CN105392777B - 作为gpr120激动剂的联芳基衍生物 - Google Patents
作为gpr120激动剂的联芳基衍生物 Download PDFInfo
- Publication number
- CN105392777B CN105392777B CN201480036409.7A CN201480036409A CN105392777B CN 105392777 B CN105392777 B CN 105392777B CN 201480036409 A CN201480036409 A CN 201480036409A CN 105392777 B CN105392777 B CN 105392777B
- Authority
- CN
- China
- Prior art keywords
- difluoro
- phenoxy
- pyridin
- acid
- butyric acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 102100040134 Free fatty acid receptor 4 Human genes 0.000 title claims description 21
- 101000890672 Homo sapiens Free fatty acid receptor 4 Proteins 0.000 title claims description 20
- 239000000556 agonist Substances 0.000 title claims description 16
- 125000005841 biaryl group Chemical class 0.000 title abstract 3
- 238000000034 method Methods 0.000 claims abstract description 20
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 13
- 206010061218 Inflammation Diseases 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 208000004930 Fatty Liver Diseases 0.000 claims abstract description 11
- 208000008589 Obesity Diseases 0.000 claims abstract description 11
- 230000004054 inflammatory process Effects 0.000 claims abstract description 11
- 235000020824 obesity Nutrition 0.000 claims abstract description 11
- 208000002249 Diabetes Complications Diseases 0.000 claims abstract description 10
- 206010012655 Diabetic complications Diseases 0.000 claims abstract description 10
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 10
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 691
- 239000000203 mixture Substances 0.000 claims description 183
- -1 2-cyclopentyloxy-pyridin-3-yl Chemical group 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 150000005347 biaryls Chemical class 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- DLZWLOWHPPFPRY-UHFFFAOYSA-N 2-[1-[[2,6-difluoro-4-(3-propan-2-yloxyphenyl)phenyl]sulfanylmethyl]cyclopropyl]acetic acid Chemical compound CC(C)OC1=CC=CC(C=2C=C(F)C(SCC3(CC(O)=O)CC3)=C(F)C=2)=C1 DLZWLOWHPPFPRY-UHFFFAOYSA-N 0.000 claims description 4
- XNCOYEKNXFAUBP-UHFFFAOYSA-N 2-[1-[[4-(2-cyclobutylsulfanylpyridin-3-yl)-2,6-difluorophenoxy]methyl]cyclopropyl]acetic acid Chemical compound FC=1C=C(C=2C(=NC=CC=2)SC2CCC2)C=C(F)C=1OCC1(CC(=O)O)CC1 XNCOYEKNXFAUBP-UHFFFAOYSA-N 0.000 claims description 4
- KLVBRQILWOVSPD-UHFFFAOYSA-N 4-[2,6-difluoro-4-(2-piperidin-1-ylpyridin-3-yl)phenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CN=C1N1CCCCC1 KLVBRQILWOVSPD-UHFFFAOYSA-N 0.000 claims description 4
- OHWQPOTYNFYYRK-UHFFFAOYSA-N 4-[2,6-difluoro-4-(3-pyrrolidin-1-ylphenyl)phenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(N2CCCC2)=C1 OHWQPOTYNFYYRK-UHFFFAOYSA-N 0.000 claims description 4
- PDBLRYUXTKQEGJ-UHFFFAOYSA-N 4-[2,6-difluoro-4-(6-phenoxypyridin-2-yl)phenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(OC=2C=CC=CC=2)=N1 PDBLRYUXTKQEGJ-UHFFFAOYSA-N 0.000 claims description 4
- CZSAKXHXKVRTDE-UHFFFAOYSA-N 4-[2,6-difluoro-4-(6-propan-2-yloxypyridin-2-yl)phenoxy]butanoic acid Chemical compound CC(C)OC1=CC=CC(C=2C=C(F)C(OCCCC(O)=O)=C(F)C=2)=N1 CZSAKXHXKVRTDE-UHFFFAOYSA-N 0.000 claims description 4
- WIJJZFZCPZQFJS-UHFFFAOYSA-N 4-[2,6-difluoro-4-(6-propan-2-yloxypyridin-2-yl)phenyl]sulfanylbutanoic acid Chemical compound CC(C)OC1=CC=CC(C=2C=C(F)C(SCCCC(O)=O)=C(F)C=2)=N1 WIJJZFZCPZQFJS-UHFFFAOYSA-N 0.000 claims description 4
- JXYMUMUAOMQMSE-UHFFFAOYSA-N 4-[2,6-difluoro-4-(6-propoxypyridin-2-yl)phenoxy]butanoic acid Chemical compound CCCOC1=CC=CC(C=2C=C(F)C(OCCCC(O)=O)=C(F)C=2)=N1 JXYMUMUAOMQMSE-UHFFFAOYSA-N 0.000 claims description 4
- MJIHTXRLLGJVAM-UHFFFAOYSA-N 4-[2,6-difluoro-4-[2-(propan-2-ylamino)phenyl]phenoxy]butanoic acid Chemical compound CC(C)NC1=CC=CC=C1C1=CC(F)=C(OCCCC(O)=O)C(F)=C1 MJIHTXRLLGJVAM-UHFFFAOYSA-N 0.000 claims description 4
- CSMDUYWPCYKTJO-UHFFFAOYSA-N 4-[2,6-difluoro-4-[2-(propan-2-ylamino)pyridin-3-yl]phenoxy]butanoic acid Chemical compound CC(C)NC1=NC=CC=C1C1=CC(F)=C(OCCCC(O)=O)C(F)=C1 CSMDUYWPCYKTJO-UHFFFAOYSA-N 0.000 claims description 4
- VMTBUEUMVCQQLP-UHFFFAOYSA-N 4-[2,6-difluoro-4-[2-(propylamino)phenyl]phenoxy]butanoic acid Chemical compound CCCNC1=CC=CC=C1C1=CC(F)=C(OCCCC(O)=O)C(F)=C1 VMTBUEUMVCQQLP-UHFFFAOYSA-N 0.000 claims description 4
- NOSCEBMDURNFBP-UHFFFAOYSA-N 4-[2,6-difluoro-4-[3-(propan-2-ylamino)phenyl]phenoxy]butanoic acid Chemical compound CC(C)NC1=CC=CC(C=2C=C(F)C(OCCCC(O)=O)=C(F)C=2)=C1 NOSCEBMDURNFBP-UHFFFAOYSA-N 0.000 claims description 4
- WAFNLWDUHGNVKF-UHFFFAOYSA-N 4-[2,6-difluoro-4-[6-(2-methylprop-1-enyl)pyridin-2-yl]phenoxy]butanoic acid Chemical compound CC(C)=CC1=CC=CC(C=2C=C(F)C(OCCCC(O)=O)=C(F)C=2)=N1 WAFNLWDUHGNVKF-UHFFFAOYSA-N 0.000 claims description 4
- ANCUSKNKFLHDDN-UHFFFAOYSA-N 4-[4-(2-cyclobutylsulfanylpyridin-3-yl)-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CN=C1SC1CCC1 ANCUSKNKFLHDDN-UHFFFAOYSA-N 0.000 claims description 4
- FSDIHQFPBKXMSF-UHFFFAOYSA-N 4-[4-(2-cyclobutylsulfanylpyridin-3-yl)-2,6-difluorophenoxy]pentanoic acid Chemical compound C1=C(F)C(OC(CCC(O)=O)C)=C(F)C=C1C1=CC=CN=C1SC1CCC1 FSDIHQFPBKXMSF-UHFFFAOYSA-N 0.000 claims description 4
- XZLQOQQREACVLP-UHFFFAOYSA-N 4-[4-(2-cyclopentylphenyl)-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC=C1C1CCCC1 XZLQOQQREACVLP-UHFFFAOYSA-N 0.000 claims description 4
- RRKJCHFRHOQLNR-UHFFFAOYSA-N 4-[4-(2-phenoxyphenyl)phenoxy]butanoic acid Chemical compound C1=CC(OCCCC(=O)O)=CC=C1C1=CC=CC=C1OC1=CC=CC=C1 RRKJCHFRHOQLNR-UHFFFAOYSA-N 0.000 claims description 4
- QBPMSZJWIBFZOV-UHFFFAOYSA-N 4-[4-(2-propan-2-ylsulfanylpyridin-3-yl)phenoxy]butanoic acid Chemical compound CC(C)SC1=NC=CC=C1C1=CC=C(OCCCC(O)=O)C=C1 QBPMSZJWIBFZOV-UHFFFAOYSA-N 0.000 claims description 4
- WVBKBCDTZGQJPD-UHFFFAOYSA-N 4-[4-(3-cyclobutyloxyphenyl)phenyl]sulfanylbutanoic acid Chemical compound C1=CC(SCCCC(=O)O)=CC=C1C1=CC=CC(OC2CCC2)=C1 WVBKBCDTZGQJPD-UHFFFAOYSA-N 0.000 claims description 4
- IQZVIWUZGWJZRY-UHFFFAOYSA-N 4-[4-(3-cyclopentyloxyphenyl)-2,3-difluorophenoxy]butanoic acid Chemical compound FC1=C(F)C(OCCCC(=O)O)=CC=C1C1=CC=CC(OC2CCCC2)=C1 IQZVIWUZGWJZRY-UHFFFAOYSA-N 0.000 claims description 4
- MNHWMSRQEGGSJV-UHFFFAOYSA-N 4-[4-(3-propan-2-yloxyphenyl)phenyl]sulfanylbutanoic acid Chemical compound CC(C)OC1=CC=CC(C=2C=CC(SCCCC(O)=O)=CC=2)=C1 MNHWMSRQEGGSJV-UHFFFAOYSA-N 0.000 claims description 4
- MJOYMHGPUMCYKV-UHFFFAOYSA-N 4-[4-(6-anilinopyridin-2-yl)-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(NC=2C=CC=CC=2)=N1 MJOYMHGPUMCYKV-UHFFFAOYSA-N 0.000 claims description 4
- GABHFAKWFDYXGZ-UHFFFAOYSA-N 4-[4-(6-cyclobutyloxypyridin-2-yl)-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(OC2CCC2)=N1 GABHFAKWFDYXGZ-UHFFFAOYSA-N 0.000 claims description 4
- KGCHJYQUKOCYLY-UHFFFAOYSA-N 4-[4-(6-cyclobutyloxypyridin-2-yl)-2,6-difluorophenoxy]pentanoic acid Chemical compound C1=C(F)C(OC(CCC(O)=O)C)=C(F)C=C1C1=CC=CC(OC2CCC2)=N1 KGCHJYQUKOCYLY-UHFFFAOYSA-N 0.000 claims description 4
- CTALMPONZJZWBR-UHFFFAOYSA-N 4-[4-(6-cyclobutyloxypyridin-2-yl)-2-methylphenoxy]butanoic acid Chemical compound C1=C(OCCCC(O)=O)C(C)=CC(C=2N=C(OC3CCC3)C=CC=2)=C1 CTALMPONZJZWBR-UHFFFAOYSA-N 0.000 claims description 4
- NFMRDXVZHHGAJL-UHFFFAOYSA-N 4-[4-(6-cyclopentyloxypyridin-2-yl)-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(OC2CCCC2)=N1 NFMRDXVZHHGAJL-UHFFFAOYSA-N 0.000 claims description 4
- KGRQZDVXKJZHQU-UHFFFAOYSA-N 4-[4-(6-phenoxypyridin-2-yl)phenoxy]butanoic acid Chemical compound C1=CC(OCCCC(=O)O)=CC=C1C1=CC=CC(OC=2C=CC=CC=2)=N1 KGRQZDVXKJZHQU-UHFFFAOYSA-N 0.000 claims description 4
- XXKSYMIJJQHLKE-UHFFFAOYSA-N 4-[4-[2-(cyclopentylamino)-5-fluorophenyl]-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC(F)=CC=C1NC1CCCC1 XXKSYMIJJQHLKE-UHFFFAOYSA-N 0.000 claims description 4
- SBNRGSPPAIDBQJ-UHFFFAOYSA-N 4-[4-[2-(cyclopentylmethyl)pyridin-3-yl]-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CN=C1CC1CCCC1 SBNRGSPPAIDBQJ-UHFFFAOYSA-N 0.000 claims description 4
- MJOVZDZTOYKFRI-UHFFFAOYSA-N 4-[4-[2-(cyclopropylmethylamino)phenyl]-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC=C1NCC1CC1 MJOVZDZTOYKFRI-UHFFFAOYSA-N 0.000 claims description 4
- BZAIEPJJTFZOPW-UHFFFAOYSA-N 4-[4-[3-(cyclobutylamino)phenyl]-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(NC2CCC2)=C1 BZAIEPJJTFZOPW-UHFFFAOYSA-N 0.000 claims description 4
- VZSSIKWGCUEUBA-UHFFFAOYSA-N 4-[4-[3-(cyclopentylmethyl)phenyl]-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(CC2CCCC2)=C1 VZSSIKWGCUEUBA-UHFFFAOYSA-N 0.000 claims description 4
- NGUVOERLGAXDSO-UHFFFAOYSA-N 4-[4-[6-(cyclobutylmethyl)pyridin-2-yl]-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(CC2CCC2)=N1 NGUVOERLGAXDSO-UHFFFAOYSA-N 0.000 claims description 4
- YAAJVDLEFZODPP-UHFFFAOYSA-N 4-[4-[6-(cyclopropylmethoxy)pyridin-2-yl]-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(OCC2CC2)=N1 YAAJVDLEFZODPP-UHFFFAOYSA-N 0.000 claims description 4
- CFAHVXGDJQKFAM-UHFFFAOYSA-N 4-[4-[6-(cyclopropylmethylamino)pyridin-2-yl]-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(NCC2CC2)=N1 CFAHVXGDJQKFAM-UHFFFAOYSA-N 0.000 claims description 4
- YUANCYFDXNJEKW-UHFFFAOYSA-N 6-[2,6-difluoro-4-(2-propylsulfanylpyridin-3-yl)phenoxy]hexanoic acid Chemical compound CCCSC1=NC=CC=C1C1=CC(F)=C(OCCCCCC(O)=O)C(F)=C1 YUANCYFDXNJEKW-UHFFFAOYSA-N 0.000 claims description 4
- XSMVITSQILLGJC-UHFFFAOYSA-N C(C)(C)SC1=CC=CC(=N1)C1=CC=C(OCCCC(=O)O)C=C1 Chemical compound C(C)(C)SC1=CC=CC(=N1)C1=CC=C(OCCCC(=O)O)C=C1 XSMVITSQILLGJC-UHFFFAOYSA-N 0.000 claims description 4
- MBEDVVJPCMIDKN-UHFFFAOYSA-N C1(CC1)CNC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CC1)CNC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F MBEDVVJPCMIDKN-UHFFFAOYSA-N 0.000 claims description 4
- OAIDWRNGRAXPIJ-UHFFFAOYSA-N C1(CC1)CNC=1C=C(C=CC1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CC1)CNC=1C=C(C=CC1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F OAIDWRNGRAXPIJ-UHFFFAOYSA-N 0.000 claims description 4
- BXXWQTFZRNQEFS-UHFFFAOYSA-N C1(CC1)COC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C(=C1)F)F Chemical compound C1(CC1)COC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C(=C1)F)F BXXWQTFZRNQEFS-UHFFFAOYSA-N 0.000 claims description 4
- WSZOGZYQCOYMOV-UHFFFAOYSA-N C1(CCC1)CC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCC1)CC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F WSZOGZYQCOYMOV-UHFFFAOYSA-N 0.000 claims description 4
- UDKVYFSSBAUEQX-UHFFFAOYSA-N C1(CCC1)CC=1C=C(C=CC1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCC1)CC=1C=C(C=CC1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F UDKVYFSSBAUEQX-UHFFFAOYSA-N 0.000 claims description 4
- QJBFOEPJCNMDBZ-UHFFFAOYSA-N C1(CCC1)OC=1C=C(C=CC1)C1=CC(=C(OCC2(CC2)CC(=O)O)C(=C1)F)F Chemical compound C1(CCC1)OC=1C=C(C=CC1)C1=CC(=C(OCC2(CC2)CC(=O)O)C(=C1)F)F QJBFOEPJCNMDBZ-UHFFFAOYSA-N 0.000 claims description 4
- VTMGSJIFVABOFE-CYBMUJFWSA-N C1(CCC1)OC=1C=C(C=CC1)C1=CC(=C(O[C@@H](CCC(=O)O)C)C(=C1)F)F Chemical compound C1(CCC1)OC=1C=C(C=CC1)C1=CC(=C(O[C@@H](CCC(=O)O)C)C(=C1)F)F VTMGSJIFVABOFE-CYBMUJFWSA-N 0.000 claims description 4
- HQRDXRVRNFFTJR-UHFFFAOYSA-N C1(CCC1)OC=1C=C(C=CC1)C1=CC=C(C=N1)OCCCC(=O)O Chemical compound C1(CCC1)OC=1C=C(C=CC1)C1=CC=C(C=N1)OCCCC(=O)O HQRDXRVRNFFTJR-UHFFFAOYSA-N 0.000 claims description 4
- HWZUSFOMBAPCIC-UHFFFAOYSA-N C1(CCC1)SC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C(=C1)F)F HWZUSFOMBAPCIC-UHFFFAOYSA-N 0.000 claims description 4
- FSDIHQFPBKXMSF-GFCCVEGCSA-N C1(CCC1)SC1=NC=CC=C1C1=CC(=C(O[C@@H](CCC(=O)O)C)C(=C1)F)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC(=C(O[C@@H](CCC(=O)O)C)C(=C1)F)F FSDIHQFPBKXMSF-GFCCVEGCSA-N 0.000 claims description 4
- FSDIHQFPBKXMSF-LBPRGKRZSA-N C1(CCC1)SC1=NC=CC=C1C1=CC(=C(O[C@H](CCC(=O)O)C)C(=C1)F)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC(=C(O[C@H](CCC(=O)O)C)C(=C1)F)F FSDIHQFPBKXMSF-LBPRGKRZSA-N 0.000 claims description 4
- AIBOLCZOQGCAHH-UHFFFAOYSA-N C1(CCCC1)C1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)C1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F AIBOLCZOQGCAHH-UHFFFAOYSA-N 0.000 claims description 4
- JXHHAFHQIXPNSZ-UHFFFAOYSA-N C1(CCCC1)C1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)C1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F JXHHAFHQIXPNSZ-UHFFFAOYSA-N 0.000 claims description 4
- XPXLCGWSOAGCMR-UHFFFAOYSA-N C1(CCCC1)CC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)CC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F XPXLCGWSOAGCMR-UHFFFAOYSA-N 0.000 claims description 4
- DMKXMMPWFSGDGR-UHFFFAOYSA-N C1(CCCC1)CC1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)CC1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F DMKXMMPWFSGDGR-UHFFFAOYSA-N 0.000 claims description 4
- MFHAMKZNDYQDCH-UHFFFAOYSA-N C1(CCCC1)NC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)NC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F MFHAMKZNDYQDCH-UHFFFAOYSA-N 0.000 claims description 4
- FFLDQGGDRNPRRT-UHFFFAOYSA-N C1(CCCC1)NC=1C=C(C=CC1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)NC=1C=C(C=CC1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F FFLDQGGDRNPRRT-UHFFFAOYSA-N 0.000 claims description 4
- ABSYDFGPIHMKJX-UHFFFAOYSA-N C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C(=C1)F)F ABSYDFGPIHMKJX-UHFFFAOYSA-N 0.000 claims description 4
- WMLRCLQMNGNGBR-UHFFFAOYSA-N C1(CCCC1)OC=1C=C(C=CC1)C1=CC=C(C=N1)OCCCC(=O)O Chemical compound C1(CCCC1)OC=1C=C(C=CC1)C1=CC=C(C=N1)OCCCC(=O)O WMLRCLQMNGNGBR-UHFFFAOYSA-N 0.000 claims description 4
- PFKMXFGCGVRVNQ-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C(=C1)F)F PFKMXFGCGVRVNQ-UHFFFAOYSA-N 0.000 claims description 4
- GCBDODGWYWRTFC-CYBMUJFWSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(O[C@@H](CCC(=O)O)C)C(=C1)F)F Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(O[C@@H](CCC(=O)O)C)C(=C1)F)F GCBDODGWYWRTFC-CYBMUJFWSA-N 0.000 claims description 4
- IFNSJZCCQQTDMQ-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC=C(OCCCC(=O)O)C=C1 Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC=C(OCCCC(=O)O)C=C1 IFNSJZCCQQTDMQ-UHFFFAOYSA-N 0.000 claims description 4
- YNKDCLJEWRHYGU-UHFFFAOYSA-N ClC=1C=CC(=C(C1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F)NC1CCCC1 Chemical compound ClC=1C=CC(=C(C1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F)NC1CCCC1 YNKDCLJEWRHYGU-UHFFFAOYSA-N 0.000 claims description 4
- FKNZJECBWFZYDH-UHFFFAOYSA-N FC1(CN(CC1)C1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F)F Chemical compound FC1(CN(CC1)C1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F)F FKNZJECBWFZYDH-UHFFFAOYSA-N 0.000 claims description 4
- UCKHAJKUHNWNDU-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C1=CC(=CC=C1)NCCC)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C1=CC(=CC=C1)NCCC)F UCKHAJKUHNWNDU-UHFFFAOYSA-N 0.000 claims description 4
- MYLLLHTXCVHDAO-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C1=NC(=CC=C1)NC(C)C)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C1=NC(=CC=C1)NC(C)C)F MYLLLHTXCVHDAO-UHFFFAOYSA-N 0.000 claims description 4
- DVYSDSDTLDAOIE-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)CC(C)C)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)CC(C)C)F DVYSDSDTLDAOIE-UHFFFAOYSA-N 0.000 claims description 4
- ABBNRGGURCARHX-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)N1CCCC1)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)N1CCCC1)F ABBNRGGURCARHX-UHFFFAOYSA-N 0.000 claims description 4
- AXLPPNLIRCHIAV-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OCC1=COC=C1)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OCC1=COC=C1)F AXLPPNLIRCHIAV-UHFFFAOYSA-N 0.000 claims description 4
- QFEKHLMRMGXOIO-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OCC1COCC1)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OCC1COCC1)F QFEKHLMRMGXOIO-UHFFFAOYSA-N 0.000 claims description 4
- IXFOVPWYTFXOLU-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OCC1OCCC1)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OCC1OCCC1)F IXFOVPWYTFXOLU-UHFFFAOYSA-N 0.000 claims description 4
- ZRHUNYISLNKRIM-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OCC=1OC=CC1)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OCC=1OC=CC1)F ZRHUNYISLNKRIM-UHFFFAOYSA-N 0.000 claims description 4
- APUZADOJKNMBCX-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)SCCC)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)SCCC)F APUZADOJKNMBCX-UHFFFAOYSA-N 0.000 claims description 4
- IYHDPSQJCZCDGD-UHFFFAOYSA-N FC1=C(OCCCCC(=O)O)C(=CC(=C1)C1=NC(=CC=C1)OC(C)C)F Chemical compound FC1=C(OCCCCC(=O)O)C(=CC(=C1)C1=NC(=CC=C1)OC(C)C)F IYHDPSQJCZCDGD-UHFFFAOYSA-N 0.000 claims description 4
- TVHCTEMGUDLEBN-UHFFFAOYSA-N FC1=C(OCCCCC(=O)O)C(=CC(=C1)C1=NC(=CC=C1)SC(C)C)F Chemical compound FC1=C(OCCCCC(=O)O)C(=CC(=C1)C1=NC(=CC=C1)SC(C)C)F TVHCTEMGUDLEBN-UHFFFAOYSA-N 0.000 claims description 4
- DLQLUMUTDSBENW-UHFFFAOYSA-N FC1=C(OCCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OC1CCOCC1)F Chemical compound FC1=C(OCCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OC1CCOCC1)F DLQLUMUTDSBENW-UHFFFAOYSA-N 0.000 claims description 4
- XWUDRDPGUXFFSC-UHFFFAOYSA-N FC1=C(OCCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OC1COCC1)F Chemical compound FC1=C(OCCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OC1COCC1)F XWUDRDPGUXFFSC-UHFFFAOYSA-N 0.000 claims description 4
- LSDBKHPDMFCPIJ-UHFFFAOYSA-N FC1=C(OCCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)SC(C)C)F Chemical compound FC1=C(OCCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)SC(C)C)F LSDBKHPDMFCPIJ-UHFFFAOYSA-N 0.000 claims description 4
- CWIYUAJVKXQIDO-UHFFFAOYSA-N FC1=C(OCCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)SCCC)F Chemical compound FC1=C(OCCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)SCCC)F CWIYUAJVKXQIDO-UHFFFAOYSA-N 0.000 claims description 4
- BRRPDCHQPZFRKQ-OAHLLOKOSA-N FC1=C(O[C@@H](CCC(=O)O)C)C(=CC(=C1)C1=CC(=CC=C1)OC1=CC=CC=C1)F Chemical compound FC1=C(O[C@@H](CCC(=O)O)C)C(=CC(=C1)C1=CC(=CC=C1)OC1=CC=CC=C1)F BRRPDCHQPZFRKQ-OAHLLOKOSA-N 0.000 claims description 4
- YJMWVTINSRLPGH-UHFFFAOYSA-N FC=1C=C(C=C(C1OCCCC(=O)O)F)C1=C(C=CC=C1)OC1=CC=CC=C1 Chemical compound FC=1C=C(C=C(C1OCCCC(=O)O)F)C1=C(C=CC=C1)OC1=CC=CC=C1 YJMWVTINSRLPGH-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- KMWPUGUAAXTHMI-UHFFFAOYSA-N 4-[2,6-difluoro-4-(2-phenoxypyridin-3-yl)phenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CN=C1OC1=CC=CC=C1 KMWPUGUAAXTHMI-UHFFFAOYSA-N 0.000 claims description 3
- BXXLQGOAKQHBAC-UHFFFAOYSA-N 4-[2,6-difluoro-4-(2-propan-2-yloxypyridin-3-yl)phenoxy]butanoic acid Chemical compound CC(C)OC1=NC=CC=C1C1=CC(F)=C(OCCCC(O)=O)C(F)=C1 BXXLQGOAKQHBAC-UHFFFAOYSA-N 0.000 claims description 3
- JMCYEEQKCPWZMR-UHFFFAOYSA-N 4-[2,6-difluoro-4-(2-propan-2-ylsulfanylpyridin-3-yl)phenoxy]butanoic acid Chemical compound CC(C)SC1=NC=CC=C1C1=CC(F)=C(OCCCC(O)=O)C(F)=C1 JMCYEEQKCPWZMR-UHFFFAOYSA-N 0.000 claims description 3
- AERWSLMEUPKZGJ-UHFFFAOYSA-N 4-[2,6-difluoro-4-(2-propoxypyridin-3-yl)phenyl]sulfanylbutanoic acid Chemical compound CCCOC1=NC=CC=C1C1=CC(F)=C(SCCCC(O)=O)C(F)=C1 AERWSLMEUPKZGJ-UHFFFAOYSA-N 0.000 claims description 3
- PBLGMTWAKXMYQN-UHFFFAOYSA-N 4-[2,6-difluoro-4-(2-pyrrol-1-ylpyridin-3-yl)phenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CN=C1N1C=CC=C1 PBLGMTWAKXMYQN-UHFFFAOYSA-N 0.000 claims description 3
- WYLABCOHBNVGEO-UHFFFAOYSA-N 4-[2,6-difluoro-4-(6-piperidin-1-ylpyridin-2-yl)phenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(N2CCCCC2)=N1 WYLABCOHBNVGEO-UHFFFAOYSA-N 0.000 claims description 3
- ACZJQBYYNLEVGN-UHFFFAOYSA-N 4-[2,6-difluoro-4-(6-propan-2-ylsulfanylpyridin-2-yl)phenoxy]butanoic acid Chemical compound CC(C)SC1=CC=CC(C=2C=C(F)C(OCCCC(O)=O)=C(F)C=2)=N1 ACZJQBYYNLEVGN-UHFFFAOYSA-N 0.000 claims description 3
- YGZWRCUODFLRAQ-UHFFFAOYSA-N 4-[2,6-difluoro-4-(6-propan-2-ylsulfanylpyridin-2-yl)phenyl]sulfanylbutanoic acid Chemical compound CC(C)SC1=CC=CC(C=2C=C(F)C(SCCCC(O)=O)=C(F)C=2)=N1 YGZWRCUODFLRAQ-UHFFFAOYSA-N 0.000 claims description 3
- DVKJIPDJNXCILR-UHFFFAOYSA-N 4-[2,6-difluoro-4-(6-propylsulfanylpyridin-2-yl)phenoxy]butanoic acid Chemical compound CCCSC1=CC=CC(C=2C=C(F)C(OCCCC(O)=O)=C(F)C=2)=N1 DVKJIPDJNXCILR-UHFFFAOYSA-N 0.000 claims description 3
- FBOGZGNTJUZQMN-UHFFFAOYSA-N 4-[2,6-difluoro-4-(6-pyrrolidin-1-ylpyridin-2-yl)phenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(N2CCCC2)=N1 FBOGZGNTJUZQMN-UHFFFAOYSA-N 0.000 claims description 3
- RTLNGKFMXIZGPB-UHFFFAOYSA-N 4-[2,6-difluoro-4-[2-(3-methylbutylsulfanyl)pyridin-3-yl]phenoxy]butanoic acid Chemical compound CC(C)CCSC1=NC=CC=C1C1=CC(F)=C(OCCCC(O)=O)C(F)=C1 RTLNGKFMXIZGPB-UHFFFAOYSA-N 0.000 claims description 3
- JCOSQDQBDIPRRL-UHFFFAOYSA-N 4-[2,6-difluoro-4-[2-(oxan-4-yloxy)pyridin-3-yl]phenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CN=C1OC1CCOCC1 JCOSQDQBDIPRRL-UHFFFAOYSA-N 0.000 claims description 3
- AZRHGJZPYNBGQY-UHFFFAOYSA-N 4-[2,6-difluoro-4-[2-(oxolan-3-yloxy)pyridin-3-yl]phenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CN=C1OC1COCC1 AZRHGJZPYNBGQY-UHFFFAOYSA-N 0.000 claims description 3
- YHAGNJOQFLWTGV-UHFFFAOYSA-N 4-[2-chloro-4-(6-propan-2-ylsulfanylpyridin-2-yl)phenoxy]butanoic acid Chemical compound CC(C)SC1=CC=CC(C=2C=C(Cl)C(OCCCC(O)=O)=CC=2)=N1 YHAGNJOQFLWTGV-UHFFFAOYSA-N 0.000 claims description 3
- WYPQOWUULRYVKG-UHFFFAOYSA-N 4-[2-fluoro-4-(2-propan-2-ylsulfanylpyridin-3-yl)phenyl]sulfanylbutanoic acid Chemical compound CC(C)SC1=NC=CC=C1C1=CC=C(SCCCC(O)=O)C(F)=C1 WYPQOWUULRYVKG-UHFFFAOYSA-N 0.000 claims description 3
- PVXAGWVYHONRHT-UHFFFAOYSA-N 4-[2-fluoro-4-(6-propan-2-yloxypyridin-2-yl)phenyl]sulfanylbutanoic acid Chemical compound CC(C)OC1=CC=CC(C=2C=C(F)C(SCCCC(O)=O)=CC=2)=N1 PVXAGWVYHONRHT-UHFFFAOYSA-N 0.000 claims description 3
- IUMIFTQFMHFVIR-UHFFFAOYSA-N 4-[2-fluoro-4-(6-propan-2-ylsulfanylpyridin-2-yl)phenoxy]butanoic acid Chemical compound CC(C)SC1=CC=CC(C=2C=C(F)C(OCCCC(O)=O)=CC=2)=N1 IUMIFTQFMHFVIR-UHFFFAOYSA-N 0.000 claims description 3
- LGYJAAPECSQGOM-UHFFFAOYSA-N 4-[4-(2-butan-2-ylsulfanylpyridin-3-yl)-2,6-difluorophenoxy]butanoic acid Chemical compound CCC(C)SC1=NC=CC=C1C1=CC(F)=C(OCCCC(O)=O)C(F)=C1 LGYJAAPECSQGOM-UHFFFAOYSA-N 0.000 claims description 3
- FRGFSMCTULBWMX-UHFFFAOYSA-N 4-[4-(2-cyclobutyloxypyridin-3-yl)-2-fluorophenyl]sulfanylbutanoic acid Chemical compound C1=C(F)C(SCCCC(=O)O)=CC=C1C1=CC=CN=C1OC1CCC1 FRGFSMCTULBWMX-UHFFFAOYSA-N 0.000 claims description 3
- MMMBHIOHEYRKLI-UHFFFAOYSA-N 4-[4-(2-cyclobutyloxypyridin-3-yl)phenyl]sulfanylbutanoic acid Chemical compound C1=CC(SCCCC(=O)O)=CC=C1C1=CC=CN=C1OC1CCC1 MMMBHIOHEYRKLI-UHFFFAOYSA-N 0.000 claims description 3
- UVYNFKHFRVOFHR-UHFFFAOYSA-N 4-[4-(2-cyclobutylsulfanylpyridin-3-yl)-2,5-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=CC(F)=C1C1=CC=CN=C1SC1CCC1 UVYNFKHFRVOFHR-UHFFFAOYSA-N 0.000 claims description 3
- ROGWZXKOVQRUHY-UHFFFAOYSA-N 4-[4-(2-cyclobutylsulfanylpyridin-3-yl)-2,6-difluorophenyl]sulfanylbutanoic acid Chemical compound C1=C(F)C(SCCCC(=O)O)=C(F)C=C1C1=CC=CN=C1SC1CCC1 ROGWZXKOVQRUHY-UHFFFAOYSA-N 0.000 claims description 3
- QLPDCAJRIYTJCR-UHFFFAOYSA-N 4-[4-(2-cyclobutylsulfanylpyridin-3-yl)-2,6-dimethylphenoxy]butanoic acid Chemical compound CC1=C(OCCCC(O)=O)C(C)=CC(C=2C(=NC=CC=2)SC2CCC2)=C1 QLPDCAJRIYTJCR-UHFFFAOYSA-N 0.000 claims description 3
- REXQXPBBKTVIDR-UHFFFAOYSA-N 4-[4-(2-cyclobutylsulfanylpyridin-3-yl)-2-fluorophenyl]sulfanylbutanoic acid Chemical compound C1=C(F)C(SCCCC(=O)O)=CC=C1C1=CC=CN=C1SC1CCC1 REXQXPBBKTVIDR-UHFFFAOYSA-N 0.000 claims description 3
- MJVJUFOAXBQFHZ-UHFFFAOYSA-N 4-[4-(2-cyclobutylsulfanylpyridin-3-yl)-2-methoxyphenoxy]butanoic acid Chemical compound C1=C(OCCCC(O)=O)C(OC)=CC(C=2C(=NC=CC=2)SC2CCC2)=C1 MJVJUFOAXBQFHZ-UHFFFAOYSA-N 0.000 claims description 3
- RBISTJBOAXIOLE-UHFFFAOYSA-N 4-[4-(2-cyclobutylsulfanylpyridin-3-yl)phenoxy]butanoic acid Chemical compound C1=CC(OCCCC(=O)O)=CC=C1C1=CC=CN=C1SC1CCC1 RBISTJBOAXIOLE-UHFFFAOYSA-N 0.000 claims description 3
- ZBJHSBYKGYSPAI-UHFFFAOYSA-N 4-[4-(2-cyclobutylsulfanylpyridin-3-yl)phenyl]sulfanylbutanoic acid Chemical compound C1=CC(SCCCC(=O)O)=CC=C1C1=CC=CN=C1SC1CCC1 ZBJHSBYKGYSPAI-UHFFFAOYSA-N 0.000 claims description 3
- DZCYVYBVXGEETA-UHFFFAOYSA-N 4-[4-(2-cyclopentyloxyphenyl)-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC=C1OC1CCCC1 DZCYVYBVXGEETA-UHFFFAOYSA-N 0.000 claims description 3
- XTXUPPIODYKDMT-UHFFFAOYSA-N 4-[4-(2-cyclopentyloxyphenyl)phenoxy]butanoic acid Chemical compound C1=CC(OCCCC(=O)O)=CC=C1C1=CC=CC=C1OC1CCCC1 XTXUPPIODYKDMT-UHFFFAOYSA-N 0.000 claims description 3
- DFIHFGOZBHEOCY-UHFFFAOYSA-N 4-[4-(2-cyclopentylsulfanylpyridin-3-yl)-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CN=C1SC1CCCC1 DFIHFGOZBHEOCY-UHFFFAOYSA-N 0.000 claims description 3
- IYSAIKRRLYIHHV-UHFFFAOYSA-N 4-[4-(2-cyclopentylsulfanylpyridin-3-yl)phenyl]sulfanylbutanoic acid Chemical compound C1=CC(SCCCC(=O)O)=CC=C1C1=CC=CN=C1SC1CCCC1 IYSAIKRRLYIHHV-UHFFFAOYSA-N 0.000 claims description 3
- GBJANRSNYZVXKM-UHFFFAOYSA-N 4-[4-(2-propan-2-yloxyphenyl)phenoxy]butanoic acid Chemical compound CC(C)OC1=CC=CC=C1C1=CC=C(OCCCC(O)=O)C=C1 GBJANRSNYZVXKM-UHFFFAOYSA-N 0.000 claims description 3
- SXJXCPBCENEYIU-UHFFFAOYSA-N 4-[4-(2-propan-2-yloxypyridin-3-yl)phenyl]sulfanylbutanoic acid Chemical compound CC(C)OC1=NC=CC=C1C1=CC=C(SCCCC(O)=O)C=C1 SXJXCPBCENEYIU-UHFFFAOYSA-N 0.000 claims description 3
- ALJFQNXHRIXUDJ-UHFFFAOYSA-N 4-[4-(2-propylsulfanylpyridin-3-yl)phenoxy]butanoic acid Chemical compound CCCSC1=NC=CC=C1C1=CC=C(OCCCC(O)=O)C=C1 ALJFQNXHRIXUDJ-UHFFFAOYSA-N 0.000 claims description 3
- LJCXBGOVJBEFJN-UHFFFAOYSA-N 4-[4-(3-cyclopentyloxyphenyl)-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(OC2CCCC2)=C1 LJCXBGOVJBEFJN-UHFFFAOYSA-N 0.000 claims description 3
- SOBVEZXHUQPOKF-UHFFFAOYSA-N 4-[4-(3-cyclopentylphenyl)-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(C2CCCC2)=C1 SOBVEZXHUQPOKF-UHFFFAOYSA-N 0.000 claims description 3
- YFIDHWIOSWGBNX-UHFFFAOYSA-N 4-[4-(6-cyclobutyloxypyridin-2-yl)-2,6-difluorophenyl]sulfanylbutanoic acid Chemical compound C1=C(F)C(SCCCC(=O)O)=C(F)C=C1C1=CC=CC(OC2CCC2)=N1 YFIDHWIOSWGBNX-UHFFFAOYSA-N 0.000 claims description 3
- IOSBNYCOGFROCD-UHFFFAOYSA-N 4-[4-(6-cyclobutyloxypyridin-2-yl)-2-(trifluoromethyl)phenoxy]butanoic acid Chemical compound C1=C(C(F)(F)F)C(OCCCC(=O)O)=CC=C1C1=CC=CC(OC2CCC2)=N1 IOSBNYCOGFROCD-UHFFFAOYSA-N 0.000 claims description 3
- CZSVDGKNXJMVON-UHFFFAOYSA-N 4-[4-(6-cyclobutylsulfanylpyridin-2-yl)-2,5-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=CC(F)=C1C1=CC=CC(SC2CCC2)=N1 CZSVDGKNXJMVON-UHFFFAOYSA-N 0.000 claims description 3
- VDZUSUSIKCIACM-UHFFFAOYSA-N 4-[4-(6-cyclobutylsulfanylpyridin-2-yl)phenyl]sulfanylbutanoic acid Chemical compound C1=CC(SCCCC(=O)O)=CC=C1C1=CC=CC(SC2CCC2)=N1 VDZUSUSIKCIACM-UHFFFAOYSA-N 0.000 claims description 3
- MYKQLQNPGMHYIH-UHFFFAOYSA-N 4-[4-(6-cyclopentyloxypyridin-2-yl)-2,6-difluorophenyl]sulfanylbutanoic acid Chemical compound C1=C(F)C(SCCCC(=O)O)=C(F)C=C1C1=CC=CC(OC2CCCC2)=N1 MYKQLQNPGMHYIH-UHFFFAOYSA-N 0.000 claims description 3
- UPZJSXRITNBXGU-UHFFFAOYSA-N 4-[4-(6-cyclopentylsulfanylpyridin-2-yl)-2,6-difluorophenyl]sulfanylbutanoic acid Chemical compound C1=C(F)C(SCCCC(=O)O)=C(F)C=C1C1=CC=CC(SC2CCCC2)=N1 UPZJSXRITNBXGU-UHFFFAOYSA-N 0.000 claims description 3
- INNXXKGBSIOZPA-UHFFFAOYSA-N 4-[4-(6-propan-2-yloxypyridin-2-yl)phenyl]sulfanylbutanoic acid Chemical compound CC(C)OC1=CC=CC(C=2C=CC(SCCCC(O)=O)=CC=2)=N1 INNXXKGBSIOZPA-UHFFFAOYSA-N 0.000 claims description 3
- GQNRQRLRKADICD-UHFFFAOYSA-N 4-[4-(6-propoxypyridin-2-yl)phenyl]sulfanylbutanoic acid Chemical compound CCCOC1=CC=CC(C=2C=CC(SCCCC(O)=O)=CC=2)=N1 GQNRQRLRKADICD-UHFFFAOYSA-N 0.000 claims description 3
- BLHOEVHJURBCBH-UHFFFAOYSA-N 4-[4-[2-(cyclobutylmethoxy)pyridin-3-yl]-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CN=C1OCC1CCC1 BLHOEVHJURBCBH-UHFFFAOYSA-N 0.000 claims description 3
- BQNDGBPQSJNFOP-UHFFFAOYSA-N 4-[4-[2-(cyclopentylamino)-5-fluorophenyl]-2-fluorophenyl]sulfanylbutanoic acid Chemical compound C1=C(F)C(SCCCC(=O)O)=CC=C1C1=CC(F)=CC=C1NC1CCCC1 BQNDGBPQSJNFOP-UHFFFAOYSA-N 0.000 claims description 3
- XQKGVQFJQUAKCH-UHFFFAOYSA-N 4-[4-[2-(cyclopentylamino)-5-fluorophenyl]phenyl]sulfanylbutanoic acid Chemical compound C1=CC(SCCCC(=O)O)=CC=C1C1=CC(F)=CC=C1NC1CCCC1 XQKGVQFJQUAKCH-UHFFFAOYSA-N 0.000 claims description 3
- UJIXUGHNYGPUKT-UHFFFAOYSA-N 4-[4-[2-(cyclopentylamino)phenyl]-2-fluorophenyl]sulfanylbutanoic acid Chemical compound C1=C(F)C(SCCCC(=O)O)=CC=C1C1=CC=CC=C1NC1CCCC1 UJIXUGHNYGPUKT-UHFFFAOYSA-N 0.000 claims description 3
- LSXTZFGBXVQPBK-UHFFFAOYSA-N 4-[4-[2-(cyclopropylmethoxy)pyridin-3-yl]-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CN=C1OCC1CC1 LSXTZFGBXVQPBK-UHFFFAOYSA-N 0.000 claims description 3
- ZJEONEAEBPTMRN-UHFFFAOYSA-N 4-[4-[2-(cyclopropylmethylamino)phenyl]-2,6-difluorophenyl]sulfanylbutanoic acid Chemical compound C1=C(F)C(SCCCC(=O)O)=C(F)C=C1C1=CC=CC=C1NCC1CC1 ZJEONEAEBPTMRN-UHFFFAOYSA-N 0.000 claims description 3
- LANGLCYXUFQAMF-UHFFFAOYSA-N 4-[4-[2-(cyclopropylmethylsulfanyl)pyridin-3-yl]-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CN=C1SCC1CC1 LANGLCYXUFQAMF-UHFFFAOYSA-N 0.000 claims description 3
- ZOEGUEDUJXAOGN-UHFFFAOYSA-N 4-[4-[2-(cyclopropylmethylsulfanyl)pyridin-3-yl]phenoxy]butanoic acid Chemical compound C1=CC(OCCCC(=O)O)=CC=C1C1=CC=CN=C1SCC1CC1 ZOEGUEDUJXAOGN-UHFFFAOYSA-N 0.000 claims description 3
- JMRUOOKQDMCBAW-UHFFFAOYSA-N C(C)(C)(C)SC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C(C)(C)(C)SC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F JMRUOOKQDMCBAW-UHFFFAOYSA-N 0.000 claims description 3
- NNDSBJFAXIQWRM-UHFFFAOYSA-N C(C)(C)OC1=NC=CC=C1C1=CC=C(C=C1)SC(CCC(=O)O)C Chemical compound C(C)(C)OC1=NC=CC=C1C1=CC=C(C=C1)SC(CCC(=O)O)C NNDSBJFAXIQWRM-UHFFFAOYSA-N 0.000 claims description 3
- QAZARCQYAYGSCI-UHFFFAOYSA-N C(C)(C)OC1=NC=CC=C1C1=CC=C(C=C1)SCCCCC(=O)O Chemical compound C(C)(C)OC1=NC=CC=C1C1=CC=C(C=C1)SCCCCC(=O)O QAZARCQYAYGSCI-UHFFFAOYSA-N 0.000 claims description 3
- BPCFIEZEMULLQK-UHFFFAOYSA-N C(C)(C)SC1=NC=CC=C1C1=CC=C(C=C1)SCCCC(=O)O Chemical compound C(C)(C)SC1=NC=CC=C1C1=CC=C(C=C1)SCCCC(=O)O BPCFIEZEMULLQK-UHFFFAOYSA-N 0.000 claims description 3
- OTINYIQZSLBQQL-UHFFFAOYSA-N C(C)SC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C(C)SC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F OTINYIQZSLBQQL-UHFFFAOYSA-N 0.000 claims description 3
- GINGROLQJMREFT-UHFFFAOYSA-N C(CC)NC1=C(C=CC=C1)C1=CC=C(OCCCC(=O)O)C=C1 Chemical compound C(CC)NC1=C(C=CC=C1)C1=CC=C(OCCCC(=O)O)C=C1 GINGROLQJMREFT-UHFFFAOYSA-N 0.000 claims description 3
- SQYTUHQVNNBYAX-UHFFFAOYSA-N C(CC)OC=1C=C(C=CC1)C1=CC=C(C=C1)SCCCC(=O)O Chemical compound C(CC)OC=1C=C(C=CC1)C1=CC=C(C=C1)SCCCC(=O)O SQYTUHQVNNBYAX-UHFFFAOYSA-N 0.000 claims description 3
- NMEAMTYWUAVPPP-UHFFFAOYSA-N C(CCC)SC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C(CCC)SC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F NMEAMTYWUAVPPP-UHFFFAOYSA-N 0.000 claims description 3
- GVFBISVPUDKWML-UHFFFAOYSA-N C1(CC1)CNC1=C(C=CC=C1)C1=CC=C(OCCCC(=O)O)C=C1 Chemical compound C1(CC1)CNC1=C(C=CC=C1)C1=CC=C(OCCCC(=O)O)C=C1 GVFBISVPUDKWML-UHFFFAOYSA-N 0.000 claims description 3
- AJDJIYDOFBPQQQ-UHFFFAOYSA-N C1(CC1)CNC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F Chemical compound C1(CC1)CNC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F AJDJIYDOFBPQQQ-UHFFFAOYSA-N 0.000 claims description 3
- SJQCJXUINBRBLU-UHFFFAOYSA-N C1(CC1)COC1=C(C=CC=C1)C1=CC(=C(C(=C1)F)OCCCC(=O)O)F Chemical compound C1(CC1)COC1=C(C=CC=C1)C1=CC(=C(C(=C1)F)OCCCC(=O)O)F SJQCJXUINBRBLU-UHFFFAOYSA-N 0.000 claims description 3
- RBBMSKOIBOXMOE-UHFFFAOYSA-N C1(CC1)COC1=C(C=CC=C1)C1=CC=C(C=C1)OCCCC(=O)O Chemical compound C1(CC1)COC1=C(C=CC=C1)C1=CC=C(C=C1)OCCCC(=O)O RBBMSKOIBOXMOE-UHFFFAOYSA-N 0.000 claims description 3
- DVWCRJXYQWYXSR-UHFFFAOYSA-N C1(CC1)COC1=CC=CC(=N1)C1=CC(=C(C(=C1)F)SCCCC(=O)O)F Chemical compound C1(CC1)COC1=CC=CC(=N1)C1=CC(=C(C(=C1)F)SCCCC(=O)O)F DVWCRJXYQWYXSR-UHFFFAOYSA-N 0.000 claims description 3
- BYCNLHJICUABTM-UHFFFAOYSA-N C1(CC1)COC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F Chemical compound C1(CC1)COC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F BYCNLHJICUABTM-UHFFFAOYSA-N 0.000 claims description 3
- HDHUJXFWXWZVFM-UHFFFAOYSA-N C1(CC1)COC1=NC=CC=C1C1=CC=C(C=C1)SCCCC(=O)O Chemical compound C1(CC1)COC1=NC=CC=C1C1=CC=C(C=C1)SCCCC(=O)O HDHUJXFWXWZVFM-UHFFFAOYSA-N 0.000 claims description 3
- FDKQYNJDRATRBJ-UHFFFAOYSA-N C1(CC1)CSC1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CC1)CSC1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F FDKQYNJDRATRBJ-UHFFFAOYSA-N 0.000 claims description 3
- YIKZUENFINQBNJ-UHFFFAOYSA-N C1(CC1)OC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CC1)OC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F YIKZUENFINQBNJ-UHFFFAOYSA-N 0.000 claims description 3
- XNUSYMIFYJLPPW-UHFFFAOYSA-N C1(CC1)OC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C(=C1)F)F Chemical compound C1(CC1)OC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C(=C1)F)F XNUSYMIFYJLPPW-UHFFFAOYSA-N 0.000 claims description 3
- HERXCDFUOCTTBE-UHFFFAOYSA-N C1(CC1)SC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CC1)SC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F HERXCDFUOCTTBE-UHFFFAOYSA-N 0.000 claims description 3
- VUHRGFBVDXYTFI-UHFFFAOYSA-N C1(CCC1)COC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F Chemical compound C1(CCC1)COC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F VUHRGFBVDXYTFI-UHFFFAOYSA-N 0.000 claims description 3
- DKHBOROYEBOLEJ-UHFFFAOYSA-N C1(CCC1)COC1=NC=CC=C1C1=CC(=C(C=C1)SCCCC(=O)O)F Chemical compound C1(CCC1)COC1=NC=CC=C1C1=CC(=C(C=C1)SCCCC(=O)O)F DKHBOROYEBOLEJ-UHFFFAOYSA-N 0.000 claims description 3
- MAKFOXBSQMOZQJ-UHFFFAOYSA-N C1(CCC1)COC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCC1)COC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C(=C1)F)F MAKFOXBSQMOZQJ-UHFFFAOYSA-N 0.000 claims description 3
- PIAAQHKJXLDWMR-UHFFFAOYSA-N C1(CCC1)NC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCC1)NC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F PIAAQHKJXLDWMR-UHFFFAOYSA-N 0.000 claims description 3
- VNOXIQLTHAKMBA-UHFFFAOYSA-N C1(CCC1)NC1=C(C=CC=C1)C1=CC=C(OCCCC(=O)O)C=C1 Chemical compound C1(CCC1)NC1=C(C=CC=C1)C1=CC=C(OCCCC(=O)O)C=C1 VNOXIQLTHAKMBA-UHFFFAOYSA-N 0.000 claims description 3
- HYIRCBPBKQJKRC-UHFFFAOYSA-N C1(CCC1)OC1=C(C=CC=C1)C1=CC(=C(C(=C1)F)OCCCC(=O)O)F Chemical compound C1(CCC1)OC1=C(C=CC=C1)C1=CC(=C(C(=C1)F)OCCCC(=O)O)F HYIRCBPBKQJKRC-UHFFFAOYSA-N 0.000 claims description 3
- JVSUHNLAUYTHNG-UHFFFAOYSA-N C1(CCC1)OC1=CC=CC(=N1)C1=CC=C(C=C1)SCCCC(=O)O Chemical compound C1(CCC1)OC1=CC=CC(=N1)C1=CC=C(C=C1)SCCCC(=O)O JVSUHNLAUYTHNG-UHFFFAOYSA-N 0.000 claims description 3
- JSFAWTBNWDYZEO-UHFFFAOYSA-N C1(CCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F Chemical compound C1(CCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F JSFAWTBNWDYZEO-UHFFFAOYSA-N 0.000 claims description 3
- LYFDVDVGNVZSCK-UHFFFAOYSA-N C1(CCC1)OC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCC1)OC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F LYFDVDVGNVZSCK-UHFFFAOYSA-N 0.000 claims description 3
- AMXVKNDOXBJWBG-UHFFFAOYSA-N C1(CCC1)OC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCC1)OC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C(=C1)F)F AMXVKNDOXBJWBG-UHFFFAOYSA-N 0.000 claims description 3
- VFTZAAZKJOOSKI-UHFFFAOYSA-N C1(CCC1)OC=1C=C(C=CC1)C1=CC(=C(C(=C1)F)SCCCC(=O)O)F Chemical compound C1(CCC1)OC=1C=C(C=CC1)C1=CC(=C(C(=C1)F)SCCCC(=O)O)F VFTZAAZKJOOSKI-UHFFFAOYSA-N 0.000 claims description 3
- AQYZYKGRYNGALN-UHFFFAOYSA-N C1(CCC1)SC1=CC=CC(=N1)C1=CC(=C(C(=C1)F)SCCCC(=O)O)F Chemical compound C1(CCC1)SC1=CC=CC(=N1)C1=CC(=C(C(=C1)F)SCCCC(=O)O)F AQYZYKGRYNGALN-UHFFFAOYSA-N 0.000 claims description 3
- NVEYDINNXSQLES-UHFFFAOYSA-N C1(CCC1)SC1=CC=CC(=N1)C1=CC(=C(C=C1)SCCCC(=O)O)F Chemical compound C1(CCC1)SC1=CC=CC(=N1)C1=CC(=C(C=C1)SCCCC(=O)O)F NVEYDINNXSQLES-UHFFFAOYSA-N 0.000 claims description 3
- YISCBKKBETZYGJ-UHFFFAOYSA-N C1(CCC1)SC1=NC=CC=C1C1=C(C=C(OCCCC(=O)O)C=C1F)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=C(C=C(OCCCC(=O)O)C=C1F)F YISCBKKBETZYGJ-UHFFFAOYSA-N 0.000 claims description 3
- UFSJYNCHOSVKOY-UHFFFAOYSA-N C1(CCC1)SC1=NC=CC=C1C1=CC(=C(OCC2C(C2)C(=O)O)C(=C1)F)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC(=C(OCC2C(C2)C(=O)O)C(=C1)F)F UFSJYNCHOSVKOY-UHFFFAOYSA-N 0.000 claims description 3
- UHWRRMOHVHHUJL-UHFFFAOYSA-N C1(CCC1)SC1=NC=CC=C1C1=CC(=C(OCCC(C(=O)O)C)C(=C1)F)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC(=C(OCCC(C(=O)O)C)C(=C1)F)F UHWRRMOHVHHUJL-UHFFFAOYSA-N 0.000 claims description 3
- HFXGFBXXSHSKEI-UHFFFAOYSA-N C1(CCCC1)COC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)COC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F HFXGFBXXSHSKEI-UHFFFAOYSA-N 0.000 claims description 3
- OBUPKZXCEFNRDH-UHFFFAOYSA-N C1(CCCC1)NC1=C(C=CC=C1)C1=CC(=C(C(=C1)F)SCCCC(=O)O)F Chemical compound C1(CCCC1)NC1=C(C=CC=C1)C1=CC(=C(C(=C1)F)SCCCC(=O)O)F OBUPKZXCEFNRDH-UHFFFAOYSA-N 0.000 claims description 3
- WNHQGJDKWHBNPU-UHFFFAOYSA-N C1(CCCC1)NC1=C(C=CC=C1)C1=CC=C(C=C1)SCCCC(=O)O Chemical compound C1(CCCC1)NC1=C(C=CC=C1)C1=CC=C(C=C1)SCCCC(=O)O WNHQGJDKWHBNPU-UHFFFAOYSA-N 0.000 claims description 3
- DPZAUVQLOSLBRJ-UHFFFAOYSA-N C1(CCCC1)NC1=C(C=CC=C1)C1=CC=C(OCCCC(=O)O)C=C1 Chemical compound C1(CCCC1)NC1=C(C=CC=C1)C1=CC=C(OCCCC(=O)O)C=C1 DPZAUVQLOSLBRJ-UHFFFAOYSA-N 0.000 claims description 3
- NXUKMQCBXOBNLM-UHFFFAOYSA-N C1(CCCC1)NC1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)NC1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F NXUKMQCBXOBNLM-UHFFFAOYSA-N 0.000 claims description 3
- DJSIYHPNXQQFDF-UHFFFAOYSA-N C1(CCCC1)NC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F Chemical compound C1(CCCC1)NC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F DJSIYHPNXQQFDF-UHFFFAOYSA-N 0.000 claims description 3
- VGHGDBOAXXCHLZ-UHFFFAOYSA-N C1(CCCC1)NC1=NC=CC=C1C1=CC(=C(C=C1)SCCCC(=O)O)F Chemical compound C1(CCCC1)NC1=NC=CC=C1C1=CC(=C(C=C1)SCCCC(=O)O)F VGHGDBOAXXCHLZ-UHFFFAOYSA-N 0.000 claims description 3
- OESBZDYFMVIDSG-UHFFFAOYSA-N C1(CCCC1)NC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)NC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F OESBZDYFMVIDSG-UHFFFAOYSA-N 0.000 claims description 3
- ANRGWWKKNSSELK-UHFFFAOYSA-N C1(CCCC1)OC1=C(C=C(C=C1)C)C1=CC=C(C=C1)SCCCC(=O)O Chemical compound C1(CCCC1)OC1=C(C=C(C=C1)C)C1=CC=C(C=C1)SCCCC(=O)O ANRGWWKKNSSELK-UHFFFAOYSA-N 0.000 claims description 3
- SANSELSYRQPGDH-UHFFFAOYSA-N C1(CCCC1)OC1=C(C=C(C=C1)F)C1=CC(=C(C(=C1)F)SCCCC(=O)O)F Chemical compound C1(CCCC1)OC1=C(C=C(C=C1)F)C1=CC(=C(C(=C1)F)SCCCC(=O)O)F SANSELSYRQPGDH-UHFFFAOYSA-N 0.000 claims description 3
- GZLWSIKFCTYCLX-UHFFFAOYSA-N C1(CCCC1)OC1=C(C=C(C=C1)F)C1=CC(=C(C=C1)SCCCC(=O)O)F Chemical compound C1(CCCC1)OC1=C(C=C(C=C1)F)C1=CC(=C(C=C1)SCCCC(=O)O)F GZLWSIKFCTYCLX-UHFFFAOYSA-N 0.000 claims description 3
- XOAKIOFWUFCZIW-UHFFFAOYSA-N C1(CCCC1)OC1=C(C=C(C=C1)F)C1=CC=C(C=C1)SCCCC(=O)O Chemical compound C1(CCCC1)OC1=C(C=C(C=C1)F)C1=CC=C(C=C1)SCCCC(=O)O XOAKIOFWUFCZIW-UHFFFAOYSA-N 0.000 claims description 3
- MGTVOAHDHCHDIY-UHFFFAOYSA-N C1(CCCC1)OC1=C(C=C(C=C1F)C)C1=CC(=C(C=C1)SCCCC(=O)O)F Chemical compound C1(CCCC1)OC1=C(C=C(C=C1F)C)C1=CC(=C(C=C1)SCCCC(=O)O)F MGTVOAHDHCHDIY-UHFFFAOYSA-N 0.000 claims description 3
- KYGBNPQVGCJRMJ-UHFFFAOYSA-N C1(CCCC1)OC1=C(C=CC(=C1)OC)C1=CC(=C(C(=C1)F)SCCCC(=O)O)F Chemical compound C1(CCCC1)OC1=C(C=CC(=C1)OC)C1=CC(=C(C(=C1)F)SCCCC(=O)O)F KYGBNPQVGCJRMJ-UHFFFAOYSA-N 0.000 claims description 3
- UMMMVOMZBPRJAK-UHFFFAOYSA-N C1(CCCC1)OC1=C(C=CC(=C1)OC)C1=CC(=C(C=C1)SCCCC(=O)O)F Chemical compound C1(CCCC1)OC1=C(C=CC(=C1)OC)C1=CC(=C(C=C1)SCCCC(=O)O)F UMMMVOMZBPRJAK-UHFFFAOYSA-N 0.000 claims description 3
- FHPBRWYLDFPSQI-UHFFFAOYSA-N C1(CCCC1)OC1=C(C=CC(=C1)OC)C1=CC=C(C=C1)SCCCC(=O)O Chemical compound C1(CCCC1)OC1=C(C=CC(=C1)OC)C1=CC=C(C=C1)SCCCC(=O)O FHPBRWYLDFPSQI-UHFFFAOYSA-N 0.000 claims description 3
- VOGVXQFWHQRXEC-UHFFFAOYSA-N C1(CCCC1)OC1=CC=C(C(=C1C1=CC(=C(C=C1)SCCCC(=O)O)F)F)C Chemical compound C1(CCCC1)OC1=CC=C(C(=C1C1=CC(=C(C=C1)SCCCC(=O)O)F)F)C VOGVXQFWHQRXEC-UHFFFAOYSA-N 0.000 claims description 3
- SBRLTDUZTVTFOW-UHFFFAOYSA-N C1(CCCC1)OC1=CC=CC(=N1)C1=CC=C(C=C1)SCCCC(=O)O Chemical compound C1(CCCC1)OC1=CC=CC(=N1)C1=CC=C(C=C1)SCCCC(=O)O SBRLTDUZTVTFOW-UHFFFAOYSA-N 0.000 claims description 3
- DZCVKGSYHVBNCV-UHFFFAOYSA-N C1(CCCC1)OC1=NC(=CC=C1C1=CC(=C(C=C1)SCCCC(=O)O)F)C Chemical compound C1(CCCC1)OC1=NC(=CC=C1C1=CC(=C(C=C1)SCCCC(=O)O)F)C DZCVKGSYHVBNCV-UHFFFAOYSA-N 0.000 claims description 3
- RTFBQUAJECGYPI-UHFFFAOYSA-N C1(CCCC1)OC1=NC=C(C=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F)C Chemical compound C1(CCCC1)OC1=NC=C(C=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F)C RTFBQUAJECGYPI-UHFFFAOYSA-N 0.000 claims description 3
- KLFHDBDAXFJGBH-UHFFFAOYSA-N C1(CCCC1)OC1=NC=C(C=C1C1=CC(=C(C=C1)SCCCC(=O)O)F)C Chemical compound C1(CCCC1)OC1=NC=C(C=C1C1=CC(=C(C=C1)SCCCC(=O)O)F)C KLFHDBDAXFJGBH-UHFFFAOYSA-N 0.000 claims description 3
- KSCHYCNDOMEWRW-UHFFFAOYSA-N C1(CCCC1)OC1=NC=C(C=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F)C Chemical compound C1(CCCC1)OC1=NC=C(C=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F)C KSCHYCNDOMEWRW-UHFFFAOYSA-N 0.000 claims description 3
- YRSQUTQDMVUUNL-UHFFFAOYSA-N C1(CCCC1)OC1=NC=C(C=C1C1=CC=C(C=C1)SCCCC(=O)O)C Chemical compound C1(CCCC1)OC1=NC=C(C=C1C1=CC=C(C=C1)SCCCC(=O)O)C YRSQUTQDMVUUNL-UHFFFAOYSA-N 0.000 claims description 3
- DDWWJXGSBFASMA-UHFFFAOYSA-N C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)SC(CCC(=O)O)C)F Chemical compound C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)SC(CCC(=O)O)C)F DDWWJXGSBFASMA-UHFFFAOYSA-N 0.000 claims description 3
- LSOXASSMFCHZKH-UHFFFAOYSA-N C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F Chemical compound C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F LSOXASSMFCHZKH-UHFFFAOYSA-N 0.000 claims description 3
- OFGHWNDIFVOGSO-UHFFFAOYSA-N C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCCC(=O)O)F Chemical compound C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCCC(=O)O)F OFGHWNDIFVOGSO-UHFFFAOYSA-N 0.000 claims description 3
- VMAKNNZITDPJJV-UHFFFAOYSA-N C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(C=C1)SCCCC(=O)O)F Chemical compound C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(C=C1)SCCCC(=O)O)F VMAKNNZITDPJJV-UHFFFAOYSA-N 0.000 claims description 3
- ZVRWCBOLUCMNPF-UHFFFAOYSA-N C1(CCCC1)OC1=NC=CC=C1C1=CC=C(C=C1)SC(CCC(=O)O)C Chemical compound C1(CCCC1)OC1=NC=CC=C1C1=CC=C(C=C1)SC(CCC(=O)O)C ZVRWCBOLUCMNPF-UHFFFAOYSA-N 0.000 claims description 3
- DNQNJGFJCLXKPI-UHFFFAOYSA-N C1(CCCC1)OC1=NC=CC=C1C1=CC=C(C=C1)SCCCC(=O)O Chemical compound C1(CCCC1)OC1=NC=CC=C1C1=CC=C(C=C1)SCCCC(=O)O DNQNJGFJCLXKPI-UHFFFAOYSA-N 0.000 claims description 3
- KBRRYCCUDGAMRM-UHFFFAOYSA-N C1(CCCC1)OC1=NC=CC=C1C1=CC=C(C=C1)SCCCCC(=O)O Chemical compound C1(CCCC1)OC1=NC=CC=C1C1=CC=C(C=C1)SCCCCC(=O)O KBRRYCCUDGAMRM-UHFFFAOYSA-N 0.000 claims description 3
- WUXBAZHPWSNHJO-UHFFFAOYSA-N C1(CCCC1)OC=1C=C(C=CC1)C1=CC(=C(C(=C1)F)SCCCC(=O)O)F Chemical compound C1(CCCC1)OC=1C=C(C=CC1)C1=CC(=C(C(=C1)F)SCCCC(=O)O)F WUXBAZHPWSNHJO-UHFFFAOYSA-N 0.000 claims description 3
- RQCPFFYHKIMQSP-UHFFFAOYSA-N C1(CCCC1)OC=1C=C(C=CC1)C1=CC=C(C=C1)SCCCC(=O)O Chemical compound C1(CCCC1)OC=1C=C(C=CC1)C1=CC=C(C=C1)SCCCC(=O)O RQCPFFYHKIMQSP-UHFFFAOYSA-N 0.000 claims description 3
- CVDPJAXSOPHNKP-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)SC(CCC(=O)O)C)F Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)SC(CCC(=O)O)C)F CVDPJAXSOPHNKP-UHFFFAOYSA-N 0.000 claims description 3
- PNTQOXIHMGFZSF-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCC(=O)O)F PNTQOXIHMGFZSF-UHFFFAOYSA-N 0.000 claims description 3
- ARSLGTHGRQHSTI-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCCC(=O)O)F Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCCC(=O)O)F ARSLGTHGRQHSTI-UHFFFAOYSA-N 0.000 claims description 3
- OCVKTLJGQOETQE-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(C=C1)SCCCC(=O)O)F Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(C=C1)SCCCC(=O)O)F OCVKTLJGQOETQE-UHFFFAOYSA-N 0.000 claims description 3
- AAJPGDMLLYDNDW-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC=C(C=C1)SC(CCC(=O)O)C Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC=C(C=C1)SC(CCC(=O)O)C AAJPGDMLLYDNDW-UHFFFAOYSA-N 0.000 claims description 3
- DYEUGYKDABCGPH-UHFFFAOYSA-N C1(CCCCC1)OC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCCC1)OC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F DYEUGYKDABCGPH-UHFFFAOYSA-N 0.000 claims description 3
- GWBQNBATBFVETM-UHFFFAOYSA-N CC(C)(C)COC1=C(C=CC=N1)C1=CC(F)=C(OCCCC(O)=O)C(F)=C1 Chemical compound CC(C)(C)COC1=C(C=CC=N1)C1=CC(F)=C(OCCCC(O)=O)C(F)=C1 GWBQNBATBFVETM-UHFFFAOYSA-N 0.000 claims description 3
- ZBXFYLPCGDLYCT-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C1=NC(=CC=C1)OCCC)F)SCCCC(=O)O Chemical compound FC1=C(C(=CC(=C1)C1=NC(=CC=C1)OCCC)F)SCCCC(=O)O ZBXFYLPCGDLYCT-UHFFFAOYSA-N 0.000 claims description 3
- UKEOKAUKHBZZGU-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C1=NC(=CC=C1)SCCC)F)SCCCC(=O)O Chemical compound FC1=C(C(=CC(=C1)C1=NC(=CC=C1)SCCC)F)SCCCC(=O)O UKEOKAUKHBZZGU-UHFFFAOYSA-N 0.000 claims description 3
- OOVYCIIEXBNTSS-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C=1C(=NC=CC1)NC(C)C)F)SCCCC(=O)O Chemical compound FC1=C(C(=CC(=C1)C=1C(=NC=CC1)NC(C)C)F)SCCCC(=O)O OOVYCIIEXBNTSS-UHFFFAOYSA-N 0.000 claims description 3
- NNGKTBPCYYXSID-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C=1C(=NC=CC1)OC(C)C)F)SC(CCC(=O)O)C Chemical compound FC1=C(C(=CC(=C1)C=1C(=NC=CC1)OC(C)C)F)SC(CCC(=O)O)C NNGKTBPCYYXSID-UHFFFAOYSA-N 0.000 claims description 3
- AZWKOKDHOGQYEV-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C=1C(=NC=CC1)OC(C)C)F)SCCCC(=O)O Chemical compound FC1=C(C(=CC(=C1)C=1C(=NC=CC1)OC(C)C)F)SCCCC(=O)O AZWKOKDHOGQYEV-UHFFFAOYSA-N 0.000 claims description 3
- LKONJPJHXBTOTJ-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C=1C(=NC=CC1)OC(C)C)F)SCCCCC(=O)O Chemical compound FC1=C(C(=CC(=C1)C=1C(=NC=CC1)OC(C)C)F)SCCCCC(=O)O LKONJPJHXBTOTJ-UHFFFAOYSA-N 0.000 claims description 3
- BDQWVANZNOTVQC-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C=1C(=NC=CC1)OCC(F)(F)F)F)SCCCC(=O)O Chemical compound FC1=C(C(=CC(=C1)C=1C(=NC=CC1)OCC(F)(F)F)F)SCCCC(=O)O BDQWVANZNOTVQC-UHFFFAOYSA-N 0.000 claims description 3
- WHIHDUPXASLPQO-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C=1C(=NC=CC1)SC(C)C)F)SCCCC(=O)O Chemical compound FC1=C(C(=CC(=C1)C=1C(=NC=CC1)SC(C)C)F)SCCCC(=O)O WHIHDUPXASLPQO-UHFFFAOYSA-N 0.000 claims description 3
- WBHTVVQWQXDBJP-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C=1C(=NC=CC1)SCCC)F)SCCCC(=O)O Chemical compound FC1=C(C(=CC(=C1)C=1C(=NC=CC1)SCCC)F)SCCCC(=O)O WBHTVVQWQXDBJP-UHFFFAOYSA-N 0.000 claims description 3
- VZSRICJBSKBLSO-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C=1C(=NC=CC1)SCCC)F)SCCCCC(=O)O Chemical compound FC1=C(C(=CC(=C1)C=1C(=NC=CC1)SCCC)F)SCCCCC(=O)O VZSRICJBSKBLSO-UHFFFAOYSA-N 0.000 claims description 3
- BZSSPYKGBNJMMH-UHFFFAOYSA-N FC1=C(C=CC(=C1)C=1C(=NC=C(C1)C)OC(C)C)SCCCC(=O)O Chemical compound FC1=C(C=CC(=C1)C=1C(=NC=C(C1)C)OC(C)C)SCCCC(=O)O BZSSPYKGBNJMMH-UHFFFAOYSA-N 0.000 claims description 3
- BVISHEDQRHTIIX-UHFFFAOYSA-N FC1=C(C=CC(=C1)C=1C(=NC=CC1)NC(C)C)SCCCC(=O)O Chemical compound FC1=C(C=CC(=C1)C=1C(=NC=CC1)NC(C)C)SCCCC(=O)O BVISHEDQRHTIIX-UHFFFAOYSA-N 0.000 claims description 3
- VOPOFCCMXIBNSU-UHFFFAOYSA-N FC1=C(C=CC(=C1)C=1C(=NC=CC1)OC(C)C)SCCCC(=O)O Chemical compound FC1=C(C=CC(=C1)C=1C(=NC=CC1)OC(C)C)SCCCC(=O)O VOPOFCCMXIBNSU-UHFFFAOYSA-N 0.000 claims description 3
- XCEVERATEBOQTJ-UHFFFAOYSA-N FC1=C(C=CC(=C1)C=1C(=NC=CC1)OC1CCOCC1)SCCCC(=O)O Chemical compound FC1=C(C=CC(=C1)C=1C(=NC=CC1)OC1CCOCC1)SCCCC(=O)O XCEVERATEBOQTJ-UHFFFAOYSA-N 0.000 claims description 3
- ZUXQEAHLTNHVIJ-UHFFFAOYSA-N FC1=C(C=CC(=C1)C=1C(=NC=CC1)OC1COCC1)SCCCC(=O)O Chemical compound FC1=C(C=CC(=C1)C=1C(=NC=CC1)OC1COCC1)SCCCC(=O)O ZUXQEAHLTNHVIJ-UHFFFAOYSA-N 0.000 claims description 3
- LUGGTJYLJDJEHK-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C1=CC(=CC=C1)OC1=CC=CC=C1)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C1=CC(=CC=C1)OC1=CC=CC=C1)F LUGGTJYLJDJEHK-UHFFFAOYSA-N 0.000 claims description 3
- CADASFOYFZKSMR-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C1=NC(=CC=C1)CC(C)C)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C1=NC(=CC=C1)CC(C)C)F CADASFOYFZKSMR-UHFFFAOYSA-N 0.000 claims description 3
- LLIXPYGPXLJZCP-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C1=NC(=CC=C1)N(C1=CC=CC=C1)C)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C1=NC(=CC=C1)N(C1=CC=CC=C1)C)F LLIXPYGPXLJZCP-UHFFFAOYSA-N 0.000 claims description 3
- VOWMJRNRPRTUQV-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OCC(C)C)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OCC(C)C)F VOWMJRNRPRTUQV-UHFFFAOYSA-N 0.000 claims description 3
- WSMDZRYGIZESLJ-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OCCOC)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OCCOC)F WSMDZRYGIZESLJ-UHFFFAOYSA-N 0.000 claims description 3
- CXSUHNWHODYORG-UHFFFAOYSA-N FC1=C(OCCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OC(C)C)F Chemical compound FC1=C(OCCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OC(C)C)F CXSUHNWHODYORG-UHFFFAOYSA-N 0.000 claims description 3
- XOEOIJQHYKDHFD-UHFFFAOYSA-N FC=1C=C(C=C(C1OCCCC(=O)O)F)C1=C(C=CC=C1)OC(C)C Chemical compound FC=1C=C(C=C(C1OCCCC(=O)O)F)C1=C(C=CC=C1)OC(C)C XOEOIJQHYKDHFD-UHFFFAOYSA-N 0.000 claims description 3
- IJFNTAWGCABNRR-UHFFFAOYSA-N FC=1C=C(C=C(C1SCCCC(=O)O)F)C1=C(C=CC=C1)NC(C)C Chemical compound FC=1C=C(C=C(C1SCCCC(=O)O)F)C1=C(C=CC=C1)NC(C)C IJFNTAWGCABNRR-UHFFFAOYSA-N 0.000 claims description 3
- FSSRMFKHICQFOU-UHFFFAOYSA-N FC=1C=C(C=C(C1SCCCC(=O)O)F)C1=C(C=CC=C1)NCCC Chemical compound FC=1C=C(C=C(C1SCCCC(=O)O)F)C1=C(C=CC=C1)NCCC FSSRMFKHICQFOU-UHFFFAOYSA-N 0.000 claims description 3
- ISLLTJKTMDXTDB-UHFFFAOYSA-N FC=1C=C(C=C(C1SCCCC(=O)O)F)C1=CC(=CC=C1)OC(C)C Chemical compound FC=1C=C(C=C(C1SCCCC(=O)O)F)C1=CC(=CC=C1)OC(C)C ISLLTJKTMDXTDB-UHFFFAOYSA-N 0.000 claims description 3
- SZHKIYZDFNKMBG-UHFFFAOYSA-N FC=1C=C(C=CC1SCCCC(=O)O)C1=C(C(=CC(=C1)C)F)OC(C)C Chemical compound FC=1C=C(C=CC1SCCCC(=O)O)C1=C(C(=CC(=C1)C)F)OC(C)C SZHKIYZDFNKMBG-UHFFFAOYSA-N 0.000 claims description 3
- HFTZQAUQGKMOCI-UHFFFAOYSA-N FC=1C=C(C=CC1SCCCC(=O)O)C1=C(C(=CC(=C1)C)F)OCCC Chemical compound FC=1C=C(C=CC1SCCCC(=O)O)C1=C(C(=CC(=C1)C)F)OCCC HFTZQAUQGKMOCI-UHFFFAOYSA-N 0.000 claims description 3
- RBCBNQWWVPEZLT-UHFFFAOYSA-N FC=1C=C(C=CC1SCCCC(=O)O)C1=C(C=C(C=C1)OC)OC(C)C Chemical compound FC=1C=C(C=CC1SCCCC(=O)O)C1=C(C=C(C=C1)OC)OC(C)C RBCBNQWWVPEZLT-UHFFFAOYSA-N 0.000 claims description 3
- LALBTULADVIRHP-UHFFFAOYSA-N FC=1C=C(C=CC1SCCCC(=O)O)C1=C(C=C(C=C1)OCCC)OCCC Chemical compound FC=1C=C(C=CC1SCCCC(=O)O)C1=C(C=C(C=C1)OCCC)OCCC LALBTULADVIRHP-UHFFFAOYSA-N 0.000 claims description 3
- KOSUIHSFYLEOGV-UHFFFAOYSA-N FC=1C=C(C=CC1SCCCC(=O)O)C1=C(C=CC(=C1)F)OC(C)C Chemical compound FC=1C=C(C=CC1SCCCC(=O)O)C1=C(C=CC(=C1)F)OC(C)C KOSUIHSFYLEOGV-UHFFFAOYSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- HIYNICFSTFBOHR-UHFFFAOYSA-N O(C1=CC=CC=C1)C=1C=C(C=CC1)C1=CC=C(C=C1)SCCCC(=O)O Chemical compound O(C1=CC=CC=C1)C=1C=C(C=CC1)C1=CC=C(C=C1)SCCCC(=O)O HIYNICFSTFBOHR-UHFFFAOYSA-N 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- NFOFUTLHWXPONK-UHFFFAOYSA-N 4-[4-(6-cyclobutylsulfanylpyridin-2-yl)-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(SC2CCC2)=N1 NFOFUTLHWXPONK-UHFFFAOYSA-N 0.000 claims description 2
- ZQWMADBEEHVLNM-UHFFFAOYSA-N 4-[4-(6-cyclopentylsulfanylpyridin-2-yl)-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CC(SC2CCCC2)=N1 ZQWMADBEEHVLNM-UHFFFAOYSA-N 0.000 claims description 2
- DMAJWTXAOKRXPZ-UHFFFAOYSA-N 5-[2-fluoro-4-(2-propan-2-yloxypyridin-3-yl)phenoxy]pentanoic acid Chemical compound CC(C)OC1=NC=CC=C1C1=CC=C(OCCCCC(O)=O)C(F)=C1 DMAJWTXAOKRXPZ-UHFFFAOYSA-N 0.000 claims description 2
- XXHSVPLDPVGTHF-UHFFFAOYSA-N 5-[4-(2-cyclopentylsulfanylpyridin-3-yl)-2-fluorophenoxy]pentanoic acid Chemical compound C1=C(F)C(OCCCCC(=O)O)=CC=C1C1=CC=CN=C1SC1CCCC1 XXHSVPLDPVGTHF-UHFFFAOYSA-N 0.000 claims description 2
- ZKDCWIQCGIUFDZ-UHFFFAOYSA-N C(C#CC)OC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C(C#CC)OC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F ZKDCWIQCGIUFDZ-UHFFFAOYSA-N 0.000 claims description 2
- LERPGHFMJTXBDH-UHFFFAOYSA-N C1(CC1)COC1=NC=CC=C1C1=CC(=C(OCCCCCC(=O)O)C(=C1)F)F Chemical compound C1(CC1)COC1=NC=CC=C1C1=CC(=C(OCCCCCC(=O)O)C(=C1)F)F LERPGHFMJTXBDH-UHFFFAOYSA-N 0.000 claims description 2
- XJLCFRUYLBRZGS-UHFFFAOYSA-N C1(CCC1)COC1=NC=CC=C1C1=CC(=C(OCCCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCC1)COC1=NC=CC=C1C1=CC(=C(OCCCCCC(=O)O)C(=C1)F)F XJLCFRUYLBRZGS-UHFFFAOYSA-N 0.000 claims description 2
- ZUNFJHWCPUBVNV-UHFFFAOYSA-N C1(CCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCCC(=O)O)F Chemical compound C1(CCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCCC(=O)O)F ZUNFJHWCPUBVNV-UHFFFAOYSA-N 0.000 claims description 2
- HRUNVYWWYVNTPO-UHFFFAOYSA-N C1(CCC1)OC1=NC=CC=C1C1=CC(=C(OCCCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCC1)OC1=NC=CC=C1C1=CC(=C(OCCCCCC(=O)O)C(=C1)F)F HRUNVYWWYVNTPO-UHFFFAOYSA-N 0.000 claims description 2
- WMRRMHRPPNHOBV-UHFFFAOYSA-N C1(CCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCCCC(=O)O)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCCCC(=O)O)F WMRRMHRPPNHOBV-UHFFFAOYSA-N 0.000 claims description 2
- CYABGDCQUJSUIV-UHFFFAOYSA-N C1(CCC1)SC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C=C1)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C=C1)F CYABGDCQUJSUIV-UHFFFAOYSA-N 0.000 claims description 2
- JSIKEOKHJKPVJG-UHFFFAOYSA-N C1(CCC1)SC1=NC=CC=C1C1=CC(=C(OCCCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC(=C(OCCCCCC(=O)O)C(=C1)F)F JSIKEOKHJKPVJG-UHFFFAOYSA-N 0.000 claims description 2
- GPFHICAQEISDMF-UHFFFAOYSA-N C1(CCC1)SC1=NC=CC=C1C1=CC=C(C=C1)SCCCCC(=O)O Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC=C(C=C1)SCCCCC(=O)O GPFHICAQEISDMF-UHFFFAOYSA-N 0.000 claims description 2
- NWDPJWVZWBUVFS-UHFFFAOYSA-N C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCCCC(=O)O)F Chemical compound C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCCCC(=O)O)F NWDPJWVZWBUVFS-UHFFFAOYSA-N 0.000 claims description 2
- MHYCPXIBIJUBOZ-UHFFFAOYSA-N C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C=C1)F Chemical compound C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)O)C=C1)F MHYCPXIBIJUBOZ-UHFFFAOYSA-N 0.000 claims description 2
- BYPFGXVGBNDXEX-UHFFFAOYSA-N C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(OCCCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(OCCCCCC(=O)O)C(=C1)F)F BYPFGXVGBNDXEX-UHFFFAOYSA-N 0.000 claims description 2
- SSAGMLQQTDKVAR-UHFFFAOYSA-N C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(OCCCCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(OCCCCCCC(=O)O)C(=C1)F)F SSAGMLQQTDKVAR-UHFFFAOYSA-N 0.000 claims description 2
- SJSRGDOHGUDRQN-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCCCC(=O)O)F Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCCCC(=O)O)F SJSRGDOHGUDRQN-UHFFFAOYSA-N 0.000 claims description 2
- TVFAXLLRFCUKMD-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(OCCCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(OCCCCCC(=O)O)C(=C1)F)F TVFAXLLRFCUKMD-UHFFFAOYSA-N 0.000 claims description 2
- ZDIWOYHKKHFLIZ-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC=C(C=C1)SCCCCC(=O)O Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC=C(C=C1)SCCCCC(=O)O ZDIWOYHKKHFLIZ-UHFFFAOYSA-N 0.000 claims description 2
- IKQYEDGLNKBFLE-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C=1C(=NC=CC1)SCCC)F)SCCCCCC(=O)O Chemical compound FC1=C(C(=CC(=C1)C=1C(=NC=CC1)SCCC)F)SCCCCCC(=O)O IKQYEDGLNKBFLE-UHFFFAOYSA-N 0.000 claims description 2
- UUIPLSGTNANJOR-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OC)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OC)F UUIPLSGTNANJOR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 125000003342 alkenyl group Chemical group 0.000 claims 2
- 125000000304 alkynyl group Chemical group 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims 1
- 125000005466 alkylenyl group Chemical group 0.000 claims 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 962
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 10
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 7
- 206010022489 Insulin Resistance Diseases 0.000 abstract description 6
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 abstract description 4
- 210000002540 macrophage Anatomy 0.000 abstract description 4
- 210000001789 adipocyte Anatomy 0.000 abstract description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 3
- 230000002265 prevention Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 210000004185 liver Anatomy 0.000 abstract description 2
- 210000003205 muscle Anatomy 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 abstract 1
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1222
- 238000005160 1H NMR spectroscopy Methods 0.000 description 622
- 238000006243 chemical reaction Methods 0.000 description 404
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 176
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 120
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 98
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 90
- 235000019439 ethyl acetate Nutrition 0.000 description 86
- 239000012044 organic layer Substances 0.000 description 81
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 80
- 238000004519 manufacturing process Methods 0.000 description 73
- 238000004587 chromatography analysis Methods 0.000 description 67
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 55
- VBMTYUZGSBFPEP-UHFFFAOYSA-N ethyl 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butanoate Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)B1OC(C(O1)(C)C)(C)C)F)=O VBMTYUZGSBFPEP-UHFFFAOYSA-N 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 53
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 53
- 229910000024 caesium carbonate Inorganic materials 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- 238000004440 column chromatography Methods 0.000 description 47
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 39
- WCDCAXVNBOLWNO-UHFFFAOYSA-N 2-fluoro-3-iodopyridine Chemical compound FC1=NC=CC=C1I WCDCAXVNBOLWNO-UHFFFAOYSA-N 0.000 description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 35
- 239000007864 aqueous solution Substances 0.000 description 35
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 34
- 239000011541 reaction mixture Substances 0.000 description 34
- BIRWWJBIPMSECF-UHFFFAOYSA-N C(C)OC(CCCSC1=C(C=C(C=C1)B1OC(C(O1)(C)C)(C)C)F)=O Chemical compound C(C)OC(CCCSC1=C(C=C(C=C1)B1OC(C(O1)(C)C)(C)C)F)=O BIRWWJBIPMSECF-UHFFFAOYSA-N 0.000 description 30
- 229910000104 sodium hydride Inorganic materials 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 238000010992 reflux Methods 0.000 description 27
- 229910000029 sodium carbonate Inorganic materials 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 239000003480 eluent Substances 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 238000001035 drying Methods 0.000 description 22
- HEKYUINMRRLFNY-UHFFFAOYSA-N C(C)OC(CCCSC1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C)=O Chemical compound C(C)OC(CCCSC1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C)=O HEKYUINMRRLFNY-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 20
- 239000002480 mineral oil Substances 0.000 description 20
- 235000010446 mineral oil Nutrition 0.000 description 20
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 20
- OBPMKYQNSFVEKZ-UHFFFAOYSA-N C(C)OC(CCCSC1=C(C=C(C=C1F)B1OC(C(O1)(C)C)(C)C)F)=O Chemical compound C(C)OC(CCCSC1=C(C=C(C=C1F)B1OC(C(O1)(C)C)(C)C)F)=O OBPMKYQNSFVEKZ-UHFFFAOYSA-N 0.000 description 18
- ZRCRUOILKSZXNN-UHFFFAOYSA-N C1(CCC1)SC1=NC=CC=C1I Chemical class C1(CCC1)SC1=NC=CC=C1I ZRCRUOILKSZXNN-UHFFFAOYSA-N 0.000 description 18
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 18
- 235000011056 potassium acetate Nutrition 0.000 description 17
- WDVYWDXJAICLFJ-UHFFFAOYSA-N ethyl 4-sulfanylbutanoate Chemical compound CCOC(=O)CCCS WDVYWDXJAICLFJ-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- 101150003085 Pdcl gene Proteins 0.000 description 15
- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 125000004361 3,4,5-trifluorophenyl group Chemical group [H]C1=C(F)C(F)=C(F)C([H])=C1* 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 12
- DKHOLESHKMZZQH-UHFFFAOYSA-N ethyl 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate Chemical compound FC1=C(OCCCCC(=O)OCC)C(=CC(=C1)B1OC(C(O1)(C)C)(C)C)F DKHOLESHKMZZQH-UHFFFAOYSA-N 0.000 description 12
- FILKGCRCWDMBKA-UHFFFAOYSA-N 2,6-dichloropyridine Chemical compound ClC1=CC=CC(Cl)=N1 FILKGCRCWDMBKA-UHFFFAOYSA-N 0.000 description 11
- 238000000605 extraction Methods 0.000 description 11
- FEYDZHNIIMENOB-UHFFFAOYSA-N 2,6-dibromopyridine Chemical compound BrC1=CC=CC(Br)=N1 FEYDZHNIIMENOB-UHFFFAOYSA-N 0.000 description 10
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 10
- NSPQVGRIZQTEQH-UHFFFAOYSA-N 2-cyclopentyloxy-3-iodopyridine Chemical class IC1=CC=CN=C1OC1CCCC1 NSPQVGRIZQTEQH-UHFFFAOYSA-N 0.000 description 10
- MXOOTBPBNFQVQE-UHFFFAOYSA-N 3-iodo-2-propan-2-yloxypyridine Chemical class CC(C)OC1=NC=CC=C1I MXOOTBPBNFQVQE-UHFFFAOYSA-N 0.000 description 10
- 125000000753 cycloalkyl group Chemical group 0.000 description 10
- DKXJYQXDMGAESG-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1I Chemical class C1(CCCC1)SC1=NC=CC=C1I DKXJYQXDMGAESG-UHFFFAOYSA-N 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- KXVUSQIDCZRUKF-UHFFFAOYSA-N bromocyclobutane Chemical compound BrC1CCC1 KXVUSQIDCZRUKF-UHFFFAOYSA-N 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- KJRCEJOSASVSRA-UHFFFAOYSA-N propane-2-thiol Chemical compound CC(C)S KJRCEJOSASVSRA-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- USVZFSNDGFNNJT-UHFFFAOYSA-N cyclopenta-1,4-dien-1-yl(diphenyl)phosphane (2,3-dichlorocyclopenta-1,4-dien-1-yl)-diphenylphosphane iron(2+) Chemical compound [Fe++].c1cc[c-](c1)P(c1ccccc1)c1ccccc1.Clc1c(cc[c-]1Cl)P(c1ccccc1)c1ccccc1 USVZFSNDGFNNJT-UHFFFAOYSA-N 0.000 description 8
- ULQLSUMGMISQGT-UHFFFAOYSA-N ethyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butanoate Chemical compound C1=CC(OCCCC(=O)OCC)=CC=C1B1OC(C)(C)C(C)(C)O1 ULQLSUMGMISQGT-UHFFFAOYSA-N 0.000 description 8
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 8
- PYBAIUXEASKLJJ-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)F)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)F)F PYBAIUXEASKLJJ-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Substances N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- WFWQWTPAPNEOFE-UHFFFAOYSA-N (3-hydroxyphenyl)boronic acid Chemical compound OB(O)C1=CC=CC(O)=C1 WFWQWTPAPNEOFE-UHFFFAOYSA-N 0.000 description 6
- KTQYJNVSVKKLGQ-UHFFFAOYSA-N 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(F)=C(O)C(F)=C1 KTQYJNVSVKKLGQ-UHFFFAOYSA-N 0.000 description 6
- AVAWGCJARZESGD-UHFFFAOYSA-N 2-chloro-6-cyclobutyloxypyridine Chemical compound ClC1=CC=CC(OC2CCC2)=N1 AVAWGCJARZESGD-UHFFFAOYSA-N 0.000 description 6
- IRSLULXVIKGHBM-UHFFFAOYSA-N 4-bromo-2,6-difluorobenzenethiol Chemical compound FC1=CC(Br)=CC(F)=C1S IRSLULXVIKGHBM-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YELHSYPLIPGDJJ-UHFFFAOYSA-N C1(CCC1)OC1=NC=CC=C1I Chemical compound C1(CCC1)OC1=NC=CC=C1I YELHSYPLIPGDJJ-UHFFFAOYSA-N 0.000 description 6
- RSRDJCLLPHFQQX-UHFFFAOYSA-N IC=1C(=NC=CC1)SCCC Chemical class IC=1C(=NC=CC1)SCCC RSRDJCLLPHFQQX-UHFFFAOYSA-N 0.000 description 6
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- NQLNSEFQGNAJHL-UHFFFAOYSA-N methyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfanylpropanoate Chemical compound COC(C(C)SC1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C)=O NQLNSEFQGNAJHL-UHFFFAOYSA-N 0.000 description 6
- HBLOAVMELLBZKA-UHFFFAOYSA-N n-cyclopentyl-2-iodoaniline Chemical compound IC1=CC=CC=C1NC1CCCC1 HBLOAVMELLBZKA-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- ILSBVXOYWKUWLJ-UHFFFAOYSA-N 2-(cyclopropylmethoxy)-3-iodopyridine Chemical compound IC1=CC=CN=C1OCC1CC1 ILSBVXOYWKUWLJ-UHFFFAOYSA-N 0.000 description 5
- HQUQTERWIXPUFP-UHFFFAOYSA-N 2-chloro-6-propan-2-ylsulfanylpyridine Chemical class CC(C)SC1=CC=CC(Cl)=N1 HQUQTERWIXPUFP-UHFFFAOYSA-N 0.000 description 5
- VRQMDVIJVVUAPI-UHFFFAOYSA-N 3-bromo-2-cyclopentyloxy-5-methylpyridine Chemical compound BrC=1C(=NC=C(C1)C)OC1CCCC1 VRQMDVIJVVUAPI-UHFFFAOYSA-N 0.000 description 5
- RCEZJTWOYGEFNM-UHFFFAOYSA-N 3-iodo-2-propan-2-ylsulfanylpyridine Chemical class CC(C)SC1=NC=CC=C1I RCEZJTWOYGEFNM-UHFFFAOYSA-N 0.000 description 5
- GPRPSJPFAAGLCA-UHFFFAOYSA-N 4-bromo-2,6-difluorophenol Chemical compound OC1=C(F)C=C(Br)C=C1F GPRPSJPFAAGLCA-UHFFFAOYSA-N 0.000 description 5
- BWQKYITVMABYTA-UHFFFAOYSA-N C(C)OC(CCCCSC1=C(C=C(C=C1F)B1OC(C(O1)(C)C)(C)C)F)=O Chemical compound C(C)OC(CCCCSC1=C(C=C(C=C1F)B1OC(C(O1)(C)C)(C)C)F)=O BWQKYITVMABYTA-UHFFFAOYSA-N 0.000 description 5
- WDGINKZROJOUEO-UHFFFAOYSA-N C1(CCC1)COC1=NC=CC=C1I Chemical compound C1(CCC1)COC1=NC=CC=C1I WDGINKZROJOUEO-UHFFFAOYSA-N 0.000 description 5
- WVDYBOADDMMFIY-UHFFFAOYSA-N Cyclopentanethiol Chemical compound SC1CCCC1 WVDYBOADDMMFIY-UHFFFAOYSA-N 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- AFRWBGJRWRHQOV-UHFFFAOYSA-N ethyl 5-bromopentanoate Chemical compound CCOC(=O)CCCCBr AFRWBGJRWRHQOV-UHFFFAOYSA-N 0.000 description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
- PVXVSMCFGCEDHY-UHFFFAOYSA-N 1-bromo-2-cyclopentyloxy-4-methoxybenzene Chemical compound COC1=CC=C(Br)C(OC2CCCC2)=C1 PVXVSMCFGCEDHY-UHFFFAOYSA-N 0.000 description 4
- ZSDQQJHSRVEGTJ-UHFFFAOYSA-N 2-(6-amino-1h-indol-3-yl)acetonitrile Chemical compound NC1=CC=C2C(CC#N)=CNC2=C1 ZSDQQJHSRVEGTJ-UHFFFAOYSA-N 0.000 description 4
- FDWFALZJAVBTDO-UHFFFAOYSA-N 2-bromo-1-cyclopentyloxy-4-fluorobenzene Chemical compound BrC1=CC(F)=CC=C1OC1CCCC1 FDWFALZJAVBTDO-UHFFFAOYSA-N 0.000 description 4
- PFMAUMFDMPLSPL-UHFFFAOYSA-N 2-bromo-6-fluoro-4-methylphenol Chemical compound CC1=CC(F)=C(O)C(Br)=C1 PFMAUMFDMPLSPL-UHFFFAOYSA-N 0.000 description 4
- RBQOILDHZGNUQT-UHFFFAOYSA-N 2-bromo-6-propan-2-yloxypyridine Chemical compound CC(C)OC1=CC=CC(Br)=N1 RBQOILDHZGNUQT-UHFFFAOYSA-N 0.000 description 4
- VADKRMSMGWJZCF-UHFFFAOYSA-N 2-bromophenol Chemical compound OC1=CC=CC=C1Br VADKRMSMGWJZCF-UHFFFAOYSA-N 0.000 description 4
- LEQFLIHYPJQSFX-UHFFFAOYSA-N 2-iodo-n-propan-2-ylaniline Chemical compound CC(C)NC1=CC=CC=C1I LEQFLIHYPJQSFX-UHFFFAOYSA-N 0.000 description 4
- KPNZEUINWRAIER-UHFFFAOYSA-N 2-iodo-n-propylaniline Chemical class CCCNC1=CC=CC=C1I KPNZEUINWRAIER-UHFFFAOYSA-N 0.000 description 4
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 description 4
- AJGQBMYDBNTQSW-UHFFFAOYSA-N 2-triethylphosphaniumylacetate Chemical compound CC[P+](CC)(CC)CC([O-])=O AJGQBMYDBNTQSW-UHFFFAOYSA-N 0.000 description 4
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 4
- DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 4
- FTBCOQFMQSTCQQ-UHFFFAOYSA-N 4-bromobenzenethiol Chemical compound SC1=CC=C(Br)C=C1 FTBCOQFMQSTCQQ-UHFFFAOYSA-N 0.000 description 4
- FMHKPLXYWVCLME-UHFFFAOYSA-N 4-hydroxy-valeric acid Chemical compound CC(O)CCC(O)=O FMHKPLXYWVCLME-UHFFFAOYSA-N 0.000 description 4
- CLNNBQDAAGDAHI-UHFFFAOYSA-N 6-chloro-1h-pyridin-2-one Chemical compound OC1=CC=CC(Cl)=N1 CLNNBQDAAGDAHI-UHFFFAOYSA-N 0.000 description 4
- HCYYIDRHRNVEPU-UHFFFAOYSA-N 6-chloro-1h-pyridine-2-thione Chemical compound SC1=CC=CC(Cl)=N1 HCYYIDRHRNVEPU-UHFFFAOYSA-N 0.000 description 4
- RPEMMZOELXFJQF-UHFFFAOYSA-N C(C)OC(CCCSC1=CC=C(C=C1)C1=CC(=CC=C1)O)=O Chemical compound C(C)OC(CCCSC1=CC=C(C=C1)C1=CC(=CC=C1)O)=O RPEMMZOELXFJQF-UHFFFAOYSA-N 0.000 description 4
- ATJNSRSWPJTJBB-UHFFFAOYSA-N ClC1=NC(=CC=C1)SC1CCC1 Chemical class ClC1=NC(=CC=C1)SC1CCC1 ATJNSRSWPJTJBB-UHFFFAOYSA-N 0.000 description 4
- ZYNYXTUGLKSXEM-LLVKDONJSA-N FC1=C(O[C@@H](CCC(=O)OC)C)C(=CC(=C1)B1OC(C(O1)(C)C)(C)C)F Chemical compound FC1=C(O[C@@H](CCC(=O)OC)C)C(=CC(=C1)B1OC(C(O1)(C)C)(C)C)F ZYNYXTUGLKSXEM-LLVKDONJSA-N 0.000 description 4
- XJIMFNKIQRSPNW-UHFFFAOYSA-N IC=1C(=NC=CC1)OC1CCOCC1 Chemical class IC=1C(=NC=CC1)OC1CCOCC1 XJIMFNKIQRSPNW-UHFFFAOYSA-N 0.000 description 4
- MYTZOXXHZOKFKC-UHFFFAOYSA-N IC=1C(=NC=CC1)OC1COCC1 Chemical class IC=1C(=NC=CC1)OC1COCC1 MYTZOXXHZOKFKC-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000007822 coupling agent Substances 0.000 description 4
- LPKBEZZFKBPJMO-UHFFFAOYSA-N ethyl 4-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butanoate Chemical compound C(C)OC(CCCOC1=C(C=C(C(=C1)F)B1OC(C(O1)(C)C)(C)C)F)=O LPKBEZZFKBPJMO-UHFFFAOYSA-N 0.000 description 4
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 4
- 229940125396 insulin Drugs 0.000 description 4
- 208000030159 metabolic disease Diseases 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 4
- FXSRSHXMWZJOGA-UHFFFAOYSA-N n-(cyclopropylmethyl)-2-iodoaniline Chemical compound IC1=CC=CC=C1NCC1CC1 FXSRSHXMWZJOGA-UHFFFAOYSA-N 0.000 description 4
- CPSLAOSRXZDBFK-UHFFFAOYSA-N n-cyclopentyl-4-fluoro-2-iodoaniline Chemical compound IC1=CC(F)=CC=C1NC1CCCC1 CPSLAOSRXZDBFK-UHFFFAOYSA-N 0.000 description 4
- HNBDRPTVWVGKBR-UHFFFAOYSA-N n-pentanoic acid methyl ester Natural products CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 4
- SUVIGLJNEAMWEG-UHFFFAOYSA-N propane-1-thiol Chemical compound CCCS SUVIGLJNEAMWEG-UHFFFAOYSA-N 0.000 description 4
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 3
- UKGJZDSUJSPAJL-YPUOHESYSA-N (e)-n-[(1r)-1-[3,5-difluoro-4-(methanesulfonamido)phenyl]ethyl]-3-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]prop-2-enamide Chemical compound CCCC1=NC(C(F)(F)F)=CC=C1\C=C\C(=O)N[C@H](C)C1=CC(F)=C(NS(C)(=O)=O)C(F)=C1 UKGJZDSUJSPAJL-YPUOHESYSA-N 0.000 description 3
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 3
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 3
- IIXPTSUWKTZRRW-UHFFFAOYSA-N 1-bromo-2-(cyclopropylmethoxy)benzene Chemical compound BrC1=CC=CC=C1OCC1CC1 IIXPTSUWKTZRRW-UHFFFAOYSA-N 0.000 description 3
- ZDVBXRWKMPYOEL-UHFFFAOYSA-N 1-bromo-2-cyclopentyloxybenzene Chemical compound BrC1=CC=CC=C1OC1CCCC1 ZDVBXRWKMPYOEL-UHFFFAOYSA-N 0.000 description 3
- MMORVPBHAHXAHH-UHFFFAOYSA-N 1-bromo-2-propan-2-yloxybenzene Chemical compound CC(C)OC1=CC=CC=C1Br MMORVPBHAHXAHH-UHFFFAOYSA-N 0.000 description 3
- AHDAKFFMKLQPTD-UHFFFAOYSA-N 1-bromo-3-phenoxybenzene Chemical compound BrC1=CC=CC(OC=2C=CC=CC=2)=C1 AHDAKFFMKLQPTD-UHFFFAOYSA-N 0.000 description 3
- LVDNSBZUAAXPPZ-UHFFFAOYSA-N 2-(3,5-difluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound C1=C(F)C(OC)=C(F)C=C1B1OC(C)(C)C(C)(C)O1 LVDNSBZUAAXPPZ-UHFFFAOYSA-N 0.000 description 3
- KHGMUWBYGFWGCZ-UHFFFAOYSA-N 2-bromo-5-methoxyphenol Chemical compound COC1=CC=C(Br)C(O)=C1 KHGMUWBYGFWGCZ-UHFFFAOYSA-N 0.000 description 3
- HSZNWZZPSFVZJF-UHFFFAOYSA-N 2-bromo-6-(diethoxyphosphorylmethyl)pyridine Chemical compound CCOP(=O)(OCC)CC1=CC=CC(Br)=N1 HSZNWZZPSFVZJF-UHFFFAOYSA-N 0.000 description 3
- RSULZHLVTPZLIW-UHFFFAOYSA-N 2-bromo-6-cyclopentylsulfanylpyridine Chemical compound BrC1=CC=CC(SC2CCCC2)=N1 RSULZHLVTPZLIW-UHFFFAOYSA-N 0.000 description 3
- JROFSFBGPCHTHB-UHFFFAOYSA-N 2-bromo-6-propoxypyridine Chemical compound CCCOC1=CC=CC(Br)=N1 JROFSFBGPCHTHB-UHFFFAOYSA-N 0.000 description 3
- JBFPNYCXEMRSHH-UHFFFAOYSA-N 2-bromo-n-cyclobutylaniline Chemical compound BrC1=CC=CC=C1NC1CCC1 JBFPNYCXEMRSHH-UHFFFAOYSA-N 0.000 description 3
- WDEQKYKBGRZOLI-UHFFFAOYSA-N 2-chloro-6-(cyclopropylmethylsulfanyl)pyridine Chemical compound ClC1=CC=CC(SCC2CC2)=N1 WDEQKYKBGRZOLI-UHFFFAOYSA-N 0.000 description 3
- YMSKNXMGXCKQEQ-UHFFFAOYSA-N 2-chloro-6-cyclopentyloxypyridine Chemical compound ClC1=CC=CC(OC2CCCC2)=N1 YMSKNXMGXCKQEQ-UHFFFAOYSA-N 0.000 description 3
- FTBCXEHMCFPRRF-UHFFFAOYSA-N 2-chloro-6-phenoxypyridine Chemical compound ClC1=CC=CC(OC=2C=CC=CC=2)=N1 FTBCXEHMCFPRRF-UHFFFAOYSA-N 0.000 description 3
- KDBNSRRLAJSKEF-UHFFFAOYSA-N 2-chloro-6-propan-2-yloxypyridine Chemical class CC(C)OC1=CC=CC(Cl)=N1 KDBNSRRLAJSKEF-UHFFFAOYSA-N 0.000 description 3
- LMLXGCAZONOZKO-UHFFFAOYSA-N 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(O)C(F)=C1 LMLXGCAZONOZKO-UHFFFAOYSA-N 0.000 description 3
- IMTWJWYFQVHWSE-UHFFFAOYSA-N 3-(3,4,5-trifluorophenyl)phenol Chemical compound OC1=CC=CC(C=2C=C(F)C(F)=C(F)C=2)=C1 IMTWJWYFQVHWSE-UHFFFAOYSA-N 0.000 description 3
- LRASCRYBYKGLKQ-UHFFFAOYSA-N 3-chloro-2-propan-2-ylsulfanylpyridine Chemical class CC(C)SC1=NC=CC=C1Cl LRASCRYBYKGLKQ-UHFFFAOYSA-N 0.000 description 3
- WYLVNASPZUFUJS-UHFFFAOYSA-N 3-phenylmethoxypyridine-2-carbaldehyde Chemical compound O=CC1=NC=CC=C1OCC1=CC=CC=C1 WYLVNASPZUFUJS-UHFFFAOYSA-N 0.000 description 3
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 3
- SPZXMLVKWNIZLO-UHFFFAOYSA-N 4-[4-[2-(cyclopropylamino)pyridin-3-yl]-2,6-difluorophenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CN=C1NC1CC1 SPZXMLVKWNIZLO-UHFFFAOYSA-N 0.000 description 3
- XPYSWZHGVRFILU-UHFFFAOYSA-N 4-[5-(2-cyclobutylsulfanylpyridin-3-yl)pyridin-2-yl]oxypentanoic acid Chemical compound C1=NC(OC(CCC(O)=O)C)=CC=C1C1=CC=CN=C1SC1CCC1 XPYSWZHGVRFILU-UHFFFAOYSA-N 0.000 description 3
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 3
- BFQSQUAVMNHOEF-UHFFFAOYSA-N 4-bromo-2,6-difluoroaniline Chemical compound NC1=C(F)C=C(Br)C=C1F BFQSQUAVMNHOEF-UHFFFAOYSA-N 0.000 description 3
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- NPZXFYFPAJVOMV-UHFFFAOYSA-N BrC1=NC(=CC=C1)SC1CCC1 Chemical compound BrC1=NC(=CC=C1)SC1CCC1 NPZXFYFPAJVOMV-UHFFFAOYSA-N 0.000 description 3
- HWNNHMVVZDKQTG-UHFFFAOYSA-N C(C)(C)(C)[Si](OC1CC(CC1)OC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F)(C)C Chemical compound C(C)(C)(C)[Si](OC1CC(CC1)OC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F)(C)C HWNNHMVVZDKQTG-UHFFFAOYSA-N 0.000 description 3
- RSRLPSMGVVWZLB-UHFFFAOYSA-N C(C)(C)SC1=NC=CC=C1C1=CC=C(C=C1)O Chemical compound C(C)(C)SC1=NC=CC=C1C1=CC=C(C=C1)O RSRLPSMGVVWZLB-UHFFFAOYSA-N 0.000 description 3
- YPZXHTAISQSUCK-UHFFFAOYSA-N C(C)OC(CCCCSC1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C)=O Chemical compound C(C)OC(CCCCSC1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C)=O YPZXHTAISQSUCK-UHFFFAOYSA-N 0.000 description 3
- QMCDKZYBHGNUGG-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)C=C(C)C)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)C=C(C)C)F)=O QMCDKZYBHGNUGG-UHFFFAOYSA-N 0.000 description 3
- RUOAAFXZNZUYFH-UHFFFAOYSA-N C1(CC1)OC1=NC=CC=C1I Chemical class C1(CC1)OC1=NC=CC=C1I RUOAAFXZNZUYFH-UHFFFAOYSA-N 0.000 description 3
- UDXPNYBOOYNFNJ-UHFFFAOYSA-N C1(CCC1)OC1=CC(=CC=C1)I Chemical compound C1(CCC1)OC1=CC(=CC=C1)I UDXPNYBOOYNFNJ-UHFFFAOYSA-N 0.000 description 3
- HOKOUDUCTSPLQV-UHFFFAOYSA-N C1(CCC1)SC1=NC=CC=C1C1=CC=C(C=C1)OC Chemical class C1(CCC1)SC1=NC=CC=C1C1=CC=C(C=C1)OC HOKOUDUCTSPLQV-UHFFFAOYSA-N 0.000 description 3
- ZIGNYQVLVKFREE-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC=C(C=C1)O Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC=C(C=C1)O ZIGNYQVLVKFREE-UHFFFAOYSA-N 0.000 description 3
- HAIIHJRSWNVKOI-UHFFFAOYSA-N CN(CCOC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F)C Chemical compound CN(CCOC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F)C HAIIHJRSWNVKOI-UHFFFAOYSA-N 0.000 description 3
- ZEFPMEIMNMYAEE-UHFFFAOYSA-N COC(C(C)SC1=C(C=C(C=C1F)B1OC(C(O1)(C)C)(C)C)F)=O Chemical compound COC(C(C)SC1=C(C=C(C=C1F)B1OC(C(O1)(C)C)(C)C)F)=O ZEFPMEIMNMYAEE-UHFFFAOYSA-N 0.000 description 3
- JMWQFNSYNPSIAT-UHFFFAOYSA-N COC1=CC=C(C=C1)C=1C(=NC=CC1)S Chemical compound COC1=CC=C(C=C1)C=1C(=NC=CC1)S JMWQFNSYNPSIAT-UHFFFAOYSA-N 0.000 description 3
- QMRZPNRZNDVJNN-UHFFFAOYSA-N COC1=CC=C(CSC2=NC=CC=C2C2=CC=C(C=C2)OC)C=C1 Chemical compound COC1=CC=C(CSC2=NC=CC=C2C2=CC=C(C=C2)OC)C=C1 QMRZPNRZNDVJNN-UHFFFAOYSA-N 0.000 description 3
- VNRTVJKXQVGAMB-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C=1C(=NC=CC1)SC(C)C)F)O Chemical compound FC1=C(C(=CC(=C1)C=1C(=NC=CC1)SC(C)C)F)O VNRTVJKXQVGAMB-UHFFFAOYSA-N 0.000 description 3
- BUQFGOXUVMGXDT-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)N1CCN(CC1)C)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)N1CCN(CC1)C)F BUQFGOXUVMGXDT-UHFFFAOYSA-N 0.000 description 3
- VNCIOYQMCCZXDM-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)N1N=CC(=C1)C)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)N1N=CC(=C1)C)F VNCIOYQMCCZXDM-UHFFFAOYSA-N 0.000 description 3
- ZFZFVVITHXVLCP-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OC1=NOC(=C1)C)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OC1=NOC(=C1)C)F ZFZFVVITHXVLCP-UHFFFAOYSA-N 0.000 description 3
- KFSOKMGCEDDKEI-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OC1CC(CC1)O)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OC1CC(CC1)O)F KFSOKMGCEDDKEI-UHFFFAOYSA-N 0.000 description 3
- GFSKAHDKOJCRJO-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OCC1(COC1)C)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)OCC1(COC1)C)F GFSKAHDKOJCRJO-UHFFFAOYSA-N 0.000 description 3
- OBNNYAADMZCTSH-UHFFFAOYSA-N FC=1C=C(C=C(C=1O)F)C1=C(C=CC=C1)OC1=CC=CC=C1 Chemical compound FC=1C=C(C=C(C=1O)F)C1=C(C=CC=C1)OC1=CC=CC=C1 OBNNYAADMZCTSH-UHFFFAOYSA-N 0.000 description 3
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 3
- HGTCSRNZFVAELU-UHFFFAOYSA-N IC=1C(=NC=CC=1)SCC1=CC=C(C=C1)OC Chemical class IC=1C(=NC=CC=1)SCC1=CC=C(C=C1)OC HGTCSRNZFVAELU-UHFFFAOYSA-N 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
- 102100040918 Pro-glucagon Human genes 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- DGLFSNZWRYADFC-UHFFFAOYSA-N chembl2334586 Chemical compound C1CCC2=CN=C(N)N=C2C2=C1NC1=CC=C(C#CC(C)(O)C)C=C12 DGLFSNZWRYADFC-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- WEMTXCOQGNENQZ-UHFFFAOYSA-N cyclobutanethiol Chemical compound SC1CCC1 WEMTXCOQGNENQZ-UHFFFAOYSA-N 0.000 description 3
- RMTFDHQLMGPSTQ-UHFFFAOYSA-N ethyl 4-(4-bromophenyl)sulfanylbutanoate Chemical compound CCOC(=O)CCCSC1=CC=C(Br)C=C1 RMTFDHQLMGPSTQ-UHFFFAOYSA-N 0.000 description 3
- DZVJPXBPUGYKBZ-UHFFFAOYSA-N ethyl 4-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butanoate Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1)B1OC(C(O1)(C)C)(C)C)Cl)=O DZVJPXBPUGYKBZ-UHFFFAOYSA-N 0.000 description 3
- SCQQHTQSJMTCPC-UHFFFAOYSA-N ethyl 4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butanoate Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1)B1OC(C(O1)(C)C)(C)C)F)=O SCQQHTQSJMTCPC-UHFFFAOYSA-N 0.000 description 3
- QMUDIKQKBRFNHM-UHFFFAOYSA-N ethyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy]butanoate Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1)B1OC(C(O1)(C)C)(C)C)C(F)(F)F)=O QMUDIKQKBRFNHM-UHFFFAOYSA-N 0.000 description 3
- FYLONIWABFGHJB-UHFFFAOYSA-N ethyl 4-bromo-2-methylbutanoate Chemical compound CCOC(=O)C(C)CCBr FYLONIWABFGHJB-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 235000021588 free fatty acids Nutrition 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
- XKADOGNWNALTMJ-UHFFFAOYSA-N methyl 2-(4-bromophenyl)sulfanylpropanoate Chemical compound COC(=O)C(C)SC1=CC=C(Br)C=C1 XKADOGNWNALTMJ-UHFFFAOYSA-N 0.000 description 3
- ACEONLNNWKIPTM-UHFFFAOYSA-N methyl 2-bromopropanoate Chemical compound COC(=O)C(C)Br ACEONLNNWKIPTM-UHFFFAOYSA-N 0.000 description 3
- ACHJFGYOUCOVQP-UHFFFAOYSA-N methyl 4-hydroxypentanoate Chemical compound COC(=O)CCC(C)O ACHJFGYOUCOVQP-UHFFFAOYSA-N 0.000 description 3
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 3
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- AVOWPOFIQZSVGV-UHFFFAOYSA-N (2-phenoxyphenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1OC1=CC=CC=C1 AVOWPOFIQZSVGV-UHFFFAOYSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 2
- NQMRYYAAICMHPE-UHFFFAOYSA-N (4-methoxyphenyl)boron Chemical compound [B]C1=CC=C(OC)C=C1 NQMRYYAAICMHPE-UHFFFAOYSA-N 0.000 description 2
- PTDVPWWJRCOIIO-UHFFFAOYSA-N (4-methoxyphenyl)methanethiol Chemical compound COC1=CC=C(CS)C=C1 PTDVPWWJRCOIIO-UHFFFAOYSA-N 0.000 description 2
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 2
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 2
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 2
- JSRLURSZEMLAFO-UHFFFAOYSA-N 1,3-dibromobenzene Chemical compound BrC1=CC=CC(Br)=C1 JSRLURSZEMLAFO-UHFFFAOYSA-N 0.000 description 2
- SKCNYQBWULWGAP-UHFFFAOYSA-N 1-(3-bromophenyl)pyrrolidine Chemical compound BrC1=CC=CC(N2CCCC2)=C1 SKCNYQBWULWGAP-UHFFFAOYSA-N 0.000 description 2
- XIESZHKIMVIQCK-UHFFFAOYSA-N 1-(6-chloropyridin-2-yl)-n,n-dimethylpyrrolidin-3-amine Chemical compound C1C(N(C)C)CCN1C1=CC=CC(Cl)=N1 XIESZHKIMVIQCK-UHFFFAOYSA-N 0.000 description 2
- WMUSXDBGJXRKJF-UHFFFAOYSA-N 1-(cyclopenten-1-yl)-2-nitrobenzene Chemical class [O-][N+](=O)C1=CC=CC=C1C1=CCCC1 WMUSXDBGJXRKJF-UHFFFAOYSA-N 0.000 description 2
- LRBUYBWDQQOZBM-UHFFFAOYSA-N 1-(cyclopenten-1-yl)-3-nitrobenzene Chemical class [O-][N+](=O)C1=CC=CC(C=2CCCC=2)=C1 LRBUYBWDQQOZBM-UHFFFAOYSA-N 0.000 description 2
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 2
- KTGJJGQCAZWTHZ-UHFFFAOYSA-N 1-bromo-2,4-dipropoxybenzene Chemical compound CCCOC1=CC=C(Br)C(OCCC)=C1 KTGJJGQCAZWTHZ-UHFFFAOYSA-N 0.000 description 2
- LZSYGJNFCREHMD-UHFFFAOYSA-N 1-bromo-2-(bromomethyl)benzene Chemical compound BrCC1=CC=CC=C1Br LZSYGJNFCREHMD-UHFFFAOYSA-N 0.000 description 2
- MTGDTSXTUQQOPV-UHFFFAOYSA-N 1-bromo-2-(cyclobutylmethyl)benzene Chemical compound BrC1=C(C=CC=C1)CC1CCC1 MTGDTSXTUQQOPV-UHFFFAOYSA-N 0.000 description 2
- NXDOSTWUTNXBCV-UHFFFAOYSA-N 1-bromo-2-(cyclopentylmethyl)benzene Chemical compound BrC1=C(C=CC=C1)CC1CCCC1 NXDOSTWUTNXBCV-UHFFFAOYSA-N 0.000 description 2
- KZNPAENULHRFLO-UHFFFAOYSA-N 1-bromo-2-cyclobutyloxybenzene Chemical compound BrC1=CC=CC=C1OC1CCC1 KZNPAENULHRFLO-UHFFFAOYSA-N 0.000 description 2
- ZPCJPJQUVRIILS-UHFFFAOYSA-N 1-bromo-3-(bromomethyl)benzene Chemical compound BrCC1=CC=CC(Br)=C1 ZPCJPJQUVRIILS-UHFFFAOYSA-N 0.000 description 2
- VQYJKQODZUNCLA-UHFFFAOYSA-N 1-bromo-3-(cyclobutylmethyl)benzene Chemical compound BrC1=CC(=CC=C1)CC1CCC1 VQYJKQODZUNCLA-UHFFFAOYSA-N 0.000 description 2
- WBYTZTMIUVDKHU-UHFFFAOYSA-N 1-bromo-3-(cyclopentylmethyl)benzene Chemical compound BrC1=CC=CC(CC2CCCC2)=C1 WBYTZTMIUVDKHU-UHFFFAOYSA-N 0.000 description 2
- SQWHABAKTKOIIR-UHFFFAOYSA-N 1-bromo-3-cyclopentyloxybenzene Chemical compound BrC1=CC=CC(OC2CCCC2)=C1 SQWHABAKTKOIIR-UHFFFAOYSA-N 0.000 description 2
- UROIOUZJFPEICO-UHFFFAOYSA-N 1-bromo-4-methoxy-2-propan-2-yloxybenzene Chemical compound COC1=CC=C(Br)C(OC(C)C)=C1 UROIOUZJFPEICO-UHFFFAOYSA-N 0.000 description 2
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 2
- FURLICLVZFURQK-UHFFFAOYSA-N 1-cyclopentyl-2-iodobenzene Chemical compound IC1=CC=CC=C1C1CCCC1 FURLICLVZFURQK-UHFFFAOYSA-N 0.000 description 2
- OVGZKUTYUFZOKH-UHFFFAOYSA-N 1-cyclopentyl-3-iodobenzene Chemical compound IC1=CC=CC(C2CCCC2)=C1 OVGZKUTYUFZOKH-UHFFFAOYSA-N 0.000 description 2
- MAKFMOSBBNKPMS-UHFFFAOYSA-N 2,3-dichloropyridine Chemical compound ClC1=CC=CN=C1Cl MAKFMOSBBNKPMS-UHFFFAOYSA-N 0.000 description 2
- VUPFPJVJEDZUQT-UHFFFAOYSA-N 2-(2-methylpropyl)pyridin-3-ol Chemical compound CC(C)CC1=NC=CC=C1O VUPFPJVJEDZUQT-UHFFFAOYSA-N 0.000 description 2
- ZSXBTGOKJTWASH-UHFFFAOYSA-N 2-bromo-3-fluoro-4-methylphenol Chemical compound CC1=CC=C(O)C(Br)=C1F ZSXBTGOKJTWASH-UHFFFAOYSA-N 0.000 description 2
- PYSNKVYGLPCQPE-UHFFFAOYSA-N 2-bromo-3-phenylmethoxypyridine Chemical compound BrC1=NC=CC=C1OCC1=CC=CC=C1 PYSNKVYGLPCQPE-UHFFFAOYSA-N 0.000 description 2
- FHTYTXKWEZZFCQ-UHFFFAOYSA-N 2-bromo-4-chloro-n-cyclopentylaniline Chemical compound BrC1=CC(Cl)=CC=C1NC1CCCC1 FHTYTXKWEZZFCQ-UHFFFAOYSA-N 0.000 description 2
- HFSLIMXPHXLCKX-UHFFFAOYSA-N 2-bromo-4-fluoro-1-propan-2-yloxybenzene Chemical compound CC(C)OC1=CC=C(F)C=C1Br HFSLIMXPHXLCKX-UHFFFAOYSA-N 0.000 description 2
- MEYRABVEYCFHHB-UHFFFAOYSA-N 2-bromo-4-fluorophenol Chemical compound OC1=CC=C(F)C=C1Br MEYRABVEYCFHHB-UHFFFAOYSA-N 0.000 description 2
- LSRDTCMNGSMEEI-UHFFFAOYSA-N 2-bromo-6-(bromomethyl)pyridine Chemical compound BrCC1=CC=CC(Br)=N1 LSRDTCMNGSMEEI-UHFFFAOYSA-N 0.000 description 2
- GDGDRHMJIWOWRA-UHFFFAOYSA-N 2-bromo-6-(cyclopropylmethoxy)pyridine Chemical compound BrC1=CC=CC(OCC2CC2)=N1 GDGDRHMJIWOWRA-UHFFFAOYSA-N 0.000 description 2
- HYKRHERRZBPQPB-UHFFFAOYSA-N 2-bromo-6-cyclopentyloxypyridine Chemical compound BrC1=CC=CC(OC2CCCC2)=N1 HYKRHERRZBPQPB-UHFFFAOYSA-N 0.000 description 2
- RQINYFYGGDEZDI-UHFFFAOYSA-N 2-bromo-6-cyclopentylpyridine Chemical compound BrC1=CC=CC(C2CCCC2)=N1 RQINYFYGGDEZDI-UHFFFAOYSA-N 0.000 description 2
- DNFDDDWPODPCHU-UHFFFAOYSA-N 2-bromo-6-fluorophenol Chemical compound OC1=C(F)C=CC=C1Br DNFDDDWPODPCHU-UHFFFAOYSA-N 0.000 description 2
- VROJKSSJOLYHHR-UHFFFAOYSA-N 2-bromo-6-propan-2-ylsulfanylpyridine Chemical compound CC(C)SC1=CC=CC(Br)=N1 VROJKSSJOLYHHR-UHFFFAOYSA-N 0.000 description 2
- HVMYXKNQXAMABN-UHFFFAOYSA-N 2-bromo-6-propylsulfanylpyridine Chemical compound CCCSC1=CC=CC(Br)=N1 HVMYXKNQXAMABN-UHFFFAOYSA-N 0.000 description 2
- HBKJZGOCTNRSHF-UHFFFAOYSA-N 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(O)C(Cl)=C1 HBKJZGOCTNRSHF-UHFFFAOYSA-N 0.000 description 2
- XBDIVNMAZGTMTR-UHFFFAOYSA-N 2-chloro-6-(cyclopropylmethoxy)pyridine Chemical compound ClC1=CC=CC(OCC2CC2)=N1 XBDIVNMAZGTMTR-UHFFFAOYSA-N 0.000 description 2
- ZRSSXJSKNXCPKN-UHFFFAOYSA-N 2-chloro-6-cyclopentylsulfanylpyridine Chemical compound ClC1=CC=CC(SC2CCCC2)=N1 ZRSSXJSKNXCPKN-UHFFFAOYSA-N 0.000 description 2
- RLCPWOMTHWJBGU-UHFFFAOYSA-N 2-chloro-6-piperidin-1-ylpyridine Chemical class ClC1=CC=CC(N2CCCCC2)=N1 RLCPWOMTHWJBGU-UHFFFAOYSA-N 0.000 description 2
- WJHYIQODSHTJNI-UHFFFAOYSA-N 2-chloro-6-propoxypyridine Chemical compound CCCOC1=CC=CC(Cl)=N1 WJHYIQODSHTJNI-UHFFFAOYSA-N 0.000 description 2
- NMVIJKRKDPHZSN-UHFFFAOYSA-N 2-chloro-6-propylsulfanylpyridine Chemical class CCCSC1=CC=CC(Cl)=N1 NMVIJKRKDPHZSN-UHFFFAOYSA-N 0.000 description 2
- VBMNALSMDIURFG-UHFFFAOYSA-N 2-chloro-6-pyrrolidin-1-ylpyridine Chemical compound ClC1=CC=CC(N2CCCC2)=N1 VBMNALSMDIURFG-UHFFFAOYSA-N 0.000 description 2
- RNEFHIAHLCMFLV-UHFFFAOYSA-N 2-cyclopentylaniline Chemical compound NC1=CC=CC=C1C1CCCC1 RNEFHIAHLCMFLV-UHFFFAOYSA-N 0.000 description 2
- GTEZBAJJMIPFSE-UHFFFAOYSA-N 2-ethylsulfanyl-3-iodopyridine Chemical class CCSC1=NC=CC=C1I GTEZBAJJMIPFSE-UHFFFAOYSA-N 0.000 description 2
- FVMFLPPFTXQBMR-UHFFFAOYSA-N 2-methyl-3-phenylmethoxypyridine Chemical compound CC1=NC=CC=C1OCC1=CC=CC=C1 FVMFLPPFTXQBMR-UHFFFAOYSA-N 0.000 description 2
- WWKXCYNPIQEAKJ-UHFFFAOYSA-N 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol Chemical compound C1=C(O)C(C)=CC(B2OC(C)(C)C(C)(C)O2)=C1 WWKXCYNPIQEAKJ-UHFFFAOYSA-N 0.000 description 2
- AQSRRZGQRFFFGS-UHFFFAOYSA-N 2-methylpyridin-3-ol Chemical compound CC1=NC=CC=C1O AQSRRZGQRFFFGS-UHFFFAOYSA-N 0.000 description 2
- NFNOAHXEQXMCGT-UHFFFAOYSA-N 2-phenylmethoxyacetaldehyde Chemical compound O=CCOCC1=CC=CC=C1 NFNOAHXEQXMCGT-UHFFFAOYSA-N 0.000 description 2
- VEYBLUKIJYXTQK-UHFFFAOYSA-N 2-tert-butylsulfanyl-6-chloropyridine Chemical compound CC(C)(C)SC1=CC=CC(Cl)=N1 VEYBLUKIJYXTQK-UHFFFAOYSA-N 0.000 description 2
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 2
- YGYGASJNJTYNOL-CQSZACIVSA-N 3-[(4r)-2,2-dimethyl-1,1-dioxothian-4-yl]-5-(4-fluorophenyl)-1h-indole-7-carboxamide Chemical compound C1CS(=O)(=O)C(C)(C)C[C@@H]1C1=CNC2=C(C(N)=O)C=C(C=3C=CC(F)=CC=3)C=C12 YGYGASJNJTYNOL-CQSZACIVSA-N 0.000 description 2
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 2
- IKMYONSIBTXMPU-UHFFFAOYSA-N 3-bromo-5-methyl-2-propan-2-yloxypyridine Chemical compound CC(C)OC1=NC=C(C)C=C1Br IKMYONSIBTXMPU-UHFFFAOYSA-N 0.000 description 2
- XXXBREDJSDZJOH-UHFFFAOYSA-N 3-bromo-n-cyclobutylaniline Chemical compound BrC1=CC=CC(NC2CCC2)=C1 XXXBREDJSDZJOH-UHFFFAOYSA-N 0.000 description 2
- GTBOEGVJRXDUBU-UHFFFAOYSA-N 3-bromo-n-cyclopentylaniline Chemical class BrC1=CC=CC(NC2CCCC2)=C1 GTBOEGVJRXDUBU-UHFFFAOYSA-N 0.000 description 2
- GOYKMCQGGDXHGB-UHFFFAOYSA-N 3-bromo-n-propan-2-ylaniline Chemical compound CC(C)NC1=CC=CC(Br)=C1 GOYKMCQGGDXHGB-UHFFFAOYSA-N 0.000 description 2
- CMGLNHDCVVLYJQ-UHFFFAOYSA-N 3-bromo-n-propylaniline Chemical compound CCCNC1=CC=CC(Br)=C1 CMGLNHDCVVLYJQ-UHFFFAOYSA-N 0.000 description 2
- VVOXPRDOWRUPMZ-UHFFFAOYSA-N 3-chloro-2-cyclopentylsulfanylpyridine Chemical compound ClC1=CC=CN=C1SC1CCCC1 VVOXPRDOWRUPMZ-UHFFFAOYSA-N 0.000 description 2
- GKOAOTLECSFQKC-UHFFFAOYSA-N 3-cyclopentylaniline Chemical compound NC1=CC=CC(C2CCCC2)=C1 GKOAOTLECSFQKC-UHFFFAOYSA-N 0.000 description 2
- GUUWZDBHSBLCBA-UHFFFAOYSA-N 3-iodo-2-(2,2,2-trifluoroethoxy)pyridine Chemical compound FC(F)(F)COC1=NC=CC=C1I GUUWZDBHSBLCBA-UHFFFAOYSA-N 0.000 description 2
- JVVIVAQZNSROHX-UHFFFAOYSA-N 3-iodo-2-phenoxypyridine Chemical class IC1=CC=CN=C1OC1=CC=CC=C1 JVVIVAQZNSROHX-UHFFFAOYSA-N 0.000 description 2
- WWMBXRKMRZDRFH-UHFFFAOYSA-N 3-iodo-2-propoxypyridine Chemical compound CCCOC1=NC=CC=C1I WWMBXRKMRZDRFH-UHFFFAOYSA-N 0.000 description 2
- XJKJHWMKYQKQIJ-UHFFFAOYSA-N 3-iodo-2-pyrrolidin-1-ylpyridine Chemical class IC1=CC=CN=C1N1CCCC1 XJKJHWMKYQKQIJ-UHFFFAOYSA-N 0.000 description 2
- ASHGTJPOSUFTGB-UHFFFAOYSA-N 3-methoxyphenol Chemical compound COC1=CC=CC(O)=C1 ASHGTJPOSUFTGB-UHFFFAOYSA-N 0.000 description 2
- VFCTUUBAONBDJU-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-(3,4,5-trifluorophenyl)-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(F)=C(F)C(F)=C1 VFCTUUBAONBDJU-UHFFFAOYSA-N 0.000 description 2
- WRSYNQIGZJULQH-UHFFFAOYSA-N 4-(2-phenoxyphenyl)phenol Chemical compound O(C1=CC=CC=C1)C1=C(C=CC=C1)C1=CC=C(C=C1)O WRSYNQIGZJULQH-UHFFFAOYSA-N 0.000 description 2
- QFHWWOMWOKEOOV-UHFFFAOYSA-N 4-(3-iodopyridin-2-yl)morpholine Chemical compound IC1=CC=CN=C1N1CCOCC1 QFHWWOMWOKEOOV-UHFFFAOYSA-N 0.000 description 2
- WZSVHNDUFOKGNN-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenol Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(O)C(C(F)(F)F)=C1 WZSVHNDUFOKGNN-UHFFFAOYSA-N 0.000 description 2
- VJPPLCNBDLZIFG-ZDUSSCGKSA-N 4-[(3S)-3-(but-2-ynoylamino)piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Chemical compound C(C#CC)(=O)N[C@@H]1CN(CCC1)C1=C2C(=C(NC2=C(C=C1F)C(=O)N)C)C VJPPLCNBDLZIFG-ZDUSSCGKSA-N 0.000 description 2
- SOFZIAPXSKIEDV-UHFFFAOYSA-N 4-[2,6-difluoro-4-(2-propan-2-ylsulfanylpyridin-4-yl)phenoxy]butanoic acid Chemical compound C1=NC(SC(C)C)=CC(C=2C=C(F)C(OCCCC(O)=O)=C(F)C=2)=C1 SOFZIAPXSKIEDV-UHFFFAOYSA-N 0.000 description 2
- BZSCHGNXDRCWGY-UHFFFAOYSA-N 4-[2,6-difluoro-4-[2-(2-fluoroethoxy)pyridin-3-yl]phenoxy]butanoic acid Chemical compound C1=C(F)C(OCCCC(=O)O)=C(F)C=C1C1=CC=CN=C1OCCF BZSCHGNXDRCWGY-UHFFFAOYSA-N 0.000 description 2
- WCLNOCHKVLKKLU-UHFFFAOYSA-N 4-[2-fluoro-4-(2-pyrrolidin-1-ylpyridin-3-yl)phenyl]sulfanylbutanoic acid Chemical compound C1=C(F)C(SCCCC(=O)O)=CC=C1C1=CC=CN=C1N1CCCC1 WCLNOCHKVLKKLU-UHFFFAOYSA-N 0.000 description 2
- CBGUPONMMXOXLL-UHFFFAOYSA-N 4-[4-(6-cyclopentylsulfanylpyridin-2-yl)phenyl]sulfanylbutanoic acid Chemical compound C1=CC(SCCCC(=O)O)=CC=C1C1=CC=CC(SC2CCCC2)=N1 CBGUPONMMXOXLL-UHFFFAOYSA-N 0.000 description 2
- XYWIPYBIIRTJMM-IBGZPJMESA-N 4-[[(2S)-2-[4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-5-methoxy-2-oxopyridin-1-yl]butanoyl]amino]-2-fluorobenzamide Chemical compound CC[C@H](N1C=C(OC)C(=CC1=O)C1=C(C=CC(Cl)=C1)N1C=C(N=N1)C(F)(F)F)C(=O)NC1=CC(F)=C(C=C1)C(N)=O XYWIPYBIIRTJMM-IBGZPJMESA-N 0.000 description 2
- BYZMZJIWCQTYSR-UHFFFAOYSA-N 4-bromo-2,5-difluorophenol Chemical compound OC1=CC(F)=C(Br)C=C1F BYZMZJIWCQTYSR-UHFFFAOYSA-N 0.000 description 2
- UMDYPUFAKPKDSC-UHFFFAOYSA-N 4-bromo-2,6-difluorobenzenesulfonyl chloride Chemical compound FC1=CC(Br)=CC(F)=C1S(Cl)(=O)=O UMDYPUFAKPKDSC-UHFFFAOYSA-N 0.000 description 2
- PDPGERGWEOJVDC-UHFFFAOYSA-N 4-bromo-2-(trifluoromethyl)phenol Chemical compound OC1=CC=C(Br)C=C1C(F)(F)F PDPGERGWEOJVDC-UHFFFAOYSA-N 0.000 description 2
- XNYBZLRIUHNRQY-UHFFFAOYSA-N 4-bromo-2-fluorobenzenesulfonyl chloride Chemical compound FC1=CC(Br)=CC=C1S(Cl)(=O)=O XNYBZLRIUHNRQY-UHFFFAOYSA-N 0.000 description 2
- KENIDQSHNHNYOY-UHFFFAOYSA-N 4-bromo-2-fluorobenzenethiol Chemical compound FC1=CC(Br)=CC=C1S KENIDQSHNHNYOY-UHFFFAOYSA-N 0.000 description 2
- IWJGMJHAIUBWKT-UHFFFAOYSA-N 4-bromo-2-methylphenol Chemical compound CC1=CC(Br)=CC=C1O IWJGMJHAIUBWKT-UHFFFAOYSA-N 0.000 description 2
- HKJCELUUIFFSIN-UHFFFAOYSA-N 5-bromo-1,2,3-trifluorobenzene Chemical compound FC1=CC(Br)=CC(F)=C1F HKJCELUUIFFSIN-UHFFFAOYSA-N 0.000 description 2
- CDOQKISJPOWBKC-UHFFFAOYSA-N 5-bromo-1,3-difluoro-2-methoxybenzene Chemical compound COC1=C(F)C=C(Br)C=C1F CDOQKISJPOWBKC-UHFFFAOYSA-N 0.000 description 2
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 2
- ZZUFUBSHEXLUFW-UHFFFAOYSA-N 6-chloro-n-(cyclopropylmethyl)pyridin-2-amine Chemical compound ClC1=CC=CC(NCC2CC2)=N1 ZZUFUBSHEXLUFW-UHFFFAOYSA-N 0.000 description 2
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 2
- ZRPZPNYZFSJUPA-UHFFFAOYSA-N ARS-1620 Chemical compound Oc1cccc(F)c1-c1c(Cl)cc2c(ncnc2c1F)N1CCN(CC1)C(=O)C=C ZRPZPNYZFSJUPA-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- VLWHKZHGCHORRH-UHFFFAOYSA-N BrC1=C(C(=CC(=C1)C)F)OC(C)C Chemical compound BrC1=C(C(=CC(=C1)C)F)OC(C)C VLWHKZHGCHORRH-UHFFFAOYSA-N 0.000 description 2
- HQDTWKPYRKQEJE-UHFFFAOYSA-N BrC1=C(C(=CC(=C1)C)F)OC1CCCC1 Chemical compound BrC1=C(C(=CC(=C1)C)F)OC1CCCC1 HQDTWKPYRKQEJE-UHFFFAOYSA-N 0.000 description 2
- WXCKULRZHVJFAP-UHFFFAOYSA-N BrC1=C(C(=CC(=C1)C)F)OCCC Chemical compound BrC1=C(C(=CC(=C1)C)F)OCCC WXCKULRZHVJFAP-UHFFFAOYSA-N 0.000 description 2
- TYETUXLWISPMFG-UHFFFAOYSA-N BrC1=C(C(=CC=C1)F)OC1CCCC1 Chemical compound BrC1=C(C(=CC=C1)F)OC1CCCC1 TYETUXLWISPMFG-UHFFFAOYSA-N 0.000 description 2
- PTJRDQIQQNMWSH-UHFFFAOYSA-N BrC1=C(C=CC(=C1F)C)OC1CCCC1 Chemical compound BrC1=C(C=CC(=C1F)C)OC1CCCC1 PTJRDQIQQNMWSH-UHFFFAOYSA-N 0.000 description 2
- UVEFNLOROBBXDX-UHFFFAOYSA-N BrC1=CC(=C(OCC2(CC2)CO)C(=C1)F)F Chemical compound BrC1=CC(=C(OCC2(CC2)CO)C(=C1)F)F UVEFNLOROBBXDX-UHFFFAOYSA-N 0.000 description 2
- HZBFWAWPJNHNPO-RXMQYKEDSA-N BrC1=CC(=C(O[C@@H](C=O)C)C(=C1)F)F Chemical compound BrC1=CC(=C(O[C@@H](C=O)C)C(=C1)F)F HZBFWAWPJNHNPO-RXMQYKEDSA-N 0.000 description 2
- CIERDHCMVCERSO-RXMQYKEDSA-N BrC1=CC(=C(O[C@@H](CO)C)C(=C1)F)F Chemical compound BrC1=CC(=C(O[C@@H](CO)C)C(=C1)F)F CIERDHCMVCERSO-RXMQYKEDSA-N 0.000 description 2
- HZBFWAWPJNHNPO-YFKPBYRVSA-N BrC1=CC(=C(O[C@H](C=O)C)C(=C1)F)F Chemical compound BrC1=CC(=C(O[C@H](C=O)C)C(=C1)F)F HZBFWAWPJNHNPO-YFKPBYRVSA-N 0.000 description 2
- CIERDHCMVCERSO-YFKPBYRVSA-N BrC1=CC(=C(O[C@H](CO)C)C(=C1)F)F Chemical compound BrC1=CC(=C(O[C@H](CO)C)C(=C1)F)F CIERDHCMVCERSO-YFKPBYRVSA-N 0.000 description 2
- CQXALHSQARBCQE-UHFFFAOYSA-N BrC1=NC(=CC=C1)C=C1CCCC1 Chemical compound BrC1=NC(=CC=C1)C=C1CCCC1 CQXALHSQARBCQE-UHFFFAOYSA-N 0.000 description 2
- LRHDPFWLTYVRKZ-UHFFFAOYSA-N BrC=1C(=NC(=CC1)C)OC1CCCC1 Chemical compound BrC=1C(=NC(=CC1)C)OC1CCCC1 LRHDPFWLTYVRKZ-UHFFFAOYSA-N 0.000 description 2
- ULGCEMPXGMCGJS-UHFFFAOYSA-N C(C)(C)NC1=C(C=CC=C1)C1=CC=C(OCCCC(=O)O)C=C1 Chemical compound C(C)(C)NC1=C(C=CC=C1)C1=CC=C(OCCCC(=O)O)C=C1 ULGCEMPXGMCGJS-UHFFFAOYSA-N 0.000 description 2
- KTRCVIPEEGSZHB-UHFFFAOYSA-N C(C)(C)OC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F Chemical compound C(C)(C)OC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F KTRCVIPEEGSZHB-UHFFFAOYSA-N 0.000 description 2
- DICBFXWEWOIGKG-UHFFFAOYSA-N C(C)(C)SC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F Chemical compound C(C)(C)SC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F DICBFXWEWOIGKG-UHFFFAOYSA-N 0.000 description 2
- VALLPTHSUJVWMN-UHFFFAOYSA-N C(C)(C)SC1=NC=CC=C1C1=CC=C(C=C1)OC Chemical class C(C)(C)SC1=NC=CC=C1C1=CC=C(C=C1)OC VALLPTHSUJVWMN-UHFFFAOYSA-N 0.000 description 2
- HZRWRJOEWVYNPH-UHFFFAOYSA-N C(C)OC(=O)C1C(C1)COC1=C(C=C(C=C1F)B1OC(C(O1)(C)C)(C)C)F Chemical compound C(C)OC(=O)C1C(C1)COC1=C(C=C(C=C1F)B1OC(C(O1)(C)C)(C)C)F HZRWRJOEWVYNPH-UHFFFAOYSA-N 0.000 description 2
- XZYAHRCEYCHKTR-UHFFFAOYSA-N C(C)OC(C=CC(C)SC1=C(C=C(C=C1F)C=1C(=NC=CC1)OC1CCCC1)F)=O Chemical compound C(C)OC(C=CC(C)SC1=C(C=C(C=C1F)C=1C(=NC=CC1)OC1CCCC1)F)=O XZYAHRCEYCHKTR-UHFFFAOYSA-N 0.000 description 2
- VLRRUQUDXAWSDC-UHFFFAOYSA-N C(C)OC(C=CC(C)SC1=C(C=C(C=C1F)C=1C(=NC=CC1)SC1CCCC1)F)=O Chemical compound C(C)OC(C=CC(C)SC1=C(C=C(C=C1F)C=1C(=NC=CC1)SC1CCCC1)F)=O VLRRUQUDXAWSDC-UHFFFAOYSA-N 0.000 description 2
- MEAWTYOJNIHEFS-UHFFFAOYSA-N C(C)OC(C=CC(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)OC(C)C)=O Chemical compound C(C)OC(C=CC(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)OC(C)C)=O MEAWTYOJNIHEFS-UHFFFAOYSA-N 0.000 description 2
- LRJFJTYVOOOHPY-UHFFFAOYSA-N C(C)OC(CCC(C)SC1=C(C=C(C=C1F)C=1C(=NC=CC1)OC(C)C)F)=O Chemical compound C(C)OC(CCC(C)SC1=C(C=C(C=C1F)C=1C(=NC=CC1)OC(C)C)F)=O LRJFJTYVOOOHPY-UHFFFAOYSA-N 0.000 description 2
- NVYRPTNJPAHCAZ-UHFFFAOYSA-N C(C)OC(CCC(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)OC1CCCC1)=O Chemical compound C(C)OC(CCC(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)OC1CCCC1)=O NVYRPTNJPAHCAZ-UHFFFAOYSA-N 0.000 description 2
- JAJTVHFENDPJHX-UHFFFAOYSA-N C(C)OC(CCC(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)SC1CCCC1)=O Chemical compound C(C)OC(CCC(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)SC1CCCC1)=O JAJTVHFENDPJHX-UHFFFAOYSA-N 0.000 description 2
- NFAIFSWLQVLRCS-UHFFFAOYSA-N C(C)OC(CCCCOC1=C(C=C(C=C1F)C=1C(=NC=CC=1)OC1CCCC1)F)=O Chemical compound C(C)OC(CCCCOC1=C(C=C(C=C1F)C=1C(=NC=CC=1)OC1CCCC1)F)=O NFAIFSWLQVLRCS-UHFFFAOYSA-N 0.000 description 2
- MIJHHMAECXCXDL-UHFFFAOYSA-N C(C)OC(CCCCSC1=C(C=C(C=C1F)Br)F)=O Chemical compound C(C)OC(CCCCSC1=C(C=C(C=C1F)Br)F)=O MIJHHMAECXCXDL-UHFFFAOYSA-N 0.000 description 2
- CMADZFPHZURTHH-UHFFFAOYSA-N C(C)OC(CCCCSC1=CC=C(C=C1)Br)=O Chemical compound C(C)OC(CCCCSC1=CC=C(C=C1)Br)=O CMADZFPHZURTHH-UHFFFAOYSA-N 0.000 description 2
- TZYNTYUMVUIEDE-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1C)Br)C)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1C)Br)C)=O TZYNTYUMVUIEDE-UHFFFAOYSA-N 0.000 description 2
- UDPYMKLOUVQCKS-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C1=C(C=CC=C1)OC1=CC=CC=C1)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C1=C(C=CC=C1)OC1=CC=CC=C1)F)=O UDPYMKLOUVQCKS-UHFFFAOYSA-N 0.000 description 2
- OTYKREFAPASBKI-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)C=O)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)C=O)F)=O OTYKREFAPASBKI-UHFFFAOYSA-N 0.000 description 2
- CXVDFESUPTYPPG-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C=1C(=NC=CC=1)OC1CC(CC1)O)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C=1C(=NC=CC=1)OC1CC(CC1)O)F)=O CXVDFESUPTYPPG-UHFFFAOYSA-N 0.000 description 2
- FXGHTOKAOVQOAW-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C=1C(=NC=CC=1)SC1CCC1)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C=1C(=NC=CC=1)SC1CCC1)F)=O FXGHTOKAOVQOAW-UHFFFAOYSA-N 0.000 description 2
- DOVIYMZTMQXOKX-UHFFFAOYSA-N C(C)OC(CCCOC1=CC(=C(C(=C1)F)Br)F)=O Chemical compound C(C)OC(CCCOC1=CC(=C(C(=C1)F)Br)F)=O DOVIYMZTMQXOKX-UHFFFAOYSA-N 0.000 description 2
- OIRJTLHHSFPOMC-UHFFFAOYSA-N C(C)OC(CCCOC1=CC=C(C=C1)C1=C(C=CC=C1)OC1=CC=CC=C1)=O Chemical compound C(C)OC(CCCOC1=CC=C(C=C1)C1=C(C=CC=C1)OC1=CC=CC=C1)=O OIRJTLHHSFPOMC-UHFFFAOYSA-N 0.000 description 2
- IORNRCHFBAABLB-UHFFFAOYSA-N C(C)OC(CCCOC1=CC=C(C=C1)C=1C(=NC=CC=1)SC(C)C)=O Chemical compound C(C)OC(CCCOC1=CC=C(C=C1)C=1C(=NC=CC=1)SC(C)C)=O IORNRCHFBAABLB-UHFFFAOYSA-N 0.000 description 2
- REFIKVMPGVAFRT-UHFFFAOYSA-N C(C)OC(CCCOC1=CC=C(C=C1)C=1C(=NC=CC=1)SC1CCCC1)=O Chemical compound C(C)OC(CCCOC1=CC=C(C=C1)C=1C(=NC=CC=1)SC1CCCC1)=O REFIKVMPGVAFRT-UHFFFAOYSA-N 0.000 description 2
- BLNVDTSMTDGHBV-UHFFFAOYSA-N C(C)OC(CCCOC=1C=NC(=CC=1)C1=CC(=CC=C1)O)=O Chemical compound C(C)OC(CCCOC=1C=NC(=CC=1)C1=CC(=CC=C1)O)=O BLNVDTSMTDGHBV-UHFFFAOYSA-N 0.000 description 2
- QKRZZBCTUYYERA-UHFFFAOYSA-N C(C)OC(CCCSC1=C(C=C(C=C1)Br)F)=O Chemical compound C(C)OC(CCCSC1=C(C=C(C=C1)Br)F)=O QKRZZBCTUYYERA-UHFFFAOYSA-N 0.000 description 2
- FIIRUGXERPYBHG-UHFFFAOYSA-N C(C)OC(CCCSC1=C(C=C(C=C1F)Br)F)=O Chemical compound C(C)OC(CCCSC1=C(C=C(C=C1F)Br)F)=O FIIRUGXERPYBHG-UHFFFAOYSA-N 0.000 description 2
- PAMGQTFWYRIOIA-UHFFFAOYSA-N C(C)OC(CCCSC1=C(C=C(C=C1F)C1=NC(=CC=C1)OC(C)C)F)=O Chemical compound C(C)OC(CCCSC1=C(C=C(C=C1F)C1=NC(=CC=C1)OC(C)C)F)=O PAMGQTFWYRIOIA-UHFFFAOYSA-N 0.000 description 2
- IWPQVGLUIRGZSX-UHFFFAOYSA-N C(C)OC(CCCSC1=CC=C(C=C1)C1=C(C=CC(=C1)C)OC1CCCC1)=O Chemical compound C(C)OC(CCCSC1=CC=C(C=C1)C1=C(C=CC(=C1)C)OC1CCCC1)=O IWPQVGLUIRGZSX-UHFFFAOYSA-N 0.000 description 2
- PFZJXBBLEYHATF-UHFFFAOYSA-N C(C)OC(CCCSC1=CC=C(C=C1)C1=CC(=CC=C1)OC(C)C)=O Chemical compound C(C)OC(CCCSC1=CC=C(C=C1)C1=CC(=CC=C1)OC(C)C)=O PFZJXBBLEYHATF-UHFFFAOYSA-N 0.000 description 2
- PDMLPUSXIFKFHQ-UHFFFAOYSA-N C(C)OC(CCCSC1=CC=C(C=C1)C1=CC(=CC=C1)OC1CCC1)=O Chemical compound C(C)OC(CCCSC1=CC=C(C=C1)C1=CC(=CC=C1)OC1CCC1)=O PDMLPUSXIFKFHQ-UHFFFAOYSA-N 0.000 description 2
- ASSJFJZGIICKFT-UHFFFAOYSA-N C(C)OC(CCCSCC1=CC=C(C=C1)OC)=O Chemical compound C(C)OC(CCCSCC1=CC=C(C=C1)OC)=O ASSJFJZGIICKFT-UHFFFAOYSA-N 0.000 description 2
- GPYYJWYUGLGIOF-UHFFFAOYSA-N C(C1=CC=CC=C1)OC=1C(=NC=CC1)C1CCCC1 Chemical compound C(C1=CC=CC=C1)OC=1C(=NC=CC1)C1CCCC1 GPYYJWYUGLGIOF-UHFFFAOYSA-N 0.000 description 2
- OHKNXPYBCGCWFJ-UHFFFAOYSA-N C(C1=CC=CC=C1)OC=1C(=NC=CC1)C=C(C)C Chemical compound C(C1=CC=CC=C1)OC=1C(=NC=CC1)C=C(C)C OHKNXPYBCGCWFJ-UHFFFAOYSA-N 0.000 description 2
- ONGSNQLSTUTZDB-UHFFFAOYSA-N C(C1=CC=CC=C1)OC=1C(=NC=CC1)C=C1CCCC1 Chemical compound C(C1=CC=CC=C1)OC=1C(=NC=CC1)C=C1CCCC1 ONGSNQLSTUTZDB-UHFFFAOYSA-N 0.000 description 2
- FVWIZOXBJQZNAQ-UHFFFAOYSA-N C(CC)OC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F Chemical compound C(CC)OC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F FVWIZOXBJQZNAQ-UHFFFAOYSA-N 0.000 description 2
- USCNKMHKVAMISR-UHFFFAOYSA-N C(CC)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)F)F Chemical compound C(CC)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)F)F USCNKMHKVAMISR-UHFFFAOYSA-N 0.000 description 2
- CUQCROOFRQDEDM-UHFFFAOYSA-N C(CC)SC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F Chemical compound C(CC)SC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F CUQCROOFRQDEDM-UHFFFAOYSA-N 0.000 description 2
- NLBJYAXQVHEBNX-UHFFFAOYSA-N C(CCC)SC1=NC=CC=C1I Chemical class C(CCC)SC1=NC=CC=C1I NLBJYAXQVHEBNX-UHFFFAOYSA-N 0.000 description 2
- OZBSMHIIJLTYEB-UHFFFAOYSA-N C1(CC1)CNC1=NC=CC=C1I Chemical compound C1(CC1)CNC1=NC=CC=C1I OZBSMHIIJLTYEB-UHFFFAOYSA-N 0.000 description 2
- WRLSZGIQYKSQRD-UHFFFAOYSA-N C1(CC1)COC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F Chemical compound C1(CC1)COC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F WRLSZGIQYKSQRD-UHFFFAOYSA-N 0.000 description 2
- NPEDDCPBISDDMN-UHFFFAOYSA-N C1(CC1)CSC1=NC=CC=C1C1=CC(=C(C(=C1)F)OC)F Chemical compound C1(CC1)CSC1=NC=CC=C1C1=CC(=C(C(=C1)F)OC)F NPEDDCPBISDDMN-UHFFFAOYSA-N 0.000 description 2
- DXHWTIJHFOZIBP-UHFFFAOYSA-N C1(CC1)CSC1=NC=CC=C1C1=CC=C(C=C1)OC Chemical compound C1(CC1)CSC1=NC=CC=C1C1=CC=C(C=C1)OC DXHWTIJHFOZIBP-UHFFFAOYSA-N 0.000 description 2
- HXOXBMWGZDHPMH-UHFFFAOYSA-N C1(CC1)SC1=NC=CC=C1I Chemical class C1(CC1)SC1=NC=CC=C1I HXOXBMWGZDHPMH-UHFFFAOYSA-N 0.000 description 2
- PMXSKGLXRLGMDJ-UHFFFAOYSA-N C1(CCC1)OC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F Chemical compound C1(CCC1)OC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F PMXSKGLXRLGMDJ-UHFFFAOYSA-N 0.000 description 2
- GABBIFFBJIRZTA-UHFFFAOYSA-N C1(CCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)F)F Chemical compound C1(CCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)F)F GABBIFFBJIRZTA-UHFFFAOYSA-N 0.000 description 2
- IEMPXZBLQRXPPX-UHFFFAOYSA-N C1(CCC1)OC=1C=C(C=CC=1)C1=CC(=C(C(=C1)F)F)F Chemical group C1(CCC1)OC=1C=C(C=CC=1)C1=CC(=C(C(=C1)F)F)F IEMPXZBLQRXPPX-UHFFFAOYSA-N 0.000 description 2
- MZPNYPXZRBRRCK-UHFFFAOYSA-N C1(CCC1)SC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F Chemical compound C1(CCC1)SC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F MZPNYPXZRBRRCK-UHFFFAOYSA-N 0.000 description 2
- RCXLYIZVDVMJIL-UHFFFAOYSA-N C1(CCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)F)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)F)F RCXLYIZVDVMJIL-UHFFFAOYSA-N 0.000 description 2
- LMKVPMJVWUMMCR-UHFFFAOYSA-N C1(CCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)O)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)O)F LMKVPMJVWUMMCR-UHFFFAOYSA-N 0.000 description 2
- DHSDRHVIZKPGHZ-UHFFFAOYSA-N C1(CCCC1)OC1=C(C=CC=C1F)C1=CC(=C(C=C1)SCCCC(=O)O)F Chemical compound C1(CCCC1)OC1=C(C=CC=C1F)C1=CC(=C(C=C1)SCCCC(=O)O)F DHSDRHVIZKPGHZ-UHFFFAOYSA-N 0.000 description 2
- KGXHAOQESFVJPP-UHFFFAOYSA-N C1(CCCC1)OC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F Chemical compound C1(CCCC1)OC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F KGXHAOQESFVJPP-UHFFFAOYSA-N 0.000 description 2
- GDEDTNQVQKNBNU-UHFFFAOYSA-N C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)O)F Chemical compound C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(C(=C1)F)O)F GDEDTNQVQKNBNU-UHFFFAOYSA-N 0.000 description 2
- IXMLSBAXBRVKOZ-UHFFFAOYSA-N C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound C1(CCCC1)OC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F IXMLSBAXBRVKOZ-UHFFFAOYSA-N 0.000 description 2
- YDJHRRPWMDJNHQ-UHFFFAOYSA-N C1(CCCC1)OC=1C=C(C=CC1)C1=CC(=C(C(=C1)F)SCCO)F Chemical compound C1(CCCC1)OC=1C=C(C=CC1)C1=CC(=C(C(=C1)F)SCCO)F YDJHRRPWMDJNHQ-UHFFFAOYSA-N 0.000 description 2
- PCMFDCMVQXSHLP-UHFFFAOYSA-N C1(CCCC1)SC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F Chemical compound C1(CCCC1)SC1=NC(=CC=C1)C1=CC(=C(C(=C1)F)F)F PCMFDCMVQXSHLP-UHFFFAOYSA-N 0.000 description 2
- BLJGWSPEONCTHO-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)F)F Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(C(=C1)F)F)F BLJGWSPEONCTHO-UHFFFAOYSA-N 0.000 description 2
- AKLHILCAMRSXRP-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC=C(C=C1)OC Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC=C(C=C1)OC AKLHILCAMRSXRP-UHFFFAOYSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 2
- LQFWAXYNUIKRPQ-UHFFFAOYSA-N CCOC(=O)CCCOc1ccc(Br)cc1OC Chemical compound CCOC(=O)CCCOc1ccc(Br)cc1OC LQFWAXYNUIKRPQ-UHFFFAOYSA-N 0.000 description 2
- SXAJORRZXORHKJ-UHFFFAOYSA-N CN(C1CN(CC1)C1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F)C Chemical compound CN(C1CN(CC1)C1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)O)C(=C1)F)F)C SXAJORRZXORHKJ-UHFFFAOYSA-N 0.000 description 2
- YJXTUUKTJMCGCJ-UHFFFAOYSA-N COC(C(C)SC1=C(C=C(C=C1F)Br)F)=O Chemical compound COC(C(C)SC1=C(C=C(C=C1F)Br)F)=O YJXTUUKTJMCGCJ-UHFFFAOYSA-N 0.000 description 2
- SJYHTDLBNDORMJ-UHFFFAOYSA-N COC(C(C)SC1=C(C=C(C=C1F)C=1C(=NC=CC1)OC(C)C)F)=O Chemical compound COC(C(C)SC1=C(C=C(C=C1F)C=1C(=NC=CC1)OC(C)C)F)=O SJYHTDLBNDORMJ-UHFFFAOYSA-N 0.000 description 2
- KKTCWLZFBJKOQL-UHFFFAOYSA-N COC(C(C)SC1=C(C=C(C=C1F)C=1C(=NC=CC1)OC1CCCC1)F)=O Chemical compound COC(C(C)SC1=C(C=C(C=C1F)C=1C(=NC=CC1)OC1CCCC1)F)=O KKTCWLZFBJKOQL-UHFFFAOYSA-N 0.000 description 2
- APFIQORXXNBHGM-UHFFFAOYSA-N COC(C(C)SC1=C(C=C(C=C1F)C=1C(=NC=CC1)SC1CCCC1)F)=O Chemical compound COC(C(C)SC1=C(C=C(C=C1F)C=1C(=NC=CC1)SC1CCCC1)F)=O APFIQORXXNBHGM-UHFFFAOYSA-N 0.000 description 2
- MPYRXCGCWWRLTL-UHFFFAOYSA-N COC(C(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)F)=O Chemical compound COC(C(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)F)=O MPYRXCGCWWRLTL-UHFFFAOYSA-N 0.000 description 2
- FWMFWKWVLPVVJO-UHFFFAOYSA-N COC(C(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)OC(C)C)=O Chemical compound COC(C(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)OC(C)C)=O FWMFWKWVLPVVJO-UHFFFAOYSA-N 0.000 description 2
- RSZYDUMKVFGRPU-UHFFFAOYSA-N COC(CC1(CC1)CSC1=C(C=C(C=C1F)C1=CC(=CC=C1)OC(C)C)F)=O Chemical compound COC(CC1(CC1)CSC1=C(C=C(C=C1F)C1=CC(=CC=C1)OC(C)C)F)=O RSZYDUMKVFGRPU-UHFFFAOYSA-N 0.000 description 2
- DZRBWEALKUPEIY-UHFFFAOYSA-N COC(CSC1=C(C=C(C=C1F)Br)F)=O Chemical compound COC(CSC1=C(C=C(C=C1F)Br)F)=O DZRBWEALKUPEIY-UHFFFAOYSA-N 0.000 description 2
- YNOPOFNIFQNESH-UHFFFAOYSA-N COC(CSC1=C(C=C(C=C1F)C1=CC(=CC=C1)O)F)=O Chemical compound COC(CSC1=C(C=C(C=C1F)C1=CC(=CC=C1)O)F)=O YNOPOFNIFQNESH-UHFFFAOYSA-N 0.000 description 2
- CCHJQLWOSYKEIF-UHFFFAOYSA-N COC(CSC1=C(C=C(C=C1F)C1=CC(=CC=C1)OC1CCCC1)F)=O Chemical compound COC(CSC1=C(C=C(C=C1F)C1=CC(=CC=C1)OC1CCCC1)F)=O CCHJQLWOSYKEIF-UHFFFAOYSA-N 0.000 description 2
- BKNIVYQSDZDKAA-UHFFFAOYSA-N COC1=CC=C(C=C1)C=1C(=NC=CC1)SCCC Chemical compound COC1=CC=C(C=C1)C=1C(=NC=CC1)SCCC BKNIVYQSDZDKAA-UHFFFAOYSA-N 0.000 description 2
- GCDFDPYRCWIEHK-UHFFFAOYSA-N ClCCSC1=C(C=C(C=C1F)C1=CC(=CC=C1)OC1CCCC1)F Chemical group ClCCSC1=C(C=C(C=C1F)C1=CC(=CC=C1)OC1CCCC1)F GCDFDPYRCWIEHK-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- IXEQATQNYNGHQE-UHFFFAOYSA-N FC(S(=O)(=O)OC=1C(=NC=CC1)C1CCCC1)(F)F Chemical compound FC(S(=O)(=O)OC=1C(=NC=CC1)C1CCCC1)(F)F IXEQATQNYNGHQE-UHFFFAOYSA-N 0.000 description 2
- QILAOMUYLFHQKT-UHFFFAOYSA-N FC(S(=O)(=O)OC=1C(=NC=CC1)CC1CCCC1)(F)F Chemical compound FC(S(=O)(=O)OC=1C(=NC=CC1)CC1CCCC1)(F)F QILAOMUYLFHQKT-UHFFFAOYSA-N 0.000 description 2
- MLNWOZXALYPGFX-UHFFFAOYSA-N FC1=C(C(=CC(=C1)C=1C(=NC=CC1)N1C=CC=C1)F)O Chemical compound FC1=C(C(=CC(=C1)C=1C(=NC=CC1)N1C=CC=C1)F)O MLNWOZXALYPGFX-UHFFFAOYSA-N 0.000 description 2
- DRMPKXDIJCHUNZ-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)N1CCOCC1)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)N1CCOCC1)F DRMPKXDIJCHUNZ-UHFFFAOYSA-N 0.000 description 2
- GGAAUOLWUVUZKW-UHFFFAOYSA-N FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)NCC1CCOCC1)F Chemical compound FC1=C(OCCCC(=O)O)C(=CC(=C1)C=1C(=NC=CC1)NCC1CCOCC1)F GGAAUOLWUVUZKW-UHFFFAOYSA-N 0.000 description 2
- OXSCBNLIGZUBMA-UHFFFAOYSA-N FC=1C=C(C=C(C=1F)F)C1=CC(=CC=C1)OC(C)C Chemical group FC=1C=C(C=C(C=1F)F)C1=CC(=CC=C1)OC(C)C OXSCBNLIGZUBMA-UHFFFAOYSA-N 0.000 description 2
- WIKMKFGOZZBYQC-UHFFFAOYSA-N FC=1C=C(C=C(C=1OC)F)C1=C(C=CC=C1)OC1=CC=CC=C1 Chemical group FC=1C=C(C=C(C=1OC)F)C1=C(C=CC=C1)OC1=CC=CC=C1 WIKMKFGOZZBYQC-UHFFFAOYSA-N 0.000 description 2
- HWFXYHDNJAEKOF-UHFFFAOYSA-N FC=1C=C(C=C(C=1OC)F)C=1C(=NC=CC=1)SC(C)C Chemical compound FC=1C=C(C=C(C=1OC)F)C=1C(=NC=CC=1)SC(C)C HWFXYHDNJAEKOF-UHFFFAOYSA-N 0.000 description 2
- BHEIOWXPLMLZLW-UHFFFAOYSA-N FC=1C=C(C=C(C=1OC)F)C=1C(=NC=CC=1)SCC1=CC=C(C=C1)OC Chemical compound FC=1C=C(C=C(C=1OC)F)C=1C(=NC=CC=1)SCC1=CC=C(C=C1)OC BHEIOWXPLMLZLW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 description 2
- GMEUIENORMBXPP-UHFFFAOYSA-N IC=1C(=NC=CC1)NCC1CCOCC1 Chemical compound IC=1C(=NC=CC1)NCC1CCOCC1 GMEUIENORMBXPP-UHFFFAOYSA-N 0.000 description 2
- ZNCRTEYVAKKVNM-UHFFFAOYSA-N IC=1C(=NC=CC1)OC1=NOC(=C1)C Chemical class IC=1C(=NC=CC1)OC1=NOC(=C1)C ZNCRTEYVAKKVNM-UHFFFAOYSA-N 0.000 description 2
- JUHZRSSXQLIXHG-UHFFFAOYSA-N IC=1C(=NC=CC1)OCC1(COC1)C Chemical compound IC=1C(=NC=CC1)OCC1(COC1)C JUHZRSSXQLIXHG-UHFFFAOYSA-N 0.000 description 2
- MMLNBZVAIZOVHH-UHFFFAOYSA-N IC=1C(=NC=CC1)OCC1COCC1 Chemical compound IC=1C(=NC=CC1)OCC1COCC1 MMLNBZVAIZOVHH-UHFFFAOYSA-N 0.000 description 2
- MFYRAKSYEAAACR-UHFFFAOYSA-N IC=1C(=NC=CC1)OCC1OCCC1 Chemical compound IC=1C(=NC=CC1)OCC1OCCC1 MFYRAKSYEAAACR-UHFFFAOYSA-N 0.000 description 2
- XDVNDPJJQLPXEU-UHFFFAOYSA-N IC=1C(=NC=CC1)OCCN(C)C Chemical compound IC=1C(=NC=CC1)OCCN(C)C XDVNDPJJQLPXEU-UHFFFAOYSA-N 0.000 description 2
- GIJGXNFNUUFEGH-UHFFFAOYSA-N Isopentyl mercaptan Chemical compound CC(C)CCS GIJGXNFNUUFEGH-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 2
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 2
- QAPXQGBQAUOWLW-UHFFFAOYSA-N N1(CC1)CCOC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F Chemical compound N1(CC1)CCOC1=NC=CC=C1C1=CC(=C(OCCCC(=O)O)C(=C1)F)F QAPXQGBQAUOWLW-UHFFFAOYSA-N 0.000 description 2
- BUHGPDPAPFFWHU-UHFFFAOYSA-N N1(CC1)CCOC1=NC=CC=C1I Chemical compound N1(CC1)CCOC1=NC=CC=C1I BUHGPDPAPFFWHU-UHFFFAOYSA-N 0.000 description 2
- HTYUUXXXJCASBG-UHFFFAOYSA-N O1C(=CC=C1)COC1=NC=CC=C1I Chemical compound O1C(=CC=C1)COC1=NC=CC=C1I HTYUUXXXJCASBG-UHFFFAOYSA-N 0.000 description 2
- VICYWHLSDXQETM-UHFFFAOYSA-N O1C=C(C=C1)COC1=NC=CC=C1I Chemical compound O1C=C(C=C1)COC1=NC=CC=C1I VICYWHLSDXQETM-UHFFFAOYSA-N 0.000 description 2
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- 229910002666 PdCl2 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 2
- YAINYZJQSQEGND-UHFFFAOYSA-N [1-(hydroxymethyl)cyclopropyl]methanol Chemical compound OCC1(CO)CC1 YAINYZJQSQEGND-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical group OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Chemical group 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- LOCHFZBWPCLPAN-UHFFFAOYSA-N butane-2-thiol Chemical compound CCC(C)S LOCHFZBWPCLPAN-UHFFFAOYSA-N 0.000 description 2
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- KZZKOVLJUKWSKX-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1CCC1 KZZKOVLJUKWSKX-UHFFFAOYSA-N 0.000 description 2
- KTHXBEHDVMTNOH-UHFFFAOYSA-N cyclobutanol Chemical compound OC1CCC1 KTHXBEHDVMTNOH-UHFFFAOYSA-N 0.000 description 2
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 2
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 description 2
- IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 2
- GUDMZGLFZNLYEY-UHFFFAOYSA-N cyclopropylmethanol Chemical compound OCC1CC1 GUDMZGLFZNLYEY-UHFFFAOYSA-N 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- HPMPAVDPNXYCKD-FMIVXFBMSA-N ethyl (e)-2-methyl-4-phenylmethoxybut-2-enoate Chemical compound CCOC(=O)C(\C)=C\COCC1=CC=CC=C1 HPMPAVDPNXYCKD-FMIVXFBMSA-N 0.000 description 2
- WPTIXUDEALSQOF-UHFFFAOYSA-N ethyl 2-(phenylmethoxymethyl)cyclopropane-1-carboxylate Chemical compound CCOC(=O)C1CC1COCC1=CC=CC=C1 WPTIXUDEALSQOF-UHFFFAOYSA-N 0.000 description 2
- MTRYNNKQVLMHCO-UHFFFAOYSA-N ethyl 4-(4-bromo-2,5-difluorophenoxy)butanoate Chemical compound CCOC(=O)CCCOC1=CC(F)=C(Br)C=C1F MTRYNNKQVLMHCO-UHFFFAOYSA-N 0.000 description 2
- KUJZRGGUWFAHPG-UHFFFAOYSA-N ethyl 4-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butanoate Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1)B1OC(C(O1)(C)C)(C)C)OC)=O KUJZRGGUWFAHPG-UHFFFAOYSA-N 0.000 description 2
- IJXDAGRWAWUTHW-UHFFFAOYSA-N ethyl 4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butanoate Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1)B1OC(C(O1)(C)C)(C)C)C)=O IJXDAGRWAWUTHW-UHFFFAOYSA-N 0.000 description 2
- BJHRIEHLNOVIBD-UHFFFAOYSA-N ethyl 4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butanoate Chemical compound C(C)OC(CCCOC1=CC(=C(C(=C1)F)B1OC(C(O1)(C)C)(C)C)F)=O BJHRIEHLNOVIBD-UHFFFAOYSA-N 0.000 description 2
- JKZALKYOSIOAAH-UHFFFAOYSA-N ethyl 4-[4-[2-[3-[tert-butyl(dimethyl)silyl]oxycyclopentyl]oxypyridin-3-yl]-2,6-difluorophenoxy]butanoate Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C=1C(=NC=CC=1)OC1CC(CC1)O[Si](C)(C)C(C)(C)C)F)=O JKZALKYOSIOAAH-UHFFFAOYSA-N 0.000 description 2
- YARDKGCSTRNORB-UHFFFAOYSA-N ethyl 4-hydroxy-2-methylbutanoate Chemical compound CCOC(=O)C(C)CCO YARDKGCSTRNORB-UHFFFAOYSA-N 0.000 description 2
- DCNAWFMPMKZTEC-UHFFFAOYSA-N ethyl 6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]hexanoate Chemical compound FC1=C(OCCCCCC(=O)OCC)C(=CC(=C1)B1OC(C(O1)(C)C)(C)C)F DCNAWFMPMKZTEC-UHFFFAOYSA-N 0.000 description 2
- DXBULVYHTICWKT-UHFFFAOYSA-N ethyl 6-bromohexanoate Chemical compound CCOC(=O)CCCCCBr DXBULVYHTICWKT-UHFFFAOYSA-N 0.000 description 2
- AGMKVZDPATUSMS-UHFFFAOYSA-N ethyl pent-2-enoate Chemical compound CCOC(=O)C=CCC AGMKVZDPATUSMS-UHFFFAOYSA-N 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- QRUDPBHCPMSJFN-UHFFFAOYSA-M magnesium;cyclobutane;bromide Chemical compound [Mg+2].[Br-].C1C[CH-]C1 QRUDPBHCPMSJFN-UHFFFAOYSA-M 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- WZRCJSPRTLEBEW-SSDOTTSWSA-N methyl (Z,4R)-4-(4-bromo-2,6-difluorophenoxy)pent-2-enoate Chemical compound BrC1=CC(=C(O[C@@H](C=C/C(=O)OC)C)C(=C1)F)F WZRCJSPRTLEBEW-SSDOTTSWSA-N 0.000 description 2
- ZYNYXTUGLKSXEM-UHFFFAOYSA-N methyl 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate Chemical compound COC(CCC(C)OC1=C(C=C(C=C1F)B1OC(C(O1)(C)C)(C)C)F)=O ZYNYXTUGLKSXEM-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- XITQUSLLOSKDTB-UHFFFAOYSA-N nitrofen Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC1=CC=C(Cl)C=C1Cl XITQUSLLOSKDTB-UHFFFAOYSA-N 0.000 description 2
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- LZMJNVRJMFMYQS-UHFFFAOYSA-N poseltinib Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(OC=C2)C2=N1 LZMJNVRJMFMYQS-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- PAEWRQPSWKOOFR-UHFFFAOYSA-N tert-butyl-[3-(3-iodopyridin-2-yl)oxycyclopentyl]oxy-dimethylsilane Chemical compound C(C)(C)(C)[Si](OC1CC(CC1)OC1=NC=CC=C1I)(C)C PAEWRQPSWKOOFR-UHFFFAOYSA-N 0.000 description 2
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- IIHPVYJPDKJYOU-UHFFFAOYSA-N triphenylcarbethoxymethylenephosphorane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OCC)C1=CC=CC=C1 IIHPVYJPDKJYOU-UHFFFAOYSA-N 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- GTJUPSNUGOBNMF-UHFFFAOYSA-M zinc;cyclopentane;bromide Chemical compound Br[Zn+].C1CC[CH-]C1 GTJUPSNUGOBNMF-UHFFFAOYSA-M 0.000 description 2
- SFUIGUOONHIVLG-UHFFFAOYSA-N (2-nitrophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1[N+]([O-])=O SFUIGUOONHIVLG-UHFFFAOYSA-N 0.000 description 1
- NLQMSBJFLQPLIJ-UHFFFAOYSA-N (3-methyloxetan-3-yl)methanol Chemical compound OCC1(C)COC1 NLQMSBJFLQPLIJ-UHFFFAOYSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- XDDGKNRSCDEWBR-UHFFFAOYSA-N (6-bromopyridin-2-yl)methanol Chemical compound OCC1=CC=CC(Br)=N1 XDDGKNRSCDEWBR-UHFFFAOYSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- WQONPSCCEXUXTQ-UHFFFAOYSA-N 1,2-dibromobenzene Chemical compound BrC1=CC=CC=C1Br WQONPSCCEXUXTQ-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- INXKVYFOWNAVMU-UHFFFAOYSA-N 2,5-difluorophenol Chemical compound OC1=CC(F)=CC=C1F INXKVYFOWNAVMU-UHFFFAOYSA-N 0.000 description 1
- CKKOVFGIBXCEIJ-UHFFFAOYSA-N 2,6-difluorophenol Chemical compound OC1=C(F)C=CC=C1F CKKOVFGIBXCEIJ-UHFFFAOYSA-N 0.000 description 1
- VYONOYYDEFODAJ-UHFFFAOYSA-N 2-(1-Aziridinyl)ethanol Chemical compound OCCN1CC1 VYONOYYDEFODAJ-UHFFFAOYSA-N 0.000 description 1
- ZYXIOXNUKBMPQJ-UHFFFAOYSA-N 2-(4-benzylmorpholin-4-ium-2-yl)acetate Chemical compound C1COC(CC(=O)O)CN1CC1=CC=CC=C1 ZYXIOXNUKBMPQJ-UHFFFAOYSA-N 0.000 description 1
- ZOQOPXVJANRGJZ-UHFFFAOYSA-N 2-(trifluoromethyl)phenol Chemical compound OC1=CC=CC=C1C(F)(F)F ZOQOPXVJANRGJZ-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- IDGZQKSMZMQRMF-UHFFFAOYSA-N 2-[1-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]cyclopropyl]acetonitrile Chemical compound FC1=C(OCC2(CC2)CC#N)C(=CC(=C1)B1OC(C(O1)(C)C)(C)C)F IDGZQKSMZMQRMF-UHFFFAOYSA-N 0.000 description 1
- SYTBIFURTZACKR-UHFFFAOYSA-N 2-bromo-4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1Br SYTBIFURTZACKR-UHFFFAOYSA-N 0.000 description 1
- MTIDYGLTAOZOGU-UHFFFAOYSA-N 2-bromo-4-methylphenol Chemical compound CC1=CC=C(O)C(Br)=C1 MTIDYGLTAOZOGU-UHFFFAOYSA-N 0.000 description 1
- KBBNPYQELNBTGD-UHFFFAOYSA-N 2-bromo-6-cyclobutyloxypyridine Chemical compound BrC1=CC=CC(OC2CCC2)=N1 KBBNPYQELNBTGD-UHFFFAOYSA-N 0.000 description 1
- YKHQFTANTNMYPP-UHFFFAOYSA-N 2-bromopyridin-3-ol Chemical compound OC1=CC=CN=C1Br YKHQFTANTNMYPP-UHFFFAOYSA-N 0.000 description 1
- KJKIPRQNFDUULB-UHFFFAOYSA-N 2-chloro-4-iodopyridine Chemical compound ClC1=CC(I)=CC=N1 KJKIPRQNFDUULB-UHFFFAOYSA-N 0.000 description 1
- WJKISRFVKIOBCQ-UHFFFAOYSA-N 2-fluoro-4-methylphenol Chemical compound CC1=CC=C(O)C(F)=C1 WJKISRFVKIOBCQ-UHFFFAOYSA-N 0.000 description 1
- GGDYAKVUZMZKRV-UHFFFAOYSA-N 2-fluoroethanol Chemical compound OCCF GGDYAKVUZMZKRV-UHFFFAOYSA-N 0.000 description 1
- HFHFGHLXUCOHLN-UHFFFAOYSA-N 2-fluorophenol Chemical compound OC1=CC=CC=C1F HFHFGHLXUCOHLN-UHFFFAOYSA-N 0.000 description 1
- YYVPZQADFREIFR-UHFFFAOYSA-N 3,3-difluoropyrrolidine;hydrochloride Chemical compound [Cl-].FC1(F)CC[NH2+]C1 YYVPZQADFREIFR-UHFFFAOYSA-N 0.000 description 1
- SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 1
- NLXIOZRBFNUITF-UHFFFAOYSA-N 3-[tert-butyl(dimethyl)silyl]oxycyclopentan-1-ol Chemical compound CC(C)(C)[Si](C)(C)OC1CCC(O)C1 NLXIOZRBFNUITF-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- KDRFZHZRRVPEGJ-UHFFFAOYSA-N 3-bromo-n-(cyclopropylmethyl)aniline Chemical compound BrC1=CC=CC(NCC2CC2)=C1 KDRFZHZRRVPEGJ-UHFFFAOYSA-N 0.000 description 1
- MNOJRWOWILAHAV-UHFFFAOYSA-N 3-bromophenol Chemical compound OC1=CC=CC(Br)=C1 MNOJRWOWILAHAV-UHFFFAOYSA-N 0.000 description 1
- GJOOCAXPERKNMN-UHFFFAOYSA-N 3-fluoro-4-methylphenol Chemical compound CC1=CC=C(O)C=C1F GJOOCAXPERKNMN-UHFFFAOYSA-N 0.000 description 1
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 1
- XDPCNPCKDGQBAN-UHFFFAOYSA-N 3-hydroxytetrahydrofuran Chemical compound OC1CCOC1 XDPCNPCKDGQBAN-UHFFFAOYSA-N 0.000 description 1
- FXTKWBZFNQHAAO-UHFFFAOYSA-N 3-iodophenol Chemical compound OC1=CC=CC(I)=C1 FXTKWBZFNQHAAO-UHFFFAOYSA-N 0.000 description 1
- ZNRGSYUVFVNSAW-UHFFFAOYSA-N 3-nitrophenylboronic acid Chemical compound OB(O)C1=CC=CC([N+]([O-])=O)=C1 ZNRGSYUVFVNSAW-UHFFFAOYSA-N 0.000 description 1
- UCFSYHMCKWNKAH-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OBOC1(C)C UCFSYHMCKWNKAH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- BICZJRAGTCRORZ-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(O)C=C1 BICZJRAGTCRORZ-UHFFFAOYSA-N 0.000 description 1
- JZAVCMMYGSROJP-UHFFFAOYSA-N 4-bromo-2,3-difluorophenol Chemical compound OC1=CC=C(Br)C(F)=C1F JZAVCMMYGSROJP-UHFFFAOYSA-N 0.000 description 1
- ZLVFYUORUHNMBO-UHFFFAOYSA-N 4-bromo-2,6-dimethylphenol Chemical compound CC1=CC(Br)=CC(C)=C1O ZLVFYUORUHNMBO-UHFFFAOYSA-N 0.000 description 1
- VIBJPUXLAKVICD-UHFFFAOYSA-N 4-bromo-2-chlorophenol Chemical compound OC1=CC=C(Br)C=C1Cl VIBJPUXLAKVICD-UHFFFAOYSA-N 0.000 description 1
- GZRMNMGWNKSANY-UHFFFAOYSA-N 4-bromo-2-fluoroaniline Chemical compound NC1=CC=C(Br)C=C1F GZRMNMGWNKSANY-UHFFFAOYSA-N 0.000 description 1
- RYVOZMPTISNBDB-UHFFFAOYSA-N 4-bromo-2-fluorophenol Chemical compound OC1=CC=C(Br)C=C1F RYVOZMPTISNBDB-UHFFFAOYSA-N 0.000 description 1
- WHSIIJQOEGXWSN-UHFFFAOYSA-N 4-bromo-2-methoxyphenol Chemical compound COC1=CC(Br)=CC=C1O WHSIIJQOEGXWSN-UHFFFAOYSA-N 0.000 description 1
- HHGOLZGZHXELSW-UHFFFAOYSA-N 4-bromo-3,5-difluorophenol Chemical compound OC1=CC(F)=C(Br)C(F)=C1 HHGOLZGZHXELSW-UHFFFAOYSA-N 0.000 description 1
- MPCCNXGZCOXPMG-UHFFFAOYSA-N 4-bromobenzene-1,3-diol Chemical compound OC1=CC=C(Br)C(O)=C1 MPCCNXGZCOXPMG-UHFFFAOYSA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- SETOTRGVPANENO-UHFFFAOYSA-N 4-fluoro-2-iodoaniline Chemical compound NC1=CC=C(F)C=C1I SETOTRGVPANENO-UHFFFAOYSA-N 0.000 description 1
- VSMDINRNYYEDRN-UHFFFAOYSA-N 4-iodophenol Chemical compound OC1=CC=C(I)C=C1 VSMDINRNYYEDRN-UHFFFAOYSA-N 0.000 description 1
- NDMZZQRNZFWMEZ-UHFFFAOYSA-N 5-bromo-1h-pyridin-2-one Chemical compound OC1=CC=C(Br)C=N1 NDMZZQRNZFWMEZ-UHFFFAOYSA-N 0.000 description 1
- BKLJUYPLUWUEOQ-UHFFFAOYSA-N 6-bromopyridin-2-amine Chemical compound NC1=CC=CC(Br)=N1 BKLJUYPLUWUEOQ-UHFFFAOYSA-N 0.000 description 1
- PTEFNEALEPSHLC-UHFFFAOYSA-N 6-bromopyridin-3-ol Chemical compound OC1=CC=C(Br)N=C1 PTEFNEALEPSHLC-UHFFFAOYSA-N 0.000 description 1
- QWFHFNGMCPMOCD-UHFFFAOYSA-N 6-bromopyridine-2-carbaldehyde Chemical compound BrC1=CC=CC(C=O)=N1 QWFHFNGMCPMOCD-UHFFFAOYSA-N 0.000 description 1
- NUKXRZVOIWRVFT-UHFFFAOYSA-N 6-chloro-n-cyclopentylpyridin-2-amine Chemical compound ClC1=CC=CC(NC2CCCC2)=N1 NUKXRZVOIWRVFT-UHFFFAOYSA-N 0.000 description 1
- ARCAJAOOPOKGBU-UHFFFAOYSA-N 6-chloro-n-phenylpyridin-2-amine Chemical class ClC1=CC=CC(NC=2C=CC=CC=2)=N1 ARCAJAOOPOKGBU-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- JLEWQMLCQDWNQT-SSDOTTSWSA-N BrC1=CC(=C(O[C@@H](CCC(=O)OC)C)C(=C1)F)F Chemical compound BrC1=CC(=C(O[C@@H](CCC(=O)OC)C)C(=C1)F)F JLEWQMLCQDWNQT-SSDOTTSWSA-N 0.000 description 1
- HAUNIFBBZDQMPE-ZJELKQJVSA-N BrC1=CC(=C(O[C@H](/C=C/C(=O)OCC)C)C(=C1)F)F Chemical compound BrC1=CC(=C(O[C@H](/C=C/C(=O)OCC)C)C(=C1)F)F HAUNIFBBZDQMPE-ZJELKQJVSA-N 0.000 description 1
- GPEMNWYYNOHVFA-QMMMGPOBSA-N BrC1=CC(=C(O[C@H](CCC(=O)OCC)C)C(=C1)F)F Chemical compound BrC1=CC(=C(O[C@H](CCC(=O)OCC)C)C(=C1)F)F GPEMNWYYNOHVFA-QMMMGPOBSA-N 0.000 description 1
- GUQFMYGJGVJPNE-UHFFFAOYSA-N BrC1=NC(=CC=C1)C=C1CCC1 Chemical compound BrC1=NC(=CC=C1)C=C1CCC1 GUQFMYGJGVJPNE-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- QDMBDYFNXQGBQU-UHFFFAOYSA-N C(C)(C)SC1=CC=CC(=N1)C1=CC=C(OCCCC(=O)OCC)C=C1 Chemical compound C(C)(C)SC1=CC=CC(=N1)C1=CC=C(OCCCC(=O)OCC)C=C1 QDMBDYFNXQGBQU-UHFFFAOYSA-N 0.000 description 1
- WABIPUDPIRTYHQ-UHFFFAOYSA-N C(C)OC(C=CC(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)F)=O Chemical compound C(C)OC(C=CC(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)F)=O WABIPUDPIRTYHQ-UHFFFAOYSA-N 0.000 description 1
- JQOHDJBAAYRICM-UHFFFAOYSA-N C(C)OC(C=CC(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)OC1CCCC1)=O Chemical compound C(C)OC(C=CC(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)OC1CCCC1)=O JQOHDJBAAYRICM-UHFFFAOYSA-N 0.000 description 1
- GSWBBANIHWABBJ-UHFFFAOYSA-N C(C)OC(CCC(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)F)=O Chemical compound C(C)OC(CCC(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)F)=O GSWBBANIHWABBJ-UHFFFAOYSA-N 0.000 description 1
- BCONHUFFJLNEKF-UHFFFAOYSA-N C(C)OC(CCCCCSC1=C(C=C(C=C1F)B1OC(C(O1)(C)C)(C)C)F)=O Chemical compound C(C)OC(CCCCCSC1=C(C=C(C=C1F)B1OC(C(O1)(C)C)(C)C)F)=O BCONHUFFJLNEKF-UHFFFAOYSA-N 0.000 description 1
- FGXACUSHPIRKSK-UHFFFAOYSA-N C(C)OC(CCCCCSC1=C(C=C(C=C1F)Br)F)=O Chemical compound C(C)OC(CCCCCSC1=C(C=C(C=C1F)Br)F)=O FGXACUSHPIRKSK-UHFFFAOYSA-N 0.000 description 1
- CLJHTFWWVUBJQX-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C(=C(C=C1)Br)F)F)=O Chemical compound C(C)OC(CCCOC1=C(C(=C(C=C1)Br)F)F)=O CLJHTFWWVUBJQX-UHFFFAOYSA-N 0.000 description 1
- GAVYYKWDSXRVTL-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C(=C(C=C1)C1=CC(=CC=C1)O)F)F)=O Chemical compound C(C)OC(CCCOC1=C(C(=C(C=C1)C1=CC(=CC=C1)O)F)F)=O GAVYYKWDSXRVTL-UHFFFAOYSA-N 0.000 description 1
- HJPIYCZKGWHKNU-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C(=C(C=C1)C1=CC(=CC=C1)OC1CCCC1)F)F)=O Chemical compound C(C)OC(CCCOC1=C(C(=C(C=C1)C1=CC(=CC=C1)OC1CCCC1)F)F)=O HJPIYCZKGWHKNU-UHFFFAOYSA-N 0.000 description 1
- REKNUNKEDCBKKM-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1)C1=NC(=CC=C1)OC1CCC1)C(F)(F)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1)C1=NC(=CC=C1)OC1CCC1)C(F)(F)F)=O REKNUNKEDCBKKM-UHFFFAOYSA-N 0.000 description 1
- HTNJJJVKYUJNAG-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1)C1=NC(=CC=C1)OC1CCC1)C)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1)C1=NC(=CC=C1)OC1CCC1)C)=O HTNJJJVKYUJNAG-UHFFFAOYSA-N 0.000 description 1
- UKJMMQLBXWUQTF-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C1=CC(=NC=C1)Cl)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C1=CC(=NC=C1)Cl)F)=O UKJMMQLBXWUQTF-UHFFFAOYSA-N 0.000 description 1
- YPVQLXILBWIGIB-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C1=CC(=NC=C1)SC(C)C)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C1=CC(=NC=C1)SC(C)C)F)=O YPVQLXILBWIGIB-UHFFFAOYSA-N 0.000 description 1
- BCGMMYYBXOILNH-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)NC1CCCC1)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)NC1CCCC1)F)=O BCGMMYYBXOILNH-UHFFFAOYSA-N 0.000 description 1
- YIVDIXYBTNRVJG-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)OC(C)C)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)OC(C)C)F)=O YIVDIXYBTNRVJG-UHFFFAOYSA-N 0.000 description 1
- XOTWVWXNXHCOLS-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)OC1=CC=CC=C1)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)OC1=CC=CC=C1)F)=O XOTWVWXNXHCOLS-UHFFFAOYSA-N 0.000 description 1
- GTYAMKFNOROSLT-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)OC1CCC1)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)OC1CCC1)F)=O GTYAMKFNOROSLT-UHFFFAOYSA-N 0.000 description 1
- OQDJLPILCQPWGE-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)OC1CCCC1)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)OC1CCCC1)F)=O OQDJLPILCQPWGE-UHFFFAOYSA-N 0.000 description 1
- FWRBVBIGGKWJSZ-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)OCC1CC1)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)OCC1CC1)F)=O FWRBVBIGGKWJSZ-UHFFFAOYSA-N 0.000 description 1
- KJJDXZRCPWQYAT-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)OCCC)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)OCCC)F)=O KJJDXZRCPWQYAT-UHFFFAOYSA-N 0.000 description 1
- QBGQQMXBINKLRF-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)SC(C)C)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)SC(C)C)F)=O QBGQQMXBINKLRF-UHFFFAOYSA-N 0.000 description 1
- QAOJLDSUPTXKND-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C=1C(=NC=CC1)F)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C=1C(=NC=CC1)F)F)=O QAOJLDSUPTXKND-UHFFFAOYSA-N 0.000 description 1
- IHXLTRAPCNNINF-UHFFFAOYSA-N C(C)OC(CCCOC1=C(C=C(C=C1F)C=1C(=NC=CC=1)SCCC)F)=O Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1F)C=1C(=NC=CC=1)SCCC)F)=O IHXLTRAPCNNINF-UHFFFAOYSA-N 0.000 description 1
- YNLUBCFLVXQJIY-UHFFFAOYSA-N C(C)OC(CCCOC1=CC=C(C=C1)C1=NC(=CC=C1)OC1=CC=CC=C1)=O Chemical compound C(C)OC(CCCOC1=CC=C(C=C1)C1=NC(=CC=C1)OC1=CC=CC=C1)=O YNLUBCFLVXQJIY-UHFFFAOYSA-N 0.000 description 1
- OENXREGODDARLF-UHFFFAOYSA-N C(C)OC(CCCOC=1C=NC(=CC=1)Br)=O Chemical compound C(C)OC(CCCOC=1C=NC(=CC=1)Br)=O OENXREGODDARLF-UHFFFAOYSA-N 0.000 description 1
- CRSYZVRSDFLNME-UHFFFAOYSA-N C(C)OC(CCCOC=1C=NC(=CC=1)C1=CC(=CC=C1)OC1CCC1)=O Chemical compound C(C)OC(CCCOC=1C=NC(=CC=1)C1=CC(=CC=C1)OC1CCC1)=O CRSYZVRSDFLNME-UHFFFAOYSA-N 0.000 description 1
- YLXYPDSTAGIKJX-UHFFFAOYSA-N C(C)OC(CCCOC=1C=NC(=CC=1)C1=CC(=CC=C1)OC1CCCC1)=O Chemical compound C(C)OC(CCCOC=1C=NC(=CC=1)C1=CC(=CC=C1)OC1CCCC1)=O YLXYPDSTAGIKJX-UHFFFAOYSA-N 0.000 description 1
- GKXMAAZLSMPKKI-UHFFFAOYSA-N C(C)OC(CCCSC1=CC=C(C=C1)C1=C(C=CC(=C1)C)O)=O Chemical compound C(C)OC(CCCSC1=CC=C(C=C1)C1=C(C=CC(=C1)C)O)=O GKXMAAZLSMPKKI-UHFFFAOYSA-N 0.000 description 1
- VDZMCLNKEXJFGR-UHFFFAOYSA-N C1(CC1)CNC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CC1)CNC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F VDZMCLNKEXJFGR-UHFFFAOYSA-N 0.000 description 1
- UKRXQQWQKZOHBP-UHFFFAOYSA-N C1(CC1)CNC1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CC1)CNC1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F UKRXQQWQKZOHBP-UHFFFAOYSA-N 0.000 description 1
- BBLSERORJCLRBH-UHFFFAOYSA-N C1(CC1)CNC1=NC=CC=C1C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CC1)CNC1=NC=CC=C1C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F BBLSERORJCLRBH-UHFFFAOYSA-N 0.000 description 1
- QBJIGVNHCXJVAQ-UHFFFAOYSA-N C1(CC1)CNC=1C=C(C=CC=1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CC1)CNC=1C=C(C=CC=1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F QBJIGVNHCXJVAQ-UHFFFAOYSA-N 0.000 description 1
- RNZZVXSLIYQEFX-UHFFFAOYSA-N C1(CC1)COC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CC1)COC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)OCC)C(=C1)F)F RNZZVXSLIYQEFX-UHFFFAOYSA-N 0.000 description 1
- NBWZWWRZWCOMLV-UHFFFAOYSA-N C1(CCC1)CC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCC1)CC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F NBWZWWRZWCOMLV-UHFFFAOYSA-N 0.000 description 1
- LTXYEKXIJZWCKW-UHFFFAOYSA-N C1(CCC1)CC1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCC1)CC1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F LTXYEKXIJZWCKW-UHFFFAOYSA-N 0.000 description 1
- KWPLVNSGUCGZKQ-UHFFFAOYSA-N C1(CCC1)CC=1C=C(C=CC=1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCC1)CC=1C=C(C=CC=1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F KWPLVNSGUCGZKQ-UHFFFAOYSA-N 0.000 description 1
- CELWJCYTGIQOSA-UHFFFAOYSA-N C1(CCC1)COC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCCC(=O)O)F Chemical compound C1(CCC1)COC1=NC=CC=C1C1=CC(=C(C(=C1)F)SCCCCC(=O)O)F CELWJCYTGIQOSA-UHFFFAOYSA-N 0.000 description 1
- FJKMEPDWSVDAPQ-UHFFFAOYSA-N C1(CCC1)NC=1C=C(C=CC=1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCC1)NC=1C=C(C=CC=1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F FJKMEPDWSVDAPQ-UHFFFAOYSA-N 0.000 description 1
- AZZYCJGQULURJW-UHFFFAOYSA-N C1(CCC1)OC=1C=C(C=CC=1)C1=CC(=C(OCC2(CC2)CC#N)C(=C1)F)F Chemical compound C1(CCC1)OC=1C=C(C=CC=1)C1=CC(=C(OCC2(CC2)CC#N)C(=C1)F)F AZZYCJGQULURJW-UHFFFAOYSA-N 0.000 description 1
- CJXBDFCZOSGMMX-CQSZACIVSA-N C1(CCC1)OC=1C=C(C=CC=1)C1=CC(=C(O[C@@H](CCC(=O)OC)C)C(=C1)F)F Chemical compound C1(CCC1)OC=1C=C(C=CC=1)C1=CC(=C(O[C@@H](CCC(=O)OC)C)C(=C1)F)F CJXBDFCZOSGMMX-CQSZACIVSA-N 0.000 description 1
- NLBQWZXPMUSDEC-UHFFFAOYSA-N C1(CCC1)SC1=NC=CC=C1C1=CC(=C(OCC2(CC2)CC#N)C(=C1)F)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC(=C(OCC2(CC2)CC#N)C(=C1)F)F NLBQWZXPMUSDEC-UHFFFAOYSA-N 0.000 description 1
- UHYGQFZWWMKAPZ-UHFFFAOYSA-N C1(CCC1)SC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)OCC)C(=C1)F)F UHYGQFZWWMKAPZ-UHFFFAOYSA-N 0.000 description 1
- BVPKNFMRPXFVTR-CYBMUJFWSA-N C1(CCC1)SC1=NC=CC=C1C1=CC(=C(O[C@@H](CCC(=O)OC)C)C(=C1)F)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC(=C(O[C@@H](CCC(=O)OC)C)C(=C1)F)F BVPKNFMRPXFVTR-CYBMUJFWSA-N 0.000 description 1
- NPBZOMLFADUODP-AWEZNQCLSA-N C1(CCC1)SC1=NC=CC=C1C1=CC(=C(O[C@H](CCC(=O)OCC)C)C(=C1)F)F Chemical compound C1(CCC1)SC1=NC=CC=C1C1=CC(=C(O[C@H](CCC(=O)OCC)C)C(=C1)F)F NPBZOMLFADUODP-AWEZNQCLSA-N 0.000 description 1
- ANMMWYMVFKNMSI-UHFFFAOYSA-N C1(CCCC1)=CC1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCCC1)=CC1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F ANMMWYMVFKNMSI-UHFFFAOYSA-N 0.000 description 1
- FROVRFQAOZXPTR-UHFFFAOYSA-N C1(CCCC1)C1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCCC1)C1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F FROVRFQAOZXPTR-UHFFFAOYSA-N 0.000 description 1
- RPIBIQGWIKACHB-UHFFFAOYSA-N C1(CCCC1)C1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCCC1)C1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F RPIBIQGWIKACHB-UHFFFAOYSA-N 0.000 description 1
- DDORVZFDWSFIHV-UHFFFAOYSA-N C1(CCCC1)C1=NC=CC=C1C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCCC1)C1=NC=CC=C1C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F DDORVZFDWSFIHV-UHFFFAOYSA-N 0.000 description 1
- OWDCDEAFIIWMSR-UHFFFAOYSA-N C1(CCCC1)CC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCCC1)CC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F OWDCDEAFIIWMSR-UHFFFAOYSA-N 0.000 description 1
- TXIJIIYCDCAGID-UHFFFAOYSA-N C1(CCCC1)CC1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCCC1)CC1=CC=CC(=N1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F TXIJIIYCDCAGID-UHFFFAOYSA-N 0.000 description 1
- IQQPAIOSAAYMBW-UHFFFAOYSA-N C1(CCCC1)CC1=NC=CC=C1C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCCC1)CC1=NC=CC=C1C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F IQQPAIOSAAYMBW-UHFFFAOYSA-N 0.000 description 1
- QTLYDYYMXVSIOS-UHFFFAOYSA-N C1(CCCC1)CC=1C=C(C=CC=1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCCC1)CC=1C=C(C=CC=1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F QTLYDYYMXVSIOS-UHFFFAOYSA-N 0.000 description 1
- DDZLRDVJJXGAEI-UHFFFAOYSA-N C1(CCCC1)NC1=C(C=C(C=C1)F)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCCC1)NC1=C(C=C(C=C1)F)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F DDZLRDVJJXGAEI-UHFFFAOYSA-N 0.000 description 1
- KVNZXKWOCUKZRI-UHFFFAOYSA-N C1(CCCC1)NC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCCC1)NC1=C(C=CC=C1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F KVNZXKWOCUKZRI-UHFFFAOYSA-N 0.000 description 1
- YLOIDTPJPAHZOC-UHFFFAOYSA-N C1(CCCC1)NC=1C=C(C=CC=1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCCC1)NC=1C=C(C=CC=1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F YLOIDTPJPAHZOC-UHFFFAOYSA-N 0.000 description 1
- SJMFFGWOSKDYMV-UHFFFAOYSA-N C1(CCCC1)OC=1C=C(C=CC=1)C1=C(C(=CC(=C1)F)F)SCCCC(=O)O Chemical compound C1(CCCC1)OC=1C=C(C=CC=1)C1=C(C(=CC(=C1)F)F)SCCCC(=O)O SJMFFGWOSKDYMV-UHFFFAOYSA-N 0.000 description 1
- CFQHXQFGOFZBEY-UHFFFAOYSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)OCC)C(=C1)F)F Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(OCCCCC(=O)OCC)C(=C1)F)F CFQHXQFGOFZBEY-UHFFFAOYSA-N 0.000 description 1
- ZSVKSWBAFCIRLW-CQSZACIVSA-N C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(O[C@@H](CCC(=O)OC)C)C(=C1)F)F Chemical compound C1(CCCC1)SC1=NC=CC=C1C1=CC(=C(O[C@@H](CCC(=O)OC)C)C(=C1)F)F ZSVKSWBAFCIRLW-CQSZACIVSA-N 0.000 description 1
- 125000000172 C5-C10 aryl group Chemical group 0.000 description 1
- KOPSAEYDPBXBDT-UHFFFAOYSA-N CCOC(=O)C=C.C1=CC=CC=C1[PH2](C=1C=CC=CC=1)C1=CC=CC=C1 Chemical compound CCOC(=O)C=C.C1=CC=CC=C1[PH2](C=1C=CC=CC=1)C1=CC=CC=C1 KOPSAEYDPBXBDT-UHFFFAOYSA-N 0.000 description 1
- YOPOOGSZIASGRF-UHFFFAOYSA-N CCOC(=O)CCCOC1=C(F)C=C(C=C1F)C1=CC=CN=C1OCC1=COC=C1 Chemical compound CCOC(=O)CCCOC1=C(F)C=C(C=C1F)C1=CC=CN=C1OCC1=COC=C1 YOPOOGSZIASGRF-UHFFFAOYSA-N 0.000 description 1
- GJBGLAIJGXZJJD-UHFFFAOYSA-N CN(CCOC1=NC=CC=C1C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F)C Chemical compound CN(CCOC1=NC=CC=C1C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F)C GJBGLAIJGXZJJD-UHFFFAOYSA-N 0.000 description 1
- FUUDPVMJILPTOH-UHFFFAOYSA-N COC(C(C(=O)OC)CCSC1=C(C=C(C=C1F)F)C1=CC(=CC=C1)OC1CCCC1)=O Chemical compound COC(C(C(=O)OC)CCSC1=C(C=C(C=C1F)F)C1=CC(=CC=C1)OC1CCCC1)=O FUUDPVMJILPTOH-UHFFFAOYSA-N 0.000 description 1
- PMTUZAYZCHAMAN-UHFFFAOYSA-N COC(C(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)OC1CCCC1)=O Chemical compound COC(C(C)SC1=CC=C(C=C1)C=1C(=NC=CC1)OC1CCCC1)=O PMTUZAYZCHAMAN-UHFFFAOYSA-N 0.000 description 1
- VDNWVVOHKOEXPW-UHFFFAOYSA-N COC(CC1(CC1)CSC1=C(C=C(C=C1F)Br)F)=O Chemical compound COC(CC1(CC1)CSC1=C(C=C(C=C1F)Br)F)=O VDNWVVOHKOEXPW-UHFFFAOYSA-N 0.000 description 1
- RIGPRRSHVLMICI-UHFFFAOYSA-N COC(CC1(CC1)CSC1=C(C=C(C=C1F)C1=CC(=CC=C1)O)F)=O Chemical compound COC(CC1(CC1)CSC1=C(C=C(C=C1F)C1=CC(=CC=C1)O)F)=O RIGPRRSHVLMICI-UHFFFAOYSA-N 0.000 description 1
- FPERKPXSXZDXOO-UHFFFAOYSA-N COC(CCC(C)OC1=C(C=C(C=C1F)C1=NC(=CC=C1)OC1CCC1)F)=O Chemical compound COC(CCC(C)OC1=C(C=C(C=C1F)C1=NC(=CC=C1)OC1CCC1)F)=O FPERKPXSXZDXOO-UHFFFAOYSA-N 0.000 description 1
- BVPKNFMRPXFVTR-UHFFFAOYSA-N COC(CCC(C)OC1=C(C=C(C=C1F)C=1C(=NC=CC=1)SC1CCC1)F)=O Chemical compound COC(CCC(C)OC1=C(C=C(C=C1F)C=1C(=NC=CC=1)SC1CCC1)F)=O BVPKNFMRPXFVTR-UHFFFAOYSA-N 0.000 description 1
- STAHGKPSTVCQDO-UHFFFAOYSA-N COC(CCC(C)OC1=NC=C(C=C1)B1OC(C(O1)(C)C)(C)C)=O Chemical compound COC(CCC(C)OC1=NC=C(C=C1)B1OC(C(O1)(C)C)(C)C)=O STAHGKPSTVCQDO-UHFFFAOYSA-N 0.000 description 1
- JYWWNXIDGZKZFJ-UHFFFAOYSA-N COC(CCC(C)OC1=NC=C(C=C1)Br)=O Chemical compound COC(CCC(C)OC1=NC=C(C=C1)Br)=O JYWWNXIDGZKZFJ-UHFFFAOYSA-N 0.000 description 1
- SFBDAQUJNQVIRI-UHFFFAOYSA-N COC(CCC(C)OC1=NC=C(C=C1)C=1C(=NC=CC=1)SC1CCC1)=O Chemical compound COC(CCC(C)OC1=NC=C(C=C1)C=1C(=NC=CC=1)SC1CCC1)=O SFBDAQUJNQVIRI-UHFFFAOYSA-N 0.000 description 1
- BVDNJCTZXYFZPX-UHFFFAOYSA-N COC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)N(C1=CC=CC=C1)C)F)=O Chemical compound COC(CCCOC1=C(C=C(C=C1F)C1=NC(=CC=C1)N(C1=CC=CC=C1)C)F)=O BVDNJCTZXYFZPX-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- KVINBKIRSFFASO-UHFFFAOYSA-N ClC=1C=CC(=C(C=1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F)NC1CCCC1 Chemical compound ClC=1C=CC(=C(C=1)C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F)NC1CCCC1 KVINBKIRSFFASO-UHFFFAOYSA-N 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- QQYGDZGZSHYLJY-UHFFFAOYSA-N FC(S(=O)(=O)OC=1C(=NC=CC1)CC(C)C)(F)F Chemical compound FC(S(=O)(=O)OC=1C(=NC=CC1)CC(C)C)(F)F QQYGDZGZSHYLJY-UHFFFAOYSA-N 0.000 description 1
- PJSDCTWPVOOWBW-UHFFFAOYSA-N FC1(CN(CC1)C1=NC=CC=C1C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F)F Chemical compound FC1(CN(CC1)C1=NC=CC=C1C1=CC(=C(OCCCC(=O)OCC)C(=C1)F)F)F PJSDCTWPVOOWBW-UHFFFAOYSA-N 0.000 description 1
- PXOWPQYRPHWRCE-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C1=C(C=CC=C1)NC(C)C)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C1=C(C=CC=C1)NC(C)C)F PXOWPQYRPHWRCE-UHFFFAOYSA-N 0.000 description 1
- HHJQLSSVWVNICM-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C1=C(C=CC=C1)NCCC)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C1=C(C=CC=C1)NCCC)F HHJQLSSVWVNICM-UHFFFAOYSA-N 0.000 description 1
- DOSIWFWQQHPOBU-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C1=CC(=CC=C1)N1CCCC1)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C1=CC(=CC=C1)N1CCCC1)F DOSIWFWQQHPOBU-UHFFFAOYSA-N 0.000 description 1
- LNVOPFHZCFMEGF-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C1=CC(=CC=C1)NC(C)C)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C1=CC(=CC=C1)NC(C)C)F LNVOPFHZCFMEGF-UHFFFAOYSA-N 0.000 description 1
- XHNQJLUVKRSEFK-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C1=CC(=CC=C1)NCCC)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C1=CC(=CC=C1)NCCC)F XHNQJLUVKRSEFK-UHFFFAOYSA-N 0.000 description 1
- WKDLGBISSKSDOH-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C1=NC(=CC=C1)NC(C)C)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C1=NC(=CC=C1)NC(C)C)F WKDLGBISSKSDOH-UHFFFAOYSA-N 0.000 description 1
- KLOWXSJQZBPTLU-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)CC(C)C)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)CC(C)C)F KLOWXSJQZBPTLU-UHFFFAOYSA-N 0.000 description 1
- PVIBYLKJPSVXMG-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)N1CCCC1)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)N1CCCC1)F PVIBYLKJPSVXMG-UHFFFAOYSA-N 0.000 description 1
- RTRZWNZSGWWZBG-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)N1CCCCC1)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)N1CCCCC1)F RTRZWNZSGWWZBG-UHFFFAOYSA-N 0.000 description 1
- GRBURQSANSDNKF-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)N1CCN(CC1)C)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)N1CCN(CC1)C)F GRBURQSANSDNKF-UHFFFAOYSA-N 0.000 description 1
- CBVMNWYJTYJCAP-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)N1N=CC(=C1)C)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)N1N=CC(=C1)C)F CBVMNWYJTYJCAP-UHFFFAOYSA-N 0.000 description 1
- UNLKRSWGYYHLBU-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)NC(C)C)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)NC(C)C)F UNLKRSWGYYHLBU-UHFFFAOYSA-N 0.000 description 1
- CPRMHRMGFWDULD-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)OC1=NOC(=C1)C)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)OC1=NOC(=C1)C)F CPRMHRMGFWDULD-UHFFFAOYSA-N 0.000 description 1
- KXORRMBCKSDQNX-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)OCC1(COC1)C)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)OCC1(COC1)C)F KXORRMBCKSDQNX-UHFFFAOYSA-N 0.000 description 1
- HUXRIXJPAMEEHK-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)OCC1COCC1)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)OCC1COCC1)F HUXRIXJPAMEEHK-UHFFFAOYSA-N 0.000 description 1
- LQRCONNMWZTQBI-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)OCC1OCCC1)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)OCC1OCCC1)F LQRCONNMWZTQBI-UHFFFAOYSA-N 0.000 description 1
- VHKKCIYPRKRMRF-UHFFFAOYSA-N FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)OCC=1OC=CC=1)F Chemical compound FC1=C(OCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)OCC=1OC=CC=1)F VHKKCIYPRKRMRF-UHFFFAOYSA-N 0.000 description 1
- MRJVLUOYVPFWQF-UHFFFAOYSA-N FC1=C(OCCCCC(=O)OCC)C(=CC(=C1)C1=NC(=CC=C1)OC(C)C)F Chemical compound FC1=C(OCCCCC(=O)OCC)C(=CC(=C1)C1=NC(=CC=C1)OC(C)C)F MRJVLUOYVPFWQF-UHFFFAOYSA-N 0.000 description 1
- WEHBIVMECHBAFC-UHFFFAOYSA-N FC1=C(OCCCCC(=O)OCC)C(=CC(=C1)C1=NC(=CC=C1)SC(C)C)F Chemical compound FC1=C(OCCCCC(=O)OCC)C(=CC(=C1)C1=NC(=CC=C1)SC(C)C)F WEHBIVMECHBAFC-UHFFFAOYSA-N 0.000 description 1
- MKIBYLKPLHHOJP-UHFFFAOYSA-N FC1=C(OCCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)OC1CCOCC1)F Chemical compound FC1=C(OCCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)OC1CCOCC1)F MKIBYLKPLHHOJP-UHFFFAOYSA-N 0.000 description 1
- ZILQEHYNVBYKNW-UHFFFAOYSA-N FC1=C(OCCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)OC1COCC1)F Chemical compound FC1=C(OCCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)OC1COCC1)F ZILQEHYNVBYKNW-UHFFFAOYSA-N 0.000 description 1
- MOIKGWGZJQCEDW-UHFFFAOYSA-N FC1=C(OCCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)SC(C)C)F Chemical compound FC1=C(OCCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)SC(C)C)F MOIKGWGZJQCEDW-UHFFFAOYSA-N 0.000 description 1
- VOVRFJGWGHDZQQ-UHFFFAOYSA-N FC1=C(OCCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)SCCC)F Chemical compound FC1=C(OCCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)SCCC)F VOVRFJGWGHDZQQ-UHFFFAOYSA-N 0.000 description 1
- UXMDZJZOVHNAPY-UHFFFAOYSA-N FC1=C(OCCCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)SCCC)F Chemical compound FC1=C(OCCCCCC(=O)OCC)C(=CC(=C1)C=1C(=NC=CC=1)SCCC)F UXMDZJZOVHNAPY-UHFFFAOYSA-N 0.000 description 1
- RLQZHTWDDGNRFI-MRXNPFEDSA-N FC1=C(O[C@@H](CCC(=O)OC)C)C(=CC(=C1)C1=CC(=CC=C1)OC1=CC=CC=C1)F Chemical compound FC1=C(O[C@@H](CCC(=O)OC)C)C(=CC(=C1)C1=CC(=CC=C1)OC1=CC=CC=C1)F RLQZHTWDDGNRFI-MRXNPFEDSA-N 0.000 description 1
- HHYJLLFLWGEBJR-LBPRGKRZSA-N FC1=C(O[C@H](CCC(=O)OCC)C)C(=CC(=C1)B1OC(C(O1)(C)C)(C)C)F Chemical compound FC1=C(O[C@H](CCC(=O)OCC)C)C(=CC(=C1)B1OC(C(O1)(C)C)(C)C)F HHYJLLFLWGEBJR-LBPRGKRZSA-N 0.000 description 1
- PTODHJJWGLNCAB-UHFFFAOYSA-N FC=1C=C(C=C(C=1OC)F)C=1C(=NC=CC=1)S Chemical compound FC=1C=C(C=C(C=1OC)F)C=1C(=NC=CC=1)S PTODHJJWGLNCAB-UHFFFAOYSA-N 0.000 description 1
- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 1
- 101710142055 Free fatty acid receptor 4 Proteins 0.000 description 1
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 1
- 101150026303 HEX1 gene Proteins 0.000 description 1
- 101000886868 Homo sapiens Gastric inhibitory polypeptide Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- UBXYXCRCOKCZIT-UHFFFAOYSA-N biphenyl-3-ol Chemical group OC1=CC=CC(C=2C=CC=CC=2)=C1 UBXYXCRCOKCZIT-UHFFFAOYSA-N 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- WQAQPCDUOCURKW-UHFFFAOYSA-N butanethiol Chemical compound CCCCS WQAQPCDUOCURKW-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- GFHNAMRJFCEERV-UHFFFAOYSA-L cobalt chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Co+2] GFHNAMRJFCEERV-UHFFFAOYSA-L 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical compound O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- WPOPOPFNZYPKAV-UHFFFAOYSA-N cyclobutylmethanol Chemical compound OCC1CCC1 WPOPOPFNZYPKAV-UHFFFAOYSA-N 0.000 description 1
- 125000001352 cyclobutyloxy group Chemical group C1(CCC1)O* 0.000 description 1
- BNZSBPKOMCJCNW-UHFFFAOYSA-N cyclobutylsulfanylcyclobutane Chemical compound C1CCC1SC1CCC1 BNZSBPKOMCJCNW-UHFFFAOYSA-N 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- HAAOHBCJARVREN-UHFFFAOYSA-N cyclopenten-1-yl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CCCC1 HAAOHBCJARVREN-UHFFFAOYSA-N 0.000 description 1
- WZYWSVSFFTZZPE-UHFFFAOYSA-M cyclopentyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C1CCCC1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WZYWSVSFFTZZPE-UHFFFAOYSA-M 0.000 description 1
- ISQVBYGGNVVVHB-UHFFFAOYSA-N cyclopentylmethanol Chemical compound OCC1CCCC1 ISQVBYGGNVVVHB-UHFFFAOYSA-N 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- NQUFBBVYXNYYDX-UHFFFAOYSA-N cyclopropanethiol Chemical compound SC1CC1 NQUFBBVYXNYYDX-UHFFFAOYSA-N 0.000 description 1
- YOXHCYXIAVIFCZ-UHFFFAOYSA-N cyclopropanol Chemical compound OC1CC1 YOXHCYXIAVIFCZ-UHFFFAOYSA-N 0.000 description 1
- 230000020335 dealkylation Effects 0.000 description 1
- 238000006900 dealkylation reaction Methods 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- CNXMDTWQWLGCPE-UHFFFAOYSA-N ditert-butyl-(2-phenylphenyl)phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 CNXMDTWQWLGCPE-UHFFFAOYSA-N 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- HGAWOXJBIQKWTP-UHFFFAOYSA-N ethyl 4-[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butanoate Chemical compound C(C)OC(CCCOC1=C(C=C(C=C1C)B1OC(C(O1)(C)C)(C)C)C)=O HGAWOXJBIQKWTP-UHFFFAOYSA-N 0.000 description 1
- NEHSLYYQRJWEDT-UHFFFAOYSA-N ethyl 5-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate Chemical compound C(C)OC(CCCCOC1=C(C=C(C=C1)B1OC(C(O1)(C)C)(C)C)F)=O NEHSLYYQRJWEDT-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- RIKMMFOAQPJVMX-UHFFFAOYSA-N fomepizole Chemical compound CC=1C=NNC=1 RIKMMFOAQPJVMX-UHFFFAOYSA-N 0.000 description 1
- 229960004285 fomepizole Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- STJIISDMSMJQQK-UHFFFAOYSA-N furan-3-ylmethanol Chemical compound OCC=1C=COC=1 STJIISDMSMJQQK-UHFFFAOYSA-N 0.000 description 1
- XPFVYQJUAUNWIW-UHFFFAOYSA-N furfuryl alcohol Chemical compound OCC1=CC=CO1 XPFVYQJUAUNWIW-UHFFFAOYSA-N 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- KGVPNLBXJKTABS-UHFFFAOYSA-N hymexazol Chemical compound CC1=CC(O)=NO1 KGVPNLBXJKTABS-UHFFFAOYSA-N 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 239000005433 ionosphere Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- ZWTRVNAGPBMQAC-RXMQYKEDSA-N methyl (2R)-2-(4-bromo-2,6-difluorophenoxy)propanoate Chemical compound BrC1=CC(=C(O[C@@H](C(=O)OC)C)C(=C1)F)F ZWTRVNAGPBMQAC-RXMQYKEDSA-N 0.000 description 1
- ZWTRVNAGPBMQAC-YFKPBYRVSA-N methyl (2S)-2-(4-bromo-2,6-difluorophenoxy)propanoate Chemical compound BrC1=CC(=C(O[C@H](C(=O)OC)C)C(=C1)F)F ZWTRVNAGPBMQAC-YFKPBYRVSA-N 0.000 description 1
- LPEKGGXMPWTOCB-GSVOUGTGSA-N methyl (R)-lactate Chemical compound COC(=O)[C@@H](C)O LPEKGGXMPWTOCB-GSVOUGTGSA-N 0.000 description 1
- LPEKGGXMPWTOCB-VKHMYHEASA-N methyl (S)-lactate Chemical compound COC(=O)[C@H](C)O LPEKGGXMPWTOCB-VKHMYHEASA-N 0.000 description 1
- JRHLVNAWLWIHDN-UHFFFAOYSA-N methyl 2-[1-(sulfanylmethyl)cyclopropyl]acetate Chemical compound COC(=O)CC1(CS)CC1 JRHLVNAWLWIHDN-UHFFFAOYSA-N 0.000 description 1
- AKJIHUBPMGDXGA-UHFFFAOYSA-N methyl 2-[1-[[[1-(2-methoxy-2-oxoethyl)cyclopropyl]methyldisulfanyl]methyl]cyclopropyl]acetate Chemical compound C1CC1(CC(=O)OC)CSSCC1(CC(=O)OC)CC1 AKJIHUBPMGDXGA-UHFFFAOYSA-N 0.000 description 1
- PVSJXEDBEXYLML-UHFFFAOYSA-N methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate Chemical compound COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F PVSJXEDBEXYLML-UHFFFAOYSA-N 0.000 description 1
- MKIJJIMOAABWGF-UHFFFAOYSA-N methyl 2-sulfanylacetate Chemical compound COC(=O)CS MKIJJIMOAABWGF-UHFFFAOYSA-N 0.000 description 1
- KRKZQPVFNIGTIU-UHFFFAOYSA-N methyl 4-methylsulfanyl-4-sulfanylidenebutanoate Chemical compound CSC(=S)CCC(=O)OC KRKZQPVFNIGTIU-UHFFFAOYSA-N 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- AVAWMINJNRAQFS-UHFFFAOYSA-N n,n-dimethylpyrrolidin-3-amine Chemical compound CN(C)C1CCNC1 AVAWMINJNRAQFS-UHFFFAOYSA-N 0.000 description 1
- FMASTMURQSHELY-UHFFFAOYSA-N n-(4-fluoro-2-methylphenyl)-3-methyl-n-[(2-methyl-1h-indol-4-yl)methyl]pyridine-4-carboxamide Chemical compound C1=CC=C2NC(C)=CC2=C1CN(C=1C(=CC(F)=CC=1)C)C(=O)C1=CC=NC=C1C FMASTMURQSHELY-UHFFFAOYSA-N 0.000 description 1
- UYFBSIJFMJLIAZ-UHFFFAOYSA-N n-(cyclopropylmethyl)aniline Chemical compound C1CC1CNC1=CC=CC=C1 UYFBSIJFMJLIAZ-UHFFFAOYSA-N 0.000 description 1
- FTNFEHXDETWERN-UHFFFAOYSA-N n-[bis(aziridin-1-yl)phosphoryl]-2,6-dimethyl-5-[(4-propan-2-yloxyphenyl)methyl]pyrimidin-4-amine Chemical compound C1=CC(OC(C)C)=CC=C1CC1=C(C)N=C(C)N=C1NP(=O)(N1CC1)N1CC1 FTNFEHXDETWERN-UHFFFAOYSA-N 0.000 description 1
- XHXVAJHZTIXQQD-UHFFFAOYSA-N n-[bis(aziridin-1-yl)phosphoryl]-5-[(4-butoxyphenyl)methyl]-2,6-dimethylpyrimidin-4-amine Chemical compound C1=CC(OCCCC)=CC=C1CC1=C(C)N=C(C)N=C1NP(=O)(N1CC1)N1CC1 XHXVAJHZTIXQQD-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000006772 olefination reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- LMYJGUNNJIDROI-UHFFFAOYSA-N oxan-4-ol Chemical compound OC1CCOCC1 LMYJGUNNJIDROI-UHFFFAOYSA-N 0.000 description 1
- IPBPLHNLRKRLPJ-UHFFFAOYSA-N oxan-4-ylmethanamine Chemical compound NCC1CCOCC1 IPBPLHNLRKRLPJ-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- PCPUMGYALMOCHF-UHFFFAOYSA-N oxolan-3-ylmethanol Chemical compound OCC1CCOC1 PCPUMGYALMOCHF-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000036186 satiety Effects 0.000 description 1
- 235000019627 satiety Nutrition 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- YFAIGPGRLHDLKU-UHFFFAOYSA-N tert-butyl n-(6-bromopyridin-2-yl)-n-propan-2-ylcarbamate Chemical compound CC(C)(C)OC(=O)N(C(C)C)C1=CC=CC(Br)=N1 YFAIGPGRLHDLKU-UHFFFAOYSA-N 0.000 description 1
- ZPOIEEISPMGDRW-UHFFFAOYSA-N tert-butyl n-(cyclopropylmethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC1CC1 ZPOIEEISPMGDRW-UHFFFAOYSA-N 0.000 description 1
- UQCWXKSHRQJGPH-UHFFFAOYSA-M tetrabutylazanium;fluoride;hydrate Chemical compound O.[F-].CCCC[N+](CCCC)(CCCC)CCCC UQCWXKSHRQJGPH-UHFFFAOYSA-M 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- HHBXWXJLQYJJBW-UHFFFAOYSA-M triphenyl(propan-2-yl)phosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C(C)C)C1=CC=CC=C1 HHBXWXJLQYJJBW-UHFFFAOYSA-M 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/53—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
- C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/12—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Child & Adolescent Psychology (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Metal-Oxide And Bipolar Metal-Oxide Semiconductor Integrated Circuits (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及式1的的联芳基衍生物、制备它们的方法、包含它们的药物组合物及其用途。由于在巨噬细胞、脂肪细胞等中的抗炎作用,本发明的式1的联芳基衍生物在胃肠道中促进GLP‑1形成并且在肝中或在肌肉中改善胰岛素抵抗,并因此可以有效地用于预防或治疗糖尿病、糖尿病并发症、肥胖症、非酒精性脂肪肝、脂肪性肝炎、骨质疏松症或炎症。
Description
技术领域
本发明涉及作为GPR120激动剂的新联芳基衍生物、制备它们的方法、包含它们作为活性组分的药物组合物及其用途。本文中GPR120激动剂是指一种化合物,其通过在胃肠道和抗炎作用中促进GLP-1可以有效地用于预防或治疗糖尿病、糖尿病并发症、肥胖症、非酒精性脂肪肝、脂肪性肝炎、骨质疏松症或炎症。
背景技术
糖尿病分为两种类型─即胰岛素依赖的1型糖尿病和非胰岛素依赖的(胰岛素抗性的)2型糖尿病,90%或更多的糖尿病患者是2型糖尿病。
被注意到可能用于治疗2型糖尿病的GPR120激动剂已知具有(1)由在肠细胞内增加肠降血糖素激素的作用导致的抗糖尿病效果,(2)在巨噬细胞中的抗炎作用,和(3)改善脂细胞中胰岛素抵抗的作用。还已知它们可能治疗1型糖尿病,这是因为它们通过抗炎作用改善胰腺细胞增殖。
G蛋白-偶联受体120(GPR120)丰富地表达于肠、肺、脂肪组织和诱导炎症的巨噬细胞,并通过长链游离脂肪酸(FFA)被激活。GPR120通过FFA刺激胰高血糖素样肽-1(GLP-1)的分泌。已知GLP-1(肠降血糖素激素)取决于血糖水平刺激胰腺中胰岛素的分泌,并且还具有改善胰岛素抵抗、β细胞增殖、食欲不振和饱腹感的增加的作用。近来,已知GPR120与改善胰岛素抵抗和抗炎作用相关,因此,它被认为是用于开发药物以有效改善胰岛素抵抗、2型糖尿病和涉及低水平慢性炎症的肥胖症的靶标。另外,在1型糖尿病的动物实验中,GPR120激动剂被报道为通过β细胞的增殖作用改善胰岛素的分泌。
因为GPR120还具有抗炎作用,所以它们也被报道为可能治疗与炎症相关的疾病─例如,脂肪性肝炎、类风湿关节炎等。
考虑到上述情况,对GPR120激动剂的研究在积极进行中。在提出作为GPR120激动剂的代表性化合物中,两个芳基基团通过中心桥结构连接,并且特征在于两个芳基基团之一被羧酸取代。GPR120激动剂化合物公开在WO2011/159297、WO2010/080537、WO2010/104195、WO2010/048207、WO2009/147990、WO2008/066131、WO2008/103500和WO2008/139879中。
发明公开
技术问题
本发明的目的是提供作为GPR120激动剂的新联芳基衍生物。
本发明的另一个目的是提供用于制备所述联芳基衍生物的方法。
本发明的仍然另一个目的是提供用于预防和治疗糖尿病、糖尿病并发症、肥胖症、非酒精性脂肪肝、脂肪性肝炎、骨质疏松症或炎症的药物组合物和用于制备所述组合物的方法,所述药物组合物包含作为活性组分的所述联芳基衍生物。
本发明的仍然另一个目的是提供预防和治疗糖尿病、糖尿病并发症、肥胖症、非酒精性脂肪肝、脂肪性肝炎、骨质疏松症或炎症的方法,所述方法使用所述联芳基衍生物作为活性组分。
解决问题的方案
因此,本发明提供式1的联芳基衍生物或其药学上可接受的盐或异构体:
[式1]
其中,
A和B独立地表示苯基或吡啶,
R1-D-和R2-E-中的任意一个可以不存在,D和E独立地表示碳、氮、氧或硫,或表示直接键,且R1和R2中的任意一个可以不存在,或R1和R2独立地表示氢、卤素、任选取代的C1-C6-烷基、C3-C10-环烷基、C2-C6-烯基、C2-C6-炔基、C3-C10-杂环烷基、C1-C6-烷基-C3-C10-环烷基、C1-C6-烷基-C3-C10-杂环烷基、芳基、C1-C6-烷基芳基、杂芳基或C1-C6-烷基-C5-C6-杂芳基,并且当D和E表示氮或碳时,R1和R2可以表示两个或三个任选取代的C1-C6-烷基、C3-C10-环烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-烷基-C3-C10-环烷基、芳基或C1-C6-烷基芳基,其可以相同或不同,
G表示-J-(CR5R6)p,其中J表示氧或硫,R5和R6独立地表示氢、卤素、任选取代的烷基或环烷基、羟基或胺,并在相同或不同碳上被取代的R5和R6可以连接以形成任选取代的环烷基或环杂烷基,
R3和R4不能独立地存在,这取决于m或n的数目,或独立地表示氢、卤素或任选取代的C1-C6-烷基或C1-C6-烷氧基,
R7表示氢、烷基或环烷基,
m和n独立地表示0-5的整数,且
p表示1-6的整数。
本发明的式1的化合物可以形成药学上可接受的盐,其包括酸-加成盐,其由无机酸如盐酸、硫酸、硝酸、磷酸、氢溴酸和氢碘酸;有机酸如酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡糖酸、苯甲酸、乳酸、富马酸、马来酸和水杨酸;或磺酸如甲磺酸、乙磺酸、苯磺酸和对甲苯磺酸形成,其形成包含药学上可接受的阴离子的非-毒性酸加成盐。例如,药学上可接受的羧酸盐包括与碱金属或碱土金属如锂、钠、钾、钙和镁形成的盐;与氨基酸如赖氨酸、精氨酸和胍形成的盐;有机盐如二环己基胺、N-甲基-D-葡糖胺、三(羟基甲基)甲胺、二乙醇胺、胆碱和三乙胺。通过常规方法可以将本发明的式1的化合物转化为它们的盐。
此外,因为本发明的式1的化合物可以具有非对称碳中心和非对称轴或平面,它们可以以E-或Z-异构体、R-或S-异构体、外消旋混合物或非对映异构体混合物和各个非对映异构体存在,它们全部在本发明范围内。
本文中除非另外指定,术语“式1的化合物”用于表示式1的所有化合物,包括其药学上可接受的盐和异构体。
本文中使用的术语定义如下。
卤素或卤代是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
烷基是指直链或支链的烃,并优选C1-C6-烷基。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、乙炔、乙烯基、三氟甲基等。
环烷基是指部分或完全饱和的单或稠合环烃,并优选C3-C10-环烷基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环己烯基等。
芳基是指芳族烃,优选C5-C10-芳基,并且包括但不限于苯基、萘基等。
杂芳基是指芳族烃,其形成包含至少一个选自N、O和S的杂原子的单或稠合环,并优选C3-C9-杂芳基。杂芳基的实例包括但不限于吡啶基、嘧啶基、哒嗪基、噁二唑基、异噁二唑基(isoxadiazolyl)、四唑基、三唑基、吲哚基、异噁唑基、噁唑基、噻唑基、咪唑基、噻吩基、苯并噻唑、苯并咪唑、1,2,3,4-四氢异喹啉基、噻唑并吡啶基等。
杂环基是指部分或完全饱和的烃,其形成包含至少一个选自N、O和S的杂原子的单或稠合环,并优选C3-C10-杂环基。杂环基的实例包括但不限于吡咯烷基、哌啶基、吗啉基、咪唑啉基、哌嗪基、四氢呋喃、四氢噻喃等。
芳基烷基和杂芳基烷基是指通过结合上述芳基与烷基或者杂芳基与烷基而形成的基团。实例包括但不限于苄基、噻吩甲基、嘧啶甲基等。
上述的胺、烷基、环烷基、芳基、杂芳基、杂环基、芳基烷基和杂芳基烷基可以被至少一个选自以下组的基团取代:烷基、环烷基、杂环基、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基烷基、氧代、氰基、卤素、硝基、-OR、-OC(O)R、-OC(O)OR、SR、-S(O)R、-S(O)2R、-C(O)R、-C(O)OR、-C(S)R、-C(O)NRR、-NR2、-NRCHO、-NRC(O)R、-NRC(O)NRR、-C(S)NRR、-NRC(S)R和-NRC(S)NRR,其中R独立地选自氢、烷基、环烷基、杂环基、芳基、杂芳基、芳基烷基和杂芳基烷基,并且当两个R被取代时,它们可以连接以形成环烷基或杂环基。
根据本发明的代表性的式1化合物包括、但不限于以下的化合物:
4-[4-(6-苯氧基-2-吡啶基)苯氧基]丁酸;
4-[2,6-二氟-4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸;
4-[2,6-二氟-4-(6-苯氧基-2-吡啶基)苯氧基]丁酸;
4-[2-氯-4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸;
4-[2-氟-4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸;
4-[4-(6-环戊基硫基-2-吡啶基)-2,6-二氟-苯氧基]丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-2-甲氧基-苯氧基]-丁酸;
4-[2,6-二氟-4-(2-异丙基硫基-4-吡啶基)苯氧基]丁酸;
4-[4-[6-(环戊氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二甲基-苯氧基]-丁酸;
4-[4-[3-(环戊氧基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-(6-吡咯烷-1-基-2-吡啶基)苯氧基]丁酸;
4-[4-(2-仲丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-[3-(环戊氧基)苯基]-2,3-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[6-(1-哌啶基)-2-吡啶基]苯氧基]丁酸;
4-[4-(6-苯胺基-2-吡啶基)-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[6-(N-甲基苯胺基)-2-吡啶基]苯氧基]丁酸;
4-[4-[6-(环戊基氨基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-[6-(环丙基甲基硫基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-(6-环丁基硫基-2-吡啶基)-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-(6-丙基硫基-2-吡啶基)苯氧基]丁酸;
4-[2,6-二氟-4-(6-异丙氧基-2-吡啶基)苯氧基]丁酸;
4-[2,6-二氟-4-(6-丙氧基-2-吡啶基)苯氧基]丁酸;
4-[4-[6-(环丙基甲氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-[6-(环丁氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-[6-(环丁氧基)-2-吡啶基]-2-甲基-苯氧基]丁酸;
4-[4-[6-(环丁氧基)-2-吡啶基]-2-(三氟甲基)苯氧基]丁酸;
4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸;
4-[4-[6-(环丁氧基)-2-吡啶基]-2,6-二氟-苯氧基]戊酸;
4-[[5-(2-环丁基硫基-3-吡啶基)-2-吡啶基]氧基]戊酸;
4-{2,6-二氟-4-[2-(3-甲基-丁基硫基)-吡啶-3-基]-苯氧基}-丁酸;
4-{2,6-二氟-4-[2-(2-氟-乙氧基)-吡啶-3-基]-苯氧基}-丁酸;
2-[1-[[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]甲基]环丙基]乙酸;
2-[1-[[4-[3-(环丁氧基)苯基]-2,6-二氟-苯氧基]甲基]环丙基]乙酸;
4-[[6-[3-(环丁氧基)苯基]-3-吡啶基]氧基]丁酸;
4-[[6-[3-(环戊氧基)苯基]-3-吡啶基]氧基]丁酸;
4-(2'-苯氧基-联苯-4-基氧基)-丁酸;
4-[4-(2-异丙基硫基-吡啶-3-基)-苯氧基]-丁酸;
4-(3,5-二氟-2'-苯氧基-联苯-4-基氧基)-丁酸;
4-[4-(2-环戊基硫基-吡啶-3-基)-苯氧基]-丁酸;
4-[2,6-二氟-4-(2-异丙基硫基-吡啶-3-基)-苯氧基]-丁酸;
4-[2,6-二氟-4-(2-苯氧基-吡啶-3-基)-苯氧基]-丁酸;
4-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯氧基]-丁酸;
4-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-环丙基甲氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-环丙基甲基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-苯氧基]-丁酸;
4-[4-(2-环丙基甲基硫基-吡啶-3-基)-苯氧基]-丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-丙基硫基-吡啶-3-基)-苯氧基]-丁酸;
4-(3,5-二氟-2'-异丙氧基-联苯-4-基氧基)-丁酸;
4-(2'-环丁氧基-3,5-二氟-联苯-4-基氧基)-丁酸;
4-(2'-环丙基甲氧基-3,5-二氟-联苯-4-基氧基)-丁酸;
4-(2'-环戊基氧基-3,5-二氟-联苯-4-基氧基)-丁酸;
4-(2'-环戊基氧基-联苯-4-基氧基)-丁酸;
4-(2'-异丙氧基-联苯-4-基氧基)-丁酸;
4-(2'-环丙基甲氧基-联苯-4-基氧基)-丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-2-甲基-丁酸;
2-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基甲基]-环丙烷甲酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-2,5-二氟-苯氧基]-丁酸;
4-[4-(6-环丁基硫基-吡啶-2-基)-2,5-二氟-苯氧基]-丁酸;
4-[4-(2-叔丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
6-[2,6-二氟-4-(2-丙基硫基-3-吡啶基)苯氧基]己酸;
4-{2,6-二氟-4-[6-(2-甲基-丙烯基)-吡啶-2-基]-苯氧基}-丁酸;
4-[2,6-二氟-4-(6-异丁基-吡啶-2-基)-苯氧基]-丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-3,5-二氟-苯氧基]-丁酸;
4-{2,6-二氟-4-[2-(四氢-吡喃-4-基氧基)-吡啶-3-基]-苯氧基}-丁酸;
4-{2,6-二氟-4-[2-(四氢-呋喃-3-基氧基)-吡啶-3-基]-苯氧基}-丁酸;
4-[4-(2-环丁氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-{2,6-二氟-4-[2-(2-甲氧基-乙氧基)-吡啶-3-基]-苯氧基}-丁酸;
4-[2,6-二氟-4-(2-吡咯烷-1-基-3-吡啶基)苯氧基]丁酸;
4-[4-[2-(环戊基氨基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-[2-(环丙基甲基氨基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-[6-(环丙基甲基氨基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[2-(异丙基氨基)-3-吡啶基]苯氧基]丁酸;
4-[4-[2-(环丙基氨基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[6-(异丙基氨基)-2-吡啶基]苯氧基]丁酸;
4-[4-[2-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-[3-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[2-(丙基氨基)苯基]苯氧基]丁酸;
4-[4-[2-(环丙基甲基氨基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[2-(异丙基氨基)苯基]苯氧基]丁酸;
4-[4-[2-(环戊基氨基)苯基]苯氧基]丁酸;
4-[4-[2-(环丙基甲基氨基)苯基]苯氧基]丁酸;
4-[4-[2-(丙基氨基)苯基]苯氧基]丁酸;
4-[4-[2-(异丙基氨基)苯基]苯氧基]丁酸;
4-[4-[2-(环丁基氨基)苯基]苯氧基]丁酸;
4-[4-[2-(环丁基氨基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-[3-(环丙基甲基氨基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[3-(异丙基氨基)苯基]苯氧基]丁酸;
4-[2,6-二氟-4-(3-吡咯烷-1-基苯基)苯氧基]丁酸;
4-[4-[3-(环丁基氨基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[3-(丙基氨基)苯基]苯氧基]丁酸;
4-[4-[5-氯-2-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-[2-(环戊基氨基)-5-氟-苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-(3-环戊基苯基)-2,6-二氟-苯氧基]丁酸;
4-[4-[3-(环戊基甲基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-[2-(环戊基甲基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-[6-(环戊基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-[2-(环丁基甲基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-[3-(环丁基甲基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-[6-(环丁基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-(2-环戊基苯基)-2,6-二氟-苯氧基]丁酸;
4-[4-(6-环戊基-2-吡啶基)-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-(2-异丁基-3-吡啶基)苯氧基]丁酸;
4-[4-(2-环戊基-3-吡啶基)-2,6-二氟-苯氧基]丁酸;
4-[4-[2-(环戊基甲基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-(2-吡咯-1-基-3-吡啶基)苯氧基]丁酸;
4-[2,6-二氟-4-[2-(4-甲基吡唑-1-基)-3-吡啶基]苯氧基]丁酸;
4-[2,6-二氟-4-(2-吗啉代-3-吡啶基)苯氧基]丁酸;
4-[2,6-二氟-4-[2-(四氢吡喃-4-基甲基氨基)-3-吡啶基]苯氧基]丁酸;
4-[2,6-二氟-4-[2-(1-哌啶基)-3-吡啶基]苯氧基]丁酸;
(4S)-4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸;
(4R)-4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸;
(4R)-4-[4-[3-(环丁氧基)苯基]-2,6-二氟-苯氧基]戊酸;
(4R)-4-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸;
(4R)-4-[2,6-二氟-4-(3-苯氧基苯基)苯氧基]戊酸;
4-(3'-环丁氧基-联苯-4-基硫基)-丁酸;
4-(3'-异丙氧基-联苯-4-基硫基)-丁酸;
[1-(3,5-二氟-3'-异丙氧基-联苯-4-基硫基甲基)-环丙基]-乙酸;
4-(3'-环戊基氧基-3,5-二氟-联苯-4-基硫基)-丁酸;
4-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(2-环丙基甲氧基-吡啶-3-基)-苯基硫基]-丁酸;
4-(3'-苯氧基-联苯-4-基硫基)-丁酸;
4-(3'-环戊基氧基-联苯-4-基硫基)-丁酸;
4-(3'-丙氧基-联苯-4-基硫基)-丁酸;
4-[4-(6-环丁氧基-吡啶-2-基)-苯基硫基]-丁酸;
4-[4-(6-环戊基氧基-吡啶-2-基)-苯基硫基]-丁酸;
4-[4-(6-异丙氧基-吡啶-2-基)-苯基硫基]-丁酸;
4-[4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(6-丙氧基-吡啶-2-基)-苯基硫基]-丁酸;
4-[4-(6-环戊基硫基-吡啶-2-基)-苯基硫基]-丁酸;
4-(3'-环丁氧基-3,5-二氟-联苯-4-基硫基)-丁酸;
4-(3,5-二氟-3'-异丙氧基-联苯-4-基硫基)-丁酸;
4-[2,6-二氟-4-(6-丙氧基-吡啶-2-基)-苯基硫基]-丁酸;
4-[2,6-二氟-4-(6-异丙氧基-吡啶-2-基)-苯基硫基]-丁酸;
4-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-丁酸;
4-[2,6-二氟-4-(2-丙氧基-吡啶-3-基)-苯基硫基]-丁酸;
4-[2,6-二氟-4-(6-异丙基硫基-吡啶-2-基)-苯基硫基]-丁酸;
4-[2,6-二氟-4-(6-丙基硫基-吡啶-2-基)-苯基硫基]-丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(2-环丁氧基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(2-环丁氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[2,6-二氟-4-(2-异丙基硫基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(2-异丙基硫基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(2-环戊基硫基-吡啶-3-基)-苯基硫基]-丁酸;
4-[2-氟-4-(6-异丙氧基-吡啶-2-基)-苯基硫基]-丁酸;
4-[4-(2-环戊基氧基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(6-环丁氧基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(6-环戊基氧基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(6-环丁基硫基-吡啶-2-基)-苯基硫基]-丁酸;
4-[4-(6-环丙基甲氧基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(6-环丁基硫基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(6-环戊基硫基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸;
4-(2'-环戊基氨基-3-氟-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氨基-3,5-二氟-联苯-4-基硫基)-丁酸;
4-[2'-(环丙基甲基-氨基)-3,5-二氟-联苯-4-基硫基]-丁酸;
4-[2-氟-4-(2-异丙基硫基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(2-环戊基硫基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-(3,5-二氟-2'-异丙基氨基-联苯-4-基硫基)-丁酸;
4-(3,5-二氟-2'-丙基氨基-联苯-4-基硫基)-丁酸;
4-[4-(2-环丙基甲氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(6-环丁基硫基-吡啶-2-基)-2-氟-苯基硫基]-丁酸;
4-[4-(2-环戊基氨基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-[2-氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(2-环丁氧基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-[2-氟-4-(2-吡咯烷-1-基-吡啶-3-基)-苯基硫基]-丁酸;
4-[2-氟-4-(2-异丙基氨基-吡啶-3-基)-苯基硫基]-丁酸;
4-(2'-环戊基氨基-3,5'-二氟-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氨基-5'-氟-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-5'-甲基-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-4'-甲氧基-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-5'-氟-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-3,5'-二氟-联苯-4-基硫基)-丁酸;
4-[4-(2-环戊基氧基-5-甲基-吡啶-3-基)-苯基硫基]-丁酸;
4-(2'-环戊基氧基-3,5,5'-三氟-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-3-氟-4'-甲氧基-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-3,5-二氟-4'-甲氧基-联苯-4-基硫基)-丁酸;
4-(3-氟-2'-异丙氧基-4'-甲氧基-联苯-4-基硫基)-丁酸;
4-[4-(2-环戊基氧基-5-甲基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-[2-氟-4-(2-异丙氧基-5-甲基-吡啶-3-基)-苯基硫基]-丁酸;
4-(3,5'-二氟-2'-异丙氧基-联苯-4-基硫基)-丁酸;
4-[4-(2-环戊基氧基-6-甲基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-(3,3'-二氟-2'-异丙氧基-5'-甲基-联苯-4-基硫基)-丁酸;
4-(3,3'-二氟-5'-甲基-2'-丙氧基-联苯-4-基硫基)-丁酸;
4-(3-氟-2',4'-二丙氧基-联苯-4-基硫基)-丁酸;
4-(6'-环戊基氧基-3,2'-二氟-3'-甲基-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-3,3'-二氟-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-3,3'-二氟-5'-甲基-联苯-4-基硫基)-丁酸;
5-[4-(2-环丁基甲氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸;
5-[4-(2-环丙氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸;
4-[4-(2-环戊基氧基-5-甲基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-戊酸;
4-[4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊酸;
4-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸;
4-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸;
4-[4-[2-(2-二甲基氨基乙基氧基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯氧基]-丁酸;
4-[4-(2-环丙基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-乙基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-(2'-环戊基氨基-联苯-4-基硫基)-丁酸;
4-[4-(2-环戊基氧基-5-甲基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸;
4-[2,6-二氟-4-(3-苯氧基苯基)苯氧基]丁酸;
4-[4-[6-[3-(二甲基氨基)吡咯烷-1-基]-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
5-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯氧基]-戊酸;
5-[4-(2-环丁氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸;
4-[4-[2-(3,3-二氟吡咯烷-1-基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[2-(4-甲基哌嗪-1-基)-3-吡啶基]苯氧基]丁酸;
4-[2,6-二氟-4-[2-(5-甲基异噁唑-3-基)氧基-3-吡啶基]苯氧基]丁酸;
4-[4-[2-[2-(氮杂环丙烷-1-基)乙氧基]-3-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[2-(3-呋喃基甲氧基)-3-吡啶基]苯氧基]丁酸;
4-[2,6-二氟-4-[2-(2-呋喃基甲氧基)-3-吡啶基]苯氧基]丁酸;
4-[2,6-二氟-4-[2-[(3-甲基氧杂环丁烷-3-基)甲氧基]-3-吡啶基]苯氧基]丁酸;
4-[2,6-二氟-4-[2-(四氢呋喃-3-基甲氧基)-3-吡啶基]苯氧基]丁酸;
4-[2,6-二氟-4-[2-(四氢呋喃-2-基甲氧基)-3-吡啶基]苯氧基]丁酸;
4-[4-(2-环丁基甲氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-环丙氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-(4-{2-[3-(叔丁基-二甲基-甲硅烷氧基)-环戊基氧基]-吡啶-3-基}-2,6-二氟-苯氧基)-丁酸;
4-{2,6-二氟-4-[2-(3-羟基-环戊基氧基)-吡啶-3-基]-苯氧基}-丁酸;
4-[4-(2-环己基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-环戊基甲氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[2,6-二氟-4-(2-异丁氧基-吡啶-3-基)-苯氧基]-丁酸;
4-{4-[2-(2,2-二甲基-丙氧基)-吡啶-3-基]-2,6-二氟-苯氧基}-丁酸;
5-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸;
5-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸;
5-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸;
5-[2,6-二氟-4-(2-异丙基硫基-3-吡啶基)苯氧基]戊酸;
5-[2,6-二氟-4-(2-丙基硫基-3-吡啶基)苯氧基]戊酸;
5-[2,6-二氟-4-(6-异丙基硫基-2-吡啶基)苯氧基]戊酸;
5-[2,6-二氟-4-(6-异丙氧基-2-吡啶基)苯氧基]戊酸;
5-[4-[2-(环丙基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]戊酸;
5-[2,6-二氟-4-(2-四氢呋喃-3-基氧基-3-吡啶基)苯氧基]戊酸;
5-[2,6-二氟-4-(2-四氢吡喃-4-基氧基-3-吡啶基)苯氧基]戊酸;
4-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊酸;
4-[4-(2-环戊基硫基-吡啶-3-基)-苯基硫基]-戊酸;
4-{2-氟-4-[2-(四氢-吡喃-4-基氧基)-吡啶-3-基]-苯基硫基}-丁酸;
4-{2-氟-4-[2-(四氢呋喃-3-基氧基)-吡啶-3-基]-苯基硫基}-丁酸;
4-[4-(2-环丁基甲氧基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-{2,6-二氟-4-[2-(2,2,2-三氟-乙氧基)-吡啶-3-基]-苯基硫基}-丁酸;
4-[4-(2-环丁基甲氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(2-环戊基氨基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[2,6-二氟-4-(2-异丙基氨基-吡啶-3-基)-苯基硫基]-丁酸;
4-{4-[2-(环丙基甲基-氨基)-吡啶-3-基]-2,6-二氟-苯基硫基}-丁酸;
5-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸;
5-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊酸;
5-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-戊酸;
5-[4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊酸;
5-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸;
5-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯基硫基]-戊酸;
5-[4-(2-环戊基硫基-吡啶-3-基)-苯基硫基]-戊酸;
5-[4-(2-环丁基硫基-吡啶-3-基)-苯基硫基]-戊酸;
5-[4-(2-环丁基甲氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸;
5-[4-(2-环丁氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸;
6-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-己酸;
7-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-庚酸;
5-[2-氟-4-(2-异丙氧基-吡啶-3-基)-苯氧基]-戊酸;
5-[4-(2-环戊基硫基-吡啶-3-基)-2-氟-苯氧基]-戊酸;
5-[4-(2-环丁基硫基-吡啶-3-基)-2-氟-苯氧基]-戊酸;
5-[4-(2-环戊基氧基-吡啶-3-基)-2-氟-苯氧基]-戊酸;
4-[2,6-二氟-4-(2-甲氧基-吡啶-3-基)-苯氧基]-丁酸;
4-[4-(2-烯丙基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-丁-2-炔基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
6-[4-[2-(环丁氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸;
6-[4-[2-(环丁基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸;
6-[4-[2-(环丙基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸;
6-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]己酸;
6-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]己酸;
6-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-己酸;
6-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-己酸;
6-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-己酸;和
6-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯基硫基]-己酸。
除非另外指出,本文中所使用的术语和缩写保留它们的原始含义。
本发明还提供制备式1的化合物的方法。在下文中为了说明本发明,基于示例性反应解释制备式1的化合物的方法。然而,本领域技术人员能够基于式1的结构通过不同的方法制备式1的化合物,并且这样的方法应被解释为在本发明的范围之内。即,式1的化合物可以通过本文中所描述的方法或通过组合现有技术中公开的不同方法来制备,其应被解释为在本发明的范围之内。因此,制备式1的化合物的方法并不限定于下面的方法。
如在以下的反应方案1中所表示的,本发明的式1的化合物可以通过化合物2和化合物3在常规金属催化剂存在下的C-C偶合反应,以及如果必要的话,另外的水解来制备。
[反应方案1]
此外,如在以下的反应方案2中所表示的,本发明的式1的化合物可以通过化合物4和化合物5、化合物6或化合物7在常规的碱或偶合剂存在下的偶合反应,以及如果必要的话,另外的水解来制备。在反应方案2中,化合物4和7的Z-R7和J独立地表示卤素、OH、SH或O-烷基。当Z-R7是O-烷基时,其通过脱烷基化反应被转化为OH,之后进行偶合反应。
[反应方案2]
如在以下的反应方案3中所表示的,具有不同取代基的式1的化合物还可以通过一系列的反应步骤来制备。具体地,可以通过使用常规的还原剂将式I的化合物还原为化合物I-1,并且可以通过使用氧化剂将化合物I-1氧化为醛化合物(化合物I-2)。可以通过使用常规的烯化反应如HWE(霍纳尔-沃兹沃思-埃蒙斯(Horner-Wadsworth-Emmons))反应制备化合物I-3。化合物I-3可以经还原和水解转化为具有不同取代基的式I的化合物
[反应方案3]
如在以下的反应方案4中所表示的,本发明的式1的化合物可以通过使被J基团取代的化合物8与化合物9或化合物10在常规的碱、金属催化剂或偶合剂存在下反应来制备。在反应方案4中,J和Y独立地表示卤素、OH、SH或NH2。当J是胺时,可以进行化合物8和化合物11之间的“还原-氨基化反应”。
[反应方案4]
如在以下的反应方案5中所表示的,在上述反应方案1中,化合物3可以通过化合物12和化合物5、化合物6或化合物7在常规的碱或偶合剂存在下的偶合反应来制备。在反应方案5中,J和Z-R7如在上述反应方案2中所定义。
[反应方案5]
如在以下的反应方案6中所表示的,在上述反应方案2中,化合物4可以通过化合物2和化合物12在常规的偶合剂如金属催化剂存在下的偶合反应来制备。
[反应方案6]
在上述反应方案1-6中,
X表示卤素、硼酸或-OSO2CF3,
Y表示硼酸、卤素或硼酸酯,且
A、B、D、E、G、R1、R2、R3、R4、R7、m、n和p如在式1的化合物的定义中所描述。
在上述反应中,过渡金属如钯(Pd)可以用作常规的金属催化剂。上述反应可以在对反应不具有不利影响的常规溶剂中进行。优选的溶剂包括但不限于二甲基甲酰胺、二甲基乙酰胺、四氢呋喃、乙腈、甲醇、乙醇、水、1,2-二氯乙烷、二甲亚砜、乙醚、甲基叔丁基醚、二氯甲烷、氯仿及其混合物。
在上述反应中,未加以解释的化合物是已知化合物或容易从已知化合物通过已知方法或类似方法得到的化合物。
通过上述方法得到的式1的化合物可以通过常规方法如重结晶、离子电泳(ionospheresis)、硅胶柱色谱法或离子-交换色谱法从反应产物中分离或纯化。
如上所述,本发明的化合物、原料或用于制备它们的中间体可以通过多种方法制备,所述方法应被解释为在本发明的范围之内。
本发明的式1的化合物具有GPR120激动剂作用。因此本发明提供作为GPR120激动剂的药物组合物,所述药物组合物包含作为活性组分的式1的化合物、其药学上可接受的盐或异构体。在体内转化为式I的化合物的各种前药也在本发明的范围之内。
可以被本发明的作为GPR120激动剂的药物组合物预防或治疗的示例性疾病包括但不限于代谢紊乱如糖尿病、糖尿病并发症、肥胖症、非酒精性脂肪肝、脂肪性肝炎、骨质疏松症和炎症。
此外,本发明提供制备用于预防或治疗代谢紊乱如糖尿病、糖尿病并发症、肥胖症、非酒精性脂肪肝、脂肪性肝炎、骨质疏松症或炎症的组合物的方法,所述方法包括混合作为活性组分的式1的化合物、其药学上可接受的盐或异构体与药学上可接受的载体的步骤。
根据本发明,“药物组合物”或“用于降低血糖水平的组合物”除了本发明的活性组分之外还可以包含其他组分如载体、稀释剂、赋形剂等。因此,如果必要,所述药物组合物可以包含药学上可接受的载体、稀释剂、赋形剂或其组合。所述药物组合物有利于将化合物施用到体内。施用化合物的各种方法包括但不限于口服、注射、气溶胶、肠胃外和局部施用。
在本文中,“载体”是指有利于将化合物加入到细胞或组织中的化合物。例如,二甲亚砜(DMSO)是有利于将多种有机化合物施用到活细胞或组织中的常规的载体。
在本文中,“稀释剂”是指不仅稳定生物活性形式而且被稀释在溶解化合物的溶剂中的化合物。在这一领域中,在缓冲剂中溶解的盐用作稀释剂。常规使用的缓冲剂是模拟体液中盐形式的磷酸盐缓冲盐水。因为缓冲溶液可以在低浓度控制溶液的pH,缓冲稀释剂几乎不改变化合物的生物活性。
在本文中,“药学上可接受的”是指这样的性质,即不破坏化合物的生物活性和物理性质。
本发明的化合物可以配制成各种药学上施用的剂型。在本发明的药物组合物的制备中,考虑到待制备的剂型,将活性组分─具体地,式1的化合物或其药学上可接受的盐或异构体─与所选择的药学上可接受的载体混合。例如,本发明的药物组合物可以配制为所需要的注射剂、口服制剂等。
本发明的化合物可以通过常规方法使用已知的药物载体和赋形剂进行配制,并添加到单元或多-单元容器中。制剂可以是在油或含水溶剂中的溶液、混悬液或乳液并包含常规的分散剂、助悬剂或稳定剂。此外,化合物可以是例如在使用前溶于灭菌无热原水的干粉形式。本发明的化合物可以通过使用常规的栓剂基质如可可脂或其他甘油酯配制成为栓剂。用于口服施用的固体形式包括胶囊剂、片剂、丸剂、粉末剂和颗粒剂。优选胶囊剂和片剂。优选片剂和丸剂是包有肠溶衣的。固体形式通过将本发明的化合物与至少一种选自惰性稀释剂如蔗糖、乳糖或淀粉的载体、润滑剂如硬脂酸镁、崩解剂、粘合剂等混合来制备。
如果需要,本发明的化合物可以与其他药物─例如其他抗糖尿病药─组合施用。
本发明的化合物的剂量由考虑了患者体重、年龄和疾病情况的医师处方决定。根据施用的频率和强度,用于成人的典型剂量为约0.3-500mg/天。用于成人的肌内或静脉内施用的典型每日剂量为约1-300mg/天,其可以以分开的单位剂型施用。一些患者需要更高的每日剂量。
本发明还提供用于预防或治疗疾病的方法,所述方法通过使用有效量的作为GPR120激动剂的活性组分的式1的化合物或其药学上可接受的盐或异构体来进行。由GPR120激动剂治疗的代表性的疾病包括但不限于代谢紊乱如上述的糖尿病、糖尿病并发症、肥胖症、非酒精性脂肪肝、脂肪性肝炎、骨质疏松症、炎症等。在本文中,术语“治疗”用于指在表现出疾病症状的患者中阻止、延迟或改善所述疾病的进展。术语“预防”用于指在处于表现出疾病症状的风险中的患者中阻止、延迟或改善所述疾病的指征,即使所述患者还没有表现出所述症状。
发明的有利效果
本发明的式1的联芳基衍生物促进GLP-1在胃肠道中的形成并因为在巨噬细胞、脂细胞中的抗炎作用而在肝中或肌肉中改善胰岛素抵抗,并因此能够有效地用于预防或治疗代谢性疾病如糖尿病、糖尿病并发症、肥胖症、非酒精性脂肪肝、脂肪性肝炎、骨质疏松症或炎症。
发明的实施方式
本发明通过以下的实施例更详细地加以解释。然而,这些实施例仅仅是用来说明本发明,而本发明的范围不是由它们限定。
在下文中,M是指摩尔浓度,而N是指当量浓度。此外,用在以下制备和实施例中的缩写如下所示:
BBr3:三溴化硼
BINAP:2,2'-双(二苯基膦基)-1,1'-联萘
Br2:溴
CH3CN:乙腈
Cs2CO3:碳酸铯
DCM:二氯甲烷
DMF:N,N-二甲基甲酰胺
DMSO:二甲亚砜
DPPF:1,1'-双(二苯基膦基)二茂铁
EtOAc:乙酸乙酯
EtOH:乙醇
Et2O:乙醚
HCl:盐酸
Hex:正己烷
K2CO3:碳酸钾
LAH:氢化铝锂
MeOH:甲醇
MgSO4:硫酸镁
NaBH4:硼氢化钠
NaCl:氯化钠
Na2CO3:碳酸钠
NaH:氢化钠
NaOH:氢氧化钠
NBS:N-溴代琥珀酰亚胺
Pd/C:钯/碳
PdCl2(dppf)-DCM:1,1'-双(二苯基膦基)二茂铁-钯(II)二氯化物二氯甲烷
PdCl2(PPh3)2:双(三苯基膦)钯(II)二氯化物
Pd2(dba)3:三(二亚苄基丙酮)二钯(0)
Pd(PPh3)4:四(三苯基膦)钯(0)
SOCl2:亚硫酰氯
SPhos:2-二环己基膦基-2',6'-二甲氧基联苯
TBAF:氟化四丁基铵水合物
TEA:三乙胺
TFA:三氟乙酸
THF:四氢呋喃
XPhos:2-二环己基膦基-2',4',6'-三异丙基联苯
制备例1:4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯
步骤A:4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚
将4-氯苯酚(2g,15.5mmol)、双(频哪醇合)二硼(5.92g,23.3mmol)、乙酸钾(4.58g,46.6mmol)和Xphos(0.3g,0.62mmol)溶于30mL的1,4-二噁烷并将混合物充N2气5分钟。向其中添加Pd2(dba)3(0.14g,0.15mmol)并将混合物在110℃搅拌1小时。将混合物通过C盐过滤,然后通过柱色谱法纯化,得到标题化合物(3.4g,99%)。
1H NMR(CDCl3)δ7.71(2H,d),6.82(2H,d),5.00(1H,s),1.33(12H,s)。
步骤B:4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯
将从步骤A获得的4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚(0.32g,1.4mmol)溶于5mL的DMF。向其中添加K2CO3(0.39g,2.8mmol)和4-丁酸乙酯(0.22mL,1.54mmol)并将混合物在60℃搅拌1小时。将固体除去并将混合物通过柱色谱法纯化,得到标题化合物(0.38g,82%)。
1H NMR(CDCl3)δ7.73(2H,d),6.87(2H,d),4.14(2H,q),4.03(2H,t),2.51(2H,t),2.11(2H,m),1.32(12H,s),1.25(3H,t)。
制备例2:4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯
步骤A:4-溴-2,6-二氟-苯酚
将2,6-二氟苯酚(1.02g,7.8mmol)溶于15mL的DMF,并在0℃向其中添加NBS(1.40g,7.84mmol)。将反应混合物在室温搅拌24小时并浓缩。向其中添加50mL的水并将混合物用Et2O萃取。将萃取物用MgSO4干燥,得到标题化合物(1.41g,86%)。
1H NMR(CDCl3)δ7.08(2H,m),5.42(1H,brs)。
步骤B:2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚
将从步骤A获得的4-溴-2,6-二氟-苯酚(1.414g,6.76mmol)、双(频哪醇合)二硼(1.8g,7.09mmol)、乙酸钾(2.66g,27mmol)和DPPF(0.19g,0.34mmol)溶于23mL的1,4-二噁烷,并将混合物充N2气5分钟。向其中添加PdCl2(dppf)-DCM(0.27g,0.34mmol)并将混合物在80℃搅拌3小时。将混合物通过C盐过滤并通过色谱法纯化,得到标题化合物(1.366g,79%)。
1H NMR(CDCl3)δ7.33(2H,m),5.25(1H,s),1.32(12H,s)。
步骤C:4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯
将从步骤B获得的2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚(1.87g,7.3mmol)、Cs2CO3(4.76g,14.6mmol)和4-溴-丁酸乙酯(1.42g,7.3mmol)溶于24mL的DMF。将混合物在室温搅拌24小时。将固体过滤,并将滤液通过柱色谱法纯化,得到标题化合物(1.66g,61%)。
1H NMR(CDCl3)δ7.29(2H,m),4.21(2H,t),4.14(2H,q),2.56(2H,t),2.07(2H,m),1.32(12H,s),1.25(3H,t)。
制备例3:4-[2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯
步骤A:2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚
将4-溴-2-氯苯酚(2.0g,9.6mmol)、双(频哪醇合)二硼(2.81g,11mmol)、乙酸钾(3.78g,38.5mmol)和DPPF(0.27g,0.49mmol)溶于32mL的1,4-二噁烷。将混合物充N2气5分钟。向其中添加PdCl2(dppf)-DCM(0.4g,0.49mmol)并将混合物在回流下搅拌3小时。将混合物通过C盐过滤并通过色谱法纯化,得到标题化合物(1.91g,77%)。
1H NMR(CDCl3)δ7.77(1H,s),7.62(1H,dd),7.00(1H,d),5.73(1H,s),1.36(12H,s)。
步骤B:4-[2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯
将从步骤A获得的2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚(0.43g,1.7mmol),4-溴-丁酸乙酯(0.25mL,1.7mmol)和Cs2CO3(0.66g,2mmol)溶于5mL的DMF。将反应混合物在室温搅拌16小时。将混合物浓缩并通过色谱法纯化,得到标题化合物(0.47g,75%)。
1H NMR(CDCl3)δ7.79(1H,d),7.63(1H,dd),6.89(1H,d),4.15(2H,t),4.10(2H,q),2.56(2H,t),2.16(2H,m),1.33(12H,s),1.25(3H,t)。
制备例4:4-[2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯
步骤A:2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚
将4-溴-2-氟苯酚(1,9g,9.9mmol)、双(频哪醇合)二硼(2.9g,11.4mmol)、乙酸钾(3.90g,39.7mmol)和DPPF(0.27g,0.49mmol)溶于32mL的1,4-二噁烷。将混合物充N2气5分钟。向其中添加PdCl2(dppf)-DCM(0.4g,0.49mmol)并将混合物在回流下搅拌4小时。将混合物通过C盐过滤,然后通过柱色谱法纯化,得到标题化合物(2.2g,93%)。
1H NMR(CDCl3)δ7.49(2H,m),6.98(1H,t),5.31(1H,brs),1.33(12H,s)。
步骤B:4-[2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯
从步骤A获得的2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚(0.56g,2.3mmol),4-溴-丁酸乙酯(0.34mL,2.3mmol)和Cs2CO3(0.92g,2.8mmol)溶于8mL的DMF。将反应混合物在室温搅拌16小时。将混合物浓缩并通过色谱法纯化,得到标题化合物(0.52g,63%)。
1H NMR(CDCl3)δ7.49(2H,m),6.93(1H,t),4.15(2H,t),4.10(2H,q),2.53(2H,t),2.15(2H,m),1.33(12H,s),1.25(3H,t)。
制备例5:2-氯-6-环戊基硫基-吡啶
将2,6-二氯吡啶(3.08g,20.7mmol)和Cs2CO3(6.8g,20.7mmol)溶于40mL的DMF。向其中添加环戊基硫醇(2.17mL,20.7mmol)并将混合物在80℃搅拌16小时。将固体过滤并将滤液浓缩,得到标题化合物(4.24g,95%)。
1H NMR(CDCl3)δ7.40(1H,t),7.06(1H,d),6.97(1H,d),4.01(1H,m),2.22(2H,m),1.76(2H,m),1.64(4H,m)。
制备例6:4-[2-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯
将4-溴-2-甲氧基-苯酚(0.41g,2.02mmol)和4-溴-丁酸乙酯(0.39g,2.02mmol)以与制备例4的步骤B相同的方式反应,得到4-(4-溴-2-甲氧基-苯氧基)-丁酸乙酯(0.55g,86%)。
将4-(4-溴-2-甲氧基-苯氧基)-丁酸乙酯(130mg,0.41mmol)和双(频哪醇合)二硼(125mg,0.49mmol)以与制备例4的步骤A相同的方式反应,得到标题化合物(80mg,54%)。
1H NMR(CDCl3)δ7.39(1H,d),7.28(1H,s),6.88(1H,d),4.14(2H,q),4.09(2H,t),3.89(3H,s),2.52(2H,t),2.14(2H,m),1.33(12H,s),1.26(3H,t)。
制备例7:4-[4-(2-氯-4-吡啶基)-2,6-二氟-苯氧基]丁酸乙酯
将2mL的THF和0.5mL的水加入从制备例2获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.1g,0.27mmol),2-氯-4-碘吡啶(0.078g,0.32mmol)和K2CO3(0.112g,0.81mmol)。将混合物充N2气5分钟。向其中添加PdCl2(dppf)-DCM(0.011g,0.013mmol)并将混合物在80℃搅拌16小时。向其中添加水并将反应混合物用EtOAc萃取。将萃取物用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.084g,87%)。
1H NMR(CDCl3)δ8.44(1H,d),7.45(1H,d),7.33(1H,dd),7.17(2H,m),4.26(2H,t),4.17(2H,q),2.58(2H,t),2.11(2H,m),1.27(3H,t)。
制备例8:2-氯-6-(环戊氧基)吡啶
将6-氯-2-吡啶醇(1.95g,15mmol)和K2CO3(4.16g,30mmol)溶于50mL的DMF。向其中添加环戊基溴(1.94mL,18mmol)并将混合物在80℃搅拌24小时。将固体除去并将滤液浓缩,得到标题化合物(2.92g,98%)。
1H NMR(CDCl3)δ7.47(1H,t),6.84(1H,d),6.51(1H,d),5.38(1H,m),1.97(2H,m),1.79(4H,m),1.62(2H,m)。
制备例9:1-溴-3-(环戊氧基)苯
将44mL的CH3CN加入3-溴苯酚(2.31g,13.3mmol)和K2CO3(1.84g,13.3mmol),并将混合物在回流下搅拌1小时。向其中添加溴代环戊烷(1.43mL,13.3mmol)并将反应混合物在回流下搅拌16小时。将混合物通过C盐过滤,然后通过柱色谱法纯化,得到标题化合物(1.5g,46%)。
1H NMR(CDCl3)δ7.11(1H,t),7.02(2H,m),6.80(1H,dd),4.72(1H,m),1.94-1.73(6H,m),1.62(2H,m)。
制备例10:2-氯-6-吡咯烷-1-基-吡啶
将2,6-二氯吡啶(2.08g,14mmol)和吡咯烷(1.0g,14mmol)、Cs2CO3(4.58g,14mmol)溶于28mL的DMF并将混合物在80℃搅拌16小时。将混合物通过C盐过滤,在减压下浓缩并用水稀释。将混合物用EtOAc萃取并将萃取物用MgSO4干燥,得到标题化合物(2.31g,90%)。
1H NMR(CDCl3)δ7.32(1H,t),6.49(1H,d),6.20(1H,d),3.43(4H,m),1.99(4H,m)。
制备例11:4-[2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯
将4-溴-2,6-二甲基-苯酚(1.0g,4.97mmol)和4-溴-丁酸乙酯(0.97g,4.97mmol)以与制备例4的步骤B相同的方式反应,得到4-(4-溴-2,6-二甲基-苯氧基)-丁酸乙酯(1.4g,89%)。
将4-(4-溴-2,6-二甲基-苯氧基)-丁酸乙酯(200mg,0.63mmol)和双(频哪醇合)二硼(193mg,0.76mmol)以与制备例4的步骤A相同的方式反应,得到标题化合物(60mg,26%)。
1H NMR(CDCl3)δ7.47(2H,s),4.16(2H,q),3.80(2H,t),2.60(2H,t),2.25(6H,s),2.14(2H,m),1.32(12H,s),1.27(3H,t)。
制备例12:4-(4-溴-2,3-二氟-苯氧基)丁酸乙酯
将4-溴-2,3-二氟苯酚(0.45g,2mmol)溶于10mL的DMF并将溶液冷却至0℃。向其中添加NaH(60%,在矿物油中,0.11g,2.6mmol)并将混合物30分钟搅拌。向其中添加4-溴-丁酸乙酯(0.37mL,2.4mmol)并将反应混合物在室温搅拌16小时。将混合物在减压下浓缩,添加氯化铵水溶液并用EtOAc萃取。将分离的有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.533g,76%)。
1H NMR(CDCl3)δ7.19(1H,m),6.66(1H,m),4.16(2H,q),4.09(2H,t),2.52(2H,t),2.14(2H,m),1.26(3H,t)。
制备例13:4-[2,3-二氟-4-(3-羟基苯基)苯氧基]丁酸乙酯
将从制备例12获得的4-(4-溴-2,3-二氟-苯氧基)丁酸乙酯(0.108g,0.33mmol)和3-羟基苯基硼酸(0.059g,0.43mmol)溶于1.7mL的1,4-二噁烷和2M的Na2CO3水溶液(0.5mL,1mmol)。将混合物充N2气5分钟。向其中添加Pd(PPh3)4(0.019g,0.016mmol)并将反应混合物在回流下搅拌1小时。将有机层用EtOAc萃取并通过色谱法纯化,得到标题化合物(0.089g,79%)。
1H NMR(CDCl3)δ7.29(1H,t),7.06(2H,m),6.98(1H,d),6.84(1H,dd),6.78(1H,m),5.15(1H,brs),4.16(4H,m),2.56(2H,t),2.17(2H,m),1.27(3H,t)。
制备例14:2-氯-6-(1-哌啶基)吡啶
将2,6-二氯吡啶(2.0g,13.5mmol),哌啶(1.33mL,13.5mmol)和Cs2CO3(4.4g,13.5mmol)溶于27mL的DMF,并将混合物在80℃搅拌16小时。将混合物通过C盐过滤,在减压下浓缩并用水稀释。将混合物用EtOAc萃取并将萃取物通过柱色谱法纯化,得到标题化合物(1.91g,72%)。
1H NMR(CDCl3)δ7.34(1H,t),6.52(1H,d),6.47(1H,d),3.52(4H,m),1.64(6H,m)。
制备例15:6-氯-N-苯基-吡啶-2-胺
将2,6-二氯吡啶(2.0g,13.5mmol),苯胺(1.23mL,13.5mmol),BINAP(0.33g,0.53mmol)和叔丁醇钠(1.82g,18.9mmol)溶于27mL的甲苯。将混合物充N2气5分钟。向其中添加Pd2(dba)3(0.25g,0.27mmol)并将混合物在80℃搅拌3小时。将混合物通过C盐过滤,然后通过柱色谱法纯化,得到标题化合物(1.32g,48%)。
1H NMR(CDCl3)δ7.43(1H,t),7.35(2H,t),7.27(2H,m),7.10(1H,t),6.75(1H,d),6.73(1H,d),6.57(1H,brs)。
制备例16:6-氯-N-环戊基-吡啶-2-胺
将2,6-二氯吡啶(2g,13.5mmol)溶于14mL的吡啶,并向其中添加环戊胺(4mL,40.5mmol)。将反应混合物在回流下搅拌24小时。将混合物在减压下浓缩,然后通过柱色谱法纯化,得到标题化合物(1.2g,44%)。
1H NMR(CDCl3)δ7.34(1H,t),6.54(1H,d),6.25(1H,d),4.69(1H,brs),3.91(1H,m),2.01(2H,m),1.72(2H,m),1.63(2H,m),1.47(2H,m)。
制备例17:2-叔丁基硫基-6-氯-吡啶
将2,6-二氯吡啶(2.0g,13.5mmol)和Cs2CO3(8.8g,27mmol)溶于27mL的DMF。向其中添加2-甲基-2-丙硫醇(1.68mL,14.8mmol)并将混合物在80℃搅拌16小时。将固体除去并将滤液在减压下浓缩,得到标题化合物(2.4g,88%)。
1H NMR(CDCl3)δ7.42(1H,t),7.15(1H,d),7.04(1H,d),1.56(9H,s)。
制备例18:2-氯-6-(环丙基甲基硫基)吡啶
步骤A:6-氯吡啶-2-硫醇
将从制备例17获得的2-叔丁基硫基-6-氯-吡啶(1.98g,9.8mmol)溶于50mL的乙酰氯。向其中缓慢地添加分别溶于2.5mL的乙酰氯和乙酸的0.05mL(0.098mmol)的Br2。将混合物在室温搅拌4小时,在减压下浓缩并通过色谱法纯化,得到标题化合物(0.787g,55%)。
1H NMR(CDCl3)δ7.57(2H,m),7.15(1H,m)。
步骤B:2-氯-6-(环丙基甲基硫基)吡啶
将从步骤A获得的6-氯吡啶-2-硫醇(0.2g,1.3mmol)溶于4.6mL的DMF。向其中添加Cs2CO3(0.9g,2.6mmol)和(溴甲基)环丙烷(0.16mL,1.6mmol),并将反应混合物在室温搅拌16小时并进一步在70℃搅拌30分钟。将混合物在减压下浓缩并通过色谱法纯化,得到标题化合物(0.206g,75%)。
1H NMR(CDCl3)δ7.40(1H,t),7.08(1H,d),6.98(1H,d),3.12(2H,d),1.15(1H,m),0.59(2H,m),0.33(2H,m)。
制备例19:2-氯-6-环丁基硫基-吡啶
将从制备例18的步骤A获得的6-氯吡啶-2-硫醇(0.2g,1.3mmol)溶于4.6mL的DMF。向其中添加Cs2CO3(0.9g,2.6mmol)和溴代环丁烷(0.16mL,1.6mmol),并将反应混合物在室温搅拌16小时并进一步在70℃搅拌4小时。将混合物在减压下浓缩并通过色谱法纯化,得到标题化合物(0.16g,58%)。
1H NMR(CDCl3)δ7.40(1H,t),6.98(2H,m),4.30(1H,m),2.56(2H,m),2.08(4H,m)。
制备例20:2-氯-6-丙基硫基-吡啶
将从制备例18步骤A获得的6-氯吡啶-2-硫醇(0.2g,1.3mmol)溶于4.6mL的DMF。向其中添加Cs2CO3(0.9g,2.6mmol)和碘丙烷(0.16mL,1.6mmol),并将反应混合物在室温搅拌16小时并进一步在70℃搅拌30分钟。将混合物在减压下浓缩并通过色谱法纯化,得到标题化合物(0.18g,70%)。
1H NMR(CDCl3)δ7.40(1H,t),7.07(1H,d),6.97(1H,d),3.14(2H,t),1.74(2H,m),1.04(3H,t)。
制备例21:2-氯-6-异丙氧基-吡啶
将异丙醇(0.97g,16.1mmol)溶于45mL的THF并将溶液冷却至0℃。向其中添加NaH(55%,在矿物油中,0.7g,16mmol)并将混合物在室温搅拌1小时。向其中添加2,6-二氯吡啶(2.0g,13.5mmol)并将反应混合物在回流下搅拌16小时。将混合物在室温冷却,添加水(20mL),然后用EtOAc萃取。将分离的有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(1.917g,82%)。
1H NMR(CDCl3)δ7.48(1H,t),6.83(1H,d),6.58(1H,d),5.29(1H,m),1.34(6H,d)。
制备例22:2-氯-6-丙氧基-吡啶
将30mL的DMF加入6-氯-2-吡啶醇(2.0g,15mmol),1-碘丙烷(2.75g,16mmol)和K2CO3(4.27g,30mmol)并将反应混合物在80℃搅拌16小时。将混合物在减压下浓缩,添加水,然后用EtOAc萃取。将分离的有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(1.146g,43%)。
1H NMR(CDCl3)δ7.50(1H,t),6.87(1H,d),6.63(1H,d),4.24(2H,t),1.80(2H,m),1.02(3H,t)。
制备例23:2-氯-6-(环丙基甲氧基)-吡啶
将15mL的DMF加入6-氯-2-吡啶醇(1.0g,7.7mmol),K2CO3(2.13g,15.4mmol)和(溴甲基)环丙烷(1.1g,8.1mmol)并将反应混合物在80℃搅拌16小时。将混合物在减压下浓缩并通过色谱法纯化,得到标题化合物(0.65g,45%)。
1H NMR(CDCl3)δ7.50(1H,t),6.87(1H,d),6.67(1H,d),4.12(2H,d),1.26(1H,m),0.62(2H,m),0.36(2H,m)。
制备例24:2-氯-6-(环丁氧基)-吡啶
将5mL的DMF加入6-氯-2-吡啶醇(0.2g,1.5mmol),溴代环丁烷(0.26g,1.8mmol)和K2CO3(0.43g,3mmol)并将反应混合物在80℃搅拌16小时。将混合物在减压下浓缩并通过色谱法纯化,得到标题化合物(0.28g,98%)。
1H NMR(CDCl3)δ7.49(1H,t),6.86(1H,d),6.59(1H,d),5.16(1H,m),2.46(2H,m),2.13(2H,m),1.83(1H,m),1.66(1H,m)。
制备例25:4-[2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯
步骤A:4-溴-2-甲基-苯酚
将溶于4.8mL DMSO的48%HBr水溶液(4.8mL)缓慢加入溶于9.6mL乙酸的邻甲酚(1.04g,9.6mmol)。将混合物在室温搅拌16小时,然后缓慢地添加NaHCO3水溶液。将混合物用Et2O萃取并将萃取物用MgSO4干燥,得到标题化合物(1.82g,99%)。
1H NMR(DMSO-d6)δ9.62(1H,brs),7.22(1H,d),7.12(1H,dd),6.72(1H,d),2.09(3H,s)。
步骤B:2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚
将4.6mL的1,4-二噁烷加入从步骤A获得的4-溴-2-甲基-苯酚(0.26g,1.4mmol)、双(频哪醇合)二硼(0.39g,1.5mmol)和乙酸钾(0.41g,4.1mmol)。将混合物充N2气5分钟。向其中添加PdCl2(dppf)-DCM(0.057g,0.07mmol)并将混合物在回流下搅拌16小时。将固体除去并将混合物通过柱色谱法纯化,得到标题化合物(0.228g,70%)。
1H NMR(DMSO-d6)δ9.70(1H,brs),7.37(1H,d),7.32(1H,dd),6.75(1H,d),2.09(3H,s),1.25(12H,s)。
步骤C:4-[2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯
将从步骤B获得的2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚(0.228g,0.97mmol)溶于3.2mL的DMF。向其中添加Cs2CO3(0.8g,2.43mmol)和4-溴-丁酸乙酯(0.15mL,1.06mmol),并将混合物在室温搅拌16小时。将固体除去并将混合物通过柱色谱法纯化,得到标题化合物(0.268g,79%)。
1H NMR(CDCl3)δ7.60(1H,dd),7.58(1H,d),6.79(1H,d),4.13(2H,q),4.03(2H,t),2.53(2H,t),2.20(3H,s),2.15(2H,m),1.33(12H,s),1.25(3H,t)。
制备例26:4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2-(三氟甲基)苯氧基]丁酸乙酯
步骤A:4-溴-2-(三氟甲基)苯酚
将2-羟基三氟甲苯(1.0g,6.2mmol)溶于20mL的氯仿。向其中缓慢地添加Br2(0.98g,6.2mmol)并将混合物在室温搅拌16小时。向其中添加硫代硫酸钠水溶液并将混合物用DCM萃取。将分离的有机层用MgSO4干燥,得到标题化合物(0.97g,65%)。
1H NMR(DMSO-d6)δ10.93(1H,brs),7.63(2H,m),6.99(1H,dd)。
步骤B:4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2-(三氟甲基)苯酚
将13mL的1,4-二噁烷加入从步骤A获得的4-溴-2-(三氟甲基)苯酚(0.97g,4mmol)、双(频哪醇合)二硼(1.13g,4.4mmol)、乙酸钾(1.18g,12mmol)和DPPF(0.11g,0.2mmol)。将混合物充N2气5分钟。向其中添加PdCl2(dppf)-DCM(0.164g,0.2mmol)并将混合物在回流下搅拌1小时。将混合物通过C盐过滤以除去固体,然后通过柱色谱法纯化,得到标题化合物(0.76g,65%)。
1H NMR(DMSO-d6)δ11.02(1H,brs),7.72(2H,m),7.02(1H,dd),1.27(12H,s)。
步骤C:4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2-(三氟甲基)苯氧基]丁酸乙酯
将从步骤B获得的4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2-(三氟甲基)苯酚(0.36g,1.26mmol)溶于4.2mL的DMF。向其中添加Cs2CO3(0.81g,2.52mmol)和4-溴-丁酸乙酯(0.2mL,1.38mmol)并将混合物在室温搅拌16小时。将固体除去并将混合物通过柱色谱法纯化,得到标题化合物(0.374g,74%)。
1H NMR(CDCl3)δ7.99(1H,d),7.90(1H,dd),6.95(1H,dd),4.13(4H,m),2.54(2H,t),2.14(2H,m),1.33(12H,s),1.25(3H,t)。
制备例27:4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸甲酯
步骤A:4-羟基戊酸
将r-戊内酯(0.97g,9.68mmol)溶于10mL的1,4-二噁烷。向其中添加1N NaOH水溶液(10.6mL,10.6mmol)并将混合物搅拌1小时。使用1N HCl水溶液,将反应混合物的pH调节至5并将混合物用EtOAc萃取。将有机层用MgSO4干燥,得到标题化合物(0.88g,74%)。
1H NMR(CDCl3)δ3.89(1H,m),2.51(2H,t),1.82(1H,m),1.75(1H,m),1.24(3H,d)。
步骤B:4-羟基戊酸甲酯
将从步骤A获得的4-羟基戊酸(0.62g,5.25mmol)溶于17mL的THF,并向其中缓慢地添加重氮甲烷(0.25M,在Et2O中,31mL,7.88mmol)。将混合物在室温搅拌1小时,然后在减压下浓缩。将浓缩物通过柱色谱法纯化,得到标题化合物(0.42g,60%)。
1H NMR(CDCl3)δ3.84(1H,m),3.68(3H,s),2.46(2H,t),1.82(1H,m),1.74(1H,m),1.21(3H,d)。
步骤C:4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸甲酯
将从步骤B获得的4-羟基戊酸甲酯(0.05g,0.39mmol),从制备例2的步骤B获得的2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚(0.1g,0.39mmol)和三苯基膦(0.1g,0.39mmol)溶于4mL的THF,并将混合物缓慢冷却至0℃。向其中缓慢地添加偶氮二甲酸二异丙酯(0.077mL,0.39mmol)并将反应混合物在室温搅拌18小时。将混合物在减压下浓缩并通过色谱法纯化,得到标题化合物(0.1g,70%)。
1H NMR(CDCl3)δ7.31(2H,m),4.38(1H,m),3.68(3H,s),2.59(2H,t),2.00(2H,m),1.32(12H,s),1.25(3H,d)。
制备例28:4-[[5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2-吡啶基]氧基]戊酸甲酯
步骤A:4-[(5-溴-2-吡啶基)氧基]戊酸甲酯
将5-溴-2(1H)吡啶酮(0.05g,0.29mmol),4-羟基戊酸甲酯(0.047g,0.29mmol)和三苯基膦(0.075g,0.29mmol)溶于3mL的THF。向其中添加偶氮二甲酸二异丙酯(0.056mL,0.29mmol)并将反应混合物在室温搅拌16小时。将混合物在减压下浓缩并通过色谱法纯化,得到标题化合物(0.051g,62%)。
1H NMR(CDCl3)δ8.15(1H,m),7.60(1H,m),6.58(1H,d),5.18(1H,m),3.65(3H,s),2.41(2H,m),2.00(2H,m),1.31(3H,d)。
步骤B:甲基4-[[5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2-吡啶基]氧基]戊酸甲酯
将从步骤A获得的4-[(5-溴-2-吡啶基)氧基]戊酸甲酯(0.05g,0.17mmol)、双(频哪醇合)二硼(0.048g,0.19mmol)和乙酸钾(0.067g,0.68mmol)溶于1mL的1,4-二噁烷,并将混合物充N2气5分钟。向其中添加PdCl2(dppf)-DCM(0.007g,0.009mmol)并将反应混合物在80℃搅拌2小时。将混合物通过C盐过滤并通过色谱法纯化,得到标题化合物(0.038g,65%)。
1H NMR(CDCl3)δ8.05(1H,m),7.89(1H,m),6.64(1H,d),5.30(1H,m),3.65(3H,s),2.44(2H,m),2.01(2H,m),1.34(3H,d),1.26(12H,s)。
制备例29:2-(4-溴-苯基硫基)-丙酸甲酯
将4-溴-苯硫醇(0.5g,2.64mmol),NaH(60%,在矿物油中,0.11g,2.64mmol)和2-溴丙酸甲酯(0.32mL,2.91mmol)以与制备例12相同的方式反应,得到标题化合物(0.58g,80%)。
1H-NMR(CDCl3)δ7.43(2H,d),7.30(2H,d),3.76(1H,q),3.66(3H,s),1.47(3H,d)。
制备例30:2-[1-[[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]甲基]环丙基]乙腈
步骤A:[1-(羟基甲基)环丙基]甲醇
将LAH(0.28g,7.52mmol)溶于10mL的THF,并将溶液冷却至-18℃。向其中缓慢地添加在7mL的在THF中的1,1-环丙烷甲酸二乙酯(1.0g,5.37mmol),并将反应混合物在室温搅拌16小时。向其中添加0.3mL的水和0.3mL的4M NaOH水溶液。将混合物用C盐过滤并通过色谱法纯化,得到标题化合物(0.2g,35%)。
1H NMR(CDCl3)δ3.62(4H,s),2.35(2H,brs),0.53(4H,s)。
步骤B:[1-[(4-溴-2,6-二氟-苯氧基)甲基]环丙基]甲醇
将从步骤A获得的[1-(羟基甲基)环丙基]甲醇(0.2g,1.96mmol),4-溴-2,6-二氟-苯酚(0.314g,1.5mmol)和三苯基膦(0.393g,1.5mmol)溶于24mL的THF。向其中添加偶氮甲酸二异丙酯(0.3mL,1.5mmol)并将反应混合物在室温搅拌16小时。将混合物在减压下浓缩并通过色谱法纯化,得到标题化合物(0.307g,70%)。
1H NMR(CDCl3)δ7.08(2H,m),4.08(2H,s),3.68(2H,d),1.84(1H,t,OH),0.62(4H,m)。
步骤C:甲磺酸[1-[(4-溴-2,6-二氟-苯氧基)甲基]环丙基]甲酯
将从步骤B获得的[1-[(4-溴-2,6-二氟-苯氧基)甲基]环丙基]甲醇(0.3g,1mmol)溶于5mL的DCM,并将溶液冷却至0℃。向其中顺序地添加甲磺酰氯(0.09mL,1.12mmol)和TEA(0.21mL,1.5mmol),并将混合物在0℃搅拌40分钟。向其中添加5mL的水并将混合物用DCM萃取,得到标题化合物(0.4g,99%)。
1H NMR(CDCl3)δ7.09(2H,m),4.29(2H,s),4.01(2H,s),3.05(3H,s),0.77(2H,m),0.73(2H,m)。
步骤D:2-[1-[(4-溴-2,6-二氟-苯氧基)甲基]环丙基]乙腈
将从步骤C获得的甲磺酸[1-[(4-溴-2,6-二氟-苯氧基)甲基]环丙基]甲酯(0.4g,1mmol)溶于5mL的DMF。向其中添加氰化钠(0.054g,1.1mmol)并将反应混合物在60℃搅拌16小时。将混合物在减压下浓缩。向其中添加水并将混合物用EtOAc萃取。将萃取物通过柱色谱法纯化,得到标题化合物(0.205g,63%)。
1H NMR(CDCl3)δ7.09(2H,m),3.98(2H,s),2.72(2H,s),0.75(2H,m),0.70(2H,m)。
步骤E:2-[1-[[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]甲基]环丙基]乙腈
将从步骤D获得的2-[1-[(4-溴-2,6-二氟-苯氧基)甲基]环丙基]乙腈(0.2g,0.67mmol)、双(频哪醇合)二硼(0.172g,0.67mmol)、乙酸钾(0.266g,2.71mmol)和DPPF(0.019g,0.033mmol)溶于4mL的1,4-二噁烷。将混合物充N2气5分钟。向其中添加PdCl2(dppf)-DCM(0.027g,0.033mmol)并将混合物在80℃搅拌2小时。将混合物通过C盐过滤并通过色谱法纯化,得到标题化合物(0.185g,79%)。
1H NMR(CDCl3)δ7.32(2H,m),4.04(2H,s),2.75(2H,s),1.33(12H,s),0.73(2H,m),0.68(2H,m)。
制备例31:4-[[6-(3-羟基苯基)-3-吡啶基]氧基]丁酸乙酯
步骤A:4-[(6-溴-3-吡啶基)氧基]丁酸乙酯
将2-溴-5-羟基吡啶(1.07g,6.18mmol)溶于20mL的DMF。向其中添加K2CO3(1.7g,12.4mmol)和4-溴-丁酸乙酯(1.2g,6.18mmol),并将反应混合物在室温搅拌16小时。将混合物在减压下浓缩。向其中添加水并将混合物用EtOAc萃取,得到标题化合物(1.67g,94%)。
1H NMR(CDCl3)δ8.04(1H,m),7.36(1H,d),7.09(1H,m),4.15(2H,q),4.04(2H,t),2.51(2H,t),2.13(2H,m),1.26(3H,t)。
步骤B:4-[[6-(3-羟基苯基)-3-吡啶基]氧基]丁酸乙酯
将从步骤A获得的4-[(6-溴-3-吡啶基)氧基]丁酸乙酯(0.3g,1mmol)和3-羟基苯基硼酸(0.172g,1.25mmol)溶于3mL的1,2-二甲氧基乙烷和Na2CO3(2M水溶液,1.6mL,3.2mmol)。将混合物充N2气5分钟。向其中添加PdCl2(PPh3)2(0.036g,0.052mmol)并将反应混合物在80℃搅拌3小时。向其中添加水并将混合物用EtOAc萃取。将有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.129g,41%)。
1H NMR(CDCl3)δ8.34(1H,m),7.62(1H,d),7.48(1H,m),7.41(1H,m),7.29(1H,t),7.25(1H,m),6.85(1H,m),5.75(1H,brs),4.16(2H,q),4.10(2H,t),2.54(2H,t),2.16(2H,m),1.26(3H,t)。
制备例32:2'-苯氧基-联苯-4-醇
将2-苯氧基苯基硼酸(0.033g,0.15mmol)和4-碘苯酚(0.034g,0.15mmol)溶于3mL的H2O,并将混合物充N2气5分钟。向其中添加Pd/C(催化量)和K2CO3(0.064g,0.46mmol),并将反应混合物在室温搅拌16小时。向其中添加1N HCl并将混合物用EtOAc萃取。将分离的有机层用MgSO4干燥并通过柱色谱法纯化(洗脱剂,EtOAc/Hex=1/4),得到标题化合物(0.022g,55%)。
1H-NMR(CDCl3)δ7.46(3H,m),7.25(3H,m),7.20(1H,m),7.00(2H,6.90(2H,m),6.89(2H,m),4.65(1H,s)。
制备例33:4-(2-异丙基硫基-吡啶-3-基)-苯酚
步骤A:3-氯-2-异丙基硫基-吡啶
在0℃向溶于干DMF(2mL)的异丙基硫醇(0.102g,1.351mmol)中缓慢逐滴添加NaH(60%)(0.07g,1.75mmol)。将混合物搅拌30分钟,添加到装有2,3-二氯吡啶(0.53g,3.58mmol)的烧瓶中,并在室温搅拌1小时。向其中添加NH4Cl水溶液之后,将有机层通过用EtOAc萃取来分离。将有机层用无水MgSO4干燥并通过色谱法纯化(洗脱剂,EtOAc/Hex=1/4),得到标题化合物(0.062g,24%)。
1H-NMR(CDCl3)δ8.35(1H,m),7.52(1H,m),6.94(1H,m),4.05(1H,m),1.43(6H,d)。
步骤B:2-异丙基硫基-3-(4-甲氧基-苯基)-吡啶
将从步骤A获得的3-氯-2-异丙基硫基-吡啶(0.02g,0.10mmol)和(4-甲氧基-苯基)-硼酸(0.024g,0.15mmol)溶于DMF。将混合物充N2气5分钟。向其中添加Pd2(dba)3(催化量)和Sphos(催化量),并将反应混合物在80℃搅拌16小时。向其中添加NaCl水溶液之后,将混合物用EtOAc萃取。将分离的有机层用MgSO4干燥并通过色谱法纯化(洗脱剂,EtOAc/Hex=1/4),得到标题化合物(0.01g,37%)。
1H-NMR(CDCl3)δ8.41(1H,m),7.35(3H,m),7.02(1H,m),6.95(2H,m),4.06(1H,m),3.84(3H,s),1.35(6H,d)。
步骤C:4-(2-异丙基硫基-吡啶-3-基)-苯酚
将从步骤B获得的2-异丙基硫基-3-(4-甲氧基-苯基)-吡啶(0.02g,0.07mmol)溶于DCM(3mL),并将溶液冷却至-78℃。向其中缓慢地添加BBr3(1.0M,在DCM中,0.116mL,0.11mmol),并将混合物在室温搅拌3小时。反应完成时,将混合物冷却至-20℃。向残余物中添加甲醇以稀释。将混合物用DCM萃取。将有机层用MgSO4干燥并在减压下浓缩。所得的残余物通过柱色谱法纯化(洗脱剂,EtOAc/Hex=1/3),得到标题化合物(15mg,75%)。
1H-NMR(CDCl3)δ8.41(1H,m),7.34(1H,m),7.26(2H,m),7.02(1H,m),6.89(2H,m),4.79(1H,s),4.05(1H,m),1.35(6H,d)。
制备例34:3,5-二氟-2'-苯氧基-联苯-4-醇
步骤A:3,5-二氟-4-甲氧基-2'-苯氧基-联苯
将2-苯氧基苯基硼酸(0.045g,0.21mmol)和5-溴-1,3-二氟-2-甲氧基-苯(0.031g,0.14mmol)溶于异丙醇/水(1/1)。向其中添加Pd/C(催化量)和Na3PO412H2O(0.186g,0.49mmol),并将混合物在80℃搅拌1小时。将混合物通过C盐过滤,并用EtOAc萃取以分离有机层。将有机层用MgSO4干燥并通过色谱法纯化(洗脱剂,EtOAc/Hex=1/20),得到标题化合物(0.026g,40%)。
1H-NMR(CDCl3)δ7.40(1H,m),7.30(3H,m),7.20(1H,m),7.11(2H,m),7.05(1H,m),6.97(1H,m),6.91(2H,m),4.00(3H,s)。
步骤B:3,5-二氟-2'-苯氧基-联苯-4-醇
将从步骤A获得的3,5-二氟-4-甲氧基-2'-苯氧基-联苯(0.026g,0.083mmol)以与制备例33的步骤C相同的方式反应,得到标题化合物(0.018g,72%)。
1H-NMR(CDCl3)δ7.40(1H,m),7.30(3H,m),7.20(1H,m),7.11(2H,m),7.05(1H,m),6.96(1H,m),6.91(2H,m),5.08(1H,s)。
制备例35:4-(2-环戊基硫基-吡啶-3-基)-苯酚
步骤A:3-氯-2-环戊基硫基-吡啶
将环戊基硫醇(0.477g,4.67mmol)溶于干DMF(2mL)并将溶液冷却至0℃。向其中缓慢地逐滴添加NaH(60%)(0.24g,6.03mmol)并将混合物搅拌30分钟。将混合物加入装有2,3-二氯吡啶(0.69g,4.67mmol)的烧瓶并在室温搅拌1小时。向反应混合物中添加NH4Cl水溶液并将混合物用EtOAc萃取以分离有机层。将有机层用无水MgSO4干燥并通过色谱法纯化(洗脱剂,EtOAc/Hex=1/4),得到标题化合物(0.61g,61%)。
1H-NMR(CDCl3)δ8.33(1H,m),7.51(1H,m),6.92(1H,m),4.09(1H,m),2.23(2H,m),1.79(2H,m),1.66(4H,m)。
步骤B:2-环戊基硫基-3-(4-甲氧基-苯基)-吡啶
将从步骤A获得的3-氯-2-环戊基硫基-吡啶(0.057g,0.266mmol)以与制备例33的步骤B相同的方式反应,得到标题化合物(0.046g,61%)。
1H-NMR(CDCl3)δ8.41(1H,m),7.36(3H,m),7.01(1H,m),6.96(2H,m),4.08(1H,m),3.85(3H,s),2.19(2H,m),1.70(2H,m),1.66(4H,m)。
步骤C:4-(2-环戊基硫基-吡啶-3-基)-苯酚
将从步骤B获得的2-环戊基硫基-3-(4-甲氧基-苯基)-吡啶(0.046g,0.161mmol)以与制备例33的步骤C相同的方式反应,得到标题化合物(0.024g,55%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.33(3H,m),7.01(1H,m),6.98(2H,m),4.87(1H,s),4.09(1H,m),2.18(2H,m),1.70(2H,m),1.66(4H,m)。
制备例36:3-碘-2-苯氧基-吡啶
将2-氟-3-碘-吡啶(0.054g,0.24mmol)和Cs2CO3(0.158g,0.266mmol)和苯酚(0.025g,0.266mmol)溶于2mL的DMF。将反应混合物在80℃搅拌16小时。向其中添加NaCl水溶液并将混合物用EtOAc萃取以分离有机层。将有机层用无水MgSO4干燥并通过色谱法纯化(洗脱剂,EtOAc/Hex=1/7),得到标题化合物(0.058g,71%)。
1H-NMR(CDCl3)δ8.15(1H,m),8.08(1H,m),7.40(2H,m),7.26(1H,m),7.15(2H,m),6.75(1H,m)。
制备例37:3-碘-2-异丙氧基-吡啶
将异丙醇(0.043g,717mmol)溶于干DMF(3mL),并在0℃向其中缓慢地逐滴添加NaH(60%)(0.03g,0.71mmol)。将混合物搅拌30分钟。将反应混合物加入装有2-氟-3-碘-吡啶(0.10g,0.44mmol)的烧瓶,并在室温搅拌1小时。向其中添加NH4Cl水溶液并将混合物用EtOAc萃取以分离有机层。将有机层用无水MgSO4干燥并通过色谱法纯化(洗脱剂,EtOAc/Hex=1/4),得到标题化合物(0.029g,24%)。
1H-NMR(CDCl3)δ8.08(1H,m),8.00(1H,m),6.59(1H,m),5.27(1H,m),1.38(6H,d)。
制备例38:2-环戊氧基-3-碘-吡啶
将环戊醇和2-氟-3-碘-吡啶(0.10g,0.44mmol)以与制备例37相同的方式反应,得到标题化合物(0.091g,70%)。
1H-NMR(CDCl3)δ8.09(1H,m),7.99(1H,m),6.59(1H,m),5.43(1H,m),2.00(2H,m),1.94(4H,m),1.66(2H,m)。
制备例39:2-环戊基硫基-3-碘-吡啶
将2-氟-3-碘-吡啶(0.065g,0.29mmol)、Cs2CO3(0.19g,0.58mmol)和环戊基硫醇(0.03g,0.291mmol)溶于2mL的DMF。将反应混合物在80℃搅拌2小时。向其中添加NaCl水溶液并将混合物用EtOAc萃取以分离有机层。将有机层用MgSO4干燥并通过色谱法纯化(洗脱剂,EtOAc/Hex=1/4),得到标题化合物(0.053g,65%)。
1H-NMR(CDCl3)δ8.38(1H,m),7.89(1H,m),6.68(1H,m),4.00(1H,m),2.22(2H,m),1.80(2H,m),1.66(4H,m)。
制备例40:2-环丙基甲氧基-3-碘-吡啶
将环丙基-甲醇(0.089g,1.23mmol)溶于干DMF(2mL),并在0℃向其中缓慢地逐滴添加NaH(60%)(0.054g,1.35mmol)。将混合物搅拌30分钟,缓慢地加入装有2-氟-3-碘-吡啶(0.137g,0.617mmol)的烧瓶中,然后在室温搅拌1小时。向其中添加NH4Cl水溶液并将混合物用EtOAc萃取以分离有机层。将有机层用无水MgSO4干燥并通过色谱法纯化(洗脱剂,EtOAc/Hex=1/5),得到标题化合物(0.141g,83%)。
1H-NMR(CDCl3)δ8.07(1H,m),8.00(1H,m),6.61(1H,m),4.20(2H,d),1.32(1H,m),0.60(2H,m),0.39(2H,m)。
制备例41:2-环丙基甲基硫基-3-(3,5-二氟-4-甲氧基-苯基)-吡啶
步骤A:3-碘-2-(4-甲氧基-苄基硫基)-吡啶
将2-氟-3-碘-吡啶(0.42g,1.8mmol)和(4-甲氧基苯基)甲硫醇(0.43g,2.8mmol)以与制备例12相同的方式反应,得到标题化合物(0.56g,84%)。
1H-NMR(CDCl3)δ8.43(1H,m),7.93(1H,m),7.32(2H,d),6.85(2H,d),6.74(1H,m),4.35(2H,s),3.79(3H,s)。
步骤B:3-(3,5-二氟-4-甲氧基-苯基)-2-(4-甲氧基-苄基硫基)-吡啶
将从步骤A获得的3-碘-2-(4-甲氧基-苄基硫基)-吡啶(0.1g,0.28mmol)和从制备例238获得的2-(3,5-二氟-4-甲氧基-苯基)-4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷(0.11g,0.42mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.08g,77%)。
1H-NMR(CDCl3)δ8.47(1H,m),7.36(1H,m),7.30(2H,d),7.07(1H,m),6.96(2H,m),6.81(2H,d),4.38(2H,s),4.03(3H,s),3.78(3H,s)。
步骤C:3-(3,5-二氟-4-甲氧基-苯基)-吡啶-2-硫醇
将从步骤B获得的3-(3,5-二氟-4-甲氧基-苯基)-2-(4-甲氧基-苄基硫基)-吡啶(0.033g,0.097mmol)溶于TFA(2mL)。向其中缓慢地添加茴香醚(0.5mL)和三氟甲磺酸(0.2mL),并将混合物在70℃搅拌1小时。在0℃,向其中缓慢地添加碳酸氢钠水溶液并将混合物用EtOAc萃取。将有机层用MgSO4干燥,在减压下蒸发并用Et2O重结晶,得到标题化合物(0.033g,61%)。
1H-NMR(DMSO-d6)δ7.72(1H,m),7.57(1H,m),7.42(2H,m),6.84(1H,m),3.96(3H,s)。
步骤D:2-环丙基甲基硫基-3-(3,5-二氟-4-甲氧基-苯基)-吡啶
将从步骤C获得的3-(3,5-二氟-4-甲氧基-苯基)-吡啶-2-硫醇(0.033g,0.13mmol)溶于干DMF(1.5mL),并在0℃向其中缓慢地逐滴添加NaH(60%)(0.01g,0.195mmol)。将混合物搅拌30分钟。在0℃向其中缓慢地逐滴添加溴甲基环丙烷(0.021g,0.156mmol),并将反应混合物在室温搅拌2小时。向其中添加NH4Cl水溶液并将混合物用EtOAc萃取以分离有机层。将有机层用MgSO4干燥,通过柱色谱法纯化(洗脱剂,EtOAc/Hex=1/5),得到标题化合物(0.032g,82%)。
1H-NMR(CDCl3)δ8.42(1H,m),7.33(1H,m),7.00(3H,m),4.06(3H,s),3.12(2H,d),1.12(1H,m),0.57(2H,m),0.29(2H,m)。
制备例42:2-环丁基硫基-3-(4-甲氧基-苯基)-吡啶
步骤A:2-(4-甲氧基-苄基硫基)-3-(4-甲氧基-苯基)-吡啶
将从制备例41的步骤A获得的3-碘-2-(4-甲氧基-苄基硫基)-吡啶(0.1g,0.28mmol)和(4-甲氧基苯基)硼酸(0.085g,0.56mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.075g,79%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.36(1H,m),7.33(4H,m),7.05(1H,m),6.93(2H,d),6.80(2H,d),4.36(2H,s),3.83(3H,s),3.76(3H,s)。
步骤B:3-(4-甲氧基-苯基)-吡啶-2-硫醇
将从步骤A获得的2-(4-甲氧基-苄基硫基)-3-(4-甲氧基-苯基)-吡啶(0.212g,0.628mmol)以与制备例41的步骤C相同的方式反应,得到标题化合物(0.109g,80%)。
1H-NMR(DMSO-d6)δ7.65(1H,m),7.55(2H,d),7.48(1H,m),6.93(2H,d),6.82(1H,m),3.78(3H,s)。
步骤C:2-环丁基硫基-3-(4-甲氧基-苯基)-吡啶
将从步骤B获得的3-(4-甲氧基-苯基)-吡啶-2-硫醇(0.212g,0.628mmol),NaH(0.012g,0.294mmol)和溴代-环丁烷(0.024g,0.176mmol)以与制备例41的步骤D相同的方式反应,得到标题化合物(0.0094g,24%)。
1H-NMR(CDCl3)δ8.37(1H,m),7.34(3H,m),7.02(3H,m),4.42(1H,m),3.86(3H,s),2.49(2H,m),2.03(4H,m)。
制备例43:2-环丙基甲基硫基-3-(4-甲氧基-苯基)-吡啶
将从制备例42的步骤A获得的2-(4-甲氧基-苄基硫基)-3-(4-甲氧基-苯基)-吡啶(0.04g,0.184mmol)以与制备例41的步骤C和D相同的方式反应,得到标题化合物(0.02g,44%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.37(3H,m),7.02(3H,m),4.09(2H,m),3.86(3H,s),1.09(1H,m),0.54(2H,m),0.27(2H,m)。
制备例44:2-环丁基硫基-3-碘-吡啶
步骤A:环丁基硫醇
将镁(0.99g,40.74mmol)溶于THF(20mL)。在50℃,向其中缓慢地添加在THF(5mL)中的环丁基溴(5.0g,37.03mmol)并将混合物在回流下搅拌2小时。在0℃,缓慢地添加硫(1.06g,33.33mmol)并将混合物在50℃搅拌2小时。在0℃,向其中缓慢地添加LAH(0.843g,22.22mmol)并将混合物在回流下搅拌30分钟。在0℃,用氯化铵水溶液(20mL)和1N HCl(20mL)终止反应。将混合物用Et2O(30mL*3)萃取以分离有机层。将有机层用MgSO4干燥并用于下一反应。
步骤B:2-环丁基硫基-3-碘-吡啶
将从步骤A获得的环丁基硫醇(0.069g,0.782mmol)和2-氟-3-碘-吡啶(0.1g,0.43mmol)溶于DMF(3mL)。向其中添加Cs2CO3(0.26g,0.86mmol)并将反应混合物在80℃加热下搅拌。向其中添加NaCl水溶液并将混合物用EtOAc萃取。将有机层用MgSO4干燥并通过色谱法纯化(洗脱剂,EtOAc/Hex=1/4),得到标题化合物(0.115g,91%)。
1H-NMR(CDCl3)δ8.36(1H,m),7.90(1H,m),6.69(1H,m),4.33(1H,m),2.54(2H,m),2.14(2H,m),2.05(2H,m)。
制备例45:3-(4-甲氧基-苯基)-2-丙基硫基-吡啶
将从制备例42步骤B获得的3-(4-甲氧基-苯基)-吡啶-2-硫醇(0.053g,0.243mmol),NaH(0.02g,0.487mmol)和1-碘-丙烷(0.049g,0.292mmol)以与制备例41的步骤D相同的方式反应,得到标题化合物(0.023g,36%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.36(3H,m),7.03(1H,m),6.98(2H,m),3.86(3H,s),3.13(2H,m),1.68(2H,m),1.01(3H,m)。
制备例46:1-溴-2-异丙氧基-苯
将2-溴-苯酚(0.373g,2.15mmol)和2-溴-丙烷(0.291g,2.371mmol)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.257g,55%)。
1H-NMR(CDCl3)δ7.52(1H,m),7.25(1H,m),6.91(1H,m),6.80(1H,m),4.54(1H,m),1.38(6H,d)。
制备例47:1-溴-2-环丁氧基-苯
将2-溴-苯酚(0.235g,1.35mmol)和溴代-环丁烷(0.201g,1.49mmol)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.061g,19%)。
1H-NMR(CDCl3)δ7.53(1H,m),7.19(1H,m),6.76(1H,m),6.80(1H,m),4.68(1H,m),2.46(2H,m),2.27(2H,m),1.88(1H,m),1.68(1H,m)。
制备例48:1-溴-2-环丙基甲氧基-苯
将2-溴-苯酚(0.235g,1.35mmol)和溴甲基-环丙烷(0.201g,1.49mmol)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.267g,86%)。
1H-NMR(CDCl3)δ7.54(1H,m),7.22(1H,m),6.90(1H,m),6.83(1H,m),3.89(2H,d),1.31(1H,m),0.63(2H,m),0.40(2H,m)。
制备例49:1-溴-2-环戊氧基-苯
将2-溴-苯酚(0.366g,2.11mmol)和溴代-环戊烷(0.341g,2.32mmol)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.369g,72%)。
1H-NMR(CDCl3)δ7.51(1H,m),7.25(1H,m),6.88(1H,m),6.78(1H,m),4.80(1H,m),1.88(6H,m),1.65(2H,m)。
制备例50:4-溴-2-甲基丁酸乙酯
步骤A:(E)-4-苄基氧基-2-甲基-2-丁烯酸乙酯
将苄基氧基-乙醛(0.95g,6.35mmol)溶于苯(21mL),并在室温向其中添加(1-乙氧基羰基亚乙基)三苯基正膦(2.76g,7.63mmol)。将混合物在70℃搅拌16小时。反应完全之后,将混合物在减压下浓缩并通过色谱法纯化(洗脱剂,EtOAc/Hex=1/4),得到标题化合物(1.31g,94%)。
1H-NMR(CDCl3)δ7.35(5H,m),6.86(1H,m),4.54(2H,s),4.19(4H,m),1.81(3H,m),1.28(3H,m)。
步骤B:4-羟基-2-甲基丁酸乙酯
将从步骤A获得的(E)-4-苄基氧基-2-甲基-2-丁烯酸乙酯(1.31g,5.97mmol)溶于EtOAc/MeOH(8/2)(20mL),并向其中添加10%Pd/C(0.13g)。将混合物在H2气氛中在室温搅拌12小时。反应完全之后,将混合物通过C盐过滤,在减压下浓缩并通过色谱法纯化(洗脱剂,EtOAc/Hex=1/2),得到标题化合物(0.726g,98%)。
1H-NMR(CDCl3)δ4.13(2H,m),3.68(2H,m),2.62(1H,m),1.19(1H,m),1.70(1H,m),1.56(1H,m),1.24(3H,m),1.18(3H,d)。
步骤C:4-溴-2-甲基丁酸乙酯
将NBS(2.14g,12.05mmol)溶于DCM(10mL),并向其中添加三苯基膦(2.94g,11.22mmol)。将混合物搅拌10分钟。向其中添加吡啶(0.38g,4.80mmol),然后添加从步骤B获得的4-羟基-2-甲基-丁酸乙酯(0.586g,4.00mmol)。将混合物搅拌16小时。反应完全之后,将混合物在减压下浓缩并通过色谱法纯化(洗脱剂,EtOAc/Hex=1/4),得到小量标题化合物(0.061g,7.3%)。
1H-NMR(CDCl3)δ4.13(2H,m),3.41(2H,m),2.67(1H,m),2.27(1H,m),1.91(1H,m),1.26(3H,m),1.19(3H,d)。
制备例51:4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯酚
将在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.193g,0.66mmol)和在制备例2的步骤B中获得的2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚(0.254g,0.992mmol)以与实施例50的步骤A相同的方式反应,得到标题化合物(0.078g,40%)。
1H-NMR(CDCl3)δ8.39(1H,m),7.30(1H,m),6.98(3H,m),5.15(1H,s),4.40(1H,m),2.49(2H,m),2.02(4H,m)。
制备例52:2-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯氧基甲基]-环丙烷甲酸乙酯
步骤A:(E/Z)-4-苄基氧基-丁-2-烯酸乙酯
将苄基氧基-乙醛(0.95g,6.35mmol)和2-(三苯基正膦亚基)乙酸乙酯(1.36g,3.92mmol)以与制备例50的步骤A相同的方式反应,得到标题化合物(E/Z混合物)(0.043g,40%)。
1H-NMR(CDCl3)δ7.34(5H,m),6.96(0.62H,m),6.42(0.38H,m),6.13(0.62H,m),5.82(0.38H,m),4.56(2H,s),4.19(4H,m),1.27(3H,m)。
步骤B:2-苄基氧基甲基-环丙烷甲酸乙酯
在将在步骤A中获得的(E/Z)-4-苄基氧基-丁-2-烯酸乙酯(0.36g,1.63mmol)溶于THF(5mL)之后,向其中添加重氮甲烷(30mL,8.23mmol,0.25M Et2O)。在将反应物冷却至0-5℃之后,向其中缓慢地添加乙酸钯(II)(0.022g,0.098mmol),并将混合物在室温搅拌1小时。反应终止之后,向反应物添加水,然后萃取。将有机层在减压下浓缩并将残余物通过柱色谱法纯化(洗脱剂:EtOAc/Hex=1/4),得到标题化合物(0.119g,31%)。
1H-NMR(CDCl3)δ7.32(5H,m),4.51(2H,s),4.10(2H,m),3.41(2H,m),1.70(1H,m),1.55(1H,m),1.24(4H,m),0.85(1H,m)。
步骤C:2-羟基甲基-环丙烷甲酸乙酯
将在步骤B中获得的2-苄基氧基甲基-环丙烷甲酸乙酯(0.119g,0.50mmol)以与制备例50的步骤B相同的方式反应,得到标题化合物(0.067g,91%)。
1H-NMR(CDCl3)δ4.13(2H,s),3.60(1H,m),3.50(1H,m),1.70(1H,m),1.55(2H,m),1.20(4H,m),0.85(1H,m)。
步骤D:2-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯氧基甲基]-环丙烷甲酸乙酯
在将在步骤C中获得的2-羟基甲基-环丙烷甲酸乙酯(0.067g,0.46mmol)、在制备例2的步骤B中获得的2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚(0.118g,0.46mmol)和三苯基膦(0.121g,0.46mmol)溶于THF(5mL)之后,向其中添加偶氮二甲酸二异丙酯并将混合物在室温搅拌16小时。将反应物在减压下浓缩并通过色谱法纯化,得到标题化合物(0.084g,47%)。
1H-NMR(CDCl3)δ7.28(2H,m),4.11(3H,m),4.00(1H,m),1.85(1H,m),1.60(1H,m),1.29(12H,s),1.25(4H,m),0.85(1H,m)。
制备例53:4-[2,5-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯氧基]丁酸乙酯
步骤A:4-溴-2,5-二氟-苯酚
将2,5-二氟-苯酚(0.70g,2.4mmol)溶于氯仿(18mL),并0℃在向其中逐滴添加溶于氯仿(2mL)的溴(0.431g,5.4mmol)。将混合物反应16小时,并通过添加NaS2O3水溶液将反应终止。将反应物用水稀释,并用EtOAc萃取。将有机层分离并用MgSO4干燥并继续进行下一步。
1H-NMR(CDCl3)δ7.25(1H,m),6.83(1H,m),5.23(1H,s)。
步骤B:4-(4-溴-2,5-二氟-苯氧基)丁酸乙酯
将在步骤A中获得的4-溴-2,5-二氟-苯酚(0.865g,4.13mmol)以与实施例38的步骤A相同的方式反应,得到标题化合物(1.07g,79%)。
1H-NMR(CDCl3)δ7.24(1H,m),6.78(1H,m),4.15(2H,q),4.05(2H,t),2.53(2H,t),2.13(2H,m),1.25(3H,t)。
步骤C:4-[2,5-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯氧基]-丁酸乙酯
将在步骤B中获得的4-(4-溴-2,5-二氟-苯氧基)-丁酸乙酯(1.07g,3.31mmol)、双(频哪醇合)二硼(0.88g,3.47mmol)、乙酸钾(1.30g,13.24mmol)和DPPF(0.092g,0.16mmol)溶于1,4-二噁烷(20mL),将混合物充N2气5分钟,然后向其中添加PdCl2(dppf)-DCM(0.135g,0.16mmol)。将反应物在80℃搅拌16小时,并使用C盐过滤,并通过柱色谱法纯化,得到标题化合物(0.727g,59%)。
1H-NMR(CDCl3)δ7.37(1H,m),6.16(1H,m),4.13(2H,q),4.06(2H,t),2.52(2H,t),2.14(2H,m),1.30(12H,s),1.25(3H,t)。
制备例54:4-[3,5-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯
将4-溴-3,5-二氟-苯酚(1.1g,5.26mmol)和4-溴-丁酸乙酯(1.03g,5.26mmol)以与制备例4的步骤B相同的方式反应,得到4-(4-溴-3,5-二氟-苯氧基)-丁酸乙酯(0.90g,54%)。
然后,将4-(4-溴-3,5-二氟-苯氧基)-丁酸乙酯(0.37g,1.15mmol)和双(频哪醇合)二硼(0.35g,1.37mmol)以与制备例4的步骤A相同的方式反应,得到标题化合物(0.10g,24%)。
1H-NMR(CDCl3)δ6.38(2H,m),4.15(2H,q),3.98(2H,t),2.49(2H,t),2.11(2H,m),1.35(12H,s),1.26(3H,t)。
制备例55:4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯酚
将在制备例38中获得的2-环戊氧基-3-碘-吡啶(0.52g,1.8mmol)和在制备例2的步骤B中获得的2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚(0.46g,1.8mmol)以与制备例13相同的方式反应,得到标题化合物(0.35g,67%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.56(1H,m),7.17(2H,m),6.93(1H,m),5.96(1H,bs),5.51(1H,m),1.94(2H,m),1.82(2H,m),1.74(2H,m),1.63(2H,m)。
制备例56:4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸
将在制备例109中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸乙酯(1.7g,5.01mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(1.5g,96%)。
1H-NMR(CDCl3)δ8.22(1H,m),7.82(1H,m),7.29(1H,m),7.15(2H,m),4.27(2H,t),2.68(2H,t),2.14(2H,m)。
制备例57:4-[2,6-二氟-4-(6-甲酰基-吡啶-2-基)-苯氧基]-丁酸乙酯
将6-溴-吡啶-2-甲醛(0.50g,2.7mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(1.0g,2.7mmol)以与制备例13相同的方式反应,得到标题化合物(0.40g,43%)。
1H-NMR(CDCl3)δ10.1(1H,s),7.93(2H,m),7.86(1H,d),7.69(2H,m),4.27(2H,t),4.16(2H,q),2.62(2H,t),2.13(2H,m),1.28(3H,t)。
制备例58:3-碘-2-(四氢-吡喃-4-基氧基)-吡啶
将四氢吡喃-4-醇(0.45g,4.44mmol)和2-氟-3-碘-吡啶(0.66g,2.96mmol)以与制备例37相同的方式反应,得到标题化合物(0.80g,89%)。
1H-NMR(CDCl3)δ8.07(1H,d),8.01(1H,d),6.63(1H,m),5.30(1H,m),4.01(2H,m),3.68(2H,m),2.04(2H,m),1.85(2H,m)。
制备例59:3-碘-2-(四氢-呋喃-3-基氧基)-吡啶
将四氢呋喃-3-醇(0.39g,4.44mmol)和2-氟-3-碘-吡啶(0.66g,2.96mmol)以与制备例37相同的方式反应,得到标题化合物(0.68g,80%)。
1H-NMR(CDCl3)δ8.08(1H,m),8.03(1H,m),6.65(1H,m),5.53(1H,m),4.12(1H,m),4.06(1H,m),3.94(2H,m),2.23(2H,m)。
制备例60:1-环丁氧基-3-碘-苯
在将3-碘苯酚(0.5g,2.27mmol)溶于CH3CN(5mL)之后,向其中添加Cs2CO3(2.22g,6.81mmol)和溴代环丁烷(0.21mL,2.27mmol)。将混合物在80-85℃搅拌10小时,并将反应物冷却并使用C盐过滤。将残余物在减压下浓缩并通过色谱法纯化(洗脱剂:EtOAc/Hex=1/10),得到标题化合物(0.45g,72%)。
1H NMR(400MHz,CDCl3)δ7.25-7.20(m,1H),7.17-7.13(m,1H),6.92(t,1H),6.77-6.72(m,1H),4.59-4.50(m,1H),2.44-2.33(m,2H),2.19-2.05(m,2H),1.88-1.77(m,1H),1.70-1.57(m,1H)。
制备例61:2-环丁基甲氧基-3-碘-吡啶
将环丁基-甲醇(0.37g,4.31mmol)和2-氟-3-碘-吡啶(0.60g,2.69mmol)以与制备例37相同的方式反应,得到标题化合物(0.75g,96%)。
1H-NMR(CDCl3)δ8.08(1H,m),8.02(1H,m),6.63(1H,m),4.29(2H,d),2.79(1H,m),2.12(2H,m),1.96(4H,m)。
制备例62:2-环丙氧基-3-碘-吡啶
将环丙醇(0.20g,3.43mmol)和2-氟-3-碘-吡啶(0.51g,2.29mmol)以与制备例37相同的方式反应,得到标题化合物(0.30g,50%)。
1H-NMR(CDCl3)δ8.16(1H,d),8.01(1H,d),6.68(1H,m),4.30(1H,m),0.82(4H,m)。
制备例63:2,6-二氟-4-(2-异丙基硫基-吡啶-3-基)-苯酚
步骤A:3-(3,5-二氟-4-甲氧基-苯基)-2-异丙基硫基-吡啶
将在制备例33的步骤A中获得的3-氯-2-异丙基硫基-吡啶(0.04g,0.213mmol)和在制备例238中获得的2-(3,5-二氟-4-甲氧基-苯基)-4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷(0.086g,0.139mmol)以与制备例33的步骤B相同的方式反应,得到标题化合物(0.015g,24%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.33(1H,m),7.00(3H,m),4.05(4H,m),1.37(6H,d)。
步骤B:2,6-二氟-4-(2-异丙基硫基-吡啶-3-基)-苯酚
将在步骤A中获得的3-(3,5-二氟-4-甲氧基-苯基)-2-异丙基硫基-吡啶(0.015g,0.05mmol)以与制备例33的步骤C相同的方式反应,得到标题化合物(0.012g,85%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.33(1H,m),7.00(3H,m),5.25(1H,s),4.06(1H,m),1.37(6H,d)。
制备例64:N-环戊基-3-碘-吡啶基-2-胺
在将2-氟-3-碘-吡啶(0.3g,1.34mmol)、环戊胺(0.34g,4mmol)和二异丙基乙胺(0.46mL,2.68mmol)溶于CH3CN(3.3mL)之后,通过使用微波将混合物在110℃搅拌2小时。将反应物在减压下浓缩并通过色谱法纯化,得到标题化合物(0.155g,40%)。
1H-NMR(CDCl3)δ8.07(1H,d),7.80(1H,d),6.28(1H,m),4.88(1H,brs),4.30(1H,m),2.10(2H,m),1.75(2H,m),1.65(2H,m),1.48(2H,m)。
制备例65:6-氯-N-(环丙基甲基)吡啶-2-胺
将2,6-二氯吡啶(0.15g,10mmol)、环丙基甲胺(1.3mL,15mmol)、(2-联苯基)二叔丁基膦(0.15g,0.5mmol)和叔丁醇钠(1.44g,15mmol)溶于甲苯(50mL),向其中缓慢地添加乙酸钯(II)(0.11g,0.05mmol),并将混合物在80℃搅拌6小时。将反应物在减压下浓缩并通过色谱法纯化,得到标题化合物(0.21g,8.8%)。
1H-NMR(CDCl3)δ7.33(1H,t),6.56(1H,d),6.24(1H,d),3.10(2H,m),1.06(1H,m),0.54(2H,m),0.25(2H,m)。
制备例66:3-碘-N-异丙基-吡啶基-2-胺
将2-氟-3-碘-吡啶(0.15g,0.67mmol)和丙-2-胺(0.17mL,2mmol)以与制备例64相同的方式反应,得到标题化合物(0.047g,27%)。
1H-NMR(CDCl3)δ8.06(1H,m),7.80(1H,d),6.28(1H,m),4.73(1H,brs),4.20(1H,m),1.25(6H,d)。
制备例67:N-环丙基-3-碘-吡啶基-2-胺
将2-氟-3-碘-吡啶(0.15g,0.67mmol)和环丙胺(0.14mL,2mmol)以与制备例64相同的方式反应,得到标题化合物(0.013g,8%)。
1H-NMR(CDCl3)δ8.17(1H,m),7.82(1H,m),6.37(1H,m),5.17(1H,brs),2.78(1H,m),0.86(2H,m),0.56(2H,m)。
制备例68:N-(6-溴-2-吡啶基)氨基甲酸叔丁酯
将6-溴-吡啶-2-基胺(0.717g,4.14mmol)、TEA(0.75mL,5.39mmol)和二甲基氨基吡啶(0.1g,0.83mmol)溶于DCM(6mL),在室温向其中缓慢地添加溶于DCM(1.4mL)的叔丁氧基羰基叔丁基碳酸酯(1.08g,4.96mmol)。将混合物在室温搅拌3小时,并在减压下浓缩,并通过柱色谱法纯化,得到标题化合物(0.648g,57%)。
1H-NMR(CDCl3)δ7.88(1H,d),7.50(1H,t),7.20(1H,brs),7.12(1H,d),1.51(9H,s)。
制备例69:N-(6-溴-2-吡啶基)-N-异丙基-氨基甲酸叔丁酯
在将在制备例68中获得的N-(6-溴-2-吡啶基)氨基甲酸叔丁酯(0.2g,0.73mmol)溶于DMF(2.5mL)之后,向其中缓慢地添加NaH(60%,在矿物油中,0.048g,1.1mmol),并将混合物在室温搅拌30分钟。向其中添加2-溴丙烷(0.14mL,1.46mmol)并将混合物在室温搅拌16小时。将反应物在减压下浓缩,并添加氯化铵水溶液,然后用EtOAc萃取。将有机层分离并用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.06g,26%)。
1H-NMR(CDCl3)δ7.84(1H,t),7.27(1H,d),7.21(1H,d),4.55(1H,m),1.44(9H,s),1.30(6H,d)。
制备例70:N-环戊基-2-碘苯胺
在将2-碘苯胺(0.39g,1.78mmol)溶于二氯乙烷(6mL)之后,向其中添加环戊酮(0.15g,1.78mmol)和乙酸(0.11mL,1.96mmol),并将混合物在室温搅拌16小时。向其中添加三乙酰氧基硼氢化钠(0.56g,2.67mmol)并将混合物搅拌5小时。将反应物用水稀释并用DCM萃取。将有机层分离并用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.12g,23%)。
1H-NMR(CDCl3)δ7.64(1H,d),7.18(1H,t),6.60(1H,d),6.40(1H,t),4.14(1H,brs),3.80(1H,m),2.02(2H,m),1.76(2H,m),1.63(2H,m),1.53(2H,m)。
制备例71:3-溴-N-环戊基苯胺
将3-溴苯胺(0.306g,1.78mmol)和环戊酮(0.15g,1.78mmol)以与制备例70相同的方式反应,得到标题化合物(0.347g,81%)。
1H-NMR(CDCl3)δ6.98(1H,t),6.77(1H,d),6.72(1H,m),6.49(1H,m),3.77(2H,m),2.02(2H,m)。1.72(2H,m),1.62(2H,m),1.45(2H,m)。
制备例72:2-碘-N-丙基苯胺
将2-碘苯胺(0.5g,2.3mmol)和丙醛(0.22mL,3.0mmol)以与制备例70相同的方式反应,得到标题化合物(0.39g,60%)。
1H-NMR(CDCl3)δ7.65(1H,d),7.20(1H,t),6.56(1H,d),6.42(1H,t),4.15(1H,brs),3.12(2H,q),1.70(2H,m),1.03(3H,t)。
制备例73:N-(环丙基甲基)-2-碘苯胺
将2-碘苯胺(0.5g,2.3mmol)和环丙基甲醛(0.2mL,2.76mmol)以与制备例70相同的方式反应,得到标题化合物(0.5g,80%)。
1H-NMR(CDCl3)δ7.66(1H,d),7.20(1H,t),6.54(1H,d),6.43(1H,t),4.27(1H,brs),3.00(2H,m),1.15(1H,m),0.60(2H,m),0.28(2H,m)。
制备例74:2-碘-N-异丙基苯胺
2-碘苯胺(0.5g,2.3mmol)和丙酮(0.25mL,3.42mmol)以与制备例70相同的方式反应,得到标题化合物(0.4g,66%)。
1H-NMR(CDCl3)δ7.69(1H,d),7.23(1H,t),6.60(1H,d),6.45(1H,t),4.03(1H,brs),3.70(1H,m),1.31(6H,d)。
制备例75:2-溴-N-环丁基苯胺
在将1,2-二溴苯(0.3g,1.27mmol)、环丁基胺(0.22mL,2.54mmol)、Cs2CO3(0.83g,2.54mmol)和4,5-双(二苯基膦基)-9,9-二甲基呫吨(0.073mg,0.13mmol)溶于1,4-二噁烷(12mL)之后,向其中添加Pd2(dba)3(0.03g,0.03mmol)并将混合物在回流下搅拌16小时。将反应物通过使用C盐过滤并通过柱色谱法纯化,得到标题化合物(0.136g,47%)。
1H-NMR(CDCl3)δ7.39(1H,d),7.15(1H,t),6.54(2H,m),4.42(1H,brs),3.92(1H,m),2.45(2H,m),1.87(4H,m)。
制备例76:3-溴-N-(环丙基甲基苯胺
将3-溴苯胺(0.5g,2.9mmol)和环丙基甲醛(0.26mL,3.48mmol)以与制备例70相同的方式反应,得到标题化合物(0.413g,62%)。
1H-NMR(CDCl3)δ6.99(1H,t),6.79(1H,d),6.73(1H,m),6.51(1H,m),3.86(1H,brs),2.93(2H,d),1.07(1H,m),0.56(2H,m),0.24(2H,m)。
制备例77:3-溴-N-异丙基苯胺
将3-溴苯胺(0.5g,2.9mmol)和丙酮(0.43mL,5.8mmol)以与制备例70相同的方式反应,得到标题化合物(0.6g,96%)。
1H-NMR(CDCl3)δ7.00(1H,t),6.77(1H,d),6.70(1H,m),6.46(1H,m),3.60(1H,m),3.51(1H,brs),1.20(6H,d)。
制备例78:1-(3-溴苯基)吡咯烷
在将1,3-二溴苯(1.0g,4.24mmol)、吡咯烷(0.43mL,5.0mmol)、叔丁醇钠(1.14g,11.87mmol)和BINAP(0.2g,0.32mmol)溶于甲苯(17mL)之后,向其中添加Pd2(dba)3(0.097g,0.1mmol)并将混合物在回流下搅拌4小时。将反应物通过使用C盐过滤并通过柱色谱法纯化,得到标题化合物(0.52g,54%)。
1H-NMR(CDCl3)δ7.05(1H,t),6.75(1H,d),6.67(1H,m),6.45(1H,m),3.26(4H,m),2.00(4H,m)。
制备例79:3-溴-N-丙基苯胺
将3-溴苯胺(1.45g,8.42mmol)和丙醛(0.49g,8.42mmol)以与制备例70相同的方式反应,得到标题化合物(0.22g,12%)。
1H-NMR(CDCl3)δ6.99(1H,t),6.78(1H,d),6.72(1H,m),6.50(1H,m),3.70(1H,brs),3.05(2H,t),1.66(2H,m),1.00(3H,t)。
制备例80:3-溴-N-环丁基苯胺
将1,3-二溴苯(0.45mL,3.7mmol)和环丁基胺(0.53g,7.45mmol)以与制备例75相同的方式反应,得到标题化合物(0.028g,3%)。
1H-NMR(CDCl3)δ7.00(1H,t),6.79(1H,d),6.66(1H,m),6.45(1H,m),3.87(2H,m),2.42(2H,m),1.81(4H,m)。
制备例81:2-溴-4-氯-N-环戊基苯胺
将2-溴-4-氯苯胺(0.508g,2.46mmol)和环戊酮(0.207g,2.46mmol)以与制备例70相同的方式反应,得到标题化合物(0.083g,12%)。
1H-NMR(CDCl3)δ7.39(1H,m),7.12(1H,m),6.57(1H,m),4.25(1H,brs),3.76(1H,m),2.03(2H,m),1.76(2H,m),1.63(2H,m),1.50(2H,m)。
制备例82:N-环戊基-4-氟-2-碘苯胺
将4-氟-2-碘-苯胺(2.0g,18mmol)和环戊酮(0.195g,2.32mmol)以与制备例70相同的方式反应,得到标题化合物(0.19g,27%)。
1H-NMR(CDCl3)δ7.40(1H,m),6.95(1H,m),6.52(1H,m),3.93(1H,brs),3.75(1H,m),2.03(2H,m),1.76(2H,m),1.64(2H,m),1.51(2H,m)。
制备例83:三氟甲磺酸环戊烯-1-酯
将环戊酮(0.3g,3.6mmol)溶于THF(10mL),并将混合物冷却至-78℃。向其中缓慢地添加双(三甲基甲硅烷基)氨基锂(1.0M,在THF中,3.3mL,3.3mmol),并将混合物搅拌50分钟。向其中缓慢地添加N-苯基-双(三氟甲磺酰亚胺)(1.17g,3.27mmol),并将混合物搅拌16小时。向反应物添加氯化铵水溶液,然后用Et2O萃取。将有机层分离并用MgSO4干燥,并通过柱色谱法纯化,并在20℃在减压下浓缩,得到标题化合物(0.196g,27%)。
1H-NMR(CDCl3)δ5.63(1H,m),2.57(2H,m),2.42(2H,m),2.03(2H,m)。
制备例84:1-(环戊烯-1-基)-3-硝基-苯
在向在制备例83中获得的三氟甲磺酸环戊烯-1-酯(0.525g,2.43mmol)和(3-硝基苯基)硼酸(0.81g,4.86mmol)中添加1N NaOH水溶液(7.29mL,7.29mmol)和1,4-二噁烷(24mL)之后,将混合物充N2气5分钟,然后向其中添加PdCl2(dppf)-DCM(0.10g,0.12mmol)和DPPF(0.067g,0.12mmol),并将混合物在回流下搅拌16小时。向反应物添加水,然后用EtOAc萃取,并用MgSO4干燥。将残余物通过柱色谱法纯化,得到标题化合物(0.055g,12%)。
1H-NMR(CDCl3)δ8.24(1H,m),8.04(1H,m),7.72(1H,d),7.48(1H,t),6.35(1H,m),2.74(2H,m),2.58(2H,m),2.07(2H,m)。
制备例85:3-环戊基苯胺
将在制备例84中获得的1-(环戊烯-1-基)-3-硝基-苯(0.073g,0.39mmol)以与制备例50的步骤B相同的方式反应,得到标题化合物(0.06g,95%)。
1H-NMR(CDCl3)δ7.05(1H,t),6.66(1H,d),6.58(1H,m),6.52(1H,m),3.59(2H,brs),2.90(1H,m),2.02(2H,m),1.78(2H,m),1.66(2H,m),1.55(2H,m)。
制备例86:1-环戊基-3-碘-苯
在将在制备例85中获得的3-环戊基苯胺(0.06g,0.37mmol)溶于6M HCl水溶液(1.9mL)之后,在0℃向其中缓慢地添加亚硝酸钠(0.5M水溶液,1.2mL,0.6mmol)。将混合物在0℃搅拌10分钟,并缓慢地添加碘化钾(1.0M水溶液,0.9mL,0.9mmol),然后将混合物搅拌40分钟。在向其中添加碳酸氢钠水溶液以将溶液的pH调节为10之后,将反应物用EtOAc萃取,并将有机层用MgSO4干燥,得到标题化合物(0.07g,70%)。
1H-NMR(CDCl3)δ7.58(1H,m),7.50(1H,d),7.19(1H,d),7.00(1H,t),2.92(1H,m),2.04(2H,m),1.80(2H,m),1.68(2H,m),1.58(2H,m)。
制备例87:1-溴-3-(环戊基甲基)苯
在0℃向环戊基溴化镁(2.0M,在Et2O中,2.4mL,4.8mmol)中添加催化的碘化铜(I),并将混合物搅拌30分钟。向其中缓慢地添加溶解在THF(10mL)中的1-溴-3-(溴甲基)苯(1.0g,4mmol),并将混合物搅拌16小时。向反应物添加磷酸二氢钾水溶液并用EtOAc萃取。将有机层用MgSO4干燥并通过柱色谱法纯化,得到标题化合物(0.116g,12%)。
1H-NMR(CDCl3)δ7.33(1H,m),7.32(1H,m),7.12(1H,t),7.09(1H,m),2.57(2H,d),2.06(1H,m),1.70(2H,m),1.64(2H,m),1.53(2H,m),1.17(2H,m)。
制备例88:1-溴-2-(环戊基甲基)苯
将1-溴-2-(溴甲基)苯(1.0g,4mmol)以与制备例87相同的方式反应,得到标题化合物(0.24g,25%)。
1H-NMR(CDCl3)δ7.51(1H,d),7.20(2H,m),7.03(1H,m),2.74(2H,d),2.20(1H,m),1.68(4H,m),1.26(4H,m)。
制备例89:2-溴-6-(溴甲基)吡啶
在将(6-溴-2-吡啶基)甲醇(0.768g,4.08mmol)和三苯基膦(1.12g,4.28mmol)溶于DCM(7mL)之后,在0℃向其中添加四溴化碳(1.48g,4.45mmol),然后将混合物搅拌2小时。将反应物在减压下浓缩并将残余物通过柱色谱法纯化,得到标题化合物(0.527g,51%)。
1H-NMR(CDCl3)δ7.55(1H,t),7.42(2H,m),4.49(2H,s)。
制备例90:2-溴-6-(二乙氧基磷酰基甲基)吡啶
在将在制备例89中获得的2-溴-6-(溴甲基)吡啶(0.527g,2.1mmol)和三乙基亚磷酸酯(0.36mL,2.1mmol)溶于甲苯(4mL)之后,将混合物在回流下搅拌5天,然后在减压下浓缩,得到标题化合物(0.718g,99%)。
1H-NMR(CDCl3)δ7.50(1H,t),7.37(2H,m),4.10(4H,m),3.38(2H,d),1.29(6H,t)。
制备例91:2-溴-6-(亚环戊基甲基)吡啶
在将在制备例90中获得的2-溴-6-(二乙氧基磷酰基甲基)吡啶(0.24g,0.7mmol)和环戊酮(0.058mg,0.7mmol)溶于THF(3.5mL)之后,向其中缓慢地添加双(三甲基甲硅烷基)氨基锂(1.0M,在THF中,0.84mL,0.84mmol),并将混合物搅拌4小时。向反应物添加水,然后用EtOAc萃取。将有机层分离并用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.115g,68%)。
1H-NMR(CDCl3)δ7.43(1H,t),7.19(1H,d),7.12(1H,d),6.40(1H,m),2.73(2H,m),2.52(2H,m),1.80(2H,m),1.68(2H,m)。
制备例92:1-溴-2-(环丁基甲基)苯
将1-溴-2-(溴甲基)苯(0.4g,1.6mmol)和环丁基溴化镁(1.0M,在THF中)以与制备例87相同的方式反应,得到标题化合物(0.06g,17%)。
1H-NMR(CDCl3)δ7.50(1H,d),7.20(1H,t),7.16(1H,m),7.03(1H,m),2.83(2H,d),2.67(1H,m),2.05(2H,m),1.85(2H,m),1.75(2H,m)。
制备例93:1-溴-3-(环丁基甲基)苯
将1-溴-3-(溴甲基)苯(0.4g,1.6mmol)和环丁基溴化镁(1.0M,在THF中)以与制备例87相同的方式反应,得到标题化合物(0.03g,8%)。
1H-NMR(CDCl3)δ7.28(2H,m),7.12(1H,t),7.05(1H,m),2.66(2H,d),2.55(1H,m),2.03(2H,m),1.83(2H,m),1.71(2H,m)。
制备例94:2-溴-6-(亚环丁基甲基)吡啶
将在制备例90中获得的2-溴-6-(二乙氧基磷酰基甲基)吡啶(0.225g,0.73mmol)和环丁酮(0.051g,0.73mmol)以与制备例91相同的方式反应,得到标题化合物(0.1g,61%)。
1H-NMR(CDCl3)δ7.42(1H,t),7.19(1H,d),7.04(1H,d),6.18(1H,m),3.13(2H,m),2.92(2H,m),2.13(2H,m)。
制备例95:1-(环戊烯-1-基)-2-硝基-苯
将在制备例83中获得的三氟甲磺酸环戊烯-1-酯(0.196g,0.9mmol)和(2-硝基苯基)硼酸(0.226g,1.36mmol)以与制备例13相同的方式反应,得到标题化合物(0.085g,50%)。
1H-NMR(CDCl3)δ7.74(1H,d),7.54(1H,t),7.35(2H,m),5.84(1H,m),2.58(2H,m),2.50(2H,m),2.02(2H,m)。
制备例96:2-环戊基苯胺
将在制备例95中获得的1-(环戊烯-1-基)-2-硝基-苯(0.085g,0.45mmol)以与制备例85相同的方式反应,得到标题化合物(0.061g,84%)。
1H-NMR(CDCl3)δ7.13(1H,d),7.01(1H,t),6.75(1H,t),6.68(1H,d),3.66(2H,brs),2.98(1H,m),2.04(2H,m),1.80(2H,m),1.69(4H,m)。
制备例97:1-环戊基-2-碘-苯
将在制备例96中获得的2-环戊基苯胺(0.061g,0.38mmol)以与制备例85相同的方式反应,得到标题化合物(0.067g,65%)。
1H-NMR(CDCl3)δ7.91(1H,m),7.27(2H,m),6.87(1H,m),3.24(1H,m),2.12(2H,m),1.82(2H,m),1.72(2H,m),1.53(2H,m)。
制备例98:2-溴-6-环戊基-吡啶
在将2,6-二溴吡啶(0.41g,1.73mmol)、碘化铜(I)(0.078g,0.41mmol)和PdCl2(dppf)-DCM(0.167g,0.20mmol)溶于THF(3.5mL)之后,将混合物充N2气5分钟。向反应物缓慢地添加环戊基溴化锌(0.5M,在THF中,4.1mL,2.05mmol),并将混合物在室温搅拌16小时。向反应物添加Hex并通过色谱法纯化,得到标题化合物(0.175g,44%)。
1H-NMR(CDCl3)δ7.42(1H,t),7.27(1H,d),7.12(1H,d),3.14(1H,m),2.07(2H,m),1.79(6H,m)。
制备例99:3-苄基氧基-2-甲基-吡啶
在向2-甲基吡啶-3-醇(1.25g,11mmol)添加CH3CN(32mL)和氢氧化四丁基铵(40wt%水溶液,2.97g,11mmol)之后,将混合物在室温搅拌30分钟。将反应物在减压下浓缩,并添加溴甲基苯(1.37mL,11mmol)和CH3CN(63mL),并将混合物在回流下搅拌4小时。将反应物在减压下浓缩并通过色谱法纯化,得到标题化合物(1.94g,88%)。
1H-NMR(CDCl3)δ8.08(1H,m),7.41(4H,m),7.35(1H,m),7.11(1H,d),7.07(1H,m),5.09(2H,s),2.53(3H,s)。
制备例100:3-苄基氧基吡啶-2-甲醛
在将在制备例99中获得的3-苄基氧基-2-甲基-吡啶(0.36g,1.8mmol)溶于1,4-二噁烷(30mL)之后,向其中添加二氧化硒(0.4g,3.6mmol)并将混合物在回流下搅拌4天。向反应物添加碳酸氢钠水溶液,然后用EtOAc萃取。将有机层用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.29g,75%)。
1H-NMR(CDCl3)δ10.44(1H,s),8.41(1H,m),7.40(7H,m),5.26(2H,s)。
制备例101:3-苄基氧基-2-(2-甲基丙-1-烯基)吡啶
向异丙基三苯基鏻碘化物(0.7g,1.6mmol)添加THF(10mL),并冷却至0℃。在向其中缓慢地添加双(三甲基甲硅烷基)氨基锂(1.0M,在THF中,1.6mL,1.6mmol)之后,将混合物搅拌10分钟,并向其中缓慢地添加溶于THF(5mL)的在制备例100中获得的3-苄基氧基吡啶-2-甲醛(0.29g,1.35mmol)。将混合物在室温搅拌2小时,并添加氯化铵水溶液,然后用EtOAc萃取。将有机层用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.03g,9%)。
1H-NMR(CDCl3)δ8.19(1H,m),7.37(5H,m),7.14(1H,d),7.02(1H,m),6.57(1H,s),5.09(2H,s),2.08(3H,s),1.97(3H,s)。
制备例102:2-异丁基吡啶-3-醇
将在制备例101中获得的3-苄基氧基-2-(2-甲基丙-1-烯基)吡啶(0.03g,0.12mmol)以与制备例50的步骤B相同的方式反应,得到标题化合物(0.023g,99%)。
1H-NMR(CDCl3)δ8.00(1H,m),7.95(1H,m),7.34(1H,m),2.90(2H,d),2.54(1H,m),0.94(6H,d)。
制备例103:(2-异丁基-3-吡啶基)三氟甲磺酸酯
向在制备例102中获得的2-异丁基吡啶-3-醇(0.023g,0.15mmol)添加DCM(0.8mL)、TEA(0.023mL,0.17mmol)和N-苯基-双(三氟甲磺酰亚胺)(0.06g,0.17mmol),并将混合物在室温搅拌16小时。向反应物添加水,并用DCM萃取,然后通过柱色谱法纯化,得到标题化合物(0.017g,40%)。
1H-NMR(CDCl3)δ8.57(1H,m),7.58(1H,m),7.25(1H,m),2.79(2H,d),2.22(1H,m),0.95(6H,d)。
制备例104:3-苄基氧基-2-溴-吡啶
将2-溴-3-吡啶醇(10g,57mmol)和溴甲基苯(7.2mL,60mmol)以与制备例8相同的方式反应,得到标题化合物(15g,99%)。
1H-NMR(CDCl3)δ8.00(1H,m),7.44(2H,m),7.40(2H,m),7.32(1H,m),7.18(2H,m),5.19(2H,s)。
制备例105:3-苄基氧基-2-环戊基-吡啶
向在制备例104中获得的3-苄基氧基-2-溴-吡啶(1.32g,5mmol)添加甲苯(10mL)、乙酸钯(II)(0.17g,0.75mmol)和SPhos(0.62g,1.5mmol),然后冷却至0℃。向反应物缓慢地添加环戊基锌溴化物(0.5M,在THF中,15mL,7.5mmol),并在室温搅拌4小时。然后向反应物添加氯化铵水溶液,并用EtOAc萃取。将有机层用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.832g,65%)。
1H-NMR(CDCl3)δ8.15(1H,m),7.42(4H,m),7.40(1H,m),7.12(1H,m),7.05(1H,m),5.08(2H,s),3.64(1H,m),1.99(2H,m),1.85(4H,m),1.67(2H,m)。
制备例106:(2-环戊基-3-吡啶基)三氟甲磺酸酯
将在制备例105中获得的3-苄基氧基-2-环戊基-吡啶(0.5g,2mmol)以与制备例50的步骤B和制备例103相同的方式依次反应,得到标题化合物(0.376g,66%)。
1H-NMR(CDCl3)δ8.58(1H,m),7.54(1H,m),7.22(1H,m),3.49(1H,m),2.05(2H,m),1.89(4H,m),1.72(2H,m)。
制备例107:3-苄基氧基-2-(亚环戊基甲基)吡啶
将在制备例100中获得的3-苄基氧基吡啶-2-甲醛(0.3g,1.4mmol)和环戊基三苯基鏻溴化物(0.87g,2.11mmol)以与制备例101相同的方式反应,得到标题化合物(0.096g,26%)。
1H-NMR(CDCl3)δ8.19(1H,m),7.42(4H,m),7.32(1H,m),7.10(1H,m),6.99(1H,m),6.83(1H,m),5.09(2H,s),2.84(2H,m),2.54(2H,m),1.76(2H,m),1.68(2H,m)。
制备例108:[2-(环戊基甲基)-3-吡啶基]三氟甲磺酸酯
将在制备例107中获得的3-苄基氧基-2-(亚环戊基甲基)吡啶(0.096g,0.36mmol)以与制备例50的步骤B和制备例103相同的方式依次反应,得到标题化合物(0.04g,36%)。
1H-NMR(CDCl3)δ8.56(1H,m),7.58(1H,m),7.25(1H,m),2.92(2H,d),2.37(1H,m),1.72(4H,m),1.56(2H,m),1.26(2H,m)。
制备例109:4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸乙酯
将2-氟-3-碘-吡啶(0.394g,1.77mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.72g,1.94mmol)以与制备例13相同的方式反应,得到标题化合物(0.55g,92%)。
1H-NMR(CDCl3)δ8.22(1H,m),7.83(1H,m),7.30(1H,m),7.15(2H,m),4.25(2H,t),4.15(2H,q),2.59(2H,t),2.10(2H,m),1.27(3H,t)。
制备例110:4-(3-碘-2-吡啶基)吗啉
将2-氟-3-碘-吡啶(0.3g,1.34mmol)和吗啉(0.35g,4mmol)以与制备例64相同的方式反应,得到标题化合物(0.12g,28%)。
1H-NMR(CDCl3)δ8.27(1H,m),8.07(1H,m),6.68(1H,m),3.88(4H,m),3.28(4H,m)。
制备例111:3-碘-N-(四氢吡喃-4-基甲基)吡啶-2-胺
将2-氟-3-碘-吡啶(0.3g,1.34mmol)和4-氨基甲基四氢吡喃(0.46g,4mmol)以与制备例64相同的方式反应,得到标题化合物(0.24g,56%)。
1H-NMR(CDCl3)δ8.06(1H,m),7.81(1H,m),6.32(1H,m),5.00(1H,brs),4.00(2H,m),3.41(2H,m),3.36(2H,m),1.90(1H,m),1.70(2H,m),1.38(2H,m)。
制备例112:(2R)-2-(4-溴-2,6-二氟-苯氧基)丙酸甲酯
将在制备例2的步骤A中获得的4-溴-2,6-二氟-苯酚(2.57g,12.3mmol)和(S)-乳酸甲酯(1.28g,12.3mmol)以与制备例27的步骤C相同的方式反应,得到标题化合物(3.28g,90%)。
1H-NMR(CDCl3)δ7.08(2H,m),4.79(1H,m),3.77(3H,s),1.62(3H,d)。
制备例113:(2R)-2-(4-溴-2,6-二氟-苯氧基)丙-1-醇
将在制备例112中获得的(2R)-2-(4-溴-2,6-二氟-苯氧基)丙酸甲酯(3.28g,11.1mmol)以与制备例30的步骤A相同的方式反应,得到标题化合物(2.80g,94%)。
1H NMR(CDCl3)δ7.10(2H,m),4.33(1H,m),3.75(1H,m),3.70(1H,m),2.08(1H,brs),1.31(3H,d)。
制备例114:(2R)-2-(4-溴-2,6-二氟-苯氧基)丙醛
向DCM(75mL)添加草酰氯(1.08mL,12.6mmol),并冷却至-78℃。向其中缓慢地添加溶于DCM(37mL)的DMSO(1.93mL,27.3mmol),并将混合物搅拌2小时。向混合物缓慢地添加依次溶于DCM(37mL)和TEA(7.0mL,50mmol)的在制备例113中获得的(2R)-2-(4-溴-2,6-二氟-苯氧基)丙-1-醇(2.80g,10.48mmol)。将混合物在室温搅拌1小时,并添加1N HCl水溶液,然后用DCM萃取。将有机层用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(2.28g,58%)。
1H NMR(CDCl3)δ9.85(1H,s),7.13(2H,m),4.51(1H,m),1.48(3H,d)。
制备例115:(Z,4R)-4-(4-溴-2,6-二氟-苯氧基)戊-2-烯酸甲酯
将双(2,2,2-三氟乙基)(甲氧基羰基甲基)膦酸酯(1.2g,3.77mmol)溶于THF(30mL),冷却至0℃,并依次添加碘化钠(0.67g,4.52mmol)和1,8-二氮杂二环[5.4.0]十一碳-7-烯(0.62mL,4.15mmol)。将混合物在10分钟后冷却至-78℃,缓慢地添加溶于THF(8mL)的在制备例114中获得的(2R)-2-(4-溴-2,6-二氟-苯氧基)丙醛(1.0g,3.77mmol)。将反应物在0℃搅拌1小时,添加氯化铵水溶液,然后用EtOAc萃取。将有机层用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.7g,58%)。
1H NMR(CDCl3)δ7.05(2H,m),6.37(1H,m),5.81(2H,m),3.68(3H,s),1.51(3H,d)。
制备例116:(4R)-4-(4-溴-2,6-二氟-苯氧基)戊酸甲酯
将在制备例115中获得的(Z,4R)-4-(4-溴-2,6-二氟-苯氧基)戊-2-烯酸甲酯(0.66g,2mmol)以与制备例50的步骤B相同的方式反应,得到标题化合物(0.45g,70%)。
1H NMR(CDCl3)δ7.08(2H,m),4.28(1H,m),3.69(3H,s),2.58(2H,t),2.00(2H,m),1.27(3H,d)。
制备例117:(4R)-4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸甲酯
将在制备例116中获得的(4R)-4-(4-溴-2,6-二氟-苯氧基)戊酸甲酯(0.45g,1.4mmol)以与制备例1的步骤A相同的方式反应,得到标题化合物(0.062g,13%)。
1H NMR(CDCl3)δ7.31(2H,m),4.38(1H,m),3.68(3H,s),2.59(2H,t),2.00(2H,m),1.32(12H,s),1.25(3H,d)。
制备例118:(2S)-2-(4-溴-2,6-二氟-苯氧基)丙酸甲酯
将在制备例2的步骤A中获得的4-溴-2,6-二氟-苯酚(1.0g,4.7mmol)和(R)-乳酸甲酯(0.49g,4.7mmol)以与制备例27的步骤C相同的方式反应,得到标题化合物(1.17g,83%)。
1H-NMR(CDCl3)δ7.08(2H,m),4.79(1H,m),3.77(3H,s),1.62(3H,d)。
制备例119:(2S)-2-(4-溴-2,6-二氟-苯氧基)丙-1-醇
将在制备例118中获得的(2S)-2-(4-溴-2,6-二氟-苯氧基)丙酸甲酯(1.17g,4.0mmol)以与制备例30的步骤A相同的方式反应,得到标题化合物(0.9g,85%)。
1H NMR(CDCl3)δ7.10(2H,m),4.33(1H,m),3.75(1H,m),3.70(1H,m),2.08(1H,brs),1.31(3H,d)。
制备例120:(2S)-2-(4-溴-2,6-二氟-苯氧基)丙醛
将在制备例119中获得的(2S)-2-(4-溴-2,6-二氟-苯氧基)丙-1-醇(0.9g,3.3mmol)以与制备例114相同的方式反应,得到标题化合物(0.61g,68%)。
1H NMR(CDCl3)δ9.85(1H,s),7.13(2H,m),4.51(1H,m),1.48(3H,d)。
制备例121:(E,4S)-4-(4-溴-2,6-二氟-苯氧基)戊-2-烯酸乙酯
将在制备例120中获得的(2S)-2-(4-溴-2,6-二氟-苯氧基)丙醛(0.61g,2.3mmol)和(三苯基正膦亚基)乙酸乙酯(0.8g,2.3mmol)以与制备例50的步骤A相同的方式反应,得到标题化合物(0.69g,90%,E/Z=2/1)。
1H NMR(CDCl3)δ(Z-异构体)7.05(2H,m),6.34(1H,m),5.81(2H,m),4.14(2H,q),1.51(3H,d),1.26(3H,t)。
(E-异构体)δ7.08(2H,m),6.93(1H,m),6.03(1H,d),4.83(1H,m),4.20(2H,q),1.48(3H,d),1.29(3H,t)。
制备例122:(4S)-4-(4-溴-2,6-二氟-苯氧基)戊酸乙酯
将在制备例121中获得的(E,4S)-4-(4-溴-2,6-二氟-苯氧基)戊-2-烯酸乙酯(0.49g,1.4mmol)以与制备例50的步骤B相同的方式反应,得到标题化合物(0.326g,71%)。
1H NMR(CDCl3)δ7.08(2H,m),4.29(1H,m),4.14(2H,q),2.58(2H,t),2.00(2H,m),1.27(6H,m)。
制备例123:(4S)-4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸乙酯
将在制备例122中获得的(4S)-4-(4-溴-2,6-二氟-苯氧基)戊酸乙酯(0.326g,1mmol)以与制备例1的步骤A相同的方式反应,得到标题化合物(0.237g,62%)。
1H NMR(CDCl3)δ7.31(2H,m),4.37(1H,m),4.13(2H,q),2.58(2H,t),2.00(2H,m),1.33(12H,s),1.27(6H,m)。
制备例124:1-(6-氯-2-吡啶基)-N,N-二甲基-吡咯烷-3-胺
将2,6-二氯吡啶(1g,6.75mmol)和N,N-二甲基吡咯烷-3-胺(0.77g,6.75mmol)以与制备例5相同的方式反应,得到标题化合物(1.42g,90%)。
1H NMR(CDCl3)δ7.35(1H,t),6.52(1H,m),6.20(1H,m),3.75(1H,m),3.63(1H,m),3.39(1H,m),3.22(1H,m),2.78(1H,m),2.31(6H,s),2.23(1H,m),1.93(1H,m)。
制备例125:2-氯-6-异丙基硫基-吡啶
将2,6-二氯吡啶(3.0g,20.3mmol)和丙-2-硫醇(1.88mL,20.3mmol)以与制备例37相同的方式反应,得到标题化合物(3.63g,95%)。
1H-NMR(CDCl3)δ7.40(1H,t),7.05(1H,t),6.98(1H,t),4.00(1H,m),1.40(6H,d)。
制备例126:2-氯-6-苯氧基-吡啶
将2,6-二氯吡啶(2.0g,13.5mmol)和苯酚(1.4mL,14.9mmol)以与制备例37相同的方式反应,得到标题化合物(3.5g,84%)。
1H-NMR(CDCl3)δ7.62(1H,t),7.41(2H,m),7.21(1H,t),7.14(2H,d),6.74(2H,d)。
制备例127:2-溴-5-甲氧基-苯酚
在将3-甲氧基-苯酚(1g,8.05mmol)溶于CS2(4mL)之后,向其中添加Br2(0.4mL)并将混合物在室温搅拌2小时。向反应物添加Na2S2O3水溶液,然后用EtOAc萃取。将有机层分离并用MgSO4干燥,并在减压下浓缩,得到标题化合物(1.05g,64%)。
1H-NMR(CDCl3)δ7.31(1H,d),6.59(1H,m),6.40(1H,m),5.45(1H,s),3.79(3H,s)。
制备例128:1-溴-2-环戊基氧基-4-甲氧基-苯
将在实制备施例127中获得的2-溴-5-甲氧基-苯酚(0.2g,0.98mmol)、溴代-环戊烷(0.16mL)和Cs2CO3(0.96g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.26g,96%)。
1H-NMR(CDCl3)δ7.38(1H,d),6.47(1H,m),6.36(1H,m),4.75(1H,m),3.79(3H,s),1.88(6H,m),1.61(2H,m)。
制备例129:2-溴-1-环戊基氧基-4-氟-苯
将2-溴-4-氟-苯酚(0.3g,1.57mmol)、溴代-环戊烷(0.25mL)和Cs2CO3(1.53g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.38g,93%)。
1H-NMR(CDCl3)δ7.27(1H,m),6.94(1H,m),6.82(1H,m),4.73(1H,m),1.86(6H,m),1.62(2H,m)。
制备例130:3-溴-5-甲基-吡啶基-2-醇
将5-甲基-吡啶基-2-醇(1g,9.16mmol)和Br2(0.47mL)以与制备例127相同的方式反应,得到标题化合物(1.7g,98%)。
1H-NMR(CDCl3)δ7.73(1H,s),7.22(1H,s),2.10(3H,s)。
制备例131:3-溴-2-环戊基氧基-5-甲基-吡啶
将在制备例130中获得的3-溴-5-甲基-吡啶基-2-醇(0.5g,2.66mmol)、溴代-环戊烷(0.43mL)和Cs2CO3(2.6g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.25g,37%)。
1H-NMR(CDCl3)δ7.86(1H,s),7.60(1H,s),5.38(1H,m),2.21(3H,s),1.93(2H,m),1.82(4H,m),1.61(2H,m)。
制备例132:1-溴-2-异丙氧基-4-甲氧基-苯
将在制备例127中获得的2-溴-5-甲氧基-苯酚(0.2g,0.98mmol)、2-溴-丙烷(0.14mL)和Cs2CO3(0.96g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.23g,94%)。
1H-NMR(CDCl3)δ7.39(1H,d),6.48(1H,m),6.39(1H,m),4.51(1H,m),3.77(3H,s),1.37(6H,d)。
制备例133:3-溴-2-异丙氧基-5-甲基-吡啶
将在制备例130中获得的3-溴-5-甲基-吡啶基-2-醇(0.3g,2.66mmol)、2-溴-丙烷(0.22mL)和Cs2CO3(1.56g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.09g,25%)。
1H-NMR(CDCl3)δ7.85(1H,s),7.62(1H,s),5.26(1H,m),2.21(3H,s),1.35(6H,d)。
制备例134:2-溴-4-氟-1-异丙氧基-苯
将2-溴-4-氟-苯酚(0.3g,1.57mmol)、2-溴-丙烷(0.22mL)和Cs2CO3(1.53g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.33g,89%)。
1H-NMR(CDCl3)δ7.28(1H,m),6.94(1H,m),6.88(1H,m),4.44(1H,m),1.32(6H,d)。
制备例135:3-溴-6-甲基-吡啶基-2-醇
将6-甲基-吡啶基-2-醇(0.3g,2.7mmol)和Br2(0.14mL)以与制备例127相同的方式反应,得到标题化合物(0.09g,18%)。
1H-NMR(CDCl3)δ7.48(1H,d),6.32(1H,d),2.43(3H,s)。
制备例136:3-溴-2-环戊基氧基-6-甲基-吡啶
将在制备例135中获得的3-溴-6-甲基-吡啶基-2-醇(0.09g,0.50mmol)、溴代-环戊烷(0.08mL)和Cs2CO3(0.49g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.12g,93%)。
1H-NMR(CDCl3)δ7.60(1H,d),6.40(1H,d),5.30(1H,m),2.53(3H,s),1.94(2H,m),1.78(4H,m),1.61(2H,m)。
制备例137:2-溴-6-氟-4-甲基-苯酚
将2-氟-4-甲基-苯酚(0.4g,3.17mmol)和Br2(0.16mL)以与制备例127相同的方式反应,得到标题化合物(0.37g,56%)。
1H-NMR(CDCl3)δ7.07(1H,s),6.87(1H,m),5.32(1H,s),2.26(3H,s)。
制备例138:1-溴-3-氟-2-异丙氧基-5-甲基-苯
将在制备例137中获得的2-溴-6-氟-4-甲基-苯酚(0.10g,0.49mmol)、2-溴-丙烷(0.07mL)和Cs2CO3(0.48g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.11g,88%)。
1H-NMR(CDCl3)δ7.12(1H,s),6.84(1H,m),4.45(1H,m),2.26(3H,s),1.34(6H,d)。
制备例139:1-溴-3-氟-5-甲基-2-丙氧基-苯
将在制备例137中获得的2-溴-6-氟-4-甲基-苯酚(0.10g,0.49mmol)、1-溴-丙烷(0.07mL)和Cs2CO3(0.48g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.10g,85%)。
1H-NMR(CDCl3)δ7.11(1H,s),6.83(1H,m),3.99(2H,t),2.26(3H,s),1.80(2H,m),1.05(3H,t)。
制备例140:1-溴-2,4-二丙氧基-苯
将4-溴-苯-1,3-二醇(0.1g,0.53mmol),1-溴-丙烷(0.10mL)和Cs2CO3(0.52g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.13g,93%)。
1H-NMR(CDCl3)δ7.37(1H,d),6.46(1H,m),6.36(1H,m),3.94(2H,t),3.86(2H,t),1.84(2H,m),1.78(2H,m),1.06(3H,t),1.02(3H,t)。
制备例141:2-溴-3-氟-4-甲基-苯酚
将3-氟-4-甲基-苯酚(0.3g,2.38mmol)和Br2(0.12mL)以与制备例127相同的方式反应,得到标题化合物(0.37g,75%)。
1H-NMR(CDCl3)δ7.03(1H,m),6.83(1H,m),5.35(1H,s),2.26(3H,s)。
制备例142:2-溴-1-环戊基氧基-3-氟-4-甲基-苯
将在制备例141中获得的2-溴-3-氟-4-甲基-苯酚(0.10g,0.49mmol)、溴代-环戊烷(0.08mL)和Cs2CO3(0.48g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.09g,67%)。
1H-NMR(CDCl3)δ7.11(1H,m),6.84(1H,m),4.66(1H,m),2.29(3H,s),1.90(4H,m),1.75(2H,m),1.60(2H,m)。
制备例143:2-溴-6-氟-苯酚
将2-氟-苯酚(0.32g,2.85mmol)和Br2(0.14mL)以与制备例127相同的方式反应,得到标题化合物(0.53g,97%)。
1H-NMR(CDCl3)δ7.25(1H,m),7.14(1H,d),6.88(1H,t),5.20(1H,s)。
制备例144:1-溴-2-环戊基氧基-3-氟-苯
将在制备例143中获得的2-溴-6-氟-苯酚(0.10g,0.52mmol)、溴代-环戊烷(0.08mL)和Cs2CO3(0.51g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.13g,96%)。
1H-NMR(CDCl3)δ7.23(1H,m),7.15(1H,m),6.83(1H,t),4.75(1H,m),1.89-1.78(6H,m),1.63(2H,m)。
制备例145:1-溴-2-环戊基氧基-3-氟-5-甲基-苯
将在制备例137中获得的2-溴-6-氟-4-甲基-苯酚(0.10g,0.49mmol)、溴代-环戊烷(0.08mL)和Cs2CO3(0.48g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.12g,87%)。
1H-NMR(CDCl3)δ7.13(1H,s),6.84(1H,d),4.87(1H,m),2.27(3H,s),1.94(4H,m),1.75(2H,m),1.60(2H,m)。
制备例146:6-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]己酸乙酯
向在制备例2的步骤B中获得的2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚(1.11g,4.34mmol)、6-溴己酸乙酯(0.97g,4.34mmol)和Cs2CO3(2.83g,8.68mmol)添加CH3CN(15mL),并将混合物在回流下搅拌2小时。将残余物分离并在减压下浓缩,得到标题化合物(1.4g,80%)。
1H-NMR(CDCl3)δ7.31(2H,m),4.17(2H,m),4.14(2H,q),2.32(2H,t),1.77(2H,m),1.68(2H,m),1.51(2H,m),1.32(12H,s),1.24(3H,t)。
制备例147:5-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯氧基]-戊酸乙酯
向在制备例4步骤A中获得的2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚(0.50g,2.10mmol)、5-溴戊酸乙酯(0.53g,2.52mmol)和Cs2CO3(1.37g,4.20mmol)添加CH3CN(7mL),并将混合物在回流下搅拌2小时。将残余物分离并在减压下浓缩,得到标题化合物(0.40g,52%)。
1H-NMR(CDCl3)δ7.50(2H,t),6.92(1H,t),4.13(2H,q),4.06(2H,t),2.39(2H,t),1.92-1.77(4H,m),1.32(12H,s),1.24(3H,t)。
制备例148:4-(4-溴-苯基硫基)丁酸乙酯
将4-溴-苯硫醇(0.5g,2.64mmol)、NaH(60%,在矿物油中,0.11g,2.64mmol)和4-溴-丁酸乙酯(0.42mL,2.91mmol)以与制备例12相同的方式反应,得到标题化合物(0.80g,99%)。
1H-NMR(CDCl3)δ7.38(2H,d),7.19(2H,d),4.13(2H,q),2.93(2H,t),2.43(2H,t),1.93(2H,m),1.24(3H,t)。
制备例149:4-(3'-羟基-联苯-4-基硫基)丁酸乙酯
将在制备例148中获得的4-(4-溴-苯基硫基)-丁酸乙酯(0.92g,3.04mmol)、3-羟基苯基硼酸(0.42g,3.04mmol)、2M Na2CO3溶液(3mL)和Pd(PPh3)4(0.18g,0.15mmol)以与制备例13相同的方式反应,得到标题化合物(0.27g,28%)。
1H-NMR(CDCl3)δ7.48(2H,d),7.38(2H,d),7.28(1H,t),7.13(1H,m),7.02(1H,m),6.81(1H,m),5.00(1H,s),4.13(2H,q),2.99(2H,t),2.49(2H,t),2.00(2H,m),1.25(3H,t)。
制备例150:[1-(1-甲氧基羰基甲基-环丙基甲基二硫基甲基)-环丙基]-乙酸甲酯
在将(1-巯基甲基-环丙基)-乙酸甲酯(1g,6.2mmol)溶于甲醇(20mL)之后,向其中添加I2(0.79g,3.1mmol)并将混合物在室温搅拌1小时。向反应物添加水,然后用EtOAc萃取。将有机层分离并用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.80g,40%)。
1H-NMR(CDCl3)δ3.68(6H,s),2.89(4H,s),2.44(4H,s),0.62(4H,m),0.56(4H,m)。
制备例151:[1-(4-溴-2,6-二氟-苯基硫基甲基)-环丙基]-乙酸甲酯
在75℃向在制备例150中获得的[1-(1-甲氧基羰基甲基-环丙基甲基二硫基甲基)-环丙基]-乙酸甲酯(0.40g,1.25mmol)和4-溴-2,6-二氟苯基胺(0.2g,0.96mmol)充N2气。向其中缓慢地滴加亚硝酸异戊酯(0.33mL,2.50mmol),并将混合物在75℃搅拌1小时。将反应物在减压下浓缩并通过色谱法纯化,得到标题化合物(0.10g,29%)。
1H-NMR(CDCl3)δ7.10(2H,d),3.66(3H,s),2.99(2H,s),2.55(2H,s),0.45(2H,m),0.36(2H,m)。
制备例152:[1-(3,5-二氟-3'-羟基-联苯-4-基硫基甲基)-环丙基]-乙酸甲酯
将在制备例151中获得的[1-(4-溴-2,6-二氟-苯基硫基甲基)-环丙基]-乙酸甲酯(0.10g,0.28mmol)、3-羟基苯基硼酸(0.04g,0.28mmol),2M Na2CO3水溶液(0.3mL)和Pd(PPh3)4(0.02g,0.01mmol)以与制备例13相同的方式反应,得到标题化合物(0.02g,19%)。
1H-NMR(CDCl3)δ7.32(1H,t),7.12(3H,m),7.03(1H,s),6.89(1H,m),5.51(1H,s),3.65(3H,s),3.00(2H,s),2.57(2H,s),0.45-0.39(4H,m)。
制备例153:甲氧基羰基甲基二硫基-乙酸甲酯
将巯基-乙酸甲酯(1g,9.4mmol)和I2(1.19g,4.7mmol)以与制备例150相同的方式反应,得到标题化合物(0.50g,25%)。
1H-NMR(CDCl3)δ3.75(6H,s),3.58(4H,s)。
制备例154:(4-溴-2,6-二氟-苯基硫基)-乙酸甲酯
将在制备例153中获得的甲氧基羰基甲基二硫基-乙酸甲酯(0.9g,4.28mmol)、4-溴-2,6-二氟苯基胺(0.5g,2.40mmol)和亚硝酸异戊酯(0.84mL,6.25mmol)以与制备例151相同的方式反应,得到标题化合物(0.30g,42%)。
1H-NMR(CDCl3)δ7.13(2H,d),3.67(3H,s),3.52(2H,s)。
制备例155:(3,5-二氟-3'-羟基-联苯-4-基硫基)-乙酸甲酯
将在制备例154中获得的(4-溴-2,6-二氟-苯基硫基)-乙酸甲酯(0.12g,0.40mmol)、3-羟基苯基硼酸(0.06g,0.40mmol)、2M Na2CO3水溶液(0.4mL)和Pd(PPh3)4(0.02g,0.02mmol)以与制备例13相同的方式反应,得到标题化合物(0.04g,30%)。
1H-NMR(CDCl3)δ7.31(1H,t),7.15(2H,d),7.11(1H,m),7.00(1H,s),6.88(1H,m),4.84(1H,s),3.69(3H,s),3.58(2H,s)。
制备例156:(3'-环戊基氧基-3,5-二氟-联苯-4-基硫基)-乙酸甲酯
将在制备例155中获得的(3,5-二氟-3'-羟基-联苯-4-基硫基)-乙酸甲酯(0.037g,0.12mmol)、溴代-环戊烷(0.02mL)和Cs2CO3(0.12g,0.36mmol)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.035g,77%)。
1H-NMR(CDCl3)δ7.33(1H,t),7.16(2H,d),7.07(1H,m),7.02(1H,s),6.90(1H,m),4.80(1H,m),3.69(3H,s),3.57(2H,s),1.92-1.80(6H,m),1.63(2H,m)。
制备例157:2-(3'-环戊基氧基-3,5-二氟-联苯-4-基硫基)-乙醇
在将在制备例156中获得的(3'-环戊基氧基-3,5-二氟-联苯-4-基硫基)-乙酸甲酯(0.034g,0.09mmol)溶于THF(1mL)之后,在0℃向其中添加LiBH4(0.09g,0.18mmol),并将混合物在室温搅拌2小时。向反应物添加水,然后用EtOAc萃取。将有机层分离并用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.027g,87%)。
1H-NMR(CDCl3)δ7.33(1H,t),7.16(2H,d),7.07(1H,m),7.02(1H,s),6.91(1H,m),4.81(1H,m),3.65(2H,q),3.04(2H,t),2.24(1H,t),1.92-1.80(6H,m),1.63(2H,m)。
制备例158:4-(2-氯-乙基硫基)-3'-环戊基氧基-3,5-二氟-联苯
在将在制备例157中获得的2-(3'-环戊基氧基-3,5-二氟-联苯-4-基硫基)-乙醇(0.027g,0.08mmol)溶于CH3CN(1mL)之后,在0℃向其中添加SOCl2(0.01mL,0.15mmol),并将混合物在室温搅拌1小时。将反应物在减压下浓缩,得到标题化合物(0.028g,98%)。
1H-NMR(CDCl3)δ7.34(1H,t),7.17(2H,d),7.08(1H,m),7.03(1H,s),6.91(1H,m),4.81(1H,m),3.62(2H,t),3.17(2H,t),1.93-1.81(6H,m),1.64(2H,m)。
制备例159:4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯
将在制备例148中获得的4-(4-溴-苯基硫基)-丁酸乙酯(0.83g,2.7mmol)、双(频哪醇合)二硼(0.76g,3.0mmol)、乙酸钾(0.67g,6.8mmol)和二氯[1,1'-双(二苯基膦基)二茂铁]钯(II)(0.20g,0.27mmol)以与制备例1的步骤A相同的方式反应,得到标题化合物(0.73g,75%)。
1H-NMR(CDCl3)δ7.70(2H,d),7.27(2H,d),4.11(2H,q),2.99(2H,t),2.44(2H,t),1.96(2H,m),1.32(12H,s),1.24(3H,t)。
制备例160:4-(4-甲氧基-苄基硫基)丁酸乙酯
将(4-甲氧基-苯基)-甲硫醇(0.5g,3.24mmol)、NaH(60%,在矿物油中,0.13g,3.24mmol)和4-溴-丁酸乙酯(0.51mL,3.57mmol)以与制备例12相同的方式反应,得到标题化合物(0.70g,80%)。
1H-NMR(CDCl3)δ7.22(2H,d),6.83(2H,d),4.12(2H,q),3.79(3H,s),3.65(2H,s),2.43(2H,t),2.38(2H,t),1.87(2H,m),1.24(3H,t)。
制备例161:4-巯基丁酸乙酯
在将在制备例160中获得的4-(4-甲氧基-苄基硫基)-丁酸乙酯(0.7g,2.61mmol)溶于TFA(5mL)之后,向其中添加茴香醚(1.5mL)和三氟甲磺酸(0.5mL),并将混合物在室温搅拌1小时。向反应物添加NaHCO3水溶液,然后用EtOAc萃取。将有机层分离并用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.37g,95%)。
1H-NMR(CDCl3)δ4.13(2H,q),3.11(2H,t),2.41(2H,t),1.99(2H,m),1.26(3H,t)。
制备例162:3',4',5'-三氟-联苯-3-醇
将5-溴-1,2,3-三氟-苯(0.20g,0.95mmol)、3-羟基苯基硼酸(0.13g,0.95mmol),2M Na2CO3水溶液(0.9mL)和Pd(PPh3)4(0.055g,0.05mmol)以与制备例13相同的方式反应,得到标题化合物(0.18g,83%)。
1H-NMR(CDCl3)δ7.30(1H,t),7.17(2H,m),7.06(1H,m),6.95(1H,s),6.85(1H,m),4.91(1H,s)。
制备例163:3'-环丁氧基-3,4,5-三氟-联苯
将在制备例162中获得的3',4',5'-三氟-联苯-3-醇(0.05g,0.22mmol)、溴代-环丁烷(0.03mL)和Cs2CO3(0.22g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.04g,64%)。
1H-NMR(CDCl3)δ7.32(1H,t),7.15(2H,m),7.04(1H,m),6.92(1H,s),6.82(1H,m),4.68(1H,m),2.46(2H,m),2.20(2H,m),1.88(1H,m),1.71(1H,m)。
制备例164:3,4,5-三氟-3'-异丙氧基-联苯
将在制备例162中获得的3',4',5'-三氟-联苯-3-醇(0.05g,0.22mmol)、2-溴-丙烷(0.03mL)和Cs2CO3(0.22g)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.06g,100%)。
1H-NMR(CDCl3)δ7.32(1H,t),7.18(2H,m),7.03(1H,m),6.99(1H,s),6.89(1H,m),4.60(1H,m),1.35(6H,d)。
制备例165:4,4,5,5-四甲基-2-(3,4,5-三氟-苯基)-[1,3,2]二氧杂硼杂环戊烷
将5-溴-1,2,3-三氟-苯(0.50g,2.37mmol)、双(频哪醇合)二硼(0.66g,2.61mmol)、乙酸钾(0.58g,5.92mmol)和反式-二氯双(三苯基膦)钯(II)(0.17g,0.24mmol)以与制备例1的步骤A相同的方式反应,得到标题化合物(0.24g,39%)。
1H-NMR(CDCl3)δ7.36(2H,m),1.35(12H,s)。
制备例166:2-丙氧基-6-(3,4,5-三氟-苯基)-吡啶
将在制备例165中获得的4,4,5,5-四甲基-2-(3,4,5-三氟-苯基)-[1,3,2]二氧杂硼杂环戊烷(0.03g,0.12mmol)、在制备例227中获得的2-溴-6-丙氧基-吡啶(0.027,0.13mmol)、2M Na2CO3水溶液(0.2mL)和Pd(PPh3)4(0.007g,0.006mmol)以与制备例13相同的方式反应,得到标题化合物(0.023g,74%)。
1H-NMR(CDCl3)δ7.64(3H,m),7.23(1H,d),6.71(1H,d),4.35(2H,t),1.84(2H,m),1.05(3H,t)。
制备例167:2-异丙氧基-6-(3,4,5-三氟-苯基)-吡啶
将在制备例165中获得的4,4,5,5-四甲基-2-(3,4,5-三氟-苯基)-[1,3,2]二氧杂硼杂环戊烷(0.054g,0.21mmol)、在制备例228中获得的2-溴-6-异丙氧基-吡啶(0.050g,0.23mmol)、2M Na2CO3水溶液(0.3mL)和Pd(PPh3)4(0.012g,0.01mmol)以与制备例13相同的方式反应,得到标题化合物(0.02g,32%)。
1H-NMR(CDCl3)δ7.63(3H,m),7.22(1H,d),6.67(1H,d),5.44(1H,m),1.40(6H,d)。
制备例168:4-溴-2,6-二氟-苯硫醇
步骤A:4-溴-2,6-二氟-苯磺酰氯
在将CuCl2(0.77g,5.77mmol)溶于水(200mL)之后,在0℃向其中添加SOCl2(29mL,0.40mol),并将混合物在室温搅拌18小时。然后,将4-溴-2,6-二氟苯胺(20g,0.096mol)溶于HCl(240mL)和水(900mL),并在0℃向其中添加溶于水(200mL)的NaNO2(7g,0.10mol)溶液。向混合物添加所制备的亚硫酰氯溶液,并反应1小时,得到固态的标题化合物(24g,85%)。
步骤B:4-溴-2,6-二氟-苯硫醇
在将在步骤A中获得的4-溴-2,6-二氟-苯磺酰氯(24g,0.08mol)溶于THF(270mL)之后,向其中添加PPh3(75g,0.28mol)。然后,将混合物在室温搅拌15分钟,添加水,并在室温搅拌18小时。向反应物添加水,然后用EtOAc萃取。将有机层分离并用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(15g,83%)。
1H-NMR(CDCl3)δ7.10(2H,d),3.58(1H,s)。
制备例169:4-(4-溴-2,6-二氟-苯基硫基)丁酸乙酯
将在制备例168中获得的4-溴-2,6-二氟-苯硫醇(15g,0.066mol)、NaH(60%,在矿物油中,2.6g,0.066mol)和4-溴-丁酸乙酯(10mL,0.073mol)以与制备例12相同的方式反应,得到标题化合物(18.56g,82%)。
1H-NMR(CDCl3)δ7.11(2H,d),4.11(2H,q),2.90(2H,t),2.43(2H,t),1.82(2H,m),1.24(3H,t)。
制备例170:4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯
将在制备例169中获得的4-(4-溴-2,6-二氟-苯基硫基)-丁酸乙酯(11.6g,0.034mol)、双(频哪醇合)二硼(9.5g,0.038mol)、乙酸钾(8.4g,0.085mol)和二氯[1,1'-双(二苯基膦基)二茂铁]钯(II)(2.5g,0.003mol)以与制备例1的步骤A相同的方式反应,得到标题化合物(10.6g,80%)。
1H-NMR(CDCl3)δ7.30(2H,d),4.09(2H,q),2.94(2H,t),2.43(2H,t),1.83(2H,m),1.33(12H,s),1.22(3H,t)。
制备例171:2-丙氧基-3-(3,4,5-三氟-苯基)-吡啶
将在制备例165中获得的4,4,5,5-四甲基-2-(3,4,5-三氟-苯基)-[1,3,2]二氧杂硼杂环戊烷(0.05g,0.19mmol)、在制备例202中获得的3-碘-2-丙氧基-吡啶(0.056g,0.21mmol)、2M Na2CO3水溶液(0.3mL)和Pd(PPh3)4(0.011g,0.01mmol)以与制备例13相同的方式反应,得到标题化合物(0.02g,43%)。
1H-NMR(CDCl3)δ8.15(1H,m),7.55(1H,m),7.21(2H,m),6.95(1H,m),4.31(2H,t),1.77(2H,m),1.00(3H,t)。
制备例172:2-异丙基硫基-6-(3,4,5-三氟-苯基)-吡啶
将在制备例165中获得的4,4,5,5-四甲基-2-(3,4,5-三氟-苯基)-[1,3,2]二氧杂硼杂环戊烷(0.050g,0.19mmol)、在制备例201中获得的2-溴-6-异丙基硫基-吡啶(0.049g,0.21mmol)、2M Na2CO3水溶液(0.3mL)和Pd(PPh3)4(0.011g,0.01mmol)以与制备例13相同的方式反应,得到标题化合物(0.035g,64%)。
1H-NMR(CDCl3)δ7.67(2H,m),7.53(1H,t),7.32(1H,d),7.12(1H,d),4.11(1H,m),1.46(6H,d)。
制备例173:2-丙基硫基-6-(3,4,5-三氟-苯基)-吡啶
将在制备例165中获得的将4,4,5,5-四甲基-2-(3,4,5-三氟-苯基)-[1,3,2]二氧杂硼杂环戊烷(0.050g,0.19mmol)、在制备例229中获得的2-溴-6-丙基硫基-吡啶(0.049g,0.21mmol)、2M Na2CO3水溶液(0.3mL)和Pd(PPh3)4(0.011g,0.01mmol)以与制备例13相同的方式反应,得到标题化合物(0.03g,57%)。
1H-NMR(CDCl3)δ7.66(2H,m),7.53(1H,t),7.32(1H,d),7.14(1H,d),3.22(2H,t),1.80(2H,m),1.09(3H,t)。
制备例174:2-环丁基硫基-3-(3,4,5-三氟-苯基)-吡啶
将在制备例165中获得的4,4,5,5-四甲基-2-(3,4,5-三氟-苯基)-[1,3,2]二氧杂硼杂环戊烷(0.050g,0.19mmol)、在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.062g,0.21mmol)、2M Na2CO3水溶液(0.3mL)和Pd(PPh3)4(0.011g,0.01mmol)以与制备例13相同的方式反应,得到标题化合物(0.056g,98%)。
1H-NMR(CDCl3)δ8.43(1H,m),7.33(1H,m),7.04(3H,m),4.43(1H,m),2.52(2H,m),2.05(4H,m)。
制备例175:2-环丁氧基-3-(3,4,5-三氟-苯基)-吡啶
将在制备例165中获得的4,4,5,5-四甲基-2-(3,4,5-三氟-苯基)-[1,3,2]二氧杂硼杂环戊烷(0.050g,0.19mmol)、在制备例200中获得的2-环丁氧基-3-碘-吡啶(0.059g,0.21mmol)、2M Na2CO3水溶液(0.3mL)和Pd(PPh3)4(0.011g,0.01mmol)以与制备例13相同的方式反应,得到标题化合物(0.01g,18%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.55(1H,m),7.25(2H,m),6.93(1H,m),5.28(1H,m),2.46(2H,m),2.12(2H,m),1.82(1H,m),1.68(1H,m)。
制备例176:2-环戊基硫基-3-(3,4,5-三氟-苯基)-吡啶
将在制备例165中获得的4,4,5,5-四甲基-2-(3,4,5-三氟-苯基)-[1,3,2]二氧杂硼杂环戊烷(0.050g,0.19mmol)、在制备例39中获得的2-环戊基硫基-3-碘-吡啶(0.065g,0.21mmol)、2M Na2CO3水溶液(0.3mL)和Pd(PPh3)4(0.011g,0.01mmol)以与制备例13相同的方式反应,得到标题化合物(0.02g,33%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.31(1H,m),7.05(3H,m),4.10(1H,m),2.19(2H,m),1.72-1.52(6H,m)。
制备例177:4-溴-2-氟-苯磺酰氯
将4-溴-2-氟-苯胺(1g,5.26mmol)以与制备例168步骤A相同的方式反应,得到标题化合物(0.49g,34%)。
1H-NMR(CDCl3)δ7.85(1H,m),7.55(2H,m)。
制备例178:4-溴-2-氟-苯硫醇
将在制备例177中获得的4-溴-2-氟-苯磺酰氯(0.49g,1.79mmol)以与制备例168的步骤B相同的方式反应,得到标题化合物(0.37g,99%)。
1H-NMR(CDCl3)δ7.23(1H,m),7.16(2H,m),3.57(1H,s)。
制备例179:4-(4-溴-2-氟-苯基硫基)丁酸乙酯
将在制备例178中获得的4-溴-2-氟-苯硫醇(0.37g,1.81mmol)、NaH(60%,在矿物油中,0.07g,1.81mmol)和4-溴-丁酸乙酯(0.28mL,1.99mmol)以与制备例12相同的方式反应,得到标题化合物(0.43g,75%)。
1H-NMR(CDCl3)δ7.23(3H,m),4.12(2H,q),2.92(2H,t),2.44(2H,t),1.90(2H,m),1.25(3H,t)。
制备例180:4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯
将在制备例179中获得的4-(4-溴-2-氟-苯基硫基)-丁酸乙酯(0.43g,1.36mmol)、双(频哪醇合)二硼(0.34g,1.50mmol)、乙酸钾(0.33g,3.4mmol)和二氯[1,1'-双(二苯基膦基)二茂铁]钯(II)(0.10g,0.14mmol)以与制备例1的步骤A相同的方式反应,得到标题化合物(0.27g,53%)。
1H-NMR(CDCl3)δ7.50(1H,d),7.43(1H,d),7.32(1H,t),4.11(2H,q),2.98(2H,t),2.45(2H,t),1.93(2H,m),1.33(12H,s),1.24(3H,t)。
制备例181:2-环丁氧基-6-(3,4,5-三氟-苯基)-吡啶
将在制备例165中获得的4,4,5,5-四甲基-2-(3,4,5-三氟-苯基)-[1,3,2]二氧杂硼杂环戊烷(0.050g,0.19mmol)、在制备例230中获得的2-溴-6-(环丁氧基)-吡啶(0.044g,0.19mmol)、2M Na2CO3水溶液(0.3mL)和Pd(PPh3)4(0.011g,0.01mmol)以与制备例13相同的方式反应,得到标题化合物(0.03g,49%)。
1H-NMR(CDCl3)δ7.64(3H,m),7.22(1H,d),6.67(1H,d),5.25(1H,m),2.52(2H,m),2.19(2H,m),1.87(1H,m),1.76(1H,m)。
制备例182:2-环戊基氧基-6-(3,4,5-三氟-苯基)-吡啶
将在制备例165中获得的4,4,5,5-四甲基-2-(3,4,5-三氟-苯基)-[1,3,2]二氧杂硼杂环戊烷(0.050g,0.19mmol)、在制备例231中获得的2-溴-6-(环戊氧基)吡啶(0.047g,0.19mmol)、2M Na2CO3水溶液(0.3mL)和Pd(PPh3)4(0.011g,0.01mmol)以与制备例13相同的方式反应,得到标题化合物(0.035g,62%)。
1H-NMR(CDCl3)δ7.67-7.59(3H,m),7.19(1H,d),6.67(1H,d),5.49(1H,m),2.03(2H,m),1.85(4H,m),1.65(2H,m)。
制备例183:2-环丙基甲氧基-6-(3,4,5-三氟-苯基)-吡啶
将在制备例165中获得的4,4,5,5-四甲基-2-(3,4,5-三氟-苯基)-[1,3,2]二氧杂硼杂环戊烷(0.04g,0.15mmol)、在制备例232中获得的2-溴-6-(环丙基甲氧基)-吡啶(0.035g,0.15mmol)、2M Na2CO3水溶液(0.2mL)和Pd(PPh3)4(0.01g,0.01mmol)以与制备例13相同的方式反应,得到标题化合物(0.034g,80%)。
1H-NMR(CDCl3)δ7.64(3H,m),7.24(1H,d),6.74(1H,d),4.23(2H,d),1.33(1H,m),0.64(2H,m),0.39(2H,m)。
制备例184:2-环丁基硫基-6-(3,4,5-三氟-苯基)-吡啶
将在制备例165中获得的4,4,5,5-四甲基-2-(3,4,5-三氟-苯基)-[1,3,2]二氧杂硼杂环戊烷(0.050g,0.19mmol)、在制备例233中获得的2-溴-6-环丁基硫基-吡啶(0.047g,0.19mmol)、2M Na2CO3水溶液(0.3mL)和Pd(PPh3)4(0.011g,0.01mmol)以与制备例13相同的方式反应,得到标题化合物(0.03g,52%)。
1H-NMR(CDCl3)δ7.66(2H,m),7.53(1H,t),7.29(1H,d),7.06(1H,d),4.41(1H,m),2.60(2H,m),2.20-2.10(4H,m)。
制备例185:2-环戊基硫基-6-(3,4,5-三氟-苯基)-吡啶
将在制备例165中获得的4,4,5,5-四甲基-2-(3,4,5-三氟-苯基)-[1,3,2]二氧杂硼杂环戊烷(0.050g,0.19mmol)、在制备例234中获得的2-溴-6-环戊基硫基-吡啶(0.050g,0.19mmol)、2M Na2CO3水溶液(0.3mL)和Pd(PPh3)4(0.011g,0.01mmol)以与制备例13相同的方式反应,得到标题化合物(0.042g,71%)。
1H-NMR(CDCl3)δ7.66(2H,m),7.52(1H,t),7.27(1H,d),7.11(1H,d),4.13(1H,m),2.22(2H,m),1.80-1.63(6H,m)。
制备例186:4-(2'-羟基-5'-甲基-联苯-4-基硫基)丁酸乙酯
将在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.1g,0.28mmol)和2-溴-4-甲基-苯酚(0.038mL,0.31mmol)以与制备例13相同的方式反应,得到标题化合物(0.02g,21%)。
1H-NMR(CDCl3)δ7.47(2H,d),7.39(2H,d),7.02(2H,m),6.86(1H,d),5.00(1H,s),4.12(2H,q),3.00(2H,t),2.47(2H,t),2.30(3H,s),1.99(2H,m),1.25(3H,t)。
制备例187:4-(2'-环戊基氧基-5'-甲基-联苯-4-基硫基)丁酸乙酯
将在制备例186中获得的4-(2'-羟基-5'-甲基-联苯-4-基硫基)-丁酸乙酯(0.02g,0.06mmol)、溴代-环戊烷(0.01mL)和Cs2CO3(0.06g,0.18mmol)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.02g,83%)。
1H-NMR(CDCl3)δ7.45(2H,d),7.32(2H,d),7.10(1H,s),7.04(1H,m),6.85(1H,d),4.67(1H,m),4.12(2H,q),3.00(2H,t),2.48(2H,t),2.31(3H,s),1.98(2H,m),1.78(4H,m),1.64-1.53(4H,m),1.25(3H,t)。
制备例188:2-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丙酸甲酯
步骤A:2-(4-溴-苯基硫基)-丙酸甲酯
将4-溴-苯硫醇(0.5g,2.64mmol)、NaH(60%,在矿物油中,0.11g,2.64mmol)和2-溴丙酸甲酯(0.32mL,2.91mmol)以与制备例12相同的方式反应,得到标题化合物(0.58g,80%)。
1H-NMR(CDCl3)δ7.43(2H,d),7.30(2H,d),3.76(1H,q),3.66(3H,s),1.47(3H,d)。
步骤B:2-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丙酸甲酯
将在步骤A中获得的2-(4-溴-苯基硫基)-丙酸甲酯(0.62g,2.2mmol)、双(频哪醇合)二硼(0.63g,2.4mmol)、乙酸钾(0.55g,5.6mmol)和二氯[1,1'-双(二苯基膦基)二茂铁]钯(II)(0.16g,0.22mmol)以与制备例1的步骤A相同的方式反应,得到标题化合物(0.30g,42%)。
1H-NMR(CDCl3)δ7.72(2H,d),7.40(2H,d),3.88(1H,q),3.67(3H,s),1.51(3H,d),1.33(12H,s)。
制备例189:2-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-丙酸甲酯
将在制备例188中获得的2-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丙酸甲酯(0.15g,0.46mmol)和在制备例38中获得的2-环戊氧基-3-碘-吡啶(0.16g,0.56mmol)以与制备例13相同的方式反应,得到标题化合物(0.045g,27%)。
1H-NMR(CDCl3)δ8.13(1H,m),7.59(1H,m),7.50(2H,d),7.46(2H,d),6.91(1H,m),5.50(1H,m),3.88(1H,m),3.68(3H,s),1.93(2H,m),1.82-1.58(6H,m),1.53(3H,d)。
制备例190:(E)-4-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-戊-2-烯酸乙酯
在将在制备例189中获得的2-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-丙酸甲酯(0.07g,0.19mmol)溶于DCM(1mL)之后,在-78℃向其中添加DIBAL-H(1.5M甲苯,0.15mL,0.21mol)。然后,在搅拌下用30分钟向其中添加通过将NaH(60%,在矿物油中,0.009g,0.23mmol)和膦基乙酸三乙酯(0.053g,0.23mmol)溶于DCM(1mL)所制备的溶液,并将混合物在室温搅拌18小时。向反应物添加酒石酸钾钠水溶液,然后用DCM萃取。将有机层分离并用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.023g,29%)。
1H-NMR(CDCl3)δ8.13(1H,m),7.59(1H,m),7.49(2H,d),7.40(2H,d),6.90(2H,m),5.64(1H,d),5.50(1H,m),4.16(2H,m),3.85(1H,m),1.93(2H,m),1.82-1.58(6H,m),1.46(3H,d),1.24(3H,t)。
制备例191:4-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-戊酸乙酯
在将在制备例190中获得的(E)-4-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-戊-2-烯酸乙酯(0.023g,0.06mmol)溶于乙醇(0.8mL)和THF(0.3mL)之后,向其中添加氯化钴(II)六水合物(0.016g,0.07mmol)。然后,在0℃向其中添加NaBH4(0.005g,0.14mol),并将混合物在室温搅拌4小时。向反应物添加水,然后用Et2O萃取。将有机层分离并用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.01g,43%)。
1H-NMR(CDCl3)δ8.13(1H,m),7.59(1H,m),7.49(2H,d),7.40(2H,d),6.91(1H,m),5.51(1H,m),4.14(2H,q),3.30(1H,m),2.53(2H,m),1.93(4H,m),1.81-1.60(6H,m),1.35(3H,d),1.24(3H,t)。
制备例192:2-[4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-丙酸甲酯
将在制备例188中获得的2-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丙酸甲酯(0.15g,0.46mmol)和在制备例37中获得的3-碘-2-异丙氧基-吡啶(0.15g,0.56mmol)以与制备例13相同的方式反应,得到标题化合物(0.043g,27%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.57(1H,m),7.53(2H,d),7.47(2H,d),6.91(1H,m),5.39(1H,m),3.83(1H,m),3.69(3H,s),1.55(3H,d),1.33(6H,d)。
制备例193:(E)-4-[4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊-2-烯酸乙酯
将在制备例192中获得的2-[4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-丙酸甲酯(0.054g,0.16mmol)、DIBAL-H(1.5M甲苯,0.12mL,0.18mol)、NaH(60%,在矿物油中,0.008g,0.19mmol)和膦基乙酸三乙酯(0.044g,0.19mmol)以与制备例190相同的方式反应,得到标题化合物(0.025g,41%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.59(1H,m),7.52(2H,d),7.42(2H,d),6.92(2H,m),5.67(1H,d),5.39(1H,m),4.18(2H,q),3.85(1H,m),1.46(3H,d),1.34(6H,d),1.25(3H,t)。
制备例194:2-(4-溴-2,6-二氟-苯基硫基)-丙酸甲酯
将在制备例168中获得的4-溴-2,6-二氟-苯硫醇(0.45g,2.0mmol)、NaH(60%,在矿物油中,0.08g,2.0mmol)和2-溴丙酸甲酯(0.24mL,2.2mmol)以与制备例12相同的方式反应,得到标题化合物(0.52g,83%)。
1H-NMR(CDCl3)δ7.14(2H,d),3.72(1H,q),3.69(3H,s),1.45(3H,d)。
制备例195:2-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丙酸甲酯
将在制备例194中获得的2-(4-溴-2,6-二氟-苯基硫基)-丙酸甲酯(0.52g,1.67mmol)、双(频哪醇合)二硼(0.47g,1.84mmol)、乙酸钾(0.41g,4.18mmol)和二氯[1,1'-双(二苯基膦基)二茂铁]钯(II)(0.12g,0.17mmol)以与制备例1的步骤A相同的方式反应,得到标题化合物(0.27g,45%)。
1H-NMR(CDCl3)δ7.32(2H,d),3.80(1H,q),3.64(3H,s),1.46(3H,d),1.33(12H,s)。
制备例196:2-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-丙酸甲酯
将在制备例195中获得的2-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丙酸甲酯(0.1g,0.28mmol)和在制备例38中获得的2-环戊氧基-3-碘-吡啶(0.12g,0.42mmol)以与制备例13相同的方式反应,得到标题化合物(0.052g,47%)。
1H-NMR(CDCl3)δ8.18(1H,m),7.62(1H,m),7.22(2H,d),6.95(1H,m),5.54(1H,m),3.80(1H,m),3.66(3H,s),1.95(2H,m),1.82-1.63(6H,m),1.48(3H,d)。
制备例197:(E)-4-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊-2-烯酸乙酯
将在制备例196中获得的2-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-丙酸甲酯(0.052g,0.13mmol)、DIBAL-H(1.5M甲苯,0.10mL,0.14mol)、NaH(60%,在矿物油中,0.006g,0.16mmmol)和膦基乙酸三乙酯(0.035g,0.16mmol)以与制备例190相同的方式反应,得到标题化合物(0.041g,71%)。
1H-NMR(CDCl3)δ8.18(1H,m),7.61(1H,m),7.19(2H,d),6.95(1H,m),6.85(1H,m),5.60(1H,d),5.52(1H,m),4.14(2H,m),3.95(1H,m),1.95(2H,m),1.81-1.64(6H,m),1.48(3H,d),1.24(3H,t)。
制备例198:2-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-丙酸甲酯
将在制备例195中获得的2-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丙酸甲酯(0.1g,0.28mmol)和在制备例39中获得的2-环戊基硫基-3-碘-吡啶(0.13g,0.42mmol)以与制备例13相同的方式反应,得到标题化合物(0.064g,56%)。
1H-NMR(CDCl3)δ8.46(1H,m),7.36(1H,m),7.07(3H,m),4.10(1H,m),3.83(1H,m),3.69(3H,s),2.19(2H,m),1.72-1.55(6H,m),1.54(3H,d)。
制备例199:(E)-4-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊-2-烯酸乙酯
将在制备例196中获得的2-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-丙酸甲酯(0.064g,0.15mmol)、DIBAL-H(1.5M甲苯,0.11mL,0.17mol)、NaH(60%,在矿物油中,0.008g,0.19mmol)和膦基乙酸三乙酯(0.042g,0.19mmol)以与制备例190相同的方式反应,得到标题化合物(0.039g,55%)。
1H-NMR(CDCl3)δ8.45(1H,m),7.33(1H,m),7.04(3H,m),6.81(1H,m),5.60(1H,d),4.15(3H,m),3.95(1H,m),2.19(2H,m),1.72-1.51(6H,m),1.47(3H,d),1.25(3H,t)。
制备例200:2-环丁氧基-3-碘-吡啶
将环丁醇(0.064g,1.34mmol)和2-氟-3-碘-吡啶(0.2g,0.89mmol)以与制备例37相同的方式反应,得到标题化合物(0.16g,66%)。
1H-NMR(CDCl3)δ8.07(1H,m),8.00(1H,m),6.61(1H,m),5.18(1H,m),2.47(2H,m),2.20(2H,m),1.84(1H,m),1.67(1H,m)。
制备例201:2-溴-6-异丙基硫基-吡啶
在将2,6-二溴吡啶(0.2g,0.84mmol)和Cs2CO3(0.41g,1.27mmol)溶于DMF(4mL)之后,向其中添加丙-2-硫醇(0.08mL,0.84mmol)并将混合物在室温搅拌8小时。向反应物添加水,然后用EtOAc萃取。将有机层分离并用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.17g,89%)。
1H NMR(CDCl3)δ7.28(1H,t),7.11(1H,d),7.08(1H,d),3.98(1H,m),1.41(6H,d)。
制备例202:3-碘-2-丙氧基-吡啶
将丙醇(0.1mL,1.34mmol)和2-氟-3-碘-吡啶(0.2g,0.89mmol)以与制备例37相同的方式反应,得到标题化合物(0.11g,46%)。
1H-NMR(CDCl3)δ8.08(1H,m),8.00(1H,m),6.61(1H,m),4.28(2H,t),1.82(2H,m),1.04(3H,t)。
制备例203:3-碘-2-丙基硫基-吡啶
在向2-氟-3-碘-吡啶(2.08g,9.3mmol)和丙-1-硫醇(0.89mL,9.8mmol)添加CH3CN(31mL)和Cs2CO3(3.33g,10.2mmol)之后,将混合物在回流下搅拌5小时。将反应物冷却至室温并分离,并将残余物通过柱色谱法纯化,得到标题化合物(1.58g,60%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.92(1H,m),6.71(1H,m),3.13(2H,t),1.75(2H,m),1.06(3H,t)。
制备例204:3-碘-2-吡咯烷-1-基-吡啶
在将2-氟-3-碘-吡啶(0.3g,1.34mmol)溶于DMF(5mL)之后,向其中添加TEA(0.19mL,1.34mmol)和吡咯烷(0.17mL,2.02mmol),并将混合物在60℃搅拌4小时。向反应物添加水,然后用EtOAc萃取。将有机层分离并用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.36g,98%)。
1H NMR(CDCl3)δ8.11(1H,m),7.97(1H,m),6.39(1H,m),3.65(4H,m),1.92(4H,m)。
制备例205:3-[(3-碘-2-吡啶基)氧基]-5-甲基-异噁唑
将2-氟-3-碘-吡啶(0.3g,1.34mmol)和5-甲基异噁唑-3-醇(0.147g,1.47mmol)以与制备例37相同的方式在80℃反应,得到标题化合物(0.15g,37%)。
1H-NMR(CDCl3)δ8.17(2H,m),6.87(1H,m),6.03(1H,s),2.44(3H,s)。
制备例206:2-[(3-碘-2-吡啶基)氧基]-N,N-二甲基-乙胺
将2-氟-3-碘-吡啶(0.3g,1.34mmol)和2-(二甲基氨基)乙醇(0.131g,1.47mmol)以与制备例37相同的方式在80℃反应,得到标题化合物(0.29g,75%)。
1H-NMR(CDCl3)δ8.09(1H,m),8.02(1H,m),6.64(1H,m),4.46(2H,t),2.79(2H,t),2.38(6H,s)。
制备例207:2-[2-(氮杂环丙烷-1-基)乙氧基]-3-碘-吡啶
将2-氟-3-碘-吡啶(0.3g,1.34mmol)和2-(氮杂环丙烷-1-基)乙醇(0.117g,1.34mmol)以与制备例37相同的方式在80℃反应,得到标题化合物(0.19g,49%)。
1H-NMR(CDCl3)δ8.09(1H,m),8.02(1H,m),6.64(1H,m),4.52(2H,t),2.65(2H,t),1.82(2H,m),1.35(2H,m)。
制备例208:2-(3-呋喃基甲氧基)-3-碘-吡啶
将2-氟-3-碘-吡啶(0.3g,1.34mmol)和3-呋喃基甲醇(0.132g,1.34mmol)以与制备例37相同的方式在80℃反应,得到标题化合物(0.36g,89%)。
1H-NMR(CDCl3)δ8.12(1H,m),8.04(1H,m),7.56(1H,s),7.41(1H,s),6.65(1H,m),6.53(1H,m),5.30(2H,s)。
制备例209:2-(2-呋喃基甲氧基)-3-碘-吡啶
将2-氟-3-碘-吡啶(0.3g,1.34mmol)和2-呋喃基甲醇(0.132g,1.34mmol)以与制备例37相同的方式在80℃反应,得到标题化合物(0.334g,83%)。
1H-NMR(CDCl3)δ8.12(1H,m),8.03(1H,m),7.44(1H,m),6.67(1H,m),6.47(1H,m),6.37(1H,m),5.38(2H,s)。
制备例210:3-碘-2-[(3-甲基氧杂环丁烷-3-基)甲氧基]吡啶
将2-氟-3-碘-吡啶(0.3g,1.34mmol)和(3-甲基氧杂环丁烷-3-基)甲醇(0.137g,1.34mmol)以与制备例37相同的方式在80℃反应,得到标题化合物(0.30g,74%)。
1H-NMR(CDCl3)δ8.11(1H,m),8.04(1H,m),6.67(1H,m),4.68(2H,d),4.46(2H,d),4.40(2H,s),1.48(3H,s)。
制备例211:3-碘-2-(四氢呋喃-3-基甲氧基)吡啶
将2-氟-3-碘-吡啶(0.3g,1.34mmol)和四氢呋喃-3-基甲醇(0.137g,1.34mmol)以与制备例37相同的方式在80℃反应,得到标题化合物(0.30g,74%)。
1H-NMR(CDCl3)δ8.08(1H,m),8.02(1H,m),6.65(1H,m),4.34(1H,m),4.24(1H,m),3.94(2H,m),3.80(1H,m),3.73(1H,m),2.78(1H,m),2.11(1H,m),1.80(1H,m)。
制备例212:3-碘-2-(四氢呋喃-2-基甲氧基)吡啶
将2-氟-3-碘-吡啶(0.3g,1.34mmol)和四氢呋喃-2-基甲醇(0.137g,1.34mmol)以与制备例37相同的方式在80℃反应,得到标题化合物(0.31g,76%)。
1H-NMR(CDCl3)δ8.08(1H,m),8.01(1H,m),6.63(1H,m),4.34(3H,m),3.99(1H,m),3.86(1H,m),2.08(2H,m),1.92(2H,m)。
制备例213:2-[3-(叔丁基-二甲基-甲硅烷氧基)-环戊基氧基]-3-碘-吡啶
将3-(叔丁基-二甲基-甲硅烷氧基)-环戊醇(0.44g,2.02mmol)和2-氟-3-碘-吡啶(0.30g,1.35mmol)以与制备例37相同的方式反应,得到标题化合物(0.39g,69%)。
1H-NMR(CDCl3)δ8.08(1H,m),7.99(1H,m),6.60(1H,m),5.49(1H,m),4.49(1H,m),2.23(1H,m),2.04(3H,m),1.80(1H,m),1.62(1H,m),0.88(9H,s),0.06(6H,s)。
制备例214:2-[4-(2-氟-吡啶-3-基)-苯基硫基]-丙酸甲酯
将在制备例188中获得的2-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丙酸甲酯(0.52g,1.62mmol)和2-氟-3-碘-吡啶(0.54g,2.43mmol)以与制备例13相同的方式反应,得到标题化合物(0.27g,57%)。
1H-NMR(CDCl3)δ8.20(1H,m),7.87(1H,m),7.55(4H,m),7.30(1H,m),3.88(1H,m),3.71(3H,s),1.53(3H,d)。
制备例215:(E)-4-[4-(2-氟-吡啶-3-基)-苯基硫基]-戊-2-烯酸乙酯
将在制备例214中获得的2-[4-(2-氟-吡啶-3-基)-苯基硫基]-丙酸甲酯(0.27g,0.92mmol)以与制备例190相同的方式反应,得到标题化合物(0.17g,54%)。
1H-NMR(CDCl3)δ8.20(1H,m),7.85(1H,m),7.52(4H,m),7.27(1H,m),6.88(1H,q),5.65(1H,d),4.16(2H,q),3.86(1H,m),1.46(3H,d),1.25(3H,t)。
制备例216:4-[4-(2-氟-吡啶-3-基)-苯基硫基]-戊酸乙酯
在将在制备例215中获得的(E)-4-[4-(2-氟-吡啶-3-基)-苯基硫基]-戊-2-烯酸乙酯(0.17g,0.5mmol)溶于1,2-二甲氧基乙烷(5mL)之后,向其中添加对甲苯磺酰肼(0.65g,3.51mmol)并将混合物在回流下搅拌5分钟。然后,向其中添加1.4M NaOAc水溶液(3.6mL)并将混合物在回流下搅拌18小时。将反应物用水稀释,然后用DCM萃取。将有机层分离并用MgSO4干燥,并通过柱色谱法纯化,得到标题化合物(0.1g,59%)。
1H-NMR(CDCl3)δ8.20(1H,m),7.87(1H,m),7.53-7.44(4H,m),7.28(1H,m),4.14(2H,q),3.35(1H,m),2.54(2H,t),1.94(2H,m),1.32(3H,d),1.26(3H,t)。
制备例217:4-[4-(2-环戊基硫基-吡啶-3-基)-苯基硫基]-戊酸乙酯
将在制备例216中获得的4-[4-(2-氟-吡啶-3-基)-苯基硫基]-戊酸乙酯(0.03g,0.09mmol)、环戊基硫醇(0.01mL,0.09mmol)和Cs2CO3(0.044g,0.13mmol)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.004g,10%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.41(2H,d),7.35(3H,m),7.02(1H,m),4.13(2H,q),3.30(1H,m),2.52(2H,m),2.17(2H,m),1.92(2H,m),1.71-1.48(6H,m),1.34(3H,d),1.26(3H,t)。
制备例218:2-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-丙酸甲酯
将在制备例188中获得的2-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丙酸甲酯(0.07g,0.19mmol)和在制备例37中获得的3-碘-2-异丙氧基-吡啶(0.077g,0.29mmol)以与制备例13相同的方式反应,得到标题化合物(0.05g,71%)。
1H-NMR(CDCl3)δ8.15(1H,m),7.60(1H,m),7.21(2H,d),6.93(1H,m),5.42(1H,m),3.77(1H,m),3.67(3H,s),1.50(3H,d),1.35(6H,d)。
制备例219:4-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊酸乙酯
将在制备例218中获得的2-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-丙酸甲酯(0.05g,0.14mmol)以与制备例190和制备例191相同的方式依次反应,得到标题化合物(0.015g,26%)。
1H-NMR(CDCl3)δ8.21(1H,m),7.65(1H,m),7.24(2H,d),6.97(1H,m),5.46(1H,m),4.17(2H,q),3.36(1H,m),2.60(2H,m),1.93(2H,m),1.40(6H,d),1.34(3H,d),1.27(3H,t)。
制备例220:3-碘-2-(2,2,2-三氟-乙氧基)-吡啶
将2,2,2-三氟乙醇(0.098mL,1.34mmol)和2-氟-3-碘-吡啶(0.2g,0.89mmol)以与制备例37相同的方式反应,得到标题化合物(0.22g,81%)。
1H-NMR(CDCl3)δ8.08(2H,m),6.74(1H,m),4.78(2H,m)。
制备例221:5-(4-溴-2,6-二氟-苯基硫基)-戊酸乙酯
将在制备例168中获得的4-溴-2,6-二氟-苯硫醇(0.5g,2.22mmol)、NaH(60%,在矿物油中,0.1g,2.44mmol)和5-溴戊酸乙酯(0.387mL,2.44mmol)以与制备例12相同的方式反应,得到标题化合物(0.7g,89%)。
1H-NMR(CDCl3)δ7.10(2H,d),4.10(2H,q),2.84(2H,t),2.27(2H,t),1.72(2H,m),1.56(2H,m),1.23(3H,t)。
制备例222:5-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-戊酸乙酯
将在制备例221中获得的5-(4-溴-2,6-二氟-苯基硫基)-戊酸乙酯(0.7g,1.99mmol)、双(频哪醇合)二硼(0.56g,2.19mmol)、乙酸钾(0.49g,4.99mmol)和二氯[1,1'-双(二苯基膦基)二茂铁]钯(II)(0.15g,0.20mmol)以与制备例1的步骤A相同的方式反应,得到标题化合物(0.42g,53%)。
1H-NMR(CDCl3)δ7.30(2H,d),4.08(2H,q),2.90(2H,t),2.26(2H,t),1.72(2H,m),1.54(2H,m),1.32(12H,s),1.23(3H,t)。
制备例223:5-(4-溴-苯基硫基)-戊酸乙酯
将4-溴-苯硫醇(0.5g,2.64mmol),NaH(60%,在矿物油中,0.12g,2.91mmol)和5-溴戊酸乙酯(0.46mL,2.91mmol)以与制备例12相同的方式反应,得到标题化合物(0.78g,93%)。
1H-NMR(CDCl3)δ7.38(2H,d),7.16(2H,d),4.11(2H,q),2.88(2H,t),2.30(2H,t),1.75(2H,m),1.65(2H,m),1.23(3H,t)。
制备例224:5-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-戊酸乙酯
将在制备例223中获得的5-(4-溴-苯基硫基)-戊酸乙酯(0.78g,2.46mmol)、双(频哪醇合)二硼(0.69g,2.70mmol)、乙酸钾(0.6g,6.15mmol)和二氯[1,1'-双(二苯基膦基)二茂铁]钯(II)(0.18g,0.25mmol)以与制备例1的步骤A相同的方式反应,得到标题化合物(0.73g,81%)。
1H-NMR(CDCl3)δ7.68(2H,d),7.25(2H,d),4.10(2H,q),2.94(2H,t),2.30(2H,t),1.75(2H,m),1.68(2H,m),1.32(12H,s),1.22(3H,t)。
制备例225:5-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸乙酯
在向在制备例2的步骤B中获得的2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚(2.23g,8.7mmol)、5-溴戊酸乙酯(1.82g,8.7mmol)和Cs2CO3(5.67g,17.4mmol)添加CH3CN(29mL)之后,将混合物在回流下搅拌2小时。将反应物分离并将残余物通过柱色谱法纯化,得到标题化合物(2.40g,72%)。
1H-NMR(CDCl3)δ7.30(2H,m),4.18(2H,t),4.13(2H,q),2.37(2H,t),1.81(4H,m),1.32(12H,s),1.25(3H,t)。
制备例226:3-碘-2-异丙基硫基-吡啶
将2-氟-3-碘-吡啶(0.3g,1.34mmol)、Cs2CO3(0.66g,1.34mmol)和丙-2-硫醇(0.125mL,1.34mmol)以与制备例201相同的方式反应,得到标题化合物(0.21g,56%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.92(1H,m),6.69(1H,m),3.95(1H,m),1.39(6H,d)。
制备例227:2-溴-6-丙氧基-吡啶
将丙醇(0.07mL,0.92mmol)和2,6-二溴吡啶(0.2g,0.84mmol)以与制备例37相同的方式反应,得到标题化合物(0.067g,36%)。
1H-NMR(CDCl3)δ7.39(1H,t),7.03(1H,d),6.65(1H,d),4.23(2H,t),1.76(2H,m),1.00(3H,t)。
制备例228:2-溴-6-异丙氧基-吡啶
将丙-2-醇(0.065mL,0.84mmol)和2,6-二溴吡啶(0.2g,0.84mmol)以与制备例37相同的方式反应,得到标题化合物(0.027g,14%)。
1H-NMR(CDCl3)δ7.37(1H,t),7.00(1H,d),6.60(1H,d),5.27(1H,m),1.33(6H,d)。
制备例229:2-溴-6-丙基硫基-吡啶
将2,6-二溴吡啶(0.2g,0.84mmol)、Cs2CO3(0.412g,1.27mmol)和丙硫醇(0.076mL,0.84mmol)以与制备例201相同的方式反应,得到标题化合物(0.184g,93%)。
1H-NMR(CDCl3)δ7.27(1H,t),7.11(2H,m),3.13(2H,t),1.74(2H,m),1.04(3H,t)。
制备例230:2-溴-6-(环丁氧基)-吡啶
将环丁醇(0.06mL,0.84mmol)和2,6-二溴吡啶(0.2g,0.84mmol)以与制备例37相同的方式反应,得到标题化合物(0.06g,31%)。
1H-NMR(CDCl3)δ7.39(1H,t),7.01(1H,d),6.61(1H,d),5.14(1H,m),2.45(2H,m),2.11(2H,m),1.82(1H,m),1.65(1H,m)。
制备例231:2-溴-6-(环戊氧基)吡啶
将环戊醇(0.077mL,0.84mmol)和2,6-二溴吡啶(0.2g,0.84mmol)以与制备例37相同的方式反应,得到标题化合物(0.09g,44%)。
1H-NMR(CDCl3)δ7.36(1H,t),7.00(1H,d),6.60(1H,d),5.36(1H,m),1.98(2H,m),1.77(4H,m),1.61(2H,m)。
制备例232:2-溴-6-(环丙基甲氧基)-吡啶
将环丙基甲醇(0.068mL,0.84mmol)和2,6-二溴吡啶(0.2g,0.84mmol)以与制备例37相同的方式反应,得到标题化合物(0.1g,53%)。
1H-NMR(CDCl3)δ7.39(1H,t),7.03(1H,d),6.70(1H,d),4.12(2H,d),1.24(1H,m),0.59(2H,m),0.35(2H,m)。
制备例233:2-溴-6-环丁基硫基-吡啶
将环丁基硫醇(0.074g,0.84mmol)和2,6-二溴吡啶(0.2g,0.84mmol)以与制备例37相同的方式反应,得到标题化合物(0.047g,22%)。
1H-NMR(CDCl3)δ7.27(1H,t),7.11(1H,d),7.00(1H,d),4.28(1H,m),2.53(2H,m),2.08(4H,m)。
制备例234:2-溴-6-环戊基硫基-吡啶
将环戊基硫醇(0.09mL,0.84mmol)和2,6-二溴吡啶(0.2g,0.84mmol)以与制备例37相同的方式反应,得到标题化合物(0.2g,92%)。
1H-NMR(CDCl3)δ7.27(1H,t),7.12(1H,d),7.08(1H,d),3.98(1H,m),2.21(2H,m),1.76(2H,m),1.63(4H,m)。
制备例235:环丙基甲基-(3-碘-吡啶-2-基)-胺
在将2-氟-3-碘-吡啶(0.3g,1.34mmol)溶于DMF(4mL)之后,向其中添加环丙烷甲胺(0.173mL,2.02mmol)和三乙胺(0.186mL,1.34mmol),并将混合物在110℃搅拌18小时。将反应物在减压下浓缩并通过色谱法纯化,得到标题化合物(0.09g,24%)。
1H-NMR(CDCl3)δ8.05(1H,d),7.80(1H,d),6.29(1H,m),5.01(1H,brs),3.26(2H,t),1.12(1H,m),0.54(2H,m),0.27(2H,m)。
制备例236:6-(4-溴-2,6-二氟-苯基硫基)己酸乙酯
将在制备例168中获得的4-溴-2,6-二氟-苯硫醇(0.455g,2.02mmol)、NaH(60%,在矿物油中,0.09g,2.22mmol)和6-溴己酸乙酯(0.496g,2.22mmol)以与制备例12相同的方式反应,得到标题化合物(0.7g,94%)。
1H-NMR(CDCl3)δ7.10(2H,d),4.11(2H,q),2.83(2H,t),2.26(2H,t),1.60(2H,m),1.54(2H,m),1.42(2H,m),1.23(3H,t)。
制备例237:6-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-己酸乙酯
将在制备例236中获得的6-(4-溴-2,6-二氟-苯基硫基)己酸乙酯(0.7g,1.91mmol)、双(频哪醇合)二硼(0.53g,2.10mmol)、乙酸钾(0.467g,4.76mmol)和二氯[1,1'-双(二苯基膦基)二茂铁]钯(II)(0.14g,0.19mmol)以与制备例1的步骤A相同的方式反应,得到标题化合物(0.4g,50%)。
1H-NMR(CDCl3)δ7.28(2H,d),4.12(2H,q),2.90(2H,t),2.28(2H,t),1.64-1.55(4H,m),1.45(2H,m),1.34(12H,s),1.24(3H,t)。
制备例238:2-(3,5-二氟-4-甲氧基-苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷
将5-溴-1,3-二氟-2-甲氧基-苯(1.04g,4.66mmol)以与制备例2的步骤B相同的方式反应,得到标题化合物(0.85g,68%)。
1H-NMR(CDCl3)δ7.32(2H,m),4.03(3H,s),1.33(12H,s)。
制备例239:2-环丙基硫基-3-碘-吡啶
将2-氟-3-碘-吡啶(0.1g,0.34mmol)、Cs2CO3(0.335g,1.03mmol)和环丙基硫醇(0.02mL,0.51mmol)以与制备例39相同的方式反应,得到标题化合物(0.06g,63%)。
1H-NMR(CDCl3)δ8.47(1H,m),7.90(1H,m),6.74(1H,m),2.38(1H,m),1.10(2H,m),0.68(2H,m)。
制备例240:2-乙基硫基-3-碘-吡啶
将2-氟-3-碘-吡啶(0.475g,2.13mmol)、Cs2CO3(3.47g,10.65mmol)和乙硫醇(0.239mL,3.19mmol)以与制备例39相同的方式反应,得到标题化合物(0.512g,90%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.92(1H,m),6.72(1H,m),3.16(2H,q),1.39(3H,t)。
制备例241:2-丁基硫基-3-碘-吡啶
将2-氟-3-碘-吡啶(0.262g,1.17mmol)、Cs2CO3(1.91g,5.87mmol)和丁硫醇(0.189mL,1.76mmol)以与制备例39相同的方式反应,得到标题化合物(0.228g,66%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.92(1H,m),6.71(1H,m),3.15(2H,t),1.73(2H,m),1.50(2H,m),0.95(3H,t)。
实施例1:4-[4-(6-苯氧基-2-吡啶基)苯氧基]丁酸
步骤A:4-[4-(6-苯氧基-2-吡啶基)苯氧基]丁酸乙酯
将在制备例1的步骤B中获得的4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.04g,0.12mmol)和在制备例126中获得的2-氯-6-苯氧基-吡啶(0.025g,0.12mmol)溶于0.2mL的2M碳酸钠水溶液和0.6mL的1,4-二噁烷,并向其中加入N25分钟。向其中添加Pd(PPh3)4(0.014g,0.012mmol)并将生成物在回流下搅拌1小时。在结束反应之后,向反应溶液添加水并用EtOAc萃取以分离有机层。将有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.034g,75%)。
1H NMR(CDCl3)δ7.86(2H,d),7.68(1H,t),7.39(3H,m),7.21(3H,m),6.90(2H,d),6.70(1H,d),4.14(2H,q),4.04(2H,t),2.52(2H,t),2.12(2H,m),1.26(3H,t)。
步骤B:4-[4-(6-苯氧基-2-吡啶基)苯氧基]丁酸
将在步骤A中获得的4-[4-(6-苯氧基-2-吡啶基)苯氧基]丁酸乙酯(0.034g,0.09mmol)溶于各0.3mL的THF、MeOH和1N NaOH水溶液,并将生成物在室温搅拌4小时。在结束反应之后,将有机层除去,并通过使用1N HCl水溶液将pH调节至3。将沉淀物干燥,得到标题化合物(0.019g,60%)。
1H NMR(CDCl3)δ7.86(2H,d),7.68(1H,t),7.39(3H,m),7.21(3H,m),6.90(2H,d),6.70(1H,d),4.05(2H,t),2.60(2H,t),2.14(2H,m)。
实施例2:4-[2,6-二氟-4-(6-异丙基硫基-2-吡啶基)苯氧基丁酸
步骤A:4-[2,6-二氟-4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸乙酯
将在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.06g,0.16mmol)和在制备例125中获得的2-氯-6-异丙基硫基-吡啶(0.037g,0.2mmol)溶于0.24mL的2M Na2CO3水溶液和1.6mL的1,4-二噁烷,并向其中加入N25分钟。向其中添加Pd(PPh3)4(0.018g,0.015mmol)并将生成物在回流下搅拌16小时。在结束反应之后,将生成物用水稀释,并通过用EtOAc萃取将有机层分离。将有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.05g,78%)。
1H NMR(CDCl3)δ7.58(2H,m),7.52(1H,t),7.31(1H,d),7.08(1H,d),4.23(2H,m),4.16(2H,q),4.15(1H,m),2.58(2H,t),2.11(2H,m),1.47(6H,d),1.27(3H,t)。
步骤B:4-[2,6-二氟-4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸
将在步骤A中获得的4-[2,6-二氟-4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸乙酯(50mg,0.12mmol)溶于各0.4mL的1N NaOH、THF和EtOH,并将生成物在室温搅拌2小时。在结束反应之后,将有机层除去,并通过使用1N HCl将pH调节至3。将有机层分离并通过色谱法纯化,得到标题化合物(0.04g,85%)。
1H NMR(CDCl3)δ7.60(2H,m),7.52(1H,t),7.31(1H,d),7.09(1H,d),4.25(2H,m),4.13(1H,m),2.67(2H,t),2.12(2H,m),1.47(6H,d)。
实施例3:4-[2,6-二氟-4-(6-苯氧基-2-吡啶基)苯氧基]丁酸
步骤A:4-[2,6-二氟-4-(6-苯氧基-2-吡啶基)苯氧基]丁酸乙酯
使用在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.032g,0.086mmol)和在制备例126中获得的2-氯-6-苯氧基-吡啶(0.018g,0.087mmol)以与实施例1的步骤A相同的方式反应,得到标题化合物(0.026g,72%)。
1H NMR(CDCl3)δ7.73(1H,t),7.44(4H,m),7.36(1H,d),7.24(1H,t),7.20(2H,m),6.81(1H,d),4.19(2H,t),4.13(2H,q),2.56(2H,t),2.08(2H,m),1.26(3H,t)。
步骤B:4-[2,6-二氟-4-(6-苯氧基-2-吡啶基)苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-(6-苯氧基-2-吡啶基)苯氧基]丁酸乙酯(0.025g,0.06mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.018g,77%)。
1H NMR(CDCl3)δ7.72(1H,t),7.44(4H,m),7.36(1H,d),7.24(1H,t),7.20(2H,m),6.81(1H,d),4.21(2H,t),2.64(2H,t),2.10(2H,m)。
实施例4:4-[2-氯-4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸
使用在制备例3的步骤B中获得的4-[2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.052g,0.14mmol)和在制备例125中获得的2-氯-6-异丙基硫基-吡啶(0.026g,0.14mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.012g,23%)。
1H NMR(CDCl3)δ8.05(1H,d),7.88(1H,dd),7.48(1H,t),7.32(1H,d),7.06(1H,d),6.98(1H,d),4.16(2H,t),4.12(1H,m),2.67(2H,t),2.20(2H,m),1.46(6H,d)。
实施例5:4-[2-氟-4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸
使用在制备例4的步骤B中获得4-[2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.053g,0.15mmol)和在制备例125中获得的2-氯-6-异丙基硫基-吡啶(0.028g,0.15mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.007g,13%)。
1H NMR(CDCl3)δ7.82(1H,dd),7.73(1H,dd),7.50(1H,t),7.33(1H,d),7.04(2H,m),4.17(2H,t),4.11(1H,m),2.64(2H,t),2.19(2H,m),1.47(6H,d)。
实施例6:4-[4-(6-环戊基硫基-2-吡啶基)-2,6-二氟-苯氧基丁酸
使用在制备例5中获得的2-氯-6-环戊基硫基-吡啶(0.044g,0.2mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.068g,0.18mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.008g,10%)。
1H NMR(CDCl3)δ7.60(2H,m),7.50(1H,t),7.30(1H,d),7.10(1H,d),4.26(2H,t),4.16(1H,m),2.67(2H,t),2.24(2H,m),2.12(2H,m),1.80(2H,m),1.70(4H,m)。
实施例7:4-[4-(2-环丁基硫基-吡啶-3-基)-2-甲氧基-苯氧基]-丁酸
将在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.060g,0.21mmol)和在制备例6中获得的4-[2-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.075g,0.21mmol)以与实施例1相同的方式反应,得到标题化合物(0.050g,60%)。
1H NMR(CDCl3)δ8.38(1H,m),7.38(1H,m),7.02(1H,m),6.94(3H,m),4.27(1H,m),4.14(2H,t),3.88(3H,s),2.66(2H,t),2.49(2H,m),2.21(2H,m),2.00(4H,m)。
实施例8:4-[2,6-二氟-4-(2-异丙基硫基-4-吡啶基)苯氧基丁酸
步骤A:4-[2,6-二氟-4-(2-异丙基硫基-4-吡啶基)苯氧基]丁酸乙酯
将0.7mL的DMF加入在制备例7中获得的4-[4-(2-氯-4-吡啶基)-2,6-二氟-苯氧基]丁酸乙酯(0.025g,0.07mmol)、Cs2CO3(0.046g,0.14mmol)和2-丙硫醇(0.013mL,0.14mmol),并将生成物在80℃搅拌4小时。将反应溶液在减压下浓缩并通过色谱法纯化,得到标题化合物(0.007g,25%)。
1H NMR(CDCl3)δ8.43(1H,d),7.46(1H,d),7.34(1H,dd),7.32(1H,m),7.18(1H,m),4.20(2H,t),4.17(3H,m),2.63(2H,t),2.13(2H,m),1.34(6H,d),1.28(3H,t)。
步骤B:4-[2,6-二氟-4-(2-异丙基硫基-4-吡啶基)苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-(2-异丙基硫基-4-吡啶基)苯氧基]丁酸乙酯(0.007g,0.018mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.004g,55%)。
1H NMR(CDCl3)δ8.43(1H,d),7.46(1H,d),7.35(1H,m),7.32(1H,m),7.20(1H,dd),4.21(2H,t),3.55(1H,m),2.73(2H,t),2.15(2H,m),1.35(6H,d)。
实施例9:4-[4-[6-(环戊氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[6-(环戊氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯
将在制备例8中获得的2-氯-6-(环戊氧基)吡啶(0.055g,0.27mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.068g,0.18mmol)以与实施例1的步骤A相同的方式反应,得到标题化合物(0.051g,68%)。
1H NMR(CDCl3)δ7.58(3H,m),7.18(1H,d),6.63(1H,d),5.50(1H,m),4.22(2H,t),4.16(2H,m),2.58(2H,t),2.12(2H,m),2.06(2H,m),1.82(4H,m),1.65(2H,m),1.27(3H,t)。
步骤B:4-[4-[6-(环戊氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[6-(环戊氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯(0.05g,0.12mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.023g,50%)。
1H NMR(CDCl3)δ7.59(3H,m),7.18(1H,d),6.63(1H,d),5.50(1H,m),4.24(2H,t),2.67(2H,t),2.14(2H,m),2.04(2H,m),1.82(4H,m),1.65(2H,m)。
实施例10:4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二甲基-苯氧基]-丁酸
将在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.048g,0.16mmol)和在制备例11中获得的4-[2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.060g,0.16mmol)以与实施例1相同的方式反应,得到标题化合物(0.040g,61%)。
1H NMR(CDCl3)δ8.37(1H,m),7.33(1H,m),7.05(2H,s),6.99(1H,m),4.42(1H,m),3.89(2H,t),2.71(2H,t),2.49(2H,m),2.30(6H,s),2.18(2H,m),2.07(4H,m)。
实施例11:4-[4-[3-(环戊氧基)苯基]-2,6-二氟-苯氧基]丁酸
使用在制备例9中获得的1-溴-3-(环戊氧基)苯(0.04g,0.16mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.05g,0.13mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.01g,20%)。
1H NMR(CDCl3)δ7.30(1H,t),7.11(2H,m),7.04(1H,d),7.00(1H,m),6.87(1H,dd),4.81(1H,m),4.22(2H,t),2.65(2H,t),2.12(2H,m),1.95(2H,m),1.88(2H,m),1.82(2H,m),1.64(2H,m)。
实施例12:4-[2,6-二氟-4-(6-吡咯烷-1-基-2-吡啶基)苯氧基]丁酸
使用在制备例10中获得的2-氯-6-吡咯烷-1-基-吡啶(0.028g,0.15mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.051g,0.13mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.006g,13%)。
1H NMR(CDCl3)δ7.62(2H,m),7.46(1H,t),6.90(1H,d),6.32(1H,d),4.20(2H,t),3.53(4H,t),2.65(2H,t),2.12(2H,t),2.01(4H,m)。
实施例13:4-[4-(2-仲丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用丁-2-硫醇(27mg,0.29mmol)和在制备例109中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸乙酯(100mg,0.29mmol)以与制备例5和实施例1的步骤B相同的方式顺序反应,得到标题化合物(65mg,54%)。
1H NMR(CDCl3)δ8.43(1H,m),7.32(1H,m),7.01(3H,m),4.26(2H,t),3.96(1H,m),2.69(2H,t),2.14(2H,m),1.73(2H,m),1.33(3H,d),1.00(3H,t)。
实施例14:4-[4-[3-(环戊氧基)苯基]-2,3-二氟-苯氧基]丁酸
步骤A:4-[4-[3-(环戊氧基)苯基]-2,3-二氟-苯氧基]丁酸乙酯
将1.5mL的乙腈加入在制备例13中获得的4-[2,3-二氟-4-(3-羟基苯基)苯氧基]丁酸乙酯(0.089g,0.26mmol)、环戊基溴(0.034g,0.31mmol)和K2CO3(0.036g,0.26mmol),并将生成物在回流下搅拌16小时。在结束反应之后,将反应溶液在减压下浓缩并通过色谱法纯化,得到标题化合物(0.042g,39%)。
1H NMR(CDCl3)δ7.31(1H,t),7.10(1H,m),7.04(1H,dd),7.00(1H,d),6.88(1H,dd),6.78(1H,m),4.79(1H,m),4.15(4H,m),2.55(2H,t),2.16(2H,m),1.92(4H,m),1.80(2H,m),1.62(2H,m),1.27(3H,t)。
步骤B:4-[4-[3-(环戊氧基)苯基]-2,3-二氟-苯氧基]丁酸
将在步骤A中获得的4-[4-[3-(环戊氧基)苯基]-2,3-二氟-苯氧基]丁酸乙酯(0.041g,0.1mmol)溶于各0.5mL的EtOH和NaOH(1M水溶液)中,并将生成物在室温搅拌1小时。在结束反应之后,向其中添加EtOAc并通过使用1N HCl水溶液将水层调节至pH4。将有机层分离并通过色谱法纯化,得到标题化合物(0.036g,96%)。
1H NMR(CDCl3)δ7.31(1H,t),7.09(1H,m),7.04(1H,dd),7.00(1H,d),6.88(1H,dd),6.78(1H,dd),4.79(1H,m),4.15(2H,t),2.63(2H,t),2.18(2H,m),1.90(4H,m),1.81(2H,m),1.62(2H,m)。
实施例15:4-[2,6-二氟-4-[6-(1-哌啶基)-2-吡啶基]苯氧基]丁酸
使用在制备例14中获得的2-氯-6-(1-哌啶基)吡啶(0.09g,0.45mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.154g,0.41mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.06g,39%)。
1H NMR(CDCl3)δ7.56(2H,m),7.49(1H,t),6.92(1H,d),6.60(1H,d),4.22(2H,t),3.61(4H,brs),2.64(2H,t),2.10(2H,m),1.67(6H,brs)。
实施例16:4-[4-(6-苯胺基-2-吡啶基)-2,6-二氟-苯氧基]丁酸
使用在制备例15中获得的6-氯-N-苯基-吡啶基-2-胺(0.09g,0.44mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.148g,0.4mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.037g,24%)。
1H NMR(CDCl3)δ7.54(3H,m),7.37(4H,m),7.08(2H,m),6.83(1H,brs),6.82(1H,d),4.24(2H,t),2.66(2H,t),2.11(2H,m)。
实施例17:4-[2,6-二氟-4-[6-(N-甲基苯胺基)-2-吡啶基]苯氧基丁酸
步骤A:4-[2,6-二氟-4-[6-(N-甲基苯胺基)-2-吡啶基]苯氧基]丁酸甲酯
将在实施例16中获得的4-[4-(6-苯胺基-2-吡啶基)-2,6-二氟-苯氧基]丁酸(0.033g,0.085mmol)溶于1mL的DMF,并向其中添加叔丁醇钾(0.036g,0.34mmol)和碘甲烷(0.02mL,0.34mmol)。将生成物在室温搅拌16小时。在结束反应之后,将反应溶液在减压下浓缩并通过色谱法纯化,得到标题化合物(0.02g,57%)。
1H NMR(CDCl3)δ7.63(2H,m),7.42(2H,m),7.36(1H,t),7.30(2H,m),7.24(1H,m),6.98(1H,d),6.48(1H,d),4.22(2H,t),3.70(3H,s),3.57(3H,s),2.62(2H,t),2.11(2H,m)。
步骤B:4-[2,6-二氟-4-[6-(N-甲基苯胺基)-2-吡啶基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[6-(N-甲基苯胺基)-2-吡啶基]苯氧基]丁酸甲酯(0.02g,0.048mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.013g,66%)。
1H NMR(CDCl3)δ7.62(2H,m),7.42(2H,m),7.36(1H,m),7.30(2H,m),7.24(1H,m),6.98(1H,d),6.48(1H,d),4.21(2H,t),3.58(3H,s),2.67(2H,t),2.12(2H,m)。
实施例18:4-[4-[6-(环戊基氨基)-2-吡啶基]-2,6-二氟-苯氧基丁酸
步骤A:4-[4-[6-(环戊基氨基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例16中获得的6-氯-N-环戊基-吡啶基-2-胺(0.05g,0.25mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.06g,0.16mmol)以与实施例1的步骤A相同的方式反应,得到标题化合物(0.03g,48%)。
1H NMR(CDCl3)δ7.50(2H,m),7.46(1H,t),6.90(1H,d),6.35(1H,d),4.65(1H,d),4.20(2H,t),4.15(2H,q),4.05(1H,m),2.58(2H,t),2.08(4H,m),1.76(2H,m),1.66(2H,m),1.52(2H,m),1.26(3H,t)。
步骤B:4-[4-[6-(环戊基氨基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[6-(环戊基氨基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯(0.03g,0.07mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.026g,93%)。
1H NMR(CDCl3)δ7.47(3H,m),6.87(1H,d),6.36(1H,d),4.22(2H,t),4.02(1H,m),2.64(2H,t),2.10(4H,m),1.78(2H,m),1.65(2H,m),1.52(2H,m)。
实施例19:4-[4-[6-(环丙基甲基硫基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在制备例18的步骤B中获得的2-氯-6-(环丙基甲基硫基)吡啶(0.033g,0.16mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.05g,0.135mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.03g,58%)。
1H NMR(CDCl3)δ7.58(2H,m),7.52(1H,t),7.30(1H,d),7.14(1H,d),4.25(2H,t),3.22(2H,d),2.67(2H,t),2.12(2H,m),1.21(1H,m),0.62(2H,m),0.36(2H,m)。
实施例20:4-[4-(6-环丁基硫基-2-吡啶基)-2,6-二氟-苯氧基丁酸
使用在制备例19中获得的2-氯-6-环丁基硫基-吡啶(0.033g,0.165mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.05g,0.135mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.035g,68%)。
1H NMR(CDCl3)δ7.58(2H,m),7.52(1H,t),7.30(1H,d),7.04(1H,d),4.42(1H,m),4.25(2H,t),2.68(2H,t),2.60(2H,m),2.12(6H,m)。
实施例21:4-[2,6-二氟-4-(6-丙基硫基-2-吡啶基)苯氧基]丁酸
使用在制备例20中获得的2-氯-6-丙基硫基-吡啶(0.03g,0.16mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.05g,0.135mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.037g,75%)。
1H NMR(CDCl3)δ7.58(2H,m),7.52(1H,t),7.30(1H,d),7.12(1H,d),4.25(2H,t),3.23(2H,t),2.67(2H,t),2.12(2H,m),1.81(2H,m),1.08(3H,t)。
实施例22:4-[2,6-二氟-4-(6-异丙氧基-2-吡啶基)苯氧基]丁酸
步骤A:4-[2,6-二氟-4-(6-异丙氧基-2-吡啶基)苯氧基]丁酸乙酯
使用在制备例21中获得的2-氯-6-异丙氧基-吡啶(0.03g,0.17mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.05g,0.135mmol)以与实施例1的步骤A相同的方式反应,得到标题化合物(0.038g,74%)。
1H NMR(CDCl3)δ7.57(3H,m),7.19(1H,d),6.63(1H,d),5.44(1H,m),4.22(2H,t),4.16(2H,q),2.59(2H,t),2.10(2H,m),1.40(6H,d),1.27(3H,t),
步骤B:4-[2,6-二氟-4-(6-异丙氧基-2-吡啶基)苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-(6-异丙氧基-2-吡啶基)苯氧基]丁酸乙酯(0.037g,0.1mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.03g,88%)。
1H NMR(CDCl3)δ7.61(1H,t),7.56(2H,m),7.19(1H,d),6.63(1H,d),5.44(1H,m),4.24(2H,t),2.67(2H,t),2.11(2H,m),1.40(6H,d)。
实施例23:4-[2,6-二氟-4-(6-丙氧基-2-吡啶基)苯氧基]丁酸
步骤A:4-[2,6-二氟-4-(6-丙氧基-2-吡啶基)苯氧基]丁酸乙酯
使用在制备例22中获得的2-氯-6-丙氧基-吡啶(0.03g,0.17mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.05g,0.135mmol)以与实施例1的步骤A相同的方式反应,得到标题化合物(0.026g,40%)。
1H NMR(CDCl3)δ7.62(1H,t),7.58(2H,m),7.21(1H,d),6.69(1H,d),4.35(2H,t),4.22(2H,t),4.16(2H,q),2.59(2H,t),2.10(2H,m),1.84(2H,m),1.27(3H,t),1.06(3H,t)。
步骤B:4-[2,6-二氟-4-(6-丙氧基-2-吡啶基)苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-(6-丙氧基-2-吡啶基)苯氧基]丁酸乙酯(0.026g,0.068mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.018g,81%)。
1H NMR(CDCl3)δ7.60(1H,t),7.58(2H,m),7.21(1H,d),6.68(1H,d),4.35(2H,t),4.24(2H,t),2.67(2H,t),2.11(2H,m),1.83(2H,m),1.06(3H,t)。
实施例24:4-[4-[6-(环丙基甲氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[6-(环丙基甲氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例23中获得的2-氯-6-(环丙基甲氧基)-吡啶(0.033g,0.18mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.05g,0.135mmol)以与实施例1的步骤A相同的方式反应,得到标题化合物(0.050g,95%)。
1H NMR(CDCl3)δ7.61(1H,t),7.57(2H,m),7.21(1H,d),6.72(1H,d),4.22(4H,m),4.16(2H,q),2.58(2H,t),2.10(2H,m),1.33(1H,m),1.26(3H,t),0.64(2H,m),0.39(2H,m)。
步骤B:4-[4-[6-(环丙基甲氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[6-(环丙基甲氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯(0.05g,0.127mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.034g,73%)。
1H NMR(CDCl3)δ7.62(1H,t),7.57(2H,m),7.21(1H,d),6.73(1H,d),4.23(4H,m),2.67(2H,t),2.11(2H,m),1.33(1H,m),0.64(2H,m),0.39(2H,m)。
实施例25:4-[4-[6-(环丁氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[6-(环丁氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例24中获得的2-氯-6-(环丁氧基)-吡啶(0.033g,0.18mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.05g,0.135mmol)以与实施例1的步骤A相同的方式反应,得到标题化合物(0.042g,80%)。
1H NMR(CDCl3)δ7.61(1H,t),7.56(2H,m),7.21(1H,d),6.65(1H,d),5.26(1H,m),4.22(2H,t),4.15(2H,q),2.60(2H,t),2.52(2H,m),2.19(2H,m),2.10(2H,m),1.87(1H,m),1.76(1H,m),1.27(3H,t)。
步骤B:4-[4-[6-(环丁氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[6-(环丁氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯(0.042g,0.1mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.024g,61%)。
1H NMR(CDCl3)δ7.61(1H,t),7.56(2H,m),7.21(1H,d),6.65(1H,d),5.25(1H,m),4.24(2H,t),2.67(2H,t),2.52(2H,m),2.19(2H,m),2.11(2H,m),1.87(1H,m),1.76(1H,m)。
实施例26:4-[4-[6-(环丁氧基)-2-吡啶基]-2-甲基-苯氧基]丁酸
步骤A:4-[4-[6-(环丁氧基)-2-吡啶基]-2-甲基-苯氧基]丁酸乙酯
使用在制备例24中获得的2-氯-6-(环丁氧基)-吡啶(0.041g,0.22mmol)和在制备例25的步骤C中获得的4-[2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.059g,0.17mmol)以与实施例1的步骤A相同的方式反应,得到标题化合物(0.031g,49%)。
1H NMR(CDCl3)δ7.80(2H,m),7.57(1H,t),7.25(1H,d),6.86(1H,d),6.56(1H,d),5.56(1H,m),4.15(2H,q),4.06(2H,t),2.56(2H,t),2.54(2H,m),2.28(3H,s),2.18(2H,m),2.16(2H,m),1.87(1H,m),1.74(1H,m),1.27(3H,t)。
步骤B:4-[4-[6-(环丁氧基)-2-吡啶基]-2-甲基-苯氧基]丁酸
使用在步骤A中获得的4-[4-[6-(环丁氧基)-2-吡啶基]-2-甲基-苯氧基]丁酸乙酯(0.031g,0.08mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.013g,45%)。
1H NMR(CDCl3)δ7.80(2H,m),7.56(1H,t),7.24(1H,d),6.87(1H,d),6.56(1H,d),5.25(1H,m),4.08(2H,t),2.63(2H,t),2.52(2H,m),2.28(3H,s),2.18(4H,m),1.87(1H,m),1.72(1H,m)。
实施例27:4-[4-[6-(环丁氧基)-2-吡啶基]-2-(三氟甲基)苯氧基丁酸
步骤A:4-[4-[6-(环丁氧基)-2-吡啶基]-2-(三氟甲基)苯氧基]丁酸乙酯
使用在制备例24中获得的2-氯-6-(环丁氧基)-吡啶(0.035g,0.19mmol)和在制备例26的步骤C中获得的4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2-(三氟甲基)苯氧基]丁酸乙酯(0.061g,0.15mmol)以与实施例1的步骤A相同的方式反应,得到标题化合物(0.041g,63%)。
1H NMR(CDCl3)δ8.24(1H,d),8.13(1H,dd),7.61(1H,t),7.25(1H,m),7.05(1H,dd),6.62(1H,d),5.25(1H,m),4.15(4H,m),2.57(4H,m),2.17(4H,m),1.87(1H,m),1.74(1H,m),1.26(3H,t)。
步骤B:4-[4-[6-(环丁氧基)-2-吡啶基]-2-(三氟甲基)苯氧基]丁酸
使用在步骤A中获得的4-[4-[6-(环丁氧基)-2-吡啶基]-2-(三氟甲基)苯氧基]丁酸乙酯(0.04g,0.09mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.03g,84%)。
1H NMR(CDCl3)δ8.24(1H,d),8.12(1H,dd),7.60(1H,t),7.26(1H,d),7.04(1H,m),6.62(1H,d),5.25(1H,m),4.17(2H,t),2.65(2H,m),2.52(2H,m),2.20(4H,m),1.87(1H,m),1.73(1H,m)。
实施例28:4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸
步骤A:4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸甲酯
将在制备例27的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸甲酯(0.053g,0.14mmol)和在制备例44的步骤B中获得的2-环丁基硫基-3-碘-吡啶(0.045g,0.15mmol)溶于0.7mL的1,2-二甲氧基乙烷和Na2CO3(2M水溶液,0.21mL,0.43mmol),并向其中加入N25分钟。向其中添加PdCl2(PPh3)2(0.005g,0.007mmol)并将生成物在80℃搅拌3小时。在结束反应之后,向反应溶液添加3mL的水并用EtOAc萃取。将有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.046g,79%)。
1H NMR(CDCl3)δ8.41(1H,m),7.33(1H,m),7.01(3H,m),4.41(2H,m),3.69(3H,s),2.63(2H,t),2.51(2H,m),2.05(6H,m),1.33(3H,d)。
步骤B:4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸
使用在步骤A中获得的4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸甲酯(0.069g,0.17mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.045g,67%)。
1H NMR(CDCl3)δ8.41(1H,m),7.33(1H,m),7.00(3H,m),4.41(2H,m),2.71(2H,t),2.52(2H,m),2.05(6H,m),1.35(3H,d)。
实施例29:4-[4-[6-(环丁氧基)-2-吡啶基]-2,6-二氟-苯氧基]戊酸
步骤A:4-[4-[6-(环丁氧基)-2-吡啶基]-2,6-二氟-苯氧基]戊酸甲酯
将在制备例27的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸甲酯(0.04g,0.11mmol)和在制备例24中获得的2-氯-6-(环丁氧基)-吡啶(0.02g,0.11mmol)溶于1mL的1,2-二甲氧基乙烷和Na2CO3(2M水溶液,0.16mL,0.32mmol),并向其中加入N25分钟。向其中添加Pd(PPh3)4(0.011g,0.01mmol)并将生成物在80℃搅拌2小时。在结束反应之后,向反应溶液添加3mL的水并用EtOAc萃取。将有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.028g,66%)。
1H NMR(CDCl3)δ7.58(3H,m),7.22(1H,d),6.66(1H,d),5.26(1H,m),4.38(1H,m),3.70(3H,s),2.64(2H,t),2.53(2H,m),2.19(2H,m),2.03(2H,m),1.89(1H,m),1.74(1H,m),1.31(3H,d)。
步骤B:4-[4-[6-(环丁氧基)-2-吡啶基]-2,6-二氟-苯氧基]戊酸
使用在步骤A中获得的4-[4-[6-(环丁氧基)-2-吡啶基]-2,6-二氟-苯氧基]戊酸甲酯(0.027g,0.07mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.02g,76%)。
1H NMR(CDCl3)δ7.60(3H,m),7.21(1H,d),6.65(1H,d),5.26(1H,m),4.40(1H,m),2.70(2H,t),2.53(2H,m),2.20(2H,m),2.05(2H,m),1.86(1H,m),1.76(1H,m),1.32(3H,d)。
实施例30:4-[[5-(2-环丁基硫基-3-吡啶基)-2-吡啶基]氧基]戊酸
步骤A:4-[[5-(2-环丁基硫基-3-吡啶基)-2-吡啶基]氧基]戊酸甲酯
将0.6mL的1,2-二甲氧基乙烷加入在制备例28的步骤B中获得的4-[[5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2-吡啶基]氧基]戊酸甲酯(0.038g,0.11mmol)、在制备例44的步骤B中获得2-环丁基硫基-3-碘-吡啶(0.033g,0.11mmol)和Na2CO3(2M水溶液,0.17mL,0.34mmol),并向其中加入N25分钟。向其中添加PdCl2(PPh3)2(0.004g,0.005mmol)并将生成物在80℃搅拌16小时。向反应物添加水并用EtOAc萃取。将有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.006g,14%)。
1H NMR(CDCl3)δ8.40(1H,m),8.12(1H,m),7.66(1H,m),7.35(1H,m),7.05(1H,m),6.73(1H,d),5.29(1H,m),4.43(1H,m),3.67(3H,s),2.50(4H,m),2.04(6H,m),1.37(3H,d)。
步骤B:4-[[5-(2-环丁基硫基-3-吡啶基)-2-吡啶基]氧基]戊酸
使用在步骤A中获得的4-[[5-(2-环丁基硫基-3-吡啶基)-2-吡啶基]氧基]戊酸甲酯(0.006g,0.016mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.005g,90%)。
1H NMR(MeOH-d4)δ8.56(1H,m),8.33(1H,m),8.17(1H,m),7.98(1H,m),7.55(1H,m),7.33(1H,d),5.23(1H,m),4.36(1H,m),2.53(2H,m),2.46(2H,m),2.05(6H,m),1.42(3H,d)。
实施例31:4-{2,6-二氟-4-[2-(3-甲基-丁基硫基)-吡啶-3-基]-苯氧基}-丁酸
使用3-甲基-丁-1-硫醇(31mg,0.29mmol)和在制备例109中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸乙酯(100mg,0.29mmol)以与制备例5和实施例1的步骤B相同的方式顺序反应,得到标题化合物(75mg,60%)。
1H NMR(CDCl3)δ8.43(1H,m),7.33(1H,m),7.03(3H,m),4.26(2H,t),3.18(2H,t),2.69(2H,t),2.14(2H,m),1.70(1H,m),1.56(2H,m),0.93(6H,d)。
实施例32:4-{2,6-二氟-4-[2-(2-氟-乙氧基)-吡啶-3-基]-苯氧基}-丁酸
使用2-氟-乙醇(29mg,0.45mmol)和在制备例56中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸(70mg,0.22mmol)以与制备例37相同的方式反应,得到标题化合物(5mg,6%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.61(1H,m),7.18(2H,m),6.99(1H,m),4.80(1H,m),4.69(1H,m),4.67(1H,m),4.62(1H,m),4.25(2H,t),2.69(2H,t),2.13(2H,m)。
实施例33:2-[1-[[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]甲基]环丙基]乙酸
步骤A:2-[1-[[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]甲基]环丙基]乙腈
将在制备例44的步骤B中获得的2-环丁基硫基-3-碘-吡啶(0.064g,0.22mmol)和在制备例30的步骤E中获得的2-[1-[[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]甲基]环丙基]乙腈(0.092g,0.26mmol)溶于2mL的1,2-二甲氧基乙烷和Na2CO3(2M水溶液,0.33mL,0.66mmol),并向其中加入N25分钟。向其中添加PdCl2(PPh3)2(0.008g,0.011mmol)并将生成物在80℃搅拌2小时。向反应物添加水并用EtOAc萃取。将有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.043g,50%)。
1H NMR(CDCl3)δ8.41(1H,m),7.33(1H,m),7.00(3H,m),4.42(1H,m),4.06(2H,s),2.77(2H,s),2.51(2H,m),2.04(4H,m),0.77(4H,m)。
步骤B:2-[1-[[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]甲基]环丙基]乙酸
将在步骤A中获得的2-[1-[[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]甲基]环丙基]乙腈(0.042g,0.108mmol)溶于1mL的乙醇,并向其中添加NaOH(6M水溶液,0.11mL,6.6mmol)。将生成物在100℃搅拌16小时。通过使用HCl水溶液将pH调节至3,然后将反应物用EtOAc萃取。将有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.008g,18%)。
1H NMR(CDCl3)δ8.41(1H,m),7.32(1H,m),6.98(3H,m),4.41(1H,m),4.11(2H,s),2.66(2H,s),2.52(2H,m),2.04(4H,m),0.66(4H,m)。
实施例34:2-[1-[[4-[3-(环丁氧基)苯基]-2,6-二氟-苯氧基甲基环丙基]乙酸
步骤A:2-[1-[[4-[3-(环丁氧基)苯基]-2,6-二氟-苯氧基]甲基]环丙基]乙腈
将在制备例60中获得的1-环丁氧基-3-碘-苯(0.06g,0.22mmol)和在制备例30的步骤E中获得的2-[1-[[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]甲基]环丙基]乙腈(0.092g,0.26mmol)溶于2mL的1,2-二甲氧基乙烷和Na2CO3(2M水溶液,0.33mL,0.66mmol),并向其中加入N25分钟。向其中添加Pd(PPh3)4(0.025g,0.022mmol)并将生成物在80℃搅拌3小时。向反应物添加水并用EtOAc萃取。将有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.067g,83%)。
1H NMR(CDCl3)δ7.31(1H,t),7.12(2H,m),7.06(1H,d),6.94(1H,m),6.81(1H,m),4.69(1H,m),4.03(2H,s),2.77(2H,s),2.47(2H,m),2.20(2H,m),1.88(1H,m),1.72(1H,m),0.74(4H,m)。
步骤B:2-[1-[[4-[3-(环丁氧基)苯基]-2,6-二氟-苯氧基]甲基]环丙基]乙酸
将在步骤A中获得的2-[1-[[4-[3-(环丁氧基)苯基]-2,6-二氟-苯氧基]甲基]环丙基]乙腈(0.067g,0.18mmol)溶于2mL的EtOH,并向其中添加NaOH(6M水溶液,0.18mL,1.08mmol)。将生成物在100℃搅拌16小时。通过使用HCl水溶液将pH调节至3,然后将反应物用EtOAc萃取。将有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.04g,55%)。
1H NMR(CDCl3)δ7.29(1H,t),7.08(3H,m),6.93(1H,m),6.80(1H,m),4.69(1H,m),4.11(2H,s),2.65(2H,s),2.48(2H,m),2.19(2H,m),1.88(1H,m),1.72(1H,m),0.66(4H,m)。
实施例35:4-[[6-[3-(环丁氧基)苯基]-3-吡啶基]氧基]丁酸
步骤A:4-[[6-[3-(环丁氧基)苯基]-3-吡啶基]氧基]丁酸乙酯
将在制备例31的步骤B中获得的4-[[6-(3-羟基苯基)-3-吡啶基]氧基]丁酸乙酯(0.061g,0.2mmol)溶于2mL的DMF并冷却至0℃。向其中添加NaH(60%,在矿物油中,0.012g,0.3mmol)并将生成物在0℃搅拌1小时。向其中添加溴代环丁烷(0.027g,0.2mmol)并将生成物在70℃搅拌6小时。在将反应溶液在减压下浓缩之后,添加水并用EtOAc萃取。将有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.014g,19%)。
1H NMR(CDCl3)δ8.35(1H,m),7.62(1H,d),7.45(1H,m),7.41(1H,m),7.32(1H,t),7.24(1H,m),6.83(1H,m),4.75(1H,m),4.16(2H,q),4.10(2H,t),2.54(2H,t),2.50(2H,m),2.17(4H,m),1.86(1H,m),1.72(1H,m),1.27(3H,t)。
步骤B:4-[[6-[3-(环丁氧基)苯基]-3-吡啶基]氧基]丁酸
使用在步骤A中获得的4-[[6-[3-(环丁氧基)苯基]-3-吡啶基]氧基]丁酸乙酯(0.014g,0.039mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.013g,99%)。
1H NMR(CDCl3)δ8.39(1H,m),7.62(1H,d),7.44(1H,d),7.37(1H,m),7.32(1H,t),7.27(1H,m),6.83(1H,m),4.74(1H,m),4.13(2H,t),2.61(2H,t),2.48(2H,m),2.18(4H,m),1.87(1H,m),1.70(1H,m)。
实施例36:4-[[6-[3-(环戊氧基)苯基]-3-吡啶基]氧基]丁酸
步骤A:4-[[6-[3-(环戊氧基)苯基]-3-吡啶基]氧基]丁酸乙酯
将在制备例31的步骤B中获得的4-[[6-(3-羟基苯基)-3-吡啶基]氧基]丁酸乙酯(0.068g,0.22mmol)溶于2mL的DMF并冷却至0℃。向其中添加NaH(60%,在矿物油中,0.013g,0.33mmol)并将生成物在0℃搅拌1小时。向其中添加溴代环戊烷(0.033g,0.2mmol)并将生成物在70℃搅拌16小时。在将反应溶液在减压下浓缩之后,添加水并用EtOAc萃取。将有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.028g,34%)。
1H NMR(CDCl3)δ8.35(1H,m),7.63(1H,d),7.45(2H,m),7.32(1H,t),7.25(1H,m),6.88(1H,m),4.87(1H,m),4.16(2H,q),4.10(2H,t),2.54(2H,t),2.15(2H,m),1.92(4H,m),1.82(2H,m),1.62(2H,m),1.27(3H,t)。
步骤B:4-[[6-[3-(环戊氧基)苯基]-3-吡啶基]氧基]丁酸
使用在步骤A中获得的4-[[6-[3-(环戊氧基)苯基]-3-吡啶基]氧基]丁酸乙酯(0.028g,0.075mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.02g,77%)。
1H NMR(CDCl3+甲醇-d4)δ8.68(1H,m),7.92(1H,m),7.83(1H,m),7.48(3H,m),7.06(1H,m),4.99(1H,m),4.29(2H,t),2.53(2H,t),2.19(2H,m),2.00(2H,m),1.87(2H,m),1.80(2H,m),1.64(2H,m)。
实施例37:4-(2'-苯氧基-联苯-4-基氧基)-丁酸
步骤A:4-(2'-苯氧基-联苯-4-基氧基)丁酸乙酯
将2'-苯氧基-联苯-4-醇(0.022g,0.083mmol)、Cs2CO3(0.055g,0.16mmol)和4-溴丁酸乙酯(0.027g,0.10mmol)溶于2mL的DMF,并将生成物在室温搅拌2小时。将固体过滤并通过柱色谱法纯化(洗脱剂:EtOAc/Hex=1/4),得到标题化合物(0.026g,86%)。
1H-NMR(CDCl3)δ7.46(3H,m),7.26(2H,m),7.19(1H,m),7.00(3H,m),6.89(2H,m),6.84(2H,m),4.15(2H,q),4.00(2H,t),2.50(2H,t),2.10(2H,m),1.25(3H,t)。
步骤B:4-(2'-苯氧基-联苯-4-基氧基)-丁酸
将在步骤A中获得的4-(2'-苯氧基-联苯-4-基氧基)-丁酸乙酯(26mg,0.071mmol)溶于各1mL的1N NaOH、TFH和MeOH,并将生成物在室温搅拌3小时。在除去有机溶剂之后,通过使用1N HCl将pH调节至3,并将反应物用EtOAc萃取。将有机层用无水MgSO4干燥并通过色谱法纯化(洗脱剂:EtOAc/Hex=1/2),得到标题化合物(0.018g,75%)。
1H-NMR(MeOD)δ7.46(3H,m),7.31(1H,m),7.25(3H,m),7.01(2H,m),6.89(2H,d),6.82(2H,d),4.02(2H,t),2.48(2H,t),2.04(2H,m)。
实施例38:4-[4-(2-异丙基硫基-吡啶-3-基)-苯氧基]-丁酸
步骤A:4-[4-(2-异丙基硫基-吡啶-3-基)-苯氧基]-丁酸乙酯
将在制备例33中获得的4-(2-异丙基硫基-吡啶-3-基)-苯酚(0.015g,0.061mmol)、碳酸铯(0.04g,0.12mmol)和4-溴丁酸乙酯(0.014g,0.07mmol)溶于2mL的DMF,并将生成物在室温搅拌24小时。向反应溶液添加NaCl水溶液并用EtOAc萃取以分离有机层。将有机层用无水MgSO4干燥并通过色谱法纯化(洗脱剂:EtOAc/Hex=1/4),得到标题化合物(0.01g,45%)。
1H-NMR(CDCl3)δ8.41(1H,m),7.32(3H,m),7.02(1H,m),6.94(2H,m),4.16(2H,q),4.04(3H,m),2.53(2H,t),2.13(2H,m),1.35(6H,d),1.27(3H,t)。
步骤B:4-[4-(2-异丙基硫基-吡啶-3-基)-苯氧基]-丁酸
使用在步骤A中获得的4-[4-(2-异丙基硫基-吡啶-3-基)-苯氧基]-丁酸乙酯(0.01g,0.02mmol)以与实施例37的步骤B相同的方式反应,得到标题化合物(0.006g,65%)。
1H-NMR(CDCl3)δ8.41(1H,m),7.32(3H,m),7.02(1H,m),6.95(2H,m),4.06(3H,m),2.62(2H,t),2.15(2H,m),1.35(6H,d)。
实施例39:4-(3,5-二氟-2'-苯氧基-联苯-4-基氧基)-丁酸
步骤A:4-(3,5-二氟-2'-苯氧基-联苯-4-基氧基)丁酸乙酯
使用在制备例34中获得的3,5-二氟-2'-苯氧基-联苯-4-醇(0.017g,0.056mmol)和4-溴丁酸乙酯(0.013g,0.068mmol)以与实施例37的步骤A相同的方式反应,得到标题化合物(0.023g,95%)。
1H-NMR(CDCl3)δ7.40(1H,m),7.30(3H,m),7.20(1H,m),7.11(2H,m),7.05(1H,m),6.97(1H,m),6.91(2H,m),4.15(4H,m),2.56(2H,t),2.07(2H,m),1.27(3H,t)。
步骤B:4-(3,5-二氟-2'-苯氧基-联苯-4-基氧基)-丁酸
使用在步骤A中获得的4-(3,5-二氟-2'-苯氧基-联苯-4-基氧基)-丁酸乙酯(0.022g,0.053mmol)以与实施例37的步骤B相同的方式反应,得到标题化合物(0.014g,69%)。
1H-NMR(CDCl3)δ7.40(1H,m),7.30(3H,m),7.20(1H,m),7.11(2H,m),7.05(1H,m),6.97(1H,m),6.91(2H,d),4.19(2H,t),2.64(2H,t),2.08(2H,m)。
实施例40:4-[4-(2-环戊基硫基-吡啶-3-基)-苯氧基]-丁酸
步骤A:4-[4-(2-环戊基硫基-吡啶-3-基)-苯氧基]-丁酸乙酯
使用在制备例35中获得的4-(2-环戊基硫基-吡啶-3-基)-苯酚(0.024g,0.088mmol)以与实施例38的步骤A相同的方式反应,得到标题化合物(0.03g,88%)。
1H-NMR(CDCl3)δ8.38(1H,m),7.32(3H,m),7.01(1H,m),6.94(2H,m),4.14(2H,q),4.05(3H,m),2.52(2H,t),2.13(4H,m),1.60(2H,m),1.66(4H,m),1.26(3H,t)。
步骤B:4-[4-(2-环戊基硫基-吡啶-3-基)-苯氧基]-丁酸
使用在步骤A中获得的4-[4-(2-环戊基硫基-吡啶-3-基)-苯氧基]-丁酸乙酯(0.03g,0.077mmol)以与实施例37的步骤B相同的方式反应,得到标题化合物(0.017g,63%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.32(3H,m),7.01(1H,m),6.95(2H,m),4.07(3H,m),2.62(2H,t),2.15(4H,m),1.69(2H,m),1.58(4H,m)。
实施例41:4-[2,6-二氟-4-(2-异丙基硫基-吡啶-3-基)-苯氧基]-丁酸
使用在制备例63中获得的2,6-二氟-4-(2-异丙基硫基-吡啶-3-基)-苯酚(0.015g,0.053mmol)以与实施例38的步骤A和B相同的方式反应,得到标题化合物(0.005g,27%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.32(1H,m),7.03(1H,m),6.99(2H,m),4.25(2H,t),4.06(1H,m),2.67(2H,t),2.13(2H,m),1.37(6H,d)。
实施例42:4-[2,6-二氟-4-(2-苯氧基-吡啶-3-基)-苯氧基]-丁酸
使用在制备例36中获得的3-碘-2-苯氧基-吡啶(0.043g,0.144mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.048g,0.131mmol)以与制备例33的步骤B和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.004g,7%)。
1H-NMR(CDCl3)δ8.42(1H,m),7.12(1H,m),7.40(2H,m),7.22(3H,m),7.11(3H,m),4.23(2H,t),2.65(2H,t),2.11(2H,m)。
实施例43:4-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯氧基]-丁酸
使用在制备例37中获得的3-碘-2-异丙氧基-吡啶(0.029g,0.11mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.034g,0.091mmol)以与实施例1的步骤A和B相同的方式反应,得到标题化合物(0.011g,21%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.55(1H,m),7.15(2H,m),6.91(1H,m),5.41(1H,m),4.24(2H,t),2.67(2H,t),2.13(2H,m),1.37(6H,d)。
实施例44:4-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用在制备例38中获得的2-环戊氧基-3-碘-吡啶(0.042g,0.14mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.045g,0.121mmol)以与实施例1的步骤A和B相同的方式反应,得到标题化合物(0.021g,41%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.55(1H,m),7.15(2H,m),6.91(1H,m),5.52(1H,m),4.24(2H,t),2.67(2H,t),2.13(2H,m),1.95(2H,m),1.78(4H,m),1.65(2H,m)。
实施例45:4-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用在制备例39中获得的2-环戊基硫基-3-碘-吡啶(0.026g,0.09mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.031g,0.083mmol)以与实施例1的步骤A和B相同的方式反应,得到标题化合物(0.009g,25%)。
1H-NMR(CDCl3)δ8.42(1H,m),7.30(1H,m),7.02(3H,m),4.25(2H,t),4.07(1H,m),2.67(2H,t),2.15(4H,m),1.69(2H,m),1.58(4H,m)。
实施例46:4-[4-(2-环丙基甲氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用在制备例40中获得的2-环丙基甲氧基-3-碘-吡啶(0.05g,0.181mmol)和在制备例2的步骤C中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.061g,0.165mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.022g,34%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.57(1H,m),7.20(2H,m),6.94(1H,m),4.23(4H,m),2.67(2H,t),2.12(2H,m),1.42(1H,m),0.59(2H,m),0.34(2H,m)。
实施例47:4-[4-(2-环丙基甲基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用在制备例41中获得的2-环丙基甲基硫基-3-(3,5-二氟-4-甲氧基-苯基)-吡啶(0.033g,0.107mmol)以与制备例33的步骤C、实施例38的步骤A和实施例37的步骤B相同的方式顺序反应,得到标题化合物(0.0088g,13%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.31(1H,m),7.02(3H,m),4.26(2H,m),3.11(2H,m),2.69(2H,m),2.15(2H,m),1.15(1H,m),0.57(2H,m),0.34(2H,m)。
实施例48:4-[4-(2-环丁基硫基-吡啶-3-基)-苯氧基]-丁酸
使用在制备例42中获得的2-环丁基硫基-3-(4-甲氧基-苯基)-吡啶(0.009g,0.034mmol)以与制备例33的步骤C、实施例38的步骤A和实施例37的步骤B相同的方式顺序反应,得到标题化合物(0.0034g,28%)。
1H-NMR(CDCl3)δ8.38(1H,m),7.34(3H,m),7.02(3H,m),4.42(1H,m),4.08(2H,m),2.62(2H,m),2.49(2H,m),2.16(2H,m),2.01(4H,m)。
实施例49:4-[4-(2-环丙基甲基硫基-吡啶-3-基)-苯氧基]-丁酸
使用在制备例43中获得的2-环丙基甲基硫基-3-(4-甲氧基-苯基)-吡啶(0.02g,0.073mmol)以与制备例33的步骤C、实施例38的步骤A和实施例37的步骤B相同的方式顺序反应,得到标题化合物(0.0031g,12%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.37(3H,m),7.02(3H,m),4.09(2H,m),3.09(2H,m),2.63(2H,m),2.13(2H,m),1.09(1H,m),0.54(2H,m),0.27(2H,m)。
实施例50:4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
步骤A:4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]丁酸乙酯
将在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.15g,0.394mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.12g,0.329mmol)溶于1mL的2M Na2CO3水溶液和2mL的1,2-二甲氧基乙烷,并向其中充N25分钟。向其中添加PdCl2(PPh3)2(0.012g,0.016mmol)并将生成物在回流下搅拌5小时。在结束反应之后,将生成物用水稀释并用EtOAc萃取。将有机层用MgSO4干燥并通过色谱法纯化(洗脱剂:EtOAc/Hex=1/4),得到标题化合物(0.084g,62%)。
1H-NMR(CDCl3)δ8.41(1H,m),7.32(1H,m),7.01(3H,m),4.42(1H,m),4.24(2H,m),4.16(2H,q),2.59(2H,m),2.69(2H,m),2.13(3H,m),2.06(3H,m),1.28(3H,t)。
步骤B:4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
将在步骤A中获得的4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸乙酯(0.068g,0.166mmol)以与实施例37的步骤B相同的方式反应,得到标题化合物(0.031g,50%)。
1H-NMR(CDCl3)δ8.41(1H,m),7.32(1H,m),7.01(3H,m),4.41(1H,m),4.26(2H,m),2.69(2H,m),2.51(2H,m),2.15(3H,m),2.06(3H,m)。
实施例51:4-[4-(2-丙基硫基-吡啶-3-基)-苯氧基]-丁酸
使用在制备例45中获得的3-(4-甲氧基-苯基)-2-丙基硫基-吡啶(0.023g,0.088mmol)以与制备例33的步骤C、实施例38的步骤A和实施例37的步骤B相同的方式顺序反应,得到标题化合物(0.005g,18%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.34(3H,m),7.02(1H,m),6.95(2H,m),4.08(2H,m),3.12(2H,m),2.62(2H,m),2.16(2H,m),1.70(2H,m),1.00(3H,t)。
实施例52:4-(3,5-二氟-2'-异丙氧基-联苯-4-基氧基)-丁酸
使用在制备例46中获得的1-溴-2-异丙氧基-苯(0.051g,0.237mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.067g,0.182mmol)以与实施例50的步骤A和实施例37步骤B相同的方式顺序反应,得到标题化合物(0.022g,35%)。
1H-NMR(CDCl3)δ7.28(2H,m),7.14(2H,m),6.98(2H,m),4.49(1H,m),4.23(2H,t),2.69(2H,m),2.12(2H,m),1.29(6H,d)。
实施例53:4-(2'-环丁氧基-3,5-二氟-联苯-4-基氧基)-丁酸
使用在制备例47中获得的1-溴-2-环丁氧基-苯(0.023g,0.101mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.029g,0.0779mmol)以与实施例50的步骤A和实施例37步骤B相同的方式顺序反应,得到标题化合物(0.01g,35%)。
1H-NMR(CDCl3)δ7.28(2H,m),7.15(2H,m),6.99(1H,m),6.80(1H,m),4.65(1H,m),4.23(2H,m),2.68(2H,m),2.44(2H,m),2.17(4H,m),1.85(1H,m),1.70(1H,m)。
实施例54:4-(2'-环丙基甲氧基-3,5-二氟-联苯-4-基氧基)-丁酸
使用在制备例48中获得的1-溴-2-环丙基甲氧基-苯(0.054g,0.23mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.067g,0.182mmol)以与实施例50的步骤A和实施例37步骤B相同的方式顺序反应,得到标题化合物(0.021g,32%)。
1H-NMR(CDCl3)δ7.29(2H,m),7.16(2H,m),6.99(1H,m),6.94(1H,m),4.23(2H,m),3.83(2H,m),2.69(2H,m),2.13(2H,m),1.22(1H,m),0.61(2H,m),0.31(2H,m)。
实施例55:4-(2'-环戊基氧基-3,5-二氟-联苯-4-基氧基)-丁酸
使用在制备例49中获得的1-溴-2-环戊氧基-苯(0.079g,0.33mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.093g,0.25mmol)以与实施例50的步骤A和实施例37步骤B相同的方式顺序反应,得到标题化合物(0.047g,50%)。
1H-NMR(CDCl3)δ7.28(2H,m),7.13(2H,m),6.96(2H,m),4.77(1H,m),4.23(2H,m),2.68(2H,t),2.12(2H,m),1.86(4H,m),1.64(2H,m),1.55(2H,m)。
实施例56:4-(2'-环戊基氧基-联苯-4-基氧基)-丁酸
使用在制备例49中获得的1-溴-2-环戊氧基-苯(0.063g,0.26mmol)和在制备例1中获得的4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.067g,0.20mmol)以与实施例50的步骤A和实施例37步骤B相同的方式顺序反应,得到标题化合物(0.027g,39%)。
1H-NMR(CDCl3)δ7.46(2H,m),7.28(2H,m),6.97(2H,m),6.89(2H,m),4.74(1H,m),4.07(2H,m),2.62(2H,t),2.15(2H,m),1.82(4H,m),1.64(2H,m),1.55(2H,m)。
实施例57:4-(2'-异丙氧基-联苯-4-基氧基)-丁酸
使用在制备例46中获得的1-溴-2-异丙氧基-苯(0.058g,0.26mmol)和在制备例1中获得的4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.069g,0.20mmol)以与实施例50的步骤A和实施例37步骤B相同的方式顺序反应,得到标题化合物(0.026g,40%)。
1H-NMR(CDCl3)δ7.48(2H,m),7.28(2H,m),6.96(2H,m),6.90(2H,m),4.41(1H,m),4.06(2H,m),2.61(2H,t),2.14(2H,m),1.24(6H,d)。
实施例58:4-(2'-环丙基甲氧基-联苯-4-基氧基)-丁酸
使用在制备例48中获得的1-溴-2-环丙基甲氧基-苯(0.059g,0.26mmol)和在制备例1中获得的4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.066g,0.19mmol)以与实施例50的步骤A和实施例37步骤B相同的方式顺序反应,得到标题化合物(0.024g,36%)。
1H-NMR(CDCl3)δ7.51(2H,m),7.29(2H,m),6.99(2H,m),6.92(2H,m),4.06(2H,m),3.79(2H,d),2.61(2H,t),2.14(2H,m),1.19(1H,m),0.55(2H,m),0.26(2H,m)。
实施例59:4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-2-甲基-丁酸
使用在制备例51中获得的4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯酚(0.078g,0.26mmol)和在制备例50中获得的4-溴-2-甲基-丁酸乙酯(0.055g,0.266mmol)以与实施例37的步骤A和B相同的方式顺序反应,得到标题化合物(0.043g,40%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.30(1H,m),6.98(3H,m),4.41(1H,m),4.26(2H,m),2.89(1H,m),2.50(2H,m),2.25(1H,m),2.02(4H,m),1.90(1H,m),1.31(3H,d)。
实施例60:2-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基甲基]-环丙烷甲酸
使用在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.035g,0.12mmol)和在制备例52的步骤D中获得的2-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯氧基甲基]-环丙烷甲酸乙酯(0.042g,0.112mmol)以与实施例50的步骤A和实施例37步骤B相同的方式顺序反应,得到标题化合物(0.013g,27%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.32(1H,m),7.00(3H,m),4.40(1H,m),4.16(1H,m),4.05(1H,m),2.50(2H,m),2.03(5H,m),1.72(1H,m),1.35(1H,m),1.06(1H,m)。
实施例61:4-[4-(2-环丁基硫基-吡啶-3-基)-2,5-二氟-苯氧基]-丁酸
使用在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.11g,0.38mmol)和在制备例53的步骤C中获得的4-[2,5-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯氧基]-丁酸乙酯(0.132g,0.35mmol)以与实施例50的步骤A和实施例37步骤B相同的方式顺序反应,得到标题化合物(0.061g,44%)。
1H-NMR(CDCl3)δ8.41(1H,m),7.35(1H,m),7.00(2H,m),6.78(1H,m),4.41(1H,m),4.11(2H,m),2.64(2H,m),2.48(2H,m),2.19(2H,m),2.02(4H,m)。
实施例62:4-[4-(6-环丁基硫基-吡啶-2-基)-2,5-二氟-苯氧基]-丁酸
使用在制备例19中获得的2-氯-6-环丁基硫基-吡啶(0.081g,0.40mmol)和在制备例53的步骤C中获得的4-[2,5-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯氧基]-丁酸乙酯(0.14g,0.37mmol)以与实施例50的步骤A和实施例37步骤B相同的方式顺序反应,得到标题化合物(0.057g,39%)。
1H-NMRδ(CDCl3)7.89(1H,m),7.49(2H,m),7.00(1H,m),6.78(1H,m),4.38(1H,m),4.11(2H,m),2.63(4H,m),2.19(6H,m)。
实施例63:4-[4-(2-叔丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用2-甲基-丙-2-硫醇(27mg,0.29mmol)和在制备例109中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸乙酯(100mg,0.29mmol)以与制备例5和实施例1的步骤B相同的方式顺序反应,得到标题化合物(55mg,46%)。
1H NMR(CDCl3)δ8.45(1H,m),7.33(1H,m),7.04(1H,m),6.95(2H,m),4.27(2H,t),2.69(2H,t),2.15(2H,m),1.55(9H,s)。
实施例64:6-[2,6-二氟-4-(2-丙基硫基-3-吡啶基)苯氧基]己酸
步骤A:6-[2,6-二氟-4-(2-丙基硫基-3-吡啶基)苯氧基]己酸乙酯
使用在制备例203中获得的3-碘-2-丙基硫基-吡啶(0.073g,0.26mmol)和在制备例146中获得的6-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]己酸乙酯(0.11g,0.27mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.076g,69%)。
1H-NMR(CDCl3)δ8.43(1H,m),7.33(1H,m),7.04(1H,m),7.00(2H,m),4.19(2H,t),4.13(2H,q),3.14(2H,t),2.34(2H,t),1.81(2H,m),1.73(4H,m),1.53(2H,m),1.28(3H,t),1.02(3H,t)。
步骤B:6-[2,6-二氟-4-(2-丙基硫基-3-吡啶基)苯氧基]己酸
使用在步骤A中获得的6-[2,6-二氟-4-(2-丙基硫基-3-吡啶基)苯氧基]己酸乙酯(0.076g,0.18mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.068g,96%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.35(1H,m),7.04(1H,m),6.99(2H,m),4.20(2H,t),3.15(2H,t),2.42(2H,t),1.83(2H,m),1.72(4H,m),1.58(2H,m),1.02(3H,t)。
实施例65:4-{2,6-二氟-4-[6-(2-甲基-丙烯基)-吡啶-2-基]-苯氧基}-丁酸
步骤A:4-{2,6-二氟-4-[6-(2-甲基-丙烯基)-吡啶-2-基]-苯氧基}-丁酸乙酯
使用在制备例57中获得的4-[2,6-二氟-4-(6-甲酰基-吡啶-2-基)-苯氧基]-丁酸乙酯(0.25g,0.72mmol)以与制备例101相同的方式反应,得到标题化合物(80mg,30%)。
步骤B:4-{2,6-二氟-4-[6-(2-甲基-丙烯基)-吡啶-2-基]-苯氧基}-丁酸
使用在步骤A中获得的4-{2,6-二氟-4-[6-(2-甲基-丙烯基)-吡啶-2-基]-苯氧基}-丁酸乙酯(20mg,0.05mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(17mg,97%)。
1H NMR(CDCl3)δ7.68(1H,t),7.62(2H,m),7.41(1H,m),7.10(1H,d),6.35(1H,s),4.25(2H,t),2.68(2H,t),2.21(3H,s),2.13(2H,m),1.98(3H,s)。
实施例66:4-[2,6-二氟-4-(6-异丁基-吡啶-2-基)-苯氧基]-丁酸
使用在实施例65的步骤A中获得的4-{2,6-二氟-4-[6-(2-甲基-丙烯基)-吡啶-2-基]-苯氧基}-丁酸乙酯(60mg,0.16mmol)以与制备例50的步骤B和实施例1的步骤B相同的方式顺序反应,得到标题化合物(40mg,86%)。
1H NMR(CDCl3)δ7.65(1H,t),7.59(2H,m),7.43(1H,d),7.06(1H,d),4.24(2H,t),2.70(4H,m),2.22(1H,m),2.12(2H,m),0.96(6H,d)。
实施例67:4-[4-(2-环丁基硫基-吡啶-3-基)-3,5-二氟-苯氧基]-丁酸
将在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.040g,0.14mmol)和在制备例54中获得的4-[3,5-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.051g,0.14mmol)以与实施例1相同的方式反应,得到标题化合物(0.005g,10%)。
1H NMR(CDCl3)δ8.45(1H,m),7.37(1H,m),7.04(1H,m),6.56(2H,m),4.45(1H,m),4.06(2H,t),2.61(2H,t),2.59(2H,m),2.17(2H,m),2.05(4H,m)。
实施例68:4-{2,6-二氟-4-[2-(四氢-吡喃-4-基氧基)-吡啶-3-基]-苯氧基}-丁酸
将在制备例58中获得的3-碘-2-(四氢-吡喃-4-基氧基)-吡啶(0.040g,0.13mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.049g,0.13mmol)以与实施例1相同的方式反应,得到标题化合物(0.035g,68%)。
1H NMR(CDCl3)δ8.12(1H,m),7.57(1H,m),7.14(2H,m),6.95(1H,m),5.37(1H,m),4.24(2H,t),3.90(2H,m),3.64(2H,m),2.67(2H,t),2.13(4H,m),1.82(2H,m)。
实施例69:4-{2,6-二氟-4-[2-(四氢-呋喃-3-基氧基)-吡啶-3-基]-苯氧基}-丁酸
将在制备例59中获得的3-碘-2-(四氢-呋喃-3-基氧基)-吡啶(0.040g,0.14mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.051g,0.14mmol)以与实施例1相同的方式反应,得到标题化合物(0.030g,58%)。
1H NMR(CDCl3)δ8.12(1H,m),7.57(1H,m),7.13(2H,m),6.98(1H,m),5.63(1H,m),4.24(2H,t),4.07(1H,m),3.94(3H,m),2.68(2H,t),2.25(1H,m),2.14(3H,m)。
实施例70:4-[4-(2-环丁氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
将在制备例200中获得的2-环丁氧基-3-碘-吡啶(0.040g,0.15mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.054g,0.15mmol)以与实施例1相同的方式反应,得到标题化合物(0.020g,38%)。
1H NMR(CDCl3)δ8.12(1H,m),7.57(1H,m),7.18(2H,m),6.93(1H,m),5.28(1H,m),4.24(2H,t),2.69(2H,t),2.47(2H,m),2.12(4H,m),1.83(1H,m),1.69(1H,m)。
实施例71:4-{2,6-二氟-4-[2-(2-甲氧基-乙氧基)-吡啶-3-基]-苯氧基}-丁酸
使用2-甲氧基-乙醇(51mg,0.67mmol)和在制备例56中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸(70mg,0.22mmol)以与制备例37相同的方式反应,得到标题化合物(55mg,67%)。
1H NMR(CDCl3)δ8.14(1H,m),7.59(1H,m),7.22(2H,m),6.96(1H,m),4.54(2H,t),4.24(2H,t),3.76(2H,t),3.42(3H,s),2.68(2H,t),2.12(2H,m)。
实施例72:4-[2,6-二氟-4-(2-吡咯烷-1-基-3-吡啶基)苯氧基]丁酸
步骤A:4-[2,6-二氟-4-(2-吡咯烷-1-基-3-吡啶基)苯氧基]丁酸乙酯
将1.2mL的DMF加入在制备例109中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸乙酯(0.078g,0.23mmol)、吡咯烷(0.022g,0.32mmol)和Cs2CO3(0.15g,0.46mmol),并将生成物在50℃搅拌8小时。将反应溶液在减压下浓缩并通过色谱法纯化,得到标题化合物(0.056g,62%)。
1H-NMR(CDCl3)δ8.16(1H,m),7.31(1H,m),6.90(2H,m),6.69(1H,m),4.21(2H,t),4.17(2H,q),3.15(4H,m),2.59(2H,t),2.12(2H,m),1.80(4H,m),1.27(3H,t)。
步骤B:4-[2,6-二氟-4-(2-吡咯烷-1-基-3-吡啶基)苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-(2-吡咯烷-1-基-3-吡啶基)苯氧基]丁酸乙酯(0.056g,0.14mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.038g,73%)。
1H-NMR(CDCl3)δ8.19(1H,m),7.33(1H,m),6.90(2H,m),6.70(1H,m),4.23(2H,t),3.17(4H,m),2.67(2H,t),2.12(2H,m),1.81(4H,m)。
实施例73:4-[4-[2-(环戊基氨基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在制备例64中获得的N-环戊基-3-碘-吡啶基-2-胺(0.03g,0.1mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.043g,0.11mmol)以与实施例29的步骤A和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.02g,50%)。
1H-NMR(CDCl3)δ8.15(1H,m),7.19(1H,m),6.94(2H,m),6.60(1H,m),4.45(1H,brs),4.33(1H,m),4.25(2H,t),2.68(2H,t),2.15(2H,m),2.05(2H,m),1.64(4H,m),1.34(2H,m)。
实施例74:4-[4-[2-(环丙基甲基氨基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[2-(环丙基甲基氨基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例109中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸乙酯(0.078g,0.23mmol)和N-(环丙基甲基)氨基甲酸叔丁酯(0.047g,0.27mmol)以与实施例72的步骤A相同的方式反应,得到标题化合物(0.025g,29%)。
1H-NMR(CDCl3)δ8.13(1H,m),7.21(1H,m),6.98(2H,m),6.62(1H,m),4.62(1H,m),4.24(2H,t),4.17(2H,q),3.26(2H,m),2.59(2H,m),2.12(2H,m),1.27(3H,t),1.05(1H,m),0.49(2H,m),0.20(2H,m)。
步骤B:4-[4-[2-(环丙基甲基氨基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[2-(环丙基甲基氨基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯(0.026g,0.066mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.02g,82%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.22(1H,m),6.99(2H,m),6.62(1H,m),4.64(1H,brs),4.24(2H,t),3.24(2H,d),2.63(2H,t),2.12(2H,m),1.05(1H,m),0.48(2H,m),0.20(2H,m)。
实施例75:4-[4-[6-(环丙基甲基氨基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[6-(环丙基甲基氨基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例65中获得的6-氯-N-(环丙基甲基)吡啶-2-胺(0.17g,0.93mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.34g,0.93mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.125g,34%)。
1H-NMR(CDCl3)δ7.54(2H,m),7.45(1H,t),6.91(1H,d),6.34(1H,m),4.70(1H,m),4.20(2H,t),4.15(2H,q),3.19(2H,t),2.58(2H,t),2.09(2H,m),1.28(3H,t),1.13(1H,m),0.55(2H,m),0.28(2H,m)。
步骤B:4-[4-[6-(环丙基甲基氨基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[6-(环丙基甲基氨基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯(0.32g,0.34mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.115g,99%)。
1H-NMR(CDCl3)δ7.50(3H,m),6.90(1H,d),6.35(1H,d),4.22(2H,t),3.20(2H,d),2.66(2H,t),2.10(2H,m),1.12(1H,m),0.55(2H,m),0.29(2H,m)。
实施例76:4-[2,6-二氟-4-[2-(异丙基氨基)-3-吡啶基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[2-(异丙基氨基)-3-吡啶基]苯氧基]丁酸乙酯
使用在制备例66中获得的3-碘-N-异丙基-吡啶基-2-胺(0.045g,0.17mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.063g,0.17mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.047g,74%)。
1H-NMR(CDCl3)δ8.13(1H,m),7.19(1H,m),6.93(2H,m),6.60(1H,m),4.25(4H,m),4.17(2H,q),2.59(2H,t),2.12(2H,m),1.27(3H,t),1.20(6H,d)。
步骤B:4-[2,6-二氟-4-[2-(异丙基氨基)-3-吡啶基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[2-(异丙基氨基)-3-吡啶基]苯氧基]丁酸乙酯(0.046g,0.12mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.023g,54%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.20(1H,m),6.95(2H,m),6.62(1H,m),4.25(3H,m),2.65(2H,t),2.13(2H,m),1.18(6H,d)。
实施例77:4-[4-[2-(环丙基氨基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[2-(环丙基氨基)-3-吡啶基]-2,6-二氟-苯氧基丁酸乙酯
使用在制备例67中获得的N-环丙基-3-碘-吡啶基-2-胺(0.05g,0.19mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.07g,0.19mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.043g,60%)。
1H-NMR(CDCl3)δ8.24(1H,m),7.22(1H,m),6.92(2H,m),6.69(1H,m),4.76(1H,brs),4.23(2H,t),4.16(2H,q),2.75(1H,m),2.58(2H,t),2.11(2H,m),1.27(3H,t),0.80(2H,m),0.47(2H,m)。
步骤B:4-[4-[2-(环丙基氨基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[2-(环丙基氨基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯(0.043g,0.11mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.015g,39%)。
1H-NMR(CDCl3)δ8.25(1H,m),7.22(1H,m),6.90(2H,m),6.69(1H,m),4.82(1H,brs),4.25(2H,t),2.75(1H,m),2.66(2H,t),2.13(2H,m),0,80(2H,m),0.47(2H,m)。
实施例78:4-[2,6-二氟-4-[6-(异丙基氨基)-2-吡啶基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[6-(异丙基氨基)-2-吡啶基]苯氧基]丁酸乙酯
将在制备例69中获得的N-(6-溴-2-吡啶基)-N-异丙基-氨基甲酸叔丁酯(0.06g,0.19mmol)溶于0.4mL的TFA和0.4mL的DCM,并将生成物在室温搅拌5小时。将反应物在减压下浓缩并使用在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.07g,0.19mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.028g,39%)。
1H-NMR(CDCl3)δ7.54(2H,m),7.45(1H,t),6.90(1H,d),6.31(1H,d),4.43(1H,brs),4.21(2H,t),4.15(2H,q),4.00(1H,m),2.58(2H,t),2.10(2H,m),1.26(9H,m)。
步骤B:4-[2,6-二氟-4-[6-(异丙基氨基)-2-吡啶基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[6-(异丙基氨基)-2-吡啶基]苯氧基]丁酸乙酯(0.028g,0.07mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.017g,65%)。
1H-NMR(CDCl3)δ7.52(2H,m),7.46(1H,t),6.88(1H,d),6.33(1H,d),4.22(2H,t),3.97(1H,m),2.66(2H,t),2.10(2H,m),1.26(6H,d)。
实施例79:4-[4-[2-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[2-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例70中获得的N-环戊基-2-碘-苯胺(0.046g,0.16mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.05g,0.135mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.044g,81%)。
1H-NMR(CDCl3)δ7.21(1H,t),7.00(3H,m),6.71(2H,m),4.23(2H,t),4.15(2H。q),3.79(2H,m),2.60(2H,t),2.12(2H,m),1.98(2H,m),1.62(4H,m),1.41(2H,m),1.27(3H,t)。
步骤B:4-[4-[2-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[2-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸乙酯(0.044g,0.11mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.035g,85%)。
1H-NMR(CDCl3)δ7.21(1H,t),7.00(1H,m),6.98(2H,m),6.75(2H,m),4.24(2H,t),3.76(1H,m),2.68(2H,t),2.13(2H,m),1.99(2H,m),1.67(2H,m),1.60(2H,m),1.41(2H,m)。
实施例80:4-[4-[3-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[3-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例71中获得的3-溴-N-环戊基-苯胺(0.039g,0.16mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.05g,0.135mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.024g,44%)。
1H-NMR(CDCl3)δ7.20(1H,t),7.07(2H,m),6.79(1H,d),6.68(1H,m),6.59(1H,m),4.20(2H,t),4.15(2H,q),3.85(1H,m),3.77(1H,brs),2.58(2H,t),2.10(4H,m),1.74(2H,m),1.65(2H,m),1.48(2H,m),1.27(3H,t)。
步骤B:4-[4-[3-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[3-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸乙酯(0.024g,0.06mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.021g,94%)。
1H-NMR(CDCl3)δ7.23(1H,t),7.09(2H,m),6.87(1H,m),6.82(1H,m),6.72(1H,m),4.21(2H,t),3.82(1H,m),2.67(2H,t),2.12(2H,m),2.04(2H,m),1.76(2H,m),1.63(2H,m),1.58(2H,m)。
实施例81:4-[2,6-二氟-4-[2-(丙基氨基)苯基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[2-(丙基氨基)苯基]苯氧基]丁酸乙酯
使用在制备例72中获得的2-碘-N-丙基-苯胺(0.056g,0.21mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.066g,0.18mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.048g,57%)。
1H-NMR(CDCl3)δ7.25(1H,t),7.02(1H,d),6.99(2H,m),6.73(1H,t),6.69(1H,d),4.23(2H,t),4.16(2H,q),3.82(1H,brs),3.07(2H,t),2.59(2H,t),2.11(2H,m),1.62(2H,m),1.27(3H,t),0.96(3H,t)。
步骤B:4-[2,6-二氟-4-[2-(丙基氨基)苯基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[2-(丙基氨基)苯基]苯氧基]丁酸乙酯(0.048g,0.12mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.023g,51%)。
1H-NMR(CDCl3)δ7.23(1H,t),7.00(3H,m),6.74(1H,t),6.69(1H,d),4.23(2H,t),3.07(2H,t),2.68(2H,t),2.13(2H,m),1.60(2H,m),0.94(3H,t)。
实施例82:4-[4-[2-(环丙基甲基氨基)苯基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[2-(环丙基甲基氨基)苯基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例73中获得的N-(环丙基甲基)-2-碘-苯胺(0.059g,0.21mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.066g,0.18mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.048g,58%)。
1H-NMR(CDCl3)δ7.22(1H,t),7.00(3H,m),6.74(1H,t),6.69(1H,d),4.23(2H,t),4.16(2H,q),3.97(1H,brs),2.96(2H,d),2.60(2H,t),2.12(2H,m),1.27(3H,t),1.04(1H,m),0.50(2H,m),0.18(2H,m)。
步骤B:4-[4-[2-(环丙基甲基氨基)苯基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[2-(环丙基甲基氨基)苯基]-2,6-二氟-苯氧基]丁酸乙酯(0.048g,0.12mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.042g,97%)。
1H-NMR(CDCl3)δ7.23(1H,t),7.00(3H,m),6.76(1H,t),6.70(1H,d),4.24(2H,t),2.96(2H,d),2.68(2H,t),2.13(2H,m),1.03(1H,m),0.52(2H,m),0.18(2H,m)。
实施例83:4-[2,6-二氟-4-[2-(异丙基氨基)苯基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[2-(异丙基氨基)苯基]苯氧基]丁酸乙酯
使用在制备例74中获得的2-碘-N-异丙基-苯胺(0.05g,0.19mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.059g,0.16mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.043g,60%)。
1H-NMR(CDCl3)δ7.22(1H,t),7.00(1H,d),6.95(2H,m),6.70(2H,m),4.23(2H,t),4.17(2H,q),3.03(2H,m),2.59(2H,t),2.11(2H,m),1.26(3H,t),1.17(6H,d)。
步骤B:4-[2,6-二氟-4-[2-(异丙基氨基)苯基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[2-(异丙基氨基)苯基]苯氧基]丁酸乙酯(0.043g,0.11mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.038g,99%)。
1H-NMR(CDCl3)δ7.23(1H,t),7.00(1H,d),6.95(2H,m),6.72(2H,m),4.24(2H,t),3.63(1H,m),2.68(2H,t),2.13(2H,m),1.17(6H,d)。
实施例84:4-[4-[2-(环戊基氨基)苯基]苯氧基]丁酸
使用在制备例70中获得的N-环戊基-2-碘-苯胺(0.068g,0.24mmol)和在制备例1中获得的4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.061g,0.18mmol)以与实施例28的步骤A和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.01g,15%)。
1H-NMR(CDCl3)δ7.31(2H,m),7.20(1H,t),7.02(1H,d),6.95(2H,m),6.72(2H,m),4.07(2H,t),3.78(1H,m),2.62(2H,t),2.17(2H,m),1.95(2H,m),1.58(4H,m),1.38(2H,m)。
实施例85:4-[4-[2-(环丙基甲基氨基)苯基]苯氧基]丁酸
使用在制备例73中获得的N-(环丙基甲基)-2-碘-苯胺(0.057g,0.21mmol)和在制备例1中获得的4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.061g,0.18mmol)以与实施例28的步骤A和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.015g,23%)。
1H-NMR(CDCl3)δ7.35(2H,m),7.20(1H,t),7.06(1H,m),6.97(2H,m),6.73(1H,t),6.68(1H,d),4.07(2H,t),2.95(2H,d),2.63(2H,m),2.16(2H,m),1.02(1H,m),0.47(2H,m),0.15(2H,m)。
实施例86:4-[4-[2-(丙基氨基)苯基]苯氧基]丁酸
使用在制备例72中获得的2-碘-N-丙基-苯胺(0.056g,0.21mmol)和在制备例1中获得的4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.061g,0.18mmol)以与实施例28的步骤A和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.007g,11%)。
1H-NMR(CDCl3)δ7.32(2H,m),7.21(1H,t),7.05(1H,d),6.95(2H,m),6.72(1H,t),6.68(1H,d),4.07(2H,t),3.05(2H,t),2.62(2H,t),2.17(2H,m),1.55(2H,m),0.91(3H,t)。
实施例87:4-[4-[2-(异丙基氨基)苯基]苯氧基]丁酸
使用在制备例74中获得的2-碘-N-异丙基-苯胺(0.05g,0.19mmol)和在制备例1中获得的4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.053g,0.16mmol)以与实施例28的步骤A和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.008g,15%)。
1H-NMR(CDCl3)δ7.30(2H,m),7.19(1H,t),7.04(1H,d),6.95(2H,m),6.69(2H,m),4.07(2H,t),3.63(1H,m),2.63(2H,t),2.16(2H,m),1.14(6H,d)。
实施例88:4-[4-[2-(环丁基氨基)苯基]苯氧基]丁酸
使用在制备例75中获得的2-溴-N-环丁基-苯胺(0.07g,0.21mmol)和在制备例1中获得的4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.095g,0.42mmol)以与实施例28的步骤A和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.007g,0.1%)。
1H-NMR(CDCl3)δ7.33(2H,m),7.19(1H,t),7.06(1H,d),6.97(2H,m),6.73(1H,t),6.58(1H,d),4.12(2H,t),3.91(1H,m),2.63(2H,t),2.36(2H,m),2.17(2H,m),1.75(4H,m)。
实施例89:4-[4-[2-(环丁基氨基)苯基]-2,6-二氟-苯氧基]丁酸
使用在制备例75中获得的2-溴-N-环丁基-苯胺(0.136g,0.6mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.1g,0.27mmol)以与实施例28的步骤A和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.004g,0.04%)。
1H-NMR(CDCl3)δ7.21(1H,t),6.99(3H,m),6.73(1H,t),6.58(1H,d),4.24(2H,t),3.89(1H,m),2.68(2H,t),2.40(2H,m),2.13(2H,m),1.77(4H,m)。
实施例90:4-[4-[3-(环丙基甲基氨基)苯基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[3-(环丙基甲基氨基)苯基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例76中获得的3-溴-N-(环丙基甲基)苯胺(0.063g,0.23mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.072g,0.19mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.04g,54%)。
1H-NMR(CDCl3)δ7.21(1H,t),7.09(2H,m),6.80(1H,d),6.70(1H,m),6.60(1H,m),4.18(4H,m),3.95(1H,brs),3.00(2H,d),2.59(2H,t),2.10(2H,m),1.27(3H,t),1.10(1H,m),0.57(2H,m),0.26(2H,m)。
步骤B:4-[4-[3-(环丙基甲基氨基)苯基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[3-(环丙基甲基氨基)苯基]-2,6-二氟-苯氧基]丁酸乙酯(0.04g,0.1mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.026g,72%)。
1H-NMR(CDCl3)δ7.21(1H,t),7.11(2H,m),6.80(1H,d),6.70(1H,m),6.61(1H,m),4.21(2H,t),3.00(2H,d),2.67(2H,t),2.12(2H,m),1.18(1H,m),0.57(2H,m),0.27(2H,m)。
实施例91:4-[2,6-二氟-4-[3-(异丙基氨基)苯基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[3-(异丙基氨基)苯基]苯氧基]丁酸乙酯
使用在制备例77中获得的3-溴-N-异丙基-苯胺(0.06g,0.23mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.072g,0.19mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.043g,60%)。
1H-NMR(CDCl3)δ7.20(1H,t),7.09(2H,m),6.78(1H,d),6.66(1H,m),6.57(1H,m),4.18(4H,m),3.68(1H,m),3.60(1H,brs),2.59(2H,t),2.12(2H,m),1.27(9H,m)。
步骤B:4-[2,6-二氟-4-[3-(异丙基氨基)苯基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[3-(异丙基氨基)苯基]苯氧基]丁酸乙酯(0.043g,0.11mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.032g,83%)。
1H-NMR(CDCl3)δ7.20(1H,t),7.10(2H,m),6.78(1H,d),6.67(1H,m),6.58(1H,m),4.21(2H,t),3.69(1H,m),2.67(2H,t),2.11(2H,m),1.24(6H,d)。
实施例92:4-[2,6-二氟-4-(3-吡咯烷-1-基苯基)苯氧基]丁酸
步骤A:4-[2,6-二氟-4-(3-吡咯烷-1-基苯基)苯氧基]丁酸乙酯
使用在制备例78中获得的1-(3-溴苯基)吡咯烷(0.039g,0.17mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.053g,0.14mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.037g,60%)。
1H-NMR(CDCl3)δ7.26(1H,m),7.13(2H,m),6.77(1H,d),6.63(1H,m),6.57(1H,m),4.18(4H,m),3.33(4H,m),2.59(2H,t),2.11(2H,m),2.03(4H,m),1.26(3H,t)。
步骤B:4-[2,6-二氟-4-(3-吡咯烷-1-基苯基)苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-(3-吡咯烷-1-基苯基)苯氧基]丁酸乙酯(0.033g,0.09mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.014g,45%)。
1H-NMR(CDCl3)δ7.26(1H,m),7.14(2H,m),6.76(1H,d),6.62(1H,m),6.58(1H,m),4.21(2H,t),3.33(4H,m),2.67(2H,t),2.12(2H,m),2.03(4H,m)。
实施例93:4-[4-[3-(环丁基氨基)苯基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[3-(环丁基氨基)苯基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例80中获得的3-溴-N-环丁基-苯胺(0.028g,0.12mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.045g,0.12mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.019g,40%)。
1H-NMR(CDCl3)δ7.19(1H,t),7.10(2H,m),6.81(1H,d),6.63(1H,m),6.55(1H,m),4.20(2H,t),4.14(2H,q),3.95(2H,m),2.60(2H,t),2.44(2H,m),2.10(2H,m),1.85(4H,m),1.27(3H,t)。
步骤B:4-[4-[3-(环丁基氨基)苯基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[3-(环丁基氨基)苯基]-2,6-二氟-苯氧基]丁酸乙酯(0.019g,0.05mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.014g,77%)。
1H-NMR(CDCl3)δ7.20(1H,t),7.07(2H,m),6.81(1H,d),6.63(1H,m),6.54(1H,m),4.21(2H,t),3.96(1H,m),2.67(2H,t),2.45(2H,m),2.11(2H,m),1.84(4H,m)。
实施例94:4-[2,6-二氟-4-[3-(丙基氨基)苯基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[3-(丙基氨基)苯基]苯氧基]丁酸乙酯
使用在制备例79中获得的3-溴-N-丙基-苯胺(0.07g,0.3mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.08g,0.21mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.029g,37%)。
1H-NMR(CDCl3)δ7.21(1H,t),7.09(2H,m),6.80(1H,d),6.69(1H,m),6.61(1H,m),4.20(2H,t),4.14(2H,q),3.75(1H,brs),3.13(2H,t),2.58(2H,t),2.10(2H,m),1.66(2H,m),1.27(3H,t),1.02(3H,t)。
步骤B:4-[2,6-二氟-4-[3-(丙基氨基)苯基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[3-(丙基氨基)苯基]苯氧基]丁酸乙酯(0.029g,0.076mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.021g,78%)。
1H-NMR(CDCl3)δ7.21(1H,t),7.11(2H,m),6.80(1H,d),6.69(1H,m),6.60(1H,m),4.21(2H,t),3.13(2H,t),2.67(2H,t),2.11(2H,m),1.66(2H,m),1.02(3H,t)。
实施例95:4-[4-[5-氯-2-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[5-氯-2-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例81中获得的2-溴-4-氯-N-环戊基-苯胺(0.083g,0.3mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.112g,0.3mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.1g,76%)。
1H-NMR(CDCl3)δ7.16(1H,m),6.97(1H,m),6.92(2H,m),6.61(1H,d),4.24(2H,t),4.15(2H,q),3,74(2H,m),2.57(2H,t),2.13(2H,m),1.98(2H,m),1.62(4H,m),1.39(2H,m),1.26(3H,t)。
步骤B:4-[4-[5-氯-2-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[5-氯-2-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸乙酯(0.1g,0.23mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.059g,63%)。
1H-NMR(CDCl3)δ7.15(1H,m),6.98(1H,m),6.92(2H,m),6.62(1H,d),4.25(2H,t),3.73(1H,m),2.67(2H,t),2.13(2H,m),1.92(2H,m),1.64(4H,m),1.38(2H,m)。
实施例96:4-[4-[2-(环戊基氨基)-5-氟-苯基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[2-(环戊基氨基)-5-氟-苯基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例82中获得的N-环戊基-4-氟-2-碘-苯胺(0.055g,0.18mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.066g,0.18mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.053g,70%)。
1H-NMR(CDCl3)δ6.96(3H,m),6.77(1H,m),6.63(1H,m),4.23(2H,t),4.15(2H,q),3.72(1H,m),3.60(1H,brs),2.59(2H,t),2.11(2H,m),1.96(2H,m),1.64(4H,m),1.38(2H,m),1.27(3H,t)。
步骤B:4-[4-[2-(环戊基氨基)-5-氟-苯基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[2-(环戊基氨基)-5-氟-苯基]-2,6-二氟-苯氧基]丁酸乙酯(0.053g,0.125mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.004g,8%)。
1H-NMR(CDCl3)δ6.96(3H,m),6.76(1H,m),6.64(1H,m),4.25(2H,t),3.71(1H,m),2.68(2H,t),2.13(2H,m),1.99(2H,m),1.62(4H,m),1.38(2H,m)。
实施例97:4-[4-(3-环戊基苯基)-2,6-二氟-苯氧基]丁酸
使用在制备例86中获得的1-环戊基-3-碘-苯(0.045g,0.16mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.061g,0.16mmol)以与实施例29的步骤A和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.017g,30%)。
1H-NMR(CDCl3)δ7.36(2H,m),7.30(1H,m),7.26(1H,m),7.12(2H,m),4.23(2H,t),3.04(1H,m),2.67(2H,t),2.11(4H,m),1.83(2H,m),1.72(2H,m),1.62(2H,m)。
实施例98:4-[4-[3-(环戊基甲基)苯基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[3-(环戊基甲基)苯基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例87中获得的1-溴-3-(环戊基甲基)苯(0.115g,0.48mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.118g,0.32mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.08g,62%)。
1H-NMR(CDCl3)δ7.31(3H,m),7.15(1H,d),7.11(2H,m),4.21(2H,t),4.15(2H,q),2.66(2H,d),2.58(2H,t),2.10(3H,m),1.72(2H,m),1.65(2H,m),1.52(2H,m),1.27(3H,t),1.20(2H,m)。
步骤B:4-[4-[3-(环戊基甲基)苯基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[3-(环戊基甲基)苯基]-2,6-二氟-苯氧基]丁酸乙酯(0.08g,0.2mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.07g,94%)。
1H-NMR(CDCl3)δ7.31(3H,m),7.17(1H,m),7.11(2H,m),4.22(2H,t),2.67(4H,m),2.11(3H,m),1.72(2H,m),1.65(2H,m),1.53(2H,m),1.22(2H,m)。
实施例99:4-[4-[2-(环戊基甲基)苯基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[2-(环戊基甲基)苯基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例88中获得的1-溴-2-(环戊基甲基)苯(0.24g,1mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.24g,0.66mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.13g,49%)。
1H-NMR(CDCl3)δ7.29(2H,m),7.21(1H,m),7.12(1H,d),6.84(2H,m),4.22(2H,t),4.17(2H,q),2.60(4H,m),2.12(2H,m),1.89(1H,m),1.58(4H,m),1.43(2H,m),1.28(3H,t),1.02(2H,m)。
步骤B:4-[4-[2-(环戊基甲基)苯基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[2-(环戊基甲基)苯基]-2,6-二氟-苯氧基]丁酸乙酯(0.13g,0.32mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.1g,83%)。
1H-NMR(CDCl3)δ7.28(2H,m),7.21(1H,m),7.12(1H,d),6.82(2H,m),4.24(2H,t),2.68(2H,t),2.59(2H,d),2.14(2H,m),1.90(1H,m),1.57(2H,m),1.52(2H,m),1.43(2H,m),1.02(2H,m)。
实施例100:4-[4-[6-(环戊基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[6-(亚环戊基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例91中获得的2-溴-6-(亚环戊基甲基)吡啶(0.13g,0.54mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.155g,0.42mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.15g,89%)。
1H-NMR(CDCl3)δ7.63(3H,m),7.39(1H,d),7.12(1H,d),6.50(1H,m),4.23(2H,t),4.16(2H,q),2.88(2H,m),2.57(4H,m),2.10(2H,m),1.84(2H,m),1.71(2H,m),1.27(3H,t)。
步骤B:4-[4-[6-(环戊基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯
使用在步骤A中获得的4-[4-[6-(亚环戊基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯(0.15g,0.37mmol)以与制备例50的步骤B相同的方式反应,得到标题化合物(0.15g,99%)。
1H-NMR(CDCl3)δ7.63(1H,t),7.59(2H,m),7.43(1H,d),7.07(1H,t),4.21(2H,t),4.14(2H,q),2.82(2H,d),2.58(2H,t),2.34(1H,m),2.10(2H,m),1.65(8H,m),1.27(3H,t)。
步骤C:4-[4-[6-(环戊基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在步骤B中获得的4-[4-[6-(环戊基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯(0.15g,0.37mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.106g,76%)。
1H-NMR(CDCl3)δ7.63(1H,t),7.57(2H,m),7.43(1H,d),7.07(1H,d),4.23(2H,t),2.82(2H,d),2.66(2H,t),2.34(1H,m),2.12(2H,m),1.74(2H,m),1.66(2H,m),1.54(2H,m),1.27(2H,m)。
实施例101:4-[4-[2-(环丁基甲基)苯基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[2-(环丁基甲基)苯基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例92中获得的1-溴-2-(环丁基甲基)苯(0.06g,0.26mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.08g,0.21mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.035g,43%)。
1H-NMR(CDCl3)δ7.28(1H,m),7.21(2H,m),7.12(1H,m),6.82(2H,m),4.23(2H,t),4.16(2H,q),2.66(2H,d),2.60(2H,t),2.41(1H,m),2.13(2H,m),1.95(2H,m),1.76(2H,m),1.57(2H,m),1.27(3H,t)。
步骤B:4-[4-[2-(环丁基甲基)苯基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[2-(环丁基甲基)苯基]-2,6-二氟-苯氧基]丁酸乙酯(0.035g,0.09mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.02g,61%)。
1H-NMR(CDCl3)δ7.78(1H,m),7.21(2H,m),7.12(1H,m),6.84(2H,m),4.24(2H,t),2.67(4H,m),2.41(1H,m),2.13(2H,m),1.95(2H,m),1.75(2H,m),1.57(2H,m)。
实施例102:4-[4-[3-(环丁基甲基)苯基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[3-(环丁基甲基)苯基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例93中获得的1-溴-3-(环丁基甲基)苯(0.03g,0.13mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.041g,0.11mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.012g,28%)。
1H-NMR(CDCl3)δ7.32(3H,m),7.10(3H,m),4.21(2H,t),4.15(2H,q),2.75(2H,d),2.59(3H,m),2.10(4H,m),1.85(2H,m),1.74(2H,m),1.27(3H,t)。
步骤B:4-[4-[3-(环丁基甲基)苯基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[3-(环丁基甲基)苯基]-2,6-二氟-苯氧基]丁酸乙酯(0.012g,0.03mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.01g,92%)。
1H-NMR(MeOH-d4)δ7.34(3H,m),7.22(2H,m),7.16(1H,m),4.19(2H,t),2.75(2H,d),2.61(1H,m),2.56(2H,t),2.06(4H,m),1.85(2H,m),1.76(2H,m)。
实施例103:4-[4-[6-(环丁基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[6-(亚环丁基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例94中获得的2-溴-6-(亚环丁基甲基)吡啶(0.096g,0.43mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.105g,0.28mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.085g,75%)。
1H-NMR(CDCl3)δ7.64(1H,t),7.60(2H,m),7.38(1H,d),7.04(1H,d),6.27(1H,m),4.23(2H,t),4.17(2H,q),3.27(2H,m),2.94(2H,m),2.59(2H,t),2.18(2H,m),2.10(2H,m),1.27(3H,t)。
步骤B:4-[4-[6-(环丁基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯
使用在步骤A中获得的4-[4-[6-(亚环丁基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯(0.085g,0.22mmol)以与制备例50的步骤B相同的方式反应,得到标题化合物(0.082g,95%)。
1H-NMR(CDCl3)δ7.62(1H,t),7.57(2H,m),7.42(1H,d),7.04(1H,d),4.22(2H,t),2.16(2H,q),2.92(2H,d),2.79(1H,m),2.57(2H,t),2.10(4H,m),1.88(2H,m),1.80(2H,m),1.27(3H,t)。
步骤C:4-[4-[6-(环丁基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在步骤B中获得的4-[4-[6-(环丁基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯(0.08g,0.2mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.075g,99%)。
1H-NMR(CDCl3)δ7.62(1H,t),7.57(2H,m),7.42(1H,d),7.04(1H,d),4.23(2H,t),2.93(2H,d),2.78(1H,m),2.67(2H,t),2.11(4H,m),1.89(2H,m),1.80(2H,m)。
实施例104:4-[4-(2-环戊基苯基)-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-(2-环戊基苯基)-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例97中获得的1-环戊基-2-碘-苯(0.065g,0.23mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.073g,0.2mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.036g,46%)。
1H-NMR(CDCl3)δ7.37(2H,m),7.18(1H,t),7.11(1H,d),6.82(2H,m),4.22(2H,t),4.15(2H,q),3.00(1H,m),2.60(2H,t),2.12(2H,m),1.91(2H,m),1.79(2H,m),1.58(4H,m),1.27(3H,t)。
步骤B:4-[4-(2-环戊基苯基)-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-(2-环戊基苯基)-2,6-二氟-苯氧基]丁酸乙酯(0.036g,0.09mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.03g,92%)。
1H-NMR(CDCl3)δ7.36(2H,m),7.18(1H,t),7.11(1H,d),6.82(2H,m),4.23(2H,t),2.99(1H,m),2.67(2H,t),2.14(2H,m),1.92(2H,m),1.80(2H,m),1.59(4H,m)。
实施例105:4-[4-(6-环戊基-2-吡啶基)-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-(6-环戊基-2-吡啶基)-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例98中获得的2-溴-6-环戊基-吡啶(0.1g,0.44mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.125g,0.34mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.091g,68%)。
1H-NMR(CDCl3)δ7.60(3H,m),7.43(1H,d),7.10(1H,d),4.20(2H,t),4.14(2H,q),3.21(1H,m),2.56(2H,t),2.09(4H,m),1.86(4H,m),1.72(2H,m),1.26(3H,t)。
步骤B:4-[4-(6-环戊基-2-吡啶基)-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-(6-环戊基-2-吡啶基)-2,6-二氟-苯氧基]丁酸乙酯(0.09g,0.23mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.07g,84%)。
1H-NMR(CDCl3)δ7.62(3H,m),7.42(1H,d),7.11(1H,d),4.23(2H,t),3.22(1H,m),2.67(2H,t),2.12(4H,m),1.86(4H,m),1.71(2H,m)。
实施例106:4-[2,6-二氟-4-(2-异丁基-3-吡啶基)苯氧基]丁酸
步骤A:4-[2,6-二氟-4-(2-异丁基-3-吡啶基)苯氧基]丁酸乙酯
使用在制备例103中获得的(2-异丁基-3-吡啶基)三氟甲磺酸酯(0.017g,0.06mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.026g,0.07mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.013g,57%)。
1H-NMR(CDCl3)δ8.57(1H,m),7.44(1H,m),7.16(1H,m),6.83(2H,m),4.26(2H,t),4.16(2H,q),2.65(2H,d),2.61(2H,t),2.13(3H,m),1.26(3H,t),0.80(6H,d)。
步骤B:4-[2,6-二氟-4-(2-异丁基-3-吡啶基)苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-(2-异丁基-3-吡啶基)苯氧基]丁酸乙酯(0.013g,0.034mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.004g,32%)。
1H-NMR(CDCl3)δ8.60(1H,m),7.42(1H,m),7.20(1H,m),6.82(2H,m),4.27(2H,t),2.67(4H,m),2.15(2H,m),2.05(1H,m),0.78(6H,d)。
实施例107:4-[4-(2-环戊基-3-吡啶基)-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-(2-环戊基-3-吡啶基)-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例106中获得的(2-环戊基-3-吡啶基)三氟甲磺酸酯(0.376g,1.27mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.51g,1.4mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.284g,57%)。
1H-NMR(CDCl3)δ8.60(1H,m),7.41(1H,m),7.12(1H,m),6.83(2H,m),4.24(2H,t),4.16(2H,q),3.16(1H,m),2.60(2H,t),2.12(2H,m),1.87(6H,m),1.59(2H,m),1.27(3H,t)。
步骤B:4-[4-(2-环戊基-3-吡啶基)-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-(2-环戊基-3-吡啶基)-2,6-二氟-苯氧基]丁酸乙酯(0.18g,0.46mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.15g,90%)。
1H-NMR(CDCl3)δ8.62(1H,m),7.41(1H,m),7.14(1H,m),6.84(2H,m),4.27(2H,t),3.16(1H,m),2.69(2H,t),2.14(2H,m),1.89(6H,m),1.60(2H,m)。
实施例108:4-[4-[2-(环戊基甲基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[2-(环戊基甲基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例108中获得的[2-(环戊基甲基)-3-吡啶基]三氟甲磺酸酯(0.04g,0.13mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.052g,0.14mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.037g,70%)。
1H-NMR(CDCl3)δ8.56(1H,m),7.43(1H,m),7.16(1H,m),6.82(2H,m),4.24(2H,t),4.15(2H,q),2.78(2H,d),2.60(2H,t),2.23(1H,m),2.12(2H,m),1.53(6H,m),1.27(3H,t),1.04(2H,m)。
步骤B:4-[4-[2-(环戊基甲基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[2-(环戊基甲基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯(0.037g,0.09mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.022g,65%)。
1H-NMR(CDCl3)δ8.58(1H,m),7.45(1H,m),7.17(1H,m),6.85(2H,m),4.26(2H,t),2.80(2H,d),2.67(2H,t),2.16(3H,m),1.55(6H,m),1.03(2H,m)。
实施例109:4-[2,6-二氟-4-(2-吡咯-1-基-3-吡啶基)苯氧基]丁酸
使用在制备例109中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸乙酯(0.1g,0.29mmol)和吡咯(0.04g,0.59mmol)以与制备例37相同的方式反应,得到2,6-二氟-4-(2-吡咯-1-基-3-吡啶基)苯酚。将所得到2,6-二氟-4-(2-吡咯-1-基-3-吡啶基)苯酚与4-溴-丁酸乙酯以与制备例12相同的方式反应,得到4-[2,6-二氟-4-(2-吡咯-1-基-3-吡啶基)苯氧基]丁酸乙酯。将所得到的4-[2,6-二氟-4-(2-吡咯-1-基-3-吡啶基)苯氧基]丁酸乙酯以与实施例1的步骤B相同的方式反应,得到标题化合物(0.07g,0.07%)。
1H-NMR(CDCl3)δ8.51(1H,m),7.71(1H,m),7.30(1H,m),6.82(2H,m),6.71(2H,m),6.19(2H,m),4.23(2H,t),2.65(2H,t),2.12(2H,m)。
实施例110:4-[2,6-二氟-4-[2-(4-甲基吡唑-1-基)-3-吡啶基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[2-(4-甲基吡唑-1-基)-3-吡啶基]苯氧基]丁酸乙酯
使用在制备例109中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸乙酯(0.071g,0.21mmol)和4-甲基吡唑(0.021g,0.25mmol)以与实施例72的步骤A相同的方式反应,得到标题化合物(0.054g,64%)。
1H-NMR(CDCl3)δ8.50(1H,m),7.76(1H,m),7.70(1H,s),7.37(1H,s),7.36(1H,m),6.68(2H,m),4.20(2H,t),4.15(2H,q),2.57(2H,t),2.10(5H,m),1.27(3H,t)。
步骤B:4-[2,6-二氟-4-[2-(4-甲基吡唑-1-基)-3-吡啶基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[2-(4-甲基吡唑-1-基)-3-吡啶基]苯氧基]丁酸乙酯(0.054g,0.13mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.016g,33%)。
1H-NMR(CDCl3)δ8.51(1H,m),7.76(1H,m),7.70(1H,s),7.38(1H,s),7.36(1H,m),6.69(2H,m),4.22(2H,t),2.64(2H,m),2.11(5H,m)。
实施例111:4-[2,6-二氟-4-(2-吗啉代-3-吡啶基)苯氧基]丁酸
使用在制备例110中获得的4-(3-碘-2-吡啶基)吗啉(0.056g,0.19mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.072g,0.19mmol)以与实施例72和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.009g,12%)。
1H-NMR(CDCl3)δ8.26(1H,m),7.43(1H,m),7.19(2H,m),6.96(1H,m),4.25(2H,t),3.67(4H,m),3.10(4H,m),2.67(2H,t),2.12(2H,m)。
实施例112:4-[2,6-二氟-4-[2-(四氢吡喃-4-基甲基氨基)-3-吡啶基]苯氧基]丁酸
使用在制备例111中获得的3-碘-N-(四氢吡喃-4-基甲基)吡啶-2-胺(0.063g,0.2mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.075g,0.2mmol)以与实施例72和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.003g,4%)。
1H-NMR(CDCl3)δ8.13(1H,m),7.22(1H,m),6.94(2H,m),6.64(1H,m),4.57(1H,brs),4.28(2H,t),3.97(2H,m),3.38(2H,m),3.31(2H,m),2.67(2H,t),2.13(2H,m),1.88(1H,m),1.61(2H,m),1.34(2H,m)。
实施例113:4-[2,6-二氟-4-[2-(1-哌啶基)-3-吡啶基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[2-(1-哌啶基)-3-吡啶基]苯氧基]丁酸乙酯
使用在制备例109中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸乙酯(0.1g,0.29mmol)、哌啶(0.05g,0.58mmol)和DMSO以与实施例72的步骤A相同的方式反应,得到标题化合物(0.022g,19%)。
1H-NMR(CDCl3)δ8.22(1H,m),7.38(1H,m),7.19(2H,m),6.87(1H,m),4.22(2H,t),4.15(2H,q),3.03(4H,m),2.60(2H,t),2.11(2H,m),1.52(6H,m),1.27(3H,t)。
步骤B:4-[2,6-二氟-4-[2-(1-哌啶基)-3-吡啶基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[2-(1-哌啶基)-3-吡啶基]苯氧基]丁酸乙酯(0.021g,0.05mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.014g,74%)。
1H-NMR(CDCl3)δ8.24(1H,m),7.40(1H,m),7.19(2H,m),6.89(1H,m),4.23(2H,t),3.05(4H,m),2.67(2H,t),2.13(2H,m),1.53(6H,m)。
实施例114:(4S)-4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸
步骤A:(4S)-4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸乙酯
使用在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.077g,0.26mmol)和在制备例123中获得的(4S)-4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸乙酯(0.095g,0.24mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.067g,60%)。
1H NMR(CDCl3)δ8.41(1H,m),7.33(1H,m),7.00(3H,m),4.41(2H,m),4.16(2H,q),2.61(2H,t),2.60(2H,m),2.05(6H,m),1.33(3H,d),1.27(3H,t)。
步骤B:(4S)-4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸
使用在步骤A中获得的(4S)-4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸乙酯(0.067g,0.16mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.033g,52%)。
1H NMR(CDCl3)δ8.41(1H,m),7.33(1H,m),7.00(3H,m),4.41(2H,m),2.71(2H,t),2.52(2H,m),2.05(6H,m),1.35(3H,d)。
实施例115:(4R)-4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸
步骤A:(4R)-4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸甲酯
使用在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.051g,0.18mmol)和在制备例117中获得的(4R)-4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸甲酯(0.062g,0.16mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.04g,61%)。
1H NMR(CDCl3)δ8.41(1H,m),7.33(1H,m),7.01(3H,m),4.41(2H,m),3.69(3H,s),2.63(2H,t),2.51(2H,m),2.05(6H,m),1.33(3H,d)。
步骤B:(4R)-4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸
使用在步骤A中获得的(4R)-4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸甲酯(0.04g,0.1mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.039g,99%)。
1H NMR(CDCl3)δ8.41(1H,m),7.33(1H,m),7.00(3H,m),4.41(2H,m),2.71(2H,t),2.52(2H,m),2.05(6H,m),1.35(3H,d)。
实施例116:(4R)-4-[4-[3-(环丁氧基)苯基]-2,6-二氟-苯氧基]戊酸
步骤A:(4R)-4-[4-[3-(环丁氧基)苯基]-2,6-二氟-苯氧基]戊酸甲酯
使用在制备例60中获得的1-环丁氧基-3-碘-苯(0.049g,0.18mmol)和在制备例117中获得的(4R)-4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸甲酯(0.055g,0.15mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.039g,71%)。
1H NMR(CDCl3)δ7.31(1H,t),7.09(3H,m),6.94(1H,m),6.80(1H,m),4.69(1H,m),4.34(1H,m),3.70(3H,s),2.62(2H,t),2.47(2H,m),2.20(2H,m),2.04(2H,m),1.88(1H,m),1.71(1H,m),1.31(3H,d)。
步骤B:(4R)-4-[4-[3-(环丁氧基)苯基]-2,6-二氟-苯氧基]戊酸
使用在步骤A中获得的(4R)-4-[4-[3-(环丁氧基)苯基]-2,6-二氟-苯氧基]戊酸甲酯(0.039g,0.1mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.031g,82%)。
1H NMR(CDCl3)δ7.31(1H,t),7.12(3H,m),6.95(1H,m),6.80(1H,m),4.69(1H,m),4.36(1H,m),2.70(2H,t),2.46(2H,m),2.20(2H,m),2.05(2H,m),1.88(1H,m),1.71(1H,m),1.30(3H,d)。
实施例117:(4R)-4-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸
步骤A:(4R)-4-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸甲酯
使用在制备例39中获得的2-环戊基硫基-3-碘-吡啶(0.054g,0.18mmol)和在制备例117中获得的(4R)-4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸甲酯(0.055g,0.15mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.045g,66%)。
1H NMR(CDCl3)δ8.42(1H,m),7.32(1H,m),7.00(3H,m),4.37(1H,m),4.08(1H,m),3.70(3H,s),2.63(2H,t),2.20(2H,m),2.04(2H,m),1.72(2H,m),1.64(2H,m),1.57(2H,m),1.33(3H,d)。
步骤B:(4R)-4-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸
使用在步骤A中获得的(4R)-4-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸甲酯(0.045g,0.1mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.041g,95%)。
1H NMR(CDCl3)δ8.43(1H,m),7.32(1H,m),7.00(3H,m),4.39(1H,m),4.09(1H,m),2.70(2H,t),2.20(2H,m),2.04(2H,m),1.71(2H,m),1.62(4H,m),1.34(3H,d)。
实施例118:(4R)-4-[2,6-二氟-4-(3-苯氧基苯基)苯氧基]戊酸
步骤A:(4R)-4-[2,6-二氟-4-(3-苯氧基苯基)苯氧基]戊酸甲酯
使用在制备例117中获得的(4R)-4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸甲酯(0.055g,0.15mmol)和1-溴-3-苯氧基-苯(0.044g,0.18mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.044g,72%)。
1H NMR(CDCl3)δ7.37(3H,m),7.23(1H,m),7.14(2H,m),7.08(2H,m),7.04(2H,m),6.99(1H,m),4.34(1H,m),3.69(3H,s),2.62(2H,t),2.02(2H,m),1.30(3H,d)。
步骤B:(4R)-4-[2,6-二氟-4-(3-苯氧基苯基)苯氧基]戊酸
使用在步骤A中获得的(4R)-4-[2,6-二氟-4-(3-苯氧基苯基)苯氧基]戊酸甲酯(0.044g,0.1mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.041g,96%)。
1H NMR(CDCl3)δ7.36(3H,m),7.23(1H,m),7.14(2H,m),7.09(2H,m),7.04(2H,m),6.99(1H,m),4.35(1H,m),2.68(2H,t),2.03(2H,m),1.30(3H,d)。
实施例119:4-(3'-环丁氧基-联苯-4-基硫基)-丁酸
步骤A:4-(3'-环丁氧基-联苯-4-基硫基)丁酸乙酯
使用在制备例149中获得的4-(3'-羟基-联苯-4-基硫基)-丁酸乙酯(0.1g,0.32mmol)、溴代-环丁烷(0.044mL)和Cs2CO3(0.31g,0.95mmol)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.075g,64%)。
1H-NMR(CDCl3)δ7.48(2H,d),7.38(2H,d),7.30(1H,t),7.12(1H,m),7.00(1H,s),6.78(1H,m),4.69(1H,m),4.12(2H,q),3.00(2H,t),2.47(4H,m),2.20(2H,m),1.98(2H,m),1.86(1H,m),1.70(1H,m),1.24(3H,t)。
步骤B:4-(3'-环丁氧基-联苯-4-基硫基)-丁酸
使用在步骤A中获得的4-(3'-环丁氧基-联苯-4-基硫基)-丁酸乙酯(0.075g,0.20mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.02g,28%)。
1H-NMR(CDCl3)δ7.48(2H,d),7.38(2H,d),7.30(1H,t),7.12(1H,m),7.00(1H,s),6.78(1H,m),4.68(1H,m),3.01(2H,t),2.54(2H,t),2.46(2H,m),2.20(2H,m),2.00(2H,m),1.85(1H,m),1.70(1H,m)。
实施例120:4-(3'-异丙氧基-联苯-4-基硫基)-丁酸
步骤A:4-(3'-异丙氧基-联苯-4-基硫基)丁酸乙酯
使用在制备例149中获得的4-(3'-羟基-联苯-4-基硫基)-丁酸乙酯(0.11g,0.35mmol)、2-溴-丙烷(0.049mL)和Cs2CO3(0.34g,1.04mmol)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.12g,96%)。
1H-NMR(CDCl3)δ7.50(2H,d),7.39(2H,d),7.31(1H,t),7.12(1H,m),7.07(1H,s),6.86(1H,m),4.60(1H,m),4.13(2H,q),3.00(2H,t),2.47(2H,t),1.98(2H,m),1.36(6H,d),1.24(3H,t)。
步骤B:4-(3'-异丙氧基-联苯-4-基硫基)-丁酸
使用在步骤A中获得的4-(3'-异丙氧基-联苯-4-基硫基)-丁酸乙酯(0.12g,0.33mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.10g,95%)。
1H-NMR(CDCl3)δ7.50(2H,d),7.39(2H,d),7.31(1H,t),7.12(1H,m),7.07(1H,s),6.86(1H,m),4.60(1H,m),3.01(2H,t),2.54(2H,t),2.00(2H,m),1.34(6H,d)。
实施例121:[1-(3,5-二氟-3'-异丙氧基-联苯-4-基硫基甲基)-环丙基]-乙酸
步骤A:[1-(3,5-二氟-3'-异丙氧基-联苯-4-基硫基甲基)-环丙基]-乙酸甲酯
使用在制备例152中获得的[1-(3,5-二氟-3'-羟基-联苯-4-基硫基甲基)-环丙基]-乙酸甲酯(0.02g,0.05mmol),2-溴-丙烷(0.008mL)和Cs2CO3(0.05g,0.16mmol)以与制备例44的步骤B相同的方式反应,得到标题化合物(0.006g,27%)。
1H-NMR(CDCl3)δ7.34(1H,t),7.13-7.08(3H,m),7.04(1H,s),6.91(1H,m),4.61(1H,m),3.64(3H,s),3.01(2H,s),2.56(2H,s),1.35(6H,d),0.45-0.38(4H,m)。
步骤B:[1-(3,5-二氟-3'-异丙氧基-联苯-4-基硫基甲基)-环丙基]-乙酸
使用在步骤A中获得的[1-(3,5-二氟-3'-异丙氧基-联苯-4-基硫基甲基)-环丙基]-乙酸甲酯(0.006g,0.015mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.004g,69%)。
1H-NMR(CDCl3)δ7.33(1H,t),7.13-7.05(4H,m),6.90(1H,m),4.60(1H,m),3.01(2H,s),2.62(2H,s),1.36(6H,d),0.46-0.35(4H,m)。
实施例122:4-(3'-环戊基氧基-3,5-二氟-联苯-4-基硫基)-丁酸
步骤A:2-[2-(3'-环戊基氧基-3,5-二氟-联苯-基硫基)-乙基]-丙二酸二甲酯
将NaH(60%,在矿物油中,0.005g,0.12mmol)溶于1mL的DMF。向其中添加丙二酸二甲酯(0.013mL,0,12mmol)并将生成物在室温搅拌15分钟。向其中添加在制备例158中获得的4-(2-氯-乙基硫基)-3'-环戊基氧基-3,5-二氟-联苯(0.03g,0.08mmol)并将生成物在65℃搅拌18小时。向反应溶液添加水并用EtOAc萃取。将有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.01g,25%)。
步骤B:4-(3'-环戊基氧基-3,5-二氟-联苯-基硫基)-丁酸
将在步骤A中获得的2-[2-(3'-环戊基氧基-3,5-二氟-联苯-基硫基)-乙基]-丙二酸二甲酯(0.01g,0.02mmol)溶于各0.3mL的EtOH和THF。向其中添加0.2mL的4N KOH并将反应物在60℃搅拌1小时。将反应溶液在减压下浓缩,然后向其中添加水。通过使用2N HCl将pH调节至3,然后将反应物用EtOAc萃取。将分离的有机层用MgSO4干燥并在减压下浓缩。将浓缩的有机层溶于1mL的吡啶,并将生成物在80℃搅拌18小时。将反应溶液在减压下浓缩,然后向其中添加水。通过使用2N HCl将pH调节至3,然后将反应物用EtOAc萃取。将分离的有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.002g,20%)。
1H-NMR(CDCl3)δ7.32(1H,t),7.13(2H,m),7.08(1H,m),7.02(1H,s),6.90(1H,m),4.81(1H,m),2.94(2H,t),2.55(2H,t),1.92-1.81(8H,m),1.64(2H,m)。
实施例123:4-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.056g,0.16mmol)和在制备例38中获得的2-环戊氧基-3-碘-吡啶(0.046g,0.16mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.025g,44%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.56(1H,m),7.49(2H,d),7.36(2H,d),6.90(1H,m),5.50(1H,m),3.02(2H,t),2.56(2H,t),2.03-1.92(4H,m),1.84-1.60(6H,m)。
实施例124:4-[4-(2-环丙基甲氧基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.08g,0.29mmol)和在制备例40中获得的2-环丙基甲氧基-3-碘-吡啶(0.10g,0.29mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.02g,25%)。
1H-NMR(CDCl3)δ8.10(1H,m),7.59(1H,m),7.55(2H,d),7.38(2H,d),6.95(1H,m),4.20(2H,d),3.04-3.01(2H,t),2.57-2.54(2H,t),2.02-1.99(2H,m),1.27(1H,m),0.55(2H,m),0.33(2H,m)。
实施例125:4-(3'-苯氧基-联苯-4-基硫基)-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.03g,0.11mmol)和1-溴-3-苯氧基-苯(0.03g,0.12mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.005g,16%)。
1H-NMR(CDCl3)δ7.48(2H,d),7.38-7.26(6H,m),7.25(1H,s),7.1(1H,t),7.05(2H,d),6.97(1H,m),3.00(2H,t),2.54(2H,t),1.98(2H,m)。
实施例126:4-(3'-环戊基氧基-联苯-4-基硫基)-丁酸
使用在制备例149中获得的4-(3'-羟基-联苯-4-基硫基)-丁酸乙酯(0.056g,0.17mmol)、溴代-环戊烷(0.030mL)和Cs2CO3(0.17g,0.53mmol)以与实施例119的步骤A和B相同的方式顺序反应,得到标题化合物(0.052g,82%)。
1H-NMR(CDCl3)δ7.49(2H,d),7.38(2H,d),7.30(1H,t),7.12(1H,m),7.06(1H,s),6.85(1H,m),4.81(1H,m),3.01(2H,t),2.54(2H,t),2.00-1.81(8H,m),1.62(2H,m)。
实施例127:4-(3'-丙氧基-联苯-4-基硫基)-丁酸
使用在制备例149中获得的4-(3'-羟基-联苯-4-基硫基)-丁酸乙酯(0.053g,0.17mmol)、2-溴-丙烷(0.023mL)和Cs2CO3(0.16g,0.50mmol)以与实施例119的步骤A和B相同的方式顺序反应,得到标题化合物(0.045g,81%)。
1H-NMR(CDCl3)δ7.50(2H,d),7.38(2H,d),7.32(1H,t),7.12(1H,m),7.09(1H,s),6.87(1H,m),3.97(2H,t),3.01(2H,t),2.55(2H,t),2.00(2H,m),1.82(2H,m),1.05(3H,t)。
实施例128:4-[4-(6-环丁氧基-吡啶-2-基)-苯基硫基]-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例24中获得的2-氯-6-(环丁氧基)-吡啶(0.033g,0.16mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.005g,10%)。
1H-NMR(CDCl3)δ7.93(2H,d),7.59(1H,t),7.38(2H,d),7.28(1H,d),6.61(1H,d),5.26(1H,m),3.02(2H,t),2.56-2.53(4H,m),2.19(2H,m),2.01(2H,m),1.85(1H,q),1.73(1H,m)。
实施例129:4-[4-(6-环戊基氧基-吡啶-2-基)-苯基硫基]-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例8中获得的2-氯-6-(环戊氧基)吡啶(0.036g,0.16mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.004g,8%)。
1H-NMR(CDCl3)δ7.95(2H,d),7.57(1H,t),7.38(2H,d),7.26(1H,d),6.60(1H,d),5.50(1H,m),3.02(2H,t),2.54(2H,t),2.10-1.97(4H,m),1.82(4H,m),1.63(2H,m)。
实施例130:4-[4-(6-异丙氧基-吡啶-2-基)-苯基硫基]-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.031g,0.09mmol)和在制备例228中获得的2-溴-6-异丙氧基-吡啶(0.021g,0.10mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.011g,37%)。
1H-NMR(CDCl3)δ7.94(2H,d),7.59(1H,t),7.38(2H,d),7.26(1H,d),6.60(1H,d),5.46(1H,m),3.02(2H,t),2.54(2H,t),2.00(2H,m),1.39(6H,d)。
实施例131:4-[4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.11g,0.32mmol)和在制备例37中获得的3-碘-2-异丙氧基-吡啶(0.12g,0.35mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.05g,34%)。
1H-NMR(CDCl3)δ8.11(1H,m),7.57(1H,m),7.50(2H,d),7.35(2H,d),6.90(1H,m),5.38(1H,m),3.02(2H,t),2.56(2H,t),2.02(2H,m),1.33(6H,d)。
实施例132:4-[4-(6-丙氧基-吡啶-2-基)-苯基硫基]-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.06g,0.17mmol)和在制备例227中获得的2-溴-6-丙氧基-吡啶(0.041g,0.19mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.03g,52%)。
1H-NMR(CDCl3)δ7.94(2H,d),7.59(1H,t),7.39(2H,d),7.28(1H,d),6.65(1H,d),4.36(2H,t),3.02(2H,t),2.54(2H,t),2.00(2H,m),1.82(2H,m),1.04(3H,t)。
实施例133:4-[4-(6-环戊基硫基-吡啶-2-基)-苯基硫基]-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.06g,0.17mmol)和在制备例234中获得的2-溴-6-环戊基硫基-吡啶(0.049g,0.19mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.02g,28%)。
1H-NMR(CDCl3)δ7.95(2H,d),7.50(1H,t),7.40-7.38(3H,m),7.05(1H,d),4.17(1H,m),3.03(2H,t),2.55(2H,t),2.24(2H,m),2.00(2H,m),1.82-1.63(6H,m)。
实施例134:4-(3'-环丁氧基-3,5-二氟-联苯-4-基硫基)-丁酸
使用在制备例163中获得的3'-环丁氧基-3,4,5-三氟-联苯(0.02g,0.07mmol)、Cs2CO3(0.022g,0.07mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.01g,0.07mmol)以与实施例137的步骤A和B相同的方式顺序反应,得到标题化合物(0.001g,4%)。
1H-NMR(CDCl3)δ7.32(1H,t),7.13(2H,d),7.12(1H,m),6.96(1H,s),6.84(1H,m),4.68(1H,m),2.94(2H,t),2.55(2H,t),2.47(2H,m),2.19(2H,m),1.87(3H,m),1.71(1H,m)。
实施例135:4-(3,5-二氟-3'-异丙氧基-联苯-4-基硫基)-丁酸
使用在制备例164中获得的3,4,5-三氟-3'-异丙氧基-联苯(0.06g,0.23mmol)、Cs2CO3(0.074g,0.23mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.034g,0.23mmol)以与实施例137的步骤A和B相同的方式顺序反应,得到标题化合物(0.011g,13%)。
1H-NMR(CDCl3)δ7.33(1H,t),7.13(2H,d),7.09(1H,m),7.04(1H,s),6.92(1H,m),4.60(1H,m),2.94(2H,t),2.55(2H,t),1.87(2H,m),1.35(6H,d)。
实施例136:4-[2,6-二氟-4-(6-丙氧基-吡啶-2-基)-苯基硫基]-丁酸
使用在制备例166中获得的2-丙氧基-6-(3,4,5-三氟-苯基)-吡啶(0.02g,0.08mmol)、Cs2CO3(0.028g,0.08mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.01g,0.08mmol)以与实施例137的步骤A和B相同的方式顺序反应,得到标题化合物(0.008g,24%)。
1H-NMR(CDCl3)δ7.63-7.59(3H,m),7.27(1H,d),6.71(1H,d),4.35(2H,t),2.96(2H,t),2.54(2H,t),1.88-1.82(4H,m),1.05(3H,t)。
实施例137:4-[2,6-二氟-4-(6-异丙氧基-吡啶-2-基)-苯基硫基]-丁酸
步骤A:4-[2,6-二氟-4-(6-异丙氧基-吡啶-2-基)-苯基硫基]-丁酸乙酯
将在制备例167中获得的2-异丙氧基-6-(3,4,5-三氟-苯基)-吡啶(0.02g,0.07mmol)溶于1mL的DMF,并向其中添加Cs2CO3(0.024g,0.07mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.011g,0.07mmol)。将生成物在65℃搅拌4小时。并向反应溶液添加水并用EtOAc萃取。将分离的有机层用MgSO4干燥并通过色谱法纯化,得到标题化合物(0.017g,58%)。
步骤B:4-[2,6-二氟-4-(6-异丙氧基-吡啶-2-基)-苯基硫基]-丁酸
将在步骤A中获得的4-[2,6-二氟-4-(6-异丙氧基-吡啶-2-基)-苯基硫基]-丁酸乙酯(0.017g,0.04mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.011g,73%)。
1H-NMR(CDCl3)δ7.63-7.57(3H,m),7.23(1H,d),6.67(1H,d),5.44(1H,m),2.97(2H,t),2.55(2H,t),1.88(2H,m),1.40(6H,d)。
实施例138:4-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(1.22g,3.16mmol)和在制备例37中获得的3-碘-2-异丙氧基-吡啶(1.24g,4.74mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.78g,67%)。
1H-NMR(CDCl3)δ8.15(1H,m),7.60(1H,m),7.19(2H,d),6.93(1H,m),5.40(1H,m),2.96(2H,t),2.56(2H,t),1.90(2H,m),1.36(6H,d)。
实施例139:4-[2,6-二氟-4-(2-丙氧基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例171中获得的2-丙氧基-3-(3,4,5-三氟-苯基)-吡啶(0.02g,0.08mmol)、Cs2CO3(0.027g,0.08mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.012g,0.08mmol)以与实施例137的步骤A和B相同的方式顺序反应,得到标题化合物(0.009g,30%)。
1H-NMR(CDCl3)δ8.16(1H,m),7.60(1H,m),7.20(2H,d),6.95(1H,m),4.32(2H,t),2.96(2H,t),2.54(2H,t),1.89(2H,m),1.80(2H,m),1.00(3H,t)。
实施例140:4-[2,6-二氟-4-(6-异丙基硫基-吡啶-2-基)-苯基硫基]-丁酸
使用在制备例172中获得的2-异丙基硫基-6-(3,4,5-三氟-苯基)-吡啶(0.035g,0.12mmol)、Cs2CO3(0.04g,0.12mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.018g,0.12mmol)以与实施例137的步骤A和B相同的方式顺序反应,得到标题化合物(0.022g,46%)。
1H-NMR(CDCl3)δ7.62-7.53(3H,m),7.37(1H,d),7.13(1H,d),4.14(1H,m),2.98(2H,t),2.56(2H,t),1.89(2H,m),1.45(6H,d)。
实施例141:4-[2,6-二氟-4-(6-丙基硫基-吡啶-2-基)-苯基硫基]-丁酸
使用在制备例173中获得的2-丙基硫基-6-(3,4,5-三氟-苯基)-吡啶(0.03g,0.11mmol)、Cs2CO3(0.035g,0.11mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.016g,0.11mmol)以与实施例137的步骤A和B相同的方式顺序反应,得到标题化合物(0.024g,57%)。
1H-NMR(CDCl3)δ7.62-7.53(3H,m),7.37(1H,d),7.16(1H,d),3.24(2H,t),2.98(2H,t),2.56(2H,t),1.92-1.77(4H,m),1.09(3H,t)。
实施例142:4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸
使用在制备例174中获得的2-环丁基硫基-3-(3,4,5-三氟-苯基)-吡啶(0.056g,0.19mmol)、Cs2CO3(0.093g,0.19mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.028g,0.19mmol)以与实施例137的步骤A和B相同的方式顺序反应,得到标题化合物(0.03g,40%)。
1H-NMR(CDCl3)δ8.42(1H,m),7.34(1H,m),7.02(3H,m),4.42(1H,m),2.98(2H,t),2.58-2.48(4H,m),2.10-1.89(6H,m)。
实施例143:4-[4-(2-环丁氧基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.018g,0.05mmol)和在制备例200中获得的2-环丁氧基-3-碘-吡啶(0.016g,0.06mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.004g,23%)。
1H-NMR(CDCl3)δ8.09(1H,m),7.58(1H,m),7.52(2H,d),7.36(2H,d),6.91(1H,m),5.26(1H,m),3.02(2H,t),2.56-2.42(4H,m),2.15-1.99(4H,m),1.81(1H,m),1.67(1H,m)。
实施例144:4-[4-(2-环丁氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸
使用在制备例175中获得的2-环丁氧基-3-(3,4,5-三氟-苯基)-吡啶(0.01g,0.03mmol)、Cs2CO3(0.012g,0.03mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.005g,0.03mmol)以与实施例137的步骤A和B相同的方式顺序反应,得到标题化合物(0.002g,17%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.60(1H,m),7.21(2H,d),6.95(1H,m),5.27(1H,m),2.97(2H,t),2.56-2.42(4H,m),2.12(2H,m),1.91-1.81(3H,m),1.69(1H,m)。
实施例145:4-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.063g,0.16mmol)和在制备例38中获得的2-环戊氧基-3-碘-吡啶(0.052g,0.18mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.025g,39%)。
1H-NMR(CDCl3)δ8.17(1H,m),7.58(1H,m),7.17(2H,d),6.92(1H,m),5.51(1H,m),2.96(2H,t),2.55(2H,m),1.98-1.87(4H,m),1.81-1.73(4H,m),1.63(2H,m)。
实施例146:4-[2,6-二氟-4-(2-异丙基硫基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.02g,0.05mmol)和在制备例226中获得的3-碘-2-异丙基硫基-吡啶(0.015g,0.054mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.007g,36%)。
1H-NMR(CDCl3)δ8.45(1H,m),7.36(1H,m),7.04-7.00(3H,m),4.06(1H,m),2.98(2H,t),2.57(2H,t),1.91(2H,m),1.34(6H,d)。
实施例147:4-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸
使用在制备例176中获得的2-环戊基硫基-3-(3,4,5-三氟-苯基)-吡啶(0.02g,0.06mmol)、Cs2CO3(0.02g,0.06mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.01g,0.06mmol)以与实施例137的步骤A和B相同的方式顺序反应,得到标题化合物(0.007g,26%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.34(1H,m),7.03-7.01(3H,m),4.09(1H,m),2.98(2H,t),2.57(2H,t),2.18(2H,m),1.91(2H,m),1.72-1.52(6H,m)。
实施例148:4-[4-(2-异丙基硫基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例226中获得的3-碘-2-异丙基硫基-吡啶(0.044g,0.16mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.013g,27%)。
1H-NMR(CDCl3)δ8.41(1H,m),7.39-7.32(5H,m),7.02(1H,m),4.04(1H,m),3.04(2H,t),2.55(2H,t),2.03(2H,m),1.34(6H,d)。
实施例149:4-[4-(2-环戊基硫基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例39中获得的2-环戊基硫基-3-碘-吡啶(0.048g,0.16mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.011g,20%)。
1H-NMR(CDCl3)δ8.41(1H,m),7.39-7.32(5H,m),7.02(1H,m),4.04(1H,m),3.03(2H,t),2.55(2H,t),2.18(2H,m),2.02(2H,m),1.72-1.52(6H,m)。
实施例150:4-[2-氟-4-(6-异丙氧基-吡啶-2-基)-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.13mmol)和在制备例228中获得的2-溴-6-异丙氧基-吡啶(0.032g,0.15mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.014g,29%)。
1H-NMR(CDCl3)δ7.73-7.71(2H,m),7.59(1H,t),7.42(1H,t),7.25(1H,m),6.64(1H,d),5.45(1H,m),3.00(2H,t),2.54(2H,t),1.95(2H,m),1.38(6H,d)。
实施例151:4-[4-(2-环戊基氧基-吡啶-3-基)-2-氟-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.13mmol)和在制备例38中获得的2-环戊氧基-3-碘-吡啶(0.04g,0.15mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.027g,54%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.57(1H,m),7.38(1H,t),7.29-7.27(2H,m),6.91(1H,m),5.50(1H,m),3.00(2H,t),2.55(2H,t),1.98-1.93(4H,m),1.86-1.59(6H,m)。
实施例152:4-[4-(2-环丁基硫基-吡啶-3-基)-2-氟-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.13mmol)和在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.04g,0.15mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.032g,62%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.41(1H,t),7.33(1H,m),7.15(2H,m),7.02(1H,m),4.42(1H,m),3.02(2H,t),2.57(2H,t),2.55(2H,m),2.10-1.97(6H,m)。
实施例153:4-[4-(2-环丁基硫基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.046g,0.16mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.015g,29%)。
1H-NMR(CDCl3)δ8.38(1H,m),7.37-7.34(5H,m),7.02(1H,m),4.41(1H,m),3.03(2H,t),2.57(2H,t),2.54(2H,m),2.10-1.97(6H,m)。
实施例154:4-[4-(6-环丁氧基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸
使用在制备例181中获得的2-环丁氧基-6-(3,4,5-三氟-苯基)-吡啶(0.03g,0.11mmol)、Cs2CO3(0.035g,0.11mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.016g,0.11mmol)以与实施例137的步骤A和B相同的方式顺序反应,得到标题化合物(0.011g,27%)。
1H-NMR(CDCl3)δ7.64-7.57(3H,m),7.27(1H,d),6.69(1H,d),5.26(1H,m),2.96(2H,t),2.57-2.51(4H,m),2.18(2H,m),1.87(3H,m),1.76(1H,m)。
实施例155:4-[4-(6-环戊基氧基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸
使用在制备例182中获得的2-环戊基氧基-6-(3,4,5-三氟-苯基)-吡啶(0.035g,0.12mmol)、Cs2CO3(0.039g,0.12mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.018g,0.12mmol)以与实施例137的步骤A和B相同的方式顺序反应,得到标题化合物(0.016g,34%)。
1H-NMR(CDCl3)δ7.62-7.58(3H,m),7.24(1H,d),6.67(1H,d),5.50(1H,m),2.96(2H,t),2.54(2H,t),2.03(2H,m),1.89-1.78(6H,m),1.65(2H,m)。
实施例156:4-[4-(6-环丁基硫基-吡啶-2-基)-苯基硫基]-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.011g,0.03mmol)和在制备例233中获得的2-溴-6-环丁基硫基-吡啶(0.008g,0.03mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.003g,27%)。
1H-NMR(CDCl3)δ7.94(2H,d),7.49(1H,t),7.40-7.37(3H,m),7.00(1H,d),4.44(1H,m),3.03(2H,t),2.63-2.53(4H,m),2.20-1.98(6H,m)。
实施例157:4-[4-(6-环丙基甲氧基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸
使用在制备例183中获得的2-环丙基甲氧基-6-(3,4,5-三氟-苯基)-吡啶(0.034g,0.12mmol)、Cs2CO3(0.04g,0.12mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.018g,0.12mmol)以与实施例137的步骤A和B相同的方式顺序反应,得到标题化合物(0.012g,26%)。
1H-NMR(CDCl3)δ7.65(1H,t),7.59(2H,d),7.27(1H,d),6.76(1H,d),4.24(2H,d),2.96(2H,t),2.54(2H,t),1.87(2H,m),1.32(1H,m),0.64(2H,m),0.39(2H,m)。
实施例158:4-[4-(6-环丁基硫基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸
使用在制备例184中获得的2-环丁基硫基-6-(3,4,5-三氟-苯基)-吡啶(0.03g,0.1mmol)、Cs2CO3(0.033g,0.1mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.015g,0.1mmol)以与实施例137的步骤A和B相同的方式顺序反应,得到标题化合物(0.016g,40%)。
1H-NMR(CDCl3)δ7.60(2H,d),7.53(1H,t),7.35(1H,d),7.07(1H,d),4.42(1H,m),2.98(2H,t),2.63-2.53(4H,m),2.20-2.10(4H,m),1.88(2H,m)。
实施例159:4-[4-(6-环戊基硫基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸
使用在制备例185中获得的2-环戊基硫基-6-(3,4,5-三氟-苯基)-吡啶(0.04g,0.13mmol)、Cs2CO3(0.044g,0.13mmol)和在制备例161中获得的4-巯基-丁酸乙酯(0.02g,0.13mmol)以与实施例137的步骤A和B相同的方式顺序反应,得到标题化合物(0.016g,29%)。
1H-NMR(CDCl3)δ7.61(2H,d),7.53(1H,t),7.35(1H,d),7.13(1H,d),4.16(1H,m),2.97(2H,t),2.54(2H,t),2.24(2H,m),1.89-1.69(8H,m)。
实施例160:4-(2'-环戊基氨基-3-氟-联苯-4-基硫基)-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.13mmol)和在制备例70中获得的N-环戊基-2-碘-苯胺(0.043g,0.15mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.022g,40%)。
1H-NMR(CDCl3)δ7.42(1H,t),7.23(1H,m),7.15(2H,m),7.02(1H,m),6.72(2H,m),3.77(1H,m),3.01(2H,t),2.56(2H,t),1.98(4H,m),1.60(4H,m),1.37(2H,m)。
实施例161:4-(2'-环戊基氨基-3,5-二氟-联苯-4-基硫基)-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.06g,0.16mmol)和在制备例70中获得的N-环戊基-2-碘-苯胺(0.05g,0.17mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.013g,21%)。
1H-NMR(CDCl3)δ7.23(1H,m),7.01(3H,m),6.72(2H,m),3.77(1H,m),2.97(2H,t),2.56(2H,t),2.03-1.89(4H,m),1.66-1.58(4H,m),1.40(2H,m)。
实施例162:4-[2'-(环丙基甲基-氨基)-3,5-二氟-联苯-4-基硫基]-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.054g,0.14mmol)和在制备例73中获得的N-(环丙基甲基)-2-碘-苯胺(0.042g,0.15mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.011g,21%)。
1H-NMR(CDCl3)δ7.25(1H,m),7.05(3H,m),6.74(1H,t),6.68(1H,d),2.96(4H,m),2.57(2H,t),1.91(2H,m),1.04(1H,m),0.49(2H,m),0.18(2H,m)。
实施例163:4-[2-氟-4-(2-异丙基硫基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例226中获得的3-碘-2-异丙基硫基-吡啶(0.057g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.023g,46%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.44-7.35(2H,m),7.15(2H,m),7.05(1H,m),4.07(1H,m),3.01(2H,t),2.57(2H,t),1.99(2H,m),1.36(6H,d)。
实施例164:4-[4-(2-环戊基硫基-吡啶-3-基)-2-氟-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.04g,0.11mmol)和在制备例39中获得的2-环戊基硫基-3-碘-吡啶(0.05g,0.16mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.014g,33%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.43-7.35(2H,m),7.17(2H,m),7.05(1H,m),4.09(1H,m),3.01(2H,t),2.57(2H,t),2.18(2H,m),1.99(2H,m),1.73-1.53(6H,m)。
实施例165:4-(3,5-二氟-2'-异丙基氨基-联苯-4-基硫基)-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.13mmol)和在制备例74中获得的2-碘-N-异丙基-苯胺(0.05g,0.14mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.033g,70%)。
1H-NMR(CDCl3)δ7.24(1H,m),7.02(3H,m),6.72(2H,m),3.64(1H,m),2.98(2H,t),2.58(2H,t),1.93(2H,m),1.17(6H,d)。
实施例166:4-(3,5-二氟-2'-丙基氨基-联苯-4-基硫基)-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.13mmol)和在制备例72中获得的2-碘-N-丙基-苯胺(0.05g,0.14mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.023g,48%)。
1H-NMR(CDCl3)δ7.25(1H,m),7.04(3H,m),6.73(2H,m),3.07(2H,t),2.97(2H,t),2.58(2H,t),1.91(2H,m),1.57(2H,m),0.94(3H,t)。
实施例167:4-[4-(2-环丙基甲氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.13mmol)和在制备例40中获得的2-环丙基甲氧基-3-碘-吡啶(0.07g,0.26mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.025g,51%)。
1H-NMR(CDCl3)δ8.15(1H,m),7.62(1H,m),7.24(2H,d),6.96(1H,m),4.23(2H,d),2.97(2H,t),2.56(2H,t),1.90(2H,m),1.29(1H,m),0.59(2H,m),0.34(2H,m)。
实施例168:4-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.13mmol)和在制备例203中获得的3-碘-2-丙基硫基-吡啶(0.07g,0.26mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.03g,61%)。
1H-NMR(CDCl3)δ8.45(1H,m),7.36(1H,m),7.07-7.01(3H,m),3.15(2H,t),2.99(2H,t),2.58(2H,t),1.92(2H,m),1.71(2H,m),1.02(3H,t)。
实施例169:4-[4-(6-环丁基硫基-吡啶-2-基)-2-氟-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.04g,0.11mmol)和在制备例19中获得的2-氯-6-环丁基硫基-吡啶(0.04g,0.22mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.009g,21%)。
1H-NMR(CDCl3)δ7.74(2H,m),7.51(1H,t),7.43(1H,t),7.36(1H,d),7.03(1H,d),4.41(1H,m),3.02(2H,t),2.61-2.53(4H,m),2.21-2.07(4H,m),1.99(2H,m)。
实施例170:4-[4-(2-环戊基氨基-吡啶-3-基)-2-氟-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例64中获得的N-环戊基-3-碘-吡啶基-2-胺(0.06g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.016g,32%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.44(1H,t),7.21(1H,m),7.12(2H,m),6.61(1H,m),4.32(1H,m),3.02(2H,t),2.56(2H,t),2.09-1.97(4H,m),1.61(4H,m),1.33(2H,m)。
实施例171:4-[2-氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例37中获得的3-碘-2-异丙氧基-吡啶(0.053g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.019g,40%)。
1H-NMR(CDCl3)δ8.13(1H,m),7.58(1H,m),7.39-7.30(3H,m),6.92(1H,m),5.40(1H,m),3.00(2H,t),2.56(2H,t),1.98(2H,m),1.35(6H,d)。
实施例172:4-[4-(2-环丁氧基-吡啶-3-基)-2-氟-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例200中获得的2-环丁氧基-3-碘-吡啶(0.056g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.015g,30%)。
1H-NMR(CDCl3)δ8.11(1H,m),7.58(1H,m),7.40-7.32(3H,m),6.93(1H,m),5.25(1H,m),3.01(2H,t),2.57-2.42(4H,m),2.11(2H,m),1.97(2H,m),1.82(1H,m),1.67(1H,m)。
实施例173:4-[2-氟-4-(2-吡咯烷-1-基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例204中获得的3-碘-2-吡咯烷-1-基-吡啶(0.056g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.03g,61%)。
1H-NMR(CDCl3)δ8.20(1H,m),7.40-7.36(2H,m),7.10-7.05(2H,m),6.71(1H,m),3.16(4H,m),3.01(2H,t),2.56(2H,t),1.97(2H,m),1.80(4H,m)。
实施例174:4-[2-氟-4-(2-异丙基氨基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例66中获得的3-碘-N-异丙基-吡啶基-2-胺(0.053g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.029g,61%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.46(1H,t),7.24(1H,m),7.15-7.10(2H,m),6.62(1H,m),4.25(1H,m),3.04(2H,t),2.57(2H,t),2.00(2H,m),1.19(6H,d)。
实施例175:4-(2'-环戊基氨基-3,5'-二氟-联苯-4-基硫基)-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例82中获得的N-环戊基-4-氟-2-碘-苯胺(0.046g,0.15mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.02g,39%)。
1H-NMR(CDCl3)δ7.43(1H,t),7.13(2H,m),6.92(1H,m),6.78(1H,m),6.62(1H,m),3.71(1H,m),3.01(2H,t),2.55(2H,t),1.99-1.91(4H,m),1.61(4H,m),1.36(2H,m)。
实施例176:4-(2'-环戊基氨基-5'-氟-联苯-4-基硫基)-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例82中获得的N-环戊基-4-氟-2-碘-苯胺(0.048g,0.16mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.028g,52%)。
1H-NMR(CDCl3)δ7.39(2H,d),7.29(2H,d),6.91(1H,m),6.79(1H,m),6.62(1H,m),3.71(1H,m),3.03(2H,t),2.55(2H,t),2.02-1.93(4H,m),1.59(4H,m),1.36(2H,m)。
实施例177:4-(2'-环戊基氧基-5'-甲基-联苯-4-基硫基)-丁酸
使用在制备例187中获得的4-(2'-环戊基氧基-5'-甲基-联苯-4-基硫基)-丁酸乙酯(0.02g,0.05mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.01g,55%)。
1H-NMR(CDCl3)δ7.45(2H,d),7.34(2H,d),7.10(1H,s),7.04(1H,m),6.86(1H,d),4.67(1H,m),3.00(2H,t),2.53(2H,t),2.31(3H,s),1.98(2H,m),1.77(4H,m),1.64-1.53(4H,m)。
实施例178:4-(2'-环戊基氧基-4'-甲氧基-联苯-4-基硫基)-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.025g,0.07mmol)和在制备例128中获得的1-溴-2-环戊基氧基-4-甲氧基-苯(0.02g,0.07mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.002g,7%)。
1H-NMR(CDCl3)δ7.45(2H,d),7.34(2H,d),7.10(1H,s),7.04(1H,d),6.86(1H,d),4.67(1H,m),3.00(2H,t),2.53(2H,t),2.31(3H,s),1.98(2H,m),1.77(4H,m),1.64-1.53(4H,m)。
实施例179:4-(2'-环戊基氧基-5'-氟-联苯-4-基硫基)-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例129中获得的2-溴-1-环戊基氧基-4-氟-苯(0.04g,0.16mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.003g,5%)。
1H-NMR(CDCl3)δ7.43(2H,d),7.32(2H,d),7.02(1H,m),6.95(1H,m),6.88(1H,m),4.63(1H,m),3.01(2H,t),2.53(2H,t),1.99(2H,m),1.75(4H,m),1.63-1.52(4H,m)。
实施例180:4-(2'-环戊基氧基-3,5'-二氟-联苯-4-基硫基)-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.1g,0.27mmol)和在制备例129中获得的2-溴-1-环戊基氧基-4-氟-苯(0.1g,0.4mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.047g,44%)。
1H-NMR(CDCl3)δ7.38(1H,t),7.27-7.24(2H,m),7.03(1H,m),6.97(1H,m),6.89(1H,m),4.66(1H,m),3.01(2H,t),2.55(2H,t),1.98(2H,m),1.79(4H,m),1.70-1.47(4H,m)。
实施例181:4-[4-(2-环戊基氧基-5-甲基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.1g,0.28mmol)和在制备例131中获得的3-溴-2-环戊基氧基-5-甲基-吡啶(0.11g,0.43mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.03g,28%)。
1H-NMR(CDCl3)δ7.91(1H,s),7.48(2H,d),7.40(1H,s),7.34(2H,d),5.44(1H,m),3.01(2H,t),2.54(2H,t),2.26(3H,s),2.01(2H,m),1.90(2H,m),1.78-1.58(6H,m)。
实施例182:4-(2'-环戊基氧基-3,5,5'-三氟-联苯-4-基硫基)-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.036g,0.09mmol)和在制备例129中获得的2-溴-1-环戊基氧基-4-氟-苯(0.026g,0.1mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.002g,4%)。
1H-NMR(CDCl3)δ7.11(2H,d),7.02(2H,m),6.89(1H,m),4.68(1H,m),2.95(2H,t),2.53(2H,m),1.89-1.79(6H,m),1.66-1.58(4H,m)。
实施例183:4-(2'-环戊基氧基-3-氟-4'-甲氧基-联苯-4-基硫基)-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.13mmol)和在制备例128中获得的1-溴-2-环戊基氧基-4-甲氧基-苯(0.04g,0.15mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.005g,9%)。
1H-NMR(CDCl3)δ7.38(1H,t),7.28-7.21(4H,m),6.53(1H,m),4.74(1H,m),3.83(3H,s),2.98(2H,t),2.55(2H,t),1.99(2H,m),1.84(4H,m),1.71-1.58(4H,m)。
实施例184:4-(2'-环戊基氧基-3,5-二氟-4'-甲氧基-联苯-4-基硫基)-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.13mmol)和在制备例128中获得的1-溴-2-环戊基氧基-4-甲氧基-苯(0.04g,0.14mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.004g,7%)。
1H-NMR(CDCl3)δ7.22(1H,m),7.10(2H,d),6.55(2H,m),4.76(1H,m),3.84(3H,s),2.94(2H,t),2.56(2H,t),1.91-1.86(6H,m),1.71(2H,m),1.62(2H,m)。
实施例185:4-(3-氟-2'-异丙氧基-4'-甲氧基-联苯-4-基硫基)-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.13mmol)和在制备例132中获得的1-溴-2-异丙氧基-4-甲氧基-苯(0.04g,0.15mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.007g,13%)。
1H-NMR(CDCl3)δ7.37(1H,t),7.30-7.22(3H,m),6.56(2H,m),4.47(1H,m),3.84(3H,s),2.99(2H,t),2.56(2H,t),1.96(2H,m),1.29(6H,d)。
实施例186:4-[4-(2-环戊基氧基-5-甲基-吡啶-3-基)-2-氟-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例131中获得的3-溴-2-环戊基氧基-5-甲基-吡啶(0.05g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.018g,34%)。
1H-NMR(CDCl3)δ7.96(1H,s),7.43(1H,s),7.38(1H,t),7.31-7.25(2H,m),5.47(1H,m),3.00(2H,t),2.55(2H,t),2.27(3H,s),1.98-1.93(4H,m),1.78-1.61(6H,m)。
实施例187:4-[2-氟-4-(2-异丙氧基-5-甲基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例133中获得的3-溴-2-异丙氧基-5-甲基-吡啶(0.05g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.017g,34%)。
1H-NMR(CDCl3)δ7.94(1H,s),7.43(1H,s),7.41(1H,t),7.38-7.30(2H,m),5.34(1H,m),3.00(2H,t),2.55(2H,t),2.27(3H,s),1.97(2H,m),1.32(6H,d)。
实施例188:4-(3,5'-二氟-2'-异丙氧基-联苯-4-基硫基)-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例134中获得的2-溴-4-氟-1-异丙氧基-苯(0.05g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.02g,40%)。
1H-NMR(CDCl3)δ7.39(1H,t),7.33-7.27(2H,m),7.05-6.90(3H,m),4.33(1H,m),3.01(2H,t),2.56(2H,t),1.97(2H,m),1.24(6H,d)。
实施例189:4-[4-(2-环戊基氧基-6-甲基-吡啶-3-基)-2-氟-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例136中获得的3-溴-2-环戊基氧基-6-甲基-吡啶(0.05g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.011g,20%)。
1H-NMR(CDCl3)δ7.39(2H,m),7.01(2H,m),6.55(1H,d),5.34(1H,m),2.99(2H,t),2.54(2H,t),2.39(3H,s),2.01-1.91(4H,m),1.81(4H,m),1.62(2H,m)。
实施例190:4-(3,3'-二氟-2'-异丙氧基-5'-甲基-联苯-4-基硫基)-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例138中获得的1-溴-3-氟-2-异丙氧基-5-甲基-苯(0.05g,
0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.022g,43%)。
1H-NMR(CDCl3)δ7.39(1H,t),7.31(2H,m),6.91(2H,m),3.97(1H,m),2.99(2H,t),2.55(2H,t),2.33(3H,s),1.94(2H,m),1.05(6H,d)。
实施例191:4-(3,3'-二氟-5'-甲基-2'-丙氧基-联苯-4-基硫基)-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例139中获得的1-溴-3-氟-5-甲基-2-丙氧基-苯(0.05g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.02g,39%)。
1H-NMR(CDCl3)δ7.39(1H,t),7.26(2H,m),6.91(2H,m),3.72(2H,t),2.99(2H,t),2.55(2H,t),2.31(3H,s),1.94(2H,m),1.55(2H,m),0.82(3H,t)。
实施例192:4-(3-氟-2',4'-二丙氧基-联苯-4-基硫基)-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例140中获得的1-溴-2,4-二丙氧基-苯(0.056g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.033g,60%)。
1H-NMR(CDCl3)δ7.37(1H,t),7.28-7.21(3H,m),6.53(2H,m),3.93(4H,m),2.98(2H,t),2.55(2H,t),1.95(2H,m),1.87-1.72(4H,m),1.05(3H,m),0.98(3H,m)。
实施例193:4-(6'-环戊基氧基-3,2'-二氟-3'-甲基-联苯-4-基硫基)-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例142中获得的2-溴-1-环戊基氧基-3-氟-4-甲基-苯(0.056g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.035g,63%)。
1H-NMR(CDCl3)δ7.41(1H,t),7.31-7.26(2H,m),6.89-6.83(2H,m),4.03(1H,m),3.00(2H,t),2.56(2H,t),2.31(3H,s),1.94(2H,m),1.57(4H,m),1.40(4H,m)。
实施例194:4-(2'-环戊基氧基-3,3'-二氟-联苯-4-基硫基)-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例144中获得的1-溴-2-环戊基氧基-3-氟-苯(0.053g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.01g,18%)。
1H-NMR(CDCl3)δ7.42(1H,t),7.30-7.21(4H,m),7.01(1H,t),4.84(1H,m),2.99(2H,t),2.55(2H,t),1.99-1.83(8H,m),1.64(2H,m)。
实施例195:4-(2'-环戊基氧基-3,3'-二氟-5'-甲基-联苯-4-基硫基)-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例145中获得的1-溴-2-环戊基氧基-3-氟-5-甲基-苯(0.053g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.025g,45%)。
1H-NMR(CDCl3)δ7.40(1H,t),7.38-7.26(2H,m),6.91(2H,m),4.46(1H,m),2.99(2H,t),2.55(2H,t),2.32(3H,s),1.94(2H,m),1.65(2H,m),1.47-1.39(6H,m)。
实施例196:5-[4-(2-环丁基甲氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸
使用在制备例61中获得的2-环丁基甲氧基-3-碘-吡啶(0.040g,0.14mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.053g,0.14mmol)以与实施例1的步骤A和B相同的方式反应,得到标题化合物(0.029g,54%)。
1H NMR(CDCl3)δ8.14(1H,m),7.59(1H,m),7.16(2H,m),6.94(1H,m),4.33(2H,d),4.20(2H,t),2.79(1H,m),2.48(2H,t),2.14(2H,m),2.00-1.80(8H,m)。
实施例197:5-[4-(2-环丙氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸
使用在制备例62中获得的2-环丙氧基-3-碘-吡啶(0.040g,0.15mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.059g,0.15mmol)以与实施例1的步骤A和B相同的方式反应,得到标题化合物(0.024g,43%)。
1H NMR(CDCl3)δ8.23(1H,m),7.57(1H,m),7.07(2H,m),7.00(1H,m),4.34(1H,m),4.18(2H,t),2.48(2H,t),1.89(4H,m),0.82(2H,m),0.75(2H,m)。
实施例198:4-[4-(2-环戊基氧基-5-甲基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.13mmol)和在制备例131中获得的3-溴-2-环戊基氧基-5-甲基-吡啶(0.05g,0.26mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.02g,40%)。
1H-NMR(CDCl3)δ7.97(1H,s),7.42(1H,s),7.16(2H,d),5.47(1H,m),2.95(2H,t),2.55(2H,t),2.27(3H,s),1.92(4H,m),1.88-1.62(6H,m)。
实施例199:4-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-戊酸
使用在制备例191中获得的4-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-戊酸乙酯(0.01g,0.02mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.005g,48%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.57(1H,m),7.49(2H,d),7.41(2H,d),6.90(1H,m),5.49(1H,m),3.29(1H,m),2.59(2H,t),1.93-1.91(4H,m),1.82-1.59(6H,m),1.34(3H,d)。
实施例200:4-[4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊酸
使用在制备例193中获得的(E)-4-[4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊-2-烯酸乙酯(0.025g,0.07mmol)以与制备例191和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.005g,20%)。
1H-NMR(CDCl3)δ8.11(1H,m),7.57(1H,m),7.51(2H,d),7.42(2H,d),6.90(1H,m),5.38(1H,m),3.29(1H,m),2.60(2H,t),1.93(2H,m),1.34(9H,m)。
实施例201:4-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸
使用在制备例197中获得的(E)-4-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊-2-烯酸乙酯(0.04g,0.09mmol)以与制备例191和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.01g,26%)。
1H-NMR(CDCl3)δ8.17(1H,m),7.61(1H,m),7.19(2H,d),6.93(1H,m),5.51(1H,m),3.31(1H,m),2.62(2H,t),1.94(2H,m),1.86-1.73(6H,m),1.63(2H,m),1.30(3H,d)。
实施例202:4-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸
使用在制备例199中获得的(E)-4-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊-2-烯酸乙酯(0.04g,0.09mmol)以与制备例191和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.005g,12%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.34(1H,m),7.03(3H,m),4.08(1H,m),3.32(1H,m),2.62(2H,t),2.19(2H,m),1.87(2H,m),1.71-1.51(6H,m),1.30(3H,d)。
实施例203:4-[4-[2-(2-二甲基氨基乙基氧基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[2-(2-二甲基氨基乙基氧基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例206中获得的2-[(3-碘-2-吡啶基)氧基]-N,N-二甲基-乙胺(0.117g,0.4mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.163g,0.44mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.06g,37%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.58(1H,m),7.22(2H,m),6.96(1H,m),4.49(2H,t),4.21(2H,t),4.15(2H,q),2.72(2H,t),2.59(2H,t),2.31(6H,s),2.11(2H,m),1.27(3H,t)。
步骤B:4-[4-[2-(2-二甲基氨基乙基氧基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[2-(2-二甲基氨基乙基氧基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯(0.06g,0.15mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.02g,38%)。
1H-NMR(MeOH-d4)δ8.14(1H,m),7.73(1H,m),7.21(2H,m),7.08(1H,m),4.63(2H,t),2.19(2H,t),3.23(2H,t),2.63(6H,s),2.40(2H,t),2.02(2H,m)。
实施例204:4-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯氧基]-丁酸
步骤A:4-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯氧基]-丁酸乙酯
将在制备例203中获得的3-碘-2-丙基硫基-吡啶(0.114g,0.410mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.142g,0.383mmol)溶于2mL的2M碳酸钠水溶液和4mL的1,2-二甲氧基乙烷,并向其中加入N25分钟。向其中添加双(三苯基膦)钯(II)二氯化物(0.013g,0.019mmol)并将生成物在80℃搅拌16小时。在结束反应之后,将生成物用水稀释并用乙酸乙酯萃取。将有机层用无水MgSO4干燥并通过色谱法纯化(洗脱剂:EtOAc/Hex=1/4),得到标题化合物(0.113g,74%)。
1H-NMR(CDCl3)δ8.42(1H,m),7.32(1H,m),7.01(3H,m),4.22(2H,t),4.15(2H,q),3.13(2H,t),2.58(2H,t),2.11(2H,m),1.68(2H,m),1.25(3H,t),1.01(3H,t)。
步骤B:4-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯氧基]-丁酸
将在步骤A中获得的4-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯氧基]-丁酸乙酯(0.026g,0.065mmol)溶于THF/MeOH/水(1:1:1,3mL)。向其中添加1N NaOH(12mg,0.50mmol)并将生成物在室温搅拌2小时。在结束反应之后,将生成物在减压下浓缩,并将残余物用水稀释。通过使用1N HCl将水层的pH调节至2-3,并将反应物用乙酸乙酯萃取。将有机层用无水MgSO4干燥并通过色谱法纯化(洗脱剂:EtOAc/Hex=1/1),得到标题化合物(0.014g,58%)。
1H-NMR(CDCl3)δ8.43(1H,m),7.32(1H,m),7.01(3H,m),4.26(2H,t),3.14(2H,t),2.68(2H,t),2.14(2H,m),1.69(2H,m),1.02(3H,t)。
实施例205:4-[4-(2-环丙基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用在制备例239中获得的2-环丙基硫基-3-碘-吡啶(0.06g,0.21mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.074g,0.202mmol)以与实施例1相同的方式反应,得到标题化合物(0.03g,38%)。
1H-NMR(CDCl3)δ8.52(1H,m),7.34(1H,m),7.09(1H,m),6.95(2H,m),4.25(2H,m),2.67(2H,t),2.40(1H,m),2.12(2H,m),1.07(2H,m),0.59(2H,m)。
实施例206:4-[4-(2-乙基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用在制备例240中获得的2-乙基硫基-3-碘-吡啶(0.098g,0.369mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.127g,0.345mmol)以与实施例1相同的方式反应,得到标题化合物(0.03g,35%)。
1H-NMR(CDCl3)δ8.45(1H,m),7.34(1H,m),7.05(1H,m),6.99(2H,m),4.26(2H,t),3.17(2H,q),2.68(2H,t),2.13(2H,m),1.33(3H,t)。
实施例207:4-[4-(2-丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用在制备例241中获得的2-丁基硫基-3-碘-吡啶(0.102g,0.347mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.12g,0.325mmol)以与实施例1相同的方式反应,得到标题化合物(0.052g,39%)。
1H-NMR(CDCl3)δ8.43(1H,m),7.33(1H,d),7.04(1H,m),6.99(2H,m),4.26(2H,t),3.17(2H,t),2.68(2H,t),2.14(2H,m),1.66(2H,m),1.44(2H,m),0.93(3H,t)。
实施例208:4-(2'-环戊基氨基-联苯-4-基硫基)-丁酸.
使用在制备例159中获得的4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例70中获得的N-环戊基-2-碘-苯胺(0.045g,0.16mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.02g,40%)。
1H-NMR(CDCl3)δ7.39(2H,d),7.33(2H,d),7.21(1H,t),7.03(1H,m),6.72(2H,m),3.77(1H,m),3.03(2H,t),2.56(2H,t),2.03-1.95(4H,m),1.61(4H,m),1.38(2H,m)。
实施例209:4-[4-(2-环戊基氧基-5-甲基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.05g,0.13mmol)和在制备例131中获得的3-溴-2-环戊基氧基-5-甲基-吡啶(0.05g,0.20mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.027g,52%)。
1H-NMR(CDCl3)δ7.95(1H,s),7.39(1H,s),7.12(2H,d),5.46(1H,m),4.22(2H,t),2.66(2H,t),2.27(3H,s),2.12(2H,m),1.92(2H,m),1.80-1.72(4H,m),1.62(2H,m)。
实施例210:4-[4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸
步骤A:4-[4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸乙酯
使用在制备例1中获得的4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.143g,0.43mmol)和在制备例125中获得的2-氯-6-异丙基硫基-吡啶(0.03g,0.16mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.036g,62%)。
1H NMR(CDCl3)δ7.97(2H,d),7.48(1H,t),7.35(1H,d),7.02(1H,d),6.95(2H,d),4.14(3H,m),4.07(2H,t),2.53(2H,t),2.14(2H,m),1.46(6H,d),1.26(3H,t)。
步骤B:4-[4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸
使用在步骤A中获得的4-[4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸乙酯(0.036g,0.1mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.019g,57%)。
1H NMR(CDCl3)δ7.98(2H,d),7.48(1H,t),7.35(1H,m),7.02(1H,m),6.96(2H,m),4.16(1H,m),4.09(2H,t),2.61(2H,t),2.14(2H,m),1.46(6H,d)。
实施例211:4-[2,6-二氟-4-(3-苯氧基苯基)苯氧基]丁酸
使用在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.090g,0.24mmol)和1-溴-3-苯氧基-苯(0.06g,0.24mmol)以与实施例29的步骤A和B相同的方式顺序反应,得到标题化合物(0.078g,80%)。
1H NMR(CDCl3)δ7.36(3H,m),7.23(1H,m),7.13(2H,m),7.08(2H,m),7.04(2H,m),6.99(1H,m),4.21(2H,t),2.66(2H,t),2.11(2H,m)。
实施例212:4-[4-[6-[3-(二甲基氨基)吡咯烷-1-基]-2-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在制备例124中获得的1-(6-氯-2-吡啶基)-N,N-二甲基-吡咯烷-3-胺(0.04g,0.18mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.066g,0.18mmol)以与实施例29的步骤A和实施例1的步骤B相同的方式顺序反应,得到标题化合物(3.3mg,5%)。
1H NMR(CDCl3)δ7.43(3H,m),6.88(1H,m),6.31(1H,m),4.21(2H,t),3.85(1H,m),3.74(1H,m),3.48(2H,m),3.17(1H,m),2.56(2H,t),2.47(6H,s),2.27(1H,m),2.24(1H,m),2.08(2H,m)。
实施例213:5-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯氧基]-戊酸
使用在制备例37中获得的3-碘-2-异丙氧基-吡啶(0.040g,0.15mmol)和在制备例225中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸乙酯(0.058g,0.15mmol)以与实施例1相同的方式反应,得到标题化合物(0.038g,68%)。
1H NMR(CDCl3)δ8.13(1H,m),7.56(1H,m),7.16(2H,m),6.92(1H,m),5.41(1H,m),4.20(2H,t),2.49(2H,t),1.89(4H,m),1.36(6H,d)。
实施例214:5-[4-(2-环丁氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸
使用在制备例200中获得的2-环丁氧基-3-碘-吡啶(0.040g,0.15mmol)和在制备例225中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸乙酯(0.056g,0.15mmol)以与实施例1相同的方式反应,得到标题化合物(0.033g,60%)。
1H NMR(CDCl3)δ8.12(1H,m),7.57(1H,m),7.18(2H,m),6.94(1H,m),5.28(1H,m),4.20(2H,t),2.48(4H,m),2.13(2H,m),1.89(5H,m),1.72(1H,m)。
实施例215:4-[4-[2-(3,3-二氟吡咯烷-1-基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸
步骤A:4-[4-[2-(3,3-二氟吡咯烷-1-基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯
使用在制备例109中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸乙酯(0.09g,0.27mmol)和3,3-二氟吡咯烷盐酸盐(0.11g,0.8mmol)以与实施例72的步骤A相同的方式反应,得到标题化合物(0.007g,6%)。
1H NMR(CDCl3)δ8.20(1H,m),7.38(1H,m),6.98(2H,m),6.84(1H,m),4.24(2H,t),4.16(2H,q),4.45(4H,m),2.59(2H,t),2.27(2H,m),2.13(2H,m),1.27(3H,t)。
步骤B:4-[4-[2-(3,3-二氟吡咯烷-1-基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在步骤A中获得的4-[4-[2-(3,3-二氟吡咯烷-1-基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸乙酯(0.007g,0.016mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.006g,98%)。
1H NMR(CDCl3)δ8.21(1H,m),7.38(1H,m),6.95(2H,m),6.8(1H,m),4.25(2H,t),3.43(4H,m),2.68(2H,t),2.28(2H,m),2.14(2H,m)。
实施例216:4-[2,6-二氟-4-[2-(4-甲基哌嗪-1-基)-3-吡啶基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[2-(4-甲基哌嗪-1-基)-3-吡啶基]苯氧基]丁酸乙酯
使用在制备例109中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸乙酯(0.09g,0.27mmol)和1-甲基哌嗪(0.088g,0.8mmol)以与实施例72的步骤A相同的方式反应,得到标题化合物(0.007g,6%)。
1H NMR(CDCl3)δ8.23(1H,m),7.38(1H,m),7.16(2H,m),6.92(1H,m),4.23(2H,t),4.17(2H,q),3.14(4H,m),2.60(2H,t),2.40(4H,m),2.30(3H,s),2.11(2H,m),1.27(3H,t)。
步骤B:4-[2,6-二氟-4-[2-(4-甲基哌嗪-1-基)-3-吡啶基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[2-(4-甲基哌嗪-1-基)-3-吡啶基]苯氧基]丁酸乙酯(0.007g,0.016mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.0013g,20%)。
1H NMR(CDCl3)δ8.21(1H,m),7.40(1H,m),7.08(2H,m),6.91(1H,m),4.26(2H,t),3.23(4H,m),2.62(4H,m),2.52(2H,t),2.39(3H,s),2.07(2H,m)。
实施例217:4-[2,6-二氟-4-[2-(5-甲基异噁唑-3-基)氧基-3-吡啶基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[2-(5-甲基异噁唑-3-基)氧基-3-吡啶基]苯氧基]丁酸乙酯
使用在制备例205中获得的3-[(3-碘-2-吡啶基)氧基]-5-甲基-异噁唑(0.15g,0.5mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.20g,0.54mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.14g,67%)。
1H-NMR(CDCl3)δ8.21(1H,m),7.75(1H,m),7.20(3H,m),6.02(1H,s),4.23(2H,t),4.15(2H,q),2.58(2H,t),2.43(3H,s),2.12(2H,m),1.27(3H,t)。
步骤B:4-[2,6-二氟-4-[2-(5-甲基异噁唑-3-基)氧基-3-吡啶基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[2-(5-甲基异噁唑-3-基)氧基-3-吡啶基]苯氧基]丁酸乙酯(0.14g,0.33mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.1g,78%)。
1H-NMR(CDCl3)δ8.21(1H,m),7.74(1H,m),7.17(3H,m),6.02(1H,s),4.25(2H,t),2.67(2H,t),2.43(3H,s),2.12(2H,m)。
实施例218:4-[4-[2-[2-(氮杂环丙烷-1-基)乙氧基]-3-吡啶基]-2,6-二氟-苯氧基]丁酸
使用在制备例207中获得的2-[2-(氮杂环丙烷-1-基)乙氧基]-3-碘-吡啶(0.095g,0.33mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.133g,0.36mmol)以与实施例28的步骤A和实施例1的步骤B相同的方式顺序反应,得到标题化合物(0.001g,0.1%)。
1H-NMR(MeOH-d4)δ8.11(1H,m),7.72(1H,m),7.25(2H,m),7.04(1H,m),4.51(2H,m),4.18(2H,t),2.67(2H,t),2.45(2H,t),2.02(2H,m),1.73(2H,m),1.34(2H,m)。
实施例219:4-[2,6-二氟-4-[2-(3-呋喃基甲氧基)-3-吡啶基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[2-(3-呋喃基甲氧基)-3-吡啶基]苯氧基]丁酸乙酯
使用在制备例208中获得的2-(3-呋喃基甲氧基)-3-碘-吡啶(0.107g,0.36mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.10g,0.27mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.058g,51%)。
1H-NMR(CDCl3)δ8.17(1H,m),7.59(1H,m),7.48(1H,m),7.40(1H,m),7.14(2H,m),6.98(1H,m),6.47(1H,m),5.34(2H,s),4.21(2H,t),4.15(2H,q),2.58(2H,t),2.10(2H,m),1.27(3H,t)。
步骤B:4-[2,6-二氟-4-[2-(3-呋喃基甲氧基)-3-吡啶基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[2-(3-呋喃基甲氧基)-3-吡啶基]苯氧基]丁酸乙酯(0.058g,0.14mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.054g,99%)。
1H-NMR(CDCl3)δ8.18(1H,m),7.59(1H,m),7.48(1H,m),7.41(1H,m),7.14(2H,m),6.98(1H,m),6.47(1H,m),5.33(2H,s),4.23(2H,t),2.67(2H,t),2.11(2H,m)。
实施例220:4-[2,6-二氟-4-[2-(2-呋喃基甲氧基)-3-吡啶基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[2-(2-呋喃基甲氧基)-3-吡啶基]苯氧基]丁酸乙酯
使用在制备例209中获得的2-(2-呋喃基甲氧基)-3-碘-吡啶(0.12g,0.4mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.18g,0.49mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.108g,65%)。
1H-NMR(CDCl3)δ8.17(1H,m),7.59(1H,m),7.23(1H,m),7.13(2H,m),7.00(1H,m),6.41(1H,m),6.35(1H,m),5.42(2H,s),4.20(2H,m),4.14(2H,q),2.57(2H,t),2.10(2H,m),1.27(3H,t)。
步骤B:4-[2,6-二氟-4-[2-(2-呋喃基甲氧基)-3-吡啶基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[2-(2-呋喃基甲氧基)-3-吡啶基]苯氧基]丁酸乙酯(0.108g,0.26mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.077g,76%)。
1H-NMR(CDCl3)δ8.17(1H,m),7.58(1H,m),7.43(1H,m),7.14(2H,m),7.00(1H,m),6.42(1H,m),6.35(1H,m),5.42(2H,s),4.21(2H,t),2.66(2H,t),2.10(2H,m)。
实施例221:4-[2,6-二氟-4-[2-[(3-甲基氧杂环丁烷-3-基)甲氧基]-3-吡啶基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[2-[(3-甲基氧杂环丁烷-3-基)甲氧基]-3-吡啶基]苯氧基]丁酸乙酯
使用在制备例210中获得的3-碘-2-[(3-甲基氧杂环丁烷-3-基)甲氧基]吡啶(0.12g,0.4mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.18g,0.49mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.10g,59%)。
1H-NMR(CDCl3)δ8.15(1H,m),7.61(1H,m),7.15(2H,m),7.00(1H,m),4.58(2H,d),4.48(2H,s),4.42(2H,d),4.23(2H,t),4.16(2H,q),2.59(2H,t),2.11(2H,m),1.39(3H,s),1.27(3H,t)。
步骤B:4-[2,6-二氟-4-[2-[(3-甲基氧杂环丁烷-3-基)甲氧基]-3-吡啶基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[2-[(3-甲基氧杂环丁烷-3-基)甲氧基]-3-吡啶基]苯氧基]丁酸乙酯(0.10g,0.24mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.047g,48%)。
1H-NMR(CDCl3)δ8.15(1H,m),7.60(1H,m),7.13(2H,m),7.00(1H,m),4.62(2H,d),4.43(4H,m),4.27(2H,t),2.63(2H,t),2.10(2H,m),1.40(3H,s)。
实施例222:4-[2,6-二氟-4-[2-(四氢呋喃-3-基甲氧基)-3-吡啶基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[2-(四氢呋喃-3-基甲氧基)-3-吡啶基]苯氧基]丁酸乙酯
使用在制备例211中获得的3-碘-2-(四氢呋喃-3-基甲氧基)吡啶(0.12g,0.4mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.18g,0.49mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.15g,89%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.59(1H,m),7.13(2H,m),6.98(1H,m),4.38(1H,m),4.28(1H,m),4.22(2H,t),4.16(2H,q),3.88(2H,m),3.78(1H,m),3.65(1H,m),2.75(1H,m),2.59(2H,t),2.11(3H,m),1.73(1H,m),1.27(3H,t)。
步骤B:4-[2,6-二氟-4-[2-(四氢呋喃-3-基甲氧基)-3-吡啶基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[2-(四氢呋喃-3-基甲氧基)-3-吡啶基]苯氧基]丁酸乙酯(0.15g,0.36mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.11g,79%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.58(1H,m),7.11(2H,m),6.99(1H,m),4.38(1H,m),4.26(3H,m),3.89(2H,m),3.78(1H,m),3.64(1H,m),2.74(1H,m),2.67(2H,t),2.12(3H,m),1.74(1H,m)。
实施例223:4-[2,6-二氟-4-[2-(四氢呋喃-2-基甲氧基)-3-吡啶基]苯氧基]丁酸
步骤A:4-[2,6-二氟-4-[2-(四氢呋喃-2-基甲氧基)-3-吡啶基]苯氧基]丁酸乙酯
使用在制备例212中获得的3-碘-2-(四氢呋喃-2-基甲氧基)吡啶(0.12g,0.4mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.18g,0.49mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.13g,77%)。
1H-NMR(CDCl3)δ8.31(1H,m),7.58(1H,m),7.20(2H,m),6.96(1H,m),4.40(2H,m),4.29(1H,m),4.21(2H,t),4.16(2H,q),3.89(1H,m),3.79(1H,m),2.59(2H,t),2.10(2H,m),2.01(1H,m),1.90(2H,m),1.77(1H,m),1.27(3H,t)。
步骤B:4-[2,6-二氟-4-[2-(四氢呋喃-2-基甲氧基)-3-吡啶基]苯氧基]丁酸
使用在步骤A中获得的4-[2,6-二氟-4-[2-(四氢呋喃-2-基甲氧基)-3-吡啶基]苯氧基]丁酸乙酯(0.13g,0.31mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.10g,82%)。
1H-NMR(CDCl3)δ8.13(1H,m),7.58(1H,m),7.18(2H,m),6.97(1H,m),4.42(1H,m),4.36(1H,m),4.30(1H,m),4.24(2H,t),3.88(1H,m),3.81(1H,m),2.66(2H,t),2.11(2H,m),2.03(1H,m),1.90(2H,m),1.77(1H,m)。
实施例224:4-[4-(2-环丁基甲氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用在制备例61中获得的2-环丁基甲氧基-3-碘-吡啶(0.040g,0.14mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.051g,0.14mmol)以与实施例1相同的方式反应,得到标题化合物(0.025g,48%)。
1H NMR(CDCl3)δ8.14(1H,m),7.58(1H,m),7.16(2H,m),6.94(1H,m),4.32(2H,t),4.24(2H,t),2.77(1H,m),2.69(2H,t),2.13(4H,m),1.88(4H,m)。
实施例225:4-[4-(2-环丙氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用在制备例62中获得的2-环丙氧基-3-碘-吡啶(0.040g,0.14mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.051g,0.14mmol)以与实施例1相同的方式反应,得到标题化合物(0.025g,52%)。
1H NMR(CDCl3)δ8.23(1H,m),7.57(1H,m),7.07(2H,m),6.98(1H,m),4.35(1H,m),4.24(2H,t),2.68(2H,t),2.12(2H,m),0.82(4H,m)。
实施例226:4-(4-{2-[3-(叔丁基-二甲基-甲硅烷氧基)-环戊基氧基]-吡啶-3-基}-2,6-二氟-苯氧基)-丁酸
步骤A:4-(4-{2-[3-(叔丁基-二甲基-甲硅烷氧基)-环戊基氧基]-吡啶-3-基}-2,6-二氟-苯氧基)丁酸乙酯
使用在制备例213中获得的2-[3-(叔丁基-二甲基-甲硅烷氧基)-环戊基氧基]-3-碘-吡啶(0.10g,0.24mmol)和在制备例2中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]丁酸乙酯(0.088g,0.24mmol)以与实施例1的步骤A相同的方式反应,得到标题化合物(0.12g,94%)。
步骤B:4-(4-{2-[3-(叔丁基-二甲基-甲硅烷氧基)-环戊基氧基]-吡啶-3-基}-2,6-二氟-苯氧基)-丁酸
使用在步骤A中获得的4-(4-{2-[3-(叔丁基-二甲基-甲硅烷氧基)-环戊基氧基]-吡啶-3-基}-2,6-二氟-苯氧基)-丁酸乙酯(20mg,0.04mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(15mg,79%)。
1H NMR(CDCl3)δ8.14(1H,m),7.54(1H,m),7.13(2H,m),6.92(1H,m),5.59(1H,m),4.41(1H,m),4.24(2H,t),2.69(2H,t),2.28(1H,m),2.13(2H,m),2.03(3H,m),1.75(1H,m),1.61(1H,m),0.91(9H,s),0.08(6H,s)。
实施例227:4-{2,6-二氟-4-[2-(3-羟基-环戊基氧基)-吡啶-3-基]-苯氧基}-丁酸
步骤A:4-{2,6-二氟-4-[2-(3-羟基-环戊基氧基)-吡啶-3-基]-苯氧基}-丁酸乙酯
将在实施例226的步骤A中获得的4-(4-{2-[3-(叔丁基-二甲基-甲硅烷氧基)-环戊基氧基]-吡啶-3-基}-2,6-二氟-苯氧基)-丁酸乙酯(0.10g,0.19mmol)溶于1mL的四氢呋喃。向其中添加TBAF(0.28mL,0.28mmol,1.0M,在THF中)并将生成物在室温搅拌3小时。用水和乙酸乙酯进行萃取,并将反应物用盐水洗涤。将生成物用MgSO4干燥,浓缩并通过色谱法纯化,得到标题化合物(60mg,76%)。
步骤B:4-{2,6-二氟-4-[2-(3-羟基-环戊基氧基)-吡啶-3-基]-苯氧基}-丁酸
使用在步骤A中获得的4-{2,6-二氟-4-[2-(3-羟基-环戊基氧基)-吡啶-3-基]-苯氧基}-丁酸乙酯(55mg,0.13mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(45mg,88%)。
1H NMR(CDCl3)δ8.15(1H,m),7.55(1H,m),7.11(2H,m),6.94(1H,m),5.64(1H,m),4.50(1H,m),4.25(2H,t),2.68(2H,t),2.28(1H,m),2.13(5H,m),1.83(1H,m),1.66(1H,m)。
实施例228:4-[4-(2-环己基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用环己醇(45mg,0.45mmol)和在制备例56中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸(70mg,0.22mmol)以与制备例37相同的方式反应,得到标题化合物(40mg,45%)。
1H NMR(CDCl3)δ8.13(1H,m),7.56(1H,m),7.18(2H,m),6.92(1H,m),5.18(1H,m),4.24(2H,t),2.69(2H,t),2.13(2H,m),1.96(2H,m),1.70(2H,m),1.58(3H,m),1.45(2H,m),1.35(1H,m)。
实施例229:4-[4-(2-环戊基甲氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用环戊基-甲醇(45mg,0.45mmol)和在制备例56中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸(70mg,0.22mmol)以与制备例37相同的方式反应,得到标题化合物(55mg,62%)。
1H NMR(CDCl3)δ8.14(1H,m),7.57(1H,m),7.18(2H,m),6.95(1H,m),4.24(4H,m),2.69(2H,t),2.37(1H,m),2.13(2H,m),1.80(2H,m),1.62(4H,m),1.36(2H,m)。
实施例230:4-[2,6-二氟-4-(2-异丁氧基-吡啶-3-基)-苯氧基]-丁酸
使用2-甲基-丙-1-醇(33mg,0.45mmol)和在制备例56中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸(70mg,0.22mmol)以与制备例37相同的方式反应,得到标题化合物(50mg,61%)。
1H NMR(CDCl3)δ8.14(1H,m),7.58(1H,m),7.17(2H,m),6.95(1H,m),4.25(2H,t),4.13(2H,d),2.69(2H,t),2.13(3H,m),1.00(6H,d)。
实施例231:4-{4-[2-(2,2-二甲基-丙氧基)-吡啶-3-基]-2,6-二氟-苯氧基}-丁酸
使用2,2-二甲基-丙-1-醇(40mg,0.45mmol)和在制备例56中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸(70mg,0.22mmol)以与制备例37相同的方式反应,得到标题化合物(40mg,47%)。
1H NMR(CDCl3)δ8.15(1H,m),7.58(1H,m),7.18(2H,m),6.95(1H,m),4.25(2H,t),4.02(2H,s),2.69(2H,t),2.13(2H,m),0.98(9H,s)。
实施例232:5-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸
步骤A:5-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸乙酯
使用5-溴-戊酸乙酯(43mg,0.21mmol)和在制备例55中获得的4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯酚(50mg,0.17mmol)以与制备例2的步骤C相同的方式反应,得到标题化合物(50mg,69%)。
步骤B:5-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸
使用在步骤A中获得的5-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸乙酯(45mg,0.11mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(36mg,86%)。
1H NMR(CDCl3)δ8.15(1H,m),7.56(1H,m),7.15(2H,m),6.92(1H,m),5.51(1H,m),4.19(2H,t),2.47(2H,t),2.00-1.70(10H,m),1.64(2H,m)。
实施例233:5-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸
步骤A:5-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸乙酯
使用在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.064g,0.22mmol)和在制备例225中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸乙酯(0.095g,0.247mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.07g,75%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.32(1H,m),7.02(1H,m),6.98(2H,m),4.42(1H,m),4.21(2H,t),4.15(2H,q),2.51(2H,m),2.41(2H,t),2.04(4H,m),1.86(4H,m),1.27(3H,t)。
步骤B:5-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸
使用在步骤A中获得的5-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸乙酯(0.07g,0.16mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.065g,99%)。
1H-NMR(CDCl3)δ8.41(1H,m),7.31(1H,m),7.03(1H,m),6.97(2H,m),4.43(1H,m),4.21(2H,t),2.52(4H,m),2.10(4H,m),1.90(4H,m)。
实施例234:5-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸
步骤A:5-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸乙酯
使用在制备例39中获得的2-环戊基硫基-3-碘-吡啶(0.067g,0.22mmol)和在制备例225中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸乙酯(0.095g,0.25mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.057g,59%)。
1H-NMR(CDCl3)δ8.43(1H,m),7.32(1H,m),7.02(1H,m),6.98(2H,m),4.20(2H,t),4.16(2H,q),4.11(1H,m),2.40(2H,t),2.20(2H,m),1.86(4H,m),1.73(2H,m),1.62(4H,m),1.27(3H,t)。
步骤B:5-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸
使用在步骤A中获得的5-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸乙酯(0.057g,0.13mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.051g,97%)。
1H-NMR(CDCl3)δ8.43(1H,m),7.31(1H,m),7.03(1H,m),6.97(2H,m),4.21(2H,t),4.10(1H,m),2.48(2H,t),2.20(2H,m),1.89(4H,m),1.72(2H,m),1.60(4H,m)。
实施例235:5-[2,6-二氟-4-(2-异丙基硫基-3-吡啶基)苯氧基]戊酸
步骤A:5-[2,6-二氟-4-(2-异丙基硫基-3-吡啶基)苯氧基]戊酸乙酯
使用在制备例226中获得的3-碘-2-异丙基硫基-吡啶(0.062g,0.22mmol)和在制备例225中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸乙酯(0.095g,0.25mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.063g,70%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.33(1H,m),7.03(1H,m),6.97(2H,m),4.20(2H,t),4.15(2H,q),4.07(1H,m),2.41(2H,t),1.87(4H,m),1.37(6H,d),1.27(3H,t)。
步骤B:5-[2,6-二氟-4-(2-异丙基硫基-3-吡啶基)苯氧基]戊酸
使用在步骤A中获得的5-[2,6-二氟-4-(2-异丙基硫基-3-吡啶基)苯氧基]戊酸乙酯(0.063g,0.155mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.058g,98%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.34(1H,m),7.02(1H,m),6.96(2H,m),4.21(2H,t),4.06(1H,m),2.48(2H,t),1.89(4H,m),1.36(6H,d)。
实施例236:5-[2,6-二氟-4-(2-丙基硫基-3-吡啶基)苯氧基]戊酸
步骤A:5-[2,6-二氟-4-(2-丙基硫基-3-吡啶基)苯氧基]戊酸乙酯
使用在制备例203中获得的3-碘-2-丙基硫基-吡啶(0.062g,0.22mmol)和在制备例225中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸乙酯(0.095g,0.25mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.04g,44%)。
1H-NMR(CDCl3)δ8.43(1H,m),7.33(1H,m),7.03(1H,m),6.99(2H,m),4.20(2H,t),4.14(2H,q),3.15(2H,t),2.39(2H,t),1.86(4H,m),1.69(2H,m),1.27(3H,t),1.02(3H,t)。
步骤B:5-[2,6-二氟-4-(2-丙基硫基-3-吡啶基)苯氧基]戊酸
使用在步骤A中获得的5-[2,6-二氟-4-(2-丙基硫基-3-吡啶基)苯氧基]戊酸乙酯(0.04g,0.1mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.022g,58%)。
1H-NMR(CDCl3)δ8.43(1H,m),7.34(1H,m),7.03(1H,m),6.99(2H,m),4.2(2H,t),3.14(2H,t),2.49(2H,t),1.89(4H,m),1.67(2H,m),1.02(3H,t)。
实施例237:5-[2,6-二氟-4-(6-异丙基硫基-2-吡啶基)苯氧基]戊酸
步骤A:5-[2,6-二氟-4-(6-异丙基硫基-2-吡啶基)苯氧基]戊酸乙酯
使用在制备例125中获得的2-氯-6-异丙基硫基-吡啶(0.05g,0.26mmol)和在制备例225中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸乙酯(0.098g,0.25mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.068g,65%)。
1H-NMR(CDCl3)δ7.58(2H,m),7.52(1H,t),7.31(1H,d),7.08(1H,d),4.20(2H,t),4.14(3H,m),2.40(2H,t),1.85(4H,m),1.47(6H,d),1.26(3H,t)。
步骤B:5-[2,6-二氟-4-(6-异丙基硫基-2-吡啶基)苯氧基]戊酸
使用在步骤A中获得的5-[2,6-二氟-4-(6-异丙基硫基-2-吡啶基)苯氧基]戊酸乙酯(0.068g,0.16mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.046g,73%)。
1H-NMR(CDCl3)δ7.59(2H,m),7.52(1H,t),7.31(1H,d),7.08(1H,d),4.22(2H,t),4.14(1H,m),2.47(2H,t),1.87(4H,m),1.48(6H,d)。
实施例238:5-[2,6-二氟-4-(6-异丙氧基-2-吡啶基)苯氧基]戊酸
步骤A:5-[2,6-二氟-4-(6-异丙氧基-2-吡啶基)苯氧基]戊酸乙酯
使用在制备例21中获得的2-氯-6-异丙氧基-吡啶(0.039g,0.22mmol)和在制备例225中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸乙酯(0.098g,0.25mmol)以与实施例29的步骤A相同的方式反应,得到标题化合物(0.079g,89%)。
1H-NMR(CDCl3)δ7.57(3H,m),7.19(1H,d),6.63(1H,d),5.45(1H,m),4.19(2H,t),4.14(2H,q),2.40(2H,t),1.85(4H,m),1.40(6H,d),1.27(3H,t)。
步骤B:5-[2,6-二氟-4-(6-异丙氧基-2-吡啶基)苯氧基]戊酸
使用在步骤A中获得的5-[2,6-二氟-4-(6-异丙氧基-2-吡啶基)苯氧基]戊酸乙酯(0.079g,0.2mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.070g,96%)。
1H-NMR(CDCl3)δ7.58(3H,m),7.19(1H,d),6.63(1H,d),5.44(1H,m),4.20(2H,t),2.47(2H,t),1.87(4H,m),1.40(6H,d)。
实施例239:5-[4-[2-(环丙基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]戊酸
步骤A:5-[4-[2-(环丙基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]戊酸乙酯
使用在制备例40中获得的2-环丙基甲氧基-3-碘-吡啶(0.062g,0.22mmol)和在制备例225中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸乙酯(0.095g,0.25mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.072g,79%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.58(1H,m),7.22(2H,m),6.95(1H,m),4.22(2H,d),4.19(2H,t),4.14(2H,q),2.40(2H,t),1.85(4H,m),1.26(4H,m),0.60(2H,m),0.35(2H,m)。
步骤B:5-[4-[2-(环丙基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]戊酸
使用在步骤A中获得的5-[4-[2-(环丙基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]戊酸乙酯(0.072g,0.18mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.067g,99%)。
1H-NMR(CDCl3)δ8.13(1H,m),7.58(1H,m),7.21(2H,m),6.94(1H,m),4.21(4H,m),2.48(2H,t),1.88(4H,m),1.30(1H,m),0.60(2H,m),0.34(2H,m)。
实施例240:5-[2,6-二氟-4-(2-四氢呋喃-3-基氧基-3-吡啶基)苯氧基]戊酸
步骤A:5-[2,6-二氟-4-(2-四氢呋喃-3-基氧基-3-吡啶基)苯氧基]戊酸乙酯
使用在制备例59中获得的3-碘-2-(四氢呋喃-3-基氧基)-吡啶(0.066g,0.22mmol)和在制备例225中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸乙酯(0.095g,0.25mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.06g,63%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.58(1H,m),7.14(2H,m),6.97(1H,m),5.63(1H,m),4.19(2H,t),4.14(2H,q),4.10(1H,m),3.93(3H,m),2.40(2H,t),2.25(1H,m),2.15(1H,m),1.85(4H,m),1.26(3H,t)。
步骤B:5-[2,6-二氟-4-(2-四氢呋喃-3-基氧基-3-吡啶基)苯氧基]戊酸
使用在步骤A中获得的5-[2,6-二氟-4-(2-四氢呋喃-3-基氧基-3-吡啶基)苯氧基]戊酸乙酯(0.06g,0.14mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.055g,99%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.58(1H,m),7.12(2H,m),6.98(1H,m),5.65(1H,m),4.21(2H,t),4.07(1H,m),3.93(3H,m),2.46(2H,t),2.25(1H,m),2.15(1H,m),1.86(4H,m)。
实施例241:5-[2,6-二氟-4-(2-四氢吡喃-4-基氧基-3-吡啶基)苯氧基]戊酸
步骤A:5-[2,6-二氟-4-(2-四氢吡喃-4-基氧基-3-吡啶基)苯氧基]戊酸乙酯
使用在制备例58中获得的3-碘-2-(四氢吡喃-4-基氧基)-吡啶(0.069g,0.22mmol)和在制备例225中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]戊酸乙酯(0.095g,0.25mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.071g,72%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.58(1H,m),7.15(2H,m),6.95(1H,m),5.37(1H,m),4.20(2H,t),4.14(2H,q),3.91(2H,m),3.63(2H,m),2.41(2H,t),2.06(2H,m),1.85(6H,m),1.27(3H,t)。
步骤B:5-[2,6-二氟-4-(2-四氢吡喃-4-基氧基-3-吡啶基)苯氧基]戊酸
使用在步骤A中获得的5-[2,6-二氟-4-(2-四氢吡喃-4-基氧基-3-吡啶基)苯氧基]戊酸乙酯(0.071g,0.16mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.054g,83%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.58(1H,m),7.15(2H,m),6.95(1H,m),5.38(1H,m),4.21(2H,t),3.90(2H,m),3.64(2H,m),2.47(2H,t),2.06(2H,m),1.88(4H,m),1.80(2H,m)。
实施例242:4-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊酸
将在制备例219中获得的4-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊酸乙酯(0.015g,0.04mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.008g,57%)。
1H-NMR(CDCl3)δ8.16(1H,m),7.60(1H,m),7.21(2H,d),6.93(1H,m),5.40(1H,m),3.31(1H,m),2.62(2H,m),1.86(2H,m),1.36(6H,d),1.31(3H,d)。
实施例243:4-[4-(2-环戊基硫基-吡啶-3-基)-苯基硫基]-戊酸
将在制备例217中获得的4-[4-(2-环戊基硫基-吡啶-3-基)-苯基硫基]-戊酸乙酯(0.004g,0.01mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.002g,54%)。
1H-NMR(CDCl3)δ8.41(1H,m),7.42(2H,d),7.35(3H,m),7.02(1H,m),4.06(1H,m),3.31(1H,m),2.58(2H,m),2.17(2H,m),1.93(2H,m),1.69-1.51(6H,m),1.36(3H,d)。
实施例244:4-{2-氟-4-[2-(四氢吡喃-4-基氧基)-吡啶-3-基]-苯基硫基}-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例58中获得的3-碘-2-(四氢吡喃-4-基氧基)-吡啶(0.06g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.03g,66%)。
1H-NMR(CDCl3)δ8.13(1H,m),7.62(1H,m),7.42(1H,m),7.32(2H,m),6.96(1H,m),5.37(1H,m),3.88(2H,m),3.63(2H,m),3.02(2H,t),2.56(2H,t),2.08(2H,m),1.98(2H,m),1.80(2H,m)。
实施例245:4-{2-氟-4-[2-(四氢呋喃-3-基氧基)-吡啶-3-基]-苯基硫基}-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例59中获得的3-碘-2-(四氢呋喃-3-基氧基)-吡啶(0.06g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.028g,54%)。
1H-NMR(CDCl3)δ8.13(1H,m),7.62(1H,m),7.42(1H,m),7.29(2H,m),6.98(1H,m),5.66(1H,m),4.02(2H,m),3.93(2H,m),3.03(2H,t),2.54(2H,t),2.26(1H,m),2.14(1H,m),1.95(2H,m)。
实施例246:4-[4-(2-环丁基甲氧基-吡啶-3-基)-2-氟-苯基硫基]-丁酸
使用在制备例180中获得的4-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.05g,0.14mmol)和在制备例61中获得的2-环丁基甲氧基-3-碘-吡啶(0.06g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.03g,60%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.62(1H,m),7.42-7.29(3H,m),6.96(1H,m),4.32(2H,d),3.01(2H,t),2.77(1H,m),2.56(2H,t),2.09(2H,m),2.01-1.83(6H,m)。
实施例247:4-{2,6-二氟-4-[2-(2,2,2-三氟-乙氧基)-吡啶-3-基]-苯基硫基}-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.04g,0.1mmol)和在制备例220中获得的3-碘-2-(2,2,2-三氟-乙氧基)-吡啶(0.05g,0.15mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.019g,45%)。
1H-NMR(CDCl3)δ8.17(1H,m),7.69(1H,m),7.16(2H,d),7.09(1H,m),4.82(2H,q),2.97(2H,t),2.56(2H,t),1.88(2H,m)。
实施例248:4-[4-(2-环丁基甲氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.04g,0.1mmol)和在制备例61中获得的2-环丁基甲氧基-3-碘-吡啶(0.045g,0.15mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.022g,55%)。
1H-NMR(CDCl3)δ8.16(1H,m),7.61(1H,m),7.20(2H,d),6.96(1H,m),4.32(2H,d),2.95(2H,t),2.77(1H,m),2.54(2H,t),2.09(2H,m),2.01-1.83(6H,m)。
实施例249:4-[4-(2-环戊基氨基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.04g,0.1mmol)和在制备例64中获得的N-环戊基-3-碘-吡啶基-2-胺(0.045g,0.15mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.02g,49%)。
1H-NMR(CDCl3)δ8.16(1H,m),7.23(1H,m),7.01(2H,d),6.63(1H,m),4.34(1H,m),2.99(2H,t),2.55(2H,t),2.07(2H,m),1.92(2H,m),1.64(4H,m),1.35(2H,m)。
实施例250:4-[2,6-二氟-4-(2-异丙基氨基-吡啶-3-基)-苯基硫基]-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.04g,0.1mmol)和在制备例66中获得的3-碘-N-异丙基-吡啶基-2-胺(0.04g,0.15mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.017g,44%)。
1H-NMR(CDCl3)δ8.16(1H,m),7.23(1H,m),7.01(2H,d),6.62(1H,m),4.26(1H,m),3.00(2H,t),2.58(2H,t),1.92(2H,m),1.20(6H,d)。
实施例251:4-{4-[2-(环丙基甲基-氨基)-吡啶-3-基]-2,6-二氟-苯基硫基}-丁酸
使用在制备例170中获得的4-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-丁酸乙酯(0.04g,0.1mmol)和在制备例235中获得的环丙基甲基-(3-碘-吡啶-2-基)-胺(0.043g,0.15mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.013g,31%)。
1H-NMR(CDCl3)δ8.15(1H,m),7.25(1H,m),7.02(2H,d),6.65(1H,m),3.26(2H,d),3.00(2H,t),2.57(2H,t),1.90(2H,m),1.05(1H,m),0.50(2H,m),0.21(2H,m)。
实施例252:5-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸
使用在制备例222中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-戊酸乙酯(0.055g,0.14mmol)和在制备例38中获得的2-环戊氧基-3-碘-吡啶(0.06g,0.21mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.029g,51%)。
1H-NMR(CDCl3)δ8.17(1H,m),7.59(1H,m),7.16(2H,d),6.92(1H,m),5.52(1H,m),2.92(2H,t),2.36(2H,t),1.95(2H,m),1.76(6H,m),1.64(4H,m)。
实施例253:5-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊酸
使用在制备例222中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-戊酸乙酯(0.05g,0.12mmol)和在制备例37中获得的3-碘-2-异丙氧基-吡啶(0.05g,0.19mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.023g,48%)。
1H-NMR(CDCl3)δ8.16(1H,m),7.59(1H,m),7.18(2H,d),6.92(1H,m),5.40(1H,m),2.92(2H,t),2.36(2H,t),1.79(2H,m),1.66(2H,m),1.35(6H,d)。
实施例254:5-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-戊酸
使用在制备例224中获得的5-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-戊酸乙酯(0.05g,0.14mmol)和在制备例38中获得的2-环戊氧基-3-碘-吡啶(0.06g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.026g,51%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.56(1H,m),7.47(2H,d),7.32(2H,d),6.90(1H,m),5.49(1H,m),2.97(2H,t),2.37(2H,t),1.93(2H,m),1.82-1.65(8H,m),1.60(2H,m)。
实施例255:5-[4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊酸
使用在制备例224中获得的5-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-戊酸乙酯(0.05g,0.14mmol)和在制备例37中获得的3-碘-2-异丙氧基-吡啶(0.054g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.026g,55%)。
1H-NMR(CDCl3)δ8.11(1H,m),7.58(1H,m),7.49(2H,d),7.32(2H,d),6.90(1H,m),5.39(1H,m),2.97(2H,t),2.39(2H,t),1.82-1.69(4H,m),1.34(6H,d)。
实施例256:5-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸
使用在制备例222中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-戊酸乙酯(0.05g,0.12mmol)和在制备例39中获得的2-环戊基硫基-3-碘-吡啶(0.057g,0.19mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.014g,26%)。
1H-NMR(CDCl3)δ8.45(1H,m),7.34(1H,m),7.03(3H,m),4.09(1H,m),2.93(2H,t),2.37(2H,t),2.20(2H,m),1.79-1.52(10H,m)。
实施例257:5-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯基硫基]-戊酸
使用在制备例222中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-戊酸乙酯(0.05g,0.12mmol)和在制备例203中获得的3-碘-2-丙基硫基-吡啶(0.052g,0.19mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.023g,46%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.35(1H,m),7.03(3H,m),3.15(2H,t),2.93(2H,t),2.37(2H,t),1.80(2H,m),1.65(4H,m),1.02(3H,t)。
实施例258:5-[4-(2-环戊基硫基-吡啶-3-基)-苯基硫基]-戊酸
使用在制备例224中获得的5-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-戊酸乙酯(0.05g,0.14mmol)和在制备例39中获得的2-环戊基硫基-3-碘-吡啶(0.062g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.029g,54%)。
1H-NMR(CDCl3)δ8.40(1H,m),7.34(5H,m),7.01(1H,m),4.08(1H,m),2.98(2H,t),2.39(2H,t),2.18(2H,m),1.81-1.52(10H,m)。
实施例259:5-[4-(2-环丁基硫基-吡啶-3-基)-苯基硫基]-戊酸
使用在制备例224中获得的5-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-戊酸乙酯(0.05g,0.14mmol)和在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.06g,0.2mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.03g,58%)。
1H-NMR(CDCl3)δ8.39(1H,m),7.35(5H,m),7.01(1H,m),4.42(1H,m),2.98(2H,t),2.48(2H,m),2.40(2H,t),2.02(4H,m),1.79(4H,m)。
实施例260:5-[4-(2-环丁基甲氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸
使用在制备例222中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-戊酸乙酯(0.05g,0.12mmol)和在制备例61中获得的2-环丁基甲氧基-3-碘-吡啶(0.054g,0.19mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.019g,38%)。
1H-NMR(CDCl3)δ8.16(1H,m),7.62(1H,m),7.20(2H,d),6.96(1H,m),4.33(2H,d),2.92(2H,t),2.77(1H,m),2.34(2H,t),2.09(2H,m),1.87(4H,m),1.78(2H,m),1.64(2H,m)。
实施例261:5-[4-(2-环丁氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸
使用在制备例222中获得的5-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-戊酸乙酯(0.05g,0.12mmol)和在制备例200中获得的2-环丁氧基-3-碘-吡啶(0.052g,0.19mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.019g,38%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.60(1H,m),7.21(2H,d),6.94(1H,m),5.27(1H,m),2.92(2H,t),2.47(2H,m),2.36(2H,t),2.12(2H,m),1.80(3H,m),1.65(3H,m)。
实施例262:6-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-己酸
使用6-溴己酸乙酯(46mg,0.21mmol)和在制备例55中获得的4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯酚(50mg,0.17mmol)以与实施例232的步骤A和B相同的方式反应,得到标题化合物(43mg,62%)。
1H NMR(CDCl3)δ8.15(1H,m),7.56(1H,m),7.14(2H,m),6.91(1H,m),5.51(1H,m),4.19(2H,t),2.41(2H,t),1.95(2H,m),1.83(4H,m),1.74(4H,m),1.57(4H,m)。
实施例263:7-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-庚酸
使用7-溴-庚酸乙酯(49mg,0.21mmol)和在制备例55中获得的4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯酚(50mg,0.17mmol)以与制备例2的步骤C相同的方式反应,得到标题化合物(45mg,59%)。
1H NMR(CDCl3)δ8.14(1H,m),7.57(1H,m),7.14(2H,m),6.91(1H,m),5.52(1H,m),4.18(2H,t),2.39(2H,t),1.95(2H,m),1.85-1.40(14H,m)。
实施例264:5-[2-氟-4-(2-异丙氧基-吡啶-3-基)-苯氧基]-戊酸
使用在制备例37中获得的3-碘-2-异丙氧基-吡啶(0.030g,0.11mmol)和在制备例147中获得的5-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯氧基]-戊酸乙酯(0.042g,0.11mmol)以与实施例1的步骤A和B相同的方式反应,得到标题化合物(0.023g,58%)。
1H NMR(CDCl3)δ8.10(1H,m),7.55(1H,m),7.38(1H,m),7.25(1H,d),6.97(1H,t),6.90(1H,m),5.40(1H,m),4.10(2H,t),2.49(2H,t),1.91(4H,m),1.43(6H,d)。
实施例265:5-[4-(2-环戊基硫基-吡啶-3-基)-2-氟-苯氧基]-戊酸
使用在制备例39中获得的2-环戊基硫基-3-碘-吡啶(0.030g,0.10mmol)和在制备例147中获得的5-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯氧基]-戊酸乙酯(0.036g,0.10mmol)以与实施例1的步骤A和B相同的方式反应,得到标题化合物(0.026g,68%)。
1H NMR(CDCl3)δ8.41(1H,m),7.32(1H,m),7.17(1H,m),7.12(1H,d),7.01(2H,m),4.10(3H,m),2.49(2H,t),2.19(2H,m),1.91(4H,m),1.75-1.50(6H,m)。
实施例266:5-[4-(2-环丁基硫基-吡啶-3-基)-2-氟-苯氧基]-戊酸
使用在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.030g,0.10mmol)和在制备例147中获得的5-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯氧基]-戊酸乙酯(0.038g,0.10mmol)以与实施例1的步骤A和B相同的方式反应,得到标题化合物(0.024g,62%)。
1H NMR(CDCl3)δ8.39(1H,m),7.34(1H,m),7.15(2H,m),7.02(2H,m),4.43(1H,m),4.11(2H,t),2.50(4H,m),2.04(4H,m),1.92(4H,m)。
实施例267:5-[4-(2-环戊基氧基-吡啶-3-基)-2-氟-苯氧基]-戊酸
使用在制备例38中获得的2-环戊氧基-3-碘-吡啶(0.030g,0.10mmol)和在制备例147中获得的5-[2-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯氧基]-戊酸乙酯(0.038g,0.10mmol)以与实施例1相同的方式反应,得到标题化合物(0.026g,67%)。
1H NMR(CDCl3)δ8.11(1H,m),7.57(1H,m),7.34(1H,m),7.25(1H,m),6.96(1H,t),6.90(1H,m),5.51(1H,m),4.10(2H,t),2.49(2H,t),2.00-1.60(12H,m)。
实施例268:4-[2,6-二氟-4-(2-甲氧基-吡啶-3-基)-苯氧基]-丁酸
使用甲醇(26mg,0.80mmol)和在制备例56中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸(50mg,0.16mmol)以与制备例37相同的方式反应,得到标题化合物(35mg,67%)。
1H NMR(CDCl3)δ8.17(1H,m),7.57(1H,m),7.14(2H,m),6.98(1H,m),4.24(2H,t),3.98(3H,s),2.68(2H,t),2.13(2H,m)。
实施例269:4-[4-(2-烯丙基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用丙-2-烯-1-醇(47mg,0.80mmol)和在制备例56中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸(50mg,0.16mmol)以与制备例37相同的方式反应,得到标题化合物(7mg,12%)。
1H NMR(CDCl3)δ8.15(1H,m),7.58(1H,m),7.15(2H,m),6.98(1H,m),6.09(1H,m),5.36(1H,m),5.24(1H,m),4.91(2H,m),4.24(2H,t),2.68(2H,t),2.13(2H,m)。
实施例270:4-[4-(2-丁-2-炔基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸
使用丁-2-炔-1-醇(47mg,0.80mmol)和在制备例56中获得的4-[2,6-二氟-4-(2-氟-3-吡啶基)苯氧基]丁酸(50mg,0.16mmol)以与制备例37相同的方式反应,得到标题化合物(35mg,60%)。
1H NMR(CDCl3)δ8.17(1H,m),7.58(1H,m),7.17(2H,m),7.00(1H,m),5.00(2H,m),4.24(2H,t),2.68(2H,t),2.13(2H,m),1.85(3H,t)。
实施例271:6-[4-[2-(环丁氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸
步骤A:6-[4-[2-(环丁氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸乙酯
使用在制备例200中获得的2-环丁氧基-3-碘-吡啶(0.072g,0.26mmol)和在制备例146中获得的6-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]己酸乙酯(0.11g,0.27mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.064g,59%)。
1H-NMR(CDCl3)δ8.11(1H,m),7.56(1H,m),7.20(2H,m),6.93(1H,m),5.28(1H,m),4.15(4H,m),2.49(2H,m),2.44(2H,t),2.14(2H,m),1.82(3H,m),1.72(3H,m),1.55(2H,m),1.26(3H,t)。
步骤B:6-[4-[2-(环丁氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸
使用在步骤A中获得的6-[4-[2-(环丁氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸乙酯(0.064g,0.15mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.058g,97%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.57(1H,m),7.17(2H,m),6.93(1H,m),5.27(1H,m),4.18(2H,t),2.48(2H,m),1.41(2H,t),2.14(2H,m),1.83(3H,m),1.71(3H,m),1.59(2H,m),
实施例272:6-[4-[2-(环丁基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸
步骤A:6-[4-[2-(环丁基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸乙酯
使用在制备例61中获得的2-环丁基甲氧基-3-碘-吡啶(0.076g,0.26mmol)和在制备例146中获得的6-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]己酸乙酯(0.11g,0.27mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.058g,97%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.58(1H,m),7.17(2H,m),6.95(1H,m),4.32(2H,d),4.15(4H,m),2.80(1H,m),2.34(2H,t),2.10(2H,m),1.92(4H,m),1.82(2H,m),1.75(2H,m),1.54(2H,m),1.26(3H,t)。
步骤B:6-[4-[2-(环丁基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸
使用在步骤A中获得的6-[4-[2-(环丁基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸乙酯(0.064g,0.15mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.067g,99%)。
1H-NMR(CDCl3)δ8.14(1H,m),7.58(1H,m),7.17(2H,m),6.93(1H,m),4.32(2H,d),4.17(2H,t),2.78(1H,m),2.41(2H,t),2.10(2H,m),1.89(2H,m),1.96(1H,m),1.88(3H,m),1.82(2H,m),1.73(2H,m)。
实施例273:6-[4-[2-(环丙基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸
步骤A:6-[4-[2-(环丙基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸乙酯
使用在制备例40中获得的2-环丙基甲氧基-3-碘-吡啶(0.072g,0.26mmol)和在制备例146中获得的6-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]己酸乙酯(0.11g,0.27mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.075g,69%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.59(1H,m),7.23(2H,m),6.94(1H,m),4.22(2H,d),4.15(4H,m),2.34(2H,t),1.80(2H,m),1.72(2H,m),1.55(2H,m),1.26(4H,m),0.60(2H,m),0.35(2H,m)。
步骤B:6-[4-[2-(环丙基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸
使用在步骤A中获得的6-[4-[2-(环丙基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸乙酯(0.075g,0.18mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.049g,69%)。
1H-NMR(CDCl3)δ8.12(1H,m),7.58(1H,m),7.22(2H,m),6.95(1H,m),4.22(2H,d),4.18(2H,t),2.41(2H,t),1.82(2H,m),1.73(2H,m),1.58(2H,m),1.31(1H,m),0.60(2H,m),0.35(2H,m)。
实施例274:6-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]己酸
步骤A:6-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]己酸乙酯
使用在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.076g,0.26mmol)和在制备例146中获得的6-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]己酸乙酯(0.11g,0.27mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.067g,59%)。
1H-NMR(CDCl3)δ8.41(1H,m),7.33(1H,m),7.03(1H,m),6.95(2H,m),4.43(1H,m),4.19(2H,t),4.14(2H,q),2.52(2H,m),2.35(2H,t),2.06(4H,m),1.82(2H,m),1.73(2H,m),1.55(2H,m),1.26(3H,t)。
步骤B:6-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]己酸
使用在步骤A中获得的6-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]己酸乙酯(0.067g,0.15mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.057g,91%)。
1H-NMR(CDCl3)δ8.41(1H,m),7.32(1H,m),7.02(1H,m),6.99(2H,m),4.42(1H,m),4.19(2H,t),2.52(2H,m),2.42(2H,t),2.05(4H,m),1.82(2H,m),1.74(2H,m),1.58(2H,m)。
实施例275:6-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]己酸
步骤A:6-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]己酸乙酯
使用在制备例39中获得的2-环戊基硫基-3-碘-吡啶(0.079g,0.26mmol)和在制备例146中获得的6-[2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯氧基]己酸乙酯(0.11g,0.27mmol)以与实施例28的步骤A相同的方式反应,得到标题化合物(0.080g,68%)。
1H-NMR(CDCl3)δ8.43(1H,m),7.32(1H,m),7.03(1H,m),6.98(2H,m),4.20(2H,t),4.13(3H,m),2.34(2H,t),2.20(2H,m),1.82(2H,m),1.72(4H,m),1.65(2H,m),1.59(4H,m),1.26(3H,t)。
步骤B:6-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]己酸
使用在步骤A中获得的6-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]己酸乙酯(0.080g,0.17mmol)以与实施例1的步骤B相同的方式反应,得到标题化合物(0.067g,89%)。
1H-NMR(CDCl3)δ8.43(1H,m),7.33(1H,m),7.03(1H,m),6.98(2H,m),4.19(2H,t),4.10(1H,m),2.41(2H,t),2.20(2H,m),1.83(2H,m),1.73(4H,m),1.63(2H,m),1.56(4H,m)。
实施例276:6-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-己酸
使用在制备例237中获得的6-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-己酸乙酯(0.05g,0.12mmol)和在制备例38中获得的2-环戊氧基-3-碘-吡啶(0.052g,0.18mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.029g,58%)。
1H-NMR(CDCl3)δ8.17(1H,m),7.59(1H,m),7.16(2H,d),6.92(1H,m),5.52(1H,m),2.90(2H,t),2.33(2H,t),1.94(2H,m),1.82-1.71(4H,m),1.63(6H,m),1.48(2H,m)。
实施例277:6-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-己酸
使用在制备例237中获得的6-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-己酸乙酯(0.05g,0.12mmol)和在制备例39中获得的2-环戊基硫基-3-碘-吡啶(0.055g,0.18mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.032g,60%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.34(1H,m),7.02(3H,m),4.08(1H,m),2.91(2H,t),2.34(2H,t),2.19(2H,m),1.78-1.48(12H,m)。
实施例278:6-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-己酸
使用在制备例237中获得的6-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-己酸乙酯(0.05g,0.12mmol)和在制备例44中获得的2-环丁基硫基-3-碘-吡啶(0.053g,0.18mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.029g,56%)。
1H-NMR(CDCl3)δ8.42(1H,m),7.35(1H,m),7.02(3H,m),4.42(1H,m),2.92(2H,t),2.49(2H,m),2.35(2H,t),2.03(4H,m),1.63(4H,m),1.49(2H,m)。
实施例279:6-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯基硫基]-己酸
使用在制备例237中获得的6-[2,6-二氟-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基硫基]-己酸乙酯(0.05g,0.12mmol)和在制备例203中获得的3-碘-2-丙基硫基-吡啶(0.05g,0.18mmol)以与实施例1的步骤A和B相同的方式顺序反应,得到标题化合物(0.027g,55%)。
1H-NMR(CDCl3)δ8.44(1H,m),7.35(1H,m),7.03(3H,m),3.14(2H,t),2.92(2H,t),2.34(2H,t),1.69-1.62(6H,m),1.49(2H,m),1.02(3H,t)。
实验例1:GPR120激动剂的活性测定(基于细胞的试验)
将CHO-K1细胞表达的Ga16和hGPR120分配到96孔板的各个孔中(3×104个细胞/100μl/孔),然后在5%CO2、37℃培养箱中培养18小时。将每个孔用包括2%DMSO的100μl钙5染料(Molecular Devices)溶液进行处理,然后在5%CO2、37℃培养箱中培养1小时。在96孔板中制备系列稀释的GPR120激动剂,终浓度为0.5%DMSO。使用Plexs tation II将每个孔用50μl激动剂化合物进行处理,然后在Ex 48nm、EM 52nm测定荧光。
将由系列稀释的GPR120激动剂增加的荧光计算为相对百分比(%)值,基于通过仅1%DMSO处理表示的荧光。EC50是指显示由激动剂处理增加的最大荧光的50%的激动剂浓度。通过使用统计软件(Prizm)进行测量的计算。
通过上述实验获得的实施例化合物的激动剂效果以EC50单位(μM)示于以下表1中。基于以下标准表示活性:
A=>20μM,B=20-2μM,C=2-0.2μM,D=<0.2μM
如表中所示,大部分本发明的新化合物具有优异的GPR120激动剂效果(EC50),小于0.2μM。
【表1】
Claims (6)
1.式1的联芳基衍生物或其药学上可接受的盐:
[式1]
其中,
A和B独立地表示苯基或吡啶,条件是当B是苯基时,-G-COOR7取代在苯基的对位,并且当B是吡啶时,-G-COOR7取代在吡啶的3位,
R2-E-可以不存在,
D和E独立地表示碳、氮、氧或硫,或表示直接键,并且R2可以不存在,或者
R1表示卤素;任选被卤素、C3-C10环烷基、C1-C6烷氧基或C3-C10杂环烷基取代的C1-C6烷基;C3-C10环烷基;C2-C6烯基;C2-C6炔基;任选被卤素取代的C3-C10杂环烷基;苯基;C3-C9杂芳基或C1-C6烷基-C5-C6杂芳基,
R2表示氢;卤素;任选被卤素或C3-C10环烷基取代的C1-C6烷基;C3-C10环烷基;C2-C6烯基;C2-C6炔基;C3-C10杂环烷基;苯基;或C3-C9杂芳基,并且
当D和E表示氮或碳时,R1和R2可以表示2个或3个C1-C6烷基或苯基,其可以相同或不同,
条件是当A为苯基且D或E为氧时,R1或R2不为C1-C6烷基,
条件是当A为苯基且D或E为直接键时,R1或R2不为卤素、C1-C6烷基、苯基或C3-C9杂芳基,且
条件是当A是吡啶并且D或E是直接键时,R1或R2不是吡啶基或苯基,
G表示-J-(CR5R6)p,其中J表示氧或硫,R5和R6独立地表示氢、C1-C6烷基或C3-C10环烷基,并在相同或不同碳上被取代的R5和R6可以连接以形成C3-C10环烷基,
R3和R4独立地表示氢、卤素、C1-C6烷基或C1-C6烷氧基,
R7表示氢或C1-C6烷基,
m和n独立地表示0-5的整数,且
p表示1-6的整数,条件是p不为1,
其中所述杂环烷基和杂芳基具有至少一个选自N、O和S的杂原子。
2.联芳基衍生物或其药学上可接受的盐,其选自以下化合物:
4-[4-(6-苯氧基-2-吡啶基)苯氧基]丁酸;
4-[2,6-二氟-4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸;
4-[2,6-二氟-4-(6-苯氧基-2-吡啶基)苯氧基]丁酸;
4-[2-氯-4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸;
4-[2-氟-4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸;
4-[4-(6-环戊基硫基-2-吡啶基)-2,6-二氟-苯氧基]丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-2-甲氧基-苯氧基]-丁酸;
4-[4-[6-(环戊氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二甲基-苯氧基]-丁酸;
4-[4-[3-(环戊氧基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-(6-吡咯烷-1-基-2-吡啶基)苯氧基]丁酸;
4-[4-(2-仲丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-[3-(环戊氧基)苯基]-2,3-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[6-(1-哌啶基)-2-吡啶基]苯氧基]丁酸;
4-[4-(6-苯胺基-2-吡啶基)-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[6-(N-甲基苯胺基)-2-吡啶基]苯氧基]丁酸;
4-[4-[6-(环戊基氨基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-[6-(环丙基甲基硫基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-(6-环丁基硫基-2-吡啶基)-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-(6-丙基硫基-2-吡啶基)苯氧基]丁酸;
4-[2,6-二氟-4-(6-异丙氧基-2-吡啶基)苯氧基]丁酸;
4-[2,6-二氟-4-(6-丙氧基-2-吡啶基)苯氧基]丁酸;
4-[4-[6-(环丙基甲氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-[6-(环丁氧基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-[6-(环丁氧基)-2-吡啶基]-2-甲基-苯氧基]丁酸;
4-[4-[6-(环丁氧基)-2-吡啶基]-2-(三氟甲基)苯氧基]丁酸;
4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸;
4-[4-[6-(环丁氧基)-2-吡啶基]-2,6-二氟-苯氧基]戊酸;
4-{2,6-二氟-4-[2-(3-甲基-丁基硫基)-吡啶-3-基]-苯氧基}-丁酸
2-[1-[[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]甲基]环丙基]乙酸;
2-[1-[[4-[3-(环丁氧基)苯基]-2,6-二氟-苯氧基]甲基]环丙基]乙酸;
4-[[6-[3-(环丁氧基)苯基]-3-吡啶基]氧基]丁酸;
4-[[6-[3-(环戊氧基)苯基]-3-吡啶基]氧基]丁酸;
4-(2'-苯氧基-联苯-4-基氧基)-丁酸;
4-[4-(2-异丙基硫基-吡啶-3-基)-苯氧基]-丁酸;
4-(3,5-二氟-2'-苯氧基-联苯-4-基氧基)-丁酸;
4-[4-(2-环戊基硫基-吡啶-3-基)-苯氧基]-丁酸;
4-[2,6-二氟-4-(2-异丙基硫基-吡啶-3-基)-苯氧基]-丁酸;
4-[2,6-二氟-4-(2-苯氧基-吡啶-3-基)-苯氧基]-丁酸;
4-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯氧基]-丁酸;
4-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-环丙基甲氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-环丙基甲基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-苯氧基]-丁酸;
4-[4-(2-环丙基甲基硫基-吡啶-3-基)-苯氧基]-丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-丙基硫基-吡啶-3-基)-苯氧基]-丁酸;
4-(3,5-二氟-2'-异丙氧基-联苯-4-基氧基)-丁酸;
4-(2'-环丁氧基-3,5-二氟-联苯-4-基氧基)-丁酸;
4-(2'-环丙基甲氧基-3,5-二氟-联苯-4-基氧基)-丁酸;
4-(2'-环戊基氧基-3,5-二氟-联苯-4-基氧基)-丁酸;
4-(2'-环戊基氧基-联苯-4-基氧基)-丁酸;
4-(2'-异丙氧基-联苯-4-基氧基)-丁酸;
4-(2'-环丙基甲氧基-联苯-4-基氧基)-丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-2-甲基-丁酸;
2-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基甲基]-环丙烷甲酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-2,5-二氟-苯氧基]-丁酸;
4-[4-(6-环丁基硫基-吡啶-2-基)-2,5-二氟-苯氧基]-丁酸;
4-[4-(2-叔丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
6-[2,6-二氟-4-(2-丙基硫基-3-吡啶基)苯氧基]己酸;
4-{2,6-二氟-4-[6-(2-甲基-丙烯基)-吡啶-2-基]-苯氧基}-丁酸;
4-[2,6-二氟-4-(6-异丁基-吡啶-2-基)-苯氧基]-丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-3,5-二氟-苯氧基]-丁酸;
4-{2,6-二氟-4-[2-(四氢-吡喃-4-基氧基)-吡啶-3-基]-苯氧基}-丁酸;
4-{2,6-二氟-4-[2-(四氢-呋喃-3-基氧基)-吡啶-3-基]-苯氧基}-丁酸;
4-[4-(2-环丁氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-{2,6-二氟-4-[2-(2-甲氧基-乙氧基)-吡啶-3-基]-苯氧基}-丁酸;
4-[2,6-二氟-4-(2-吡咯烷-1-基-3-吡啶基)苯氧基]丁酸;
4-[4-[2-(环戊基氨基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-[2-(环丙基甲基氨基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-[6-(环丙基甲基氨基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[2-(异丙基氨基)-3-吡啶基]苯氧基]丁酸;
4-[2,6-二氟-4-[6-(异丙基氨基)-2-吡啶基]苯氧基]丁酸;
4-[4-[2-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-[3-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[2-(丙基氨基)苯基]苯氧基]丁酸;
4-[4-[2-(环丙基甲基氨基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[2-(异丙基氨基)苯基]苯氧基]丁酸;
4-[4-[2-(环戊基氨基)苯基]苯氧基]丁酸;
4-[4-[2-(环丙基甲基氨基)苯基]苯氧基]丁酸;
4-[4-[2-(丙基氨基)苯基]苯氧基]丁酸;
4-[4-[2-(异丙基氨基)苯基]苯氧基]丁酸;
4-[4-[2-(环丁基氨基)苯基]苯氧基]丁酸;
4-[4-[2-(环丁基氨基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-[3-(环丙基甲基氨基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[3-(异丙基氨基)苯基]苯氧基]丁酸;
4-[2,6-二氟-4-(3-吡咯烷-1-基苯基)苯氧基]丁酸;
4-[4-[3-(环丁基氨基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[3-(丙基氨基)苯基]苯氧基]丁酸;
4-[4-[5-氯-2-(环戊基氨基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-[2-(环戊基氨基)-5-氟-苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-(3-环戊基苯基)-2,6-二氟-苯氧基]丁酸;
4-[4-[3-(环戊基甲基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-[2-(环戊基甲基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-[6-(环戊基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-[2-(环丁基甲基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-[3-(环丁基甲基)苯基]-2,6-二氟-苯氧基]丁酸;
4-[4-[6-(环丁基甲基)-2-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[4-(2-环戊基苯基)-2,6-二氟-苯氧基]丁酸;
4-[4-(6-环戊基-2-吡啶基)-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-(2-异丁基-3-吡啶基)苯氧基]丁酸;
4-[4-(2-环戊基-3-吡啶基)-2,6-二氟-苯氧基]丁酸;
4-[4-[2-(环戊基甲基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-(2-吡咯-1-基-3-吡啶基)苯氧基]丁酸;
4-[2,6-二氟-4-[2-(1-哌啶基)-3-吡啶基]苯氧基]丁酸;
(4S)-4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸;
(4R)-4-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸;
(4R)-4-[4-[3-(环丁氧基)苯基]-2,6-二氟-苯氧基]戊酸;
(4R)-4-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸;
(4R)-4-[2,6-二氟-4-(3-苯氧基苯基)苯氧基]戊酸;
4-(3'-环丁氧基-联苯-4-基硫基)-丁酸;
4-(3'-异丙氧基-联苯-4-基硫基)-丁酸;
[1-(3,5-二氟-3'-异丙氧基-联苯-4-基硫基甲基)-环丙基]-乙酸;
4-(3'-环戊基氧基-3,5-二氟-联苯-4-基硫基)-丁酸;
4-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(2-环丙基甲氧基-吡啶-3-基)-苯基硫基]-丁酸;
4-(3'-苯氧基-联苯-4-基硫基)-丁酸;
4-(3'-环戊基氧基-联苯-4-基硫基)-丁酸;
4-(3'-丙氧基-联苯-4-基硫基)-丁酸;
4-[4-(6-环丁氧基-吡啶-2-基)-苯基硫基]-丁酸;
4-[4-(6-环戊基氧基-吡啶-2-基)-苯基硫基]-丁酸;
4-[4-(6-异丙氧基-吡啶-2-基)-苯基硫基]-丁酸;
4-[4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(6-丙氧基-吡啶-2-基)-苯基硫基]-丁酸;
4-[4-(6-环戊基硫基-吡啶-2-基)-苯基硫基]-丁酸;
4-(3'-环丁氧基-3,5-二氟-联苯-4-基硫基)-丁酸;
4-(3,5-二氟-3'-异丙氧基-联苯-4-基硫基)-丁酸;
4-[2,6-二氟-4-(6-丙氧基-吡啶-2-基)-苯基硫基]-丁酸;
4-[2,6-二氟-4-(6-异丙氧基-吡啶-2-基)-苯基硫基]-丁酸;
4-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-丁酸;
4-[2,6-二氟-4-(2-丙氧基-吡啶-3-基)-苯基硫基]-丁酸;
4-[2,6-二氟-4-(6-异丙基硫基-吡啶-2-基)-苯基硫基]-丁酸;
4-[2,6-二氟-4-(6-丙基硫基-吡啶-2-基)-苯基硫基]-丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(2-环丁氧基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(2-环丁氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[2,6-二氟-4-(2-异丙基硫基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(2-异丙基硫基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(2-环戊基硫基-吡啶-3-基)-苯基硫基]-丁酸;
4-[2-氟-4-(6-异丙氧基-吡啶-2-基)-苯基硫基]-丁酸;
4-[4-(2-环戊基氧基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-[4-(2-环丁基硫基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(6-环丁氧基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(6-环戊基氧基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(6-环丁基硫基-吡啶-2-基)-苯基硫基]-丁酸;
4-[4-(6-环丙基甲氧基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(6-环丁基硫基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(6-环戊基硫基-吡啶-2-基)-2,6-二氟-苯基硫基]-丁酸;
4-(2'-环戊基氨基-3-氟-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氨基-3,5-二氟-联苯-4-基硫基)-丁酸;
4-[2'-(环丙基甲基-氨基)-3,5-二氟-联苯-4-基硫基]-丁酸;
4-[2-氟-4-(2-异丙基硫基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(2-环戊基硫基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-(3,5-二氟-2'-异丙基氨基-联苯-4-基硫基)-丁酸;
4-(3,5-二氟-2'-丙基氨基-联苯-4-基硫基)-丁酸;
4-[4-(2-环丙基甲氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(6-环丁基硫基-吡啶-2-基)-2-氟-苯基硫基]-丁酸;
4-[4-(2-环戊基氨基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-[2-氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-丁酸;
4-[4-(2-环丁氧基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-[2-氟-4-(2-吡咯烷-1-基-吡啶-3-基)-苯基硫基]-丁酸;
4-[2-氟-4-(2-异丙基氨基-吡啶-3-基)-苯基硫基]-丁酸;
4-(2'-环戊基氨基-3,5'-二氟-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氨基-5'-氟-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-5'-甲基-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-4'-甲氧基-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-5'-氟-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-3,5'-二氟-联苯-4-基硫基)-丁酸;
4-[4-(2-环戊基氧基-5-甲基-吡啶-3-基)-苯基硫基]-丁酸;
4-(2'-环戊基氧基-3,5,5'-三氟-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-3-氟-4'-甲氧基-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-3,5-二氟-4'-甲氧基-联苯-4-基硫基)-丁酸;
4-(3-氟-2'-异丙氧基-4'-甲氧基-联苯-4-基硫基)-丁酸;
4-[4-(2-环戊基氧基-5-甲基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-[2-氟-4-(2-异丙氧基-5-甲基-吡啶-3-基)-苯基硫基]-丁酸;
4-(3,5'-二氟-2'-异丙氧基-联苯-4-基硫基)-丁酸;
4-[4-(2-环戊基氧基-6-甲基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-(3,3'-二氟-2'-异丙氧基-5'-甲基-联苯-4-基硫基)-丁酸;
4-(3,3'-二氟-5'-甲基-2'-丙氧基-联苯-4-基硫基)-丁酸;
4-(3-氟-2',4'-二丙氧基-联苯-4-基硫基)-丁酸;
4-(6'-环戊基氧基-3,2'-二氟-3'-甲基-联苯-4-基硫基)-丁酸;
4-(2'-环戊基氧基-3,3'-二氟-5'-甲基-联苯-4-基硫基)-丁酸;
5-[4-(2-环丁基甲氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸;
5-[4-(2-环丙氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸;
4-[4-(2-环戊基氧基-5-甲基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-戊酸;
4-[4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊酸;
4-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸;
4-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸;
4-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯氧基]-丁酸;
4-[4-(2-环丙基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-乙基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-丁基硫基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-(2'-环戊基氨基-联苯-4-基硫基)-丁酸;
4-[4-(2-环戊基氧基-5-甲基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(6-异丙基硫基-2-吡啶基)苯氧基]丁酸;
4-[2,6-二氟-4-(3-苯氧基苯基)苯氧基]丁酸;
5-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯氧基]-戊酸;
5-[4-(2-环丁氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸;
4-[4-[2-(3,3-二氟吡咯烷-1-基)-3-吡啶基]-2,6-二氟-苯氧基]丁酸;
4-[2,6-二氟-4-[2-(5-甲基异噁唑-3-基)氧基-3-吡啶基]苯氧基]丁酸;
4-[2,6-二氟-4-[2-(3-呋喃基甲氧基)-3-吡啶基]苯氧基]丁酸;
4-[2,6-二氟-4-[2-(2-呋喃基甲氧基)-3-吡啶基]苯氧基]丁酸;
4-[2,6-二氟-4-[2-(四氢呋喃-3-基甲氧基)-3-吡啶基]苯氧基]丁酸;
4-[2,6-二氟-4-[2-(四氢呋喃-2-基甲氧基)-3-吡啶基]苯氧基]丁酸;
4-[4-(2-环丁基甲氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-环丙氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-环己基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-环戊基甲氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[2,6-二氟-4-(2-异丁氧基-吡啶-3-基)-苯氧基]-丁酸;
4-{4-[2-(2,2-二甲基-丙氧基)-吡啶-3-基]-2,6-二氟-苯氧基}-丁酸;
5-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-戊酸;
5-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸;
5-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]戊酸;
5-[2,6-二氟-4-(2-异丙基硫基-3-吡啶基)苯氧基]戊酸;
5-[2,6-二氟-4-(2-丙基硫基-3-吡啶基)苯氧基]戊酸;
5-[2,6-二氟-4-(6-异丙基硫基-2-吡啶基)苯氧基]戊酸;
5-[2,6-二氟-4-(6-异丙氧基-2-吡啶基)苯氧基]戊酸;
5-[4-[2-(环丙基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]戊酸;
5-[2,6-二氟-4-(2-四氢呋喃-3-基氧基-3-吡啶基)苯氧基]戊酸;
5-[2,6-二氟-4-(2-四氢吡喃-4-基氧基-3-吡啶基)苯氧基]戊酸;
4-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊酸;
4-[4-(2-环戊基硫基-吡啶-3-基)-苯基硫基]-戊酸;
4-{2-氟-4-[2-(四氢-吡喃-4-基氧基)-吡啶-3-基]-苯基硫基}-丁酸;
4-{2-氟-4-[2-(四氢呋喃-3-基氧基)-吡啶-3-基]-苯基硫基}-丁酸;
4-[4-(2-环丁基甲氧基-吡啶-3-基)-2-氟-苯基硫基]-丁酸;
4-{2,6-二氟-4-[2-(2,2,2-三氟-乙氧基)-吡啶-3-基]-苯基硫基}-丁酸;
4-[4-(2-环丁基甲氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[4-(2-环戊基氨基-吡啶-3-基)-2,6-二氟-苯基硫基]-丁酸;
4-[2,6-二氟-4-(2-异丙基氨基-吡啶-3-基)-苯基硫基]-丁酸;
4-{4-[2-(环丙基甲基-氨基)-吡啶-3-基]-2,6-二氟-苯基硫基}-丁酸;
5-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸;
5-[2,6-二氟-4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊酸;
5-[4-(2-环戊基氧基-吡啶-3-基)-苯基硫基]-戊酸;
5-[4-(2-异丙氧基-吡啶-3-基)-苯基硫基]-戊酸;
5-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸;
5-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯基硫基]-戊酸;
5-[4-(2-环戊基硫基-吡啶-3-基)-苯基硫基]-戊酸;
5-[4-(2-环丁基硫基-吡啶-3-基)-苯基硫基]-戊酸;
5-[4-(2-环丁基甲氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸;
5-[4-(2-环丁氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-戊酸;
6-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-己酸;
7-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-庚酸;
5-[2-氟-4-(2-异丙氧基-吡啶-3-基)-苯氧基]-戊酸;
5-[4-(2-环戊基硫基-吡啶-3-基)-2-氟-苯氧基]-戊酸;
5-[4-(2-环丁基硫基-吡啶-3-基)-2-氟-苯氧基]-戊酸;
5-[4-(2-环戊基氧基-吡啶-3-基)-2-氟-苯氧基]-戊酸;
4-[2,6-二氟-4-(2-甲氧基-吡啶-3-基)-苯氧基]-丁酸;
4-[4-(2-烯丙基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
4-[4-(2-丁-2-炔基氧基-吡啶-3-基)-2,6-二氟-苯氧基]-丁酸;
6-[4-[2-(环丁氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸;
6-[4-[2-(环丁基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸;
6-[4-[2-(环丙基甲氧基)-3-吡啶基]-2,6-二氟-苯氧基]己酸;
6-[4-(2-环丁基硫基-3-吡啶基)-2,6-二氟-苯氧基]己酸;
6-[4-(2-环戊基硫基-3-吡啶基)-2,6-二氟-苯氧基]己酸;
6-[4-(2-环戊基氧基-吡啶-3-基)-2,6-二氟-苯基硫基]-己酸;
6-[4-(2-环戊基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-己酸;
6-[4-(2-环丁基硫基-吡啶-3-基)-2,6-二氟-苯基硫基]-己酸;和
6-[2,6-二氟-4-(2-丙基硫基-吡啶-3-基)-苯基硫基]-己酸。
3.药物组合物,作为GPR120激动剂,其包含权利要求1或2的联芳基衍生物或其药学上可接受的盐和药学上可接受的载体。
4.药物组合物,用于预防或治疗糖尿病、糖尿病并发症、肥胖症、非酒精性脂肪肝、脂肪性肝炎、骨质疏松症或炎症,其包含权利要求1或2的联芳基衍生物或其药学上可接受的盐和药学上可接受的载体。
5.组合物,用于降低血糖水平,其包含权利要求1或2的联芳基衍生物或其药学上可接受的盐和药学上可接受的载体。
6.制备用于预防或治疗糖尿病、糖尿病并发症、肥胖症、非酒精性脂肪肝、脂肪性肝炎、骨质疏松症或炎症的组合物的方法,其包括混合权利要求1或2的联芳基衍生物或其药学上可接受的盐和药学上可接受的载体的步骤。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2013-0074927 | 2013-06-27 | ||
KR20130074927 | 2013-06-27 | ||
PCT/KR2014/005688 WO2014209034A1 (en) | 2013-06-27 | 2014-06-26 | Biaryl derivatives as gpr120 agonists |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105392777A CN105392777A (zh) | 2016-03-09 |
CN105392777B true CN105392777B (zh) | 2020-09-22 |
Family
ID=52142283
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201480036409.7A Active CN105392777B (zh) | 2013-06-27 | 2014-06-26 | 作为gpr120激动剂的联芳基衍生物 |
Country Status (21)
Country | Link |
---|---|
US (1) | US10221138B2 (zh) |
EP (2) | EP3628661A1 (zh) |
JP (1) | JP6322704B2 (zh) |
KR (1) | KR101662217B1 (zh) |
CN (1) | CN105392777B (zh) |
AU (2) | AU2014299457B2 (zh) |
BR (1) | BR112015032370B1 (zh) |
CA (1) | CA2912747C (zh) |
CY (1) | CY1122742T1 (zh) |
DK (1) | DK3013796T3 (zh) |
ES (1) | ES2784489T3 (zh) |
HR (1) | HRP20200386T1 (zh) |
HU (1) | HUE049425T2 (zh) |
LT (1) | LT3013796T (zh) |
MX (1) | MX2015016543A (zh) |
PL (1) | PL3013796T3 (zh) |
PT (1) | PT3013796T (zh) |
RS (1) | RS60128B9 (zh) |
RU (1) | RU2641003C2 (zh) |
SI (1) | SI3013796T1 (zh) |
WO (1) | WO2014209034A1 (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101942752B1 (ko) * | 2012-11-05 | 2019-01-28 | 주식회사 엘지화학 | Gpr120 효능제로서의 티오아릴 유도체 |
KR101829290B1 (ko) * | 2014-12-24 | 2018-02-19 | 주식회사 엘지화학 | Gpr120 효능제로서의 바이아릴 유도체 |
CA2974060C (en) | 2015-02-05 | 2022-08-30 | Piramal Enterprises Limited | Compounds containing carbon-carbon linker as gpr120 agonists |
EP3281937A1 (en) | 2016-08-09 | 2018-02-14 | Dompé farmaceutici S.p.A. | Sulfonamides as gpr40- and gpr120-agonists |
US10800773B2 (en) | 2016-09-12 | 2020-10-13 | Integral Health, Inc. | Monocyclic compounds useful as GPR120 modulators |
CA3041038A1 (en) | 2016-09-12 | 2018-03-15 | Numerate, Inc. | Bicyclic compounds useful as gpr120 modulators |
AU2018287777B2 (en) | 2017-06-20 | 2020-05-21 | Shandong Danhong Pharmaceutical Co., Ltd. | SSAO inhibitor |
UA128288C2 (uk) | 2018-03-08 | 2024-05-29 | Інсайт Корпорейшн | СПОЛУКИ АМІНОПІРАЗИНДІОЛУ ЯК ІНГІБІТОРИ PI3K-<font face="Symbol">g</font> |
CN111868035A (zh) | 2018-03-15 | 2020-10-30 | 阿克萨姆股份公司 | 取代的吡唑ffa4/gpr120受体激动剂 |
US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
KR102275536B1 (ko) | 2021-02-16 | 2021-07-09 | 주식회사 듀오백 | 의자 좌판의 레그 서포터 구조 |
AR128613A1 (es) | 2022-02-25 | 2024-05-29 | Lhotse Bio Inc | Compuestos y composiciones para el tratamiento de afecciones asociadas con la actividad del receptor de lpa |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0317204A2 (en) * | 1987-11-13 | 1989-05-24 | Chisso Corporation | Alpha-aryloxypropionic acid esters |
CN1127504A (zh) * | 1993-07-16 | 1996-07-24 | 巴斯福股份公司 | 具有除草活性的取代2-苯基吡啶 |
CN101663298A (zh) * | 2007-02-22 | 2010-03-03 | Irm责任有限公司 | 作为g蛋白偶联受体调节剂的噻唑衍生物 |
WO2010104195A1 (en) * | 2009-03-11 | 2010-09-16 | Banyu Pharmaceutical Co.,Ltd. | Novel isoindolin-1-one derivative |
WO2011159297A1 (en) * | 2010-06-16 | 2011-12-22 | Metabolex, Inc. | Gpr120 receptor agonists and uses thereof |
CN102378753A (zh) * | 2009-03-31 | 2012-03-14 | 肾脏科学股份有限公司 | 纤溶酶原激活物抑制因子-1抑制剂 |
CN103068801A (zh) * | 2010-06-16 | 2013-04-24 | 亚德生化公司 | 硫代乙酸盐化合物、组合物及其使用方法 |
Family Cites Families (55)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE586247A (zh) * | 1959-01-07 | |||
US4181729A (en) * | 1979-03-21 | 1980-01-01 | Pfizer Inc. | Phenyl or phenoxy substituted spiro-imidazolidinedione derivatives |
IT1211135B (it) | 1981-11-24 | 1989-09-29 | Ausonia Farma Srl | Composti ad attivita'analgesica e antiinfiammatoria, processo per la loro preparazione e relative composizioni farmaceutiche. |
US5145790A (en) * | 1990-05-04 | 1992-09-08 | Abbott Laboratories | Reagents and method for detecting polychlorinated biphenyls |
FR2665159B1 (fr) | 1990-07-24 | 1992-11-13 | Rhone Poulenc Sante | Nouveaux derives de la pyridine et de la quinoleine, leur preparation et les compositions pharmaceutiques qui les contiennent. |
US5665777A (en) * | 1995-11-14 | 1997-09-09 | Abbott Laboratories | Biphenyl hydroxamate inhibitors of matrix metalloproteinases |
US6566384B1 (en) | 1996-08-07 | 2003-05-20 | Darwin Discovery Ltd. | Hydroxamic and carboxylic acid derivatives having MMP and TNF inhibitory activity |
US6300514B1 (en) * | 1997-06-25 | 2001-10-09 | Ono Pharmaceutical Co., Ltd. | Aryl (sulfide, sulfoxide and sulfone) derivatives and drugs containing the same as the active ingredient |
EA003585B1 (ru) | 1997-11-21 | 2003-06-26 | Фармация Энд Апджон Компани | α-ГИДРОКСИ, -АМИНО И ГАЛОИДНЫЕ ПРОИЗВОДНЫЕ β-СУЛЬФОНИЛГИДРОКСАМОВЫХ КИСЛОТ В КАЧЕСТВЕ ИНГИБИТОРОВ МАТРИКСНЫХ МЕТАЛЛОПРОТЕИНАЗ |
US6232322B1 (en) | 1998-05-12 | 2001-05-15 | American Home Products Corporation | Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia |
CA2330557A1 (en) | 1998-05-12 | 1999-11-18 | Robert Emmett Mcdevitt | Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia |
US6699896B1 (en) | 1998-05-12 | 2004-03-02 | Wyeth | Oxazole-aryl-carboxylic acids useful in the treatment of insulin resistance and hyperglycemia |
FR2780402B1 (fr) * | 1998-06-30 | 2001-04-27 | Adir | Nouveaux composes acides carboxyliques et hydroxamiques inhibiteurs de metalloproteases, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR2791982B1 (fr) * | 1999-04-06 | 2002-12-27 | Inst Nat Sante Rech Med | Inhibiteurs de lta4 hydrolase et leurs applications therapeutiques. |
WO2002014282A1 (fr) * | 2000-08-11 | 2002-02-21 | Eisai Co., Ltd. | Composes 2-aminopyridine et leur utilisation comme medicaments |
JP2002128731A (ja) * | 2000-10-25 | 2002-05-09 | Fujirebio Inc | フェノキシ化合物 |
JP2002175617A (ja) * | 2000-12-06 | 2002-06-21 | Sony Corp | 磁気記録媒体 |
NZ526453A (en) * | 2001-01-31 | 2005-01-28 | Pfizer Prod Inc | Nicotinamide biaryl derivatives useful as inhibitors of PDE4 isozymes |
US7109354B2 (en) * | 2002-05-28 | 2006-09-19 | 3-Dimensional Pharmaceuticals, Inc. | Thiophene amidines, compositions thereof, and methods of treating complement-mediated diseases and conditions |
ES2282667T3 (es) * | 2002-06-25 | 2007-10-16 | Merck Frosst Canada Ltd. | Inhibidores de pde4 8-(biaril)quinolinas. |
WO2004010996A1 (ja) * | 2002-07-29 | 2004-02-05 | Shizuoka Coffein Co., Ltd. | 1,3アゾール誘導体及び同誘導体を含む血栓症治療のための医薬組成物 |
DE10250743A1 (de) | 2002-10-31 | 2004-05-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Amid-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel |
ES2308142T3 (es) | 2003-02-14 | 2008-12-01 | Kissei Pharmaceutical Co., Ltd. | Derivados aminoalcohol, composiciones farmaceuticas que los contienen, y sus usos. |
SE0301010D0 (sv) * | 2003-04-07 | 2003-04-07 | Astrazeneca Ab | Novel compounds |
EP1620422A2 (en) | 2003-04-30 | 2006-02-01 | The Institutes for Pharmaceutical Discovery, LLC | Phenyl substituted carboxylic acids as inhibitors of protein tyrosine phosphatase-1b |
ITRM20030305A1 (it) | 2003-06-20 | 2004-12-21 | Sigma Tau Ind Farmaceuti | Preparazione di nuovi derivati di acidi fenil o fenossialchil mono e dicarbossilici utili nel trattamento dell'iperglicemia e dell'ipertrigliceridemia tipiche del diabete del tipo ii. |
JP4922615B2 (ja) | 2003-11-26 | 2012-04-25 | 武田薬品工業株式会社 | 受容体機能調節剤 |
JP2005247822A (ja) | 2004-02-04 | 2005-09-15 | Horiba Biotechnology Co Ltd | コプラナーpcbハプテン、コプラナーpcbに対する抗体およびそれを用いる免疫学的測定方法 |
CA2551909C (en) | 2004-02-12 | 2011-10-11 | Transtech Pharma, Inc. | Substituted azole derivatives, compositions, and methods of use |
FR2869611B1 (fr) | 2004-05-03 | 2006-07-28 | Merck Sante Soc Par Actions Si | Derives de l'acide hexenoique, procedes pour leur preparation, compositions pharmaceutiques les contenant et applications en therapeutique |
EP2289560B1 (en) | 2004-07-08 | 2015-04-22 | Novo Nordisk A/S | Polypeptide protracting tags comprising a tetrazole moiety |
GB0422057D0 (en) * | 2004-10-05 | 2004-11-03 | Astrazeneca Ab | Novel compounds |
KR101388355B1 (ko) | 2005-11-10 | 2014-04-22 | 후지필름 가부시키가이샤 | 조성물, 필름 및 액정 디스플레이 |
AU2007265373B2 (en) * | 2006-06-29 | 2013-02-21 | Atnx Spv, Llc | Biaryl compositions and methods for modulating a kinase cascade |
PT2041071E (pt) | 2006-06-29 | 2014-09-23 | Kinex Pharmaceuticals Llc | Composições de biarilo e processos para a regulação de uma cascata de cinases |
FR2903984B1 (fr) | 2006-07-24 | 2008-10-03 | Genfit Sa | Derives d'imidazolones substitues, preparation et utilisations |
JP2010504295A (ja) * | 2006-09-21 | 2010-02-12 | ノバルティス アーゲー | サイトカイン介在疾患の処置に有用なピロール誘導体 |
CA2668713C (en) | 2006-12-01 | 2015-09-08 | Banyu Pharmaceutical Co., Ltd. | Novel phenyl-isoxazol-3-ol derivative |
JP5420400B2 (ja) | 2007-04-26 | 2014-02-19 | 国立大学法人京都大学 | Gタンパク質共役型レセプター作動剤 |
EP2154131A4 (en) | 2007-04-26 | 2011-09-21 | Pharmafrontier Co Ltd | INHIBITOR OF THE G-PROTEIN-COUPLED RECEPTOR AND PHARMACEUTICAL PRODUCT |
WO2009011285A1 (ja) * | 2007-07-13 | 2009-01-22 | Taisho Pharmaceutical Co., Ltd. | ヘテロアリールベンゼン化合物 |
WO2009151800A1 (en) * | 2008-05-07 | 2009-12-17 | Merck & Co., Inc. | Soluble epoxide hydrolase inhibitors, compositions containing such compounds and methods of treatment |
JPWO2009147990A1 (ja) | 2008-06-02 | 2011-10-27 | Msd株式会社 | 新規イソオキサゾール誘導体 |
WO2009147211A1 (en) * | 2008-06-04 | 2009-12-10 | Biovitrum Ab (Publ) | New compounds v |
KR20100022592A (ko) * | 2008-08-20 | 2010-03-03 | 주식회사 코리아티슈뱅크 | 골형성단백질이 코팅된 골이식재 |
WO2010048149A2 (en) * | 2008-10-20 | 2010-04-29 | Kalypsys, Inc. | Heterocyclic modulators of gpr119 for treatment of disease |
NZ592603A (en) | 2008-10-21 | 2013-02-22 | Metabolex Inc | Aryl gpr120 receptor agonists and uses thereof |
AR074760A1 (es) | 2008-12-18 | 2011-02-09 | Metabolex Inc | Agonistas del receptor gpr120 y usos de los mismos en medicamentos para el tratamiento de diabetes y el sindrome metabolico. |
CN102421739A (zh) | 2009-04-22 | 2012-04-18 | 安斯泰来制药株式会社 | 羧酸化合物 |
US8586776B2 (en) | 2009-11-05 | 2013-11-19 | Fibrostatin, S.L. | GPBP inhibition using Q2 peptidomimetics |
EP2619185A1 (en) * | 2010-09-24 | 2013-07-31 | Ranbaxy Laboratories Limited | Matrix metalloproteinase inhibitors |
KR101530141B1 (ko) | 2010-12-17 | 2015-06-18 | 미쓰비시 타나베 파마 코퍼레이션 | 연속 아리시클릭 화합물 |
EP2681197A1 (en) * | 2011-03-04 | 2014-01-08 | Novartis AG | Tetrasubstituted cyclohexyl compounds as kinase inhibitors |
WO2013056679A1 (en) | 2011-10-21 | 2013-04-25 | Beijing Hanmi Pharmaceutical Co., Ltd | Novel heteroaryl-amino derivatives |
ES2690315T3 (es) * | 2012-06-15 | 2018-11-20 | Mitsubishi Tanabe Pharma Corporation | Compuestos de imidazol y triazol como inhibidores de DGAT-1 |
-
2014
- 2014-06-26 EP EP19207933.3A patent/EP3628661A1/en active Pending
- 2014-06-26 AU AU2014299457A patent/AU2014299457B2/en active Active
- 2014-06-26 ES ES14818620T patent/ES2784489T3/es active Active
- 2014-06-26 PT PT148186208T patent/PT3013796T/pt unknown
- 2014-06-26 BR BR112015032370-7A patent/BR112015032370B1/pt active IP Right Grant
- 2014-06-26 MX MX2015016543A patent/MX2015016543A/es unknown
- 2014-06-26 JP JP2016523650A patent/JP6322704B2/ja active Active
- 2014-06-26 LT LTEP14818620.8T patent/LT3013796T/lt unknown
- 2014-06-26 CN CN201480036409.7A patent/CN105392777B/zh active Active
- 2014-06-26 EP EP14818620.8A patent/EP3013796B9/en active Active
- 2014-06-26 RS RS20200286A patent/RS60128B9/sr unknown
- 2014-06-26 WO PCT/KR2014/005688 patent/WO2014209034A1/en active Application Filing
- 2014-06-26 RU RU2016102313A patent/RU2641003C2/ru active
- 2014-06-26 KR KR1020140078807A patent/KR101662217B1/ko active IP Right Grant
- 2014-06-26 CA CA2912747A patent/CA2912747C/en active Active
- 2014-06-26 DK DK14818620.8T patent/DK3013796T3/da active
- 2014-06-26 SI SI201431518T patent/SI3013796T1/sl unknown
- 2014-06-26 PL PL14818620T patent/PL3013796T3/pl unknown
- 2014-06-26 US US14/894,928 patent/US10221138B2/en active Active
- 2014-06-26 HU HUE14818620A patent/HUE049425T2/hu unknown
-
2017
- 2017-05-19 AU AU2017203392A patent/AU2017203392B2/en active Active
-
2020
- 2020-03-09 HR HRP20200386TT patent/HRP20200386T1/hr unknown
- 2020-03-12 CY CY20201100218T patent/CY1122742T1/el unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0317204A2 (en) * | 1987-11-13 | 1989-05-24 | Chisso Corporation | Alpha-aryloxypropionic acid esters |
CN1127504A (zh) * | 1993-07-16 | 1996-07-24 | 巴斯福股份公司 | 具有除草活性的取代2-苯基吡啶 |
CN101663298A (zh) * | 2007-02-22 | 2010-03-03 | Irm责任有限公司 | 作为g蛋白偶联受体调节剂的噻唑衍生物 |
WO2010104195A1 (en) * | 2009-03-11 | 2010-09-16 | Banyu Pharmaceutical Co.,Ltd. | Novel isoindolin-1-one derivative |
CN102378753A (zh) * | 2009-03-31 | 2012-03-14 | 肾脏科学股份有限公司 | 纤溶酶原激活物抑制因子-1抑制剂 |
WO2011159297A1 (en) * | 2010-06-16 | 2011-12-22 | Metabolex, Inc. | Gpr120 receptor agonists and uses thereof |
CN103068801A (zh) * | 2010-06-16 | 2013-04-24 | 亚德生化公司 | 硫代乙酸盐化合物、组合物及其使用方法 |
Non-Patent Citations (1)
Title |
---|
RN:1182268-18-3、1182245-58-4、1182244-95-6、1182222-49-6;ACS,STN Registry数据库;《ACS,STN Registry数据库》;20090910 * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105392777B (zh) | 作为gpr120激动剂的联芳基衍生物 | |
CN107567443A (zh) | 作为gpr120激动剂的联芳基衍生物 | |
JP5322951B2 (ja) | グルカゴン受容体の新規アンタゴニスト | |
UA80437C2 (en) | Diaryl ethers as opioid receptor antagonist | |
TWI610917B (zh) | 作爲gpr120促效劑之硫基芳基衍生物 | |
WO1999001423A1 (en) | Glucagon antagonists/inverse agonists | |
WO2021003295A1 (en) | Modulators of hsd17b13 and methods of use thereof | |
AU2001278650A1 (en) | Phenoxybenzylamine derivatives as selective serotonin re-uptake inhibitors | |
EP1890993A2 (en) | Benzoic acid derivatives that are modulators or antagonists of glyr | |
CN107162921B (zh) | 一类苯氧乙酸衍生物、其制备方法及其作为药物的用途 | |
AU2013291866B2 (en) | Imidazopyridine derivative used in the treatment of diabetes | |
AU2002244898B2 (en) | Phenyl heterocyclyl ether derivatives as serotonin re-uptake inhibitors | |
KR20140074363A (ko) | 바닐로이드 수용체 리간드로서의 아릴 또는 n-헤테로아릴 치환된 메탄설폰아미드 유도체 | |
EP1881950A1 (en) | New compounds i |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20170828 Address after: Seoul, South Kerean Applicant after: LG Chemical Ltd. Address before: Seoul, South Kerean Applicant before: LG Life Sciences Ltd |
|
TA01 | Transfer of patent application right | ||
GR01 | Patent grant | ||
GR01 | Patent grant |