以由溴-呋喃并吲唑(20)藉由羰基化反應獲得。可以使通式(20)之溴化物在室溫與180℃之間的溫度下,較佳在100℃下,在極性溶劑(諸如二甲亞碸)中,在一氧化碳源(諸如六羰基鉬)存在下或在1與20巴之間之壓力(高壓釜)的一氧化碳氛圍下,較佳在15巴之一氧化碳氛圍(高壓釜)下,且在適合的鈀催化劑(諸如乙酸鈀或雙(三苯膦)二氯化鈀(II))存在下,較佳在乙酸鈀存在下,以及在配位體(諸如1,1'-雙(二苯基膦基)二茂鐵)及適合鹼(諸如乙酸鉀)存在下反應12-24小時。
通式(Ia)之8-甲基-呋喃并吲唑可以如流程1中自(9)合成通式(I)之呋喃并吲唑所述,由通式(21)之適合官能化羧酸藉由與適當胺HN(R5
)(R6
) (III)發生醯胺偶合反應而合成。
或者,通式(Ia)之8-甲基-呋喃并吲唑可以直接由通式(20)之芳基溴化物藉由與適當的胺HN(R5
)(R6
) (III)在鈀催化的羰基化條件下反應合成。對於此羰基化而言,可應用熟習此項技術者已知之所有方法。可使式(20)之溴化物與適當胺(III)在室溫與溶劑沸點之間的溫度下,較佳在110-140℃ (壓力管)下,在極性非質子溶劑(諸如二㗁烷)中,在一氧化碳源(諸如六羰基鉬)存在下或在1巴與20巴之間之壓力(高壓釜)的一氧化碳氛圍下且在鈀催化劑(諸如乙酸鈀(II))及鹼(諸如碳酸鈉)存在下反應。可能需要將諸如四氟硼酸三-第三丁基鏻之配位體添加至混合物中。
製得通式(Ia)之8-甲基-呋喃并吲唑的替代方法描繪於流程4中。通式(24)之8-甲基-呋喃并吲唑可根據流程1及流程3中所述的相應程序、以通式(1)之1,3-二羰基化合物為起始物、經由(16)及(22a)或(22b)及(23)、藉由四個步驟獲得。
通式(24)化合物又可以藉由熟習此項技術者已知的所有甲醯化方法進行甲醯化,以得到通式(25)之醛。可以在0℃與室溫之間的溫度下,在維斯邁爾-哈克條件(Vilsmeier-Haack conditions)下,在N,N
-二甲基羧醯胺及磷醯氯之混合物存在下,使通式(24)之呋喃反應1-18小時。
通式(Ia)之羧醯胺可以直接由通式(24)之醛、類似於Synthesis 2003, 7, 1055-1064所述的程序獲得。可使通式(24)之醛與適當胺(III)在0℃與溶劑沸點之間的溫度下,較佳在室溫下,在溶劑(如四氫呋喃、二氯甲烷或二甲亞碸,較佳為四氫呋喃)中,在氰化物鹽(如氰化鈉或氰化鉀)存在下及在氧化劑(如二氧化錳(IV))存在下反應24-96小時。
特定實例描述於實驗章節中。
根據第二態樣,本發明涵蓋製備如上文所定義之通式(I)化合物的方法,該等方法包含以下步驟:使通式(II)之中間物化合物:,
其中R為H或OH或OMe或OEt且R1
、R2
、R3
、R4
、R7a
及R7b
如針對如上文所定義之通式(I)化合物所定義,
與通式(III)化合物發生反應:,
其中R5
及R6
如上文所定義之通式(I)化合物中所定義,
藉此得到通式(I)化合物:,
其中R1
、R2
、R3
、R5
、R6
、R7a
及R7b
如上文所定義。
根據第三態樣,本發明涵蓋製備如上文所定義之通式(I)化合物之方法,該等方法包含以下步驟:允許通式(II)之中間物化合物:,
其中R為H、OH、OMe或OEt且R1
、R2
、R3
、R4
、R7a
及R7b
如上文所定義之通式(I)化合物中所定義,
與通式(III)化合物發生反應:,
其中R5
及R6
如上文所定義之通式(I)化合物中所定義,
藉此得到通式(I)化合物:,
其中R1
、R2
、R3
、R5
、R6
、R7a
及R7b
如上文所定義,
接著視情況使用相應(i)溶劑及/或(ii)鹼或酸將該化合物轉化為溶劑合物、鹽及/或此類鹽之溶劑合物。
本發明涵蓋製備本發明之通式(I)化合物的方法,該等方法包含如本文實驗章節中所述之步驟。
根據第四態樣,本發明涵蓋適用於製備上述通式(I)化合物之中間物化合物。
根據第五態樣,本發明涵蓋該等中間物化合物用於製備如上文所定義之通式(I)化合物的用途。
特定言之,本發明涵蓋通式(II)之中間物化合物的用途:,
其中R為H或OH或OMe或OEt且R1
、R2
、R3
、R4
、R7a
及R7b
如上述通式(I)化合物中所定義;其用於製備如上文所定義之通式(I)化合物。
本發明涵蓋本文在下述實例章節中所揭示的中間物化合物。
本發明涵蓋上述通式(II)之中間物化合物在本發明之任何實施例或態樣內的任何子組合。
本發明之通式(I)化合物可如本文所述,藉由熟習此項技術者已知之任何方法轉化為任何鹽,較佳為醫藥學上可接受之鹽。類似地,本發明之通式(I)化合物之任何鹽可藉由熟習此項技術者已知之任何方法轉化為游離化合物。
本發明之通式(I)化合物展現可能尚未預測到之有價值的藥理學廣譜作用。已驚人地發現本發明化合物為有效的GPR84拮抗劑且因此,該等化合物可用於治療或預防人類及動物的疾病,詳言之,自體免疫疾病,諸如多發性硬化症、牛皮癬、牛皮癬性關節炎、類風濕性關節炎、僵直性脊椎炎、全身性紅斑狼瘡、原發及繼發自體免疫葡萄膜炎;發炎病症,如子宮內膜異位、發炎眼病、發炎腎病、發炎肝病,如非酒精性、酒精性及毒性脂肪肝疾病;肺病,如哮喘、特發性肺纖維化、慢性阻塞性肺病;以及代謝及代謝內分泌病症,如代謝症候群、抗胰島素症、I型及II型糖尿病,以及多囊性卵巢症候群(PCOS)病症、神經病變性及發炎性疼痛病症。
本發明化合物可以用於抑制、拮抗、阻滯、降低、減少GPR84信號轉導、活性及細胞功能。此方法包含向有需要之哺乳動物(包括人類)投與有效治療病症之量的本發明化合物或其醫藥學上可接受之鹽、異構體、多晶型物、代謝物、水合物、溶劑合物或酯。
詳言之,人類及動物的自體免疫疾病,諸如多發性硬化症、牛皮癬、牛皮癬性關節炎、類風濕性關節炎、僵直性脊椎炎、全身性紅斑狼瘡、原發及繼發自體免疫葡萄膜炎、發炎病症,如子宮內膜異位、發炎眼病、發炎腎病、發炎肝病,如非酒精性、酒精性及毒性脂肪肝疾病;肺病,如哮喘、特發性肺纖維化、慢性阻塞性肺病以及代謝及代謝內分泌病症,如代謝症候群、抗胰島素症、I型及II型糖尿病,以及多囊性卵巢症候群(PCOS)病症、神經病變性及發炎性疼痛病症。
本發明亦提供治療PCOS及症狀之方法。
此等病症在人類中已得到良好表徵,且在其他哺乳動物中亦以類似病源學存在,且可藉由投與本發明之醫藥組合物來治療。
如本發明文本中所用,術語「治療(treating)」或「治療(treatment)」係以習知方式使用,例如管理或照護個體以用於對抗、緩解、減少、減輕、改善疾病或病症之病狀,諸如PCOS或IPF。
本發明化合物尤其可用於治療及預防,亦即,預防及治療人類及動物的自體免疫疾病,諸如多發性硬化症、牛皮癬、牛皮癬性關節炎、類風濕性關節炎、僵直性脊椎炎、全身性紅斑狼瘡、原發及繼發自體免疫葡萄膜炎、發炎病症(如子宮內膜異位)、發炎眼病、發炎腎病、發炎肝病,如非酒精性、酒精性及毒性脂肪肝疾病;肺病,如哮喘、特發性肺纖維化、慢性阻塞性肺病;以及代謝及代謝內分泌病症,如代謝症候群、抗胰島素症、I型及II型糖尿病,以及多囊性卵巢症候群(PCOS)病症、神經病變性及發炎性疼痛病症。
根據另一態樣,本發明涵蓋如上文所述之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽(尤其其醫藥學上可接受之鹽),或該等化合物混合物,其用於治療或預防人類及動物的疾病,詳言之,自體免疫疾病,諸如多發性硬化症、牛皮癬、牛皮癬性關節炎、類風濕性關節炎、僵直性脊椎炎、全身性紅斑狼瘡、原發及繼發自體免疫葡萄膜炎、發炎病症,如子宮內膜異位、發炎眼病、發炎腎病、發炎肝病,如非酒精性、酒精性及毒性脂肪肝疾病;肺病,如哮喘、特發性肺纖維化、慢性阻塞性肺病以及代謝及代謝內分泌病症,如代謝症候群、抗胰島素症、I型及II型糖尿病,以及多囊性卵巢症候群(PCOS)病症、神經病變性及發炎性疼痛病症。
本發明化合物之醫藥活性可以根據其作為GPR84拮抗劑的活性來解釋。
根據另一態樣,本發明涵蓋如上文所述之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及其鹽(尤其其醫藥學上可接受之鹽)或該等化合物混合物的用途,其用於治療或預防人類及動物的疾病,詳言之,自體免疫疾病,諸如多發性硬化症、牛皮癬、牛皮癬性關節炎、類風濕性關節炎、僵直性脊椎炎、全身性紅斑狼瘡、原發及繼發自體免疫葡萄膜炎、發炎病症,如子宮內膜異位、發炎眼病、發炎腎病、發炎肝病,如非酒精性、酒精性及毒性脂肪肝疾病;肺病,如哮喘、特發性肺纖維化、慢性阻塞性肺病,以及代謝及代謝內分泌病症,如代謝症候群、抗胰島素症、I型及II型糖尿病,以及多囊性卵巢症候群(PCOS)病症、神經病變性及發炎性疼痛病症。
根據另一態樣,本發明涵蓋上述式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或其鹽(尤其其醫藥學上可接受之鹽)或該等化合物混合物的用途,其用於預防或治療人類及動物的疾病,詳言之,自體免疫疾病,諸如多發性硬化症、牛皮癬、牛皮癬性關節炎、類風濕性關節炎、僵直性脊椎炎、全身性紅斑狼瘡、原發及繼發自體免疫葡萄膜炎、發炎病症,如子宮內膜異位、發炎眼病、發炎腎病、發炎肝病,如非酒精性、酒精性及毒性脂肪肝疾病;肺病,如哮喘、特發性肺纖維化、慢性阻塞性肺病,以及代謝及代謝內分泌病症,如代謝症候群、抗胰島素症、I型及II型糖尿病,以及多囊性卵巢症候群(PCOS)病症、神經病變性及發炎疼痛病症。
根據另一態樣,本發明涵蓋如上文所述之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽(尤其其醫藥學上可接受之鹽)或該等化合物混合物的用途,其用於治療或預防人類及動物之疾病的方法,詳言之,自體免疫疾病,諸如多發性硬化症、牛皮癬、牛皮癬性關節炎、類風濕性關節炎、僵直性脊椎炎、全身性紅斑狼瘡、原發及繼發自體免疫葡萄膜炎、發炎病症,如子宮內膜異位、發炎眼病、發炎腎病、發炎肝病,如非酒精性、酒精性及毒性脂肪肝疾病;肺病,如哮喘、特發性肺纖維化、慢性阻塞性肺病以及代謝及代謝內分泌病症,如代謝症候群、抗胰島素症、I型及II型糖尿病,以及多囊性卵巢症候群(PCOS)病症、神經病變性及發炎性疼痛病症。
根據另一態樣,本發明涵蓋如上文所述之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及其鹽(尤其其醫藥學上可接受之鹽)或該等化合物混合物的用途,其用於製備供預防或治療人類及動物之疾病的醫藥組合物,較佳為藥劑,該等疾病特定而言:自體免疫疾病,諸如多發性硬化症、牛皮癬、牛皮癬性關節炎、類風濕性關節炎、僵直性脊椎炎、全身性紅斑狼瘡、原發及繼發自體免疫葡萄膜炎、發炎病症,如子宮內膜異位、發炎眼病、發炎腎病、發炎肝病,如非酒精性、酒精性及毒性脂肪肝疾病;肺病,如哮喘、特發性肺纖維化、慢性阻塞性肺病;以及代謝及代謝內分泌病症,如代謝症候群、抗胰島素症、I型及II型糖尿病,以及多囊性卵巢症候群(PCOS)病症、神經病變性及發炎疼痛病症。
根據另一態樣,本發明涵蓋使用有效量的上述通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及其鹽(尤其其醫藥學上可接受之鹽)或該等化合物混合物治療或預防疾病的方法,該等疾病特定而言:自體免疫疾病,諸如多發性硬化症、牛皮癬、牛皮癬性關節炎、類風濕性關節炎、僵直性脊椎炎、全身性紅斑狼瘡、原發及繼發自體免疫葡萄膜炎、發炎病症,如子宮內膜異位、發炎眼病、發炎腎病、發炎肝病,如非酒精性、酒精性及毒性脂肪肝疾病;肺病,如哮喘、特發性肺纖維化、慢性阻塞性肺病以及代謝及代謝內分泌病症,如代謝症候群、抗胰島素症、I型及II型糖尿病,以及多囊性卵巢症候群(PCOS)病症、神經病變性及發炎性疼痛病症。
根據另一態樣,本發明涵蓋醫藥組合物,特定言之,藥劑,其包含如上文所述之通式(I)化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物、鹽(尤其醫藥學上可接受之鹽)或該等化合物混合物;及一或多種賦形劑,尤其一或多種醫藥學上可接受之賦形劑。可使用習知程序將此類醫藥組合物製備成適當劑型。
本發明此外涵蓋醫藥組合物,特定言之,藥劑,其包含至少一種本發明化合物,習知地連同一或多種醫藥學上適合之賦形劑一起;及其用於上述目的之用途。
本發明化合物可具有全身及/或局部活性。出於此目的,其可以適合方式投與,諸如經口、非經腸、肺、鼻、舌下、舌、口腔、直腸、陰道、真皮、經皮、結膜或耳途徑,或呈植入物或血管內支架形式。
就此等投藥路徑而言,本發明化合物可以適合的投藥形式投與。
為了經口投藥,可將本發明化合物調配成此項技術中已知之快速及/或以經調節之方式遞送本發明化合物的劑型,諸如錠劑(無包衣或包衣錠劑,例如延遲溶解或不溶的腸溶性或控制釋放包衣)、口服崩解錠劑、膜/粉片、膜/凍乾製劑、膠囊(例如硬或軟明膠膠囊)、糖衣錠劑、顆粒、丸劑、散劑、乳液、懸浮液、氣溶膠或溶液。可將本發明化合物以結晶及/或非晶型及/或溶解形式併入該等劑型中。
非經腸投藥可在避免吸收步驟之情況下(例如靜脈內、動脈內、心內、脊椎內或腰內)或在包括吸收之情況下(例如肌肉內、皮下、皮內、經皮或腹膜內)實現。適用於非經腸投藥之投藥形式尤其為供注射及輸注用之製劑,其呈溶液、懸浮液、乳液、凍乾製劑或無菌散劑形式。
適於其他投藥途徑之實例為用於吸入之醫藥形式[尤其粉末吸入劑、霧化劑]、滴鼻劑、鼻用溶液、鼻用噴霧劑;經舌、舌下或口腔投藥之錠劑/薄膜/粉片/膠囊;栓劑;滴眼劑、眼膏、洗眼液、眼部插入物、滴耳劑、耳噴霧劑、耳用散劑、沖耳劑、耳塞;陰道膠囊、水性懸浮液(洗劑,震盪混合物(mixturae agitandae))、親脂性懸浮液、乳液、軟膏、乳膏、經皮治療系統(諸如貼片)、牛乳、糊劑、發泡體、敷粉、植入物或血管內支架。
可以將本發明化合物併入所述投藥形式中。此可以本身已知之方式藉由與醫藥學上適合之賦形劑混合來實現。醫藥學上適合之賦形劑尤其包括
● 填充劑及載劑(例如纖維素、微晶纖維素(諸如Avicel®
)、乳糖、甘露糖醇、澱粉、磷酸鈣(諸如Di-Cafos®
)),
● 軟膏基質(例如石油膏、石蠟、三酸甘油酯、蠟、毛絨蠟、毛絨蠟醇、羊毛蠟、親水性軟膏、聚乙二醇),
● 栓劑用基質(例如聚乙二醇、可可脂、硬脂肪),
● 溶劑(例如水、乙醇、異丙醇、甘油、丙二醇、中鏈長度三酸甘油酯、脂肪油、5液體聚乙二醇、石蠟),
● 界面活性劑、乳化劑、分散劑或濕潤劑(例如十二烷基硫酸鈉)、卵磷脂、磷脂、脂肪醇(諸如Lanette®
)、去水山梨糖醇脂肪酸酯(諸如Span®)、聚氧化乙烯去水山梨糖醇脂肪酸酯(諸如Tween®)、聚氧化乙烯脂肪酸甘油酯(諸如Cremophor®)、聚氧化乙烯脂肪酸酯、聚氧化乙烯脂肪醇醚、甘油脂肪酸酯、泊洛沙姆(poloxamer)(諸如Pluronic®
),
● 緩衝劑、酸及鹼(例如磷酸鹽、碳酸鹽、檸檬酸、乙酸、鹽酸、氫氧化鈉溶液、碳酸銨、胺丁三醇(trometamol)、三乙醇胺),
● 等張劑(例如葡萄糖、氯化鈉),
● 吸附劑(例如高分散型二氧化矽),
● 增黏劑、凝膠形成劑、增稠劑及/或黏合劑(例如聚乙烯吡咯啶酮、甲基纖維素、羥丙基甲基纖維素、羥丙基纖維素、羧甲基纖維素鈉、澱粉、卡波姆(carbomer)、聚丙烯酸(諸如Carbopol®
)、褐藻酸鹽、明膠),
● 崩解劑(例如改質澱粉、羧甲基纖維素鈉、乙醇酸澱粉鈉(諸如Explotab®)、交聯聚乙烯吡咯啶酮、交聯羧甲纖維素鈉(諸如AcDiSol®)),
● 流動調節劑、潤滑劑、滑動劑及脫模劑(例如硬脂酸鎂、硬脂酸、滑石、高分散型二氧化矽(諸如Aerosil®)),
● 包衣材料(例如糖、蟲膠)及快速溶解或以經調節之方式溶解之膜或擴散膜用的成膜劑(例如聚乙烯吡咯啶酮(諸如Kollidon®
)、聚乙烯醇、羥丙基甲基纖維素、羥丙基纖維素、乙基纖維素、鄰苯二甲酸羥丙基甲基纖維素、乙酸纖維素、鄰苯二甲酸乙酸纖維素、聚丙烯酸酯、聚甲基丙烯酸酯(諸如Eudragit®
)),
● 膠囊材料(例如明膠、羥丙基甲基纖維素),
● 合成聚合物(例如聚乳酸交酯、聚乙交酯、聚丙烯酸酯、聚甲基丙烯酸酯(諸如Eudragit®)、聚乙烯吡咯啶酮(諸如Kollidon®)、聚乙烯醇、聚乙烯乙酸酯、聚氧化乙烯、聚乙二醇及其共聚物及嵌段共聚物),
● 塑化劑(例如聚乙二醇、丙二醇、甘油、三乙酸甘油酯(triacetine)、三乙醯基檸檬酸酯、鄰苯二甲酸二丁酯),
● 穿透增強劑,
● 穩定劑(例如抗氧化劑,諸如抗壞血酸、抗壞血酸棕櫚酸酯、抗壞血酸鈉、丁基羥基苯甲醚、丁基羥基甲苯、沒食子酸丙酯),
● 防腐劑(例如對羥苯甲酸酯、山梨酸、硫柳汞、苯紮氯銨(benzalkonium chloride)、氯己定乙酸酯(chlorhexidine acetate)、苯甲酸鈉),
● 著色劑(例如無機顏料,諸如氧化鐵、二氧化鈦),
● 調味劑、甜味劑、風味及/或氣味遮蔽劑。
本發明另外係關於一種醫藥組合物,其包含本發明之至少一種化合物,習知地連同一或多種醫藥學適合賦形劑;及本發明之其用途。
實驗章節
NMR峰形式如其在頻譜中出現的那樣陳述,不考慮可能的高階效應。
所選化合物之1
H-NMR資料以1
H-NMR峰清單形式列出。其中,各信號峰均指定δ值(ppm),繼之為信號強度,在圓括號中報導。不同峰之δ值-信號強度對用逗號隔開。因此,峰清單用以下通用形式描述:δ1
(強度1
), δ2
(強度2
), ... , δi
(強度i
), ... , δn
(強度n
)。
尖銳信號強度與所列印之NMR譜中之信號高度(cm)相關。與其他信號相比,此資料可與信號強度之真實比率相關。在寬信號之情況下,顯示超過一個峰或信號中心以及其相對強度(相較於頻譜中所顯示之最強信號)。1
H-NMR峰清單類似於經典的1
H-NMR讀數,且因此通常含有經典NMR解釋中所列之所有峰。另外,類似於經典1
H-NMR列印輸出,峰清單可以展示溶劑信號、來源於特定目標化合物之立體異構體的信號、雜質峰、13
C衛星峰及/或自旋側頻帶。立體異構體之峰及/或雜質之峰所顯示之強度典型地低於目標化合物之峰(例如純度> 90%)。此類立體異構體及/或雜質可能為特定製造方法所特有的,且因此其峰可有助於基於「副產物指紋」鑑別製造方法之再現。藉由已知方法(MestReC、ACD模擬或藉由使用憑經驗評估之期望值)計算目標化合物之峰的專家在需要時,可以視情況使用額外的強度過濾器分離出目標化合物之峰。此類操作類似於經典1
H-NMR解釋中之峰挑選。以峰清單形式報導NMR資料之詳細描述可見於公開案「專利申請案內之NMR峰清單資料之引用」(參見http://www.researchdisclosure.com/searching-disclosures, 研究揭示資料庫(Research Disclosure Database)第605005期, 2014, 2014年8月1日)。在峰挑選例行程序中,如研究揭示資料庫第605005號中所述,參數「最小高度」可在1%與4%之間調節。然而,視化學結構而定及/或視所量測化合物之濃度而定,將參數「最小高度」設置為<1%可為合理的。
化學名稱係使用得自ACD/Labs之ACD/Name軟體產生。在一些情況下,使用市售試劑之公認名稱替代ACD/Name產生之名稱。
下表1列出用於此段及實例章節中所用的縮寫(就其在正文主體內未解釋而言)。其他縮寫具有其本身為熟習此項技術者所慣用的含義。
下表列出本文所用之縮寫。表 1 :縮寫
縮寫 | 含義 |
br. | NMR中之寬信號 |
br. s. | 寬單峰 |
CDI | 二-1H -咪唑-1-基甲酮 |
conc. | 濃縮 |
CPME | 環戊基甲基醚 |
d | 二重峰 |
dd | 雙二重峰 |
ddd | 兩個雙二重峰 |
dt | 雙三重峰 |
DCM | 二氯甲烷 |
DEA | 二乙胺 |
DIPEA | N,N -二異丙基乙胺 |
DMAP | N,N -二甲基吡啶-4-胺 |
DMF | N,N -二甲基羧醯胺 |
DMSO | 二甲亞碸 |
EDC | N -(3-二甲胺基丙基)-N' -乙基碳化二亞胺鹽酸鹽 |
ESI | 電噴霧電離 |
ESIpos | 正電噴霧電離 |
ESIneg | 負電噴霧電離 |
EtOAc | 乙酸乙酯 |
EtOH | 乙醇 |
eq. | 當量 |
GP | 通用程序 |
h | 小時 |
HATU | 六氟磷酸O -(7-氮雜苯并三唑-1-基)-1,1,3,3-四甲基 |
HCl | 鹽酸 |
HCOOH | 甲酸 |
HPLC, LC | 高效液相層析 |
LC-MS / LCMS | 液相層析-質譜 |
m | 多重峰 |
min | 分鐘 |
MS | 質譜 |
MeCN | 乙腈 |
MeOH | 甲醇 |
NMR | 核磁共振 |
q | 四重峰 |
quint | 五重峰 |
Rt | 滯留時間 |
rt | 室溫 |
s | 單峰 |
sept | 七重峰 |
t | 三重峰 |
TFA | 三氟乙酸 |
THF | 四氫呋喃 |
TMAD | N ,N ,N' ,N' -四甲基偶氮二羧醯胺 |
UPLC | 超高效液相層析 |
UPLC-MS | 超高效液相層析-質譜 |
本申請案中所述之本發明之各種態樣藉由以下實例來說明,該等實例不以任何方式限制本發明。
本文所述之實例測試實驗用於說明本發明且本發明不限於所示出之實例。
實驗章節 - 通用部分
其合成未描述於實驗部分中的所有試劑均可市購,或為已知化合物,或可由熟習此項技術者利用已知方法由已知化合物形成。
根據本發明方法製成之化合物及中間物可能需要純化。有機化合物之純化為熟習此項技術者所熟知且該化合物可存在若干種純化方法。在一些情況下,可能不需要純化。在一些情況下,化合物可藉由結晶純化。在一些情況下,雜質可藉由使用適合溶劑來攪拌移除。在一些情況下,可以使用例如預裝填矽膠濾柱(例如Biotage SNAP濾柱KP-Sil®
或KP-NH®
與Biotage自動純化系統(SP4®
或Isolera Four®
)的組合)及溶離劑(諸如己烷/乙酸乙酯或DCM/甲醇之梯度),藉由層析(特定言之,急驟管柱層析)來純化化合物。在一些情況下,可以使用例如Waters自動純化器,藉由製備型HPLC純化化合物,該自動純化器裝備有二極體陣列偵測器及/或在線電噴霧電離質譜儀與適合之預裝填逆相管柱及溶離劑(諸如水及乙腈之梯度)之組合,該等溶離劑可以含有添加劑,諸如三氟乙酸、甲酸或氨水。
在一些情況下,如上文所述之純化方法可以提供具有足夠鹼性或酸性官能基之呈鹽形式的本發明彼等化合物,諸如三氟乙酸鹽或甲酸鹽(在本發明化合物具有足夠鹼性之情況下),或銨鹽(在本發明化合物具有足夠酸性之情況下)。此類型之鹽可藉由熟習此項技術者已知之多種方法分別轉化為其游離鹼或游離酸形式,或在後續生物學分析中作為鹽來使用。應瞭解,如所分離且如本文描述之本發明化合物之特定形式(例如鹽、游離鹼等)不一定是該化合物可應用於生物學分析中以便定量特定生物活性之唯一形式。
UPLC-MS 標準程序
如下文所述執行分析型UPLC-MS。除非指定負模式(ESI-),否則報導得自正模式電噴霧電離的質量(m/z)。在大部分情況下使用方法1。若不然,則其予以指定。
方法1
:
儀器:Waters Acquity UPLC-MS SQD 3001;管柱:Acquity UPLC BEH C18 1.7 µm,50×2.1 mm;溶離劑A:水 + 0.2 vol%氨,溶離劑B:乙腈;梯度:0-1.6 min 1-99% B,1.6-2.0 min 99% B;流量:0.8 mL/min;溫度:60℃;注射:2 µl;DAD掃描:210-400 nm;ELSD。
方法2
:
儀器:Waters Acquity UPLC-MS SQD 3001;管柱:Acquity UPLC BEH C18 1.7 µm,50x2.1 mm;溶離劑A:水 + 0.1 vol%甲酸,溶離劑B:乙腈;梯度:0-1.6 min 1-99% B,1.6-2.0 min 99% B;流量:0.8 mL/min;溫度:60℃;注射:2 µL;DAD掃描:210-400 nm。LC-MS 標準程序
方法A
:
儀器:Waters Acquity UPLCMS SingleQuad;管柱:Acquity UPLC BEH C18 1.7 µm,50x2.1 mm;溶離劑A:水 + 0.2 vol%氨水(32%),溶離劑B:乙腈;梯度:0-1.6 min 1-99% B,1.6-2.0 min 99% B;流量:0.8 mL/min;溫度:60℃;DAD掃描:210-400 nm。
方法B
:5-95AB, Shimadzu
儀器:SHIMADZU LCMS-2020 SingleQuad;管柱:Chromolith@Flash RP-18E 25-2 MM;溶離劑A:水 + 0.0375 vol%三氟乙酸,溶離劑B:乙腈 + 0.01875 vol%三氟乙酸;梯度:0-0.8 min,5-95% B,0.8-1.2 min 95% B;流量:1.5 mL/min;溫度:50℃;PDA:220 nm及254 nm。
方法C
:5-95AB, Agilent
儀器:Agilent 1100\G1956A SingleQuad;管柱:Kinetex@ 5 μm EVO C18 30*2.1 mm;溶離劑A:水 + 0.0375 vol%三氟乙酸,溶離劑B:乙腈 + 0.01875 vol%三氟乙酸;梯度:0-0.8 min 5-95% B,0.8-1.2 min 95% B;流量:1.5 mL/min;溫度:50℃;PDA:220 nm及254 nm。
方法D
:5-95CD, Shimadzu
儀器:SHIMADZU LCMS-2020 SingleQuad;管柱:Kinetex EVO C18 2.1*30 mm,5 μm;溶離劑A:水 + 0.025 vol%氫氧化銨,溶離劑B:乙腈;梯度:0-0.8 min,5-95% B,0.8-1.2 min 95% B;流量:1.5 mL/min;溫度:40℃;PDA:220 nm及254 nm。
方法E
:5-95CD, Shimadzu
儀器:SHIMADZU LCMS-2020 SingleQuad;管柱:Kinetex EVO C18 2.1*30 mm,5 μm;溶離劑A:水 + 0.025 vol%氫氧化銨,溶離劑B:乙腈;梯度:0-0.8 min,5-95% B,0.8-1.2 min,95% B;流量1.5 ml/min;溫度:40℃;PDA:220 nm及254 nm。
藉由分析型對掌性HPLC執行對映異構體的分析表徵。在個別實例之描述中,提及所應用之HPLC程序。
純化方法 :
使用預裝填二氧化矽及預裝填之改質二氧化矽濾柱的Biotage IsoleraTM
層析系統(http://www.biotage.com/product-area/flash-purification)。製備型 HPLC , 方法 A
:儀器:泵浦:Labomatic HD-5000或HD-3000,機頭HDK 280,低壓力梯度模組ND-B1000;手動注射閥:Rheodyne 3725i038;偵測器:Knauer Azura UVD 2.15;收集器:Labomatic Labocol Vario-4000;管柱:Chromatorex RP C-18 10 µm,125x30 mm;溶離劑A:水 + 0.2 vol-%氨(32%),溶離劑B:乙腈;
梯度A:0 - 15 min 1 - 25% B;流量:60 ml/min;
梯度B:0 - 15 min 10 - 50% B;流量:60 ml/min;
梯度C:0 - 15 min 15 - 55% B;流量:60 ml/min;
梯度D:0 - 15 min 30 - 70% B;流量:60 ml/min;
梯度E:0 - 15 min 40 - 80% B;流量:60 ml/min;
梯度F:0 - 15 min 65 - 100% B;流量:60 ml/min;
溫度:25℃;溶解度:max. 250 mg/2 ml二甲亞碸;注射:1 x 2 ml;偵測:UV 254 nm;軟體:SCPA PrepCon5。製備型 HPLC , 方法 B
:儀器:泵浦:Labomatic HD-5000或HD-3000,機頭HDK 280,低壓力梯度模組ND-B1000;手動注射閥:Rheodyne 3725i038;偵測器:Knauer Azura UVD 2.15;收集器:Labomatic Labocol Vario-4000;管柱:Chromatorex RP C-18 10 µm,125x30 mm;溶離劑A:水 + 0.1 vol%甲酸(99%),溶離劑B:乙腈;
梯度A:0 - 15 min 1 - 25% B;流量:60 ml/min;
梯度B:0 - 15 min 10 - 50% B;流量:60 ml/min;
梯度C:0 - 15 min 15 - 55% B;流量:60 ml/min;
梯度D:0 - 15 min 30 - 70% B;流量:60 ml/min;
梯度E:0 - 15 min 40 - 80% B;流量:60 ml/min;
梯度F:0 - 15 min 65 - 100% B;流量:60 ml/min;
溫度:25℃;溶解度:max. 250 mg/2 ml二甲亞碸;注射:1 x 2 ml;偵測:UV 254 nm;軟體:SCPA PrepCon5。
實驗章節 - 通用程序 通用程序 A (GP A) :
α-甲醯化反應(3
→4a/b
,流程1;或17
→18a/b
,流程3;或16
→22a/b
,流程4)
(條件 A
:烯胺形成);類似於H. Bredereck等人, Liebigs Ann. Chem. 1980, 3, 344-357及WO2010/078427,第222頁。
在室溫下,向各別酮(1 eq.)於甲苯中的溶液中添加1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(布雷德奈克試劑,CAS編號[5815-08-7];1.2-5 eq.)或1,1-二甲氧基-N,N-
二甲基甲胺(1.2-5 eq.)且反應混合物在100-120℃下攪拌直至TLC及/或LCMS指示起始物質完全消耗為止(隔夜或長達6天)。在減壓下濃縮反應混合物且不經進一步純化步驟即用於後續反應。
α-甲醯化反應(3
→4a/b
,流程1;或17
→18a/b
,流程3;或16
→22a/b
,流程4)
(條件 B
:烯醇形成);類似於M.L.Hammond等人, J. Med. Chem. 1989, 32, 1006-1020及D.J.Goldsmith等人, J. Org. Chem. 1980, 45, 3989-3993及G.Grandolini等人, Gazzetta Chimica Italiana 1976, 106, 1083-1094。
在0℃下,向羧酸乙酯(CAS編號[109-94-4];2.0-6.0 eq.)於甲苯中的溶液中添加氫化鈉(3.0 eq.,60%純度)。攪拌0.5小時之後,向上述混合物中添加各別酮(1.0 eq.)於甲苯中的溶液。反應混合物在室溫或45℃下攪拌直至TLC及/或LCMS指示起始物質完全消耗為止(典型地為2小時或長達隔夜)。反應混合物用2 N鹽酸水溶液淬滅且分離各相。水相用乙酸乙酯萃取且合併之有機相用鹽水洗滌,經無水硫酸鈉乾燥,過濾且在減壓下濃縮。所得粗所需產物不經進一步純化步驟即用於後續反應。
通用程序 B (GP B) :
呋喃并吲唑形成(4a/b
→5
,流程1;或18a/b
→19
,流程3;或22a/b
→23
,流程4);類似於G.Grandolini等人, Gazzetta Chimica Italiana 1976, 106, 1083-1094及W.A.Remers等人, J. Heterocycl. Chem. 1975, 12, 421-422。
在室溫下,向各別烯胺或烯醇(1.0 eq.)於乙醇中的溶液中添加水合肼1:1 (CAS編號[7803-57-8];5.0 eq.)或肼二鹽酸鹽(CAS編號[5341-61-7];2.0 eq.)於水或乙醇中的溶液。反應混合物在60-70℃下攪拌直至TLC及/或LCMS指示起始物質完全消耗為止(典型地為2小時或長達隔夜)。在0℃下用次氯酸鈉淬滅之後,兩相混合物在減壓下濃縮。將殘餘物直接提供至管柱層析(SiO2
)或分配於水與乙酸乙酯之間。水層用乙酸乙酯萃取且合併之有機層用鹽水洗滌,過濾且在減壓下濃縮,得到粗標題化合物,適當時經由管柱層析(SiO2
)來純化。
通用程序 C (GP C) :
呋喃并吲唑烷基化(5
→8
,流程1;或19
→20
,流程3;或23
→24
,流程4)
(條件 A
:光延反應;類似於D.L. Selwood等人, J. Med. Chem. 2009, 52, 2694-2707)
在室溫下,向各別呋喃并吲唑(1.0 eq.)及醇(1-2 eq.)於甲苯中的溶液中添加三-正丁基膦(CAS編號[998-40-3];1.5-3 eq.)及N,N,N'
,N'
-四甲基偶氮二羧醯胺(TMAD,CAS編號[10465-78-8];1.5-3 eq.)且反應混合物在室溫下攪拌直至TLC及/或LCMS指示起始物質完全消耗為止(典型地為隔夜)。反應混合物用水稀釋且分離各相。水相用二氯甲烷萃取(兩至三次),合併之有機相經MgSO4
或Na2
SO4
乾燥,過濾且濃縮。對所得粗物質進行管柱層析(SiO2
),得到所需烷基化產物。通常,獲得2位經取代的吲唑作為主要產物。
呋喃并吲唑烷基化(5
→8
,流程1;或19
→20
,流程3;或23
→24
,流程4)
(條件 B
:與烷基(假)鹵化物反應)
各別呋喃并吲唑(1.0 eq.)及烷基(假)鹵化物(1.5-3 eq.)於乙腈或乙酸乙酯中分溶液在室溫下用碳酸鉀(5 -15 eq.)及N,N-
二甲基吡啶-4-胺(DMAP,CAS編號[1122-58-3];2.5 mol%)處理。反應混合物在60-70℃下攪拌直至TLC及/或LCMS指示起始物質完全消耗為止(典型地為隔夜或長達數天)。將反應混合物冷卻至室溫且過濾。在減壓下濃縮濾液且對殘餘物進行管柱層析(SiO2
),得到所需烷基化產物。
通用程序 D (GP D) :
呋喃并吲唑酯之皂化(8
→9
,流程1)
在室溫下,用氫氧化鋰水溶液(2 M,15 eq.)處理各別呋喃并吲唑酯(1.0 eq.)於四氫呋喃與乙醇(1:1)之混合物中的溶液。在一些情況下,改用含有氫氧化鈉水溶液(30 eq.)的THF。反應混合物在60-70℃下攪拌直至TLC及/或LCMS指示起始物質完全消耗為止(典型地為隔夜)。將反應混合物冷卻至室溫,用鹽酸水溶液酸化至pH 3-5且用乙酸乙酯萃取。所需羧酸在水相中沈澱(潛在地以HCl鹽形式)且可以藉由過濾及乾燥分離且不經進一步純化步驟即用於後續反應中。或者,分離各相,有機相用鹽水洗滌,經Na2
SO2
乾燥,過濾且在減壓下濃縮,得到所需羧酸,其不經進一步純化步驟即用於後續反應。
通用程序 E (GP E) :
呋喃并吲唑溴化物之羧基化(20
→21
,流程3)
在氬氣氛圍下將呋喃并吲唑溴化物(1.0 eq.)置於鋼質高壓釜中且溶解於二甲亞碸(約15 mL/mmol )中。添加乙酸鈀(II)(5.0 mol%)、1,1'-雙(二苯基膦基)二茂鐵(CAS編號[12150-46-8];0.20 eq.)及乙酸鉀(4.0 eq.)且混合物用一氧化碳淨化3次。在20℃下、在約11巴之一氧化碳壓力下攪拌混合物30分鐘。將高壓釜再次設置在真空下,接著施加約15巴之一氧化碳壓力,且將混合物加熱至100℃直至TLC及/或LCMS指示起始物質完全消耗為止(通常23小時),產生約18巴之最高壓力。將反應物冷卻至室溫,釋放壓力,且將反應混合物添加至冰水中。混合物用1 M HCl水溶液(約pH 2.5)酸化,攪拌20分鐘且用二氯甲烷或乙酸乙酯稀釋。分離各相,且用二氯甲烷或乙酸乙酯萃取水相。將合併之有機相乾燥,過濾且在減壓下濃縮。所得粗羧酸不經進一步純化即轉送至下一步驟。
通用程序 F (GP F) :
呋喃并吲唑之維斯邁爾-哈克甲醯化(Vilsmeier-Haack formylation)(24
→25
,流程4)
在冰冷卻下,將磷醯氯(10 eq.)逐滴添加至N,N
-二甲基羧醯胺(10 eq.)中且攪拌15分鐘。逐滴添加呋喃并吲唑(1.0 eq.)於N,N-
二甲基羧醯胺中的溶液,將混合物升溫至室溫且攪拌直至TLC及/或LCMS指示起始物質完全消耗為止(通常1-2小時)。將反應混合物添加至冰水中且藉由添加氫氧化鈉水溶液(4 M)將pH調節至約9。混合物用二氯甲烷萃取,分離各相,且將合併之有機相乾燥,過濾且在減壓下濃縮。所得粗醛在適當時經由管柱層析(SiO2
)純化。
通用程序 G (GP G) :
醯胺形成(9
→(I)
,流程1;或21
→(Ia)
,流程3)
(條件 A
:醯胺偶合)
羧酸或相應鹽(1.0 eq.)於DMF中的溶液用HATU (1.5 eq.)及DIPEA (3.0 eq.)處理且在室溫下攪拌數分鐘,接著添加胺組分(1-1.5 eq.)且在室溫下繼續攪拌直至TLC及/或LCMS指示起始物質完全消耗為止(通常隔夜)。在大多數情況下,過濾反應混合物且藉由製備型HPLC純化,得到所需醯胺。在一些情況下,反應混合物用水稀釋且用乙酸乙酯萃取。將有機相乾燥,過濾且藉由管柱層析(SiO2
)純化,得到所需醯胺。
或者,羧酸或相應鹽(1.0 eq.)於DMF中的溶液用2,4,6-三丙基-1,3,5,2,4,6-三氧雜三磷雜環己烷2,4,6-三氧化物(T3P,50 wt%於DMF中的溶液,1.5-3 eq.)、DIPEA (3-5 eq.)及胺組分(1-1.5 eq.)處理且在室溫下攪拌反應混合物直至TLC及/或LCMS指示起始物質完全消耗為止(通常隔夜)。過濾反應混合物且藉由製備型HPLC純化,得到所需醯胺。
醯胺形成(20
→(Ia)
,流程3)
(條件 B
:溴化物進行羰基化而直接產生醯胺)
呋喃并吲唑溴化物(1.0 eq.)於1,4-二㗁烷(含有約1%水)中的溶液用相應胺(3-5 eq.)、六羰基鉬(CAS編號[13939-06-5];2.0 eq.)、碳酸鈉(CAS編號[497-19-8];3.0 eq.)、四氟硼酸三-第三丁基鏻(CAS編號[131274-22-1];0.10 eq.)及乙酸鈀(II)(CAS編號[3375-31-3];0.20 eq.)處理。反應混合物在120-140℃下劇烈攪拌直至TLC及/或LCMS指示起始物質完全消耗為止(通常18小時)。將混合物冷卻至室溫,經矽藻土濾出固體且用乙酸乙酯沖洗。在減壓下濃縮濾液且藉由製備型HPLC純化所得粗產物。
醯胺形成(25
→(Ia)
,流程4)
(條件 C
:醛轉化為醯胺);類似於J.K. Taylor等人, Synthesis 2003, 7, 1055-1064。
呋喃并吲唑醛(1.0 eq.)於DMSO或THF中的溶液用相應胺(5.0 eq.)、氰化鈉(1.0 eq.)及二氧化錳(IV)(15 eq.)處理且在室溫下攪拌30分鐘。添加額外量的二氧化錳(IV)(15 eq.)且在室溫下繼續攪拌直至TLC及/或LCMS指示起始物質完全消耗為止(24小時或長達數天)。反應混合物經矽藻土過濾,在減壓下濃縮濾液且所得粗產物藉由製備型HPLC純化,得到所需醯胺。
通用程序 H (GP H) :
醯胺形成(9
→(I)
,流程1;或21
→(Ia)
,流程3)
(條件 A
:醯胺偶合)
羧酸或相應鹽(1.0 eq.)於DMF中的溶液用HATU (1.5 eq.)及DIPEA (3-6 eq.)處理且在室溫下攪拌數分鐘,接著添加胺組分(1-1.5 eq.)且在室溫下繼續攪拌直至TLC及/或LCMS指示起始物質完全消耗為止(通常隔夜)。在大多數情況下,反應混合物用飽和氯化銨稀釋且用乙酸乙酯萃取。合併之有機相用水洗滌,藉由疏水性過濾乾燥且藉由製備型HPLC純化,得到所需醯胺。在一些情況下,過濾反應混合物且藉由製備型HPLC純化,得到所需醯胺。
醯胺形成(9
→(I)
,流程1;或21
→(Ia)
,流程3)
(條件 B
:醯胺偶合)
羧酸或相應鹽(1.0 eq.)於DMF中的溶液用HATU (1.5 eq.)及DIPEA (3-6 eq.)處理且在室溫下攪拌數分鐘,接著添加胺組分(1-2 eq.)且在室溫下繼續攪拌直至TLC及/或LCMS指示起始物質完全消耗為止(通常隔夜)。在大多數情況下,用乙酸乙酯及水稀釋反應混合物。用乙酸乙酯萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,且過濾或疏水性過濾且藉由製備型HPLC純化,得到所需醯胺。在一些情況下,過濾反應混合物且藉由製備型HPLC純化,得到所需醯胺。
(條件 C
:醯胺偶合)
羧酸或相應鹽(1.0 eq.)於THF (及有時溶解於DMF)中的溶液用HATU (1.5 eq.)及DIPEA (3-6 eq.)處理且在室溫下攪拌數分鐘,接著添加胺組分(1-2 eq.)且在室溫下繼續攪拌直至TLC及/或LCMS指示起始物質完全消耗為止(通常72小時)。在大多數情況下,反應混合物用飽和NaHCO3
/水(1:5)及乙酸乙酯稀釋且攪拌30分鐘。分離各相且乙酸乙酯相用水萃取。合併之有機相經Na2
SO4
乾燥,且過濾或疏水性過濾且藉由製備型HPLC純化,得到所需醯胺。在一些情況下,過濾反應混合物且藉由製備型HPLC純化,得到所需醯胺。( 條件 D
:醯胺偶合)
羧酸或相應鹽(1.0 eq.)於DMF或THF中的溶液用HATU (1.5 eq.)及DIPEA (3-6 eq.)處理且在室溫下攪拌數分鐘,接著添加胺組分(1-1.5 eq.)且在室溫下繼續攪拌直至TLC及/或LCMS指示起始物質完全消耗為止(通常隔夜)。在大多數情況下,反應混合物用飽和碳酸氫鈉/水稀釋且用乙酸乙酯萃取。合併之有機相用鹽水洗滌,藉由疏水性過濾乾燥或經硫酸鈉乾燥且藉由製備型HPLC純化,得到所需醯胺。在一些情況下,過濾反應混合物且藉由製備型HPLC純化,得到所需醯胺。
實驗章節 - 中間物 中間物 1 : 步驟 1 (5E/Z
)-5-[( 二甲基胺基 ) 亞甲基 ]-6,7- 二氫 -1- 苯并呋喃 -4(5H
)- 酮
根據GP A (條件A),在100℃下,使6,7-二氫-1-苯并呋喃-4(5H
)-酮(市售,CAS編號[16806-93-2];5.00 g,36.7 mmol)與1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(布雷德奈克試劑,CAS編號[5815-08-7];1.20 eq.,7.68 g,44.1 mmol)在甲苯(100 mL)中反應2小時。添加額外量的1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(1.20 eq.,7.68 g,44.1 mmol)且在100℃下繼續攪拌另外6小時。在減壓下濃縮反應混合物且所得粗標題化合物不經進一步純化步驟即用於後續反應中。
UPLC-MS (方法1
): Rt
= 0.83 min; MS (ESIpos): m/z = 192 [M+H]+
。
步驟 2 4,5- 二氫 -1H
- 呋喃并 [2,3-g] 吲唑
根據GP B,在70℃下,使得自步驟1的粗(5E/Z)-5-[(二甲基胺基)亞甲基]-6,7-二氫-1-苯并呋喃-4(5H
)-酮(1.0 eq.,7.0 g,37 mmol)與水合肼1:1 (5.0 eq.,8.9 mL,180 mmol)在乙醇(100 mL)中反應3小時,管柱層析(SiO2
,DCM/MeOH)後,得到標題化合物(5.6 g,35%,歷經兩個步驟)。
UPLC-MS (方法1
): Rt
= 0.80 min; MS (ESIpos): m/z = 161 [M+H]+
。
步驟 3 2-[( 吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑
根據GP C (條件B),在75℃下,使得自步驟2的4,5-二氫-1H
-呋喃并[2,3-g]吲唑(1.0 eq.,5.6 g,35 mmol)與2-(溴甲基)吡啶(1.2 eq.,7.2 g,42 mmol)、碳酸鉀(15 eq.,73 g,530 mmol)及DMAP (2.5 mol%,110 mg,880 µmol)在EtOAc (150 mL)中反應3天,管柱層析(SiO2
,DCM/MeOH)後,得到標題化合物(6.0 g,52%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.86 (s, 4H), 5.34 (s, 2H), 6.62 (d, 1H), 7.03-7.05 (m, 1H), 7.27-7.31 (m, 1H), 7.57-7.60 (m, 2H), 7.76 (dt, 1H), 8.52-8.53 (m, 1H)。
UPLC-MS (方法1
): Rt
= 0.96 min; MS (ESIpos): m/z = 252 [M+H]+
。
步驟 4 2-[( 吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲醛
根據GP F,在室溫下,使得自步驟3的2-[(吡啶-2-基)甲基]-4,5-二氫-2H-
呋喃并[2,3-g]吲唑(1.00 eq.,1.00 g,3.98 mmol)與三氯化磷(CAS編號[10025-87-3];5.0 eq.,1.9 mL,20 mmol)及DMF (5.0 eq.,1.5 mL,20 mmol)反應1小時,管柱層析(SiO2
,DCM/MeOH)且隨後進行製備型HPLC後,得到標題化合物(63 mg,5%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.91-2.95 (m, 2H), 3.00-3.04 (m, 2H), 5.39 (s, 2H), 7.09 (d, 1H), 7.31 (ddd, 1H), 7.67 (s, 1H), 7.70 (s, 1H), 7.77 (dt, 1H), 8.52-8.54 (m, 1H), 9.52 (s, 1H)。
UPLC-MS (方法1
): Rt
= 0.83 min; MS (ESIpos): m/z = 280 [M+H]+
。
中間物 2 : 步驟 1 8- 甲基 -2-[( 吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件B),在75℃下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.0 eq.,3.0 g,12 mmol)與2-(溴甲基)吡啶(1.6 eq.,3.4 g,20 mmol)、碳酸鉀(15.0 eq.,25.3 g,183 mmol)及DMAP (2.5 mol%,37 mg,300 µmol)在EtOAc (200 mL)中反應44小時。添加額外量的2-(溴甲基)吡啶(1.3 eq.,2.7 g,16 mmol)及DMAP (2.5 mol%,37 mg,300 µmol)且在75℃下繼續攪拌另外3天,管柱層析(SiO2
,己烷/DCM)後,得到標題化合物(3.7 g,71%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.46 (s, 3H), 2.85-2.95 (m, 4H), 4.26 (q, 2H), 5.39 (s, 2H), 7.07 (d, 1H), 7.31 (ddd, 1H), 7.65 (s, 1H), 7.77 (dt, 1H), 8.53-8.55 (m, 1H)。
UPLC-MS (方法1
): Rt
= 1.15 min; MS (ESIpos): m/z = 338 [M+H]+
。
步驟 2 8- 甲基 -2-[( 吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-7-羧酸乙酯(3.68 g,10.9 mmol)與氫氧化鋰水溶液(2 M;15 eq.,82 mL,160 mmol)在乙醇與THF之1:1混合物(40 mL)中反應隔夜。用6 N鹽酸水溶液(pH 2-3)酸化且用EtOAc稀釋後,形成沈澱物,藉由過濾分離。沈澱物用EtOAc溶解,經Na2
SO2
乾燥,過濾且在減壓下濃縮,得到所需羧酸(1.9 g,54%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 2.84-2.93 (m, 4H), 5.39 (s, 2H), 7.07 (d, 1H), 7.32 (dd, 1H), 7.65 (s, 1H), 7.78 (dt, 1H), 8.53-8.55 (m, 1H), 12.80 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.50 min; MS (ESIpos): m/z = 310 [M+H]+
。
中間物 3 : 步驟 1 8- 甲基 -2-[( 吡啶 -3- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.0 eq.,1.0 g,4.1 mmol)與(吡啶-3-基)甲醇(1.10 eq.,487 mg,4.47 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,1.6 mL,6.5 mmol)及TMAD (CAS編號[10465-78-8];1.6 eq.,1.1 g,6.5 mmol)在甲苯(30 mL)中反應隔夜,管柱層析(Si -NH SiO2
,DCM/MeOH)且用己烷濕磨後,得到標題化合物(1.6 g,75%純度,70%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.48 (s, 3H), 2.83-2.93 (m, 4H), 4.26 (q, 2H), 5.35 (s, 2H), 7.36-7.39 (m, 1H), 7.64 (t, 1H), 7.66 (s, 1H), 8.50 (dd, 1H), 8.52 (d, 1H)。
UPLC-MS (方法1
): Rt
= 1.10 min; MS (ESIpos): m/z = 338 [M+H]+
。
步驟 2 8- 甲基 -2-[( 吡啶 -3- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(吡啶-3-基)甲基]-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.50 g,75%純度,3.33 mmol)與氫氧化鋰水溶液(2 M;15 eq.,82 mL,160 mmol)在乙醇與THF之1:1混合物(20 mL)中反應隔夜。用4 N鹽酸水溶液(pH 4)酸化後,形成沈澱物,藉由過濾分離且乾燥,得到所需羧酸(331 mg,77%純度,25%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.46 (s, 3H), 2.82-2.91 (m, 4H), 5.34 (s, 2H), 7.38 (ddd, 1H), 7.64-7.67 (m, 2H), 8.50 (dd, 1H), 8.52 (d, 1H), 12.83 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.47 min; MS (ESIpos): m/z = 310 [M+H]+
。
中間物 4 : 步驟 1 8- 甲基 -2-[( 吡啶 -4- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.0 eq.,1.0 g,4.1 mmol)與(吡啶-4-基)甲醇(1.10 eq.,487 mg,4.47 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,1.6 mL,6.5 mmol)及TMAD (CAS編號[10465-78-8];1.6 eq.,1.1 g,6.5 mmol)在甲苯(30 mL)中反應隔夜。添加額外量的(吡啶-4-基)甲醇(0.40 eq.,175 mg,1.6 mmol)、三-正丁基膦(0.4 eq.,0.4 mL,1.6 mmol)及TMAD (0.4 eq.,0.3 g,1.6 mmol)且繼續攪拌2天,管柱層析(Si -NH SiO2
,DCM/MeOH)後,得到標題化合物(3 g,20%純度,44%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.47 (s, 3H), 2.87-2.97 (m, 4H), 4.26 (q, 2H), 5.37 (s, 2H), 7.13-7.15 (m, 2H), 7.68 (s, 1H), 8.52-8.53 (m, 2H)。
UPLC-MS (方法1
): Rt
= 1.09 min; MS (ESIpos): m/z = 338 [M+H]+
。
步驟 2 8- 甲基 -2-[( 吡啶 -4- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(吡啶-4-基)甲基]-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(3 g,20%純度,4 mmol)與氫氧化鋰水溶液(2 M;15 eq.,31 mL,61 mmol)在乙醇與THF之1:1混合物(22 mL)中反應隔夜。用4 N鹽酸水溶液(pH 4)酸化後,形成沈澱物,藉由過濾分離且乾燥,得到所需羧酸(467 mg,35%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.45 (s, 3H), 2.85-2.94 (m, 4H), 5.37 (s, 2H), 7.13-7.15 (m, 2H), 7.67 (s, 1H), 8.52-8.53 (m, 2H), 12.81 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.50 min; MS (ESIpos): m/z = 310 [M+H]+
。
中間物 5 : 步驟 1 2-( 環丙基甲基 )-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.0 eq.,1.0 g,4.1 mmol)與環丙基甲醇(1.5 eq.,490 µL,6.1 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,1.6 mL,6.5 mmol)及TMAD (CAS編號[10465-78-8];1.6 eq.,1.1 g,6.5 mmol)在甲苯(20 mL)中反應隔夜,管柱層析(Si-HP SiO2
,己烷/EtOAc)後,得到標題化合物(957 mg,75%)以及相應N1-異構體(155 mg,12%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.33-0.37 (m, 2H), 0.49-0.54 (m, 2H), 1.18-1.26 (m, 1H), 1.30 (t, 3H), 2.83-2.93 (m, 4H), 3.92 (d, 2H), 4.27 (q, 2H), 7.56 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.31 min; MS (ESIpos): m/z = 301 [M+H]+
。
步驟 2 2-( 環丙基甲基 )-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的2-(環丙基甲基)-8-甲基-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,955 mg,3.18 mmol)與氫氧化鋰水溶液(2 M;15 eq.,24 mL,48 mmol)在乙醇與THF之1:1混合物(22 mL)中反應隔夜。用6 N鹽酸水溶液(pH 4)酸化後,形成沈澱物,藉由過濾分離,用水洗滌且乾燥,得到所需羧酸(945 mg,100%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.33-0.37 (m, 2H), 0.49-0.54 (m, 2H), 1.17-1.27 (m, 1H), 2.48 (s, 3H), 2.82-2.91 (m, 4H), 3.91 (d, 2H), 7.54 (s, 1H), 12.81 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.55 min; MS (ESIpos): m/z = 273 [M+H]+
。
中間物 6 : 步驟 1 2-{[(2R/S)-2,3- 二氫 [1,4] 二氧雜環己烯并 [2,3-b] 吡啶 -2- 基 ] 甲基 }-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件B),在60℃下,使8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.0 eq.,930 mg,3.78 mmol)與4-甲基苯-1-磺酸[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基]甲酯(如以下文獻中所述製備:G. Guillaumet等人, Tetrahedron 2004, 60, 6461-6473, cpd. 16B;1.5 eq.,1.8 g,5.7 mmol)、碳酸鉀(15 eq.,7.8 g,57 mmol)及DMAP (0.30 eq.,140 mg,1.1 mmol)於MeCN (50 mL)中反應9天,2倍管柱層析(Si-HP SiO2
,己烷/EtOAc)後,得到標題化合物(443 mg,28%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.84-2.94 (m, 4H), 4.18-4.29 (m, 3H), 4.36-4.48 (m, 2H), 4.53 (dd, 1H), 4.62-4.66 (m, 1H), 6.96 (dd, 1H), 7.31 (dd, 1H), 7.56 (s, 1H), 7.77 (dd, 1H)。
UPLC-MS (方法1
): Rt
= 1.17 min; MS (ESIpos): m/z = 396 [M+H]+
。
步驟 2 2-{[(2R/S)-2,3- 二氫 [1,4] 二氧雜環己烯并 [2,3-b] 吡啶 -2- 基 ] 甲基 }-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
在GP D之變型中,在70℃下,使得自步驟1的2-{[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基]甲基}-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00eq.,418 mg,1.06 mmol)與氫氧化鈉水溶液(4 M;30eq.,7.9 mL,32 mmol)在THF (6 mL)中反應隔夜。用6 N鹽酸水溶液(pH 2)酸化且用EtOAc稀釋後,形成沈澱物,藉由過濾分離。保存濾液。沈澱物用EtOAc溶解,經Na2
SO2
乾燥,過濾且在減壓下濃縮,得到第一批所需羧酸(190 mg,47%)。分離以上所得濾液,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到第二批所需羧酸(160 mg,39%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.48 (s, 3H), 2.83-2.92 (m, 4H), 4.20 (dd, 1H), 4.36-4.47 (m, 2H), 4.52 (dd, 1H), 4.62-4.67 (m, 1H), 6.96 (dd, 1H), 7.31 (dd, 1H), 7.55 (s, 1H), 7.76 (dd, 1H), 12.83 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.51 min; MS (ESIpos): m/z = 368 [M+H]+
中間物 7 : 步驟 1 8- 甲基 -2-{[6-( 三氟甲基 ) 吡啶 -2- 基 ] 甲基 }-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件B),在60℃下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,500 mg,2.03 mmol)與2-(氯甲基)-6-(三氟甲基)吡啶(1.5 eq.,596 mg,3.05 mmol)、碳酸鉀(15.0 eq.,4.21 g,30.5 mmol)在MeCN (10 mL)中反應3天,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(493 mg,57%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.46 (s, 3H), 2.87-2.96 (m, 4H), 4.26 (q, 2H), 5.52 (s, 2H), 7.27 (d, 1H), 7.72 (s, 1H), 7.84 (d, 1H), 8.08 (t, 1H)。
UPLC-MS (方法1
): Rt
= 1.36 min; MS (ESIpos): m/z = 406 [M+H]+
。
步驟 2 8- 甲基 -2-{[6-( 三氟甲基 ) 吡啶 -2- 基 ] 甲基 }-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-{[6-(三氟甲基)吡啶-2-基]甲基}-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-7-羧酸乙酯(438 mg,1.19 mmol)與氫氧化鋰水溶液(1 M;15 eq.,18 mL,18 mmol)在乙醇與THF之1:1混合物(35 mL)中反應隔夜。反應混合物用4 N HCl水溶液(pH 4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(405 mg,87%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 2.86-2.94 (m, 4H), 5.51 (s, 2H), 7.26 (d, 1H), 7.71 (s, 1H), 7.84 (d, 1H), 8.08 (t, 1H), 12.84 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.66 min; MS (ESIpos): m/z = 378 [M+H]+
。
中間物 8 : 步驟 1 8- 甲基 -2-{[5-( 三氟甲基 ) 吡啶 -2- 基 ] 甲基 }-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
在GP C (條件B)之變型中,8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,171 mg,694 µmol)於DMF (6 mL)中的冰冷溶液用氫化鈉(CAS編號[7646-69-7];55%純度,1.2 eq.,36 mg,830 µmol)處理30分鐘,接著添加2-(溴甲基)-5-(三氟甲基)吡啶(1.20 eq.,200 mg,833 µmol),使反應混合物升溫至室溫且繼續攪拌45分鐘。反應混合物用飽和氯化銨水溶液及EtOAc稀釋,分離各相,且用EtOAc萃取水相。合併之有機相經Na2
SO4
乾燥,過濾,在減壓下濃縮且對所得物質進行管柱層析(Si-NH SiO2
,DCM/MeOH),得到標題化合物(81 mg,24%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.46 (s, 3H), 2.87-2.96 (m, 4H), 4.26 (q, 2H), 5.54 (s, 2H), 7.25 (d, 1H), 7.71 (s, 1H), 8.21 (dd, 1H), 8.95 (d, 1H)。
UPLC-MS (方法1
): Rt
= 1.34 min; MS (ESIpos): m/z = 406 [M+H]+
。
步驟 2 8- 甲基 -2-{[5-( 三氟甲基 ) 吡啶 -2- 基 ] 甲基 }-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-{[5-(三氟甲基)吡啶-2-基]甲基}-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-7-羧酸乙酯(76.0 mg,187 µmol)與氫氧化鋰水溶液(1 M;30 eq.,5.6 mL,5.6 mmol)在乙醇與THF之1:1混合物(20 mL)反應隔夜。反應混合物用4 N HCl水溶液(pH 4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(71 mg,84%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 2.86-2.94 (m, 4H), 5.53 (s, 2H), 7.25 (d, 1H), 7.70 (s, 1H), 8.21 (d, 1H), 8.95 (d, 1H), 12.80 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.62 min; MS (ESIpos): m/z = 378 [M+H]+
。
中間物 9-1 及 9-2 : 步驟 1 2-[(3- 氯 -5- 氟吡啶 -2- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件B),在60℃下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,500 mg,2.03 mmol)與2-(溴甲基)-3-氯-5-氟吡啶(1.5 eq.,684 mg,3.05 mmol)、碳酸鉀(15.0 eq.,4.21 g,30.5 mmol)在MeCN (10 mL)中反應3天,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(364 mg,44%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.44 (s, 3H), 2.83-2.93 (m, 4H), 4.26 (q, 2H), 5.51 (s, 2H), 7.56 (s, 1H), 8.16 (dd, 1H), 8.58 (d, 1H)。
UPLC-MS (方法1
): Rt
= 1.33 min; MS (ESIpos): m/z = 390/392 [M+H]+
( Cl同位素模式)。
步驟 2 2-[(3- 氯 -5- 氟吡啶 -2- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸 ( 中間物 9-1) , 及 2-[(3- 氯 -5- 乙氧基吡啶 -2- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸 ( 中間物 9-2)
根據GP D,在70℃下,使得自步驟1的2-[(3-氯-5-氟吡啶-2-基)甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq,355 mg,911 µmol)與氫氧化鋰水溶液(1 M;15eq.,14 mL,14 mmol)在乙醇與THF之1:1混合物(27 mL)中反應隔夜。反應混合物用4 N HCl水溶液(pH 4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到標題化合物之1:1混合物(405 mg)。9-1
:UPLC-MS (方法1
): Rt
= 0.60 min; MS (ESIpos): m/z = 362/364 [M+H]+
(Cl同位素模式)。9-2
:UPLC-MS (方法1
): Rt
= 0.67 min; MS (ESIpos): m/z = 388/390 [M+H]+
(Cl同位素模式)。
中間物 10 : 步驟 1 2-[(3- 氯吡啶 -2- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件B),在60℃下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售,1.00 eq.,250 mg,1.02 mmol)與3-氯-2-(氯甲基)吡啶(1.50 eq.,247 mg,1.52 mmol)、碳酸鉀(15 eq.,2.1 g,15 mmol)在MeCN (5 mL)中反應隔夜,過濾之後,得到粗標題化合物(388 mg,95%),其不進一步純化。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.44 (s, 3H), 2.84-2.94 (m, 4H), 4.26 (q, 2H), 5.53 (s, 2H), 7.42 (dd, 1H), 7.56 (s, 1H), 7.98 (dd, 1H), 8.50 (dd, 1H)。
UPLC-MS (方法1
): Rt
= 1.29 min; MS (ESIpos): m/z = 372/374 [M+H]+
(Cl同位素模式)。
步驟 2 2-[(3- 氯吡啶 -2- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的2-[(3-氯吡啶-2-基)甲基]-8-甲基-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,382 mg,1.03 mmol)與氫氧化鋰水溶液(1 M;15 eq.,7.7 mL,15 mmol)在乙醇與THF之1:1混合物(10 mL)中反應3天。用4 N鹽酸水溶液(pH 4)酸化且用EtOAc稀釋後,形成沈澱物,藉由過濾分離,用水洗滌且乾燥,得到第一批所需羧酸(204 mg,57%)。分離濾液,且用EtOAc萃取水相。合併之有機相經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到第二批所需羧酸(123 mg,31%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.42 (s, 3H), 2.83-2.91 (m, 4H), 5.52 (s, 2H), 7.42 (dd, 1H), 7.55 (s, 1H), 7.98 (dd, 1H), 8.50 (dd, 1H), 12.81 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.56 min; MS (ESIpos): m/z = 344/346 [M+H]+
(Cl同位素模式)。
中間物 11 : 步驟 1 8- 甲基 -2-[(3- 甲基吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件B),在60℃下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,264 mg,1.07 mmol)與2-(氯甲基)-3-甲基吡啶氯化氫(1/1)(1.50 eq.,286 mg,1.61 mmol)、碳酸鉀(15 eq.,2.2 g,16 mmol)在MeCN (5 mL)中反應兩天,過濾之後,得到粗標題化合物(413 mg,100%),其不進一步純化。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.39 (s, 3H), 2.46 (s, 3H), 2.82-2.92 (m, 4H), 4.26 (q, 2H), 5.39 (s, 2H), 7.25 (dd, 1H), 7.47 (s, 1H), 7.62 (dd, 1H), 8.35 (dd, 1H)。
UPLC-MS (方法1
): Rt
= 1.23 min; MS (ESIpos): m/z = 352 [M+H]+
。
步驟 2 8- 甲基 -2-[(3- 甲基吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(3-甲基吡啶-2-基)甲基]-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,400 mg,1.14 mmol)與氫氧化鋰水溶液(1 M;15 eq.,17 mL,17 mmol)在乙醇與THF之1:1混合物(10 mL)中反應隔夜。用4 N鹽酸水溶液(pH 4)酸化且用EtOAc稀釋後,形成沈澱物,藉由過濾分離,用水洗滌且乾燥,得到第一批所需羧酸(209 mg,56%)。分離濾液,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到第二批所需羧酸(54 mg,12%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.39 (s, 3H), 2.44 (s, 3H), 2.81-2.90 (m, 4H), 5.38 (s, 2H), 7.25 (dd, 1H), 7.46 (s, 1H), 7.62 (dd, 1H), 8.35 (dd, 1H), 12.79 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.50 min; MS (ESIpos): m/z = 324 [M+H]+
。
中間物 12 : 步驟 1 8- 甲基 -2-[(5- 甲基吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,300 mg,1.22 mmol)與(5-甲基吡啶-2-基)甲醇(1.50 eq.,225 mg,1.83 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,490 µL,1.9 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,336 mg,1.95 mmol)在甲苯(8 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(395 mg,88%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.27 (s, 3H), 2.46 (s, 3H), 2.84-2.94 (m, 4H), 4.26 (q, 2H), 5.34 (s, 2H), 7.01 (dd, 1H), 7.58 (dd, 1H), 7.62 (s, 1H), 8.37 (dd, 1H)。
UPLC-MS (方法1
): Rt
= 1.18 min; MS (ESIpos): m/z = 352 [M+H]+
。
步驟 2 8- 甲基 -2-[(5- 甲基吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(5-甲基吡啶-2-基)甲基]-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,388 mg,1.10 mmol)與氫氧化鋰水溶液(2 M;15 eq.,8.3 mL,17 mmol)在乙醇與THF之1:1混合物(16 mL)中反應隔夜。反應混合物用6 N HCl水溶液(pH 4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(328 mg,85%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.27 (s, 3H), 2.44 (s, 3H), 2.83-2.92 (m, 4H), 5.33 (s, 2H), 7.01 (dd, 1H), 7.59 (dd, 1H), 7.61 (s, 1H), 8.37 (dd, 1H), 12.78 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.54 min; MS (ESIpos): m/z = 324 [M+H]+
。
中間物 13 : 步驟 1 (5E/Z)-5-[( 二甲基胺基 ) 亞甲基 ]-3- 甲基 -4- 側氧基 -4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧 酸甲酯
根據GP A (條件A),在100℃下,使3-甲基-4-側氧基-4,5,6,7-四氫-1-苯并呋喃-2-羧酸甲酯(市售,CAS編號[40200 -70-2];10.0 g,48.0 mmol)與1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(布雷德奈克試劑,CAS編號[5815-08-7];1.2 eq.,12 mL,58 mmol)在甲苯(100 mL)中反應隔夜。添加額外量的1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(0.50 eq.,5.0 mL,24 mmol)且在100℃下繼續攪拌另外5天。在減壓下濃縮反應混合物且所得粗標題化合物不經進一步純化步驟即用於後續反應中。
UPLC-MS (方法1
): Rt
= 0.95/1.01 min; MS (ESIpos): m/z = 264 [M+H]+
。
步驟 2 8- 甲基 -4,5- 二氫 -1H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸甲酯
根據GP B,在70℃下,使得自步驟1的粗(5E/Z)-5-[(二甲基胺基)亞甲基]-3-甲基-4-側氧基-4,5,6,7-四氫-1-苯并呋喃-2-羧酸甲酯(1.0 eq.,13 g,48 mmol)與水合肼1:1 (4.0 eq.,9.5 mL,195 mmol)在乙醇(150 mL)中反應4小時且在室溫下反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(771 mg,7%,歷經2個步驟)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.51 (s, 3H; 部分地被溶劑峰覆蓋), 2.84-2.93 (m, 4H), 3.80 (s, 3H), 7.52 (s, 1H), 12.49 (s, 1H)。
UPLC-MS (方法1
): Rt
= 0.88 min; MS (ESIpos): m/z = 233 [M+H]+
。
步驟 3 8- 甲基 -2-[(6- 甲基吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸甲酯
根據GP C (條件B),在60℃下,使得自步驟2的8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸甲酯(1.0 eq.,770 mg,3.3 mmol)與2-(溴甲基)-6-甲基吡啶(1.50 eq.,926 mg,4.98 mmol)、碳酸鉀(10 eq.,4.6 g,33 mmol)在MeCN (10 mL)中反應隔夜,過濾之後,得到粗標題化合物(1.27 g,100%),其不進一步純化。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.46-2.46 (m, 6H), 2.85-2.94 (m, 4H), 3.79 (s, 3H), 5.33 (s, 2H), 6.79 (d, 1H), 7.16 (d, 1H), 7.62-7.66 (m, 2H)。
UPLC-MS (方法1
): Rt
= 1.14 min; MS (ESIpos): m/z = 338 [M+H]+
。
步驟 4 8- 甲基 -2-[(6- 甲基吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
在GP D之變型中,在70℃下,使得自步驟3的8-甲基-2-[(6-甲基吡啶-2-基)甲基]-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-7-羧酸甲酯(1.0 eq.,1.2 g,2.2 mmol)與氫氧化鈉水溶液(4 M;30 eq.,17 mL,66 mmol)在THF (14 mL)中反應兩天。反應混合物用2 N HCl水溶液(pH 4-5)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(980 mg,85%純度,100%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.45-2.46 (m, 6H), 2.84-2.92 (m, 4H), 5.33 (s, 2H), 6.79 (d, 1H), 7.16 (d, 1H), 7.62-7.66 (m, 2H)., 12.52 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.55 min; MS (ESIpos): m/z = 324 [M+H]+
。
中間物 14-1 及 14-2 : 步驟 1 8- 甲基 -2-[(2- 甲基吡啶 -3- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,300 mg,1.22 mmol)與(2-甲基吡啶-3-基)甲醇(1.50 eq.,225 mg,1.83 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,490 µL,1.9 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,336 mg,1.95 mmol)在甲苯(8 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(315 mg,71%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.47 (s, 3H), 2.54 (s, 3H), 2.84-2.94 (m, 4H), 4.26 (q, 2H), 5.35 (s, 2H), 7.17-7.25 (m, 2H), 7.59 (s, 1H), 8.36 (dd, 1H)。
UPLC-MS (方法1
): Rt
= 1.12 min; MS (ESIpos): m/z = 352 [M+H]+
。
步驟 2 8- 甲基 -2-[(2- 甲基吡啶 -3- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸氯化氫 (1/1) , 及 8- 甲基 -2-[(2- 甲基吡啶 -3- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(2-甲基吡啶-3-基)甲基]-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,313 mg,891 µmol)與氫氧化鋰水溶液(2 M;15 eq.,6.7 mL,13 mmol)在乙醇與THF之1:1混合物(14 mL)中反應隔夜。在用6 N鹽酸水溶液(pH 4)酸化且用EtOAc稀釋之後,形成沈澱物,藉由過濾分離且乾燥,得到所需羧酸之鹽酸鹽(中間物14-1,225 mg,67%)。分離濾液,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(中間物14-2,47 mg,15%)。14-1
:1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 2.79 (s, 3H), 2.86-2.94 (m, 4H), 5.52 (s, 2H), 7.68 (s, 1H), 7.73-7.77 (m, 1H), 7.83-7.85 (m, 1H), 8.65 (dd, 1H), 12.84 (br. s., 1H)。14-1
: UPLC-MS (方法1
): Rt
= 0.50 min; MS (ESIpos): m/z = 324 [M-Cl-
]+
。
中間物 15-1 及 15-2 : 步驟 1 8- 甲基 -2-[(6- 甲基吡啶 -3- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,300 mg,1.22 mmol)與(6-甲基吡啶-3-基)甲醇(1.50 eq.,225 mg,1.83 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,490 µL,1.9 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,336 mg,1.95 mmol)在甲苯(8 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(299 mg,66%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.43 (s, 3H), 2.48 (s, 3H), 2.83-2.92 (m, 4H), 4.26 (q, 2H), 5.28 (s, 2H), 7.22 (d, 1H), 7.56 (dd, 1H), 7.63 (s, 1H), 8.40 (d, 1H)。
UPLC-MS (方法1
): Rt
= 1.17 min; MS (ESIpos): m/z = 352 [M+H]+
。
步驟 2 8- 甲基 -2-[(6- 甲基吡啶 -3- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸氯化氫 (1/1) , 及 8- 甲基 -2-[(6- 甲基吡啶 -3- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(6-甲基吡啶-3-基)甲基]-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,291 mg,828 mmol)與氫氧化鋰水溶液(2 M;15 eq.,6.2 mL,12 mmol)在乙醇與THF之1:1混合物(12 mL)中反應隔夜。在用6 N鹽酸水溶液(pH 3)酸化且用EtOAc稀釋之後,形成沈澱物,藉由過濾分離且乾燥,得到所需羧酸之鹽酸鹽(中間物15-1,195 mg,63%)。分離濾液,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(中間物15-2,44 mg,15%)。15-1
:1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.46 (s, 3H), 2.57 (s, 3H), 2.82-2.91 (m, 4H), 5.39 (s, 2H), 7.57 (d, 1H), 7.67 (s, 1H), 7.94 (d, 1H), 8.59 (d, 1H), 12.84 (br. s., 1H)。15-1
: UPLC-MS (方法1
): Rt
= 0.51 min; MS (ESIpos): m/z = 324 [M-Cl-
]+
。
中間物 16-1 及 16-2 : 步驟 1 2-[(2,6- 二甲基吡啶 -3- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,300 mg,1.22 mmol)與(2,6-二甲基吡啶-3-基)甲醇(1.50 eq.,251 mg,1.83 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,490 µL,1.9 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,336 mg,1.95 mmol)在甲苯(8 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(312 mg,63%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.39 (s, 3H), 2.47 (s, 3H), 2.83-2.93 (m, 4H), 4.26 (q, 2H), 5.29 (s, 2H), 7.04 (d, 1H), 7.20 (d, 1H), 7.55 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.23 min; MS (ESIpos): m/z = 366 [M+H]+
。
步驟 2 2-[(2,6- 二甲基吡啶 -3- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸氯化氫 (1/1) , 及 2-[(2,6- 二甲基吡啶 -3- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的2-[(2,6-二甲基吡啶-3-基)甲基]-8-甲基-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,305 mg,835 µmol)與氫氧化鋰水溶液(2 M;15 eq.,6.3 mL,13 mmol)在乙醇與THF之1:1混合物(12 mL)中反應隔夜。在用6 N鹽酸水溶液(pH 3)酸化且用EtOAc稀釋之後,形成沈澱物,藉由過濾分離且乾燥,得到所需羧酸之鹽酸鹽(中間物16-1,86 mg,27%)。分離濾液,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(中間物16-2,91 mg,24%)。16-1
:1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 2.62 (br. s., 3H), 2.74 (br. s., 3H), 2.84-2.93 (m, 4H), 5.45 (s, 2H), 7.57 (br. s., 2H), 7.65 (s, 1H), 7.81 (br. s., 1H), 12.83 (br. s., 1H)。16-1
: UPLC-MS (方法1
): Rt
= 0.58 min; MS (ESIpos): m/z = 338 [M-Cl-
]+
。
中間物 17-1 及 17-2 : 步驟 1 8- 甲基 -2-[(2- 甲基吡啶 -4- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,300 mg,1.22 mmol)與(2-甲基吡啶-4-基)甲醇(1.10 eq.,165 mg,1.34 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,490 µL,1.9 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,336 mg,1.95 mmol)在甲苯(12 mL)中反應隔夜,管柱層析(SiO2
,CH2
Cl2
/己烷)後,得到標題化合物(524 mg,44%純度,54%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.43 (s, 3H), 2.47 (s, 3H), 2.85-2.95 (m, 4H), 4.26 (q, 2H), 5.31 (s, 2H), 6.94 (d, 1H), 7.05 (s, 1H), 7.66 (s, 1H), 8.38 (d, 1H)。
UPLC-MS (方法1
): Rt
= 1.15 min; MS (ESIpos): m/z = 352 [M+H]+
。
步驟 2 8- 甲基 -2-[(2- 甲基吡啶 -4- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸氯化氫 (1/1) , 及 8- 甲基 -2-[(2- 甲基吡啶 -4- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸 , 及
根據GP D,使得自步驟1的8-甲基-2-[(2-甲基吡啶-4-基)甲基]-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,522 mg,1.22 mmol)與氫氧化鋰水溶液(2 M;17 eq.,10 mL,21 mmol)在乙醇與THF之1:1混合物(12 mL)中、在70℃下反應隔夜且在室溫下反應兩天。在用4 N鹽酸水溶液(pH 3.5)酸化且用EtOAc稀釋之後,形成沈澱物,藉由過濾分離且乾燥,得到所需羧酸之鹽酸鹽(中間物17-1,168 mg,61%)。分離濾液,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(中間物17-2,285 mg,50%純度,36%)。17-1
:1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 2.66 (s, 3H), 2.87-2.95 (m, 4H), 5.57 (s, 2H), 7.39 (d, 1H), 7.53 (s, 1H), 7.73 (s, 1H), 8.65 (d, 1H), 12.84 (br. s., 1H)。17-1
: UPLC-MS (方法1
): Rt
= 0.51 min; MS (ESIpos): m/z = 324 [M-Cl-
]+
。
中間物 18-1 及 18-2 : 步驟 1 2-[(2,6- 二甲基吡啶 -4- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,300 mg,1.22 mmol)與(2,6-二甲基吡啶-4-基)甲醇(1.50 eq.,251 mg,1.83 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,490 µL,1.9 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,336 mg,1.95 mmol)在甲苯(8 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(419 mg,83%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.22 (s, 3H), 2.41 (s, 3H), 2.47 (s, 3H), 2.85-2.95 (m, 4H), 4.26 (q, 2H), 5.28 (s, 2H), 6.71 (s, 1H), 7.00 (s, 1H), 7.62 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.29 min; MS (ESIpos): m/z = 366 [M+H]+
。
步驟 2 2-[(2,6- 二甲基吡啶 -4- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸氯化氫 (1/1) , 及 2-[(2,6- 二甲基吡啶 -4- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的2-[(2,6-二甲基吡啶-4-基)甲基]-8-甲基-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,408 mg,1.12 mmol)與氫氧化鋰水溶液(2 M;15 eq.,8.4 mL,17 mmol)在乙醇與THF之1:1混合物(16 mL)中反應隔夜。在用6 N鹽酸水溶液(pH 3)酸化且用EtOAc稀釋之後,形成沈澱物,藉由過濾分離且乾燥,得到所需羧酸之鹽酸鹽(中間物18-1,94 mg,22%)。分離濾液,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(中間物18-2,161 mg,32%)。18-1
:1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.35 (br. s., 3H), 2.45 (s, 3H), 2.55 (br. s., 3H), 2.85-2.94 (m, 4H), 5.46 (s, 2H), 6.97 (br. s., 1H), 7.33 (br. s., 1H), 7.69 (s, 1H), 12.83 (br. s., 1H)。18-1
: UPLC-MS (方法1
): Rt
= 0.58 min; MS (ESIpos): m/z = 338 [M-Cl-
]+
。
中間物 19 : 步驟 1 8- 甲基 -2-[( 嘧啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件B),在60℃下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,260 mg,1.06 mmol)與2-(氯甲基)嘧啶(1.50 eq.,204 mg,1.58 mmol)及碳酸鉀(15 eq.,2.2 g,16 mmol)在MeCN (5 mL)中反應隔夜。添加DMAP (5 mol%,6.5 mg,53 µmol)且在60℃下繼續攪拌4天,過濾之後,得到粗標題化合物(332 mg,79%),其不進一步純化。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.44 (s, 3H), 2.86-2.95 (m, 4H), 4.26 (q, 2H), 5.51 (s, 2H), 7.45 (t, 1H), 7.63 (s, 1H), 8.79-8.80 (m, 2H)。
UPLC-MS (方法1
): Rt
= 1.03 min; MS (ESIpos): m/z = 339 [M+H]+
。
步驟 2 8- 甲基 -2-[( 嘧啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(嘧啶-2-基)甲基]-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,332 mg,834 µmol)與氫氧化鋰水溶液(2 M;15 eq.,6.3 mL,13 mmol)在乙醇與THF之1:1混合物(8 mL)中反應隔夜。反應混合物用4 N HCl水溶液(pH 4)酸化且在減壓下濃縮,得到粗標題化合物以及鹽(1.8 g),其不進一步純化。
UPLC-MS (方法1
): Rt
= 0.44 min; MS (ESIpos): m/z = 311 [M+H]+
。
中間物 20 : 步驟 1 8- 甲基 -2-[( 嘧啶 -5- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,300 mg,1.22 mmol)與(嘧啶-5-基)甲醇(1.50 eq.,201 mg,1.83 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,490 µL,1.9 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,336 mg,1.95 mmol)在甲苯(8 mL)中反應隔夜,管柱層析(Si-NH SiO2
,己烷/CH2
Cl2
/MeOH)後,得到標題化合物(483 mg,52%純度,61%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.47 (s, 3H), 2.83-2.93 (m, 4H), 4.26 (q, 2H), 5.39 (s, 2H), 7.70 (s, 1H), 8.74 (s, 2H), 9.13 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.02 min; MS (ESIpos): m/z = 339 [M+H]+
。
步驟 2 8- 甲基 -2-[( 嘧啶 -5- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(嘧啶-5-基)甲基]-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,480 mg,52%純度,738 µmol)與氫氧化鋰水溶液(2 M;15 eq.,5.5 mL,11 mmol)在乙醇與THF之1:1混合物(5.2 mL)中反應隔夜。反應混合物用6 N HCl水溶液(pH 4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(439 mg,37%純度,71%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.46 (s, 3H), 2.83-2.92 (m, 4H), 5.38 (s, 2H), 7.70 (s, 1H), 8.74 (s, 2H), 9.13 (s, 1H), 12.73 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.44 min; MS (ESIpos): m/z = 311 [M+H]+
。
中間物 21 : 步驟 1 2-{[(2R)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,250 mg,1.02 mmol)與[(2R)-1,4-二㗁烷-2-基]甲醇(1.50 eq.,180 mg,1.52 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,410 µL,1.6 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,280 mg,1.62 mmol)在甲苯(8 mL)中反應隔夜。添加額外量的三-正丁基膦(0.30 eq.,76 µL,300 µmol)及TMAD (0.30 eq.,52 mg,0.31 mmol)且在室溫下繼續攪拌四天,兩次連續管柱層析(SiO2
,CH2
Cl2
/MeOH)後,得到標題化合物(739 mg,35-40%純度,74%)。
UPLC-MS (方法1
): Rt
= 1.12 min; MS (ESIpos): m/z = 347 [M+H]+
。
步驟 2 2-{[(2R)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的2-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-甲基-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,739 mg,40%純度,850 µmol)與氫氧化鋰水溶液(2 M;15 eq.,6.4 mL,13 mmol)在乙醇與THF之1:1混合物(6 mL)中反應隔夜。反應混合物用4 N HCl水溶液(pH 3)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(712 mg,41%純度,100%)。
UPLC-MS (方法1
): Rt
= 0.49 min; MS (ESIpos): m/z = 319 [M+H]+
。
中間物 22 : 步驟 1 2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,347 mg,1.41 mmol)與[(2S)-1,4-二㗁烷-2-基]甲醇(CAS編號[406913-93-7];1.50 eq.,250 mg,2.12 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,560 µL,2.3 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,389 mg,2.26 mmol)在甲苯(8 mL)中反應4天,管柱層析(Si-NH SiO2
,己烷/CH2
Cl2
)後,得到標題化合物(483 mg,65%純度,64%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 2.82-2.93 (m, 4H), 3.26 (dd, 1H), 3.45 (dt, 1H), 3.54 (dt, 1H), 3.62-3.64 (m, 1H), 3.72-3.76 (m, 2H), 3.80-3.87 (m, 1H), 4.05-4.14 (m, 2H), 4.27 (q, 2H), 7.48 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.13 min; MS (ESIpos): m/z = 347 [M+H]+
。
步驟 2 2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-甲基-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,480 mg,65%純度,900 µmol)與氫氧化鋰水溶液(2 M;23 eq.,10 mL,21 mmol)在乙醇與THF之1:1混合物(10 mL)中反應隔夜。反應混合物用4 N HCl水溶液(pH 4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(422 mg,64%純度,61%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.47 (s, 3H), 2.81-2.91 (m, 4H), 3.26 (dd, 1H), 3.44 (dt, 1H), 3.54 (dt, 1H), 3.62-3.64 (m, 1H), 3.72-3.75 (m, 2H), 3.82-3.87 (m, 1H), 4.05-4.14 (m, 2H), 7.47 (s, 1H), 12.73 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.48 min; MS (ESIpos): m/z = 319 [M+H]+
。
中間物 23 : 步驟 1 8- 甲基 -2-[( 氧雜環丁 -3- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件B),在60℃下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,270 mg,1.10 mmol)與3-(氯甲基)氧雜環丁烷(1.50 eq.,248 mg,1.64 mmol)及碳酸鉀(15 eq.,2.3 g,16 mmol)在MeCN (8 mL)中反應隔夜。添加DMAP (5 mol%,6.7 mg,55 µmol)且在60℃下繼續攪拌4天,過濾之後,得到粗標題化合物(509 mg,68%純度,100%),其不進一步純化。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.48 (s, 3H), 2.81-2.85 (m, 2H), 2.88-2.92 (m, 2H), 3.36-3.40 (m, 1H), 4.26 (q, 2H), 4.35-4.43 (m, 3H), 4.49 (d, 1H), 4.64 (dd, 2H), 7.55 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.07 min; MS (ESIpos): m/z = 317 [M+H]+
。
步驟 2 8- 甲基 -2-[( 氧雜環丁 -3- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(氧雜環丁-3-基)甲基]-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,510 mg,68%純度,1.1 mmol)與氫氧化鋰水溶液(2 M;15 eq.,8.2 mL,16 mmol)在乙醇與THF之1:1混合物(10 mL)中反應隔夜。反應混合物用4 N HCl水溶液(pH 6)中和且在減壓下濃縮,得到粗標題化合物以及鹽(1.9 g),其不經進一步純化。
UPLC-MS (方法1
): Rt
= 0.44 min; MS (ESIpos): m/z = 289 [M+H]+
。
中間物 24 : 步驟 1 8- 甲基 -2-[(3- 甲基氧雜環丁 -3- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,300 mg,1.22 mmol)與(3-甲基氧雜環丁-3-基)甲醇(1.5 eq.,190 µL,1.8 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,490 µL,1.9 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,336 mg,1.95 mmol)在甲苯(8 mL)中反應隔夜,管柱層析(Si-NH SiO2
,己烷/CH2
Cl2
)後,得到標題化合物(529 mg,52%純度,68%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.17 (s, 3H), 1.29 (t, 3H), 2.48 (s, 3H), 2.83-2.93 (m, 4H), 4.21-4.29 (m, 6H), 4.60 (d, 2H), 7.55 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.17 min; MS (ESIpos): m/z = 331 [M+H]+
。
步驟 2 8- 甲基 -2-[(3- 甲基氧雜環丁 -3- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(3-甲基氧雜環丁-3-基)甲基]-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,527 mg,52%純度,829 µmol)與氫氧化鋰水溶液(2 M;15 eq.,6.2 mL,12 mmol)在乙醇與THF之1:1混合物(6 mL)中反應隔夜。反應混合物用4 N HCl水溶液(pH 3)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(500 mg,42%純度,84%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.16 (s, 3H), 2.45 (s, 3H), 2.81-2.89 (m, 4H), 4.22 (d, 2H), 4.26 (s, 2H), 4.60 (d, 2H), 7.52 (s, 1H), 12.75 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.49 min; MS (ESIpos): m/z = 303 [M+H]+
。
中間物 25 : 步驟 1 2-[(3- 氟氧雜環丁 -3- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件B),在60℃下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,270 mg,1.10 mmol)與3-(溴甲基)-3-氟氧雜環丁烷(1.50 eq.,278 mg,1.64 mmol)及碳酸鉀(15 eq.,2.3 g,16 mmol)在MeCN (8 mL)中反應隔夜。添加DMAP (5 mol%,6.7 mg,55 µmol)且在60℃下繼續攪拌4天,過濾之後,得到粗標題化合物(433 mg,85%純度,100%),其不進一步純化。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.83-2.94 (m, 4H), 4.27 (q, 2H), 4.59-4.68 (m, 4H), 4.75-4.85 (m, 2H), 7.55 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.13 min; MS (ESIpos): m/z = 335 [M+H]+
。
步驟 2 2-[(3- 氟氧雜環丁 -3- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的2-[(3-氟氧雜環丁-3-基)甲基]-8-甲基-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,433 mg,85%純度,1.1 mmol)與氫氧化鋰水溶液(2 M;15 eq.,8.3 mL,17 mmol)在乙醇與THF之1:1混合物(10 mL)中反應隔夜。反應混合物用4 N HCl水溶液(pH 6)中和且在減壓下濃縮,得到粗標題化合物以及鹽(1.8 g),其不經進一步純化。
UPLC-MS (方法1
): Rt
= 0.46 min; MS (ESIpos): m/z = 307 [M+H]+
。
中間物 26 : 步驟 1 8- 甲基 -2-{[(2R)- 氧雜環丁 -2- 基 ] 甲基 }-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,330 mg,1.34 mmol)與[(2R)-氧雜環丁-2-基]甲醇(1.50 eq.,177 mg,2.01 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,540 µL,2.1 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,369 mg,2.14 mmol)在甲苯(5 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(197 mg,46%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.37-2.46 (m, 1H), 2.60-2.68 (m, 1H), 2.83-2.93 (m, 4H), 4.24-4.37 (m, 5H), 4.46-4.51 (m, 1H), 4.94-5.00 (m, 1H), 7.52 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.00 min; MS (ESIpos): m/z = 317 [M+H]+
。
步驟 2 8- 甲基 -2-{[(2R)- 氧雜環丁 -2- 基 ] 甲基 }-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-{[(2R)-氧雜環丁-2-基]甲基}-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,190 mg,601 µmol)與氫氧化鋰水溶液(2 M;15 eq.,4.5 mL,9.0 mmol)在乙醇與THF之1:1混合物(8 mL)中反應三天。反應混合物用6 N HCl水溶液(pH 4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(198 mg,91%)。
UPLC-MS (方法1
): Rt
= 0.50 min; MS (ESIpos): m/z = 289 [M+H]+
。
中間物 27 : 步驟 1 8- 甲基 -2-{[(2S)- 氧雜環丁 -2- 基 ] 甲基 }-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,330 mg,1.34 mmol)與[(2S)-氧雜環丁-2-基]甲醇(1.50 eq.,177 mg,2.01 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,540 µL,2.1 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,369 mg,2.14 mmol)在甲苯(5 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(233 mg,53%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.37-2.46 (m, 1H), 2.60-2.68 (m, 1H), 2.83-2.94 (m, 4H), 4.24-4.37 (m, 5H), 4.47-4.51 (m, 1H), 4.94-5.00 (m, 1H), 7.52 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.11 min; MS (ESIpos): m/z = 317 [M+H]+
。
步驟 2 8- 甲基 -2-{[(2S)- 氧雜環丁 -2- 基 ] 甲基 }-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-{[(2S)-氧雜環丁-2-基]甲基}-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,228 mg,721 µmol)與氫氧化鋰水溶液(2 M;15 eq.,5.4 mL,11 mmol)在乙醇與THF之1:1混合物(10 mL)中反應三天。反應混合物用4 N HCl水溶液(pH 4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(198 mg,86%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.38-2.45 (m, 1H), 2.47 (s, 3H), 2.60-2.68 (m, 1H), 2.82-2.91 (m, 4H), 4.24-4.36 (m, 3H), 4.46-4.51 (m, 1H), 4.94-5.00 (m, 1H), 7.50 (s, 1H), 12.80 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.50 min; MS (ESIpos): m/z = 289 [M+H]+
。
中間物 28 : 步驟 1 8- 甲基 -2-{[(2R)-4- 甲基嗎啉 -2- 基 ] 甲基 }-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,313 mg,1.27 mmol)與[(2R)-4-甲基嗎啉-2-基]甲醇(CAS編號[1159598-35-2];1.50 eq.,250 mg,1.91 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,510 µL,2.0 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,350 mg,2.03 mmol)在甲苯(8 mL)中反應隔夜。添加額外量的三-正丁基膦(0.30 eq.,95 µL,0.38 mmol)及TMAD (0.30 eq.,66 mg,0.38 mmol)且在室溫下繼續攪拌三天,管柱層析(Si-NH SiO2
,CH2
Cl2
/MeOH)後,得到標題化合物(921 mg,44%純度,88%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 1.72-1.78 (m, 1H), 1.96 (dt, 1H), 2.16 (s, 3H), 2.54-2.57 (m, 1H), 2.63-2.66 (m, 1H), 2.82-2.86 (m, 3H), 2.89-2.93 (m, 2H), 3.45 (dt, 1H), 3.74-3.80 (m, 2H), 4.10 (d, 2H), 4.27 (q, 2H), 7.48 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.10 min; MS (ESIpos): m/z = 360 [M+H]+
。
比旋光度: [α]D 20
= -7.2° +/- 0.49° (C = 10.0 mg/mL, 甲醇)。
步驟 2 8- 甲基 -2-{[(2R)-4- 甲基嗎啉 -2- 基 ] 甲基 }-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-{[(2R)-4-甲基嗎啉-2-基]甲基}-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,912 mg,44%純度,1.12 mmol)與氫氧化鋰水溶液(2 M;15 eq.,8.4 mL,17 mmol)在乙醇與THF之1:1混合物(12 mL)中反應隔夜。反應混合物用4 N HCl水溶液(pH 4)酸化且在減壓下濃縮,得到粗標題化合物以及鹽(1.15 g),其不進一步純化。
UPLC-MS (方法1
): Rt
= 0.50 min; MS (ESIpos): m/z = 332 [M+H]+
。
中間物 29 : 步驟 1 8- 甲基 -2-{[(2S)-4- 甲基嗎啉 -2- 基 ] 甲基 }-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,313 mg,1.27 mmol)與[(2S)-4-甲基嗎啉-2-基]甲醇(CAS編號[1159598-33-0];1.50 eq.,250 mg,1.91 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,510 µL,2.0 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,350 mg,2.03 mmol)在甲苯(8 mL)中反應隔夜。添加額外量的三-正丁基膦(0.30 eq.,95 µL,0.38 mmol)及TMAD (0.30 eq.,66 mg,0.38 mmol)且在室溫下繼續攪拌三天,管柱層析(Si-NH SiO2
,CH2
Cl2
/MeOH)後,得到標題化合物(192 mg,85%純度,36%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 1.72-1.77 (m, 1H), 1.96 (dt, 1H), 2.16 (s, 3H), 2.54-2.57 (m, 1H), 2.63-2.67 (m, 1H), 2.82-2.86 (m, 3H), 2.89-2.93 (m, 2H), 3.45 (dt, 1H), 3.75-3.80 (m, 2H), 4.10 (d, 2H), 4.27 (q, 2H), 7.48 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.10 min; MS (ESIpos): m/z = 360 [M+H]+
。
步驟 2 8- 甲基 -2-{[(2S)-4- 甲基嗎啉 -2- 基 ] 甲基 }-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-{[(2S)-4-甲基嗎啉-2-基]甲基}-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,192 mg,85%純度,534 µmol)與氫氧化鋰水溶液(2 M;15 eq.,4.0 mL,8.0 mmol)在乙醇與THF之1:1混合物(6 mL)中反應隔夜。反應混合物用4 N HCl水溶液(pH 4)酸化且在減壓下濃縮,得到粗標題化合物以及鹽(691 mg),其不進一步純化。
UPLC-MS (方法1
): Rt
= 0.50 min; MS (ESIpos): m/z = 332 [M+H]+
。
中間物 30 : 步驟 1 8- 甲基 -2-[(2R)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,300 mg,1.22 mmol)與(2R)-四氫呋喃-2-基甲醇(CAS編號[22415-59-4];1.1 eq.,130 µL,1.3 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,490 µL,1.9 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,336 mg,1.95 mmol)在甲苯(8 mL)中反應隔夜,管柱層析(Si-NH SiO2
,CH2
Cl2
/MeOH)後,得到標題化合物(470 mg,68%純度,79%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.54-1.57 (m, 1H), 1.75-1.82 (m, 2H), 1.90-1.97 (m, 1H), 2.82-2.93 (m, 4H), 3.60-3.65 (m, 1H), 3.72-3.78 (m, 1H), 4.03-4.17 (m, 3H), 4.27 (q, 2H), 7.49 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.22 min; MS (ESIpos): m/z = 331 [M+H]+
。
步驟 2 8- 甲基 -2-[(2R)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,使得自步驟1的8-甲基-2-[(2R)-四氫呋喃-2-基甲基]-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,470 mg,68%純度,967 µmol)與氫氧化鋰水溶液(2 M;18 eq.,8.5 mL,17 mmol)在乙醇與THF之1:1混合物(8 mL)中、在70℃下反應24小時且隨後在室溫下反應兩天。反應混合物用4 N HCl水溶液(pH 4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(380 mg,69%純度,76%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.54-1.57 (m, 1H), 1.75-1.82 (m, 2H), 1.88-1.97 (m, 1H), 2.47 (s, 3H), 2.81-2.90 (m, 4H), 3.60-3.65 (m, 1H), 3.72-3.78 (m, 1H), 4.02-4.17 (m, 3H), 7.47 (s, 1H), 12.73 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.52 min; MS (ESIpos): m/z = 303 [M+H]+
。
中間物 31 : 步驟 1 8- 甲基 -2-[(2S)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,300 mg,1.22 mmol)與(2S)-四氫呋喃-2-基甲醇(CAS編號[57203-01-7];1.1 eq.,130 µL,1.3 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,490 µL,1.9 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,336 mg,1.95 mmol)在甲苯(8 mL)中反應隔夜,管柱層析(Si-NH SiO2
,CH2
Cl2
/MeOH)後,得到標題化合物(437 mg,72%純度,78%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.54-1.57 (m, 1H), 1.75-1.82 (m, 2H), 1.90-1.97 (m, 1H), 2.82-2.93 (m, 4H), 3.60-3.65 (m, 1H), 3.72-3.78 (m, 1H), 4.03-4.16 (m, 3H), 4.27 (q, 2H), 7.48 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.22 min; MS (ESIpos): m/z = 331 [M+H]+
。
步驟 2 8- 甲基 -2-[(2S)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,使得自步驟1的8-甲基-2-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,435 mg,72%純度,948 µmol)與氫氧化鋰水溶液(2 M;21 eq.,9.9 mL,20 mmol)在乙醇與THF之1:1混合物(10 mL)中、在70℃下反應24小時且隨後在室溫下反應兩天。反應混合物用4 N HCl水溶液(pH 4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(373 mg,78%純度,73%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.54-1.57 (m, 1H), 1.75-1.82 (m, 2H), 1.88-1.96 (m, 1H), 2.47 (s, 3H), 2.81-2.90 (m, 4H), 3.60-3.65 (m, 1H), 3.72-3.78 (m, 1H), 4.02-4.16 (m, 3H), 7.47 (s, 1H), 12.72 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.51 min; MS (ESIpos): m/z = 303 [M+H]+
。
中間物 32 : 步驟 1 2-{[1-( 第三丁氧基羰基 ) 氮雜環丁 -3- 基 ] 甲基 }-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,330 mg,1.34 mmol)與3-(羥基甲基)氮雜環丁烷-1-甲酸第三丁酯(CAS編號[142253-56-3];1.50 eq.,376 mg,2.01 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,540 µL,2.1 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,369 mg,2.14 mmol)在甲苯(9 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(420 mg,69%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.35 (s, 9H), 2.81-2.98 (m, 5H), 3.66-3.69 (m, 2H), 3.88 (br. s., 2H), 4.24-4.29 (m, 4H), 7.58 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.34 min; MS (ESIpos): m/z = 416 [M+H]+
。
步驟 2 2-{[1-( 第三丁氧基羰基 ) 氮雜環丁 -3- 基 ] 甲基 }-8- 甲基 -4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,使得自步驟1的2-{[1-(第三丁氧基羰基)氮雜環丁-3-基]甲基}-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,417 mg,1.00 mmol)與氫氧化鋰水溶液(2 M;15 eq.,7.5 mL,15 mmol)在乙醇與THF之1:1混合物(8 mL)中、在70℃下反應24小時且隨後在室溫下反應兩天。反應混合物用4 N HCl水溶液(pH 4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(327 mg,76%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.35 (s, 9H), 2.47 (s, 3H), 2.80-2.96 (m, 5H), 3.66-3.69 (m, 2H), 3.85-3.94 (m, 2H), 4.26 (d, 2H), 7.56 (s, 1H), 12.85 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.65 min; MS (ESIpos): m/z = 388 [M+H]+
。
中間物 33 : 步驟 1 8- 甲基 -2-[(3R)- 四氫呋喃 -3- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,300 mg,1.22 mmol)與(3R)-四氫呋喃-3-基甲醇(CAS編號[124506-31-6];1.5 eq.,187 mg,1.83 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,490 µL,1.9 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,336 mg,1.95 mmol)在甲苯(8 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(465 mg,100%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.56-1.65 (m, 1H), 1.88-1.96 (m, 1H), 2.65-2.74 (m, 1H), 2.81-2.94 (m, 4H), 3.49 (dd, 1H), 3.59-3.68 (m, 2H), 3.73-3.80 (m, 1H), 4.00-4.09 (m, 2H), 4.27 (q, 2H), 7.56 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.17 min; MS (ESIpos): m/z = 331 [M+H]+
。
步驟 2 8- 甲基 -2-[(3R)- 四氫呋喃 -3- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,使得自步驟1的8-甲基-2-[(3R)-四氫呋喃-3-基甲基]-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,458 mg,1.39 mmol)與氫氧化鋰水溶液(2 M;15 eq.,10 mL,21 mmol)在乙醇與THF之1:1混合物(20 mL)中、在70℃下反應隔夜且在室溫下反應兩天。反應混合物用6 N HCl水溶液(pH 3)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(166 mg,38%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.56-1.65 (m, 1H), 1.88-1.96 (m, 1H), 2.47 (s, 3H), 2.63-2.72 (m, 1H), 2.81-2.91 (m, 4H), 3.49 (dd, 1H), 3.59-3.68 (m, 2H), 3.74-3.78 (m, 1H), 3.99-4.08 (m, 2H), 7.54 (s, 1H), 12.78 (br. s. ,1H)。
UPLC-MS (方法1
): Rt
= 0.48 min; MS (ESIpos): m/z = 303 [M+H]+
。
中間物 34 : 步驟 1 8- 甲基 -2-[(3S)- 四氫呋喃 -3- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,402 mg,1.63 mmol)與(3S)-四氫呋喃-3-基甲醇(CAS編號[124391-75-9];1.5 eq.,250 mg,2.45 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,650 µL,2.6 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,450 mg,2.61 mmol)在甲苯(8 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(365 mg,67%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.56-1.65 (m, 1H), 1.88-1.96 (m, 1H), 2.65-2.74 (m, 1H), 2.82-2.93 (m, 4H), 3.49 (dd, 1H), 3.59-3.68 (m, 2H), 3.73-3.79 (m, 1H), 4.00-4.09 (m, 2H), 4.26 (q, 2H), 7.56 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.11 min; MS (ESIpos): m/z = 331 [M+H]+
。
步驟 2 8- 甲基 -2-[(3S)- 四氫呋喃 -3- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(3S)-四氫呋喃-3-基甲基]-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,357 mg,1.08 mmol)與氫氧化鋰水溶液(2 M;15 eq.,8.1 mL,16 mmol)在乙醇與THF之1:1混合物(16 mL)中反應隔夜。反應混合物用6 N HCl水溶液(pH 4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(311 mg,86%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.56-1.65 (m, 1H), 1.88-1.96 (m, 1H), 2.48 (s, 3H), 2.63-2.72 (m, 1H), 2.81-2.92 (m, 4H), 3.49 (dd, 1H), 3.59-3.68 (m, 2H), 3.74-3.78 (m, 1H), 4.00-4.09 (m, 2H), 7.55 (s, 1H), 12.78 (br. s. ,1H)。
UPLC-MS (方法1
): Rt
= 0.47 min; MS (ESIpos): m/z = 303 [M+H]+
。
中間物 35 : 步驟 1 2- 氯 -4,4,4- 三氟 -3- 側氧基丁酸乙酯
在-5至0℃下,向4,4,4-三氟-3-側氧基丁酸乙酯(1.00 eq.,500 mmol,92.0 g)於二氯甲烷(100 mL)中的溶液中添加硫醯氯(CAS編號[7791-25-5];1.10 eq.,550 mmol,44 mL)於二氯甲烷(50 mL)中的溶液。使反應混合物升溫至室溫且在此溫度下攪拌12小時。將混合物傾入水中且用乙酸乙酯萃取。有機層用鹽水洗滌且在減壓下濃縮。所得物質藉由管柱層析(100-200目,石油醚:乙酸乙酯=50:1,接著5:1)純化,得到呈黃色油狀的2-氯-4,4,4-三氟-3-側氧基丁酸乙酯(66.0 g,60%)。1
H NMR (400 MHz, CDCl3
) δ [ppm]: 1.34 (t, 3H), 4.33 (q, 2H), 4.48 (s, 1H)。
步驟 2 4- 側氧基 -3-( 三氟甲基 )-4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧酸乙酯
在20℃下,向環己烷-1,3-二酮(1.00 eq.,44.6 mmol,5.00 g)於甲苯(15 mL)中的溶液中添加得自步驟1的2-氯-4,4,4-三氟-3-側氧基丁酸乙酯(2.20 eq,98.1 mmol,21.4 g)且隨後在100℃下攪拌反應混合物36小時。將混合物傾入水中且用乙酸乙酯萃取。有機層用鹽水洗滌且在減壓下濃縮。所得物質藉由管柱層析(100-200目,石油醚:乙酸乙酯=50:1,接著20:1)純化,得到呈黃色油狀的4-側氧基-3-(三氟甲基)-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(7.2 g,57%)。1
H NMR (400 MHz, CDCl3
) δ [ppm]: 1.40 (t, 3H), 2.23 (quint, 2H), 2.59-2.62 (m, 2H), 2.99 (t, 2H), 4.43 (q, 2H), 4.48 (s, 1H)。
LC-MS (方法B
): Rt
= 0.89 min; MS (ESIpos): m/z = 277 [M+H]+
。
步驟 3 (5E/Z)-5-( 羥基亞甲基 )-4- 側氧基 -3-( 三氟甲基 )-4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧酸乙酯
根據GP A (條件B),在0℃下,用氫化鈉(CAS編號[7646-69-7];3.00 eq.,43.4 mmol,1.74 g,60%純度)處理羧酸乙酯(CAS編號[109-94-4];6.0 eq.,87 mmol,7.0 mL)於甲苯(40 mL)中的溶液。攪拌0.5小時之後,向混合物中添加得自步驟2之4-側氧基-3-(三氟甲基)-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(1.00 eq.,14.5 mmol,4.00 g)於甲苯(10 mL)中的溶液。反應混合物在室溫下攪拌2小時且用2 N HCl水溶液(pH~3)淬滅。分離各相,且用乙酸乙酯萃取水相。合併之有機相用鹽水洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到呈棕色油狀之粗(5E/Z)-5-(羥基亞甲基)-4-側氧基-3-(三氟甲基)-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(4.4 g,100%),其不進一步純化。1
H NMR (400 MHz, CDCl3
) δ [ppm]: 1.41 (t, 3H), 2.70 (t, 2H), 2.97 (t, 2H), 4.44 (q, 2H), 4.48 (s, 1H), 7.37-7.40 (m, 1H), 13.48-13.50 (m, 1H)。
LC-MS (方法B
): Rt
= 0.73 min; MS (ESIpos): m/z = 305 [M+H]+
。
步驟 4 8-( 三氟甲基 )-4,5- 二氫 -1H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP B,在室溫下,用肼二鹽酸鹽(CAS編號[5341-61-7];2.0 eq.,29 mmol,3.0 g)於水(20 mL)中的溶液處理得自步驟3之粗(5E/Z)-5-(羥基亞甲基)-4-側氧基-3-(三氟甲基)-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(1.0 eq.,15 mmol,4.4 g)於乙醇(60 mL)中的溶液。反應混合物在60℃下攪拌2小時,用碳酸鈉飽和水溶液(pH ~9)淬滅且用乙酸乙酯萃取。有機相用鹽水洗滌,經無水硫酸鈉乾燥,過濾且濃縮。所得物質藉由管柱層析(100-200目,石油醚:乙酸乙酯=20:1,接著2:1)純化且溶解於甲醇中。再次濃縮混合物,得到呈黃色固體狀的8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(2.2 g,51%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.31 (t, 3H), 2.86-2.90 (m, 2H), 2.97-3.01 (m, 2H), 4.34 (q, 2H), 7.58 (s, 1H), 12.64 (br s, 1H)。
LC-MS (方法B
): Rt
= 0.70 min; MS (ESIpos): m/z = 301 [M+H]+
。
步驟 5 2-[( 吡啶 -2- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使得自步驟4的8-(三氟甲基)-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,500 mg,1.67 mmol)與(吡啶-2-基)甲醇(1.1 eq.,200 mg,1.83 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,660 µL,2.7 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,459 mg,2.66 mmol)在甲苯(21 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(322 mg,48%;以及264 mg的另一種產物溶離份,其含有約15%的相應N1-區位異構體)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 2.87-2.91 (m, 2H), 2.98-3.02 (m, 2H), 4.34 (q, 2H), 5.40 (s, 2H), 7.09 (d, 1H), 7.31 (ddd, 1H), 7.71 (s, 1H), 7.78 (dt, 1H), 8.54 (ddd, 1H)。
UPLC-MS (方法1
): Rt
= 1.34 min; MS (ESIpos): m/z = 392 [M+H]+
。
步驟 6 2-[( 吡啶 -2- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟5的2-[(吡啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,320 mg,818 µmol)與氫氧化鋰水溶液(2 M;15 eq.,6.1 mL,12 mmol)在乙醇與THF之1:1混合物(12 mL)中反應2.5小時。反應混合物用2 N HCl水溶液(pH 4)酸化且將所形成之沈澱物濾出。固體用水及EtOAc洗滌且乾燥,得到所需羧酸(255 mg,83%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.86-2.90 (m, 2H), 2.95-2.99 (m, 2H), 5.39 (s, 2H), 7.08 (d, 1H), 7.31 (dd, 1H), 7.69 (s, 1H), 7.78 (dt, 1H), 8.54 (ddd, 1H), 13.89 (br. s., 1H)。19
F NMR (377 MHz, DMSO-d6) δ [ppm]: -54.73 (s, 3F)。
UPLC-MS (方法1
): Rt
= 0.52 min; MS (ESIpos): m/z = 364 [M+H]+
。
中間物 36 : 步驟 1 2- 氯 -3- 環丙基 -3- 側氧基丙酸甲酯
在0℃下,向3-環丙基-3-側氧基丙酸甲酯(1.00 eq.,20.0 g,141 mmol)於二氯甲烷(150 mL)中的溶液中添加硫醯氯(0.99 eq.,12 mL,140 mmol)。在25℃下攪拌反應混合物2小時。將水(200 mL)添加至混合物中且分離出有機層。有機層用飽和碳酸氫鈉、鹽水洗滌且在減壓下濃縮,得到殘餘物。殘餘物藉由管柱層析(石油醚:乙酸乙酯=50:1,接著20:1)純化,得到呈黃色油狀的2-氯-3-環丙基-3-側氧基丙酸甲酯(27.0 g,98%)。1
H NMR (400 MHz, CDCl3
): δ [ppm] = 1.07-1.11 (m, 2H), 1.17-1.21 (m, 2H), 2.27-2.33 (m, 1H), 3.86 (s, 3H), 4.95 (s, 1H)。
LC-MS (方法C
): Rt
= 0.55 min; MS (ESIpos): m/z = 177 [M+H]+
。
步驟 2 3- 環丙基 -4- 側氧基 -4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧酸甲酯
在室溫下,向得自步驟1之2-氯-3-環丙基-3-側氧基丙酸甲酯(1.00 eq.,17.0 g,96.3 mmol)於1,2-二氯乙烷(100 mL)中的混合物中添加環己烷-1,3-二酮(1.00 eq.,10.8 g,96.3 mmol)及三乙胺(1.2 eq.,16 mL,120 mmol)。在50℃下、在氮氣保護下攪拌混合物60小時。藉由鹽酸水溶液(12 M)將pH調節至約1且再攪拌混合物16小時。將水添加至混合物中且分離有機層。用乙酸乙酯萃取水相。合併之有機層用飽和碳酸鈉溶液洗滌,經無水硫酸鈉乾燥,過濾且在減壓下濃縮,得到殘餘物。殘餘物藉由急驟管柱層析(石油醚:乙酸乙酯=1:0至5:1)純化,得到呈淡黃色固體狀之3-環丙基-4-側氧基-4,5,6,7-四氫-1-苯并呋喃-2-羧酸甲酯(8.0 g,35%)。1
H NMR (400 MHz, DMSO-d6): δ [ppm] = 0.86-0.91 (m, 2H), 1.20-1.23 (m, 2H), 2.01-2.07 (m, 2H), 2.41-2.44 (m, 2H), 2.65-2.72 (m, 1H), 2.90 (t, 2H), 3.81 (s, 3H)。
LC-MS (方法C
): Rt
= 0.80 min; MS (ESIpos): m/z = 235 [M+H]+
。
步驟 3 (5E/Z)-3- 環丙基 -5-( 羥基亞甲基 )-4- 側氧基 -4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧酸甲酯
根據GP A (條件B),在0℃下,用羧酸甲酯(3.0 eq.,2.4 mL,38 mmol)及得自步驟2的3-環丙基-4-側氧基-4,5,6,7-四氫-1-苯并呋喃-2-羧酸甲酯(1.00 eq.,3.00 g,12.8 mmol)處理氫化鈉(2.00 eq.,1.02 g,60%純度,25.6 mmol)於甲苯(60 mL)中的混合物。在40℃下攪拌混合物12小時且隨後用飽和氯化銨水溶液淬滅且用水稀釋。用乙酸乙酯萃取混合物,有機相用鹽水洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到(5E/Z)-3-環丙基-5-(羥基亞甲基)-4-側氧基-4,5,6,7-四氫-1-苯并呋喃-2-羧酸甲酯(3.50 g),其不經進一步純化即直接使用。
LC-MS (方法C
): Rt
= 0.84 min; MS (ESIpos): m/z = 263 [M+H]+
。
步驟 4 8- 環丙基 -4,5- 二氫 -1H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸甲酯
根據GP B,在25℃下,向得自步驟3之粗(5E/Z)-3-環丙基-5-(羥基亞甲基)-4-側氧基-4,5,6,7-四氫-1-苯并呋喃-2-羧酸甲酯(3.50 g,13.3 mmol)於甲醇(50 mL)及水(5.0 mL)中的溶液中添加肼二鹽酸鹽(3.00 eq.,4.20 g,40.0 mmol)。在50℃下攪拌混合物1小時。在0℃下將混合物緩慢添加至碳酸鈉飽和水溶液中。收集沈澱物且藉由急驟管柱層析(石油醚:乙酸乙酯=1:0至1:1)純化,得到呈黃色固體狀的8-環丙基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸甲酯(1.50 g,42%,歷經兩個步驟)。1
H NMR (400 MHz, DMSO-d6): δ [ppm] = 0.88-0.93 (m, 2H), 1.52-1.54 (m, 2H), 2.74-2.87 (m, 5H), 3.80 (s, 3H), 7.51 (s, 1H), 12.46 (br s, 1H)。
LC-MS (方法D
): Rt
= 0.89 min; MS (ESIpos): m/z = 259 [M+H]+
。
步驟 5 8- 環丙基 -2-[( 吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸甲酯
根據GP C (條件A),在室溫下,使得自步驟4的8-環丙基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸甲酯(1.00 eq.,400 mg,1.55 mmol)與(吡啶-2-基)甲醇(1.1 eq.,186 mg,1.70 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,620 µL,2.5 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,427 mg,2.48 mmol)於甲苯(20 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(391 mg,69%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.83-0.88 (m, 2H), 1.43-1.47 (m, 2H), 2.68-2.75 (m, 1H), 2.78-2.89 (m, 4H), 3.79 (s, 3H), 5.36 (s, 2H), 7.04 (d, 1H), 7.31 (ddd, 1H), 7.64 (s, 1H), 7.78 (dt, 1H), 8.54 (ddd, 1H)。
UPLC-MS (方法1
): Rt
= 1.18 min; MS (ESIpos): m/z = 350 [M+H]+
。
步驟 6 8- 環丙基 -2-[( 吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟5的8-環丙基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-7-羧酸甲酯(1.00 eq.,385 mg,1.10 mmol)與氫氧化鋰水溶液(2 M;15 eq.,8.3 mL,17 mmol)在乙醇與THF之1:1混合物(18 mL)中反應4小時。在減壓下濃縮反應混合物,濃縮物用2 N HCl水溶液(pH 3)酸化且將所形成之沈澱物濾出。固體用水及EtOAc洗滌且乾燥,得到所需羧酸(360 mg,93%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.79-0.84 (m, 2H), 1.41-1.45 (m, 2H), 2.73-2.87 (m, 5H), 5.37 (s, 2H), 7.06 (d, 1H), 7.33 (dd, 1H), 7.64 (s, 1H), 7.80 (dt, 1H), 8.54-8.56 (m, 1H), 12.83 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.55 min; MS (ESIpos): m/z = 336 [M+H]+
。
中間物 37 : 步驟 1 3 , 6,6- 三甲基 -6,7- 二氫 -1- 苯并呋喃 -4(5H
)- 酮
類似於K. Kanematsu等人, Heterocycles 1990, 31, 6, 1003-1006及J. Org. Chem. 1993, 58, 3960-3968:
向3-溴丙-1-炔(CAS編號[106-96-7];2.00 eq.,25 mL,290 mmol)於無水乙腈(20 mL)中的溶液中添加甲硫醚(CAS編號:[75-18-3];0.57 eq.,6.0 mL,82 mmol)且反應混合物在避光燒瓶中、在室溫下攪拌隔夜。添加乙醇鈉(1.1 eq.,37 mL於乙醇中的21%溶液,160 mmol)及5,5-二甲基環己烷-1,3-二酮(CAS編號[126-81-8];1.00 eq.,20.0 g,143 mmol)於乙醇(365 mL)中的溶液且將混合物加熱至回流維持1.5小時。反應混合物用水稀釋,在減壓下濃縮且所得殘餘物用二氯甲烷萃取。合併之有機層在減壓下濃縮,殘餘物用甲苯(150 mL)溶解且在室溫下用4-甲基苯磺酸(CAS編號[104-15-4];1.11 eq.,27.3 g,159 mmol)處理隔夜。用NaHCO3
飽和水溶液淬滅反應混合物,分離各層,且用二氯甲烷萃取水層。合併之有機層用疏水性過濾器過濾,在減壓下濃縮且對所得粗產物進行管柱層析(SiO2
,己烷/EtOAc),得到標題化合物(9.4 g,34%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.04 (s, 6H), 2.09 (d, 3H), 2.30 (s, 2H), 2.74 (s, 2H), 7.43-7.44 (m, 1H)。
UPLC-MS (方法1
): Rt
= 1.11 min; MS (ESIpos): m/z = 179 [M+H]+
。
步驟 2 2- 溴 -3 , 6,6- 三甲基 -6,7- 二氫 -1- 苯并呋喃 -4(5H
)- 酮
類似於US6,048,880;實例2,步驟2 (第20頁):
得自步驟1的3,6,6-三甲基-6,7-二氫-1-苯并呋喃-4(5H
)-酮(1.00 eq.,7.64 g,42.9 mmol)於吡啶(60 mL)中的溶液用1-溴吡咯啶-2,5-二酮(NBS,CAS編號[128-08-5];1.01 eq.,7.71 g,43.3 mmol)處理且在室溫下攪拌兩天。添加額外量的1-溴吡咯啶-2,5-二酮(1.00 eq.,7.63 g,42.9 mmol)且在室溫下繼續攪拌隔夜。反應混合物用2 N HCl水溶液(pH 4)酸化且用二氯甲烷萃取。合併之有機層經Na2
SO4
乾燥,過濾,在減壓下濃縮且對粗產物進行管柱層析(SiO2
,己烷/EtOAc),得到標題化合物(5.7 g,52%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.05 (s, 6H), 2.05 (s, 3H), 2.32 (s, 2H), 2.76 (s, 2H)。
UPLC-MS (方法1
): Rt
= 1.32 min; MS (ESIpos): m/z = 257/259 [M+H]+
(Br同位素模式)。
步驟 3 (5E/Z)-2- 溴 -5-[( 二甲基胺基 ) 亞甲基 ]-3,6,6- 三甲基 -6,7- 二氫 -1- 苯并呋喃 -4(5H
)- 酮
根據GP A (條件A),在100℃下,使得自步驟2的2-溴-3,6,6-三甲基-6,7-二氫-1-苯并呋喃-4(5H
)-酮(1.00 eq.,3.50 g,13.6 mmol)與1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(布雷德奈克試劑,CAS編號[5815-08-7];1.20 eq.,3.37 mL,16.3 mmol)在甲苯(35 mL)中反應3小時。添加額外量的1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(1.20 eq.,3.37 mL,16.3 mmol)且在100℃下繼續攪拌另外24小時。添加額外量的1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(1.20 eq.,3.37 mL,16.3 mmol)且在100℃下繼續攪拌10小時且隨後在室溫下攪拌三天。在減壓下濃縮反應混合物且所得粗標題化合物不經進一步純化步驟即用於後續反應中。
UPLC-MS (方法1
): Rt
= 1.33/1.37 min; MS (ESIpos): m/z = 312/314 [M+H]+
(Br同位素模式)。步驟 4 7- 溴 -4,4,8- 三甲基 -4,5- 二氫 -1H
- 呋喃并 [2,3-g] 吲唑
根據GP B,在70℃下,使得自步驟3的粗(5E/Z)-2-溴-5-[(二甲基胺基)亞甲基]-3,6,6-三甲基-6,7-二氫-1-苯并呋喃-4(5H
)-酮(1.0 eq.,4.3 g,14 mmol)與水合肼1:1 (5.0 eq.,3.3 mL,68 mmol)在乙醇(50 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(1.38 g,35%,歷經兩個步驟)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.22 (s, 6H), 2.13 (s, 3H), 2.66 (s, 2H), 7.53 (s, 1H), 12.39 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.25 min; MS (ESIpos): m/z = 281/283 [M+H]+
(Br同位素模式)。
步驟 5 7- 溴 -4,4,8- 三甲基 -2-[( 吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑
根據GP C (條件B),在75℃下,使得自步驟4的7-溴-4,4,8-三甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑(1.0 eq.,5.6 g,35 mmol)與2-(溴甲基)吡啶(1.5 eq.,1.2 g,6.9 mmol)、碳酸鉀(15 eq.,9.6 g,69 mmol)及DMAP (14 mg,120 µmol,2.5 mol%)在EtOAc (75 mL)中反應隔夜。添加額外量的2-(溴甲基)吡啶(0.75 eq.,600 mg,3.5 mmol)且在75℃下繼續攪拌另外3天,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(200 mg,7%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.26 (s, 6H), 2.08 (s, 3H), 2.69 (s, 2H), 5.36 (s, 2H), 7.04 (d, 1H), 7.31 (ddd, 1H), 7.69 (s, 1H), 7.78 (dt, 1H), 8.53-8.55 (m, 1H)。
UPLC-MS (方法1
): Rt
= 1.39 min; MS (ESIpos): m/z = 371/373 [M+H]+
(Br同位素模式)。
中間物 38: 步驟 1 3- 甲基 -5H
- 螺 [[1] 苯并呋喃 -6,1'- 環丙 ]-4(7H
)- 酮
類似於K. Kanematsu等人, Heterocycles 1990, 31, 6, 1003-1006及J. Org. Chem. 1993, 58, 3960-3968:
向3-溴丙-1-炔(CAS編號[106-96-7];2.00 eq.,12 mL,145 mmol)於無水乙腈(10 mL)中的溶液中添加甲硫醚(CAS編號:[75-18-3];0.57 eq.,3.0 mL,41 mmol)且反應混合物在避光燒瓶中、在室溫下攪拌隔夜。添加乙醇鈉(1.1 eq.,19 mL於乙醇中的21%溶液,81 mmol)及螺[2.5]辛烷-5,7-二酮(CAS編號[893411-52-4];1.00 eq.,10.0 g,72.4 mmol)於乙醇(190 mL)中的溶液且將混合物加熱至回流維持1.5小時。反應混合物用水稀釋,在減壓下濃縮且所得殘餘物用二氯甲烷萃取。合併之有機層在減壓下濃縮,殘餘物用甲苯(75 mL)溶解且在室溫下用4-甲基苯磺酸(CAS編號[104-15-4];4 mol%,0.50 g,2.9 mmol)處理隔夜。用NaHCO3
飽和水溶液淬滅反應混合物,分離各層,且用二氯甲烷萃取水層。合併之有機層用疏水性過濾器過濾,在減壓下濃縮且對所得粗產物進行管柱層析(SiO2
,己烷/EtOAc),得到標題化合物(3.8 g,29%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.42-0.44 (m, 2H), 0.47-0.50 (m, 2H), 2.11 (d, 3H), 2.28 (s, 2H), 2.75 (s, 2H), 7.44 (m, 1H)。
UPLC-MS (方法1
): Rt
= 1.07 min; MS (ESIpos): m/z = 177 [M+H]+
。
步驟 2 2- 溴 -3- 甲基 -5H- 螺 [[1] 苯并呋喃 -6,1'- 環丙 ]-4(7H
)- 酮
得自步驟1之3-甲基-5H-螺[[1]苯并呋喃-6,1'-環丙]-4(7H
)-酮(1.00 eq.,3.80 g,21.6 mmol)於吡啶(30 mL)中的溶液用1-溴吡咯啶-2,5-二酮(NBS,CAS編號[128-08-5];1.01 eq.,3.88 g,21.8 mmol)處理且在室溫下攪拌隔夜。添加額外量的1-溴吡咯啶-2,5-二酮(1.00 eq.,3.84 g,21.6 mmol)且在室溫下繼續攪拌隔夜。反應混合物用2 N HCl水溶液(pH 4)酸化且用二氯甲烷萃取。合併之有機層經Na2
SO4
乾燥,過濾,在減壓下濃縮且對粗產物進行管柱層析(SiO2
,己烷/EtOAc),得到標題化合物(2.68 g,46%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.42-0.46 (m, 2H), 0.48-0.52 (m, 2H), 2.07 (s, 3H), 2.31 (s, 2H), 2.78 (s, 2H)。
UPLC-MS (方法1
): Rt
= 1.28 min; MS (ESIpos): m/z = 255/257 [M+H]+
(Br同位素模式)。
步驟 3 (5E/Z)-2- 溴 -5-[( 二甲基胺基 ) 亞甲基 ]-3- 甲基 -5H
- 螺 [[1] 苯并呋喃 -6,1'- 環丙 ]-4(7H
)- 酮
根據GP A (條件A),在100℃下,使得自步驟2的2-溴-3-甲基-5H-
螺[[1]苯并呋喃-6,1'-環丙]-4(7H
)-酮(1.00 eq.,2.00 g,7.84 mmol)與1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(布雷德奈克試劑,CAS編號[5815-08-7];1.2 eq.,1.9 mL,9.4 mmol)在甲苯(20 mL)中反應隔夜。在減壓下濃縮反應混合物且所得粗標題化合物不經進一步純化步驟即用於後續反應中。
UPLC-MS (方法1
): Rt
= 1.33 min; MS (ESIpos): m/z = 310/312 [M+H]+
(Br同位素模式)。
步驟 4 7'- 溴 -8'- 甲基 -1',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]
根據GP B,在70℃下,使得自步驟3的粗(5E/Z)-2-溴-5-[(二甲基胺基)亞甲基]-3-甲基-5H
-螺[[1]苯并呋喃-6,1'-環丙]-4(7H
)-酮(1.0 eq.,2.5 g,8.1 mmol)與水合肼1:1 (5.0 eq.,2.0 mL,40 mmol)在乙醇(35 mL)中反應5小時,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(1.3 g,59%,歷經兩個步驟)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.78-0.80 (m, 2H), 0.82-0.85 (m, 2H), 2.14 (s, 3H), 2.78 (s, 2H), 7.29 (s, 1H), 12.33 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.20 min; MS (ESIpos): m/z = 279/281 [M+H]+
(Br同位素模式)。
步驟 5 7'- 溴 -8'- 甲基 -2'-[( 吡啶 -2- 基 ) 甲基 ]-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]
根據GP C (條件A),在室溫下,使得自步驟4的7'-溴-8'-甲基-1',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑] (1.00 eq.,300 mg,1.22 mmol)與(吡啶-2-基)甲醇(1.1 eq.,376 mg,3.45 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,1.2 mL,5.0 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,864 mg,5.02 mmol)在甲苯(40 mL)中反應兩天,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(933 mg,72%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.78-0.82 (m, 2H), 0.84-0.88 (m, 2H), 2.09 (s, 3H), 2.80 (s, 2H), 5.34 (s, 2H), 7.03 (d, 1H), 7.33 (ddd, 1H), 7.44 (s, 1H), 7.80 (dt, 1H), 8.54 (ddd, 1H)。
UPLC-MS (方法1
): Rt
= 1.33 min; MS (ESIpos): m/z = 370/372 [M+H]+
(Br同位素模式)。
步驟 6 8'- 甲基 -2'-[( 吡啶 -2- 基 ) 甲基 ]-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP E,在鋼質高壓釜(50 mL)中,在100℃下,在約15巴之一氧化碳壓力下,使得自步驟5的7'-溴-8'-甲基-2'-[(吡啶-2-基)甲基]-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑] (1.00 eq.,500 mg,1.35 mmol)在DMSO (20 mL)中、在雙(二苯基膦基)二茂鐵(CAS編號[12150-46-8];0.200 eq.,155 mg,271 µmol)、乙酸鈀(II)(5.0 mol%,15 mg,68 µmol)及乙酸鉀(4.0 eq.,530 mg,5.40 mmol)存在下羰基化23小時,處理後,得到粗標題化合物(0.9 g,32%純度,65%),其不經進一步純化步驟即用於後續反應。
UPLC-MS (方法1
): Rt
= 0.64 min; MS (ESIpos): m/z = 336 [M+H]+
。
中間物 39: 7'- 溴 -8'- 甲基 -2'-[( 吡啶 -3- 基 ) 甲基 ]-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]
根據GP C (條件A),在室溫下,使得自中間物38步驟4的7'-溴-8'-甲基-1',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑] (1.00 eq.,200 mg,716 µmol)與(吡啶-3-基)甲醇(1.10 eq.,86.0 mg,788 µmol)、三-正丁基膦(CAS編號[998-40-3];1.60 eq.,286 µL,1.15 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,197 mg,1.15 mmol)在甲苯(10 mL)中反應隔夜,管柱層析(SiO2
,CH2
Cl2
/MeOH)後,得到標題化合物(430 mg,38%純度,62%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.77-0.81 (m, 2H), 0.83-0.87 (m, 2H), 2.11 (s, 3H), 2.79 (s, 2H), 5.28 (s, 2H), 7.38 (dd, 1H), 7.44 (s, 1H), 7.60-7.62 (m, 1H), 8.48-8.50 (m, 2H)。
UPLC-MS (方法1
): Rt
= 1.31 min; MS (ESIpos): m/z = 370/372 [M+H]+
(Br同位素模式)。
中間物 40-1: 步驟 1 7'- 溴 -2'-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8'- 甲基 -2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]
根據GP C (條件A),在室溫下,使得自中間物38步驟4的7'-溴-8'-甲基-1',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑] (1.00 eq.,700 mg,2.51 mmol)與[(2S)-1,4-二㗁烷-2-基]甲醇(CAS編號[406913-93-7];1.10 eq.,326 mg,2.76 mol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,1.0 mL,4.0 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,691 mg,4.01 mmol)在甲苯(32 mL)中反應兩天,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(595 mg,65%純度,41%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.76-0.80 (m, 2H), 0.82-0.85 (m, 2H), 2.12 (s, 3H), 2.77-2.78 (m, 2H), 3.24 (dd, 1H), 3.43 (dt, 1H), 3.53 (dt, 1H), 3.61-3.64 (m, 1H), 3.69-3.73 (m, 2H), 3.78-3.84 (m, 1H), 3.97-4.07 (m, 2H), 7.25 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.31 min; MS (ESIpos): m/z = 379/381 [M+H]+
(Br同位素模式)。
步驟 2 2'-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8'- 甲基 -2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP E,在鋼質高壓釜(90 mL)中,在100℃下,在約16巴之一氧化碳壓力下,使得自步驟1的7'-溴-2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑] (1.00 eq.,989 mg,2.61 mmol)在DMSO (40 mL)中、在雙(二苯基膦基)二茂鐵(CAS編號[12150-46-8];0.201 eq.,300 mg,524 µmol)、乙酸鈀(II)(5.0 mol%,29 mg,130 µmol)及乙酸鉀(4.00 eq.,1.02 g,10.4 mmol)存在下羰基化23小時,處理後,得到粗標題化合物(0.67 g,60%純度,45%),其不經進一步純化步驟即用於後續反應中。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.78-0.87 (m, 4H), 2.85-2.86 (m, 2H), 3.25 (dd, 1H), 3.44 (dt, 1H), 3.54 (dt, 1H), 3.61-3.64 (m, 1H), 3.70-3.74 (m, 2H), 3.80-3.86 (m, 1H), 4.00-4.06 (m, 2H), 7.29 (s, 1H), 12.86 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.51 min; MS (ESIpos): m/z = 345 [M+H]+
。
中間物 40-2: 7'- 溴 -N,N,
8'- 三甲基螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-2'(5'H
)- 羧醯胺
自中間物40-1步驟1之反應混合物分離(166 mg,18%)。
中間物 41: 步驟 1 3- 甲基 -4- 側氧基 -4,7- 二氫 -5H
- 螺 [[1] 苯并呋喃 -6,1'- 環丙烷 ]-2- 羧酸乙酯
在室溫下,向螺[2.5]辛烷-5,7-二酮(CAS編號[893411-52-4];1.00 eq.,5.00 g,36.2 mmol)於1,2-二氯乙烷(80 mL)中的混合物中添加2-氯-3-側氧基丁酸乙酯(CAS編號[609 -15-4];1.0 eq.,5.0 mL,36 mmol)及三乙胺(1.2 eq,6.1 mL,43 mmol)且在50℃下攪拌混合物15小時。藉由2 N HCl水溶液將pH調節至約2且接著在室溫下繼續攪拌另外7小時。將水添加至混合物中且分離有機層。有機層用水洗滌,經疏水性過濾器過濾,在減壓下濃縮且對所得粗產物進行管柱層析(SiO2
,己烷/EtOAc),得到標題化合物(3.5 g,36%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.44-0.48 (m, 2H), 0.50-0.54 (m, 2H), 1.29 (t, 3H), 2.35 (s, 2H), 2.47 (s, 3H), 2.86 (s, 2H), 4.29 (q, 2H)。
UPLC-MS (方法1
): Rt
= 1.14 min; MS (ESIpos): m/z = 249 [M+H]+
。
步驟 2 (5E/Z)-5-[( 二甲基胺基 ) 亞甲基 ]-3- 甲基 -4- 側氧基 -4,7- 二氫 -5H
- 螺 [[1] 苯并呋喃 -6,1'- 環丙烷 ]-2- 羧酸乙酯
根據GP A (條件A),在100℃下,使得自步驟1的3-甲基-4-側氧基-4,7-二氫-5H-
螺[[1]苯并呋喃-6,1'-環丙烷]-2-羧酸乙酯(1.00 eq.,3.40 g,13.7 mmol)與1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(布雷德奈克試劑,CAS編號[5815-08-7];1.2 eq.,3.4 mL,16 mmol)在甲苯(35 mL)中反應5天。在減壓下濃縮反應混合物且所得粗標題化合物不經進一步純化步驟即用於後續反應中。
UPLC-MS (方法1
): Rt
= 1.16/1.23 min; MS (ESIpos): m/z = 304 [M+H]+
。
步驟 3 8'- 甲基 -1',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP B,在70℃下,使得自步驟2的粗(5E/Z)-5-[(二甲基胺基)亞甲基]-3-甲基-4-側氧基-4,7-二氫-5H-
螺[[1]苯并呋喃-6,1'-環丙烷]-2-羧酸乙酯(1.0 eq.,4.2 g,14 mmol)與水合肼1:1 (5.0 eq.,3.3 mL,68 mmol)在乙醇(35 mL)中反應5小時,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(1.49 g,84%純度,34%,歷經兩個步驟)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.80-0.82 (m, 2H), 0.85-0.88 (m, 2H), 1.30 (t, 3H), 2.53 (s, 3H), 2.87 (s, 2H), 4.27 (q, 2H), 7.34 (s, 1H), 12.44 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.03 min; MS (ESIpos): m/z = 273 [M+H]+
。
步驟 4 2'-( 環丙基甲基 )-8'- 甲基 -2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),在室溫下,使得自步驟3的8'-甲基-1',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(1.00 eq.,400 mg,1.47 mmol)與環丙基甲醇(1.5 eq.,180 µL,2.2 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,590 µL,2.4 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,405 mg,2.35 mmol)在甲苯(7 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(263 mg,49%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.31-0.35 (m, 2H), 0.48-0.53 (m, 2H), 0.79-0.83 (m, 2H), 0.85-0.89 (m, 2H), 1.16-1.24 (m, 1H), 1.29 (t, 3H), 2.52 (s, 3H), 2.87 (s, 2H), 3.88 (d, 2H), 4.27 (q, 2H), 7.37 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.40 min; MS (ESIpos): m/z = 327 [M+H]+
。
步驟 5 2'-( 環丙基甲基 )-8'- 甲基 -2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,使得自步驟4的2'-(環丙基甲基)-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(1.00 eq.,260 mg,797 µmol)與氫氧化鋰水溶液(2 M;15 eq.,6.0 mL,12 mmol)在乙醇與THF之1:1混合物(12 mL)中、在70℃下反應4小時且在室溫下反應4天。在減壓下濃縮反應混合物,濃縮物用2 N HCl水溶液(pH 3)酸化且將所形成之沈澱物濾出。固體用水及EtOAc洗滌且乾燥,得到所需羧酸(146 mg,55%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.33-0.34 (m, 2H), 0.50-0.52 (m, 2H), 0.80-0.86 (m, 4H), 1.17-1.23 (m, 1H), 2.83 (s, 2H), 3.87 (d, 2H), 7.34 (s, 1H)。
UPLC-MS (方法1
): Rt
= 0.59 min; MS (ESIpos): m/z = 299 [M+H]+
。
中間物 42: 步驟 1 3- 甲基 -4- 側氧基 -4,7- 二氫 -5H
- 螺 [[1] 苯并呋喃 -6,1'- 環丁烷 ]-2- 羧酸乙酯
在室溫下,向螺[3.5]壬烷-6,8-二酮(CAS編號[221342-48-9];1.00 eq.,2.00 g,13.1 mmol)於1,2-二氯乙烷(30 mL)中的混合物中添加2-氯-3-側氧基丁酸乙酯(CAS編號[609-15-4];1.0 eq.,1.8 mL,13 mmol)及三乙胺(1.2 eq,2.2 mL,16 mmol)且在50℃下攪拌混合物三天且接著在室溫下靜置另外三天。藉由2 N HCl水溶液將pH調節至約2且接著在室溫下繼續攪拌另外兩小時。將水添加至混合物中且分離有機層。有機層用水洗滌,經疏水性過濾器過濾,在減壓下濃縮且對所得粗產物進行管柱層析(SiO2
,己烷/EtOAc),得到標題化合物(955 mg,26%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.77-1.94 (m, 6H), 2.44 (s, 3H), 2.62 (s, 2H), 3.09 (s, 2H), 4.28 (q, 2H)。
UPLC-MS (方法1
): Rt
= 1.23 min; MS (ESIpos): m/z = 263 [M+H]+
。
步驟 2 (5E/Z)-5-[( 二甲基胺基 ) 亞甲基 ]-3- 甲基 -4- 側氧基 -4,7- 二氫 -5H
- 螺 [[1] 苯并呋喃 -6,1'- 環丁烷 ]-2- 羧酸乙酯
根據GP A (條件A),在100℃下,使得自步驟1的3-甲基-4-側氧基-4,7-二氫-5H-
螺[[1]苯并呋喃-6,1'-環丁烷]-2-羧酸乙酯(1.00 eq.,500 mg,1.91 mmol)與1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(布雷德奈克試劑,CAS編號[5815-08-7];1.2 eq.,470 µL,2.3 mmol)在甲苯(5 mL)中反應三天。在減壓下濃縮反應混合物且所得粗標題化合物不經進一步純化步驟即用於後續反應中。
UPLC-MS (方法1
): Rt
= 1.23/1.25 min; MS (ESIpos): m/z = 318 [M+H]+
。
步驟 3 8'- 甲基 -1',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP B,在70℃下,使得自步驟2的粗(5E/Z)-5-[(二甲基胺基)亞甲基]-3-甲基-4-側氧基-4,7-二氫-5H-
螺[[1]苯并呋喃-6,1'-環丁烷]-2-羧酸乙酯(1.0 eq.,600 mg,1.9 mmol)與水合肼1:1 (5.0 eq.,460 µL,9.5 mmol)在乙醇(5 mL)中反應13小時,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(134 mg,25%,歷經兩個步驟)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 1.93-2.13 (m, 6H), 3.05 (s, 2H), 4.27 (q, 2H), 7.79 (s, 1H), 12.54 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.12 min; MS (ESIpos): m/z = 287 [M+H]+
。
步驟 4 8'- 甲基 -2'-[( 吡啶 -2- 基 ) 甲基 ]-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),在室溫下,使得自步驟3的8'-甲基-1',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(1.00 eq.,130 mg,454 µmol)與(吡啶-2-基)甲醇(1.1 eq.,55 mg,500 µmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,180 µL,730 µmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,125 mg,726 µmol)在甲苯(7.5 mL)中反應兩天,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(111 mg,58%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.89-2.13 (m, 6H), 2.45 (s, 3H), 3.08 (s, 2H), 4.26 (q, 2H), 5.41 (s, 2H), 7.06 (d, 1H), 7.31 (ddd, 1H), 7.78 (dt, 1H), 7.94 (s, 1H), 8.55 (ddd, 1H)。
UPLC-MS (方法1
): Rt
= 1.27 min; MS (ESIpos): m/z = 378 [M+H]+
。
步驟 5 8'- 甲基 -2'-[( 吡啶 -2- 基 ) 甲基 ]-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,使得自步驟4的8'-甲基-2'-[(吡啶-2-基)甲基]-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(1.00 eq.,100 mg,265 µmol)與氫氧化鋰水溶液(2 M;15 eq.,2.0 mL,4.0 mmol)在乙醇與THF之1:1混合物(4 mL)中、在70℃下反應4小時且在室溫下反應隔夜。在減壓下濃縮反應混合物,濃縮物用2 N HCl水溶液(pH 3)酸化且將所形成之沈澱物濾出。固體用水及EtOAc洗滌且乾燥,得到所需羧酸(70 mg,64%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.91-2.05 (m, 2H), 2.06-2.13 (m, 4H), 2.42 (s, 3H), 3.03 (s, 2H), 5.40 (s, 2H), 7.05 (d, 1H), 7.31 (ddd, 1H), 7.78 (dt, 1H), 7.92 (s, 1H), 8.54 (ddd, 1H)。
UPLC-MS (方法1
): Rt
= 0.63 min; MS (ESIpos): m/z = 350 [M+H]+
。
中間物 43: 8- 甲基 -N
-[(2S)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -1H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
在氬氣氛圍下,向1-[(2S)-四氫呋喃-2-基]甲胺(CAS編號[7175-81-7];3.0 eq.,1.3 mL,12 mmol)於二氯甲烷(20 mL)中的冰冷溶液中逐滴添加三甲基鋁(CAS編號[75-24-1];3.0 eq.,2.0 M於甲苯中的溶液,6.1 mL,12 mmol)且繼續攪拌5分鐘。向此混合物中逐滴添加8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,1.00 g,4.06 mmol)於二氯甲烷(10 mL)中的懸浮液。使反應混合物升溫至室溫且攪拌一小時,接著使其升溫至40℃且在40℃下繼續攪拌四天。反應混合物用酒石酸鉀鈉飽和水溶液淬滅,分離各相,且用二氯甲烷萃取水相兩次。合併之有機相用鹽水洗滌,經MgSO4
乾燥,過濾且在減壓下濃縮。對所得粗物質進行管柱層析(Si-NH SiO2
,EtOAc/MeOH)且隨後用乙腈濕磨,得到標題化合物(453 mg,35%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.54-1.62 (m, 1H), 1.73-1.92 (m, 3H), 2.83-2.92 (m, 4H), 3.18-3.28 (m, 2H), 3.58-3.64 (m, 1H), 3.74-3.79 (m, 1H), 3.91-3.98 (m, 1H), 7.50 (s, 1H), 7.97 (t, 1H), 12.41 (s, 1H)。
UPLC-MS (方法1
): Rt
= 0.82 min; MS (ESIpos): m/z = 302 [M+H]+
。
中間物 44: 步驟 1 8- 甲基 -2-[ 苯基 (2
H2
) 甲基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,304 mg,1.23 mmol)與苯基(2
H2
)甲醇(CAS編號[21175-64-4];1.5 eq.,190 µL,1.9 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,490 µL,2.0 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,340 mg,1.98 mmol)在甲苯(8 mL)中反應三天,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(364 mg,83%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.48 (s, 3H), 2.83-2.93 (m, 4H), 4.26 (q, 2H), 7.22-7.36 (m, 5H), 7.61 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.33 min; MS (ESIpos): m/z = 339 [M+H]+
。
步驟 2 8- 甲基 -2-[ 苯基 (2
H2
) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,使得自步驟1的8-甲基-2-[苯基(2
H2
)甲基]-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,355 mg,1.05 mmol)與氫氧化鋰水溶液(2 M;15 eq.,7.9 mL,16 mmol)在乙醇與THF之1:1混合物(14 mL)中、在70℃下反應隔夜且在室溫下反應兩天。反應混合物用6 N HCl水溶液(pH 3-4)酸化,接著形成沈澱物。沈澱物藉由過濾分離,用水洗滌且在減壓下乾燥,得到所需羧酸(214 mg,64%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.46 (s, 3H), 2.82-2.91 (m, 4H), 7.23-7.30 (m, 3H), 7.33-7.37 (m, 2H), 7.59 (s, 1H), 12.80 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.58 min; MS (ESIpos): m/z = 311 [M+H]+
。
中間物 45: 步驟 1 2-[(5- 環丙基 -1,2,4- 㗁二唑 -3- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,300 mg,1.22 mmol)與(5-環丙基-1,2,4-㗁二唑-3-基)甲醇(CAS編號[915920-06-8];1.5 eq.,256 mg,1.83 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,490 µL,1.9 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,336 mg,1.95 mmol)在甲苯(8 mL)中反應三天,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(363 mg,73%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.06-1.10 (m, 2H), 1.21-1.25 (m, 2H), 1.29 (t, 3H), 2.29-2.36 (m, 1H), 2.46 (s, 3H), 2.84-2.94 (m, 4H), 4.26 (q, 2H), 5.41 (s, 2H), 7.62 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.19 min; MS (ESIpos): m/z = 369 [M+H]+
。
步驟 2 2-[(5- 環丙基 -1,2,4- 㗁二唑 -3- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的2-[(5-環丙基-1,2,4-㗁二唑-3-基)甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,354 mg,961 µmol)與氫氧化鋰水溶液(2 M;15 eq.,7.2 mL,14 mmol)在乙醇與THF之1:1混合物(14 mL)中反應隔夜。反應混合物用6 N HCl水溶液(pH 3-4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(275 mg,76%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.06-1.10 (m, 2H), 1.20-1.25 (m, 2H), 2.29-2.36 (m, 1H), 2.44 (s, 3H), 2.82-2.92 (m, 4H), 5.41 (s, 2H), 7.61 (s, 1H), 12.81 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.51 min; MS (ESIpos): m/z = 341 [M+H]+
。
中間物 46: 步驟 1 2-{2-[( 第三丁氧基羰基 ) 胺基 ] 乙基 }-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,350 mg,1.42 mmol)與(2-羥基乙基)胺基甲酸第三丁酯(CAS編號[26690-80-2];1.50 eq.,344 mg,2.13 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,570 µL,2.3 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,392 mg,2.27 mmol)在甲苯(8 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)且隨後用乙腈濕磨後,得到標題化合物(285 mg,46%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.36 (s, 9H), 2.81-2.92 (m, 4H), 3.25-3.30 (m, 2H), 4.08 (t, 2H), 4.27 (q, 2H), 6.95 (t, 1H), 7.47 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.21 min; MS (ESIpos): m/z = 390 [M+H]+
。
步驟 2 2-{2-[( 第三丁氧基羰基 ) 胺基 ] 乙基 }-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的2-{2-[(第三丁氧基羰基)胺基]乙基}-8-甲基-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,280 mg,719 µmol)與氫氧化鋰水溶液(2 M;15 eq.,5.4 mL,11 mmol)在乙醇與THF之1:1混合物(9 mL)中反應隔夜。反應混合物用6 N HCl水溶液(pH 4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸(301 mg,100%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.36 (s, 9H), 2.47 (s, 3H), 2.80-2.89 (m, 4H), 3.25-3.30 (m, 2H), 4.08 (t, 2H), 6.94 (t, 1H), 7.45 (s, 1H), 12.68 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.54 min; MS (ESIpos): m/z = 362 [M+H]+
。
中間物 47: 步驟 1 2-{2-[4-( 第三丁氧基羰基 ) 哌 𠯤 -1- 基 ] 乙基 }-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,350 mg,1.42 mmol)與4-(2-羥基乙基)哌𠯤-1-甲酸第三丁酯(CAS編號[77279-24-4];1.50 eq.,491 mg,2.13 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,570 µL,2.3 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,392 mg,2.27 mmol)在甲苯(8 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)且隨後用乙腈濕磨後,得到標題化合物(567 mg,83%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.39 (s, 9H), 2.37-2.39 (m, 4H), 2.49 (s, 3H), 2.70 (t, 2H), 2.82-2.92 (m, 4H), 3.27-3.30 (m, 4H), 4.18 (t, 2H), 4.26 (q, 2H), 7.54 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.32 min; MS (ESIpos): m/z = 459 [M+H]+
。
步驟 2 2-{2-[4-( 第三丁氧基羰基 ) 哌 𠯤 -1- 基 ] 乙基 }-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸氯化氫 (1/1)
根據GP D,在70℃下,使得自步驟1的2-{2-[4-(第三丁氧基羰基)哌𠯤-1-基]乙基}-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,560 mg,1.22 mmol)與氫氧化鋰水溶液(2 M;15 eq.,9.2 mL,18 mmol)在乙醇與THF之1:1混合物(18 mL)中反應隔夜。反應混合物用6 N HCl水溶液(pH 3-4)酸化且用EtOAc稀釋。分離各相,且用EtOAc萃取水相。合併之有機相用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到所需羧酸之HCl鹽(518 mg,86%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.41 (s, 9H), 2.84-2.93 (m, 4H), 3.05-3.20 (m, 4H), 3.50-3.57 (m, 4H), 4.01 (br. s., 2H), 4.53 (br. s., 2H), 7.61 (s, 1H), 10.35 (br. s., 1H), 12.85 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.62 min; MS (ESIpos): m/z = 431 [M-Cl-
]+
。
中間物 48: 步驟 1 2'-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8'- 甲基 -2',5'- 二氫螺 [ 環丁烷 -1',4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),在室溫下,使8'-甲基-1',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(根據中間物42步驟3製備;1.00 eq.,500 mg,1.75 mmol)與[(2S)-1,4-二㗁烷-2-基]甲醇(CAS編號[406913-93-7];1.10 eq.,227 mg,1.92 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,700 µL,2.8 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,481 mg,2.79 mmol)在甲苯(30 mL)反應2天,管柱層析(SiO2
,己烷/乙酸乙酯)後,得到標題化合物(291 mg,86%純度,34%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 2.06-2.13 (m, 6H), 2.49 (s, 3H), 3.05-3.06 (m, 2H), 3.28 (dd, 1H), 3.46 (dt, 1H), 3.56 (dt, 1H), 3.62-3.65 (m, 1H), 3.73-3.76 (m, 2H), 3.85-3.91 (m, 1H), 4.10-4.12 (m, 2H), 4.27 (q, 2H), 7.76 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.26 min; MS (ESIpos): m/z = 387 [M+H]+
。
步驟 2 2'-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8'- 甲基 -2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,使得自步驟1的2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-甲基-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(1.00 eq.,240 mg,621 µmol)與氫氧化鋰水溶液(2 M;15 eq.,4.7 mL,9.3 mmol)在乙醇與THF之1:1混合物(10 mL)中、在70℃下反應4小時且在室溫下反應3天。在減壓下濃縮反應混合物,濃縮物用2 N HCl水溶液(pH 3)酸化且將所形成之沈澱物濾出。固體用水及EtOAc洗滌且乾燥,得到所需羧酸(209 mg,60%純度,56%)。
UPLC-MS (方法1
): Rt
= 0.56 min; MS (ESIpos): m/z = 359 [M+H]+
。
中間物 49: 步驟 1 2-[(6- 氰基吡啶 -3- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),使8-甲基-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,245 mg,994 µmol)與5-(羥甲基)吡啶-2-甲腈(CAS編號[58553-48-3];1.50 eq.,200 mg,1.49 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,400 µL,1.6 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,274 mg,1.59 mmol)在甲苯(8 mL)中、在室溫下反應隔夜且在40℃下反應一天。添加額外量的三-正丁基膦(1.0 eq.,250 µL,1.0 mmol)及TMAD (1.0 eq.,170 mg,1.0 mmol)且在40℃下繼續攪拌10天,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(72 mg,18%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.47 (s, 3H), 2.86-2.94 (m, 4H), 4.26 (q, 2H), 5.48 (s, 2H), 7.71 (s, 1H), 7.82 (dd, 1H), 8.03 (dd, 1H), 8.86-8.87 (m, 1H)。
UPLC-MS (方法1
): Rt
= 1.20 min; MS (ESIpos): m/z = 363 [M+H]+
。
步驟 2 2-[(6- 羧基吡啶 -3- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,使得自步驟1的2-[(6-氰基吡啶-3-基)甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,72.0 mg,199 µmol)與氫氧化鋰水溶液(2 M;15 eq.,1.5 mL,3.0 mmol)在乙醇與THF之1:1混合物(2 mL)中、在70℃下反應隔夜且在室溫下反應2天。反應混合物用6 N HCl水溶液(pH 3)酸化且在減壓下濃縮,且所得粗二羧酸(268 mg)不經進一步純化即使用。
UPLC-MS (方法1
): Rt
= 0.18 min; MS (ESIpos): m/z = 354 [M+H]+
。
中間物 50: 步驟 1 4- 側氧基 -3-( 三氟甲基 )-4,7- 二氫 -5H
- 螺 [[1] 苯并呋喃 -6,1'- 環丙烷 ]-2- 羧酸乙酯
向螺[2.5]辛烷-5,7-二酮(CAS編號[893411-52-4];1.00 eq.,67.5 mmol,9.33 g)於甲苯(30 mL)中的溶液中添加2-氯-4,4,4-三氟-3-側氧基丁酸乙酯(參見中間物35,步驟1;2.2 eq,150 mmol,23 mL)且反應混合物隨後在100℃下攪拌43小時。將混合物傾入水中且用乙酸乙酯萃取兩次。合併之有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮。所得物質藉由管柱層析(Si-NH SiO2
,己烷/EtOAc)純化,得到標題化合物(3.2 g,15%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.48-0.51 (m, 2H), 0.54-0.57 (m, 2H), 1.30 (t, 3H), 2.45 (s, 2H), 2.96 (s, 2H), 4.36 (q, 2H)。
UPLC-MS (方法1
): Rt
= 1.22 min; MS (ESIpos): m/z = 303 [M+H]+
。
步驟 2 (5E/Z)-5-[( 二甲基胺基 ) 亞甲基 ]-4- 側氧基 -3-( 三氟甲基 )-4,7- 二氫 -5H
- 螺 [[1] 苯并呋喃 -6,1'- 環丙烷 ]-2- 羧酸乙酯
根據GP A (條件A),在100℃下,使得自步驟1的4-側氧基-3-(三氟甲基)-4,7-二氫-5H-
螺[[1]苯并呋喃-6,1'-環丙烷]-2-羧酸乙酯(1.00 eq.,1.53 g,5.06 mmol)與1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(布雷德奈克試劑,CAS編號[5815-08-7];1.2 eq.,1.1 mL,6.1 mmol)在甲苯(30 mL)中反應29小時。添加額外量的1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(1.5 eq.,1.4 mL,7.6 mmol)且在100℃下繼續攪拌另外19小時。在減壓下濃縮反應混合物且所得粗標題化合物不經進一步純化步驟即用於後續反應中。
UPLC-MS (方法1
): Rt
= 1.23/1.29 min; MS (ESIpos): m/z = 358 [M+H]+
。
步驟 3 8'-( 三氟甲基 )-1',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP B,在70℃下,使得自步驟2的粗(5E/Z)-5-[(二甲基胺基)亞甲基]-4-側氧基-3-(三氟甲基)-4,7-二氫-5H-
螺[[1]苯并呋喃-6,1'-環丙烷]-2-羧酸乙酯(1.00 eq.,1.81 g,5.06 mmol)與肼二鹽酸鹽(CAS編號[5341-61-7];2.0 eq.,1.1 g,10 mmol)在乙醇(13 mL)與水(2 mL)之混合物中反應1小時,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(192 mg,11%,歷經兩個步驟)。1
H NMR (500 MHz, DMSO-d6) δ [ppm]: 0.83-0.86 (m, 2H), 0.88-0.91 (m, 2H), 1.31 (t, 3H), 2.97 (s, 2H), 4.35 (q, 2H), 7.42 (s, 1H), 12.62 (s, 1H)。19
F NMR (470 MHz, DMSO-d6) δ [ppm]: -55.0 (s)。
UPLC-MS (方法1
): Rt
= 1.15 min; MS (ESIpos): m/z = 327 [M+H]+
。
步驟 4 2'-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),在室溫下,使得自步驟3的8'-(三氟甲基)-1',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(1.00 eq.,142 mg,435 µmol)與[(2S)-1,4-二㗁烷-2-基]甲醇(CAS編號[406913-93-7];1.1 eq.,77 mg,650 µmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,170 µL,700 µmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,120 mg,696 µmol)在甲苯(5 mL)中反應5天,管柱層析(SiO2
,己烷/乙酸乙酯)後,得到標題化合物(97 mg,52%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.79-0.91 (m, 4H), 1.31 (t, 3H), 2.92-3.02 (m, 2H), 3.25 (dd, 1H), 3.43 (dt, 1H), 3.53 (dt, 1H), 3.61-3.64 (m, 1H), 3.71-3.75 (m, 2H), 3.79-3.85 (m, 1H), 4.10-4.11 (m, 2H), 4.35 (q, 2H), 7.38 (s, 1H)。
UPLC-MS (方法1
): Rt
= 1.29 min; MS (ESIpos): m/z = 427 [M+H]+
。
步驟 5 2'-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,在70℃下,使得自步驟4的2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(1.0 eq.,97 mg,230 µmol)與氫氧化鋰水溶液(2 M;15 eq.,1.7 mL,3.4 mmol)在乙醇與THF之1:1混合物(4 mL)反應4小時。反應混合物用2 N HCl水溶液(pH 2)酸化且將所形成之沈澱物濾出。固體用水及EtOAc洗滌且乾燥,得到第一批所需羧酸(57 mg,60%)。合併之濾液及洗滌溶液用乙酸乙酯再萃取(兩次),合併之有機相經Na2
SO4
乾燥,過濾且在減壓下濃縮,得到第二批所需羧酸(34 mg,87%純度,33%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.79-0.92 (m, 4H), 2.90-2.99 (m, 2H), 3.25 (dd, 1H), 3.43 (dt, 1H), 3.53 (dt, 1H), 3.61-3.64 (m, 1H), 3.70-3.75 (m, 2H), 3.80-3.85 (m, 1H), 4.00-4.11 (m, 2H), 7.37 (s, 1H), 13.94 (br. s., 1H)。
UPLC-MS (方法1
): Rt
= 0.55 min; MS (ESIpos): m/z = 399 [M+H]+
。
中間物 51: 步驟 1 2-[(4- 氟吡啶 -2- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
將8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.0 eq,100 mg,406 µmol)、2-(氯甲基)-4-氟吡啶(1.5 eq,88.7 mg,609 µmol)及碳酸銫(CAS編號[534-17-8],3.0 eq,397 mg,1.22 mmol)添加至DMF (3.0 ml)中且在氮氣下、在室溫下攪拌24小時隔夜。再次添加2,2-(氯甲基)-4-氟吡啶(1.5 eq,88.7 mg,609 µmol)及碳酸銫(CAS編號[534-17-8],3.0 eq,397 mg,1.22 mmol)且在室溫下、在氮氣下攪拌隔夜。過濾反應混合物且用乙酸乙酯洗滌。蒸發濾液且藉由管柱層析(SiO2
,己烷/乙酸乙酯)純化,得到產物(53.1 mg,37%產率)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.27 - 1.31 (m, 3 H) 2.46 (s, 3 H) 2.85 - 2.94 (m, 4 H) 4.23 - 4.29 (m, 2 H) 5.40 (s, 2 H) 7.19 - 7.22 (m, 1H) 7.65 (s, 1 H) 7.71 (td, 1 H) 8.55 (d, 1 H)
LC-MS (方法1): Rt
= 1.22 min; MS (ESIpos): m/z = 356 [M+H]+
步驟 2 2-[(4- 氟吡啶 -2- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的2-[(4-氟吡啶-2-基)甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,53.0 mg,149 µmol)與氫氧化鋰水溶液(2 M;5 eq,370 µL,750 µmol)在乙醇與THF之1:1混合物(2.0 mL)中反應隔夜。用6 N鹽酸水溶液酸化(pH 2)後,進行蒸發。向殘餘物中添加DCM (20 ml)及i-PrOH (1 ml)且在室溫下攪拌。傾析DCM相且蒸發。接著添加THF (20 ml)且共蒸發。粗物質(75 mg)不經進一步純化步驟即用於後續反應中。
LC-MS (方法1): Rt
= 0.52 min; MS (ESIpos): m/z = 328 [M+H]+
中間物 52: 步驟 1 8- 甲基 -2-[( 噠 𠯤 -3- 基 ) 甲基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.0 eq,180 mg,731 µmol)及3-(氯甲基)噠𠯤氯化物(CAS編號[27349-66-2],1.5 eq,180 mg,1096 µmol)於DMF (24.0 ml)中的溶液在氮氣下用碳酸銫(CAS編號[534-17-8],20.0 eq.,4.76 g,14.6 mmol)處理且在80℃下攪拌隔夜。將固體過濾且用乙酸乙酯洗滌且蒸發。殘餘物藉由管柱層析(SiO2
,己烷/乙酸乙酯)純化,得到產物(87 mg,35%產率)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.27 - 1.31 (m, 3 H) 2.46 (s, 3 H) 2.85 - 2.95 (m, 4 H) 4.21 - 4.30 (m, 2 H) 5.63 (s, 2 H) 7.38 - 7.43 (m, 1 H), 7.67 - 7.71 (m, 1 H) 7.72 (s, 1 H) 9.13 - 9.22 (m, 1 H)
LC-MS (方法1): Rt
= 1.02 min; MS (ESIpos): m/z = 339 [M+H]+
步驟 2 8- 甲基 -2-[( 噠 𠯤 -3- 基 ) 甲基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(噠𠯤-3-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,87.0 mg,257 µmol)與氫氧化鋰水溶液(2 M;5 eq,640 µL,1.3 mmol)在乙醇與THF之1:1混合物(5.0 mL)中反應隔夜。用6 N鹽酸水溶液酸化(pH 2)後,將所得混合物蒸發。向殘餘物中添加DCM (50 ml)及i-PrOH (4 x 5 ml)且在室溫下攪拌30分鐘。添加己烷直至沈澱為止,過濾,用己烷/DCM (1:1)洗滌且蒸發。向殘餘物中添加DCM及鹽水(2 ml)且攪拌。分離各相,且蒸發DCM相,得到產物(35.0 mg,44%產率)。
LC-MS (方法2): Rt
= 0.72 min; MS (ESIpos): m/z = 311 [M+H]+
中間物 53: 步驟 1 2-[(6- 氯吡啶 -3- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,250 mg,1.05 mmol)與(6-氯吡啶-3-基)甲醇(1.5 eq.,218 mg,1.52 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,0.4 mL,1.6 mmol)及TMAD (CAS編號[10465-81-3];1.6 eq.,279 mg,1.6 mmol)在甲苯(5.8 ml)中反應隔夜。過濾反應混合物且用水萃取。用DCM萃取水相兩次。合併之有機層(DCM及甲苯相)經疏水性濾紙乾燥且蒸發,得到粗物質。接著藉由管柱層析(SiO2
,己烷/EtOAc)純化,得到標題化合物(140 mg,36%產率)。
LC-MS (方法1): Rt
= 1.28 min; MS (ESIpos): m/z = 372 [M+H]+
步驟 2 2-[(6- 乙基吡啶 -3- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
將得自步驟1的2-[(6-氯吡啶-3-基)甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,350 mg,941 µmol)溶解於二㗁烷(22 ml)中且用氮氣沖洗。首先添加1,1'-雙(二苯膦基)二茂鐵二氯鈀(II)(76.8 mg,94.1 µmol;CAS-RN:[72287-26-4])且接著逐滴添加含有二乙基鋅的己烷(CAS編號[557-20-0],4.5 eq,4.2 ml,1.0 M,4.2 mmol)。所得反應混合物在100℃下攪拌4小時。向反應混合物中添加水及DCM。分離各層,且水層用DCM及乙酸乙酯萃取。有機層藉由疏水性過濾乾燥且蒸發。粗物質藉由矽膠管柱層析(己烷/DCM)純化,得到標題化合物(187 mg,55%產率)。
LC-MS (方法1): Rt
= 1.26 min; MS (ESIpos): m/z = 366 [M+H]+
步驟 3 2-[(6- 乙基吡啶 -3- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟2的2-[(6-乙基吡啶-3-基)甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,94.0 mg,257 µmol)與氫氧化鋰水溶液(2 M;5 eq,640 µL,1.3 mmol)在乙醇與THF之1:1混合物(3.0 mL)中反應隔夜。用6 N鹽酸水溶液酸化(pH 2)後,將所得混合物蒸發。向殘餘物中添加DCM (30 ml)、水(20 ml)及i-PrOH (2 ml)。用DCM/i-PrOH (9:1)萃取水相。合併之有機相經疏水性濾紙乾燥且蒸發,得到作為粗物質的產物(55 mg,63%產率),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 0.56 min; MS (ESIpos): m/z = 338 [M+H]+
中間物 54: 步驟 1 8- 甲基 -2-[(1,3- 㗁唑 -2- 基 ) 甲基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
在室溫下,使8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,100 mg,406 µmol)與(1,3-㗁唑-2-基)甲醇(CAS編號[14774-37-9],1.5 eq.,60.4 mg,609 µmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,160 µL,650 µmol)及1,1'-(氮雜二羰基)二哌啶(CAS編號[10465-81-3];1.6 eq.,112 mg,650 µmol)在甲苯(3.0 ml)中反應隔夜。添加相同量之試劑且在室溫下再次攪拌隔夜。過濾反應混合物且用水萃取。水相用DCM再萃取。合併有機層且經疏水性濾紙乾燥且蒸發,得到粗物質。接著藉由管柱層析(NH,SiO2
,己烷/DCM)純化,得到標題化合物(60 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 1.10 min; MS (ESIpos): m/z = 328 [M+H]+
步驟 2 8- 甲基 -2-[(1,3- 㗁唑 -2- 基 ) 甲基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(1,3-㗁唑-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,60 mg,183 µmol)與氫氧化鋰水溶液(2 M;15 eq,1.4 mL,2.7 mmol)在乙醇與THF之1:1混合物(1.3 mL)中反應隔夜。用6 N鹽酸水溶液酸化(pH 2)後,將所得混合物蒸發。所得粗物質不經進一步純化步驟即用於後續反應(90 mg)。
LC-MS (方法1): Rt
= 0.47 min; MS (ESIpos): m/z = 300 [M+H]+
中間物 55: 步驟 1 8- 甲基 -2-[( 㗁烷 -4- 基 ) 甲基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
在室溫下,使8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;1.00 eq.,100 mg,406 µmol)與(㗁烷-4-基)甲醇(CAS編號[14774-37-9],1.5 eq.,70.8 mg,609 µmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,160 µL,650 µmol)及1,1'-(氮雜二羰基)二哌啶(CAS編號[10465-81-3];1.6 eq.,112 mg,650 µmol)在甲苯(3.0 ml)中反應隔夜。添加相同量之試劑且在室溫下再次攪拌隔夜。過濾反應混合物且用水萃取。用DCM萃取水相。合併之有機層經疏水性濾紙乾燥且蒸發,得到粗物質。接著藉由管柱層析(NH,SiO2
,己烷/DCM)純化,得到標題化合物(314 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 1.21 min; MS (ESIpos): m/z = 345 [M+H]+
步驟 2 8- 甲基 -2-[( 㗁烷 -4- 基 ) 甲基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-甲基-2-[(㗁烷-4-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,210 mg,610 µmol)與氫氧化鋰水溶液(2 M;15 eq,4.6 mL,9.1 mmol)在乙醇與THF之1:1混合物(4.3 mL)中反應隔夜。用6 N鹽酸水溶液酸化(pH 2)後,將所得混合物蒸發,且粗物質不經進一步純化步驟即用於後續反應(350 mg)。
LC-MS (方法1): Rt
= 0.53 min; MS (ESIpos): m/z = 317 [M+H]+
中間物 56: 步驟 1 8- 甲基 -2-{[(2R 及 2S)- 㗁烷 -2- 基 ] 甲基 }-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯 ( 外消旋物 )
根據GP C (條件A),將8-甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;100 mg,406 µmol)及[(2R及2S)-㗁烷-2-基]甲醇(外消旋物,70.8 mg,609 µmol,CAS-RN:[100-72-1])連同TMAD (112 mg,650 µmol,CAS編號[10465-78-8])一起懸浮於甲苯(3 mL)中。小心地添加三-正丁基膦(160 µl,650 µmol,CAS編號[998-40-3])且在室溫下攪拌反應混合物18小時。接著再添加TMAD (112 mg,650 µmol)及三-正丁基膦(160 µl,650 µmol)且繼續在室溫下攪拌18小時且在45℃下攪拌4小時。添加額外的三-正丁基膦(160 µl,650 µmol)之後,在室溫下延長攪拌3天。過濾之後,向濾液中添加水,且用二氯甲烷萃取水相。蒸發有機層之後,粗物質用己烷-二氯甲烷(1:0至3:2)溶離、藉由Biotage Isolera™層析(SNAP KP-NH-28 g)純化,得到標題化合物(100 mg,72%產率)。
LC-MS (方法1): Rt
= 1.33 min; MS (ESIpos): m/z = 345 [M+H]+
步驟 2
8-甲基-2-{[(2R及2S)-㗁烷-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-甲酸(外消旋物)
根據GP D,在70℃下,使得自步驟1的8-甲基-2-{[(2R及2S)-㗁烷-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(外消旋物,100 mg,290 µmol)與氫氧化鋰水溶液(15 eq,2.2 ml,2.0 M,4.4 mmol)在乙醇與THF之1:1混合物(4.1 mL)中反應隔夜。反應混合物用6 N HCl水溶液(pH 4)酸化且真空濃縮。所得粗產物(140 mg)不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 0.59 min; MS (ESIpos): m/z = 317 [M+H]+
中間物 57: 步驟 1 2-[(6- 甲基吡啶 -3- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使得自中間物35步驟4的8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,325 mg,1.08 mmol)與(6-甲基吡啶-3-基)甲醇(CAS編號[34107-46-5],1.7 eq.,227 mg,1.84 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,430 µL,1.7 mmol)及TMAD (CAS編號[10465-78-8];1.6 eq.,298 mg,1.73 mmol)在甲苯(10 ml)中反應隔夜。過濾反應混合物且用水萃取。水相用DCM再萃取。有機相經Na2
SO4
乾燥,過濾且在減壓下蒸發,得到粗物質。粗物質接著藉由管柱層析(NH,SiO2
,己烷/DCM)純化,得到標題產物(460.5 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 1.24 min; MS (ESIpos): m/z = 406 [M+H]+
步驟 2 2-[(6- 甲基吡啶 -3- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的2-[(6-甲基吡啶-3-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,460 mg,1.13 mmol)與氫氧化鋰水溶液(2 M;5 eq,2.8 mL,5.7 mmol)在乙醇與THF之1:1混合物(9.2 mL)中反應隔夜。用6 N鹽酸水溶液酸化(pH 2)後,將所得混合物蒸發。向粗物質中添加DCM (75 ml)及i-PrOH (2×0.5 ml)且在室溫下攪拌。傾析DCM相且將剩餘固體溶解於DCM (75 ml)及i-PrOH (5 ml)中且在室溫下攪拌且傾析所得DCM相且蒸發溶液,產生呈固體狀之產物(226 mg,53%產率)。
LC-MS (方法1): Rt
= 0.56 min; MS (ESIpos): m/z = 378 [M+H]+
中間物 58 : 步驟 1 8- 環丙基 -2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸甲酯
根據GP C (條件A),在室溫下,使得自中間物36步驟4的8-環丙基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸甲酯(1.0 eq.,250 mg,968 µmol)與[(2S)-1,4-二㗁烷-2-基]甲醇(CAS編號[406913-93-7],1.5 eq.,172 mg,1.45 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,380 µL,1.5 mmol)及TMAD (CAS編號[10465-78-8];1.6 eq.,267 mg,1.55 mmol)在甲苯(5.5 ml)中反應隔夜。過濾反應混合物且用水萃取。合併之水相用DCM再萃取。合併之有機層經Na2
SO4
乾燥,過濾且蒸發。粗物質藉由管柱層析(SiO2
,己烷/DCM)純化,得到標題化合物(350 mg)。
LC-MS (方法1): Rt
= 1.19 min; MS (ESIpos): m/z = 359 [M+H]+
步驟 2 8- 環丙基 -2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的8-環丙基-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸甲酯(1.0 eq,350 mg,977 µmol)與氫氧化鋰水溶液(2 M;5 eq,2.4 mL,4.9 mmol)在乙醇與THF之1:1混合物(5.0 mL)中反應隔夜。用6 N鹽酸水溶液酸化(pH 2)後,將所得混合物在減壓下蒸發。向殘餘物中添加DCM (40 ml)及i-PrOH (1 ml)且在室溫下攪拌30分鐘。分離有機相且在減壓下蒸發,得到標題化合物(400 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 0.51 min; MS (ESIpos): m/z = 345 [M+H]+
中間物 59 : 步驟 1 8'- 甲基 -2'-[( 吡啶 -4- 基 ) 甲基 ]-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),將8'-甲基-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(190 mg,664 µmol,中間物42 (步驟3))及(吡啶-4-基)甲醇(109 mg,995 µmol,CAS-RN:[586-95-8])連同TMAD (183 mg,1.06 mmol;CAS編號[10465-78-8])一起懸浮於甲苯(3.8 mL)中。小心地添加三-正丁基膦(260 µl,1.1 mmol,CAS編號[998-40-3])且反應混合物在室溫下攪拌18小時。向反應混合物中添加水且接著真空濃縮。殘餘物用3 ml乙腈稀釋且藉由製備型HPLC (方法A,梯度D)純化。合併產物溶離份且真空濃縮,得到18.0 mg (6%產率,79%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.01-2.15 (m, 6H), 2.46 (s, 3H), 3.01-3.15 (m, 2H), 4.26 (q, 2H), 5.39 (s, 2H), 7.13-7.16 (m, 2H), 7.97 (s, 1H), 8.52-8.55 (m, 2H)
LC-MS (方法1): Rt
= 1.27 min; MS (ESIpos): m/z = 378 [M+H]+
步驟 2 8'- 甲基 -2'-[( 吡啶 -4- 基 ) 甲基 ]-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,在室溫下,使得自步驟1的8'-甲基-2'-[(吡啶-4-基)甲基]-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(18.0 mg,79%純度,37.7 µmol)與氫氧化鋰水溶液(2190 µl,2.0 M,380 µmol)在THF (430 µl)中反應隔夜。在30℃下再攪拌2小時之後,反應混合物用2 N HCl水溶液(pH 2)酸化且真空濃縮且不進一步純化即用於下一步驟中(12 mg,91%產率)。
LC-MS (方法2): Rt
= 0.77 min; MS (ESIpos): m/z = 350 [M+H]+
。
中間物 60: 步驟 1 8'- 甲基 -2'-[(5- 甲基吡啶 -2- 基 ) 甲基 ]-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),將8'-甲基-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(190 mg,664 µmol,中間物42 (步驟3))及(5-甲基吡啶-2-基)甲醇(123 mg,995 µmol,CAS-RN:[22940-71-2])連同TMAD (183 mg,1.06 mmol;CAS編號[10465-78-8])一起懸浮於甲苯(3.8 mL)中。小心地添加三-正丁基膦(260 µl,1.1 mmol,CAS編號[998-40-3])且反應混合物在室溫下攪拌18小時。向反應混合物中添加水且接著真空濃縮。殘餘物用3 ml乙腈稀釋且藉由製備型HPLC (方法A,梯度E)純化。合併產物溶離份且真空濃縮,得到49.5 mg (16%產率,85%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.99-2.14 (m, 6H), 2.27 (s, 3H), 2.45 (s, 3H), 3.07 (s, 2H), 4.26 (q, 2H), 5.36 (s, 2H), 7.01 (d, 1H), 7.56-7.62 (m, 1H), 7.91 (s, 1H), 8.36-8.40 (m, 1H)。
LC-MS (方法1): Rt
= 1.37 min; MS (ESIpos): m/z = 392 [M+H]+
步驟 2 8'- 甲基 -2'-[(5- 甲基吡啶 -2- 基 ) 甲基 ]-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,在室溫下,使得自步驟1的8'-甲基-2'-[(5-甲基吡啶-2-基)甲基]-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(49.5 mg,85%純度,107 µmol)與氫氧化鋰水溶液(540 µl,2.0 M,1.1 mmol)在THF (1.2 ml)中反應隔夜。在30℃下再攪拌2小時之後,反應混合物用2 N HCl水溶液(pH 2)酸化且真空濃縮且不進一步純化即用於下一步驟中(35 mg,90%產率)。
LC-MS (方法2): Rt
= 1.03 min; MS (ESIpos): m/z = 364 [M+H]+
中間物 61 : 步驟 1 8- 甲基 -2-[2-( 吡啶 -2- 基 ) 乙基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件B),在25℃下,向碳酸銫(1.59 g,4.87 mmol;CAS-RN:[534-17-8])於N,N-
二甲基羧醯胺(6.0 mL)中的混合物中添加8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;400 mg,1.62 mmol)及甲烷磺酸2-(吡啶-2-基)乙酯(981 mg,4.87 mmol)。在60℃下攪拌混合物12小時。向混合物中再添加甲烷磺酸2-(吡啶-2-基)乙酯(981 mg,4.87 mmol)且接著在60℃下攪拌另外8小時。向混合物中添加水且接著用乙酸乙酯萃取。合併之有機層在減壓下濃縮,得到殘餘物。殘餘物藉由製備型HPLC純化[儀器:ACSWH-GX-C;管柱:Phenomenex Gemini-NX C18 75*30mm*3um;溶離劑A:水(0.225%甲酸/水),溶離劑B:乙腈;梯度:0-10 min 10-40% B;流量25 ml/min;溫度:室溫;偵測器:UV 220/254 nm.],隨後進行凍乾,得到250 mg (41%產率,94%純度)呈淡黃色固體狀之標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 2.78-2.84 (m, 2H), 2.86-2.91 (m, 2H), 3.25 (t, 2H), 4.26 (q, 2H), 4.45 (t, 2H), 7.21-7.28 (m, 2H), 7.45 (s, 1H), 7.69 (td, 1H), 8.52 (d, 1H)(甲基信號位於DMSO下方)。
LC-MS (方法B): Rt
= 0.68 min; MS (ESIpos): m/z = 352 [M+H]+
步驟 2 8- 甲基 -2-[2-( 吡啶 -2- 基 ) 乙基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在室溫下,使得自步驟1的8-甲基-2-[2-(吡啶-2-基)乙基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(150 mg,427 µmol)與氫氧化鋰水溶液(4.3 ml,1.0 M,4.3 mmol)在THF (750 µL)中反應隔夜。在30℃下再攪拌2小時之後,反應混合物用2 N HCl水溶液(pH 2)酸化且真空濃縮且將所得沈澱物濾出,得到123 mg (88%產率,99%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.33 (s, 3H), 2.75-2.93 (m, 4H), 3.50 (br t, 2H), 4.57 (t, 2H), 7.51 (s, 1H), 7.81 (br d, 2H), 8.36 (br t, 1H), 8.78 (dd, 1H), 12.76 (br s, 1H)。
LC-MS (方法1): Rt
= 0.55 min; MS (ESIpos): m/z = 324 [M+H]+
中間物 62: 步驟 1 三氟甲烷磺酸 2,2- 二氟 -2-( 吡啶 -2- 基 ) 乙酯
在0℃下,向2,2-二氟-2-(吡啶-2-基)乙-1-醇(300 mg,1.89 mmol;CAS-RN:[267875-65-0])於乙腈(5.0 mL)中的溶液中添加三氟甲烷磺酸酐(380 µl,2.3 mmol;CAS-RN:[358-23-6])及吡啶(240 µl,3.0 mmol)。在25℃下攪拌混合物1小時。向混合物中添加水且用乙酸乙酯萃取。合併之有機層經無水硫酸鈉乾燥,過濾且在減壓下濃縮,得到540 mg (粗)標題化合物。
LC-MS (方法C): Rt
= 0.85 min; MS (ESIpos): m/z = 292 [M+H]+
步驟 2 2-[2,2- 二氟 -2-( 吡啶 -2- 基 ) 乙基 ]-8- 甲基 -4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件B),在25℃下,向8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;300 mg,1.22 mmol)及三氟甲烷磺酸2,2-二氟-2-(吡啶-2-基)乙酯(532 mg,1.83 mmol,中間物62 (步驟1))於乙腈(5.0 mL)中的攪拌溶液中添加碳酸鉀(337 mg,2.44 mmol)。在50℃下攪拌混合物12小時。向混合物中添加水且接著用乙酸乙酯萃取水層。有機相用鹽水洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由急驟層析(矽膠,用石油醚-乙酸乙酯1:0至2:1溶離)純化,得到255 mg (50%產率,93%純度)呈黃色油狀的標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.39 (s, 3H), 2.80-2.94 (m, 4H), 4.26 (q, 2H), 5.02 (t, 2H), 7.52 (s, 1H), 7.59 (dd, 1H), 7.66 (d, 1H), 7.98 (td, 1H), 8.74 (d, 1H)。
LC-MS (方法B): Rt
= 0.85 min; MS (ESIpos): m/z = 388 [M+H]+
。
步驟 3 2-[2,2- 二氟 -2-( 吡啶 -2- 基 ) 乙基 ]-8- 甲基 -4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在室溫下,使得自步驟2的2-[2,2-二氟-2-(吡啶-2-基)乙基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(150 mg,387 µmol)與氫氧化鋰水溶液(3.9 ml,1.0 M,3.9 mmol)在THF (680 µL)中反應隔夜。在50℃下再攪拌4小時之後,反應混合物用2 N HCl水溶液(pH 2)酸化且將所得沈澱物濾出,得到116 mg (80%產率,96%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.37 (s, 3H), 2.79-2.92 (m, 4H), 5.01 (t, 2H), 7.51 (s, 1H), 7.59 (dd, 1H), 7.63-7.71 (m, 1H), 7.98 (td, 1H), 8.74 (d, 1H), 12.21-13.27 (m, 1H)。
LC-MS (方法1): Rt
= 0.59 min; MS (ESIpos): m/z = 360 [M+H]+
中間物 63: 步驟 1 8'- 甲基 -2'-[(6- 甲基吡啶 -3- 基 ) 甲基 ]-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),在室溫下,使得自中間物41步驟3的8'-甲基-1',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(1.00 eq.,150 mg,551 µmol)與(6-甲基吡啶-3-基)甲醇(CAS編號[34107-46-5],1.5 eq.,102 mg,826 µmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,220 µL,880 µmol)及TMAD (CAS編號[10465-78-8];1.6 eq.,152 mg,530 µmol)在甲苯(3.1 ml)中反應隔夜。過濾反應混合物且用水萃取。用DCM萃取水相。合併之有機層經Na2
SO4
乾燥,過濾且在減壓下蒸發。粗物質藉由管柱層析(SiO2
,己烷/EtOAc)純化,得到標題化合物(309 mg)。
LC-MS (方法1): Rt
= 1.24 min; MS (ESIpos): m/z = 378 [M+H]+
步驟 2 8'- 甲基 -2'-[(6- 甲基吡啶 -3- 基 ) 甲基 ]-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,在70℃下,使得自步驟1的8'-甲基-2'-[(6-甲基吡啶-3-基)甲基]-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(1.0 eq,308 mg,816 µmol)與氫氧化鋰水溶液(2 M;5 eq,2.0 mL,4.1 mmol)在乙醇與THF之1:1混合物(11.0 mL)反應隔夜。用6 N鹽酸水溶液酸化(pH 2)後,將所得混合物在減壓下蒸發。向殘餘物中添加DCM (50 ml)及i-PrOH (5×1 ml)且在室溫下攪拌。傾析DCM相且蒸發,得到標題化合物(306 mg),其不經進一步純化即直接用於下一步驟中。
LC-MS (方法1): Rt
= 0.56 min; MS (ESIpos): m/z = 350 [M+H]+
中間物 64: 2-[( 氮雜環丁 -3- 基 ) 甲基 ]-8- 甲基 -4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯氯化氫 (1/1)
2-{[1-(第三丁氧基羰基)氮雜環丁-3-基]甲基}-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(4.00 g,9.63 mmol,中間物32 (步驟1))於含4 M HCl之二㗁烷(20 mL)中的溶液在25℃下攪拌2小時。過濾混合物,收集固體。在減壓下乾燥固體,得到3.40 g (100%產率)呈淡棕色固體狀之標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.17 (t, 3H), 1.98 (s, 3H), 2.81-2.95 (m, 4H), 3.13-3.23 (m, 1H), 3.76-3.87 (m, 2H), 3.88-3.99 (m, 2H), 4.26 (q, 2H), 4.35 (d, 2H), 7.55 (s, 1H)
中間物 65: 步驟 1 2'-[(6- 甲基吡啶 -3- 基 ) 甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),將8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(150 mg,68%純度,313 µmol,中間物50 (步驟3))及(6-甲基吡啶-3-基)甲醇(46.2 mg,375 µmol)、CAS-RN:[34107-46-5])連同TMAD (86.1 mg,500 µmol;CAS編號[10465-78-8])一起懸浮於甲苯(2.8 mL)中。小心地添加三-正丁基膦(120 µl,500 µmol,CAS編號[998-40-3])且在室溫下攪拌反應混合物隔夜。進一步添加TMAD (53.8 mg,313 µmol)及三-正丁基膦(75 µl,313 µmol)且在室溫下繼續攪拌24小時。向反應混合物中添加水且接著真空濃縮。殘餘物用2 ml乙腈稀釋且藉由製備型HPLC (方法A,梯度D)純化。合併產物溶離份且真空濃縮,得到97.0 mg (60%產率,84%純度)標題化合物。1
H NMR (500 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 1.55-1.66 (m, 4H), 2.43 (s, 3H), 2.96 (s, 2H), 4.34 (q, 2H), 5.25 (s, 2H), 7.22 (d, 1H), 7.51 (s, 1H), 7.54 (dd 1H), 8.38 (d, 1H)。
LC-MS (方法1): Rt
= 1.32 min; MS (ESIpos): m/z = 432 [M+H]+
步驟 2 2'-[(6- 甲基吡啶 -3- 基 ) 甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,2'-[(6-甲基吡啶-3-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(97.0 mg,225 µmol,中間物65 (步驟1))溶解於四氫呋喃(400 µL)中且添加氫氧化鋰水溶液(2.2 ml,1.0 M,2.2 mmol;CAS-RN:[1310-65-2])。在室溫下攪拌反應混合物隔夜。用氯化氫水溶液(4 M)中和之後,繼續攪拌30分鐘。真空濃縮反應混合物,得到90.0 mg (81%產率,82%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.58-1.68 (m, 4H), 2.70 (s, 3H), 2.96 (s, 2H), 5.46 (s, 2H), 7.58 (s, 1H), 7.87 (d, 1H), 8.25 (dd, 1H), 8.72 (d, 1H)。
LC-MS (方法1): Rt
= 0.61 min; MS (ESIpos): m/z = 404 [M+H]+
中間物 66: 步驟 1 2'-[(5- 甲基吡啶 -2- 基 ) 甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),將8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(150 mg,68%純度,313 µmol,中間物50 (步驟3))及(5-甲基吡啶-2-基)甲醇(46.2 mg,375 µmol)、CAS-RN:[22940-71-2])連同TMAD (86.1 mg,500 µmol;CAS編號[10465-78-8])一起懸浮於甲苯(2.8 mL)中。小心地添加三-正丁基膦(120 µl,500 µmol,CAS編號[998-40-3])且在室溫下攪拌反應混合物隔夜。進一步添加TMAD (53.8 mg,313 µmol)及三-正丁基膦(75 µl,313 µmol)且在室溫下繼續攪拌24小時。向反應混合物中添加水且接著真空濃縮。殘餘物用2 ml乙腈稀釋且藉由製備型HPLC (方法A,梯度E)純化。合併產物溶離份且真空濃縮,得到63.9 mg (36%產率,75%純度)標題化合物。1
H NMR (500 MHz, DMSO-d6) δ [ppm]: 0.87-0.93 (m, 4H), 1.30 (t, 3H), 2.26 (s, 3H), 2.98 (s, 2H), 4.34 (q, 2H), 5.30 (s, 2H), 7.00 (d, 1H), 7.51 (s, 1H), 7.57-7.60 (m, 1H), 8.35-8.37 (m, 1H)
LC-MS (方法1): Rt
= 1.38 min; MS (ESIpos): m/z = 432 [M+H]+
步驟 2 2'-[(5- 甲基吡啶 -2- 基 ) 甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,將2'-[(5-甲基吡啶-2-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(63.9 mg,148 µmol,中間物66 (步驟1))溶解於四氫呋喃(260 µL)中且添加氫氧化鋰水溶液(1.5 mL,1.0 M,1.5 mmol;CAS-RN:[1310-65-2])。在室溫下攪拌反應混合物隔夜。用氯化氫水溶液(4 M)中和之後,繼續攪拌30分鐘。真空濃縮反應混合物,得到55.0 mg (86%產率,93%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.82-0.86 (m, 2H), 0.90-0.95 (m, 2H), 2.34 (s, 3H), 2.96 (s, 2H), 5.45 (s, 2H), 7.20 (d, 1H), 7.57 (s, 1H), 7.88 (br d, 1H), 8.52 (s, 1H)。
LC-MS (方法1): Rt
= 0.66 min; MS (ESIpos): m/z = 404 [M+H]+
中間物 67: 步驟 1 2'-[( 吡啶 -4- 基 ) 甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),將8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(95.0 mg,291 µmol,中間物50 (步驟3))及(吡啶-4-基)甲醇(41.3 mg,379 µmol,CAS-RN:[586-95-8])連同TMAD (80.2 mg,466 µmol;CAS編號[10465-78-8])一起懸浮於甲苯(1.5 mL)中。小心地添加三-正丁基膦(120 µl,470 µmol,CAS編號[998-40-3])且在室溫下攪拌反應混合物隔夜。向反應混合物中添加水且接著真空濃縮。殘餘物用2 ml乙腈稀釋且藉由製備型HPLC (方法A,梯度D)純化。合併產物溶離份且真空濃縮,得到40.0 mg (33%產率,99%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.83-0.87 (m, 2H), 0.91-0.95 (m, 2H), 1.30 (t, 3H), 3.00 (s, 2H), 4.34 (q, 2H), 5.34 (s, 2H), 7.11-7.14 (m, 2H), 7.56 (s, 1H), 8.50-8.54 (m, 2H)。
LC-MS (方法1): Rt
= 1.26 min; MS (ESIpos): m/z = 418 [M+H]+
步驟 2 2'-[( 吡啶 -4- 基 ) 甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,將2'-[(吡啶-4-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(40.0 mg,95.8 µmol,中間物67 (步驟1))溶解於四氫呋喃(170 µL)中且添加氫氧化鋰水溶液(960 µl,1.0 M,960 µmol;CAS-RN:[1310-65-2])。在室溫下攪拌反應混合物隔夜。用氯化氫水溶液(4 M)中和之後,濾出所得沈澱物,得到36.7 mg (96%產率,98%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.82-0.88 (m, 2H), 0.93-0.97 (m, 2H), 2.99 (s, 2H), 5.55 (s, 2H), 7.49 (d, 2H), 7.60 (s, 1H), 8.70-8.79 (m, 2H), 14.01 (br s, 1H)。
LC-MS (方法1): Rt
= 0.56 min; MS (ESIpos): m/z = 390 [M+H]+
中間物 68: 步驟 1 2'-[( 吡啶 -2- 基 ) 甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),將8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(95.0 mg,291 µmol,中間物50 (步驟3))及(吡啶-2-基)甲醇(41.3 mg,379 µmol,CAS-RN:[586-98-1])連同TMAD (80.2 mg,466 µmol;CAS編號[10465-78-8])一起懸浮於甲苯(1.5 mL)中。小心地添加三-正丁基膦(120 µl,470 µmol,CAS編號[998-40-3])且在室溫下攪拌反應混合物隔夜。向反應混合物中添加水且接著真空濃縮。殘餘物用2 ml乙腈稀釋且藉由製備型HPLC (方法A,梯度D)純化。合併產物溶離份且真空濃縮,得到47.0 mg (39%產率,99%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.82-0.88 (m, 2H), 0.89-0.95 (m, 2H), 1.30 (t, 3H), 2.99 (s, 2H), 4.34 (q, 2H), 5.36 (s, 2H), 7.07 (d, 1H), 7.31 (ddd, 1H), 7.55 (s, 1H), 7.77 (td, 1H), 8.50-8.56 (m, 1H)。
LC-MS (方法1): Rt
= 1.32 min; MS (ESIpos): m/z = 418 [M+H]+
步驟 2 2'-[( 吡啶 -2- 基 ) 甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,將2'-[(吡啶-2-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(47.3 mg,113 µmol,中間物68 (步驟1))溶解於四氫呋喃(200 µL)中且添加氫氧化鋰水溶液(1.1 mL,1.0 M,1.1 mmol;CAS-RN:[1310-65-2])。在室溫下攪拌反應混合物隔夜。用氯化氫水溶液(4 M)中和之後,濾出所得沈澱物,得到30.4 mg (67%產率,97%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.81-0.88 (m, 2H), 0.89-0.94 (m, 2H), 2.96 (s, 2H), 5.36 (s, 2H), 7.08 (d, 1H), 7.30-7.37 (m, 1H), 7.54 (s, 1H), 7.80 (td1H), 8.50-8.57 (m, 1H), 13.93 (br s, 1H)。
LC-MS (方法1): Rt
= 0.59 min; MS (ESIpos): m/z = 390 [M+H]+
中間物 69: 步驟 1 藉由光延反應 (Mitsunobu Reaction) : 2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
在室溫下,使8-(三氟甲基)-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧酸乙酯(中間物35 (步驟4),1.00 eq.,1.50 g,5.00 mmol)與[(2S)-1,4-二㗁烷-2-基]甲醇(1.2 eq.,708 mg,6.00 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,2.0 mL,8.0 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,1.38 g,7.99 mmol)在甲苯(15 mL)中反應隔夜。在攪拌的同時用乙酸乙酯及水稀釋反應混合物。用4 N HCl水溶液酸化至pH 2之後,分離各相。用乙酸乙酯萃取水相且合併之有機相經疏水性濾紙乾燥且濃縮。對所得粗物質進行管柱層析(SiO2
,己烷/乙酸乙酯),得到標題化合物(1.73 g,82%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.31 (t, 3H), 2.83 - 2.90 (m, 2H), 2.96 - 3.02 (m, 2H), 3.24 - 3.29 (m, 1H), 3.40 - 3.48 (m, 1H), 3.50 - 3.57 (m, 1H), 3.61 - 3.64 (m, 1H), 3.70-3.77 (m, 2H), 3.79-3.87 (m, 1H), 4.08 - 4.17 (m, 2H), 4.32 - 4-37 (m, 2H), 7.55 (s, 1H)
LC-MS (方法1): Rt
= 1.22 min; MS (ESIpos): m/z = 401 [M+H]+ 藉由與甲烷磺酸 [(2R)-1,4- 二㗁烷 -2- 基 ] 甲酯發生烷基化反應 :
在氬氣下,在室溫下,8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(中間物35 (步驟4),1.00 eq.,18.3 g,60.9 mmol)在預除氣的二㗁烷(730 mL)中用碳酸銫(3 eq.,59.5 g,182 mmol)處理。添加甲烷磺酸[(2R)-1,4-二㗁烷-2-基]甲酯(1.8 eq.,21.5 g,110 mmol)且所得反應混合物用氬氣除氣。在100℃下加熱混合物18小時。反應混合物再次用氬氣淨化且進一步在100℃下加熱24小時。將反應物冷卻至室溫且濾出固體且用乙酸乙酯(400 mL)洗滌。濾液用水洗滌,經疏水性濾紙乾燥且在減壓下蒸發,得到呈油狀之粗物質。藉由矽膠管柱層析(乙酸乙酯/己烷)純化,得到標題化合物(11.5 g,47%)。藉由與三氟甲烷磺酸 [(2R)-1,4- 二㗁烷 -2- 基 ] 甲酯發生烷基化反應 :
在室溫下將8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-甲酸酯(中間物35 (步驟4),1.00 eq.,35.3 g,117 mmol)懸浮於乙腈(400 mL)中。向反應混合物中添加碳酸銫(3 eq.,115 g,353 mmol),隨後緩慢添加三氟甲烷磺酸[(2R)-1,4-二㗁烷-2-基]甲酯(1,8 eq.,55.8 g,211 mmol)於乙腈(100 mL)中的溶液。在20分鐘之後,觀測到溫度稍微升高(20℃至29℃)。用冰浴將反應物冷卻至室溫。在室溫下攪拌反應混合物18小時。在攪拌且用冷水冷卻的同時,向反應混合物中添加乙酸乙酯(500 mL)、水(200 mL)及6 N HCl水溶液(60 mL)。分離各層。有機層用NH4
Cl飽和水溶液、NaCl飽和水溶液洗滌,且經Na2
SO4
乾燥且在40℃下、在減壓下蒸發。將粗物質溶解於CH2
Cl2
(400 mL)中且用水(150 mL)洗滌。有機層經Na2
SO4
乾燥且在40℃下、在減壓下蒸發。向所得粗物質中添加乙醇/己烷(1:1,100 mL)。將混合物在音波下短暫置放,其中形成固體。固體藉由抽吸收集且用乙醇/己烷(1:1,20 mL)洗滌。所收集之固體再次用乙醇/己烷(1:1,80 mL)處理且在音波下短暫置放且在室溫下攪拌30分鐘。固體藉由抽吸收集且用乙醇/己烷(1:1,20 mL)洗滌,得到呈淺米色固體狀之標題化合物(21 g,45%)。合併的濾液在減壓下蒸發且所得油狀物藉由矽膠管柱層析(乙醇/己烷)純化,隨後用乙醇/己烷(1:1,20 mL)濕磨,得到額外量之呈白色固體狀的標題化合物(10 g,21%)。
步驟 2 2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
在70℃下,使2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,1.96 g,4.90 mmol;中間物69步驟1)與氫氧化鋰水溶液(2 M;10 eq.,24.0 mL,49 mmol)在THF (56 mL)中反應2小時。反應混合物用2 N HCl水溶液酸化。所形成的沈澱物經由抽吸濾出且乾燥,得到所需羧酸(1.80 g,97%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.82 - 2.89 (m, 2H), 2.92 - 3.00 (m, 2H), 3.22 - 3.29 (m, 1H), 3.44 (td, 1H), 3.49 - 3.57 (m, 1H), 3.62 (br d, 1H), 3.69 - 3.78 (m, 2H), 3.78 - 3.87 (m, 1H), 4.04 - 4 .17 (m, 2H), 7.54 (s, 1H), 13.89 (br s, 1H)
LC-MS (方法2): Rt
= 0.87 min; MS (ESIpos): m/z = 373 [M+H]+
中間物 70: 步驟 1 2-{[(2R)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
在氬氣下,向8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(300 mg,999 µmol,中間物35 (步驟4))中添加碳酸銫(977 mg,3.00 mmol;CAS-RN:[534-17-8])於乙腈(2.0 ml)中的懸浮液。緩慢添加含有三氟甲烷磺酸[(2S)-1,4-二㗁烷-2-基]甲酯(474 mg,95%純度,1.80 mmol)的乙腈(2.0 ml),且在室溫下將反應混合物攪拌18小時。向反應混合物中添加乙酸乙酯(50 mL)、水(10 mL)及6 N HCl (0.5 mL)且分離所得相,且有機層用飽和氯化銨水溶液及鹽水洗滌,經無水硫酸鈉乾燥,經無水過濾器過濾且真空濃縮。粗物質藉由Biotage Isolera™層析(SNAP KP-Sil-25 g,用己烷-乙酸乙酯1:0至3:2溶離)純化,得到148 mg (37%產率,90%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29-1.33 (m, 3H), 2.84 - 2.88 (m, 2H), 2.97 - 3.02 (m, 2H), 3.24 - 3.29 (m, 1H), 3.41 - 3.47 (m, 1H), 3.50 - 3.56 (m, 1H), 3.61 - 3.64 (m, 1H), 3.71-3.77 (m, 2H), 3.79-3.85 (m, 1H), 4.06 - 4.17 (m, 2H), 4.32 - 4-37 (m, 2H), 7.55 (s, 1H)
LC-MS (方法1): Rt
= 1.22 min; MS (ESIpos): m/z = 401 [M+H]+
步驟 2 2-{[(2R)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,將2-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(148 mg,370 µmol,中間物70 (步驟1))溶解於四氫呋喃(590 µL)與甲醇(590 µL)之混合物中且添加氫氧化鋰水溶液(370 µl,2.0 M,740 µmol;CAS-RN:[1310-65-2])。在室溫下攪拌反應混合物隔夜。用氯化氫水溶液(6 M)中和至pH 4之後,在減壓下、在60℃下蒸發反應混合物。將殘餘物懸浮於二氯甲烷中且添加鹽水,且攪拌30分鐘之後,有機層經無水硫酸鈉乾燥,過濾且真空濃縮,得到標題化合物(151 mg),其不經進一步純化即直接用於下一步驟中。
LC-MS (方法1): Rt
= 0.54 min; MS (ESIpos): m/z = 373 [M+H]+
中間物 71: 步驟 1 2-[( 㗁烷 -4- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使得自中間物35步驟4的8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,200 mg,666 µmol)與(㗁烷-4-基)甲醇(CAS編號[14774-37-9],1.5 eq.,116 mg,999 µmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,260 µL,1.1 mmol)及TMAD (CAS編號[10465-78-8];1.6 eq.,184 mg,1.07 mmol)在甲苯(15.0 ml)中反應隔夜。過濾反應混合物且用水萃取。合併之水相用DCM萃取,且合併DCM及甲苯相,用Na2
SO4
乾燥,過濾且在減壓下蒸發。粗物質藉由管柱層析(SiO2
,己烷/DCM)純化,得到標題化合物(270 mg,>100%產率)。
LC-MS (方法1): Rt
= 1.30 min; MS (ESIpos): m/z = 399 [M+H]+
步驟 2 2-[( 㗁烷 -4- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的2-[(㗁烷-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,270 mg,678 µmol)與氫氧化鋰水溶液(2 M;5 eq,1.7 mL,3.4 mmol)在乙醇與THF之1:1混合物(3.5 mL)中反應隔夜。用6 N鹽酸水溶液酸化(pH 2)後,將所得混合物在減壓下蒸發。向殘餘物中添加DCM (40 ml)及i-PrOH (1 ml)且在室溫下攪拌30分鐘。分離各相,且在減壓下蒸發有機層,得到呈粗物質形式之標題化合物(360 mg),其不經進一步純化即直接用於下一步驟中。
LC-MS (方法1): Rt
= 0.58 min; MS (ESIpos): m/z = 371 [M+H]+
中間物 72: 步驟 1 3-( 二氟甲基 )-4- 側氧基 -4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧酸乙酯
在室溫下,向環己烷-1,3-二酮(1.0 eq.,14.0 g,125 mmol)於甲苯(60 ml)中的溶液中添加2-氯-4,4-二氟-3-側氧基丁酸乙酯(1.2 eq.,30.1 g,150 mmol)。在110℃下攪拌反應混合物16小時。濃縮混合物,得到殘餘物。其接著用乙酸乙酯稀釋且用飽和碳酸氫鈉、鹽水洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。粗殘餘物藉由急驟管柱層析(600-700目,石油醚:乙酸乙酯=1:0至4:1)純化,得到呈黃色固體狀的標題化合物(5.80 g,18%產率)。1
H NMR (400 MHz, DMSO-d6): δ [ppm]: 7.40 (t, 1H), 4.36 (q, 2H), 2.99 (t, 2H), 2.52-2.51 (m, 2H), 2.14-2.10 (m, 2H), 1.31 (t, 3H)。
LC-MS (方法E): Rt
= 0.90 min; MS (ESIpos): m/z = 259 [M+H]+
步驟 2 3-( 二氟甲基 )-5-( 羥基亞甲基 )-4- 側氧基 -4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧酸乙酯
在0℃下,向氫化鈉氫化物(CAS編號[7646-69-7];2.0 eq.,1.8 g,60%純度,44.9 mmol)於甲苯(30 ml)中的溶液中添加得自步驟1的3-(二氟甲基)-4-側氧基-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(1.0 eq.,5.80 g,22.5 mmol)及羧酸乙酯(CAS編號[109-94-4];3.0 eq.,67 mmol,5.4 mL)於甲苯(30 ml)中的溶液。在80℃下攪拌混合物12小時。混合物用乙酸乙酯稀釋且接著在0℃下,用乙醇/水(80 ml,v/v=1:1)淬滅。接著用氯化氫水溶液(2.0 M)將混合物pH調節至約6。接著用乙酸乙酯萃取混合物且合併之有機層在減壓下濃縮,得到殘餘物(6.60 g,73%純度,75%產率)。殘餘物不經進一步純化即直接使用。
LC-MS (方法C
): Rt
= 0.77 min; MS (ESIpos): m/z = 287.1 [M+H]+
。
步驟 3 8-( 二氟甲基 )-4,5- 二氫 -1H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
在25℃下,向3-(二氟甲基)-5-(羥基亞甲基)-4-側氧基-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(1.0 eq.,200 mg,0.70 mmol)於乙醇(2 mL)中的混合物中添加肼二鹽酸鹽(CAS編號[5341-61-7],1.5 eq.,110 mg,1.05 mmol)於水(0.2 mL)中的溶液。在25℃下攪拌混合物2小時。在0℃下將反應混合物添加至飽和碳酸氫鈉溶液中且接著用乙酸乙酯萃取。合併之有機層在減壓下濃縮,得到殘餘物。殘餘物藉由急驟管柱層析(石油醚:乙酸乙酯=1:0至3:1)純化,得到呈黃色固體狀之標題化合物(60 mg,30%產率)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.56 (s, 1H), 7.46 (t, 1H), 4.34 (q, 2H), 3.00-2.96 (m, 2H), 2.91-2.87 (m, 2H), 1.32 (t, 3H).LC-MS (方法C
): Rt
= 0.75 min; MS (ESIpos): m/z = 283.1 [M+H]+
。
步驟 4 8-( 二氟甲基 )-2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
將得自步驟3的8-(二氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,500 mg,1.77 mmol)及碳酸銫(CAS編號[534-17-8],3.0 eq,1.73 g,5.31 mmol)添加至1,4-二㗁烷(20 ml)中。接著向混合物中添加甲烷磺酸[(2R)-1,4-二㗁烷-2-基]甲酯(1.8 eq.,626 mg,3.19 mmol)且在100℃下攪拌48小時。將混合物冷卻至室溫之後,添加乙酸乙酯及水,且分離各相。乾燥乙酸乙酯相且在減壓下蒸發,產生呈棕色油狀之標題化合物(659 mg,97%產率),其不經進一步純化即直接用於下一步驟中。
LC-MS (方法1): Rt
= 1.15 min; MS (ESIpos): m/z = 383 [M+H]+
步驟 5 8-( 二氟甲基 )-2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
在70℃下,使得自步驟4的8-(二氟甲基)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,659 mg,1.72 mmol)與氫氧化鋰水溶液(2 M;5.0 eq.,4.3 mL,8.6 mmol)在THF (13 mL)及乙醇(13 mL)中反應18小時。反應混合物用DCM稀釋且用6 N HCl水溶液(pH 4)酸化且所得混合物在減壓下蒸發。向殘餘物中添加DCM (100 ml)及鹽水(1 mL)且所得混合物在室溫下攪拌1小時。接著添加i-PrOH (0.2 mL)且在室溫下進一步攪拌1小時。過濾DCM相,將固體與DCM (40 ml)一起攪拌。合併之DCM相在減壓下蒸發,得到標題化合物(462 mg,76%產率)。
LC-MS (方法1): Rt
= 0.51 min; MS (ESIpos): m/z = 355 [M+H]+
中間物 73: 步驟 1 (6±)-3,6- 二甲基 -4- 側氧基 -4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧酸乙酯
將5-甲基環己烷-1,3-二酮(CAS編號[4341-24-6],1.0 eq,10.0 g,79.3 mmol)及2-氯-3-側氧基丁酸乙酯(CAS編號[609 -15-4],1.0 eq,11 ml,79 mmol)溶解於DCM (181 mL)及三乙胺(CAS編號[121-44-8],1.2 eq,13 ml,95 mmol)中。反應混合物在50℃下攪拌18小時且在室溫下攪拌48小時。添加額外的2-氯-3-側氧基丁酸乙酯(CAS編號[609 -15-4],0.5 eq,5.5 ml,39.5 mmol)及三乙胺(CAS編號[121-44-8],0.6 eq,6.5 ml,47.5 mmol)且在50℃下攪拌反應混合物18小時。接著添加2 N HCl且所得反應混合物在室溫下進一步攪拌18小時(pH 2)。向反應混合物中添加水且分離所得相。有機層藉由疏水性過濾乾燥且在減壓下蒸發。粗物質藉由管柱層析(SiO2
,己烷/乙酸乙酯)純化,得到標題化合物(9.58 g,51%產率)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.06 - 1.11 (m, 3 H) 1.27 - 1.31 (m, 3 H) 2.28 - 2.42 (m, 3 H) 2.45 (s, 3 H) 2.60 - 2.68 (m, 1 H) 2.94 - 3.06 (m, 1 H) 4.28 (d, 2 H)
LC-MS (方法1): Rt
= 1.15 min; MS (ESIpos): m/z = 237 [M+H]+
步驟 2 (6±)-5-[( 二甲基胺基 ) 亞甲基 ]-3,6- 二甲基 -4- 側氧基 -4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧酸乙酯
根據GP A (條件A),在100℃下,使得自步驟1的(6±)-3,6-二甲基-4-側氧基-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(1.0 eq,9.5 g,40.2 mmol)與1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(布雷德奈克試劑,CAS編號[5815-08-7];1.20 eq.,10.0 ml,48.0 mmol)在甲苯(100 mL)中反應隔夜。在減壓下濃縮反應混合物且所得粗標題化合物(11.7 g)不經進一步純化步驟即用於後續反應中。
LC-MS (方法1): Rt
= 1.12 min and 1.17 min; MS (ESIpos): m/z = 292 [M+H]+
步驟 3 (4±)-4,8- 二甲基 -4,5- 二氫 -1H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP B,在70℃下,使得自步驟2的(6±)-5-[(二甲基胺基)亞甲基]-3,6-二甲基-4-側氧基-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(1.0 eq.,11.8 g,40.4 mmol)與水合肼1:1 (CAS編號[7803-57-8],5.0 eq.,9.8 mL,200 mmol)在乙醇(200 mL)中反應5小時。接著在減壓下蒸發反應混合物。向殘餘物中添加水及乙酸乙酯。分離各相,且用乙酸乙酯萃取水相兩次。合併之有機相藉由疏水性過濾乾燥且蒸發,管柱層析(SiO2
,己烷/乙酸乙酯)後,得到呈固體狀之標題化合物(2.38 g,23%產率)。
LC-MS (方法1): Rt
= 1.07 min; MS (ESIpos): m/z = 261 [M+H]+
步驟 4 (4±)-4,8- 二甲基 -2-[( 吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件B),在75℃下,使得自步驟3的(4±)-4,8-二甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,500 mg,1.92 mmol)與2-(溴甲基)吡啶(1.5 eq.,496 mg,2.88 mmol)、碳酸鉀(CAS編號[584-08-7],15 eq.,3.98 g,28.8 mmol)及DMAP (CAS編號[1122-58-3],0.05 eq,11.7 mg,96.0 µmol)在乙酸乙酯(2.4 mL)中反應隔夜。向反應混合物中添加額外量的2-(溴甲基)吡啶(1.5 eq.,496 mg,2.88 mmol)、碳酸鉀(CAS編號[584-08-7],15 eq.,3.98 g,28.8 mmol)及DMAP (CAS編號[1122-58-3],0.05 eq,11.7 mg,96.0 µmol)且在75℃下攪拌隔夜。過濾固體且用乙酸乙酯洗滌。乙酸乙酯相用水萃取,分離,經疏水性濾紙乾燥且蒸發,管柱層析(SiO2
,己烷/乙酸乙酯)後,得到標題化合物(154 mg,23%產率)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.27 - 1.31 (m, 6 H) 2.46 (s, 3 H) 2.54 - 2.61 (m, 1 H) 3.00 - 3.06 (m, 1 H) 3.14 - 3.22 (m, 1 H) 4.23 - 4.29 (m, 2 H) 5.40 (s, 2 H) 7.07 - 7.09 (m, 1 H) 7.29 - 7.33 (m, 1 H) 7.70 - 7.71 (m, 1 H) 7.76 - 7.80 (m, 1H) 8.51 - 8.65 (m, 1 H)
LC-MS (方法1): Rt
= 1.21 min; MS (ESIpos): m/z = 352 [M+H]+
步驟 5 (4±)-4,8- 二甲基 -2-[( 吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟4的(4±)-4,8-二甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,154 mg,438 µmol)與氫氧化鋰水溶液(2 M;5 eq,1.1 mL,2.2 mmol)在乙醇與THF之1:1混合物(3.4 mL)中反應隔夜。用6 N鹽酸水溶液酸化(pH 2)後,將所得混合物在減壓下蒸發。向殘餘物中添加DCM (50 ml)及i-PrOH (4 x 5 ml)且進一步在室溫下攪拌30分鐘。接著添加己烷直至發生沈澱。固體藉由抽吸收集且用DCM/己烷(1:1)洗滌,得到呈固體狀之標題化合物(128 mg,90%產率)。
LC-MS (方法1): Rt
= 0.55 min; MS (ESIpos): m/z = 324 [M+H]+
中間物 74: 步驟 1 (4±)-2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-4,8- 二甲基 -4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使得自中間物73步驟3的(4±)-4,8-二甲基-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,500 mg,1.92 mmol)與[(2S)-1,4-二㗁烷-2-基]甲醇(CAS編號[34107-46-5],1.5 eq.,340 mg,2.88 mmol)、三-正丁基膦(1.6 eq.,621 mg,3.07 mmol)及TMAD (CAS編號[10465-78-8];1.6 eq.,529 mg,3.07 mmol)在甲苯(17 ml)中反應隔夜。過濾反應混合物且用水萃取。用DCM萃取水相兩次。DCM及甲苯相經Na2
SO4
乾燥,過濾且在減壓下蒸發,得到粗物質,其藉由管柱層析(NH,SiO2
,己烷/DCM)純化,得到混雜有n-Bu3
P=O的標題化合物(473 mg)。
LC-MS (方法1): Rt
= 1.21 min; MS (ESIpos): m/z = 361 [M+H]+
步驟 2 (4±)-2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-4,8- 二甲基 -4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的(4±)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,8-二甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,473 mg,656 µmol)與氫氧化鋰水溶液(2 M;5 eq,1.6 mL,3.3 mmol)在乙醇與THF之1:1混合物(5.0 mL)中反應隔夜。用6 N鹽酸水溶液酸化(pH 2)後,將所得混合物在減壓下蒸發。向殘餘物中添加DCM (50 ml)及i-PrOH (12 ml)且繼續攪拌,同時緩慢添加己烷直至發生沈澱。濾出固體且用己烷/DCM (1:1)洗滌。在減壓下蒸發濾液,得到呈粗物質形式之標題化合物(227 mg),其不經進一步純化即直接用於下一步驟中。
LC-MS (方法1): Rt
= 0.52 min; MS (ESIpos): m/z = 333 [M+H]+
中間物 75: 步驟 1 (6±)-6- 甲基 -4- 側氧基 -3-( 三氟甲基 )-4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧酸乙酯 ( 外消旋物 )
將5-甲基環己烷-1,3-二酮(市售,CAS編號[4341-24-6],1.0 eq,12.0 g,95.3 mmol)懸浮於甲苯(4.0 ml)中,且接著添加2-氯-4,4,4-三氟-3-側氧基丁酸乙酯(CAS編號[363-58-6],1.2 eq,18 ml,114 mmol)且所得混合物在100℃下、在氮氣下攪拌18小時直至TLC及/或LCMS指示起始物質完全消耗為止。反應混合物在減壓下濃縮且藉由管柱層析(SiO2
,DCM/己烷)純化,得到呈固體狀之標題化合物(4.3 g,16%產率)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.09 (d, 3 H) 1.30 (t, 3 H) 2.32 - 2.42 (m, 2 H) 2.51 - 2.55 (m, 1 H) 2.69 - 2.76 (m, 1 H) 3.07 - 3.12 (m, 1 H) 4.33 - 4.39 (m, 2 H)
LC-MS (方法1): Rt
= 1.21 min; MS (ESIpos): m/z = 291 [M+H]+
步驟 2 (6±)-5-( 羥基亞甲基 )-6- 甲基 -4- 側氧基 -3-( 三氟甲基 )-4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧酸乙酯 ( 外消旋物 )
根據GP A (條件B),在0℃下,用氫化鈉(CAS編號[7646-69-7];3.00 eq.,103 mmol,413 mg,60%純度)處理羧酸乙酯(CAS編號[109-94-4];6.0 eq.,21 mmol,1.7 mL)於甲苯(15 mL)中的溶液。攪拌0.5小時之後,向上述混合物中添加得自步驟1的(6±)-6-甲基-4-側氧基-3-(三氟甲基)-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(1.00 eq.,3.45 mmol,1.00 g)於甲苯(5 mL)中的溶液。在室溫下攪拌反應混合物18小時。反應混合物用乙酸乙酯(50 ml)稀釋且用飽和氯化銨溶液(5×2 ml,pH~5)淬滅。分離各相,且有機相用半飽和鹽水(10 ml)洗滌。合併之水相用乙酸乙酯(50 ml)萃取。合併之有機相經無水濾紙乾燥且濃縮。殘餘物接著用己烷(25 ml)濕磨,在乾燥之後,得到呈粗油狀之標題化合物(1.2 g),其不經進一步純化即直接用於下一步驟中。
LC-MS (方法1): Rt
= 0.65 min; MS (ESIneg): m/z = 317 [M-H]-
步驟 3 (4±)-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -1H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯 ( 外消旋物 )
根據GP B,在60℃下,使乙醇(8.5 ml)中之得自步驟2的(6±)-5-(羥基亞甲基)-6-甲基-4-側氧基-3-(三氟甲基)-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(1.0 eq.,1.20 g,2.04 mmol,54%純度)與水(2.6 mL)中的肼二鹽酸鹽(CAS編號[5341-61-7],2.0 eq.,427 mg,4.07 mmol)反應2小時。將反應混合物冷卻至室溫之後,將其用DCM (150 ml)稀釋且與2 N HCl (10 mL,pH 5)溶液一起攪拌。分離各相,且用鹽水(25 ml)洗滌DCM相。合併之水相用DCM (50 ml)萃取。合併之DCM相經疏水性濾紙乾燥且在減壓下蒸發。殘餘物藉由管柱層析(SiO2
,己烷/EtOAc)純化,得到標題化合物(250 mg,39%產率)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.26 - 1.33 (m, 6 H) 2.60 - 2.68 (m, 1 H) 3.07 - 3.13 (m, 1H) 3.17 - 3.20 (m, 1 H) 4.44 (q, 2 H) 7.63 (s, 1 H) 12.68 (br. s, 1 H)
LC-MS (方法1): Rt
= 1.15 min; MS (ESIpos): m/z = 315 [M+H]+
步驟 4 (4±)-4- 甲基 -2-[( 吡啶 -2- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件B),在室溫下,在氮氣氛圍下,用碳酸鉀(CAS編號[1122-58-7],15 eq,1.65 g,11.9 mmol)及N,N-
二甲基吡啶-4-胺(DMAP,CAS編號[1122-58-3];0.05 eq,4.86 mg,39.8 µmol)處理得自中間物75步驟3的(4±)-4-甲基-8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,250 mg,796 µmol)及2-(溴甲基)吡啶(CAS編號[55401-97-3],1.5 eq.,205 mg,1.19 mmol)於乙酸乙酯(11 ml)中的溶液。在70℃下攪拌反應混合物隔夜。將反應混合物冷卻至室溫,過濾且在減壓下濃縮且對殘餘物進行管柱層析(SiO2
,己烷/EtOAc),得到標題化合物(179 mg,56%產率)。
LC-MS (方法1): Rt
= 1.30 min; MS (ESIpos): m/z = 406 [M+H]+
步驟 5 (4±)-4- 甲基 -2-[( 吡啶 -2- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟4的(4±)-4-甲基-2-[(吡啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,179 mg,442 µmol)與氫氧化鋰水溶液(2 M;5 eq,1.1 mL,2.2 mmol)在乙醇與THF之1:1混合物(5.2 mL)中反應隔夜。用4 N鹽酸水溶液酸化(pH 2)後,將所得混合物在減壓下蒸發。向殘餘物中添加DCM (30 ml)、水(20 ml)及i-PrOH (2 ml)。在層分離期間,形成固體。藉由抽吸收集固體,得到呈米色固體狀之標題化合物(54.0 mg,32%產率)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (d, 3 H) 2.60 - 2.67 (m, 1 H) 3.05 - 3.11 (m, 1 H) 3.17 - 3.23 (m, 1 H) 5.40 (s, 2 H) 7.08 - 7.10 (m, 1 H) 7.29 - 7.33 (m, 1 H) 7.74 (s, 1H) 7.76 - 7.80 (m, 1 H) 8.53 - 8.55 (m, 1 H) 13.73 - 14.10 (br. s, 1 H)
LC-MS (方法1): Rt
= 0.56 min; MS (ESIpos): m/z = 378 [M+H]+
中間物 76: 步驟 1 (4±)-4- 甲基 -2-[(5- 甲基吡啶 -2- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在氮氣下,向甲苯(2.7 mL)中添加得自中間物75步驟3的(4±)-4-甲基-8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(150 mg,477 µmol)、(5-甲基吡啶-2-基)甲醇(88.2 mg,716 µmol)及TMAD (131 mg,764 µmol;CAS-RN:[10465-78-8])。向經攪拌的反應混合物中小心地添加三丁基膦(190 µl,760 mol;CAS-RN: [998-40-3])且在室溫下攪拌17小時。過濾反應混合物且用水萃取。水層用二氯甲烷萃取且合併之有機層(甲苯及DCM相)經無水過濾器過濾且真空濃縮。粗物質藉由Biotage Isolera™層析(SNAP KP-Sil-10 g,用己烷-乙酸乙酯1:0至2:1溶離)純化,得到標題化合物(236 mg)。該物質不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 1.37 min; MS (ESIpos): m/z = 420 [M+H]+
步驟 2 (4±)-4- 甲基 -2-[(5- 甲基吡啶 -2- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,將(4±)-4-甲基-2-[(5-甲基吡啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(200 mg,477 µmol,中間物76 (步驟1))溶解於四氫呋喃(5.6 mL)與乙醇(5.6 mL)之混合物中且添加氫氧化鋰水溶液(1.2 ml,2.0 M,2.4 mmol;CAS-RN:[1310-65-2])。在70℃下攪拌反應混合物隔夜。用氯化氫水溶液(4 M)中和至pH3之後,將所得混合物真空濃縮。向殘餘物中添加乙酸乙酯及水。用乙酸乙酯萃取水層。合併之有機層藉由疏水性過濾乾燥且蒸發,得到呈粗物質形式之標題化合物(233 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 0.61 min; MS (ESIpos): m/z = 392 [M+H]+
中間物 77: 步驟 1 (4±)-4- 甲基 -2-[(6- 甲基吡啶 -3- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使得自中間物75步驟3的(4±)-4-甲基-8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,150 mg,477 µmol)與(6-甲基吡啶-3-基)甲醇(1.5 eq.,88.2 mg,716 µmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,190 µL,760 µmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,131 mg,764 µmol)在甲苯(2.7 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(145 mg,71%)。
LC-MS (方法1): Rt
= 1.30 min; MS (ESIpos): m/z = 420 [M+H]+
步驟 2 (4±)-4- 甲基 -2-[(6- 甲基吡啶 -3- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的(4±)-4-甲基-2-[(6-甲基吡啶-3-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,145 mg,346 µmol)與氫氧化鋰水溶液(2 M;5 eq.,860 µL,1.7 mmol)在乙醇與THF之1:1混合物(4.1 mL)中反應隔夜。用4 N鹽酸水溶液酸化(pH 3)後,將所得混合物在減壓下蒸發。向殘餘物中添加DCM/i-PrOH 9:1及水。水相用DCM/i-PrOH 9:1萃取兩次且合併之有機相藉由疏水性過濾乾燥且蒸發,得到呈米色固體狀之標題化合物(117 mg,86%產率)。粗物質不經進一步純化即用於下一步驟。
LC-MS (方法1): Rt
= 0.58 min; MS (ESIpos): m/z = 392 [M+H]+
中間物 78: 步驟 1 (4±)-2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使得自中間物75步驟3的(4±)-4-甲基-8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,750 mg,2.39 mmol)與[(2S)-1,4-二㗁烷-2-基]甲醇(1.5 eq.,423 mg,3.58 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,950 µL,3.8 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,657 mg,3.82 mmol)在甲苯(14.0 ml)中反應隔夜。過濾反應混合物且用水萃取。用DCM萃取水相兩次。DCM及甲苯相經Na2
SO4
乾燥,過濾且蒸發,在反覆的管柱層析(SiO2
,己烷/DCM,且接著用己烷/EtOAc)後,得到標題化合物(528 mg,54%產率)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.26 - 1.28 (m, 3 H) 1.29 - 1.33 (m, 3 H) 2.61 - 2.65 (m, 1 H) 3.06 - 3.12 (m, 1H) 3.15 - 3.21 (m, 1H) 3.24 - 3.30 (m, 1 H) 3.40 - 3.57 (m, 2 H) 3.62 - 3.64 (m, 1 H) 3.72 - 3.78 (m, 2 H) 3.79 - 3.88 (m, 1 H) 4.07 - 4.15 (m, 2 H) 4.32 - 4.37 (m, 2 H) 7.55 (s, 1 H)。
LC-MS (方法1): Rt
= 1.27 min; MS (ESIpos): m/z = 415 [M+H]+
步驟 2 (4±)-2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
(4±)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(527 mg,1.27 mmol,中間物78 (步驟1))溶解於四氫呋喃(9.8 mL)與乙醇(9.8 mL)之混合物中,且添加氫氧化鋰水溶液(3.2 ml,2.0 M,6.36 mmol;CAS-RN:[1310-65-2])。在70℃下攪拌反應混合物隔夜。反應混合物用DCM稀釋且用氯化氫水溶液(6 M)中和至pH 2,且真空濃縮所得混合物。向殘餘物中添加DCM (50 mL)及i-PrOH (1 mL)且所得混合物在室溫下攪拌隔夜。濾出固體,用額外的DCM洗滌且合併之濾液在減壓下蒸發,得到粗泡沫狀之標題化合物(445 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 0.55 min; MS (ESIpos): m/z = 387 [M+H]+
中間物 79: 步驟 1-a (4R 或 4S)-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -1H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯 ( 對映異構體 1 , 立體化學未定義 )
中間物75步驟3之對映異構體(2.5 g,7.96 mmol)係藉由製備型SFC方法(儀器:Sepiatec:Prep SFC100;管柱:Chiralpak IC 5µ 250x30mm;溶離劑A:CO2;溶離劑B:2-丙醇 + 0.4 vol%二乙胺;等度:10%B;流量:100 ml/min;溫度:40℃;BPR:150巴;UV:280 nm)且藉由SFC方法(儀器:Agilent:1260,Aurora SFC模組;管柱:Chiralpak IC 5µ 100x4.6mm;溶離劑A:CO2;溶離劑B:2-丙醇 + 0.4 vol%二乙胺;等度:15%B;流量:4 ml/min;溫度:37.5℃;BPR:100巴;UV:280 nm)加以分析表徵。使用二氯甲烷/甲醇/DMSO 1:1:0.2製備注射溶液(總共15 mL)
對映異構體1:
Rt
= 1.05 min, 912 mg, 36%產率
[α]D 20
= -29.2°(c=1, DMSO)1
H NMR與中間物75步驟3相同。
步驟 1-b (4S 或 4R)-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -1H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯 ( 對映異構體 2 , 立體化學未定義 )
中間物75步驟3之對映異構體(2.5 g,7.96 mmol)係藉由製備型SFC方法(儀器:Sepiatec:Prep SFC100;管柱:Chiralpak IC 5µ 250x30mm;溶離劑A:CO2;溶離劑B:2-丙醇 + 0.4 vol%二乙胺;等度:10%B;流量:100 ml/min;溫度:40℃;BPR:150巴;UV:280 nm)且藉由SFC方法(儀器:Agilent:1260,Aurora SFC模組;管柱:Chiralpak IC 5µ 100x4.6mm;溶離劑A:CO2;溶離劑B:2-丙醇 + 0.4 vol%二乙胺;等度:15%B;流量:4 ml/min;溫度:37.5℃;BPR:100巴;UV:280 nm)加以分析表徵。使用二氯甲烷/甲醇/DMSO 1:1:0.2製備注射溶液(總共15 mL)
對映異構體2:
Rt
= 1.32 min, 880 mg, 35%產率
[α]D 20
= +51.9°(c=1, DMSO)1
H NMR與中間物75步驟3相同。
步驟 2 (4R 或 4S)-2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
將得自步驟1-a的(4R或4S)-4-甲基-8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(200 mg,636 µmol)(對映異構體1)及碳酸銫(622 mg,1.91 mmol;CAS-RN:[534-17-8])添加至1,4-二㗁烷(8 ml)中。接著向混合物中添加甲烷磺酸[(2R)-1,4-二㗁烷-2-基]甲酯(225 mg,1.15 mmol)且在100℃下攪拌18小時。冷卻混合物至室溫後,濾出固體且用EtOAc洗滌。在減壓下蒸發濾液。殘餘物用DCM及水稀釋。蒸發有機相,產生呈油狀之標題化合物(251 mg)。粗物質不經進一步純化即直接用於下一步驟。
LC-MS (方法1): Rt
= 1.29 min; MS (ESIpos): m/z = 415 [M+H]+
步驟 3 (4R 或 4S)-2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,將(4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(251 mg,606 µmol,中間物79 (步驟2))溶解於四氫呋喃(4.7 mL)與乙醇(4.7 mL)之混合物中且添加氫氧化鋰水溶液(1.5 ml,2.0 M,3.0 mmol;CAS-RN:[1310-65-2])。在70℃下攪拌反應混合物隔夜。用氯化氫水溶液(6 M)中和至pH4之後,將所得混合物真空濃縮。用二氯甲烷(50 mL)及鹽水(0.2 mL)處理殘餘物且在室溫下攪拌所得混合物30分鐘。濾出固體且在減壓下蒸發濾液,得到呈泡沫狀之標題化合物(200 mg,85%產率)。粗物質不經進一步純化即用於下一步驟。
LC-MS (方法1): Rt
= 0.6 min; MS (ESIpos): m/z = 387 [M+H]+
中間物 80: 步驟 1 (4R 或 4S)-4- 甲基 -2-[( 㗁烷 -4- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
在室溫下,將得自中間物79步驟1-a的(4R或4S)-4-甲基-8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(410 mg,1.3 mmol)(對映異構體1)懸浮於乙腈(2.9 mL)中。向反應混合物中添加碳酸銫(3 eq.,1.27 g,3.9 mol),接著添加乙腈(1 mL)中之三氟甲烷磺酸四氫哌喃-4-基甲酯(1.8 eq.,0.58 g,2.35 mmol)且在室溫下攪拌所得反應混合物1小時。向反應混合物中添加EtOAc及H2
O且短暫攪拌。分離各層,且有機層經疏水性濾紙乾燥且在減壓下蒸發。粗殘餘物用EtOAc:己烷(1:3,2 mL)處理且在音波下短暫置放。在室溫下攪拌30分鐘之後,濾出白色固體且在減壓下蒸發濾液,得到呈棕色油狀的標題化合物(479 mg,89%產率),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 1.27 min; MS (ESIpos): m/z = 413 [M+H]+
步驟 2 (4R 或 4S)-4- 甲基 -2-[( 㗁烷 -4- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
在室溫下,使得自步驟1的(4R或4S)-4-甲基-2-[(㗁烷-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,479 mg,1.16 mmol)與氫氧化鋰水溶液(2 M;2.0 eq.,1.2 mL,2.3 mmol)在THF (1.2 mL)及甲醇(1.2 ml)中反應18小時。反應混合物用6 N HCl水溶液酸化至pH 2且所得混合物在減壓下蒸發。與THF共蒸餾之後,獲得標題化合物(800 mg),其作為粗物質用於下一步驟中。
LC-MS (方法2): Rt
= 0.68 min; MS (ESIpos): m/z = 385 [M+H]+
中間物 81: 步驟 1 (6±)-3- 甲基 -4- 側氧基 -6-( 三氟甲基 )-4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧酸乙酯
將5-(三氟甲基)環己烷-1,3-二酮(CAS編號[124612-15-3],1.0 eq,10.0 g,55.5 mmol)、2-氯-3-側氧基丁酸乙酯(CAS編號[609 -15-4],1.0 eq,7.7 ml,56 mmol)及三乙胺(CAS編號[121-44-8],1.2 eq,9.3 ml,67 mmol)添加至1,2-二氯乙烷(127 ml)中且在50℃下攪拌18小時。向混合物中添加6 N HCl水溶液(16 ml)且所得混合物在室溫下攪拌2小時(pH 5至pH 2)。分離各相且用水洗滌有機相,經疏水性濾紙乾燥且蒸發。粗物質藉由管柱層析(SiO2
,己烷/乙酸乙酯)純化,得到標題化合物與中間產物(結構未顯示)之混合物。將此混合物溶解於1,2-二氯乙烷中且用6 N HCl水溶液處理且在室溫下攪拌18小時。分離各相,且有機相藉由疏水性過濾乾燥且蒸發。粗物質通過管柱層析(SiO2
,己烷/乙酸乙酯)純化,產生標題化合物(5.6 g,35%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3 H) 2.46 (s, 3 H) 2.59 - 2.74 (m, 2 H) 3.07 - 3.14 (m, 1 H) 3.22 - 3.29 (m, 1 H) 3.44 - 3.53 (m, 1 H) 4.30 (q, 2 H)
LC-MS (方法1): Rt
= 1.21 min; MS (ESIpos): m/z = 291 [M+H]+
步驟 2 (6±)-5-[( 二甲基胺基 ) 亞甲基 ]-3- 甲基 -4- 側氧基 -6-( 三氟甲基 )-4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧酸乙酯
根據GP A (條件A),在100℃下,使得自步驟1的(6±)-3-甲基-4-側氧基-6-(三氟甲基)-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(1.0 eq,5.38 g,18.5 mmol)與1-第三丁氧基-N,N,N'
,N'
-四甲基甲二胺(布雷德奈克試劑,CAS編號[5815-08-7];1.20 eq.,4.6 ml,22.0 mmol)在甲苯(48 mL)中反應9小時。在減壓下濃縮反應混合物,得到呈粗物質形式之標題化合物(6.50 g),其不經進一步純化步驟即用於後續反應中。
LC-MS (方法1): Rt
= 1.18 min; MS (ESIpos): m/z = 346 [M+H]+
步驟 3 (4±)-8- 甲基 -4-( 三氟甲基 )-4,5- 二氫 -1H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP B,在70℃下,使得自步驟2的(6±)-5-[(二甲基胺基)亞甲基]-3-甲基-4-側氧基-6-(三氟甲基)-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(1.0 eq.,6.50 g,18.8 mmol)與水合肼1:1 (5.0 eq.,4.6 mL,94 mmol)在乙醇(100 mL)中反應5小時。在減壓下蒸發混合物。向殘餘物中添加乙酸乙酯且用水洗滌。接著蒸發有機相,且藉由管柱層析(SiO2
,己烷/乙酸乙酯)純化殘餘物,得到標題化合物(840 mg,14%產率)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3 H) 2.52 (s, 3 H) 3.08 - 3.14 (m, 1 H) 3.30 - 3.37 (m, 1 H) 4.20 - 4.30 (m, 3 H) 7.76 (s, 1 H) 12.89 (br.s, 1 H)
LC-MS (方法1): Rt
= 1.11 min; MS (ESIpos): m/z = 315 [M+H]+
步驟 4 (4±)-2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8- 甲基 -4-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使得自步驟3的(4±)-8-甲基-4-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,500 mg,1.59 mmol)與[(2S)-1,4-二㗁烷-2-基]甲醇(CAS編號[406913-93-7],1.5 eq.,282 mg,2.39 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,630 µL,2.55 mmol)及TMAD (CAS編號[10465-78-8];1.6 eq.,438 mg,2.55 mmol)在甲苯(50 ml)中反應隔夜。過濾反應混合物且用水萃取。合併之水相用DCM萃取兩次。合併DCM及甲苯相,經Na2
SO4
乾燥,過濾且蒸發,得到粗物質,接著藉由管柱層析(Si-NH,己烷/DCM)純化,得到標題化合物(559 mg,85%產率)。該物質不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 1.25 min; MS (ESIpos): m/z = 415 [M+H]+
步驟 5 (4±)-2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8- 甲基 -4-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟4的(4±)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-甲基-4-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,559 mg,1.35 mmol)與氫氧化鋰水溶液(2 M;5 eq,3.4 mL,6.7 mmol)在乙醇(5 mL)與THF (5.0 mL)之1:1混合物中反應隔夜。用6 N鹽酸水溶液酸化(pH 2)後,將所得混合物蒸發。將所得粗物質溶解於乙酸乙酯(20 ml)中且添加鹽水(0.5 ml)且短暫攪拌混合物。分離各相,且有機相再次與鹽水一起攪拌。蒸發有機相,產生呈粗黃色固體狀之標題化合物(430 mg),其不經進一步純化即直接用於下一步驟中。
LC-MS (方法1): Rt
= 0.56 min; MS (ESIpos): m/z = 387 [M+H]+
中間物 82: 步驟 1 6,6- 二甲基 -4- 側氧基 -3-( 三氟甲基 )-4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧酸乙酯
在室溫下,向5,5-二甲基環己烷-1,3-二酮(20.0 g,143 mmol)於甲苯(20 ml)中的混合物中添加2-氯-4,4,4-三氟-3-側氧基丁酸乙酯(37.4 g,171 mmol)。在氮氣保護下,在100℃下攪拌混合物12小時。向混合物中添加水,接著用乙酸乙酯萃取。有機相用飽和碳酸氫鈉溶液、鹽水洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。藉由管柱層析(1000目,石油醚:乙酸乙酯=1:0,接著50:1)純化殘餘物,得到呈黃色油狀之粗6,6-二甲基-4-側氧基-3-(三氟甲基)-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯。粗產物藉由逆相管柱層析(儀器:Agela-OCTOPUS;管柱:Welch Ultimate XB_C18 150*400 mm 20/40 µm;溶離劑A:水,溶離劑B:乙腈;梯度:0-105 min 10-58% B;流量150 ml/min;溫度:室溫;偵測器:UV 220/254 nm)進一步純化,得到呈黃色油狀的6,6-二甲基-4-側氧基-3-(三氟甲基)-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(11.6 g,27%產率)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 4.36 (q, 2H), 2.94 (s, 2H), 2.49 (s, 2H), 1.30 (t, 3H), 1.07 (s, 6H)。
步驟 2 5-( 羥基亞甲基 )-6,6- 二甲基 -4- 側氧基 -3-( 三氟甲基 )-4,5,6,7- 四氫 -1- 苯并呋喃 -2- 羧酸乙酯
在室溫下,向氫化鈉(341 mg,60%純度,8.55 mmol)於甲苯(10 ml)中的溶液中添加得自步驟1的6,6-二甲基-4-側氧基-3-(三氟甲基)-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(1 g,3.29 mmol)及羧酸乙酯(0.82 ml,10.2 mmol)於甲苯(5 ml)中的溶液。將乙醇(0.19 ml)添加至以上混合物中且在30℃下攪拌混合物2小時。反應混合物藉由2 N鹽酸(pH~3)淬滅且用乙酸乙酯萃取。有機相用鹽水洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到呈棕色油狀之5-(羥基亞甲基)-6,6-二甲基-4-側氧基-3-(三氟甲基)-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(1.09 g,粗物質),其不經進一步純化即直接用於下一後續步驟中。
步驟 3 4,4- 二甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
在25℃下,向得自步驟2的5-(羥基亞甲基)-6,6-二甲基-4-側氧基-3-(三氟甲基)-4,5,6,7-四氫-1-苯并呋喃-2-羧酸乙酯(8.50 g,25.6 mmol)於乙醇(80 ml)中的混合物中添加肼二鹽酸鹽(4.03 g,38.4 mmol)於水(15 ml)中的溶液。在40℃下攪拌混合物2小時。濃縮混合物,得到殘餘物。殘餘物用飽和碳酸鈉調節至pH~9且用乙酸乙酯萃取。有機相用鹽水洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由管柱層析(100-200目,石油醚:乙酸乙酯=20:1,接著1:1)純化,得到呈白色固體狀的4,4-二甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(540 mg,92%純度,6%產率)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.69 (s, 1H), 7.63 (s, 1H), 4.36 (q, 2H), 2.84 (s, 2H), 1.30 (t, 3H), 1.22 (s, 6H)。
LC-MS (方法B
): Rt
= 0.802 min; MS (ESIpos): m/z = 329.0 [M+H]+
。
步驟 4 2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-4,4- 二甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
將得自步驟3的4,4-二甲基-8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(250 mg,762 µmol)及碳酸銫(744 mg,2.29 mmol;CAS-RN:[534-17-8])添加至1,4-二㗁烷(10 ml)中。接著向混合物中添加甲烷磺酸[(2R)-1,4-二㗁烷-2-基]甲酯(269 mg,1.37 mmol)且在100℃下攪拌48小時。將混合物冷卻至室溫之後,用乙酸乙酯及水稀釋反應混合物。將乙酸乙酯相乾燥且蒸發,產生呈棕色油狀之粗標題化合物(356 mg)。
LC-MS (方法1): Rt
= 1.33 min; MS (ESIpos): m/z = 429 [M+H]+
步驟 5 2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-4,4- 二甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,將2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,4-二甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(350 mg,817 µmol,中間物82 (步驟4))溶解於四氫呋喃(6.3 mL)與乙醇(6.3 mL)之混合物中且添加氫氧化鋰水溶液(2.0 ml,2.0 M,4.1 mmol;CAS-RN:[1310-65-2])。在70℃下攪拌反應混合物隔夜。將反應混合物冷卻至室溫且用二氯甲烷稀釋。用氯化氫水溶液(6 M)中和至pH 4之後,將所得混合物真空濃縮。殘餘物用二氯甲烷(50 mL)及鹽水(0.5 mL)處理且在室溫下攪拌1小時。接著將2-丙醇(0.5 mL)添加至攪拌混合物中且進一步在室溫下攪拌1小時。分離各相,且過濾有機相,且在減壓下蒸發濾液,得到呈淺黃色泡沫狀之粗標題化合物(287 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 0.59 min; MS (ESIpos): m/z = 401 [M+H]+
中間物 83: 步驟 1 4- 側氧基 -3-( 三氟甲基 )-4,7- 二氫 -5H- 螺 [[1] 苯并呋喃 -6,1'- 環丁烷 ]-2- 羧酸乙酯
將螺[3.5]壬烷-6,8-二酮(1.00 g,6.57 mmol;CAS-RN:[221342-48-9])、2-氯-4,4,4-三氟-3-側氧基丁酸乙酯(1.0 ml,6.6 mmol;CAS-RN:[363-58-6])及三乙胺(1.4 ml,9.9 mmol;CAS-RN:[121-44-8])溶解於二㗁烷(2.0 mL)中且在100℃下攪拌隔夜。真空濃縮反應混合物且粗物質藉由Biotage Isolera™層析(SNAP KP-Sil-10 g,用己烷-乙酸乙酯1:0至4:1溶離)純化,得到270 mg (12%產率,93%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 1.80-1.96 (m, 6H), 2.71 (s, 2H), 3.18 (s, 2H), 4.36 (q, 2H)。
LC-MS (方法1): Rt
= 1.32 min; MS (ESIpos): m/z = 317 [M+H]+
步驟 2 5-( 羥基亞甲基 )-4- 側氧基 -3-( 三氟甲基 )-4,7- 二氫 -5H- 螺 [[1] 苯并呋喃 -6,1'- 環丁烷 ]-2- 羧酸乙酯
根據GP A (條件B),在0℃下,向氫化鈉(439 mg,60%純度,11.0 mmol;CAS-RN:[7646-69-7])於甲苯(7.3 mL)中之懸浮液中添加4-側氧基-3-(三氟甲基)-4,7-二氫-5H-螺[[1]苯并呋喃-6,1'-環丁烷]-2-羧酸乙酯(1.16 g,3.65 mmol,中間物83 (步驟1))。在室溫下攪拌30分鐘之後,將混合物再冷卻至0℃且添加羧酸乙酯(1.5 ml,18 mmol;CAS-RN:[109-94-4])。添加乙酸乙酯(150 mL)及4 N HCl (40 mL,逐份)之前,在室溫下攪拌反應混合物隔夜。在相分離之後,有機層用鹽水洗滌,經無水過濾器過濾且真空濃縮,得到1.43 g (粗)標題化合物。
LC-MS (方法2): Rt
= 1.45 min; MS (ESIpos): m/z = 345 [M+H]+
步驟 3 8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
在25℃下,向5-(羥基亞甲基)-4-側氧基-3-(三氟甲基)-4,7-二氫-5H-螺[[1]苯并呋喃-6,1'-環丁烷]-2-羧酸乙酯(1.40 g,4.07 mmol,中間物83 (步驟2))於乙醇(12 mL)中的混合物中添加肼單鹽酸鹽(362 mg,5.29 mmol;CAS編號[2644 -70-4])於水(5.0 ml)中的溶液。在70℃下攪拌混合物1小時。在0℃下將混合物添加至飽和碳酸氫鈉溶液中且接著用二氯甲烷萃取。合併之有機層用鹽水洗滌,過濾且在減壓下濃縮,得到1.11 g (71%產率,89%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.31 (t, 3H), 1.92-2.06 (m, 2H), 2.08-2.16 (m, 4H), 3.14 (s, 2H), 4.34 (q, 2H), 7.86 (d, 1H), 12.71 (s, 1H)。
LC-MS (方法1): Rt
= 1.27 min; MS (ESIpos): m/z = 341 [M+H]+
。
步驟 4 2'-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),將8'-(三氟甲基)-1',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(250 mg,735 µmol,中間物83 (步驟3))及[(2S)-1,4-二㗁烷-2-基]甲醇(130 mg,1.10 mmol,CAS-RN:[406913-93-7])連同TMAD (202 mg,1.18 mmol;CAS編號[10465-78-8])一起懸浮於甲苯(4.2 mL)中。小心地添加三-正丁基膦(290 µl,1.2 mmol,CAS編號[998-40-3])且在室溫下攪拌反應混合物隔夜。向反應混合物中添加水且接著真空濃縮。殘餘物用1 ml乙腈稀釋且藉由製備型HPLC (方法A,梯度E)純化。合併產物溶離份且真空濃縮,得到60.0 mg (17%產率,90%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.31 (t, 3H), 2.00-2.17 (m, 6H), 3.15 (s, 2H), 3.28 (dd, 1H), 3.41-3.49 (m, 1H), 3.51-3.59 (m, 1H), 3.63 (br d, 1H), 3.75 (dt, 2H), 3.82-3.91 (m, 1H), 4.09-4.15 (m, 2H), 4.34 (q, 2H), 7.82 (s, 1H)。
LC-MS (方法1): Rt
= 1.38 min; MS (ESIpos): m/z = 441 [M+H]+
步驟 5 2'-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,在室溫下,使2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-(三氟甲基)-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(60.0 mg,136 µmol,中間物83 (步驟4))與氫氧化鋰水溶液(680 µl,2.0 M,1.4 mmol)在THF (1.6 ml)中反應隔夜。進一步在30℃下攪拌1小時之後,反應混合物用2 N HCl水溶液(pH 2)酸化且攪拌30分鐘。沈澱物藉由過濾收集且不經進一步純化即用於下一步驟中,57.2 mg (91%純度,93%產率)。1
H NMR (500 MHz, DMSO-d6) δ [ppm]: 2.01-2.17 (m, 6H), 3.12 (s, 2H), 3.28 (dd, 1H), 3.45 (td, 1H), 3.55 (td, 1H), 3.58-3.61 (m, 1H), 3.63 (br d, 1H), 3.75 (dt, 2H), 3.83-3.90 (m, 1H), 4.08-4.16 (m, 2H), 7.81 (s, 1H), 13.58-14.28 (m, 1H)。
LC-MS (方法2): Rt
= 1.04 min; MS (ESIpos): m/z = 413 [M+H]+
中間物 84: 步驟 1 2'-[( 吡啶 -2- 基 ) 甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),將8'-(三氟甲基)-1',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(70.0 mg,206 µmol,中間物83 (步驟3))及(吡啶-2-基)甲醇(33.7 mg,309 µmol;CAS-RN:[586-98-1])連同TMAD (56.7 mg,329 µmol;CAS編號[10465-78-8])一起懸浮於甲苯(1.2 mL)中。小心地添加三-正丁基膦(82 µl,330 µmol,CAS編號[998-40-3])且在室溫下攪拌反應混合物隔夜。向反應混合物中添加水且接著真空濃縮。粗物質藉由Biotage Isolera™層析(SNAP KP-Sil-10 g,用己烷-乙酸乙酯1:0至1:1溶離)純化,得到52.6 mg (59%產率,99%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.31 (t, 3H), 1.87-1.98 (m, 1H), 2.03-2.18 (m, 5H), 3.17 (s, 2H), 4.34 (q, 2H), 5.42 (s, 2H), 7.09 (d, 1H), 7.32 (ddd, 1H), 7.79 (td, 1H), 7.99 (s, 1H), 8.49-8.58 (m, 1H)。
LC-MS (方法1): Rt
= 1.39 min; MS (ESIpos): m/z = 432 [M+H]+
步驟 2 2'-[( 吡啶 -2- 基 ) 甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,在50℃下,使2'-[(吡啶-2-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(58.0 mg,134 µmol,中間物84 (步驟1))與氫氧化鋰水溶液(670 µl,2.0 M,1.3 mmol;CAS-RN:[1310-65-2])在THF (1.5 ml)中反應1小時。反應混合物用4 N HCl水溶液(pH 2)酸化且攪拌30分鐘。沈澱物藉由過濾收集且不經進一步純化即用於下一步驟中(50.2 mg,92%純度,99%產率)。1
H NMR (500 MHz, DMSO-d6) δ [ppm]: 1.89-1.98 (m, 1H), 2.01-2.18 (m, 5H), 3.14 (s, 2H), 5.47 (s, 2H), 7.16 (d, 1H), 7.42 (dd, 1H), 7.86-7.93 (m, 1H), 8.00 (s, 1H), 8.61 (d, 1H), 13.97 (br s, 1H)。
LC-MS (方法1): Rt
= 0.66 min; MS (ESIpos): m/z = 404 [M+H]+
中間物 85: 步驟 1 2'-[(5- 甲基吡啶 -2- 基 ) 甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),將8'-(三氟甲基)-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(250 mg,735 µmol,中間物83 (步驟3))及(5-甲基吡啶-2-基)甲醇(136 mg,1.10 mmol,CAS-RN:[22940-71-2])連同TMAD (202 mg,1.18 mmol;CAS編號[10465-78-8])一起懸浮於甲苯(4.2 mL)中。小心地添加三-正丁基膦(290 µl,1.2 mmol,CAS編號[998-40-3])且在室溫下攪拌反應混合物隔夜。向反應混合物中添加水且接著真空濃縮。殘餘物用1 ml乙腈稀釋且藉由製備型HPLC (方法A,梯度E)純化。合併產物溶離份且真空濃縮,得到102.0 mg (20%產率,65%純度)標題化合物。
LC-MS (方法1): Rt
= 1.41 min; MS (ESIpos): m/z = 446 [M+H]+
步驟 2 2'-[(5- 甲基吡啶 -2- 基 ) 甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,在室溫下,使2'-[(5-甲基吡啶-2-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(102 mg,229 µmol,中間物85 (步驟1))與氫氧化鋰水溶液(1.1 ml,2.0 M,2.3 mmol;CAS-RN:[1310-65-2])在THF (2.6 ml)中反應隔夜。反應混合物用4 N HCl水溶液(pH 2)酸化且攪拌30分鐘。真空濃縮之後,產物不經進一步純化即用於下一步驟中(90.0 mg,75%純度,80%產率)。
LC-MS (方法2): Rt
= 1.06 min; MS (ESIpos): m/z = 418 [M+H]+
中間物 86: 步驟 1 2'-[( 吡啶 -4- 基 ) 甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧酸乙酯
根據GP C (條件A),使8'-(三氟甲基)-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(300 mg,564 µmol,中間物83 (步驟3))及(吡啶-4-基)甲醇(92.4 mg,846 µmol,CAS-RN:[586-95-8])連同TMAD (155 mg,903 µmol;CAS編號[10465-78-8])一起懸浮於甲苯(3.2 mL)中。小心地添加三-正丁基膦(220 µl,900 µmol;CAS編號[998-40-3])且在室溫下攪拌反應混合物隔夜。向反應混合物中添加水且接著真空濃縮。殘餘物用1 ml乙腈稀釋且藉由製備型HPLC (方法A,梯度E)純化。合併產物溶離份且真空濃縮,得到189.0 mg (78%產率)標題化合物。
LC-MS (方法1): Rt
= 1.33 min; MS (ESIpos): m/z = 432 [M+H]+
步驟 2 2'-[( 吡啶 -4- 基 ) 甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丁烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 甲酸
根據GP D,在室溫下,使2'-[(吡啶-4-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧酸乙酯(189 mg,438 µmol,中間物86 (步驟1))與氫氧化鋰水溶液(2.2 ml,2.0 M,4.4 mmol;CAS-RN:[1310-65-2])在THF (5.0 ml)中反應隔夜。反應混合物用4 N HCl水溶液(pH 2)酸化且攪拌30分鐘。真空濃縮至一半體積之後,凍乾殘餘物。殘餘物用1 ml乙腈稀釋且藉由製備型HPLC (方法B,梯度B)純化。合併產物溶離份且真空濃縮,得到43.3 mg (17%產率,63%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.90-2.18 (m, 6H), 3.14 (s, 2H), 5.39 (s, 2H), 7.14-7.17 (m, 2H), 8.00 (s, 1H), 8.52-8.56 (m, 2H), 13.95 (br s, 1H)
LC-MS (方法2): Rt
= 0.88 min; MS (ESIpos): m/z = 404 [M+H]+
中間物 87: 步驟 1 2-( 環丙基甲基 )-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C (條件A),在室溫下,使得自中間物35步驟4的8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,100 mg,333 µmol)與環丙基甲醇(CAS編號[2516-33-8],1.5 eq.,36.0 mg,500 µmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,130 µL,530 µmol)及TMAD (CAS編號[10465-78-8];1.6 eq.,150 µg,530 µmol)在甲苯(8.0 ml)中反應隔夜。用水萃取反應混合物兩次。合併之水相用DCM萃取三次。合併DCM及甲苯相,用NaCl乾燥,過濾且蒸發。粗物質藉由管柱層析(SiO2
,己烷/EtOAc)純化,得到標題化合物(78 mg,66%產率)。
LC-MS (方法1): Rt
= 1.38 min; MS (ESIpos): m/z = 355 [M+H]+
步驟 2 2-( 環丙基甲基 )-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在70℃下,使得自步驟1的2-(環丙基甲基)-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,78.0 mg,220 µmol)與氫氧化鋰水溶液(2 M;5 eq,550 µL,1.1 mmol)在乙醇與THF之1:1混合物(5.0 mL)中反應隔夜。在用6 N鹽酸水溶液酸化(pH 2)之後,在減壓下蒸發所得混合物。向殘餘物中添加DCM (30 ml)、水(20 ml)及i-PrOH (4×2 ml)且在室溫下攪拌1小時。分離各相且用DCM萃取水相三次。合併之DCM相用鹽水洗滌,經疏水性濾紙乾燥且蒸發,得到標題化合物(62.0 mg,86%產率)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.33 - 0.37 (m, 2 H) 0.48 - 0.54 (m, 2 H) 1.15 - 1.20 (m, 1 H) 2.84 - 2.88 (m, 2 H) 2.94 - 2.98 (m, 2 H) 3.92 (d, 2 H) 7.61 (s, 1 H) 13.73 - 14.07 (br. s, 1 H)
LC-MS (方法1): Rt
= 0.60 min; MS (ESIpos): m/z = 327 [M+H]+
中間物 88: 步驟 1 2-{[1-( 第三丁氧基羰基 ) 哌啶 -4- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
在室溫下,使得自中間物35步驟4的8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,1.71 g,5.70 mmol)與4-{[(三氟甲磺醯基)氧基]甲基}哌啶-1-甲酸第三丁酯(1.8 eq.,3.75 g,95%純度,10.3 mmol)、碳酸銫(3 eq.,5.57 g,17.1 mmol)在乙腈(41 mL)中反應18小時。將混合物傾入乙酸乙酯(50 ml)及水(20 ml)中。分離各相且乙酸乙酯相用鹽水(20 ml)洗滌且經疏水性濾紙乾燥。蒸發濾液,管柱層析(SiO2
,己烷/乙酸乙酯)後,得到標題化合物(1.26 g,44%產率)。
LC-MS (方法1): Rt
= 1.51 min; MS (ESIpos): m/z = 440 [M-tBu]+
步驟 2 2-[( 哌啶 -4- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯 (HCl 鹽 )
向1,4-二㗁烷(14 mL)中之得自步驟1的2-{[1-(第三丁氧基羰基)哌啶-4-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,1.26 g,2.53 mmol)中添加HCl之1,4-二㗁烷溶液(10.0 eq,6.3 mL,4.0 M,25.0 mml)且在室溫下攪拌18小時。在減壓下蒸發反應混合物。向殘餘物中添加DCM (20 ml)且在減壓下進一步蒸發,得到呈粗物質形式之標題化合物(900 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 1.19 min; MS (ESIpos): m/z = 398 [M+H]+
步驟 3 2-{[1-( 甲氧基乙醯基 ) 哌啶 -4- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
將得自中間物88步驟2的2-[(哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,250 mg,629 µmol,HCl鹽形式)懸浮於DCM (3.0 ml)中。向反應物中添加三乙胺(CAS編號[121-44-8],2.5 eq.,220 µl,1.6 mmol),隨後添加甲氧基乙醯氯(CAS編號[38870-89-2],1.1 eq.,63 µl,690 µmol)且所得混合物在室溫下攪拌5小時。蒸發反應混合物且向殘餘物中添加己烷/乙酸乙酯(95:5,10 ml)及DCM (300 µl),同時攪拌。藉由抽吸收集固體且用己烷/乙酸乙酯(95:5,2×1 ml)洗滌,產生呈粗固體狀之標題化合物(362 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 1.18 min; MS (ESIpos): m/z = 470 [M+H]+
步驟 4 2-{[1-( 甲氧基乙醯基 ) 哌啶 -4- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
使得自步驟3的2-{[1-(甲氧基乙醯基)哌啶-4-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,360 mg,767 µmol)與氫氧化鋰水溶液(2 M;2.0 eq.,770 µL,1.5 mmol)在THF (3.00 mL)及甲醇(3.0 mL)中、在室溫下反應18小時且接著在55℃反應5小時。向反應混合物中添加額外的氫氧化鋰水溶液(2 M;2.0 eq.,770 µL,1.5 mmol)且在60℃下進一步攪拌18小時。將反應混合物冷卻至室溫,用6 N HCl水溶液酸化至pH2且在減壓下蒸發所得混合物。殘餘物與THF (2x25 ml)共蒸餾之後,獲得呈粗物質形式之標題化合物(626 mg),其不經進一步純化即直接用於下一步驟中。
LC-MS (方法1): Rt
= 0.56 min; MS (ESIpos): m/z = 442 [M+H]+
中間物 89: 步驟 1 2-{[1-( 環丙烷羰基 ) 哌啶 -4- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
將得自中間物88步驟2的2-[(哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,250 mg,629 µmol,HCl鹽形式)懸浮於DCM (3.0 ml)中。向反應物中添加三乙胺(CAS編號[121-44-8],2.5 eq.,220 µl,1.6 mmol),隨後環丙烷碳醯氯(CAS編號[4023-34-1],1.1 eq.,63 µl,690 µmol)且所得混合物在室溫下攪拌5小時。蒸發反應混合物且向殘餘物中添加己烷/乙酸乙酯(95:5,10 ml)及DCM (300 µl),同時攪拌。藉由抽吸收集固體且用己烷/乙酸乙酯(95:5,2×1 ml)洗滌,產生呈粗固體狀之標題化合物(370 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 1.28 min; MS (ESIpos): m/z = 466 [M+H]+
步驟 2 2-{[1-( 環丙烷羰基 ) 哌啶 -4- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
使得自步驟1的2-{[1-(環丙烷羰基)哌啶-4-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,370 mg,795 µmol)與氫氧化鋰水溶液(2 M;2.0 eq.,795 µL,1.6 mmol)在THF (820 µL)及甲醇(820 µl)中、在室溫下反應18小時且接著在55℃下反應5小時。向反應混合物中添加額外的氫氧化鋰水溶液(2 M;2.0 eq.,795 µL,1.6 mmol)且在60℃下進一步攪拌18小時。將反應混合物冷卻至室溫,用6 N HCl水溶液酸化至pH2且在減壓下蒸發所得混合物。殘餘物與THF (2x25 ml)共蒸餾之後,獲得呈粗物質形式之標題化合物(447 mg),其不經進一步純化即直接用於下一步驟中。
LC-MS (方法1): Rt
= 0.61 min; MS (ESIpos): m/z = 438 [M+H]+
中間物 90: 步驟 1 2-[(1- 苯甲醯基哌啶 -4- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
將得自中間物88步驟2的2-[(哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,250 mg,629 µmol,HCl鹽形式)懸浮於DCM (3.0 ml)中。向反應物中添加三乙胺(CAS編號[121-44-8],2.5 eq.,220 µl,1.57 mmol),隨後添加苯甲醯氯(CAS編號[98-88-4],1.1 eq.,80 µl,690 µmol)且所得混合物在室溫下攪拌5小時。蒸發反應混合物且向殘餘物中添加己烷/乙酸乙酯(95:5,10 ml)及DCM (300 µl),同時攪拌。藉由抽吸收集固體且用己烷/乙酸乙酯(95:5,2×1 ml)洗滌,產生呈粗固體狀之標題化合物(340 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 1.35 min; MS (ESIpos): m/z = 502 [M+H]+
步驟 2 2-[(1- 苯甲醯基哌啶 -4- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
使得自步驟1的2-[(1-苯甲醯基哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,340 mg,678 µmol)與氫氧化鋰水溶液(2 M;2.0 eq.,680 µL,1.36 mmol)在THF (700 µL)及甲醇(700 µl)中、在室溫下反應18小時且接著在55℃下反應5小時。向反應混合物中添加額外的氫氧化鋰水溶液(2 M;2.0 eq.,680 µL,1.36 mmol)且在60℃下進一步攪拌18小時。將反應混合物冷卻至室溫,用6 N HCl水溶液酸化至pH2且在減壓下蒸發所得混合物。在殘餘物與THF (2×25 ml)共蒸餾之後,獲得呈粗棕色油狀之標題化合物(460 mg),其不經進一步純化即直接用於下一步驟中。
LC-MS (方法1): Rt
= 0.67 min; MS (ESIpos): m/z = 474 [M+H]+
中間物 91: 步驟 1 8- 甲基 -2-[2-( 吡啶 -3- 基 ) 丙 -2- 基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
根據GP C(條件A),在氮氣氛圍下,將8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;100 mg,406 µmol)及2-(吡啶-3-基)丙-2-醇(66.8 mg,487 µmol;CAS-RN:[15031-77-3])溶解於甲苯(3.7 mL)中。添加三-正丁基膦(160 µl,650 µmol;CAS-RN:[998-40-3])及TMAD (112 mg,650 µmol;CAS-RN:[10465-78-8])且在室溫下攪拌反應混合物隔夜。用水淬滅之後,真空濃縮反應混合物且殘餘物用2 ml乙腈稀釋且藉由製備型HPLC (方法A,梯度C)純化。合併產物溶離份且真空濃縮,得到23.5 mg (16%產率,98%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.95 (s, 6H), 2.46 (s, 3H), 2.86-2.97 (m, 4H), 4.26 (q, 2H), 7.28-7.36 (m, 1H), 7.38-7.45 (m, 1H), 7.76 (s, 1H), 8.23 (d, 1H), 8.43 (dd, 1H)。
LC-MS (方法1): Rt
= 1.29 min; MS (ESIpos): m/z = 366 [M+H]+
步驟 2 8- 甲基 -2-[2-( 吡啶 -3- 基 ) 丙 -2- 基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在室溫下,使8-甲基-2-[2-(吡啶-3-基)丙-2-基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(20.0 mg,54.7 µmol)(中間物91 (步驟1))與氫氧化鋰水溶液(550 µl,1.0 M,550 µmol;CAS-RN:[1310-65-2])在THF (68 µL)中反應隔夜。反應混合物用4 N HCl水溶液(pH 2)酸化且真空濃縮,得到18.0 mg (96%產率,98%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.96 (s, 6H), 2.43 (s, 3H), 2.84-3.00 (m, 4H), 7.46-7.55 (m, 1H), 7.60 (br s, 1H), 7.78 (s, 1H), 8.33 (s, 1H), 8.54 (br d, 1H), 12.35-13.12 (m, 1H)
LC-MS (方法1): Rt
= 0.57 min; MS (ESIpos): m/z = 338 [M+H]+
中間物 92: 步驟 1 8- 甲基 -4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
根據GP D,在室溫下,使8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(市售;380 mg,1.54 mmol)與氫氧化鋰水溶液(7.7 ml,1.0 M,7.7 mmol;CAS-RN:[1310-65-2])於THF (1.9 mL)中反應隔夜。反應混合物用4 N HCl水溶液(pH 2)酸化且攪拌30分鐘。沈澱物藉由過濾收集且不經進一步純化即用於下一步驟中(337 mg,97%產率,97%純度)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.74-3.01 (m, 4H), 7.54 (s, 1H)(甲基信號位於DMSO下方)
LC-MS (方法2): Rt
= 0.69 min; MS (ESIpos): m/z = 219 [M+H]+
步驟 2 8- 甲基 -N-[(3R)- 氧雜環戊 -3- 基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
根據GP G (條件A),在室溫下,使8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-甲酸(286 mg,1.31 mmol,中間物92 (步驟1))與(3R)-氧雜環戊-3-胺(148 mg,1.70 mmol,CAS-RN:[111769-26-7])、HATU (797 mg,2.10 mmol;CAS-RN:[148893-10-1])及N,N-
二異丙基乙胺(910 µl,5.2 mmol;CAS-RN:[7087-68-5])在DMF (3.6 mL)中反應隔夜,製備型HPLC後,得到標題化合物(215 mg,53%產率,93%純度)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.87-1.98 (m, 1H), 2.04-2.15 (m, 1H), 2.49 (br s, 3H), 2.82- 2.94 (m, 4H), 3.53 (dd, 1H), 3.70 (td, 1H), 3.79-3.87 (m, 2H), 4.34-4.47 (m, 1H), 7.50 (s, 1H), 8.17 (d, 1H), 12.42 (br s, 1H)。
LC-MS (方法1): Rt
= 0.77 min; MS (ESIpos): m/z = 288 [M+H]+
中間物 93: 步驟 1 (4R 或 4S)-2-{[1-( 第三丁氧基羰基 ) 哌啶 -4- 基 ] 甲基 }-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
在室溫下,將得自中間物79步驟1-a的(4R或4S)-4-甲基-8-(三氟甲基)-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.03 g,3.3 mmol)(對映異構體1)懸浮於乙腈(35 mL)中。向反應混合物中添加碳酸銫(3 eq.,3.19 g,9.8 mol),隨後添加含有4-{[(三氟甲磺醯基)氧基]甲基}哌啶-1-甲酸第三丁酯(1.8 eq.,2.27 g,90%純度,5.88 mmol)的乙腈(6 mL)且所得反應混合物在室溫下攪拌1小時。向反應混合物中添加EtOAc、H2
O及6 N HCl水溶液且短暫攪拌,同時冷卻(使用水浴)。添加額外的水,且分離所得層,且有機層用NH4
Cl飽和水溶液、鹽水洗滌,經MgSO4
乾燥且在減壓下蒸發。粗物質通過管柱層析(SiO2
,己烷/乙酸乙酯)純化,產生呈黃色油狀的標題化合物(1.2 g,58%純度),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 1.62 min; MS (ESIpos): m/z = 456 [M-tBu]+
步驟 2 (4R 或 4S)-4- 甲基 -2-[( 哌啶 -4- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯 (HCl 鹽 )
向含有得自步驟1之(4R或4S)-2-{[1-(第三丁氧基羰基)哌啶-4-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq,1.2 g,2.35 mmol)的1,4-二㗁烷(12 mL)中添加HCl之1,4-二㗁烷溶液(10.0 eq,5.9 ml,4.0 M,23.5 mml)且在室溫下攪拌18小時。在減壓下蒸發反應混合物。向殘餘物中添加DCM且進一步在減壓下蒸發,得到呈黃色泡沫狀之粗標題化合物(1.2 g),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 1.44 min; MS (ESIpos): m/z = 412 [M+H]+
步驟 3 (4R 或 4S)-2-{[1-( 環丙烷羰基 ) 哌啶 -4- 基 ] 甲基 }-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
將得自中間物93步驟2的(4R或4S)-4-甲基-2-[(哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,250 mg,607 µmol,HCl鹽形式)懸浮於DCM (2.9 ml)中。向反應物中添加三乙胺(CAS編號[121-44-8],3.0 eq.,254 µl,1.8 mmol),隨後添加環丙烷碳醯氯(CAS編號[4023-34-1],1.5 eq.,83 µl,911 µmol)且所得混合物在室溫下攪拌72小時。蒸發反應混合物且向殘餘物中添加己烷/乙酸乙酯(4:1,10 ml),同時攪拌。藉由抽吸收集固體且用己烷/乙酸乙酯(9:1,2×1 ml)洗滌,產生呈粗固體狀之標題化合物(360 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 1.78 min; MS (ESIpos): m/z = 480 [M+H]+
步驟 4 (4R 或 4S)-2-{[1-( 環丙烷羰基 ) 哌啶 -4- 基 ] 甲基 }-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
在室溫下,使得自步驟3的(4R或4S)-2-{[1-(環丙烷羰基)哌啶-4-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,360 mg,75 µmol)與氫氧化鋰水溶液(2 M;2.0 eq.,752 µL,1.5 mmol)在THF (6 mL)及甲醇(6 mL)中反應18小時。將反應混合物冷卻至室溫,用6 N HCl水溶液酸化至pH4且所得懸浮液在室溫下攪拌5分鐘。在減壓下蒸發所得混合物。向殘餘物中添加DCM (50 mL)及鹽水(0.2 mL)且在室溫下攪拌30分鐘。濾出固體且用DCM沖洗。在減壓下蒸發濾液,得到呈黃色泡沫狀之粗標題化合物(240 mg),其不經進一步純化即直接用於下一步驟中。
LC-MS (方法1): Rt
= 0.67 min; MS (ESIpos): m/z = 452 [M+H]+
中間物 94: 步驟 1 (4R 或 4S)-2-[(1- 乙醯基哌啶 -4- 基 ) 甲基 ]-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
將得自中間物93步驟2的(4R或4S)-4-甲基-2-[(哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,250 mg,607 µmol,HCl鹽形式)懸浮於DCM (15 ml)中。向反應物中添加三乙胺(CAS編號[121-44-8],3 eq.,254 µl,1.8 mmol),隨後添加乙醯氯(2 eq.,86.7 µl,1.22 mmol)且所得混合物在室溫下攪拌72小時。蒸發反應混合物且向殘餘物中添加己烷/乙酸乙酯(4:1,10 ml),同時攪拌。濾出固體且用己烷/乙酸乙酯(9:1,2x 1 ml)洗滌。將合併的濾液蒸發,得到粗物質,接著藉由製備型HPLC (方法A,梯度D)純化,產生標題化合物(100 mg,36%產率)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.94 - 1.06 (m, 1H) 1.08 - 1.20 (m, 1H) 1.26 - 1.32 (m, 6H) 1.49 - 1.56 (m, 2H) 1.96 (s, 3H) 1.98 - 2.05 (m, 1H) 2.44 - 2.48 (m, 1H) 2.60 - 2.64 (m, 1H) 2.93 - 3.00 (m, 1H) 3.06 - 3.12 (m, 1H) 3.14 - 3.20 (m, 1H) 3.77 - 3.80 (m, 1H) 3.98 (d, 2H) 4.31 - 4.37 (m, 3H) 7.60 (s, 1H)
LC-MS (方法1): Rt
= 1.24 min; MS (ESIpos): m/z = 454 [M+H]+
步驟 2 (4R 或 4S)-2-[(1- 乙醯基哌啶 -4- 基 ) 甲基 ]-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
在室溫下,使得自步驟1的(4R或4S)-2-[(1-乙醯基哌啶-4-基)甲基]-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,100 mg,221 µmol)與氫氧化鋰水溶液(2 M;2.0 eq.,221 µL,0.44 mmol)在THF (2 mL)及甲醇(2 mL)中反應18小時。反應混合物用6 N HCl水溶液酸化至pH4且所得懸浮液在室溫下攪拌5分鐘。在減壓下蒸發混合物。殘餘物與甲苯共蒸餾之後,獲得呈粗物質形式之標題化合物(150 mg),其不經進一步純化即直接用於下一步驟中。
LC-MS (方法1): Rt
= 0.59 min; MS (ESIpos): m/z = 426 [M+H]+
中間物 95: 步驟 1 (4R 或 4S)-2-{[1-(1- 羥基環丙烷 -1- 羰基 ) 哌啶 -4- 基 ] 甲基 }-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
在氬氣下,將1-羥基-1-環丙烷甲酸(2.00 eq,124 mg,1.22 mmol)溶解於四氫呋喃(5 mL)中,且添加HATU (1.15 eq.,265 mg,0.70 mmol)及DIPEA (3.0 eq.,0.32 mL,1.82 mmol)且所得混合物在室溫下攪拌幾分鐘。向此混合物中添加得自中間物93步驟2的(4R或4S)-4-甲基-2-[(哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-甲酸酯(1.0 eq.,250 mg,607 µmol,HCl鹽形式)及DMF (1 mL)且進一步在室溫下攪拌72小時。反應混合物用乙酸乙酯、碳酸氫鈉飽和水溶液及水稀釋且所得混合物攪拌30分鐘。分離相應層,且有機層用水洗滌,經由疏水性濾紙過濾且在減壓下濃縮。粗殘餘物藉由製備型HPLC (方法A,梯度D)純化,產生標題化合物(100 mg,33%產率)。1
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.712 (1.00), 0.724 (3.26), 0.731 (3.89), 0.740 (1.59), 0.850 (1.69), 0.859 (3.39), 0.866 (2.54), 0.878 (1.19), 0.932 (0.48), 0.948 (0.47), 1.124 (0.56), 1.147 (0.54), 1.267 (8.35), 1.284 (8.92), 1.289 (8.22), 1.307 (16.00), 1.325 (7.21), 1.531 (1.51), 1.559 (1.29), 2.009 (0.41), 2.028 (0.55), 2.037 (0.64), 2.045 (0.52), 2.323 (0.83), 2.327 (1.15), 2.331 (0.82), 2.518 (4.49), 2.523 (2.95), 2.597 (1.35), 2.623 (1.58), 2.639 (1.67), 2.665 (2.57), 2.669 (1.55), 2.673 (1.03), 3.061 (1.52), 3.079 (2.27), 3.102 (1.17), 3.120 (2.08), 3.147 (0.67), 3.164 (0.88), 3.172 (0.72), 3.179 (0.61), 3.188 (0.82), 3.205 (0.47), 3.966 (3.65), 3.983 (3.55), 4.315 (2.14), 4.333 (6.54), 4.351 (6.44), 4.368 (2.10), 6.267 (4.12), 7.612 (5.42)。
LC-MS (方法1): Rt
= 1.24 min; MS (ESIpos): m/z = 496 [M+H]+
步驟 2 (4R 或 4S)-2-{[1-(1- 羥基環丙烷 -1- 羰基 ) 哌啶 -4- 基 ] 甲基 }-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸 及 (4R 或 4S)-4- 甲基 -2-[[1-(2- 側氧基丁醯基 )-4- 哌啶基 ] 甲基 ]-8-( 三氟甲基 )-4,5- 二氫呋喃并 [2,3-g] 吲唑 -7- 甲酸 ( 呈 1:1 混合物形式 )
在室溫下,使得自步驟1的(4R或4S)-2-{[1-(1-羥基環丙烷-1-羰基)哌啶-4-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,100 mg,202 µmol)與氫氧化鋰水溶液(2 M;2.0 eq.,202 µL,0.4 mmol)在THF (2 mL)及甲醇(2 mL)中反應18小時。反應混合物用6 N HCl水溶液酸化至pH4且所得懸浮液在室溫下攪拌5分鐘。在減壓下蒸發混合物。殘餘物與甲苯共蒸餾之後,獲得呈粗物質形式之標題化合物(160 mg),其不經進一步純化即直接用於下一步驟中。
LC-MS (方法1):
Rt
= 0.61 min; MS (ESIpos): m/z = 468 [M+H]+
Rt
= 0.67 min; MS (ESIpos): m/z = 468 [M+H]+
中間物 96: 步驟 1 (4R 或 4S)-4- 甲基 -2-{[1-(1- 甲基環丙烷 -1- 羰基 ) 哌啶 -4- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
在氬氣下,將1-甲基環丙烷-1-甲酸(2.00 eq,122 mg,1.22 mmol)溶解於四氫呋喃(5 mL)中,且添加HATU (1.15 eq.,265 mg,0.70 mmol)及DIPEA (3.0 eq.,0.32 mL,1.82 mmol)且所得混合物在室溫下攪拌幾分鐘。向此混合物中添加得自中間物93步驟2的(4R或4S)-4-甲基-2-[(哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-甲酸酯(1.0 eq.,250 mg,607 µmol,HCl鹽形式)及DMF (1 mL)且進一步在室溫下攪拌72小時。反應混合物用乙酸乙酯、碳酸氫鈉飽和水溶液及水稀釋且所得混合物攪拌30分鐘。分離相應層,且有機層用水洗滌,經由疏水性濾紙過濾且在減壓下濃縮。粗殘餘物藉由製備型HPLC (方法A,梯度E)純化,產生標題化合物(100 mg,33%產率)。1
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.496 (1.18), 0.507 (3.90), 0.512 (3.86), 0.523 (1.54), 0.729 (1.34), 0.739 (3.81), 0.743 (3.66), 0.755 (1.15), 1.090 (0.69), 1.147 (0.59), 1.192 (16.00), 1.265 (7.38), 1.281 (7.77), 1.289 (6.52), 1.307 (13.44), 1.325 (6.28), 1.534 (1.36), 1.564 (1.12), 1.998 (0.37), 2.010 (0.42), 2.017 (0.49), 2.027 (0.58), 2.036 (0.48), 2.046 (0.41), 2.323 (1.25), 2.327 (1.80), 2.331 (1.28), 2.518 (7.54), 2.523 (4.71), 2.596 (1.24), 2.622 (1.42), 2.638 (1.50), 2.664 (2.75), 2.669 (2.17), 2.673 (1.54), 2.715 (0.30), 2.723 (0.32), 2.732 (0.35), 2.737 (0.35), 2.746 (0.37), 2.752 (0.37), 2.758 (0.37), 2.767 (0.36), 2.774 (0.36), 2.782 (0.34), 2.786 (0.34), 2.795 (0.31), 2.803 (0.29), 2.806 (0.27), 3.060 (1.35), 3.078 (1.95), 3.102 (0.99), 3.120 (1.82), 3.146 (0.63), 3.163 (0.79), 3.188 (0.75), 3.205 (0.46), 3.971 (3.37), 3.989 (3.30), 4.208 (1.48), 4.241 (1.40), 4.315 (1.66), 4.332 (5.40), 4.350 (5.26), 4.368 (1.55), 7.603 (4.83)。
LC-MS (方法1): Rt
= 1.37 min; MS (ESIpos): m/z = 494 [M+H]+
步驟 2 (4R 或 4S)-4- 甲基 -2-{[1-(1- 甲基環丙烷 -1- 羰基 ) 哌啶 -4- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
在室溫下,使得自步驟1的(4R或4S)-4-甲基-2-{[1-(1-甲基環丙烷-1-羰基)哌啶-4-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,100 mg,203 µmol)與氫氧化鋰水溶液(2 M;2.0 eq.,221 µL,0.44 mmol)在THF (2 mL)及甲醇(2 mL)中反應18小時。反應混合物用6 N HCl水溶液酸化至pH4且所得懸浮液在室溫下攪拌5分鐘。在減壓下蒸發混合物。殘餘物與甲苯共蒸餾之後,獲得呈粗物質形式之標題化合物(140 mg),其不經進一步純化即直接用於下一步驟中。
LC-MS (方法1): Rt
= 0.68 min; MS (ESIpos): m/z = 466 [M+H]+
中間物 97: 步驟 1 2-[(1- 乙醯基哌啶 -4- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
將得自中間物88步驟2的2-[(哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,225 mg,566 µmol,HCl鹽形式)懸浮於中DCM (2.7 ml)。向反應物中添加三乙胺(CAS編號[121-44-8],2.5 eq.,197 µl,1.42 mmol),隨後添加乙醯氯(1.5 eq.,60 µl,0.85 mmol)且所得混合物在室溫下攪拌5小時。蒸發反應混合物且向殘餘物中添加己烷/乙酸乙酯(7:3,10 ml),同時攪拌。濾出固體且用己烷/乙酸乙酯(9:1,2x 1 ml)洗滌。將合併的濾液蒸發,得到粗物質,接著藉由製備型HPLC (方法A,梯度C)純化,產生標題化合物(92 mg,35%產率)。1
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.959 (0.20), 0.979 (0.45), 0.989 (0.47), 1.010 (0.51), 1.020 (0.48), 1.040 (0.23), 1.097 (0.20), 1.118 (0.44), 1.127 (0.49), 1.147 (0.52), 1.157 (0.48), 1.178 (0.24), 1.288 (4.70), 1.306 (10.35), 1.324 (4.90), 1.481 (0.60), 1.516 (1.00), 1.555 (0.52), 1.921 (0.24), 1.961 (16.00), 1.992 (0.45), 2.001 (0.52), 2.011 (0.42), 2.019 (0.36), 2.029 (0.29), 2.075 (0.79), 2.444 (0.46), 2.518 (3.25), 2.523 (2.08), 2.841 (0.87), 2.861 (2.87), 2.879 (2.10), 2.931 (0.48), 2.962 (2.95), 2.980 (3.38), 2.999 (1.15), 3.763 (0.61), 3.796 (0.57), 3.965 (3.15), 3.983 (3.11), 4.315 (1.84), 4.333 (4.88), 4.350 (4.74), 4.368 (1.35), 7.558 (4.29)。
LC-MS (方法1): Rt
= 1.15 min; MS (ESIpos): m/z = 440 [M+H]+
步驟 2 2-[(1- 乙醯基哌啶 -4- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
在室溫下,使得自步驟1的2-[(1-乙醯基哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,90 mg,204 µmol)與氫氧化鋰水溶液(2 M;2.0 eq.,205 µL,0.41 mmol)在THF (0.33 mL)及甲醇(0.33 mL)中反應18小時。向反應混合物中添加額外的氫氧化鋰水溶液(2 M;2.0 eq.,205 µL,0.41 mmol)且在60℃下加熱5小時。反應混合物用6 N HCl水溶液酸化至pH 4且所得懸浮液在減壓下蒸發。殘餘物用DCM (50 mL)處理且在攪拌的同時,逐滴添加飽和鹽水溶液(300 µL)且所得混合物進一步在室溫下攪拌30分鐘。分離各相且有機層經Na2
SO4
乾燥,過濾且在減壓下蒸發,得到呈粗物質形式之標題化合物(117 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 0.51 min; MS (ESIpos): m/z = 412 [M+H]+
中間物 98: 步驟 1 2-{[1-( 環丙基甲基 ) 哌啶 -4- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
將得自中間物88步驟2的2-[(哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,225 mg,566 µmol,HCl鹽形式)溶解於DMF (5 ml)中。向溶液中添加碳酸鉀(3.0 eq.,234 mg,1.7 mmol)且在室溫下攪拌5分鐘。向反應混合物中逐滴添加(溴甲基)環丙烷(1.5 eq.,82 µl,0.85 mmol)且所得混合物在80℃下攪拌18小時。將反應混合物冷卻至室溫且用乙酸乙酯及水稀釋。分離各相,且將有機相乾燥,過濾且在減壓下蒸發。所得粗殘餘物藉由藉由製備型HPLC純化(方法A,梯度F)純化,產生標題化合物(34 mg,13%產率)。1
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.007 (1.05), 0.018 (3.68), 0.030 (4.04), 0.044 (1.33), 0.399 (1.27), 0.409 (3.15), 0.413 (3.18), 0.419 (1.78), 0.424 (1.74), 0.429 (3.43), 0.433 (3.29), 0.444 (1.26), 0.773 (0.77), 0.786 (1.17), 1.155 (0.54), 1.177 (1.40), 1.184 (1.50), 1.207 (1.72), 1.214 (1.56), 1.237 (0.90), 1.288 (7.23), 1.306 (16.00), 1.316 (1.36), 1.324 (7.49), 1.345 (0.49), 1.363 (0.97), 1.382 (0.48), 1.458 (1.91), 1.488 (1.52), 1.719 (0.82), 1.737 (0.68), 1.797 (1.35), 1.822 (2.40), 1.851 (1.38), 2.074 (1.26), 2.106 (5.72), 2.123 (5.85), 2.518 (11.04), 2.523 (6.74), 2.836 (1.42), 2.857 (4.33), 2.876 (3.17), 2.897 (2.19), 2.925 (2.15), 2.959 (3.36), 2.976 (4.98), 2.999 (1.44), 3.221 (0.58), 3.370 (0.78), 3.938 (4.70), 3.955 (4.50), 4.314 (2.05), 4.332 (6.77), 4.350 (6.72), 4.368 (2.04), 4.377 (0.42), 4.419 (0.43), 4.437 (0.42), 7.461 (0.53), 7.550 (6.25), 8.549 (0.43), 8.661 (0.47)。
LC-MS (方法1): Rt
= 1.46 min; MS (ESIpos): m/z = 452 [M+H]+
步驟 2 2-{[1-( 環丙基甲基 ) 哌啶 -4- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
在室溫下,使得自步驟1的2-{[1-(環丙基甲基)哌啶-4-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,33 mg,73 µmol)與氫氧化鋰水溶液(2 M;2.0 eq.,73 µL,146 µmol)在THF (0.12 mL)及甲醇(0.12 mL)中反應18小時。向反應混合物中添加額外的氫氧化鋰水溶液(2 M;2.0 eq.,73 µL,146 mmol)且在60℃下加熱5小時。反應混合物用6 N HCl水溶液酸化至pH 4且所得懸浮液在減壓下蒸發。殘餘物用DCM (50 mL)處理且在攪拌的同時,逐滴添加飽和鹽水溶液(300 µL)且所得混合物進一步在室溫下攪拌30分鐘。分離各相且有機層經Na2
SO4
乾燥,過濾且在減壓下蒸發,得到呈粗物質形式之標題化合物(68 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 0.68 min; MS (ESIpos): m/z = 424 [M+H]+
中間物 99: 步驟 1 2-[(1- 乙基哌啶 -4- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
將得自中間物88步驟2的2-[(哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,225 mg,566 µmol,HCl鹽形式)溶解於DMF (5 ml)中。向溶液中添加三乙胺(CAS編號[121-44-8],2.5 eq.,197 µl,1.42 mmol)且在室溫下攪拌5分鐘。向反應混合物中逐滴添加碘乙烷(1.5 eq.,68 µl,850 µmol)且所得混合物在室溫下攪拌18小時。用乙酸乙酯及水稀釋反應混合物。分離各相,且將有機相乾燥,過濾且在減壓下蒸發。所得粗殘餘物藉由藉由製備型HPLC純化 (方法A,梯度F)純化,產生標題化合物(18 mg,7%產率)。1
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.911 (0.55), 0.937 (4.91), 0.955 (11.71), 0.973 (5.13), 1.125 (0.40), 1.134 (0.45), 1.155 (1.12), 1.164 (1.21), 1.186 (1.37), 1.194 (1.25), 1.216 (0.63), 1.225 (0.58), 1.288 (7.07), 1.298 (0.89), 1.306 (16.00), 1.315 (1.29), 1.323 (7.13), 1.333 (0.54), 1.457 (1.57), 1.486 (1.28), 1.693 (0.50), 1.712 (0.68), 1.734 (1.55), 1.758 (2.18), 1.787 (1.10), 2.231 (1.43), 2.249 (4.71), 2.266 (4.52), 2.285 (1.35), 2.337 (0.55), 2.518 (6.23), 2.523 (4.05), 2.678 (0.54), 2.796 (1.78), 2.825 (1.80), 2.834 (1.98), 2.855 (3.81), 2.874 (2.71), 2.958 (2.87), 2.975 (4.43), 2.994 (1.25), 2.998 (1.25), 3.933 (4.14), 3.951 (4.01), 4.314 (1.91), 4.332 (6.32), 4.349 (6.24), 4.359 (0.53), 4.367 (1.85), 7.461 (0.41), 7.550 (5.72)。
LC-MS (方法1): Rt
= 1.37 min; MS (ESIpos): m/z = 426 [M+H]+
步驟 2 2-[(1- 乙基哌啶 -4- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
在室溫下,使得自步驟1的2-[(1-乙基哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.00 eq.,18 mg,42 µmol)與氫氧化鋰水溶液(2 M;2.0 eq.,42 µL,84 µmol)在THF (0.07 mL)及甲醇(0.07 mL)中反應18小時。反應混合物用6 N HCl水溶液酸化至pH 4且所得懸浮液在減壓下蒸發。殘餘物用DCM (50 mL)處理且在攪拌的同時,逐滴添加飽和鹽水溶液(300 µL)且所得混合物進一步在室溫下攪拌30分鐘。分離各相且有機層經MgSO4
乾燥,過濾且在減壓下蒸發,得到呈粗物質形式之標題化合物(34 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 0.63 min; MS (ESIpos): m/z = 398 [M+H]+
中間物 100: 步驟 1 2-[(1- 甲基哌啶 -4- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧酸乙酯
在氮氣氛圍下,將得自中間物88步驟2的2-[(哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(1.0 eq.,225 mg,566 µmol,HCl鹽形式)溶解於甲醇(3 ml)中。向溶液中添加乙酸(2 eq.,65 µl,1.13 mmol)且在室溫下攪拌5分鐘。向反應混合物中逐份添加氰基硼氫化鈉(2 eq.,71 mg,1.13 µmol)且在室溫下攪拌5分鐘。向所得反應混合物中添加甲醛水溶液(37重量%,2 eq.,85 µl,1.13 µmol)且在60℃下加熱混合物18小時。將反應混合物冷卻至室溫且用DCM稀釋且使用2 N NaOH水溶液中和至pH10。在室溫下攪拌10分鐘之後,分離各相且在減壓下濃縮水相,得到呈粗物質形式之標題化合物(880 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 1.27 min; MS (ESIpos): m/z = 412 [M+H]+
步驟 2 2-[(1- 甲基哌啶 -4- 基 ) 甲基 ]-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 甲酸
在室溫下,使得自步驟1的2-[(1-甲基哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧酸乙酯(880 mg,粗物質形式,理論上:1.00 eq.,232 mg,563 µmol)與氫氧化鋰水溶液(2 M;2.0 eq.,564 µL,1.13 mmol)在THF (0.9 mL)及甲醇(0.9 mL)中反應18小時。反應混合物用6 N HCl水溶液酸化至pH 4且所得懸浮液在減壓下蒸發。殘餘物用DCM (50 mL)處理且在攪拌的同時,逐滴添加飽和鹽水溶液(300 µL)且所得混合物進一步在室溫下攪拌30分鐘。分離各相且有機層經MgSO4
乾燥,過濾且在減壓下蒸發,得到粗物質。粗物質用DCM/EtOH (9:1)之混合物處理且濾出固體,用DCM洗滌且所得濾液在減壓下蒸發,得到呈粗物質形式之標題化合物(465 mg),其不經進一步純化即用於下一步驟中。
LC-MS (方法1): Rt
= 0.57 min; MS (ESIpos): m/z = 384 [M+H]+
實驗章節 - 實例 實例 1 : 2-( 吡啶 -2- 基甲基 )-N
-[(2S)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
根據GP G (條件C),在室溫下,使2-[(吡啶-2-基)甲基]-4,5-二氫-2H-
呋喃并2,3-g]吲唑-7-甲醛(中間物1;1.00 eq.,50.0 mg,179 µmol)與1-[(2S)-四氫呋喃-2-基]甲胺(CAS編號[7175-81-7];5.0 eq.,90.5 mg,895 µmol)、氰化鈉(1.0 eq.,8.8 mg,180 µmol)及二氧化錳(IV)(15.0 eq.,233 mg,2.69 mmol)在THF (2 mL)中反應30分鐘。添加額外量的二氧化錳(IV)(15.0 eq.,233 mg,2.69 mmol)且繼續在室溫下攪拌20小時。反應混合物經矽藻土過濾,濾液用二氯甲烷稀釋且用水及鹽水洗滌。有機相經Na2
SO4
乾燥,過濾且在減壓下濃縮。所得粗產物藉由製備型HPLC純化,得到標題化合物(33 mg,47%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.52-1.60 (m, 1H), 1.74-1.91 (m, 3H), 2.87-2.97 (m, 4H), 3.20-3.29 (m, 2H), 3.58-3.64 (m, 1H), 3.73-3.78 (m, 1H), 3.90-3.97 (m, 1H), 5.37 (s, 2H), 7.07 (d, 1H), 7.21 (s, 1H), 7.31 (ddd, 1H), 7.64 (s, 1H), 7.77 (dt, 1H), 8.31 (t, 1H), 8.54 (ddd, 1H)。
LC-MS (方法A
): Rt
= 0.87 min; MS (ESIpos): m/z = 379 [M+H]+
。
實例 2: 8- 甲基 -N
-[(4- 甲基苯基 ) 甲基 ]-2-[( 吡啶 -2- 基 ) 甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
根據GP G (條件A),在室溫下,使8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-7-甲酸(中間物2;1.00 eq.,55.0 mg,178 µmol)與1-(4-甲基苯基)甲胺(1.2 eq.,27 µL,210 µmol)、HATU (CAS編號[148893-10-1];1.5 eq.,101 mg,267 µmol)及N,N-
二異丙基乙胺(CAS編號[7087-68-5];3.0 eq.,93 µL,530 µmol)在DMF (2 mL)中反應隔夜,製備型HPLC後,得到標題化合物(30 mg,38%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.26 (s, 3H), 2.45 (s, 3H), 2.85-2.93 (m, 4H), 4.33 (d, 2H), 5.38 (s, 2H), 7.07 (d, 1H), 7.10-7.12 (m, 2H), 7.17-7.19 (m, 2H), 7.31 (ddd, 1H), 7.63 (s, 1H), 7.77 (dt, 1H), 8.54 (ddd, 1H), 8.62 (t, 1H)。
LC-MS (方法A
): Rt
= 1.20 min; MS (ESIpos): m/z = 413 [M+H]+
。
實例 3 : 8- 甲基 -2-( 吡啶 -2- 基甲基 )-N
-[(2R/S)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
根據GP G (條件A),在室溫下,使8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-甲酸(中間物2;1.00 eq.,55.0 mg,178 µmol)與1-[(2R/S)-四氫呋喃-2-基]甲胺(CAS編號[4795-29-3];1.2 eq.,22 µL,210 µmol)、HATU (CAS編號[148893-10-1];1.5 eq.,101 mg,267 µmol)及N,N
-二異丙基乙胺(CAS編號[7087-68-5];3.0 eq.,93 µL,530 µmol)在DMF (2 mL)中反應隔夜,製備型HPLC後,得到標題化合物(40 mg,53%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.61 (m, 1H), 1.74-1.90 (m, 3H), 2.44 (s, 3H), 2.86-2.93 (m, 4H), 3.18-3.26 (m, 2H), 3.58-3.64 (m, 1H), 3.73-3.78 (m, 1H), 3.91-3.97 (m, 1H), 5.38 (s, 2H), 7.07 (d, 1H), 7.31 (ddd, 1H), 7.63 (s, 1H), 7.77 (dt, 1H), 7.98 (t, 1H), 8.53-8.54 (m, 1H)。
LC-MS (方法A
): Rt
= 0.97 min; MS (ESIpos): m/z = 393 [M+H]+
。
實例3之外消旋物質之對映異構體係藉由對掌性製備型HPLC分離(儀器:PrepCon Labomatic HPLC;管柱:Chiralpak IE 5 µm 250x30 mm;溶離劑A:第三丁基甲基醚 + 0.1%二乙胺;溶離劑B:乙醇;等度:90% A + 10% B;流量:40 mL/min;溫度:25℃;偵測:UV 254 nm)且藉由對掌性HPLC加以分析表徵(儀器:Agilent 1260 HPLC;管柱:Chiralpak IE 3 µm 100x4.6 mm;溶離劑A:第三丁基甲基醚 + 0.1%二乙胺;溶離劑B:乙醇;等度:90% A + 10% B;流量:1.4 mL/min;溫度:25℃;偵測:UV:254 nm):實例 3-1 : 8- 甲基 -2-( 吡啶 -2- 基甲基 )-N
-[(2R)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
Rt
= 3.91 min; [α]D 20
= -16.3° +/- 1.79° (C = 10.0 mg/mL, 甲醇)實例 3-2 : 8- 甲基 -2-( 吡啶 -2- 基甲基 )-N
-[(2S)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
Rt
= 5.00 min; [α]D 20
= +14.8° +/- 1.89° (C = 10.0 mg/mL, 甲醇)表 2 : 以給定中間物及市售胺 ( 或其鹽 ) 為起始物, 應用指定的通用程序 , 類似於實例 3 來製備以下實例 (4 至 147) 。
實例 | 結構 IUPAC- 名稱 | 分析型資料 | 製備或分離方法 |
4 | 8-甲基-N -[2-(4-甲基哌𠯤-1-基)乙基]-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.134 (13.81), 2.297 (1.26), 2.323 (2.11), 2.327 (2.46), 2.331 (2.01), 2.388 (2.65), 2.405 (4.09), 2.423 (2.65), 2.438 (16.00), 2.522 (4.49), 2.665 (1.23), 2.669 (1.63), 2.673 (1.20), 2.739 (0.45), 2.888 (10.62), 3.267 (0.91), 3.283 (2.03), 3.300 (2.19), 5.381 (6.98), 7.057 (1.85), 7.077 (1.95), 7.289 (0.94), 7.303 (1.10), 7.308 (1.12), 7.320 (1.10), 7.632 (5.03), 7.750 (1.04), 7.754 (1.04), 7.769 (1.77), 7.773 (1.74), 7.788 (0.94), 7.793 (0.91), 7.906 (0.75), 7.921 (1.61), 7.935 (0.75), 8.529 (1.47), 8.539 (1.55), 8.541 (1.53). LC-MS (方法A ); Rt = 0.85 min, m/z = 435 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
5 | 8-甲基-N -[(1,2,4-㗁二唑-3-基)甲基]-2-[(吡啶-2-基)甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 2.86-2.93 (m, 4H), 4.54 (d, 2H), 5.39 (s, 2H), 7.07 (d, 1H), 7.31 (ddd, 1H), 7.64 (s, 1H), 7.78 (dt, 1H), 8.54 (ddd, 1H), 8.75 (t, 1H), 9.54 (s, 1H). LC-MS (方法A ); Rt = 0.85 min, m/z = 391 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
6 | 8-甲基-N -(1,2-㗁唑-3-基甲基)-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.454 (16.00), 2.518 (1.95), 2.522 (1.21), 2.755 (0.45), 2.889 (2.88), 2.897 (8.51), 2.905 (3.29), 4.452 (3.32), 4.467 (3.30), 5.385 (6.42), 6.487 (3.97), 6.492 (4.36), 7.060 (1.76), 7.079 (1.84), 7.289 (0.89), 7.291 (0.87), 7.301 (0.93), 7.304 (0.96), 7.308 (1.13), 7.310 (0.97), 7.320 (1.03), 7.322 (0.94), 7.639 (5.08), 7.750 (1.09), 7.754 (1.06), 7.769 (1.79), 7.774 (1.86), 7.788 (0.98), 7.793 (0.98), 8.527 (1.17), 8.530 (1.34), 8.532 (1.36), 8.534 (1.23), 8.539 (1.22), 8.542 (1.38), 8.544 (1.27), 8.546 (1.15), 8.703 (0.73), 8.718 (1.58), 8.733 (0.71), 8.812 (3.54), 8.815 (3.26). LC-MS (方法A ); Rt = 0.90 min, m/z = 390 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
7 | N -[(5-環丙基-1,2-㗁唑-3-基)甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.821 (0.77), 0.832 (2.58), 0.838 (2.57), 0.844 (2.54), 0.847 (1.52), 0.850 (2.70), 0.860 (1.11), 0.993 (1.10), 1.003 (2.52), 1.010 (2.36), 1.014 (1.26), 1.021 (1.13), 1.024 (2.72), 1.031 (2.25), 1.042 (0.84), 1.606 (0.62), 2.081 (0.77), 2.090 (0.83), 2.094 (0.47), 2.102 (1.49), 2.111 (0.48), 2.114 (0.77), 2.123 (0.74), 2.452 (16.00), 2.518 (3.26), 2.523 (2.28), 2.893 (10.23), 2.898 (3.49), 3.566 (1.11), 4.340 (3.22), 4.355 (3.20), 5.385 (6.22), 6.089 (6.38), 7.060 (1.74), 7.080 (1.82), 7.290 (0.89), 7.293 (0.84), 7.302 (0.95), 7.305 (0.95), 7.309 (1.02), 7.311 (0.93), 7.321 (1.02), 7.323 (0.95), 7.639 (5.18), 7.751 (1.14), 7.755 (1.11), 7.770 (1.80), 7.775 (1.94), 7.789 (1.01), 7.794 (1.01), 8.528 (1.16), 8.530 (1.31), 8.532 (1.32), 8.535 (1.22), 8.540 (1.17), 8.542 (1.34), 8.544 (1.22), 8.547 (1.14), 8.634 (0.71), 8.649 (1.56), 8.664 (0.68). LC-MS (方法A ); Rt = 1.07 min, m/z = 430 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
8 | 8-甲基-N -[(5-甲基-1,2-㗁唑-3-基)甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.336 (0.60), 2.352 (11.98), 2.354 (11.85), 2.451 (16.00), 2.518 (6.29), 2.522 (3.99), 2.678 (0.52), 2.888 (3.26), 2.894 (9.97), 2.900 (3.39), 3.566 (2.98), 4.356 (3.34), 4.372 (3.31), 5.385 (6.39), 6.134 (3.47), 6.136 (3.42), 7.061 (1.72), 7.080 (1.80), 7.289 (0.86), 7.293 (0.89), 7.302 (0.91), 7.305 (0.99), 7.308 (1.04), 7.311 (0.91), 7.320 (1.02), 7.324 (0.94), 7.638 (5.06), 7.751 (1.07), 7.755 (1.15), 7.770 (1.83), 7.774 (1.91), 7.789 (0.94), 7.794 (0.91), 8.527 (1.12), 8.530 (1.33), 8.532 (1.31), 8.534 (1.23), 8.539 (1.17), 8.542 (1.36), 8.544 (1.23), 8.546 (1.15), 8.662 (0.73), 8.677 (1.57), 8.693 (0.70). LC-MS (方法A ); Rt = 0.99 min, m/z = 404 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
9 | N -[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.933 (1.22), 0.935 (0.43), 0.949 (1.24), 2.306 (0.91), 2.336 (0.51), 2.456 (16.00), 2.518 (6.12), 2.522 (3.81), 2.659 (0.51), 2.756 (0.51), 2.879 (1.02), 2.892 (2.59), 2.905 (5.54), 2.914 (3.07), 3.430 (0.63), 3.445 (0.51), 3.450 (0.69), 3.465 (1.12), 3.480 (0.58), 3.521 (0.58), 3.536 (1.14), 3.552 (0.74), 3.566 (2.39), 3.571 (0.71), 4.130 (1.07), 4.148 (1.22), 4.160 (1.19), 4.177 (1.37), 4.355 (0.79), 4.360 (0.99), 4.372 (0.79), 4.377 (0.84), 4.437 (1.50), 4.443 (1.42), 4.466 (1.30), 4.472 (1.09), 5.386 (6.40), 6.932 (2.21), 6.944 (2.03), 6.952 (2.29), 6.963 (2.26), 7.064 (1.78), 7.084 (1.85), 7.291 (0.97), 7.293 (0.99), 7.302 (3.33), 7.306 (3.35), 7.309 (1.32), 7.312 (1.12), 7.322 (3.40), 7.325 (2.59), 7.632 (0.41), 7.640 (5.03), 7.735 (2.29), 7.740 (2.59), 7.747 (2.46), 7.752 (3.25), 7.757 (1.32), 7.771 (1.90), 7.776 (1.93), 7.790 (0.99), 7.795 (0.97), 8.366 (0.69), 8.381 (1.47), 8.396 (0.69), 8.529 (1.24), 8.531 (1.40), 8.533 (1.45), 8.535 (1.27), 8.541 (1.30), 8.543 (1.42), 8.545 (1.37), 8.547 (1.17). LC-MS (方法A ); Rt = 0.97 min, m/z = 458 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
10 | N -(2-羥基-2-甲基丙基)-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.082 (16.00), 2.450 (9.71), 2.518 (2.68), 2.522 (1.68), 2.673 (0.49), 2.886 (1.55), 2.897 (2.45), 2.903 (2.59), 2.915 (2.00), 3.182 (2.12), 3.197 (2.12), 4.626 (4.38), 5.385 (4.13), 7.057 (1.10), 7.077 (1.16), 7.289 (0.54), 7.292 (0.54), 7.301 (0.58), 7.305 (0.59), 7.308 (0.66), 7.311 (0.59), 7.320 (0.64), 7.323 (0.59), 7.580 (0.42), 7.595 (0.90), 7.610 (0.42), 7.636 (3.12), 7.750 (0.68), 7.755 (0.70), 7.769 (1.15), 7.774 (1.16), 7.788 (0.59), 7.794 (0.59), 8.528 (0.71), 8.531 (0.79), 8.532 (0.85), 8.535 (0.72), 8.540 (0.74), 8.543 (0.82), 8.545 (0.80), 8.547 (0.69). LC-MS (方法A ); Rt = 0.88 min, m/z = 381 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
11 | 8-甲基-N -{[5-(嗎啉-4-基甲基)-1,2-㗁唑-3-基]甲基}-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.331 (1.14), 2.382 (3.40), 2.394 (4.56), 2.404 (3.50), 2.456 (16.00), 2.518 (6.62), 2.522 (4.07), 2.878 (1.31), 2.896 (9.97), 2.903 (3.82), 3.542 (4.32), 3.554 (5.53), 3.565 (4.22), 3.608 (1.19), 3.637 (9.33), 4.402 (3.42), 4.417 (3.40), 5.385 (7.57), 6.312 (5.51), 7.060 (1.96), 7.079 (2.03), 7.290 (1.04), 7.305 (1.24), 7.308 (1.24), 7.321 (1.19), 7.640 (5.23), 7.750 (1.09), 7.755 (1.09), 7.770 (1.96), 7.774 (1.93), 7.789 (0.99), 7.794 (0.97), 8.530 (1.61), 8.532 (1.61), 8.542 (1.61), 8.688 (0.84), 8.703 (1.81), 8.719 (0.82). LC-MS (方法A ); Rt = 0.92 min, m/z = 489 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
12 | 8-甲基-2-(吡啶-2-基甲基)-N -(2-{4-[5-(三氟甲基)吡啶-2-基]哌𠯤-1-基}乙基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.447 (16.00), 2.472 (1.82), 2.515 (4.31), 2.518 (2.77), 2.522 (1.96), 2.881 (2.55), 2.890 (5.99), 2.898 (3.08), 3.349 (1.72), 3.362 (1.62), 3.376 (0.64), 3.606 (2.73), 3.616 (3.37), 3.625 (2.41), 5.381 (6.48), 6.945 (1.65), 6.963 (1.67), 7.061 (1.74), 7.077 (1.79), 7.291 (0.85), 7.294 (0.84), 7.301 (0.85), 7.303 (0.92), 7.306 (0.97), 7.309 (0.88), 7.317 (0.92), 7.318 (0.92), 7.632 (4.90), 7.753 (1.04), 7.757 (1.12), 7.769 (3.00), 7.772 (2.62), 7.784 (1.23), 7.788 (2.07), 7.792 (1.15), 7.992 (0.70), 8.004 (1.51), 8.015 (0.73), 8.396 (1.76), 8.401 (1.69), 8.528 (1.12), 8.530 (1.25), 8.532 (1.22), 8.533 (1.08), 8.538 (1.13), 8.540 (1.29), 8.541 (1.23), 8.543 (1.09). LC-MS (方法A ); Rt = 1.25 min, m/z = 564 [M-H]⁻. | 中間物2; GP G (條件A,使用T3P) |
13 | 8-甲基-2-(吡啶-2-基甲基)-N -(2-{4-[3-(三氟甲基)苯基]哌𠯤-1-基}乙基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.448 (13.47), 2.518 (3.20), 2.522 (2.00), 2.554 (2.05), 2.567 (2.79), 2.579 (2.20), 2.673 (0.51), 2.880 (2.35), 2.888 (6.73), 2.896 (2.65), 3.208 (2.20), 3.221 (2.75), 3.232 (2.08), 3.337 (16.00), 3.350 (1.81), 3.367 (1.38), 3.383 (0.56), 5.380 (5.11), 7.045 (1.03), 7.057 (1.66), 7.060 (1.47), 7.064 (1.22), 7.077 (1.58), 7.153 (1.52), 7.207 (0.73), 7.228 (0.86), 7.233 (0.78), 7.287 (0.75), 7.290 (0.77), 7.299 (0.78), 7.302 (0.81), 7.306 (0.86), 7.309 (0.83), 7.318 (0.84), 7.321 (0.81), 7.388 (0.80), 7.408 (1.25), 7.427 (0.57), 7.631 (4.34), 7.748 (0.91), 7.753 (0.93), 7.768 (1.55), 7.772 (1.60), 7.787 (0.84), 7.791 (0.81), 7.982 (0.56), 7.997 (1.23), 8.011 (0.56), 8.526 (0.93), 8.528 (1.12), 8.531 (1.10), 8.532 (1.03), 8.538 (0.98), 8.540 (1.15), 8.543 (1.07), 8.545 (0.95). LC-MS (方法A ); Rt = 1.32 min, m/z = 563 [M-H]⁻. | 中間物2; GP G (條件A,使用T3P) |
14 | N -{[5-(3-甲氧基苯基)-1,2-㗁唑-3-基]甲基}-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.472 (11.91), 2.518 (1.41), 2.522 (0.90), 2.893 (2.01), 2.902 (5.58), 2.910 (2.31), 3.811 (0.44), 3.821 (16.00), 3.831 (0.50), 4.475 (2.18), 4.490 (2.16), 5.387 (4.59), 6.965 (5.30), 7.037 (0.68), 7.044 (0.85), 7.051 (1.09), 7.060 (1.88), 7.063 (1.60), 7.067 (1.43), 7.083 (1.44), 7.289 (0.65), 7.293 (0.65), 7.301 (0.68), 7.305 (0.72), 7.308 (0.77), 7.311 (0.71), 7.320 (0.76), 7.323 (0.70), 7.384 (1.22), 7.388 (1.42), 7.392 (1.64), 7.401 (0.45), 7.419 (1.88), 7.425 (1.56), 7.429 (1.43), 7.434 (3.05), 7.436 (2.97), 7.641 (3.66), 7.751 (0.83), 7.755 (0.82), 7.771 (1.34), 7.775 (1.40), 7.790 (0.72), 7.794 (0.73), 8.528 (0.84), 8.531 (0.99), 8.532 (0.96), 8.535 (0.90), 8.541 (0.86), 8.543 (1.01), 8.545 (0.92), 8.547 (0.84), 8.748 (0.55), 8.763 (1.25), 8.778 (0.53). LC-MS (方法A ); Rt = 1.18 min, m/z = 496 [M+H]⁺. | 中間物2; GP G (條件A,使用T3P) |
15 | 8-甲基-N -[(4-甲基-1,2,5-㗁二唑-3-基)甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.374 (16.00), 2.445 (11.53), 2.515 (0.91), 2.518 (0.86), 2.522 (0.67), 2.890 (1.80), 2.900 (4.08), 2.907 (2.19), 4.555 (2.92), 4.566 (2.87), 5.385 (4.72), 7.058 (1.19), 7.074 (1.25), 7.291 (0.58), 7.294 (0.59), 7.301 (0.62), 7.303 (0.66), 7.306 (0.68), 7.309 (0.62), 7.317 (0.65), 7.318 (0.65), 7.640 (3.29), 7.753 (0.73), 7.757 (0.71), 7.768 (1.22), 7.772 (1.25), 7.784 (0.64), 7.787 (0.63), 8.528 (0.72), 8.530 (0.84), 8.532 (0.89), 8.534 (0.79), 8.538 (0.78), 8.540 (0.86), 8.541 (0.83), 8.543 (0.74), 8.796 (0.53), 8.807 (1.14), 8.819 (0.52). LC-MS (方法A ); Rt = 0.99 min, m/z = 403 [M-H]⁻. | 中間物2; GP G (條件A,使用T3P) |
16 | N -[(5-環丙基-1,2-㗁唑-4-基)甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.949 (0.72), 0.958 (2.17), 0.963 (2.29), 0.968 (1.99), 0.970 (1.73), 0.973 (2.29), 0.980 (1.12), 1.038 (1.03), 1.045 (2.23), 1.050 (1.75), 1.055 (1.31), 1.060 (1.16), 1.062 (2.38), 1.067 (1.74), 1.077 (0.70), 1.298 (0.40), 2.285 (0.73), 2.291 (0.75), 2.295 (0.43), 2.301 (1.34), 2.308 (0.46), 2.312 (0.70), 2.318 (0.73), 2.365 (0.46), 2.450 (16.00), 2.515 (1.92), 2.518 (1.79), 2.522 (1.37), 2.639 (0.45), 2.881 (2.91), 2.887 (8.47), 2.893 (3.17), 4.237 (3.59), 4.249 (3.53), 5.381 (6.74), 7.059 (1.73), 7.075 (1.81), 7.291 (0.82), 7.293 (0.89), 7.301 (0.88), 7.303 (0.97), 7.306 (0.99), 7.308 (0.92), 7.316 (0.97), 7.318 (1.00), 7.632 (4.92), 7.752 (1.01), 7.756 (1.08), 7.768 (1.72), 7.771 (1.67), 7.783 (0.96), 7.787 (0.94), 8.345 (5.80), 8.528 (1.11), 8.529 (1.31), 8.531 (1.31), 8.533 (1.15), 8.537 (1.06), 8.539 (1.29), 8.541 (1.29), 8.543 (1.13), 8.582 (0.75), 8.594 (1.59), 8.605 (0.73). LC-MS (方法A ); Rt = 1.04 min, m/z = 430 [M+H]⁺. | 中間物2; GP G (條件A,使用T3P) |
17 | N -{[5-(2-氯苯基)-1,2-㗁唑-3-基]甲基}-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.464 (16.00), 2.515 (1.40), 2.518 (1.27), 2.522 (1.00), 2.878 (0.48), 2.893 (2.70), 2.902 (4.45), 2.906 (4.56), 2.915 (3.27), 2.929 (0.51), 4.516 (3.53), 4.529 (3.46), 5.387 (7.06), 7.018 (7.13), 7.061 (1.86), 7.077 (1.90), 7.293 (0.90), 7.303 (1.02), 7.306 (1.05), 7.316 (1.00), 7.506 (0.58), 7.516 (1.66), 7.520 (2.00), 7.523 (1.87), 7.529 (3.81), 7.535 (2.05), 7.538 (1.95), 7.542 (1.93), 7.552 (0.73), 7.557 (0.41), 7.640 (5.03), 7.656 (2.05), 7.660 (1.28), 7.663 (1.03), 7.670 (1.30), 7.675 (1.50), 7.753 (1.02), 7.756 (1.03), 7.768 (1.84), 7.772 (1.82), 7.784 (0.90), 7.787 (0.94), 7.891 (1.87), 7.896 (1.40), 7.903 (1.06), 7.906 (1.10), 7.910 (1.67), 8.531 (1.34), 8.532 (1.32), 8.540 (1.37), 8.542 (1.32), 8.778 (0.83), 8.790 (1.83), 8.802 (0.81). LC-MS (方法A ); Rt = 1.23 min, m/z = 500 [M+H]⁺. | 中間物2; GP G (條件A,使用T3P) |
18 | N -[(5-異丙基-1,2-㗁唑-3-基)甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.208 (16.00), 1.225 (15.90), 2.457 (11.68), 2.518 (1.31), 2.522 (0.83), 2.889 (2.25), 2.895 (6.73), 2.902 (2.41), 3.024 (0.69), 3.039 (0.90), 3.057 (0.67), 4.375 (2.42), 4.391 (2.40), 5.385 (4.63), 6.124 (3.35), 6.126 (3.35), 7.060 (1.28), 7.079 (1.34), 7.289 (0.63), 7.292 (0.62), 7.301 (0.67), 7.304 (0.71), 7.308 (0.74), 7.310 (0.66), 7.320 (0.72), 7.323 (0.66), 7.639 (3.63), 7.750 (0.75), 7.755 (0.77), 7.769 (1.30), 7.774 (1.30), 7.788 (0.64), 7.794 (0.65), 8.528 (0.83), 8.530 (0.93), 8.532 (0.96), 8.534 (0.86), 8.540 (0.87), 8.542 (0.96), 8.545 (0.91), 8.546 (0.79), 8.661 (0.54), 8.676 (1.18), 8.691 (0.52). LC-MS (方法A ); Rt = 1.12 min, m/z = 432 [M+H]⁺. | 中間物2; GP G (條件A,使用T3P) |
19-1 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.441 (16.00), 2.515 (1.61), 2.518 (1.41), 2.522 (1.10), 2.883 (2.78), 2.893 (6.07), 2.900 (3.25), 3.165 (0.70), 3.180 (0.91), 3.185 (1.35), 3.192 (1.49), 3.204 (2.14), 3.208 (1.55), 3.219 (0.76), 3.227 (1.69), 3.231 (1.47), 3.244 (0.92), 3.258 (0.69), 3.420 (0.44), 3.425 (0.54), 3.442 (1.09), 3.447 (1.17), 3.464 (0.93), 3.469 (0.86), 3.515 (0.76), 3.520 (0.86), 3.538 (1.12), 3.543 (1.15), 3.560 (0.53), 3.565 (0.71), 3.609 (1.55), 3.614 (1.00), 3.621 (0.69), 3.628 (1.52), 3.633 (1.26), 3.685 (1.18), 3.689 (1.04), 3.713 (2.03), 3.737 (0.88), 5.383 (7.04), 7.062 (1.77), 7.078 (1.83), 7.293 (0.85), 7.294 (0.88), 7.302 (0.93), 7.304 (0.98), 7.307 (1.00), 7.317 (0.98), 7.319 (0.96), 7.633 (4.83), 7.754 (1.02), 7.758 (1.06), 7.770 (1.72), 7.773 (1.75), 7.785 (0.96), 7.789 (0.93), 8.047 (0.73), 8.059 (1.58), 8.071 (0.73), 8.529 (1.09), 8.531 (1.26), 8.533 (1.29), 8.535 (1.17), 8.539 (1.16), 8.541 (1.33), 8.543 (1.27). LC-MS (方法A ); Rt = 0.89 min, m/z = 407 [M-H]⁻. | 中間物2; GP G (條件A,使用T3P) |
19-2 | N-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.441 (16.00), 2.515 (1.58), 2.518 (1.60), 2.522 (1.25), 2.882 (2.57), 2.890 (5.32), 2.892 (5.62), 2.900 (3.23), 3.164 (0.71), 3.176 (0.53), 3.180 (0.86), 3.185 (1.32), 3.192 (1.48), 3.204 (2.11), 3.207 (1.50), 3.219 (0.74), 3.227 (1.65), 3.231 (1.42), 3.243 (0.89), 3.258 (0.66), 3.419 (0.48), 3.424 (0.59), 3.441 (1.07), 3.446 (1.17), 3.463 (0.94), 3.468 (0.86), 3.515 (0.76), 3.519 (0.84), 3.538 (1.12), 3.543 (1.12), 3.559 (0.53), 3.565 (0.71), 3.608 (1.42), 3.613 (0.94), 3.621 (0.61), 3.627 (1.40), 3.632 (1.20), 3.684 (1.14), 3.689 (0.99), 3.712 (1.88), 3.736 (0.81), 5.381 (6.77), 7.062 (1.73), 7.078 (1.81), 7.292 (0.89), 7.294 (0.84), 7.301 (0.86), 7.304 (0.94), 7.307 (0.99), 7.309 (0.89), 7.317 (0.94), 7.319 (0.92), 7.632 (4.93), 7.754 (1.02), 7.757 (1.07), 7.769 (1.91), 7.773 (1.86), 7.784 (0.97), 7.788 (1.02), 8.048 (0.71), 8.060 (1.53), 8.072 (0.69), 8.528 (1.12), 8.530 (1.25), 8.532 (1.25), 8.534 (1.09), 8.538 (1.07), 8.540 (1.22), 8.541 (1.22), 8.543 (1.09). LC-MS (方法A ); Rt = 0.89 min, m/z = 407 [M-H]⁻. | 中間物2; GP G (條件A,使用T3P) |
20 | 8-甲基-2-(吡啶-2-基甲基)-N -(4H -1,2,4-三唑-3-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.450 (16.00), 2.518 (2.53), 2.522 (1.57), 2.891 (3.50), 2.898 (10.01), 2.905 (3.63), 4.459 (2.72), 4.474 (2.75), 5.386 (7.11), 7.067 (1.93), 7.087 (2.01), 7.289 (0.98), 7.293 (0.96), 7.302 (1.02), 7.305 (1.11), 7.308 (1.18), 7.311 (1.08), 7.320 (1.14), 7.323 (1.05), 7.640 (5.45), 7.752 (1.18), 7.756 (1.21), 7.771 (2.01), 7.775 (2.02), 7.790 (1.01), 7.795 (1.04), 8.529 (1.60), 8.531 (1.80), 8.533 (1.78), 8.535 (1.62), 8.541 (1.53), 8.543 (1.69), 8.545 (1.58), 8.547 (1.40). LC-MS (方法A ); Rt = 0.63 min, m/z = 390 [M+H]⁺. | 中間物2; GP G (條件A,使用T3P) |
21 | 8-甲基-N ,2-聯(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.458 (16.00), 2.515 (1.95), 2.518 (1.81), 2.522 (1.41), 2.758 (0.44), 2.884 (0.57), 2.900 (2.50), 2.908 (3.86), 2.914 (4.07), 2.924 (3.19), 2.938 (0.58), 4.491 (3.16), 4.503 (3.16), 5.390 (6.89), 7.066 (1.74), 7.082 (1.83), 7.243 (0.90), 7.253 (0.98), 7.256 (0.98), 7.267 (0.98), 7.291 (1.70), 7.306 (2.70), 7.320 (1.04), 7.644 (4.62), 7.733 (0.95), 7.736 (1.01), 7.748 (1.70), 7.752 (1.69), 7.757 (1.08), 7.761 (1.23), 7.764 (1.06), 7.767 (1.00), 7.773 (1.81), 7.777 (1.76), 7.788 (0.95), 7.792 (1.01), 8.494 (1.20), 8.496 (1.26), 8.502 (1.08), 8.504 (1.22), 8.506 (1.22), 8.507 (1.09), 8.533 (1.09), 8.535 (1.23), 8.536 (1.26), 8.538 (1.18), 8.542 (1.18), 8.544 (1.32), 8.546 (1.26), 8.658 (0.74), 8.670 (1.62), 8.682 (0.76). LC-MS (方法A ); Rt = 0.94 min, m/z = 400 [M+H]⁺. | 中間物2; GP G (條件A,使用T3P) |
22 | 8-甲基-N -(1H -吡唑-3-基甲基)-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.974 (0.47), 1.978 (0.49), 2.365 (0.75), 2.453 (16.00), 2.465 (0.41), 2.515 (3.21), 2.518 (3.07), 2.522 (2.40), 2.639 (0.80), 2.885 (10.57), 2.890 (3.39), 4.378 (1.71), 4.390 (1.70), 5.383 (7.00), 6.134 (1.42), 7.060 (1.78), 7.076 (1.86), 7.293 (1.04), 7.294 (1.04), 7.302 (1.13), 7.304 (1.17), 7.307 (1.19), 7.317 (1.26), 7.319 (1.21), 7.625 (0.57), 7.632 (5.04), 7.641 (0.57), 7.703 (1.61), 7.754 (1.11), 7.757 (1.09), 7.769 (1.94), 7.773 (1.91), 7.784 (1.01), 7.788 (1.01), 7.816 (0.42), 7.820 (0.49), 8.529 (1.17), 8.531 (1.29), 8.533 (1.34), 8.535 (1.27), 8.539 (1.29), 8.541 (1.40), 8.543 (1.29), 8.544 (1.13). LC-MS (方法A ); Rt = 0.84 min, m/z = 389 [M+H]⁺. | 中間物2; GP G (條件A,使用T3P) |
23 | 8-甲基-2-(吡啶-2-基甲基)-N -(1,3-噻唑-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.074 (0.83), 2.465 (16.00), 2.515 (1.82), 2.518 (1.76), 2.522 (1.39), 2.765 (1.16), 2.884 (0.52), 2.900 (2.46), 2.909 (3.84), 2.914 (4.05), 2.923 (3.08), 2.937 (0.51), 4.655 (3.65), 4.667 (3.70), 5.391 (6.59), 7.064 (1.67), 7.080 (1.73), 7.294 (0.83), 7.296 (0.83), 7.304 (0.87), 7.306 (0.88), 7.310 (0.92), 7.311 (0.88), 7.319 (0.93), 7.321 (0.90), 7.600 (4.43), 7.607 (4.79), 7.646 (4.62), 7.713 (4.46), 7.719 (3.52), 7.756 (1.06), 7.760 (1.07), 7.772 (1.69), 7.775 (1.76), 7.787 (0.95), 7.791 (0.93), 8.532 (1.04), 8.534 (1.17), 8.535 (1.21), 8.537 (1.12), 8.541 (1.17), 8.543 (1.27), 8.545 (1.17), 8.546 (1.02), 8.652 (0.42), 8.984 (0.74), 8.996 (1.58), 9.008 (0.74). LC-MS (方法A ); Rt = 0.93 min, m/z = 406 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
24 | 8-甲基-N -(1,2-㗁唑-4-基甲基)-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.322 (0.59), 2.326 (0.79), 2.331 (0.59), 2.452 (16.00), 2.522 (2.85), 2.664 (0.62), 2.669 (0.81), 2.673 (0.61), 2.753 (0.59), 2.887 (11.30), 4.252 (3.34), 4.267 (3.35), 5.382 (7.01), 7.057 (1.86), 7.077 (1.96), 7.291 (0.97), 7.303 (1.12), 7.306 (1.17), 7.318 (1.21), 7.633 (5.03), 7.749 (1.06), 7.753 (1.08), 7.768 (1.84), 7.772 (1.84), 7.787 (1.00), 7.792 (0.98), 8.532 (7.66), 8.538 (1.63), 8.540 (1.71), 8.542 (1.60), 8.581 (0.86), 8.596 (1.68), 8.611 (0.78), 8.819 (4.55). LC-MS (方法A ); Rt = 0.90 min, m/z = 388 [M-H]⁻. | 中間物2; GP G (條件A,使用HATU) |
25 | 8-甲基-2-(吡啶-2-基甲基)-N -{[5-(三氟甲基)-1,2-㗁唑-3-基]甲基}-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.062 (0.66), 2.365 (0.84), 2.426 (0.41), 2.457 (16.00), 2.515 (4.08), 2.518 (3.56), 2.522 (2.75), 2.758 (0.72), 2.893 (2.68), 2.903 (5.78), 2.911 (3.21), 4.526 (3.63), 4.538 (3.59), 5.387 (6.81), 7.065 (1.74), 7.081 (1.81), 7.294 (0.97), 7.306 (1.01), 7.309 (1.10), 7.318 (1.13), 7.335 (3.02), 7.337 (3.11), 7.643 (4.63), 7.755 (1.08), 7.759 (1.08), 7.771 (1.71), 7.774 (1.78), 7.786 (0.95), 7.790 (1.08), 8.530 (1.24), 8.532 (1.36), 8.534 (1.35), 8.541 (1.38), 8.782 (0.77), 8.794 (1.67), 8.806 (0.79). LC-MS (方法A ); Rt = 1.14 min, m/z = 458 [M+H]⁺. | 中間物2; GP G (條件A,使用T3P) |
26 | 8-甲基-N -[(4-甲基-1,2-㗁唑-3-基)甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.967 (12.48), 1.969 (12.22), 1.996 (0.59), 1.998 (0.61), 2.448 (16.00), 2.514 (2.01), 2.518 (1.68), 2.522 (1.28), 2.748 (0.77), 2.886 (3.31), 2.891 (10.01), 2.897 (3.54), 4.439 (3.90), 4.450 (3.84), 5.385 (7.25), 7.057 (1.82), 7.073 (1.89), 7.293 (0.94), 7.303 (1.04), 7.306 (1.18), 7.316 (1.06), 7.636 (4.99), 7.752 (1.02), 7.756 (1.06), 7.768 (1.79), 7.771 (1.79), 7.783 (0.97), 7.787 (0.98), 8.532 (1.36), 8.534 (1.25), 8.540 (1.44), 8.574 (2.79), 8.575 (2.85), 8.582 (0.97), 8.594 (1.92), 8.606 (0.88). LC-MS (方法A ); Rt = 0.97 min, m/z = 402 [M-H]⁻. | 中間物2; GP G (條件A,使用T3P) |
27 | N -[(3,5-二甲基-1,2-㗁唑-4-基)甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.205 (16.00), 2.237 (0.58), 2.384 (14.62), 2.416 (0.56), 2.441 (13.71), 2.515 (4.38), 2.518 (3.66), 2.522 (2.80), 2.741 (0.53), 2.877 (2.84), 2.883 (8.14), 2.889 (2.96), 4.117 (3.08), 4.128 (3.08), 5.378 (6.02), 7.054 (1.52), 7.070 (1.59), 7.292 (0.88), 7.302 (0.88), 7.305 (0.91), 7.315 (0.86), 7.629 (4.22), 7.751 (0.86), 7.755 (0.89), 7.767 (1.45), 7.770 (1.51), 7.782 (0.77), 7.786 (0.75), 8.519 (0.75), 8.530 (2.57), 8.540 (1.61). LC-MS (方法A ); Rt = 0.98 min, m/z = 418 [M+H]⁺. | 中間物2; GP G (條件A,使用T3P) |
28 | N -[2-(3,3-二甲基-2-氧氮雜環丁-1-基)乙基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.123 (16.00), 2.306 (4.58), 2.326 (0.71), 2.438 (8.28), 2.669 (0.66), 2.879 (5.03), 2.892 (7.28), 3.022 (0.62), 3.091 (4.89), 3.216 (0.80), 3.230 (1.67), 3.244 (1.28), 3.304 (1.09), 5.383 (6.29), 7.029 (0.55), 7.043 (1.25), 7.062 (1.24), 7.289 (0.89), 7.301 (1.13), 7.305 (1.16), 7.318 (1.07), 7.634 (3.44), 7.746 (0.80), 7.750 (0.84), 7.765 (1.54), 7.769 (1.53), 7.784 (0.83), 7.789 (0.84), 8.167 (0.46), 8.182 (0.94), 8.196 (0.47), 8.530 (1.48), 8.541 (1.55). LC-MS (方法A ); Rt = 0.91 min, m/z = 434 [M+H]⁺. | 中間物2; GP G (條件A,使用T3P) |
29 | N -(2-甲氧基乙基)-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 2.86-2.91 (m, 4H), 3.23-3.25 (m, 5H), 3.40-3.43 (m, 2H), 5.38 (s, 2H), 7.07 (d, 1H), 7.31 (ddd, 1H), 7.63 (s, 1H), 7.77 (dt, 1H), 8.01 (t, 1H), 8.54 (ddd, 1H). LC-MS (方法A ); Rt = 0.91 min, m/z = 367 [M+H]⁺. | 中間物2; GP G (條件A,使用T3P) |
30 | [(2R/S)-2-(胺基甲基)吡咯啶-1-基][8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-基]甲酮 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.76-1.89 (m, 4H), 2.40-2.44 (m, 3H), 2.88 (br. s., 4H), 3.19-3.22 (m, 1H), 3.66-3.91 (m, 3H), 4.09-4.29 (m, 1H), 5.38 (s, 2H), 7.05 (d, 1H), 7.31 (ddd, 1H), 7.63 (s, 1H), 7.77 (dt, 1H), 8.54 (ddd, 1H). LC-MS (方法A ); Rt = 0.90 min, m/z = 392 [M+H]⁺. | 中間物2; GP G (條件A,使用T3P) |
31 | 3-[({[8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-基]羰基}胺基)甲基]-1,2-㗁唑-4-甲酸 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.144 (1.60), 1.162 (3.51), 1.180 (1.68), 2.327 (0.53), 2.403 (0.40), 2.444 (16.00), 2.523 (1.73), 2.665 (0.42), 2.669 (0.58), 2.673 (0.42), 2.747 (0.51), 2.888 (11.60), 3.005 (0.40), 3.024 (1.07), 3.041 (1.07), 3.060 (0.42), 3.341 (1.54), 4.614 (3.13), 4.628 (3.14), 5.384 (6.88), 7.056 (1.96), 7.075 (2.04), 7.287 (1.09), 7.299 (1.22), 7.304 (1.32), 7.316 (1.24), 7.633 (5.21), 7.748 (1.10), 7.752 (1.14), 7.767 (1.98), 7.771 (1.96), 7.786 (1.00), 7.791 (1.08), 8.529 (1.51), 8.531 (1.56), 8.538 (1.36), 8.541 (1.55), 8.543 (1.48), 9.072 (0.45), 9.166 (1.58). LC-MS (方法A ); Rt = 0.57 min, m/z = 434 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
32 | 8-甲基-N -(1,3-㗁唑-2-基甲基)-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.899 (0.66), 0.915 (1.37), 0.932 (1.14), 1.198 (0.94), 1.471 (1.01), 1.974 (0.68), 1.978 (0.68), 2.412 (0.41), 2.435 (3.11), 2.447 (16.00), 2.518 (8.71), 2.523 (5.90), 2.708 (0.41), 2.748 (1.01), 2.816 (1.09), 2.831 (0.56), 2.838 (0.66), 2.879 (3.54), 2.886 (2.46), 2.894 (3.70), 2.902 (8.89), 2.911 (3.92), 2.928 (0.89), 2.940 (0.63), 4.479 (3.87), 4.494 (3.90), 5.387 (7.27), 5.403 (0.66), 7.055 (0.46), 7.067 (1.92), 7.086 (1.97), 7.139 (4.78), 7.141 (4.78), 7.290 (1.27), 7.305 (1.44), 7.308 (1.52), 7.321 (1.47), 7.631 (1.14), 7.642 (5.14), 7.752 (1.29), 7.756 (1.29), 7.771 (2.15), 7.776 (2.18), 7.785 (0.46), 7.790 (1.22), 7.795 (1.27), 8.030 (4.89), 8.032 (4.78), 8.531 (1.95), 8.533 (2.03), 8.543 (1.95), 8.545 (1.90), 8.719 (0.81), 8.734 (1.70), 8.748 (0.81). LC-MS (方法A ); Rt = 0.87 min, m/z = 390 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
33-1 | 8-甲基-2-(吡啶-2-基甲基)-N -[(3S)-四氫呋喃-3-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.552 (0.48), 1.566 (0.73), 1.585 (0.77), 1.600 (0.55), 1.871 (0.65), 1.886 (0.71), 1.891 (0.51), 1.896 (0.44), 1.902 (0.61), 1.916 (0.55), 2.442 (16.00), 2.456 (0.95), 2.476 (0.85), 2.518 (2.00), 2.523 (1.35), 2.883 (2.87), 2.892 (7.47), 2.902 (3.29), 3.154 (1.09), 3.162 (1.05), 3.172 (1.52), 3.176 (1.54), 3.188 (1.05), 3.195 (1.07), 3.429 (1.19), 3.442 (1.23), 3.450 (1.47), 3.464 (1.39), 3.564 (0.63), 3.583 (1.37), 3.601 (1.47), 3.620 (0.89), 3.628 (1.52), 3.645 (1.70), 3.649 (1.56), 3.667 (1.19), 3.691 (0.77), 3.705 (0.91), 3.711 (1.29), 3.725 (1.25), 3.731 (0.69), 3.745 (0.53), 5.381 (6.55), 7.060 (1.76), 7.079 (1.84), 7.289 (0.91), 7.291 (0.93), 7.301 (0.95), 7.303 (1.01), 7.308 (1.15), 7.310 (1.01), 7.320 (1.05), 7.322 (0.99), 7.630 (4.93), 7.750 (1.11), 7.754 (1.13), 7.769 (1.80), 7.773 (1.80), 7.788 (0.93), 7.793 (0.95), 8.237 (0.69), 8.252 (1.45), 8.266 (0.69), 8.527 (1.21), 8.529 (1.37), 8.531 (1.47), 8.534 (1.25), 8.539 (1.29), 8.541 (1.37), 8.543 (1.35), 8.546 (1.13). LC-MS (方法A ); Rt = 0.90 min, m/z = 393 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
33-2 | 8-甲基-2-(吡啶-2-基甲基)-N -[(3R)-四氫呋喃-3-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.552 (0.46), 1.566 (0.72), 1.586 (0.75), 1.600 (0.55), 1.866 (0.39), 1.871 (0.65), 1.886 (0.75), 1.892 (0.55), 1.897 (0.49), 1.902 (0.65), 1.906 (0.65), 1.917 (0.59), 1.922 (0.49), 1.937 (0.39), 2.442 (16.00), 2.456 (0.98), 2.518 (3.06), 2.523 (2.12), 2.743 (3.10), 2.884 (2.80), 2.893 (6.88), 2.902 (3.10), 3.154 (1.04), 3.162 (1.01), 3.172 (1.47), 3.176 (1.47), 3.188 (1.01), 3.195 (1.08), 3.429 (1.17), 3.442 (1.21), 3.450 (1.47), 3.464 (1.37), 3.564 (0.65), 3.583 (1.40), 3.601 (1.66), 3.604 (1.37), 3.621 (1.11), 3.628 (1.53), 3.645 (1.69), 3.649 (1.56), 3.661 (0.42), 3.667 (1.24), 3.691 (0.81), 3.706 (0.95), 3.711 (1.30), 3.725 (1.27), 3.731 (0.78), 3.745 (0.59), 5.382 (6.29), 5.805 (1.08), 7.060 (1.66), 7.079 (1.76), 7.289 (0.88), 7.292 (0.88), 7.301 (0.95), 7.304 (1.01), 7.308 (1.66), 7.311 (0.98), 7.320 (1.14), 7.323 (0.98), 7.331 (0.85), 7.631 (4.92), 7.750 (1.11), 7.755 (1.21), 7.758 (0.81), 7.769 (1.86), 7.774 (1.89), 7.781 (0.75), 7.788 (1.01), 7.794 (1.04), 8.237 (0.65), 8.252 (1.37), 8.266 (0.65), 8.527 (1.14), 8.529 (1.30), 8.532 (1.37), 8.534 (1.34), 8.539 (1.34), 8.541 (1.47), 8.544 (1.34), 8.546 (1.24), 8.633 (1.21). LC-MS (方法A ); Rt = 0.90 min, m/z = 393 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
34 | 8-甲基-N -[(1-甲基-1H -吡唑-3-基)甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.447 (12.27), 2.518 (1.68), 2.523 (1.22), 2.748 (0.45), 2.883 (9.36), 3.760 (0.50), 3.769 (16.00), 3.781 (0.70), 4.310 (2.50), 4.326 (2.48), 5.382 (4.90), 6.096 (2.69), 6.102 (2.70), 7.057 (1.34), 7.076 (1.40), 7.288 (0.71), 7.291 (0.70), 7.300 (0.72), 7.303 (0.76), 7.307 (0.82), 7.309 (0.75), 7.319 (0.85), 7.321 (0.75), 7.552 (2.31), 7.558 (2.26), 7.632 (4.03), 7.749 (0.86), 7.754 (0.92), 7.768 (1.46), 7.773 (1.51), 7.787 (0.82), 7.792 (0.80), 8.368 (0.54), 8.383 (1.17), 8.398 (0.52), 8.527 (0.90), 8.529 (1.03), 8.532 (1.08), 8.534 (1.00), 8.539 (0.98), 8.541 (1.06), 8.544 (1.01), 8.546 (0.89). LC-MS (方法A ); Rt = 0.89 min, m/z = 403 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
35 | 8-甲基-N -[(2R/S)-氧雜環丁-2-基甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.370 (0.41), 2.393 (0.48), 2.398 (0.60), 2.402 (0.43), 2.415 (0.49), 2.419 (0.54), 2.445 (16.00), 2.518 (1.30), 2.523 (0.87), 2.569 (0.41), 2.574 (0.53), 2.588 (0.53), 2.594 (0.57), 2.602 (0.45), 2.609 (0.44), 2.616 (0.42), 2.798 (0.58), 2.884 (2.59), 2.891 (8.02), 2.900 (3.13), 2.968 (0.46), 3.097 (0.49), 3.213 (0.53), 3.391 (0.65), 3.405 (0.44), 3.410 (0.78), 3.425 (1.36), 3.439 (0.69), 3.455 (0.72), 3.470 (1.30), 3.485 (0.83), 3.488 (0.48), 3.504 (0.57), 4.383 (0.57), 4.397 (1.22), 4.406 (0.68), 4.413 (0.98), 4.420 (1.20), 4.435 (0.71), 4.462 (0.73), 4.477 (0.64), 4.480 (0.92), 4.483 (1.00), 4.494 (0.70), 4.497 (0.75), 4.501 (0.83), 4.516 (0.54), 4.754 (0.75), 4.770 (0.91), 4.773 (0.94), 4.789 (0.74), 5.383 (6.29), 7.059 (1.69), 7.079 (1.76), 7.289 (0.83), 7.291 (0.86), 7.300 (0.90), 7.303 (0.94), 7.307 (0.97), 7.310 (0.99), 7.319 (0.99), 7.322 (0.94), 7.634 (4.84), 7.749 (1.08), 7.754 (1.10), 7.768 (1.74), 7.773 (1.77), 7.788 (0.96), 7.792 (0.96), 8.109 (0.64), 8.124 (1.32), 8.138 (0.63), 8.527 (1.13), 8.529 (1.22), 8.532 (1.32), 8.534 (1.11), 8.539 (1.19), 8.542 (1.26), 8.544 (1.26), 8.546 (1.05). LC-MS (方法A ); Rt = 0.86 min, m/z = 379 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
35-1 | 實例35之對映異構體1 | Rt = 3.47 min | 分析型方法: 儀器:Agilent:1260,Aurora SFC模組;管柱:Chiralpak IA 5 µm,100x4.6 mm;溶離劑A:CO2 ;溶離劑B:甲醇 + 0.2 vol%氨水(32%);等度:20% B;流量:4 mL/min;溫度:37.5℃;BPR:100巴;UV:254 nm. |
35-2 | 實例35之對映異構體2 | Rt = 6.20 min | |
36 | 8-甲基-N -(氧雜環丁-3-基甲基)-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.442 (16.00), 2.518 (1.34), 2.522 (0.93), 2.742 (0.40), 2.881 (2.67), 2.890 (7.18), 2.899 (3.07), 3.102 (0.52), 3.121 (0.79), 3.138 (0.55), 3.446 (1.76), 3.462 (2.41), 3.478 (1.57), 4.308 (2.55), 4.323 (5.35), 4.338 (2.71), 4.583 (3.23), 4.599 (3.29), 4.603 (3.45), 4.617 (2.77), 5.381 (6.29), 7.061 (1.66), 7.081 (1.73), 7.288 (0.86), 7.291 (0.86), 7.300 (0.91), 7.303 (0.98), 7.307 (1.02), 7.310 (0.93), 7.319 (0.99), 7.322 (0.91), 7.631 (4.74), 7.750 (1.06), 7.754 (1.11), 7.769 (1.85), 7.773 (1.84), 7.788 (0.95), 7.792 (0.91), 8.297 (0.65), 8.312 (1.36), 8.327 (0.62), 8.526 (1.11), 8.529 (1.29), 8.531 (1.31), 8.533 (1.21), 8.538 (1.12), 8.541 (1.31), 8.543 (1.21), 8.545 (1.12). LC-MS (方法A ); Rt = 0.83 min, m/z = 379 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
37 | N -[(3-氟氧雜環丁-3-基)甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.456 (16.00), 2.518 (0.84), 2.522 (0.58), 2.889 (2.47), 2.900 (4.13), 2.906 (4.33), 2.917 (3.09), 2.934 (0.41), 3.675 (1.43), 3.691 (1.43), 3.723 (1.42), 3.738 (1.44), 4.559 (1.15), 4.580 (1.94), 4.611 (1.23), 4.632 (2.00), 4.638 (2.20), 4.660 (1.24), 4.690 (2.03), 4.712 (1.25), 5.385 (6.41), 7.065 (1.74), 7.085 (1.83), 7.289 (0.85), 7.292 (0.88), 7.301 (0.89), 7.304 (0.96), 7.308 (0.98), 7.311 (0.92), 7.320 (0.96), 7.323 (0.95), 7.639 (4.68), 7.750 (1.01), 7.755 (1.02), 7.770 (1.76), 7.774 (1.79), 7.789 (0.92), 7.794 (0.91), 8.436 (0.67), 8.451 (1.45), 8.467 (0.66), 8.528 (1.11), 8.530 (1.27), 8.533 (1.31), 8.534 (1.17), 8.540 (1.15), 8.542 (1.27), 8.545 (1.23), 8.546 (1.08). LC-MS (方法A ); Rt = 0.89 min, m/z = 397 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
38 | 8-甲基-N -{[(2R/S)-4-甲基嗎啉-2-基]甲基}-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.656 (0.85), 1.682 (1.17), 1.710 (0.90), 1.917 (0.50), 1.937 (0.92), 1.945 (0.92), 1.965 (0.54), 1.973 (0.49), 2.152 (12.47), 2.440 (16.00), 2.518 (1.08), 2.522 (0.76), 2.537 (0.91), 2.567 (0.81), 2.651 (0.99), 2.669 (0.45), 2.678 (1.00), 2.882 (2.89), 2.890 (8.01), 2.898 (3.11), 3.181 (0.51), 3.200 (0.79), 3.215 (1.34), 3.230 (1.30), 3.245 (1.21), 3.261 (0.82), 3.279 (0.49), 3.427 (0.49), 3.433 (0.61), 3.455 (1.13), 3.461 (1.12), 3.483 (0.67), 3.489 (0.55), 3.536 (0.58), 3.542 (0.71), 3.551 (0.51), 3.561 (0.70), 3.566 (0.56), 3.747 (0.85), 3.751 (0.85), 3.755 (0.67), 3.771 (0.59), 3.775 (0.74), 3.778 (0.70), 5.382 (6.66), 7.058 (1.75), 7.078 (1.83), 7.288 (0.87), 7.291 (0.85), 7.300 (0.92), 7.303 (0.95), 7.307 (1.02), 7.319 (1.00), 7.633 (4.82), 7.749 (0.97), 7.754 (0.96), 7.769 (1.67), 7.773 (1.67), 7.788 (0.87), 7.792 (0.85), 8.018 (0.70), 8.032 (1.47), 8.047 (0.67), 8.527 (1.12), 8.529 (1.30), 8.531 (1.33), 8.534 (1.14), 8.539 (1.14), 8.541 (1.32), 8.543 (1.26). LC-MS (方法A ); Rt = 0.87 min, m/z = 422 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
38-1 | 實例38之對映異構體1 | Rt = 6.99 min | 分析型方法: 儀器:Waters Alliance 2695;管柱:YMC Cellulose SC 3 µm,100x4.6 mm;溶離劑A:己烷 + 0.1 vol%二乙胺;溶離劑B:2-丙醇;等度:70% A + 30% B;流量:1.4 mL/min;溫度:25℃;UV:254 nm. |
38-2 | 實例38之對映異構體2 | Rt = 8.91 min | |
39 | 8-甲基-N -{[(2R/S)-5-側氧基四氫呋喃-2-基]甲基}-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.92), 1.172 (1.83), 1.190 (0.96), 1.904 (0.58), 1.922 (0.49), 1.932 (0.42), 1.936 (0.68), 1.954 (0.66), 1.959 (0.44), 1.987 (3.76), 2.189 (0.40), 2.194 (0.42), 2.204 (0.63), 2.209 (0.44), 2.212 (0.56), 2.226 (0.79), 2.240 (0.41), 2.439 (0.46), 2.451 (16.00), 2.468 (1.44), 2.483 (2.44), 2.518 (2.39), 2.523 (1.86), 2.751 (0.53), 2.889 (2.52), 2.900 (5.86), 2.910 (3.11), 3.319 (0.40), 3.406 (0.88), 3.420 (1.63), 3.431 (1.89), 3.447 (0.88), 4.017 (0.82), 4.034 (0.81), 4.628 (0.76), 4.644 (1.08), 4.658 (0.74), 5.385 (6.39), 7.060 (1.74), 7.080 (1.81), 7.289 (0.89), 7.291 (0.88), 7.301 (0.94), 7.303 (0.95), 7.308 (1.02), 7.310 (0.95), 7.320 (1.03), 7.322 (0.96), 7.637 (4.88), 7.750 (1.10), 7.754 (1.07), 7.770 (1.79), 7.774 (1.93), 7.789 (1.00), 7.793 (1.00), 8.300 (0.68), 8.315 (1.45), 8.330 (0.67), 8.528 (1.10), 8.530 (1.31), 8.532 (1.29), 8.534 (1.21), 8.540 (1.18), 8.542 (1.36), 8.544 (1.25), 8.546 (1.13). UPLC-MS (方法1 ); Rt = 0.84 min, m/z = 407 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
39-1 | 實例39之對映異構體1 | Rt = 4.18 min | 分析型方法: 儀器:Agilent:1260,Aurora SFC模組;管柱:Chiralpak IA 5 µm,100x4.6 mm;溶離劑A:CO2 ;溶離劑B:乙醇 + 0.2 vol%氨水(32%);等度:25% B;流量:4 mL/min;溫度:37.5℃;BPR:100巴;UV:254 nm. |
39-2 | 實例39之對映異構體2 | Rt = 6.46 min | |
40 | 8-甲基-N -(1-甲基-1H -吡唑-3-基)-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.485 (16.00), 2.521 (0.89), 2.525 (0.58), 2.882 (0.46), 2.900 (2.75), 2.911 (6.39), 2.921 (3.20), 3.763 (15.32), 5.395 (6.68), 6.498 (3.41), 6.504 (3.34), 7.067 (1.76), 7.087 (1.84), 7.294 (0.89), 7.296 (0.92), 7.306 (0.96), 7.308 (1.01), 7.313 (1.07), 7.325 (1.09), 7.578 (2.85), 7.584 (2.82), 7.652 (4.67), 7.756 (0.98), 7.760 (1.00), 7.775 (1.70), 7.779 (1.71), 7.795 (0.87), 7.799 (0.88), 8.536 (1.34), 8.538 (1.38), 8.540 (1.24), 8.548 (1.35), 8.550 (1.29), 10.137 (3.27). LC-MS (方法A ); Rt = 0.93 min, m/z = 389 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
41 | 8-甲基-N -(吡啶-3-基)-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.528 (16.00), 2.826 (0.86), 2.908 (0.55), 2.913 (0.59), 2.924 (0.93), 2.931 (2.49), 2.948 (2.21), 2.984 (2.35), 3.001 (2.81), 3.009 (0.94), 3.019 (0.69), 3.025 (0.64), 5.408 (6.78), 7.087 (1.80), 7.107 (1.88), 7.299 (0.92), 7.302 (0.91), 7.312 (0.98), 7.315 (1.05), 7.318 (1.12), 7.321 (1.01), 7.330 (1.11), 7.333 (1.03), 7.342 (1.26), 7.354 (1.25), 7.364 (1.25), 7.375 (1.27), 7.673 (4.57), 7.763 (1.09), 7.767 (1.08), 7.783 (1.81), 7.787 (1.84), 7.802 (1.00), 7.806 (1.01), 8.163 (0.98), 8.167 (1.22), 8.169 (1.12), 8.173 (1.07), 8.184 (0.96), 8.188 (1.09), 8.190 (1.11), 8.194 (0.97), 8.272 (2.08), 8.276 (1.98), 8.284 (2.02), 8.287 (1.78), 8.538 (1.22), 8.541 (1.39), 8.543 (1.46), 8.545 (1.27), 8.550 (1.30), 8.553 (1.40), 8.555 (1.36), 8.557 (1.15), 8.935 (2.42), 8.940 (2.46), 10.251 (3.28). LC-MS (方法A ); Rt = 0.94 min, m/z = 386 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
42 | 8-甲基-N -(2-苯基乙基)-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.52), 2.443 (16.00), 2.520 (7.38), 2.525 (4.77), 2.742 (0.49), 2.792 (1.63), 2.810 (2.30), 2.830 (1.74), 2.889 (12.79), 3.391 (1.16), 3.407 (1.77), 3.428 (1.72), 3.444 (0.88), 5.385 (7.12), 7.059 (1.89), 7.078 (1.95), 7.183 (0.68), 7.201 (1.84), 7.220 (3.33), 7.237 (4.15), 7.282 (3.30), 7.301 (3.57), 7.314 (1.49), 7.319 (1.48), 7.323 (1.63), 7.635 (5.29), 7.753 (1.04), 7.758 (1.13), 7.772 (1.84), 7.777 (1.82), 7.791 (0.93), 7.796 (0.88), 8.164 (0.79), 8.178 (1.64), 8.193 (0.77), 8.535 (1.48), 8.544 (1.45). LC-MS (方法A ); Rt = 1.17 min, m/z = 413 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
43 | N -(4-氰基苯基)-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.012 (0.44), -0.004 (11.85), 1.109 (0.45), 1.127 (1.04), 1.144 (0.48), 1.172 (1.94), 1.189 (1.96), 2.273 (1.66), 2.331 (0.56), 2.518 (3.74), 2.525 (16.00), 2.673 (0.56), 2.822 (0.81), 2.870 (2.20), 2.902 (0.60), 2.907 (0.61), 2.925 (2.47), 2.943 (2.11), 2.983 (2.27), 2.999 (2.77), 3.006 (0.97), 3.018 (0.66), 3.024 (0.64), 5.379 (0.99), 5.404 (6.56), 7.080 (1.82), 7.100 (1.91), 7.296 (0.94), 7.298 (1.04), 7.308 (1.10), 7.310 (1.06), 7.315 (1.12), 7.317 (1.12), 7.327 (1.09), 7.329 (1.00), 7.626 (0.70), 7.671 (4.58), 7.758 (1.13), 7.763 (1.35), 7.772 (4.27), 7.777 (3.11), 7.782 (2.23), 7.790 (1.72), 7.795 (5.14), 7.801 (1.52), 7.993 (5.12), 7.999 (1.56), 8.011 (1.39), 8.016 (3.91), 8.533 (1.29), 8.535 (1.43), 8.537 (1.57), 8.539 (1.45), 8.545 (1.36), 8.547 (1.43), 8.549 (1.36), 8.552 (1.19), 10.436 (2.40). LC-MS (方法A ); Rt = 1.13 min, m/z = 410 [M+H]⁺. | 中間物2; GP G (條件A,使用HATU) |
44 | 8-甲基-2-(吡啶-3-基甲基)-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.547 (0.49), 1.564 (0.67), 1.571 (0.49), 1.579 (0.58), 1.588 (0.40), 1.593 (0.40), 1.771 (0.55), 1.778 (0.67), 1.793 (1.22), 1.810 (1.35), 1.828 (1.32), 1.839 (0.73), 1.843 (0.61), 1.848 (0.61), 1.856 (0.86), 1.871 (0.58), 1.873 (0.55), 1.878 (0.40), 2.456 (16.00), 2.518 (3.46), 2.523 (2.36), 2.859 (2.60), 2.869 (5.02), 2.872 (5.29), 2.883 (3.24), 3.209 (1.10), 3.214 (1.10), 3.224 (2.05), 3.229 (1.96), 3.239 (1.13), 3.245 (1.13), 3.580 (0.46), 3.596 (0.95), 3.599 (0.92), 3.616 (1.28), 3.634 (0.67), 3.730 (0.61), 3.744 (0.92), 3.747 (1.13), 3.761 (0.95), 3.764 (0.95), 3.782 (0.64), 3.924 (0.98), 3.940 (1.50), 3.956 (0.92), 5.335 (6.21), 7.360 (1.07), 7.362 (1.10), 7.372 (1.10), 7.374 (1.13), 7.380 (1.25), 7.382 (1.25), 7.392 (1.25), 7.394 (1.25), 7.641 (5.87), 7.650 (1.04), 7.660 (0.76), 7.666 (1.13), 7.670 (0.80), 7.967 (0.67), 7.981 (1.44), 7.997 (0.67), 8.489 (1.53), 8.493 (1.62), 8.500 (1.59), 8.505 (1.59), 8.514 (2.05), 8.519 (1.99). LC-MS (方法A ); Rt = 0.93 min, m/z = 393 [M+H]⁺. | 中間物3; GP G (條件A,使用HATU) |
45 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-(吡啶-3-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.931 (0.80), 0.948 (0.81), 2.456 (16.00), 2.473 (0.44), 2.518 (1.31), 2.522 (0.88), 2.859 (2.51), 2.869 (4.67), 2.873 (4.96), 2.883 (3.15), 3.157 (0.57), 3.177 (1.81), 3.192 (1.43), 3.202 (1.53), 3.206 (2.06), 3.212 (0.85), 3.230 (1.90), 3.243 (0.85), 3.261 (0.56), 3.417 (0.47), 3.438 (1.01), 3.444 (1.08), 3.465 (0.90), 3.471 (0.85), 3.508 (0.78), 3.513 (0.85), 3.536 (1.03), 3.542 (1.08), 3.563 (0.43), 3.568 (0.69), 3.603 (1.62), 3.609 (1.22), 3.619 (0.59), 3.627 (1.28), 3.634 (1.28), 3.679 (1.16), 3.685 (0.95), 3.708 (2.01), 3.713 (1.72), 3.738 (0.84), 5.335 (5.97), 7.359 (1.08), 7.361 (1.06), 7.371 (1.11), 7.373 (1.13), 7.379 (1.24), 7.381 (1.21), 7.391 (1.26), 7.393 (1.23), 7.641 (5.45), 7.650 (1.00), 7.660 (0.78), 7.665 (1.13), 7.670 (0.77), 8.043 (0.69), 8.059 (1.47), 8.073 (0.66), 8.488 (1.61), 8.492 (1.62), 8.500 (1.68), 8.504 (1.58), 8.514 (2.02), 8.518 (1.97). LC-MS (方法A ); Rt = 0.85 min, m/z = 409 [M+H]⁺. | 中間物3; GP G (條件A,使用HATU) |
46 | 8-甲基-2-(吡啶-4-基甲基)-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.550 (0.48), 1.565 (0.68), 1.574 (0.51), 1.582 (0.58), 1.590 (0.41), 1.595 (0.41), 1.774 (0.54), 1.779 (0.68), 1.795 (1.22), 1.813 (1.36), 1.831 (1.26), 1.842 (0.75), 1.851 (0.58), 1.859 (0.82), 1.873 (0.54), 2.446 (16.00), 2.518 (3.87), 2.523 (2.55), 2.674 (0.68), 2.886 (2.72), 2.895 (7.10), 2.905 (3.23), 3.212 (1.15), 3.217 (1.12), 3.228 (2.14), 3.232 (2.07), 3.243 (1.15), 3.247 (1.19), 3.582 (0.44), 3.598 (0.92), 3.602 (0.92), 3.619 (1.26), 3.636 (0.68), 3.732 (0.61), 3.749 (1.12), 3.764 (0.95), 3.767 (0.95), 3.785 (0.61), 3.927 (0.99), 3.943 (1.46), 3.959 (0.92), 5.363 (5.84), 7.135 (3.60), 7.139 (2.24), 7.146 (2.24), 7.150 (3.63), 7.655 (4.96), 7.974 (0.68), 7.990 (1.46), 8.005 (0.68), 8.515 (4.52), 8.520 (2.72), 8.527 (2.65), 8.531 (4.48). LC-MS (方法A ); Rt = 0.92 min, m/z = 391 [M-H]⁻. | 中間物4; GP G (條件A,使用HATU) |
47 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-(吡啶-4-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.447 (16.00), 2.518 (0.88), 2.523 (0.58), 2.886 (2.54), 2.897 (6.53), 2.906 (3.11), 3.162 (0.57), 3.181 (1.82), 3.196 (1.43), 3.204 (1.50), 3.209 (1.82), 3.216 (0.85), 3.233 (2.23), 3.247 (0.85), 3.266 (0.57), 3.420 (0.47), 3.440 (0.99), 3.446 (1.09), 3.468 (0.88), 3.474 (0.85), 3.511 (0.75), 3.516 (0.84), 3.539 (1.04), 3.545 (1.08), 3.565 (0.43), 3.572 (0.70), 3.607 (1.48), 3.614 (0.97), 3.623 (0.61), 3.632 (1.37), 3.637 (1.18), 3.682 (1.15), 3.688 (0.96), 3.711 (2.00), 3.717 (1.70), 3.741 (0.84), 5.364 (5.55), 7.135 (3.46), 7.139 (2.21), 7.146 (2.29), 7.150 (3.64), 7.656 (5.03), 8.053 (0.69), 8.068 (1.46), 8.083 (0.67), 8.516 (4.94), 8.520 (2.98), 8.527 (2.90), 8.530 (4.70). LC-MS (方法A ); Rt = 0.84 min, m/z = 409 [M+H]⁺. | 中間物4; GP G (條件A,使用HATU) |
48 | 2-(環丙基甲基)-8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.330 (0.56), 0.342 (2.14), 0.346 (1.81), 0.353 (1.97), 0.357 (2.04), 0.368 (0.79), 0.491 (0.81), 0.501 (1.76), 0.506 (1.93), 0.511 (0.98), 0.516 (0.88), 0.521 (1.93), 0.526 (1.81), 0.537 (0.63), 1.201 (0.46), 1.208 (0.44), 1.220 (0.81), 1.232 (0.46), 1.240 (0.46), 1.553 (0.44), 1.570 (0.63), 1.577 (0.46), 1.586 (0.53), 1.775 (0.49), 1.782 (0.65), 1.797 (1.09), 1.815 (1.23), 1.832 (1.16), 1.844 (0.65), 1.854 (0.53), 1.858 (0.63), 1.862 (0.74), 1.876 (0.51), 1.879 (0.49), 2.476 (16.00), 2.518 (2.55), 2.522 (1.65), 2.791 (0.42), 2.853 (2.28), 2.855 (2.35), 2.865 (3.65), 2.871 (3.92), 2.883 (3.02), 2.901 (0.42), 3.214 (1.00), 3.219 (0.98), 3.229 (1.88), 3.235 (1.76), 3.244 (1.02), 3.250 (1.04), 3.584 (0.39), 3.599 (0.84), 3.603 (0.84), 3.620 (1.16), 3.638 (0.65), 3.734 (0.58), 3.748 (0.84), 3.751 (1.04), 3.766 (0.88), 3.769 (0.86), 3.771 (0.70), 3.787 (0.60), 3.898 (3.76), 3.916 (3.83), 3.929 (0.98), 3.945 (1.39), 3.960 (0.84), 7.535 (4.30), 7.956 (0.58), 7.970 (1.23), 7.986 (0.58). LC-MS (方法A ); Rt = 1.25 min, m/z = 356 [M+H]⁺. | 中間物5; GP G (條件A,使用HATU) |
49 | 2-(環丙基甲基)-N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.331 (0.55), 0.342 (2.17), 0.346 (1.83), 0.354 (2.02), 0.358 (2.08), 0.368 (0.81), 0.492 (0.83), 0.502 (1.77), 0.506 (1.94), 0.511 (1.01), 0.517 (0.94), 0.522 (1.95), 0.527 (1.84), 0.537 (0.66), 1.201 (0.46), 1.209 (0.45), 1.221 (0.80), 1.233 (0.44), 1.240 (0.45), 2.477 (16.00), 2.518 (2.12), 2.523 (1.48), 2.791 (0.54), 2.836 (0.44), 2.855 (2.24), 2.867 (3.58), 2.873 (3.80), 2.885 (2.98), 2.903 (0.44), 3.163 (0.55), 3.183 (1.63), 3.197 (1.37), 3.207 (1.49), 3.212 (1.98), 3.217 (0.86), 3.233 (1.44), 3.236 (1.65), 3.248 (0.86), 3.267 (0.54), 3.422 (0.45), 3.443 (0.96), 3.449 (1.05), 3.470 (0.89), 3.476 (0.84), 3.513 (0.77), 3.518 (0.86), 3.541 (1.02), 3.547 (1.03), 3.568 (0.44), 3.573 (0.69), 3.608 (1.45), 3.624 (0.61), 3.633 (1.28), 3.639 (1.14), 3.686 (1.09), 3.693 (0.91), 3.715 (1.82), 3.720 (1.43), 3.743 (0.79), 3.899 (3.75), 3.917 (3.72), 7.537 (4.44), 8.035 (0.60), 8.050 (1.30), 8.065 (0.59). LC-MS (方法A ); Rt = 1.01 min, m/z = 372 [M+H]⁺. | 中間物5; GP G (條件A,使用HATU) |
50 | N -[(5-環丙基-1,2-㗁唑-3-基)甲基]-2-[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.822 (1.95), 0.834 (6.68), 0.840 (6.68), 0.846 (6.49), 0.849 (4.09), 0.852 (6.93), 0.862 (2.77), 0.932 (2.02), 0.949 (2.02), 0.995 (2.71), 1.005 (6.17), 1.012 (6.11), 1.016 (3.21), 1.023 (2.90), 1.026 (6.87), 1.033 (5.67), 1.044 (2.08), 2.071 (1.01), 2.083 (1.95), 2.092 (2.08), 2.095 (1.13), 2.104 (3.78), 2.113 (1.26), 2.117 (1.89), 2.125 (1.83), 2.138 (0.88), 2.337 (1.20), 2.518 (15.43), 2.523 (10.46), 2.678 (1.26), 2.687 (0.50), 2.801 (0.76), 2.842 (0.44), 2.857 (0.82), 2.874 (6.49), 2.886 (15.75), 2.895 (8.00), 2.913 (0.88), 2.928 (0.44), 4.177 (2.65), 4.194 (2.96), 4.207 (3.02), 4.223 (3.15), 4.345 (8.13), 4.360 (8.13), 4.372 (1.76), 4.390 (3.34), 4.408 (3.91), 4.422 (3.46), 4.433 (3.91), 4.458 (1.39), 4.470 (1.32), 4.506 (3.15), 4.511 (3.97), 4.535 (2.96), 4.541 (2.96), 4.615 (0.82), 4.620 (0.94), 4.626 (1.20), 4.632 (2.39), 4.637 (1.64), 4.643 (1.76), 4.649 (2.08), 4.665 (0.57), 6.093 (16.00), 6.943 (5.17), 6.954 (5.04), 6.962 (5.48), 6.974 (5.42), 7.294 (5.86), 7.299 (6.17), 7.314 (5.48), 7.318 (5.17), 7.544 (12.16), 7.754 (5.42), 7.759 (5.98), 7.766 (5.92), 7.771 (5.10), 8.644 (1.95), 8.659 (4.28), 8.674 (1.89). LC-MS (方法A ); Rt = 1.13 min, m/z = 488 [M+H]⁺. | 中間物6; GP G (條件A,使用HATU) |
50-1 | 實例50之對映異構體1 | Rt = 5.61 min | 分析型方法: 儀器:Agilent HPLC 1260;管柱:Amylose SA 3 µm,100x4.6 mm;溶離劑A:己烷 + 0.1 vol%二乙胺(99%);溶離劑B:乙醇;梯度:20-50% B歷時7 min;流量:1.4 mL/min;溫度:25℃;DAD:220 nm. |
50-2 | 實例50之對映異構體2 | Rt = 6.60 min | |
51 | 2-[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N -[(2R/S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (2.78), 0.935 (0.86), 0.948 (2.74), 0.953 (0.44), 1.553 (0.46), 1.569 (0.64), 1.577 (0.48), 1.585 (0.56), 1.775 (0.52), 1.781 (0.66), 1.796 (1.16), 1.815 (1.28), 1.832 (1.22), 1.844 (0.68), 1.853 (0.56), 1.858 (0.64), 1.861 (0.76), 1.876 (0.52), 2.318 (0.44), 2.480 (16.00), 2.518 (5.01), 2.523 (3.26), 2.869 (2.36), 2.880 (4.31), 2.885 (4.33), 2.896 (2.84), 3.215 (0.94), 3.220 (0.98), 3.230 (1.80), 3.235 (1.78), 3.245 (0.98), 3.250 (1.04), 3.584 (0.42), 3.599 (0.90), 3.603 (0.90), 3.620 (1.18), 3.638 (0.64), 3.734 (0.56), 3.751 (1.10), 3.765 (0.92), 3.769 (0.92), 3.786 (0.60), 3.929 (0.94), 3.946 (1.40), 3.961 (0.88), 4.177 (0.98), 4.194 (1.10), 4.207 (1.14), 4.223 (1.20), 4.351 (0.48), 4.368 (0.52), 4.387 (1.30), 4.405 (1.50), 4.418 (1.32), 4.430 (1.50), 4.454 (0.50), 4.466 (0.50), 4.505 (1.22), 4.511 (1.48), 4.535 (1.14), 4.541 (1.12), 4.630 (0.90), 4.636 (0.62), 4.641 (0.66), 4.647 (0.78), 6.942 (1.94), 6.953 (1.94), 6.962 (2.04), 6.973 (2.10), 7.295 (2.14), 7.299 (2.42), 7.314 (2.00), 7.318 (2.06), 7.538 (4.67), 7.754 (2.10), 7.758 (2.26), 7.766 (2.12), 7.770 (2.04), 7.977 (0.68), 7.992 (1.44), 8.007 (0.66). LC-MS (方法A ); Rt = 1.06 min, m/z = 451 [M+H]⁺. | 中間物6; GP G (條件A,使用HATU) |
52 | 2-[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.552 (0.41), 1.568 (0.53), 1.584 (0.47), 1.781 (0.65), 1.796 (1.83), 1.814 (1.18), 1.831 (1.12), 1.843 (0.77), 1.857 (0.77), 1.875 (0.47), 2.074 (6.67), 2.336 (0.83), 2.479 (16.00), 2.518 (10.10), 2.522 (6.67), 2.678 (0.89), 2.686 (5.79), 2.727 (7.14), 2.869 (3.25), 2.879 (4.66), 2.888 (10.69), 2.895 (3.07), 2.912 (0.59), 3.214 (0.89), 3.219 (0.89), 3.229 (1.54), 3.235 (1.54), 3.245 (0.89), 3.250 (0.94), 3.583 (0.41), 3.602 (0.83), 3.620 (1.06), 3.637 (0.65), 3.709 (0.47), 3.733 (0.59), 3.747 (0.89), 3.750 (0.94), 3.765 (0.77), 3.768 (0.83), 3.785 (0.53), 3.929 (0.89), 3.945 (1.18), 3.960 (0.71), 4.176 (0.83), 4.193 (0.89), 4.206 (0.94), 4.222 (1.00), 4.350 (0.41), 4.368 (0.41), 4.386 (1.06), 4.404 (1.24), 4.417 (1.06), 4.429 (1.24), 4.454 (0.47), 4.465 (0.41), 4.504 (1.00), 4.510 (1.24), 4.534 (0.94), 4.540 (0.94), 4.629 (0.77), 4.640 (0.53), 4.646 (0.65), 6.941 (1.65), 6.953 (1.77), 6.961 (1.77), 6.973 (1.89), 7.294 (1.83), 7.298 (1.95), 7.313 (1.71), 7.318 (1.71), 7.537 (3.78), 7.754 (1.95), 7.757 (1.77), 7.766 (1.89), 7.769 (1.77), 7.950 (1.06), 7.979 (0.59), 7.994 (1.18), 8.009 (0.59), 8.546 (0.59). UPLC-MS (方法1 ); Rt = 1.01 min, m/z = 451 [M+H]⁺. | 中間物6; GP G (條件A,使用HATU) |
52-1 | 實例52之非對映異構體1 | Rt = 4.93 min | 分析型方法: 儀器:Agilent HPLC 1260;管柱:Amylose SA 3 µm,100x4.6 mm;溶離劑A:己烷 + 0.1 vol%二乙胺(99%);溶離劑B:乙醇;溶離劑C:MtBE;等度:60% A + 15% B + 25% C;流量:1.4 mL/min;溫度:25℃;DAD:280 nm. |
52-2 | 實例52之非對映異構體2 | Rt = 9.03 min | |
53 | 2-[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N -(4-甲基苯甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.264 (7.58), 2.484 (16.00), 2.518 (5.80), 2.523 (3.98), 2.869 (1.83), 2.882 (4.07), 2.891 (2.22), 4.175 (0.77), 4.192 (0.84), 4.205 (0.86), 4.221 (0.91), 4.328 (1.83), 4.343 (1.85), 4.368 (0.42), 4.387 (0.96), 4.404 (1.14), 4.418 (1.01), 4.430 (1.11), 4.504 (0.89), 4.509 (1.14), 4.533 (0.86), 4.539 (0.84), 4.630 (0.69), 4.636 (0.47), 4.641 (0.49), 4.646 (0.59), 6.941 (1.56), 6.953 (1.43), 6.961 (1.60), 6.973 (1.56), 7.104 (1.70), 7.124 (2.86), 7.177 (3.21), 7.197 (1.80), 7.294 (1.68), 7.298 (1.88), 7.313 (1.56), 7.317 (1.56), 7.537 (3.56), 7.754 (1.70), 7.758 (1.73), 7.766 (1.58), 7.770 (1.60), 8.614 (0.54), 8.630 (1.16), 8.646 (0.52). LC-MS (方法A ); Rt = 1.26 min, m/z = 471 [M+H]⁺. | 中間物6; GP G (條件A,使用HATU) |
53-1 | 實例53之對映異構體1 | Rt = 2.46 min | 分析型方法: 儀器:Agilent HPLC 1260;管柱:Chiralpak AD-H 3 µm,150x4.6 mm;溶離劑A:甲醇 + 0.1 vol%二乙胺(99%);溶離劑B:乙醇;等度:50% A + 50% B;流量:1.4 mL/min;溫度:25℃;DAD:280 nm. |
53-2 | 實例53之對映異構體2 | Rt = 4.34 min | |
54 | 2-[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N -[2-(4-甲基哌𠯤-1-基)乙基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.135 (11.99), 2.298 (0.89), 2.318 (1.28), 2.322 (1.92), 2.326 (2.28), 2.331 (1.81), 2.336 (1.14), 2.392 (2.00), 2.409 (3.03), 2.426 (1.92), 2.477 (16.00), 2.518 (7.26), 2.522 (4.59), 2.659 (0.64), 2.664 (1.28), 2.669 (1.70), 2.673 (1.25), 2.678 (0.58), 2.868 (2.31), 2.878 (4.62), 2.881 (4.81), 2.891 (2.75), 3.271 (0.70), 3.288 (1.56), 3.304 (1.81), 4.175 (0.92), 4.192 (1.00), 4.205 (1.06), 4.222 (1.11), 4.349 (0.42), 4.367 (0.47), 4.386 (1.14), 4.404 (1.36), 4.417 (1.20), 4.429 (1.36), 4.453 (0.47), 4.465 (0.45), 4.504 (1.11), 4.510 (1.34), 4.534 (1.06), 4.540 (1.00), 4.629 (0.83), 4.634 (0.58), 4.639 (0.61), 4.646 (0.72), 6.941 (1.86), 6.953 (1.89), 6.961 (1.92), 6.973 (2.06), 7.293 (1.95), 7.298 (2.25), 7.313 (1.78), 7.317 (1.86), 7.536 (4.31), 7.754 (1.92), 7.758 (2.09), 7.766 (2.06), 7.770 (1.78), 7.916 (0.64), 7.931 (1.36), 7.945 (0.61). LC-MS (方法A ); Rt = 0.94 min, m/z = 493 [M+H]⁺. | 中間物6; GP G (條件A,使用HATU) |
55 | 2-[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N -(1,2-㗁唑-3-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.98), 0.948 (0.98), 2.074 (5.60), 2.331 (2.71), 2.336 (1.23), 2.344 (0.43), 2.518 (16.00), 2.522 (9.97), 2.673 (2.71), 2.678 (1.23), 2.802 (0.74), 2.845 (0.49), 2.857 (0.92), 2.876 (6.15), 2.886 (11.32), 2.891 (11.38), 2.902 (7.20), 2.919 (0.98), 2.933 (0.49), 4.177 (2.46), 4.193 (2.71), 4.206 (2.89), 4.223 (3.02), 4.354 (1.23), 4.372 (1.29), 4.391 (3.20), 4.408 (3.75), 4.422 (3.32), 4.433 (3.82), 4.456 (8.31), 4.470 (8.74), 4.505 (3.08), 4.511 (3.69), 4.534 (3.02), 4.541 (2.83), 4.614 (0.80), 4.621 (0.92), 4.632 (2.28), 4.638 (1.60), 4.643 (1.72), 4.648 (2.03), 6.491 (9.78), 6.495 (9.23), 6.942 (4.92), 6.954 (4.62), 6.961 (5.17), 6.973 (5.05), 7.294 (5.23), 7.298 (5.97), 7.313 (4.98), 7.318 (4.98), 7.544 (11.38), 7.754 (5.42), 7.758 (5.60), 7.766 (5.17), 7.770 (5.11), 8.712 (1.85), 8.727 (4.06), 8.742 (1.85), 8.814 (8.18), 8.819 (7.94). LC-MS (方法A ); Rt = 1.00 min, m/z = 448 [M+H]⁺. | 中間物6; GP G (條件A,使用HATU) |
55-1 | 實例55之對映異構體1 | Rt = 5.34 min | 分析型方法: 儀器:Agilent HPLC 1260;管柱:Amylose SA 3 µm,100x4.6 mm;溶離劑A:己烷 + 0.1 vol%二乙胺(99%);溶離劑B:乙醇;梯度:20-50% B歷時7 min;流量:1.4 mL/min;溫度:25℃;DAD:220 nm. |
55-2 | 實例55之對映異構體2 | Rt = 6.88 min | |
56 | 8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-2-{[6-(三氟甲基)吡啶-2-基]甲基}-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.549 (0.47), 1.566 (0.68), 1.574 (0.50), 1.582 (0.58), 1.595 (0.42), 1.774 (0.53), 1.780 (0.68), 1.795 (1.18), 1.813 (1.34), 1.831 (1.26), 1.841 (0.68), 1.851 (0.55), 1.859 (0.79), 1.873 (0.55), 2.075 (4.74), 2.332 (1.11), 2.336 (0.47), 2.442 (16.00), 2.518 (6.34), 2.523 (4.16), 2.678 (0.47), 2.897 (3.03), 2.903 (9.63), 2.910 (3.34), 3.212 (1.11), 3.217 (1.08), 3.228 (2.08), 3.232 (2.00), 3.243 (1.11), 3.247 (1.16), 3.582 (0.42), 3.598 (0.92), 3.601 (0.89), 3.619 (1.26), 3.637 (0.71), 3.732 (0.63), 3.746 (0.92), 3.749 (1.13), 3.764 (0.95), 3.767 (0.95), 3.784 (0.66), 3.927 (0.97), 3.943 (1.47), 3.959 (0.92), 5.509 (6.26), 5.759 (5.95), 7.257 (1.68), 7.276 (1.74), 7.694 (5.11), 7.834 (1.74), 7.853 (2.08), 7.978 (0.71), 7.993 (1.50), 8.008 (0.71), 8.062 (1.08), 8.082 (1.87), 8.102 (0.87). LC-MS (方法A ); Rt = 1.16 min, m/z = 461 [M+H]⁺. | 中間物7; GP G (條件A,使用HATU) |
57 | 8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-2-{[5-(三氟甲基)吡啶-2-基]甲基}-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.44), 0.948 (0.40), 1.549 (0.49), 1.565 (0.71), 1.572 (0.49), 1.580 (0.58), 1.594 (0.40), 1.773 (0.58), 1.779 (0.71), 1.794 (1.20), 1.812 (1.38), 1.830 (1.29), 1.841 (0.76), 1.851 (0.58), 1.858 (0.80), 1.872 (0.53), 2.332 (1.91), 2.336 (0.84), 2.434 (16.00), 2.518 (9.96), 2.522 (6.49), 2.673 (1.96), 2.678 (0.84), 2.902 (9.69), 2.909 (3.33), 3.211 (1.11), 3.215 (1.07), 3.226 (2.04), 3.230 (2.00), 3.242 (1.07), 3.246 (1.11), 3.582 (0.44), 3.597 (0.93), 3.601 (0.93), 3.618 (1.24), 3.636 (0.71), 3.731 (0.62), 3.748 (1.16), 3.763 (0.93), 3.766 (0.93), 3.784 (0.67), 3.925 (0.93), 3.942 (1.47), 3.958 (0.89), 5.527 (4.80), 7.241 (1.60), 7.262 (1.64), 7.684 (5.02), 7.974 (0.67), 7.989 (1.42), 8.004 (0.67), 8.198 (1.07), 8.202 (1.07), 8.218 (1.02), 8.223 (0.98), 8.547 (0.62), 8.948 (1.78), 8.954 (1.78). LC-MS (方法A); Rt = 1.28 min, m/z = 461 [M+H]⁺. | 中間物8; GP G (條件A,使用HATU) |
58 | 2-[(3-氯-5-氟吡啶-2-基)甲基]-8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.173 (0.62), 1.232 (1.05), 1.324 (0.53), 1.547 (0.53), 1.563 (0.70), 1.570 (0.53), 1.579 (0.62), 1.587 (0.44), 1.777 (0.70), 1.793 (1.23), 1.810 (1.41), 1.828 (1.32), 1.839 (0.70), 1.849 (0.62), 1.856 (0.88), 1.870 (0.53), 1.988 (0.79), 2.337 (1.05), 2.416 (16.00), 2.518 (16.00), 2.523 (11.08), 2.539 (1.14), 2.679 (1.14), 2.718 (0.97), 2.728 (9.23), 2.863 (2.55), 2.874 (6.07), 2.883 (3.34), 2.888 (10.55), 3.205 (0.97), 3.211 (1.05), 3.221 (1.93), 3.226 (1.85), 3.237 (1.05), 3.242 (1.05), 3.371 (0.79), 3.579 (0.44), 3.596 (0.88), 3.599 (0.88), 3.616 (1.32), 3.634 (0.70), 3.729 (0.62), 3.746 (1.05), 3.761 (0.88), 3.764 (0.97), 3.782 (0.70), 3.922 (0.97), 3.939 (1.41), 3.954 (0.88), 5.497 (5.80), 5.758 (10.55), 7.537 (4.84), 7.951 (1.41), 7.974 (1.41), 7.988 (0.70), 8.147 (1.85), 8.153 (2.11), 8.168 (1.85), 8.174 (2.02), 8.545 (0.62), 8.558 (0.44), 8.571 (3.96), 8.577 (3.78). UPLC-MS (方法1 ); Rt = 1.17 min, m/z = 445 [M+H]⁺. | 中間物 9-1及9-2 (1:1混合物); GP G (條件A,使用HATU) |
59 | 2-[(3-氯-5-乙氧基吡啶-2-基)甲基]-8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (5.07), 1.172 (10.62), 1.190 (5.28), 1.232 (0.54), 1.310 (2.76), 1.327 (6.47), 1.344 (2.79), 1.563 (0.44), 1.777 (0.44), 1.792 (0.78), 1.810 (0.89), 1.828 (0.85), 1.838 (0.48), 1.848 (0.41), 1.855 (0.54), 1.907 (1.16), 1.987 (16.00), 2.331 (1.46), 2.336 (0.65), 2.416 (0.68), 2.426 (9.43), 2.518 (8.00), 2.522 (5.00), 2.673 (1.46), 2.678 (0.68), 2.847 (1.60), 2.857 (2.79), 2.862 (3.00), 2.872 (2.08), 3.205 (0.71), 3.211 (0.68), 3.221 (1.29), 3.226 (1.23), 3.236 (0.71), 3.242 (0.75), 3.595 (0.61), 3.598 (0.61), 3.616 (0.85), 3.634 (0.48), 3.729 (0.41), 3.746 (0.75), 3.761 (0.61), 3.764 (0.61), 3.782 (0.44), 3.922 (0.65), 3.938 (0.95), 3.954 (0.58), 3.999 (1.29), 4.017 (3.74), 4.035 (3.64), 4.053 (1.16), 4.106 (0.78), 4.124 (2.79), 4.141 (2.72), 4.159 (0.78), 5.409 (4.19), 7.471 (3.00), 7.611 (2.25), 7.617 (2.31), 7.954 (0.44), 7.969 (0.92), 7.984 (0.44), 8.227 (2.62), 8.234 (2.42). UPLC-MS (方法1 ); Rt = 1.25 min, m/z = 471 [M+H]⁺. | 中間物 9-1及9-2 (1:1混合物); GP G (條件A,使用HATU) |
60 | 2-[(3-氯吡啶-2-基)甲基]-8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.547 (0.47), 1.563 (0.67), 1.571 (0.49), 1.579 (0.56), 1.771 (0.55), 1.777 (0.68), 1.792 (1.17), 1.810 (1.35), 1.827 (1.26), 1.839 (0.71), 1.848 (0.59), 1.856 (0.81), 1.870 (0.55), 1.873 (0.53), 1.877 (0.40), 2.332 (0.65), 2.418 (16.00), 2.518 (3.39), 2.523 (2.13), 2.673 (0.65), 2.868 (2.67), 2.877 (7.40), 2.885 (3.08), 3.206 (1.03), 3.212 (1.02), 3.221 (1.93), 3.227 (1.82), 3.237 (1.05), 3.242 (1.08), 3.579 (0.43), 3.595 (0.90), 3.599 (0.88), 3.616 (1.23), 3.634 (0.65), 3.729 (0.62), 3.744 (0.90), 3.746 (1.11), 3.762 (0.91), 3.764 (0.93), 3.782 (0.64), 3.923 (0.94), 3.939 (1.41), 3.955 (0.88), 5.514 (7.14), 7.397 (1.75), 7.408 (1.66), 7.417 (1.85), 7.428 (1.79), 7.538 (4.89), 7.957 (0.70), 7.967 (2.55), 7.970 (3.33), 7.987 (2.77), 7.991 (2.45), 8.485 (2.07), 8.489 (2.16), 8.497 (2.02), 8.500 (1.93). LC-MS (方法A ); Rt = 1.09 min, m/z = 427 [M+H]⁺. | 中間物 10; GP G (條件A,使用HATU) |
61 | 2-[(3-氯吡啶-2-基)甲基]-N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.418 (16.00), 2.518 (3.03), 2.523 (2.16), 2.869 (2.58), 2.878 (6.88), 2.887 (3.05), 3.155 (0.57), 3.176 (1.48), 3.190 (1.40), 3.201 (1.61), 3.205 (2.02), 3.225 (1.39), 3.230 (1.63), 3.240 (0.86), 3.259 (0.56), 3.417 (0.46), 3.438 (1.00), 3.444 (1.10), 3.465 (0.90), 3.471 (0.87), 3.508 (0.78), 3.513 (0.86), 3.536 (1.06), 3.542 (1.08), 3.563 (0.44), 3.569 (0.70), 3.603 (1.60), 3.609 (1.31), 3.618 (0.58), 3.627 (1.22), 3.633 (1.27), 3.679 (1.14), 3.686 (0.95), 3.708 (1.94), 3.714 (1.69), 3.738 (0.82), 5.515 (6.98), 7.397 (1.68), 7.409 (1.77), 7.417 (1.76), 7.429 (1.93), 7.539 (5.02), 7.967 (2.20), 7.970 (2.27), 7.988 (2.13), 7.991 (2.04), 8.036 (0.69), 8.052 (1.44), 8.066 (0.66), 8.485 (2.13), 8.489 (2.21), 8.497 (2.06), 8.500 (1.98). LC-MS (方法A ); Rt = 1.00 min, m/z = 443 [M+H]⁺. | 中間物 10; GP G (條件A,使用HATU) |
62 | 8-甲基-2-[(3-甲基吡啶-2-基)甲基]-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.547 (0.49), 1.563 (0.68), 1.571 (0.51), 1.579 (0.57), 1.592 (0.40), 1.770 (0.53), 1.776 (0.70), 1.791 (1.21), 1.810 (1.36), 1.827 (1.31), 1.838 (0.74), 1.843 (0.61), 1.848 (0.57), 1.855 (0.83), 1.869 (0.55), 1.876 (0.40), 2.074 (1.74), 2.332 (0.93), 2.336 (0.42), 2.398 (12.33), 2.437 (16.00), 2.518 (5.68), 2.522 (3.60), 2.673 (0.93), 2.678 (0.42), 2.843 (2.54), 2.853 (4.32), 2.858 (4.64), 2.869 (3.20), 2.888 (0.45), 3.205 (1.02), 3.211 (1.04), 3.221 (1.99), 3.226 (1.89), 3.236 (1.10), 3.242 (1.10), 3.578 (0.42), 3.594 (0.93), 3.598 (0.91), 3.615 (1.25), 3.633 (0.68), 3.729 (0.61), 3.746 (1.14), 3.760 (0.93), 3.764 (0.95), 3.781 (0.64), 3.922 (0.97), 3.938 (1.48), 3.953 (0.91), 5.375 (7.27), 7.231 (1.31), 7.243 (1.38), 7.250 (1.48), 7.262 (1.53), 7.447 (4.83), 7.605 (1.29), 7.608 (1.38), 7.624 (1.21), 7.627 (1.23), 7.955 (0.68), 7.969 (1.42), 7.984 (0.70), 8.337 (1.25), 8.340 (1.31), 8.349 (1.29), 8.352 (1.25). LC-MS (方法A ); Rt = 1.15 min, m/z = 407 [M+H]⁺. | 中間物 11; GP G (條件A,使用HATU) |
63 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(3-甲基吡啶-2-基)甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.94), 0.948 (0.92), 2.075 (1.44), 2.397 (11.92), 2.438 (16.00), 2.465 (0.40), 2.518 (2.70), 2.523 (1.88), 2.843 (2.29), 2.845 (2.34), 2.855 (3.91), 2.860 (4.21), 2.871 (3.03), 2.890 (0.41), 3.155 (0.57), 3.176 (1.45), 3.189 (1.40), 3.200 (1.61), 3.205 (2.01), 3.225 (1.41), 3.229 (1.62), 3.240 (0.87), 3.259 (0.55), 3.417 (0.46), 3.437 (1.00), 3.444 (1.09), 3.464 (0.90), 3.471 (0.86), 3.507 (0.76), 3.513 (0.84), 3.535 (1.05), 3.542 (1.08), 3.562 (0.43), 3.568 (0.71), 3.603 (1.57), 3.608 (1.36), 3.617 (0.59), 3.626 (1.20), 3.632 (1.28), 3.678 (1.13), 3.684 (0.94), 3.707 (1.94), 3.713 (1.69), 3.738 (0.82), 5.376 (6.93), 7.231 (1.32), 7.243 (1.38), 7.250 (1.48), 7.262 (1.51), 7.449 (4.93), 7.604 (1.07), 7.606 (1.25), 7.608 (1.30), 7.610 (1.09), 7.623 (0.99), 7.625 (1.16), 7.627 (1.15), 7.629 (0.98), 8.034 (0.67), 8.049 (1.44), 8.064 (0.65), 8.337 (1.21), 8.340 (1.23), 8.349 (1.20), 8.352 (1.16). LC-MS (方法A ); Rt = 0.96 min, m/z = 423 [M+H]⁺. | 中間物 11; GP G (條件A,使用HATU) |
64 | 8-甲基-2-[(5-甲基吡啶-2-基)甲基]-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.553 (0.42), 1.565 (0.42), 1.568 (0.62), 1.575 (0.57), 1.581 (0.53), 1.592 (0.52), 1.778 (0.50), 1.783 (0.47), 1.795 (0.74), 1.798 (0.67), 1.809 (0.71), 1.813 (0.82), 1.826 (0.59), 1.839 (0.54), 1.842 (0.47), 1.846 (0.59), 1.852 (0.69), 1.861 (0.61), 1.869 (0.42), 1.875 (0.47), 1.878 (0.41), 2.269 (10.04), 2.440 (16.00), 2.516 (2.22), 2.520 (2.08), 2.523 (1.69), 2.640 (0.59), 2.873 (2.40), 2.881 (4.36), 2.884 (4.61), 2.893 (3.03), 3.214 (0.99), 3.221 (1.02), 3.226 (1.87), 3.233 (1.73), 3.238 (1.03), 3.245 (1.03), 3.588 (0.45), 3.604 (0.99), 3.618 (1.16), 3.632 (0.67), 3.737 (0.58), 3.749 (0.91), 3.751 (1.05), 3.763 (1.02), 3.765 (0.87), 3.780 (0.64), 3.930 (0.97), 3.943 (1.45), 3.956 (0.91), 5.327 (5.84), 7.000 (1.84), 7.016 (1.95), 7.574 (1.03), 7.577 (1.01), 7.590 (1.04), 7.594 (1.06), 7.600 (4.73), 7.966 (0.69), 7.978 (1.40), 7.990 (0.67), 8.367 (1.77), 8.371 (1.73). LC-MS (方法A ); Rt = 1.03 min, m/z = 407 [M+H]⁺. | 中間物 12; GP G (條件A,使用HATU) |
65 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(5-甲基吡啶-2-基)甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.269 (10.58), 2.370 (0.44), 2.400 (0.46), 2.440 (16.00), 2.516 (3.88), 2.520 (3.49), 2.523 (2.77), 2.640 (0.93), 2.741 (0.49), 2.857 (0.46), 2.873 (2.62), 2.881 (4.41), 2.886 (4.72), 2.894 (3.18), 3.165 (0.70), 3.180 (0.88), 3.186 (1.35), 3.192 (1.49), 3.205 (2.05), 3.209 (1.51), 3.219 (0.71), 3.228 (1.75), 3.231 (1.48), 3.244 (0.95), 3.258 (0.66), 3.307 (0.41), 3.420 (0.44), 3.426 (0.53), 3.442 (1.10), 3.448 (1.15), 3.465 (0.93), 3.470 (0.86), 3.516 (0.77), 3.521 (0.88), 3.539 (1.10), 3.544 (1.11), 3.561 (0.56), 3.566 (0.75), 3.609 (1.64), 3.621 (0.68), 3.628 (1.45), 3.633 (1.33), 3.686 (1.18), 3.690 (1.04), 3.713 (1.97), 3.738 (0.89), 5.327 (6.11), 7.000 (1.98), 7.016 (2.07), 7.574 (1.09), 7.577 (1.09), 7.590 (1.06), 7.594 (1.12), 7.601 (4.85), 8.045 (0.73), 8.057 (1.55), 8.069 (0.72), 8.367 (1.84), 8.371 (1.84). LC-MS (方法A ); Rt = 0.95 min, m/z = 423 [M+H]⁺. | 中間物 12; GP G (條件A,使用HATU) |
66 | 8-甲基-2-[(6-甲基吡啶-2-基)甲基]-N -[(2R/S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.550 (0.49), 1.567 (0.68), 1.574 (0.50), 1.582 (0.58), 1.590 (0.43), 1.595 (0.42), 1.773 (0.55), 1.779 (0.70), 1.794 (1.24), 1.812 (1.38), 1.830 (1.31), 1.841 (0.74), 1.851 (0.61), 1.856 (0.72), 1.858 (0.83), 1.873 (0.58), 1.876 (0.55), 1.880 (0.41), 2.446 (16.00), 2.461 (15.04), 2.518 (1.43), 2.523 (0.98), 2.881 (2.82), 2.890 (7.60), 2.898 (3.21), 3.212 (1.13), 3.217 (1.11), 3.228 (2.13), 3.232 (2.04), 3.243 (1.14), 3.247 (1.16), 3.582 (0.44), 3.598 (0.93), 3.601 (0.94), 3.618 (1.28), 3.636 (0.68), 3.732 (0.62), 3.746 (0.94), 3.749 (1.16), 3.764 (0.96), 3.767 (0.98), 3.784 (0.64), 3.927 (0.98), 3.943 (1.49), 3.959 (0.91), 5.325 (6.48), 6.788 (1.72), 6.807 (1.79), 7.152 (1.73), 7.171 (1.88), 7.620 (5.15), 7.643 (3.07), 7.662 (1.48), 7.967 (0.72), 7.982 (1.49), 7.996 (0.70). LC-MS (方法A ); Rt = 1.06 min, m/z = 407 [M+H]⁺. | 中間物 13; GP G (條件A,使用HATU) |
66-1 | 實例66之對映異構體1 | Rt = 2.37 min | 分析型方法: 儀器:Agilent HPLC 1260;管柱:Amylose SA 3 µm,100x4.6 mm;溶離劑A:己烷 + 0.1 vol%二乙胺(99%);溶離劑B:乙醇;梯度:20-50% B歷時7 min;流量:1.4 mL/min;溫度:25℃;DAD:254 nm. |
66-2 | 實例66之對映異構體2 | Rt = 3.05 min | |
67 | N -[2-(氮雜環丁-1-基)乙基]-8-甲基-2-[(6-甲基吡啶-2-基)甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.905 (0.72), 1.922 (1.86), 1.940 (2.44), 1.957 (1.83), 1.974 (0.49), 2.323 (0.58), 2.327 (0.83), 2.332 (0.60), 2.425 (2.97), 2.441 (16.00), 2.461 (15.67), 2.518 (2.86), 2.523 (2.09), 2.654 (0.43), 2.665 (0.67), 2.669 (1.03), 2.673 (0.69), 2.772 (0.49), 2.851 (0.60), 2.858 (1.36), 2.880 (2.51), 2.888 (7.35), 2.896 (2.88), 3.081 (4.38), 3.088 (1.29), 3.098 (8.26), 3.104 (2.68), 3.116 (4.66), 3.136 (0.75), 4.684 (0.64), 5.324 (6.29), 6.788 (1.51), 6.807 (1.58), 7.152 (1.72), 7.171 (1.84), 7.559 (0.42), 7.618 (5.16), 7.623 (1.80), 7.643 (2.95), 7.662 (1.39), 7.859 (0.62), 7.874 (1.30), 7.888 (0.60), 8.581 (0.40), 8.794 (0.40). LC-MS (方法A ); Rt = 1.01 min, m/z = 406 [M+H]⁺. | 中間物 13; GP G (條件A,使用HATU) |
68 | N -[(5-環丙基-1,2-㗁唑-3-基)甲基]-8-甲基-2-[(6-甲基吡啶-2-基)甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.821 (0.79), 0.832 (2.61), 0.838 (2.57), 0.845 (2.43), 0.848 (1.46), 0.851 (2.60), 0.860 (1.14), 0.994 (1.01), 1.003 (2.44), 1.010 (2.39), 1.015 (1.22), 1.021 (1.14), 1.024 (2.60), 1.031 (2.19), 1.042 (0.83), 2.081 (0.75), 2.090 (0.79), 2.094 (0.46), 2.102 (1.45), 2.111 (0.47), 2.115 (0.73), 2.123 (0.70), 2.457 (16.00), 2.461 (15.48), 2.518 (2.15), 2.523 (1.48), 2.886 (2.93), 2.892 (9.21), 2.898 (3.18), 4.342 (3.08), 4.357 (3.06), 5.328 (5.84), 6.089 (6.20), 6.789 (1.58), 6.808 (1.64), 7.154 (1.61), 7.173 (1.74), 7.625 (5.95), 7.644 (2.99), 7.663 (1.47), 8.635 (0.69), 8.651 (1.55), 8.666 (0.68). LC-MS (方法A ); Rt = 1.14 min, m/z = 444 [M+H]⁺. | 中間物 13; GP G (條件A,使用HATU) |
69 | 8-甲基-2-[(6-甲基吡啶-2-基)甲基]-N -[2-(吡咯啶-1-基)乙基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.658 (2.40), 1.666 (4.40), 1.675 (2.40), 2.327 (0.44), 2.444 (16.00), 2.461 (14.79), 2.534 (1.82), 2.669 (0.42), 2.879 (2.78), 2.886 (7.65), 2.894 (2.95), 3.276 (0.85), 3.292 (1.94), 3.308 (2.16), 5.323 (5.73), 6.788 (1.55), 6.807 (1.61), 7.152 (1.57), 7.171 (1.69), 7.618 (4.22), 7.623 (1.67), 7.642 (2.56), 7.662 (1.23), 7.937 (0.65), 7.951 (1.35), 7.966 (0.63). LC-MS (方法A ); Rt = 1.09 min, m/z = 420 [M+H]⁺. | 中間物 13; GP G (條件A,使用HATU) |
70 | N -[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-2-[(6-甲基吡啶-2-基)甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.63), 0.948 (0.63), 2.461 (16.00), 2.518 (2.05), 2.523 (1.29), 2.890 (1.56), 2.900 (2.97), 2.904 (3.06), 2.914 (1.80), 3.451 (0.42), 3.466 (0.66), 3.537 (0.67), 3.553 (0.43), 4.130 (0.58), 4.148 (0.70), 4.160 (0.67), 4.177 (0.79), 4.355 (0.46), 4.361 (0.57), 4.372 (0.46), 4.377 (0.48), 4.438 (0.85), 4.443 (0.79), 4.467 (0.76), 4.472 (0.63), 5.329 (3.70), 6.792 (1.03), 6.811 (1.06), 6.932 (1.23), 6.944 (1.20), 6.952 (1.27), 6.964 (1.30), 7.154 (1.06), 7.173 (1.15), 7.302 (1.35), 7.306 (1.30), 7.322 (1.29), 7.325 (1.11), 7.627 (3.33), 7.645 (1.81), 7.664 (0.88), 7.736 (1.32), 7.740 (1.36), 7.747 (1.23), 7.752 (1.21), 8.367 (0.43), 8.382 (0.90), 8.397 (0.42). LC-MS (方法A ); Rt = 1.04 min, m/z = 472 [M+H]⁺. | 中間物 13; GP G (條件A,使用HATU) |
71 | 8-甲基-N -[(1-甲基-1H -吡唑-3-基)甲基]-2-[(6-甲基吡啶-2-基)甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.455 (13.22), 2.463 (12.30), 2.520 (0.63), 2.525 (0.44), 2.883 (9.07), 3.771 (16.00), 3.783 (0.51), 4.315 (2.58), 4.330 (2.58), 5.327 (4.96), 6.100 (2.71), 6.105 (2.82), 6.788 (1.34), 6.807 (1.38), 7.153 (1.36), 7.172 (1.47), 7.555 (2.34), 7.560 (2.37), 7.621 (4.20), 7.624 (1.84), 7.643 (2.46), 7.663 (1.21), 8.372 (0.59), 8.387 (1.27), 8.401 (0.57). LC-MS (方法A ); Rt = 0.96 min, m/z = 417 [M+H]⁺. | 中間物 13; GP G (條件A,使用HATU) |
72 | 8-甲基-2-[(6-甲基吡啶-2-基)甲基]-N -(1,3-㗁唑-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.454 (16.00), 2.464 (15.03), 2.520 (0.98), 2.525 (0.68), 2.757 (0.42), 2.895 (2.63), 2.904 (6.83), 2.913 (3.03), 4.483 (3.60), 4.498 (3.52), 5.332 (6.14), 6.797 (1.64), 6.817 (1.70), 7.142 (4.59), 7.144 (4.93), 7.155 (1.73), 7.174 (1.82), 7.631 (5.15), 7.647 (3.07), 7.666 (1.51), 8.032 (5.23), 8.034 (4.97), 8.721 (0.74), 8.736 (1.62), 8.751 (0.72). LC-MS (方法A ); Rt = 0.95 min, m/z = 404 [M+H]⁺. | 中間物 13; GP G (條件A,使用HATU) |
73 | 8-甲基-2-[(2-甲基吡啶-3-基)甲基]-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.553 (0.45), 1.565 (0.44), 1.569 (0.64), 1.575 (0.59), 1.582 (0.55), 1.592 (0.54), 1.778 (0.53), 1.783 (0.50), 1.795 (0.78), 1.799 (0.76), 1.814 (0.87), 1.829 (0.64), 1.839 (0.56), 1.846 (0.61), 1.852 (0.71), 1.861 (0.63), 1.869 (0.44), 1.872 (0.48), 1.878 (0.40), 2.447 (16.00), 2.516 (3.10), 2.520 (2.64), 2.523 (2.11), 2.545 (14.47), 2.640 (0.70), 2.855 (0.56), 2.871 (2.48), 2.880 (3.75), 2.886 (4.01), 2.895 (3.17), 2.910 (0.61), 3.216 (1.07), 3.222 (1.06), 3.228 (1.94), 3.234 (1.83), 3.240 (1.07), 3.246 (1.09), 3.589 (0.49), 3.604 (1.05), 3.618 (1.21), 3.632 (0.68), 3.738 (0.62), 3.752 (1.07), 3.764 (1.01), 3.780 (0.65), 3.931 (1.00), 3.944 (1.49), 3.956 (0.97), 5.344 (6.08), 7.179 (0.82), 7.189 (0.84), 7.195 (1.46), 7.204 (1.53), 7.232 (1.59), 7.235 (1.70), 7.247 (0.92), 7.251 (0.85), 7.569 (4.61), 7.970 (0.70), 7.982 (1.47), 7.995 (0.70), 8.350 (1.35), 8.353 (1.41), 8.359 (1.39), 8.362 (1.34). LC-MS (方法A ); Rt = 0.97 min, m/z = 407 [M+H]⁺. | 中間物 14-1; GP G (條件A,使用HATU) |
74 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(2-甲基吡啶-3-基)甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.448 (16.00), 2.516 (2.61), 2.520 (2.32), 2.523 (1.83), 2.545 (15.44), 2.756 (0.61), 2.856 (0.63), 2.871 (2.55), 2.881 (3.74), 2.887 (4.03), 2.897 (3.26), 2.912 (0.66), 3.166 (0.73), 3.181 (0.92), 3.187 (1.38), 3.193 (1.51), 3.205 (2.18), 3.209 (1.57), 3.221 (0.76), 3.229 (1.69), 3.233 (1.45), 3.245 (0.91), 3.260 (0.70), 3.421 (0.42), 3.426 (0.53), 3.443 (1.13), 3.448 (1.19), 3.465 (0.95), 3.470 (0.85), 3.517 (0.78), 3.522 (0.90), 3.539 (1.11), 3.545 (1.12), 3.561 (0.56), 3.567 (0.71), 3.609 (1.65), 3.622 (0.66), 3.630 (1.48), 3.634 (1.32), 3.685 (1.19), 3.690 (1.07), 3.708 (1.22), 3.713 (1.94), 3.738 (0.86), 5.344 (6.31), 7.179 (0.87), 7.189 (0.89), 7.194 (1.54), 7.204 (1.61), 7.231 (1.69), 7.235 (1.76), 7.247 (0.95), 7.250 (0.89), 7.570 (4.92), 8.050 (0.76), 8.062 (1.61), 8.074 (0.74), 8.350 (1.45), 8.353 (1.47), 8.359 (1.45), 8.362 (1.36). LC-MS (方法A ); Rt = 0.89 min, m/z = 423 [M+H]⁺. | 中間物 14-1; GP G (條件A,使用HATU) |
75 | 8-甲基-2-[(6-甲基吡啶-3-基)甲基]-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.549 (0.49), 1.566 (0.69), 1.574 (0.51), 1.582 (0.59), 1.589 (0.43), 1.774 (0.55), 1.779 (0.70), 1.794 (1.25), 1.813 (1.39), 1.830 (1.34), 1.841 (0.76), 1.851 (0.60), 1.858 (0.85), 1.872 (0.59), 1.879 (0.42), 2.433 (13.98), 2.456 (16.00), 2.520 (3.90), 2.525 (2.46), 2.830 (0.41), 2.849 (2.59), 2.860 (4.40), 2.865 (4.69), 2.877 (3.24), 2.894 (0.46), 3.210 (1.11), 3.215 (1.10), 3.225 (2.09), 3.231 (1.99), 3.240 (1.13), 3.246 (1.14), 3.581 (0.45), 3.598 (0.95), 3.601 (0.95), 3.618 (1.29), 3.636 (0.68), 3.731 (0.63), 3.748 (1.18), 3.764 (0.96), 3.766 (0.97), 3.784 (0.64), 3.925 (1.00), 3.942 (1.52), 3.957 (0.93), 5.273 (6.06), 7.216 (2.01), 7.236 (2.24), 7.543 (1.49), 7.549 (1.49), 7.563 (1.29), 7.569 (1.32), 7.606 (4.89), 7.965 (0.73), 7.980 (1.52), 7.995 (0.70), 8.396 (2.09), 8.401 (2.08). LC-MS (方法A ); Rt = 1.14 min, m/z = 407 [M+H]⁺. | 中間物 15-1 + 15-2; GP G (條件A,使用HATU) |
76 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(6-甲基吡啶-3-基)甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.934 (0.41), 0.951 (0.41), 2.433 (14.10), 2.457 (16.00), 2.520 (2.84), 2.525 (1.89), 2.758 (0.65), 2.831 (0.44), 2.851 (2.62), 2.861 (4.30), 2.866 (4.57), 2.878 (3.32), 2.896 (0.51), 3.159 (0.61), 3.179 (1.76), 3.193 (1.50), 3.203 (1.69), 3.208 (2.23), 3.213 (0.98), 3.232 (1.93), 3.244 (0.92), 3.263 (0.61), 3.419 (0.50), 3.440 (1.10), 3.446 (1.18), 3.467 (0.98), 3.474 (0.94), 3.510 (0.83), 3.515 (0.90), 3.538 (1.12), 3.544 (1.17), 3.565 (0.46), 3.571 (0.73), 3.605 (1.80), 3.611 (1.50), 3.621 (0.66), 3.629 (1.35), 3.635 (1.45), 3.681 (1.26), 3.687 (1.05), 3.710 (2.19), 3.716 (1.92), 3.740 (0.92), 5.273 (6.01), 7.215 (2.01), 7.236 (2.28), 7.543 (1.50), 7.549 (1.51), 7.563 (1.34), 7.569 (1.35), 7.607 (5.08), 8.042 (0.74), 8.057 (1.56), 8.072 (0.71), 8.396 (2.09), 8.401 (2.06). LC-MS (方法A ); Rt = 1.06 min, m/z = 423 [M+H]⁺. | 中間物 15-1 + 15-2; GP G (條件A,使用HATU) |
77 | 2-[(2,6-二甲基吡啶-3-基)甲基]-8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.934 (0.47), 0.951 (0.46), 1.551 (0.52), 1.567 (0.72), 1.575 (0.54), 1.583 (0.62), 1.591 (0.46), 1.778 (1.26), 1.796 (1.31), 1.813 (1.44), 1.831 (1.37), 1.841 (0.78), 1.851 (0.63), 1.858 (0.89), 1.874 (0.60), 2.334 (0.75), 2.338 (0.46), 2.390 (13.42), 2.423 (0.76), 2.447 (16.00), 2.520 (3.99), 2.525 (2.47), 2.676 (0.71), 2.837 (0.53), 2.857 (2.69), 2.868 (4.27), 2.874 (4.52), 2.886 (3.28), 2.904 (0.53), 3.212 (1.18), 3.217 (1.17), 3.227 (2.20), 3.232 (2.10), 3.242 (1.20), 3.248 (1.20), 3.583 (0.46), 3.599 (0.99), 3.602 (1.00), 3.619 (1.32), 3.637 (0.69), 3.733 (0.63), 3.750 (1.21), 3.765 (0.99), 3.767 (1.00), 3.785 (0.63), 3.927 (1.04), 3.943 (1.54), 3.959 (0.95), 5.284 (6.01), 7.032 (1.85), 7.051 (2.30), 7.199 (2.63), 7.218 (2.06), 7.526 (5.01), 7.967 (0.78), 7.982 (1.59), 7.997 (0.75). LC-MS (方法A ); Rt = 1.21 min, m/z = 421 [M+H]⁺. | 中間物 16-1 + 16-2; GP G (條件A,使用HATU) |
78 | 2-[(2,6-二甲基吡啶-3-基)甲基]-N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.334 (1.11), 2.390 (14.00), 2.448 (16.00), 2.520 (6.19), 2.525 (3.81), 2.545 (0.60), 2.676 (1.08), 2.838 (0.60), 2.858 (2.77), 2.869 (4.25), 2.876 (4.53), 2.887 (3.37), 2.906 (0.59), 3.160 (0.63), 3.180 (1.85), 3.194 (1.57), 3.205 (1.77), 3.209 (2.29), 3.233 (2.13), 3.246 (0.97), 3.264 (0.65), 3.310 (0.62), 3.414 (0.42), 3.420 (0.52), 3.441 (1.14), 3.447 (1.23), 3.469 (0.99), 3.474 (0.98), 3.511 (0.84), 3.517 (0.90), 3.539 (1.18), 3.545 (1.22), 3.566 (0.47), 3.572 (0.76), 3.591 (0.40), 3.607 (1.90), 3.612 (1.64), 3.621 (0.71), 3.630 (1.46), 3.636 (1.54), 3.681 (1.33), 3.688 (1.11), 3.710 (2.33), 3.716 (2.12), 3.741 (0.97), 5.284 (6.21), 7.032 (1.93), 7.051 (2.39), 7.199 (2.70), 7.218 (2.15), 7.527 (5.15), 8.046 (0.80), 8.061 (1.70), 8.076 (0.78). LC-MS (方法A ); Rt = 1.12 min, m/z = 437 [M+H]⁺. | 中間物 16-1 + 16-2; GP G (條件A,使用HATU) |
79 | 8-甲基-2-[(2-甲基吡啶-4-基)甲基]-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.863 (0.42), 1.549 (0.48), 1.566 (0.67), 1.574 (0.48), 1.582 (0.57), 1.774 (0.54), 1.779 (0.70), 1.795 (1.25), 1.813 (1.34), 1.831 (1.21), 1.841 (0.70), 1.851 (0.57), 1.858 (0.80), 1.873 (0.54), 2.337 (0.42), 2.430 (14.56), 2.447 (16.00), 2.518 (5.59), 2.523 (3.77), 2.674 (0.96), 2.679 (0.42), 2.881 (2.49), 2.892 (6.10), 2.902 (3.00), 3.212 (1.09), 3.217 (1.02), 3.228 (2.01), 3.232 (1.92), 3.243 (1.05), 3.248 (1.09), 3.582 (0.48), 3.598 (0.93), 3.602 (0.93), 3.619 (1.21), 3.637 (0.64), 3.732 (0.64), 3.749 (1.09), 3.764 (0.89), 3.767 (0.93), 3.784 (0.64), 3.927 (0.93), 3.943 (1.41), 3.958 (0.86), 5.302 (5.46), 6.929 (1.21), 6.941 (1.21), 7.052 (2.33), 7.634 (4.66), 7.970 (0.64), 7.986 (1.37), 8.001 (0.64), 8.375 (2.04), 8.388 (1.98). LC-MS (方法A ); Rt = 0.96 min, m/z = 407 [M+H]⁺. | 中間物 17-2; GP G (條件A,使用HATU) |
80 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(2-甲基吡啶-4-基)甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (1.10), 0.948 (1.16), 2.336 (1.10), 2.430 (15.02), 2.447 (16.00), 2.518 (14.21), 2.523 (9.82), 2.678 (1.10), 2.882 (2.43), 2.893 (5.78), 2.903 (3.06), 3.161 (0.58), 3.180 (1.85), 3.194 (1.39), 3.204 (1.56), 3.209 (1.91), 3.215 (0.87), 3.232 (2.14), 3.245 (0.87), 3.264 (0.58), 3.280 (0.40), 3.419 (0.52), 3.440 (1.04), 3.446 (1.10), 3.467 (0.92), 3.473 (0.87), 3.510 (0.75), 3.516 (0.87), 3.538 (1.04), 3.544 (1.10), 3.565 (0.40), 3.571 (0.69), 3.606 (1.62), 3.621 (0.58), 3.630 (1.27), 3.636 (1.33), 3.680 (1.10), 3.687 (0.92), 3.710 (1.96), 3.715 (1.79), 3.741 (0.87), 5.302 (5.49), 6.928 (1.21), 6.941 (1.21), 7.051 (2.37), 7.635 (4.91), 8.050 (0.69), 8.066 (1.44), 8.081 (0.64), 8.375 (2.14), 8.388 (2.08), 8.550 (0.52). LC-MS (方法A ); Rt = 0.87 min, m/z = 423 [M+H]⁺. | 中間物 17-2; GP G (條件A,使用HATU) |
81 | 2-[(2,6-二甲基吡啶-4-基)甲基]-8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.552 (0.55), 1.569 (0.78), 1.576 (0.58), 1.585 (0.65), 1.598 (0.48), 1.776 (0.57), 1.781 (0.77), 1.797 (1.32), 1.814 (1.48), 1.832 (1.42), 1.843 (0.82), 1.853 (0.65), 1.861 (0.90), 1.875 (0.61), 1.882 (0.46), 2.168 (0.42), 2.221 (13.16), 2.389 (0.54), 2.414 (15.51), 2.453 (16.00), 2.520 (3.79), 2.524 (2.35), 2.880 (3.01), 2.890 (7.62), 2.899 (3.44), 3.215 (1.26), 3.220 (1.20), 3.230 (2.24), 3.235 (2.16), 3.245 (1.20), 3.250 (1.24), 3.584 (0.47), 3.600 (1.01), 3.603 (1.02), 3.621 (1.33), 3.638 (0.69), 3.734 (0.67), 3.751 (1.23), 3.766 (1.02), 3.769 (1.02), 3.787 (0.63), 3.929 (1.05), 3.945 (1.56), 3.961 (0.97), 5.274 (6.86), 6.704 (2.85), 7.002 (2.87), 7.595 (5.09), 7.968 (0.77), 7.983 (1.59), 7.997 (0.74). LC-MS (方法A ); Rt = 1.28 min, m/z = 421 [M+H]⁺. | 中間物 18-1 + 18-2; GP G (條件A,使用HATU) |
82 | 2-[(2,6-二甲基吡啶-4-基)甲基]-N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.221 (13.56), 2.414 (15.49), 2.453 (16.00), 2.520 (4.13), 2.524 (2.58), 2.881 (3.06), 2.891 (7.44), 2.901 (3.45), 3.163 (0.61), 3.182 (1.98), 3.198 (1.57), 3.206 (1.72), 3.211 (2.13), 3.234 (2.35), 3.248 (0.99), 3.267 (0.62), 3.416 (0.42), 3.421 (0.52), 3.442 (1.14), 3.448 (1.21), 3.469 (0.99), 3.475 (0.96), 3.512 (0.84), 3.518 (0.91), 3.541 (1.16), 3.546 (1.23), 3.567 (0.48), 3.573 (0.76), 3.593 (0.44), 3.608 (1.87), 3.624 (0.75), 3.633 (1.61), 3.638 (1.47), 3.684 (1.34), 3.690 (1.12), 3.712 (2.37), 3.718 (2.08), 3.742 (1.00), 5.275 (6.96), 6.703 (2.98), 7.003 (3.00), 7.596 (5.07), 8.048 (0.79), 8.063 (1.68), 8.078 (0.79). LC-MS (方法A ); Rt = 1.22 min, m/z = 437 [M+H]⁺. | 中間物 18-1 + 18-2; GP G (條件A,使用HATU) |
83 | 8-甲基-2-(嘧啶-2-基甲基)-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.548 (0.47), 1.564 (0.68), 1.572 (0.51), 1.580 (0.58), 1.588 (0.41), 1.772 (0.54), 1.778 (0.72), 1.793 (1.24), 1.811 (1.38), 1.829 (1.34), 1.840 (0.74), 1.850 (0.60), 1.857 (0.82), 1.872 (0.56), 1.879 (0.41), 2.414 (16.00), 2.467 (1.30), 2.518 (4.59), 2.523 (3.09), 2.895 (11.10), 3.208 (1.11), 3.213 (1.11), 3.223 (2.08), 3.228 (2.00), 3.238 (1.15), 3.243 (1.15), 3.580 (0.45), 3.597 (0.93), 3.600 (0.95), 3.617 (1.28), 3.635 (0.68), 3.730 (0.64), 3.747 (1.15), 3.763 (0.97), 3.765 (0.97), 3.783 (0.64), 3.924 (0.99), 3.941 (1.50), 3.956 (0.93), 5.496 (7.08), 7.433 (1.67), 7.445 (3.32), 7.458 (1.71), 7.610 (5.07), 7.961 (0.72), 7.976 (1.46), 7.992 (0.70), 8.786 (8.57), 8.798 (8.36). LC-MS (方法A ); Rt = 0.88 min, m/z = 394 [M+H]⁺. | 中間物 19; GP G (條件A,使用HATU) |
84 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-(嘧啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.336 (0.49), 2.414 (16.00), 2.518 (5.91), 2.523 (4.08), 2.679 (0.51), 2.716 (0.54), 2.897 (10.22), 2.902 (3.47), 3.157 (0.57), 3.178 (1.62), 3.191 (1.44), 3.202 (1.59), 3.206 (2.13), 3.226 (1.44), 3.231 (1.64), 3.242 (0.92), 3.260 (0.57), 3.412 (0.44), 3.418 (0.51), 3.439 (1.05), 3.445 (1.13), 3.466 (0.92), 3.472 (0.87), 3.509 (0.80), 3.514 (0.90), 3.537 (1.08), 3.543 (1.10), 3.564 (0.49), 3.570 (0.72), 3.604 (1.67), 3.610 (1.31), 3.619 (0.67), 3.628 (1.31), 3.634 (1.34), 3.680 (1.18), 3.687 (1.00), 3.710 (2.03), 3.715 (1.75), 3.739 (0.87), 5.496 (6.73), 7.433 (1.62), 7.445 (3.31), 7.458 (1.62), 7.611 (5.09), 8.040 (0.67), 8.055 (1.44), 8.070 (0.67), 8.786 (8.68), 8.798 (7.76). LC-MS (方法A ); Rt = 0.79 min, m/z = 410 [M+H]⁺. | 中間物 19; GP G (條件A,使用HATU) |
85 | 8-甲基-2-(嘧啶-5-基甲基)-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.934 (0.59), 0.946 (0.59), 1.548 (0.47), 1.560 (0.68), 1.565 (0.80), 1.571 (0.74), 1.577 (0.65), 1.583 (0.59), 1.587 (0.56), 1.762 (0.44), 1.774 (0.77), 1.779 (0.71), 1.791 (1.09), 1.794 (0.98), 1.805 (1.04), 1.809 (1.15), 1.826 (0.86), 1.834 (0.77), 1.839 (0.71), 1.842 (0.95), 1.848 (1.06), 1.857 (0.95), 1.865 (0.59), 1.870 (0.71), 1.874 (0.62), 1.882 (0.50), 1.887 (0.47), 2.074 (0.44), 2.368 (0.56), 2.452 (16.00), 2.514 (4.82), 2.518 (4.91), 2.522 (4.14), 2.529 (7.04), 2.627 (0.59), 2.785 (1.09), 2.801 (0.77), 2.847 (0.47), 2.862 (2.78), 2.871 (3.90), 2.876 (4.67), 2.885 (3.52), 2.899 (0.71), 3.210 (1.04), 3.217 (1.33), 3.222 (2.22), 3.229 (2.34), 3.234 (1.72), 3.241 (1.33), 3.585 (0.65), 3.600 (1.42), 3.614 (1.66), 3.628 (1.01), 3.734 (0.86), 3.747 (1.39), 3.759 (1.36), 3.761 (1.21), 3.776 (0.89), 3.926 (1.06), 3.939 (1.51), 3.951 (0.98), 5.377 (6.12), 5.606 (2.54), 7.439 (2.78), 7.680 (4.55), 7.972 (0.71), 7.984 (1.36), 7.996 (0.62), 8.139 (0.56), 8.543 (4.50), 8.741 (9.97), 9.104 (1.95), 9.128 (4.26). LC-MS (方法A ); Rt = 0.85 min, m/z = 394 [M+H]⁺. | 中間物 20; GP G (條件A,使用HATU) |
86 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-(嘧啶-5-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.934 (1.40), 0.947 (1.27), 2.368 (0.80), 2.452 (16.00), 2.514 (7.15), 2.518 (7.24), 2.522 (5.97), 2.530 (3.22), 2.642 (0.85), 2.786 (0.47), 2.847 (0.51), 2.863 (2.50), 2.872 (3.68), 2.878 (4.11), 2.886 (3.22), 2.902 (0.59), 3.161 (0.72), 3.176 (0.80), 3.182 (1.65), 3.188 (1.48), 3.201 (2.16), 3.205 (1.74), 3.216 (0.76), 3.224 (1.82), 3.229 (1.40), 3.241 (0.89), 3.256 (0.72), 3.417 (0.55), 3.422 (0.63), 3.439 (1.23), 3.444 (1.35), 3.461 (1.06), 3.466 (1.02), 3.512 (0.80), 3.517 (0.93), 3.536 (1.19), 3.541 (1.14), 3.557 (0.59), 3.562 (0.72), 3.605 (1.82), 3.618 (0.72), 3.625 (1.44), 3.630 (1.48), 3.680 (1.27), 3.686 (1.10), 3.704 (1.23), 3.709 (1.99), 3.734 (0.93), 5.378 (6.18), 5.605 (1.10), 7.440 (1.19), 7.680 (4.40), 8.051 (0.72), 8.063 (1.44), 8.075 (0.63), 8.542 (1.86), 8.741 (9.99), 9.105 (0.85), 9.128 (4.36). LC-MS (方法A ); Rt = 0.77 min, m/z = 410 [M+H]⁺. | 中間物 20; GP G (條件A,使用HATU) |
87 | 2-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.845 (1.29), 0.863 (3.16), 0.881 (1.88), 1.312 (0.59), 1.331 (0.70), 1.352 (0.82), 1.375 (0.53), 1.395 (0.47), 1.481 (0.47), 1.513 (0.53), 1.534 (0.53), 1.553 (0.82), 1.562 (0.53), 1.570 (0.88), 1.577 (0.64), 1.585 (0.70), 1.599 (0.59), 1.615 (0.47), 1.761 (0.47), 1.782 (0.94), 1.797 (1.35), 1.815 (1.41), 1.833 (1.29), 1.844 (0.76), 1.858 (0.70), 1.862 (0.76), 1.876 (0.53), 2.318 (0.76), 2.470 (16.00), 2.518 (9.67), 2.523 (6.86), 2.633 (1.00), 2.660 (0.76), 2.740 (0.47), 2.758 (0.53), 2.762 (0.47), 2.829 (0.70), 2.848 (2.29), 2.860 (2.93), 2.869 (3.05), 2.882 (2.81), 2.900 (0.64), 3.214 (1.00), 3.219 (1.00), 3.230 (1.99), 3.234 (2.81), 3.245 (1.17), 3.250 (1.17), 3.259 (1.35), 3.263 (1.41), 3.287 (1.58), 3.419 (0.47), 3.440 (0.94), 3.446 (1.00), 3.467 (0.88), 3.473 (0.76), 3.510 (0.70), 3.516 (0.82), 3.539 (0.94), 3.545 (0.94), 3.565 (0.59), 3.572 (0.59), 3.584 (0.70), 3.603 (1.35), 3.620 (2.17), 3.639 (1.11), 3.719 (2.05), 3.734 (0.88), 3.748 (2.23), 3.751 (2.11), 3.766 (1.00), 3.769 (1.05), 3.772 (0.88), 3.787 (0.64), 3.817 (0.41), 3.824 (0.53), 3.829 (0.53), 3.835 (0.47), 3.841 (0.64), 3.929 (0.94), 3.945 (1.41), 3.961 (0.82), 4.036 (0.47), 4.072 (1.70), 4.084 (1.88), 4.088 (1.82), 4.097 (1.58), 7.348 (0.47), 7.461 (4.51), 7.966 (0.64), 7.981 (1.35), 7.996 (0.64), 8.548 (0.59). LC-MS (方法A ); Rt = 0.93 min, m/z = 402 [M+H]⁺. | 中間物 21; GP G (條件A,使用HATU) |
88 | N ,2-雙[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.74), 0.948 (0.72), 2.470 (16.00), 2.518 (4.16), 2.523 (2.85), 2.831 (0.61), 2.849 (2.29), 2.862 (3.03), 2.871 (3.22), 2.884 (3.03), 2.902 (0.67), 3.164 (0.57), 3.183 (1.87), 3.197 (1.44), 3.207 (1.57), 3.211 (2.00), 3.235 (2.76), 3.247 (0.94), 3.259 (1.42), 3.263 (1.50), 3.282 (0.43), 3.287 (1.39), 3.415 (0.59), 3.422 (0.65), 3.442 (1.63), 3.448 (1.59), 3.469 (1.41), 3.474 (1.31), 3.512 (1.24), 3.516 (1.24), 3.540 (1.78), 3.545 (1.96), 3.566 (0.76), 3.573 (1.11), 3.610 (1.91), 3.615 (2.05), 3.633 (1.46), 3.639 (1.78), 3.654 (0.43), 3.685 (1.22), 3.691 (1.04), 3.714 (3.11), 3.719 (3.61), 3.747 (2.18), 3.753 (1.18), 3.818 (0.44), 3.824 (0.55), 3.829 (0.57), 3.834 (0.52), 3.841 (0.67), 3.848 (0.48), 4.072 (1.79), 4.085 (2.05), 4.089 (2.02), 4.097 (1.72), 7.462 (4.83), 8.045 (0.70), 8.059 (1.50), 8.074 (0.68). LC-MS (方法A ); Rt = 0.85 min, m/z = 418 [M+H]⁺. | 中間物 21; GP G (條件A,使用HATU) |
89 | 2-[(2S)-1,4-二㗁烷-2-基甲基]-8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.553 (0.46), 1.569 (0.67), 1.577 (0.48), 1.585 (0.56), 1.598 (0.41), 1.775 (0.51), 1.782 (0.67), 1.797 (1.16), 1.815 (1.30), 1.832 (1.24), 1.844 (0.68), 1.853 (0.55), 1.858 (0.66), 1.862 (0.78), 1.876 (0.52), 1.879 (0.51), 2.075 (2.92), 2.470 (16.00), 2.518 (3.51), 2.523 (2.43), 2.633 (0.48), 2.829 (0.63), 2.846 (2.29), 2.860 (3.13), 2.869 (3.30), 2.882 (3.02), 2.900 (0.68), 3.214 (1.01), 3.220 (1.01), 3.230 (2.02), 3.235 (2.83), 3.245 (1.15), 3.250 (1.15), 3.259 (1.45), 3.263 (1.37), 3.288 (1.38), 3.419 (0.44), 3.440 (0.93), 3.446 (1.04), 3.468 (0.87), 3.473 (0.81), 3.510 (0.72), 3.516 (0.85), 3.539 (1.00), 3.545 (1.00), 3.565 (0.44), 3.572 (0.61), 3.584 (0.45), 3.600 (0.91), 3.603 (0.96), 3.620 (2.01), 3.639 (1.13), 3.644 (0.83), 3.719 (1.88), 3.725 (1.28), 3.734 (0.74), 3.748 (2.29), 3.751 (2.10), 3.754 (1.77), 3.766 (0.97), 3.769 (0.97), 3.771 (0.78), 3.787 (0.63), 3.817 (0.42), 3.824 (0.53), 3.829 (0.55), 3.834 (0.49), 3.841 (0.67), 3.848 (0.46), 3.929 (0.96), 3.946 (1.43), 3.961 (0.89), 4.072 (1.77), 4.084 (2.02), 4.088 (1.98), 4.097 (1.68), 7.461 (4.72), 7.964 (0.66), 7.979 (1.39), 7.995 (0.64). LC-MS (方法A ); Rt = 0.95 min, m/z = 402 [M+H]⁺. | 中間物 22; GP G (條件A,使用HATU) |
90 | N -[(2R)-1,4-二㗁烷-2-基甲基]-2-[(2S)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.318 (0.63), 2.470 (16.00), 2.518 (7.91), 2.523 (5.63), 2.679 (0.67), 2.831 (0.56), 2.849 (2.25), 2.861 (2.99), 2.871 (3.16), 2.884 (2.92), 2.902 (0.63), 3.162 (0.56), 3.182 (1.65), 3.197 (1.34), 3.207 (1.51), 3.211 (2.04), 3.218 (0.81), 3.235 (2.99), 3.249 (0.88), 3.259 (1.41), 3.263 (1.37), 3.287 (1.37), 3.415 (0.56), 3.421 (0.60), 3.442 (1.58), 3.448 (1.55), 3.469 (1.37), 3.475 (1.27), 3.512 (1.13), 3.516 (1.13), 3.518 (1.09), 3.540 (1.65), 3.545 (1.83), 3.567 (0.70), 3.573 (0.98), 3.610 (1.83), 3.616 (1.90), 3.633 (1.41), 3.639 (1.69), 3.685 (1.16), 3.691 (0.95), 3.714 (2.92), 3.719 (3.45), 3.747 (2.04), 3.817 (0.42), 3.824 (0.53), 3.829 (0.56), 3.835 (0.49), 3.841 (0.67), 4.072 (1.76), 4.085 (2.00), 4.089 (1.90), 4.097 (1.65), 7.462 (4.64), 8.044 (0.67), 8.059 (1.41), 8.074 (0.67). LC-MS (方法A ); Rt = 0.85 min, m/z = 418 [M+H]⁺. | 中間物 22; GP G (條件A,使用HATU) |
91 | 8-甲基-2-(氧雜環丁-3-基甲基)-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.550 (0.48), 1.567 (0.65), 1.574 (0.48), 1.583 (0.58), 1.595 (0.41), 1.780 (0.69), 1.795 (1.16), 1.814 (1.34), 1.831 (1.27), 1.842 (0.72), 1.852 (0.62), 1.859 (0.79), 1.874 (0.55), 2.074 (4.15), 2.459 (16.00), 2.518 (7.40), 2.523 (4.97), 2.586 (0.51), 2.821 (0.69), 2.839 (2.50), 2.852 (3.32), 2.861 (3.53), 2.874 (3.12), 2.892 (0.72), 3.210 (1.10), 3.216 (1.06), 3.226 (2.09), 3.231 (1.95), 3.241 (1.16), 3.246 (1.16), 3.357 (0.79), 3.376 (0.96), 3.395 (0.65), 3.582 (0.45), 3.598 (0.93), 3.601 (0.93), 3.619 (1.23), 3.636 (0.69), 3.732 (0.62), 3.749 (1.10), 3.764 (0.93), 3.766 (0.93), 3.785 (0.58), 3.926 (0.93), 3.943 (1.44), 3.958 (0.86), 4.342 (3.84), 4.360 (3.73), 4.402 (2.57), 4.418 (5.31), 4.433 (2.78), 4.620 (3.19), 4.635 (3.29), 4.639 (3.56), 4.655 (2.67), 7.530 (4.45), 7.960 (0.65), 7.974 (1.37), 7.990 (0.65). LC-MS (方法A ); Rt = 0.90 min, m/z = 372 [M+H]⁺. | 中間物 23; GP G (條件A,使用HATU) |
92 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-(氧雜環丁-3-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.46), 0.949 (0.46), 2.459 (16.00), 2.518 (4.36), 2.523 (3.04), 2.771 (0.42), 2.822 (0.61), 2.839 (2.33), 2.841 (2.34), 2.853 (3.10), 2.862 (3.38), 2.876 (3.08), 2.893 (0.72), 3.159 (0.59), 3.180 (1.55), 3.193 (1.44), 3.204 (1.64), 3.209 (2.10), 3.213 (0.92), 3.229 (1.51), 3.233 (1.75), 3.245 (0.92), 3.263 (0.61), 3.357 (0.74), 3.361 (0.63), 3.376 (0.98), 3.391 (0.59), 3.395 (0.65), 3.413 (0.61), 3.420 (0.52), 3.440 (1.07), 3.447 (1.16), 3.468 (0.96), 3.474 (0.90), 3.510 (0.81), 3.516 (0.89), 3.538 (1.11), 3.544 (1.13), 3.565 (0.48), 3.571 (0.76), 3.606 (1.66), 3.611 (1.40), 3.621 (0.65), 3.630 (1.27), 3.636 (1.33), 3.682 (1.18), 3.688 (1.00), 3.711 (2.03), 3.717 (1.73), 3.741 (0.87), 4.343 (3.82), 4.361 (3.75), 4.402 (2.71), 4.418 (5.63), 4.433 (2.95), 4.620 (3.41), 4.635 (3.43), 4.639 (3.86), 4.655 (2.95), 7.530 (4.80), 8.038 (0.66), 8.053 (1.42), 8.068 (0.66). LC-MS (方法A ); Rt = 0.81 min, m/z = 388 [M+H]⁺. | 中間物 23; GP G (條件A,使用HATU) |
93 | 8-甲基-2-[(3-甲基氧雜環丁-3-基)甲基]-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.165 (12.32), 1.554 (0.41), 1.569 (0.61), 1.576 (0.55), 1.582 (0.49), 1.592 (0.51), 1.778 (0.47), 1.783 (0.47), 1.795 (0.73), 1.798 (0.67), 1.810 (0.69), 1.813 (0.77), 1.826 (0.57), 1.838 (0.51), 1.842 (0.45), 1.846 (0.57), 1.852 (0.65), 1.861 (0.61), 1.874 (0.45), 1.878 (0.41), 2.074 (0.77), 2.368 (0.41), 2.457 (16.00), 2.514 (3.16), 2.518 (3.26), 2.522 (2.65), 2.843 (0.59), 2.858 (2.28), 2.867 (3.18), 2.874 (3.40), 2.884 (3.01), 2.899 (0.65), 3.216 (1.02), 3.221 (1.00), 3.228 (1.87), 3.233 (1.73), 3.240 (1.00), 3.246 (1.04), 3.588 (0.45), 3.604 (0.98), 3.618 (1.12), 3.632 (0.65), 3.737 (0.59), 3.749 (0.88), 3.751 (1.02), 3.763 (1.00), 3.766 (0.83), 3.768 (0.71), 3.780 (0.65), 3.931 (0.96), 3.944 (1.38), 3.956 (0.92), 4.214 (5.05), 4.225 (5.37), 4.259 (6.92), 4.595 (4.36), 4.606 (3.91), 7.527 (4.25), 7.961 (0.63), 7.973 (1.30), 7.985 (0.65). LC-MS (方法A ); Rt = 0.97 min, m/z = 386 [M+H]⁺. | 中間物 24; GP G (條件A,使用HATU) |
94 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(3-甲基氧雜環丁-3-基)甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.165 (12.23), 2.368 (0.41), 2.457 (16.00), 2.514 (3.62), 2.518 (3.68), 2.522 (2.98), 2.627 (0.43), 2.844 (0.58), 2.857 (2.16), 2.859 (2.23), 2.869 (3.02), 2.876 (3.28), 2.886 (2.87), 2.900 (0.66), 3.166 (0.66), 3.181 (0.79), 3.186 (1.24), 3.193 (1.35), 3.205 (1.97), 3.209 (1.41), 3.221 (0.66), 3.229 (1.50), 3.233 (1.33), 3.245 (0.84), 3.260 (0.62), 3.425 (0.47), 3.442 (0.99), 3.447 (1.05), 3.464 (0.84), 3.469 (0.77), 3.517 (0.69), 3.521 (0.77), 3.539 (1.01), 3.544 (1.03), 3.561 (0.49), 3.567 (0.64), 3.609 (1.35), 3.622 (0.56), 3.629 (1.29), 3.634 (1.14), 3.684 (1.03), 3.690 (0.90), 3.708 (1.03), 3.713 (1.67), 3.738 (0.75), 4.213 (5.16), 4.225 (5.33), 4.259 (6.77), 4.594 (4.31), 4.606 (4.09), 7.527 (4.16), 8.041 (0.64), 8.053 (1.37), 8.065 (0.62). LC-MS (方法A ); Rt = 0.89 min, m/z = 402 [M+H]⁺. | 中間物 24; GP G (條件A,使用HATU) |
95 | 2-[(3-氟氧雜環丁-3-基)甲基]-8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.552 (0.46), 1.569 (0.66), 1.576 (0.48), 1.584 (0.55), 1.776 (0.52), 1.781 (0.66), 1.797 (1.17), 1.815 (1.31), 1.832 (1.23), 1.843 (0.69), 1.853 (0.55), 1.858 (0.66), 1.861 (0.77), 1.875 (0.52), 2.074 (5.27), 2.468 (16.00), 2.518 (3.51), 2.523 (2.37), 2.839 (0.52), 2.857 (2.39), 2.858 (2.51), 2.869 (3.77), 2.876 (3.91), 2.888 (3.08), 2.906 (0.52), 3.214 (1.06), 3.219 (1.06), 3.230 (1.99), 3.234 (1.89), 3.245 (1.08), 3.250 (1.11), 3.583 (0.43), 3.599 (0.91), 3.603 (0.88), 3.620 (1.20), 3.638 (0.65), 3.733 (0.60), 3.748 (0.88), 3.751 (1.11), 3.765 (0.91), 3.768 (0.92), 3.786 (0.62), 3.929 (0.94), 3.945 (1.42), 3.961 (0.86), 4.591 (1.31), 4.614 (4.08), 4.642 (1.37), 4.669 (3.22), 4.766 (1.80), 4.788 (1.42), 4.819 (1.77), 4.842 (1.42), 7.525 (3.83), 7.976 (0.66), 7.992 (1.37), 8.006 (0.65). LC-MS (方法A ); Rt = 0.96 min, m/z = 390 [M+H]⁺. | 中間物 25; GP G (條件A,使用HATU) |
96 | N -[(2R)-1,4-二㗁烷-2-基甲基]-2-[(3-氟氧雜環丁-3-基)甲基]-8-甲基-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.075 (2.02), 2.468 (16.00), 2.518 (5.30), 2.523 (3.70), 2.839 (0.51), 2.859 (2.32), 2.871 (3.49), 2.878 (3.74), 2.890 (3.01), 2.908 (0.55), 3.162 (0.55), 3.181 (1.81), 3.197 (1.40), 3.206 (1.52), 3.211 (1.97), 3.216 (0.83), 3.234 (1.95), 3.248 (0.85), 3.266 (0.55), 3.421 (0.46), 3.442 (1.01), 3.448 (1.08), 3.469 (0.87), 3.475 (0.85), 3.511 (0.76), 3.517 (0.83), 3.540 (1.03), 3.546 (1.06), 3.566 (0.44), 3.573 (0.69), 3.608 (1.54), 3.624 (0.62), 3.632 (1.33), 3.639 (1.19), 3.684 (1.15), 3.690 (0.94), 3.712 (2.00), 3.719 (1.65), 3.742 (0.83), 4.591 (1.31), 4.615 (3.40), 4.642 (1.38), 4.664 (2.04), 4.669 (3.08), 4.766 (1.77), 4.788 (1.40), 4.818 (1.77), 4.841 (1.45), 7.527 (3.88), 8.055 (0.67), 8.070 (1.40), 8.085 (0.62). LC-MS (方法A ); Rt = 0.87 min, m/z = 406 [M+H]⁺. | 中間物 25; GP G (條件A,使用HATU) |
97 | 8-甲基-2-[(2R)-氧雜環丁-2-基甲基]-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.554 (0.44), 1.570 (0.62), 1.578 (0.46), 1.586 (0.52), 1.777 (0.49), 1.783 (0.65), 1.798 (1.12), 1.817 (1.24), 1.834 (1.18), 1.846 (0.67), 1.855 (0.55), 1.863 (0.75), 1.877 (0.51), 2.324 (0.73), 2.329 (0.99), 2.334 (0.73), 2.397 (0.43), 2.419 (0.54), 2.425 (0.66), 2.430 (0.49), 2.437 (0.45), 2.442 (0.59), 2.447 (0.73), 2.473 (16.00), 2.520 (3.45), 2.525 (2.20), 2.620 (0.51), 2.634 (0.56), 2.640 (0.55), 2.647 (0.46), 2.655 (0.42), 2.662 (0.77), 2.667 (1.01), 2.671 (1.08), 2.676 (0.78), 2.680 (0.42), 2.859 (2.24), 2.870 (4.52), 2.875 (4.03), 2.885 (2.86), 3.216 (1.06), 3.220 (1.04), 3.231 (1.97), 3.236 (1.90), 3.246 (1.06), 3.251 (1.12), 3.585 (0.42), 3.601 (0.85), 3.605 (0.85), 3.622 (1.15), 3.639 (0.63), 3.735 (0.59), 3.750 (0.84), 3.752 (1.02), 3.767 (0.86), 3.770 (0.86), 3.788 (0.57), 3.930 (0.90), 3.947 (1.37), 3.962 (0.83), 4.241 (0.55), 4.252 (0.60), 4.277 (1.53), 4.288 (1.54), 4.307 (2.04), 4.323 (2.45), 4.330 (0.82), 4.337 (0.88), 4.344 (1.57), 4.359 (1.24), 4.460 (0.64), 4.474 (0.67), 4.478 (0.83), 4.481 (0.89), 4.492 (0.73), 4.495 (0.76), 4.499 (0.72), 4.513 (0.52), 4.955 (0.63), 4.966 (0.61), 4.970 (0.73), 4.974 (0.66), 4.985 (0.58), 7.498 (4.43), 7.967 (0.61), 7.983 (1.26), 7.997 (0.59). LC-MS (方法A ); Rt = 0.91 min, m/z = 372 [M+H]⁺. | 中間物 26; GP G (條件A,使用HATU) |
98 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(2R)-氧雜環丁-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.320 (0.43), 2.324 (0.96), 2.329 (1.33), 2.334 (0.99), 2.338 (0.48), 2.397 (0.47), 2.402 (0.40), 2.407 (0.45), 2.414 (0.40), 2.419 (0.56), 2.425 (0.72), 2.430 (0.52), 2.436 (0.49), 2.442 (0.63), 2.447 (0.78), 2.473 (16.00), 2.520 (7.23), 2.525 (4.50), 2.620 (0.60), 2.634 (0.63), 2.640 (0.61), 2.647 (0.51), 2.655 (0.48), 2.662 (0.91), 2.666 (1.29), 2.671 (1.42), 2.676 (1.05), 2.680 (0.57), 2.841 (0.43), 2.860 (2.36), 2.872 (4.67), 2.876 (3.98), 2.887 (2.95), 2.905 (0.46), 3.165 (0.55), 3.184 (1.80), 3.199 (1.43), 3.208 (1.54), 3.212 (1.86), 3.233 (1.50), 3.236 (1.74), 3.248 (0.91), 3.266 (0.57), 3.416 (0.42), 3.422 (0.50), 3.443 (1.03), 3.450 (1.14), 3.471 (0.92), 3.477 (0.89), 3.514 (0.79), 3.519 (0.87), 3.542 (1.05), 3.548 (1.09), 3.569 (0.45), 3.574 (0.70), 3.610 (1.59), 3.625 (0.66), 3.634 (1.37), 3.639 (1.28), 3.686 (1.15), 3.692 (0.99), 3.715 (1.98), 3.720 (1.67), 3.743 (0.86), 4.241 (0.59), 4.253 (0.65), 4.277 (1.56), 4.288 (1.65), 4.308 (1.83), 4.323 (2.05), 4.328 (1.02), 4.336 (0.96), 4.344 (1.63), 4.359 (1.17), 4.460 (0.67), 4.474 (0.71), 4.477 (0.91), 4.480 (0.95), 4.492 (0.77), 4.495 (0.83), 4.499 (0.80), 4.513 (0.56), 4.955 (0.66), 4.966 (0.66), 4.970 (0.79), 4.974 (0.74), 4.985 (0.64), 4.989 (0.40), 7.499 (4.71), 8.047 (0.64), 8.062 (1.40), 8.077 (0.65). LC-MS (方法A ); Rt = 0.83 min, m/z = 388 [M+H]⁺. | 中間物 26; GP G (條件A,使用HATU) |
99 | 8-甲基-2-[(2S)-氧雜環丁-2-基甲基]-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.555 (0.43), 1.571 (0.61), 1.579 (0.45), 1.587 (0.55), 1.777 (0.50), 1.783 (0.67), 1.798 (1.12), 1.816 (1.25), 1.834 (1.19), 1.845 (0.66), 1.855 (0.55), 1.863 (0.75), 1.877 (0.51), 2.320 (0.54), 2.398 (0.40), 2.420 (0.53), 2.426 (0.64), 2.431 (0.45), 2.437 (0.40), 2.442 (0.54), 2.447 (0.68), 2.472 (16.00), 2.520 (6.06), 2.525 (3.97), 2.619 (0.49), 2.634 (0.54), 2.640 (0.54), 2.647 (0.42), 2.655 (0.42), 2.662 (0.98), 2.859 (2.22), 2.870 (4.53), 2.875 (4.12), 2.885 (2.91), 3.215 (0.94), 3.222 (0.97), 3.230 (1.76), 3.237 (1.69), 3.245 (0.98), 3.253 (0.99), 3.585 (0.41), 3.601 (0.84), 3.605 (0.83), 3.622 (1.15), 3.640 (0.62), 3.735 (0.58), 3.752 (1.02), 3.768 (0.87), 3.770 (0.87), 3.788 (0.57), 3.930 (0.90), 3.946 (1.33), 3.962 (0.84), 4.241 (0.56), 4.252 (0.60), 4.276 (1.53), 4.288 (1.61), 4.308 (1.92), 4.322 (2.27), 4.329 (0.83), 4.336 (0.90), 4.344 (1.64), 4.359 (1.30), 4.460 (0.65), 4.474 (0.68), 4.477 (0.85), 4.481 (0.90), 4.492 (0.75), 4.495 (0.78), 4.499 (0.73), 4.513 (0.52), 4.955 (0.63), 4.966 (0.61), 4.970 (0.74), 4.974 (0.68), 4.985 (0.58), 7.498 (4.56), 7.966 (0.59), 7.982 (1.27), 7.997 (0.58). LC-MS (方法A ); Rt = 0.91 min, m/z = 372 [M+H]⁺. | 中間物 27; GP G (條件A,使用HATU) |
100 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(2S)-氧雜環丁-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.324 (0.84), 2.329 (1.19), 2.334 (0.85), 2.397 (0.42), 2.419 (0.52), 2.425 (0.65), 2.430 (0.48), 2.436 (0.42), 2.442 (0.56), 2.447 (0.70), 2.473 (16.00), 2.520 (4.46), 2.525 (2.91), 2.619 (0.53), 2.634 (0.56), 2.640 (0.56), 2.647 (0.45), 2.655 (0.43), 2.662 (0.82), 2.667 (1.16), 2.671 (1.28), 2.676 (0.91), 2.681 (0.47), 2.859 (2.33), 2.871 (4.57), 2.877 (3.93), 2.887 (2.96), 2.905 (0.42), 3.163 (0.57), 3.184 (1.49), 3.197 (1.36), 3.208 (1.54), 3.213 (1.95), 3.220 (0.76), 3.236 (2.21), 3.251 (0.83), 3.269 (0.58), 3.423 (0.47), 3.444 (0.99), 3.450 (1.08), 3.471 (0.89), 3.477 (0.85), 3.513 (0.75), 3.519 (0.81), 3.541 (1.03), 3.548 (1.07), 3.568 (0.44), 3.574 (0.69), 3.609 (1.57), 3.625 (0.60), 3.633 (1.29), 3.640 (1.24), 3.686 (1.12), 3.692 (0.94), 3.715 (1.95), 3.721 (1.62), 3.744 (0.82), 4.241 (0.58), 4.253 (0.62), 4.277 (1.55), 4.288 (1.63), 4.308 (1.87), 4.323 (2.12), 4.329 (0.93), 4.336 (0.92), 4.344 (1.65), 4.360 (1.24), 4.460 (0.66), 4.474 (0.69), 4.477 (0.87), 4.481 (0.90), 4.492 (0.76), 4.495 (0.79), 4.499 (0.75), 4.513 (0.53), 4.955 (0.65), 4.966 (0.64), 4.970 (0.76), 4.974 (0.69), 4.985 (0.61), 7.499 (4.64), 8.046 (0.64), 8.061 (1.38), 8.075 (0.63). LC-MS (方法A ); Rt = 0.83 min, m/z = 388 [M+H]⁺. | 中間物 27; GP G (條件A,使用HATU) |
101 | 8-甲基-2-{[(2R)-4-甲基嗎啉-2-基]甲基}-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.504 (0.51), 1.553 (0.44), 1.569 (0.57), 1.577 (0.44), 1.585 (0.51), 1.722 (0.76), 1.749 (1.14), 1.775 (1.14), 1.781 (0.83), 1.797 (1.14), 1.815 (1.27), 1.832 (1.21), 1.844 (0.70), 1.853 (0.57), 1.862 (0.83), 1.876 (0.51), 1.936 (0.44), 1.957 (0.83), 1.964 (0.83), 1.985 (0.57), 1.992 (0.57), 2.156 (11.37), 2.170 (1.02), 2.318 (1.14), 2.469 (16.00), 2.518 (14.79), 2.523 (10.03), 2.547 (1.21), 2.575 (0.76), 2.635 (0.76), 2.782 (1.08), 2.828 (0.57), 2.846 (2.22), 2.858 (2.79), 2.867 (2.98), 2.881 (2.73), 2.898 (0.63), 3.214 (0.89), 3.220 (0.89), 3.229 (1.65), 3.235 (1.59), 3.244 (0.89), 3.250 (0.95), 3.422 (0.44), 3.428 (0.57), 3.449 (1.02), 3.456 (1.02), 3.478 (0.57), 3.483 (0.44), 3.600 (0.89), 3.620 (1.21), 3.638 (0.63), 3.734 (0.63), 3.754 (1.90), 3.766 (1.33), 3.769 (1.40), 3.777 (1.14), 3.786 (1.33), 3.929 (0.89), 3.945 (1.33), 3.961 (0.83), 4.083 (2.86), 4.098 (2.79), 7.457 (4.32), 7.962 (0.63), 7.977 (1.33), 7.991 (0.63), 8.463 (0.44), 8.552 (0.76). LC-MS (方法A ); Rt = 0.92 min, m/z = 415 [M+H]⁺. | 中間物 28; GP G (條件A,使用HATU) |
102 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-{[(2R)-4-甲基嗎啉-2-基]甲基}-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (2.38), 0.935 (0.71), 0.948 (2.38), 0.953 (0.40), 1.352 (0.48), 1.721 (0.71), 1.748 (1.03), 1.774 (0.79), 1.936 (0.40), 1.957 (0.79), 1.964 (0.79), 1.985 (0.55), 2.155 (11.33), 2.170 (1.19), 2.318 (1.43), 2.469 (16.00), 2.518 (15.37), 2.523 (11.25), 2.543 (1.98), 2.573 (0.63), 2.635 (0.71), 2.754 (1.19), 2.782 (1.35), 2.829 (0.48), 2.847 (1.98), 2.859 (2.61), 2.869 (2.85), 2.883 (2.61), 2.900 (0.55), 3.162 (0.48), 3.182 (1.50), 3.196 (1.19), 3.207 (1.35), 3.211 (1.74), 3.218 (0.71), 3.235 (1.90), 3.249 (0.79), 3.268 (0.63), 3.283 (0.40), 3.422 (0.87), 3.428 (0.63), 3.442 (1.03), 3.449 (1.82), 3.456 (1.11), 3.469 (0.95), 3.476 (1.19), 3.512 (0.71), 3.518 (0.79), 3.540 (1.03), 3.547 (0.95), 3.567 (0.48), 3.573 (0.71), 3.608 (1.35), 3.633 (1.19), 3.638 (1.11), 3.684 (1.03), 3.691 (0.87), 3.713 (1.74), 3.748 (1.03), 3.753 (1.27), 3.784 (1.11), 4.085 (2.77), 4.099 (2.69), 7.459 (4.20), 8.041 (0.63), 8.056 (1.35), 8.071 (0.63), 8.464 (0.55), 8.551 (0.71). LC-MS (方法A ); Rt = 0.85 min, m/z = 431 [M+H]⁺. | 中間物 28; GP G (條件A,使用HATU) |
103 | 8-甲基-2-{[(2S)-4-甲基嗎啉-2-基]甲基}-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.553 (0.47), 1.569 (0.68), 1.577 (0.50), 1.586 (0.57), 1.593 (0.42), 1.721 (0.81), 1.749 (1.17), 1.775 (1.15), 1.782 (0.73), 1.797 (1.15), 1.815 (1.28), 1.832 (1.25), 1.844 (0.68), 1.853 (0.55), 1.858 (0.65), 1.862 (0.76), 1.876 (0.52), 1.936 (0.47), 1.956 (0.86), 1.964 (0.86), 1.985 (0.52), 1.992 (0.44), 2.155 (12.45), 2.318 (0.50), 2.323 (1.10), 2.327 (1.57), 2.332 (1.10), 2.336 (0.47), 2.469 (16.00), 2.518 (5.22), 2.523 (3.78), 2.546 (0.76), 2.574 (0.70), 2.635 (0.84), 2.665 (1.75), 2.669 (1.88), 2.673 (1.17), 2.678 (0.50), 2.827 (0.63), 2.846 (2.27), 2.858 (2.98), 2.867 (3.21), 2.881 (2.95), 2.898 (0.65), 3.214 (1.04), 3.219 (1.02), 3.230 (1.98), 3.234 (1.91), 3.245 (1.04), 3.249 (1.12), 3.422 (0.44), 3.428 (0.57), 3.450 (1.02), 3.456 (1.02), 3.478 (0.60), 3.483 (0.47), 3.584 (0.42), 3.600 (0.86), 3.603 (0.89), 3.620 (1.20), 3.638 (0.65), 3.734 (0.65), 3.751 (1.91), 3.754 (1.93), 3.760 (1.33), 3.766 (1.38), 3.769 (1.44), 3.778 (1.20), 3.786 (1.38), 3.929 (0.94), 3.945 (1.44), 3.960 (0.89), 4.083 (3.11), 4.098 (3.00), 7.457 (4.49), 7.962 (0.65), 7.977 (1.41), 7.993 (0.65). LC-MS (方法A ); Rt = 0.92 min, m/z = 415 [M+H]⁺. | 中間物 29; GP G (條件A,使用HATU) |
104 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-{[(2S)-4-甲基嗎啉-2-基]甲基}-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (1.04), 0.948 (1.04), 1.721 (0.75), 1.748 (1.04), 1.774 (0.81), 1.936 (0.43), 1.956 (0.81), 1.964 (0.84), 1.984 (0.52), 1.992 (0.43), 2.155 (12.28), 2.169 (0.46), 2.318 (0.55), 2.322 (1.18), 2.327 (1.70), 2.332 (1.24), 2.336 (0.55), 2.469 (16.00), 2.518 (7.24), 2.523 (5.02), 2.543 (1.27), 2.575 (0.66), 2.635 (0.84), 2.665 (1.87), 2.669 (2.08), 2.673 (1.30), 2.678 (0.58), 2.829 (0.55), 2.846 (2.08), 2.860 (2.65), 2.869 (3.08), 2.882 (2.80), 2.900 (0.63), 3.164 (0.52), 3.182 (1.79), 3.198 (1.35), 3.206 (1.50), 3.211 (1.85), 3.231 (1.38), 3.235 (1.64), 3.247 (0.86), 3.265 (0.55), 3.415 (0.40), 3.422 (0.86), 3.428 (0.61), 3.442 (1.07), 3.449 (1.96), 3.456 (1.10), 3.469 (0.95), 3.476 (1.24), 3.483 (0.52), 3.512 (0.75), 3.518 (0.84), 3.540 (1.01), 3.547 (1.04), 3.567 (0.43), 3.573 (0.69), 3.608 (1.47), 3.623 (0.58), 3.632 (1.27), 3.639 (1.18), 3.685 (1.10), 3.691 (0.92), 3.713 (1.90), 3.719 (1.59), 3.748 (1.12), 3.753 (1.33), 3.760 (1.24), 3.769 (0.58), 3.778 (1.07), 3.784 (1.15), 4.084 (3.03), 4.099 (2.91), 7.459 (4.47), 8.042 (0.66), 8.057 (1.44), 8.072 (0.66). LC-MS (方法A ); Rt = 0.85 min, m/z = 431 [M+H]⁺. | 中間物 29; GP G (條件A,使用HATU) |
105 | 8-甲基-2-[(2R)-四氫呋喃-2-基甲基]-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.553 (0.60), 1.570 (0.87), 1.573 (0.78), 1.585 (0.89), 1.591 (0.83), 1.600 (0.74), 1.615 (0.49), 1.622 (0.60), 1.753 (0.69), 1.770 (2.25), 1.775 (0.87), 1.782 (0.96), 1.787 (2.86), 1.796 (1.34), 1.806 (1.92), 1.815 (1.36), 1.823 (0.89), 1.832 (1.23), 1.843 (0.67), 1.853 (0.54), 1.861 (0.78), 1.876 (0.51), 1.878 (0.51), 1.886 (0.51), 1.903 (0.65), 1.917 (0.58), 1.934 (0.78), 1.950 (0.62), 2.318 (0.42), 2.470 (16.00), 2.518 (5.13), 2.523 (3.62), 2.828 (0.49), 2.848 (2.34), 2.858 (3.46), 2.866 (3.75), 2.878 (3.03), 2.897 (0.51), 3.214 (1.03), 3.219 (1.03), 3.229 (1.94), 3.234 (1.87), 3.244 (1.03), 3.249 (1.07), 3.584 (0.42), 3.596 (0.76), 3.599 (0.96), 3.603 (0.91), 3.613 (1.41), 3.616 (1.52), 3.620 (1.32), 3.633 (1.70), 3.638 (0.78), 3.650 (0.71), 3.724 (0.78), 3.734 (0.67), 3.741 (1.70), 3.744 (0.87), 3.748 (0.98), 3.751 (1.16), 3.757 (1.14), 3.761 (1.36), 3.766 (0.98), 3.769 (0.96), 3.777 (0.65), 3.786 (0.65), 3.929 (0.91), 3.944 (1.41), 3.960 (0.87), 4.038 (0.69), 4.054 (1.12), 4.074 (1.72), 4.088 (1.27), 4.098 (2.16), 4.104 (0.58), 4.111 (0.67), 4.121 (1.14), 4.124 (1.14), 4.130 (1.12), 4.140 (0.47), 7.463 (4.66), 7.959 (0.62), 7.974 (1.34), 7.989 (0.62). LC-MS (方法A ); Rt = 1.00 min, m/z = 386 [M+H]⁺. | 中間物 30; GP G (條件A,使用HATU) |
106 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(2R)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.41), 0.948 (0.41), 1.573 (0.49), 1.589 (0.56), 1.601 (0.51), 1.605 (0.48), 1.622 (0.58), 1.752 (0.59), 1.769 (2.11), 1.786 (2.63), 1.805 (1.69), 1.822 (0.66), 1.903 (0.60), 1.917 (0.54), 1.933 (0.78), 1.950 (0.65), 2.470 (16.00), 2.518 (2.48), 2.523 (1.67), 2.829 (0.53), 2.847 (2.30), 2.860 (3.47), 2.867 (3.73), 2.879 (3.09), 2.898 (0.57), 3.163 (0.56), 3.182 (1.85), 3.197 (1.42), 3.206 (1.54), 3.211 (1.99), 3.231 (1.50), 3.235 (1.77), 3.247 (0.86), 3.266 (0.54), 3.421 (0.47), 3.442 (1.00), 3.448 (1.11), 3.469 (0.90), 3.475 (0.86), 3.512 (0.78), 3.518 (0.87), 3.540 (1.04), 3.547 (1.07), 3.567 (0.43), 3.573 (0.70), 3.596 (0.85), 3.608 (1.61), 3.613 (2.31), 3.623 (0.70), 3.633 (2.99), 3.638 (1.34), 3.650 (0.91), 3.685 (1.14), 3.691 (0.95), 3.713 (1.95), 3.719 (1.65), 3.740 (2.35), 3.757 (0.95), 3.760 (1.29), 3.777 (0.57), 4.038 (0.72), 4.055 (1.11), 4.074 (1.71), 4.088 (1.26), 4.098 (2.17), 4.104 (0.63), 4.111 (0.69), 4.121 (1.09), 4.124 (1.08), 4.130 (1.11), 4.140 (0.47), 7.464 (4.73), 8.038 (0.66), 8.053 (1.41), 8.068 (0.65). LC-MS (方法A ); Rt = 0.93 min, m/z = 402 [M+H]⁺. | 中間物 30; GP G (條件A,使用HATU) |
107 | 8-甲基-N ,2-雙[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.553 (0.61), 1.562 (0.40), 1.570 (0.92), 1.577 (0.61), 1.585 (0.83), 1.592 (0.77), 1.600 (0.78), 1.605 (0.60), 1.608 (0.43), 1.615 (0.53), 1.622 (0.62), 1.752 (0.68), 1.769 (2.23), 1.775 (0.83), 1.782 (0.99), 1.786 (2.83), 1.796 (1.32), 1.799 (1.21), 1.806 (1.93), 1.815 (1.37), 1.822 (0.92), 1.832 (1.24), 1.844 (0.67), 1.853 (0.54), 1.858 (0.63), 1.861 (0.77), 1.876 (0.53), 1.878 (0.51), 1.886 (0.55), 1.903 (0.67), 1.917 (0.58), 1.933 (0.77), 1.950 (0.64), 2.470 (16.00), 2.518 (2.86), 2.523 (1.94), 2.828 (0.49), 2.848 (2.39), 2.858 (3.44), 2.865 (3.66), 2.878 (2.99), 2.896 (0.52), 3.213 (1.00), 3.219 (1.00), 3.228 (1.87), 3.235 (1.77), 3.244 (1.02), 3.250 (1.06), 3.584 (0.43), 3.596 (0.76), 3.599 (0.97), 3.603 (0.91), 3.613 (1.41), 3.616 (1.50), 3.620 (1.32), 3.633 (1.75), 3.638 (0.78), 3.650 (0.74), 3.724 (0.77), 3.734 (0.68), 3.740 (1.75), 3.744 (0.85), 3.748 (0.97), 3.751 (1.17), 3.757 (1.18), 3.760 (1.39), 3.766 (0.98), 3.769 (0.97), 3.771 (0.76), 3.777 (0.66), 3.786 (0.64), 3.928 (0.92), 3.944 (1.43), 3.960 (0.86), 4.038 (0.69), 4.054 (1.10), 4.074 (1.73), 4.088 (1.27), 4.098 (2.20), 4.104 (0.56), 4.111 (0.67), 4.123 (1.17), 4.130 (1.12), 4.140 (0.47), 7.463 (4.55), 7.959 (0.63), 7.974 (1.33), 7.989 (0.62). LC-MS (方法A ); Rt = 1.00 min, m/z = 386 [M+H]⁺. | 中間物 31; GP G (條件A,使用HATU) |
108 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.573 (0.46), 1.589 (0.54), 1.601 (0.48), 1.605 (0.45), 1.622 (0.55), 1.753 (0.57), 1.769 (2.00), 1.786 (2.48), 1.806 (1.61), 1.822 (0.63), 1.903 (0.57), 1.917 (0.52), 1.934 (0.75), 1.950 (0.61), 2.470 (16.00), 2.518 (4.39), 2.523 (3.12), 2.829 (0.50), 2.849 (2.30), 2.860 (3.16), 2.867 (3.50), 2.879 (2.88), 2.898 (0.52), 3.162 (0.55), 3.182 (1.59), 3.196 (1.36), 3.206 (1.46), 3.211 (1.98), 3.217 (0.79), 3.235 (1.77), 3.248 (0.82), 3.266 (0.55), 3.422 (0.45), 3.442 (0.95), 3.448 (1.04), 3.469 (0.84), 3.475 (0.80), 3.511 (0.75), 3.517 (0.84), 3.540 (1.00), 3.546 (1.04), 3.566 (0.41), 3.573 (0.68), 3.596 (0.80), 3.608 (1.55), 3.613 (2.29), 3.623 (0.64), 3.633 (2.75), 3.638 (1.32), 3.650 (0.86), 3.685 (1.07), 3.691 (0.89), 3.713 (1.86), 3.719 (1.59), 3.723 (1.11), 3.740 (2.27), 3.757 (0.91), 3.760 (1.25), 3.777 (0.54), 4.038 (0.70), 4.055 (1.07), 4.074 (1.63), 4.088 (1.21), 4.098 (2.07), 4.104 (0.59), 4.111 (0.66), 4.121 (1.04), 4.124 (1.05), 4.130 (1.05), 4.140 (0.45), 7.464 (4.64), 8.038 (0.63), 8.053 (1.36), 8.069 (0.61). LC-MS (方法A ); Rt = 0.92 min, m/z = 402 [M+H]⁺. | 中間物 31; GP G (條件A,使用HATU) |
109 | 3-[(8-甲基-7-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}-4,5-二氫-2H -呋喃并[2,3-g]吲唑-2-基)甲基]氮雜環丁烷-1-甲酸第三丁酯 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.352 (16.00), 1.362 (1.66), 1.384 (0.80), 1.814 (0.44), 1.831 (0.40), 2.468 (5.19), 2.518 (3.21), 2.523 (2.18), 2.841 (0.76), 2.853 (1.03), 2.862 (1.12), 2.874 (0.95), 3.227 (0.63), 3.231 (0.60), 3.619 (0.41), 3.943 (0.48), 4.249 (0.93), 4.267 (0.90), 7.554 (1.43), 7.976 (0.48). LC-MS (方法A ); Rt = 1.15 min, m/z = 471 [M+H]⁺. | 中間物 32; GP G (條件A,使用HATU) |
110 | 3-[(7-{[(2R)-1,4-二㗁烷-2-基甲基]胺甲醯基}-8-甲基-4,5-二氫-2H -呋喃并[2,3-g]吲唑-2-基)甲基]氮雜環丁烷-1-甲酸第三丁酯 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.48), 0.948 (0.49), 1.339 (0.44), 1.352 (16.00), 1.362 (1.21), 2.468 (5.30), 2.518 (4.27), 2.523 (2.99), 2.843 (0.75), 2.855 (1.01), 2.864 (1.10), 2.876 (0.95), 3.180 (0.51), 3.194 (0.46), 3.205 (0.51), 3.209 (0.70), 3.233 (0.59), 3.606 (0.53), 3.630 (0.44), 3.637 (0.46), 3.682 (0.70), 3.689 (0.57), 3.712 (0.70), 3.717 (0.60), 4.249 (0.93), 4.268 (0.92), 7.556 (1.45), 8.055 (0.49). LC-MS (方法A ); Rt = 1.08 min, m/z = 485 [M-H]⁻. | 中間物 32; GP G (條件A,使用HATU) |
111 | 8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-2-[(3R)-四氫呋喃-3-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.555 (0.52), 1.567 (0.76), 1.570 (0.80), 1.586 (1.06), 1.598 (1.15), 1.615 (1.05), 1.632 (0.62), 1.777 (0.55), 1.783 (0.74), 1.799 (1.28), 1.817 (1.48), 1.834 (1.34), 1.846 (0.77), 1.855 (0.63), 1.862 (0.86), 1.869 (0.40), 1.880 (0.87), 1.895 (0.75), 1.900 (1.00), 1.907 (0.40), 1.915 (0.92), 1.921 (0.58), 1.925 (0.50), 1.931 (0.65), 1.945 (0.56), 2.324 (0.60), 2.329 (0.84), 2.333 (0.61), 2.474 (16.00), 2.520 (3.69), 2.525 (2.32), 2.597 (0.77), 2.666 (1.11), 2.671 (1.32), 2.675 (0.87), 2.686 (0.76), 2.704 (0.57), 2.832 (0.73), 2.850 (2.69), 2.863 (3.64), 2.871 (3.91), 2.884 (3.17), 2.901 (0.71), 3.215 (1.12), 3.220 (1.14), 3.231 (2.17), 3.235 (2.12), 3.246 (1.24), 3.250 (1.26), 3.467 (1.17), 3.481 (1.18), 3.489 (1.48), 3.502 (1.40), 3.585 (0.60), 3.596 (0.74), 3.605 (1.16), 3.616 (1.66), 3.622 (1.52), 3.634 (1.52), 3.639 (1.03), 3.645 (1.63), 3.653 (0.91), 3.663 (1.72), 3.667 (1.49), 3.684 (1.18), 3.734 (1.08), 3.753 (2.48), 3.767 (2.16), 3.773 (1.47), 3.788 (1.14), 3.931 (1.01), 3.947 (1.53), 3.962 (0.93), 4.030 (2.50), 4.047 (2.64), 7.537 (4.72), 7.962 (0.73), 7.977 (1.49), 7.992 (0.69). LC-MS (方法A ); Rt = 1.11 min, m/z = 386 [M+H]⁺. | 中間物 33; GP G (條件A,使用HATU) |
112 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(3R)-四氫呋喃-3-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.584 (0.44), 1.598 (0.66), 1.617 (0.70), 1.632 (0.55), 1.900 (0.61), 1.914 (0.68), 1.920 (0.47), 1.931 (0.58), 1.945 (0.52), 2.324 (0.59), 2.329 (0.79), 2.334 (0.57), 2.475 (16.00), 2.520 (2.94), 2.525 (1.90), 2.545 (0.44), 2.667 (1.05), 2.671 (1.21), 2.676 (0.79), 2.681 (0.62), 2.686 (0.68), 2.704 (0.51), 2.756 (0.46), 2.833 (0.65), 2.851 (2.44), 2.864 (3.31), 2.872 (3.55), 2.885 (3.01), 2.903 (0.67), 3.164 (0.57), 3.184 (1.72), 3.198 (1.45), 3.208 (1.56), 3.213 (2.13), 3.218 (0.93), 3.236 (1.85), 3.249 (0.88), 3.268 (0.57), 3.423 (0.47), 3.444 (1.04), 3.450 (1.12), 3.467 (1.34), 3.471 (1.11), 3.477 (1.13), 3.481 (1.38), 3.489 (1.47), 3.503 (1.37), 3.514 (0.82), 3.519 (0.88), 3.542 (1.08), 3.548 (1.12), 3.569 (0.46), 3.575 (0.72), 3.596 (0.91), 3.616 (2.44), 3.625 (0.74), 3.634 (2.72), 3.640 (1.56), 3.645 (1.80), 3.653 (1.03), 3.663 (1.72), 3.667 (1.46), 3.684 (2.13), 3.692 (1.03), 3.714 (2.06), 3.721 (1.78), 3.733 (0.82), 3.747 (1.48), 3.753 (1.38), 3.767 (1.19), 3.773 (0.63), 3.787 (0.51), 4.028 (2.30), 4.031 (2.33), 4.047 (2.47), 7.538 (4.60), 8.042 (0.68), 8.057 (1.45), 8.072 (0.67). LC-MS (方法A ); Rt = 1.03 min, m/z = 402 [M+H]⁺. | 中間物 33; GP G (條件A,使用HATU) |
113 | 8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-2-[(3S)-四氫呋喃-3-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.556 (0.45), 1.572 (0.67), 1.578 (0.63), 1.591 (0.80), 1.595 (0.64), 1.600 (0.73), 1.609 (0.50), 1.616 (0.72), 1.628 (0.55), 1.781 (0.52), 1.786 (0.50), 1.798 (0.76), 1.800 (0.72), 1.812 (0.73), 1.816 (0.85), 1.833 (0.63), 1.842 (0.57), 1.845 (0.51), 1.849 (0.60), 1.855 (0.70), 1.864 (0.64), 1.872 (0.43), 1.878 (0.50), 1.881 (0.41), 1.889 (0.63), 1.900 (0.40), 1.905 (0.69), 1.916 (0.71), 1.921 (0.45), 1.924 (0.40), 1.929 (0.60), 1.940 (0.56), 2.370 (0.41), 2.474 (16.00), 2.516 (3.32), 2.520 (3.05), 2.523 (2.45), 2.671 (0.50), 2.686 (0.67), 2.700 (0.51), 2.837 (0.64), 2.849 (2.48), 2.861 (2.84), 2.871 (2.97), 2.883 (3.02), 2.897 (0.64), 3.218 (1.05), 3.224 (1.07), 3.230 (1.98), 3.236 (1.83), 3.242 (1.08), 3.248 (1.09), 3.471 (1.18), 3.482 (1.20), 3.488 (1.46), 3.499 (1.38), 3.591 (0.48), 3.604 (1.16), 3.606 (1.11), 3.618 (2.14), 3.634 (1.72), 3.649 (1.68), 3.664 (1.63), 3.667 (1.45), 3.681 (1.22), 3.738 (0.91), 3.749 (1.02), 3.754 (2.31), 3.766 (2.11), 3.770 (1.39), 3.782 (1.08), 3.933 (1.01), 3.947 (1.48), 3.959 (0.95), 4.029 (2.12), 4.032 (2.12), 4.044 (2.23), 4.047 (2.06), 7.537 (4.47), 7.962 (0.71), 7.974 (1.42), 7.986 (0.67). LC-MS (方法A ); Rt = 0.95 min, m/z = 386 [M+H]⁺. | 中間物 34; GP G (條件A,使用HATU) |
114 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(3S)-四氫呋喃-3-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.589 (0.42), 1.601 (0.65), 1.616 (0.68), 1.628 (0.52), 1.904 (0.59), 1.916 (0.67), 1.920 (0.45), 1.929 (0.57), 1.940 (0.54), 2.474 (16.00), 2.516 (2.23), 2.520 (2.03), 2.523 (1.64), 2.671 (0.50), 2.686 (0.64), 2.701 (0.49), 2.757 (0.48), 2.787 (0.51), 2.838 (0.59), 2.850 (2.36), 2.862 (2.62), 2.873 (2.73), 2.884 (2.78), 2.896 (0.59), 3.169 (0.67), 3.184 (0.82), 3.189 (1.26), 3.196 (1.41), 3.209 (1.93), 3.212 (1.42), 3.223 (0.70), 3.232 (1.59), 3.236 (1.36), 3.248 (0.88), 3.263 (0.66), 3.423 (0.41), 3.428 (0.50), 3.445 (1.05), 3.451 (1.12), 3.468 (1.02), 3.471 (1.59), 3.481 (1.22), 3.488 (1.46), 3.498 (1.33), 3.519 (0.72), 3.524 (0.84), 3.542 (1.06), 3.547 (1.11), 3.563 (0.57), 3.568 (0.73), 3.602 (0.92), 3.618 (2.18), 3.625 (0.72), 3.632 (2.69), 3.649 (1.97), 3.663 (1.68), 3.666 (1.44), 3.680 (1.22), 3.689 (1.16), 3.694 (1.00), 3.717 (1.85), 3.738 (1.36), 3.749 (0.86), 3.754 (1.26), 3.765 (1.23), 3.770 (0.63), 3.781 (0.54), 4.029 (2.01), 4.033 (2.03), 4.044 (2.13), 4.048 (1.95), 7.537 (4.37), 8.041 (0.67), 8.053 (1.41), 8.065 (0.65). LC-MS (方法A ); Rt = 0.87 min, m/z = 402 [M+H]⁺. | 中間物 34; GP G (條件A,使用HATU) |
115 | 2-(吡啶-2-基甲基)-N -[(2S)-四氫呋喃-2-基甲基]-8-(三氟甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.933 (3.11), 0.937 (0.93), 0.950 (3.17), 0.954 (0.48), 1.540 (1.10), 1.543 (1.05), 1.553 (0.88), 1.556 (0.98), 1.560 (1.57), 1.568 (1.46), 1.576 (1.20), 1.584 (0.96), 1.589 (1.38), 1.606 (0.88), 1.773 (0.73), 1.779 (0.54), 1.788 (1.31), 1.794 (1.67), 1.809 (3.02), 1.827 (2.97), 1.841 (1.47), 1.845 (1.94), 1.861 (1.65), 1.866 (0.90), 1.870 (1.12), 1.878 (1.26), 1.883 (1.12), 1.889 (1.49), 1.900 (0.96), 1.904 (1.11), 1.907 (1.12), 1.911 (1.03), 1.921 (0.84), 1.925 (0.72), 1.928 (0.77), 1.942 (0.50), 2.521 (1.53), 2.525 (0.99), 2.872 (1.16), 2.878 (1.27), 2.889 (1.90), 2.896 (5.95), 2.913 (5.18), 2.932 (0.60), 2.944 (5.64), 2.947 (5.37), 2.962 (7.25), 2.971 (2.05), 2.980 (1.63), 2.987 (1.48), 3.255 (4.67), 3.271 (9.18), 3.285 (4.82), 3.598 (1.06), 3.614 (2.18), 3.617 (2.45), 3.634 (2.94), 3.652 (1.73), 3.741 (1.44), 3.757 (2.61), 3.762 (1.75), 3.774 (2.52), 3.777 (2.23), 3.779 (1.92), 3.795 (1.51), 3.920 (0.70), 3.936 (2.17), 3.952 (3.64), 3.967 (2.29), 3.983 (0.53), 5.395 (16.00), 7.073 (4.20), 7.093 (4.39), 7.294 (2.04), 7.297 (2.10), 7.306 (2.14), 7.309 (2.29), 7.313 (2.45), 7.316 (2.17), 7.325 (2.35), 7.328 (2.21), 7.683 (10.56), 7.755 (2.55), 7.759 (2.67), 7.774 (4.44), 7.778 (4.46), 7.793 (2.25), 7.798 (2.19), 8.531 (2.64), 8.534 (3.06), 8.536 (3.05), 8.538 (2.75), 8.543 (2.71), 8.546 (3.14), 8.548 (2.90), 8.550 (2.60), 8.701 (1.55), 8.716 (3.28), 8.730 (1.54). LC-MS (方法A ); Rt = 1.03 min, m/z = 445 [M-H]⁻. | 中間物 35; GP G (條件A,使用HATU) |
116 | N -[(2R)-1,4-二㗁烷-2-基甲基]-2-(吡啶-2-基甲基)-8-(三氟甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.933 (1.04), 0.950 (1.03), 2.077 (2.72), 2.521 (1.33), 2.525 (0.86), 2.873 (1.27), 2.878 (1.36), 2.890 (2.09), 2.897 (5.95), 2.914 (5.08), 2.948 (5.43), 2.950 (5.29), 2.965 (7.34), 2.974 (2.20), 2.984 (1.65), 2.990 (1.54), 3.189 (0.74), 3.198 (2.95), 3.204 (1.47), 3.222 (4.51), 3.226 (4.28), 3.238 (3.86), 3.250 (5.98), 3.265 (3.52), 3.281 (2.24), 3.299 (1.28), 3.315 (0.83), 3.424 (0.97), 3.430 (1.17), 3.451 (2.54), 3.457 (2.74), 3.478 (2.27), 3.484 (2.11), 3.526 (1.94), 3.531 (2.15), 3.554 (2.65), 3.561 (2.72), 3.581 (1.09), 3.587 (1.89), 3.614 (3.08), 3.621 (3.08), 3.629 (2.03), 3.645 (3.40), 3.661 (0.62), 3.667 (0.76), 3.696 (2.91), 3.703 (2.40), 3.725 (4.83), 3.731 (3.83), 3.754 (2.05), 5.396 (16.00), 7.076 (4.28), 7.096 (4.49), 7.294 (2.13), 7.297 (2.19), 7.306 (2.23), 7.309 (2.33), 7.313 (2.44), 7.316 (2.29), 7.325 (2.40), 7.328 (2.30), 7.684 (10.66), 7.755 (2.73), 7.759 (2.71), 7.774 (4.31), 7.779 (4.51), 7.793 (2.37), 7.798 (2.39), 8.531 (2.76), 8.534 (3.11), 8.536 (3.19), 8.538 (2.82), 8.543 (2.80), 8.546 (3.18), 8.548 (2.99), 8.550 (2.65), 8.737 (1.65), 8.753 (3.49), 8.767 (1.63). LC-MS (方法A ); Rt = 0.95 min, m/z = 461 [M-H]⁻. | 中間物 35; GP G (條件A,使用HATU) |
117 | N -[(1-甲基-1H-吡唑-3-基)甲基]-2-(吡啶-2-基甲基)-8-(三氟甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.933 (0.62), 0.950 (0.63), 2.520 (0.93), 2.525 (0.60), 2.873 (0.44), 2.882 (0.59), 2.891 (2.02), 2.908 (1.88), 2.932 (2.04), 2.934 (1.93), 2.949 (2.41), 2.959 (0.67), 2.967 (0.51), 2.975 (0.46), 3.783 (16.00), 4.346 (2.83), 4.361 (2.80), 5.393 (5.38), 6.116 (2.74), 6.122 (2.67), 7.071 (1.43), 7.091 (1.49), 7.292 (0.70), 7.296 (0.71), 7.305 (0.74), 7.308 (0.78), 7.311 (0.84), 7.314 (0.76), 7.323 (0.79), 7.326 (0.74), 7.584 (2.36), 7.590 (2.35), 7.681 (3.53), 7.753 (0.84), 7.757 (0.83), 7.772 (1.41), 7.777 (1.44), 7.791 (0.75), 7.796 (0.74), 8.530 (0.92), 8.532 (1.03), 8.534 (1.07), 8.536 (0.94), 8.542 (0.94), 8.544 (1.03), 8.546 (1.01), 8.548 (0.86), 9.067 (0.59), 9.082 (1.22), 9.097 (0.57). LC-MS (方法A ); Rt = 0.92 min, m/z = 457 [M+H]⁺. | 中間物 35; GP G (條件A,使用HATU) |
118 | N -(1,3-㗁唑-2-基甲基)-2-(吡啶-2-基甲基)-8-(三氟甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (1.60), 0.008 (1.47), 2.334 (0.93), 2.520 (4.59), 2.525 (2.92), 2.676 (0.96), 2.882 (1.28), 2.887 (1.40), 2.899 (2.16), 2.905 (5.94), 2.923 (4.98), 2.959 (5.37), 2.962 (5.23), 2.977 (7.19), 2.985 (2.23), 2.996 (1.64), 3.001 (1.52), 4.538 (8.49), 4.552 (8.52), 5.399 (16.00), 5.761 (0.88), 7.082 (4.12), 7.102 (4.37), 7.170 (11.02), 7.172 (10.94), 7.295 (2.09), 7.297 (2.09), 7.307 (2.21), 7.309 (2.31), 7.314 (2.48), 7.316 (2.28), 7.326 (2.38), 7.328 (2.26), 7.693 (10.48), 7.757 (2.48), 7.761 (2.60), 7.776 (4.34), 7.780 (4.39), 7.795 (2.16), 7.800 (2.11), 8.069 (11.85), 8.071 (11.53), 8.531 (2.63), 8.534 (3.09), 8.536 (3.12), 8.538 (2.80), 8.543 (2.72), 8.546 (3.17), 8.548 (2.97), 8.550 (2.65), 9.348 (1.62), 9.363 (3.51), 9.378 (1.60). LC-MS (方法A ); Rt = 0.90 min, m/z = 444 [M+H]⁺. | 中間物 35; GP G (條件A,使用HATU) |
119 | 8-環丙基-2-(吡啶-2-基甲基)-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.742 (1.46), 0.751 (4.78), 0.757 (4.41), 0.765 (2.92), 0.773 (4.55), 0.779 (4.85), 0.788 (1.54), 0.919 (0.54), 0.933 (4.71), 0.937 (1.40), 0.950 (4.80), 0.954 (0.72), 1.354 (1.58), 1.362 (4.70), 1.368 (6.05), 1.376 (6.27), 1.382 (4.32), 1.391 (1.60), 1.559 (1.17), 1.569 (0.93), 1.572 (1.06), 1.576 (1.65), 1.583 (1.21), 1.592 (1.39), 1.599 (0.93), 1.604 (1.07), 1.621 (0.83), 1.766 (0.69), 1.772 (0.51), 1.780 (1.29), 1.786 (1.66), 1.802 (2.88), 1.819 (3.23), 1.837 (2.76), 1.851 (1.75), 1.857 (1.26), 1.859 (1.33), 1.864 (1.57), 1.868 (1.89), 1.883 (1.28), 1.885 (1.20), 1.890 (0.95), 1.900 (0.82), 1.906 (0.74), 1.921 (0.47), 2.406 (0.51), 2.424 (0.49), 2.521 (1.67), 2.526 (1.18), 2.785 (0.75), 2.796 (1.52), 2.811 (5.92), 2.826 (6.97), 2.838 (7.69), 2.852 (8.56), 2.870 (1.59), 2.880 (0.95), 2.897 (0.76), 2.911 (1.60), 2.920 (1.62), 2.926 (1.09), 2.934 (3.09), 2.942 (1.18), 2.947 (1.46), 2.956 (1.50), 2.970 (0.61), 3.232 (4.29), 3.248 (8.46), 3.263 (4.60), 3.589 (1.07), 3.605 (2.25), 3.609 (2.29), 3.626 (3.04), 3.643 (1.65), 3.740 (1.48), 3.754 (2.14), 3.757 (2.75), 3.771 (2.34), 3.775 (2.39), 3.792 (1.58), 3.923 (0.67), 3.939 (2.32), 3.955 (3.64), 3.971 (2.28), 3.986 (0.50), 5.351 (16.00), 7.035 (4.22), 7.054 (4.42), 7.291 (2.18), 7.294 (2.14), 7.303 (2.25), 7.306 (2.30), 7.310 (2.54), 7.313 (2.32), 7.322 (2.48), 7.325 (2.32), 7.621 (11.82), 7.757 (2.77), 7.761 (2.84), 7.776 (4.50), 7.780 (4.43), 7.795 (2.31), 7.800 (2.40), 7.947 (1.69), 7.961 (3.60), 7.976 (1.67), 8.531 (2.88), 8.533 (3.13), 8.535 (3.32), 8.538 (2.85), 8.543 (2.92), 8.545 (3.24), 8.547 (3.13), 8.550 (2.70). LC-MS (方法A ); Rt = 1.20 min, m/z = 419 [M+H]⁺. | 中間物 36; GP G (條件A,使用HATU) |
120 | 8-環丙基-N -[(2R)-1,4-二㗁烷-2-基甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.745 (1.34), 0.754 (4.47), 0.760 (4.12), 0.768 (2.85), 0.776 (4.36), 0.782 (4.47), 0.791 (1.46), 0.919 (1.07), 0.933 (9.18), 0.937 (2.96), 0.950 (9.25), 0.954 (1.54), 1.356 (1.59), 1.364 (4.49), 1.370 (5.68), 1.378 (5.96), 1.385 (4.22), 1.393 (1.60), 2.406 (1.01), 2.424 (0.96), 2.521 (1.86), 2.525 (1.19), 2.785 (0.78), 2.797 (1.51), 2.813 (6.08), 2.827 (7.05), 2.839 (7.68), 2.854 (7.94), 2.871 (1.60), 2.882 (0.93), 2.894 (0.76), 2.908 (1.52), 2.916 (1.55), 2.922 (0.99), 2.930 (2.89), 2.938 (1.02), 2.943 (1.79), 2.952 (1.42), 2.959 (0.99), 2.966 (0.61), 2.975 (0.64), 3.166 (0.60), 3.181 (1.27), 3.191 (2.84), 3.200 (2.05), 3.215 (6.73), 3.219 (4.09), 3.229 (3.02), 3.243 (6.41), 3.258 (2.12), 3.277 (1.23), 3.292 (0.69), 3.420 (0.90), 3.426 (1.11), 3.446 (2.48), 3.453 (2.66), 3.474 (2.15), 3.480 (2.08), 3.519 (1.82), 3.524 (1.98), 3.547 (2.54), 3.553 (2.65), 3.568 (0.61), 3.574 (1.00), 3.580 (1.72), 3.611 (3.49), 3.626 (2.14), 3.635 (2.91), 3.642 (3.30), 3.650 (1.68), 3.658 (0.59), 3.665 (0.74), 3.691 (2.95), 3.698 (2.40), 3.720 (5.07), 3.747 (2.15), 5.352 (16.00), 7.034 (4.23), 7.054 (4.43), 7.292 (2.10), 7.294 (2.05), 7.304 (2.23), 7.306 (2.29), 7.311 (2.45), 7.323 (2.38), 7.622 (11.28), 7.757 (2.29), 7.762 (2.29), 7.776 (4.04), 7.781 (4.08), 7.795 (2.06), 7.800 (2.02), 8.031 (1.76), 8.047 (3.74), 8.061 (1.72), 8.533 (3.11), 8.535 (3.11), 8.543 (2.78), 8.545 (3.12), 8.547 (2.96). LC-MS (方法A ); Rt = 1.12 min, m/z = 435 [M+H]⁺. | 中間物 36; GP G (條件A,使用HATU) |
121 | 8-環丙基-N -[(1-甲基-1H-吡唑-3-基)甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (6.25), 0.742 (0.51), 0.751 (1.57), 0.757 (1.47), 0.765 (1.00), 0.773 (1.51), 0.779 (1.59), 0.788 (0.52), 0.933 (0.41), 0.949 (0.42), 1.356 (0.56), 1.364 (1.57), 1.370 (2.01), 1.379 (2.06), 1.384 (1.47), 1.393 (0.54), 2.520 (0.75), 2.525 (0.49), 2.789 (0.56), 2.809 (2.16), 2.819 (3.21), 2.826 (3.43), 2.838 (2.94), 2.856 (0.47), 2.920 (0.51), 2.928 (0.53), 2.942 (1.02), 2.956 (0.50), 2.965 (0.48), 3.775 (16.00), 4.325 (2.72), 4.341 (2.75), 5.351 (5.32), 5.760 (5.02), 6.106 (2.67), 6.112 (2.81), 7.031 (1.44), 7.051 (1.51), 7.290 (0.71), 7.292 (0.73), 7.302 (0.76), 7.304 (0.81), 7.308 (0.83), 7.311 (0.78), 7.321 (0.80), 7.323 (0.79), 7.559 (2.39), 7.565 (2.41), 7.619 (3.92), 7.755 (0.80), 7.760 (0.85), 7.774 (1.44), 7.779 (1.47), 7.793 (0.75), 7.798 (0.73), 8.353 (0.61), 8.368 (1.33), 8.383 (0.60), 8.529 (0.93), 8.532 (1.06), 8.534 (1.12), 8.536 (0.95), 8.541 (0.96), 8.544 (1.08), 8.546 (1.06), 8.548 (0.89). LC-MS (方法A ); Rt = 0.98 min, m/z = 429 [M+H]⁺. | 中間物 36; GP G (條件A,使用HATU) |
122 | 8-環丙基-N -(1,3-㗁唑-2-基甲基)-2-(吡啶-2-基甲基)-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.75-0.79 (m, 2H), 1.37-1.40 (m, 2H), 2.79-2.95 (m, 5H), 4.50 (d, 2H), 5.35 (s, 2H), 7.05 (d, 1H), 7.14 (d, 1H), 7.31 (ddd, 1H), 7.63 (s, 1H), 7.78 (dt, 1H), 8.03 (d, 1H), 8.53-8.55 (m, 1H), 8.72 (t, 1H). LC-MS (方法A ); Rt = 0.97 min, m/z = 416 [M+H]⁺. | 中間物 36; GP G (條件A,使用HATU) |
123 | 8'-甲基-N -[(1-甲基-1H -吡唑-3-基)甲基]-2'-(吡啶-2-基甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | LC-MS (方法A); Rt = 0.96 min, m/z = 429 [M+H]⁺. | 中間物 38; GP G (條件A,使用HATU) |
124 | 8'-甲基-N -(1,3-㗁唑-2-基甲基)-2'-(吡啶-2-基甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.80-0.92 (m, 2H), 1.03-1.14 (m, 2H), 2.47 (s, 3H), 2.72 (s, 2H), 4.56 (d, 2H), 5.45 (s, 2H), 7.11-7.20 (m, 2H), 7.29-7.34 (m, 1H), 7.62 (s, 1H), 7.75-7.82 (m, 1H), 8.04 (d, 1H), 8.53-8.55 (m, 1H), 8.72 (t, 1H). LC-MS (方法A ); Rt = 0.96 min, m/z = 416 [M+H]⁺. | 中間物 38; GP G (條件A,使用HATU) |
125 | 2'-[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-N -[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.787 (4.84), 0.806 (7.12), 0.826 (2.28), 0.852 (2.57), 0.871 (10.06), 0.919 (1.91), 0.934 (13.80), 0.951 (13.28), 1.331 (0.88), 1.532 (0.59), 1.552 (1.61), 1.569 (2.20), 1.577 (1.76), 1.585 (1.98), 1.598 (1.69), 1.613 (1.25), 1.783 (2.50), 1.799 (4.40), 1.817 (4.92), 1.834 (4.33), 1.847 (2.79), 1.864 (2.64), 1.879 (2.13), 1.896 (1.47), 1.917 (0.88), 1.960 (1.61), 2.024 (1.10), 2.329 (4.48), 2.357 (4.77), 2.389 (0.73), 2.407 (1.83), 2.424 (1.83), 2.449 (1.61), 2.667 (4.92), 2.671 (4.92), 2.764 (1.25), 2.788 (2.64), 2.832 (11.52), 2.844 (11.60), 2.887 (2.13), 2.927 (0.66), 2.943 (1.17), 2.960 (1.47), 2.976 (1.17), 2.992 (0.88), 3.031 (1.03), 3.076 (0.81), 3.220 (7.56), 3.236 (9.54), 3.249 (7.85), 3.273 (4.11), 3.412 (1.54), 3.433 (3.60), 3.439 (3.60), 3.461 (3.16), 3.466 (2.94), 3.506 (2.57), 3.512 (2.57), 3.535 (3.60), 3.540 (3.60), 3.568 (2.06), 3.585 (1.54), 3.604 (3.96), 3.619 (6.97), 3.639 (5.14), 3.711 (7.93), 3.735 (7.71), 3.750 (4.33), 3.769 (3.52), 3.786 (1.98), 3.818 (2.28), 3.823 (2.28), 3.836 (2.57), 3.913 (1.17), 3.930 (3.08), 3.946 (4.40), 3.961 (2.79), 3.977 (0.88), 3.988 (1.76), 4.005 (1.39), 4.023 (5.28), 4.042 (7.71), 4.056 (4.84), 4.080 (1.54), 4.092 (1.17), 7.180 (0.73), 7.272 (3.01), 7.279 (16.00), 7.953 (2.28), 7.969 (4.48), 7.983 (2.13), 8.553 (0.81). LC-MS (方法A ); Rt = 1.05 min, m/z = 428 [M+H]⁺. | 中間物 40-1; GP G (條件A,使用HATU) |
126 | N -[(2R)-1,4-二㗁烷-2-基甲基]-2'-[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.44), 0.146 (0.45), 0.767 (0.69), 0.775 (0.52), 0.788 (2.74), 0.797 (2.52), 0.802 (2.88), 0.808 (4.49), 0.827 (1.32), 0.853 (1.40), 0.862 (1.48), 0.873 (6.54), 0.935 (1.70), 0.938 (0.58), 0.951 (1.72), 1.960 (1.28), 2.320 (0.84), 2.325 (1.96), 2.329 (2.76), 2.334 (1.99), 2.339 (0.88), 2.521 (10.84), 2.525 (6.87), 2.542 (1.04), 2.662 (1.04), 2.667 (3.37), 2.671 (2.93), 2.676 (2.08), 2.681 (0.93), 2.764 (1.01), 2.790 (1.21), 2.833 (7.63), 2.845 (7.47), 2.889 (1.10), 3.154 (0.60), 3.170 (1.21), 3.184 (3.46), 3.203 (3.42), 3.208 (3.76), 3.213 (3.92), 3.219 (5.43), 3.237 (4.54), 3.244 (3.61), 3.249 (4.64), 3.273 (3.37), 3.284 (1.20), 3.381 (0.45), 3.406 (0.90), 3.412 (1.13), 3.416 (1.07), 3.423 (1.24), 3.433 (2.27), 3.439 (2.71), 3.443 (2.80), 3.449 (2.70), 3.460 (2.19), 3.467 (2.28), 3.470 (2.69), 3.477 (2.10), 3.507 (1.73), 3.512 (3.28), 3.519 (2.27), 3.534 (2.41), 3.541 (4.61), 3.548 (2.84), 3.562 (1.17), 3.568 (2.37), 3.574 (1.81), 3.595 (1.00), 3.610 (5.15), 3.615 (4.89), 3.625 (1.85), 3.640 (4.53), 3.655 (0.98), 3.688 (2.73), 3.695 (2.62), 3.712 (6.99), 3.741 (5.19), 3.800 (0.58), 3.806 (0.58), 3.813 (0.87), 3.818 (1.23), 3.824 (1.28), 3.830 (1.13), 3.837 (1.55), 3.842 (1.17), 3.854 (0.77), 3.860 (0.66), 3.988 (1.15), 4.006 (0.72), 4.025 (3.57), 4.044 (4.58), 4.057 (3.28), 4.080 (1.10), 4.092 (0.84), 7.181 (1.00), 7.281 (16.00), 8.032 (1.52), 8.047 (3.27), 8.062 (1.47). LC-MS (方法A ); Rt = 1.07 min, m/z = 444 [M+H]⁺. | 中間物 40-1; GP G (條件A,使用HATU) |
127 | 2'-[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-N -[(1-甲基-1H -吡唑-3-基)甲基]-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.76-0.89 (m, 4H), 2.82-2.83 (m, 2H), 3.24 (dd, 1H), 3.43 (dt, 1H), 3.54 (dt, 1H), 3.61-3.64 (m, 1H), 3.70-3.74 (m, 2H), 3.77 (s, 3H), 3.82-3.86 (m, 1H), 3.99-4.09 (m, 2H), 4.32 (d, 2H), 6.10 (d, 1H), 7.27 (s, 1H), 7.56 (d, 1H), 8.37 (t, 1H). LC-MS (方法A ); Rt = 0.93 min, m/z = 438 [M+H]⁺. | 中間物 40-1; GP G (條件A,使用HATU) |
128 | 2'-[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-N -(1,3-㗁唑-2-基甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.17), 0.008 (3.27), 0.772 (0.78), 0.779 (0.61), 0.793 (2.96), 0.803 (2.76), 0.807 (3.10), 0.813 (4.60), 0.835 (1.23), 0.861 (1.23), 0.873 (1.60), 0.884 (6.94), 0.889 (4.83), 0.902 (0.89), 0.936 (2.04), 0.952 (2.01), 1.302 (1.53), 1.320 (3.57), 1.335 (1.06), 1.339 (1.63), 1.354 (0.44), 1.753 (0.51), 2.329 (1.91), 2.334 (1.43), 2.338 (0.75), 2.520 (6.77), 2.525 (4.36), 2.671 (2.01), 2.676 (1.60), 2.754 (0.78), 2.766 (6.23), 2.794 (1.46), 2.801 (1.29), 2.844 (7.66), 2.857 (7.52), 2.887 (1.43), 2.901 (1.36), 2.911 (0.44), 2.931 (0.99), 2.948 (0.99), 3.222 (2.38), 3.246 (2.89), 3.250 (2.86), 3.275 (2.89), 3.369 (0.71), 3.397 (0.61), 3.407 (0.85), 3.413 (0.99), 3.434 (2.21), 3.440 (2.45), 3.462 (1.97), 3.468 (2.14), 3.508 (1.67), 3.514 (1.84), 3.524 (0.61), 3.536 (2.31), 3.543 (2.31), 3.564 (1.06), 3.569 (1.40), 3.615 (2.49), 3.642 (1.97), 3.662 (0.48), 3.709 (4.63), 3.715 (4.29), 3.738 (4.02), 3.744 (3.40), 3.803 (0.61), 3.811 (0.65), 3.816 (0.95), 3.822 (1.33), 3.828 (1.50), 3.833 (1.53), 3.840 (1.84), 3.846 (1.23), 3.857 (0.99), 3.992 (1.23), 4.009 (0.82), 4.028 (3.68), 4.045 (4.05), 4.049 (4.29), 4.062 (3.44), 4.085 (1.29), 4.097 (0.99), 4.476 (0.92), 4.487 (8.07), 4.503 (8.10), 4.517 (0.78), 4.557 (1.63), 4.572 (1.63), 5.761 (0.51), 7.090 (1.67), 7.144 (10.72), 7.146 (10.55), 7.162 (2.28), 7.164 (2.25), 7.289 (16.00), 8.036 (10.49), 8.038 (10.76), 8.055 (2.35), 8.057 (2.35), 8.560 (2.31), 8.710 (1.70), 8.724 (3.68), 8.739 (1.60), 9.003 (0.61). LC-MS (方法A ); Rt = 0.91 min, m/z = 425 [M+H]⁺. | 中間物 40-1; GP G (條件A,使用HATU) |
129 | 2'-(環丙基甲基)-8'-甲基-N -[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.311 (1.22), 0.322 (4.85), 0.326 (4.06), 0.334 (4.44), 0.337 (4.62), 0.348 (1.74), 0.466 (0.60), 0.470 (0.46), 0.483 (2.15), 0.493 (4.10), 0.497 (4.21), 0.503 (2.19), 0.509 (2.08), 0.513 (4.36), 0.518 (4.02), 0.528 (1.39), 0.590 (0.43), 0.791 (1.87), 0.804 (4.62), 0.809 (5.94), 0.817 (3.40), 0.826 (1.17), 0.852 (1.23), 0.860 (3.05), 0.868 (5.91), 0.873 (4.21), 0.886 (1.77), 0.931 (0.63), 0.948 (0.64), 1.149 (0.46), 1.161 (0.83), 1.167 (0.91), 1.179 (1.23), 1.187 (1.13), 1.191 (0.90), 1.199 (1.82), 1.207 (0.89), 1.211 (1.05), 1.219 (1.13), 1.231 (0.97), 1.237 (0.64), 1.304 (0.93), 1.323 (2.17), 1.342 (0.92), 1.551 (0.98), 1.560 (0.76), 1.563 (0.87), 1.567 (1.36), 1.575 (1.00), 1.584 (1.15), 1.591 (0.86), 1.596 (0.88), 1.613 (0.76), 1.761 (0.60), 1.767 (0.46), 1.775 (1.08), 1.782 (1.39), 1.797 (2.44), 1.815 (2.77), 1.832 (2.48), 1.846 (1.45), 1.854 (1.26), 1.858 (1.35), 1.863 (1.58), 1.877 (1.16), 1.884 (0.88), 1.895 (0.78), 1.898 (0.68), 1.901 (0.68), 1.915 (0.46), 2.518 (3.56), 2.523 (2.41), 2.763 (3.55), 2.835 (15.26), 2.933 (0.49), 2.950 (0.48), 3.219 (3.05), 3.234 (6.16), 3.249 (3.31), 3.301 (0.72), 3.582 (0.86), 3.598 (1.86), 3.601 (1.85), 3.618 (2.48), 3.637 (1.39), 3.732 (1.21), 3.746 (1.79), 3.750 (2.24), 3.764 (1.95), 3.767 (1.94), 3.785 (1.29), 3.861 (7.98), 3.879 (7.87), 3.911 (0.59), 3.927 (1.92), 3.943 (2.97), 3.959 (1.85), 3.974 (0.47), 4.294 (0.77), 4.312 (0.76), 7.083 (0.96), 7.344 (16.00), 7.940 (1.36), 7.955 (2.84), 7.970 (1.31), 8.594 (1.39). LC-MS (方法A ); Rt = 1.19 min, m/z = 382 [M+H]⁺. | 中間物 41; GP G (條件A,使用HATU) |
130 | 2'-(環丙基甲基)-N -[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.311 (1.27), 0.322 (4.94), 0.326 (4.05), 0.334 (4.49), 0.338 (4.45), 0.348 (1.71), 0.467 (0.58), 0.483 (2.14), 0.494 (4.10), 0.498 (4.18), 0.503 (2.17), 0.509 (2.05), 0.514 (4.24), 0.518 (3.90), 0.529 (1.41), 0.792 (1.89), 0.805 (4.69), 0.810 (5.82), 0.818 (3.36), 0.827 (1.05), 0.852 (1.19), 0.862 (3.02), 0.870 (5.83), 0.874 (4.09), 0.888 (1.71), 1.162 (0.58), 1.168 (0.74), 1.173 (0.84), 1.180 (1.15), 1.187 (1.09), 1.190 (0.97), 1.199 (1.80), 1.208 (0.82), 1.211 (1.01), 1.219 (1.06), 1.231 (0.84), 1.305 (0.81), 1.323 (1.94), 1.342 (0.85), 1.903 (0.69), 1.988 (0.71), 2.075 (4.47), 2.332 (1.06), 2.518 (4.50), 2.523 (3.36), 2.678 (0.44), 2.763 (3.27), 2.836 (14.91), 2.935 (0.45), 2.952 (0.44), 3.154 (0.51), 3.168 (1.05), 3.183 (3.10), 3.187 (1.82), 3.202 (3.22), 3.207 (3.47), 3.212 (3.39), 3.230 (2.96), 3.236 (3.38), 3.246 (2.02), 3.264 (1.10), 3.275 (0.46), 3.280 (0.64), 3.415 (0.76), 3.421 (0.97), 3.442 (2.13), 3.448 (2.28), 3.469 (2.04), 3.475 (1.80), 3.511 (1.66), 3.516 (1.83), 3.539 (2.25), 3.546 (2.21), 3.566 (0.98), 3.572 (1.50), 3.592 (0.75), 3.607 (3.25), 3.623 (1.39), 3.632 (2.69), 3.637 (2.51), 3.647 (0.71), 3.653 (0.74), 3.687 (2.45), 3.693 (2.04), 3.715 (3.96), 3.741 (1.85), 3.861 (7.90), 3.879 (7.81), 4.295 (0.70), 4.312 (0.70), 7.079 (0.81), 7.346 (16.00), 8.021 (1.36), 8.036 (2.92), 8.051 (1.36), 8.597 (1.30). LC-MS (方法A ); Rt = 1.11 min, m/z = 398 [M+H]⁺. | 中間物 41; GP G (條件A,使用HATU) |
131 | 2'-(環丙基甲基)-N -[(2R)-1,4-二㗁烷-2-基甲基]-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.311 (1.20), 0.322 (4.83), 0.325 (4.02), 0.334 (4.42), 0.337 (4.60), 0.347 (1.71), 0.483 (1.77), 0.493 (3.93), 0.497 (4.25), 0.502 (2.14), 0.509 (2.01), 0.513 (4.30), 0.518 (4.02), 0.528 (1.38), 0.791 (1.80), 0.804 (4.58), 0.809 (5.93), 0.817 (3.43), 0.827 (1.05), 0.852 (1.08), 0.861 (2.95), 0.869 (5.80), 0.874 (4.22), 0.887 (1.74), 0.931 (1.09), 0.948 (1.08), 1.167 (0.54), 1.179 (1.03), 1.187 (1.00), 1.199 (1.73), 1.207 (0.76), 1.211 (0.94), 1.218 (0.99), 1.230 (0.57), 1.236 (0.44), 2.074 (0.50), 2.332 (1.56), 2.336 (0.73), 2.518 (7.23), 2.522 (4.63), 2.673 (1.55), 2.678 (0.67), 2.836 (15.20), 3.153 (0.53), 3.167 (1.09), 3.182 (3.12), 3.186 (1.90), 3.202 (3.21), 3.206 (3.48), 3.211 (3.46), 3.214 (2.67), 3.230 (2.99), 3.235 (3.44), 3.245 (1.83), 3.264 (1.14), 3.279 (0.74), 3.292 (0.46), 3.415 (0.81), 3.420 (0.98), 3.441 (2.04), 3.447 (2.28), 3.468 (1.88), 3.475 (1.79), 3.510 (1.64), 3.516 (1.82), 3.539 (2.17), 3.545 (2.23), 3.565 (0.88), 3.572 (1.44), 3.592 (0.67), 3.607 (3.26), 3.622 (1.20), 3.631 (2.64), 3.637 (2.56), 3.646 (0.51), 3.653 (0.60), 3.686 (2.36), 3.693 (2.00), 3.715 (3.97), 3.740 (1.70), 3.861 (7.98), 3.879 (7.89), 7.345 (16.00), 8.021 (1.40), 8.036 (2.94), 8.052 (1.32). LC-MS (方法A ); Rt = 1.11 min, m/z = 398 [M+H]⁺. | 中間物 41; GP G (條件A,使用HATU) |
132 | 8'-甲基-2'-(吡啶-2-基甲基)-N -[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.552 (0.51), 1.569 (0.70), 1.576 (0.53), 1.585 (0.59), 1.597 (0.48), 1.779 (0.56), 1.785 (0.73), 1.800 (1.27), 1.818 (1.40), 1.836 (1.14), 1.851 (0.81), 1.859 (0.60), 1.863 (0.66), 1.868 (0.81), 1.883 (0.56), 1.890 (0.43), 1.948 (0.41), 1.954 (0.47), 1.967 (0.60), 1.977 (0.50), 1.990 (0.59), 2.013 (0.82), 2.032 (0.67), 2.051 (0.43), 2.075 (0.66), 2.089 (0.52), 2.103 (2.79), 2.118 (2.66), 2.125 (2.11), 2.143 (0.75), 2.434 (16.00), 2.520 (1.60), 2.525 (1.11), 3.037 (7.64), 3.219 (1.83), 3.234 (3.56), 3.249 (1.92), 3.586 (0.45), 3.602 (0.98), 3.605 (1.00), 3.623 (1.30), 3.641 (0.71), 3.737 (0.65), 3.751 (0.92), 3.754 (1.20), 3.769 (1.03), 3.772 (1.03), 3.790 (0.67), 3.931 (1.01), 3.947 (1.55), 3.963 (0.96), 5.405 (6.33), 7.054 (1.84), 7.073 (1.92), 7.297 (0.90), 7.299 (0.95), 7.309 (0.96), 7.311 (1.04), 7.315 (1.07), 7.318 (1.00), 7.328 (1.03), 7.330 (1.02), 7.760 (1.13), 7.765 (1.20), 7.779 (1.94), 7.784 (1.95), 7.798 (0.99), 7.803 (0.99), 7.923 (7.80), 7.960 (0.73), 7.975 (1.55), 7.990 (0.72), 8.541 (1.25), 8.543 (1.40), 8.545 (1.46), 8.548 (1.28), 8.553 (1.30), 8.555 (1.48), 8.557 (1.37), 8.560 (1.20). LC-MS (方法A ); Rt = 1.14 min, m/z = 433 [M+H]⁺. | 中間物 42; GP G (條件A,使用HATU) |
133 | N -[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-2'-(吡啶-2-基甲基)-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.919 (0.41), 0.933 (3.38), 0.937 (1.08), 0.950 (3.45), 0.954 (0.54), 1.955 (0.42), 1.969 (0.58), 1.978 (0.49), 1.992 (0.63), 2.014 (0.80), 2.034 (0.56), 2.051 (0.43), 2.075 (0.61), 2.104 (3.09), 2.119 (2.64), 2.144 (0.84), 2.407 (0.41), 2.424 (0.80), 2.434 (16.00), 2.520 (2.37), 2.525 (1.61), 3.037 (7.40), 3.169 (0.53), 3.185 (1.61), 3.203 (1.56), 3.210 (1.77), 3.214 (2.22), 3.229 (1.40), 3.239 (1.61), 3.245 (0.95), 3.264 (0.49), 3.419 (0.40), 3.425 (0.50), 3.446 (1.04), 3.452 (1.15), 3.473 (0.96), 3.479 (0.90), 3.514 (0.81), 3.520 (0.91), 3.543 (1.12), 3.549 (1.14), 3.569 (0.44), 3.576 (0.75), 3.597 (0.40), 3.612 (1.51), 3.619 (0.96), 3.628 (0.67), 3.636 (1.44), 3.642 (1.14), 3.691 (1.19), 3.697 (1.02), 3.719 (2.04), 3.745 (0.88), 5.406 (6.12), 7.054 (1.81), 7.073 (1.88), 7.297 (0.89), 7.300 (0.92), 7.309 (0.91), 7.312 (1.01), 7.316 (1.08), 7.318 (0.96), 7.328 (1.03), 7.331 (0.96), 7.760 (1.16), 7.765 (1.17), 7.779 (1.85), 7.784 (1.87), 7.799 (1.00), 7.803 (1.02), 7.925 (7.76), 8.040 (0.71), 8.055 (1.54), 8.070 (0.70), 8.541 (1.16), 8.543 (1.37), 8.545 (1.36), 8.548 (1.26), 8.553 (1.23), 8.555 (1.43), 8.557 (1.28), 8.560 (1.19). LC-MS (方法A ); Rt = 1.06 min, m/z = 449 [M+H]⁺. | 中間物 42; GP G (條件A,使用HATU) |
134 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8'-甲基-2'-(吡啶-2-基甲基)-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.929 (1.25), 0.946 (1.29), 1.945 (0.40), 1.951 (0.44), 1.964 (0.61), 1.974 (0.51), 1.987 (0.65), 2.009 (0.82), 2.029 (0.60), 2.047 (0.46), 2.071 (0.66), 2.099 (3.19), 2.114 (2.75), 2.139 (0.89), 2.331 (0.43), 2.430 (16.00), 2.518 (2.15), 2.522 (1.33), 2.673 (0.41), 3.033 (7.60), 3.166 (0.56), 3.182 (1.65), 3.200 (1.60), 3.206 (1.82), 3.210 (2.28), 3.226 (1.48), 3.235 (1.62), 3.242 (1.02), 3.261 (0.55), 3.321 (0.53), 3.397 (0.90), 3.414 (0.76), 3.421 (0.77), 3.442 (1.10), 3.448 (1.35), 3.469 (1.06), 3.475 (1.01), 3.510 (0.88), 3.516 (0.97), 3.538 (1.17), 3.545 (1.19), 3.565 (0.47), 3.571 (0.79), 3.593 (0.43), 3.608 (1.60), 3.615 (1.01), 3.632 (1.51), 3.687 (1.23), 3.693 (1.05), 3.715 (2.16), 3.741 (0.94), 5.401 (6.37), 7.051 (1.81), 7.071 (1.91), 7.294 (0.88), 7.297 (0.92), 7.306 (0.94), 7.309 (1.03), 7.313 (1.11), 7.315 (1.00), 7.325 (1.06), 7.327 (0.99), 7.757 (1.09), 7.762 (1.10), 7.776 (1.87), 7.781 (1.92), 7.795 (1.00), 7.800 (0.99), 7.919 (8.03), 8.044 (0.73), 8.059 (1.60), 8.074 (0.75), 8.536 (1.21), 8.539 (1.32), 8.541 (1.44), 8.543 (1.22), 8.548 (1.25), 8.551 (1.39), 8.553 (1.38), 8.555 (1.16). LC-MS (方法A ); Rt = 1.04 min, m/z = 449 [M+H]⁺. | 中間物 42; GP G (條件A,使用HATU) |
135 | 8-甲基-2-[苯基(2 H2 )甲基]-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.48), 0.008 (1.41), 1.551 (0.47), 1.567 (0.67), 1.575 (0.51), 1.583 (0.56), 1.591 (0.39), 1.596 (0.41), 1.774 (0.51), 1.780 (0.66), 1.795 (1.14), 1.814 (1.31), 1.831 (1.24), 1.842 (0.69), 1.852 (0.54), 1.859 (0.79), 1.874 (0.52), 2.461 (16.00), 2.520 (3.60), 2.524 (2.32), 2.857 (2.40), 2.859 (2.49), 2.868 (4.57), 2.873 (4.85), 2.883 (3.13), 3.212 (1.05), 3.217 (1.05), 3.227 (2.00), 3.232 (1.91), 3.243 (1.09), 3.248 (1.12), 3.583 (0.41), 3.598 (0.90), 3.602 (0.88), 3.619 (1.22), 3.637 (0.66), 3.733 (0.62), 3.750 (1.11), 3.765 (0.90), 3.768 (0.94), 3.785 (0.64), 3.927 (0.96), 3.943 (1.44), 3.959 (0.90), 7.243 (1.99), 7.246 (2.72), 7.250 (1.37), 7.257 (0.90), 7.263 (5.04), 7.267 (3.88), 7.275 (0.56), 7.282 (2.04), 7.288 (0.51), 7.296 (1.37), 7.300 (1.69), 7.304 (0.73), 7.325 (0.69), 7.328 (2.38), 7.330 (3.41), 7.334 (1.35), 7.345 (2.14), 7.349 (3.63), 7.353 (0.88), 7.361 (0.54), 7.365 (1.31), 7.369 (0.75), 7.586 (5.49), 7.960 (0.67), 7.975 (1.41), 7.990 (0.64), 8.553 (0.51). LC-MS (方法A ); Rt = 1.20 min, m/z = 394 [M+H]⁺. | 中間物 44; GP G (條件A,使用HATU) |
136 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[苯基(2 H2 )甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.18), 0.008 (2.03), 0.934 (0.52), 0.951 (0.52), 2.338 (0.47), 2.461 (16.00), 2.520 (5.04), 2.524 (3.29), 2.662 (0.47), 2.859 (2.50), 2.870 (4.40), 2.874 (4.65), 2.885 (3.09), 3.161 (0.57), 3.180 (1.71), 3.194 (1.43), 3.204 (1.56), 3.209 (2.05), 3.214 (0.91), 3.233 (1.81), 3.246 (0.87), 3.264 (0.57), 3.308 (0.54), 3.421 (0.45), 3.441 (0.99), 3.447 (1.09), 3.468 (0.89), 3.474 (0.87), 3.511 (0.77), 3.517 (0.84), 3.539 (1.04), 3.545 (1.06), 3.566 (0.42), 3.572 (0.69), 3.607 (1.66), 3.612 (1.26), 3.622 (0.59), 3.631 (1.29), 3.637 (1.31), 3.682 (1.14), 3.688 (0.96), 3.711 (2.00), 3.717 (1.73), 3.741 (0.84), 7.243 (1.90), 7.246 (2.62), 7.250 (1.34), 7.257 (0.91), 7.263 (4.72), 7.267 (3.81), 7.275 (0.57), 7.282 (1.93), 7.288 (0.47), 7.296 (1.24), 7.300 (1.63), 7.304 (0.69), 7.328 (2.28), 7.330 (3.29), 7.334 (1.31), 7.345 (2.13), 7.349 (3.56), 7.353 (0.87), 7.361 (0.52), 7.366 (1.29), 7.369 (0.72), 7.587 (5.27), 8.040 (0.69), 8.054 (1.46), 8.070 (0.67). LC-MS (方法A ); Rt = 1.13 min, m/z = 410 [M+H]⁺. | 中間物 44; GP G (條件A,使用HATU) |
137 | 2-[(5-環丙基-1,2,4-㗁二唑-3-基)甲基]-8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.11), 0.008 (1.94), 1.061 (0.62), 1.072 (2.54), 1.079 (2.63), 1.083 (2.23), 1.091 (2.63), 1.100 (0.92), 1.208 (0.88), 1.217 (2.42), 1.225 (2.01), 1.238 (2.80), 1.245 (1.94), 1.257 (0.62), 1.551 (0.50), 1.568 (0.69), 1.575 (0.52), 1.584 (0.57), 1.596 (0.43), 1.775 (0.55), 1.781 (0.71), 1.796 (1.23), 1.814 (1.37), 1.832 (1.33), 1.843 (0.73), 1.853 (0.59), 1.860 (0.81), 1.875 (0.55), 2.296 (0.45), 2.308 (0.88), 2.317 (1.02), 2.320 (1.00), 2.324 (1.21), 2.329 (3.08), 2.334 (1.16), 2.338 (1.02), 2.341 (1.00), 2.350 (0.85), 2.438 (16.00), 2.520 (4.91), 2.525 (3.13), 2.542 (0.47), 2.662 (0.45), 2.666 (1.00), 2.671 (1.40), 2.676 (1.00), 2.680 (0.45), 2.870 (2.70), 2.882 (5.71), 2.892 (3.27), 3.212 (1.09), 3.218 (1.09), 3.227 (2.01), 3.233 (1.94), 3.243 (1.11), 3.248 (1.11), 3.310 (0.55), 3.583 (0.45), 3.599 (0.95), 3.602 (0.92), 3.620 (1.28), 3.638 (0.69), 3.733 (0.64), 3.750 (1.16), 3.766 (0.95), 3.768 (0.97), 3.786 (0.64), 3.928 (1.00), 3.944 (1.49), 3.959 (0.92), 5.403 (8.01), 7.598 (4.98), 7.982 (0.71), 7.997 (1.52), 8.012 (0.71). LC-MS (方法A ); Rt = 1.08 min, m/z = 424 [M+H]⁺. | 中間物 45; GP G (條件A,使用HATU) |
138 | 2-[(5-環丙基-1,2,4-㗁二唑-3-基)甲基]-N -[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.49), 0.008 (1.41), 1.061 (0.65), 1.071 (2.66), 1.079 (2.75), 1.083 (2.38), 1.090 (2.84), 1.100 (1.17), 1.208 (0.93), 1.217 (2.51), 1.225 (2.19), 1.238 (2.92), 1.245 (2.12), 1.257 (0.71), 2.296 (0.45), 2.308 (0.95), 2.317 (1.08), 2.320 (1.06), 2.324 (1.15), 2.329 (3.10), 2.334 (1.13), 2.338 (1.04), 2.341 (1.13), 2.350 (0.89), 2.361 (0.45), 2.439 (16.00), 2.520 (4.72), 2.525 (3.07), 2.542 (0.56), 2.667 (0.91), 2.671 (1.26), 2.676 (0.93), 2.680 (0.43), 2.871 (2.77), 2.884 (5.76), 2.894 (3.33), 2.912 (0.41), 3.161 (0.61), 3.181 (1.93), 3.195 (1.56), 3.205 (1.71), 3.210 (2.25), 3.234 (2.08), 3.246 (0.97), 3.265 (0.63), 3.415 (0.41), 3.421 (0.50), 3.441 (1.10), 3.448 (1.19), 3.469 (0.95), 3.475 (0.93), 3.512 (0.82), 3.517 (0.89), 3.540 (1.15), 3.546 (1.19), 3.566 (0.48), 3.573 (0.76), 3.607 (1.80), 3.623 (0.69), 3.631 (1.47), 3.638 (1.43), 3.683 (1.28), 3.690 (1.08), 3.712 (2.27), 3.718 (1.91), 3.741 (0.93), 4.646 (1.02), 5.404 (8.25), 7.599 (5.15), 8.060 (0.78), 8.074 (1.65), 8.090 (0.76). LC-MS (方法A ); Rt = 1.00 min, m/z = 440 [M+H]⁺. | 中間物 45; GP G (條件A,使用HATU) |
139 | [2-(8-甲基-7-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}-4,5-二氫-2H -呋喃并[2,3-g]吲唑-2-基)乙基]胺甲酸第三丁酯 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.50), 0.008 (1.39), 1.157 (0.59), 1.174 (0.51), 1.234 (0.84), 1.301 (0.88), 1.365 (16.00), 1.569 (0.51), 1.577 (0.40), 1.585 (0.48), 1.783 (0.55), 1.798 (1.06), 1.816 (1.03), 1.834 (0.95), 1.846 (0.59), 1.863 (0.59), 1.878 (0.44), 2.076 (0.48), 2.324 (1.35), 2.329 (1.83), 2.333 (1.32), 2.477 (11.17), 2.524 (6.00), 2.666 (1.35), 2.671 (1.83), 2.676 (1.35), 2.824 (0.40), 2.842 (1.76), 2.854 (2.64), 2.862 (2.89), 2.874 (2.16), 2.892 (0.48), 3.215 (0.81), 3.219 (0.84), 3.230 (1.57), 3.234 (1.54), 3.250 (1.06), 3.272 (1.65), 3.286 (1.90), 3.371 (0.40), 3.603 (0.70), 3.622 (0.88), 3.640 (0.48), 3.735 (0.40), 3.752 (0.81), 3.769 (0.70), 3.930 (0.70), 3.946 (1.03), 3.962 (0.62), 4.061 (0.92), 4.077 (1.65), 4.093 (0.77), 6.942 (0.73), 7.445 (1.79), 7.963 (0.51), 7.978 (1.10), 7.994 (0.51). UPLC-MS (方法1 ); Rt = 1.12 min, m/z = 443 [M-H]⁻. | 中間物 46; GP G (條件A,使用HATU) |
140 | [2-(7-{[(2R)-1,4-二㗁烷-2-基甲基]胺甲醯基}-8-甲基-4,5-二氫-2H -呋喃并[2,3-g]吲唑-2-基)乙基]胺甲酸第三丁酯 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.700 (0.41), 0.768 (0.50), 1.157 (1.52), 1.234 (1.24), 1.300 (1.05), 1.365 (16.00), 2.324 (1.24), 2.329 (1.66), 2.333 (1.24), 2.478 (11.48), 2.667 (1.27), 2.671 (1.63), 2.675 (1.21), 2.825 (0.44), 2.844 (1.74), 2.856 (2.65), 2.863 (2.84), 2.876 (2.10), 2.894 (0.44), 3.183 (1.16), 3.197 (1.02), 3.212 (1.54), 3.236 (1.41), 3.249 (0.88), 3.272 (1.79), 3.287 (1.93), 3.444 (0.80), 3.449 (0.83), 3.471 (0.69), 3.477 (0.66), 3.513 (0.55), 3.519 (0.58), 3.541 (0.77), 3.546 (0.83), 3.574 (0.47), 3.609 (1.32), 3.634 (1.10), 3.686 (0.88), 3.692 (0.77), 3.715 (1.63), 3.744 (0.72), 4.061 (0.94), 4.077 (1.71), 4.093 (0.80), 6.942 (0.74), 6.957 (0.41), 7.447 (1.82), 8.042 (0.58), 8.058 (1.10), 8.072 (0.55). UPLC-MS (方法1 ); Rt = 1.05 min, m/z = 461 [M+H]⁺. | 中間物 46; GP G (條件A,使用HATU) |
141 | 4-[2-(8-甲基-7-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}-4,5-二氫-2H -呋喃并[2,3-g]吲唑-2-基)乙基]哌𠯤-1-甲酸第三丁酯 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.157 (0.64), 1.175 (1.25), 1.192 (0.64), 1.372 (1.34), 1.389 (16.00), 1.799 (2.29), 1.816 (0.60), 1.833 (0.52), 1.989 (2.21), 2.077 (6.46), 2.367 (0.85), 2.380 (1.23), 2.392 (0.89), 2.470 (4.93), 2.520 (1.02), 2.525 (0.64), 2.680 (0.56), 2.689 (0.75), 2.697 (1.00), 2.713 (0.54), 2.730 (0.63), 2.844 (0.85), 2.857 (1.23), 2.865 (1.31), 2.877 (1.04), 2.891 (0.72), 3.214 (0.43), 3.220 (0.41), 3.230 (0.73), 3.234 (0.70), 3.245 (0.46), 3.250 (0.47), 3.289 (1.13), 3.604 (0.45), 3.622 (0.49), 3.752 (0.49), 3.767 (0.40), 3.946 (0.50), 4.019 (0.53), 4.037 (0.52), 4.154 (0.46), 4.170 (0.93), 4.187 (0.44), 7.515 (1.53), 7.974 (0.54). UPLC-MS (方法1 ); Rt = 1.23 min, m/z = 514 [M+H]⁺. | 中間物 47; GP G (條件A,使用HATU) |
142 | 4-[2-(7-{[(2R)-1,4-二㗁烷-2-基甲基]胺甲醯基}-8-甲基-4,5-二氫-2H -呋喃并[2,3-g]吲唑-2-基)乙基]哌𠯤-1-甲酸第三丁酯 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.88), 0.008 (0.86), 0.747 (0.64), 0.767 (0.68), 1.157 (2.55), 1.175 (1.98), 1.192 (1.10), 1.235 (0.97), 1.373 (0.53), 1.389 (16.00), 1.990 (1.91), 2.077 (8.25), 2.367 (0.85), 2.380 (1.23), 2.391 (0.90), 2.470 (5.29), 2.520 (4.61), 2.525 (2.87), 2.689 (0.40), 2.697 (0.96), 2.713 (0.50), 2.846 (0.83), 2.858 (1.16), 2.867 (1.25), 2.879 (0.99), 3.183 (0.57), 3.197 (0.50), 3.208 (0.57), 3.212 (0.73), 3.236 (0.64), 3.289 (1.16), 3.609 (0.59), 3.638 (0.46), 3.685 (0.40), 3.714 (0.72), 4.019 (0.44), 4.037 (0.46), 4.154 (0.44), 4.171 (0.90), 4.187 (0.42), 7.517 (1.47), 8.054 (0.53). UPLC-MS (方法1 ); Rt = 1.16 min, m/z = 530 [M+H]⁺. | 中間物 47; GP G (條件A,使用HATU) |
143 | 2'-[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-N -[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.554 (0.51), 1.563 (0.41), 1.567 (0.46), 1.570 (0.72), 1.578 (0.54), 1.586 (0.61), 1.594 (0.41), 1.599 (0.50), 1.780 (0.57), 1.786 (0.74), 1.801 (1.28), 1.819 (1.38), 1.837 (1.11), 1.852 (0.81), 1.860 (0.60), 1.864 (0.65), 1.869 (0.82), 1.884 (0.58), 1.886 (0.57), 1.891 (0.46), 1.901 (0.44), 1.907 (0.49), 1.922 (0.48), 1.929 (0.41), 1.947 (0.56), 1.965 (0.42), 1.971 (0.50), 1.982 (0.54), 2.002 (0.62), 2.020 (0.77), 2.038 (0.49), 2.069 (1.55), 2.086 (2.79), 2.105 (1.43), 2.131 (0.48), 2.462 (16.00), 2.518 (1.39), 2.523 (0.98), 2.627 (0.60), 3.016 (7.40), 3.221 (1.61), 3.236 (3.22), 3.250 (2.33), 3.273 (1.36), 3.278 (1.43), 3.302 (1.36), 3.423 (0.40), 3.429 (0.49), 3.450 (1.00), 3.456 (1.10), 3.477 (0.88), 3.483 (0.83), 3.525 (0.70), 3.531 (0.80), 3.554 (1.00), 3.560 (0.99), 3.581 (0.51), 3.587 (1.14), 3.603 (0.99), 3.606 (1.06), 3.623 (2.29), 3.641 (0.81), 3.652 (0.90), 3.721 (1.09), 3.728 (1.99), 3.737 (1.39), 3.751 (1.75), 3.755 (2.56), 3.769 (1.15), 3.772 (1.12), 3.790 (0.68), 3.861 (0.55), 3.867 (0.64), 3.877 (0.54), 3.885 (0.71), 3.891 (0.52), 3.932 (1.02), 3.948 (1.56), 3.963 (0.95), 4.092 (2.08), 4.097 (2.15), 4.109 (2.33), 7.735 (7.25), 7.955 (0.70), 7.970 (1.52), 7.985 (0.70). LC-MS (方法A ); Rt = 1.12 min, m/z = 442 [M+H]⁺. | 中間物 48; GP G (條件A,使用HATU) |
144 | N ,2'-雙[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (0.75), 0.931 (0.46), 0.948 (0.46), 1.929 (0.42), 1.934 (0.41), 1.948 (0.60), 1.959 (0.42), 1.962 (0.43), 1.971 (0.54), 1.983 (0.55), 1.987 (0.44), 2.002 (0.62), 2.019 (0.73), 2.038 (0.50), 2.068 (1.70), 2.084 (2.67), 2.099 (1.55), 2.113 (1.27), 2.133 (0.51), 2.462 (16.00), 2.518 (2.14), 2.523 (1.44), 2.627 (0.67), 3.016 (7.24), 3.172 (0.50), 3.187 (1.57), 3.191 (0.99), 3.206 (1.69), 3.211 (2.03), 3.215 (2.14), 3.221 (1.15), 3.229 (1.51), 3.240 (1.77), 3.249 (1.68), 3.264 (0.58), 3.273 (1.43), 3.278 (1.62), 3.302 (1.53), 3.425 (0.73), 3.429 (0.64), 3.452 (1.79), 3.473 (1.21), 3.477 (1.40), 3.480 (1.39), 3.514 (0.92), 3.520 (1.08), 3.525 (0.81), 3.531 (0.87), 3.543 (1.23), 3.549 (1.41), 3.553 (1.19), 3.559 (1.07), 3.569 (0.53), 3.575 (0.85), 3.580 (0.59), 3.587 (0.74), 3.597 (0.43), 3.613 (1.72), 3.620 (1.75), 3.628 (1.58), 3.637 (1.65), 3.642 (1.29), 3.652 (1.22), 3.693 (1.24), 3.699 (1.10), 3.720 (3.10), 3.727 (3.08), 3.749 (1.66), 3.755 (1.72), 3.861 (0.56), 3.867 (0.64), 3.877 (0.55), 3.884 (0.72), 3.891 (0.53), 4.093 (2.11), 4.097 (2.17), 4.109 (2.39), 7.589 (0.41), 7.737 (7.76), 8.036 (0.75), 8.052 (1.58), 8.066 (0.70). LC-MS (方法A ); Rt = 1.03 min, m/z = 458 [M+H]⁺. | 中間物 48; GP G (條件A,使用HATU) |
145 | N -[(2R)-1,4-二㗁烷-2-基甲基]-2'-[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.931 (1.65), 0.934 (0.53), 0.947 (1.63), 1.929 (0.44), 1.934 (0.44), 1.947 (0.63), 1.957 (0.45), 1.961 (0.45), 1.970 (0.56), 1.982 (0.56), 2.000 (0.65), 2.018 (0.77), 2.037 (0.54), 2.059 (1.06), 2.068 (1.74), 2.084 (2.67), 2.101 (1.49), 2.111 (1.33), 2.132 (0.55), 2.461 (16.00), 2.518 (2.08), 2.523 (1.34), 2.626 (0.79), 2.991 (0.40), 3.015 (7.27), 3.169 (0.56), 3.186 (1.79), 3.203 (1.56), 3.211 (1.80), 3.216 (2.36), 3.233 (1.50), 3.239 (1.83), 3.248 (2.20), 3.267 (0.75), 3.272 (1.60), 3.276 (1.61), 3.301 (1.61), 3.311 (0.46), 3.316 (0.51), 3.385 (0.46), 3.425 (0.80), 3.428 (0.70), 3.451 (1.91), 3.473 (1.26), 3.476 (1.46), 3.478 (1.47), 3.514 (0.96), 3.520 (1.15), 3.523 (0.89), 3.529 (0.91), 3.542 (1.28), 3.549 (1.58), 3.558 (1.14), 3.569 (0.56), 3.575 (0.92), 3.585 (0.78), 3.597 (0.47), 3.612 (1.78), 3.620 (1.85), 3.627 (1.65), 3.636 (1.74), 3.642 (1.32), 3.651 (1.27), 3.692 (1.29), 3.698 (1.19), 3.720 (3.17), 3.726 (3.20), 3.748 (1.76), 3.754 (1.81), 3.860 (0.58), 3.867 (0.67), 3.876 (0.56), 3.884 (0.74), 3.891 (0.55), 4.092 (2.20), 4.097 (2.26), 4.109 (2.52), 7.589 (0.50), 7.735 (7.87), 8.038 (0.77), 8.053 (1.61), 8.067 (0.73). LC-MS (方法A ); Rt = 1.03 min, m/z = 458 [M+H]⁺. | 中間物 48; GP G (條件A,使用HATU) |
146 | 8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-2-[(6-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}吡啶-3-基)甲基]-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.50), -0.008 (4.09), 0.008 (4.34), 0.146 (0.50), 1.537 (0.62), 1.555 (0.99), 1.564 (0.99), 1.569 (0.99), 1.585 (1.24), 1.600 (0.62), 1.776 (1.12), 1.794 (1.98), 1.812 (1.98), 1.832 (1.98), 1.843 (1.49), 1.850 (1.36), 1.860 (1.74), 1.875 (1.12), 1.892 (0.74), 1.914 (0.50), 2.334 (2.98), 2.338 (1.36), 2.443 (15.01), 2.520 (16.00), 2.524 (10.42), 2.676 (3.10), 2.680 (1.36), 2.907 (8.06), 2.915 (3.22), 3.213 (1.12), 3.220 (1.12), 3.229 (1.98), 3.234 (2.11), 3.244 (1.12), 3.249 (1.24), 3.279 (0.74), 3.295 (0.99), 3.312 (3.97), 3.361 (2.23), 3.379 (0.74), 3.584 (0.99), 3.603 (1.98), 3.621 (2.60), 3.638 (1.49), 3.735 (1.24), 3.752 (2.23), 3.767 (1.98), 3.787 (1.12), 3.929 (1.12), 3.945 (1.61), 3.959 (1.49), 3.973 (1.24), 3.988 (0.87), 5.467 (4.84), 7.375 (1.36), 7.379 (1.36), 7.387 (1.36), 7.392 (1.36), 7.692 (4.71), 7.823 (2.36), 7.980 (0.74), 7.995 (1.61), 8.011 (0.74), 8.550 (2.23), 8.596 (2.23), 8.610 (2.23), 8.648 (0.62), 8.663 (1.24), 8.679 (0.62). LC-MS (方法A ); Rt = 1.07 min, m/z = 520 [M+H]⁺. | 中間物 49; GP G (條件A,使用HATU) |
147 | N -[(2R)-1,4-二㗁烷-2-基甲基]-2-[(6-{[(2R)-1,4-二㗁烷-2-基甲基]胺甲醯基}吡啶-3-基)甲基]-8-甲基-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.76), -0.008 (7.51), 0.008 (6.75), 0.146 (0.76), 2.324 (4.79), 2.329 (6.31), 2.333 (4.57), 2.445 (8.93), 2.524 (16.00), 2.666 (4.79), 2.671 (6.31), 2.675 (4.57), 2.908 (4.90), 3.181 (1.20), 3.197 (1.20), 3.211 (1.41), 3.218 (1.52), 3.234 (1.63), 3.248 (1.20), 3.440 (1.09), 3.467 (0.87), 3.515 (0.87), 3.544 (1.41), 3.571 (0.87), 3.605 (1.52), 3.632 (1.52), 3.656 (0.87), 3.676 (1.96), 3.712 (2.18), 3.744 (1.20), 5.467 (3.16), 7.379 (0.87), 7.391 (0.87), 7.693 (2.83), 7.822 (1.74), 8.059 (0.54), 8.073 (0.98), 8.549 (1.52), 8.601 (1.52), 8.613 (1.41), 8.738 (0.87). LC-MS (方法A ); Rt = 0.93 min, m/z = 552 [M+H]⁺. | 中間物 49; GP G (條件A,使用HATU) |
實例 148 : 4,4,8- 三甲基 -2-( 吡啶 -2- 基甲基 )-N
-[(2S)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
根據GP G (條件B),使7-溴-4,4,8-三甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑(中間物37;1.00 eq.,100 mg,269 µmol)與1-[(2S)-四氫呋喃-2-基]甲胺(CAS編號[7175 81-7];5.0 eq.,140 µL,1.30 mmol)、六羰基鉬(CAS編號[13939-06-5];2.0 eq.,142 mg,537 µmol)、碳酸鈉(CAS編號[497-19-8];3.0 eq.,85 mg,810 µmol)、四氟硼酸三-第三丁基鏻(CAS編號[131274-22-1];0.10 eq.,7.8 mg,27 µmol)及乙酸鈀(II)(CAS編號[3375-31-3];0.20 eq.,12 mg,54 µmol)在140℃下反應6小時且在室溫下反應隔夜。添加額外量的六羰基鉬(2.0 eq.,142 mg,537 µmol)、碳酸鈉(3.0 eq.,85 mg,810 µmol)、四氟硼酸三-第三丁基鏻(0.10 eq.,7.8 mg,27 µmol)及乙酸鈀(II)(0.20 eq.,12 mg,54 µmol)且在140℃下攪拌混合物另外4.5小時。將反應混合物冷卻至室溫,經矽藻土濾出固體且用乙酸乙酯沖洗。在減壓下濃縮濾液且所得粗產物藉由製備型HPLC純化,得到標題化合物(5.3 mg,4%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.26 (s, 6H), 1.55-1.61 (m, 1H), 1.76-1.91 (m, 3H), 2.45 (s, 3H), 2.75 (s, 2H), 3.21-3.24 (m, 2H), 3.58-3.64 (m, 1H), 3.72-3.82 (m, 1H), 3.91-3.98 (m, 1H), 5.38 (s, 2H), 7.07 (d, 1H), 7.31 (ddd, 1H), 7.71 (s, 1H), 7.78 (dt, 1H), 7.99 (t, 1H), 8.54 (ddd, 1H)。
LC-MS (方法A
): Rt
= 1.09 min; MS (ESIpos): m/z = 421 [M+H]+
.表 3 : 以給定的溴中間物及市售胺為起始物 , 類似於實例 148 來製備以下實例 (149 至 154) 。
實例 | 結構 IUPAC- 名稱 | 分析型資料 | 中間物 |
149 | 8'-甲基-2'-(吡啶-2-基甲基)-N -[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.806 (1.08), 0.819 (2.86), 0.824 (3.50), 0.832 (1.98), 0.840 (0.76), 0.851 (0.46), 0.857 (0.70), 0.875 (2.92), 0.884 (3.64), 0.901 (1.04), 0.939 (0.72), 0.957 (0.40), 0.979 (0.40), 1.541 (0.72), 1.557 (0.96), 1.565 (0.80), 1.574 (0.88), 1.586 (0.70), 1.602 (0.52), 1.753 (0.42), 1.772 (0.92), 1.788 (1.58), 1.806 (1.72), 1.824 (1.52), 1.837 (0.98), 1.843 (0.82), 1.850 (0.86), 1.854 (0.96), 1.869 (0.72), 1.876 (0.54), 1.886 (0.44), 1.892 (0.42), 2.458 (16.00), 2.518 (1.36), 2.850 (8.32), 3.210 (1.92), 3.226 (3.72), 3.241 (2.02), 3.574 (0.54), 3.594 (1.20), 3.611 (1.52), 3.628 (0.80), 3.724 (0.72), 3.741 (1.36), 3.756 (1.16), 3.759 (1.20), 3.776 (0.70), 3.919 (1.12), 3.936 (1.68), 3.951 (1.04), 5.333 (7.30), 7.027 (2.00), 7.047 (2.10), 7.284 (1.04), 7.296 (1.20), 7.300 (1.26), 7.312 (1.24), 7.448 (6.90), 7.743 (1.12), 7.747 (1.14), 7.762 (1.90), 7.766 (1.92), 7.781 (0.98), 7.786 (1.02), 7.949 (0.82), 7.964 (1.72), 7.979 (0.82), 8.517 (1.60), 8.519 (1.66), 8.529 (1.70), 8.531 (1.68). LC-MS (方法A ); Rt = 1.03 min, m/z = 419 [M+H]⁺. | 中間物38,步驟5 |
150 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8'-甲基-2'-(吡啶-2-基甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.811 (0.94), 0.824 (2.41), 0.829 (3.04), 0.837 (1.78), 0.846 (0.58), 0.872 (0.58), 0.880 (1.52), 0.888 (2.99), 0.907 (0.94), 2.463 (16.00), 2.518 (2.05), 2.523 (2.41), 2.855 (7.61), 2.902 (0.52), 3.150 (0.47), 3.164 (0.63), 3.178 (1.57), 3.183 (1.05), 3.199 (1.78), 3.202 (1.99), 3.207 (1.84), 3.212 (1.47), 3.227 (1.68), 3.231 (1.89), 3.242 (1.05), 3.261 (0.58), 3.411 (0.52), 3.417 (0.63), 3.438 (1.15), 3.444 (1.26), 3.465 (1.00), 3.471 (0.94), 3.507 (0.89), 3.513 (1.00), 3.535 (1.21), 3.542 (1.26), 3.562 (0.52), 3.568 (0.79), 3.589 (0.42), 3.604 (1.84), 3.619 (0.73), 3.629 (1.47), 3.634 (1.47), 3.681 (1.26), 3.687 (1.15), 3.710 (2.20), 3.738 (1.00), 5.337 (6.40), 7.033 (1.84), 7.052 (1.94), 7.286 (0.94), 7.289 (0.94), 7.298 (1.00), 7.301 (1.05), 7.305 (1.10), 7.307 (1.00), 7.317 (1.10), 7.319 (1.00), 7.452 (8.45), 7.747 (1.15), 7.752 (1.21), 7.766 (1.94), 7.771 (1.99), 7.785 (1.05), 7.790 (1.00), 7.824 (0.68), 8.034 (0.73), 8.049 (1.57), 8.064 (0.73), 8.519 (1.21), 8.521 (1.42), 8.523 (1.42), 8.525 (1.26), 8.531 (1.26), 8.533 (1.42), 8.535 (1.36), 8.537 (1.21). LC-MS (方法A ); Rt = 0.96 min, m/z = 435 [M+H]⁺. | 中間物38,步驟5 |
151 | 8'-甲基-2'-(吡啶-3-基甲基)-N -[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.797 (0.89), 0.807 (2.43), 0.811 (2.84), 0.818 (1.54), 0.871 (1.29), 0.877 (2.84), 0.882 (2.12), 0.891 (0.89), 1.547 (0.44), 1.563 (0.62), 1.569 (0.57), 1.576 (0.50), 1.587 (0.52), 1.775 (0.52), 1.780 (0.49), 1.784 (0.42), 1.792 (0.76), 1.795 (0.69), 1.806 (0.71), 1.810 (0.81), 1.822 (0.57), 1.826 (0.59), 1.836 (0.52), 1.839 (0.49), 1.843 (0.52), 1.850 (0.62), 1.855 (0.49), 1.859 (0.59), 1.867 (0.42), 1.870 (0.47), 1.876 (0.42), 1.905 (0.49), 2.477 (16.00), 2.514 (2.84), 2.518 (2.90), 2.522 (2.38), 2.840 (7.25), 3.216 (1.29), 3.228 (2.57), 3.242 (1.34), 3.584 (0.45), 3.599 (0.99), 3.613 (1.14), 3.627 (0.71), 3.732 (0.60), 3.744 (0.91), 3.746 (1.04), 3.749 (0.69), 3.758 (1.04), 3.760 (0.87), 3.763 (0.72), 3.775 (0.69), 3.925 (0.96), 3.938 (1.49), 3.951 (0.96), 5.294 (5.81), 7.361 (1.06), 7.363 (1.04), 7.371 (1.11), 7.372 (1.02), 7.377 (1.16), 7.378 (1.18), 7.387 (1.24), 7.388 (1.18), 7.457 (8.21), 7.617 (0.77), 7.620 (1.23), 7.625 (0.82), 7.633 (0.69), 7.636 (1.06), 7.641 (0.72), 7.952 (0.65), 7.964 (1.43), 7.976 (0.65), 8.490 (1.66), 8.493 (3.27), 8.499 (2.97), 8.502 (1.58). LC-MS (方法A ); Rt = 0.99 min, m/z = 419 [M+H]⁺. | 中間物39 |
152 | N -[(2R)-1,4-二㗁烷-2-基甲基]-8'-甲基-2'-(吡啶-3-基甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.797 (0.91), 0.808 (2.57), 0.811 (2.96), 0.819 (1.61), 0.872 (1.39), 0.879 (3.00), 0.883 (2.26), 0.893 (0.91), 0.934 (0.43), 0.947 (0.48), 1.270 (7.87), 1.294 (8.65), 2.368 (0.70), 2.477 (16.00), 2.514 (6.43), 2.518 (6.35), 2.522 (5.17), 2.627 (0.78), 2.841 (7.61), 3.168 (0.65), 3.183 (2.04), 3.195 (1.52), 3.202 (1.52), 3.206 (1.91), 3.214 (0.78), 3.226 (2.17), 3.239 (0.91), 3.254 (0.61), 3.417 (0.43), 3.422 (0.61), 3.439 (1.09), 3.444 (1.17), 3.461 (0.96), 3.466 (0.87), 3.512 (0.83), 3.517 (0.91), 3.534 (1.13), 3.539 (1.13), 3.556 (0.52), 3.561 (0.70), 3.605 (1.61), 3.610 (1.30), 3.617 (0.65), 3.625 (1.35), 3.630 (1.35), 3.683 (1.17), 3.688 (1.00), 3.707 (1.78), 3.711 (1.91), 3.734 (0.83), 5.294 (6.13), 7.361 (1.09), 7.371 (1.13), 7.377 (1.22), 7.387 (1.26), 7.458 (8.17), 7.617 (0.87), 7.621 (1.22), 7.625 (0.83), 7.633 (0.74), 7.637 (1.13), 7.641 (0.70), 8.033 (0.74), 8.045 (1.57), 8.057 (0.70), 8.490 (1.87), 8.493 (3.48), 8.499 (3.00), 8.502 (1.61). LC-MS (方法A ); Rt = 0.92 min, m/z = 435 [M+H]⁺. | 中間物39 |
153 | N 2' ,N 2' ,8'-三甲基-N 7' -[(2S)-四氫呋喃-2-基甲基]螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-2',7'(5'H )-二羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.918 (0.52), 0.938 (3.14), 0.944 (2.04), 0.961 (1.99), 0.967 (3.42), 0.987 (0.58), 1.555 (0.48), 1.571 (0.66), 1.579 (0.49), 1.587 (0.57), 1.600 (0.44), 1.779 (0.58), 1.785 (0.73), 1.800 (1.24), 1.819 (1.35), 1.836 (1.17), 1.850 (0.73), 1.858 (0.58), 1.862 (0.65), 1.867 (0.78), 1.881 (0.53), 1.888 (0.41), 1.898 (0.42), 2.520 (2.76), 2.525 (16.00), 2.904 (7.36), 3.146 (2.92), 3.227 (1.33), 3.229 (1.29), 3.243 (2.43), 3.260 (1.32), 3.585 (0.45), 3.602 (0.95), 3.605 (0.95), 3.622 (1.22), 3.640 (0.68), 3.735 (0.63), 3.750 (0.90), 3.752 (1.13), 3.767 (0.96), 3.770 (0.97), 3.788 (0.64), 3.935 (0.95), 3.951 (1.45), 3.966 (0.90), 7.829 (8.89), 8.061 (0.68), 8.076 (1.42), 8.090 (0.65). LC-MS (方法A ); Rt = 1.11 min, m/z = 399 [M+H]⁺. | 中間物40-2 |
154 | N 7' -[(2R)-1,4-二㗁烷-2-基甲基]-N 2' ,N 2' ,8'-三甲基螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-2',7'(5'H )-二羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.919 (0.54), 0.940 (3.41), 0.945 (2.22), 0.962 (2.11), 0.968 (3.71), 0.989 (0.61), 2.526 (16.00), 2.905 (7.77), 3.146 (3.20), 3.177 (1.22), 3.188 (1.67), 3.196 (1.16), 3.212 (3.01), 3.216 (1.84), 3.227 (1.51), 3.241 (2.30), 3.258 (0.96), 3.277 (0.62), 3.418 (0.42), 3.424 (0.50), 3.445 (1.10), 3.452 (1.17), 3.472 (0.98), 3.479 (0.93), 3.514 (0.84), 3.519 (0.94), 3.542 (1.15), 3.548 (1.20), 3.569 (0.48), 3.575 (0.75), 3.610 (1.36), 3.615 (1.35), 3.623 (0.95), 3.638 (1.52), 3.690 (1.29), 3.696 (1.09), 3.719 (2.16), 3.745 (0.96), 7.830 (8.99), 8.136 (0.74), 8.150 (1.56), 8.166 (0.71). LC-MS (方法A ); Rt = 1.01 min, m/z = 415 [M+H]⁺. | 中間物40-2 |
實例 155 : 3- 氟 -3-[(8- 甲基 -7-{[(2S)- 四氫呋喃 -2- 基甲基 ] 胺甲醯基 }-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -2- 基 ) 甲基 ] 氮雜環丁烷 -1- 甲酸苯甲酯
根據GP C (條件A),在室溫下,使8-甲基-N
-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧醯胺(中間物43;1.00 eq.,192 mg,637 µmol)與3-氟-3-(羥基甲基)氮雜環丁烷-1-甲酸苯甲酯(CAS編號[1374658-54-4];1.50 eq.,229 mg,956 µmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,250 µL,1.0 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,336 mg,1.95 mmol)在甲苯(6 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(219 mg,64%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.60 (m, 1H), 1.75-1.90 (m, 3H), 2.47 (s, 3H), 2.81-2.91 (m, 4H), 3.20-3.27 (m, 2H), 3.58-3.64 (m, 1H), 3.73-3.79 (m, 1H), 3.91-4.05 (m, 3H), 4.30-4.37 (m, 2H), 4.62 (d, 2H), 5.05 (s, 2H), 7.30-7.38 (m, 5H), 7.53 (s, 1H), 8.00 (t, 1H)。
UPLC-MS (方法1
): Rt
= 1.20 min; MS (ESIpos): m/z = 523 [M+H]+
。
實例 156 : 3-[(8- 甲基 -7-{[(2S)- 四氫呋喃 -2- 基甲基 ] 胺甲醯基 }-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -2- 基 ) 甲基 ] 氮雜環丁烷 -1- 甲酸苯甲酯
根據GP C (條件A),在室溫下,使得自步驟1的8-甲基-N
-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-1H
-呋喃并[2,3-g]吲唑-7-羧醯胺(中間物43;1.00 eq.,233 mg,773 µmol)與3-(羥基甲基)氮雜環丁烷-1-甲酸苯甲酯(CAS編號[618446-42-7];1.50 eq.,208 µL,1.16 mmol)、三-正丁基膦(CAS編號[998-40-3];1.6 eq.,310 µL,1.2 mmol)及TMAD (CAS編號[10465-78-8];1.60 eq.,213 mg,1.24 mmol)在甲苯(15 mL)中反應隔夜,管柱層析(SiO2
,己烷/EtOAc)後,得到標題化合物(420 mg,80%純度,86%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.61 (m, 1H), 1.73-1.91 (m, 3H), 2.46 (s, 3H), 2.81-2.90 (m, 4H), 2.95-3.05 (m, 1H), 3.18-3.28 (m, 2H), 3.58-3.64 (m, 1H), 3.73-3.78 (m, 3H), 3.91-3.97 (m, 3H), 4.29 (d, 2H), 5.01 (s, 2H), 7.28-7.38 (m, 5H), 7.54 (s, 1H), 7.98 (t, 1H)。
UPLC-MS (方法1
): Rt
= 1.15 min; MS (ESIpos): m/z = 505 [M+H]+
.實例 157: 2-[(3- 氟氮雜環丁 -3- 基 ) 甲基 ]-8- 甲基 -N
-[(2S)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
3-氟-3-[(8-甲基-7-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-2-基)甲基]氮雜環丁烷-1-甲酸苯甲酯(實例155;1.00 eq.,207 mg,396 µmol)於乙醇(5 mL)中之攪拌溶液用氬氣淨化3次,用鈀(10%/炭;10 mol%,4.2 mg,3.9 µmol)處理且再次抽真空。將反應混合物設置於氫氣氛圍下且在室溫下攪拌隔夜。由於轉化不完全,因此經矽藻土過濾混合物且殘餘物用乙醇沖洗且隨後用乙醇與二氯甲烷(1:1)之混合物沖洗。在減壓下濃縮濾液且使所得物質經受如上文所述的氫化條件且再次攪拌隔夜。經矽藻土過濾反應混合物且殘餘物用乙醇沖洗且隨後用乙醇與二氯甲烷(1:1)之混合物沖洗。在減壓下濃縮濾液,得到粗標題化合物(189 mg,78%純度,99%)。對少量粗產物(28 mg)進行製備型HPLC,得到分析純溶離份(5.8 mg)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.61 (m, 1H), 1.75-1.91 (m, 3H), 2.48 (s, 3H), 2.83-2.91 (m, 4H), 3.18-3.28 (m, 2H), 3.49-3.64 (m, 5H), 3.73-3.79 (m, 1H), 3.91-3.98 (m, 1H), 4.50 (s, 1H), 4.56 (s, 1H), 7.47 (s, 1H), 7.99 (t, 1H)。
LC-MS (方法A
): Rt
= 0.89 min; MS (ESIpos): m/z = 389 [M+H]+
。
實例 158 : 2-( 氮雜環丁 -3- 基甲基 )-8- 甲基 -N
-[(2S)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
類似於實例157,使3-[(8-甲基-7-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-2-基)甲基]氮雜環丁烷-1-甲酸苯甲酯(實例156;1.00 eq.,350 mg,694 µmol)在乙醇(6 mL)中、在室溫下、在鈀(10%/炭;10 mol%,7.4 mg,7.0 µmol)及鹽酸水溶液(1 N,500 µL)存在下氫化,管柱層析(Si-NH SiO2
,DCM/MeOH)後,得到標題化合物(105 mg,43%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.61 (m, 1H), 1.74-1.91 (m, 3H), 2.46 (s, 3H), 2.81-2.90 (m, 4H), 2.95-3.02 (m, 1H), 3.18-3.28 (m, 4H), 3.46-3.50 (m, 1H), 3.58-3.64 (m, 2H), 3.73-3.78 (m, 1H), 3.84 (t, 1H), 3.91-3.97 (m, 1H), 4.24 (d, 2H), 7.49 (s, 1H), 7.97 (t, 1H)。
UPLC-MS (方法1
): Rt
= 0.86 min; MS (ESIpos): m/z = 371 [M+H]+
。
實例 159 : 2-( 氮雜環丁 -3- 基甲基 )-N
-[(2R)-1,4- 二㗁烷 -2- 基甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
3-[(7-{[(2R)-1,4-二㗁烷-2-基甲基]胺甲醯基}-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-2-基)甲基]氮雜環丁烷-1-甲酸第三丁酯(實例110;1.0 eq.,27 mg,56 µmol)於CPME (2 mL)中的混合物用鹽酸(3 M於CPME中;CAS編號[7647-01-0];10 eq.,180 µL,550 µmol)處理且在室溫下攪拌18小時。將所形成的沈澱物濾出且藉由製備型HPLC純化,得到標題化合物(3.7 mg,17%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.46 (s, 3H), 2.81-2.89 (m, 4H), 2.94-3.01 (m, 1H), 3.14-3.29 (m, 5H), 3.41-3.57 (m, 4H), 3.59-3.65 (m, 2H), 3.68-3.74 (m, 2H), 3.82 (t, 1H), 4.24 (d, 2H), 7.49-7.53 (m, 1H), 8.05 (t, 1H)。
LC-MS (方法A
): Rt
= 0.81 min; MS (ESIpos): m/z = 387 [M+H]+
。
實例 160 : 2-(2- 胺基乙基 )-8- 甲基 -N
-[(2S)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
[2-(8-甲基-7-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-2-基)乙基]胺基甲酸第三丁酯(實例139;1.00 eq.,118 mg,265 µmol)於二氯甲烷(1.5 mL)中的混合物用TFA (CAS編號[76-05-1];10 eq.,200 µL,2.7 mmol)處理且在室溫下攪拌隔夜。反應混合物用二氯甲烷及飽和碳酸氫鈉水溶液稀釋且分離各相。水相用乙酸乙酯萃取(兩次),合併之有機相用疏水性過濾器且在減壓下濃縮。所得TFA鹽用二氯甲烷溶解且在室溫下、在攪拌下用10%氫氧化銨水溶液處理。分離各相,且在減壓下濃縮有機相,得到呈游離鹼形式之粗標題化合物(52 mg,51%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.61 (m, 1H), 1.78-1.89 (m, 3H), 2.47 (s, 3H), 2.82-2.91 (m, 6H), 3.18-3.27 (m, 2H), 3.58-3.64 (m, 1H), 3.73-3.79 (m, 1H), 3.91-3.98 (m, 1H), 3.99-4.05 (m, 2H), 7.49 (s, 1H), 7.97 (t, 1H)。
UPLC-MS (方法1
): Rt
= 0.82 min; MS (ESIpos): m/z = 345 [M+H]+
。
實例 161 : 2-(2- 胺基乙基 )-N
-[(2R)-1,4- 二㗁烷 -2- 基甲基 ]-8- 甲基 -4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
類似於實例160,在室溫下,使[2-(7-{[(2R)-1,4-二㗁烷-2-基甲基]胺甲醯基}-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-2-基)乙基]胺基甲酸第三丁酯(實例140;1.0 eq.,64 mg,139 µmol)與TFA (CAS編號[76-05-1];10 eq.,110 µL,1.4 mmol)在二氯甲烷(1 mL)中反應隔夜,處理後,得到粗標題化合物(21 mg,38%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.47 (s, 3H), 2.83-2.92 (m, 6H), 3.15-3.25 (m, 3H), 3.44 (dt, 1H), 3.54 (dt, 1H), 3.59-3.65 (m, 2H), 3.68-3.74 (m, 2H), 4.03 (t, 2H), 7.49 (s, 1H), 8.05 (t, 1H)。
UPLC-MS (方法1
): Rt
= 0.75 min; MS (ESIpos): m/z = 361 [M+H]+
。
實例 162 : 8- 甲基 -2-[2-( 哌 𠯤 -1- 基 ) 乙基 ]-N
-[(2S)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
類似於實例160,在室溫下,使4-[2-(8-甲基-7-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-2-基)乙基]哌𠯤-1-甲酸第三丁酯(實例141;1.00 eq.,215 mg,419 µmol)與TFA (CAS編號[76-05-1];10 eq.,320 µL,4.2 mmol)在二氯甲烷(2.5 mL)中反應隔夜,處理後,得到粗標題化合物(82 mg,40%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.61 (m, 1H), 1.76-1.90 (m, 3H), 2.35 (br. s., 4H), 2.47 (s, 3H), 2.60-2.69 (m, 6H), 2.81-2.90 (m, 4H), 3.18-3.27 (m, 2H), 3.57-3.64 (m, 1H), 3.71-3.80 (m, 1H), 3.91-3.97 (m, 1H), 4.15 (t, 2H), 7.50 (s, 1H), 7.97 (t, 1H)。
UPLC-MS (方法1
): Rt
= 0.86 min; MS (ESIpos): m/z = 414 [M+H]+
。
實例 163: N -[(2R)-1,4- 二㗁烷 -2- 基甲基 ]-8- 甲基 -2-[2-( 哌 𠯤 -1- 基 ) 乙基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
類似於實例160,在室溫下,使4-[2-(7-{[(2R)-1,4-二㗁烷-2-基甲基]胺甲醯基}-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-2-基)乙基]哌𠯤-1-甲酸第三丁酯(實例142;1.00 eq.,151 mg,285 µmol)與TFA (CAS編號[76-05-1];10 eq.,220 µL,2.9 mmol)在二氯甲烷(1.5 mL)反應隔夜,處理後,得到粗標題化合物(30 mg,21%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.35 (br. s., 4H), 2.47 (s, 3H), 2.62-2.69 (m, 6H), 2.81-2.91 (m, 4H), 3.16-3.26 (m, 3H), 3.45 (dt, 1H), 3.54 (dt, 1H), 3.59-3.65 (m, 2H), 3.68-3.74 (m, 2H), 4.15 (t, 2H), 7.51 (s, 1H), 8.05 (t, 1H)。
UPLC-MS (方法1
): Rt
= 0.76 min; MS (ESIpos): m/z = 430 [M+H]+
。
實例 164 : 2-[(1- 乙醯基氮雜環丁 -3- 基 ) 甲基 ]-8- 甲基 -N-[(2S)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
2-(氮雜環丁-3-基甲基)-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-7-羧醯胺(實例158;1.00 eq.,60.0 mg,162 µmol)於二氯甲烷(2 mL)中的溶液用乙醯氯(CAS編號[75-36-5];1.0 eq.,12 µL,160 µmol)及三乙胺(1.5 eq.,34 µL,240 µmol)處理且在室溫下攪拌5小時。反應混合物用水及乙酸乙酯淬滅。分離各相,且用乙酸乙酯萃取水相。合併之有機相用疏水性過濾器過濾,在減壓下濃縮且對所得物質進行製備型HPLC,得到標題化合物(1.6 mg,2%)。
LC-MS (方法A
): Rt
= 0.88 min; MS (ESIpos): m/z = 413 [M+H]+
。
實例 165 : 2-[(1- 乙醯基 -3- 氟氮雜環丁 -3- 基 ) 甲基 ]-8- 甲基 -N
-[(2S)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
2-[(3-氟氮雜環丁-3-基)甲基]-8-甲基-N
-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-
呋喃并[2,3-g]吲唑-7-羧醯胺(實例157;1.00 eq.,53.0 mg,136 µmol)於DMF (1.5 mL)中的溶液用乙醯氯(CAS編號[75-36-5];1.0 eq.,10 µL,140 µmol)及三乙胺(1.5 eq.,29 µL,200 µmol)處理且在室溫下攪拌3小時。反應混合物用水及乙酸乙酯淬滅。分離各相,且用乙酸乙酯萃取水相。合併之有機相用疏水性過濾器過濾,在減壓下濃縮且對所得物質進行製備型HPLC,得到標題化合物(14 mg,22%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.61 (m, 1H), 1.75-1.90 (m, 6H), 2.48 (s, 3H), 2.83-2.92 (m, 4H), 3.18-3.27 (m, 2H), 3.58-3.64 (m, 1H), 3.73-3.79 (m, 1H), 3.82-3.98 (m, 2H), 4.18-4.28 (m, 2H), 4.41-4.50 (m, 1H), 4.59 (s, 1H), 4.65 (s, 1H), 7.53 (s, 1H), 8.00 (t, 1H)。
LC-MS (方法A
): Rt
= 0.92 min; MS (ESIpos): m/z = 431 [M+H]+
。
實例 166 : 2-{[3- 氟 -1-( 甲基磺醯基 ) 氮雜環丁 -3- 基 ] 甲基 }-8- 甲基 -N
-[(2S)- 四氫呋喃 -2- 基甲基 ]-4,5- 二氫 -2H
- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
2-[(3-氟氮雜環丁-3-基)甲基]-8-甲基-N
-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧醯胺(實例157;1.00 eq.,53.0 mg,136 µmol)於DMF (1.5 mL)中的溶液用甲磺醯氯(CAS編號[124-63-0];1.0 eq.,11 µL,140 µmol)及三乙胺(1.5 eq.,29 µL,200 µmol)處理且在室溫下攪拌3小時。反應混合物用水及乙酸乙酯淬滅。分離各相,且用乙酸乙酯萃取水相。合併之有機相用疏水性過濾器過濾,在減壓下濃縮且對所得物質進行製備型HPLC,得到標題化合物(12 mg,18%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.61 (m, 1H), 1.76-1.91 (m, 3H), 2.48 (s, 3H), 2.83-2.92 (m, 4H), 3.08 (s, 3H), 3.21-3.25 (m, 2H), 3.58-3.64 (m, 1H), 3.73-3.79 (m, 1H), 3.91-3.98 (m, 1H), 4.05-4.13 (m, 2H), 4.19-4.26 (m, 2H), 4.59 (s, 1H), 4.64 (s, 1H), 7.56 (s, 1H), 8.00 (t, 1H)。
LC-MS (方法A
): Rt
= 0.98 min; MS (ESIpos): m/z = 467 [M+H]+
。
實例 167: 3- 氟 -3-[(8- 甲基 -7-{[(2S)- 四氫呋喃 -2- 基甲基 ] 胺甲醯基 }-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -2- 基 ) 甲基 ] 氮雜環丁烷 -1- 羧酸甲酯
2-[(3-氟氮雜環丁-3-基)甲基]-8-甲基-N
-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H
-呋喃并[2,3-g]吲唑-7-羧醯胺(實例157;1.00 eq.,53.0 mg,136 µmol)於DMF (1.5 mL)中的溶液用氯羧酸甲酯(CAS編號[79-22-1];1.0 eq.,11 µL,140 µmol)及三乙胺(1.5 eq.,29 µL,200 µmol)處理且在室溫下攪拌3小時。反應混合物用水及乙酸乙酯淬滅。分離各相,且用乙酸乙酯萃取水相。合併之有機相用疏水性過濾器過濾,在減壓下濃縮且對所得物質進行製備型HPLC,得到標題化合物(9.5 mg,15%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.61 (m, 1H), 1.76-1.91 (m, 3H), 2.47 (s, 3H), 2.83-2.92 (m, 4H), 3.18-3.28 (m, 2H), 3.57-3.64 (m, 4H), 3.73-3.79 (m, 1H), 3.91-4.03 (m, 3H), 4.26-4.33 (m, 2H), 4.58 (s, 1H), 4.64 (s, 1H), 7.52 (s, 1H), 8.00 (t, 1H)。
LC-MS (方法A
): Rt
= 1.01 min; MS (ESIpos): m/z = 447 [M+H]+
。
實例 168 : 2'-[(2S)-1,4- 二㗁烷 -2- 基甲基 ]-N
-[(2S)- 四氫呋喃 -2- 基甲基 ]-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧醯胺
根據GP G (條件A),在室溫下,使2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-甲酸(中間物50;1.0 eq.,45 mg,110 µmol)與1-[(2S)-四氫呋喃-2-基]甲胺(CAS編號[7175-81-7];1.5 eq.,17 µL,170 µmol)、HATU (CAS編號[148893-10-1];1.5 eq.,64 mg,170 µmol)及N,N-
二異丙基乙胺(CAS編號[7087-68-5];3.0 eq.,59 µL,340 µmol)在DMF (1.5 mL)中反應5天,製備型HPLC後,得到標題化合物(26 mg,45%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.80-0.91 (m, 4H), 1.54-1.60 (m, 1H), 1.77-1.94 (m, 3H), 2.86-2.96 (m, 2H), 3.22-3.29 (m, 3H), 3.43 (dt, 1H), 3.53 (dt, 1H), 3.60-3.65 (m, 2H), 3.71-3.83 (m, 4H), 3.83-3.98 (m, 1H), 4.00-4.10 (m, 2H), 7.35 (s, 1H), 8.72 (t, 1H)。19
F NMR (377 MHz, DMSO-d6) δ [ppm]: -55.15 (s, 3F)。
UPLC-MS (方法1
): Rt
= 1.09 min; MS (ESIpos): m/z = 482 [M+H]+
。
實例 169: N -{[(2R)-1,4- 二㗁烷 -2- 基 ] 甲基 }-2'-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8'-( 三氟甲基 )-2',5'- 二氫螺 [ 環丙烷 -1,4'- 呋喃并 [2,3-g] 吲唑 ]-7'- 羧醯胺
根據GP G (條件A),在室溫下,使2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-甲酸(中間物50;1.0 eq.,45 mg,110 µmol)與1-[(2R)-1,4-二㗁烷-2-基]甲胺鹽酸鹽(1:1)(CAS編號[1523541-84-5];1.2 eq.,21 mg,140 µmol)、HATU (CAS編號[148893-10-1];1.5 eq.,64 mg,170 µmol)及N,N-
二異丙基乙胺(CAS編號[7087-68-5];3.0 eq.,59 µL,340 µmol)在DMF (1.5 mL)中反應5天,製備型HPLC後,得到標題化合物(29 mg,50%)。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.80-0.92 (m, 4H), 2.86-2.96 (m, 2H), 3.19-3.30 (m, 4H), 3.40-3.48 (m, 2H), 3.50-3.58 (m, 2H), 3.58-3.66 (m, 3H), 3.70-3.75 (m, 4H), 3.80-3.84 (m, 1H), 4.00-4.10 (m, 2H), 7.35 (s, 1H), 8.76 (t, 1H)。19
F NMR (377 MHz, DMSO-d6) δ [ppm]: -54.99 (s, 3F)。
UPLC-MS (方法1
): Rt
= 1.00 min; MS (ESIpos): m/z = 498 [M+H]+
。表 4 : 以給定中間物及市售胺 ( 或其鹽 ) 為起始物, 應用指定的通用程序 , 類似於實例 3 來製備以下實例 (170 至 211) 。
表 5 : 以給定中間物及市售胺 ( 或其鹽 ) 為起始物, 應用指定的通用程序 , 類似於實例 169 來製備以下實例 (212 至 316) 。
實例 | 結構 IUPAC- 名稱 | 分析型資料 | 製備或分離方法 |
170 | N-{[(2±)-5,5-二甲基氧雜環戊-2-基]甲基}-8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.863 (0.47), 0.881 (1.20), 0.899 (0.59), 1.139 (12.49), 1.151 (1.29), 1.200 (12.39), 1.219 (1.24), 1.234 (0.41), 1.649 (0.56), 1.657 (0.70), 1.673 (2.40), 1.679 (3.40), 1.683 (3.55), 1.702 (0.89), 1.718 (0.43), 1.723 (0.43), 1.937 (0.42), 1.951 (0.74), 1.961 (0.46), 1.973 (0.63), 2.338 (0.85), 2.442 (16.00), 2.520 (8.44), 2.525 (5.93), 2.680 (0.80), 2.743 (1.44), 2.885 (2.85), 2.892 (8.97), 2.899 (3.06), 3.205 (0.93), 3.215 (1.01), 3.221 (1.75), 3.229 (1.73), 3.236 (1.04), 3.244 (0.99), 4.009 (0.74), 4.024 (0.98), 4.039 (0.59), 5.384 (6.36), 5.807 (0.54), 7.060 (1.75), 7.080 (1.82), 7.291 (0.87), 7.294 (0.91), 7.303 (0.91), 7.306 (0.98), 7.312 (1.24), 7.322 (1.05), 7.325 (0.96), 7.335 (0.46), 7.635 (5.02), 7.752 (1.05), 7.757 (1.10), 7.761 (0.45), 7.771 (1.83), 7.776 (1.88), 7.790 (1.00), 7.795 (0.98), 7.903 (0.67), 7.918 (1.40), 7.933 (0.66), 8.529 (1.11), 8.531 (1.31), 8.534 (1.31), 8.536 (1.27), 8.541 (1.25), 8.543 (1.41), 8.546 (1.28), 8.548 (1.22), 8.637 (0.60). LC-MS (方法1): Rt = 1.15 min; MS (ESIpos): m/z = 421 [M+H]+ | 中間物2 GP H 條件B 2 mg,1%產率,95%純度 外消旋物 |
171 | 8-甲基-N-[(㗁烷-4-基)甲基]-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (8.00), 1.111 (0.46), 1.130 (0.97), 1.141 (1.10), 1.162 (1.17), 1.173 (1.06), 1.192 (0.53), 1.203 (0.47), 1.531 (1.51), 1.564 (1.25), 1.729 (0.40), 1.739 (0.44), 1.749 (0.51), 1.758 (0.61), 1.767 (0.46), 2.306 (0.69), 2.404 (0.71), 2.438 (16.00), 2.522 (2.75), 2.673 (0.72), 2.880 (4.00), 2.888 (9.86), 2.895 (3.71), 3.063 (1.85), 3.079 (2.92), 3.096 (1.69), 3.207 (1.10), 3.211 (1.25), 3.236 (2.26), 3.240 (2.27), 3.265 (1.38), 3.808 (1.45), 3.815 (1.43), 3.837 (1.34), 3.843 (1.25), 5.380 (7.22), 7.056 (1.87), 7.076 (1.96), 7.289 (0.99), 7.291 (1.00), 7.303 (1.12), 7.308 (1.16), 7.320 (1.09), 7.629 (5.18), 7.749 (1.12), 7.754 (1.09), 7.769 (1.84), 7.773 (1.82), 7.788 (0.95), 7.792 (0.91), 8.116 (0.75), 8.132 (1.55), 8.146 (0.72), 8.529 (1.52), 8.531 (1.54), 8.541 (1.48), 8.543 (1.44). LC-MS (方法1): Rt = 0.98 min; MS (ESIneg): m/z = 405 [M-H]⁻ | 中間物2 GP H 條件B 30 mg,22%產率,95%純度 |
172 | 8-甲基-N-{[(2±)-㗁烷-2-基]甲基}-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (1.90), 0.948 (1.85), 1.103 (0.28), 1.108 (0.28), 1.132 (0.49), 1.144 (0.36), 1.149 (0.33), 1.408 (0.86), 1.410 (0.86), 1.415 (0.89), 1.425 (1.27), 1.536 (0.48), 1.539 (0.43), 1.565 (0.39), 1.568 (0.41), 1.741 (0.48), 1.745 (0.45), 1.747 (0.47), 1.750 (0.51), 1.754 (0.51), 1.765 (0.37), 2.331 (4.37), 2.404 (8.20), 2.522 (16.00), 2.669 (5.89), 2.673 (4.34), 2.788 (0.39), 2.798 (0.51), 2.807 (1.40), 2.824 (1.28), 2.852 (1.35), 2.870 (1.47), 2.877 (0.46), 2.879 (0.52), 3.155 (0.63), 3.165 (0.72), 3.171 (1.07), 3.179 (1.09), 3.187 (0.81), 3.193 (0.74), 3.828 (0.46), 3.834 (0.54), 3.855 (0.45), 3.864 (0.44), 5.619 (3.04), 6.806 (0.98), 6.825 (0.97), 7.261 (0.53), 7.275 (0.60), 7.280 (0.57), 7.293 (0.58), 7.422 (3.27), 7.710 (0.57), 7.715 (0.55), 7.730 (0.95), 7.735 (0.91), 7.749 (0.47), 7.754 (0.50), 8.035 (0.83), 8.520 (0.80), 8.522 (0.82), 8.524 (0.78), 8.532 (0.87), 8.534 (0.82), 8.545 (0.87). LC-MS (方法1): Rt = 1.09 min; MS (ESIpos): m/z = 407 [M+H]⁺ | 中間物2 GP H 條件B 1.3 mg,1%產率,95%純度 外消旋物 |
173 | 8-甲基-N-{[(2±)-2-甲基氧雜環戊-2-基]甲基}-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.934 (0.66), 0.951 (0.67), 1.100 (0.73), 1.119 (13.39), 1.518 (0.61), 1.529 (0.76), 1.536 (0.81), 1.549 (0.63), 1.829 (0.41), 1.845 (1.15), 1.855 (2.27), 1.862 (2.14), 1.868 (2.50), 1.875 (1.78), 1.884 (1.17), 2.334 (1.63), 2.338 (0.73), 2.412 (0.72), 2.448 (16.00), 2.520 (7.88), 2.525 (5.08), 2.676 (1.67), 2.680 (0.74), 2.866 (0.46), 2.885 (2.62), 2.895 (4.63), 2.899 (4.89), 2.910 (3.13), 3.233 (1.92), 3.240 (1.80), 3.248 (1.77), 3.256 (1.85), 3.722 (1.55), 3.738 (2.82), 3.754 (1.43), 5.385 (6.60), 7.057 (1.74), 7.077 (1.81), 7.294 (0.91), 7.306 (0.99), 7.310 (1.02), 7.322 (0.95), 7.325 (0.92), 7.636 (4.92), 7.689 (0.67), 7.705 (1.40), 7.721 (0.68), 7.752 (1.04), 7.757 (1.08), 7.771 (1.79), 7.776 (1.80), 7.790 (0.92), 7.795 (0.89), 8.530 (1.14), 8.532 (1.34), 8.534 (1.36), 8.537 (1.20), 8.542 (1.12), 8.544 (1.30), 8.546 (1.23), 8.549 (1.10). LC-MS (方法1): Rt = 1.08 min; MS (ESIneg): m/z = 405 [M-H]⁻ | 中間物2 GP H 條件B 29 mg,21%產率,95%純度 外消旋物 |
174 | N-{[(2±)-4,4-二氟氧雜環戊-2-基]甲基}-8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.882 (0.64), 2.334 (1.13), 2.338 (0.49), 2.447 (16.00), 2.520 (5.45), 2.525 (3.48), 2.539 (0.61), 2.680 (0.50), 2.888 (2.67), 2.896 (7.77), 2.905 (3.08), 3.357 (1.39), 3.371 (0.67), 3.406 (0.52), 3.422 (0.98), 3.438 (0.73), 3.456 (0.52), 3.792 (0.46), 3.819 (0.63), 3.823 (0.60), 3.831 (0.46), 3.850 (0.62), 3.857 (0.63), 3.889 (0.52), 4.009 (0.44), 4.038 (1.15), 4.067 (1.03), 4.253 (0.64), 4.270 (0.94), 4.287 (0.58), 5.385 (6.33), 7.063 (1.70), 7.083 (1.77), 7.292 (0.89), 7.294 (0.88), 7.304 (0.92), 7.306 (0.95), 7.311 (1.01), 7.313 (0.93), 7.323 (0.99), 7.325 (0.91), 7.638 (4.94), 7.753 (1.09), 7.757 (1.10), 7.772 (1.78), 7.776 (1.72), 7.791 (0.93), 7.796 (0.92), 8.166 (0.65), 8.181 (1.39), 8.196 (0.65), 8.530 (1.14), 8.532 (1.28), 8.534 (1.32), 8.536 (1.17), 8.542 (1.21), 8.544 (1.30), 8.546 (1.25), 8.548 (1.08). LC-MS (方法1): Rt = 1.06 min; MS (ESIpos): m/z = 429 [M+H]+ | 中間物2 GP H 條件B 33 mg,23%產率,95%純度 外消旋物 |
175 | 8-甲基-N-[(4-甲基四氫呋喃-2-基)甲基]-2-(2-吡啶基甲基)-4,5-二氫呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.956 (1.90), 0.972 (2.18), 0.979 (6.50), 0.996 (6.72), 1.116 (0.43), 1.138 (0.80), 1.147 (0.50), 1.160 (0.48), 1.169 (0.83), 1.190 (0.47), 1.460 (0.11), 1.478 (0.18), 1.491 (0.14), 1.496 (0.13), 1.509 (0.22), 1.527 (0.14), 1.775 (0.12), 1.789 (0.12), 1.794 (0.14), 1.808 (0.16), 1.819 (0.11), 1.825 (0.12), 1.839 (0.12), 2.062 (0.35), 2.080 (0.57), 2.097 (0.55), 2.111 (0.57), 2.127 (0.45), 2.204 (0.32), 2.224 (0.48), 2.242 (0.47), 2.262 (0.33), 2.332 (0.68), 2.439 (16.00), 2.518 (3.03), 2.523 (2.10), 2.594 (0.19), 2.673 (0.68), 2.740 (0.21), 2.882 (2.93), 2.889 (8.94), 2.896 (3.14), 3.138 (0.27), 3.159 (0.35), 3.177 (0.30), 3.195 (0.35), 3.211 (0.67), 3.222 (1.25), 3.242 (2.27), 3.262 (2.15), 3.276 (1.85), 3.294 (1.09), 3.750 (1.04), 3.769 (1.44), 3.788 (0.97), 3.863 (0.28), 3.880 (0.32), 3.900 (0.25), 3.934 (0.22), 3.950 (0.65), 3.965 (0.67), 3.971 (0.67), 3.981 (0.29), 3.986 (0.57), 4.002 (0.19), 4.026 (0.16), 4.041 (0.18), 4.045 (0.17), 4.059 (0.14), 5.382 (6.26), 7.058 (1.60), 7.078 (1.66), 7.289 (0.87), 7.291 (0.84), 7.300 (0.89), 7.303 (0.93), 7.307 (1.01), 7.310 (0.95), 7.319 (0.99), 7.632 (5.02), 7.749 (1.08), 7.754 (1.05), 7.769 (1.71), 7.773 (1.77), 7.788 (0.95), 7.792 (0.94), 7.957 (0.66), 7.972 (1.39), 7.986 (0.64), 8.527 (1.10), 8.529 (1.29), 8.532 (1.29), 8.534 (1.15), 8.539 (1.14), 8.541 (1.29), 8.544 (1.22), 8.546 (1.05). LC-MS (方法1): Rt = 1.07 min; MS (ESIpos): m/z = 407 [M+H]+ | 中間物2 GP H 條件B 29 mg,21%產率,95%純度 四種異構體的混合物 |
176 | 8-甲基-N-{[(2±,5±)-5-甲基氧雜環戊-2-基]甲基}-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.104 (1.59), 1.120 (1.62), 1.153 (7.15), 1.168 (7.28), 1.351 (0.48), 1.370 (0.60), 1.389 (0.45), 1.399 (0.45), 1.417 (0.26), 1.565 (0.11), 1.576 (0.09), 1.582 (0.12), 1.597 (0.14), 1.606 (0.26), 1.618 (0.33), 1.621 (0.29), 1.634 (0.46), 1.640 (0.31), 1.649 (0.48), 1.652 (0.41), 1.659 (0.40), 1.663 (0.41), 1.668 (0.27), 1.675 (0.33), 1.821 (0.24), 1.840 (0.50), 1.861 (0.76), 1.873 (0.44), 1.878 (0.49), 1.890 (0.71), 1.896 (0.84), 1.904 (0.63), 1.911 (0.57), 1.913 (0.56), 1.925 (0.50), 1.928 (0.48), 1.932 (0.38), 1.933 (0.36), 1.939 (0.39), 1.946 (0.34), 1.949 (0.30), 1.961 (0.28), 1.968 (0.16), 1.974 (0.14), 1.981 (0.15), 1.986 (0.12), 1.990 (0.13), 1.996 (0.11), 2.000 (0.07), 2.004 (0.11), 2.010 (0.08), 2.014 (0.07), 2.025 (0.07), 2.443 (16.00), 2.520 (2.07), 2.525 (1.40), 2.885 (2.97), 2.892 (8.72), 2.899 (3.06), 3.206 (0.35), 3.226 (1.49), 3.241 (2.87), 3.256 (1.54), 3.847 (0.53), 3.862 (0.86), 3.877 (0.65), 3.882 (0.65), 3.897 (0.51), 3.905 (0.74), 3.920 (0.95), 3.937 (0.68), 3.952 (0.19), 4.007 (0.11), 4.023 (0.19), 4.027 (0.12), 4.038 (0.15), 4.042 (0.17), 4.056 (0.14), 4.061 (0.19), 4.077 (0.25), 4.093 (0.16), 5.384 (6.63), 7.061 (1.79), 7.080 (1.86), 7.290 (0.91), 7.293 (0.88), 7.302 (0.94), 7.306 (0.97), 7.309 (1.06), 7.321 (1.02), 7.635 (5.13), 7.752 (1.10), 7.756 (1.07), 7.771 (1.77), 7.776 (1.81), 7.790 (0.95), 7.795 (0.94), 7.944 (0.59), 7.959 (1.29), 7.974 (0.67), 8.529 (1.17), 8.531 (1.34), 8.534 (1.34), 8.536 (1.18), 8.541 (1.19), 8.543 (1.33), 8.546 (1.25), 8.548 (1.08). LC-MS (方法1): Rt = 1.07 min; MS (ESIpos): m/z = 407 [M+H]+ | 中間物2 GP H 條件B 39 mg,28%產率,95%純度 反式與順式異構體的混合物 |
177 | 2,5-去氫-1,3,4-三去氧-3-甲基-1-({8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羰基}胺基)-D-蘇式-戊糖醇(外消旋物) | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.928 (7.56), 0.946 (7.81), 0.957 (0.56), 1.509 (0.50), 1.513 (0.41), 1.523 (0.70), 1.527 (0.58), 1.538 (0.61), 1.543 (0.75), 1.553 (0.49), 1.557 (0.57), 2.011 (0.44), 2.016 (0.55), 2.026 (0.44), 2.029 (0.61), 2.035 (0.57), 2.041 (0.46), 2.044 (0.54), 2.050 (0.55), 2.060 (0.57), 2.065 (0.47), 2.235 (0.59), 2.253 (0.83), 2.270 (0.56), 2.334 (1.01), 2.338 (0.45), 2.441 (16.00), 2.520 (5.28), 2.525 (3.36), 2.676 (1.04), 2.680 (0.46), 2.742 (0.74), 2.883 (2.64), 2.892 (7.32), 2.901 (3.19), 3.133 (0.45), 3.140 (0.43), 3.153 (1.02), 3.166 (0.54), 3.173 (0.69), 3.187 (0.57), 3.298 (0.73), 3.313 (1.53), 3.359 (0.85), 3.583 (0.65), 3.598 (0.78), 3.603 (1.65), 3.619 (1.61), 3.624 (0.96), 3.640 (0.82), 3.792 (0.70), 3.808 (0.81), 3.813 (1.37), 3.827 (1.35), 3.832 (0.72), 3.847 (0.57), 3.862 (0.63), 3.874 (0.84), 3.883 (0.72), 3.890 (0.74), 3.897 (0.80), 3.910 (0.55), 5.384 (6.41), 7.061 (1.72), 7.081 (1.81), 7.290 (0.84), 7.294 (0.87), 7.302 (0.87), 7.306 (0.96), 7.309 (1.03), 7.312 (0.93), 7.321 (1.09), 7.325 (0.95), 7.634 (4.83), 7.752 (1.01), 7.757 (1.12), 7.771 (1.82), 7.776 (1.87), 7.790 (0.98), 7.795 (0.96), 7.822 (0.69), 7.837 (1.30), 7.851 (0.69), 8.529 (1.08), 8.531 (1.25), 8.534 (1.32), 8.536 (1.21), 8.541 (1.20), 8.543 (1.35), 8.546 (1.34), 8.548 (1.20). LC-MS (方法1): Rt = 1.08 min; MS (ESIpos): m/z = 407 [M+H]⁺ | 中間物2 GP H 條件B 15 mg,11%產率,92%純度 外消旋物 |
178 | 8-甲基-N-{[(6±)-5-氧雜螺[2.4]庚-6-基]甲基}-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.496 (0.58), 0.512 (1.19), 0.528 (1.19), 0.569 (0.89), 0.581 (2.01), 0.585 (1.46), 0.598 (2.72), 0.603 (2.02), 0.614 (1.35), 0.626 (1.53), 0.642 (0.91), 0.934 (0.46), 0.951 (0.47), 1.647 (0.94), 1.663 (0.97), 1.678 (1.23), 1.693 (1.23), 1.856 (1.19), 1.873 (1.35), 1.886 (1.03), 1.903 (0.95), 2.334 (0.87), 2.338 (0.41), 2.442 (16.00), 2.520 (4.59), 2.525 (2.85), 2.676 (0.87), 2.884 (3.05), 2.892 (9.13), 2.899 (3.40), 3.295 (0.45), 3.313 (1.85), 3.370 (0.54), 3.530 (1.87), 3.550 (3.24), 3.600 (3.36), 3.619 (2.00), 4.137 (1.04), 4.152 (1.52), 4.168 (1.02), 5.384 (6.73), 7.062 (1.82), 7.082 (1.89), 7.291 (0.91), 7.294 (0.92), 7.303 (0.96), 7.306 (1.01), 7.310 (1.07), 7.313 (1.01), 7.322 (1.04), 7.325 (0.99), 7.635 (5.20), 7.752 (1.09), 7.757 (1.08), 7.772 (1.77), 7.776 (1.82), 7.791 (0.96), 7.795 (0.96), 8.007 (0.72), 8.022 (1.53), 8.037 (0.72), 8.529 (1.18), 8.532 (1.33), 8.534 (1.40), 8.536 (1.20), 8.541 (1.24), 8.544 (1.39), 8.547 (1.54). LC-MS (方法1): Rt = 1.11 min; MS (ESIpos): m/z = 419 [M+H]+ | 中間物2 GP H 條件B 17 mg,12%產率,95%純度 外消旋物 |
179 | N-{[(2±)-3,3-二甲基氧雜環戊-2-基]甲基}-8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.938 (12.06), 1.049 (15.08), 1.685 (1.21), 1.698 (1.82), 1.704 (1.34), 1.718 (2.53), 1.737 (0.96), 2.334 (0.93), 2.338 (0.44), 2.440 (16.00), 2.520 (4.74), 2.525 (3.05), 2.676 (0.95), 2.680 (0.43), 2.883 (3.17), 2.889 (9.94), 2.896 (3.43), 3.067 (0.45), 3.080 (0.53), 3.088 (0.51), 3.101 (0.97), 3.115 (0.54), 3.122 (0.71), 3.136 (0.60), 3.365 (0.97), 3.374 (0.63), 3.383 (0.67), 3.389 (0.54), 3.398 (0.60), 3.469 (1.35), 3.479 (1.35), 3.491 (1.36), 3.500 (1.05), 3.644 (0.54), 3.657 (0.59), 3.665 (1.50), 3.677 (1.38), 3.686 (1.00), 3.698 (0.79), 3.736 (0.82), 3.755 (2.23), 3.776 (1.82), 3.795 (0.55), 5.384 (6.57), 7.058 (1.78), 7.078 (1.86), 7.290 (0.89), 7.293 (0.89), 7.302 (0.93), 7.305 (0.96), 7.309 (1.04), 7.312 (0.99), 7.322 (1.02), 7.324 (0.97), 7.634 (5.14), 7.752 (1.10), 7.756 (1.16), 7.771 (1.84), 7.775 (1.82), 7.790 (0.92), 7.795 (0.93), 7.871 (0.72), 7.885 (1.42), 7.900 (0.69), 8.529 (1.15), 8.531 (1.31), 8.534 (1.35), 8.536 (1.21), 8.541 (1.19), 8.543 (1.31), 8.546 (1.28), 8.548 (1.11). LC-MS (方法1): Rt = 1.16 min; MS (ESIpos): m/z = 421 [M+H]+ | 中間物2 GP H 條件B 16 mg,11%產率,95%純度 外消旋物 |
180 | N-{[(6±)-2,5-二氧雜螺[3.4]辛-6-基]甲基}-8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.588 (0.60), 1.604 (0.66), 1.619 (0.76), 1.635 (0.74), 1.876 (0.45), 1.891 (0.71), 1.910 (0.76), 1.925 (0.47), 2.048 (0.48), 2.068 (0.87), 2.080 (0.83), 2.087 (0.42), 2.099 (1.51), 2.119 (0.60), 2.160 (0.66), 2.174 (0.73), 2.180 (0.75), 2.193 (0.76), 2.206 (0.46), 2.211 (0.42), 2.443 (16.00), 2.520 (4.04), 2.525 (2.63), 2.888 (2.71), 2.897 (7.12), 2.907 (3.17), 3.182 (0.85), 3.197 (1.78), 3.209 (1.77), 3.224 (0.92), 4.054 (0.92), 4.070 (1.44), 4.086 (0.90), 4.442 (1.82), 4.451 (1.78), 4.458 (2.20), 4.467 (2.25), 4.557 (2.34), 4.574 (1.87), 4.586 (2.22), 4.602 (1.73), 5.385 (6.39), 7.061 (1.75), 7.080 (1.84), 7.291 (0.94), 7.294 (0.92), 7.303 (0.98), 7.306 (1.00), 7.310 (1.08), 7.313 (1.01), 7.322 (1.07), 7.325 (1.00), 7.636 (5.14), 7.752 (1.12), 7.757 (1.16), 7.771 (1.87), 7.776 (1.84), 7.790 (0.95), 7.795 (0.96), 8.052 (0.69), 8.067 (1.48), 8.082 (0.66), 8.529 (1.17), 8.532 (1.28), 8.534 (1.38), 8.536 (1.16), 8.541 (1.24), 8.544 (1.32), 8.546 (1.32), 8.548 (1.25). LC-MS (方法1): Rt = 0.95 min; MS (ESIpos): m/z = 435 [M+H]+ | 中間物2 GP H 條件B 16 mg,11%產率,95%純度 外消旋物 |
181 | N-{[(2±)-6,6-二甲基-1,4-二㗁烷-2-基]甲基}-8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.933 (0.84), 0.950 (0.85), 1.044 (12.82), 1.060 (0.44), 1.234 (10.78), 2.441 (16.00), 2.520 (4.37), 2.524 (2.68), 2.885 (2.95), 2.892 (8.94), 2.901 (3.36), 2.989 (0.41), 3.007 (1.09), 3.035 (1.77), 3.063 (1.24), 3.096 (1.66), 3.113 (1.03), 3.126 (2.12), 3.146 (2.12), 3.161 (0.87), 3.362 (0.44), 3.426 (2.29), 3.453 (1.93), 3.709 (1.05), 3.715 (1.18), 3.737 (0.98), 3.744 (1.06), 3.875 (0.54), 3.886 (0.48), 3.895 (0.58), 5.384 (6.59), 7.058 (1.81), 7.077 (1.91), 7.290 (0.90), 7.293 (0.89), 7.302 (0.96), 7.306 (1.00), 7.309 (1.14), 7.321 (1.07), 7.324 (0.98), 7.635 (5.32), 7.752 (1.08), 7.756 (1.15), 7.771 (1.89), 7.775 (1.90), 7.790 (1.00), 7.794 (0.94), 8.032 (0.73), 8.047 (1.51), 8.063 (0.70), 8.529 (1.19), 8.531 (1.36), 8.533 (1.39), 8.536 (1.26), 8.541 (1.24), 8.543 (1.43), 8.545 (1.32), 8.548 (1.20). LC-MS (方法1): Rt = 1.07 min; MS (ESIpos): m/z = 437 [M+H]+ | 中間物2 GP H 條件B 18 mg,12%產率,95%純度 外消旋物 |
182 | 2-[(4-氟吡啶-2-基)甲基]-8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.550 (0.49), 1.566 (0.70), 1.574 (0.51), 1.582 (0.59), 1.590 (0.44), 1.774 (0.54), 1.781 (0.68), 1.796 (1.22), 1.814 (1.36), 1.831 (1.29), 1.842 (0.73), 1.852 (0.60), 1.860 (0.80), 1.874 (0.57), 1.881 (0.43), 2.334 (1.11), 2.338 (0.51), 2.441 (16.00), 2.520 (5.91), 2.525 (3.73), 2.742 (0.58), 2.878 (2.66), 2.887 (7.26), 2.896 (3.16), 3.211 (1.08), 3.217 (1.09), 3.227 (2.03), 3.232 (1.97), 3.243 (1.11), 3.247 (1.15), 3.583 (0.44), 3.599 (0.93), 3.603 (0.92), 3.619 (1.26), 3.638 (0.69), 3.733 (0.60), 3.750 (1.14), 3.764 (0.94), 3.768 (0.97), 3.785 (0.63), 3.927 (0.96), 3.943 (1.43), 3.959 (0.88), 5.390 (5.71), 7.185 (1.13), 7.196 (1.17), 7.206 (1.26), 7.218 (1.23), 7.630 (4.95), 7.693 (0.96), 7.700 (0.98), 7.715 (1.72), 7.722 (1.72), 7.736 (0.86), 7.744 (0.92), 7.969 (0.68), 7.983 (1.41), 7.999 (0.65), 8.539 (2.46), 8.547 (2.47). LC-MS (方法1): Rt = 1.07 min; MS (ESIpos): m/z = 411 [M+H]+ | 中間物51 GP H 條件B 19 mg,29%產率,95%純度 |
183 | 2-[(5-氟吡啶-3-基)甲基]-8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (4.40), 1.546 (0.68), 1.562 (0.95), 1.570 (0.77), 1.579 (0.81), 1.588 (0.69), 1.608 (0.47), 1.777 (1.04), 1.793 (1.79), 1.810 (1.98), 1.827 (1.84), 1.839 (1.22), 1.855 (1.23), 1.870 (0.89), 1.888 (0.53), 2.455 (16.00), 2.761 (0.52), 2.865 (3.87), 2.877 (8.26), 2.888 (4.21), 2.905 (0.60), 3.214 (1.70), 3.225 (2.92), 3.229 (2.92), 3.240 (1.78), 3.245 (1.72), 3.263 (0.47), 3.579 (0.58), 3.597 (1.38), 3.616 (1.68), 3.634 (0.82), 3.729 (0.73), 3.746 (1.52), 3.764 (1.35), 3.782 (0.66), 3.924 (1.23), 3.939 (1.76), 3.955 (1.13), 5.387 (7.82), 7.584 (1.39), 7.608 (1.41), 7.667 (5.14), 7.971 (0.98), 7.986 (1.90), 8.001 (0.96), 8.385 (3.27), 8.518 (2.92), 8.525 (2.92). LC-MS (方法1): Rt = 1.04 min; MS (ESIpos): m/z = 411 [M+H]+ | 中間物51 GP H 條件B 17 mg,17%產率,95%純度 |
184 | 8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-2-[(噠𠯤-3-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.546 (0.48), 1.563 (0.67), 1.570 (0.51), 1.579 (0.57), 1.586 (0.42), 1.771 (0.53), 1.777 (0.69), 1.793 (1.21), 1.810 (1.35), 1.828 (1.31), 1.839 (0.74), 1.848 (0.60), 1.856 (0.81), 1.870 (0.57), 1.877 (0.42), 2.336 (0.54), 2.436 (16.00), 2.518 (6.44), 2.522 (4.06), 2.673 (1.20), 2.678 (0.52), 2.736 (0.86), 2.883 (2.85), 2.890 (8.89), 2.898 (3.23), 3.208 (1.06), 3.213 (1.04), 3.223 (2.00), 3.228 (1.92), 3.238 (1.08), 3.244 (1.12), 3.295 (0.58), 3.580 (0.42), 3.596 (0.89), 3.599 (0.90), 3.616 (1.22), 3.634 (0.68), 3.729 (0.59), 3.746 (1.11), 3.755 (0.70), 3.761 (0.93), 3.764 (0.92), 3.782 (0.62), 3.924 (0.94), 3.939 (1.45), 3.955 (0.88), 5.621 (6.71), 7.392 (1.68), 7.396 (1.67), 7.413 (1.92), 7.417 (1.91), 7.675 (2.04), 7.687 (2.25), 7.699 (5.23), 7.709 (1.88), 7.973 (0.67), 7.988 (1.41), 8.003 (0.65), 9.170 (1.63), 9.174 (1.77), 9.182 (1.73), 9.186 (1.57). LC-MS (方法2): Rt = 0.87 min; MS (ESIpos): m/z = 394 [M+H]+ | 中間物52 GP H 條件B 6 mg,27%產率,95%純度 |
185 | N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-甲基-2-[(噠𠯤-3-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.337 (0.61), 2.437 (16.00), 2.518 (7.61), 2.523 (5.02), 2.540 (0.46), 2.674 (1.42), 2.679 (0.65), 2.736 (1.15), 2.885 (2.78), 2.892 (8.58), 2.900 (3.23), 3.157 (0.60), 3.177 (1.73), 3.191 (1.44), 3.202 (1.56), 3.206 (2.13), 3.212 (0.89), 3.230 (1.91), 3.243 (0.95), 3.261 (0.64), 3.276 (0.42), 3.411 (0.44), 3.418 (0.52), 3.438 (1.05), 3.444 (1.12), 3.466 (0.97), 3.472 (0.89), 3.508 (0.80), 3.514 (0.90), 3.536 (1.13), 3.542 (1.12), 3.563 (0.50), 3.569 (0.74), 3.604 (1.68), 3.610 (1.42), 3.619 (0.68), 3.627 (1.28), 3.634 (1.34), 3.679 (1.20), 3.685 (0.99), 3.708 (2.00), 3.713 (1.83), 3.738 (0.87), 3.755 (1.40), 5.622 (6.81), 6.048 (0.45), 7.393 (1.75), 7.397 (1.68), 7.414 (1.96), 7.418 (1.99), 7.676 (2.22), 7.689 (2.20), 7.701 (5.40), 7.710 (2.05), 8.052 (0.72), 8.067 (1.48), 8.082 (0.68), 8.714 (0.43), 9.171 (1.62), 9.175 (1.68), 9.183 (1.65), 9.187 (1.62). LC-MS (方法2): Rt = 0.79 min; MS (ESIpos): m/z = 410 [M+H]⁺ | 中間物52 GP H 條件B 5 mg,19%產率,90%純度 |
186 | 2-[(6-乙基吡啶-3-基)甲基]-8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.156 (0.99), 1.169 (5.78), 1.175 (2.48), 1.189 (13.11), 1.194 (1.49), 1.208 (5.73), 1.232 (0.45), 1.548 (0.54), 1.563 (0.72), 1.571 (0.55), 1.579 (0.65), 1.593 (0.45), 1.771 (0.64), 1.777 (0.72), 1.792 (1.28), 1.810 (1.46), 1.827 (1.36), 1.838 (0.84), 1.843 (0.72), 1.848 (0.73), 1.856 (0.86), 1.863 (0.46), 1.870 (0.62), 1.877 (0.43), 1.888 (0.41), 2.458 (16.00), 2.479 (3.24), 2.518 (4.52), 2.523 (2.85), 2.682 (1.76), 2.701 (4.16), 2.720 (3.74), 2.739 (1.14), 2.765 (0.50), 2.848 (2.59), 2.858 (4.27), 2.864 (4.56), 2.874 (3.26), 2.893 (0.48), 3.208 (1.20), 3.214 (1.11), 3.223 (2.26), 3.229 (1.94), 3.238 (1.23), 3.244 (1.11), 3.579 (0.44), 3.595 (1.04), 3.599 (0.95), 3.616 (1.29), 3.634 (0.70), 3.729 (0.63), 3.743 (0.97), 3.746 (1.16), 3.761 (1.04), 3.764 (0.96), 3.782 (0.68), 3.923 (1.00), 3.939 (1.51), 3.955 (0.90), 5.278 (5.72), 5.543 (0.75), 6.540 (0.58), 7.227 (1.92), 7.247 (2.18), 7.419 (0.95), 7.568 (1.49), 7.573 (1.51), 7.587 (1.28), 7.594 (1.34), 7.614 (4.69), 7.962 (0.68), 7.977 (1.43), 7.991 (0.68), 8.422 (1.95), 8.426 (1.95). LC-MS (方法1): Rt = 1.10 min; MS (ESIpos): m/z = 421 [M+H]+ | 中間物53 GP H 條件A 5 mg,7%產率,90%純度 |
187 | N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-[(6-乙基吡啶-3-基)甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.169 (5.44), 1.189 (12.04), 1.207 (5.70), 2.459 (16.00), 2.518 (2.66), 2.523 (1.64), 2.682 (1.33), 2.701 (3.79), 2.720 (3.63), 2.739 (1.15), 2.766 (1.23), 2.830 (0.40), 2.849 (2.51), 2.860 (4.19), 2.865 (4.46), 2.876 (3.20), 2.894 (0.44), 3.157 (0.59), 3.177 (1.77), 3.191 (1.48), 3.201 (1.63), 3.206 (2.17), 3.211 (0.95), 3.230 (1.97), 3.242 (1.01), 3.261 (0.69), 3.276 (0.48), 3.411 (0.45), 3.417 (0.54), 3.438 (1.10), 3.444 (1.17), 3.465 (1.00), 3.471 (0.92), 3.508 (0.82), 3.513 (0.90), 3.535 (1.12), 3.542 (1.14), 3.563 (0.51), 3.568 (0.73), 3.603 (1.73), 3.609 (1.42), 3.618 (0.71), 3.627 (1.33), 3.634 (1.38), 3.679 (1.22), 3.685 (1.03), 3.708 (2.10), 3.713 (1.83), 3.738 (0.90), 5.278 (5.81), 5.701 (0.41), 7.226 (1.97), 7.247 (2.32), 7.568 (1.50), 7.573 (1.53), 7.587 (1.36), 7.593 (1.37), 7.615 (4.84), 8.041 (0.71), 8.056 (1.49), 8.071 (0.69), 8.422 (2.05), 8.426 (2.05), 8.614 (0.49). LC-MS (方法1): Rt = 1.04 min; MS (ESIpos): m/z = 437 [M+H]+ | 中間物53 GP H 條件A 18 mg,24%產率,93%純度 |
188 | 8-甲基-2-[(1,3-㗁唑-2-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.551 (0.48), 1.567 (0.67), 1.575 (0.50), 1.583 (0.57), 1.596 (0.42), 1.774 (0.57), 1.780 (0.74), 1.796 (1.25), 1.813 (1.41), 1.831 (1.33), 1.843 (0.74), 1.852 (0.59), 1.860 (0.81), 1.874 (0.56), 1.881 (0.41), 2.334 (0.58), 2.440 (16.00), 2.520 (2.54), 2.525 (1.65), 2.676 (0.60), 2.871 (2.64), 2.882 (6.22), 2.892 (3.20), 3.211 (1.06), 3.217 (1.06), 3.226 (1.98), 3.232 (1.85), 3.241 (1.08), 3.248 (1.09), 3.583 (0.46), 3.599 (0.94), 3.602 (0.94), 3.619 (1.26), 3.637 (0.70), 3.733 (0.63), 3.750 (1.13), 3.764 (0.92), 3.767 (0.94), 3.785 (0.63), 3.927 (0.98), 3.943 (1.48), 3.959 (0.89), 5.480 (8.37), 7.213 (4.35), 7.215 (4.44), 7.619 (4.83), 7.981 (0.68), 7.996 (1.43), 8.010 (0.66), 8.101 (4.67), 8.103 (4.95). LC-MS (方法1): Rt = 0.95 min; MS (ESIpos): m/z = 383 [M+H]+ | 中間物54 GP H 條件B 9 mg,9%產率,95%純度 |
189 | 8-甲基-2-[(㗁烷-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.209 (0.83), 1.218 (0.92), 1.239 (1.12), 1.250 (1.00), 1.269 (0.50), 1.280 (0.44), 1.404 (1.37), 1.432 (0.99), 1.553 (0.53), 1.570 (0.71), 1.577 (0.53), 1.586 (0.61), 1.593 (0.44), 1.777 (0.56), 1.783 (0.70), 1.799 (1.24), 1.816 (1.39), 1.834 (1.32), 1.845 (0.76), 1.854 (0.59), 1.862 (0.83), 1.877 (0.57), 1.884 (0.42), 2.006 (0.45), 2.015 (0.55), 2.025 (0.42), 2.471 (16.00), 2.520 (3.54), 2.525 (2.30), 2.613 (1.22), 2.827 (0.61), 2.845 (2.69), 2.857 (3.93), 2.865 (4.33), 2.877 (3.30), 2.895 (0.63), 3.220 (1.98), 3.230 (2.47), 3.234 (2.40), 3.246 (2.93), 3.250 (3.03), 3.276 (1.19), 3.585 (0.46), 3.602 (0.96), 3.605 (0.97), 3.622 (1.30), 3.639 (0.71), 3.735 (0.66), 3.752 (1.18), 3.767 (1.00), 3.770 (1.03), 3.778 (0.53), 3.788 (0.74), 3.805 (1.37), 3.811 (1.31), 3.833 (1.24), 3.840 (1.14), 3.933 (3.58), 3.951 (3.37), 3.962 (1.06), 7.481 (4.63), 7.956 (0.72), 7.971 (1.48), 7.986 (0.69). LC-MS (方法1): Rt = 1.05 min; MS (ESIpos): m/z = 400 [M+H]+ | 中間物55 GP H 條件B 16 mg,8%產率,95%純度 |
190 | 8-甲基-2-{[(2±)-㗁烷-2-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.861 (1.11), 0.878 (3.04), 0.896 (1.48), 1.164 (0.48), 1.194 (0.61), 1.223 (0.40), 1.340 (0.51), 1.358 (0.66), 1.373 (0.68), 1.396 (0.70), 1.448 (2.19), 1.552 (1.27), 1.569 (1.33), 1.584 (1.40), 1.613 (0.56), 1.760 (0.97), 1.781 (1.14), 1.797 (1.44), 1.814 (1.38), 1.832 (1.27), 1.845 (0.72), 1.861 (0.80), 1.876 (0.56), 1.893 (0.34), 2.467 (16.00), 2.518 (5.85), 2.522 (3.71), 2.607 (0.76), 2.824 (0.69), 2.842 (2.37), 2.855 (3.01), 2.862 (2.81), 2.877 (2.82), 2.895 (0.68), 3.212 (1.08), 3.218 (1.10), 3.228 (2.01), 3.233 (1.95), 3.243 (1.17), 3.249 (1.20), 3.267 (0.76), 3.295 (1.19), 3.603 (1.45), 3.620 (1.78), 3.637 (0.93), 3.733 (0.60), 3.751 (1.12), 3.768 (0.97), 3.786 (0.63), 3.827 (0.80), 3.854 (0.71), 3.913 (0.30), 3.929 (0.97), 3.944 (1.44), 3.960 (0.91), 4.021 (1.87), 4.029 (2.00), 4.039 (2.42), 4.064 (0.29), 7.426 (4.55), 7.595 (0.27), 7.621 (0.27), 7.960 (0.68), 7.975 (1.41), 7.990 (0.66). LC-MS (方法1): Rt = 1.16 min; MS (ESIpos): m/z = 400 [M+H]+ | 中間物56 GP H 條件B 2 mg,2%產率,90%純度 兩種異構體的混合物. |
191 | N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-[(6-甲基吡啶-3-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.51), 0.948 (0.55), 2.429 (16.00), 2.518 (7.85), 2.523 (5.44), 2.835 (0.72), 2.839 (0.72), 2.858 (3.00), 2.876 (2.45), 2.922 (2.62), 2.938 (3.60), 2.945 (1.37), 2.957 (0.96), 2.963 (0.86), 3.193 (1.44), 3.198 (0.76), 3.217 (2.65), 3.221 (1.96), 3.232 (2.00), 3.245 (3.10), 3.259 (1.75), 3.275 (1.13), 3.294 (0.66), 3.309 (0.66), 3.420 (0.50), 3.426 (0.63), 3.447 (1.29), 3.454 (1.40), 3.474 (1.11), 3.481 (1.06), 3.521 (0.93), 3.526 (1.03), 3.549 (1.31), 3.556 (1.37), 3.576 (0.58), 3.582 (0.91), 3.616 (1.82), 3.640 (1.73), 3.691 (1.48), 3.697 (1.23), 3.720 (2.55), 3.749 (1.14), 3.754 (1.06), 5.281 (7.04), 7.214 (2.30), 7.234 (2.60), 7.547 (1.70), 7.552 (1.74), 7.566 (1.52), 7.573 (1.57), 7.649 (5.25), 8.396 (2.44), 8.401 (2.43), 8.728 (0.84), 8.743 (1.76), 8.758 (0.85). LC-MS (方法1): Rt = 0.99 min; MS (ESIpos): m/z = 477 [M+H]⁺ | 中間物57 GP H 條件B 16 mg,7%產率,98%純度 |
192 | 2-[(6-甲基吡啶-3-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.535 (0.56), 1.555 (0.78), 1.564 (0.76), 1.572 (0.64), 1.584 (0.70), 1.601 (0.44), 1.790 (0.86), 1.806 (1.57), 1.824 (1.55), 1.842 (1.01), 1.857 (0.81), 1.874 (0.69), 1.885 (0.74), 1.902 (0.62), 1.918 (0.46), 2.429 (16.00), 2.518 (13.89), 2.523 (9.60), 2.839 (0.74), 2.858 (3.01), 2.876 (2.57), 2.917 (2.72), 2.934 (3.62), 2.953 (0.91), 2.959 (0.84), 3.249 (2.20), 3.264 (4.65), 3.280 (2.52), 3.594 (0.51), 3.613 (1.26), 3.630 (1.50), 3.648 (0.85), 3.737 (0.72), 3.754 (1.44), 3.770 (1.28), 3.790 (0.72), 3.930 (1.11), 3.946 (1.76), 3.961 (1.18), 5.281 (7.15), 7.214 (2.26), 7.233 (2.57), 7.545 (1.66), 7.551 (1.72), 7.565 (1.52), 7.571 (1.55), 7.647 (5.18), 8.396 (2.40), 8.400 (2.44), 8.692 (0.83), 8.707 (1.67), 8.722 (0.81). LC-MS (方法1): Rt = 1.07 min; MS (ESIpos): m/z = 461 [M+H]⁺ | 中間物57 GP H 條件B 45 mg,13%產率,98%純度 |
193 | 8-環丙基-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (16.00), 0.806 (3.14), 0.813 (2.95), 0.828 (3.05), 0.835 (3.13), 0.851 (0.71), 0.868 (1.15), 0.886 (0.64), 0.931 (1.47), 0.948 (1.45), 1.415 (3.34), 1.418 (3.33), 2.326 (1.49), 2.331 (1.11), 2.522 (4.92), 2.669 (1.55), 2.673 (1.13), 2.753 (0.81), 2.760 (0.97), 2.768 (1.35), 2.778 (4.10), 2.794 (4.01), 2.819 (4.26), 2.836 (4.71), 2.846 (1.31), 2.853 (1.08), 2.861 (0.85), 2.927 (0.47), 2.941 (1.08), 2.949 (1.05), 2.955 (0.81), 2.963 (1.80), 2.972 (0.79), 2.977 (1.00), 2.985 (0.93), 2.999 (0.41), 3.166 (0.41), 3.181 (0.90), 3.190 (1.91), 3.199 (1.47), 3.214 (4.46), 3.228 (2.33), 3.243 (4.64), 3.259 (1.74), 3.271 (2.53), 3.276 (3.01), 3.300 (3.01), 3.409 (1.06), 3.416 (1.30), 3.424 (1.14), 3.436 (2.07), 3.445 (2.80), 3.452 (2.18), 3.464 (1.78), 3.472 (2.34), 3.479 (1.64), 3.512 (1.46), 3.518 (2.54), 3.523 (1.62), 3.546 (3.58), 3.573 (1.81), 3.578 (1.42), 3.614 (4.02), 3.625 (2.04), 3.642 (3.89), 3.664 (0.66), 3.692 (2.17), 3.697 (1.90), 3.721 (7.04), 3.750 (4.23), 3.804 (0.62), 3.818 (1.19), 3.825 (1.24), 3.832 (1.05), 3.841 (1.16), 3.856 (0.63), 4.054 (5.97), 4.068 (4.47), 7.455 (6.84), 8.030 (1.22), 8.044 (2.54), 8.059 (1.20). LC-MS (方法1): Rt = 1.01 min; MS (ESIpos): m/z = 444 [M+H]+ | 中間物58 GP H 條件B 55 mg,28%產率,95%純度 |
194 | 8-環丙基-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.002 (2.66), 0.803 (6.72), 0.810 (6.04), 0.825 (6.25), 0.831 (6.66), 1.159 (1.11), 1.232 (1.20), 1.402 (4.19), 1.413 (6.47), 1.416 (6.44), 1.427 (3.97), 1.541 (0.57), 1.560 (1.75), 1.577 (2.38), 1.584 (1.86), 1.593 (2.04), 1.605 (1.63), 1.622 (1.22), 1.754 (0.45), 1.765 (1.04), 1.780 (1.90), 1.786 (2.37), 1.801 (4.17), 1.820 (4.59), 1.838 (3.91), 1.851 (2.58), 1.860 (1.99), 1.864 (2.24), 1.869 (2.63), 1.883 (1.90), 1.900 (1.16), 1.907 (1.09), 1.922 (0.66), 2.332 (2.52), 2.336 (1.17), 2.518 (13.16), 2.522 (8.36), 2.673 (2.57), 2.752 (1.54), 2.759 (1.80), 2.768 (2.40), 2.777 (8.36), 2.794 (7.96), 2.818 (8.78), 2.834 (10.77), 2.845 (2.53), 2.853 (2.23), 2.860 (1.78), 2.931 (1.01), 2.945 (2.11), 2.954 (2.18), 2.960 (1.43), 2.967 (3.99), 2.976 (1.42), 2.981 (1.97), 2.990 (1.92), 3.003 (0.83), 3.233 (5.95), 3.248 (15.21), 3.263 (6.65), 3.272 (5.11), 3.276 (4.80), 3.301 (5.13), 3.410 (1.29), 3.417 (1.58), 3.437 (3.31), 3.443 (3.59), 3.464 (2.96), 3.471 (2.79), 3.513 (2.43), 3.518 (2.77), 3.541 (3.48), 3.547 (3.51), 3.568 (1.53), 3.574 (2.18), 3.589 (1.58), 3.609 (4.71), 3.615 (4.21), 3.625 (4.74), 3.643 (5.12), 3.722 (7.08), 3.739 (2.63), 3.753 (7.60), 3.757 (8.27), 3.771 (3.43), 3.774 (3.49), 3.792 (2.16), 3.804 (0.99), 3.810 (0.98), 3.819 (2.00), 3.826 (2.23), 3.834 (1.76), 3.843 (2.10), 3.857 (1.16), 3.863 (0.96), 3.923 (0.99), 3.939 (3.30), 3.955 (5.09), 3.970 (3.12), 3.986 (0.70), 4.054 (12.99), 4.069 (8.94), 7.454 (16.00), 7.944 (2.42), 7.958 (5.13), 7.974 (2.37). LC-MS (方法1): Rt = 1.11 min; MS (ESIpos): m/z = 428 [M+H]+ | 中間物58 GP H 條件B 28 mg,14%產率,95%純度 |
195 | N-{[(2±)-5,5-二甲基氧雜環戊-2-基]甲基}-2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.784 (1.57), 0.803 (2.31), 0.824 (0.73), 0.850 (0.87), 0.860 (1.05), 0.870 (3.84), 0.932 (0.50), 0.948 (0.48), 1.137 (16.00), 1.154 (0.77), 1.198 (15.96), 1.221 (0.66), 1.230 (0.63), 1.650 (0.76), 1.658 (0.92), 1.673 (3.49), 1.679 (4.04), 1.683 (5.02), 1.697 (0.84), 1.701 (1.08), 1.716 (0.54), 1.722 (0.55), 1.939 (0.51), 1.956 (0.96), 1.975 (0.90), 1.988 (0.42), 2.336 (1.10), 2.446 (0.70), 2.518 (10.73), 2.523 (7.19), 2.678 (0.94), 2.786 (0.50), 2.829 (3.70), 2.841 (3.66), 2.885 (0.53), 3.217 (2.42), 3.227 (2.55), 3.230 (2.46), 3.242 (2.93), 3.245 (2.94), 3.270 (1.70), 3.294 (1.00), 3.307 (1.53), 3.366 (1.04), 3.370 (1.05), 3.381 (0.59), 3.403 (0.65), 3.410 (0.75), 3.430 (1.30), 3.437 (1.43), 3.457 (1.17), 3.464 (1.13), 3.504 (0.97), 3.509 (1.07), 3.532 (1.26), 3.539 (1.27), 3.559 (0.58), 3.565 (0.77), 3.612 (1.40), 3.640 (1.09), 3.703 (2.34), 3.708 (2.65), 3.731 (1.95), 3.737 (2.16), 3.815 (0.72), 3.821 (0.76), 3.827 (0.68), 3.834 (0.91), 3.840 (0.69), 3.851 (0.48), 3.857 (0.44), 3.986 (0.71), 4.003 (0.69), 4.008 (1.04), 4.022 (2.84), 4.040 (3.50), 4.053 (2.10), 4.077 (0.67), 4.089 (0.55), 7.276 (9.11), 7.882 (0.82), 7.897 (1.71), 7.912 (0.81). LC-MS (方法1): Rt = 1.22 min; MS (ESIpos): m/z = 456 [M+H]+ | 中間物40-1 GP H 條件B 37 mg,17%產率,90%純度 兩種異構體的混合物 |
196 | N-{[(2±)-6,6-二甲基-1,4-二㗁烷-2-基]甲基}-2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.803 (0.85), 0.861 (5.79), 0.878 (16.00), 0.896 (7.93), 0.926 (0.63), 0.944 (1.19), 0.963 (0.64), 0.985 (0.64), 1.002 (0.77), 1.023 (1.11), 1.044 (5.90), 1.063 (1.78), 1.217 (1.26), 1.234 (4.94), 1.253 (1.53), 1.323 (1.17), 1.341 (2.50), 1.359 (3.18), 1.373 (3.09), 1.386 (2.32), 1.417 (1.81), 1.437 (1.38), 1.543 (2.23), 1.572 (2.65), 1.583 (2.03), 1.597 (1.81), 1.612 (1.20), 1.997 (0.31), 2.018 (0.43), 2.755 (0.93), 2.816 (0.50), 2.830 (1.53), 2.842 (1.55), 2.987 (1.47), 3.009 (0.61), 3.037 (0.90), 3.065 (0.75), 3.097 (0.84), 3.125 (1.04), 3.147 (0.92), 3.217 (0.74), 3.245 (0.82), 3.270 (0.77), 3.426 (1.42), 3.436 (0.99), 3.454 (1.23), 3.509 (0.51), 3.532 (0.61), 3.538 (0.59), 3.565 (0.35), 3.613 (0.68), 3.638 (0.67), 3.708 (1.31), 3.737 (1.21), 3.827 (0.45), 3.834 (0.54), 3.839 (0.47), 3.857 (0.46), 3.870 (0.41), 4.022 (0.75), 4.040 (1.12), 4.054 (0.80), 4.077 (0.39), 4.089 (0.32), 4.504 (0.35), 7.278 (3.12), 7.414 (0.38), 8.012 (0.28), 8.027 (0.63), 8.043 (0.31), 8.151 (0.22). LC-MS (方法1): Rt = 1.13 min; MS (ESIpos): m/z = 472 [M+H]+ | 中間物40-1 GP H 條件B 37 mg,14%產率,80%純度 兩種異構體的混合物 |
197 | N-{[(2±)-4,4-二氟氧雜環戊-2-基]甲基}-2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.786 (2.81), 0.806 (4.62), 0.827 (1.14), 0.852 (1.43), 0.861 (2.16), 0.872 (7.22), 0.879 (6.33), 1.231 (0.52), 2.160 (0.37), 2.181 (0.39), 2.196 (0.84), 2.205 (0.44), 2.209 (0.47), 2.216 (0.87), 2.230 (0.66), 2.243 (0.83), 2.252 (0.60), 2.262 (0.79), 2.278 (0.44), 2.297 (0.43), 2.518 (12.18), 2.523 (8.55), 2.541 (1.37), 2.789 (1.08), 2.833 (7.46), 2.845 (7.40), 2.888 (1.08), 3.218 (2.42), 3.242 (2.94), 3.247 (2.94), 3.271 (2.92), 3.364 (2.63), 3.378 (1.38), 3.410 (1.72), 3.423 (2.16), 3.430 (2.56), 3.437 (3.65), 3.458 (2.74), 3.464 (1.99), 3.504 (1.58), 3.509 (1.80), 3.532 (2.24), 3.539 (2.23), 3.565 (1.33), 3.613 (2.48), 3.640 (1.88), 3.704 (4.39), 3.710 (4.64), 3.738 (3.68), 3.791 (1.12), 3.817 (2.63), 3.822 (2.72), 3.829 (2.08), 3.850 (1.99), 3.857 (2.06), 3.888 (1.16), 3.987 (1.21), 4.009 (1.20), 4.022 (3.77), 4.040 (6.61), 4.055 (3.53), 4.066 (2.58), 4.078 (1.22), 4.091 (1.18), 4.237 (0.55), 4.254 (1.45), 4.271 (2.13), 4.286 (1.38), 7.280 (16.00), 8.148 (1.61), 8.163 (3.29), 8.177 (1.55). LC-MS (方法1): Rt = 1.13 min; MS (ESIpos): m/z = 464 [M+H]+ | 中間物40-1 GP H 條件B 19 mg,9%產率,95%純度 兩種異構體的混合物 |
198 | 2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-甲基-N-{[(2±,5±)-5-甲基氧雜環戊-2-基]甲基}-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.783 (3.72), 0.802 (6.04), 0.823 (1.44), 0.848 (1.81), 0.869 (8.90), 1.069 (1.05), 1.101 (6.06), 1.116 (6.55), 1.134 (2.65), 1.149 (16.00), 1.164 (15.38), 1.185 (2.15), 1.193 (1.28), 1.221 (0.46), 1.293 (1.17), 1.312 (2.46), 1.331 (1.86), 1.350 (1.86), 1.369 (1.99), 1.395 (1.74), 1.417 (0.97), 1.602 (0.97), 1.614 (1.16), 1.632 (1.37), 1.644 (1.33), 1.823 (0.69), 1.841 (1.42), 1.862 (2.30), 1.879 (2.26), 1.895 (2.63), 1.913 (2.08), 1.927 (1.97), 1.958 (1.18), 1.996 (1.14), 2.008 (2.41), 2.755 (4.00), 2.784 (1.22), 2.815 (2.93), 2.828 (8.42), 2.840 (8.48), 2.883 (1.16), 2.917 (0.85), 2.935 (0.73), 3.216 (4.95), 3.229 (5.18), 3.244 (11.39), 3.259 (5.51), 3.269 (5.37), 3.313 (8.68), 3.429 (5.72), 3.435 (5.24), 3.457 (3.78), 3.463 (3.80), 3.502 (2.52), 3.508 (2.62), 3.530 (3.32), 3.536 (3.31), 3.563 (1.85), 3.611 (3.84), 3.638 (3.03), 3.706 (6.96), 3.735 (5.83), 3.832 (2.67), 3.844 (2.75), 3.859 (3.11), 3.874 (2.30), 3.879 (2.36), 3.902 (2.32), 3.919 (2.67), 3.934 (1.80), 3.950 (0.56), 3.984 (1.47), 4.002 (1.24), 4.020 (5.38), 4.038 (8.08), 4.052 (5.00), 4.075 (2.79), 4.087 (1.71), 4.145 (0.56), 4.468 (0.43), 4.496 (0.97), 4.507 (0.81), 4.617 (0.52), 7.090 (1.01), 7.273 (15.54), 7.406 (0.94), 7.926 (1.52), 7.941 (3.38), 7.954 (2.25), 8.151 (0.91), 8.539 (1.56), 8.890 (0.98), 10.144 (1.03). LC-MS (方法1): Rt = 1.16 min; MS (ESIpos): m/z = 442 [M+H]+ | 中間物40-1 GP H 條件B 11 mg,3%產率,90%純度 反式與順式異構體的混合物 |
199 | 2-[[(2S)-1,4-二㗁烷-2-基]甲基]-8-甲基-N-[(4-甲基四氫呋喃-2-基)甲基]螺[5H-呋喃并[2,3-g]吲唑-4,1'-環丙烷]-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.764 (0.61), 0.784 (2.54), 0.798 (2.74), 0.804 (4.33), 0.825 (0.95), 0.849 (1.16), 0.858 (1.32), 0.868 (6.25), 0.939 (0.40), 0.958 (3.06), 0.974 (3.78), 0.981 (15.53), 0.998 (16.00), 1.010 (0.95), 1.019 (0.84), 1.117 (1.04), 1.139 (1.85), 1.147 (1.17), 1.161 (1.14), 1.169 (2.00), 1.192 (1.21), 1.314 (0.79), 1.333 (0.44), 2.012 (0.84), 2.066 (0.85), 2.084 (1.33), 2.101 (1.31), 2.116 (1.37), 2.132 (1.11), 2.207 (0.80), 2.226 (1.23), 2.245 (1.17), 2.264 (0.82), 2.318 (1.15), 2.518 (14.14), 2.523 (8.91), 2.660 (1.13), 2.755 (1.19), 2.784 (1.03), 2.816 (1.84), 2.827 (7.22), 2.839 (7.07), 2.883 (1.03), 3.139 (0.48), 3.159 (0.60), 3.178 (0.56), 3.201 (0.73), 3.217 (3.52), 3.222 (3.18), 3.232 (0.99), 3.242 (7.67), 3.263 (3.86), 3.270 (4.48), 3.282 (6.49), 3.297 (3.80), 3.372 (0.51), 3.403 (0.84), 3.410 (0.98), 3.430 (2.04), 3.437 (2.27), 3.458 (1.88), 3.464 (1.89), 3.504 (1.55), 3.509 (1.68), 3.532 (2.15), 3.539 (2.10), 3.559 (0.95), 3.565 (1.22), 3.612 (2.36), 3.639 (1.81), 3.703 (4.04), 3.708 (4.44), 3.731 (3.46), 3.737 (3.72), 3.750 (2.63), 3.769 (3.41), 3.789 (2.30), 3.796 (0.68), 3.803 (0.73), 3.810 (0.94), 3.815 (1.20), 3.821 (1.36), 3.827 (1.15), 3.833 (1.54), 3.839 (1.22), 3.851 (0.80), 3.857 (0.78), 3.863 (0.64), 3.880 (0.57), 3.900 (0.42), 3.936 (0.54), 3.951 (1.53), 3.957 (0.75), 3.967 (1.65), 3.972 (1.60), 3.986 (1.84), 4.003 (1.16), 4.021 (3.52), 4.041 (4.77), 4.053 (3.41), 4.077 (1.26), 4.089 (0.89), 7.276 (15.10), 7.942 (1.42), 7.957 (3.02), 7.972 (1.35), 8.149 (0.72), 8.542 (0.52), 8.893 (0.69), 10.146 (0.76). LC-MS (方法1): Rt = 1.15 min; MS (ESIpoa): m/z = 442 [M+H]+ | 中間物40-1 GP H 條件B 27 mg,6%產率,90%純度 反式與順式異構體的混合物 |
200 | 2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-甲基-N-{[(6±)-5-氧雜螺[2.4]庚-6-基]甲基}-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.495 (1.39), 0.512 (2.89), 0.528 (3.12), 0.540 (1.29), 0.569 (2.25), 0.580 (4.92), 0.585 (3.95), 0.599 (6.80), 0.602 (5.60), 0.613 (3.96), 0.626 (4.36), 0.641 (2.67), 0.656 (1.30), 0.784 (3.01), 0.804 (5.37), 0.825 (1.41), 0.850 (1.53), 0.858 (1.83), 0.868 (7.52), 1.314 (1.34), 1.647 (2.14), 1.662 (2.22), 1.677 (2.82), 1.693 (2.94), 1.857 (2.71), 1.874 (3.07), 1.888 (2.47), 1.905 (2.23), 2.007 (1.18), 2.659 (1.17), 2.757 (2.19), 2.785 (1.27), 2.819 (1.95), 2.828 (8.21), 2.840 (8.44), 2.884 (1.27), 3.217 (2.65), 3.242 (3.32), 3.246 (3.53), 3.271 (3.41), 3.286 (0.96), 3.402 (2.27), 3.409 (2.27), 3.430 (3.07), 3.436 (3.30), 3.458 (2.52), 3.464 (2.64), 3.504 (2.01), 3.509 (2.21), 3.529 (5.30), 3.538 (3.45), 3.549 (7.98), 3.559 (1.88), 3.565 (1.96), 3.598 (7.99), 3.618 (6.48), 3.639 (2.85), 3.704 (4.93), 3.709 (5.50), 3.737 (4.52), 3.815 (1.49), 3.821 (1.57), 3.827 (1.57), 3.834 (1.98), 3.839 (1.65), 3.851 (1.16), 3.985 (1.24), 4.021 (3.89), 4.040 (5.42), 4.053 (3.97), 4.077 (1.53), 4.089 (1.22), 4.120 (0.88), 4.136 (2.56), 4.152 (3.65), 4.168 (2.51), 7.277 (16.00), 7.989 (1.73), 8.004 (3.72), 8.019 (1.83), 8.543 (0.89). LC-MS (方法1): Rt = 1.17 min; MS (ESIpos): m/z = 454 [M+H]⁺ | 中間物40-1 GP H 條件 29 mg,13%產率,90%純度 兩種異構體的混合物 |
201 | 2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(6±)-2,5-二氧雜螺[3.4]辛-6-基]甲基}-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.767 (0.61), 0.786 (2.67), 0.807 (4.17), 0.829 (1.07), 0.852 (1.89), 0.873 (6.75), 0.932 (1.47), 0.948 (1.45), 1.316 (0.44), 1.350 (0.47), 1.567 (0.57), 1.586 (1.32), 1.598 (0.95), 1.603 (1.45), 1.618 (1.83), 1.634 (1.79), 1.654 (1.02), 1.862 (0.63), 1.879 (1.07), 1.893 (1.59), 1.912 (1.70), 1.927 (1.05), 1.944 (0.69), 2.049 (1.05), 2.069 (1.96), 2.081 (1.85), 2.088 (0.97), 2.100 (3.31), 2.120 (1.35), 2.160 (1.50), 2.175 (1.64), 2.181 (1.72), 2.194 (1.68), 2.206 (1.07), 2.212 (0.98), 2.226 (0.75), 2.318 (1.17), 2.518 (14.16), 2.523 (9.25), 2.758 (0.54), 2.792 (1.00), 2.836 (7.39), 2.848 (7.35), 2.891 (1.06), 3.169 (0.41), 3.187 (1.73), 3.202 (3.33), 3.211 (3.35), 3.218 (4.28), 3.226 (1.88), 3.242 (3.02), 3.246 (3.04), 3.271 (2.84), 3.289 (1.11), 3.295 (1.16), 3.303 (1.24), 3.368 (1.36), 3.375 (1.16), 3.384 (0.95), 3.404 (1.05), 3.410 (1.22), 3.431 (2.29), 3.437 (2.59), 3.458 (2.17), 3.464 (2.02), 3.504 (1.60), 3.509 (1.81), 3.532 (2.20), 3.539 (2.21), 3.559 (1.02), 3.565 (1.41), 3.613 (2.53), 3.641 (2.00), 3.704 (4.19), 3.709 (4.77), 3.732 (3.49), 3.737 (3.91), 3.798 (0.67), 3.805 (0.72), 3.816 (1.33), 3.821 (1.36), 3.828 (1.24), 3.834 (1.61), 3.840 (1.19), 3.852 (0.86), 3.858 (0.73), 3.986 (1.05), 4.003 (0.73), 4.022 (3.41), 4.041 (5.16), 4.055 (5.25), 4.070 (3.26), 4.078 (1.56), 4.086 (2.18), 4.102 (0.61), 4.442 (3.99), 4.458 (5.02), 4.469 (5.06), 4.555 (5.22), 4.572 (4.20), 4.584 (4.96), 4.600 (3.83), 7.278 (16.00), 8.032 (1.46), 8.047 (3.18), 8.062 (1.50). LC-MS (方法1): Rt = 1.00 min; MS (ESIneg): m/z = 468 [M-H]⁻ | 中間物40-1 GP H 條件 46.4 mg,20%產率,90%純度 兩種異構體的混合物 |
201-1 | 2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(6R或6S)-2,5-二氧雜螺[3.4]辛-6-基]甲基}-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 實例201之對映異構體1 | Rt = 1.58 min1 H NMR (400 MHz, DMSO-d6) δ ppm 0.77 - 0.81 (m, 2H), 0.86 - 0.89 (m, 2H), 1.56 - 1.67 (m, 1 H) 1.85 - 1.95 (m, 1 H) 2.04 - 2.12 (m, 1 H) 2.15 - 2.23 (m, 1 H) 2.49 (s, 3H, 在DMSO峰下), 2.83 - 2.89 (m, 2 H) 3.20 - 3.27 (m, 3 H) 3.40 - 3.47 (m, 1 H) 3.50 - 3.58 (m, 1 H) 3.60 - 3.65 (m, 1 H) 3.70 - 3.74 (m, 2 H) 3.79 - 3.86 (m, 1 H) 3.98 - 4.10 (m, 3 H) 4.44 - 4.47 (m, 2 H) 4.55 - 4.60 (m, 2 H) 7.28 (s, 1 H) 8.03 - 8.06 (m, 1H) | 分析型方法: 儀器:Agilent:1260,Aurora SFC模組;管柱:Chiralpak IA 5µ 100x4.6mm;溶離劑A:CO2;溶離劑B:乙醇 + 0.2 vol%氨水(32%);等度:30% B;流量:4 ml/min;溫度:37.5℃;BPR:100巴;UV:254 nm): |
201-2 | 2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(6S或6R)-2,5-二氧雜螺[3.4]辛-6-基]甲基}-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 實例201之對映異構體2 | Rt = 2.73 min1 H NMR (400 MHz, DMSO-d6) δ ppm 0.79 - 0.81 (m, 2H), 0.86 - 0.88 (m, 2H), 1.56 - 1.67 (m, 1 H) 1.86 - 1.95 (m, 1 H) 2.04 - 2.12 (m, 1 H) 2.16 - 2.23 (m, 1 H) 2.49 (s, 3H, 在DMSO峰下), 2.79 - 2.89 (m, 2 H) 3.17 - 3.27 (m, 3 H) 3.40 - 3.47 (m, 1 H) 3.50 - 3.56 (m, 1 H) 3.60 - 3.64 (m, 1 H) 3.70 - 3.74 (m, 2 H) 3.80 - 3.86 (m, 1 H) 3.98 - 4.09 (m, 3 H) 4.43 - 4.47 (m, 2 H) 4.55 - 4.61 (m, 2 H) 7.28 (s, 1 H) 8.05 (t, 1H) | |
202 | 8'-甲基-2'-(吡啶-4-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 1.53-1.62 (m, 1H), 1.77-1.88 (m, 3H), 1.93-2.17 (m, 6H), 2.44 (s, 3H), 3.04 (s, 2H), 3.23 (t, 2H), 3.58-3.64 (m, 1H), 3.72-3.81 (m, 1H), 3.95 (quin, 1H), 5.38 (s, 2H), 7.13-7.17 (m, 2H), 7.95 (s, 1H), 7.98 (t, 1H), 8.50-8.55 (m, 2H) LC-MS (方法1): Rt = 1.09 min; MS (ESIpos): m/z = 433 [M+H]⁺ | 中間物59及CAS-RN:[7175-81-7] GP G 條件A 15 mg,89%產率,95%純度 % d. Th.) |
203 | 8'-甲基-2'-[(5-甲基吡啶-2-基)甲基]-N-[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 1.51-1.63 (m, 1H), 1.75-1.90 (m, 3H), 1.94-2.15 (m, 6H), 2.27 (s, 3H), 2.43 (s, 3H), 3.03 (s, 2H), 3.23 (t, 2H), 3.56-3.66 (m, 1H), 3.71-3.81 (m, 1H), 3.94 (quin, 1H), 5.35 (s, 2H), 7.01 (d, 1H), 7.57-7.62 (m, 1H), 7.88 (s, 1H), 7.97 (t, 1H), 8.36-8.39 (m, 1H) LC-MS (方法1): Rt = 1.21 min; MS (ESIpos): m/z = 447 [M+H]⁺ | 中間物60及CAS-RN:[7175-81-7] GP G 條件A 7.6 mg,17%產率,94%純度 % d. Th.) |
204 | 8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-2-[2-(吡啶-2-基)乙基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 1.54-1.61 (m, 1H), 1.74-1.91 (m, 3H), 2.47 (s, 3H), 2.78-2.83 (m, 2H), 2.84-2.89 (m, 2H), 3.20-3.28 (m, 4H), 3.57-3.64 (m, 1H), 3.76 (ddd, 1H), 3.94 (quin, 1H), 4.44 (t, 2H), 7.23 (ddd, 1H), 7.26 (d, 1H), 7.43 (s, 1H), 7.69 (td, 1H), 7.97 (t, 1H), 8.51-8.53 (m, 1H). LC-MS (方法1): Rt = 1.04 min; MS (ESIneg): m/z = 405 [M-H]⁻ | 中間物61及CAS-RN:[7175-81-7] GP G 條件A 22.5 mg (44%產率,99%純度) |
205 | N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-甲基-2-[2-(吡啶-2-基)乙基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 2.47 (s, 3H), 2.78-2.83 (m, 2H), 2.84-2.89 (m, 2H), 3.17-3.28 (m, 5H), 3.42-3.48 (m, 1H), 3.54 (td, 1H), 3.59-3.66 (m, 2H), 3.68-3.75 (m, 2H), 4.44 (t, 2H), 7.22-7.25 (m, 1H), 7.26 (d, 1H), 7.43 (s, 1H), 7.69 (td, 1H), 8.05 (t, 1H), 8.48-8.55 (m, 1H). LC-MS (方法1): Rt = 0.96 min; MS (ESIneg): m/z = 421 [M-H]⁻ | 中間物61及CAS-RN:[1523541-84-5] GP G 條件A 30.2 mg (56%產率,97%純度) |
206 | 8-甲基-N-[(1,3-㗁唑-2-基)甲基]-2-[2-(吡啶-2-基)乙基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.48 (s, 3H), 2.79-2.91 (m, 4H), 3.25 (t, 2H), 4.45 (t, 2H), 4.49 (d, 2H), 7.14 (d, 1H), 7.21-7.24 (m, 1H), 7.26 (d, 1H), 7.44 (s, 1H), 7.70 (td, 1H), 8.03 (d, 1H), 8.50-8.55 (m, 1H), 8.72 (t, 1H). LC-MS (方法1): Rt = 0.94 min; MS (ESIneg): m/z = 402 [M-H]⁻ | 中間物61及CAS-RN:[885331-17-9] GP G 條件A 24.6 mg (48%產率,98%純度) |
207 | 2-[2,2-二氟-2-(吡啶-2-基)乙基]-8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.62 (m, 1H), 1.75-1.91 (m, 3H), 2.37 (s, 3H), 2.80-2.92 (m, 4H), 3.17-3.28 (m, 2H), 3.57-3.65 (m, 1H), 3.71-3.79 (m, 1H), 3.94 (quin, 1H), 5.01 (t, 2H), 7.50 (s, 1H), 7.59 (dd, 1H), 7.64-7.69 (m, 1H), 7.93-8.01 (m, 2H), 8.74 (d, 1H). LC-MS (方法1): Rt = 1.12 min; MS (ESIneg): m/z = 441 [M-H]⁻ | 中間物62及CAS-RN:[7175-81-7] GP G 條件A 32.9 mg (69%產率,98%純度) |
208 | 2-[2,2-二氟-2-(吡啶-2-基)乙基]-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.37 (s, 3H), 2.80-2.92 (m, 4H), 3.14-3.28 (m, 3H), 3.39-3.49 (m, 1H), 3.50-3.58 (m, 1H), 3.58-3.66 (m, 2H), 3.67-3.76 (m, 2H), 5.01 (t, 2H), 7.50 (s, 1H), 7.57-7.62 (m, 1H), 7.66 (dt, 1H), 7.98 (td, 1H), 8.06 (t, 1H), 8.74 (d, 1H). LC-MS (方法1): Rt = 1.04 min; MS (ESIneg): m/z = 457 [M-H]⁻ | 中間物62及CAS-RN:[1523541-84-5] GP G 條件A 29.8 mg (60%產率,97%純度) |
209 | 2-[2,2-二氟-2-(吡啶-2-基)乙基]-8-甲基-N-[(1,3-㗁唑-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.37 (s, 3H), 2.83-2.92 (m, 4H), 4.48 (d, 2H), 5.01 (t, 2H), 7.14 (d, 1H), 7.51 (s, 1H), 7.59 (dd, 1H), 7.66 (dt, 1H), 7.98 (td, 1H), 8.03 (d, 1H), 8.67-8.80 (m, 2H). LC-MS (方法1): Rt = 1.02 min; MS (ESIneg): m/z = 438 [M-H]⁻ | 中間物62及CAS-RN:[885331-17-9] GP G 條件A 19.2 mg (39%產率,95%純度) |
210 | N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8'-甲基-2'-[(6-甲基吡啶-3-基)甲基]-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.011 (0.49), -0.003 (16.00), 0.005 (0.44), 0.783 (0.78), 0.795 (2.02), 0.800 (2.45), 0.809 (1.31), 0.861 (1.22), 0.870 (2.57), 0.887 (0.81), 0.931 (1.75), 0.934 (0.62), 0.948 (1.80), 2.430 (11.34), 2.477 (13.34), 2.518 (3.43), 2.522 (2.17), 2.832 (6.22), 3.161 (0.46), 3.176 (1.35), 3.195 (1.33), 3.200 (1.44), 3.205 (1.48), 3.209 (1.26), 3.224 (1.27), 3.229 (1.46), 3.240 (0.76), 3.258 (0.47), 3.305 (0.42), 3.379 (0.69), 3.409 (0.44), 3.416 (0.52), 3.436 (0.93), 3.442 (1.00), 3.464 (0.83), 3.470 (0.78), 3.505 (0.72), 3.511 (0.76), 3.533 (0.95), 3.540 (0.98), 3.566 (0.62), 3.601 (1.43), 3.607 (1.32), 3.616 (0.55), 3.625 (1.07), 3.631 (1.19), 3.679 (1.02), 3.685 (0.88), 3.707 (1.76), 3.735 (0.77), 5.229 (4.75), 7.212 (1.65), 7.231 (1.88), 7.421 (6.10), 7.516 (1.24), 7.522 (1.25), 7.536 (1.07), 7.542 (1.10), 8.030 (0.60), 8.045 (1.30), 8.060 (0.60), 8.370 (1.73), 8.375 (1.75). LC-MS (方法1): Rt = 1.02 min; MS (ESIneg): m/z = 447 [M-H]- | 中間物63 GP H 條件A 15 mg,7%產率,95%純度 |
211 | 8'-甲基-2'-[(6-甲基吡啶-3-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.011 (0.58), -0.002 (16.00), 0.005 (0.50), 0.782 (0.54), 0.795 (1.42), 0.800 (1.76), 0.809 (0.93), 0.860 (1.02), 0.869 (2.04), 0.886 (0.70), 1.560 (0.44), 1.776 (0.41), 1.792 (0.74), 1.810 (0.83), 1.828 (0.74), 1.839 (0.44), 1.857 (0.49), 2.430 (8.12), 2.476 (10.11), 2.518 (3.81), 2.522 (2.41), 2.831 (4.42), 3.212 (0.92), 3.227 (1.80), 3.243 (1.00), 3.594 (0.57), 3.597 (0.57), 3.614 (0.76), 3.631 (0.40), 3.744 (0.67), 3.759 (0.57), 3.762 (0.56), 3.921 (0.63), 3.937 (0.89), 3.953 (0.55), 5.229 (3.35), 7.212 (1.16), 7.231 (1.32), 7.420 (4.50), 7.516 (0.87), 7.522 (0.87), 7.536 (0.76), 7.542 (0.75), 7.950 (0.42), 7.964 (0.90), 7.980 (0.41), 8.371 (1.23), 8.376 (1.21). LC-MS (方法1): Rt = 1.10 min; MS (ESIpos): m/z = 433 [M+H]+ | 中間物63 GP H 條件A 18 mg,9%產率,95%純度 |
實例 | 結構 IUPAC- 名稱 | 分析型資料 | 製備或分離方法 | ||||
212 | N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2'-[(6-甲基吡啶-3-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.80-0.86 (m, 2H), 0.88-0.92 (m, 2H), 2.43 (s, 3H), 2.91 (s, 2H), 3.18-3.28 (m, 3H), 3.40-3.49 (m, 1H), 3.51-3.59 (m, 1H), 3.59-3.66 (m, 2H), 3.68-3.76 (m, 2H), 5.24 (s, 2H), 7.22 (d, 1H), 7.48 (s, 1H), 7.54 (dd, 1H), 8.38 (d, 1H), 8.76 (t, 1H). LC-MS (方法1): Rt = 1.06 min; MS (ESIpos): m/z = 503 [M+H]⁺ | 中間物65及CAS-RN:[1523541-84-5] GP G (條件A,使用HATU) 6.7 mg (12%產率,98%純度). | ||||
213 | 2'-[(6-甲基吡啶-3-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.86-0.91 (m, 4H), 1.54-1.63 (m, 1H), 1.77-1.94 (m, 3H), 2.43 (s, 3H), 2.90 (s, 2H), 3.27 (t, 2H), 3.58-3.66 (m, 1H), 3.72-3.80 (m, 1H), 3.94 (quin, 1H), 5.24 (s, 2H), 7.22 (d, 1H), 7.48 (s, 1H), 7.53 (dd, 1H), 8.33-8.40 (m, 1H), 8.72 (t, 1H). LC-MS (方法1): Rt = 1.14 min; MS (ESIpos): m/z = 487 [M+H]⁺ | 中間物65及CAS-RN:[7175-81-7] GP G (條件A,使用HATU) 9.8 mg (16%產率,90%純度). | ||||
214 | 2'-[(5-甲基吡啶-2-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.82-0.87 (m, 2H), 0.88-0.93 (m, 2H), 1.53-1.62 (m, 1H), 1.80-1.94 (m, 3H), 2.27 (s, 3H), 2.92 (s, 2H), 3.27 (t, 2H), 3.58-3.66 (m, 1H), 3.76 (dt, 1H), 3.94 (quin, 1H), 5.29 (s, 2H), 6.99 (d, 1H), 7.48 (s, 1H), 7.54-7.61 (m, 1H), 8.33-8.40 (m, 1H), 8.72 (t, 1H). LC-MS (方法1): Rt = 1.21 min; MS (ESIpos): m/z = 487 [M+H]⁺ | 中間物66及CAS-RN:[7175-81-7] GP G (條件A,使用HATU) 6.2 mg (16%產率,83%純度). | ||||
215 | N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2'-[(5-甲基吡啶-2-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.84-0.86 (m, 2H), 0.90-0.92 (m, 2H), 2.27 (s, 3H), 2.92 (s, 2H), 3.18-3.28 (m, 3H), 3.41-3.49 (m, 1H), 3.51-3.59 (m, 1H), 3.59-3.67 (m, 2H), 3.68-3.77 (m, 2H), 5.29 (s, 2H), 7.00 (d, 1H), 7.48 (s, 1H), 7.55-7.63 (m, 1H), 8.32-8.40 (m, 1H), 8.76 (t, 1H). LC-MS (方法1): Rt = 1.12 min; MS (ESIpos): m/z = 503 [M+H]⁺ | 中間物66及CAS-RN:[1523541-84-5] GP G (條件A,使用HATU) 5.8 mg (17%產率,97%純度). | ||||
216 | N-[(2R)-1,4-二㗁烷-2-基甲基]-2'-(吡啶-4-基甲基)-8'-(三氟甲基)-2',5'-二氫螺[環丙-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.82-0.89 (m, 2H), 0.89-0.95 (m, 2H), 2.94 (s, 2H), 3.18-3.30 (m, 3H), 3.41-3.50 (m, 1H), 3.51-3.59 (m, 1H), 3.59-3.67 (m, 2H), 3.68-3.77 (m, 2H), 5.33 (s, 2H), 7.07-7.17 (m, 2H), 7.53 (s, 1H), 8.47-8.57 (m, 2H), 8.72-8.80 (m, 1H) LC-MS (方法1): Rt = 1.02 min; MS (ESIpos): m/z = 489 [M+H]⁺ | 中間物67及CAS-RN:[1523541-84-5] GP G (條件A,使用HATU) 12.5 mg (54%產率,98%純度) | ||||
217 | 2'-(吡啶-4-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丙-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.82-0.89 (m, 2H), 0.89-0.95 (m, 2H), 1.53-1.61 (m, 1H), 1.75-1.94 (m, 3H), 2.94 (s, 2H), 3.27 (t, 2H), 3.58-3.67 (m, 1H), 3.76 (td, 1H), 3.94 (quin, 1H), 5.33 (s, 2H), 7.09-7.14 (m, 2H), 7.53 (s, 1H), 8.50-8.55 (m, 2H), 8.73 (t, 1H) LC-MS (方法1): Rt = 1.10 min; MS (ESIpos): m/z = 473 [M+H]⁺ | 中間物67及CAS-RN:[7175-81-7] GP G (條件A,使用HATU) 12.7 mg (58%產率,99%純度) | ||||
218 | N-{[(2S)-氧雜環戊-2-基]甲基}-2'-[(吡啶-2-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.81-0.88 (m, 2H), 0.89-0.95 (m, 2H), 1.52-1.61 (m, 1H), 1.74-1.94 (m, 3H), 2.93 (s, 2H), 3.27 (t, 2H), 3.58-3.66 (m, 1H), 3.76 (dt, 1H), 3.94 (quin, 1H), 5.35 (s, 2H), 7.05 (d, 1H), 7.31 (ddd, 1H), 7.52 (s, 1H), 7.77 (td, 1H), 8.51-8.55 (m, 1H), 8.73 (t, 1H). LC-MS (方法1): Rt = 1.16 min; MS (ESIpos): m/z = 473 [M+H]⁺ | 中間物68及CAS-RN:[7175-81-7] GP G (條件A,使用HATU) 10.9 mg (59%產率,99%純度) | ||||
219 | N-[(2R)-1,4-二㗁烷-2-基甲基]-2'-(吡啶-2-基甲基)-8'-(三氟甲基)-2',5'-二氫螺[環丙-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 0.83-0.89 (m, 2H), 0.89-0.93 (m, 2H), 2.93 (s, 2H), 3.17-3.29 (m, 3H), 3.41-3.49 (m, 1H), 3.51-3.59 (m, 1H), 3.60-3.67 (m, 2H), 3.68-3.77 (m, 2H), 5.35(s, 2H), 7.06 (d, 1H), 7.31 (ddd, 1H), 7.52 (s, 1H), 7.77 (td, 1.77 Hz, 1H), 8.50-8.57 (m, 1H), 8.76 (t, 1H) LC-MS (方法1): Rt = 1.06 min; MS (ESIpos): m/z = 489 [M+H]⁺ | 中間物68及CAS-RN:[1523541-84-5] GP G (條件A,使用HATU) 13.4 mg (70%產率,99%純度) | ||||
220 | N,2-雙{[(2R)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (5.18), 2.331 (1.89), 2.336 (0.86), 2.518 (10.80), 2.523 (6.99), 2.673 (1.98), 2.678 (0.99), 2.842 (2.30), 2.846 (2.34), 2.865 (9.33), 2.883 (7.55), 2.930 (8.03), 2.932 (8.08), 2.948 (11.22), 2.955 (4.14), 2.967 (2.76), 2.972 (2.71), 3.188 (1.18), 3.197 (4.61), 3.203 (2.46), 3.221 (7.76), 3.226 (6.47), 3.237 (10.12), 3.250 (9.45), 3.264 (8.63), 3.280 (3.97), 3.290 (5.80), 3.298 (2.93), 3.383 (0.41), 3.406 (1.54), 3.412 (1.90), 3.424 (1.92), 3.433 (4.21), 3.439 (4.29), 3.450 (4.25), 3.457 (5.03), 3.461 (4.44), 3.467 (3.49), 3.478 (3.70), 3.485 (3.41), 3.502 (2.89), 3.508 (3.39), 3.525 (3.56), 3.531 (7.12), 3.537 (4.16), 3.553 (4.66), 3.559 (5.46), 3.564 (3.00), 3.580 (1.90), 3.586 (3.16), 3.613 (8.80), 3.628 (3.64), 3.643 (7.77), 3.660 (1.10), 3.666 (1.28), 3.696 (4.66), 3.702 (4.14), 3.725 (8.64), 3.730 (9.95), 3.737 (6.50), 3.749 (4.52), 3.759 (5.12), 3.765 (4.05), 3.789 (1.24), 3.796 (1.09), 3.802 (1.90), 3.808 (2.13), 3.813 (2.21), 3.819 (2.07), 3.826 (2.62), 3.832 (1.82), 3.842 (1.32), 3.849 (1.08), 4.052 (1.24), 4.068 (0.74), 4.088 (6.96), 4.097 (7.58), 4.104 (7.52), 4.110 (6.96), 4.133 (1.27), 4.146 (0.71), 7.467 (0.40), 7.525 (16.00), 8.734 (2.58), 8.749 (5.30), 8.764 (2.43). LC-MS (方法1): Rt = 0.93 min; MS (ESIpos): m/z = 472 [M+H]⁺ | 中間物70及CAS-RN:[1523541-84-5] GP G (條件A,使用HATU) 29.2 mg (30%產率,98%純度) | ||||
221 | 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (0.48), 1.524 (0.53), 1.541 (1.79), 1.543 (1.70), 1.553 (1.50), 1.560 (2.55), 1.569 (2.37), 1.577 (1.98), 1.584 (1.66), 1.590 (2.26), 1.606 (1.44), 1.759 (0.51), 1.773 (1.16), 1.779 (0.92), 1.788 (2.12), 1.794 (2.79), 1.810 (5.00), 1.828 (5.03), 1.845 (3.37), 1.861 (2.76), 1.866 (1.66), 1.871 (1.94), 1.878 (2.19), 1.883 (1.91), 1.890 (2.48), 1.900 (1.68), 1.904 (1.99), 1.907 (2.00), 1.911 (1.76), 1.921 (1.47), 1.928 (1.34), 1.942 (0.85), 2.074 (1.03), 2.518 (7.06), 2.523 (5.04), 2.841 (2.23), 2.846 (2.35), 2.865 (9.77), 2.883 (8.40), 2.926 (8.76), 2.928 (8.73), 2.944 (11.58), 2.952 (4.35), 2.963 (2.98), 2.968 (2.81), 3.237 (4.39), 3.255 (7.94), 3.261 (6.89), 3.269 (15.57), 3.285 (8.59), 3.290 (6.41), 3.406 (1.43), 3.412 (1.76), 3.433 (3.82), 3.440 (4.22), 3.461 (3.59), 3.467 (3.36), 3.503 (2.84), 3.509 (3.25), 3.532 (3.97), 3.537 (4.00), 3.558 (1.92), 3.564 (2.46), 3.597 (1.92), 3.613 (7.57), 3.634 (6.63), 3.652 (3.21), 3.714 (4.15), 3.731 (4.26), 3.738 (6.56), 3.741 (6.15), 3.758 (7.46), 3.765 (4.92), 3.774 (4.55), 3.776 (4.13), 3.789 (1.64), 3.794 (3.50), 3.802 (2.16), 3.808 (2.28), 3.812 (2.41), 3.818 (2.18), 3.825 (2.74), 3.842 (1.38), 3.849 (1.17), 3.920 (1.23), 3.936 (3.55), 3.951 (5.82), 3.967 (3.70), 3.982 (0.93), 4.051 (1.24), 4.068 (0.72), 4.087 (7.26), 4.097 (7.88), 4.104 (8.01), 4.110 (7.40), 4.132 (1.33), 4.145 (0.79), 7.524 (16.00), 8.697 (2.59), 8.712 (5.41), 8.727 (2.59). LC-MS (方法1): Rt = 1.02 min; MS (ESIpos): m/z = 456 [M+H]+ | 中間物69 GP G 條件A 416 mg,84%產率,99%純度 | ||||
222 | N-{[(2±)-4,4-二氟氧雜環戊-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.15 - 2.30 (m, 1 H) 2.53 - 2.61 (m, 1 H) 2.84 - 2.89 (m, 2 H) 2.93 - 2.97 (m, 2 H) 3.23 - 3.30 (m, 1 H) 3.37 - 3.49 (m, 3 H) 3.49 - 3.57 (m, 1 H) 3.60 - 3.65 (m, 1 H) 3.70 - 3.92 (m, 4 H) 4.01 - 4.13 (m, 3 H) 4.24 - 4.32 (m, 1 H) 7.53 (s, 1 H) 8.85 (t, 1H) LC-MS (方法1): Rt = 1.09 min; MS (ESIpos): m/z = 492 [M+H]+ | 中間物69 GP H 條件A 10 mg,4%產率,95%純度 兩種異構體的混合物 | ||||
222-1 | N-{[(2R或2S)-4,4-二氟氧雜環戊-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 實例222之非對映異構體1 | Rt = 8.18 min1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.15 - 2.30 (m, 1 H) 2.53 - 2.61 (m, 1 H) 2.84 - 2.89 (m, 2 H) 2.93 - 2.97 (m, 2 H) 3.23 - 3.30 (m, 1 H) 3.37 - 3.49 (m, 3 H) 3.49 - 3.57 (m, 1 H) 3.61 - 3.65 (m, 1 H) 3.71 - 3.91 (m, 4 H) 4.02 - 4.13 (m, 3 H) 4.25 - 4.32 (m, 1 H) 7.53 (s, 1 H) 8.85 (t, 1H) | 分析型方法: 儀器:Waters Alliance 2695;管柱:YMC Cellulose SB 3µ,100×4.6;溶離劑A:己烷+ 0.1 vol%二乙胺;溶離劑B:乙醇;等度:90% A + 10% B;流量:1.4 ml/min;溫度:25℃;UV:254 nm | ||||
222-2 | N-{[(2S或2R)-4,4-二氟氧雜環戊-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 實例222之非對映異構體2 | Rt = 9.19 min1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.15 - 2.30 (m, 1 H) 2.53 - 2.61 (m, 1 H) 2.84 - 2.89 (m, 2 H) 2.93 - 2.97 (m, 2 H) 3.23 - 3.30 (m, 1 H) 3.38 - 3.49 (m, 3 H) 3.49 - 3.57 (m, 1 H) 3.61 - 3.65 (m, 1 H) 3.71 - 3.91 (m, 4 H) 4.02 - 4.15 (m, 3 H) 4.25 - 4.32 (m, 1 H) 7.53 (s, 1 H) 8.85 (t, 1H) | |||||
223 | N-{[(2±)-5,5-二甲基氧雜環戊-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | LC-MS (方法1): Rt = 1.18 min; MS (ESIpos): m/z = 484 [M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.14 (s, 3 H) 1.20 (s, 3 H) 1.66 - 1.73 (m, 3 H) 1.91 - 2.02 (m, 1 H) 2.83 - 2.90 (m, 2 H) 2.91 - 2.98 (m, 2 H) 3.22 - 3.30 (m, 3 H) 3.40 - 3.48 (m, 1 H) 3.49 - 3.58 (m, 1 H) 3.60 - 3.66 (m, 1 H) 3.70 - 3.78 (m, 2 H) 3.79 - 3.87 (m, 1 H) 3.99 - 4.07 (m, 1 H) 4.08 - 4.12 (m, 2 H) 7.52 (s, 1 H) 8.66 (t, 1H) | 中間物69 GP H 條件A 54 mg,21%產率,99%純度 兩種異構體的混合物 | ||||
223-1 | N-{[(2R或2S)-5,5-二甲基氧雜環戊-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 實例223之非對映異構體1 | Rt = 3.58 min1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.14 (s, 3 H) 1.20 (s, 3 H) 1.66 - 1.73 (m, 3 H) 1.91 - 2.02 (m, 1 H) 2.83 - 2.90 (m, 2 H) 2.91 - 2.98 (m, 2 H) 3.22 - 3.30 (m, 3 H) 3.40 - 3.48 (m, 1 H) 3.49 - 3.58 (m, 1 H) 3.61 - 3.64 (m, 1 H) 3.70 - 3.78 (m, 2 H) 3.79 - 3.87 (m, 1 H) 3.99 - 4.07 (m, 1 H) 4.08 - 4.12 (m, 2 H) 7.52 (s, 1 H) 8.65 (t, 1H) | 分析型方法: 儀器:Waters Alliance 2695;管柱:Chiralpak IG 3µ,100×4.6;溶離劑A:己烷 + 0.1 vol%二乙胺;溶離劑B:乙醇;等度:50% A + 50% B;流量:1.4 ml/min;溫度:25℃;UV:220 nm | ||||
223-2 | N-{[(2S或2R)-5,5-二甲基氧雜環戊-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 實例223之非對映異構體2 | Rt = 4.94 min1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.15 (s, 3 H) 1.20 (s, 3 H) 1.66 - 1.73 (m, 3 H) 1.91 - 2.02 (m, 1 H) 2.83 - 2.90 (m, 2 H) 2.91 - 2.98 (m, 2 H) 3.22 - 3.30 (m, 3 H) 3.40 - 3.48 (m, 1 H) 3.49 - 3.58 (m, 1 H) 3.61 - 3.64 (m, 1 H) 3.70 - 3.78 (m, 2 H) 3.79 - 3.87 (m, 1 H) 3.99 - 4.07 (m, 1 H) 4.08 - 4.12 (m, 2 H) 7.52 (s, 1 H) 8.66 (t, 1H) | |||||
224 | 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(2±,5±)-5-甲基氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.113 (3.94), 1.124 (4.19), 1.158 (15.40), 1.170 (16.00), 1.232 (0.49), 1.367 (0.74), 1.372 (1.10), 1.387 (1.37), 1.394 (1.00), 1.401 (0.86), 1.409 (0.92), 1.425 (0.60), 1.607 (0.73), 1.616 (0.64), 1.631 (1.07), 1.641 (0.88), 1.653 (0.86), 1.662 (0.58), 1.856 (0.48), 1.871 (0.98), 1.887 (1.59), 1.897 (0.93), 1.901 (1.11), 1.907 (1.41), 1.912 (2.04), 1.916 (1.24), 1.921 (1.31), 1.924 (1.18), 1.938 (0.91), 1.948 (0.78), 1.964 (0.59), 1.994 (0.76), 2.514 (5.34), 2.518 (4.86), 2.522 (3.96), 2.847 (1.51), 2.864 (5.78), 2.879 (4.47), 2.929 (4.77), 2.943 (5.88), 2.958 (1.57), 2.961 (1.67), 3.233 (0.69), 3.242 (2.93), 3.251 (1.01), 3.261 (4.70), 3.265 (3.65), 3.273 (3.82), 3.284 (5.71), 3.294 (2.02), 3.313 (1.15), 3.364 (0.90), 3.412 (0.99), 3.417 (1.19), 3.434 (2.26), 3.439 (2.45), 3.456 (1.90), 3.461 (1.72), 3.507 (1.56), 3.512 (1.79), 3.531 (2.19), 3.536 (2.18), 3.552 (1.12), 3.557 (1.30), 3.613 (2.32), 3.637 (1.77), 3.717 (2.19), 3.732 (2.32), 3.737 (3.90), 3.755 (1.99), 3.760 (2.24), 3.794 (0.65), 3.809 (1.20), 3.813 (1.35), 3.817 (1.21), 3.823 (1.54), 3.828 (1.12), 3.837 (0.72), 3.842 (0.64), 3.865 (1.14), 3.877 (1.84), 3.882 (1.03), 3.889 (1.42), 3.893 (1.36), 3.905 (1.04), 3.912 (1.51), 3.925 (2.09), 3.938 (1.53), 3.951 (0.45), 4.034 (0.48), 4.050 (0.46), 4.058 (1.07), 4.072 (0.90), 4.087 (4.21), 4.097 (5.12), 4.101 (4.89), 4.107 (4.12), 4.126 (0.85), 4.136 (0.58), 7.522 (9.22), 8.681 (1.20), 8.693 (2.64), 8.705 (1.37). LC-MS (方法1): Rt = 1.11 min; MS (ESIpos): m/z = 470 [M+H]+ | 中間物69 GP H 條件A 20 mg,13%產率,99%純度 順式/反式異構體的混合物 | ||||
224-1 | 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(2R或2S,5R或5S)-5-甲基氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 實例224之非對映異構體1 | Rt = 3.66 min1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.17 (d, 3H) 1.35 - 1.43 (m, 1 H) 1.59 - 1.69 (m, 1 H) 1.85 - 1.97 (m, 2 H) 2.84 - 2.88 (m, 2 H) 2.93 - 2.97 (m, 2 H) 3.24 - 3.30 (m, 3 H) 3.41 - 3.48 (m, 1 H) 3.49 - 3.56 (m, 1 H) 3.61 - 3.64 (m, 1 H) 3.71 - 3.76 (m, 2 H) 3.79 - 3.85 (m, 1 H) 3.86 - 3.96 (m, 2 H) 4.04 - 4.15 (m, 2 H) 7.52 (s, 1 H) 8.69 (t, 1H) | 分析型方法: 儀器:Thermo Fisher UltiMate 3000;管柱:Chiralpak IF 3µ,100×4.6;溶離劑A:己烷 + 0.1 vol%二乙胺;溶離劑B:2-丙醇;等度:70% A + 30% B;流量:1.4 ml/min;溫度:25℃;UV:254 nm | ||||
224-2 | 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(2S或2R,5S或5R)-5-甲基氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 實例224之非對映異構體2 | Rt = 5.84 min1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.17 (d, 3H) 1.35 - 1.43 (m, 1 H) 1.59 - 1.69 (m, 1 H) 1.85 - 2.00 (m, 2 H) 2.84 - 2.88 (m, 2 H) 2.93 - 2.97 (m, 2 H) 3.24 - 3.30 (m, 3 H) 3.41 - 3.48 (m, 1 H) 3.49 - 3.56 (m, 1 H) 3.61 - 3.64 (m, 1 H) 3.71 - 3.76 (m, 2 H) 3.79 - 3.85 (m, 1 H) 3.86 - 3.96 (m, 2 H) 4.04 - 4.15 (m, 2 H) 7.52 (s, 1 H) 8.69 (t, 1H). | |||||
225 | 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-[2-(1H-1,2,3-三唑-1-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.83-2.90 (m, 2H), 2.91-2.98 (m, 2H), 3.26 (dd, 1H), 3.40-3.48 (m, 1H), 3.49-3.57 (m, 1H), 3.62 (br d, 1H), 3.66-3.77 (m, 4H), 3.78-3.88 (m, 1H), 4.03-4.16 (m, 2H), 4.56 (t, 2H), 7.52 (s, 1H), 7.72 (d, 1H), 8.12 (d, 1H), 8.86 (t, 1H). LC-MS (方法1): Rt = 0.84 min; MS (ESIneg): m/z = 465 [M-H]⁻ | 中間物69及CAS-RN:[4320-94-9] GP G 條件A 66.9 mg (76%產率,99%純度) | ||||
226 | 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-(1,3-噻唑-2-基甲基)-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.85-2.91 (m, 2H), 2.93-3.01 (m, 2H), 3.27 (dd, 1H), 3.41-3.48 (m, 1H), 3.49-3.58 (m, 1H), 3.63 (br d, 1H), 3.71-3.78 (m, 2H), 3.78-3.86 (m, 1H), 4.03-4.18 (m, 2H), 4.72 (d, 2H), 7.54 (s, 1H), 7.65 (d, 1H), 7.74 (d, 1H), 9.59 (t, 1H) LC-MS (方法1): Rt = 0.95 min; MS (ESIpos): m/z = 469 [M+H]⁺ | 中間物69及CAS-RN:[53332-78-8] GP G 條件A 52.3 mg (58%產率,97%純度) | ||||
227 | 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[(5-甲基吡𠯤-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.48 (s, 3H), 2.84-2.91 (m, 2H), 2.93-2.99 (m, 2H), 3.26 (dd, 1H), 3.40-3.48 (m, 1H), 3.50-3.57 (m, 1H), 3.63 (br d, 1H), 3.70-3.78 (m, 2H), 3.79-3.86 (m, 1H), 4.04-4.16 (m, 2H), 4.54 (d, 2H), 7.53 (s, 1H), 8.49 (s, 2H), 9.32 (t, 1H) LC-MS (方法1): Rt = 0.93 min; MS (ESIpos): m/z = 478 [M+H]⁺ | 中間物69及CAS-RN:[132664-85-8 GP G 條件A 67.2 mg (70%產率,93%純度) | ||||
228 | 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-(吡𠯤-2-基甲基)-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.84-2.90 (m, 2H), 2.94-2.99 (m, 2H), 3.27 (dd, 1H), 3.40-3.48 (m, 1H), 3.49-3.57 (m, 1H), 3.63 (br d, 1H), 3.70-3.78 (m, 2H), 3.78-3.86 (m, 1H), 4.04-4.16 (m, 2H), 4.59 (d, 2H), 7.53 (s, 1H), 8.55 (d, 1H), 8.61 (dd, 1H), 8.64 (d, 1H), 9.36 (t, 1H) LC-MS (方法1): Rt = 0.89 min; MS (ESIneg): m/z = 462 [M-H]⁻ | 中間物69及CAS-RN:[20010-99-5] GP G 條件A 65.3 mg (68%產率,91%純度) | ||||
229 | 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[(1-甲基-1H-咪唑-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.83-2.89 (m, 2H), 2.90-2.96 (m, 2H), 3.26 (dd, 1H), 3.39-3.47 (m, 1H), 3.50-3.57 (m, 1H), 3.60 (s, 3H), 3.61-3.65 (m, 1H), 3.70-3.78 (m, 2H), 3.78-3.85 (m, 1H), 4.03-4.15 (m, 2H), 4.27 (d, 2H), 6.96 (d, 1H), 7.49 (d, 1H), 7.52 (s, 1H), 8.93 (t, 1H) LC-MS (方法1): Rt = 0.87 min; MS (ESIpos): m/z = 466 [M+H]⁺ | 中間物69及CAS-RN:[486414-83-9] GP G 條件A 40.4 mg (46%產率,99%純度) | ||||
230 | 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-(1,3-噻唑-5-基甲基)-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.83-2.89 (m, 2H), 2.91-2.97 (m, 2H), 3.26 (dd, 1H), 3.40-3.48 (m, 1H), 3.49-3.57 (m, 1H), 3.62 (br d, 1H), 3.69-3.77 (m, 2H), 3.78-3.87 (m, 1H), 4.01-4.15 (m, 2H), 4.64 (d, 2H), 7.52 (s, 1H), 7.81 (d, 1H), 8.99 (d, 1H), 9.40 (t, 1H) LC-MS (方法1): Rt = 0.82 min; MS (ESIneg): m/z = 467 [M-H]⁻ | 中間物69及CAS-RN:[131052-46-5] GP G 條件A 54.8 mg (61%產率,98%純度) | ||||
231 | 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[2-(4-甲基吡啶-2-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.28 (s, 3H), 2.83-2.89 (m, 2H), 2.90-2.97 (m, 4H), 3.26 (dd, 1H), 3.39-3.47 (m, 1H), 3.50-3.60 (m, 3H), 3.63 (br d, 1H), 3.70-3.78 (m, 2H), 3.78-3.86 (m, 1H), 4.04-4.15 (m, 2H), 7.07 (d, 1H), 7.12 (s, 1H), 7.52 (s, 1H), 8.36 (d, 1H), 8.82 (t, 1H) LC-MS (方法1): Rt = 1.06 min; MS (ESIpos): m/z = 491 [M+H]⁺ | 中間物69及CAS-RN:[851670-49-0] GP G 條件A 53.6 mg (50%產率,98%純度) | ||||
232 | 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-[2-(1H-咪唑-1-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.83-2.90 (m, 2H), 2.91-2.97 (m, 2H), 3.26 (dd, 1H), 3.40-3.48 (m, 1H), 3.50-3.59 (m, 3H), 3.63 (br d, 1H), 3.70-3.77 (m, 2H), 3.78-3.85 (m, 1H), 4.10 (dd, 2H), 4.15 (t, 2H), 6.88 (t, 1H), 7.16 (t, 1H), 7.52 (s, 1H), 7.59 (t, 1H), 8.84 (t, 1H). LC-MS (方法1): Rt = 0.87 min; MS (ESIneg): m/z = 464 [M-H]⁻ | 中間物69及CAS-RN:[93668-43-0] GP G 條件A 63.5 mg (61%產率,96%純度) | ||||
233 | 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[2-(吡啶-2-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm] .2.82-2.91 (m, 2H), 2.91-3.02 (m, 4H), 3.26 (dd, 1H), 3.38-3.48 (m, 1H), 3.52 (dd, 1H), 3.55-3.65 (m, 3H), 3.70-3.77 (m, 2H), 3.78-3.86 (m, 1H), 4.03-4.15 (m, 2H), 7.23 (ddd, 1H), 7.29 (d, 1H), 7.52 (s, 1H), 7.72 (td, 1H), 8.48-8.53 (m, 1H), 8.82 (t, 1H) LC-MS (方法1): Rt = 0.87 min; MS (ESIpos): m/z = 477 [M+H]⁺ | 中間物69及CAS-RN:[2706-56-1] GP G 條件A 62.4 mg (60%產率,99%純度) | ||||
234 | 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[2-(3-甲基-1H-吡唑-1-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.15 (s, 3H), 2.82-2.90 (m, 2H), 2.91-2.98 (m, 2H), 3.26 (dd, 1H), 3.40-3.47 (m, 1H), 3.52 (dd, 1H), 3.55-3.66 (m, 3H), 3.70-3.77 (m, 2H), 3.78-3.86 (m, 1H), 4.05-4.15 (m, 2H), 4.17 (t, 2H), 5.99 (d, 1H), 7.53 (s, 1H), 7.56 (d, 1H), 8.81 (t, 1H) LC-MS (方法1): Rt = 0.93 min; MS (ESIpos): m/z = 480 [M+H]⁺ | 中間物69及CAS-RN:[62821-90-3] GP G 條件A 53.2 mg (61%產率,97%純度) | ||||
235 | 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[2-(1H-咪唑-4-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.83-2.89 (m, 4H), 2.91-2.97 (m, 2H), 3.26 (dd, 1H), 3.40-3.57 (m, 4H), 3.63 (br d, 1H), 3.70-3.77 (m, 2H), 3.78-3.87 (m, 1H), 4.03-4.15 (m, 2H), 7.32 (ddd, 1H), 7.52 (s, 1H), 7.67 (dt, 1H), 8.42 (dd, 1H), 8.45 (d, 1H), 8.83 (t, 1H) LC-MS (方法1): Rt = 0.74 min; MS (ESIneg): m/z = 464 [M-H]⁻ | 中間物69及CAS-RN:[56-92-8] GP G 條件A 68.3 mg (66%產率,96%純度) | ||||
236 | 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[2-(吡啶-3-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.83-2.89 (m, 4H), 2.91-2.97 (m, 2H), 3.26 (dd, 1H), 3.40-3.57 (m, 4H), 3.63 (br d, 1H), 3.70-3.77 (m, 2H), 3.78-3.87 (m, 1H), 4.03-4.15 (m, 2H), 7.32 (ddd, 1H), 7.52 (s, 1H), 7.67 (dt, 1H), 8.42 (dd, 1H), 8.45 (d, 1H), 8.83 (t, 1H) LC-MS (方法1): Rt = 0.92 min; MS (ESIneg): m/z = 475 [M-H]⁻ | 中間物69及CAS-RN:[20173-24-4] GP G 條件A 64.2 mg (61%產率,97%純度) | ||||
237 | 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[2-(1,3-噻唑-2-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.84-2.89 (m, 2H), 2.92-2.98 (m, 2H), 3.22-3.30 (m, 3H), 3.39-3.47 (m, 1H), 3.49-3.65 (m, 4H), 3.70-3.78 (m, 2H), 3.78-3.86 (m, 1H), 4.00-4.16 (m, 2H), 7.53 (s, 1H), 7.61 (d, 1H), 7.73 (d, 1H), 8.89 (t, 1H) LC-MS (方法1): Rt = 0.88 min; MS (ESIpos): m/z = 483 [M+H]⁺ | 中間物69及CAS-RN:[18453-07-1] GP G 條件A 61.3 mg (59%產率,99%純度) | ||||
238 | 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[(6-甲基吡啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.46 (s, 3H), 2.84-2.91 (m, 2H), 2.93-3.00 (m, 2H), 3.27 (dd, 1H), 3.40-3.49 (m, 1H), 3.50-3.58 (m, 1H), 3.63 (br d, 1H), 3.70-3.79 (m, 2H), 3.78-3.87 (m, 1H), 4.01-4.17 (m, 2H), 4.48 (d, 2H), 7.12 (dd, 2H), 7.53 (s, 1H), 7.66 (t, 1H), 9.28 (t, 1H) LC-MS (方法1): Rt = 1.07 min; MS (ESIpos): m/z = 477 [M+H]⁺ | 中間物69及CAS-RN:[6627-60-7] GP G 條件A 70.1 mg (64%產率,94%純度) | ||||
239 | 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-(1,3-㗁唑-4-基甲基)-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.83-2.90 (m, 2H), 2.91-2.97 (m, 2H), 3.26 (dd, 1H), 3.40-3.47 (m, 1H), 3.53 (td, 1H), 3.63 (br d, 1H), 3.70-3.78 (m, 2H), 3.78-3.86 (m, 1H), 4.04-4.15 (m, 2H), 4.33 (d, 2H), 7.53 (s, 1H), 7.97 (d, 1H), 8.33 (d, 1H), 9.13 (t, 1H). LC-MS (方法1): Rt = 0.92 min; MS (ESIpos): m/z = 453 [M+H]⁺ | 中間物69及CAS-RN:[847490-98-6] GP G 條件A 73.6 mg (73%產率,96%純度) | ||||
240 | 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-[2-(吡𠯤-2-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.21 (d, 3H), 2.83-2.89 (m, 2H), 2.91-2.97 (m, 2H), 3.26 (dd, 1H), 3.40-3.48 (m, 1H), 3.49-3.56 (m, 1H), 3.60-3.68 (m, 3H), 3.70-3.77 (m, 2H), 3.78-3.87 (m, 1H), 4.04-4.17 (m, 2H), 4.48 (t, 2H), 7.53 (s, 1H), 7.82 (s, 1H), 8.85 (t, 1H). LC-MS (方法1): Rt = 0.90 min; MS (ESIpos): m/z = 478 [M+H]⁺ | 中間物69及CAS-RN:[5321-59-5] GP G 條件A 72.6 mg (69%產率,98%純度) | ||||
241 | 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-[2-(4-甲基-1H-1,2,3-三唑-1-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]:2.82-2.89 (m, 2H), 2.91-2.96 (m, 2H), 3.04 (t, 2H), 3.26 (dd, 1H), 3.39-3.47 (m, 1H), 3.49-3.57 (m, 1H), 3.59-3.65 (m, 3H), 3.70-3.77 (m, 2H), 3.78-3.85 (m, 1H), 4.02-4.15 (m, 2H), 7.52 (s, 1H), 8.50 (d, 1H), 8.56-8.59 (m, 2H), 8.84 (t, 1H) LC-MS (方法1): Rt = 0.87 min; MS (ESIpos): m/z = 481 [M+H]⁺ | 中間物69及CAS-RN:[1086601-35-5] GP G 條件A 67.8 mg (64%產率,98%純度) | ||||
242 | N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-[(㗁烷-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.002 (1.19), 0.931 (2.75), 0.934 (0.93), 0.948 (2.84), 0.952 (0.48), 1.173 (1.01), 1.184 (1.20), 1.203 (2.84), 1.214 (3.17), 1.235 (3.83), 1.246 (3.45), 1.265 (1.74), 1.276 (1.56), 1.343 (0.56), 1.401 (4.92), 1.428 (3.48), 1.953 (0.63), 1.963 (1.18), 1.973 (1.28), 1.981 (1.48), 1.991 (1.86), 2.000 (1.42), 2.009 (1.22), 2.019 (1.04), 2.332 (1.96), 2.336 (0.84), 2.518 (9.07), 2.523 (5.87), 2.539 (0.42), 2.678 (0.87), 2.836 (2.18), 2.841 (2.20), 2.859 (9.32), 2.877 (7.60), 2.921 (7.96), 2.924 (8.08), 2.940 (11.11), 2.946 (3.93), 2.958 (2.82), 2.964 (2.59), 3.186 (1.07), 3.195 (4.79), 3.200 (2.83), 3.207 (3.54), 3.212 (4.66), 3.220 (8.66), 3.224 (6.37), 3.235 (11.50), 3.241 (8.21), 3.249 (10.54), 3.263 (7.12), 3.278 (3.91), 3.297 (2.27), 3.313 (2.18), 3.423 (1.48), 3.429 (1.80), 3.449 (3.90), 3.456 (4.23), 3.476 (3.43), 3.483 (3.29), 3.524 (2.95), 3.530 (3.36), 3.552 (4.01), 3.558 (4.19), 3.578 (1.61), 3.585 (2.86), 3.604 (1.42), 3.611 (4.35), 3.619 (5.39), 3.626 (3.26), 3.635 (2.56), 3.643 (5.39), 3.649 (4.00), 3.658 (1.01), 3.665 (1.18), 3.694 (4.55), 3.701 (3.75), 3.723 (7.82), 3.729 (6.62), 3.752 (3.28), 3.798 (4.37), 3.805 (4.33), 3.828 (4.00), 3.834 (3.83), 3.945 (11.67), 3.963 (11.50), 7.541 (16.00), 8.717 (2.54), 8.732 (5.33), 8.746 (2.53). LC-MS (方法1): Rt = 1.02 min; MS (ESIpos): m/z = 470 [M+H]+ | 中間物71 GP H 條件B 55 mg,33%產率,95%純度 | ||||
243 | 2-[(㗁烷-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.002 (0.42), 1.173 (1.08), 1.184 (1.20), 1.203 (2.63), 1.213 (2.94), 1.235 (3.72), 1.246 (3.18), 1.265 (1.63), 1.276 (1.43), 1.401 (4.45), 1.428 (3.17), 1.522 (0.52), 1.539 (1.66), 1.551 (1.36), 1.555 (1.49), 1.558 (2.24), 1.567 (2.08), 1.575 (1.74), 1.583 (1.40), 1.588 (1.96), 1.605 (1.23), 1.758 (0.45), 1.772 (1.01), 1.779 (0.76), 1.787 (1.85), 1.793 (2.32), 1.808 (4.31), 1.827 (4.18), 1.844 (2.73), 1.860 (2.27), 1.865 (1.30), 1.869 (1.60), 1.876 (1.78), 1.881 (1.63), 1.888 (2.08), 1.898 (1.35), 1.902 (1.59), 1.905 (1.60), 1.910 (1.44), 1.919 (1.15), 1.926 (1.09), 1.941 (0.88), 1.953 (0.60), 1.962 (1.07), 1.972 (1.20), 1.981 (1.37), 1.990 (1.71), 2.000 (1.28), 2.009 (1.09), 2.018 (0.93), 2.318 (0.93), 2.518 (9.83), 2.523 (6.49), 2.537 (0.49), 2.542 (0.50), 2.835 (1.84), 2.839 (1.93), 2.853 (3.21), 2.858 (8.35), 2.876 (6.81), 2.917 (7.33), 2.919 (7.17), 2.935 (10.19), 2.943 (3.39), 2.954 (2.40), 2.960 (2.29), 3.207 (2.87), 3.212 (3.49), 3.237 (6.28), 3.241 (6.49), 3.252 (6.92), 3.267 (16.00), 3.282 (7.26), 3.299 (1.17), 3.375 (0.89), 3.380 (0.49), 3.596 (1.49), 3.615 (3.47), 3.633 (4.18), 3.651 (2.37), 3.740 (1.99), 3.757 (3.78), 3.772 (3.63), 3.775 (3.23), 3.793 (4.98), 3.798 (4.10), 3.805 (3.96), 3.827 (3.64), 3.834 (3.49), 3.918 (1.08), 3.934 (3.60), 3.944 (11.37), 3.950 (7.36), 3.962 (11.45), 3.981 (0.91), 7.539 (14.20), 8.680 (2.22), 8.694 (4.62), 8.709 (2.19). LC-MS (方法1): Rt = 1.11 min; MS (ESIpos): m/z = 454 [M+H]+ | 中間物71 GP H 條件B 42 mg,26%產率,95%純度 | ||||
244 | 8-(二氟甲基)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.172 (0.57), 1.987 (0.98), 2.074 (1.66), 2.518 (16.00), 2.522 (10.77), 2.860 (1.47), 2.879 (6.00), 2.896 (5.14), 2.939 (5.23), 2.956 (6.54), 2.975 (1.67), 2.980 (1.54), 3.179 (1.03), 3.193 (4.35), 3.217 (4.16), 3.221 (4.03), 3.227 (3.59), 3.243 (5.20), 3.268 (4.40), 3.271 (4.27), 3.285 (3.41), 3.296 (4.32), 3.301 (2.91), 3.413 (1.49), 3.421 (1.26), 3.428 (1.65), 3.434 (2.62), 3.440 (2.97), 3.449 (2.89), 3.455 (3.19), 3.462 (2.63), 3.468 (2.40), 3.476 (2.57), 3.482 (2.38), 3.504 (1.98), 3.510 (2.45), 3.516 (2.34), 3.521 (2.50), 3.533 (2.91), 3.539 (3.17), 3.544 (3.24), 3.550 (3.05), 3.559 (1.56), 3.566 (2.04), 3.570 (1.68), 3.577 (1.91), 3.612 (5.35), 3.641 (5.02), 3.658 (1.72), 3.665 (1.86), 3.673 (1.58), 3.688 (1.00), 3.702 (3.37), 3.716 (5.63), 3.730 (3.33), 3.741 (5.92), 3.746 (7.54), 3.769 (2.20), 3.775 (2.88), 3.786 (1.02), 3.805 (1.46), 3.809 (1.52), 3.823 (1.73), 3.839 (0.90), 4.049 (0.93), 4.065 (0.58), 4.084 (4.22), 4.098 (5.59), 4.110 (4.16), 4.133 (0.94), 4.146 (0.61), 7.422 (0.55), 7.473 (2.00), 7.501 (10.82), 7.610 (4.18), 7.746 (1.68), 8.696 (1.70), 8.712 (3.52), 8.726 (1.70). LC-MS (方法1): Rt = 0.92 min; MS (ESIneg): m/z = 452 [M-H]⁻ | 中間物72 GP H 條件C 108 mg,35%產率,95%純度 | ||||
245 | 8-(二氟甲基)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (1.01), 1.531 (0.48), 1.549 (1.49), 1.564 (1.42), 1.568 (2.21), 1.577 (2.03), 1.585 (1.81), 1.593 (1.38), 1.598 (1.89), 1.614 (1.25), 1.754 (0.47), 1.768 (1.05), 1.774 (0.80), 1.783 (1.85), 1.789 (2.48), 1.804 (4.31), 1.822 (4.37), 1.841 (2.92), 1.854 (1.83), 1.864 (1.65), 1.871 (2.10), 1.877 (1.77), 1.883 (2.08), 1.893 (1.39), 1.897 (1.61), 1.904 (1.43), 1.914 (1.16), 1.921 (1.08), 1.936 (0.69), 2.075 (0.57), 2.327 (4.41), 2.332 (3.20), 2.336 (1.41), 2.518 (16.00), 2.523 (11.50), 2.669 (4.49), 2.673 (3.16), 2.678 (1.34), 2.855 (1.81), 2.860 (1.87), 2.879 (8.15), 2.897 (6.87), 2.938 (7.01), 2.955 (9.01), 2.962 (3.06), 2.974 (2.12), 2.980 (2.01), 3.212 (0.70), 3.227 (1.54), 3.244 (5.48), 3.261 (6.67), 3.268 (5.71), 3.272 (6.25), 3.278 (6.19), 3.296 (6.96), 3.312 (2.81), 3.408 (1.25), 3.414 (1.71), 3.435 (3.29), 3.441 (3.67), 3.462 (3.05), 3.468 (2.88), 3.504 (2.46), 3.510 (2.85), 3.533 (3.48), 3.539 (3.47), 3.560 (1.60), 3.566 (2.23), 3.591 (1.67), 3.611 (6.29), 3.627 (4.59), 3.645 (4.36), 3.716 (3.44), 3.736 (2.88), 3.741 (5.52), 3.746 (7.33), 3.750 (6.20), 3.768 (5.97), 3.774 (5.20), 3.788 (2.76), 3.799 (1.71), 3.805 (1.82), 3.810 (1.93), 3.816 (1.77), 3.822 (2.29), 3.829 (1.58), 3.840 (1.14), 3.846 (0.93), 3.941 (0.98), 3.957 (3.20), 3.974 (4.41), 3.989 (2.93), 4.005 (0.76), 4.048 (1.35), 4.065 (0.89), 4.084 (6.00), 4.097 (7.45), 4.100 (7.29), 4.109 (5.65), 4.133 (1.28), 4.145 (0.89), 7.421 (0.59), 7.480 (2.84), 7.500 (15.43), 7.617 (6.03), 7.754 (2.35), 8.553 (0.44), 8.655 (2.25), 8.670 (4.77), 8.685 (2.21). LC-MS (方法1): Rt = 1.00 min; MS (ESIneg): m/z = 436 [M-H]⁻ | 中間物72 GP H 條件C 83 mg,28%產率,98%純度 | ||||
246 | (4±)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4,8-二甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.280 (6.58), 1.297 (6.63), 2.440 (16.00), 2.522 (3.53), 2.551 (1.16), 2.567 (1.19), 2.583 (0.57), 2.592 (1.24), 2.713 (0.68), 2.960 (1.07), 2.978 (1.36), 3.001 (0.98), 3.020 (1.10), 3.159 (0.94), 3.179 (2.49), 3.194 (2.01), 3.203 (2.35), 3.208 (2.71), 3.226 (1.76), 3.232 (1.90), 3.242 (1.14), 3.261 (0.66), 3.276 (0.42), 3.413 (0.46), 3.419 (0.54), 3.440 (1.20), 3.446 (1.27), 3.467 (1.04), 3.473 (1.01), 3.509 (0.89), 3.515 (0.93), 3.537 (1.23), 3.544 (1.28), 3.564 (0.55), 3.570 (0.80), 3.606 (1.98), 3.622 (0.84), 3.630 (1.71), 3.636 (1.54), 3.652 (0.40), 3.682 (1.43), 3.689 (1.21), 3.712 (2.49), 3.740 (1.08), 5.385 (7.26), 7.067 (1.98), 7.086 (2.10), 7.294 (0.98), 7.307 (1.14), 7.310 (1.20), 7.323 (1.12), 7.682 (4.44), 7.684 (4.55), 7.755 (1.08), 7.759 (1.11), 7.774 (1.88), 7.778 (1.90), 7.794 (1.02), 7.798 (1.00), 8.043 (0.83), 8.058 (1.74), 8.073 (0.84), 8.536 (1.57), 8.546 (1.54), 8.548 (1.54). LC-MS (方法1): Rt = 1.00 min; MS (ESIneg): m/z = 421 [M-H]- | 中間物73 GP H 條件B 16 mg,18%產率,95%純度 兩種異構體的混合物 | ||||
247 | (4±)-4,8-二甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.280 (6.39), 1.296 (6.42), 1.548 (0.54), 1.565 (0.75), 1.572 (0.57), 1.580 (0.66), 1.593 (0.51), 1.774 (0.60), 1.779 (0.79), 1.794 (1.38), 1.812 (1.57), 1.830 (1.42), 1.843 (0.83), 1.856 (0.76), 1.860 (0.88), 1.874 (0.63), 1.881 (0.47), 1.891 (0.40), 2.439 (16.00), 2.517 (4.63), 2.522 (3.70), 2.548 (1.21), 2.565 (1.24), 2.582 (0.53), 2.590 (1.28), 2.673 (0.69), 2.712 (0.64), 2.959 (1.16), 2.977 (1.46), 3.000 (1.07), 3.019 (1.20), 3.157 (0.47), 3.174 (0.72), 3.181 (0.56), 3.193 (0.67), 3.199 (0.72), 3.211 (1.54), 3.214 (1.60), 3.227 (2.65), 3.245 (1.43), 3.581 (0.49), 3.600 (1.07), 3.618 (1.40), 3.636 (0.77), 3.731 (0.64), 3.748 (1.22), 3.766 (1.07), 3.784 (0.64), 3.926 (1.03), 3.943 (1.55), 3.958 (0.95), 5.385 (7.04), 7.067 (1.87), 7.086 (1.98), 7.291 (0.95), 7.294 (0.96), 7.304 (1.00), 7.307 (1.07), 7.310 (1.16), 7.313 (1.06), 7.322 (1.08), 7.325 (1.04), 7.681 (4.39), 7.683 (4.37), 7.755 (1.09), 7.759 (1.14), 7.774 (1.89), 7.778 (1.88), 7.794 (1.00), 7.798 (0.97), 7.965 (0.78), 7.980 (1.63), 7.995 (0.77), 8.532 (1.24), 8.534 (1.41), 8.536 (1.50), 8.538 (1.32), 8.544 (1.33), 8.546 (1.43), 8.548 (1.43), 8.550 (1.23). LC-MS (方法1): Rt = 1.08 min; MS (ESIneg): m/z = 405 [M-H]- | 中間物73 GP H 條件B 16 mg,19%產率,95%純度 兩種異構體的混合物 | ||||
248 | (4±)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,8-二甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.258 (4.08), 1.265 (4.12), 1.275 (4.28), 1.281 (4.00), 2.470 (16.00), 2.522 (9.09), 2.549 (2.05), 2.574 (1.45), 2.755 (0.43), 2.938 (0.74), 2.943 (0.78), 2.957 (0.99), 2.962 (0.92), 2.980 (0.67), 2.986 (0.70), 2.998 (0.76), 3.004 (0.78), 3.124 (0.60), 3.141 (0.87), 3.148 (0.97), 3.163 (1.24), 3.183 (2.58), 3.197 (1.83), 3.207 (2.18), 3.212 (2.78), 3.231 (2.07), 3.236 (2.44), 3.247 (1.46), 3.266 (2.29), 3.281 (0.77), 3.294 (1.48), 3.416 (0.93), 3.421 (0.94), 3.443 (2.11), 3.449 (2.16), 3.470 (1.80), 3.476 (1.82), 3.512 (1.53), 3.518 (1.31), 3.540 (2.12), 3.546 (1.91), 3.568 (1.03), 3.573 (1.13), 3.616 (2.58), 3.633 (2.23), 3.639 (2.09), 3.687 (1.62), 3.692 (1.43), 3.716 (4.44), 3.745 (2.55), 3.847 (0.78), 4.071 (1.28), 4.084 (2.48), 4.096 (2.29), 7.508 (3.32), 8.043 (0.91), 8.057 (1.89), 8.073 (0.89). LC-MS (方法1): Rt = 0.98 min; MS (ESIpos): m/z = 432 [M+H]+ | 中間物74 GP H 條件B 15 mg,10%產率,95%純度 兩種異構體的混合物 | ||||
249 | (4±)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,8-二甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.257 (4.00), 1.264 (4.13), 1.274 (4.28), 1.281 (3.97), 1.551 (0.60), 1.568 (0.84), 1.576 (0.68), 1.584 (0.73), 1.596 (0.57), 1.613 (0.44), 1.781 (0.88), 1.797 (1.56), 1.815 (1.74), 1.833 (1.55), 1.846 (0.96), 1.863 (1.01), 1.877 (0.74), 1.895 (0.46), 2.469 (16.00), 2.522 (5.60), 2.545 (1.76), 2.570 (1.12), 2.937 (0.72), 2.943 (0.75), 2.955 (0.92), 2.962 (0.91), 2.979 (0.67), 2.985 (0.65), 2.997 (0.75), 3.003 (0.73), 3.122 (0.56), 3.140 (0.82), 3.157 (0.65), 3.165 (0.75), 3.182 (0.50), 3.214 (1.42), 3.218 (1.40), 3.230 (2.77), 3.233 (2.79), 3.244 (1.97), 3.249 (1.71), 3.267 (1.87), 3.292 (1.24), 3.416 (0.42), 3.427 (0.40), 3.436 (0.72), 3.443 (0.85), 3.448 (0.79), 3.454 (0.80), 3.464 (0.69), 3.475 (0.69), 3.481 (0.57), 3.507 (0.48), 3.513 (0.56), 3.521 (0.51), 3.526 (0.52), 3.535 (0.69), 3.541 (0.76), 3.549 (0.71), 3.556 (0.73), 3.568 (0.47), 3.583 (0.94), 3.602 (1.35), 3.620 (2.82), 3.638 (1.17), 3.647 (1.08), 3.723 (2.55), 3.751 (3.37), 3.768 (1.34), 3.786 (0.69), 3.847 (0.75), 3.930 (1.19), 3.946 (1.76), 3.961 (1.09), 4.070 (1.26), 4.077 (1.57), 4.084 (2.46), 4.095 (2.18), 7.507 (3.37), 7.964 (0.88), 7.980 (1.85), 7.994 (0.91). LC-MS (方法1): Rt = 1.06 min; MS (ESIpos): m/z = 416 [M+H]+ | 中間物74 GP H 條件B 25 mg,17%產率,95%純度 兩種異構體的混合物 | ||||
250 | (4±)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-2-[(吡啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.286 (14.45), 1.303 (15.06), 2.323 (1.51), 2.327 (2.17), 2.331 (1.66), 2.447 (0.41), 2.518 (16.00), 2.523 (11.29), 2.595 (2.75), 2.621 (2.77), 2.636 (2.93), 2.663 (3.70), 2.669 (2.37), 2.673 (1.68), 3.025 (2.61), 3.044 (3.54), 3.067 (2.40), 3.085 (2.86), 3.178 (1.21), 3.195 (4.06), 3.219 (5.91), 3.236 (3.82), 3.247 (5.44), 3.257 (2.77), 3.262 (2.58), 3.278 (2.04), 3.421 (1.32), 3.428 (1.56), 3.449 (2.73), 3.455 (2.99), 3.476 (2.43), 3.482 (2.31), 3.522 (1.95), 3.528 (2.19), 3.551 (2.73), 3.557 (2.82), 3.577 (1.08), 3.583 (1.89), 3.619 (3.47), 3.626 (2.25), 3.642 (3.70), 3.664 (0.89), 3.695 (3.03), 3.700 (2.54), 3.723 (5.17), 3.751 (2.25), 5.395 (15.85), 7.079 (4.44), 7.099 (4.68), 7.295 (2.18), 7.298 (2.30), 7.307 (2.33), 7.310 (2.48), 7.314 (2.63), 7.317 (2.51), 7.326 (2.59), 7.329 (2.49), 7.727 (9.74), 7.729 (9.75), 7.758 (2.71), 7.762 (2.82), 7.777 (4.62), 7.781 (4.67), 7.796 (2.35), 7.800 (2.29), 8.533 (2.88), 8.535 (3.27), 8.537 (3.50), 8.539 (3.02), 8.545 (3.04), 8.547 (3.46), 8.549 (3.37), 8.552 (3.16), 8.736 (1.43), 8.751 (3.01), 8.766 (1.49). LC-MS (方法1): Rt = 1.06 min; MS (ESIpos): m/z = 477 [M+H]+ | 中間物75 GP H 條件A 36 mg,54%產率,98%純度 兩種異構體的混合物 | ||||
251 | (4±)-4-甲基-2-[(5-甲基-2-吡啶基)甲基]-N-[[(2S)-四氫呋喃-2-基]甲基]-8-(三氟甲基)-4,5-二氫呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.879 (0.46), 1.277 (8.70), 1.294 (8.74), 1.537 (0.78), 1.556 (1.06), 1.564 (1.00), 1.572 (0.90), 1.586 (0.96), 1.602 (0.58), 1.770 (0.53), 1.791 (1.24), 1.807 (2.18), 1.825 (2.16), 1.843 (1.38), 1.859 (1.10), 1.869 (0.92), 1.876 (0.96), 1.881 (0.90), 1.888 (1.06), 1.902 (0.89), 1.908 (0.77), 1.919 (0.60), 2.269 (16.00), 2.424 (0.52), 2.523 (4.02), 2.541 (2.92), 2.581 (1.49), 2.607 (1.59), 2.622 (1.71), 2.665 (1.13), 2.669 (1.46), 2.673 (1.17), 2.739 (0.74), 2.753 (2.75), 3.015 (1.62), 3.032 (2.13), 3.056 (1.48), 3.074 (1.79), 3.164 (0.70), 3.181 (1.02), 3.190 (0.83), 3.198 (0.78), 3.207 (0.96), 3.225 (0.61), 3.250 (2.77), 3.265 (5.50), 3.280 (3.17), 3.377 (1.37), 3.594 (0.80), 3.613 (1.81), 3.631 (2.05), 3.649 (1.06), 3.738 (0.91), 3.754 (1.81), 3.771 (1.57), 3.791 (0.80), 3.916 (0.41), 3.932 (1.40), 3.948 (2.03), 3.963 (1.31), 5.337 (9.13), 7.016 (2.99), 7.036 (3.17), 7.577 (1.77), 7.581 (1.79), 7.597 (1.69), 7.601 (1.69), 7.689 (5.89), 8.370 (3.12), 8.694 (1.06), 8.709 (2.10), 8.724 (1.04). LC-MS (方法1): Rt = 1.16 min; MS (ESIpos): m/z = 475 [M+H]+ | 中間物76 GP H 條件B 8 mg,5%產率,98%純度 兩種異構體的混合物 | ||||
252 | (4±)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-2-[(6-甲基吡啶-3-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.262 (7.51), 1.279 (7.71), 2.401 (2.07), 2.430 (16.00), 2.539 (1.95), 2.569 (1.49), 2.596 (1.56), 2.611 (1.50), 2.637 (1.51), 3.001 (1.33), 3.019 (1.66), 3.043 (1.11), 3.060 (1.40), 3.157 (0.91), 3.183 (1.14), 3.193 (1.71), 3.217 (2.75), 3.231 (1.84), 3.245 (3.10), 3.255 (1.74), 3.276 (1.14), 3.426 (0.83), 3.447 (1.56), 3.454 (1.64), 3.474 (1.28), 3.480 (1.27), 3.526 (1.11), 3.554 (1.58), 3.582 (0.98), 3.616 (2.30), 3.640 (2.37), 3.693 (1.78), 3.721 (3.23), 3.749 (1.40), 5.284 (7.36), 5.335 (0.42), 7.155 (0.29), 7.176 (0.39), 7.218 (2.42), 7.238 (2.75), 7.270 (0.25), 7.276 (0.25), 7.290 (0.17), 7.296 (0.18), 7.516 (0.86), 7.557 (1.76), 7.562 (1.79), 7.576 (1.61), 7.582 (1.61), 7.697 (4.88), 8.108 (0.35), 8.112 (0.34), 8.400 (2.75), 8.405 (2.75), 8.730 (0.92), 8.745 (1.85), 8.759 (0.93), 8.890 (0.19). LC-MS (方法1): Rt = 1.05 min; MS (ESIpos): m/z = 491 [M+H]+ | 中間物77 GP H 條件A 26 mg,34%產率,90%純度 兩種異構體的混合物 | ||||
253 | (4±)-4-甲基-2-[(6-甲基吡啶-3-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.263 (7.06), 1.279 (7.15), 1.536 (0.55), 1.539 (0.53), 1.548 (0.47), 1.551 (0.52), 1.555 (0.79), 1.563 (0.74), 1.572 (0.64), 1.580 (0.51), 1.585 (0.72), 1.601 (0.45), 1.785 (0.66), 1.791 (0.86), 1.806 (1.54), 1.824 (1.53), 1.842 (0.99), 1.858 (0.82), 1.863 (0.48), 1.867 (0.58), 1.875 (0.64), 1.879 (0.57), 1.887 (0.75), 1.897 (0.48), 1.901 (0.57), 1.903 (0.57), 1.908 (0.53), 1.918 (0.42), 2.431 (16.00), 2.518 (2.83), 2.523 (1.88), 2.540 (0.77), 2.565 (1.15), 2.591 (1.26), 2.606 (1.32), 2.633 (1.44), 2.674 (0.47), 2.999 (1.34), 3.016 (1.75), 3.039 (1.20), 3.058 (1.49), 3.141 (0.50), 3.157 (0.72), 3.166 (0.55), 3.175 (0.51), 3.183 (0.67), 3.249 (2.12), 3.264 (4.32), 3.280 (2.35), 3.594 (0.53), 3.610 (1.11), 3.613 (1.25), 3.630 (1.48), 3.648 (0.85), 3.737 (0.67), 3.753 (1.34), 3.770 (1.16), 3.772 (1.10), 3.790 (0.67), 3.931 (1.05), 3.947 (1.56), 3.963 (1.01), 5.284 (6.79), 7.218 (2.33), 7.238 (2.60), 7.556 (1.73), 7.561 (1.73), 7.576 (1.49), 7.582 (1.54), 7.694 (4.67), 7.696 (4.66), 8.400 (2.42), 8.405 (2.42), 8.692 (0.79), 8.708 (1.63), 8.722 (0.77). LC-MS (方法1): Rt = 1.13 min; MS (ESIpos): m/z = 475 [M+H]+ | 中間物77 GP H 條件A 12 mg,18%產率,98%純度 兩種異構體的混合物 | ||||
254 | (4±)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.269 (7.91), 1.276 (8.23), 1.286 (8.65), 1.293 (7.98), 2.518 (16.00), 2.523 (11.32), 2.576 (1.69), 2.580 (1.60), 2.602 (1.57), 2.607 (1.54), 2.618 (1.67), 2.622 (1.55), 2.644 (1.69), 2.649 (1.60), 3.006 (1.49), 3.013 (1.48), 3.024 (1.96), 3.031 (1.94), 3.047 (1.35), 3.054 (1.42), 3.065 (1.63), 3.072 (1.65), 3.149 (1.07), 3.166 (1.57), 3.175 (1.23), 3.198 (2.91), 3.222 (4.30), 3.225 (4.27), 3.239 (3.10), 3.250 (5.34), 3.260 (2.57), 3.267 (4.05), 3.271 (3.91), 3.275 (3.49), 3.281 (1.65), 3.295 (2.81), 3.299 (3.01), 3.405 (0.82), 3.425 (2.37), 3.431 (2.01), 3.451 (4.16), 3.457 (3.39), 3.478 (3.40), 3.485 (2.30), 3.497 (1.17), 3.502 (1.26), 3.516 (1.03), 3.525 (3.36), 3.531 (3.33), 3.545 (1.54), 3.553 (3.63), 3.559 (3.26), 3.580 (1.47), 3.586 (1.84), 3.614 (5.13), 3.628 (2.41), 3.645 (5.24), 3.667 (0.88), 3.698 (3.04), 3.704 (2.56), 3.726 (7.35), 3.747 (4.43), 3.754 (4.24), 3.774 (1.45), 3.793 (0.50), 3.833 (1.30), 4.050 (0.42), 4.085 (2.45), 4.094 (4.94), 4.101 (4.25), 4.110 (3.87), 4.130 (0.51), 7.567 (9.09), 8.733 (1.66), 8.748 (3.45), 8.763 (1.65). LC-MS (方法1): Rt = 1.02 min; MS (ESIpos): m/z = 486 [M+H]+ | 中間物78 GP H 條件B 143 mg,49%產率,95%純度 兩種異構體的混合物 | ||||
254-1 | (4R或4S)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 實例254之非對映異構體1 | Rt = 3.25 min1 H NMR (400 MHz, DMSO-d6) δ [ppm]:1.28 (d, 3H) 2.58 - 2.65 (m, 1 H) 3.00 - 3.07 (m, 1 H) 3.15 - 3.30 (m, 5 H) 3.39 - 3.50 (m, 2 H) 3.51 - 3.59 (m, 2 H) 3.61 - 3.67 (m, 3 H) 3.70 - 3.77 (m, 4 H) 3.83 - 3.88 (m, 1 H) 4.06 - 4.13 (m, 2 H) 7.57 (m, 1 H) 8.75 (t, 1H). [α]D 20 = -41.4°(c=1, DMSO) | 分析型方法: 儀器:Thermo Fisher UltiMate 3000;管柱:YMC Cellulose SC 3µ,100×4.6;溶離劑A:己烷 + 0.1 vol%二乙胺;溶離劑B:乙醇;等度:70% A + 30% B;流量:1.4 ml/min;溫度:25℃;UV:254 nm | ||||
254-2 | (4R或4S)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 實例254之非對映異構體2 | Rt = 3.86 min1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.28 (d, 3 H) 2.58 - 2.64 (m, 1 H) 3.01 - 3.07 (m, 1 H) 3.13 - 3.31 (m, 5 H) 3.41 - 3.49 (m, 2 H) 3.49 - 3.59 (m, 2 H) 3.61 - 3.67 (m, 3 H) 3.70 - 3.77 (m, 4 H) 3.79 - 3.86 (m, 1 H) 4.05 - 4.14 (m, 2 H) 7.57 (m, 1 H) 8.75 (t, 1H). [α]D 20 = +16.6° (c=1, DMSO) | |||||
255 | (4±)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.25 - 1.30 (m, 3 H) 1.52 - 1.61 (m, 1 H) 1.75 - 1.96 (m, 3 H) 2.57 - 2.65 (m, 1 H) 2.99 - 3.08 (m, 1 H) 3.13 - 3.22 (m, 1 H) 3.24 - 3.30 (m, 3 H) 3.39 - 3.57 (m, 2 H) 3.60 - 3.67 (m, 2 H) 3.70 - 3.80 (m, 3 H) 3.80 - 3.89 (m, 1 H) 3.92 - 3.99 (m, 1 H) 4.08 - 4.11 (m, 2 H) 7.57 (s, 1 H) 8.70 - 8.73 (m, 1 H). LC-MS (方法1): Rt = 1.11 min; MS (ESIpos): m/z = 470 [M+H]+ | 中間物78 GP H 條件B 67 mg,24%產率,95%純度 兩種異構體的混合物 | ||||
255-1 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 實例255之非對映異構體1 | Rt = 3.83 min1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.28 (d, 3H) 1.52 - 1.58 (m, 1 H) 1.75 - 1.96 (m, 3 H) 2.58 - 2.65 (m, 1 H) 3.01 - 3.06 (m, 1 H) 3.13 - 3.22 (m, 1 H) 3.24 - 3.30 (m, 3 H) 3.39 - 3.57 (m, 2 H) 3.60 - 3.64 (m, 2 H) 3.70 - 3.80 (m, 3 H) 3.80 - 3.89 (m, 1 H) 3.92 - 3.99 (m, 1 H) 4.08 - 4.11 (m, 2 H) 7.57 (s, 1 H) 8.71 (t, 1H). [α]D 20 = -4.6° (c=1, DMSO) | 分析型方法: 儀器:Thermo Fisher UltiMate 3000;管柱:YMC Cellulose SB 3µ,100×4.6;溶離劑A:己烷 + 0.1 vol%三氟乙酸;溶離劑B:2-丙醇;等度:80% A + 20% B;流速:1.4 ml/min;溫度:25℃;UV:254 nm | ||||
255-2 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 實例255之非對映異構體2 | Rt = 4.31 min1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.27 (d, 3H) 1.52 - 1.57 (m, 1 H) 1.75 - 1.94 (m, 3 H) 2.58 - 2.65 (m, 1 H) 3.01 - 3.06 (m, 1 H) 3.13 - 3.22 (m, 1 H) 3.25 - 3.30 (m, 3 H) 3.39 - 3.57 (m, 2 H) 3.60 - 3.64 (m, 2 H) 3.70 - 3.80 (m, 3 H) 3.80 - 3.89 (m, 1 H) 3.92 - 3.99 (m, 1 H) 4.09 - 4.12 (m, 2 H) 7.57 (s, 1 H) 8.71 (t, 1H). [α]D 20 = +8.3° (c=1, DMSO) | |||||
256 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1,3-㗁唑-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.280 (14.96), 1.296 (15.48), 2.318 (0.73), 2.322 (1.66), 2.326 (2.39), 2.331 (1.64), 2.518 (16.00), 2.522 (11.14), 2.596 (2.54), 2.605 (0.84), 2.623 (2.82), 2.638 (2.85), 2.664 (4.84), 2.668 (2.96), 2.673 (1.93), 3.013 (2.82), 3.031 (3.91), 3.055 (2.73), 3.073 (3.15), 3.160 (1.11), 3.177 (1.59), 3.185 (1.26), 3.193 (1.20), 3.202 (1.51), 3.219 (0.87), 3.244 (2.90), 3.269 (3.55), 3.273 (3.48), 3.297 (3.40), 3.400 (1.07), 3.406 (1.33), 3.427 (2.49), 3.433 (2.70), 3.454 (2.28), 3.461 (2.08), 3.516 (1.67), 3.523 (2.03), 3.545 (2.58), 3.552 (2.69), 3.572 (1.18), 3.578 (1.77), 3.611 (2.64), 3.639 (2.14), 3.721 (2.83), 3.728 (2.93), 3.735 (3.11), 3.747 (2.41), 3.757 (2.60), 3.764 (2.64), 3.822 (0.72), 3.828 (0.78), 3.835 (1.43), 3.842 (1.57), 3.851 (1.41), 3.860 (1.78), 3.866 (1.32), 3.875 (0.93), 3.882 (0.80), 4.062 (0.64), 4.098 (5.29), 4.104 (5.47), 4.114 (5.80), 4.117 (5.60), 4.139 (0.66), 4.536 (6.60), 4.552 (7.05), 7.170 (13.26), 7.172 (12.05), 7.574 (9.95), 7.576 (9.80), 8.069 (14.15), 8.071 (13.13), 9.345 (1.72), 9.359 (3.82), 9.373 (1.72). LC-MS (方法1): Rt = 1.00 min; MS (ESIneg): m/z = 467 [M+H]+ | 中間物79 GP H 條件D 36 mg,28%產率,95%純度 | ||||
257 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1-甲基-1H-吡唑-3-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.271 (4.49), 1.288 (4.66), 2.518 (5.76), 2.522 (4.02), 2.565 (0.94), 2.592 (1.01), 2.607 (0.93), 2.634 (0.94), 2.987 (0.83), 3.006 (1.17), 3.029 (0.81), 3.047 (0.92), 3.160 (0.49), 3.186 (0.44), 3.241 (0.87), 3.266 (1.08), 3.270 (1.03), 3.294 (1.06), 3.404 (0.42), 3.425 (0.76), 3.431 (0.84), 3.452 (0.70), 3.459 (0.62), 3.514 (0.51), 3.521 (0.61), 3.544 (0.78), 3.550 (0.81), 3.577 (0.52), 3.609 (0.81), 3.638 (0.64), 3.723 (1.04), 3.732 (0.96), 3.753 (0.92), 3.760 (0.83), 3.782 (16.00), 3.796 (0.66), 3.832 (0.44), 3.838 (0.50), 3.847 (0.44), 3.855 (0.55), 3.862 (0.42), 4.092 (1.65), 4.098 (1.66), 4.108 (1.84), 4.344 (2.26), 4.360 (2.40), 6.118 (2.80), 6.124 (2.75), 7.562 (2.99), 7.564 (3.00), 7.585 (2.37), 7.590 (2.33), 9.062 (0.57), 9.078 (1.25), 9.092 (0.58). LC-MS (方法1): Rt = 1.01 min; MS (ESIpos): m/z = 480 [M+H]⁺ | 中間物79 GP H 條件A 30 mg,23%產率,95%純度 | ||||
258 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(5-甲基吡𠯤-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.21 - 1.32 (m, 3 H) 2.55 - 2.64 (m, 1 H) 2.96 - 3.09 (m, 1 H) 3.10 - 3.23 (m, 1 H) 3.24 - 3.31 (m, 1 H) 3.39 - 3.49 (m, 1 H) 3.49 - 3.66 (m, 2 H) 3.69 - 3.78 (m, 2 H) 3.80 - 3.94 (m, 1 H) 4.03 - 4.20 (m, 2 H) 4.47 - 4.65 (m, 2 H) 7.41 - 7.68 (m, 1 H) 8.41 - 8.54 (m, 2 H) 9.22 - 9.38 (m, 1 H). LC-MS (方法1): Rt = 1.01 min; MS (ESIneg): m/z = 490 [M-H]⁻ | 中間物79 GP H 條件A 68.3 mg,53%產率,98%純度 | ||||
259 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1,3-噻唑-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.23 - 1.37 (m, 3 H) 2.56 - 2.67 (m, 1 H), 2.96 - 3.09 (m, 1 H) 3.13 - 3.22 (m, 1 H) 3.23 - 3.30 (m, 1 H) 3.37 - 3.47 (m, 1 H), 3.49 - 3.67 (m, 2 H) 3.69 - 3.78 (m, 2 H) 3.80 - 3.92 (m, 1 H) 4.05 - 4.22 (m, 2 H), 4.65 - 4.88 (m, 2 H) 7.53 - 7.63 (m, 1 H) 7.64 - 7.70 (m, 1 H) 7.71 - 7.80 (m, 1 H), 9.45 - 9.66 (m, 1 H). LC-MS (方法1): Rt = 1.04 min; MS (ESIpos): m/z = 483 [M+H]⁺ | 中間物79 GP H 條件A 73.6 mg,58%產率,98%純度 | ||||
260 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(吡𠯤-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (d, 3H), 2.63 (dd, 1H), 3.05 (dd, 1H), 3.14-3.23 (m, 1H), 3.27 (dd, 1H), 3.40-3.47 (m, 1H), 3.51-3.59 (m, 1H), 3.63 (br d, 1H), 3.74 (dt, 2H), 3.82-3.90 (m, 1H), 4.05-4.16 (m, 2H), 4.59 (d, 2H), 7.57 (d, 1H), 8.56 (d, 1H), 8.61 (dd, 1H), 8.64 (d, 1H), 9.35 (t, 1H). LC-MS (方法1): Rt = 0.99 min; MS (ESIneg): m/z = 476 [M-H]⁻ | 中間物79 GP G 條件A 37.5 mg,59%產率,98%純度 | ||||
261 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1,3-㗁唑-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.28 (d, 3H), 2.61 (dd, 1H), 3.03 (dd, 1H), 3.14-3.21 (m, 1H), 3.27 (dd, 1H), 3.39-3.46 (m, 1H), 3.51-3.59 (m, 1H), 3.63 (br d, 1H), 3.71-3.77 (m, 2H), 3.81-3.89 (m, 1H), 4.05-4.15 (m, 2H), 4.33 (d, 2H), 7.57 (d, 1H), 7.96-7.98 (m, 1H), 8.33 (d, 1H), 9.13 (t, 1H). LC-MS (方法1): Rt = 1.00 min; MS (ESIneg): m/z = 465 [M-H]⁻ | 中間物79 GP G 條件A 34.2 mg,55%產率,97%純度 | ||||
262 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-N-{[2-(三氟甲基)嘧啶-5-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.23 - 1.33 (m, 3 H) 2.53 - 2.64 (m, 1 H) 2.98 - 3.09 (m, 1 H) 3.12 - 3.20 (m, 1 H) 3.20 - 3.29 (m, 1 H) 3.38 - 3.49 (m, 1 H) 3.50 - 3.67 (m, 2 H) 3.69 - 3.78 (m, 2 H) 3.81 - 3.91 (m, 1 H) 4.05 - 4.17 (m, 2 H) 4.47 - 4.70 (m, 2 H) 7.53 - 7.68 (m, 1 H) 8.91 - 9.13 (m, 2 H) 9.29 - 9.47 (m, 1 H). LC-MS (方法1): Rt = 1.17 min; MS (ESIneg): m/z = 544 [M-H]⁻ | 中間物79 GP G 條件A 36.2 mg,41%產率,95%純度 | ||||
263 | (4R或4S)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-2-[(㗁烷-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.184 (0.69), 1.194 (0.60), 1.214 (2.12), 1.244 (2.52), 1.255 (1.81), 1.270 (15.98), 1.286 (16.00), 1.408 (3.17), 1.438 (2.37), 1.969 (0.83), 1.979 (0.91), 1.988 (1.10), 1.998 (1.34), 2.007 (1.00), 2.016 (0.88), 2.026 (0.72), 2.038 (0.47), 2.327 (3.36), 2.332 (2.42), 2.336 (1.11), 2.518 (15.13), 2.523 (10.05), 2.566 (2.56), 2.592 (2.76), 2.608 (2.85), 2.634 (3.15), 2.669 (3.42), 2.673 (2.43), 2.678 (1.07), 3.002 (2.86), 3.019 (3.77), 3.043 (2.57), 3.061 (3.22), 3.143 (1.13), 3.159 (1.68), 3.169 (1.32), 3.178 (1.27), 3.186 (1.98), 3.195 (3.80), 3.202 (2.63), 3.219 (6.35), 3.223 (5.95), 3.237 (6.86), 3.243 (7.33), 3.247 (7.98), 3.257 (4.64), 3.273 (4.83), 3.292 (1.64), 3.308 (2.13), 3.423 (1.07), 3.429 (1.29), 3.449 (2.77), 3.456 (3.03), 3.476 (2.43), 3.483 (2.32), 3.524 (2.09), 3.530 (2.38), 3.552 (2.91), 3.559 (2.98), 3.578 (1.30), 3.585 (2.01), 3.596 (0.47), 3.620 (3.78), 3.627 (2.37), 3.644 (3.89), 3.660 (0.76), 3.666 (0.86), 3.696 (3.51), 3.702 (2.76), 3.725 (5.56), 3.752 (2.45), 3.802 (3.05), 3.808 (3.06), 3.831 (2.81), 3.837 (2.68), 3.948 (7.59), 3.966 (7.45), 4.079 (0.44), 5.758 (0.73), 7.581 (9.73), 7.629 (0.67), 8.718 (1.80), 8.733 (3.75), 8.747 (1.76). LC-MS (方法1): Rt = 1.08 min; MS (ESIneg): m/z = 484 [M+H]⁺ | 中間物80 GP H 條件C 49.5 mg,17%產率,95%純度 | ||||
264 | (4或4S)-4-甲基-2-[(㗁烷-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.214 (1.09), 1.244 (1.30), 1.269 (8.23), 1.286 (8.24), 1.406 (1.65), 1.437 (1.24), 1.518 (0.48), 1.538 (0.67), 1.558 (0.91), 1.566 (0.85), 1.574 (0.71), 1.587 (0.82), 1.604 (0.52), 1.772 (0.43), 1.793 (0.97), 1.809 (1.83), 1.827 (1.78), 1.844 (1.12), 1.860 (0.97), 1.870 (0.66), 1.877 (0.72), 1.889 (0.84), 1.899 (0.57), 1.903 (0.65), 1.910 (0.60), 1.921 (0.47), 1.969 (0.43), 1.987 (0.68), 1.997 (0.68), 2.332 (2.64), 2.336 (1.17), 2.518 (16.00), 2.523 (10.69), 2.562 (1.44), 2.588 (1.44), 2.603 (1.51), 2.629 (1.58), 2.673 (2.66), 2.678 (1.18), 2.999 (1.45), 3.017 (1.97), 3.040 (1.34), 3.058 (1.60), 3.142 (0.58), 3.159 (0.84), 3.168 (0.64), 3.177 (0.62), 3.185 (0.80), 3.216 (1.39), 3.245 (2.65), 3.251 (2.69), 3.267 (5.76), 3.282 (3.14), 3.373 (0.65), 3.596 (0.72), 3.615 (1.45), 3.633 (1.69), 3.651 (0.96), 3.740 (0.87), 3.757 (1.56), 3.773 (1.45), 3.776 (1.37), 3.794 (1.40), 3.802 (1.59), 3.808 (1.57), 3.830 (1.44), 3.837 (1.39), 3.918 (0.43), 3.934 (1.36), 3.948 (5.24), 3.965 (5.15), 7.579 (5.00), 8.682 (0.90), 8.697 (1.87), 8.711 (0.88). LC-MS (方法1): Rt = 1.16 min; MS (ESIneg): m/z = 468 [M+H]+ | 中間物80 GP H 條件C 57 mg,21%產率,95%純度 | ||||
265 | (4±)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-甲基-4-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.233 (0.43), 2.481 (16.00), 2.520 (5.15), 2.525 (3.51), 2.545 (0.83), 2.756 (0.78), 3.019 (0.66), 3.032 (0.68), 3.063 (0.91), 3.076 (0.89), 3.189 (1.19), 3.218 (1.27), 3.239 (1.77), 3.254 (0.89), 3.273 (1.63), 3.289 (0.92), 3.451 (1.15), 3.479 (1.01), 3.503 (0.43), 3.515 (0.65), 3.520 (0.69), 3.532 (0.74), 3.549 (0.98), 3.560 (0.60), 3.576 (0.56), 3.615 (1.53), 3.638 (1.33), 3.692 (1.03), 3.699 (0.90), 3.721 (2.83), 3.750 (1.92), 3.779 (0.44), 3.832 (0.12), 3.839 (0.12), 3.847 (0.29), 3.854 (0.33), 3.862 (0.23), 3.871 (0.41), 3.878 (0.36), 3.886 (0.34), 3.892 (0.35), 3.902 (0.22), 3.909 (0.29), 3.916 (0.21), 3.926 (0.14), 3.931 (0.12), 4.151 (1.64), 4.165 (1.96), 4.212 (0.14), 4.238 (0.28), 4.250 (0.28), 4.251 (0.29), 4.262 (0.40), 4.274 (0.37), 4.284 (0.29), 4.298 (0.22), 7.714 (1.59), 7.728 (1.53), 8.104 (0.61), 8.118 (1.28), 8.133 (0.58). LC-MS (方法1): Rt = 1.02 min; MS (ESIpos): m/z = 486 [M+H]+ | 中間物81 GP H 條件B 47 mg,25%產率,95%純度 兩種異構體的混合物 | ||||
265-1 | (4R或4S)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-甲基-4-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 實例265之非對映異構體1 | Rt = 3.74 min1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.48 - 2.88 (s, 3 H) 3.04 (dd, 1H) 3.15 - 3.30 (m, 5 H) 3.41 - 3.48 (m, 2 H) 3.51 - 3.57 (m, 2 H) 3.58 - 3.66 (m, 3 H) 3.64 - 3.75 (m, 4 H) 3.87 - 3.92 (m, 1 H) 4.12 - 4.20 (m, 2 H) 4.22 - 4.30 (m, 1 H) 7.73 (s, 1 H) 8.12 (t, 1H). | 分析型方法: 儀器:Waters Alliance 2695;管柱:YMC Cellulose SB 3µ,100×4.6;溶離劑A:己烷 + 0.1 vol%二乙胺;溶離劑B:乙醇;等度:80% A + 20% B;流量:1.4 ml/min;溫度:25℃;UV:254 nm | ||||
265-2 | (4R或4S)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-甲基-4-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 實例265之非對映異構體2 | Rt = 4.35 min1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.48 - 2.88 (s, 3 H) 3.04 (dd, 1H) 3.15 - 3.30 (m, 5 H) 3.41 - 3.48 (m, 2 H) 3.51 - 3.57 (m, 2 H) 3.58 - 3.66 (m, 3 H) 3.69 - 3.78 (m, 4 H) 3.83 - 3.89 (m, 1 H) 4.15 - 4.16 (m, 2 H) 4.21 - 4.30 (m, 1 H) 7.71 (s, 1 H) 8.12 (t, 1H). | |||||
266 | (4±)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-4-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.225 (0.46), 1.234 (0.48), 1.550 (0.44), 1.568 (0.55), 1.577 (0.43), 1.584 (0.48), 1.597 (0.46), 1.786 (0.75), 1.801 (1.23), 1.820 (1.32), 1.838 (0.99), 1.853 (0.72), 1.861 (0.57), 1.871 (0.70), 1.882 (0.50), 1.910 (0.50), 2.044 (0.43), 2.320 (0.77), 2.342 (2.28), 2.481 (16.00), 2.520 (7.44), 2.525 (4.84), 2.662 (0.76), 3.020 (0.81), 3.032 (0.80), 3.064 (1.04), 3.077 (0.93), 3.224 (1.26), 3.239 (2.56), 3.255 (1.45), 3.274 (1.50), 3.279 (1.18), 3.288 (1.06), 3.298 (1.35), 3.302 (1.73), 3.311 (2.10), 3.434 (0.58), 3.440 (0.57), 3.451 (0.68), 3.457 (0.71), 3.468 (0.46), 3.478 (0.67), 3.483 (0.61), 3.499 (0.58), 3.532 (0.81), 3.559 (0.65), 3.587 (0.61), 3.607 (1.07), 3.625 (2.11), 3.642 (1.00), 3.652 (0.88), 3.726 (1.68), 3.736 (0.98), 3.752 (2.68), 3.772 (1.40), 3.790 (0.58), 3.848 (0.41), 3.854 (0.44), 3.871 (0.56), 3.878 (0.49), 3.894 (0.49), 3.909 (0.46), 3.916 (0.53), 3.933 (1.01), 3.949 (1.32), 3.964 (0.82), 4.149 (2.14), 4.164 (2.41), 4.171 (1.09), 4.260 (0.56), 4.272 (0.64), 7.713 (2.12), 7.727 (1.33), 8.031 (0.63), 8.047 (1.31), 8.061 (0.63). LC-MS (方法1): Rt = 1.08 min; MS (ESIpos): m/z = 470 [M+H]+ | 中間物81 GP H 條件B 4.5 mg,2%產率,95%純度 兩種異構體的混合物 | ||||
267 | N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,4-二甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.55), 1.172 (1.14), 1.181 (0.66), 1.190 (0.62), 1.249 (16.00), 1.261 (15.70), 1.988 (1.97), 2.518 (13.13), 2.523 (9.04), 2.812 (10.66), 3.189 (0.48), 3.200 (2.16), 3.224 (3.77), 3.228 (2.77), 3.238 (3.28), 3.252 (4.11), 3.264 (3.86), 3.269 (2.73), 3.278 (1.93), 3.294 (2.73), 3.412 (0.79), 3.419 (1.04), 3.426 (0.91), 3.433 (1.13), 3.440 (1.79), 3.446 (2.06), 3.453 (2.02), 3.460 (2.11), 3.468 (1.70), 3.474 (1.58), 3.480 (1.78), 3.487 (1.65), 3.514 (1.30), 3.519 (1.52), 3.526 (1.56), 3.532 (1.71), 3.542 (1.82), 3.549 (1.99), 3.554 (2.29), 3.561 (2.26), 3.569 (1.01), 3.575 (1.20), 3.580 (0.99), 3.587 (1.48), 3.618 (4.23), 3.633 (1.72), 3.647 (3.68), 3.671 (0.65), 3.704 (2.14), 3.710 (1.97), 3.728 (5.11), 3.756 (3.75), 3.818 (0.52), 3.833 (1.02), 3.839 (1.14), 3.849 (0.94), 3.856 (1.24), 3.863 (0.91), 3.872 (0.61), 4.018 (0.45), 4.035 (0.41), 4.083 (4.19), 4.097 (4.84), 7.491 (0.59), 7.593 (10.60), 8.741 (1.18), 8.756 (2.43), 8.771 (1.18). LC-MS (方法1): Rt = 1.07 min; MS (ESIneg): m/z = 498 [M-H]⁻ | 中間物82 GP H 條件C 61 mg,32%產率,95%純度 | ||||
268 | 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,4-二甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.249 (5.15), 1.259 (5.05), 1.542 (0.26), 1.561 (0.35), 1.570 (0.33), 1.578 (0.26), 1.591 (0.31), 1.607 (0.19), 1.796 (0.39), 1.812 (0.68), 1.829 (0.71), 1.848 (0.42), 1.865 (0.29), 1.884 (0.32), 1.896 (0.34), 1.912 (0.26), 1.927 (0.19), 2.074 (16.00), 2.327 (0.99), 2.332 (0.72), 2.518 (4.68), 2.523 (3.12), 2.669 (1.03), 2.673 (0.74), 2.808 (3.68), 3.240 (0.61), 3.253 (1.06), 3.268 (2.62), 3.283 (1.15), 3.294 (0.85), 3.419 (0.25), 3.440 (0.53), 3.446 (0.57), 3.468 (0.48), 3.474 (0.44), 3.514 (0.38), 3.520 (0.44), 3.542 (0.55), 3.549 (0.54), 3.575 (0.34), 3.597 (0.27), 3.618 (1.12), 3.634 (0.71), 3.652 (0.62), 3.727 (0.99), 3.733 (0.68), 3.757 (1.32), 3.775 (0.57), 3.795 (0.35), 3.833 (0.32), 3.839 (0.35), 3.856 (0.39), 3.922 (0.16), 3.938 (0.49), 3.955 (0.79), 3.970 (0.52), 4.082 (1.41), 4.096 (1.58), 7.591 (3.44), 8.706 (0.37), 8.721 (0.76), 8.736 (0.37). LC-MS (方法1): Rt = 1.15 min; MS (ESIpos): m/z = 484 [M+H]⁺ | 中間物82 GP H 條件C 33 mg,18%產率,95%純度 | ||||
269 | N-[(2R)-1,4-二㗁烷-2-基甲基]-2'-[(2S)-1,4-二㗁烷-2-基甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.89-2.18 (m, 6H), 3.09 (s, 2H), 3.17-3.31 (m, 4H), 3.40-3.50 (m, 2H), 3.51-3.60 (m, 2H), 3.60-3.67 (m, 3H), 3.69-3.77 (m, 4H), 3.82-3.90 (m, 1H), 4.07-4.16 (m, 2H), 7.80 (s, 1H), 8.75 (t, 1H) LC-MS (方法1): Rt = 1.08 min; MS (ESIpos): m/z = 512 [M+H]⁺ | 中間物83及CAS-RN:[1523541-84-5] GP G 條件A 14.9 mg (44%產率,95%純度) | ||||
270 | 2'-[(2S)-1,4-二㗁烷-2-基甲基]-N-[(1-甲基-1H-吡唑-3-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.88-2.18 (m, 6H), 3.08 (s, 2H), 3.28 (dd, 1H), 3.40-3.49 (m, 1H), 3.50-3.59 (m, 1H), 3.63 (br d, 1H), 3.75 (dd, 2H), 3.79 (s, 3H), 3.83-3.89 (m, 1H), 4.06-4.14 (m, 2H), 4.35 (d, 2H), 6.13 (d, 1H), 7.59 (d, 1H), 7.79 (s, 1H), 9.08 (t, 1H) LC-MS (方法1): Rt = 1.07 min; MS (ESIpos): m/z = 506 [M+H]⁺ | 中間物83及CAS-RN:[612511-81-6] GP G 條件A 12.1 mg (36%產率,95%純度) | ||||
271 | 2'-[(2S)-1,4-二㗁烷-2-基甲基]-N-[(2S)-四氫呋喃-2-基甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.62 (m, 1H), 1.75-2.00 (m, 4H), 2.01-2.15 (m, 5H), 3.09 (s, 2H), 3.24-3.31 (m, 3H), 3.40-3.49 (m, 1H), 3.51-3.61 (m, 1H), 3.61-3.67 (m, 2H), 3.72-3.79 (m, 3H), 3.82-4.01 (m, 2H), 4.06-4.16 (m, 2H), 7.79 (s, 1H), 8.72 (t, 1H). LC-MS (方法1): Rt = 1.16 min; MS (ESIpos): m/z = 496 [M+H]⁺ | 中間物83及CAS-RN:[7175-81-7] GP G 條件A 6.9 mg (34%產率,90%純度) | ||||
272 | 2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-[(1,3-㗁唑-2-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.92-2.16 (m, 6H), 3.10 (s, 2H), 3.25-3.31 (m, 1H), 3.42-3.50 (m, 1H), 3.51-3.59 (m, 1H), 3.64 (br d, 1H), 3.72-3.79 (m, 2H), 3.82-3.91 (m, 1H), 4.06-4.18 (m, 2H), 4.55 (d, 2H), 7.17 (d, 1H), 7.80 (s, 1H), 8.07 (d, 1H), 9.37 (t, 1H). LC-MS (方法1): Rt = 1.08 min; MS (ESIpos): m/z = 493 [M+H]⁺ | 中間物83及CAS-RN:[885331-17-9] GP G 條件A 4.20 mg (21%產率,90%純度) | ||||
273 | N-[(2R)-1,4-二㗁烷-2-基甲基]-2'-(吡啶-2-基甲基)-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.90-2.07 (m, 2H), 2.08-2.18 (m, 4H), 3.11 (s, 2H),3.19-3.28 (m, 3H), 3.41-3.49 (m, 1H), 3.52-3.59 (m, 1H), 3.60-3.67 (m, 2H), 3.70-3.76 (m, 2H), 5.41 (s, 2H), 7.08 (d, 1H), 7.32 (ddd, 1H), 7.78 (td, 1H), 7.97 (s, 1H), 8.53-8.56 (m, 1H), 8.76 (t, 1H) LC-MS (方法1): Rt = 1.12 min; MS (ESIpos): m/z = 503 [M+H]⁺ | 中間物84及CAS-RN:[1523541-84-5] GP G 條件A 14.2 mg (43%產率,95%純度) | ||||
274 | 2'-(吡啶-2-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.64 (m, 1H), 1.74-2.01 (m, 4H), 2.02-2.17 (m, 5H), 3.11 (s, 2H), 3.27 (t, 2H), 3.59-3.66 (m, 1H), 3.74-3.81 (m, 1H), 3.95 (quin, 1H), 5.41 (s, 2H), 7.08 (d, 1H), 7.32 (ddd, 1H), 7.78 (td, 1H), 7.96 (s, 1H), 8.51-8.58 (m, 1H), 8.72 (t, 1H). LC-MS (方法1): Rt = 1.17 min; MS (ESIpos): m/z = 487 [M+H]⁺ | 中間物84及CAS-RN:[7175-81-7] GP G 條件A 20.3 mg (65%產率,96%純度) | ||||
275 | N-(1,3-㗁唑-2-基甲基)-2'-(吡啶-2-基甲基)-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.90-2.19 (m, 6H), 3.12 (s, 2H), 4.55 (d, 2H), 5.41 (s, 2H), 7.09 (d, 1H), 7.17 (d, 1H), 7.32 (dd, 1H), 7.79 (td, 1H), 7.97 (s, 1H), 8.07 (d, 1H), 8.53-8.57 (m, 1H), 9.37 (t, 1H) LC-MS (方法1): Rt = 1.09 min; MS (ESIpos): m/z = 484 [M+H]⁺ | 中間物84及CAS-RN:[885331-17-9] GP G 條件A 4.1 mg (5%產率,90%純度) | ||||
276 | N-[(1-甲基-1H-吡唑-3-基)甲基]-2'-(吡啶-2-基甲基)-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.89-2.18 (m, 6H), 3.09 (s, 2H), 3.78 (s, 3H), 4.35(d, 2H), 5.41 (s, 2H), 6.13 (d, 1H), 7.07 (d, 1H), 7.31 (ddd, 1H), 7.59 (d, 1H), 7.78 (td, 1H), 7.96 (s, 1H), 8.50-8.58 (m, 1H), 9.08 (t, 1H) LC-MS (方法1): Rt = 1.10 min; MS (ESIpos): m/z = 497 [M+H]⁺ | 中間物84及CAS-RN:[612511-81-6] GP G 條件A 8.6 mg (10%產率,90%純度) | ||||
277 | 2'-[(5-甲基吡啶-2-基)甲基]-N-[(2S)-四氫呋喃-2-基甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.52-1.62 (m, 1H), 1.72-1.96 (m, 3H), 1.97-2.17 (m, 6H), 2.27 (s, 3H), 3.10 (s, 2H), 3.27 (t, 2H), 3.56-3.68 (m, 1H), 3.77 (ddd, 1H), 3.95 (quin, 1H), 5.35 (s, 2H), 7.02 (d, 1H), 7.56-7.62 (m, 1H), 7.93 (s, 1H), 8.36-8.41 (m, 1H), 8.71 (t, 1H). LC-MS (方法1): Rt = 1.23 min; MS (ESIpos): m/z = 501 [M+H]⁺ | 中間物85及CAS-RN:[7175-81-7] GP G 條件A 6.2 mg (16%產率,95%純度) | ||||
278 | N-[(2R)-1,4-二㗁烷-2-基甲基]-2'-[(5-甲基吡啶-2-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.95-2.17 (m, 6H), 2.27 (s, 3H), 3.10 (s, 2H), 3.18-3.29 (m, 3H), 3.42-3.49 (m, 1H), 3.51-3.59 (m, 1H), 3.60-3.67 (m, 2H), 3.69-3.78 (m, 2H), 5.35 (s, 2H), 7.02 (d, 1H), 7.56-7.63 (m, 1H), 7.93 (s, 1H), 8.36-8.41 (m, 1H), 8.75 (t, 1H) LC-MS (方法1): Rt = 1.16 min; MS (ESIpos): m/z = 517 [M+H]⁺ | 中間物85及CAS-RN:[1523541-84-5] GP G 條件A 8.6 mg (21%產率,91%純度) | ||||
279 | N-[(1-甲基-1H-吡唑-3-基)甲基]-2'-[(5-甲基吡啶-2-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.91-2.17 (m, 6H), 2.27 (s, 3H), 3.08 (s, 2H), 3.78 (s, 3H), 4.35 (d, 2H), 5.35 (s, 2H), 6.12 (d, 1H), 7.02 (d, 1H), 7.56-7.62 (m, 2H), 7.92 (s, 1H), 8.36-8.41 (m, 1H), 9.07 (t, 1H). LC-MS (方法1): Rt = 1.17 min; MS (ESIneg): m/z = 509 [M-H]⁻ | 中間物85及CAS-RN:[ 612511-81-6] GP G 條件A 3.0 mg (8%產率,95%純度) | ||||
280 | 2'-(吡啶-4-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.62 (m, 1H), 1.78-2.07 (m, 4H), 2.08-2.16 (m, 5H), 3.11 (s, 2H), 3.27 (t, 2H), 3.58-3.67 (m, 1H), 3.73-3.82 (m, 1H), 3.91-3.99 (m, 1H), 5.39 (s, 2H), 7.13-7.18 (m, 2H), 7.99 (s, 1H), 8.51-8.56 (m, 2H), 8.73 (t, 1H) LC-MS (方法1): Rt = 1.01 min; MS (ESIneg): m/z = 501 [M-H]⁺ | 中間物86及CAS-RN:[7175-81-7] GP G 條件A 10.8 mg (48%產率,82%純度) | ||||
281 | N-[(2R)-1,4-二㗁烷-2-基甲基]-2'-(吡啶-4-基甲基)-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.92-2.19 (m, 6H), 3.12 (s, 2H), 3.19-3.28 (m, 3H), 3.46 (td, 1H), 3.52-3.59 (m, 1H), 3.60-3.67 (m, 2H), 3.68-3.78 (m,2H), 5.43 (s, 2H), 7.22 (d, 2H), 8.00 (s, 1H), 8.57 (d, 2H), 8.76 (t, 1H) LC-MS (方法1): Rt = 1.06 min; MS (ESIpos): m/z = 487 [M+H]⁺ | 中間物86及CAS-RN:[1523541-84-5] GP G 條件A 6.9 mg (29%產率,81%純度) | ||||
282 | 2-(環丙基甲基)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.332 (0.48), 0.343 (2.00), 0.347 (1.74), 0.355 (1.92), 0.370 (0.72), 0.486 (0.69), 0.497 (1.62), 0.501 (1.69), 0.506 (0.90), 0.516 (1.72), 0.521 (1.57), 0.532 (0.54), 1.205 (0.72), 1.224 (0.60), 2.518 (16.00), 2.522 (11.04), 2.852 (0.64), 2.870 (2.20), 2.888 (1.88), 2.931 (2.08), 2.948 (2.51), 2.967 (0.68), 2.973 (0.62), 3.196 (0.93), 3.201 (0.69), 3.221 (1.90), 3.236 (1.37), 3.249 (2.50), 3.262 (1.39), 3.279 (1.62), 3.297 (1.08), 3.315 (2.81), 3.322 (4.01), 3.386 (3.58), 3.424 (1.11), 3.450 (1.14), 3.456 (1.30), 3.464 (0.45), 3.477 (0.98), 3.483 (0.93), 3.524 (0.70), 3.530 (0.85), 3.552 (1.12), 3.585 (0.70), 3.619 (1.22), 3.643 (1.21), 3.695 (1.01), 3.724 (1.72), 3.751 (0.81), 3.909 (3.44), 3.927 (3.42), 7.600 (3.49), 8.536 (1.12), 8.727 (0.57), 8.742 (1.14), 8.757 (0.53). LC-MS (方法1): Rt = 1.11 min; MS (ESIpos): m/z = 426 [M+H]+ | 中間物87 GP H 條件B 16 mg,19%產率,95%純度 | ||||
283 | N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[1-(甲氧基乙醯基)哌啶-4-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.007 (0.19), 1.016 (0.20), 1.038 (0.21), 1.046 (0.21), 1.120 (0.20), 1.125 (0.21), 1.128 (0.20), 1.138 (0.12), 1.151 (0.22), 1.155 (0.21), 1.513 (0.63), 1.543 (0.49), 1.993 (0.19), 2.001 (0.23), 2.009 (0.26), 2.019 (0.21), 2.331 (1.04), 2.518 (6.47), 2.523 (4.60), 2.673 (1.05), 2.844 (0.37), 2.862 (1.42), 2.880 (1.31), 2.925 (1.30), 2.943 (1.88), 2.962 (0.44), 2.967 (0.41), 3.196 (0.77), 3.220 (1.33), 3.225 (1.16), 3.235 (0.96), 3.249 (1.83), 3.257 (16.00), 3.262 (1.18), 3.278 (0.63), 3.297 (0.55), 3.429 (0.33), 3.450 (0.63), 3.456 (0.67), 3.477 (0.55), 3.484 (0.52), 3.525 (0.49), 3.530 (0.55), 3.553 (0.66), 3.559 (0.64), 3.585 (0.47), 3.620 (0.84), 3.643 (0.84), 3.695 (0.78), 3.701 (0.72), 3.723 (1.39), 3.752 (0.71), 3.956 (1.52), 3.973 (1.64), 4.011 (1.17), 4.059 (1.14), 4.093 (0.29), 4.276 (0.28), 4.309 (0.26), 7.536 (2.44), 8.722 (0.43), 8.736 (0.90), 8.751 (0.41). LC-MS (方法1): Rt = 0.89 min; MS (ESIneg): m/z = 539 [M-H]⁻ | 中間物88 GP H 條件C 24 mg,11%產率,95%純度 | ||||
284 | 2-{[1-(甲氧基乙醯基)哌啶-4-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.015 (0.20), 1.037 (0.21), 1.126 (0.20), 1.150 (0.20), 1.510 (0.58), 1.542 (0.75), 1.559 (0.53), 1.567 (0.41), 1.575 (0.32), 1.589 (0.36), 1.605 (0.22), 1.773 (0.22), 1.794 (0.43), 1.810 (0.78), 1.827 (0.75), 1.845 (0.49), 1.861 (0.41), 1.877 (0.33), 1.889 (0.39), 1.903 (0.29), 1.921 (0.21), 1.941 (0.13), 2.010 (0.26), 2.518 (2.76), 2.523 (2.06), 2.843 (0.32), 2.862 (1.39), 2.879 (1.32), 2.921 (1.37), 2.939 (1.88), 2.958 (0.43), 2.964 (0.40), 2.997 (0.17), 3.225 (0.17), 3.257 (16.00), 3.268 (2.28), 3.283 (1.24), 3.597 (0.27), 3.616 (0.61), 3.634 (0.75), 3.651 (0.44), 3.718 (0.30), 3.741 (0.56), 3.758 (0.80), 3.773 (0.67), 3.776 (0.58), 3.794 (0.40), 3.919 (0.19), 3.934 (0.56), 3.954 (1.70), 3.972 (1.71), 4.012 (1.14), 4.059 (1.11), 4.093 (0.28), 4.276 (0.26), 4.307 (0.25), 7.534 (2.42), 7.953 (0.13), 8.682 (0.41), 8.697 (0.88), 8.712 (0.41). LC-MS (方法1): Rt = 1.00 min; MS (ESIneg): m/z = 523 [M-H]⁻ | 中間物88 GP H 條件C 22 mg,10%產率,95%純度 | ||||
285 | 2-{[1-(環丙烷羰基)哌啶-4-基]甲基}-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.653 (4.01), 0.674 (6.50), 0.994 (0.63), 1.024 (0.69), 1.140 (0.66), 1.169 (0.67), 1.504 (1.15), 1.567 (0.97), 1.595 (0.77), 1.914 (0.63), 1.933 (1.23), 1.938 (0.95), 1.947 (2.14), 1.964 (1.10), 1.977 (0.61), 2.007 (0.63), 2.017 (0.75), 2.026 (0.85), 2.035 (1.02), 2.045 (0.82), 2.064 (0.59), 2.075 (0.50), 2.318 (1.12), 2.323 (2.59), 2.327 (3.73), 2.332 (2.62), 2.336 (1.11), 2.518 (16.00), 2.523 (11.74), 2.660 (1.16), 2.665 (2.70), 2.669 (3.80), 2.673 (2.68), 2.679 (1.26), 2.841 (1.28), 2.846 (1.28), 2.865 (5.49), 2.883 (4.41), 2.929 (4.76), 2.945 (6.65), 2.952 (2.39), 2.964 (1.64), 2.969 (1.63), 2.999 (0.52), 3.029 (0.92), 3.062 (0.51), 3.187 (0.63), 3.197 (2.96), 3.202 (1.47), 3.221 (5.03), 3.225 (3.69), 3.236 (3.53), 3.250 (6.01), 3.264 (3.31), 3.280 (2.18), 3.298 (1.41), 3.314 (2.02), 3.423 (0.97), 3.430 (1.20), 3.450 (2.48), 3.457 (2.67), 3.478 (2.24), 3.484 (2.07), 3.525 (1.85), 3.531 (2.04), 3.553 (2.55), 3.559 (2.60), 3.580 (1.08), 3.586 (1.82), 3.606 (0.95), 3.613 (2.71), 3.621 (3.21), 3.627 (1.99), 3.644 (3.28), 3.660 (0.71), 3.667 (0.81), 3.696 (2.82), 3.701 (2.29), 3.724 (4.69), 3.730 (3.95), 3.753 (1.99), 3.967 (5.95), 3.985 (5.90), 4.205 (0.81), 4.237 (0.84), 4.308 (0.91), 4.339 (0.83), 7.540 (9.78), 8.720 (1.62), 8.735 (3.54), 8.750 (1.66). LC-MS (方法1): Rt = 0.94 min; MS (ESIneg): m/z = 535 [M-H]⁻ | 中間物89 GP H 條件C 41 mg,18%產率,95%純度 | ||||
286 | 2-{[1-(環丙烷羰基)哌啶-4-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.654 (6.93), 0.673 (11.20), 0.994 (1.11), 1.023 (1.22), 1.139 (1.17), 1.166 (1.20), 1.497 (1.94), 1.522 (1.96), 1.540 (2.64), 1.543 (2.59), 1.560 (4.07), 1.568 (3.92), 1.576 (3.27), 1.584 (2.69), 1.590 (3.40), 1.605 (2.35), 1.758 (0.54), 1.773 (1.27), 1.779 (0.92), 1.788 (2.17), 1.794 (2.75), 1.810 (4.87), 1.828 (4.72), 1.845 (3.09), 1.861 (2.67), 1.866 (1.48), 1.871 (1.79), 1.878 (2.13), 1.882 (1.84), 1.890 (2.41), 1.900 (1.62), 1.904 (1.93), 1.907 (1.91), 1.911 (1.98), 1.921 (1.81), 1.928 (2.97), 1.947 (3.72), 1.963 (1.94), 1.978 (1.11), 2.007 (1.13), 2.017 (1.30), 2.025 (1.52), 2.034 (1.78), 2.043 (1.42), 2.053 (1.19), 2.062 (0.99), 2.327 (4.06), 2.331 (2.87), 2.336 (1.28), 2.518 (15.60), 2.523 (10.84), 2.556 (1.16), 2.669 (4.17), 2.673 (2.88), 2.678 (1.38), 2.841 (2.14), 2.845 (2.22), 2.864 (9.11), 2.882 (7.77), 2.923 (8.53), 2.934 (4.87), 2.941 (11.65), 2.948 (3.94), 2.960 (2.82), 2.966 (2.76), 2.996 (3.71), 3.029 (1.65), 3.060 (0.92), 3.254 (7.30), 3.268 (14.11), 3.283 (7.80), 3.597 (1.79), 3.614 (3.59), 3.616 (3.90), 3.634 (4.74), 3.652 (2.78), 3.740 (2.31), 3.756 (4.17), 3.757 (4.27), 3.761 (2.86), 3.773 (4.22), 3.776 (3.61), 3.794 (2.43), 3.920 (1.16), 3.936 (3.53), 3.951 (6.28), 3.966 (13.96), 3.984 (10.67), 4.205 (1.42), 4.239 (1.49), 4.308 (1.59), 4.341 (1.44), 7.539 (16.00), 8.684 (2.67), 8.700 (5.70), 8.714 (2.69). LC-MS (方法1): Rt = 0.99 min; MS (ESIpos): m/z = 521 [M+H]⁺ | 中間物89 GP H 條件C 54 mg,26%產率,98%純度 | ||||
287 | 2-[(1-苯甲醯基哌啶-4-基)甲基]-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.134 (0.47), 1.144 (0.58), 1.165 (1.40), 1.175 (1.46), 1.195 (1.58), 1.206 (1.49), 1.225 (0.77), 1.237 (0.67), 1.513 (0.50), 1.598 (0.50), 2.051 (0.63), 2.059 (0.77), 2.336 (1.09), 2.518 (16.00), 2.523 (11.35), 2.679 (1.17), 2.754 (0.48), 2.836 (1.00), 2.841 (1.02), 2.860 (3.92), 2.877 (3.37), 2.922 (3.76), 2.938 (4.78), 2.957 (1.43), 2.962 (1.40), 3.185 (0.49), 3.195 (2.22), 3.199 (1.14), 3.219 (3.95), 3.223 (2.84), 3.233 (2.76), 3.247 (4.65), 3.261 (2.51), 3.276 (1.65), 3.295 (1.15), 3.311 (1.46), 3.422 (0.70), 3.428 (0.92), 3.449 (1.90), 3.455 (2.07), 3.476 (1.75), 3.482 (1.63), 3.523 (1.76), 3.528 (2.03), 3.551 (2.33), 3.558 (2.36), 3.578 (1.06), 3.584 (1.56), 3.603 (0.78), 3.618 (2.61), 3.625 (1.62), 3.634 (1.24), 3.642 (2.50), 3.648 (1.97), 3.657 (0.55), 3.663 (0.59), 3.693 (2.18), 3.700 (1.80), 3.722 (3.64), 3.727 (3.08), 3.751 (1.54), 3.981 (3.22), 3.998 (3.22), 4.448 (0.43), 7.331 (3.04), 7.334 (2.02), 7.336 (1.89), 7.340 (4.21), 7.349 (5.12), 7.355 (5.14), 7.364 (0.81), 7.418 (2.00), 7.421 (1.67), 7.426 (6.20), 7.429 (5.86), 7.431 (3.82), 7.437 (8.23), 7.443 (8.52), 7.452 (0.81), 7.544 (7.58), 8.718 (1.30), 8.732 (2.78), 8.747 (1.27). LC-MS (方法1): Rt = 1.09 min; MS (ESIneg): m/z = 571 [M-H]⁻ | 中間物90 GP H 條件C 31 mg,15%產率,95%純度 | ||||
288 | 2-[(1-苯甲醯基哌啶-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.133 (0.74), 1.144 (0.99), 1.165 (2.26), 1.173 (2.35), 1.195 (2.55), 1.206 (2.36), 1.225 (1.26), 1.235 (1.08), 1.352 (0.49), 1.496 (1.52), 1.520 (0.83), 1.537 (1.67), 1.557 (2.28), 1.565 (2.19), 1.574 (2.01), 1.582 (1.80), 1.587 (2.35), 1.603 (1.79), 1.757 (0.45), 1.771 (0.94), 1.778 (0.76), 1.787 (1.70), 1.792 (2.07), 1.808 (3.75), 1.826 (3.57), 1.844 (2.43), 1.859 (1.97), 1.864 (1.12), 1.868 (1.38), 1.876 (1.56), 1.880 (1.41), 1.887 (1.82), 1.898 (1.18), 1.902 (1.44), 1.904 (1.39), 1.908 (1.27), 1.919 (1.06), 1.940 (0.60), 2.059 (1.23), 2.337 (1.53), 2.518 (16.00), 2.523 (10.91), 2.679 (1.75), 2.736 (0.80), 2.834 (1.57), 2.840 (1.63), 2.859 (6.27), 2.876 (5.56), 2.918 (6.18), 2.935 (7.72), 2.953 (2.27), 2.959 (2.18), 2.995 (1.22), 3.251 (5.52), 3.266 (10.61), 3.281 (5.95), 3.552 (0.66), 3.596 (1.52), 3.611 (2.85), 3.615 (3.06), 3.632 (3.59), 3.650 (2.09), 3.739 (1.85), 3.756 (3.28), 3.771 (3.04), 3.774 (2.71), 3.792 (1.86), 3.917 (0.92), 3.932 (2.63), 3.949 (4.47), 3.964 (3.17), 3.980 (5.92), 3.997 (5.22), 4.430 (0.68), 7.331 (4.93), 7.334 (3.26), 7.336 (3.07), 7.340 (6.82), 7.349 (8.23), 7.355 (8.10), 7.364 (1.27), 7.402 (0.61), 7.418 (3.28), 7.421 (2.80), 7.426 (9.96), 7.429 (9.36), 7.431 (6.15), 7.437 (13.06), 7.443 (13.62), 7.452 (1.11), 7.542 (12.00), 8.680 (2.07), 8.695 (4.42), 8.709 (1.97). LC-MS (方法1): Rt = 1.06 min; MS (ESIpos): m/z = 557 [M+H]⁺ | 中間物90 GP H 條件C 35 mg,18%產率,98%純度 | ||||
289 | 8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-2-[2-(吡啶-3-基)丙-2-基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.53-1.62 (m, 1H), 1.76-1.89 (m, 3H), 1.95 (s, 6H), 2.43 (s, 3H), 2.85-2.95 (m, 4H), 3.17-3.27 (m, 2H), 3.57-3.64 (m, 1H), 3.72-3.80 (m, 1H), 3.88-4.00 (m, 1H), 7.30-7.36 (m, 1H), 7.39-7.44 (m, 1H), 7.74 (s, 1H), 7.98 (t, 1H), 8.22 (dd, 1H), 8.43 (dd, 1H). LC-MS (方法1): Rt = 1.12 min; MS (ESIpos): m/z = 421 [M+H]+ . | 中間物91及CAS-RN:[7175-81-7] GP G 條件A 10.3 mg (43%產率,93%純度) | ||||
290 | (4R或4S)-2-{[1-(環丙烷羰基)哌啶-4-基]甲基}-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.654 (4.29), 0.674 (6.94), 0.995 (0.63), 1.002 (0.66), 1.013 (0.71), 1.019 (0.74), 1.025 (0.72), 1.028 (0.71), 1.031 (0.68), 1.038 (0.62), 1.130 (0.60), 1.146 (0.74), 1.152 (0.70), 1.158 (0.71), 1.166 (0.71), 1.173 (0.76), 1.272 (14.64), 1.289 (15.14), 1.508 (1.99), 1.539 (2.02), 1.559 (2.58), 1.567 (2.60), 1.575 (2.36), 1.589 (2.29), 1.605 (1.78), 1.794 (1.82), 1.810 (3.32), 1.828 (3.28), 1.846 (2.15), 1.862 (1.84), 1.890 (1.60), 1.950 (2.05), 2.024 (0.81), 2.031 (0.95), 2.041 (1.20), 2.050 (0.92), 2.058 (0.78), 2.518 (16.00), 2.523 (11.88), 2.569 (2.73), 2.595 (2.80), 2.610 (2.80), 2.636 (3.01), 3.004 (3.24), 3.022 (4.37), 3.045 (3.10), 3.064 (3.57), 3.164 (1.54), 3.190 (1.42), 3.252 (4.14), 3.268 (9.11), 3.283 (5.62), 3.597 (1.16), 3.616 (2.66), 3.634 (3.18), 3.652 (1.81), 3.741 (1.53), 3.758 (2.89), 3.774 (2.68), 3.795 (1.74), 3.935 (2.34), 3.951 (3.99), 3.968 (7.76), 3.986 (6.24), 4.211 (0.92), 4.240 (0.92), 4.245 (0.95), 4.311 (0.99), 4.318 (0.95), 4.322 (0.86), 4.342 (0.87), 4.345 (0.87), 7.579 (9.73), 8.684 (1.87), 8.699 (3.99), 8.715 (1.79). LC-MS (方法1): Rt = 1.16 min; MS (ESIpos): m/z = 535 [M+H]+ | 中間物93 GP H 條件C 41 mg,32%產率,98%純度 |
291 | (4R或4S)-2-{[1-(環丙烷羰基)哌啶-4-基]甲基}-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.654 (4.82), 0.674 (7.85), 1.011 (0.79), 1.019 (0.80), 1.022 (0.78), 1.026 (0.80), 1.129 (0.67), 1.131 (0.66), 1.142 (0.79), 1.148 (0.81), 1.156 (0.79), 1.158 (0.77), 1.164 (0.79), 1.169 (0.79), 1.173 (0.80), 1.175 (0.79), 1.273 (16.00), 1.289 (15.94), 1.497 (1.12), 1.527 (1.31), 1.544 (0.88), 1.553 (0.88), 1.572 (1.20), 1.575 (1.19), 1.586 (0.95), 1.588 (0.92), 1.593 (0.91), 1.596 (0.93), 1.601 (0.98), 1.935 (1.42), 1.950 (2.21), 1.966 (1.28), 2.013 (0.77), 2.023 (0.88), 2.032 (1.04), 2.041 (1.24), 2.051 (1.00), 2.061 (0.83), 2.069 (0.69), 2.518 (14.02), 2.523 (9.86), 2.572 (3.01), 2.598 (3.37), 2.613 (3.08), 2.640 (3.25), 3.007 (3.42), 3.024 (4.80), 3.048 (3.21), 3.066 (3.75), 3.148 (1.14), 3.166 (1.63), 3.196 (3.92), 3.204 (1.87), 3.220 (5.09), 3.224 (5.78), 3.238 (4.57), 3.249 (5.37), 3.259 (4.27), 3.275 (2.72), 3.294 (2.05), 3.423 (1.23), 3.430 (1.55), 3.450 (2.96), 3.457 (3.20), 3.477 (2.58), 3.484 (2.51), 3.525 (2.26), 3.530 (2.60), 3.553 (3.12), 3.559 (3.14), 3.580 (1.30), 3.586 (2.16), 3.621 (3.80), 3.629 (2.47), 3.644 (4.03), 3.697 (3.44), 3.703 (2.83), 3.725 (5.78), 3.753 (2.42), 3.969 (6.73), 3.987 (6.65), 4.209 (1.02), 4.212 (1.02), 4.221 (0.86), 4.233 (0.88), 4.239 (1.05), 4.244 (1.08), 4.247 (1.04), 4.314 (1.12), 4.332 (0.86), 4.338 (0.96), 4.343 (1.02), 7.582 (10.73), 8.722 (2.05), 8.736 (4.43), 8.751 (2.00). LC-MS (方法1): Rt = 1.08 min; MS (ESIpos): m/z = 551 [M+H]+ | 中間物93 GP H 條件C 48 mg,36%產率,98%純度 |
292 | (4R或4S)-2-[(1-乙醯基哌啶-4-基)甲基]-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.987 (0.56), 1.004 (0.47), 1.017 (0.59), 1.127 (0.62), 1.158 (0.65), 1.272 (5.97), 1.288 (6.07), 1.489 (0.82), 1.523 (1.47), 1.539 (1.32), 1.559 (1.56), 1.567 (1.44), 1.575 (1.01), 1.583 (0.69), 1.588 (0.87), 1.605 (0.53), 1.773 (0.42), 1.789 (0.80), 1.794 (1.03), 1.810 (1.87), 1.828 (1.82), 1.845 (1.17), 1.861 (1.00), 1.866 (0.58), 1.871 (0.70), 1.878 (0.80), 1.883 (0.69), 1.890 (0.91), 1.900 (0.60), 1.904 (0.72), 1.911 (0.65), 1.921 (0.54), 1.928 (0.52), 1.942 (0.45), 1.963 (16.00), 1.995 (0.58), 2.004 (0.65), 2.337 (0.50), 2.444 (0.64), 2.518 (5.93), 2.523 (3.87), 2.567 (1.31), 2.593 (1.39), 2.608 (1.50), 2.634 (1.55), 2.933 (0.58), 2.961 (1.03), 3.002 (1.27), 3.020 (1.36), 3.044 (0.88), 3.062 (1.12), 3.146 (0.53), 3.162 (0.79), 3.171 (0.65), 3.180 (0.61), 3.188 (0.73), 3.206 (0.43), 3.252 (2.29), 3.268 (4.97), 3.283 (2.85), 3.597 (0.67), 3.616 (1.49), 3.633 (1.82), 3.651 (1.01), 3.741 (0.90), 3.758 (2.12), 3.761 (1.74), 3.773 (2.13), 3.776 (1.88), 3.794 (1.47), 3.919 (0.45), 3.935 (1.36), 3.951 (2.99), 3.956 (4.19), 3.966 (2.30), 3.974 (3.91), 4.314 (0.76), 4.343 (0.73), 7.573 (5.38), 8.686 (1.03), 8.701 (2.15), 8.716 (1.00). LC-MS (方法1): Rt = 1.05 min; MS (ESIpos): m/z = 509 [M+H]+ | 中間物94 GP H 條件C 23 mg,38%產率,98%純度 |
293 | (4R或4S)-2-{[1-(1-羥基環丙烷-1-羰基)哌啶-4-基]甲基}-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.731 (8.18), 0.860 (8.04), 1.111 (1.84), 1.114 (1.78), 1.129 (2.01), 1.274 (15.79), 1.291 (15.80), 1.492 (3.89), 1.559 (5.99), 1.794 (2.73), 1.810 (4.69), 1.827 (4.65), 1.845 (3.12), 1.862 (2.48), 1.866 (1.99), 1.870 (2.19), 1.878 (2.26), 1.883 (2.20), 1.889 (2.25), 1.907 (2.05), 1.963 (2.06), 2.024 (1.70), 2.035 (1.74), 2.634 (4.01), 3.003 (3.29), 3.022 (4.10), 3.045 (2.91), 3.063 (3.36), 3.164 (3.23), 3.173 (2.99), 3.183 (3.20), 3.190 (3.46), 3.268 (16.00), 3.283 (14.67), 3.616 (3.49), 3.634 (4.05), 3.757 (3.98), 3.777 (3.48), 3.955 (10.09), 3.973 (8.61), 4.297 (0.89), 4.305 (0.99), 4.311 (1.01), 4.313 (1.03), 4.317 (1.03), 4.322 (1.06), 4.326 (1.08), 4.331 (1.15), 4.335 (1.06), 4.339 (1.14), 4.343 (1.24), 4.346 (1.12), 4.350 (1.14), 4.357 (1.21), 4.362 (1.04), 4.376 (1.01), 4.379 (1.11), 4.391 (1.05), 4.402 (0.89), 7.586 (10.27), 8.699 (4.64). LC-MS (方法1): Rt = 1.06 min; MS (ESIpos): m/z = 551 [M+H]+ | 中間物95 GP H 條件C 7 mg,12%產率,95%純度 |
294 | (4R或4S)-2-[(1-乙醯基哌啶-4-基)甲基]-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.987 (0.54), 1.003 (0.48), 1.016 (0.58), 1.128 (0.61), 1.159 (0.63), 1.272 (5.91), 1.289 (6.00), 1.491 (0.80), 1.526 (1.30), 1.561 (0.64), 1.963 (16.00), 2.004 (0.63), 2.336 (0.75), 2.448 (0.72), 2.518 (8.24), 2.523 (5.29), 2.571 (1.22), 2.597 (1.31), 2.612 (1.45), 2.638 (1.54), 2.678 (0.75), 2.933 (0.56), 2.961 (0.99), 3.005 (1.12), 3.024 (1.32), 3.048 (0.87), 3.065 (1.12), 3.146 (0.54), 3.163 (0.76), 3.189 (1.12), 3.195 (1.98), 3.203 (1.04), 3.220 (2.57), 3.224 (2.96), 3.237 (2.31), 3.244 (1.58), 3.249 (2.81), 3.259 (2.22), 3.275 (1.41), 3.293 (0.97), 3.423 (0.55), 3.429 (0.68), 3.450 (1.47), 3.456 (1.61), 3.477 (1.31), 3.484 (1.22), 3.524 (1.09), 3.530 (1.29), 3.552 (1.54), 3.559 (1.55), 3.579 (0.62), 3.585 (1.07), 3.621 (1.98), 3.628 (1.19), 3.644 (2.04), 3.667 (0.42), 3.696 (1.72), 3.703 (1.47), 3.725 (2.92), 3.753 (1.45), 3.801 (0.73), 3.957 (3.81), 3.975 (3.71), 4.314 (0.75), 4.345 (0.70), 7.576 (5.34), 8.721 (1.06), 8.736 (2.20), 8.751 (0.98). LC-MS (方法1): Rt = 0.98 min; MS (ESIpos): m/z = 525 [M+H]+ | 中間物94 GP H 條件C 22 mg,35%產率,98%純度 |
295 | (4R或4S)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[1-(1-羥基環丙烷-1-羰基)哌啶-4-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.724 (6.06), 0.731 (6.96), 0.741 (2.91), 0.850 (3.16), 0.860 (6.51), 0.879 (2.29), 1.003 (1.48), 1.130 (1.14), 1.275 (15.48), 1.292 (15.39), 1.500 (5.27), 1.532 (2.84), 1.561 (2.44), 2.015 (0.88), 2.024 (1.01), 2.028 (0.94), 2.033 (1.20), 2.043 (0.99), 2.052 (0.88), 2.518 (16.00), 2.523 (10.23), 2.539 (2.04), 2.571 (2.52), 2.597 (2.84), 2.612 (3.04), 2.639 (3.26), 3.007 (2.87), 3.024 (3.99), 3.048 (2.71), 3.066 (3.18), 3.148 (1.28), 3.166 (1.88), 3.196 (4.17), 3.220 (5.38), 3.225 (5.92), 3.238 (4.25), 3.249 (6.12), 3.259 (4.28), 3.275 (3.40), 3.430 (1.74), 3.450 (3.25), 3.457 (3.48), 3.478 (2.73), 3.484 (2.63), 3.525 (2.24), 3.530 (2.39), 3.553 (3.10), 3.559 (3.10), 3.586 (2.21), 3.621 (3.84), 3.629 (2.46), 3.645 (4.12), 3.697 (3.44), 3.703 (2.89), 3.726 (5.79), 3.753 (2.43), 3.957 (6.41), 3.974 (6.40), 4.352 (0.60), 4.361 (0.60), 7.587 (9.82), 8.723 (1.72), 8.737 (3.65), 8.752 (1.68). LC-MS (方法1): Rt = 0.98 min; MS (ESIpos): m/z = 567 [M+H]+ | 中間物95 GP H 條件C 16 mg,25%產率,95%純度 |
296 | (4R或4S)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-2-{[1-(2-側氧基丁醯基)哌啶-4-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.985 (7.07), 1.003 (16.00), 1.021 (7.28), 1.071 (0.45), 1.087 (0.52), 1.100 (0.68), 1.115 (0.67), 1.145 (0.64), 1.156 (0.70), 1.187 (0.66), 1.272 (6.56), 1.287 (6.62), 1.496 (1.65), 1.535 (0.91), 1.573 (0.81), 1.592 (0.92), 1.623 (0.76), 2.068 (0.61), 2.076 (0.72), 2.085 (0.58), 2.318 (0.57), 2.323 (1.27), 2.327 (1.82), 2.332 (1.31), 2.336 (0.56), 2.518 (5.85), 2.523 (3.95), 2.539 (0.53), 2.569 (1.34), 2.595 (1.46), 2.611 (1.57), 2.637 (1.65), 2.660 (0.70), 2.665 (1.55), 2.669 (2.41), 2.674 (2.31), 2.694 (3.37), 2.697 (3.32), 2.713 (3.99), 2.734 (1.33), 3.004 (1.69), 3.025 (1.92), 3.045 (1.19), 3.048 (1.14), 3.064 (1.87), 3.145 (0.59), 3.163 (0.87), 3.188 (1.19), 3.195 (2.26), 3.203 (1.14), 3.219 (3.06), 3.223 (3.30), 3.237 (2.41), 3.248 (3.37), 3.258 (2.32), 3.274 (1.60), 3.293 (1.43), 3.423 (0.80), 3.429 (0.95), 3.450 (2.21), 3.456 (2.71), 3.477 (1.75), 3.483 (1.92), 3.524 (1.33), 3.530 (1.49), 3.552 (1.78), 3.559 (1.80), 3.578 (0.73), 3.585 (1.23), 3.620 (2.28), 3.627 (1.42), 3.644 (2.35), 3.660 (0.44), 3.667 (0.53), 3.696 (1.97), 3.702 (1.64), 3.725 (3.33), 3.752 (1.39), 3.979 (2.82), 3.996 (2.84), 4.204 (0.87), 4.238 (0.83), 7.582 (5.97), 8.722 (1.01), 8.737 (2.22), 8.751 (1.02). LC-MS (方法1): Rt = 1.10 min; MS (ESIneg): m/z = 565 [M-H]- | 中間物95 GP H 條件C 13 mg,21%產率,98%純度 |
297 | (4R或4S)-4-甲基-2-{[1-(2-側氧基丁醯基)哌啶-4-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.985 (7.18), 1.003 (16.00), 1.021 (7.50), 1.071 (0.43), 1.086 (0.56), 1.101 (0.67), 1.114 (0.69), 1.157 (0.74), 1.187 (0.71), 1.272 (6.78), 1.286 (6.82), 1.508 (0.46), 1.538 (1.64), 1.558 (1.63), 1.566 (1.81), 1.574 (1.61), 1.587 (1.87), 1.604 (1.03), 1.624 (0.81), 1.773 (0.52), 1.788 (0.93), 1.793 (1.14), 1.810 (2.11), 1.827 (2.10), 1.845 (1.33), 1.861 (1.13), 1.866 (0.67), 1.870 (0.81), 1.877 (0.89), 1.889 (1.07), 1.900 (0.67), 1.904 (0.80), 1.910 (0.73), 1.921 (0.57), 2.076 (0.72), 2.085 (0.62), 2.318 (0.89), 2.322 (2.00), 2.327 (2.92), 2.332 (2.07), 2.336 (0.90), 2.518 (10.33), 2.523 (6.76), 2.565 (1.32), 2.591 (1.43), 2.607 (1.55), 2.633 (1.69), 2.660 (0.98), 2.665 (2.26), 2.669 (3.44), 2.673 (2.97), 2.694 (3.44), 2.697 (3.40), 2.713 (4.09), 2.731 (1.33), 3.004 (1.75), 3.022 (1.76), 3.032 (1.23), 3.043 (1.35), 3.063 (1.90), 3.144 (0.59), 3.162 (0.84), 3.188 (0.82), 3.204 (0.49), 3.252 (2.62), 3.267 (5.80), 3.282 (3.35), 3.459 (0.99), 3.494 (0.87), 3.596 (0.74), 3.616 (1.69), 3.633 (2.07), 3.651 (1.18), 3.741 (0.99), 3.757 (1.84), 3.773 (1.76), 3.776 (1.57), 3.794 (1.02), 3.918 (0.51), 3.934 (1.47), 3.950 (2.45), 3.965 (1.82), 3.979 (3.07), 3.996 (2.91), 4.204 (0.90), 4.235 (0.86), 7.578 (6.14), 7.580 (6.06), 8.684 (1.20), 8.699 (2.55), 8.714 (1.17). LC-MS (方法1): Rt = 1.18 min; MS (ESIneg): m/z = 549 [M-H]- | 中間物95 GP H 條件C 11 mg,18%產率,98%純度 |
298 | (4R或4S)-4-甲基-2-{[1-(1-甲基環丙烷-1-羰基)哌啶-4-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.496 (1.23), 0.508 (4.00), 0.512 (3.85), 0.523 (1.51), 0.730 (1.42), 0.739 (3.88), 0.743 (3.67), 0.755 (1.16), 1.085 (0.71), 1.090 (0.71), 1.106 (0.60), 1.111 (0.62), 1.192 (16.00), 1.272 (7.27), 1.289 (7.42), 1.495 (1.44), 1.539 (1.76), 1.559 (1.80), 1.567 (1.86), 1.605 (0.50), 1.794 (0.92), 1.810 (1.68), 1.828 (1.64), 1.846 (1.05), 1.862 (0.90), 1.878 (0.72), 1.890 (0.84), 1.905 (0.64), 1.922 (0.46), 2.005 (0.45), 2.014 (0.52), 2.023 (0.60), 2.031 (0.50), 2.518 (5.88), 2.523 (3.79), 2.567 (1.23), 2.593 (1.34), 2.608 (1.47), 2.634 (1.56), 2.740 (0.33), 2.746 (0.33), 2.751 (0.34), 2.755 (0.35), 2.760 (0.34), 2.763 (0.34), 2.766 (0.33), 2.772 (0.33), 3.003 (1.37), 3.022 (1.83), 3.044 (1.27), 3.063 (1.52), 3.147 (0.59), 3.164 (0.84), 3.190 (0.79), 3.207 (0.51), 3.252 (2.10), 3.268 (4.38), 3.283 (2.74), 3.597 (0.60), 3.616 (1.35), 3.634 (1.63), 3.652 (0.91), 3.741 (0.78), 3.758 (1.47), 3.774 (1.42), 3.794 (0.79), 3.919 (0.40), 3.935 (1.19), 3.951 (2.14), 3.963 (3.63), 3.980 (3.38), 4.208 (1.51), 4.241 (1.44), 7.576 (4.85), 8.688 (0.90), 8.703 (1.90), 8.717 (0.89). LC-MS (方法1): Rt = 1.18 min; MS (ESIneg): m/z = 547 [M-H]- | 中間物96 GP H 條件C 20 mg,33%產率,98%純度 |
299 | (4R或4S)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-2-{[1-(1-甲基環丙烷-1-羰基)哌啶-4-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.497 (1.18), 0.508 (3.91), 0.512 (3.75), 0.523 (1.47), 0.729 (1.37), 0.739 (3.75), 0.743 (3.54), 0.755 (1.11), 1.060 (0.46), 1.092 (0.65), 1.102 (0.57), 1.113 (0.56), 1.123 (0.48), 1.192 (16.00), 1.272 (7.28), 1.289 (7.26), 1.502 (1.74), 1.535 (1.20), 1.564 (1.04), 2.005 (0.39), 2.014 (0.48), 2.022 (0.56), 2.031 (0.47), 2.040 (0.38), 2.518 (6.28), 2.523 (4.13), 2.570 (1.21), 2.596 (1.33), 2.612 (1.44), 2.638 (1.55), 2.734 (0.35), 2.772 (0.35), 3.006 (1.34), 3.024 (1.85), 3.047 (1.28), 3.065 (1.55), 3.148 (0.59), 3.164 (0.84), 3.196 (1.91), 3.220 (2.49), 3.224 (2.74), 3.238 (1.81), 3.249 (2.94), 3.259 (1.77), 3.274 (1.44), 3.423 (0.80), 3.429 (0.89), 3.450 (1.49), 3.457 (1.63), 3.478 (1.30), 3.484 (1.21), 3.525 (1.07), 3.530 (1.17), 3.553 (1.46), 3.559 (1.45), 3.580 (0.60), 3.586 (1.01), 3.622 (1.80), 3.628 (1.13), 3.645 (1.86), 3.697 (1.55), 3.703 (1.29), 3.726 (2.61), 3.753 (1.10), 3.963 (3.16), 3.980 (3.07), 4.208 (1.43), 4.240 (1.36), 7.578 (4.79), 8.741 (1.45). LC-MS (方法1): Rt = 1.10 min; MS (ESIpos): m/z = 565 [M+H]+ | 中間物96 GP H 條件C 28 mg,45%產率,98%純度 |
300 | N,2-雙{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (5.72), 2.331 (1.93), 2.523 (9.38), 2.673 (2.07), 2.842 (2.54), 2.846 (2.66), 2.865 (9.97), 2.883 (8.19), 2.931 (8.77), 2.948 (11.53), 2.954 (4.81), 2.967 (3.06), 2.972 (2.90), 3.188 (1.43), 3.197 (4.71), 3.202 (2.70), 3.221 (8.27), 3.225 (7.10), 3.237 (10.46), 3.250 (10.13), 3.264 (10.02), 3.280 (4.72), 3.290 (6.44), 3.298 (4.19), 3.307 (4.18), 3.383 (1.01), 3.406 (1.97), 3.412 (2.16), 3.424 (2.30), 3.433 (4.84), 3.439 (4.80), 3.450 (4.76), 3.457 (5.63), 3.460 (5.06), 3.466 (3.98), 3.478 (3.88), 3.484 (3.74), 3.502 (3.16), 3.508 (3.51), 3.525 (3.85), 3.530 (7.48), 3.537 (4.77), 3.553 (4.89), 3.559 (6.02), 3.580 (2.01), 3.586 (3.15), 3.613 (9.84), 3.627 (4.28), 3.643 (8.87), 3.659 (1.45), 3.666 (1.52), 3.696 (5.12), 3.702 (4.63), 3.725 (9.87), 3.730 (11.08), 3.737 (7.40), 3.748 (5.21), 3.758 (5.86), 3.765 (4.63), 3.789 (1.47), 3.796 (1.36), 3.808 (2.43), 3.812 (2.55), 3.818 (2.39), 3.825 (2.90), 3.842 (1.48), 3.849 (1.17), 4.051 (1.20), 4.068 (0.75), 4.087 (7.26), 4.097 (8.01), 4.104 (8.17), 4.110 (7.45), 4.132 (1.17), 4.145 (0.72), 7.525 (16.00), 8.734 (2.82), 8.749 (5.72), 8.764 (2.70). LC-MS (方法1): Rt = 0.91 min; MS (ESIpos): m/z = 472 [M+H]+ | 中間物69 GP H 條件D 60 mg,45%產率,95%純度 |
301 | 2-{[(2R)-1,4-二㗁烷-2-基]甲基}-N-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.073 (2.80), 2.331 (3.15), 2.522 (14.16), 2.673 (3.08), 2.846 (2.69), 2.865 (10.02), 2.883 (8.38), 2.931 (8.96), 2.948 (11.37), 2.967 (2.99), 2.972 (2.82), 3.188 (1.42), 3.197 (4.73), 3.202 (2.84), 3.221 (8.61), 3.236 (10.51), 3.249 (10.56), 3.264 (10.67), 3.280 (5.36), 3.290 (7.18), 3.298 (5.28), 3.405 (2.51), 3.412 (2.71), 3.423 (2.53), 3.433 (5.03), 3.439 (4.92), 3.450 (4.91), 3.457 (5.84), 3.466 (4.02), 3.477 (3.93), 3.484 (3.81), 3.502 (3.20), 3.507 (3.51), 3.525 (3.94), 3.530 (7.38), 3.536 (4.73), 3.553 (5.07), 3.558 (6.04), 3.580 (2.08), 3.585 (3.18), 3.613 (10.07), 3.627 (4.40), 3.642 (8.95), 3.666 (1.48), 3.695 (5.12), 3.702 (4.67), 3.725 (10.23), 3.730 (11.24), 3.737 (7.55), 3.748 (5.47), 3.758 (5.86), 3.764 (4.62), 3.789 (1.41), 3.812 (2.52), 3.818 (2.36), 3.825 (2.91), 3.842 (1.49), 4.052 (1.13), 4.068 (0.76), 4.087 (7.32), 4.096 (8.07), 4.104 (8.21), 4.109 (7.47), 4.132 (1.24), 4.145 (0.75), 7.524 (16.00), 8.734 (2.84), 8.749 (5.76), 8.764 (2.82). LC-MS (方法1): Rt = 0.89 min; MS (ESIpos): m/z = 472 [M+H]+ | 中間物70 GP H 條件D 36 mg,36%產率,95%純度 |
302 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(2-甲基嘧啶-5-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.270 (5.96), 1.287 (6.00), 2.518 (2.96), 2.523 (1.91), 2.579 (1.07), 2.594 (16.00), 2.605 (1.46), 2.620 (1.19), 2.646 (1.23), 2.999 (1.11), 3.018 (1.49), 3.041 (1.07), 3.059 (1.24), 3.147 (0.44), 3.164 (0.65), 3.173 (0.51), 3.181 (0.48), 3.191 (0.60), 3.240 (1.10), 3.264 (1.40), 3.268 (1.39), 3.293 (1.39), 3.396 (0.46), 3.402 (0.51), 3.423 (1.03), 3.429 (1.10), 3.450 (0.89), 3.457 (0.84), 3.513 (0.67), 3.519 (0.80), 3.542 (1.01), 3.548 (1.09), 3.568 (0.47), 3.575 (0.71), 3.609 (1.14), 3.637 (0.90), 3.721 (1.54), 3.729 (1.25), 3.744 (0.97), 3.751 (1.28), 3.757 (1.06), 3.830 (0.60), 3.837 (0.67), 3.846 (0.56), 3.854 (0.73), 3.861 (0.55), 4.093 (2.28), 4.098 (2.26), 4.109 (2.55), 4.405 (2.79), 4.419 (2.86), 7.567 (4.00), 8.643 (10.45), 8.651 (0.90), 9.295 (0.67), 9.309 (1.50), 9.324 (0.67). LC-MS (方法1): Rt = 0.92 min; MS (ESIpos): m/z = 492 [M+H]+ | 中間物79 GP H 條件D 50 mg,66%產率,95%純度 |
303 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(5-甲基嘧啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.289 (8.86), 1.306 (8.88), 2.259 (16.00), 2.331 (0.85), 2.518 (4.54), 2.523 (2.88), 2.612 (1.45), 2.639 (1.54), 2.665 (0.93), 2.669 (1.27), 2.674 (1.06), 2.680 (2.01), 3.031 (1.63), 3.049 (2.23), 3.072 (1.48), 3.090 (1.84), 3.170 (0.67), 3.186 (0.97), 3.196 (0.75), 3.203 (0.71), 3.212 (0.91), 3.230 (0.56), 3.248 (1.78), 3.272 (2.06), 3.276 (2.08), 3.301 (2.21), 3.402 (0.60), 3.409 (0.73), 3.429 (1.50), 3.436 (1.60), 3.457 (1.27), 3.464 (1.19), 3.520 (1.00), 3.526 (1.15), 3.549 (1.50), 3.555 (1.55), 3.575 (0.68), 3.582 (1.01), 3.613 (1.62), 3.642 (1.28), 3.724 (1.71), 3.731 (1.78), 3.737 (1.84), 3.751 (1.42), 3.760 (1.57), 3.766 (1.54), 3.825 (0.45), 3.832 (0.46), 3.839 (0.85), 3.846 (0.94), 3.855 (0.82), 3.863 (1.03), 3.870 (0.77), 3.879 (0.53), 3.885 (0.44), 4.100 (3.20), 4.106 (3.25), 4.116 (3.54), 4.575 (4.14), 4.590 (4.24), 7.578 (5.92), 8.623 (12.02), 9.124 (1.16), 9.138 (2.58), 9.153 (1.15). LC-MS (方法1): Rt = 1.04 min; MS (ESIpos): m/z = 492 [M+H]+ | 中間物79 GP H 條件D 36 mg,45%產率,95%純度 |
304 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(嘧啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.291 (11.62), 1.307 (11.61), 2.323 (1.38), 2.327 (1.92), 2.331 (1.39), 2.336 (0.64), 2.518 (7.04), 2.523 (4.45), 2.617 (1.86), 2.643 (2.06), 2.658 (2.52), 2.665 (1.64), 2.669 (2.07), 2.673 (1.49), 2.678 (0.92), 2.685 (2.39), 3.034 (2.15), 3.053 (2.92), 3.076 (1.93), 3.094 (2.42), 3.172 (0.87), 3.189 (1.26), 3.198 (0.98), 3.205 (0.92), 3.215 (1.15), 3.232 (0.72), 3.249 (2.34), 3.273 (2.75), 3.278 (2.72), 3.301 (2.99), 3.403 (0.80), 3.409 (1.00), 3.430 (1.96), 3.436 (2.11), 3.457 (1.66), 3.464 (1.55), 3.521 (1.27), 3.526 (1.53), 3.549 (1.97), 3.556 (2.05), 3.576 (0.87), 3.582 (1.34), 3.614 (2.08), 3.642 (1.63), 3.725 (2.16), 3.732 (2.26), 3.738 (2.39), 3.751 (1.82), 3.761 (1.99), 3.767 (1.98), 3.827 (0.58), 3.833 (0.58), 3.840 (1.09), 3.847 (1.23), 3.856 (1.06), 3.864 (1.34), 3.871 (1.01), 3.880 (0.69), 3.886 (0.58), 4.065 (0.45), 4.101 (4.18), 4.107 (4.26), 4.117 (4.61), 4.143 (0.45), 4.620 (5.98), 4.635 (6.24), 7.405 (2.91), 7.417 (5.93), 7.429 (2.98), 7.578 (7.70), 7.580 (7.66), 8.782 (15.68), 8.794 (16.00), 9.154 (1.54), 9.169 (3.35), 9.183 (1.51). LC-MS (方法1): Rt = 0.97 min; MS (ESIpos): m/z = 478 [M+H]+ | 中間物79 GP H 條件D 46 mg,62%產率,95%純度 |
305 | 2-[(1-乙醯基哌啶-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.977 (0.41), 0.986 (0.42), 1.007 (0.46), 1.017 (0.44), 1.118 (0.41), 1.126 (0.42), 1.148 (0.46), 1.157 (0.42), 1.480 (0.53), 1.518 (0.88), 1.539 (0.73), 1.559 (1.12), 1.567 (0.84), 1.576 (0.57), 1.583 (0.43), 1.589 (0.59), 1.788 (0.58), 1.793 (0.71), 1.809 (1.28), 1.828 (1.25), 1.845 (0.82), 1.861 (0.69), 1.870 (0.47), 1.877 (0.54), 1.882 (0.48), 1.889 (0.64), 1.899 (0.41), 1.903 (0.50), 1.910 (0.45), 1.924 (0.41), 1.961 (16.00), 1.987 (0.42), 1.997 (0.48), 2.331 (1.16), 2.337 (0.52), 2.445 (0.57), 2.518 (5.61), 2.523 (3.69), 2.673 (1.12), 2.678 (0.51), 2.839 (0.56), 2.844 (0.57), 2.862 (2.43), 2.880 (2.03), 2.924 (2.41), 2.940 (3.05), 2.947 (1.08), 2.959 (1.38), 2.964 (1.25), 2.990 (0.42), 3.253 (1.98), 3.268 (3.82), 3.283 (2.16), 3.597 (0.45), 3.613 (0.96), 3.616 (1.00), 3.633 (1.23), 3.651 (0.72), 3.740 (0.65), 3.757 (1.58), 3.761 (1.30), 3.773 (1.39), 3.776 (1.16), 3.794 (1.12), 3.934 (0.96), 3.954 (3.12), 3.966 (1.71), 3.972 (2.80), 4.308 (0.55), 4.340 (0.54), 7.533 (4.18), 8.684 (0.72), 8.699 (1.47), 8.713 (0.67). LC-MS (方法1): Rt = 0.92 min; MS (ESIpos): m/z = 495 [M+H]+ | 中間物97 GP H 條件C 28 mg,53%產率,98%純度 |
306 | 2-[(1-乙醯基哌啶-4-基)甲基]-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.976 (0.62), 1.009 (0.68), 1.128 (0.61), 1.150 (0.69), 1.352 (0.44), 1.480 (0.82), 1.518 (1.27), 1.555 (1.04), 1.961 (16.00), 2.073 (1.13), 2.845 (0.82), 2.863 (3.01), 2.880 (2.63), 2.926 (3.19), 2.943 (3.48), 2.962 (1.85), 2.990 (0.62), 3.196 (1.46), 3.220 (2.81), 3.235 (2.24), 3.249 (3.50), 3.263 (2.66), 3.279 (2.67), 3.423 (1.58), 3.449 (1.76), 3.456 (1.76), 3.477 (1.40), 3.483 (1.35), 3.524 (1.09), 3.530 (1.11), 3.558 (1.47), 3.585 (0.99), 3.620 (2.07), 3.644 (2.00), 3.694 (1.55), 3.723 (2.79), 3.753 (1.64), 3.795 (0.84), 3.955 (3.45), 3.972 (3.37), 4.307 (0.84), 4.340 (0.80), 7.534 (4.75), 8.542 (0.64), 8.721 (0.90), 8.735 (1.88), 8.750 (0.90). LC-MS (方法1): Rt = 0.88 min; MS (ESIpos): m/z = 511 [M+H]+ | 中間物97 GP H 條件C 30 mg,55%產率,95%純度 |
307 | 2-{[1-(環丙基甲基)哌啶-4-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (2.55), 0.018 (8.58), 0.022 (8.22), 0.030 (9.00), 0.044 (2.87), 0.399 (3.12), 0.409 (7.61), 0.414 (7.81), 0.419 (4.13), 0.424 (3.93), 0.429 (8.16), 0.433 (7.76), 0.444 (2.81), 0.766 (1.66), 0.770 (1.71), 0.773 (1.68), 0.778 (1.45), 0.786 (2.67), 0.794 (1.41), 0.798 (1.52), 0.802 (1.57), 0.806 (1.37), 1.154 (1.12), 1.183 (3.20), 1.206 (3.64), 1.235 (1.71), 1.458 (4.29), 1.488 (3.44), 1.539 (2.00), 1.559 (2.61), 1.567 (2.43), 1.576 (2.03), 1.589 (2.28), 1.605 (1.45), 1.715 (1.87), 1.772 (1.57), 1.793 (5.43), 1.809 (5.93), 1.827 (10.05), 1.845 (4.63), 1.869 (2.18), 1.877 (2.28), 1.888 (2.59), 1.903 (2.00), 1.920 (1.48), 1.941 (0.96), 2.107 (13.45), 2.123 (13.18), 2.518 (13.07), 2.523 (8.65), 2.540 (1.06), 2.673 (2.63), 2.839 (2.45), 2.858 (9.34), 2.876 (7.76), 2.897 (5.04), 2.921 (11.25), 2.936 (13.18), 2.955 (2.84), 2.961 (2.63), 3.252 (7.48), 3.268 (14.65), 3.283 (7.91), 3.597 (1.74), 3.616 (4.01), 3.633 (4.86), 3.651 (2.80), 3.740 (2.34), 3.757 (4.36), 3.773 (4.32), 3.775 (3.71), 3.793 (2.43), 3.927 (10.53), 3.934 (5.97), 3.944 (11.00), 3.950 (7.99), 3.966 (3.92), 3.981 (1.01), 4.331 (0.70), 4.349 (0.68), 7.436 (1.15), 7.458 (0.75), 7.524 (16.00), 7.883 (0.70), 7.906 (0.65), 8.636 (1.06), 8.681 (2.67), 8.696 (5.62), 8.711 (2.61). LC-MS (方法1): Rt = 1.27 min; MS (ESIneg): m/z = 505 [M-H]- | 中間物98 GP H 條件C 14 mg,73%產率,95%純度 |
308 | 2-[(1-甲基哌啶-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.151 (0.67), 1.171 (1.26), 1.180 (1.29), 1.203 (1.43), 1.210 (1.33), 1.232 (1.07), 1.435 (1.55), 1.462 (1.22), 1.539 (0.68), 1.542 (0.65), 1.555 (0.69), 1.559 (0.98), 1.567 (0.91), 1.575 (0.73), 1.583 (0.62), 1.588 (0.81), 1.605 (0.52), 1.659 (0.45), 1.668 (0.49), 1.677 (0.56), 1.687 (0.68), 1.696 (0.52), 1.705 (0.47), 1.726 (1.16), 1.731 (1.23), 1.760 (2.08), 1.772 (0.72), 1.788 (1.67), 1.809 (1.78), 1.827 (1.71), 1.845 (1.14), 1.860 (0.93), 1.865 (0.55), 1.869 (0.65), 1.876 (0.74), 1.881 (0.68), 1.888 (0.86), 1.899 (0.56), 1.902 (0.67), 1.905 (0.66), 1.909 (0.60), 1.920 (0.49), 1.926 (0.46), 2.107 (16.00), 2.337 (0.60), 2.518 (6.75), 2.523 (4.48), 2.673 (1.46), 2.678 (0.89), 2.693 (1.79), 2.722 (1.66), 2.832 (0.83), 2.837 (0.84), 2.856 (3.35), 2.874 (2.65), 2.917 (2.82), 2.919 (2.79), 2.934 (4.06), 2.941 (1.40), 2.953 (0.96), 2.959 (0.92), 3.252 (2.67), 3.267 (5.16), 3.282 (2.92), 3.596 (0.64), 3.613 (1.28), 3.616 (1.38), 3.633 (1.65), 3.650 (0.96), 3.740 (0.84), 3.755 (1.50), 3.757 (1.54), 3.760 (1.05), 3.773 (1.48), 3.775 (1.30), 3.778 (1.09), 3.793 (0.89), 3.922 (3.99), 3.939 (4.10), 3.950 (2.26), 3.965 (1.31), 7.528 (5.50), 8.681 (0.90), 8.696 (1.86), 8.710 (0.87). LC-MS (方法1): Rt = 1.09 min; MS (ESIneg): m/z = 465 [M-H]- | 中間物100 GP H 條件C 11 mg,8%產率,95%純度 |
309 | N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-[(1-甲基哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.150 (0.42), 1.172 (1.11), 1.180 (1.20), 1.203 (1.38), 1.211 (1.28), 1.232 (0.72), 1.241 (0.59), 1.436 (1.63), 1.462 (1.27), 1.659 (0.44), 1.669 (0.48), 1.677 (0.58), 1.687 (0.69), 1.696 (0.53), 1.706 (0.48), 1.726 (1.20), 1.731 (1.26), 1.755 (2.03), 1.760 (2.01), 1.784 (1.08), 2.107 (16.00), 2.518 (4.46), 2.523 (2.86), 2.693 (1.89), 2.722 (1.75), 2.833 (0.83), 2.838 (0.84), 2.857 (3.36), 2.874 (2.70), 2.922 (2.88), 2.938 (4.05), 2.945 (1.50), 2.957 (1.00), 2.963 (0.95), 3.195 (1.70), 3.200 (0.90), 3.219 (2.96), 3.224 (2.21), 3.235 (2.11), 3.249 (3.49), 3.262 (1.97), 3.278 (1.35), 3.297 (1.04), 3.423 (0.65), 3.429 (0.77), 3.449 (1.49), 3.455 (1.58), 3.476 (1.27), 3.483 (1.24), 3.524 (1.11), 3.530 (1.24), 3.552 (1.52), 3.559 (1.56), 3.579 (0.65), 3.585 (1.06), 3.620 (2.01), 3.626 (1.25), 3.643 (2.01), 3.658 (0.41), 3.665 (0.47), 3.694 (1.66), 3.700 (1.40), 3.723 (2.86), 3.728 (2.43), 3.752 (1.20), 3.922 (3.95), 3.940 (3.90), 7.530 (5.61), 8.719 (0.92), 8.734 (1.94), 8.748 (0.92). LC-MS (方法1): Rt = 0.95 min; MS (ESIneg): m/z = 481 [M-H]- | 中間物100 GP H 條件C 34 mg,26%產率,98%純度 |
310 | 2-{[1-(環丙基甲基)哌啶-4-基]甲基}-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (2.45), 0.018 (8.53), 0.022 (8.17), 0.030 (8.93), 0.034 (8.25), 0.044 (2.80), 0.399 (2.88), 0.409 (7.44), 0.414 (7.53), 0.419 (4.02), 0.424 (3.86), 0.429 (8.04), 0.433 (7.65), 0.444 (2.73), 0.754 (0.91), 0.766 (1.65), 0.769 (1.69), 0.773 (1.71), 0.786 (2.66), 0.798 (1.62), 0.802 (1.66), 1.154 (1.18), 1.176 (3.03), 1.183 (3.27), 1.206 (3.78), 1.214 (3.44), 1.236 (2.08), 1.459 (4.33), 1.487 (3.49), 1.498 (3.93), 1.688 (1.15), 1.706 (1.50), 1.715 (1.76), 1.724 (1.43), 1.743 (1.05), 1.797 (3.01), 1.822 (5.28), 1.850 (2.85), 2.107 (13.10), 2.123 (12.96), 2.337 (1.20), 2.518 (15.59), 2.523 (10.22), 2.678 (1.32), 2.836 (2.35), 2.840 (2.42), 2.859 (9.17), 2.877 (7.59), 2.897 (5.05), 2.924 (12.16), 2.940 (11.91), 2.947 (4.28), 2.959 (2.82), 2.964 (2.64), 3.186 (1.11), 3.195 (4.67), 3.200 (2.41), 3.220 (8.23), 3.224 (6.27), 3.235 (5.64), 3.249 (9.88), 3.262 (5.36), 3.278 (3.91), 3.297 (3.72), 3.423 (2.04), 3.429 (2.33), 3.450 (4.20), 3.456 (4.52), 3.477 (3.71), 3.483 (3.53), 3.524 (3.09), 3.530 (3.42), 3.552 (4.24), 3.559 (4.32), 3.579 (1.83), 3.585 (3.03), 3.605 (1.68), 3.620 (5.53), 3.627 (3.43), 3.643 (5.60), 3.659 (1.15), 3.665 (1.25), 3.694 (4.62), 3.700 (3.88), 3.723 (7.84), 3.729 (6.64), 3.752 (3.36), 3.928 (10.11), 3.945 (9.91), 7.526 (16.00), 8.546 (0.78), 8.720 (2.45), 8.734 (5.25), 8.749 (2.45). LC-MS (方法1): Rt = 1.11 min; MS (ESIneg): m/z = 521 [M-H]- | 中間物98 GP H 條件C 10 mg,52%產率,95%純度 |
311 | 2-[(1-乙基哌啶-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.914 (0.63), 0.937 (6.72), 0.955 (16.00), 0.973 (6.90), 1.123 (0.49), 1.133 (0.58), 1.154 (1.48), 1.163 (1.59), 1.185 (1.83), 1.192 (1.66), 1.215 (0.81), 1.224 (0.72), 1.457 (2.10), 1.484 (1.70), 1.508 (0.80), 1.538 (0.89), 1.541 (0.85), 1.550 (0.74), 1.554 (0.83), 1.558 (1.28), 1.566 (1.19), 1.574 (0.99), 1.583 (0.80), 1.588 (1.11), 1.604 (0.71), 1.689 (0.69), 1.708 (0.83), 1.717 (1.09), 1.729 (1.95), 1.734 (2.09), 1.757 (3.15), 1.762 (3.03), 1.772 (1.22), 1.787 (2.54), 1.792 (2.56), 1.808 (2.49), 1.826 (2.43), 1.844 (1.60), 1.859 (1.32), 1.864 (0.77), 1.869 (0.94), 1.876 (1.05), 1.881 (0.94), 1.888 (1.25), 1.898 (0.80), 1.902 (0.92), 1.905 (0.93), 1.909 (0.87), 1.919 (0.69), 1.926 (0.65), 1.940 (0.41), 2.231 (1.89), 2.249 (6.31), 2.266 (6.22), 2.284 (1.75), 2.337 (0.67), 2.518 (7.15), 2.523 (4.76), 2.678 (0.73), 2.796 (2.41), 2.825 (2.37), 2.832 (2.28), 2.857 (4.68), 2.874 (3.71), 2.917 (3.97), 2.919 (3.94), 2.935 (5.65), 2.942 (1.93), 2.954 (1.36), 2.960 (1.29), 3.252 (3.84), 3.267 (7.41), 3.282 (4.34), 3.596 (0.90), 3.612 (1.83), 3.615 (2.01), 3.633 (2.38), 3.650 (1.37), 3.739 (1.21), 3.754 (2.12), 3.756 (2.19), 3.759 (1.53), 3.772 (2.06), 3.775 (1.85), 3.776 (1.59), 3.792 (1.25), 3.921 (5.52), 3.939 (5.69), 3.949 (3.19), 3.965 (1.88), 3.980 (0.46), 7.436 (0.48), 7.523 (7.83), 8.682 (1.24), 8.696 (2.61), 8.711 (1.22). LC-MS (方法1): Rt = 1.17 min; MS (ESIneg): m/z = 479 [M-H]- | 中間物99 GP H 條件C 1.4 mg,14%產率,95%純度 |
312 | N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-[(1-乙基哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.914 (0.41), 0.938 (4.08), 0.956 (9.64), 0.973 (4.17), 1.163 (0.99), 1.185 (1.12), 1.224 (0.49), 1.457 (1.33), 1.495 (4.36), 1.735 (1.32), 1.758 (1.84), 1.788 (0.89), 2.232 (1.17), 2.249 (3.87), 2.267 (3.69), 2.285 (1.09), 2.327 (4.41), 2.331 (3.13), 2.336 (1.40), 2.518 (16.00), 2.523 (10.47), 2.540 (3.30), 2.673 (3.04), 2.678 (1.37), 2.797 (1.49), 2.826 (1.46), 2.834 (1.38), 2.858 (2.88), 2.876 (2.21), 2.924 (2.42), 2.940 (3.44), 2.959 (0.82), 2.964 (0.80), 3.195 (1.56), 3.219 (2.64), 3.224 (2.06), 3.234 (1.93), 3.249 (3.35), 3.262 (2.04), 3.278 (1.98), 3.423 (1.08), 3.429 (1.15), 3.450 (1.61), 3.456 (1.65), 3.477 (1.32), 3.483 (1.31), 3.524 (1.08), 3.530 (1.23), 3.552 (1.42), 3.559 (1.47), 3.579 (0.66), 3.585 (1.03), 3.620 (1.79), 3.643 (1.76), 3.693 (1.46), 3.700 (1.21), 3.723 (2.49), 3.752 (1.09), 3.923 (3.27), 3.941 (3.22), 7.526 (4.95), 8.719 (0.74), 8.734 (1.56), 8.749 (0.79). LC-MS (方法1): Rt = 1.09 min; MS (ESIneg): m/z = 495 [M-H]- | 中間物99 GP H 條件C 2.2 mg,21%產率,95%純度 |
313 | 2,5-去氫-1,3,4-三去氧-1-{[(4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羰基]胺基}-4-甲基戊糖醇(順式/反式異構體的混合物) | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.99 (d, 3H), 1.16 (dt, 1H), 1.28 (d, 3H), 2.12 (dt, 1H), 2.19-2.30 (m, 1H), 2.61 (dd, 1H), 3.03 (dd, 1H), 3.13-3.22 (m, 1H), 3.23-3.28 (m, 2H), 3.29-3.32 (m, 1H), 3.39-3.47 (m, 1H), 3.51-3.58 (m, 1H), 3.62 (br d, 1H), 3.71-3.76 (m, 2H), 3.76-3.81 (m, 1H), 3.81-3.90 (m, 1H), 3.98 (dq, 1H), 4.05-4.15 (m, 2H), 7.56 (d, 1H), 8.67-8.76 (m, 1H), 1H在DMSO下. LC-MS (方法1): Rt = 1.21 min; MS (ESIpos): m/z = 484 [M+H]+ | 中間物79 GP G 條件A 47 mg,40%產率,96%純度 |
314 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1-甲基-1H-咪唑-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.28 (d, 3H), 2.59 (dd, 1H), 3.01 (dd, 1H), 3.12-3.21 (m, 1H), 3.27 (dd, 1H), 3.39-3.47 (m, 1H), 3.51-3.59 (m, 1H), 3.60 (s, 3H), 3.63 (d, 1H), 3.70-3.77 (m, 2H), 3.81-3.89 (m, 1H), 4.05-4.15 (m, 2H), 4.27 (dd, 2H), 6.96 (d, 1H), 7.49 (d, 1H), 7.56 (d, 1H), 8.93 (t, 1H). LC-MS (方法1): Rt = 0.96 min; MS (ESIpos): m/z = 480 [M+H]+ | 中間物79 GP G 條件A 17 mg,27%產率,97%純度 |
315 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(6-甲基吡啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (d, 3H), 2.46 (s, 3H), 2.63 (dd, 1H), 3.05 (dd, 1H), 3.14-3.23 (m, 1H), 3.27 (dd, 1H), 3.40-3.47 (m, 1H), 3.51-3.59 (m, 1H), 3.63 (br d, 1H), 3.74 (dt, 2H), 3.82-3.89 (m, 1H), 4.04-4.17 (m, 2H), 4.48 (d, 2H), 7.09-7.12 (m, 1H), 7.14 (d, 1H), 7.57 (d, 1H), 7.66 (t, 1H), 9.28 (t, 1H). LC-MS (方法1): Rt = 1.14 min; MS (ESIpos): m/z = 491 [M+H]+ | 中間物79 GP G 條件A 31 mg,47%產率,95%純度 |
316 | (4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1,3-噻唑-5-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.28 (d, 3H), 2.61 (dd, 1H), 3.02 (dd, 1H), 3.18 (dt, 1H), 3.27 (dd, 1H), 3.39-3.47 (m, 1H), 3.50-3.58 (m, 1H), 3.62 (br d, 1H), 3.74 (dt, 2H), 3.81-3.88 (m, 1H), 4.03-4.15 (m, 2H), 4.64 (d, 2H), 7.57 (d, 1H), 7.81 (d, 1H), 8.99 (d, 1H), 9.40 (t, 1H) LC-MS (方法1): Rt = 1.03 min; MS (ESIpos): m/z = 483 [M+H]+ | 中間物79 GP G 條件A 40 mg,61%產率,97%純度 |
實例 317 : 8- 甲基 -N-{[(2S)- 氧雜環戊 -2- 基 ] 甲基 }-2-[(1±)-1-( 吡啶 -2- 基 ) 乙基 ]-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
根據GP C (條件A),在氮氣氛圍下,將8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺(30.0 mg,99.6 µmol,中間物43)連同(1±)-1-(吡啶-2-基)乙-1-醇(14.7 mg,119 µmol;CAS-RN:[18728-61-5])一起溶解於中甲苯(1 mL)。添加三-正丁基膦(40 µl,160 µmol;CAS RN:[998-40-3])及TMAD (27.4 mg,159 µmol;CAS-RN:[10465-78-8])且繼續在室溫下攪拌隔夜。反應物用水稀釋且真空濃縮。殘餘物用2 ml乙腈稀釋且藉由製備型HPLC (方法A,梯度C)純化。合併產物溶離份且真空濃縮,得到20.4 mg (49%產率,98%純度)標題化合物。1
H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.52-1.62 (m, 1H), 1.84-1.92 (m, 3H), 1.82 (d, 3H), 2.45 (s, 3H), 2.84-2.92 (m, 4H), 3.18-3.27 (m, 2H), 3.56-3.67 (m, 1H), 3.76 (td, 1H), 3.94 (quin, 1H), 5.61 (q, 1H), 7.09 (d, 1H), 7.29 (ddd, 1H), 7.68 (s, 1H), 7.76 (td, 1H), 7.98 (t, 1H), 8.49-8.57 (m, 1H)。
LC-MS (方法1): Rt
= 1.09 min; MS (ESIpos): m/z = 407 [M+H]+
類似於實例317所述的程序,由相應中間物製備以下實例。
318 | 8-甲基-2-[(5-甲基吡啶-2-基)甲基]-N-[(3R)-氧雜環戊-3-基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 | 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.87-1.97 (m, 1H), 2.02-2.14 (m, 1H), 2.27 (s, 3H), 2.44 (s, 3H), 2.52-2.53 (m, 1H), 2.84-2.92 (m, 4H), 3.53 (dd, 1H), 3.69 (td, 1H), 3.78-3.88 (m, 2H), 5.32 (s, 2H), 7.01 (d, 1H), 7.56-7.59 (m, 1H), 7.60 (s, 1H), 8.18 (d, 1H), 8.33-8.39 (m, 1H). LC-MS (方法1): Rt = 0.99 min; MS (ESIneg): m/z = 391 [M-H]⁻ | 中間物92及CAS-RN:[22940-71-2] 19.6 mg (26%產率,1%純度) |
實例 319 : 2-[(5- 氰基吡啶 -2- 基 ) 甲基 ]-8- 甲基 -N-{[(2S)- 氧雜環戊 -2- 基 ] 甲基 }-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
向乙酸乙酯(5 ml)中添加8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-1H-呋喃并[2,3-g]吲唑-7-羧醯胺(中間物43,1.00 eq,100 mg,332 µmol)、6-溴甲基-菸鹼腈(CAS編號[158626-15-4],1.5 eq,98.1 mg,498 µmol)、DMAP (CAS編號[1122-58-3],0.025 eq,1.01 mg,8.30 µmol)及碳酸鉀(CAS編號[584-08-7],15 eq,688 mg,4.98 mmol)且在70℃下、在氮氣下攪拌18小時。在冷卻至室溫後,向反應混合物中添加6-氯甲基-菸鹼腈(CAS編號[83640-36-2],1.5 eq,76.0 mg,498 µmol)且在70℃下攪拌3小時。過濾反應混合物且添加額外碳酸鉀(CAS編號[584-08-7],15.0 eq,688 mg,4.98 mmol)且在70℃下攪拌18小時。在冷卻至室溫後,向反應混合物中添加碳酸銫(CAS編號[534-17-8],5.00 eq,541 mg,1.66 mmol)且在70℃下攪拌18小時。在冷卻至室溫後,過濾反應混合物且藉由製備型HPLC (方法A,條件C)純化,隨後藉由管柱層析(SiO2
,己烷/EtOAc)純化,得到標題化合物(21.0 mg,13%產率)。1
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.698 (0.75), 0.771 (0.65), 0.851 (0.72), 0.868 (0.94), 0.887 (0.73), 0.906 (1.21), 0.924 (0.63), 1.162 (2.03), 1.232 (2.59), 1.256 (1.73), 1.296 (1.06), 1.332 (0.88), 1.348 (0.65), 1.548 (0.58), 1.565 (0.76), 1.581 (0.66), 1.609 (0.45), 1.779 (0.70), 1.795 (1.22), 1.812 (1.38), 1.830 (1.32), 1.841 (0.82), 1.858 (0.91), 1.875 (0.60), 2.074 (1.80), 2.428 (16.00), 2.518 (15.89), 2.523 (10.87), 2.901 (8.84), 2.908 (3.38), 3.210 (1.04), 3.215 (1.09), 3.226 (1.99), 3.230 (1.95), 3.241 (1.12), 3.245 (1.21), 3.582 (0.43), 3.601 (0.89), 3.618 (1.26), 3.636 (0.68), 3.731 (0.59), 3.749 (1.11), 3.766 (0.96), 3.783 (0.64), 3.926 (0.98), 3.942 (1.47), 3.957 (0.91), 5.513 (5.98), 7.195 (1.92), 7.214 (2.05), 7.674 (5.03), 7.976 (0.67), 7.991 (1.47), 8.006 (0.70), 8.089 (1.92), 8.276 (2.08), 8.282 (2.16), 8.297 (2.00), 8.302 (1.90), 8.998 (2.16), 9.000 (2.28), 9.003 (2.23), 9.006 (1.96)。
LC-MS (方法1): Rt
= 1.03 min; MS (ESIpos): m/z = 418 [M+H]+
實例 320 : N-{[(2R)-1,4- 二㗁烷 -2- 基 ] 甲基 }-2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
在氬氣下。將2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-甲酸(中間物69,1.00 eq.,10.1 g,27.1 mmol)溶解於四氫呋喃(110 mL)中,添加HATU (1.15 eq.,11.8 g,31.2 mmol)及DIPEA (3.0 eq.,14.1 mL,81 mmol)且所得混合物在室溫下攪拌幾分鐘。向此混合物中添加(R)-(1,4-二㗁烷-2-基)甲胺鹽酸鹽(1.1 eq.,4.58 g,29.8 mmol)且在室溫下攪拌混合物16小時。反應混合物用乙酸乙酯及飽和碳酸氫鈉水溶液稀釋且分離相應層。有機層用飽和氯化鈉水溶液洗滌且所得有機相經由濾紙過濾且在減壓下濃縮。發生沈澱且所得白色固體在抽吸下收集且用乙酸乙酯洗滌,在旋轉式蒸發器中、在50℃下、在真空下乾燥之後,得到所需產物(9.7 g,76%產率)。1
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.83-2.89 (m, 2H), 2.92-2.98 (m, 2H), 3.19-3.31 (m, 4H), 3.40-3.49 (m, 2H), 3.50-3.59 (m, 2H), 3.60-3.68 (m, 3H), 3.69-3.77 (m, 4H), 3.79-3.83 (m, 1H), 4.05-4.15 (m, 2H), 7.52 (s, 1H), 8.75 (t, 1H)
LC-MS (方法1): Rt
= 0.92 min; MS (ESIpos): m/z = 472 [M+H]+
[α]D 20
= -11.07° (c=1, DMSO)
實例 321: N-[(5- 環丙基吡 𠯤 -2- 基 ) 甲基 ]-2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
在氬氣下,將2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-甲酸(中間物69,1.00 eq,60 mg,0.16 mmol)溶解於四氫呋喃(2.1 mL)中,且添加HATU (1.5 eq.,92 mg,0.24 mmol)及DIPEA (3.0 eq.,84 µL,0.48 mmol)且所得混合物在室溫下攪拌幾分鐘。向此混合物中添加(5-環丙基吡𠯤-2-基)甲胺(2.0 eq.,48 mg,0.32 mmol)且進一步在室溫下攪拌18小時。反應混合物用乙酸乙酯及飽和碳酸氫鈉水溶液稀釋且分離相應層。有機層用飽和氯化鈉水溶液洗滌且所得有機相經MgSO4
乾燥,過濾且在減壓下濃縮。殘餘物用3 ml DMSO稀釋且藉由製備型HPLC (方法A,梯度D)純化。合併產物溶離份且真空濃縮,得到24.7 mg (29%產率,95%純度)標題化合物。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 0.90 - 0.94 (m, 2H) 1.00 - 1.05 (m, 2H) 2.16 - 2.22 (m, 1H) 2.85 - 2.89 (m, 2H) 2.94 - 2.98 (m, 2H) 3.24 - 3.29 (m, 1H) 3.41 - 3.47 (m, 1H) 3.51 - 3.56 (m, 1H) 3.61 - 3.64 (m, 1H) 3.71 - 3.77 (m, 2H) 3.79 - 3.86 (m, 1H) 4.05 - 4.15 (m, 2H) 4.51 - 4.52 (m, 2H) 7.52 (s, 1H) 8.41 - 8.42 (m, 1H) 8.56 - 8.57 (m, 1H) 9.28 - 9.31 (m, 1H)
LC-MS (方法1): Rt
= 1.08 min; MS (ESIpos): m/z = 504 [M+H]+
實例 322 : (4R 或 4S)-N-[(5- 環丙基吡 𠯤 -2- 基 ) 甲基 ]-2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
在氬氣下,將(4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-甲酸(中間物79,1.00 eq,60 mg,0.15 mmol)溶解於四氫呋喃(2.0 mL)中,且添加HATU (1.5 eq.,88 mg,0.23 mmol)及DIPEA (3.0 eq.,81 µL,0.47 mmol)且所得混合物在室溫下攪拌幾分鐘。向此混合物中添加(5-環丙基吡𠯤-2-基)甲胺(2.0 eq.,46 mg,0.31 mmol)且進一步在室溫下攪拌18小時。反應混合物用乙酸乙酯及飽和碳酸氫鈉水溶液稀釋且分離相應層。有機層用飽和氯化鈉水溶液洗滌且所得有機相經MgSO4
乾燥,過濾且在減壓下濃縮。殘餘物用3 ml DMSO稀釋且藉由製備型HPLC (方法A,梯度D)純化。合併產物溶離份且真空濃縮,得到15 mg (18%產率,95%純度)標題化合物。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 0.90 - 0.94 (m, 2H) 1.00 - 1.05 (m, 2H) 1.28 - 1.29 (m, 3H) 2.16 - 2.22 (m, 1H) 2.59 - 2.66 (m, 1H) 3.01 - 3.07 (m, 1H) 3.14 - 3.22 (m, 1H) 3.24 - 3.30 (m, 1H) 3.40 - 3.46 (m, 1H) 3.51 - 3.56 (m, 1H) 3.61 - 3.64 (m, 1H) 3.72 - 3.76 (m, 2H) 3.81 - 3.88 (m, 1H) 4.05 - 4.15 (m, 2H) 4.51 - 4.52 (m, 2H) 7.57 (s, 1H) 8.42 - 8.43 (m, 1H) 8.56 - 8.57 (m, 1H) 9.28 - 9.31 (m, 1H)
LC-MS (方法1): Rt
= 1.14 min; MS (ESIneg): m/z = 516 [M-H]-
實例 323 : (4R 或 4S)-N-[(5- 氯吡 𠯤 -2- 基 ) 甲基 ]-2-{[(2S)-1,4- 二㗁烷 -2- 基 ] 甲基 }-4- 甲基 -8-( 三氟甲基 )-4,5- 二氫 -2H- 呋喃并 [2,3-g] 吲唑 -7- 羧醯胺
在氬氣下,將(4R或4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-甲酸(中間物79,1.00 eq,60 mg,0.15 mmol)溶解於四氫呋喃(2.0 mL)中,且添加HATU (1.5 eq.,88 mg,0.23 mmol)及DIPEA (3.0 eq.,81 µL,0.47 mmol)且所得混合物在室溫下攪拌幾分鐘。向此混合物中添加(5-氯吡𠯤-2-基)甲胺(2.0 eq.,45 mg,0.31 mmol)且進一步在室溫下攪拌18小時。反應混合物用乙酸乙酯及飽和碳酸氫鈉水溶液稀釋且分離相應層。有機層用飽和氯化鈉水溶液洗滌且所得有機相經MgSO4
乾燥,過濾且在減壓下濃縮。殘餘物用4 ml DMSO稀釋且藉由製備型HPLC (方法A,梯度D)純化。合併產物溶離份且真空濃縮,得到38.8 mg (49%產率,95%純度)標題化合物。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 1.28 - 1.30 (m, 3H) 2.59 - 2.66 (m, 1H) 3.01 - 3.07 (m, 1H) 3.14 - 3.22 (m, 1H) 3.24 - 3.30 (m, 1H) 3.41 - 3.46 (m, 1H) 3.52 - 3.57 (m, 1H) 3.61 - 3.64 (m, 1H) 3.72 - 3.76 (m, 2H) 3.81 - 3.88 (m, 1H) 4.06 - 4.15 (m, 2H) 4.58 - 4.60 (m, 2H) 7.56 - 7.57 (m, 1H) 8.50 - 8.51 (m, 1H) 8.76 - 8.77 (m, 1H) 9.35 - 9.38 (m, 1H)
LC-MS (方法1): Rt
= 1.13 min; MS (ESIneg): m/z = 510 [M-H]-
實驗章節 - 生物學分析
本發明化合物之活體外活性可經以下分析中證明:用於鑑別細胞 GPR84 拮抗劑的 cAMP HTRF® 分析
藉由使用基於均相時差式螢光(Homogenous Time-Resolved Fluorescence;HTRF®)之分析(#62AM5PEJ, Cisbio, Condolet, France),可偵測Gi偶聯GPR84受體之抑制作用。使用穩定表現人類GPR84受體的CHO-K1細胞(購自DiscoveRx,現為Eurofins)且用毛喉素(Forskolin)(F6886, Sigma, Germany)處理以刺激膜腺苷醯環化酶且藉此形成非特異性cAMP。天然或小分子促效劑(例如6-正辛基胺基尿嘧啶,內部)活化Gi偶聯GPR84會使得細胞cAMP形成被抑制,從而可再次藉由拮抗劑釋放至此受體。在此HTRF分析中偵測及定量細胞cAMP含量係根據螢光cAMP示蹤劑(cAMP-d2)與Eu穴狀化合物標記之抗cAMP抗體之間的相互作用達成。337 nm激發之後,此配對允許搭配物之間產生螢光共振能量轉移(FRET)且使FRET誘導665 nm及620 nm發射,後者代表Eu穴狀化合物標記之抗cAMP抗體的背景信號。在任何細胞cAMP不存在的情況下(與示蹤劑結合至抗體無競爭)獲得最大信號。鑒於GPR84之Gi偶聯特性與偵測系統之競爭性質的組合,促效劑處理應引起HTRF信號增加,原因在於cAMP含量降低。在毛喉素、促效劑及化合物存在下發生的任何信號減少指示拮抗劑介導的GPR84信號傳導消除。
為了分析,將表現hGPR84之CHO-K1細胞的冷凍等分試樣(由acCELLerate製備,Hamburg, Germany)解凍且在含有cAMP-d2 (1:20稀釋,隨套組#62AM5PEJ供應,Cisbio, Condolet, France)的分析培養基(哈姆氏F12營養混合物(Ham's F12 Nutrient Mix),Thermo Fisher Scientific, Waltham, USA;5%胎牛血清,Biomol, Hamburg, Germany)中製備細胞懸浮液(1.67E+06個細胞/毫升)。使細胞在37℃下恢復20分鐘之後,向預分配的分析盤(Greiner Bio-One, Kremsmuenster, Austria)中每孔添加3 µL包括cAMP-d2的細胞懸浮液,該分析盤每孔含有50 nl含測試化合物的100% DMSO,或100%DMSO作為對照。隨後係室溫下的30分鐘培育步驟。刺激時間始於每孔添加2 µL含有2.5xEC80
促效劑6-OAU及2.5xEC90
毛喉素(陰性對照:2.5xEC90
毛喉素於分析培養基中)的分析培養基且在室溫下持續30分鐘。藉由每孔添加3 µL含有cAMP Eu穴狀化合物抗體(1:20稀釋)的溶解緩衝液(兩者均隨套組#62AM5PEJ供應,Cisbio, Condolet, France)來中止反應。為實現完全溶解,在室溫下培育盤60分鐘,隨後在HTRF讀取器中量測,例如PHERAstar (BMG Labtech, Ortenberg, Germany)。
依據665 nm (FRET)及620 nm (Eu穴狀化合物之背景信號)的螢光發射,計算比率(665 nm發射除以620 nm發射 x 10000)且將資料標準化(不含測試化合物的反應物,僅100% DMSO = 0%抑制;除促效劑之外的所有其他分析組分 = 100%抑制)。在同一微量滴定盤上進行劑量反應測試時,對20 µM至0.07 nM範圍內之11種不同濃度(20 µM、5.7 µM、1.6 µM、0.47 µM、0.13 µM、38 nM、11 nM、3.1 nM、0.89 nM、0.25及0.07 nM;分析之前,以100倍濃度的含量製備連續稀釋液,儲備溶液在100% DMSO中1:3.5連續稀釋)的化合物進行測試,每種濃度收集雙重複值。藉由4參數擬合、使用商業軟體套裝(Genedata Screener, Basel, Switzerland)計算IC50
值。
實例在所選生物學分析中測試一或多次。當測試超過一次時,資料係以平均值或以中值報導,其中
● 平均值(亦稱為算術平均值)表示所得值之總和除以測試次數,且
● 中值表示一組值當以升序或降序排列時之中間數。若資料集中之值個數為奇數,則中值為中間值。若資料集中之值個數為偶數,則中值為兩個中間值之算術平均值。
實例被合成一或多次。當合成超過一次時,生物學分析資料表示利用獲自一或多次合成批料測試的資料集所計算的平均值或中值。表 6 : GPR84 cAMP HTRF® 分析中的效能 , 該效能以 IC50
[µM] 示出。
表 6 ( 續 )
表 6 ( 續 )
表 6 ( 續 )
表 6 ( 續 )
表 6 ( 續 )
實例 | GPR84 IC50 [µM] | 實例 | GPR84 IC50 [µM] |
1 | 1.00 | 31 | >20 |
2 | 0.078 | 32 | 0.15 |
3 | 0.24 | 33-1 | 1.89 |
3-1 | 1.16 | 33-2 | 2.89 |
3-2 | 0.11 | 34 | 0.28 |
4 | 1.62 | 35 | 0.47 |
5 | 1.41 | 35-1 | 0.18 |
6 | 0.80 | 35-2 | 0.77 |
7 | 0.15 | 36 | 1.72 |
8 | 0.21 | 37 | 9.50 |
9 | 0.19 | 38 | 0.70 |
10 | >20 | 38-1 | 1.42 |
11 | >20 | 38-2 | 3.52 |
12 | 2.76 | 39 | 0.96 |
13 | 1.65 | 39-1 | 0.67 |
14 | 4.79 | 39-2 | 7.05 |
15 | 2.00 | 40 | 0.67 |
16 | 11.2 | 41 | 5.42 |
17 | 10.1 | 42 | 1.53 |
18 | 0.097 | 43 | 11.1 |
19-1 | 0.064 | 44 | 0.018 |
19-2 | 0.83 | 45 | 0.029 |
20 | 5.07 | 46 | 0.013 |
21 | 0.30 | 47 | 0.019 |
22 | 0.34 | 48 | 0.097 |
23 | 0.16 | 49 | 0.11 |
24 | 6.56 | 50 | 0.035 |
25 | 0.16 | 50-1 | 0.11 |
26 | 1.19 | 50-2 | 0.017 |
27 | 17.5 | 51 | 0.056 |
28 | 4.57 | 52 | 0.042 |
29 | 0.29 | 52-1 | 0.095 |
30 | 3.57 | 52-2 | 0.016 |
實例 | GPR84 IC50 [µM] | 實例 | GPR84 IC50 [µM] |
53 | 0.032 | 80 | 0.057 |
53-1 | 0.022 | 81 | 0.38 |
53-2 | 0.072 | 82 | 0.44 |
54 | 0.55 | 83 | 0.18 |
55 | 0.049 | 84 | 0.18 |
55-1 | 0.34 | 85 | 0.26 |
55-2 | 0.043 | 86 | 0.18 |
56 | 0.092 | 87 | 0.20 |
57 | 0.19 | 88 | 0.11 |
58 | 0.24 | 89 | 0.040 |
59 | 0.070 | 90 | 0.047 |
60 | 0.027 | 91 | 0.064 |
61 | 0.020 | 92 | 0.13 |
62 | 0.11 | 93 | 0.017 |
63 | 0.060 | 94 | 0.021 |
64 | 0.028 | 95 | 0.031 |
65 | 0.026 | 96 | 0.047 |
66 | 0.16 | 97 | 0.62 |
66-1 | 0.063 | 98 | 0.47 |
66-2 | 0.66 | 99 | 0.21 |
67 | 1.81 | 100 | 0.31 |
68 | 0.17 | 101 | 1.54 |
69 | 0.75 | 102 | 0.76 |
70 | 0.077 | 103 | 0.17 |
71 | 0.36 | 104 | 0.18 |
72 | 0.24 | 105 | 0.072 |
73 | 0.14 | 106 | 0.077 |
74 | 0.16 | 107 | 0.035 |
75 | 0.060 | 108 | 0.058 |
76 | 0.065 | 109 | 0.011 |
77 | 0.17 | 110 | 0.010 |
78 | 0.19 | 111 | 0.14 |
79 | 0.058 | 112 | 0.32 |
實例 | GPR84 IC50 [µM] | 實例 | GPR84 IC50 [µM] |
113 | 0.091 | 146 | 0.047 |
114 | 0.20 | 147 | 0.13 |
115 | 0.027 | 148 | 0.035 |
116 | 0.028 | 149 | 0.010 |
117 | 0.055 | 150 | 0.011 |
118 | 0.024 | 151 | 0.009 |
119 | 0.028 | 152 | 0.012 |
120 | 0.051 | 153 | 0.24 |
121 | 0.067 | 154 | 0.27 |
122 | 0.061 | 155 | 0.013 |
123 | 0.12 | 156 | 0.009 |
124 | 0.18 | 157 | 0.18 |
125 | 0.051 | 158 | 1.55 |
126 | 0.039 | 159 | 1.96 |
127 | 0.17 | 160 | 2.54 |
128 | 0.11 | 161 | 6.52 |
129 | 0.055 | 162 | 6.74 |
130 | 1.29 | 163 | >20 |
131 | 0.035 | 164 | 0.98 |
132 | 0.020 | 165 | 0.11 |
133 | 0.94 | 166 | 0.11 |
134 | 0.043 | 167 | 0.060 |
135 | 0.026 | 168 | 0.010 |
136 | 0.025 | 169 | 0.013 |
137 | 0.045 | 170 | 0.030 |
138 | 0.043 | 171 | 3.69 |
139 | 0.080 | 172 | 12 |
140 | 0.083 | 173 | 7.07 |
141 | 0.70 | 174 | 0.097 |
142 | 0.67 | 175 | 0.061 |
143 | 0.077 | 176 | 0.118 |
144 | 7.39 | 177 | 2.60 |
145 | 0.11 | 178 | 0.092 |
實例 | GPR84 IC50 [µM] | 實例 | GPR84 IC50 [µM] |
179 | 6.41 | 216 | 0.006 |
180 | 0.210 | 217 | 0.006 |
181 | 0.102 | 218 | 0.009 |
182 | 0.168 | 219 | 0.007 |
183 | 0.213 | 220 | 0.018 |
184 | 0.447 | 221 | 0.008 |
185 | 0.551 | 222 | 0.020 |
186 | 0.063 | 222-1 | 0.012 |
187 | 0.040 | 222-2 | 0.054 |
188 | 0.223 | 223 | 0.023 |
189 | 0.109 | 223-1 | 0.012 |
190 | 0.238 | 223-2 | 0.051 |
191 | 0.008 | 224 | 0.018 |
192 | 0.006 | 224-1 | 0.016 |
193 | 0.032 | 224-2 | 0.154 |
194 | 0.030 | 226 | 0.016 |
195 | 0.029 | 227 | 0.024 |
196 | 0.182 | 228 | 0.038 |
197 | 0.098 | 229 | 0.089 |
198 | 0.094 | 230 | 0.881 |
199 | 0.079 | 231 | 1.39 |
200 | 0.111 | 233 | 1.12 |
201 | 0.080 | 234 | 3.47 |
201-1 | 0.683 | 235 | 1.60 |
201-2 | 0.112 | 236 | 8.76 |
202 | 0.077 | 237 | 0.496 |
203 | 0.022 | 238 | 0.500 |
210 | 0.016 | 239 | 0.136 |
211 | 0.017 | 240 | 2.81 |
212 | 0.004 | 242 | 0.029 |
213 | 0.007 | 243 | 0.026 |
214 | 0.005 | 244 | 0.053 |
215 | 0.003 | 245 | 0.061 |
實例 | GPR84 IC50 [µM] | 實例 | GPR84 IC50 [µM] |
246 | 0.075 | 273 | 0.009 |
247 | 0.066 | 274 | 0.010 |
248 | 0.145 | 275 | 0.141 |
249 | 0.122 | 276 | 0.156 |
250 | 0.017 | 277 | 0.008 |
251 | 0.009 | 278 | 0.010 |
252 | 0.009 | 279 | 0.053 |
253 | 0.005 | 280 | 0.016 |
254 | 0.006 | 281 | 0.021 |
254-1 | 0.010 | 282 | 0.010 |
254-2 | 0.046 | 283 | 0.139 |
255 | 0.005 | 284 | 0.086 |
255-1 | 0.003 | 285 | 0.021 |
255-2 | 0.016 | 286 | 0.011 |
256 | 0.014 | 287 | 0.010 |
257 | 0.025 | 288 | 0.101 |
258 | 0.005 | 289 | 0.801 |
259 | 0.005 | 290 | 0.004 |
260 | 0.024 | 291 | 0.005 |
261 | 0.063 | 292 | 0.006 |
262 | 0.195 | 293 | 0.007 |
263 | 0.013 | 294 | 0.008 |
264 | 0.013 | 295 | 0.008 |
265 | 0.238 | 296 | 0.009 |
265-1 | 0.185 | 297 | 0.013 |
265-2 | 1.21 | 298 | 0.009 |
266 | 0.607 | 299 | 0.024 |
267 | 0.057 | 300 | 0.322 |
268 | 0.038 | 301 | 0.723 |
269 | 0.027 | 302 | 1.51 |
270 | 0.192 | 303 | 0.006 |
271 | 0.026 | 304 | 0.013 |
272 | 0.042 | 305 | 0.016 |
實例 | GPR84 IC50 [µM] |
306 | 0.027 |
307 | 0.062 |
308 | 0.151 |
309 | 0.154 |
310 | 0.197 |
311 | 0.202 |
312 | 0.760 |
313 | 0.021 |
314 | 0.040 |
315 | 0.266 |
316 | 0.374 |
317 | 0.578 |
318 | 8.31 |
319 | 1.12 |
320 | 0.012 |
321 | 0.003 |
322 | 0.002 |
323 | 0.003 |
本發明化合物用於治療PCOS及相關症狀及疼痛病症的適合性可在以下動物模型中證實:活體內分析 1 : GPR84 配位體及拮抗劑在 PCOS 模型中的表徵
在DHT驅動的大鼠PCOS模型中量測實例3-2活體內治療POCS的功效。將漢-威斯達大鼠(Han-Wistar rat)在3週齡時隨機分成三個實驗組[對照組(n=10)、DHT (n=10),及DHT + 實例3-2 (n=10)]且皮下植入60-d連續DHT釋放丸劑(80 µg/d,Bayer AG, Germany)。選擇DHT劑量以模擬患有PCOS之女性的高雄激素狀態。對照組接受不含生物活性DHT分子的相同丸劑。動物接受標準食物,僅最後一週用高脂肪膳食置換標準食物。大鼠自21日齡開始稱重,兩週一次。投藥26天之後,得出研究結論。實例3-2治療之動物的體重增加小於未治療之對照組。利用單因子變異數分析進行統計分析,隨後使用GraphPad PRISM軟體針對媒劑對照組進行邦弗朗尼氏多重比較檢驗(Bonferroni's multiple comparison test),*p<0.05。表 7 : GPR84 拮抗劑在大鼠 DHT-PCOS 模型中的功效
活體內分析 2 : 實例 3-2 在 CFA 疼痛模型中的作用
實例 | mg/kg p.o. :早晨劑量 s.c. :晚上劑量 | 相對於媒劑對照組的相對體重 |
媒劑 | 媒劑 | 100% |
DHT-媒劑 | 媒劑 | 111% |
DHT - 實例3-2 | p.o.: 60 mg/kg於PEG400/H2 O中 s.c.:60 mg/kg於苯甲酸苯甲酯/蓖麻油(1:9)中 | 103%* (相對於DHT-媒劑組為顯著的) |
在動態承重(DWB)模型中,在完全弗氏佐劑(CFA)投與之後(24小時),量測實例3-2在活體內對發炎爪之發炎疼痛的功效。在小鼠CFA炎症模型中,使用預防性配置,研究實例3-2之重複預防性治療在重複經口投藥(3次)之後對疼痛的作用。CFA注射之前的2小時及第0天稍後的6-8小時,投與GPR84拮抗劑實例3-2 (20或60 mg/kg,3次劑量)。在CFA施用之後的第24小時,在DWB測試之前的2小時給與第三劑量的實例3-2。利用單因子變異數分析進行統計分析,隨後使用GraphPad PRISM軟體針對媒劑對照組進行邦弗朗尼氏多重比較檢驗,*p<0.05。表 8 : GPR84 拮抗劑在 CFA 疼痛模型中之效果
實例 | mg/kg p.o. | 重量分佈 ( 注射爪之重量 %) 平均值 +/-SD |
媒劑 | 43 +/- 20 | |
實例3-2 | 3x 20 mg | 60 +/- 21 (相對於媒劑組為不顯著的) |
實例3-2 | 3x 60 mg | 83 +/- 18 (相對於媒劑組為顯著的) |
本發明化合物之活體內活性可在以下分析中證明:活體內分析 3 : 在腎臟纖維化 (UUO) 模型中的效果
評估實例在腎臟纖維化模型中的抗纖維化效果。對可獲自Charles River之雄性史泊格多利大鼠(Sprague Dawley rat)(年齡:7至8週)進行研究。大鼠連續吸入異氟醚麻醉,且經由腹中部切口暴露左側輸尿管。藉由絲縫合線兩點結紮來阻塞中段輸尿管。假手術大鼠(n=6)經歷相同的程序,但其中將左側輸尿管阻塞。
將大鼠隨機分為三組(每組n=12)且給與媒劑及實例化合物,UUO之後立刻開始,每日兩次。手術之後第九天,在肢端麻醉下收集血液樣品以及腎臟。將血液樣品離心之後,分離血清。經由Ella自動化免疫分析系統,根據製造商方案評估血清骨橋蛋白含量。將腎臟分割成兩份。一份在液氮中快速冷凍用於RNA分析。另一份在Davidson的固定劑中儲存用於製備組織學切片。自所收集腎臟之部分分離出總RNA。將腎臟組織均質化,且獲得RNA且轉錄成cDNA。使用TaqMan即時PCR,分析發炎及纖維化標記物在腎臟組織中的腎mRNA表現。為了在蛋白質層面上評估纖維化,使用標準程序將石蠟組織切片用α-平滑肌肌動蛋白(αSMA)及天狼星紅/快綠膠原蛋白染色劑染色。
使用Axio Scan Z1 (Zeiss)顯微鏡及Zen軟體,藉由電腦影像分析獲得腎臟內之α-平滑肌肌動蛋白(αSMA)陽性面積以及天狼星紅(膠原蛋白)陽性面積的定量量測值。
所有資料用平均值±S.D.表示。各組之間的差異係藉由單向ANOVA聯合多重比較用的鄧尼特氏校正(Dunnett's corrections)加以分析。統計顯著性定義為p<0.05。活體內分析 4 : 對二氧化矽誘導之肺纖維化的作用
在治療性治療配置中,評估實例在二氧化矽小鼠肺纖維化模型中的抗纖維化及消炎作用。
成年C57BL/6JR雄性小鼠(18-20 g;9週齡)購自(Janvier Labs, Germany)。小鼠在含有異氟醚(3% v/v)的室中麻醉且氣管內施加溶解於70 µl無菌磷酸鹽緩衝鹽水中的2.5 mg細晶二氧化矽DQ12。對照動物接受相同體積的磷酸鹽緩衝鹽水。二氧化矽滴注之後的第10天開始,動物在隨後的20天期間接受GPR84拮抗劑實例(p.o. bid)或尼達尼布(nintedanib)之乙烷磺酸鹽(60 mg/kg p.o bid)。二氧化矽滴注之後的30天,小鼠經由腹膜內注射氯胺酮/美托咪啶(ketamine/medetomidine)(50 mg/kg及0.33 mg/kg,i.p.)與皮下注射特吉昔(temgesic)(0.06 mg/kg s.c.)的組合來麻醉,且獲得EDTA血漿樣品用於藥物動力學測定實例血漿含量及測定生物標記物。放血之後,將導管插入氣管且將動物的肺灌洗(支氣管肺泡灌洗液,BALF)三次,每次使用0.5 ml冰冷PBS。接著將動物的肺切除,稱重且在乾冰上快速冷凍用於生物標記物分析。使用Bio-Plex細胞介素陣列系統(BIORAD)測定細胞介素,使用ELISA (R&D Systems)測定原膠原Iα1且使用HPLC (Waters)測定羥基脯胺酸。使用ELISA (Cayman)量測13,14-二氫-15酮-PGF2α。
資料用每組12隻動物的平均值±SEM呈現。使用不成對的斯圖登氏t檢驗(Student's t-test)執行統計分析。P值<0.05視為顯著。活體內分析 5 : 在博萊黴素誘導之小鼠肺纖維化模型中的作用
在另一個臨床前肺纖維化模型中評估實例化合物。對獲自德國Charles River的雄性C57BL/6N小鼠(到達時8週齡)進行研究。實驗開始之前至少一天,將所有動物隨機分成11組(每組n=7-12)。第7天開始直至第20天(第1組-第6組)或第20天開始直至第34天(第7組-第11組),大鼠每天兩次(p.o.)給與媒劑、尼達尼布及實例化合物。
第2組-第11組的所有動物在D0鼻內投與1 mg/kg劑量之博萊黴素(Bleomycin)。鼻內投藥之前,腹膜內使用氯胺酮與甲苯噻𠯤(xylazine)之組合將小鼠麻醉。
每天兩次對動物進行臨床檢查。將動物在D0、D1稱重,D4開始每天稱重直至D34。在第21天及第34天,在麻醉之後,分別自第2組-第6組及第7組-第11組獲取血液樣品(除第1組之外)。在第21天及第34天,分別自第1組-第6組及第7組-第11組獲取肺樣品。藉由輕緩地打開胸腔且藉由沿著胸骨及肋骨側面切割及修整背部來切除肺。使用精確的分析天平將肺個別地稱重且記錄重量。將肺置放於含有10%緩衝福馬林之標記瓶中以供進一步組織病理學評估Ashcroft/Matsuse分數,膠原蛋白I定量)。
使用MS Excel處理用於評估體重及肺重量的資料。統計學分析及圖形展示係使用Graphpad Prism軟體(8.1.1.版)執行。使用單向ANOVA或曼-惠特尼檢驗(Mann-Whitney test)。體重變化係使用混合型效應分析。當p<0.05時,各組之間的差異視為統計學上顯著的。
為了組織病理學評估,將整個肺包埋於石蠟中且根據克洛斯曼的三色染色法(Crossman's Trichrome)染色(Gray P. The Microtomist's Formulary and Guide. Robert E. Krieger Publishing Co.出版)。使用Ashcroft評分之Matsuse變型(Ashcroft H等人, J Clin Pathol (1988) 41:467-70;Matsuse T等人, Eur Respir J (1999) 13:71-77)評估肺組織學變化。
使用抗膠原蛋白1A1 (COL1A1)抗體執行膠原蛋白免疫組織化學。使用Bloxall pH 9 (PT Link modul, DAKO)執行抗原修復。將載片與初級兔多株抗COL1A1抗體一起培育1小時(1:2000),隨後使用ImmPRESS偵測套組(Vector)(Autostainer Link48, DAKO)。使用數位影像分析軟體(Calopix軟體, TRIBVN, France)評估新生膠原蛋白1A1 (COL1A1)沈積含量。
統計學分析及圖形展示係使用GraphPad Prism軟體(8.1.1.版)執行。採用曼-惠特尼檢驗。當p<0.05時,各組之間的差異視為統計學上顯著的。活體內分析 6 : 在腎損傷 (ZSF1) 模型中的效果
評估實例化合物在ZSF1大鼠(腎病模型)中的腎保護作用。
研究中使用總共45隻雄性肥胖ZSF1大鼠及30隻瘦同窩幼畜(Charles River)。動物在14週齡時分配至5個實驗組之一:瘦對照動物不接受藥物治療12週(Ln-ZSF1組);肥胖對照動物接受媒劑治療12週(Ln-媒劑組);肥胖動物接受媒劑治療12週(Ob-媒劑組);肥胖動物接受飲用水中之依那普利(enalapril)(每天) 12週(Ob-依那普利組);或肥胖動物接受實例化合物12週(Ob-GPR84)。
在治療第0、4、8、12週時進行代謝籠研究。收集量測期的尿液且在-80℃下儲存用於量測肌酐、尿液總蛋白質、白蛋白及葡萄糖。分析血漿樣品之三酸甘油酯及膽固醇及未酯化脂肪酸。
將腎臟分割成兩份。一份在液氮中快速冷凍用於RNA分析。另一份在Davidson的固定劑中儲存用於製備組織學切片。自所收集腎臟之部分分離出總RNA。將腎臟組織均質化,且獲得RNA且轉錄成cDNA。使用TaqMan即時PCR,分析發炎及纖維化標記物在腎臟組織中的腎mRNA表現。為了在蛋白質層面上評估纖維化,使用標準程序將石蠟組織切片用α-平滑肌肌動蛋白(αSMA)及天狼星紅/快綠膠原蛋白染色劑染色。
使用Axio Scan Z1 (Zeiss)顯微鏡及Zen軟體,藉由電腦影像分析獲得腎臟內之α-平滑肌肌動蛋白(αSMA)陽性面積以及天狼星紅(膠原蛋白)陽性面積的定量量測值。活體內分析 7 : GPR84 配位體及拮抗劑在 HFD-PCOS 模型中的表徵
在使用高脂肪膳食之DHT驅動大鼠PCOS模型中量測實例化合物在活體內治療POCS的功效。漢-威斯達大鼠在15週齡時隨機分成實驗組[DHT (n=10),及DHT + 實例化合物(n=10)]且植入60-d連續DHT釋放丸劑(80 µg/d,Bayer AG, Germany)。選擇DHT劑量以模擬患有PCOS之女性的高雄激素狀態。對照組接受不含生物活性DHT分子的相同丸劑。動物接受高脂肪膳食(RD12492)。大鼠兩週一次稱重。投藥28天之後,得出研究結論。相較於未治療之對照組,分析代謝、纖維化及發炎概況,包括胰島素含量及脂聯素/瘦素比率。使用MSD (中尺度)量測血漿胰島素、脂聯素及瘦素。使用不成對t檢驗及格拉布氏檢驗(Grubbs test)執行統計分析,以便利用GraphPad PRISM軟體鑑別離群值,*p<0.05。活體內分析 8
:在48小時CFA疼痛模型中的效果
投與完全弗氏佐劑(CFA,50 µl)之後,量測實例化合物在活體內對發炎爪之發炎性疼痛的功效,在48小時之後進行馮弗雷量測(von Frey measurement)。使用預防性配置,研究實例化合物之重複預防性治療在大鼠(漢威斯達雌性,8週)炎症CFA模型中、在重複投與之後對疼痛的作用。投與GPR84拮抗劑實例化合物,第一次施用係在第0天注射CFA之前的2小時。在CFA施用之後的第48小時,在馮弗雷測試之前的2小時給與實例化合物(5次重複量測)。使用不成對t檢驗及格拉布氏檢驗執行統計分析,以便利用GraphPad PRISM軟體鑑別離群值,*p<0.05。活體內分析 9 : 在奧沙利鉑 (Oxaliplatin) 誘導疼痛模型中的效果
在奧沙利鉑誘導之大鼠6週神經病變性疼痛模型中,量測實例化合物在活體內對化學療法(奧沙利鉑;OPNP))誘導之疼痛的功效。
實驗使用約9週齡的史泊格多利雄性大鼠。大鼠隨機分成實驗組(例如n=10)。藉由施用奧沙利鉑(2 mg/kg)、每天一次、歷時5天來誘導疼痛。投與GPR84拮抗劑實例化合物,第一次施用係在d1。使大鼠適應環境30分鐘,隨後開始行為測試。治療之前,對所有動物進行馮弗雷測試作為基線量測。為了評估機械性異常疼痛,藉由將馮弗雷纖絲(遞增重量;0.4、0.6、1.4、2、4、6、8、15 g)施加於右後爪中心來量測縮爪臨限值。投與測試物之前(基線)且給藥後每週一次、1小時、2小時及4小時進行馮弗雷測試直至實驗結束為止。使用單因子變異數分析進行統計分析,隨後使用GraphPad PRISM軟體針對媒劑對照組進行杜奈特多重比較檢驗,*p<0.05。活體內分析 10 : 在鏈佐黴素 (Streptozotocin , STZ) 誘導之神經病變性疼痛模型中的效果
該研究評估實例化合物在鏈佐黴素(STZ)誘導之神經病變性疼痛模型中逆轉糖尿病性神經病變的鎮痛作用。在史泊格多利雄性大鼠中,藉由在研究第0天給與鏈佐黴素(STZ,60 mg/kg)來誘導糖尿病。藉由在研究第3天量測血糖含量來證實糖尿病發展。在研究第10天,測試所有動物對馮弗雷纖絲的敏感度且展示退縮力臨限值減小(兩隻後爪的平均疼痛臨限值≤15 g)的糖尿病動物(>300 mg/dL)納入研究中。研究第5天(或替代地,第10天)開始用實例化合物或媒劑治療動物直至第25天為止。利用馮弗雷測試來測試機械疼痛敏感度,該測試量測動物的退縮力臨限值。使用單因子變異數分析進行統計分析,隨後使用GraphPad PRISM軟體針對媒劑對照組進行杜奈特多重比較檢驗,*p<0.05。活體內分析 11 : 在 CDAA-HFD NASH 大鼠模型中的效果
該研究評估實例化合物治療8週對雄性CDAA-HFD大鼠之NAFLD活性評分(包括纖維化階段)的影響。約14週齡雄性史泊格多利大白鼠接受CDAA-HFD膳食(Gubra, A16092003) 4週用於誘導肝纖維化且在研究期間接受該CDAA-HFD膳食。大鼠隨機分成實驗組(例如n=12)(媒劑及實例化合物)。研究第28天開始直至第14週結束,用實例化合物或單獨的媒劑治療動物。
剖檢之後,利用Kleiner等人(2005)概述的臨床準則,使用經蘇木精(Hematoxylin)及曙紅(Eosin)(H&E)染色的肝臟樣品對NAS及纖維化階段分別進行評分。總NAS表示脂肪變性、炎症及腫脹之分數總和,且在0-8範圍內。
Claims (8)
- 一種通式(I)化合物, 或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或該等化合物混合物, 其中: R1 表示氫、C1 -C4 烷基或C1 -C4 鹵烷基; R2 表示氫、C1 -C4 烷基或C1 -C4 鹵烷基;或 R1 及R2 與其所連接之碳原子一起形成3員至6員環烷基或雜環烷基環; R3 表示C3 -C6 環烷基、3員至6員雜環烷基、與苯基或雜芳基稠合的雜環烷基,或雜芳基,其中該等基團彼此獨立地視情況經R8 取代一或多次,或 R3 表示苯基,其彼此獨立地視情況經R8 取代一或多次,且另外,R7a 及R7b 表示氘; R4 表示氫、C1 -C4 烷基、C1 -C4 鹵烷基或C3 -C6 環烷基; R5 、R6 彼此獨立地表示氫、C1 -C4 烷基、C2 -C4 羥基烷基、(C1 -C4 烷氧基)-(C2 -C4 烷基)-、C3 -C6 環烷基、C1 -C4 鹵烷基、C3 -C6 鹵環烷基、3員至6員雜環烷基、雜螺環烷基、苯基、雜芳基、與苯基或雜芳基稠合的雜環烷基、3員至6員雜環烷基-(C1 -C3 烷基)-、雜螺環烷基-(C1 -C3 烷基)-、(與苯基或雜芳基稠合的雜環烷基)-(C1 -C3 烷基)-、苯基-(C1 -C3 烷基)-或雜芳基-(C1 -C3 烷基)-,其中該3員至6員雜環烷基、雜螺環烷基、與苯基或雜芳基稠合的雜環烷基、苯基或雜芳基彼此獨立地視情況經R9 取代一或多次,或 R5 及R6 連同其所連接之氮原子一起形成3員至6員含氮雜環,該含氮雜環視情況含有一個選自O、NH及S之額外雜原子或含雜原子基團,且可彼此獨立地視情況經R9 取代一或多次; R7a 表示氫、氘或C1 -C4 烷基; R7b 表示氫、氘或C1 -C4 烷基; R8 表示鹵素、氰基、C1 -C4 烷基、C1 -C4 鹵烷基、C1 -C3 烷氧基、C1 -C3 鹵烷氧基、C3 -C6 環烷基、C3 -C6 環烷基-(C1 -C3 烷基)-、R13 -(C=O)-、R10 -O-(C=O)-、R11 -NH-(C=O)-,或R12 -(SO2 )-; R9 表示鹵素、氰基、C1 -C4 烷基、C1 -C4 鹵烷基、H2 N-C1 -C4 烷基、C1 -C3 烷氧基、C1 -C3 鹵烷氧基、C3 -C6 環烷基、R10 -O-(C=O)-、側氧基、5員至6員雜環烷基-、5員至6員雜環烷基-(C1 -C3 烷基)-、苯基或雜芳基,其中該苯基或雜芳基彼此獨立地視情況經鹵素、C1 -C4 烷基、C1 -C4 鹵烷基、C1 -C3 烷氧基或C1 -C3 鹵烷氧基取代一或多次; R10 表示氫、C1 -C4 烷基,或苯基-CH2 -; R11 表示氫、C1 -C4 烷基,或5員至6員雜環烷基-(C1 -C3 烷基)-; R12 表示C1 -C4 烷基或苯基; R13 表示C1 -C4 烷基、C1 -C4 鹵烷基、(C1 -C4 烷氧基)-(C1 -C4 烷基)-、C1 -C4 烷基-(C=O)-、C3 -C6 環烷基或苯基,其中該C3 -C6 環烷基視情況經C1 -C4 烷基或羥基取代且該苯基彼此獨立地視情況經鹵素、C1 -C4 烷基、C1 -C4 鹵烷基、C1 -C3 烷氧基或C1 -C3 鹵烷氧基取代一或多次。
- 如請求項1之化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或該等化合物混合物,其中 R1 表示氫、C1 -C4 烷基或C1 -C4 鹵烷基; R2 表示氫或C1 -C4 烷基;或 R1 及R2 與其所連接之碳原子一起形成3員至4員環烷基或雜環烷基環; R3 表示C3 -C6 環烷基、4員至6員雜環烷基、與雜芳基稠合的雜環烷基,或雜芳基,其中該等基團彼此獨立地視情況經R8 取代一或多次,或 R3 表示苯基,其彼此獨立地視情況經R8 取代一或多次,且另外,R7a 及R7b 表示氘; R4 表示氫、C1 -C4 烷基、C1 -C4 鹵烷基或C3 -C6 環烷基; R5 、R6 彼此獨立地表示氫、C2 -C4 羥基烷基、(C1 -C4 烷氧基)-(C2 -C4 烷基)-、3員至6員雜環烷基、雜螺環烷基、苯基、雜芳基、4員至6員雜環烷基-(C1 -C3 烷基)-、雜螺環烷基-(C1 -C3 烷基)-、(與雜芳基稠合的雜環烷基)-(C1 -C3 烷基)-,或雜芳基-(C1 -C3 烷基)-,其中該3員至6員雜環烷基、苯基或雜芳基彼此獨立地視情況經R9 取代一或多次,或 R5 及R6 與其所連接之氮原子一起形成5員含氮雜環,其視情況可經R9 取代一次; R7a 表示氫、氘或甲基; R7b 表示氫、氘或甲基; R8 表示鹵素、氰基、C1 -C4 烷基、C1 -C4 鹵烷基、C1 -C3 烷氧基、C3 -C6 環烷基、C3 -C6 環烷基-(C1 -C3 烷基)-、R13 -(C=O)-、R10 -O-(C=O)-、R11 -NH-(C=O)-,或R12 -(SO2 )-; R9 表示鹵素、氰基、C1 -C4 烷基、C1 -C4 鹵烷基、H2 N-C1 -C4 烷基、C3 -C6 環烷基、R10 -O-(C=O)-、側氧基、6員雜環烷基-(C1 -C3 烷基)-、苯基或雜芳基,其中該苯基或雜芳基彼此獨立地視情況經鹵素、C1 -C4 鹵烷基或C1 -C3 烷氧基取代一或多次; R10 表示氫、C1 -C4 烷基,或苯基-CH2 -; R11 表示5員至6員雜環烷基-(C1 -C3 烷基)-; R12 表示C1 -C4 烷基; R13 表示C1 -C4 烷基、(C1 -C4 烷氧基)-(C1 -C4 烷基)-、C1 -C4 烷基-(C=O)-、C3 -C6 環烷基或苯基,其中該C3 -C6 環烷基視情況經甲基或羥基取代。
- 如請求項1或2之化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或該等化合物混合物,其中: R1 表示氫、甲基或三氟甲基; R2 表示氫或甲基;或 R1 及R2 與其所連接之碳原子一起形成3員至4員環烷基環; R3 表示環丙基、4員至6員雜環烷基、2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基,或雜芳基,其中該等基團彼此獨立地視情況經R8 取代一或多次,或 R3 表示苯基,其彼此獨立地視情況經R8 取代一或多次,且另外,R7a 及R7b 表示氘; R4 表示氫、甲基、C1 鹵烷基或環丙基; R5 表示氫; R6 表示甲氧基-乙基、5員雜芳基、4員至6員雜環烷基-(C1 -C2 烷基)-、雜螺環烷基-甲基、2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基,或5員至6員雜芳基-(C1 -C2 烷基)-,其中該4員至6員雜環烷基或雜芳基彼此獨立地視情況經R9 取代一或多次; R7a 表示氫、氘或甲基; R7b 表示氫、氘或甲基; R8 表示氟、氯、C1 -C2 烷基、三氟甲基、C1 -C3 烷氧基、環丙基、環丙基甲基、R13 -(C=O)-、R10 -O-(C=O)-、R11 -NH-(C=O)-,或R12 -(SO2 )-; R9 表示氟、氯、C1 -C3 烷基、三氟甲基、環丙基或側氧基; R10 表示C1 -C4 烷基,或苯基-CH2 -; R11 表示5員至6員雜環烷基-甲基; R12 表示甲基; R13 表示甲基、甲氧基甲基、乙基-(C=O)-、環丙基或苯基,其中該環丙基視情況經甲基或羥基取代。
- 如請求項1或2之化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或該等化合物混合物,其中: R1 表示氫或甲基; R2 表示氫或甲基;或 R1 及R2 與其所連接之碳原子一起形成3員至4員環烷基環; R3 表示環丙基、2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基、氧雜環丁-3-基、氧雜環戊-3-基、氧雜環戊-2-基、3-甲基氧雜環丁-3-基、3-氟氧雜環丁-3-基、吡啶-4-基、吡啶-3-基、吡啶-2-基、㗁烷-4-基、1,4-二㗁烷-2-基、6-甲基吡啶-3-基、5-甲基吡啶-2-基、3-甲基吡啶-2-基、2-甲基吡啶-4-基、6-甲基吡啶-2-基、3-氯吡啶-2-基、6-乙基吡啶-3-基、1-乙醯基哌啶-4-基、3-氯-5-乙氧基吡啶-2-基、1-苯甲醯基哌啶-4-基,或選自以下之基團: ,或 R3 表示苯基,且另外,R7a 及R7b 表示氘; R4 表示甲基、二氟甲基、三氟甲基或環丙基; R5 表示氫; R6 表示(氧雜環戊-2-基)甲基、(1,3-㗁唑-4-基)甲基、(1,2-㗁唑-3-基)甲基、(4-甲基氧雜環戊-2-基)甲基、(嘧啶-2-基)甲基、(吡𠯤-2-基)甲基、(5-甲基氧雜環戊-2-基)甲基、(5-甲基氧雜環戊-2-基)甲基、(1,4-二㗁烷-2-基)甲基、(4-甲基苯基)甲基、(5-甲基嘧啶-2-基)甲基、(5-甲基吡𠯤-2-基)甲基、(5-氯吡𠯤-2-基)甲基、(5-環丙基-吡𠯤-2-基)甲基、2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基、1,3-㗁唑-2-基甲基、1,3-噻唑-2-基甲基、(1-甲基-1H-吡唑-3-基)甲基、(1-甲基-1H-咪唑-4-基)甲基、(5-異丙基-1,2-㗁唑-3-基)甲基、(5-環丙基-1,2-㗁唑-3-基)甲基、(5,5-二甲基四氫呋喃-2-基)甲基、(4,4-二氟四氫呋喃-2-基)甲基、(6,6-二甲基-1,4-二㗁烷-2-基)甲基、5-氧雜螺[2.4]庚-6-基甲基,或2,6-二氧雜螺[3.4]辛-7-基甲基; R7a 表示氫; R7b 表示氫。
- 如請求項1或2之化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或該等化合物混合物,其選自由以下組成之群: 2-(吡啶-2-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[(4-甲基苯基)甲基]-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(吡啶-2-基甲基)-N-[(2R/S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(吡啶-2-基甲基)-N-[(2R)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(吡啶-2-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[2-(4-甲基哌𠯤-1-基)乙基]-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[(1,2,4-㗁二唑-3-基)甲基]-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-(1,2-㗁唑-3-基甲基)-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(5-環丙基-1,2-㗁唑-3-基)甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[(5-甲基-1,2-㗁唑-3-基)甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-(2-羥基-2-甲基丙基)-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-{[5-(嗎啉-4-基甲基)-1,2-㗁唑-3-基]甲基}-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(吡啶-2-基甲基)-N-(2-{4-[5-(三氟甲基)吡啶-2-基]哌𠯤-1-基}乙基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(吡啶-2-基甲基)-N-(2-{4-[3-(三氟甲基)苯基]哌𠯤-1-基}乙基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[5-(3-甲氧基苯基)-1,2-㗁唑-3-基]甲基}-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[(4-甲基-1,2,5-㗁二唑-3-基)甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(5-環丙基-1,2-㗁唑-4-基)甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[5-(2-氯苯基)-1,2-㗁唑-3-基]甲基}-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(5-異丙基-1,2-㗁唑-3-基)甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(吡啶-2-基甲基)-N-(4H-1,2,4-三唑-3-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N,2-聯(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-(1H-吡唑-3-基甲基)-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(吡啶-2-基甲基)-N-(1,3-噻唑-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-(1,2-㗁唑-4-基甲基)-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(吡啶-2-基甲基)-N-{[5-(三氟甲基)-1,2-㗁唑-3-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[(4-甲基-1,2-㗁唑-3-基)甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(3,5-二甲基-1,2-㗁唑-4-基)甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[2-(3,3-二甲基-2-氧氮雜環丁-1-基)乙基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-(2-甲氧基乙基)-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 [(2R/S)-2-(胺基甲基)吡咯啶-1-基][8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-基]甲酮 [(2R)-2-(胺基甲基)吡咯啶-1-基][8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-基]甲酮 [(2S)-2-(胺基甲基)吡咯啶-1-基][8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-基]甲酮 3-[({[8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-基]羰基}胺基)甲基]-1,2-㗁唑-4-甲酸 8-甲基-N-(1,3-㗁唑-2-基甲基)-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(吡啶-2-基甲基)-N-[(3S)-四氫呋喃-3-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(吡啶-2-基甲基)-N-[(3R)-四氫呋喃-3-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[(1-甲基-1H-吡唑-3-基)甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[(2R/S)-氧雜環丁-2-基甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[(2R)-氧雜環丁-2-基甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[(2S)-氧雜環丁-2-基甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-(氧雜環丁-3-基甲基)-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(3-氟氧雜環丁-3-基)甲基]-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-{[(2R/S)-4-甲基嗎啉-2-基]甲基}-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-{[(2R)-4-甲基嗎啉-2-基]甲基}-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-{[(2S)-4-甲基嗎啉-2-基]甲基}-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-{[(2R/S)-5-側氧基四氫呋喃-2-基]甲基}-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-{[(2R)-5-側氧基四氫呋喃-2-基]甲基}-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-{[(2S)-5-側氧基四氫呋喃-2-基]甲基}-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-(1-甲基-1H-吡唑-3-基)-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-(吡啶-3-基)-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-(2-苯基乙基)-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-(4-氰基苯基)-8-甲基-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(吡啶-3-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-(吡啶-3-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(吡啶-4-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-(吡啶-4-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-(環丙基甲基)-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-(環丙基甲基)-N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(5-環丙基-1,2-㗁唑-3-基)甲基]-2-[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(5-環丙基-1,2-㗁唑-3-基)甲基]-2-[(2R)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(5-環丙基-1,2-㗁唑-3-基)甲基]-2-[(2S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-[(2R/S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2R)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-[(2R/S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-[(2R/S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2R)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-(4-甲基苯甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2R)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-(4-甲基苯甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-(4-甲基苯甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-[2-(4-甲基哌𠯤-1-基)乙基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2R)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-[2-(4-甲基哌𠯤-1-基)乙基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-[2-(4-甲基哌𠯤-1-基)乙基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-(1,2-㗁唑-3-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2R)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-(1,2-㗁唑-3-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-N-(1,2-㗁唑-3-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-2-{[6-(三氟甲基)吡啶-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N -[(2S)-四氫呋喃-2-基甲基]-2-{[5-(三氟甲基)吡啶-2-基]甲基}-4,5-二氫-2H -呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(3-氯-5-氟吡啶-2-基)甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(3-氯-5-乙氧基吡啶-2-基)甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(3-氯吡啶-2-基)甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(3-氯吡啶-2-基)甲基]-N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(3-甲基吡啶-2-基)甲基]-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(3-甲基吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(5-甲基吡啶-2-基)甲基]-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(5-甲基吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(6-甲基吡啶-2-基)甲基]-N-[(2R/S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(6-甲基吡啶-2-基)甲基]-N-[(2R)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(6-甲基吡啶-2-基)甲基]-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[2-(氮雜環丁-1-基)乙基]-8-甲基-2-[(6-甲基吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(5-環丙基-1,2-㗁唑-3-基)甲基]-8-甲基-2-[(6-甲基吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(6-甲基吡啶-2-基)甲基]-N-[2-(吡咯啶-1-基)乙基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R/S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-2-[(6-甲基吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-2-[(6-甲基吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2S)-2,3-二氫[1,4]二氧雜環己烯并[2,3-b]吡啶-2-基甲基]-8-甲基-2-[(6-甲基吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[(1-甲基-1H-吡唑-3-基)甲基]-2-[(6-甲基吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(6-甲基吡啶-2-基)甲基]-N-(1,3-㗁唑-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(2-甲基吡啶-3-基)甲基]-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(2-甲基吡啶-3-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(6-甲基吡啶-3-基)甲基]-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(6-甲基吡啶-3-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2,6-二甲基吡啶-3-基)甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2,6-二甲基吡啶-3-基)甲基]-N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(2-甲基吡啶-4-基)甲基]-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(2-甲基吡啶-4-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2,6-二甲基吡啶-4-基)甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2,6-二甲基吡啶-4-基)甲基]-N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(嘧啶-2-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-(嘧啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(嘧啶-5-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-(嘧啶-5-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N,2-雙[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-1,4-二㗁烷-2-基甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-2-[(2S)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-(氧雜環丁-3-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-(氧雜環丁-3-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(3-甲基氧雜環丁-3-基)甲基]-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(3-甲基氧雜環丁-3-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(3-氟氧雜環丁-3-基)甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-2-[(3-氟氧雜環丁-3-基)甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(2R)-氧雜環丁-2-基甲基]-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(2R)-氧雜環丁-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(2S)-氧雜環丁-2-基甲基]-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(2S)-氧雜環丁-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-{[(2R)-4-甲基嗎啉-2-基]甲基}-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-{[(2R)-4-甲基嗎啉-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-{[(2S)-4-甲基嗎啉-2-基]甲基}-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-{[(2S)-4-甲基嗎啉-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(2R)-四氫呋喃-2-基甲基]-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(2R)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N,2-雙[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 3-[(8-甲基-7-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-2-基)甲基]氮雜環丁烷-1-甲酸第三丁酯 3-[(7-{[(2R)-1,4-二㗁烷-2-基甲基]胺甲醯基}-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-2-基)甲基]氮雜環丁烷-1-甲酸第三丁酯 8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-2-[(3R)-四氫呋喃-3-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(3R)-四氫呋喃-3-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-2-[(3S)-四氫呋喃-3-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[(3S)-四氫呋喃-3-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-(吡啶-2-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-2-(吡啶-2-基甲基)-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(1-甲基-1H-吡唑-3-基)甲基]-2-(吡啶-2-基甲基)-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-(1,3-㗁唑-2-基甲基)-2-(吡啶-2-基甲基)-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-環丙基-2-(吡啶-2-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-環丙基-N-[(2R)-1,4-二㗁烷-2-基甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-環丙基-N-[(1-甲基-1H-吡唑-3-基)甲基]-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-環丙基-N-(1,3-㗁唑-2-基甲基)-2-(吡啶-2-基甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8'-甲基-N-[(1-甲基-1H-吡唑-3-基)甲基]-2'-(吡啶-2-基甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 8'-甲基-N-(1,3-㗁唑-2-基甲基)-2'-(吡啶-2-基甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-N-[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-2'-[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-N-[(1-甲基-1H-吡唑-3-基)甲基]-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-N-(1,3-㗁唑-2-基甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-(環丙基甲基)-8'-甲基-N-[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-(環丙基甲基)-N-[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-(環丙基甲基)-N-[(2R)-1,4-二㗁烷-2-基甲基]-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 8'-甲基-2'-(吡啶-2-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-2'-(吡啶-2-基甲基)-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8'-甲基-2'-(吡啶-2-基甲基)-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 8-甲基-2-[苯基(2H2)甲基]-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[苯基(2H2)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(5-環丙基-1,2,4-㗁二唑-3-基)甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(5-環丙基-1,2,4-㗁二唑-3-基)甲基]-N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 [2-(8-甲基-7-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-2-基)乙基]胺甲酸第三丁酯 [2-(7-{[(2R)-1,4-二㗁烷-2-基甲基]胺甲醯基}-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-2-基)乙基]胺甲酸第三丁酯 4-[2-(8-甲基-7-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-2-基)乙基]哌𠯤-1-甲酸第三丁酯 4-[2-(7-{[(2R)-1,4-二㗁烷-2-基甲基]胺甲醯基}-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-2-基)乙基]哌𠯤-1-甲酸第三丁酯 2'-[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-N-[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N,2'-雙[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-2'-[(2S)-1,4-二㗁烷-2-基甲基]-8'-甲基-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-2-[(6-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}吡啶-3-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-2-[(6-{[(2R)-1,4-二㗁烷-2-基甲基]胺甲醯基}吡啶-3-基)甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 4,4,8-三甲基-2-(吡啶-2-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8'-甲基-2'-(吡啶-2-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8'-甲基-2'-(吡啶-2-基甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 8'-甲基-2'-(吡啶-3-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8'-甲基-2'-(吡啶-3-基甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N2' ,N2' ,8'-三甲基-N7' -[(2S)-四氫呋喃-2-基甲基]螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-2',7'(5'H)-二羧醯胺 N7' -[(2R)-1,4-二㗁烷-2-基甲基]-N2' ,N2' ,8'-三甲基螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-2',7'(5'H)-二羧醯胺 3-氟-3-[(8-甲基-7-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-2-基)甲基]氮雜環丁烷-1-甲酸苯甲酯 3-[(8-甲基-7-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-2-基)甲基]氮雜環丁烷-1-甲酸苯甲酯 2-[(3-氟氮雜環丁-3-基)甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-(氮雜環丁-3-基甲基)-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-(氮雜環丁-3-基甲基)-N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-(2-胺基乙基)-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-(2-胺基乙基)-N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[2-(哌𠯤-1-基)乙基]-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-8-甲基-2-[2-(哌𠯤-1-基)乙基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(1-乙醯基氮雜環丁-3-基)甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(1-乙醯基-3-氟氮雜環丁-3-基)甲基]-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[3-氟-1-(甲基磺醯基)氮雜環丁-3-基]甲基}-8-甲基-N-[(2S)-四氫呋喃-2-基甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 3-氟-3-[(8-甲基-7-{[(2S)-四氫呋喃-2-基甲基]胺甲醯基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-2-基)甲基]氮雜環丁烷-1-羧酸甲酯 2'-[(2S)-1,4-二㗁烷-2-基甲基]-N-[(2S)-四氫呋喃-2-基甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-{[(2±)-5,5-二甲基氧雜環戊-2-基]甲基}-8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[(㗁烷-4-基)甲基]-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-{[(2±)-㗁烷-2-基]甲基}-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-{[(2±)-2-甲基氧雜環戊-2-基]甲基}-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2±)-4,4-二氟氧雜環戊-2-基]甲基}-8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-[(4-甲基四氫呋喃-2-基)甲基]-2-(2-吡啶基甲基)-4,5-二氫呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-{[(2±,5±)-5-甲基氧雜環戊-2-基]甲基}-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2,5-去氫-1,3,4-三去氧-3-甲基-1-({8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羰基}胺基)-D-蘇式-戊糖醇(外消旋物) 8-甲基-N-{[(6±)-5-氧雜螺[2.4]庚-6-基]甲基}-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2±)-3,3-二甲基氧雜環戊-2-基]甲基}-8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(6±)-2,5-二氧雜螺[3.4]辛-6-基]甲基}-8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2±)-6,6-二甲基-1,4-二㗁烷-2-基]甲基}-8-甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(4-氟吡啶-2-基)甲基]-8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(5-氟吡啶-3-基)甲基]-8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-2-[(噠𠯤-3-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-甲基-2-[(噠𠯤-3-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(6-乙基吡啶-3-基)甲基]-8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-[(6-乙基吡啶-3-基)甲基]-8-甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(1,3-㗁唑-2-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(㗁烷-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-{[(2±)-㗁烷-2-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-[(6-甲基吡啶-3-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(6-甲基吡啶-3-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-環丙基-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-環丙基-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2±)-5,5-二甲基氧雜環戊-2-基]甲基}-2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-{[(2±)-6,6-二甲基-1,4-二㗁烷-2-基]甲基}-2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-{[(2±)-4,4-二氟氧雜環戊-2-基]甲基}-2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-甲基-N-{[(2±,5±)-5-甲基氧雜環戊-2-基]甲基}-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2-[[(2S)-1,4-二㗁烷-2-基]甲基]-8-甲基-N-[(4-甲基四氫呋喃-2-基)甲基]螺[5H-呋喃并[2,3-g]吲唑-4,1'-環丙烷]-7-羧醯胺 2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-8'-甲基-N-{[(6±)-5-氧雜螺[2.4]庚-6-基]甲基}-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(6±)-2,5-二氧雜螺[3.4]辛-6-基]甲基}-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(6R)-2,5-二氧雜螺[3.4]辛-6-基]甲基}-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(6S)-2,5-二氧雜螺[3.4]辛-6-基]甲基}-8'-甲基-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 8'-甲基-2'-(吡啶-4-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 8'-甲基-2'-[(5-甲基吡啶-2-基)甲基]-N-[(2S)-四氫呋喃-2-基甲基]-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8'-甲基-2'-[(6-甲基吡啶-3-基)甲基]-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 8'-甲基-2'-[(6-甲基吡啶-3-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2'-[(6-甲基吡啶-3-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-[(6-甲基吡啶-3-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-[(5-甲基吡啶-2-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2'-[(5-甲基吡啶-2-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-2'-(吡啶-4-基甲基)-8'-(三氟甲基)-2',5'-二氫螺[環丙-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-(吡啶-4-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丙-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-{[(2S)-氧雜環戊-2-基]甲基}-2'-[(吡啶-2-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丙烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-2'-(吡啶-2-基甲基)-8'-(三氟甲基)-2',5'-二氫螺[環丙-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N,2-雙{[(2R)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2±)-4,4-二氟氧雜環戊-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2R)-4,4-二氟氧雜環戊-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2S)-4,4-二氟氧雜環戊-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2±)-5,5-二甲基氧雜環戊-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2R)-5,5-二甲基氧雜環戊-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2S)-5,5-二甲基氧雜環戊-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(2±, 5±)-5-甲基氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(2R, 5R)-5-甲基氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(2S, 5R)-5-甲基氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(2R, 5S)-5-甲基氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(2S, 5S)-5-甲基氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-(1,3-噻唑-2-基甲基)-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[(5-甲基吡𠯤-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-(吡𠯤-2-基甲基)-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[(1-甲基-1H-咪唑-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-(1,3-噻唑-5-基甲基)-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[2-(4-甲基吡啶-2-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[2-(吡啶-2-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[2-(3-甲基-1H-吡唑-1-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[2-(1H-咪唑-4-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[2-(吡啶-3-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[2-(1,3-噻唑-2-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-[(6-甲基吡啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(2S)-1,4-二㗁烷-2-基甲基]-N-(1,3-㗁唑-4-基甲基)-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-[2-(吡𠯤-2-基)乙基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-[(㗁烷-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(㗁烷-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-(二氟甲基)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-(二氟甲基)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4±)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4,8-二甲基-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4±)-4,8-二甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-2-[(吡啶-2-基)甲基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4±)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,8-二甲基-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4±)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,8-二甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4±)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-2-[(吡啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4±)-4-甲基-2-[(5-甲基-2-吡啶基)甲基]-N-[[(2S)-四氫呋喃-2-基]甲基]-8-(三氟甲基)-4,5-二氫呋喃并[2,3-g]吲唑-7-羧醯胺 (4±)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-2-[(6-甲基吡啶-3-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4±)-4-甲基-2-[(6-甲基吡啶-3-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4±)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4±)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1,3-㗁唑-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1,3-㗁唑-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1-甲基-1H-吡唑-3-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1-甲基-1H-吡唑-3-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(5-甲基吡𠯤-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(5-甲基吡𠯤-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1,3-噻唑-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1,3-噻唑-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(吡𠯤-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(吡𠯤-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1,3-㗁唑-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1,3-㗁唑-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-N-{[2-(三氟甲基)嘧啶-5-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-N-{[2-(三氟甲基)嘧啶-5-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-2-[(㗁烷-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-2-[(㗁烷-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-4-甲基-2-[(㗁烷-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-4-甲基-2-[(㗁烷-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4±)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-甲基-4-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-甲基-4-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-甲基-4-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4±)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-4-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-(4R)-4-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-(4S)-4-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,4-二甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4,4-二甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-2'-[(2S)-1,4-二㗁烷-2-基甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-[(2S)-1,4-二㗁烷-2-基甲基]-N-[(1-甲基-1H-吡唑-3-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-[(2S)-1,4-二㗁烷-2-基甲基]-N-[(2S)-四氫呋喃-2-基甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-{[(2S)-1,4-二㗁烷-2-基]甲基}-N-[(1,3-㗁唑-2-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁烷-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-2'-(吡啶-2-基甲基)-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-(吡啶-2-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-(1,3-㗁唑-2-基甲基)-2'-(吡啶-2-基甲基)-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-[(1-甲基-1H-吡唑-3-基)甲基]-2'-(吡啶-2-基甲基)-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-[(5-甲基吡啶-2-基)甲基]-N-[(2S)-四氫呋喃-2-基甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-2'-[(5-甲基吡啶-2-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-[(1-甲基-1H-吡唑-3-基)甲基]-2'-[(5-甲基吡啶-2-基)甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2'-(吡啶-4-基甲基)-N-[(2S)-四氫呋喃-2-基甲基]-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 N-[(2R)-1,4-二㗁烷-2-基甲基]-2'-(吡啶-4-基甲基)-8'-(三氟甲基)-2',5'-二氫螺[環丁-1,4'-呋喃并[2,3-g]吲唑]-7'-羧醯胺 2-(環丙基甲基)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[1-(甲氧基乙醯基)哌啶-4-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[1-(甲氧基乙醯基)哌啶-4-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[1-(環丙烷羰基)哌啶-4-基]甲基}-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[1-(環丙烷羰基)哌啶-4-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(1-苯甲醯基哌啶-4-基)甲基]-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(1-苯甲醯基哌啶-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-2-[2-(吡啶-3-基)丙-2-基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[1-(環丙烷羰基)哌啶-4-基]甲基}-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[1-(環丙烷羰基)哌啶-4-基]甲基}-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[1-(環丙烷羰基)哌啶-4-基]甲基}-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[1-(環丙烷羰基)哌啶-4-基]甲基}-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-[(1-乙醯基哌啶-4-基)甲基]-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-[(1-乙醯基哌啶-4-基)甲基]-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[1-(1-羥基環丙烷-1-羰基)哌啶-4-基]甲基}-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[1-(1-羥基環丙烷-1-羰基)哌啶-4-基]甲基}-4-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-[(1-乙醯基哌啶-4-基)甲基]-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-[(1-乙醯基哌啶-4-基)甲基]-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[1-(1-羥基環丙烷-1-羰基)哌啶-4-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[1-(1-羥基環丙烷-1-羰基)哌啶-4-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-2-{[1-(2-側氧基丁醯基)哌啶-4-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-2-{[1-(2-側氧基丁醯基)哌啶-4-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-4-甲基-2-{[1-(2-側氧基丁醯基)哌啶-4-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-4-甲基-2-{[1-(2-側氧基丁醯基)哌啶-4-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-4-甲基-2-{[1-(1-甲基環丙烷-1-羰基)哌啶-4-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-4-甲基-2-{[1-(1-甲基環丙烷-1-羰基)哌啶-4-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-2-{[1-(1-甲基環丙烷-1-羰基)哌啶-4-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-4-甲基-2-{[1-(1-甲基環丙烷-1-羰基)哌啶-4-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N,2-雙{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[(2R)-1,4-二㗁烷-2-基]甲基}-N-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(2-甲基嘧啶-5-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(2-甲基嘧啶-5-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(5-甲基嘧啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(5-甲基嘧啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(嘧啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(嘧啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(1-乙醯基哌啶-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(1-乙醯基哌啶-4-基)甲基]-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[1-(環丙基甲基)哌啶-4-基]甲基}-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(1-甲基哌啶-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-[(1-甲基哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-{[1-(環丙基甲基)哌啶-4-基]甲基}-N-{[(2R)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(1-乙基哌啶-4-基)甲基]-N-{[(2S)-氧雜環戊-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-[(1-乙基哌啶-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2,5-去氫-1,3,4-三去氧-1-{[(4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羰基]胺基}-4-甲基戊糖醇 2,5-去氫-1,3,4-三去氧-1-{[(4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羰基]胺基}-4-甲基戊糖醇 (4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1-甲基-1H-咪唑-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1-甲基-1H-咪唑-4-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(6-甲基吡啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(6-甲基吡啶-2-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1,3-噻唑-5-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-N-[(1,3-噻唑-5-基)甲基]-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-2-[(1±)-1-(吡啶-2-基)乙基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 8-甲基-2-[(5-甲基吡啶-2-基)甲基]-N-[(3R)-氧雜環戊-3-基]-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 2-[(5-氰基吡啶-2-基)甲基]-8-甲基-N-{[(2S)-氧雜環戊-2-基]甲基}-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-{[(2R)-1,4-二㗁烷-2-基]甲基}-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 N-[(5-環丙基吡𠯤-2-基)甲基]-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-N-[(5-環丙基吡𠯤-2-基)甲基]-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-N-[(5-環丙基吡𠯤-2-基)甲基]-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4R)-N-[(5-氯吡𠯤-2-基)甲基]-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 (4S)-N-[(5-氯吡𠯤-2-基)甲基]-2-{[(2S)-1,4-二㗁烷-2-基]甲基}-4-甲基-8-(三氟甲基)-4,5-二氫-2H-呋喃并[2,3-g]吲唑-7-羧醯胺 或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或該等化合物混合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP19217856 | 2019-12-19 | ||
EP19217856.4 | 2019-12-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW202136271A true TW202136271A (zh) | 2021-10-01 |
Family
ID=68965797
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW109144136A TW202136271A (zh) | 2019-12-19 | 2020-12-14 | 呋喃并吲唑衍生物 |
Country Status (21)
Country | Link |
---|---|
US (1) | US20230112499A1 (zh) |
EP (1) | EP4077334A1 (zh) |
JP (1) | JP2023508908A (zh) |
KR (1) | KR20220118480A (zh) |
CN (1) | CN115135656A (zh) |
AR (1) | AR120856A1 (zh) |
AU (1) | AU2020408908A1 (zh) |
BR (1) | BR112022011237A2 (zh) |
CA (1) | CA3164963A1 (zh) |
CL (1) | CL2022001644A1 (zh) |
CO (1) | CO2022008338A2 (zh) |
CR (1) | CR20220291A (zh) |
DO (1) | DOP2022000126A (zh) |
EC (1) | ECSP22047527A (zh) |
GE (1) | GEP20247585B (zh) |
IL (1) | IL293968A (zh) |
JO (1) | JOP20220156A1 (zh) |
MX (1) | MX2022007685A (zh) |
PE (1) | PE20221786A1 (zh) |
TW (1) | TW202136271A (zh) |
WO (1) | WO2021122415A1 (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20220119094A (ko) | 2019-12-19 | 2022-08-26 | 아비나스 오퍼레이션스, 인코포레이티드 | 안드로겐 수용체의 표적화된 분해를 위한 화합물 및 방법 |
WO2022179940A1 (en) * | 2021-02-23 | 2022-09-01 | Bayer Aktiengesellschaft | Furoindazole derivatives as gpr84 antagonists |
CN115109072A (zh) * | 2021-03-18 | 2022-09-27 | 武汉人福创新药物研发中心有限公司 | 一种gpr84拮抗剂及其制备方法和用途 |
EP4330260A1 (en) * | 2021-04-29 | 2024-03-06 | Bayer Aktiengesellschaft | Furoindazole derivatives as antagonists or inhibitors of gpr84 |
WO2024083705A1 (en) | 2022-10-18 | 2024-04-25 | Bayer Aktiengesellschaft | Furoindazole derivatives for the treatment of pain |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT853083E (pt) | 1997-01-06 | 2001-12-28 | Pfizer | Composto de piridilfurano e piridiltiofeno e sua utilizacao farmaceutica |
AU727654B2 (en) | 1997-06-13 | 2000-12-21 | Yamanouchi Pharmaceutical Co., Ltd. | Tricyclic pyrazole derivative |
WO2001083487A1 (fr) | 2000-04-28 | 2001-11-08 | Yamanouchi Pharmaceutical Co., Ltd. | Derive de froindazole |
WO2009023773A2 (en) * | 2007-08-15 | 2009-02-19 | University Of Miami | Galactokinase inhibitors |
WO2009086303A2 (en) | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
AU2009335016A1 (en) | 2008-12-30 | 2011-08-18 | Arqule, Inc. | Substituted pyrazolo [3, 4-b] pyridine compounds |
JPWO2011071136A1 (ja) | 2009-12-11 | 2013-04-22 | アステラス製薬株式会社 | 線維筋痛症治療剤 |
EP2675440B1 (en) | 2011-02-14 | 2020-03-25 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
AR089284A1 (es) | 2011-12-22 | 2014-08-13 | Galapagos Nv | Dihidropirimidinoisoquinolinonas y composiciones farmaceuticas de las mismas para el tratamiento de trastornos inflamatorios |
EP2935262B1 (en) * | 2012-12-20 | 2017-03-15 | Galapagos NV | Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders (gpr84 antagonists) |
GB201411241D0 (en) * | 2014-06-25 | 2014-08-06 | Galapagos Nv | Novel dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders |
WO2016085990A1 (en) * | 2014-11-24 | 2016-06-02 | The Regents Of The University Of Michigan | Compositions and methods relating to inhibiting serine hyrdoxymethyltransferase 2 activity |
GB201506894D0 (en) | 2015-04-23 | 2015-06-10 | Galapagos Nv | Novel dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders |
KR102305710B1 (ko) | 2017-03-06 | 2021-09-30 | 상하이 인스티튜트 오브 마테리아 메디카 차이니즈 아카데미 오브 싸이언시즈 | Gpr84 수용체 길항제 및 이의 용도 |
EP3700527A4 (en) * | 2017-10-25 | 2021-03-10 | Children's Medical Center Corporation | PAPD5 INHIBITORS AND THEIR METHODS OF USE |
-
2020
- 2020-12-14 TW TW109144136A patent/TW202136271A/zh unknown
- 2020-12-14 CN CN202080097024.7A patent/CN115135656A/zh active Pending
- 2020-12-14 KR KR1020227024304A patent/KR20220118480A/ko unknown
- 2020-12-14 US US17/786,268 patent/US20230112499A1/en active Pending
- 2020-12-14 JO JOP/2022/0156A patent/JOP20220156A1/ar unknown
- 2020-12-14 AU AU2020408908A patent/AU2020408908A1/en active Pending
- 2020-12-14 PE PE2022001093A patent/PE20221786A1/es unknown
- 2020-12-14 CA CA3164963A patent/CA3164963A1/en active Pending
- 2020-12-14 GE GEAP202016005A patent/GEP20247585B/en unknown
- 2020-12-14 BR BR112022011237A patent/BR112022011237A2/pt unknown
- 2020-12-14 EP EP20823813.9A patent/EP4077334A1/en active Pending
- 2020-12-14 IL IL293968A patent/IL293968A/en unknown
- 2020-12-14 CR CR20220291A patent/CR20220291A/es unknown
- 2020-12-14 WO PCT/EP2020/085905 patent/WO2021122415A1/en active Application Filing
- 2020-12-14 JP JP2022537545A patent/JP2023508908A/ja active Pending
- 2020-12-14 MX MX2022007685A patent/MX2022007685A/es unknown
- 2020-12-21 AR ARP200103594A patent/AR120856A1/es unknown
-
2022
- 2022-06-14 EC ECSENADI202247527A patent/ECSP22047527A/es unknown
- 2022-06-15 DO DO2022000126A patent/DOP2022000126A/es unknown
- 2022-06-15 CO CONC2022/0008338A patent/CO2022008338A2/es unknown
- 2022-06-16 CL CL2022001644A patent/CL2022001644A1/es unknown
Also Published As
Publication number | Publication date |
---|---|
CO2022008338A2 (es) | 2022-07-08 |
US20230112499A1 (en) | 2023-04-13 |
ECSP22047527A (es) | 2022-07-29 |
WO2021122415A9 (en) | 2022-06-30 |
KR20220118480A (ko) | 2022-08-25 |
JOP20220156A1 (ar) | 2023-01-30 |
PE20221786A1 (es) | 2022-11-22 |
AR120856A1 (es) | 2022-03-23 |
MX2022007685A (es) | 2022-07-19 |
IL293968A (en) | 2022-08-01 |
CL2022001644A1 (es) | 2023-02-24 |
AU2020408908A1 (en) | 2022-06-30 |
JP2023508908A (ja) | 2023-03-06 |
CR20220291A (es) | 2022-08-10 |
CN115135656A (zh) | 2022-09-30 |
BR112022011237A2 (pt) | 2022-08-30 |
EP4077334A1 (en) | 2022-10-26 |
WO2021122415A1 (en) | 2021-06-24 |
CA3164963A1 (en) | 2021-06-24 |
DOP2022000126A (es) | 2022-07-15 |
GEP20247585B (en) | 2024-01-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TW202136271A (zh) | 呋喃并吲唑衍生物 | |
RU2659219C2 (ru) | ТЕТРАГИДРОИМИДАЗО[1,5-d][1,4]ОКСАЗЕПИНОВОЕ ПРОИЗВОДНОЕ | |
JP5824055B2 (ja) | N1−ピラゾロスピロケトンアセチル−CoAカルボキシラーゼ阻害剤 | |
TW202110446A (zh) | 用於治療nash/nafld及相關疾病之組合 | |
CN107531703B (zh) | 用于治疗炎症性疾病的二氢吡啶并异喹啉酮类及其药物组合物 | |
EP3121177B1 (en) | Combinations of trpv4 antagonists | |
AU2021306414A1 (en) | Fused imidazole derivative, preparation method therefor, and medical use thereof | |
US20200230137A1 (en) | Substituted amines for treating cardiac diseases | |
KR20140117427A (ko) | 염증성 질환의 치료를 위한 신규의 다이하이드로피리미디노아이소퀴놀리논 및 그의 약학 조성물 | |
EA028654B1 (ru) | Пиримидиновые и пиридиновые соединения и их применение | |
WO2021026803A1 (en) | Piperidinyl-methyl-purineamines as nsd2 inhibitors and anti-cancer agents | |
JP2021515767A (ja) | Erk5阻害剤の同定及び使用 | |
KR20170003667A (ko) | 카르복스아미드 유도체 | |
WO2023224894A1 (en) | Macrocycles as lrrk2 inhibitors, pharmaceutical compositions, and uses thereof | |
JP2022526364A (ja) | 炎症性障害の治療のための新規化合物及びその医薬組成物 | |
JP2022526553A (ja) | 炎症性障害の治療のための新規化合物及びその医薬組成物 | |
CA3211437A1 (en) | Furoindazole derivatives as gpr84 antagonists | |
EP4079725A1 (en) | N-carboxamidopyrazoline derivative serving as p2x3 receptor antagonist and applications | |
EP4330260A1 (en) | Furoindazole derivatives as antagonists or inhibitors of gpr84 | |
JP2022526176A (ja) | 炎症性障害の治療のための新規化合物及びその医薬組成物 | |
WO2016021562A1 (ja) | シアノチオフェン誘導体 | |
US11130752B2 (en) | Aminopyrimidine compound | |
WO2024083705A1 (en) | Furoindazole derivatives for the treatment of pain | |
TW202225156A (zh) | 己酮糖激酶抑制劑及其用途 | |
EP3782997A1 (en) | Fused pyrimidine compounds and pharmaceutical compositions thereof for the treatment of fibrotic diseases |