CN112384509A - 弗林蛋白酶抑制剂 - Google Patents
弗林蛋白酶抑制剂 Download PDFInfo
- Publication number
- CN112384509A CN112384509A CN201980046497.1A CN201980046497A CN112384509A CN 112384509 A CN112384509 A CN 112384509A CN 201980046497 A CN201980046497 A CN 201980046497A CN 112384509 A CN112384509 A CN 112384509A
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- CN
- China
- Prior art keywords
- methyl
- pyridin
- oxy
- dichlorophenyl
- piperidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 102000004961 Furin Human genes 0.000 title abstract description 72
- 108090001126 Furin Proteins 0.000 title abstract description 72
- 239000003112 inhibitor Substances 0.000 title abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 131
- 238000000034 method Methods 0.000 claims abstract description 39
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 33
- 208000005069 pulmonary fibrosis Diseases 0.000 claims abstract description 13
- -1 chloro, methyl Chemical group 0.000 claims description 301
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 270
- 125000000217 alkyl group Chemical group 0.000 claims description 187
- 239000001257 hydrogen Substances 0.000 claims description 100
- 229910052739 hydrogen Inorganic materials 0.000 claims description 100
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 90
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 87
- 150000003839 salts Chemical class 0.000 claims description 81
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 69
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 62
- 125000001424 substituent group Chemical group 0.000 claims description 56
- 229910052757 nitrogen Inorganic materials 0.000 claims description 47
- 229920006395 saturated elastomer Polymers 0.000 claims description 44
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 43
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 239000000460 chlorine Substances 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 29
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 28
- 229910052801 chlorine Inorganic materials 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 27
- 125000002950 monocyclic group Chemical group 0.000 claims description 27
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 27
- 229910052731 fluorine Inorganic materials 0.000 claims description 25
- 239000011737 fluorine Substances 0.000 claims description 25
- 125000004043 oxo group Chemical group O=* 0.000 claims description 24
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 22
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 239000001301 oxygen Substances 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 17
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 16
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 12
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 12
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims description 12
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 229910052717 sulfur Chemical group 0.000 claims description 9
- 239000011593 sulfur Chemical group 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 6
- 235000019260 propionic acid Nutrition 0.000 claims description 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000001425 triazolyl group Chemical group 0.000 claims description 5
- OZHKYLOHMGGREF-UHFFFAOYSA-N 1-[3-[6-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl)pyridin-3-yl]oxy-5-(3,5-dichlorophenyl)phenyl]-N-methylmethanamine Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=C1)OC=1C=NC(=CC=1)N1CC2CNCC2C1)CNC OZHKYLOHMGGREF-UHFFFAOYSA-N 0.000 claims description 4
- RHMYVCZSMOIFAS-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CCC1)C RHMYVCZSMOIFAS-UHFFFAOYSA-N 0.000 claims description 4
- AZEJIKZNBHEXCM-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)C AZEJIKZNBHEXCM-UHFFFAOYSA-N 0.000 claims description 4
- PMWGLSGYZGTXKW-UHFFFAOYSA-N 2-[1-[[2-[2-(1,4-diazabicyclo[3.2.1]octan-4-yl)pyrimidin-5-yl]oxy-6-(3,5-dichlorophenyl)pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound N12CCN(C(CC1)C2)C1=NC=C(C=N1)OC1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)C1=CC(=CC(=C1)Cl)Cl PMWGLSGYZGTXKW-UHFFFAOYSA-N 0.000 claims description 4
- YLKNCNAEPRSZSL-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(=O)O YLKNCNAEPRSZSL-UHFFFAOYSA-N 0.000 claims description 4
- GOXVJENOKGAJKU-UHFFFAOYSA-N 4-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]-2-methylbutanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(C(=O)O)C GOXVJENOKGAJKU-UHFFFAOYSA-N 0.000 claims description 4
- JGIWSUHSDNOZJZ-UHFFFAOYSA-N CC(CC(OC(N)=O)=O)N(CC1)CCN1C(N=C1)=NC=C1OC1=NC(C2=CC(Cl)=CC(Cl)=C2)=CC(CN2CCC(CNC(C)=O)CC2)=C1 Chemical compound CC(CC(OC(N)=O)=O)N(CC1)CCN1C(N=C1)=NC=C1OC1=NC(C2=CC(Cl)=CC(Cl)=C2)=CC(CN2CCC(CNC(C)=O)CC2)=C1 JGIWSUHSDNOZJZ-UHFFFAOYSA-N 0.000 claims description 4
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- WQAWEUZTDVWTDB-UHFFFAOYSA-N dimethyl(oxo)phosphanium Chemical compound C[P+](C)=O WQAWEUZTDVWTDB-UHFFFAOYSA-N 0.000 claims description 4
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 4
- KOOCFNGOLFXEKM-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC1=NC=C(N=C1)N1CCN(CC1)C KOOCFNGOLFXEKM-UHFFFAOYSA-N 0.000 claims description 3
- MJOIKKFWKPJNJM-UHFFFAOYSA-N 2-[1-[[6-(3,5-dichlorophenyl)-3-methyl-2-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=C(C(=N1)OC1=NC=C(N=C1)N1CCN(CC1)C)C)CN1CCC(CC1)CC(=O)O MJOIKKFWKPJNJM-UHFFFAOYSA-N 0.000 claims description 3
- DIZGFRSKRZZKAK-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(=O)O DIZGFRSKRZZKAK-UHFFFAOYSA-N 0.000 claims description 3
- DZPXARBHSNBMCW-HXUWFJFHSA-N (2R)-3-[1-[[2-(3,5-dichlorophenyl)-6-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]-2-methylpropanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)C[C@H](C(=O)O)C)OC=1C=NC(=NC=1)N1CCN(CC1)C DZPXARBHSNBMCW-HXUWFJFHSA-N 0.000 claims description 2
- TWTTXAQDAAXFEM-HXUWFJFHSA-N (2R)-3-[1-[[2-(3,5-dichlorophenyl)-6-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]-2-methylpropanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)C[C@H](C(=O)O)C)OC=1N=NC(=CC=1)N1CCN(CC1)C TWTTXAQDAAXFEM-HXUWFJFHSA-N 0.000 claims description 2
- DZPXARBHSNBMCW-FQEVSTJZSA-N (2S)-3-[1-[[2-(3,5-dichlorophenyl)-6-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]-2-methylpropanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)C[C@@H](C(=O)O)C)OC=1C=NC(=NC=1)N1CCN(CC1)C DZPXARBHSNBMCW-FQEVSTJZSA-N 0.000 claims description 2
- TWTTXAQDAAXFEM-FQEVSTJZSA-N (2S)-3-[1-[[2-(3,5-dichlorophenyl)-6-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]-2-methylpropanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)C[C@@H](C(=O)O)C)OC=1N=NC(=CC=1)N1CCN(CC1)C TWTTXAQDAAXFEM-FQEVSTJZSA-N 0.000 claims description 2
- NKKNUMPNQBYZRN-UHFFFAOYSA-N 1-[1-[[2-(3,5-dichlorophenyl)-6-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]oxycyclopropane-1-carboxylic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)OC1(CC1)C(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)C NKKNUMPNQBYZRN-UHFFFAOYSA-N 0.000 claims description 2
- XWUNSCLZJGAQAA-UHFFFAOYSA-N 1-[1-[[2-(3,5-dichlorophenyl)-6-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]propan-2-ol Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(C)O)OC=1C=NC(=NC=1)N1CCN(CC1)C XWUNSCLZJGAQAA-UHFFFAOYSA-N 0.000 claims description 2
- OQHOMPBZZAFXAU-UHFFFAOYSA-N 1-[1-[[2-(3,5-dichlorophenyl)-6-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]propan-2-one Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(C)=O)OC=1C=NC(=NC=1)N1CCN(CC1)C OQHOMPBZZAFXAU-UHFFFAOYSA-N 0.000 claims description 2
- FAMNPBHEJZCMHX-UHFFFAOYSA-N 1-[1-[[2-(3,5-dichlorophenyl)-6-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]oxycyclopropane-1-carboxylic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)OC1(CC1)C(=O)O)OC1=NC=C(N=C1)N1CCN(CC1)C FAMNPBHEJZCMHX-UHFFFAOYSA-N 0.000 claims description 2
- SOMRWFBPSUFXCP-UHFFFAOYSA-N 1-[2-(3,5-dichlorophenyl)-6-[2-[4-(3-methylsulfonylpropyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]-N-methylmethanamine Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CNC)OC=1C=NC(=NC=1)N1CCN(CC1)CCCS(=O)(=O)C SOMRWFBPSUFXCP-UHFFFAOYSA-N 0.000 claims description 2
- VDDJCWROUASGBF-UHFFFAOYSA-N 1-[2-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]ethyl]cyclopropane-1-carboxylic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CCC1(CC1)C(=O)O VDDJCWROUASGBF-UHFFFAOYSA-N 0.000 claims description 2
- GTOFOFPZTPNLJI-UHFFFAOYSA-N 1-[3-(3,5-dichlorophenyl)-5-[6-(3,3-dimethylpiperazin-1-yl)pyridin-3-yl]oxyphenyl]-N-methylmethanamine Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=C1)OC=1C=NC(=CC=1)N1CC(NCC1)(C)C)CNC GTOFOFPZTPNLJI-UHFFFAOYSA-N 0.000 claims description 2
- INCXLXRJUWTJAR-UHFFFAOYSA-N 1-[3-(3,5-dichlorophenyl)-5-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]oxyphenyl]-N-methylmethanamine Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=C1)OC=1C=NC(=CC=1)N1CCN(CC1)C)CNC INCXLXRJUWTJAR-UHFFFAOYSA-N 0.000 claims description 2
- CKHJHYXFPIUYOD-UHFFFAOYSA-N 1-[3-[6-(1,4-diazepan-1-yl)pyridin-3-yl]oxy-5-(3,5-dichlorophenyl)phenyl]-N-methylmethanamine Chemical compound N1(CCNCCC1)C1=CC=C(C=N1)OC=1C=C(C=C(C=1)C1=CC(=CC(=C1)Cl)Cl)CNC CKHJHYXFPIUYOD-UHFFFAOYSA-N 0.000 claims description 2
- WYVOFQCRMBNKGB-SFTDATJTSA-N 1-[3-[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyridin-3-yl]oxy-5-(3,5-dichlorophenyl)phenyl]-N-methylmethanamine Chemical compound [C@@H]12N(C[C@@H](NC1)C2)C2=CC=C(C=N2)OC=2C=C(C=C(C2)C2=CC(=CC(=C2)Cl)Cl)CNC WYVOFQCRMBNKGB-SFTDATJTSA-N 0.000 claims description 2
- ANBGZCPUKYJMEV-UHFFFAOYSA-N 1-[5-[3-(3,5-dichlorophenyl)-5-(methylaminomethyl)phenoxy]pyridin-2-yl]piperidin-4-amine Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=C1)CNC)OC=1C=CC(=NC=1)N1CCC(CC1)N ANBGZCPUKYJMEV-UHFFFAOYSA-N 0.000 claims description 2
- NVJCSGDMHPKXOW-UHFFFAOYSA-N 1-[5-[3-(3,5-dichlorophenyl)-5-[(2-methoxyethylamino)methyl]phenoxy]pyridin-2-yl]-N-methylpiperidin-4-amine Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=C1)CNCCOC)OC=1C=CC(=NC=1)N1CCC(CC1)NC NVJCSGDMHPKXOW-UHFFFAOYSA-N 0.000 claims description 2
- WXAWSOSENJECMG-UHFFFAOYSA-N 1-[5-[6-(3-chloro-5-methylphenyl)-4-(methylaminomethyl)pyridin-2-yl]oxypyridin-2-yl]piperidin-4-amine Chemical compound ClC=1C=C(C=C(C=1)C)C1=CC(=CC(=N1)OC=1C=CC(=NC=1)N1CCC(CC1)N)CNC WXAWSOSENJECMG-UHFFFAOYSA-N 0.000 claims description 2
- WDAYBDXLXUXMOV-UHFFFAOYSA-N 1-[[1-[[2-(3,5-dichlorophenyl)-6-(2-piperazin-1-ylpyrimidin-5-yl)oxypyridin-4-yl]methyl]piperidin-4-yl]methyl]-3-methylurea Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CNC(=O)NC)OC=1C=NC(=NC=1)N1CCNCC1 WDAYBDXLXUXMOV-UHFFFAOYSA-N 0.000 claims description 2
- DLIIAMDDSBJZQZ-UHFFFAOYSA-N 1-[[1-[[2-(3,5-dichlorophenyl)-6-(6-piperazin-1-ylpyridin-3-yl)oxypyridin-4-yl]methyl]-4-hydroxypiperidin-4-yl]methyl]-3-methylurea Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)(O)CNC(=O)NC)OC=1C=NC(=CC=1)N1CCNCC1 DLIIAMDDSBJZQZ-UHFFFAOYSA-N 0.000 claims description 2
- KPMPEWPLXPVVIN-UHFFFAOYSA-N 1-[[1-[[2-(3,5-dichlorophenyl)-6-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]methyl]-3-methylurea Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CNC(=O)NC)OC=1C=NC(=NC=1)N1CCN(CC1)C KPMPEWPLXPVVIN-UHFFFAOYSA-N 0.000 claims description 2
- USJUUVXZEGTZAO-UHFFFAOYSA-N 1-[[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(2-hydroxyethyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]methyl]-3-methylurea Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CNC(=O)NC)OC=1C=NC(=NC=1)N1CCN(CC1)CCO USJUUVXZEGTZAO-UHFFFAOYSA-N 0.000 claims description 2
- JTZDFWQPNAEAQN-UHFFFAOYSA-N 1-[[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(2-methoxyethyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]methyl]-3-methylurea Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CNC(=O)NC)OC=1C=NC(=NC=1)N1CCN(CC1)CCOC JTZDFWQPNAEAQN-UHFFFAOYSA-N 0.000 claims description 2
- FBNHKNOITKSSBL-UHFFFAOYSA-N 1-[[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(3-hydroxypropyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]methyl]-3-methylurea Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CNC(=O)NC)OC=1C=NC(=NC=1)N1CCN(CC1)CCCO FBNHKNOITKSSBL-UHFFFAOYSA-N 0.000 claims description 2
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- MJGDEMMDRQQTFT-DEOSSOPVSA-N 2-[(7S)-4-[[2-(3,5-dichlorophenyl)-6-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]-1,4-oxazepan-7-yl]ethanol Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCO[C@@H](CC1)CCO)OC=1C=NC(=NC=1)N1CCN(CC1)C MJGDEMMDRQQTFT-DEOSSOPVSA-N 0.000 claims description 2
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- AHNYKNJXYRHFTJ-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-(6-fluoro-1,4-diazepan-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCNCC(C1)F AHNYKNJXYRHFTJ-UHFFFAOYSA-N 0.000 claims description 2
- NCSPMNRHMIVKBF-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-(6-fluoro-4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC(C1)F)C NCSPMNRHMIVKBF-UHFFFAOYSA-N 0.000 claims description 2
- JCYVGILALJXHJG-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-(6-hydroxy-1,4-diazepan-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCNCC(C1)O JCYVGILALJXHJG-UHFFFAOYSA-N 0.000 claims description 2
- BLBHGPCWQIYXOF-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-(6-hydroxy-4,6-dimethyl-1,4-diazepan-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC(C1)(C)O)C BLBHGPCWQIYXOF-UHFFFAOYSA-N 0.000 claims description 2
- NGKDDRVRCYHOEH-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-(6-hydroxy-4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC(C1)O)C NGKDDRVRCYHOEH-UHFFFAOYSA-N 0.000 claims description 2
- CTFGGUUIKCFANT-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-(6-methoxy-4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC(C1)OC)C CTFGGUUIKCFANT-UHFFFAOYSA-N 0.000 claims description 2
- JTKHTEMATCXRRP-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CC2N(C(C1)C2)C JTKHTEMATCXRRP-UHFFFAOYSA-N 0.000 claims description 2
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- NENSRYYLZNRUSQ-ZEQRLZLVSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1[C@@H]2CN([C@H](C1)C2)C NENSRYYLZNRUSQ-ZEQRLZLVSA-N 0.000 claims description 2
- LYDQKYGPLCCBIN-SFHVURJKSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1C[C@@H](NCC1)C LYDQKYGPLCCBIN-SFHVURJKSA-N 0.000 claims description 2
- ZMLSGPFKTLQRBT-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CC(CC1)NC ZMLSGPFKTLQRBT-UHFFFAOYSA-N 0.000 claims description 2
- KMZRPZHTZYJNCM-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(1,3-dihydroxypropan-2-yl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)C(CO)CO KMZRPZHTZYJNCM-UHFFFAOYSA-N 0.000 claims description 2
- QVMPXIXVHHAEGH-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(1-hydroxypropan-2-yl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)C(CO)C QVMPXIXVHHAEGH-UHFFFAOYSA-N 0.000 claims description 2
- AYLXYASCQWNACW-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)CC(CO)O AYLXYASCQWNACW-UHFFFAOYSA-N 0.000 claims description 2
- RVQJNKOIZKJNGH-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(2-fluoroethyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)CCF RVQJNKOIZKJNGH-UHFFFAOYSA-N 0.000 claims description 2
- XZKGLRKBFXECOM-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(2-hydroxyethyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)CCO XZKGLRKBFXECOM-UHFFFAOYSA-N 0.000 claims description 2
- WZXUTZNFFFBBEK-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(2-methoxyethyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)CCOC WZXUTZNFFFBBEK-UHFFFAOYSA-N 0.000 claims description 2
- MFYJWGWIBQDEHK-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(2H-triazol-4-ylmethyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound N1N=NC=C1CN1CCN(CC1)C1=NC=C(C=N1)OC1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)C1=CC(=CC(=C1)Cl)Cl MFYJWGWIBQDEHK-UHFFFAOYSA-N 0.000 claims description 2
- LCRJZDOELKQBHQ-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(3-hydroxy-2,2-dimethylpropyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)CC(CO)(C)C LCRJZDOELKQBHQ-UHFFFAOYSA-N 0.000 claims description 2
- YLJJABGXZWXZOR-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(3-hydroxy-3-methylbutyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(C)(C)O YLJJABGXZWXZOR-UHFFFAOYSA-N 0.000 claims description 2
- OETPDWYLICVMMI-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(3-hydroxybutyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(C)O OETPDWYLICVMMI-UHFFFAOYSA-N 0.000 claims description 2
- PYXXTSDGIBYDFY-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(3-methylsulfinylbutyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(C)S(=O)C PYXXTSDGIBYDFY-UHFFFAOYSA-N 0.000 claims description 2
- IJYMLGZIEOKWBI-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(3-methylsulfonylbutyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(C)S(=O)(=O)C IJYMLGZIEOKWBI-UHFFFAOYSA-N 0.000 claims description 2
- SNPSOUBNBXTISO-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(3-methylsulfonylpropyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)CCCS(=O)(=O)C SNPSOUBNBXTISO-UHFFFAOYSA-N 0.000 claims description 2
- DMZBFQQCFPWAPD-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(3-sulfamoylpropyl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)CCCS(N)(=O)=O DMZBFQQCFPWAPD-UHFFFAOYSA-N 0.000 claims description 2
- VEPVVRISRPIOHE-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(4-hydroxybutan-2-yl)piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)C(C)CCO VEPVVRISRPIOHE-UHFFFAOYSA-N 0.000 claims description 2
- BMMWWERINDBDLN-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-(dimethylamino)piperidin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCC(CC1)N(C)C BMMWWERINDBDLN-UHFFFAOYSA-N 0.000 claims description 2
- MSPWBBKJKNRIQD-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-[(1-hydroxycyclopropyl)methyl]piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)CC1(CC1)O MSPWBBKJKNRIQD-UHFFFAOYSA-N 0.000 claims description 2
- BUVTTYFXRWVEJU-HXUWFJFHSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-[(2R)-2-hydroxypropyl]piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)C[C@@H](C)O BUVTTYFXRWVEJU-HXUWFJFHSA-N 0.000 claims description 2
- HHEWUAIKSZWNGP-HXUWFJFHSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-[(2R)-2-hydroxypropyl]piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]oxyacetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)OCC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)C[C@@H](C)O HHEWUAIKSZWNGP-HXUWFJFHSA-N 0.000 claims description 2
- SPMMCBXXGGNOQR-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-[2-(1-hydroxycyclopropyl)ethyl]piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)CCC1(CC1)O SPMMCBXXGGNOQR-UHFFFAOYSA-N 0.000 claims description 2
- QXEDGKCVXMPAJI-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-[2-(methylcarbamoyloxy)ethyl]piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)CCOC(NC)=O QXEDGKCVXMPAJI-UHFFFAOYSA-N 0.000 claims description 2
- IVHYHWFSBVJZCQ-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-[4-(dimethylamino)butan-2-yl]piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)C(C)CCN(C)C IVHYHWFSBVJZCQ-UHFFFAOYSA-N 0.000 claims description 2
- FVNYZWBRFJBAIU-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[2-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C(=NC(=CC=1)N1CCN(CC1)C)C FVNYZWBRFJBAIU-UHFFFAOYSA-N 0.000 claims description 2
- VAHDKDRTZYNHEO-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[4-(4-methylpiperazin-1-yl)phenoxy]pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC1=CC=C(C=C1)N1CCN(CC1)C VAHDKDRTZYNHEO-UHFFFAOYSA-N 0.000 claims description 2
- HNGLYJIAKWIQQA-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[4-methyl-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C(=NC(=NC=1)N1CCN(CC1)C)C HNGLYJIAKWIQQA-UHFFFAOYSA-N 0.000 claims description 2
- ZTWBCCPQWWLZLX-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[5-(4-ethyl-1,4-diazepan-1-yl)pyrazin-2-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC1=NC=C(N=C1)N1CCN(CCC1)CC ZTWBCCPQWWLZLX-UHFFFAOYSA-N 0.000 claims description 2
- RAPZVVBHTMJSSW-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[5-(4-methyl-1,4-diazepan-1-yl)pyrazin-2-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC1=NC=C(N=C1)N1CCN(CCC1)C RAPZVVBHTMJSSW-UHFFFAOYSA-N 0.000 claims description 2
- NNUHWWTXXUDNHE-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]ethanol Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CCO)OC1=NC=C(N=C1)N1CCN(CC1)C NNUHWWTXXUDNHE-UHFFFAOYSA-N 0.000 claims description 2
- PERHFORZCSCUIA-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[5-(4-propan-2-ylpiperazin-1-yl)pyrazin-2-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC1=NC=C(N=C1)N1CCN(CC1)C(C)C PERHFORZCSCUIA-UHFFFAOYSA-N 0.000 claims description 2
- IIYJQAXGYXNWOQ-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC1=NC=C(N=C1)N1CC2N(C(C1)C2)C IIYJQAXGYXNWOQ-UHFFFAOYSA-N 0.000 claims description 2
- OTAKXBCHSYLASG-ZEQRLZLVSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[5-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazin-2-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC1=NC=C(N=C1)N1[C@@H]2CN([C@H](C1)C2)C OTAKXBCHSYLASG-ZEQRLZLVSA-N 0.000 claims description 2
- MZPJNTCIHJSRHN-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[5-[4-(2-hydroxy-2-methylpropyl)piperazin-1-yl]pyrazin-2-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC1=NC=C(N=C1)N1CCN(CC1)CC(C)(C)O MZPJNTCIHJSRHN-UHFFFAOYSA-N 0.000 claims description 2
- UMUGTCQFDCHWHO-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[5-[4-(3-hydroxybutyl)piperazin-1-yl]pyrazin-2-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC1=NC=C(N=C1)N1CCN(CC1)CCC(C)O UMUGTCQFDCHWHO-UHFFFAOYSA-N 0.000 claims description 2
- HMAFPPFRBPONJR-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[5-[4-(3-methylsulfonylpropyl)piperazin-1-yl]pyrazin-2-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC1=NC=C(N=C1)N1CCN(CC1)CCCS(=O)(=O)C HMAFPPFRBPONJR-UHFFFAOYSA-N 0.000 claims description 2
- RCOZJDHVNBQPAH-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=C(C=1)F)N1CCN(CC1)C RCOZJDHVNBQPAH-UHFFFAOYSA-N 0.000 claims description 2
- DCIXUHUBDVQGRE-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-(4-ethyl-1,4-diazepan-1-yl)pyridazin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1N=NC(=CC=1)N1CCN(CCC1)CC DCIXUHUBDVQGRE-UHFFFAOYSA-N 0.000 claims description 2
- BAYKAFJIRABTNR-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-(4-ethylpiperazin-1-yl)pyridazin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1N=NC(=CC=1)N1CCN(CC1)CC BAYKAFJIRABTNR-UHFFFAOYSA-N 0.000 claims description 2
- BZMPIZOXEYVNHG-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-(4-methyl-1,4-diazepan-1-yl)pyridazin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1N=NC(=CC=1)N1CCN(CCC1)C BZMPIZOXEYVNHG-UHFFFAOYSA-N 0.000 claims description 2
- XSYRJHRGZVWTDL-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=CC=1)N1CCN(CCC1)C XSYRJHRGZVWTDL-UHFFFAOYSA-N 0.000 claims description 2
- LGPNZGMLMRORRG-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1N=NC(=CC=1)N1CCN(CC1)C LGPNZGMLMRORRG-UHFFFAOYSA-N 0.000 claims description 2
- FFWQPDJAOXPCGQ-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]ethanol Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CCO)OC=1N=NC(=CC=1)N1CCN(CC1)C FFWQPDJAOXPCGQ-UHFFFAOYSA-N 0.000 claims description 2
- AWMJWDCCUXONEH-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=CC=1)N1CCN(CC1)C AWMJWDCCUXONEH-UHFFFAOYSA-N 0.000 claims description 2
- VGVQHRSYPNRELX-DQEYMECFSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyridazin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1N=NC(=CC=1)N1[C@@H]2CN([C@H](C1)C2)CC VGVQHRSYPNRELX-DQEYMECFSA-N 0.000 claims description 2
- WVEQHAXSIHJQNF-ZEQRLZLVSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyridazin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1N=NC(=CC=1)N1[C@@H]2CN([C@H](C1)C2)C WVEQHAXSIHJQNF-ZEQRLZLVSA-N 0.000 claims description 2
- NUTYHECMBAOZIB-DQEYMECFSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=CC=1)N1[C@@H]2CN([C@H](C1)C2)C NUTYHECMBAOZIB-DQEYMECFSA-N 0.000 claims description 2
- PXHSRGZVZWWOSI-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-[4-(2-hydroxyethyl)piperazin-1-yl]pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=CC=1)N1CCN(CC1)CCO PXHSRGZVZWWOSI-UHFFFAOYSA-N 0.000 claims description 2
- CZTOGJLVLISLTA-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-[4-(2-methoxyethyl)piperazin-1-yl]pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=CC=1)N1CCN(CC1)CCOC CZTOGJLVLISLTA-UHFFFAOYSA-N 0.000 claims description 2
- VGBJOWWKCHRYDK-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-[4-(3-methylsulfonylpropyl)piperazin-1-yl]pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]-N-ethylacetamide Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)NCC)OC=1C=NC(=CC=1)N1CCN(CC1)CCCS(=O)(=O)C VGBJOWWKCHRYDK-UHFFFAOYSA-N 0.000 claims description 2
- DHKNGKGYCUONKT-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-[4-(3-methylsulfonylpropyl)piperazin-1-yl]pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=CC=1)N1CCN(CC1)CCCS(=O)(=O)C DHKNGKGYCUONKT-UHFFFAOYSA-N 0.000 claims description 2
- YQZXMUCZGZCQQB-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-[4-(3-sulfamoylpropyl)piperazin-1-yl]pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=CC=1)N1CCN(CC1)CCCS(N)(=O)=O YQZXMUCZGZCQQB-UHFFFAOYSA-N 0.000 claims description 2
- OTCLOANOPONIOE-OAQYLSRUSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[6-[4-[(2R)-2-hydroxypropyl]piperazin-1-yl]pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=CC=1)N1CCN(CC1)C[C@@H](C)O OTCLOANOPONIOE-OAQYLSRUSA-N 0.000 claims description 2
- KOUVZSVAYWEVGP-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-propan-2-ylamino]pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)N(C=1C=NC(=NC=1)N1CCN(CC1)C)C(C)C KOUVZSVAYWEVGP-UHFFFAOYSA-N 0.000 claims description 2
- HXLIPKCQIMNKQD-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]amino]pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)NC=1C=NC(=NC=1)N1CCN(CC1)C HXLIPKCQIMNKQD-UHFFFAOYSA-N 0.000 claims description 2
- MEXGBWBRSSAHCM-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[ethyl-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]amino]pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)N(C=1C=NC(=NC=1)N1CCN(CC1)C)CC MEXGBWBRSSAHCM-UHFFFAOYSA-N 0.000 claims description 2
- IOJDGVMUMJJVRT-UHFFFAOYSA-N 2-[1-[[2-(3,5-dichlorophenyl)-6-[methyl-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]amino]pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)N(C=1C=NC(=NC=1)N1CCN(CC1)C)C IOJDGVMUMJJVRT-UHFFFAOYSA-N 0.000 claims description 2
- OTDGDFRWRZRFGC-UHFFFAOYSA-N 2-[1-[[2-(3-chloro-5-fluorophenyl)-6-[2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)F)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CCC1)C OTDGDFRWRZRFGC-UHFFFAOYSA-N 0.000 claims description 2
- NJCICWFDIHZRTG-UHFFFAOYSA-N 2-[1-[[2-[2-(1,4-diazepan-1-yl)pyrimidin-5-yl]oxy-6-(3,5-dichlorophenyl)pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound N1(CCNCCC1)C1=NC=C(C=N1)OC1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)C1=CC(=CC(=C1)Cl)Cl NJCICWFDIHZRTG-UHFFFAOYSA-N 0.000 claims description 2
- OWXJTTCCGNEYPG-UHFFFAOYSA-N 2-[1-[[2-[2-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl)pyrimidin-5-yl]oxy-6-(3,5-dichlorophenyl)pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)OC=1C=NC(=NC=1)N1CC2CNCC2C1 OWXJTTCCGNEYPG-UHFFFAOYSA-N 0.000 claims description 2
- FNYXWJCLQVJDDY-UHFFFAOYSA-N 2-[1-[[2-[2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrimidin-5-yl]oxy-6-(3,5-dichlorophenyl)pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound C12CN(CC(N1)C2)C1=NC=C(C=N1)OC1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)C1=CC(=CC(=C1)Cl)Cl FNYXWJCLQVJDDY-UHFFFAOYSA-N 0.000 claims description 2
- DBDSKIYILUCOAH-UHFFFAOYSA-N 2-[1-[[2-[2-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl]oxy-6-(3,5-dichlorophenyl)-3-fluoropyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound C12CN(CC(CC1)N2)C1=NC=C(C=N1)OC1=NC(=CC(=C1F)CN1CCC(CC1)CC(=O)O)C1=CC(=CC(=C1)Cl)Cl DBDSKIYILUCOAH-UHFFFAOYSA-N 0.000 claims description 2
- ZMTFZELEZNPAST-UHFFFAOYSA-N 2-[1-[[2-[2-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl]oxy-6-(3,5-dichlorophenyl)pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound C12CN(CC(CC1)N2)C1=NC=C(C=N1)OC1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)C1=CC(=CC(=C1)Cl)Cl ZMTFZELEZNPAST-UHFFFAOYSA-N 0.000 claims description 2
- LZUMWNRBZQQEOM-UHFFFAOYSA-N 2-[1-[[2-[2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-5-yl]oxy-6-(3,5-dichlorophenyl)pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound C1CC11NCCN(C1)C1=NC=C(C=N1)OC1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)C1=CC(=CC(=C1)Cl)Cl LZUMWNRBZQQEOM-UHFFFAOYSA-N 0.000 claims description 2
- JQOLXWIADFCQHK-UHFFFAOYSA-N 2-[1-[[2-[2-(4-aminopiperidin-1-yl)pyrimidin-5-yl]oxy-6-(3,5-dichlorophenyl)pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound NC1CCN(CC1)C1=NC=C(C=N1)OC1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)C1=CC(=CC(=C1)Cl)Cl JQOLXWIADFCQHK-UHFFFAOYSA-N 0.000 claims description 2
- HFBZNXHRBLBXGE-UHFFFAOYSA-N 2-[1-[[2-[2-(4-cyclopropylpiperazin-1-yl)pyrimidin-5-yl]oxy-6-(3,5-dichlorophenyl)pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound C1(CC1)N1CCN(CC1)C1=NC=C(C=N1)OC1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)C1=CC(=CC(=C1)Cl)Cl HFBZNXHRBLBXGE-UHFFFAOYSA-N 0.000 claims description 2
- QPAOXJWKOIWCDO-UHFFFAOYSA-N 2-[1-[[2-[2-[4-amino-4-(2-hydroxyethyl)piperidin-1-yl]pyrimidin-5-yl]oxy-6-(3,5-dichlorophenyl)pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound NC1(CCN(CC1)C1=NC=C(C=N1)OC1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)C1=CC(=CC(=C1)Cl)Cl)CCO QPAOXJWKOIWCDO-UHFFFAOYSA-N 0.000 claims description 2
- ORLQRZQCDFPHTG-UHFFFAOYSA-N 2-[1-[[2-[2-[4-amino-4-(hydroxymethyl)piperidin-1-yl]pyrimidin-5-yl]oxy-6-(3,5-dichlorophenyl)pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound NC1(CCN(CC1)C1=NC=C(C=N1)OC1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)C1=CC(=CC(=C1)Cl)Cl)CO ORLQRZQCDFPHTG-UHFFFAOYSA-N 0.000 claims description 2
- CHGIIXAUSXILJF-UHFFFAOYSA-N 2-[1-[[2-[5-(1,4-diazabicyclo[3.2.1]octan-4-yl)pyrazin-2-yl]oxy-6-(3,5-dichlorophenyl)pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound N12CCN(C(CC1)C2)C=1N=CC(=NC=1)OC1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)C1=CC(=CC(=C1)Cl)Cl CHGIIXAUSXILJF-UHFFFAOYSA-N 0.000 claims description 2
- IFQCINQMEYSKER-UHFFFAOYSA-N 2-[1-[[2-[6-(1,4-diazabicyclo[3.2.1]octan-4-yl)pyridazin-3-yl]oxy-6-(3,5-dichlorophenyl)pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound N12CCN(C(CC1)C2)C1=CC=C(N=N1)OC1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)C1=CC(=CC(=C1)Cl)Cl IFQCINQMEYSKER-UHFFFAOYSA-N 0.000 claims description 2
- MIIPWEPBHOOZOT-UHFFFAOYSA-N 2-[1-[[2-[6-(1,4-diazepan-1-yl)pyridin-3-yl]oxy-6-(3,5-dichlorophenyl)pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound N1(CCNCCC1)C1=CC=C(C=N1)OC1=NC(=CC(=C1)CN1CCC(CC1)CC(=O)O)C1=CC(=CC(=C1)Cl)Cl MIIPWEPBHOOZOT-UHFFFAOYSA-N 0.000 claims description 2
- SWDIGXKGTIKYKO-ZEQRLZLVSA-N 2-[1-[[2-[6-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyridin-3-yl]oxy-6-(3,5-dichlorophenyl)pyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound [C@@H]12N(C[C@@H](NC1)C2)C2=CC=C(C=N2)OC2=NC(=CC(=C2)CN2CCC(CC2)CC(=O)O)C2=CC(=CC(=C2)Cl)Cl SWDIGXKGTIKYKO-ZEQRLZLVSA-N 0.000 claims description 2
- WFNAXACWYNJCRT-UHFFFAOYSA-N 2-[1-[[3-(3,5-dichlorophenyl)-5-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxyphenyl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=C1)OC=1C=NC(=NC=1)N1CCN(CC1)C)CN1CCC(CC1)CC(=O)O WFNAXACWYNJCRT-UHFFFAOYSA-N 0.000 claims description 2
- ITBAOFWGDGCSEF-UHFFFAOYSA-N 2-[1-[[5-(3,5-dichlorophenyl)-2-fluoro-3-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxyphenyl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=C(C(=C1)OC=1C=NC(=NC=1)N1CCN(CC1)C)F)CN1CCC(CC1)CC(=O)O ITBAOFWGDGCSEF-UHFFFAOYSA-N 0.000 claims description 2
- RMSSDEZLJBZPAT-UHFFFAOYSA-N 2-[1-[[6-(3,5-dichlorophenyl)-3-fluoro-2-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=C(C(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)C)F)CN1CCC(CC1)CC(=O)O RMSSDEZLJBZPAT-UHFFFAOYSA-N 0.000 claims description 2
- QMSJTWDTLACGJG-UHFFFAOYSA-N 2-[1-[[6-(3,5-dichlorophenyl)-3-fluoro-2-[2-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=C(C(=N1)OC=1C=NC(=NC=1)N1CC2CCC(C1)N2C)F)CN1CCC(CC1)CC(=O)O QMSJTWDTLACGJG-UHFFFAOYSA-N 0.000 claims description 2
- MAAQFHPMDQYLSZ-UHFFFAOYSA-N 2-[1-[[6-(3,5-dichlorophenyl)-3-fluoro-2-[2-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=C(C(=N1)OC=1C(=NC(=CC=1)N1CCN(CC1)C)C)F)CN1CCC(CC1)CC(=O)O MAAQFHPMDQYLSZ-UHFFFAOYSA-N 0.000 claims description 2
- WDKJKCSRACACCB-UHFFFAOYSA-N 2-[1-[[6-(3,5-dichlorophenyl)-3-fluoro-2-[4-methyl-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=C(C(=N1)OC=1C(=NC(=NC=1)N1CCN(CC1)C)C)F)CN1CCC(CC1)CC(=O)O WDKJKCSRACACCB-UHFFFAOYSA-N 0.000 claims description 2
- ATQPNXUCZUGEIL-UHFFFAOYSA-N 2-[1-[[6-(3,5-dichlorophenyl)-3-fluoro-2-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=C(C(=N1)OC1=NC=C(N=C1)N1CCN(CC1)C)F)CN1CCC(CC1)CC(=O)O ATQPNXUCZUGEIL-UHFFFAOYSA-N 0.000 claims description 2
- JNVCTTMGSQPPKK-UHFFFAOYSA-N 2-[1-[[6-(3,5-dichlorophenyl)-3-fluoro-2-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=C(C(=N1)OC=1N=NC(=CC=1)N1CCN(CC1)C)F)CN1CCC(CC1)CC(=O)O JNVCTTMGSQPPKK-UHFFFAOYSA-N 0.000 claims description 2
- UUZZKGHOAMZHJI-UHFFFAOYSA-N 2-[1-[[6-(3,5-dichlorophenyl)-3-fluoro-2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=C(C(=N1)OC=1C=NC(=CC=1)N1CCN(CC1)C)F)CN1CCC(CC1)CC(=O)O UUZZKGHOAMZHJI-UHFFFAOYSA-N 0.000 claims description 2
- ZZFLKXNHUWOYBT-UHFFFAOYSA-N 2-[1-[[6-(3,5-dichlorophenyl)-3-methyl-2-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=C(C(=N1)OC=1N=NC(=CC=1)N1CCN(CC1)C)C)CN1CCC(CC1)CC(=O)O ZZFLKXNHUWOYBT-UHFFFAOYSA-N 0.000 claims description 2
- YRPKDMKWHSUYKS-UHFFFAOYSA-N 2-[1-[[6-(3,5-dichlorophenyl)-3-methyl-2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=C(C(=N1)OC=1C=NC(=CC=1)N1CCN(CC1)C)C)CN1CCC(CC1)CC(=O)O YRPKDMKWHSUYKS-UHFFFAOYSA-N 0.000 claims description 2
- KJSBUZCREZKGJL-UHFFFAOYSA-N 2-[2-[[2-(3,5-dichlorophenyl)-6-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]acetic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CC2C(C1)CC(C2)CC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)C KJSBUZCREZKGJL-UHFFFAOYSA-N 0.000 claims description 2
- WGRNTRPTSUMYAD-UHFFFAOYSA-N 2-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]acetic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)CC(=O)O WGRNTRPTSUMYAD-UHFFFAOYSA-N 0.000 claims description 2
- GBLKCQPGPROIOJ-UHFFFAOYSA-N 2-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]ethanesulfonic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)CCS(=O)(=O)O GBLKCQPGPROIOJ-UHFFFAOYSA-N 0.000 claims description 2
- VEBQXOBSVMVIKY-UHFFFAOYSA-N 2-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]ethylphosphonic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)CCP(O)(O)=O VEBQXOBSVMVIKY-UHFFFAOYSA-N 0.000 claims description 2
- QZSRTHDKVBOSRL-UHFFFAOYSA-N 2-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]ethylboronic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CCB(O)O QZSRTHDKVBOSRL-UHFFFAOYSA-N 0.000 claims description 2
- HRYHXFHXZVJLJK-UHFFFAOYSA-N 2-[4-[[2-(3,5-dichlorophenyl)-6-(6-piperazin-1-ylpyridin-3-yl)oxypyridin-4-yl]methyl]piperazin-1-yl]-N-methylacetamide Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCN(CC1)CC(=O)NC)OC=1C=NC(=CC=1)N1CCNCC1 HRYHXFHXZVJLJK-UHFFFAOYSA-N 0.000 claims description 2
- UNIDEGTZLGHJTK-UHFFFAOYSA-N 2-[[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]methyl]butanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)CC(C(=O)O)CC UNIDEGTZLGHJTK-UHFFFAOYSA-N 0.000 claims description 2
- WGBUVBWWWKVESR-ISILISOKSA-N 3-[(1S,5R)-3-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1C[C@H]2CC[C@@H](C1)N2CCC(=O)O WGBUVBWWWKVESR-ISILISOKSA-N 0.000 claims description 2
- ISUBQZLSVNOIDI-QFIPXVFZSA-N 3-[(2S)-4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]-2-methylpiperazin-1-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1C[C@@H](N(CC1)CCC(=O)O)C ISUBQZLSVNOIDI-QFIPXVFZSA-N 0.000 claims description 2
- KPYRQEHFHYFONR-NRFANRHFSA-N 3-[(2S)-4-[5-[6-(3,5-dichlorophenyl)-4-[[4-[(methoxycarbonylamino)methyl]piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]-2-methylpiperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1C[C@@H](N(CC1)CCC(=O)O)C)CN1CCC(CC1)CNC(=O)OC KPYRQEHFHYFONR-NRFANRHFSA-N 0.000 claims description 2
- YSIBHUAVANCUQW-UHFFFAOYSA-N 3-[1-[[2-(3,5-dichlorophenyl)-6-(2-piperazin-1-ylpyrimidin-5-yl)oxypyridin-4-yl]methyl]piperidin-4-yl]-2-methylpropanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(C(=O)O)C)OC=1C=NC(=NC=1)N1CCNCC1 YSIBHUAVANCUQW-UHFFFAOYSA-N 0.000 claims description 2
- NFEXBHGYAKOEIC-UHFFFAOYSA-N 3-[1-[[2-(3,5-dichlorophenyl)-6-(6-piperazin-1-ylpyridin-3-yl)oxypyridin-4-yl]methyl]piperidin-4-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CCC(=O)O)OC=1C=NC(=CC=1)N1CCNCC1 NFEXBHGYAKOEIC-UHFFFAOYSA-N 0.000 claims description 2
- NDHVYFLDZGNGOP-UHFFFAOYSA-N 3-[1-[[2-(3,5-dichlorophenyl)-6-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]azetidin-3-yl]butanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CC(C1)C(CC(=O)O)C)OC=1C=NC(=NC=1)N1CCN(CC1)C NDHVYFLDZGNGOP-UHFFFAOYSA-N 0.000 claims description 2
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- DZPXARBHSNBMCW-UHFFFAOYSA-N 3-[1-[[2-(3,5-dichlorophenyl)-6-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]-2-methylpropanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(C(=O)O)C)OC=1C=NC(=NC=1)N1CCN(CC1)C DZPXARBHSNBMCW-UHFFFAOYSA-N 0.000 claims description 2
- FTJAICRAXZPDTP-UHFFFAOYSA-N 3-[1-[[2-(3,5-dichlorophenyl)-6-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CCC(=O)O)OC=1C=NC(=NC=1)N1CCN(CC1)C FTJAICRAXZPDTP-UHFFFAOYSA-N 0.000 claims description 2
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- SMGBCEXNTVJFOQ-FOIFJWKZSA-N 3-[1-[[2-(3,5-dichlorophenyl)-6-[2-[4-[(2R)-2-hydroxypropyl]piperazin-1-yl]pyrimidin-5-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]-2-methylpropanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(C(=O)O)C)OC=1C=NC(=NC=1)N1CCN(CC1)C[C@@H](C)O SMGBCEXNTVJFOQ-FOIFJWKZSA-N 0.000 claims description 2
- WGUQOFTUYAZYJE-UHFFFAOYSA-N 3-[1-[[2-(3,5-dichlorophenyl)-6-[5-(4-methyl-1,4-diazepan-1-yl)pyrazin-2-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]-2-methylpropanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(C(=O)O)C)OC1=NC=C(N=C1)N1CCN(CCC1)C WGUQOFTUYAZYJE-UHFFFAOYSA-N 0.000 claims description 2
- GUWZQPRSWCZCLV-UHFFFAOYSA-N 3-[1-[[2-(3,5-dichlorophenyl)-6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]-2-methylpropanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CC(C(=O)O)C)OC=1C=NC(=CC=1)N1CCN(CC1)C GUWZQPRSWCZCLV-UHFFFAOYSA-N 0.000 claims description 2
- WIWOEJXBVFWBJO-UHFFFAOYSA-N 3-[1-[[2-(3,5-dichlorophenyl)-6-[6-[4-(2-hydroxyethyl)piperazin-1-yl]pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CCC(=O)O)OC=1C=NC(=CC=1)N1CCN(CC1)CCO WIWOEJXBVFWBJO-UHFFFAOYSA-N 0.000 claims description 2
- GWKPDJYVHOUQAY-UHFFFAOYSA-N 3-[1-[[2-(3,5-dichlorophenyl)-6-[6-[4-(3-methylsulfonylpropyl)piperazin-1-yl]pyridin-3-yl]oxypyridin-4-yl]methyl]piperidin-4-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NC(=CC(=C1)CN1CCC(CC1)CCC(=O)O)OC=1C=NC(=CC=1)N1CCN(CC1)CCCS(=O)(=O)C GWKPDJYVHOUQAY-UHFFFAOYSA-N 0.000 claims description 2
- KZEVTBLQOMIVNT-UHFFFAOYSA-N 3-[1-[[3-(3,5-dichlorophenyl)-5-[2-[4-(2-hydroxyethyl)piperazin-1-yl]pyrimidin-5-yl]oxyphenyl]methyl]piperidin-4-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=C1)OC=1C=NC(=NC=1)N1CCN(CC1)CCO)CN1CCC(CC1)CCC(=O)O KZEVTBLQOMIVNT-UHFFFAOYSA-N 0.000 claims description 2
- FZABWKUTLZYFGR-UHFFFAOYSA-N 3-[3-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CC2CCC(C1)N2CCC(=O)O FZABWKUTLZYFGR-UHFFFAOYSA-N 0.000 claims description 2
- OCCYVWVAGIUREZ-UHFFFAOYSA-N 3-[3-[5-[6-(3,5-dichlorophenyl)-4-[[4-[(methoxycarbonylamino)methyl]piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CC2CCC(C1)N2CCC(=O)O)CN1CCC(CC1)CNC(=O)OC OCCYVWVAGIUREZ-UHFFFAOYSA-N 0.000 claims description 2
- RRLIAQQUJJPJTD-UHFFFAOYSA-N 3-[4-[5-[3-(3,5-dichlorophenyl)-5-[[4-[(methylcarbamoylamino)methyl]piperidin-1-yl]methyl]phenoxy]pyrimidin-2-yl]piperazin-1-yl]-2-methylpropanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=C1)CN1CCC(CC1)CNC(=O)NC)OC=1C=NC(=NC=1)N1CCN(CC1)CC(C(=O)O)C RRLIAQQUJJPJTD-UHFFFAOYSA-N 0.000 claims description 2
- INIFTEFZBYVVRK-UHFFFAOYSA-N 3-[4-[5-[3-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-5-(3,5-dichlorophenyl)phenoxy]pyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC=1C=C(C=C(C=1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(=O)O INIFTEFZBYVVRK-UHFFFAOYSA-N 0.000 claims description 2
- HGJQQOUZHCDZMX-UHFFFAOYSA-N 3-[4-[5-[3-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-5-(3,5-dichlorophenyl)phenoxy]pyrimidin-2-yl]piperazin-1-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC=1C=C(C=C(C=1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(=O)O HGJQQOUZHCDZMX-UHFFFAOYSA-N 0.000 claims description 2
- HAFOUJCBWUBLTN-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(2-amino-2-oxoethyl)piperazin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]propanoic acid Chemical compound NC(CN1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(=O)O)=O HAFOUJCBWUBLTN-UHFFFAOYSA-N 0.000 claims description 2
- PPZLCSSCMFXLEO-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(2-carbamoyloxyethyl)piperazin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound C(N)(=O)OCCN1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(=O)O PPZLCSSCMFXLEO-UHFFFAOYSA-N 0.000 claims description 2
- WYTHEEPLFPJTGI-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(2-carbamoyloxyethyl)piperazin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]propanoic acid Chemical compound C(N)(=O)OCCN1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(=O)O WYTHEEPLFPJTGI-UHFFFAOYSA-N 0.000 claims description 2
- IGISMSHVUOFFFA-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(3-amino-3-oxopropyl)piperazin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]propanoic acid Chemical compound NC(CCN1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(=O)O)=O IGISMSHVUOFFFA-UHFFFAOYSA-N 0.000 claims description 2
- GCSCMNUYGUOWFY-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxy-3-fluoropyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=C(C(=NC=1)N1CCN(CC1)CCC(=O)O)F GCSCMNUYGUOWFY-UHFFFAOYSA-N 0.000 claims description 2
- SOOLCUDZAZNWHC-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrazin-2-yl]piperazin-1-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1N=CC(=NC=1)N1CCN(CC1)CCC(=O)O SOOLCUDZAZNWHC-UHFFFAOYSA-N 0.000 claims description 2
- SQNPBLTTXRJFDR-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]-1,4-diazepan-1-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CCC1)CCC(=O)O SQNPBLTTXRJFDR-UHFFFAOYSA-N 0.000 claims description 2
- BXJGZCOEQLYXOK-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]-2,2-dimethylpiperazin-1-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CC(N(CC1)CCC(=O)O)(C)C BXJGZCOEQLYXOK-UHFFFAOYSA-N 0.000 claims description 2
- MYIOGWRORXATBZ-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]-2,2-dimethylpropanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)CC(C(=O)O)(C)C MYIOGWRORXATBZ-UHFFFAOYSA-N 0.000 claims description 2
- PGUCQMJFBJMXGX-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]butanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)C(CC(=O)O)C PGUCQMJFBJMXGX-UHFFFAOYSA-N 0.000 claims description 2
- NLQBEDHVGYRHAZ-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]-2-hydroxypropanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CC(C(=O)O)O NLQBEDHVGYRHAZ-UHFFFAOYSA-N 0.000 claims description 2
- ATBAQBLKRFTELF-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]-2-methylpropanamide Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CC(C(=O)N)C ATBAQBLKRFTELF-UHFFFAOYSA-N 0.000 claims description 2
- FJBKTIFXTBIKFY-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]-2-methylpropanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CC(C(=O)O)C FJBKTIFXTBIKFY-UHFFFAOYSA-N 0.000 claims description 2
- VYYLLVDEHPHISD-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]-N-methylpropanamide Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(=O)NC VYYLLVDEHPHISD-UHFFFAOYSA-N 0.000 claims description 2
- XBTFDELNNXKOQL-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]butanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)C(CC(=O)O)C XBTFDELNNXKOQL-UHFFFAOYSA-N 0.000 claims description 2
- OJEZMYXSGCZVCU-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]cyclobutane-1-carboxylic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)C1CC(C1)C(=O)O OJEZMYXSGCZVCU-UHFFFAOYSA-N 0.000 claims description 2
- UZCPNKCNMLNQDF-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3-bromo-5-fluorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)F)Br)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(=O)O UZCPNKCNMLNQDF-UHFFFAOYSA-N 0.000 claims description 2
- GTVPXSCDPKRMDA-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3-chloro-5-fluorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)F)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(=O)O GTVPXSCDPKRMDA-UHFFFAOYSA-N 0.000 claims description 2
- NQDSJNTVTYBYGV-UHFFFAOYSA-N 3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-[3-chloro-5-(difluoromethyl)phenyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)C(F)F)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(=O)O NQDSJNTVTYBYGV-UHFFFAOYSA-N 0.000 claims description 2
- BGXBDFVQPYZDLY-UHFFFAOYSA-N 3-[4-[5-[4-[[4-[(cyclopropanecarbonylamino)methyl]piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound C1(CC1)C(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(=O)O BGXBDFVQPYZDLY-UHFFFAOYSA-N 0.000 claims description 2
- SOUOUKOCSPXAGN-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-(methylaminomethyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(=O)O)CNC SOUOUKOCSPXAGN-UHFFFAOYSA-N 0.000 claims description 2
- ISLDIHMIPGDOMM-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-(2-methylsulfonylethyl)piperidin-1-yl]methyl]pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(=O)O)CN1CCC(CC1)CCS(=O)(=O)C ISLDIHMIPGDOMM-UHFFFAOYSA-N 0.000 claims description 2
- ZPFLLYVHVNYWKO-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-(2-sulfamoylethyl)piperidin-1-yl]methyl]pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(=O)O)CN1CCC(CC1)CCS(N)(=O)=O ZPFLLYVHVNYWKO-UHFFFAOYSA-N 0.000 claims description 2
- CUZGBMRVPFIDGG-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-(dimethylphosphorylmethyl)piperidin-1-yl]methyl]pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(=O)O)CN1CCC(CC1)CP(=O)(C)C CUZGBMRVPFIDGG-UHFFFAOYSA-N 0.000 claims description 2
- SYVGOKUTDSGVOF-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-(methylcarbamoyloxymethyl)piperidin-1-yl]methyl]pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(=O)O)CN1CCC(CC1)COC(NC)=O SYVGOKUTDSGVOF-UHFFFAOYSA-N 0.000 claims description 2
- QPHCUAVSHDYATD-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-(methylcarbamoyloxymethyl)piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]cyclobutane-1-carboxylic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)C1CC(C1)C(=O)O)CN1CCC(CC1)COC(NC)=O QPHCUAVSHDYATD-UHFFFAOYSA-N 0.000 claims description 2
- MKKBPROGCXUAMN-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-(methylcarbamoyloxymethyl)piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(=O)O)CN1CCC(CC1)COC(NC)=O MKKBPROGCXUAMN-UHFFFAOYSA-N 0.000 claims description 2
- MACKPBPMUDSERF-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-(methylsulfonylmethyl)piperidin-1-yl]methyl]pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(=O)O)CN1CCC(CC1)CS(=O)(=O)C MACKPBPMUDSERF-UHFFFAOYSA-N 0.000 claims description 2
- IZVBHOGCZSHVDH-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-(sulfamoylmethyl)piperidin-1-yl]methyl]pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(=O)O)CN1CCC(CC1)CS(N)(=O)=O IZVBHOGCZSHVDH-UHFFFAOYSA-N 0.000 claims description 2
- UZSRCCAUCAXPSD-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-[(ethoxycarbonylamino)methyl]piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(=O)O)CN1CCC(CC1)CNC(=O)OCC UZSRCCAUCAXPSD-UHFFFAOYSA-N 0.000 claims description 2
- NKTCQGNRVMEMDD-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-[(methoxycarbonylamino)methyl]piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(=O)O)CN1CCC(CC1)CNC(=O)OC NKTCQGNRVMEMDD-UHFFFAOYSA-N 0.000 claims description 2
- DQVSCMUKWLHSNX-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-[(methylcarbamoylamino)methyl]piperidin-1-yl]methyl]pyridin-2-yl]oxy-3-fluoropyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=C(C(=NC=1)N1CCN(CC1)CCC(=O)O)F)CN1CCC(CC1)CNC(=O)NC DQVSCMUKWLHSNX-UHFFFAOYSA-N 0.000 claims description 2
- XHGOUJUCYUYWRN-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-[(methylcarbamoylamino)methyl]piperidin-1-yl]methyl]pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(=O)O)CN1CCC(CC1)CNC(=O)NC XHGOUJUCYUYWRN-UHFFFAOYSA-N 0.000 claims description 2
- CYOIADMGZQAPHK-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-[(methylcarbamoylamino)methyl]piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]-2-methylpropanamide Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)CC(C(=O)N)C)CN1CCC(CC1)CNC(=O)NC CYOIADMGZQAPHK-UHFFFAOYSA-N 0.000 claims description 2
- WPYCEJOOFZXOJZ-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-[(methylcarbamoylamino)methyl]piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]cyclobutane-1-carboxylic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)C1CC(C1)C(=O)O)CN1CCC(CC1)CNC(=O)NC WPYCEJOOFZXOJZ-UHFFFAOYSA-N 0.000 claims description 2
- AMIIINFQRNFYAA-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-[(methylcarbamoylamino)methyl]piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(=O)O)CN1CCC(CC1)CNC(=O)NC AMIIINFQRNFYAA-UHFFFAOYSA-N 0.000 claims description 2
- VCNPPXARUSGRDF-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-[2-(ethylamino)-2-oxoethyl]piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(=O)O)CN1CCC(CC1)CC(=O)NCC VCNPPXARUSGRDF-UHFFFAOYSA-N 0.000 claims description 2
- ISOYIASXTSAFHJ-UHFFFAOYSA-N 3-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-fluoro-4-[(methoxycarbonylamino)methyl]piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]propanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(=O)O)CN1CCC(CC1)(CNC(=O)OC)F ISOYIASXTSAFHJ-UHFFFAOYSA-N 0.000 claims description 2
- ITPTZODFBKNBBO-UHFFFAOYSA-N 3-[4-[6-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridazin-3-yl]piperazin-1-yl]-2-methylpropanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC1=CC=C(N=N1)N1CCN(CC1)CC(C(=O)O)C ITPTZODFBKNBBO-UHFFFAOYSA-N 0.000 claims description 2
- RGHZSFBXQDAKFN-UHFFFAOYSA-N 3-[4-[6-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridazin-3-yl]piperazin-1-yl]propanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC1=CC=C(N=N1)N1CCN(CC1)CCC(=O)O RGHZSFBXQDAKFN-UHFFFAOYSA-N 0.000 claims description 2
- GYOSYUQTOXVNCP-UHFFFAOYSA-N 4-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)-3-fluoropyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]-2-methylbutanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=C(C(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(C(=O)O)C)F GYOSYUQTOXVNCP-UHFFFAOYSA-N 0.000 claims description 2
- CMJICMREVNDFAO-UHFFFAOYSA-N 4-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrazin-2-yl]piperazin-1-yl]-2-methylbutanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1N=CC(=NC=1)N1CCN(CC1)CCC(C(=O)O)C CMJICMREVNDFAO-UHFFFAOYSA-N 0.000 claims description 2
- BVVOGLXAECFGHV-UHFFFAOYSA-N 4-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]-2-ethylbutanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(C(=O)O)CC BVVOGLXAECFGHV-UHFFFAOYSA-N 0.000 claims description 2
- CSSLXMCVNNKBHV-UHFFFAOYSA-N 4-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]-2-methylbutanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)CCC(C(=O)O)C CSSLXMCVNNKBHV-UHFFFAOYSA-N 0.000 claims description 2
- DVOOTSMSNCPOFK-UHFFFAOYSA-N 4-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]-4-oxobutanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)C(CCC(=O)O)=O DVOOTSMSNCPOFK-UHFFFAOYSA-N 0.000 claims description 2
- JIULTJUKZWNUQG-UHFFFAOYSA-N 4-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyridin-2-yl]piperazin-1-yl]butanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=CC(=NC=1)N1CCN(CC1)CCCC(=O)O JIULTJUKZWNUQG-UHFFFAOYSA-N 0.000 claims description 2
- OAVQNRHRSBTVGG-UHFFFAOYSA-N 4-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]-2,2-dimethylbutanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(C(=O)O)(C)C OAVQNRHRSBTVGG-UHFFFAOYSA-N 0.000 claims description 2
- JLACYFGBVQGNHJ-UHFFFAOYSA-N 4-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-yl]methyl]-6-(3,5-dichlorophenyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]pentanoic acid Chemical compound C(C)(=O)NCC1CCN(CC1)CC1=CC(=NC(=C1)C1=CC(=CC(=C1)Cl)Cl)OC=1C=NC(=NC=1)N1CCN(CC1)C(CCC(=O)O)C JLACYFGBVQGNHJ-UHFFFAOYSA-N 0.000 claims description 2
- HPJBUIGUSYRIAI-UHFFFAOYSA-N 4-[4-[5-[6-(3,5-dichlorophenyl)-4-(pyrrolidin-1-ylmethyl)pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]-2-methylbutanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(C(=O)O)C)CN1CCCC1 HPJBUIGUSYRIAI-UHFFFAOYSA-N 0.000 claims description 2
- NUMDZCFGFDCLCT-UHFFFAOYSA-N 4-[4-[5-[6-(3,5-dichlorophenyl)-4-[(4-fluoropiperidin-1-yl)methyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]butan-2-ol Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(C)O)CN1CCC(CC1)F NUMDZCFGFDCLCT-UHFFFAOYSA-N 0.000 claims description 2
- WJNXGNTWORRSAZ-UHFFFAOYSA-N 4-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-(2-hydroxyethyl)piperidin-1-yl]methyl]pyridin-2-yl]oxypyrazin-2-yl]piperazin-1-yl]-2-methylbutanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1N=CC(=NC=1)N1CCN(CC1)CCC(C(=O)O)C)CN1CCC(CC1)CCO WJNXGNTWORRSAZ-UHFFFAOYSA-N 0.000 claims description 2
- HJHBNVSRWHXPGI-UHFFFAOYSA-N 4-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-(2-hydroxyethyl)piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]-2-methylbutanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(C(=O)O)C)CN1CCC(CC1)CCO HJHBNVSRWHXPGI-UHFFFAOYSA-N 0.000 claims description 2
- MABJBRSZIXNTOI-UHFFFAOYSA-N 4-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-(methylcarbamoyloxymethyl)piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]pentanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)C(CCC(=O)O)C)CN1CCC(CC1)COC(NC)=O MABJBRSZIXNTOI-UHFFFAOYSA-N 0.000 claims description 2
- IJBYETSSEQCWTD-UHFFFAOYSA-N 4-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-[(methoxycarbonylamino)methyl]piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]pentanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)C(CCC(=O)O)C)CN1CCC(CC1)CNC(=O)OC IJBYETSSEQCWTD-UHFFFAOYSA-N 0.000 claims description 2
- COPABGSOKALTJG-UHFFFAOYSA-N 4-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-[(propanoylamino)methyl]piperidin-1-yl]methyl]pyridin-2-yl]oxypyrazin-2-yl]piperazin-1-yl]-2-methylbutanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1N=CC(=NC=1)N1CCN(CC1)CCC(C(=O)O)C)CN1CCC(CC1)CNC(CC)=O COPABGSOKALTJG-UHFFFAOYSA-N 0.000 claims description 2
- SIWIJYQEDLRAFS-UHFFFAOYSA-N 4-[4-[5-[6-(3,5-dichlorophenyl)-4-[[4-[(propanoylamino)methyl]piperidin-1-yl]methyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-yl]-2-methylbutanoic acid Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=NC(=NC=1)N1CCN(CC1)CCC(C(=O)O)C)CN1CCC(CC1)CNC(CC)=O SIWIJYQEDLRAFS-UHFFFAOYSA-N 0.000 claims description 2
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- BDQWEDIAAYRWAD-UHFFFAOYSA-N tert-butyl 4-[5-[6-(3,5-dichlorophenyl)-4-methoxycarbonylpyridin-2-yl]oxy-3-fluoropyridin-2-yl]piperazine-1-carboxylate Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=CC(=CC(=N1)OC=1C=C(C(=NC=1)N1CCN(CC1)C(=O)OC(C)(C)C)F)C(=O)OC BDQWEDIAAYRWAD-UHFFFAOYSA-N 0.000 description 1
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- JYUQEWCJWDGCRX-UHFFFAOYSA-N tert-butyl 4-formylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C=O)CC1 JYUQEWCJWDGCRX-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
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- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
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- 230000009466 transformation Effects 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N trifluoromethanesulfonic anhydride Substances FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical class C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 1
- MHNHYTDAOYJUEZ-UHFFFAOYSA-N triphenylphosphane Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 MHNHYTDAOYJUEZ-UHFFFAOYSA-N 0.000 description 1
- 238000005533 tritiation Methods 0.000 description 1
- 239000002750 tryptase inhibitor Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000007919 viral pathogenicity Effects 0.000 description 1
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- 235000019165 vitamin E Nutrition 0.000 description 1
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- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
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- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 229960004764 zafirlukast Drugs 0.000 description 1
- MWLSOWXNZPKENC-UHFFFAOYSA-N zileuton Chemical compound C1=CC=C2SC(C(N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-UHFFFAOYSA-N 0.000 description 1
- 229940052267 zyflo Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Images
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Abstract
本发明涉及作为弗林蛋白酶抑制剂的新的根据式(I)的化合物,包含它们的药物组合物,它们的制备方法,以及它们在治疗纤维化疾病中的用途,包括肺纤维化、肾纤维化、肝纤维化、皮肤纤维化、眼纤维化、心脏纤维化和其它混杂纤维化病症。该公开的化合物也可用于治疗其它弗林蛋白酶‑介导的病症,包括但不限于,高血压、癌症、传染病和遗传疾病(例如,囊性纤维化病(CF))和神经退行性疾病。
Description
相关申请
本申请根据35 U.S.C.§119(e)要求2018年5月11日提交的美国临时申请U.S.S.N.62/670,050的优先权,其整个内容在此引入作为参考。
技术领域
本发明涉及抑制弗林蛋白酶(furin)的化合物,因此可用于治疗弗林蛋白酶介导的疾病,包括纤维化疾病。所公开的化合物还可用于治疗其他弗林蛋白酶介导的疾病,包括但不限于高血压、癌症、传染病、遗传疾病和神经退行性疾病。
背景技术
许多酶、受体和分泌的蛋白质的无活性前体蛋白需要加工和成熟以发挥其生物学功能(Thomas G.Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766)。前肽序列的溶蛋白性裂解取决于钙依赖性内切蛋白酶的前蛋白转化酶(PC)家族。该PC家族由以下丝氨酸蛋白酶组成:前蛋白转化酶枯草杆菌蛋白酶kexin 1(PCSK1)、PCSK2、弗林蛋白酶/PCSK3、PCSK4、PCSK5、PCSK6/配对的碱性氨基酸裂解酶4(PACE4)、PCSK7、PCSK8/枯草杆菌蛋白酶kexin同工酶1(SK-1)/膜结合转录因子肽酶位点1(MBTPS1)和PCSK9(ThomasG.Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766;Nakayama K.Biochem.J.1997,327(3),625-635;Klein-Szanto AJ,Bassi DE.Biochem.Pharmacol.2017,140,8-15;Turpeinen H,Ortutay Z,Pesu M.Curr.Genomics 2013,14(7),453-467)(https://www.genenames.org)。在这些PCSK中,弗林蛋白酶(PCSK3)被良好表征,并且是研究最广泛的具有多种生物学功能的家族成员。
弗林蛋白酶是一种794个氨基酸的1型跨膜蛋白,在许多细胞类型中普遍表达(Thomas G.Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766)。它由PCSK中常见的高度保守的结构域结构组成,包括N端信号肽、抑制性前结构域、催化肽酶S8/S53结构域、P结构域、富含半胱氨酸的区域和胞质结构域(Thomas G.Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766;Turpeinen H,Ortutay Z,Pesu M.Curr.Genomics 2013,14(7),453-467)。前结构域对于弗林蛋白酶的正确折叠、激活和运输是必不可少的,而P结构域通过调节pH/钙依赖性自蛋白水解裂解过程来调节催化结构域的酶活性(Thomas G.Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766;Turpeinen H,Ortutay Z,Pesu M.Curr.Genomics 2013,14(7),453-467)。最后,弗林蛋白酶的胞质结构域既可以有效地从质膜内化,又可以从质膜到高尔基体反面网络结构(trans-Golgi network)(TGN)的快速恢复(ThomasG.Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766)。
弗林蛋白酶主要定位在高尔基体反面网络结构(TGN)和内体系统中,在那里它在体内处理了其大多数不同的底物。弗林蛋白酶的内切蛋白酶活性不会因其前结构域片段的释放而被掩盖,从而使弗林蛋白酶可以反式功能性处理底物(ThomasG.Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766)。弗林蛋白酶切割的共有位点位于羧基末端精氨酸(Arg)残基之后,其是序列-Arg-X-Lys/Arg-Arg↓-(Lys是赖氨酸,X是任何氨基酸,↓表示切割位点)。基于该底物肽氨基酸基序,弗林蛋白酶具有>400个预测的目标蛋白质底物,包括激素、生长因子、酶、受体、神经肽和感染因子(Turpeinen H,Ortutay Z,PesuM.Curr.Genomics 2013,14(7),453-467;Shiryaev SA,Chernov AV,Golubkov VS,ThomsenER,Chudin E,Chee MS,等人PLoS One 2013,8(1),e54290)(https://www.ebi.ac.uk/merops)。弗林蛋白酶依赖性蛋白水解过程的生物学作用的重要性可以进一步通过敲除小鼠的各种研究的表型来例证。
种系弗林蛋白酶敲除小鼠研究证明弗林蛋白酶在胚胎发育中具有重要作用,在10.5到11.5天之间发生了胚胎致死。观察到腹腔闭合和轴向旋转失败,以及绒毛膜尿囊融合不存在。弗林蛋白酶敲低对内皮细胞的影响导致心血管缺陷,其包括中隔和瓣膜缺损,这可能归因于TGF-β的加工受损(Turpeinen H,Ortutay Z,Pesu M.Curr.Genomics 2013,14(7),453-467;Roebroek AJ,Umans L,Pauli IG,Robertson EJ,van Leuven F,Van de VenWJ,等人Development 1998,125(24),4863-4876;Seidah NG,Prat A.Nat.Rev.DrugDiscov.2012,11(5),367-383;Constam DB,Robertson EJ.Development 2000,127(2),245-254;Susan-Resiga D,Essalmani R,Hamelin J,Asselin MC,Benjannet S,Chamberland A,等人J.Biol.Chem.2011,286(26),22785-22794)。然而,敲除在成年小鼠肝脏中的弗林蛋白酶(诱导型Mx1-Cre转基因)并不是致命的,并且裂解了弗林蛋白酶的典型底物,尽管效率较低,但这表明PCSK之间可能存在冗余(Klein-Szanto AJ,BassiDE.Biochem.Pharmacol.2017,140,8-15;Roebroek AJ,Taylor NA,Louagie E,Pauli I,Smeijers L,Snellinx A,等人J.Biol.Chem.2004,279(51),53442-53450)。此外,由于缺陷性TGFβ1信号传导,T细胞中弗林蛋白酶的靶向缺失导致调节性T细胞和效应T细胞功能受损(Pesu M,Watford WT,Wei L,Xu L,Fuss I,Strober W,等人Nature2008,455(7210),246-250)。这些观察暗示弗林蛋白酶在TGFβ生物学中的作用以及弗林蛋白酶抑制剂对TGFβ依赖性疾病的潜在治疗用途。
器官纤维化是伤口愈合反应异常的结果,导致胶原蛋白沉积过多。结缔组织疤痕导致组织功能逐渐丧失并最终导致器官衰竭(Nanthakumar CB,Hatley RJ,Lemma S,Gauldie J,Marshall RP,Macdonald SJ.Nat.Rev.Drug Discov.2015,14(10),693-720)。TGFβ家族成员在纤维化中起关键作用(Dubois CM,Blanchette F,Laprise MH,Leduc R,Grondin F,Seidah NG.Am.J.Pathol.2001,158(1),305-316),且TGFβ1在心脏、肺和肾等纤维化器官中的升高(Pohlers D,Brenmoehl J,I,Müller CK,Leipner C,Schultze-Mosgau S,等人Biochimica et Biophysica Acta(BBA)-Molecular Basis of Disease2009,1792(8),746-756;Thomas BJ,Kan OK,Loveland KL,Elias JA,Bardin PG.Am.J.Respir.Cell.Mol.Biol.2016,55(6),759-766)。大多数细胞将Pre-pro-TGFβ1合成为单个390个氨基酸的肽段。弗林蛋白酶依赖性加工事件预计在紧随生长因子的NH2-末端Ala 279残基之前的Arg-His-Arg-Arg序列之后发生(Constam DB.Seminars in Cell&DevelopmentalBiology2014,32,85-97)。成熟的TGFβ形成25KDa二聚体,在分泌到细胞外基质中之前,它与具体结合蛋白(例如TGFβ潜在相关肽(LAP)(前体序列的NH2末端部分)和大的潜在结合蛋白(LTBP))复合(Constam DB.Seminars in Cell&Developmental Biology 2014,32,85-97;Robertson IB,Horiguchi M,Zilberberg L,Dabovic B,Hadjiolova K,Rifkin DB.Matrixbiology,Journal of the International Society for Matrix Biology 2015,47,44-53)。活性成熟的TGFβ1必须先从潜在复合物中释放出来,然后才能发挥其生物学作用。TGFβ的生物学效应是通过典型的SMAD依赖性信号传导和受体激活后涉及PI3K/ATK、Erk和p38的非典型途径介导的(Zhang YE.Cell Research 2009,19(1),128-139)。TGFβ1通过促进正常上皮细胞向活性成纤维细胞的转化以及随后胶原蛋白的合成和沉积来驱动纤维化反应(Biernacka A,Dobaczewski M,Frangogiannis NG.Growth Factors(Chur,Switzerland)2011,29(5),196-202)。因此,使用弗林蛋白酶抑制剂的治疗干预将阻止Pre-pro-TGFβ1的正常加工,因此通过减少纤维化疾病中的生物活性TGFβ可以提供益处。
鉴于其底物的多样性,弗林蛋白酶的治疗干预也可能有益于诸如高血压、癌症、传染病、呼吸道疾病和神经退行性疾病等疾病(Thomas G.Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766;Nakayama K.Biochem.J.1997,327(3),625-635;Shiryaev SA,Chernov AV,Golubkov VS,Thomsen ER,Chudin E,Chee MS,等人PLoS One2013,8(1),e54290;BennettBD,Denis P,Haniu M,Teplow DB,Kahn S,Louis JC,等人J.Biol.Chem.2000,275(48),37712-37717;Takahashi RH,Nagao T,Gouras GK.Pathology International 2017,67(4),185-193)。高血压是血液对动脉壁施加增加的力量的病症。肾素-血管紧张素系统和调节钠电解质平衡的分子会影响血压并与弗林蛋白酶活性有关(Turpeinen H,Ortutay Z,Pesu M.Curr.Genomics 2013,14(7),453-467;Cousin C,Bracquart D,Contrepas A,Corvol P,Muller L,Nguyen G.Hypertension 2009,53(6),1077-1082)。最近的两项大规模遗传协会研究(GWAS)表明弗林蛋白酶遗传学是高血压的危险因素。一项研究利用GWAS方法研究了超过200,000名欧洲人后裔,从而确定了与收缩压和舒张压升高相关的Furin-FES基因座中的单核苷酸多态性(SNP;rs2521501)(Ehret GB,Munroe PB,Rice KM,Bochud M,Johnson AD,等人Nature2011,478(7367),103-109)。在第二项多中心研究中发现了另外两个弗林蛋白酶多形性(rs2071410和rs6227),其分别与收缩压和舒张压相关,该研究对2100种候选基因中的50,000种SNP进行了基因分型(Turpeinen H,Ortutay Z,PesuM.Curr.Genomics 2013,14(7),453-467;Ganesh SK,Tragante V,Guo W,Guo Y,LanktreeMB,Smith EN,等人Hum.Mol.Genet.2013,22(8),1663-1678)。有了如此强大的人类遗传学证据,弗林蛋白酶活性的调节可能是高血压的治疗方法。
癌症是一组涉及异常、不受控制的细胞生长的疾病,其可能扩散到身体的其他部位(转移)。有些弗林蛋白酶底物与癌症进展相关的各种过程有关,例如增殖、抗凋亡、迁移/侵袭、转移和血管生成。在这些过程中弗林蛋白酶靶向的底物是生长因子及其受体、基质金属蛋白酶、细胞粘附分子和血管生成/淋巴管生成因子(Shiryaev SA,Chernov AV,Golubkov VS,Thomsen ER,Chudin E,Chee MS,等人PLoS One2013,8(1),e54290;Jaaks P,Bernasconi M.Int.J.Cancer2017,141(4),654-663;Bassi DE,Mahloogi H,Al-Saleem L,Lopez De Cicco R,Ridge JA,Klein-Szanto AJ.Mol.Carcinog.2001,31(4),224-232)。许多生长因子及其受体对于凋亡和生存机制之间的平衡很重要。因此,生长因子的失调在癌症的发展中起作用。除了不受控制的生长之外,胞外基质(ECM)降解对于癌细胞逃脱主要部位也是必需的。同样,ECM重塑是转移小生境的发展所必需的,使癌细胞能够在转移部位生存、定居和增殖(Bonnans C,Chou J,Werb Z.Nat.Rev.Mol.Cell.Biol.2014,15(12),786-801)。介导ECM降解的许多此类酶(如MMP和ADAM蛋白酶)需要通过弗林蛋白酶进行蛋白水解激活(Maquoi E,Noel A,Frankenne F,Angliker H,Murphy G,Foidart JM.FEBSLett.1998,424(3),262-266;Yana I,Weiss SJ.Mol.Biol.Cell2000,11(7),2387-2401;Kang T,Nagase H,Pei D.Cancer Res.2002,62(3),675-681;Wang X,PeiD.J.Biol.Chem.2001,276(38),35953-35960;Loechel F,Gilpin BJ,Engvall E,Albrechtsen R,Wewer UM.J.Biol.Chem.1998,273(27),16993-16997;Schlondorff J,Becherer JD,Blobel CP.Biochem.J.2000,347(1),131-138)。最后,血管生成是血管形成的过程,其支持肿瘤的生长。弗林蛋白酶处理血管内皮生长因子VEGF-C和VEGF-D,使其能够促进VEGF信号传导,从而刺激血管生成和淋巴管生成(Joukov V,Sorsa T,Kumar V,Jeltsch M,Claesson-Welsh L,Cao Y,等人EMBO J.1997,16(13),3898-3911;McColl BK,Paavonen K,Karnezis T,Harris NC,Davydova N,Rothacker J,等人FASEB J.2007,21(4),1088-1098)。因此,弗林蛋白酶活性的治疗性干预将通过阻断促进癌细胞生长和扩散的多个关键生物学过程来限制癌细胞的生长。
传染病可能从一个人传播到另一个人,并且是由诸如细菌、病毒、寄生虫或真菌等病原微生物引起的。致病性是微生物剂引起疾病的能力,毒力是生物致病的程度。为了使病毒进入宿主细胞并复制,包膜糖蛋白必须被蛋白水解激活(Nakayama K.Biochem.J.1997,327(3),625-635)。包膜糖蛋白的加工在某些情况下可能影响病毒致病性(NakayamaK.Biochem.J.1997,327(3),625-635)。许多强毒病毒(如人类免疫缺陷病毒(HIV),禽流感病毒,麻疹病毒,呼吸道合胞病毒(RSV),埃博拉病毒,炭疽和寨卡病毒(ZIKV))的糖蛋白前体在与弗林蛋白酶识别一致的共有序列标记的位点被裂解(ThomasG.Nat.Rev.Mol.Cell.Biol.2002,3(10),753-766;2,36-38)。当弗林蛋白酶抑制剂α1-PDX在细胞中表达时,HIV糖蛋白160的切割和感染性病毒的产生被阻断(NakayamaK.Biochem.J.1997,327(3),625-635)。因此可以想到在大流行情况或生物战中弗林蛋白酶抑制剂的治疗用途。
囊性纤维化病(CF)是欧洲和北美常见的限制生命的常染色体隐性遗传疾病(Hoffman LR,Ramsey BW.CHEST 2013,143(1),207-213)。一层薄薄的流体在肺部的呼吸道中流动,促进了粘膜纤毛清除,其通过去除吸入的病原体,有助于先天免疫防御。氯和钠通过气道上皮的运输调节了这种流体的体积。由于缺乏囊性纤维化病跨膜传导调节剂(CFTR),该调节在囊性纤维化病中消失了,该调节剂介导氯分泌以及随后的钠再吸收和跨上皮的流体平衡。上皮钠通道(ENaC)的过度吸收是开始CF病理生理的液体层消耗的一个促成因素。通道活化蛋白酶(CAPs)(例如弗林蛋白酶)催化ENaC的内切蛋白酶解,并增加钠通道电导,否则该钠通道电导将保持较低水平(Reihill JA,Walker B,Hamilton RA,Ferguson TE,Elborn JS,Stutts MJ,等人Am.J.Respir.Crit.Care Med.2016,194(6),701-710;Myerburg MM,Harvey PR,Heidrich EM,Pilewski JM,Butterworth MB.Am.J.Respir.Cell.Mol.Biol.2010,43(6),712-719)。弗林蛋白酶抑制剂可有效阻断钠的再吸收(Reihill JA,Walker B,Hamilton RA,Ferguson TE,Elborn JS,Stutts MJ,等人Am.J.Respir.Crit.Care Med.2016,194(6),701-710),因此提供了弗林蛋白酶抑制剂治疗CF的潜在用途的概念证据。
阿尔茨海默氏病(AD)是一种进行性、多因素和异质性神经退行性疾病,可导致进行性认知功能减退。大脑中含有淀粉样β(Aβ)的斑块和由高磷酸化tau组成的神经元纤维缠结是AD的神经病理学标志(Takahashi RH,Nagao T,Gouras GK.Pathology International2017,67(4),185-193;Rangachari V,Dean DN,Rana P,Vaidya A,Ghosh P.Biochimica etBiophysica Acta(BBA)-Biomembranes 2018,https://doi.org/10.1016/j.bbamem.2018.03.004;Crews L,Masliah E.Human Molecular Genetics 2010,19(R1),R12-R20)。淀粉样蛋白前体蛋白(APP)是包含单个跨膜结构域的完整膜蛋白(TakahashiRH,Nagao T,Gouras GK.Pathology International 2017,67(4),185-193;Rangachari V,Dean DN,Rana P,Vaidya A,Ghosh P.Biochimica et Biophysica Acta(BBA)-Biomembranes 2018,https://doi.org/10.1016/j.bbamem.2018.03.004)。淀粉样蛋白肽可以通过天冬氨酰蛋白酶β-(BACE)和γ-分泌酶对APP的顺序切割而形成(Takahashi RH,Nagao T,Gouras GK.Pathology International 2017,67(4),185-193;Rangachari V,Dean DN,Rana P,Vaidya A,Ghosh P.Biochimica et Biophysica Acta(BBA)-Biomembranes 2018,https://doi.org/10.1016/j.bbamem.2018.03.004;Fiala JC.ActaNeuropathologica 2007,114(6),551-571)。APP的溶蛋白性裂解产生Aβ1-42单体,其在病理条件下可组装成潜在有毒的低聚物和斑块形式(Takahashi RH,Nagao T,GourasGK.Pathology International 2017,67(4),185-193;Rangachari V,Dean DN,Rana P,Vaidya A,Ghosh P.Biochimica et Biophysica Acta(BBA)-Biomembranes 2018,https://doi.org/10.1016/j.bbamem.2018.03.004;Fiala JC.Acta Neuropathologica2007,114(6),551-571)。提示淀粉样蛋白沉积是由分泌Aβ的神经胶质引起的。该蛋白质自发聚集为激活小胶质细胞的淀粉样蛋白丝。然后活化的小胶质细胞分泌导致轴突营养不良和细胞死亡的氧化物质和炎性细胞因子(Rangachari V,Dean DN,Rana P,Vaidya A,GhoshP.Biochimica et Biophysica Acta(BBA)-Biomembranes 2018,https://doi.org/10.1016/j.bbamem.2018.03.004;Crews L,Masliah E.Human Molecular Genetics 2010,19(R1),R12-R20;Fiala JC.Acta Neuropathologica 2007,114(6),551-571)。APP和早老素(γ-分泌酶复合物的组成部分)的突变,导致分泌酶改变APP的加工过程,并增加促噬斑形成性Aβ肽的产生(Dai MH,Zheng H,Zeng LD,Zhang Y.Oncotarget 2018,9(19),15132-15143),表明分泌酶在疾病进展中的重要性。因此,APP加工的药理学调节一直是治疗AD的重要策略,最近的临床试验评估了BACE和γ-分泌酶抑制剂(Panza F,Seripa D,SolfrizziV,Imbimbo BP,Lozupone M,Leo A,等人Expert Opinion on Emerging Drugs 2016,21(4),377-391)。BACE前肽共享弗林蛋白酶的共有序列,并且显示BACE前肽的加工取决于活性弗林蛋白酶(Bennett BD,Denis P,Haniu M,Teplow DB,Kahn S,Louis JC,等人J.Biol.Chem.2000,275(48),37712-37717)。因此,选择性弗林蛋白酶抑制剂可潜在地用于治疗与弗林蛋白酶加工失调有关的AD和神经退行性疾病。
已知的弗林蛋白酶抑制剂本质上是肽类的并且衍生自天然底物基序序列,或者被设计为具有赖氨酸和精氨酸侧链的拟肽化合物,从而能够与弗林蛋白酶高亲和力结合。通过掺入反应性氯甲基酮(CMK)部分来鉴定有效的肽类弗林蛋白酶抑制剂(WO 2009/023306A2;Garten W,Hallenberger S,Ortmann D,Schafer W,Vey M,Angliker H,等人Biochimie 1994,76(3-4),217-225)。这种非选择性的CMK肽(癸酰基-Arg-Val-Lys-Arg-CMK)在催化的Ser368残基处与弗林蛋白酶的活性位点接合,形成四面体半缩酮,其不可逆地烷基化His194残基。卤代甲基酮的这种众所周知的不可逆的蛋白酶抑制机制提供了非常高且持久的效力,但是也可以解释非选择性蛋白酶的抑制作用,尤其是针对其他PCSK家族成员的抑制作用。已发现弗林蛋白酶抑制剂可保护巨噬细胞免于炭疽的处理(WO 2013/138666A1)并恢复CF细胞中的流体平衡(Reihill JA,Walker B,Hamilton RA,FergusonTE,Elborn JS,Stutts MJ,等人Am.J.Respir.Crit.Care Med.2016,194(6),701-710)。药理学上弗林蛋白酶抑制的另一种策略是使用天然存在的α-1-抗胰蛋白酶血清蛋白酶抑制剂α1-PDX的工程化变异体。α1-PDX是一种丝氨酸蛋白酶抑制剂超家族宽蛋白酶抑制剂,对弗林蛋白酶和PCSK 5/6具有高特异性,Ki值低至600 pM(Couture F,Kwiatkowska A,DoryYL,Day R.Expert Opinion on Therapeutic Patents2015,25(4),379-396)。α1-PDX通过与催化性丝氨酸形成四面体加合物与弗林蛋白酶形成抗SDS的复合物。将表达α1-PDX或弗林蛋白酶前片段(prosegment)(作为前蛋白抑制剂)的癌细胞注入免疫功能低下的小鼠中,从而导致多种肿瘤和转移瘤的数量减少。
迄今为止,据报道弗林蛋白酶的有效抑制剂是含有多元残基的肽衍生物或拟肽,以实现高抑制力。由于抑制剂的高碱性、反应性和肽结构,其化学和药代动力学特性限制了其作为临床治疗剂的用途。弗林蛋白酶在健康和高度未满足医疗需求的疾病中扮演着多种生物学角色。因此,期望具有药物样性质的有效且选择性的小分子弗林蛋白酶抑制剂作为在许多疾病如器官纤维化、高血压、癌症、感染性疾病、神经退行性疾病和CF中提供治疗益处的有吸引力的方法。本发明描述了新型弗林蛋白酶抑制剂的结构和生物学特性。
发明内容
本发明涉及根据式(I)的化合物或其药学上可接受的盐:
其中:
A1、A2、A3、A4、A5和A6各自独立地为N、CH或CR6;
X为O或NR8;
R1和R2各自独立地为氢、(C1-C4)烷基或H2N(C1-C4)烷基-;
或R1和R2与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的独立选自氧、氮和硫的杂原子,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、-OCONR8R9、-CO2R8、-C(O)CO2R8、R7、-OR7、-NHR8、-NR7R8、-C(O)R7、-CONHR8、-CONR7R8和-SO2R7;
各个R3独立地选自卤素、甲基、氟甲基、二氟甲基和三氟甲基;
R4和R5各自独立地为氢、(C1-C4)烷基或(C1-C4)烷氧基(C2-C4)烷基-;
或R4和R5与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的独立选自氧、氮和硫的杂原子,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、-OCONR8R9、-CO2R8、-C(O)CO2R8、-SO2(C1-C4)烷基、R7、-OR7、-NHR8、-NR7R8、-N(R8)C(O)R9、-N(R8)SO2R9、-N(R8)CONR8R9、-N(R8)CON(R8)SO2R9、-C(O)R7、-CONHR8、-CONR7R8和-P(O)R8R9;
各个R6独立地选自卤素、(C1-C4)烷基、卤代(C1-C4)烷基、羟基和(C1-C4)烷氧基;
各个R7独立地选自(C1-C6)烷基、(C2-C6)烯基、卤代(C1-C6)烷基、(C3-C6)环烷基和(C3-C6)环烷基(C1-C4)烷基-,其各自任选取代有1或2个独立选自以下的取代基:三唑基、四唑基、-CO2R8、-CONR8R9、-CON(R8)CO2(C1-C4)烷基、羟基、氧代、(C1-C4)烷氧基、-OCONR8R9、-OCON(R8)C(O)R9、(C1-C4)烷基、HO(C1-C4)烷基-、-NR8R9、-N(O)R8R9、-N(R8)C(O)R9、-N(R8)CO2(C1-C4)烷基、-N(R8)CH2CO2R9、-N(R8)CONR8R9、-N(R8)CON(R8)C(O)R9、-N(R8)CON(R8)CO2(C1-C4)烷基、-N(R8)SO2R9、-N(R8)CON(R8)SO2R9、-SO(C1-C4)烷基、-SO2(C1-C4)烷基、-SO3R8、-SO2NR8R9、-B(OH)2、-P(O)R8R9和-P(O)(OR8)(OR9);
各个R8和R9独立地为氢、(C1-C4)烷基或(C3-C6)环烷基;且
n为1、2、3或4;
或其药学上可接受的盐。
本发明另一方面涉及包含式(I)的化合物和药学上可接受的赋形剂的药物组合物。
在另一方面,提供了式(I)的化合物或其药学上可接受的盐或溶剂合物在制备用于治疗弗林蛋白酶介导的疾病如纤维化疾病的药物中的用途。
在另一方面,本发明提供式(I)的化合物或其药学上可接受的盐,其用于治疗弗林蛋白酶介导的疾病。本发明进一步提供式(I)的化合物或其药学上可接受的盐作为活性治疗物质,用于治疗弗林蛋白酶介导的疾病。
在另一方面,本发明提供式(I)的化合物或其药学上可接受的盐,其用于治疗。
在另一方面,本发明提供式(I)的化合物或其药学上可接受的盐,其用于治疗纤维化疾病。
在另一方面,本发明提供共同给药本发明的式(I)的化合物与其它活性成分的方法。
本发明另一方面涉及包含式(I-a)的化合物和药学上可接受的赋形剂的药物组合物。
在另一方面,提供了式(I-a)的化合物或其药学上可接受的盐或溶剂合物在制备用于治疗弗林蛋白酶介导的疾病如纤维化疾病的药物中的用途。
在另一方面,本发明提供式(I-a)的化合物或其药学上可接受的盐,其用于治疗弗林蛋白酶介导的疾病。本发明进一步提供式(I-a)的化合物或其药学上可接受的盐作为活性治疗物质,用于治疗弗林蛋白酶介导的疾病。
在另一方面,本发明提供式(I-a)的化合物或其药学上可接受的盐,其用于治疗。
在另一方面,本发明提供式(I-a)的化合物或其药学上可接受的盐,其用于治疗纤维化疾病。
在另一方面,本发明提供共同给药本发明的式(I-a)的化合物与其它活性成分的方法。
附图简述
图1描绘了具有极化的CF或非CF人支气管上皮的跨上皮细胞电阻(transepithelial electrical resistance)(TEER)测定。
图2描绘了当上皮钠通道活跃时的TEER测定。
图3描绘了当上皮钠通道关闭(抑制)时的TEER测定。
图4描绘了当上皮钠通道活跃时在TEER测定中用于流体吸收的渗透驱动力。
图5描绘了当上皮钠通道关闭时在TEER测定中没有用于流体吸收的渗透驱动力。
图6显示了使用实施例11用极化的CF人支气管上皮细胞(CF delF508)的TEER测定的结果。
图7显示了使用极化的CF人支气管上皮细胞(CF delF508)的TEER测定的结果,将实施例11与卡莫司他和抑肽酶进行了比较。
图8显示了使用抑肽酶用极化的CF人支气管上皮细胞(CF delF508)的TEER测定的结果。
图9显示了使用卡莫司他用极化的CF人支气管上皮细胞(CF delF508)的TEER测定的结果。
图10显示了使用DMSO(对照)用极化的CF人支气管上皮细胞(CF delF508)的流体转运测定的结果。
图11显示了使用实施例11用极化的CF人支气管上皮细胞(CF delF508)的流体转运测定的结果。
图12显示了使用抑肽酶用极化的CF人支气管上皮细胞(CF delF508)的流体转运测定的结果。
图13显示了使用卡莫司他用极化的CF人支气管上皮细胞(CF delF508)的流体转运测定的结果。
图14显示了对照(DMSO)、实施例11、卡莫司他和抑肽酶之间的流体损失的结果。
图15显示了对照(DMSO)、实施例11、卡莫司他和抑肽酶之间的流体损失的结果。
图16显示了对照(DMSO)、实施例11、卡莫司他和抑肽酶之间的流体损失和滞留的培养基水平。
发明详述
本发明涉及如上定义的式(I)的化合物或其药学上可接受的盐。
本发明还涉及式(I-a)的化合物或其药学上可接受的盐:
其中:
A1、A2、A3、A4、A5、A6和A7各自独立地为N、CH或CR6;
X为O或NR8;
R1和R2各自独立地为氢、(C1-C4)烷基或H2N(C1-C4)烷基-;
或R1和R2与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的独立选自氧、氮和硫的杂原子,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、-OCONR8R9、-CO2R8、-C(O)CO2R8、R7、-OR7、-NHR8、-NR7R8、-C(O)R7、-CONHR8、-CONR7R8、和-SO2R7;
各个R3独立地选自卤素、甲基、氟甲基、二氟甲基和三氟甲基;
R4和R5各自独立地为氢、(C1-C4)烷基或(C1-C4)烷氧基(C2-C4)烷基-;
或R4和R5与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的独立选自氧、氮和硫的杂原子,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、-OCONR8R9、-CO2R8、-C(O)CO2R8、-SO2(C1-C4)烷基、R7、-OR7、-NHR8、-NR7R8、-N(R8)C(O)R9、-N(R8)SO2R9、-N(R8)CONR8R9、-N(R8)CON(R8)SO2R9、-C(O)R7、-CONHR8、-CONR7R8和-P(O)R8R9;
各个R6独立地选自卤素、(C1-C4)烷基、卤代(C1-C4)烷基、羟基和(C1-C4)烷氧基;
各个R7独立地选自(C1-C6)烷基、(C2-C6)烯基、卤代(C1-C6)烷基、(C3-C6)环烷基和(C3-C6)环烷基(C1-C4)烷基-,其各自任选取代有1或2个独立选自以下的取代基:三唑基、四唑基、-CO2R8、-CONR8R9、-CON(R8)CO2(C1-C4)烷基、羟基、氧代、(C1-C4)烷氧基、-OCONR8R9、-OCON(R8)C(O)R9、(C1-C4)烷基、HO(C1-C4)烷基-、-NR8R9、-N(O)R8R9、-N(R8)C(O)R9、-N(R8)CO2(C1-C4)烷基、-N(R8)CH2CO2R9、-N(R8)CONR8R9、-N(R8)CON(R8)C(O)R9、-N(R8)CON(R8)CO2(C1-C4)烷基、-N(R8)SO2R9、-N(R8)CON(R8)SO2R9、-SO(C1-C4)烷基、-SO2(C1-C4)烷基、-SO3R8、-SO2NR8R9、-B(OH)2、-P(O)R8R9和-P(O)(OR8)(OR9);
各个R8和R9独立地为氢、(C1-C4)烷基或(C3-C6)环烷基;且
n为1、2、3或4。
本发明还涉及式(II)的化合物或其药学上可接受的盐:
其中:
A1、A2、A3、A4和A5各自独立地为N或CH,其中A1、A2、A3、A4和A5中的一个、两个或三个为N;
X1和X2各自独立地为NR10或C(R11)R12;
R1a、R1b、R1c和R2a各自独立地为氢、氟、(C1-C4)烷基、HO(C1-C4)烷基-、羟基或-CONR8R9,其中R1a、R1b、R1c和R2a中至少两个为氢;
或X1为NR10,R1a和R2a一起表示-CH2-或-(CH2)2-,且R1b和R1c各自为氢;
或X1为NR10,R1c和R2a一起表示-CH2-或-(CH2)2-,且R1a和R1b各自为氢;
或X1为NR10,R1c和R10一起表示-CH2-或-(CH2)2-,且R1a、R1b和R2a各自为氢;
或X1为NR10,R1a和R1b与它们连接的碳原子一起表示(C3-C6)环烷基,且R1c和R2a各自为氢;
各个R3独立地选自氟、氯、甲基、氟甲基、二氟甲基和三氟甲基;
R6a为氢、氟、氯或甲基;
各个R7独立地选自(C1-C4)烷基、(C2-C4)烯基、卤代(C1-C4)烷基、(C3-C6)环烷基和(C3-C6)环烷基(C1-C2)烷基-,其各自任选取代有1或2个独立选自以下的取代基:-CO2R8、-CONR8R9、羟基、氧代、(C1-C4)烷氧基、-OCONR8R9、HO(C1-C4)烷基-、-NR8R9、-N(R8)C(O)R9、-N(R8)CO2(C1-C4)烷基、-N(R8)CH2CO2R9、-N(R8)CONR8R9、-N(R8)SO2R9、-SO(C1-C4)烷基、-SO2(C1-C4)烷基、-SO3R8、-SO2NR8R9和-P(O)(OR8)(OR9);
各个R8和R9独立地为氢或(C1-C4)烷基;
各个R10独立地选自氢、R7、-C(O)R7、-CONHR8、-CONR7R8、-C(O)CO2R8和-SO2R7;
各个R11独立地选自氢、-OR7、-NHR8、-NR7R8和R7;
各个R12独立地选自氢、卤素、羟基、-CO2R8、-CONHR8和-CONR8R9,其中当R12为羟基时,R11为氢或R7;
m为1或2;且
n为1、2或3。
本发明进一步涉及式(III)的化合物或其药学上可接受的盐:
其中:
A1、A2和A3各自独立地为N或CH,其中A1、A2和A3中的一个或两个为N;
X2a为NR10b或C(R11a)R12a;
R1c为氢;
R3a和R3b各自独立地为氟或氯;
R6a为氢、氟、氯或甲基;
R10a为氢、(C1-C4)烷基或(C3-C6)环烷基,其中所述(C1-C4)烷基或(C3-C6)环烷基任选取代有-CO2H、-CONH2、-CONH(C1-C4)烷基、-CON((C1-C4)烷基)((C1-C4)烷基)、羟基、(C1-C4)烷氧基、-SO2(C1-C4)烷基或-SO2NH2;
或R1c和R10a一起表示-CH2-或-(CH2)2-;
R10b为(C1-C4)烷基,其任选取代有-CONH2、-CONH(C1-C4)烷基或-CON((C1-C4)烷基)((C1-C4)烷基);
R11a为(C1-C4)烷基或(C1-C4)烷氧基,其各自任选取代有1或2个独立选自以下的取代基:-CO2H、-CONH2、-CONH(C1-C4)烷基、-CON((C1-C4)烷基)((C1-C4)烷基)、羟基、-OCONH(C1-C4)烷基、-NHCO(C1-C4)烷基、-NHCO2(C1-C4)烷基和-NHCONH(C1-C4)烷基;
R12a为氢、羟基或氟,其中当R12a为羟基时,R11a为(C1-C4)烷基,其任选取代有1或2个独立选自以下的取代基:-CO2H、-CONH2、-CONH(C1-C4)烷基、-CON((C1-C4)烷基)((C1-C4)烷基)、羟基、-OCONH(C1-C4)烷基、-NHCO(C1-C4)烷基、-NHCO2(C1-C4)烷基和-NHCONH(C1-C4)烷基;且
m为1或2。
本发明进一步涉及式(IV)的化合物或其药学上可接受的盐:
其中:
A2和A3各自独立地为N或CH,其中A2或A3至少之一为N;
R3a和R3b各自独立地为氟或氯;
R10a为氢、(C1-C4)烷基或(C3-C6)环烷基,其中所述(C1-C4)烷基或(C3-C6)环烷基任选取代有-CO2H、-CONH2、-CONH(C1-C4)烷基、-CON((C1-C4)烷基)((C1-C4)烷基)、羟基、(C1-C4)烷氧基、-SO2(C1-C4)烷基或-SO2NH2;
R11a为(C1-C4)烷基或(C1-C4)烷氧基,其各自任选取代有1或2个独立选自以下的取代基:-CO2H、-CONH2、-CONH(C1-C4)烷基、-CON((C1-C4)烷基)((C1-C4)烷基)、羟基、-OCONH(C1-C4)烷基、-NHCO(C1-C4)烷基、-NHCO2(C1-C4)烷基和-NHCONH(C1-C4)烷基;且
R12a为氢、羟基或氟,其中当R12a为羟基时,R11a为(C1-C4)烷基,其任选取代有1或2个独立选自以下的取代基:-CO2H、-CONH2、-CONH(C1-C4)烷基、-CON((C1-C4)烷基)((C1-C4)烷基)、羟基、-OCONH(C1-C4)烷基、-NHCO(C1-C4)烷基、-NHCO2(C1-C4)烷基和-NHCONH(C1-C4)烷基。
在一个实施方案中,A1、A2、A3、A4、A5、A6和A7各自独立地为N、CH或CR6,其中A1、A2、A3、A4、A5、A6和A7中的0、1、2或3个为N。在另一实施方案中,A1、A2、A3、A4、A5、A6和A7各自独立地为N、CH或CR6,其中A1、A2、A3、A4、A5、A6和A7中的两个或三个为N。在一个实施方案中,A1、A2、A3、A4、A5和A6各自独立地为N、CH或CR6,其中A1、A2、A3、A4、A5和A6中的0、1、2或3个为N。在另一实施方案中,A1、A2、A3、A4、A5和A6各自独立地为N、CH或CR6,其中A1、A2、A3、A4、A5和A6中的两个或三个为N。在另一实施方案中,A1、A2、A3、A4和A5各自独立地为N或CH,其中A1、A2、A3、A4和A5中的两个或三个为N。在另一实施方案中,A1、A2、A3、A4和A5各自独立地为N或CH,其中A1、A2、A3、A4和A5中的三个为N。在另一实施方案中,A1、A2、A3、A4和A5各自独立地为N或CH,其中A1、A2、A3、A4和A5中的两个为N。在另一实施方案中,A1、A2和A3各自独立地为N或CH,其中A1、A2和A3中的两个为N。在另一实施方案中,A1、A2和A3各自独立地为N或CH,其中A1、A2和A3中的一个为N。在另一实施方案中,A1和A2中的一个为N且另一个为CH。在另一实施方案中,A1和A2各自为CH。在另一实施方案中,A1为N或CH。在另一实施方案中,A2为N或CH。在另一实施方案中,A3为N或CH。在另一实施方案中,A4为N或CH。在另一实施方案中,A5为N或CH。在另一实施方案中,A6为N或CH。在另一实施方案中,A6为CH或CR6。在一个具体实施方案中,A1为N。在另一具体实施方案中,A1为CH。在另一具体实施方案中,A2为N。在另一具体实施方案中,A2为CH。在另一具体实施方案中,A3为N。在另一具体实施方案中,A3为CH。在另一具体实施方案中,A4为N。在另一具体实施方案中,A4为CH。在另一具体实施方案中,A5为N。在另一具体实施方案中,A5为CH。在另一具体实施方案中,A6为N。在另一具体实施方案中,A6为CH。在另一具体实施方案中,A7为N。在另一具体实施方案中,A7为CH。在另一具体实施方案中,A1和A2各自为N。在另一具体实施方案中,A1和A3各自为N。在另一具体实施方案中,A2和A3各自为N。在另一具体实施方案中,A1和A4各自为N。在另一具体实施方案中,A3和A5各自为N。在另一具体实施方案中,A4和A6各自为CH。在另一具体实施方案中,A5和A7各自为N。
在一个实施方案中,X为O或NR8,其中R8为(C1-C4)烷基。在另一实施方案中,X为NR8,其中R8为(C1-C4)烷基。在一个具体实施方案中,X为O。
在一个实施方案中,R1和R2各自独立地为氢、(C1-C4)烷基或H2N(C1-C4)烷基-。在另一实施方案中,R1和R2各自独立地为氢或H2N(C1-C4)烷基-。在另一实施方案中,R1和R2与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的独立选自氧、氮和硫的杂原子,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、-OCONR8R9、-CO2R8、-C(O)CO2R8、R7、-OR7、-NHR8、-NR7R8、-C(O)R7、-CONHR8、-CONR7R8和-SO2R7。在另一实施方案中,R1和R2与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的氮杂原子,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、R7、-OR7、-NHR8、-NR7R8和-C(O)R7。在另一实施方案中,R1和R2与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个另外的氮杂原子,其中所述环任选取代有一个取代基,该取代基为R7。在另一实施方案中,R1和R2与它们连接的氮原子一起表示6-或7-元单环,其任选包含一个或两个另外的独立选自氧、氮和硫的杂原子,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、-OCONR8R9、-CO2R8、-C(O)CO2R8、R7、-OR7、-NHR8、-NR7R8、-C(O)R7、-CONHR8、-CONR7R8和-SO2R7。在另一实施方案中,R1和R2与它们连接的氮原子一起表示6-或7-元单环,其任选包含一个或两个另外的氮杂原子,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、R7、-OR7、-NHR8、-NR7R8和-C(O)R7。在另一实施方案中,R1和R2与它们连接的氮原子一起表示6-或7-元单环,其任选包含一个另外的氮杂原子,其中所述环任选取代有一个取代基,该取代基为R7。
在一个实施方案中,各个R3独立地选自卤素、甲基和二氟甲基。在另一实施方案中,各个R3独立地选自氟、氯、溴、甲基和二氟甲基。在一个实施方案中,各个R3独立地为卤素。在另一实施方案中,各个R3独立地选自氟、氯和溴。在另一实施方案中,各个R3独立地为氟或氯。在一个具体实施方案中,各个R3为氯。
在一个实施方案中,R4和R5各自独立地为氢、(C1-C4)烷基或(C1-C4)烷氧基(C2-C4)烷基-。在另一实施方案中,R4和R5与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的独立选自氧、氮和硫的杂原子,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、-OCONR8R9、-CO2R8、-C(O)CO2R8、-SO2(C1-C4)烷基、R7、-OR7、-NHR8、-NR7R8、-N(R8)C(O)R9、-N(R8)SO2R9、-N(R8)CONR8R9、-N(R8)CON(R8)SO2R9、-C(O)R7、-CONHR8、-CONR7R8和-P(O)R8R9。在另一实施方案中,R4和R5与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的独立选自氧和氮的杂原子,其中所述环任选取代有1或2个独立选自以下的取代基:卤素、羟基、氧代、-CO2R8、R7、-OR7、-NHR8、-N(R8)C(O)R9、-N(R8)SO2R9、-N(R8)CONR8R9、-N(R8)CON(R8)SO2R9、-C(O)R7和-P(O)R8R9。在另一实施方案中,R4和R5与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的独立选自氧和氮的杂原子,其中所述环任选取代有一个取代基,该取代基为R7。在另一实施方案中,R4和R5与它们连接的氮原子一起表示6-或7-元单环,其任选包含一个或两个另外的独立选自氧和氮的杂原子,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、-OCONR8R9、-CO2R8、-C(O)CO2R8、-SO2(C1-C4)烷基、R7、-OR7、-NHR8、-NR7R8、-N(R8)C(O)R9、-N(R8)SO2R9、-N(R8)CONR8R9、-N(R8)CON(R8)SO2R9、-C(O)R7、-CONHR8、-CONR7R8和-P(O)R8R9。在另一实施方案中,R4和R5与它们连接的氮原子一起表示6-或7-元单环,其任选包含一个或两个另外的独立选自氧和氮的杂原子,其中所述环任选取代有1或2个独立选自以下的取代基:卤素、羟基、氧代、-CO2R8、R7、-OR7、-NHR8、-N(R8)C(O)R9、-N(R8)SO2R9、-N(R8)CONR8R9、-N(R8)CON(R8)SO2R9、-C(O)R7和-P(O)R8R9。在另一实施方案中,R4和R5与它们连接的氮原子一起表示6-或7-元单环,其任选包含一个或两个另外的独立选自氧和氮的杂原子,其中所述环任选取代有一个取代基,该取代基为R7。在另一实施方案中,R4和R5与它们连接的氮原子一起表示6-元单环,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、-OCONR8R9、-CO2R8、-C(O)CO2R8、-SO2(C1-C4)烷基、R7、-OR7、-NHR8、-NR7R8、-N(R8)C(O)R9、-N(R8)SO2R9、-N(R8)CONR8R9、-N(R8)CON(R8)SO2R9、-C(O)R7、-CONHR8、-CONR7R8和-P(O)R8R9。在另一实施方案中,R4和R5与它们连接的氮原子一起表示6-元单环,其中所述环任选取代有1或2个独立选自以下的取代基:卤素、羟基、氧代、-CO2R8、R7、-OR7、-NHR8、-N(R8)C(O)R9、-N(R8)SO2R9、-N(R8)CONR8R9、-N(R8)CON(R8)SO2R9、-C(O)R7和-P(O)R8R9。在另一实施方案中,R4和R5与它们连接的氮原子一起表示6-元单环,其中所述环任选取代有一个取代基,该取代基为R7。
在一个实施方案中,各个R6独立地选自卤素和(C1-C4)烷基。在另一实施方案中,各个R6独立地为卤素。在另一实施方案中,各个R6独立地选自氟、氯、溴和甲基。在另一实施方案中,各个R6独立地选自氟、氯和溴。在另一实施方案中,各个R6独立地为氟或氯。在一个具体实施方案中,各个R6为氟。在另一具体实施方案中,各个R6为氯。在另一实施方案中,各个R6独立地为(C1-C4)烷基。在另一具体实施方案中,各个R6为甲基。
在一个实施方案中,各个R7独立地选自(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C6)环烷基和(C3-C6)环烷基(C1-C4)烷基-,其各自任选取代有1或2个独立选自以下的取代基:三唑基、四唑基、-CO2R8、-CONR8R9、-CON(R8)CO2(C1-C4)烷基、羟基、(C1-C4)烷氧基、-OCONR8R9、-OCON(R8)C(O)R9、(C1-C4)烷基、HO(C1-C4)烷基-、-NR8R9、-N(O)R8R9、-N(R8)C(O)R9、-N(R8)CO2(C1-C4)烷基、-N(R8)CONR8R9、-N(R8)CON(R8)C(O)R9、-N(R8)CON(R8)CO2(C1-C4)烷基、-N(R8)SO2R9、-N(R8)CON(R8)SO2R9、-SO(C1-C4)烷基、-SO2(C1-C4)烷基、-SO3R8、-SO2NR8R9、-B(OH)2、-P(O)R8R9和-P(O)(OR8)(OR9)。在另一实施方案中,各个R7独立地选自(C1-C4)烷基、(C2-C4)烯基、卤代(C1-C4)烷基、(C3-C6)环烷基和(C3-C6)环烷基(C1-C2)烷基-,其各自任选取代有1或2个独立选自以下的取代基:-CO2R8、-CONR8R9、羟基、氧代、(C1-C4)烷氧基、-OCONR8R9、HO(C1-C4)烷基-、-NR8R9、-N(R8)C(O)R9、-N(R8)CO2(C1-C4)烷基、-N(R8)CH2CO2R9、-N(R8)CONR8R9、-N(R8)SO2R9、-SO(C1-C4)烷基、-SO2(C1-C4)烷基、-SO3R8、-SO2NR8R9和-P(O)(OR8)(OR9)。在另一实施方案中,各个R7独立地选自(C1-C4)烷基、(C2-C4)烯基、卤代(C1-C4)烷基、(C3-C6)环烷基和(C3-C6)环烷基(C1-C2)烷基-,其各自任选取代有1或2个独立选自以下的取代基:-CO2R8、-CONR8R9、羟基、(C1-C4)烷氧基、-OCONR8R9、HO(C1-C4)烷基-、-NR8R9、-N(R8)C(O)R9、-N(R8)CO2(C1-C4)烷基、-N(R8)CONR8R9、-N(R8)SO2R9、-SO(C1-C4)烷基、-SO2(C1-C4)烷基、-SO3R8、-SO2NR8R9和-P(O)(OR8)(OR9)。在另一实施方案中,各个R7为(C1-C6)烷基,其任选取代有一个取代基,该取代基为-CO2H、羟基、-N(R8)C(O)R9或-SO(C1-C4)烷基。在另一实施方案中,各个R7为(C1-C4)烷基,其任选取代有一个取代基,该取代基为-CO2H、羟基、-N(R8)C(O)R9或-SO(C1-C4)烷基。
在一个实施方案中,各个R8和R9独立地为氢或(C1-C4)烷基。在另一实施方案中,各个R8和R9独立地为(C1-C4)烷基。在另一实施方案中,R8和R9各自为甲基。在另一实施方案中,各个R8和R9为氢。在另一实施方案中,R8为氢且R9为(C1-C4)烷基。在另一实施方案中,R8为氢且R9为甲基。在另一实施方案中,R8为(C1-C4)烷基。在另一实施方案中,R8为甲基。在另一实施方案中,R8为氢。在另一实施方案中,R9为(C1-C4)烷基。在另一实施方案中,R9为甲基。在另一实施方案中,R9为氢。
在一个实施方案中,n为1、2或3。在另一实施方案中,n为2或3。在另一实施方案中,n为2。
在一个实施方案中,X1和X2各自独立地为NR10。在另一实施方案中,X1和X2各自独立地为C(R11)R12。在另一实施方案中,X1为NR10。在另一实施方案中,X1为C(R11)R12。在另一实施方案中,X2为NR10。在另一实施方案中,X2为C(R11)R12。在另一实施方案中,X1为NR10且X2为C(R11)R12。在另一实施方案中,X1为C(R11)R12且X2为NR10。
在一个实施方案中,X2a为NR10b。在另一实施方案中,X2a为C(R11a)R12a。
在一个实施方案中,R1a、R1b、R1c和R2a各自独立地为氢、氟、(C1-C4)烷基、HO(C1-C4)烷基-、羟基或-CONR8R9,其中R1a、R1b、R1c和R2a中至少两个为氢。在另一实施方案中,R1a、R1b、R1c和R2a各自为氢。在一个具体实施方案中,R1c为氢。
在一个实施方案中,X1为NR10,R1a和R2a一起表示-CH2-或-(CH2)2-,且R1b和R1c各自为氢。在另一实施方案中,X1为NR10,R1c和R2a一起表示-CH2-或-(CH2)2-,且R1a和R1b各自为氢。在另一实施方案中,X1为NR10,R1c和R10一起表示-CH2-或-(CH2)2-,且R1a、R1b和R2a各自为氢。在另一实施方案中,X1为NR10,R1a和R1b与它们连接的碳原子一起表示(C3-C6)环烷基,且R1c和R2a各自为氢。
在一个实施方案中,R3a和R3b各自为氟。在另一实施方案中,R3a和R3b各自为氯。在另一实施方案中,R3a为氟且R3b为氯。
在一个实施方案中,R6a为氢或甲基。
在一个实施方案中,各个R10独立地选自氢、R7、-C(O)R7、-CONHR8、-CONR7R8、-C(O)CO2R8和-SO2R7。在另一实施方案中,各个R10独立地选自氢和R7。在另一实施方案中,各个R10为R7。
在一个实施方案中,R10a为氢、(C1-C4)烷基或(C3-C6)环烷基,其中所述(C1-C4)烷基或(C3-C6)环烷基任选取代有-CO2H、-CONH2、-CONH(C1-C4)烷基、-CON((C1-C4)烷基)((C1-C4)烷基)、羟基、(C1-C4)烷氧基、-SO2(C1-C4)烷基或-SO2NH2。在另一实施方案中,R10a为(C1-C4)烷基,其任选取代有-CO2H、-CONH2、-CONH(C1-C4)烷基、-CON((C1-C4)烷基)((C1-C4)烷基)、羟基、(C1-C4)烷氧基、-SO2(C1-C4)烷基或-SO2NH2。在另一实施方案中,R10a为(C1-C4)烷基,其任选取代有-CO2H、羟基或-SO2(C1-C4)烷基。
在一个实施方案中,R1c和R10a一起表示-CH2-或-(CH2)2-。
在一个实施方案中,各个R11为R7。在另一实施方案中,R10和R11各自独立地为R7。
在一个实施方案中,R11a为(C1-C4)烷基,其任选取代有1或2个独立选自以下的取代基:-CO2H、-CONH2、-CONH(C1-C4)烷基、-CON((C1-C4)烷基)((C1-C4)烷基)、羟基、-OCONH(C1-C4)烷基、-NHCO(C1-C4)烷基、-NHCO2(C1-C4)烷基和-NHCONH(C1-C4)烷基。在另一实施方案中,R11a为(C1-C4)烷基,其任选取代有一个取代基,该取代基为-CO2H或-NHCO(C1-C4)烷基。
在一个实施方案中,各个R12独立地选自氢、卤素和羟基。在另一实施方案中,各个R12为氢。
在一个实施方案中,R12a为氢。
在一个实施方案中,m为1。在另一实施方案中,m为2。
在一个实施方案中,本发明涉及式(I)的化合物或其药学上可接受的盐,
其中:
A1、A2、A3、A4、A5和A6各自独立地为N、CH或CR6,其中A1、A2、A3、A4、A5和A6中的0、1、2或3个为N;
X为O或NR8;
R1和R2各自独立地为氢或H2N(C1-C4)烷基-;
或R1和R2与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的氮杂原子,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、R7、-OR7、-NHR8、-NR7R8和-C(O)R7;
各个R3独立地选自卤素、甲基和二氟甲基;
R4和R5各自独立地为氢、(C1-C4)烷基或(C1-C4)烷氧基(C2-C4)烷基-;
或R4和R5与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的独立选自氧和氮的杂原子,其中所述环任选取代有1或2个独立选自以下的取代基:卤素、羟基、氧代、-CO2R8、R7、-OR7、-NHR8、-N(R8)C(O)R9、-N(R8)SO2R9、-N(R8)CONR8R9、-N(R8)CON(R8)SO2R9、-C(O)R7和-P(O)R8R9;
各个R6独立地选自卤素和(C1-C4)烷基;
各个R7独立地选自(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C6)环烷基和(C3-C6)环烷基(C1-C4)烷基-,其各自任选取代有1或2个独立选自以下的取代基:三唑基、四唑基、-CO2R8、-CONR8R9、-CON(R8)CO2(C1-C4)烷基、羟基、(C1-C4)烷氧基、-OCONR8R9、-OCON(R8)C(O)R9、(C1-C4)烷基、HO(C1-C4)烷基-、-NR8R9、-N(O)R8R9、-N(R8)C(O)R9、-N(R8)CO2(C1-C4)烷基、-N(R8)CONR8R9、-N(R8)CON(R8)C(O)R9、-N(R8)CON(R8)CO2(C1-C4)烷基、-N(R8)SO2R9、-N(R8)CON(R8)SO2R9、-SO(C1-C4)烷基、-SO2(C1-C4)烷基、-SO3R8、-SO2NR8R9、-B(OH)2、-P(O)R8R9和-P(O)(OR8)(OR9);
各个R8和R9独立地为氢、(C1-C4)烷基或(C3-C6)环烷基;且
n为2或3。
在另一实施方案中,本发明涉及式(I)的化合物或其药学上可接受的盐,
其中:
A1和A2各自为CH;
或A1和A2之一为N且另一个为CH;
A3和A5各自为N;
A4为CH;
A6为CH或CR6;
X为O;
R1和R2与它们连接的氮原子一起表示6-或7-元单环,其任选包含一个另外的氮杂原子,其中所述环任选取代有一个取代基,该取代基为R7;
各个R3独立地选自氟、氯和溴;
R4和R5与它们连接的氮原子一起表示6-元单环,其中所述环任选取代有一个取代基,该取代基为R7;
R6为甲基;
各个R7为(C1-C6)烷基,其任选取代有一个取代基,该取代基为-CO2H、羟基、-N(R8)C(O)R9或-SO(C1-C4)烷基;
各个R8和R9独立地为氢或(C1-C4)烷基;且
n为2。
在一个实施方案中,本发明涉及式(II)的化合物或其药学上可接受的盐,
其中:
A1、A2、A3、A4和A5各自独立地为N或CH,其中A1、A2、A3、A4和A5中的两个或三个为N;
X1和X2各自独立地为NR10或C(R11)R12;
R1a、R1b、R1c和R2a各自为氢;
或X1为NR10,R1a和R2a一起表示-CH2-或-(CH2)2-,且R1b和R1c各自为氢;
或X1为NR10,R1c和R2a一起表示-CH2-或-(CH2)2-,且R1a和R1b各自为氢;
或X1为NR10,R1c和R10一起表示-CH2-或-(CH2)2-,且R1a、R1b和R2a各自为氢;
各个R3独立地选自卤素、甲基和二氟甲基;
R6a为氢、氟、氯或甲基;
各个R7独立地选自(C1-C4)烷基、(C2-C4)烯基、卤代(C1-C4)烷基、(C3-C6)环烷基和(C3-C6)环烷基(C1-C2)烷基-,其各自任选取代有1或2个独立选自以下的取代基:-CO2R8、-CONR8R9、羟基、(C1-C4)烷氧基、-OCONR8R9、HO(C1-C4)烷基-、-NR8R9、-N(R8)C(O)R9、-N(R8)CO2(C1-C4)烷基、-N(R8)CONR8R9、-N(R8)SO2R9、-SO(C1-C4)烷基、-SO2(C1-C4)烷基、-SO3R8、-SO2NR8R9和-P(O)(OR8)(OR9);
各个R8和R9独立地为氢或(C1-C4)烷基;
各个R10独立地选自氢和R7;
各个R11为R7;
各个R12独立地选自氢、卤素和羟基;
m为1或2;且
n为2或3。
在另一实施方案中,本发明涉及式(II)的化合物或其药学上可接受的盐,
其中:
A1和A2各自为CH;
或A1和A2之一为N且另一个为CH;
A3和A5各自为N;
A4为CH;
X1为NR10且X2为C(R11)R12;
R1a、R1b、R1c和R2a各自为氢;
或X1为NR10,R1c和R10一起表示-CH2-或-(CH2)2-,且R1a、R1b和R2a各自为氢;
各个R3独立地为氟或氯;
R6a为氢或甲基;
各个R7为(C1-C4)烷基,其任选取代有一个取代基,该取代基为-CO2H、羟基、-N(R8)C(O)R9或-SO(C1-C4)烷基;
各个R8和R9独立地为氢或(C1-C4)烷基;
R10和R11各自独立地为R7;
R12为氢;
m为1或2;且
n为2或3。
在一个实施方案中,本发明涉及式(III)的化合物或其药学上可接受的盐,
其中:
A1和A2各自为CH;
或A1和A2之一为N且另一个为CH;
A3为N;
X2a为C(R11a)R12a;
R1c为氢;
R3a和R3b各自为氯;
R6a为氢或甲基;
R10a为(C1-C4)烷基,其任选取代有-CO2H、羟基或-SO2(C1-C4)烷基;
或R1c和R10a一起表示-CH2-或-(CH2)2-;
R11a为(C1-C4)烷基,其任选取代有一个取代基,该取代基为-CO2H或-NHCO(C1-C4)烷基;
R12a为氢;且
m为1或2。
本发明的具体化合物包括:
2-(4-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌嗪-1-基)-N-甲基乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)乙酰胺;
3-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
1-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)-3-甲基脲;
((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)氨基甲酸甲酯;
2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙烷磺酸;
(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲磺酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酰胺;
N-((1-((2-((6-(4-(2-(1H-四唑-5-基)乙基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基亚磺酰基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(4-(甲基磺酰基)丁-2-基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基亚磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(甲基磺酰基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(甲基磺酰基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(4-羟基丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(1-羟基丙-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基环丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(1,3-二羟基丙-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-((1s,3s)-3-羟基-3-甲基环丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-((1r,3r)-3-羟基-3-甲基环丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((反式)-3-(甲基磺酰氨基)环丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((顺式)-3-(甲基磺酰氨基)环丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-((6-(4-(2-氨基乙基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2,4-二羟基丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基)膦酸;
氨基甲酸2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基酯;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(N-甲基甲磺酰氨基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-4-氧代丁酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-(羟基甲基)环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-羟基环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-N-乙基乙酰胺;
1-(2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)-N-甲基甲胺;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(氨磺酰基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((甲基磺酰基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
N-((1-((5-(4-氨基苯氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((5-((5-氨基嘧啶-2-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(甲基磺酰氨基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
N-((1-((5-((5-氨基吡啶-2-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((5-((6-氨基-5-氟吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙烷-1-磺酰胺;
((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
3-(4-(5-((6-(3,5-二氯苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-氟-4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙醇;
2-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸;
3-(4-(5-((4-((4-(2-(氨基甲酰基氧基)乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((4-((4-(2-(氨基甲酰基氧基)乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
3-(3-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-3,8-二氮杂双环[3.2.1]辛-8-基)丙酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-((4-(2-羟基乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
3-(4-(5-((4-((4-(环丙烷甲酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-((4-(丙酰氨基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-((4-氟哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁-2-醇;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-(二氟甲基)苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
((1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
N-((1-((3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
N-((1-((2-(3,5-二氯苯基)-6-((2-(8-甲基-3,8-二氮杂双环[3.2.1]辛-3-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
5-((4-((4-((1H-四唑-5-基)甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶;
甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
1-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((4-((4-(3-氨基-3-氧代丙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((4-((4-(2-氨基-2-氧代乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-(((1R,7S,8r)-8-(甲基磺酰氨基)-4-氮杂双环[5.1.0]辛-4-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-(((1R,7S,8r)-8-(甲基磺酰氨基)-4-氮杂双环[5.1.0]辛-4-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
4-(4-(5-((4-(((1R,7S,8r)-8-乙酰氨基-4-氮杂双环[5.1.0]辛-4-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-(吡咯烷-1-基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
3-(4-(5-((4-((4-(环丙烷甲酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((二甲基磷酰基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酰胺;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙烷磺酰胺;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)嘧啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((6-(3,5-二氯苯基)-2-((6-(哌嗪-1-基)吡啶-3-基)氧基)嘧啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((5-氟-6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-N-甲基丙酰胺;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酰胺;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酰胺;
1-(5-((3',5'-二氯-5-(((2-甲氧基乙基)氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)-N-甲基哌啶-4-胺;
1-(3',5'-二氯-5-((6-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)-N-甲基甲胺;
N1-(5-((3',5'-二氯-5-(吗啉代甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)乙烷-1,2-二胺;
1-(5-((3',5'-二氯-5-((甲基氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌啶-4-胺;
N1-(5-((3',5'-二氯-5-((甲基氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)丙烷-1,3-二胺;
1-(3',5'-二氯-5-((6-(3,3-二甲基哌嗪-1-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)-N-甲基甲胺;
1-(5-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)-N-甲基甲胺;
1-(3',5'-二氯-5-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)-N-甲基甲胺;
N-((1-((5-((6-((2-氨基-2-甲基丙基)氨基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((5-((6-((3S,4R)-4-氨基-3-氟哌啶-1-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((3',5'-二氯-5-((6-(3-氧代六氢咪唑并[1,5-a]吡嗪-7(1H)-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-(5-((6-(3-氯-5-甲基苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌啶-4-胺;
N-((1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((3',5'-二氯-5-((2-(4-(3-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(1-((3',5'-二氯-5-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)丙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-溴-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
2-(1-((3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-((2-(1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-((2-(4-氨基哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-N,N-二甲基乙胺氧化物;
N-((1-((2-(3,5-二氯苯基)-6-((5-氟-6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(6-羟基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(4-氨基-4-(2-羟基乙基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)二甲基氧化膦;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)氮杂环丁烷-3-基)丁酸;
2-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)吡咯烷-3-基)氧基)乙酸;
2-(2-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)八氢环戊二烯并[c]吡咯-5-基)乙酸;
3-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙酸;
3-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
2-(1-((2-((2-(1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
(S)-3-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
1-(7-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-2,7-二氮杂螺[3.5]壬-2-基)-2-羟基乙酮;
(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸;
(R)-3-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
1-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙-2-醇;
3-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-羟基丙酸;
2-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸;
9-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-2-氧杂-4,9-二氮杂螺[5.5]十一烷-3-酮;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)环丙烷羧酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(6-甲氧基-4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(6-氟-4-甲基-1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(1-((2-(3,5-二氯苯基)-6-((2-(6-羟基-4,6-二甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(6-氟-4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((4-甲基-2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-甲基-6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-(4-(4-甲基哌嗪-1-基)苯氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-氟-6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(3-(甲基氨基)吡咯烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
(S)-2-(4-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-1,4-氧氮杂环庚烷-7-基)乙醇;
N-((1R,5S,6r)-3-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-3-氮杂双环[3.1.0]己-6-基)乙酰胺;
1-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙-2-酮;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基-1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(1-((2-((2-(4-氨基哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
(S)-2-(1-((2-(3,5-二氯苯基)-6-((2-(3-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(3,3-二甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(3,6-二氮杂双环[3.1.1]庚-3-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(3,8-二氮杂双环[3.2.1]辛-3-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(4,7-二氮杂螺[2.5]辛-7-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(4-氨基-4-(羟基甲基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((3',5'-二氯-5-((2-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(4-(6-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)哒嗪-3-基)哌嗪-1-基)丙酸;
3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
(3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰基)氨基甲酸甲酯;
1-(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)乙基)环丙烷羧酸;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-2-甲基丁酸;
(3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰基)氨基甲酸甲酯;
(3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酰基)氨基甲酸甲酯;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2,3-二羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1-甲基哌嗪1-氧化物;
4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,1-双(2-羟基乙基)哌嗪-1-鎓;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,1-二甲基哌嗪-1-鎓;
N-((1-((2-((6-(4-氨基-3-氟哌啶-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-((1S,4S)-5-(2-(甲基磺酰基)乙基)-2,5-二氮杂双环[2.2.1]庚-2-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-((6-((3S,4R)-3-(氨基甲基)-4-羟基吡咯烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-((1R,5S)-3-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛-8-基)丙酸;
(S)-3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-2-甲基哌嗪-1-基)丙酸;
2-(1-((2-((6-((1S,4S)-2,5-二氮杂双环[2.2.1]庚-2-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-2-乙基丁酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-2,2-二甲基丙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-基)丙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-2,2-二甲基哌嗪-1-基)丙酸;
N-((1-((2-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(甲基氨基)哌啶-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(3-(羟基甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-((6-(4-氨基哌啶-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(3,3-二甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-((6-(4-氨基-3,3-二甲基哌啶-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-((6-(2,7-二氮杂螺[4.4]壬-2-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-(3',5'-二氯-5-((6-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)-N-甲基甲胺;
1-(5-((6-((1S,4S)-2,5-二氮杂双环[2.2.1]庚-2-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)-N-甲基甲胺;
2-(1-((2-(3,5-二氯苯基)-6-((6-((1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚-2-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基亚磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)戊酸;
甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-羟基丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)环丁烷羧酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)戊酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)环丁烷羧酸;
((1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)环丁烷羧酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)戊酸;
((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
2-((1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛-8-基)乙酸;
2-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)-2-甲基丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(6-羟基-4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(二甲基氨基)哌啶-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(6-甲基-3,6-二氮杂双环[3.1.1]庚-3-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-((1-羟基环丙基)甲基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-乙基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-((1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚-2-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-((1S,4S)-5-乙基-2,5-二氮杂双环[2.2.1]庚-2-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(4-环丙基哌嗪-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-乙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-异丙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-氟乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-羟基丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(甲基氨基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(二甲基氨基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-((甲基氨基甲酰基)氧基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(2-甲氧基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-甲氧基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-氨磺酰基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-甲氧基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丁酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-甲氧基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(3-氨磺酰基丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-氨磺酰基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-甲氧基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙烷-1-磺酰胺;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-甲氧基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酰胺;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-羟基-4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰胺;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((乙氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(2-(乙基氨基)-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-基)丙酸;
3-(1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙酸;
3-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-4,5-二氟苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰胺;
1-((1-((2-(3-氯-5-氟苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
((1-((2-(3-氯-5-氟苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(2-(甲基磺酰基)乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(2-氨磺酰基乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-(1-羟基环丙基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基-3-甲基丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基-2,2-二甲基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丁酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-氨磺酰基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙烷磺酸;
2-((4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)甲基)丁酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-氨磺酰基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丙酰胺;
3-(4-(5-((3',5'-二氯-5-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丙酸;
N-((1-((3',5'-二氯-5-((6-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
(S)-3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-基)丙酸;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(3-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)-3,8-二氮杂双环[3.2.1]辛-8-基)丙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸甲酯;
(R)-2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
(R)-2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(1-((2-(3,5-二氯苯基)-6-((2-(4-((R)-2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
(R)-N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基-2-甲基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-氟-2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
(R)-甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
(R)-甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
(R)-1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
(R)-1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
(R)-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
1-((1-((3',5'-二氯-5-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙酸;
N-((1-((2-(3-氯-5-氟苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-羟基丙酸;
(R)-2-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸;
((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)硼酸;
(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)乙基)硼酸;
((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)二甲基氧化膦;
(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸;
((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)硼酸;
(2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙基)硼酸;
乙酰基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
N-1-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-N'-甲氧基羰基脲;
N-(((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酰基)甲磺酰胺;
N-(((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酰基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氨基甲酰基)甲磺酰胺;
1-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)脲;
(S)-(4-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-1,4-氧氮杂环庚烷-7-基)甲醇;
(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)二甲基氧化膦;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(1,4-二氮杂双环[3.2.1]辛-4-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-((2-(3,8-二氮杂双环[3.2.1]辛-3-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
((1-((2-((2-(1,4-二氮杂双环[3.2.1]辛-4-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
(1R,7S,8r)-4-((2-((2-(1,4-二氮杂双环[3.2.1]辛-4-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸;
4-(5-((6-(3,5-二氯苯基)-4-((4-氟哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂双环[3.2.1]辛烷;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基-1,4-二氮杂环庚烷-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-((4-(2-羟基乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)-2-甲基丁酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙醇;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-(2-羟基-2-甲基丙基)哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((6-(1,4-二氮杂双环[3.2.1]辛-4-基)哒嗪-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-乙基-1,4-二氮杂环庚烷-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-((1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚-2-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-异丙基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((5-(1,4-二氮杂双环[3.2.1]辛-4-基)吡嗪-2-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-(3-羟基丁基)哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙醇;
3-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基-1,4-二氮杂环庚烷-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(6-甲基-3,6-二氮杂双环[3.1.1]庚-3-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
1-((1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)环丙烷羧酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-乙基-1,4-二氮杂环庚烷-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基-1,4-二氮杂环庚烷-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-((1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚-2-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-乙基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙醇;
(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸;
(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((6-(4-甲基-1,4-二氮杂环庚烷-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸;
3-(4-(6-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)哒嗪-3-基)哌嗪-1-基)-2-甲基丙酸;
(R)-3-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
(S)-3-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-((1S,4S)-5-乙基-2,5-二氮杂双环[2.2.1]庚-2-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(4-(5-((4-(((1R,7S,8r)-8-乙酰氨基-4-氮杂双环[5.1.0]辛-4-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸甲酯;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2,2-二甲基丁酸;
2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-(3-氯-5-氟苯基)-6-((2-(4-(4-(甲基磺酰基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3-氯-5-氟苯基)-6-((2-(4-(4-(甲基磺酰基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
2-(1-((2-(3-氯-5-氟苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-(异丙基(2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((3',5'-二氯-4-氟-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-氟-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-氟-2-((2-(8-甲基-3,8-二氮杂双环[3.2.1]辛-3-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-氟-2-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-氟-2-((4-甲基-2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)-3-氟吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
2-(1-((2-((2-(3,8-二氮杂双环[3.2.1]辛-3-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-氟-2-((2-甲基-6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-氟-2-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸甲酯;
2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(4-((1H-1,2,3-三唑-5-基)甲基)哌嗪-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-(甲基(2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-(乙基(2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-氟-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)丙酰胺;
4-(4-(5-((6-(3,5-二氯苯基)-4-((4-(丙酰氨基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)-2-甲基丁酸;
N-((1-((2-(3,5-二氯苯基)-6-((5-(4-(1-羟基丙-2-基)哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
((1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)-2-甲基丁酸;
(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(8-甲基-3,8-二氮杂双环[3.2.1]辛-3-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;和
2-(1-((2-(3,5-二氯苯基)-6-((2-(6-氟-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
或其药学上可接受的盐。
本发明特别感兴趣的具体化合物包括:
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(1,4-二氮杂双环[3.2.1]辛-4-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;和
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
或其药学上可接受的盐。
本发明最感兴趣的具体化合物包括:
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(1,4-二氮杂双环[3.2.1]辛-4-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;和
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
或其药学上可接受的盐。
通常,但不是绝对地,本发明的盐是药学上可接受的盐。所公开的含有碱性胺或其他碱性官能团的化合物的盐可通过本领域已知的任意合适的方法制备,包括将游离碱用无机酸或用有机酸处理,所述无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等,所述有机酸例如乙酸、三氟乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、吡喃糖苷酸(pyranosidyl acid)(如葡萄糖醛酸或半乳糖醛酸)、α-羟酸(如枸橼酸或酒石酸)、氨基酸(如天冬氨酸或谷氨酸)、芳族酸(如苯甲酸或肉桂酸)、磺酸(如对甲苯磺酸、甲磺酸或乙磺酸)等。药学上可接受的盐的实例包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、苯乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、γ-羟基丁酸盐、乙醇酸盐、酒石酸盐、扁桃酸盐和磺酸盐,例如二甲苯磺酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐和萘-2-磺酸盐。
所公开的含有羧酸或其他酸性官能团的化合物的盐可通过与合适的碱反应制备。该药学上可接受的盐可用提供药学上可接受阳离子的碱制成,其包括碱金属盐(尤其是钠和钾盐)、碱土金属盐(尤其是钙和镁盐)、铝盐和铵盐,以及由生理学上可接受的有机碱制成的盐,所述有机碱例如三甲胺、三乙胺、吗啉、吡啶、哌啶、甲基吡啶、二环己基胺、N,N’-二苄基乙二胺、2-羟基乙胺、双-(2-羟基乙基)胺、三-(2-羟基乙基)胺、普鲁卡因、二苄基哌啶、去氢枞胺、N,N’-双去氢枞胺、葡萄糖胺、N-甲基葡糖胺、可力丁、奎宁、喹啉和碱性氨基酸,例如赖氨酸和精氨酸。
其他盐(不是药学上可接受的)可用于制备本发明化合物且这些应被认为形成本发明的另一方面。这些盐例如草酸盐或三氟乙酸盐,尽管本身不是药学上可接受的,但是其可用于制备在获得本发明化合物及其药学上可接受的盐中用作中间体的盐。
式(I)的化合物可以结晶或非结晶形式,或作为其混合物存在。式(I-a)的化合物也可以结晶或非结晶形式,或作为其混合物存在。本领域技术人员将理解,对于结晶或非结晶化合物,可形成药学上可接受的溶剂合物。在结晶溶剂合物中,溶剂分子在结晶过程中被引入结晶晶格。溶剂合物可包括非水溶剂,例如,但不限于乙醇、异丙醇、DMSO、乙酸、乙醇胺或乙酸乙酯,或它们可包括水作为被引入该结晶晶格的溶剂。其中水作为被引入结晶晶格的溶剂的溶剂合物通常被称为“水合物”。水合物包括化学计量的水合物以及含有可变量的水的组合物。本发明包括所有这些溶剂合物。
本领域技术人员将进一步理解,以结晶形式存在的本发明的化合物,包括其各种溶剂合物,可呈现出多晶型现象(即能够以不同的晶体结构存在)。这些不同的结晶形式通常被称为“多晶型物”。本发明包括所有这样的多晶型物。多晶型物具有相同的化学组成,但是在包装、几何排列和该结晶固态的其他描述性属性中有所不同。因此,多晶型物可具有不同的物理性质,例如形状、密度、硬度、可变形性、稳定性和溶出性质。多晶型物通常呈现出不同的熔点、IR光谱和X射线粉末衍射图,其可用于鉴定。本领域技术人员将理解,不同多晶型物可通过以下产生,例如,改变或调整在制备该化合物中所用的反应条件或试剂。例如,温度、压力或溶剂的改变可导致多晶型物。此外,在一些条件下,一种多晶型物可自发地转变成另一种多晶型物。
式(I)化合物或其盐可以立体异构体形式存在(例如,其含有一个或多个不对称碳原子)。式(I-a)的化合物或其盐也可以立体异构体形式存在。单一立体异构体(对映异构体和非对映异构体)和这些的混合物包括在本发明的范围内。同样地,应理解式(I)或式(I-a)化合物或盐除了式中所示,可存在互变异构体形式且这些也包括在本发明的范围内。应理解本发明包括上文所定义的具体基团的全部组合和子集。本发明的范围包括立体异构体的混合物以及纯的对映异构体或对映异构体/非对映异构体富集的混合物。应理解,本发明包括上文定义的具体基团的所有组合和子集。
本发明还包括同位素标记的化合物,其与式(I)及以下所述的那些相同,但是其一个或多个原子被具有与自然界常见的原子质量或原子数不同的原子质量或原子数的原子所代替。本发明还包括同位素标记的式(I-a)的化合物。可引入本发明化合物及其药学上可接受的盐的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素,例如2H、3H、11C、13C、14C、15N、17O、18O、31P、32P、35S、18F、36Cl、123I和125I。
含有上述同位素和/或其他原子的其他同位素的本发明化合物和所述化合物的药学上可接受的盐在本发明的范围内。同位素标记的本发明化合物,例如放射性同位素(3H或14C)被引入的那些,用于药物和/或底物组织分布测试。氚化(即,3H)和碳-14(即,14C)同位素,由于其易于制备和检测,因此是特别优选的。11C和18F同位素尤其用于PET(正电子发射断层扫描),且125I同位素尤其用于SPECT(单光子发射型计算机断层扫描),其全部用于脑成像。此外,使用较重同位素(例如氘,即,2H)的取代,由于更好的代谢稳定性,可提供一些治疗优势,例如延长的体内半衰期或降低的剂量需求,并因此在一些情况下是优选的。同位素标记的式(I)化合物和本发明下列化合物通常可通过以下方式制备:进行下列方案和/或实施例所公开的操作,通过用易得的同位素标记的试剂替代非同位素标记的试剂。同位素标记的式(I-a)化合物通常也可通过以下方式制备:进行下列方案和/或实施例所公开的操作,通过用易得的同位素标记的试剂替代非同位素标记的试剂。
本发明进一步提供药物组合物(也称为药物制剂),其包含式(I)的化合物或其药学上可接受的盐和一种或多种赋形剂(在药物领域也称为载体和/或稀释剂)。本公开还提供药物组合物,其包含式(I-a)的化合物或其药学上可接受的盐和一种或多种赋形剂。所述赋形剂在与该制剂的其他成分相容以及对其接受者(即,患者)无毒方面是可接受的。
在某些实施方案中,本文所述的化合物以有效量在药物组合物中提供。在某些实施方案中,所述有效量为治疗有效量。在某些实施方案中,所述有效量为预防性有效量。在某些实施方案中,治疗有效量为有效抑制弗林蛋白酶的异常活性的量。在某些实施方案中,治疗有效量为有效治疗疾病(例如,与弗林蛋白酶的异常活性相关的疾病(例如,纤维化疾病,包括肺纤维化(例如,特发性肺纤维化、非特异性间质性肺炎(NSIP)、普通型间质性肺炎(UIP)、赫曼斯基-普德拉克综合征、进行性块状纤维变性(煤矿工人尘肺病的并发症)、结缔组织疾病-相关的肺纤维化、哮喘和COPD中的气道纤维化、急性呼吸窘迫综合征(ARDS)相关的纤维化、急性肺损伤;辐射-诱导的纤维化;家族性肺纤维化;肺动脉高压)、肾纤维化(例如,糖尿病肾病、IgA肾病、狼疮性肾炎;局灶性节段性肾小球硬化症(FSGS)、移植肾病、自身免疫性肾病、药物诱发肾病、高血压-相关的肾病、肾源性系统性纤维化)、肝纤维化(例如,病毒-诱导的纤维化(例如丙型或乙型肝炎)、自身免疫性肝炎、原发性胆汁性肝硬化、酒精性肝病、非酒精性脂肪性肝疾病,包括非酒精性脂肪肝病(NASH)、先天性肝纤维化、原发性硬化性胆管炎、药物诱发性肝炎、肝硬化)、皮肤纤维化(例如,肥厚性瘢痕、硬皮病、瘢痕疙瘩、皮肌炎、嗜酸细胞性筋膜炎、杜普伊特伦挛缩(Dupytrens contracture)、埃勒斯-当洛斯综合征、佩罗尼氏病、营养不良性大疱性表皮松解、口腔粘膜下纤维化)、眼纤维化(例如,AMD、糖尿病性黄斑水肿、干眼、青光眼)、心脏纤维化(例如,充血性心力衰竭、心内膜心肌纤维化症、肥厚型心肌病(HCM)、扩张型心肌病(DCM)、致心律失常性右室心肌病(ARVC)、高血压心脏病、心脏结节病和其它形式的心力衰竭)和其它混杂纤维化病症(例如,纵隔纤维化、骨髓纤维化、腹膜后纤维化、克罗恩病、神经纤维瘤病、子宫平滑肌瘤(纤维瘤)、慢性器官移植排斥))的量。
在某些实施方案中,所述有效量为有效抑制弗林蛋白酶的活性达至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%或至少98%的量。在某些实施方案中,所述有效量为有效抑制弗林蛋白酶的活性不超过10%、不超过20%、不超过30%、不超过40%、不超过50%、不超过60%、不超过70%、不超过80%、不超过90%、不超过95%或不超过98%的量。
合适的药学上可接受的赋形剂将根据所选的特定剂型而变化。此外,可针对其在组合物中发挥的特定功能来选择合适的药学上可接受的赋形剂。例如,可针对其有利于生产均一剂型的能力来选择某些药学上可接受的赋形剂。可针对其有利于生产稳定剂型的能力来选择某些药学上可接受的赋形剂。可针对一旦向患者施用,其有利于将本发明一种或多种化合物从一个器官或身体的一部分携带或转运到另一个器官或身体的另一部分的能力来选择某些药学上可接受的赋形剂。可针对其提高患者依从性的能力来选择某些药学上可接受的赋形剂。
合适的药学上可接受的赋形剂包括以下类型的赋形剂:稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、造粒剂、涂层剂、润湿剂、溶剂、共溶剂、悬浮剂、乳化剂、甜味剂、调味剂、掩味剂、着色剂、防结块剂、保湿剂(hemectant)、螯合剂、增塑剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。技术人员将认识到,某些药学上可接受的赋形剂可起到不止一种作用并且可根据制剂中存在的赋形剂的多少以及制剂中存在何种其它成分来起到别的功能。
技术人员具备本领域的知识和技能从而使其能够选择合适的药学上可接受的赋形剂并以适当的量用于本发明。此外,存在许多对技术人员而言是现成的资源,这些资源描述了药学上可接受的赋形剂并可用于选择合适的药学上可接受的赋形剂。实例包括:Remington’s Pharmaceutical Sciences(Mack Publishing Company),The Handbook ofPharmaceutical Additives(Gower Publishing Limited),和The Handbook ofPharmaceutical Excipients(the American Pharmaceutical Association and thePharmaceutical Press)。
本发明的药物组合物使用本领域技术人员已知的技术和方法制备。本领域通常使用的一些方法描述于Remington’s Pharmaceutical Sciences(Mack PublishingCompany)。
药物组合物可以是每单位剂量含有预定量活性成分的单位剂型。该单位可含有治疗有效量的式(I)化合物或其盐或部分治疗有效剂量,使得多个单位剂型可在给定时间内施用以达到所需治疗有效剂量。该单位可含有治疗有效量的式(I-a)化合物或其盐或部分治疗有效剂量,使得多个单位剂型可在给定时间内施用以达到所需治疗有效剂量。优选的单位剂量制剂是含有上文所述的日剂量或亚剂量活性成分或其适当部分的那些。此外,该药物组合物可通过药学领域任意熟知的方法制备。
药物组合物可适用于经任意适当途径的给药,例如,通过口服(包括口腔或舌下)、直肠、鼻内、局部(包括口腔、舌下或经皮)、阴道或胃肠外(包括皮下、肌内、静脉内或皮内)途径。这样的组合物可通过药学领域任何已知的方法制备,例如,通过将活性成分与赋形剂联合。
当药物组合物适合口服给药时,其可以是离散单元,例如片剂或胶囊剂;粉剂或颗粒剂;水性或非水液体中的溶液或混悬液;可食用泡沫或泡沫状物(whip);水包油液体乳剂或油包水液体乳剂。本发明化合物或其盐或本发明的药物组合物还可被掺入糖果、华夫饼和/或舌胶带(tongue tape)制剂以作为“快速溶解”药物进行给药。
例如,对于片剂或胶囊形式的口服给药,该活性药物成分可与口服、无毒的药学上可接受的惰性载体(例如乙醇、甘油、水等)组合。粉剂或颗粒剂是通过将化合物粉碎成合适的细微尺寸并与经类似研磨的药物载体(例如可食用碳水化合物,如淀粉或甘露醇)混合来制备。调味剂、防腐剂、分散剂和着色剂也可存在。
胶囊剂是通过以下制成的:制备上述粉末混合物并将其填充到成形的明胶或非胶质鞘。在填充操作之前,可将助流剂和润滑剂,例如胶体二氧化硅、滑石、硬脂酸镁、硬脂酸钙、固体聚乙二醇加至该粉末混合物。还可加入崩解剂或增溶剂,例如琼脂、碳酸钙或碳酸钠,使得当该胶囊被摄取时,提高该药物的利用率。
此外,当需要或必要时,还可将适当的粘合剂、润滑剂、崩解剂和着色剂掺入该混合物中。适当的粘合剂包括淀粉、明胶、天然糖(例如葡萄糖或β-乳糖)、玉米甜味剂、天然和合成树胶(例如阿拉伯胶、西黄蓍胶)、海藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。在这些剂型中所使用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括但不限于,淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
片剂是通过如下制备的,例如,制备粉末混合物、制粒或预压(slugging)、加入润滑剂和崩解剂,以及压制成片。粉末混合物是通过如下制备的,将适当粉碎的化合物与以下物质进行混合:上文所述的稀释剂或碱,以及任选地粘合剂,例如羧甲基纤维素和藻酸盐、明胶或聚乙烯吡咯烷酮;溶液延缓剂例如石蜡;吸收促进剂例如季盐;和/或吸收剂例如膨润土、高岭土或磷酸二钙。所述粉末混合物可通过如下制粒:润湿粘合剂例如糖浆、淀粉糊、阿拉伯胶或纤维素或聚合物材料的溶液,并通过筛网。对于制粒的替代方法,可将该粉末混合物在压片机上运行,产生破碎成颗粒的不完全成形的小丸。通过加入硬脂酸、硬脂酸盐、滑石或矿物油,可将该颗粒润滑以防止粘附至片剂成形模具。然后将经润滑的混合物压制成片剂。还可将本发明的化合物或盐与散粒的惰性载体混合并直接压制成片而无需经历制粒或预压步骤。可提供由虫胶的隔离层、糖或聚合物材料的涂层以及蜡的抛光涂层组成的澄清不透明的保护涂层。可将染料加至这些涂层中以区别不同的剂量。
可以剂量单位形式制备口服液,例如溶液、糖浆和酏剂,使得给定量含有预定量的活性成分。糖浆可通过如下制备,将本发明化合物或其盐溶于适当调味的水溶液中,而酏剂是使用无毒醇媒介物制备的。混悬液可通过如下配制,将本发明的化合物或盐分散于无毒媒介物中。还可加入增溶剂和乳化剂(例如乙氧基化异硬脂醇和聚氧乙烯山梨醇醚)、防腐剂、调味添加剂(例如薄荷油)、天然甜味剂、糖精或其他人造甜味剂等。
在适当情况下,用于口服给药的剂量单位制剂可被微胶囊化。也可通过,例如将微粒材料涂布或包埋于聚合物、蜡等中来制备该制剂以延长或维持释放。
在本发明中,片剂和胶囊剂是药物组合物递送的优选口服形式。
在另一方面,本发明涉及适于通过吸入向患者给药的剂型。吸入是指无论是通过口腔还是通过鼻道吸入患者的肺部。例如,本发明的化合物可以干粉、气雾剂、混悬剂或溶液的形式吸入肺中。
通过吸入而递送至肺部的干粉组合物通常包含细粉形式的本发明的化合物连同细粉形式的一种或多种药学上可接受的赋形剂。特别适用于干粉剂的药学上可接受的赋形剂是本领域技术人员已知的,其包括乳糖、淀粉、甘露糖醇以及单糖、二糖和多糖。
可通过贮存式干粉吸入器(RDPI)向患者施用干粉剂,所述贮存式干粉吸入器具有适于以干粉形式保存多个(未计量的剂量)药物的贮存器。RDPI通常包括用于计量从贮存器到递送位置的每个药物剂量的装置。例如,计量装置可包括计量杯,其可以从第一位置移动到第二位置,在所述第一位置,杯子可装满来自贮存器的药物,而在所述第二位置,量好的药物剂量被提供给患者用于吸入。
可选地,干粉剂可以胶囊(例如明胶或塑料)、滤筒或泡罩包装方式提供以用于多剂量干粉吸入器(MDPI)。MDPI是这样一种吸入器,其中药物被包括在多剂量包装内,所述多剂量包装含有(或另外携带)多个确定剂量(或其份数)的药物。当干粉剂以泡罩包装的方式提供时,其包括多个泡罩以容纳干粉形式的药物。泡罩通常以规则方式排列以便于药物从中释放。例如,泡罩可以大致圆环状排列在碟形的泡罩包装上,或泡罩可以例如包括扁条或条带的形式延长。每个胶囊、滤筒或泡罩可以,例如,含有20μg-10mg本发明的化合物。
可以通过将本发明的化合物悬浮或溶解到液化推进剂中来配制气雾剂。合适的推进剂包括:卤代烃、烃和其它液化气体。具有代表性的推进剂包括:三氯氟甲烷(推进剂11)、二氯氟甲烷(推进剂12)、二氯四氟乙烷(推进剂114)、四氟乙烷(HFA-134a)、1,1-二氟乙烷(HFA-152a)、二氟甲烷(HFA-32)、五氟乙烷(HFA-12)、七氟丙烷(HFA-227a)、全氟丙烷、全氟丁烷、全氟戊烷、丁烷、异丁烷和戊烷。通常将通过计量剂量吸入器(MDI)向患者施用包含本发明的化合物的气雾剂。此类装置是本领域技术人员已知的。
气雾剂可含有通常与多剂量吸入器一起使用的额外的药学上可接受的赋形剂(如表面活性剂、润滑剂、共溶剂和其它赋形剂)以改善制剂的物理稳定性、气阀性能、溶解性或口味。
还可以通过喷雾器向患者施用包含本发明的化合物的悬浮液和溶液。用于喷雾的溶剂或悬浮剂可以是任何药学上可接受的液体如水、盐水溶液、酒精或二醇(例如,乙醇、异丙醇、甘油、丙二醇、聚乙二醇等)或其混合物。盐水溶液使用的盐在给药后几乎没有或没有显示出药理活性。两类有机盐如碱金属盐或卤化铵盐(例如,氯化钠、氯化钾或有机盐,如钾、钠和铵盐)或有机酸(例如,抗坏血酸、柠檬酸、乙酸、酒石酸等)均可用于此目的。
其它的药学上可接受的赋形剂可被添加到悬浮液或溶液中。本发明的化合物可通过加入以下物质来稳定:无机酸,例如盐酸、硝酸、硫酸和/或磷酸;有机酸,例如抗坏血酸、柠檬酸、乙酸和酒石酸等;络合剂如EDTA或柠檬酸及其盐;或抗氧化剂如维生素E或抗坏血酸。可以单独或同时使用这些物质以稳定本发明的化合物。可添加防腐剂如苯扎氯铵或苯甲酸及其盐。可添加表面活性剂以特别改善悬浮液的物理稳定性。这些表面活性剂包括卵磷脂、二辛基磺基琥珀酸二钠、油酸和失水山梨醇酯。
适用于直肠给药的药物组合物可以栓剂或灌肠剂形式存在。
适用于阴道给药的药物组合物可以子宫托、棉塞、乳膏、凝胶、糊剂、泡沫或喷雾制剂的形式存在。
适于肠胃外给药的药物制剂包括:水性和非水性的无菌注射溶液,所述注射溶液可含有抗氧化剂、缓冲液、抑菌剂和使得组合物与预期接受者的血液等渗的溶质;以及水性和非水性的无菌悬浮液,其可包含悬浮剂和增稠剂。药物组合物可以存在于单位剂量或多剂量容器(例如密闭的安瓿和小瓶)中,并且可保存在冷冻干燥的(冻干的)条件下,仅需在使用前立即加入无菌液体载体(例如水)用于注射。临时注射溶液和悬浮液可由无菌粉剂、颗粒剂和片剂制备。
应理解,除了上面特别提及的成分,该药物组合物可根据所探讨的制剂类型包含本领域常规的其他试剂,例如适用于口服给药的那些可包含调味剂。
药物组合物可以单位剂量形式存在,每单位剂量含有预定量的活性成分。根据所治疗的病症、给药途径和患者的年龄、体重和状况,该单位剂量可包含例如0.5mg至1g,优选1mg至700mg,更优选5mg至100mg的式(I)化合物,或药物组合物可以以每单位剂量包含预定量的活性成分的单位剂量形式存在。这样的单位剂量可以包含例如0.5mg至1g,优选1mg至700mg,更优选5mg至100mg的式(I-a)的化合物,或者药物组合物可以以每单位剂量包含预定量的活性成分的单位剂量形式存在。优选的单位剂量组合物是那些包含如上文所述的日剂量或亚剂量,或其适当分数的活性成分的组合物。此外,可以通过药学领域众所周知的任何方法来制备这样的药物组合物。
本发明化合物的治疗有效量将取决于许多因素,包括例如,预期接受者的年龄和体重、需要治疗的确切病症和其严重性、该制剂的性质和给药途径,且其最终由开处方人员慎重决定。但是,治疗肺纤维化的式(I)化合物的有效量的通常范围是每天0.001-100mg/kg接受者的体重,适当地范围为每天0.01至10mg/kg体重。但是,治疗肺纤维化的式(I-a)化合物的有效量的通常范围是每天0.001-100mg/kg接受者的体重,适当地范围为每天0.01至10mg/kg体重。对于70kg成年哺乳动物,每天的实际量将适当地为7-700mg,且该量可以每日单一剂量给予或以每天若干(例如2、3、4、5或6个)亚剂量给予,使得总的日剂量相同。吸入的日剂量范围为10μg-10mg/天,优选10μg-2mg/天,且更优选50μg-500μg/天。有效量的盐或溶剂合物等可按式(I)或式(I-a)化合物本身的有效量的比例来确定。预期类似的剂量将适用于治疗上述其他病症。
根据本发明另一方面提供了制备药物组合物的方法,该方法包括使式(I)的化合物或其盐与至少一种赋形剂混合(或共混)。根据本发明另一方面提供了制备药物组合物的方法,该方法包括使式(I-a)的化合物或其盐与至少一种赋形剂混合(或共混)。
本发明还提供治疗哺乳动物,尤其是人的方法。可通过本文提供的方法和组合物治疗的疾病状态包括但不限于,纤维化疾病。纤维化疾病涉及修复或反应过程中在器官或组织中形成过量的纤维结缔组织。疾病可包括但不限于肺纤维化,例如特发性肺纤维化、非特异性间质性肺炎(NSIP)、普通型间质性肺炎(UIP)、赫曼斯基-普德拉克综合征、进行性块状纤维变性(煤矿工人尘肺病的并发症)、结缔组织疾病-相关的肺纤维化、哮喘和COPD中的气道纤维化、急性呼吸窘迫综合征(ARDS)相关的纤维化、急性肺损伤;辐射-诱导的纤维化;家族性肺纤维化;肺动脉高压);肾纤维化(糖尿病肾病、IgA肾病、狼疮性肾炎;局灶性节段性肾小球硬化症(FSGS)、移植肾病、自身免疫性肾病、药物诱发肾病、高血压-相关的肾病、肾源性系统性纤维化);肝纤维化(病毒-诱导的纤维化(例如丙型或乙型肝炎)、自身免疫性肝炎、原发性胆汁性肝硬化、酒精性肝病、非酒精性脂肪性肝疾病,包括非酒精性脂肪肝病(NASH)、先天性肝纤维化、原发性硬化性胆管炎、药物诱发性肝炎、肝硬化);皮肤纤维化(肥厚性瘢痕、硬皮病、瘢痕疙瘩、皮肌炎、嗜酸细胞性筋膜炎、杜普伊特伦挛缩、埃勒斯-当洛斯综合征、佩罗尼氏病、营养不良性大疱性表皮松解、口腔粘膜下纤维化);眼纤维化(AMD、糖尿病性黄斑水肿、干眼、青光眼);心脏纤维化(充血性心力衰竭、心内膜心肌纤维化症、肥厚型心肌病(HCM)、扩张型心肌病(DCM)、致心律失常性右室心肌病(ARVC)、高血压心脏病、心脏结节病和其它形式的心力衰竭)和其它混杂纤维化病症(纵隔纤维化、骨髓纤维化、腹膜后纤维化、克罗恩病、神经纤维瘤病、子宫平滑肌瘤(纤维瘤)、慢性器官移植排斥)。
可以通过本文提供的方法和组合物治疗的其他疾病状态包括但不限于高血压、癌症、传染性疾病(例如人类免疫缺陷病毒(HIV)、禽流感病毒、麻疹病毒、呼吸道合胞病毒(RSV)、埃博拉病毒、炭疽和寨卡病毒(ZIKV))、呼吸道疾病(例如囊性纤维化病(CF))和神经元变性(例如阿尔茨海默氏病(AD))疾病。
本发明化合物可以与其他治疗剂(特别是可以增强化合物活性或处置时间的药剂)组合或联合施用。根据本发明的组合疗法包括至少一种本发明化合物的施用和至少一种其他治疗方法的使用,包括一种或多种其他治疗剂的施用。可与本发明化合物组合使用的其他治疗剂包括但不限于:抗原免疫治疗、抗组胺剂、皮质类固醇(例如,丙酸氟替卡松、糠酸氟替卡松、丙酸倍氯米松、布地奈德、环索奈德、糠酸莫米松、曲安西龙、氟尼缩松)、NSAID、白三烯调节剂(例如孟鲁司特、扎鲁司特、普仑司特)iNOS抑制剂、类胰蛋白酶抑制剂、IKK2抑制剂、p38抑制剂、Syk抑制剂、弹性蛋白酶抑制剂、β-2整联蛋白拮抗剂、腺苷a2a激动剂、趋化因子拮抗剂如CCR3拮抗剂或CCR4拮抗剂、介质释放抑制剂如色甘酸钠、5-脂氧合酶抑制剂(zyflo)、DP1拮抗剂、DP2拮抗剂、pI3Kδ抑制剂、ITK抑制剂、LP(溶血磷脂)抑制剂或FLAP(5-脂氧合酶激活蛋白)抑制剂(例如3-(3-(叔丁基硫基)-1-(4-(6-乙氧基吡啶-3-基)苄基)-5-((5-甲基吡啶-2-基)甲氧基)-1H-吲哚-2-基)-2,2-二甲基丙酸钠)、甲氨蝶呤和类似药剂;单克隆抗体疗法如抗IgE、抗TNF、抗IL-5、抗IL-6、抗IL-12、抗IL-1和类似药剂;受体疗法例如依那西普和类似药剂;抗原非特异性免疫疗法(例如干扰素或其它细胞因子/趋化因子、细胞因子/趋化因子受体调节剂、细胞因子激动剂或拮抗剂、TLR激动剂和类似药剂))、TGFβ合成抑制剂例如吡非尼酮、靶向血管内皮生长因子(VEGF)、血小板-衍生的生长因子(PDGF)和成纤维细胞生长因子(FGF)受体激酶的酪氨酸激酶抑制剂例如尼达尼布(intedanib)(BIBF-1120)和甲磺酸伊马替尼(Gleevec)、内皮素受体拮抗剂例如安立生坦或马昔腾坦、抗氧化剂如N-乙酰基半胱氨酸(NAC或富露施)、广谱抗生素如四环素例如米诺环素盐酸盐、磷酸二酯酶5(PDE5)抑制剂例如西地那非或αvβ6整联蛋白拮抗剂例如单克隆抗体如WO2003/100033A2中所述的那些。
本文所用的术语“共同给药”及其衍生词语是指同时给药或以任意单独的方式相继给药本文所述的弗林蛋白酶抑制化合物和一种或多种其他活性成分。当向有治疗需要的患者给药时,本文所用术语一种或多种其他活性成分还包括已知的或被证明有有益性质的任意化合物或治疗剂。优选地,如果所述给药不是同时的,那么该化合物以彼此极接近的时间进行给药。此外,所述化合物是否以相同剂型给药并不重要,例如一种化合物可口服给药而另一化合物可静脉给药。
本公开的另一方面涉及试剂盒,其包括具有如本文所述的化合物或其药物组合物的容器。本文所述的试剂盒可包括单剂量或多剂量的化合物或药物组合物。试剂盒可用于本公开的方法。在某些实施方案中,试剂盒进一步包括使用化合物或药物组合物的说明书。本文所述的试剂盒还可包括监管机构(例如美国食品和药物管理局(FDA))所需的信息(例如,处方信息)。
本文阐述了本发明的一个或多个实施方案的细节。根据发明详述、实施例、附图和权利要求书,本发明的其他特征、目的和优点将是显而易见的。
定义
术语在其可接受的含义内使用。以下定义旨在澄清而非限制所定义的术语。
如本文所述,术语"烷基"是指具有指定数量碳原子的饱和、直链或支链的烃部分。术语"(C1-C6)烷基"是指包含1至6个碳原子的烷基部分。示例性烷基包括但不限于,甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基和己基。
“烷氧基”是指通过氧连接原子连接的包含上文定义的烷基的基团。术语“(C1-C4)烷氧基”是指通过氧连接原子连接的具有至少1个且至多4个碳原子的直链或支链的烃基团。用于本发明的示例性“(C1-C4)烷氧基”包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基和叔丁氧基。
当术语“烷基”与其它取代基组合使用时,如“卤代(C1-C6)烷基”、“(C3-C6)环烷基(C1-C4)烷基-”、或“(C1-C4)烷氧基(C2-C4)烷基-”,术语“烷基”预期包括二价直链或支链的烃基团,其中所述连接点是通过烷基部分。术语“卤代(C1-C6)烷基”是指在包含1-6个碳原子的烷基部分的一个或多个碳原子上具有一个或多个可相同或不同的卤原子的基团,该烷基部分是直链或支链碳基团。用于本发明的"卤代(C1-C6)烷基"基团的实例包括但不限于-CH2F(氟甲基)、-CHF2(二氟甲基)、-CF3(三氟甲基)、-CCl3(三氯甲基)、1,1-二氟乙基、2-氟-2-甲基丙基、2,2-二氟丙基、2,2,2-三氟乙基和六氟异丙基。用于本发明的“(C3-C6)环烷基(C1-C4)烷基-”基团的实例包括但不限于,环丁基甲基、环戊基甲基、环己基甲基、环丁基乙基、环戊基乙基和环己基乙基。用于本发明的“(C1-C4)烷氧基(C2-C4)烷基-”基团的实例包括但不限于,甲氧基乙基、甲氧基异丙基、乙氧基乙基、乙氧基异丙基、异丙氧基乙基、异丙氧基异丙基、叔丁氧基乙基和叔丁氧基异丙基。
当使用术语“烯基”(或“亚烯基”)时,其是指包含指定数量的碳原子和至少1个且至多3个碳-碳双键的直链或支链的烃链。实例包括乙烯基(或亚乙烯基)和丙烯基(或亚丙烯基)。
如本文所述,术语“环烷基”是指包含指定数量的碳原子的非芳族、饱和的环状烃环。术语“(C3-C6)环烷基”是指具有三至六个环碳原子的非芳族环状烃环。用于本发明的示例性“(C3-C6)环烷基”基团包括环丙基、环丁基、环戊基和环己基。
术语“卤素”和“卤代”表示氟、氯、溴或碘取代基。
“氧代”表示双键键合的氧部分;例如,如果直接连接到碳原子上,则形成羰基部分(C=O)。
“羟基(hydroxy)”或“羟基(hydroxyl)”预期是指基团-OH。
如本文所述,术语“任选地”是指随后描述的事件可能会或可能不会发生,并且包括已发生的事件和未发生的事件。
如本文所述,术语“治疗”是指缓解特定疾病,消除或减轻该疾病的一个或多个症状,减慢或消除该疾病的进展,并延迟该疾病在先前患病或诊断的患者或受试者中的复发。
如本文所用,术语“有效量”是指将引起例如研究者或临床医生寻求的组织、系统、动物或人的生物学或医学反应的药物或药剂的量。
术语“治疗有效量”是指与没有接受该量的相应受试者相比导致疾病、病症或副作用的改善治疗、治愈或改进、或者降低疾病或病症进展速率的任何量。该术语在其范围内还包括有效增强正常生理功能的量。为了用于治疗,可以将治疗有效量的式(I)化合物及其盐作为原料化学品给药。为了用于治疗,可以将治疗有效量的式(I-a)化合物及其盐作为原料化学品给药。另外,活性成分可以作为药物组合物存在。
术语“遗传疾病”是指由受试者的基因组中的一种或多种异常引起的疾病,例如从受试者出生起就存在的疾病。遗传疾病可能是遗传性的,可能是从父母的基因传承下来的。遗传疾病也可能是由受试者的DNA和/或RNA的突变或变化引起的。在这种情况下,如果遗传病发生在种系中,将是可遗传的。示例性遗传疾病包括但不限于呼吸系统疾病(例如,囊性纤维化病)、神经退行性疾病(例如,阿尔茨海默氏病)和冠状动脉疾病。
术语“神经疾病”是指神经系统的任何疾病,包括涉及中枢神经系统(脑、脑干和小脑)、周围神经系统(包括颅神经)和自主神经系统(其部分位于中枢和周围神经系统中)的疾病。神经退行性疾病是指以神经细胞丧失为特征的一种神经疾病,包括但不限于阿尔茨海默氏病、帕金森氏病、肌萎缩性侧索硬化症、tau病变(包括额颞痴呆)和亨廷顿病。
术语“抑制(inhibition)”、“抑制(inhibiting)”、“抑制(inhibit)”或“抑制剂”是指化合物相对载体降低、减慢、停止或阻止细胞中特定生物过程的活性(例如弗林蛋白酶活性)的能力。
在某些实施方案中,本文所述的试剂盒包括第一容器,该第一容器包含本文所述的化合物或药物组合物。在某些实施方案中,本文所述的试剂盒用于治疗和/或预防疾病,如纤维化疾病,包括肺纤维化、其它混杂纤维化病症、高血压、癌症、传染病、遗传疾病或神经退行性疾病。
在某些实施方案中,本文描述的试剂盒进一步包括使用试剂盒中包括的化合物或药物组合物的说明书。本文所述的试剂盒还可包括监管机构如美国食品和药物管理局(FDA)要求的信息。在某些实施方案中,试剂盒中包括的信息为处方信息。在某些实施方案中,试剂盒和说明书提供了用于治疗纤维化疾病、其它混杂纤维化病症、高血压、癌症、传染病、遗传疾病或神经退行性疾病的方法。本文所述的试剂盒可包括一种或多种本文所述的另外的药剂作为单独的组合物。
化合物制备
缩写
Ac2O 乙酸酐
AcOH 乙酸
AIBN 偶氮二异丁腈
aq. 水溶液
BBr3 三溴化硼
BF3·OEt2 三氟化硼乙醚络合物
BH3·DMS 硼烷二甲硫醚络合物
(±)-BINAP 外消旋的2,2'-双(二苯基膦基)-1,1'-联萘
Bn 苄基
BnOH 苄醇
Boc2O 二碳酸二叔丁酯
BPin 4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷
Br2 溴
CaCl2 氯化钙
CBr4 四溴化碳
CbzCl 氯甲酸苄基酯
CCl4 四氯化碳
CDI 1,1'-羰基二咪唑
Cl2 氯气
Cs2CO3 碳酸铯
CuI 碘化铜(I)
CuSO4 硫酸铜(II)
DAST 二乙基氨基三氟化硫
DCE 二氯乙烷
DCM或CH2Cl2 二氯甲烷
DEAD 偶氮二甲酸二乙酯
Dess-Martin 1,1,1-三(乙酰基氧基)-1,1-二氢-1,2-苯并碘氧杂环戊烷-3-(1H)-酮
DIAD 偶氮二甲酸二异丙酯
DIEA 二异丙基乙基胺
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
DPPA 叠氮磷酸二苯酯
EA或EtOAc 乙酸乙酯
EDC 1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺
ES-LCMS 电喷雾液相色谱法-质谱分析
EtI 碘乙烷
EtMgBr 乙基溴化镁
Et3N 三乙胺
EtOH 乙醇
g 克
Grubbs I 苯亚甲基-双(三环己基膦)二氯化钌
h 小时
H2 氢气
HATU O-(7-氮杂苯并三唑-1-基)-N,N,N’,N”-四甲基脲鎓六氟磷酸盐
HCl 盐酸
H2O 水
HOBt 羟基苯并三唑
HPLC 高效液相色谱法
in vacuo 在真空
i-PrOH 异丙醇
[Ir(COD)OMe]2 二-μ-甲氧基双(1,5-环辛二烯)二铱(I)
KCN 氰化钾
K2CO3 碳酸钾
KI 碘化钾
KOAc 乙酸钾
K3PO4 磷酸钾
L 升
LAH或LiAlH4 氢化铝锂
LCMS 液相色谱法-质谱分析
LiHMDS 双(三甲基甲硅烷基)氨基锂
LiOH 氢氧化锂
LiOH·H2O 氢氧化锂一水合物
M 摩尔浓度
m-CPBA 间氯过苯甲酸
MeCN 乙腈
MeI 碘甲烷
MeMgBr 甲基溴化镁
MeNH2 甲胺
MeOH 甲醇
MgSO4 硫酸镁
min 分钟
mL 毫升
mmol 毫摩尔
mol 摩尔
MsCl 甲磺酰氯
MTBE 甲基叔丁基醚
N 正常
N2 氮气
NaBH4 硼氢化钠
NaBH3CN 氰基硼氢化钠
NaBH(OAc)3 三乙酰氧基硼氢化钠
NaCN 氰化钠
NaH 氢化钠
NaHCO3 碳酸氢钠
NaOH 氢氧化钠
Na2SO4 硫酸钠
NBS N-溴代琥珀酰亚胺
n-BuLi 正丁基锂
n-BuMgCl 正丁基氯化镁
NH3 氨
NH4Cl 氯化铵
NH4OAc 乙酸铵
NH4OH 氢氧化铵
NMP N-甲基-2-吡咯烷酮
NMR 核磁共振
OTf 三氟甲磺酸酯(盐)
Pd(OAc)2 乙酸钯(II)
Pd/C 钯/碳
PdCl2(dppf) [1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)
Pd2(dba)3 三(二亚苄基丙酮)二钯(0)
Pd(OH)2 氢氧化钯(II)
Pd(PPh3)2Cl2 双(三苯基膦)二氯化钯(II)
PE 石油醚
POCl3 磷酰氯
PPh3 三苯基膦
p-TsCl 对甲苯磺酰氯
p-TsOH 对甲苯磺酸
SFC 超临界流体色谱法
SOCl2 亚硫酰氯
TBAF 四正丁基氟化铵
TBS 叔丁基二甲基甲硅烷基
TBSCl 叔丁基二甲基甲硅烷基氯
t-BuOH 叔丁基醇
t-BuOK 叔丁醇钾
t-BuONa 叔丁醇钠
TFA 三氟乙酸
Tf2O 三氟甲磺酸酐
THF 四氢呋喃
TLC 薄层色谱
TMS-N3 三甲基甲硅烷基叠氮化物
TosMIC 对甲苯磺酰基甲基异腈
Xantphos 4,5-双(二苯基膦基)-9,9-二甲基呫吨
Zn 锌金属
通用合成方案
本发明的化合物可以通过多种方法制备,包括众所周知的标准合成方法。下面列出了说明性的一般合成方法,然后在工作实施例中制备了本发明的具体化合物。技术人员将理解,如果本文所述的取代基与本文所述的合成方法不相容,则可以用对反应条件稳定的合适的保护基保护该取代基。可以在反应顺序的适当位置去除保护基,以提供所需的中间体或目标化合物。在以下描述的所有方案中,根据合成化学的一般原理,在必要时使用针对敏感或反应性基团的保护基。根据有机合成的标准方法(T.W.Green和P.G.M.Wuts,(1991)Protecting Groups in Organic Synthesis,John Wiley&Sons,对于保护基团引入作为参考)来处理保护基团。使用本领域技术人员显而易见的方法在化合物合成的方便阶段除去这些基团。方法的选择以及反应条件和执行顺序应与本发明化合物的制备相一致。起始原料是可商购的,或者是使用本领域技术人员已知的方法由可商购的起始原料制得的。
某些式(I)的化合物可根据方案1、2或3或类似方法制备。
方案1
方案2
方案3
实验
下列实施例说明了本发明。这些实施例无意于限制本发明的范围,而是为技术人员提供指导以制备和使用本发明的化合物、组合物和方法。尽管描述了本发明的特定实施方案,但是本领域技术人员将理解,可以在不脱离本发明的精神和范围的情况下进行各种改变和修改。除非另有说明,否则试剂是可商购的或根据文献中的步骤制备。在过程、方案和实施例的描述中使用的符号和惯例与当代科学文献中使用的符号和惯例一致,例如,Journal of the American Chemical Society或Journal of Biological Chemistry。
在实施例中:
制备型HPLC在Gilson UV/VIS-156上进行,并在220/254nm处进行紫外检测,Gilson 281自动收集。HPLC柱通常使用ASB-C18 21.2x150mm或Phenomenex21.2x150mm。HPLC梯度(酸性条件,0.01%HCl或0.1%甲酸)使用0-100%乙腈与水和相应的酸,梯度形状针对单个分离进行了优化。除非特别说明,否则化合物在HCl系统中分离,因此以HCl盐形式获得。但是,这些化合物也可以分离并用作游离碱。优化了HPLC梯度(碱性条件,0.05%NH3·H2O或中性条件,0.01%NH4HCO3)进行单独分离。
化学位移以百万分之一(ppm)单位表示。偶合常数(J)以赫兹(Hz)为单位。分裂模式描述了明显的多重性,并指定为s(单峰),d(双峰),t(三重峰),dd(双二重峰),dt(双三重峰),dq(双四重峰),m(多重峰),br(宽峰)。
快速柱色谱在硅胶上进行。
使用的命名程序是ACDLAB 11.0Namebatch,ACD IUPAC或ChemDraw。
中间体
中间体1:2,6-二氯异烟酸甲酯,盐酸盐
在0℃向2,6-二氯异烟酸(300g,1563mmol)在MeOH(2L)中的溶液中分批添加SOCl2(0.228L,3125mmol)。将混合物在70℃搅拌14h。将反应混合物浓缩且添加饱和NaHCO3水溶液(500mL)。将混合物用DCM(500mL×3)萃取。合并的有机层用盐水(200mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到2,6-二氯异烟酸甲酯(300g,1311mmol,84.0%产率),其为灰白色固体:1H NMR(400MHz,CD3OD)δppm 7.87(s,2H),3.96(s,3H);ES-LCMS m/z 206.1,208.1[M+H]+.
中间体2:N-(哌啶-4-基甲基)乙酰胺,盐酸盐
步骤1:4-(乙酰氨基甲基)哌啶-1-甲酸叔丁酯
向4-(氨基甲基)哌啶-1-甲酸叔丁酯(150g,700mmol)在DCM(1.2L)中的混合物中滴加Ac2O(93g,910mmol)。将混合物在15℃搅拌2h。将溶液浓缩以得到淡黄色油状物4-(乙酰氨基甲基)哌啶-1-甲酸叔丁酯(180g,697mmol,100.0%产率):1H NMR(400MHz,CDCl3)δppm 5.67(br.s,1H),4.09(br.s,2H),3.18-2.99(m,2H),2.66(t,J=11.7Hz,2H),1.98(s,3H),1.71-1.55(m,3H),1.43(s,9H),1.10(m,2H);ES-LCMS m/z 157.1[M-t-Bu+H]+.
步骤2:N-(哌啶-4-基甲基)乙酰胺,盐酸盐
将4-(乙酰氨基甲基)哌啶-1-甲酸叔丁酯(360g,1404mmol)溶于HCl溶液(4M在EtOAc中,1L,4mol)。然后将反应混合物在15℃搅拌0.5h。形成大量固体且反应完成。产物N-(哌啶-4-基甲基)乙酰胺盐酸盐通过过滤获得为白色固体(265g,1307mmol,93.0%产率):1H NMR(400MHz,CD3OD)δppm 3.41(d,J=12.1Hz,2H),3.22(d,J=6.4Hz,2H),2.99(t,J=12.3Hz,2H),2.13(s,3H),1.99-1.85(m,3H),1.52-1.39(m,2H)。
中间体3:2-(哌啶-4-基)乙酸甲酯,盐酸盐
向2-(1-(叔丁氧基羰基)哌啶-4-基)乙酸(62g,255mmol)在MeOH(300mL)中的溶液中添加二氯化硫(40mL,353mmol)。将混合物在50℃搅拌10h,然后浓缩以得到白色固体的2-(哌啶-4-基)乙酸甲酯,盐酸盐(50g,245mmol,96.0%产率):1H NMR(400MHz,CD3OD)δppm3.68(s,3H),3.43-3.33(m,2H),3.01(t,J=12.8Hz,2H),2.40-2.29(m,2H),2.09(m,1H),1.97(d,J=14.1Hz,2H),1.57-1.41(m,2H);ES-LCMS m/z 158.2[M+H]+.
中间体4:4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
步骤1:5-(苄基氧基)-2-氯嘧啶
向2-氯嘧啶-5-醇(45g,345mmol)在DMF(1L)中的混合物中添加Cs2CO3(337g,1034mmol)和(溴甲基)苯(49.1mL,414mmol)。将混合物在15℃在N2气氛搅拌8h。然后将混合物浓缩且添加饱和NaHCO3水溶液(150mL)。水层用EtOAc(500mL x2)萃取,且合并的萃取物用盐水(150mL x2)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色油状物的5-(苄基氧基)-2-氯嘧啶(78g,318mmol,92.0%产率):1H NMR(400MHz,CD3OD)δppm 8.45(s,2H),7.52-7.29(m,5H),5.23(s,2H);ES-LCMS m/z 221.2,223.1[M+H]+.
步骤2:4-(5-(苄基氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向5-(苄基氧基)-2-氯嘧啶(15g,61.2mmol)和哌嗪-1-甲酸叔丁酯(17.09g,92mmol)在DMF(200mL)中的混合物中添加Cs2CO3(59.8g,184mmol)。将混合物在120℃搅拌10h。将反应混合物浓缩且通过硅胶柱色谱法(PE/EtOAc=5/1)纯化。将所有通过TLC(PE/EA=3/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到白色固体的4-(5-(苄基氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(10g,25.6mmol,41.9%产率):1H NMR(400MHz,CDCl3)δppm8.13(s,2H),7.43-7.31(m,5H),5.03(s,2H),3.75-3.65(m,4H),3.56-3.43(m,4H),1.49(s,9H);ES-LCMS m/z 371.3[M+H]+.
步骤3:4-(5-羟基嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-(苄基氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(10g,25.6mmol)在MeOH(30mL)中的溶液中添加Pd/C(10wt%,2.73g,2.56mmol)。将混合物在1atm H2气氛在15℃搅拌0.5h。将混合物过滤且浓缩以得到淡黄色固体的4-(5-羟基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(7.5g,22.74mmol,89.0%产率):1H NMR(400MHz,CD3OD)δppm 8.03(s,2H),3.70-3.59(m,4H),3.50(d,J=4.5Hz,4H),1.50(s,9H);ES-LCMS m/z 225.2[M-t-Bu+H]+.
步骤4:4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向2,6-二氯异烟酸甲酯,盐酸盐(6.7g,27.4mmol)和4-(5-羟基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(7.4g,22.44mmol)在DMF(80mL)中的混合物中添加K2CO3(9.30g,67.3mmol)。将混合物在50℃搅拌10h。然后将溶液浓缩且添加饱和NaHCO3水溶液(150mL)。水层用DCM(500mL x2)萃取,且合并的萃取物用盐水(150mL x2)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=5/1)纯化。将所有通过TLC(PE/EA=3/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到黄色油状物4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(8.4g,16.80mmol,74.9%产率):1H NMR(400MHz,CD3OD)δppm 8.31(s,2H),7.62(s,1H),7.51(s,1H),3.99(s,3H),3.90-3.80(m,4H),3.55(m,4H),1.51(s,9H);ES-LCMS m/z 394.2,396.1[M-t-Bu+H]+.
步骤5:4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(8g,16.00mmol)和(3,5-二氯苯基)硼酸(7.63g,40.0mmol)在DMF(100mL)中的混合物中添加K2CO3(6.64g,48.0mmol)和PdCl2(dppf)(0.586g,0.800mmol)。将混合物在80℃在N2气氛搅拌2h。将混合物浓缩且通过硅胶柱色谱法(PE/EtOAc=5/1)纯化。将所有通过TLC(PE/EA=3/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到无色油状物4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(7.4g,11.22mmol,70.1%产率):1H NMR(400MHz,CDCl3)δppm 8.30(s,2H),7.95(s,1H),7.75(d,J=1.3Hz,2H),7.48(s,1H),7.37(s,1H),4.00(s,3H),3.89-3.75(m,4H),3.60-3.45(m,4H),1.49(s,9H);ES-LCMS m/z 504.1,506.1[M-t-Bu+H]+.
步骤6:4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(7.4g,11.22mmol)在MeOH(150mL)中的混合物中添加NaBH4(2.123g,56.1mmol)。将混合物在15℃在N2气氛搅拌10分钟,然后浓缩且添加饱和NaHCO3水溶液(150mL)。水层用DCM(500mL x2)萃取且合并的萃取物用盐水(150mL x2)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色油状物4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(7.2g,10.82mmol,96.0%产率):1H NMR(400MHz,CD3OD)δppm8.35(s,2H),7.81(s,2H),7.60(s,1H),7.44(s,1H),7.06(s,1H),4.75(s,2H),3.89-3.82(m,4H),3.54(m,4H),1.51(s,9H);ES-LCMS m/z 532.2,534.2[M+H]+.
步骤7:4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(4.5g,6.76mmol)在DCM(150mL)中的混合物中添加MsCl(0.79mL,10.14mmol)和DIEA(3.54mL,20.28mmol)。将混合物在15℃在N2气氛搅拌10分钟。然后将溶液浓缩且添加饱和NaHCO3水溶液(150mL)。水层用DCM(500mL x2)萃取,且合并的萃取物用盐水(150mLx2)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色油状物4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(5g,6.55mmol,97.0%产率):1H NMR(400MHz,CD3OD)δppm 8.37(s,2H),7.85(s,2H),7.48(s,1H),7.41(s,1H),7.16(s,1H),3.86(d,J=5.5Hz,6H),3.55(s,4H),3.25-3.23(m,3H),1.51(s,9H);ES-LCMS m/z 554.2,556.2[M-t-Bu+H]+.
中间体5:4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
步骤1:1-(5-(苄基氧基)嘧啶-2-基)-1,4-二氮杂环庚烷
向5-(苄基氧基)-2-氯嘧啶(4g,17.22mmol)和Cs2CO3(11.22g,34.4mmol)在DMF(50mL)中的溶液中添加1,4-二氮杂环庚烷(3.45g,34.4mmol)。然后将反应混合物在130℃搅拌12h。将固体过滤掉且将溶液浓缩以得到粗产物,其通过硅胶色谱法(PE/EtOAc=1/0至1/2)纯化。将所有通过TLC(PE/EtOAc=2/1,Rf=0.15)发现包含产物的级分合并且浓缩以得到淡黄色固体的1-(5-(苄基氧基)嘧啶-2-基)-1,4-二氮杂环庚烷(4.0g,12.97mmol,75.0%产率):1H NMR(400MHz,CDCl3)δppm 8.17-7.97(m,2H),7.45-7.25(m,5H),5.00(s,2H),3.92-3.65(m,4H),3.12-2.96(m,2H),2.90-2.71(m,2H),1.95-1.82(m,2H);ES-LCMSm/z 285.2[M+H]+.
步骤2:4-(5-(苄基氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
向1-(5-(苄基氧基)嘧啶-2-基)-1,4-二氮杂环庚烷(4g,12.97mmol)和DIEA(5.03g,38.9mmol)在DCM(50mL)中的溶液中添加Boc2O(3.61mL,15.57mmol)。然后将反应混合物在20℃搅拌12h。添加DCM(50mL)且用柠檬酸水溶液(50mL×3)洗涤。有机层用Na2SO4干燥且浓缩以得到淡黄色固体的4-(5-(苄基氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(3.9g,9.13mmol,70.4%产率):1H NMR(400MHz,CDCl3)δppm 8.11(d,J=2.6Hz,2H),7.44-7.28(m,5H),5.05(d,J=3.1Hz,2H),3.82(t,J=5.1Hz,2H),3.72(q,J=5.6Hz,2H),3.55(td,J=5.7,19.4Hz,2H),3.39-3.31(m,2H),1.92-1.81(m,2H),1.32(s,9H);ES-LCMSm/z 385.2[M+H]+.
步骤3:4-(5-羟基嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
向4-(5-(苄基氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(3.9g,9.13mmol)在MeOH(50mL)中的溶液中添加Pd/C(10wt%,0.972g,0.913mmol)。然后将反应混合物在20℃在H2气氛(15psi)搅拌1h。将固体过滤掉且将溶液浓缩以得到黄色油状物4-(5-羟基嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(2.9g,8.87mmol,97.0%产率):1H NMR(400MHz,CDCl3)δppm7.97(d,J=2.2Hz,2H),3.80(t,J=5.7Hz,2H),3.70(q,J=5.6Hz,2H),3.61-3.52(m,2H),3.36(s,2H),1.91-1.79(m,2H),1.36(d,J=15.9Hz,9H);ES-LCMSm/z 295.2[M+H]+.
步骤4:4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
向4-(5-羟基嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(2.9g,8.87mmol)和2,6-二氯异烟酸甲酯(3.08g,13.30mmol)在DMF(50mL)中的溶液中添加K2CO3(2.451g,17.73mmol)。然后将反应混合物在80℃搅拌2h。将固体过滤掉且将溶液浓缩以得到粗产物,其通过柱色谱(PE/EtOAc=1/0至1/1)纯化。将所有通过TLC(PE/EtOAc=5/1,Rf=0.45)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(3.2g,6.78mmol,76.0%产率):1HNMR(400MHz,CDCl3)δppm 8.22(s,2H),7.56(s,1H),7.39(s,1H),3.96(s,3H),3.92-3.85(m,2H),3.80-3.74(m,2H),3.57(s,2H),3.42-3.29(m,2H),1.97(q,J=6.1Hz,2H),1.43(d,J=7.9Hz,9H);ES-LCMSm/z464.2,466.2[M+H]+.
步骤5:4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
在N2气氛向4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(3.2g,6.78mmol)和(3,5-二氯苯基)硼酸(1.940g,10.17mmol)在DMF(50mL)中的溶液中添加K2CO3(1.873g,13.55mmol)和PdCl2(dppf)(0.248g,0.339mmol)。然后将反应混合物在80℃搅拌2h。将溶液浓缩以得到粗产物,其通过柱色谱(PE/EtOAc=1/0至1/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.55)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(3.1g,4.88mmol,72.0%产率):1HNMR(400MHz,CDCl3)δppm 8.29(s,2H),7.96(s,1H),7.77(d,J=0.9Hz,2H),7.49(s,1H),7.37(s,1H),4.00(s,3H),3.94-3.86(m,2H),3.79(d,J=5.3Hz,2H),3.58(d,J=4.4Hz,2H),3.40-3.27(m,2H),2.04-1.97(m,2H),1.45(d,J=6.2Hz,9H);ES-LCMS m/z 574.2,576.2[M+H]+.
步骤6:4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
在20℃下,向4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1.2g,1.889mmol)在MeOH(50mL)中的溶液中分批添加NaBH4(0.429g,11.33mmol)。然后将反应混合物在20℃搅拌1h。TLC(PE/EtOAc=3/1,Rf=0.55)显示反应完成。将溶液浓缩且添加DCM(50mL)。有机层用水(50mL)和盐水(50mL)洗涤。合并的有机层用Na2SO4干燥且浓缩以得到淡黄色固体的4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1.1g,1.707mmol,90.0%产率):1H NMR(400MHz,CDCl3)δppm 8.15-8.00(m,2H),7.56(s,2H),7.30-7.22(m,1H),7.17(s,1H),6.78(s,1H),4.65(s,2H),3.74(s,2H),3.63(d,J=4.9Hz,2H),3.42(s,2H),3.24-3.09(m,2H),1.86(s,2H),1.29(d,J=4.4Hz,9H);ES-LCMSm/z546.2,548.2[M+H]+.
步骤7:4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1.1g,1.707mmol)和DIEA(0.662g,5.12mmol)在DCM(20mL)中的溶液中添加MsCl(0.2mL,2.56mmol)。然后将反应混合物在0℃搅拌10分钟。添加水(50mL)且用DCM(25mL×3)萃取。合并的有机层用Na2SO4干燥且浓缩以得到黄色固体的4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1.25g,1.629mmol,95.0%产率):1H NMR(400MHz,CDCl3)δppm8.28(s,2H),7.72(s,2H),7.42(s,1H),7.37(s,1H),6.96(s,1H),5.29(s,2H),3.96-3.88(m,2H),3.79(d,J=5.0Hz,2H),3.58(d,J=4.0Hz,2H),3.39-3.28(m,2H),3.13(s,3H),2.02(m,2H),1.45(d,J=5.5Hz,9H);ES-LCMS m/z 624.2,626.2[M+H]+.
中间体6:4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
步骤1:5-(苄基氧基)-2-溴吡啶
向6-溴吡啶-3-醇(30g,172mmol)和(溴甲基)苯(35.4g,207mmol)在DMF(300mL)中的溶液中添加K2CO3(35.7g,259mmol)。将混合物在20℃搅拌2h。然后将混合物过滤且将滤液浓缩,在DCM(500mL)和饱和NaHCO3水溶液(300mL)之间分离。合并的有机萃取物用盐水(200mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=5/1)纯化。将所有通过TLC(PE/EtOAc=5/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到棕色固体的5-(苄基氧基)-2-溴吡啶(40g,148mmol,86.0%产率):1H NMR(400MHz,CDCl3)δppm8.13(d,J=2.9Hz,1H),7.49-7.29(m,6H),7.21-7.09(m,1H),5.08(s,2H);ES-LCMSm/z264.0,266.0[M+H]+.
步骤2:4-(5-(苄基氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
在N2气氛向哌嗪-1-甲酸叔丁酯(30.5g,164mmol)和Cs2CO3(89g,273mmol)在THF(500mL)中的混合物中添加Pd2(dba)3(12.48g,13.63mmol)、5-(苄基氧基)-2-溴吡啶(36g,136mmol)和(±)-BINAP(8.49g,13.63mmol)。将混合物在70℃搅拌12h,然后浓缩,在DCM(500mL)和饱和NaHCO3水溶液(200mL)之间分离。合并的有机萃取物用盐水(200mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=4/1)纯化。将所有通过TLC(PE/EtOAc=4/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(5-(苄基氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(50g,122mmol,89.0%产率):1H NMR(400MHz,CDCl3)δppm 8.39(d,J=2.6Hz,1H),8.23(d,J=8.8Hz,1H),7.99(d,J=3.1Hz,1H),7.40-7.36(m,5H),5.03(s,2H),3.53(d,J=5.3Hz,4H),3.39(d,J=5.3Hz,4H),1.48(s,9H);ES-LCMS m/z 370.3[M+H]+.
步骤3:4-(5-羟基吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-(苄基氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(45g,122mmol)在MeOH(500mL)中的溶液中添加Pd/C(10wt%,12.96g,12.18mmol)。将混合物在20℃在H2气氛在50psi搅拌10h。将溶液过滤且浓缩以得到淡黄色油状物4-(5-羟基吡啶-2-基)哌嗪-1-甲酸叔丁酯(26g,88mmol,72.6%产率):1H NMR(400MHz,CDCl3)δppm 7.86(br.s,1H),7.18-7.04(m,1H),6.61(d,J=8.8Hz,1H),3.62-3.47(m,4H),3.33(d,J=4.0Hz,4H),1.47(s,9H);ES-LCMS m/z 280.2[M+H]+.
步骤4:4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向2,6-二氯异烟酸甲酯(8g,38.8mmol)和K2CO3(10.73g,78mmol)在DMF(200mL)中的混合物中添加4-(5-羟基吡啶-2-基)哌嗪-1-甲酸叔丁酯(14.10g,50.5mmol)。将混合物在80℃搅拌2h。然后将溶液浓缩,在DCM(600mL)和饱和NaHCO3溶液(300mL)之间分离。合并的有机萃取物用盐水(200mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=1/1)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.3)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(15g,30.1mmol,77.0%产率):1H NMR(400MHz,CDCl3)δppm 8.07(d,J=2.6Hz,1H),7.54(s,1H),7.37-7.27(m,2H),6.68(d,J=8.8Hz,1H),3.95-3.91(m,3H),3.56-3.54(m,8H),1.48(s,9H);ES-LCMS m/z 449.1,451.1[M+H]+.
步骤5:4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
在N2气氛向4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(15g,33.4mmol)和(3,5-二氯苯基)硼酸(8.93g,46.8mmol)在1,4-二噁烷(200mL)中的溶液中添加PdCl2(dppf)(2.445g,3.34mmol)和K2CO3(13.85g,100mmol)。将混合物在90℃搅拌4h。添加水(200mL),然后用DCM(200mL×3)萃取。合并有机层,用Na2SO4干燥,过滤且浓缩。粗物质通过柱色谱(PE/EtOAc=1/1)纯化以得到棕色固体的4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(10g,16.27mmol,48.7%产率):1H NMR(400MHz,CDCl3)δppm 8.13(d,J=2.6Hz,1H),7.93(s,1H),7.78(d,J=1.3Hz,2H),7.54-7.38(m,2H),7.38-7.33(m,1H),6.73(d,J=9.3Hz,1H),3.98(s,3H),3.56-3.54(m,8H),1.49(s,9H);ES-LCMS m/z 559.1,561.1[M+H]+.
步骤6:4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(9.9g,17.70mmol)在MeOH(300mL)中的溶液中添加NaBH4(2.008g,53.1mmol)。溶液在20℃搅拌0.5h。添加饱和NH4Cl水溶液(10mL)且将溶液浓缩,在DCM(300mL)和饱和NaHCO3溶液(100mL)之间分离。合并的有机萃取物用盐水洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=1/1)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到淡黄色油状物4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(8g,13.55mmol,77.0%产率):1H NMR(400MHz,CDCl3)δppm 8.10(d,J=2.6Hz,1H),7.75(d,J=1.8Hz,2H),7.44-7.38(m,2H),7.33(s,1H),6.84(s,1H),6.72(d,J=8.8Hz,1H),4.78(d,J=3.5Hz,2H),3.56-3.54(m,8H),1.49(s,9H);ES-LCMS m/z 531.1,533.1[M+H]+.
步骤7:4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(6g,11.29mmol)和DIEA(2.92g,22.58mmol)在DCM(200mL)中的溶液中添加MsCl(1.552g,13.55mmol)。溶液在20℃搅拌0.5h。然后溶液用水(100mL×3)洗涤。有机层用Na2SO4干燥,过滤且浓缩以得到棕色油状物4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(6g,8.86mmol,78.0%产率):1HNMR(400MHz,CDCl3)δppm 8.12(d,J=2.6Hz,1H),7.73(d,J=1.8Hz,2H),7.46-7.32(m,3H),6.88(s,1H),6.73(d,J=9.3Hz,1H),5.26(s,2H),3.58-3.55(m,8H),3.10(s,3H),1.49(s,9H);ES-LCMS m/z 609.1,611.1[M+H]+.
中间体7:(2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲醇,3盐酸盐
向4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(2.5g,3.39mmol)在MeOH(20mL)中的溶液中添加HCl溶液(4M在MeOH中,20mL,80mmol)。将混合物在20℃搅拌0.5h。将混合物浓缩以得到棕色固体的(2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲醇,3盐酸盐(1.8g,2.483mmol,73.3%产率):1H NMR(400MHz,CD3OD)δppm 8.29-8.19(m,2H),7.83(d,J=1.5Hz,2H),7.70(s,1H),7.66-7.61(m,1H),7.49(s,1H),7.19(s,1H),4.79(s,2H),4.11-4.06(m,4H),3.56-3.51(m,4H);ES-LCMS m/z 431.1,433.1[M+H]+.
中间体8:3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
步骤1:3-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
向(2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲醇,3盐酸盐(1.8g,2.483mmol)、K2CO3(1.030g,7.45mmol)在DMF(5mL)中的混合物中添加3-溴丙酸乙酯(1.349g,7.45mmol)。将混合物在80℃搅拌3h,然后浓缩且残余物用DCM(100mL)和水(100mL)稀释。水相用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物,其在硅胶上通过硅胶柱色谱法(DCM/MeOH=1/0至10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到棕色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(1.2g,2.073mmol,83.0%产率):1H NMR(400MHz,CDCl3)δppm8.08(d,J=2.6Hz,1H),7.78-7.73(m,2H),7.39(td,J=5.8,3.0Hz,2H),7.32(s,1H),6.81(s,1H),6.70(d,J=9.3Hz,1H),4.79-4.72(m,2H),4.14(q,J=7.1Hz,2H),3.52(d,J=5.3Hz,4H),2.77-2.72(m,2H),2.63-2.54(m,6H),1.25(t,J=7.1Hz,3H);ES-LCMS m/z531.1,533.1[M+H]+.
步骤2:3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
向3-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(0.15g,0.259mmol)、DIEA(0.136mL,0.777mmol)在DCM(50mL)中的混合物中添加MsCl(0.040mL,0.518mmol)。将混合物在20℃搅拌0.5h,然后添加水(50mL),且用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到棕色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(160mg,0.191mmol,73.5%产率):1H NMR(400MHz,CDCl3)δppm 8.07(br.s,1H),7.71(br.s,2H),7.40-7.33(m,2H),7.20(br.s,1H),6.82(d,J=11.5Hz,1H),6.69(d,J=8.8Hz,1H),5.28-5.18(m,2H),4.15-4.07(m,2H),3.51(br.s,4H),3.13-3.03(m,3H),2.76-2.66(m,2H),2.60-2.49(m,6H),1.27-1.20(m,3H);ES-LCMS m/z 609.2,611.2[M+H]+.
中间体9:4-(5-溴嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向哌嗪-1-甲酸叔丁酯(28.9g,155mmol)在DMF(200mL)中的溶液中添加5-溴-2-氯嘧啶(20g,103mmol)和Cs2CO3(101g,310mmol)。将混合物在80℃搅拌10h。然后粗产物在DCM(500mL)和饱和NaHCO3溶液(300mL)之间分离。合并的有机萃取物用盐水(200mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=3/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到白色固体的4-(5-溴嘧啶-2-基)哌嗪-1-甲酸叔丁酯(38g,100mmol,96.0%产率):1H NMR(400MHz,CD3OD)δppm8.39(s,2H),3.87-3.74(m,4H),3.50(s,4H),1.57-1.45(m,9H);ES-LCMS m/z 287.1,289.1[M-t-Bu+H]+.
中间体10:4-(5-((3',5'-二氯-5-(羟基甲基)-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
步骤1:3-溴-5-羟基苯甲醛
在-10℃向甲苯(200mL)和n-BuLi(3.0M在THF中,167mL,417mmol)的混合物中添加n-BuMgCl(2.0M在THF中,59.5mL,119mmol)。将反应混合物在-10℃搅拌0.5h,然后经0.5h滴加3,5-二溴苯酚(50g,198mmol)在甲苯(200mL)中的溶液。在-10℃再搅拌0.5h后,将反应混合物冷却至-40℃,且经0.4h滴加DMF(309mL,3.97mol)。然后将反应混合物缓慢温热至20℃且搅拌10.5h。该反应在0℃用HCl水溶液(10%)小心淬灭且用EtOAc(500mL×3)萃取。合并的有机萃取物用水(500mL x2)和盐水(500mL×3)洗涤,用Na2SO4干燥且过滤。粗物质通过硅胶柱色谱法(PE/EtOAc=7/1至4/1)纯化。将所有通过TLC(PE/EA=3/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到淡黄色固体的3-溴-5-羟基苯甲醛(15g,52.2mmol,26.3%产率):1H NMR(400MHz,CD3OD)δppm 9.82(s,1H),7.47(s,1H),7.22(d,J=2.0Hz,2H);ES-LCMSm/z 201.2[M+H]+.
步骤2:3',5'-二氯-5-羟基-[1,1'-联苯]-3-甲醛
向(3,5-二氯苯基)硼酸(84g,438mmol)和3-溴-5-羟基苯甲醛(80g,398mmol)在1,4-二噁烷(2L)中的溶液中添加Cs2CO3(389g,1194mmol)和PdCl2(dppf)(1.456g,1.990mmol)。然后将混合物在80℃在N2气氛搅拌8h。混合物用稀HCl(水溶液,1.0M)调节至pH=6且浓缩以得到棕色固体,将其进一步用H2O(2L)稀释,过滤以得到白色固体的3',5'-二氯-5-羟基-[1,1'-联苯]-3-甲醛(110g,268mmol,67.3%产率):1H NMR(400MHz,CD3OD)δppm9.96(s,1H),7.62(d,J=1.5Hz,3H),7.52(d,J=2.0Hz,1H),7.31(d,J=4.4Hz,2H);ES-LCMS m/z 267.1[M+H]+.
步骤3:3',5'-二氯-5-(羟基甲基)-[1,1'-联苯]-3-醇
向3',5'-二氯-5-羟基-[1,1'-联苯]-3-甲醛(3g,8.99mmol)在MeOH(50mL)中的溶液中添加NaBH4(2g,52.9mmol)。然后,将混合物在20℃搅拌1h。添加饱和NH4Cl水溶液(40mL)且将溶液浓缩,然后在DCM(50mL)和饱和NaHCO3(30mL)溶液之间分离。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=3/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.2)发现包含产物的级分合并且浓缩以得到白色固体的3',5'-二氯-5-(羟基甲基)-[1,1'-联苯]-3-醇(2.5g,8.52mmol,95.0%产率):1H NMR(400MHz,CD3OD)δppm 7.55(d,J=2.0Hz,2H),7.41(t,J=1.8Hz,1H),7.07(s,1H),6.90(d,J=16.1Hz,2H),4.62(s,2H)。
步骤4:4-(5-((3',5'-二氯-5-(羟基甲基)-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-溴嘧啶-2-基)哌嗪-1-甲酸叔丁酯(2.89g,7.58mmol)和3',5'-二氯-5-(羟基甲基)-[1,1'-联苯]-3-醇(2g,6.32mmol)在DMSO(10mL)中的混合物中添加CuI(0.060g,0.316mmol)、吡啶甲酸(0.039g,0.316mmol)和K3PO4(4.02g,18.95mmol)。溶液在130℃在N2气氛搅拌10h。添加饱和NH4Cl水溶液(40mL)且将溶液浓缩,然后在DCM(50mL)和饱和NaHCO3溶液(50mL)之间分离。合并的有机萃取物用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=1/0至1/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.45)发现包含产物的级分合并且浓缩以得到棕色固体的4-(5-((3',5'-二氯-5-(羟基甲基)-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(850mg,1.441mmol,22.8%产率):1H NMR(400MHz,CDCl3)δppm 8.19(s,2H),7.39(s,2H),7.33(t,J=1.9Hz,1H),7.21(s,1H),7.00(s,1H),6.94(s,1H),4.71(s,2H),3.78(d,J=5.3Hz,4H),3.50(d,J=4.9Hz,4H),1.48(s,9H);ES-LCMS m/z 475.2,477.2[M-t-Bu+H]+.
步骤5:4-(5-((3',5'-二氯-5-(羟基甲基)-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
在0℃向4-(5-((3',5'-二氯-5-(羟基甲基)-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(850mg,1.441mmol)和DIEA(559mg,4.32mmol)在DCM(10mL)中的溶液中添加MsCl(0.168mL,2.162mmol)。然后将反应混合物在0℃搅拌10min。添加水(50mL)且水相用DCM(25mL×3)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色油状物4-(5-((3',5'-二氯-5-(((甲基磺酰基)氧基)甲基)-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(950mg,1.403mmol,97.0%产率):1H NMR(400MHz,CD3OD)δppm 8.30-8.26(m,2H),7.73(d,J=3.1Hz,1H),7.61-7.57(m,2H),7.28-7.23(m,1H),7.07(s,1H),6.77(d,J=9.0Hz,1H),5.28(s,2H),3.80(d,J=5.1Hz,4H),3.56-3.52(m,4H),3.10(s,3H),1.48(s,9H);ES-LCMS m/z 553.1,555.1[M-t-Bu+H]+.
中间体11:4-(5-((6-(3-氯-5-氟苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
步骤1:4-(5-((6-(3-氯-5-氟苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(750mg,1.167mmol)在DMF(5mL)中的溶液中添加(3-氯-5-氟苯基)硼酸(305mg,1.750mmol)、PdCl2(dppf)(85mg,0.117mmol)和K2CO3(484mg,3.50mmol)。将混合物在80℃在N2气氛搅拌1h。将混合物浓缩且通过硅胶柱色谱法(PE/EtOAc=3/1)纯化。将所有通过TLC(PE/EA=3/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到黄色固体的4-(5-((6-(3-氯-5-氟苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(500mg,0.643mmol,55.1%产率):1H NMR(400MHz,CD3OD)δppm 8.38(s,1H),7.45-7.35(3H),7.16-7.15(m,1H),6.61-6.60(m,1H),6.51-6.40(m,1H),3.75(s,3H),3.50-3.40(m,8H),1.45(s,9H);ES-LCMSm/z 488.2[M-t-Bu+H]+.
步骤2:4-(5-((6-(3-氯-5-氟苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3-氯-5-氟苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(500mg,0.643mmol)在MeOH(20mL)中的混合物中添加NaBH4(48.7mg,1.287mmol)。将混合物在15℃搅拌20min,然后浓缩。添加水(50mL)且将混合物用DCM(50mLx2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到白色固体的4-(5-((6-(3-氯-5-氟苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.543mmol,84.0%产率):1H NMR(400MHz,CD3OD)δppm8.32(s,1H),7.71(s,1H),7.59-7.53(m,2H),7.33-7.30(m,1H),7.22-7.18(m,1H),7.04(s,1H),4.73(s,2H),3.84-3.80(m,4H),3.52(s,4H),1.49(s,9H);ES-LCMS m/z 516.2,518.2[M+H]+.
步骤3:4-(5-((6-(3-氯-5-氟苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3-氯-5-氟苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1g,1.357mmol)在DCM(20mL)中的混合物中添加MsCl(0.159mL,2.035mmol)和DIEA(0.711mL,4.07mmol)。将混合物在25℃搅拌20分钟,然后添加H2O(100mL)。将混合物用DCM(100mL x2)萃取且合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色油状物4-(5-((6-(3-氯-5-氟苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(800mg,0.902mmol,66.5%产率):1H NMR(400MHz,CD3OD)δppm 8.80(s,1H),7.77(s,1H),7.73-7.70(m,2H),7.60-7.57(m,1H),7.29-7.19(m,2H),5.45(s,2H),3.97-3.89(m,4H),3.73-3.59(m,4H),3.21(s,3H),1.49(s,9H);ES-LCMS m/z 538.2,540.2[M+H]+.
中间体12:4-(5-((6-(3-氯-4,5-二氟苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
步骤1:(E)-2,6-二异丙基-N-(吡啶-2-基亚甲基)苯胺
在装配Dean-Stark分离器(trap)的圆底烧瓶中将2,6-二异丙基苯胺(2.70mL,11.28mmol)添加至2-吡啶甲醛(0.822mL,11.28mmol)在甲苯(100mL)中的溶液中,然后添加催化量的p-TsOH(0.1g)。将反应混合物在140℃回流24h以去除水。将反应混合物冷却至25℃,然后用水(100mL)洗涤一次,且将溶液浓缩。所得残余物通过硅胶柱色谱法(PE/EtOAc=4/1)纯化。将所有通过TLC(DCM/MeOH=30/1,Rf=0.7)发现包含产物的级分合并且浓缩以得到棕色油状物的(E)-2,6-二异丙基-N-(吡啶-2-基亚甲基)苯胺(450mg,1.351mmol,12.0%产率):1H NMR(400MHz,CDCl3)δppm 8.73(d,J=4.9Hz,1H),8.31(s,1H),8.27(d,J=7.9Hz,1H),7.85(t,J=7.3Hz,1H),7.41(dd,J=5.3,6.6Hz,1H),7.20-7.11(m,3H),2.97(d,J=6.7,13.9Hz,2H),1.18(d,J=6.6Hz,12H)。
步骤2:2-(3-氯-4,5-二氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷
向1-氯-2,3-二氟苯(3g,20.20mmol)和4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷)(6.15g,24.24mmol)在正庚烷(30mL)中的溶液中添加(E)-2,6-二异丙基-N-(吡啶-2-基亚甲基)苯胺(0.336g,1.010mmol)和氯代(1,5-环辛二烯)铱(I)二聚体(0.678g,1.010mmol)。将反应混合物在110℃在N2气氛搅拌12h。然后添加DCM(50mL)且将混合物用NaHCO3水溶液(20mL)洗涤。水相用DCM(50mL x2)萃取且合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤,浓缩,然后经硅胶柱色谱法(PE/EA=1/0)纯化。将所有通过TLC(PE/EA =2/1,Rf=0.3)发现包含产物的级分合并且浓缩以得到无色油状物的2-(3-氯-4,5-二氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(800mg,2.62mmol,12.9%产率):1H NMR(400MHz,CDCl3)δppm 7.60(d,J=6.6Hz,1H),7.48(t,J=8.2Hz,1H),1.33(s,12H);ES-LCMSm/z275.1[M+H]+.
步骤3:4-(5-((6-(3-氯-4,5-二氟苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(700mg,1.400mmol)和2-(3-氯-4,5-二氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(700mg,2.295mmol)在1,4-二噁烷(20mL)中的混合物中添加K2CO3(581mg,4.20mmol)和PdCl2(dppf)(51.2mg,0.070mmol)。将混合物在80℃在N2气氛搅拌6h。将混合物浓缩且通过硅胶柱色谱法(PE/EtOAc=5/1)纯化。将所有通过TLC(PE/EA =3/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到无色油状物4-(5-((6-(3-氯-4,5-二氟苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(800mg,1.025mmol,73.2%产率):1H NMR(400MHz,CDCl3)δppm8.30(s,1H),8.25(s,1H),7.93(s,1H),7.73(d,J=5.7Hz,1H),7.68-7.60(m,1H),7.48(s,1H),4.01(s,3H),3.83(d,J=5.3Hz,4H),3.53(d,J=3.5Hz,4H),1.50(s,9H);ES-LCMS m/z 506.1[M-t-Bu+H]+.
步骤4:4-(5-((6-(3-氯-4,5-二氟苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3-氯-4,5-二氟苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(750mg,0.961mmol)在MeOH(15mL)中的混合物中添加NaBH4(327mg,8.65mmol)。将混合物在15℃搅拌20分钟。然后将溶液浓缩且添加饱和NaHCO3溶液(150mL)。水层用DCM(500mL×3)萃取,且合并的萃取物用盐水(150mL x2)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色油状物4-(5-((6-(3-氯-4,5-二氟苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(750mg,0.843mmol,88.0%产率):1H NMR(400MHz,CDCl3)δppm 8.29(s,2H),7.69(d,J=5.5Hz,1H),7.65-7.55(m,1H),7.40(s,1H),6.92(s,1H),4.81(s,2H),3.81(d,J=5.0Hz,4H),3.52(d,J=3.5Hz,4H),1.50(s,9H);ES-LCMS m/z 478.2[M-t-Bu+H]+.
步骤5:4-(5-((6-(3-氯-4,5-二氟苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3-氯-4,5-二氟苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(750mg,0.843mmol)在DCM(15mL)中的混合物中添加DIEA(0.442mL,2.53mmol)。在15℃添加MsCl(0.079mL,1.011mmol),然后将混合物在N2气氛搅拌15分钟。将混合物浓缩且添加饱和NaHCO3溶液(150mL)。水层用DCM(150mL x2)萃取,且合并的萃取物用盐水(150mL x2)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色油状物4-(5-((6-(3-氯-4,5-二氟苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(880mg,0.820mmol,97.0%产率):1H NMR(400MHz,CDCl3)δppm 8.30(s,2H),7.68(d,J=5.0Hz,1H),7.64-7.55(m,1H),7.41-7.37(m,1H),6.96(s,1H),5.32-5.28(m,2H),3.83(d,J=4.5Hz,4H),3.54(s.,4H),3.13(d,J=7.0Hz,3H),1.50(s,9H);ES-LCMS m/z 556.1[M-t-Bu+H]+.
中间体13:((5-((6-溴吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯
步骤1:3',5'-二氯-5-((甲基氨基)甲基)-[1,1'-联苯]-3-醇
向3',5'-二氯-5-羟基-[1,1'-联苯]-3-甲醛(90g,337mmol)在DCM(2L)中的溶液中添加MeNH2在EtOH中的溶液(192g,674mmol)。然后将混合物在20℃在N2气氛搅拌8h。添加AcOH以将pH调节至6,且在0℃将NaBH(OAc)3(143g,674mmol)添加至混合物。将混合物在20℃搅拌4h,然后将溶液过滤且浓缩。粗物质通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到淡黄色固体的3',5'-二氯-5-((甲基氨基)甲基)-[1,1'-联苯]-3-醇(85g,271mmol,80.0%产率):1HNMR(400MHz,CD3OD)δppm 7.55(d,J=2.0Hz,2H),7.41(t,J=1.7Hz,1H),7.19(s,1H),7.05(s,1H),6.94(s,1H),4.11(s,2H),2.67(s,3H);ES-LCMS m/z 282.0,284.0[M+H]+.
步骤2:((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯
在0℃向3',5'-二氯-5-((甲基氨基)甲基)-[1,1'-联苯]-3-醇(85g,301mmol)和DIEA(58.4g,452mmol)在DCM(2L)中的悬浮液中添加(Boc)2O(64.4g,295mmol),且将反应混合物在20℃在N2气氛搅拌12h。反应混合物用DCM(1L)稀释且用饱和NaHCO3溶液(2L x2)洗涤。有机相用Na2SO4干燥且过滤。粗物质通过硅胶柱色谱法(PE/EtOAc=10/1至5/1)纯化。将所有通过TLC(PE/EA=5/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到淡黄色固体的((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯(50g,105mmol,34.7%产率):1H NMR(400MHz,CD3OD)δppm 7.49(d,J=2.0Hz,2H),7.39(s,1H),6.90(d,J=7.1Hz,2H),6.71(s,1H),4.41(s,2H),2.84(s,3H),1.47(s,9H);ES-LCMS m/z 325.9,327.9[M-t-Bu+H]+.
步骤3:((5-((6-溴吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯
向((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯(1g,2.62mmol)和2-溴-5-氟吡啶(1.381g,7.85mmol)在DMF(30mL)中的溶液中添加Cs2CO3(4.26g,13.08mmol)。将混合物在80℃搅拌8h。将混合物过滤,浓缩且通过硅胶(PE/EtOAc=4/1)纯化以得到((5-((6-溴吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯(1.3g,2.294mmol,88.0%产率):1H NMR(400MHz,CDCl3)δppm 8.22-8.14(m,1H),7.53-7.42(m,1H),7.42-7.32(m,3H),7.22-7.17(m,2H),7.07(br.s,1H),6.89(br.s,1H),4.45(br.s,2H),2.84(s,3H),1.46(br.s,9H);ES-LCMSm/z 480.9,482.9,484.9[M-t-Bu+H]+.
中间体14:N-((1-((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺
步骤1:3-羟基-5-(甲氧基甲氧基)苯甲酸甲酯
在0℃向3,5-二羟基苯甲酸甲酯(200g,1189mmol)在丙酮(1L)中的混合物中滴加氯(甲氧基)甲烷(105g,1308mmol)、K2CO3(493g,3568mmol)。将混合物在0℃搅拌20h,然后浓缩。将残余物溶于DCM(1L)中,且将溶液用水(1L×3)洗涤。有机相用Na2SO4干燥,过滤,浓缩且通过硅胶(EtOAc/PE,0-50%)纯化。将级分(EtOAc/PE=5/1,Rf=0.4)合并且浓缩以得到白色固体的3-羟基-5-(甲氧基甲氧基)苯甲酸甲酯(60g,226mmol,19.0%产率):1H NMR(400MHz,CD3OD)δppm 7.28-7.25(m,1H),7.18(d,J=1.10Hz,1H),6.75(t,J=2.32Hz,1H),5.18-5.16(m,2H),3.89(s,3H),3.47(s,3H);ES-LCMS m/z 213.1[M+H]+.
步骤2:3-羟基-5-(((三氟甲基)磺酰基)氧基)苯甲酸甲酯
在20℃向3-羟基-5-(甲氧基甲氧基)苯甲酸甲酯(200g,943mmol)在DCM(1L)中的混合物中添加Tf2O(175mL,1037mmol)、DIEA(247mL,1414mmol)。将混合物在20℃搅拌2h,然后用水(1L×3)洗涤。有机相用Na2SO4干燥且过滤。将滤液浓缩以得到棕色固体的3-羟基-5-(((三氟甲基)磺酰基)氧基)苯甲酸甲酯(220g,586mmol,62.2%产率):1H NMR(400MHz,CDCl3)δppm 7.71(s,1H),7.46(s,1H),7.29(s,1H),3.90(s,3H);ES-LCMS m/z 301.0[M+H]+.
步骤3:3',5'-二氯-5-羟基-[1,1'-联苯]-3-甲酸甲酯
在80℃在N2气氛向3-羟基-5-(((三氟甲基)磺酰基)氧基)苯甲酸甲酯(100g,333mmol)在1,4-二噁烷(1.5L)和水(500mL)中的混合物中添加(3,5-二氯苯基)硼酸(63.6g,333mmol)、K2CO3(138g,999mmol)、PdCl2(dppf)-CH2Cl2加合物(27.2g,33.3mmol)。将混合物在80℃在N2气氛搅拌4h。然后将反应混合物浓缩且将残余物溶于DCM(1L),用水(1L×3)洗涤。有机相用Na2SO4干燥,过滤,浓缩且通过硅胶(EtOAc/PE=3/1,Rf=0.4)纯化以得到白色固体3',5'-二氯-5-羟基-[1,1'-联苯]-3-甲酸甲酯(80g,215mmol,64.7%产率):1HNMR(400MHz,CDCl3)δppm 7.72(s,1H),7.46(s,1H),7.43-7.37(m,2H),7.33-7.28(m,1H),7.15(s,1H),3.88(s,3H);ES-LCMS m/z 297.1[M+H]+.
步骤4:3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-甲酸甲酯
在20℃向3',5'-二氯-5-羟基-[1,1'-联苯]-3-甲酸甲酯(80g,269mmol)在DCM(1L)中的混合物中添加氯(甲氧基)甲烷(26.0mL,538mmol)、DIEA(188mL,1077mmol)。将混合物在20℃搅拌2h,然后浓缩,且所得粗物质溶于DCM(1L)。将混合物用水(1L×3)洗涤,且有机相用Na2SO4干燥,过滤,且浓缩。粗物质在硅胶上通过二氧化硅柱色谱法(EtOAc/PE=5/1,Rf=0.4)纯化,得到棕色固体的3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-甲酸甲酯(60g,141mmol,52.3%产率):1H NMR(400MHz,CDCl3)δppm 7.88-7.81(m,1H),7.75-7.69(m,1H),7.46(d,J=1.71Hz,2H),7.40-7.32(m,2H),5.25(s,2H),3.96-3.91(m,3H),3.52-3.48(m,3H);ES-LCMS m/z 341.1[M+H]+.
步骤5:(3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲醇
在-10℃向3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-甲酸甲酯(8.3g,19.46mmol)在THF(80mL)中的溶液中添加LiAlH4(0.886g,23.35mmol)。将混合物在-10℃搅拌20min,然后通过添加水(1mL)和NaOH(水溶液,10%,1mL)淬灭。将混合物过滤且浓缩以得到黄色油状物(3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲醇(8g,19.16mmol,98.0%产率):1H NMR(400MHz,CD3OD)δppm 7.54(d,J=1.5Hz,2H),7.40(s,1H),7.21(s,1H),7.12(d,J=9.5Hz,2H),5.26(s,2H),4.65(s,2H),3.49(s,3H);ES-LCMS m/z 335.1,337.1[M+Na]+.
步骤6:甲磺酸(3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲基酯
向(3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲醇(8g,19.16mmol)在DCM(80mL)中的溶液中添加MsCl(1.792mL,22.99mmol)和DIEA(10.23mL,57.5mmol)。将混合物在10℃搅拌0.5h,然后浓缩且在DCM(300mL)和饱和NaHCO3溶液(300mL)之间分配。合并的有机萃取物用盐水(200mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色油状物甲磺酸(3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲基酯(8g,15.33mmol,80.0%产率):1HNMR(400MHz,CD3OD)δppm7.54(s,2H),7.42(s,1H),7.29(s,1H),7.25(s,1H),7.17(s,1H),5.27(s,2H),4.88(s,2H),3.50(s,3H),3.12(s,3H);ES-LCMS m/z 413.1,415.1[M+Na]+.
步骤7:N-((1-((3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺
向甲磺酸(3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲基酯(8g,15.33mmol)在DMF(50mL)中的混合物中添加K2CO3(8.48g,61.3mmol)和N-(哌啶-4-基甲基)乙酰胺,盐酸盐(6.22g,30.7mmol)。将混合物在15℃在N2气氛搅拌10h,然后浓缩且添加饱和NaHCO3溶液(150mL)。水层用DCM(300mL x2)萃取且合并的萃取物用盐水(150mL x2)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(DCM/MeOH=5/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到黄色油状物的N-((1-((3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(7g,12.41mmol,81.0%产率):1H NMR(400MHz,CD3OD)δppm7.58(d,J=1.5Hz,2H),7.44(d,J=1.5Hz,1H),7.25(s,1H),7.19(s,1H),7.09(s,1H),5.31-5.22(m,2H),3.58-3.54(m,2H),3.52-3.48(m,3H),3.08(d,J=6.5Hz,2H),2.96(d,J=11.3Hz,2H),2.06(t,J=10.9Hz,2H),1.95(s,3H),1.73(d,J=12.5Hz,2H),1.61-1.45(m,1H),1.39-1.23(m,2H);ES-LCMSm/z 451.3,453.3[M+H]+.
步骤8:N-((1-((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺
向N-((1-((3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(7g,12.41mmol)在水(30mL)中的混合物中添加浓HCl(30mL,238mmol)。将混合物在15℃在N2气氛搅拌10h,然后浓缩以得到黄色固体的N-((1-((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(6.2g,12.18mmol,98.0%产率):1HNMR(400MHz,CD3OD)δppm7.63(d,J=1.5Hz,2H),7.46(s,1H),7.32(s,1H),7.14(s,1H),7.05(s,1H),4.36-4.27(m,2H),3.56(d,J=12.0Hz,2H),3.20(d,J=6.0Hz,2H),3.10(br.s,2H),2.09(br.s,3H),1.99(d,J=14.1Hz,2H),1.90-1.87(m,1H),1.68-1.50(m,2H);ES-LCMS m/z 407.2,409.2[M+H]+.
中间体15:N-((1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
步骤1:2-(苄基氧基)-6-氯异烟酸甲酯
在25℃向苯基甲醇(15.75g,146mmol)在DMF(500mL)中的溶液中添加NaH(7.57g,189mmol)。将混合物在25℃搅拌0.5h后,添加2,6-二氯异烟酸甲酯(30g,146mmol)在DMF(100mL)中的溶液且将混合物在25℃搅拌12h。将混合物过滤且将滤液浓缩以得到残余物,将其通过柱色谱纯化以得到无色油状物的2-(苄基氧基)-6-氯异烟酸甲酯(16g,57.6mmol,39.6%产率):1H NMR(400MHz,CDCl3)δppm 7.43-7.36(m,3H),7.36-7.26(m,4H),5.32(s,2H),3.87(s,3H);ES-LCMS m/z 278.1[M+H]+.
步骤2:2-(苄基氧基)-6-(3,5-二氯苯基)异烟酸甲酯
将2-(苄基氧基)-6-氯异烟酸甲酯(12g,43.2mmol)、(3,5-二氯苯基)硼酸(12.37g,64.8mmol)、PdCl2(dppf)(6.32g,8.64mmol)和K2CO3(11.94g,86mmol)在1,4-二噁烷(200mL)中的混合物在80℃在N2气氛搅拌12h。将混合物过滤且将滤液浓缩。残余物通过柱色谱纯化以得到无色油状物的2-(苄基氧基)-6-(3,5-二氯苯基)异烟酸甲酯(13g,33.5mmol,77.0%产率):1H NMR(400MHz,CDCl3)δppm 7.96-7.92(m,1H),7.91-7.87(m,2H),7.85-7.80(m,2H),7.42-7.38(m,5H),5.50(s,2H),3.92(d,J=2.0Hz,3H);ES-LCMS m/z388.0,389.9[M+H]+.
步骤3:(2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲醇
在-78℃向2-(苄基氧基)-6-(3,5-二氯苯基)异烟酸甲酯(12g,30.9mmol)在THF(300mL)中的溶液中添加LiAlH4(2.35g,61.8mmol)。将混合物温热至25℃保持12h。反应在0℃通过添加NaOH水溶液(20%,10mL)淬灭,然后过滤且浓缩。残余物通过柱色谱纯化以得到黄色油状物(2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲醇(10.7g,29.7mmol,96.0%产率):1H NMR(400MHz,CDCl3)δppm 7.83-7.78(m,1H),7.46-7.41(m,1H),7.40-7.36(m,1H),7.30(d,J=4.0Hz,4H),7.23(s,3H),5.29(s,2H),4.68(d,J=4.9Hz,2H);ES-LCMS m/z359.9,362.0[M+H]+.
步骤4:甲磺酸(2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基酯
在0℃向(2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲醇(3.0g,8.33mmol)和DIEA(2.91mL,16.66mmol)在DCM(40mL)中的溶液中添加MsCl(0.779mL,9.99mmol)。将混合物在25℃搅拌3h。添加DCM(100mL),用水(30mL×3)洗涤,且用Na2SO4干燥。将有机相浓缩以得到黄色油状物甲磺酸(2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基酯(3.0g,6.84mmol,82.0%产率):1H NMR(400MHz,CDCl3)δppm 7.80-7.78(m,2H),7.43-7.41(m,2H),7.40-7.36(m,1H),7.36-7.31(m,5H),5.42(s,2H),5.16(s,2H),3.01(s,3H);ES-LCMS m/z437.9,439.9[M+H]+.
步骤5:N-((1-((2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向甲磺酸(2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基酯(3.0g,6.84mmol)和K2CO3(1.892g,13.69mmol)在DMF(30mL)中的溶液中添加N-(哌啶-4-基甲基)乙酰胺(1.069g,6.84mmol)。将混合物在80℃搅拌12h。冷却至室温后,将混合物过滤且将滤液浓缩。残余物通过柱色谱纯化以得到黄色油状物的N-((1-((2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(3.0g,6.02mmol,88.0%产率):1H NMR(400MHz,CDCl3)δppm 7.93-7.84(m,2H),7.53-7.47(m,2H),7.46-7.42(m,1H),7.41-7.34(m,4H),7.34-7.30(m,1H),5.47-5.44(m,2H),3.54-3.50(m,2H),3.18-3.11(m,2H),2.91-2.77(m,4H),2.11-2.07(m,3H),1.71-1.67(m,2H),1.55-1.49(m,1H),1.32-1.23(m,2H);ES-LCMS m/z 498.1,500.1[M+H]+.
步骤6:N-((1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向N-((1-((2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(2.0g,4.01mmol)在THF(20mL)中的溶液中添加浓HCl(15mL,180mmol)。将混合物在80℃搅拌4h,然后浓缩。残余物通过柱色谱纯化以得到棕色固体的N-((1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(1.0g,2.449mmol,61.0%产率):1HNMR(400MHz,CD3OD)δppm 7.74-7.66(m,2H),7.61-7.54(m,1H),6.81-6.72(m,1H),6.57-6.48(m,1H),3.44(s,2H),3.09-3.02(m,2H),2.95-2.86(m,2H),2.12-2.00(m,2H),1.92(s,3H),1.76-1.65(m,2H),1.60-1.45(m,1H),1.38-1.21(m,2H);ES-LCMS m/z 408.2,410.1[M+H]+.
步骤7:N-((1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
将N-((1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(1g,2.449mmol)、2-溴-5-氟吡啶(0.646g,3.67mmol)和Cs2CO3(3.99g,12.25mmol)在NMP(15mL)中的混合物在130℃搅拌16h。将混合物冷却至室温且过滤。将滤液浓缩且残余物通过硅胶柱色谱法(MeOH/DCM=1/10)纯化两次。将所有通过TLC(MeOH/DCM=1/10)发现包含产物的级分合并且浓缩以得到棕色固体的N-((1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(580mg,0.504mmol,20.6%产率):1HNMR(400MHz,CDCl3)δppm 8.36-8.30(m,1H),7.73(d,J=1.7Hz,1H),7.68(d,J=1.7Hz,1H),7.54-7.51(m,1H),7.50-7.47(m,1H),7.45(s,1H),7.35-7.31(m,1H),7.01-6.93(m,1H),3.53(s,2H),3.18-3.14(m,2H),2.88(d,J=10.8Hz,2H),2.00-1.96(m,5H),1.73-1.60(m,2H),1.53(d,J=4.2Hz,1H),1.32(d,J=7.6Hz,2H);ES-LCMS m/z 563.0,564.9[M+H]+.
中间体16:2-(1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
步骤1:2-(1-((2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向甲磺酸(2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基酯(27g,52.7mmol)和2-(哌啶-4-基)乙酸甲酯,盐酸盐(12.90g,63.3mmol)在DMF(400mL)中的混合物中添加K2CO3(21.86g,158mmol)。将混合物在70℃搅拌10h,然后浓缩。将残余物与DCM(300mL)混合且过滤。将滤液浓缩以得到黄色油状物的2-(1-((2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(25g,46.3mmol,88.0%产率):1H NMR(400MHz,CD3OD)δppm7.97(s,2H),7.50-7.45(m,4H),7.39-7.35(m,2H),7.28-7.26(m,1H),6.83(s,1H),5.47(s,2H),3.65(s,3H),3.55(s,2H),2.91-2.89(m,2H),2.28-2.27(m,2H),2.08-2.06(m,2H),1.78-1.71(m,3H),1.36-1.32(m,2H);ES-LCMS m/z 499.3,501.3[M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将2-(1-((2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(25g,46.3mmol)和TFA(300mL,3894mmol)的混合物在50℃搅拌1h。将混合物浓缩。将残余物倒入冰水(200mL)中,用饱和Na2CO3溶液中和至pH为8,然后用DCM/MeOH(10/1,100mL×3)萃取。合并的有机层浓缩且残余物在硅胶上通过柱色谱法(DCM/MeOH=1/0至10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到黄色油状物。黄色油状物在PE/EtOAc(5/1,100mL)中研磨,然后过滤。滤饼用PE/EtOAc(5/1,10mL)洗涤且干燥以得到黄色固体的2-(1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(17g,34.7mmol,74.9%产率):1H NMR(400MHz,CD3OD)δppm7.80(s,2H),7.64(s,1H),6.92(s,1H),6.70(s,1H),4.16(s,2H),3.69(s,3H),3.50-3.48(m,2H),3.01-2.98(m,2H),2.39-2.37(m,2H),2.03-2.00(m,3H),1.56-1.54(m,2H);ES-LCMS m/z 409.2,411.2[M+H]+.
步骤3:2-(1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(14.5g,29.6mmol)和2-溴-5-氟吡啶(17.59mL,148mmol)在NMP(300mL)中的混合物中添加K2CO3(12.26g,89mmol)。将混合物在150℃搅拌30h,然后过滤且将滤液浓缩。残余物经硅胶柱色谱法(PE/EtOAc=5/1至1/1至DCM/MeOH=10/1)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到粗产物,将其进一步通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化。将所需级分合并且浓缩至约100mL,然后用饱和Na2CO3溶液碱化至pH=8且用DCM/MeOH(10/1,100mL×3)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到白色固体的2-(1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(6.15g,10.87mmol,36.8%产率):1H NMR(400MHz,CD3OD)δppm8.34(s,1H),7.82(s,2H),7.77(s,1H),7.75-7.66(m,2H),7.47(s,1H),7.18(s,1H),4.01(s,2H),3.66(s,3H),3.24-3.22(m,2H),2.62-2.60(m,2H),2.34-2.32(m,2H),1.91-1.87(m,3H),1.51-1.43(m,2H);ES-LCMS m/z 564.2,566.1[M+H]+.
中间体17:4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯
步骤1:5-(苄基氧基)-2-氯-3-氟吡啶
向6-氯-5-氟吡啶-3-醇(1g,6.78mmol)、K2CO3(2.81g,20.33mmol)在DMF(15mL)中的混合物中添加(溴甲基)苯(2.319g,13.56mmol)。将反应混合物在20℃搅拌2h,然后过滤且浓缩。残余物在DCM(50mL)和H2O(20mL)之间分离。水相用DCM(50mL x2)萃取。合并有机相且用盐水(30mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色固体的5-(苄基氧基)-2-氯-3-氟吡啶(1.3g,4.38mmol,64.6%产率):1H NMR(400MHz,CDCl3)δppm 8.04-7.95(m,1H),7.40-7.35(m,5H),7.10(dd,J=2.6,9.4Hz,1H),5.09(s,2H);ES-LCMS m/z 238.0,240.0[M+H]+.
步骤2:4-(5-(苄基氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯
在N2气氛将哌嗪-1-甲酸叔丁酯(2.038g,10.94mmol)、(±)-BINAP(0.681g,1.094mmol)、5-(苄基氧基)-2-氯-3-氟吡啶(1.3g,5.47mmol)、Pd2(dba)3(0.501g,0.547mmol)和叔丁醇钠(1.577g,16.41mmol)在THF(20mL)中的混合物加热至65℃保持12h。将混合物浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=2/1)纯化。将所有通过TLC(EtOAc/PE=1/3,Rf=0.5)发现包含产物的级分合并且浓缩以得到黄色固体的4-(5-(苄基氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯(1g,2.323mmol,42.5%产率):1H NMR(400MHz,CDCl3)δppm 7.82(d,J=2.5Hz,1H),7.43-7.39(m,4H),7.37-7.33(m,1H),7.02(dd,J=2.0,13.1Hz,1H),5.05(s,2H),3.61-3.51(m,4H),3.35-3.22(m,4H),1.48(s,9H);ES-LCMSm/z 388.2[M+H]+.
步骤3:4-(3-氟-5-羟基吡啶-2-基)哌嗪-1-甲酸叔丁酯
在H2气氛在50psi将4-(5-(苄基氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯(1g,2.58mmol)、Pd/C(0.275g,0.258mmol)在MeOH(20mL)中的混合物加热至50℃保持10h。将混合物过滤且浓缩以得到粗产物,其为黄色固体的4-(3-氟-5-羟基吡啶-2-基)哌嗪-1-甲酸叔丁酯(800mg,2.153mmol,83.0%产率):1H NMR(400MHz,CD3OD)δppm 7.62(d,J=2.2Hz,1H),7.05-6.91(m,1H),3.61-3.48(m,4H),3.20-3.12(m,4H),1.49-1.45(m,9H);ES-LCMSm/z 298.1[M+H]+.
步骤4:2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)-5-氟吡啶-3-基)氧基)-6-氯异烟酸
在N2气氛将4-(3-氟-5-羟基吡啶-2-基)哌嗪-1-甲酸叔丁酯(1.3g,4.37mmol)、2,6-二氯异烟酸甲酯(1.802g,8.74mmol)和K2CO3(1.813g,13.12mmol)在THF(10mL)中的混合物加热至65℃保持3h。将挥发物浓缩以得到粗产物,其通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到黄色固体的2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)-5-氟吡啶-3-基)氧基)-6-氯异烟酸(800mg,1.237mmol,28.3%产率):1H NMR(400MHz,CDCl3)δppm7.21-7.09(m,1H),6.60(br.s,2H),6.53-6.47(m,1H),2.78(br.s,4H),2.59(s,4H),0.69(br.s,9H);ES-LCMS m/z397.1,399.1[M-t-Bu+H]+.
步骤5:2-氯-6-((5-氟-6-(哌嗪-1-基)吡啶-3-基)氧基)异烟酸甲酯
向2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)-5-氟吡啶-3-基)氧基)-6-氯异烟酸(800mg,1.767mmol)在MeOH(10mL)中的混合物中添加SOCl2(1.289mL,17.67mmol)。将混合物在60℃搅拌5h,然后冷却且浓缩以得到棕色油状物的2-氯-6-((5-氟-6-(哌嗪-1-基)吡啶-3-基)氧基)异烟酸甲酯(600mg,1.472mmol,83.0%产率):1H NMR(400MHz,CDCl3)δppm7.96(d,J=2.2Hz,1H),7.63-7.57(m,1H),7.41(s,1H),7.28(d,J=2.2Hz,1H),3.97(s,3H),3.84(br.s,4H),3.37(d,J=4.4Hz,4H);ES-LCMSm/z 367.1,369.0[M+H]+.
步骤6:4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯
将2-氯-6-((5-氟-6-(哌嗪-1-基)吡啶-3-基)氧基)异烟酸甲酯(600mg,1.636mmol)、Boc2O(0.570mL,2.454mmol)和DIEA(0.857mL,4.91mmol)在DCM(10mL)中的混合物在15℃搅拌6h。将混合物用水(30mL)稀释,然后用DCM(50mL×3)萃取。有机层用盐水洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过硅胶柱色谱法(PE/EtOAc=4/1)纯化。将所有通过TLC(EtOAc/PE=1/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到黄色油状物4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯(800mg,1.456mmol,89.0%产率):1H NMR(400MHz,CDCl3)δppm 7.95(d,J=2.2Hz,1H),7.59(s,1H),7.39(s,1H),7.20(d,J=2.2Hz,1H),3.96(s,3H),3.57(d,J=4.9Hz,4H),3.42(br.s,4H),1.48(s,9H);ES-LCMSm/z411.0,413.0[M-t-Bu+H]+.
步骤7:4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯
将4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯(0.8g,1.713mmol)、PdCl2(dppf)(0.125g,0.171mmol)、K2CO3(0.474g,3.43mmol)、(3,5-二氯苯基)硼酸(0.49g,2.57mmol)在1,4-二噁烷(10mL)和水(1mL)中的混合物在65℃在N2气氛加热8h。将挥发物浓缩以得到粗产物,其在DCM(30mL)和H2O(20mL)之间分配,用DCM(50mL x2)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过硅胶柱色谱法(PE/EtOAc=4/1)纯化。将所有通过TLC(EtOAc/PE=1/3,Rf=0.6)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯(800mg,1.178mmol,68.7%产率):1H NMR(400MHz,CD3OD)δppm8.11(s,1H),8.02(d,J=1.8Hz,1H),7.85(d,J=1.3Hz,2H),7.57-7.52(m,2H),7.48(s,1H),4.02-3.96(m,3H),3.59(br.s,4H),3.44(d,J=5.3Hz,4H),1.49(s,9H);ES-LCMS m/z 577.1,579.1[M+H]+.
步骤8:4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯
将4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯(800mg,1.385mmol)、NaBH4(524mg,13.85mmol)在MeOH(10mL)中的混合物在25℃搅拌2h。将挥发物浓缩以得到粗产物,将其在DCM(50mL)和H2O(20mL)之间分离。水相用DCM(50mL x2)萃取且合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过硅胶柱色谱法(DCM/MeOH=4/1)纯化。将所有通过TLC(DCM/MeOH=1/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯(500mg,0.819mmol,59.1%产率):1H NMR(400MHz,CDCl3)δppm 8.04-7.98(m,1H),7.75(d,J=1.5Hz,2H),7.45(s,1H),7.36(s,1H),7.30(dd,J=2.0,12.5Hz,1H),6.92(s,1H),4.87-4.76(m,2H),3.63-3.54(m,4H),3.44(d,J=5.0Hz,4H),1.50(s,9H);ES-LCMSm/z 549.1,551.1[M+H]+.
步骤9:4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯
在25℃向4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯(500mg,0.910mmol)、DIEA(0.477mL,2.73mmol)在DCM(10mL)中的混合物中添加MsCl(0.106mL,1.365mmol)。将混合物搅拌20分钟,然后添加NaHCO3溶液(水溶液,5wt%,10mL)。将混合物用DCM(50mL x2)萃取且合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色油状物4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯(500mg,0.637mmol,70.0%产率):1H NMR(400MHz,CDCl3)δppm 8.04-7.99(m,1H),7.73(d,J=1.5Hz,2H),7.47-7.43(m,1H),7.39-7.36(m,1H),7.31(dd,J=2.0,12.5Hz,1H),6.95(s,1H),4.63-4.57(m,2H),3.62-3.56(m,4H),3.45(d,J=5.5Hz,4H),2.79(s,3H),1.43(s,9H);ES-LCMSm/z627.1,629.1[M+H]+.
中间体18:4-(5-((3',5'-二氯-5-(((甲基磺酰基)氧基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
步骤1:5-((6-溴吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-甲酸甲酯
向2-溴-5-氟吡啶(1.895g,10.77mmol)在DMF(50mL)中的混合物中添加3',5'-二氯-5-羟基-[1,1'-联苯]-3-甲酸甲酯(2g,5.38mmol)、K2CO3(2.233g,16.15mmol)。将混合物在120℃搅拌5h,然后浓缩且在DCM(100mL)和H2O(100mL)之间分配。水相用DCM(100mL x2)萃取且合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物。粗物质通过硅胶柱色谱法(PE/EtOAc=20/1至5/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到棕色固体的5-((6-溴吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-甲酸甲酯(1500mg,2.65mmol,49.2%产率):1H NMR(400MHz,CDCl3)δppm 8.21(d,J=3.0Hz,1H),8.02(s,1H),7.65(s,1H),7.46(d,J=1.5Hz,3H),7.41-7.37(m,2H),7.28-7.24(m,1H),3.95-3.91(m,3H);ES-LCMS m/z 452.0,454.0[M+H]+.
步骤2:4-(5-((3',5'-二氯-5-(甲氧基羰基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向5-((6-溴吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-甲酸甲酯(1.5g,2.65mmol)在THF(20mL)中的混合物中添加哌嗪-1-甲酸叔丁酯(0.740g,3.97mmol)、Pd2(dba)3(0.073g,0.079mmol)、Cs2CO3(2.59g,7.95mmol)和Xantphos(0.766g,1.324mmol)。将混合物在70℃在N2气氛搅拌4h,然后浓缩且在DCM(100mL)和H2O(100mL)之间分配。水相用DCM(100mL x2)萃取且合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物。粗产物通过硅胶柱色谱法(DCM/MeOH=20/1至5/1)纯化。将所有通过TLC(DCM/MeOH=30/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到绿色固体的4-(5-((3',5'-二氯-5-(甲氧基羰基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1.6g,2.292mmol,87.0%产率):1HNMR(400M Hz,CDCl3)δppm 8.09-8.04(m,1H),7.88(s,1H),7.57-7.53(m,1H),7.43(d,J=1.8Hz,1H),7.40-7.37(m,1H),7.31-7.28(m,1H),6.93(t,J=7.7Hz,1H),6.69(d,J=9.3Hz,1H),6.52(dd,J=1.5,7.3Hz,1H),3.95-3.89(m,3H),3.56(d,J=5.3Hz,4H),3.53-3.49(m,4H),1.48(s,9H);ES-LCMSm/z 558.2,560.2[M+H]+.
步骤3:4-(5-((3',5'-二氯-5-(羟基甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
在-20℃向4-(5-((3',5'-二氯-5-(甲氧基羰基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1.6g,2.292mmol)在THF(20mL)中的混合物中添加LiAlH4(0.096g,2.52mmol)。将混合物在-20℃搅拌4h。混合物通过H2O(0.1mL)淬灭,然后通过10%NaOH的H2O溶液(0.1mL)淬灭,然后过滤且将滤液浓缩以得到绿色固体的粗产物4-(5-((3',5'-二氯-5-(羟基甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1.4g,2.111mmol,92.0%产率):1H NMR(400MHz,CDCl3)δppm 8.03-7.96(m,1H),7.34(d,J=1.8Hz,1H),7.27(t,J=1.8Hz,1H),7.19(s,1H),6.95(s,1H),6.91-6.83(m,2H),6.67-6.58(m,1H),6.49-6.43(m,1H),4.74-4.58(m,2H),3.50(d,J=5.7Hz,4H),3.46-3.41(m,4H),1.42(s,9H);ES-LCMS m/z 530.1,532.1[M+H]+.
步骤4:4-(5-((3',5'-二氯-5-(((甲基磺酰基)氧基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
在30℃向4-(5-((3',5'-二氯-5-(羟基甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(600mg,0.905mmol)、DIEA(0.5mL,2.86mmol)在DCM(50mL)中的混合物中添加MsCl(0.106mL,1.357mmol)。将混合物在30℃搅拌0.5h,然后用水(50mL×3)洗涤。有机相用Na2SO4干燥且过滤。将滤液浓缩以得到棕色固体的4-(5-((3',5'-二氯-5-(((甲基磺酰基)氧基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(700mg,0.663mmol,73.2%产率):1H NMR(400MHz,CDCl3)δppm7.32(br.s,1H),7.28(d,J=2.2Hz,2H),7.26-7.20(m,2H),7.15(br.s,1H),7.03(br.s,1H),6.92-6.89(m,1H),6.64(d,J=9.3Hz,1H),5.26(s,2H),3.50-3.48(m,8H),2.94(s,3H),1.47(s,9H);ES-LCMS m/z 608.1,610.1[M+H]+.
中间体19:甲磺酸(2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基酯
步骤1:(1-(5-(苄基氧基)嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯
向5-(苄基氧基)-2-氯嘧啶(4g,16.32mmol)和哌啶-4-基氨基甲酸叔丁酯(6.54g,32.6mmol)在DMF(100mL)中的混合物中添加Cs2CO3(15.95g,48.9mmol)。将反应混合物在80℃搅拌10h,然后过滤,浓缩且残余物通过硅胶柱色谱法(PE/EtOAc=5/1)纯化。将所有通过TLC(PE/EA=3/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到白色固体的(1-(5-(苄基氧基)嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(3.5g,8.65mmol,53.0%产率):1H NMR(400MHz,CDCl3)δppm 8.09(s,2H),7.37-7.32(m,5H),4.99(s,2H),4.49-4.46(m,3H),3.02-2.96(m,2H),2.02-1.97(m,2H),1.43(s,9H),1.35-1.33(m,2H);ES-LCMS m/z 385.2[M+H]+.
步骤2:(1-(5-羟基嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯
在H2气氛在15psi将(1-(5-(苄基氧基)嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(3.5g,8.65mmol)、Pd/C(0.920g,0.865mmol)在MeOH(50mL)中的混合物在25℃搅拌0.5h。将混合物过滤且浓缩以得到黄色固体的(1-(5-羟基嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(1.5g,4.08mmol,47.1%产率):1H NMR(400MHz,CD3OD)δppm 7.95(s,2H),4.38(d,J=13.2Hz,2H),3.74(m,1H),3.16-3.05(m,2H),2.00-1.80(m,2H),1.43(s,9H),1.38-1.36(m,2H);ES-LCMS m/z 295.2[M+H]+.
步骤3:2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-氯异烟酸甲酯
向2,6-二氯异烟酸甲酯(0.923g,4.08mmol)和(1-(5-羟基嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(1.5g,4.08mmol)在DMF(30mL)中的混合物中添加K2CO3(1.690g,12.23mmol)。将混合物在50℃搅拌10h,然后浓缩且添加饱和NaHCO3溶液(150mL)。水层用DCM(150mL x2)萃取且合并的萃取物用盐水(150mL x2)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=5/1)纯化。将所有通过TLC(PE/EA=3/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到黄色油状物的2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-氯异烟酸甲酯(600mg,1.203mmol,29.5%产率):1H NMR(400MHz,CDCl3)δppm 8.21(s,2H),7.55(s,1H),7.38-7.36(m,1H),4.66-4.60(m,2H),4.46(br.s,1H),3.95(s,3H),3.71-3.67(m,1H),3.11-2.07(m,2H),2.02-1.99(m,2H),1.44(s,9H),1.40-1.38(m,2H);ES-LCMS m/z 464.1,466.1[M+H]+.
步骤4:2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)异烟酸甲酯
向2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-氯异烟酸甲酯(0.6g,1.203mmol)和(3,5-二氯苯基)硼酸(0.574g,3.01mmol)在DMF(10mL)中的混合物中添加K2CO3(0.499g,3.61mmol)和PdCl2(dppf)(0.044g,0.060mmol)。将混合物在80℃在N2气氛搅拌0.5h。将混合物浓缩且通过硅胶柱色谱法(PE/EtOAc=5/1)纯化。将所有通过TLC(PE/EA =3/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到黄色固体的2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)异烟酸甲酯(700mg,1.097mmol,91.0%产率):1H NMR(400MHz,CDCl3)δppm 8.27(s,2H),7.95(s,1H),7.78-7.70(m,2H),7.50-7.43(m,1H),7.38-7.26(m,1H),4.74-4.59(m,2H),4.46(br.s,1H),4.01-3.93(m,3H),3.83-3.66(m,1H),3.10(t,J=11.2Hz,2H),2.03(t,J=5.1Hz,2H),1.45(s,9H),1.40-1.38(m,2H);ES-LCMS m/z 574.2,576.2[M+H]+.
步骤5:(1-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯
将2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)异烟酸甲酯(0.7g,1.097mmol)、NaBH4(0.415g,10.97mmol)在MeOH(20mL)中的混合物在25℃搅拌5h。将挥发物浓缩且残余物在DCM(50mL)和H2O(20mL)之间分配。水相用DCM(50mL x2)萃取且合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色固体的(1-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(500mg,0.668mmol,60.9%产率):1H NMR(400MHz,CD3OD)δppm8.28(s,2H),7.80(d,J=1.8Hz,2H),7.57(s,1H),7.41(t,J=1.8Hz,1H),7.02(s,1H),4.75-4.71(m,2H),4.64-4.60(m,2H),3.70-3.57(m,1H),3.18-3.04(m,2H),1.93(d,J=10.1Hz,2H),1.44(s,9H),1.40-1.38(m,2H);ES-LCMS m/z 546.1,548.1[M+H]+.
步骤6:甲磺酸(2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基酯
将(1-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(500mg,0.668mmol)、DIEA(0.350mL,2.004mmol)和MsCl(0.078mL,1.002mmol)在DCM(10mL)中的混合物在25℃搅拌20min。向该反应中添加5%NaHCO3(10mL)且用DCM(50mL x2)萃取。有机萃取物用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色油状物甲磺酸(2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基酯(580mg,0.650mmol,97.0%产率):1H NMR(400MHz,CDCl3)δppm 8.20(s,2H),7.68-7.65(m,2H),7.39-7.28(m,2H),6.88(s,1H),5.21(s,2H),4.57(d,J=13.7Hz,2H),4.41(br.s,1H),3.09-3.06(m,2H),3.04(s,3H),1.98-1.96(m,2H),1.39(s,9H),1.38-1.36(m,2H);ES-LCMS m/z 624.1,626.1[M+H]+.
中间体20:(S)-4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯
步骤1:(S)-4-(5-(苄基氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯
向5-(苄基氧基)-2-氯嘧啶(3g,12.92mmol)在DMF(100mL)中的混合物中添加(S)-2-甲基哌嗪-1-甲酸叔丁酯(5g,24.97mmol)和Cs2CO3(8.42g,25.8mmol)。将混合物在130℃搅拌12h。将混合物浓缩且通过硅胶柱色谱法(PE/EtOAc=3/1)纯化。将所有通过TLC(PE/EA=3/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到淡黄色固体的(S)-4-(5-(苄基氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(3g,5.61mmol,43.4%产率):1H NMR(400MHz,CD3OD)δppm 8.13(s,2H),7.43-7.32(m,5H),5.06(s,2H),4.36(d,J=13.2Hz,3H),3.84(br.s,1H),3.15-3.05(m,2H),2.91(d,J=4.0Hz,1H),1.47(s,9H),1.12(d,J=6.6Hz,3H);ES-LCMS m/z 385.2[M+H]+.
步骤2:(S)-4-(5-羟基嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯
向(S)-4-(5-(苄基氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(2.5g,4.68mmol)在EtOAc(50mL)中的溶液中添加Pd/C(10wt%,0.8g,0.752mmol)。将混合物在H2(15psi)下在25℃搅拌0.5h。将混合物过滤且浓缩以得到黄色固体的(S)-4-(5-羟基嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(1.8g,4.53mmol,97.0%产率):1H NMR(400MHz,CD3OD)δppm 7.99(s,2H),4.42-4.27(m,3H),3.85(br.s,1H),3.16-3.06(m,2H),2.89(d,J=3.5Hz,1H),1.47(s,9H),1.14(d,J=6.6Hz,3H);ES-LCMS m/z 239.2[M-t-Bu+H]+..
步骤3:(S)-4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯
向(S)-4-(5-羟基嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(1.8g,4.53mmol)在DMF(50mL)中的溶液中添加K2CO3(1.876g,13.58mmol)和2,6-二氯异烟酸甲酯(1.571g,6.79mmol)。将混合物在80℃搅拌2h。将混合物过滤且浓缩以得到淡黄色固体的(S)-4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(3g,4.20mmol,93.0%产率):1H NMR(400MHz,CD3OD)δppm 8.30-8.19(m,2H),7.58(s,1H),7.49-7.42(m,1H),4.61-4.47(m,2H),4.37-4.29(m,1H),3.92(s,3H),3.85(br.s,1H),3.24(dd,J=3.7,13.0Hz,2H),3.04(d,J=3.1Hz,1H),1.48(s,9H),1.17(d,J=6.6Hz,3H);ES-LCMSm/z408.1,410.1[M-t-Bu+H]+.
步骤4:(S)-4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯
向(S)-4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(2.9g,4.06mmol)在DMF(60mL)中的溶液中添加(3,5-二氯苯基)硼酸(1.163g,6.09mmol)、K2CO3(1.685g,12.19mmol)和PdCl2(dppf)(0.297g,0.406mmol)。将混合物在80℃在N2气氛搅拌2h。将混合物浓缩且通过硅胶柱色谱法(PE/EtOAc=5/1)纯化。将所有通过TLC(PE/EtOAc=5/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到黄色固体的(S)-4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(2.3g,3.56mmol,88.0%产率):1H NMR(400MHz,CD3OD)δppm8.30(s,2H),7.98(s,1H),7.74(d,J=1.8Hz,2H),7.49-7.36(m,2H),4.62-4.51(m,2H),4.38-4.29(m,1H),3.99(s,3H),3.90(d,J=13.2Hz,1H),3.28-3.19(m,2H),3.05(br.s,1H),1.49(s,9H),1.16(d,J=6.6Hz,3H);ES-LCMS m/z 518.1,520.1[M-t-Bu+H]+.
步骤5:(S)-4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯
向(S)-4-(5-((6-(3,5-二氯苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(2.2g,3.41mmol)在MeOH(50mL)中的溶液中添加NaBH4(0.645g,17.04mmol)。将混合物在20℃搅拌0.5h,然后浓缩。添加水(200mL)且将混合物用DCM(200mL x2)萃取,合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色固体的(S)-4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(2.2g,3.08mmol,90.0%产率):1H NMR(400MHz,CD3OD)δppm 8.32(s,2H),7.82(s,2H),7.61(s,1H),7.44(s,1H),7.07(s,1H),4.75(s,2H),4.65-4.58(m,2H),4.34(br.s,1H),3.93(d,J=13.1Hz,1H),3.25(d,J=11.0Hz,2H),3.08(br.s,1H),1.51(s,9H),1.19(d,J=6.5Hz,3H);ES-LCMSm/z490.1,492.1[M-t-Bu+H]+.
步骤6:(S)-4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯
向(S)-4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(1g,1.400mmol)在DCM(30mL)中的溶液中添加DIEA(0.734mL,4.20mmol)和MsCl(0.164mL,2.100mmol)。将混合物在20℃搅拌20min。添加水(50mL)且将混合物用DCM(100mL x2)萃取,合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色油状物(S)-4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(1g,1.078mmol,77.0%产率):1H NMR(400MHz,CD3OD)δppm8.31(s,2H),7.78(s,2H),7.65(d,J=12.5Hz,1H),7.44-7.39(m,1H),7.11(d,J=5.5Hz,1H),5.29(s,2H),4.57(d,J=14.6Hz,2H),4.33(br.s,1H),3.91(d,J=13.6Hz,1H),3.29-3.20(m,3H),2.87(m,3H),1.50(s,9H),1.17(br.s,3H);ES-LCMS m/z 568.1,570.1[M-t-Bu+H]+.
中间体21:3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯
步骤1:(2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲醇
向4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1g,1.690mmol)在MeOH(10mL)中的溶液中添加HCl溶液(4M在MeOH中,2mL,8.00mmol)。将混合物在20℃搅拌0.2h,然后浓缩。残余物在DCM(30mL)和饱和NaHCO3溶液(20mL)之间分配。水相用DCM(10mL x2)萃取。合并的有机萃取物用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色固体的(2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲醇(0.7g,1.376mmol,81.0%产率):1H NMR(400MHz,CD3OD)δppm8.54(s,2H),7.80(d,J=1.8Hz,2H),7.62(s,1H),7.45(t,J=1.8Hz,1H),7.10(s,1H),4.74(s,2H),4.19-4.11(m,4H),3.38-3.33(m,4H);ES-LCMS m/z 432.1,434.0[M+H]+.
步骤2:3-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯
向(2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲醇(0.5g,0.983mmol)在DMF(5.00mL)中的溶液中添加3-溴丙酸乙酯(0.214g,1.180mmol)和K2CO3(0.272g,1.966mmol)。将混合物在80℃搅拌2h。然后将溶液过滤且浓缩。粗产物在DCM(30mL)和饱和NaHCO3溶液(20mL)之间分配。水相用DCM(10mL x2)萃取。合并的有机萃取物用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(0.5g,0.808mmol,82.0%产率):1H NMR(400MHz,CD3OD)δppm 8.31(s,2H),7.81(d,J=1.8Hz,2H),7.59(s,1H),7.42(s,1H),7.04(s,1H),4.72(s,2H),4.15(q,J=7.1Hz,2H),3.90-3.78(m,4H),2.79-2.70(m,2H),2.63-2.52(m,6H),1.31-1.23(m,3H);ES-LCMS m/z 532.1,534.1[M+H]+.
步骤3:3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯
向3-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(0.5g,0.808mmol)在DCM(10mL)中的溶液中添加DIEA(0.209g,1.615mmol)和MsCl(0.370g,3.23mmol)。将混合物在30℃搅拌0.5h,然后浓缩。粗产物通过硅胶柱色谱法(DCM/MeOH=10/1至5/1)纯化。将所有通过TLC(PE/EtOAc=5/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到淡黄色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(0.5g,0.704mmol,87.0%产率):1H NMR(400MHz,CD3OD)δppm 8.37-8.29(m,2H),7.86-7.79(m,2H),7.70-7.66(m,1H),7.49-7.43(m,1H),7.12(s,1H),5.29(s,2H),4.18(q,J=7.1Hz,2H),3.89-3.83(m,4H),3 3.05(s,3H),2.81-2.70(m,2H),2.57(t,J=5.1Hz,6H),1.23-1.19(m,3H);ES-LCMSm/z 610.0,612.1[M+H]+.
中间体22:3-氯丙烷-1-磺酰胺
将气态氨鼓泡至3-氯丙烷-1-磺酰氯(5g,28.2mmol)在THF(40mL)中的冷(-78℃)溶液中。溶液在-78℃搅拌0.5h,然后浓缩且在DCM(50mL)和饱和NaHCO3溶液(30mL)之间分配。合并的有机萃取物用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到棕色固体的3-氯丙烷-1-磺酰胺(3g,18.08mmol,64.0%产率):1H NMR(400MHz,CD3OD)δppm 3.72(t,J=6.4Hz,2H),3.27-3.19(m,2H),2.32-2.21(m,2H)。
中间体23:乙烯磺酰胺
步骤1:2-溴乙烷磺酸盐
将1,2-二溴乙烷(100g,532mmol)和亚硫酸钠(22.14g,176mmol)在EtOH(250mL)和H2O(250mL)中的混合物在100℃搅拌10h,然后将反应混合物浓缩。添加EtOH(500mL)且过滤。将滤液浓缩以得到白色固体的2-溴乙烷磺酸钠(15g,56.9mmol,10.7%产率):1H NMR(400MHz,D2O)δppm 3.62(t,J=7.5Hz,2H),3.46-3.34(m,2H)。
步骤2:2-溴乙烷磺酰氯
将五氯化磷(2.5g,12.01mmol)和2-溴乙烷磺酸钠(4g,15.17mmol)的混合物在110℃搅拌2h。将反应混合物冷却,然后倒入冰中。将混合物用DCM(150mL x2)萃取,且将有机层依次用水(150mL x2)、NaHCO3溶液(150mL x2)和水(150mL x2)洗涤。有机溶液用MgSO4干燥且浓缩以得到棕色油状物的2-溴乙烷磺酰氯(1.5g,5.78mmol,38.1%产率):1H NMR(400MHz,CD3OD)δppm 4.54-4.46(m,2H),3.91-3.83(m,2H)。
步骤3:乙烯磺酰胺
将2-溴乙烷磺酰氯(1.5g,5.78mmol)在THF(35mL)中的溶液冷却至-40℃,然后将氨气缓慢鼓泡至混合物达1h。将反应过滤且浓缩以得到棕色固体的乙烯磺酰胺(500mg,3.27mmol,56.5%产率):1H NMR(400MHz,CD3OD)δppm 6.80(dd,J=9.9,16.5Hz,1H),6.15(d,J=16.3Hz,1H),5.88(d,J=10.1Hz,1H);ES-LCMS m/z 130.2[M+Na]+.
中间体24:3-(甲基磺酰基)丁醛
步骤1:3-(甲硫基)丁-1-醇
向3-(甲硫基)丁醛(2.5g,21.15mmol)在MeOH(10mL)中的溶液中添加NaBH4(1.600g,42.3mmol)。将混合物在25℃搅拌0.5h。该反应通过TLC(PE/EA=1/1,Rf=0.6)监测。将混合物过滤且浓缩以得到黄色油状物的3-(甲硫基)丁-1-醇(2g,13.31mmol,62.9%产率):1H NMR(400MHz,CD3OD)δppm 3.76-3.50(m,2H),2.96-2.69(m,1H),2.05(s,3H),1.84-1.58(m,2H),1.28(d,J=6.6Hz,3H)
步骤2:3-(甲基磺酰基)丁-1-醇
向3-(甲硫基)丁-1-醇(2g,13.31mmol)在DCM(150mL)中的溶液中添加m-CPBA(3.28g,13.31mmol)。将混合物在25℃搅拌10h。添加水(50mL)且将混合物用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤,浓缩且通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到黄色油状物的3-(甲基磺酰基)丁-1-醇(500mg,2.63mmol,19.7%产率):1H NMR(400MHz,CD3OD)δppm 3.82-3.71(m,1H),3.65(ddd,J=5.3,8.8,11.0Hz,1H),3.28-3.16(m,1H),2.91(s,3H),2.30-2.15(m,1H),1.71-1.55(m,1H),1.39(d,J=7.1Hz,3H)
步骤3:3-(甲基磺酰基)丁醛
在-78℃经5分钟向草酰氯(400mg,3.15mmol)在DCM(5mL)中的溶液中添加DMSO(0.448mL,6.31mmol,溶于5.0mL的DCM)。然后经10分钟滴加3-(甲基磺酰基)丁-1-醇(400mg,2.102mmol)在DCM(5mL)中的溶液,然后添加DIEA(2.203mL,12.61mmol)在5mL DCM中的溶液。将混合物在-78℃搅拌10min,然后温热至室温。添加冰冷的盐酸溶液(1.0M,30mL)以淬灭反应。分离两相且水相用DCM(50mL×3)萃取。将合并的有机相混合,用无水Na2SO4干燥且浓缩以得到黄色油状物的3-(甲基磺酰基)丁醛(500mg,1.997mmol,95.0%产率):1H NMR(400MHz,CDCCl3)δppm9.78(s,1H),3.32-3.19(m,2H),3.14-3.01(m,1H),2.87(s,3H),1.50(d,J=6.6Hz,3H)
中间体25:2-(哌啶-4-基)乙烷磺酰胺
步骤1:2-(哌啶-4-基)乙醇,盐酸盐
向4-(2-羟基乙基)哌啶-1-甲酸叔丁酯(8g,33.1mmol)在MeOH(50mL)中的溶液中添加HCl溶液(4M在MeOH中,10mL,40.0mmol)。将混合物在30℃搅拌0.5h,然后浓缩以得到棕色固体的2-(哌啶-4-基)乙醇,盐酸盐(5.5g,28.2mmol,85.0%产率):1H NMR(400MHz,CD3OD)δppm3.61(t,J=6.4Hz,2H),3.36(d,J=12.8Hz,2H),2.95(t,J=12.8Hz,2H),1.94(d,J=14.1Hz,2H),1.77(m,1H),1.51(q,J=6.6Hz,2H),1.46-1.32(m,2H)。
步骤2:4-(2-羟基乙基)哌啶-1-甲酸苄基酯
向2-(哌啶-4-基)乙醇,盐酸盐(5.5g,28.2mmol)、Na2CO3(11.85g,141mmol)在1,4-二噁烷(100mL)和水(100mL)中的混合物中滴加CbzCl(5.78g,33.9mmol)。然后将混合物在30℃搅拌10h。将混合物浓缩,且残余物用水(200mL)稀释,用EtOAc(100mL x2)萃取。合并的有机相用水(200mL x2)洗涤,用Na2SO4干燥,过滤,且浓缩。粗物质在硅胶上通过二氧化硅柱色谱法(DCM/MeOH=20/1,Rf=0.6)纯化以得到棕色油状物4-(2-羟基乙基)哌啶-1-甲酸苄基酯(7g,25.9mmol,92.0%产率):1H NMR(400MHz,CDCl3)δppm7.43-7.30(m,5H),5.14(s,2H),4.25-4.10(m,2H),3.72(t,J=6.65Hz,2H),2.80(br.s,2H),1.80-1.57(m,5H),1.24-1.09(m,2H);ES-LCMS m/z 264.2[M+H]+.
步骤3:4-(2-((甲基磺酰基)氧基)乙基)哌啶-1-甲酸苄基酯
向4-(2-羟基乙基)哌啶-1-甲酸苄基酯(5.5g,20.33mmol)、DIEA(7.10mL,40.7mmol)在DCM(20mL)中的混合物中添加MsCl(1.901mL,24.40mmol)。将混合物在30℃搅拌0.5h,然后浓缩。残余物在DCM(200mL)和水(200mL)之间分配,用DCM(200mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色固体的4-(2-((甲基磺酰基)氧基)乙基)哌啶-1-甲酸苄基酯(6g,14.06mmol,69.2%产率):1H NMR(400MHz,CDCl3)δppm7.31(d,J=15.4Hz,5H),5.08(d,J=15.4Hz,2H),4.34-4.03(m,4H),3.08(s,3H),2.74-2.72(m,2H),1.66-1.50(m,5H),1.14-1.09(m,2H);ES-LCMS m/z 342.2[M+H]+.
步骤4:4-(2-(乙酰基硫基)乙基)哌啶-1-甲酸苄基酯
向4-(2-((甲基磺酰基)氧基)乙基)哌啶-1-甲酸苄基酯(6g,14.06mmol)、K2CO3(5.83g,42.2mmol)在DMF(50mL)中的混合物中添加硫代乙酸(ethanethioic S-acid)(2.140g,28.1mmol)。将混合物在25℃搅拌3h直到LCMS显示反应完成。将混合物过滤且将滤液浓缩,用DCM(100mL)和水(100mL)稀释,用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物,其在硅胶上通过柱色谱法(PE/EtOAc=5/1,Rf=0.3)纯化以得到棕色固体的4-(2-(乙酰基硫基)乙基)哌啶-1-甲酸苄基酯(5g,12.44mmol,89.0%产率):1H NMR(400MHz,CDCl3)δppm 7.51-7.16(m,5H),5.21-5.00(m,2H),4.14(br.s,2H),2.90-2.67(m,4H),2.39-2.20(m,3H),1.68-1.60(d,J=10.1Hz,5H),1.10(br.s,2H);ES-LCMS m/z 322.1[M+H]+.
步骤5:4,4'-(二硫二基双(乙烷-2,1-二基))双(哌啶-1-甲酸)二苄基酯
向4-(2-(乙酰基硫基)乙基)哌啶-1-甲酸苄基酯(5g,12.44mmol)在MeOH(50mL)和水(100mL)中的溶液中添加K2CO3(8.60g,62.2mmol)。将混合物在30℃搅拌2h,然后浓缩。残余物用水(100mL)稀释,用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到棕色固体4,4'-(二硫二基双(乙烷-2,1-二基))双(哌啶-1-甲酸)二苄基酯(3.6g,5.56mmol,89.4%产率):1H NMR(400MHz,CDCl3)δppm 7.36-7.12(m,10H),5.05(s,4H),4.10(br.s,4H),2.81-2.56(m,8H),1.59(d,J=13.7Hz,10H),1.07(d,J=8.8Hz,4H);ES-LCMSm/z 557.3[M+H]+.
步骤6:4-(2-巯基乙基)哌啶-1-甲酸苄基酯
向4,4'-(二硫二基双(乙烷-2,1-二基))双(哌啶-1-甲酸)二苄基酯(1g,1.545mmol)在AcOH(10mL,175mmol)中的混合物中添加Zn粉(0.505g,7.72mmol)。将混合物在30℃搅拌5h,然后过滤。将滤液浓缩以得到棕色固体4-(2-巯基乙基)哌啶-1-甲酸苄基酯(0.90g,3.332mmol,75.0%产率):1H NMR(400MHz,CDCl3)δppm 7.50-7.17(m,5H),5.11(br.s,2H),4.17(br.s,2H),2.76(br.s,2H),2.64-2.46(m,2H),1.65(d,J=11.5Hz,4H),1.39-1.28(m,1H),1.12-1.10(m,2H);ES-LCMS m/z 280.2[M+H]+.
步骤7:4-(2-(氯磺酰基)乙基)哌啶-1-甲酸苄基酯
将搅拌下的4-(2-巯基乙基)哌啶-1-甲酸苄基酯(900mg,2.332mmol)在水(10mL)和THF(10mL)中的悬浮液冷却至-10℃,然后在-10℃至0℃将Cl2气鼓泡通过反应混合物达10分钟。混合物在N2下吹洗以去除过量氯,然后浓缩。残余物用DCM(50mL)和水(50mL)稀释,用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到棕色油状物4-(2-(氯磺酰基)乙基)哌啶-1-甲酸苄基酯(1g,1.521mmol,65.2%产率):1H NMR(400MHz,CDCl3)δppm 7.35-7.23(m,5H),5.06(s,2H),4.15(d,J=11.9Hz,2H),2.71-2.69(m,2H),2.60-2.50(m,2H),1.97-1.91(m,4H),1.64(d,J=13.7Hz,1H)。1.22-1.16(m,2H);ES-LCMS m/z 346.2[M+H]+.
步骤8:4-(2-氨磺酰基乙基)哌啶-1-甲酸苄基酯
在-40℃向4-(2-(氯磺酰基)乙基)哌啶-1-甲酸苄基酯(1g,1.521mmol)在THF(10mL)中的溶液中鼓泡氨气20min。将混合物浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,且冻干干燥以得到白色固体的4-(2-氨磺酰基乙基)哌啶-1-甲酸苄基酯(200mg,0.613mm ol,40.3%产率):1H NMR(400MHz,CD3OD)δppm7.42-7.28(m,5H),5.12(s,2H),4.16(d,J=13.1Hz,2H),3.17-3.09(m,2H),2.85(br s,2H),1.82-1.71(m,4H),1.66(t,J=7.3Hz,1H),1.19-1.08(m,2H);ES-LCMS m/z 327.2[M+H]+.
步骤9:2-(哌啶-4-基)乙烷磺酰胺
向4-(2-氨磺酰基乙基)哌啶-1-甲酸苄基酯(200mg,0.613mmol)在MeOH(15mL)中的溶液中添加Pd/C(10wt%,65.2mg,0.061mmol)。将混合物在20℃在H2气氛(15psi)下搅拌0.5h。将混合物过滤且将滤液浓缩以得到棕色固体的2-(哌啶-4-基)乙烷磺酰胺(130mg,0.541mmol,88.0%产率):1H NMR(400MHz,CD3OD)δppm 3.24-3.16(m,1H),3.14-3.06(m,2H),2.93-2.86(m,2H),2.77(dt,J=2.8,12.7Hz,1H),1.80-1.71(m,4H),1.48-1.39(m,1H),1.31-1.22(m,2H);ES-LCMS m/z 193.5[M+H]+.
中间体26:3-(哌啶-4-基)丙酸乙酯
步骤1:(E)-4-(3-乙氧基-3-氧代丙-1-烯-1-基)哌啶-1-甲酸叔丁酯
向2-(二乙氧基磷酰基)乙酸乙酯(32.0mL,211mmol)在THF(300mL)中的溶液中添加t-BuOK(23.68g,211mmol)。在25℃搅拌0.5h后,添加4-甲酰基哌啶-1-甲酸叔丁酯(30g,141mmol)。将混合物在相同温度搅拌1.5h。TLC(PE/EtOAc=3/1,Rf=0.61)显示反应完成。将混合物浓缩且添加水(500mL)。将混合物用DCM(200mL×3)萃取且合并的有机层用Na2SO4干燥,浓缩以得到粗产物,其在120g硅胶上通过快速色谱法(PE/EtOAc=1/0至2/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.61)发现包含产物的级分合并且浓缩以得到淡黄色油状物(E)-4-(3-乙氧基-3-氧代丙-1-烯-1-基)哌啶-1-甲酸叔丁酯(32g,102mmol,72.3%产率):1H NMR(400MHz,CDCl3)δppm 6.88(dd,J=6.4,15.7Hz,1H),5.81-5.74(m,1H),4.21-4.15(m,2H),4.14-4.03(m,2H),2.74(t,J=11.9Hz,2H),2.27(dd,J=3.7,7.3Hz,1H),1.71(d,J=12.8Hz,2H),1.44(s,9H),1.33-1.23(m,5H);ES-LCMS m/z 184.2[M-Boc+H]+.
步骤2:4-(3-乙氧基-3-氧代丙基)哌啶-1-甲酸叔丁酯
向(E)-4-(3-乙氧基-3-氧代丙-1-烯-1-基)哌啶-1-甲酸叔丁酯(32g,102mmol)在MeOH(300mL)中的溶液中添加Pd/C(10wt%,5g,4.70mmol)。将混合物在25℃在50psi在H2气氛搅拌12h。将混合物过滤且将滤液浓缩以得到淡黄色油状物4-(3-乙氧基-3-氧代丙基)哌啶-1-甲酸叔丁酯(27g,85mmol,84.0%产率):1H NMR(400MHz,CDCl3)δppm 4.11(q,J=7.4Hz,4H),2.64(t,J=11.9Hz,2H),2.30(t,J=7.7Hz,2H),1.63(d,J=13.7Hz,2H),1.59-1.53(m,2H),1.43(s,9H),1.37(td,J=3.7,7.5Hz,1H),1.24(t,J=7.1Hz,3H),1.12-1.00(m,2H);ES-LCMS m/z 186.2[M-Boc+H]+.
步骤3:3-(哌啶-4-基)丙酸乙酯
将4-(3-乙氧基-3-氧代丙基)哌啶-1-甲酸叔丁酯(13g,41.0mmol)溶于HCl溶液(4.0M在MeOH中,60mL,240mmol)。将反应混合物在15℃搅拌10min,然后浓缩。添加NaHCO3水溶液且用DCM(50mL x5)萃取。合并的有机层用Na2SO4干燥且浓缩以得到淡黄色油状物的3-(哌啶-4-基)丙酸乙酯(8g,38.9mmol,95.0%产率):1H NMR(400MHz,CDCl3)δppm 4.11(q,J=7.1Hz,2H),3.10(d,J=12.3Hz,2H),2.56(s,2H),2.30(t,J=7.7Hz,2H),1.68(d,J=12.8Hz,2H),1.60-1.52(m,2H),1.43-1.34(m,1H),1.28-1.08(m,5H);ES-LCMS m/z 186.2[M+H]+.
中间体27:2-甲基-3-(哌啶-4-基)丙酸乙酯,盐酸盐
步骤1:4-(3-乙氧基-2-甲基-3-氧代丙基)哌啶-1-甲酸叔丁酯
在0℃向4-(3-乙氧基-3-氧代丙基)哌啶-1-甲酸叔丁酯(3g,9.46mmol)在THF(40mL)中的溶液中添加LiHMDS(3.17g,18.92mmol)。将混合物在0℃搅拌0.5h。然后添加MeI(1.611g,11.35mmol)且将混合物在25℃搅拌7.5h。将混合物用5mL饱和NH4Cl水溶液淬灭。分离有机相,浓缩且通过硅胶柱色谱法(PE/EtOAc=0-100/30)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到无色油状物4-(3-乙氧基-2-甲基-3-氧代丙基)哌啶-1-甲酸叔丁酯(2g,6.01mmol,63.5%产率):1H NMR(400MHz,CDCl3)δppm4.16-3.92(m,4H),2.63(t,J=11.2Hz,2H),2.55-2.44(m,1H),1.72-1.52(m,4H),1.43(s,10H),1.23(t,J=7.1Hz,3H),1.16-0.99(m,5H);ES-LCMS m/z 200.2[M-Boc+H]+.
步骤2:2-甲基-3-(哌啶-4-基)丙酸乙酯,盐酸盐
将4-(3-乙氧基-2-甲基-3-氧代丙基)哌啶-1-甲酸叔丁酯(2g,6.01mmol)溶于HCl溶液(4.0M在EtOAc中,24mL,96mmol)。将混合物在20℃搅拌0.5h,然后浓缩以得到棕色固体的2-甲基-3-(哌啶-4-基)丙酸乙酯,盐酸盐(1.5g,5.09mmol,85.0%产率):1H NMR(400MHz,CDCl3)δppm 4.17-4.09(m,4H),4.46-3.50(m,2H),2.86-2.70(m,2H),2.53-2.40(m,1H),2.10-2.01(m,4H),1.82-1.56(m,4H),1.41-1.29(m,3H);ES-LCMS m/z 200.3[M+H]+.
中间体28:4-(氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯
步骤1:1-氧杂-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯
在0℃向三甲基碘化锍(trimethylsulfonium iodide)(26.5g,120mmol)在DMSO(100mL)中的溶液中添加NaH(4.82g,120mmol)。将混合物在0℃搅拌0.5h后,添加4-氧代哌啶-1-甲酸叔丁酯(20g,100mmol)且溶液在25℃搅拌12h。将溶液倒入冰水(500mL),用EtOAc(200mL×3)萃取。合并的有机相用Na2SO4干燥,浓缩。残余物通过柱色谱法纯化,用PE/EtOAc=3/1洗脱以得到无色油状物的1-氧杂-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯(13g,54.9mmol,54.7%产率):1H NMR(400MHz,CDCl3)δppm 3.77-3.62(m,2H),3.48-3.35(m,2H),2.67(s,2H),1.86-1.73(m,2H),1.54-1.37(m,11H);ES-LCMS m/z 158.1[M-t-Bu+H]+.
步骤2:4-(氨基甲基)-4-羟基哌啶-1-甲酸叔丁酯
将1-氧杂-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯(26g,122mmol)在氨水(200mL,3484mmol)中的溶液在50℃搅拌12h。将混合物浓缩以得到无色油状物4-(氨基甲基)-4-羟基哌啶-1-甲酸叔丁酯(27g,94mmol,77.0%产率):1H NMR(400MHz,CDCl3)δppm 3.90-3.75(m,2H),3.60-3.49(m,1H),3.43-3.32(m,1H),3.23-3.07(m,2H),2.70(s,2H),1.55(br.s,2H),1.43(s,9H);ES-LCMS m/z 175.0[M-t-Bu+H]+.
步骤3:4-(氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯
在0℃向4-(氨基甲基)-4-羟基哌啶-1-甲酸叔丁酯(25g,109mmol)和咪唑(11.08g,163mmol)在DCM(200mL)中的溶液中添加TBSCl(19.63g,130mmol)在DCM(100mL)中的溶液。然后,将混合物在25℃搅拌12h。将溶液溶于DCM(300mL)且用水(100mL×3)洗涤。有机相用Na2SO4干燥且浓缩以得到棕色油状物4-(氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯(36g,84mmol,77.0%产率):1H NMR(400MHz,CDCl3)δppm3.71-3.60(m,2H),3.48-3.38(m,1H),3.31-3.21(m,2H),3.19-3.09(m,1H),2.68(s,2H),1.55-1.52(m,2H),1.44(s,9H),0.85(s,9H),0.03-0.02(m,6H);ES-LCMS m/z 289.2[M+H]+.
中间体29:(哌啶-4-基甲基)氨基甲酸乙酯,盐酸盐
步骤1:4-(((乙氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯
向4-(氨基甲基)哌啶-1-甲酸叔丁酯(10g,46.7mmol)和DIEA(12.06g,93mmol)在DCM(100mL)中的溶液中滴加氯甲酸乙酯(5.57g,51.3mmol)。将混合物在0℃搅拌0.5h。添加DCM(500mL)且混合物依次用1N HCl(100mL)、NaHCO3水溶液(300mL)和水(300mL x2)洗涤。有机层用Na2SO4干燥,过滤且浓缩以得到淡黄色油状物4-(((乙氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯(9g,28.3mmol,60.6%产率):1H NMR(400MHz,CDCl3)δppm 4.80(br.s,1H),4.23-3.93(m,4H),3.03(br.s,2H),2.64(t,J=11.7Hz,2H),1.68-1.56(m,3H),1.42(s,9H),1.20(t,J=6.8Hz,3H),1.13-1.03(m,2H);ES-LCMS m/z 231.2.[M-t-Bu+H]+.
步骤2:(哌啶-4-基甲基)氨基甲酸乙酯,盐酸盐
向4-(((乙氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯(9g,28.3mmol)在EtOAc(50mL)中的溶液中滴加HCl溶液(4.0M在EtOAc中,30mL,120mmol)。将混合物在25℃搅拌0.5h,然后浓缩以得到粉色固体(哌啶-4-基甲基)氨基甲酸乙酯,盐酸盐(7.5g,26.9mmol,95.0%产率):1H NMR(400MHz,CD3OD)δppm 4.11-4.01(m,2H),3.40(d,J=12.8Hz,2H),3.04(d,J=6.6Hz,2H),2.97(t,J=12.3Hz,2H),1.92(d,J=13.7Hz,2H),1.49-1.35(m,3H),1.25-1.18(m,3H);ES-LCMS m/z 187.2[M+H]+.
中间体30:N-乙基-2-(哌啶-4-基)乙酰胺,盐酸盐
步骤1:4-(2-(乙基氨基)-2-氧代乙基)哌啶-1-甲酸叔丁酯
向2-(1-(叔丁氧基羰基)哌啶-4-基)乙酸(10g,32.9mmol)和乙胺,盐酸盐(5.36g,65.8mmol)在DCM(100mL)中的溶液中添加DIEA(34.5mL,197mmol)和HATU(25.00g,65.8mmol)。将反应混合物在30℃搅拌8h直到TLC(PE/EtOAc=3/1)显示反应完成。将混合物浓缩且残余物通过快速色谱法(PE/EtOAc=10/1至1/1,)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.25)发现包含产物的级分合并且浓缩以得到无色油状物4-(2-(乙基氨基)-2-氧代乙基)哌啶-1-甲酸叔丁酯(5g,14.79mmol,45.0%产率):1H NMR(400MHz,CDCl3)δppm3.33-3.21(m,2H),2.77-2.56(m,4H),2.11-1.98(m,2H),1.95-1.93(m,1H),1.64(d,J=13.2Hz,2H),1.41(s,9H),1.40-1.38(m,2H),1.10(t,J=7.3Hz,3H);ES-LCMS m/z 215.0[M-t-Bu+H]+.
步骤2:N-乙基-2-(哌啶-4-基)乙酰胺,盐酸盐
将4-(2-(乙基氨基)-2-氧代乙基)哌啶-1-甲酸叔丁酯(5g,14.79mmol)溶于HCl溶液(4.0M在MeOH中,24mL,96mmol)。将混合物在20℃搅拌0.5h,然后浓缩以得到棕色固体N-乙基-2-(哌啶-4-基)乙酰胺,盐酸盐(3g,10.16mmol,68.7%产率):1H NMR(400MHz,CDCl3)δppm 3.77-3.55(m,2H),3.19-2.87(m,4H),2.86(m,2H),1.97-1.78(m,1H),1.51(br.s,4H),1.42(d,J=4.4Hz,3H)。
中间体31:3-(氮杂环丁烷-3-基)丁酸乙酯,TFA盐
步骤1:3-(甲氧基(甲基)氨基甲酰基)氮杂环丁烷-1-甲酸叔丁酯
将CDI(6.04g,37.3mmol)分批添加至1-(叔丁氧基羰基)氮杂环丁烷-3-甲酸(5g,24.85mmol)在THF(50mL)中的溶液中。将混合物在15℃搅拌2h。添加N,O-二甲基羟胺,盐酸盐(3.64g,37.3mmol)和DIEA(13.02mL,74.5mmol)在MeCN(50mL)中的悬浮液。所得混合物在15℃搅拌8h。将挥发物浓缩,然后添加水(100mL)和EtOAc(100mL)。分离有机层,依次用5%柠檬酸水溶液(100mL)、水(100mL)和盐水(100mL)洗涤,然后用无水MgSO4干燥且浓缩以得到淡黄色油状物的3-(甲氧基(甲基)氨基甲酰基)氮杂环丁烷-1-甲酸叔丁酯(5g,17.40mmol,70.0%产率):1H NMR(400MHz,CD3OD)δppm 4.11-3.97(m,4H),3.85-3.74(m,1H),3.69(s,3H),3.20(s,3H),1.43(s,9H);ES-LCMS m/z 189.1[M-t-Bu+H]+.
步骤2:3-乙酰基氮杂环丁烷-1-甲酸叔丁酯
将3-(甲氧基(甲基)氨基甲酰基)氮杂环丁烷-1-甲酸叔丁酯(4g,13.92mmol)在THF(70mL)中的溶液经0.5h滴加至MeMgBr(13.92mL,41.8mmol)在THF(30mL)中的溶液中。反应温度保持在0℃。添加后,将混合物在15℃搅拌2.5h。将混合物冷却至0℃且添加10%柠檬酸水溶液(50mL)。分离有机层且水层用EtOAc(200mL)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色油状物的3-乙酰基氮杂环丁烷-1-甲酸叔丁酯(3g,12.05mmol,87.0%产率):1H NMR(400MHz,CD3OD)δppm4.10-3.97(m,4H),3.59(s,1H),2.18(s,3H),1.45(s,9H);ES-LCMS m/z 144.1[M-t-Bu+H]+.
步骤3:(E)-3-(4-乙氧基-4-氧代丁-2-烯-2-基)氮杂环丁烷-1-甲酸叔丁酯
向2-(二乙氧基磷酰基)乙酸乙酯(2.70g,12.05mmol)在THF(30mL)中的溶液中添加t-BuOK(1.352g,12.05mmol)。将混合物在15℃搅拌2h,然后添加3-乙酰基氮杂环丁烷-1-甲酸叔丁酯(2g,8.03mmol)在THF(20mL)中的溶液。将混合物在15℃搅拌6h,然后用H2O(50mL)淬灭。将混合物用DCM(200mL x2)萃取,合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=2/1)纯化。将所有通过TLC(PE/EtOAc=2/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到无色油状物的(E)-3-(4-乙氧基-4-氧代丁-2-烯-2-基)氮杂环丁烷-1-甲酸叔丁酯(2.5g,7.43mmol,92.0%产率):1H NMR(400MHz,CD3OD)δppm5.77(s,1H),4.20-4.10(m,4H),3.87(t,J=7.0Hz,2H),3.49-3.37(m,1H),2.23-2.04(m,3H),1.47-1.45(m,9H),1.31-1.26(m,3H);ES-LCMSm/z 270.2[M+H]+
步骤4:3-(4-乙氧基-4-氧代丁-2-基)氮杂环丁烷-1-甲酸叔丁酯
向(E)-3-(4-乙氧基-4-氧代丁-2-烯-2-基)氮杂环丁烷-1-甲酸叔丁酯(2g,5.94mmol)在MeOH(50mL)中的溶液中添加Pd/C(10wt%,1.897g,1.782mmol)。将混合物在15℃在H2气氛(15psi)搅拌0.5h,然后过滤且浓缩以得到无色油状物的3-(4-乙氧基-4-氧代丁-2-基)氮杂环丁烷-1-甲酸叔丁酯(2g,5.53mmol,93.0%产率):1H NMR(400MHz,CD3OD)δppm4.15(q,J=7.4Hz,2H),3.96(d,J=8.0Hz,2H),3.64(br.s,2H),2.32(d,J=10.0Hz,2H),2.17-2.01(m,2H),1.45(s,9H),1.27(t,J=7.3Hz,3H),0.94(d,J=6.0Hz,3H);ES-LCMS m/z 216.2[M-t-Bu+H]+.
步骤5:3-(氮杂环丁烷-3-基)丁酸乙酯,TFA盐
向3-(4-乙氧基-4-氧代丁-2-基)氮杂环丁烷-1-甲酸叔丁酯(1g,2.76mmol)在DCM(10mL)中的溶液中添加TFA(2mL,26.0mmol)。将混合物在15℃搅拌0.5h,然后浓缩以得到无色油状物的3-(氮杂环丁烷-3-基)丁酸乙酯,TFA盐(1g,2.454mmol,89.0%产率):1H NMR(400MHz,CD3OD)δppm4.23-3.79(m,6H),2.82-2.71(m,1H),2.45-2.39(m,3H)1.23-1.19(m,3H),0.89(d,J=5.3Hz,3H);ES-LCMS m/z 172.2[M+H]+.
中间体32:2-(吡咯烷-3-基氧基)乙酸乙酯,盐酸盐
步骤1:3-(2-乙氧基-2-氧代乙氧基)吡咯烷-1-甲酸叔丁酯
在N2气氛在0℃向3-羟基吡咯烷-1-甲酸叔丁酯(3g,16.02mmol)在THF(50mL)中的悬浮液中添加NaH(0.961g,24.03mmol)。将反应混合物在0℃搅拌0.5h,然后添加2-溴乙酸乙酯(5.35g,32.0mmol)。将反应混合物在20℃在N2气氛搅拌9.5h。将混合物用饱和NH4Cl水溶液(30mL)淬灭,用EtOAc(30mL×3)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗物质。粗物质通过快速色谱法(PE/EtOAc=3/1,Rf=0.5)纯化,将所需级分浓缩以得到无色油状物3-(2-乙氧基-2-氧代乙氧基)吡咯烷-1-甲酸叔丁酯(3g,8.78mmol,54.8%产率):1HNMR(400MHz,CDCl3)δppm 4.22(q,J=7.1Hz,2H),4.15(br.s,1H),4.11-4.02(m,2H),3.57-3.34(m,4H),2.11-1.88(m,2H),1.45(s,9H),1.31-1.25(m,3H);ES-LCMS m/z 218.2[M-t-Bu+H]+.
步骤2:2-(吡咯烷-3-基氧基)乙酸乙酯,盐酸盐
向3-(2-乙氧基-2-氧代乙氧基)吡咯烷-1-甲酸叔丁酯(3g,8.78mmol)在DCM(30mL)中的悬浮液中添加HCl溶液(4.0M在EtOAc中,20mL,80mmol)。将反应混合物在15℃搅拌0.5h,然后浓缩以得到无色胶状物粗品2-(吡咯烷-3-基氧基)乙酸乙酯,盐酸盐(1.5g,5.72mmol,65.2%产率):1H NMR(400MHz,CDCl3)δppm 4.37(br.s,1H),4.21(q,J=7.3Hz,2H),4.13-4.07(m,2H),3.92(br.s,1H),3.62-3.38(m,4H),2.25(dd,J=5.6,13.9Hz,1H),2.15-2.05(m,1H),1.31-1.25(m,3H)。
中间体33:2-(八氢环戊二烯并[c]吡咯-5-基)乙酸乙酯,盐酸盐
步骤1:5-(2-乙氧基-2-氧代亚乙基)六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯
向2-(二乙氧基磷酰基)乙酸乙酯(1.493g,6.66mmol)在THF(10mL)中的溶液中添加t-BuOK(0.747g,6.66mmol)。在15℃搅拌0.5h后,添加5-氧代六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(1g,4.44mmol)。将混合物在相同温度搅拌11.5h直到TLC(PE/EtOAc=3/1,Rf=0.58)显示反应完成。将挥发物浓缩且添加水(50mL)。将混合物用DCM(20mL×3)萃取且合并的有机层用Na2SO4干燥且浓缩以得到粗产物,其通过快速色谱法(PE/EtOAc=1/0至2/1,PE/EtOAc=3/1,Rf=0.58)纯化以得到淡黄色油状物5-(2-乙氧基-2-氧代亚乙基)六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(600mg,1.844mmol,41.5%产率):1H NMR(400MHz,CDCl3)δppm 5.76(s,1H),4.06(q,J=7.1Hz,2H),3.46(d,J=7.1Hz,2H),3.07(dd,J=4.2,10.8Hz,1H),3.02-2.90(m,2H),2.76-2.55(m,4H),2.36(d,J=14.1Hz,1H),1.38(s,9H),1.23-1.12(m,3H);ES-LCMS m/z 240.2[M-t-Bu+H]+.
步骤2:5-(2-乙氧基-2-氧代乙基)六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯
在H2气氛(15psi)下向5-(2-乙氧基-2-氧代亚乙基)六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(600mg,1.844mmol)在MeOH(20mL)中的溶液中添加Pd/C(10wt%,200mg,0.188mmol)。将混合物在15℃搅拌8h,然后过滤。将滤液浓缩以得到无色油状物5-(2-乙氧基-2-氧代乙基)六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(500mg,1.429mmol,77.0%产率):1H NMR(400MHz,CDCl3)δppm 4.11(q,J=7.1Hz,2H),3.41(s,2H),3.21(s,2H),2.59(s,2H),2.38-2.21(m,3H),2.18-2.05(m,2H),1.44(s,9H),1.24(t,J=7.1Hz,3H),1.07(s,2H)。ES-LCMS m/z 242.2[M-t-Bu+H]+.
步骤3:2-(八氢环戊二烯并[c]吡咯-5-基)乙酸乙酯,盐酸盐
将5-(2-乙氧基-2-氧代乙基)六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(500mg,1.429mmol)溶于HCl溶液(4.0M在EtOAc中,6mL,24.00mmol)。将反应混合物在15℃搅拌0.5h。将溶液浓缩以得到淡黄色油状物的2-(八氢环戊二烯并[c]吡咯-5-基)乙酸乙酯,盐酸盐(380mg,1.382mmol,97.0%产率):1H NMR(400MHz,CDCl3)δppm 4.13-4.05(m,2H),3.21(s,4H),2.91-2.81(m,2H),2.42(d,J=6.2Hz,2H),2.27-2.12(m,3H),1.39-1.28(m,2H),1.26-1.18(m,3H);ES-LCMS m/z 198.3[M+H]+.
中间体34:(3,3-二甲基哌啶-4-基)氨基甲酸苄基酯
步骤1:4-氨基-3,3-二甲基哌啶-1-甲酸叔丁酯
向3,3-二甲基-4-氧代哌啶-1-甲酸叔丁酯(1.2g,5.28mmol)在MeOH(10mL)中的溶液中添加NH4OAc(4.07g,52.8mmol)。将混合物在15℃在N2气氛搅拌10h,然后添加NaBH3CN(0.995g,15.84mmol)且再搅拌2h。将混合物过滤且浓缩以得到无色油状物4-氨基-3,3-二甲基哌啶-1-甲酸叔丁酯(600mg,2.102mmol,39.8%产率):1H NMR(400MHz,CD3OD)δppm4.00(d,J=13.2Hz,2H),3.64(d,J=13.2Hz,2H),2.49(dd,J=4.2,11.0Hz,1H),1.67-1.52(m,2H),1.43(s,9H),0.93(s,3H),0.81(s,3H);ES-LCMS m/z 173.1[M+H]+.
步骤2:4-(((苄基氧基)羰基)氨基)-3,3-二甲基哌啶-1-甲酸叔丁酯
向4-氨基-3,3-二甲基哌啶-1-甲酸叔丁酯(400mg,1.752mmol)和DIEA(679mg,5.26mmol)在DCM(8mL)中的混合物中添加CbzCl(448mg,2.63mmol)。将混合物在15℃搅拌1h,然后浓缩。残余物通过制备型TLC(PE/EtOAc=10/3,Rf=0.6)纯化以得到黄色油状物4-(((苄基氧基)羰基)氨基)-3,3-二甲基哌啶-1-甲酸叔丁酯(500mg,1.104mmol,63.0%产率):1H NMR(400MHz,CDCl3)δppm 7.40-7.29(m,5H),5.15-5.05(m,2H),4.60(d,J=9.5Hz,1H),3.83-3.60(m,1H),3.57-3.45(m,1H),2.80(br.s,1H),2.62(br.s,1H),1.77-1.67(m,1H),1.55-1.47(m,1H),1.45(s,9H),0.94(s,3H),0.82(s,3H);ES-LCMS m/z 263.2[M-Boc+H]+.
步骤3:(3,3-二甲基哌啶-4-基)氨基甲酸苄基酯
向4-(((苄基氧基)羰基)氨基)-3,3-二甲基哌啶-1-甲酸叔丁酯(300mg,0.828mmol)在DCM(10mL)中的溶液中添加TFA(1887mg,16.55mmol)。将混合物在15℃搅拌0.5h,然后添加水(50mL)。水相用固体Na2CO3调节至pH=9,然后用DCM(15mL x2)萃取。合并的萃取物用盐水(15mL x2)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色油状物的(3,3-二甲基哌啶-4-基)氨基甲酸苄基酯(200mg,0.686mmol,83.0%产率):1H NMR(400MHz,CDCl3)δppm 7.40-7.29(m,5H),5.14-5.04(m,2H),4.61(d,J=9.5Hz,1H),3.55-3.46(m,1H),3.04(d,J=12.6Hz,1H),2.72-2.59(m,2H),2.48(d,J=12.6Hz,1H),1.72-1.67(m,1H),1.42-1.40(m,1H),0.90(d,J=3.7Hz,6H);ES-LCMS m/z 263.2[M+H]+.
中间体35:2-(哌啶-4-基)乙酰胺
步骤1:4-(2-氨基-2-氧代乙基)哌啶-1-甲酸叔丁酯
向2-(1-(叔丁氧基羰基)哌啶-4-基)乙酸(5g,20.55mmol)和DIEA(14.36mL,82mmol)在DCM(100mL)中的溶液中添加NH4Cl(10.99g,206mmol)和HATU(15.63g,41.1mmol)。将反应混合物在30℃搅拌8h,然后浓缩且通过快速色谱法(DCM/MeOH=100/1至10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到白色固体的4-(2-氨基-2-氧代乙基)哌啶-1-甲酸叔丁酯(3g,9.90mmol,48.2%产率):1HNMR(400MHz,CDCl3)δppm 5.82-5.52(m,2H),4.12-3.95(m,2H),2.77-2.61(m,2H),2.06-1.88(m,2H),1.72(d,J=12.8Hz,2H),1.54-1.40(m,9H),1.13(dq,J=4.0,12.3Hz,2H);ES-LCMS m/z 187.2[M-t-Bu+H]+.
步骤2:2-(哌啶-4-基)乙酰胺,盐酸盐
将4-(2-氨基-2-氧代乙基)哌啶-1-甲酸叔丁酯(0.8g,2.64mmol)溶于HCl溶液(4.0M在EtOAc中,10mL,40mmol)。将混合物在20℃搅拌0.5h。将混合物浓缩以得到白色固体的2-(哌啶-4-基)乙酰胺,盐酸盐(0.5g,2.239mmol,85.0%产率):1H NMR(400MHz,CDCl3)δppm 3.16-3.10(m,4H),2.12-2.02(m,2H),1.43-1.40(m,5H)。
中间体36:4-(2-(甲基磺酰基)乙基)哌啶,盐酸盐
步骤1:4-(2-(甲硫基)乙基)哌啶-1-甲酸叔丁酯
在25℃向4-(2-((甲基磺酰基)氧基)乙基)哌啶-1-甲酸叔丁酯(3.75g,9.76mmol)和甲硫醇钠(2.74g,39.0mmol)在DMF(50mL)中的溶液中添加K2CO3(2.70g,19.52mmol)。将反应混合物在25℃搅拌12h,然后过滤。将滤液浓缩以得到粗产物,其通过快速色谱法在硅胶柱色谱(PE/EtOAc=1/0至1/1,PE/EtOAc=3/1,Rf=0.45)上纯化以得到黄色油状物4-(2-(甲硫基)乙基)哌啶-1-甲酸叔丁酯(1.5g,5.20mmol,53.3%产率):1H NMR(400MHz,CDCl3)δppm 4.06(s,2H),2.67(t,J=11.9Hz,2H),2.54-2.46(m,2H),2.11-2.02(m,3H),1.65(d,J=12.8Hz,2H),1.55-1.48(m,3H),1.44(s,9H),1.13-1.03(m,2H);ES-LCMS m/z 160.2[M-Boc+H]+.
步骤2:4-(2-(甲基磺酰基)乙基)哌啶-1-甲酸叔丁酯
在25℃向4-(2-(甲硫基)乙基)哌啶-1-甲酸叔丁酯(500mg,1.735mmol)在DCM(10mL)中的溶液中添加m-CPBA(704mg,3.47mmol)。将反应混合物在25℃搅拌12h。将固体过滤掉且将混合物浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=1/0至1/3,PE/EtOAc=1/1,Rf=0.25)纯化以得到淡黄色固体的4-(2-(甲基磺酰基)乙基)哌啶-1-甲酸叔丁酯(350mg,0.961mmol,55.4%产率):1H NMR(400MHz,CDCl3)δppm 4.15-4.07(m,2H),2.78-2.65(m,4H),2.58(s,3H),1.84-1.77(m,1H),1.69-1.64(m,2H),1.63-1.48(m,2H),1.56(s,9H),1.17-1.09(m,2H);ES-LCMS m/z 236.1[M-t-Bu+H]+.
步骤3:4-(2-(甲基磺酰基)乙基)哌啶,盐酸盐
将4-(2-(甲基磺酰基)乙基)哌啶-1-甲酸叔丁酯(350mg,0.961mmol)溶于HCl溶液(4.0M在EtOAc中,8mL,32.0mmol)。将反应混合物在15℃搅拌10分钟。然后将混合物浓缩以得到白色固体的4-(2-(甲基磺酰基)乙基)哌啶,盐酸盐(235mg,0.929mmol,97.0%产率):1H NMR(400MHz,CD3OD)δppm 3.40(d,J=12.8Hz,2H),3.24-3.14(m,2H),3.04-2.90(m,5H),1.99(d,J=12.8Hz,2H),1.83-1.72(m,3H),1.48-1.36(m,2H)。
中间体37:(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯
步骤1:(2S,4R)-4-羟基吡咯烷-2-甲酸甲酯,盐酸盐
在-15℃向(2S,4R)-4-羟基吡咯烷-2-甲酸(90g,686mmol)在MeOH(1L)中的悬浮液中滴加SOCl2(100mL,1373mmol)。将混合物在20℃搅拌20h,然后浓缩以得到白色固体的(2S,4R)-4-羟基吡咯烷-2-甲酸甲酯,盐酸盐(100g,523mmol,76.0%产率):1H NMR(400MHz,DMSO-d6)δppm 9.89(br.s,1H),5.64(br.s,1H),4.53-4.35(m,2H),3.74(s,3H),3.36(dd,J=4.4,11.9Hz,1H),3.06(d,J=12.0Hz,1H),2.23-2.15(m,1H),2.13-2.03(m,1H);ES-LCMS m/z 146.2[M+H]+.
步骤2:(2S,4R)-4-羟基-1-甲苯磺酰基吡咯烷-2-甲酸甲酯
在0℃向(2S,4R)-4-羟基吡咯烷-2-甲酸甲酯,盐酸盐(100g,523mmol)和Et3N(219mL,1569mmol)在DCM(1500mL)中的悬浮液中分批添加p-TsCl(120g,628mmol)。将混合物在20℃搅拌18h,然后添加水(500mL)。有机萃取物用饱和NaHCO3溶液(500mL x2)、盐水(500mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到淡黄色固体的(2S,4R)-4-羟基-1-甲苯磺酰基吡咯烷-2-甲酸甲酯(105g,228mmol,43.5%产率):1H NMR(400MHz,CDCl3)δppm7.78(d,J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),4.51-4.36(m,2H),3.78-3.71(m,3H),3.62(dd,J=11.6,4.0Hz,1H),3.39(d,J=11.6Hz,1H),2.43(s,3H),2.26-2.18(m,1H),2.16-2.05(m,1H);ES-LCMS m/z 300.1[M+H]+.
步骤3:(3R,5S)-5-(羟基甲基)-1-甲苯磺酰基吡咯烷-3-醇
在N2气氛下将LiAlH4(12.34g,325mmol)悬浮于800mL无水THF且在剧烈搅拌下冷却至0℃。在低于5℃滴加(2S,4R)-4-羟基-1-甲苯磺酰基吡咯烷-2-甲酸甲酯(100g,217mmol)在400mL无水THF中的溶液。将反应温热至20℃且搅拌18h。然后将反应混合物冷却至0℃且添加水(13mL),然后添加15%NaOH(13mL)和水(39mL)。悬浮液搅拌20分钟且用EtOAc(200mL)稀释,用80g MgSO4处理,然后再搅拌20min。将固体过滤掉且将滤液浓缩以得到淡黄色固体的(3R,5S)-5-(羟基甲基)-1-甲苯磺酰基吡咯烷-3-醇(74.29g,210mmol,97.0%产率):1H NMR(400MHz,DMSO-d6)δppm 7.72-7.64(m,2H),7.45-7.36(m,2H),4.85-4.69(m,2H),4.26-4.16(m,1H),3.63-3.52(m,2H),3.42-3.39(m,2H),2.91(dd,J=10.0,4.8Hz,1H),2.42-2.36(m,3H),1.92(d,J=12.4,5.2Hz,1H),1.52-1.43(m,1H);ES-LCMSm/z 272.2[M+H]+.
步骤4:甲磺酸((2S,4R)-4-((甲基磺酰基)氧基)-1-甲苯磺酰基吡咯烷-2-基)甲基酯
在0℃向(3R,5S)-5-(羟基甲基)-1-甲苯磺酰基吡咯烷-3-醇(78g,221mmol)和Et3N(139mL,994mmol)在DCM(1.3L)中的溶液中滴加MsCl(157mL,2010mmol)。将混合物温热至20℃且在20℃搅拌20h。该反应用水(500mL)淬灭。水相用DCM(600mL x2)萃取。合并有机相且用饱和NaHCO3溶液(500mL x2)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色油状物甲磺酸((2S,4R)-4-((甲基磺酰基)氧基)-1-甲苯磺酰基吡咯烷-2-基)甲基酯(100g,161mmol,73.0%产率):1H NMR(400MHz,CDCl3)δppm 7.81-7.74(m,2H),7.38(d,J=8.0Hz,2H),5.10(br.s,1H),4.62-4.54(m,1H),4.47(dd,J=10.8,2.4Hz,1H),4.05-3.96(m,1H),3.75-3.68(m,2H),3.14-3.09(m,3H),2.73-2.65(m,3H),2.45(s,3H),2.36-2.24(m,2H);ES-LCMSm/z428.1[M+H]+.
步骤5:(1S,4S)-2-苄基-5-甲苯磺酰基-2,5-二氮杂双环[2.2.1]庚烷
向甲磺酸((2S,4R)-4-((甲基磺酰基)氧基)-1-甲苯磺酰基吡咯烷-2-基)甲基酯(100g,161mmol)在甲苯(1L)中的悬浮液中添加苯基甲胺(60.5g,564mmol)。将混合物在100℃搅拌18h。将混合物冷却至室温且过滤。将滤液浓缩且残余物用PE洗涤,过滤且干燥以得到淡黄色固体的(1S,4S)-2-苄基-5-甲苯磺酰基-2,5-二氮杂双环[2.2.1]庚烷(60g,154mmol,96.0%产率):1H NMR(400MHz,CDCl3)δppm 7.74(d,J=8.0Hz,2H),7.36-7.23(m,7H),4.28(br.s,1H),3.72-3.59(m,3H),3.46-3.38(m,1H),3.03(dd,J=9.6,2.0Hz,1H),2.83(dd,J=10.0,2.4Hz,1H),2.71-2.62(m,1H),2.48-2.41(m,3H),1.71(d,J=9.6Hz,1H),1.11(d,J=9.6Hz,1H);ES-LCMSm/z 343.2[M+H]+.
步骤6:(1S,4S)-2-苄基-2,5-二氮杂双环[2.2.1]庚烷,2氢溴酸盐
向(1S,4S)-2-苄基-5-甲苯磺酰基-2,5-二氮杂双环[2.2.1]庚烷(60g,154mmol)在乙酸(600mL)中的悬浮液中添加溴化氢在乙酸中的溶液(120mL,419mmol)。将混合物在70℃搅拌20h。所得悬浮液冷却且将沉淀过滤,用PE洗涤且干燥以得到黄色固体的(1S,4S)-2-苄基-2,5-二氮杂双环[2.2.1]庚烷,2氢溴酸盐(60g,146mmol,95.0%产率):1H NMR(400MHz,DMSO-d6)δppm 9.54-9.18(m,2H),7.66(d,J=3.6Hz,2H),7.56-7.37(m,3H),4.67-4.31(m,4H),3.74-3.61(m,1H),3.47(br.s,3H),2.07(d,J=11.6Hz,2H)。
步骤7:(1S,4S)-5-苄基-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯
将(1S,4S)-2-苄基-2,5-二氮杂双环[2.2.1]庚烷,2氢溴酸盐(60g,146mmol)和Et3N(60.9mL,437mmol)溶于DCM(600mL)。将反应混合物冷却至0℃。在0℃下将Boc2O(35.5mL,153mmol)添加至上述溶液。将混合物在20℃搅拌18h,然后用水(300mL)淬灭。有机相用饱和NaHCO3水溶液(水溶液,300mL x2)洗涤,用Na2SO4干燥,过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=20/1至5/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到淡黄色固体的(1S,4S)-5-苄基-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(45g,140mmol,96.0%产率):1H NMR(400MHz,CDCl3)δppm7.48-7.18(m,5H),4.44-4.24(m,1H),3.77(d,J=8.0Hz,2H),3.69-3.45(m,2H),3.26-3.14(m,1H),3.01-2.86(m,1H),2.80-2.55(m,1H),1.93-1.84(m,1H),1.77-1.65(m,1H),1.50(br.s,9H);ES-LCMS m/z 289.3[M+H]+.
步骤8:(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯
向(1S,4S)-5-苄基-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(15g,46.8mmol)在MeOH(150mL)中的悬浮液中添加Pd/C(10wt%,4.98g,4.68mmol)。将混合物在50℃在H2气氛(50psi)搅拌18h。将溶液过滤且浓缩以得到残余物,将其溶于DCM(120mL),用Na2SO4干燥,过滤且浓缩以得到灰白色固体的(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(8g,39.9mmol,85.0%产率):1H NMR(400MHz,CDCl3)δppm 4.49-4.25(m,1H),3.69(br.s,1H),3.44-3.29(m,1H),3.16(dd,J=17.2,10.4Hz,1H),3.09-2.93(m,2H),1.79-1.63(m,2H),1.58(br.s,1H),1.45(d,J=4.8Hz,9H);ES-LCMSm/z199.2[M+H]+.
中间体38:2-亚甲基丁酸乙酯
步骤1:2-(二乙氧基磷酰基)丁酸乙酯
向2-(二乙氧基磷酰基)乙酸乙酯(15g,66.9mmol)在DMSO(50mL)中的溶液中添加t-BuOK(9.01g,80mmol)和EtI(12.52g,80mmol)。将混合物在50℃搅拌1h。将混合物溶于EtOAc(200mL)且用饱和NH4Cl溶液(100mL x2)洗涤。将有机相浓缩以得到黄色油状物的2-(二乙氧基磷酰基)丁酸乙酯(16g,57.1mmol,85.0%产率):1H NMR(400MHz,CDCl3)δppm4.25-3.98(m,6H),2.86-2.71(m,1H),1.95-1.80(m,2H),1.30-1.15(m,9H),0.91(t,J=7.3Hz,3H);ES-LCMS m/z 253.1[M+H]+.
步骤2:2-亚甲基丁酸乙酯
向2-(二乙氧基磷酰基)丁酸乙酯(16g,57.1mmol)和多聚甲醛(5.14g,171mmol)在THF(10mL)和水(80mL)中的溶液中添加K2CO3(15.78g,114mmol)。将混合物在80℃搅拌3h。TLC(PE/EtOAc=10/1,Rf=0.5)显示反应完成。将混合物用DCM(200mL x2)萃取且合并的有机层用Na2SO4干燥,浓缩以得到无色油状物的2-亚甲基丁酸乙酯(10g,54.6mmol,96.0%产率):1H NMR(400MHz,CDCl3)δppm 6.12(s,1H),5.50(s,1H),4.20(q,J=7.4Hz,2H),2.48-2.13(m,2H),1.28(d,J=7.1Hz,3H),1.07(t,J=7.5Hz,3H)。
中间体39:甲磺酸3-(甲基磺酰基)丙基酯
步骤1:3-(甲基磺酰基)丙-1-醇
在15℃向3-(甲硫基)丙-1-醇(20g,188mmol)在DCM(200mL)中的溶液中添加m-CPBA(98g,565mmol)。然后将反应混合物在15℃搅拌12h直到TLC显示反应完成。将固体过滤掉。将H2O(200mL)添加至滤液且用DCM(250mL x2)萃取,合并的有机层用NaHSO3水溶液(200mL)和盐水(200mL)洗涤,用Na2SO4干燥且浓缩以得到粗产物。粗产物通过硅胶柱色谱法(MeOH/DCM=5/95)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到黄色油状物的3-(甲基磺酰基)丙-1-醇(2.5g,16.28mmol,8.6%产率):1H NMR(400MHz,CDCl3)δppm 3.78(t,J=6.0Hz,2H),3.21-3.10(m,2H),2.92(s,3H),2.18(br.s,1H),2.13-1.99(m,2H)。
步骤2:甲磺酸3-(甲基磺酰基)丙基酯
在15℃向3-(甲基磺酰基)丙-1-醇(0.5g,3.26mmol)在DCM(10mL)中的溶液中添加MsCl(0.381mL,4.88mmol)、DIEA(1.706mL,9.77mmol)。将反应混合物在15℃搅拌20min,然后添加DCM(50mL)。将混合物用饱和NaHCO3水溶液(20mL)洗涤。有机层用盐水洗涤,用Na2SO4干燥且浓缩以得到棕色固体的甲磺酸3-(甲基磺酰基)丙基酯(0.4g,1.480mmol,45.4%产率):1H NMR(400MHz,CDCl3)δppm 4.39(t,J=6.0Hz,2H),3.18(t,J=7.5Hz,2H),3.04(s,3H),2.95(s,3H),2.38-2.28(m,2H)
中间体40:3-(甲基磺酰基)丙醛
在-78℃在N2气氛向草酰氯(8.38mL,98mmol)在DCM(120mL)中的溶液中滴加DMSO(15.27g,195mmol)。将混合物搅拌1h后,在-78℃在N2气氛将3-(甲基磺酰基)丙-1-醇(10g,65.1mmol)经0.5h添加至混合物。将混合物搅拌1h且将DIEA(68.3mL,391mmol)在-78℃在N2气氛添加至该反应。然后将混合物经0.5h温热至0℃且在0℃再搅拌1h。将反应溶液用DCM(250mL×3)萃取,且合并的有机相用无水Na2SO4干燥且在减压下浓缩。粗产物通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到淡黄色油状物的3-(甲基磺酰基)丙醛(2.5g,14.69mmol,22.6%产率):1H NMR(400MHz,CDCl3)δppm 9.82(s,1H),3.37-3.33(m,2H),3.09(t,J=7.1Hz,2H),2.95(s,3H)。
中间体41:1-甲基-3-(哌啶-4-基甲基)脲,盐酸盐
步骤1:4-((3-甲基脲基)甲基)哌啶-1-甲酸叔丁酯
在0℃向4-(氨基甲基)哌啶-1-甲酸叔丁酯(70g,327mmol)和Et3N(45.5mL,327mmol)在DCM(1L)中的混合物中滴加甲基氨基甲酰氯(24.77mL,392mmol)。将混合物在25℃搅拌12h,然后添加DCM(500mL)和水(800mL)。水层用DCM(500mL x2)萃取。合并的有机层用5%HCl溶液(500mL)、10%NaHCO3溶液(500mL)和水(500mL)洗涤。有机相用Na2SO4干燥,过滤,且浓缩以得到白色固体的4-((3-甲基脲基)甲基)哌啶-1-甲酸叔丁酯(88g,292mmol,89.0%产率):1H NMR(400MHz,CDCl3)δppm4.55(br.s,1H),4.40(br.s,1H),4.03(m,2H),3.12-2.92(m,2H),2.70(s,3H),2.60(m,2H),1.72-1.58(m,4H),1.38(s,9H),1.03(dd,J=3.79,12.10Hz,1H);ES-LCMS m/z 216.0[M-t-Bu+H]+.
步骤2:1-甲基-3-(哌啶-4-基甲基)脲,盐酸盐
将4-((3-甲基脲基)甲基)哌啶-1-甲酸叔丁酯(85g,313mmol)在MeOH(600mL)中的溶液与HCl溶液(4.0M在MeOH中,250mL,1.0mol)在30℃搅拌2h。将混合物浓缩以得到黄色固体的1-甲基-3-(哌啶-4-基甲基)脲,盐酸盐(70g,303mmol,97.0%产率):1H NMR(400MHz,CD3OD)δppm 3.42(d,J=13.05Hz,2H),3.18-3.09(m,2H),3.05-2.93(m,2H),2.76(s,3H),1.96(d,J=13.55Hz,2H),1.89-1.78(m,1H),1.52-1.34(m,2H)。
中间体42:(哌啶-4-基甲基)氨基甲酸甲酯,盐酸盐
步骤1:4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯
向4-(氨基甲基)哌啶-1-甲酸叔丁酯(70g,327mmol)和DIEA(211g,1633mmol)在DCM(1L)中的溶液中滴加氯甲酸甲酯(37g,392mmol)。将混合物在0℃搅拌0.5h,然后添加DCM(500mL)。将混合物用1N HCl(300mL)、饱和NaHCO3溶液(300mL)和水(300mL x2)洗涤。有机层用Na2SO4干燥,过滤且浓缩以得到淡黄色油状物4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯(85g,297mmol,91.0%产率):1H NMR(400MHz,CDCl3)δppm 4.08(br.s,2H),3.71-3.60(m,3H),3.04(br.s,2H),2.64(br.s,2H),1.69-1.54(m,3H),1.42(s,9H),1.16-1.01(m,2H);ES-LCMS m/z 295.0[M+Na]+.
步骤2:(哌啶-4-基甲基)氨基甲酸甲酯,盐酸盐
向4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯(86g,316mmol)在MeOH(500mL)中的溶液中添加HCl溶液(4.0M在MeOH中,400mL,1.6mol)。溶液在20℃搅拌0.5h,然后浓缩以得到白色固体的(哌啶-4-基甲基)氨基甲酸甲酯,盐酸盐(65g,296mmol,94.0%产率):1H NMR(400MHz,CD3OD)δppm 3.69-3.58(m,3H),3.44-3.35(m,2H),3.04(d,J=6.8Hz,2H),2.95(t,J=12.5Hz,2H),1.97-1.87(m,2H),1.85-1.72(m,1H),1.47-1.31(m,2H)。
中间体43:N-((4-((叔丁基二甲基甲硅烷基)氧基)哌啶-4-基)甲基)乙酰胺
步骤1:1-氧杂-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯
在室温向三甲基碘化锍(23.19g,105mmol)在DMSO(350mL)中的溶液中分批添加NaH(4.22g,105mmol)。在相同温度搅拌2h后,添加4-氧代哌啶-1-甲酸叔丁酯(20g,100mmol)。然后将反应混合物在20℃搅拌12h。将溶剂真空去除且添加水(500mL),然后用MTBE(200mL×3)萃取。真空去除有机层以得到粗产物,其在120g硅胶上通过快速色谱法(从PE/EA=10/1至PE/EA=8/1)纯化以提供1-氧杂-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯(13g,54.9mmol,54.7%产率),其为灰白色固体:1H NMR(400MHz,CDCl3)δppm 3.70(d,J=12.8Hz,2H),3.41(ddd,J=3.6,9.6,13.2Hz,2H),2.72-2.63(m,2H),1.80-1.75(m,2H),1.50-1.35(m,11H);ES-LCMS m/z157.9[M-t-Bu+H]+.
步骤2:4-(氨基甲基)-4-羟基哌啶-1-甲酸叔丁酯
在室温将1-氧杂-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯(11g,51.6mmol)溶于NH3/H2O(120mL)。然后将反应混合物在50℃搅拌12h。将溶剂真空去除以得到4-(氨基甲基)-4-羟基哌啶-1-甲酸叔丁酯(11.5g,44.9mmol,87.0%产率):1H NMR(400MHz,CDCl3)δppm 3.85-3.73(m,2H),3.18(br s.,2H),2.60-2.48(m,2H),1.58-1.43(m,13H);ES-LCMS m/z 175.1[M-t-Bu+H]+.
步骤3:4-(氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯
在室温向4-(氨基甲基)-4-羟基哌啶-1-甲酸叔丁酯(9g,39.1mmol)和4H-咪唑(3.99g,58.6mmol)在DCM(200mL)中的溶液中添加TBSCl(7.07g,46.9mmol)。然后将反应混合物在15℃搅拌12h。将溶剂真空去除以得到粗产物,其在80g硅胶上通过快速色谱法(从PE:EA=1:1至PE:EA=0:1经50分钟)纯化以提供4-(氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯(6g,15.67mmol,40.1%产率),其为灰白色固体:1H NMR(400MHz,CDCl3)δppm 3.59(brs.,2H),3.31(ddd,J=3.4,9.6,13.1Hz,2H),2.58(s,2H),1.74-1.62(m,2H),1.42(dd,J=3.8,9.2Hz,2H),1.36(s,9H),0.78(s,3H),0.00(s,2H);ES-LCMS m/z 289.1[M-t-Bu+H]+.
步骤4:4-(乙酰氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯
在室温向4-(氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯(3.1g,9.00mmol)和N-乙基-N-异丙基丙-2-胺(3.49g,27.0mmol)在DCM(60mL)中的溶液中添加乙酰氯(0.902mL,10.80mmol)。然后将反应混合物在15℃搅拌1h。添加水(60mL)且用DCM(30mL X 2)萃取。合并的有机层用Na2SO4干燥且真空浓缩以得到4-(乙酰氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯(3.5g,8.15mmol,91.0%产率),其为灰白色油状物:1H NMR(400MHz,CDCl3)δppm 5.50(s,1H),3.38-3.20(m,6H),1.87(s,3H),1.35-1.31(m,9H),1.10(d,J=6.1Hz,4H),0.78(s,9H),0.00(s,6H);ES-LCMS m/z 287.1[M-Boc+H]+.
步骤5:N-((4-((叔丁基二甲基甲硅烷基)氧基)哌啶-4-基)甲基)乙酰胺
在室温向4-(乙酰氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯(3.5g,9.05mmol)在DCM(50mL)中的溶液中添加2,2,2-三氟乙酸(12mL,9.05mmol)。然后将反应混合物在15℃搅拌2h。将溶剂真空去除且添加饱和NaHCO3水溶液(60mL),用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到N-((4-((叔丁基二甲基甲硅烷基)氧基)哌啶-4-基)甲基)乙酰胺(2.6g,8.17mmol,90.0%产率),其为灰白色固体:1HNMR(400MHz,CDCl3)δppm 3.54(qd,J=6.6,10.5Hz,1H),3.28(d,J=6.1Hz,2H),3.14(s,2H),3.01-2.92(m,1H),1.92(s,3H),1.89-1.81(m,2H),1.59(d,J=14.2Hz,2H),0.74(s,9H),0.06(s,6H);ES-LCMS m/z 287.1[M+H]+.
中间体44:N,N-二甲基-2-(哌啶-4-基)乙胺氧化物,盐酸盐
步骤1:4-(2-(1,3-二氧代异吲哚啉-2-基)乙基)哌啶-1-甲酸叔丁酯
向4-(2-羟基乙基)哌啶-1-甲酸叔丁酯(2.7g,11.77mmol)和异吲哚啉-1,3-二酮(1.906g,12.95mmol)在THF(30mL)中的混合物中添加PPh3(4.01g,15.31mmol)和DIAD(3.43mL,17.66mmol)。将混合物在15℃在N2气氛搅拌10h,然后浓缩。残余物通过硅胶柱色谱法(PE/EtOAc=5/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(2-(1,3-二氧代异吲哚啉-2-基)乙基)哌啶-1-甲酸叔丁酯(3g,7.11mmol,60.4%产率):1H NMR(400MHz,CD3OD)δppm 7.91-7.76(m,4H),4.07(d,J=13.1Hz,2H),3.74(t,J=7.3Hz,2H),2.74(br.s,2H),1.82(d,J=12.5Hz,2H),1.63(q,J=7.0Hz,2H),1.47(m,9H),1.31(t,J=6.0Hz,1H),1.12(dq,J=4.0,12.4Hz,2H);ES-LCMSm/z 259.2[M-Boc+H]+.
步骤2:4-(2-氨基乙基)哌啶-1-甲酸叔丁酯
向4-(2-(1,3-二氧代异吲哚啉-2-基)乙基)哌啶-1-甲酸叔丁酯(2g,5.58mmol)在DCM(10mL)中的溶液中添加水合肼(85%,1.972g,33.5mmol)。将混合物在15℃搅拌1h,然后过滤。将滤液浓缩以得到黄色油状物4-(2-氨基乙基)哌啶-1-甲酸叔丁酯(1.4g,5.21mmol,93.0%产率):1H NMR(400MHz,CD3OD)δppm 4.04(d,J=12.8Hz,2H),2.83-2.60(m,4H),1.68(d,J=12.3Hz,2H),1.58-1.51(m,1H),1.49-1.37(m,10H),1.31-1.21(m,1H),1.15-0.99(m,2H);ES-LCMS m/z 173.2[M-t-Bu+H]+.
步骤3:4-(2-(二甲基氨基)乙基)哌啶-1-甲酸叔丁酯
向4-(2-氨基乙基)哌啶-1-甲酸叔丁酯(1.4g,6.13mmol)在MeOH(15mL)中的溶液中添加甲醛(水溶液,30%,5.40mL,36.8mmol)和甲酸(0.235mL,6.13mmol)。将混合物在15℃在N2气氛搅拌11h,然后添加NaBH3CN(3.08g,49.1mmol)且再搅拌1h。将溶液浓缩且添加饱和NaHCO3溶液(15mL)。水层用DCM(150mL x2)萃取且合并的萃取物用盐水(15mL x2)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(DCM/MeOH=5/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到淡黄色油状物4-(2-(二甲基氨基)乙基)哌啶-1-甲酸叔丁酯(1.3g,4.06mmol,66.2%产率):1H NMR(400MHz,CD3OD)δppm4.08(d,J=13.6Hz,2H),3.06-2.96(m,2H),2.86-2.69(m,8H),1.73(d,J=12.5Hz,2H),1.67-1.55(m,3H),1.47(s,9H),1.22-1.06(m,2H);ES-LCMSm/z 257.3[M+H]+.
步骤4:2-(1-(叔丁氧基羰基)哌啶-4-基)-N,N-二甲基乙胺氧化物
向4-(2-(二甲基氨基)乙基)哌啶-1-甲酸叔丁酯(1g,3.90mmol)在DCM(15mL)中的混合物中添加m-CPBA(1.010g,5.85mmol)。将混合物在15℃搅拌1h。将混合物浓缩且通过硅胶柱色谱法(DCM/MeOH=5/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.3)发现包含产物的级分合并且浓缩以得到黄色油状物的2-(1-(叔丁氧基羰基)哌啶-4-基)-N,N-二甲基乙胺氧化物(950mg,2.96mmol,76.0%产率):1H NMR(400MHz,CD3OD)δppm 4.08(d,J=13.1Hz,2H),3.40(dd,J=4.3,7.8Hz,2H),3.21(s,6H),2.78(br.s,2H),1.88-1.78(m,2H),1.73(d,J=12.0Hz,2H),1.58-1.46(m,10H),1.18(dq,J=4.0,12.2Hz,2H);ES-LCMS m/z273.3[M+H]+.
步骤5:N,N-二甲基-2-(哌啶-4-基)乙胺氧化物,盐酸盐
将2-(1-(叔丁氧基羰基)哌啶-4-基)-N,N-二甲基乙胺氧化物(950mg,3.49mmol)在HCl(4.0M在异丙基醚中,3mL,12mmol)中的混合物在15℃搅拌0.5h。将反应混合物浓缩以得到黄色固体的N,N-二甲基-2-(哌啶-4-基)乙胺氧化物,盐酸盐(950mg,3.41mmol,98.0%产率):1H NMR(400MHz,CD3OD)δppm3.80-3.76(m,2H),3.54(br.s,6H),3.44-3.41(m,2H),3.06-3.03(m,2H),2.02-2.00(m,2H),1.94-1.91(m,2H),1.81-1.78(m,1H),1.56-1.53(m,2H);ES-LCMS m/z 173.4[M+H]+.
中间体45:4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶-2-醇
步骤1:6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-醇
将(2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲醇(20g,55.5mmol)溶于TFA(90mL,1168mmol)。将混合物在50℃搅拌4h。向残余物中添加MeOH(200mL)和DIEA(20mL)且在25℃搅拌2h。将混合物浓缩以得到6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-醇(15g,52.8mmol,95.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 7.40-7.35(m,3H),7.29-7.28(m,1H),7.19-7.08(m,1H),4.69(s,2H);ES-LCMS m/z 270.0,272.0[M+H]+.
步骤2:4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)吡啶-2-醇
将TBSCl(26.5g,176mmol)、6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-醇(10g,35.2mmol)和咪唑(23.94g,352mmol)在CHCl3(150mL)中的混合物在80℃搅拌10h。向混合物中添加H2O(150mL)。然后将混合物用DCM(100mL×3)萃取。合并的有机层用盐水(150mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(PE/EtOAc=10/1至2/1,TLC:PE/EtOAc=3/1,Rf=0.6)纯化以得到4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)吡啶-2-醇(15g,32.8mmol,93.0%产率):1H NMR(400MHz,CDCl3)δppm7.62(d,J=2.0Hz,2H),7.43(t,J=1.9Hz,1H),6.63(q,J=1.1Hz,1H),6.44(d,J=1.3Hz,1H),4.64(d,J=1.1Hz,2H),0.99-0.94(m,9H),0.16-0.10(m,6H);ES-LCMS m/z 384.1,386.1[M+H]+.
步骤3:3-溴-4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)吡啶-2-醇
向4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)吡啶-2-醇(2.5g,5.46mmol)和NH4OAc(0.421g,5.46mmol)在AcOH(50mL)中的混合物中滴加Br2(0.225mL,4.37mmol)在AcOH(20mL)中的溶液。将混合物在20℃搅拌5min。向该混合物中添加H2O(200mL),且形成白色沉淀。过滤后,滤饼用水(50mL×3)洗涤。滤饼真空干燥以得到3-溴-4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)吡啶-2-醇(2.5g,4.50mmol,82.0%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 7.74(d,J=1.8Hz,2H),7.47(t,J=1.8Hz,1H),6.91(s,1H),4.69(s,2H),1.01-0.98(m,9H),0.18-0.16(m,6H);ES-LCMS m/z 462.0,464.0,466.0[M+H]+.
步骤4:4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶-2-醇
在N2气氛向3-溴-4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)吡啶-2-醇(1.7g,3.06mmol)、2,4,6-三甲基-1,3,5,2,4,6-三氧杂三硼杂环己烷(15.37g,122mmol)和K2CO3(1.269g,9.18mmol)在1,4-二噁烷(45mL)和水(4.5mL)中的混合物中添加PdCl2(dppf)-CH2Cl2加合物(0.750g,0.918mmol)。然后将反应混合物在110℃在N2气氛搅拌2h。将混合物过滤且将滤液浓缩。残余物通过快速色谱法(从PE/EtOAc=5/1至2/1,TLC:PE/EtOAc=3/1,Rf=0.6)纯化以得到4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶-2-醇(540mg,1.220mmol,39.9%产率),其为灰白色固体:1H NMR(400MHz,CDCl3)δppm 7.64(d,J=1.5Hz,2H),7.27-7.21(m,1H),6.72(s,1H),4.51(s,2H),1.98(s,3H),0.83(s,9H),0.00(s,6H);ES-LCMS m/z 398.1,400.1[M+H]+.
中间体46:2-(1-((2-(3,5-二氯苯基)-6-((2-(甲基亚磺酰基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
步骤1:2-(甲硫基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)嘧啶
向5-溴-2-(甲硫基)嘧啶(3g,14.63mmol)和4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷)(4.46g,17.55mmol)在1,4-二噁烷(200mL)中的溶液中添加乙酸钾(2.154g,21.94mmol)和PdCl2(dppf)(0.535g,0.731mmol)。然后将反应混合物在80℃在N2气氛搅拌12h。将溶剂浓缩以得到粗产物,将其通过40g硅胶(从纯的PE至PE/EtOAc=3/1,Rf=0.40(PE/EtOAc=3/1))纯化以得到淡黄色固体的2-(甲硫基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)嘧啶(2.1g,7.50mmol,51.2%产率):1H NMR(400MHz,CDCl3)δppm 8.75(s,2H),2.56(s,3H),1.31(s,12H);ES-LCMSm/z 171.2[M-pin+H]+.
步骤2:2-(甲硫基)嘧啶-5-醇
在10℃向2-(甲硫基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)嘧啶(2.05g,7.32mmol)在THF(20mL)和水(20.00mL)中的溶液中添加过硼酸钠四水合物(3.38g,21.95mmol)。然后将混合物搅拌12h。添加饱和NH4Cl溶液(50mL)以淬灭反应且用DCM(30mLx10)萃取。合并的有机层用Na2SO4干燥且浓缩以得到淡黄色固体的2-(甲硫基)嘧啶-5-醇(1.1g,6.96mmol,95.0%产率):1H NMR(400MHz,CDCl3)δppm 8.16-8.12(m,2H),2.49(s,3H);ES-LCMS m/z 143.2[M+H]+.
步骤3:2-氯-6-((2-(甲硫基)嘧啶-5-基)氧基)异烟酸甲酯
向2-(甲硫基)嘧啶-5-醇(1.1g,6.96mmol)和2,6-二氯异烟酸甲酯(2.295g,11.14mmol)在DMF(20mL)中的溶液中添加K2CO3(2.89g,20.89mmol)。然后将反应混合物加热至80℃保持2h。将固体过滤掉且将溶剂浓缩以得到粗产物,其通过快速色谱法(从纯的PE至PE/EtOAc=3/1,TLC:Rf=0.50)纯化以得到淡黄色固体的2-氯-6-((2-(甲硫基)嘧啶-5-基)氧基)异烟酸甲酯(1.2g,3.46mmol,49.8%产率):1H NMR(400MHz,CDCl3)δppm 8.46(s,2H),7.60(s,1H),7.45(s,1H),3.95(s,3H),2.57(s,3H);ES-LCMSm/z312.1,314.2[M+H]+.
步骤4:2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氧基)异烟酸甲酯
在N2气氛向2-氯-6-((2-(甲硫基)嘧啶-5-基)氧基)异烟酸甲酯(1.2g,3.46mmol)和(3,5-二氯苯基)硼酸(1.058g,5.54mmol)在DMF(12mL)中的溶液中添加K2CO3(0.958g,6.93mmol)和PdCl2(dppf)(0.127g,0.173mmol)。然后将反应混合物在80℃搅拌2h。过滤后,将滤液浓缩以得到粗产物,其在40g硅胶上通过快速色谱法(从纯的PE至PE/EtOAc=3/1,Rf=0.55(PE/EtOAc=3/1))纯化以得到淡黄色固体的2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氧基)异烟酸甲酯(1.2g,2.56mmol,73.8%产率):1H NMR(400MHz,CDCl3)δppm8.59-8.49(m,2H),8.00(d,J=1.1Hz,1H),7.71(d,J=2.0Hz,2H),7.54(d,J=0.9Hz,1H),7.39-7.34(m,1H),4.01(s,3H),2.63-2.59(m,3H);ES-LCMS m/z 422.1,424.1[M+H]+.
步骤5:(2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氧基)吡啶-4-基)甲醇
在-40℃向2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氧基)异烟酸甲酯(6g,12.79mmol)在THF(100mL)中的溶液中分批添加LAH(0.388g,10.23mmol)。然后将反应混合物在-40℃搅拌30min。添加NaOH水溶液(1mL,10%)和H2O(1mL)以淬灭反应。将固体过滤掉且去除溶剂。向粗残余物添加石油醚(500mL)和EtOAc(100mL),将混合物在40℃搅拌1h。将混合物过滤,滤饼用石油醚(100mL x2)洗涤以得到(2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氧基)吡啶-4-基)甲醇(4.5g,8.27mmol,64.7%产率),其为棕色固体:1H NMR(400MHz,CDCl3)δppm 8.49-8.46(m,2H),7.63(s,2H),7.40(s,1H),7.19(s,1H),6.94(s,1H),4.78(d,J=5.3Hz,2H),2.55(s,3H);ES-LCMS m/z 394.0,396.1[M+H]+.
步骤6:甲磺酸(2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氧基)吡啶-4-基)甲基酯
在0℃向(2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氧基)吡啶-4-基)甲醇(7g,12.87mmol)和DIEA(4.05mL,23.21mmol)在DCM(150mL)中的溶液中添加MsCl(1.304mL,16.73mmol)。然后将反应混合物在0℃搅拌0.5h。添加水(100mL)且用DCM(200mL x2)萃取。合并的有机层用Na2SO4干燥且浓缩以得到黄色固体的甲磺酸(2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氧基)吡啶-4-基)甲基酯(7.5g,11.11mmol,86.0%产率):1H NMR(400MHz,CDCl3)δppm 8.55-8.51(m,2H),7.66(d,J=1.8Hz,2H),7.44(s,1H),7.37(d,J=2.0Hz,1H),7.02(s,1H),5.31-5.27(m,2H),3.13(s,3H),2.61(s,3H);ES-LCMS m/z 472.0,474.0[M+H]+.
步骤7:2-(1-((2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向甲磺酸(2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氧基)吡啶-4-基)甲基酯(7.5g,11.11mmol)和DIEA(9.71mL,55.6mmol)在DMF(150mL)中的混合物中添加2-(哌啶-4-基)乙酸甲酯,盐酸盐(5.4g,25.09mmol)。将反应混合物在30℃搅拌12h。将混合物浓缩以得到粗产物。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.6)纯化以得到2-(1-((2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(7.2g,9.45mmol,85.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 8.55(s,2H),7.74(s,2H),7.35(s,1H),7.27(s,1H),7.22(s,1H),3.99(s,2H),3.67(s,3H),3.29(s,2H),3.14-3.05(m,2H),2.62(s,3H),2.33(d,J=6.2Hz,2H),2.05-1.95(m,2H),1.87(s,3H);ES-LCMS m/z 533.2,535.2[M+H]+.
步骤8:2-(1-((2-(3,5-二氯苯基)-6-((2-(甲基亚磺酰基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(7.2g,9.45mmol)在MeOH(100mL)中的溶液中添加Oxone(4.65g,7.56mmol)。然后将反应混合物在20℃搅拌12h。将固体过滤掉且添加Na2SO3水溶液(80mL)且用DCM(200mL x2)萃取。合并的有机层用Na2SO4干燥且浓缩以得到残余物。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.3)纯化以得到2-(1-((2-(3,5-二氯苯基)-6-((2-(甲基亚磺酰基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(4.5g,6.55mmol,69.3%产率),其为棕色固体:1H NMR(400MHz,CDCl3)δppm8.88(s,2H),7.65(d,J=1.8Hz,2H),7.51(s,1H),7.35(t,J=1.9Hz,1H),7.07(s,1H),3.67(s,3H),3.57(s,2H),2.99(s,3H),2.89-2.85(m,2H),2.27(d,J=7.1Hz,2H),2.14-2.08(m,2H),1.84(dt,J=3.7,7.5Hz,1H),1.74(d,J=12.1Hz,2H),1.42-1.35(m,2H);ES-LCMS m/z 549.2,551.2[M+H]+.
中间体47:14-二氮杂双环[3.2.1]辛烷
步骤1:2-(3-氧代哌嗪-2-基)乙酸乙酯
将乙烷-1,2-二胺(30g,499mmol)和马来酸二乙酯(86g,499mmol)在i-PrOH(1200mL)中的混合物在60℃搅拌16h。将该混合物浓缩以得到2-(3-氧代哌嗪-2-基)乙酸乙酯(100g,483mmol,97.0%产率),其为白色固体:1H NMR(400MHz,CD3OD)δppm 4.22-4.08(m,2H),3.74-3.57(m,1H),3.44-3.21(m,2H),3.12-2.79(m,2H),2.78-2.55(m,2H),1.25(tt,J=4.3,7.2Hz,3H)。
步骤2:2-(1-苄基-3-氧代哌嗪-2-基)乙酸乙酯
向2-(3-氧代哌嗪-2-基)乙酸乙酯(84g,406mmol)在EtOH(500mL)中的悬浮液中添加(溴甲基)苯(76g,447mmol)。将反应混合物在60℃搅拌12h。将该反应混合物浓缩以得到残余物,将其溶于水(200mL)和EtOAc(200mL)的混合物,用2M HCl调节至pH=1。将混合物用EtOAc(200mL x2)萃取,水层用2N NaOH溶液调节至pH=11,用EtOAc(200mL x2)萃取,用Na2SO4干燥,浓缩以得到残余物。向残余物中添加PE(200mL)。过滤后,收集滤饼以得到2-(1-苄基-3-氧代哌嗪-2-基)乙酸乙酯(65g,115mmol,28.4%产率),其为白色固体:1H NMR(400MHz,DMSO)δppm 7.85(s,1H),7.33-7.16(m,5H),4.10-3.94(m,2H),3.85(d,J=13.5Hz,1H),3.36(s,1H),3.23(t,J=5.3Hz,1H),3.15-2.98(m,2H),2.93-2.84(m,1H),2.80-2.69(m,2H),2.32(ddd,J=4.0,8.4,12.3Hz,1H),1.13(t,J=7.2Hz,3H);ES-LCMS m/z 277.3[M+H]+.
步骤3:2-(1-苄基哌嗪-2-基)乙醇
在0℃向2-(1-苄基-3-氧代哌嗪-2-基)乙酸乙酯(20g,35.5mmol)在THF(400mL)中的悬浮液中分批添加LAH(8.08g,213mmol)。将反应混合物在20℃在N2气氛搅拌16h。在0℃该反应混合物用H2O(8.08mL),然后用10%NaOH溶液(8.08mL)淬灭。然后将混合物过滤且将滤液浓缩以得到2-(1-苄基哌嗪-2-基)乙醇(10g,34.0mmol,96.0%产率),其为淡黄色油状物:1H NMR(400MHz,CD3OD)δppm 7.48-7.12(m,5H),4.07(d,J=13.2Hz,1H),3.73-3.57(m,2H),3.22(d,J=13.2Hz,1H),3.01-2.92(m,1H),2.82-2.73(m,1H),2.72-2.59(m,3H),2.49-2.41(m,1H),2.16-2.08(m,1H),2.01(dtd,J=3.2,7.2,14.3Hz,1H),1.72(qd,J=7.1,13.8Hz,1H)。
步骤4:4-苄基-1,4-二氮杂双环[3.2.1]辛烷
在0℃向PPh3(17.86g,68.1mmol)在THF(600mL)中的悬浮液中添加DEAD(10.78mL,68.1mmol)。将反应混合物在20℃在N2气氛搅拌0.5h。将2-(1-苄基哌嗪-2-基)乙醇(10g,34.0mmol)在THF(200mL)中的溶液添加至反应混合物且将混合物在20℃搅拌11.5h。将该反应混合物浓缩。将残余物溶于EtOAc(100mL)和水(100mL)中,用2N HCl溶液调节至pH=1。分离水层,用EtOAc(100mL x2)洗涤,然后用2N NaOH溶液调节至pH=11。将混合物用EtOAc(100mL x2)萃取。合并的有机层用盐水(100mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从DCM/MeOH=100/1至10/1,TLC:DCM/MeOH=10/1,Rf=0.3)纯化以得到4-苄基-1,4-二氮杂双环[3.2.1]辛烷(6g,26.7mmol,78.0%产率),其为黄色固体:1H NMR(400MHz,CD3OD)δppm 7.60-7.02(m,5H),3.49-3.39(m,2H),3.25-3.19(m,1H),3.01-2.80(m,4H),2.63(dd,J=4.4,13.5Hz,1H),2.52(dd,J=4.5,12.2Hz,2H),2.45-2.35(m,1H),2.14(dddd,J=2.3,5.6,8.2,13.7Hz,1H),1.56(tdd,J=5.3,10.7,13.6Hz,1H);ES-LCMSm/z 203.2[M+H]+.
步骤5:1,4-二氮杂双环[3.2.1]辛烷
在N2气氛向4-苄基-1,4-二氮杂双环[3.2.1]辛烷(12g,53.4mmol)在MeOH(150mL)中的溶液中添加Pd/C(10wt%,11.36g,10.68mmol)。将混合物在H2气氛(50psi)在50℃搅拌36h。然后将混合物过滤且将滤液浓缩以得到1,4-二氮杂双环[3.2.1]辛烷(4.7g,35.6mmol,66.7%产率),其为淡黄色油状物:1H NMR(400MHz,CD3OD)δppm 3.60(d,J=2.9Hz,1H),3.19-3.02(m,5H),2.79(dt,J=4.3,12.1Hz,2H),2.69(d,J=11.5Hz,1H),2.12-2.02(m,2H)。
中间体48:2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氨基)异烟酸甲酯
步骤1:2-((叔丁氧基羰基)氨基)-6-氯异烟酸甲酯
向2,6-二氯异烟酸甲酯(1000mg,4.85mmol)、氨基甲酸叔丁酯(910mg,7.77mmol)、Xantphos(281mg,0.485mmol)、K3PO4(3085mg,14.56mmol)在THF(40mL)中的混合物中添加Pd2(dba)3(444mg,0.485mmol)。将反应混合物在80℃在N2气氛搅拌12h。将混合物过滤且浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=3/1,TLC:PE/EtOAc=3/1,Rf=0.7)纯化以得到2-((叔丁氧基羰基)氨基)-6-氯异烟酸甲酯(1.1g,3.45mmol,71.1%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 8.37(d,J=1.1Hz,1H),7.46(d,J=1.1Hz,1H),3.93(s,3H),1.52(s,9H);ES-LCMS m/z 231.1,233.1[M-t-Bu+H]+.
步骤2:2-((叔丁氧基羰基)氨基)-6-(3,5-二氯苯基)异烟酸甲酯
在N2气氛向2-((叔丁氧基羰基)氨基)-6-氯异烟酸甲酯(1100mg,3.45mmol)和(3,5-二氯苯基)硼酸(1977mg,10.36mmol)在DMF(30mL)中的溶液中添加K2CO3(1432mg,10.36mmol)和PdCl2(dppf)(253mg,0.345mmol)。然后将反应混合物在85℃搅拌3h。将混合物过滤且浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=5/1,TLC:PE/EtOAc=5/1,Rf=0.6)纯化以得到2-((叔丁氧基羰基)氨基)-6-(3,5-二氯苯基)异烟酸甲酯(1.1g,2.215mmol,64.2%产率),其为淡黄色固体:1H NMR(400MHz,CDCl3)δppm 8.47(d,J=0.9Hz,1H),7.93(d,J=1.1Hz,1H),7.90(d,J=2.0Hz,2H),7.40(t,J=1.9Hz,1H),3.98(s,3H),0.00(s,9H);ES-LCMS m/z 341.0,343.0[M-t-Bu+H]+.
步骤3:2-氨基-6-(3,5-二氯苯基)异烟酸甲酯
将2-((叔丁氧基羰基)氨基)-6-(3,5-二氯苯基)异烟酸甲酯(1.0800g,2.175mmol)溶于TFA(5mL,64.9mmol)和DCM(15mL)。将混合物在20℃搅拌0.5h。将反应混合物浓缩。残余物在DCM(100mL)和饱和Na2CO3水溶液(80mL)之间分配。将混合物用DCM(50mL×3)萃取。有机层用盐水(80mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(PE/EtOAc=5/1至2/1,TLC:PE/EtOAc=5/1,Rf=0.5)纯化以得到2-氨基-6-(3,5-二氯苯基)异烟酸甲酯(750mg,2.019mmol,93.0%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm7.91(d,J=1.8Hz,2H),7.47(d,J=1.1Hz,1H),7.44(t,J=1.9Hz,1H),7.08(d,J=1.1Hz,1H),3.92(s,3H);ES-LCMS m/z 297.0,299.0[M+H]+.
步骤4:2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氨基)异烟酸甲酯
向2-氨基-6-(3,5-二氯苯基)异烟酸甲酯(650mg,1.750mmol)、5-溴-2-(甲硫基)嘧啶(538mg,2.63mmol)、Xantphos(101mg,0.175mmol)、K3PO4(1112mg,5.25mmol)在THF(30mL)中的混合物中添加Pd2(dba)3(160mg,0.175mmol)。在N2气氛将反应混合物在80℃搅拌12h。将混合物过滤且浓缩。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=20/1,TLC:DCM/MeOH=20/1,Rf=0.65)纯化以得到2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氨基)异烟酸甲酯(750mg,1.424mmol,81.0%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 7.95(d,J=1.8Hz,2H),7.75(s,1H),7.52-7.50(m,1H),7.38(br s,1H),7.37-7.35(m,1H),7.32-7.30(m,1H),3.97(s,3H),2.66-2.53(m,3H);ES-LCMS m/z 421.0,423.0[M+H]+.
中间体49:2-(1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯
步骤1:2-(1-((2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯
向甲磺酸(2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基酯(39.6g,81mmol)和2-(哌啶-4-基)乙酸乙酯,盐酸盐(28.1g,122mmol)在DMF(450mL)中的溶液中添加K2CO3(33.7g,244mmol)。将混合物在60℃搅拌12h。将固体过滤掉且将溶剂真空去除以得到粗产物,其通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.65)纯化以得到2-(1-((2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯(42g,77mmol,95.0%产率),其为淡黄色固体:1H NMR(400MHz,CDCl3)δppm 7.96(s,3H),7.48(br d,J=7.5Hz,2H),7.43-7.28(m,4H),6.92(br s,1H),5.46(s,2H),4.17-4.10(m,2H),3.65(s,1H),3.51-3.24(m,2H),3.09-3.05(m,1H),2.62(br s,2H),2.30(br s,2H),1.97-1.72(m,5H),1.24(d,J=7.9Hz,3H);ES-LCMS m/z 513.2,515.2[M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯
向2-(1-((2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯(42g,77mmol)在DCM(150mL)中的溶液中添加TFA(150mL,1947mmol)。然后将反应混合物在25℃搅拌12h。将溶剂真空去除且添加饱和NaHCO3水溶液(500mL)。将混合物用DCM(200mL×3)萃取。合并的有机层用Na2SO4干燥,过滤且真空浓缩以得到2-(1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯(34g,68.3mmol,88.0%产率),其为淡黄色固体:1H NMR(400MHz,CDCl3)δppm 7.61(s,2H),7.42(s,1H),6.90(s,1H),6.54(s,1H),4.14-4.08(m,2H),4.02(s,2H),3.68-3.55(m,2H),2.69(s,2H),2.30(d,J=6.6Hz,2H),1.95(d,J=14.1Hz,3H),1.80-1.69(m,2H),1.25-1.19(m,3H);ES-LCMS m/z 423.2,425.1[M+H]+.
中间体50:(1R,7S,8r)-8-氨基-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯,盐酸盐
步骤1:N-苄基-N-(丁-3-烯-1-基)丁-3-烯-1-胺
向4-溴丁-1-烯(151g,1120mmol)和苯基甲胺(60g,560mmol)在DMF(500mL)中的溶液中添加K2CO3(232g,1680mmol)。将混合物在80℃搅拌12h。过滤后,将滤液浓缩。粗残余物通过快速色谱法(从纯的PE至PE/EtOAc=100/1至10/1,TLC:PE/EtOAc=10/1,Rf=0.65)纯化以得到N-苄基-N-(丁-3-烯-1-基)丁-3-烯-1-胺(75g,327mmol,58.5%产率),其为淡黄色油状物:1H NMR(400MHz,CDCl3)δppm 7.29-7.13(m,5H),5.71(tdd,J=6.7,10.3,17.1Hz,2H),5.08-4.80(m,4H),3.53(s,2H),2.50-2.43(m,4H),2.21-2.12(m,4H);ES-LCMS m/z216.2[M+H]+.
步骤2:二(丁-3-烯-1-基)氨基甲酸苄基酯
向N-苄基-N-(丁-3-烯-1-基)丁-3-烯-1-胺(75g,327mmol)在甲苯(500mL)中的溶液中添加CbzCl(56.1mL,393mmol)。将混合物在110℃搅拌12h。将混合物浓缩。粗残余物通过快速色谱法(从纯的PE至PE/EtOAc=10/1,TLC:PE/EtOAc=10/1,Rf=0.5)纯化以得到二(丁-3-烯-1-基)氨基甲酸苄基酯(73g,197mmol,60.2%产率),其为淡黄色油状物:1H NMR(400MHz,CDCl3)δppm 7.39-7.30(m,5H),5.87-5.57(m,2H),5.13(s,2H),5.12-4.92(m,4H),3.31(s,4H),2.39-2.21(m,4H);ES-LCMS m/z 260.2[M+H]+.
步骤3:2,3,6,7-四氢-1H-氮杂环庚三烯-1-甲酸苄基酯
向二(丁-3-烯-1-基)氨基甲酸苄基酯(36g,97mmol)在DCM(3600mL)中的悬浮液中添加Grubbs I(4.07g,4.86mmol)。将反应混合物在N2气氛在40℃搅拌12h。将反应混合物浓缩以得到粗物质。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=10/1,TLC:PE/EtOAc=10/1,Rf=0.6)纯化以得到2,3,6,7-四氢-1H-氮杂环庚三烯-1-甲酸苄基酯(22.2g,87mmol,90.0%产率),其为黄色油状物:1H NMR(400MHz,CD3OD)δppm 7.38-7.24(m,5H),5.77-5.67(m,2H),5.12(s,2H),3.55-3.45(m,4H),2.28(d,J=4.2Hz,4H);ES-LCMS m/z232.2[M+H]+.
步骤4:(1R,7S,8r)-4-氮杂双环[5.1.0]辛烷-4,8-二甲酸4-苄基8-乙基酯
在N2气氛在110℃向搅拌下的2,3,6,7-四氢-1H-氮杂环庚三烯-1-甲酸苄基酯(23g,90mmol)和CuSO4(1.444g,9.05mmol)的悬浮液中经2h添加重氮乙酸乙酯(94mL,905mmol)。将反应混合物在110℃搅拌5h。反应混合物浓缩以得到粗物质。将该反应混合物浓缩以得到粗物质。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=90/5,TLC:PE/EtOAc=10/1,Rf=0.6)纯化合并且浓缩以得到淡黄色油状物,将其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸条件)纯化,且冻干以得到(1R,7S,8r)-4-氮杂双环[5.1.0]辛烷-4,8-二甲酸4-苄基8-乙基酯(8.9g,26.6mmol,29.4%产率),其为黄色油状物:1H NMR(400MHz,CD3OD)δppm7.38-7.27(m,5H),5.09(d,J=1.5Hz,2H),4.11-4.06(m,2H),3.52-3.37(m,4H),2.24(d,J=9.5Hz,2H),1.70-1.59(m,5H),1.25-1.21(m,3H);ES-LCMSm/z 318.2[M+H]+.
步骤5:(1R,7S,8r)-4-((苄基氧基)羰基)-4-氮杂双环[5.1.0]辛烷-8-甲酸
向(1R,7S,8r)-4-氮杂双环[5.1.0]辛烷-4,8-二甲酸4-苄基8-乙基酯(8g,23.95mmol)在MeOH(100mL)和H2O(20mL)中的溶液中添加LiOH·H2O(5.02g,120mmol)。将混合物在50℃搅拌2h。将混合物浓缩。向残余物中添加H2O(50mL),用1N HCl酸化至pH=6.5-7。将沉淀过滤且真空干燥以得到(1R,7S,8r)-4-((苄基氧基)羰基)-4-氮杂双环[5.1.0]辛烷-8-甲酸(5.6g,18.58mmol,78.0%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm7.43-7.27(m,5H),5.11(s,2H),3.42(br s,4H),2.29(br s,2H),1.75(br s,2H),1.71-1.58(m,3H);ES-LCMS m/z:290.1[M+H]+.
步骤6:(1R,7S,8r)-8-(叠氮基羰基)-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯
在0℃向(1R,7S,8r)-4-((苄基氧基)羰基)-4-氮杂双环[5.1.0]辛烷-8-甲酸(1.5g,4.98mmol)在DCM(20mL)和DMF(0.2mL)中的溶液中添加草酰氯(0.509mL,5.97mmol)。在相同温度搅拌1h后,将反应混合物浓缩且溶于丙酮(20mL)。添加叠氮化钠(0.971g,14.93mmol)在水(2mL)中的溶液。然后将反应在25℃再搅拌2.5h。添加饱和NaHCO3水溶液(50mL)且用DCM(30mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到(1R,7S,8r)-8-(叠氮基羰基)-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯(1.55g,4.44mmol,89.0%产率),其为淡黄色油状物:1H NMR(400MHz,CDCl3)δppm7.43-7.24(m,5H),5.11(d,J=1.98Hz,2H),3.65-3.38(m,4H),2.49-2.08(m,3H),1.81-1.43(m,4H);ES-LCMS m/z:315.2[M+H]+.
步骤7:(1R,7S,8r)-8-((叔丁氧基羰基)氨基)-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯
将(1R,7S,8r)-8-(叠氮基羰基)-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯(1.55g,4.44mmol)在t-BuOH(15mL)中的溶液在100℃搅拌2h。添加饱和NaHCO3水溶液(60mL)且用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到(1R,7S,8r)-8-((叔丁氧基羰基)氨基)-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯(1.75g,3.88mmol,88.0%产率),其为淡黄色油状物:1H NMR(400MHz,CDCl3)δppm 7.32-7.20(m,5H),5.03(s,2H),4.65(brs,1H),3.71-3.42(m,2H),3.24-3.08(m,2H),2.38-2.14(m,3H),1.57(br s,2H),1.37(s,9H),1.07(br s,2H);ES-LCMSm/z 305.2[M-t-Bu+H]+.
步骤8:(1R,7S,8r)-8-氨基-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯,盐酸盐
将(1R,7S,8r)-8-((叔丁氧基羰基)氨基)-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯(1.75g,3.88mmol)溶于HCl溶液(4M在MeOH中,20mL,80mmol)。然后将反应混合物在20℃搅拌0.5h。将反应混合物浓缩以得到(1R,7S,8r)-8-氨基-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯,盐酸盐(1.35g,3.64mmol,94.0%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 7.47-7.12(m,5H),5.07(brs,2H),3.64-3.41(m,3H),2.65-2.14(m,4H),1.67-1.35(m,4H);ES-LCMS m/z 261.0[M+H]+.
中间体51:4-溴-2-甲基丁酸甲酯
在0℃向3-甲基二氢呋喃-2(3H)-酮(30g,300mmol)在DCM(500mL)中的溶液中分批添加BBr3(34.0mL,360mmol)。将反应混合物在30℃搅拌8h。将MeOH(100mL)添加至混合物且搅拌8h。将混合物添加至DCM(500mL)和饱和NaHCO3水溶液(600mL)中。将混合物用DCM(150mL x2)萃取。有机层用盐水(200mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到粗产物,其为黄色油状物的4-溴-2-甲基丁酸甲酯(50g,244mmol,81.0%产率):1H NMR(400MHz,CDCl3)δppm 3.70(s,3H),3.50-3.36(m,2H),2.72(t,J=7.03Hz,1H),2.35-2.17(m,1H),2.00-1.85(m,1H),1.20(d,J=7.28Hz,3H);ES-LCMS m/z 195.0,197.0[M+H]+.
中间体52:二甲基(哌啶-4-基甲基)氧化膦
步骤1:4-((二甲基磷酰基)(羟基)甲基)哌啶-1-甲酸苄基酯
向4-甲酰基哌啶-1-甲酸苄基酯(2g,8.09mmol)和二甲基氧化膦(0.757g,9.71mmol)在i-PrOH(20mL)中的溶液中添加Et3N(2.455g,24.26mmol)。然后将反应混合物在90℃搅拌10h。添加水(30mL)且用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥且浓缩以得到粗产物。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.4)纯化以得到4-((二甲基磷酰基)(羟基)甲基)哌啶-1-甲酸苄基酯(1.5g,3.69mmol,45.6%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm7.33-7.16(m,5H),5.04(br s,2H),4.37(br s,1H),4.15(br s,2H),3.49(br s,1H),2.72(br s,2H),2.11-1.73(m,4H),1.44(dd,J=4.5,12.7Hz,6H);ES-LCMS m/z 326.2[M+H]+.
步骤2:4-((二甲基磷酰基)亚甲基)哌啶-1-甲酸苄基酯
在20℃向4-((二甲基磷酰基)(羟基)甲基)哌啶-1-甲酸苄基酯(1200mg,2.95mmol)在DCM(30mL)中的溶液中添加DAST(1.170mL,8.85mmol)。然后,将混合物在N2气氛在20℃搅拌3h。在0℃反应混合物通过添加饱和NaHCO3水溶液(50mL)淬灭。将混合物用DCM(100mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,且冻干干燥以得到4-((二甲基磷酰基)亚甲基)哌啶-1-甲酸苄基酯(210mg,0.608mmol,20.6%产率),其为无色油状物:1HNMR(400MHz,CD3OD)δppm 7.29(d,J=2.2Hz,5H),5.46-5.27(m,1H),5.07(d,J=8.6Hz,2H),3.57-3.46(m,4H),2.81(br s,2H),2.22(br s,2H),1.53-1.49(m,6H);ES-LCMSm/z308.2[M+H]+.
步骤3:二甲基(哌啶-4-基甲基)氧化膦
将4-((二甲基磷酰基)亚甲基)哌啶-1-甲酸苄基酯(200mg,0.579mmol)和Pd/C(10wt%,339mg,0.319mmol)在MeOH(20mL)中的混合物在20℃在H2(15psi)下搅拌1h。将混合物过滤且将滤液浓缩以得到二甲基(哌啶-4-基甲基)氧化膦(140mg,0.479mmol,83.0%产率),其为棕色固体:1H NMR(400MHz,CD3OD)δppm 3.03(s,2H),2.30(s,2H),2.08-1.99(m,4H),1.75(d,J=11.5Hz,3H),1.50-1.48(m,6H)。
中间体53:1-(2-溴乙基)环丙醇
向冷却至0℃的3-溴丙酸乙酯(500mg,2.76mmol)在THF(30mL)中的溶液中添加四异丙氧基钛(79mg,0.276mmol),然后添加EtMgBr(1M在THF中,8.29mL,8.29mmol)。将混合物在0℃搅拌2h。将混合物在0℃用饱和NH4Cl水溶液(2mL)淬灭。混合物在EtOAc(15mL)和水(15mL)之间分配。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物,其通过快速色谱法(PE/EtOAc=5/1)纯化以得到1-(2-溴乙基)环丙醇(400mg,2.181mmol,79.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 3.66-3.55(m,2H),2.14-2.10(m,2H),0.85-0.78(m,2H),0.59-0.52(m,2H)。
中间体54:1-(2-溴乙基)环丙烷甲酸甲酯
步骤1:5-氧杂螺[2.4]庚-4-酮
在0℃在N2气氛向3-亚甲基二氢呋喃-2(3H)-酮(5g,51.0mmol)、BF3·OEt2(0.646mL,5.10mmol)和Pd(OAc)2(0.080g,0.357mmol)在乙醚(50mL)中的溶液中滴加三甲基甲硅烷基重氮甲烷(15.72g,138mmol)。然后将混合物在26℃在N2气氛搅拌5h。将混合物过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=50/1至4/1,TLC:PE/EtOAc=5/1,Rf=0.7)纯化以得到5-氧杂螺[2.4]庚-4-酮(150mg,1.204mmol,2.4%产率),其为黄色油状物:1HNMR(400MHz,CDCl3)δppm 4.35(t,J=7.5Hz,2H),2.24(t,J=7.5Hz,2H),1.22-1.15(m,2H),0.93-0.85(m,2H);ES-LCMSm/z 113.1[M+H]+.
步骤2:1-(2-溴乙基)环丙烷甲酸甲酯
在0℃在N2气氛向5-氧杂螺[2.4]庚-4-酮(150mg,1.204mmol)在DCM(10mL)中的混合物中添加BBr3(0.171mL,1.806mmol)。然后将混合物在25℃在N2气氛搅拌8h。将MeOH(10.0mL)添加至混合物且在25℃搅拌8h。在0℃下反应混合物通过添加饱和NaHCO3水溶液(30mL)淬灭。将混合物用EtOAc(50mL×3)萃取。合并的有机层用盐水(30mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到1-(2-溴乙基)环丙烷甲酸甲酯(200mg,0.676mmol,56.2%产率),其为棕色油状物:1H NMR(400MHz,CDCl3)δppm 3.69-3.65(m,3H),3.60-3.58(m,2H),2.41-2.38(m,2H),1.95(d,J=2.4Hz,2H),1.81(t,J=2.1Hz,2H)。
中间体55:2-羟基-3-(哌啶-4-基)丙酸甲酯,盐酸盐
步骤1:4-(2-甲氧基-2-氧代乙基)哌啶-1-甲酸叔丁酯
向2-(哌啶-4-基)乙酸甲酯,盐酸盐(15g,69.7mmol)和DIEA(27.0g,209mmol)在DCM(300mL)中的溶液中添加Boc2O(19.42mL,84mmol)。然后将反应混合物在20℃搅拌12h。将混合物用乙酸水溶液(200mL x2)和饱和NaHCO3水溶液(200mL)洗涤,用Na2SO4干燥且真空浓缩以得到4-(2-甲氧基-2-氧代乙基)哌啶-1-甲酸叔丁酯(17g,59.5mmol,85.0%产率),其为淡黄色油状物:1H NMR(400MHz,CDCl3)δ4.07(s,2H),3.70(t,J=5.5Hz,2H),2.69(t,J=11.5Hz,2H),1.75-1.60(m,3H),1.55-1.49(m,2H),1.48-1.30(m,9H),1.18-1.03(m,2H);ES-LCMS m/z 202.2[M-t-Bu+H]+.
步骤2:4-(2-羟基乙基)哌啶-1-甲酸叔丁酯
向4-(2-甲氧基-2-氧代乙基)哌啶-1-甲酸叔丁酯(17g,59.5mmol)在THF(300mL)中的溶液中分批添加LAH(2.482g,65.4mmol)。然后将反应混合物在0℃搅拌30min。添加水(2.5mL)和NaOH水溶液(2.5mL,10%)以淬灭反应。将固体过滤掉且将溶剂真空去除以得到4-(2-羟基乙基)哌啶-1-甲酸叔丁酯(12g,49.7mmol,84.0%产率),其为淡黄色油状物:1HNMR(400MHz,CDCl3)δppm 4.07(s,2H),3.70(t,J=5.5Hz,2H),2.69(t,J=11.5Hz,2H),1.75-1.60(m,3H),1.55-1.49(m,2H),1.48-1.30(m,9H),1.18-1.03(m,2H);ES-LCMS m/z:174.2[M-t-Bu+H]+.
步骤3:4-(2-氧代乙基)哌啶-1-甲酸叔丁酯
将草酰氯(2.65mL,31.1mmol)在40mL DCM中的溶液冷却至-78℃。经30分钟滴加DMSO(4.41mL,62.1mmol)在DCM(30mL)中的溶液。在添加结束时将反应溶液经20分钟温热至-70℃,然后经30min滴加4-(2-羟基乙基)哌啶-1-甲酸叔丁酯(5g,20.71mmol)在DCM(30mL)中的溶液。将滴液漏斗用5-mL部分的二氯甲烷洗涤,然后经20分钟添加DIEA(21.71mL,124mmol)在20mL DCM中的溶液,然后将反应烧瓶从浴中取出且经60min使之温热至0℃。混合物通过TLC(PE:EtOAc=2:1,Rf=0.55)监测。将反应溶液转移至添加30mL冰冷的1M HCl溶液的250mL分液漏斗中。分离两相,水相用二氯甲烷(50mL×3)萃取,且合并的有机相用pH=7的磷酸盐缓冲水溶液(100mL x4)洗涤,然后用无水硫酸钠干燥且在减压下浓缩以得到淡黄色油状物4-(2-氧代乙基)哌啶-1-甲酸叔丁酯(4.8g,19.01mmol,92.0%产率):1H NMR(400MHz,CDCl3)δppm 9.78(d,J=1.3Hz,1H),4.08(s,2H),2.73(t,J=11.7Hz,2H),2.38(d,J=7.1Hz,2H),2.11-1.96(m,1H),1.68(d,J 2.8Hz,2H),1.61-134(m,9H),1.30-1.08(m,2H);ES-LCMSm/z:172.2[M-t-Bu+H]+.
步骤4:4-(2-氰基-2-羟基乙基)哌啶-1-甲酸叔丁酯
向4-(2-氧代乙基)哌啶-1-甲酸叔丁酯(2g,7.92mmol)在水(20mL)中的溶液中添加偏亚硫酸氢钠(1.505g,7.92mmol)。在15℃搅拌2h后,添加NaCN(0.776g,15.84mmol)。然后将混合物在15℃搅拌10h。添加水(50mL)且用DCM(50mL x2)萃取,且合并的有机相用饱和NaHCO3水溶液(50mL)和盐水(50mL)洗涤,然后用无水硫酸钠干燥且浓缩以得到淡黄色油状物4-(2-氰基-2-羟基乙基)哌啶-1-甲酸叔丁酯(2g,7.08mmol,89.0%产率):1H NMR(400MHz,CDCl3)δ4.63-4.52(m,1H),4.09(s,2H),3.81-3.66(m,2H),2.71(s,2H),1.76-1.63(m,3H),1.55-1.35(m,9H),1.25-1.06(m,2H);ES-LCMS m/z:199.2[M-t-Bu+H]+.
步骤5:2-羟基-3-(哌啶-4-基)丙酸甲酯,盐酸盐
将4-(2-氰基-2-羟基乙基)哌啶-1-甲酸叔丁酯(1.9g,6.72mmol)溶于HCl溶液(4M在MeOH中,30mL,120mmol)。然后将混合物在15℃搅拌12h。将溶剂真空去除以得到2-羟基-3-(哌啶-4-基)丙酸甲酯,盐酸盐(1.5g,5.70mmol,85.0%产率),其为淡黄色固体:1H NMR(400MHz,CDCl3)δppm 4.58(dd,J=3.5,9.7Hz,1H),4.31-4.04(m,3H),3.43-3.36(m,2H),3.05-2.97(m,2H),2.07(d,J=14.1Hz,1H),1.94(d,J=11.9Hz,2H),1.77-1.66(m,2H),1.54-1.42(m,2H)。
中间体56:N-((1R,7S,8r)-4-氮杂双环[5.1.0]辛-8-基)乙酰胺,三氟乙酸盐
步骤1:(1R,7S,8r)-8-乙酰氨基-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯
在25℃向(1R,7S,8r)-8-氨基-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯,盐酸盐(500mg,1.348mmol)在DCM(10mL)中的溶液中添加DIEA(209mg,1.617mmol)和Ac2O(165mg,1.617mmol)。然后将混合物在25℃搅拌12h。将溶剂浓缩以得到粗产物,其通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,Rf=0.50(DCM/MeOH=10/1))纯化以得到淡黄色油状物(1R,7S,8r)-8-乙酰氨基-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯(415mg,1.167mmol,87.0%产率):1H NMR(400MHz,CDCl3)δppm 7.40-7.28(m,5H),5.55(brs,1H),5.10(s,2H),3.77-3.47(m,2H),3.34-3.15(m,2H),2.63-2.21(m,3H),1.64(s,3H),1.62-1.44(m,2H),1.26-1.10(m,2H);ES-LCMS m/z 303.0[M+H]+.
步骤2:N-((1R,7S,8r)-4-氮杂双环[5.1.0]辛-8-基)乙酰胺,三氟乙酸盐
(1R,7S,8r)-8-(甲基磺酰氨基)-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯(360mg,1.064mmol)在TFA(5mL,64.9mmol)中的溶液在50℃搅拌1.5h。将混合物浓缩以得到N-((1R,7S,8r)-4-氮杂双环[5.1.0]辛-8-基)乙酰胺,三氟乙酸盐(400mg,1.134mmol,97.0%产率),其为黄色油状物:1H NMR(400MHz,CD3OD)δppm 3.39-3.34(m,2H),3.12-3.02(m,2H),2.52-2.42(m,3H),1.87(s,3H),1.49(dd,J=9.26,17.20Hz,2H),1.25(s,2H);ES-LCMS m/z169.2[M+H]+.
中间体57:N-(哌啶-4-基甲基)环丙烷甲酰胺,三氟乙酸盐
步骤1:4-(环丙烷甲酰氨基甲基)哌啶-1-甲酸叔丁酯
向环丙烷羧酸(1g,11.62mmol)、DIEA(6.09mL,34.8mmol)和EDC(4.45g,23.23mmol)在DMF(30mL)中的溶液中添加4-(氨基甲基)哌啶-1-甲酸叔丁酯(2.74g,12.78mmol)和HOBt(3.56g,23.23mmol)。然后将混合物在26℃搅拌12h。将混合物浓缩,然后添加10%柠檬酸(40mL)。将混合物用DCM(100mL×3)萃取。合并的有机层用盐水(40mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=20/1至1/1,TLC:PE/EtOAc=1/1,Rf=0.5)纯化以得到4-(环丙烷甲酰氨基甲基)哌啶-1-甲酸叔丁酯(1.4g,4.46mmol,38.4%产率),其为无色油状物:1H NMR(400MHz,CDCl3)δppm 5.88(s,1H),4.15-4.06(m,2H),3.15(s,2H),2.66(s,2H),1.71-1.59(m,3H),1.43(s,9H),1.36-1.29(m,1H),1.17-1.05(m,2H),1.00-0.90(m,2H),0.77-0.66(m,2H);ES-LCMS m/z 227.2[M+H-t-Bu]+.
步骤2:N-(哌啶-4-基甲基)环丙烷甲酰胺,三氟乙酸盐
向4-(环丙烷甲酰氨基甲基)哌啶-1-甲酸叔丁酯(700mg,2.231mmol)在DCM(5mL)中的溶液中添加TFA(1mL,12.98mmol)。将混合物在25℃搅拌0.5h。将混合物浓缩以得到N-(哌啶-4-基甲基)环丙烷甲酰胺,三氟乙酸盐(0.7g,2.126mmol,95.0%产率),其为无色油状物:1H NMR(400MHz,CD3OD)δppm 3.39(d,J=12.5Hz,2H),3.14(d,J=6.5Hz,2H),2.96(dt,J=2.5,12.8Hz,2H),1.93(d,J=14.1Hz,2H),1.87-1.74(m,1H),1.59-1.54(m,1H),1.46-1.34(m,2H),0.86-0.79(m,2H),0.78-0.71(m,2H);ES-LCMS m/z 183.2[M+H]+.
中间体58:6-氟-4-(5-羟基嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
步骤1:4-(5-(苄基氧基)嘧啶-2-基)-6-氟-1,4-二氮杂环庚烷-1-甲酸叔丁酯
向4-(5-(苄基氧基)嘧啶-2-基)-6-羟基-1,4-二氮杂环庚烷-1-甲酸叔丁酯(760mg,1.708mmol)在DCM(20mL)中的溶液中添加DAST(0.237mL,1.793mmol)。将混合物在20℃搅拌15分钟。然后将混合物浓缩以得到残余物,将其在DCM(30mL)和H2O(20mL)之间分配,用DCM(30mL x2)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过快速色谱法(20%EtOAc:80%石油醚,TLC:PE/EtOAc=5/1)纯化以得到淡黄色固体的4-(5-(苄基氧基)嘧啶-2-基)-6-氟-1,4-二氮杂环庚烷-1-甲酸叔丁酯(700mg,1.652mmol,97.0%产率):1H NMR(400MHz,CD3OD)δppm 8.15(d,J=13.9Hz,2H),7.43-7.28(m,5H),5.10-5.05(m,2H),4.42-4.24(m,1H),4.24-4.16(m,2H),3.76-3.41(m,6H),1.48-1.29(m,9H);ES-LCMS m/z 403.3[M+H]+.
步骤2:6-氟-4-(5-羟基嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
向4-(5-(苄基氧基)嘧啶-2-基)-6-氟-1,4-二氮杂环庚烷-1-甲酸叔丁酯(650mg,1.534mmol)在MeOH(50mL)中的溶液中添加Pd/C(10wt%,163mg,0.153mmol)。然后将反应混合物在20℃在H2气氛(16psi)搅拌1h。将固体过滤掉且将溶剂真空去除以得到6-氟-4-(5-羟基嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(500mg,1.281mmol,83.0%产率),其为黄色油状物:1H NMR(400MHz,CD3OD)δ7.98(s,2H),4.35-4.31(m,1H),4.35-4.28(m,1H),4.25-4.12(m,2H),3.78-3.60(m,2H),3.53-3.44(m,4H),1.38(d,J=19.0Hz,9H);ES-LCMSm/z 313.3[M+H]+.
中间体59:2-(3-氯-5-(二氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷
步骤1:3-氯-5-(二氟甲基)苯酚
向3-氯-5-羟基苯甲醛(2g,12.77mmol)在DCM(20mL)中的溶液中滴加DAST(3.38mL,25.5mmol)。将混合物在10℃搅拌2h。添加水(50mL)且将混合物用DCM(2x50mL)萃取,合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色油状物的3-氯-5-(二氟甲基)苯酚(1.5g,6.72mmol,52.6%产率):1H NMR(400MHz,CD3OD)δppm 6.97(s,1H),6.90(s,1H),6.85(s,1H),6.80-6.50(m,1H)
步骤2:三氟甲磺酸3-氯-5-(二氟甲基)苯基酯
向3-氯-5-(二氟甲基)苯酚(700mg,3.14mmol)在DCM(20mL)中的溶液中添加DIEA(1.643mL,9.41mmol)和Tf2O(1.060mL,6.27mmol)。将混合物在10℃搅拌3h。添加水(50mL)且将混合物用DCM(2x50mL)萃取,合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色油状物的三氟甲磺酸3-氯-5-(二氟甲基)苯基酯(1g,1.610mmol,51.3%产率):1H NMR(400MHz,CD3OD)δppm 7.72(s,1H),7.67(s,1H),7.55(s,1H),7.04-6.69(m,1H)
步骤3:2-(3-氯-5-(二氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷
在N2气氛下向搅拌下的三氟甲磺酸3-氯-5-(二氟甲基)苯基酯(1g,1.610mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷)(0.613g,2.414mmol)和KOAc(0.474g,4.83mmol)在1,4-二噁烷(10mL)中的悬浮液中添加PdCl2(dppf)(0.118g,0.161mmol)。在N2气氛下将反应混合物在80℃搅拌5h。过滤后,将滤液浓缩。向残余物中添加DCM(30mL)和水(30mL),用DCM(30mL×3)萃取。合并的有机层用Na2SO4干燥,过滤且蒸发以得到粗物质2-(3-氯-5-(二氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(0.8g,1.386mmol,86.0%产率),其为深色油状物,将其直接用于下一步:1H NMR(400MHz,CD3OD)δppm 7.86-7.68(m,1H),7.65-7.49(m,2H),7.08-6.62(m,1H),1.24-1.21(m,12H)
中间体60:2-(哌啶-4-基氧基)乙酸乙酯,盐酸盐
步骤1:4-(2-乙氧基-2-氧代乙氧基)哌啶-1-甲酸叔丁酯
在15℃在N2气氛向4-羟基哌啶-1-甲酸叔丁酯(10g,49.7mmol)在THF(200mL)中的溶液中添加60%NaH(3.97g,99mmol)。将混合物在15℃搅拌1h。然后,添加2-溴乙酸乙酯(16.60g,99mmol)且将混合物在50℃搅拌9h。添加水(2mL)且将混合物浓缩以得到残余物,将其在DCM(150mL)和饱和NaHCO3水溶液(150mL)之间分配,用DCM(150mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且蒸发以得到4-(2-乙氧基-2-氧代乙氧基)哌啶-1-甲酸叔丁酯(3g,7.31mmol,14.7%产率),其为无色油状物:1H NMR(400MHz,CD3OD)δppm4.23 4.09(m,4H),3.76-3.58(m,3H),3.14(t,J=10.4Hz,2H),1.89-1.81(m,2H),1.57-1.48(m,2H),1.45(s,9H),1.27(t,J=7.2Hz,3H);ES-LCMS m/z 232.1[M-t-Bu+H]+.
步骤2:2-(哌啶-4-基氧基)乙酸乙酯,盐酸盐
向4-(2-乙氧基-2-氧代乙氧基)哌啶-1-甲酸叔丁酯(3g,7.31mmol)在DCM(10mL)中的溶液中添加HCl溶液(4M在EtOAc中,10mL,40.0mmol)。将混合物在10℃搅拌20min。将混合物浓缩以得到黄色固体的2-(哌啶-4-基氧基)乙酸乙酯,盐酸盐(2g,7.15mmol,98.0%产率):1H NMR(400MHz,CD3OD)δppm4.21-4.12(m,4H),3.90-3.72(m,1H),3.37-3.31(m,2H),3.18-3.03(m,2H),2.08-1.94(m,4H),1.31-1.25(m,3H);ES-LCMS m/z 188.1[M+H]+.
中间体61:(S)-2-(1,4-氧氮杂环庚烷-7-基)乙酸甲酯
步骤1:(S)-4-(苄基氨基)-2-羟基丁酸
在25℃向(S)-4-氨基-2-羟基丁酸(13.5g,113mmol)、NaOH(4.85g,121mmol)在水(120mL)中的溶液中添加苯甲醛(12.26mL,121mmol)。然后将混合物在25℃搅拌30min。将混合物冷却至0℃且经30min添加NaBH4(2.92g,77mmol)。将混合物在25℃搅拌11h。将混合物用EtOAc(100mL)洗涤。水相用12N HCl溶液酸化至pH=6,收集固体且干燥以得到(S)-4-(苄基氨基)-2-羟基丁酸(23g,33.0mmol,29.1%产率),其为白色固体:1H NMR(400MHz,CD3OD)δppm 7.40-7.20(m,5H),4.01-3.91(m,1H),3.82-3.72(m,2H),2.90-2.71(m,2H),2.08-1.94(m,1H),1.89-1.75(m,1H);ES-LCMS m/z 210.2[M+H]+.
步骤2:(S)-4-苄基-3-氧代-1,4-氧氮杂环庚烷-7-甲酸
在0℃向(S)-4-(苄基氨基)-2-羟基丁酸(23g,33.0mmol)、NaOH(14g,350mmol)在水(150mL)中的溶液中滴加2-氯乙酰氯(11.2mL,141mmol)。然后将混合物在25℃搅拌12h。反应混合物用DCM(15mL x2)萃取,水相用12M HCl溶液酸化至pH=3。将固体过滤且干燥以得到浅色油状物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干以得到(S)-4-苄基-3-氧代-1,4-氧氮杂环庚烷-7-甲酸(7g,27.1mmol,82.0%产率),其为无色油状物:1H NMR(400MHz,CD3OD)δppm 7.40-7.21(m,5H),4.61(d,J=2.4Hz,2H),4.52-4.36(m,2H),4.29(dd,J=4.6,9.5Hz,1H),3.64-3.44(m,2H),2.32-2.18(m,1H),2.05-1.92(m,1H);ES-LCMS m/z 250.3[M+H]+.
步骤3:(S)-(4-苄基-1,4-氧氮杂环庚烷-7-基)甲醇
在0℃向(S)-4-苄基-3-氧代-1,4-氧氮杂环庚烷-7-甲酸(5g,19.35mmol)在THF(80mL)中的溶液中分批添加LAH(2.204g,58.1mmol)。然后将混合物在25℃搅拌12h。混合物通过H2O(2.2mL),然后通过10%NaOH溶液(2.2mL)淬灭。然后将混合物过滤且将滤液浓缩以得到(S)-(4-苄基-1,4-氧氮杂环庚烷-7-基)甲醇(3.8g,14.60mmol,75.0%产率),其为淡黄色油状物:1H NMR(400MHz,CD3OD)δppm 7.39-7.19(m,5H),3.93-3.84(m,1H),3.83-3.75(m,1H),3.71-3.58(m,3H),3.51-3.37(m,2H),2.79-2.71(m,1H),2.68-2.60(m,2H),1.96-1.85(m,1H),1.79-1.66(m,1H);ES-LCMSm/z 222.2[M+H]+.
步骤4:(S)-(1,4-氧氮杂环庚烷-7-基)甲醇
在N2气氛向(S)-(4-苄基-1,4-氧氮杂环庚烷-7-基)甲醇(3.8g,14.60mmol)在MeOH(50mL)中的溶液中添加Pd/C(10wt%,1.553g,1.460mmol)。然后将混合物在25℃在H2气氛(50psi)搅拌12h。然后将混合物过滤且将滤液浓缩以得到(S)-(1,4-氧氮杂环庚烷-7-基)甲醇(1.9g,12.31mmol,84.0%产率),其为淡黄色油状物:1H NMR(400MHz,CD3OD)δppm4.18-4.02(m,1H),3.88-3.66(m,2H),3.59-3.34(m,2H),2.89-2.66(m,4H),2.04(m,1H),1.94-1.90(m,1H)。
步骤5:(S)-7-(羟基甲基)-1,4-氧氮杂环庚烷-4-甲酸苄基酯
向(S)-(1,4-氧氮杂环庚烷-7-基)甲醇(1.9g,12.31mmol)和DIEA(4.30mL,24.62mmol)在DCM(80mL)中的溶液中滴加CbzCl(1.933mL,13.54mmol)。然后将混合物在25℃搅拌2h。将混合物浓缩,然后添加水(30mL)。将混合物用DCM(50mL x2)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(PE/EtOAc=5/1至1/1,TLC:PE/EtOAc=1/1,Rf=0.2)纯化以得到(S)-7-(羟基甲基)-1,4-氧氮杂环庚烷-4-甲酸苄基酯(1.7g,5.84mmol,47.5%产率),其为黄色油状物:1H NMR(400MHz,CD3OD)δppm7.40-7.25(m,5H),5.20-5.08(m,2H),4.00(m,1H),3.80-3.33(m,8H),1.98-1.83(m,1H),1.65-1.50(m,1H);ES-LCMSm/z 288.2[M+Na]+.
步骤6:(S)-7-(((甲基磺酰基)氧基)甲基)-1,4-氧氮杂环庚烷-4-甲酸苄基酯
在0℃向(S)-7-(羟基甲基)-1,4-氧氮杂环庚烷-4-甲酸苄基酯(850mg,2.92mmol)、Et3N(0.865mL,4.38mmol)在DCM(30mL)中的溶液中添加MsCl(0.250mL,3.21mmol)。然后将混合物搅拌10min。向该混合物中添加水(20mL)。将混合物用DCM(30mLx2)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到(S)-7-(((甲基磺酰基)氧基)甲基)-1,4-氧氮杂环庚烷-4-甲酸苄基酯(1.1g,2.81mmol,96.0%产率),其为淡黄色油状物:1H NMR(400MHz,CD3OD)δppm 7.40-7.27(m,5H),5.19-5.11(m,2H),4.21-4.11(m,2H),4.07-3.97(m,1H),3.75(d,J=13.2Hz,2H),3.66-3.43(m,4H),3.06(s,3H),2.02-1.90(m,1H),1.75-1.58(m,1H);ES-LCMS m/z 344.2[M+H]+.
步骤7:(S)-7-(氰基甲基)-1,4-氧氮杂环庚烷-4-甲酸苄基酯
向(S)-7-(((甲基磺酰基)氧基)甲基)-1,4-氧氮杂环庚烷-4-甲酸苄基酯(1.1g,2.81mmol)在DMSO(20mL)中的溶液中添加KCN(0.549g,8.44mmol)。然后将混合物在80℃搅拌10h。向该混合物中添加饱和NaHCO3水溶液(30mL)。将混合物用DCM(50mL x2)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(PE/EtOAc=5/1至1/1,TLC:PE/EtOAc=1/1,Rf=0.45)纯化以得到(S)-7-(氰基甲基)-1,4-氧氮杂环庚烷-4-甲酸苄基酯(700mg,2.493mmol,89.0%产率),其为淡黄色油状物:1H NMR(400MHz,CD3OD)δppm 7.46-7.16(m,5H),5.18-5.10(m,2H),4.07-3.96(m,1H),3.82-3.42(m,6H),2.73-2.53(m,2H),2.06-1.92(m,1H),1.80-1.65(m,1H);ES-LCMS m/z 275.2[M+H]+.
步骤8:(S)-7-(2-甲氧基-2-氧代乙基)-1,4-氧氮杂环庚烷-4-甲酸苄基酯
在20℃将(S)-7-(氰基甲基)-1,4-氧氮杂环庚烷-4-甲酸苄基酯(700mg,2.493mmol)在HCl溶液(4M在MeOH中,15mL,60.0mmol)中的溶液搅拌72h。将混合物浓缩以得到(S)-7-(2-甲氧基-2-氧代乙基)-1,4-氧氮杂环庚烷-4-甲酸苄基酯(580mg,1.887mmol,76.0%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 7.38-7.23(m,5H),5.16-5.07(m,2H),4.05-3.79(m,3H),3.66-3.63(m,3H),3.61-3.41(m,4H),2.56-2.40(m,2H),1.99-1.89(m,1H),1.69-1.56(m,1H);ES-LCMS m/z 330.1[M+Na]+
步骤9:(S)-2-(1,4-氧氮杂环庚烷-7-基)乙酸甲酯,三氟乙酸盐
将(S)-7-(2-甲氧基-2-氧代乙基)-1,4-氧氮杂环庚烷-4-甲酸苄基酯(350mg,0.994mmol)在TFA(10mL,130mmol)中的溶液在50℃搅拌2h。然后将混合物浓缩以得到(S)-2-(1,4-氧氮杂环庚烷-7-基)乙酸甲酯,三氟乙酸盐(300mg,0.909mmol,91.0%产率),其为淡黄色油状物:1H NMR(400MHz,CD3OD)δppm 4.18-4.08(m,1H),4.00(d,J=4.8,13.8Hz,1H),3.79(ddd,J=3.9,7.9,14.1Hz,1H),3.66(s,3H),3.46-3.31(m,4H),2.59-2.49(m,2H),2.20-2.13(m,1H),1.98-1.86(m,1H)。
中间体62:(1R,5S,6r)-3-氮杂双环[3.1.0]己-6-基氨基甲酸苄基酯
步骤1:(1R,5S,6s)-3-氮杂双环[3.1.0]己烷-3,6-二甲酸3-叔丁基6-乙基酯
在25℃向2,5-二氢-1H-吡咯-1-甲酸叔丁酯(10g,59.1mmol)和乙酸铑(II)二聚体(1.828g,4.14mmol)在DCM(120mL)中的混合物中滴加重氮乙酸乙酯(7.36mL,70.9mmol)。将反应混合物在25℃搅拌12h。将混合物过滤且将滤液浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=3/1,TLC:PE/EtOAc=3/1,Rf=0.7)纯化以得到(1R,5S,6s)-3-氮杂双环[3.1.0]己烷-3,6-二甲酸3-叔丁基6-乙基酯(1.3g,4.58mmol,7.8%产率),其为无色液体:1HNMR(400MHz,CDCl3)δppm 4.10(q,J=6.9Hz,2H),3.80-3.70(m,2H),3.43(t,J=9.9Hz,2H),1.90-1.84(m,2H),1.79-1.75(m,1H),1.43(s,9H),1.25(t,J=7.2Hz,3H);ES-LCMS m/z:200.1[M+H-t-Bu]+.
步骤2:(1R,5S,6s)-3-(叔丁氧基羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸
向(1R,5S,6s)-3-氮杂双环[3.1.0]己烷-3,6-二甲酸3-叔丁基6-乙基酯(500.00mg,1.763mmol)在THF(6.00mL)和H2O(6.00mL)中的溶液中添加LiOH·H2O(740mg,17.63mmol)。将反应混合物在25℃搅拌12h。将反应混合物浓缩且通过H2O(30mL)溶解。混合物用1N HCl将pH调节至4。将混合物用DCM(100mL x2)萃取。合并的有机层用盐水(30mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到(1R,5S,6s)-3-(叔丁氧基羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(350mg,1.386mmol,79.0%产率),其为淡黄色固体:1H NMR(400MHz,CDCl3)δppm 3.75(d,J=11.5Hz,2H),3.50(d,J=11.0Hz,2H),2.00-1.95(m,2H),1.81-1.75(m,1H),1.43(s,9H);ES-LCMS m/z:172.1[M+H-t-Bu]+.
步骤3:(1R,5S,6r)-6-(((苄基氧基)羰基)氨基)-3-氮杂双环[3.1.0]己烷-3-甲酸叔丁酯
向(1R,5S,6s)-3-(叔丁氧基羰基)-3-氮杂双环[3.1.0]己烷-6-甲酸(350mg,1.386mmol)、DPPA(0.329mL,1.525mmol)和Et3N(0.386mL,2.77mmol)在甲苯(10mL)中的混合物中添加BnOH(300mg,2.77mmol)。将混合物在115℃在N2气氛搅拌12h。然后将混合物浓缩以得到粗物质。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=1/1,TLC:PE/EtOAc=1/1,Rf=0.5)纯化以得到(1R,5S,6r)-6-(((苄基氧基)羰基)氨基)-3-氮杂双环[3.1.0]己烷-3-甲酸叔丁酯(380mg,1.029mmol,74.2%产率),其为棕色固体:1H NMR(400MHz,CDCl3)δppm 7.38-7.32(m,5H),5.12(s,2H),3.62-3.48(m,3H),3.39(d,J=10.6Hz,1H),2.90(s,1H),1.80(s,2H),1.40(s,9H);ES-LCMSm/z:277.1[M+H-t-Bu]+.
步骤4:(1R,5S,6r)-3-氮杂双环[3.1.0]己-6-基氨基甲酸苄基酯,盐酸盐
将(1R,5S,6r)-6-(((苄基氧基)羰基)氨基)-3-氮杂双环[3.1.0]己烷-3-甲酸叔丁酯(380mg,1.029mmol)在HCl溶液(4M在EtOAc中)(10mL,40.0mmol)中的混合物在25℃搅拌0.5h。将混合物浓缩以得到(1R,5S,6r)-3-氮杂双环[3.1.0]己-6-基氨基甲酸苄基酯,盐酸盐(300mg,1.005mmol,98.0%产率),其为棕色固体:1H NMR(400MHz,CD3OD)δppm 7.43-7.28(m,5H),5.13(s,2H),3.65-3.56(m,2H),3.33(s,1H),3.30(s,1H),2.78(t,J=6.8Hz,1H),2.17-2.12(m,2H);ES-LCMS m/z:233.2[M+H]+.
中间体63:4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-2-氯-6-(3,5-二氯苯基)-3-氟吡啶
步骤1:2-溴-5-氟异烟酸甲酯
向2-溴-5-氟异烟酸(25g,114mmol)在MeOH(150mL)中的溶液中添加SOCl2(25mL,343mmol)且将混合物在25℃搅拌18h。将反应混合物浓缩且添加DCM(40mL)。将混合物用4NNaOH中和至pH=7-8。将混合物用DCM(50mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=10/1至8/1,TLC:PE/EtOAc=2/1,Rf=0.7)纯化以得到2-溴-5-氟异烟酸甲酯(25g,89mmol,78.0%产率),其为无色固体:1H NMR(400MHz,CDCl3)δppm 8.34(d,J=1.5Hz,1H),7.88(d,J=4.9Hz,1H),3.94-3.93(m,3H);ES-LCMS m/z233.9,235.9[M+H]+.
步骤2:2-(3,5-二氯苯基)-5-氟异烟酸甲酯
将2-溴-5-氟异烟酸甲酯(7g,24.86mmol)、(3,5-二氯苯基)硼酸(7.11g,37.3mmol)、K2CO3(7.56g,54.7mmol)和PdCl2(dppf)(1.5g,2.050mmol)在1,4-二噁烷(6mL)中的溶液在80℃在N2气氛搅拌4h。粗物质通过快速色谱法(从PE/EtOAc=5/1至2/1,TLC:PE/EtOAc=3/1,Rf=0.6)纯化以得到2-(3,5-二氯苯基)-5-氟异烟酸甲酯(8g,21.33mmol,86.0%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 9.27-9.17(m,1H),8.77-8.67(m,1H),8.47-8.37(m,2H),8.02-7.90(m,1H),4.60-4.56(m,3H);ES-LCMS m/z 300.0,302.0[M+H]+.
步骤3:2-(3,5-二氯苯基)-5-氟-4-(甲氧基羰基)吡啶1-氧化物
向2-(3,5-二氯苯基)-5-氟异烟酸甲酯(9g,23.99mmol)在MeOH(30.0mL)和DCM(90mL)中的溶液中添加m-CPBA(14.79g,60.0mmol)且将混合物在25℃搅拌66h。将混合物用2N NaOH中和至pH=8。将混合物用DCM(70mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=20/1至15/1,TLC:PE/EtOAc=5/1,Rf=0.5)纯化以得到2-(3,5-二氯苯基)-5-氟-4-(甲氧基羰基)吡啶1-氧化物(5g,13.35mmol,55.6%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 8.26(t,J=5.6Hz,1H),7.96(m,J=5.8,8.5Hz,1H),7.62(m,J=1.9,5.8Hz,2H),7.45(m,J=1.9,3.9Hz,1H),3.97(d,J=6.0Hz,3H);ES-LCMS m/z 316.1,318.0[M+H]+.
步骤4:2-氯-6-(3,5-二氯苯基)-3-氟异烟酸甲酯
将2-(3,5-二氯苯基)-5-氟-4-(甲氧基羰基)吡啶1-氧化物(3g,8.01mmol)在POCl3(31.4mL,337mmol)中的溶液在80℃搅拌16h。将反应混合物浓缩以得到残余物。添加DCM(10mL)且混合物缓慢添加至10%NaOH(50mL)。将混合物用DCM(20mL×3)萃取。合并的有机层用盐水(30mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=19/1至16/1,TLC:PE/EtOAc=3/1,Rf=0.7)纯化以得到2-氯-6-(3,5-二氯苯基)-3-氟异烟酸甲酯(1.5g,3.59mmol,67.2%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 8.01(d,J=4.0Hz,1H),7.82-7.78(m,2H),7.38-7.34(m,1H),3.96(s,3H);ES-LCMS m/z 334.0,336.0[M+H]+.
步骤5:(2-氯-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲醇
向2-氯-6-(3,5-二氯苯基)-3-氟异烟酸甲酯(3g,7.62mmol)在MeOH(40mL)中的溶液中添加NaBH4(0.577g,15.24mmol)且将混合物在25℃搅拌40min。反应混合物通过添加饱和NH4Cl水溶液(50mL)淬灭。将混合物用DCM(50mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=20/1至10/1,TLC:PE/EtOAc=5/1,Rf=0.6)纯化以得到(2-氯-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲醇(3g,7.19mmol,94.0%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 8.36(d,J=3.5Hz,1H),8.35-8.28(m,2H),7.86(d,J=1.8Hz,1H),5.26(s,2H);ES-LCMS m/z 306.0,308.0[M+H]+
步骤6:4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-2-氯-6-(3,5-二氯苯基)-3-氟吡啶
向(2-氯-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲醇(3.3g,7.91mmol)在DCM(60mL)中的溶液中添加1H-咪唑(2.155g,31.6mmol)和TBSCl(4.77g,31.6mmol)且将混合物在40℃搅拌1h。添加H2O(60mL)。将混合物用DCM(50mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=10/1至5/1,TLC:PE/EtOAc=5/1,Rf=0.6)纯化以得到4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-2-氯-6-(3,5-二氯苯基)-3-氟吡啶(3.5g,7.07mmol,89.0%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 7.86-7.84(m,2H),7.83(d,J=4.4Hz,1H),7.45-7.38(m,1H),4.87(s,2H),1.00(s,9H),0.18(s,6H);ES-LCMSm/z419.8,421.8[M+H]+.
中间体64:4-(2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)乙基)哌啶
步骤1:4-(2,2-二溴乙烯基)哌啶-1-甲酸叔丁酯
在0℃向4-甲酰基哌啶-1-甲酸叔丁酯(9g,42.2mmol)和PPh3(22.14g,84mmol)在DCM(100mL)中的混合物中分批添加CBr4(28.0g,84mmol)。将反应混合物在0℃在N2气氛搅拌3h。然后将反应混合物在20℃在N2气氛搅拌12h。将反应混合物过滤且将滤液浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=5/1,Rf=0.7(PE/EtOAc=5/1))纯化以得到4-(2,2-二溴乙烯基)哌啶-1-甲酸叔丁酯(6.91g,16.82mmol,39.9%产率),其为白色固体:1HNMR(400MHz,CDCl3)δppm 6.16(d,J=8.8Hz,1H),4.00(s,2H),2.70(t,J=12.0Hz,2H),2.43-2.31(m,1H),1.64(d,J=10.8Hz,2H),1.39(s,9H),1.31-1.21(m,2H);ES-LCMSm/z312.0,314.0,316.0[M-t-Bu+H]+.
步骤2:(E)-4-(2-溴乙烯基)哌啶-1-甲酸叔丁酯
在0℃向4-(2,2-二溴乙烯基)哌啶-1-甲酸叔丁酯(5.91g,14.39mmol)在MeOH(40mL)和THF(20.00mL)中的混合物中添加NH4Cl(6.16g,115mmol),将反应混合物在0℃在N2气氛搅拌30分钟。然后添加锌(3.76g,57.6mmol)且所有反应混合物在20℃在N2气氛搅拌12h。过滤后,将滤液浓缩以得到(E)-4-(2-溴乙烯基)哌啶-1-甲酸叔丁酯(4.3g,14.08mmol,98.0%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 6.21-5.85(m,2H),4.06(s,2H),2.82-2.64(m,2H),2.21-2.05(m,1H),1.66(d,J=13.0Hz,2H),1.44-1.42(m,9H),1.35-1.21(m,2H);ES-LCMSm/z 234.0,236.0[M-t-Bu+H]+.
步骤3:(E)-4-(2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)乙烯基)哌啶-1-甲酸叔丁酯
将(E)-4-(2-溴乙烯基)哌啶-1-甲酸叔丁酯(2.3g,7.53mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷)(2.87g,11.29mmol)、PPh3(0.197g,0.753mmol)、KOAc(1.478g,15.06mmol)和Pd2(dba)3(0.345g,0.376mmol)在1,4-二噁烷(30mL)中的混合物在110℃搅拌12h。将反应混合物过滤且将滤液浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=5/1,Rf=0.7(PE/EtOAc=5/1))纯化以得到(E)-4-(2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)乙烯基)哌啶-1-甲酸叔丁酯(2g,2.97mmol,39.4%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 5.43(dd,J=1.5,18.1Hz,1H),5.03-4.96(m,1H),2.78-2.70(m,4H),2.22-2.15(m,1H),1.69(d,J=16.3Hz,4H),1.45(s,9H),1.27(s,12H);ES-LCMSm/z 238.2[M-Boc+H]+.
步骤4:4-(2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)乙基)哌啶-1-甲酸叔丁酯
向(E)-4-(2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)乙烯基)哌啶-1-甲酸叔丁酯(2g,2.97mmol)在MeOH(30mL)中的混合物中添加Pd/C(10wt%,3.16g,2.97mmol)。将混合物在20℃在H2气氛(15psi)搅拌10分钟。将反应混合物过滤且将滤液浓缩以得到4-(2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)乙基)哌啶-1-甲酸叔丁酯(1.6g,2.358mmol,80.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 2.70-2.57(m,4H),1.62(d,J=12.3Hz,2H),1.42(d,J=2.0Hz,9H),1.21(s,12H),1.09-0.93(m,4H),0.88-0.84(m,1H),0.78-0.70(m,2H);ES-LCMS m/z 240.2[M+H]+.
步骤5:4-(2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)乙基)哌啶,三氟乙酸盐
向4-(2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)乙基)哌啶-1-甲酸叔丁酯(600mg,0.884mmol)在DCM(16mL)中的溶液中添加TFA(4mL,51.9mmol)。将混合物在30℃搅拌0.5h。将混合物浓缩以得到4-(2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)乙基)哌啶,三氟乙酸盐(420mg,0.595mmol,67.2%产率),其为棕色油状物:1H NMR(400MHz,CDCl3)δppm 3.47(d,J=11.0Hz,2H),2.93(d,J=11.0Hz,2H),1.93(d,J=12.3Hz,2H),1.47-1.38(m,4H),1.36-1.34(m,1H),1.28-1.25(m,12H),0.91-0.75(m,2H);ES-LCMS m/z 240.1[M+H]+.
中间体65:2,2-二甲基-3-(哌嗪-1-基)丙酸甲酯
步骤1:4-(3-羟基-2,2-二甲基丙酰基)哌嗪-1-甲酸叔丁酯
向3-羟基-2,2-二甲基丙酸(3g,25.4mmol)、DIEA(13.31mL,76mmol)和哌嗪-1-甲酸叔丁酯(5.68g,30.5mmol)在DCM(100mL)中的溶液中添加EDC(9.74g,50.8mmol)和HOBt(7.78g,50.8mmol)。然后将混合物在26℃搅拌8h。向混合物中添加水(80mL)。将混合物用EtOAc(100mL×3)萃取。合并的有机层用盐水(60mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=20/1至2/1,TLC:PE/EtOAc=3/1,Rf=0.4)纯化以得到4-(3-羟基-2,2-二甲基丙酰基)哌嗪-1-甲酸叔丁酯(6g,18.86mmol,74.3%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 3.63-3.58(m,4H),3.52-3.48(m,2H),3.45-3.38(m,4H),1.49-1.47(m,9H),1.30-1.25(m,6H);ES-LCMS m/z 287.1[M+H]+.
步骤2:4-(3-羟基-2,2-二甲基丙基)哌嗪-1-甲酸叔丁酯
在26℃向4-(3-羟基-2,2-二甲基丙酰基)哌嗪-1-甲酸叔丁酯(5g,15.71mmol)在THF(70mL)中的溶液中分批添加BH3·DMS(3.14mL,31.4mmol)。然后将混合物在80℃搅拌3h。将混合物用MeOH(10mL)淬灭且浓缩。粗物质通过快速色谱法(从PE/EtOAc=5/1至1/1,TLC:PE/EtOAc=3/1,Rf=0.3)纯化以得到4-(3-羟基-2,2-二甲基丙基)哌嗪-1-甲酸叔丁酯(3g,9.91mmol,63.1%产率),其为无色油状物:1H NMR(400MHz,CDCl3)δppm 3.50(s,2H),3.42(brs,4H),2.54(brs,4H),2.39(s,2H),1.47-1.43(m,9H),0.93(s,6H);ES-LCMS m/z273.2[M+H]+.
步骤3:2,2-二甲基-3-(哌嗪-1-基)丙-1-醇,2盐酸盐
向4-(3-羟基-2,2-二甲基丙基)哌嗪-1-甲酸叔丁酯(2g,6.61mmol)在EtOAc(10mL)中的溶液中添加HCl溶液(4M在EtOAc中,5mL,20.00mmol)。将混合物在26℃搅拌0.5h。将混合物浓缩以得到白色固体的2,2-二甲基-3-(哌嗪-1-基)丙-1-醇,2盐酸盐(1.6g,5.55mmol,84.0%产率):1H NMR(400MHz,CD3OD)δppm 3.90(br s,1H),3.77-3.59(m,6H),3.58-3.51(m,3H),3.34(s,2H),1.12(s,6H);ES-LCMS m/z 173.2[M+H]+.
步骤4:4-(3-羟基-2,2-二甲基丙基)哌嗪-1-甲酸苄基酯
在0℃向2,2-二甲基-3-(哌嗪-1-基)丙-1-醇,2盐酸盐(1.6g,5.55mmol)和DIEA(2.91mL,16.64mmol)在DCM(50mL)中的溶液中滴加CbzCl(1.188mL,8.32mmol)。然后将混合物在26℃搅拌8h。将混合物用水(20mL)淬灭。将混合物用DCM(100mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=5/1至1/1,TLC:PE/EtOAc=3/1,Rf=0.5)纯化以得到4-(3-羟基-2,2-二甲基丙基)哌嗪-1-甲酸苄基酯(1.8g,5.29mmol,95.0%产率),其为淡黄色油状物:1H NMR(400MHz,CDCl3)δppm7.37-7.27(m,5H),5.10(s,2H),3.57-3.44(m,6H),2.54(br s,4H),2.38(s,2H),0.91(s,6H);ES-LCMS m/z 307.3[M+H]+.
步骤5:3-(4-((苄基氧基)羰基)哌嗪-1-基)-2,2-二甲基丙酸
在0℃向4-(3-羟基-2,2-二甲基丙基)哌嗪-1-甲酸苄基酯(1.3g,3.82mmol)在丙酮(5mL)中的溶液中添加Jones试剂(5mL)(Jones试剂:将氧化铬(VI)(1g,10.00mmol)在H2SO4(1mL,18.76mmol)中的溶液用水稀释至5mL)。将混合物在26℃搅拌4h。在0℃将反应混合物通过i-PrOH(10mL)淬灭。将混合物在0℃搅拌10min。将氢氧化铵(10mL)添加至混合物。然后将混合物过滤且浓缩以得到3-(4-((苄基氧基)羰基)哌嗪-1-基)-2,2-二甲基丙酸(300mg,0.655mmol,44.6%产率),其为棕色油状物。1H NMR(400MHz,CDCl3)δppm 7.28(brs,5H),5.11(br s,2H),3.64-3.41(m,6H),2.79-2.50(m,4H),1.47-0.66(m,6H);ES-LCMSm/z 321.2[M+H]+.
步骤6:4-(3-甲氧基-2,2-二甲基-3-氧代丙基)哌嗪-1-甲酸苄基酯
在0℃向3-(4-((苄基氧基)羰基)哌嗪-1-基)-2,2-二甲基丙酸(1500mg,3.28mmol)在MeOH(10.0mL)和DCM(10.0mL)中的溶液中添加(重氮基甲基)三甲基甲硅烷(2M在己烷中)(3.28mL,6.55mmol)。将反应混合物在0℃搅拌1h。然后将混合物浓缩以得到残余物。粗物质通过快速色谱法(从PE/EtOAc=20/1至2/1,TLC:PE/EtOAc=3/1,Rf=0.6)纯化以得到4-(3-甲氧基-2,2-二甲基-3-氧代丙基)哌嗪-1-甲酸苄基酯(600mg,1.669mmol,50.9%产率),其为淡黄色油状物:1H NMR(400MHz,CDCl3)δppm 7.40-7.24(m,5H),5.09(d,J=4.0Hz,2H),3.63(d,J=4.2Hz,3H),3.41(d,J=4.9Hz,4H),2.51-2.31(m,6H),1.14(d,J=4.2Hz,6H);ES-LCMSm/z335.2[M+H]+.
步骤7:2,2-二甲基-3-(哌嗪-1-基)丙酸甲酯
在26℃向4-(3-甲氧基-2,2-二甲基-3-氧代丙基)哌嗪-1-甲酸苄基酯(600mg,1.669mmol)在MeOH(10.0mL)中的溶液中添加Pd/C(10wt%,1776mg,1.669mmol)。将反应混合物在26℃在H2气氛在15psi搅拌2h。然后将混合物过滤且浓缩以得到黄色油状物的2,2-二甲基-3-(哌嗪-1-基)丙酸甲酯(250mg,0.999mmol,59.8%产率):1H NMR(400MHz,CD3OD)δppm 3.67-3.60(m,3H),2.85-2.76(m,3H),2.57-2.34(m,7H),1.16-1.11(m,6H);ES-LCMSm/z 201.2[M+H]+.
中间体66:1-((1-((叔丁基二甲基甲硅烷基)氧基)环丙基)甲基)哌嗪
步骤1:4-(1-羟基环丙烷羰基)哌嗪-1-甲酸苄基酯
向哌嗪-1-甲酸苄基酯(5g,22.70mmol)、1-羟基环丙烷羧酸(2.78g,27.2mmol)、DIEA(39.6mL,227mmol)在DCM(150mL)中的混合物中添加EDC(6.53g,34.0mmol)和HOBt(5.21g,34.0mmol)。然后,将混合物在20℃搅拌10h。将混合物浓缩且将残余物用DCM(100mL)和水(100mL)稀释,用DCM(200mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且蒸发以得到粗产物。粗产物通过快速色谱法(DCM/MeOH=20:1,Rf=0.5)纯化以得到4-(1-羟基环丙烷羰基)哌嗪-1-甲酸苄基酯(6g,18.89mmol,83.0%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 7.40-7.29(m,5H),5.15(s,2H),3.71(br.s.,4H),3.57-3.50(m,4H),1.09-1.04(m,2H),0.95-0.91(m,2H);ES-LCMS m/z 305.2[M+H]+.
步骤2:4-((1-羟基环丙基)甲基)哌嗪-1-甲酸苄基酯
向4-(1-羟基环丙烷羰基)哌嗪-1-甲酸苄基酯(5.5g,17.62mmol)在THF(100mL)中的溶液中添加BH3·DMS(4mL,40.0mmol)。然后,将混合物在50℃搅拌4h。反应溶液通过MeOH(20mL)淬灭。将混合物浓缩以得到粗产物。粗产物通过快速色谱法(DCM/MeOH=20:1,Rf=0.5)纯化以得到4-((1-羟基环丙基)甲基)哌嗪-1-甲酸苄基酯(3g,8.27mmol,46.9%产率),其为无色油状物:1H NMR(400MHz,CDCl3)δppm 7.04-6.88(m,5H),4.76(s,2H),3.23-3.10(m,4H),2.20(br.s.,4H),2.12(s,2H),0.45(t,J=5.7Hz,2H),0.06-0.03(m,2H);ES-LCMS m/z 291.2[M+H]+.
步骤3:4-((1-((叔丁基二甲基甲硅烷基)氧基)环丙基)甲基)哌嗪-1-甲酸苄基酯
向4-((1-羟基环丙基)甲基)哌嗪-1-甲酸苄基酯(3g,8.27mmol)、1H-咪唑(1.688g,24.80mmol)在DCM(100mL)中的溶液中添加TBSCl(2.492g,16.53mmol)。然后,将混合物在40℃搅拌16h。反应混合物用DCM(50mL)和水(100mL)稀释,用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且蒸发以得到粗产物。粗产物通过快速色谱法(PE/EtOAc=5:1,Rf=0.5)纯化以得到4-((1-((叔丁基二甲基甲硅烷基)氧基)环丙基)甲基)哌嗪-1-甲酸苄基酯(3g,7.31mmol,88.0%产率),其为无色油状物:1H NMR(400MHz,CDCl3)δppm 7.31-7.19(m,5H),5.03(s,2H),3.44-3.37(m,4H),2.40(br.s.,4H),2.34(s,2H),0.74(s,9H),0.64-0.59(m,2H),0.41-0.36(m,2H),0.00(s,6H);ES-LCMS m/z 405.3[M+H]+.
步骤4:1-((1-((叔丁基二甲基甲硅烷基)氧基)环丙基)甲基)哌嗪
向4-((1-((叔丁基二甲基甲硅烷基)氧基)环丙基)甲基)哌嗪-1-甲酸苄基酯(3g,7.31mmol)在MeOH(40mL)中的混合物中添加Pd/C(10wt%,0.778g,0.731mmol)。将混合物在20℃在H2气氛(40psi)搅拌10h。然后将溶液过滤且浓缩以得到1-((1-((叔丁基二甲基甲硅烷基)氧基)环丙基)甲基)哌嗪(2g,6.28mmol,86.0%产率),其为无色油状物:1H NMR(400MHz,CDCl3)δppm2.90(t,J=4.5Hz,4H),2.54(br.s.,4H),2.36(s,2H),0.75(s,9H),0.64-0.58(m,2H),0.40-0.37(m,2H),0.00(s,6H);ES-LCMSm/z271.2[M+H]+.
中间体67:2-氧杂-4,9-二氮杂螺[5.5]十一烷-3-酮
步骤1:4-氰基哌啶-1-甲酸叔丁酯
在-10℃向4-氧代哌啶-1-甲酸叔丁酯(5g,25.09mmol)、TosMIC(7.35g,37.6mmol)和EtOH(2.93mL,50.2mmol)在DME(150mL)中的溶液中添加t-BuOK(8.45g,75mmol)。将反应混合物在-10℃搅拌2h。然后将反应混合物温热至25℃且搅拌12h。然后将混合物过滤且浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=3/1,TLC:PE/EtOAc=5/1,Rf=0.4)纯化以得到4-氰基哌啶-1-甲酸叔丁酯(3.5g,14.15mmol,56.4%产率),其为棕色油状物:1HNMR(400MHz,CDCl3)δppm 3.64(ddd,J=3.7,7.1,13.6Hz,2H),3.32(ddd,J=3.6,7.8,13.9Hz,2H),2.79(tt,J=4.1,7.8Hz,1H),1.91-1.74(m,4H),1.44(s,9H);ES-LCMSm/z155.1[M-t-Bu+H]+.
步骤2:4-氰基哌啶-1,4-二甲酸1-叔丁基4-乙基酯
在-78℃在N2气氛向4-氰基哌啶-1-甲酸叔丁酯(3.50g,14.15mmol)在THF(50mL)中的溶液中添加LiHMDS(1M在THF中,28.3mL,28.3mmol)。将反应混合物搅拌1h。然后添加氯甲酸乙酯(3mL,31.2mmol)。将反应混合物搅拌1h。然后将混合物在25℃搅拌12h。混合物通过饱和NH4Cl水溶液淬灭。然后将混合物在DCM(100mL)和H2O(100mL)之间分配,用DCM(150mL×3)萃取。合并的有机层用盐水(100mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=5/1,TLC:PE/EtOAc=5/1,Rf=0.6)纯化以得到4-氰基哌啶-1,4-二甲酸1-叔丁基4-乙基酯(3.9g,11.64mmol,82.0%产率),其为无色油状物:1HNMR(400MHz,CDCl3)δppm 4.30-4.20(m,2H),4.08(s,2H),3.08(s,2H),2.07-1.89(m,4H),1.45-1.40(m,9H),1.34-1.26(m,3H);ES-LCMS m/z 183.1[M-Boc+H]+.
步骤3:4-氰基-4-(羟基甲基)哌啶-1-甲酸叔丁酯
向4-氰基哌啶-1,4-二甲酸1-叔丁基4-乙基酯(3.8g,11.35mmol)在MeOH(30mL)中的溶液中添加NaBH4(1.288g,34.0mmol)。将反应混合物在25℃搅拌0.5h。混合物通过饱和NH4Cl水溶液(20mL)淬灭且用DCM(100mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=10/1至3/1,TLC:PE/EtOAc=3/1,Rf=0.3)纯化以得到4-氰基-4-(羟基甲基)哌啶-1-甲酸叔丁酯(2.6g,9.74mmol,86.0%产率),其为灰白色固体:1H NMR(400MHz,CDCl3)δppm 4.16(s,2H),3.66(d,J=6.2Hz,2H),3.02(s,2H),2.37(t,J=6.4Hz,1H),1.95(d,J=13.2Hz,2H),1.45(s,11H);ES-LCMS m/z 141.2[M+H-Boc]+.
步骤4:4-(氨基甲基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯
在0℃在N2气氛向4-氰基-4-(羟基甲基)哌啶-1-甲酸叔丁酯(1.5g,5.62mmol)在THF(15mL)中的溶液中添加LiAlH4(0.640g,16.85mmol)。将反应混合物在0℃搅拌1h。混合物通过H2O(1.5mL)淬灭,然后通过10%NaOH溶液(1.5mL)淬灭。将混合物过滤且将滤液浓缩以得到4-(氨基甲基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯(1.2g,2.95mmol,52.5%产率),其为无色油状物:1H NMR(400MHz,CDCl3)δppm 4.34(s,2H),3.73-3.66(m,4H),2.83-2.80(m,4H),2.27(s,2H),1.44(s,9H);ES-LCMS m/z 189.2[M-t-Bu+H]+.
步骤5:3-氧代-2-氧杂-4,9-二氮杂螺[5.5]十一烷-9-甲酸叔丁酯
向4-(氨基甲基)-4-(羟基甲基)哌啶-1-甲酸叔丁酯(1.2g,2.95mmol)和DIEA(1.029mL,5.89mmol)在DCM(10mL)中的混合物中添加二(1H-咪唑-1-基)甲酮(0.573g,3.54mmol)。然后将混合物在25℃搅拌3h。合并的反应混合物浓缩以得到粗物质。粗物质通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干以得到3-氧代-2-氧杂-4,9-二氮杂螺[5.5]十一烷-9-甲酸叔丁酯(50mg,0.175mmol,5.9%产率),其为白色固体:1HNMR(400MHz,CD3OD)δppm 4.11(s,2H),3.54(d,J=13.2Hz,2H),3.40-3.35(m,2H),3.18(s,2H),1.53(t,J=5.8Hz,4H),1.45(s,9H);.ES-LCMS m/z215.1[M-t-Bu+H]+.
步骤6:2-氧杂-4,9-二氮杂螺[5.5]十一烷-3-酮,盐酸盐
将3-氧代-2-氧杂-4,9-二氮杂螺[5.5]十一烷-9-甲酸叔丁酯(50mg,0.175mmol)和HCl溶液(4M在EtOAc中,3mL,12.00mmol)的混合物在20℃搅拌0.5h。然后将混合物浓缩以得到2-氧杂-4,9-二氮杂螺[5.5]十一烷-3-酮,盐酸盐(35mg,0.152mmol,87.0%产率),其为灰白色固体:1H NMR(400MHz,CD3OD)δppm 4.18(s,2H),3.27-3.23(m,4H),1.81(t,J=5.7Hz,4H),1.38(d,J=6.0Hz,2H)。
中间体68:1-(哌啶-4-基)丙-2-醇,三氟乙酸盐
步骤1:4-(2-氧代乙基)哌啶-1-甲酸叔丁酯
经30分钟向冷却至-78℃的草酰氯(13.39mL,157mmol)在DCM(160mL)中的溶液中滴加DMSO(16.71mL,235mmol)在DCM(120mL)中的溶液。添加完成后,将混合物经20分钟温热至-70℃。然后经30min向该混合物中滴加4-(2-羟基乙基)哌啶-1-甲酸叔丁酯(20g,78mmol)在DCM(120mL)中的溶液。随后,经20分钟添加DIEA(82mL,471mmol)在DCM(80mL)中的溶液,然后将反应烧瓶从浴中取出,并经60min使其温热至0℃。将反应溶液转移至添加有冰冷的0.5N HCl溶液(240mL)的1000mL分液漏斗。分离两相,水相用DCM(200mL×3)萃取。合并的有机相用Na2SO4干燥,过滤且浓缩以得到淡黄色油状物4-(2-氧代乙基)哌啶-1-甲酸叔丁酯(16.5g,65.3mmol,83.0%产率):1H NMR(400MHz,CDCl3)δppm 9.77(s,1H),4.07(s,2H),2.73(bt,J=12.5Hz,2H),2.37(dd,J=1.7,6.7Hz,2H),2.11-1.93(m,1H),1.68(d,J=13.2Hz,2H),1.48-1.38(m,9H),1.26-1.03(m,2H)
步骤2:4-(2-羟基丙基)哌啶-1-甲酸叔丁酯
在N2气氛向冷却至0℃的4-(2-氧代乙基)哌啶-1-甲酸叔丁酯(1g,3.96mmol)在THF(20mL)中的溶液中滴加MeMgBr(3M在THF中,1.980mL,5.94mmol)。将混合物在0℃搅拌2h。将混合物用饱和NH4Cl水溶液(20mL)淬灭,用EtOAc(30mL x2)萃取。有机层用Na2SO4干燥,过滤且浓缩。残余物通过快速色谱法(从纯的PE至PE/EtOAc=5/1,TLC:PE/EtOAc=3:1,Rf=0.3)纯化以得到无色油状物4-(2-羟基丙基)哌啶-1-甲酸叔丁酯(700mg,2.59mmol,65.4%产率):1H NMR(400MHz,CDCl3)δppm 4.08-4.01(m,2H),3.86(s,1H),2.66-2.63(m,2H),1.67-1.65(m,1H),1.57-1.54(m,2H),1.38(s,9H),1.24-1.19(m,6H),1.14-1.13(m,2H);ES-LCMSm/z:188.1[M-t-Bu+H]+.
步骤3:1-(哌啶-4-基)丙-2-醇,三氟乙酸盐
向4-(2-羟基丙基)哌啶-1-甲酸叔丁酯(700mg,2.59mmol)在DCM(20mL)中的溶液中添加TFA(5mL,64.9mmol)。将混合物在20℃搅拌2h。将混合物浓缩以得到棕色油状物的1-(哌啶-4-基)丙-2-醇,三氟乙酸盐(700mg,2.313mmol,89.0%产率):1H NMR(400MHz,CD3OD)δppm 5.28-5.20(m,1H),3.38-3.34(m,2H),2.98-2.95(m,2H),2.00-1.98(m,2H),1.79-1.77(m,2H),1.64-1.55(m,1H),1.49-1.40(m,2H),1.38-1.37(m,3H);ES-LCMS m/z:144.1[M+H]+.
中间体69:2-(4-氨基哌啶-4-基)乙酸乙酯,2盐酸盐
步骤1:4-氨基-4-(2-乙氧基-2-氧代乙基)哌啶-1-甲酸叔丁酯
在85℃在N2气氛向3-乙氧基-3-氧代丙酸(13.26g,100mmol)和NH4OAc(10.83g,141mmol)在EtOH(200mL)中的混合物中分批添加4-氧代哌啶-1-甲酸叔丁酯(20g,100mmol)。然后将反应混合物在85℃搅拌3h。将混合物浓缩,然后添加饱和NaHCO3水溶液(100mL)。将混合物用DCM(100mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过快速色谱法(从纯的DCM至DCM/MeOH=10/1;TLC:DCM/MeOH=8/1,Rf=0.5)纯化以得到4-氨基-4-(2-乙氧基-2-氧代乙基)哌啶-1-甲酸叔丁酯(12g,33.5mmol,33.4%产率),其为棕色油状物:1H NMR(400MHz,CDCl3)δppm 4.23-4.13(m,2H),3.73-3.59(m,2H),3.42(d,J=13.5Hz,2H),2.77(s,2H),2.02-1.87(m,2H),1.79(s,2H),1.43(s,9H),1.31-1.20(m,3H);ES-LCMS m/z 287.4[M+H]+.
步骤2:2-(4-氨基哌啶-4-基)乙酸乙酯,2盐酸盐
在25℃向4-氨基-4-(2-乙氧基-2-氧代乙基)哌啶-1-甲酸叔丁酯(15g,41.9mmol)的混合物中分批添加HCl溶液(4M在EtOAc中,100mL)。然后将反应混合物在25℃搅拌0.5h。将混合物浓缩以得到2-(4-氨基哌啶-4-基)乙酸乙酯,2盐酸盐(12g,37.0mmol,88.0%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 4.27-4.15(m,2H),3.47-3.34(m,2H),3.29-3.25(m,2H),2.99(s,2H),2.27-2.12(m,4H),1.31-1.23(m,3H)。
中间体70:6-((叔丁基二甲基甲硅烷基)氧基)-4-(5-羟基嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
步骤1:N1,N2-二苄基乙烷-1,2-二胺
向乙烷-1,2-二胺(22.27mL,333mmol)和分子筛(8g,333mmol)在MeOH(400mL)中的混合物中添加苯甲醛(67.3mL,666mmol)。然后,将混合物在80℃在N2气氛搅拌4h,然后通过冰浴冷却。然后缓慢添加NaBH4(54.1g,1431mmol)且将混合物在0℃搅拌4h。饱和NH4Cl水溶液(800mL)缓慢添加至混合物。将混合物过滤且浓缩以得到残余物,将其在DCM(500mL)和饱和NaHCO3水溶液(500mL)之间分配,用DCM(500mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩。粗产物通过快速色谱法(DCM/MeOH=20:1至10/1,TLC:DCM/MeOH=10:1,Rf=0.5)纯化以得到N1,N2-二苄基乙烷-1,2-二胺(42g,140mmol,42.0%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 7.31(d,J=4.4Hz,10H),3.71(s,4H),2.71(s,4H);ES-LCMSm/z 241.3[M+H]+.
步骤2:1,4-二苄基-1,4-二氮杂环庚烷-6-醇
向N1,N2-二苄基乙烷-1,2-二胺(5g,16.64mmol)在甲苯(100mL)中的溶液中添加1,3-二溴丙-2-醇(3.81g,17.47mmol)和Et3N(4.64mL,33.3mmol)。将混合物在125℃搅拌7h。将混合物浓缩以得到残余物,将其在DCM(30mL)和H2O(20mL)之间分配,用DCM(30mLx2)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过快速色谱法(DCM/MeOH=20/1至10/1,TLC:PE/EtOAc=1:1Rf=0.5)纯化以得到淡黄色油状物的1,4-二苄基-1,4-二氮杂环庚烷-6-醇(3.8g,10.26mmol,61.6%产率):1H NMR(400MHz,CD3OD)δppm7.40-7.17(m,10H),3.85-3.78(m,1H),3.71-3.61(m,4H),2.89(dd,J=4.4,12.8Hz,2H),2.73-2.59(m,6H);ES-LCMS m/z 297.1[M+H]+.
步骤3:1,4-二氮杂环庚烷-6-醇
向1,4-二苄基-1,4-二氮杂环庚烷-6-醇(3.8g,10.26mmol)在MeOH(10mL)中的溶液中添加Pd/C(10wt%,800mg,0.752mmol)。将混合物在25℃在H2气氛(50psi)搅拌8h。将混合物过滤且浓缩以得到黄色油状物的1,4-二氮杂环庚烷-6-醇(1.2g,8.26mmol,81.0%产率):1H NMR(400MHz,CDCl3)δppm 3.80-3.73(m,1H),3.05-2.94(m,4H),2.90-2.77(m,4H),2.30(br.s,2H)。
步骤4:1-(5-(苄基氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-6-醇
向5-(苄基氧基)-2-氯嘧啶(850mg,3.66mmol)和1,4-二氮杂环庚烷-6-醇(1063mg,7.32mmol)在DMSO(100mL)中的混合物中添加DIEA(0.639mL,3.66mmol)。将混合物在130℃搅拌8h。将混合物浓缩以得到粗产物,其通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.12)纯化以得到1-(5-(苄基氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-6-醇(1g,3.06mmol,84.0%产率),其为淡黄色固体:1H NMR(400MHz,CDCl3)δ8.01(s,2H),7.35-7.20(m,5H),4.94(s,2H),4.13(td,J=4.2,8.7Hz,1H),4.03-3.76(m,4H),3.16-3.07(m,1H),3.01-2.86(m,3H);ES-LCMS m/z 301.1[M+H]+.
步骤5:4-(5-(苄基氧基)嘧啶-2-基)-6-羟基-1,4-二氮杂环庚烷-1-甲酸叔丁酯
向1-(5-(苄基氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-6-醇(1g,3.06mmol)和DIEA(1.188g,9.19mmol)在DCM(50mL)中的溶液中添加Boc2O(0.711mL,3.06mmol)。然后将反应混合物在20℃搅拌12h。添加DCM(50mL)且用柠檬酸水溶液(10%,50mL×3)洗涤。有机层用Na2SO4干燥且真空浓缩以得到4-(5-(苄基氧基)嘧啶-2-基)-6-羟基-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1g,2.460mmol,80.0%产率),其为淡黄色固体:1H NMR(400MHz,CDCl3)δppm8.02(s,2H),7.35-7.27(m,5H),4.95(s,2H),4.01(d,J=13.7Hz,1H),3.90(dd,J=6.0,14.3Hz,1H),3.78-3.66(m,1H),3.64-3.45(m,2H),3.38(dd,J=4.9,15.4Hz,1H),3.11-3.01(m,1H),2.94-2.83(m,1H),2.51(dd,J=9.0,14.3Hz,1H),1.40(s,9H);ES-LCMS m/z401.2[M+H]+.
步骤6:4-(5-(苄基氧基)嘧啶-2-基)-6-((叔丁基二甲基甲硅烷基)氧基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
向4-(5-(苄基氧基)嘧啶-2-基)-6-羟基-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1g,2.460mmol)、1H-咪唑(0.502g,7.38mmol)在DCM(100mL)中的溶液中添加TBSCl(0.741g,4.92mmol)。然后,将混合物在40℃搅拌20h。将混合物浓缩且将该反应混合物用DCM(100mL)和水(100mL)稀释,用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩。粗残余物通过快速色谱法(从PE/EtOAc=8/1至5/1,TLC:PE/EtOAc=5:1,Rf=0.5)纯化以得到4-(5-(苄基氧基)嘧啶-2-基)-6-((叔丁基二甲基甲硅烷基)氧基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1.3g,2.432mmol,99.0%产率),其为淡黄色固体:1H NMR(400MHz,CDCl3)δppm7.96(s,2H),7.32-7.19(m,5H),4.87(d,J=3.5Hz,2H),4.30-4.11(m,2H),3.86-3.75(m,1H),3.65(dd,J=3.5,14.1Hz,1H),3.24-3.11(m,1H),3.07-2.95(m,2H),2.80(dd,J=9.0,13.9Hz,1H),2.66(dd,J=9.5,13.5Hz,1H),1.25-1.15(m,9H),0.84-0.73(m,9H),0.08-0.02(m,6H);ES-LCMS m/z 515.3[M+H]+.
步骤7:6-((叔丁基二甲基甲硅烷基)氧基)-4-(5-羟基嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
向4-(5-(苄基氧基)嘧啶-2-基)-6-((叔丁基二甲基甲硅烷基)氧基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1.3g,2.432mmol)在MeOH(50mL)中的溶液中添加Pd/C(10wt%,0.259g,0.243mmol)。然后将反应混合物在20℃在H2气氛(16psi)搅拌1h。过滤后,将滤液浓缩以得到6-((叔丁基二甲基甲硅烷基)氧基)-4-(5-羟基嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1g,2.256mmol,93.0%产率),其为黄色油状物:1H NMR(400MHz,CD3OD)δppm7.99-7.92(m,2H),4.44-4.33(m,2H),4.14-3.91(m,3H),3.88-3.76(m,1H),3.15-3.03(m,2H),2.90(dt,J=4.2,13.6Hz,1H),1.30(d,J=9.3Hz,9H),0.96-0.90(m,9H),0.21-0.13(m,6H);ES-LCMS m/z 425.3[M+H]+.
中间体71:6-氟-1,4-二氮杂环庚烷
步骤1:1,4-二苄基-6-氟-1,4-二氮杂环庚烷
在0℃向1,4-二苄基-1,4-二氮杂环庚烷-6-醇(3g,8.10mmol)在DCM(50mL)中的混合物中添加DAST(1.605mL,12.15mmol)。将混合物在20℃搅拌0.5h。反应混合物在0℃通过添加饱和NaHCO3水溶液(50mL)淬灭。将混合物用DCM(50mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过快速色谱法(从EtOAc/PE=0/1至1/2,TLC:EtOAc/PE=1/3,Rf=0.5)纯化以得到1,4-二苄基-6-氟-1,4-二氮杂环庚烷(900mg,2.56mmol,31.7%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 7.31-7.18(m,10H),4.59(dd,J=4.4,9.9Hz,1H),4.10-3.96(m,2H),3.54-3.47(m,2H),2.80-2.64(m,4H),2.37-2.13(m,4H);ES-LCMS m/z 298.8[M+H]+.
步骤2:6-氟-1,4-二氮杂环庚烷
向1,4-二苄基-6-氟-1,4-二氮杂环庚烷(300mg,0.855mmol)在MeOH(10mL)中的混合物中添加Pd/C(10wt%,455mg,0.427mmol)。将混合物在50℃在H2(50psi)下搅拌12h。将混合物过滤,用MeOH(20mL x2)洗涤。将滤液浓缩以得到6-氟-1,4-二氮杂环庚烷(110mg,0.745mmol,87.0%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 4.44-4.36(m,1H),2.99-2.91(m,4H),2.83-2.34(m,4H)。
中间体72:2-乙基-4-(哌嗪-1-基)丁酸甲酯,2盐酸盐
步骤1:4-(4-甲氧基-4-氧代丁基)哌嗪-1-甲酸叔丁酯
将哌嗪-1-甲酸叔丁酯(3g,16.11mmol)、4-溴丁酸甲酯(4.37g,24.16mmol)和K2CO3(6.68g,48.3mmol)在MeCN(60mL)中的混合物在80℃搅拌6h。将混合物过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=10/1至2/1,TLC:PE/EtOAc=3/1,Rf=0.4)纯化以得到4-(4-甲氧基-4-氧代丁基)哌嗪-1-甲酸叔丁酯(4.5g,14.14mmol,88.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 3.67(s,3H),3.45-3.35(m,4H),2.36(dt,J=1.4,7.2Hz,8H),1.81(q,J=7.2Hz,2H),1.46(s,9H);ES-LCMSm/z287.2[M+H]+.
步骤2:4-(3-(甲氧基羰基)戊基)哌嗪-1-甲酸叔丁酯
在-78℃向二异丙基胺(1.792mL,12.57mmol)在THF(50mL)中的混合物滴加n-BuLi(2.5M在己烷中,5.03mL,12.57mmol)。然后将混合物在-78℃搅拌0.5h。在-78℃在N2气氛将4-(4-甲氧基-4-氧代丁基)哌嗪-1-甲酸叔丁酯(2g,6.29mmol)滴加至混合物。然后将混合物在0℃在N2气氛搅拌0.5h。在-78℃将碘乙烷(1.524mL,18.86mmol)添加至混合物。然后将混合物在26℃在N2气氛搅拌7h。混合物在0℃通过添加饱和NH4Cl水溶液(20mL)淬灭。将混合物用EtOAc(100mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=5/1至2/1,TLC:PE/EtOAc=5/1,Rf=0.6)纯化以得到4-(3-(甲氧基羰基)戊基)哌嗪-1-甲酸叔丁酯(1.5g,4.29mmol,68.3%产率),其为淡黄色油状物。1H NMR(400MHz,CDCl3)δppm 3.65(s,3H),3.37(d,J=4.0Hz,4H),2.37-2.20(m,7H),1.68-1.49(m,4H),1.43(s,9H),0.87(t,J=7.4Hz,3H);ES-LCMS m/z 315.3[M+H]+.
步骤3:2-乙基-4-(哌嗪-1-基)丁酸甲酯,2盐酸盐
在26℃向4-(3-(甲氧基羰基)戊基)哌嗪-1-甲酸叔丁酯(500mg,1.431mmol)在EtOAc(10mL)中的溶液中添加HCl溶液(4M在EtOAc中)(5mL,20.00mmol)。然后将混合物在26℃搅拌0.5h。将混合物浓缩以得到2-乙基-4-(哌嗪-1-基)丁酸甲酯,2盐酸盐(450mg,1.332mmol,93.0%产率),其为浅色固体:1H NMR(400MHz,CD3OD)δppm 4.17-3.39(m,11H),3.28-3.18(m,2H),2.53-2.41(m,1H),2.16-1.90(m,2H),1.77-1.57(m,2H),0.92(t,J=7.4Hz,3H);ES-LCMS m/z 215.1[M+H]+.
中间体73:4,7-二氮杂螺[2.5]辛烷-4-甲酸叔丁酯
步骤1:1-((叔丁氧基羰基)氨基)环丙烷羧酸
向1-氨基环丙烷羧酸(30g,297mmol)和四甲基氢氧化铵(27.0g,297mmol)在MeCN(400mL)中的溶液中添加Boc2O(130g,593mmol)。然后将反应混合物在15℃搅拌24h。将混合物浓缩且溶于EtOAc(500mL)。将混合物用饱和柠檬酸溶液(200mL x2)洗涤。有机相用Na2SO4干燥,浓缩以得到1-((叔丁氧基羰基)氨基)环丙烷羧酸(30g,142mmol,47.7%产率),其为白色固体:1H NMR(400MHz,DMSO-d6)δppm 12.26(br.s.,1H),7.40(s,1H),1.37(s,9H),1.29-1.22(m,2H),1.02-0.89(m,2H);ES-LCMSm/z 146.1[M-t-Bu+H]+.
步骤2:2-(N-苄基-1-((叔丁氧基羰基)氨基)环丙烷甲酰氨基)乙酸乙酯
向2-(苄基氨基)乙酸乙酯(27.4g,142mmol)、EDC(32.6g,170mmol)、HOBt(26.0g,170mmol)和1-((叔丁氧基羰基)氨基)环丙烷羧酸(30g,142mmol)在DMF(500mL)中的溶液中添加DIEA(124mL,708mmol)。然后将反应混合物在15℃搅拌12h。将混合物浓缩且溶于DCM(1L)。将混合物用饱和柠檬酸溶液(500mL x2)和10%NaOH水溶液(500mL)洗涤。有机相用Na2SO4干燥,浓缩以得到2-(N-苄基-1-((叔丁氧基羰基)氨基)环丙烷甲酰氨基)乙酸乙酯(40g,94mmol,66.7%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 7.38-7.27(m,3H),7.21(d,J=7.0Hz,2H),5.30-4.49(m,4H),4.19-4.14(m,2H),1.35(s.,9H),1.27-1.23(m,3H),1.23-0.76(m,4H);ES-LCMS m/z 321.1[M-t-Bu+H]+.
步骤3:(1-((苄基(2-羟基乙基)氨基)甲基)环丙基)氨基甲酸叔丁酯
将2-(N-苄基-1-((叔丁氧基羰基)氨基)环丙烷甲酰氨基)乙酸乙酯(15g,35.4mmol)在THF(100mL)中的溶液滴加至LiAlH4(13.45g,354mmol)在THF(400mL)中的混合物中。然后将反应混合物在0℃搅拌1h。向溶液添加H2O(13.5mL)、10%NaOH水溶液(13.5mL)和H2O(40.5mL)。然后将混合物过滤且浓缩以得到粗产物,其通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.53)纯化以得到(1-((苄基(2-羟基乙基)氨基)甲基)环丙基)氨基甲酸叔丁酯(3.75g,11.7mmol,22.5%产率),其为棕色油状物:1HNMR(400MHz,CDCl3)δppm7.37-7.22(m,5H),3.75-3.64(m,2H),3.59(t,J=5.1Hz,2H),2.80-2.68(m,2H),2.61(s,2H),1.44(s,9H),0.84-0.74(m,2H),0.65-0.52(m,2H);ES-LCMSm/z 321.3[M+H]+.
步骤4:2-(((1-氨基环丙基)甲基)(苄基)氨基)乙醇
将(1-((苄基(2-羟基乙基)氨基)甲基)环丙基)氨基甲酸叔丁酯(10g,28.1mmol)溶于HCl溶液(4M在EtOAc中,50mL,200mmol)。将混合物在20℃搅拌0.5h。将混合物浓缩且溶于DCM(100mL)。将混合物用饱和NaHCO3水溶液(50mL)洗涤且用Na2SO4干燥,浓缩以得到2-(((1-氨基环丙基)甲基)(苄基)氨基)乙醇(6g,24.51mmol,87.0%产率),其为棕色油状物:1HNMR(400MHz,CDCl3)δppm 6.98-6.86(m,5H),3.37-3.30(m,2H),3.25(t,J=5.1Hz,2H),2.35(t,J=4.9Hz,2H),2.10(s,2H),0.32-0.14(m,2H),0.06-0.07(m,2H);ES-LCMS m/z221.1[M+H]+.
步骤5:7-苄基-4,7-二氮杂螺[2.5]辛烷
向2-(((1-氨基环丙基)甲基)(苄基)氨基)乙醇(6g,24.51mmol)和PPh3(9.64g,36.8mmol)在THF(50mL)中的溶液中添加DIAD(7.15mL,36.8mmol)。然后将反应混合物在15℃在N2气氛搅拌8h。将混合物用EtOAc(100mL)稀释,且用饱和NaHCO3水溶液(50mL)洗涤。然后有机相在EtOAc(150mL)和1N HCl溶液(50mL)之间分配。水相用NaOH固体调节至pH=9且用EtOAc(200mL x2)萃取。合并的有机相用Na2SO4干燥,浓缩以得到7-苄基-4,7-二氮杂螺[2.5]辛烷(7g,20.76mmol,85.0%产率),其为棕色油状物:1H NMR(400MHz,CDCl3)δppm7.38-7.25(m,5H),3.49(s,2H),2.97(t,J=4.9Hz,2H),2.55-2.37(m,2H),2.22(s,2H),0.65-0.54(m,2H),0.48-0.36(m,2H)。
步骤6:7-苄基-4,7-二氮杂螺[2.5]辛烷-4-甲酸叔丁酯
向7-苄基-4,7-二氮杂螺[2.5]辛烷(7g,20.76mmol)和DIEA(14.50mL,83mmol)在DCM(200mL)中的溶液中添加Boc2O(9.64mL,41.5mmol)。然后将反应混合物在15℃搅拌8h。将混合物浓缩且通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.7)纯化以得到7-苄基-4,7-二氮杂螺[2.5]辛烷-4-甲酸叔丁酯(6g,17.86mmol,86.0%产率),其为棕色固体:1H NMR(400MHz,CDCl3)δppm 7.37-7.24(m,5H),3.64-3.52(m,2H),3.47(s,2H),2.47(s.,2H),2.20(s.,2H),1.52-1.43(m,9H),0.95(s.,2H),0.67(s.,2H);ES-LCMS m/z 303.3[M+H]+.
步骤7:4,7-二氮杂螺[2.5]辛烷-4-甲酸叔丁酯
在N2气氛向7-苄基-4,7-二氮杂螺[2.5]辛烷-4-甲酸叔丁酯(6g,17.86mmol)在MeOH(50mL)中的溶液中添加Pd/C(10wt%,1.900g,1.786mmol)。然后将反应混合物在15℃在H2气氛(15psi)搅拌8h。将混合物过滤且浓缩以得到4,7-二氮杂螺[2.5]辛烷-4-甲酸叔丁酯(3.9g,16.53mmol,93.0%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 3.60-3.37(m,2H),2.83(d,J=4.4Hz,2H),2.64(s.,2H),1.51-1.38(m,9H),1.05-0.85(m,2H),0.70(s.,2H);ES-LCMS m/z 303.3[M+H]+.
中间体74:2,2,3,3,9,9,10,10-八甲基-4,8-二氧杂-3,9-二硅杂十一烷(disilaundecan)-6-酮
向1,3-二羟基丙-2-酮(5g,55.5mmol)和1H-咪唑(11.34g,167mmol)在DCM(80mL)中的溶液中添加TBSCl(16.73g,111mmol)。然后,将混合物在40℃搅拌16h。向该混合物中添加饱和NH4Cl水溶液(30mL),用DCM(80mL x2)萃取。合并的有机层用盐水(30mL)洗涤且用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=10:1,TLC PE/EtOAc=10:1,Rf=0.7)纯化以得到无色油状物的2,2,3,3,9,9,10,10-八甲基-4,8-二氧杂-3,9-二硅杂十一烷-6-酮(7.277g,18.27mmol,32.9%产率):1H NMR(400MHz,CDCl3)δppm4.40(s,4H),0.91(s,18H),0.08(s,12H)。
中间体75:(1-(5-(苄基氧基)嘧啶-2-基)-4-(羟基甲基)哌啶-4-基)氨基甲酸叔丁酯
步骤1:4-氨基哌啶-4-甲酸甲酯,2盐酸盐
将4-氨基-1-(叔丁氧基羰基)哌啶-4-甲酸(3g,12.28mmol)在HCl溶液(4M在MeOH中)(50mL,200mmol)中的混合物在80℃搅拌1h。然后将混合物浓缩以得到4-氨基哌啶-4-甲酸甲酯,2盐酸盐(2.8g,11.51mmol,94.0%产率),其为灰白色固体:1H NMR(400MHz,CD3OD)δppm 3.91(s,3H),3.53-3.46(m,2H),3.44-3.35(m,2H),2.47(d,J=14.8Hz,2H),2.23(ddd,J=4.6,10.9,14.9Hz,2H);ES-LCMS m/z 159.2[M+H]+.
步骤2:4-氨基-1-(5-(苄基氧基)嘧啶-2-基)哌啶-4-甲酸甲酯
将4-氨基哌啶-4-甲酸甲酯,2盐酸盐(2.8g,11.51mmol)、5-(苄基氧基)-2-氯嘧啶(3.17g,13.81mmol)和DIEA(8.04mL,46.0mmol)在DMSO(30mL)中的混合物在120℃在N2气氛搅拌12h。然后添加水(50mL)。将混合物用DCM(150mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到粗物质。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.4)纯化以得到4-氨基-1-(5-(苄基氧基)嘧啶-2-基)哌啶-4-甲酸甲酯(1.5g,3.94mmol,34.3%产率),其为棕色油状物:1H NMR(400MHz,CDCl3)δppm 8.09(s,2H),7.40-7.28(m,5H),4.99(s,2H),3.99(td,J=4.8,13.5Hz,2H),3.71(s,3H),3.65(ddd,J=3.3,9.8,13.3Hz,2H),2.05(ddd,J=4.1,9.7,13.6Hz,2H),1.57-1.50(m,2H);ES-LCMS m/z 343.4[M+H]+.
步骤3:(4-氨基-1-(5-(苄基氧基)嘧啶-2-基)哌啶-4-基)甲醇
在0℃向4-氨基-1-(5-(苄基氧基)嘧啶-2-基)哌啶-4-甲酸甲酯(1.5g,3.94mmol)在THF(20mL)中的溶液中添加LiAlH4(0.299g,7.89mmol)。然后将混合物在0℃在N2气氛搅拌1h。然后将混合物用2M NaOH水溶液(3mL)淬灭。然后将混合物过滤且浓缩以得到(4-氨基-1-(5-(苄基氧基)嘧啶-2-基)哌啶-4-基)甲醇(1.2g,3.44mmol,87.0%产率),其为灰白色固体:1H NMR(400MHz,CDCl3)δppm 8.04(s,2H),7.35-7.25(m,5H),4.94(s,2H),4.02-3.94(m,2H),3.44(ddd,J=3.4,9.9,13.6Hz,2H),3.32(s,2H),1.59-1.52(m,2H),1.45-1.38(m,2H);ES-LCMS m/z 315.3[M+H]+.
步骤4:(1-(5-(苄基氧基)嘧啶-2-基)-4-(羟基甲基)哌啶-4-基)氨基甲酸叔丁酯
在20℃向(4-氨基-1-(5-(苄基氧基)嘧啶-2-基)哌啶-4-基)甲醇(550mg,1.575mmol)在DCM(10mL)中的溶液中添加DIEA(0.550mL,3.15mmol)和Boc2O(0.731mL,3.15mmol)。然后将混合物在20℃搅拌12h。然后将混合物浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=1/1,TLC:PE/EtOAc=1/1,Rf=0.5)纯化以得到(1-(5-(苄基氧基)嘧啶-2-基)-4-(羟基甲基)哌啶-4-基)氨基甲酸叔丁酯(500mg,1.113mmol,70.7%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 8.10(s,2H),7.40-7.28(m,5H),5.00(s,2H),4.10(td,J=4.5,13.8Hz,2H),3.71(d,J=5.7Hz,2H),3.35(ddd,J=3.1,10.4,13.6Hz,2H),1.93(d,J=13.9Hz,2H),1.67(ddd,J=4.2,10.1,13.9Hz,2H),1.42(s,9H);ES-LCMS m/z:415.2[M+H]+.
中间体76:2-甲基-2-(哌啶-4-基氧基)丙酸乙酯
步骤1:4-羟基哌啶-1-甲酸苄基酯
向哌啶-4-醇(7g,69.2mmol)、NaOH(8.30g,208mmol)在1,4-二噁烷(100mL)和H2O(100mL)中的混合物中添加氯甲酸苄酯(23.61g,138mmol)。然后,将混合物在20℃搅拌16h。将混合物用DCM(200mL)和水(200mL)稀释,用DCM(200mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩。粗产物通过快速色谱法(从纯的PE至PE/EtOAc=1/1,TLC:PE/EtOAc=1/1,Rf=0.3)纯化以得到4-羟基哌啶-1-甲酸苄基酯(13g,49.7mmol,71.9%产率),其为棕色油状物:1H NMR(400MHz,CDCl3)δppm 7.40-7.25(m,5H),5.12(s,2H),3.96-3.82(m,3H),3.14(ddd,J=3.2,9.8,13.3Hz,2H),1.85(br s,2H),1.48(d,J=8.6Hz,2H);ES-LCMSm/z 236.2[M+H]+.
步骤2:4-((1-乙氧基-2-甲基-1-氧代丙-2-基)氧基)哌啶-1-甲酸苄基酯
在0℃在N2气氛向4-羟基哌啶-1-甲酸苄基酯(4g,15.30mmol)在DMF(20mL)中的混合物中添加60%NaH(0.918g,22.95mmol)。溶液在0℃搅拌30min。然后,2-溴-2-甲基丙酸乙酯(4.48g,22.95mmol)添加至混合物且将混合物在100℃在N2气氛搅拌11.5h。将反应混合物浓缩且该反应混合物用DCM(100mL)和水(100mL)稀释,用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩。粗产物通过快速色谱法(从纯的PE至PE/EtOAc=3/1,TLC:PE/EtOAc=3/1,Rf=0.7)纯化以得到4-((1-乙氧基-2-甲基-1-氧代丙-2-基)氧基)哌啶-1-甲酸苄基酯(2g,1.145mmol,7.48%产率),其为棕色油状物:1H NMR(400MHz,DMSO-d6)δppm 7.41-7.38(m,5H),5.10-5.09(m,2H),4.19-3.99(m,2H),3.65-3.61(m,3H),3.42-3.39(m,2H),1.89(s,6H),1.86(d,J=3.5Hz,2H),1.61-1.58(m,2H),1.25-1.16(m,3H);ES-LCMSm/z 350.2[M+H]+.
步骤3:2-甲基-2-(哌啶-4-基氧基)丙酸乙酯
在N2气氛向4-((1-乙氧基-2-甲基-1-氧代丙-2-基)氧基)哌啶-1-甲酸苄基酯(2000mg,1.145mmol)在EtOH(50mL)中的混合物中添加Pd/C(10wt%,365mg,0.343mmol)。将混合物在20℃在H2气氛(40psi)搅拌10h。然后将溶液过滤且浓缩以得到2-甲基-2-(哌啶-4-基氧基)丙酸乙酯(1g,0.929mmol,81.0%产率),其为无色油状物:1H NMR(400MHz,CDCl3)δppm4.28-4.07(m,2H),3.09(br s,3H),2.85-2.82(m,2H),1.97-1.94(m,2H),1.68-1.65(m,2H),1.41(br s,6H),1.33-1.27(m,3H);ES-LCMSm/z 216.2[M+H]+.
中间体77:1-(哌啶-4-基氧基)环丙烷羧酸,三氟乙酸盐
步骤1:4-溴哌啶-1-甲酸叔丁酯
向4-羟基哌啶-1-甲酸叔丁酯(20g,99mmol)和CBr4(33.0g,99mmol)在DCM(200mL)中的混合物中添加PPh3(26.1g,99mmol)。溶液在20℃搅拌5h。将溶液浓缩且通过快速色谱法(从PE/EtOAc=50/1至3/1,TLC:PE/EtOAc=3/1,Rf=0.6)纯化以得到4-溴哌啶-1-甲酸叔丁酯(14g,47.7mmol,48.0%产率),其为无色油状物:1H NMR(400MHz,CDCl3)δppm 4.38-4.24(m,1H),3.75-3.54(m,2H),3.35-3.18(m,2H),2.19-1.97(m,2H),1.97-1.78(m,2H),1.57-1.29(m,9H);ES-LCMS m/z 208.1,210.1[M-t-Bu+H]+.
步骤2:1-((1-(叔丁氧基羰基)哌啶-4-基)氧基)环丙烷羧酸
在0℃在N2气氛向1-羟基环丙烷羧酸(1.5g,14.69mmol)在DMF(50mL)中的混合物中添加60%NaH(1.293g,32.3mmol)。溶液在0℃搅拌30分钟。然后,将4-溴哌啶-1-甲酸叔丁酯(4.31g,14.69mmol)和KI(7.32g,44.1mmol)添加至混合物且将混合物在30℃在N2气氛搅拌11.5h。将反应混合物浓缩。混合物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,且冻干以得到1-((1-(叔丁氧基羰基)哌啶-4-基)氧基)环丙烷羧酸,其为白色固体(300mg,0.841mmol,5.72%产率):1H NMR(400MHz,CD3OD)δppm 3.63(d,J=4.9Hz,2H),3.26-3.19(m,1H),2.11(dd,J=4.9,14.3Hz,1H),1.97-1.81(m,3H),1.66-1.56(m,2H),1.45(s,9H),1.29-1.25(m,2H),1.08-1.01(m,2H);ES-LCMS m/z 308.2[M+Na]+
步骤3:1-(哌啶-4-基氧基)环丙烷羧酸,三氟乙酸盐
向1-((1-(叔丁氧基羰基)哌啶-4-基)氧基)环丙烷羧酸(300mg,0.841mmol)在DCM(10mL)中的混合物中添加TFA(5mL,64.9mmol)。然后将混合物在20℃搅拌30分钟,然后浓缩以得到1-(哌啶-4-基氧基)环丙烷羧酸,三氟乙酸盐(280mg,0.655mmol,78.0%产率),其为黄色固体:1H NMR(400MHz,CD3OD)δppm 3.97-3.95(m,1H),3.38(br s,2H),3.12(br s,2H),2.01(d,J=3.5Hz,2H),1.77(d,J=3.5Hz,2H),1.25-1.21(m,2H),1.06-1.02(m,2H)。
中间体78:4-(5-羟基-4-甲基嘧啶-2-基)哌嗪-1-甲酸叔丁酯
步骤1:2-氯-5-甲氧基-4-甲基嘧啶
向2,4,6-三甲基-1,3,5,2,4,6-三氧杂三硼杂环己烷(5.26g,41.9mmol)和2,4-二氯-5-甲氧基嘧啶(5g,27.9mmol)在THF(100mL)中的溶液中添加K3PO4(11.86g,55.9mmol)和Pd(PPh3)2Cl2(1.961g,2.79mmol)。然后将混合物在80℃在N2气氛搅拌16h。将混合物浓缩以得到残余物。然后将残余物溶于水(50mL)。将混合物用EtOAc(100mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=50/1至4/1,TLC:PE/EtOAc=5/1,Rf=0.7)纯化以得到2-氯-5-甲氧基-4-甲基嘧啶(2g,12.11mmol,43.3%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 8.05(s,1H),3.92(s,3H),2.53-2.40(m,3H);ES-LCMS m/z 159.0,161.0[M+H]+.
步骤2:4-(5-甲氧基-4-甲基嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向哌嗪-1-甲酸叔丁酯(7.89g,42.4mmol)和2-氯-5-甲氧基-4-甲基嘧啶(2.8g,16.95mmol)在DMSO(50mL)中的溶液中添加DIEA(8.88mL,50.8mmol)。将混合物在120℃在N2气氛搅拌8h。向混合物中添加水(80mL)。将混合物用EtOAc(100mL×3)萃取。合并的有机层用盐水(60mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=20/1至2/1,TLC:PE/EtOAc=3/1,Rf=0.6)纯化以得到4-(5-甲氧基-4-甲基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(4g,11.67mmol,68.9%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 7.89(s,1H),3.78(s,3H),3.72-3.65(m,4H),3.48(dd,J=4.1,6.1Hz,4H),2.32(s,3H),1.48(s,9H);ES-LCMS m/z 309.2[M+H]+.
步骤3:4-甲基-2-(哌嗪-1-基)嘧啶-5-醇
在-78℃在N2气氛向4-(5-甲氧基-4-甲基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(3.5g,10.21mmol)在DCM(100mL)中的溶液中滴加BBr3(3.86mL,40.9mmol)。然后将混合物在26℃在N2气氛搅拌8h。混合物在-78℃用MeOH(20mL)淬灭。将混合物浓缩以得到4-甲基-2-(哌嗪-1-基)嘧啶-5-醇(4.5g,9.27mmol,91.0%产率),其为红色固体:1H NMR(400MHz,CD3OD)δppm 7.94-7.69(m,1H),4.18-4.10(m,4H),3.50-3.42(m,4H),2.56(s,3H);ES-LCMS m/z195.3[M+H]+.
步骤4:4-(5-((叔丁氧基羰基)氧基)-4-甲基嘧啶-2-基)哌嗪-1-甲酸叔丁酯
在26℃向4-甲基-2-(哌嗪-1-基)嘧啶-5-醇(4.5g,9.27mmol)和DIEA(4.86mL,27.8mmol)在DCM(20mL)中的溶液中分批添加Boc2O(3.23mL,13.90mmol)。然后将混合物在26℃搅拌8h。将混合物浓缩以得到残余物。粗物质通过快速色谱法(从PE/EtOAc=10/1至3/1,TLC:PE/EtOAc=3/1,Rf=0.7)纯化以得到4-(5-((叔丁氧基羰基)氧基)-4-甲基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(3.8g,9.15mmol,99.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 8.02(s,1H),3.81-3.66(m,4H),3.50-3.38(m,4H),2.26(s,3H),1.53(s,9H),1.47(s,9H);ES-LCMS m/z 395.2[M+H]+.
步骤5:4-(5-羟基-4-甲基嘧啶-2-基)哌嗪-1-甲酸叔丁酯
将4-(5-((叔丁氧基羰基)氧基)-4-甲基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(3.8g,9.15mmol)和K2CO3(6.32g,45.8mmol)在MeOH(50mL)中的混合物在26℃搅拌1h。将混合物过滤且浓缩以得到4-(5-羟基-4-甲基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(2.7g,8.90mmol,97.0%产率),其为黄色固体:1H NMR(400MHz,CD3OD)δppm 7.81-7.53(m,1H),3.50-3.39(m,8H),2.29(s,3H),1.46(s,9H);ES-LCMS m/z 295.2[M+H]+.
中间体79:3-((叔丁基二甲基甲硅烷基)氧基)-3-甲基环丁酮
步骤1:3-(苄基氧基)-1-甲基环丁醇
在-78℃在N2气氛向3-(苄基氧基)环丁酮(1g,5.67mmol)在甲苯(10mL)和THF(1mL)中的溶液中添加MeMgBr(3M的乙醚溶液,2.84mL,8.51mmol)。然后将反应混合物在-78℃搅拌1h。混合物通过饱和NH4Cl水溶液(50mL)淬灭。将混合物用DCM(150mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=1/1,TLC:PE/EtOAc=3/1,Rf=0.3)纯化以得到3-(苄基氧基)-1-甲基环丁醇(850mg,3.98mmol,70.1%产率),其为无色液体:1H NMR(400MHz,CDCl3)δppm 7.36-7.29(m,5H),4.42-4.38(m,2H),3.71(五重峰,J=6.8Hz,1H),2.47-2.38(m,2H),2.12-2.04(m,2H),1.29(s,3H)。
步骤2:(3-(苄基氧基)-1-甲基环丁氧基)(叔丁基)二甲基硅烷
在20℃向3-(苄基氧基)-1-甲基环丁醇(0.85g,3.98mmol)在DCM(15mL)中的溶液中添加咪唑(0.813g,11.94mmol)和TBSCl(1.799g,11.94mmol)。然后将混合物在20℃搅拌12h。然后添加水(50mL)。将混合物用DCM(100mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=1/1,TLC:PE/EtOAc=3/1,Rf=0.7)纯化以得到(3-(苄基氧基)-1-甲基环丁氧基)(叔丁基)二甲基硅烷(1g,2.94mmol,73.8%产率),其为无色油状物:1H NMR(400MHz,CDCl3)δppm 7.28-7.20(m,5H),4.35-4.30(m,2H),3.59(q,J=6.9Hz,1H),2.34-2.26(m,2H),2.11-2.02(m,2H),1.21(s,3H),0.82-0.79(m,9H),0.00(s,6H)。
步骤3:3-((叔丁基二甲基甲硅烷基)氧基)-3-甲基环丁醇
在N2气氛向(3-(苄基氧基)-1-甲基环丁氧基)(叔丁基)二甲基硅烷(1g,2.94mmol)在MeOH(30mL)中的溶液中添加Pd/C(10wt%,0.625g,0.587mmol)。然后将混合物在50℃在H2气氛(50psi)搅拌12h。将混合物过滤且将滤液浓缩以得到3-((叔丁基二甲基甲硅烷基)氧基)-3-甲基环丁醇(0.7g,2.91mmol,99.0%产率),其为无色油状物:1H NMR(400MHz,CDCl3)δppm 3.91-3.80(m,1H),2.42-2.35(m,2H),2.04-1.94(m,2H),1.22(s,3H),0.83-0.80(m,9H),0.01-0.00(m,6H)。
步骤4:3-((叔丁基二甲基甲硅烷基)氧基)-3-甲基环丁酮
向3-((叔丁基二甲基甲硅烷基)氧基)-3-甲基环丁醇(500mg,2.080mmol)在DCM(10mL)中的溶液中添加Dess-Martin(1323mg,3.12mmol)。然后将混合物在20℃在N2气氛搅拌12h。混合物通过饱和NaHCO3水溶液(50mL)淬灭。将混合物用DCM(100mL×3)萃取。合并的有机层用盐水(30mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=1/1,TLC:PE/EtOAc=3/1,Rf=0.7)纯化以得到3-((叔丁基二甲基甲硅烷基)氧基)-3-甲基环丁酮(400mg,1.679mmol,81.0%产率),其为棕色油状物:1H NMR(400MHz,CDCl3)δppm 3.12-3.03(m,2H),2.89-2.80(m,2H),1.48(s,3H),0.77(s,9H),0.00(s,6H);ES-LCMS m/z:214.5[M+H]+.
中间体80:二甲基(哌啶-4-基)氧化膦
步骤1:4-(二甲基磷酰基)-4-羟基哌啶-1-甲酸苄基酯
向4-氧代哌啶-1-甲酸苄基酯(1g,4.29mmol)和二甲基氧化膦(0.402g,5.14mmol)在i-PrOH(20mL)中的溶液中添加Et3N(1.301g,12.86mmol)。然后将反应混合物在90℃搅拌10h。添加H2O(30mL)且用DCM(30mL x2)萃取。合并的有机层用Na2SO4干燥且浓缩。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.3)纯化以得到4-(二甲基磷酰基)-4-羟基哌啶-1-甲酸苄基酯(600mg,1.725mmol,40.2%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 7.38-7.27(m,5H),5.12(s,2H),4.11(d,J=7.1Hz,2H),3.26(br s,2H),1.84-1.75(m,2H),1.66(br s,2H),1.45(s,3H),1.42(s,3H);ES-LCMSm/z312.2[M+H]+.
步骤2:4-(二甲基磷酰基)-5,6-二氢吡啶-1(2H)-甲酸苄基酯
在20℃向4-(二甲基磷酰基)-4-羟基哌啶-1-甲酸苄基酯(300mg,0.862mmol)在DCM(5mL)中的混合物中添加DAST(0.228mL,1.725mmol)。然后,将混合物在20℃在N2气氛搅拌3h。反应混合物在0℃通过添加饱和NaHCO3水溶液(20mL)淬灭。将混合物用DCM(20mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(DCM/MeOH=30/1至10/1,TLC:DCM/MeOH=10/1,Rf=0.6)纯化以得到4-(二甲基磷酰基)-5,6-二氢吡啶-1(2H)-甲酸苄基酯(120mg,0.368mmol,42.7%产率),其为黄色油状物:1HNMR(400MHz,CDCl3)δppm 7.37-7.29(m,5H),6.60-6.52(m,1H),5.17-5.13(m,2H),4.13(q,J=3.0Hz,2H),3.63(t,J=5.4Hz,2H),2.30-2.22(m,2H),1.52(s,3H),1.49(s,3H);ES-LCMS m/z 294.2[M+H]+.
步骤3:二甲基(哌啶-4-基)氧化膦
将4-(二甲基磷酰基)-5,6-二氢吡啶-1(2H)-甲酸苄基酯(120mg,0.368mmol)和Pd/C(10wt%,392mg,0.368mmol)在MeOH(10mL)中的混合物在20℃在H2气氛(15psi)搅拌1h。将混合物过滤且将滤液浓缩以得到二甲基(哌啶-4-基)氧化膦(70mg,0.304mmol,83.0%产率),其为棕色油状物:1H NMR(400MHz,CD3OD)δppm 3.15-3.08(m,2H),3.01-2.96(m,2H),2.64-2.60(m,1H),1.92-1.85(m,4H),1.50(s,3H),1.47(s,3H)。
中间体81:N-((1R,7S,8r)-4-氮杂双环[5.1.0]辛-8-基)甲磺酰胺,三氟乙酸盐
步骤1:(1R,7S,8r)-8-(甲基磺酰氨基)-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯
在25℃向(1R,7S,8r)-8-氨基-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯,盐酸盐(750mg,2.022mmol)在DCM(10mL)中的溶液中添加DIEA(653mg,5.05mmol)和MsCl(278mg,2.426mmol)。然后将混合物在25℃搅拌12h。将混合物浓缩以得到粗产物,其通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,Rf=0.55(DCM/MeOH=10/1))纯化以得到淡黄色油状物(1R,7S,8r)-8-(甲基磺酰氨基)-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯(760mg,1.797mmol,89.0%产率):1H NMR(400MHz,CDCl3)δppm 7.39-7.28(m,5H),5.10(s,2H),3.76-3.57(m,2H),3.29-3.16(m,2H),3.00-2.93(m,3H),2.44-2.24(m,3H),1.52(s,2H),1.41-1.26(m,2H);ES-LCMSm/z 338.9[M+H]+.
步骤2:N-((1R,7S,8r)-4-氮杂双环[5.1.0]辛-8-基)甲磺酰胺,三氟乙酸盐
将(1R,7S,8r)-8-(甲基磺酰氨基)-4-氮杂双环[5.1.0]辛烷-4-甲酸苄基酯(360mg,1.064mmol)在TFA(5mL,64.9mmol)中的混合物在50℃搅拌1.5h。将混合物浓缩以得到N-((1R,7S,8r)-4-氮杂双环[5.1.0]辛-8-基)甲磺酰胺,三氟乙酸盐(335mg,0.842mmol,99.0%产率),其为淡黄色油状物:1H NMR(400MHz,CD3OD)δppm 3.37(dd,J=5.84,13.56Hz,2H),3.10(t,J=12.02Hz,2H),2.97-2.91(m,3H),2.55-2.42(m,3H),1.53-1.33(m,4H)。
中间体82:2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯
步骤1:4-氰基哌啶-1,4-二甲酸1-叔丁基4-乙基酯
在N2气氛向冷却至-78℃的4-氰基哌啶-1-甲酸叔丁酯(45g,214mmol)在THF(1L)中的溶液中滴加LiHMDS(1M在THF中,364mL,364mmol。然后溶液在-78℃搅拌0.5h。然后滴加氯甲酸乙酯(34.8g,321mmol)。将溶液温热至20℃且搅拌2h。将混合物通过添加饱和NH4Cl水溶液(1L)淬灭。将混合物浓缩以去除THF。残余物用DCM(1L x2)萃取。合并的有机层用盐水(500mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到4-氰基哌啶-1,4-二甲酸1-叔丁基4-乙基酯(48g,119mmol,55.6%产率),其为棕色油状物:1H NMR(400MHz,CDCl3)δppm 4.11(q,J=7.1Hz,2H),4.00-3.89(m,2H),2.94(s,2H),1.92-1.84(m,2H),1.82-1.74(m,2H),1.28(s,9H),1.16(t,J=7.2Hz,3H);ES-LCMS m/z 183.2[M-Boc+H]+.
步骤2:4-氰基-4-(羟基甲基)哌啶-1-甲酸叔丁酯
向4-氰基哌啶-1,4-二甲酸1-叔丁基4-乙基酯(48g,119mmol)在MeOH(1L)中的溶液中分批添加NaBH4(11.26g,298mmol)。溶液在20℃搅拌1.5h。将混合物用饱和NH4Cl溶液(500mL)淬灭,然后浓缩。然后粗产物在DCM(500mL)和饱和NaHCO3水溶液(500mL)之间分配。合并的有机萃取物用盐水(200mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到4-氰基-4-(羟基甲基)哌啶-1-甲酸叔丁酯(40g,117mmol,98.0%产率),其为棕色固体:1H NMR(400MHz,CD3OD)δppm 4.12(d,J=13.9Hz,2H),3.56(s,2H),3.13-2.88(m,2H),1.89(d,J=13.5Hz,2H),1.46-1.43(m,11H);ES-LCMS m/z 141.2[M-Boc+H]+.
步骤3:4-氰基-4-((甲苯磺酰基氧基)甲基)哌啶-1-甲酸叔丁酯
向4-氰基-4-(羟基甲基)哌啶-1-甲酸叔丁酯(33g,96mmol)和Et3N(19.45g,192mmol)在DCM(300mL)中的溶液中添加DMAP(1.174g,9.61mmol)和4-甲基苯-1-磺酰氯(21.99g,115mmol)。将混合物在20℃搅拌10h。然后溶液用水(500mL×3)洗涤。有机层用Na2SO4干燥,过滤且浓缩。粗产物通过快速色谱法(从纯的PE至PE/EtOAc=3/1;TLC:PE/EtOAc=3/1,Rf=0.6)纯化以得到4-氰基-4-((甲苯磺酰基氧基)甲基)哌啶-1-甲酸叔丁酯(22g,50.2mmol,52.2%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 7.79(d,J=8.2Hz,2H),7.36(d,J=8.4Hz,2H),4.20-4.07(m,2H),3.96(s,2H),2.98(s,2H),2.45(s,3H),1.87(d,J=13.5Hz,2H),1.49-1.44(m,2H),1.43(s,9H);ES-LCMS m/z 295.2[M-Boc+H]+.
步骤4:2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯
向冷却至0℃的LiAlH4(0.173g,4.56mmol)在THF(20mL)中的悬浮液中分批添加4-氰基-4-((甲苯磺酰基氧基)甲基)哌啶-1-甲酸叔丁酯(1g,2.281mmol)。将混合物在0℃搅拌1h。随后添加水(0.2mL)和1N NaOH(0.2mL)。过滤后,将滤液浓缩以得到2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯(700mg,1.547mmol,67.8%产率),其为白色固体:1H NMR(400MHz,CD3OD)δppm 3.40-3.30(m,8H),1.71-1.67(m,4H),1.42(s,9H);ES-LCMS m/z171.2[M-t-Bu+H]+.
实施例
实施例1:2-(4-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌嗪-1-基)-N-甲基乙酰胺,5盐酸盐
步骤1:4-(5-((6-(3,5-二氯苯基)-4-((4-(2-(甲基氨基)-2-氧代乙基)哌嗪-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(600mg,0.984mmol)和K2CO3(272mg,1.969mmol)在DMF(20mL)中的溶液中添加N-甲基-2-(哌嗪-1-基)乙酰胺(186mg,1.181mmol)。将反应混合物在80℃搅拌12h。将固体过滤掉且将混合物浓缩以得到粗产物,其在硅胶上通过快速色谱法(DCM/MeOH=1/0至5/1)纯化。将所有通过TLC(DCM/MeOH=5/1,Rf=0.45)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-(2-(甲基氨基)-2-氧代乙基)哌嗪-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(500mg,0.598mmol,60.7%产率):1H NMR(400MHz,CDCl3)δppm 8.12(d,J=2.9Hz,1H),7.74(d,J=1.8Hz,2H),7.43(d,J=6.4Hz,1H),7.39(s,1H),7.33(t,J=1.8Hz,1H),6.83(s,1H),6.73(d,J=9.0Hz,1H),3.60-3.50(m,12H),3.03(s,2H),2.84(d,J=5.1Hz,3H),2.58(br.s,6H),1.49(s,9H);ES-LCMS m/z 670.5,672.0[M+H]+.
步骤2:2-(4-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌嗪-1-基)-N-甲基乙酰胺,5盐酸盐
向4-(5-((6-(3,5-二氯苯基)-4-((4-(2-(甲基氨基)-2-氧代乙基)哌嗪-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.596mmol)在DCM(10mL)中的混合物中添加TFA(2mL,26mmol)。然后将反应混合物在25℃搅拌20min。将溶液浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到黄色固体的2-(4-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌嗪-1-基)-N-甲基乙酰胺,5盐酸盐(51.8mg,0.068mmol,11.4%产率):1H NMR(400MHz,CD3OD)δppm8.21(d,J=2.7Hz,1H),8.14(d,J=7.1Hz,1H),8.00(s,1H),7.89(d,J=2.0Hz,2H),7.56-7.50(m,2H),7.40(s,1H),4.43(br.s,2H),4.04-3.99(m,6H),3.67(br.s,4H),3.54-3.46(m,8H),2.81(s,3H);ES-LCMS m/z 570.3,572.3[M+H]+.
实施例2:N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)乙酰胺
步骤1:4-(5-((4-((4-(乙酰氨基甲基)-4-羟基哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.656mmol)和K2CO3(181mg,1.313mmol)在DMF(15mL)中的悬浮液中添加N-((4-羟基哌啶-4-基)甲基)乙酰胺N-((4-羟基哌啶-4-基)甲基)乙酰胺(135mg,0.787mmol)。然后将反应混合物在80℃搅拌12h。将固体过滤掉且将溶液浓缩以得到粗产物,其在硅胶上通过快速柱色谱法(DCM/MeOH=1/0至10/1)纯化以得到淡黄色固体的4-(5-((4-((4-(乙酰氨基甲基)-4-羟基哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.475mmol,72.4%产率):1H NMR(400MHz,CDCl3)δppm8.13(d,J=2.6Hz,1H),7.76(d,J=1.8Hz,2H),7.46-7.41(m,2H),7.34(s,1H),6.83(s,1H),6.73(d,J=9.0Hz,1H),3.56(d,J=8.6Hz,12H),3.31(d,J=6.0Hz,2H),2.61(m,2H),2.47(m,2H),2.04(s,3H),1.64(br.s,4H),1.49(s,9H);ES-LCMSm/z687.3,689.0[M+H]+.
步骤2:N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)乙酰胺
向4-(5-((4-((4-(乙酰氨基甲基)-4-羟基哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.583mmol)在DCM(10mL)中的混合物中添加TFA(2mL,26mmol)。然后将反应混合物在25℃搅拌16h。将溶液浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到淡黄色固体的N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)乙酰胺,4盐酸盐(146.85mg,0.201mmol,34.4%产率):1H NMR(400MHz,CD3OD)δppm 8.22-8.15(m,2H),8.01(s,1H),7.87(d,J=1.2Hz,2H),7.56(d,J=9.0Hz,1H),7.49(s,1H),7.41(s,1H),4.48(br.s,2H),4.03(br.s,4H),3.56-3.29(m,8H),3.26(s,2H),2.06-1.95(m,5H),1.79(d,J=14.2Hz,2H);ES-LCMS m/z 585.3,587.3[M+H]+.
实施例3:3-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙酸,4盐酸盐
步骤1:4-(2-羟基乙基)哌啶-1-甲酸叔丁酯
向2-(1-(叔丁氧基羰基)哌啶-4-基)乙酸(30g,123mmol)在THF(200mL)中的溶液中添加BH3·DMS(61.7mL,617mmol)。将混合物在20℃搅拌2h。反应混合物用MeOH(100mL)淬灭。然后将混合物浓缩以得到4-(2-羟基乙基)哌啶-1-甲酸叔丁酯(28g,98mmol,79.0%产率):1H NMR(400MHz,CD3OD)δppm 4.04(d,J=13.2Hz,2H),3.70-3.65(m,2H),2.73(br.s,2H),1.82-1.55(m,4H),1.51-1.39(m,10H),1.15-0.99(m,2H);ES-LCMS m/z 174.1[M-t-Bu+H]+.
步骤2:4-(2-((甲基磺酰基)氧基)乙基)哌啶-1-甲酸叔丁酯
向4-(2-羟基乙基)哌啶-1-甲酸叔丁酯(10g,43.6mmol)在DCM(50mL)中的溶液中添加DIEA(22.85mL,131mmol)。添加MsCl(11.28mL,146mmol)且将混合物在20℃搅拌0.5h。然后将混合物浓缩以得到残余物,将其在DCM(300mL)和H2O(200mL)之间分配,用DCM(300mLx2)萃取。合并的有机层用盐水(200mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到棕色油状物4-(2-((甲基磺酰基)氧基)乙基)哌啶-1-甲酸叔丁酯(12g,23.42mmol,53.7%产率):1HNMR(400MHz,CD3OD)δppm 4.29-4.26(m,2H),4.06(d,J=2.2Hz,2H),3.04(s,3H),2.74(br.s,2H),1.69(d,J=5.6Hz,4H),1.43(s,10H),1.12-1.07(m,2H);ES-LCMS m/z 252.0[M-t-Bu+H]+.
步骤3:4-(2-氰基乙基)哌啶-1-甲酸叔丁酯
向4-(2-((甲基磺酰基)氧基)乙基)哌啶-1-甲酸叔丁酯(12g,39.0mmol)在DMF(50mL)中的溶液中添加KCN(7.8g,120mmol)。将混合物在80℃搅拌12h,然后浓缩。添加H2O(200mL)且pH调节至10,然后用DCM(300mL×3)萃取。合并的有机层用盐水(200mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过硅胶柱色谱法(PE/EtOAc=1/0至1/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到棕色油状物4-(2-氰基乙基)哌啶-1-甲酸叔丁酯(6.0g,20.14mmol,51.6%产率):1H NMR(400MHz,CD3OD)δppm4.11-4.05(m,2H),2.77(br.s,2H),2.48(m,2H),1.74(d,J=12.3Hz,2H),1.64-1.60(m,2H),1.54-1.31(m,10H),1.16-1.05(m,2H);ES-LCMS m/z 183.1[M-t-Bu+H]+.
步骤4:3-(1-(叔丁氧基羰基)哌啶-4-基)丙酸
向4-(2-氰基乙基)哌啶-1-甲酸叔丁酯(3g,12.59mmol)在MeOH(30mL)和H2O(30.0mL)中的溶液中添加NaOH(1.007g,25.2mmol)。将混合物在20℃搅拌12h,然后浓缩。残余物在DCM(300mL)和H2O(200mL)之间分配。分离有机相且用水(100mL x2)萃取。向合并的水相添加HCl水溶液(1M,100mL)直到pH=6,然后用DCM(300mL×3)萃取。合并的有机相用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩得到黄色固体的3-(1-(叔丁氧基羰基)哌啶-4-基)丙酸(1.3g,4.45mmol,35.3%产率):1H NMR(400MHz,CDCl3)δppm 4.08(br.s,2H),2.66(br.s,2H),2.38(t,J=7.6Hz,2H),1.70-1.55(m,4H),1.49-1.37(m,10H),1.09(dq,J=4.2,12.2Hz,2H);ES-LCMS m/z 202.1[M-t-Bu+H]+.
步骤5:3-(哌啶-4-基)丙酸,三氟乙酸盐
向3-(1-(叔丁氧基羰基)哌啶-4-基)丙酸(500mg,1.710mmol)在DCM(10mL)中的混合物中添加TFA(2mL,26.0mmol)。将反应在15℃搅拌1h,然后浓缩以得到无色油状物的3-(哌啶-4-基)丙酸,三氟乙酸盐(300mg,0.774mmol,45.3%产率):1H NMR(400MHz,CD3OD)δppm3.39-3.30(m,2H),2.94(t,J=12.8Hz,2H),2.45-2.26(m,2H),1.94(d,J=14.1Hz,2H),1.61(t,J=5.7Hz,3H),1.43-1.32(m,2H)。
步骤6:3-(1-((2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)丙酸
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(500mg,0.656mmol)在DMF(10mL)中的混合物中添加3-(哌啶-4-基)丙酸,三氟乙酸盐(305mg,0.788mmol)和K2CO3(272mg,1.969mmol)。将反应在60℃搅拌5h。将混合物过滤且浓缩以得到黄色油状物的3-(1-((2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)丙酸(200mg,0.149mmol,22.7%产率):1H NMR(400MHz,CD3OD)δppm 8.06-8.02(m,1H),7.81(d,J=1.8Hz,2H),7.67-7.55(m,1H),7.52-7.47(m,1H),7.43-7.39(m,1H),6.99-6.93(m,2H),4.09(s,4H),3.54(br.s,4H),2.52(d,J=2.6Hz,4H),2.18(d,J=7.5Hz,4H),1.71-1.64(m,4H),1.52-1.49(m,12H);ES-LCMSm/z670.3,672.3[M+H]+.
步骤7:3-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙酸,4盐酸盐
向3-(1-((2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)丙酸(200mg,0.149mmol)在DCM(20mL)中的溶液中添加TFA(2mL,26.0mmol)。将混合物在15℃搅拌1h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的3-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙酸,4盐酸盐(15mg,0.021mmol,13.9%产率):1H NMR(400MHz,CD3OD)δppm 8.21(d,J=2.6Hz,1H),8.11(dd,J=2.2,9.7Hz,1H),7.97(s,1H),7.88(d,J=1.8Hz,2H),7.55-7.45(m,2H),7.39(s,1H),4.60-4.39(m,2H),4.10-3.90(m,4H),3.68-3.53(m,2H),3.51-3.42(m,4H),3.11(t,J=11.7Hz,2H),2.46-2.29(m,2H),2.01(d,J=13.2Hz,2H),1.73-1.50(m,5H);ES-LCMSm/z 570.2,572.2[M+H]+.
实施例4:2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
步骤1:2-(哌啶-4-基)乙酸乙酯,三氟乙酸盐
向4-(2-乙氧基-2-氧代乙基)哌啶-1-甲酸叔丁酯(500mg,1.843mmol)在DCM(10mL)中的混合物中添加TFA(2mL,26.0mmol)。将反应在15℃搅拌20min。将混合物浓缩以得到无色油状物的2-(哌啶-4-基)乙酸乙酯,三氟乙酸盐(750mg,1.84mmol,100.0%产率):1HNMR(400MHz,CD3OD)δppm4.14-4.09(m,2H),3.39-3.35(t,J=12.8Hz,2H),3.05-2.96(m,2H),2.33(d,J=14.1Hz,2H),1.97-1.93(d,J=14.1Hz,3H),1.47-1.43(m,2H),1.23-1.21(t,J=5.7Hz,3H);ES-LCMS m/z 172.2[M+H]+.
步骤2:4-(5-((6-(3,5-二氯苯基)-4-((4-(2-乙氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(500mg,0.656mmol)在DMF(20mL)中的混合物中添加2-(哌啶-4-基)乙酸乙酯,三氟乙酸盐(401mg,0.984mmol)和K2CO3(272mg,1.969mmol)。将反应在60℃搅拌5h。将混合物过滤且浓缩以得到黄色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-(2-乙氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(300mg,0.307mmol,46.7%产率):1H NMR(400MHz,CD3OD)δppm8.03(d,J=2.6Hz,1H),7.80(d,J=1.8Hz,2H),7.62-7.54(m,1H),7.49-7.44(m,1H),7.40(t,J=1.8Hz,1H),6.99-6.89(m,2H),4.10-4.08(m,2H),3.58-3.51(m,10H),2.88-2.83(m,2H),2.25(d,J=6.6Hz,2H),2.09(m,2H),1.79(m,1H),1.72(d,J=12.8Hz,2H),1.49(s,9H),1.34-1.27(m,2H),1.19(m,3H);ES-LCMS m/z 684.3,686.3[M+H]+.
步骤3:2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4盐酸盐
向4-(5-((6-(3,5-二氯苯基)-4-((4-(2-乙氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(300mg,0.307mmol)在MeOH(10mL)中的溶液中添加HCl溶液(4.0M在MeOH中,5mL,20.00mmol)。将混合物在15℃搅拌0.5h,然后浓缩以得到黄色油状物的2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4盐酸盐(200mg,0.195mmol,63.7%产率):1H NMR(400MHz,CD3OD)δppm 8.34-8.18(m,2H),8.09-8.05(m,2H),7.90(d,J=1.8Hz,1H),7.69-7.63(m,1H),7.60-7.35(m,2H),4.47(s,2H),4.13-4.07(m,4H),3.78-3.60(m,2H),3.59-3.43(m,6H),3.18-3.10(m,2H),2.31-2.29(m,2H),2.10-2.07(m,1H),1.71-1.67(m,2H),1.31-1.29(m,2H),1.25(m,3H);ES-LCMS m/z 570.3,572.3[M+H]+.
步骤4:2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
向2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4盐酸盐(200mg,0.195mmol)在MeOH(10mL)和H2O(2mL)中的混合物中添加NaOH(46.89mg,1.173mmol)。将反应在15℃搅拌2h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(59.96mg,0.084mmol,43.1%产率):1H NMR(400MHz,CD3OD)δppm8.20(d,J=2.6Hz,1H),8.03(dd,J=2.6,9.3Hz,1H),7.97-7.91(m,1H),7.88(d,J=1.8Hz,2H),7.51(t,J=1.8Hz,1H),7.44(d,J=9.3Hz,1H),7.36(s,1H),4.45(s,2H),3.99-3.95(m,4H),3.59(d,J=11.9Hz,2H),3.49-3.44(m,4H),3.14(t,J=11.9Hz,2H),2.37-2.25(m,2H),2.06(d,J=14.1Hz,3H),1.75-1.58(m,2H);ES-LCMS m/z 556.2,558.2[M+H]+.
实施例5:1-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)-3-甲基脲,4盐酸盐
步骤1:4-(5-((6-(3,5-二氯苯基)-4-((4-羟基-4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
在25℃向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1.1g,1.805mmol)和1-((4-羟基哌啶-4-基)甲基)-3-甲基脲(0.405g,2.166mmol)在DMF(20mL)中的溶液中添加K2CO3(0.499g,3.61mmol)。将混合物在80℃搅拌12h,然后过滤。将滤液浓缩且将残余物溶于DCM(100mL),用水(30mL×3)洗涤且用Na2SO4干燥。将有机相浓缩以得到黄色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-羟基-4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1.2g,1.541mmol,85.0%产率):1H NMR(400MHz,CDCl3)δppm 8.08-7.98(m,1H),7.71-7.52(m,2H),7.35-7.22(m,2H),7.19(s,1H),6.73(s,1H),6.63(d,J=9.2Hz,1H),3.47-3.45(m,6H),3.13(d,J=6.0Hz,2H),2.97-2.85(m,4H),2.70(s,3H),2.51-2.48(m,2H),2.44-2.40(m,2H),1.70-1.61(m,4H),1.42(s,9H);ES-LCMS m/z 700.3,702.3[M+H]+.
步骤2:1-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)-3-甲基脲,4盐酸盐
在25℃向4-(5-((6-(3,5-二氯苯基)-4-((4-羟基-4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1.2g,1.713mmol)在DCM(20mL)中的溶液中添加TFA(5mL,64.9mmol)。将混合物在25℃搅拌12h,然后浓缩。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到棕色固体的1-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)-3-甲基脲,4盐酸盐(182.24mg,0.241mmol,14.1%产率):1H NMR(400MHz,CD3OD)δppm8.23-8.16(m,2H),8.01-7.96(m,1H),7.87(d,J=1.5Hz,2H),7.61-7.53(m,1H),7.52-7.48(m,1H),7.44-7.38(m,1H),4.47(s,2H),4.07-3.97(m,4H),3.51-3.46(m,4H),3.44-3.35(m,4H),3.26-3.17(m,2H),2.69(s,3H),1.98-1.95(m,2H),1.83-1.74(m,2H);ES-LCMSm/z 600.3,602.2[M+H]+.
实施例6:((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)氨基甲酸甲酯,4盐酸盐
步骤1:4-((叔丁基二甲基甲硅烷基)氧基)-4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯
在0℃向4-(氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯(18g,52.2mmol)和DIEA(18.25mL,104mmol)在DCM(200mL)中的溶液中添加氯甲酸甲酯(7.40g,78mmol)。将混合物在25℃搅拌4h,然后用DCM(250mL)稀释且用水(100mL×3)洗涤。有机相用Na2SO4干燥且浓缩。残余物通过用(PE/EA=4/1)洗脱的柱色谱法纯化以得到黄色油状物4-((叔丁基二甲基甲硅烷基)氧基)-4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯(12g,20.86mmol,39.9%产率):1H NMR(400MHz,CDCl3)δppm3.67(d,J=5.1Hz,3H),3.54-3.45(m,2H),3.43-3.35(m,2H),3.23(s,2H),1.56(m,4H),1.44(s,9H),0.88(s,9H),0.11(s,6H);ES-LCMSm/z 303.2[M-Boc+H]+.
步骤2:((4-((叔丁基二甲基甲硅烷基)氧基)哌啶-4-基)甲基)氨基甲酸甲酯
在25℃向4-((叔丁基二甲基甲硅烷基)氧基)-4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯(2.0g,4.97mmol)在DCM(20mL)中的溶液中添加TFA(5.0mL,64.9mmol)。将混合物在25℃搅拌1h,然后浓缩以得到棕色油状物的((4-((叔丁基二甲基甲硅烷基)氧基)哌啶-4-基)甲基)氨基甲酸甲酯(1.4g,3.70mmol,74.5%产率):1H NMR(400MHz,CD3OD)δppm3.45(s,3H),3.09-3.07(m,2H),3.07-2.99(m,4H),1.74-1.67(m,2H),1.56-1.50(m,2H),0.74(s,9H),0.00(s,6H);ES-LCMS m/z 303.2[M+H]+.
步骤3:4-(5-((4-((4-((叔丁基二甲基甲硅烷基)氧基)-4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
将4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(90mg,0.148mmol)、((4-((叔丁基二甲基甲硅烷基)氧基)哌啶-4-基)甲基)氨基甲酸甲酯(53.6mg,0.177mmol)和K2CO3(30.6mg,0.221mmol)在DMF(20mL)中的混合物在80℃搅拌12h。将混合物过滤且将滤液浓缩以得到棕色油状物4-(5-((4-((4-((叔丁基二甲基甲硅烷基)氧基)-4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(110mg,0.121mmol,82.0%产率):1H NMR(400MHz,CDCl3)δppm 8.08-8.00(m,1H),7.92-7.88(m,1H),7.69-7.59(m,2H),7.36-7.31(m,1H),7.24-7.21(m,1H),6.73-6.69(m,1H),6.65-6.58(m,1H),3.56(s,3H),3.41(s,2H),3.20-3.15(m,4H),2.90-2.86(m,2H),2.80(s,2H),2.74-2.64(m,4H),2.52-2.41(m,2H),1.60-1.53(m,4H),1.50(s,9H),0.80(s,9H),0.03(s,6H);ES-LCMSm/z 815.2,817.2[M+H]+.
步骤4:((4-((叔丁基二甲基甲硅烷基)氧基)-1-((3',5'-二氯-5-((6-(哌嗪-1-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯,4三氟乙酸盐
在25℃向4-(5-((4-((4-((叔丁基二甲基甲硅烷基)氧基)-4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(90mg,0.110mmol)在DCM(20mL)中的溶液中添加TFA(5mL,64.9mmol)。将混合物在25℃搅拌2h,然后浓缩以得到棕色油状物的((4-((叔丁基二甲基甲硅烷基)氧基)-1-((3',5'-二氯-5-((6-(哌嗪-1-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯,4三氟乙酸盐(70mg,0.054mmol,48.8%产率):1H NMR(400MHz,CD3OD)δppm7.81-7.76(m,1H),7.65-7.59(m,2H),7.42-7.34(m,2H),7.32-7.28(m,1H),7.09-7.04(m,1H),6.91-6.85(m,1H),3.65(s,2H),3.45(s,3H),3.30-3.15(m,6H),3.08-2.98(m,8H),1.71-1.68(m,2H),1.54-1.50(m,2H),0.74(s,9H),0.00(s,6H);ES-LCMS m/z 715.3,717.4[M+H]+.
步骤5:((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)氨基甲酸甲酯,4盐酸盐
将((4-((叔丁基二甲基甲硅烷基)氧基)-1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯,4三氟乙酸盐(70mg,0.054mmol)在4.0M HCl(在MeOH中)(20mL,80mmol)中的溶液在25℃搅拌2h,然后浓缩。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)氨基甲酸甲酯,4盐酸盐(31.34mg,0.042mmol,42.9%产率):1H NMR(400MHz,CD3OD)δppm8.18-8.13(m,1H),7.91-7.87(m,1H),7.85(d,J=1.7Hz,3H),7.52-7.48(m,1H),7.32-7.29(m,1H),7.28-7.23(m,1H),4.47-4.42(m,2H),3.93-3.86(m,4H),3.62(s,3H),3.41(d,J=5.4Hz,8H),3.16(s,2H),1.99-1.85(m,2H),1.82-1.75(m,2H);ES-LCMS m/z 601.3,603.3[M+H]+.
实施例7:2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙烷磺酸,4盐酸盐
步骤1:2-(1-(叔丁氧基羰基)哌啶-4-基)乙烷磺酸
向亚硫酸钠(0.861g,6.83mmol)在水(40mL)中的溶液中添加4-(2-((甲基磺酰基)氧基)乙基)哌啶-1-甲酸叔丁酯(1g,2.277mmol)和EtOH(40.0mL)。将反应混合物在110℃搅拌12h。混合物用1N HCl(水溶液)将pH调节至6,然后浓缩。向残余物中添加MeOH(20mL),且然后将混合物过滤。将滤液蒸发以得到白色固体的2-(1-(叔丁氧基羰基)哌啶-4-基)乙烷磺酸(1g,2.045mmol,90.0%产率):1H NMR(400MHz,CD3OD)δppm4.09-4.02(m,2H),3.36(br.s,2H),2.84-2.80(m,2H),1.78-1.68(m,5H),1.44(s,9H),1.38-1.29(m,2H);ES-LCMSm/z 238.1[M-t-Bu+H]+.
步骤2:2-(哌啶-4-基)乙烷磺酸,盐酸盐
向2-(1-(叔丁氧基羰基)哌啶-4-基)乙烷磺酸(1g,2.045mmol)在EtOAc(5mL)中的混合物中添加HCl溶液(4M在EtOAc中,5mL,20.00mmol)。将反应在25℃搅拌0.5h。将溶液浓缩以得到黄色固体的2-(哌啶-4-基)乙烷磺酸,盐酸盐(500mg,1.552mmol,76.0%产率):1HNMR(400MHz,CD3OD)δppm 3.71-3.32(m,2H),3.07-2.50(m,4H),2.11-1.66(m,3H),1.62-1.02(m,4H);ES-LCMS m/z 194.1[M+H]+.
步骤3:2-(1-((2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙烷磺酸,3盐酸盐
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(200mg,0.246mmol)在DMF(3mL)中的混合物中添加2-(哌啶-4-基)乙烷磺酸(119mg,0.369mmol)和K2CO3(102mg,0.738mmol)。将反应在60℃搅拌5h。将混合物过滤,浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到黄色固体的2-(1-((2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙烷磺酸,3盐酸盐(80mg,0.093mmol,37.8%产率):1H NMR(400MHz,CD3OD)δppm 8.20(d,J=2.6Hz,1H),7.87(d,J=1.8Hz,3H),7.57-7.49(m,2H),7.39-7.32(m,2H),4.45-4.43(m,2H),3.97-3.93(m,4H),3.81-3.78(m,2H),3.70(br.s,2H),3.58(d,J=11.9Hz,2H),3.10-3.01(m,2H),2.84(s,2H),2.04(d,J=14.1Hz,2H),1.84-1.67(m,5H),1.56-1.43(m,9H);ES-LCMS m/z 706.3,708.2[M+H]+.
步骤4:2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙烷磺酸,4盐酸盐
向2-(1-((2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙烷磺酸,3盐酸盐(80mg,0.093mmol)在EtOAc(5mL)中的混合物中添加HCl溶液(4.0M在EtOAc中,2mL,8.00mmol)。将反应在25℃搅拌0.5h,然后浓缩。添加水(20mL)且混合物冻干干燥以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙烷磺酸,4盐酸盐(40.55mg,0.054mmol,57.9%产率):1H NMR(400MHz,CD3OD)δppm 8.20(d,J=2.5Hz,1H),7.89-7.86(m,4H),7.53(s,1H),7.30(s,2H),4.45(s,2H),3.93(s,4H),3.60(d,J=11.5Hz,2H),3.44(d,J=5.0Hz,4H),3.16-3.08(m,2H),2.87(d,J=7.5Hz,2H),2.07(d,J=14.6Hz,2H),2.04-1.55(m,3H),1.54-1.44(m,2H);ES-LCMS m/z 606.3,608.3[M+H]+.
实施例8:(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲磺酸,4盐酸盐
步骤1:4-(羟基甲基)哌啶-1-甲酸苄基酯
向哌啶-4-基甲醇(8g,69.5mmol)、Na2CO3(29.2g,347mmol)在1,4-二噁烷(100mL)和水(100mL)中的混合物中滴加CbzCl(14.22g,83mmol)。将混合物在30℃搅拌2h,然后浓缩。所得粗物质在EtOAc(200mL)和水(200mL)之间分配。分离水层且用EtOAc(100mL x2)萃取,且将有机相合并,用水(200mL x2)洗涤,用Na2SO4干燥,过滤,且浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=20/1至10/1至5/1,PE/EtOAc=5/1,Rf=0.5)纯化以得到棕色油状物4-(羟基甲基)哌啶-1-甲酸苄基酯(12g,29.1mmol,41.9%产率):1H NMR(400MHz,CDCl3)δppm7.39-7.27(m,5H),5.18-5.04(m,2H),4.20(br.s,2H),3.48(d,J=6.2Hz,2H),2.77(br.s,2H),1.81-1.61(m,4H),1.15(d,J=10.1Hz,1H);ES-LCMS m/z 205.3[M+H]+.
步骤2:4-(((甲基磺酰基)氧基)甲基)哌啶-1-甲酸苄基酯
在20℃,向4-(羟基甲基)哌啶-1-甲酸苄基酯(5g,12.13mmol)和DIEA(7.84g,60.7mmol)在DCM(120mL)中的溶液中添加MsCl(4.17g,36.4mmol)。将混合物在20℃搅拌0.5h,然后浓缩。残余物用DCM(100mL)和水(100mL)稀释,分离且水相用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到棕色固体的4-(((甲基磺酰基)氧基)甲基)哌啶-1-甲酸苄基酯(4g,9.77mmol,81.0%产率):1H NMR(400MHz,CDCl3)δppm7.38-7.26(m,5H),5.11(s,2H),4.22(d,J=5.7Hz,2H),4.09(d,J=5.7Hz,2H),2.99(s,3H),2.84-2.70(m,2H),1.92(m,1H),1.75(d,J=12.3Hz,2H),1.30-1.14(m,2H);ES-LCMS m/z 328.2[M+H]+.
步骤3:(1-((苄基氧基)羰基)哌啶-4-基)甲磺酸
向亚硫酸钠(0.924g,7.33mmol)在水(40mL)中的溶液中添加4-(((甲基磺酰基)氧基)甲基)哌啶-1-甲酸苄基酯(1g,2.444mmol)和EtOH(40.0mL)。将反应混合物在110℃搅拌12h,然后冷却。混合物用1N HCl(水溶液)将pH调节至6,然后浓缩。添加MeOH(20mL)且将混合物过滤。将滤液蒸发以得到白色固体的(1-((苄基氧基)羰基)哌啶-4-基)甲磺酸(1g,2.419mmol,99.0%产率):1H NMR(400MHz,CD3OD)δppm7.49-7.14(m,5H),5.10(br.s,2H),4.22-4.00(m,2H),3.01-2.71(m,4H),2.13-1.94(m,2H),1.82-1.57(m,1H),1.32-1.04(m,2H);ES-LCMS m/z 314.2[M+H]+.
步骤4:哌啶-4-基甲磺酸,三氟乙酸盐
将(1-((苄基氧基)羰基)哌啶-4-基)甲磺酸(900mg,2.177mmol)在TFA(2mL)中的溶液在60℃搅拌12h。将该反应混合物浓缩以得到灰白色固体的哌啶-4-基甲磺酸,三氟乙酸盐(600mg,1.534mmol,70.5%产率):1H NMR(400MHz,CD3OD)δppm 3.37(d,J=13.2Hz,2H),3.09-2.94(m,2H),2.84-2.74(m,2H),2.30-1.89(m,3H),1.63-1.44(m,2H)。
步骤5:(1-((2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲磺酸,3盐酸盐
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(250mg,0.308mmol)和哌啶-4-基甲磺酸,三氟乙酸盐(226mg,0.615mmol)在DMF(10mL)中的悬浮液中添加K2CO3(255mg,1.846mmol)。将反应混合物在60℃搅拌12h,然后过滤且浓缩。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的(1-((2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲磺酸,3盐酸盐(150mg,0.076mmol,24.7%产率):1H NMR(400MHz,CDCl3)δppm7.91(br.s,1H),7.84(br.s,1H),7.59(br.s,2H),7.20-7.14(m,2H),7.00(br.s,1H),6.88(d,J=8.8Hz,1H),4.11(d,J=10.6Hz,2H),3.69(br.s,4H),3.56(br.s,2H),3.48(br.s,2H),3.26(d,J=12.3Hz,2H),2.84(br.s,2H),2.59(d,J=5.7Hz,2H),2.04(d,J=14.6Hz,2H),1.95(br.s,1H),1.51(br.s,2H),1.43-1.23(m,9H);ES-LCMS m/z 692.2,694.2[M+H]+.
步骤6:(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲磺酸,4盐酸盐
向(1-((2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲磺酸,3盐酸盐(150mg,0.076mmol)在EtOAc(10mL)中的悬浮液中添加HCl溶液(4.0M在EtOAc中,5mL,20mmol)。将反应混合物在25℃搅拌1h,然后浓缩。将残余物溶于水(10mL)且冻干以得到灰白色固体的(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲磺酸,4盐酸盐(52.92mg,0.070mmol,92.0%产率):1H NMR(400MHz,CD3OD)δppm 8.16(d,J=2.6Hz,1H),7.87-7.76(m,4H),7.50(s,1H),7.27-7.20(m,2H),4.41(s,2H),3.92-3.85(m,4H),3.57(d,J=11.9Hz,2H),3.43-3.37(m,4H),3.16-3.06(m,2H),2.78(d,J=6.2Hz,2H),2.29(d,J=14.1Hz,2H),2.17(br.s,1H),1.65-1.52(m,2H);ES-LCMS m/z 592.2,594.2[M+H]+.
实施例9:N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
步骤1:4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
将N-((1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(580mg,1.028mmol)、哌嗪-1-甲酸叔丁酯(574mg,3.08mmol)、(±)-BINAP(12.80mg,0.021mmol)、18-冠-6(815mg,3.08mmol)、Pd2(dba)3(47.1mg,0.051mmol)和叔丁醇钠(296mg,3.08mmol)在THF(15mL)中的混合物在65℃在N2气氛搅拌2h。将混合物过滤且将滤液浓缩。将残余物溶于DCM(50mL)且用盐水(50mL)洗涤,用MgSO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(MeOH/DCM=1/10)纯化,然后进一步通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到淡黄色固体的4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(81mg,0.094mmol,9.1%产率):1H NMR(400MHz,CD3OD)δppm8.24-8.17(m,1H),8.00(d,J=6.8Hz,1H),7.94(s,1H),7.91-7.86(m,2H),7.54(t,J=1.9Hz,1H),7.44-7.39(m,1H),7.36(s,1H),4.49-4.43(m,2H),4.01-3.94(m,4H),3.62(d,J=12.3Hz,2H),3.50-3.44(m,4H),3.18-3.07(m,4H),2.06-1.96(m,6H),1.87(m,1H),1.67-1.50(m,10H);ES-LCMS m/z669.3,671.3[M+H]+.
步骤2:N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
将4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(81mg,0.121m mol)和TFA(2mL,26.0mmol)在DCM(8mL)中的混合物在25℃搅拌0.5h。然后将混合物浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(37.43mg,0.052mmol,43.1%产率):1H NMR(400MHz,CD3OD)δppm 8.19(d,J=2.4Hz,1H),8.06(d,J=9.5Hz,1H),7.92(s,1H),7.86(d,J=1.7Hz,2H),7.51(s,1H),7.45(d,J=9.8Hz,1H),7.35(s,1H),4.43(s,2H),4.01-3.93(m,4H),3.59(d,J=12.7Hz,2H),3.49-3.41(m,4H),3.15-3.03(m,4H),2.03-1.91(m,5H),1.83(br.s,1H),1.63-1.50(m,2H);ES-LCMSm/z 569.0,571.0[M+H]+.
实施例10:2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙酸,4盐酸盐
步骤1:2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙酸乙酯
向N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(1g,1.756mmol)和2-溴乙酸乙酯(0.352g,2.107mmol)在DMF(100mL)中的溶液中添加K2CO3(0.485g,3.51mmol)。将反应在25℃搅拌8h。将混合物浓缩且通过硅胶柱色谱法纯化。将所有通过TLC(MeOH/DCM=1/10,Rf=0.4)发现包含产物的级分合并且浓缩以得到棕色固体的2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙酸乙酯(0.7g,1.07mmol,61.3%产率):1H NMR(400MHz,CDCl3)δppm 8.13(s,1H),7.77(s,2H),7.44-7.39(m,2H),7.33(s,1H),6.81(s,1H),6.73(d,J=9.2Hz,1H),4.23-4.19(m,2H),3.63-3.60(m,4H),3.50(s,2H),3.29(br.s,2H),3.18-3.15(m,2H),2.85-2.79(m,2H),2.75-2.72(m,4H),2.03-2.00(m,2H),1.98(s,3H),1.70-1.45(m,3H),1.32-1.28(m,2H),1.27-1.20(m,3H);ES-LCMS m/z655.3,657.3[M+H]+.
步骤2:2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙酸,4盐酸盐
向2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙酸乙酯(1.27g,1.937mmol)在MeOH(6mL)和H2O(1mL)中的溶液中添加NaOH(0.155g,3.87mmol)。将反应在15℃搅拌24h。将混合物浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到白色固体的2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙酸,4盐酸盐(716.3mg,0.924mmol,47.7%产率):1H NMR(400MHz,CD3OD)δppm 8.18(d,J=2.6Hz,1H),7.90(br.s,1H),7.89-7.73(m,3H),7.51(t,J=1.8Hz,1H),7.37-7.25(m,2H),4.43(s,2H),4.23(s,2H),4.10-3.90(br.s,4H),3.61-3.58(m,6H),3.12-3.06(m,4H),2.01-1.94(m,5H),1.85-1.76(m,1H),1.60-1.51(m,2H);ES-LCMS m/z 627.3,629.3[M+H]+.
实施例11:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
步骤1:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
向N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(20g,33.4mmol)和3-溴丙酸乙酯(18.12g,100mmol)在DMF(350mL)中的溶液中添加K2CO3(13.83g,100mmol)。然后将反应混合物在80℃搅拌12h。将固体过滤掉且将溶液浓缩以得到淡黄色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(17.6g,24.97mmol,74.8%产率):1H NMR(400MHz,CDCl3)δppm 8.10(d,J=3.1Hz,1H),7.74(d,J=1.8Hz,2H),7.43-7.35(m,2H),7.31(s,1H),6.78(s,1H),6.70(d,J=9.3Hz,1H),5.55(brs,1H),4.14(q,J=7.1Hz,2H),3.58-3.50(m,4H),3.47(s,2H),3.14(t,J=6.4Hz,2H),2.88-2.82(m,2H),2.77-2.70(m,2H),2.64-2.56(m,4H),2.55-2.49(m,2H),2.04-1.94(m,5H),1.66(d,J=12.8Hz,2H),1.54-1.46(m,1H),1.35-1.21(m,5H);ES-LCMSm/z 669.3,671.3[M+H]+.
步骤2:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
向3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(17.6g,24.97mmol)在THF(200mL)中的溶液中添加LiOH·H2O(2.096g,49.9mmol)和水(2mL)。然后将反应混合物在25℃搅拌12h。添加1NHCl以将pH调节至6,然后浓缩以得到粗产物,将其用EA/MeOH=10/1(500mL)和THF(500mL)洗涤。收集固体以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化。将浓HCl添加至合并的纯化级分以调节至pH为2,且冻干以得到淡黄色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐(15g,23.09mmol,92.0%产率):1H NMR(400MHz,CD3OD)δppm 8.23(s,1H),8.20-8.16(m,1H),7.99(s,1H),7.89(s,2H),7.55(d,J=12Hz,1H),7.51(s,1H),7.40(s,1H),4.46(s,2H),3.80-3.40(m,10H),3.30-3.20(m,2H),3.15-3.07(m,4H),2.96-2.94(m,2H),2.00-1.92(m,5H),1.90-1.79(m,1H),1.62-1.53(m,2H);ES-LCMS m/z 641.3,643.2[M+H]+.
实施例12:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
向N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(1.5g,1.887mmol)和DIEA(1.219g,9.44mmol)在DCM(20mL)中的溶液中添加(甲基磺酰基)乙烯(0.240g,2.265mmol)。然后将反应混合物在15℃搅拌12h。将溶液浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(672mg,0.806mmol,42.7%产率):1H NMR(400MHz,CD3OD)δppm8.26(d,J=2.5Hz,1H),8.22-8.15(m,1H),8.02(s,1H),7.91(d,J=1.5Hz,2H),7.59(d,J=9.5Hz,1H),7.53(s,1H),7.43(s,1H),4.58-4.45(m,2H),4.14(br.s,4H),3.90-3.80(m,4H),3.70(s,4H),3.62(d,J=12.0Hz,2H),3.23-3.05(m,7H),2.07-1.96(m,5H),1.88(br.s,1H),1.72-1.56(m,2H);ES-LCMS m/z 675.2,677.2[M+H]+.
实施例13:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰胺,4盐酸盐
向N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(120mg,0.211mmol)和3-溴丙酰胺(64.0mg,0.421mmol)在DMF(8mL)中的混合物中添加K2CO3(58.2mg,0.421mmol)。将反应在60℃搅拌12h。将固体过滤掉且将溶液浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到白色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酰胺,4盐酸盐(73.66mg,0.093mmol,44.2%产率):1H NMR(400MHz,CD3OD)δppm8.20(br.s,1H),7.94-7.79(m,4H),7.54(s,1H),7.35-7.26(m,2H),4.57(s,2H),3.94(br.s,4H),3.66-3.42(m,8H),3.19-3.05(m,4H),2.85(t,J=6.5Hz,2H),2.06-1.95(m,5H),1.86(br.s,1H),1.56(d,J=13.6Hz,2H);ES-LCMS m/z640.3,642.3[M+H]+.
实施例14:N-((1-((2-((6-(4-(2-(1H-四唑-5-基)乙基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
步骤1:N-((1-((2-((6-(4-(2-氰基乙基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(300mg,0.377mmol)在DCM(20mL)中的混合物中添加丙烯腈(2.03g,38.3mmol)和DIEA(0.659mL,3.77mmol)。将混合物在40℃搅拌3h,然后冷却且过滤。将滤液浓缩且通过硅胶柱色谱法(DCM/MeOH=10/1,Rf=0.5)纯化以得到棕色固体的N-((1-((2-((6-(4-(2-氰基乙基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(300mg,0.270mmol,71.5%产率):1H NMR(400MHz,CDCl3)δppm 8.05-8.01(m,1H),7.83(d,J=1.8Hz,2H),7.68(s,1H),7.49(dd,J=2.9,9.0Hz,1H),7.42(t,J=1.8Hz,1H),7.01(s,1H),6.92(s,1H),3.75-3.68(m,4H),3.57-3.55(m,4H),3.29-3.22(m,2H),3.12-3.01(m,4H),2.75-2.69(m,2H),2.68-2.60(m,4H),1.94(s,3H),1.81-1.68(m,3H),1.64-1.53(m,2H);ES-LCMS m/z 622.4,624.3[M+H]+.
步骤2:N-((1-((2-((6-(4-(2-(1H-四唑-5-基)乙基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
向N-((1-((2-((6-(4-(2-氰基乙基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(150mg,0.135mmol)在甲苯(20mL)中的混合物中添加叠氮基三丁基锡(1mL,3.65mmol)。将混合物在高压灭菌器中在110℃搅拌10h。将反应混合物浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的N-((1-((2-((6-(4-(2-(1H-四唑-5-基)乙基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(28.77mg,0.035mmol,26.3%产率):1H NMR(400MHz,CD3OD)δppm 8.22(dd,J=2.5,10.0Hz,1H),8.17(d,J=2.5Hz,1H),8.00(s,1H),7.91(d,J=1.5Hz,2H),7.62(d,J=9.5Hz,1H),7.55(s,1H),7.43(s,1H),4.48(s,2H),4.12-3.81(m,6H),3.79-3.70(m,2H),3.62-3.60(m,2H),3.45-3.40(m,4H),3.17-3.03(m,4H),2.02-1.95(m,5H),1.88(br.s,1H),1.69-1.54(m,2H);ES-LCMSm/z 655.3,657.3[M+H]+.
实施例15:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基亚磺酰基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
步骤1:2-(甲硫基)乙醛
在-78℃经5分钟向草酰氯(2.78mL,32.6mmol)在DCM(15mL)中的溶液中滴加DMSO(4.62mL,65.1mmol)在DCM(10mL)中的溶液。在相同温度搅拌0.5h后,经10分钟滴加2-(甲硫基)乙醇(2g,21.70mmol)在DCM(10mL)中的溶液且再搅拌0.5h。然后经5分钟添加DIEA(22.74mL,130mmol)在DCM(10mL)中的溶液。将反应经1.5h温热至0℃,然后添加30mL冰冷的1N HCl溶液。分离两相,水相用DCM(50mL×3)萃取,且合并的有机相用盐水(50mL)洗涤,用Na2SO4干燥且在减压下浓缩以得到黄色油状物的2-(甲硫基)乙醛(800mg,7.10mmol,32.7%产率):1H NMR(400MHz,CDCl3)δppm 9.39(t,J=3.5Hz,1H),3.51(s,2H),1.96(s,3H)。
步骤2:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲硫基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向2-(甲硫基)乙醛(151mg,1.343mmol)、乙酸(0.05mL,0.873mmol)、N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(300mg,0.448mmol)在MeOH(10mL)中的溶液中添加分子筛(200mg,0.448mmol)且在50℃搅拌70h。然后,将NaBH3CN(84mg,1.343mmol)添加至混合物且将混合物在25℃搅拌2h。将混合物过滤且浓缩。粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到淡黄色固体的N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲硫基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(70mg,0.079mmol,17.7%产率):1H NMR(400MHz,CD3OD)δppm 8.20(d,J=2.2Hz,1H),8.00(d,J=7.1Hz,1H),7.94(s,1H),7.88(d,J=1.8Hz,2H),7.51(s,1H),7.42(d,J=9.7Hz,1H),7.35(s,1H),4.44(s,2H),3.78(br.s,2H),3.60(d,J=11.5Hz,4H),3.53-3.39(m,4H),3.27-3.02(m,6H),2.99-2.91(m,2H),2.21(s,3H),2.02-1.93(m,5H),1.85(s,1H),1.63-1.53(m,2H);ES-LCMS m/z 643.3,645.3[M+H]+.
步骤3:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基亚磺酰基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
向N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲硫基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(60mg,0.068mmol)在MeOH(5mL)和H2O(1mL)中的溶液中添加(20.90mg,0.034mmol)。将混合物在25℃搅拌2h,然后添加1N HCl(水溶液)以将pH调节至6-7。将溶液浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到淡黄色固体的N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基亚磺酰基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(19.81mg,0.025mmol,36.2%产率):1H NMR(400MHz,CD3OD)δppm 8.23(d,J=2.2Hz,1H),8.14(dd,J=2.2,9.7Hz,1H),7.95(s,1H),7.88(d,J=1.8Hz,2H),7.58-7.46(m,2H),7.38(s,1H),4.44(s,2H),4.20-4.00(m,4H),3.89-3.54(m,8H),3.53-3.40(m,2H),3.20-3.00(m,4H),2.79(s,3H),2.08-1.89(m,5H),1.85(s,1H),1.67-1.52(m,2H);ES-LCMS m/z 659.3,661.3[M+H]+.
实施例16-25(表1)通过类似于实施例15所述的方法制备。
表1
实施例26:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((反式)-3-(甲基磺酰氨基)环丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
实施例27:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((顺式)-3-(甲基磺酰氨基)环丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
步骤1:(3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)环丁基)氨基甲酸叔丁酯
将(3-氧代环丁基)氨基甲酸叔丁酯(74.1mg,0.400mmol)、乙酸(2mg,0.033mmol)、N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(200mg,0.334mmol)和分子筛(0.2g)在DCM(8mL)中的混合物在25℃搅拌12h。然后,将NaBH3CN(41.9mg,0.667mmol)添加至混合物且将混合物在25℃搅拌2h。将反应混合物浓缩,用额外DCM(50mL)稀释且用饱和NaHCO3溶液(水溶液,50mL x2)洗涤。有机相用Na2SO4干燥,过滤且浓缩以得到黄色油状物的(3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)环丁基)氨基甲酸叔丁酯(250mg,0.284mmol,85.0%产率):1H NMR(400MHz,CD3OD)δppm 8.06(d,J=3.0Hz,1H),7.85(d,J=1.5Hz,2H),7.66(s,1H),7.53(dd,J=2.5,9.0Hz,1H),7.45(s,1H),7.02(s,1H),6.97(d,J=9.0Hz,1H),4.20(t,J=6.0Hz,1H),3.63(s,2H),3.61(d,J=4.5Hz,4H),3.16-3.03(m,6H),2.62(m,4H),2.39(m,1H),2.16(m,4H),1.96(s,3H),1.77(d,J=12.0Hz,2H),1.58(br.s,1H),1.45(br.s,9H),1.38(d,J=15.6Hz,2H);ES-LCMS m/z738.4,740.3[M+H]+.
步骤2:N-((1-((2-((6-(4-(3-氨基环丁基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,5三氟乙酸盐
向(3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)环丁基)氨基甲酸叔丁酯(250mg,0.284mmol)在DCM(8mL)中的溶液中添加TFA(2mL,26.0mmol)。将反应在25℃搅拌0.5h,然后浓缩以得到黄色油状物的N-((1-((2-((6-(4-(3-氨基环丁基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,5三氟乙酸盐(300mg,0.199mmol,69.8%产率):1H NMR(400MHz,CDCl3)δppm 8.11(br.s,1H),7.71-7.59(m,4H),7.35(s,1H),7.01-6.88(m,2H),4.21(br.s,2H),3.98(m,1H),3.51-3.46(m,4H),3.22(m,2H),3.07(m 2H),3.00-2.80(m,4H),2.74-2.57(m,3H),1.95(s,3H),1.80-1.75(m,4H),1.62(m,3H),1.29-1.22(m,2H);ES-LCMSm/z 638.3,640.3[M+H]+.
步骤3:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((反式)-3-(甲基磺酰氨基)环丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((顺式)-3-(甲基磺酰氨基)环丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向N-((1-((2-((6-(4-(3-氨基环丁基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,5三氟乙酸盐(300mg,0.199mmol)在DCM(8mL)中的溶液中添加DIEA(0.243mL,1.390mmol)。将MsCl(0.023mL,0.298mmol)添加至反应且将反应在25℃搅拌0.5h,然后浓缩。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化且冻干以得到白色固体的N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((反式)-3-(甲基磺酰氨基)环丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(42.14mg,0.058mmol,29.4%产率)和白色固体的N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((顺式)-3-(甲基磺酰氨基)环丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(18.72mg,0.026mmol,13.2%产率):(反式)1H NMR(400MHz,CD3OD)δppm 8.06(d,J=2.8Hz,1H),7.84(d,J=1.8Hz,2H),7.64(s,1H),7.52(dd,J=2.9,9.2Hz,1H),7.44(t,J=1.8Hz,1H),7.00(s,1H),6.96(d,J=9.3Hz,1H),4.10-3.97(m,1H),3.63(s,2H),3.62-3.57(m,4H),3.10(d,J=6.8Hz,2H),2.97(d,J=11.3Hz,3H),2.93(s,3H),2.57(t,J=4.6Hz,4H),2.47(ddd,J=5.4,8.0,13.0Hz,2H),2.28-2.17(m,2H),2.12(t,J=11.0Hz,2H),1.96(s,3H),1.75(d,J=11.8Hz,2H),1.63-1.49(m,1H),1.41-1.27(m,2H);ES-LCMSm/z716.2,718.2[M+H]+.(顺式)1H NMR(400MHz,CD3OD)δppm 8.05(d,J=3.0Hz,1H),7.84(d,J=1.5Hz,2H),7.64(s,1H),7.52(dd,J=2.8,9.3Hz,1H),7.45(s,1H),7.00(s,1H),6.96(d,J=9.5Hz,1H),3.70-3.55(m,7H),3.10(d,J=6.5Hz,2H),2.99-2.91(m,5H),2.70-2.49(m,7H),2.10(t,J=11.0Hz,2H),1.96(s,3H),1.94-1.86(m,2H),1.74(d,J=12.0Hz,2H),1.55(br.s,1H),1.37-1.30(m,2H);ES-LCMS m/z 716.2,718.2[M+H]+.
实施例28:N-((1-((2-((6-(4-(2-氨基乙基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,5盐酸盐
步骤1:(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基)氨基甲酸叔丁酯.
向N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(400mg,0.702mmol)和(2-溴乙基)氨基甲酸叔丁酯(315mg,1.405mmol)在DMF(20mL)中的混合物中添加DIEA(0.368mL,2.107mmol)。然后将反应混合物在80℃搅拌12h。将溶液浓缩以得到淡黄色固体的(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基)氨基甲酸叔丁酯(250mg,0.281mmol,40.0%产率):1H NMR(400MHz,CDCl3)δppm 8.12(d,J=9.8Hz,1H),7.85(d,J=18.8Hz,3H),7.44(d,J=6.4Hz,2H),7.33(d,J=5.9Hz,1H),6.77(dd,J=4.8,8.9Hz,1H),3.92(s,2H),3.75-3.68(m,6H),3.55-3.48(m,4H),3.32-3.28(m,2H),3.17-3.10(m,6H),1.99(s,3H),1.90-1.75(m,5H),1.45(s,9H);ES-LCMS m/z 712.3,714.3[M+H]+.
步骤2:N-((1-((2-((6-(4-(2-氨基乙基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,5盐酸盐
将(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基)氨基甲酸叔丁酯(250mg,0.351mmol)在4.0MEtOAc(20mL,80mmol)中的溶液在25℃搅拌0.5h。将溶液浓缩且残余物用制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到淡黄色固体N-((1-((2-((6-(4-(2-氨基乙基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,5盐酸盐(156.68mg,0.194mmol,55.3%产率):1H NMR(400MHz,CD3OD)δppm 8.28-8.24(m,2H),8.02(s,1H),7.91(d,J=1.8Hz,2H),7.67-7.63(m,1H),7.56-7.54(m,1H),7.44(s,1H),4.58-4.46(m,2H),4.21(br.s,2H),3.72(br.s,2H),3.60(dd,J=5.9,17.4Hz,8H),3.41-3.34(m,2H),3.19-3.11(m,4H),2.03-1.98(m,5H),1.89(br.s,1H),1.71-1.60(m,2H);ES-LCMSm/z 612.3,614.3[M+H]+.
实施例29:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2,4-二羟基丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
步骤1:4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-3-氧代丁酸乙酯
在25℃向N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(100mg,0.176mmol)和4-溴-3-氧代丁酸乙酯(44.0mg,0.211mmol)在DMF(5mL)中的溶液中添加DIEA(0.031mL,0.176mmol)。将混合物在25℃搅拌12h。将溶液浓缩。残余物通过用(PE/DCM=1/1Rf=0.4)洗脱的柱色谱法纯化以得到棕色油状物的4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-3-氧代丁酸乙酯(100mg,0.115mmol,65.3%产率):1H NMR(400MHz,CD3OD)δppm 8.23-8.19(m,1H),8.04-7.96(m,2H),7.89(d,J=1.8Hz,2H),7.55-7.50(m,1H),7.45-7.41(m,1H),7.39-7.36(m,1H),4.61(s,2H),4.46(s,2H),4.14-4.09(m,4H),4.02-3.88(m,4H),3.60(m,6H),3.17-3.04(m,4H),2.04-1.93(m,5H),1.89-1.72(m,1H),1.67-1.51(m,2H),1.31(t,J=7.1Hz,3H);ES-LCMS m/z 697.3,699.3[M+H]+.
步骤2:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2,4-二羟基丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
向4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-3-氧代丁酸乙酯(50mg,0.072mmol)在MeOH(20mL)中的溶液中添加NaBH4(10mg,0.264mmol)。将混合物在25℃搅拌1h。将混合物浓缩。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到白色固体的N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2,4-二羟基丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(14.88mg,0.018mmol,25.0%产率):1H NMR(400MHz,CD3OD)δppm 8.19-8.15(m,1H),7.86(d,J=1.8Hz,2H),7.83-7.76(m,2H),7.55-7.48(m,1H),7.29(s,1H),7.26-7.22(m,1H),4.54-4.35(m,5H),4.25(br.s,1H),3.86-3.69(m,4H),3.60(d,J=11.9Hz,2H),3.43-3.40(m,4H),3.13(br.s,4H),2.58(d,J=6.2Hz,1H),2.04-1.92(m,5H),1.83(br.s,2H),1.75-1.71(m,1H),1.53(d,J=14.1Hz,2H);ES-LCMS m/z 657.3,659.3[M+H]+.
实施例30:(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基)膦酸,4盐酸盐
步骤1:(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基)膦酸二乙酯
将N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(200mg,0.252mmol)、K2CO3(174mg,1.258mmol)和乙烯基膦酸二乙酯(83mg,0.503mmol)(25%)在水(3mL)和1,4-二噁烷(5mL)中的混合物在100℃在N2气氛搅拌8h。向反应混合物中添加水(10mL),然后用DCM(50mL×3)萃取。有机层用盐水(30mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色油状物的(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基)膦酸二乙酯(200mg,0.218mmol,87.0%产率):1H NMR(400MHz,CDCl3)δppm 8.11(d,J=2.6Hz,1H),7.75(d,J=1.8Hz,2H),7.45-7.36(m,2H),7.32(s,1H),6.80(s,1H),6.72(d,J=8.8Hz,1H),4.10(m,4H),3.54(d,J=4.9Hz,4H),3.48(s,2H),3.15(t,J=6.4Hz,2H),2.84(m,2H),2.77-2.66(m,2H),2.63-2.56(m,4H),2.10-1.97(m,4H),1.95(s,3H),1.72-1.60(m,5H),1.31(m,6H);ES-LCMSm/z 733.2,735.2[M+H]+.
步骤2:(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基)膦酸,4盐酸盐
将(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基)膦酸二乙酯(150mg,0.164mmol)在浓HCl(3mL)和水(3mL)中的混合物在100℃搅拌3h。将混合物浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基)膦酸,4盐酸盐(70.4mg,0.085mmol,51.7%产率):1H NMR(400MHz,CD3OD)δppm 8.19(d,J=2.6Hz,1H),7.91-7.85(m,4H),7.51(t,J=1.8Hz,1H),7.37-7.29(m,2H),4.80(s,2H),4.57-4.40(m,2H),3.64-3.44(m,8H),3.38-3.33(m,2H),3.18-3.03(m,4H),2.36-2.24(m,2H),2.06-1.91(m,6H),1.64-1.47(m,2H);ES-LCMS m/z 677.2,679.1[M+H]+.
实施例31:氨基甲酸2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基酯,4盐酸盐
向N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(900mg,0.587mmol)在DCM(10mL)中的溶液中添加CDI(114mg,0.704mmol)和DIEA(0.5mL,2.86mmol)。将混合物在25℃搅拌5h,然后添加氢氧化铵(0.2mL,5.14mmol)且将混合物在25℃再搅拌7h。将反应混合物浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的氨基甲酸2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基酯,4盐酸盐(219.42mg,0.273mmol,46.5%产率):1H NMR(400MHz,CD3OD)δppm8.22(br.s,1H),7.95(br.s,2H),7.90(s,2H),7.53(s,1H),7.37(br.s,2H),4.52-4.41(m,4H),4.15-4.04(m,1H),3.97(d,J=5.0Hz,1H),3.84(br.s,2H),3.69-3.50(m,6H),3.42(br.s,2H),3.21-3.05(m,4H),2.07-1.94(m,5H),1.87(br.s,1H),1.68-1.53(m,2H);ES-LCMS m/z 656.2,658.2[M+H]+.
实施例32:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(N-甲基甲磺酰氨基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
步骤1:甲磺酸2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基酯
在0℃向搅拌的N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(200mg,0.306mmol)和DIEA(0.161mL,0.919mmol)在DCM(10mL)中的悬浮液中添加MsCl(0.031mL,0.398mmol)。将反应混合物在25℃搅拌0.5h。添加水(30mL)且用DCM(30mL×3)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到淡黄色胶状物的甲磺酸2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基酯(260mg,0.292mmol,95.0%产率):1H NMR(400MHz,CDCl3)δppm 8.08(d,J=2.6Hz,1H),7.86-7.69(m,3H),7.46(dd,J=2.6,9.3Hz,1H),7.33(s,1H),7.06(br s,1H),6.80(d,J=9.3Hz,1H),4.68(br s,1H),4.20(br s,2H),4.19-3.90(m,2H),3.64-3.61(m,2H),3.57-3.40(m,8H),3.28-3.15(m,2H),3.07(s,3H),2.88-2.73(m,4H),1.92(s,3H),1.82-1.73(m,5H);ES-LCMSm/z691.1,693.1[M+H]+.
步骤2:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基氨基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
将甲磺酸2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基酯(260mg,0.292mmol)在甲胺(30%在乙醇中,10mL,0.292mmol)中的混合物在25℃搅拌12h。将该反应混合物浓缩且残余物在DCM(50mL)和水(30mL)之间分配,用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到淡黄色固体N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基氨基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(220mg,0.278mmol,95.0%产率):1H NMR(400MHz,CDCl3)δppm 8.13(d,J=3.1Hz,1H),7.78(d,J=1.8Hz,2H),7.46-7.37(m,2H),7.34(s,1H),6.81(s,1H),6.73(d,J=9.3Hz,1H),5.56(br.s,1H),3.60-3.52(m,4H),3.17(t,J=6.4Hz,2H),2.88(d,J=11.5Hz,2H),2.74(t,J=6.0Hz,2H),2.66-2.53(m,8H),2.48(s,3H),2.08-1.94(m,5H),1.69-1.64(m,2H),1.60-1.53(m,1H),1.36-1.29(m,2H);ES-LCMS m/z 626.3,628.4[M+H]+.
步骤3:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(N-甲基甲磺酰氨基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
向N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基氨基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(200mg,0.253mmol)和DIEA(0.133mL,0.759mmol)在DCM(5mL)中的悬浮液中添加MsCl(0.030mL,0.380mmol)。将反应混合物在25℃搅拌1h。将反应混合物浓缩且残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到淡黄色固体N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(N-甲基甲磺酰氨基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(113.21mg,0.131mmol,51.9%产率):1H NMR(400MHz,CD3OD)δppm8.22(d,J=2.6Hz,1H),8.12(dd,J=2.6,9.7Hz,1H),7.99(s,1H),7.88(d,J=1.8Hz,2H),7.56-7.47(m,2H),7.39(s,1H),4.46(s,2H),4.03-3.43(m,14H),3.19-3.05(m,4H),3.03-2.92(m,6H),2.03-1.93(m,5H),1.86(br.s,1H),1.69-1.56(m,2H);ES-LCMS m/z 704.2,706.2[M+H]+.
实施例33:4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-4-氧代丁酸,3盐酸盐
步骤1:4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-4-氧代丁酸甲酯
将N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(200mg,0.316mmol)、4-甲氧基-4-氧代丁酸(50.1mg,0.379mmol)、DIEA(0.331mL,1.896mmol)和HATU(180mg,0.474mmol)在DMF(10mL)中的混合物在20℃搅拌10h。将混合物浓缩且残余物在DCM(30mL)和H2O(20mL)之间分配,用DCM(30mLx2)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过硅胶柱色谱法(DCM/MeOH=20/1/10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到棕色固体的4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-4-氧代丁酸甲酯(200mg,0.266mmol,84.0%产率):1H NMR(400MHz,CD3OD)δppm 8.58(d,J=4.0Hz,1H),8.30-8.22(m,1H),8.05(d,J=2.6Hz,1H),7.80(d,J=1.8Hz,2H),7.45(t,J=1.8Hz,1H),7.16(s,1H),6.96(d,J=9.3Hz,1H),4.31(s,2H),3.76-3.70(m,5H),3.67-3.65(m,2H),3.55-3.45(m,4H),3.26-3.19(m,2H),3.12(d,J=6.6Hz,2H),3.00-2.97(m,2H),2.79-2.58(m,4H),2.03-1.96(m,5H),1.93-1.81(m,1H),1.64-1.51(m,2H);ES-LCMS m/z 683.2,685.2[M+H]+.
步骤2:4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-4-氧代丁酸,3盐酸盐。
将4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-4-氧代丁酸甲酯(200mg,0.266mmol)、氢氧化钠(21.30mg,0.532mmol)在MeOH(5mL)和水(2mL)中的混合物在20℃搅拌10h。然后将混合物浓缩且残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-4-氧代丁酸,3盐酸盐(40.34mg,0.049mmol,18.3%产率):1HNMR(400MHz,CD3OD)δppm 8.21(d,J=11.5Hz,1H),8.14(d,J=2.5Hz,1H),7.98(br.s,1H),7.90(d,J=2.0Hz,2H),7.58(d,J=10.0Hz,1H),7.55(s,1H),7.42(s,1H),4.48(s,2H),3.95-3.79(m,8H),3.62(d,J=11.5Hz,2H),3.18-3.07(m,4H),2.76-2.71(m,2H),2.70-2.63(m,2H),2.04-1.97(m,5H),1.88-1.86(m,1H),1.63-1.61(m,2H);ES-LCMSm/z 669.2,671.2[M+H]+.
实施例34:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-(羟基甲基)环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
步骤1:1-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-羰基)环丙烷甲酸甲酯
向4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯,3盐酸盐(2g,2.77mmol)、1-(甲氧基羰基)环丙烷羧酸(0.379g,2.63mmol)、DIEA(4.84mL,27.7mmol)在DMF(30mL)中的混合物中添加HATU(2.105g,5.54mmol)。将混合物在25℃搅拌2h,然后浓缩。残余物用DCM(100mL)和水(100mL)稀释,用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(DCM/MeOH=10/1,Rf=0.6)纯化以得到黄色固体的1-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-羰基)环丙烷甲酸甲酯(1.1g,1.932mmol,69.8%产率):1HNMR(400MHz,CD3OD)δppm7.98(d,J=2.8Hz,1H),7.70(s,2H),7.64(s,1H),7.45-7.39(m,2H),6.87-6.81(m,2H),4.63(s,2H),3.71-3.62(m,7H),3.55-3.48(m,4H),1.48-1.43(m,2H),1.30-1.25(m,2H);ES-LCMS m/z 557.2,559.2[M+H]+.
步骤2:1-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-羰基)环丙烷甲酸甲酯
向1-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-羰基)环丙烷甲酸甲酯(1.1g,1.932mmol)和DIEA(1.026mL,5.79mmol)在DCM(20mL)中的溶液中添加MsCl(0.314mL,3.86mmol)。溶液在20℃搅拌0.5h。然后溶液用水(50mL×3)洗涤。有机层用Na2SO4干燥,过滤且浓缩以得到黄色固体的1-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-羰基)环丙烷甲酸甲酯(1.2g,1.764mmol,91.0%产率):1H NMR(400MHz,CDCl3)δppm 8.07(d,J=2.6Hz,1H),7.66(d,J=1.8Hz,2H),7.42-7.27(m,3H),6.84(s,1H),6.70(d,J=8.8Hz,1H),5.20(s,2H),3.77-3.71(m,2H),3.68(s,3H),3.60(d,J=5.7Hz,2H),3.53(dd,J=5.3,15.9Hz,4H),3.05(s,3H),1.50-1.46(m,2H),1.33-1.29(m,2H);ES-LCMS m/z 635.1,637.1[M+H]+.
步骤3:1-(4-(5-((4-((4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-羰基)环丙烷羧酸
向1-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-羰基)环丙烷甲酸甲酯(1.2g,1.764mmol)、K2CO3(1.3g,9.41mmol)在DMF(10mL)中的混合物中添加(哌啶-4-基甲基)氨基甲酸叔丁酯(0.567g,2.65mmol)。将混合物在30℃搅拌8h,然后冷却且过滤。将滤液浓缩且残余物通过二氧化硅柱色谱法(DCM/MeOH=10/1,Rf=0.4)纯化以得到棕色固体的1-(4-(5-((4-((4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-羰基)环丙烷羧酸(700mg,0.757mmol,42.9%产率):1H NMR(400MHz,CDCl3)δppm 8.08(s,1H),7.73(s,2H),7.43-7.29(m,3H),7.04(s,1H),6.49(d,J=7.5Hz,1H),4.80(s,2H),3.82-3.63(m,6H),3.49-3.47(m,4H),3.18-3.16(m,2H),3.04-3.00(m,2H),1.77-1.74(m,3H),1.43(s,9H),1.30-1.26(m,4H),1.24(s,2H);ES-LCMS m/z 739.3,741.3[M+H]+.
步骤4:((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-(羟基甲基)环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯
向1-(4-(5-((4-((4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-羰基)环丙烷羧酸(150mg,0.162mmol)在THF(30mL)中的混合物中添加BH3·DMS(0.032mL,0.324mmol)。将混合物在30℃搅拌2h,然后用MeOH(20mL)淬灭。将反应浓缩以得到白色固体的((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-(羟基甲基)环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯(230mg,0.090mmol,55.8%产率):1H NMR(400MHz,CDCl3)δppm8.02(br.s,1H),7.67(br.s,2H),7.38-7.21(m,3H),6.97(br.s,1H),6.45(br.s,1H),4.73(s,2H),3.76-3.56(m,5H),3.42-3.40(m,5H),3.12-3.10(m,2H),2.98-2.97(m,2H),2.52-2.33(m,4H),1.67-1.65(m,3H),1.37(s,9H),1.30-1.18(m,6H);ES-LCMS m/z 711.3,713.3[M+H]+.
步骤5:(1-((4-(5-((4-((4-(氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)甲基)环丙基)甲醇,5盐酸盐
向((1-((2-(3,5-二氯苯基)-6-((6-(4-(1-(羟基甲基)环丙烷羰基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯(230mg,0.089mmol)在MeOH(20mL)中的溶液中添加HCl溶液(4.0M在MeOH中,10mL,40.0mmol)。将混合物在30℃搅拌0.5h,然后浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到棕色固体的(1-((4-(5-((4-((4-(氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)甲基)环丙基)甲醇,5盐酸盐(35mg,0.039mmol,44.0%产率):1H NMR(400MHz,CD3OD)δppm 8.17(d,J=2.6Hz,1H),7.99(s,1H),7.88(d,J=1.8Hz,2H),7.81(dd,J=2.6,9.3Hz,1H),7.49(s,1H),7.34(s,1H),7.25(d,J=9.3Hz,1H),4.46(s,4H),3.94-3.93(m,2H),3.67-3.58(m,4H),3.51-3.36(m,4H),3.29-3.10(m,4H),2.92(d,J=6.2Hz,2H),2.11-2.00(m,3H),1.76-1.73(m,2H),0.88-0.75(m,4H);ES-LCMS m/z 611.3,613.3[M+H]+.
步骤6:乙酸(1-((4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)甲基)环丙基)甲酯
向(1-((4-(5-((4-((4-(氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)甲基)环丙基)甲醇,5盐酸盐(30mg,0.033mmol)和DIEA(0.059mL,0.335mmol)在DCM(5mL)中的溶液中添加Ac2O(3.79μL,0.040mmol)。溶液在20℃搅拌0.5h,然后用水(50mL×3)洗涤。有机层用Na2SO4干燥,过滤且浓缩以得到棕色固体的乙酸(1-((4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)甲基)环丙基)甲酯(32mg,0.032mmol,96.0%产率):1H NMR(400MHz,CDCl3)δppm 8.05(s,1H),7.70(d,J=1.8Hz,2H),7.37-7.32(m,2H),7.27(s,1H),6.74(s,1H),6.66(d,J=9.3Hz,1H),3.61(d,J=6.6Hz,2H),3.51-3.48(m,8H),3.10(t,J=6.4Hz,2H),2.82-2.81(m,2H),2.68-2.66(m,4H),2.61-2.49(m,2H),1.94-1.92(m,6H),1.63-1.60(m,3H),1.32-1.15(m,2H),0.52-0.48(m,2H),0.42-0.38(m,2H);ES-LCMSm/z695.3,697.4[M+H]+.
步骤7:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-(羟基甲基)环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
向乙酸(1-((4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)甲基)环丙基)甲酯(32mg,0.032mmol)在THF(5mL)和水(5mL)中的混合物中添加LiOH·H2O(6.76mg,0.161mmol)。将混合物在30℃搅拌20min,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到灰白色固体的N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-(羟基甲基)环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(11.13mg,0.014mmol,43.2%产率):1H NMR(400MHz,CD3OD)δppm8.20(d,J=2.2Hz,1H),8.03(dd,J=2.4,9.5Hz,1H),7.93(s,1H),7.87(d,J=1.3Hz,2H),7.51(s,1H),7.44(d,J=9.3Hz,1H),7.35(s,1H),4.44(s,4H),3.97-3.95(m,2H),3.64-3.54(m,5H),3.35-3.34(m,5H),3.17-3.02(m,4H),2.06-1.93(m,5H),1.84-1.83(m,1H),1.66-1.53(m,2H),0.81-0.67(m,4H);ES-LCMS m/z 653.3,655.3[M+H]+.
实施例35:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-(羟基甲基)环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
步骤1:1-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-2,2,2-三氟乙酮
向(2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲醇,3盐酸盐(1.9g,3.22mmol)和DIEA(5.69mL,32.2mmol)在DCM(120mL)中的溶液中添加2,2,2-三氟乙酸酐(0.749mL,3.86mmol)。溶液在20℃搅拌0.5h,然后浓缩,用DCM(100mL)和水(100mL)稀释且用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到棕色固体的1-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-2,2,2-三氟乙酮(1.7g,2.87mmol,89.0%产率):1H NMR(400MHz,CDCl3)δppm 8.12(d,J=2.6Hz,1H),7.73(d,J=1.8Hz,2H),7.47-7.39(m,2H),7.32(s,1H),6.87(s,1H),6.74(d,J=8.8Hz,1H),4.76(s,2H),3.84-3.81(m,2H),3.75(d,J=4.9Hz,2H),3.63(dd,J=5.7,11.0Hz,4H);ES-LCMS m/z 527.1,529.1[M+H]+.
步骤2:甲磺酸(2-(3,5-二氯苯基)-6-((6-(4-(2,2,2-三氟乙酰基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基酯
向1-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-2,2,2-三氟乙酮(1.7g,2.87mmol)和DIEA(2.004mL,11.48mmol)在DCM(50mL)中的混合物中添加MsCl(0.447mL,5.74mmol)。将混合物在20℃搅拌0.5h,然后用DCM(100mL)和水(100mL)稀释,用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到棕色固体的甲磺酸(2-(3,5-二氯苯基)-6-((6-(4-(2,2,2-三氟乙酰基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基酯(2.2g,2.60mmol,91.0%产率):1H NMR(400MHz,CDCl3)δppm8.08(d,J=2.2Hz,1H),7.66(d,J=1.3Hz,2H),7.43-7.27(m,3H),6.85(s,1H),6.70(d,J=8.8Hz,1H),5.25-5.16(m,2H),3.79(d,J=4.4Hz,2H),3.72-3.68(m,2H),3.60(dd,J=5.3,11.0Hz,4H),3.09-3.02(m,3H);ES-LCMS m/z 605.1,607.1[M+H]+.
步骤3:((1-((2-(3,5-二氯苯基)-6-((6-(4-(2,2,2-三氟乙酰基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯
向甲磺酸(2-(3,5-二氯苯基)-6-((6-(4-(2,2,2-三氟乙酰基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基酯(2.2g,2.60mmol)和K2CO3(1.3g,9.41mmol)在DMF(10mL)中的混合物中添加(哌啶-4-基甲基)氨基甲酸叔丁酯(0.836g,3.90mmol)。将混合物在30℃搅拌2h,然后冷却且过滤。将滤液浓缩以得到棕色固体的((1-((2-(3,5-二氯苯基)-6-((6-(4-(2,2,2-三氟乙酰基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯(2g,2.178mmol,84.0%产率):1H NMR(400MHz,CDCl3)δppm 8.11-8.08(m,1H),7.75-7.72(m,1H),7.71-7.68(m,1H),7.47-7.39(m,1H),7.37(d,J=2.6Hz,1H),7.29(t,J=1.8Hz,1H),6.84-6.76(m,1H),6.75-6.68(m,1H),3.76-3.69(m,4H),3.65-3.59(m,2H),3.52-3.48(m,2H),3.30(d,J=12.6Hz,2H),3.02-2.99(m,4H),2.02-1.91(m,2H),1.79(d,J=12.8Hz,2H),1.65(d,J=12.6Hz,3H),1.41-1.40(m,9H);ES-LCMS m/z 723.3,725.3[M+H]+.
步骤4:((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-(羟基甲基)环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯
向((1-((2-(3,5-二氯苯基)-6-((6-(4-(2,2,2-三氟乙酰基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯(1.7g,1.851mmol)在THF(5mL)和水(5mL)中的混合物中添加NaOH(0.148g,3.70mmol)。将混合物在30℃搅拌20min,然后浓缩,用DCM(100mL)和水(100mL)稀释,用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物。粗产物通过硅胶柱色谱法(DCM/MeOH=20/1,Rf=0.5)纯化以得到棕色固体的((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯(1.2g,1.663mmol,90.0%产率):1H NMR(400MHz,CDCl3)δppm 8.10(d,J=2.4Hz,1H),7.77-7.73(m,2H),7.42-7.37(m,2H),7.31(d,J=1.3Hz,1H),6.79(s,1H),6.75-6.68(m,1H),3.54-3.50(m,4H),3.48(s,2H),3.05-3.00(m,6H),2.85(d,J=10.8Hz,2H),2.03-1.96(m,2H),1.66(d,J=12.1Hz,3H),1.41(s,9H),1.33-1.26(m,2H);ES-LCMS m/z 627.3,629.3[M+H]+.
步骤5:((1-((2-(3,5-二氯苯基)-6-((6-(4-(1-羟基环丙烷羰基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯
向((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯(300mg,0.416mmol)、1-羟基环丙烷羧酸(85mg,0.499mmol)、DIEA(0.726mL,4.16mmol)在DMF(5mL)中的混合物中添加EDC(80mg,0.416mmol)和HOBt(63.7mg,0.416mmol)。将混合物在25℃搅拌10h,然后浓缩且用DCM(50mL)和水(50mL)稀释,用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物。粗产物通过硅胶柱色谱法(DCM/MeOH=20/1,Rf=0.5)纯化以得到棕色固体((1-((2-(3,5-二氯苯基)-6-((6-(4-(1-羟基环丙烷羰基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯(240mg,0.294mmol,70.8%产率):1H NMR(400MHz,CDCl3)δppm 8.09(d,J=2.5Hz,1H),7.78(d,J=8.0Hz,1H),7.68-7.61(m,3H),7.40(dd,J=2.5,9.0Hz,1H),6.90(s,1H),6.69-6.60(m,1H),3.88-3.86(m,4H),3.57-3.48(m,4H),3.29(d,J=11.0Hz,2H),3.02-2.95(m,2H),2.50-2.47(m,2H),1.79-1.76(m,2H),1.70-1.69(m,1H),1.48-1.47(m,2H),1.41(s,9H),1.17-1.07(m,2H),1.04-0.98(m,2H),0.92-0.81(m,2H);ES-LCMSm/z 711.4,713.4[M+H]+.
步骤6:((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-羟基环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯
向((1-((2-(3,5-二氯苯基)-6-((6-(4-(1-羟基环丙烷羰基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯(230mg,0.282mmol)在THF(5mL)中的混合物中添加BH3·DMS(0.085mL,0.846mmol)。将混合物在30℃搅拌2h。反应溶液通过MeOH(20mL)淬灭。将反应浓缩以得到粗产物。粗产物通过硅胶柱色谱法(DCM/MeOH=10/1,Rf=0.5)纯化以得到棕色固体的((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-羟基环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯(180mg,0.132mmol,46.6%产率):1H NMR(400MHz,CDCl3)δppm 8.06(d,J=2.6Hz,1H),7.68-7.65(m,2H),7.40-7.36(m,2H),7.26(s,1H),6.81(s,1H),6.67(d,J=9.3Hz,1H),3.73-3.72(m,4H),3.42(s,2H),3.05-3.00(m,6H),2.98-2.96(m 4H),2.84(br.s,2H),2.09-2.08(m,3H),1.70-1.65(m,2H),1.39-1.36(m,9H),0.90-0.85(m,2H),0.45-0.40(m,2H);ES-LCMS m/z 697.4,699.4[M+H]+.
步骤7:1-((4-(5-((4-((4-(氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)甲基)环丙醇,5盐酸盐
将((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-羟基环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯(180mg,0.132mmol)在HCl溶液(4.0M在EtOAc中,5mL,20.00mmol)中的溶液在20℃搅拌1h。将混合物浓缩以得到棕色固体的1-((4-(5-((4-((4-(氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)甲基)环丙醇,5盐酸盐(110mg,0.111mmol,85.0%产率):1H NMR(400MHz,CD3OD)δppm 8.20(br.s,1H),8.06-7.94(m,2H),7.92-7.85(m,2H),7.52-7.50(m,2H),7.41-7.36(m,1H),4.51-4.39(m,4H),4.00-3.80(m,4H),3.69-3.55(m,4H),3.50-3.36(m,4H),2.90-2.88(m,2H),2.10-2.00(m,3H),1.80-1.71(m,2H),0.98-0.90(m,2H),0.88-0.77(m,2H);ES-LCMSm/z 597.3,599.3[M+H]+.
步骤8:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-羟基环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
向1-((4-(5-((4-((4-(氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)甲基)环丙醇,5盐酸盐(110mg,0.111mmol)和DIEA(0.197mL,1.114mmol)在DCM(3mL)中的溶液中添加Ac2O(0.023mL,0.245mmol)。溶液在20℃搅拌0.5h,然后浓缩以得到棕色固体,将其溶于THF(20mL)和水(5mL),然后将LiOH·H2O(16.53mg,0.394mmol)添加至溶液。将混合物在30℃搅拌2h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-羟基环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(48.85mg,0.062mmol,79.0%产率):1H NMR(400MHz,CD3OD)δppm8.33-8.21(m,2H),8.04(s,1H),7.90(d,J=1.3Hz,2H),7.67(d,J=9.7Hz,1H),7.51(s,1H),7.45(s,1H),4.47(br.s,4H),3.96(d,J=11.5Hz,2H),3.84(d,J=11.9Hz,2H),3.65-3.49(m,4H),3.44(s,2H),3.22-3.06(m,4H),2.07-1.95(m,5H),1.89(br.s,1H),1.66(d,J=12.3Hz,2H),1.00-0.93(m,2H),0.87-0.80(m,2H);ES-LCMS m/z 639.2,641.2[M+H]+.
实施例36:2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-N-乙基乙酰胺
步骤1:4-(5-((6-(3,5-二氯苯基)-4-((4-(2-(乙基氨基)-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1.1g,1.624mmol)和K2CO3(0.673g,4.87mmol)在DMF(15mL)中的混合物中添加N-乙基-2-(哌啶-4-基)乙酰胺,盐酸盐(0.576g,1.949mmol)。将混合物在80℃搅拌12h,然后过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(DCM/MeOH=10/1,Rf=0.6)纯化以得到黄色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-(2-(乙基氨基)-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(800mg,0.975mmol,60.0%产率):1H NMR(400MHz,CDCl3)δppm8.29(s,2H),7.99(s,1H),7.70(d,J=1.3Hz,2H),7.39(s,1H),7.30(s,1H),6.89(s,1H),3.82-3.79(m,4H),3.65-3.64(m,4H),3.53-3.49(m,6H),3.08(t,J=6.0Hz,2H),2.02-2.00(m,2H),1.84(br.s,2H),1.70-1.68(m,3H),1.48(s,9H),1.29-1.26(m,3H);ES-LCMS m/z 683.3,685.3[M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-N-乙基乙酰胺,4盐酸盐
将4-(5-((6-(3,5-二氯苯基)-4-((4-(2-(乙基氨基)-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(800mg,0.975mmol)在HCl溶液(4.0M在MeOH中,5mL,88mmol)中的溶液在20℃搅拌0.5h。将反应浓缩以得到棕色固体的2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-N-乙基乙酰胺,4盐酸盐(800mg,0.950mmol,97.0%产率):1H NMR(400MHz,CD3OD)δppm 8.28(dd,J=2.4,9.9Hz,1H),8.23(d,J=2.2Hz,1H),8.07(s,1H),7.89(d,J=1.3Hz,2H),7.66(d,J=10.1Hz,1H),7.51-7.47(m,1H),7.46-7.42(m,1H),4.47(s,2H),4.11-4.06(m,4H),3.54-3.49(m,4H),3.31-3.29(m,2H),3.24-3.12(m,4H),2.22(d,J=7.1Hz,2H),2.10(br.s,1H),1.96(d,J=13.7Hz,2H),1.78-1.68(m,2H),1.12(t,J=7.3Hz,3H);ES-LCMSm/z583.3,585.3[M+H]+.
步骤3:2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-N-乙基乙酰胺
向2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-N-乙基乙酰胺,3盐酸盐(200mg,0.250mmol)、AcOH(1.431μL,0.025mmol)和分子筛(200mg,0.250mmol)在MeOH(10mL)中的混合物中添加3-(甲基磺酰基)丙醛(170mg,1.000mmol)。将混合物在20℃在N2气氛搅拌10h,然后添加NaBH3CN(15.71mg,0.250mmol)。将混合物在20℃搅拌0.5h,然后过滤且浓缩以得到残余物,将其在DCM(50mL)和饱和NaHCO3溶液(水溶液,50mL)之间分配,分离且水相用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化且冻干干燥以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-N-乙基乙酰胺(41.56mg,0.059mmol,23.6%产率):1H NMR(400MHz,CD3OD)δppm8.03(d,J=2.6Hz,1H),7.83(d,J=1.8Hz,2H),7.63(s,1H),7.50(dd,J=2.9,9.0Hz,1H),7.43(s,1H),6.98-6.92(m,2H),4.60(s,2H),3.61-3.54(m,6H),3.22(d,J=10.1Hz,2H),3.18(d,J=7.5Hz,2H),2.99(s,2H),2.92(d,J=11.5Hz,2H),2.65-2.61(m,3H),2.57(t,J=7.3Hz,2H),2.10(d,J=6.6Hz,2H),2.07(d,J=7.5Hz,2H),1.70(d,J=13.2Hz,3H),1.40-1.28(m,4H),1.10(t,J=7.3Hz,3H);ES-LCMS m/z 703.3,705.3[M+H]+.
实施例37:1-(2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)-N-甲基甲胺,4盐酸盐
步骤1:(5-((6-(3,5-二氯苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1g,1.474mmol)在MeCN(5mL)中的溶液中添加甲胺(在EtOH中,1.895g,7.37mmol)。将混合物在20℃搅拌10h,然后浓缩以得到粗产物,其通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到白色固体的(5-((6-(3,5-二氯苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(200mg,0.334mmol,22.7%产率):1H NMR(400MHz,CDCl3)δppm 8.30(s,2H),7.74(d,J=1.8Hz,2H),7.43(s,1H),7.34(d,J=1.8Hz,1H),7.26(s,1H),3.83(br.s,6H),3.53(d,J=4.4Hz,4H),2.50(s,3H),1.49(s,9H);ES-LCMSm/z 545.2,547.1[M+H]+.
步骤2:4-(5-((4-((((苄基氧基)羰基)(甲基)氨基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(200mg,0.334mmol)和DIEA(0.2mL,1.145mmol)在DCM(5mL)中的混合物中添加CbzCl(0.057mL,0.401mmol)。将混合物在20℃搅拌1h,然后浓缩至粗产物,其通过硅胶柱色谱法(PE/EtOAc=3/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到棕色固体的4-(5-((4-((((苄基氧基)羰基)(甲基)氨基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(150mg,0.219mmol,65.4%产率):1H NMR(400MHz,CD3OD)δppm 8.31(br.s,2H),7.76-7.67(m,2H),7.44-7.33(m,4H),7.25(br.s,2H),6.91-6.78(m,2H),5.21-5.14(m,2H),4.59(br.s,2H),3.84-3.79(m,4H),3.51(br.s,4H),3.02(br.s,3H),1.49(s,9H);ES-LCMS m/z 679.2,681.2[M+H]+.
步骤3:((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)(甲基)氨基甲酸苄基酯,3盐酸盐
将4-(5-((4-((((苄基氧基)羰基)(甲基)氨基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(150mg,0.219mmol)在HCl溶液(4M在EtOAc中,10mL,40.0mmol)中的溶液在20℃搅拌0.5h。将混合物浓缩以得到棕色固体的((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)(甲基)氨基甲酸苄基酯,4盐酸盐(150mg,0.186mmol,85.0%产率):1H NMR(400MHz,CD3OD)δppm8.50-8.46(m,2H),7.77(br.s,1H),7.70(br.s,1H),7.46-7.19(m,7H),6.90-6.85(m,1H),5.22-5.13(m,2H),4.62(br.s,2H),4.14(t,J=4.9Hz,4H),3.36-3.33(m,4H),3.04(s,3H);ES-LCMS m/z579.1,581.1[M+H]+.
步骤4:((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)(甲基)氨基甲酸苄基酯
向((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)(甲基)氨基甲酸苄基酯,3盐酸盐(160mg,0.188mmol)、AcOH(1.076μL,0.019mmol)和分子筛(200mg,0.188mmol)在MeOH(10mL)中的混合物中添加3-(甲基磺酰基)丙醛(128mg,0.752mmol)。将混合物在20℃在N2气氛搅拌4h,然后添加NaBH3CN(11.81mg,0.188mmol)且将混合物在20℃再搅拌0.5h。将反应过滤且浓缩以得到残余物,将其在DCM(50mL)和饱和NaHCO3水溶液(50mL)之间分配,分离且用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物,其通过制备型TLC纯化且冻干干燥以得到黄色固体的((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)(甲基)氨基甲酸苄基酯(120mg,0.142mmol,76.0%产率):1H NMR(400MHz,CD3OD)δppm8.32(br.s,2H),7.81-7.69(m,2H),7.48-7.23(m,7H),6.93-6.82(m,1H),5.26-5.12(m,2H),4.62(s,2H),3.89-3.87(m,4H),3.25-3.23(m,4H),3.05(s,3H),2.59-2.57(m,4H),2.17(s,3H),2.11-2.04(m,2H);ES-LCMS m/z 699.1,701.1[M+H]+.
步骤5:1-(2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)-N-甲基甲胺,4盐酸盐
将((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)(甲基)氨基甲酸苄基酯(120mg,0.142mmol)在TFA(5mL,64.9mmol)中的溶液在50℃搅拌10h。将反应浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的1-(2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)-N-甲基甲胺,4盐酸盐(43.9mg,0.061mmol,43.2%产率):1H NMR(400MHz,CD3OD)δppm8.46(s,2H),7.85(s,2H),7.79(s,1H),7.52(br.s,1H),7.23(s,1H),4.35(s,2H),3.73(br.s,2H),3.50-3.37(m,6H),3.23(br.s,4H),3.06(s,3H),2.83(s,3H),2.40-2.29(m,2H);ES-LCMS m/z 565.1,567.1[M+H]+.
实施例38:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(氨磺酰基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
步骤1:4-((乙酰基硫基)甲基)哌啶-1-甲酸苄基酯
向4-(((甲基磺酰基)氧基)甲基)哌啶-1-甲酸苄基酯(4g,9.77mmol)、K2CO3(4.05g,29.3mmol)在DMF(50mL)中的混合物中添加硫代乙S-酸(ethanethioic S-acid)(1.488g,19.55mmol)。将混合物在25℃搅拌3h,然后浓缩。残余物用DCM(100mL)和水(100mL)稀释,分离且水相用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物。粗产物通过硅胶柱色谱法(PE/EtOAc=10/1至3/1)纯化。将所有通过TLC(PE/EtOAc=5/1,Rf=0.3)发现包含产物的级分合并且浓缩以得到棕色固体的4-((乙酰基硫基)甲基)哌啶-1-甲酸苄基酯(3g,7.32mmol,74.9%产率):1H NMR(400MHz,CDCl3)δppm7.47-7.08(m,5H),5.10(s,2H),4.29-4.04(m,2H),2.90-2.59(m,4H),2.32(s,3H),1.81-1.67(m,2H),1.64-1.57(m,1H),1.25-1.06(m,2H);ES-LCMS m/z 308.2[M+H]+.
步骤2:4,4’-(二硫二基双(亚甲基))双(哌啶-1-甲酸)二苄基酯
向4-((乙酰基硫基)甲基)哌啶-1-甲酸苄基酯(2.4g,5.86mmol)在MeOH(20mL)和水(10mL)中的溶液中添加K2CO3(809mg,5.86mmol)。将混合物在30℃搅拌2h,然后用水(100mL)稀释,用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到棕色固体的4,4’-(二硫二基双(亚甲基))双(哌啶-1-甲酸)二苄基酯(2g,2.65mmol,90.0%产率):1H NMR(400MHz,CDCl3)δppm 7.40-7.29(m,10H),5.13(s,4H),4.25-4.13(m,4H),2.79(br.s,4H),2.61(d,J=6.0Hz,4H),1.88-1.78(m,6H),1.17(d,J=9.5Hz,4H);ES-LCMS m/z529.2[M+H]+.
步骤3:4-(巯基甲基)哌啶-1-甲酸苄基酯
向4,4’-(二硫二基双(亚甲基))双(哌啶-1-甲酸)二苄基酯(1900mg,2.52mmol)在乙酸(10mL,175mmol)中的混合物中添加锌粉(822mg,12.58mmol)。将混合物在20℃搅拌0.5h,然后过滤。将滤液浓缩以得到棕色固体的4-(巯基甲基)哌啶-1-甲酸苄基酯(1200mg,4.38mmol,87.0%产率):1H NMR(400MHz,CDCl3)δppm7.38-7.24(m,5H),5.11(s,2H),4.19(br.s,2H),2.75(br.s,2H),2.44(t,J=7.3Hz,2H),1.82(d,J=12.3Hz,2H),1.59-1.50(m,1H),1.13(d,J=10.1Hz,2H);ES-LCMS m/z 266.2[M+H]+.
步骤4:4-((氯磺酰基)甲基)哌啶-1-甲酸苄基酯
将4-(巯基甲基)哌啶-1-甲酸苄基酯(600mg,2.189mmol)在水(10mL)和THF(10mL)中的搅拌悬浮液在0-5℃用氯气鼓泡20min。混合物用N2吹洗以去除过量氯,然后浓缩。残余物用DCM(50mL)和水(50mL)稀释,用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到棕色油状物4-((氯磺酰基)甲基)哌啶-1-甲酸苄基酯(900mg,0.651mmol,29.7%产率):1H NMR(400MHz,CDCl3)δppm7.36-7.23(m,5H),5.08-5.03(m,2H),4.14-4.06(m,2H),2.80-2.77(m,2H),2.56-2.53(m,2H),1.93-1.82(m,3H),1.20-1.15(m,2H);ES-LCMS m/z 332.0[M+H]+.
步骤5:4-(氨磺酰基甲基)哌啶-1-甲酸苄基酯
将4-((氯磺酰基)甲基)哌啶-1-甲酸苄基酯(900mg,0.651mmol)在THF(10mL)中的溶液冷却至-40℃,然后用氨气缓慢吹洗20min。将混合物浓缩且残余物溶于DCM(100mL)和水(100mL),用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到棕色固体的4-(氨磺酰基甲基)哌啶-1-甲酸苄基酯(110mg,0.343mmol,52.7%产率):1H NMR(400MHz,CD3OD)δppm 7.40-7.31(m,5H),5.13(s,2H),4.14(d,J=13.6Hz,2H),3.06(d,J=6.5Hz,2H),2.92(br.s,2H),2.26-2.17(m,1H),1.98(d,J=12.5Hz,2H),1.30(dd,J=3.8,12.3Hz,2H);ES-LCMS m/z 313.1[M+H]+.
步骤6:哌啶-4-基甲磺酰胺
向4-(氨磺酰基甲基)哌啶-1-甲酸苄基酯(110mg,0.343mmol)在MeOH(15mL)中的溶液中添加10%Pd/C(36.5mg,0.034mmol)。将反应混合物在20℃在H2气氛(15psi)搅拌0.5h,然后过滤。将滤液浓缩以得到棕色固体的哌啶-4-基甲磺酰胺(60mg,0.303mmol,88.0%产率):1H NMR(400MHz,CD3OD)δppm 3.17-2.93(m,4H),2.42-2.13(m,3H),2.11-1.91(m,2H),1.64-1.44(m,2H);ES-LCMS m/z 179.1[M+H]+.
步骤7:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(氨磺酰基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
向3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(160mg,0.191mmol)和K2CO3(132mg,0.953mmol)在DMF(10mL)中的混合物中添加哌啶-4-基甲磺酰胺(60mg,0.303mmol)。将混合物在20℃搅拌0.5h,然后浓缩。残余物溶于DCM(50mL)和水(50mL),用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到棕色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(氨磺酰基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(200mg,0.085mmol,44.6%产率):1H NMR(400MHz,CDCl3)δppm 7.68(s,2H),7.52(s,2H),7.47(s,2H),7.18-7.14(m,1H),7.00(s,1H),4.13(m,2H),3.49-3.45(m,12H),3.17-3.02(m,4H),2.73-2.71(m,2H),2.34-2.31(m,2H),1.98-1.92(m,2H),1.65-1.60(m,3H),1.27-1.21(m,3H);ES-LCMS m/z 691.3,693.2[M+H]+.
步骤8:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(氨磺酰基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
向3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(氨磺酰基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(200mg,0.085mmol)在THF(5mL)和水(5mL)中的混合物中添加LiOH·H2O(17.84mg,0.425mmol)。将混合物在30℃搅拌3h,然后用HCl溶液(水溶液,2.0M)将pH调节至5-7。将混合物浓缩且残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(氨磺酰基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐(10.3mg,0.013mmol,15.0%产率):1H NMR(400MHz,CD3OD)δppm8.18(d,J=2.9Hz,1H),7.90(s,1H),7.87(d,J=1.8Hz,2H),7.84(dd,J=2.9,9.3Hz,1H),7.51(t,J=1.8Hz,1H),7.31(s,1H),7.27(d,J=9.5Hz,1H),4.44(s,2H),3.74-3.57(m,4H),3.53(t,J=6.9Hz,4H),3.34-3.30(m,4H),3.27-3.14(m,2H),3.11(d,J=6.2Hz,2H),2.93(t,J=6.9Hz,2H),2.29-2.26(m,3H),1.81-1.66(m,2H);ES-LCMSm/z663.2,665.2[M+H]+.
实施例39:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((甲基磺酰基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸
步骤1:4-(((甲基磺酰基)氧基)甲基)哌啶-1-甲酸叔丁酯
在0℃向4-(羟基甲基)哌啶-1-甲酸叔丁酯(3g,13.93mmol)和DIEA(5.40g,41.8mmol)在DCM(50mL)中的溶液中添加MsCl(1.303mL,16.72mmol)。将反应混合物在0℃搅拌10min,然后添加水(50mL)且用DCM(25mL×3)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色油状物4-(((甲基磺酰基)氧基)甲基)哌啶-1-甲酸叔丁酯(4g,12.95mmol,93.0%产率):1H NMR(400MHz,CDCl3)δppm 4.14(s,2H),4.06(d,J=6.6Hz,2H),3.00(s,3H),2.70(t,J=12.1Hz,2H),1.95-1.86(m,1H),1.73(d,J=13.2Hz,2H),1.44(s,9H),1.25-1.18(m,2H);ES-LCMS m/z 238.2[M-t-Bu+H]+.
步骤2:4-((甲硫基)甲基)哌啶-1-甲酸叔丁酯
在25℃向4-(((甲基磺酰基)氧基)甲基)哌啶-1-甲酸叔丁酯(4g,12.95mmol)和甲硫醇钠(3.63g,51.8mmol)在DMF(50mL)中的溶液中添加K2CO3(3.58g,25.9mmol)。将反应混合物在25℃搅拌12h,然后过滤且将滤液浓缩以得到粗产物,其在硅胶上通过快速色谱法(PE/EtOAc=1/0至1/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.45)发现包含产物的级分合并且浓缩以得到黄色油状物4-((甲硫基)甲基)哌啶-1-甲酸叔丁酯(1.6g,5.87mmol,45.3%产率):1H NMR(400MHz,CDCl3)δppm 4.14-4.04(m,2H),2.68(t,J=12.1Hz,2H),2.41(d,J=6.6Hz,2H),2.08(s,3H),1.79(d,J=13.2Hz,2H),1.62-1.60(m,1H),1.44(s,9H),1.17-1.07(m,2H);ES-LCMS m/z 190.2[M-t-Bu+H]+.
步骤3:4-((甲基磺酰基)甲基)哌啶-1-甲酸叔丁酯
在25℃向4-((甲硫基)甲基)哌啶-1-甲酸叔丁酯(500mg,1.834mmol)在DCM(10mL)中的溶液中添加m-CPBA(745mg,3.67mmol)。将反应混合物在25℃搅拌12h,然后过滤。残余物浓缩以得到粗产物,其在硅胶上通过快速色谱法(PE/EtOAc=1/0至1/3)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.25)发现包含产物的级分合并且浓缩以得到以得到淡黄色固体的4-((甲基磺酰基)甲基)哌啶-1-甲酸叔丁酯(310mg,0.894mmol,48.8%产率):1H NMR(400MHz,CDCl3)δppm 4.11(s,2H),2.96(d,J=6.0Hz,2H),2.94(s,3H),2.77(t,J=11.3Hz,2H),2.28-2.21(m,1H),1.94(d,J=12.5Hz,2H),1.45(s,9H),1.33-1.29(m,2H);ES-LCMS m/z 222.1[M-t-Bu+H]+.
步骤4:4-((甲基磺酰基)甲基)哌啶
将4-((甲基磺酰基)甲基)哌啶-1-甲酸叔丁酯(200mg,0.577mmol)在4.0M HCl(在EtOAc中)(10mL,40.0mmol)中的混合物在25℃搅拌0.5h。形成白色沉淀。过滤后,将滤饼干燥以得到白色固体的4-((甲基磺酰基)甲基)哌啶,盐酸盐(130mg,0.547mmol,95.0%产率):1H NMR(400MHz,CD3OD)δppm 3.39(d,J=12.8Hz,2H),3.19(d,J=6.6Hz,2H),3.10-3.03(m,2H),3.01(s,3H),2.42-2.33(m,1H),2.19(d,J=14.6Hz,2H),1.69-1.57(m,2H);ES-LCMS m/z 178.1[M+H]+.
步骤5:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((甲基磺酰基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
向3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(230mg,0.287mmol)和4-((甲基磺酰基)甲基)哌啶,盐酸盐(130mg,0.547mmol)在DMF(10mL)中的溶液中添加K2CO3(119mg,0.862mmol)。将反应混合物在80℃搅拌12h,然后过滤。残余物浓缩以得到黄色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((甲基磺酰基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(230mg,0.200mmol,69.6%产率):1H NMR(400MHz,CD3OD)δppm8.02(d,J=2.9Hz,1H),7.85-7.76(m,2H),7.61(s,1H),7.50-7.45(m,1H),7.43-7.37(m,1H),6.97(s,1H),6.94-6.89(m,1H),4.15(q,J=7.1Hz,2H),3.61-3.58(m,2H),3.56-3.51(m,4H),3.11(d,J=6.4Hz,2H),2.99(s,3H),2.92(d,J=11.9Hz,2H),2.78-2.74(m,2H),2.65-2.62(m,4H),2.60-2.54(m,2H),2.20-2.11(m,2H),2.08-2.01(m,1H),1.96(d,J=11.5Hz,2H),1.55-1.43(m,2H),1.26(t,J=7.2Hz,3H);ES-LCMSm/z 690.3,692.2[M+H]+.
步骤6:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((甲基磺酰基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸
向3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((甲基磺酰基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(230mg,0.200mmol)在MeOH(10mL)中的溶液中添加NaOH(15.98mg,0.400mmol)的水(1mL)溶液。将反应混合物在25℃搅拌12h。添加1N HCl以将pH调节至4-5。将溶液浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((甲基磺酰基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐(89.96mg,0.104mmol,52.3%产率):1H NMR(400MHz,CD3OD)δppm 8.23(d,J=2.5Hz,1H),8.03-7.98(m,1H),7.97(s,1H),7.90(d,J=1.5Hz,2H),7.54(s,1H),7.42(d,J=9.5Hz,1H),7.38(s,1H),4.47(s,2H),3.63(d,J=12.0Hz,10H),3.28-3.11(m,6H),3.03(s,3H),2.97(t,J=6.8Hz,2H),2.42(s,1H),2.30-2.27(m,2H),1.83(q,J=2.0Hz,2H);ES-LCMS m/z 662.2,664.2[M+H]+.
实施例40:1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲,4盐酸盐
步骤1:1-((1-((2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲
将包含2-(苄基氧基)-4-(氯甲基)-6-(3,5-二氯苯基)吡啶(40%)和甲磺酸(2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基酯(60%)的6.3g混合物添加至1-甲基-3-(哌啶-4-基甲基)脲盐酸盐(3.46g,16.64mmol)和K2CO3(8.62mL,49.9mmol)在DMF(75mL)中的溶液中。将混合物在65℃搅拌8h,然后冷却且添加H2O(200mL)。形成粉色沉淀。将混合物过滤且将滤饼干燥以得到粉色固体的1-((1-((2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲(6.7g,11.74mmol,70.6%产率):1H NMR(400MHz,CDCl3)δppm 7.94-7.81(m,2H),7.50(d,J=7.3Hz,2H),7.44-7.27(m,5H),6.77(s,1H),5.46(s,2H),4.38(br.s,1H),4.24(d,J=4.2Hz,1H),3.46(s,2H),3.08(t,J=6.2Hz,2H),2.86(d,J=13.5Hz,2H),2.77(d,J=4.9Hz,3H),2.03-1.92(m,2H),1.50-1.48(m,1H),1.36-1.22(m,2H);ES-LCMS m/z 513.2,515.2[M+H]+.
步骤2:1-((1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲盐酸盐
将1-((1-((2-(苄基氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲(6.7g,12.40mmol)和浓HCl溶液(30mL,365mmol)在DCM(30mL)中的混合物在85℃搅拌4h。粗物质浓缩以得到黄色固体的1-((1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲盐酸盐(5.3g,9.80mmol,79.0%产率):1H NMR(400MHz,DMSO-d6)δppm 8.01(d,J=1.8Hz,2H),7.70(d,J=1.8Hz,2H),6.78(s,1H),4.27-4.14(m,2H),3.44-3.29(m,2H),3.14-3.10(m,2H),2.90(s,3H),2.72-2.71(m,2H),1.78-1.76(m,2H),1.58-1.55(m,3H);ES-LCMSm/z 423.2,425.2[M+H]+.
步骤3:1-((1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲
将1-((1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲(2g,4.72mmol)、2-溴-5-氟吡啶(4.16g,23.62mmol)和K2CO3(1.959g,14.17mmol)在DMF(30mL)中的混合物在140℃搅拌8h。将混合物浓缩且残余物在DCM(100mL)和H2O(100mL)之间分配。分离有机层,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(DCM/MeOH=1/0至20/1)纯化。将所有通过TLC(DCM/MeOH=20/1,Rf=0.25)发现包含产物的级分合并且浓缩以得到黄色固体的1-((1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲(390mg,0.606mmol,12.8%产率):1H NMR(400MHz,CD3OD)δppm 8.31(d,J=2.6Hz,1H),7.83-7.74(m,2H),7.72-7.61(m,3H),7.43(s,1H),7.09(s,1H),3.68-3.58(m,2H),3.07-2.88(m,4H),2.67(s,3H),2.10(t,J=11.0Hz,2H),1.72(d,J=11.9Hz,2H),1.50-1.47(m,1H),1.37-1.20(m,2H);ES-LCMSm/z580.1,582.1[M+H]+.
步骤4:1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲,4盐酸盐
将1-((1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲(250mg,0.432mmol)、2-(哌嗪-1-基)乙醇(112mg,0.863mmol)、Xantphos(24.97mg,0.043mmol)、Cs2CO3(422mg,1.295mmol)和Pd2(dba)3(19.76mg,0.022mmol)在THF(5mL)中的混合物在80℃在N2气氛搅拌8h。将混合物过滤且将滤液浓缩。残余物通过制备型TLC(DCM/MeOH=9/1,Rf=0.15)纯化以得到黄色固体,将其进一步通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到白色固体的1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲,4盐酸盐(15.26mg,0.02mmol,4.5%产率):1H NMR(400MHz,CD3OD)δppm8.06-7.99(m,2H),7.98-7.93(m,1H),7.90(d,J=1.8Hz,2H),7.52(s,1H),7.37(s,1H),7.17(d,J=9.7Hz,1H),4.44(s,2H),4.18(d,J=14.1Hz,2H),3.94-3.86(m,2H),3.60(d,J=10.1Hz,4H),3.38-3.33(m,2H),3.24-3.01(m,11H),2.08-1.78(m,3H),1.75-1.54(m,2H);ES-LCMS m/z 628.3,630.3[M+H]+.
实施例41:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
步骤1:4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(0.5g,0.632mmol)和1-甲基-3-(哌啶-4-基甲基)脲盐酸盐(0.192g,0.758mmol)在DMF(10mL)中的混合物中添加K2CO3(0.262g,1.895mmol)。将混合物在80℃搅拌2h。然后将溶液过滤且浓缩。粗产物在DCM(40mL)和饱和NaHCO3水溶液(20mL)之间分配。合并的有机萃取物用盐水(10mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过硅胶柱色谱法(PE/EtOAc=1/1)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到棕色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(300mg,0.394mmol,62.4%产率):1H NMR(400MHz,CD3OD)δppm 8.06-8.01(m,1H),7.81(d,J=1.8Hz,2H),7.61(s,1H),7.53-7.46(m,1H),7.41(t,J=1.8Hz,1H),7.00-6.92(m,2H),3.62-3.46(m,10H),3.05-2.98(m,2H),2.93(d,J=11.5Hz,2H),2.68(s,3H),2.08(t,J=10.8Hz,2H),1.72(d,J=11.5Hz,2H),1.49(s,10H),1.35-1.25(m,2H);ES-LCMS m/z 684.2,686.2[M+H]+.
步骤2:1-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲
向4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(300mg,0.394mmol)在EtOAc(10mL)中的溶液中添加HCl溶液(4.0M在EtOAc中,3mL,12.00mmol)。将混合物在20℃搅拌10min,然后浓缩且在DCM(50mL)和饱和NaHCO3水溶液(30mL)之间分配。合并的有机萃取物用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色固体的1-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲(200mg,0.294mmol,74.6%产率):1H NMR(400MHz,CD3OD)δppm 8.30-8.22(m,2H),8.06(s,1H),7.90(d,J=1.8Hz,2H),7.65(d,J=9.7Hz,1H),7.53-7.48(m,1H),7.45(s,1H),4.61-4.45(m,2H),4.13-4.05(m,4H),3.60(d,J=11.9Hz,2H),3.54-3.49(m,4H),3.16-3.08(m,4H),2.75-2.73(m,3H),1.99(d,J=13.7Hz,2H),1.87(br.s,1H),1.71-1.58(m,2H);ES-LCMS m/z 584.2,586.2[M+H]+.
步骤3:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
向1-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲(200mg,0.342mmol)在DMF(10mL)中的溶液中添加K2CO3(142mg,1.026mmol)和3-溴丙酸乙酯(74.3mg,0.411mmol)。将混合物在80℃搅拌8h,然后浓缩。添加水(20mL)且将混合物用DCM(20mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色油状物的3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(150mg,0.175mmol,51.2%产率):1H NMR(400MHz,CD3OD)δppm 8.01(d,J=2.6Hz,1H),7.80(d,J=1.3Hz,2H),7.60(s,1H),7.47(dd,J=2.6,9.3Hz,1H),7.40(s,1H),6.96-6.91(m,2H),4.18(q,J=7.6Hz,2H),3.59-3.58(m,2H),3.33(s,3H),3.03-2.97(m,5H),2.91(d,J=11.0Hz,2H),2.84(s,2H),2.73-2.68(m,4H),2.66(s,3H),2.06(t,J=11.0Hz,2H),1.70(d,J=11.5Hz,2H),1.48-1.42(m,2H),1.28(br.s,4H);ES-LCMS m/z 684.2,686.2[M+H]+.
步骤4:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
向3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(200mg,0.292mmol)在MeOH(10mL)和水(2mL)中的溶液中添加NaOH(23.37mg,0.584mmol)。将混合物在15℃搅拌0.5h。将混合物浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐(38.6mg,0.047mmol,16.0%产率):1H NMR(400MHz,CD3OD)δppm 8.20(br.s,1H),7.95(br.s,1H),7.86(br.s,3H),7.54-7.29(m,3H),4.55-4.35(m,4H),3.68-3.49(m,6H),3.06(d,J=5.7Hz,5H),2.95(br.s,4H),2.68(br.s,4H),1.97(d,J=13.7Hz,2H),1.80(br.s,1H),1.57(br.s,2H);ES-LCMSm/z656.2,658.2[M+H]+.
实施例42:N-((1-((5-(4-氨基苯氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,2盐酸盐
步骤1:N-((1-((3',5'-二氯-5-(4-硝基苯氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺
向N-((1-((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(500mg,1.227mmol)和1-氟-4-硝基苯(208mg,1.473mmol)在MeCN(100mL)中的溶液中添加K2CO3(509mg,3.68mmol)。将反应混合物在80℃搅拌16h,然后过滤。将滤液浓缩以得到粗产物,将其通过柱纯化以得到N-((1-((3',5'-二氯-5-(4-硝基苯氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(450mg,0.852mmol,69.4%产率):1H NMR(400MHz,CDCl3)δppm 8.22(d,J=9.2Hz,2H),7.42(d,J=1.6Hz,2H),7.37-7.35(m,2H),7.12(d,J=8.8Hz,2H),7.04(d,J=9.2Hz,2H),5.49(br.s,1H),3.54(s,2H),3.16-3.12(m,2H),2.89-2.87(m,2H),2.01-1.97(m,5H),1.69-1.65(m,2H),1.52-1.51(m,1H),1.32-1.19(m,2H);ES-LCMSm/z 528.1,530.1[M+H]+.
步骤2:N-((1-((5-(4-氨基苯氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,2盐酸盐
向N-((1-((3',5'-二氯-5-(4-硝基苯氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(350mg,0.662mmol)在AcOH(20mL)中的溶液中添加Zn粉(433mg,6.62mmol)。将反应混合物在80℃搅拌16h,然后过滤。将滤液浓缩且残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到N-((1-((5-(4-氨基苯氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,2盐酸盐(157.76mg,0.274mmol,41.4%产率):1H NMR(400MHz,CD3OD)δppm 7.69(s,1H),7.64(m,2H),7.48-7.45(m,3H),7.39-7.34(m,2H),7.26-7.24(m,2H),4.37(s,2H),3.55-3.52(m,2H),3.15-3.13(m,2H),3.08-3.02(m,2H),2.00-1.94(m,5H),1.88-1.86(m,1H),1.62-1.53(m,2H);ES-LCMS m/z 498.2,500.2[M+H]+.
实施例43:N-((1-((5-((5-氨基嘧啶-2-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺
步骤1:N-((1-((3',5'-二氯-5-((5-硝基嘧啶-2-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺
将N-((1-((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(200mg,0.491mmol)、2-氯-5-硝基嘧啶(78mg,0.491mmol)和DIEA(0.257mL,1.473mmol)在i-PrOH(2mL)中的混合物在170℃在微波中搅拌1h。将混合物浓缩以得到残余物,将其通过制备型TLC(PE/EtOAc=3/1,Rf=0.5)纯化以得到N-((1-((3',5'-二氯-5-((5-硝基嘧啶-2-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(40mg,0.075mmol,15.3%产率):1H NMR(400MHz,CD3OD)δppm 9.41(s,1H),9.09(s,1H),7.84(s,1H),7.78(s,1H),7.73(d,J=1.5Hz,2H),7.54(d,J=1.5Hz,2H),4.45(s,2H),3.62(d,J=12.5Hz,2H),3.17-3.12(m,2H),3.11-3.02(m,2H),2.01-1.97(m,5H),1.85-1.83(m,1H),1.58-1.46(m,2H);ES-LCMS m/z 530.2,532.2[M+H]+.
步骤2:N-((1-((5-((5-氨基嘧啶-2-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺
将Pd/C(10wt%,4.01mg,0.038mmol)、N-((1-((3',5'-二氯-5-((5-硝基嘧啶-2-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(20mg,0.038mmol)在EtOAc(10mL)中的混合物在25℃在H2气氛(50psi)搅拌15min。将混合物过滤且将滤液浓缩。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到N-((1-((5-((5-氨基嘧啶-2-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,2盐酸盐(1.7mg,2.94μmol,7.8%产率):1H NMR(400MHz,CD3OD)δppm 8.13(s,2H),7.67-7.62(m,3H),7.55(br.s,1H),7.48(br.s,1H),7.34(br.s,1H),4.36(s,2H),3.56(d,J=12.3Hz,2H),3.09(d,J=6.6Hz,2H),3.03(d,J=12.3Hz,2H),1.99-1.91(m,5H),1.80-1.77(m,1H),1.43(m,2H);ES-LCMSm/z 500.1,502.1[M+H]+.
实施例44:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(甲基磺酰氨基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
步骤1:3-(4-(5-((4-((4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
向3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(830mg,1.157mmol)和(哌啶-4-基甲基)氨基甲酸叔丁酯(496mg,2.315mmol)在DMF(10mL)中的溶液中添加K2CO3(480mg,3.47mmol)。将反应混合物在80℃搅拌12h。将固体过滤掉且将溶液浓缩以得到粗产物,其通过快速色谱柱(从纯的DCM至DCM/MeOH=10/1,DCM/MeOH=10/1,Rf=0.55)纯化以得到淡黄色固体3-(4-(5-((4-((4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(750mg,0.928mmol,80.0%产率):1H NMR(400MHz,CD3OD)δppm 8.05(s,1H),7.84(s,2H),7.65(s,1H),7.51(d,J=3.2Hz,1H),7.45(s,1H),6.97-6.94(m,2H),4.20-4.16(m,2H),3.58(s,2H),3.57-3.56(m,4H),2.97-2.94(m,4H),2.80-2.75(m,2H),2.67-2.61(m,4H),2.60-2.52(m,2H),2.15-2.08(m,2H),1.76-1.70(m,2H),1.50-1.45(m,10H),1.30-1.27(m,5H);ES-LCMSm/z 727.4,729.4[M+H]+.
步骤2:3-(4-(5-((4-((4-(氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
将3-(4-(5-((4-((4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(750mg,0.928mmol)溶于HCl溶液(4.0M在EtOAc中,3mL,12.00mmol)。将反应混合物在15℃搅拌10min,然后浓缩以得到淡黄色固体的3-(4-(5-((4-((4-(氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯,5盐酸盐(850mg,0.873mmol,94.0%产率):1HNMR(400MHz,CD3OD)δppm 8.29-8.26(m,1H),8.12(s,1H),8.03(s,1H),7.93(d,J=1.5Hz,2H),7.67(d,J=9.5Hz,1H),7.57-7.48(m,2H),4.62-4.37(m,4H),4.25(q,J=7.2Hz,2H),3.93-3.72(m,4H),3.70-3.48(m,6H),3.30-3.19(m,2H),3.05(s,2H),2.95(d,J=6.0Hz,2H),2.09(d,J=12.0Hz,3H),1.88-1.75(m,2H),1.37-1.25(m,3H);ES-LCMS m/z 627.4,629.4[M+H]+.
步骤3:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(甲基磺酰氨基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
向3-(4-(5-((4-((4-(氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯,5盐酸盐(150mg,0.154mmol)和DIEA(159mg,1.232mmol)在DCM(5mL)中的溶液中添加MsCl(21.17mg,0.185mmol)。将反应混合物在15℃搅拌12h,然后浓缩以得到黄色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(甲基磺酰氨基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(180mg,0.128mmol,83.0%产率):1H NMR(400MHz,CDCl3)δppm8.05(d,J=2.9Hz,1H),7.71-7.67(m,2H),7.38-7.32(m,2H),7.28-7.25(m,1H),6.74(s,1H),6.65(d,J=9.3Hz,1H),4.09(q,J=7.1Hz,2H),3.51-3.47(m,4H),3.44-3.41(m,2H),2.97(t,J=6.5Hz,2H),2.89(s,3H),2.83-2.76(m,2H),2.72-2.68(m,2H),2.55(d,J=4.9Hz,4H),2.49-2.44(m,2H),1.96-1.91(m,2H),1.68(d,J=11.9Hz,2H),1.50-1.42(m,3H),1.17-1.12(m,3H);ES-LCMSm/z 705.3,707.3[M+H]+.
步骤4:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(甲基磺酰氨基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
向3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(甲基磺酰氨基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(180mg,0.128mmol)在MeOH(10mL)中的溶液中添加NaOH(10.20mg,0.255mmol)的水(1mL)溶液。将反应混合物在15℃搅拌12h,然后添加1N HCl以将pH调节至6。将溶液浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(甲基磺酰氨基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐(20.10mg,0.024mmol,19.1%产率):1H NMR(400MHz,CD3OD)δppm 8.23(br.s,1H),8.16(s,1H),7.98(s,1H),7.89(s,2H),7.55(s,1H),7.51(s,1H),7.41(s,1H),4.46(s,4H),3.96-3.37(m,10H),3.30-3.27(m,2H),3.13-3.10(m,2H),3.01-3.00(m,2H),2.93(s,3H),2.06(d,J=11.5Hz,2H),1.88-1.86(m,1H),1.66-1.63(m,2H);ES-LCMSm/z 677.3,679.3[M+H]+.
实施例45:N-((1-((5-((5-氨基吡啶-2-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐
向N-((1-((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(100mg,0.245mmol)和2-氟-5-硝基吡啶(41.9mg,0.295mmol)在DMF(50mL)中的混合物中添加K2CO3(67.9mg,0.491mmol)。将混合物在80℃在N2气氛搅拌4h。将混合物通过硅藻土垫过滤。将滤液浓缩且添加水(30mL)。水层用DCM(30mL×3)萃取且有机层用MgSO4干燥且浓缩以得到黑色固体,将其溶于EtOAc(50mL)。然后在N2气氛添加Pd/C(10wt%,30mg)且将混合物在H2气氛(50psi)在25℃搅拌16h。过滤后,将滤液浓缩且残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到棕色油状物的N-((1-((5-((5-氨基吡啶-2-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐(6.53mg,10.60μmol,5.6%产率):1H NMR(400MHz,CD3OD)δppm 8.17-8.16(m,1H),7.93-7.90(m,1H),7.75(s,1H),7.68-7.67(m,2H),7.59-7.58(m,1H),7.49-7.48(m,2H),7.28-7.26(m,1H),4.39(s,2H),3.58-3.55(m,2H),3.30-3.28(m,2H),3.12-3.01(m,2H),1.98-1.95(m,2H),1.84-1.79(m,3H),1.57-1.54(m,1H),1.51-1.47(m,2H);ES-LCMS m/z 499.1,501.1[M+H]+.
实施例46:N-((1-((5-((6-氨基-5-氟吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,2盐酸盐
步骤1:5-溴-N-(2,4-二甲氧基苄基)-3-氟吡啶-2-胺
将5-溴-2,3-二氟吡啶(71mg,0.366mmol)和(2,4-二甲氧基苯基)甲胺(1.5g,8.78mmol)的混合物在100℃搅拌16h。混合物用硅胶柱色谱法(PE/EtOAc=2/1)纯化以得到5-溴-N-(2,4-二甲氧基苄基)-3-氟吡啶-2-胺(60mg,0.158mmol,43.2%产率):1H NMR(400MHz,CDCl3)δppm 7.95(s,1H),7.24-7.22(m,2H),6.47(s,1H),6.45-6.41(m,1H),4.55(s,2H),3.83(s,3H),3.77(s,3H);ES-LCMS m/z 341.0,343.0[M+H]+.
步骤2:N-((1-((3',5'-二氯-5-((6-((2,4-二甲氧基苄基)氨基)-5-氟吡啶-3-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺
将N-((1-((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(84mg,0.205mmol)、5-溴-N-(2,4-二甲氧基苄基)-3-氟吡啶-2-胺(60mg,0.176mmol)、吡啶甲酸(3.79mg,0.031mmol)、K3PO4(131mg,0.616mmol)和CuI(3.91mg,0.021mmol)在DMSO(15mL)中的混合物在140℃搅拌24h。将混合物浓缩且用柱色谱法(DCM/MeOH=15/1)纯化以得到N-((1-((3',5'-二氯-5-((6-((2,4-二甲氧基苄基)氨基)-5-氟吡啶-3-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(30mg,0.036mmol,17.5%产率):1H NMR(400MHz,CD3OD)δppm 7.70-7.67(m,3H),7.55-7.50(m,2H),7.45-7.42(m,2H),7.31-7.30(m,1H),7.21-7.15(m,2H),6.97(s,1H),3.90-3.85(m,5H),3.82-3.78(m,5H),3.10-3.05(m,6H),1.93(s,3H),1.80-1.75(m,2H),1.27-1.23(m,3H);ES-LCMS m/z 667.1,669.1[M+H]+.
步骤3:N-((1-((5-((6-氨基-5-氟吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,2盐酸盐
将N-((1-((3',5'-二氯-5-((6-((2,4-二甲氧基苄基)氨基)-5-氟吡啶-3-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(30mg,0.045mmol)在TFA(2mL)中的混合物在25℃搅拌2h。将混合物浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到N-((1-((5-((6-氨基-5-氟吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,2盐酸盐(1.41mg,2.285μmol,5.1%产率):1H NMR(400MHz,CD3OD)δppm7.92(d,J=2.4Hz,1H),7.89(s,1H),7.73(s,2H),7.67(m,1H),7.61-7.48(m,2H),7.36(s,1H),4.35(s,2H),3.54-3.51(m,2H),3.11-3.09(m,2H),3.04-2.98(m,2H),2.02-1.93(m,7H),1.55-1.48(m,1H);ES-LCMS m/z 517.1,519.1[M+H]+.
实施例47:1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲,4盐酸盐
步骤1:2-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)乙酸乙酯
向1-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲,4盐酸盐(400mg,0.438mmol)在MeCN(5mL)中的混合物中添加DIEA(0.391mL,2.188mmol)和2-溴乙酸乙酯(0.053mL,0.481mmol)。将反应在15℃在N2气氛搅拌10h,然后浓缩。添加饱和NaHCO3水溶液(15mL)且水层用DCM(150mL x2)萃取。合并的萃取物用盐水(150mL x2)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色固体的2-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)乙酸乙酯(300mg,0.313mmol,71.5%产率):1H NMR(400MHz,CD3OD)δppm8.34(s,2H),7.84(d,J=1.5Hz,2H),7.68(s,1H),7.46(s,1H),7.07(s,1H),4.24-4.19(m,2H),3.95-3.84(m,4H),3.66(s,2H),3.28-3.23(m,4H),3.08-3.03(m,2H),2.98(d,J=11.0Hz,2H),2.72-2.68(m,5H),2.14(t,J=10.5Hz,2H),1.76(d,J=11.5Hz,2H),1.53-1.50(m,1H),1.37-1.35(m,2H),1.32-1.29(m,3H);ES-LCMS m/z 671.3,673.3[M+H]+.
步骤2:1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲,4盐酸盐
向2-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)乙酸乙酯(300mg,0.313mmol)在THF(10mL)中的混合物中添加LiAlH4(17.80mg,0.469mmol)。将反应在-20℃搅拌10min,然后用1mL水淬灭。将混合物过滤且浓缩。混合物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲,4盐酸盐(37.11mg,0.048mmol,15.3%产率):1H NMR(400MHz,CD3OD)δppm 8.48(s,2H),7.92-7.85(m,3H),7.54(s,1H),7.33(s,1H),4.93(br.s,2H),4.45(s,2H),4.01-3.92(m,2H),3.75(d,J=12.0Hz,2H),3.62(d,J=12.5Hz,2H),3.55-3.43(m,2H),3.38(d,J=5.5Hz,2H),3.28-3.22(m,2H),3.17-3.04(m,4H),2.73-2.68(m,3H),2.02(d,J=14.1Hz,3H),1.55(d,J=14.1Hz,2H);ES-LCMS m/z 629.4,631.4[M+H]+.
实施例48:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙烷-1-磺酰胺,4盐酸盐
向1-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲(250mg,0.367mmol)在NMP(5mL)中的溶液中添加3-氯丙烷-1-磺酰胺(152mg,0.918mmol)和DIEA(0.192mL,1.102mmol)。溶液在120℃在微波下搅拌3h。然后将混合物浓缩以得到残余物,将其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙烷-1-磺酰胺,4盐酸盐(21.98mg,0.026mmol,7.0%产率):1H NMR(400MHz,CD3OD)δppm 8.48-8.44(m,2H),7.91(s,1H),7.87(d,J=1.3Hz,2H),7.50(s,1H),7.31(s,1H),4.94(d,J=14.6Hz,2H),4.43(s,2H),3.72(d,J=12.3Hz,2H),3.59(d,J=11.9Hz,2H),3.50-3.37(m,5H),3.27-3.15(m,5H),3.12-3.03(m,4H),2.72-2.66(m,3H),2.38-2.29(m,2H),1.98(d,J=13.7Hz,2H),1.80(br.s,1H),1.61-1.48(m,2H);ES-LCMS m/z 706.2,708.2[M+H]+.
实施例49:((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯,4盐酸盐
步骤1:4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(4g,5.44mmol)和(哌啶-4-基甲基)氨基甲酸甲酯盐酸盐(1.433g,6.53mmol)在DMF(20mL)中的溶液中添加K2CO3(3.69g,16.31mmol)。将混合物在20℃搅拌6h,然后过滤且浓缩。残余物在DCM(30mL)和饱和NaHCO3溶液(20mL)之间分配且水相用DCM(10mL x2)萃取。合并的有机萃取物用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(3.8g,5.15mmol,95.0%产率):1HNMR(400MHz,CD3OD)δppm 8.32(s,2H),7.81-7.76(m,2H),7.62(s,1H),7.41(t,J=1.8Hz,1H),7.02(s,1H),3.87-3.78(m,4H),3.69-3.56(m,5H),3.51-3.50(m,4H),3.04-2.95(m,2H),2.92(d,J=11.0Hz,2H),2.07(t,J=10.8Hz,2H),1.71(d,J=11.9Hz,2H),1.50-1.49(m,10H),1.36-1.23(m,2H);ES-LCMS m/z 686.2,688.2[M+H]+.
步骤2:((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯,4盐酸盐
向4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(3.8g,5.15mmol)在MeOH(30mL)中的溶液中添加HCl溶液(4.0M在EtOAc中,10mL,40.0mmol)。将混合物在20℃搅拌0.2h。然后将溶液浓缩且在DCM(50mL)和饱和NaHCO3(30mL)溶液之间分配。水相用DCM(30mL x2)萃取。合并的有机萃取物用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到白色固体的((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯(3.4g,4.99mmol,97%产率)。150mg粗产物溶于DMSO(5mL),通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯,4盐酸盐(63.37mg,0.086mmol,39.1%产率):1H NMR(400MHz,CD3OD)δppm 8.48(s,2H),7.99(s,1H),7.87(d,J=1.8Hz,2H),7.47(t,J=1.8Hz,1H),7.38-7.33(m,1H),4.56-4.55(m,2H),4.21-4.09(m,4H),3.66-3.56(m,5H),3.40-3.34(m,4H),3.12(t,J=12.1Hz,2H),3.04(d,J=6.2Hz,2H),1.97(d,J=13.2Hz,2H),1.83-1.80(m,1H),1.68-1.52(m,2H);ES-LCMSm/z 586.3,588.2[M+H]+.
实施例50:3-(4-(5-((6-(3,5-二氯苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
步骤1:4-(5-((6-(3,5-二氯苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
将4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(0.55g,0.902mmol)溶于甲胺(30%在EtOH中,20mL,0.902mmol)。将反应在15℃搅拌12h,然后浓缩以得到棕色油状物4-(5-((6-(3,5-二氯苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(0.6g,0.771mmol,85.0%产率):1H NMR(400MHz,CDCl3)δppm 8.15-8.05(m,1H),7.81-7.73(m,1H),7.67(d,J=1.8Hz,1H),7.46-7.26(m,3H),6.81(d,J=8.4Hz,1H),6.75-6.62(m,1H),3.84(s,2H),3.64-3.16(m,8H),2.49(s,3H),1.47(s,9H);ES-LCMS m/z 544.3,546.3[M+H]+.
步骤2:4-(5-((4-((((苄基氧基)羰基)(甲基)氨基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(0.5g,0.918mmol)和DIEA(0.321mL,1.837mmol)在DCM(40mL)中的溶液中添加CbzCl(0.262mL,1.837mmol)。将混合物在0℃搅拌1.5h。有机相用饱和NaHCO3水溶液(50mL x2)和盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到棕色油状物4-(5-((4-((((苄基氧基)羰基)(甲基)氨基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(0.59g,0.696mmol,76.0%产率):1H NMR(400MHz,CDCl3)δppm 8.21-8.06(m,1H),7.81-7.59(m,2H),7.41-7.30(m,8H),6.82-6.62(m,2H),5.19(d,J=16.6Hz,2H),4.53(d,J=12.5Hz,2H),3.57(br.s,4H),3.54(d,J=5.5Hz,3H),3.05-2.91(m,4H),1.50(s,9H);ES-LCMSm/z678.3,680.3[M+H]+.
步骤3:((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)(甲基)氨基甲酸苄基酯
将4-(5-((4-((((苄基氧基)羰基)(甲基)氨基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(0.59g,0.869mmol)溶于4.0M HCl的EtOAc溶液(30mL,120mmol)中。将混合物在25℃搅拌1h,然后浓缩。将残余物溶于DCM(50mL),用饱和NaHCO3溶液(20mL)洗涤。将有机相浓缩以得到棕色固体的((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)(甲基)氨基甲酸苄基酯(0.55g,0.761mmol,87.0%产率):1H NMR(400MHz,CDCl3)δppm 10.09-9.73(m,1H),8.20-7.92(m,1H),7.52(d,J=16.8Hz,2H),7.35-7.21(m,9H),6.98-6.64(m,1H),5.16(d,J=15.0Hz,2H),4.64-4.51(m,2H),4.50-4.11(m,4H),3.98-3.46(m,4H),3.01-2.86(m,3H);ES-LCMS m/z 578.3,580.3[M+H]+.
步骤4:3-(4-(5-((4-((((苄基氧基)羰基)(甲基)氨基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
向((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)(甲基)氨基甲酸苄基酯(0.55g,0.951mmol)和3-溴丙酸乙酯(0.207g,1.141mmol)在DMF(30mL)中的溶液中添加K2CO3(0.263g,1.902mmol)。将反应在80℃搅拌12h,然后浓缩且通过硅胶色谱法(DCM/MeOH=20/1)纯化。将所有通过TLC(MeOH/DCM=1/10,Rf=0.4)发现包含产物的级分合并且浓缩以得到棕色固体的3-(4-(5-((4-((((苄基氧基)羰基)(甲基)氨基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(0.7g,0.825mmol,87.0%产率):1H NMR(400MHz,CDCl3)δppm 8.11-8.00(m,1H),7.93(s,2H),7.71-7.57(m,2H),7.35-7.27(m,6H),6.75-6.57(m,2H),5.13(d,J=17.2Hz,2H),4.65-4.58(m,2H),4.55-4.40(m,2H),4.10(q,J=7.1Hz,2H),3.53-3.47(m,4H),3.38(s,3H),3.02-2.92(m,4H),2.72(t,J=7.7Hz,2H),1.22(t,J=7.1Hz,3H);ES-LCMS m/z 678.3,680.3[M+H]+.
步骤5:3-(4-(5-((4-((((苄基氧基)羰基)(甲基)氨基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸
向3-(4-(5-((4-((((苄基氧基)羰基)(甲基)氨基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(0.70g,1.032mmol)在MeOH(30mL)和H2O(1mL)中的溶液中添加NaOH(0.083g,2.063mmol)。将反应混合物在25℃搅拌8h,然后通过1NHCl溶液将pH调节至7。将混合物浓缩以得到白色固体的3-(4-(5-((4-((((苄基氧基)羰基)(甲基)氨基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸(0.8g,0.861mmol,83.0%产率):1H NMR(400MHz,CD3OD)δppm 8.19(s,3H),7.97(s,2H),7.87(s,3H),7.74(s,1H),7.57-7.50(m,4H),5.10(d,J=17.2Hz,2H),4.43(s,2H),4.38-4.36(m,2H),3.63-3.50(m,4H),3.32-3.22(m,4H),3.05-3.03(m,2H),2.83(s,3H);ES-LCMSm/z 650.3,652.3[M+H]+.
步骤6:3-(4-(5-((6-(3,5-二氯苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
将3-(4-(5-((4-((((苄基氧基)羰基)(甲基)氨基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸(0.5g,0.769mmol)溶于TFA(30mL)且在50℃搅拌2h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到白色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐(66.24mg,0.096mmol,12.5%产率):1H NMR(400MHz,CD3OD)δppm 8.21(d,J=2.5Hz,1H),7.96(dd,J=2.5,9.5Hz,1H),7.91-7.82(m,3H),7.53(s,1H),7.40(d,J=9.5Hz,1H),7.28(s,1H),4.38(s,4H),3.94-3.38(m,8H),2.97(t,J=7.0Hz,2H),2.85(s,3H);ES-LCMS m/z 516.2,518.2[M+H]+.
实施例51:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-氟-4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
步骤1:4-((叔丁基二甲基甲硅烷基)氧基)-4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯
在0℃向4-(氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯(5g,11.61mmol)、DIEA(8.11mL,46.4mmol)在DCM(50mL)中的溶液中添加氯甲酸甲酯(1.371mL,17.41mmol)。将反应混合物在0℃搅拌0.5h,然后过滤,浓缩且通过快速色谱法(PE/EtOAc=100/0至4/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到白色固体4-((叔丁基二甲基甲硅烷基)氧基)-4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯(3.3g,6.56mmol,56.5%产率):1H NMR(400MHz,CDCl3)δppm3.67(d,J=4.4Hz,3H),3.49(br.s,2H),3.44-3.34(m,2H),3.26(br.s,2H),1.56(br.s,4H),1.45(d,J=4.9Hz,9H),1.02-0.77(m,9H),0.27-0.03(m,6H);ES-LCMS m/z425.2[M+Na]+.
步骤2:4-羟基-4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯
向4-((叔丁基二甲基甲硅烷基)氧基)-4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯(3.3g,6.56mmol)在THF(30mL)中的溶液中添加TBAF(1M在THF中,13.11mL,13.11mmol)。将反应混合物在25℃搅拌6h。添加水(50mL)且用DCM(50mL×3)萃取。合并的有机层用Na2SO4干燥且浓缩且通过快速色谱法(DCM/MeOH=100/0至10/1)纯化。将所有通过TLC(DCM/MeOH=20/1,Rf=0.15)发现包含产物的级分合并且浓缩以得到无色油状物4-羟基-4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯(1.9g,5.93mmol,90.0%产率):1HNMR(400MHz,CDCl3)δppm 3.83-3.64(m,2H),3.59(s,3H),3.10(br.s,4H),1.59-1.39(m,4H),1.39-1.32(m,9H)
步骤3:4-氟-4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯
在-78℃,向4-羟基-4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯(1.9g,5.93mmol)在DCM(30mL)中的溶液中添加DAST(1.019mL,7.71mmol)。将反应混合物在-78℃搅拌2h,然后浓缩且通过快速色谱法(PE/EA=100/0至4/1)纯化。将所有通过TLC(PE/EA=3/1,Rf=0.3)发现包含产物的级分合并且浓缩以得到白色固体的4-氟-4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯(0.3g,0.827mmol,13.9%产率):1H NMR(400MHz,CDCl3)δppm3.67(br.s,3H),3.49(d,J=4.9Hz,2H),3.36(d,J=19.4Hz,2H),3.07(br.s,2H),1.85-1.75(m,2H),1.67-1.51(m,2H),1.50-1.44(m,9H)。
步骤4:((4-氟哌啶-4-基)甲基)氨基甲酸甲酯
将4-氟-4-(((甲氧基羰基)氨基)甲基)哌啶-1-甲酸叔丁酯(0.3g,0.827mmol)溶于HCl溶液(4.0M在EtOAc中,10mL,40mmol)。将反应在20℃搅拌0.5h,然后浓缩以得到棕色固体的((4-氟哌啶-4-基)甲基)氨基甲酸甲酯,盐酸盐(0.2g,0.706mmol,85.0%产率):1HNMR(400MHz,CDCl3)δppm3.80-3.62(m,3H),3.60(br.s,2H),3.48-3.11(m,4H),2.49-1.85(m,4H)
步骤5:4-(5-((6-(3,5-二氯苯基)-4-((4-氟-4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(0.4g,0.516mmol)和((4-氟哌啶-4-基)甲基)氨基甲酸甲酯,盐酸盐(0.175g,0.619mmol)在MeCN(15mL)中的溶液中添加K2CO3(0.214g,1.547mmol)。将反应混合物在80℃搅拌6h,然后过滤,浓缩且通过制备型TLC(PE/EtOAc=1/1,Rf=0.5)纯化以得到棕色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-氟-4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(0.2g,0.255mmol,49.5%产率):1H NMR(400MHz,CDCl3)δppm 8.34(s,2H),8.30(s,2H),7.71(s,1H),7.43(s,1H),7.34(s,1H),6.91(s,1H),3.84-3.81(m,4H),3.68(s,3H),3.57-3.54(m,2H),3.53-3.52(m,4H),3.51-3.37(m,2H),2.70-2.68(m,2H),2.42-2.40(m,2H),1.87-1.84(m,2H),1.62-1.58(m,2H),1.49(s,9H);ES-LCMS m/z 704.2,706.2[M+H]+.
步骤6:((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氟哌啶-4-基)甲基)氨基甲酸甲酯
将4-(5-((6-(3,5-二氯苯基)-4-((4-氟-4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(0.2g,0.255mmol)溶于4.0MHCl的EtOAc溶液(10mL,40mmol)中。将反应在20℃搅拌0.5h,然后浓缩且溶于DCM(30mL)。将混合物用饱和NaHCO3溶液洗涤且用Na2SO4干燥,浓缩以得到棕色固体的((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氟哌啶-4-基)甲基)氨基甲酸甲酯(0.16g,0.245mmol,96.0%产率):1H NMR(400MHz,CDCl3)δppm 8.34-8.26(m,2H),7.74(d,J=1.8Hz,2H),7.47-7.39(m,1H),7.36(s,1H),6.91(s,1H),3.94-3.80(m,4H),3.70(s,3H),3.58(s,2H),3.50-3.32(m,2H),3.08-2.95(m,4H),2.70(d,J=11.5Hz,2H),2.41(t,J=10.6Hz,2H),1.99-1.78(m,4H);ES-LCMS m/z 604.2,606.3[M+H]+.
步骤7:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-氟-4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
向((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氟哌啶-4-基)甲基)氨基甲酸甲酯(0.14g,0.214mmol)和3-溴丙酸(0.983g,6.42mmol)在MeCN(30mL)中的溶液中添加DIEA(0.935mL,5.35mmol)。将反应混合物在80℃搅拌5h,然后浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-((4-氟-4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸,4盐酸盐(76.72mg,0.093mmol,43.5%产率):1H NMR(400MHz,CD3OD)δppm8.45(s,2H),8.00-7.94(m,1H),7.87(d,J=1.8Hz,2H),7.48(s,1H),7.35(s,1H),4.50(s,2H),3.85-3.57(m,6H),3.56-3.47(m,4H),3.47-3.30(m,7H),3.29-3.15(m,2H),2.92(t,J=7.1Hz,2H),2.25-2.01(m,4H);ES-LCMSm/z676.3,678.2[M+H]+.
实施例52:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙醇
步骤1:2-(哌啶-4-基)乙醇
在20℃,向4-(2-羟基乙基)哌啶-1-甲酸叔丁酯(800mg,2.79mmol)在DCM(20mL)中的混合物中添加HCl溶液(4.0M在EtOAc中,20mL,80mmol)。将混合物在20℃搅拌0.5h,然后浓缩。残余物在DCM(250mL)和饱和NaHCO3水溶液(250mL)之间分配。分离且水相用DCM(250mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到棕色固体的2-(哌啶-4-基)乙醇(400mg,2.477mmol,89.0%产率):1H NMR(400MHz,CD3OD)δppm3.62(t,J=6.6Hz,2H),3.37(d,J=12.8Hz,2H),2.97(t,J=12.6Hz,2H),1.95(d,J=14.1Hz,2H),1.78(m,1H),1.53(q,J=6.6Hz,2H),1.47-1.35(m,2H)。
步骤2:4-(5-((6-(3,5-二氯苯基)-4-((4-(2-羟基乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(600mg,0.835mmol)在DMF(50mL)中的混合物中添加K2CO3(346mg,2.506mmol)和2-(哌啶-4-基)乙醇(337mg,2.088mmol)。将混合物在25℃搅拌7h,然后过滤,浓缩且通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.6)分析发现包含产物的级分合并且浓缩以得到黄色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-(2-羟基乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.398mmol,47.6%产率):1H NMR(400MHz,CDCl3)δppm 8.30(s,2H),7.74-7.67(m,2H),7.41(s,1H),7.33(br.s,1H),6.91-6.87(m,1H),4.06(br.s,2H),3.82(br.s,4H),3.70(br.s,4H),2.74-2.62(m,2H),2.02(t,J=11.2Hz,2H),1.71-1.60(m,5H),1.44(s,9H),1.35-1.25(m,2H),1.15-1.04(m,2H);LC-MS m/z 643.4,645.4[M+H]+.
步骤3:2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙醇
向4-(5-((6-(3,5-二氯苯基)-4-((4-(2-羟基乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.398mmol)在EtOAc(5mL)中的混合物中添加HCl溶液(4.0M在EtOAc中,5mL,20.00mmol)。将反应在25℃搅拌20min,然后添加饱和NaHCO3溶液(10mL)且将混合物用DCM(20mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙醇(308mg,0.385mmol,97.0%产率):1H NMR(400MHz,CD3OD)δppm8.74-8.69(m,2H),8.12-8.08(m,2H),7.91(d,J=1.8Hz,1H),7.83-7.79(m,1H),7.47-7.44(m,1H),4.48(s,2H),4.26-4.19(m,4H),3.44(d,J=4.4Hz,4H),3.39(br.s,2H),3.15(t,J=11.9Hz,2H),3.01-2.96(m,2H),1.95(d,J=15.4Hz,3H),1.66(d,J=11.5Hz,2H),1.46-1.40(m,2H);LC-MS m/z 543.3,545.3[M+H]+.
步骤4:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙醇
向2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙醇(308mg,0.385mmol)在MeOH(5mL)和DCM(5mL)中的溶液中添加多聚甲醛(34.7mg,1.156mmol)、AcOH(4.41μL,0.077mmol)和分子筛(300mg,0.385mmol)。将反应混合物在25℃在N2气氛搅拌5h,然后添加NaBH3CN(72.7mg,1.156mmol)。将反应在25℃搅拌2h,然后过滤,浓缩以得到残余物,将其在DCM(30mL)和H2O(20mL)之间分配,用DCM(30mLx2)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化且冻干以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙醇(51.2mg,0.092mmol,23.8%产率):1H NMR(400MHz,CD3OD)δppm 8.31(s,2H),7.81(s,2H),7.64(s,1H),7.42(br.s,1H),7.03(s,1H),3.86(br.s,4H),3.60(br.s,4H),2.92(d,J=9.7Hz,2H),2.53(br.s,4H),2.34(s,3H),2.09(t,J=11.5Hz,2H),1.73(d,J=12.8Hz,2H),1.49(br.s,3H),1.30(d,J=10.6Hz,2H);LC-MS m/z 557.4,559.3[M+H]+.
实施例53:2-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸,4盐酸盐
步骤1:4-(2-乙氧基-2-氧代乙氧基)哌啶-1-甲酸叔丁酯
在20℃在N2气氛经1h向4-羟基哌啶-1-甲酸叔丁酯(3g,14.91mmol)在THF(20mL)中的溶液中添加NaH(0.894g,22.36mmol)。然后添加2-溴乙酸乙酯(7.47g,44.7mmol)且将混合物在50℃搅拌9h。添加水(2mL)且将混合物浓缩以得到残余物,将其在DCM(50mL)和饱和NaHCO3水溶液(50mL)之间分配,用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物。粗产物通过硅胶柱色谱法(PE/EtOAc=1/2)纯化。将所有通过TLC(EtOAc=100%,Rf=0.6)发现包含产物的级分合并且浓缩以得到无色油状物4-(2-乙氧基-2-氧代乙氧基)哌啶-1-甲酸叔丁酯(1.2g,3.76mmol,25.2%产率):1H NMR(400MHz,CDCl3)δppm 4.26-4.16(m,2H),4.13-4.05(m,2H),3.77(br.s,2H),3.62-3.51(m,1H),3.13-3.00(m,2H),1.84(br.s,2H),1.62-1.53(m,2H),1.45(s,9H),1.31-1.23(m,3H);ES-LCMS m/z 232.2[M-t-Bu+H]+.
步骤2:2-(哌啶-4-基氧基)乙酸甲酯,盐酸盐
将4-(2-乙氧基-2-氧代乙氧基)哌啶-1-甲酸叔丁酯(1.2g,3.76mmol)在4.0MMeOH(10mL,40.0mmol)中的溶液在20℃搅拌10min,然后浓缩以得到白色固体的2-(哌啶-4-基氧基)乙酸甲酯,盐酸盐(0.8g,3.62mmol,96.0%产率):1H NMR(400MHz,CD3OD)δppm4.24-4.18(m,2H),3.77-3.72(m,3H),3.38-3.29(m,4H),3.14(d,J=6.6Hz,1H),2.07-2.00(m,2H),1.97-1.89(m,2H);ES-LCMS m/z 174.1[M+H]+.
步骤3:4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙氧基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(600mg,0.885mmol)和K2CO3(367mg,2.65mmol)在DMF(10mL)中的混合物中添加2-(哌啶-4-基氧基)乙酸甲酯,盐酸盐(400mg,1.812mmol)。将混合物在20℃搅拌10h,然后过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到白色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙氧基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(500mg,0.637mmol,72.0%产率):1H NMR(400MHz,CDCl3)δppm 8.24(s,2H),7.76-7.67(m,3H),7.26(s,2H),4.07(s,2H),3.77(m,4H),3.69(s,3H),3.62(s,2H),3.47(m,4H),3.13-2.90(m,4H),1.85(m,4H),1.43(s,9H);ES-LCMSm/z 687.4,689.3[M+H]+.
步骤4:2-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸甲酯,4盐酸盐
将4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙氧基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(500mg,0.637mmol)在HCl溶液(4.0M在MeOH中,5mL,20.0mmol)中的溶液在20℃搅拌15min。将反应混合物浓缩以得到黄色固体的2-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸甲酯,4盐酸盐(420mg,0.428mmol,67.3%产率):1H NMR(400MHz,CD3OD)δppm 8.60(s,2H),8.04(br.s,1H),7.90(d,J=1.8Hz,2H),7.49(s,1H),7.40(s,1H),4.51-4.45(m,2H),4.23-4.21(m,2H),4.20-4.16(m,4H),3.77-3.68(m,4H),3.39-3.32(m,6H),3.21-3.11(m,2H),2.15(m,3H),1.91(m,1H);ES-LCMS m/z 587.0,589.0[M+H]+.
步骤5:2-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸甲酯
向2-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸甲酯,4盐酸盐(400mg,0.408mmol)、甲酸(0.036mL,0.816mmol)和分子筛(600mg,0.408mmol)在MeOH(10mL)中的混合物中添加多聚甲醛(61.3mg,2.040mmol)。将混合物在20℃在N2气氛搅拌10h。然后添加NaBH3CN(77mg,1.224mmol)且将混合物在20℃搅拌0.5h。将反应混合物过滤且浓缩以得到残余物,将其在DCM(20mL)和饱和NaHCO3水溶液(20mL)之间分配,用DCM(20mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到白色固体的2-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸甲酯(220mg,0.296mmol,72.6%产率):1HNMR(400MHz,CDCl3)δppm 8.28-8.19(m,2H),7.66(s,2H),7.35(s,1H),7.27(br.s,1H),6.82(s,1H),4.07(s,2H),3.81(br.s,4H),3.69(s,3H),3.64(m,1H),3.47(s,2H),3.40(br.s,1H),2.71(m,2H),2.46(m,4H),2.30(s,3H),2.18(m,2H),1.86(m,2H),1.66(m,2H);ES-LCMSm/z 601.3,603.3[M+H]+.
步骤6:2-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸,4盐酸盐
向2-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸甲酯(220mg,0.296mmol)在THF(5mL)和水(5.00mL)中的溶液中添加NaOH(59.2mg,1.481mmol)。将混合物在50℃搅拌10h,然后浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的2-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸,4盐酸盐(155.57mg,0.212mmol,71.6%产率):1H NMR(400MHz,CD3OD)δppm 8.46(s,2H),7.95(br.s,1H),7.88(d,J=1.8Hz,2H),7.50(s,1H),7.33(br.s,1H),4.94(s,2H),4.48-4.42(m,2H),4.18(s,2H),3.86(br.s,1H),3.61(d,J=12.3Hz,2H),3.49-3.33(m,5H),3.23-3.14(m,3H),2.96(s,3H),2.21-2.13(m,2H),2.07(d,J=11.9Hz,2H);ES-LCMSm/z 587.3,589.3[M+H]+.
实施例54:3-(4-(5-((4-((4-(2-(氨基甲酰基氧基)乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸,5盐酸盐
步骤1:4-(5-((6-(3,5-二氯苯基)-4-((4-(2-羟基乙基)哌嗪-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(500mg,0.614mmol)和2-(哌嗪-1-基)乙醇(120mg,0.921mmol)在DMF(10mL)中的悬浮液中添加Cs2CO3(600mg,1.843mmol)。将反应混合物在30℃搅拌12h,然后过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(MeOH/DCM=1/9)纯化。将所有通过TLC(MeOH/DCM=1/10,Rf=0.4)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-(2-羟基乙基)哌嗪-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.589mmol,96.0%产率):1H NMR(400MHz,CDCl3)δppm 8.29-8.27(m,2H),7.73-7.65(m,2H),7.41(s,1H),7.33(br.s,1H),6.90(s,1H),3.81(m,4H),3.62(t,J=5.1Hz,2H),3.54(s,2H),3.52(m,4H),2.66-2.45(m,10H),1.48(s,9H);ES-LCMSm/z 644.2,646.2[M+H]+.
步骤2:4-(5-((4-((4-(2-(氨基甲酰基氧基)乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-((4-(2-羟基乙基)哌嗪-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(350mg,0.515mmol)、DIEA(0.9mL,5.15mmol)在DCM(5mL)中的悬浮液中添加CDI(418mg,2.58mmol)。将反应混合物在30℃搅拌2h,然后添加NH4OH(5mL,0.515mmol)。将混合物在30℃再搅拌10h,然后在DCM(50mL)和水(30mL)之间分配,用DCM(50mL×3)萃取。合并的有机层用Na2SO4干燥,过滤且蒸发以得到粗产物,其通过硅胶柱色谱法(MeOH/DCM=1/9)纯化。将所有通过TLC(MeOH/DCM=1/10,Rf=0.45)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(5-((4-((4-(2-(氨基甲酰基氧基)乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(360mg,0.492mmol,95.0%产率):1H NMR(400MHz,CDCl3)δppm 8.32(s,2H),7.73(d,J=1.8Hz,2H),7.42(s,1H),7.35(s,1H),6.93(s,1H),4.65(br.s,2H),4.22(t,J=5.7Hz,2H),3.91-3.78(m,4H),3.62-3.49(m,6H),3.05(br.s,2H),2.68(t,J=5.5Hz,2H),2.58-2.46(m,6H),1.50(s,9H);ES-LCMS m/z 687.3,689.3[M+H]+.
步骤3:氨基甲酸2-(4-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌嗪-1-基)乙基酯,5盐酸盐
向4-(5-((4-((4-(2-(氨基甲酰基氧基)乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(360mg,0.492mmol)在EtOAc(10mL)中的悬浮液中添加HCl溶液(4.0M在EtOAc中,10mL,96mmol)。将反应混合物在25℃搅拌0.5h,然后浓缩以得到粗物质氨基甲酸2-(4-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌嗪-1-基)乙基酯,5盐酸盐(300mg,0.238mmol,48.5%产率):1H NMR(400MHz,CD3OD)δppm 8.47(s,2H),8.01(s,1H),7.91(d,J=1.8Hz,2H),7.51(t,J=1.9Hz,1H),7.37(s,1H),4.50-4.40(m,4H),4.19-4.14(m,4H),3.80(d,J=11.5Hz,4H),3.65-3.57(m,6H),3.36(d,J=5.3Hz,4H);ES-LCMS m/z 587.2,589.3[M+H]+.
步骤4:3-(4-(5-((4-((4-(2-(氨基甲酰基氧基)乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯
向氨基甲酸2-(4-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌嗪-1-基)乙基酯,5盐酸盐(300mg,0.238mmol)和3-溴丙酸乙酯(129mg,0.715mmol)在DMF(10mL)中的悬浮液中添加K2CO3(263mg,1.906mmol)。将反应混合物在70℃搅拌12h,然后过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(MeOH/DCM=1/9)纯化。将所有通过TLC(DCM:MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到淡黄色固体的3-(4-(5-((4-((4-(2-(氨基甲酰基氧基)乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(200mg,0.218mmol,92.0%产率):1H NMR(400MHz,CDCl3)δppm8.30(s,2H),7.74(s,2H),7.42(s,1H),7.35(s,1H),6.91(s,1H),4.70(br.s,2H),4.22(t,J=5.7Hz,2H),4.18(m,2H),3.86(m,6H),2.78(t,J=7.3Hz,2H),2.66-2.39(m,16H),1.23(m,3H);ES-LCMS m/z 687.2,689.2[M+H]+.
步骤5:3-(4-(5-((4-((4-(2-(氨基甲酰基氧基)乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸,5盐酸盐
向3-(4-(5-((4-((4-(2-(氨基甲酰基氧基)乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(200mg,0.218mmol)在THF(5mL)中的悬浮液中添加LiOH·H2O(45.8mg,1.091mmol)的水(5mL)溶液。将反应混合物在25℃搅拌12h,然后用1N HCl将pH调节至7且该粗物质通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且将所需级分冻干以得到白色固体的3-(4-(5-((4-((4-(2-(氨基甲酰基氧基)乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸,5盐酸盐(93.71mg,0.111mmol,51.0%产率):1H NMR(400MHz,CD3OD)δppm 8.43(s,2H),7.81(d,J=1.3Hz,2H),7.77-7.72(m,1H),7.50-7.44(m,1H),7.23-7.18(m,1H),4.44-4.35(m,2H),4.04-3.96(m,2H),3.95-3.88(m,1H),3.69(br.s,2H),3.60-3.37(m,10H),3.35(d,J=4.9Hz,1H),3.25-3.02(m,6H),2.93(t,J=7.1Hz,2H);ES-LCMS m/z 659.2,661.2[M+H]+.
实施例55-61(表2)通过类似于实施例54所述的方法制备。
表2
实施例62:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
步骤1:4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(5g,7.78mmol)在DMF(10mL)中的溶液中添加K2CO3(3.23g,23.34mmol)和(哌啶-4-基甲基)氨基甲酸甲酯,盐酸盐(2.56g,11.67mmol)。将反应在25℃搅拌5h,然后过滤,浓缩且通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)分析发现包含产物的级分合并且浓缩以得到黄色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(6g,6.55mmol,84.0%产率):1H NMR(400MHz,CD3OD)δppm8.29(s,2H),7.73(d,J=2.2Hz,2H),7.56(s,1H),7.35(t,J=1.8Hz,1H),6.96(s,1H),3.80-3.77(m,4H),3.61(s,3H),3.54(s,2H),3.48(br.s,4H),2.89(d,J=11.0Hz,2H),2.10-1.92(m,4H),1.69(d,J=11.9Hz,2H),1.48(s,9H),1.28-1.14(m,3H);LC-MS m/z 686.3,688.3[M+H]+.
步骤2:((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯
向4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(6g,6.55mmol)在EtOAc(100mL)中的混合物中添加HCl溶液(4.0M在EtOAc中,20mL,80mmol)。将反应在25℃搅拌0.5h,然后添加饱和NaHCO3水溶液(200mL)。将混合物用DCM(200mL x2)萃取且合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色固体的((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯(4g,5.80mmol,88.0%产率):1HNMR(400MHz,CD3OD)δppm 8.41-8.24(m,2H),7.80(d,J=1.8Hz,2H),7.62(s,1H),7.41(t,J=1.8Hz,1H),7.02(s,1H),3.83-3.79(m,4H),3.63-3.58(m,5H),3.00(d,J=6.2Hz,2H),2.94-2.85(m,6H),2.07(t,J=10.8Hz,2H),1.71(d,J=11.5Hz,2H),1.49(s,1H),1.37-1.22(m,2H);LC-MS m/z 586.3,588.3[M+H]+.
步骤3:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯
向((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯(250mg,0.341mmol)在DMF(5mL)中的混合物中添加DIEA(0.179mL,1.023mmol)和3-溴丙酸乙酯(93mg,0.511mmol)。将反应在25℃搅拌5小时。添加水(20mL)且将混合物用DCM(20mL x2)萃取,合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色油状物的3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(200mg,0.204mmol,59.8%产率):1H NMR(400MHz,CD3OD)δppm 8.39-8.36(m,2H),7.88-7.81(m,3H),7.49-7.45(m,1H),7.25-7.11(m,1H),4.20-4.16(m,2H),3.98-3.91(m,6H),3.69(m,3H),3.63(m,2H),3.07-3.03(m,2H),2.92-2.86(m,2H),2.79-2.72(m,4H),2.71-2.64(m,2H),2.53-2.46(m,2H),1.89-1.82(m,2H),1.70-1.61(m,1H),1.60-1.53(m,2H),1.29-1.25(m,3H);LC-MS m/z686.3,688.3[M+H]+.
步骤4:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
向3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(200mg,0.204mmol)在MeOH(5mL)和水(1mL)中的混合物中添加LiOH·H2O(25.7mg,0.612mmol)。将反应在25℃搅拌2h。将混合物过滤,浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸,4盐酸盐(76.12mg,0.093mmol,45.5%产率):1H NMR(400MHz,CD3OD)δppm8.48(s,2H),7.94(s,1H),7.89(d,J=1.5Hz,2H),7.52(s,1H),7.34(s,1H),4.46(br.s,2H),3.71-3.33(m,15H),3.09(br.s,4H),2.94(t,J=7.0Hz,2H),2.01(d,J=13.6Hz,2H),1.86(br.s,1H),1.61(br.s,2H);LC-MSm/z 658.3,660.3[M+H]+.
实施例63:((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯,4盐酸盐
向((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯(400mg,0.587mmol)和多聚甲醛(35.2mg,1.173mmol)在MeOH(10mL)中的溶液中添加甲酸(2.70mg,0.059mmol)和分子筛(0.587mmol)。将反应在25℃在N2气氛搅拌5h。然后添加NaBH3CN(111mg,1.760mmol)且将反应在25℃再搅拌2h。将混合物过滤,浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)乙基)哌啶-4-基)甲基)氨基甲酸甲酯,4盐酸盐(114.54mg,0.150mmol,25.6%产率):1H NMR(400MHz,CD3OD)δppm 8.45(s,2H),7.96(s,1H),7.86(d,J=1.8Hz,2H),7.47(t,J=1.8Hz,1H),7.38-7.32(m,1H),4.93(d,J=14.6Hz,2H),4.59-4.40(m,2H),3.69-3.54(m,6H),3.46-3.34(m,3H),3.25-3.15(m,2H),3.11(t,J=12.3Hz,2H),3.05(d,J=6.6Hz,2H),2.97(s,3H),2.05-1.92(m,2H),1.83(d,J=3.5Hz,1H),1.67-1.52(m,2H);LC-MS m/z600.2,602.2[M+H]+.
实施例64-72(表3)通过类似于实施例63所述的方法制备。
表3
实施例73:甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯
步骤1:4-(5-((6-(3,5-二氯苯基)-4-((4-(羟基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(5g,6.45mmol)在DMF(80mL)中的混合物中添加K2CO3(2.68g,19.36mmol)和哌啶-4-基甲醇(1.115g,9.68mmol)。将反应在25℃搅拌5h,然后添加水(100mL)且将混合物用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤,浓缩且通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.7)发现包含产物的级分合并且浓缩以得到黄色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-(羟基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(4g,5.90mmol,91.0%产率):1H NMR(400MHz,CDCl3)δppm 8.29(s,2H),7.71(s,2H),7.41(s,1H),7.32(br.s,1H),6.90(s,1H),3.81(br.s,4H),2.94(s,4H),2.87(s,4H),2.04(t,J=11.2Hz,2H),1.74(d,J=12.3Hz,2H),1.66(m,4H),1.48(s,9H),1.37-1.30(m,2H);ES-LCMS m/z629.3631.3[M+H]+.
步骤2:4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-((4-(羟基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(4g,5.90mmol)在DCM(40mL)中的混合物中添加DIEA(5.15mL,29.5mmol)和CDI(2.390g,14.74mmol)。将反应在25℃搅拌5h。添加甲胺(30wt%在乙醇中,12.21g,118mmol)。将反应在25℃搅拌2h,然后浓缩且通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到黄色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(4g,5.46mmol,93.0%产率):1H NMR(400MHz,CD3OD)δppm 8.32(s,2H),7.80(d,J=1.8Hz,2H),7.62(s,1H),7.41(t,J=1.8Hz,1H),7.03(s,1H),3.90(d,J=6.2Hz,2H),3.82(s,2H),3.62-3.59(m,2H),3.51(br.s,2H),2.99(s,2H),2.93(d,J=11.0Hz,2H),2.86(s,2H),2.68(s,3H),2.09(t,J=11.0Hz,2H),1.73(d,J=12.8Hz,2H),1.49(s,9H),1.43-1.32(m,2H),1.24-1.14(m,1H);ES-LCMS m/z 686.3,688.3[M+H]+.
步骤3:甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯,4盐酸盐
向4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(4g,5.46mmol)在EtOAc(20mL)中的混合物中添加HCl溶液(4.0M在EtOAc中,20mL,80.00mmol)。将反应在25℃搅拌0.5h,然后添加饱和NaHCO3水溶液(100mL)且将混合物用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色固体的甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯(3.4g,5.36mmol,98.0%产率)。将150mg(0.243mmol)该物质用制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干干燥以得到白色固体的甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯,4盐酸盐(53.51mg,0.072mmol,29.6%产率):1H NMR(400MHz,CD3OD)δppm 8.49(d,J=3.1Hz,2H),8.00(br.s,1H),7.87(s,2H),7.48(br.s,1H),7.36(br.s,1H),4.46(br.s,2H),4.14(br.s,4H),3.96(d,J=5.3Hz,2H),3.61(d,J=11.9Hz,2H),3.35(br.s,4H),3.14(t,J=11.9Hz,2H),2.72-2.65(m,3H),2.00(d,J=12.3Hz,3H),1.71(br.s,2H);ES-LCMS m/z 586.2,588.3[M+H]+.
实施例74:甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯,4盐酸盐
步骤1:4-(5-((6-(3,5-二氯苯基)-4-((4-(羟基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(5g,6.94mmol)在DMF(80mL)中的混合物中添加哌啶-4-基甲醇(1.199g,10.41mmol)和K2CO3(2.88g,20.82mmol)。将反应在25℃搅拌5h,然后添加水(200mL)。将混合物用DCM(300mL x2)萃取且合并的有机层用Na2SO4干燥,过滤,浓缩且通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.7)发现包含产物的级分合并且浓缩以得到黄色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-(羟基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(4g,4.77mmol,68.8%产率):1H NMR(400MHz,CD3OD)δppm 8.02-7.95(m,2H),7.74(d,J=1.8Hz,1H),7.54(s,1H),7.45(dd,J=2.9,9.0Hz,1H),7.34(t,J=1.8Hz,1H),6.96-6.86(m,2H),3.59-3.48(m,10H),3.39(d,J=6.2Hz,2H),2.90(d,J=11.5Hz,2H),2.85-2.78(m,2H),2.04-1.93(m,2H),1.74(br.s,1H),1.48(s,9H),1.29-1.22(m,2H);ES-LCMS m/z628.3,630.3[M+H]+.
步骤2:4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-((4-(羟基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(4g,4.77mmol)在DCM(100mL)中的混合物中添加DIEA(4.17mL,23.86mmol)和CDI(3.10g,19.09mmol)。将反应在25℃搅拌5h,然后添加甲胺(30wt%在乙醇中,9.88g,95mmol)。将反应在25℃搅拌2h。将混合物浓缩且通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到黄色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(3.5g,4.44mmol,93.0%产率):1H NMR(400MHz,CD3OD)δppm8.02(d,J=2.6Hz,1H),7.75(d,J=1.8Hz,2H),7.53(s,1H),7.45(dd,J=2.9,9.0Hz,1H),7.35(t,J=1.8Hz,1H),6.93-6.85(m,2H),3.87(d,J=5.7Hz,2H),3.54-3.46(m,10H),2.94-2.81(m,4H),2.68(s,3H),1.69(d,J=12.8Hz,2H),1.48(s,9H),1.35(br.s,1H),1.26-1.12(m,2H);ES-LCMS m/z 685.3,687.3[M+H]+.
步骤3:甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯,4盐酸盐
向4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(5g,6.20mmol)在EtOAc(50mL)中的混合物中添加HCl溶液(4.0M在EtOAc中,20mL,80mmol)。将反应在25℃搅拌0.5h,然后添加饱和NaHCO3水溶液(200mL)。将混合物用DCM(200mL x2)萃取且合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色固体的甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯(3.5g,5.43mmol,88.0%产率)。将200mg(0.34mmol)该物质用制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干干燥以得到白色固体的甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯,4盐酸盐(54.17mg,0.073mmol,1.17%产率):1H NMR(400MHz,CD3OD)δppm8.21(br.s,1H),8.13-7.99(m,2H),7.88(br.s,2H),7.55-7.37(m,3H),4.50(br.s,2H),4.10-3.94(m,6H),3.63(d,J=11.5Hz,2H),3.50(br.s,4H),3.19(t,J=12.3Hz,2H),2.71(br.s,3H),2.03(d,J=12.5Hz,3H),1.75(br.s,2H);ES-LCMS m/z 585.3,587.3[M+H]+.
实施例75:1-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲,4盐酸盐
步骤1:4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(3g,3.87mmol)和K2CO3(1.605g,11.62mmol)在DMF(50mL)中的混合物中添加1-甲基-3-(哌啶-4-基甲基)脲,盐酸盐(1.177g,4.65mmol)。将混合物在20℃搅拌10h,然后浓缩以得到粗产物,其通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到黄色固体4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1.8g,2.510mmol,64.8%产率):1H NMR(400MHz,CDCl3)δppm8.30(s,2H),7.72(d,J=1.3Hz,2H),7.40(s,1H),7.33(s,1H),6.90(s,1H),4.54-4.11(m,4H),3.82(d,J=4.9Hz,4H),3.52(br.s,6H),3.09(t,J=6.2Hz,2H),2.88(d,J=11.0Hz,2H),2.78(d,J=4.9Hz,3H),2.02(t,J=10.8Hz,2H),1.49(s,9H);ES-LCMS m/z 685.2,687.2[M+H]+.
步骤2:1-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲,4盐酸盐
将4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(250mg,0.349mmol)在HCl溶液(4.0M在EtOAc中,5mL,20.00mmol)中的溶液在20℃搅拌15min。将反应混合物浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到黄色固体1-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲,4盐酸盐(56.94mg,0.078mmol,22.3%产率):1H NMR(400MHz,CD3OD)δppm8.47(s,2H),7.95(br.s,1H),7.88(d,J=1.3Hz,2H),7.50(s,1H),7.33(br.s,1H),4.43(s,2H),4.17-4.10(m,4H),3.59(d,J=11.9Hz,2H),3.36-3.31(m,4H),3.16-3.04(m,4H),2.72(br.s,3H),1.98(d,J=13.7Hz,2H),1.84(br.s,1H),1.59(d,J=12.8Hz,2H);ES-LCMSm/z 585.3,587.3[M+H]+.
实施例76:((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯,4盐酸盐
步骤1:4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(11g,14.98mmol)和(哌啶-4-基甲基)氨基甲酸甲酯盐酸盐(3.95g,17.97mmol)在DMF(200mL)中的溶液中添加K2CO3(10.17g,44.9mmol)。将混合物在80℃搅拌2h,然后过滤且浓缩。粗产物在DCM(200mL)和饱和NaHCO3水溶液(50mL)之间分配。水相用DCM(50mL x2)萃取。合并的有机萃取物用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。残余物通过硅胶柱色谱法(PE/EtOAc=1/1)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到棕色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(10g,12.25mmol,82.0%产率):1H NMR(400MHz,CD3OD)δppm 7.97(s,2H),7.80(d,J=1.8Hz,2H),7.60(s,1H),7.49(dd,J=2.9,9.0Hz,1H),7.40(t,J=1.8Hz,1H),6.96(d,J=2.6Hz,1H),3.61(s,3H),3.59-3.47(m,10H),3.08-3.00(m,2H),2.92(d,J=11.5Hz,2H),2.12-2.02(m,2H),1.71(d,J=11.9Hz,2H),1.50-1.45(m,9H),1.35-1.21(m,3H);ES-LCMSm/z 685.3,687.3[M+H]+.
步骤2:((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯,4盐酸盐
向4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(10g,12.25mmol)在MeOH(40mL)中的溶液中添加HCl溶液(4.0M在EtOAc中,20mL,80mmol)。将混合物在20℃搅拌0.5h,然后浓缩且在DCM(200mL)和饱和NaHCO3水溶液(200mL)之间分配。水相用DCM(100mL x2)萃取。合并的有机萃取物用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色固体的((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯(8.0g,12.16mmol,99%产率)。将0.2g该物质用制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干以得到白色固体的((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯,4盐酸盐(128.41mg,0.175mmol,1.40%产率):1H NMR(400MHz,CD3OD)δppm 8.22(d,J=2.6Hz,1H),8.16(dd,J=2.6,9.7Hz,1H),7.98(s,1H),7.88(d,J=1.8Hz,2H),7.58-7.49(m,2H),7.40(s,1H),4.45(s,2H),4.07-3.98(m,4H),3.66-3.55(m,5H),3.53-3.46(m,4H),3.16-3.02(m,4H),1.98(d,J=13.7Hz,2H),1.83(br.s,1H),1.65-1.53(m,2H);ES-LCMS m/z 585.3,587.3[M+H]+.
实施例77:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
步骤1:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(羟基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
向3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(300mg,0.391mmol)在DMF(5mL)中的溶液中添加K2CO3(270mg,1.956mmol)和哌啶-4-基甲醇(67.6mg,0.587mmol)。将混合物在80℃搅拌10h,然后过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到淡黄色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(羟基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(200mg,0.224mmol,57.2%产率):1H NMR(400MHz,CD3OD)δppm8.05(d,J=3.0Hz,1H),7.84(d,J=1.5Hz,2H),7.63(s,1H),7.51(dd,J=3.0,9.0Hz,1H),7.43(s,1H),6.99(s,1H),6.95(d,J=9.0Hz,1H),4.21-4.15(m,2H),3.61(s,2H),3.59-3.54(m,5H),3.43(d,J=6.5Hz,4H),2.96(d,J=11.0Hz,2H),2.76(d,J=7.0Hz,2H),2.68(s,1H),2.65(br.s,2H),2.61(d,J=7.0Hz,2H),2.11(t,J=11.0Hz,3H),1.78(d,J=11.0Hz,4H),1.55-1.47(m,1H);ES-LCMS m/z 628.3,630.3[M+H]+.
步骤2:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
向3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(羟基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(150mg,0.168mmol)和DIEA(0.146mL,0.839mmol)在DCM(15mL)中的混合物中添加CDI(32.6mg,0.201mmol)。将混合物在25℃搅拌3h,然后添加甲胺(30wt%在乙醇中,45.7mg,0.201mmol)且将混合物在25℃再搅拌7h。将混合物浓缩以得到棕色固体3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(120mg,0.126mmol,75.0%产率):1H NMR(400MHz,CD3OD)δppm8.05(s,1H),7.95(s,1H),7.70(d,J=1.8Hz,2H),7.49(br.s,1H),7.33(s,2H),7.27(s,1H),4.22(br.s,2H),4.11-4.05(m,4H),3.89(br.s,3H),3.67(m,4H),3.48(m,4H),3.43(m,4H),2.56-2.54(m,2H),2.36(m,2H),1.97(d,J=10.6Hz,4H),1.66-1.64(m,1H),1.22(br.s,3H);ES-LCMS m/z 685.3,687.3[M+H]+.
步骤3:3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
向3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(100mg,0.105mmol)在THF(2mL)和水(2mL)中的溶液中添加LiOH·H2O(22.03mg,0.525mmol)。将混合物在25℃搅拌12h,然后浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐(48.29mg,0.060mmol,57.2%产率):1H NMR(400MHz,CD3OD)δppm 8.24(br.s,1H),8.13(br.s,1H),8.03(br.s,1H),7.91(s,2H),7.53(br.s,2H),7.43(br.s,1H),4.49(br.s,2H),3.98(d,J=5.0Hz,2H),3.67-3.54(m,8H),3.37-3.34(m,2H),3.20-3.14(m,2H),2.98(d,J=6.5Hz,3H),2.74-2.69(m,4H),2.03(d,J=11.5Hz,4H),1.73(br.s,1H);ES-LCMSm/z657.3,659.3[M+H]+.
实施例78:3-(4-(5-((4-((4-(3-氨基-3-氧代丙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸
步骤1:4-((2-(3,5-二氯苯基)-6-((2-(4-(3-乙氧基-3-氧代丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌嗪-1-甲酸叔丁酯
向3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(0.48g,0.676mmol)和哌嗪-1-甲酸叔丁酯(0.151g,0.811mmol)在DMF(5mL)中的混合物中添加K2CO3(0.280g,2.028mmol)。将混合物在80℃搅拌6h,然后过滤且浓缩。粗产物在DCM(30mL)和饱和NaHCO3水溶液(20mL)之间分配。水相用DCM(20mL x2)洗涤。合并的有机萃取物用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过硅胶柱色谱法(PE/EtOAc=1/1)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-((2-(3,5-二氯苯基)-6-((2-(4-(3-乙氧基-3-氧代丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌嗪-1-甲酸叔丁酯(0.4g,0.377mmol,55.7%产率):1H NMR(400MHz,CD3OD)δppm 8.35-8.26(m,2H),7.78(d,J=1.8Hz,2H),7.61(s,1H),7.43-7.38(m,1H),7.04(s,1H),4.19-4.10(m,2H),3.86-3.79(m,2H),3.44(d,J=16.8Hz,8H),3.33-3.28(m,2H),2.76-2.70(m,2H),2.60-2.54(m,4H),2.47(d,J=4.4Hz,2H),2.43-2.38(m,2H),1.45(s,9H),1.29-1.22(m,3H);ES-LCMS m/z700.2,702.2[M+H]+.
步骤2:3-(4-(5-((6-(3,5-二氯苯基)-4-(哌嗪-1-基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯
向4-((2-(3,5-二氯苯基)-6-((2-(4-(3-乙氧基-3-氧代丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌嗪-1-甲酸叔丁酯(400mg,0.377mmol)在MeOH(10mL)中的溶液中添加HCl溶液(4.0M在MeOH中,2mL,8.00mmol)。将混合物在20℃搅拌1h,然后浓缩且在DCM(30mL)和饱和NaHCO3水溶液(20mL)之间分配。水相用DCM(10mL x2)萃取。合并的有机萃取物用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色固体的3-(4-(5-((6-(3,5-二氯苯基)-4-(哌嗪-1-基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(240mg,0.364mmol,97.0%产率):1H NMR(400MHz,CD3OD)δppm 8.46-8.44(m,2H),8.04(s,1H),7.92-7.85(m,2H),7.51-7.46(m,1H),7.39(s,1H),4.56(s,2H),4.20(q,J=7.2Hz,2H),3.73-3.58(m,8H),3.54-3.49(m,4H),3.41(t,J=13.0Hz,2H),3.25-3.21(m,4H),2.95-2.93(m,2H),1.28(t,J=7.2Hz,3H);ES-LCMS m/z 600.4,602.4[M+H]+.
步骤3:3-(4-(5-((4-((4-(3-氨基-3-氧代丙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯
向3-(4-(5-((6-(3,5-二氯苯基)-4-(哌嗪-1-基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(0.23g,0.349mmol)和3-氯丙酰胺(0.075g,0.697mmol)在DMF(10mL)中的混合物中添加KI(0.116g,0.697mmol)和K2CO3(0.193g,1.394mmol)。将混合物在80℃搅拌6h,然后过滤且浓缩以得到棕色固体的3-(4-(5-((4-((4-(3-氨基-3-氧代丙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(160mg,0.152mmol,43.7%产率):1H NMR(400MHz,CD3OD)δppm 8.47-8.42(m,2H),8.05(s,1H),7.88(d,J=1.8Hz,2H),7.50-7.43(m,1H),7.38(s,1H),4.57(s,2H),4.20(q,J=7.1Hz,2H),4.15-4.09(m,4H),3.88-3.66(m,8H),3.60(t,J=7.1Hz,2H),3.37-3.30(m,8H),3.02-2.93(m,2H),1.27(t,J=7.1Hz,3H);ES-LCMS m/z 671.3,673.3[M+H]+.
步骤4:3-(4-(5-((4-((4-(3-氨基-3-氧代丙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸,5盐酸盐
向3-(4-(5-((4-((4-(3-氨基-3-氧代丙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(0.15g,0.143mmol)在MeOH(10mL)和水(10mL)中的混合物中添加LiOH·H2O(0.018g,0.429mmol)。将混合物在20℃搅拌8h,然后浓缩。粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的3-(4-(5-((4-((4-(3-氨基-3-氧代丙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸,5盐酸盐(60mg,0.073mmol,50.8%产率):1H NMR(400MHz,CD3OD)δppm8.46-8.37(m,2H),7.90-7.77(m,3H),7.49(t,J=1.8Hz,1H),7.27(s,1H),4.20(br.s,2H),3.70(d,J=12.3Hz,2H),3.62(br.s,4H),3.55-3.47(m,4H),3.40(d,J=14.1Hz,8H),3.27-3.15(m,2H),2.91(t,J=7.1Hz,2H),2.80(t,J=6.6Hz,2H);ES-LCMSm/z 643.3,645.3[M+H]+.
实施例79-85(表4)通过类似于实施例78所述的方法制备。
表4
实施例86:2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酰胺,4盐酸盐
向2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4盐酸盐(300mg,0.335mmol)的混合物中添加氨在MeOH中的溶液(5mL)。将混合物在80℃搅拌5h,然后浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酰胺,4盐酸盐(22.32mg,0.032mmol,9.50%产率):1H NMR(400MHz,CD3OD)δppm 8.45(s,2H),7.92(s,1H),7.87(d,J=1.8Hz,2H),7.50(s,1H),7.31(s,1H),4.59-4.39(m,2H),4.18-4.08(m,4H),3.58(d,J=11.9Hz,2H),3.33(d,J=5.3Hz,4H),3.12(t,J=11.9Hz,2H),2.22(d,J=6.6Hz,2H),2.02(d,J=14.6Hz,3H),1.71-1.56(m,2H);ES-LCMS m/z 556.3,558.2[M+H]+.
实施例87:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙烷磺酰胺,4盐酸盐
步骤1:(2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲醇,3盐酸盐
向4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1g,1.503mmol)在MeOH(20mL)中的溶液中添加HCl溶液(4.0M在MeOH中,20mL,80mmol)。将反应在20℃搅拌0.5h,然后浓缩以得到棕色固体的(2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲醇,3盐酸盐(820mg,1.317mmol,88.0%产率):1H NMR(400MHz,CD3OD)δppm 8.70(br.s,2H),7.82(br.s,2H),7.67(s,1H),7.47(s,1H),7.20-7.13(m,1H),4.78(br.s,2H),4.24(br.s,4H),3.44(br.s,4H);ES-LCMS m/z432.1,434.0[M+H]+.
步骤2:(2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲醇和甲酸(2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基酯
向(2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲醇,3盐酸盐(0.8g,1.285mmol)在甲酸(5mL)中的混合物中添加甲醛(37%的H2O溶液,3.09g,25.7mmol)。溶液在100℃搅拌2h,然后浓缩且在DCM(50mL)和饱和NaHCO3水溶液(30mL)之间分配。水层用DCM(50mL x2)萃取。合并的有机萃取物用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到(2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲醇(0.8g,1.144mmol,89.0%产率)和甲酸(2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基酯(0.8g,0.234mmol,18.2%产率)的混合物,其为棕色固体:1H NMR(400MHz,CD3OD)δppm 8.46(s,2H),7.83(s,2H),7.68-7.63(m,1H),7.47(s,1H),7.10(s,1H),4.76(br.s,2H),3.75(s,4H),3.26(s,4H),2.98(s,3H);ES-LCMS m/z446.1,448.1[M+H]+and ES-LCMS m/z 474.1,476.1[M+H]+.
步骤3:3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
向甲酸(2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基酯(0.8g,0.234mmol)和(2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲醇(0.8g,1.505mmol)在MeOH(30mL)和水(10mL)中的溶液中添加K2CO3(0.162g,1.172mmol)。将混合物在20℃搅拌1h,然后浓缩且在DCM(50mL)和水(40mL)溶液之间分配。水相用DCM(50mL×3)萃取。合并的有机萃取物用Na2SO4干燥,过滤且浓缩以得到白色固体的(2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲醇(0.65g,1.188mmol,50.7%产率):1H NMR(400MHz,CDCl3)δppm8.11(s,2H),7.57(s,2H),7.16(s,2H),6.75(s,1H),4.55(s,2H),3.69(br.s,4H),2.38(br.s,4H),2.19(s,3H);LCMSm/z 446.1,448.1[M+H]+.
步骤4:甲磺酸(2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基酯
向(2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲醇(0.15g,0.274mmol)和DIEA(0.146mL,0.823mmol)在DCM(20mL)中的溶液中添加MsCl(0.045mL,0.548mmol)。溶液在20℃搅拌0.5h,然后用水(20mL×3)洗涤。有机层用Na2SO4干燥,过滤且浓缩。将混合物浓缩以得到棕色油状物的甲磺酸(2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基酯(180mg,0.235mmol,86.0%产率):1HNMR(400MHz,CDCl3)δppm 8.38(d,J=17.6Hz,2H),7.69(br.s,2H),7.44(br.s,1H),7.39(br.s,1H),7.00(br.s,1H),5.31(br.s,2H),3.92(s,3H),3.77(br.s,4H),3.57(br.s,4H),2.91-2.77(m,3H);LCMSm/z 524.0,526.0[M+H]+.
步骤5:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙烷磺酰胺,4盐酸盐
向甲磺酸(2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基酯(180mg,0.235mmol)、K2CO3(97mg,0.704mmol)在DMF(5mL)中的混合物中添加2-(哌啶-4-基)乙烷磺酰胺(67.7mg,0.282mmol)。将混合物在25℃搅拌2h,然后浓缩。残余物用DCM(50mL)和水(50mL)稀释,用DCM(50mL x2)萃取。合并的有机萃取物用Na2SO4干燥,过滤且浓缩。粗产物通过硅胶柱色谱法(DCM/MeOH=10/1,Rf=0.5)纯化以得到棕色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙烷磺酰胺,4盐酸盐(10.07mg,0.013mmol,5.5%产率):1H NMR(400MHz,CD3OD)δppm 8.49-8.42(m,2H),7.90(s,1H),7.87(d,J=1.8Hz,2H),7.51(d,J=1.8Hz,1H),7.31(s,1H),4.43(s,2H),3.59(d,J=7.5Hz,5H),3.39(br.s,2H),3.25-3.04(m,7H),2.97(s,3H),2.05(d,J=13.2Hz,2H),1.88-1.78(m,3H),1.56(d,J=13.7Hz,2H);ES-LCMS m/z620.2,622.2[M+H]+.
实施例88:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰胺
向N-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(250mg,0.279mmol)在MeCN(5mL)中的混合物中添加DIEA(180mg,1.396mmol)和3-溴丙酰胺(46.7mg,0.307mmol)。将反应在15℃在N2气氛搅拌10h。将混合物浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化且冻干干燥以得到白色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰胺(39.31mg,0.060mmol,21.5%产率):1H NMR(400MHz,CD3OD)δppm8.34(s,2H),7.85(d,J=1.5Hz,2H),7.68(s,1H),7.46(s,1H),7.07(s,1H),3.95-3.84(m,4H),3.64(s,2H),3.10(d,J=6.5Hz,2H),2.96(d,J=12.0Hz,2H),2.79-2.72(m,2H),2.62(t,J=4.8Hz,4H),2.49(t,J=7.3Hz,2H),2.17-2.06(m,2H),1.96(s,3H),1.75(d,J=11.5Hz,2H),1.42-1.23(m,3H);ES-LCMS m/z641.3,643.3[M+H]+.
实施例89:N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)嘧啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
步骤1:6-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-2-氯嘧啶-4-甲酸甲酯
向2,6-二氯嘧啶-4-甲酸甲酯(600mg,2.90mmol)在MeCN(100mL)中的混合物中添加4-(5-羟基吡啶-2-基)哌嗪-1-甲酸叔丁酯(972mg,3.48mmol)、K2CO3(1202mg,8.70mmol)。将混合物在30℃搅拌12h,然后过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(MeOH/DCM=10/1,Rf=0.4)纯化以得到棕色固体的6-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-2-氯嘧啶-4-甲酸甲酯(500mg,0.889mmol,30.7%产率):1H NMR(400MHz,CDCl3)δppm 8.01(d,J=2.65Hz,1H),7.46(s,1H),7.29(dd,J=2.87,9.04Hz,1H),6.64(d,J=9.04Hz,1H),3.96(s,3H),3.49(s,8H),1.43(s,9H);ES-LCMS m/z450.1[M+H]+.
步骤2:6-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-2-(3,5-二氯苯基)嘧啶-4-甲酸甲酯
向6-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-2-氯嘧啶-4-甲酸甲酯(500mg,1.111mmol)、(3,5-二氯苯基)硼酸(212mg,1.111mmol)、K2CO3(461mg,3.33mmol)在1,4-二噁烷(100mL)中的混合物中添加PdCl2(dppf)(81mg,0.111mmol)。将混合物在80℃在N2气氛搅拌3h。将反应混合物浓缩且残余物在DCM(100mL)和水(100mL)之间分配,用DCM(100mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物。粗产物通过硅胶柱色谱法(DCM/MeOH=20/1至10/1,DCM/MeOH=10/1,Rf=0.5)纯化以得到棕色固体的6-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-2-(3,5-二氯苯基)嘧啶-4-甲酸甲酯(400mg,0.571mmol,51.4%产率):1H NMR(400MHz,CDCl3)δppm 8.19(d,J=1.71Hz,1H),8.12(d,J=2.69Hz,1H),7.52-7.38(m,3H),7.27-7.21(m,1H),6.78-6.72(m,1H),4.04(s,3H),3.57(m,8H),1.48(s,9H);ES-LCMS m/z 560.1,562.1[M+H]+.
步骤3:4-(5-((2-(3,5-二氯苯基)-6-(羟基甲基)嘧啶-4-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向6-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-2-(3,5-二氯苯基)嘧啶-4-甲酸甲酯(500mg,0.892mmol)在EtOH(100mL)中的溶液中添加NaBH4(675mg,17.84mmol)。将混合物在70℃搅拌1h,然后浓缩。将残余物溶于DCM(100mL)且将混合物用水(100mL×3)洗涤。有机相用Na2SO4干燥,过滤且浓缩以得到棕色固体的4-(5-((2-(3,5-二氯苯基)-6-(羟基甲基)嘧啶-4-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.601mmol,67.4%产率):1H NMR(400MHz,CDCl3)δppm 8.18(d,J=2.01Hz,2H),8.12(d,J=2.51Hz,1H),7.45-7.39(m,2H),6.84-6.79(m,1H),6.75(d,J=9.03Hz,1H),4.79(d,J=4.52Hz,2H),3.58(br.s,8H),1.50-1.48(m,9H);ES-LCMS m/z 532.2,534.2[M+H]+.
步骤4:4-(5-((2-(3,5-二氯苯基)-6-(((甲基磺酰基)氧基)甲基)嘧啶-4-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
在30℃向4-(5-((2-(3,5-二氯苯基)-6-(羟基甲基)嘧啶-4-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(300mg,0.563mmol)在DCM(50mL)中的混合物中添加MsCl(2.041mL,26.2mmol)、Et3N(2.356mL,16.90mmol)。将混合物在30℃搅拌1h,然后浓缩。所得粗物质溶于DCM(50mL)且将混合物用水(50mL×3)洗涤。有机层用Na2SO4干燥,过滤,且浓缩以得到棕色油状物4-(5-((2-(3,5-二氯苯基)-6-(((甲基磺酰基)氧基)甲基)嘧啶-4-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.524mmol,93.0%产率):1H NMR(400MHz,CDCl3)δppm8.16(d,J=1.51Hz,1H),8.13-8.09(m,2H),7.44(d,J=2.01Hz,2H),7.00(s,1H),6.75(d,J=9.03Hz,1H),5.29(s,2H),3.68(td,J=6.34,12.92Hz,8H),3.18(s,3H),1.42(s,9H);ES-LCMSm/z 610.2,612.2[M+H]+.
步骤5:4-(5-((6-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-2-(3,5-二氯苯基)嘧啶-4-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((2-(3,5-二氯苯基)-6-(((甲基磺酰基)氧基)甲基)嘧啶-4-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.655mmol)在DMF(100mL)中的混合物中添加N-(哌啶-4-基甲基)乙酰胺,盐酸盐(151mg,0.786mmol)和K2CO3(272mg,1.966mmol)。将混合物在80℃搅拌5h,然后冷却,过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(MeOH:DCM=10/1,Rf=0.4)纯化以得到棕色固体的4-(5-((6-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-2-(3,5-二氯苯基)嘧啶-4-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(300mg,0.358mmol,54.6%产率):1H NMR(400MHz,CDCl3)δppm 8.19(d,J=1.96Hz,1H),8.10-8.05(m,2H),7.37-7.31(m,2H),6.94(s,1H),6.72-6.66(m,1H),3.80-3.70(m,2H),3.51(br.s,8H),3.14-3.07(m,4H),2.15-2.10(m,2H),1.93(s,5H),1.65(d,J=12.72Hz,3H),1.44-1.40(m,9H);ES-LCMSm/z 670.3,672.3[M+H]+.
步骤6:N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)嘧啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
向4-(5-((6-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-2-(3,5-二氯苯基)嘧啶-4-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(290mg,0.432mmol)在DCM(20mL)中的溶液中添加TFA(5mL,64.9mmol)。将反应在20℃搅拌1h。将混合物浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到白色固体的N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)嘧啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(78.88mg,0.109mmol,25.1%产率):1H NMR(400MHz,CD3OD)δppm 8.34-8.25(m,3H),8.14(dd,J=2.51,9.54Hz,1H),7.65(s,1H),7.54(d,J=10.04Hz,1H),7.41-7.31(m,1H),4.63(s,2H),4.11-3.99(m,4H),3.76(d,J=12.55Hz,2H),3.54-3.46(m,4H),3.27-3.11(m,4H),2.13-1.95(m,5H),1.92(br.s,1H),1.72-1.53(m,2H);ES-LCMS m/z 570.2,572.2[M+H]+.
实施例90:N-((1-((6-(3,5-二氯苯基)-2-((6-(哌嗪-1-基)吡啶-3-基)氧基)嘧啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
步骤1:2-氯-6-(3,5-二氯苯基)嘧啶-4-甲酸甲酯
在N2气氛向2,6-二氯嘧啶-4-甲酸甲酯(5g,24.15mmol)和K2CO3(6.68g,48.3mmol)在1,4-二噁烷(200mL)中的溶液中添加(3,5-二氯苯基)硼酸(5.53g,29.0mmol)和PdCl2(dppf)(1.767g,2.42mmol)。将混合物在80℃搅拌12h,然后浓缩且在DCM(300mL)和饱和NaHCO3水溶液(100mL)之间分配。合并的有机萃取物用盐水(100mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=3/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到淡黄色固体的2-氯-6-(3,5-二氯苯基)嘧啶-4-甲酸甲酯(4g,11.34mmol,46.9%产率):1H NMR(400MHz,CDCl3)δppm 8.31(s,1H),8.06(d,J=2.0Hz,2H),7.57(t,J=1.9Hz,1H),4.08(s,3H);ES-LCMS m/z 316.9,318.9[M+H]+.
步骤2:2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)嘧啶-4-甲酸甲酯
向2-氯-6-(3,5-二氯苯基)嘧啶-4-甲酸甲酯(1g,3.15mmol)和K2CO3(0.870g,6.30mmol)在DMF(20mL)中的混合物中添加4-(5-羟基吡啶-2-基)哌嗪-1-甲酸叔丁酯(0.880g,3.15mmol)。将混合物在80℃搅拌12h。将溶液浓缩且在DCM(50mL)和饱和NaHCO3水溶液(30mL)之间分配。合并的有机萃取物用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=1/1)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.3)发现包含产物的级分合并且浓缩以得到淡黄色固体的2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)嘧啶-4-甲酸甲酯(1.2g,1.328mmol,42.2%产率):1H NMR(400MHz,CD3OD)δppm 8.25(s,1H),8.11(d,J=2.6Hz,1H),8.02(d,J=1.8Hz,2H),7.65-7.60(m,1H),7.56(dd,J=2.8,9.2Hz,1H),6.95(d,J=9.3Hz,1H),4.02-3.96(m,3H),3.56(s,8H),1.49(s,9H);ES-LCMS m/z 560.1,562.1[M+H]+.
步骤3:4-(5-((4-(3,5-二氯苯基)-6-(羟基甲基)嘧啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向2-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)嘧啶-4-甲酸甲酯(1.2g,2.141mmol)在MeOH(50mL)中的溶液中添加NaBH4(0.243g,6.42mmol)。溶液在20℃搅拌2h。添加饱和NH4Cl水溶液(10mL)且将溶液浓缩。然后将粗产物添加至饱和NaHCO3水溶液(50mL),用DCM(50mL x2)萃取。合并的有机萃取物用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=1/1)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到淡黄色油状物4-(5-((4-(3,5-二氯苯基)-6-(羟基甲基)嘧啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1g,1.127mmol,52.6%产率):1H NMR(400MHz,CD3OD)δppm7.98(d,J=1.8Hz,2H),7.74(d,J=2.9Hz,2H),7.60(t,J=1.8Hz,1H),7.52(dd,J=2.9,9.0Hz,1H),6.98-6.92(m,1H),4.65(s,2H),3.55(br.s,8H),1.51-1.48(m,9H);ES-LCMS m/z 532.2,534.2[M+H]+.
步骤4:4-(5-((4-(3,5-二氯苯基)-6-(((甲基磺酰基)氧基)甲基)嘧啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((4-(3,5-二氯苯基)-6-(羟基甲基)嘧啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1g,1.878mmol)和DIEA(0.485g,3.76mmol)在DCM(20mL)中的混合物中添加MsCl(0.258g,2.254mmol)。将混合物在20℃搅拌10min,然后浓缩且在DCM(50mL)和饱和NaHCO3水溶液(30mL)之间分配。合并的有机萃取物用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到淡黄色固体的4-(5-((4-(3,5-二氯苯基)-6-(((甲基磺酰基)氧基)甲基)嘧啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(0.6g,0.865mmol,46.0%产率):1H NMR(400MHz,CD3OD)δppm 8.08(d,J=2.6Hz,2H),8.04(d,J=1.8Hz,1H),7.53(dd,J=2.9,9.3Hz,2H),6.86(d,J=9.3Hz,2H),5.30(s,2H),3.55(br.s,8H),3.21-3.11(m,3H),1.48(s,9H);ES-LCMS m/z610.1,612.1[M+H]+.
步骤5:4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)嘧啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((4-(3,5-二氯苯基)-6-(((甲基磺酰基)氧基)甲基)嘧啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(0.6g,0.983mmol)和K2CO3(0.272g,1.966mmol)在DMF(10mL)中的混合物中添加N-(哌啶-4-基甲基)乙酰胺盐酸盐(0.189g,0.983mmol)。将混合物在80℃搅拌12h,然后浓缩且在DCM(50mL)和饱和NaHCO3水溶液(30mL)之间分配。合并的有机萃取物用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=1/1)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.3)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)嘧啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(0.3g,0.358mmol,36.4%产率):1H NMR(400MHz,CDCl3)δppm 8.10(d,J=2.9Hz,1H),7.87(d,J=1.8Hz,1H),7.45(dd,J=2.9,9.3Hz,3H),6.63(d,J=9.3Hz,2H),3.65-3.55(m,8H),3.21-3.14(m,4H),2.86-2.75(m,4H),2.10-2.08(m,5H),1.82-1.81(m,1H),1.69-1.67(m,2H),1.48(s,9H);ES-LCMS m/z670.2,672.2[M+H]+.
步骤6:N-((1-((6-(3,5-二氯苯基)-2-((6-(哌嗪-1-基)吡啶-3-基)氧基)嘧啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
向4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)嘧啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(300mg,0.447mmol)在DCM(10mL)中的溶液中添加TFA(2.0g,17.9mmol)。溶液在20℃搅拌0.5h,然后浓缩。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到淡黄色固体的N-((1-((6-(3,5-二氯苯基)-2-((6-(哌嗪-1-基)吡啶-3-基)氧基)嘧啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(26mg,0.036mmol,8.1%产率):1H NMR(400MHz,CD3OD)δppm 8.28(d,J=2.3Hz,1H),8.25(dd,J=2.5,9.8Hz,1H),8.10(d,J=1.5Hz,2H),8.03-7.97(m,1H),7.71(s,1H),7.61(d,J=9.8Hz,1H),4.60(s,2H),4.13-4.05(m,4H),3.74(d,J=12.0Hz,2H),3.59-3.50(m,4H),3.23-3.07(m,4H),2.01-1.99(m,5H),1.88(br.s,1H),1.70-1.55(m,2H);ES-LCMS m/z 570.2,572.2[M+H]+.
实施例91:N-((1-((2-(3,5-二氯苯基)-6-((5-氟-6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)乙酰胺,4盐酸盐
步骤1:4-(乙酰氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯
向4-(氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯(15g,43.5mmol)和DIEA(11.25g,87mmol)在DCM(300mL)中的溶液中添加乙酰氯(5.13g,65.3mmol)。将反应混合物在20℃搅拌12h。添加水(50mL),然后用DCM(300mL x2)萃取。合并的有机层用Na2SO4干燥,浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=5/1)纯化。将所有通过TLC(PE/EA=3/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(乙酰氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯(6g,13.97mmol,32.1%产率):1H NMR(400MHz,CD3OD)δppm 3.58(td,J=3.8,13.2Hz,2H),3.06(br.s,2H),1.80(s,3H),1.49-1.23(m,15H),0.77(s,9H),0.00(s,6H);ES-LCMS m/z 409.2[M+Na]+.
步骤2:N-((4-((叔丁基二甲基甲硅烷基)氧基)哌啶-4-基)甲基)乙酰胺
向4-(乙酰氨基甲基)-4-((叔丁基二甲基甲硅烷基)氧基)哌啶-1-甲酸叔丁酯(6g,15.52mmol)在DCM(20mL)中的溶液中添加TFA(3mL,38.9mmol)。将反应混合物在20℃搅拌0.5h,然后浓缩以得到黄色油状物的N-((4-((叔丁基二甲基甲硅烷基)氧基)哌啶-4-基)甲基)乙酰胺的TFA盐(4g,11.17mmol,72.0%产率):1H NMR(400MHz,CD3OD)δppm 3.39(s,2H),3.31-3.24(m,4H),2.01(s,3H),1.97-1.88(m,2H),1.78(br.s,2H),0.97(s,9H),0.23(s,6H);ES-LCMS m/z 287.0[M+H]+.
步骤3:4-(5-((4-((4-(乙酰氨基甲基)-4-羟基哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯
将4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯(500mg,0.797mmol)、N-((4-((叔丁基二甲基甲硅烷基)氧基)哌啶-4-基)甲基)乙酰胺(457mg,1.594mmol)和K2CO3(330mg,2.390mmol)在DMF(10mL)中的混合物在N2气氛加热至90℃保持12h。将反应混合物过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(DCM/MeOH=9/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到黄色固体的4-(5-((4-((4-(乙酰氨基甲基)-4-羟基哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.512mmol,64.2%产率):1H NMR(400MHz,CD3OD)δppm 7.82-7.71(m,3H),7.65(s,1H),7.48(dd,J=2.2,12.8Hz,1H),7.41(s,1H),7.06-6.97(m,1H),3.66-3.61(m,2H),3.57(br.s,4H),3.40(d,J=4.9Hz,4H),3.21(s,2H),2.63(d,J=11.5Hz,2H),2.54-2.41(m,2H),1.96(s,3H),1.57(d,J=12.8Hz,4H),1.47(s,9H);ES-LCMS m/z 703.2,705.2[M+H]+.
步骤4:N-((1-((2-(3,5-二氯苯基)-6-((5-氟-6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)乙酰胺,4盐酸盐
将4-(5-((4-((4-(乙酰氨基甲基)-4-羟基哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.568mmol)和TFA(10%的DCM溶液,10mL)的混合物在15℃搅拌0.5h。将溶液浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到白色固体的N-((1-((2-(3,5-二氯苯基)-6-((5-氟-6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)乙酰胺,4盐酸盐(216.99mg,0.290mmol,50.9%产率):1H NMR(400MHz,CD3OD)δppm 8.08(d,J=2.2Hz,1H),7.99(s,1H),7.88(d,J=1.8Hz,2H),7.64(dd,J=2.2,12.8Hz,1H),7.49(t,J=1.8Hz,1H),7.34(s,1H),4.58-4.43(m,2H),3.78-3.70(m,4H),3.48-3.34(m,8H),3.27(s,2H),2.06-1.95(m,5H),1.86-1.77(m,2H);ES-LCMS m/z 603.2,605.2[M+H]+.
实施例92:N-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
步骤1:4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(200mg,0.328mmol)、N-(哌啶-4-基甲基)乙酰胺盐酸盐(127mg,0.655mmol)在DMF(5mL)中的混合物中添加K2CO3(181mg,1.310mmol)。将反应在50℃在N2气氛搅拌8h,然后浓缩。添加饱和NaHCO3水溶液(15mL)且水层用DCM(150mL x2)萃取。合并的萃取物用盐水(15mL x2)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色油状物4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(200mg,0.18mmol,54.6%产率):1H NMR(400MHz,CDCl3)δppm 8.33-8.21(m,3H),7.78-7.64(m,2H),7.48-7.28(m,2H),3.82(br.s,4H),3.52(br.s,4H),3.25-3.07(m,4H),2.85-2.90(m,4H),1.99(d,J=2.5Hz,3H),1.90-1.80(m,5H),1.49-1.40(m,9H);ES-LCMS m/z 670.3,672.3[M+H]+.
步骤2:N-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
向4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(100mg,0.149mmol)在DCM(10mL)中的混合物中添加TFA(0.287mL,3.73mmol)。将反应在15℃在N2气氛搅拌10分钟,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到黄色固体的N-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(5.39mg,7.45μmol,5.0%产率):1H NMR(400MHz,CD3OD)δppm 8.45(s,2H),7.91(s,1H),7.87(d,J=1.8Hz,2H),7.51(t,J=1.8Hz,1H),7.34-7.27(m,1H),4.43(s,2H),4.15-4.10(m,4H),3.60(d,J=12.3Hz,2H),3.34(d,J=5.3Hz,4H),3.14-3.05(m,4H),2.02-1.94(m,5H),1.85(br.s,1H),1.62-1.51(m,2H);ES-LCMS m/z 570.3,572.3[M+H]+.
实施例93:N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
步骤1:2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)乙酸乙酯
向N-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(400mg,0.447mmol)在MeCN(5mL)中的混合物中添加DIEA(289mg,2.234mmol)和2-溴乙酸乙酯(82mg,0.491mmol)。将反应在15℃在N2气氛搅拌10h,然后过滤且浓缩以得到黄色固体的2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)乙酸乙酯(350mg,0.426mmol,95.0%产率):1H NMR(400MHz,CDCl3)δppm 8.23(s,2H),7.95(s,2H),7.68(s,2H),7.22(s,1H),4.13(q,J=5.7Hz,2H),3.84(d,J=4.4Hz,4H),3.76(s,2H),3.67-3.63(m,4H),3.08(d,J=6.6Hz,4H),2.60(d,J=4.4Hz,4H),1.94(d,J=5.7Hz,6H),1.76-1.66(m,2H),1.21(t,J=3.7Hz,3H);ES-LCMS m/z 656.3,658.3[M+H]+.
步骤2:N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
在-20℃向2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)乙酸乙酯(250mg,0.305mmol)在THF(10mL)中的混合物中添加LiAlH4(17.34mg,0.457mmol)。将反应在-20℃在N2气氛搅拌10h,然后通过1mL水淬灭。将混合物过滤且浓缩,然后用制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(48.42mg,0.063mmol,20.8%产率):1H NMR(400MHz,CD3OD)δppm8.48(s,2H),7.94-7.85(m,3H),7.54(s,1H),7.33(s,1H),4.93(br.s,2H),4.45(s,2H),4.01-3.91(m,2H),3.75(d,J=12.5Hz,2H),3.62(d,J=12.0Hz,2H),3.48(t,J=12.3Hz,2H),3.40-3.35(m,3H),3.31-3.21(m,2H),3.17-3.07(m,3H),2.06-1.94(m,5H),1.87(br.s,1H),1.64-1.50(m,2H);ES-LCMSm/z614.3,616.3[M+H]+.
实施例94:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-N-甲基丙酰胺,4盐酸盐
步骤1:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯和3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸
向N-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(300mg,0.479mmol)和K2CO3(397mg,2.87mmol)在DMF(15mL)中的混合物中添加3-溴丙酸乙酯(173mg,0.957mmol)。然后,将混合物在80℃搅拌12h。混合物冷却且过滤。将滤液浓缩以得到3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(350mg,0.089mmol,18.5%产率)和3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸(350mg,0.234mmol,48.9%产率)的混合物,其为棕色固体:1H NMR(400MHz,CDCl3)δppm8.10-8.04(m,2H),7.88(d,J=1.3Hz,2H),7.60(d,J=8.8Hz,1H),7.47(s,1H),7.28(s,1H),4.47(s,2H),4.43-4.32(m,4H),4.24-4.07(m,4H),3.88-3.77(m,4H),3.63-3.47(m,6H),3.18-3.12(m,2H),2.02-1.95(m,5H),1.88(br.s,1H),1.63(d,J=11.9Hz,2H),1.30-1.25(m,3H);ES-LCMSm/z670.2,672.2[M+H]+;ES-LCMS m/z 642.2,644.2[M+H]+.
步骤2:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸
向3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(350mg,0.089mmol)和3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸(350mg,0.234mmol)在THF(5mL)和水(5mL)中的混合物中添加LiOH·H2O(30mg,0.715mmol)。然后将混合物在30℃搅拌3h。将反应浓缩且该反应混合物用DCM(100mL)和水(100mL)稀释,用H2O(100mL x2)萃取。合并的水层用10%HCl水溶液调节至pH为6-7。然后将混合物浓缩以得到棕色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸(250mg,0.311mmol,96.0%产率):1H NMR(400MHz,CDCl3)δppm 8.09(dd,J=2.6,8.4Hz,2H),7.83(s,1H),7.71(s,2H),7.43(br.s,1H),7.05(d,J=5.7Hz,1H),3.83-3.74(m,4H),3.44-3.37(m,6H),3.20-3.13(m,4H),3.11-3.01(m,4H),2.57(d,J=6.2Hz,2H),1.96-1.90(m,5H),1.78(d,J=11.5Hz,1H),1.43-1.33(m,2H);ES-LCMS m/z 642.2,644.2[M+H]+.
步骤3:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸甲酯,4盐酸盐
向3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸(200mg,0.249mmol)在MeOH(20mL)中的溶液中添加HCl溶液(4.0M在MeOH中,10mL,40mmol)。将混合物在30℃搅拌0.5h,然后浓缩。反应混合物用H2O(50mL)稀释,然后用DCM(50mL×3)洗涤。水相浓缩以得到棕色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸甲酯,4盐酸盐(220mg,0.172mmol,69.1%产率):1H NMR(400MHz,CDCl3)δppm8.32(s,2H),7.82(d,J=1.8Hz,2H),7.66(s,1H),7.44(s,1H),7.05(s,1H),4.63(s,4H),3.87-3.81(m,3H),3.69(s,3H),3.63(s,2H),3.08(d,J=7.1Hz,2H),2.95(d,J=11.9Hz,3H),2.79-2.72(m,2H),2.63-2.57(m,4H),2.14-2.07(m,3H),1.73(d,J=11.9Hz,2H),1.30(d,J=17.2Hz,3H);ES-LCMS m/z 656.2,658.3[M+H]+.
步骤4:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-N-甲基丙酰胺,4盐酸盐
在高压灭菌器中将3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸甲酯,4盐酸盐(180mg,0.141mmol)和甲胺(30%在乙醇中,10mL)的溶液在70℃搅拌16h。将混合物浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到黄色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-N-甲基丙酰胺,4盐酸盐(50.39mg,0.062mmol,44.1%产率):1H NMR(400MHz,CD3OD)δppm 8.47(s,2H),7.93(s,1H),7.87(d,J=1.8Hz,2H),7.50(s,1H),7.33(s,1H),4.43(s,2H),3.70(d,J=11.9Hz,2H),3.59(d,J=11.9Hz,2H),3.53-3.40(m,4H),3.36-3.31(m,2H),3.27-3.03(m,6H),2.83-2.72(m,5H),2.02-1.94(m,5H),1.85(br.s,1H),1.65-1.52(m,2H);ES-LCMSm/z655.3,657.3[M+H]+.
实施例95:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酰胺,4盐酸盐
步骤1:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酸乙酯
向N-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(300mg,0.479mmol)和(E)-丁-2-烯酸乙基酯(1092mg,9.57mmol)的悬浮液中添加DIEA(309mg,2.393mmol)。将反应混合物在150℃在微波下搅拌3h。将该反应混合物浓缩以得到粗物质。粗产物通过二氧化硅柱色谱法(DCM/MeOH=9/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到棕色胶状物的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酸乙酯(280mg,0.290mmol,60.5%产率):1H NMR(400MHz,CDCl3)δppm 8.22(s,2H),7.66(d,J=1.8Hz,2H),7.34(br.s,1H),7.27(s,1H),6.82(s,1H),5.47(br.s,1H),4.15-4.05(q,J=7.1Hz,2H),3.81-3.65(m,4H),3.52(s,3H),3.17(t,J=6.3Hz,2H),2.89-2.71(d,J=10.4Hz,3H),2.67-2.57(m,4H),2.28(dd,J=7.8,14.4Hz,1H),2.08-2.00(m,3H),1.99(s,3H),1.42-1.29(m,4H),1.26(t,J=7.1Hz,3H),1.08(d,J=6.6Hz,3H);ES-LCMSm/z684.3,686.2[M+H]+.
步骤2:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酰胺,4盐酸盐
在-78℃将氨气鼓泡至3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酸乙酯(280mg,0.290mmol)在MeOH(5mL)中的悬浮液中达0.5h。将反应混合物在封闭管中在70℃搅拌48h。冷却至室温后,将反应混合物浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且将所需级分冻干以得到白色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酰胺,4盐酸盐(21.96mg,0.027mmol,9.4%产率):1H NMR(400MHz,CD3OD)δppm 8.45(s,2H),7.93(s,1H),7.87(d,J=1.3Hz,2H),7.49(s,1H),7.32(s,1H),5.01(d,J=13.7Hz,2H),4.53-4.40(m,2H),3.85(qd,J=6.6,13.2Hz,1H),3.72-3.54(m,4H),3.45-3.34(m,3H),3.26-3.03(m,5H),2.85(dd,J=6.4,16.1Hz,1H),2.71-2.63(m,1H),2.05-1.92(m,5H),1.85(br.s,1H),1.67-1.51(m,2H),1.42(d,J=6.6Hz,3H);ES-LCMS m/z 655.2,657.3[M+H]+.
实施例96:4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酰胺
步骤1:4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酸乙酯
向N-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(1g,1.578mmol)和4-溴丁酸甲酯(0.857g,4.73mmol)在MeCN(50mL)中的溶液中添加K2CO3(0.872g,6.31mmol)。将反应混合物在80℃搅拌5h,然后过滤,浓缩且通过快速色谱法(DCM/MeOH=100至10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到棕色固体4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酸甲酯(0.8g,0.852mmol,54.0%产率):1H NMR(400MHz,CDCl3)δppm 8.27(s,2H),7.95(br.s,2H),7.88(br.s,1H),7.55-7.45(br.s,1H),7.29(br.s,1H),3.75(s,2H),3.65(s,3H),3.40(s,4H),3.29-3.10(m,6H),3.09-3.00(m,6H),2.39(s,2H),2.05(d,J=9.7Hz,5H),1.95(br.s,1H),1.85-1.75(m,2H),1.59-1.55(m,2H);ES-LCMS m/z 670.2,672.2[M+H]+.
步骤2:4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酰胺,4盐酸盐
在-78℃将氨气鼓泡至4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酸甲酯(0.5g,0.533mmol)在MeOH(10mL)中的悬浮液中达0.5h。然后在封闭管中将反应混合物在80℃搅拌72h。将溶液浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到棕色固体的4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酰胺,4盐酸盐(48.75mg,0.061mmol,11.4%产率):1HNMR(400MHz,CD3OD)δppm 8.65-8.53(m,2H),8.03(s,1H),7.89(d,J=1.3Hz,2H),7.48(s,1H),7.40(s,1H),4.90(d,J=14.6Hz,2H),4.46(s,2H),3.75(d,J=11.9Hz,2H),3.65-3.31(m,6H),3.29-3.06(m,6H),2.58-2.45(m,2H),2.16-2.05(m,5H),2.03-1.80(m,3H),1.79-1.57(m,2H);ES-LCMS m/z 655.3,657.3[M+H]+.
实施例97:1-(5-((3',5'-二氯-5-(((2-甲氧基乙基)氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)-N-甲基哌啶-4-胺
步骤1:1-(5-溴吡啶-2-基)哌啶-4-酮
将5-溴-2-氟吡啶(2.130g,12.11mmol)、哌啶-4-酮(1.0g,10.09mmol)和K2CO3(4.18g,30.3mmol)悬浮于DMF(20mL)。将反应混合物在100℃在N2气氛搅拌4h,然后浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=1/0至1/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到黄色固体的1-(5-溴吡啶-2-基)哌啶-4-酮(1.3g,4.59mmol,45.5%产率):1H NMR(400MHz,CDCl3)δppm 8.22(d,J=2.2Hz,1H),7.58(dd,J=2.4,9.0Hz,1H),6.65(d,J=9.0Hz,1H),3.88(t,J=6.1Hz,4H),2.58-2.43(m,4H);ES-LCMS m/z 254.9,256.9[M+H]+.
步骤2:(1-(5-溴吡啶-2-基)哌啶-4-基)(甲基)氨基甲酸叔丁酯
将甲胺(30%在EtOH中,2.0mL,5.10mmol)、1-(5-溴吡啶-2-基)哌啶-4-酮(1.3g,5.10mmol)和分子筛悬浮于1,2-二氯乙烷(50mL)且在40℃搅拌12h。添加NaBH(OAc)3(5.40g,25.5mmol)且搅拌5h。然后添加DIEA(2.67mL,15.29mmol)和Boc2O(2.366mL,10.19mmol),且将混合物再搅拌3h。该反应用饱和NaHCO3水溶液淬灭。分离且将有机层通过水、盐水洗涤,用MgSO4干燥且浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=1/0至1/1)纯化。将所有通过TLC(PE/EtOAc=5/1,Rf=0.3)发现包含产物的级分合并且浓缩以得到黄色油状物的(1-(5-溴吡啶-2-基)哌啶-4-基)(甲基)氨基甲酸叔丁酯(1.12g,2.12mmol,47.5%产率):1H NMR(400MHz,CDCl3)δppm 8.17(d,J=2.2Hz,1H),7.51(dd,J=2.4,9.0Hz,1H),6.57(d,J=9.0Hz,1H),4.12(dd,J=2.4,9.0Hz,2H),2.92-2.81(m,2H),2.70(s,3H),1.70-1.67(m,5H),1.46(s,9H);ES-LCMS m/z 370.1,372.1[M+H]+.
步骤3:N-((3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲基)-2-甲氧基乙胺
将2-甲氧基乙胺(0.288g,3.83mmol)、甲磺酸(3’,5’-二氯-5-(甲氧基甲氧基)-[1,1’-联苯]-3-基)甲基酯(1g,2.56mmol)和K2CO3(1.060g,7.67mmol)悬浮于MeCN(30mL)。将混合物在80℃搅拌6h,然后浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=1/0至2/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到黄色油状物的N-((3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲基)-2-甲氧基乙胺(980mg,2.382mmol,93.0%产率):1H NMR(400MHz,CDCl3)δppm 7.49-7.42(m,2H),7.31(t,J=1.6Hz,1H),7.17-7.12(m,1H),7.08-6.99(m,2H),5.26-5.18(m,2H),3.87-3.81(m,2H),3.55-3.44(m,6H),3.38-3.31(m,2H),2.88-2.77(m,2H);ES-LCMS m/z 370.1,372.1[M+H]+.
步骤4:3',5'-二氯-5-(((2-甲氧基乙基)氨基)甲基)-[1,1'-联苯]-3-醇
向N-((3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲基)-2-甲氧基乙胺(0.98g,2.65mmol)在DCM(10mL)中的溶液中一次性添加2M HCl溶液(2mL,4.00mmol)。将反应混合物在25℃搅拌6h,然后浓缩以得到黄色油状物的3',5'-二氯-5-(((2-甲氧基乙基)氨基)甲基)-[1,1'-联苯]-3-醇(880mg,2.158mmol,82.0%产率);ES-LCMS m/z 326.0,328.0[M+H]+.
步骤5:((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)(2-甲氧基-乙基)氨基甲酸叔丁酯
将3',5'-二氯-5-(((2-甲氧基乙基)氨基)甲基)-[1,1'-联苯]-3-醇(1.28g,3.92mmol)、Boc2O(1.822mL,7.85mmol)和DIEA(2.056mL,11.77mmol)悬浮于DCM(20mL)。将反应在20℃搅拌6h,然后浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=1/0至1/1)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到黄色油状物的((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)(2-甲氧基乙基)氨基甲酸叔丁酯(1.13g,2.12mmol,54.0%产率):1H NMR(400MHz,CDCl3)δppm 7.42(d,J=1.7Hz,2H),7.33(s,1H),7.28-7.26(m,1H),7.23(s,1H),7.07(br.s,1H),4.55(br.s,2H),3.47-3.40(m,2H),3.36-3.28(m,5H),1.48-1.40(m,9H);ES-LCMS m/z 448.1,450.1[M+Na]+.
步骤6:((5-((6-(4-((叔丁氧基羰基)(甲基)氨基)哌啶-1-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(2-甲氧基乙基)氨基甲酸叔丁酯
将(1-(5-溴吡啶-2-基)哌啶-4-基)(甲基)氨基甲酸叔丁酯(521mg,1.407mmol)、CuI(44.7mg,0.235mmol)、((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)(2-甲氧基乙基)氨基甲酸叔丁酯(500mg,1.173mmol)、吡啶甲酸(57.8mg,0.469mmol)和K3PO4(747mg,3.52mmol)悬浮于DMSO(20mL)。将反应混合物在130℃在N2气氛搅拌20h,然后过滤。滤液用DCM(200mL)稀释,然后通过水(20mL×3)、盐水(20mL×3)洗涤且用MgSO4干燥。固体通过过滤去除且将滤液浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=1/0至1/1)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到黄色油状物的((5-((6-(4-((叔丁氧基羰基)(甲基)氨基)哌啶-1-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(2-甲氧基乙基)氨基甲酸叔丁酯(320mg,0.402mmol,34.3%产率):1H NMR(400MHz,CDCl3)δppm8.03(d,J=2.6Hz,1H),7.38-7.30(m,3H),7.25-7.21(m,1H),7.05(s,1H),6.94(d,J=10.1Hz,1H),6.82(br.s,1H),6.69(d,J=9.0Hz,1H),4.33(d,J=12.8Hz,2H),3.54-3.38(m,4H),3.30(s,4H),2.93-2.77(m,4H),2.73(br.s,3H),1.74(br.s,4H),1.47(s,18H);ES-LCMSm/z 715.3,717.3[M+H]+.
步骤7:1-(5-((3',5'-二氯-5-(((2-甲氧基乙基)氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)-N-甲基哌啶-4-胺,3盐酸盐
向((5-((6-(4-((叔丁氧基羰基)(甲基)氨基)哌啶-1-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(2-甲氧基乙基)氨基甲酸叔丁酯(320mg,0.447mmol)在DCM(15mL)中的溶液中添加TFA(5.0mL,64.9mmol)。将反应在20℃搅拌2h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的1-(5-((3',5'-二氯-5-(((2-甲氧基乙基)氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)-N-甲基哌啶-4-胺,3盐酸盐(38.46mg,0.062mmol,13.7%产率):1H NMR(400MHz,CD3OD)δppm7.97(dd,J=2.7,9.8Hz,1H),7.88(d,J=2.7Hz,1H),7.66(d,J=1.7Hz,2H),7.61(s,1H),7.55(d,J=10.0Hz,1H),7.49(t,J=1.7Hz,1H),7.45(s,1H),7.39(s,1H),4.35(d,J=14.2Hz,2H),4.30(s,2H),3.72-3.66(m,2H),3.54-3.35(m,6H),3.28-3.24(m,2H),2.80-2.72(m,3H),2.31(d,J=11.0Hz,2H),1.85(dq,J=3.8,12.2Hz,2H);ES-LCMSm/z 515.2,517.2[M+H]+.
实施例98:1-(3',5'-二氯-5-((6-(哌嗪-1-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)-N-甲基甲胺,3盐酸盐
向((5-((6-溴吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯(0.2g,0.372mmol)和K2CO3(0.103g,0.743mmol)在NMP(3mL)中的混合物中添加哌嗪-1-甲酸叔丁酯(0.138g,0.743mmol)。将反应在160℃在微波下搅拌3h,然后过滤,浓缩。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到1-(3',5'-二氯-5-((6-(哌嗪-1-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)-N-甲基甲胺,3盐酸盐(61.53mg,0.111mmol,30.0%产率):1H NMR(400MHz,CD3OD)δppm 8.00(d,J=2.7Hz,1H),7.97-7.85(m,1H),7.63(s,2H),7.56(br.s,1H),7.49(s,1H),7.48-7.37(m,2H),7.31(br.s,1H),4.25(s,2H),3.97(br.s,4H),3.46(br.s,4H),2.74(s,3H);ES-LCMS m/z443.1,445.1[M+H]+.
实施例99:N1-(5-((3',5'-二氯-5-(吗啉代甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)乙烷-1,2-二胺,3盐酸盐
步骤1:(2-((5-溴吡啶-2-基)氨基)乙基)氨基甲酸叔丁酯
向5-溴-2-氟吡啶(1g,5.68mmol)和(2-氨基乙基)氨基甲酸叔丁酯(0.910g,5.68mmol)在MeCN(10mL)中的溶液中添加K2CO3(0.785g,5.68mmol)。将反应混合物在100℃搅拌16h,然后过滤且浓缩。粗产物通过硅胶柱色谱法(PE/EtOAc=1/1)纯化。将所有发现包含产物的级分合并且浓缩以得到白色固体的(2-((5-溴吡啶-2-基)氨基)乙基)氨基甲酸叔丁酯(1.5g,4.74mmol,83.0%产率):1H NMR(400MHz,CDCl3)δppm 8.08(d,J=2.2Hz,1H),7.43(dd,J=2.4,8.8Hz,1H),6.31(d,J=8.8Hz,1H),4.89(br.s,1H),3.41(q,J=5.5Hz,2H),3.33(d,J=5.4Hz,2H),1.42(s,9H);ES-LCMS m/z 316.0,318.0[M+H]+.
步骤2:4-((3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲基)吗啉
向甲磺酸(3’,5’-二氯-5-(甲氧基甲氧基)-[1,1’-联苯]-3-基)甲基酯(3g,7.67mmol)和K2CO3(3.18g,23.00mmol)在MeCN(50mL)中的溶液中添加吗啉(1.336g,15.33mmol)。将混合物在80℃搅拌12h,然后过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=5/1)纯化。将所有通过TLC(PE/EA=5/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-((3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲基)吗啉(2g,4.97mmol,64.8%产率):1H NMR(400MHz,CDCl3)δppm 7.37(d,J=1.5Hz,2H),7.26(d,J=1.5Hz,1H),7.07(s,1H),7.00(d,J=15.0Hz,2H),5.15(s,2H),3.64-3.60(m,2H),3.44(m,4H),3.42(s,3H),2.41(m,4H);ES-LCMS m/z 382.0,384.0[M+H]+.
步骤3:3',5'-二氯-5-(吗啉代甲基)-[1,1'-联苯]-3-醇
向4-((3',5'-二氯-5-(甲氧基甲氧基)-[1,1'-联苯]-3-基)甲基)吗啉(2.2g,5.75mmol)在DCM(100mL)中的溶液中添加浓HCl(2mL,24.6mmol)。将混合物在20℃搅拌12h,然后浓缩以得到3',5'-二氯-5-(吗啉代甲基)-[1,1'-联苯]-3-醇(2g,5.32mmol,92.0%产率):1H NMR(400MHz,CD3OD)δppm 7.60(d,J=1.8Hz,2H),7.46-7.42(m,1H),7.30(s,1H),7.12(t,J=1.9Hz,1H),7.04(s,1H),4.38-4.32(m,2H),4.03(dd,J=2.9,13.0Hz,2H),3.84-3.76(m,2H),3.40(d,J=12.6Hz,2H),3.27-3.18(m,2H),ES-LCMSm/z338.0,340.0[M+H]+.
步骤4:(2-((5-((3',5'-二氯-5-(吗啉代甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)氨基)乙基)氨基甲酸叔丁酯
向(2-((5-溴吡啶-2-基)氨基)乙基)氨基甲酸叔丁酯(300mg,0.949mmol)、3',5'-二氯-5-(吗啉代甲基)-[1,1'-联苯]-3-醇(289mg,0.854mmol)、Cs2CO3(618mg,1.898mmol)和2-(二甲基氨基)乙酸(19.57mg,0.190mmol)在1,4-二噁烷(10mL)中的悬浮液中添加CuI(36.1mg,0.190mmol)。将反应混合物在110℃在N2气氛搅拌16h,然后过滤且浓缩。粗产物通过硅胶柱色谱法(PE/EtOAc=4/1)纯化。将所有发现包含产物的级分合并且浓缩以得到黄色油状物的(2-((5-((3',5'-二氯-5-(吗啉代甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)氨基)乙基)氨基甲酸叔丁酯(220mg,0.384mmol,40.4%产率):1H NMR(400MHz,CDCl3)δppm7.94(d,J=2.6Hz,1H),7.41-7.29(m,3H),7.22-7.13(m,2H),6.94(s,2H),6.46(d,J=8.8Hz,1H),3.70(t,J=4.4Hz,4H),3.52-3.42(m,4H),3.38(d,J=5.1Hz,2H),2.45(br.s,4H),1.43(s,9H);ES-LCMS m/z 573.2,575.2[M+H]+.
步骤5:N1-(5-((3',5'-二氯-5-(吗啉代甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)乙烷-1,2-二胺,3盐酸盐
向(2-((5-((3',5'-二氯-5-(吗啉代甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)氨基)乙基)氨基甲酸叔丁酯(180mg,0.314mmol)和2,6-二甲基吡啶(0.366mL,3.14mmol)在DCM(0.5mL)中的溶液中滴加三氟甲磺酸叔丁基二甲基甲硅烷基酯(0.721mL,3.14mmol)。将反应混合物在20℃在N2气氛搅拌8h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到N1-(5-((3',5'-二氯-5-(吗啉代甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)乙烷-1,2-二胺,3盐酸盐(54.01mg,0.091mmol,29.0%产率):1H NMR(400MHz,CD3OD)δppm 7.95(dd,J=2.6,9.7Hz,1H),7.88(d,J=2.4Hz,1H),7.67(d,J=1.7Hz,2H),7.63(s,1H),7.50(d,J=1.7Hz,2H),7.45(s,1H),7.25(d,J=9.8Hz,1H),4.41(s,2H),4.03(d,J=10.5Hz,2H),3.90-3.73(m,4H),3.39(d,J=12.2Hz,2H),3.31(br.s,2H),3.27-3.18(m,2H);ES-LCMS m/z 473.1,475.1[M+H]+.
实施例100:1-(5-((3',5'-二氯-5-((甲基氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌啶-4-胺,3盐酸盐
步骤1:((5-((6-(4-((叔丁氧基羰基)氨基)哌啶-1-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯
向((5-((6-溴吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯(0.2g,0.372mmol)和哌啶-4-基氨基甲酸叔丁酯(0.089g,0.446mmol)在NMP(50mL)中的溶液中添加Cs2CO3(0.363g,1.115mmol)。将混合物在160℃在微波下搅拌2h。将有机层过滤且将滤液浓缩以得到((5-((6-(4-((叔丁氧基羰基)氨基)哌啶-1-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯(0.2g,0.182mmol,49.1%产率):1H NMR(400MHz,CDCl3)δppm 8.06-8.00(m,1H),7.42-7.36(m,2H),7.34-7.27(m,2H),7.26-7.22(m,2H),7.16(s,1H),6.69(d,J=9.3Hz,1H),3.68(d,J=13.0Hz,2H),3.42-3.32(m,2H),3.01-2.95(m,2H),2.93-2.87(m,3H),2.74-2.64(m,3H),1.89-1.82(m,4H),1.46-1.44(m,18H)。
步骤2:1-(5-((3',5'-二氯-5-((甲基氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌啶-4-胺,3盐酸盐
向((5-((6-(4-((叔丁氧基羰基)氨基)哌啶-1-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯(150mg,0.228mmol)在DCM(10mL)中的溶液中添加TFA(1300mg,11.4mmol)。将混合物在20℃搅拌1h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到1-(5-((3',5'-二氯-5-((甲基氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌啶-4-胺,3盐酸盐(60mg,0.106mmol,46.4%产率):1H NMR(400MHz,DMSO-d6)δppm 9.29(s,2H),8.22(s,3H),7.98(s,1H),7.78(s,2H),7.68(m,1H),7.64(m,1H),7.53(m,1H),7.44(m,1H),7.13(m,1H),7.05(m,2H),4.30-4.27(m,2H),4.10-4.09(m,2H),3.27(m,1H),2.94(m,2H),2.51(s,3H),1.98-1.95(m,2H),1.57-1.54(m,2H);ES-LCMS m/z 456.9,458.7[M+H]+.
实施例101:N1-(5-((3',5'-二氯-5-((甲基氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)丙烷-1,3-二胺
步骤1:(3-((5-溴吡啶-2-基)氨基)丙基)氨基甲酸叔丁酯
向5-溴-2-氟吡啶(5g,28.4mmol)在MeOH(100mL)中的混合物中添加K2CO3(11.78g,85mmol)和(3-氨基丙基)氨基甲酸叔丁酯(9.90g,56.8mmol)。将混合物在80℃搅拌16h,然后过滤。将滤液浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=2/1)纯化。将所有通过TLC(PE/EtOAc=2/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到白色固体的(3-((5-溴吡啶-2-基)氨基)丙基)氨基甲酸叔丁酯(3g,8.18mmol,28.8%产率):1H NMR(400MHz,CDCl3)δppm 8.07(d,J=2.21Hz,1H),7.41(dd,J=2.09,8.71Hz,1H),6.29(d,J=8.82Hz,1H),3.34(q,J=6.39Hz,2H),3.19(q,J=5.88Hz,2H),1.71(q,J=6.39Hz,2H),1.43(s,9H);ES-LCMSm/z 330.1[M+H]+.
步骤2:((5-((6-((3-((叔丁氧基羰基)氨基)丙基)氨基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯
向((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯(800mg,2.093mmol)在1,4-二噁烷(120mL)中的混合物中添加(3-((5-溴吡啶-2-基)氨基)丙基)氨基甲酸叔丁酯(1037mg,3.14mmol)、2-(二甲基氨基)乙酸(86mg,0.837mmol)、CuI(80mg,0.419mmol)和Cs2CO3(1364mg,4.19mmol)。将混合物在N2气氛在120℃搅拌48h,然后过滤。将滤液浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=3/2)纯化。将所有通过TLC(PE/EtOAc=3/2,Rf=0.4)发现包含产物的级分合并且浓缩以得到白色固体的((5-((6-((3-((叔丁氧基羰基)氨基)丙基)氨基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯(1g,1.583mmol,76.0%产率):1H NMR(400MHz,CD3OD)δppm7.77(s,1H),7.53(s,2H),7.43(s,1H),7.25(dd,J=2.69,9.05Hz,1H),7.15(s,2H),6.76(br.s,1H),6.57(d,J=9.05Hz,1H),4.41(s,2H),3.32(J=6.85Hz,2H),3.14(t,J=6.85Hz,2H),2.81(s,3H),1.75(t,J=6.72Hz,2H),1.46-1.36(m,18H);ES-LCMS m/z631.2,633.2[M+H]+.
步骤3:N1-(5-((3',5'-二氯-5-((甲基氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)丙烷-1,3-二胺,3盐酸盐
向((5-((6-((3-((叔丁氧基羰基)氨基)丙基)氨基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯(1.1g,1.742mmol)在DCM(40mL)中的混合物中缓慢添加TFA(5mL)。将混合物在25℃搅拌0.5h,然后过滤。将滤液浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到灰白色固体的N1-(5-((3',5'-二氯-5-((甲基氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)丙烷-1,3-二胺,3盐酸盐(371.86mg,0.688mmol,39.5%产率):1H NMR(400MHz,CD3OD)δppm7.89(dd,J=2.76,9.79Hz,1H),7.82(d,J=2.51Hz,1H),7.68(d,J=2.01Hz,2H),7.61(s,1H),7.54-7.52(m,1H),7.47(s,1H),7.37(s,1H),7.24(d,J=9.54Hz,1H),4.29(s,2H),3.57(t,J=7.03Hz,2H),3.17-3.11(m,2H),2.78(s,3H),2.13(q,J=7.28Hz,2H);ES-LCMSm/z 431.1,433.1[M+H]+.
实施例102:1-(3',5'-二氯-5-((6-(3,3-二甲基哌嗪-1-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)-N-甲基甲胺,3盐酸盐
将((5-((6-溴吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)(甲基)氨基甲酸叔丁酯(300mg,0.557mmol)、2,2-二甲基哌嗪-1-甲酸叔丁酯(500mg,2.333mmol)和Cs2CO3(545mg,1.672mmol)在NMP(5mL)中的混合物在190℃在微波下搅拌1.5h,然后过滤。将滤液浓缩且残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到淡黄色固体的1-(3',5'-二氯-5-((6-(3,3-二甲基哌嗪-1-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)-N-甲基甲胺,3盐酸盐(10.01mg,0.017mmol,3.1%产率):1H NMR(400MHz,CD3OD)δppm 8.02-7.93(m,2H),7.64(d,J=2.0Hz,2H),7.59(s,1H),7.52(d,J=10.5Hz,1H),7.49(t,J=1.7Hz,1H),7.43(s,1H),7.34(s,1H),4.25(s,2H),4.01-3.95(m,2H),3.86(s,2H),3.54-3.47(m,2H),2.75(s,3H),1.56-1.48(m,6H);ES-LCMS m/z 471.1,473.2[M+H]+.
实施例103-104(表5)通过类似于实施例102所述的方法制备。
表5
实施例105:N-((1-((5-((6-((2-氨基-2-甲基丙基)氨基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐
步骤1:(1-((5-溴吡啶-2-基)氨基)-2-甲基丙-2-基)氨基甲酸叔丁酯
向2-甲基丙烷-1,2-二胺(2.3g,26.1mmol)和吡啶(2.53mL,31.3mmol)在NMP(0.5mL)中的溶液中添加5-溴-2-氟吡啶(3.67g,20.87mmol)。将反应在100℃搅拌16h。然后添加Boc2O(12.12mL,52.2mmol)且将混合物浓缩且通过硅胶柱色谱法(PE/EtOAc=1/0至3/1)纯化以得到(1-((5-溴吡啶-2-基)氨基)-2-甲基丙-2-基)氨基甲酸叔丁酯(1.8g,5.23mmol,20.0%产率):1H NMR(400MHz,CDCl3)δppm 8.05(d,J=2.0Hz,1H),7.48-7.35(m,1H),6.41-6.31(m,1H),3.46(d,J=6.1Hz,2H),1.46-1.37(m,9H),1.31(s,6H);ES-LCMS m/z 344.0,346.0[M+H]+.
步骤2:(1-((5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)吡啶-2-基)氨基)-2-甲基丙-2-基)氨基甲酸叔丁酯
向N-((1-((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(0.5g,1.227mmol)、(1-((5-溴吡啶-2-基)氨基)-2-甲基-丙-2-基)氨基甲酸叔丁酯(0.423g,1.227mmol)、Cs2CO3(0.400g,1.227mmol)和2-(二甲基氨基)乙酸(0.040mL,0.368mmol)在1,4-二噁烷(30mL)中的混合物中添加CuI(0.024mL,0.123mmol)。将反应在100℃在N2气氛搅拌16h,然后过滤,浓缩且通过硅胶柱色谱法(DCM/MeOH=1/0至5/1)纯化。将所有通过TLC(DCM/MeOH=3/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到棕色固体的(1-((5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)吡啶-2-基)氨基)-2-甲基丙-2-基)氨基甲酸叔丁酯(150mg,0.179mmol,14.6%产率):1H NMR(400MHz,CDCl3)δppm 7.91(d,J=2.7Hz,1H),7.43-7.29(m,2H),7.19-7.15(m,3H),6.89-6.78(m,2H),6.56-6.48(m,1H),4.27-4.08(m,2H),3.51(m,2H),3.49-3.45(m,2H),3.16-3.13(m,2H),2.89-2.78(m,2H),1.97-1.90(m,5H),1.85-1.80(m,1H),1.50(m,2H),1.41(s,9H),1.35(s,6H);ES-LCMS m/z 670.1,672.1[M+H]+.
步骤3:N-((1-((5-((6-((2-氨基-2-甲基丙基)氨基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐
向(1-((5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)吡啶-2-基)氨基)-2-甲基丙-2-基)氨基甲酸叔丁酯(150mg,0.224mmol)在DCM(20mL)中的溶液中添加TFA(2mL,0.224mmol)。将反应在30℃搅拌4h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到淡黄色固体的N-((1-((5-((6-((2-氨基-2-甲基丙基)氨基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐(51.13mg,0.072mmol,32.1%产率):1H NMR(400MHz,CD3OD)δppm 7.99(dd,J=2.5,9.8Hz,1H),7.87(d,J=2.4Hz,1H),7.68(d,J=1.8Hz,2H),7.66-7.60(m,1H),7.53-7.43(m,3H),7.38(d,J=9.7Hz,1H),4.42-4.29(m,2H),3.77(s,2H),3.52(d,J=11.9Hz,2H),3.13(d,J=6.4Hz,2H),3.03(t,J=12.2Hz,2H),2.03-1.91(m,5H),1.84(br.s,1H),1.68-1.53(m,2H),1.49(s,6H);ES-LCMS m/z 570.2,572.3[M+H]+.
实施例106:N-((1-((5-((6-((顺式)-4-氨基-3-氟哌啶-1-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐
步骤1:4-(苄基氨基)-3-氟哌啶-1-甲酸叔丁酯
将苯基甲胺(4.93g,46.0mmol)、3-氟-4-氧代哌啶-1-甲酸叔丁酯(2.0g,9.21mmol)和分子筛(2g,9.21mmol)的混合物悬浮于DCE(150mL)且在40℃搅拌15h。添加三乙酰氧基硼氢化钠(9.76g,46.0mmol)且在40℃在N2气氛搅拌5h。反应用饱和NaHCO3水溶液(100mL)缓慢淬灭且用EtOAc(200mL)萃取。有机层用H2O(200mL x2)、盐水(200mL)洗涤,用无水Na2SO4干燥,过滤且真空浓缩以得到粗物质。粗物质通过硅胶柱色谱法(从纯的PE至PE/EA=10/1-1/1,TLC:PE/EA=1/1,Rf=0.3)纯化且浓缩以得到4-(苄基氨基)-3-氟哌啶-1-甲酸叔丁酯(2.1g,6.40mmol,69.5%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 7.30-7.27(m,3H),7.25-7.12(m,2H),4.76-4.57(m,1H),4.25(br d,J=7.1Hz,1H),4.16-3.83(m,2H),3.01-2.47(m,4H),1.76-1.57(m,2H),1.39(s,9H);ES-LCMSm/z 309.2[M+H]+.
步骤2:4-氨基-3-氟哌啶-1-甲酸叔丁酯
在N2气氛向4-(苄基氨基)-3-氟哌啶-1-甲酸叔丁酯(2.0g,6.10mmol)在甲醇(100mL)中的溶液中添加20%Pd(OH)2(0.428g,0.610mmol)。将反应混合物在50℃在50psiH2气氛搅拌16h。然后将混合物过滤且将滤液浓缩以得到4-氨基-3-氟哌啶-1-甲酸叔丁酯(1.1g,4.79mmol,79.0%产率),其为淡黄色油状物:1H NMR(400MHz,CDCl3)δppm 4.65-4.44(m,1H),4.28(br d,J=7.7Hz,1H),4.15-3.83(m,1H),3.06-2.77(m,3H),1.71-1.61(m,2H),1.44(s,9H);ES-LCMS m/z 163.2[M-t-Bu+H]+.
步骤3:4-乙酰氨基-3-氟哌啶-1-甲酸叔丁酯
向4-氨基-3-氟哌啶-1-甲酸叔丁酯(1g,4.35mmol)在DCM(50mL)中的溶液中滴加乙酰氯(0.410g,5.22mmol),然后添加DIEA(1.520mL,8.70mmol)。将反应混合物在20℃在N2气氛搅拌12h。将反应用饱和NaHCO3水溶液(100mL)缓慢淬灭且用EtOAc(200mL)萃取。有机层用H2O(200mL x2)、盐水(200mL)洗涤,用无水Na2SO4干燥,过滤且真空浓缩以得到粗物质。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=1/1)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.3)发现包含产物的级分合并且浓缩以得到黄色油状物4-乙酰氨基-3-氟哌啶-1-甲酸叔丁酯(850mg,3.10mmol,71.3%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm4.72-4.55(m,1H),4.43-4.11(m,2H),4.09-3.99(m,1H),3.04-2.69(m,2H),2.00(s,3H),1.73-1.66(m,2H),1.44(s,9H);ES-LCMS m/z 205.2[M-t-Bu+H]+.
步骤4:N-(3-氟哌啶-4-基)乙酰胺,三氟乙酸盐
将4-乙酰氨基-3-氟哌啶-1-甲酸叔丁酯(800mg,3.08mmol)溶于TFA/DCM(20%,20mL)。将反应混合物在25℃搅拌3h,然后浓缩以得到棕色油状物的N-(3-氟哌啶-4-基)乙酰胺,三氟乙酸盐(700mg,1.53mmol,49.7%产率):1H NMR(400MHz,CDCl3)δppm 4.18-3.94(m,1H),3.61-3.48(m,1H),3.47-2.83(m,4H),2.18-1.93(m,1H),1.93-1.88(m,3H),1.85-1.67(m,1H)。
步骤5:N-((顺式)-1-(5-溴吡啶-2-基)-3-氟哌啶-4-基)乙酰胺
将5-溴-2-氟吡啶(900mg,5.11mmol)、N-(3-氟哌啶-4-基)乙酰胺,三氟乙酸盐(1683mg,6.14mmol)和DIEA(1.786mL,10.23mmol)在NMP(2.0mL)中的悬浮液在微波中在160℃搅拌3h。冷却至室温后,向混合物中添加DCM(100mL)且通过水(100x5mL)洗涤。有机层用MgSO4干燥,然后浓缩。粗产物通过硅胶柱色谱法(DCM/MeOH=20/1至5/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.7)发现包含产物的级分合并且浓缩以得到黄色固体的N-((顺式)-1-(5-溴吡啶-2-基)-3-氟哌啶-4-基)乙酰胺(1.2g,3.04mmol,59.4%产率):1H NMR(400MHz,CDCl3)δppm 8.07(d,J=2.5Hz,1H),7.47(dd,J=2.5,9.0Hz,1H),6.55(d,J=9.0Hz,1H),4.83-4.65(m,1H),4.58-4.51(m,1H),4.30-4.23(m,1H),4.15-4.01(m,1H),3.10-2.94(m,1H),2.92-2.84(m,1H),1.94(s,3H),1.81-1.74(m,2H);ES-LCMS m/z 316.2,318.2[M+H]+.
步骤6:((顺式)-1-(5-溴吡啶-2-基)-3-氟哌啶-4-基)氨基甲酸叔丁酯
向N-((顺式)-1-(5-溴吡啶-2-基)-3-氟哌啶-4-基)乙酰胺(600mg,1.898mmol)在1,4-二噁烷(20mL)中的溶液中添加HCl水溶液(2.0M,4.74mL,9.49mmol)。将反应混合物在120℃在N2气氛搅拌16h。添加NaOH(759mg,18.98mmol),然后添加Boc2O(0.881mL,3.80mmol)。将反应混合物再搅拌4h且浓缩以得到残余物,将其溶于DCM(200mL)且用盐水(20mL x2)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过硅胶柱色谱法(PE/EtOAc=2/1)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到白色固体的((顺式)-1-(5-溴吡啶-2-基)-3-氟哌啶-4-基)氨基甲酸叔丁酯(250mg,0.601mmol,31.7%产率):1H NMR(400MHz,CDCl3)δppm 8.20-8.13(m,1H),7.56-7.48(m,1H),6.59(d,J=9.0Hz,1H),4.70-4.60(m,1H),4.37-4.23(m,1H),3.29-3.21(m,1H),3.13-2.95(m,1H),2.94-2.81(m,2H),1.93-1.77(m,2H),1.46-1.45(m,9H);ES-LCMSm/z 374.0,376.0[M+H]+.
步骤7:((顺式)-1-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)吡啶-2-基)-3-氟哌啶-4-基)氨基甲酸叔丁酯
将((顺式)-1-(5-溴吡啶-2-基)-3-氟哌啶-4-基)氨基甲酸叔丁酯(70mg,0.187mmol)、N-((1-((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(76mg,0.187mmol)、CuI(3.31mg,0.017mmol)、2-(二甲基氨基)乙酸(3.05mg,0.030mmol)和Cs2CO3(78.35mg,0.240mmol)在1,4-二噁烷(3mL)中的混合物在N2气氛在100℃搅拌18h。然后将混合物通过硅藻土垫过滤且将滤液浓缩以得到粗产物,其通过制备型TLC(DCM/MeOH=10/1,Rf=3.5)纯化以得到淡黄色固体的((顺式)-1-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)吡啶-2-基)-3-氟哌啶-4-基)氨基甲酸叔丁酯(30mg,0.039mmol,20.6%产率):1H NMR(400MHz,CDCl3)δppm8.01(d,J=2.6Hz,1H),7.42(s,3H),7.33(s,1H),7.30-7.27(m,1H),7.05(s,2H),6.75(d,J=9.3Hz,1H),4.95-4.90(m,1H),4.85-4.80(m,1H),3.80(s,2H),3.48(s,2H),3.20-3.10(m,4H),2.95-1.85(m,2H),2.55-1.45(m,2H),2.01-1.98(m,5H),1.83(br.s,1H),1.69-1.65(m,2H),1.59-1.55(m,2H),1.43(s,9H);ES-LCMS m/z 700.1,702.1[M+H]+.
步骤8:N-((1-((5-((6-((顺式)-4-氨基-3-氟哌啶-1-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐
向((顺式)-1-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)吡啶-2-基)-3-氟哌啶-4-基)氨基甲酸叔丁酯(30mg,0.043mmol)在DCM(5mL)中的溶液中添加TFA(1mL,12.98mmol)。将反应混合物在30℃搅拌2h,然后浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到黄色固体的N-((1-((5-((6-((顺式)-4-氨基-3-氟哌啶-1-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐(11.04mg,0.015mmol,35.3%产率):1H NMR(400MHz,CD3OD)δppm 8.03(br.s,1H),7.93(br.s,1H),7.68(br.s,3H),7.59(d,J=7.3Hz,1H),7.50-7.45(m,3H),5.30-5.12(m,1H),4.70(br.s,1H),4.46-4.32(m,3H),3.93-3.63(m,2H),3.51(br.s,3H),3.25-2.86(m,4H),2.14(br.s,2H),1.94(s,5H),1.83(br.s,1H),1.59(br.s,2H);ES-LCMS m/z 600.3,602.3[M+H]+.
实施例107:N-((1-((3',5'-二氯-5-((6-(3-氧代六氢咪唑并[1,5-a]吡嗪-7(1H)-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,2盐酸盐
步骤1:2-(羟基甲基)哌嗪-1,4-二甲酸4-苄基1-叔丁基酯
将2-(羟基甲基)哌嗪-1-甲酸叔丁酯(5g,23.12mmol)、CbzCl(3.47mL,24.27mmol)和Et3N(9.67mL,69.4mmol)在DCM(75mL)中的混合物在25℃搅拌12h。混合物依次用饱和柠檬酸水溶液(50mL)、饱和NaHCO3水溶液(50mL)和盐水(50mL)洗涤。有机萃取物用Na2SO4干燥,过滤且浓缩以得到淡黄色油状物2-(羟基甲基)哌嗪-1,4-二甲酸4-苄基1-叔丁基酯(6.3g,14.38mmol,62.2%产率):1H NMR(400MHz,CDCl3)δppm 7.45-7.26(m,5H),5.14(br.s,2H),4.24-3.95(m,3H),3.84(br.s,1H),3.57(br.s,2H),2.98(br.s,3H),1.44(s,9H);ES-LCMS m/z 251.1[M-Boc+H]+.
步骤2:2-((1,3-二氧代异吲哚啉-2-基)甲基)哌嗪-1,4-二甲酸4-苄基1-叔丁基酯
将2-(羟基甲基)哌嗪-1,4-二甲酸4-苄基1-叔丁基酯(4.3g,12.27mmol)、异吲哚啉-1,3-二酮(1.805g,12.27mmol)、PPh3(3.86g,14.73mmol)和DIAD(3.58mL,18.41mmol)在DCM(80mL)中的混合物在25℃在N2气氛搅拌16h。将混合物用盐水(30mL x2)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=4/1)纯化。将所有通过TLC(PE/EA=5/1,Rf=0.3)发现包含产物的级分合并且浓缩以得到黄色固体的2-((1,3-二氧代异吲哚啉-2-基)甲基)哌嗪-1,4-二甲酸4-苄基1-叔丁基酯(4.6g,8.63mmol,70.4%产率):1HNMR(400MHz,CD3OD)δppm 7.85-7.74(m,5H),7.44-7.21(m,4H),5.18(br.s,2H),4.21-4.09(m,3H),4.05-3.70(m,3H),3.61-3.46(m,1H),3.11(br.s,1H),2.91(br.s,1H),1.13-0.95(m,9H);ES-LCMS m/z 380.2[M-Boc+H]+.
步骤3:2-((1,3-二氧代异吲哚啉-2-基)甲基)哌嗪-1-甲酸叔丁酯
将2-((1,3-二氧代异吲哚啉-2-基)甲基)哌嗪-1,4-二甲酸4-苄基1-叔丁基酯(4.6g,9.59mmol)和Pd/C(10wt%,0.5g,0.470mmol)在DMF(60mL)中的混合物在25℃在50psi H2气氛搅拌16h。将混合物过滤且将滤液浓缩以得到淡黄色固体的2-((1,3-二氧代异吲哚啉-2-基)甲基)哌嗪-1-甲酸叔丁酯(2.8g,6.89mmol,71.8%产率):1H NMR(400MHz,CDCl3)δppm 7.91-7.59(m,3H),7.57-7.38(m,1H),4.87-4.60(m,1H),4.59-4.35(m,1H),4.25-4.07(m,1H),3.72-3.51(m,2H),3.49-3.16(m,2H),2.85-2.73(m,2H),1.59-0.93(m,9H);ES-LCMS m/z 346.1[M+H]+.
步骤4:N-((1-((5-((6-溴吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺
将N-((1-((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(2g,4.91mmol)、2-溴-5-氟吡啶(4.32g,24.55mmol)和Cs2CO3(8.00g,24.55mmol)在DMF(30mL)中的混合物在130℃搅拌24h。将混合物浓缩且残余物用H2O(100mL)稀释且用EtOAc(100mL×3)萃取。合并有机层,用Na2SO4干燥且过滤且浓缩。所得混合物通过硅胶柱色谱法(DCM/MeOH=1/0至10/1)纯化。将所有通过TLC(DCM/MeOH=20/1,Rf=0.3)发现包含产物的级分合并且浓缩以得到黄色固体的N-((1-((5-((6-溴吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(1.3g,1.962mmol,40.0%产率):1H NMR(400MHz,CD3OD)δppm 8.14(d,J=2.9Hz,1H),7.62-7.52(m,3H),7.46-7.41(m,2H),7.39(dd,J=8.7,3.1,Hz,1H),7.28(s,1H),7.09(s,1H),3.62-3.52(m,2H),3.08-2.99(m,2H),2.91(d,J=11.5Hz,2H),2.03(t,J=10.8Hz,2H),1.91(s,3H),1.76-1.62(m,2H),1.50(d,J=3.7Hz,1H),1.30-1.21(m,2H);ES-LCMSm/z 564.1,566.1[M+H]+.
步骤5:N-((1-((3',5'-二氯-5-((6-(3-氧代六氢咪唑并[1,5-a]吡嗪-7(1H)-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,2盐酸盐
将N-((1-((5-((6-溴吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(150mg,0.266mmol)、2-((1,3-二氧代异吲哚啉-2-基)甲基)哌嗪-1-甲酸叔丁酯(110mg,0.320mmol)、叔丁醇钠(77mg,0.799mmol)、(±)-BINAP(6.63mg,10.65μmol)、18-冠-6(211mg,0.799mmol)和Pd2(dba)3(4.88mg,5.33μmol)在THF(10mL)中的混合物在65℃在N2气氛搅拌16h。将混合物浓缩且残余物在DCM(50mL)和H2O(50mL)之间分配。有机层用盐水(50mL x2)洗涤,用Na2SO4干燥,过滤且将滤液浓缩。粗产物悬浮于PE(50mL)中且过滤。收集固体且进一步通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到淡黄色固体的N-((1-((3',5'-二氯-5-((6-(3-氧代六氢咪唑并[1,5-a]吡嗪-7(1H)-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,2盐酸盐(47.97mg,0.067mmol,25.1%产率):1H NMR(400MHz,CD3OD)δppm 8.20(d,J=2.4Hz,1H),8.10(d,J=9.3Hz,1H),7.80(dd,J=9.3,2.6Hz,1H),7.68-7.58(m,3H),7.50(s,1H),7.45-7.39(m,1H),7.32(br.s,1H),4.35(s,2H),4.33-4.25(m,1H),4.24-4.12(m,2H),3.88(dd,J=10.5,4.5Hz,1H),3.63-3.49(m,3H),3.48-3.34(m,2H),3.15-3.08(m,3H),3.02(t,J=12.1Hz,2H),2.02-1.90(m,5H),1.82(br.s,1H),1.57-1.43(m,2H);ES-LCMS m/z 623.2,625.2[M+H]+.
实施例108:1-(5-((6-(3-氯-5-甲基苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌啶-4-胺,4盐酸盐
步骤1:甲磺酸(2,6-二氯吡啶-4-基)甲基酯
向(2,6-二氯吡啶-4-基)甲醇(6g,33.7mmol)和DIEA(8.71g,67.4mmol)在DCM(100mL)中的溶液中添加MsCl(3.86g,33.7mmol)。然后将反应加热至25℃保持1h。然后将溶液浓缩且在DCM(50mL x2)和水(50mL)之间分配。合并的有机萃取物用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到甲磺酸(2,6-二氯吡啶-4-基)甲基酯(6g,18.74mmol,55.6%产率):1H NMR(400MHz,CDCl3)δppm7.28(s,2H),5.18(s,2H),3.12(s,3H);ES-LCMS m/z256.0[M+H]+.
步骤2:1-(2,6-二氯吡啶-4-基)-N-甲基甲胺
向甲磺酸(2,6-二氯吡啶-4-基)甲基酯(6g,23.43mmol)在AcOH(50mL)中的溶液中添加甲胺(181g,2343mmol)。然后将反应加热至25℃保持2h。然后将溶液浓缩且通过二氧化硅柱色谱法(PE/EtOAc=2/1)纯化。将所有通过TLC(PE/EtOAc=2/1,Rf=0.3)发现包含产物的级分合并且浓缩以得到淡黄色固体的1-(2,6-二氯吡啶-4-基)-N-甲基甲胺(5g,22.24mmol,95.0%产率):1H NMR(400MHz,CD3OD)δppm 7.25(s,2H),3.74(s,2H),2.43(s,3H);ES-LCMS m/z 191.0[M+H]+.
步骤3:((2,6-二氯吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯
向1-(2,6-二氯吡啶-4-基)-N-甲基甲胺(3g,15.70mmol)在DCM(50mL)中的溶液中添加Boc2O(3.43g,15.70mmol)。然后将反应加热至25℃保持8h。然后将溶液浓缩且通过二氧化硅柱色谱法(PE/EtOAc=10/1)纯化。将所有通过TLC(PE/EtOAc=5/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到淡黄色油状物的((2,6-二氯吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯(3.9g,12.05mmol,77.0%产率):1H NMR(400MHz,CDCl3)δppm 7.09(s,2H),4.38(br.s,2H),2.88(d,J=15.4Hz,3H),1.51-1.41(m,9H);ES-LCMS m/z 291.0[M+H]+.
步骤4:(1-(5-(苄基氧基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯
将5-(苄基氧基)-2-溴吡啶(2g,7.57mmol)、哌啶-4-基氨基甲酸叔丁酯(1.668g,8.33mmol)、(±)-BINAP(0.094g,0.151mmol)、t-BuONa(1.092g,11.36mmol)和Pd2(dba)3(0.069g,0.076mmol)在甲苯(30mL)中的混合物在65℃在N2气氛搅拌15h。将混合物浓缩且通过硅胶柱色谱法(PE/EtOAc=4/1)纯化。将所有通过制备型TLC(PE/EA=3/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到淡黄色固体(1-(5-(苄基氧基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(400mg,0.939mmol,12.4%产率):1H NMR(400MHz,CDCl3)δppm 7.95(d,J=2.9Hz,1H),7.43-7.29(m,5H),7.17(d,J=6.6Hz,1H),6.63(d,J=9.0Hz,1H),5.08-4.97(m,2H),4.44(br.s,1H),4.11-3.95(m,2H),3.70-3.51(m,2H),2.89(t,J=11.6Hz,2H),2.01(d,J=13.9Hz,2H),1.44(s,9H);ES-LCMS m/z 384.1[M+H]+.
步骤5:(1-(5-羟基吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯
将(1-(5-(苄基氧基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(600mg,1.565mmol)、Pd/C(10wt%,1665mg,1.565mmol)在MeOH(10mL)中的混合物在25℃在H2气氛(15psi)搅拌10h。将反应混合物过滤且浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=2/1)纯化。将所有通过TLC(PE/EA=1/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到淡黄色油状物的(1-(5-羟基吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(400mg,1.254mmol,80.0%产率):1H NMR(400MHz,CDCl3)δppm 7.81(d,J=2.9Hz,1H),7.04(dd,J=2.9,9.0Hz,1H),6.56(d,J=9.0Hz,1H),4.42(br.s,1H),4.09-3.80(m,2H),3.57(br.s,2H),2.91-2.69(m,2H),1.95(d,J=10.8Hz,2H),1.38(s,9H);ES-LCMS m/z 294.1[M+H]+.
步骤6:((2-((6-(4-((叔丁氧基羰基)氨基)哌啶-1-基)吡啶-3-基)氧基)-6-氯吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯
向((2,6-二氯吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯(328mg,1.125mmol)和K2CO3(424mg,3.07mmol)在MeCN(10mL)中的混合物中添加(1-(5-羟基吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(300mg,1.023mmol)。将反应在80℃在N2气氛搅拌14h,然后过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=9/1)纯化。将所有通过TLC(PE/EA=3/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到淡黄色固体的((2-((6-(4-((叔丁氧基羰基)氨基)哌啶-1-基)吡啶-3-基)氧基)-6-氯吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯(200mg,0.343mmol,33.5%产率):1H NMR(400MHz,CDCl3)δppm 8.04(d,J=2.9Hz,1H),7.32(dd,J=2.8,9.2Hz,1H),6.84(s,1H),6.69(d,J=9.3Hz,1H),6.58(br.s,1H),4.49(br.s,1H),4.36(d,J=19.2Hz,2H),4.21-4.10(m,2H),3.68(br.s,2H),2.98(t,J=11.5Hz,2H),2.86(d,J=12.1Hz,3H),2.04(t,J=5.0Hz,2H),1.52-1.38(m,18H);ES-LCMS m/z 548.1,550.2[M+H]+.
步骤7:((2-((6-(4-((叔丁氧基羰基)氨基)哌啶-1-基)吡啶-3-基)氧基)-6-(3-氯-5-甲基苯基)吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯
在N2气氛在20℃向((2-((6-(4-((叔丁氧基羰基)氨基)哌啶-1-基)吡啶-3-基)氧基)-6-(3-氯-5-甲基苯基)吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯(180mg,0.282mmol)在1,4-二噁烷(10mL)中的溶液中添加(3-氯-5-甲基苯基)硼酸(96mg,0.564mmol)、K2CO3(78mg,0.564mmol)和PdCl2(dppf)(10.32mg,0.014mmol)。然后将该反应脱气且用N2填充三次,然后在80℃搅拌15h。将反应混合物浓缩。粗物质通过硅胶柱色谱法(PE/EtOAc=4/1)纯化。将所有通过制备型TLC(PE/EA=3/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到淡黄色油状物的((2-((6-(4-((叔丁氧基羰基)氨基)哌啶-1-基)吡啶-3-基)氧基)-6-(3-氯-5-甲基苯基)吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯(100mg,0.139mmol,49.4%产率):1H NMR(400MHz,CDCl3)δppm 8.05(d,J=2.6Hz,1H),7.58(br.s,1H),7.50(s,1H),7.35(dd,J=2.8,9.2Hz,1H),7.10(br.s,1H),6.72-6.62(m,2H),6.55(br.s,1H),4.39(br.s,1H),4.37(d,J=17.0Hz,4H),4.11(d,J=13.2Hz,2H),3.63(br.s,1H),3.42(s,3H),2.82(br.s,4H),2.29(s,3H),1.39(s,18H);ES-LCMS m/z 638.2,640.2[M+H]+.
步骤8:1-(5-((6-(3-氯-5-甲基苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌啶-4-胺,4盐酸盐
将((2-((6-(4-((叔丁氧基羰基)氨基)哌啶-1-基)吡啶-3-基)氧基)-6-(3-氯-5-甲基苯基)吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯(100mg,0.157mmol)在TFA(10%的DCM溶液,10mL)中的溶液在20℃搅拌0.5h。将反应浓缩且残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干干燥以得到白色固体的1-(5-((6-(3-氯-5-甲基苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌啶-4-胺,4盐酸盐(27.69mg,0.047mmol,30.3%产率):1H NMR(400MHz,D2O)δppm 7.80-7.78(m,2H),7.43(s,1H),7.31(d,J=5.5Hz,2H),7.21(d,J=9.7Hz,1H),7.08(s,1H),6.92(s,1H),4.14(s,2H),4.03(d,J=13.9Hz,2H),3.45(t,J=11.4Hz,1H),3.18(t,J=12.3Hz,2H),2.62(s,3H),2.19-2.04(m,5H),1.62(dq,J=3.7,12.2Hz,2H);ES-LCMS m/z 438.0,440.0[M+H]+.
实施例109:N-((1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
步骤1:N-((1-((2-((5-氯吡嗪-2-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向2,5-二氯吡嗪(0.952g,6.39mmol)和N-((1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(1.5g,3.20mmol)在DMF(30mL)中的溶液中添加K2CO3(0.883g,6.39mmol)。将反应混合物在120℃搅拌12h,然后过滤且浓缩以得到粗产物,其通过硅胶(DCM/MeOH=1/0至10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.6)发现包含产物的级分合并以得到黄色固体的N-((1-((2-((5-氯吡嗪-2-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(1.2g,2.130mmol,66.6%产率):1H NMR(400MHz,CDCl3)δppm 8.36(s,1H),8.26(s,1H),7.71(d,J=1.3Hz,2H),7.53(s,1H),7.34(s,1H),7.06(s,1H),5.61(s,1H),3.56(s,2H),3.15(t,J=6.4Hz,2H),2.88(d,J=9.7Hz,2H),2.08-2.00(m,2H),1.97(s,3H),1.69(d,J=12.3Hz,2H),1.52(td,J=3.7,7.2Hz,1H),1.36-1.26(m,2H);ES-LCMS m/z 520.2,522.2[M+H]+.
步骤2:4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯
向N-((1-((3',5'-二氯-5-((5-氯吡嗪-2-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(1.2g,2.134mmol)、哌嗪-1-甲酸叔丁酯(0.795g,4.27mmol)、Xantphos(0.025g,0.043mmol)、Cs2CO3(2.086g,6.40mmol)在THF(15mL)中的混合物中添加Pd2(dba)3(0.098g,0.107mmol)。将反应在80℃在N2气氛搅拌6h,然后过滤且浓缩以得到粗产物,其通过硅胶(DCM/MeOH=1/0至10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并以得到黄色固体的4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(1.3g,1.547mmol,72.5%产率):1H NMR(400MHz,CDCl3)δppm 8.12(s,1H),7.84(s,1H),7.70(d,J=1.3Hz,2H),7.42(s,1H),7.32(s,1H),6.95(s,1H),5.52(br.s,1H),3.58(d,J=3.1Hz,8H),3.56(s,2H),3.16(t,J=6.2Hz,2H),2.88(d,J=11.0Hz,2H),2.03-1.95(m,5H),1.68(d,J=11.9Hz,2H),1.57-1.52(m,1H),1.50-1.42(m,9H),1.34-1.24(m,2H);ES-LCMS m/z670.3,672.4[M+H]+.
步骤3:N-((1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(350mg,0.470mmol)在DCM(8mL)中的溶液中添加TFA(2mL,26.0mmol)。将反应混合物在25℃搅拌0.1h,然后浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化且冻干以得到淡黄色固体的N-((1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(191.81mg,0.332mmol,70.7%产率):1H NMR(400MHz,CD3OD)δppm 8.11(d,J=1.3Hz,1H),7.96(s,1H),7.78(d,J=1.8Hz,2H),7.66(s,1H),7.43(t,J=1.8Hz,1H),7.04(s,1H),3.69-3.52(m,6H),3.13-3.04(m,2H),3.02-2.83(m,6H),2.08(t,J=10.8Hz,2H),1.93(s,3H),1.72(d,J=11.9Hz,2H),1.54-1.46(m,1H),1.37-1.26(m,2H);ES-LCMS m/z 570.2,572.2[M+H]+.
实施例110:N-((1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向N-((1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4三氟乙酸盐(300mg,0.244mmol)在MeOH(5mL)中的溶液中添加多聚甲醛(366mg,12.18mmol)和甲酸(11.21mg,0.244mmol)。在20℃搅拌20h后,添加NaBH3CN(77mg,1.218mmol)且将混合物再搅拌4h。添加饱和NaHCO3水溶液(50mL)且用DCM(30mL×3)萃取。合并的有机层用Na2SO4干燥且浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化且冻干以得到白色固体的N-((1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(106.34mg,0.180mmol,73.8%产率):1H NMR(400MHz,CD3OD)δppm 8.12(s,1H),7.98(s,1H),7.78(s,2H),7.66(s,1H),7.43(s,1H),7.04(s,1H),3.65(s,4H),3.62(s,2H),3.07(d,J=6.6Hz,2H),2.94(d,J=11.5Hz,2H),2.61(s,4H),2.37(s,3H),2.08(t,J=11.5Hz,2H),1.93(s,3H),1.72(d,J=12.3Hz,2H),1.53(s,1H),1.35-1.26(m,2H);ES-LCMS m/z 584.3,586.3[M+H]+.
实施例111:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)丙酸
步骤1:N-((1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向N-((1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4三氟乙酸盐(350mg,0.307mmol)和3-溴丙酸乙酯(167mg,0.921mmol)在DMF(12mL)中的溶液中添加K2CO3(212mg,1.534mmol)。将反应混合物在80℃搅拌12h,然后过滤且浓缩以得到淡黄色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)丙酸乙酯(210mg,0.282mmol,92.0%产率):1H NMR(400MHz,CD3OD)δppm 8.11(s,1H),7.84(s,1H),7.71(d,J=1.8Hz,2H),7.43(s,1H),7.32(s,1H),6.94(s,1H),5.54(s,1H),4.16(q,J=7.1Hz,2H),3.64-3.56(m,4H),3.53(s,2H),3.16(t,J=6.2Hz,2H),2.89(d,J=11.0Hz,2H),2.77(t,J=7.3Hz,2H),2.66-2.59(m,4H),2.57-2.51(m,4H),2.04-1.95(m,5H),1.53(s,1H),1.35-1.24(m,5H);ES-LCMS m/z 670.2,672.2[M+H]+.
步骤2:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)丙酸
向3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)丙酸乙酯(210mg,0.282mmol)在THF(5mL)中的溶液中添加LiOH·H2O(23.65mg,0.564mmol)在水(1mL)中的溶液。将反应混合物在25℃搅拌12h。添加1N HCl以将pH调节至6,然后将溶液浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)丙酸(107.28mg,0.165mmol,58.6%产率):1H NMR(400MHz,CD3OD)δppm 8.16(d,J=0.9Hz,1H),8.04(d,J=0.9Hz,1H),7.78(d,J=1.8Hz,2H),7.68(s,1H),7.44(t,J=1.8Hz,1H),7.07(s,1H),3.85-3.73(m,4H),3.68(s,2H),3.24-3.04(m,8H),2.99(d,J=11.5Hz,2H),2.58(t,J=6.8Hz,2H),2.20-2.13(m,2H),1.93(s,3H),1.74(d,J=11.9Hz,2H),1.55(s,1H),1.38-1.28(m,2H);ES-LCMS m/z 642.2,644.2[M+H]+.
实施例112:2-(1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1:2-(1-((2-((5-氯吡嗪-2-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2,5-二氯吡嗪(371mg,2.492mmol)和2-(1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(400mg,0.831mmol)在DMF(10mL)中的溶液中添加K2CO3(230mg,1.661mmol)。将反应混合物在80℃搅拌12h,然后过滤且浓缩以得到粗产物,其通过快速色谱法(DCM/MeOH=1/0至10/1,DCM/MeOH=10/1,Rf=0.55)纯化以得到淡黄色固体的2-(1-((2-((5-氯吡嗪-2-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(450mg,0.763mmol,92.0%产率):1H NMR(400MHz,CDCl3)δppm 8.26(s,1H),7.73(s,2H),7.57-7.51(m,1H),7.39-7.32(m,2H),7.07(s,1H),3.72-3.64(m,3H),3.56(s,2H),2.86(d,J=11.0Hz,2H),2.30-2.22(m,2H),2.12-2.01(m,2H),1.82(ddd,J=4.0,7.5,11.0Hz,1H),1.72(d,J=12.3Hz,2H),1.41-1.29(m,2H);ES-LCMS m/z 521.1,523.1[M+H]+.
步骤2:4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯
向2-(1-((2-((5-氯吡嗪-2-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(450mg,0.763mmol)、哌嗪-1-甲酸叔丁酯(142mg,0.763mmol)、Xantphos(44.1mg,0.076mmol)、Cs2CO3(745mg,2.288mmol)在THF(20mL)中的混合物中添加Pd2(dba)3(69.8mg,0.076mmol)。将反应在80℃在N2气氛搅拌2h。将固体过滤掉且将溶剂真空去除以得到粗产物,其通过快速色谱法(从DCM:MeOH=1:0至DCM:MeOH=10:1持续30分钟,DCM:MeOH=10:1(Rf=0.50))纯化以得到4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(420mg,0.501mmol,65.6%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 8.14-8.10(m,1H),7.85(s,1H),7.72-7.67(m,2H),7.43(s,1H),7.32(s,1H),6.95(s,1H),3.67(s,3H),3.58(d,J=4.0Hz,8H),3.52(s,2H),2.88-2.84(m,2H),2.26(d,J=7.1Hz,2H),2.05(t,J=10.6Hz,2H),1.83-1.78(m,1H),1.71(d,J=12.8Hz,2H),1.55-1.44(m,9H),1.35(d,J=12.3Hz,2H);ES-LCMS m/z 671.3,673.3[M+H]+.
步骤3:2-(1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐
向4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(200mg,0.238mmol)在DCM(8mL)中的溶液中添加TFA(2mL,26.0mmol)。将反应混合物在25℃搅拌10min,然后浓缩以得到黄色固体的2-(1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐(210mg,0.163mmol,68.6%产率):1H NMR(400MHz,CD3OD)δppm8.12(s,1H),7.87-7.83(m,1H),7.82-7.76(m,2H),7.50(t,J=1.8Hz,1H),7.27(s,1H),4.43(,2H),4.01-3.79(m,4H),3.66(s,3H),3.59(d,J=10.6Hz,2H),3.47-3.32(m,4H),3.12(t,J=12.3Hz,2H),2.36(d,J=5.7Hz,2H),2.04(d,J=15.0Hz,3H),1.63-1.50(m,2H);ES-LCMS m/z 571.3,573.3[M+H]+.
步骤4:2-(1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐(210mg,0.163mmol)在THF(5mL)中的溶液中添加LiOH·H2O(68.6mg,1.635mmol)在水(1mL)中的溶液。将反应混合物在25℃搅拌12h,然后添加1N HCl以将pH调节至8。浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸(34.86mg,0.062mmol,37.7%产率):1HNMR(400MHz,D2O)δppm 8.16(s,1H),8.01(s,1H),7.80(d,J=1.3Hz,2H),7.75(s,1H),7.51(s,1H),7.22(s,1H),4.29(s,2H),3.85-3.72(m,4H),3.47(d,J=11.9Hz,2H),3.36-3.23(m,4H),3.01(t,J=12.6Hz,2H),2.28(d,J=6.6Hz,2H),2.08-1.96(m,3H),1.52(d,J=13.2Hz,2H);ES-LCMS m/z 557.2,559.2[M+H]+.
实施例113:N-((1-((3',5'-二氯-5-((2-(4-(3-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺
步骤1:3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯
向N-((1-((3',5'-二氯-5-((2-(哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐(200mg,0.221mmol)在Me3CN(5mL)中的混合物中添加DIEA(143mg,1.105mmol)和3-溴丙酸乙酯(0.031mL,0.243mmol)。将反应在80℃在N2气氛搅拌10h,然后浓缩以得到棕色油状物的3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(250mg,0.187mmol,84.0%产率):1H NMR(400MHz,CD3OD)δppm 8.26(s,2H),7.60(s,2H),7.46(s,1H),7.37(br.s,1H),7.20(br.s,1H),7.02(br.s,1H),4.25-4.13(m,2H),3.83(br.s,6H),3.59-3.43(m,2H),3.08(d,J=6.5Hz,3H),3.02-2.97(m,2H),2.80-2.71(m,2H),2.63-2.51(m,4H),2.18(br.s,2H),1.95(s,3H),1.75(d,J=11.0Hz,2H),1.55(d,J=6.5Hz,2H),1.24-1.15(m,3H);ES-LCMS m/z 669.4,671.3[M+H]+.
步骤2:N-((1-((3',5'-二氯-5-((2-(4-(3-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐
向3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(250mg,0.187mmol)在THF(10mL)中的混合物中添加LiAlH4(10.63mg,0.280mmol)。将反应在-20℃在N2气氛搅拌10分钟,然后用1mL水淬灭。将混合物过滤,浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干干燥以得到白色固体N-((1-((3',5'-二氯-5-((2-(4-(3-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐(11.75mg,0.015mmol,8.1%产率):1H NMR(400MHz,CD3OD)δppm 8.40(s,2H),7.66(d,J=1.5Hz,2H),7.57(s,1H),7.52(s,1H),7.41(s,1H),7.32(s,1H),4.94(br.s,2H),4.36(s,2H),4.12(t,J=5.0Hz,1H),3.77-3.69(m,2H),3.54(d,J=12.0Hz,2H),3.47-3.34(m,6H),3.29-3.18(m,2H),3.13(d,J=6.5Hz,2H),3.09-2.99(m,2H),2.09-1.94(m,6H),1.84(br.s,1H),1.61-1.46(m,2H);LCMS m/z 627.3,629.4[M+H]+.
实施例114:3-(1-((3',5'-二氯-5-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)丙酸
步骤1:4-(5-((3',5'-二氯-5-((4-(3-乙氧基-3-氧代丙基)哌啶-1-基)甲基)-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((3',5'-二氯-5-(((甲基磺酰基)氧基)甲基)-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(950mg,1.403mmol)和3-(哌啶-4-基)丙酸乙酯(433mg,2.104mmol)在DMF(10mL)中的溶液中添加K2CO3(582mg,4.21mmol)。将反应混合物在25℃搅拌12h,然后过滤且浓缩以得到粗产物,其通过快速色谱法(DCM/MeOH=1/0至10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.45)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(5-((3',5'-二氯-5-((4-(3-乙氧基-3-氧代丙基)哌啶-1-基)甲基)-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(900mg,1.159mmol,83.0%产率):1H NMR(400MHz,CD3OD)δppm 8.28(s,2H),7.59(d,J=2.0Hz,2H),7.46(s,1H),7.37-7.28(m,1H),7.18(s,1H),7.04-6.95(m,1H),4.61(s,2H),4.16-4.10(m,2H),3.88-3.75(m,4H),3.53(s,4H),2.96-2.90(m,2H),2.35(t,J=7.8Hz,2H),2.05(d,J=10.5Hz,2H),1.73(d,J=11.5Hz,2H),1.65-1.54(m,3H),1.51(s,9H),1.31-1.23(m,5H);ES-LCMS m/z 698.3,700.3[M+H]+.
步骤2:3-(1-((3',5'-二氯-5-((2-(哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)丙酸乙酯,3盐酸盐
将4-(5-((3',5'-二氯-5-((4-(3-乙氧基-3-氧代丙基)哌啶-1-基)甲基)-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(900mg,1.159mmol)溶于HCl溶液(4.0M在EtOAc中,12mL,48.00mmol)。将反应混合物在25℃搅拌10min,然后浓缩以得到淡黄色固体的3-(1-((3',5'-二氯-5-((2-(哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)丙酸乙酯,3盐酸盐(910mg,1.157mmol,100.0%产率):1H NMR(400MHz,CD3OD)δppm 8.40(s,2H),7.66(d,J=1.5Hz,2H),7.57(s,1H),7.52(s,1H),7.40(s,1H),7.30(s,1H),4.35(s,2H),4.19-4.05(m,8H),3.52(d,J=12.5Hz,2H),3.06(s,2H),2.39(t,J=7.0Hz,2H),1.98(s,2H),1.63(s,3H),1.56-1.39(m,4H),1.26(t,J=7.0Hz,3H);ES-LCMSm/z 598.3,600.3[M+H]+.
步骤3:3-(1-((3',5'-二氯-5-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)丙酸乙酯
向3-(1-((3',5'-二氯-5-((2-(哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)丙酸乙酯,3盐酸盐(140mg,0.178mmol)和DIEA(138mg,1.068mmol)在MeOH(20mL)中的溶液中添加氧杂环丙烷(39.2mg,0.890mmol)的MeOH(1mL)溶液。将反应混合物在80℃搅拌12h,然后浓缩以得到淡黄色固体的3-(1-((3',5'-二氯-5-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)丙酸乙酯(125mg,0.097mmol,54.6%产率):1H NMR(400MHz,CDCl3)δppm 8.25-8.15(m,2H),7.38(d,J=1.3Hz,2H),7.32(s,1H),7.22(s,1H),6.99(d,J=7.1Hz,2H),4.09(d,J=7.1Hz,2H),3.89(s,4H),3.75-3.70(m,2H),3.46(s,2H),3.03-2.94(m,4H),2.74-2.65(m,6H),2.27(d,J=7.5Hz,2H),2.11(d,J=11.0Hz,2H),1.68(d,J=11.9Hz,3H),1.27-1.18(m,5H);ES-LCMS m/z 642.3,644.3[M+H]+.
步骤4:3-(1-((3',5'-二氯-5-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)丙酸
向3-(1-((3',5'-二氯-5-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)丙酸乙酯(125mg,0.097mmol)在THF(5mL)中的溶液中添加NaOH(7.78mg,0.195mmol)的H2O(1mL)溶液。将反应混合物在25℃搅拌12h,然后添加1NHCl以将pH调节至4~5,然后浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化且冻干以得到白色固体的3-(1-((3',5'-二氯-5-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)丙酸(21.96mg,0.036mmol,36.6%产率):1H NMR(400MHz,CD3OD)δppm 8.28(s,2H),7.61(d,J=1.8Hz,2H),7.47(s,1H),7.43(s,1H),7.31(s,1H),7.06(s,1H),4.01(s,2H),3.95-3.80(m,4H),3.76(t,J=5.7Hz,2H),3.23(d,J=11.9Hz,2H),2.87-2.55(m,8H),2.24(t,J=7.5Hz,2H),1.88(d,J=13.2Hz,2H),1.65-1.55(m,2H),1.49(s,1H),1.40-1.29(m,2H);ES-LCMSm/z 614.3,616.2[M+H]+.
实施例115:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
步骤1:4-(5-((6-(3-氯-5-氟苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1g,1.559mmol)、(3-氯-5-氟苯基)硼酸(0.408g,2.339mmol)和K2CO3(0.647g,4.68mmol)在1,4-二噁烷(30mL)中的悬浮液中添加PdCl2(dppf)(0.114g,0.156mmol)。将反应混合物在80℃搅拌12h,然后过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=3/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到黄色胶状物的4-(5-((6-(3-氯-5-氟苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1g,1.565mmol,100.0%产率):1H NMR(400MHz,CDCl3)δppm 8.13(d,J=2.6Hz,1H),7.94(s,1H),7.69(s,1H),7.52(d,J=9.7Hz,1H),7.46-7.37(m,2H),7.10(d,J=7.9Hz,1H),6.73(d,J=8.8Hz,1H),4.02-3.93(m,3H),3.56(d,J=6.2Hz,8H),1.48(s,9H);ES-LCMS m/z 543.2,545.2[M+H]+.
步骤2:4-(5-((6-(3-氯-5-氟苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
在N2气氛在-20℃向搅拌下的4-(5-((6-(3-氯-5-氟苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1g,1.565mmol)在THF(20mL)中的悬浮液中分批添加LiAlH4(0.089g,2.348mmol)。将反应混合物在-20℃搅拌20分钟直到TLC(PE/EtOAc=3/1,Rf=0.1)显示该反应完成。该反应混合物用10%NaOH(0.1mL)和水(0.2mL)淬灭,然后过滤。滤液用MgSO4干燥,过滤且浓缩以得到黄色胶状物的4-(5-((6-(3-氯-5-氟苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(900mg,1.398mmol,89.0%产率):1H NMR(400MHz,CDCl3)δppm 8.05(d,J=2.6Hz,1H),7.61(s,1H),7.44(d,J=9.7Hz,1H),7.39-7.28(m,2H),7.01(d,J=8.4Hz,1H),6.79(s,1H),6.66(d,J=8.8Hz,1H),4.79-4.65(m,2H),3.49(dd,J=5.7,16.3Hz,8H),1.43(s,9H);ES-LCMS m/z 515.3[M+H]+.
步骤3:4-(5-((6-(3-氯-5-氟苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
在N2气氛在0℃向搅拌下的4-(5-((6-(3-氯-5-氟苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(900mg,1.398mmol)和Et3N(0.585mL,4.19mmol)在DCM(20mL)中的悬浮液中添加MsCl(0.142mL,1.818mmol)。将反应混合物在0℃搅拌0.5h直到TLC(PE/EtOAc=3/1,Rf=0.65)显示该反应完成。向混合物中添加水(50mL),然后用DCM(30mL×3)萃取。将合并的有机层合并且用Na2SO4干燥,过滤且浓缩以得到黄色油状物4-(5-((6-(3-氯-5-氟苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(900mg,1.214mmol,87.0%产率):1H NMR(400MHz,CDCl3)δppm 8.11(d,J=2.6Hz,1H),7.64(s,1H),7.52-7.33(m,3H),7.09(d,J=8.4Hz,1H),6.89(s,1H),6.72(d,J=9.3Hz,1H),5.26(s,2H),3.55(d,J=8.4Hz,8H),3.10(s,3H),1.48(s,9H);ES-LCMS m/z593.1,595.1[M+H]+.
步骤4:4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3-氯-5-氟苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(900mg,1.214mmol)和N-(哌啶-4-基甲基)乙酰胺,盐酸盐(295mg,1.457mmol)在DMF(20mL)中的悬浮液中添加K2CO3(336mg,2.428mmol)。将反应混合物在50℃搅拌12h,然后过滤且浓缩以得到粗产物,其通过硅胶柱(DCM/MeOH=10/1,Rf=0.5)纯化以得到淡黄色固体的4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(700mg,0.857mmol,70.6%产率):1H NMR(400MHz,CDCl3)δppm 8.14(d,J=2.6Hz,1H),7.67(s,1H),7.50(d,J=9.7Hz,1H),7.47-7.39(m,2H),7.07(d,J=7.9Hz,1H),6.85(s,1H),6.74(d,J=9.3Hz,1H),5.56(s,1H),3.67-3.42(m,8H),3.17(t,J=6.4Hz,2H),2.89(s,4H),2.11-1.94(m,4H),1.75-1.60(m,5H),1.50(s,9H),1.41-1.21(m,2H);ES-LCMS m/z 653.4,655.4[M+H]+.
步骤5:N-((1-((2-(3-氯-5-氟苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(0.7g,0.857mmol)在DCM(10mL)中的悬浮液中添加TFA(3mL,38.9mmol)。将反应混合物在15℃搅拌12h,然后浓缩。残余物用DCM(50mL)稀释且用饱和NaHCO3水溶液将pH调节至8,用DCM(30mL×3)萃取。合并的有机层用Na2SO4干燥,过滤且蒸发以得到淡黄色胶状物的N-((1-((2-(3-氯-5-氟苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(550mg,0.788mmol,92.0%产率):1HNMR(400MHz,CDCl3)δppm 8.14(d,J=2.2Hz,1H),7.68(s,1H),7.52(d,J=10.1Hz,1H),7.46-7.36(m,2H),7.08(d,J=8.4Hz,1H),6.83(s,1H),6.74(d,J=8.8Hz,1H),5.54(s,1H),3.65-3.54(m,4H),3.52(s,2H),3.17(t,J=6.4Hz,2H),3.12-3.02(m,4H),2.87(s,1H),2.11-1.94(m,5H),1.70(d,J=12.3Hz,2H),1.54(s,1H),1.39-1.23(m,4H);ES-LCMSm/z 553.4[M+H]+.
步骤6:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
向N-((1-((2-(3-氯-5-氟苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(200mg,0.287mmol)和3-溴丙酸乙酯(78mg,0.430mmol)在MeCN(10mL)中的悬浮液中添加K2CO3(119mg,0.860mmol)。将反应混合物在80℃搅拌12h,然后过滤且浓缩以得到淡黄色胶状物的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(250mg,0.275mmol,96.0%产率):1H NMR(400MHz,CDCl3)δppm 8.11(d,J=2.6Hz,1H),7.66(s,1H),7.49(d,J=9.7Hz,1H),7.43-7.35(m,2H),7.06(d,J=7.9Hz,1H),6.81(s,1H),6.71(d,J=8.8Hz,1H),5.50(s,1H),4.15(q,J=7.4Hz,2H),3.57-3.51(m,4H),3.15(t,J=6.4Hz,2H),2.92-2.81(m,2H),2.79-2.71(m,2H),2.66-2.57(m,4H),2.56-2.47(m,2H),1.99(d,J=7.1Hz,5H),1.67(d,J=11.9Hz,3H),1.37-1.21(m,7H);ES-LCMS m/z 653.4,655.4[M+H]+.
步骤7:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
向3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(250mg,0.275mmol)在THF(10mL)和H2O(3mL)中的悬浮液中添加LiOH·H2O(57.8mg,1.377mmol)。将反应混合物在15℃搅拌2h,然后浓缩。将残余物溶于DMSO(10mL),用1N HCl将pH调节至4,然后通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐(116.78mg,0.148mmol,53.8%产率):1H NMR(400MHz,CD3OD)δppm8.25(s,1H),8.17(s,1H),8.01(s,1H),7.83(s,1H),7.65(d,J=9.5Hz,1H),7.58(d,J=9.8Hz,1H),7.41(s,1H),7.31(d,J=8.5Hz,1H),4.48(s,2H),3.78(s,3H),3.65-3.33(m,9H),3.24-3.05(m,4H),2.98(t,J=6.9Hz,2H),2.06-1.94(m,5H),1.88(s,1H),1.63(d,J=12.0Hz,2H);ES-LCMSm/z 625.3[M+H]+.
实施例116:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-溴-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
步骤1:4-(5-((6-(3-溴-5-氟苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-氯-4-(甲氧基羰基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(5g,7.80mmol)和(3-溴-5-氟苯基)硼酸(1.365g,6.24mmol)在DMF(150mL)中的混合物中添加K2CO3(3.23g,23.39mmol)和PdCl2(dppf)(0.285g,0.390mmol)。将反应在80℃在N2气氛搅拌2h,然后过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(PE/EtOAc=5/1)纯化。将所有通过TLC(PE/EA=5/1,Rf=0.6)分析发现包含产物的级分合并且浓缩以得到黄色油状物。该黄色油状物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到淡黄色固体。将固体溶于DCM(100mL),然后用饱和NaHCO3水溶液、盐水(20mL)洗涤,然后用Na2SO4干燥,过滤且浓缩以得到棕色固体的4-(5-((6-(3-溴-5-氟苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(650mg,0.996mmol,12.8%产率):1H NMR(400MHz,CDCl3)δppm 8.17(d,J=2.6Hz,1H),8.04-7.90(m,2H),7.85(s,1H),7.56(d,J=9.7Hz,1H),7.48(dd,J=2.6,9.3Hz,1H),7.44(s,1H),6.77(d,J=9.3Hz,1H),3.99(s,3H),3.59(d,J=3.1Hz,8H),1.49(s,9H);ES-LCMS m/z 587.2,589.2[M+H]+.
步骤2:2-(3-溴-5-氟苯基)-6-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)异烟酸
将4-(5-((6-(3-溴-5-氟苯基)-4-(甲氧基羰基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(650mg,0.996mmol)和NaOH(80mg,1.992mmol)在MeOH(10mL)和H2O(1mL)中的混合物在25℃搅拌2h。反应用1N HCl将pH调节至6。将混合物浓缩以得到残余物,将其用水洗涤,然后浓缩以得到白色固体的2-(3-溴-5-氟苯基)-6-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)异烟酸(600mg,0.921mmol,92.0%产率):1H NMR(400MHz,CD3OD)δppm 8.06(d,J=2.6Hz,1H),8.02(s,1H),7.90(s,1H),7.62(d,J=9.7Hz,1H),7.51(dd,J=3.1,9.3Hz,1H),7.38(s,1H),7.33(d,J=7.9Hz,1H),6.96(d,J=9.3Hz,1H),3.72(t,J=6.6Hz,2H),3.59-3.50(m,6H),1.65-1.33(m,9H);ES-LCMS m/z 572.9,574.9[M+H]+.
步骤3:4-(5-((6-(3-溴-5-氟苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
在25℃向2-(3-溴-5-氟苯基)-6-((6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)氧基)异烟酸(450mg,0.691mmol)在THF(5mL)中的混合物中分批添加BH3·DMS(2mL,20.00mmol)。将反应在50℃搅拌2h,然后用MeOH(2mL)淬灭,过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(DCM/MeOH=95:5)纯化。将所有通过TLC(DCM/MeOH=20/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(5-((6-(3-溴-5-氟苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(390mg,0.679mmol,98.0%产率):1HNMR(400MHz,CDCl3)δppm 8.06(d,J=2.6Hz,1H),7.76(s,1H),7.48(d,J=9.7Hz,1H),7.39-7.31(m,2H),7.16(d,J=7.9Hz,1H),6.79(s,1H),6.66(d,J=9.3Hz,1H),4.77-4.69(m,2H),3.51(d,J=5.7Hz,4H),3.47(d,J=5.7Hz,4H),1.43(s,9H);ES-LCMS m/z 558.9,560.9[M+H]+.
步骤4:4-(5-((6-(3-溴-5-氟苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
在25℃向4-(5-((6-(3-溴-5-氟苯基)-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.696mmol)和DIEA(0.365mL,2.089mmol)在DCM(10mL)中的溶液中添加MsCl(0.081mL,1.045mmol)。将反应混合物在25℃搅拌20min,然后添加DCM(50mL)和饱和NaHCO3水溶液(20mL)。水相用DCM(100mL x2)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥且浓缩以得到棕色固体的4-(5-((6-(3-溴-5-氟苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.605mmol,87.0%产率):1H NMR(400MHz,CDCl3)δppm 8.12(d,J=2.6Hz,1H),7.81(s,1H),7.53(d,J=9.3Hz,1H),7.46-7.39(m,2H),7.23(d,J=1.8Hz,1H),6.88(s,1H),6.73(d,J=8.8Hz,1H),4.57(s,2H),3.56(d,J=8.4Hz,8H),2.78(s,3H),1.49(s,9H);ES-LCMSm/z637.2,639.2[M+H]+.
步骤5:4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-溴-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
将4-(5-((6-(3-溴-5-氟苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.605mmol)、N-(哌啶-4-基甲基)乙酰胺,盐酸盐(184mg,0.908mmol)和K2CO3(251mg,1.816mmol)在DMF(10mL)中的混合物在80℃在N2气氛搅拌6h。将混合物过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(DCM/MeOH=95/5)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-溴-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(380mg,0.514mmol,85.0%产率)。1H NMR(400MHz,CDCl3)δppm 8.13(d,J=2.6Hz,1H),8.01(s,1H),7.81(s,1H),7.53(d,J=10.6Hz,1H),7.46-7.37(m,2H),7.22(d,J=7.9Hz,1H),6.83(s,1H),6.73(d,J=9.3Hz,1H),5.52(br.s,1H),3.61-3.50(m,8H),3.16(t,J=6.4Hz,2H),2.88(s,4H),2.06-1.96(m,5H),1.69(d,J=12.8Hz,2H),1.49(s,9H),1.32(d,J=10.6Hz,2H);ES-LCMS m/z 697.0,698.9[M+H]+.
步骤6:N-((1-((2-(3-溴-5-氟苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
将4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-溴-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(530mg,0.717mmol)和HCl溶液(4.0M在EtOAc中,5mL,20.00mmol)在EtOAc(10mL)中的混合物在25℃搅拌0.5h,然后过滤。滤饼用EtOAc(50mL)洗涤且浓缩以得到黄色固体的N-((1-((2-(3-溴-5-氟苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(480mg,0.610mmol,85.0%产率):1H NMR(400MHz,CD3OD)δppm 8.27-8.20(m,2H),7.99(s,1H),7.95(s,1H),7.67(d,J=9.3Hz,1H),7.63-7.57(m,1H),7.46-7.39(m,2H),4.58-4.43(m,2H),4.06-4.03(m,2H),3.64-3.56(m,2H),3.53-3.47(m,3H),3.17-3.10(m,3H),3.03-2.96(m,2H),2.87(s,2H),1.99-1.95(m,3H),1.85(d,J=3.5Hz,1H),1.68-1.57(m,4H);ES-LCMS m/z 597.0,599.0[M+H]+.
步骤7:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-溴-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯
在26℃,在N2气氛将3-溴丙酸乙酯(92mg,0.508mmol)和N-((1-((2-(3-溴-5-氟苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(200mg,0.254mmol)和DIEA(0.222mL,1.270mmol)在DMF(10mL)中的混合物搅拌2h,然后浓缩以得到棕色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-溴-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(250mg,0.187mmol,73.5%产率):1H NMR(400MHz,CD3OD)δppm8.08(d,J=2.5Hz,1H),7.94(s,1H),7.81(s,1H),7.67(d,J=10.0Hz,1H),7.55(d,J=9.0Hz,1H),7.38(d,J=8.0Hz,1H),7.13(s,1H),7.01(d,J=9.0Hz,1H),4.62(s,1H),4.01(s,2H),3.67(s,4H),3.16-3.05(m,4H),3.03-2.95(m,3H),2.88(s,5H),2.71(t,J=7.0Hz,3H),2.59(s,2H),2.00(s,1H),1.86(d,J=13.6Hz,2H),1.71(s,1H),1.56(d,J=6.0Hz,2H),1.25(d,J=6.0Hz,3H);ES-LCMS m/z 697.3,699.3[M+H]+.
步骤8:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-溴-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐
将3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-溴-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸乙酯(320mg,0.239mmol)和NaOH(28.7mg,0.717mmol)在MeOH(10mL)和H2O(2mL)中的混合物在25℃搅拌2h,然后浓缩。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-溴-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐(131.32mg,0.161mmol,67.4%产率):1H NMR(400MHz,CD3OD)δppm8.22(d,J=2.6Hz,1H),8.13(dd,J=2.6,9.7Hz,1H),7.96(d,J=10.1Hz,2H),7.66(d,J=9.3Hz,1H),7.52(d,J=9.7Hz,1H),7.45-7.41(m,1H),7.39(s,1H),4.59-4.30(m,4H),3.86-3.65(m,3H),3.64-3.52(m,5H),3.48(s,2H),3.21-3.05(m,4H),2.96(t,J=6.8Hz,2H),2.05-1.94(m,5H),1.86(s,1H),1.68-1.54(m,2H);ES-LCMSm/z 669.3,671.2[M+H]+.
实施例117:2-(1-((3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸
步骤1:5-((2-(4-(叔丁氧基羰基)哌嗪-1-基)嘧啶-5-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-甲酸
向4-(5-溴嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1.129g,2.96mmol)和3',5'-二氯-5-羟基-[1,1'-联苯]-3-甲酸甲酯(1g,2.69mmol)在DMSO(15mL)中的混合物中添加CuI(0.026g,0.135mmol)、吡啶甲酸(0.331g,2.69mmol)和K3PO4(1.715g,8.08mmol)。溶液在130℃在N2气氛搅拌10h,然后添加饱和NH4Cl水溶液(40mL)。将混合物浓缩且残余物在DCM(200mL)和饱和NaHCO3水溶液(100mL)之间分配。合并的有机萃取物用盐水(200mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(DCM/MeOH=1/1)纯化。将所有通过制备型TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到棕色油状物的5-((2-(4-(叔丁氧基羰基)哌嗪-1-基)嘧啶-5-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-甲酸(1g,1.100mmol,40.9%产率):1H NMR(400MHz,DMSO-d6)δppm 8.43-8.38(m,2H),7.92-7.87(m,1H),7.79-7.74(m,2H),7.64(d,J=2.0Hz,2H),7.40(br.s,1H),3.74-3.70(m,4H),3.47-3.45(m,4H),1.43(s,9H);ES-LCMSm/z 489.1,491.0[M-t-Bu+H]+.
步骤2:3',5'-二氯-5-((2-(哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-甲酸甲酯
向5-((2-(4-(叔丁氧基羰基)哌嗪-1-基)嘧啶-5-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-甲酸(1g,1.100mmol)在MeOH(15mL)中的混合物中缓慢添加SOCl2(0.131g,1.100mmol)。将反应在40℃搅拌10h,然后浓缩以得到棕色油状物的3',5'-二氯-5-((2-(哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-甲酸甲酯,2盐酸盐(900mg,1.015mmol,92.0%产率):1H NMR(400MHz,DMSO-d6)δppm 8.45(s,2H),7.94-7.88(m,2H),7.69-7.67(m,1H),7.63(s,2H),7.42(s,1H),3.96(d,J=5.0Hz,4H),3.84(s,3H),3.18-3.15(m,4H);ES-LCMSm/z 459.2,461.2[M+H]+.
步骤3:3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-甲酸甲酯
向3',5'-二氯-5-((2-(哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-甲酸甲酯,2盐酸盐(1.7g,1.916mmol)在MeOH(20mL)中的混合物中添加甲醛(37%在H2O中,1.244g,9.58mmol)和甲酸(0.441g,9.58mmol)。在15℃在N2气氛将反应搅拌8h,然后添加NaBH(OAc)3(2.437g,11.50mmol)且再搅拌2h。将溶液浓缩且添加饱和NaHCO3水溶液(150mL)。水层用DCM(150mL x2)萃取且合并的萃取物用盐水(15mL x2)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过硅胶柱色谱法(DCM/MeOH=5/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到棕色油状物的3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-甲酸甲酯(600mg,1.039mmol,54.2%产率):1H NMR(400MHz,CD3OD)δppm 8.29(d,J=5.5Hz,2H),7.97(s,1H),7.61(d,J=1.5Hz,2H),7.54(s,1H),7.52(s,1H),7.49(s,1H),3.94(s,3H),3.86-3.82(m,4H),3.37-3.32(m,4H),2.62(s,3H);ES-LCMS m/z 473.1,475.1[M+H]+.
步骤4:(3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲醇
在-20℃向3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-甲酸甲酯(600mg,1.039mmol)在THF(10mL)中的混合物中添加LiAlH4(79mg,2.079mmol)。在-20℃在N2气氛将反应搅拌10分钟,然后用1mL水淬灭。将混合物过滤且浓缩,然后用额外DCM(50mL)稀释且用饱和NaHCO3水溶液(30mL x2)洗涤。有机相用Na2SO4干燥,过滤且浓缩以得到棕色油状物的(3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲醇(550mg,0.753mmol,72.5%产率):1H NMR(400MHz,CD3OD)δppm 8.29-8.24(m,2H),7.58(d,J=1.8Hz,2H),7.46(s,1H),7.34(s,1H),7.16(s,1H),7.00(s,1H),4.67-4.65(m,2H),3.92-3.77(m,8H),2.64(s,3H);ES-LCMS m/z 445.2,447.2[M+H]+.
步骤5:甲磺酸(3’,5’-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1’-联苯]-3-基)甲基酯
向(3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲醇(550mg,0.753mmol)和DIEA(292mg,2.260mmol)在DCM(10mL)中的混合物中添加MsCl(0.088mL,1.130mmol)。将反应在15℃搅拌10h。反应混合物用额外DCM(50mL)稀释且用饱和NaHCO3水溶液(50mL x2)洗涤。有机相用Na2SO4干燥,过滤且浓缩以得到棕色油状物的甲磺酸(3’,5’-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1’-联苯]-3-基)甲基酯(600mg,0.550mmol,73.0%产率):1H NMR(400MHz,CD3OD)δppm 8.37-8.33(m,2H),7.57(d,J=1.8Hz,2H),7.47(s,1H),7.44-7.40(m,1H),7.19(s.,1H),7.10-7.06(m,1H),4.69(s,2H),4.01-3.94(m,2H),3.65-3.54(m,2H),3.37(s.,3H),3.30(s.,3H),2.68(s,4H);ES-LCMSm/z 523.2,525.2[M+H]+.
步骤6:2-(1-((3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸甲酯
向甲磺酸(3’,5’-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)[1,1’-联苯]-3-基)甲基酯(200mg,0.183mmol)在DMF(5mL)中的混合物中添加K2CO3(101mg,0.734mmol)和2-(哌啶-4-基)乙酸甲酯,盐酸盐(79mg,0.367mmol)。将反应在15℃在N2气氛搅拌10h,然后浓缩且添加饱和NaHCO3溶液(150mL)。水层用DCM(300mL x2)萃取且合并的萃取物用盐水(150mL x2)洗涤,用Na2SO4干燥,过滤且浓缩以得到棕色油状物的2-(1-((3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸甲酯(200mg,0.154mmol,84.0%产率):1H NMR(400MHz,CD3OD)δppm8.32-8.29(m,1H),8.28-8.26(m,1H),7.60(s,2H),7.47(s,1H),7.35(s.,1H),7.19(s,1H),7.07-6.99(m,1H),3.85(s,4H),3.56(s,2H),3.37(s,4H),3.34-3.34(m,4H),2.37(d,J=1.5Hz,2H),2.29(s,3H),2.18-2.16(m,2H),1.96-1.93(m,4H)1.75(s,2H);ES-LCMS m/z 584.3,586.3[M+H]+.
步骤7:2-(1-((3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸
向2-(1-((3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸甲酯(200mg,0.154mmol)在THF(3mL)和H2O(1mL)中的溶液中添加LiOH·H2O(32.3mg,0.770mmol)。将反应在15℃在N2气氛搅拌15分钟,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的2-(1-((3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸,3盐酸盐(9.53mg,0.014mmol,9.1%产率):1H NMR(400MHz,D2O)δppm 7.97(s,2H),7.28(s,3H),7.03-6.87(m,3H),4.48(d,J=13.6Hz,2H),4.10(s,2H),3.50(d,J=11.0Hz,2H),3.34-3.18(m,4H),3.07(d,J=11.0Hz,2H),2.86(s,5H),2.20(d,J=5.0Hz,2H),1.94-1.69(m,3H),1.39(d,J=11.0Hz,2H);ES-LCMS m/z 570.2,572.2[M+H]+.
实施例118:N-((1-((2-((2-(1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
步骤1:4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1.25g,1.629mmol)和N-(哌啶-4-基甲基)乙酰胺,盐酸盐(0.496g,2.444mmol)在DMF(20mL)中的溶液中添加K2CO3(0.675g,4.89mmol)。将反应混合物在80℃搅拌12h,然后过滤且浓缩以得到粗产物,其在硅胶上通过快速色谱法(DCM/MeOH=1/0至10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.55)发现包含产物的级分合并且浓缩以得到黄色固体的4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1.05g,1.316mmol,81.0%产率):1H NMR(400MHz,CDCl3)δppm 8.28(s,2H),8.01(s,1H),7.73(d,J=1.3Hz,2H),7.41(s,1H),7.33(s,1H),6.90(s,1H),5.58(s,1H),3.95-3.86(m,2H),3.84-3.67(m,4H),3.58(d,J=4.4Hz,2H),3.53-3.47(m,2H),3.39-3.27(m,2H),3.16(t,J=6.4Hz,2H),2.90(s,2H),2.07-1.95(m,7H),1.86-1.83(m,1H),1.45(d,J=7.1Hz,9H),1.39-1.28(m,2H);ES-LCMS m/z 684.3,686.3[M+H]+.
步骤2:N-((1-((2-((2-(1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
将4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(250mg,0.313mmol)溶于HCl溶液(4M在MeOH中,8mL,32.0mmol)。将反应混合物在25℃搅拌0.5h,然后浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到淡黄色固体的N-((1-((2-((2-(1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(94.61mg,0.128mmol,40.7%产率):1H NMR(400MHz,CD3OD)δppm 8.73-8.66(m,2H),8.01(s,1H),7.93(d,J=1.8Hz,2H),7.53-7.50(m,1H),7.43(s,1H),4.46(s,2H),4.29-4.23(m,2H),4.00(t,J=6.0Hz,2H),3.59(d,J=11.9Hz,2H),3.53-3.47(m,2H),3.45-3.39(m,2H),3.19-3.06(m,4H),2.34-2.27(m,2H),2.04-1.94(m,5H),1.89(s,1H),1.70-1.60(m,2H);ES-LCMS m/z 584.3,586.3[M+H]+.
实施例119-125(表6)通过类似于实施例118所述的方法制备。
表6
实施例126:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
步骤1:4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1.25g,1.601mmol)和2-(哌啶-4-基)乙酸甲酯,盐酸盐(0.490g,2.402mmol)在DMF(20mL)中的溶液中添加K2CO3(0.664g,4.80mmol)。将反应混合物在80℃搅拌1h,然后过滤且浓缩以得到粗产物,其在硅胶上通过快速色谱法(PE/EtOAc=1/0至1/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.65)发现包含产物的级分合并且浓缩以得到淡黄色固体的4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1.25g,1.550mmol,97.0%产率):1H NMR(400MHz,CDCl3)δppm 8.27(s,2H),7.97(s,1H),7.96(d,J=1.8Hz,2H),7.32(s,1H),7.02(s,1H),3.88-3.86(m,2H),3.82-3.78(m,4H),3.66(s,3H),3.38-3.36(m,2H),3.24-3.18(m,2H),3.08-3.06(m,2H),2.30-2.28(m,2H),2.21-2.03(m,2H),1.98-1.94(m,4H),1.62(s,3H),1.46(s,9H);ES-LCMS m/z 685.4,687.3[M+H]+.
步骤2:2-(1-((2-((2-(1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1.25g,1.550mmol)溶于HCl溶液(4.0M在MeOH中,15mL,60.0mmol)。将反应混合物在20℃搅拌0.5h,然后浓缩以得到淡黄色固体的2-(1-((2-((2-(1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4盐酸盐(1.3g,1.338mmol,86.0%产率):1HNMR(400MHz,CD3OD)δppm 8.63(s,2H),7.99(s,1H),7.92(d,J=1.8Hz,2H),7.51(t,J=1.8Hz,1H),7.40(s,1H),4.45(s,2H),4.23(d,J=5.7Hz,2H),4.00(t,J=6.2Hz,2H),3.66(s,3H),3.57(d,J=7.1Hz,2H),3.50-3.47(m,2H),3.40(d,J=5.3Hz,2H),3.18-3.10(m,2H),2.29(d,J=5.7Hz,2H),2.13-2.08(m,1H),2.05-2.01(m,2H),1.73-1.64(m,2H);ES-LCMSm/z 585.3,587.3[M+H]+.
步骤3:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-((2-(1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4盐酸盐(250mg,0.257mmol)在MeOH(5mL)中的溶液中添加多聚甲醛(386mg,12.86mmol)和甲酸(11.84mg,0.257mmol)的MeOH(5mL)溶液。在20℃搅拌24h后,添加NaBH3CN(81mg,1.286mmol)且将混合物在20℃再搅拌2h。添加饱和NaHCO3水溶液(50mL)且用DCM(30mL×3)萃取。合并的有机层用Na2SO4干燥且浓缩以得到淡黄色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(210mg,0.245mmol,95.0%产率):1H NMR(400MHz,CD3OD)δppm 8.35-8.20(m,2H),7.82-7.66(m,2H),7.46-7.38(m,1H),7.33(s,1H),6.89(s,1H),4.02-3.92(m,2H),3.84(t,J=6.4Hz,2H),3.69-3.64(m,3H),3.57-3.48(m,2H),2.86(d,J=11.5Hz,2H),2.76-2.68(m,2H),2.63-2.53(m,2H),2.44-2.36(m,3H),2.30-2.23(m,2H),2.16-1.97(m,4H),1.83(d,J=11.5Hz,1H),1.72(d,J=12.8Hz,2H),1.41-1.29(m,2H);ES-LCMS m/z 599.3,601.3[M+H]+.
步骤4:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4盐酸盐(210mg,0.197mmol)在THF(5mL)中的溶液中添加LiOH·H2O(41.4mg,0.986mmol)的水(1mL)溶液。将反应混合物在50℃搅拌12h,然后添加1N HCl以将pH调节至6~7。将反应混合物浓缩且残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(90.09mg,0.122mmol,61.9%产率):1H NMR(400MHz,CD3OD)δppm 8.55(s,2H),7.97(s,1H),7.91(d,J=1.8Hz,2H),7.51(s,1H),7.38(s,1H),4.55-4.48(m,1H),4.45(s,2H),4.02-3.91(m,3H),3.75(dd,J=5.3,13.2Hz,1H),3.58(d,J=12.3Hz,3H),3.42-3.33(m,2H),3.15(t,J=12.1Hz,2H),2.96(s,3H),2.40-2.29(m,4H),2.12-2.00(m,3H),1.74-1.62(m,2H);ES-LCMS m/z 585.3,587.3[M+H]+.
实施例127-155(表7)通过类似于实施例126所述的方法制备。
表7
实施例156:2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基-1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1:2-(1-((2-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(500mg,0.885mmol)、1,4-二氮杂环庚烷(133mg,1.327mmol)、Xantphos(51.2mg,0.088mmol)、Cs2CO3(865mg,2.65mmol)在THF(10mL)中的混合物中添加Pd2(dba)3(81mg,0.088mmol)。将反应在75℃在N2气氛搅拌24h,然后过滤且浓缩。粗产物通过硅胶柱色谱法(DCM/MeOH=1/0至8/1,TLC:DCM/MeOH=10/1,Rf=0.3)纯化以得到黄色固体的2-(1-((2-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(300mg,0.462mmol,52.2%产率):1H NMR(400MHz,CD3OD)δppm8.00(s,1H),7.83(s,2H),7.61(s,1H),7.47(d,J=7.6Hz,1H),7.42(s,1H),6.97(s,1H),6.81(d,J=9.6Hz,1H),3.90(s,2H),3.77(t,J=5.6Hz,2H),3.64(s,3H),3.60-3.58(m,2H),3.21-3.19(m,2H),3.06-3.04(m,2H),2.92-2.89(m,2H),2.27(d,J=6.4Hz,2H),2.16-2.03(m,4H),1.75-1.72(m,3H),1.40-1.29(m,2H);ES-LCMSm/z 584.3,586.3[M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基-1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(300mg,0.462mmol)在MeOH(5mL)中的溶液中添加多聚甲醛(693mg,23.10mmol)和甲酸(21.26mg,0.462mmol)的MeOH(5mL)溶液。在30℃搅拌20h后,添加NaBH3CN(145mg,2.310mmol)且将混合物在30℃搅拌8h。将混合物浓缩,添加DCM/MeOH(10/1,50mL)且用饱和NaHCO3(50mL)水溶液洗涤。水层用DCM(30mL x2)萃取。合并的有机层用Na2SO4干燥且浓缩以得到黄色固体的2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基-1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(250mg,0.360mmol,78.0%产率):1H NMR(400MHz,CD3OD)δppm7.99(d,J=2.8Hz,1H),7.86(d,J=2.0Hz,2H),7.63(s,1H),7.48-7.44(m,2H),6.98(s,1H),6.77(d,J=8.8Hz,1H),3.86-3.85(m,2H),3.71-3.69(m,2H),3.67(s,3H),3.61(s,2H),2.95-2.93(m,2H),2.85-2.78(m,2H),2.71-2.63(m,2H),2.42(s,3H),2.30(d,J=7.2Hz,2H),2.13-2.10(m,4H),1.87-1.71(m,3H),1.38-1.31(m,2H);ES-LCMS m/z 598.3,600.4[M+H]+.
步骤3:2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基-1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基-1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(250mg,0.360mmol)在THF(5mL)和水(1mL)中的溶液中添加LiOH·H2O(60.4mg,1.440mmol)。将混合物在20℃搅拌30h。将混合物用1NHCl酸化至pH=5-6,然后浓缩。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到淡黄色固体的2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基-1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(161.91mg,0.222mmol,61.6%产率):1H NMR(400MHz,CD3OD)δppm8.17-8.13(m,2H),7.95(s,1H),7.90(d,J=1.6Hz,2H),7.53(s,1H),7.48-.45(m,1H),7.39(s,1H),4.45(s,2H),4.32-4.21(m,1H),4.15-4.05(m,1H),3.87(s,1H),3.81-3.78(m,2H),3.70-3.68(m,1H),3.60-3.57(m,2H),3.46-3.42(m,2H),3.14(t,J=12.0Hz,2H),2.99(s,3H),2.55-2.40(m,2H),2.33-2.31(m,2H),2.08-2.05(m,3H),1.67-1.64(m,2H);ES-LCMSm/z 584.3,586.3[M+H]+.
实施例157:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
步骤1:N-((1-((2-((6-氯哒嗪-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向N-((1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(3g,6.39mmol)和3,6-二氯哒嗪(1.428g,9.59mmol)在DMF(50mL)中的悬浮液中添加Cs2CO3(6.25g,19.18mmol)。将反应混合物在130℃搅拌12h,然后过滤且浓缩。残余物通过ISCO(DCM/MeOH=10/1,Rf=0.5)纯化且将所需级分浓缩以得到棕色固体的N-((1-((2-((6-氯哒嗪-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(700mg,1.259mmol,19.7%产率):1H NMR(400MHz,CDCl3)δppm 7.73(d,J=1.8Hz,2H),7.59(d,J=9.3Hz,1H),7.55(s,1H),7.40(d,J=8.8Hz,1H),7.36(d,J=1.8Hz,1H),7.17-7.12(m,1H),5.56(br.s,1H),3.57(s,2H),3.21-3.12(m,3H),2.94-2.84(m,3H),2.08-2.03(m,2H),2.00-1.98(m,3H),1.58-1.48(m,1H),1.35-1.26(m,2H);ES-LCMS m/z 520.2,522.2[M+H]+.
步骤2:4-(6-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)哒嗪-3-基)哌嗪-1-甲酸叔丁酯
在N2气氛下向搅拌下的N-((1-((2-((6-氯哒嗪-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(540mg,0.971mmol)、哌嗪-1-甲酸叔丁酯(271mg,1.456mmol)和Cs2CO3(949mg,2.91mmol)在THF(10mL)中的悬浮液中添加Xantphos(56.2mg,0.097mmol)和Pd2(dba)3(89mg,0.097mmol)。将反应混合物在80℃在N2气氛搅拌12h,然后过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(DCM/MeOH=1/0至20/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到棕色固体的4-(6-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)哒嗪-3-基)哌嗪-1-甲酸叔丁酯(300mg,0.164mmol,16.9%产率):1H NMR(400MHz,CDCl3)δppm 7.67(br.s,2H),7.44-7.37(m,1H),7.28(d,J=6.2Hz,1H),7.13-7.08(m,1H),7.03(d,J=10.6Hz,1H),6.82(d,J=9.7Hz,1H),5.58-5.44(m,2H),4.28(d,J=12.8Hz,2H),3.56-3.50(m,4H),3.15-3.05(m,4H),2.88-2.76(m,4H),1.93(d,J=3.5Hz,5H),1.64(br.s,1H),1.53-1.33(m,9H),1.27-1.21(m,2H);ES-LCMSm/z 670.2,672.3[M+H]+.
步骤3:N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4三氟乙酸盐
向4-(6-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)哒嗪-3-基)哌嗪-1-甲酸叔丁酯(300mg,0.164mmol)在DCM(10mL)中的悬浮液中添加TFA(2.5mL,32.4mmol)。将反应混合物在15℃搅拌5h,然后浓缩以得到棕色胶状物N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4三氟乙酸盐(300mg,0.148mmol,91.0%产率):1H NMR(400MHz,CDCl3)δppm7.96-7.90(m,1H),7.89-7.81(m,3H),7.72-7.66(m,1H),7.64(s,1H),7.48(br.s,1H),4.43(br.s,2H),4.27(d,J=13.2Hz,2H),3.92(br.s,2H),3.60(br.s,3H),3.39(br.s,3H),3.23-3.16(m,2H),2.01(br.s,5H),1.83-1.76(m,1H),1.35(br.s,2H);ES-LCMS m/z570.3,572.3[M+H]+.
步骤4:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4三氟乙酸盐(300mg,0.148mmol)和多聚甲醛(44.6mg,1.484mmol)在MeOH(10mL)中的悬浮液中添加甲酸(0.017mL,0.445mmol)。将反应混合物在40℃搅拌30h。向该反应混合物中添加NaBH3CN(28.0mg,0.445mmol)。该反应混合物在40℃搅拌10h,然后过滤。滤液用水(50mL)稀释,用DCM(30mL×3)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,中性条件)纯化且将所需级分冻干以得到白色固体的N-((1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(37.59mg,0.061mmol,40.9%产率):1H NMR(400MHz,CD3OD)δppm 7.82-7.75(m,2H),7.71(s,1H),7.52(d,J=9.7Hz,1H),7.46-7.37(m,2H),7.13(s,1H),3.76-3.62(m,6H),3.07(d,J=6.6Hz,2H),2.97(d,J=11.5Hz,2H),2.70(t,J=4.9Hz,4H),2.43(s,3H),2.17-2.09(m,2H),1.93(s,3H),1.73(d,J=12.3Hz,2H),1.60-1.47(m,1H),1.38-1.27(m,2H);ES-LCMS m/z 584.3,586.3[M+H]+.
实施例158:2-(1-((2-((2-(4-氨基哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
步骤1:2-(1-((2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将甲磺酸(2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基酯(300mg,0.336mmol)、2-(哌啶-4-基)乙酸甲酯,盐酸盐(163mg,0.672mmol)和K2CO3(139mg,1.009mmol)在DMF(10mL)中的混合物在N2气氛加热至90℃保持10h。将反应混合物过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(DCM/MeOH=1/0至9/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到油状物的2-(1-((2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(200mg,0.265mmol,79.0%产率):1H NMR(400MHz,CDCl3)δppm 8.33-8.20(m,2H),7.74-7.69(m,2H),7.41-7.37(m,1H),7.35-7.28(m,1H),6.92-6.85(m,1H),4.62(d,J=13.7Hz,2H),4.47(br.s,1H),3.81-3.69(m,1H),3.65(s,2H),3.50(s,2H),3.09(t,J=11.5Hz,2H),2.84(d,J=11.5Hz,2H),2.28-2.23(m,2H),2.08-1.98(m,4H),1.84-1.76(m,1H),1.74-1.63(m,4H),1.48-1.42(m,9H),1.41-1.32(m,3H);ES-LCMS m/z 685.2,687.2[M+H]+.
步骤2:2-(1-((2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸
将2-(1-((2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(200mg,0.265mmol)和NaOH(21.23mg,0.531mmol)在MeOH(10mL)和H2O(1mL)中的混合物在25℃搅拌10h。用1N HCl将反应pH调节至7,然后用DCM(50mL×3)萃取。有机层通过盐水(30mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色固体的2-(1-((2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸(230mg,0.240mmol,90.0%产率):1HNMR(400MHz,CDCl3)δppm 8.28-8.17(m,1H),8.08(s,2H),7.12(br.s,2H),6.93(s,1H),6.71(br.s,1H),4.48(d,J=12.8Hz,2H),3.66-3.58(m,2H),3.27(br.s,2H),3.00-2.88(m,3H),2.68(br.s,4H),1.97(br.s,3H),1.86(br.s,3H),1.55(d,J=8.4Hz,3H),1.42-1.33(m,9H);ES-LCMS m/z 671.2,673.2[M+H]+.
步骤3:2-(1-((2-((2-(4-氨基哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
将2-(1-((2-((2-(4-((叔丁氧基羰基)氨基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸(230mg,0.240mmol)和TFA(2mL,26.0mmol)在DCM(10mL)中的混合物在25℃搅拌0.5h。将反应混合物过滤且浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到淡黄色固体的2-(1-((2-((2-(4-氨基哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(76.54mg,0.104mmol,43.3%产率):1H NMR(400MHz,CD3OD)δppm 8.61(s,2H),8.10-8.01(m,1H),7.92(d,J=1.0Hz,2H),7.55-7.48(m,1H),7.43(s,1H),4.83(d,J=13.6Hz,2H),4.66-4.41(m,2H),3.68-3.48(m,3H),3.31-3.12(m,4H),2.41-2.26(m,2H),2.20(d,J=12.0Hz,2H),2.14-1.98(m,3H),1.84-1.64(m,4H);ES-LCMS m/z 571.2,573.2[M+H]+.
实施例159:(S)-2-(1-((2-(3,5-二氯苯基)-6-((2-(3-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
步骤1:(S)-4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯
向(S)-4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(1g,1.078mmol)在DMF(30mL)中的溶液中添加K2CO3(0.447g,3.23mmol)和2-(哌啶-4-基)乙酸甲酯(0.282g,1.616mmol)。将反应在20℃搅拌2h,然后浓缩且通过硅胶柱色谱法(PE/EtOAc=1/1)纯化。将所有通过TLC(PE/EtOAc=1/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到黄色固体的(S)-4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(1g,0.948mmol,88.0%产率):1H NMR(400MHz,CD3OD)δppm8.31(s,2H),7.80(s,2H),7.62(s,1H),7.41(s,1H),7.06-7.04(m,1H),7.03(s,1H),4.63-4.54(m,2H),4.32-4.29(m,1H),3.82-3.78(m,1H),3.66(s,3H),3.64(s,2H),3.29-3.22(m,3H),3.11-2.80(m,4H),2.29(d,J=6.5Hz,2H),2.13-2.10(m,2H),1.76-1.73(m,3H),1.50(s,9H),1.18(d,J=6.5Hz,3H);ES-LCMS m/z 685.3,687.3[M+H]+.
步骤2:(S)-2-(1-((2-(3,5-二氯苯基)-6-((2-(3-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向(S)-4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(1g,0.948mmol)在EtOAc(20mL)中的混合物中添加HCl溶液(4.0M在EtOAc中,5mL,20.0mmol)。将反应在20℃搅拌0.5h,然后添加饱和NaHCO3水溶液(200mL)且用DCM(200mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色固体的(S)-2-(1-((2-(3,5-二氯苯基)-6-((2-(3-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(700mg,0.921mmol,97.0%产率):1H NMR(400MHz,CD3OD)δppm 8.53(br.s,2H),8.00(s,1H),7.90(br.s,2H),7.51(m,1H),7.38(m,1H),4.86(m,2H),4.47(s,2H),3.68-3.48(m,10H),3.28-3.22(m,4H),2.03(m,3H),1.78-1.58(m,2H),1.25-1.17(m,3H);ES-LCMS m/z 585.3,587.3[M+H]+.
步骤3:(S)-2-(1-((2-(3,5-二氯苯基)-6-((2-(3-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
向(S)-2-(1-((2-(3,5-二氯苯基)-6-((2-(3-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(400mg,0.526mmol)在MeOH(10mL)和水(2mL)中的混合物中添加NaOH(63.1mg,1.578mmol)。将反应在20℃搅拌5h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的(S)-2-(1-((2-(3,5-二氯苯基)-6-((2-(3-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(75.97mg,0.105mmol,19.9%产率):1H NMR(400MHz,CD3OD)δppm 8.50(s,2H),8.03(s,1H),7.88(s,2H),7.48(s,1H),7.39(s,1H),4.85(d,J=13.6Hz,2H),4.57-4.42(m,2H),3.63-3.44(m,5H),3.29-3.16(m,4H),2.41-2.28(m,2H),2.17-2.01(m,3H),1.90-1.59(m,2H),1.45(d,J=6.5Hz,3H);ES-LCMS m/z 571.3,573.3[M+H]+.
实施例160-165(表8)通过类似于实施例159所述的方法制备。
表8
实施例166:2-(1-((2-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((2-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(230mg,0.326mmol)在THF(2mL)和H2O(2mL)中的溶液中添加LiOH·H2O(54.7mg,1.303mmol)。将混合物在20℃搅拌10h,然后用1N HCl酸化至pH=5-6,然后浓缩。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的2-(1-((2-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(114.38mg,0.160mmol,49.0%产率):1H NMR(400MHz,CD3OD)δppm 8.19-8.17(m,2H),7.98(s,1H),7.91(s,2H),7.53-7.51(m,2H),7.41(s,1H),4.46(s,2H),4.18-4.15(m,2H),3.92-3.89(m,2H),3.63-3.57(m,4H),3.47-3.45(m,2H),3.15(t,J=12.0Hz,2H),2.37-2.32(m,4H),2.07-2.04(m,3H),1.69-1.66(m,2H);ES-LCMS m/z 570.3,572.3[M+H]+.
实施例167:N-((1-((3',5'-二氯-5-((2-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺
步骤1:4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-溴嘧啶-2-基)哌嗪-1-甲酸叔丁酯(0.756g,1.983mmol)和N-((1-((3',5'-二氯-5-羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,盐酸盐(1g,1.803mmol)在DMSO(10mL)中的混合物中添加CuI(0.017g,0.090mmol)、吡啶甲酸(0.011g,0.090mmol)和K3PO4(1.148g,5.41mmol)。将混合物在130℃搅拌10h。添加饱和NH4Cl水溶液(40mL)且将溶液浓缩。粗产物在DCM(500mL)和饱和NaHCO3水溶液(300mL)之间分配,用DCM(500mL x2)萃取。合并的有机萃取物用盐水(200mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶(DCM/MeOH=1/0至1/1)纯化。将所有通过TLC(DCM/MeOH=15/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到棕色油状物4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1.4g,1.673mmol,93.0%产率):1H NMR(400MHz,CD3OD)δppm 8.26(s,2H),7.56(d,J=1.5Hz,2H),7.43(s,1H),7.33(s,1H),7.15(s,1H),6.99(s,1H),3.83-3.79(m,4H),3.56(s,2H),3.53(br.s,4H),3.07(d,J=7.0Hz,2H),2.94(d,J=11.5Hz,2H),2.06(t,J=10.8Hz,2H),1.94(s,3H),1.72(d,J=12.5Hz,2H),1.51(s,10H),1.33-1.23(m,2H);ES-LCMSm/z 669.4,671.3[M+H]+.
步骤2:N-((1-((3',5'-二氯-5-((2-(哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐
向4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1.4g,1.673mmol)在DCM(8mL)中的混合物中添加HCl溶液(4.0M在EtOAc中,5mL,20mmol)。将反应在15℃在N2气氛搅拌0.5h,然后浓缩以得到棕色油状物的N-((1-((3',5'-二氯-5-((2-(哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐(1.4g,1.547mmol,92.0%产率):1H NMR(400MHz,CD3OD)δppm 8.61(s,2H),7.74-7.67(m,3H),7.56-7.48(m,3H),4.39(s,2H),4.22(br.s,4H),3.54(d,J=10.5Hz,2H),3.46(br.s,4H),3.24(d,J=5.5Hz,2H),3.14-3.04(m,2H),2.15(s,3H),1.99(d,J=13.6Hz,3H),1.66(d,J=12.5Hz,2H);ES-LCMS m/z 569.3,571.3[M+H]+.
步骤3:N-((1-((3',5'-二氯-5-((2-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺
向N-((1-((3',5'-二氯-5-((2-(哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐(200mg,0.221mmol)在DCM(8mL)中的混合物中添加(甲基磺酰基)乙烯(70.4mg,0.663mmol)和DIEA(114mg,0.884mmol)。将反应在15℃在N2气氛搅拌10h,然后过滤且浓缩。混合物通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化且冻干干燥以得到灰白色固体的N-((1-((3',5'-二氯-5-((2-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺(15.19mg,0.022mmol,9.8%产率):1H NMR(400MHz,CD3OD)δppm 8.26(s,2H),7.60(d,J=1.5Hz,2H),7.46(s,1H),7.35(s,1H),7.19(s,1H),7.00(s,1H),3.85(br.s,4H),3.58(br.s,2H),3.39-3.36(m,2H),3.11(s,3H),3.07(d,J=6.5Hz,2H),3.01-2.87(m,4H),2.63(t,J=4.8Hz,4H),2.16-2.00(m,2H),1.95(s,3H),1.73(d,J=12.0Hz,2H),1.54(br.s,1H),1.34-1.22(m,2H);ES-LCMS m/z 675.2,677.2[M+H]+.
实施例168:3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸,3盐酸盐
步骤1:3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯
向N-((1-((3',5'-二氯-5-((2-(哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺,3盐酸盐(300mg,0.354mmol)在MeCN(5mL)中的混合物中添加DIEA(228mg,1.768mmol)和3-溴丙酸乙酯(0.050mL,0.389mmol)。将反应在80℃在N2气氛搅拌10h,然后浓缩以得到棕色油状物的3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(300mg,0.269mmol,76.0%产率):1H NMR(400MHz,CD3OD)δppm 8.35(s,2H),7.69(d,J=1.5Hz,2H),7.60(s,1H),7.51(s,1H),7.42(s,1H),7.29(s,1H),4.35(br.s,2H),4.25-4.18(m,2H),3.55-3.42(m,4H),3.32-3.21(m,4H),3.13-3.10(m,6H),2.87-2.78(m,4H),1.97(s,6H),1.56(t,J=6.1Hz,2H),1.26-1.23(m,3H);ES-LCMS m/z 669.3,671.4[M+H]+.
步骤2:3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸,3盐酸盐
向3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸乙酯(300mg,0.358mmol)在MeOH(5mL)和H2O(3mL)中的混合物中添加LiOH·H2O(75mg,1.792mmol)。将反应在15℃搅拌10min,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到黄色固体的3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸,3盐酸盐(28.43mg,0.037mmol,10.3%产率):1H NMR(400MHz,CD3OD)δppm 8.41(s,2H),7.67(d,J=1.5Hz,2H),7.57(s,1H),7.52(s,1H),7.41(s,1H),7.33(br.s,1H),4.36(s,2H),3.70(d,J=12.0Hz,2H),3.58-3.39(m,6H),3.28(br.s,4H),3.14(d,J=6.5Hz,2H),3.09-2.98(m,2H),2.94(t,J=6.8Hz,2H),2.02-1.94(m,5H),1.85(br.s,1H),1.63-1.47(m,2H);ES-LCMS m/z 641.3,643.3[M+H]+.
实施例169-177(表9)通过类似于实施例168所述的方法制备。
表9
实施例178:4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1-甲基哌嗪1-氧化物,3盐酸盐
步骤1:4-甲基哌嗪-1-甲酸叔丁酯
向1-甲基哌嗪(3g,30.0mmol)和DIEA(10.46mL,59.9mmol)在DCM(100mL)中的溶液中添加Boc2O(8.34mL,35.9mmol)。将混合物在25℃搅拌1h,然后浓缩且用PE(20mL x2)洗涤以得到无色油状物4-甲基哌嗪-1-甲酸叔丁酯(4g,17.98mmol,60.0%产率):1H NMR(400MHz,CDCl3)δppm3.50-3.29(m,4H),2.31(br.s,4H),2.26(s,3H),1.43(s,9H);ES-LCMSm/z 201.2[M+H]+.
步骤2:4-(叔丁氧基羰基)-1-甲基哌嗪1-氧化物
向4-甲基哌嗪-1-甲酸叔丁酯(4g,19.97mmol)在DCM(100mL)中的溶液中分批添加3-氯过氧苯甲酸(15.10mL,100mmol)。将反应在30℃搅拌12h。将混合物用饱和Na2S2O3溶液(100mL)淬灭且在30℃搅拌0.5h。将有机相浓缩且通过快速色谱法(MeOH/DCM=0/1至1/5)纯化。将所有通过TLC(MeOH/DCM=1/10,Rf=0.25)发现包含产物的级分合并且浓缩以得到白色固体的4-(叔丁氧基羰基)-1-甲基哌嗪1-氧化物(2.5g,8.09mmol,40.5%产率):1HNMR(400MHz,CD3OD)δppm 4.01-3.97(m,2H),3.60-3.57(m,2H),3.48-3.42(m,2H),3.27-3.25(m,3H),3.23-3.20(m,2H),1.44(s,9H);ES-LCMS m/z 217.2[M+H]+.
步骤3:1-甲基哌嗪1-氧化物,盐酸盐
将4-(叔丁氧基羰基)-1-甲基哌嗪1-氧化物(2g,9.25mmol)溶于HCl溶液(4.0M在EtOAc中,30mL,120mmol)。将反应在25℃搅拌2h且形成白色固体。将混合物过滤以得到白色固体的1-甲基哌嗪1-氧化物,盐酸盐(1.3g,7.67mmol,83.0%产率):1H NMR(400MHz,CD3OD)δppm 4.27-4.08(m,4H),3.88-3.68(m,7H)。
步骤4:4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1-甲基哌嗪1-氧化物,3盐酸盐
在N2气氛,将N-((1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(150mg,0.266mmol)、1-甲基哌嗪1-氧化物,盐酸盐(81mg,0.532mmol)、Pd2(dba)3(12.17mg,0.013mmol)、(±)-BINAP(33.1mg,0.053mmol)、18-冠-6(211mg,0.797mmol)和叔丁醇钠(25.5mg,0.266mmol)在THF(15mL)中的混合物加热至65℃保持12h。将混合物浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到白色固体的4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1-甲基哌嗪1-氧化物,3盐酸盐(21.98mg,0.031mmol,11.5%产率):1HNMR(400MHz,CD3OD)δppm 8.18(d,J=2.6Hz,1H),7.91-7.83(m,4H),7.50(s,1H),7.36-7.26(m,2H),4.42(s,2H),4.37(d,J=14.1Hz,2H),3.97-3.84(m,4H),3.83-3.72(m,2H),3.63(s,3H),3.58(d,J=12.3Hz,2H),3.15-3.02(m,4H),2.03-1.95(m,3H),1.94-1.76(m,3H),1.63-1.44(m,2H);ES-LCMS m/z 599.3,601.3[M+H]+.
实施例179:1-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1-(2-羟基乙基)哌嗪-1-鎓-1-基)-2-羟基乙-1-化物(ide),氯化物
实施例180:N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
向N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(1g,1.328mmol)在MeCN(40mL)中的溶液中添加2-溴乙醇(0.249g,1.992mmol)和K2CO3(0.551g,3.98mmol)。将混合物在80℃搅拌12h,然后过滤且浓缩。混合物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到黄色固体,将其通过制备型SFC纯化以得到白色固体的N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(0.044g,0.071mmol,41.3%):1H NMR(400MHz,CD3OD)δppm 8.30-8.22(m,2H),8.01(s,1H),7.89(d,J=1.8Hz,2H),7.64(d,J=9.7Hz,1H),7.52(s,1H),7.43(s,1H),4.59-4.40(m,4H),4.00-3.93(m,2H),3.90-3.77(m,3H),3.60(d,J=11.9Hz,2H),3.54-3.36(m,5H),3.19-3.05(m,4H),2.05-1.97(m,5H),1.87(br.s,1H),1.69-1.55(m,2H);ES-LCMS m/z613.2,615.2[M+H]+和4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,1-双(2-羟基乙基)哌嗪-1-鎓氯化物(31.30mg,0.043mmol,26.6%):1H NMR(400MHz,CD3OD)δppm 8.07(d,J=2.6Hz,1H),7.83(d,J=1.8Hz,2H),7.65(s,1H),7.53(dd,J=2.9,9.0Hz,1H),7.44(t,J=1.8Hz,1H),7.02-6.96(m,2H),4.08-3.91(m,1H),3.90-3.73(m,4H),3.72-3.64(m,6H),3.62-3.55(m,2H),3.08(d,J=6.6Hz,3H),3.00(d,J=7.9Hz,5H),2.18(br.s,2H),1.93(s,3H),1.75(d,J=12.3Hz,2H),1.56(br.s,1H),1.42-1.25(m,3H);ES-LCMS m/z 657.2,659.2[M]+.
实施例181:4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,1-二甲基哌嗪-1-鎓氯化物,3盐酸盐
步骤1:4-(叔丁氧基羰基)-1,1-二甲基哌嗪-1-鎓碘化物
将哌嗪-1-甲酸叔丁酯(3g,16.11mmol)、碘甲烷(11.43g,81mmol)和K2CO3(4.45g,32.2mmol)在THF(100mL)中的混合物在25℃搅拌12h。将混合物过滤且浓缩以得到白色固体的4-(叔丁氧基羰基)-1,1-二甲基哌嗪-1-鎓碘化物(3g,8.33mmol,51.7%产率):1H NMR(400MHz,CD3OD)δppm3.79(br.s,4H),3.48(t,J=5.3Hz,4H),3.25(s,6H),1.52-1.41(m,9H);ES-LCMS m/z 215.1[M]+.
步骤2:1,1-二甲基哌嗪-1-鎓氯化物,盐酸盐
将4-(叔丁氧基羰基)-1,1-二甲基哌嗪-1-鎓碘化物(3g,8.77mmol)溶于HCl溶液(4.0M在EtOAc中,30mL,120mmol)。将反应在25℃搅拌2h直到TLC分析(DCM/MeOH=10/1,Rf=0.04)显示反应完成。将混合物浓缩以得到棕色固体的1,1-二甲基哌嗪-1-鎓氯化物,盐酸盐(1.8g,9.68mmol,73.0%产率):1H NMR(400MHz,CD3OD)δppm 3.89-3.79(m,4H),3.74(d,J=4.6Hz,4H),3.38(s,6H)。
步骤3:4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,1-二甲基哌嗪-1-鎓氯化物,3盐酸盐
将N-((1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(150mg,0.266mmol)、1,1-二甲基哌嗪-1-鎓氯化物,盐酸盐(81mg,0.435mmol)、Pd2(dba)3(12.17mg,0.013mmol)、(±)-BINAP(33.1mg,0.053mmol)、18-冠-6(211mg,0.797mmol)和叔丁醇钠(128mg,1.329mmol)在THF(15mL)中的混合物在N2气氛加热至65℃保持12h。将混合物浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化以得到棕色固体的4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,1-二甲基哌嗪-1-鎓氯化物,盐酸盐(13.85mg,0.026mmol,8.7%产率):1H NMR(400MHz,CD3OD)δppm8.27(br.s,2H),8.07(br.s,1H),7.88(br.s,2H),7.69(br.s,1H),7.54-7.38(m,2H),4.48(br.s,2H),4.19(br.s,4H),3.81(br.s,4H),3.64(br.s,2H),3.37(br.s,6H),3.18(br.s,4H),2.05(s,3H),1.98(d,J=12.8Hz,3H),1.79-1.53(m,2H);ES-LCMS m/z 597.3,599.3[M]+.
实施例182:N-((1-((2-((6-((顺式)-4-氨基-3-氟哌啶-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
步骤1:(顺式)-4-(苄基氨基)-3-氟哌啶-1-甲酸叔丁酯
在15℃向3-氟-4-氧代哌啶-1-甲酸叔丁酯(16.83mL,81mmol)在甲醇(200mL)和乙酸(2.419g,40.3mmol)中的溶液中添加苯基甲胺(9.50g,89mmol)。将反应在15℃在N2气氛搅拌15h。添加NaBH3CN(5.06g,81mmol)且再搅拌3h。然后将溶液浓缩且添加饱和NaHCO3水溶液(15mL)。水层用DCM(55mL x2)萃取,且合并的萃取物用盐水(15mL x2)洗涤,用Na2SO4干燥,过滤且浓缩以得到粗产物。粗物质通过快速色谱法(PE/EtOAc=2/1)纯化。将所有通过TLC(PE/EA=2/1,Rf=0.2)分析发现包含产物的级分合并且浓缩以得到淡黄色油状物(顺式)-4-(苄基氨基)-3-氟哌啶-1-甲酸叔丁酯(10g,19.46mmol,24.1%产率):1H NMR(400MHz,CD3OD)δppm7.45-7.21(m,5H),4.43-4.35(m,1H),4.12(d,J=7.5Hz,1H),3.88-3.83(m,2H),2.84-2.65(m,2H),1.99-1.88(m,1H),1.64(dq,J=4.3,12.5Hz,1H),1.47(s,9H);ES-LCMS m/z 309.2,[M+H]+.
步骤2:(顺式)-4-氨基-3-氟哌啶-1-甲酸叔丁酯
在N2下向搅拌下的(顺式)-4-(苄基氨基)-3-氟哌啶-1-甲酸叔丁酯(2.5g,8.11mmol)在MeOH(50mL)中的溶液中一次性添加Pd/C(10wt%,1.725g,1.621mmol)。然后将悬浮液真空脱气且用H2吹洗三次。将混合物在30psi H2在40℃搅拌10h。将反应混合物通过垫过滤且滤饼用MeOH(30mL)洗涤。合并的滤液浓缩至干以得到黄色油状物(顺式)-4-氨基-3-氟哌啶-1-甲酸叔丁酯(1.5g,5.50mmol,67.8%产率):1H NMR(400MHz,CDCl3)δppm4.58(s.,2H),4.27(s.,2H),4.10-3.83(m,2H),3.07-2.72(m,4H),1.42(s,9H);
步骤3:(顺式)-4-(((苄基氧基)羰基)氨基)-3-氟哌啶-1-甲酸叔丁酯
向(顺式)-4-氨基-3-氟哌啶-1-甲酸叔丁酯(400mg,1.833mmol)在DCM(10mL)中的溶液中添加CbzCl(469mg,2.75mmol)和DIEA(711mg,5.50mmol)。将反应混合物在30℃搅拌1h。添加H2O(20mL)且用DCM(20mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物,其通过制备型TLC(EA/PE=1/5,Rf=0.3)纯化以得到黄色固体的(顺式)-4-(((苄基氧基)羰基)氨基)-3-氟哌啶-1-甲酸叔丁酯(350mg,0.795mmol,43.4%产率):1H NMR(400MHz,CDCl3)δppm 7.40-7.27(m,5H),5.10(s,2H),4.75-4.07(m,4H),3.89-3.67(m,1H),3.03-2.73(m,2H),1.71-1.66(m,2H),1.44(s,9H);ES-LCMS m/z 375.1[M+Na]+.
步骤2:((顺式)-3-氟哌啶-4-基)氨基甲酸苄基酯
向(顺式)-4-(((苄基氧基)羰基)氨基)-3-氟哌啶-1-甲酸叔丁酯(350mg,0.993mmol)在DCM(10mL)中的溶液中添加2,2,2-三氟乙酸(2mL,27.0mmol)。将反应混合物在30℃搅拌1h,然后浓缩以得到黄色固体的((顺式)-3-氟哌啶-4-基)氨基甲酸苄基酯(193mg,0.612mmol,61.6%产率):1H NMR(400MHz,CD3OD)δppm 7.47-7.03(m,5H),5.15-5.03(m,2H),4.68-4.54(m,1H),3.76-3.61(m,1H),3.19(t,J=12.0Hz,1H),3.02(d,J=13.2Hz,1H),2.84-2.58(m,2H),1.80-1.63(m,2H);ES-LCMS m/z 253.1[M+H]+.
步骤3:N-((1-((2-((6-((顺式)-4-氨基-3-氟哌啶-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
向N-((1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(150mg,0.266mmol)在THF(2mL)中的溶液中添加18-冠-6(211mg,0.797mmol)、(±)-BINAP(16.55mg,0.027mmol)、Pd2(dba)3(24.34mg,0.027mmol)、((顺式)-3-氟哌啶-4-基)氨基甲酸苄基酯(67.1mg,0.266mmol)和2-甲基丙-2-醇钠(153mg,1.595mmol)。将反应混合物在70℃搅拌10h。添加H2O(20mL),用DCM(20mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到粗产物,其通过制备型TLC(DCM/MeOH=10/1,Rf=0.3)纯化以得到粗产物。粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的N-((1-((2-((6-((顺式)-4-氨基-3-氟哌啶-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(7.89mg,10.52μmol,3.96%产率):1H NMR(400MHz,CD3OD)δppm 8.32-7.76(m,5H),7.64(br.s,1H),7.52-7.27(m,2H),5.35-5.12(m,2H),4.67(s,2H),4.46(br.s,2H),4.01-3.45(m,5H),3.13(br.s,3H),2.69(br.s,2H),2.16(br.s,2H),1.95(br.s,4H),1.64(br.s,2H);ES-LCMS m/z601.2,603.2[M+H]+.
实施例183:N-((1-((2-(3,5-二氯苯基)-6-((6-((1S,4S)-5-(2-(甲基磺酰基)乙基)-2,5-二氮杂双环[2.2.1]庚-2-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
步骤1:(1S,4S)-5-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯
向N-((1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(500mg,0.797mmol)在THF(10mL)中的混合物中添加(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(237mg,1.196mmol)、Xantphos(231mg,0.399mmol)、Pd2(dba)3(146mg,0.159mmol)和Cs2CO3(779mg,2.392mmol)。将反应在80℃在N2气氛搅拌5h。添加饱和NaHCO3水溶液(50mL)且将混合物用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤,浓缩且通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到黄色固体的(1S,4S)-5-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(600mg,0.643mmol,81.0%产率):1H NMR(400MHz,CD3OD)δppm7.96(d,J=2.6Hz,1H),7.80(br.s,2H),7.58(s,1H),7.46(dd,J=2.9,9.0Hz,1H),7.41-7.36(m,1H),6.94(s,1H),6.63(t,J=9.3Hz,1H),4.79(br.s,1H),4.58(d,J=4.9Hz,1H),3.65-3.57(m,4H),3.48-3.36(m,4H),3.06(d,J=6.6Hz,2H),2.99-2.90(m,2H),2.10-1.98(m,3H),1.93(s,3H),1.71(d,J=11.9Hz,2H),1.57-1.41(m,9H),1.36-1.23(m,2H);ES-LCMS m/z 681.3,683.3[M+H]+.
步骤2:N-((1-((2-((6-((1S,4S)-2,5-二氮杂双环[2.2.1]庚-2-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向(1S,4S)-5-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(600mg,0.643mmol)在EtOAc(10mL)中的混合物中添加HCl溶液(4.0M在EtOAc中,5mL,20.0mmol)。将反应在25℃搅拌0.5h。添加饱和NaHCO3水溶液(50mL)且将混合物用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤,浓缩以得到黄色固体的N-((1-((2-((6-((1S,4S)-2,5-二氮杂双环[2.2.1]庚-2-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(400mg,0.585mmol,91.0%产率):1H NMR(400MHz,CD3OD)δppm 8.22(d,J=9.7Hz,1H),8.16(d,J=2.2Hz,1H),8.01(s,1H),7.90(d,J=1.3Hz,2H),7.51(s,1H),7.46-7.41(m,2H),5.25(br.s,1H),4.75(s,1H),4.46(s,2H),4.08-3.94(m,2H),3.66-3.55(m,4H),3.12(d,J=5.7Hz,4H),2.44-2.27(m,1H),2.25-2.22(m,1H),1.99-1.95(m,5H),1.94-1.77(m,1H),1.72-1.59(m,2H);ES-LCMS m/z 581.3,583.3[M+H]+.
步骤3:N-((1-((2-(3,5-二氯苯基)-6-((6-((1S,4S)-5-(2-(甲基磺酰基)乙基)-2,5-二氮杂双环[2.2.1]庚-2-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
向N-((1-((2-((6-((1S,4S)-2,5-二氮杂双环[2.2.1]庚-2-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(150mg,0.219mmol)在DCM(5mL)中的混合物中添加(甲基磺酰基)乙烯(69.8mg,0.658mmol)和DIEA(0.191mL,1.096mmol)。将反应在25℃搅拌5h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到灰白色固体的N-((1-((2-(3,5-二氯苯基)-6-((6-((1S,4S)-5-(2-(甲基磺酰基)乙基)-2,5-二氮杂双环[2.2.1]庚-2-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(82.23mg,0.098mmol,44.9%产率):1H NMR(400MHz,CD3OD)δppm 8.21-8.16(m,2H),7.97(s,1H),7.89(d,J=1.8Hz,2H),7.52(s,1H),7.41-7.37(m,2H),5.26(br.s,1H),4.85(s,1H),4.45(s,2H),4.17(d,J=11.5Hz,1H),4.12-3.95(m,3H),3.93-3.77(m,4H),3.59(d,J=11.9Hz,2H),3.16-3.08(m,7H),2.68-2.42(m,2H),2.00-1.94(m,5H),1.85(br.s,1H),1.68-1.50(m,2H);ES-LCMSm/z 687.3,689.3[M+H]+.
实施例184:N-((1-((2-((6-(反式-3-(氨基甲基)-4-羟基吡咯烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
步骤1:3-氰基-4-羟基吡咯烷-1-甲酸叔丁酯
将3-氰基-4-氧代吡咯烷-1-甲酸叔丁酯(10g,47.6mmol)在EtOH(500mL)中的溶液冷却至0℃(冰浴),且经0.1h向该溶液分批添加NaBH4(3.60g,95mmol)。将反应混合物在相同温度搅拌0.5h且浓缩。残余物用EtOAc(200mL)稀释,用水(200mL×3)洗涤,用Na2SO4干燥,且过滤。将滤液浓缩以得到残余物,将其通过柱色谱(硅胶,PE/EtOAc=1/1)纯化以得到无色油状物的3-氰基-4-羟基吡咯烷-1-甲酸叔丁酯(10g,37.7mmol,79.0%产率):1H NMR(400MHz,CD3OD)δppm 4.57-4.45(m,1H),3.85-3.45(m,3H),3.41-3.25(m,2H),1.50(s,9H)。
步骤2:3-(氨基甲基)-4-羟基吡咯烷-1-甲酸叔丁酯
向3-氰基-4-羟基吡咯烷-1-甲酸叔丁酯(10g,47.1mmol)在DMF(150mL)中的溶液中添加兰尼镍(1.383g,23.56mmol)。然后将反应在40℃在H2气氛(50psi)搅拌12h。将反应混合物过滤且将滤液浓缩以得到淡黄色油状物的3-(氨基甲基)-4-羟基吡咯烷-1-甲酸叔丁酯(10g,37.0mmol,79.0%产率):1H NMR(400MHz,CD3OD)δppm 4.39-3.99(m,1H),3.72-3.07(m,5H),2.79-2.54(m,1H),2.44-2.18(m,1H),1.48(br.s,9H)。
步骤3:反式-3-((((苄基氧基)羰基)氨基)甲基)-4-羟基吡咯烷-1-甲酸叔丁酯
在0℃向3-(氨基甲基)-4-羟基吡咯烷-1-甲酸叔丁酯(10g,46.2mmol)和DIEA(24.56mL,139mmol)在DCM(100mL)中的混合物中滴加CbzCl(9.47g,55.5mmol)。将混合物在0℃在N2气氛搅拌1h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到浅色油状物的反式-3-((((苄基氧基)羰基)氨基)甲基)-4-羟基吡咯烷-1-甲酸叔丁酯(4g,9.13mmol,19.8%产率):1H NMR(400MHz,CD3OD)δppm 7.35-7.27(m,5H),5.08-5.05(m,2H),4.08-4.02(m,1H),3.58-3.49(m,2H),3.22-3.12(m,3H),3.05(dd,J=3.9,7.6Hz,1H),2.24(dd,J=3.7,6.8Hz,1H),1.44(s,9H);ES-LCMS m/z 295.1[M-t-Bu+H]+.
步骤4:((反式-4-羟基吡咯烷-3-基)甲基)氨基甲酸苄基酯,三氟乙酸盐
向反式-3-((((苄基氧基)羰基)氨基)甲基)-4-羟基吡咯烷-1-甲酸叔丁酯(2g,5.71mmol)在DCM(10mL)中的悬浮液中添加三氟乙酸(2mL,26.9mmol)。将混合物在20℃在N2气氛搅拌0.5h,然后浓缩以得到棕色固体的((反式-4-羟基吡咯烷-3-基)甲基)氨基甲酸苄基酯,三氟乙酸盐(1.5g,3.30mmol,57.9%产率):1H NMR(400MHz,CD3OD)δppm 7.33(d,J=4.2Hz,5H),5.07(s,2H),4.28-4.22(m,1H),3.51(dd,J=7.7,12.1Hz,1H),3.35(dd,J=4.5,12.3Hz,1H),3.21-2.95(m,4H),2.43(dd,J=3.7,6.8Hz,1H);ES-LCMS m/z 251.1[M+H]+.
步骤5:((反式-1-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-4-羟基吡咯烷-3-基)甲基)氨基甲酸苄基酯
向((反式-4-羟基吡咯烷-3-基)甲基)氨基甲酸苄基酯(133mg,0.532mmol)、Pd2(dba)3(24.34mg,0.027mmol)和二环己基(2',4',6'-三异丙基-[1,1'-联苯]-2-基)膦(12.67mg,0.027mmol)在THF(5mL)中的悬浮液中添加N-((1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(150mg,0.266mmol)和Cs2CO3(173mg,0.532mmol)。将反应混合物在70℃在N2气氛搅拌12h,然后过滤且浓缩以得到淡黄色固体的((反式-1-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-4-羟基吡咯烷-3-基)甲基)氨基甲酸苄基酯(100mg,0.095mmol,35.9%产率):1H NMR(400MHz,CD3OD)δppm7.97(d,J=2.5Hz,1H),7.89-7.80(m,2H),7.77-7.73(m,1H),7.63(s,1H),7.49-7.43(m,2H),7.42-7.25(m,6H),5.13(s,2H),3.75-3.67(m,4H),3.55(s,2H),3.41-3.38(m,1H),3.09(d,J=6.5Hz,4H),2.95(d,J=11.0Hz,2H),2.14(s,2H),1.98(s,3H),1.74(d,J=10.5Hz,2H),1.55(br.s,1H),1.41-1.20(m,3H);ES-LCMS m/z 733.2,735.2[M+H]+.
步骤6:N-((1-((2-((6-(反式-3-(氨基甲基)-4-羟基吡咯烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
将((反式-1-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-4-羟基吡咯烷-3-基)甲基)氨基甲酸苄基酯(100mg,0.136mmol)在TFA(5mL,67.3mmol)中的溶液在40℃搅拌2h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到黄色固体的N-((1-((2-((6-(反式-3-(氨基甲基)-4-羟基吡咯烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(33.75mg,0.045mmol,33.2%产率):1H NMR(400MHz,CD3OD)δppm8.17(dd,J=2.1,9.8Hz,1H),8.08(d,J=2.2Hz,1H),7.99(s,1H),7.89(d,J=1.8Hz,2H),7.52(s,1H),7.40(s,1H),7.27(d,J=9.9Hz,1H),4.46(s,2H),4.07-3.97(m,2H),3.63-3.51(m,4H),3.35(dd,J=2.0,3.7Hz,1H),3.25-3.07(m,6H),2.75-2.68(m,1H),2.04-1.94(m,5H),1.86(br.s,1H),1.69-1.54(m,2H);ES-LCMS m/z599.2,601.3[M+H]+.
实施例185:3-(3-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛-8-基)丙酸,4盐酸盐
步骤1:8-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯
向N-((1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(300mg,0.478mmol)和3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(102mg,0.478mmol)在THF(10mL)中的混合物中添加Xantphos(27.7mg,0.048mmol)、Pd2(dba)3(43.8mg,0.048mmol)和Cs2CO3(468mg,1.435mmol)。将反应在70℃在N2气氛搅拌8h。添加水(20mL)且将混合物用DCM(20mL x2)萃取。合并的有机层用Na2SO4干燥,过滤,浓缩且通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.3)发现包含产物的级分合并且浓缩以得到淡黄色固体的8-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯(250mg,0.180mmol,37.6%产率):1H NMR(400MHz,CD3OD)δppm 8.32(d,J=2.2Hz,2H),8.01(d,J=2.6Hz,1H),7.47(dd,J=3.1,9.3Hz,1H),7.09(s,2H),6.96(s,1H),6.85(d,J=9.3Hz,1H),3.97-3.92(m,2H),3.62(s,2H),3.59(s,2H),3.08(br.s,4H),2.95(br.s,4H),1.95-1.85(m,5H),1.74-1.71(m,3H),1.49(s,9H),1.35-1.31(m,4H);ES-LCMS m/z 695.3,697.3[M+H]+.
步骤2:N-((1-((2-((6-(3,8-二氮杂双环[3.2.1]辛-8-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向8-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯(250mg,0.180mmol)在EtOAc(5mL)中的混合物中添加HCl溶液(4.0M在EtOAc中,5mL,20.0mmol)。将反应在25℃搅拌0.5h。添加饱和NaHCO3水溶液(50mL)且将混合物用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色固体的N-((1-((2-((6-(3,8-二氮杂双环[3.2.1]辛-8-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(200mg,0.168mmol,93.0%产率):1H NMR(400MHz,CD3OD)δppm8.35(d,J=2.2Hz,1H),8.24(br.s,1H),8.03(d,J=5.3Hz,2H),7.75-7.67(m,2H),7.51-7.44(m,2H),4.50(s,2H),4.21(s,1H),3.79-3.75(m,1H),3.60(d,J=7.1Hz,4H),3.18-3.08(m,6H),2.38-2.11(m,3H),1.98(s,6H),1.87(br.s,1H),1.65(d,J=12.3Hz,2H);ES-LCMS m/z 595.3,597.3[M+H]+.
步骤3:3-(8-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛-3-基)丙酸乙酯
向N-((1-((2-((6-(3,8-二氮杂双环[3.2.1]辛-8-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(200mg,0.168mmol)在DMF(5mL)中的混合物中添加3-溴丙酸乙酯(0.038mL,0.252mmol)和K2CO3(69.6mg,0.504mmol)。将反应在60℃搅拌5h。添加水(20mL)且将混合物用DCM(20mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到黄色的3-(8-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛-3-基)丙酸乙酯(200mg,0.144mmol,86.0%产率):1H NMR(400MHz,CD3OD)δppm8.32(s,1H),7.82-7.77(m,3H),7.52(s,1H),7.48-7.36(m,2H),7.09(s,1H),4.15(d,J=7.1Hz,2H),3.80(d,J=11.9Hz,2H),3.67-3.56(m,4H),3.20-3.03(m,6H),2.97-2.89(m,6H),2.15-2.01(m,5H),1.79-1.69(m,4H),1.61-1.45(m,1H),1.35-1.25(m,5H);ES-LCMS m/z 695.3,697.3[M+H]+.
步骤4:3-(3-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛-8-基)丙酸,4盐酸盐
向3-(3-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛-8-基)丙酸乙酯(200mg,0.144mmol)在MeOH(10mL)和水(1mL)中的混合物中添加NaOH(5.75mg,0.144mmol)。将反应在20℃搅拌2h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到淡黄色固体的3-(3-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛-8-基)丙酸,4盐酸盐(16.51mg,0.020mmol,14.1%产率):1H NMR(400MHz,CD3OD)δppm8.19(s,1H),8.03-7.93(m,2H),7.87(d,J=1.3Hz,2H),7.51(s,1H),7.35(s,2H),4.44(s,2H),4.39-4.23(m,4H),3.71(d,J=11.9Hz,1H),3.60(d,J=11.9Hz,2H),3.46(br.s,1H),3.18-3.07(m,4H),3.00(t,J=6.8Hz,2H),2.39(br.s,2H),2.19(d,J=8.4Hz,2H),2.09-1.92(m,7H),1.85(br.s,1H),1.67-1.55(m,2H);ES-LCMS m/z 667.2,669.2[M+H]+.
实施例186-189(表10)通过类似于实施例185所述的方法制备。
表10
实施例190:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-基)丙酸,4盐酸盐
步骤1:4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
在N2气氛下向搅拌下的N-((1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(500mg,0.797mmol)、1,4-二氮杂环庚烷-1-甲酸叔丁酯(240mg,1.196mmol)、(±)-BINAP(99mg,0.159mmol)、18-冠-6(211mg,0.797mmol)和t-BuONa(230mg,2.392mmol)在THF(20mL)中的悬浮液中添加Pd2(dba)3(73.0mg,0.080mmol)。将反应混合物在70℃在N2气氛搅拌12h,然后过滤且浓缩以得到粗产物,其通过柱色谱(DCM/MeOH=10/1,Rf=0.6)纯化。所需级分浓缩以得到棕色胶状物的4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(350mg,0.372mmol,46.6%产率):1H NMR(400MHz,CDCl3)δppm 8.06(d,J=2.6Hz,1H),7.76(d,J=1.8Hz,2H),7.42-7.34(m,2H),7.32(s,1H),6.81(s,1H),6.57(d,J=9.3Hz,1H),5.54(br.s,1H),3.79(t,J=5.1Hz,2H),3.61-3.60(m,4H),3.59(d,J=4.4Hz,2H),3.53-3.46(m,2H),3.35(br.s,1H),3.30-3.23(m,1H),3.16(t,J=6.4Hz,2H),2.87(d,J=11.0Hz,2H),2.06-1.94(m,7H),1.53(br.s,1H),1.43(d,J=11.0Hz,9H),1.37-1.22(m,2H);ES-LCMS m/z683.3,685.3[M+H]+.
步骤2:N-((1-((2-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
向4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(630mg,0.675mmol)在EtOAc(5mL)中的悬浮液中添加HCl溶液(4.0M在EtOAc中,20mL,80mmol)。将反应混合物在25℃搅拌0.5h,然后浓缩以得到棕色胶状物的N-((1-((2-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(500mg,0.544mmol,81.0%产率):1H NMR(400MHz,CD3OD)δppm 8.27-8.20(m,1H),8.17(d,J=2.6Hz,1H),8.00(s,1H),7.91(d,J=1.8Hz,2H),7.59(d,J=10.1Hz,1H),7.53(s,1H),7.43(s,1H),4.46(s,2H),4.22-4.13(m,2H),3.90(t,J=5.7Hz,2H),3.62-3.54(m,4H),3.51-3.43(m,2H),3.19-3.05(m,4H),2.38(br.s,2H),2.07-1.93(m,5H),1.87(br.s,1H),1.69-1.57(m,2H);ES-LCMSm/z 583.3,585.3[M+H]+.
步骤3:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-基)丙酸乙酯
向N-((1-((2-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(500mg,0.544mmol)和3-溴丙酸乙酯(492mg,2.72mmol)在DMF(20mL)中的悬浮液中添加K2CO3(451mg,3.26mmol)。将反应混合物在80℃搅拌10h,然后过滤且浓缩以得到粗产物,将其通过ISCO(DCM/MeOH=10/1,Rf=0.6)纯化且将所需级分浓缩以得到淡黄色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-基)丙酸乙酯(250mg,0.303mmol,55.7%产率):1H NMR(400MHz,CD3OD)δppm8.05(d,J=3.1Hz,1H),7.86(d,J=1.8Hz,2H),7.75(br.s,1H),7.53(dd,J=2.9,9.0Hz,1H),7.48(s,1H),7.13(br.s,1H),6.85(d,J=9.3Hz,1H),4.61(br.s,2H),4.24-4.15(m,2H),4.11(br.s,4H),3.76-3.67(m,2H),3.56-3.37(m,6H),3.11(d,J=5.3Hz,2H),2.85(t,J=6.6Hz,2H),2.69(s,2H),2.29(br.s,2H),1.94(s,3H),1.89(d,J=13.7Hz,2H),1.74(br.s,1H),1.47(br.s,2H),1.27(t,J=7.3Hz,3H);ES-LCMSm/z 683.4,685.3[M+H]+.
步骤4:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-基)丙酸,4盐酸盐
向3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-基)丙酸乙酯(250mg,0.303mmol)在THF(10mL)中的悬浮液中添加LiOH·H2O(38.2mg,0.909mmol)的H2O(3mL)溶液。将反应混合物在25℃搅拌10h,然后用1N HCl将pH调节至7且蒸发以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化。所需级分冻干以得到白色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-基)丙酸,4盐酸盐(106.1mg,0.129mmol,42.7%产率):1H NMR(400MHz,CD3OD)δppm 8.28-8.20(m,1H),8.17(d,J=2.2Hz,1H),8.03(s,1H),7.91(d,J=1.8Hz,2H),7.58(d,J=9.7Hz,1H),7.50(s,1H),7.44(s,1H),4.47(s,2H),4.25(br.s,2H),3.97-3.70(m,4H),3.66-3.32(m,7H),3.23-3.07(m,3H),2.97(t,J=7.1Hz,2H),2.64-2.37(m,2H),2.10-1.92(m,5H),1.88(br.s,1H),1.66(q,J=11.9Hz,2H);ES-LCMSm/z655.3,657.3[M+H]+.
实施例191-203(表11)通过类似于实施例190所述的方法制备。
表11
实施例204:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基亚磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1:4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(2g,2.80mmol)和2-(哌啶-4-基)乙酸甲酯,盐酸盐(1.207g,5.61mmol)在DMF(30mL)中的混合物中添加K2CO3(1.550g,11.22mmol)。将反应在15℃在N2气氛搅拌2h,然后浓缩。添加饱和NaHCO3水溶液(150mL)且水层用DCM(500mL x2)萃取,且合并的萃取物用盐水(150mL x2)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过硅胶柱色谱法(DCM/MeOH=5/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)分析发现包含产物的级分合并且浓缩以得到黄色油状物4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1.6g,2.168mmol,77.0%产率):1H NMR(400MHz,CDCl3)δppm 8.31(s,2H),7.72(d,J=1.5Hz,2H),7.41(s,1H),7.34(s,1H),6.92-6.87(m,1H),3.86-3.79(m,4H),3.67(s,3H),3.56-3.51(m,6H),2.86(d,J=11.0Hz,2H),2.27(d,J=7.0Hz,2H),2.11-2.02(m,2H),1.82(ddd,J=3.8,7.3,11.0Hz,1H),1.72(d,J=12.5Hz,2H),1.50(s,9H),1.42-1.29(m,2H);ES-CMS m/z 671.3,673.3[M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4盐酸盐
向4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1.6g,2.168mmol)在DCM(10mL)中的混合物中添加HCl溶液(4.0M在EtOAc中,5.42mL,21.68mmol)。将反应在15℃在N2气氛搅拌2h,然后浓缩以得到黄色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4盐酸盐(1.5g,1.882mmol,87.0%产率):1HNMR(400MHz,CD3OD)δppm8.69-8.47(m,2H),8.10-7.96(m,1H),7.90(s,2H),7.57-7.36(m,2H),4.47(d,J=8.0Hz,2H),4.17(d,J=5.0Hz,4H),3.68(s,3H),3.60(d,J=12.0Hz,2H),3.43-3.37(m,4H),3.24-3.11(m,2H),2.39(d,J=6.5Hz,2H),2.19-2.00(m,3H),1.70(t,J=12.8Hz,2H);ES-LCMS m/z 571.3,573.3[M+H]+.
步骤3:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲硫基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向3-(甲硫基)丁醛(0.445g,3.76mmol)、乙酸(7.18μL,0.125mmol)、2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4盐酸盐(1g,1.255mmol)在MeOH(10mL)中的溶液中添加分子筛(100mg,1.255mmol)。将反应混合物在25℃在N2气氛搅拌12h。然后,将NaBH3CN(0.237g,3.76mmol)添加至混合物且将混合物在25℃搅拌2h。将反应混合物浓缩且用DCM(300mL)稀释且用饱和NaHCO3水溶液(50mL x2)洗涤。有机相用Na2SO4干燥,过滤且浓缩,然后通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=20/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到淡黄色油状物的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲硫基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(1.2g,1.247mmol,99.0%产率):1H NMR(400MHz,CDCl3)δppm 8.29(s,2H),7.73(d,J=1.5Hz,2H),7.43-7.39(m,1H),7.34(s,1H),6.89(s,1H),3.87-3.72(m,6H),3.67(s,3H),3.52(s,2H),2.88-2.83(m,4H),2.57-2.53(m,4H),2.27(d,J=7.0Hz,2H),2.07(m,5H),1.72(d,J=10.0Hz,4H),1.70-1.65(m,1H),1.43-1.40(m,2H),1.39-1.34(m,3H);ES-LCMSm/z 673.3,675.3[M+H]+.
步骤4:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基亚磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲硫基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(650mg,0.675mmol)在MeOH(6mL)和H2O(2mL)中的溶液中添加Oxone(374mg,0.608mmol)。将反应在25℃搅拌12h,然后用饱和的Na2SO3(水溶液,3mL)淬灭。将溶液浓缩且添加饱和NaHCO3水溶液(15mL)。水层用DCM(150mLx2)萃取,且合并的萃取物用盐水(15mL x2)洗涤,用Na2SO4干燥,过滤且浓缩以得到无色油状物的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基亚磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(650mg,0.660mmol,98.0%产率):1HNMR(400MHz,CD3OD)δppm 8.33(s,2H),7.83(d,J=1.5Hz,2H),7.65(s,1H),7.45(s,1H),7.05(s,1H),3.88(t,J=4.8Hz,4H),3.70(s,3H),3.62(s,2H),2.97-2.87(m,3H),2.63-2.58(m,9H),2.30(d,J=6.5Hz,2H),2.19-2.05(m,2H),1.75-1.62(m,5H),1.46-1.34(m,2H),1.32-1.29(m,3H);ES-LCMS m/z 689.2,691.2[M+H]+.
步骤5:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基亚磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基亚磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(350mg,0.355mmol)在THF(9mL)和H2O(3mL)中的溶液中添加LiOH·H2O(74.5mg,1.776mmol)。将反应混合物在25℃搅拌0.5h。将溶液浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到灰白色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基亚磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸(89.52mg,0.132mmol,37.3%产率):1HNMR(400MHz,CD3OD)δppm8.34(s,2H),7.84(d,J=1.5Hz,2H),7.69(s,1H),7.45(s,1H),7.08(s,1H),3.95-3.84(m,4H),3.73(s,2H),3.08-2.85(m,3H),2.68-2.60(m,9H),2.27(t,J=11.3Hz,2H),2.21(d,J=6.5Hz,2H),2.18-2.06(m,1H),1.83(d,J=10.5Hz,4H),1.47-1.35(m,2H),1.34-1.29(m,3H);ES-LCMS m/z 675.3,677.3[M+H]+.
实施例205:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基亚磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(250mg,0.254mmol)溶于HCl溶液(4.0M在MeOH中,2mL,8.00mmol)且浓缩。然后,将混合物溶于MeOH(3mL)和H2O(1mL),然后添加Oxone(140mg,0.228mmol)。将反应在25℃搅拌4h,然后用饱和Na2SO3溶液(3mL)淬灭。将溶液浓缩且添加饱和NaHCO3水溶液(15mL)。水层用DCM(150mL x2)萃取,且合并的萃取物用盐水(15mL x2)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色油状物的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(230mg,0.228mmol,90.0%产率):1H NMR(400MHz,CDCl3)δppm 8.29(s,2H),7.74-7.69(m,2H),7.43-7.39(m,1H),7.33(s,1H),6.92-6.86(m,1H),3.84(br.s,4H),3.67(s,3H),3.52(s,2H),3.29-3.13(m,1H),2.87-2.84(m,5H),2.65-2.44(m,6H),2.43-2.23(m,4H),2.07(t,J=10.8Hz,2H),1.72(d,J=13.2Hz,3H),1.42-1.29(m,5H);ES-LCMSm/z 353.6,354.5[1/2M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(230mg,0.228mmol)在THF(9mL)和H2O(3mL)中的溶液中添加LiOH·H2O(47.9mg,1.141mmol)。将反应在25℃搅拌0.5h。然后将溶液浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化且冻干干燥以得到灰白色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸(26.41mg,0.037mmol,16.3%产率):1H NMR(400MHz,CD3OD)δppm8.35(s,2H),7.85(d,J=1.5Hz,2H),7.69(s,1H),7.46(s,1H),7.08(s,1H),3.89(t,J=4.8Hz,4H),3.69(s,2H),3.01-2.94(m,5H),2.71(s,3H),2.69-2.53(m,6H),2.35-2.17(m,4H),1.82(d,J=11.5Hz,3H),1.47-1.32(m,5H);ES-LCMS m/z691.2,693.2[M+H]+.
实施例206:2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
将2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4盐酸盐(250mg,0.279mmol)和NaOH(33.5mg,0.836mmol)在MeOH(10mL)和H2O(2mL)中的混合物在25℃搅拌0.5h,然后浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(118.36mg,0.167mmol,59.9%产率):1H NMR(400MHz,CD3OD)δppm 8.46-8.43(m,2H),7.89(s,1H),7.87(d,J=1.8Hz,2H),7.51(t,J=1.9Hz,1H),7.31(s,1H),4.43(s,2H),4.16-4.09(m,4H),3.56(s,2H),3.33(d,J=5.3Hz,4H),3.14(s,2H),2.33(s,2H),2.06(d,J=14.1Hz,3H),1.62(d,J=13.0Hz,2H);ES-LCMS m/z 557.1,559.1[M+H]+.
实施例207:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
步骤1:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4盐酸盐(3,000mg,3.52mmol)和甲酸(0.675mL,17.60mmol)在MeOH(50mL)中的混合物中添加多聚甲醛(528mg,17.60mmol)。溶液在20℃搅拌5h,然后添加NaBH3CN(2,212mg,35.2mmol)。将反应在20℃搅拌1h,然后浓缩且在DCM(100mL)和饱和NaHCO3水溶液(50mL)之间分配。有机萃取物用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(2500mg,3.29mmol,93.0%产率):1H NMR(400MHz,CDCl3)δppm 8.30(s,2H),7.73(d,J=1.5Hz,2H),7.41(s,1H),7.34(d,J=2.0Hz,1H),6.89(s,1H),3.89-3.81(m,4H),3.71-3.64(m,3H),3.52(s,2H),2.86(d,J=11.5Hz,2H),2.52(t,J=5.0Hz,4H),2.36(s,3H),2.30-2.24(m,2H),2.07(t,J=10.8Hz,2H),1.82-1.78(m,1H),1.72(d,J=12.5Hz,2H),1.42-1.30(m,2H);ES-LCMS m/z 585.3,587.3[M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(2.5g,3.29mmol)在THF(30mL)和水(10mL)中的混合物中添加NaOH(0.263g,6.58mmol)。将混合物在50℃搅拌5h。用HCl溶液(水溶液,2M)将混合物pH调节至5-7。将混合物浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(1406.92mg,1.956mmol,59.5%产率):1H NMR(400MHz,CD3OD)δppm8.45(s,2H),7.91-7.84(m,3H),7.51(s,1H),7.30(s,1H),4.95(d,J=14.6Hz,2H),4.43(s,2H),3.60(t,J=11.7Hz,4H),3.35-3.42(m,2H),3.23-3.07(m,4H),2.97(s,3H),2.32(d,J=6.6Hz,2H),2.07(d,J=12.3Hz,3H),1.66-1.53(m,2H);ES-LCMS m/z 571.2,573.2[M+H]+.
实施例208-233(表12)通过类似于实施例207所述的方法制备。
表12
实施例234:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-乙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-乙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(0.5g,0.694mmol)、乙醛(0.037g,0.833mmol)、分子筛(200mg,0.694mmol)和乙酸(0.042g,0.694mmol)在MeOH(5mL)中的混合物在20℃搅拌10min,然后添加NaBH3CN(0.436g,6.94mmol)。将反应在20℃搅拌20min,然后浓缩以得到棕色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-乙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(0.4g,0.428mmol,61.6%产率):1H NMR(400MHz,CDCl3)δppm8.57(s,2H),7.97(s,2H),7.84(s,1H),7.59-7.55(m,2H),3.91(s,2H),3.61(s,3H),3.57-3.55(m,4H),3.37-3.35(m,6H),2.70(s,2H),3.54-3.52(m,2H),2.09-2.06(m,4H),1.77-1.63(m,4H),1.48-1.43(m,2H);ES-LCMS m/z 599.3,601.3[M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-乙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-乙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(0.4g,0.428mmol)在THF(10mL)和H2O(5.00mL)中的溶液中添加LiOH·H2O(0.036g,0.855mmol)。将反应混合物在25℃搅拌6h,然后添加1N HCl以将pH调节至6-7。将混合物浓缩,通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-乙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸(65.5mg,0.112mmol,26.2%产率):1H NMR(400MHz,DMSO-d6)δppm 8.42(s,2H),7.88(s,2H),7.75(s,1H),7.65(s,1H),7.04(s,1H),3.74(br.s,4H),3.56(s,2H),2.82(d,J=11.0Hz,2H),2.43(d,J=4.5Hz,4H),2.38-2.33(m,2H),2.15(d,J=6.0Hz,2H),2.01(t,J=11.3Hz,2H),1.65(d,J=10.0Hz,3H),1.30-1.18(m,2H),1.04(t,J=7.0Hz,3H);ES-LCMS m/z 585.2,587.2[M+H]+.
实施例235:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-异丙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
步骤1:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-异丙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(2g,3.19mmol)、丙-2-酮(0.556g,9.57mmol)、 分子筛(200mg,3.19mmol)和乙酸(0.192g,3.19mmol)的混合物在20℃搅拌10h。然后添加NaBH3CN(2.005g,31.9mmol)且将反应在20℃搅拌4h。将混合物浓缩且在DCM(150mL)和饱和NaHCO3水溶液(30mL)之间分配。有机萃取物用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到棕色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-异丙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(1.2g,1.748mmol,54.8%产率):1H NMR(400MHz,CDCl3)δppm 8.34-8.26(m,2H),7.73(d,J=2.0Hz,2H),7.40(s,1H),7.33(t,J=1.9Hz,1H),6.88(s,1H),3.93-3.83(m,4H),3.66(s,3H),3.51(s,2H),2.85(d,J=11.5Hz,2H),2.75(m,1H),2.67-2.57(m,4H),2.26(d,J=7.1Hz,2H),2.11-2.00(m,2H),1.81(tdd,J=3.9,7.5,14.9Hz,1H),1.76-1.65(m,2H),1.43-1.29(m,2H),1.09(d,J=6.6Hz,6H);ES-LCMS m/z 613.3,615.3[M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-异丙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
将2-(1-((2-(3,5-二氯苯基)-6-((2-(4-异丙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(1.2g,1.748mmol)溶于浓HCl(10mL,122mmol)。将反应在80℃搅拌2h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-异丙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(737.95mg,0.990mmol,56.6%产率):1HNMR(400MHz,CD3OD)δppm8.45(s,2H),7.94(s,1H),7.87(d,J=2.0Hz,2H),7.49(d,J=1.5Hz,1H),7.33(s,1H),4.99(d,J=14.8Hz,2H),4.44(s,2H),3.64-3.56(m,4H),3.49-3.33(m,3H),3.27-3.08(m,4H),2.38-2.25(m,2H),2.05(d,J=12.3Hz,3H),1.71-1.56(m,2H),1.42(d,J=6.6Hz,6H);ES-LCMS m/z 599.2,601.2[M+H]+.
实施例236:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-氟乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-氟乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向K2CO3(294mg,2.126mmol)、1-溴-2-氟乙烷(270mg,2.126mmol)在DMF(50mL)中的混合物中添加2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(500mg,0.709mmol)。将混合物在130℃搅拌16h,然后过滤且浓缩以得到粗产物,其通过硅胶柱色谱法(DCM/MeOH=20/1,Rf=0.5)纯化以得到棕色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-氟乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(400mg,0.473mmol,66.7%产率):1H NMR(400MHz,CD3OD)δppm 8.45(br.s,2H),7.88(br.s,2H),7.49(s,1H),7.21(s,1H),6.71(s,1H),4.43(s,2H),4.18-4.04(m,4H),3.80(s,3H),3.51(br.s,3H),3.16(br.s,4H),2.99(s,2H),2.91-2.81(m,3H),2.48(s,2H),2.35(s,2H),1.66(s,3H);ES-LCMS m/z 617.4,619.3[M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-氟乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-氟乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(395mg,0.467mmol)的溶液添加浓HCl(10mL,122mmol)且在80℃搅拌2h。将混合物浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-氟乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(105.7mg,0.141mmol,30.2%产率):1H NMR(400MHz,CD3OD)δppm 8.46(s,2H),7.90(s,1H),7.87(d,J=2.2Hz,2H),7.51(t,J=1.8Hz,1H),7.31(s,1H),5.00-4.88(m,4H),4.43(s,2H),3.74(br.s,2H),3.68-3.65(m,1H),3.63-3.52(m,4H),3.46(d,J=12.3Hz,3H),3.14(t,J=12.1Hz,2H),2.32(d,J=6.2Hz,2H),2.07(d,J=13.2Hz,3H),1.68-1.58(m,2H);ES-LCMSm/z603.2,605.1[M+H]+.
实施例237:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-氧代丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(600mg,0.850mmol)在MeOH(1mL)中的混合物中添加DIEA(2.97mL,17.01mmol)和丁-3-烯-2-酮(0.64g,9.13mmol)。将反应在80℃搅拌7h,然后浓缩且通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到黄色油状物的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-氧代丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(400mg,0.405mmol,47.7%产率):1H NMR(400MHz,CDCl3)δppm 8.30(s,2H),7.71(s,2H),7.44(br.s,1H),7.34(s,1H),6.91(s,1H),3.86(m,4H),3.67(s,3H),3.57(m,4H),3.00-2.74(m,8H),2.27(m,2H),2.21(s,3H),2.18-2.02(m,2H),1.91-1.71(m,3H),1.50-1.33(m,2H);ES-LCMSm/z 641.4,643.3[M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-氧代丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-氧代丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(400mg,0.405mmol)在水(10mL)和MeOH(10.00mL)中的溶液中添加LiOH·H2O(51.0mg,1.216mmol)。将反应混合物在20℃搅拌0.5h,然后用1N HCl溶液将pH调节至7。将混合物浓缩以得到残余物,将其在DCM(30mL)和H2O(20mL)之间分配,分离,然后水相用DCM(30mL x2)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到棕色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-氧代丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸(290mg,0.397mmol,98.0%产率):1H NMR(400MHz,CD3OD)δppm 8.36-8.26(m,2H),7.81(s,2H),7.67(s,1H),7.43(br.s,1H),7.07(br.s,1H),3.87(br.s,4H),3.78-3.51(m,4H),3.02(d,J=11.0Hz,2H),2.78(s,2H),2.65(br.s,4H),2.29(t,J=11.5Hz,2H),2.22-2.09(m,5H),1.81(m,3H),1.39(m,2H),LC-MS m/z 627.3,629.4[M+H]+.
步骤3:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-氧代丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸(240mg,0.329mmol)在MeOH(10mL)中的溶液中添加NaBH4(12.44mg,0.329mmol)。将反应混合物在20℃搅拌0.5h。添加饱和NH4Cl水溶液(10mL),然后浓缩以得到残余物,将其在DCM(30mL)和H2O(20mL)之间分配,用DCM(30mL x2)萃取。将合并的有机层合并且用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化且冻干以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸(56.61mg,0.090mmol,27.3%产率):1H NMR(400MHz,CD3OD)δppm 8.35(s,2H),7.82(s,2H),7.67(s,1H),7.44(br.s,1H),7.07(s,1H),3.95-3.83(m,5H),3.71(br.s,2H),2.99(d,J=11.0Hz,2H),2.85-2.69(m,6H),2.29-2.18(m,4H),1.85-1.67(m,5H),1.37(d,J=11.0Hz,2H),1.20(d,J=6.2Hz,3H);LC-MS m/z 629.3,631.4[M+H]+.
实施例238:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-羟基丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-羟基丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(2g,2.83mmol)、4-羟基丁-2-酮(3.75g,42.5mmol)和乙酸(0.170g,2.83mmol)在MeOH(20mL)中的混合物中添加分子筛(100mg,2.83mmol)。在30℃搅拌24h后,添加NaBH3CN(1.781g,28.3mmol)且将反应在30℃搅拌20h。将混合物过滤且滤液用DCM(60mL)稀释,用饱和NaHCO3水溶液(50mL)洗涤。有机层用Na2SO4干燥,过滤且浓缩。粗物质经硅胶柱色谱法(DCM/MeOH=1/0至10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.5)发现包含产物的级分合并且浓缩以得到无色油状物的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-羟基丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(2.3g,2.62mmol,92.0%产率):1H NMR(400MHz,CD3OD)δppm 8.37-8.32(m,2H),7.85(d,J=1.5Hz,2H),7.67(s,1H),7.46(s,1H),7.07(s,1H),3.96-3.89(m,4H),3.78-3.71(m,2H),3.68(br s,4H),3.66-3.61(m,3H),2.94(d,J=10.0Hz,2H),2.78(br s,2H),2.71-2.63(m,3H),2.31(d,J=7.0Hz,2H),2.18-2.09(m,2H),1.76(d,J=13.6Hz,3H),1.43-1.33(m,2H),1.10(d,J=6.5Hz,3H);ES-LCMS m/z 643.4,645.4[M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-羟基丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-羟基丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(400mg,0.456mmol)在THF(5mL)和水(1mL)中的溶液中添加LiOH·H2O(76mg,1.822mmol)。将混合物在20℃搅拌48h。用1N HCl将混合物酸化至pH=5-6,然后浓缩。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-羟基丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(237.73mg,0.307mmol,67.3%产率):1H NMR(400MHz,CD3OD)δppm 8.46(s,2H),7.92(s,1H),7.88(s,2H),7.51(s,1H),7.33(s,1H),5.04-4.95(m,2H),4.44(s,2H),3.94-3.80(m,1H),3.78-3.65(m,2H),3.63-3.60(m,3H),3.43-3.34(m,2H),3.28-3.10(m,4H),2.33(d,J=6.4Hz,2H),2.19-2.01(m,4H),1.97-1.76(m,2H),1.71-1.56(m,2H),1.43(d,J=7.2Hz,2H),1.26(d,J=6.0Hz,1H);ES-LCMS m/z 629.3,631.4[M+H]+.
实施例239:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(甲基氨基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-((甲基磺酰基)氧基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-羟基丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(400mg,0.456mmol)在DCM(15mL)中的混合物中添加DIEA(0.095mL,0.547mmol)。然后添加MsCl(0.177mL,2.278mmol)且将反应在0℃在N2气氛搅拌5分钟。添加饱和NaHCO3水溶液(150mL)且水层用DCM(150mL x2)萃取。合并的萃取物用盐水(150mL x2)洗涤,用Na2SO4干燥,过滤且浓缩以得到黄色油状物的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-((甲基磺酰基)氧基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(400mg,0.333mmol,73.0%产率):1H NMR(400MHz,CDCl3)δppm8.42-8.29(m,2H),8.01(d,J=15.1Hz,1H),7.91-7.77(m,2H),7.37(br.s,2H),5.04-4.88(m,2H),4.58-4.20(m,4H),3.67(d,J=5.0Hz,3H),3.59(m 4H),3.49(s,2H),3.14-3.07(m,4H),3.06-3.01(m,4H),2.35(m,2H),1.77(m,3H),1.39-1.28(m,2H),1.23(d,J=7.0Hz,3H);ES-LCMS m/z 721.3,723.3[M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(甲基氨基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-((甲基磺酰基)氧基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(400mg,0.333mmol)在DCM(15mL)中的溶液中添加甲胺(30%的乙醇溶液,466mg,1.995mmol)。将反应在15℃在N2气氛搅拌15分钟,然后浓缩以得到黄色油状物的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(甲基氨基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(350mg,0.251mmol,75.0%产率):1H NMR(400MHz,CDCl3)δppm 8.31(s,2H),7.73(s,1H),7.46(br.s,2H),7.24-7.18(m,2H),3.67(s,3H),3.59(s,2H),3.17(d,J=9.5Hz,6H),3.09-3.08(m,2H),2.45-2.41(m,6H),2.28(m,6H),2.21-2.17(m,2H),1.92(m,3H),1.39-1.28(m,2H),1.13(m,3H);ES-LCMSm/z 656.4,658.4[M+H]+.
步骤3:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(甲基氨基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(甲基氨基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(350mg,0.251mmol)在THF(5mL)和水(1mL)中的溶液中添加LiOH·H2O(105mg,2.505mmol)。将反应在25℃搅拌0.5h,然后浓缩且通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化且冻干干燥以得到黄色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(甲基氨基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸(63.36mg,0.096mmol,38.4%产率):1H NMR(400MHz,CD3OD)δppm 8.30(s,2H),7.79(d,J=1.8Hz,2H),7.62(s,1H),7.41(t,J=1.8Hz,1H),7.00(s,1H),4.60(br.s,2H),3.91-3.77(m,4H),3.59(s,2H),3.22-3.06(m,2H),2.90(d,J=10.1Hz,3H),2.77-2.71(m,5H),2.63-2.50(m,2H),2.13(s,2H),2.02-1.89(m,1H),1.77(d,J=9.7Hz,3H),1.69-1.58(m,1H),1.39-1.28(m,2H),1.06(d,J=6.6Hz,3H);ES-LCMS m/z642.3,644.3[M+H]+.
实施例240:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(二甲基氨基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
实施例240通过类似于实施例239所述的方法制备。使用二甲基胺替代甲基胺且与哌嗪中间体反应生成最终目标,具有良好产率:1H NMR(400MHz,D2O)δppm 8.33(s,2H),7.49(s,1H),7.42(d,J=1.0Hz,2H),7.20(s,1H),7.06(s,1H),4.27(s,2H),3.56-3.42(m,5H),3.37-3.14(m,7H),3.01(t,J=12.3Hz,2H),2.84(s,6H),2.77(d,J=5.0Hz,1H),2.33-2.20(m,3H),2.08-1.88(m,4H),1.52-1.36(m,2H),1.32(d,J=6.5Hz,3H);ES-LCMS m/z 656.3,658.4[M+H]+.
实施例241:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-((甲基氨基甲酰基)氧基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
在-78℃向2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(1g,1.557mmol)在MeOH(40mL)中的溶液中添加氧杂环丙烷(0.274g,6.23mmol)和DIEA(1.632mL,9.34mmol)。将混合物在20℃搅拌8h,然后浓缩。粗产物通过硅胶柱色谱法(PE/EtOAc=3/1)纯化。将所有通过TLC(PE/EtOAc=3/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到淡黄色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(0.3g,0.434mmol,27.9%产率):1H NMR(400MHz,CD3OD)δppm 8.30(s,2H),7.78(s,2H),7.60(s,1H),7.40(s,1H),7.00(s,1H),3.89-3.81(m,4H),3.73(t,J=6.0Hz,2H),3.67-3.61(m,3H),3.57(s,2H),2.89(d,J=11.5Hz,2H),2.66-2.54(m,6H),2.27(d,J=7.1Hz,2H),2.09(t,J=11.2Hz,2H),1.82-1.68(m,3H),1.42-1.26(m,3H);ES-LCMS m/z 615.0,617.0[M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-((甲基氨基甲酰基)氧基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(0.3g,0.434mmol)在DCM(20mL)中的混合物中添加DIEA(0.227mL,1.301mmol)和CDI(0.141g,0.868mmol)。将反应在25℃搅拌5h,然后添加甲胺(30%的乙醇溶液,0.898g,8.68mmol)。将反应在25℃再搅拌2h,然后浓缩且通过硅胶柱色谱法(DCM/MeOH=10/1)纯化。将所有通过TLC(DCM/MeOH=10/1,Rf=0.6)发现包含产物的级分合并且浓缩以得到黄色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-((甲基氨基甲酰基)氧基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(0.2g,0.274mmol,63.1%产率):1H NMR(400MHz,CD3OD)δppm 8.31(s,2H),7.80(d,J=1.8Hz,2H),7.62(s,1H),7.42(s,1H),7.02(s,1H),4.26-4.18(m,2H),3.90-3.81(m,4H),3.65(s,3H),3.63(s,2H),2.96-2.87(m,2H),2.76-2.65(m,5H),2.65-2.53(m,4H),2.27(d,J=6.6Hz,2H),2.11(t,J=11.0Hz,2H),1.86-1.69(m,3H),1.39-1.33(m,2H);ES-LCMS m/z672.0,674.0[M+H]+.
步骤3:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-((甲基氨基甲酰基)氧基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-((甲基氨基甲酰基)氧基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(190mg,0.260mmol)在THF(5mL)和水(5mL)中的混合物中添加LiOH·H2O(32.7mg,0.780mmol)。将混合物在20℃搅拌4h,然后浓缩。粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-((甲基氨基甲酰基)氧基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(190.29mg,0.233mmol,90.0%产率):1H NMR(400MHz,CD3OD)δppm 8.31(s,2H),7.80(d,J=1.8Hz,2H),7.62(s,1H),7.42(s,1H),7.02(s,1H),4.26-4.18(m,2H),3.90-3.81(m,4H),3.65(s,3H),3.63(s,2H),2.96-2.87(m,2H),2.76-2.65(m,5H),2.64-2.53(m,4H),2.27(d,J=6.6Hz,2H),2.11(t,J=11.0Hz,2H),1.86-1.69(m,3H),1.39-1.33(m,2H);ES-LCMS m/z672.0,674.0[M+H]+.
实施例242:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
步骤1:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4盐酸盐(5g,5.55mmol)、甲磺酸3-(甲基磺酰基)丙基酯(4.50g,16.65mmol)和DIEA(5.82mL,33.3mmol)在MeCN(100mL)中的混合物在N2气氛加热至40℃保持10h。将反应浓缩以得到粗产物,其通过硅胶柱色谱法(MeOH/DCM=1/19)纯化。将所有通过TLC(DCM/MeOH=20/1,Rf=0.4)发现包含产物的级分合并且浓缩以得到黄色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(4.5g,4.92mmol,89.0%产率):1H NMR(400MHz,CDCl3)δppm 8.32-8.24(m,2H),7.75(br.s,2H),7.67(d,J=1.8Hz,1H),7.32(br.s,1H),7.04(br.s,1H),3.96(br.s,3H),3.45(s,3H),3.22-3.17(m,5H),3.04(s,4H),2.75(s,8H),2.36-2.26(m,6H),2.21(br.s,2H),1.77(br.s,2H);ES-LCMS m/z 691.3,693.3[M+H]+.
步骤2:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
将2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(4.5g,4.92mmol)和LiOH·H2O(1.033g,24.61mmol)在THF(30mL)和H2O(5mL)中的混合物在25℃搅拌2h。将反应浓缩以得到粗产物,然后通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化。将级分合并且用1NHCl溶液将pH调节至2,然后冻干干燥以得到粉色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(1790.91mg,2.169mmol,44.1%产率):1H NMR(400MHz,CD3OD)δppm8.46(s,2H),7.89-7.78(m,3H),7.50(t,J=1.9Hz,1H),7.32(s,1H),5.01-4.87(m,2H),4.49-4.38(m,2H),3.73(br s,1H),3.57(d,J=11.9Hz,3H),3.47-3.37(m,4H),3.36-3.32(m,3H),3.27-3.11(m,3H),3.08(s,3H),2.42-2.30(m,4H),2.06(d,J=14.8Hz,3H),1.68-1.55(m,2H);ES-LCMS m/z 677.3,679.3[M+H]+.
实施例243-280(表13)通过类似于实施例242所述的方法制备。
表13
实施例281:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丁酸,4盐酸盐
步骤1:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丁酸乙酯
向N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(200mg,0.252mmol)和(E)-乙基丁-2-烯酸酯(862mg,7.55mmol)的混合物中添加DIEA(220μl,1.258mmol)。将反应混合物在150℃在微波下搅拌2h,然后浓缩以得到棕色油状物的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丁酸乙酯(200mg,0.205mmol,81.0%产率):1H NMR(400MHz,CD3OD)δppm 8.12-8.01(m,1H),7.74-7.60(m,2H),7.44-7.30(m,2H),7.27(s,1H),6.96-6.83(m,2H),4.15-4.09(m,4H),3.79-3.51(m,5H),3.46(d,J=5.7Hz,4H),3.10(t,J=6.0Hz,2H),2.83(d,J=10.1Hz,2H),2.67-2.51(m,3H),1.99-1.90(m,5H),1.62(d,J=11.9Hz,2H),1.48(br.s,1H),1.25-1.20(m,8H);ES-LCMS m/z 683.3,685.3[M+H]+.
步骤2:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丁酸,4盐酸盐
向3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丁酸乙酯(200mg,0.205mmol)在THF(5mL)和水(3mL)中的悬浮液中添加LiOH·H2O(25.8mg,0.614mmol)。将反应混合物在20℃搅拌3h,然后用1NHCl将pH调节至5且浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丁酸,4盐酸盐(23.26mg,0.028mmol,13.7%产率):1H NMR(400MHz,CD3OD)δppm 8.20(br.s,1H),8.04(br.s,1H),7.96(br.s,1H),7.88(d,J=1.3Hz,2H),7.51(s,1H),7.46(d,J=9.3Hz,1H),7.37(br.s,1H),4.45(s,2H),3.92(d,J=4.4Hz,2H),3.83-3.31(m,10H),3.20-2.98(m,4H),2.78(dd,J=8.4,17.2Hz,1H),2.11-1.91(m,5H),1.85(br.s,1H),1.75-1.41(m,5H);ES-LCMSm/z655.3,657.3[M+H]+.
实施例282-297(表14)通过类似于实施例281所述的方法制备。
表14
实施例298:(R)-2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
步骤1:(R)-2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4盐酸盐(0.3g,0.335mmol)和DIEA(0.234mL,1.338mmol)在MeOH(4mL)中的溶液中添加(R)-2-甲基氧杂环丙烷(0.039g,0.669mmol)。将反应混合物在25℃搅拌8h,然后浓缩以得到棕色固体的(R)-2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(0.25g,0.291mmol,87.0%产率):1H NMR(400MHz,CDCl3)δppm8.36-8.26(m,2H),7.77-7.68(m,2H),7.46(br.s,1H),7.32(s,1H),6.92(s,1H),3.68-3.63(m,6H),3.11-3.05(m,4H),2.90(d,J=10.6Hz,4H),2.70-2.47(m,6H),2.16-2.05(m,3H),1.54(s,5H),1.17(d,J=6.2Hz,2H);ES-LCMS m/z 629.2,631.2[M+H]+.
步骤2:(R)-2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
向(R)-2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(0.25g,0.291mmol)在THF(10mL)和H2O(10.00mL)中的溶液中添加LiOH·H2O(0.021g,0.872mmol)。将反应混合物在30℃搅拌6h,然后浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到白色固体的(R)-2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(117.52mg,0.154mmol,53.0%产率):1H NMR(400MHz,CD3OD)δppm 8.47-8.44(m,2H),7.93(s,1H),7.87(d,J=1.8Hz,2H),7.49(t,J=1.9Hz,1H),7.33(s,1H),4.80(m,2H),4.43(s,2H),4.35-4.17(m,1H),3.72(t,J=13.0Hz,2H),3.61-3.44(m,4H),3.27-3.07(m,6H),2.32(d,J=6.6Hz,2H),2.19-1.97(m,3H),1.71-1.58(m,2H),1.25(d,J=6.2Hz,3H);ES-LCMS m/z 615.2;617.2[M+H]+.
实施例299-317(表15)通过类似于实施例298所述的方法制备。
表15
实施例318:((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)硼酸,4盐酸盐
步骤1:4-(二溴亚甲基)哌啶-1-甲酸叔丁酯
在0℃向4-氧代哌啶-1-甲酸叔丁酯(30g,151mmol)和PPh3(79g,301mmol)在DCM(800mL)中的混合物中添加CBr4(100g,301mmol),将反应混合物在0℃在N2气氛搅拌1h,然后在20℃在N2气氛搅拌12h。将混合物过滤且浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=10/1,TLC:PE/EtOAc=5/1,Rf=0.7)纯化以得到4-(二溴亚甲基)哌啶-1-甲酸叔丁酯(10g,25.9mmol,17.2%产率),其为白色固体:1H NMR(400MHz,CD3OD)δppm 3.43(t,J=5.7Hz,4H),2.52-2.46(m,4H),1.47-1.43(m,9H);ES-LCMS m/z 299.9,301.9[M-t-Bu+H]+.
步骤2:4-(溴亚甲基)哌啶-1-甲酸叔丁酯
在0℃在N2气氛,将4-(二溴亚甲基)哌啶-1-甲酸叔丁酯(9.5g,24.62mmol)和氯化铵(10.53g,197mmol)在MeOH(200mL)和THF(100mL)中的混合物搅拌1h,添加Zn(6.44g,98mmol),将反应混合物在20℃在N2气氛搅拌12h。将混合物过滤且浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=10/1,TLC:PE/EtOAc=5/1,Rf=0.65)纯化以得到4-(溴亚甲基)哌啶-1-甲酸叔丁酯(6g,19.77mmol,80.0%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 6.12(s,1H),3.45-3.39(m,4H),2.40-2.36(m,2H),2.27-2.24(m,2H),1.45(s,9H);ES-LCMSm/z 220.1,222.1[M-t-Bu+H]+.
步骤3:4-((4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)亚甲基)哌啶-1-甲酸叔丁酯
将4-(溴亚甲基)哌啶-1-甲酸叔丁酯(4g,13.18mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷)(6.69g,26.4mmol)、Ph3P(0.346g,1.318mmol)、Pd2(dba)3(1.207g,1.318mmol)和KOAc(3.88g,39.5mmol)在甲苯(120mL)中的混合物在110℃在N2气氛搅拌12h。将混合物过滤且浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=8/1,TLC:PE/EtOAc=5/1,Rf=0.6)纯化以得到4-((4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)亚甲基)哌啶-1-甲酸叔丁酯(3g,7.05mmol,53.5%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 5.09(s,1H),3.48-3.37(m,4H),2.63-2.56(m,2H),2.24(t,J=5.4Hz,2H),1.45(s,9H),1.23(s,12H);ES-LCMS m/z 224.1[M-Boc+H]+.
步骤4:4-((4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)甲基)哌啶-1-甲酸叔丁酯
向4-((4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)亚甲基)哌啶-1-甲酸叔丁酯(2.9g,6.82mmol)在MeOH(40mL)中的混合物中添加Pd/C(10wt%,1.5g,1.41mmol)。将混合物在20℃在H2气氛(15psi)搅拌15分钟。将固体过滤掉且将溶剂浓缩以得到粗产物4-((4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)甲基)哌啶-1-甲酸叔丁酯(2.5g,5.76mmol,85.0%产率),其为淡黄色油状物:1H NMR(400MHz,CD3OD)δppm 2.84-2.61(m,4H),1.71-1.52(m,4H),1.43(s,9H),1.22(s,12H),1.12-1.06(m,1H),0.71(d,J=6.6Hz,2H);ES-LCMS m/z 226.1[M-Boc+H]+.
步骤5:4-((4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)甲基)哌啶,三氟乙酸盐
将4-((4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)甲基)哌啶-1-甲酸叔丁酯(2.4g,5.53mmol)溶于TFA(4mL,51.9mmoL)和DCM(16mL)。将混合物在20℃搅拌1h。将反应混合物浓缩以得到4-((4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)甲基)哌啶,三氟乙酸盐(2.3g,4.75mmol,86.0%产率),其为淡黄色油状物:1H NMR(400MHz,CD3OD)δppm2.99-2.91(m,2H),2.84-2.60(m,2H),1.93(d,J=14.1Hz,2H),1.78(m,J=3.7,7.3,11.1Hz,1H),1.44-1.32(m,2H),1.22-1.18(m,12H),0.79(d,J=7.1Hz,2H);ES-LCMS m/z226.1[M+H]+.
步骤6:5-((6-(3,5-二氯苯基)-4-((4-((4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶
向甲磺酸(2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基酯(150mg,0.257mmol)和4-((4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)甲基)哌啶,三氟乙酸盐(499mg,1.030mmol)在DMF(10mL)中的溶液中添加DIEA(0.450mL,2.57mmol)。然后将反应混合物在40℃搅拌12h。溶剂浓缩以得到粗产物。粗物质通过快速色谱法(DCM/MeOH=50/1至10/1,TLC:DCM/MeOH=10/1,Rf=0.7)纯化以得到5-((6-(3,5-二氯苯基)-4-((4-((4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶(160mg,0.171mmol,66.6%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 8.40(s,2H),7.96(s,2H),7.82(d,J=2.0Hz,1H),7.47(br s,1H),7.15(br s,1H),4.59(br s,2H),3.73-3.67(m,4H),3.33(s,3H),3.24-3.20(m,4H),2.99-2.86(m,4H),1.98-1.95(m,2H),1.81-1.78(m,1H),1.55-1.50(m,2H),1.20(d,J=18.3Hz,12H),0.79(d,J=7.1Hz,2H);LCMSm/z 653.0,655.0[M+H]+.
步骤7:((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)硼酸,4盐酸盐
将5-((6-(3,5-二氯苯基)-4-((4-((4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶(150mg,0.161mmol)在HCl(12N,3mL,36mmol)和水(3mL)中的混合物在80℃搅拌20min。将溶剂浓缩以得到粗产物。粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)硼酸,4盐酸盐(74.37mg,0.103mmol,63.9%产率),其为白色固体:1HNMR(400MHz,CD3OD)δppm 8.44(s,2H),7.87(s,1H),7.88-7.86(m,1H),7.85(d,J=1.8Hz,2H),7.50(t,J=1.9Hz,1H),7.28(s,1H),4.93(d,J=14.3Hz,2H),4.39(s,2H),3.60(d,J=12.1Hz,2H),3.52(d,J=12.6Hz,2H),3.34(br s,2H),3.21-3.14(m,2H),3.11-3.04(m,2H),2.95(s,3H),2.00(d,J=14.6Hz,2H),1.81(br s,1H),1.55-1.47(m,2H),0.83(d,J=6.8Hz,2H);LCMS m/z 571.0,572.9[M+H]+.
实施例319:(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)乙基)硼酸,4盐酸盐
步骤1:(2-溴乙基)硼酸
在-78℃在N2气氛向1,2-二溴乙烷(8g,42.6mmol)在THF(100mL)中的溶液中滴加n-BuLi(2.5M在己烷中)(18.74mL,46.8mmol)。将反应混合物在-78℃搅拌1h。然后添加硼酸三甲酯(11.06g,106mmol)。将反应混合物在25℃搅拌12h。然后添加HCl(4M的EtOAc溶液)(5mL,20.00mmol)。然后将混合物浓缩以得到(2-溴乙基)硼酸(18g,35.3mmol,83.0%产率),其为白色固体:1H NMR(400MHz,CD3OD)δppm 3.48(t,J=6.7Hz,2H),1.71-1.65(m,2H)。
步骤2:(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)乙基)硼酸,4盐酸盐
向N-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4三氟乙酸盐(400mg,0.381mmol)和DIEA(0.684mL,3.81mmol)在DMF(30mL)中的混合物中添加(2-溴乙基)硼酸(1941mg,3.81mmol)。然后,将混合物在25℃搅拌24h。该反应用DCM(20mL)和水(20mL)稀释。将混合物用DCM(50mL×3)萃取。合并的有机层浓缩。粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化且冻干干燥以得到(粗产物:14.55mg),其为白色固体。粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)乙基)硼酸,4盐酸盐(8.68mg,10.49μmol,2.7%产率),其为白色固体:1H NMR(400MHz,CD3OD)δppm 8.47(s,2H),7.92(s,1H),7.88(d,J=1.8Hz,2H),7.52(t,J=1.8Hz,1H),7.32(s,1H),4.99-4.95(m,2H),4.44(s,2H),3.74-3.54(m,6H),3.43-3.35(m,2H),3.26-3.18(m,2H),3.16-3.08(m,4H),2.03-1.98(m,2H),1.96(s,3H),1.94-1.84(m,2H),1.66(d,J=7.3Hz,1H),1.63-1.47(m,2H);ES-LCMSm/z 642.3,644.3[M+H]+.
实施例320:((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)二甲基氧化膦,4盐酸盐
向甲磺酸(2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基酯(100mg,0.172mmol)和DIEA(111mg,0.858mmol)在DMF(3mL)中的溶液中添加二甲基(哌啶-4-基甲基)氧化膦(90mg,0.308mmol)。然后将反应混合物在25℃搅拌30h。将反应混合物浓缩以得到粗产物。粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)二甲基氧化膦,4盐酸盐(28.2mg,0.037mmol,21.7%产率):1H NMR(400MHz,CD3OD)δppm 8.51(s,2H),8.01(s,1H),7.88(d,J=1.8Hz,2H),7.47(t,J=1.9Hz,1H),7.38(s,1H),4.89(br s,2H),4.46(s,2H),3.63(d,J=12.6Hz,2H),3.57(d,J=11.7Hz,2H),3.49-3.43(m,2H),3.24-3.16(m,4H),2.96(s,3H),2.21-2.13(m,3H),1.95(br s,2H),1.81(d,J=11.9Hz,2H),1.65(d,J=12.8Hz,6H);ES-LCMS m/z 603.2,605.2[M+H]+.
实施例321-329(表16)通过类似于实施例320所述的方法制备。
表16
实施例330:(S)-(4-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-1,4-氧氮杂环庚烷-7-基)甲醇,4盐酸盐
步骤1:(S)-4-(苄基氨基)-2-羟基丁酸
在25℃向(S)-4-氨基-2-羟基丁酸(13.5g,113mmol)、NaOH(4.85g,121mmol)在水(120mL)中的溶液中添加苯甲醛(12.26mL,121mmol)。然后将混合物在25℃搅拌30min。将混合物冷却至0℃且经30min添加NaBH4(2.92g,77mmol)。将混合物在25℃搅拌11h。将混合物用EtOAc(100mL)洗涤。水相用12M HCl溶液酸化至pH=6且收集固体且干燥以得到(S)-4-(苄基氨基)-2-羟基丁酸(23g,33.0mmol,29.1%产率),其为白色固体:1H NMR(400MHz,CD3OD)δppm 7.40-7.20(m,5H),4.01-3.91(m,1H),3.82-3.72(m,2H),2.90-2.71(m,2H),2.08-1.94(m,1H),1.89-1.75(m,1H);ES-LCMS m/z 210.2[M+H]+.
步骤2:(S)-4-苄基-3-氧代-1,4-氧氮杂环庚烷-7-甲酸
在0℃向(S)-4-(苄基氨基)-2-羟基丁酸(23g,33.0mmol)、NaOH(14g,350mmol)在水(150mL)中的溶液中滴加2-氯乙酰氯(11.2mL,141mmol)。然后将混合物在25℃搅拌12h。反应混合物用DCM(15mL x2)萃取,水相用12M HCl溶液酸化至pH=3。将固体过滤且干燥以得到浅色油状物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干以得到(S)-4-苄基-3-氧代-1,4-氧氮杂环庚烷-7-甲酸(7g,27.1mmol,82.0%产率),其为无色油状物:1H NMR(400MHz,CD3OD)δppm 7.40-7.21(m,5H),4.61(d,J=2.4Hz,2H),4.52-4.36(m,2H),4.29(dd,J=4.6,9.5Hz,1H),3.64-3.44(m,2H),2.32-2.18(m,1H),2.05-1.92(m,1H);ES-LCMS m/z 250.3[M+H]+.
步骤3:(S)-4-苄基-3-氧代-1,4-氧氮杂环庚烷-7-甲酸甲酯
在0℃向(S)-4-苄基-3-氧代-1,4-氧氮杂环庚烷-7-甲酸(950mg,3.68mmol)在MeOH(15mL)中的溶液中滴加SOCl2(0.8mL,10.96mmol)。然后将混合物在30℃搅拌12h。将混合物浓缩以得到(S)-4-苄基-3-氧代-1,4-氧氮杂环庚烷-7-甲酸甲酯(910mg,3.05mmol,83.0%产率),其为淡黄色油状物:1H NMR(400MHz,CDCl3)δppm 7.36-7.24(m,5H),4.70-4.57(m,2H),4.57-4.43(m,1H),4.37-4.29(m,1H),4.27-4.17(m,1H),3.76(s,3H),3.52-3.35(m,2H),2.28-2.06(m,2H);ES-LCMS m/z 264.0[M+H]+.
步骤4:(S)-(4-苄基-1,4-氧氮杂环庚烷-7-基)甲醇
在0℃下,向(S)-4-苄基-3-氧代-1,4-氧氮杂环庚烷-7-甲酸甲酯(700mg,2.348mmol)在THF(30mL)中的溶液中分批添加LAH(267mg,7.04mmol)。然后将混合物在25℃搅拌12h。混合物在0℃依次通过H2O(0.267mL)、10%NaOH水溶液(0.267mL)淬灭。然后将混合物过滤且将滤液浓缩以得到(S)-(4-苄基-1,4-氧氮杂环庚烷-7-基)甲醇(450mg,1.220mmol,52.0%产率),其为无色油状物:1H NMR(400MHz,CDCl3)δppm 7.39-7.24(m,5H),3.90(m,1H),3.76-3.57(m,4H),3.54-3.40(m,2H),2.78-2.60(m,4H),1.89-1.81(m,1H),1.70-1.58(m,1H);ES-LCMS m/z 222.2[M+H]+.
步骤5:(S)-(1,4-氧氮杂环庚烷-7-基)甲醇
在N2气氛向(S)-(4-苄基-1,4-氧氮杂环庚烷-7-基)甲醇(350mg,0.949mmol)在MeOH(15mL)中的溶液中添加Pd/C(10wt%,101mg,0.095mmol)。然后将混合物在25℃在H2气氛(50psi)搅拌12h。然后将混合物过滤且将滤液浓缩以得到(S)-(1,4-氧氮杂环庚烷-7-基)甲醇(150mg,0.686mmol,72.3%产率),其为无色油状物:1H NMR(400MHz,CD3OD)δppm3.95(d,J=13.1Hz,1H),3.78-3.58(m,2H),3.54-3.41(m,2H),3.06-2.75(m,4H),1.97-1.84(m,1H),1.72-1.58(m,1H)。
步骤6:(S)-4-(5-((6-(3,5-二氯苯基)-4-((7-(羟基甲基)-1,4-氧氮杂环庚烷-4-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(600mg,0.885mmol)和(S)-(1,4-氧氮杂环庚烷-7-基)甲醇(150mg,0.686mmol)在DMF(10mL)中的溶液中添加DIEA(0.630mL,3.54mmol)。然后将混合物在50℃搅拌3h。然后将混合物浓缩以得到残余物。残余物通过快速色谱法(DCM/MeOH=100/1至20/1,TLC:DCM/MeOH=10/1,Rf=0.6)纯化以得到(S)-4-(5-((6-(3,5-二氯苯基)-4-((7-(羟基甲基)-1,4-氧氮杂环庚烷-4-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(450mg,0.686mmol,78.0%产率),其为黄色油状物:1H NMR(400MHz,CD3OD)δppm8.34(s,2H),7.82(s,2H),7.67(s,1H),7.44(d,J=1.6Hz,1H),7.09(s,1H),3.96-3.78(m,9H),3.53-3.45(m,6H),2.77-2.75(m,4H),1.94-1.93(m,1H),1.78-1.76(m,1H),1.49(s,9H);ES-LCMS m/z 645.3,647.3[M+H]+.
步骤7:(S)-(4-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-1,4-氧氮杂环庚烷-7-基)甲醇,4三氟乙酸盐
向(S)-4-(5-((6-(3,5-二氯苯基)-4-((7-(羟基甲基)-1,4-氧氮杂环庚烷-4-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(450mg,0.686mmol)在DCM(8mL)中的溶液中添加TFA(2mL,26.0mmol),然后将混合物在25℃搅拌0.5h。然后将混合物浓缩以得到(S)-(4-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-1,4-氧氮杂环庚烷-7-基)甲醇,4三氟乙酸盐(500mg,0.639mmol,93.0%产率),其为淡黄色油状物。1H NMR(400MHz,CD3OD)δppm 8.45(s,2H),7.85(d,J=1.8Hz,3H),7.52(t,J=1.8Hz,1H),7.30(s,1H),4.61-4.48(m,3H),4.20-4.06(m,6H),3.95-3.82(m,2H),3.67(br.s,1H),3.61-3.51(m,3H),3.47(br.s,2H),3.35(br.s,2H),2.22(d,J=19.0Hz,2H);ES-LCMS m/z 545.2,547.2[M+H]+.
步骤8:(S)-(4-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-1,4-氧氮杂环庚烷-7-基)甲醇,4盐酸盐
将多聚甲醛(253mg,8.42mmol)、(S)-(4-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-1,4-氧氮杂环庚烷-7-基)甲醇,4三氟乙酸盐(500mg,0.421mmol)在MeOH(10mL)中的混合物在25℃搅拌10h。然后将NaBH3CN(79mg,1.263mmol)添加至上述混合物且搅拌2h。然后添加饱和NaHCO3水溶液(20mL)。将混合物用DCM(50mL×3)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到残余物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干以得到(S)-(4-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-1,4-氧氮杂环庚烷-7-基)甲醇,4盐酸盐(93.32mg,0.132mmol,31.4%产率),其为白色固体:1HNMR(400MHz,CD3OD)δppm 8.46(s,2H),7.97(d,J=7.3Hz,1H),7.88(d,J=1.1Hz,2H),7.51(t,J=1.8Hz,1H),7.36(s,1H),4.97(br.s,2H),4.55(d,J=5.5Hz,2H),4.22-4.03(m,1H),3.98-3.84(m,2H),3.75-3.47(m,8H),3.41-3.35(m,2H),3.24-3.13(m,2H),2.97(s,3H),2.52-2.10(m,2H);ES-LCMSm/z 559.3,561.2[M+H]+.
1H NMR(400MHz,CD3OD+Na2CO3)δppm 8.32(s,2H),7.81(d,J=1.8Hz,2H),7.66(s,1H),7.43(t,J=1.8Hz,1H),7.08(s,1H),3.99-3.80(m,6H),3.77(s,2H),3.69(d,J=5.0,13.0Hz,1H),3.55-3.39(m,2H),2.88-2.64(m,4H),2.54(t,J=5.0Hz,4H),2.35(s,3H),2.02-1.90(m,1H),1.82-1.70(m,1H)。
实施例331:(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)二甲基氧化膦,4盐酸盐
向甲磺酸(2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基酯(100mg,0.172mmol)和二甲基(哌啶-4-基)氧化膦(70mg,0.304mmol)在DMF(20mL)中的溶液中添加DIEA(111mg,0.858mmol)。将混合物在40℃搅拌5h。将反应混合物浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干干燥以得到白色固体的(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)二甲基氧化膦,4盐酸盐(23.31mg,0.031mmol,18.3%产率):1HNMR(400MHz,CD3OD)δppm 8.46(s,2H),7.97(s,1H),7.87(d,J=1.8Hz,2H),7.49-7.46(m,1H),7.35(s,1H),4.93(br s,2H),4.48(s,2H),3.68(d,J=12.1Hz,2H),3.61(d,J=12.1Hz,2H),3.43-3.36(m,2H),3.23-3.14(m,4H),2.95(s,3H),2.16(br s,3H),2.01(d,J=6.6Hz,2H),1.56(d,J=12.8Hz,6H);ES-LCMS m/z 589.3,591.2[M+H]+.
实施例332:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
步骤1:(2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲醇
在-40℃向2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氨基)异烟酸甲酯(100mg,0.190mmol)在THF(8mL)中的溶液中分批添加LiAlH4(10.81mg,0.285mmol)。然后将反应混合物在-40℃搅拌20min。在-10℃反应混合物通过添加水(0.1mL)和1N NaOH水溶液(0.1mL)淬灭,然后添加MgSO4(500mg)。将混合物过滤且浓缩。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=20/1,TLC:DCM/MeOH=20/1,Rf=0.45)纯化以得到(2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲醇(80mg,0.177mmol,93.0%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 9.04(s,2H),7.92(d,J=2.0Hz,2H),7.45(t,J=1.9Hz,1H),7.28(s,1H),6.85(d,J=0.9Hz,1H),4.64(s,2H),2.56(s,3H);ES-LCMSm/z393.0,395.0[M+H]+.
步骤2:甲磺酸(2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲基酯
在0℃向(2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲醇(80mg,0.177mmol)和DIEA(0.093mL,0.531mmol)在DCM(5.00mL)中的溶液中添加MsCl(0.018mL,0.230mmol)。然后将反应混合物在0℃搅拌10min。添加水(20mL)且用DCM(15mLx2)萃取。合并的有机层用Na2SO4干燥且浓缩以得到黄色固体的甲磺酸(2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲基酯(110mg,0.161mmol,91.0%产率):1HNMR(400MHz,CDCl3)δppm 8.94(s,2H),7.81(s,2H),7.40-7.40(m,1H),7.14(s,1H),6.85(s,1H),4.52(s,2H),3.11(s,3H),2.60(s,3H);LCMSm/z471.1,473.1[M+H]+.
步骤3:2-(1-((2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向甲磺酸(2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲基酯(110mg,0.161mmol)和2-(哌啶-4-基)乙酸甲酯(36.6mg,0.209mmol)在DMF(8mL)中的溶液中添加DIEA(0.141mL,0.805mmol)。然后将反应混合物在20℃搅拌12h。溶剂浓缩以得到粗产物。粗物质通过快速色谱法(从DCM/MeOH=20/1至10/1,TLC:DCM/MeOH=10/1,Rf=0.65)纯化以得到淡黄色固体的2-(1-((2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(85mg,0.144mmol,89.0%产率):1H NMR(400MHz,CD3OD)δppm 9.02(s,2H),7.91(d,J=1.8Hz,2H),7.45-7.43(m,1H),7.31(s,1H),6.79(s,1H),3.66-3.61(m,5H),2.56(s,3H),2.27(s,2H),2.19-2.11(m,2H),1.83-1.79(m,1H),1.75(br s,2H),1.42-1.34(m,2H),1.21(s,2H);LCMS m/z 532.1,534.1[M+H]+.
步骤4:2-(1-((2-(3,5-二氯苯基)-6-((2-(甲基磺酰基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(85mg,0.144mmol)在MeOH(10mL)中的溶液中添加Oxone(79mg,0.129mmol)。然后将混合物在25℃搅拌12h。将固体过滤掉且添加饱和Na2SO3水溶液(15mL)且用DCM(15mL×3)萃取。将合并的有机层合并,用Na2SO4干燥,过滤且真空浓缩以得到粗产物。粗物质通过快速色谱法(从DCM/MeOH=20/1至10/1,TLC:DCM/MeOH=10/1,Rf=0.55)纯化以得到2-(1-((2-(3,5-二氯苯基)-6-((2-(甲基磺酰基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(80mg,0.099mmol,69.1%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 9.38(s,2H),7.92(d,J=1.8Hz,2H),7.45-7.44(m,1H),7.42(s,1H),6.90(s,1H),5.47(s,2H),3.63(s,3H),2.96-2.95(m,3H),2.90(br s,2H),2.27(s,2H),2.14(br s,2H),1.81(d,J=4.2Hz,1H),1.74(br s,2H),1.38(br s,2H);LCMSm/z 564.2,566.1[M+H]+.
步骤5:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将2-(1-((2-(3,5-二氯苯基)-6-((2-(甲基磺酰基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(80mg,0.099mmol)、1-甲基哌嗪(49.7mg,0.496mmol)和DIEA(64.1mg,0.496mmol)在t-BuOH(0.1mL)中的混合物在150℃在微波下搅拌1.5h。将溶剂浓缩以得到粗产物2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(80mg,0.096mmol,97.0%产率),其为黄色油状物:1HNMR(400MHz,CD3OD)δppm 8.68(s,2H),7.92(d,J=1.8Hz,2H),7.43(t,J=2.0Hz,1H),7.27-7.22(m,1H),6.68(s,1H),4.00(s,2H),3.79(br s,4H),3.63(s,3H),2.92(d,J=12.1Hz,2H),2.75-2.72(m,4H),2.35(s,3H),2.12-2.06(m,2H),1.74(br s,3H),1.34(d,J=12.8Hz,4H);LCMSm/z 584.3,586.3[M+H]+.
步骤6:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(75mg,0.090mmol)在浓HCl(1mL,8.15mmol)和水(1mL)中的混合物。将混合物在80℃搅拌15min。将溶剂浓缩以得到粗产物,粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(28.83mg,0.040mmol,44.8%产率),其为黄色固体:1H NMR(400MHz,CD3OD)δppm 8.82(s,2H),7.96(d,J=2.0Hz,2H),7.51(t,J=1.9Hz,1H),7.45(s,1H),6.92(s,1H),4.84(br s,2H),4.30(s,2H),3.59(d,J=13.5Hz,4H),3.36-3.32(m,2H),3.20-3.07(m,4H),2.95(s,3H),2.30(d,J=6.6Hz,2H),2.04(d,J=13.7Hz,3H),1.64-1.55(m,2H);ES-LCMS m/z570.2,572.2[M+H]+.
实施例333:2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1:2-((4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶-2-基)氧基)-5-氯吡嗪
将4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶-2-醇(500mg,1.130mmol)、2,5-二氯吡嗪(505mg,3.39mmol)、18-冠-6(149mg,0.565mmol)和K2CO3(468mg,3.39mmol)在DMF(15mL)中的混合物在80℃搅拌5h。过滤后,将滤液浓缩。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=5/1,TLC:PE/EtOAc=5/1,Rf=0.6)纯化以得到2-((4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶-2-基)氧基)-5-氯吡嗪(400mg,0.733mmol,64.9%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm8.37(s,1H),8.25(s,1H),7.77(s,1H),7.69(d,J=1.8Hz,2H),7.34(s,1H),4.79(s,2H),2.23(s,3H),1.01(s,9H),0.18(s,6H);ES-LCMS m/z:510.1,512.1[M+H]+.
步骤2:4-(5-((4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯
将2-((4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶-2-基)氧基)-5-氯吡嗪(340mg,0.623mmol)、Xantphos(72.1mg,0.125mmol)、Cs2CO3(609mg,1.869mmol)、Pd2(dba)3(57.0mg,0.062mmol)和哌嗪-1-甲酸叔丁酯(580mg,3.11mmol)在1,4-二噁烷(10mL)中的混合物在90℃在N2气氛搅拌14h。过滤后,将滤液浓缩。粗物质通过快速色谱法(从PE/EtOAc=5/1至2/1,TLC:PE/EtOAc=3/1,Rf=0.5)纯化以得到4-(5-((4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(300mg,0.409mmol,65.6%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 8.12(d,J=1.3Hz,1H),7.85(d,J=1.3Hz,1H),7.67-7.58(m,3H),7.31-7.26(m,1H),4.78(s,2H),3.63-3.49(m,8H),2.28(s,3H),1.50(s,9H),1.00(s,9H),0.18-0.13(m,6H);ES-LCMS m/z 660.3,662.3[M+H]+.
步骤3:4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)-3-甲基吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯
将4-(5-((4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(300mg,0.409mmol)和TBAF(1M的THF溶液)(3mL,3.00mmol)在THF(10mL)中的混合物在20℃搅拌30min。将混合物浓缩以得到粗产物。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=5/1,TLC:DCM/MeOH=20/1,Rf=0.6)纯化以得到4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)-3-甲基吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(350mg,0.320mmol,78.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 8.11(d,J=1.5Hz,1H),7.86(d,J=1.5Hz,1H),7.73(d,J=2.0Hz,1H),7.65(d,J=2.0Hz,3H),4.86(s,2H),3.58(d,J=4.4Hz,8H),2.27(s,3H),1.50(s,9H);ES-LCMSm/z 546.2,548.2[M+H]+.
步骤4:4-(5-((6-(3,5-二氯苯基)-3-甲基-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)-3-甲基吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(300mg,0.275mmol)和DIEA(106mg,0.824mmol)在DCM(20mL)中的混合物中添加MsCl(47.2mg,0.412mmol)。将混合物在0℃搅拌15min。向混合物中添加H2O(15mL),用DCM(15mL x2)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到4-(5-((6-(3,5-二氯苯基)-3-甲基-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(300mg,0.240mmol,87.0%产率),其为棕色固体:1HNMR(400MHz,CDCl3)δppm 8.13(d,J=1.3Hz,1H),7.68(d,J=1.8Hz,2H),7.62(d,J=2.0Hz,3H),5.33(s,2H),3.61-3.59(m,8H),3.13(s,3H),2.39-2.36(m,3H),1.46(d,J=0.9Hz,9H);ES-LCMS m/z 624.2,626.2[M+H]+.
步骤5:4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)-3-甲基吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-3-甲基-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(350mg,0.280mmol)和2-(哌啶-4-基)乙酸甲酯,盐酸盐(72.4mg,0.336mmol)在DMF(10mL)中的混合物中添加DIEA(181mg,1.401mmol)。将混合物在20℃搅拌12h。过滤后,将滤液浓缩。残余物通过快速色谱法(从PE/EtOAc=5/1至2/1至DCM/MeOH=10/1,TLC:PE/EtOAc=3/1,Rf=0.5)纯化以得到4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)-3-甲基吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(300mg,0.219mmol,78.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 8.10(s,1H),7.86-7.82(m,1H),7.67(s,1H),7.63-7.55(m,3H),3.80(s,2H),3.67(s,3H),3.56(d,J=5.1Hz,8H),3.13-3.03(m,2H),2.64(d,J=13.7Hz,2H),2.35(s,3H),2.08-2.05(m,2H),1.83(br s,2H),1.66-1.63(m,3H),1.48(s,9H);ES-LCMSm/z 685.3,687.3[M+H]+.
步骤6:2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐
将4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)-3-甲基吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(270mg,0.197mmol)和TFA(0.5mL,6.49mmol)在DCM(2mL)中的溶液在20℃搅拌1h。然后将混合物浓缩以得到2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐(350mg,0.168mmol,85.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 8.22(s,1H),7.93(s,1H),7.60(s,1H),7.54(d,J=1.8Hz,2H),7.34(br s,1H),4.40(br s,2H),3.91(br s,4H),3.77(br s,4H),3.68(s,3H),2.88-2.78(m,4H),2.45(s,3H),2.02(br s,2H),1.58(d,J=11.0Hz,3H),1.42-1.34(m,2H);ES-LCMS m/z 585.2,587.2[M+H]+.
步骤7:2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将多聚甲醛(50.4mg,1.680mmol)和2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐(350mg,0.168mmol)在MeOH(15mL)中的混合物在30℃搅拌10h。然后向该混合物中添加NaBH3CN(52.8mg,0.840mmol)。将全部混合物在30℃再搅拌2h。向混合物中添加饱和Na2CO3水溶液(20mL),用DCM(20mL×3)萃取。合并的有机层用盐水(30mL)洗涤,用Na2SO4干燥,过滤且浓缩。残余物用制备型TLC(DCM/MeOH=10/1,Rf=0.5)纯化以得到2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(70mg,0.097mmol,57.5%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm8.03(d,J=1.3Hz,1H),7.79(d,J=1.3Hz,1H),7.56(d,J=2.0Hz,2H),7.40(s,1H),7.21-7.20(m,1H),3.63-3.59(m,5H),3.56-3.52(m,4H),3.43(s,2H),2.83-2.75(m,2H),2.52-2.49(m,4H),2.31-2.29(m,6H),2.21-2.19(m,2H),1.73-1.61(m,3H),1.33-1.23(m,2H);ES-LCMS m/z:599.3,601.3[M+H]+.
步骤8:2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(70mg,0.097mmol)在THF(5.00mL)和水(1mL)中的溶液中添加LiOH·H2O(40.6mg,0.967mmol)。将混合物在50℃搅拌5h。将混合物浓缩。向残余物中添加MeCN(6mL)和H2O(2mL),且用1N HCl酸化至pH=7-7.5。混合物通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化,然后冻干以得到2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸(35.04mg,0.059mmol,60.6%产率),其为白色固体:1H NMR(400MHz,CD3OD)δppm8.12(d,J=1.3Hz,1H),8.00(d,J=1.3Hz,1H),7.71-7.64(m,3H),7.37(t,J=1.9Hz,1H),3.78(s,2H),3.73-3.64(m,4H),3.04(d,J=11.9Hz,2H),2.78(t,J=5.1Hz,4H),2.49(s,3H),2.41(s,3H),2.36(t,J=10.9Hz,2H),2.20(d,J=6.6Hz,2H),1.89-1.75(m,3H),1.44-1.29(m,2H);ES-LCMS m/z:585.3,587.2[M+H]+.
实施例334:2-(1-((2-((2-(1,4-二氮杂双环[3.2.1]辛-4-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
步骤1:2-(1-((2-((2-(1,4-二氮杂双环[3.2.1]辛-4-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将2-(1-((2-(3,5-二氯苯基)-6-((2-(甲基亚磺酰基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(500mg,0.728mmol)、1,4-二氮杂双环[3.2.1]辛烷(576mg,4.37mmol)和DIEA(941mg,7.28mmol)在t-BuOH(3mL)中的混合物在150℃在微波下搅拌30分钟。将反应混合物浓缩以得到粗物质,其通过快速色谱法(从纯的DCM至DCM/MeOH=50/1,TLC:DCM/MeOH=10/1,Rf=0.6)纯化以得到2-(1-((2-((2-(1,4-二氮杂双环[3.2.1]辛-4-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(148mg,0.198mmol,27.2%产率),其为黄色油状物:1H NMR(400MHz,CD3OD)δppm 8.39-8.36(m,2H),7.79(d,J=1.8Hz,2H),7.63(s,1H),7.42(t,J=1.9Hz,1H),7.04(s,1H),3.64(s,3H),3.61(s,2H),3.47-3.39(m,2H),3.39-3.33(m,3H),3.27-3.22(m,1H),3.17-3.08(m,2H),2.91(d,J=11.9Hz,2H),2.27(d,J=6.8Hz,2H),2.20-1.97(m,4H),1.73(d,J=13.2Hz,2H),1.37-1.35(m,2H),1.34-1.24(m,2H);ES-LCMSm/z 597.3,599.3[M+H]+。
步骤2:2-(1-((2-((2-(1,4-二氮杂双环[3.2.1]辛-4-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
将2-(1-((2-((2-(1,4-二氮杂双环[3.2.1]辛-4-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(650mg,0.870mmol)在3N HCl溶液(12mL,36.0mmol)中的溶液在80℃搅拌10min。将混合物浓缩以得到残余物。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干以得到2-(1-((2-((2-(1,4-二氮杂双环[3.2.1]辛-4-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(496.96mg,0.681mmol,78.0%产率),其为白色固体:1H NMR(400MHz,D2O/CD3CN=10/1)δppm 8.52(s,2H),7.84(d,J=1.8Hz,2H),7.76(s,1H),7.59(t,J=1.8Hz,1H),7.29(s,1H),5.63(d,J=6.2Hz,1H),4.59-4.52(m,1H),4.42(s,2H),3.76-3.67(m,2H),3.66-3.53(m,4H),3.53-3.44(m,3H),3.13(t,J=12.2Hz,2H),2.61-2.53(m,1H),2.42(d,J=6.6Hz,2H),2.28-2.17(m,1H),2.08(td,J=2.5,5.0Hz,3H),1.65-1.54(m,2H);ES-LCMSm/z583.3,585.3[M+H]+.
实施例335-338(表17)通过类似于实施例334所述的方法制备。
表17
实施例339:2-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1:2-(1-((2-((5-氯吡嗪-2-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯
向2-(1-((2-(3,5-二氯苯基)-6-羟基吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯(5g,10.04mmol)和2,5-二氯吡嗪(2.243g,15.06mmol)在DMF(120mL)中的溶液中添加K2CO3(2.77g,20.08mmol)。然后将反应混合物在80℃搅拌12h。将固体过滤掉且将溶剂真空去除以得到粗产物,其通过快速色谱法(从纯的PE至PE/EtOAc=3/1,TLC:PE/EtOAc=2/1,Rf=0.45)纯化以得到2-(1-((2-((5-氯吡嗪-2-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯(4.3g,7.22mmol,71.9%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 8.37(d,J=1.1Hz,1H),8.27(d,J=1.1Hz,1H),7.73(d,J=1.8Hz,2H),7.54(s,1H),7.36(t,J=1.8Hz,1H),7.07(s,1H),4.20-4.12(m,2H),3.57(s,2H),2.86(d,J=11.5Hz,2H),2.25(d,J=7.1Hz,2H),2.11-2.05(m,2H),1.82(ddd,J=3.9,7.3,11.1Hz,1H),1.73(d,J=12.6Hz,2H),1.42-1.31(m,2H),1.26-1.19(m,3H);ES-LCMSm/z535.1,537.2[M+H]+.
步骤2:4-(5-((6-(3,5-二氯苯基)-4-((4-(2-乙氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯
向2-(1-((2-((5-氯吡嗪-2-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯(4.3g,7.22mmol)、哌嗪-1-甲酸叔丁酯(4.04g,21.67mmol)、Xantphos(0.209g,0.361mmol)和Cs2CO3(7.06g,21.67mmol)在THF(100mL)中的混合物中添加Pd2(dba)3(0.331g,0.361mmol)。将反应在80℃在N2气氛搅拌6h。将固体过滤掉且将溶剂真空去除以得到粗产物,其通过快速色谱法(从纯的PE至PE:EtOAc=1:1,TLC:PE:EtOAc=1:1,Rf=0.35)纯化以得到4-(5-((6-(3,5-二氯苯基)-4-((4-(2-乙氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(4.15g,5.45mmol,75.0%产率),其为淡黄色固体:1H NMR(400MHz,CDCl3)δppm 8.13(d,J=1.3Hz,1H),7.85(d,J=1.3Hz,1H),7.71(d,J=2.0Hz,2H),7.44(s,1H),7.32(t,J=1.9Hz,1H),6.96(s,1H),4.14-4.10(m,2H),3.58(d,J=4.0Hz,8H),3.52(s,2H),2.86(d,J=11.5Hz,2H),2.24(d,J=7.1Hz,2H),2.06-2.00(m,2H),1.80(tdd,J=3.8,7.4,11.2Hz,1H),1.71(d,J=12.8Hz,2H),1.49(s,9H),1.40-1.30(m,2H),1.27-1.20(m,3H);ES-LCMS m/z 685.3,687.3[M+H]+.
步骤3:2-(1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯,4三氟乙酸盐
向4-(5-((6-(3,5-二氯苯基)-4-((4-(2-乙氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(2.6g,3.41mmol)在DCM(30mL)中的溶液中添加TFA(6mL,78mmol)。然后将反应混合物在25℃搅拌30min。将溶剂真空去除以得到2-(1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯,4三氟乙酸盐(3.8g,3.28mmol,96.0%产率),其为黄色油状物:1H NMR(400MHz,CD3OD)δppm8.22(d,J=1.1Hz,1H),8.12(d,J=1.1Hz,1H),7.84(s,1H),7.80(d,J=2.0Hz,2H),7.50(t,J=1.9Hz,1H),7.28(s,1H),4.46-4.36(m,2H),4.13(q,J=7.1Hz,2H),3.94-3.83(m,4H),3.62-3.53(m,2H),3.42-3.36(m,4H),3.12(t,J=12.7Hz,2H),2.34(d,J=6.2Hz,2H),2.04(d,J=14.6Hz,3H),1.62-1.49(m,2H),1.31-1.18(m,3H);ES-LCMSm/z585.3,587.3[M+H]+.
步骤4:2-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯
向2-(1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯,4三氟乙酸盐(3.8g,3.28mmol)在MeOH(12mL)中的溶液中添加多聚甲醛(4.93g,164mmol)。在25℃搅拌12h后,添加NaBH3CN(2.063g,32.8mmol)。然后将混合物再搅拌3h。添加饱和NaHCO3水溶液(100mL)且用DCM(50mL×3)萃取。合并的有机层用Na2SO4干燥且真空浓缩以得到2-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯(2.1g,3.15mmol,96.0%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 8.11(d,J=1.3Hz,1H),7.98(d,J=1.3Hz,1H),7.77(d,J=1.8Hz,2H),7.65(s,1H),7.42(t,J=1.9Hz,1H),7.04(s,1H),4.11(q,J=7.1Hz,2H),3.69-3.62(m,4H),3.60(s,2H),2.91(d,J=11.7Hz,2H),2.36(s,3H),2.59(t,J=5.0Hz,4H),2.26(d,J=6.8Hz,2H),2.15-2.06(m,2H),1.83-1.77(m,1H),1.73(d,J=13.0Hz,2H),1.40-1.31(m,2H),1.23(t,J=7.1Hz,3H);ES-LCMS m/z 599.3,601.3[M+H]+.
步骤5:2-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯(2.1g,3.15mmol)在THF(50mL)和水(5mL)中的溶液中添加LiOH·H2O(0.661g,15.76mmol)。然后将反应混合物在25℃搅拌12h。添加1N HCl溶液以调节pH=6-7。将溶剂真空去除以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化且冻干以得到2-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸(1511.38mg,2.62mmol,83.0%产率),其为白色固体:1H NMR(400MHz,CD3OD)δppm 8.15(s,1H),8.06(s,1H),7.85(d,J=1.8Hz,2H),7.76(s,1H),7.63(s,1H),7.00(s,1H),3.54(br s,6H),2.79(d,J=10.8Hz,2H),2.42(d,J=4.6Hz,4H),2.21(s,3H),2.13(d,J=6.4Hz,2H),2.02-1.93(m,2H),1.63(d,J=11.2Hz,3H),1.21(d,J=10.8Hz,2H);ES-LCMS m/z 571.3,573.2[M+H]+.
实施例340-366(表18)通过类似于实施例339所述的方法制备。
表18
实施例367:3-(4-(5-((4-(((1R,7S,8r)-8-乙酰氨基-4-氮杂双环[5.1.0]辛-4-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸
步骤1:3-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸甲酯
向(2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲醇,3盐酸盐(2.3g,4.05mmol)和DIEA(3.54mL,20.27mmol)在MeOH(30mL)中的混合物中添加丙烯酸甲酯(0.735mL,8.11mmol)。将反应混合物在25℃在N2气氛搅拌12h。然后将混合物浓缩。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.5)纯化以得到3-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸甲酯(2.3g,3.99mmol,98.0%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm8.22(s,2H),7.66(d,J=1.8Hz,2H),7.36(s,1H),7.31-7.28(m,1H),6.88(s,1H),4.75(s,2H),3.85-3.77(m,4H),3.67(s,3H),2.76-2.69(m,2H),2.55-2.49(m,6H);ES-LCMS m/z:518.2,520.2[M+H]+.
步骤2:3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸甲酯
向3-(4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸甲酯(2.3g,3.99mmol)和DIEA(2.092mL,11.98mmol)在DCM(30mL)中的混合物中添加MsCl(0.622mL,7.99mmol)。将反应混合物在0℃搅拌0.5h。向混合物中添加H2O(50mL),用DCM(100mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸甲酯(2.6g,3.92mmol,98.0%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm 8.32-8.27(m,2H),7.72(dd,J=1.9,4.1Hz,2H),7.43-7.36(m,2H),6.96(d,J=3.1Hz,1H),3.94-3.91(m,1H),3.86(d,J=3.3Hz,4H),3.72-3.69(m,3H),3.15-3.12(m,3H),3.04-3.00(m,1H),2.80-2.73(m,2H),2.57(d,J=3.7Hz,6H);ES-LCMS m/z596.2,598.2[M+H]+.
步骤3:3-(4-(5-((4-(((1R,7S,8r)-8-乙酰氨基-4-氮杂双环[5.1.0]辛-4-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸甲酯
向N-((1R,7S,8r)-4-氮杂双环[5.1.0]辛-8-基)乙酰胺,三氟乙酸盐(200mg,0.567mmol)和3-(4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸甲酯(250mg,0.377mmol)在DMF(6mL)中的溶液中添加DIEA(0.329mL,1.886mmol)。然后将反应混合物在20℃搅拌12h。溶剂浓缩以得到粗产物。添加水(50mL)且用DCM(30mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到3-(4-(5-((4-(((1R,7S,8r)-8-乙酰氨基-4-氮杂双环[5.1.0]辛-4-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸甲酯(300mg,0.337mmol,89.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 8.25-8.16(m,2H),7.69-7.61(m,2H),7.30-7.22(m,2H),6.85-6.74(m,1H),3.81-3.71(m,4H),3.63(s,3H),3.58-3.51(m,2H),2.75-2.63(m,4H),2.50-2.34(m,7H),2.23-2.09(m,2H),1.89-1.74(m,3H),1.51-1.36(m,2H),1.32-1.15(m,2H),1.04(s,2H);ES-LCMS m/z 668.2,670.2[M+H]+.
步骤4:4-(4-(5-((4-(((1R,7S,8r)-8-乙酰氨基-4-氮杂双环[5.1.0]辛-4-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸
向3-(4-(5-((4-(((1R,7S,8r)-8-乙酰氨基-4-氮杂双环[5.1.0]辛-4-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸甲酯(300mg,0.337mmol)在MeOH(6mL)和水(0.5mL)中的溶液中添加LiOH·H2O(42.4mg,1.010mmol)。然后将反应混合物在25℃搅拌12h。添加1N HCl以调节pH=6-7且将混合物浓缩以得到残余物,将其通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化且冻干以得到白色固体的3-(4-(5-((4-(((1R,7S,8r)-8-乙酰氨基-4-氮杂双环[5.1.0]辛-4-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸(92.42mg,0.141mmol,42.0%产率):1H NMR(400MHz,CD3OD)δppm 8.37(s,2H),7.79(d,J=1.98Hz,2H),7.62(s,1H),7.43(t,J=1.87Hz,1H),7.04(s,1H),4.03(s,4H),3.74(s,2H),3.18-3.05(m,6H),2.88(dd,J=6.95,12.68Hz,2H),2.61-2.46(m,5H),2.30-2.18(m,2H),1.86(s,3H),1.60-1.45(m,2H),1.13(s,2H);ES-LCMSm/z654.2,656.2[M+H]+.
实施例368:4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸甲酯
向N-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(3.3g,4.38mmol)和4-溴-2-甲基丁酸甲酯(2.85g,13.13mmol)在DMF(50mL)中的溶液中添加K2CO3(4.84g,35.0mmol)。然后将反应混合物在80℃搅拌12h。将固体过滤掉且将溶剂真空去除以得到粗产物,其通过色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.45)纯化以得到黄色固体的4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸甲酯(2.3g,2.88mmol,65.9%产率):1H NMR(400MHz,CDCl3)δppm8.31-8.22(m,2H),7.73-7.64(m,2H),7.43-7.36(m,1H),7.34-7.27(m,1H),6.85(s,1H),5.62(t,J=5.4Hz,1H),3.80(t,J=4.7Hz,4H),3.66(s,3H),3.48(s,2H),3.13(t,J=6.3Hz,2H),2.85(d,J=11.2Hz,2H),2.60-2.43(m,5H),2.37(t,J=7.2Hz,2H),2.09-1.89(m,7H),1.66(d,J=12.1Hz,2H),1.54-1.46(m,1H),1.36-1.25(m,2H),1.19-1.13(m,3H);ES-LCMS m/z 684.4,686.4[M+H]+.
实施例369:4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸,4盐酸盐
向4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸甲酯(1.7g,2.130mmol)在MeOH(20mL)和H2O(3mL)中的溶液中添加LiOH(0.153g,6.39mmol)。然后将反应混合物在25℃搅拌0.5h。将溶剂真空去除以得到粗产物,将其溶于MeCN(10mL)和H2O(10mL)。添加1N HCl以调节pH=6-7。混合物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸,4盐酸盐(1186.17mg,1.447mmol,67.9%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 8.63(s,2H),8.05(s,1H),7.88(d,J=1.8Hz,2H),7.47(s,1H),7.44-7.38(m,1H),4.88(d,J=14.6Hz,2H),4.47(s,2H),3.75(d,J=12.1Hz,2H),3.64-3.51(m,4H),3.43-3.29(m,2H),3.27-3.07(m,6H),2.66-2.51(m,1H),2.22-2.08(m,4H),2.01-1.88(m,4H),1.77-1.61(m,2H),1.29-1.20(m,3H);ES-LCMS m/z 670.4,672.4[M+H]+.
实施例370:4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2,2-二甲基丁酸,4盐酸盐
步骤1:3,3-二甲基二氢呋喃-2(3H)-酮
在70℃在N2气氛向NaH(5.81g,145mmol)(60%)在THF(60mL)中的混合物中添加CH3I(13.07mL,209mmol)和二氢呋喃-2(3H)-酮(5g,58.1mmol)。然后将混合物在70℃在N2气氛搅拌2h。在0℃反应混合物通过添加饱和NH4Cl水溶液(50mL)淬灭。将混合物浓缩,然后添加水(50mL)。将混合物用EtOAc(10mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从PE/EtOAc=50/1至10/1,TLC:PE/EtOAc=5/1,Rf=0.6)纯化以得到3,3-二甲基二氢呋喃-2(3H)-酮(1.3g,10.82mmol,18.6%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 4.27(t,J=6.9Hz,2H),2.12(t,J=6.9Hz,2H),1.27(s,6H);ES-LCMS m/z 115.2[M+H]+.
步骤2:4-溴-2,2-二甲基丁酸甲酯
在0℃在N2气氛向3,3-二甲基二氢呋喃-2(3H)-酮(500mg,4.16mmol)在DCM(10mL)中的混合物中添加BBr3(1.967mL,20.81mmol)。然后将混合物在25℃在N2气氛搅拌8h。将MeOH(10.0mL)添加至混合物且在25℃搅拌8h。反应混合物在0℃通过添加饱和NaHCO3水溶液(30mL)淬灭。将混合物用EtOAc(50mL×3)萃取。合并的有机层用盐水(30mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到淡黄色油状物的4-溴-2,2-二甲基丁酸甲酯(150mg,0.574mmol,13.8%产率):1H NMR(400MHz,CDCl3)δppm3.65-3.59(m,3H),3.31-3.22(m,2H),2.11-2.05(m,2H),1.17-1.12(m,6H)。
步骤3:4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2,2-二甲基丁酸甲酯
将N-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(0.2g,0.251mmol)、4-溴-2,2-二甲基丁酸甲酯(0.131g,0.503mmol)和K2CO3(0.104g,0.754mmol)在MeCN(5mL)中的混合物在80℃搅拌6h。将混合物过滤且浓缩。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.4)纯化以得到4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2,2-二甲基丁酸甲酯(120mg,0.086mmol,34.2%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm8.25-8.21(m,1H),7.95(s,2H),7.66(d,J=1.8Hz,2H),7.36(s,1H),7.28(s,1H),6.89-6.80(m,1H),4.20(t,J=6.9Hz,2H),3.81(d,J=6.8Hz,4H),3.72-3.67(m,2H),3.64-3.60(m,2H),3.48(br s,2H),3.10(t,J=6.4Hz,2H),2.56(br s,2H),2.38(br s,1H),1.97-1.91(m,10H),1.83-1.75(m,2H),1.64(d,J=11.5Hz,2H),1.20(s,6H);ES-LCMSm/z 698.0,700.0[M+H]+.
步骤4:4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2,2-二甲基丁酸,4盐酸盐
向4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2,2-二甲基丁酸甲酯(100mg,0.072mmol)在水(4mL)中的溶液中添加浓HCl溶液(2mL,24.00mmol)。然后,将混合物在80℃搅拌15min。将反应蒸发以得到残余物。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干以得到4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2,2-二甲基丁酸,4盐酸盐(13.62mg,0.016mmol,22.8%产率),其为白色固体:1H NMR(400MHz,D2O)δppm 8.28(s,2H),7.45(s,1H),7.43(d,J=1.8Hz,2H),7.20(t,J=1.9Hz,1H),7.03(s,1H),4.52(d,J=15.0Hz,2H),4.23(s,2H),3.57(d,J=12.3Hz,2H),3.43(d,J=11.7Hz,2H),3.27(t,J=12.6Hz,2H),3.15-3.06(m,2H),3.01-2.89(m,6H),1.92-1.79(m,7H),1.71(br s,1H),1.43-1.24(m,2H),1.10(s,6H);ES-LCMSm/z 684.3,686.2[M+H]+.
实施例371:2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1(2-((6-氯哒嗪-3-基)氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲醇
将4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶-2-醇(600mg,1.355mmol)、3,6-二氯哒嗪(808mg,5.42mmol)、18-冠-6(179mg,0.678mmol)和K2CO3(562mg,4.07mmol)在DMF(5mL)中的混合物在80℃搅拌5h。过滤后,将滤液浓缩。粗物质通过快速色谱法(从PE/EtOAc=5/1至2/1,TLC:PE/EtOAc=5/1,Rf=0.6)纯化以得到(2-((6-氯哒嗪-3-基)氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲醇(300mg,0.681mmol,50.2%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 7.77(s,1H),7.70(d,J=2.0Hz,2H),7.60(d,J=9.3Hz,1H),7.39(d,J=9.3Hz,1H),7.32(t,J=1.9Hz,1H),4.83(s,2H),2.25(s,3H);ES-LCMSm/z:396.0,398.0[M+H]+.
步骤2:甲磺酸(2-((6-氯哒嗪-3-基)氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基酯
向冷却至0℃的(2-((6-氯哒嗪-3-基)氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲醇(280mg,0.635mmol)和DIEA(246mg,1.906mmol)在DCM中的混合物中添加MsCl(109mg,0.953mmol)。将混合物在0℃搅拌0.2h。添加水(20mL)。将混合物用DCM(15mL×3)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到甲磺酸(2-((6-氯哒嗪-3-基)氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基酯(300mg,0.569mmol,90.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 7.81(d,J=9.0Hz,1H),7.61(d,J=1.8Hz,2H),7.53(d,J=4.9Hz,2H),7.34(d,J=9.0Hz,1H),4.58(s,2H),2.71(s,3H),2.35(s,3H);ES-LCMS m/z474.0,476.0,478.0[M+H]+.
步骤3:2-(1-((2-((6-氯哒嗪-3-基)氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向甲磺酸(2-((6-氯哒嗪-3-基)氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基酯(300mg,0.569mmol)和DIEA(368mg,2.84mmol)在DMF(10mL)中的混合物中添加2-(哌啶-4-基)乙酸甲酯,盐酸盐(245mg,1.137mmol)。将混合物在30℃搅拌10h。过滤后,将滤液浓缩。残余物通过制备型TLC(PE/EtOAc=3/1,Rf=0.6)纯化以得到2-(1-((2-((6-氯哒嗪-3-基)氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(250mg,0.420mmol,73.8%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 7.67(d,J=1.8Hz,2H),7.62-7.54(m,2H),7.37(d,J=9.0Hz,1H),7.31(s,1H),3.66(s,3H),3.51(s,2H),2.90-2.80(m,2H),2.31(s,3H),2.26(d,J=7.1Hz,2H),2.09(t,J=11.4Hz,2H),1.91-1.66(m,3H),1.40-1.29(m,2H);ES-LCMS m/z 535.1,537.1[M+H]+.
步骤4:4-(6-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)-3-甲基吡啶-2-基)氧基)哒嗪-3-基)哌嗪-1-甲酸叔丁酯
将2-(1-((2-((6-氯哒嗪-3-基)氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(250mg,0.420mmol)、Xantphos(48.6mg,0.084mmol)、Cs2CO3(410mg,1.260mmol)、Pd2(dba)3(38.5mg,0.042mmol)和哌嗪-1-甲酸叔丁酯(391mg,2.1mmol)在THF(15mL)中的混合物在80℃在N2气氛搅拌20h。添加Pd2(dba)3(38.5mg,0.042mmol)和哌嗪-1-甲酸叔丁酯(391mg,2.1mmol)且全部混合物在80℃在N2气氛再搅拌16h。混合物冷却且过滤。将滤液浓缩。粗物质通过制备型TLC(PE/EtOAc=3/1,Rf=0.3)纯化以得到4-(6-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)-3-甲基吡啶-2-基)氧基)哒嗪-3-基)哌嗪-1-甲酸叔丁酯(300mg,0.185mmol,44.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 7.66(s,2H),7.51(s,1H),7.39(br s,1H),7.28(br s,1H),7.10(d,J=9.9Hz,1H),3.66(s,3H),3.57(br s,6H),3.49(s,4H),2.90-2.84(m,2H),2.32(s,3H),2.26(d,J=7.5Hz,2H),2.08(d,J=9.0Hz,2H),1.69-1.59(m,3H),1.47(br s,9H),1.26(d,J=19.4Hz,2H);ES-LCMS m/z 685.3,687.3[M+H]+.
步骤5:2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐
将4-(6-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)-3-甲基吡啶-2-基)氧基)哒嗪-3-基)哌嗪-1-甲酸叔丁酯(300mg,0.185mmol)和TFA(2mL,26.0mmol)在DCM(10mL)中的溶液在20℃搅拌1h。将混合物浓缩以得到2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐(300mg,0.147mmol,80.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 7.61(s,2H),7.54(d,J=1.5Hz,1H),7.34(br s,2H),7.14(s,1H),4.04-3.72(m,2H),3.68(s,3H),3.25-3.20(m,2H),2.89-2.62(m,6H),2.48-2.35(m,4H),2.28-3.20(m,3H),2.02-1.95(m,3H),1.68-1.50(m,2H),1.31-1.27(m,2H);ES-LCMS m/z 585.3,587.3[M+H]+.
步骤6:2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐(300mg,0.147mmol)和甲醛(44.1mg,1.469mmol)在MeOH(10mL)中的混合物在30℃搅拌10h。向该混合物中添加NaBH3CN(46.2mg,0.734mmol)。全部混合物在30℃再搅拌2h。向混合物中添加饱和Na2CO3水溶液(20mL),用DCM(20mL×3)萃取。合并的有机层用盐水(30mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(160mg,0.133mmol,91.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 7.62(d,J=2.0Hz,2H),7.46(s,1H),7.23-7.21(m,2H),7.06-7.05(m,1H),3.61(s,3H),3.60-3.55(m,4H),3.47-3.40(m,2H),2.79-2.71(m,4H),2.60(s,3H),2.50-2.47(m,4H),2.27(s,3H),2.02-1.95(m,2H),1.67-1.50(m,3H),1.32-1.27(m,2H);ES-LCMS m/z:599.3,601.3[M+H]+.
步骤7:2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(160mg,0.133mmol)在THF(5.00mL)和水(1mL)中的溶液中添加LiOH·H2O(56.0mg,1.334mmol)。将混合物在50℃搅拌5h。将混合物浓缩。向残余物中添加MeCN(6mL)和H2O(2mL),用1N HCl酸化至pH=7-7.5。混合物通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化,然后冻干以得到2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸(23.77mg,0.039mmol,29.0%产率),其为白色固体:1H NMR(400MHz,CD3OD)δppm7.76-7.72(m,3H),7.55(d,J=9.8Hz,1H),7.42(d,J=9.3Hz,1H),7.41-7.39(m,1H),3.78-3.70(m,6H),3.03(d,J=11.5Hz,2H),2.76(t,J=5.1Hz,4H),2.48(s,3H),2.44(s,3H),2.33(t,J=11.0Hz,2H),2.23(d,J=6.8Hz,2H),1.92-1.76(m,3H),1.43-1.36(m,2H);ES-LCMSm/z:585.3,587.2[M+H]+.
实施例372:N-((1-((2-(3-氯-5-氟苯基)-6-((2-(4-(4-(甲基磺酰基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
步骤1:4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-氟苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3-氯-5-氟苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1.5g,2.146mmol)和N-(哌啶-4-基甲基)乙酰胺,盐酸盐(0.871g,4.29mmol)在DMF(15mL)中的溶液中添加DIEA(1.528mL,8.59mmol)。然后将混合物在50℃搅拌3h。然后将混合物浓缩以得到残余物,将其在DCM(30mL)和H2O(20mL)之间分配,用DCM(30mL x2)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过快速色谱法(从纯的DCM至DCM/MeOH 8/1,TLC:DCM/MeOH=10/1,Rf=0.55)纯化以得到淡黄色固体的4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-氟苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1.5g,2.112mmol,98.0%产率):1H NMR(400MHz,CD3OD)δppm 8.33(s,2H),7.71(s,1H),7.63(s,1H),7.58-7.52(m,1H),7.19(td,J=2.0,8.4Hz,1H),7.03(s,1H),3.86-3.79(m,4H),3.61(s,2H),3.52(br s,4H),3.07(d,J=6.6Hz,2H),2.93(d,J=11.7Hz,2H),2.08(t,J=10.7Hz,2H),1.72(d,J=11.7Hz,2H),1.53(br s,1H),1.51(br s,3H),1.49(s,9H),1.37-1.25(m,2H);ES-LCMS m/z 654.0,656.0[M+H]+.
步骤2:N-((1-((2-(3-氯-5-氟苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐
将4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-氟苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(730mg,1.028mmol)在HCl溶液(4M的MeOH溶液,15mL,60.0mmol)中的混合物在20℃搅拌30分钟。然后将混合物浓缩以得到N-((1-((2-(3-氯-5-氟苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(800mg,0.954mmol,93.0%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 8.48(s,2H),7.95(br s,1H),7.80(s,1H),7.61(d,J=9.7Hz,1H),7.33(br s,1H),7.27(d,J=8.2Hz,1H),4.44(br s,2H),4.13(br s,4H),3.59(br s,2H),3.34(br s,4H),3.14(br s,4H),1.98(s,5H),1.87(br s,1H),1.63(br s,2H);ES-LCMS m/z 554.0,556.1[M+H]+.
步骤3:N-((1-((2-(3-氯-5-氟苯基)-6-((2-(4-(4-(甲硫基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向4-(甲硫基)丁-2-酮(564mg,4.77mmol)、N-((1-((2-(3-氯-5-氟苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺,4盐酸盐(800mg,0.954mmol)在MeOH(15mL)中的溶液中添加分子筛(0.2g,0.954mmol)且在50℃在N2气氛搅拌84h。然后将NaBH3CN(300mg,4.77mmol)添加至混合物且将混合物在50℃搅拌12h。粗物质通过快速色谱法(从DCM/MeOH=100/1至15/1,TLC:DCM/MeOH=20/1,Rf=0.35)纯化以得到灰白色固体的N-((1-((2-(3-氯-5-氟苯基)-6-((2-(4-(4-(甲硫基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(480mg,0.626mmol,65.6%产率):1H NMR(400MHz,CD3OD)δppm 8.31(s,2H),7.73(s,1H),7.64(s,1H),7.56(d,J=9.9Hz,1H),7.20(d,J=8.4Hz,1H),7.03(s,1H),3.83(d,J=2.4Hz,4H),3.61(s,2H),3.07(d,J=6.8Hz,2H),2.93(d,J=10.8Hz,2H),2.84-2.77(m,1H),2.71-2.64(m,2H),2.63-2.50(m,4H),2.11-2.04(m,5H),1.93(s,3H),1.91-1.85(m,1H),1.72(d,J=12.6Hz,2H),1.64-1.48(m,2H),1.37-1.28(m,2H),1.05(d,J=6.6Hz,3H);ES-LCMS m/z 656.2,658.0[M+H]+.
步骤4:N-((1-((2-(3-氯-5-氟苯基)-6-((2-(4-(4-(甲基磺酰基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺
向N-((1-((2-(3-氯-5-氟苯基)-6-((2-(4-(4-(甲硫基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(400mg,0.522mmol)在MeOH(15mL)中的溶液中添加Oxone(240mg,0.390mmol)且在25℃搅拌12h。将饱和Na2SO3溶液(30mL)添加至上述混合物且将混合物浓缩以得到残余物,将其在DCM(30mL)和H2O(20mL)之间分配,用DCM(30mL x2)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化。所需级分冻干以得到白色固体的N-((1-((2-(3-氯-5-氟苯基)-6-((2-(4-(4-(甲基磺酰基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺(123.07mg,0.177mmol,33.9%产率):1H NMR(400MHz,CD3OD)δ8.31(s,2H),7.73(s,1H),7.64(s,1H),7.59-7.53(m,1H),7.20(td,J=2.0,8.3Hz,1H),7.03(s,1H),3.90-3.76(m,4H),3.61(s,2H),3.29-3.17(m,2H),3.07(d,J=6.6Hz,2H),2.98(s,3H),2.94(br d,J=11.5Hz,2H),2.87-2.78(m,1H),2.74-2.65(m,2H),2.58-2.50(m,2H),2.13-1.97(m,3H),1.93(s,3H),1.90-1.80(m,1H),1.72(br d,J=12.3Hz,2H),1.53(br d,J=3.3Hz,1H),1.37-1.25(m,2H),1.06(d,J=6.6Hz,3H);ES-LCMS m/z 688.3,690.3[M+H]+.
实施例373-374(表19)通过类似于实施例372所述的方法制备。
表19:
实施例375:2-(1-((2-(3,5-二氯苯基)-6-(异丙基(2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸
实施例375通过类似于实施例388所述的方法制备:1H NMR(400MHz,CD3OD)δppm8.53(br s,2H),7.99(br s,2H),7.52(s,1H),7.47(br s,1H),7.01(br s,1H),5.26(br s,1H),4.97(br d,J=13.2Hz,2H),4.28(br s,2H),3.67(br s,4H),3.48(br s,4H),3.10(brs,2H),3.02(br s,3H),2.36-2.21(m,2H),2.10-1.92(m,3H),1.71(br s,2H),1.27(br d,J=4.9Hz,6H);LCMS m/z 612.3,614.2[M+H]+.
实施例376:2-(1-((3',5'-二氯-4-氟-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸
步骤1:2-氟-3-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚
将2-氟-3-甲基苯酚(4.5g,35.7mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷)(22.65g,89mmol)、2,9-二甲基-1,10-菲咯啉(1.486g,7.14mmol)和[Ir(COD)OMe]2(0.904g,1.784mmol)在THF(300mL)中的混合物在80℃在N2气氛搅拌12h。将混合物浓缩以得到粗产物。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=5/1,TLC:PE/EtOAc=4/1,Rf=0.5)纯化以得到2-氟-3-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚(6g,21.42mmol,60.0%产率),其为棕色固体:1H NMR(400MHz,CD3OD)δppm 7.12-7.03(m,2H),2.23(d,J=2.2Hz,3H),1.32(s,12H);ES-LCMS m/z 253.2[M+H]+.
步骤2:3',5'-二氯-4-氟-5-甲基-[1,1'-联苯]-3-醇
在N2气氛向2-氟-3-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚(3g,10.71mmol)和1-溴-3,5-二氯苯(2.90g,12.85mmol)在1,4-二噁烷(250mL)和水(50.00mL)中的溶液中添加K2CO3(4.44g,32.1mmol)和PdCl2(dppf)(0.784g,1.071mmol)。然后将反应混合物在80℃搅拌2h。过滤后,将滤液浓缩。残余物通过快速色谱法(从纯的PE至PE/EtOAc=4/1,TLC:PE/EtOAc=4/1,Rf=0.5)纯化以得到3',5'-二氯-4-氟-5-甲基-[1,1'-联苯]-3-醇(2.5g,8.30mmol,77.0%产率),其为黄色固体:1H NMR(400MHz,CD3OD)δppm7.48(d,J=2.0Hz,2H),7.37(t,J=1.9Hz,1H),6.97-6.90(m,2H),2.30(d,J=2.2Hz,3H)。
步骤3:5-((3',5'-二氯-4-氟-5-甲基-[1,1'-联苯]-3-基)氧基)-2-(甲硫基)嘧啶
向3',5'-二氯-4-氟-5-甲基-[1,1'-联苯]-3-醇(2400mg,7.97mmol)和5-溴-2-(甲硫基)嘧啶(2451mg,11.95mmol)在1,4-二噁烷(170mL)中的混合物中添加2-(二甲基氨基)乙酸(82mg,0.797mmol)、Cs2CO3(7788mg,23.90mmol)和CuI(152mg,0.797mmol)。将混合物在90℃搅拌72h。将混合物过滤,浓缩以得到残余物,将其在DCM(500mL)和H2O(500mL)之间分配,用DCM(300mL x2)萃取。合并的有机层用盐水(400mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗产物通过快速色谱法(从纯的PE至EtOAc/PE=1/1,TLC:PE/EtOAc=2/1,Rf=0.5)纯化以得到5-((3',5'-二氯-4-氟-5-甲基-[1,1'-联苯]-3-基)氧基)-2-(甲硫基)嘧啶(1.6g,3.04mmol,38.1%产率),其为淡黄色油状物:1H NMR(400MHz,CD3OD)δppm 7.88(s,1H),7.55-7.52(m,2H),7.35(s,2H),7.12(d,J=8.5Hz,2H),2.53(s,3H),2.40(m,3H);ES-LCMS m/z 395.0,397.0[M+H]+.
步骤4:5-((3',5'-二氯-4-氟-5-甲基-[1,1'-联苯]-3-基)氧基)-2-(甲基磺酰基)嘧啶
向5-((3',5'-二氯-4-氟-5-甲基-[1,1'-联苯]-3-基)氧基)-2-(甲硫基)嘧啶(1.5g,2.85mmol)在MeOH(50mL)中的溶液中添加Oxone(1.925g,3.13mmol)。然后将反应混合物在15℃搅拌2h。将固体过滤掉且将滤液浓缩。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.7)纯化以得到5-((3',5'-二氯-4-氟-5-甲基-[1,1'-联苯]-3-基)氧基)-2-(甲基磺酰基)嘧啶(1.4g,2.457mmol,86.0%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 8.70(s,2H),7.59-7.55(m,1H),7.61-7.55(m,1H),7.53-7.45(m,2H),7.43(t,J=1.9Hz,1H),2.98(s,3H),2.43(d,J=2.0Hz,3H);ES-LCMS m/z 426.9,428.9[M+H]+.
步骤5:5-((5-(溴甲基)-3',5'-二氯-4-氟-[1,1'-联苯]-3-基)氧基)-2-(甲基磺酰基)嘧啶
将5-((3',5'-二氯-4-氟-5-甲基-[1,1'-联苯]-3-基)氧基)-2-(甲基磺酰基)嘧啶(380mg,0.667mmol)、NBS(190mg,1.067mmol)和AIBN(10.95mg,0.067mmol)在CCl4(10mL)中的混合物在85℃搅拌12h。将混合物浓缩以得到粗产物。粗物质通过快速色谱法(从PE/EtOAc=3/1至1/1,TLC:PE/EtOAc=1/1,Rf=0.6)纯化以得到5-((5-(溴甲基)-3',5'-二氯-4-氟-[1,1'-联苯]-3-基)氧基)-2-(甲基磺酰基)嘧啶(380mg,0.526mmol,79.0%产率),其为黄色油状物:1H NMR(400MHz,CD3OD)δppm 8.77-8.70(m,2H),7.74(ddd,J=2.3,6.7,18.3Hz,2H),7.65-7.62(m,1H),7.65-7.62(m,1H),7.47(t,J=1.8Hz,1H),4.69(s,2H),3.36-3.35(m,3H);ES-LCMSm/z 504.9,506.9[M+H]+.
步骤6:2-(1-((3',5'-二氯-4-氟-5-((2-(甲基磺酰基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸甲酯
向5-((5-(溴甲基)-3',5'-二氯-4-氟-[1,1'-联苯]-3-基)氧基)-2-(甲基磺酰基)嘧啶(380mg,0.526mmol)和2-(哌啶-4-基)乙酸甲酯(138mg,0.788mmol)在DMF(10mL)中的溶液中添加K2CO3(218mg,1.577mmol)。将混合物在80℃搅拌12h。将混合物过滤掉且将溶剂真空去除以得到粗产物。粗物质通过快速色谱法(从PE/EtOAc=5/1至1/1,TLC:PE/EtOAc=1/1,Rf=0.6)纯化以得到2-(1-((3',5'-二氯-4-氟-5-((2-(甲基磺酰基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸甲酯(350mg,0.466mmol,89.0%产率),其为黄色油状物:1H NMR(400MHz,CD3OD)δppm 8.73(s,2H),7.68(dd,J=3.7,6.4Hz,2H),7.64(d,J=1.8Hz,2H),7.45(t,J=1.8Hz,1H),3.70(s,2H),3.63(s,3H),3.35(s,3H),3.00-2.98(m,2H),2.25(d,J=6.6Hz,2H),2.17(t,J=11.0Hz,2H),1.73(d,J=12.3Hz,3H),1.32(d,J=12.1Hz,2H);ES-LCMS m/z 582.2,584.2[M+H]+.
步骤7:2-(1-((3',5'-二氯-4-氟-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸甲酯
将1-甲基哌嗪(466mg,4.66mmol)、2-(1-((3',5'-二氯-4-氟-5-((2-(甲基磺酰基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸甲酯(350mg,0.466mmol)和DIEA(301mg,2.328mmol)在t-BuOH(0.5mL)中的混合物在155℃在微波下搅拌2h。将混合物浓缩以得到粗产物。粗物质通过快速色谱法(从PE/EtOAc=3/1至1/1,TLC:PE/EtOAc=1/1,Rf=0.5)纯化以得到2-(1-((3',5'-二氯-4-氟-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸甲酯(300mg,0.443mmol,95.0%产率),其为黄色油状物:1H NMR(400MHz,CD3OD)δppm 8.23(s,2H),7.53(d,J=1.8Hz,2H),7.45-7.43(m,1H),7.41(t,J=1.9Hz,1H),7.23(dd,J=2.2,7.3Hz,1H),3.79(br s,2H),3.65(s,2H),3.63(s,3H),3.51(br s,4H),2.94(d,J=11.5Hz,2H),2.51(br s,2H),2.32(s,3H),2.25(d,J=6.8Hz,2H),2.17-2.10(m,2H),1.72(d,J=12.3Hz,3H),1.31(d,J=10.1Hz,2H);ES-LCMS m/z 602.3,604.3[M+H]+.
步骤8:2-(1-((3',5'-二氯-4-氟-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸,3盐酸盐
2-(1-((3',5'-二氯-4-氟-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸甲酯(280mg,0.414mmol)在浓HCl(8mL,65.2mmol)中的混合物。将该混合物在80℃搅拌20min。将溶剂浓缩以得到粗产物,粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到2-(1-((3',5'-二氯-4-氟-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸,3盐酸盐(85.15mg,0.118mmol,28.6%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm 8.40(s,2H),7.72(d,J=4.0Hz,1H),7.63(d,J=1.5Hz,2H),7.49-7.42(m,2H),4.88(br s,2H),4.50(s,2H),3.65-3.58(m,4H),3.40-3.34(m,2H),3.23-3.12(m,4H),2.96(s,3H),2.37-2.27(m,2H),2.07(d,J=12.6Hz,3H),1.73-1.52(m,2H);ES-LCMS m/z 588.2,590.2[M+H]+.
实施例377:2-(1-((6-(3,5-二氯苯基)-3-氟-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
步骤1:4-(5-((4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-氟吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
将4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-2-氯-6-(3,5-二氯苯基)-3-氟吡啶(600mg,1.212mmol)、4-(5-羟基吡啶-2-基)哌嗪-1-甲酸叔丁酯(635mg,2.182mmol)、CuI(23.08mg,0.121mmol)、Cs2CO3(1185mg,3.64mmol)和2-(二甲基氨基)乙酸(12.50mg,0.121mmol)在1,4-二噁烷(5mL)中的混合物在110℃在N2气氛搅拌24h。将混合物过滤且将滤液浓缩以得到粗物质。粗物质通过快速色谱法(从PE/EtOAc=5/1至3/1,TLC:PE/EtOAc=3/1,Rf=0.6)纯化以得到4-(5-((4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-氟吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(180mg,0.231mmol,19.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 8.16(d,J=2.8Hz,1H),7.62(d,J=1.8Hz,2H),7.58(d,J=3.5Hz,1H),7.47(m,J=2.8,9.0Hz,1H),7.41(t,J=1.8Hz,1H),7.32-7.29(m,1H),4.89(s,2H),3.57-3.53(m,8H),1.49(s,9H),0.99(s,9H),0.17(s,6H);ES-LCMS m/z 663.2,665.2[M+H]+.
步骤2:4-(5-((6-(3,5-二氯苯基)-3-氟-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-氟吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(230mg,0.295mmol)在THF(5mL)中的溶液中添加TBAF(231mg,0.884mmol)且将混合物在25℃搅拌15min。粗物质通过快速色谱法(从PE/EtOAc=5/1至3/1,TLC:PE/EtOAc=3/1,Rf=0.6)纯化以得到4-(5-((6-(3,5-二氯苯基)-3-氟-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(180mg,0.278mmol,95.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 8.16(d,J=2.9Hz,1H),7.65(d,J=1.8Hz,2H),7.60(d,J=4.0Hz,1H),7.47(dd,J=3.0,9.2Hz,1H),7.31(t,J=1.9Hz,1H),6.74(d,J=8.6Hz,1H),4.93(d,J=4.4Hz,2H),3.59-3.56(m,4H),3.56-3.53(m,4H),1.50(s,9H);ES-LCMS m/z 549.2,551.2[M+H]+.
步骤3:4-(5-((6-(3,5-二氯苯基)-3-氟-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-3-氟-4-(羟基甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(170mg,0.263mmol)在DCM(4mL)中的溶液中添加DIEA(0.138mL,0.789mmol)和MsCl(0.027mL,0.342mmol)且将混合物在29℃搅拌15min。添加饱和NaHCO3水溶液(20mL)。将混合物用DCM(20mL×3)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到4-(5-((6-(3,5-二氯苯基)-3-氟-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(160mg,0.229mmol,87.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 8.21(d,J=2.6Hz,1H),7.57(t,J=2.2Hz,1H),7.54(d,J=2.0Hz,2H),7.43(d,J=3.7Hz,1H),7.28(t,J=1.9Hz,1H),6.78(d,J=9.5Hz,1H),5.33(s,2H),3.09(s,3H),2.77(s,8H),1.42(s,9H);ES-LCMS m/z 627.2,629.2[M+H]+.
步骤4:4-(5-((6-(3,5-二氯苯基)-3-氟-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-3-氟-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(130mg,0.186mmol)和2-(哌啶-4-基)乙酸甲酯,盐酸盐(80mg,0.373mmol)在DMF(4mL)中的溶液中添加DIEA(0.163mL,0.932mmol)且将混合物在28℃搅拌12h。将反应混合物浓缩以得到残余物。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.4)纯化以得到4-(5-((6-(3,5-二氯苯基)-3-氟-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(120mg,0.160mmol,86.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm8.16(d,J=2.8Hz,1H),7.63(d,J=1.8Hz,2H),7.52-7.45(m,2H),7.31(s,1H),6.73(d,J=9.3Hz,1H),3.67(s,3H),3.57(br s,4H),3.56-3.53(m,4H),2.92(m,2H),2.28(d,J=7.0Hz,2H),2.24-2.11(m,2H),1.87-1.69(m,5H),1.39(d,J=11.8Hz,2H),0.07(s,9H);ES-LCMS m/z 688.2,690.2[M+H]+.
步骤5:2-(1-((6-(3,5-二氯苯基)-3-氟-2-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐
向4-(5-((6-(3,5-二氯苯基)-3-氟-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(130mg,0.173mmol)在DCM(3mL)中的溶液中添加TFA(0.3mL,3.89mmol)且将混合物在28℃搅拌20min。将反应混合物浓缩以得到2-(1-((6-(3,5-二氯苯基)-3-氟-2-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐(140mg,0.120mmol,69.2%产率),其为黄色油状物:1HNMR(400MHz,CDCl3)δppm 8.11(d,J=2.9Hz,1H),7.71(d,J=3.5Hz,1H),7.54(d,J=1.8Hz,2H),7.49(dd,J=2.9,9.3Hz,1H),7.26(t,J=1.8Hz,1H),6.78(d,J=9.3Hz,1H),4.33(s,2H),3.79-3.74(m,4H),3.61(s,3H),3.60-3.53(m,2H),3.32(d,J=1.8Hz,4H),2.89(d,J=14.3Hz,2H),2.31-2.25(m,2H),2.01-1.90(m,3H),1.69(q,J=11.8Hz,2H):ES-LCMS m/z 588.2,590.2[M+H]+.
步骤6:2-(1-((6-(3,5-二氯苯基)-3-氟-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((6-(3,5-二氯苯基)-3-氟-2-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐(130mg,0.111mmol)在MeOH(5mL)中的溶液中添加甲酸(0.1mL,2.61mmol)和多聚甲醛(16.68mg,0.556mmol)且将混合物在28℃搅拌15.5h。添加NaBH3CN(34.9mg,0.556mmol)且全部混合物在28℃搅拌0.5h。添加饱和NaHCO3水溶液(20mL)且将混合物用DCM(20mL×3)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到2-(1-((6-(3,5-二氯苯基)-3-氟-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(70mg,0.103mmol,93.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 8.09(d,J=2.6Hz,1H),7.56(d,J=1.8Hz,2H),7.42-7.37(m,2H),7.23(t,J=1.9Hz,1H),6.66(d,J=9.3Hz,1H),3.60(s,3H),3.57(s,2H),3.52-3.50(m,4H),2.84(br s,2H),2.51-2.48(m,4H),2.29(s,3H),2.20(d,J=7.1Hz,2H),2.11-2.05(m,2H),1.73-1.65(m,5H);ES-LCMSm/z 602.2,604.2[M+H]+.
步骤7:2-(1-((6-(3,5-二氯苯基)-3-氟-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
将2-(1-((6-(3,5-二氯苯基)-3-氟-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(65mg,0.096mmol)在4N HCl(3mL,12.00mmol)中的溶液在80℃搅拌0.5h。将反应混合物浓缩。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干以得到2-(1-((6-(3,5-二氯苯基)-3-氟-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(33.96mg,0.046mmol,48.2%产率),其为白色固体:1H NMR(400MHz,CD3OD)δppm 8.18(d,J=2.9Hz,1H),7.92(d,J=3.5Hz,1H),7.77(d,J=1.8Hz,2H),7.69(dd,J=2.8,9.4Hz,1H),7.46(t,J=1.9Hz,1H),7.13(d,J=9.0Hz,1H),4.55-4.46(m,4H),3.68-3.59(m,4H),3.49-3.30(m,2H),3.23(d,J=14.6Hz,4H),2.96(s,3H),2.31(d,J=6.6Hz,2H),2.06(d,J=12.8Hz,3H),1.69-1.54(m,2H);ES-LCMS m/z 588.2,590.2[M+H]+.
实施例378-384(表20)通过类似于实施例377所述的方法制备。
表20:
实施例385:3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸甲酯
将3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸,4盐酸盐,5H2O(135mg,0.154mmol)溶于HCl溶液(4M的MeOH溶液,5mL,20.00mmol)。然后将反应混合物在20℃搅拌12h。将溶剂浓缩以得到粗物质,其通过制备型HPLC纯化且将溶液用NaOH水溶液(1M)调节pH=7-8。将混合物用DCM(30mL×3)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩以得到3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸甲酯(54.2mg,0.080mmol,52.0%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm8.01(d,J=2.65Hz,1H),7.80(d,J=1.98Hz,2H),7.60(s,1H),7.47(dd,J=2.87,9.26Hz,1H),7.40(t,J=1.87Hz,1H),6.96(s,1H),6.92(d,J=9.04Hz,1H),3.67(s,3H),3.60(s,2H),3.56-3.50(m,4H),3.06(d,J=6.61Hz,2H),2.93(d,J=11.91Hz,2H),2.78-2.72(m,2H),2.65-2.55(m,6H),2.09(t,J=10.80Hz,2H),1.92(s,3H),1.71(d,J=11.91Hz,2H),1.52(brs,1H),1.30-1.22(m,2H);ES-LCMS m/z 655.0,657.0[M+H]+.
实施例386:2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
步骤1:2-(苄基氧基)-4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶
向18-冠-6(0.388g,1.468mmol)、K2CO3(1.218g,8.81mmol)和BnBr(1.005g,5.87mmol)在DMF(10mL)中的混合物中添加4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶-2-醇(1.3g,2.94mmol)。将混合物在80℃搅拌5h。过滤后,将滤液浓缩以得到2-(苄基氧基)-4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶(1.6g,2.62mmol,89.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm7.86(d,J=1.8Hz,2H),7.73(dd,J=1.5,7.9Hz,3H),7.45-7.43(m,3H),7.39(d,J=1.3Hz,1H),5.50(s,2H),4.72(s,2H),2.16(s,3H),0.99-0.97(m,9H),0.15-0.13(m,6H);ES-LCMSm/z 488.2,490.2[M+H]+.
步骤2:(2-(苄基氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲醇
向2-(苄基氧基)-4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-6-(3,5-二氯苯基)-3-甲基吡啶(1.5g,2.456mmol)在THF(15mL)中的溶液中添加TBAF(1M的THF溶液,5mL,5.00mmol)。将混合物在30℃搅拌30min。将混合物浓缩。粗物质通过快速色谱法(从PE/EtOAc=10/1至3/1至DCM/MeOH=10/1,TLC:PE/EtOAc=3/1,Rf=0.3)纯化以得到(2-(苄基氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲醇(0.95g,2.335mmol,95.0%产率),其为灰白色固体:1H NMR(400MHz,CDCl3)δppm 7.87(d,J=1.8Hz,2H),7.53-7.43(m,3H),7.41-7.31(m,4H),5.49(s,2H),4.75(s,2H),2.20(s,3H);ES-LCMS m/z 374.1,376.0[M+H]+.
步骤3:甲磺酸(2-(苄基氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基酯
向(2-(苄基氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲醇(0.95g,2.335mmol)和DIEA(1.240mL,7.01mmol)在DCM(30mL)中的混合物中添加MsCl(0.401g,3.50mmol)。将混合物在0℃搅拌15min。向混合物中添加H2O(15mL),用DCM(15mL x2)萃取。合并的有机层用盐水(20mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到甲磺酸(2-(苄基氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基酯(1.1g,2.189mmol,94.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 7.79(d,J=2.0Hz,2H),7.44(d,J=7.7Hz,2H),7.35-7.31(m,3H),7.27-7.22(m,2H),5.44(d,J=3.7Hz,2H),4.53(s,2H),2.71(s,3H),2.27-2.21(m,3H);ES-LCMS m/z 452.0,454.1[M+H]+.
步骤4:2-(1-((2-(苄基氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向甲磺酸(2-(苄基氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基酯(1.1g,2.189mmol)和DIEA(1.937mL,10.94mmol)在DMF(10mL)中的混合物中添加2-(哌啶-4-基)乙酸甲酯,盐酸盐(0.942g,4.38mmol)。将混合物在50℃搅拌10h。将混合物浓缩。残余物通过快速色谱法(从PE/EtOAc=10/1至2/1,TLC:PE/EtOAc=5/1,Rf=0.6)纯化以得到2-(1-((2-(苄基氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(1.15g,2.061mmol,94.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 8.01(br s,2H),7.51(d,J=7.3Hz,2H),7.47-7.37(m,3H),7.36-7.30(m,2H),5.49(s,2H),4.13(br s,2H),3.66(s,3H),3.44(br s,2H),2.78-2.53(m,2H),2.32(br s,5H),1.87(br s,3H),1.44(d,J=5.0Hz,2H);ES-LCMSm/z 513.2,515.2[M+H]+.
步骤5:2-(1-((6-(3,5-二氯苯基)-2-羟基-3-甲基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将2-(1-((2-(苄基氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(1g,1.792mmol)在TFA(5mL,64.9mmol)中的溶液在50℃搅拌4h。将反应混合物浓缩。向残余物中添加DCM/MeOH(100mL,10/1),用饱和Na2CO3水溶液(50mL)中和至pH=8-9。将混合物用DCM/MeOH(50mL,10/1)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到2-(1-((6-(3,5-二氯苯基)-2-羟基-3-甲基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(1g,1.677mmol,94.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 7.72(d,J=1.8Hz,2H),7.36(d,J=0.9Hz,1H),7.30(s,1H),3.66(s,3H),3.39(s,2H),2.83(d,J=11.7Hz,2H),2.26(d,J=7.1Hz,2H),2.20(s,3H),2.09-2.03(m,2H),1.84-1.78(m,1H),1.70(d,J=12.6Hz,2H),1.36-1.31(m,2H);ES-LCMS m/z 423.1,425.1[M+H]+.
步骤6:2-(1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((6-(3,5-二氯苯基)-2-羟基-3-甲基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(600mg,1.006mmol)和2-溴-5-氟吡啶(885mg,5.03mmol)在NMP(30mL)中的混合物中添加K2CO3(834mg,6.04mmol)。将混合物在160℃搅拌5h。过滤后,将滤液浓缩。粗物质通过快速色谱法(从纯的PE至PE/EA=5/1,TLC:PE/EA=5/1,Rf=0.6)纯化以得到2-(1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(290mg,0.355mmol,35.3%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 8.31(d,J=2.9Hz,1H),7.64(d,J=2.0Hz,2H),7.51(d,J=5.5Hz,2H),7.38(s,1H),7.30-7.29(m,1H),3.67-3.65(m,2H),3.51(s,3H),2.86(d,J=12.6Hz,4H),2.36(s,3H),2.13-2.09(m,2H),1.85-1.72(m,3H),1.36(br s,2H);ES-LCMS m/z 578.0,580.0,582.0[M+H]+.
步骤7:4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)-3-甲基吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
在N2气氛向2-(1-((2-((6-溴吡啶-3-基)氧基)-6-(3,5-二氯苯基)-3-甲基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(290mg,0.355mmol)、哌嗪-1-甲酸叔丁酯(331mg,1.777mmol)、Xantphos(20.57mg,0.036mmol)和Cs2CO3(347mg,1.066mmol)在THF(15mL)中的混合物中添加Pd2(dba)3(32.5mg,0.036mmol)。将混合物在75℃在N2气氛搅拌36h。将混合物过滤且将滤液浓缩。残余物通过制备型TLC(PE/EtOAc=4/1,Rf=0.2)纯化合并且浓缩以得到4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)-3-甲基吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(100mg,0.099mmol,27.9%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 7.62-7.51(m,2H),7.37-7.29(m,2H),7.21(dd,J=2.1,3.9Hz,2H),6.72-6.57(m,1H),3.60(s,2H),3.59(s,3H),3.49-3.44(m,4H),2.88-2.72(m,4H),2.39-2.25(m,3H),2.24-2.14(m,4H),2.06-1.99(m,2H),1.76-1.64(m,3H),1.47-1.25(m,11H);ES-LCMS m/z:684.3,686.3[M+H]+.
步骤8:2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐
将4-(5-((6-(3,5-二氯苯基)-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)-3-甲基吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(100mg,0.099mmol)和TFA(3mL,38.9mmol)在DCM(15mL)中的溶液在20℃搅拌1h。然后将混合物浓缩以得到2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐(140mg,0.094mmol,95.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 7.81-7.57(m,3H),7.46(br s,2H),7.10-7.07(m,1H),7.02-6.92(m,1H),4.10-4.01(m,2H),3.97(t,J=6.9Hz,2H),3.58-3.41(m,5H),2.99-2.73(m,2H),2.54(brs,2H),2.13(br s,3H),1.96-1.72(m,6H),1.63-1.40(m,2H),1.39-1.17(m,3H);ES-LCMSm/z 584.2,586.2[M+H]+.
步骤9:2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐(140mg,0.094mmol)和甲醛(28.3mg,0.942mmol)在MeOH中的混合物在30℃搅拌10h。然后向该混合物中添加NaBH3CN(29.6mg,0.471mmol)。全部混合物在30℃再搅拌2h。向混合物中添加饱和Na2CO3水溶液(20mL),用DCM(30mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(70mg,0.082mmol,87.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 7.70-7.48(m,2H),7.39-7.33(m,1H),7.27-7.20(m,3H),7.19-7.13(m,1H),3.60(s,2H),3.54-3.41(m,4H),3.40(br s,3H),2.79(td,J=3.8,7.6Hz,2H),2.61-2.42(m,2H),2.41-2.13(m,6H),2.10-1.96(m,2H),1.90(dt,J=2.3,11.7Hz,2H),1.76-1.70(m,1H),1.69-1.53(m,4H),1.31-1.24(m,2H);ES-LCMSm/z:598.3,600.3[M+H]+.
步骤10:2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
将2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(70mg,0.082mmol)和浓HCl(2mL,24.35mmol)的溶液在60℃搅拌0.5h。将混合物浓缩。残余物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干以得到2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(4.97mg,6.75μmol,8.25%产率),其为白色固体:1H NMR(400MHz,D2O/CD3CN=1/1)δppm 8.05(d,J=2.6Hz,1H),7.72(d,J=1.8Hz,2H),7.64-7.59(m,2H),7.46-7.43(m,1H),7.02(d,J=9.3Hz,1H),4.34(s,2H),4.26(d,J=15.4Hz,2H),3.58-3.44(m,4H),3.21(d,J=11.7Hz,2H),3.14-3.01(m,4H),2.85(s,3H),2.38(s,3H),2.27(d,J=6.4Hz,2H),2.04-1.96(m,3H),1.49(d,J=13.0Hz,2H);ES-LCMS m/z:584.2,586.3[M+H]+.
实施例387:2-(1-((2-((2-(4-((1H-1,2,3-三唑-5-基)甲基)哌嗪-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1:2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯
向K2CO3(115mg,0.832mmol)和2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯(500mg,0.757mmol)在DCE(20mL)中的混合物中滴加3-溴丙-1-炔(80%的甲苯溶液)(0.159mL,0.832mmol)。然后将混合物在25℃搅拌5h。向混合物中添加水(50mL),用DCM(30mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。残余物通过快速色谱法(从PE/EtOAc=3/1至2/1,TLC:PE/EtOAc=2/1,Rf=0.4)纯化以得到2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯(350mg,0.524mmol,69.2%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 8.30(s,2H),7.73(d,J=1.8Hz,2H),7.41(s,1H),7.34(t,J=1.8Hz,1H),6.89(s,1H),4.16-4.10(m,2H),3.94-3.85(m,4H),3.52(s,2H),3.37(d,J=2.4Hz,2H),2.90-2.82(m,2H),2.73-2.61(m,4H),2.30-2.21(m,3H),2.11-2.04(m,2H),1.80(d,J=10.6Hz,1H),1.72(d,J=13.2Hz,2H),1.42-1.30(m,2H),1.25(t,J=7.2Hz,3H);ES-LCMS m/z:623.3,625.3[M+H]+.
步骤2:2-(1-((2-((2-(4-((1H-1,2,3-三唑-5-基)甲基)哌嗪-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸
向2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸乙酯(300mg,0.449mmol)、3,3',3”-(4,4',4”-(次氮基(nitrilo)三(亚甲基))三(1H-1,2,3-三唑-4,1-二基))三(丙-1-醇)(78mg,0.180mmol)、(R)-2-((S)-1,2-二羟基乙基)-4-羟基-5-氧代-2,5-二氢呋喃-3-醇钠盐(89mg,0.449mmol)和CuSO4(14.33mg,0.090mmol)在t-BuOH(1mL)、DMSO(1mL)和水(1mL)中的混合物中添加TMS-N3(56.9mg,0.494mmol)。然后将反应混合物在25℃搅拌12h。向该混合物中添加LiOH·H2O(56.5mg,1.346mmol)且在25℃搅拌4h。将混合物用1N HCl酸化至pH=5。混合物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干以得到残余物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,碱性条件)纯化,然后冻干以得到2-(1-((2-((2-(4-((1H-1,2,3-三唑-5-基)甲基)哌嗪-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸(55.42mg,0.085mmol,19.0%产率),其为白色固体:1H NMR(400MHz,CD3OD)δppm 8.30(s,2H),7.80(d,J=2.0Hz,2H),7.77(s,1H),7.65(s,1H),7.42(t,J=1.9Hz,1H),7.04(s,1H),3.89-3.80(m,4H),3.75(s,2H),3.68(s,2H),2.97(d,J=11.7Hz,2H),2.59(t,J=5.0Hz,4H),2.28-2.12(m,4H),1.79(d,J=10.4Hz,3H),1.44-1.29(m,2H);ES-LCMS m/z 638.3,640.3[M+H]+.
实施例388:2-(1-((2-(3,5-二氯苯基)-6-(甲基(2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
步骤1:2-(3,5-二氯苯基)-6-(甲基(2-(甲硫基)嘧啶-5-基)氨基)异烟酸甲酯
向2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氨基)异烟酸甲酯(500mg,0.949mmol)、Mel(1078mg,7.60mmol)在DMF(5mL)中的混合物中添加t-BuOK(320mg,2.85mmol)。将混合物在20℃搅拌1h。将混合物过滤且浓缩。粗物质通过快速色谱法(从纯的PE至PE/EA=5/1,TLC:PE/EA=5/1,Rf=0.7)纯化以得到2-(3,5-二氯苯基)-6-(甲基(2-(甲硫基)嘧啶-5-基)氨基)异烟酸甲酯(400mg,0.735mmol,77.0%产率),其为淡黄色固体:1HNMR(400MHz,CDCl3)δppm 8.55(s,2H),7.88(d,J=1.8Hz,2H),7.67(s,1H),7.38(d,J=2.0Hz,1H),7.09(s,1H),3.92(s,3H),3.57(s,3H),2.61(s,3H);ES-LCMS m/z 435.0,437.0[M+H]+.
步骤2:(2-(3,5-二氯苯基)-6-(甲基(2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲醇
在-40℃向2-(3,5-二氯苯基)-6-(甲基(2-(甲硫基)嘧啶-5-基)氨基)异烟酸甲酯(380mg,0.698mmol)在THF(12mL)中的溶液中分批添加LiAlH4(39.8mg,1.047mmol)。然后将反应混合物在-40℃搅拌10min。在-10℃反应混合物通过添加水(1mL)和1M NaOH水溶液(1mL)淬灭,然后添加MgSO4(1.5g)。将混合物过滤且浓缩。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=20/1,TLC:DCM/MeOH=20/1,Rf=0.45)纯化以得到(2-(3,5-二氯苯基)-6-(甲基(2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲醇(330mg,0.567mmol,81.0%产率),其为淡黄色固体:1H NMR(400MHz,CD3OD)δppm8.65(s,2H),7.90(d,J=2.0Hz,2H),7.47-7.42(m,1H),7.30(s,1H),6.79(d,J=0.7Hz,1H),4.63(s,2H),3.54(s,3H),2.60(s,3H);ES-LCMS m/z 407.1,409.0[M+H]+.
步骤3:甲磺酸(2-(3,5-二氯苯基)-6-(甲基(2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲基酯
在20℃向(2-(3,5-二氯苯基)-6-(甲基(2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲醇(330.000mg,0.567mmol)和DIEA(0.594mL,3.40mmol)在DCM(10.00mL)中的溶液中添加MsCl(0.080mL,1.021mmol)。然后将反应混合物在20℃搅拌15min。添加水(80mL)且用DCM(50mL x2)萃取。合并的有机层用Na2SO4干燥且浓缩以得到甲磺酸(2-(3,5-二氯苯基)-6-(甲基(2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲基酯(340mg,0.490mmol,86.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 8.54(s,2H),7.83(d,J=2.0Hz,2H),7.40-7.36(m,1H),7.14(s,1H),6.51(s,1H),5.13(s,2H),3.54(s,3H),3.05(s,3H),2.62-2.60(m,3H);ES-LCMSm/z 485.1,487.0[M+H]+.
步骤4:2-(1-((2-(3,5-二氯苯基)-6-(甲基(2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向甲磺酸(2-(3,5-二氯苯基)-6-(甲基(2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲基酯(340mg,0.490mmol)和2-(哌啶-4-基)乙酸甲酯(111mg,0.637mmol)在DMF(10mL)中的溶液中添加DIEA(0.428mL,2.452mmol)。然后将反应混合物在20℃搅拌12h。溶剂浓缩以得到粗产物。粗物质通过快速色谱法(DCM/MeOH=20/1至10/1,TLC:DCM/MeOH=10/1,Rf=0.65)纯化以得到2-(1-((2-(3,5-二氯苯基)-6-(甲基(2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(300mg,0.439mmol,90.0%产率),其为淡黄色固体:1HNMR(400MHz,CDCl3)δppm 8.57(s,2H),8.04-8.01(m,1H),7.86(s,2H),7.37(br s,1H),7.24-7.19(m,1H),3.68(s,2H),3.57(s,3H),2.97(s,3H),2.65-2.48(m,5H),2.28(br s,2H),2.07(d,J=16.1Hz,3H),1.74(br s,4H);ES-LCMS m/z 546.2,548.2[M+H]+.
步骤5:2-(1-((2-(3,5-二氯苯基)-6-(甲基(2-(甲基亚磺酰基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((2-(3,5-二氯苯基)-6-(甲基(2-(甲硫基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(300mg,0.439mmol)在MeOH(15mL)中的溶液中添加Oxone(216mg,0.351mmol)。然后将混合物在25℃搅拌1h。将固体过滤掉且添加饱和Na2SO3水溶液(50mL)且用DCM(30mL×3)萃取。将合并的有机层合并,用Na2SO4干燥,过滤且浓缩以得到粗产物。粗物质通过快速色谱法(从DCM/MeOH=20/1至10/1,TLC:DCM/MeOH=10/1,Rf=0.55)纯化以得到2-(1-((2-(3,5-二氯苯基)-6-(甲基(2-(甲基亚磺酰基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(290mg,0.412mmol,94.0%产率),其为淡黄色固体:1HNMR(400MHz,CDCl3)δppm 8.91(s,2H),7.81(br s,2H),7.51(br s,1H),7.40(d,J=17.3Hz,1H),7.33(s,1H),4.08(d,J=9.3Hz,2H),3.49(s,3H),3.02-2.77(m,6H),2.35-2.25(m,4H),2.04-1.95(m,3H),1.88-1.84(m,2H),1.32-1.16(m,2H);ES-LCMSm/z 562.2,564.2[M+H]+.
步骤6:2-(1-((2-(3,5-二氯苯基)-6-(甲基(2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将2-(1-((2-(3,5-二氯苯基)-6-(甲基(2-(甲基亚磺酰基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(280mg,0.398mmol)、1-甲基哌嗪(199mg,1.991mmol)和DIEA(257mg,1.991mmol)在t-BuOH(1.5mL)中的混合物在150℃在微波下搅拌1.5h。将溶剂浓缩以得到2-(1-((2-(3,5-二氯苯基)-6-(甲基(2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯粗产物(310mg,0.373mmol,94.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 8.24-8.19(m,2H),7.84(d,J=2.0Hz,2H),7.28(t,J=1.9Hz,1H),7.03(s,1H),6.26(s,1H),3.85-3.81(m,4H),3.59(s,3H),3.42(s,3H),3.27(s,2H),2.74(br s,2H),2.45(t,J=5.0Hz,4H),2.30(s,3H),2.17(d,J=7.1Hz,2H),1.94-1.87(m,2H),1.70(d,J=3.7Hz,3H),1.25-1.20(m,2H);ES-LCMS m/z 598.3,600.3[M+H]+.
步骤7:2-(1-((2-(3,5-二氯苯基)-6-(甲基(2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐
2-(1-((2-(3,5-二氯苯基)-6-(甲基(2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(300mg,0.361mmol)在浓HCl(1mL,8.15mmol)和水(4mL)中的混合物。将混合物在80℃搅拌15min。将溶剂浓缩以得到粗产物,其通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化且冻干以得到2-(1-((2-(3,5-二氯苯基)-6-(甲基(2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸,4盐酸盐(239.05mg,0.327mmol,91.0%产率),其为黄色固体:1H NMR(400MHz,CD3OD)δppm 8.48(s,2H),7.99(d,J=1.8Hz,2H),7.49(t,J=1.9Hz,1H),7.43-7.41(m,1H),6.87(s,1H),4.98(br s,2H),4.24(s,2H),3.60(d,J=13.0Hz,2H),3.54(s,3H),3.50(d,J=12.8Hz,2H),3.39(br s,2H),3.27-3.20(m,2H),3.05(t,J=11.8Hz,2H),2.98(s,3H),2.30(d,J=6.6Hz,2H),2.02(d,J=13.9Hz,3H),1.65-1.55(m,2H);ES-LCMS m/z 584.2,586.2[M+H]+.
实施例389:2-(1-((2-(3,5-二氯苯基)-6-(乙基(2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸
实施例389通过类似于实施例388所述的方法制备:1H NMR(400MHz,CD3OD)δppm8.45(s,2H),8.01(d,J=2.0Hz,2H),7.50(t,J=1.9Hz,1H),7.38(s,1H),6.78(s,1H),4.98(d,J=14.6Hz,2H),4.21(s,2H),4.05(q,J=7.2Hz,2H),3.61(d,J=12.3Hz,2H),3.51-3.39(m,4H),3.29-3.23(m,2H),3.08-3.00(m,2H),2.99(s,3H),2.30(d,J=6.6Hz,2H),2.01(d,J=12.6Hz,3H),1.66-1.53(m,2H),1.31(t,J=7.1Hz,3H);LCMS m/z 598.3,600.3[M+H]+.
实施例390:2-(1-((6-(3,5-二氯苯基)-3-氟-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
步骤1:2-乙酰氧基-6-(3,5-二氯苯基)-3-氟异烟酸甲酯
将2-(3,5-二氯苯基)-5-氟-4-(甲氧基羰基)吡啶1-氧化物(8g,20.25mmol)在Ac2O(80mL,848mmol)中的溶液在110℃搅拌12h。将反应混合物浓缩以得到粗产物。粗物质通过快速色谱法(从PE/EtOAc=5/1至2/1,TLC:PE/EtOAc=3/1,Rf=0.8)纯化以得到2-乙酰氧基-6-(3,5-二氯苯基)-3-氟异烟酸甲酯(3.5g,8.65mmol,42.7%产率),其为白色固体:1H NMR(400MHz,CDCl3)8.03(d,J=3.7Hz,1H),7.79(s,2H),7.35(s,1H),3.95(s,3H),2.37(s,3H);ES-LCMS m/z 316.0,318.0[M+H-Ac]+.
步骤2:6-(3,5-二氯苯基)-3-氟-4-(羟基甲基)吡啶-2-醇
在25℃向2-乙酰氧基-6-(3,5-二氯苯基)-3-氟异烟酸甲酯(2600mg,6.42mmol)在THF(100mL)中的溶液中分批添加LiAlH4(1219mg,32.1mmol)。然后将反应混合物在25℃搅拌30min。添加NaOH水溶液(1.2mL,10%)和H2O(1.2mL)以淬灭反应。将固体过滤掉且将溶剂真空去除以得到6-(3,5-二氯苯基)-3-氟-4-(羟基甲基)吡啶-2-醇(2000mg,5.40mmol,84.0%产率),其为白色固体:1H NMR(400MHz,CDCl3)δppm7.83(d,J=2.0Hz,2H),7.31(t,J=1.9Hz,1H),6.88(d,J=4.0Hz,1H),4.64(d,J=1.1Hz,2H);ES-LCMS m/z 288.0,290.1[M+H]+.
步骤3:(2-(苄基氧基)-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲醇
向6-(3,5-二氯苯基)-3-氟-4-(羟基甲基)吡啶-2-醇(2000mg,5.40mmol)和(溴甲基)苯(1847mg,10.80mmol)在DMF(50mL)中的溶液中添加K2CO3(2239mg,16.20mmol)。然后将反应混合物在25℃搅拌2h。将固体过滤掉且将溶剂真空去除以得到粗产物。粗物质通过快速色谱法(从PE/EtOAc=50/1至3/1,TLC:PE/EtOAc=5/1,Rf=0.7)纯化以得到(2-(苄基氧基)-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲醇(2000mg,4.71mmol,87.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm7.79(d,J=1.8Hz,2H),7.50(d,J=5.1Hz,2H),7.47-7.42(m,1H),7.41-7.32(m,4H),5.54(d,J=2.6Hz,2H),4.83(s,2H);ES-LCMS m/z 378.1,380.1[M+H]+.
步骤4:甲磺酸(2-(苄基氧基)-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲基酯
向(2-(苄基氧基)-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲醇(2000mg,4.71mmol)、DIEA(1216mg,9.41mmol)在DCM(80mL)中的混合物中添加MsCl(647mg,5.65mmol)。然后,将混合物在20℃搅拌20min。该反应用DCM(20mL)和水(20mL)稀释,用DCM(30mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且蒸发以得到甲磺酸(2-(苄基氧基)-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲基酯(2300mg,4.31mmol,92.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm7.72(d,J=1.8Hz,2H),7.45(d,J=7.1Hz,2H),7.35(s,1H),7.34-7.25(m,5H),5.49(s,2H),5.26(s,2H),3.04(s,3H);ES-LCMS m/z 456.1,458.1[M+H]+.
步骤5:2-(1-((2-(苄基氧基)-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向甲磺酸(2-(苄基氧基)-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲基酯(2300mg,4.31mmol)和2-(哌啶-4-基)乙酸甲酯,盐酸盐(1857mg,8.63mmol)在DMF(80mL)中的溶液中添加DIEA(2788mg,21.57mmol)。将混合物在40℃搅拌5h。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=20/1,TLC:DCM/MeOH=20/1,Rf=0.6)纯化以得到2-(1-((2-(苄基氧基)-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(2100mg,3.57mmol,83.0%产率),其为棕色固体:1H NMR(400MHz,CD3OD)δppm 8 7.83(d,J=1.8Hz,2H),7.68(s,1H),7.51(d,J=7.5Hz,2H),7.42-7.36(m,2H),7.36-7.29(m,2H),5.53(s,2H),3.84(s,2H),3.65(s,3H),3.11(s,2H),2.36(s,2H),2.28(d,J=7.1Hz,2H),1.88(s,1H),1.79(d,=13.2Hz,2H),1.62(s,2H);ES-LCMS m/z 517.1,519.2[M+H]+.
步骤6:2-(1-((6-(3,5-二氯苯基)-3-氟-2-羟基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
将2-(1-((2-(苄基氧基)-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(2000mg,3.40mmol)在TFA(20mL,260mmol)中的溶液在50℃搅拌4h。将混合物浓缩,然后添加饱和NaHCO3水溶液(80mL)。将混合物用DCM(100mL×3)萃取。合并的有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.6)纯化以得到2-(1-((6-(3,5-二氯苯基)-3-氟-2-羟基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(1300mg,2.80mmol,82.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm7.61(s,2H),7.41(s,1H),6.69(s,1H),3.68-3.61(m,5H),3.01-2.95(m,2H),2.26(d,J=7.1Hz,4H),1.84(s,1H),1.75(d,J=12.3Hz,2H),1.47-1.33(m,2H);ES-LCMS m/z 427.1,429.1[M+H]+.
步骤7:2-(1-((2-((5-氯吡嗪-2-基)氧基)-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((6-(3,5-二氯苯基)-3-氟-2-羟基吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(400mg,0.861mmol)和2,5-二氯吡嗪(1283mg,8.61mmol)在DMF(10mL)中的混合物中添加K3PO4(914mg,4.31mmol)。将反应混合物在120℃搅拌16h。混合物冷却且过滤。将滤液浓缩以得到粗产物。粗物质通过快速色谱法(从纯的PE至PE/EtOAc=3/1,TLC:PE/EtOAc=3/1,Rf=0.6)纯化以得到2-(1-((2-((5-氯吡嗪-2-基)氧基)-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(300mg,0.453mmol,52.6%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 8.33(d,J=1.3Hz,1H),8.10(d,J=1.3Hz,1H),7.66(d,J=2.0Hz,3H),7.30(t,J=1.9Hz,1H),3.61(s,3H),3.59(s,2H),2.85-2.81(m,2H),2.22(s,2H),2.09(t,J=11.1Hz,2H),1.77(dd,J=3.7,7.5Hz,1H),1.70(s,2H),1.39-1.29(m,2H);ES-LCMSm/z539.1,541.1[M+H]+.
步骤8:4-(5-((6-(3,5-二氯苯基)-3-氟-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯
将2-(1-((2-((5-氯吡嗪-2-基)氧基)-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(200mg,0.302mmol)、Cs2CO3(500mg,1.535mmol)、哌嗪-1-甲酸叔丁酯(112mg,0.604mmol)、Xantphos(20mg,0.035mmol)和Pd2(dba)3(20mg,0.022mmol)在THF(30mL)中的混合物在80℃在N2气氛搅拌14h。混合物冷却且过滤。将滤液浓缩以得到粗产物。粗物质通过快速色谱法(从PE/EtOAc=10/1至3/1,TLC:PE/EtOAc=3/1,Rf=0.4)纯化以得到4-(5-((6-(3,5-二氯苯基)-3-氟-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(150mg,0.208mmol,68.9%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 8.15(d,J=1.3Hz,1H),7.79(d,J=1.3Hz,1H),7.64(d,J=1.8Hz,2H),7.57(d,J=3.7Hz,1H),7.31(t,J=1.9Hz,1H),3.67(s,3H),3.64(s,2H),3.57(d,J=5.3Hz,8H),2.88(d,J=11.2Hz,2H),2.27(d,J=7.1Hz,2H),2.17-2.11(m,2H),1.88-1.81(m,1H),1.73(d,J=13.0Hz,2H),1.49(s,9H),1.36(d,J=9.9Hz,2H);ES-LCMS m/z 689.3,691.3[M+H]+.
步骤9:2-(1-((6-(3,5-二氯苯基)-3-氟-2-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐
向4-(5-((6-(3,5-二氯苯基)-3-氟-4-((4-(2-甲氧基-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-甲酸叔丁酯(150mg,0.208mmol)在DCM(15mL)中的混合物中添加TFA(5mL,64.9mmol)。然后,将混合物在20℃搅拌10min。将反应浓缩以得到2-(1-((6-(3,5-二氯苯基)-3-氟-2-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐(220mg,0.168mmol,81.0%产率),其为棕色固体:1HNMR(400MHz,CD3OD)δppm8.27(d,J=1.3Hz,1H),8.10(d,J=1.3Hz,1H),7.91(d,J=3.7Hz,1H),7.74(d,J=1.8Hz,2H),7.49(t,J=1.9Hz,1H),4.54(s,2H),3.89(d,J=5.3Hz,4H),3.67(s,3H),3.63(s,2H),3.39(d,J=5.3Hz,4H),3.27-3.11(m,2H),2.36(s,2H),2.19-2.09(m,1H),2.05(d,J=14.6Hz,2H),1.58(d,J=14.3Hz,2H);ES-LCMSm/z 589.2,591.2[M+H]+.
步骤10:2-(1-((6-(3,5-二氯苯基)-3-氟-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯
向2-(1-((6-(3,5-二氯苯基)-3-氟-2-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯,4三氟乙酸盐(220mg,0.168mmol)、甲酸(0.032mL,0.842mmol)在MeOH(10mL)中的混合物中添加多聚甲醛(25.3mg,0.842mmol)。溶液在20℃搅拌10h。然后,向反应混合物中添加NaBH3CN(178mg,0.842mmol),然后在20℃搅拌2h。反应混合物通过添加饱和NaHCO3水溶液(30mL)淬灭。分离水层且用DCM(30mL x2)萃取。合并的有机层用Na2SO4干燥,过滤且蒸发以得到2-(1-((6-(3,5-二氯苯基)-3-氟-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(110mg,0.157mmol,93.0%产率),其为棕色固体:1H NMR(400MHz,CDCl3)δppm 8.07(d,J=1.3Hz,1H),7.73(d,J=1.3Hz,1H),7.58(d,J=2.0Hz,2H),7.50(d,J=3.5Hz,1H),7.27-7.24(m,1H),3.60(s,3H),3.57(s,2H),3.54(d,J=4.9Hz,4H),2.83(d,J=7.5Hz,4H),2.50(d,J=5.1Hz,4H),2.30(s,3H),2.21(s,2H),2.11-2.04(m,3H),1.67(d,J=11.7Hz,2H);ES-LCMS m/z 603.2,605.2[M+H]+.
步骤11:2-(1-((6-(3,5-二氯苯基)-3-氟-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸
将2-(1-((6-(3,5-二氯苯基)-3-氟-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸甲酯(110mg,0.157mmol)、LiOH·H2O(65.8mg,1,567mmol)在THF(5mL)和H2O(1.00mL)中的溶液在20℃搅拌30h。用2N HCl将混合物pH调节至5-6且将反应混合物浓缩以得到粗产物。粗产物通过制备型HPLC(MeCN/H2O作为洗脱剂,中性条件)纯化且冻干干燥以得到2-(1-((6-(3,5-二氯苯基)-3-氟-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸(48.41mg,0.080mmol,51.2%产率),其为白色固体:1H NMR(400MHz,DMSO-d6)δppm 8.22(d,J=1.1Hz,1H),8.01(s,1H),7.86(d,J=4.0Hz,1H),7.77(d,J=1.8Hz,2H),7.60(t,J=1.8Hz,1H),3.57(s,2H),3.52-3.49(m,4H),2.77(d,J=10.6Hz,2H),2.40-2.37(m,4H),2.18(s,3H),1.99-1.94(m,2H),1.74(d,J=6.6Hz,2H),1.61(d,J=12.3Hz,3H),1.13-1.05(m,2H);ES-LCMSm/z 589.2,591.2[M+H]+.
实施例391-396(表21)通过类似于实施例390所述的方法制备。
表21:
实施例397:(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸,4盐酸盐
步骤1:(2-(3,5-二氯苯基)-6-((2-(甲基亚磺酰基)嘧啶-5-基)氧基)吡啶-4-基)甲醇
向(2-(3,5-二氯苯基)-6-((2-(甲硫基)嘧啶-5-基)氧基)吡啶-4-基)甲醇(2g,4.31mmol)在MeOH(20mL)和DCM(10mL)中的溶液中添加Oxone(3.18g,5.17mmol)。然后将反应混合物在10℃搅拌10h。过滤后,将滤液浓缩。粗产物通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.55)纯化以得到(2-(3,5-二氯苯基)-6-((2-(甲基亚磺酰基)嘧啶-5-基)氧基)吡啶-4-基)甲醇(1.65g,3.43mmol,80.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 9.07-9.01(m,2H),7.82(d,J=1.8Hz,2H),7.74(s,1H),7.47(t,J=1.9Hz,1H),7.24(d,J=0.8Hz,1H),4.80(s,2H),3.04(s,3H);ES-LCMS m/z:410.1,412.0[M+H]+.
步骤2:4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
向(2-(3,5-二氯苯基)-6-((2-(甲基亚磺酰基)嘧啶-5-基)氧基)吡啶-4-基)甲醇(1g,2.082mmoL)和1,4-二氮杂环庚烷-1-甲酸叔丁酯(2.92g,14.57mmol)在t-BuOH(15mL)中的溶液中添加DIEA(3.64mL,20.82mmol)。然后将混合物搅拌且在130℃在微波下辐射2h。将混合物浓缩。向残余物中添加DCM/MeOH(10/1,100mL),用10%柠檬酸溶液(50mL x2)和盐水(50mL)洗涤。将有机层浓缩。残余物通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.5)纯化以得到4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(1g,1.647mmol,79.0%产率),其为黄色固体:1H NMR(400MHz,CDCl3)δppm 8.28(s,2H),7.76-7.71(m,2H),7.43(s,1H),7.34(s,1H),6.93(s,1H),4.82(s,2H),3.94-3.86(m,2H),3.84-3.74(m,2H),3.58(d,J=4.8Hz,2H),3.40-3.35(m,1H),3.30(t,J=6.1Hz,1H),2.03(br s,2H),1.49-1.44(m,9H);ES-LCMSm/z 546.2,548.2[M+H]+.
步骤3:(1R,7S,8r)-4-氮杂双环[5.1.0]辛烷-8-甲酸乙酯,TFA盐
将(1R,7S,8r)-4-氮杂双环[5.1.0]辛烷-4,8-二甲酸4-苄基8-乙基酯(2.6g,8.03mmol)和TFA(15mL)的溶液在50℃搅拌2h。LCMS显示反应完成。将混合物浓缩以得到(1R,7S,8r)-4-氮杂双环[5.1.0]辛烷-8-甲酸乙酯,TFA盐(2.9g,7.83mmol,98.0%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 4.20-4.10(m,2H),3.51(d,J=9.3Hz,2H),3.19-3.04(m,2H),2.51(d,J=15.9Hz,2H),1.82-1.59(m,5H),1.32-1.24(m,3H);ES-LCMSm/z184.1[M+H]+.
步骤4:4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
向4-(5-((6-(3,5-二氯苯基)-4-(羟基甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(500mg,0.824mmol)和DIEA(0.437mL,2.471mmol)在DCM(20mL)中的溶液中添加MsCl(0.096mL,1.235mmol)。将混合物在0℃搅拌15min。向混合物中添加水(20mL)且用DCM(20mL x 2)萃取。合并的有机层用Na2SO4干燥,过滤且蒸发以得到4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(500mg,0.721mmol,87.0%产率),其为无色油状物:1H NMR(400MHz,CDCl3)δppm 8.30(s,2H),7.73(d,J=2.0Hz,2H),7.42(s,1H),7.38(t,J=1.9Hz,1H),6.97(s,1H),5.30(s,2H),3.95-3.87(m,2H),3.83-3.77(m,2H),3.62-3.56(m,2H),3.42-3.37(m,1H),3.31(t,J=6.0Hz,1H),3.14(s,3H),2.04(br s,2H),1.47(s,9H);ES-LCMSm/z 624.2,626.1[M+H]+.
步骤5:(1R,7S,8r)-4-((2-((2-(4-(叔丁氧基羰基)-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸乙酯
向4-(5-((6-(3,5-二氯苯基)-4-(((甲基磺酰基)氧基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(500mg,0.721mmol)和(1R,7S,8r)-4-氮杂双环[5.1.0]辛烷-8-甲酸乙酯,TFA(268mg,0.721mmol)在DMF(15mL)中的溶液中添加DIEA(0.513mL,2.88mmol)。然后将混合物在20℃搅拌10h。将混合物浓缩。残余物通过快速色谱法(从PE/EtOAc=5:1至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.6)纯化以得到(1R,7S,8r)-4-((2-((2-(4-(叔丁氧基羰基)-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸乙酯(350mg,0.443mmol,61.4%产率),其为黄色固体:1H NMR(400MHz,CD3OD)δppm 8.31-8.25(m,2H),7.81-7.76(m,3H),7.66(s,1H),7.11-7.07(m,1H),4.17-4.07(m,4H),3.92-3.87(m,2H),3.80-3.78(m,2H),3.62-3.55(m,2H),3.35(d,J=6.6Hz,2H),3.21-3.19(m,2H),2.35-2.33(m,2H),1.96-1.94(m,1H),1.69-1.65(m,6H),1.46-1.41(m,2H),1.38(s,9H),1.26-1.22(m,3H);ES-LCMS m/z 711.3,713.3[M+H]+.
步骤6:(1R,7S,8r)-4-((2-((2-(1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸乙酯
向(1R,7S,8r)-4-((2-((2-(4-(叔丁氧基羰基)-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸乙酯(350mg,0.443mmol)在DCM(15mL)中的溶液中添加TFA(3mL,38.9mmol)。然后将混合物在20℃搅拌1h。然后将混合物浓缩。向残余物中添加DCM/MeOH(10/1,50mL),用2N NaOH中和至pH=7-8。有机层用盐水(50mL)洗涤,用Na2SO4干燥,过滤且浓缩以得到(1R,7S,8r)-4-((2-((2-(1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸乙酯(300mg,0.392mmol,89.0%产率),其为黄色油状物:1HNMR(400MHz,CD3OD)δppm 8.41(s,2H),7.85(d,J=1.8Hz,2H),7.51(t,J=1.9Hz,1H),7.49(s,1H),7.25(s,1H),4.48(s,2H),4.16-4.10(m,4H),4.03-3.96(m,4H),3.59(br s,2H),3.46-3.40(m,4H),2.20-2.16(m,2H),1.77-1.61(m,7H),1.23-1.20(m,3H);ES-LCMSm/z611.3,613.3[M+H]+.
步骤7:(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸乙酯
向(1R,7S,8r)-4-((2-((2-(1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸乙酯(300mg,0.392mmol)和甲酸(0.1mL,2.61mmol)在MeOH(15mL)中的溶液中添加多聚甲醛(118mg,3.92mmol)且在40℃搅拌10h。然后向该混合物中添加NaBH3CN(123mg,1.962mmol)。全部混合物在40℃再搅拌2h。向混合物中添加饱和Na2CO3溶液(30mL)和水(30mL),用DCM(50mL×3)萃取。合并的有机层用Na2SO4干燥,过滤且浓缩。粗物质通过快速色谱法(从纯的DCM至DCM/MeOH=10/1,TLC:DCM/MeOH=10/1,Rf=0.4)纯化以得到(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸乙酯(200mg,0.256mmol,65.2%产率),其为黄色油状物:1H NMR(400MHz,CDCl3)δppm 8.22(s,2H),7.66(s,2H),7.32(s,1H),7.26(s,1H),6.81(s,1H),4.04(q,J=6.8Hz,2H),3.89(d,J=4.0Hz,2H),3.78(t,J=6.0Hz,2H),3.55(s,2H),2.74-2.64(m,4H),2.59-2.51(m,2H),2.46-2.37(m,2H),2.34(s,3H),2.22-2.10(m,2H),1.99(d,J=4.9Hz,2H),1.58(br s,2H),1.52-1.39(m,3H),1.19(t,J=7.1Hz,3H);ES-LCMS m/z:625.3,627.2[M+H]+.
步骤8:(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸,4盐酸盐
向(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸乙酯(200mg,0.256mmol)在THF(5mL)和水(1mL)中的溶液中添加LiOH·H2O(32.2mg,0.767mmol)。将混合物在50℃搅拌5h。LCMS显示反应完成。将混合物浓缩。向残余物中添加MeCN(6mL)和H2O(2mL),用1N HCl酸化至pH=6.5-7。混合物通过制备型HPLC(MeCN/H2O作为洗脱剂,酸性条件)纯化,然后冻干以得到(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸,4盐酸盐(77.1mg,0.101mmol,39.4%产率),其为白色固体:1H NMR(400MHz,D2O/CD3CN=1/1)δppm 8.35(s,2H),7.78(d,J=1.8Hz,2H),7.63(s,1H),7.50(t,J=1.7Hz,1H),7.15(s,1H),4.32(br s,2H),3.87(d,J=16.5Hz,1H),3.77-3.64(m,2H),3.58(d,J=10.8Hz,1H),3.46(br s,2H),3.26-3.11(m,4H),2.81(s,3H),2.39(d,J=15.0Hz,2H),2.21(br s,2H),1.95-1.93(m,3H),1.65(br s,2H),1.53(br s,2H);ES-LCMSm/z:597.2,599.2[M+H]+.
实施例398-399(表22)通过类似于实施例397所述的方法制备。
表22:
测试方案
弗林蛋白酶测试
反应在黑色的384孔聚苯乙烯低容量板(Greiner)中进行。表达弗林蛋白酶(108-574-Tev-Flag-His),并从CHO细胞中纯化。将本发明的化合物溶解在DMSO(1.0mM)中,并通过11次稀释用DMSO以1比3连续稀释,以使最终化合物的浓度范围为0.00017至10μM。将每种浓度的0.05μL转移至测定板的相应孔中,然后使用Multidrop Combi(Thermo)将5μL 40pM弗林蛋白酶在测定缓冲液(100mM HEPES pH7.5、1mM CaCl2和0.005%Triton X-100)中的溶液加入至化合物板中,然后颠倒混合。在室温(~22℃)下将酶与化合物进行30分钟的预温育后,使用Multidrop Combi将底物FAM-QRVRRAVGIDK-TAMRA(SEQ ID NO:1)(5μL的1μM在测定缓冲液中的溶液)加入到整个测定板。将板在500Xg离心1分钟,并在室温下孵育2小时。然后使用Envision仪器(PerkinElmer)定量酶抑制作用。将数据归一化至由1μM癸酰基-Arg-Val-Arg-Lys-氯甲基酮(SEQ ID NO:2)(Calbiochem#344930或AnaSpec#808143)确定的最大抑制。
弗林蛋白酶基于细胞的测定
该测定法使用基于图像的平台来评估本发明化合物的细胞内活性。反应在经过组织培养物处理的黑色384孔透明底板(Greiner)中进行。将分析中的化合物溶解在DMSO(1.0mM)中,并通过11次稀释用DMSO以1比3连续稀释。使得最终化合物的浓度范围为0.00017至10μM,每种浓度的0.1μL转移至测定板的相应孔中。通过以下来启动测定:添加同时用BacMam递送的构建体(其含有高尔基体靶向序列)转导的U2OS细胞,然后是源自骨形态发生蛋白10(BMP10)的12-氨基酸弗林蛋白酶/PCSK切割位点,然后是在C端的GFP。弗林蛋白酶切割位点序列侧接富含甘氨酸的接头(GalNAc-T2-GGGGS-DSTARIRRNAKG-GGGGS-GFP)(SEQ ID NO:3)。简而言之,将冷冻的细胞在测定培养基(不含酚红且含5%FBS的Dulbecco改良的Eagles培养基营养混合物F-12(Ham))中解冻,并稀释后使用Multidrop Combi(Thermo)将6000细胞/孔(50μL)递送至平板。
在37℃下孵育24小时后,用Cell Mask Deep Red对细胞进行染色,将其固定在多聚甲醛中,并使用Ho33342对细胞核进行染色。高尔基体靶向的GFP在细胞内形成明亮的点状簇。在缺乏弗林蛋白酶抑制剂的情况下,内源性蛋白酶会从其N-乙酰半乳糖胺基转移酶-2高尔基体链中裂解出GFP,将GFP释放到高尔基体腔中,在那里荧光被稀释到低于测定灵敏度的阈值。在细胞可渗透的弗林蛋白酶抑制剂存在下,GFP荧光随着高尔基体内蛋白酶活性的降低而增加。细胞GFP强度是通过基于图像的采集(Incell 2200,Perkin Elmer)在40倍放大倍数下测定的,每孔测量4个视野。多尺度高帽分割(tophat segmentation)用于识别GFP标记的小点,并以每个细胞为基础定量所有小点的平均荧光。细胞毒性平行测定。
使用四参数曲线拟合方程式,使用AbaseXE 7.3分析数据。以下值用于定义四个参数中每个参数的限度和/或约束:
最小-限度-10至10
最高–90至110
斜率-限度0.5至2.0
pXC50置信区间-10
获取从各自的读板器(Perkin Elmer)获得的原始计数用于数据分析。使用以下公式生成曲线:
Y=A+[(B–A)/(1+(10^C/x)^D)]
其中:A=最小响应
B=最大响应
C=log10*XC50
D=斜率因子
x=log10化合物浓度[M]
结果记录为pXC50值(-以上公式中的C)
通常根据上述或类似的测定法测试实施例化合物,发现它们是弗林蛋白酶的抑制剂。下表列出了根据此类测定法测试的特定生物活性。重复进行分析可能会导致pIC50值有所不同。
表I.酶和细胞数据
博来霉素诱导的肺纤维化模型
可以通过将博来霉素单次滴入小鼠肺部来诱发临床前肺纤维化。开发了一种为期15天的博来霉素方案,以在体内评价本发明化合物抑制小鼠肺中TGFβ分泌和胶原沉积的能力。在滴注博来霉素的前一天,根据适当的途径和频率向小鼠施用化合物。在研究开始的当天,在氯胺酮(80mg/kg)和赛拉嗪(10mg/kg)麻醉下,将所有动物经口气管插管,并将50μL生理盐水(假手术对照组)或50μL盐水中的0.03U博来霉素(假手术对照组除外的所有组)递送至气管。每天给予化合物直至第15天研究结束。在终止日,使用CO2吸入使动物安乐死。收集右肺,用生理盐水洗涤,称重,在液氮中速冻,并在-80℃下储存以进行羟脯氨酸(胶原蛋白的特异性标记物)和TGFβ测定。
使用基于氧化锆珠的均质器(Bullet blender Gold,NextAdvance,德国),在500μL含PMSF和蛋白酶抑制剂混合物的RIPA缓冲液中将速冻的整个右肺组织匀浆。简而言之,将组织在匀浆器中于4℃旋转3次循环,每次循环10分钟,每次1000g。使用该操作获得了完全均匀的组织混合物。通过向500μL匀浆中加入1mL含PMSF和蛋白酶抑制剂混合物的RIPA缓冲液,使匀浆体积达到1.5mL。将匀浆以100-500μL的等分试样分别保存在-80℃下。
羟脯氨酸测试:
酸水解:将500μL均质化的肺实质转移至玻璃小瓶中,并添加等体积的12N HCl(最终HCl浓度:6N)。用氮气吹扫小瓶,密封并在缺氧条件下于110℃孵育过夜(16h)。
孵育后操作:将来自每个试管或标准品的35μL样品(通过羟脯氨酸原液的系列稀释制备)添加到96孔板上,并按照试剂盒操作规程进行测定(Quickzyme Biosciences:Cat#:QZBHYPR05)。最终显色后,通过比色分析在570nm下测量吸光度(使用Thermoscan光谱仪(Plate Reader))并记录结果。使用Quickzyme试剂盒中提供的羟脯氨酸标准品生成标准曲线(线性图)。
TGFβ测试:
在4℃下以13,000rpm离心肺组织匀浆(500μL)20分钟,并收集上清液用于TGFβ估算。根据制造商的手册(研发系统:Cat#SMB100B)进行测定。简而言之,通过酸活化然后中和以将潜在的TGFβ转化为活性TGFβ来活化肺匀浆,并测量上清液中的总TGFβ水平。还确定了肺上清液中的总蛋白水平。
表II.在博来霉素诱导的肺纤维化小鼠模型中,化合物对小鼠肺部TGFβ和羟脯氨酸含量的影响总结。相对于在载体处理的动物中由博来霉素诱导的水平,报道了%抑制(*p<0.05(t-检验))。
跨上皮细胞电阻测试
对于跨上皮细胞电阻(TEER)测试,上皮钠通道(ENaC)在基础条件下处于活动状态,并通过跨顶膜运输阳离子的功能显著影响跨上皮细胞电阻(RTE)。将CF delF508或非CFHBE细胞的原代培养物接种到可渗透的过滤器支持物上,并生长12-14天,以达到测量显著的RTE,用于TEER分析测量。
当ENaC在基础条件下具有活性(至少部分是由于细胞内部或顶膜的蛋白酶裂解)时,存在有限的RTE,其受流经ENaC异三聚体(αβγ或δβγ)的Na+电流影响。
当ENaC在膜上关闭(抑制)或从膜上移开时,Na+电流不会流动,RTE会增加(即,顶膜中的孔减少-由顶膜电阻和基底外侧膜电阻的总和决定RTE)。
从图6中可以看出,实施例11显示了与“仅培养基”和“DMSO(LTA)”对照相比,阿米洛利诱导的RTE增加的浓度依赖性降低(进行单向ANOVA,然后进行Tukey HSD事后分析,*p<0.05)。与相同浓度的卡莫司他和10μM的抑肽酶相比,实施例11更有效(图7)。CRC的重叠仅发生在3μM。与实施例11相比,工业标准品甲磺酸卡莫司他和抑肽酶仅具有部分抑制作用,并且具有中等抑制作用。只有中μM浓度才部分有效(图8和图9)。
实施例11显示了与“DMSO等价物”对照相比,吸收性流体转运的浓度依赖性衰减。1和3μM的较高浓度使总流体体积损失和流体损失率降低了50%(图10和图11)。在非CF HBE细胞单层中获得了相似的数据。相反,在每种测试的蛋白酶抑制剂的最高浓度下,工业标准品仅将吸收性流体转运降低了近50%(图12和图13)。在非CF HBE细胞单层中获得了相似的数据。
表III表明,3μM实施例11和50μM卡莫司他在长期过夜治疗下对阿米洛利敏感的RTEδ具有等效的抑制作用(P<0.05)(而抑肽酶则没有)。
表III.在非CF极化的人类肺叶支气管上皮细胞中用实施例11相比抑肽酶或卡莫司他进行慢性治疗的TEER数据(在TEER测试之前在培养基中过夜)。
表IV示出了用实施例11进行的急性治疗的结果,表明高达3μM的实施例11具有与抑肽酶相当的急性作用,并且比卡莫司他具有更强的作用。实施例11也适度地抑制了阿米洛利敏感的RTEδ(剩余的ENaC活性尚未被推定的ENaC抑制剂所抑制),而抑肽酶和卡莫司他则对该参数的抑制作用更强。但是研究工具蛋白酶抑制剂(抑肽酶和卡莫司他)在高得多的浓度测试。最初在有或没有ENaC抑制剂的情况下,向细胞单层的顶端添加50ml培养基以产生急性治疗数据,来影响RTE。然后加入阿米洛利以检测残留的ENaC活性,而该活性不受假定的ENaC抑制剂的抑制。
表IV.在非CF极化的人类肺叶支气管上皮细胞中用实施例11相比抑肽酶或卡莫司他进行急性治疗的TEER数据。
跨上皮流体转运测定
将CF delF508或非CF HBE细胞的原代培养物接种到可渗透的过滤器支持物上,并生长7天,以达到测量显著的RTE。然后,去除顶端培养基以启动气液界面(AFI)培养。当细胞单层紧紧地从细胞单层的基底外侧向顶端泄漏流体时,它们就准备好进行流体转运(流体吸收)测量。
两种方法被用于挑战AFI培养中的细胞单层,其中顶侧没有培养基:
(1)通过将蛋白酶抑制剂(ENaC抑制剂)添加到基底外侧培养基中来进行慢性过夜治疗。然后,将100ml细胞培养基添加到每个单层的顶端,并测量流体吸收(通过体积损失(以ml为单位))。
(2)当将蛋白酶抑制剂(ENaC抑制剂)以100ml的体积(或仅培养基或DMSO等价物为对照)添加到顶端培养基中时,进行了急性治疗。
在每种情况下,流体吸收都是针对5倍的静水压力梯度进行的(即,在基底外侧有500ml,在顶端有100μM)。
当ENaC在基础条件下具有活性(至少部分是由于细胞内部或顶膜的蛋白酶裂解)时,流过ENaC异三聚体(αβγ或δβγ)的吸收性Na+电流会产生渗透驱动力以吸收流体。
当ENaC在膜上关闭(抑制)或从膜上去除时,Na+电流不流动,并且不存在吸收流体的吸收驱动力(即,当ENaC被抑制时,跨上皮的流体吸收较少)。
等效物和范围
在权利要求书中,除非相反地指示或另外从上下文显而易见,否则例如“一(a/an)”和“所述”的冠词可以意指一或大于一。除非相反地指示或另外从上下文显而易见,否则如果一个、一个以上或所有的群组成员存在、使用于既定产品或方法中或另外与其有关,那么在群组的一或多个成员之间包括“或”的权利要求书或说明书被视为满足。本发明包括群组中恰好一个成员存在、使用于既定产品或方法中或另外与其有关的实施方案。本发明包括一个以上或所有的群组成员存在、使用于既定产品或方法中或另外与其有关的实施方案。
此外,本发明涵盖其中来自一或多条所列权利要求的一或多个限制、要素、条款和描述性用语被引入到另一条权利要求中的所有变化、组合和排列。举例来说,附属于另一权利要求的任何权利要求可以经修改以包括在附属于同一基本权利要求的任何其它权利要求中可见的一或多个限制。在要素以清单形式(例如以马库什群组(Markush group)形式)呈现时,所述要素的每一子组也被公开,并且可以从所述群组去除任何要素。应理解,一般来说,在本发明或本发明的方面被称为包含具体要素和/或特征时,本发明的或本发明的方面的某些实施方案由此类要素和/或特征组成或主要由此类要素和/或特征组成。出于简单的目的,那些实施方案尚未专门地以这些词语阐述在本文中。还应注意,术语“包含”和“含有”打算为开放的并且允许包括额外要素或步骤。在给出范围时,包括端点。此外,除非另外指明或另外从上下文和本领域的普通技术人员的理解显而易见,否则表示为范围的值可以在本发明的不同实施方案中采用所述范围内的任何特定值或子范围,除非上下文另外明确规定,否则达到所述范围下限的单位的十分之一。
本申请提及各种授权的专利、公开的专利申请、杂志文章和其它出版物,其都以引用的方式并入本文中。如果任何并入的参考文献与本说明书之间存在冲突,那么应以本说明书为准。另外,属于现有技术内的本发明的任何具体实施方案可以从权利要求中的任何一或多者明确排除。因为此类实施方案被认为是本领域的普通技术人员已知的,所以其可以被排除,即使所述排除在本文中并未明确阐述。本发明的任何具体实施方案可以出于任何原因从任何权利要求排除,无论与现有技术的存在相关与否。
本领域的技术人员顶多使用常规实验即可识别或能够确定本文所述的特定实施方案的许多等效物。本文所述的本发明的实施方案的范围并不打算限于上述描述,而是实际上如所附权利要求书中所阐述。本领域的普通技术人员将了解,可以在不脱离如随附权利要求书中定义的本发明的精神或范围的情况下对本说明书作出各种改变和修改。
序列表
<110> 葛兰素史密斯克莱知识产权发展有限公司
<120> 弗林蛋白酶抑制剂
<130> B1539.70003WO00
<140> 尚未分配
<141> 随同此处一起
<150> US 62/670,050
<151> 2018-05-11
<160> 3
<170> PatentIn版本3.5
<210> 1
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> 由FAM修饰
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> 由TAMRA修饰
<400> 1
Gln Arg Val Arg Arg Ala Val Gly Ile Asp Lys
1 5 10
<210> 2
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> 由癸酰基修饰
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> 由氯甲基酮修饰
<400> 2
Arg Val Arg Lys
1
<210> 3
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> 由GalNAc-T2修饰
<220>
<221> MISC_FEATURE
<222> (22)..(22)
<223> 由GFP修饰
<400> 3
Gly Gly Gly Gly Ser Asp Ser Thr Ala Arg Ile Arg Arg Asn Ala Lys
1 5 10 15
Gly Gly Gly Gly Gly Ser
20
Claims (21)
1.根据式(I)的化合物或其药学上可接受的盐:
其中:
A1、A2、A3、A4、A5和A6各自独立地为N、CH或CR6;
X为O或NR8;
R1和R2各自独立地为氢、(C1-C4)烷基或H2N(C1-C4)烷基-;
或R1和R2与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的独立选自氧、氮和硫的杂原子,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、-OCONR8R9、-CO2R8、-C(O)CO2R8、R7、-OR7、-NHR8、-NR7R8、-C(O)R7、-CONHR8、-CONR7R8和-SO2R7;
各个R3独立地选自卤素、甲基、氟甲基、二氟甲基和三氟甲基;
R4和R5各自独立地为氢、(C1-C4)烷基或(C1-C4)烷氧基(C2-C4)烷基-;
或R4和R5与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的独立选自氧、氮和硫的杂原子,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、-OCONR8R9、-CO2R8、-C(O)CO2R8、-SO2(C1-C4)烷基、R7、-OR7、-NHR8、-NR7R8、-N(R8)C(O)R9、-N(R8)SO2R9、-N(R8)CONR8R9、-N(R8)CON(R8)SO2R9、-C(O)R7、-CONHR8、-CONR7R8和-P(O)R8R9;
各个R6独立地选自卤素、(C1-C4)烷基、卤代(C1-C4)烷基、羟基和(C1-C4)烷氧基;
各个R7独立地选自(C1-C6)烷基、(C2-C6)烯基、卤代(C1-C6)烷基、(C3-C6)环烷基和(C3-C6)环烷基(C1-C4)烷基-,其各自任选取代有1或2个独立选自以下的取代基:三唑基、四唑基、-CO2R8、-CONR8R9、-CON(R8)CO2(C1-C4)烷基、羟基、氧代、(C1-C4)烷氧基、-OCONR8R9、-OCON(R8)C(O)R9、(C1-C4)烷基、HO(C1-C4)烷基-、-NR8R9、-N(O)R8R9、-N(R8)C(O)R9、-N(R8)CO2(C1-C4)烷基、-N(R8)CH2CO2R9、-N(R8)CONR8R9、-N(R8)CON(R8)C(O)R9、-N(R8)CON(R8)CO2(C1-C4)烷基、-N(R8)SO2R9、-N(R8)CON(R8)SO2R9、-SO(C1-C4)烷基、-SO2(C1-C4)烷基、-SO3R8、-SO2NR8R9、-B(OH)2、-P(O)R8R9和-P(O)(OR8)(OR9);
各个R8和R9独立地为氢、(C1-C4)烷基或(C3-C6)环烷基;且
n为1、2、3或4。
2.根据权利要求1的化合物或其药学上可接受的盐,其由式(II)表示:
其中:
A1、A2、A3、A4和A5各自独立地为N或CH,其中A1、A2、A3、A4和A5中的一个、两个或三个为N;
X1和X2各自独立地为NR10或C(R11)R12;
R1a、R1b、R1c和R2a各自独立地为氢、氟、(C1-C4)烷基、HO(C1-C4)烷基-、羟基或-CONR8R9,其中R1a、R1b、R1c和R2a中至少两个为氢;
或X1为NR10,R1a和R2a一起表示-CH2-或-(CH2)2-,且R1b和R1c各自为氢;
或X1为NR10,R1c和R2a一起表示-CH2-或-(CH2)2-,且R1a和R1b各自为氢;
或X1为NR10,R1c和R10一起表示-CH2-或-(CH2)2-,且R1a、R1b和R2a各自为氢;
或X1为NR10,R1a和R1b与它们连接的碳原子一起表示(C3-C6)环烷基,且R1c和R2a各自为氢;
各个R3独立地选自氟、氯、甲基、氟甲基、二氟甲基和三氟甲基;
R6a为氢、氟、氯或甲基;
各个R7独立地选自(C1-C4)烷基、(C2-C4)烯基、卤代(C1-C4)烷基、(C3-C6)环烷基和(C3-C6)环烷基(C1-C2)烷基-,其各自任选取代有1或2个独立选自以下的取代基:-CO2R8、-CONR8R9、羟基、氧代、(C1-C4)烷氧基、-OCONR8R9、HO(C1-C4)烷基-、-NR8R9、-N(R8)C(O)R9、-N(R8)CO2(C1-C4)烷基、-N(R8)CH2CO2R9、-N(R8)CONR8R9、-N(R8)SO2R9、-SO(C1-C4)烷基、-SO2(C1-C4)烷基、-SO3R8、-SO2NR8R9和-P(O)(OR8)(OR9);
各个R8和R9独立地为氢或(C1-C4)烷基;
各个R10独立地选自氢、R7、-C(O)R7、-CONHR8、-CONR7R8、-C(O)CO2R8和-SO2R7;
各个R11独立地选自氢、-OR7、-NHR8、-NR7R8和R7;
各个R12独立地选自氢、卤素、羟基、-CO2R8、-CONHR8或-CONR8R9,其中当R12为羟基时,R11为氢和R7;
m为1或2;且
n为1、2或3。
3.根据权利要求1的化合物或其药学上可接受的盐,其由式(III)表示:
其中:
A1、A2和A3各自独立地为N或CH,其中A1、A2和A3中的一个或两个为N;
X2a为NR10b或C(R11a)R12a;
R1c为氢;
R3a和R3b各自独立地为氟或氯;
R6a为氢、氟、氯或甲基;
R10a为氢、(C1-C4)烷基或(C3-C6)环烷基,其中所述(C1-C4)烷基或(C3-C6)环烷基任选取代有-CO2H、-CONH2、-CONH(C1-C4)烷基、-CON((C1-C4)烷基)((C1-C4)烷基)、羟基、(C1-C4)烷氧基、-SO2(C1-C4)烷基或-SO2NH2;
或R1c和R10a一起表示-CH2-或-(CH2)2-;
R10b为(C1-C4)烷基,其任选取代有-CONH2、-CONH(C1-C4)烷基或-CON((C1-C4)烷基)((C1-C4)烷基);
R11a为(C1-C4)烷基或(C1-C4)烷氧基,其各自任选取代有1或2个独立选自以下的取代基:-CO2H、-CONH2、-CONH(C1-C4)烷基、-CON((C1-C4)烷基)((C1-C4)烷基)、羟基、-OCONH(C1-C4)烷基、-NHCO(C1-C4)烷基、-NHCO2(C1-C4)烷基和-NHCONH(C1-C4)烷基;
R12a为氢、羟基或氟,其中当R12a为羟基时,R11a为(C1-C4)烷基,其任选取代有1或2个独立选自以下的取代基:-CO2H、-CONH2、-CONH(C1-C4)烷基、-CON((C1-C4)烷基)((C1-C4)烷基)、羟基、-OCONH(C1-C4)烷基、-NHCO(C1-C4)烷基、-NHCO2(C1-C4)烷基和-NHCONH(C1-C4)烷基;且
m为1或2。
4.根据权利要求1的化合物或其药学上可接受的盐,其中A1、A2、A3、A4、A5和A6中的0、1、2或3个为N。
5.根据权利要求1或权利要求4的化合物或其药学上可接受的盐,其中X为O。
6.根据权利要求1、4或5中任一项的化合物或其药学上可接受的盐,其中R1和R2与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的氮杂原子,其中所述环任选取代有1、2或3个独立选自以下的取代基:卤素、羟基、氧代、R7、-OR7、-NHR8、-NR7R8和-C(O)R7。
7.根据权利要求1、2、4、5或6中任一项的化合物或其药学上可接受的盐,其中各个R3独立地选自卤素、甲基和二氟甲基。
8.根据权利要求1、4、5、6或7中任一项的化合物或其药学上可接受的盐,其中R4和R5与它们连接的氮原子一起表示4-11元单环或稠合、桥接或螺双环的饱和环,其任选包含一个或两个另外的独立选自氧和氮的杂原子,其中所述环任选取代有1或2个独立选自以下的取代基:卤素、羟基、氧代、-CO2R8、R7、-OR7、-NHR8、-N(R8)C(O)R9、-N(R8)SO2R9、-N(R8)CONR8R9、-N(R8)CON(R8)SO2R9、-C(O)R7和-P(O)R8R9。
9.根据权利要求1、4、5、6、7或8中任一项的化合物或其药学上可接受的盐,其中各个R6独立地选自卤素和(C1-C4)烷基。
10.根据权利要求1、4、5、6、7、8或9中任一项的化合物或其药学上可接受的盐,其中各个R7独立地选自(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C6)环烷基和(C3-C6)环烷基(C1-C4)烷基-,其各自任选取代有1或2个独立选自以下的取代基:三唑基、四唑基、-CO2R8、-CONR8R9、-CON(R8)CO2(C1-C4)烷基、羟基、(C1-C4)烷氧基、-OCONR8R9、-OCON(R8)C(O)R9、(C1-C4)烷基、HO(C1-C4)烷基-、-NR8R9、-N(O)R8R9、-N(R8)C(O)R9、-N(R8)CO2(C1-C4)烷基、-N(R8)CONR8R9、-N(R8)CON(R8)C(O)R9、-N(R8)CON(R8)CO2(C1-C4)烷基、-N(R8)SO2R9、-N(R8)CON(R8)SO2R9、-SO(C1-C4)烷基、-SO2(C1-C4)烷基、-SO3R8、-SO2NR8R9、-B(OH)2、-P(O)R8R9和-P(O)(OR8)(OR9)。
11.根据权利要求1、4、5、6、7、8、9或10中任一项的化合物或其药学上可接受的盐,其中各个R8和R9独立地为氢或(C1-C4)烷基。
12.根据权利要求1、4、5、6、7、8、9、10或11中任一项的化合物或其药学上可接受的盐,其中n为2或3。
13.根据权利要求2的化合物或其药学上可接受的盐,其中:
A1、A2、A3、A4和A5各自独立地为N或CH,其中A1、A2、A3、A4和A5中的两个或三个为N;
X1和X2各自独立地为NR10或C(R11)R12;
R1a、R1b、R1c和R2a各自为氢;
或X1为NR10,R1a和R2a一起表示-CH2-或-(CH2)2-,且R1b和R1c各自为氢;
或X1为NR10,R1c和R2a一起表示-CH2-或-(CH2)2-,且R1a和R1b各自为氢;
或X1为NR10,R1c和R10一起表示-CH2-或-(CH2)2-,且R1a、R1b和R2a各自为氢;
各个R3独立地选自卤素、甲基和二氟甲基;
R6a为氢、氟、氯或甲基;
各个R7独立地选自(C1-C4)烷基、(C2-C4)烯基、卤代(C1-C4)烷基、(C3-C6)环烷基和(C3-C6)环烷基(C1-C2)烷基-,其各自任选取代有1或2个独立选自以下的取代基:-CO2R8、-CONR8R9、羟基、(C1-C4)烷氧基、-OCONR8R9、HO(C1-C4)烷基-、-NR8R9、-N(R8)C(O)R9、-N(R8)CO2(C1-C4)烷基、-N(R8)CONR8R9、-N(R8)SO2R9、-SO(C1-C4)烷基、-SO2(C1-C4)烷基、-SO3R8、-SO2NR8R9和-P(O)(OR8)(OR9);
各个R8和R9独立地为氢或(C1-C4)烷基;
各个R10独立地选自氢和R7;
各个R11为R7;
各个R12独立地选自氢、卤素和羟基;
m为1或2;且
n为2或3。
14.根据权利要求3的化合物或其药学上可接受的盐,其中:
A1和A2各自为CH;
或A1和A2之一为N且另一个为CH;
A3为N;
X2a为C(R11a)R12a;
R1c为氢;
R3a和R3b各自为氯;
R6a为氢或甲基;
R10a为(C1-C4)烷基,其任选取代有-CO2H、羟基或-SO2(C1-C4)烷基;
或R1c和R10a一起表示-CH2-或-(CH2)2-;
R11a为(C1-C4)烷基,其任选取代有一个取代基,该取代基为-CO2H或-NHCO(C1-C4)烷基;
R12a为氢;且
m为1或2。
15.根据权利要求1的化合物或其药学上可接受的盐,所述化合物为:
2-(4-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌嗪-1-基)-N-甲基乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)乙酰胺;
3-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
1-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)-3-甲基脲;
((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)氨基甲酸甲酯;
2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙烷磺酸;
(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲磺酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酰胺;
N-((1-((2-((6-(4-(2-(1H-四唑-5-基)乙基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基亚磺酰基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(4-(甲基磺酰基)丁-2-基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基亚磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(甲基磺酰基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(甲基磺酰基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(4-羟基丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(1-羟基丙-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基环丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(1,3-二羟基丙-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-((1s,3s)-3-羟基-3-甲基环丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-((1r,3r)-3-羟基-3-甲基环丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((反式)-3-(甲基磺酰氨基)环丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((顺式)-3-(甲基磺酰氨基)环丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-((6-(4-(2-氨基乙基)哌嗪-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2,4-二羟基丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基)膦酸;
氨基甲酸2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙基酯;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(N-甲基甲磺酰氨基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-4-氧代丁酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-(羟基甲基)环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-((1-羟基环丙基)甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-N-乙基乙酰胺;
1-(2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)-N-甲基甲胺;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(氨磺酰基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((甲基磺酰基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
N-((1-((5-(4-氨基苯氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((5-((5-氨基嘧啶-2-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(甲基磺酰氨基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
N-((1-((5-((5-氨基吡啶-2-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((5-((6-氨基-5-氟吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙烷-1-磺酰胺;
((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
3-(4-(5-((6-(3,5-二氯苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-氟-4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙醇;
2-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸;
3-(4-(5-((4-((4-(2-(氨基甲酰基氧基)乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((4-((4-(2-(氨基甲酰基氧基)乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
3-(3-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-3,8-二氮杂双环[3.2.1]辛-8-基)丙酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-((4-(2-羟基乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
3-(4-(5-((4-((4-(环丙烷甲酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-((4-(丙酰氨基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-((4-氟哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁-2-醇;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-(二氟甲基)苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
((1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
N-((1-((3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
N-((1-((2-(3,5-二氯苯基)-6-((2-(8-甲基-3,8-二氮杂双环[3.2.1]辛-3-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
5-((4-((4-((1H-四唑-5-基)甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶;
甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
1-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((4-((4-(3-氨基-3-氧代丙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((4-((4-(2-氨基-2-氧代乙基)哌嗪-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-(((1R,7S,8r)-8-(甲基磺酰氨基)-4-氮杂双环[5.1.0]辛-4-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-(((1R,7S,8r)-8-(甲基磺酰氨基)-4-氮杂双环[5.1.0]辛-4-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
4-(4-(5-((4-(((1R,7S,8r)-8-乙酰氨基-4-氮杂双环[5.1.0]辛-4-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-(吡咯烷-1-基甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
3-(4-(5-((4-((4-(环丙烷甲酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((二甲基磷酰基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酰胺;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙烷磺酰胺;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)嘧啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((6-(3,5-二氯苯基)-2-((6-(哌嗪-1-基)吡啶-3-基)氧基)嘧啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((5-氟-6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-羟基哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-N-甲基丙酰胺;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酰胺;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酰胺;
1-(5-((3',5'-二氯-5-(((2-甲氧基乙基)氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)-N-甲基哌啶-4-胺;
1-(3',5'-二氯-5-((6-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)-N-甲基甲胺;
N1-(5-((3',5'-二氯-5-(吗啉代甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)乙烷-1,2-二胺;
1-(5-((3',5'-二氯-5-((甲基氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌啶-4-胺;
N1-(5-((3',5'-二氯-5-((甲基氨基)甲基)-[1,1'-联苯]-3-基)氧基)吡啶-2-基)丙烷-1,3-二胺;
1-(3',5'-二氯-5-((6-(3,3-二甲基哌嗪-1-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)-N-甲基甲胺;
1-(5-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)-N-甲基甲胺;
1-(3',5'-二氯-5-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)-N-甲基甲胺;
N-((1-((5-((6-((2-氨基-2-甲基丙基)氨基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((5-((6-((3S,4R)-4-氨基-3-氟哌啶-1-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((3',5'-二氯-5-((6-(3-氧代六氢咪唑并[1,5-a]吡嗪-7(1H)-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-(5-((6-(3-氯-5-甲基苯基)-4-((甲基氨基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌啶-4-胺;
N-((1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((3',5'-二氯-5-((2-(4-(3-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(1-((3',5'-二氯-5-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)丙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-溴-5-氟苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
2-(1-((3',5'-二氯-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-((2-(1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-((2-(4-氨基哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-N,N-二甲基乙胺氧化物;
N-((1-((2-(3,5-二氯苯基)-6-((5-氟-6-(哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(6-羟基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(4-氨基-4-(2-羟基乙基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
((1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)二甲基氧化膦;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)氮杂环丁烷-3-基)丁酸;
2-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)吡咯烷-3-基)氧基)乙酸;
2-(2-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)八氢环戊二烯并[c]吡咯-5-基)乙酸;
3-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙酸;
3-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
2-(1-((2-((2-(1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
(S)-3-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
1-(7-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-2,7-二氮杂螺[3.5]壬-2-基)-2-羟基乙酮;
(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸;
(R)-3-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
1-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙-2-醇;
3-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-羟基丙酸;
2-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸;
9-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)-2-氧杂-4,9-二氮杂螺[5.5]十一烷-3-酮;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)环丙烷羧酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(6-甲氧基-4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(6-氟-4-甲基-1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(1-((2-(3,5-二氯苯基)-6-((2-(6-羟基-4,6-二甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(6-氟-4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((4-甲基-2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-甲基-6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-(4-(4-甲基哌嗪-1-基)苯氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-氟-6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(3-(甲基氨基)吡咯烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
(S)-2-(4-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-1,4-氧氮杂环庚烷-7-基)乙醇;
N-((1R,5S,6r)-3-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-3-氮杂双环[3.1.0]己-6-基)乙酰胺;
1-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙-2-酮;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基-1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(1-((2-((2-(4-氨基哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
(S)-2-(1-((2-(3,5-二氯苯基)-6-((2-(3-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(3,3-二甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(3,6-二氮杂双环[3.1.1]庚-3-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(3,8-二氮杂双环[3.2.1]辛-3-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(4,7-二氮杂螺[2.5]辛-7-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(4-氨基-4-(羟基甲基)哌啶-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((3',5'-二氯-5-((2-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(4-(6-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)哒嗪-3-基)哌嗪-1-基)丙酸;
3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
(3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰基)氨基甲酸甲酯;
1-(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)乙基)环丙烷羧酸;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-2-甲基丁酸;
(3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰基)氨基甲酸甲酯;
(3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酰基)氨基甲酸甲酯;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2,3-二羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1-甲基哌嗪1-氧化物;
4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,1-双(2-羟基乙基)哌嗪-1-鎓;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,1-二甲基哌嗪-1-鎓;
N-((1-((2-((6-(4-氨基-3-氟哌啶-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-((1S,4S)-5-(2-(甲基磺酰基)乙基)-2,5-二氮杂双环[2.2.1]庚-2-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-((6-((3S,4R)-3-(氨基甲基)-4-羟基吡咯烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-((1R,5S)-3-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-3,8-二氮杂双环[3.2.1]辛-8-基)丙酸;
(S)-3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-2-甲基哌嗪-1-基)丙酸;
2-(1-((2-((6-((1S,4S)-2,5-二氮杂双环[2.2.1]庚-2-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-2-乙基丁酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)-2,2-二甲基丙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-1,4-二氮杂环庚烷-1-基)丙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)-2,2-二甲基哌嗪-1-基)丙酸;
N-((1-((2-((6-(1,4-二氮杂环庚烷-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(甲基氨基)哌啶-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(3-(羟基甲基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-((6-(4-氨基哌啶-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(3,3-二甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-((6-(4-氨基-3,3-二甲基哌啶-1-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-((6-(2,7-二氮杂螺[4.4]壬-2-基)吡啶-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-(3',5'-二氯-5-((6-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)-N-甲基甲胺;
1-(5-((6-((1S,4S)-2,5-二氮杂双环[2.2.1]庚-2-基)吡啶-3-基)氧基)-3',5'-二氯-[1,1'-联苯]-3-基)-N-甲基甲胺;
2-(1-((2-(3,5-二氯苯基)-6-((6-((1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚-2-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基亚磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)戊酸;
甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-羟基丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)环丁烷羧酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)戊酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)环丁烷羧酸;
((1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)环丁烷羧酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)戊酸;
((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
2-((1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛-8-基)乙酸;
2-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)-2-甲基丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(6-羟基-4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(二甲基氨基)哌啶-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(6-甲基-3,6-二氮杂双环[3.1.1]庚-3-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-((1-羟基环丙基)甲基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-乙基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-((1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚-2-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-((1S,4S)-5-乙基-2,5-二氮杂双环[2.2.1]庚-2-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(4-环丙基哌嗪-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-乙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-异丙基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-氟乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-羟基丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(甲基氨基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(4-(二甲基氨基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-((甲基氨基甲酰基)氧基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(2-甲氧基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-甲氧基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-氨磺酰基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-甲氧基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲基氨基甲酰基)氧基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丁酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-甲氧基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(3-氨磺酰基丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-氨磺酰基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-甲氧基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(4-(5-((5-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-3',5'-二氯-[1,1'-联苯]-3-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙烷-1-磺酰胺;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-甲氧基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酰胺;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-羟基-4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰胺;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((乙氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(2-(乙基氨基)-2-氧代乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
3-(1-((2-(3,5-二氯苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)-3-氟吡啶-2-基)哌嗪-1-基)丙酸;
3-(1-((2-(3,5-二氯苯基)-6-((6-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙酸;
3-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3-氯-4,5-二氟苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酰胺;
1-((1-((2-(3-氯-5-氟苯基)-6-((2-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
((1-((2-(3-氯-5-氟苯基)-6-((2-(哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(2-(甲基磺酰基)乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(2-氨磺酰基乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-(1-羟基环丙基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基-3-甲基丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基-2,2-二甲基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丁酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丁酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-氨磺酰基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)乙烷磺酸;
2-((4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)甲基)丁酸;
N-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-氨磺酰基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(4-(5-((6-(3,5-二氯苯基)-4-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丙酰胺;
3-(4-(5-((3',5'-二氯-5-((4-((3-甲基脲基)甲基)哌啶-1-基)甲基)-[1,1'-联苯]-3-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丙酸;
N-((1-((3',5'-二氯-5-((6-(4-(2-(甲基磺酰基)乙基)哌嗪-1-基)吡啶-3-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)乙酰胺;
(S)-3-(4-(5-((6-(3,5-二氯苯基)-4-((4-(((甲氧基羰基)氨基)甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-2-甲基哌嗪-1-基)丙酸;
1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-羟基丁基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(3-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)-3,8-二氮杂双环[3.2.1]辛-8-基)丙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸甲酯;
(R)-2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
(R)-2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(1-((2-(3,5-二氯苯基)-6-((2-(4-((R)-2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
(R)-N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基-2-甲基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-(3-氟-2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
(R)-甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
(R)-甲基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
(R)-1-((1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基丙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
(R)-1-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
(R)-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
1-((1-((3',5'-二氯-5-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
3-(1-((2-(3,5-二氯苯基)-6-((6-(4-(2-羟基乙基)哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)丙酸;
N-((1-((2-(3-氯-5-氟苯基)-6-((2-(4-(2-羟基乙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-羟基丙酸;
(R)-2-((1-((2-(3,5-二氯苯基)-6-((2-(4-(2-羟基丙基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)乙酸;
((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)硼酸;
(2-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)乙基)硼酸;
((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)二甲基氧化膦;
(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸;
((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)硼酸;
(2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙基)硼酸;
乙酰基氨基甲酸(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基酯;
N-1-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-N'-甲氧基羰基脲;
N-(((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酰基)甲磺酰胺;
N-(((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酰基)乙酰胺;
N-((1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氨基甲酰基)甲磺酰胺;
1-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)脲;
(S)-(4-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-1,4-氧氮杂环庚烷-7-基)甲醇;
(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)二甲基氧化膦;
2-(1-((2-(3,5-二氯苯基)-6-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(1,4-二氮杂双环[3.2.1]辛-4-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-((2-(3,8-二氮杂双环[3.2.1]辛-3-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
((1-((2-((2-(1,4-二氮杂双环[3.2.1]辛-4-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
(1R,7S,8r)-4-((2-((2-(1,4-二氮杂双环[3.2.1]辛-4-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸;
4-(5-((6-(3,5-二氯苯基)-4-((4-氟哌啶-1-基)甲基)吡啶-2-基)氧基)嘧啶-2-基)-1,4-二氮杂双环[3.2.1]辛烷;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基-1,4-二氮杂环庚烷-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
4-(4-(5-((6-(3,5-二氯苯基)-4-((4-(2-羟基乙基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)-2-甲基丁酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙醇;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-(2-羟基-2-甲基丙基)哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((6-(1,4-二氮杂双环[3.2.1]辛-4-基)哒嗪-3-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-乙基-1,4-二氮杂环庚烷-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-((1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚-2-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-异丙基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((5-(1,4-二氮杂双环[3.2.1]辛-4-基)吡嗪-2-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-(3-羟基丁基)哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙醇;
3-(1-((2-(3,5-二氯苯基)-6-((5-(4-甲基-1,4-二氮杂环庚烷-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(6-甲基-3,6-二氮杂双环[3.1.1]庚-3-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
1-((1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)氧基)环丙烷羧酸;
2-(1-((2-(3,5-二氯苯基)-6-((5-(4-(3-(甲基磺酰基)丙基)哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-乙基-1,4-二氮杂环庚烷-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基-1,4-二氮杂环庚烷-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-((1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚-2-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-乙基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙醇;
(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸;
(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((6-(4-甲基-1,4-二氮杂环庚烷-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸;
3-(4-(6-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)哒嗪-3-基)哌嗪-1-基)-2-甲基丙酸;
(R)-3-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
(S)-3-(1-((2-(3,5-二氯苯基)-6-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)-2-甲基丙酸;
2-(1-((2-(3,5-二氯苯基)-6-((6-((1S,4S)-5-乙基-2,5-二氮杂双环[2.2.1]庚-2-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(4-(5-((4-(((1R,7S,8r)-8-乙酰氨基-4-氮杂双环[5.1.0]辛-4-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)丙酸;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸甲酯;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2,2-二甲基丁酸;
2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
N-((1-((2-(3-氯-5-氟苯基)-6-((2-(4-(4-(甲基磺酰基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3-氯-5-氟苯基)-6-((2-(4-(4-(甲基磺酰基)丁-2-基)哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
2-(1-((2-(3-氯-5-氟苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-(异丙基(2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((3',5'-二氯-4-氟-5-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)-[1,1'-联苯]-3-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-氟-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-氟-2-((2-(8-甲基-3,8-二氮杂双环[3.2.1]辛-3-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-氟-2-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-氟-2-((4-甲基-2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)-3-氟吡啶-2-基)氧基)嘧啶-2-基)哌嗪-1-基)-2-甲基丁酸;
2-(1-((2-((2-(3,8-二氮杂双环[3.2.1]辛-3-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)-3-氟吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-氟-2-((2-甲基-6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-氟-2-((6-(4-甲基哌嗪-1-基)哒嗪-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡啶-2-基)哌嗪-1-基)丙酸甲酯;
2-(1-((6-(3,5-二氯苯基)-3-甲基-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-((2-(4-((1H-1,2,3-三唑-5-基)甲基)哌嗪-1-基)嘧啶-5-基)氧基)-6-(3,5-二氯苯基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-(甲基(2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((2-(3,5-二氯苯基)-6-(乙基(2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
2-(1-((6-(3,5-二氯苯基)-3-氟-2-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;
3-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)丙酰胺;
4-(4-(5-((6-(3,5-二氯苯基)-4-((4-(丙酰氨基甲基)哌啶-1-基)甲基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)-2-甲基丁酸;
N-((1-((2-(3,5-二氯苯基)-6-((5-(4-(1-羟基丙-2-基)哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺;
1-((1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)-3-甲基脲;
((1-((2-(3,5-二氯苯基)-6-((5-(4-甲基哌嗪-1-基)吡嗪-2-基)氧基)吡啶-4-基)甲基)哌啶-4-基)甲基)氨基甲酸甲酯;
4-(4-(5-((4-((4-(乙酰氨基甲基)哌啶-1-基)甲基)-6-(3,5-二氯苯基)吡啶-2-基)氧基)吡嗪-2-基)哌嗪-1-基)-2-甲基丁酸;
(1R,7S,8r)-4-((2-(3,5-二氯苯基)-6-((2-(4-甲基-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)-4-氮杂双环[5.1.0]辛烷-8-甲酸;
2-(1-((2-(3,5-二氯苯基)-6-((2-(8-甲基-3,8-二氮杂双环[3.2.1]辛-3-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸;或
2-(1-((2-(3,5-二氯苯基)-6-((2-(6-氟-1,4-二氮杂环庚烷-1-基)嘧啶-5-基)氧基)吡啶-4-基)甲基)哌啶-4-基)乙酸。
16.药物组合物,其包含根据权利要求1-15中任一项的化合物或其药学上可接受的盐和药学上可接受的赋形剂。
17.治疗肺纤维化的方法,包括向需要该治疗的人给药治疗有效量的根据权利要求1-15中任一项的化合物或其药学上可接受的盐或根据权利要求16的药物组合物。
18.根据权利要求1-15中任一项的化合物或其药学上可接受的盐,其用于治疗。
19.根据权利要求1-15中任一项的化合物或其药学上可接受的盐,其用于治疗肺纤维化。
20.根据权利要求1-15中任一项的化合物或其药学上可接受的盐在制备用于治疗肺纤维化的药物中的用途。
21.化合物,其为:N-((1-((2-(3,5-二氯苯基)-6-((6-(哌嗪-1-基)吡啶-3-基)氧基)嘧啶-4-基)甲基)哌啶-4-基)甲基)乙酰胺。
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SG11202010914YA (en) | 2020-12-30 |
CA3099863A1 (en) | 2019-11-14 |
AU2019267166C1 (en) | 2023-11-30 |
EP3790871A1 (en) | 2021-03-17 |
US20220315556A1 (en) | 2022-10-06 |
AU2019267166B2 (en) | 2023-06-15 |
EP3790871C0 (en) | 2024-01-24 |
AU2019267166A1 (en) | 2020-11-26 |
IL278642A (zh) | 2020-12-31 |
MX2020012034A (es) | 2021-04-12 |
US11773078B2 (en) | 2023-10-03 |
IL278642B2 (en) | 2023-10-01 |
BR112020022961A2 (pt) | 2021-02-17 |
JP7350061B2 (ja) | 2023-10-02 |
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